(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/060488 Al 13 April 2017 (13.04.2017) P O PCT
(51) International Patent Classification: (74) Agent: SRINIVASAN, Ravi Chandran; 14 South Square, A61K 31/522 (2006.01) A61P 17/00 (2006.01) Gray's Inn, London Greater London WC1R 5JJ (GB). A61P 13/00 (2006.01) A61P 29/00 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/EP20 16/074094 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (22) Date: International Filing DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 7 October 2016 (07. 10.2016) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 15382492.5 >October 201 5 (09. 10.2015) EP TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, zw. (71) Applicant: ALMIRALL, S.A. [ES/ES]; Ronda del Gener al Mitre 15 1, 08022 Barcelona (ES). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: AIGUADE BOSCH, Jose; c/o Laurea Miro GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 408-410, Sant Feliu de Llobregat, 08980 Barcelona (ES). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, CONNOLLY, Stephen; 23 The Square, Tadcaster Road, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, York Yorkshire Y024 1UR (GB). EASTWOOD, Paul DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Robert; c/o Laurea Miro 408-410, Sant Feliu de Llobregat, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 08980 Barcelona (ES). GOMEZ CASTILLO, Elena; c/o SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Laurea Miro 408-410, Sant Feliu de Llobregat, 08980 Bar GW, KM, ML, MR, NE, SN, TD, TG). celona (ES). MORENO MOLLO, Immaculada Montser- rat; c/o Laurea Miro 408-410, Sant Feliu de Llobregat, Published: 08980 Barcelona (ES). ROBERTS, Richard Spurring; — with international search report (Art. 21(3)) c/o Laurea Miro 408-410, Sant Feliu de Llobregat, 08980 Barcelona (ES). SEVILLA GOMEZ, Sara; Avda. 11 de Septiembre 12, 3°, 3a, Coloma de CervelkS, 08690 Bar celona (ES).
(54) Title: NEW TRPAl ANTAGONISTS
00 00 o Formula (I) o
(57) 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 TRPAl channel inhibition or antagonism. 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 ef a/. , 1999), and further studies indicated that TRPAI was highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia. In sensory neurons, TRPA1 expression is most prevalent in small diameter neurons where it colocalizes with markers of peptidergic nociceptors such as TRPV1 , calcitonin gene-related peptide (CGRP) and substance P (Kaneko e t al. , 201 3). Moreover,
TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B-lymphocytes (Stokes e t 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-H NE) and 4-oxononenal (4-ON E), resulting from lipid peroxidation act directly on TRPA1 . ROS generated during inflammation excites airway sensory nerve fibres, and this response is largely reduced in TRPA1 -deficient mice.
Another mechanism of TRPA1 activation is modulation by G protein-coupled receptors (GPCRs) through second-messenger signalling cascades. Prostaglandin PGE2 and bradykinin (BK) are indirect activators of TRPA1 (Bessac, 2008). TRPA1 has emerged as a key regulator of neuropeptide release and neurogenic inflammation . In mammals TRPA1 is expressed in a subset of C-fibres that express TrkA and TRPV1 . These afferent nerves have cell bodies in nodose, dorsal root ganglia (DRG) and trigeminal neurons (TG), and project to a variety of peripheral targets, including skin, airways, and gastrointestinal (Gl ) tract.
TRP channels are present in both neuronal and non-neuronal cells in the skin where they are thought to play a key role in itch, regulation of barrier function , keratinocyte differentiation , hair growth , inflammation , and wound healing (reviewed in
Moran e t 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, X 1) and BAM8-22 (C1 1,
X 1) (Wilson 2011), TSLP-evoked scratching (Wilson e t al. , Cell 2013), dry skin-evoked chronic itch (Wilson e t al. 201 3), haptens-induced inflammation and itch in contact dermatitis (Liu e t al. , 2013), IL-1 3-induced itch in atopic dermatitis by IL-1 3 (Oh e t al.
201 3), IL-31 -induced Th cell-dependent itch (Cevikbas e t al., 201 3), and PGE2, bradykinin, PAR-2 ligands, etc. Overall, these studies suggest that TRPA1 would be key in the non-histaminergic itch .
TRPA1 role as a pain sensor is well-established. A gain-of-function point mutation in TRPA1 was identified as the cause of Familial Episodic Pain Syndrome, a rare human pain disorder characterized by severe upper body pain triggered by fasting and physical stress (Kremeyer e t al. , 201 0). Taming these hyperactive TRP channels by antagonists may prove clinically beneficial.
TRPA1 is required for the hypersensitivity that occurs in inflammatory pain models (Bautista e t al. 2013 , Julius 201 3). TRPA1 expression is increased by inflammatory mediators such as nerve growth factor (NGF) and following nerve injury or inflammation . Activation of TRPA1 has been shown to cause pain and neurogenic inflammation . Intrathecal TRPA1 antisense oligonucleotides administration suppressed inflammation and nerve injury-induced cold allodynia. TRPA1 gene knock-out studies showed impaired sensory function to noxious cold , chemical and mechanical stimuli, suggesting that TRPA1 represents an important target for development of therapeutics for inflammatory and neuropathic pain conditions (Obata e t al. 2003, McNamara e t al.
2007, Petrus e t 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 e t al. , 2008; reviewed in Bautista e t 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 e t al., 201 2), and dental pain (Haas e t al., 201 1), as a result from neurogenic inflammation. The activation of trigeminal TG neurons through nasal application of
TRPA1 activators causes a CGRP-dependent increase in meningeal blood flow, that has been clinically shown to correlate with migraine headache. TRPA1 could be considered a target for such conditions.
There is growing evidence, generated using TRPA1 blockers and also TRPA1 -/- mice to support a role for TRPA1 in the pathogenesis of different airway diseases including chronic cough , asthma, and COPD (Nassini et al. , 201 2b).
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 e t al. , 2009;
Birrell e t 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 e t al. , 201 2 and 201 3). 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 e t 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 e t 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 e al. , 2008; Izzo e t al., 201 2). Experimental colitis induced by dinitrobenzene sulphonic acid (DN BS) was attenuated after both pharmacological blockade and genetic inactivation of TRPA1 (Engel e t 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 e t 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 e t al. , 2008). Similar to TRPM8, TRPA1 is up-regulated in bladder mucosa in patients with bladder outlet obstruction (Du e t al. , 2008). TRPA1 agonists increased the micturition frequency models of cyclophosphamide-induced cystitis and spinal cord injury
(Andrade e t al. , 201 1; Meotti e t al. , 201 3) 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 (WO20 131031 55), amino ketones (WO201 205051 2 and Bioorg. Med. Chem. Lett. 201 2 , 22, 5485), decalins (WO 2011043954), oximes (WO2009089082,
WO2009089083 and Bioorg. Med . Chem. Lett. 201 0 , 20, 276), prolines and aminoacid derivatives (WO20 1014 1805, EP2520566, WO201 3 108857 and WO201 4049047), pyrimidinedione /xanthines based compounds (WO2007073505, WO2009002933, WO2009 118596, WO20091 44548, WO20091 5871 9, WO201 0004390,
WO20 10036821 , WO201 0075353, WO201 0 109287, WO201 0 109328,
WO20 10109329, WO201 0 109334, WO201 0 125469, WO201 0 132838,
WO20 10138879, WO201 1114 184, WO201 113201 7, WO201 2 176 105,
WO20 12085662, WO201 3023 102 and Med. Chem. Comm. 201 2 , 3 , 187), thioureas (WO2007073505, WO2009 147079 and Bioorg. Med . Chem. Lett 201 2 , 22, 797), and various other structures (such as in WO2007098252 and WO20 12 152940).
Compounds having the capacity to selectively antagonise TRPA1 are in active development by several companies. Examples of these compounds are GRC-1 7536 and HX-1 00.
Thus, there is a need for new TRPA1 antagonists or inhibitors being suitable for the treatment of the above-mentioned diseases.
SUMMARY OF THE INVENTION
Thus the present invention is directed to a bicyclic heterocycle derivative for use in the treatment of the human or animal body, which bicyclic heterocycle derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a N - oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: Formula ( I) wherein :
• G is selected from the group consisting of a C atom and a N atom;
· G2, G ,G4 and G5 are each independently selected from the group consisting of a C(R a) group, a N(R ) group and N atom;
• G6 is an N atom , G7 is a C atom , and G8 is a N atom and G9 is O atom.
• Ra is selected from the group consisting of a H atom, a linear or branched C1-4
alkyl group, a halogen atom, a linear or branched Ci-4 alkoxy group, a linear or
branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, an
oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a C1-4 monoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
• R is selected from the group consisting of a H atom and a linear or branched
C1-4 alkyl group;
· L represents a linear or branched C2-4 alkylene group unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched alkyl group, a linear or branched Ci -4 Ci -4 alkoxy group, a linear or branched haloalkyl group, a linear or branched Ci -4 Ci-
4 haloalkoxy group and a - NR'R" group; a -C(R )=C(R )- group; a C3-7
cycloalkylene group of formula (i); a -(CH2)2-3-0- group; a -(CH2 )i-2-C(0)- group; a -(CH2 )i-2-S- group; a -(CH2 )i-2-S(0)- group; a -CON H- group; a -CF2O- group; and a 4- to 6-membered N-containing heterocyclylene group, wherein at least one nitrogen atom is linked to the G7 group;
(1) wherein R' and R" each independently represent a hydrogen atom, a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 haloalkyl group;
• Q is selected from the group consisting of a monocyclic or bicyclic C 6-i4aryl group and a monocyclic or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N, O and S;
wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, a linear or branched C1-4 thioalkyl group, a linear or branched C1-4 halothioalkyl group and a cyano group;
• Or when Q represents a phenyl group, L together with Q form a 5- to 7- membered N-containing heterocyclyi fused to the phenyl group;
• n is 0 or 1; and
• represents a single or a double bond;
wherein the bicyclic heterocycle derivative is other than:
• 3-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)pyrimido[4,5-d]pyrimidin- 4(3H)-one • 6-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-1 -methyl-1 H- pyrazolo[4,3-d]pyrimidin-7(6H)-one • 1-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H-purin- 6(7H)-one
The present invention also provides a bicyclic heterocycle derivative, which bicyclic heterocycle derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a /V-oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof : Formula ( I) wherein :
• G is selected from the group consisting of a C atom and a N atom;
· G2, G ,G4 and G5 are each independently selected from the group consisting of a C(R a) group, a N(R ) group and N atom;
• G6 is an N atom , G7 is a C atom , and G8 is a N atom and G9 is O atom.
• Ra is selected from the group consisting of a H atom, a linear or branched C1-4
alkyl group, a halogen atom, a linear or branched Ci-4 alkoxy group, a linear or
branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, an
oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a C1-4 monoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
• R is selected from the group consisting of a H atom and a linear or branched
C1-4 alkyl group;
· L represents a linear or branched C2-4 alkylene group unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched alkyl group, a linear or branched Ci -4 Ci -4 alkoxy group, a linear or branched haloalkyl group, a linear or branched Ci -4 Ci-
4 haloalkoxy group and a - NR'R" group; a -C(R )=C(R )- group; a C3-7
cycloalkylene group of formula (i); a -(CH2)2-3-0- group; a -(CH2 )i-2-C(0)- group; a -(CH2 )i-2-S- group; a -(CH2 )i-2-S(0)- group; a -CON H- group; a -CF2O- group; and a 4- to 6-membered N-containing heterocyclylene group, wherein at least one nitrogen atom is linked to the G7 group;
(1) wherein R' and R" each independently represent a hydrogen atom , a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 haloalkyl group;
• Q is selected from the group consisting of a monocyclic or bicyclic C 6-i4 aryl group and a monocyclic or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N, O and S;
wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, a linear or branched C1-4 thioalkyl group, a linear or branched C1-4 halothioalkyl group and a cyano group;
• Or when Q represents a phenyl group, L together with Q form a 5- to 7- membered N-containing heterocyclyi fused to the phenyl group;
• n is 0 or 1; and
represents a single or a double bond;
wherein the bicyclic heterocycle derivative is other than :
• 3-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)pyrimido[4,5-d]pyrimidin- 4(3H)-one • 6-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-1 -methyl-1 H- pyrazolo[4,3-d]pyrimidin-7(6H)-one • 1-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H-purin- 6(7H)-one
The invention further provides synthetic processes and intermediates described herein, which are useful for preparing said bicyclic heterocycle derivatives.
