WO2015155306A1 - New trpa1 antagonists - Google Patents

New trpa1 antagonists Download PDF

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Publication number
WO2015155306A1
WO2015155306A1 PCT/EP2015/057764 EP2015057764W WO2015155306A1 WO 2015155306 A1 WO2015155306 A1 WO 2015155306A1 EP 2015057764 W EP2015057764 W EP 2015057764W WO 2015155306 A1 WO2015155306 A1 WO 2015155306A1
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propyl
acetamide
group
chlorophenoxy
pyrimidin
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PCT/EP2015/057764
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French (fr)
Inventor
Nuria Aguilar Izquierdo
Maria Antonia Buil Albero
Stephen Connolly
Paul Robert Eastwood
Richard Spurring Roberts
Sara Sevilla Gomez
Bernat Vidal Juan
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Almirall, S.A.
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Publication of WO2015155306A1 publication Critical patent/WO2015155306A1/en

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds having TRPA1 activity.
  • This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.
  • TRPA1 is a non-cation selective channel that belongs to the Transient Receptor Potential (TRP) superfamily.
  • TRP Transient Receptor Potential
  • TRPA1 was first identified from cultured lung fibroblasts (Jaquemar et al., 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 , CGRP and substance P (Kaneko et al., 2013). Moreover, TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B- lymphocytes (Stokes et al., 2006).
  • TRPA1 is activated by a variety of noxious stimuli, including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic). TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers, and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
  • noxious stimuli including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic).
  • TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers, and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
  • TRPA1 is not only sensitive to electrophiles, but is also activated by oxidizing agents.
  • Reactive oxygen species ROS
  • ROS Reactive oxygen species
  • Reactive carbonyl species like 4- hydroxynonenal (4-HNE) and 4-oxononenal (4-ONE), resulting from lipid peroxidation act directly on TRPA1 .
  • ROS generated during inflammation excites airway sensory nerve fibres, and this response is largely reduced in TRPA1 -deficient mice.
  • TRPA1 activation is modulation by G protein-coupled receptors (GPCRs) through second-messenger signalling cascades.
  • GPCRs G protein-coupled receptors
  • Prostaglandin PGE2 and bradykinin (BK) are indirect activators of TRPA1 (Bessac, 2008).
  • TRPA1 has emerged as a key regulator of neuropeptide release and neurogenic inflammation.
  • TRPA1 is expressed in a subset of C-fibres that express TrkA and TRPV1 .
  • These afferent nerves have cell bodies in nodose, DRG and TG, and project to a variety of peripheral targets, including skin, airways, and gastrointestinal (Gl) tract.
  • 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 NGF and following nerve injury or inflammation.
  • TRPA1 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).
  • TRPA1 is a promising target for the treatment of this chronic diabetic neuropathy associated with peripheral demyelination and the degeneration of nerve fibres.
  • TRPA1 may have a role in the pathogenesis of cancer and other inflammatory diseases. TRPA1 antagonists have been reported to revert oxaliplatin-induced neuropathic pain (Nativi, 2005).
  • TRPA1 Some anaesthetics, such as isoflurane or lidocaine, also activate TRPA1 , suggesting a possible role for TRPAI antagonists in post-surgical pain.
  • TRPA1 is implicated in migraine (Edelmayer et al., 2012), and dental pain (Haas et al., 201 1 ), as a result from neurogenic inflammation.
  • the activation of trigeminal TG neurons through nasal application of TRPA1 activators causes a CGRP-dependent increase in meningeal blood flow, that has been clinically shown to correlate with migraine headache.
  • TRPA1 could be considered a target for such conditions.
  • TRP channels are present in both neuronal and non-neuronal cells in the skin where they are thought to play a key role in itch, regulation of barrier function, keratinocyte differentiation, hair growth, inflammation, and wound healing (reviewed in Moran et al., 201 1 ).
  • TRPA1 is an essential component of the pathways that promote histamine- independent itch and may act as a downstream transduction channel onto which multiple pathways converge.
  • TRPA1 -/- mice to support a role for TRPA1 in the pathogenesis of different airway diseases including chronic cough, asthma, and COPD (Nassini et al., 2012b).
  • TRPA1 in the generation of irritant-induced cough reflexes.
  • Inhalation of a variety of TRPA1 agonists (acrolein, cinnamaldehyde, allyl isothiocyanate, crotonaldehyde) has been shown to produce a dose-dependent robust cough response in conscious guinea pigs and in humans (Andre et al., 2009; Birrell et al. , 2009).
  • Stimulating TRPA1 channels has been demonstrated to activate vagal bronchopulmonary C-fibres in the guinea pig and rodent lung.
  • TRPA1 agonists induced cough.
  • cough can be attenuated by TRPA1 inhibitors.
  • TRPA1 channels Antagonism of TRPA1 channels is expected to inhibit afferent nerve activation induced by cough stimulants, and represents an option for anti-tussive drugs development (Grace et al., 2012 and 2013). Moreover, patients treated with angiotensin-converting enzyme (ACE) inhibitors for hypertension have chronic cough as a side effect as result of heightened bradykinin levels. TRPA1 antagonists could represent an option to treat such side effects and chronic cough conditions.
  • ACE angiotensin-converting enzyme
  • TRPA1 -/- mice show little sign of lung inflammation, near- normal airway resistance, reduced eosinophil infiltration in the bronchi, and decreased production of proinflammatory cytokines and neuropeptides release in the airways, compared to TRPA1 +/+mice (Caceres et al., 2009). These studies point to TRPA1 as a promising target for the development of drugs aimed at treating the asthmatic response, allergen-induced airways inflammation, mucus production and airways hyper-reactivity.
  • CSE cigarette smoke extract
  • aldehydes increased Ca 2+ influx in
  • TRPA1 transfected cells and promoted neuropeptide release from isolated guinea pig airway tissue. Instillation of CSE into the trachea of wild-type mice and TRPA1 -/- mice only induced plasma protein extravasation in the wild type mice (Andree et al., 2008). These data suggest that targeting TRPA1 may have therapeutic potential in diseases caused by cigarette smoke such as COPD.
  • TRPA1 has been reported to have a critical role in mediating gastrointestinal (Gl) hypersensitivity to mechanical stimuli and serves as an important mediator of neuropeptide release triggered by inflammatory agents.
  • TRPA1 expression is elevated in the inflamed mouse gut (Yang et al., 2008; Izzo et al., 2012).
  • Experimental colitis induced by dinitrobenzene sulphonic acid (DNBS) was attenuated after both pharmacological blockade and genetic inactivation of TRPA1 (Engel et al., 201 1 ), pointing at potential of the target in Gl inflammatory conditions such as inflammatory bowel disease, Crohn's disease and ulcerative colitis, and colicky pain of Gl origin (Blackshaw et al., 2013).
  • TRPA1 is highly expressed in sensory neurons innervating bladder, urothelium, sub-urothelial space, muscle layers and around blood vessels (Streng et al. , 2008). Similar to TRPM8, TRPA1 is up-regulated in bladder mucosa in patients with bladder outlet obstruction (Du et al., 2008). TRPA1 agonists increased the micturition frequency models of cyclophosphamide-induced cystitis and spinal cord injury
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence, and cystitis.
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence, and cystitis.
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence, and cystitis.
  • TRPA1 Several properties of TRPA1 make it an attractive drug target to treat inflammatory disorders; its ability to be activated by a large variety of endogenous and exogenous inflammatory compounds makes it an ideal detector of inflammatory cues, both in acute and in chronic conditions. Its peripheral expression of TRPA1 allows systemic, but also selective targeting of drugs by inhalation, ingestion, or topical application.
  • TRPA1 modulators of varied chemical structures have been recently disclosed for the treatment or prevention of chronic and acute inflammatory diseases and other pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition or antagonism of TRPA1 .
  • TRPA1 modulators of varied chemical structures have been recently disclosed for the treatment or prevention of chronic and acute inflammatory diseases and other pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition or antagonism of TRPA1 .
  • Several structural families of antagonists are observed. These include alcohols
  • Compounds having the capacity to selectively antagonise TRPA1 are in active development by several companies.
  • An example of these compounds is GRC-17536.
  • TRPA1 antagonists or inhibitors being suitable for the treatment of the above-mentioned diseases.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, a /V-oxide or a isotopically-labeled derivative thereof for use in the treatment of the human or animal body by therapy,
  • ⁇ G 1 is selected from the group consisting of a CH group and a N atom
  • G 2 is selected from the group consisting of a C(R a ) group and a N atom;
  • G 3 and G 4 are independently selected from the group consisting of a C atom and a N atom;
  • G 5 , G 6 and G 7 are independently selected from the group consisting of a C(R b ) group, a N(R C ) group, a N atom, an O atom and a S atom;
  • Q is a monocyclic or bicyclic C6-i 4 aryl or a monocyclic or bicyclic 5- to 14- membered heteroaryl ring, unsubstituted or substituted by one or more substituents selected from a linear or branched Ci -4 alkyl group, a halogen, a Ci -4 alkoxy group, a Ci -4 haloalkyl group, a Ci -4 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a Ci -4 monoalkylamino group, a Ci -4 dialkylamino group, a C3-7 cycloalkyl group, a phenyl ring and a phenoxy group;
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched Ci -4 alkyl group, a Ci -4 haloalkyl group, a C6-i 4 aryl group and a benzyl group; or R 1 together with the Q group, the O atom and the C atom where it is attached, form a fused bicyclic 8- to 14-membered heterocyclyl ring containing at least one heteroatom selected from O, S and N;
  • R 3 and R 4 are independently selected from the group consisting of a H atom and a F atom;
  • ⁇ R a is selected from the group consisting of a H atom, a linear or branched Ci -4 alkyl group, a halogen atom, a Ci -4 alkoxy group, a Ci -4 haloalkyl group, a Ci -4 haloalkyloxy group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci- 4 monoalkylamino group and a Ci -4 dialkylamino group;
  • R b is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a C1-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyan
  • R c is selected from the group consisting of a hydrogen atom, a linear or
  • n is an integer selected from 1 or 2;
  • • represents a single or a double bond.
  • the invention provides synthetic processes and intermediates described herein, which are useful for preparing compounds of the invention.
  • the invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically-acceptable carrier.
  • the invention further provides combinations comprising a compound of the invention and one or more other therapeutic agents and pharmaceutical compositions comprising such combinations.
  • 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 pain, acute and/or chronic pruritus, 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.
  • 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.
  • 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.
  • Ci-4 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 , 2 or 3 halogen atoms. Examples include CCIs, CF 3 and CHF 2 .
  • 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 said halogen atoms. Examples of haloalkoxy groups include -OCF3 and -OCCI3.
  • C3-7 cycloalkyl embraces saturated carbocyclic radicals monocyclic or polycyclic ring having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Ce-14 aryl radical embraces typically a Ce-14, more preferably Ce- ⁇ monocyclic or bicyclic aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred.
  • a said unsubstituted or substituted Ce-14 aryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. When a Ce-14 aryl radical carries 2 or more substituents, the substituents may be the same or different.
  • monocyclic or bicyclic 5- to 14-membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 6-membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N.
  • a 5- to 14-membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl,
  • fused bicyclic 8- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated Ce-14 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N , O and S.
  • the fused bicyclic 8- to 14-membered heterocyclyl group is formed by binding R 1 to the Q group, together with the O atom and the C atom where R 1 is attached, and therefore will always have an O atom in its structure.
  • Examples include benzo[c/][1 ,3]dioxolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, [1 ,3]dioxolo[4,5- b]pyridyl, 3,4-dihydro-2/-/-pyrano[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyrazyl, or 2,3- dihydro-[1 ,4]dioxino[2,3-b]pyridyl.
  • halogen atom embraces chlorine, fluorine, bromine or iodine atoms typically a fluorine, chlorine or bromine atom.
  • halo when used as a prefix has the same meaning.
  • Ci-4 rmonoalkylamino is represented by the formula -NH(Ci-4 alkyl) where Ci-4 alkyl is as described above.
  • Representative examples include methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, and (ieri-butyl)amino group.
  • C1-4 dialkylamino as used herein is represented by the formula - N(Ci-4 alkyl)2 where C1-4 alkyl is a described above.
  • Representative examples include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group and d ⁇ tert- butyl)amino group.
  • terapéuticaally effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes: (a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;
  • pathological condition or disease susceptible to amelioration by inhibition or antagonism of TRPA1 includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with an increased TRPA1 activity.
  • disease states include, but are not limited to, acute and/or chronic pain, acute and/or chronic pruritus, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
  • pain is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g. somatic pain and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain.
  • nociceptive pain e.g. somatic pain and visceral pain
  • inflammatory pain e.g. somatic pain and visceral pain
  • idiopathic pain e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain.
  • 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.
  • inflammatory dermatological disease includes the following dermatological diseases as non-limiting examples of such dermatological diseases: acne vulgaris, actinic keratosis, eczema, atopic dermatitis, insect bite inflammation, drug-induced skin reactions, psoriasis, rosacea and seborrheic dermatitis.
  • respiratory disorder any condition or disease related to respiration or the respiratory system and includes, but is not limited to, airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, bronchiectasis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), inflammatory respiratory diseases conditions poorly responder to corticosteroids (i.e. severe COPD and asthma)", sensory hyper-reactivity, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • corticosteroids i.e. severe COPD and asthma
  • 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 or cough associated with other respiratory diseases such as idiopathic pulmonary fibrosis (IPF).
  • GFD gastroesophageal reflux disease
  • COPD COPD cough
  • UACS upper airways cough syndrome
  • IPF idiopathic cough or cough associated with other respiratory diseases such as idiopathic pulmonary fibrosis
  • gastrointestinal inflammatory disorders includes, but is not limited to, disorders such as inflammatory bowel disease, ulcerative colitis or Crohn's disease.
  • urinary tract disorders includes, but is not limited to, disorders such as urinary incontinence, bladder instability or cystitis.
  • pharmaceutically-acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, hydrofluoric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1 -hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid), triphenyl acetic and the like.
  • salts derived from formic, fumaric, hydrobromic, hydrochloric, hydrofluoric, acetic, sulfuric, methanesulfonic, xinafoic, tartaric, maleic, succinic and napadisilic acids are particularly preferred.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, 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 ie fiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as ammonia, arginine, betaine, caffeine, choline, /V,/V-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, /V-ethylmorpholine, /V-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • X " may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X " is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X " is chloride, bromide, trifluoroacetate or methanesulphonate.
  • an /V-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • solvent is water
  • 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.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l , nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 0 and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • 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.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
  • a deuterated derivative of a compound of the invention has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
  • isotopic enrichment factor ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen
  • the isotopic enrichment factor is at least 5000 (75% deuterium). In a more preferred embodiment, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In a most preferred embodiment, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.
  • the isotopic enrichment factor can be determined using conventional analytical methods known too en ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).
  • MS mass spectrometry
  • NMR nuclear magnetic resonance
  • the compounds of the invention may contain one or more chiral centers. Accordingly, the invention includes racemic mixtures, enantiomers, and mixtures enriched in one or more stereoisomer.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • the invention provides with a compound or a pharmaceutically acceptable salt, a /V-oxide or a isotopically-labeled derivative thereof of formula (I)
  • G 1 is selected from the group consisting of a CH group and a N atom
  • G 2 is selected from the group consisting of a C(R a ) group and a N atom;
  • G 3 and G 4 are independently selected from the group consisting of a C atom and a N atom;
  • G 5 , G 6 and G 7 are independently selected from the group consisting of a C(R b ) group, a N(R C ) group, a N atom, an O atom and a S atom;
  • Q is a monocyclic or bicyclic C6-i 4 aryl or a monocyclic or bicyclic 5- to 14- membered heteroaryl ring, unsubstituted or substituted by one or more substituents selected from a linear or branched Ci -4 alkyl group, a halogen, a Ci -4 alkoxy group, a Ci -4 haloalkyl group, a Ci -4 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a Ci -4 monoalkylamino group, a Ci -4 dialkylamino group, a C3-7 cycloalkyl group, a phenyl ring and a phenoxy group;
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched Ci -4 alkyl group, a Ci -4 haloalkyl group, a C6-i 4 aryl group and a benzyl group; or R 1 together with the Q group, the O atom and the C atom where it is attached, form a fused bicyclic 8- to 14-membered heterocyclyl ring containing at least one heteroatom selected from O, S and N;
  • R 3 and R 4 are independently selected from the group consisting of a H atom and a F atom;
  • R a is selected from the group consisting of a H atom , a linear or branched Ci -4 alkyl group, a halogen atom, a Ci -4 alkoxy group, a Ci -4 haloalkyl group, a Ci -4 haloalkyloxy group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 rmonoalkylamino group and a Ci-4 dialkylamino group;
  • R b is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a C1-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 rmonoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
  • R c is selected from the group consisting of a hydrogen atom, a linear or
  • ⁇ n is an integer selected from 1 or 2;
  • Q represents a phenyl group or a pyridine group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a cyano group, a C1-4 dialkylamino group, a phenyl ring and a phenoxy group.
  • substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a cyano group, a C1-4 dialkylamino group, a phenyl ring and a phenoxy group.
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group; or R 1 together with the Q group, the O atom and the C atom where it is attached form a fused bicyclic ring of formula (a), (b), (c) or (d).
  • G 1 represents a CH group and G 2 represents a N atom.
  • G 5 , G 6 and G 7 are independently selected from the group consisting of a C(R b ) group, a N(R C ) group and a N atom.
  • G 1 -G 7 are not all N atoms.
  • R b is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom and a C1-4 alkoxy group; preferably a H atom, a halogen atom, a methyl group and a methoxy group.
  • G 1 represents a CH group and G 2 represents a N atom;
  • G 5 , G 6 and G 7 are independently selected from the group consisting of a C(R b ) group, a N(R C ) group and a N atom;
  • Q represents a phenyl group or a pyridine group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, a cyano group, a Ci-4 dialkylamino group, a phenyl ring and a phenyloxy group;
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group; or R 1 together with the Q group, the O atom and the C atom where it is attached form a fused bicyclic ring of formula (a), (b), (c) or (d);
  • R b is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom and a C1-4 alkoxy group; preferably a H atom, a halogen atom, a methyl group and a methoxy group.
  • Particular individual compounds of the invention include:
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions are given (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and de-protection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • Compounds of general formula (I) may be prepared from bicyclic compounds of formula (2) wherein A is equivalent to a bicyclic group wherein G 1 -G 7 and n are as defined in Claim 1 , and an alkylating agent of formula (3) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para- toluenesulphonate or methylsulfonate and R 1 -R 4 and Q are as defined in Claim 1 .
  • the reaction is carried out by mixing a compound of formula (2) and compound of formula (3) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 80 °C.
  • Compounds of general formula (5) wherein A is as hereinbefore defined and R 10 represents an alkyl group such as methyl, ethyl, propyl, ie f-butyl, benzyl or 2- (trimethylsilyl)ethyl may be prepared from bicyclic compounds of formula (2) and an alkylating agent of formula (4) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction is carried out by mixing a compound of formula (2) and compound of formula (4) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 80 °C.
  • Compounds of general formula (6) wherein A is as hereinbefore defined may be prepared from compounds of formula (5) wherein R 10 is as hereinbefore defined by hydrolysis according to standard literature methods known to those skilled in the art of ester hydrolysis.
  • this may be through the use of a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from ambient to 50 °C.
  • a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from ambient to 50 °C.
  • an acid such as hydrochloric acid or trifluoroacetic acid in water, dichloromethane, chloroform or dioxane or a mixture thereof at a temperature from ambient to 50 °C.
  • Compounds of general formula (I) may be prepared from compounds of formula (6) wherein A is as hereinbefore defined and an amine of formula (7) wherein R 1 - R 4 and Q are as defined in Claim 1 , in the presence of a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), in the presence or absence of a catalyst such as 1 -hydroxybenzotriazole (HOBt).
  • DCC dicyclohexylcarbodiimide
  • EDC 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide
  • HOBt 1 -hydroxybenzotriazole
  • a carboxylic acid of formula (6) and an amine of formula (8) in the presence of a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDO) or benzotriazolyloxy-tris[pyrrolidino]- phosphonium hexafluorophosphate (PyBOP).
  • DCC dicyclohexylcarbodiimide
  • EEO 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • PyBOP benzotriazolyloxy-tris[pyrrolidino]- phosphonium hexafluorophosphate
  • Compounds of general formula (I) may be prepared from compounds of formula (9) and a hydroxyl compound of formula (10), wherein Q is as hereinbefore defined.
  • the reaction is carried out in the presence of a base such as caesium carbonate or potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 100 °C.
  • compounds of formula (I) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a hydrogen atom may be converted to a compound of formula (I) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a halogen atom such as chlorine, bromine or iodine.
  • the reaction may be carried out by mixing a compound of formula (I) with a halogenating reagent such as copper(ll) bromide, N- chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine, in a solvent such as acetonitrile, chloroform or dimethylformamide at a temperature from 0 °C to the boiling point of the solvent.
  • a halogenating reagent such as copper(ll) bromide, N- chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine
  • compounds of formula (2) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a hydrogen atom may be converted to a compound of formula (2) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a halogen atom such as chlorine, bromine or iodine.
  • the reaction may be carried out by mixing a compound of formula (I) 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 the boiling point of the solvent.
  • a halogenating reagent such as copper(ll) bromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine
  • compounds of formula (I) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a chlorine atom, a bromine atom or an iodine atom, herein referred to as a halogenated derivative may be converted to other compounds of formula (I) wherein groups G 5 , G 6 or G 7 which were previously substituted with a halogen atom are now substitiuted with an alkyl group, a cycloalkyl group or a haloalkyl group such as methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl or trifluoromethyl.
  • the halogenated derivative is treated with an organometallic reagent wherein the metal 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.
  • the reaction can be carried out by treating the halogenated derivative with a trialkylboroxine reagent 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 potassium carbonate, in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
  • a transition metal catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll)
  • a base such as potassium carbonate
  • compounds of formula (2) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a chlorine atom, a bromine atom or an iodine atom, herein referred to as halogenated derivative may be converted to other compounds of formula (I) wherein groups G 5 , G 6 or G 7 which were previously substituted with a halogen atom are now substitiuted with an alkyl group, a cycloalkyl group or a haloalkyl group such as methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl or trifluoromethyl.
  • the halogenated derivative is treated with an organometallic reagent wherein the metal 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.
  • the reaction can be carried out by treating a halogenated derivative with a trialkylboroxine reagent 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 potassium carbonate, in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
  • a transition metal catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]- dichloropalladium(ll)
  • a base such as potassium carbonate
  • compounds of formula (I) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with an alkoxy group such as methoxy or ethoxy may be converted to other compounds of formula (I) wherein groups G 5 , G 6 or G 7 which were previously substituted with an alkoxy group are now substitiuted with a hydroxyl group.
  • the reaction is carried out by treating a compound of formula (I) with a metal halide reagent such as boron tribromide, trimethylsilyl chloride, sodium iodide, or mixtures thereof in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
  • compounds of formula (2) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with an alkoxy group such as methoxy or ethoxy may be converted to other compounds of formula (2) wherein groups G 5 , G 6 or G 7 which were previously substituted with an alkoxy group are now substitiuted with a hydroxyl group.
  • the reaction is carried out by treating a compound of formula (2) with a metal halide reagent such as boron tribromide, trimethylsilyl chloride, sodium iodide, or mixtures thereof in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
  • Compounds of general formula (2) wherein G 1 is a CH group and G 2 is nitrogen may be prepared from compounds of formula (1 1 ) wherein R 11 represents hydrogen atom or an alkyl group such as methyl, ethyl, propyl, ie f-butyl or benzyl, and a formamide equivalent such as formamide or formamidine and salts thereof.
  • R 11 represents hydrogen atom or an alkyl group such as methyl, ethyl, propyl, ie f-butyl or benzyl, and a formamide equivalent such as formamide or formamidine and salts thereof.
  • R 11 is a hydrogen atom
  • the reaction is carried out by mixing a compound of formula (1 1 ) with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to the boiling point of the solvent to give a compound of formula (2).
  • reaction is carried out by mixing a compound of formula (1 1 ) with formamidine acetate in the presence or absence of an acid such as acetic acid at a temperature from 50°C to the boiling point of the solvent to give a compound of formula (2).
  • an acid such as acetic acid
  • Compounds of general formula (2) wherein G 1 is a CH group and G 2 is nitrogen may also be prepared from compounds of formula (12), wherein G 3 - G 7 and n are as defined in Claim 1 , and an o f/?o-formate of formula (13) wherein R 12 represents an alkyl group such as methyl or ethyl, in the presence or absence of a solvent such as acetic anhydride at a temperature from ambient to the boiling point of the solvent.
  • Intermediates of formula (15) may be prepared from compound of formula (14) and a doubly activated carbonyl reagent such as phosgene, triphosgene or carbonyl diimidazole in a solvent such as dioxane at a temperature from 0 °C to the boiling point of the solvent.
  • a doubly activated carbonyl reagent such as phosgene, triphosgene or carbonyl diimidazole
  • R 10 represents an alkyl group such as methyl, ethyl, propyl, ie f-butyl, benzyl or 2-(trimethylsilyl)ethyl
  • R 10 is as hereinbefore defined in the presence of a base such as triethylamine and in a solvent such as dioxane at a temperature from 0 °C to the boiling point of the solvent.
  • Intermediates of formula (5) wherein R 10 is as hereinbefore defined may be prepared from compounds of formula (17) by diazotization with a reagent such as sodium nitrite or isoamyl nitrite in the presence of an acid such as acetic acid in a solvent such as water.
  • a reagent such as sodium nitrite or isoamyl nitrite in the presence of an acid such as acetic acid in a solvent such as water.
  • Intermediates of the general formula (3) may also be prepared following the synthetic scheme depicted in Scheme 4.
  • the reaction is carried out by treating a compound of formula (18) with a compound of formula (10) in the presence of a dialkyi azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and a phosphine such as triphenylphosphine, in a solvent such as tetrahydrofuran, at a temperature from 0 °C to 50 °C.
  • a dialkyi azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD)
  • a phosphine such as triphenylphosphine
  • R 1 -R 4 , Q and PG-N are as hereinbefore may also be prepared from compounds of formula (20) wherein R 1 -R 4 and N-PG are as hereinbefore defined and W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction is carried out by treating a compound of formula (20) with a compound of formula (10) in the presence of a base such as caesium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 100 °C.
  • R 1 -R 4 , Q and W 1 are as hereinbefore defined may be prepared from compounds of formula (7) and an acyl halide of formula (21 ) wherein W 1 is as hereinbefore defined and W 2 represent a halogen atom such as fluorine, chlorine or bromine.
  • the reaction is carried out by treating a compound of formula (7) with a compound of formula (21 ) in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature from 0 °C to 50 °C.
  • Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Commercial intermediates are referred to in the experimental section by their lUPAC name. Ether refers to diethyl ether, unless otherwise specified. Concentration or evaporation refer to evaporation under vacuum using a Buchi rotatory evaporator.
  • Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 ⁇ ) with the solvent system indicated. Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a C18 column and using a gradient, unless otherwise stated, of water-acetonitrile/MeOH (1 :1 ) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 :1 ) in 40 column volumes.
  • the conditions "formic acid buffer” refer to the use of 0.1 % v/v formic acid in both phases.
  • the appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized.
  • Preparative H PLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector.
  • the chromatographic separations were obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 ⁇ ) column for methods A, B and C and a Symmetry C18 (2.1 x 100 mm, 3.5 ⁇ ) for method D.
  • the mobile phases were (B): formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) and (A): formic acid (0.5 ml), ammonia (0.125 ml) and water (1000 ml) (A), the gradients are specified in the following table for each method used.
  • the flow rate was 0.8 ml/min for method A and 0.4 ml/min for method B, C and D.
  • the injection volume was 5 microliter.
  • a Waters 2996 diode array was used as a UV detector.
  • Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization in a Micromass ZMD or in a Waters ZQ detectors coupled to the 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 (2.1x50mm, 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.
  • Triethylamine (0.42 mL, 3.0 mmol) was added dropwise to a stirred suspension of the title compound of PREPARATION 8 (0.192 g, 0.96 mmol) and ie/f-butyl 2- aminoacetate hydrochloride salt (0.169 g, 1 .01 mmol) in 1 ,4-dioxane (9 mL). After 20 h, the mixture was filtered and the filter cake was washed with a little 1 ,4-dioxane. The combined filtrate and washings was evaporated to give 0.27 g of the crude product which was used without further purification in the next synthetic step.
  • Oxalyl chloride (0.10 mL, 1 .15 mmol) and /V,/V-dimethylformamide (2 drops) were added to a stirred suspension of the title compound of PREPARATION 13 (0.200 g, 0.83 mmol) in dry dichloromethane (5 mL) and the mixture was stirred overnight at ambient temperature. Further oxalyl chloride (0.05 mL) was added and stirring was continued for a further 4 h before the mixture was evaporated in vacuo.
  • the reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (75 mL) and washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL) and water (2 x 50 mL). The combined organic extracts were dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by column chromatography (Biotage SNAP 50 g column, MeOH-dichloromethane gradient, 0:100 rising to 10:90) to give 452 mg of the title compound (1 .40 mmol, 57%) as a white solid.
  • the title compound of PREPARATION 62 (0.57 g, 3.80 mmol) was suspended in 12 ml dimethylformamide. /V-Bromosuccinimide (1 .49 g. 8.37 mmol) was added and the mixture was stirred at 80 °C for 16 h. The mixture was allowed to cool and was partitioned between water and ethyl acetate, forming a precipitate in the organic phase. The solid was collected by filtration and was dried in vacuo at 35 °C to give 0.50 g of the title compound (2.18 mmol, 57%) as a white solid.
  • the title compound was synthesized from the title compound of PREPARATION 65 according to the method described in Heim-Riether and Healy, J. Org. Chem. 2005, 70, 7331 .
  • 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 ambient 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) ⁇ ppm 7.40 (s, 2 H), 5.58 (s, 1 H), 3.28 (s, 3 H), 2.10 (s, 3 H).
  • Diethyl 2-fluoromalonate (15 g, 84 mmol) was suspended in 50 mL of methanol. A solution of potassium hydroxide (5.6 g, 84 mmol) in 40 mL of methanol was added and the mixture was stirred at room temperature for 2.5h. Benzylamine (27.6 mL, 250 mmol) was added and the mixture was stirred and heated at 55°C overnight. The mixture was cooled to ambient temperature and was concentrated in vacuo. The residue was triturated with ether to give a solid which was collected by filtration and washed with ether. The solid was partitioned between 5N hydrochloric acid and ethyl acetate.
  • the mixture was then heated at 55°C overnight.
  • the mixture was cooled to ambient temperature and water and an 5N aqueous hydrochloric acid were carefully added.
  • PREPARATION 81 tert-Butyl (2-fluoro-3-hydroxypropyl)carbamate
  • the title compound of PREPARATION 80 (10.9 g, 59 mmol) was suspended in 250 mL of methanol and 10% Palladium on carbon (5.4 g) wet with 5.5 mL of water was added, ammonium formate (18.8 g, 300 mmol) was added in portions and the mixture was stirred and heated at 55°C for 2h. The reaction was cooled to ambient temperature and filtered through Celite® eluting with methanol. The organic extract was evaporated under reduced pressure. The residue was re-dissolved in water and was adjusted to pH 3-4 with 5N hydrochloric acid.
  • the aqueous phase was extracted with ethyl acetate and basified to pH 9-10 with 32% potassium hydroxide solution.
  • a solution of di-tert-butyl dicarbonate (13.0g 75 mmol) in 25 mL tetrahydrofuran was added drop-wise and the mixture was stirred at room temperature for 24h.
  • the phases were separated and the aqueous layer was extracted with ethyl acetate.
  • the combined organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure.
  • PREPARATION 88 8-Methylisoquinolin-1 (2H)-one
  • the title compound of PREPARATION 87 (276 mg, 1 .73 mmol) was dissolved in 5 mL acetic anhydride and the mixture was refluxed for 4h. The solvent was evaporated under reduced pressure. 1 M Sodium hydroxide solution (5 mL, 5 mmol) was added and the mixture was heated at 80 °C overnight. The reaction was cooled to room temperature and dichloromethane was added. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure.
  • PREPARATION 92 tert-Butyl (5-methyl-4-oxo-1 ,2,3-benzotriazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 91 . Yield: 84%. Purity 94%.
  • Methyl 4-methyl-1 H-pyrazole-5-carboxylate (1 .36 g, 9.7 mmol) was dissolved in 70 ml anhydrous DMF under nitrogen and the solution cooled to -10 °C.
  • Lithium bis(trimethylsilyl)amide solution (1 M in tetrahydrofuran, 10.7 ml, 10.7 mmol) was added dropwise with stirring over 15 min.
  • O- (dipenylphosphoryl)hydroxylamine (2.73 g, 1 1 .7 mmol) was added and the mixture was stirred for 10 min at -10 °C and then 1 h at room temperature, forming a solid mass.
  • 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 as a white solid. Purity 87%.
  • the title compound of PREPARATION 97 (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%.
  • PREPARATION 104 tert-Butyl (7,9-dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetate
  • the title compound of PREPARATION 103 (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 ⁇ , 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
  • PREPARATION 106 tert-Butyl (1 , 3 -di methyl -4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)acetate Synthesized from the title compound of PREPARATION 6 and tert-Butyl bromoacetate. Yield: 100%. Purity 100%.

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Abstract

The present invention relates to compounds of formula (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 al., 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 , CGRP and substance P (Kaneko et al., 2013). Moreover, TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B- lymphocytes (Stokes et al., 2006).