The invention is also directed to a bicyclic heterocycle derivative of the invention as described herein for use in the treatment of the human or animal body by therapy.
The invention also provides a pharmaceutical composition comprising a bicyclic heterocycle derivative of the invention and a pharmaceutically-acceptable diluent or carrier. The invention also provides a bicyclic heterocycle derivative of the invention for use in the treatment of a disease or condition susceptible to amelioration by TRPA1 antagonists or inhibitors, in a mammal, in particular wherein the pathological condition or disease is selected from acute and/or chronic pruritus, acute and/or chronic pain, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders. The invention also provides the use of a bicyclic heterocycle derivative of the invention in the manufacture of a formulation or medicament for treating a disease or condition susceptible to amelioration by TRPA1 antagonists or inhibitors, in particular wherein the condition or disease is as described above.
The invention also provides a method of treating a disease or condition as described above; comprising such method administering to the mammal, a therapeutically effective amount of a bicyclic heterocycle derivative of the invention. The invention further provides a method of treatment comprising administering a therapeutically effective amount of a combination of a bicyclic heterocycle derivative of the invention together with one or more other therapeutic agents.
The invention also provides a combination product comprising (i) a bicyclic heterocycle derivative of the invention as described herein; and (ii) one or more additional active substances.
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 C2-4 alkylene embraces divalent alkyl moieties typically having from 2 to 4 carbon atoms. Analogously, the term C2-3 alkylene embraces divalent alkyl moieties typically having from 2 to 3 carbon atoms. Examples of C2-4 alkylene radicals include ethylene, propylene and butylene radicals. A said alkylene group is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. A s used herein, the term C1-4 alkoxy (or alkyloxy) embraces unsubstituted o r 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.
A s used herein, the term C1-4 thioalkyl embraces radicals containing a linear o r branched alkyl radicals of 1 to 4 carbon atoms attached to a divalent -S- radical.
Examples include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, sec- butylthio and t-butylthio.
A s used herein, the term Ci-4 haloalkyl is a linear o r branched alkyl group, which is substituted by one or more, preferably 1, 2 o r 3 halogen atoms. Examples of haloalkyl groups include CCI3, CFsand C H F2.
A s 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 o r 3 halogen atoms. Examples of haloalkoxy groups include -OCF3 and -OCCI3.
A s used herein, the term Ci-4 halothioalkyl is typically a C1-4 thioalkyl group substituted by one or more halogen atoms. Typically, it is substituted by 1, 2 o r 3 halogen atoms. Examples of halothioalkyl groups include -SCF3 and -SCCI3.
A s used herein, the term C 3-7cycloalkyl embraces saturated carbocyclic radicals monocyclic or polycyclic ring having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
A s used herein, the term C 3-7cycloalkylene embraces divalent cycloalkyl moieties typically having from 3 to 7 carbon atoms. Examples of C 3-7cycloalkylene radicals include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene radicals.
A s used herein, the term Ce-14 aryl radical embraces typically a Ce-14, more preferably Ce-ιο monocyclic o r bicyclic aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred. A said Ce-14 aryl radical is typically unsubstituted o r substituted by 1, 2 o r 3 substituents which may be the same o r different.
A s used herein, the term monocyclic o r bicyclic 5- to 14-membered heteroaryl radical embraces typically a 5- to 14- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O , S and N , preferably S and N . A 5- to 14-membered heteroaryl radical may be a single ring o r two fused rings wherein at least one ring contains a heteroatom. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzo[b]thienyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-c/]pyrimidinyl, 1/-/-pyrazolo[3,4-c/]pyrimidinyl, benzo[b]thienyl, 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 5- to 7-membered N-containing heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-7 carbocyclic ring system in which one or more, for example 1 or 2 of the carbon atoms preferably 1 carbon atom is replaced by a N atom. Analogously, the term 5- to 6-membered N- containing heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-6 carbocyclic ring system in which one or more, for example 1 or 2 of the carbon atoms preferably 1 carbon atom is replaced by a N atom. Examples include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, pyrazolinyl, pirazolidinyl, pyrazolyl, tetrazolyl, imidazolidinyl and hexahidroazepenyl. The 5- to 7-membered N-containing heterocyclyl might be fused to a phenyl ring group. Examples of the fused bicyclic include indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzotetrahydro[b]azepenyl, benzotetrahydro[c]azepenyl and benzotetrahydro[d]azepenyl.
As used herein, the term 4- to 6-membered N-containing heterocyclylene embraces divalent typically a non-aromatic, saturated or unsaturated C4-6 carbocyclic ring system, in which one or more, for example 1, 2 or 3 of the carbon atoms preferably 1 carbon atom is replaced by a N atom. Analogously, the term 4- to 5-membered N- containing heterocyclylene embraces divalent typically a non-aromatic, saturated or unsaturated C4-5 carbocyclic ring system, in which one or more, for example 1 or 2 of the carbon atoms preferably 1 carbon atom is replaced by a N atom. Examples include azetidinylene, pyrrolidylene, piperidylene, pyrrolinylene, piperazinylene and pyrrolylene.
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 C 1-4 dialkylamino as used herein is represented by the formula - N(Ci -4 alkyl )2 where C 1-4 alkyl is as described above. Representative examples include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group and d\{tert- butyl)amino group.
As used herein, some of the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "unsubstituted or substituted". This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1, 2 , 3 or 4 , substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
The term "treatment" as used herein refers to the treatment of a disease or medical condition in a human patient which includes:
(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;
(b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in a patient;
(c) suppressing the disease or medical condition, i.e., slowing the development of the disease or medical condition in a patient; or
(d) alleviating the symptoms of the disease or medical condition in a patient.
The phrase "pathological condition or disease susceptible to amelioration by inhibition or antagonism of TRPA1" includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with an increased TRPA1 activity. Such disease states include, but are not limited to, acute and/or chronic pruritus, acute and/or chronic pain, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders. The term "pruritus" is used herein in the broadest sense and refers to all types of itching and stinging sensations localized and generalized, acute intermittent and persistent. The pruritus may be dermatologic, idiopathic, allergic, metabolic, infectious, drug-induced, due to liver, kidney disease or cancer.
The term "pain" is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g. somatic pain and visceral pain; inflammatory pain; dysfunctional pain; idiopathic pain; neuropathic pain, e.g. centrally generated pain and peripherally generated pain; migraine and cancer pain.
The term "inflammatory dermatological disease" includes the following dermatological diseases as non-limiting examples of such dermatological diseases: acne vulgaris, actinic keratosis, eczema, atopic dermatitis, insect bite inflammation, drug-induced skin reactions, psoriasis, rosacea and seborrheic dermatitis.
By the term "respiratory disorder", it is meant any condition or disease related to respiration or the respiratory system and includes, but is not limited to, airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, bronchiectasis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), inflammatory respiratory diseases conditions poorly responder to corticosteroids (i.e. severe COPD and asthma), sensory hyper-reactivity, multiple chemical sensitivity and aid in smoking cessation therapy. The term "cough" refers to both acute and/or chronic cough and includes interstitial lung disease cough, post-viral cough, gastroesophageal reflux disease (GERD)-related cough, cough variant asthma, COPD cough, lung cancer cough, upper airways cough syndrome (UACS), post nasal drip cough, idiopathic cough and cough associated with other respiratory diseases such as idiopathic pulmonary fibrosis (IPF). The term "gastrointestinal inflammatory disorders" as used herein includes, but is not limited to, disorders such as inflammatory bowel disease, ulcerative colitis and Crohn's disease.
The term "urinary tract disorders" as used herein includes, but is not limited to, disorders such as urinary incontinence, bladder instability and cystitis.
The term "pharmaceutically-acceptable salt" refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, hydrofluoric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1-hydroxy-2-naphthoic acid), napadisilic
( 1 ,5-naphthalenedisulfonic acid), triphenyl acetic and the like. Particularly preferred are salts derived from formic, fumaric, hydrobromic, hydrochloric, hydrofluoric, acetic, sulfuric, methanesulfonic, xinafoic, tartaric, maleic, succinic and napadisilic acids.
Salts derived from pharmaceutically-acceptable inorganic bases include aluminium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are calcium, magnesium, potassium and sodium salts.
Salts derived from pharmaceutically-acceptable organic bases include salts of ammonia, primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as ammonia, arginine, betaine, caffeine, choline, /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-labelled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and H, carbon, such as C,
C and 4 C, chlorine, such as 6CI, fluorine, such as F, iodine, such as 2 l and 2 l, nitrogen, such as N and N, oxygen, such as 0 , 70 and 0 , phosphorus, such as 2P, and sulfur, such as S.
Isotopically-labelled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent otherwise employed.
Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the invention. As used herein, the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar % .
As used herein, the term stereoisomer means a compound that have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three- dimensional orientations of their atoms in space. The compounds of the invention may contain one or more chiral centers. Accordingly, the invention includes racemic mixtures, enantiomers, and mixtures enriched in one or more stereoisomer. The scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
As used herein, the term tautomer means two or more forms or isomers of an organic compound that readily could be interconverted into each other via a common chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. Typically G4 represents a C-H group or a N atom; and/or G5 represents a C(Ra) group or a N(R ) group.
In a preferred embodiment, wherein G2 is a N atom and n is 0, G is C atom, G3 is a N atom and G5 is a N(R ) group or G is C atom, G3 is a N(R ) group and G5 is a C(Ra) group or G is a N atom, G3 is a C(Ra) group and G5 is a C(Ra) group or G is C atom, G3 is a C(Ra) group and G5 is a N(R ) group; and preferably wherein G2 is a N atom and n is 0 , G is C atom, G3 is a N atom and G5 is a N-Me group or G is a N atom, G3 is a C-H group and G5 is a C-Me group or G is C atom, G3 is a C-H group and G5 a N-Me group.
In another preferred embodiment, wherein G2 is a N atom, G is C atom and n is 1, G3 is a C(Ra) group, G4 is a N atom or a C-H group and G5 is a C(Ra) group; and preferably wherein G2 is a N atom, G is C atom and n is 1, G3 is a C-NH2 group, G4 is a N atom and G5 is a C-Me group, or G3 is a C(Ra) group, G4 is a C-H group and G5 is a C-Me group, wherein Ra is a chlorine atom or a methoxy group.
In another preferred embodiment, wherein G2 is a N(R ) group, G is C atom and n is 0, G3 is a C(Ra) group or a N atom and G5 is a N(R ) group or a C(Ra) group; and preferably wherein G2 is a N-Me group, G is C atom and n is 0 , G3 is a C=0 group and G5 is a N-Me group or G3 is a N atom and G5 is a C(Ra) group, wherein Ra is a H atom or a methyl group.
In another preferred embodiment, wherein G2 is a N(R ) group, G is C atom and n is 1, G3 is a C(Ra) group, G4 is a C-H group and G5 is a C(Ra) group; and preferably wherein G2 is a N-H group or a N-Me group, G is C atom and n is 1, G3 is a C=0 group, G4 is a C-H group and G5 is a C-Me group.