TRPA1 is activated by a variety of noxious stimuli, including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic). TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers, and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
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, DRG and TG, and project to a variety of peripheral targets, including skin, airways, and gastrointestinal (Gl) tract.
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 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 TRPAI 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.
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), I L-13-induced itch in atopic dermatitis by I L-13 (Oh et al. 2013), I L-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.
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 et al., 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. An example of these compounds is GRC-17536.
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 The invention provides a compound of formula (I) or a pharmaceutically acceptable salt, a /V-oxide or a isotopically-labeled derivative thereof for use in the treatment of the human or animal body by therapy,
Figure imgf000007_0001
Formula (I)
wherein: · G1 is selected from the group consisting of a CH group and a N atom;
• G2 is selected from the group consisting of a C(Ra) group and a N atom;
• G3 and G4 are independently selected from the group consisting of a C atom and a N atom;
• G5, G6 and G7 are independently selected from the group consisting of a C(Rb) group, a N(RC) group, a N atom, an O atom and a S atom;
• Q is a monocyclic or bicyclic C6-i4 aryl or a monocyclic or bicyclic 5- to 14- membered heteroaryl ring, unsubstituted or substituted by one or more substituents selected from a linear or branched Ci-4 alkyl group, a halogen, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a Ci-4 monoalkylamino group, a Ci-4 dialkylamino group, a C3-7 cycloalkyl group, a phenyl ring and a phenoxy group;
• R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched Ci-4 alkyl group, a Ci-4 haloalkyl group, a C6-i4 aryl group and a benzyl group; or R1 together with the Q group, the O atom and the C atom where it is attached, form a fused bicyclic 8- to 14-membered heterocyclyl ring containing at least one heteroatom selected from O, S and N;
• R3 and R4 are independently selected from the group consisting of a H atom and a F atom; · Ra is selected from the group consisting of a H atom, a linear or branched Ci-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkyloxy group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 monoalkylamino group and a Ci-4 dialkylamino group; • Rb is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a C1-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 rmonoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
• Rc is selected from the group consisting of a hydrogen atom, a linear or
branched C1-4 alkyl group, a Ci-4 haloalkyl group and a C3-7 cycloalkyl group;
• n is an integer selected from 1 or 2; and
• = represents a single or a double bond.
The invention provides synthetic processes and intermediates described herein, which are useful for preparing compounds of the invention.
The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically-acceptable carrier. The invention further provides combinations comprising a compound of the invention and one or more other therapeutic agents and pharmaceutical compositions comprising such combinations.
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 pain, acute and/or chronic pruritus, 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. 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 Ci-4 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 , 2 or 3 halogen atoms. Examples include CCIs, CF3 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 said halogen atoms. Examples of haloalkoxy groups include -OCF3 and -OCCI3.
As used herein, the term C3-7 cycloalkyl embraces saturated carbocyclic radicals monocyclic or polycyclic ring having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, the term Ce-14 aryl radical embraces typically a Ce-14, more preferably Ce-ιο monocyclic or bicyclic aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred. A said unsubstituted or substituted Ce-14 aryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. When a Ce-14 aryl radical carries 2 or more substituents, the substituents may be the same or different.
As used herein, the term monocyclic or bicyclic 5- to 14-membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 6-membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N. A 5- to 14-membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H- pyrazolo[3,4-c/]pyrimidinyl, 1 /-/-pyrazolo[3,4-c/]pyrimidinyl, thieno[2,3-c/] pyrimidinyl, thieno[3,2-c/]pyrimidinyl and the various pyrrolopyridyl, pyridopyrimidinyl,
pyrimidopyridazinyl, pyrazinopyrimidinyl, imidazotriazinyl, pyridotriazinyl and
triazolopyrimidinyl radicals.
As used herein, the term fused bicyclic 8- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated Ce-14 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N , O and S. The fused bicyclic 8- to 14-membered heterocyclyl group is formed by binding R1 to the Q group, together with the O atom and the C atom where R1 is attached, and therefore will always have an O atom in its structure. Examples include benzo[c/][1 ,3]dioxolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, [1 ,3]dioxolo[4,5- b]pyridyl, 3,4-dihydro-2/-/-pyrano[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyrazyl, or 2,3- dihydro-[1 ,4]dioxino[2,3-b]pyridyl.
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 Ci-4 rmonoalkylamino is represented by the formula -NH(Ci-4 alkyl) where Ci-4 alkyl is as described above. Representative examples include methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, and (ieri-butyl)amino group.
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 d\{tert- butyl)amino group.
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 pain, acute and/or chronic pruritus, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
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 "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 "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 or 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 or Crohn's disease.
The term "urinary tract disorders" as used herein includes, but is not limited to, disorders such as urinary incontinence, bladder instability or 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 aluminum, 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 ie fiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as ammonia, arginine, betaine, caffeine, choline, /V,/V-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, /V-ethylmorpholine, /V-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
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. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon-14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-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 %.
Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
Typically, a deuterated derivative of a compound of the invention has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
In a preferred embodiment, the isotopic enrichment factor is at least 5000 (75% deuterium). In a more preferred embodiment, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In a most preferred embodiment, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.
The isotopic enrichment factor can be determined using conventional analytical methods known too en ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).
The compounds of the invention may contain one or more chiral centers. Accordingly, the invention includes racemic mixtures, enantiomers, and mixtures enriched in one or more stereoisomer. The scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
In a preferred embodiment, the invention provides with a compound or a pharmaceutically acceptable salt, a /V-oxide or a isotopically-labeled derivative thereof of formula (I)
Figure imgf000015_0001
Formula (I)
wherein:
G1 is selected from the group consisting of a CH group and a N atom;
G2 is selected from the group consisting of a C(Ra) group and a N atom;
G3 and G4 are independently selected from the group consisting of a C atom and a N atom;
G5, G6 and G7 are independently selected from the group consisting of a C(Rb) group, a N(RC) group, a N atom, an O atom and a S atom;
Q is a monocyclic or bicyclic C6-i4 aryl or a monocyclic or bicyclic 5- to 14- membered heteroaryl ring, unsubstituted or substituted by one or more substituents selected from a linear or branched Ci-4 alkyl group, a halogen, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a Ci-4 monoalkylamino group, a Ci-4 dialkylamino group, a C3-7 cycloalkyl group, a phenyl ring and a phenoxy group;
R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched Ci-4 alkyl group, a Ci-4 haloalkyl group, a C6-i4 aryl group and a benzyl group; or R1 together with the Q group, the O atom and the C atom where it is attached, form a fused bicyclic 8- to 14-membered heterocyclyl ring containing at least one heteroatom selected from O, S and N;
R3 and R4 are independently selected from the group consisting of a H atom and a F atom;
Ra is selected from the group consisting of a H atom , a linear or branched Ci-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkyloxy group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 rmonoalkylamino group and a Ci-4 dialkylamino group;
• Rb is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a C1-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 rmonoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
• Rc is selected from the group consisting of a hydrogen atom, a linear or
branched C1-4 alkyl group, a Ci-4 haloalkyl group and a C3-7 cycloalkyl group; · n is an integer selected from 1 or 2; and
• = represents a single or a double bond; provided that the compound is not one of the following:
/V-[3-(2,4-dichlorophenoxy)propyl]-4-methyl-1 -oxo-2(1 /-/)-phthalazineacetamide;
8-methyl-4-oxo-/V-(3-phenoxypropyl)-3(4/-/)-quinazolineacetamide;
/V-[3-(3-methylphenoxy)propyl]-4-oxo-3(4/-/)-quinazolineacetamide;
4-oxo-/V-(3-phenoxypropyl)-thieno[2,3-c/]pyrimidine-3(4/-/)-acetamide;
4-oxo-/V-[3-(2,3,5-trimethylphenoxy)propyl]-3(4/-/)- quinazolineacetamide;
8-methyl-/V-[3-(3-methylphenoxy)propyl]-4-oxo-3(4/-/)- quinazolineacetamide;
/V-[3-(3-methylphenoxy)propyl]-4-oxo-thieno[2,3-c/]pyrimidine-3(4/-/)-acetamide; 1 ,4-dihydro-1 -methyl-4-oxo-/V-[3-(2,3,5-trimethylphenoxy)propyl]-5/-/-pyrazolo[3,4- c/]pyrimidine-5-acetamide;
2-methyl-4-oxo-/V-[3-(8-quinolinyloxy)propyl]-3(4/-/)-quinazolineacetamide;
6-bromo-/V-[3-(2,4-dichlorophenoxy)propyl]-4-oxo-3(4/-/)-quinazolineacetamide; 8-methyl-4-oxo-/V-[3-(8-quinolinyloxy)propyl]-3(4/-/)-quinazolineacetamide;
6-bromo-/V-[3-(4-fluorophenoxy)propyl]-4-oxo-3(4/-/)-quinazolineacetamide;
4-methyl-1 -oxo-/V-[3-(8-quinolinyloxy)propyl]-2(1 /-/)-phthalazineacetamide;
6-fluoro-4-oxo-/V-[3-(8-quinolinyloxy)propyl]-3(4/-/)- quinazolineacetamide;
2-methyl-/V-[3-(3-methylphenoxy)propyl]-4-oxo-3(4/-/)- quinazolineacetamide; /V-[3-(2,4-dichlorophenoxy)propyl]-4-oxo-3(4/-/)-quinazolineacetamide; /V-[3-(2,4-dichlorophenoxy)propyl]-6-fluoro-4-oxo-3(4/-/)- quinazolineacetamide;
/V-[3-(4-fluorophenoxy)propyl]-4-oxo-thieno[2^
4-oxo-/V-[3-(8-quinolinyloxy)propyl]-3(4/-/)-quinazolineacetamide;
/V-[3-(2-fluorophenoxy)propyl]-1 ,4-dihydro-1 -methyl-4-oxo-5/-/-pyrazolo[3,4- c/]pyrimidine-5-acetamide;
1 ,4-dihydro-1 -methyl-4-oxo-/V-(3-phenoxypropyl)-5H-pyrazolo[3,4-(^pyrimidine-5- acetamide;
1 ,4-dihydro-1 -methyl-/V-[3-(3-methylphenoxy)propyl]-4-oxo-5/-/-pyrazolo[3,4- c/]pyrimidine-5-acetamide;
4-methyl-1 -oxo-/V-(3-phenoxypropyl)-2(1 /-/)-phthalazineacetamide;
4-oxo-/V-(3-phenoxypropyl)-3(4/-/)- quinazolineacetamide;
/V-[3-(3-methylphenoxy)propyl]-4-oxo-1 ,2,3-benzotriazine-3(4/-/)-acetamide;
/V-[3-(2-fluorophenoxy)propyl]-4-oxo-3(4/-/)- quinazolineacetamide;
/V-[3-(2-fluorophenoxy)propyl]-4-oxo-1 ,2,3-benzotriazine-3(4/-/)-acetamide;
/V-[3-(2-fluorophenoxy)propyl]-5,6-dimethyl-4-oxo-thieno[2,3-c/]pyrimidine-3(4/-/)- acetamide; or
5,6-dimethyl-4-oxo-/V-(3-phenoxypropyl)-thieno[2,3-c/]pyrimidine-3(4/-/)-acetamide.
Typically, Q represents a phenyl group or a pyridine group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a cyano group, a C1-4 dialkylamino group, a phenyl ring and a phenoxy group.
Typically, R1 and R2 are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group; or R1 together with the Q group, the O atom and the C atom where it is attached form a fused bicyclic ring of formula (a), (b), (c) or (d).
Figure imgf000017_0001
(a) (b) (c) (d) Typically, G1 represents a CH group and G2 represents a N atom.
Typically, G5, G6 and G7 are independently selected from the group consisting of a C(Rb) group, a N(RC) group and a N atom.
In a preferred embodiment, G1-G7 are not all N atoms.
Typically, Rb is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom and a C1-4 alkoxy group; preferably a H atom, a halogen atom, a methyl group and a methoxy group.
In a more preferred embodiment:
• G1 represents a CH group and G2 represents a N atom;
• G5, G6 and G7 are independently selected from the group consisting of a C(Rb) group, a N(RC) group and a N atom;
• Q represents a phenyl group or a pyridine group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, a cyano group, a Ci-4 dialkylamino group, a phenyl ring and a phenyloxy group;
• R1 and R2 are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group; or R1 together with the Q group, the O atom and the C atom where it is attached form a fused bicyclic ring of formula (a), (b), (c) or (d);
-co -co -co o
(a) (b) (c) (d) and
• Rb is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom and a C1-4 alkoxy group; preferably a H atom, a halogen atom, a methyl group and a methoxy group.
Particular individual compounds of the invention include:
2-(4-Oxopyrido[3,4-d]pyrimidin-3(4H -yl)-/V-{3-[4- (trifluoromethyl)phenoxy]propyl}acetamide; /V-{3-[(5-Chloropyridin-3-yl)oxy]propyl}-2-(4-oxoquinazolin-3(4H^-yl)acetamide;
/V-[3-(2-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4/-/)-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(6-methyl-4-oxopyrido[3,4-c ]pynmidin-3(4/-/ - yl)acetamide;
/V-[3-(3-Fluorophenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(4-Methylphenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Methoxyphenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(4-Fluorophenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)acetamide;
2-(4-Oxopyrido[4,3-c/]pyrimidin-3(4H -yl)-/V-{3-[4-
(trifluoromethyl)phenoxy]propyl}acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[4,3-c/]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,2-c/]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[2,3-c/]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[2,3-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5J-dimethoxy-4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[4,3-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chloro-4-fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c ]pynmidin-3(4/-/ - yl)acetamide;
/V-[3-(3,5-Dichlorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H^-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrimido[4,5-c/]pyridazin-3(4H^-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-oxopyrimido[4,5-c]pyridazin-6(5/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)butyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Cyanophenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
2-(6-Chloro-4-oxopyrido[3,4-c ]pynmidin-3(4H -yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4H -yl)-/V-{3-[3-
(trifluoromethyl)phenoxy]propyl}acetamide;
/V-[3-(3-Chlorophenoxy)butyl]-2-(4-oxopyrido[3,4-c ]pynmidin-3(4H -yl)acetarTiide; /V-[3-(3-Chlorophenoxy)propyl]-2-(1 -oxo-2,6-naphthyridin-2(1 /-/)-yl)acetamide;
/V-{3-[3-(Dimethylamino)phenoxy]propyl}-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-methoxy-4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrimido[4,5-c/]pyrimidin-3(4H^-yl)acetamide;
/V-[3-(4-Cyanophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(8-methoxy-4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(6-methoxy-4-oxoquinazolin-3(4/-/)-yl)acetamide;
2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)-/V-(3-phenoxypropyl)acetamide;
2-(5-Bromo-4-oxopyrido[3,4-c ]pynmidin-3(4H -yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
2-(8-Chloro-4-oxopyrido[3,4-c ]pynmidin-3(4H -yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxopyrido[3,4-c ]pynmidin-3(4/-/ - yl)acetamide;
/V-{3-[(4-Chloropyridin-2-yl)oxy]propyl}-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/ - yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3!4-c/][1 !2!3]triazin-3(4H -yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(8-methyl-4-oxopyrido[3,4-c ]pynmidin-3(4/-/ - yl)acetamide;
/V-[3-(3-Bromophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)acetamide;
/V-[2-(2,3-Dihydro-1 -benzofuran-2-yl)ethyl]-2-(4-oxopyrido[3,4-c/]pynmidin-3(4H - yl)acetamide;
/V-[3-(3-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(Biphenyl-3-yloxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H^-yl)acetamide;
/V-[3-(3,4-Difluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H^-yl)acetamide;
2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4H^-yl)-/V-[3-(3-phenoxyphenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(6-methoxy-4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)- yl)acetamide;
/V-[3-(3-Methylphenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H^-yl)acetamide; /V-[3-(3-Methoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H^-yl)acetamide; 2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4H -yl)-/V-{3-[3- (trifluoromethoxy)phenoxy]propyl}acetamide;
/V-[3-(4-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(8-methoxy-4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxothieno[2,3-c/]pyrimidin-3(4H^-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxothieno[3,2-c/]pyrimidin-3(4H^-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-4-oxo-1 !4-dihydro-5H-pyrazolo[3,4- c/]pyrimidin-5-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxoimidazo[5 -/][1 !2,4]triazin-3(4H -yl)acetamide; /V-[3-(4-Fluorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chloro-4-fluorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 ,3-dimethyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)butyl]-2-(1 !3-dimethyl-7-oxo-1 !7-dihydro-6H-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -ethyl-3-methyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
2-(3-Bromo-1 -methyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3-c/]pyrimidiri-6-yl)-/\/-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 ,3-dimethyl-4-oxo-1 !4-dihydro-5H-pyrazolo[3,4- c/]pyrimidin-5-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5 -/][1 !2!4]triazin-3(4H - yl)acetamide;
2-(7-Bromo-5-methyl-4-oxoimidazo[5!1 -/][1 !2!4]triazin-3(4H -yl)-/\/-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5J-dimethyl-4-oxoimidazo[5 -^[1 ,2,4]triazin-3(4/-/ - yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(6,8-dimethyl-4-oxoimidazo[1 !5-a][1 !3,5]triazin-3(4H - yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4,8-dioxo-7,8-dihydropyrido[3,4-c ]pynmidin-3(4H - yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4,6-dioxo-6J-dihydropyrido[3,4-c ]pynmidin-3(4H - yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(4-fluoro-1 -oxo-2,6-naphthyridin-2(1 H)-yl)acetamide; N-[3-(4-Methoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide; N-[3-(3-Chlorophenoxy)butyl]-2-(5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxoquinazolin-3(4H)-yl)acetamide;
2-(4-Bromo-1 -oxo-2,6-naphthyridin-2(1 H)-yl)-N-[3-(3-chlorophenoxy)propyl]acetamide; N-[3-(3-Chlorophenoxy)propyl]-2-(7-methyl-6-oxo-6,7-dihydro-1 H-purin-1 -yl)acetamide; N-[3-(3-Chlorophenoxy)propyl]-2-(5,8-dibromo-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide; N-[3-(3-Chlorophenoxy)propyl]-2-(7-ethyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5!8-dimethyl-4-oxopyrido[3!4-d]pyrimidin-3(4H)- yl)acetamide;
2-(3-Ethyl-1 -methyl-7-oxo-1 !7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)-N-[3-(3- ethylphenoxy)propyl]acetamide;
N-[3-(1 -Naphthyloxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide;
N-[3-(4-Bromophenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide;
N-[3-(2-Naphthyloxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide;
2-(4-Oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-N-[3-(3,4,5-trifluorophenoxy)propyl]acetamide;
N-[3-(3-Ethoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide;
2-(5-Methyl-4-oxoimidazo[5,1 -f][1 !2!4]triazin-3(4H)-yl)-N-[3-(3!4,5- trifluorophenoxy)propyl]acetamide;
N-[3-(3!4-Difluorophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-ethyl-4-oxopyrido[3!4-d]pyrimidin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(3-ethyl-1 -methyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- d]pyrimidin-6-yl)acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide;
N-{3-[(5-Chloropyridin-3-yl)oxy]propyl}-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(3-methyl-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)- yl)acetamide;
N-[3-(3-Bromophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5,8-dimethyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)-2-fluoropropyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
N-{3-[(5-Bromopyridin-3-yl)oxy]propyl}-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
2-(5-Methyl-4-oxoimidazo[5,1 -f][1 !2,4]triazin-3(4H)-yl)-N-[3-(pyridin-3- yloxy)propyl]acetamide;
N-[3-(lsoquinolin-7-yloxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetamide; N-[3-(3-Chlorophenoxy)propyl]-2-(5-cyano-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide;
2-(4-Bromo-8-methyl-1 -oxoisoquinolin-2(1 H)-yl)-N-[3-(3- chlorophenoxy)propyl]acetamide;
2-(5-Methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)-N-(3-phenoxypropyl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxo-1 ,2,3-benzotriazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxopyrazolo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(7!9-dimethyl-6!8-dioxo-6!7!8,9-tetrahydro-1 H-purin-1 - yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(7-methoxy-5-methyl-4-oxopyrido[2,3-d]pyrimidin- 3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4,7-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin- 3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-[5-methyl-7-(methylamino)-4-oxoimidazo[5,1 - f][1 ,2,4]triazin-3(4H)-yl]acetamide;
2-(7-Amino-5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)-yl)-N-[3-(3- chlorophenoxy)propyl]acetamide;
N-[3-(4-Bromo-3-chlorophenoxy)propyl]-2-(7-methyl-6-oxo-6,7-dihydro-1 H-purin-1 - yl)acetamide;
2-(7-Bromo-5-methyl-4-oxoimidazo[5!1 -f][1 ,2,4]triazin-3(4H)-yl)-N-[3-(3- cyanophenoxy)propyl]acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(5-methyl-4,7-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin- 3(4H)-yl)acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4- d]pyrimidin-5-yl)acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(7-ethyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(5,8-dimethyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide
or a pharmaceutically acceptable salt, /V-oxide, solvate, or isotopically-labeled derivative thereof.
Of particular interest are the compounds: Enantiomer 1 of /V-[3-(3-Chlorophenoxy)butyl]-2-(4-oxopyrido[3,4-c ]pyrimidin-3(4/-/ yl)acetamide;
2-(5-Bromo-4-oxopyrido[3,4-c ]pynmidin-3(4H -yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
2-(8-Chloro-4-oxopyrido[3,4-c ]pynmidin-3(4H -yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxopyrido[3,4-c ]pynmidin-3(4/-/ - yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(8-methyl-4-oxopyrido[3,4-c ]pynmidin-3(4/-/ - yl)acetamide;
/V-[3-(3-Bromophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)acetamide; /V-[3-(Biphenyl-3-yloxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H^-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(1 ,3-c/imethyl-7-oxo-1 !7-dihydro-6/-/-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)butyl]-2-(1 ,3-dimethyl-7-oxo-1 !7-dihydro-6H-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
Enantiomer 1 /V-[3-(3-Chlorophenoxy)butyl]-2-(1 ,3-dimethyl-7-oxo-1 ,7-dihydro-6/-/- pyrazolo[4,3-c/]pyrimidin-6-yl)acetamide;
2-(3-Bromo-1 -methyl-7-oxo-1 J-dihydro-6H-pyrazolo[4,3-c/]pyrimidin-6-yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5/-/-pyrazolo[3,4- c/]pyrimidin-5-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5 -/][1 !2!4]triazin-3(4H - yl)acetamide;
2-(7-Bromo-5-methyl-4-oxoimidazo[5 -/][1 !2!4]triazin-3(4H -yl)-/\/-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5J-dimethyl-4-oxoimidazo[5 -^[1 ,2,4]triazin-3(4/-/ - yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(6!8-dimethyl-4-oxoimidazo[1 ,5-a][1 !3,5]triazin-3(4H - yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxoquinazolin-3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(7-ethyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-
3(4H)-yl)acetamide;
N-[3-(3!4-Difluorophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide; N-[3-(3-Chlorophenoxy)propyl]-2-(3-ethyl-1 -methyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- d]pyrimidin-6-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(3-methyl-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)- yl)acetamide;
N-[3-(3-Bromophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5!1 -f][1 !2!4]triazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5,8-dimethyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxopyrazolo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4J-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin- 3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-[5-methyl-7-(methylamino)-4-oxoimidazo[5,1 - f][1 !2,4]triazin-3(4H)-yl]acetamide;
2-(7-Bromo-5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)-yl)-N-[3-(3- cyanophenoxy)propyl]acetamide; or
N-[3-(3-Cyanophenoxy)propyl]-2-(7-ethyl-5-methyl-4-oxoimidazo[5, 1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide or a pharmaceutically acceptable salt, /V-oxide, solvate or 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 - 4 are described in detail in the Experimental section.
Compounds of the general formula (I) may be prepared following the synthetic scheme depicted in Scheme 1.
Figure imgf000026_0001
Scheme 1
Compounds of general formula (I) may be prepared from bicyclic compounds of formula (2) wherein A is equivalent to a bicyclic group wherein G1-G7 and n are as defined in Claim 1 , and an alkylating agent of formula (3) wherein W1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para- toluenesulphonate or methylsulfonate and R1-R4 and Q are as defined in Claim 1 . The reaction is carried out by mixing a compound of formula (2) and compound of formula (3) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 80 °C.
Compounds of general formula (5) wherein A is as hereinbefore defined and R10 represents an alkyl group such as methyl, ethyl, propyl, ie f-butyl, benzyl or 2- (trimethylsilyl)ethyl may be prepared from bicyclic compounds of formula (2) and an alkylating agent of formula (4) 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 (2) and compound of formula (4) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 80 °C.
Compounds of general formula (6) wherein A is as hereinbefore defined may be prepared from compounds of formula (5) 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 ambient 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 ambient to 50 °C. Compounds of general formula (I) may be prepared from compounds of formula (6) wherein A is as hereinbefore defined and an amine of formula (7) wherein R1 - R4 and Q are as defined in Claim 1 , in the presence of a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), in the presence or absence of a catalyst such as 1 -hydroxybenzotriazole (HOBt). The reaction is carried out by mixing a compound of formula (6) and compound of formula (7) according to standard literature methods known to those skilled in the art of formation of amides to yield the compound of formula (I).
Compounds of general formula (9) wherein R1 - R4 and A are as hereinbefore defined and W1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate, may be prepared from compounds of formula (6) and an amine, or its hydrochloride or hydrobromide salt of formula (8) according to standard literature methods known to those skilled in the art of amide bond formation. Examples include:
• a carboxylic acid of formula (6) and an amine of formula (8) in the presence of a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDO) or benzotriazolyloxy-tris[pyrrolidino]- phosphonium hexafluorophosphate (PyBOP).
• pretreatment of a carboxylic acid of formula (6) with an activating agent such as oxalyl chloride in the presence of a catalytic amount of dimethylformamide followed by addition of an amine of formula (8) in the presence of a base such as triethylamine.
Compounds of general formula (I) may be prepared from compounds of formula (9) and a hydroxyl compound of formula (10), wherein Q is as hereinbefore defined. The reaction is carried out in the presence of a base such as caesium carbonate or potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 100 °C.
In some instances, compounds of formula (I) wherein one or more of the groups G5, G6 or G7 is substituted with a hydrogen atom may be converted to a compound of formula (I) wherein one or more of the groups G5, G6 or G7 is substituted with a halogen atom such as chlorine, bromine or iodine. The reaction may be carried out by mixing a compound of formula (I) with a halogenating reagent such as copper(ll) bromide, N- chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine, in a solvent such as acetonitrile, chloroform or dimethylformamide at a temperature from 0 °C to the boiling point of the solvent. In a similar way, in some instances, compounds of formula (2) wherein one or more of the groups G5, G6 or G7 is substituted with a hydrogen atom may be converted to a compound of formula (2) wherein one or more of the groups G5, G6 or G7 is substituted with a halogen atom such as chlorine, bromine or iodine. The reaction may be carried out by mixing a compound of formula (I) 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 the boiling point of the solvent.
In some instances, compounds of formula (I) wherein one or more of the groups G5, G6 or G7 is substituted with a chlorine atom, a bromine atom or an iodine atom, herein referred to as a halogenated derivative, may be converted to other compounds of formula (I) wherein groups G5, G6 or G7 which were previously substituted with a halogen atom are now substitiuted with an alkyl group, a cycloalkyl group or a haloalkyl group such as methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl or trifluoromethyl. The halogenated derivative is treated with an organometallic reagent wherein the metal 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 trialkylboroxine reagent 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 potassium carbonate, in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
In the same way, in some instances compounds of formula (2) wherein one or more of the groups G5, G6 or G7 is substituted with a chlorine atom, a bromine atom or an iodine atom, herein referred to as halogenated derivative, may be converted to other compounds of formula (I) wherein groups G5, G6 or G7 which were previously substituted with a halogen atom are now substitiuted with an alkyl group, a cycloalkyl group or a haloalkyl group such as methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl or trifluoromethyl. The halogenated derivative is treated with an organometallic reagent wherein the metal 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 a halogenated derivative with a trialkylboroxine reagent 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 potassium carbonate, in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
In some instances, compounds of formula (I) wherein one or more of the groups G5, G6 or G7 is substituted with an alkoxy group such as methoxy or ethoxy, may be converted to other compounds of formula (I) wherein groups G5, G6 or G7 which were previously substituted with an alkoxy group are now substitiuted with a hydroxyl group. The reaction is carried out by treating a compound of formula (I) with a metal halide reagent such as boron tribromide, trimethylsilyl chloride, sodium iodide, or mixtures thereof in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
In the same way, in some instances, compounds of formula (2) wherein one or more of the groups G5, G6 or G7 is substituted with an alkoxy group such as methoxy or ethoxy, may be converted to other compounds of formula (2) wherein groups G5, G6 or G7 which were previously substituted with an alkoxy group are now substitiuted with a hydroxyl group. The reaction is carried out by treating a compound of formula (2) with a metal halide reagent such as boron tribromide, trimethylsilyl chloride, sodium iodide, or mixtures thereof in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
In the case wherein G1 is a CH group and G2 is nitrogen, intermediates of the general formula (2), wherein G3 - G7 and n are as defined in Claim 1 , may be prepared following the synthetic scheme depicted in Scheme 2.
Figure imgf000030_0001
Scheme 2
Compounds of general formula (2) wherein G1 is a CH group and G2 is nitrogen may be prepared from compounds of formula (1 1 ) wherein R11 represents hydrogen atom or an alkyl group such as methyl, ethyl, propyl, ie f-butyl or benzyl, and a formamide equivalent such as formamide or formamidine and salts thereof. In one instance, wherein R11 is a hydrogen atom, the reaction is carried out by mixing a compound of formula (1 1 ) with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to the boiling point of the solvent to give a compound of formula (2). In another instance, wherein R11 is an alkyl group such as methyl, ethyl, propyl, ie f-butyl or benzyl, the reaction is carried out by mixing a compound of formula (1 1 ) with formamidine acetate in the presence or absence of an acid such as acetic acid at a temperature from 50°C to the boiling point of the solvent to give a compound of formula (2).
Compounds of general formula (2) wherein G1 is a CH group and G2 is nitrogen may also be prepared from compounds of formula (12), wherein G3 - G7 and n are as defined in Claim 1 , and an o f/?o-formate of formula (13) 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 ambient to the boiling point of the solvent.
In the case wherein G1 and G2 are both nitrogen, intermediates of the general formula (5), wherein G3 - G7 and n are as defined in Claim 1 , may be prepared following the synthetic scheme depicted in Scheme 3.
Figure imgf000031_0001
Scheme 3 Intermediates of formula (15) may be prepared from compound of formula (14) and a doubly activated carbonyl reagent such as phosgene, triphosgene or carbonyl diimidazole in a solvent such as dioxane at a temperature from 0 °C to the boiling point of the solvent.
Intermediates of formula (17) wherein R10 represents an alkyl group such as methyl, ethyl, propyl, ie f-butyl, benzyl or 2-(trimethylsilyl)ethyl may be prepared from compounds of formula (15) and an amino ester of formula (16) wherein R10 is as hereinbefore defined in the presence of a base such as triethylamine and in a solvent such as dioxane at a temperature from 0 °C to the boiling point of the solvent.
Intermediates of formula (5) wherein R10 is as hereinbefore defined may be prepared from compounds of formula (17) by diazotization with a reagent such as sodium nitrite or isoamyl nitrite in the presence of an acid such as acetic acid in a solvent such as water. Intermediates of the general formula (3) may also be prepared following the synthetic scheme depicted in Scheme 4.
Figure imgf000032_0001
Intermediates of formula (19) wherein R1 - R4 and Q are as defined in Claim 1 and PG-N represents a suitable amine protecting group selected from a carbamate group such as ethoxycarbonyl, benzyloxycarbonyl, ie f-butoxycarbonyl or an imide such as phthalamide, may be prepared from an alcohol of formula (18) wherein R1 - R4 and PG-N are as hereinbefore defined and a hydroxy compound of formula (10) wherein Q is as hereinbefore defined. The reaction is carried out by treating a compound of formula (18) with a compound of formula (10) in the presence of a dialkyi azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and a phosphine such as triphenylphosphine, in a solvent such as tetrahydrofuran, at a temperature from 0 °C to 50 °C.
Compounds of general formula (19) wherein R1-R4, Q and PG-N are as hereinbefore may also be prepared from compounds of formula (20) wherein R1-R4 and N-PG are as hereinbefore defined and 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 treating a compound of formula (20) with a compound of formula (10) in the presence of a base such as caesium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 100 °C.
Intermediates of formula (7) wherein R1-R4 and Q are as hereinbefore defined may be prepared from compounds of formula (19) wherein PG-N is as hereinbefore defined by amine deprotection according to standard literature methods for amine deprotection. In the specific case where PG-N is a ie f-butylcarbamate protecting group, the reaction is carried out by treating a compound of formula (19) with an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as water, dioxane, dichloromethane or chloroform or mixtures thereof at a temperature from 0 °C to 50 °C.
Compounds of general formula (3) R1-R4, Q and W1 are as hereinbefore defined may be prepared from compounds of formula (7) and an acyl halide of formula (21 ) wherein W1 is as hereinbefore defined and W2 represent a halogen atom such as fluorine, chlorine or bromine. The reaction is carried out by treating a compound of formula (7) with a compound of formula (21 ) in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature from 0 °C to 50 °C.
PREPARATION EXAMPLES
The syntheses of the compounds of the invention are illustrated by the following Examples (1 to 1 16) including Preparations (1 to 121 ) 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 μηη) 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 H PLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector.
The chromatographic separations were obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 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.
Figure imgf000034_0001
The flow rate was 0.8 ml/min for method A and 0.4 ml/min for method B, C and D. The injection volume was 5 microliter. A Waters 2996 diode array was used as a UV detector. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization in a Micromass ZMD or in a Waters ZQ detectors coupled to the 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 (2.1x50mm, 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.
1H Nuclear Magnetic Resonance Spectra were recorded on a Varian Mercury plus operating at a frequency of 400MHz or a Varian VNMRS operating at 600MHz and equipped with a cold probe for the 1H spectra. Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as 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 referes to 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. 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
ferf-Butyl (3-hydroxybutyl)carbamate
4-Aminobutan-2-ol (0.80 g, 9.0 mmol) was dissolved in 10 ml dichloromethane and the solution cooled to 5°C in an ice bath. Di-ie f-butyl carbonate (2.06 g, 9.4 mmol) was added portion-wise and the mixture was stirred for 4 h. The organic layer was washed sequentially with water and brine. The organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 1 .50 g (7.9 mmol, 88% yield) of the title compound as a colourless oil.
1 H N MR (400 MHz, CHLOROFORM-D) δ 4.80 (m, 1 H), 3.90 - 3.78 (m, 1 H), 3.50-3.40 (m, 1 H), 3.15 - 3.02 (m, 1 H), 3.04-2.96 (m, 1 H), 1 .44 (s, 9H), 1 .21 (d, J = 6.2 Hz, 3H).
PREPARATION 2 ferf-Butyl [3-(3-chlorophenoxy)butyl]carbamate
The title compound of Preparation 1 (1 .50 g, 7.9 mmol), 3-chlorophenol (0.84 ml, 7.95 mmol) and triphenylphosphine (3.12 g, 1 1 .9 mmol) were dissolved in 10 ml tetrahydrofuran and the solution cooled to 5 °C in an ice bath. Diethyl azodicarboxylate (1 .5 ml, 9.5 mmol) was added drop-wise and with stirring. The mixture was then stirred at reflux for 4 h. The mixture was allowed to cool and was evaporated under reduced pressure. The residue was resuspended in ether giving a precipitate and was sonicated for 5 min. The solid was collected by filtration and was washed with ether. The combined filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography using the Isolera purification system (ether-hexane gradient, 0:100 increasing to 30:70) to give 1 .73 g (5.78 mmol, 73% yield) of the title compound as a pale yellow oil. 1 H N MR (400 MHz, CHLOROFORM-D) δ 7.18 (t, J = 8.1 Hz, 1 H), 6.91 (ddd, J = 7.9, 1 .9, 0.9 Hz, 1 H), 6.88 (t, J = 2.2 Hz, 1 H), 6.77 (ddd, J = 8.3, 2.4, 0.8 Hz, 1 H), 4.42 (sextet, J = 6.7 Hz, 1 H), 3.27 (q, J = 6.3 Hz, 2H), 1 .86 (q, J = 6.7 Hz, 2H), 1 .43 (s, 9H), 1 .31 (d, J = 6.1 Hz, 3H).
PREPARATION 3
[3-(3-Chlorophenoxy)butyl]amine, hydrochloride salt The title compound of Preparation 2 (1 .73 g, 5.78 mmol) was suspended in 75 ml hydrochloric acid (4M in dioxane) and the mixture was stirred for 1 h. The mixture was evaporated under reduced pressure and the residue was re-suspended in anhydrous ether. The mixture was sonicated to give a precipitate. The solid was collected by filtration, washed with ether and dried under reduced pressure at 35 °C to give 1 .25 g (5.3 mmol, 92%) of the title compound as a white solid.
1 H N MR (400 MHz, DMSO-d6) δ 7.90 (br. s, 3H), 7.29 (t, J = 8.1 Hz, 1 H), 7.02 (t, J = 2.2 Hz, 1 H), 6.97 (ddd, J = 8.0, 1 .9, 0.8 Hz, 1 H), 6.91 (ddd, J = 8.4, 2.4, 0.8 Hz, 1 H), 4.62 (sextet, J = 6.7 Hz, 1 H), 2.94 - 2.81 (m, 2H), 1 .98 - 1 .80 (m, 2H), 1 .22 (d, J = 6.1 Hz, 3H).
PREPARATION 4
2-Chloro-yV-[3-(3-chlorophenoxy)butyl]acetamide
The title compound of Preparation 3 (0.50 g, 2.1 mmol) and triethylamine (0.65 ml, 4.6 mmol) were dissolved in 10 ml dichloromethane and the mixture cooled to 5 °C in an ice bath. Chloroacetyl chloride (0.17 ml, 2.1 mmol) was added drop-wise and with stirring and the mixture was stirred for 1 h. The mixture was poured onto ice/water, the layers were separated and the organics were washed brine. The organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 0.60 g (2.1 mmol, 99% yield) of the title compound as a dark oil.
1 H NMR (400 MHz, CHLOROFORM-D) δ 7.20 (t, J = 8.1 Hz, 1 H), 6.94 (ddd, J = 7.9, 1 .9, 0.9 Hz, 1 H), 6.90 (t, J = 2.2 Hz, 1 H), 6.79 (ddd, J = 8.3, 2.4, 0.9 Hz, 1 H), 4.49 (dqd, J = 12.1 , 6.1 , 4.2 Hz, 1 H), 4.06 (d, J = 12.4 Hz, 1 H), 4.00 (d, J = 12.4 Hz, 1 H), 3.55 (td, J = 13.2, 6.3 Hz, 1 H), 3.44 (dt, J = 13.6, 6.5 Hz, 1 H), 2.02 - 1 .85 (m, 2H), 1 .33 (d, J = 6.1 Hz, 3H).
PREPARATION 5
1 ,3-Dimethyl-1 H-pyrazolo[4,3-cf]pyrimidin-7(6H)-one
A mixture of methyl 4-amino-1 ,3-dimethyl-1 /-/-pyrazole-5-carboxylate (0.400 g, 2.36 mmol), formimidamide acetic acid salt (0.271 g, 2.6 mmol) and diisopropylethylamine (2.06 ml_, 1 1 .8 mmol) in n-butanol (2 mL) was stirred at 1 10 °C. After 3 h at 1 10 °C and subsequent cooling to ambient 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 0.34 g the title compound (2.07 mmol, 88%) as a white solid.
1H NMR (400 MHz, DMSO-de) δ ppm 12.19 (1 H, br s), 7.80 (1 H, s), 4.1 1 (3 H, s), 2.34 (3 H, s).
UPLC/MS (3 min) retention time 0.71 min.
LRMS: m/z 165 (M+1 ).
PREPARATION 6 1 ,3-Dimethyl-1 H-pyrazolo[3,4-rflpyrimidin-4(5H)-one
A suspension of 5-amino-1 ,3-dimethyl-1 /-/-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 ambient 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 of the title compound (3.84 mmol, 74%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (1 H, br s), 8.00 (1 H, s), 3.80 (3 H, s), 2.41 (3 H, s).
UPLC/MS (3 min) retention time 0.66 min. LRMS: m/z 165 (M+1 ).
PREPARATION 7 6-Methoxyquinazolin-4(3H)-one
A mixture of 2-amino-5-methoxybenzoic acid (0.400 g, 2.40 mmol) in formamide (0.83 mL, 20.8 mmol) was stirred and heated to 180 °C in a sealed tube. After 1 h at 180 °C and subsequent cooling to ambient 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 0.37 g of the title compound (2.10 mmol, 88%) as a pale brown solid. 1 H N MR (400 MHz, DMSO-de) δ ppm 12.22 (1 H, br s), 8.00 (1 H, s), 7.62 (1 H, d, J=8.8 Hz), 7.51 (1 H, d, J=2.9 Hz), 7.41 (1 H, dd, J=8.8,2.9 Hz), 3.87 (3 H , s).
HPLC/MS (9 min) retention time 3.80 min.
LRMS: m/z 177 (M+1 ).
PREPARATION 8
1 H-Pyrido[3,4-cf][1 ,3]oxazine-2,4-dione, hydrochloride salt
A solution of triphosgene (0.60 g, 2.0 mmol) in 1 ,4-dioxane (6 mL) was added to a suspension of 3-aminoisonicotinic acid (0.42 g, 3.0 mmol) in 1 ,4-dioxane (7 ml) and the mixture was stirred at ambient temperature. After 26 h, further triphosgene (0.30 g, 1 .0 mmol) in 1 ,4-dioxane (3 mL) was added and stirring was continued for a further 24 h. The suspension was filtered and the precipitate was washed with 1 ,4-dioxane and diethyl ether to give 0.61 g of the title compound (3.0 mmol, 100%) as a beige solid.
1 H N MR (400 MHz, DMSO-d6) δ ppm 12.05 (1 H, br s), 8.58 (1 H, s), 8.46 (1 H, d, J=5.1 Hz), 7.81 (1 H, d, J=5.1 Hz).
UPLC/MS (3 min) retention time 0.64 min.
LRMS: m/z 163 (M-1 ).
PREPARATION 9 ferf-Butyl 2-(3-aminoisonicotinamido)acetate
Triethylamine (0.42 mL, 3.0 mmol) was added dropwise to a stirred suspension of the title compound of PREPARATION 8 (0.192 g, 0.96 mmol) and ie/f-butyl 2- aminoacetate hydrochloride salt (0.169 g, 1 .01 mmol) in 1 ,4-dioxane (9 mL). After 20 h, the mixture was filtered and the filter cake was washed with a little 1 ,4-dioxane. The combined filtrate and washings was evaporated to give 0.27 g of the crude product which was used without further purification in the next synthetic step.
UPLC/MS (3 min) retention time 0.91 min.
LRMS: m/z 252 (M+1 ). PREPARATION 10 ferf-Butyl 2-(4-oxopyrido[3,4-d][1 ,2,3]triazin-3(4H)-yl)acetate
A solution of sodium nitrite (0.073 g, 1 .06 mmol) in water (1 .5 mL) was added dropwise to a cooled (ice-bath) solution of the crude title compound of PREPARATION 9 (0.24 g) in a mixture of glacial acetic acid (4 ml) and water (1 mL). After 1 h, the mixture was warmed to ambient temperature, stirred for a further 2 h then evaporated to dryness and the residue was purified by reverse phase chromatography to give 0.50 g of the title compound (0.19 g, 20% over two steps) as a white solid. UPLC/MS (3 min) retention time 1 .43 min.
LRMS: m/z 263 (M+1 ).
PREPARATION 1 1
2-(4-Oxopyrido[3,4-rfl[1 ,2,3]triazin-3(4H)-yl)acetic acid, hydrochloride salt A solution of the title compound of PREPARATION 10 (0.044 g, 0.17 mmol) in 4M hydrochloric acid in 1 ,4-dioxane (4 mL) was stirred at ambient temperature. After 48 h, the mixture was concentrated in vacuo to give 0.037 g of the title compound (0.15 mmol, 91 %) as a pale yellow solid.
UPLC/MS (3 min) retention time 0.57 min. LRMS: m/z 205 (M-1 ).
PREPARATION 12 ferf-Butyl 2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetate
A mixture of pyrido[3,4-c ]pyrimidin-4(3/-/)-one (3.00 g, 20.4 mmol), ie/f-butyl 2- bromoacetate (3.3 mL, 22.4 mmol) and potassium carbonate (5.64 g, 40.8 mmol) in /V,/V-dimethylformamide (60 mL) was stirred at ambient temperature for 18 h. The reaction mixture was poured onto ice water (200 mL) and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc-hexane gradient: 0: 100 rising to 100:0) to give 3.94 g of the title compound (15.1 mmol, 74%) as a white solid.
1 H NMR (400 MHz, CDCI3) δ ppm 9.18 (1 H, s), 8.74 (1 H, d, J=5.3 Hz), 8.08 (1 H, d, J=5.3 Hz), 8.05 (1 H, s), 4.64 (2 H, s), 1 .51 (9 H, s). UPLC/MS (3 min) retention time 1 .26 min.
LRMS: m/z 262 (M+1 ).
PREPARATION 13
2-(4-Oxopyrido[3,4-cf]pyrimidin-3(4H)-yl)acetic acid, hydrochloride salt A solution of the title compound of PREPARATION 12 (3.94 g, 15.1 mmol) in 4M hydrochloric acid in 1 ,4-dioxane (210 mL) was stirred at ambient temperature. After 4 h, the mixture was concentrated in vacuo to give 3.63 g of the title compound (15.0 mmol, 99%) as a pale yellow solid.
1 H N MR (400 MHz, DMSO-d6) δ ppm 9.14 (1 H, s), 8.73 (1 H , d, J=5.3 Hz), 8.53 (1 H, s), 8.03 (1 H, d, J=5.3 Hz), 4.78 (2 H, s).
HPLC/MS (9 min) retention time 3.17 min.
LRMS: m/z 206 (M+1 ).
PREPARATION 14 W-(2-Chloroethyl)-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide
Oxalyl chloride (0.10 mL, 1 .15 mmol) and /V,/V-dimethylformamide (2 drops) were added to a stirred suspension of the title compound of PREPARATION 13 (0.200 g, 0.83 mmol) in dry dichloromethane (5 mL) and the mixture was stirred overnight at ambient temperature. Further oxalyl chloride (0.05 mL) was added and stirring was continued for a further 4 h before the mixture was evaporated in vacuo. The residue was resuspended in dry dichloromethane (5 mL) and cooled in an ice-bath with stirring and 3-chloropropan-1 -amine hydrochloride (0.129 g, 0.99 mmol) and triethylamine (0.46 mL, 3.30 mmol) were added. After 2 h stirring, the mixture was quenched with water and diluted with ethyl acetate. The organic layer was filtered, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to give 0.135 g of the title compound (0.48 mmol, 55%) as a pale yellow solid.
1H NMR (400 MHz, DMSO-de) δ ppm 9.10 (1 H, s), 8.71 (1 H, d, J=5.3 Hz), 8.44 (1 H, s), 8.39 (1 H, m), 7.99 (1 H, d, J=5.3 Hz), 4.66 (2 H, s), 3.66 (2 H, t, J=6.7 Hz), 3.23 (2 H, m), 1.88 (2 H, t, J=6.7 Hz).
UPLC/MS (3 min) retention time 0.96 min.
LRMS: m/z 281 (M+1 ).
PREPARATION 15 Methyl 2-(4-oxoquinazolin-3(4H)-yl)acetate
A mixture of quinazolin-4(3/-/)-one (5.00 g, 34.2 mmol), methyl 2-bromoacetate (5.66 g, 36.6 mmol) and potassium carbonate (9.38 g, 68.0 mmol) in /V,/V-dimethylformamide (60 mL) was stirred at ambient temperature for 18 h. The reaction mixture was then poured onto ice water (200 mL) and neutralized with 12M aqueous hydrochloric acid, forming a precipitate. The precipitate was collected by filtration, washed with water (2 x 100 mL) and dried in vacuo to give 6.02 g of the title compound (27.7 mmol, 81 %) as a white solid.
Ή NMR (CHLOROFORM-D) δ ppm 3.81 (3 H, s), 4.72 (2 H, s), 7.52 (1 H, ddd, J = 8.2, 6.7, 1 .3 Hz), 7.71 -7.80 (2 H, m), 7.98 (1 H, s), 8.28-8.31 (1 H, m).
PREPARATION 16
2-(4-Oxoquinazolin-3(4H)-yl)acetic acid
A mixture of the title compound of PREPARATION 15 (5.00 g, 22.9 mmol) and sodium hydroxide (3.67 g, 91 .8 mmol) in THF/H20/MeOH (2:5:3; v/v) (100 mL) was stirred at ambient temperature for 1 h. The reaction mixture was acidified to pH 3 with 12M aqueous hydrochloric acid and the mixture extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give 3.06 g of the title compound (15.1 mmol, 65%) as a white solid. 1H NMR (DMSO-d6) δ ppm 4.79 (2 H, s), 7.59-7.66 (1 H , m), 7.76 (1 H, d, J = 8.2 Hz), 7.91 (1 H, ddd, J = 8.2, 7.1 , 1 .6 Hz), 8.21 (1 H , dd, J = 8.0, 1 .5 Hz), 8.41 (1 H , s), 13.33 (1 H, s).
PREPARATION 17 yV-(3-Bromopropyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
A mixture of the title compound of PREPARATION 16 (500 mg, 2.45 mmol), benzotriazolyloxy-tris[pyrrolidino]phosphonium hexafluorophosphate PyBOP (1 .52 g, 2.94 mmol), 3-bromopropan-1 -amine hydrobromide (648 mg, 2.96 mmol) and triethylamine (618 mg, 6.13 mmol) in /V,/V-dimethylformamide (10 ml_) was stirred at 50 °C for 2 h. The reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (75 mL) and washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL) and water (2 x 50 mL). The combined organic extracts were dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by column chromatography (Biotage SNAP 50 g column, MeOH-dichloromethane gradient, 0:100 rising to 10:90) to give 452 mg of the title compound (1 .40 mmol, 57%) as a white solid.
Ή N MR (CHLOROFORM-D) δ ppm 2.04-2.14 (2 H , m), 3.38-3.48 (4 H, m), 4.58 (2 H, s), 6.49 (1 H, s), 7.50-7.57 (1 H, m), 7.74-7.83 (2 H, m), 8.1 1 (1 H, s), 8.30 (1 H, dd, J = 8.0, 1 .4 Hz).
PREPARATION 18
[2-(2,3-Dihydro-1 -benzofuran-2-yl)ethyl]amine
[2-(1 -Benzofuran-2-yl)ethyl]amine hydrochloride (0.20 g, 1 .00 mmol) was disolved in 20 ml acetic acid. The mixture was passed over 10% palladium on carbon under hydrogen atmosphere (80 bar) at 70 °C for 24 h using the H-Cube (ThalesNano Nanotechology Inc). The mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane and 2N aqueous sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated to give 0.037 g (0.22 mmol, 22% yield) of the title compound as a pale yellow oil. Purity 100%. UPLC/MS (3 min) retention time 0.77 min. LRMS: m/z 164 (M+1 ).
PREPARATION 19 ferf-Butyl [3-(3-methylphenoxy)propyl]carbamate
Synthesized from ie f-Butyl (3-hydroxypropyl)carbamate and m-Cresol. Yield: 85%.
1H NMR (400 MHz, CHLOROFORM-D) δ 7.16 (t, J = 7.8 Hz, 1 H), 6.77 (d, J = 7.5 Hz, 1 H), 6.74 - 6.63 (m, 2H), 4.78 (br s, 1 H), 4.00 (t, J = 6.0 Hz, 2H), 3.33 (q, J = 6.2 Hz, 2H), 2.32 (s, 3H), 2.01 - 1.91 (m, 2H), 1.44 (s, 9H).
PREPARATION 20
[3-(3-Methylphenoxy)propyl]amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 19. Yield: 96%.
1H NMR (400 MHz, DMSO-d6) δ 7.93 (br. s, 3H), 7.15 (t, J = 8.0 Hz, 1 H), 6.78 - 6.67 (m, 3H), 4.01 (t, J = 6.2 Hz, 2H), 2.95 - 2.87 (m, 2H), 2.26 (s, 3H), 2.05 - 1 .92 (m, 2H).
PREPARATION 21 ferf-Butyl [3-(3-cyanophenoxy)propyl]carbamate
Synthesized from ie f-Butyl (3-hydroxypropyl)carbamate and 3-Hydroxybenzonitrile. Yield: 86%.
1H NMR (400 MHz, CHLOROFORM-D) δ 7.36 (td, J = 7.6, 1 .3 Hz, 1 H), 7.24 (dt, J = 7.6, 1 .2 Hz, 1 H), 7.13 (d, J = 1 .2 Hz, 2H), 7.13 - 7.08 (m, 1 H), 4.03 (t, J = 6.0 Hz, 2H), 3.32 (q, J = 6.4 Hz, 2H), 1.99 (pent, J = 6.4 Hz, 2H), 1.43 (s, 9H).
PREPARATION 22
3-(3-Aminopropoxy)benzonitrile, hydrochloride salt Synthesized from the title compound of PREPARATION 21 . Yield: 85%.
1 H NMR (400 MHz, DMSO-d6) δ 7.90 (br s, 3H), 7.48 (dd, J = 7.5, 0.8 Hz, 1 H), 7.43 - 7.38 (m, 2H), 7.28 (ddd, J = 8.4, 2.6, 1 .1 Hz, 1 H), 4.1 1 (t, J = 6.1 Hz, 2H), 2.94 (t, J = 6.1 Hz, 2H), 2.05 - 1 .96 (m, 2H).
PREPARATION 23 ferf-Butyl {3-[(4-chloropyridin-2-yl)oxy]propyl}carbamate
Synthesized from ie f-Butyl (3-hydroxypropyl)carbamate and 4-Chloropyridin-2-ol. Yield: 28%. 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.27 (s, 1 H), 6.60 (d, J = 2.3 Hz, 1 H), 6.23 (dd, J = 7.3, 2.3 Hz, 1 H), 3.98 (t, J = 6.5 Hz, 2H), 3.12 (q, J = 6.3 Hz, 2H), 1 .92 - 1 .83 (m, 2H), 1 .44 (s, 9H).
PREPARATION 24 {3-[(4-Chloropyridin-2-yl)oxy]propyl}amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 23. Yield: 96%.
1 H N MR (400 MHz, DMSO-d6) δ 8.02 (br s, 3H), 7.84 (d, J = 7.3 Hz, 1 H), 6.55 (d, J = 2.0 Hz, 1 H), 6.40 (dd, J = 7.2, 1 .9 Hz, 1 H), 3.95 (t, J = 6.8 Hz, 2H), 2.81 - 2.68 (m, 2H), 1 .98 - 1 .87 (m, 2H).
PREPARATION 25 ferf-Butyl [3-(4-cyanophenoxy)propyl]carbamate
Synthesized from ie f-Butyl (3-hydroxypropyl)carbamate and 4-Hydroxybenzonitrile. Yield: 25%. 1 H N MR (400 MHz, CHLOROFORM-D) δ 7.59 - 7.55 (m, 2H), 6.95 - 6.91 (m, 2H), 4.06 (t, J = 6.1 Hz, 2H), 3.32 (q, J = 6.4 Hz, 2H), 2.00 (pent, J = 6.4 Hz, 2H), 1 .43 (s, 9H). PREPARATION 26
4-(3-Aminopropoxy)benzonitrile, hydrochloride salt
Synthesized from the title compound of PREPARATION 25. Yield: 100%.
1 H N MR (400 MHz, DMSO-d6) δ 8.10 (br. s, 3H), 7.81 - 7.72 (m, 2H), 7.13 - 7.06 (m, 2H), 4.15 (t, J = 6.1 Hz, 2H), 2.92 (m, 2H), 2.09 - 1 .99 (pent, J = 6.4 Hz, 2H).
PREPARATION 27 ferf-Butyl {3-[(5-chloropyridin-3-yl)oxy]propyl}carbamate
Synthesized from ie f-Butyl (3-hydroxypropyl)carbamate and 5-Chloropyridin-3-ol. Yield: 85%.
1 H NMR (400 MHz, CH LOROFORM-D) δ 8.18 (m, 2H), 7.22 - 7.16 (m, 1 H), 4.05 (t, J = 6.0 Hz, 2H), 3.32 (q, J = 6.4 Hz, 2H), 2.00 (pent, J = 6.4 Hz, 2H), 1 .43 (s, 9H).
PREPARATION 28 {3-[(5-Chloropyridin-3-yl)oxy]propyl}amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 27. Yield: 92%.
1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 2.5 Hz, 1 H), 8.22 (d, J = 2.0 Hz, 1 H), 8.01 (br. s, 3H), 7.63 - 7.59 (m, 1 H), 4.17 (t, J = 6.1 Hz, 2H), 2.98 - 2.87 (m, 2H), 2.06 - 1 .98 (m, 2H).
PREPARATION 29 ferf-Butyl {3-[4-(trifluoromethyl)phenoxy]propyl}carbamate
Synthesized from ie f-Butyl (3-hydroxypropyl)carbamate and 4-(Trifluoromethyl)phenol. Yield: 96%. UPLC/MS (3 min) retention time 1 .99 min. LRMS: m/z 320 (M+1 ). PREPARATION 30
{3-[4-(Trifluoromethyl)phenoxy]propyl}amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 29. Yield: 94%. 1 H N MR (400 MHz, DMSO-d6) δ 7.96 (br s, 3H), 7.67 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 4.15 (t, J = 6.1 Hz, 2H), 2.99 - 2.92 (m, 2H), 2.1 1 - 1 .99 (m, 2H).
PREPARATION 31
2-Chloro-N-{3-[4-(trifluoromethyl)phenoxy]propyl}acetamide Synthesized from the title compound of PREPARATION 30 and Chloroacetyl chloride. Yield: 91 %.
1 H NMR (400 MHz, CHLOROFORM-D) δ 7.55 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 4.1 1 (t, J = 5.7 Hz, 2H), 4.07 (s, 2H), 3.55 (q , J = 6.2 Hz, 2H), 2.08 (pent, J = 6.1 Hz, 2H).
PREPARATION 32 ferf-Butyl {3-[3-(trifluoromethyl)phenoxy]propyl}carbamate
Synthesized from ferf-Butyl (3-hydroxypropyl)carbamate and 3-(Trifluoromethyl)phenol. Yield: 66%. 1 H NMR (400 MHz, CH LOROFORM-D) δ 7.38 (t, J = 8.0 Hz, 1 H), 7.22 - 7.18 (m, 1 H), 7.12 (s, 1 H), 7.06 (dd, J = 8.3, 2.5 Hz, 1 H), 4.05 (t, J = 6.0 Hz, 2H), 3.33 (q, J = 6.3 Hz, 2H), 2.00 (pent, J = 6.3 Hz, 2H), 1 .44 (s, 9H).
PREPARATION 33 {3-[3-(Trifluoromethyl)phenoxy]propyl}amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 32. Yield: 91 %. 1 H NMR (400 MHz, CH LOROFORM-D) δ 7.80 (br s, 3H), 7.38 (t, J = 8.0 Hz, 1 H), 7.22 - 7.18 (m, 3H), 4.05 (t, J = 6.0 Hz, 2H), 3.33 (q, J = 6.3 Hz, 2H), 2.00 (pent, J = 6.3 Hz, 2H).
PREPARATION 34
2-Chloro-yV-{3-[3-(trifluoromethyl)phenoxy]propyl}acetamide
Synthesized from the title compound of PREPARATION 33 and chloroacetyl chloride. Yield: 91 %.
1 H N MR (400 MHz, CHLOROFORM-D) δ 7.40 (t, J = 8.0 Hz, 1 H), 7.23 (d, J = 7.7 Hz, 1 H), 7.14 (s, 1 H), 7.1 1 - 7.05 (m, 1 H), 4.1 1 (t, J = 5.7 Hz, 2H), 4.07 (s, 2H), 3.55 (q, J = 6.2 Hz, 2H), 2.07 (pent, J = 6.3 Hz, 2H).
PREPARATION 35 ferf-Butyl [3-(3-chloro-4-fluorophenoxy)propyl]carbamate Synthesized from ferf-Butyl (3-hydroxypropyl)carbamate and 3-chloro-4-fluorophenol. Yield: 58%.
1 H NMR (400 MHz, CHLOROFORM-D) δ 7.04 (t, J = 8.8 Hz, 1 H), 6.92 (dd, J = 6.0, 3.0 Hz, 1 H), 6.71 (ddd, J = 9.2, 3.6, 3.2 Hz, 1 H), 3.96 (t, J = 6.0 Hz, 2H), 3.31 (q, J = 6.5 Hz, 2H), 2.04 - 1 .84 (m, 2H), 1 .44 (s, 9H).
PREPARATION 36
[3-(3-Chloro-4-fluorophenoxy)propyl]amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 35. Yield: 88%.
1 H N MR (400 MHz, DMSO-d6) δ 7.91 (br. s, 3H), 7.33 (t, J = 9.1 Hz, 1 H), 7.17 (dd, J = 6.1 , 3.0 Hz, 1 H), 6.94 (dt, J = 9.0, 3.5 Hz, 1 H), 4.05 (t, J = 6.1 Hz, 2H), 2.92 (t, J = 7.3 Hz, 2H), 2.04 - 1 .92 (m, 2H).
PREPARATION 37 2-Chloro-N-[3-(3-chloro-4-fluorophenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 36 and Chloroacetyl chloride. Yield: 98%.
1 H NMR (400 MHz, CH LOROFORM-D) δ 7.05 (t, J = 8.8 Hz, 1 H), 7.00 (br s, 1 H), 6.93 (dd, J = 5.9, 3.0 Hz, 1 H), 6.76 (dt, J = 9.0, 3.4 Hz, 1 H), 4.06 (s, 2H), 4.02 (t, J = 5.7 Hz, 2H), 3.53 (dd, J = 12.4, 6.2 Hz, 2H), 2.10 - 1 .97 (m, 2H).
PREPARATION 38 ferf-Butyl [3-(4-fluorophenoxy)propyl]carbamate Synthesized from ferf-Butyl (3-hydroxypropyl)carbamate and 4-Fluorophenol. Yield: 71 %.
1 H NMR (400 MHz, CHLOROFORM-D) δ 6.96 (dd, J = 9.1 , 8.3 Hz, 2H), 6.82 (dd, J = 9.2, 4.3 Hz, 2H), 4.73 (s, 2H), 3.98 (t, J = 6.0 Hz, 2H), 3.32 (q, J = 6.2 Hz, 2H), 1 .96 (pent, J = 6.4 Hz, 2H), 1 .44 (s, 9H).
PREPARATION 39
[3-(4-Fluorophenoxy)propyl]amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 38. Yield: 95%.
1 H N MR (400 MHz, DMSO-d6) δ 7.92 (br. s, 3H), 7.1 1 (t, J = 8.9 Hz, 2H), 6.94 (dd, J = 9.2, 4.4 Hz, 2H), 4.01 (t, J = 6.1 Hz, 2H), 2.98 - 2.88 (m, 2H), 2.06 - 1 .93 (m, 2H).
PREPARATION 40
2-Chloro-W-[3-(4-fluorophenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 39 and Chloroacetyl chloride. Yield: 100%.
1 H NMR (400 MHz, CHLOROFORM-D) δ 6.98 (d, J = 6.5 Hz, 2H), 6.88 - 6.82 (m, 2H), 4.06 (s, 2H), 4.06 - 4.02 (m, 2H), 3.54 (q, J = 6.0 Hz, 2H), 2.04 (pent, J = 9.7 Hz, 2H). PREPARATION 41 ferf-Butyl [3-(3,5-dichlorophenoxy)propyl]carbamate
Synthesized from ief-Butyl (3-hydroxypropyl)carbamate and 3,5-Dichlorophenol. Yield: 68%.
1H NMR (400 MHz, CHLOROFORM-D) δ 6.95 (t, J = 1.8 Hz, 1H), 6.78 (d, J = 1.8 Hz, 2H), 4.68 (br s, 1H), 3.98 (t, J = 6.0 Hz, 2H), 3.30 (q, J = 6.3 Hz, 2H), 1.97 (pent, J = 6.3 Hz, 2H), 1.44 (s, 9H).
PREPARATION 42
[3-(3,5-Dichlorophenoxy)propyl]amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 41. Yield: 91%.
1H NMR (400 MHz, DMSO-d6) δ 7.96 (br. s, 3H), 7.15 (t, J = 1.8 Hz, 1H), 7.04 (d, J = 1.8 Hz, 2H), 4.10 (t, J = 6.1 Hz, 1H), 2.91 (t, J = 7.3 Hz, 1H), 2.06- 1.92 (m, 1H).
PREPARATION 43
2-Chloro-N-[3-(3,5-dichlorophenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 42 and chloroacetyl chloride. Yield: 91%. 1H NMR (400 MHz, CHLOROFORM-D) δ 6.97 (t, J = 1.8 Hz, 1 H), 6.94 (br s, 1 H), 6.80 (d, J = 1.8 Hz, 2H), 4.07 (s, 2H), 4.04 (t, J = 5.7 Hz, 2H), 3.52 (q, J = 6.3 Hz, 2H), 2.05 (pent, J = 6.2 Hz, 2H).
PREPARATION 44 ferf-Butyl {3-[3-(dimethylamino)phenoxy]propyl}carbamate
Synthesized from ief-Butyl (3-hydroxypropyl)carbamate and 3-(Dimethylamino)phenol. Yield: 67%. 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.13 (d, J = 7.4 Hz, 1 H), 6.40 - 6.32 (m, 1 H), 6.31 - 6.25 (m, 2H), 4.79 (br s, 1 H), 4.02 (t, J = 6.0 Hz, 2H), 3.33 (q, J = 6.2 Hz, 2H), 2.93 (s, 6H), 2.01 - 1 .92 (m, 2H), 1 .44 (s, 9H).
PREPARATION 45
[3-(3-Aminopropoxy)phenyl]dimethylamine, hydrochloride salt
Synthesized from the title compound of PREPARATION 44. Yield: 100%. UPLC/MS (3 min) retention time 0.59 min. LRMS: m/z 195 (M+1 ).
PREPARATION 46
2-Chloro-yV-{3-[3-(dimethylamino)phenoxy]propyl}acetamide
Synthesized from the title compound of PREPARATION 45 and Chloroacetyl chloride. Yield: 81 %. 1 H NMR (400 MHz, CH LOROFORM-D) δ 7.15 (t, J = 8.1 Hz, 1 H), 6.41 - 6.34 (m, 1 H), 6.33 - 6.24 (m, 2H), 4.12 - 4.07 (m, 2H), 4.06 (s, 2H), 3.54 (q, J = 5.8 Hz, 2H), 2.93 (s, 6H), 2.04 (pent, J = 5.9 Hz, 2H).
PREPARATION 47 ferf-Butyl (3-(3-chlorophenoxy)propyl)carbamate
Synthesized from ferf-Butyl (3-hydroxypropyl)carbamate and 3-Chlorophenol. Yield: 79%.