In another preferred embodiment, wherein G2 is a C(Ra) group and n is 0, G is a N atom or a C atom, G3 is a N atom or a N(R ) group, G5 is a C(Ra) group or a N(R ) group; preferably wherein G2 is a C=0 group, G is a N atom, G3 is a N-H group and G5 is a C-Me group; or wherein G2 is a C-H group and G is a N atom, G3 is a N atom and G5 is a C-Me group or a C-H group or a C-CN group; or wherein G2 is a C-H group or C-Me group and G is a C atom, G3 is a N atom and G is a N-Me group; or wherein G2 is a C-Me group or a C-NH-Me group, G is a N atom, G3 is a N atom and G5 is a C-Me group.
In another preferred embodiment, wherein G2 is a C(Ra) group, G is a C atom and n is 1, G3 is a N atom or a C(Ra) group, G4 and G are C(Ra) groups; preferably wherein G2 is a C-H group, G3 and G4 are C-H groups and G is a C-Me group; or G2 is a C-H group or a C-OMe group, G3 is a N atom, G4 is a C-H group and G is a C-Me group.
In a more preferred embodiment, a compound of Formula ( I) is represented by compounds from Formula (la) to Formula (Ig):
Formula (la) Formula (lb) Formula (lc)
Formula (Id) Formula (le) Formula (If)
Formula (Ig)
Typically, Ra is selected from the group consisting of a H atom, a linear or branched
Ci-3 alkyl group, a halogen atom , a linear or branched Ci-2 alkoxy group, an oxo group, a cyano group, an amino group, a Ci-2 rmonoalkylamino group and a hydroxyl group.
In a preferred embodiment, Ra is selected from the group consisting of a H atom, a linear or branched C1-2 alkyl group, a chlorine atom , a methoxy group, an oxo group, a cyano group, an amino group, a methylamino group and a hydroxyl group.
Typically, R is selected from the group consisting of a H atom and a linear or branched C1-3 alkyl group.
In a preferred embodiment R is a H atom and a linear or branched C1-2 alkyl group.
Typically, L represents a linear or branched C2-3 alkylene group unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-2 alkyl group, a hydroxyl group, a linear or branched C i-2 alkoxy group, a linear or branched C1-2 haloalkyl group and a -NR'R" group; a -C(R )=C(R )- group; a cyclopropylene group according to formula (i); a -(CH2)2-0- group; a -(CH2)-C(0)- group; a -(CH2)-S- group; a -(CH2)-S(0)- group; a -CONH- group; a -CF2O- group; and a 4- to 5-membered N-containing heterocyclylene group, wherein at least one nitrogen atom is linked to the G7 group;
( 1)
wherein R' and R" each independently represent a hydrogen atom, a linear or branched C1-2 alkyl group or a linear or branched C1-2 haloalkyl group.
In a preferred embodiment L represents an ethylene group unsubstituted or substituted by one or more substituents selected from a fluorine atom, a methyl group, a hydroxyl group and a methoxy group; a -C(H)=C(H)- group; a-C(H)=C(Me)- group; a cyclopropylene group according to formula (i); a -(CH2)2-0- group; a -(CH2)-C(0)- group; a -(CH2)-S- group; a -(CH2)-S(0)- group; a -CONH- group; an azetidinylene group of formula (ii) and a pyrrolidylene group of formula (iii) wherein the nitrogen atom is linked to the G7 group.
(ii) (iii)
Typically, Q is selected from the group consisting of a monocyclic or bicyclic C e- 14 aryl group and a monocyclic or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N and S of formula (iv), (v), (vi) or (vii);
(iv) (v) (vi) (vii)
wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-3 alkyl group, a linear or branched C1-2 alkoxy group, a linear or branched C1-2 haloalkyl group, a linear or branched C1-2 haloalkoxy group, a linear or branched C1-2 thioalkyl group and a linear or branched C1-2 halothioalkyl group;
Or when Q represents a phenyl group, L together with Q form a 5- to 6-membered N- containing heterocyclyi fused to the phenyl group, forming a ring of formula (viii) or (ix).
(viii) (ix)
In a preferred embodiment Q is selected from the group consisting of a phenyl group, a naphthyl group, a quinolyl group or a thienyl group;
wherein the phenyl, naphthyl group, quinolyl group and thienyl groups are unsubstituted or substituted by one or more substituents selected from a chlorine atom, a bromide atom, a -CF3 group, a -OCF3 group, a -SCF3 group and an isopropyl group;
Or when Q represents a phenyl group, L together with Q form a pyrrolidinyl and piperidinyl fused to the phenyl group (as represented above in (viii) and (ix)).
In a most preferred embodiment, a compound of Formula (I) is represented by compounds from Formula (Ip) to Formula (Iv): Formula (lp) Formula (Iq) Formula (Ir)
Formula (Is) Formula (It) Formula (lu)
Formula (Iv)
wherein:
• Ra is selected from the group consisting of a H atom, a linear or branched C1-2 alkyl group or an oxo group;
• R is independently selected from the group consisting of a H atom or a linear
or branched C1-2 alkyl group;
• L represents an ethylene group substituted by a hydroxyl group; and • Q is selected from the group consisting of a phenyl group, a naphthyl group, a quinolinyl group and a thienyl group; wherein the phenyl, naphthyl, quinolinyl and thienyl groups are unsubstituted or substituted by one or more substituents selected from a chlorine atom, a bromine atom, a -CF3 group, a -OCF3 group, a -SCF3 group and an isopropyl group.
Particular individual compounds of the invention include:
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylquinazolin-4(3H)- one 3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2 4-oxadiazol-5-yl}methyl)imidazo[5 1-f][1 2,4]triazin- 4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2 4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(3-Chlorophenyl)ethyl]-1 ,2,4K)xadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5,7-dimethylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2 4-oxadiazol-5-yl}methyl)-4-oxo-3,4- dihydroimidazo[5,1-f][1 ,2,4]triazine-5-carbonitrile
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-5-methyl-7- (methylamino)imidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2 4-oxadiazol-5-yl}methyl)-5-methylpyrazolo[5,1- f][1 ,2,4]triazin-4(3H)-one
6-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one
5-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one
5-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,5-dihydro- 4H-pyrazolo[3,4-d]pyrimidin-4-one
1,3-Dimethyl-5-{[3-(2-phenylethyl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one
6-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
1-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-7 9-dimethyl-7,9-dihydro- 1H-purine-6,8-dione
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazine-4,7(3H,6H)-dione
7-Chloro-3-({3-[2-(4-chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methoxy-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one 3-({3-[2-(4-Chlorophenyl)ethyl]-1 2 4-oxadiazol-5-yl}methyl)-5-methylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2 4-oxadiazol-5-yl}methyl)-5 8-dimethylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione
7-Amino-3-({3-[2-(4-chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-5- methylpyrimido[4,5-d]pyrimidin-4(3H)-one
1-({3-[2-(3-Bromophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7-dihydro-6H- purin-6-one
1-[(3-{[(4-Chlorophenyl)thio]methyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7-methyl-1 ,7-dihydro- 6H-purin-6-one
5-[(3-{[(4-Chlorophenyl)thio]methyl}-1 ,2,4-oxadiazol-5-yl)methyl]-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
5-[(3-{[(4-Chlorophenyl)sulfinyl]methyl}-1 ,2,4-oxadiazol-5-yl)methyl]-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
6-({3-[(E)-2-(4-Chlorophenyl)vinyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro- 7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[(1 E)-2-(4-Chlorophenyl)prop-1 -en-1 -yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl- 1,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one trans 6-({3-[2-(4-Chlorophenyl)cyclopropyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
3-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
6-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
1-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7-dihydro-6H- purin-6-one
5-{[3-(1 ,3-Dihydro-2H-isoindol-2-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
1-{[3-(1 ,3-Dihydro-2H-isoindol-2-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-7-methyl-1 ,7-dihydro- 6H-purin-6-one
5-{[3-(3,4-Dihydroisoquinolin-2(1 H)-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,3-dimethyl-1 ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 5-({3-[3-(4-Chlorophenyl)azetidin-1-yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
5-({3-[3-(4-Chlorophenyl)pyrrolidin-1 -yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
N-(4-Chlorophenyl)-5-[(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)methyl]-1 ,2,4-oxadiazole-3-carboxamide
6-({3-[2-(4-Chlorophenyl)propyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-fluoroethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-methoxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-oxoethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one Ent 1
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one Ent 2
3-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
(S)-3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
(R)-3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
1-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-[(3-{2-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1 ,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(3-Bromophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one 1-[(3-{2-Hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7- methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(4-Bromophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-[(3-{2-Hydroxy-2-[3-(trifluoromethoxy)phenyl]ethyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7- methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(3,4-Dichlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-[(3-{2-[2-Fluoro-4-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1 ,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
1-[(3-{2-Hydroxy-2-[4-(trifluoromethoxy)phenyl]ethyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7- methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-Hydroxy-2-(4-isopropylphenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-[(3-{2-[4-Chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1 ,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(2-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-{[3-(2-Hydroxy-2-quinolin-2-ylethyl)-1 ,2,4-oxadiazol-5-yl]methyl}-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-({3-[2-(2,4-Dichlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-({3-[2-Hydroxy-2-(2-naphthyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-{[3-(2-Hydroxy-2-{4-[(trifluoromethyl)thio]phenyl}ethyl)-1 2,4-oxadiazol-5-yl]methyl}-7- methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(5-Bromo-2-thienyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-fl[1 ,2,4]triazin-4(3H)-one
(S)-5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-fl[1 ,2,4]triazin-4(3H)-one (R)-5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-1][1 ,2,4]triazin-4(3H)-one
7-Amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrimido[4,5-d]pyrimidin-4(3H)-one
7-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2 4-oxadiazol-5-yl)methyl)-5,7- dimethylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
5-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-1][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- ethylpyrazolo[5,1-fl[1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- fluoropyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- (trifluoromethyl)pyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
8-Bromo-1-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7- methyl-1 H-purin-6(7H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-cyclopropyl-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-ethyl-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 2 4-oxadiazol-5-yl)methyl)-7,8-dimethyl- 1H-purin-6(7H)-one
7-Amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7- (dimethylamino)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one
5-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-9-ethyl-7- methyl-1 H-purine-6 8(7H,9H)-dione 1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 2,4-oxadiazol-5-yl)methyl)-7,9-dimethy 1H-purine-6,8(7H,9H)-dione
5-((3-(4-Chlorophenethyl)-1 2 4-oxadiazol-5-yl)methyl)-2 3-dimethyl-2H-pyrazolo[3,4- d]pyrimidin-4(5H)-one
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 2 4-oxadiazol-5-yl)methyl)-2,3-dimethyl- 2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-ethyl-3- methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-isopropyl-3- methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
1-((3-(3,4-Dichlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H-purin-6(7H)- one
6-((3-(3,4-Dichlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-1 -methyl-1 H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one
1-((3-(2-(4-Chlorophenyl)-2-hydroxypropyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H- purin-6(7H)-one
5-Chloro-3-((3-(2-(4-chlorophenyl)-1-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-fl[1 ,2,4]triazin-4(3H)-one or a pharmaceutically acceptable salt, solvate, /V-oxide, tautomer, stereoisomer, or isotopically-labelled derivative thereof.