1 H N MR (400 MHz, CHLOROFORM-D) δ 7.18 (t, J = 8.1 Hz, 1 H), 6.92 (d, J = 7.1 Hz, 1 H), 6.90 - 6.87 (m, 1 H), 6.77 (dd, J = 8.4, 1 .6 Hz, 1 H), 4.00 (t, J = 6.0 Hz, 2H), 3.31 (q, J = 6.1 Hz, 2H), 2.02 - 1 .91 (m, 2H), 1 .44 (s, 9H).
PREPARATION 48 3-(3-Chlorophenoxy)propyl-1 -amine, hydrochloride salt
Synthesized from the title compound of PREPARATION 47. Yield: 97%.
1H NMR (400 MHz, DMSO-d6) δ 7.31 (br. s, 3H), 6.69 (t, J = 8.2 Hz, 1 H), 6.42 - 6.35 (m, 2H), 6.29 (d, J = 8.4 Hz, 1 H), 3.46 (t, J = 5.8 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1 .38 (pent, J = 6.5 Hz, 2H).
PREPARATION 49
2-Chloro-W-(3-(3-chlorophenoxy)propyl)acetamide
Synthesized from the title compound of PREPARATION 48. Yield: 97%. 1H NMR (400 MHz, CHLOROFORM-D) δ 7.20 (t, J = 8.1 Hz, 1 H), 7.03 (br. s, 1 H), 6.95 (ddd, J = 8.0, 1 .9, 0.9 Hz, 1 H), 6.91 (t, J = 2.2 Hz, 1 H), 6.80 (ddd, J = 8.4, 2.5, 0.8 Hz, 1 H), 4.06 (s, 2H), 4.06 (t, J = 5.7 Hz, 2H), 3.54 (q, J = 6.2 Hz, 2H), 2.05 (pent, J = 6.0 Hz, 2H).
PREPARATION 50
Pyrido[3,2-d]pyrimidin-4(3H)-one
Synthesized from 3-Aminopyridine-2-carboxylic acid. Yield: 50%.
1H NMR (400 MHz, DMSO-d6) δ 12.51 (br. s, 1 H), 8.77 (dd, J = 4.3, 1 .5 Hz, 1 H), 8.13, (s, 1 H), 8.07 (dd, J = 8.3, 1.5 Hz, 1 H), 7.79 (dd, J = 8.3, 4.3 Hz, 1 H).
PREPARATION 51 Pyrido[2,3-d]pyrimidin-4(3H)-one
Synthesized from 2-Aminonicotinic acid. Yield: 62%.
1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1 H), 8.93 (dt, J = 18.8, 9.4 Hz, 1 H), 8.50 (dd, J = 7.9, 2.0 Hz, 1 H), 8.30 (s, 1 H), 7.54 (dd, J = 7.9, 4.6 Hz, 1 H). PREPARATION 52 Pyrimido[4,5-d]pyridazin-4(3H)-one
Synthesized from 5-Aminopyridazine-4-carboxylic acid. Yield: 13%.
1H NMR (400 MHz, DMSO-d6) δ 13.14 (br. s, 1 H), 9.59 (d, J = 1 .3 Hz, 1 H), 9.55 (d, J = 1 .3 Hz, 1 H), 8.52 (s, 1 H).
PREPARATION 53 Pyrimido[4,5-c]pyridazin-5(6H)-one
The title compound was synthesized according to the method described in Styles and Morrison, Jr, J. Org. C em, 1985, 50, 346
1H NMR (400 MHz, DMSO-d6) δ 9.47 (d, J = 5.1 Hz, 1 H), 8.41 (s, 1 H), 8.24 (d, J = 5.1 Hz, 1 H).
PREPARATION 54 Pyrimido[4,5-d]pyrimidin-4(3H)-one
Synthesized from 4-Aminopyrimidine-5-carboxamide. Yield: 42%.
1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1 H), 9.38 (s, 1 H), 8.50 (s, 1 H).
PREPARATION 55 5-Methoxyquinazolin-4(3H)-one
Synthesized from 2-Amino-6-methoxybenzoic acid. Yield: 57%.
1H NMR (400 MHz, CHLOROFORM-D) δ 1 1 .03 (s, 1 H), 8.01 (s, 1 H), 7.69 (t, J = 8.2 Hz, 1 H), 7.33 (dd, J = 8.2, 0.9 Hz, 1 H), 6.98 - 6.90 (m, 1 H), 4.02 (s, 3H).
PREPARATION 56 8-Methoxyquinazolin-4(3H)-one
Synthesized from 2-Amino-3-methoxybenzoic acid. Yield: 82%.
1H NMR (600 MHz, DMSO-d6) δ 12.23 (s, 1 H), 8.00 (s, 1 H), 7.63 (dd, J = 8.0, 1 .2 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.33 (dd, J = 8.0, 1 .1 Hz, 1 H), 3.86 (s, 3H).
PREPARATION 57
6-Methoxypyrido[3,4-cf]pyrimidin-4(3H)-one
Synthesized from 5-Amino-2-methoxyisonicotinic acid. Yield: 61 %.
1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (1 H, br s), 8.75 (1 H, s), 8.02 (1 H, s), 7.28 (1 H, s), 3.95 (3 H, s).
PREPARATION 58
8-Methoxypyrido[3,4-d]pyrimidin-4(3H)-one
Synthesized from 3-Amino-2-methoxyisonicotinic acid. Yield: 66%. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.58 (1 H, br s), 8.12 (2 H, m), 7.47 (1 H, d, J=4.5 Hz), 3.97 (3 H, s).
PREPARATION 59
5-Bromopyrido[3,4-d]pyrimidin-4(3H)-one Synthesized from 3-Amino-5-bromoisonicotinic acid. Yield: 71 %. Purity 92%. UPLC/MS (3 min) retention time 0.81 min. LRMS: m/z 226 (M+1 , 1 *Br).
PREPARATION 60 8-Chloropyrido[3,4-d]pyrimidin-4(3H)-one Synthesized from 3-Amino-2-chloroisonicotinamide. Yield: 59%.
1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1 H), 8.28 (s, 1 H), 7.91 (s, 1 H).
PREPARATION 61 1 -Ethyl-3-methyl-1 ,6-dihydro-7H-pyrazolo[4,3-cGpyrimidin-7-one
Synthesized from Methyl 4-amino-1 -ethyl-3-methyl-1 H-pyrazole-5-carboxylate. Yield: 88%.
1 H N MR (600 MHz, DMSO-d6) δ 7.82 (s, 1 H), 4.49 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1 .36 (t, J = 7.2 Hz, 3H).
PREPARATION 62
1 -Methyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
Synthesized from Methyl 4-amino-1 -methyl-1 H-pyrazole-5-carboxylate. Yield: 94%. 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1 H), 7.83 (s, 1 H), 4.16 (s, 3H).
PREPARATION 63
3-Bromo-1 -methyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
The title compound of PREPARATION 62 (0.57 g, 3.80 mmol) was suspended in 12 ml dimethylformamide. /V-Bromosuccinimide (1 .49 g. 8.37 mmol) was added and the mixture was stirred at 80 °C for 16 h. The mixture was allowed to cool and was partitioned between water and ethyl acetate, forming a precipitate in the organic phase. The solid was collected by filtration and was dried in vacuo at 35 °C to give 0.50 g of the title compound (2.18 mmol, 57%) as a white solid.
1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1 H), 7.90 (s, 1 H), 4.15 (s, 3H).
PREPARATION 64 1 ,3-Dimethyl-1 ,5-dihydro-4H-pyrazolo[3,4-cf]pyrimidin-4-one
Synthesized from 5-Amino-1 ,3-dimethyl-1 H-pyrazole-4-carboxamide. Yield: 74%.
1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1 H), 7.98 (s, 1 H), 3.79 (s, 3H), 2.39 (s, 3H).
PREPARATION 65
5-Methylimidazo[5,1 - ][1 ,2,4]triazin-4(3H)-one
The title compound was synthesized according to the method described in Heim- Riether and Healy, J. Org. Chem. 2005, 70, 7331 .
1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1 H), 8.26 (s, 1 H), 7.78 (s, 1 H), 2.44 (s, 3H).
PREPARATION 66
7-Bromo-5-methylimidazo[5,1 - ][1 ,2,4]triazin-4(3H)-one
The title compound was synthesized from the title compound of PREPARATION 65 according to the method described in Heim-Riether and Healy, J. Org. Chem. 2005, 70, 7331 .
1H NMR (400 MHz, DMSO) δ 1 1.81 (s, 1 H), 7.88 (s, 1 H), 2.44 (s, 3H).
PREPARATION 67
1 -Methyl-1 H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one
The title compound was synthesized according to the method described in Albert and Tratt, J. Chem. Soc. (C), 1968, 344.
1H NMR (400 MHz, DMSO-d6) δ 12.66 (br s, 1 H), 8.08 (s, J = 2.4 Hz, 1 H), 4.33 (s, J = 2.1 Hz, 3H).
PREPARATION 68
6,8-Dimethylimidazo[1 ,5-a][1 ,3,5]triazin-4(3H)-one The title compound was synthesized according to the method described in Holtwick et al. J. Org. Chem. 1979, 44, 3835.
1 H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1 H), 2.62 (s, 3H), 2.15 (s, 3H). UPLC/MS (3 min) retention time 0.45 min. LRMS: m/z 165 (M+1 ).
PREPARATION 69
4-Fluoro-2,6-naphthyridin-1 (2H)-one
2,6-Naphthyridin-1 (2H)-one (204 mg, 1 .4 mmol) was suspended in 5 ml acetonitrile. Selectfluor© (495 mg, 1 .4 mmol) was added and the mixture was stirred at reflux overnight. Further Selectfluor© (250 mg, 0.71 mmol) was added and the mixture was stirred at reflux for 12h. The mixture was then allowed to cool and was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The organics were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography using the SP1 purification system (ethyl acetate-hexane gradient, 0:100 rising to 100:0) to give 35 mg (0.21 mmol, 15% yield) of the title compound as a white solid. Purity 100%.
1 H NMR (600 MHz, DMSO-d6) 2:1 Tautomeric mixture. Tautomer 1 : δ ppm 1 1 .62 (s, 1 H), 9.20 (d, J = 0.9 Hz, 1 H), 8.83 (d, J = 5.3 Hz, 1 H), 8.07 (ddd, J = 5.3, 2.0, 0.9 Hz, 1 H), 7.59 (t, J = 5.6 Hz, 1 H). Tautomer 2: δ ppm 9.52 (s, 1 H), 9.08 (d, J = 1 .6 Hz, 1 H), 9.04 (dd, J = 5.0, 1 .5 Hz, 1 H), 7.91 (d, J = 4.9 Hz, 1 H), 7.29 (d, J = 5.9 Hz,1 H).
UPLC/MS (3 min) retention time 0.71 min.
LRMS: m/z 165 (M+1 ).
PREPARATION 70
4-Bromo-2,6-naphthyridin-1 (2H)-one
2,6-Naphthyridin-1 (2H)-one (255 mg, 1 .74 mmol) was suspended in 6 ml of chloroform- acetonitrile (1 : 1 ). N-Bromosuccinimide (340 mg, 1 .91 mmol) was added and the mixture was stirred at room temperature for 3h. The mixture was evaporated under reduced pressure then the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated to give 377 mg of the crude title compound as a pale yellow oil. Purity 79%. UPLC/MS (3 min) retention time 0.92 min.
LRMS: m/z 225 (M+1 , 1 *Br).
PREPARATION 71
7-Methyl-1 ,7-dihydro-6H-purin-6-one Synthesized from Ethyl 4-amino-1 -methyl-1 H-imidazole-5-carboxylate and formamidine. Yield: 84%. Purity 98%.
1 H N MR (300 MHz, DMSO-d6) d 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 72
5,8-Dibromopyrido[3,4-d]pyrimidin-4(3H)-one
Synthesized from ethyl 3-amino-2,5-dibromoisonicotinate and formamide. Purity 86%. UPLC/MS (3 min) retention time 1 .29 min. LRMS: m/z 302 (M-1 , 2*Br).
PREPARATION 73 tert-Butyl (5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 65 and tert-Butyl bromoacetate. Yield: 98%. Purity 100%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.97 (s, 1 H), 7.34 (s, 1 H), 4.46 (s, 2 H), 2.62 (s, 3 H), 1.49 (s, 9 H)
UPLC/MS (3 min) retention time 1 .28 min.
LRMS: m/z 265 (M+1 ).
PREPARATION 74
(5-Methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid
Synthesized from the title compound of PREPARATION 73. Yield: 92%. Purity 100%.
1H 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 75 N-(3-Chloropropyl)-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 74. Yield: 72%. Purity 91 %.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1 H), 8.00 (s, 1 H), 4.46 (s, 2 H), 3.65 (t, J=6.64 Hz, 2 H), 3.21 (q, J=6.64 Hz, 2 H), 2.47 (s, 3 H), 1 .83 - 1 .92 (m, 2 H). UPLC/MS (3 min) retention time 0.97 min.
LRMS: m/z 284 (M+1 , 1 xCI).
PREPARATION 76
3-Methylisoxazolo[5,4-d]pyrimidin-4(5H)-one Synthesized from ethyl 5-amino-3-methylisoxazole-4-carboxylate and formamidine. Yield: 22%. Purity 99%. 1 H N MR (400 MHz, CHLOROFORM-D containing METHANOL-d4) δ ppm 8.05 (s, 1 H), 2.56 (s, 3 H).
UPLC/MS (3 min) retention time 0.64 min. LRMS: m/z 152 (M+1 ).
PREPARATION 77
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 ambient 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, 2 H), 5.58 (s, 1 H), 3.28 (s, 3 H), 2.10 (s, 3 H).
UPLC/MS (3 min) retention time 0.76 min. LRMS: m/z 164 (M+1 ).
PREPARATION 78
5,8-Dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione
Synthesized from the title compound of PREPARATION 77 and formic acid. Yield: 54%. Purity 97%.
UPLC/MS (3 min) retention time 0.72 min. LRMS: m/z 192 (M+1 ).
PREPARATION 79 3-(Benzylamino)-2-fluoro-3-oxopropanoic acid
Diethyl 2-fluoromalonate (15 g, 84 mmol) was suspended in 50 mL of methanol. A solution of potassium hydroxide (5.6 g, 84 mmol) in 40 mL of methanol was added and the mixture was stirred at room temperature for 2.5h. Benzylamine (27.6 mL, 250 mmol) was added and the mixture was stirred and heated at 55°C overnight. The mixture was cooled to ambient temperature and was concentrated in vacuo. The residue was triturated with ether to give a solid which was collected by filtration and washed with ether. The solid was partitioned between 5N hydrochloric acid and ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was dried in a vacuo at 35°C to give 15.0 g (71 mmol, 84% yield) of the title compound as a pale yellow solid. Purity 97%.
1 H NMR (300 MHz, DMSO-d6) δ ppm 9.01 (t, 1 H , J = 6.3 Hz), 7.23-7.34 (m, 5H), 5.41 (d, 1 H, J = 48 Hz), 4.33 (m, 2H).
UPLC/MS (3 min) retention time 0.75 min. LRMS: m/z 212 (M+1 ).
PREPARATION 80
3-(Benzylamino)-2-fluoropropan-1 -ol
The title compound of PREPARATION 79 (15 g, 71 mmol) was suspended in 50 mL tetrahydrofuran and cooled to 0°C in an ice-bath. Borane-methyl sulfide complex (134 mL, 270 mmol) was added and the mixture was stirred at room temperature for 4h.
The mixture was then heated at 55°C overnight. The mixture was cooled to ambient temperature and water and an 5N aqueous hydrochloric acid were carefully added.
The aqueous layer was extracted with ethyl acetate. The resulting aqueous phase was then basified with 32% sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 10.9 g (59 mmol, 86%) of the title compound as a yellow oil. Purity 95%.
1 H N MR (300 MHz, CHLOROFORM-d) δ ppm 7.26-7.37 (m, 5H), 4.61 -4.75 (m, 1 H), 3.80-3.94 (m, 4H), 2.90-3.12 (m, 2H).
UPLC/MS (3 min) retention time 0.46 min. LRMS: m/z 184 (M+1 ).
PREPARATION 81 tert-Butyl (2-fluoro-3-hydroxypropyl)carbamate The title compound of PREPARATION 80 (10.9 g, 59 mmol) was suspended in 250 mL of methanol and 10% Palladium on carbon (5.4 g) wet with 5.5 mL of water was added, ammonium formate (18.8 g, 300 mmol) was added in portions and the mixture was stirred and heated at 55°C for 2h. The reaction was cooled to ambient temperature and filtered through Celite® eluting with methanol. The organic extract was evaporated under reduced pressure. The residue was re-dissolved in water and was adjusted to pH 3-4 with 5N hydrochloric acid. The aqueous phase was extracted with ethyl acetate and basified to pH 9-10 with 32% potassium hydroxide solution. A solution of di-tert-butyl dicarbonate (13.0g 75 mmol) in 25 mL tetrahydrofuran was added drop-wise and the mixture was stirred at room temperature for 24h. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using the Isolera purification system (ethyl acetate-hexane gradient, 0:100 rising to 50:50) to give 1 .16 g (6.0 mmol, 10% yield) of the title compound as a colourless oil. Purity 95%.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 4.88 (br s, 1 H), 4.51 -4.68 (m, 1 H), 3.71 (m, 2H), 3.38-3.58 (m, 2H), 3.04 (t, 1 H, J = 7.0 Hz), 1.46 (s, 9H).
UPLC/MS (3 min) retention time 1 .02 min.
LRMS: m/z 194 (M+1 ).
PREPARATION 82 tert-Butyl [3-(3-chlorophenoxy)-2-fluoropropyl]carbamate
Synthesized from The title compound of PREPARATION 81 and 3-chlorophenol. Yield: 74%. Purity 100%. 1 H NMR (300 MHz, CHLOROFORM-D) δ ppm 7.21 (m, 1 H), 6.97 (m, 1 H), 6.93 (m, 1 H), 6.81 (dd, 1 H, J = 8.2, 2.3 Hz), 4.80-5.00 (m, 2H), 4.06-4.20 (m, 2H), 3.42-3.70 (m, 2H), 1 .47 (s, 9H).
UPLC/MS (3 min) retention time 1 .87 min. LRMS: m/z 304 (M+1 , 1 xCI).
PREPARATION 83
[3-(3-Chlorophenoxy)-2-fluoropropyl]amine Hydrochloride salt
Synthesized from the title compound of PREPARATION 82. Yield: 55%. Purity 96%. 1 H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (br s, 3H), 7.35 (m, 1 H), 7.09 (m, 1 H), 6.97 (dd, 1 H, J = 8.2, 2.0 Hz), 5.07-5.24 (m, 1 H), 4.21 -4.41 (m, 2H), 3.21 -3.31 (m, 2H).
UPLC/MS (3 min) retention time 0.91 LRMS: m/z 204 (M+1 , 1 *CI).
PREPARATION 84
1 -Amino-4-cyano-1 H-imidazole-5-carboxamide
4-Cyano-1 H-imidazole-5-carboxamide (1 .0 g, 7.35 mmol) was suspended in 80 mL dimethylformamide under nitrogen atmosphere. The mixture was cooled to -10°C and lithium bis(trimethylsilyl)amide solution (1 M in hexanes) (7.35 mL, 7.35 mmol) was added drop-wise. 0-(Diphenylphosphoryl)hydroxylamine (1 .71 g, 7.33 mmol) was added in portions and the mixture was stirred at room temperature for 2h. Water was added until total dissolution of the suspension and the mixture was evaporated under reduced pressure. The residue was triturated with methanol and the solid obtained was filtered. The solid was dried in vacuo to give 0.69 g (4.58 mmol, 62% yield) of the title compound as a white solid. Purity 97%.
1 H N MR (300 MHz, DMSO-d6) δ ppm 8.14 (br. s, 1 H), 7.87 (br. s. 1 H), 7.73 (s, 1 H), 6.52 (s, 2H).
UPLC/MS (3 min) retention time 0.26 min. LRMS: m/z 150 (M-1 ).
PREPARATION 85
4-Oxo-3,4-dihydroimidazo[5,1 -f][1 ,2,4]triazine-5-carbonitrile Synthesized from the title compound of PREPARATION 84 and formamide. Yield: 53%. Purity 100%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1 H), 7.86 (s, 1 H), 7.74 (s, 1 H). UPLC/MS (3 min) retention time 0.57 min. LRMS: m/z 162 (M+1 ).
PREPARATION 86 8-Methylisoquinoline
2-Methylbenzaldehyde (3.0 mL, 25.7 mmol) and 2,2-dimethoxyethanamine (2.8 mL, 25.7 mmol) were dissolved in 10 mL toluene and were heated at reflux overnight in a flask fitted with a Dean-Stark head. The mixture was cooled to ambient temperature and was evaporated under reduced pressure to give a crude residue of (2,2- dimethoxyethyl)[(2-methylphenyl)methylene]. The residue was dissolved in 15 mL tetrahydrofuran and the mixture was cooled to -14 °C. Ethyl chloroformate (2.7 mL, 28.2 mmol) was added and the mixture was stirred for 10 min. The mixture was then stirred at room temperature and trimethylphosphite (3.7 mL, 31 .4 mmol) was added. The reaction was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was re-dissolved in 15 mL dichloromethane, titanium (IV) chloride (16.9 mL, 154 mmol) was added and the mixture was heated at reflux for 40h. The reaction was then cooled to ambient temperature and was basified with 32% sodium hydroxide solution. The precipitate formed was filtered and washed with dichloromethane and water. The two phases of the filtrate were separated and the aqueous layer was extracted with dichloromethane. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 3.28 g (21 .3 mmol, 83% yield) of the title compound as a brown oil. Purity 93 %. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 9.46 (s, 1 H), 8.55 (d, J = 5.7 Hz, 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.64 (d, J = 5.7 Hz, 1 H), 7.60 - 7.54 (m, 1 H), 7.39 (d, J = 6.9 Hz, 1 H), 2.80 (s, 3H).
UPLC/MS (3 min) retention time 0.56 min. LRMS: m/z 144 (M+1 ).
PREPARATION 87
8-Methylisoquinoline 2 -oxide
The title compound of PREPARATION 86 (2.84 g, 19.9 mmol) was dissolved in 25 mL acetic acid. Hydrogen peroxide (8 mL, 92 mmol) was added in a total of 4 portions over a 36 h period while stirring the mixture at 65 °C. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate solution. Dichloromethane was added and the phases were separated. The aqueous layer was extracted with dichloromethane. The combined organic were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using the SP1 purification system (ispropanol-dichloromethane gradient, 0:100 rising to 10:90) to give 0.84 g (5.25 mmol, 26% yield) of the title compound as a beige solid. Purity 100%. UPLC/MS (3 min) retention time 0.87 min.
LRMS: m/z 160 (M+1 ).
PREPARATION 88 8-Methylisoquinolin-1 (2H)-one The title compound of PREPARATION 87 (276 mg, 1 .73 mmol) was dissolved in 5 mL acetic anhydride and the mixture was refluxed for 4h. The solvent was evaporated under reduced pressure. 1 M Sodium hydroxide solution (5 mL, 5 mmol) was added and the mixture was heated at 80 °C overnight. The reaction was cooled to room temperature and dichloromethane was added. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using the SP1 purification system (isopropanol-dichloromethane gradient, 0:100 rising to 10:90) to give 194 mg (1 .21 mmol, 70% yield) of the title compound. Purity 100 %. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 10.00 (s, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 7.22 (d, J = 7.3 Hz, 1 H), 7.03 (d, J = 7.1 Hz, 1 H), 6.45 (d, J = 7.1 Hz, 1 H), 2.95 (s, 3H).
UPLC/MS (3 min) retention time 1 .24 min.
LRMS: m/z 160 (M+1 ).
PREPARATION 89
4-Bromo-8-methylisoquinolin-1 (2H)-one
The title compound of PREPARATION 90 (169 mg, 1 .06 mmol) was suspended in 3 mL chloroform. N-Bromosuccinimide (210 mg, 1 .18 mmol) was added and the mixture was stirred at room temperature for 2h. The reaction was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 185 mg of the crude title compound as a pale pink solid. Used as such without further purification.
UPLC/MS (3 min) retention time 1 .58 min. LRMS: m/z 238 (M+1 , 1 *Br).
PREPARATION 90 5-Methyl-1 H-benzo[d][1 ,3]oxazine-2,4-dione
Synthesized from 2-Amino-6-methylbenzoic acid and triphosgene. Yield: 93%. Purity 100%.
1 H NMR (300 MHz, DMSO-d6) δ ppm 1 1 .60 (br s, 1 H), 7.57 (m, 1 H), 7.07 (m, 1 H), 7.00 (m, 1 H), 2.61 (s, 3H). UPLC/MS (3 min) retention time 1 .06 min. LRMS: m/z 178 (M+1 ).
PREPARATION 91 tert-Butyl N-(2-amino-6-methylbenzoyl)glycinate
Synthesized from the title compound of PREPARATION 90 and ie/f-butyl 2- aminoacetate hydrochloride salt. Yield: 57%. Purity 95%.
1 H N MR (300 MHz, CHLOROFORM-D) δ ppm 7.05 (m, 1 H), 6.51 -6.60 (m, 2H), 6.28 (br s, 1 H), 4.12 (d, 2H, J = 5.9 Hz), 2.35 (s, 3H), 1 .50 (s, 9H). UPLC/MS (3 min) retention time 1 .29 min.
LRMS: m/z 265 (M+1 ).
PREPARATION 92 tert-Butyl (5-methyl-4-oxo-1 ,2,3-benzotriazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 91 . Yield: 84%. Purity 94%.
1 H NMR (300 MHz, CHLOROFORM-D) δ ppm 8.00 (d, 1 H, J = 8.2 Hz), 7.80 (m, 1 H), 7.55 (d, 1 H, J = 7.4 Hz), 5.05 (s, 2H), 2.92 (s, 3H), 1 .59 (s, 9H).
UPLC/MS (3 min) retention time 1 .71 min.
LRMS: m/z 276 (M+1 ).
PREPARATION 93
(5-Methyl-4-oxo-1 ,2,3-benzotriazin-3(4H)-yl)acetic acid
Synthesized from the title compound of PREPARATION 92. Yield: 73%. Purity 97%.
1 H N MR (300 MHz, DMSO-d6) δ ppm 8.04 (d, 1 H , J = 8.2 Hz), 7.96 (m, 1 H), 7.72 (m, 1 H), 5.07 (s, 2H), 2.81 (s, 3H). UPLC/MS (3 min) retention time 1 LRMS: m/z 220 (M+1 ).
PREPARATION 95 Methyl 1 -amino-4-methyl-1 H-pyrazole-5-carboxylate
Methyl 4-methyl-1 H-pyrazole-5-carboxylate (1 .36 g, 9.7 mmol) was dissolved in 70 ml anhydrous DMF under nitrogen and the solution cooled to -10 °C. Lithium bis(trimethylsilyl)amide solution (1 M in tetrahydrofuran, 10.7 ml, 10.7 mmol) was added dropwise with stirring over 15 min. After stirring for a further 10 min, O- (dipenylphosphoryl)hydroxylamine (2.73 g, 1 1 .7 mmol) was added and the mixture was stirred for 10 min at -10 °C and then 1 h at room temperature, forming a solid mass. Water was added to dissolve the solids and the mixture was evaporated under reduced pressure. The solid was suspended in dichloromethane, filtered and the solid washed with further dichloromethane. The combined filtrate was evaporated to give a solid which was purified on the Isolera (methanol-dichloromethane gradient, 0:100 rising to 1 :99) to give 734 mg (4.7 mmol, 49% yield) of the title compound as a yeloow oil. Purity 100%.
1 H N MR (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 96
5-Methylpyrazolo[5,1 -f][1 ,2,4]triazin-4(3H)-one Synthesized from the title compound of PREPARATION 95 and formamide. 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 97
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 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 98 6-Methoxy-N-methylpyrimidin-4-amine
The title compound of PREPARATION 97 (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 N MR (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 99
6-(Methylamino)pyrimidin-4(3H)-one Hydrochloride salt The title compound of PREPARATION 98 (7.80 g, 56 mmol) was suspended in 1 10 ml concentrated hydrochloric acid and 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 100
6-(Methylamino)-5-nitropyrimidin-4(3H)-one
The title compound of PREPARATION 99 (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 as 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).
UPLC/MS (5 min) retention time 0.50 min. LRMS: m/z 171 (M+1 ).
PREPARATION 101
5-Amino-6-(methylamino)pyrimidin-4(3H)-one
The title compound of PREPARATION 100 (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 N MR (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 102
9-Methyl-7,9-dihydro-1 H-purine-6,8-dione
The title compound of PREPARATION 101 (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 103 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 102 and tert-butyl bromoacetate. Yield: 40%. Purity 99%.
1 H N MR (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 104 tert-Butyl (7,9-dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetate The title compound of PREPARATION 103 (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 95%.
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 105
(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 104. Yield: 99%. Purity 99%.
1 H N MR (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 106 tert-Butyl (1 , 3 -di methyl -4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)acetate Synthesized from the title compound of PREPARATION 6 and tert-Butyl bromoacetate. Yield: 100%. Purity 100%.
1 H NMR (400 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 .98 min.
LRMS: m/z 279 (M+1 ).
PREPARATION 107
(1 ,3-Dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)acetic acid Synthesized from the title compound of PREPARATION 106. Yield: 89%. Purity 100%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 13.15 (br. s., 1 H), 8.29 (s, 1 H), 4.65 (s, 2H), 3.80 (s, 3H), 2.39 (s, 3H).
UPLC/MS (3 min) retention time 0.63 min. LRMS: m/z 223 (M+1 ).
PREPARATION 108 tert-Butyl (7-methoxy-5-methyl-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)acetate
Synthesized from the title compound of PREPARATION 121 and tert-Butyl bromoacetate. Yield: 92%. Purity 93%. UPLC/MS (3 min) retention time 1 .52 min.
LRMS: m/z 306 (M+1 ).
PREPARATION 109
(7-Methoxy-5-methyl-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)acetic acid Synthesized from the title compound of PREPARATION 108. Yield: 100%. Purity 92%. 1 H N MR (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 1 10
N-[3-(3-Cyanophenoxy)propyl]-2-(7-methoxy-5-methyl-4-oxopyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 109 and the title compound of PREPARATION 22. Purity 86%.
1 H NMR (300 MHz, DMSO-d6) δ ppm 8.55 (s, 1 H), 8.40 (s, 1 H), 7.37-7.50 (m, 4H), 6.77 (s, 1 H), 4.58 (s, 2H), 4.08 (t, 2H, J = 6.5 Hz), 3.95 (s, 3H), 3.27 (m, 2H), 2.67 (s, 3H), 1 .89 (m, 2H).
UPLC/MS (5 min) retention time 2.19 min. LRMS: m/z 408 (M+1 ).
PREPARATION 1 1 1
2-Chloro-N-[3-(3-cyanophenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 22. Yield: 100%. Purity 100%. 1 H N MR (400 MHz, CHLOROFORM-D) δ ppm 7.39 (dd, J = 9.2, 7.6 Hz, 1 H), 7.28 (t, J = 1 .2 Hz, 1 H), 7.17 - 7.12 (m, 2H), 6.96 (s, 1 H), 4.26 - 3.88 (m, 4H), 3.55 (q, J = 6.3 Hz, 2H), 2.09 (pent, J = 6.1 Hz, 2H).
UPLC/MS (3 min) retention time 1 .22 min.
LRMS: m/z 253 (M+1 , 1 xCI).
PREPARATION 1 12
7-[(4-Methoxybenzyl)amino]-5-methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one The title compound of PREPARATION 66 (53 mg, 0.23 mmol), 4-methoxybenzylamine (0.30 ml, 2.3 mmol) and caesium fluoride (5 mg, 0.03 mmol) were combined in 2 ml tetrahydrofuran. The mixture was heated under microwave irradiation at 140 °C for 4 h and then 160 °C for 24 h. Further 4-methoxybenzylamine (0.15 ml, 1 .15 mmol) was added and the mixture was again heated under microwave irradiation at 160 °C for 4 h. The mixture was allowed to cool and was partitioned between water and dichloromethane. The aqueous phase was extracted three times with dichloromethane. The combined organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was partially purified by flash chromatography (methanol-dichloromethane gradient, 0:100 rising to 10:90) to give 87 mg of the crude title compound. Used as such without further purification. Purity 67%.
UPLC/MS (3 min) retention time 0.89 min.
LRMS: m/z 286 (M+1 ).
PREPARATION 1 13 tert-Butyl [7-[(4-methoxybenzyl)amino]-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl]acetate
Synthesized from the crude title compound of PREPARATION 1 12 and tert-Butyl bromoacetate. Yield: 53% over two steps. Purity 100%.
1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.30 (d, J = 8.7 Hz, 2H), 7.08 (s, 1 H), 6.87 (d, J = 8.7 Hz, 2H), 4.84 (t, J = 5.9 Hz, 1 H), 4.60 (d, J = 5.9 Hz, 2H), 4.37 (s, 2H), 3.80 (s, 3H), 2.55 (s, 3H), 1 .48 (s, 9H).
UPLC/MS (3 min) retention time 1 .49 min.
LRMS: m/z 400 (M+1 ).
PREPARATION 1 14
[7-[(4-Methoxybenzyl)amino]-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl]acetic acid, hydrochloride salt Synthesized from the title compound of PREPARATION 1 13. Yield: 95%. Purity 90%. UPLC/MS (3 min) retention time 0.89 min. LRMS: m/z 344 (M+1 ).
PREPARATION 1 15 N-[3-(3-Chlorophenoxy)propyl]-2-[7-[(4-methoxybenzyl)amino]-5-methyl-4- oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl]acetamide
Synthesized from the title compound of PREPARATION 1 14 and the title compound of PREPARATION 48. Yield: 29%. Purity 95%.
1 H N MR (400 MHz, CHLOROFORM-D) δ ppm 7.33 - 7.27 (m, 2H), 7.24 (s, 1 H), 7.16 (t, J = 8.1 Hz, 1 H), 6.92 (ddd, J = 7.9, 1 .9, 0.9 Hz, 1 H), 6.90 - 6.84 (m, 3H), 6.75 (ddd, J = 8.4, 2.4, 0.8 Hz, 1 H), 6.56 (t, J = 5.5 Hz, 1 H), 4.95 (t, J = 5.7 Hz, 1 H), 4.61 (d, J = 5.9 Hz, 2H), 4.33 (s, 2H), 3.99 (t, J = 5.8 Hz, 2H), 3.80 (s, 3H), 3.47 (q, J = 6.4 Hz, 2H), 2.54 (s, 3H), 2.00 (pent, J = 6.2 Hz, 2H).
UPLC/MS (3 min) retention time 1 .57 min. LRMS: m/z 51 1 (M+1 , 1 *CI).
PREPARATION 1 16
5-Methyl-7-(methylamino)imidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one
The title compound of PREPARATION 66 (40 mg, 0.17 mmol) methylamine solution (2M in tetrahydrofuran, 2 ml, 4 mmol) and caesium fluoride (3 mg, 0.02 mmol) were combined. The mixture was heated under microwave irradiation at 140 °C for 4 h Further methylamine solution (1 ml, 2 mmol) was added and mixture was again heated under microwave irradiation at 140 °C for 20 h and the 160 °C for 20 h. The mixture was evaporated under reduced pressure and the residue was resuspended in methylamine solution (2M in tetrahydrofuran, 3 ml, 6 mmol). The mixture was heated under microwave irradiation at 160 °C for 10 h. Evaporation under reduced pressure gave 88 mg of a residue containing the title compound. Used as such without further purification.
UPLC/MS (3 min) retention time 0.32 min. LRMS: m/z 180 (M+1 ).
PREPARATION 1 17
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.
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 183 (M+1 ).
PREPARATION 1 18
2-[(Diphenylmethylene)amino]-6-methoxy-4-methylnicotinonitrile 6-[(Diphenylmethylene)amino]-2-methoxy-4-methylnicotinonitrile A mixture of the title compounds of PREPARATION 1 17 (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. Purity 83%. UPLC/MS (3 min) retention time 1 .94 LRMS: m/z 328 (M+1 , 1 *CI).
PREPARATION 1 19 2-Amino-6-methoxy-4-methylnicotinonitrile
6-Amino-2-methoxy-4-methylnicotinonitrile
The crude mixture of the title compounds of PREPARATION 1 18 (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. Purity 100%.
UPLC/MS (3 min) retention times 1 .02 and 1 .18 min. LRMS: m/z 164 (M+1 ).
PREPARATION 120
2-Amino-6-methoxy-4-methylnicotinamide
6-Amino-2-methoxy-4-methylnicotinamide A mixture of the title compounds of PREPARATION 1 19 (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 121 7-Methoxy-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one
Synthesized from the mixture of title compounds of PREPARATION 120 and triethylorthoformate. Yield: 45%. 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 ).
EXAMPLES
EXAMPLE 1
2-(4-Oxopyrido[3,4-<^pyrimidin-3(4H)-yl)-W-{3-[4-(trifluoromethyl)phenoxy]- propyl}acetamide
Pyrido[3,4-c/]pyrimidin-4(3/-/)-one (25 mg, 0.17 mmol) and potassium carbonate (47 mg, 0.34 mmol) were suspended in 0.7 ml dimethylformamide and the mixture stirred for 20 min. The title compound of PREPARATION 31 (57 mg, 0.19 mmol) was added and the mixture was stirred for 5 h. A little water was added forming a precipitate. The solid was collected by filtration, washed with water and dried under reduced pressure at 35 °C. The solid residue was purified by reverse phase chromatography to give 34 mg (0.084 mmol, 50% yield) of the title compound as a white solid. Purity 98%.
1 H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 0.8 Hz, 1 H), 8.69 (d, J = 5.2 Hz, 1 H), 8.45 - 8.36 (m, 2H), 7.96 (dd, J = 5.2, 0.9 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.65 (s, 2H), 4.07 (t, J = 6.3 Hz, 2H), 3.26 (q, J = 6.8 Hz, 2H), 1 .88 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.49 min. LRMS: m/z 405 (M+1 ).
EXAMPLE 2
W-{3-[(5-Chloropyridin-3-yl)oxy]propyl}-2-(4-oxoquinazolin-3(4H)-yl)acetamide
The title compound of PREPARATION 16 (45 mg, 0.22 mmol), 1 -hydroxybenzotriazole, HOBt (36 mg, 0.27 mmol) and 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, EDC- HCI (51 mg, 0.27 mmol) were suspended in 1 .8 ml dichloromethane and the mixture was stirred for 45 min. The title compound of PREPARATION 28 (57 mg, 0.25 mmol) and triethylamine (0.06 ml, 0.44 mmol) were added and the mixture was stirred for 5 h forming a slight precipitate. The mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organics were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified by reverse-phase chromatography to give 38 mg (0.10 mmol, 46%) of the title compound as a white solid. Purity 98%.
1 H NMR (400 MHz, DMSO-d6) δ 8.37 (t, J = 5.5 Hz, 1 H), 8.28 (s, 1 H), 8.26 (d, J = 2.5 Hz, 1 H), 8.19 (d, J = 2.0 Hz, 1 H), 8.12 (dd, J = 8.0, 1 .1 Hz, 1 H), 7.86 - 7.79 (m, 1 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.58 - 7.49 (m, 2H), 4.62 (s, 2H), 4.10 (t, J = 6.3 Hz, 2H), 3.25 (q, J = 6.7 Hz, 2H), 1 .88 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 1 .99 min.
LRMS: m/z 371 (M+1 , 1 *CI).
EXAMPLE 3 W-[3-(2-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide
The title compound of PREPARATION 14 (68 mg, 0.24 mmol), 2-fluorophenol (24 mg, 0.27 mmol) and caesium carbonate (158 mg, 0.48 mmol) were suspended in 1 .5 ml dimethylformamide and the mixture was agitated at 70 °C for 4 h. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine. The organics were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified by reverse-phase chromatography to give 17 mg (0.048 mmol, 20%) of the title compound as a white solid. Purity 98%.
1 H N MR (400 MHz, DMSO-d6) δ ppm 9.08 (1 H , s), 8.69 (1 H , d, J=5.1 Hz), 7.96 (1 H , d, J=5.1 Hz), 7.59 (1 H, s), 6.90-7.20 (5 H, m), 4.65 (2 H, s), 4.06 (2 H, t, J=6.3 Hz), 3.26 (2 H, m), 1 .88 (2 H, m).
UPLC/MS (5 min) retention time 1 .88 min.
LRMS: m/z 355 (M+1 ).
EXAMPLE 4
W-[3-(3-Chlorophenoxy)propyl]-2-(6-methyl-4-oxopyrido[3,4-rflpyrimidin-3(4H)- yl)acetamide
The title compound of EXAMPLE 25 (28 mg, 0.069 mmol), 2,4, 6-trimethyl-1 , 3,5,2,4, 6- trioxatriborinane (1 1 μΙ, 0.079 mmol) and potassium carbonate (29 mg, 0.21 mmol) were suspended in 0.2 ml anhydrous dioxane in a Schlenk vessel. The mixture was submitted to three vacuum-argon cycles. [1 , 1 '-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (3 mg, 0.0037 mmol) was then 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 cooled to room temperature, diluted with dioxane, filtered and the solid washed with ethyl acetate. The combined filtrate was evaporated under reduced pressure and the residue was purified by reverse-phase chromatography to give 9.6 mg (0.025 mmol, 36%) of the title compound as a white solid. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (1 H, s), 8.38 (1 H, m), 8.35 (1 H, s), 7.82 (1 H, s), 7.29 (1 H, m), 6.96-7.00 (2 H , m), 6.90 (1 H, m), 4.64 (2 H , s), 4.01 (2 H, t, J=6.3 Hz), 3.24 (2 H, m), 2.62 (3 H , s), 1 .86 (2 H, m). UPLC/MS (5 min) retention time 2.31 LRMS: m/z 385 (M+1 , 1 *CI).
The following compounds were prepared using methods identical or similar to those described above, unless stated otherwise.
EXAMPLE 5 yV-[3-(3-Fluorophenoxy)propyl]-2-(4-oxoquinazolin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 17 and 3-Fluorophenol. Yield: 58%. Purity 96%.
1 H N MR (400 MHz, CH LOROFORM-D) δ 8.28 (d, J = 7.8 Hz, 1 H), 8.10 (s, 1 H), 7.8 (m, 2H), 7.52 (t, J = 6.9 Hz, 1 H), 7.17 (q, J = 8.1 Hz, 1 H), 6.71 - 6.49 (m, 4H), 4.59 (s, 2H), 3.99 (t, J = 5.9 Hz, 2H), 3.49 (q, J = 6.3 Hz, 2H), 2.01 (pent, J = 6.1 Hz, 2H).
UPLC/MS (5 min) retention time 2.31 min. LRMS: m/z 356 (M+1 ).
EXAMPLE 6 yV-[3-(4-Methylphenoxy)propyl]-2-(4-oxoquinazolin-3(4H)-yl)acetamide Synthesized from the title compound of PREPARATION 17 and 4-Cresol. Yield: 55%. Purity 95%.
1 H NMR (400 MHz, CHLOROFORM-D) δ 8.31 - 8.24 (m, 1 H), 8.09 (s, 1 H), 7.82 - 7.70 (m, 2H), 7.55 - 7.48 (m, 1 H), 7.06 - 7.01 (m, 2H), 6.77 - 6.71 (m, 2H), 6.59 (s, 1 H), 4.58 (s, 2H), 3.99 (t, J = 5.8 Hz, 2H), 3.49 (q, J = 6.4 Hz, 2H), 2.27 (s, 3H), 2.00 (pent, J = 6.4 Hz, 2H).
UPLC/MS (5 min) retention time 2.43 min.
LRMS: m/z 352 (M+1 ). EXAMPLE 7 yV-[3-(3-Methoxyphenoxy)propyl]-2-(4-oxoquinazolin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 17 and 3-Methoxyphenol. Yield: 65%. Purity 97%.
1 H N MR (400 MHz, CHLOROFORM-D) δ 8.27 (dd, J = 8.0, 0.9 Hz, 1 H), 8.10 (s, 1 H), 7.81 - 7.70 (m, 2H), 7.55 - 7.47 (m, 1 H), 7.18 - 7.10 (m, 1 H), 6.61 (s, 1 H), 6.54 - 6.48 (m, 1 H), 6.48 - 6.42 (m, 2H), 4.58 (s, 2H), 4.00 (t, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.49 (q, J = 6.5 Hz, 2H), 2.00 (pent, J = 6.3 Hz, 2H). UPLC/MS (5 min) retention time 2.21 min.
LRMS: m/z 368 (M+1 ).
EXAMPLE 8 yV-[3-(3-Chlorophenoxy)propyl]-2-(4-oxoquinazolin-3(4H)-yl)acetamide Synthesized from the title compound of PREPARATION 17 and 3-Chlorophenol. Yield: 87%. Purity 99%.
1 H N MR (400 MHz, DMSO-d6) δ ppm 8.41 (t, J=5.67 Hz, 1 H), 8.30 (s, 1 H), 8.14 (dd, J=8.01 , 1 .37 Hz, 1 H), 7.82 - 7.88 (m, 1 H), 7.70 (d, J=7.82 Hz, 1 H), 7.53 - 7.59 (m, 1 H), 7.30 (t, J=8.01 Hz, 1 H), 6.97 - 7.03 (m, 2 H), 6.92 (dd, J=8.21 , 2.34 Hz, 1 H), 4.64 (s, 2 H), 4.03 (t, J=6.45 Hz, 2 H), 3.26 (q, J=6.51 Hz, 2 H), 1 .83 - 1 .92 (m, 2 H)
UPLC/MS (5 min) retention time 2.56 min.
LRMS: m/z 372 (M+1 , 1 xCI).
EXAMPLE 9 yV-[3-(4-Fluorophenoxy)propyl]-2-(4-oxoquinazolin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 17 and 4-Fluorophenol. Yield: 31 %. Purity 99%. 1 H N MR (400 MHz, CHLOROFORM-D) δ 8.26 (dd, J = 8.0, 0.9 Hz, 1 H), 8.10 (s, 1 H), 7.84 - 7.72 (m, 2H), 7.55 - 7.49 (m, 1 H), 6.95 - 6.87 (m, 2H), 6.82 - 6.74 (m, 2H), 6.57 (s, 1 H), 4.59 (s, 2H), 3.96 (t, J = 5.8 Hz, 2H), 3.49 (q, J = 6.4 Hz, 2H), 2.00 (pent, J = 6.2 Hz, 2H). UPLC/MS (5 min) retention time 2.25 min.
LRMS: m/z 356 (M+1 ).
EXAMPLE 10
W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide Synthesized from Pyrido[3,4-c ]pyrimidin-4(3H)-one and the title compound of PREPARATION 49. Yield: 70%. Purity 100%.
1 H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 0.9 Hz, 1 H), 8.69 (d, J = 5.2 Hz, 1 H), 8.42 (s, 1 H), 8.39 (t, J = 5.6 Hz, 1 H), 7.96 (dd, J = 5.2, 0.9 Hz, 1 H), 7.33 - 7.24 (m, 1 H), 7.01 - 6.94 (m, 2H), 6.92 - 6.86 (m, 1 H), 4.65 (s, 2H), 4.00 (t, J = 6.3 Hz, 2H), 3.27 - 3.19 (m, 2H), 1 .85 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.29 min.
LRMS: m/z 373 (M+1 , 1 xCI).
EXAMPLE 1 1 2-(4-Oxopyrido[4,3-rflpyrimidin-3(4H)-yl)-N-{3-[4- (trifluoromethyl)phenoxy]propyl}acetamide
Synthesized from Pyrido[4,3-c ]pyrimidin-4(3H)-one and the title compound of PREPARATION 31 . Yield: 56%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 0.8 Hz, 1 H), 8.85 (d, J = 5.6 Hz, 1 H), 8.49 (s, 1 H), 8.41 (t, J = 5.5 Hz, 1 H), 7.67 - 7.57 (m, 3H), 7.09 (d, J = 8.5 Hz, 2H), 4.64 (s, 2H), 4.08 (t, J = 6.3 Hz, 2H), 3.26 (q, J = 6.7 Hz, 2H), 1 .89 (pent, J = 6.5 Hz, 2H).
UPLC/MS (5 min) retention time 2.41 min.
LRMS: m/z 407 (M+1 ). EXAMPLE 12
W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[4,3-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from Pyrido[4,3-c ]pyrimidin-4(3H)-one and the title compound of PREPARATION 49. Yield: 40%. Purity 100%.
1 H N MR (400 MHz, DMSO-d6) δ 9.30 (d, J = 0.8 Hz, 1 H), 8.89 - 8.81 (m, 1 H), 8.50 (s, 1 H), 8.40 (t, J = 5.4 Hz, 1 H), 7.61 (d, J = 5.6 Hz, 1 H), 7.28 (t, J = 8.1 Hz, 1 H), 7.03 - 6.94 (m, 2H), 6.90 (dd, J = 8.4, 2.4 Hz, 1 H), 4.65 (s, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.28 - 3.22 (m, 2H), 1 .86 (pent, J = 6.5 Hz, 2H). UPLC/MS (5 min) retention time 2.21 min.
LRMS: m/z 373 (M+1 , 1 *CI).
EXAMPLE 13
W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,2-<^pyrimidin-3(4H)-yl)acetamide Synthesized from the title compound of PREPARATION 50 and the title compound of PREPARATION 49. Yield: 50%. Purity 100%.
1 H N MR (400 MHz, DMSO-d6) δ 8.81 (dd, J = 4.3, 1 .5 Hz, 1 H), 8.43 - 8.35 (m, 2H), 8.12 (dd, J = 8.3, 1 .5 Hz, 1 H), 7.83 (dd, J = 8.3, 4.3 Hz, 1 H), 7.29 (t, J = 8.1 Hz, 1 H), 7.03 - 6.94 (m, 2H), 6.91 (dd, J = 8.2, 1 .8 Hz, 1 H), 4.66 (s, 2H), 4.02 (t, J = 6.3 Hz, 2H), 3.25 (q, J = 6.6 Hz, 2H), 1 .87 (pent, J = 6.4 Hz, 2H).
UPLC/MS (5 min) retention time 2.17 min.
LRMS: m/z 373 (M+1 , 1 *CI).
EXAMPLE 14 W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[2,3-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 51 and the title compound of PREPARATION 49. Yield: 52%. Purity 99%. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (dd, J = 4.3, 1.5 Hz, 1H), 8.43 - 8.35 (m, 2H), 8.12 (dd, J = 8.3, 1.5 Hz, 1H), 7.83 (dd, J = 8.3, 4.3 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.91 (dd, J = 8.2, 1.8 Hz, 1H), 4.66 (s, 2H), 4.02 (t, J = 6.3 Hz, 2H), 3.25 (q, J = 6.6 Hz, 2H), 1.87 (pent, J = 6.4 Hz, 2H). UPLC/MS (5 min) retention time 2.27 min.
LRMS: m/z373 (M+1, 1*CI).
EXAMPLE 15
W-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide Synthesized from Pyrido[3,4-c]pyrimidin-4(3H)-one and the title compound of PREPARATION 40. Yield: 72%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.75 (d, J = 5.2 Hz, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.15 (t, J = 8.7 Hz, 2H), 6.97 (dd, J = 9.1, 4.4 Hz, 2H), 4.71 (s, 2H), 4.01 (t, J = 6.2 Hz, 2H), 3.30 (q, J = 6.6 Hz, 2H), 1.90 (pent, J = 6.4 Hz, 2H).
UPLC/MS (5 min) retention time 1.98 min.
LRMS: m/z357 (M+1).
EXAMPLE 16 W-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[2,3-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 51 and the title compound of PREPARATION 40. Yield: 51%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ 8.97 (dd, J = 4.6, 2.0 Hz, 1H), 8.55 - 8.48 (m, 2H), 8.38 (t, J = 5.6 Hz, 1H), 7.57 (dd, J = 7.9, 4.6 Hz, 1H), 7.16 - 7.04 (m, 2H), 6.97 - 6.85 (m, 2H), 4.63 (s, 2H), 3.95 (t, J = 6.3 Hz, 2H), 3.24 (q, J = 6.7 Hz, 2H), 1.84 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 1.94 min. LRMS: m/z357 (M+1). EXAMPLE 17
A/-[3-(3-Chlorophenoxy)propyl]-2-(5,7-cfimethoxy-4-oxoquinazolin-3(4H)- yl)acetamide Synthesized from 5,7-Dimethoxyquinazolin-4(3H)-one and the title compound of PREPARATION 49. Yield: 47%. Purity 100%.
1 H N MR (400 MHz, DMSO-d6) δ 8.35 (t, J = 5.6 Hz, 1 H), 8.1 9 (s, 1 H), 7.34 (t, J = 8.1 Hz, 1 H), 7.07 - 7.00 (m, 2H), 6.99 - 6.90 (m, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 6.60 (d, J = 2.3 Hz, 1 H), 4.52 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.28 (q, J = 6.8 Hz, 2H), 1 .90 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.52 min.
LRMS: m/z 432 (M+1 , 1 *CI).
EXAMPLE 18 W-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[4,3-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from Pyrido[3,4-c ]pyrimidin-4(3H)-one and the title compound of PREPARATION 40. Yield: 53%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 0.8 Hz, 1 H), 8.91 (d, J = 5.6 Hz, 1 H), 8.55 (s, 1 H), 8.46 (t, J = 5.6 Hz, 1 H), 7.66 (dd, J = 5.6, 0.8 Hz, 1 H), 7.20 - 7.10 (m, 2H), 7.03 - 6.92 (m, 2H), 4.70 (s, 2H), 4.02 (t, J = 6.3 Hz, 2H), 3.30 (q, J = 6.8 Hz, 2H), 1 .91 (pent, J = 6.7 Hz, 2H).
UPLC/MS (5 min) retention time 1 .88 min.
LRMS: m/z 357 (M+1 ).
EXAMPLE 19
N-[3 -(3 -C h I o ro -4-f I u o ro p he n oxy ) p ro py I ] -2 -(4-oxo py r i d o [3 , 4-d] py ri m i d i n -3 (4H) - yl)acetamide Synthesized from Pyrido[3,4-c ]pyrimidin-4(3/-/)-one and the title compound of PREPARATION 37. Yield: 78%. Purity 96%.
1 H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 0.8 Hz, 1 H), 8.75 (d, J = 5.2 Hz, 1 H), 8.48 (s, 1 H), 8.44 (t, J = 5.7 Hz, 1 H), 8.02 (dd, J = 5.2, 0.9 Hz, 1 H), 7.36 (t, J = 9.1 Hz, 1 H), 7.19 (dd, J = 6.1 , 3.0 Hz, 1 H), 7.03 - 6.90 (m, 1 H), 4.70 (s, 2H), 4.04 (t, J = 6.3 Hz, 2H), 3.29 (q, J = 6.6 Hz, 2H), 1 .90 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.34 min.
LRMS: m/z 391 (M+1 , 1 *CI).
EXAMPLE 20
W-[3-(3,5-Dichlorophenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide
Synthesized from Pyrido[3,4-c ]pyrimidin-4(3/-/)-one and the title compound of PREPARATION 43. Yield: 82%. Purity 99%. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 0.8 Hz, 1 H), 8.75 (d, J = 5.2 Hz, 1 H), 8.48 (s, 1 H), 8.43 (t, J = 5.5 Hz, 1 H), 8.01 (dd, J = 5.2, 0.9 Hz, 1 H), 7.18 (t, J = 1 .8 Hz, 1 H), 7.06 (d, J = 1 .8 Hz, 2H), 4.70 (s, 2H), 4.09 (t, J = 6.3 Hz, 2H), 3.29 (q, J = 6.6 Hz, 2H), 1 .90 (pent, J = 6.4 Hz, 2H).
UPLC/MS (5 min) retention time 2.70 min. LRMS: m/z 407 (M+1 , 2*CI).
EXAMPLE 21
W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrimido[4,5-d]pyridazin-3(4H)- yl)acetamide Synthesized from the title compound of PREPARATION 52 and the title compound of PREPARATION 49. Yield: 24%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ 9.69 (dd, J = 8.0, 1 .3 Hz, 1 H), 8.80 (s, 1 H), 8.49 (t, J = 5.5 Hz, 1 H), 7.34 (t, J = 8.2 Hz, 1 H), 7.06 - 7.00 (m, 2H), 6.95 (ddd, J = 8.4, 2.3, 0.9 Hz, 1 H), 4.75 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.30 (q, J = 6.6 Hz, 2H), 1 .91 (pent, J = 6.5 Hz, 2H).
UPLC/MS (5 min) retention time 2.12 min. LRMS: m/z 374 (M+1 , 1 *CI).
EXAMPLE 22 yV-[3-(3-Chlorophenoxy)propyl]-2-(5-oxopyrimido[4,5-c]pyridazin-6(5H)- yl)acetamide
Synthesized from the title compound of PREPARATION 53 and the title compound of PREPARATION 49. Yield: 1 1 %. Purity 98%.
1H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 5.2 Hz, 1 H), 8.69 (s, 1 H), 8.44 (t, J = 5.6 Hz, 1 H), 8.34 (d, J = 5.2 Hz, 1 H), 7.37 - 7.29 (m, 1 H), 7.05 - 6.99 (m, 2H), 6.96 - 6.91 (m, 1 H), 4.71 (s, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.30 (dd, J = 12.8, 6.9 Hz, 2H), 1.90 (pent, J = 6.5 Hz, 2H). UPLC/MS (5 min) retention time 2.14 min.
LRMS: m/z 374 (M+1 , 1 *CI).
EXAMPLE 23 yV-[3-(3-Chlorophenoxy)butyl]-2-(4-oxoquinazolin-3(4H)-yl)acetamide Synthesized from Quinazolin-4(3H)-one and the title compound of PREPARATION 4. Yield: 65%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (1 H, m), 8.28 (1 H, s), 8.14 (1 H, dd, J=7.8,1 .6 Hz), 7.84 (1 H, m), 7.69 (1 H, d, J=7.8 Hz), 7.55 (1 H, m), 7.27 (1 H, m), 6.94- 6.99 (2 H, m), 6.91 (1 H, dd, J=8.6,2.4 Hz), 4.62 (2 H, s), 4.54 (1 H, m), 3.23 (2 H, m), 1 .68-1 .87 (2 H, m), 1 .22 (3 H, d, J=6.3 Hz).
UPLC/MS (5 min) retention time 2.63 min.
LRMS: m/z 386 (M+1 , 1 xCI). EXAMPLE 24 yV-[3-(3-Cyanophenoxy)propyl]-2-(4-oxoquinazolin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 16 and the title compound of PREPARATION 22. Yield: 44%. Purity 97%. 1 H N MR (400 MHz, DMSO-d6) δ ppm 8.38 (t, J=5.47 Hz, 1 H), 8.29 (s, 1 H), 8.14 (dd, J=8.01 , 1 .37 Hz, 1 H), 7.81 - 7.87 (m, 1 H), 7.70 (d, J=7.82 Hz, 1 H), 7.53 - 7.58 (m, 1 H), 7.46 - 7.51 (m, 1 H), 7.37 - 7.43 (m, 2 H), 7.27 - 7.31 (m, 1 H), 4.63 (s, 2 H), 4.08 (t, J=6.25 Hz, 2 H), 3.23 - 3.30 (m, 2 H), 1 .84 - 1 .93 (m, 2 H).
UPLC/MS (5 min) retention time 2.08 min. LRMS: m/z 363 (M+1 ).
EXAMPLE 25
2-(6-Chloro-4-oxopyrido[3,4-rflpyrimidin-3(4H)-yl)-yV-[3-(3- chlorophenoxy)propyl]acetamide Synthesized from 6-Chloropyrido[3,4-c/]pyrimidin-4(3/-/)-one and the title compound of PREPARATION 49. Yield: 57%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 0.6 Hz, 1 H), 8.50 (s, 1 H), 8.44 (t, J = 5.5 Hz, 1 H), 8.06 (d, J = 0.7 Hz, 1 H), 7.37 - 7.30 (m, 1 H), 7.02 (dd, J = 7.4, 1 .1 Hz, 2H), 6.97 - 6.91 (m, 1 H), 4.70 (s, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.30 (q, J = 6.5 Hz, 2H), 1 .91 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.62 min.
LRMS: m/z 407 (M+1 , 2*CI).
EXAMPLE 26 2-(4-Oxopyrido[3,4-rflpyrimidin-3(4H)-yl)-yV-{3-[3- (trifluoromethyl)phenoxy]propyl}acetamide
Synthesized from Pyrido[3,4-c ]pyrimidin-4(3/-/)-one and the title compound of PREPARATION 34. Yield: 62%. Purity 99%. 1 H N MR (400 MHz, DMSO-d6) δ 9.08 (s, 1 H), 8.69 (d, J = 5.2 Hz, 1 H), 8.45 - 8.35 (m, 2H), 7.95 (dd, J = 5.2, 0.8 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 7.29 - 7.15 (m, 3H), 4.65 (s, 2H), 4.07 (t, J = 6.2 Hz, 2H), 3.28 - 3.22 (m, 2H), 1 .93 - 1 .82 (m, 2H).
UPLC/MS (5 min) retention time 2.37 min. LRMS: m/z 407 (M+1 ).
EXAMPLE 27
W-[3-(3-Chlorophenoxy)butyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from Pyrido[3,4-c ]pyrimidin-4(3/-/)-one and the title compound of PREPARATION 4. Yield: 54%. Purity 98%.
1 H N MR (400 MHz, DMSO-d6) δ 9.14 (s, 1 H), 8.75 (d, J = 5.2 Hz, 1 H), 8.47 (s, 1 H), 8.42 (t, J = 5.6 Hz, 1 H), 8.03 (d, J = 4.5 Hz, 1 H), 7.32 (t, J = 8.1 Hz, 1 H), 7.06 - 6.97 (m, 2H), 6.94 (d, J = 8.0 Hz, 1 H), 4.70 (s, 2H), 4.65 - 4.52 (m, 1 H), 3.33 - 3.13 (m, 2H), 1 .94 - 1 .80 (m, 1 H), 1 .81 - 1 .68 (m, 1 H), 1 .27 (d, J = 6.0 Hz, 3H). UPLC/MS (5 min) retention time 2.36 min.
LRMS: m/z 387 (M+1 , 1 *CI).
Chiral preparative HPLC of EXAMPLE 27 (Daicel Chiralpak IA, 5 μηι (30x250 mm) column, eluting with ethanol-heptane (60:40)+0.1 % diethylamine, flow rate 15 ml/min, run time 40 min) separated both enantiomers. Enantiomer 1 is the first eluting enantiomer.
Enantiomer 1 yV-[3-(3-Chlorophenoxy)butyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide
Purity 99%. Enantiomeric excess >99%
Enantiomer 2 yV-[3-(3-Chlorophenoxy)butyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide
Purity 99%. Enantiomeric excess >99%
EXAMPLE 28 N-[3-(3-Chlorophenoxy)propyl]-2-(1 -oxo-2,6-naphthyridin-2(1 H)-yl)acetamide
Synthesized from 2,6-Naphthyridin-1 (2/-/)-one and the title compound of PREPARATION 49. Yield: 34%. Purity 98%.
Ή NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1 H), 8.68 (d, J = 5.3 Hz, 1 H), 8.32 (t, J = 5.5 Hz, 1 H), 8.03 (d, J = 5.3 Hz, 1 H), 7.58 (d, J = 7.3 Hz, 1 H), 7.34 (t, J = 8.1 Hz, 1 H), 7.07 - 6.99 (m, 2H), 6.95 (dd, J = 8.1 , 1 .8 Hz, 1 H), 6.78 (d, J = 7.3 Hz, 1 H), 4.66 (s, 2H), 4.07 (t, J = 6.3 Hz, 2H), 3.32 - 3.25 (m, 2H), 1 .91 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.20 min.
LRMS: m/z 372 (M+1 , 1 *CI).
EXAMPLE 29
W-{3-[3-(Dimethylamino)phenoxy]propyl}-2-(4-oxopyrido[3,4-cnpyrimidin-3(4W)- yl)acetamide
Synthesized from Pyrido[3,4-c ]pyrimidin-4(3/-/)-one and the title compound of PREPARATION 46. Yield: 58%. Purity 97%.
Ή NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 0.8 Hz, 1 H), 8.75 (d, J = 5.2 Hz, 1 H), 8.48 (s, 1 H), 8.44 (t, J = 5.5 Hz, 1 H), 8.01 (dd, J = 5.2, 0.9 Hz, 1 H), 7.09 (t, J = 8.2 Hz, 1 H), 6.35 (dd, J = 8.3, 1 .8 Hz, 1 H), 6.31 - 6.22 (m, 2H), 4.71 (s, 2H), 4.00 (t, J = 6.3 Hz, 2H), 3.29 (q, J = 6.7, 6.1 Hz, 2H), 2.90 (s, 6H), 1.90 (pent, J = 6.6 Hz, 2H). UPLC/MS (5 min) retention time 1 .30 min.
LRMS: m/z 382 (M+1 ).
EXAMPLE 30
W-[3-(3-Chlorophenoxy)propyl]-2-(5-methoxy-4-oxoquinazolin-3(4H)-yl)acetamide Synthesized from the title compound of PREPARATION 55 and the title compound of PREPARATION 49. Yield: 10%. Purity 98%.
Ή NMR (400 MHz, DMSO-d6) δ 8.37 (t, J = 5.2 Hz, 1 H), 8.24 (s, 1 H), 7.75 (t, J = 8.3 Hz, 1 H), 7.34 (t, J = 8.1 Hz, 1 H), 7.23 (d, J = 7.8 Hz, 1 H), 7.08 (d, J = 8.1 Hz, 1 H), 7.06 - 7.00 (m, 2H), 6.96 (d, J = 8.1 Hz, 1 H), 4.56 (s, 2H), 4.07 (t, J = 6.3 Hz, 2H), 3.88 (s, 3H), 3.28 (q, J = 6.5 Hz, 2H), 1.90 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.32 min.
LRMS: m/z 402 (M+1 , 1 *CI).
EXAMPLE 31
W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrimido[4,5- /]pyrimidin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 54 and the title compound of PREPARATION 49. Yield: 15%. Purity 95%.
Ή NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1 H), 9.49 (s, 1 H), 8.78 (s, 1 H), 8.49 (s, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.02 (m, 2H), 6.95 (d, J = 8.0 Hz, 1 H), 4.72 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.33 - 3.27 (m, 2H), 2.01 - 1.83 (m, 2H).
UPLC/MS (5 min) retention time 2.03 min. LRMS: m/z 374 (M+1 , 1 xCI).
EXAMPLE 32
W-[3-(4-Cyanophenoxy)propyl]-2-(4-oxopyrido[3,4-cnpyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 13 and the title compound of PREPARATION 26. Yield: 30%. Purity 99%.
Ή NMR (400 MHz, DMSO-d6) δ ppm 9.10 (d, J=0.78 Hz, 1 H), 8.71 (d, J=5.08 Hz, 1 H), 8.44 (s, 1 H), 8.41 (t, J=5.86 Hz, 1 H), 7.98 (dd, J=5.08, 0.78 Hz, 1 H), 7.73 - 7.79 (m, 2 H), 7.07 - 7.13 (m, 2 H), 4.66 (s, 2 H), 4.10 (t, J=6.25 Hz, 2 H), 3.27 (q, J=6.38 Hz, 2 H), 1.85 - 1 .94 (m, 2 H). UPLC/MS (5 min) retention time 1 .62 min.