Of particular interest are the compounds:
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)imidazo[5,1-f][1 ,2,4]triazin- 4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(3-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5,7-dimethylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one 3-({3-[2-(4-Chlorophenyl)ethyl]-1 2 4-oxadiazol-5-yl}methyl)-5-methylpyrazolo[5,1- f][1 ,2,4]triazin-4(3H)-one
6-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one
5-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,5-dihydro- 4H-pyrazolo[3,4-d]pyrimidin-4-one
6-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
1-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-7 9-dimethyl-7,9-dihydro- 1H-purine-6,8-dione
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- fl[1 ,2,4]triazine-4,7(3H,6H)-dione
7-Chloro-3-({3-[2-(4-chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-5-methylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2 4-oxadiazol-5-yl}methyl)-5 8-dimethylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione
7-Amino-3-({3-[2-(4-chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrimido[4,5-d]pyrimidin-4(3H)-one
1-({3-[2-(3-Bromophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7-dihydro-6H- purin-6-one
5-[(3-{[(4-Chlorophenyl)thio]methyl}-1 ,2,4-oxadiazol-5-yl)methyl]-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
3-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
6-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one 1-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7-dihydro-6H- purin-6-one
5-{[3-(1 ,3-Dihydro-2H-isoindol-2-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
N-(4-Chlorophenyl)-5-[(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)methyl]-1 ,2,4-oxadiazole-3-carboxamide
6-({3-[2-(4-Chlorophenyl)propyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-fluoroethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one Ent 1
3-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
(S)-3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
1-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-({3-[2-(3-Bromophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-({3-[2-(4-Bromophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-({3-[2-(3,4-Dichlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-({3-[2-Hydroxy-2-(2-naphthyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one 5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-1][1 ,2,4]triazin-4(3H)-one
(S)-5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-1][1 ,2,4]triazin-4(3H)-one
7-Amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrimido[4,5-d]pyrimidin-4(3H)-one
7-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2 4-oxadiazol-5-yl)methyl)-5,7- dimethylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
5-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-1][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- fluoropyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
8-Bromo-1-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7- methyl-1 H-purin-6(7H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-cyclopropyl-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-ethyl-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
7-Amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one
5-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-9-ethyl-7- methyl-1 H-purine-6 8(7H,9H)-dione
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 2 4-oxadiazol-5-yl)methyl)-7,9-dimethyl- 1H-purine-6,8(7H,9H)-dione 5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 2,4-oxadiazol-5-yl)methyl)-2,3-dimethy 2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-ethyl-3- methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-isopropyl-3- methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
1-((3-(3,4-Dichlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H-purin-6(7H)- one
6-((3-(3,4-Dichlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-1 -methyl-1 H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one or a pharmaceutically acceptable salt, solvate, /V-oxide, tautomer, stereoisomer, isotopically-labelled 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 - 6 are described in detail in the Experimental section.
Intermediates of the general formula (6) wherein G to G5 and n are as defined in Claim 1, and where the heterobicyclic group is also defined as a group A , may be prepared following the synthetic routes depicted in Scheme 1.
HCONH2
(5) (3) )
(4) Scheme 1
Compounds of general formula (6) may be prepared from compounds of formula (2) wherein R represents a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, ie/f-butyl or a benzyl group, and a formamide equivalent such as formamide or formamidine and salts thereof. In one instance, wherein R is a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, ie/f-butyl or a benzyl group, the reaction is carried out by mixing a compound of formula (2) with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to 200 °C to give a compound of formula (6). In another instance, wherein R is an alkyl group such as methyl, ethyl, propyl, ie/f-butyl or a benzyl group, the reaction is carried out by mixing a compound of formula (2) with formamidine acetic acid salt in the presence or absence of an acid such as acetic acid, in a solvent such as n-butanol at a temperature from 50 °C to 150 °C to give a compound of formula (6). Compounds of general formula (6) may also be prepared from compounds of formula (3). In another instance, the reaction is carried out by mixing a compound of formula (3) with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to 200 °C to give a compound of formula (6). In another instance, the reaction is carried out by mixing a compound of formula (3) with an ortho- formate of formula (5) wherein R 2 represents an alkyl group such as methyl or ethyl, in the presence or absence of a solvent such as acetic anhydride at a temperature from 50 °C to 200 °C.
Compounds of general formula (6) may also be prepared from compounds of formula (4) and formic acid, in the presence or absence of an acid such as sulphuric acid at a temperature from 50 °C to 200 °C.
In the specific case where G is a nitrogen atom and G2 to G5 and n are as defined in Claim 1, intermediates of formulas (8) and (10) may be prepared following the synthetic routes depicted in Scheme 2 .
(7) (8)
(9) (10) Scheme 2
Intermediates of formula (8), wherein wherein R is a an alkyl group such as methyl, ethyl, propyl, ie -butyl or a benzyl group, may be prepared from intermediates of formula (7) in the presence of a base such as lithium hexamethyldisilazide and an aminating agent such as 0-(diphenylphosphoryl)hydroxylamine, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from -78 °C to room temperature under an inert atmosphere such as nitrogen or argon. In a similar fashion, intermediates of formula (10) may be prepared from intermediates of formula (9) in the presence of a base such as lithium hexamethyldisilazide and an aminating agent such as O-
(diphenylphosphoryl)hydroxylamine, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from -78 °C to room temperature under an inert atmosphere such as nitrogen or argon.
Bicyclic heterocycles of general formula ( 1 1 wherein G to G5 and n are as defined in Claim 1 and independent of their attachment to other groups through the amide nitrogen may be further modified to compounds such as (12) or (14) following the synthetic routes depicted in Scheme 3 .
( 1 1) ( 12) ( 14) Scheme 3
In some instances, compounds containing a bicyclic heterocycle of formula (12) wherein one or more of the groups G2 to G5 is a carbon atom substituted with a W3 group, wherein W3 is a halogen atom such as fluorine, chlorine, bromine or iodine may be synthesized from a compound containing a bicyclic heterocycle of formula ( 1 1) wherein one or more of the groups G2 to G5 is a CH group. The reaction may be carried out by mixing a compound of formula ( 1 1) with a halogenating reagent such as 1- (chloromethyl)-4-fluoro-1 ,4- diazabicyclo[2.2.2]octane-1 ,4-diium tetrafluoroborate, copper(ll) bromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodosuccinimide, bromine or iodine, in a solvent such as acetonitrile, chloroform or dimethylformamide at a temperature from 0 °C to 100 °C.
In some instances, compounds containing a bicyclic heterocycle of formula (12) wherein W3 is a halogen atom such as bromine or iodine, prepared as described above, may be used as substrates in metal catalysed cross coupling reactions with a suitable partner such as an alkyl and/or aryl boronate, a boronic acid or a trifluoroborate salt for introduction of aryl and alkyl groups on the bicyclic heterocycle (12).
Compounds containing a bicyclic heterocycle of formula (14) wherein R 3 and R 4 are independently selected from a group containing a hydrogen atom or an alkyl group such as methyl, ethyl or isopropyl, may be synthesized from a compound containing a bicyclic heterocycle of formula (12) wherein W3 represents a halogen atom such as chlorine, bromine or iodine. The reaction may be carried out by mixing a compound of formula (12) with an amine of formula (13), in the presence or absence of a base such as diisopropylethylamine of potassium carbonate, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from 50 °C to 150 °C.
Intermediates of general formula (6), wherein G to G5 and n are as defined in Claim 1, and where the heterobicyclic group can also defined as a group A may be modified to intermediates such as (16), (17) or (19) following the synthetic routes depicted in Scheme 4 .
Scheme 4
Compounds of general formula (16) wherein A is as hereinbefore defined and R represents an alkyl group such as methyl, ethyl, propyl, ie -butyl or a benzyl group may be prepared from bicyclic compounds of formula (6) and an alkylating agent of formula (15) wherein W represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate. The reaction is carried out by mixing a compound of formula (6) and compound of formula (15) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C. Compounds of general formula (17), wherein A is as hereinbefore defined may be prepared from compounds of formula (16), wherein R is as hereinbefore defined by hydrolysis according to standard literature methods known to those skilled in the art of ester hydrolysis. In one example, this may be through the use of a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from room temperature to 50 °C. Another example is through the use of an acid such as hydrochloric acid or trifluoroacetic acid in water, dichloromethane, chloroform or dioxane or a mixture thereof at a temperature from room temperature to 50 °C.
Compounds of general formula (19), wherein A is as hereinbefore defined, may be prepared from bicyclic compounds of formula (6) and an alkylating agent of formula (18) wherein W represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate. The reaction is carried out by mixing a compound of formula (6) and compound of formula (18) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C.
Intermediates of general formula (25), wherein G6 to G9, L and Q are as defined in Claim 1, and wherein W represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate may be synthesized according to the general routes depicted in Scheme 5 .
(20) (21)
Route A W -L-Q Route B W -L-Q
(22) (22)
(23) (24) (25)
Route C Route D Route E
Scheme 5 Compounds of general formula (23) wherein G6 to G9, L and Q are as defined in Claim 1, and R represents an alkyl group such as methyl, ethyl, propyl, ie -butyl or a benzyl group may be prepared from compounds of formula (20) and an alkylating agent of formula (22) wherein W 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 (20) and a compound of formula (22) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C. An example of Route A is, but not limited to, the case where G6 to G9 represent a nitrogen atom and hence the heteroaromatic ring defined by G6 to G9 is a tetrazole.
Compounds of general formula (23) may also be prepared via a range of routes referred to as Route C. An example of Route C is, but not limited to, the case wherein G6 and G8 represent a nitrogen atom, G7 represents a carbon atom and G9 represents a sulphur atom and hence the heteroaromatic ring defined by G6 to G9 is a thiadiazole.
Compounds of general formula (27) wherein L and Q are defined according to Claim 1 may be prepared from compounds of formula (26) according to standard literature methods known to those skilled in the art of formation of amides. In one instance, this may involve first treating a compound of formula (26) with a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC), in the presence or absence of a catalyst such as 1-hydroxybenzotriazole (HOBt) and then treating the mixture with ammonia to give a compound of formula (27).
Compounds of general formula (28), wherein L and Q are as hereinbefore defined, may be prepared from compounds of formula (27) and chlorocarbonylsulfenyl chloride. The reaction is carried out by mixing a compound of formula (27) and chlorocarbonylsulfenyl chloride in a solvent such as toluene at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (28). Compounds of general formula (30), a subset of general formula (23), wherein L and Q are as hereinbefore defined and R is an alkyl group such as methyl, ethyl, propyl, ie -butyl or a benzyl group, may be prepared from compounds of formula (28) and a compound of formula (29) wherein R is hereinbefore defined. The reaction is carried out by mixing a compound of formula (28) and a compound of formula (29) in a solvent such as tetrahydrofuran at a temperature from 100 °C to 180 °C in a sealed vessel under microwave irradiation to give a compound of formula (30).
Compounds of general formula (24) wherein G to G5, L and Q are as defined in Claim 1, may be prepared from compounds of formula (21 ) and an alkylating agent of formula (22) wherein W represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate. The reaction is carried out by mixing a compound of formula (21 ) and a compound of formula (22) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C. An example of Route B is, but not limited to the case where G6, G7 and G9 represent a nitrogen atom and G8 represents a C-H group and hence the heteroaromatic ring defined by G6 to G9 is a 1,2,4-triazole.
Compounds of general formula (24) may be prepared from compounds of formula (23) and a reducing agent according to standard literature methods known to those skilled in the art of reduction of esters to alcohols. In one instance the reaction is carried out by mixing a compound of formula (23) and a reducing agent such as sodium borohydride in a solvent such as ethanol at a temperature from 0 °C to 50 °C to give a compound of formula (24).
Compounds of general formula (24) may also be prepared via range of routes referred to as Route D. An example of Route D is, but not limited to, the case wherein G6 and G9 represent a nitrogen atom, G7 represents a carbon atom and G8 represents an oxygen atom and hence the heteroaromatic ring defined by G6 to G9 is a 1,2,4- oxadiazole. Example route D
Compounds of general formula (31 ) wherein L and Q are defined according to Claim 1 may be prepared from compounds of formula (26) and dihydroxyethanimidamide according to standard literature methods known to those skilled in the art of formation of amides. In one instance, this may involve first converting a compound of formula (26) to an acid chloride with an activating agent such as thionyl chloride or phosphorous oxychloride and then reacting the acid chloride with dihydroxyethanimidamide in the presence of a base such as diisopropylehtylamine in a solvent such as tetrahydrofuran to give a compound of formula (31).