LRMS: m/z 364 (M+1 ). EXAMPLE 33 yV-[3-(3-Chlorophenoxy)propyl]-2-(8-methoxy-4-oxoquinazolin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 56 and the title compound of PREPARATION 49. Yield: 75%. Purity 99%. 1 H NMR (600 MHz, DMSO-d6) δ 8.43 (t, J = 5.5 Hz, 1 H), 8.27 (s, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 7.42 (d, J = 7.9 Hz, 1 H), 7.34 (t, J = 8.1 Hz, 1 H), 7.06 - 7.00 (m, 2H), 6.95 (dd, J = 8.3, 1 .9 Hz, 1 H), 4.66 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.29 (q, J = 6.4 Hz, 2H), 1 .91 (pent, J = 6.4 Hz, 2H).
UPLC/MS (5 min) retention time 2.50 min. LRMS: m/z 402 (M+1 , 1 xCI).
EXAMPLE 34 yV-[3-(3-Chlorophenoxy)propyl]-2-(6-methoxy-4-oxoquinazolin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 7 and the title compound of PREPARATION 49. Yield: 63%. Purity 99%.
1 H NMR (600 MHz, DMSO-d6) δ 8.43 (t, J = 5.5 Hz, 1 H), 8.22 (s, 1 H), 7.68 (d, J = 8.9 Hz, 1 H), 7.54 (d, J = 2.8 Hz, 1 H), 7.48 (dd, J = 8.9, 2.9 Hz, 1 H), 7.34 (t, J = 8.1 Hz, 1 H), 7.06 - 7.00 (m, 2H), 6.95 (dd, J = 8.3, 1 .9 Hz, 1 H), 4.66 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.91 (s, 3H), 3.29 (q, J = 6.4 Hz, 2H), 1 .91 (pent, J = 6.4 Hz, 2H). UPLC/MS (5 min) retention time 2.59 min.
LRMS: m/z 402 (M+1 , 1 *CI).
EXAMPLE 35
2-(4-Oxopyrido[3,4-<^pyrimidin-3(4H)-yl)-yV-(3-phenoxypropyl)acetamide Synthesized from the title compound of PREPARATION 14 and Phenol. Yield: 32%. Purity 99%. 1 H N MR (400 MHz, DMSO-d6) δ ppm 9.10 (1 H , s), 8.70 (1 H , d, J=5.1 Hz), 8.44 (2 H, m), 7.97 (1 H, d, J=5.5 Hz), 7.27 (2 H, m), 6.92 (3 H, m), 4.66 (2 H, s), 3.99 (2 H, t, J=6.3 Hz), 3.27 (2 H, m), 1 .87 (2 H, m).
UPLC/MS (5 min) retention time 1 .86 min. LRMS: m/z 339 (M+1 ).
EXAMPLE 36
2-(5-Bromo-4-oxopyrido[3,4-rflpyrimidin-3(4H)-yl)-yV-[3-(3- chlorophenoxy)propyl]acetamide Synthesized from the title compound of PREPARATION 59 and the title compound of PREPARATION 49. Yield: 31 %. Purity 99%.
1 H N MR (400 MHz, DMSO-d6) δ ppm 9.00 (1 H , s), 8.81 (1 H , s), 8.49 (1 H , s), 8.39 (1 H, t, J=5.5 Hz), 7.29 (1 H, m), 6.96-7.00 (2 H, m), 6.91 (1 H, m), 4.61 (2 H, s), 4.02 (2 H, t, J=6.3 Hz), 3.26 (2 H, m), 1 .87 (2 H, m). UPLC/MS (5 min) retention time 2.56 min.
LRMS: m/z 451 (M+1 , 1 *CI, 1 xBr).
EXAMPLE 37
2-(8-Chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-yV-[3-(3- chlorophenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 60 and the title compound of PREPARATION 49. Yield: 64%. Purity 98%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1 H, m), 8.49 (1 H, m), 8.41 (1 H , m), 8.00 (1 H, m), 7.30 (1 H, m), 6.89-7.02 (3 H, m), 4.67 (2 H , s), 4.01 (2 H , t, J=6.5 Hz), 3.25 (2 H, m), 1 .87 (2 H, m).
UPLC/MS (5 min) retention time 2.46 min.
LRMS: m/z 407 (M+1 , 2xCI). EXAMPLE 38
W-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxopyrido[3,4-cnpyrimidin-3(4H)- yl)acetamide
Synthesized from the title compound of EXAMPLE 36 and 2,4,6-trimethyl-l ,3,5,2,4,6- trioxatriborinane. Yield: 5%. Purity 93%.
UPLC/MS (5 min) retention time 2.43 min.
LRMS: m/z 387 (M+1 , 1 CI).
EXAMPLE 39 W-{3-[(4-Chloropyridin-2-yl)oxy]propyl}-2-(4-oxopyrido[3,4-rf]pyrirnidin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 13 and the title compound of PREPARATION 24. Yield: 29%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.1 1 (s, 1 H), 8.71 (d, J=5.08 Hz, 1 H), 8.45 (s, 1 H), 8.39 (t, J=5.67 Hz, 1 H), 7.99 (dd, J=5.47, 0.78 Hz, 1 H), 7.77 (d, J=7.42 Hz, 1 H), 6.53 (d, J=2.34 Hz, 1 H), 6.37 (dd, J=7.23, 2.54 Hz, 1 H), 4.67 (s, 2 H), 3.88 (t, J=7.03 Hz, 2 H), 3.10 (q, J=6.64 Hz, 2 H), 1.74 - 1.83 (m, 2 H)
UPLC/MS (5 min) retention time 1 .33 min.
LRMS: m/z 374 (M+1 , 1 xCI).
EXAMPLE 40
W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,4-d][1 ,2,3]triazin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 1 1 and the title compound of PREPARATION 48. Yield: 42%. Purity 93%.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (1 H, s), 9.06 (1 H, d, J=5.1 Hz), 8.38 (1 H, m), 8.12 (1 H, dd, J=5.1 , 0.8 Hz), 7.29 (1 H, m), 6.95-6.99 (2 H, m), 6.90 (1 H, m), 5.04 (2 H, s), 4.01 (2 H, t, J=6.3 Hz), 3.26 (2 H, m), 1.86 (2 H, m). UPLC/MS (5 min) retention time 2.33 LRMS: m/z 374 (M+1 , 1 CI).
EXAMPLE 41 W-[3-(3-Chlorophenoxy)propyl]-2-(8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide
Synthesized from the title compound of EXAMPLE 37 and 2,4,6-trimethyl-l ,3,5,2,4,6- trioxatriborinane. Yield: 29%. Purity 99%.
1H NMR (400 MHz, DMSO- /6) δ ppm 8.53 (1 H, d, J=5.5 Hz), 8.37-8.44 (2 H, m), 7.81 (1 H, d, J=5.5 Hz), 7.30 (1 H, m), 6.97-7.02 (2 H, m), 6.91 (1 H, m), 4.66 (2 H, s), 4.02 (2 H, t, J=6.3 Hz), 3.27 (2 H, m), 2.78 (3 H, s), 1.87 (2 H, m).
UPLC/MS (5 min) retention time 2.34 min.
LRMS: m/z 387 (M+1 , 1 CI).
EXAMPLE 42
W-[3-(3-Bromophenoxy)propyl]-2-(4-oxopyrido[3,4-cnpyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 3-Bromophenol. Yield: 14%. Purity 96%.
1H NMR (600 MHz, DMSO-c/6) δ ppm 9.1 1 (s, 1 H), 8.72 (d, J=5.28 Hz, 1 H), 8.45 (s, 1 H), 8.42 (t, J=5.58 Hz, 1 H), 7.95 - 8.02 (m, 1 H), 7.25 (t, J=7.92 Hz, 1 H), 7.10 - 7.15 (m, 2 H), 6.95 (dd, J=7.92, 2.05 Hz, 1 H), 4.67 (s, 2 H), 4.02 (t, J=6.16 Hz, 2 H), 3.26 (q, J=6.46 Hz, 2 H), 1.84 - 1.90 (m, 2 H).
UPLC/MS (5 min) retention time 2.27 min.
LRMS: m/z 417 (M+1 , 1 x Br).
EXAMPLE 43 W-[2-(2,3-Dihydro-1 -benzofuran-2-yl)ethyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H) yl)acetamide
Synthesized from the title compound of PREPARATION 13 and the title compound of PREPARATION 18. Yield: 23%. Purity 95%. 1 H N MR (400 MHz, CHLOROFORM-D) δ ppm 9.20 (1 H, s), 8.75 (1 H, d, J=5.1 Hz), 8.18 (1 H, s), 8.07 (1 H , d, J=5.1 Hz), 7.16 (1 H, d, J=6.6 Hz), 7.1 1 (1 H , m), 6.86 (1 H , m), 6.72 (1 H , d, J=8.2 Hz), 6.54 (1 H, br s), 4.85 (1 H, m), 4.62 (2 H, m), 3.64 (1 H , m), 3.47 (1 H, m), 3.33 (1 H, dd, J=15.2, 8.6 Hz), 2.89 (1 H, dd, J=15.2, 7.8 Hz), 1 .99 (2H, m). UPLC/MS (5 min) retention time 1 .84 min.
LRMS: m/z 351 (M+1 ).
EXAMPLE 44
W-[3-(3-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide Synthesized from the title compound of PREPARATION 14 and 3-Fluorophenol. Yield: 47%. Purity 99%.
1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 9.18 (s, 1 H), 8.73 (d, J=5.08 Hz, 1 H), 8.17 (s, 1 H), 8.03 (dd, J=5.08, 0.78 Hz, 1 H), 7.15 - 7.24 (m, 1 H), 6.57 - 6.71 (m, 3 H), 6.44 (s, 1 H), 4.59 (s, 2 H), 4.01 (t, J=5.67 Hz, 2 H), 3.52 (q, J=6.25 Hz, 2 H), 1 .98 - 2.08 (m, 2 H)
UPLC/MS (5 min) retention time 1 .94 min.
LRMS: m/z 357 (M+1 ).
EXAMPLE 45 W-[3-(Biphenyl-3-yloxy)propyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 3-Phenylphenol. Yield: 39%. Purity 99%. 1 H N MR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.68 (dd, J=5.47, 1 .95 Hz, 1 H), 8.36 - 8.47 (m, 2 H), 7.94 (d, J=4.30 Hz, 1 H), 7.63 - 7.68 (m, 2 H), 7.42 - 7.49 (m, 2 H), 7.33 - 7.40 (m, 2 H), 7.15 - 7.23 (m, 2 H), 6.93 (d, J=8.21 Hz, 1 H), 4.67 (s, 2 H), 4.08 (t, J=5.67 Hz, 2 H), 3.25 - 3.21 (m, 2H), 1 .88 - 1 .94 (m, 2 H). UPLC/MS (5 min) retention time 2.01 min.
LRMS: m/z 415 (M+1 ).
EXAMPLE 46
W-[3-(3,4-Difluorophenoxy)propyl]-2-(4-oxopyrido[3,4- lpyrimidin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 3,4-Difluorophenol. Yield: 25%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.71 (d, J=5.08 Hz, 1 H), 8.44 (s, 1 H), 8.40 (t, J=5.47 Hz, 1 H), 7.96 - 7.99 (m, 1 H), 7.29 - 7.39 (m, 1 H), 7.01 - 7.09 (m, 1 H), 6.72 - 6.80 (m, 1 H), 4.66 (s, 2 H), 3.99 (t, J=6.25 Hz, 2 H), 3.25 (q, J=6.64 Hz, 2 H), 1 .82 - 1 .90 (m, 2 H).
UPLC/MS (5 min) retention time 2.03 min.
LRMS: m/z 375 (M+1 ).
EXAMPLE 47
2-(4-Oxopyrido[3,4-rflpyrimidin-3(4H)-yl)-yV-[3-(3- phenoxyphenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 14 and 3-Phenoxyphenol. Yield: 19%. Purity 99%. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.69 (d, J=5.47 Hz, 1 H), 8.44 (s, 1 H), 8.37 - 8.42 (m, 1 H), 7.97 (d, J=5.08 Hz, 1 H), 7.37 - 7.42 (m, 2 H), 7.27 (t, J=8.21 Hz, 1 H), 7.12 - 7.17 (m, 1 H), 7.00 - 7.04 (m, 2 H), 6.69 - 6.74 (m, 1 H), 6.51 - 6.58 (m, 2 H), 4.66 (s, 2 H), 3.98 (t, J=6.45 Hz, 2 H), 3.21 - 3.28 (m, 2 H), 1 .83 - 1 .89 (m, 2 H).
UPLC/MS (5 min) retention time 2.62 min. LRMS: m/z 431 (M+1 ).
EXAMPLE 48
W-[3-(3-Chlorophenoxy)propyl]-2-(6-methoxy-4-oxopyrido[3,4-cnpyrimidin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 57 and the title compound of PREPARATION 49. Yield: 62%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (1 H, s), 8.38 (1 H, m), 8.22 (1 H, s), 7.30 (2 H, m), 6.97-7.02 (2 H, m), 6.91 (1 H, m), 4.62 (2 H , s), 4.02 (2 H, t, J=6.7 Hz), 3.96 (3 H, s), 3.26 (2 H, m), 1 .87 (2 H, m).
UPLC/MS (5 min) retention time 2.42 min.
LRMS: m/z 403 (M+1 , 1 *CI).
EXAMPLE 49 W-[3-(3-Methylphenoxy)propyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 14 and m-Cresol. Yield: 42%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.71 (d, J=5.08 Hz, 1 H), 8.44 (s, 1 H), 8.41 (t, J=5.67 Hz, 1 H), 7.98 (dd, J=5.28, 0.98 Hz, 1 H), 7.15 (t, J=8.01 Hz, 1 H), 6.68 - 6.76 (m, 3 H), 4.67 (s, 2 H), 3.97 (t, J=6.45 Hz, 2 H), 3.26 (q, J=6.64 Hz, 2 H), 2.27 (s, 3 H), 1 .81 - 1 .91 (m, 2 H).
UPLC/MS (5 min) retention time 2.09 min.
LRMS: m/z 353 (M+1 ).
EXAMPLE 50
W-[3-(3-Methoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide Synthesized from the title compound of PREPARATION 14 and 3-Methoxyphenol. Yield: 65%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.71 (d, J=5.08 Hz, 1 H), 8.44 (s, 1 H), 8.41 (t, J=5.67 Hz, 1 H), 7.98 (dd, J=5.08, 0.78 Hz, 1 H), 7.17 (t, J=8.21 Hz, 1 H), 6.46 - 6.53 (m, 3 H), 4.67 (s, 2 H), 3.98 (t, J=6.25 Hz, 2 H), 3.72 (s, 3 H), 3.26 (q, J=6.64 Hz, 2 H), 1 .81 - 1 .92 (m, 2 H).
UPLC/MS (5 min) retention time 1 .79 min.
LRMS: m/z 369 (M+1 ).
EXAMPLE 51
2-(4-Oxopyrido[3,4-rflpyrimidin-3(4H)-yl)-yV-{3-[3- (trifluoromethoxy)phenoxy]propyl}acetamide
Synthesized from the title compound of PREPARATION 14 and 3-(Trifluoromethoxy)- phenol. Yield: 38%. Purity 100%. 1 H NMR (600 MHz, DMSO-d6) δ ppm 9.1 1 (s, 1 H), 8.71 (d, J=5.28 Hz, 1 H), 8.42 - 8.46 (m, 2 H), 7.97 - 7.99 (m, 1 H), 7.41 (t, J=8.22 Hz, 1 H), 6.99 (dd, J=7.63, 2.35 Hz, 1 H), 6.90 - 6.94 (m, 2 H), 4.67 (s, 2 H), 4.04 (t, J=6.16 Hz, 2 H), 3.27 (q, J=6.46 Hz, 2 H), 1 .85 - 1 .91 (m, 2 H).
UPLC/MS (5 min) retention time 2.39 min. LRMS: m/z 423 (M+1 ).
EXAMPLE 52
W-[3-(4-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,4-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 4-Chlorophenol. Yield: 43%. Purity 100%.
1 H NMR (600 MHz, DMSO-d6) δ 9.07 (d, J = 0.7 Hz, 1 H), 8.68 (d, J = 5.2 Hz, 1 H), 8.41 (s, 1 H), 8.40 (t, J = 5.7 Hz, 1 H), 7.95 (dd, J = 5.2, 0.8 Hz, 1 H), 7.33 - 7.26 (m, 2H), 6.94 - 6.88 (m, 2H), 4.63 (s, 2H), 3.96 (t, J = 6.3 Hz, 2H), 3.22 (q, J = 6.6 Hz, 3H), 1 .84 (pent, J = 6.5 Hz, 2H). UPLC/MS (5 min) retention time 2.1 1 min. LRMS: m/z 373 (M+1 , 1 CI).
EXAMPLE 53 W-[3-(3-Chlorophenoxy)propyl]-2-(8-methoxy-4-oxopyrido[3,4-cnpyrimidin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 58 and the title compound of PREPARATION 49. Yield: 68%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (2 H, m), 8.19 (1 H, d, J=5.5 Hz), 7.52 (1 H, d, J=5.5 Hz), 7.31 (1 H, t, J=7.8 Hz), 6.97-7.02 (2 H, m), 6.91 (1 H, m), 4.66 (2 H, s), 4.02 (5 H, m), 3.26 (2 H, m), 1.88 (2 H, m).
UPLC/MS (5 min) retention time 2.33 min.
LRMS: m/z 403 (M+1 ), 1 *CI).
EXAMPLE 54
W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxothieno[2,3-<^pyrimidin-3(4H)-yl)acetamide
Synthesized from thieno[2,3-c/]pyrimidin-4(3H)-one and the title compound of PREPARATION 49. Yield: 75%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ 8.37 (t, J = 5.7 Hz, 1 H), 8.33 (s, 1 H), 7.60 (d, J = 5.8 Hz, 1 H), 7.38 (d, J = 5.8 Hz, 1 H), 7.28 (t, J = 8.1 Hz, 1 H), 7.01 - 6.94 (m, 2H), 6.92 - 6.85 (m, 1 H), 4.63 (s, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.24 (q, J = 6.6 Hz, 2H), 1 .85 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.50 min. LRMS: m/z 378 (M+1 , 1 CI).
EXAMPLE 55
W-[3-(3-Chlorophenoxy)propyl]-2-(4-oxothieno[3,2-<^pyrimidin-3(4H)-yl)acetamide Synthesized from Thieno[3,2-c/]pyrimidin-4(3H)-one and the title compound of PREPARATION 49. Yield: 70%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ 8.43 (t, J = 5.5 Hz, 1 H), 8.39 (s, 1 H), 8.25 (d, J = 5.2 Hz, 1 H), 7.46 (d, J = 5.2 Hz, 1 H), 7.34 (t, J = 8.1 Hz, 1 H), 7.06 - 7.00 (m, 2H), 6.95 (dd, J = 8.0, 1 .9 Hz, 1 H), 4.71 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.30 (q, J = 6.7 Hz, 2H), 1.91 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.43 min.
LRMS: m/z 378 (M+1 , 1 *CI).
EXAMPLE 56
A/-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl -4-oxo-1 ,4-dihydro-5H-pyrazolo[3, 4- d]pyrimidin-5-yl)acetamide
Synthesized from 1 -Methyl-1 H-pyrazolo[3,4-c/]pyrimidin-4(5H)-one and the title compound of PREPARATION 49. Yield: 71 %. Purity 100%. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.6 Hz, 1 H), 8.35 (s, 1 H), 8.1 1 (s, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.07 - 7.00 (m, 2H), 6.95 (dd, J = 8.1 , 1 .8 Hz, 1 H), 4.66 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.96 (s, 3H), 3.28 (q, J = 6.5 Hz, 2H), 1 .90 (pent, J = 6.4 Hz, 2H).
UPLC/MS (5 min) retention time 2.27 min. LRMS: m/z 376 (M+1 , 1 xCI).
EXAMPLE 57 yV-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- d]pyrimidin-6-yl)acetamide Synthesized from the title compound of PREPARATION 62 and the title compound of PREPARATION 49. Yield: 51 %. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.7 Hz, 1 H), 8.1 1 (s, 1 H), 8.03 (s, 1 H), 7.38 - 7.29 (m, 1 H), 7.06 - 6.99 (m, 2H), 6.95 (ddd, J = 8.4, 2.3, 1 .0 Hz, 1 H), 4.68 (s, 2H), 4.22 (s, 3H), 4.06 (t, J = 6.3 Hz, 2H), 3.34 - 3.25 (m, 2H), 1.91 (pent, J = 6.6 Hz, 2H).
UPLC/MS (5 min) retention time 2.23 min. LRMS: m/z376 (M+1, 1*CI).
EXAMPLE 58 yV-[3-(3-Chlorophenoxy)propyl]-2-(4-oxoimidazo[5,1-][1,2,4]triazin-3(4H)- yl)acetamide
Synthesized from lmidazo[5,1-/][1 ,2,4]triazin-4(3/-/)-one and the title compound of PREPARATION 49. Yield: 59%. Purity 100%.
1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 0.8 Hz, 1H), 8.40 (t, J = 5.5 Hz, 1H), 8.15 (s, 1H), 7.86 (d, J = 0.8 Hz, 1H), 7.34 (t, J = 8.2 Hz, 1H), 7.02 (dd, J = 7.6, 1.1 Hz, 2H), 6.98 - 6.90 (m, 1H), 4.55 (s, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.29 (q, J = 6.6 Hz, 2H), 1.90 (pent, J = 6.6 Hz, 2H). UPLC/MS (5 min) retention time 2.14 min.
LRMS: m/z362 (M+1, 1*CI).
EXAMPLE 59
A/-[3-(4-Fluorophenoxy)propyl]-2-(1-methyl-7-oxo-1,7-dihydro-6W-pyrazolo[4,3- d]pyrimidin-6-yl)acetamide
Synthesized from the title compound of PREPARATION 62 and the title compound of PREPARATION 40. Yield: 60%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.6 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.18 - 7.10 (m, 2H), 7.01 - 6.94 (m, 2H), 4.68 (s, 2H), 4.22 (s, 3H), 4.01 (t, J = 6.3 Hz, 2H), 3.29 (q, J = 6.7 Hz, 2H), 1.90 (pent, J = 6.5 Hz, 2H).
UPLC/MS (5 min) retention time 1.92 min.
LRMS: m/z360 (M+1). EXAMPLE 60 yV-[3-(3-Chloro-4-fluorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6H- pyrazolo[4,3-d]pyrimidin-6-yl)acetamide
Synthesized from the title compound of PREPARATION 62 and the title compound of PREPARATION 37. Yield: 47%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.5 Hz, 1 H), 8.1 1 (s, 1 H), 8.03 (s, 1 H), 7.36 (t, J = 9.1 Hz, 1 H), 7.19 (dd, J = 6.1 , 3.1 Hz, 1 H), 7.06 - 6.88 (m, 1 H), 4.67 (s, 2H), 4.22 (s, 3H), 4.05 (t, J = 6.3 Hz, 2H), 3.29 (q, J = 6.6 Hz, 2H), 1 .90 (pent, J = 6.6 Hz, 2H). UPLC/MS (5 min) retention time 2.28 min. LRMS: m/z 394 (M+1 , 1 *CI).
EXAMPLE 61
W-[3-(3-Chlorophenoxy)propyl]-2-(1 ,3-dimethyl-7-oxo-1 ,7-dihydro-6H- pyrazolo[4,3-d]pyrimidin-6-yl)acetamide
Synthesized from the title compound of PREPARATION 5 and the title compound of PREPARATION 49. Yield: 53%. Purity 98%.
1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 5.4 Hz, 1 H), 8.08 (s, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.06 - 6.99 (m, 2H), 6.95 (dd, J = 8.2, 1 .6 Hz, 1 H), 4.67 (s, 2H), 4.14 (s, 3H), 4.06 (t, J = 6.3 Hz, 2H), 3.29 (q, J = 6.5 Hz, 2H), 2.40 (s, 3H), 1.95 - 1 .86 (m, 2H).
UPLC/MS (5 min) retention time 2.33 min.
LRMS: m/z 390 (M+1 , 1 *CI).
EXAMPLE 62 W-[3-(3-Chlorophenoxy)butyl]-2-(1 ,3-dimethyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3- d]pyrimidin-6-yl)acetamide
Synthesized from the title compound of PREPARATION 5 and the title compound of PREPARATION 4. Yield: 58%. Purity 99%. 1 H N MR (400 MHz, DMSO-d6) δ 8.37 (t, J = 5.4 Hz, 1 H), 8.07 (s, 1 H), 7.32 (t, J = 8.1 Hz, 1 H), 7.04 - 6.97 (m, 2H), 6.94 (dd, J = 8.0, 2.0 Hz, 1 H), 4.66 (s, 2H), 4.63 - 4.54 (m, 1 H), 4.15 (s, 3H), 3.31 - 3.15 (m, 2H), 2.40 (s, 3H), 1 .86 (dt, J = 13.6, 6.8 Hz, 1 H), 1 .81 - 1 .67 (m, 1 H), 1 .27 (d, J = 6.0 Hz, 3H). UPLC/MS (5 min) retention time 2.46 min.
LRMS: m/z 404 (M+1 , 1 *CI).
Preparative chiral HPLC of the title compound of EXAMPLE 63 (Daicel Chiralpak IC, 5μηι (30x250 mm) column, eluting with ethanol-heptane (20:80)+0.2% diethylamine, flow rate 20 ml/min, run time 30 min) separated both enantiomers. Enantiomer 1 is the first-eluted compound.
Enantiomer 1 /V-[3-(3-Chlorophenoxy)butyl]-2-(1 ,3-dimethyl-7-oxo-1 ,7-dihydro-6H- pyrazolo[4,3-d]pyrimidin-6-yl)acetamide
Purity 99%. Enantiomeric excess >99%
Enantiomer 2 W-[3-(3-Chlorophenoxy)butyl]-2-(1 ,3-dimethyl-7-oxo-1 ,7-dihydro-6H- pyrazolo[4,3-d]pyrimidin-6-yl)acetamide
Purity 99%. Enantiomeric excess 96.5%
EXAMPLE 63 yV-[3-(3-Chlorophenoxy)propyl]-2-(1 -ethyl-3-methyl-7-oxo-1 ,7-dihydro-6H- pyrazolo[4,3-d]pyrimidin-6-yl)acetamide
Synthesized from the title compound of PREPARATION 61 and the title compound of PREPARATION 49. Yield: 57%. Purity 99%. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (1 H, m), 8.05 (1 H , s), 7.30 (1 H , m), 6.97- 7.02 (2 H, m), 6.90 (1 H , dd, J=8.2, 1 .8 Hz), 4.63 (2 H, s), 4.48 (2 H, q, J=7.0 Hz), 4.02 (2 H, t, J=6.5 Hz), 3.24 (2 H, m), 2.37 (3 H, s), 1 .87 (2 H, m), 1 .34 (3 H , t, J=7.0 Hz).
UPLC/MS (5 min) retention time 2.57 min. LRMS: m/z 404 (M+1 , 1 *CI).
EXAMPLE 64
2-(3-Bromo-1 -methyl-7-oxo-1 ,7-dihydro-6H^yrazolo[4,3-cnpyrimidin-6-yl)-yV-[3-(3- chlorophenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 63 and the title compound of PREPARATION 49. Yield: 77%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (1 H, m), 8.17 (1 H, s), 7.30 (1 H, m), 6.97- 7.02 (2 H, m), 6.91 (1 H, m), 4.65 (2 H, s), 4.16 (3 H, s), 4.02 (2 H, t, J=6.3 Hz), 3.26 (2 H, m), 1.87 (2 H, m).
UPLC/MS (5 min) retention time 2.55 min.
LRMS: m/z 454 (M+1 , 1 *CI, 1 *Br).
EXAMPLE 65 /V-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6H- [1 ,2,3]triazolo[4,5-d]pyrimidin-6-yl)acetamide
Synthesized from the title compound of PREPARATION 67 and the title compound of PREPARATION 49. Yield: 48%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (1 H, m), 8.34 (1 H, s), 7.30 (1 H, m), 6.97- 7.02 (2 H, m), 6.91 (1 H, m), 4.68 (2 H, s), 4.35 (3 H, s), 4.02 (2 H, t, J=6.3 Hz), 3.26 (2 H, m), 1.87 (2 H, m).
UPLC/MS (5 min) retention time 2.16 min. LRMS: m/z 377 (M+1 , 1 *CI).
EXAMPLE 66
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H- pyrazolo[3,4-d]pyrimidin-5-yl)acetamide Synthesized from the title compound of PREPARATION 64 and the title compound of PREPARATION 49. Yield: 77%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (1 H, m), 8.24 (1 H, s), 7.30 (1 H, m), 6.97- 7.02 (2 H, m), 6.90 (1 H, m), 4.58 (2 H, s), 4.02 (2 H, t, J=6.3 Hz), 3.82 (3H, s), 3.24 (2 H, m), 2.40 (3 H, s), 1 .86 (2 H, m).
UPLC/MS (5 min) retention time 2.30 min.
LRMS: m/z 390 (M+1 , 1 *CI).
EXAMPLE 67 W-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 - ][1 ,2,4]triazin- 3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 65 and the title compound of PREPARATION 49. Yield: 56%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (2 H, m), 7.99 (1 H, s), 7.30 (1 H, m), 6.97- 7.02 (2 H, m), 6.90 (1 H, m), 4.46 (2 H, s), 4.01 (2 H, t, J=6.3 Hz), 3.25 (2 H, m), 2.46 (3 H, s), 1 .86 (2 H, m).
UPLC/MS (5 min) retention time 2.23 min.
LRMS: m/z 376 (M+1 , 1 xCI).
EXAMPLE 68
2-(7-Bromo-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)-yV-[3-(3- chlorophenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 66 and the title compound of PREPARATION 49. Yield: 65%. Purity 99%. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (1 H, s), 8.09 (1 H, s), 7.27 (1 H, m), 6.82- 7.01 (3 H, m), 4.44 (2 H, s), 3.98 (2 H, t, J=6.3 Hz), 3.22 (2 H, m), 2.44 (3 H, s), 1 .84 (2 H, m).
UPLC/MS (5 min) retention time 2.53 min. LRMS: m/z 454 (M+1 , 1 xCI, 1 xBr).
EXAMPLE 69 yV-[3-(3-Chlorophenoxy)propyl]-2-(5,7-dimethyl-4-oxoimidazo[5,1 -f|[1 ,2,4]triazin- 3(4H)-yl)acetamide
Synthesized from the title compound of EXAMPLE 68 and 2,4, 6-trimethyl-1 ,3,5,2,4,6- trioxatriborinane. Yield: 40%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (1 H, m), 7.95 (1 H , s), 7.29 (1 H , m), 6.96- 7.00 (2 H, m), 6.90 (1 H, m), 4.44 (2 H, s), 4.00 (2 H, t, J=6.3 Hz), 3.23 (2 H, m), 2.45 (3 H, s), 2.41 (3 H, s), 1 .85 (2 H, m).
UPLC/MS (5 min) retention time 2.24 min.
LRMS: m/z 390 (M+1 , 1 *CI).
EXAMPLE 70 /V-[3-(3-Chlorophenoxy)propyl]-2-(6,8-dimethyl-4-oxoimidazo[1 ,5-a][1 ,3,5]triazin- 3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 68 and the title compound of PREPARATION 49. Yield: 21 %. Purity 97%.
1 H N MR (400 MHz, DMSO-d6) δ ppm 8.35 (1 H , s), 7.63 (1 H , s), 7.30 (1 H , m), 6.91 - 7.02 (3 H, m), 4.46 (2 H, s), 4.01 (2 H, m), 3.26 (2 H, m), 2.64 (3 H, s), 2.20 (3 H, s), 1 .86 (2 H, m).
UPLC/MS (5 min) retention time 2.16 min. LRMS: m/z 390 (M+1 , 1 *CI).
EXAMPLE 71
W-[3-(3-Chlorophenoxy)propyl]-2-(4,8-dioxo-7,8-dihydropyrido[3,4-rflpyrimidin- 3(4H)-yl)acetamide A mixture of the title compound of EXAMPLE 53 (40 mg, 0.10 mmol), chloro(trimethyl)silane (0.038 ml_, 0.30 mmol) and sodium iodide (45 mg, 0.30 mmol) in acetonitrile (1 .0 mL) was stirred and heated to 65 °C in a sealed tube. After 2 h, the solvent was removed under reduced pressure and the residue was treated with saturated aqueous sodium thiosulphate solution. After stirring at ambient temperature for 30 minutes, the precipitate obtained was filtered, washed with water and diethyl ether and dried in vacuo to give the title compound (18 mg, 47% yield) as an off white solid. Purity 99%.
1 H N MR (400 MHz, DMSO-d6) δ ppm 1 1 .99 (1 H, br s), 8.23 -8.52 (2 H, m), 7.24-7.44 (2 H, m), 6.54-7.09 (3 H, m), 4.42 (2 H, s), 4.02 (2 H, m), 3.26 (2 H, m), 1 .87 (2 H, m).
UPLC/MS (5 min) retention time 1 .89 min.
LRMS: m/z 389 (M+1 , 1 *CI).
EXAMPLE 72 W-[3-(3-Chlorophenoxy)propyl]-2-(4,6-dioxo-6 -dihydropyrido[3,4-<^pyrimidin- 3(4H)-yl)acetamide
Synthesized from the title compound of EXAMPLE 48. Yield: 46%. Purity 100%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (1 H, s), 8.39 (1 H, m), 8.06 (1 H, s), 7.30 (1 H, m), 6.97-7.02 (2 H, m), 6.91 (1 H, m), 4.57 (2 H , s), 4.01 (2 H, t, J=6.7 Hz), 3.24 (2 H, m), 1 .86 (2 H, m).
UPLC/MS (3 min) retention time 2.07 min.
LRMS: m/z 390 (M+1 , 1 *CI).
EXAMPLE 73 N-[3-(3-Chlorophenoxy)propyl]-2-(4-fluoro-1 -oxo-2,6-naphthyridin-2(1 H)- yl)acetamide
Synthesized from the title compound of PREPARATION 69 and the title compound of PREPARATION 49. Yield: 64%. Purity 92%. 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1 H), 8.86 (d, J = 5.3 Hz, 1 H), 8.31 (t, J = 5.5 Hz, 1 H), 8.10 (d, J = 4.3 Hz, 1 H), 7.90 (d, J = 6.8 Hz, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.07 - 6.98 (m, 2H), 6.95 (dd, J = 8.3, 1 .5 Hz, 1 H), 4.62 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.29 (dd, J = 12.4, 6.5 Hz, 2H), 1 .96 - 1 .85 (m, 2H). UPLC/MS (3 min) retention time 2.32 min.
LRMS: m/z 390 (M+1 , 1 *CI).
EXAMPLE 74
N-[3-(4-Methoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 4-Methoxyphenol. Yield: 45%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.71 (d, J=5.47 Hz, 1 H), 8.44 (s, 1 H), 8.40 (t, J=5.67 Hz, 1 H), 7.98 (dd, J=5.47, 0.78 Hz, 1 H), 6.82 - 6.88 (m, 3 H), 5.76 (s, 1 H), 4.67 (s, 2 H), 3.93 (t, J=6.25 Hz, 2 H), 3.69 (s, 3 H), 3.21 - 3.28 (m, 2 H), 1 .78 - 1 .90 (m, 2 H).
UPLC/MS (3 min) retention time 1 .71 min.
LRMS: m/z 369 (M+1 ).
EXAMPLE 75
N-[3-(3-Chlorophenoxy)butyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 65 and the title compound of PREPARATION 4. Yield: 43%. Purity 98%. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.27 - 8.36 (m, 2 H), 7.99 (s, 1 H), 7.28 (t, J=8.21 Hz, 1 H), 6.94 - 7.00 (m, 2 H), 6.87 - 6.92 (m, 1 H), 4.49 - 4.58 (m, 1 H), 4.46 (s, 2 H), 3.14 - 3.27 (m, 2 H), 2.47 (s, 3 H), 1 .77 - 1 .87 (m, 1 H), 1 .66 - 1 .75 (m, 1 H), 1 .23 (d, J=5.86 Hz, 3 H).
UPLC/MS (3 min) retention time 2.34 min. LRMS: m/z 390 (M+1 , 1 CI).
EXAMPLE 76
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxoquinazolin-3(4H)-yl)acetamide Synthesized from 5-Methylquinazolin-4(3H)-one and the title compound of PREPARATION 49. Yield: 89%. Purity 100%.
1H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (m, 1 H), 8.22 (s, 1 H), 7.65 (m, 1 H), 7.50 (d, 1 H, J = 7.8 Hz), 7.29 (m, 2H), 6.97-7.02 (m, 2H), 6.91 (m, 1 H), 4.56 (s, 2H), 4.03 (t, 2H, J = 6.3 Hz), 3.27 (m, 2H), 2.75 (s, 3H), 1 .88 (m, 2H). UPLC/MS (5 min) retention time 2.89 min.
LRMS: m/z 386 (M+1 , 1 *CI).
EXAMPLE 77
2-(4-Bromo-1 -oxo-2,6-naphthyridin-2(1 H)-yl)-N-[3-(3- chlorophenoxy)propyl]acetamide
Synthesized from the crude title compound of PREPARATION 70 and the title compound of PREPARATION 49. Yield: 38% over two steps. Purity 98%.
1H NMR (400 MHz, D20) δ ppm 9.16 (s, 1 H), 8.84 (d, J = 5.2 Hz, 1 H), 8.34 (t, J = 5.2 Hz, 1 H), 8.09 (d, J = 5.3 Hz, 1 H), 8.05 (s, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.02 (d, J = 7.7 Hz, 2H), 6.95 (d, J = 7.9 Hz, 1 H), 4.67 (s, 2H), 4.06 (t, J = 6.2 Hz, 2H), 3.29 (dd, J = 12.2, 6.3 Hz, 2H), 1.95 - 1 .85 (m, 2H).
UPLC/MS (3 min) retention time 2.53 min.
LRMS: m/z 450 (M+3, 1 *CI, 1 *Br).
EXAMPLE 78
N-[3-(3-Chlorophenoxy)propyl]-2-(7-methyl-6-oxo-6,7-dihydro-1 H-purin-1 - yl)acetamide Synthesized from the title compound of PREPARATION 71 and the title compound of PREPARATION 49. Yield: 76%. Purity 97%.
1H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (m, 1 H), 8.20 (s, 1 H), 8.19 (s, 1 H), 7.30 (m, 1 H), 6.97-7.01 (m, 2H), 6.89-6.93 (m, 1 H), 4.63 (s, 2H), 4.02 (t, 2H, J = 6.3 Hz), 3.95 (s, 3H), 3.25 (m, 2H), 1 .87 (m, 2H).
UPLC/MS (3 min) retention time 1 .42 min.
LRMS: m/z 376 (M+1 , 1 *CI).
EXAMPLE 79 N-[3-(3-Chlorophenoxy)propyl]-2-(5,8-dibromo-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide
Synthesized from the crude title compound of PREPARATION 72 and the title compound of PREPARATION 49. Yield: 3% over two steps. Purity 100%.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 8.24 (s, 1 H), 8.19 (s, 1 H), 7.20 (m, 1 H), 6.96 (m, 1 H), 6.91 (m, 1 H), 6.78 (m, 1 H), 6.35 (m, 1 H), 4.58 (s, 2H), 4.03 (t, 2H, J = 6.3 Hz), 3.53 (m, 2H), 2.04 (m, 2H).
UPLC/MS (5 min) retention time 3.17 min.
LRMS: m/z 529 (M+3, 1 *CI, 2*Br).
EXAMPLE 80
N-[3-(3-Chlorophenoxy)propyl]-2-(7-ethyl-5-methyl-4-oxoimidazo[5,1 - f][1 ,2,4]triazin-3(4H)-yl)acetamide
The title compound of EXAMPLE 68 (50 mg, 0.1 1 mmol), potassium ethyltrifluoroborate (23 mg, 0.17 mmol), palladium(ll) acetate (2.5 mg, 0.01 mmol) and cesium carbonate (108 mg, 0.33 mmol) were suspended in a mixture of toluene (2 mL) and water (0.2 mL) in a Shlenck tube. The mixture was submitted to three vacuum-argon cycles. Di(1 - adamantyl)-n-butylphosphine (6 mg, 0.02 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 organic layer was washed with brine, dried over anhydrous sodium sulphat, filtered and evaporated to give a solid. Purification using the Isolera (methanol-dichloromethane gradient, 0: 100 rising to 3:97) gave 22 mg /0.054 mmol, 50% yield) of the title compound as a white solid. Purity 100%.
1 H N MR (300 MHz, DMSOd) δ ppm 8.32 (m, 1 H), 7.96 (s, 1 H), 7.30 (m, 1 H), 6.97-7.01 (m, 2H), 6.88-6.93 (m, 1 H), 4.45 (s, 2H), 4.01 (t, 2H, J = 6.3 Hz), 3.24 (q, 2H, J = 6.6 Hz), 2.86 (q, 2H , J = 7.4 Hz), 2.43 (s, 3H), 1 .86 (m, 2H), 1 .25 (t, 3H , J = 7.8 Hz).
UPLC/MS (3 min) retention time 1 .58 min. LRMS: m/z 404 (M+1 , 1 *CI).
EXAMPLE 81
N-[3-(3-Chlorophenoxy)propyl]-2-(5,8-dimethyl-4-oxopyrido[3,4-d]pyrimidin- 3(4H)-yl)acetamide Synthesized from the title compound of EXAMPLE 79 and 2,4, 6-trimethyl-1 , 3,5,2,4, 6- trioxatriborinane. Yield: 86%. Purity 97%.
1 H NMR (300 MHz, DMSO-d6) δ ppm 8.40 (s, 1 H), 8.34 (s, 1 H), 7.65 (s, 1 H), 6.89-7.34 (m, 4H), 4.63 (s, 2H), 4.01 (t, 2H , J = 6.3 Hz), 3.25 (m, 2H), 2.73 (s, 3H), 2.56 (s, 3H), 1 .86 (m, 2H). UPLC/MS (5 min) retention time 2.49 min.
LRMS: m/z 401 (M+1 , 1 *CI).
EXAMPLE 82
2-(3-Ethyl-1 -methyl-7-oxo-1 -dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)-N-[3-(3- ethylphenoxy)propyl]acetamide
Synthesized from the title compound of EXAMPLE 64 and potassium ethyltrifluoroborate. Yield: 50%. Purity 97%.
1 H N MR (300 MHz, DMSO-d6) δ ppm 8.36 (t, 1 H, J = 5.5 Hz), 8.04 (s, 1 H), 7.18 (m, 1 H), 6.72-6.80 (m, 3H), 4.64 (s, 2H), 4.12 (s, 3H), 3.99 (t, 2H , J = 6.3 Hz), 3.26 (q, 2H, J = 6.6 Hz), 2.81 (q, 2H, J = 7.8 Hz), 2.57 (q, 2H, J = 7.4 Hz), 1 .84-1 .91 (m, 2H), 1.28 (t, 3H, J = 7.4 Hz), 1 .17 (t, 3H, J = 7.8 Hz).
UPLC/MS (3 min) retention time 1 .71 min.
LRMS: m/z 398 (M+1 ).
EXAMPLE 83
N-[3-(1 -Naphthyloxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 1 -Naphthol. Yield: 50%. Purity 99%. Ή NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.71 (d, J=5.08 Hz, 1 H), 8.47 - 8.54 (m, 1 H), 8.45 (s, 1 H), 8.15 - 8.20 (m, 1 H), 7.99 (d, J=5.08 Hz, 1 H), 7.84 - 7.88 (m, 1 H), 7.47 - 7.55 (m, 2 H), 7.39 - 7.47 (m, 2 H), 6.96 (d, J=7.42 Hz, 1 H), 4.69 (s, 2 H), 4.20 (t, J=6.25 Hz, 2 H), 3.39 (t, J=6.84 Hz, 2 H), 1 .99 - 2.08 (m, 2 H).
UPLC/MS (3 min) retention time 2.41 min. LRMS: m/z 389 (M+1 ).
EXAMPLE 84
N-[3-(4-Bromophenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 4-Bromophenol. Yield: 45%. Purity 99%.
Ή NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.71 (d, J=5.47 Hz, 1 H), 8.44 (s, 1 H), 8.36 - 8.43 (m, 1 H), 7.98 (d, J=5.08 Hz, 1 H), 7.41 - 7.47 (m, 2 H), 6.87 - 6.94 (m, 2 H), 4.67 (s, 2 H), 3.99 (t, J=6.25 Hz, 2 H), 3.26 (t, J=6.64 Hz, 2 H), 1.83 - 1.91 (m, 2 H).
UPLC/MS (3 min) retention time 2.28 min. LRMS: m/z 417 (M+1 , 1 xBr).
EXAMPLE 85 N-[3-(2-Naphthyloxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 2-Naphthol. Yield: 43%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.70 (d, J=5.08 Hz, 1 H), 8.45 (s, 2 H), 7.98 (d, J=5.47 Hz, 1 H), 7.77 - 7.84 (m, 3 H), 7.43 - 7.48 (m, 1 H), 7.31 - 7.38 (t, J=7.42 Hz, 1 H), 7.30 (d, J=2.34 Hz, 1 H), 7.16 (dd, J=8.99, 2.34 Hz, 1 H), 4.68 (AB quartet, J = 20 Hz, 2 H), 4.13 (t, J=6.25 Hz, 2 H), 3.30 - 3.35 (m, 2H), 1 .91 - 2.00 (m, 2 H).
UPLC/MS (3 min) retention time 2.36 min. LRMS: m/z 389 (M+1 ).
EXAMPLE 86
2-(4-Oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-N-[3-(3,4,5- trifluorophenoxy)propyl]acetamide Synthesized from the title compound of PREPARATION 14 and 3,4,5-Trifluorophenol. Yield: 29%. Purity 99%.
1 H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.71 (d, J=5.08 Hz, 1 H), 8.44 (s, 1 H), 8.39 (t, J=5.28 Hz, 1 H), 7.97 (d, J=5.08 Hz, 1 H), 6.95 (dd, J=10.16, 5.86 Hz, 2 H), 4.66 (s, 2 H), 4.01 (t, J=6.25 Hz, 2 H), 3.21 - 3.28 (m, 2 H), 1 .82 - 1 .91 (m, 2 H). UPLC/MS (3 min) retention time 2.24 min.
LRMS: m/z 393 (M+1 ).
EXAMPLE 87
N-[3-(3-Ethoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 14 and 3-Ethoxyphenol. Yield: 17%. Purity 99%. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.71 (d, J=5.08 Hz, 1 H), 8.44 (s, 1 H), 8.36 - 8.42 (m, 1 H), 7.98 (d, J=5.08 Hz, 1 H), 7.15 (t, J=8.21 Hz, 1 H), 6.43 - 6.52 (m, 3 H), 4.67 (s, 2 H), 3.94 - 4.02 (m, 4 H), 3.20 - 3.28 (m, 2 H), 1 .80 - 1.91 (m, 2 H), 1 .30 (t, J=7.03 Hz, 3 H). UPLC/MS (3 min) retention time 2.12 min.
LRMS: m/z 383 (M+1 ).
EXAMPLE 88
2-(5-Methyl-4-oxoimidazo[5,1 - [1 ,2,4]triazin-3(4H)-yl)-N-[3-(3,4,5- trifluorophenoxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 75 and 3,4,5-Trifluorophenol. Yield: 50%. Purity 96%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 - 8.35 (m, 2 H), 7.99 (s, 1 H), 6.91 - 6.99 (m, 2 H), 4.46 (s, 2 H), 4.00 (t, J=6.45 Hz, 2 H), 3.24 (q, J=6.64 Hz, 2 H), 2.46 (s, 3 H), 1.81 - 1 .89 (m, 2 H).
UPLC/MS (3 min) retention time 2.26 min.
LRMS: m/z 396 (M+1 ).
EXAMPLE 89 N-[3-(3,4-Difluorophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 75 and 3,4-Difluorophenol. Yield: 25%. Purity 98%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 - 8.34 (m, 2 H), 7.98 (s, 1 H), 7.27 - 7.36 (m, 1 H), 6.99 - 7.06 (m, 1 H), 6.71 - 6.77 (m, 1 H), 4.44 (s, 2 H), 3.97 (t, J=6.25 Hz, 2 H), 3.22 (q, J=6.64 Hz, 2 H), 2.44 (s, 3 H), 1 .79 - 1 .88 (m, 2 H).
UPLC/MS (3 min) retention time 2.07 min.
LRMS: m/z 378 (M+1 ). EXAMPLE 90
N-[3-(3-Chlorophenoxy)propyl]-2-(5-ethyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide Synthesized from the title compound of EXAMPLE 36 and potassium ethyltrifluoroborate. Yield: 13%. Purity 94%.
1H NMR (300 MHz, METHANOL-d4) δ ppm 8.88 (s, 1 H), 8.40 (s, 1 H), 8.12 (s, 1 H), 7.52 (m, 1 H), 7.12 (m, 1 H), 6.84-6.90 (m, 2H), 6.72-6.75 (m, 1 H), 4.52 (s, 2H), 3.96 (t, 2H, J = 6.3 Hz), 3.41 (q, 2H, J = 6.3 Hz), 3.19 (q, 2H, J = 7.4 Hz), 1 .94-2.00 (m, 2H), 1 .21 (t, 3H, J = 7.4 Hz).
UPLC/MS (3 min) retention time 1 .68 min.
LRMS: m/z 401 (M+1 , 1 *CI).
EXAMPLE 91 N-[3-(3-Chlorophenoxy)propyl]-2-(3-ethyl-1 -methyl-7-oxo-1 ,7-dihydro-6H- pyrazolo[4,3-d]pyrimidin-6-yl)acetamide
Synthesized from the title compound of EXAMPLE 64 and potassium ethyl trifluoroborate. Yield: 36%. Purity 93%.
1H NMR (300 MHz, DMSO-D6) δ ppm 8.35 (m, 1 H), 8.03 (s, 1 H), 7.30 (m, 1 H), 6.97- 7.00 (m, 2H), 6.91 (m, 1 H), 4.63 (s, 2H), 4.1 1 (s, 3H), 4.02 (t, 2H, J = 6.3 Hz), 3.26 (m, 2H), 2.81 (q, 2H, J = 7.4 Hz), 1 .87 (m, 2H), 1.27 (t, 3H, J = 7.4 Hz).
UPLC/MS (5 min) retention time 2.69 min.
LRMS: m/z 404 (M+1 , 1 *CI).
EXAMPLE 92
N-[3-(3-Cyanophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetamide Synthesized from the title compound of PREPARATION 74 and the title compound of PREPARATION 22. Yield: 31 %. Purity 99%.
1 H N MR (400 MHz, DMSO-d6) δ 8.38 (t, J = 8.0 Hz, 1 H), 8.37 (s, 1 H), 8.03 (s, 1 H), 7.52 (t, J = 8.1 Hz, 1 H), 7.47 - 7.39 (m, 2H), 7.35 - 7.28 (m, 1 H), 4.50 (s, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.30 (q, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1 .92 (pent, J = 6.3 Hz, 2H).
UPLC/MS (3 min) retention time 1 .74 min.
LRMS: m/z 367 (M+1 ).
EXAMPLE 93 N-{3-[(5-Chloropyridin-3-yl)oxy]propyl}-2-(5-methyl-4-oxoimidazo[5,1 - f][1 ,2,4]triazin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 74 and the title compound of PREPARATION 28. Yield: 38%. Purity 95%.
1 H NMR (400 MHz, DMSO-d6) δ 8.39 (t, J = 5.3 Hz, 1 H), 8.37 (s, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 8.25 (d, J = 2.0 Hz, 1 H), 8.03 (s, 1 H), 7.61 (t, J = 2.3 Hz, 1 H), 4.50 (s, 2H), 4.15 (t, J = 6.2 Hz, 2H), 3.30 (q, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1 .92 (pent, J = 6.5 Hz, 2H).
UPLC/MS (3 min) retention time 1 .63 min.
LRMS: m/z 377 (M+1 , 1 xCI).
EXAMPLE 94
N-[3-(3-Chlorophenoxy)propyl]-2-(3-methyl-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 76 and the title compound of PREPARATION 49. Yield: 36%. Purity 94%.
1 H N MR (400 MHz, DMSO-d6) δ ppm 8.58 (s, 1 H), 8.39 (t, J=5.67 Hz, 1 H), 7.28 (t, J=8.21 Hz, 1 H), 6.94 - 7.02 (m, 2 H), 6.86 - 6.91 (m, 1 H), 4.64 (s, 2 H), 4.00 (t, J=6.25 Hz, 2 H), 3.24 (q, J=6.38 Hz, 2 H), 2.45 (s, 3 H), 1 .80 - 1 .91 (m, 2 H). UPLC/MS (3 min) retention time 2.40 LRMS: m/z 377 (M+1 , 1 CI).
EXAMPLE 95 N-[3-(3-Bromophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 75 and 3-Bromophenol. Yield: 31%. Purity 92%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 - 8.36 (m, 2 H), 7.99 (s, 1 H), 7.24 (t, J=8.21 Hz, 1 H), 7.09 - 7.15 (m, 2 H), 6.91 - 6.98 (m, 1 H), 4.46 (s, 2 H), 4.01 (t, J=6.25 Hz, 2 H), 3.22 - 3.27 (m, 2 H), 2.46 (s, 3 H), 1.81 - 1.91 (m, 2 H).
UPLC/MS (3 min) retention time 2.29 min.
LRMS: m/z 419 (M+1 , 1 xBr).
EXAMPLE 96
N-[3-(3-Chlorophenoxy)propyl]-2-(5,8-dimethyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 78 and the title compound of PREPARATION 49. Yield: 33%. Purity 96%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (s, 1 H), 8.37 (t, J=5.47 Hz, 1 H), 7.29 (t, J=8.21 Hz, 1 H), 6.96 - 7.01 (m, 2 H), 6.89 - 6.93 (m, 1 H), 6.31 (s, 1 H), 4.57 (s, 2 H), 4.02 (t, J=6.25 Hz, 2 H), 3.56 (s, 3 H), 3.26 (q, J=6.64 Hz, 2 H), 2.48 (s, 3 H), 1.83 - 1 .92 (m, 2 H).
UPLC/MS (3 min) retention time 2.34 min. LRMS: m/z 417 (M+1 , 1 xCI).
EXAMPLE 97 N-[3-(3-Chlorophenoxy)-2-fluoropropyl]-2-(5-methyl-4-oxoimidazo[5,1 - f][1 ,2,4]triazin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 74 and the title compound of PREPARATION 83. Yield: 55%. Purity 100%. 1H NMR (300 MHz, DMSO-D6) δ ppm 8.61 (t, J = 5.5 Hz, 1 H), 8.34 (s, 1 H), 8.02 (s, 1 H), 7.32 (t, J = 8.2 Hz, 1 H), 7.00-7.05 (m, 2H), 6.94 (d, J = 7.4 Hz, 1 H), 4.81 -4.96 (m, 1 H), 4.53 (s, 2H), 4.14-4.27 (m, 2H), 3.47-3.55 (m, 2H), 2.46 (s, 3H).
UPLC/MS (5 min) retention time 2.32 min.
LRMS: m/z 394 (M+1 , 1 CI).
EXAMPLE 98
N-{3-[(5-Bromopyridin-3-yl)oxy]propyl}-2-(5-methyl-4-oxoimidazo[5,1 - f][1 ,2,4]triazin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 75 and 3-Bromopyridin-5-ol. Yield: 44%. Purity 97%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 - 8.36 (m, 2 H), 8.29 (m, 2 H), 7.99 (s, 1 H), 7.67 - 7.69 (m, 1 H), 4.46 (s, 2 H), 4.10 (t, J=6.25 Hz, 2 H), 3.26 (q, J=6.64 Hz, 2 H), 2.46 (s, 3 H), 1 .84 - 1 .92 (m, 2 H).
UPLC/MS (3 min) retention time 1 .68 min. LRMS: m/z 421 (M+1 , 1 *Br).
EXAMPLE 99
2-(5-Methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)-N-[3-(pyridin-3- yloxy)propyl]acetamide
Synthesized from the title compound of PREPARATION 75 and Pyridin-3-ol. Yield: 36%. Purity 95%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 - 8.38 (m, 2 H), 8.28 (d, J=2.74 Hz, 1 H), 8.16 (dd, J=4.49, 1 .37 Hz, 1 H), 8.00 (s, 1 H), 7.35 - 7.39 (m, 1 H), 7.29 - 7.34 (m, 1 H), 4.46 (s, 2 H), 4.07 (t, J=6.25 Hz, 2 H), 3.24 - 3.29 (m, 2 H), 2.46 (s, 3 H), 1 .84 - 1.93 (m, 2 H).
UPLC/MS (3 min) retention time 0.63 min. LRMS: m/z 343 (M+1 ).
EXAMPLE 100
N-[3-(lsoquinolin-7-yloxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 75 and lsoquinol-7-ol. Yield: 46%. Purity 97%.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (s, 1 H), 8.41 (t, J=5.47 Hz, 1 H), 8.37 (d, J=5.47 Hz, 1 H), 8.34 (s, 1 H), 8.01 (s, 1 H), 7.90 (d, J=8.99 Hz, 1 H), 7.75 (d, J=5.47 Hz, 1 H), 7.49 (d, J=2.34 Hz, 1 H), 7.43 (dd, J=8.99, 2.34 Hz, 1 H), 4.48 (s, 2 H), 4.17 (t, J=6.25 Hz, 2 H), 3.31 (m, 2H), 2.45 (s, 3 H), 1.91 - 2.04 (m, 2 H). UPLC/MS (3 min) retention time 0.93 min.
LRMS: m/z 393 (M+1 ).
EXAMPLE 101
N-[3-(3-Chlorophenoxy)propyl]-2-(5-cyano-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 85 and the title compound of PREPARATION 49. Yield: 19%. Purity 100%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (s, 1 H), 8.39 (t, J=5.28 Hz, 1 H), 8.36 (s, 1 H), 7.31 (t, J=8.01 Hz, 1 H), 6.96 - 7.01 (m, 2 H), 6.88 - 6.93 (m, 1 H), 4.57 (s, 2 H), 4.02 (t, J=6.25 Hz, 2 H), 3.23 - 3.29 (m, 2 H), 1.83 - 1 .91 (m, 2 H).
UPLC/MS (3 min) retention time 2.31 min.
LRMS: m/z 387 (M+1 , 1 xQ). EXAMPLE 102
2-(4-Bromo-8-methyl-1 -oxoisoquinolin-2(1 H)-yl)-N-[3-(3- chlorophenoxy)propyl]acetamide
Synthesized from the crude title compound of PREPARATION 89 and the title compound of PREPARATION 49. Yield: 26% over two steps. Purity 96%.
1H NMR (400 MHz, DMSO-d6) δ 8.21 (t, J = 5.6 Hz, 1 H), 7.82 (s, 1 H), 7.69 - 7.56 (m, 2H), 7.33 (d, J = 7.1 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 6.96 - 6.89 (m, 2H), 6.89 - 6.82 (m, 1 H), 4.47 (s, 2H), 3.97 (t, J = 6.3 Hz, 2H), 3.20 (q, J = 6.5 Hz, 2H), 2.74 (s, 3H), 1 .82 (pent, J = 6.4 Hz, 2H). UPLC/MS (3 min) retention time 3.24 min.
LRMS: m/z 463 (M+1 , 1 *CI, 1 *Br).
EXAMPLE 103
2-(5-Methyl-4-oxoimidazo[5,1 - [1 ,2,4]triazin-3(4H)-yl)-N-(3- phenoxypropyl)acetamide
Synthesized from the title compound of PREPARATION 75 and Phenol. Yield: 59%. Purity 95%.
1H NMR (300 MHz, DMSO-d6) δ ppm 9.07 (m, 1 H), 8.38 (m, 1 H), 8.34 (s, 1 H), 8.01 (s, 1 H), 7.26-7.30 (m, 2H), 6.90-6.95 (m, 2H), 4.47 (s, 2H), 3.99 (t, 2H, J = 6.3 Hz), 3.25 (m, 2H), 2.47 (s, 3H), 1 .84-1 .91 (m, 2H).
UPLC/MS (3 min) retention time 1 .24 min.
LRMS: m/z 342 (M+1 ).
EXAMPLE 104 N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxo-1 ,2,3-benzotriazin-3(4H)- yl)acetamide
Synthesized from the title compound of PREPARATION 93 and the title compound of PREPARATION 48. Yield: 63%. Purity 100%. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (m, 1H), 8.03 (d, 1H, J = 8.2 Hz), 7.95 (m, 1H), 7.71 (m, 1H), 7.30 (m, 1H), 6.98-7.00 (m, 2H), 6.91 (m, 1H), 4.96 (s, 2H), 4.03 (t, 2H, J = 6.3 Hz), 3.26 (m, 2H), 2.81 (s, 3H), 1.88 (m, 2H).
UPLC/MS (5 min) retention time 2.80 min. LRMS: m/z 387 (M+1 , 1 xCI).
EXAMPLE 105
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxopyrazolo[5,1-f][1,2,4]triazin- 3(4H)-yl)acetamide Synthesized from the title compound of PREPARATION 96 and the title compound of PREPARATION 49. Yield: 82%. Purity 100%.
1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (m, 1H), 8.17 (s, 1H), 7.71 (m, 1H), 7.30 (m, 1H), 6.97-7.00 (m, 2H), 6.91 (m, 1H), 4.53 (s, 2H), 4.01 (t, 2H, J = 6.3 Hz), 3.26 (m, 2H), 2.35 (s, 3H), 1.87 (m, 2H). UPLC/MS (3 min) retention time 1.59 min.
LRMS: m/z 376 (M+1, 1xCI).
EXAMPLE 106
N-[3-(3-Chlorophenoxy)propyl]-2-(7,9-dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1H- purin-1-yl)acetamide
Synthesized from the title compound of PREPARATION 105 and the title compound of PREPARATION 48. Yield: 59%. Purity 100%.
1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (m, 1H), 8.24 (s, 1H), 7.30 (m, 1H), 6.97- 7.02 (m, 2H), 6.92 (m, 1H), 4.62 (s, 2H), 4.02 (t, 2H, J = 6.5 Hz), 3.44 (s, 3H), 3.28 (s, 3H), 3.26 (m, 2H), 1.87 (m, 2H).
UPLC/MS (5 min) retention time 2.1 min.
LRMS: m/z 406 (M+1, 1xCI). EXAMPLE 107
N-[3-(3-Chlorophenoxy)propyl]-2-(7-methoxy-5-methyl-4-oxopyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 121 and the title compound of PREPARATION 49. Yield: 81 %. Purity 95%.
1H NMR (300 MHz, DMSO-d6) δ ppm 8.41 (s, 1 H), 8.36 (m, 1 H), 7.29 (m, 1 H), 6.96- 7.00 (m, 2H), 6.91 (m, 1 H), 6.78 (s, 1 H), 4.57 (s, 2H), 4.02 (t, 2H, J = 6.3 Hz), 3.94 (s, 3H), 3.26 (m, 2H), 2.67 (s, 3H), 1 .87 (m, 2H).
UPLC/MS (3 min) retention time 1 .65 min.
LRMS: m/z 417 (M+1 , 1 *CI).
EXAMPLE 108
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide Synthesized from the title compound of EXAMPLE 107. Yield: 77%. Purity 97%.
1H NMR (300 MHz, DMSO-d6) δ ppm 12.17 (br s, 1 H), 8.34-8.37 (m, 2H), 7.29 (m, 1 H), 6.96-7.00 (m, 2H), 6.91 (m, 1 H), 6.16 (s, 1 H), 4.53 (s, 2H), 4.01 (t, 2H, J = 6.3 Hz), 3.25 (m, 2H), 2.47 (s, 3H), 1 .87 (m, 2H).
UPLC/MS (3 min) retention time 1.40 min. LRMS: m/z 403 (M+1 , 1 xCI).
EXAMPLE 109
N-[3-(3-Chlorophenoxy)propyl]-2-[5-methyl-7-(methylamino)-4-oxoimidazo[5,1 - f][1 ,2,4]triazin-3(4H)-yl]acetamide
Synthesized from the crude title compound of PREPARATION 1 16 and the title compound of PREPARATION 49. Yield: 81 % over two steps. Purity 100%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (t, J = 5.6 Hz, 1 H), 7.72 (s, 1 H), 7.34 (t, J = 8.1 Hz, 1 H), 7.05 - 6.99 (m, 2H), 6.98 - 6.90 (m, 1 H), 6.55 (q, J = 4.8 Hz, 1 H), 4.38 (s, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.31 - 3.23 (m, 2H), 2.90 (d, J = 4.9 Hz, 3H), 2.38 (s, 3H), 1 .90 (pent, J = 6.8 Hz, 2H).
UPLC/MS (3 min) retention time 1.20 min.
LRMS: m/z 405 (M+1 , 1 *CI).
EXAMPLE 1 10
2-(7-Amino-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)-N-[3-(3- chlorophenoxy)propyl]acetamide
The title compound of PREPARATION 1 15 (17 mg, 0.033 mmol) was suspended in 0.5 ml dichloromethane. Trifluoroacetic acid (0.5 ml) was added drop-wise with stirring, dissolving the suspension and the mixture was stirred for 7 h at room temperature. The mixture was partitioned between dichloromethane and 4% sodium bicarbonate solution. The aqueous phase was extracted three times with dichloromethane and the combined organics were evaporated under reduced pressure. The residue was partially purified by reverse-phase chromatography to give 4.1 mg (0.010 mmol, 32 % yield) of the title compound as a white solid. Purity 87%.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.49 (s, 1 H), 7.13 (t, J = 8.1 Hz, 2H), 6.90 - 6.80 (m, 2H), 6.75 - 6.70 (m, 1 H), 4.35 (s, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.40 (q, J = 6.5 Hz, 2H), 2.49 (s, 3H), 2.03 - 1 .89 (m, 2H). UPLC/MS (3 min) retention time 1 .22 min.
LRMS: m/z 391 (M+1 , 1 *CI).
EXAMPLE 1 1 1
N-[3-(4-Bromo-3-chlorophenoxy)propyl]-2-(7-methyl-6-oxo-6,7-dihydro-1 H-purin- 1 -yl)acetamide
Synthesized from the title compound of EXAMPLE 78 and N-bromosuccinimide. Yield: 54%. Purity 92%. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (t, J = 5.4 Hz, 1H), 8.21 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 6.93 (dd, J = 8.9, 2.9 Hz, 1H), 4.66 (s, 2H), 4.07 (t, J = 6.3 Hz, 2H), 3.98 (s, 3H), 3.28 (q, J = 6.5 Hz, 2H), 1.90 (pent, J = 6.6 Hz, 2H).
UPLC/MS (3 min) retention time 1.49 min. LRMS: m/z 454 (M+1 , 1 xCI, 1 *Br).