Compounds of general formula (32), a subset of general formula (24) , wherein L and Q are as hereinbefore defined may be prepared from compounds of formula (31 ) by condensation. In one instance, a compound of formula (31 ) is treated with a base such as sodium acetate in a solvent such as ethanol at a temperature from room temperature to the boiling point of the solvent to give a compound of formula (32).
Another example of Route D is, but not limited to the case wherein G6 and G8 represent a nitrogen atom, G7 represents a carbon atom and G9 represents an oxygen atom and hence the heteroaromatic ring defined by G6 to G9 is a 1,2,4-oxadiazole. In this particular example, L is also defined as a 4- to 6-membered N-containing heterocyclylene group, or that when Q represents a phenyl group, L together with Q , as defined in Claim 1 form a 5- to 7-membered N-containing heterocyclyl fused to the phenyl group; Example route D
03} {35} {37}
Compounds of general formula (35) wherein W3 represents a halogen atom such as chlorine, bromine or iodine and PG represents a suitable alcohol protecting group selected from an ester group such as acetate or benzoate, or an acetal such as tetrahydropyranyl, may be prepared from compounds of formula (33) and compound of formula (34). The reaction is carried out by treating a compound of formula (33) with a compound of formula (34) in the presence of a base such as sodium bicarbonate in a solvent such as toluene at a temperature from 40 °C to the boiling point of the solvent to give a compound of formula (35).
Compounds of general formula (37) wherein Q is defined according to Claim 1 and PG is hereinbefore defined may be prepared from compounds of formula (35) wherein W3 is hereinbefore defined and an amine of formula (36). The reaction is carried out by treating a compound of formula (35) with a compound of formula (36) in a solvent such as ethanol at a temperature from 40 °C to the boiling point of the solvent to give a compound of formula (37). Intermediates of formula (38), a subset of general formula (24), wherein Q is defined according to Claim 1, may be prepared from compounds of formula (37), wherein PG is as hereinbefore defined, according to standard literature methods for alcohol deprotection. In the specific case where PG is a tetrahydropyranyl protecting group, the reaction is carried out by treating a compound of formula (37) with an acid catalyst such as Montmorillonite in a solvent such as water, methanol or mixtures thereof at a temperature from room temperature to the boiling point of the solvent. Compounds of general formula (25) wherein G6 to G9, L and Q are as defined in Claim 1, and W represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate may be prepared from compounds of formula (24). In one instance, where W represents a halogen atom, a compound of formula (24) is treated with a halogenating reagent such as thionyl chloride or phosphorus oxychloride in a solvent such as chloroform or toluene, at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (25).
Compounds of general formula (25) wherein may also be prepared via range of routes referred to as Route E. An example of Route E is, but not limited to, the case wherein G6 and G8 represent a nitrogen atom, G7 represents a carbon atom and G9 represents an oxygen atom and hence the heteroaromatic ring defined by G6 to G9 is a 1,2,4-oxadiazole.
Example route E
(39) (40) (42)
Compounds of general formula (40) wherein L and Q are as defined in Claim 1, may be prepared from compounds of formula (39) and hydroxylamine or salts thereof. The reaction is carried out by treating a compound of formula (39) with hydroxylamine hydrochloride, in the presence of a base such as sodium bicarbonate, in a solvent such as methanol or ethanol, at a temperature from room temperature to the boiling point of the solvent to give a compound of formula (40).
Compounds of general formula (42), a subset of general formula (25), wherein L and Q are as hereinbefore defined and wherein W represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate may be prepared from compounds of formula (40) and a compound of formula (41), wherein W2 represents either a halogen such as chlorine and hence (41 ) is an acyl chloride or a half-stoichiometric oxygen atom and hence (41 ) is an anhydride. The reaction is carried out by treating a compound of formula (40) with a compound of formula (41 ) in a solvent such as toluene at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (42). Another example of Route E is, but not limited to, the case wherein G6 represents an oxygen atom, G7 represents a carbon atom and G8 and G9 represent a nitrogen atom and hence the heteroaromatic ring defined by G6 to G9 is a 1,3,4-oxadiazole.
Ex
Compounds of general formula (43) wherein L and Q are as defined in Claim 1, may be prepared from compounds of formula (26) and hydrazine, or its hydrate, or salts thereof. The reaction may be carried out by treating a compound of formula (26) with hydrazine monohydrate in a sealed vessel at a temperature from 100 °C to 180 °C under microwave irradiation to give a compound of formula (43).
Compounds of general formula (44), wherein L and Q are hereinbefore defined and wherein W 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 (43) and a compound of formula (41), wherein W2 represents either a halogen such as chlorine and hence (41 ) is an acyl chloride or a half-stoichiometric oxygen atom and hence (41 ) is an anhydride. The reaction is carried out by treating a compound of formula (43) with a compound of formula (41 ) in the presence of a base such as triethylamine, in a solvent such as dichloromethane at a temperature from 0 °C to 50 °C to give a compound of formula (44).
Compounds of general formula (45), a subset of general formula (25), wherein L, Q and W are as hereinbefore defined may be prepared from compounds of formula (44) by dehydration. In one instance, the reaction is carried out by treating a compound of formula (44) with phosphorus oxychloride at a temperature from 50 °C to 120 °C to give a compound of formula (45).
A further example of Route E is, but not limited to, the case wherein G6 represents a nitrogen atom, G7 represents a carbon atom, G8 represent a C-H group and G9 represents an oxygen atom and hence the heteroaromatic ring defined by G6 to G9 is an oxazole. Compounds of general formula (47) wherein L and Q are as defined in Claim 1, may be prepared from compounds of formula (46) by a Strecker-type reaction followed by hydrolysis. The reaction may be carried out by first treating a compound of formula (46) with a cyanide source such as sodium cyanide and an ammonia source such as ammonium chloride in a solvent such as ethanol at a temperature from 0 °C to 50 °C, followed by treatment with an acid such as hydrochloric acid at a temperature from 50 °C to 100 °C to give a compound of formula (47).
Compounds of general formula (48) wherein L and Q are as hereinbefore defined may be prepared from compounds of formula (47) and a reducing agent according to standard literature methods known to those skilled in the art of reduction of carboxylic acids to alcohols. In one instance the reaction is carried out by mixing a compound of formula (47) and a reducing agent such as borane-dimethylsulfide complex in a solvent such as tetrahydrofuran at a temperature from 0 °C to 50 °C to give a compound of formula (48).
Compounds of general formula (49), wherein L and Q are as hereinbefore defined and wherein W 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 (48) and a compound of formula (41), wherein W2 represents either a halogen such as chlorine and hence (41 ) is an acyl chloride or a half-stoichiometric oxygen atom and hence (41 ) is an anhydride. The reaction may be carried out by treating a compound of formula (48) with a compound of formula (41 ) in the presence of a base such as triethylamine, in a solvent such as dichloromethane at a temperature from -78 °C to room temperature to give a compound of formula (49).
Compounds of general formula (50) wherein L, Q and W are as hereinbefore defined may be prepared from compounds of formula (49) and an oxidizing agent according to standard literature methods known to those skilled in the art of oxidation alcohols to aldehydes. In one instance the reaction is carried out by mixing a compound of formula (49) and an oxidizing agent such as the Dess-Martin periodinane in a solvent such as dichloromethane at a temperature from 0 °C to 50 °C to give a compound of formula (50).
Compounds of general formula (51 ), a subset of general formula (25), wherein L, Q and W are as hereinbefore defined may be prepared from compounds of formula (50) by dehydration. In one instance the reaction is carried out by mixing a compound of formula (50) and a dehydration agent such as phosphorous oxychloride at a temperature from 50 °C to 100 °C to give a compound of formula (51 ).
Compounds of the general formula (1_) wherein G6 to G9, L and Q are as defined in Claim 1, and where group A refers to the heterobicyclic group defined by G to G5 and n of Claim 1, may be prepared following the synthetic routes depicted in Scheme 6 .
W ' ¾ 7
A-H
6)
Route F
acid, edc, warm or from ester
A-H
Scheme 6
Compounds of formula (1_) may be prepared from compounds of formula (6) wherein A refers to the heterobicyclic group defined by G to G5 and n of Claim 1 and compounds of formula (25) wherein G6 to G9, L and Q are as defined in Claim 1 and W represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate. The reaction may be carried out by treating a compound of formula (6) with a compound of formula (25) in the presence of a base such as potassium carbonate, in a solvent such as dimethylformamide, at a temperature from room temperature to 50 °C to give a compound of formula (1). Compounds of general formula may also be prepared from either a compound of formula (16), wherein R is an alkyl group such as methyl, ethyl, propyl, ieri-butyl or a benzyl group, or from a compound of formula (17) via a range of routes to construct the heterocycle defined by G6 to G9, referred to as Route F. An example of Route F is, but not limited to, the case wherein G6 and G8 represent a nitrogen atom, G7 represents a carbon atom and G9 represents an oxygen atom and hence the heteroaromatic ring defined by G6 to G9 is a 1,2,4-oxadiazole. Exam le route F
Compounds of general formula (53), a subset of general formula (1_), wherein L, Q and A are as hereinbefore defined may be prepared from compounds of formula (16) wherein R is as hereinbefore defined and a compound of formula (40). The reaction may be carried out by treating a compound of formula (16) with a compound of formula (40) in the presence of a base such as potassium carbonate, in a solvent such as toluene, at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (53).
In a similar fashion, compounds of general formula (53), may also be prepared from compounds of formula (17) and a compound of formula (40). The reaction may be carried out by treating a compound of formula (17) with a compound of formula (40) in the presence of a peptide coupling reagent such as /V-(3-dimethylaminopropyl)-/V- ethylcarbodiimide hydrochloride in a solvent such as dichloroethane, dimethylformamide or mixtures thereof at temperatures from room temperature to 120 °C to give a compound of formula (53).
Another example of Route F is, but not limited to, the case wherein the heteroaromatic ring defined by G6 to G9 is a 1,2,4-oxadiazole and L is defined as a -
CH2CH(OH)- group. Example route F
(54) (55) (56) (57)
Compounds of formula (55) wherein Q is as defined in Claim 1 may be prepared from compounds of formula (54). The reaction is carried out by treating a compound of formula (54) with acetonitrile in the presence of a base such as lithium hexamethyldisilazide, in a solvent such as tetrahydrofuran, at a temperature from -78 °C to room temperature, under an inert atmosphere such as argon to give a compound of formula (55). Compounds of general formula (56) wherein Q is as hereinbefore defined may be prepared from compounds of formula (55) and hydroxylamine or salts thereof. The reaction is carried out by treating a compound of formula (55) with hydroxylamine hydrochloride, in the presence of a base such as potassium carbonate, in a solvent such as methanol or ethanol, at a temperature from room temperature to the boiling point of the solvent to give a compound of formula (56).
Compounds of general formula (57), a subset of general formula (1_), wherein Q and A are as hereinbefore defined may be prepared from compounds of formula (16) wherein R is an alkyl group such as methyl, ethyl, propyl, ie -butyl or benzyl and a compound of formula (56). The reaction may be carried out by treating a compound of formula (16) with a compound of formula (56) in the presence of a base such as potassium carbonate, in a solvent such as toluene, at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (57).
A further example of Route F is, but not limited to, the case wherein the heteroaromatic ring defined by G6 to G9 is a 1,2,4-oxadiazole and L is defined as a - CONH- group. Compounds of general formula (59), wherein A is as hereinbefore defined and R is an alkyl group such as methyl, ethyl, propyl, ie -butyl or a benzyl group may be prepared from compounds of formula ( 17) and a compound of formula (58). The reaction may be carried out by treating a compound of formula ( 17) with a compound of formula (58) in the presence of a peptide coupling reagent such as N-(3- dimethylaminopropyl)-/V -ethylcarbodiimide hydrochloride in a solvent such as dichloroethane, dimethylformamide or mixtures thereof at temperatures from room temperature to 120 °C to give a compound of formula (59).
Compounds of general formula (59), may also be prepared from compounds of formula (6) and a compound of formula (60) wherein A and R are hereinbefore defined , and W3 represents a halogen atom such as chlorine, bromine or iodine. The reaction may be carried out by treating a compound of formula (6) with a compound of formula (60) in the presence of a base such as potassium carbonate, in a solvent such as dimethylformamide, at a temperature from room temperature to 50 °C to give a compound of formula (59).
Compounds of general formula (62), a subset of general formula (1_), wherein Q and A are as hereinbefore defined may be prepared from compounds of formula (59) wherein R is hereinbefore defined and an amine of formula (6 1). In one instance, the reaction may be carried out by treating a compound of formula (59) with a compound of formula (61 ) in the presence of a Lewis acid such as trimethylaluminium, in a solvent such as chloroform, at a temperature from room temperature to the boiling point of the solvent to give a compound of formula (62). In another instance, the reaction is carried out by first hydrolysing a compound of formula (59) according to standard methods of ester hydrolysis, for example with lithium hydroxide monohydrate in water, and then treating the resulting carboxylic acid with an amine of formula (61 in the presence of a peptide coupling reagent such as /V-ethyl-/V'-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate in a solvent such as dichloromethane to give a compound of formula (62).
Compounds of general formula (52) wherein G6 to G9 and A are as hereinbefore defined may be prepared from either a compound of formula (16), wherein R is an alkyl group such as methyl, ethyl, propyl, ie -butyl or a benzyl group, or from a compound of formula (17) via a range of routes to construct the heterocycle defined by G6 to G9, referred to as Route G . An example of Route G is, but not limited to, the case wherein G6 represents a nitrogen atom, G7 represents a NH group, G8 represents a carbonyl group and G9 represents an oxygen atom and hence the heteroaromatic ring defined by G6 to G9 is a 1,3,4-oxadiazolone. Example route G
Compounds of general formula (63) wherein A is as hereinbefore defined may be prepared from compounds of formula (17) according to standard literature methods known to those skilled in the art of formation of amides. In one instance, this may involve treating a compound of formula (17) with semicarbazide in the presence of a peptide coupling reagent such as (benzotriazol-l-yloxy)tris(dimethylamino) phosphonium hexa-fluorophosphate, in the presence of a base such as triethylamine in a solvent such as dichloromethane to give a compound of formula (63). Compounds of general formula (64), a subset of general formula (52), wherein A is as hereinbefore defined may be prepared from compounds of formula (63) by cyclization. In one instance, this may involve treating a compound of formula (63) with a dehydrating agent such as trimethylsilyl tnfluoromethanesulfonate in the presence of a base such as triethylamine, in solvent such as dioxane in a sealed vessel at a temperature from 100 °C to 180 °C to give a compound of formula (64).
Compounds of general formula (1_) may additionally be prepared from compounds of formula (52) and an alkylating agent of formula (22) wherein W represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para- toluenesulphonate or methylsulfonate. The reaction is carried out by mixing a compound of formula (52) and a compound of formula (22) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C. Compounds of general formula may further be prepared from compounds of formula (19) via a range of routes to construct the heterocycle defined by G6 to G9, referred to as Route H. An example of Route H is, but not limited to, the case wherein G6 and G8 represent a nitrogen atom, G7 represents a carbon atom and G9 represents a NH group and hence the heteroaromatic ring defined by G6 to G9 is a 1,2,4-triazole. Exampl
(19) (65)
Compounds of general formula (65), a subset of general formula (1_), wherein L, Q and A are hereinbefore defined may be prepared from compounds of formula (19) and a compound of formula (43) . In one instance, the reaction may be carried out by treating a compound of formula (19) with a compound of formula (43) in the presence of a base such as 4-dimethylaminopyridine, in a solvent such as ethanol, in a sealed vessel at a temperature from 100 °C to 180 °C to give a compound of formula (65).
A further example of Route H is, but not limited to, the case wherein the heteroaromatic ring defined by G6 to G9 is a 1,2,4-oxadiazole and L is also defined as a 4- to 6-membered N-containing heterocyclylene group, or that when Q represents a phenyl group, L together with Q , as defined in Claim 1 form a 5- to 7-membered N- containing heterocyclyl fused to the phenyl group. Example route H
(19) (66) (67)
Compounds of general formula (66) wherein A is as hereinbefore defined and W 3 represents a halogen atom such as chlorine, bromine or iodine may be prepared from compounds of formula (19) and compound of formula (34). The reaction is carried out by treating a compound of formula (19) with a compound of formula (34) in the presence of a base such as sodium bicarbonate in a solvent such as toluene at a temperature from 40 °C to the boiling point of the solvent to give a compound of formula (66).
Compounds of general formula (67), a subset of general formula ( 1 ), wherein Q is defined according to Claim 1 may be prepared from compounds of formula (66) wherein W3 is as hereinbefore defined and an amine of formula (36). The reaction is carried out by treating a compound of formula (66) with a compound of formula (36) in a solvent such as ethanol at a temperature from 40 °C to the boiling point of the solvent to give a compound of formula (67).
PREPARATION EXAMPLES
The syntheses of the compounds of the invention are illustrated by the following Examples ( 1 to 95) including Preparations ( 1 to 209) 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 µ η ) with the solvent system indicated. Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a C18 column and using a gradient, unless otherwise stated, of water-acetonitrile/MeOH ( 1 : 1 )
(0.1% v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH ( 1 : 1 ) in 40 column volumes. The conditions "formic acid buffer" refer to the use of 0.1% v/v formic acid in both phases. The appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized.
Purifications in reverse phase were also made in a Biotage SP1® automated purification system equipped with a C18 column and using a gradient of, unless otherwise stated, water-acetonitrile/MeOH ( 1 :1) (0. 1% v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH ( 1 :1) in 80 column volumes. The conditions "formic acid buffer" refer to the use of 0 .1% v/v formic acid in both phases. The appropriate fractions were collected and freeze dried.
Gas chromatography was performed using a Thermo Trace Ultra gas chromatograph, coupled to a DSQ mass detector. Injections were performed on a split/splitless injector and a HP-1 MS was the capillary column. Mass spectra were obtained by electron impact ionisation at 70 eV.
Preparative HPLC-MS were performed on a Waters instrument equipped with a
2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 5 15 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 C 18 (2. 1 x 50 mm, 3.5 µ Μ) column for methods A , B and C and a Symmetry C18 (2. 1 x 100 mm, 3.5 µ Μ) 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 2 10 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.
Chromatographic separations were also obtained using a Waters 2795 system equipped with a Symmetry C 18 (2. 1 x 50 mm, 3.5 µ Μ) column for methods E. The mobile phases were (B): formic acid (0.7 ml) and acetonitrile ( 1000 ml) and (A): formic acid ( 1 ml) and water ( 1000 ml) (A), the gradients specified as follows:
The UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector. The system was equipped with an ACQU ITY UPLC BEH C-1 8 (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 2 10 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-001 0) with diode array detection and peak collection. Specific details are mentioned in the experimental section.
H Nuclear Magnetic Resonance Spectra were recorded on a Varian Mercury plus operating at a frequency of 400MHz, Varian Gemini-2000 spectrometer operating at a frequency of 300MHz or a Varian VNMRS operating at 600MHz and equipped with a cold probe for the H 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 refers to the presence of those halogens based on the standard isotope mass pattern (76% C I to 24% 7C I and 49% 79Br to 5 1% Br)
Standard synthetic methods are described the first time they are used. Compounds synthesized with similar methods are referred to only by their starting materials, without full experimental detail. Slight modifications to the general experimental methods used are permitted in these cases. Specific synthetic transformations already described in the literature are referred to only by their bibliographical reference. Other specific methods are also described in full. PREPARATIONS
PREPARATION 1
1,3-Dimethyl-1 ,5-dihydro-4H-pyrazolo[3,4-cf]pyrimidin-4-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 room temperature, a precipitate had formed. The precipitate was collected by filtration, was washed with ether and dried in a stream of air to give 0.63 g (3.84 mmol, 74% yield) of the title compound as a white solid. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 12.02 ( 1 H, br s), 8.00 ( 1 H, s), 3.80 (3H, s), 2.41 (3H, s).
UPLC/MS (3 min) retention time 0.66 min.
LRMS: m/z 165 (M+1 ).
PREPARATION 2
1,3-Dimethyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-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, 11.8 mmol) in n-butanol (2 ml) was stirred at 110 °C. After 3 h at 110 °C and subsequent cooling to room temperature, a precipitate had formed. The precipitate was collected by filtration, was washed with ether and dried in a stream of air to give 0.34 g the title compound (2.07 mmol, 88%) as a white solid. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 12.19 ( 1 H, br s), 7.80 ( 1 H, s), 4.1 1 (3H, s), 2.34 (3H, s).
UPLC/MS (3 min) retention time 0.71 min.
LRMS: m/z 165 (M+1 ). PREPARATION 3
1-Methyl-1 ,6-dihydro-7H-pyrazolo[4,3-cf]pyrimidin-7-one
Synthesized from Methyl 4-amino-1 -methyl-1 H-pyrazole-5-carboxylate and formimidamide following the procedure for PREPARATION 2 . Yield: 94%. Purity 98%.
H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (s, 1H), 7.83 (s, 1H), 4 .16 (s, 3H).
UPLC/MS (3 min) retention time 0.57 min .
LRMS: m/z 15 1 (M+ 1).
PREPARATION 4
3-Bromo-1 -methyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
/V-Bromosuccinimide ( 1 .49 g , 8.37 mmol) was added to a stirred suspension of the title compound of PREPARATION 3 (0.57 g , 3.80 mmol) in dimethylformamide ( 12 ml) and the mixture was heated to 80 °C. After 24 h, the mixture was allowed to cool to room temperature and water was added . The solid that formed was collected by filtration , washed with water and ethyl acetate and dried to give 0.47 g (2.05 mmol, 54% yield) of the title compound as a white solid. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (s, 1H), 7.90 (s, 1H), 4 .15 (s, 3H)
HPLC/MS (3 min) retention time 0.87 min.
LRMS: m/z 229, 231 (M+ 1, 1xBr).
PREPARATION 5
Ethyl 1-amino-4-methyl-1 H-imidazole-5-carboxylate
Lithium hexamethyldisilazide ( 1 M in tetrahydrofuran, 2 1.4 ml, 2 1.4 mmol) was added dropwise over 15 min to a stirred, cooled (-1 0 °C) suspension of ethyl 4-methyl-1 H- imidazole-5-carboxylate (3.00 g , 19.5 mmol) in dry dimethylformamide (200 ml) under an atmosphere of argon. After stirring for a further 10 min, O- (diphenylphosphoryl)hydroxylamine (5.45 g , 23.4 mmol) was added and the mixture was warmed to room temperature. After 6 h, water was added until a clear homogeneous solution formed and subsequently the mixture was evaporated to dryness. The resultant solid was treated with dichloromethane and the mixture was filtered and the filter cake was washed with further portions of dichloromethane. The combined filtrate and washings were evaporated to give a solid which was purified by flash chromatography (methanol-dichloromethane gradient, 0 :100 rising to 5:95) to give 1.75 g ( 10.3 mmol, 53% yield) of the title compound as a white solid. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.59 (s, 1H), 5.33 (br s, 2H), 4.37 (q , 2H, J =
7.4 Hz), 2.46 (s, 3H), 1.40 (t, 3H, J = 7.4 Hz).
UPLC/MS (3 min) retention time 0.56 min.