EXAMPLE 112
2-(7-Bromo-5-methyl-4-oxoimidazo[5,1- [1,2,4]triazin-3(4H)-yl)-N-[3-(3- cyanophenoxy)propyl]acetamide Synthesized from the title compound of PREPARATION 66 and the title compound of PREPARATION 111. Yield: 86%. Purity 100%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1H), 8.13 (d, J = 3.3 Hz, 1H), 7.45-7.39 (m, 2H), 7.32 (dd, J = 8.3, 2.5 Hz, 1H), 4.52 (s, 2H), 4.10 (t, J = 5.3 Hz, 2H), 3.27 (t, J = 5.3 Hz, 2H), 2.50 (s, 3H), 2.07 - 1.74 (m, 2H). UPLC/MS (3 min) retention time 1.31 min.
LRMS: m/z 445 (M+1, 1*Br).
EXAMPLE 113
N-[3-(3-Cyanophenoxy)propyl]-2-(5-methyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide
Synthesized from the crude title compound of PREPARATION 110. Yield: 15% over two steps. Purity 97%.
1H NMR (300 MHz, DMSO-d6) δ ppm 12.15 (br s, 1H), 8.37 (s, 1H), 8.32 (m, 1H), 7.49 (m, 1H), 7.38-7.40 (m, 2H), 7.28 (m, 1H), 6.16 (s, 1H), 4.54 (s, 2H), 4.07 (t, 2H, J = 6.5 Hz), 3.26 (m, 2H), 2.48 (s, 3H), 1.89 (m, 2H).
UPLC/MS (3 min) retention time 1.12 min.
LRMS: m/z 394 (M+1). EXAMPLE 114
N-[3-(3-Cyanophenoxy)propyl]-2-(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4- d]pyrimidin-5-yl)acetamide
Synthesized from the title compound of PREPARATION 107 and the title compound of PREPARATION 22. Yield: 81 %. Purity 100%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (t, J = 5.5 Hz, 1 H), 8.21 (s, 1 H), 7.46 (t, J = 8.2 Hz, 1 H), 7.37 (m, 2H), 7.24 - 7.29 (m, 1 H), 4.55 (s, 2H), 4.04 (t, J = 6.3 Hz, 2H), 3.80 (s, 3H), 3.23 (q, J = 6.8 Hz, 2H), 2.37 (s, 3H),1 .85 (pent, J = 6.4 Hz, 2H).
UPLC/MS (3 min) retention time 1.18 min. LRMS: m/z 381 (M+1 ).
EXAMPLE 1 15
N-[3-(3-Cyanophenoxy)propyl]-2-(7-ethyl-5-methyl-4-oxoimidazo[5,1 - f][1 ,2,4]triazin-3(4H)-yl)acetamide Synthesized from the title compound of EXAMPLE 1 12 and potassium ethyl trifluoroborate. Yield: 13%. Purity 100%.
Ή NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1 H), 7.98 (s, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.45 - 7.37 (m, 2H), 7.35 - 7.28 (m, 1 H), 4.50 (s, 2H), 4.12 (q, J = 6.4 Hz, 2H), 3.24 (q, J = 6.6 Hz, 2H), 2.91 (q, J = 7.0 Hz, 2H), 2.48 (s, 3H), 2.08 - 1 .82 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H).
UPLC/MS (3 min) retention time 1.25 min.
LRMS: m/z 395 (M+1 ).
EXAMPLE 1 16 N-[3-(3-Cyanophenoxy)propyl]-2-(5,8-dimethyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide
Synthesized from the title compound of PREPARATION 78 and the title compound of PREPARATION 1 1 1. Yield: 8%. Purity 90%. 1 H N MR (400 MHz, CHLOROFORM-D) δ ppm 8.16 (s, 1 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.23 - 7.25 (m, 1 H), 7.09 - 7.18 (m, 2H), 6.53 (s, 1 H), 6.40 (s, 1 H), 4.50 (s, 2H), 4.04 (t, J = 5.8 Hz, 2H), 3.70 (s, 3H), 3.51 (dt, J = 9.8, 5.0 Hz, 2H), 2.58 (s, 3H), 2.01 - 2.09 (m, 2H). UPLC/MS (3 min) retention time 1 .29 min. LRMS: m/z 408 (M+1 ).
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 g/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 FLI PR 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: Example FLIPR assay IC5o (nM)
1 C
2 C
3 c
4 B
5 C
6 B
7 C
8 B
9 C
10 B
1 1 C
12 B
13 C
14 B
15 C
16 C
17 B
18 C
19 B
20 B
21 B
22 B 23 B
24 C
25 B
26 C
27 B
28 C
29 C
30 C
31 C
32 C
33 B
34 B
35 B
36 A
37 A
38 A
39 C
40 B
41 A
42 A
43 C
44 B
45 A
46 B
47 C
48 C
49 B 50 B
51 C
52 B
53 B
54 C
55 C
56 C
57 B
58 C
59 C
60 B
61 A
62 A
63 B
64 A
65 A
66 A
67 A
68 A
69 A
70 A
71 C
72 C
73 B
74 C
75 B
76 A 77 B
78 B
79 B
80 A
81 B
82 B
83 B
84 B
85 B
86 B
87 C
88 B
89 A
90 B
91 A
92 B
93 B
94 A
95 A
96 A
97 B
98 B
99 C
100 B
101 B
102 C
103 B 104 B
105 A
106 B
107 B
108 A
109 A
1 10 B
1 1 1 B
1 12 A
1 13 B
1 14 B
1 15 A
1 16 B
COMBINATION PRODUCT
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: Antiinflammatory agents (such as NSAIDs, corticosteroids, calcineurin inhibitors, anti-TNF, anti-l L17, anti-l L12/I L13, anti- IL5, anti IL4/IL-13, anti- IL31 or anti-lgE antibodies, JAK inhibitors, Phosphodiesterase IV inhibitors or Syk inhibitors); Analgesics (such as paracetamol or opioids);
Immunosupressants; or antipruritic agents (such as kappa opioid agonists, mu opioid agonists, neurokinin receptor 1 antagonists, 5-HT3 antagonists, cannabinoids), Bronchodilators (such as beta-2 agonists, anticholinergics or dual beta-2 adrenoceptor agonists/muscarinic receptor antagonists); Leukotriene receptor antagonists (such as 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein inhibitors, Cysteinyl- leukotriene type 1 receptor antagonists; Decongestants; Mucolytics; Antitussives;
Expectorants; Antihistamines; Antifibrotic drugs or Proton Pump Inhibitors.
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.
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.
Examples of suitable antiinflammatory agents are corticosteroids (such as prednisone, budesonide, beclomethasone dipropionate, hydrocortisone, mometasone or fluticasone), NSAIDs (such as aspirin, ibuprofen, piketoprofen, aceclofenac, diclofenac, naproxen, celecoxib), calcineurin inhibitors (such as tacrolimus or pimecrolimus) or anti-TNF, anti-IL17, anti-l L12/I L13, anti-IL5, anti IL4/IL-13, anti- IL31 or anti-lgE antibodies, JAK inhibitors (such as tofacitinib), Phosphodiesterase IV inhibitors (such as roflumilast) or Syk inhibitors (such as fostamatinib, R-348 or PRT- 062070).
Examples of suitable analgesics are paracetamol, and opioids such as, morphine, tramadol, oxycodone or fentanyl.
Examples of suitable immunosupressants are methotrexate, cyclosporin A, mycophenolate mofetil, maraviroc or enfuvirtide. Examples of suitable antipruritic agents are kappa opioid agonists (such as nalfurafine, nalbuphine or ketazocine), neurokinin receptor 1 antagonists (such as aprepitant or fosaprepitant), 5-HT3 antagonists (such as ondansetron, tropisetron or granisetron), antidepressants (such as desvenlafaxine, doxepine, etoperidone or reboxetine), cannabinoids (such as dronabinol, nabilone or Sativex).
Examples of suitable bronchodilators are salbutamol, abediterol, indacaterol, olodaterol, formoterol, salmeterol, vilanterol, ipratropium, aclidinium bromide, tiotropium, glycopyrrolate or GSK-961081 .
Examples of suitable leukotriene receptor antagonists are montelukast, zafirlukast, pranlukast or zileuton.
Examples of suitable decongestants are ephedrine, levo-methamphetamine, naphazoline, oxymetazoline, phenylephrine, pseudoephedrine, synephrine or tetrahydrozoline.
Examples of suitable mucolytics are acetylcysteine, ambroxol, bromhexine, carbocysteine, domiodol, eprazinone, erdosteine, letosteine, neltenexine, sobrerol, stepronin or tiopronin.
Examples of suitable antitussives are dextromethorphan, codeine, morphine lidocaine, alpha intereferon, gabapentin, theobromine, benzonatate and baclofen.
Examples of suitable expectorants are antimony pentasulfide,
guaiacolsulfonate, guaifenesine, potassium iodide or tylozapol.
Examples of suitable antihistamines are ranitidine, loratadine, ebastine, cetirizine or promethazine hydrochloride.
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, stereoisomers, deuterated derivatives thereof or prodrugs 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.
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 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 or deuterated 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, inhalation, topical, nasal, rectal, percutaneous or injectable 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 salts of such compound, 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-c/ried 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 mucosal administration
The compounds of the invention can also be administered via the oral mucosal administration. Within the oral mucosal 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 mucosal 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.
Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred. Each capsule or cartridge may generally contain between 0.001 -500 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient (s) may be presented without excipients.
Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi- dose delivery, the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.
Apart from applications through dry powder inhalers the compositions of the invention can be administered in aerosols which operate via propellant gases or by means of so-called atomisers, via which solutions of pharmacologically-active substances can be sprayed under high pressure so that a mist of inhalable particles results. The advantage of these atomisers is that the use of propellant gases can be completely dispensed with.
Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1 -10 μηη, preferably 2-5 μηη. Particles having a size above 20 μηη are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation. Preferably, the particles will be crystalline.
iv) Nasal mucosal administration
The compounds of the invention may also be administered via the nasal mucosal.
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.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for
administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
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. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
vii) Rectal/lntravaginal 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 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. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
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 amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of
administration, the disposition of the compound and the discretion of the prescribing physician. 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. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
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)
Figure imgf000145_0001
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)
Figure imgf000146_0001
Formulation Example 3 (Gelatin cartridge for inhalation)
Figure imgf000146_0002
Formulation Example 4 (Formulation for inhalation with a DPI)
Figure imgf000146_0003
Formulation Example 5 (Formulation for a MDI)
Figure imgf000146_0004
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 compound of formula (I) or a pharmaceutically acceptable salt, a /V-oxide or a isotopically-labeled derivative thereof for use in the treatment of the human or animal body by therapy,
Figure imgf000148_0001
Formula (I)
wherein:
• G1 is selected from the group consisting of a CH group and a N atom;
• G2 is selected from the group consisting of a C(Ra) group and a N atom;
• G3 and G4 are independently selected from the group consisting of a C atom and a N atom; · G5, G6 and G7 are independently selected from the group consisting of a C(Rb) group, a N(RC) group, a N atom, an O atom and a S atom;
• Q is a monocyclic or bicyclic C6-i4 aryl or a monocyclic or bicyclic 5- to 14- membered heteroaryl ring, unsubstituted or substituted by one or more substituents selected from a linear or branched Ci-4 alkyl group, a halogen, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a Ci-4 monoalkylamino group, a Ci-4 dialkylamino group, a C3-7 cycloalkyl group, a phenyl ring and a phenoxy group;
• R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched Ci-4 alkyl group, a Ci-4 haloalkyl group, an C6-i4 aryl group and a benzyl group; or R1 together with the Q group, the O atom and the C atom where it is attached, form a fused bicyclic 8- to 14-membered heterocyclyl ring containing at least one heteroatom selected from O, S and N; R3 and R4 are independently selected from the group consisting of a H atom and a F atom;
Ra is selected from the group consisting of a H atom , a linear or branched C alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci- haloalkyloxy group, a C3-7 cycloalkyl group, a cyano group, an amino group, Ci-4 rmonoalkylamino group and a Ci-4 dialkylamino group;
Rb is selected from the group consisting of a H atom, a linear or branched Ci alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci- haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 rmonoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
Rc is selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a Ci-4 haloalkyl group and a C3-7 cycloalkyl group; n is an integer selected from 1 or 2; and represents a single or a double bond.
A compound for use as defined in claim 1 for use in the treatment or prevention of a pathological condition or disease susceptible to amelioration by inhibition or antagonism of TRPA1 .
A compound for use according to claim 1 or 2, wherein the pathological condition or disease is selected from acute and/or chronic pain, acute and/or chronic pruritus, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
A compound for use according to any preceding claim wherein Q represents a phenyl group or a pyridine group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a Ci-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a cyano group, a Ci-4 dialkylamino group, a phenyl ring and a phenoxy group.
5. A compound for use according to any preceding claim wherein R1 and R2 are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group; or R1 together with the Q group, the O atom and the C atom where it is attached form a fused bicyclic ring of formula (a), (b), (c) or (d).
Figure imgf000150_0001
(a) (b) (c) (d)
6. A compound for use according to any preceding claim wherein G1 represents a CH group and G2 represents a N atom.
7. A compound for use according to any preceding claim wherein G5, G6 and G7 are independently selected from the group consisting of a C(Rb) group, a N(RC) group and a N atom .
8. A compound for use according to claim 7 wherein Rb is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom and a C1-4 alkoxy group, preferably a H atom, a halogen atom, a methyl group and a methoxy group.
9. A compound for use according to claim 1 , 2 or 3 wherein:
• G1 represents a CH group and G2 represents a N atom;
• G5, G6 and G7 are independently selected from the group consisting of a C(Rb) group, a N(RC) group and a N atom;
• Q represents a phenyl group or a pyridine group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, a cyano group, a Ci-4 dialkylamino group, a phenyl ring and a phenoxy group;
• R1 and R2 are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group; or R1 together with the Q group, the O atom and the C atom where it is attached form a fused bicyclic ring of formula (a), (b), (c) or (d);
Figure imgf000151_0001
(a) (b) (c) (d) and
• Rb is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom and a C1-4 alkoxy group, preferably a H atom, a halogen atom, a methyl group and a methoxy group.
10. A compound for use according to claim 1 , 2 or 3, which is one of:
2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)-/V-{3-[4- (trifluoromethyl)phenoxy]propyl}acetamide;
/V-{3-[(5-Chloropyridin-3-yl)oxy]propyl}-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(2-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(6-methyl-4-oxopyrido[3,4-c ]pyrimidin-3(4/-/)- yl)acetamide;
/V-[3-(3-Fluorophenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(4-Methylphenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Methoxyphenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(4-Fluorophenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide;
2-(4-Oxopyrido[4,3-c/]pyrimidin-3(4H)-yl)-/V-{3-[4- (trifluoromethyl)phenoxy]propyl}acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[4,3-c/]pyrimidin-3(4/-/)-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,2-c/]pyrimidin-3(4/-/)-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[2,3-c/]pyrimidin-3(4/-/)-yl)acetamide; /V-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide; /V-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[2,3-c/]pyrimidin-3(4H)-yl)acetamid
/V-[3-(3-Chlorophenoxy)propyl]-2-(5,7-dimethoxy-4-oxoquinazolin-3(4/-/)- yl)acetamide;
/V-[3-(4-Fluorophenoxy)propyl]-2-(4-oxopyrido[4,3-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chloro-4-fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c ]pynrTiidiri-3(4/-/)- yl)acetamide;
/V-[3-(3,5-Dichlorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pynmidiri-3(4/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrimido[4,5-c/]pyridaziri-3(4/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-oxopyrimido[4,5-c]pyridazin-6(5/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)butyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Cyanophenoxy)propyl]-2-(4-oxoquinazolin-3(4/-/)-yl)acetamide;
2-(6-Chloro-4-oxopyrido[3,4-c ]pynmidin-3(4H)-yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)-/V-{3-[3- (trifluoromethyl)phenoxy]propyl}acetamide;
/V-[3-(3-Chlorophenoxy)butyl]-2-(4-oxopyrido[3,4-c ]pynmidin-3(4H)-yl)acetarTiide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -oxo-2,6-naphthyridin-2(1 /-/)-yl)acetamide;
/V-{3-[3-(Dimethylamino)phenoxy]propyl}-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-methoxy-4-oxoquinazolin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrimido[4,5-c/]pyrimidin-3(4/-/)- yl)acetamide;
/V-[3-(4-Cyanophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(8-methoxy-4-oxoquinazolin-3(4/-/)-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(6-methoxy-4-oxoquinazolin-3(4/-/)-yl)acetamide;
2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)-/V-(3-phenoxypropyl)acetamide;
2-(5-Bromo-4-oxopyrido[3,4-c ]pynmidin-3(4H)-yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
2-(8-Chloro-4-oxopyrido[3,4-c ]pynmidin-3(4H)-yl)-/V-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxopyrido[3,4-c ]pynrTiidiri-3(4/-/)- yl)acetamide;
/V-{3-[(4-Chloropyridin-2-yl)oxy]propyl}-2-(4-oxopyrido[3,4-c/]pyrirTiidiri-3(4/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/][1 !2!3]triazin-3(4H)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(8-methyl-4-oxopyrido[3,4-c ]pynrTiidiri-3(4/-/)- yl)acetamide;
/V-[3-(3-Bromophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[2-(2,3-Dihydro-1 -benzofuran-2-yl)ethyl]-2-(4-oxopyrido[3,4-c/]pynrTiidin-3(4H)- yl)acetamide;
/V-[3-(3-Fluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(Biphenyl-3-yloxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(3,4-Difluorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pynmidiri-3(4/-/)- yl)acetamide;
2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)-/V-[3-(3- phenoxyphenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(6-methoxy-4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)- yl)acetamide;
/V-[3-(3-Methylphenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(3-Methoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidiri-3(4/-/)- yl)acetamide; 2-(4-Oxopyrido[3,4-c/]pyrimidin-3(4H)-yl)-/V-{3-[3- (trifluoromethoxy)phenoxy]propyl}acetamide;
/V-[3-(4-Chlorophenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(8-methoxy-4-oxopyrido[3,4-c/]pyrimidin-3(4/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxothieno[2,3-c/]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxothieno[3,2-c/]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-4-oxo-1 ,4-dihydro-5/-/-pyrazolo[3,4- c/]pyrimidin-5-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6/-/-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-oxoimidazo[5,1 -/][1 !2!4]triazin-3(4H)- yl)acetamide;
/V-[3-(4-Fluorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6/-/-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chloro-4-fluorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6/-/- pyrazolo[4,3-c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 ,3-dimethyl-7-oxo-1 ,7-dihydro-6/-/-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)butyl]-2-(1 ,3-dimethyl-7-oxo-1 !7-dihydro-6H-pyrazolo[4,3- c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -ethyl-3-methyl-7-oxo-1 ,7-dihydro-6/-/- pyrazolo[4,3-c/]pyrimidin-6-yl)acetamide;
2-(3-Bromo-1 -methyl-7-oxo-1 J-dihydro-6H-pyrazolo[4,3-c/]pyrimidiri-6-yl)-/\/-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 -methyl-7-oxo-1 ,7-dihydro-6/-/- [1 ,2,3]triazolo[4,5-c/]pyrimidin-6-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(1 ,3-dimethyl-4-oxo-1 !4-dihydro-5/-/-pyrazolo[3,4- c/]pyrimidin-5-yl)acetamide; /V-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -/][1 !2!4]triazin-3(4H)- yl)acetamide;
2-(7-Bromo-5-methyl-4-oxoimidazo[5!1 -/][1 !2!4]triazin-3(4H)-yl)-/\/-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5J-dimethyl-4-oxoimidazo[5,1 -f|[1 ,2,4]triazin- 3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(6,8-dimethyl-4-oxoimidazo[1 ,5-a][1 ,3,5]triazin- 3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4,8-dioxo-7,8-dihydropyrido[3,4-c ]pyrimidin- 3(4/-/)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(4-fluoro-1 -oxo-2,6-naphthyridin-2(1 /-/)- yl)acetamide;
/V-[3-(4-Methoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-c/]pyrimidiri-3(4/-/)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)butyl]-2-(5-methyl-4-oxoimidazo[5,1 -/][1 !2!4]tnazin-3(4H)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxoquinazolin-3(4H)-yl)acetamide; 2-(4-Bromo-1 -oxo-2,6-naphthyridin-2(1 H)-yl)-N-[3-(3- chlorophenoxy)propyl]acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(7-methyl-6-oxo-6,7-dihydro-1 H-purin-1 - yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5,8-dibromo-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(7-ethyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5!8-dimethyl-4-oxopyrido[3!4-d]pyrimidin-3(4H)- yl)acetamide;
2-(3-Ethyl-1 -methyl-7-oxo-1 !7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)-N-[3-(3- ethylphenoxy)propyl]acetamide;
/V-[3-(1 -Naphthyloxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(4-Bromophenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide;
/V-[3-(2-Naphthyloxy)propyl]-2-(4-oxopyrido[3!4-d]pyrimidin-3(4H)-yl)acetamide;
2-(4-Oxopyrido[3!4-d]pyrimidin-3(4H)-yl)-N-[3-(3!4,5- trifluorophenoxy)propyl]acetamide; /V-[3-(3-Ethoxyphenoxy)propyl]-2-(4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetamide;
2-(5-Methyl-4-oxoimidazo[5,1 -f][1 !2!4]triazin-3(4H)-yl)-N-[3-(3!4,5- trifluorophenoxy)propyl]acetamide;
/V-[3-(3,4-Difluorophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(5-ethyl-4-oxopyrido[3!4-d]pyrimidin-3(4H)- yl)acetamide;
/V-[3-(3-Chlorophenoxy)propyl]-2-(3-ethyl-1 -methyl-7-oxo-1 ,7-dihydro-6H- pyrazolo[4,3-d]pyrimidin-6-yl)acetamide;
/V-[3-(3-Cyanophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide;
N-{3-[(5-Chloropyridin-3-yl)oxy]propyl}-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(3-methyl-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)- yl)acetamide;
N-[3-(3-Bromophenoxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5,8-dimethyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)-2-fluoropropyl]-2-(5-methyl-4-oxoimidazo[5,1 - f][1 ,2,4]triazin-3(4H)-yl)acetamide;
N-{3-[(5-Bromopyridin-3-yl)oxy]propyl}-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
2-(5-Methyl-4-oxoimidazo[5,1 -f][1 !2,4]triazin-3(4H)-yl)-N-[3-(pyridin-3- yloxy)propyl]acetamide;
N-[3-(lsoquinolin-7-yloxy)propyl]-2-(5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-cyano-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide;
2-(4-Bromo-8-methyl-1 -oxoisoquinolin-2(1 H)-yl)-N-[3-(3- chlorophenoxy)propyl]acetamide;
2-(5-Methyl-4-oxoimidazo[5!1 -f][1 ,2,4]triazin-3(4H)-yl)-N-(3- phenoxypropyl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxo-1 ,2,3-benzotriazin-3(4H)- yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4-oxopyrazolo[5!1 -f][1 !2,4]triazin-3(4H)- yl)acetamide; N-[3-(3-Chlorophenoxy)propyl]-2-(7!9-dimethyl-6!8-dioxo-6!7!8,9-tetrahydro-1 H- purin-1 -yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(7-methoxy-5-methyl-4-oxopyrido[2,3-d]pyrimidin- 3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-(5-methyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide;
N-[3-(3-Chlorophenoxy)propyl]-2-[5-methyl-7-(methylamino)-4-oxoimidazo[5,1 - f][1 !2,4]triazin-3(4H)-yl]acetamide;
2-(7-Amino-5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)-yl)-N-[3-(3- chlorophenoxy)propyl]acetamide;
N-[3-(4-Bromo-3-chlorophenoxy)propyl]-2-(7-methyl-6-oxo-6,7-dihydro-1 H-purin-1 - yl)acetamide;
2-(7-Bromo-5-methyl-4-oxoimidazo[5!1 -f][1 !2,4]triazin-3(4H)-yl)-N-[3-(3- cyanophenoxy)propyl]acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(5-methyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4- d]pyrimidin-5-yl)acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(7-ethyl-5-methyl-4-oxoimidazo[5, 1 -f][1 ,2,4]triazin- 3(4H)-yl)acetamide;
N-[3-(3-Cyanophenoxy)propyl]-2-(5,8-dimethyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)acetamide; or
a pharmaceutically acceptable salt, /V-oxide, solvate, or isotopically-labeled derivative thereof.
1 1 . A compound of formula (I) or a pharmaceutically acceptable salt, a N-oxide or a isotopically-labeled derivative thereof
Figure imgf000157_0001
Formula (I) wherein:
• G1 is selected from the group consisting of a CH group and a N atom;
• G2 is selected from the group consisting of a -C(Ra)- group and a N atom; • G3 and G4 are independently selected from the group consisting of a C atom and a N atom;
• G5, G6 and G7 are independently selected from the group consisting of a C(Rb) group, a N(RC) group, a N atom, an O atom and a S atom;
• Q is a monocyclic or bicyclic C6-i4 aryl or a monocyclic or bicyclic 5- to 14- membered heteroaryl ring, unsubstituted or substituted by one or more substituents selected from a linear or branched Ci-4 alkyl group, a halogen, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a Ci-4 monoalkylamino group, a Ci-4 dialkylamino group, a C3-7 cycloalkyl group, a phenyl ring and a phenoxy group;
• R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched Ci-4 alkyl group, a Ci-4 haloalkyl group, an C6-i4 aryl group and a benzyl group; or R1 together with the Q group, the O atom and the C atom where it is attached, form a fused bicyclic 8- to 14- membered heterocyclyl ring containing at least one heteroatom selected from O, S and N;
• R3 and R4 are independently selected from the group consisting of a H atom and a F atom;
• Ra is selected from the group consisting of a H atom , a linear or branched Ci-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkyloxy group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 monoalkylamino group and a Ci-4 dialkylamino group;
• Rb is selected from the group consisting of a H atom, a linear or branched Ci-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 monoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
• Rc is selected from the group consisting of a hydrogen atom, a linear or
branched Ci-4 alkyl group, a Ci-4 haloalkyl group and a C3-7 cycloalkyl group;
• n is an integer selected from 1 or 2; and represents a single or a double bond; provided that the compound is not one of the following:
/V-[3-(2,4-dichlorophenoxy)propyl]-4-methyl-1 -oxo-2(1 /-/)-phthalazineacetamide;
8-methyl-4-oxo-/V-(3-phenoxypropyl)-3(4/-/)-quinazolineacetamide;
/V-[3-(3-methylphenoxy)propyl]-4-oxo-3(4/-/)-quinazolineacetamide; 4-oxo-/V-(3-phenoxypropyl)-thieno[2,3-c/]pyrimidine-3(4/-/)-acetamide;
4-oxo-/V-[3-(2,3,5-trimethylphenoxy)propyl]-3(4/-/)- quinazolineacetamide;
8-methyl-/V-[3-(3-methylphenoxy)propyl]-4-oxo-3(4/-/)- quinazolineacetamide;
/V-[3-(3-methylphenoxy)propyl]-4-oxo-thieno[2,3-c/]pyrimidine-3(4/-/)-acetamide;
1 ,4-dihydro-1 -methyl-4-oxo-/V-[3-(2,3,5-trimethylphenoxy)propyl]-5/-/-pyrazolo[3,4- c/]pyrimidine-5-acetamide;
2-methyl-4-oxo-/V-[3-(8-quinolinyloxy)propyl]-3(4/-/)-quinazolineacetamide;
6-bromo-/V-[3-(2,4-dichlorophenoxy)propyl]-4-oxo-3(4/-/)-quinazolineacetamide;
8-methyl-4-oxo-/V-[3-(8-quinolinyloxy)propyl]-3(4/-/)-quinazolineacetamide;
6-bromo-/V-[3-(4-fluorophenoxy)propyl]-4-oxo-3(4/-/)-quinazolineacetamide; 4-methyl-1 -oxo-/V-[3-(8-quinolinyloxy)propyl]-2(1 /-/)-phthalazineacetamide;
6-fluoro-4-oxo-/V-[3-(8-quinolinyloxy)propyl]-3(4/-/)- quinazolineacetamide;
2-methyl-/V-[3-(3-methylphenoxy)propyl]-4-oxo-3(4/-/)- quinazolineacetamide;
/V-[3-(2,4-dichlorophenoxy)propyl]-4-oxo-3(4/-/)-quinazolineacetamide;
/V-[3-(2,4-dichlorophenoxy)propyl]-6-fluoro-4-oxo-3(4/-/)- quinazolineacetamide; /V-[3-(4-fluorophenoxy)propyl]-4-oxo-thieno[2,3-c ]pyrimidine-3(4/-/)-acetamide;
4-oxo-/V-[3-(8-quinolinyloxy)propyl]-3(4/-/)-quinazolineacetamide;
/V-[3-(2-fluorophenoxy)propyl]-1 ,4-dihydro-1 -methyl-4-oxo-5/-/-pyrazolo[3,4- c/]pyrimidine-5-acetamide;
1 ,4-dihydro-1 -methyl-4-oxo-/V-(3-phenoxypropyl)-5/-/-pyrazolo[3,4-c/]pyrimidine-5- acetamide; 1 ,4-dihydro-1 -methyl-/V-[3-(3-methylphenoxy)propyl]-4-oxo-5/-/-pyrazolo[3,4- c/]pyrimidine-5-acetamide;
4-methyl-1 -oxo-/V-(3-phenoxypropyl)-2(1 /-/)-phthalazineacetamide;
4-oxo-/V-(3-phenoxypropyl)-3(4/-/)- quinazolineacetamide; /V-[3-(3-methylphenoxy)propyl]-4-oxo-1 ,2,3-benzotriazine-3(4/-/)-acetamide;
/V-[3-(2-fluorophenoxy)propyl]-4-oxo-3(4/-/)- quinazolineacetamide;
/V-[3-(2-fluorophenoxy)propyl]-4-oxo-1 ,2,3-benzotriazine-3(4/-/)-acetamide;
/V-[3-(2-fluorophenoxy)propyl]-5,6-dimethyl-4-oxo-thieno[2,3-c/]pyrimidine-3(4/-/)- acetamide; or 5,6-dimethyl-4-oxo-/V-(3-phenoxypropyl)-thieno[2,3-c/]pyrimidine-3(4/-/)-acetamide.
12. A compound according to claim 1 1 for use in the treatment of the human or animal body.
13. A pharmaceutical composition comprising at least a compound as defined in claims 1 to 1 1 in association with a pharmaceutically acceptable diluent or carrier.
14. Use of a compound as defined in any one of claims 1 to 12 for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claims 2 or 3.
15. A method for treating a subject afflicted with a pathological condition or disease as defined in claims 2 or 3, which comprises administering to said subject an effective amount of a compound as defined in any one of claims 1 to 1 1 , or a pharmaceutical composition as defined in claim 13.
16. A combination product comprising (i) at least a compound as defined in any one of claims 1 to 1 1 , and (ii) one or more active ingredients selected from: a. Antiinflammatory agents (such as NSAI Ds, corticosteroids, calcineurin
inhibitors, anti-TNF, anti-I L17, anti-l L12/I L13, anti-I L5, anti-I L4/I L-13, anti- I L31 or anti-lgE antibodies, JAK inhibitors, Phosphodiesterase IV inhibitors or Syk inhibitors); b. Analgesics (such as paracetamol or opioids); c. Immunosupressants; d. Antipruritic agents (such as kappa opioid agonists, neurokinin receptor 1 antagonists, 5-HT3 antagonists, antidepressants, cannabinoids); e. Bronchodilators (such as beta-2 agonists, anticholinergics or dual beta-2 adrenoceptor agonists/muscarinic receptor antagonists); f. Leukotriene receptor antagonists (such as 5-lipoxygenase inhibitors, 5- lipoxygenase activating protein inhibitors or Cysteinyl-leukotriene type 1 receptor antagonists); g. Decongestants; h. Mucolytics; i. Antitussives; j. Expectorants; k. Antihistamines; I. Antifibrotics; or m. Proton Pump Inhibitors for simultaneous, separate or sequential use in the treatment of the human or animal body.
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WO2017060488A1 (en) 2015-10-09 2017-04-13 Almirall, S.A. New trpa1 antagonists
CN107840845A (en) * 2016-09-19 2018-03-27 上海璃道医药科技有限公司 The new application of aminated compounds
CN110770237A (en) * 2017-07-04 2020-02-07 萨内卡制药公司 Process for the preparation of morphinan compounds
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WO2021074198A1 (en) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Novel tetrazoles
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CN115023416B (en) * 2019-12-13 2024-04-02 森特萨制药(英国)有限公司 4- ((2-oxopyridin-1 (2H) -yl) methyl) benzamide for the treatment of alpha 1-antitrypsin deficiency
WO2022058344A1 (en) 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines as sos1 inhibitors
WO2022058946A1 (en) 2020-09-18 2022-03-24 Université Grenoble Alpes Astrocytic trpa1 channel inhibition as a novel neuroprotective therapeutic target in the prodromal phases of alzheimer's disease
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CN112794860A (en) * 2021-03-24 2021-05-14 上海肇钰医药科技有限公司 Oxazole pyrimidone amide compound or medicinal salt thereof, preparation method and application
WO2022219035A1 (en) 2021-04-14 2022-10-20 Bayer Aktiengesellschaft Phosphorus derivatives as novel sos1 inhibitors
EP4074317A1 (en) 2021-04-14 2022-10-19 Bayer AG Phosphorus derivatives as novel sos1 inhibitors
IT202100015098A1 (en) 2021-06-09 2022-12-09 Flonext S R L TRPA1 CHANNEL ANTAGONIST COMPOUND FOR USE IN DEGENERATIVE DISEASES OF THE RETINA
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