LRMS: m/z 170 (M+1 ).
PREPARATION 6
5-Methylimidazo[5,1 - ][1,2,4]triazin-4(3H)-one
A solution of the title compound of PREPARATION 5 ( 1 .73 g, 10.2 mmol) in formamide (6 ml) was stirred and heated to 180 °C in a sealed tube. After 3.5 h at 180 °C, the mixture was cooled to room temperature. The mixture was diluted with ethyl acetate and the solid that formed was triturated with several portions of ethyl acetate, collected by filtration and dried in a stream of air to give 1.3 1 g (8.7 mmol , 85% yield) of the title compound as a white solid. Purity 95%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 8.26 (s, 1H), 7.78 (s, 1H), 2.44 (s, 3H).
HPLC/MS (3 min) retention time 0.51 min.
LRMS: m/z 15 1 (M+1 ).
PREPARATION 7
7-Bromo-5-methylimidazo[5,1-/][1,2,4]triazin-4(3H)-one
N-Bromosuccinimide (0.25 g , 1.40 mmol) was added to a stirred suspension of the title compound of PREPARATION 6 (0.20 g, 1.33 mmol) in dimethylformamide (8 ml). After
6 h, further N-bromosuccinimide (0.25 g , 1.40 mmol) was added and stirring was continued at room temperature. After 7.5 h, the mixture was diluted with 4% aqueous sodium hydrogen carbonate solution and the solid that formed was filtered, washed with water and dried to give 0 .178 g (0.78 mmol, 58% yield) of the title compound as a white solid . Purity 98%.
H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 7.88 (s, 1H), 2.44 (s, 3H).
UPLC/MS (3 min) retention time 0.8 1 min.
LRMS: m/z 229, 231 (M+ 1, 1* Br).
PREPARATION 8
5-Methylimidazo[5, 1- ][1,2,4]triazine-4,7(3H,6H)-dione
The title compound of PREPARATION 7 (54 mg, 0.24 mmol) was suspended in 2 ml acetic acid. Potassium acetate ( 100 mg, 3 .1 mmol) was added and the mixture was heated at 160 °C under microwave irradiation for 3 h. The mixture was concentrated under reduced pressure to give 198 mg of a residue containing the title compound. Used as such without further purification . UPLC Purity 97%.
UPLC/MS (3 min) retention time 0.35 min.
LRMS: m/z 167 (M+1 ).
PREPARATION 9
5-Methyl-7-(methylamino)imidazo[5, 1- ][1,2,4]triazin-4(3H)-one
The title compound of PREPARATION 7 (40 mg, 0.17 mmol) was combined with methylamine (2M in tetrahydrofuran, 2 ml, 4 mmol) and cesium fluoride (3 mg, 0.02 mmol). The mixture was heated at 140 °C under microwave irradiation for 23 h and then at 160 °C for 20 h. The mixture was evaporated under reduced pressure. The residue was resuspended in methylamine (2M in tetrahydrofuran , 3 ml, 6 mmol) and the mixture was heated at 160 °C under microwave irradiation for a further 10 h. The mixture was concentrated under reduced pressure to give 88 mg of a residue containing the title compound. Used as such without further purification. UPLC purity >90%. UPLC/MS (3 min) retention time 0.32 min.
LRMS: m/z 180 (M+1 ).
PREPARATION 10
Ethyl 2,4-dimethyl-1 H-imidazole-5-carboxylate
Thionyl chloride (20 ml) was added to a stirred suspension of 2,4-dimethyl-1 H- imidazole-5-carboxylic acid (5.0 g, 35.7 mmol) in ethanol (75 ml) and the mixture was stirred and heated to reflux. Further thionyl chloride ( 15 ml) was added in three portions over 3 days. Subsequently the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 1M aqueous sodium hydroxide solution. The organic layer was washed with brine, dried and evaporated to give 3.40 g (20.2 mmol, 57% yield) of the title compound as a white solid. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 9.65 (br s, 1H), 4.33 (q, 2H, J = 7.0 Hz), 2.45
(s, 3H), 2.42 (s, 3H), 1.37 (t, 3H, J = 7.0 Hz).
UPLC/MS (3 min) retention time 0.53 min.
LRMS: m/z 169 (M+1 ).
PREPARATION 11
Ethyl 1-amino-2,4-dimethyl-1 H-imidazole-5-carboxylate
Synthesized from the title compound of PREPARATION 10 and O- (diphenylphosphoryl)hydroxylamine following the method of PREPARATION 5 . Yield: 87%. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 5.21 (br s, 2H), 4.33 (q, 2H, J = 7.0 Hz), 2.42
(s, 3H), 2.4 1 (s, 3H), 1.39 (t, 3H, J = 7.0 Hz).
UPLC/MS (3 min) retention time 0.51 min.
LRMS: m/z 184 (M+1 ). PREPARATION 12
5,7-Dimethylimidazo[5,1 - ][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 11 and formamide following the method of PREPARATION 6. Yield: 76%. Purity 98%.
H NMR (300 MHz, DMSO-d6) δ ppm 11.35 (br s, 1H), 7.77 (s, 1H), 2.43 (s, 3H), 2.42 (s, 3H).
UPLC/MS (3 min) retention time 0.38 min.
LRMS: m/z 165 (M+1 ).
PREPARATION 13
(Azidomethyl)benzene
Sodium azide ( 1 .73 g , 26.6 mmol) was added to a solution of benzyl bromide (2.10 ml, 17.7 mmol) in dry dimethylformamide (42 ml) under an atmosphere of nitrogen and the mixture was stirred at room temperature overnight. Subsequently, the mixture was diluted with water and extracted with pentane. The organic layer was washed with water, brine, dried, and evaporated to give 2.32 g (17.4 mmol, 99% yield) of the title compound as an oil. Purity 95%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.40 (m, 5H), 4.40 (s, 2H).
UPLC/MS (3 min) retention time 1.63 min.
LRMS: m/z No ionization.
PREPARATION 14
5-Amino-1 -benzyl-1 -1,2,3-triazole-4-carboxamide
Cyanoacetamide ( 1 .47 g , 17.5 mmol) and the title compound of PREPARATION 13 (2.32 g, 17.4 mmol) were added sequentially to a solution of sodium ethoxide (6.5 ml of a 21% solution in ethanol) in absolute ethanol (10 ml) and the mixture was stirred and heated to reflux. After 3.5 h, the reaction mixture was cooled to room temperature and the resulting precipitate was filtered and washed with ethanol and water and dried in vacuo to give 2.8 1 g ( 12.9 mmol, 74% yield) of the title compound as a white solid. Purity 99%.
H NMR (300 MHz, DMSO-d6) δ ppm 7.43 (br s, 1H), 7 .19-7.37 (m, 5H), 7.07 (br s, 1H), 6.38 (s, 2H), 5.41 (s, 2H).
UPLC/MS (3 min) retention time 1.04 min.
LRMS: m/z 2 18 (M+1 ).
PREPARATION 15
4-Amino-5-(aminocarbonyl)-3-benzyl-1 -methyl-1 H-1 ,2,3-triazol-3-ium bromide
A stirred suspension of the title compound of PREPARATION 14 ( 1 .50 g , 6.9 1 mmol) and methyl toluene-p-sulphonate ( 1 .52 ml, 10.1 mmol) in dimethylsulphoxide (0.75 ml) was placed in an oil bath preheated to 150 °C. After 5 min, the almost homogenous melt was cooled causing solidification to occur. Ethanol ( 15 ml) was added and the mixture was cooled to 0 °C. The precipitate was filtered off, washed with a little cold ethanol (5 ml) and dried to give 1.29 g (3. 19 mmol, 46% yield) of the title compound as a yellow solid . Purity 95%.
UPLC/MS (3 min) retention time 0.68 min.
LRMS: m/z 232 (cation M).
PREPARATION 16
4-Amino-1 -methyl-1 H-1,2,3-triazole-5-carboxamide para-toluene sulfonate salt
10% Palladium on carbon (0.34 g) was added to a stirred suspension of the title compound of PREPARATION 15 ( 1 .28 g , 3 .15 mmol) in absolute ethanol (50 ml). The mixture was evacuated and hydrogen was introduced via a balloon and stirring was continued at room temperature under an atmosphere of hydrogen for 48 h. The mixture was then filtered through Celite and the filtercake was washed with ethanol. The combined filtrate and washings were evaporated and the sticky solid was triturated with diethylether and dried to give 0.830 g (2.64 mmol, 84% yield) of the title compound as a white solid. Purity 100%. UPLC/MS (3 min) retention time 0.30 min .
LRMS: m/z 142 (M+1 ).
PREPARATION 17
1-Methyl-1 H-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7(6H)-one
Synthesized from the title compound of PREPARATION 16 and formamide following the method of PREPARATION 6. Yield : 66%. Purity 95%.
H NMR (400 MHz, DMSO-d6) δ ppm 12.66 (br. s, 1H), 8.08 (s, J = 2.4 Hz, 1H), 4.33 (s, J = 2 .1 Hz, 3H).
UPLC/MS (3 min) retention time 0.44 min.
LRMS: m/z 152 (M+1 ).
PREPARATION 18
1-Amino-4-cyano-1 H-imidazole-5-carboxamide
Synthesized from 4-cyano-1 H-imidazole-5-carboxamide and O- (diphenylphosphoryl)hydroxylamine following the method of PREPARATION 5 . Yield: 62%. Purity 97%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 6.7 1 (s, 2H).
UPLC/MS (5 min) retention time 0.32 min.
LRMS: m/z 152 (M+1 ).
PREPARATION 19
4-0x0-3, 4-dihydroimidazo[5, 1- ][1,2,4]triazine-5-carbonitrile
Synthesized from the title compound of PREPARATION 18 and triethyl orthoformate following the method of PREPARATION 1. Yield: 53%. Purity 100%. UPLC/MS (5 min) retention time 0.57 min .
LRMS: m/z 162 (M+1 ).
PREPARATION 20
2-Amino-1 ,4-dimethyl-6-oxo-1 ,6-dihydropyridine-3-carbonitrile
N-methyl-3-oxobutanamide (400 mg, 2.43 mmol) and malonitrile ( 160 mg, 2.43 mmol) were suspended in 10 ml of ethanol. Five drops of piperidine were added and the mixture was stirred and heated at 80°C overnight. The mixture was then cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography using the Isolera purification system (ethyl acetate-hexane gradient, 0 :100 rising to 100:0) to give 95 mg (0.58 mmol , 24% yield) of the title compound as a yellow solid. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 7.40 (s, 2 H), 5.58 (s, 1H), 3.28 (s, 3H), 2 .10 (s, 3H).
UPLC/MS (3 min) retention time 0.76 min.
LRMS: m/z 164 (M+1 ).
PREPARATION 2 1
5,8-Dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione
The title compound of PREPARATION 20 (73 mg, 0.44 mmol) was suspended in 0.75 ml formic acid. 2 Drops of concentrated sulphuric acid were added and the mixture was stirred at 100 °C for 12 days. The mixture was allowed to cool and was diluted with water forming a precipitate. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organics were washed twice with water, twice with brine, dried over anhydrous magnesium sulphate, filtered and evaporated to give 38 mg (0. 19 mmol, 42% yield) of the title compound as a white solid. Purity 95%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.24 ( 1 H, s), 6.23 ( 1 H, s), 3.52 (3H , s), 2.50 (3H , s). UPLC/MS (3 min) retention time 0.72 min.
LRMS: m/z 192 (M+1 ).
PREPARATION 22
Methyl 1-amino-4-methyl-1 H-pyrazole-5-carboxylate
Synthesized from Methyl 4-methyl-1 /-/-pyrazole-5-carboxylate and O- (diphenylphosphoryl)hydroxylamine following the method of PREPARATION 5 . Yield: 49%. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7 .15 (s, 1H), 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 23
5-Methylpyrazolo[5, 1- ][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 22 and formamide following the method of PREPARATION 6. Yield : 52%. Purity 98%.
H NMR (300 MHz, DMSO-d6) δ ppm 12.2 (br s, 1H), 7.95 (s, 1H), 7.60 (s, 1H), 2.33 (s, 3H).
UPLC/MS (3 min) retention time 0.67 min.
LRMS: m/z 15 1 (M+1 ).
PREPARATION 24
6-Chloro-W-methylpyrimidin-4-amine
4,6-Dichloropyrimidine ( 10 g , 67 mmol) was dissolved in 100 ml isopropanol and the solution was cooled to 0 °C, reprecipitating. Methylamine solution (33% w/w, 17 ml, 140 mmol) was added slowly with stirring and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure. The residue was resuspended in water, stirred for 15 min and then filtered. The solid was dried under reduced pressure. The filtrate was extracted three times with ethyl acetate. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The solid obtained was combined with the first precipitate to give 8.50 g (59 mmol, 88% yield) of the title compound as a white solid. Purity 87%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.40 (s, 1H), 6.38 (s, 1H), 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 25
6-Methoxy-W-methylpyrimidin-4-amine
The title compound of PREPARATION 24 (8.5 g, 59 mmol) was dissolved in 100 ml methanol. Sodium methoxide (19.8 g , 370 mmol) was added in several portions over a 4 day period while the mixture was stirred at reflux. The mixture was allowed to cool and was evaporated under reduced pressure. The solid residue was resuspended in dichloromethane and was stirred for 1 h. The solution was filtered and the filtrate was evaporated under reduced pressure to give 7.80 g (56 mmol, 95% yield) of the title compound as a white solid. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.10 (s, 1H), 7.00 (s, 1H), 5.62 (s, 1H), 3.80 (s, 3H), 3.10 (s, 3H)
UPLC/MS (3 min) retention time 0.45 min.
LRMS: m/z 140 (M+1 ).
PREPARATION 26
6-(Methylamino)pyrimidin-4(3H)-one hydrochloride The title compound of PREPARATION 25 (7.80 g , 56 mmol) was suspended in 110 ml concentrated hydrochloric acid and the mixture was stirred at 60 °C for 2 days. The mixture was then evaporated under reduced pressure to give 10.0 g (56 mmol, 99% yield) of the title compound as a white solid. Purity 100%.
UPLC/MS (3 min) retention time 0.32 min.
LRMS: m/z 126 (M+1 ).
PREPARATION 27
6-(Methylamino)-5-nitropyrimidin-4(3H)-one
The title compound of PREPARATION 26 (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%.
H NMR (300 MHz, DMSO-d6) δ ppm 9.42 (br s, 1H), 8.04 (s, 1H), 3.00 (d , 3H, J = 4.7 Hz).
HPLC/MS (5 min) retention time 0.50 min .
LRMS: m/z 171 (M+ 1).
PREPARATION 28
5-Amino-6-(methylamino)pyrimidin-4(3H)-one
The title compound of PREPARATION 27 ( 1 .18 g , 6.9 mmol) was dissolved in 35 ml methanol. Raney nickel ( . 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%. H NMR (300 MHz, DMSO-d6) δ ppm 7.53 (s, 1H), 5.66 (m, 1H), 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 29
9-Methyl-7,9-dihydro-1 H-purine-6,8-dione
The title compound of PREPARATION 28 (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%.
H NMR (300 MHz, DMSO-d6) δ ppm 12.42 (br s, 1H), 11.20 (br s, 1H), 7.97 (s, 1H), 3.20 (s, 3H).
UPLC/MS (3 min) retention time 0.30 min.
LRMS: m/z 167 (M+1 ).
PREPARATION 30
2-Chloro-6-methoxy-4-methylnicotinonitrile
6-Chloro-2-methoxy-4-methylnicotinonitrile
2,6-Dichloro-4-methylnicotinonitrile (3.70 g, 19.8 mmol) was suspended in 30 ml methanol. Sodium methoxide solution (25% in methanol, 4.3 ml, 18.8 mmol) was added carefully with stirring and the mixture was stirred for 90 min. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 3.43 g ( 18.8 mmol, 100% yield) of an approx 1:1 mixture of the title compounds as white solid. Used directly without further purification . Combined purity 96%. Isomer 1: H NMR (300 MHz, Chloroform-d) δ ppm 6.6 1 (s, 1H), 3.99 (s, 3H), 2.50 (s, 3H).
UPLC/MS (3 min) retention time 1.48 min.
LRMS: m/z no ionization
Isomer 2 : H NMR (300 MHz, Chloroform-d) δ ppm 6.6 1 (s, 1H), 3.99 (s, 3H), 2.50 (s, 3H).
UPLC/MS (3 min) retention time 1.50 min .
LRMS: m/z no ionization
PREPARATION 3 1
2-[(Diphenylmethylene)amino]-6-methoxy-4-methylnicotinonitrile
6-[(Diphenylmethylene)amino]-2-methoxy-4-methylnicotinonitrile
A mixture of the title compounds of PREPARATION 30 ( 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(l l) acetate (0.04 g , 0.18 mmol) and 2,2'- bis(diphenylphosphino)-1 ,1'-binaphthalene (0. 16 g , 0.26 mmol) were added , the reaction vessel was sealed and the mixture was stirred at 100 °C for 4 h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 3.45 g of a crude mixture of the title compounds as white solid. Used directly without further purification. Combined purity 83%.
UPLC/MS (3 min) retention time 1.94 and 1.96 min .
LRMS: m/z 328 (M+1 ).
PREPARATION 32
2-Amino-6-methoxy-4-methylnicotinonitrile 6-Amino-2-methoxy-4-methylnicotinonitrile
The crude mixture of the title compounds of PREPARATION 31 (3.45 g) was dissolved in 25 ml tetrahydrofuran. Dilute hydrochloric acid (2M, 3 ml, 6 mmol) was added and the mixture was stirred for 90 min. The mixture was neutralized with 4% sodium bicarbonate solution and the organic solvent was evaporated under reduced pressure. The mixture was extracted with ethyl acetate, the organic layer was washed consecutively with water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was stirred in dichloromethane and the suspension was filtered. The solid was dried in vacuo to give 0.84 g of a mixture of the title compounds. The filtrate was evaporated and purified using the Isolera (methanol-dichloromethane gradient, 0 :100 rising to 2:98) to give a further 0.33 g product. Total yield 1.17 g (7.2 mmol, 83% yield over two steps) as an approx 1:1 mixture of regioisomers. Combined purity 100%.
UPLC/MS (3 min) retention time 1.02 and 1.18 min .
LRMS: m/z 164 (M+1 ).
PREPARATION 33
2-Amino-6-methoxy-4-methylnicotinamide
6-Amino-2-methoxy-4-methylnicotinamide
A mixture of the mixture of title compounds of PREPARATION 32 (7 10 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:
H NMR (300 MHz, DMSO-d6) δ ppm 7.45 (br s, 1H), 7.40 (br s, 1H), 5.9 1 (br s, 2H),
5.83 (s, 1H), 3.72 (s, 3H), 2.20 (s, 3H).
UPLC/MS (3 min) retention time 0.53 min.
LRMS: m/z 182 (M+1 ). PREPARATION 34
7-Methoxy-5-methylpyrido[2,3-rflpyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 33 and triethylorthoformate following the method of PREPARATION 1. Yield: 61%. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 12.3 (br s, 1H), 8.17 (s, 1H), 6.70 (s, 1H), 3.90 (s, 3H), 2.65 (s, 3H).
UPLC/MS (3 min) retention time 0.92 min.
LRMS: m/z 192 (M+1 ).
PREPARATION 35
2-Amino-6-chloro-4-methylnicotinonitrile
6-Amino-2-chloro-4-methylnicotinonitrile
A suspension of 2,6-dichloro-4-methylnicotinonitrile ( 1 .39 g , 7.43 mmol) in concentrated aqueous ammonia solution (40 ml) was stirred and heated to 50 °C in a pressure vessel. After 48 h, the mixture was cooled in an ice bath and the resultant precipitate was filtered, washed with water and dried to give 1.15 g (6.88 mmol, 93% yield) of the title compounds, in a 2:1 mixture, as a white solid. Combined purity 99%
Major isomer: UPLC/MS (3 min) retention time 0.99 min.
LRMS: m/z 168 (M+1 , 1xCI).
Minor isomer: UPLC/MS (3 min) retention time 1.13 min.
LRMS: m/z 168 (M+1 , 1xCI).
PREPARATION 36
2-Amino-6-chloro-4-methylnicotinamide
6-Amino-2-chloro-4-methylnicotinamide A mixture of the title compounds of PREPARATION 35 ( 1 .43 g, 8.53 mmol) in concentrated sulphuric acid ( 14 ml) was stirred and heated to 40 °C. After 96 h, the mixture was cooled, poured onto ice/water and neutralized with solid sodium hydrogen carbonate. The precipitate was filtered, washed with water and dried to give 1.10 g (5.93 mmol, 70%) of the title compounds, in a 2 :1 mixture, as a white solid. Combined purity 96%.
Major isomer: H NMR (300 MHz, DMSO-d6) δ ppm 7.71 (br s, 1H), 7.43 (br s, 1H), 6.34 (br s, 2H), 6.21 (s, 1H), 2 .12 (s, 3H).
UPLC/MS (3 min) retention time 0.32 min.
LRMS: m/z 186 (M+ 1, 1*CI).
Minor isomer: H NMR (300 MHz, DMSO-d6) δ ppm 7.78 (br s, 1H), 7.61 (br s, 1H), 6.50 (s, 1H), 6 .15 (br s, 2H), 2.20 (s, 3H).
UPLC/MS (3 min) retention time 0.7 1 min.
LRMS: m/z 186 (M+ 1, 1*CI).
PREPARATION 37
7-Chloro-5-methylpyrido[2,3-rflpyrimidin-4(3H)-one
Synthesized from the mixture of title compounds of PREPARATION 36 and triethylorthoformate following the method of PREPARATION 1. Yield: 35%. Purity 98%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.45 (s, 1H), 2.76 (s, 3H).
UPLC/MS (3 min) retention time 0.88 min.
LRMS: m/z 196 (M+ 1, 1*CI).
PREPARATION 38
2-Cyano-3-(dimethylamino)but-2-enamide
1,1-Dimethoxy-/V,/V-dimethylethanamine (5.20 ml, 35.6 mmol) was added dropwise to a suspension of cyanoacetamide (3.00 g , 35.7 mmol) in absolute ethanol (65 ml) and the mixture was stirred and heated to reflux. After 2.5 h, the mixture was cooled and the precipitate was filtered, washed with ethanol and dried to give 3.08 g (20. 1 mmol , 57% yield) of the title compound (mixture of cis/trans isomers) as a yellow solid. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 6.60 (br s, 2H), 3.04 (s, 3H), 2.98 (s, 3H), 2.20
(s, 3H).
UPLC/MS (3 min) retention time 0.46 min.
LRMS: m/z 154 (M+1 ).
PREPARATION 39
2,4-Diamino-6-methylpyrimidine-5-carboxamide
Guanidine hydrochloride ( 1 .92 g , 20. 1 mmol) was added to a suspension of the title compound of PREPARATION 38 (3.08 g, 20. 1 mmol) and triethylamine (5.60 ml, 40.2 mmol) in ethanol (70 ml) and dimethylformamide (20 ml) and the mixture was stirred and heated to reflux. After 9 d, the mixture was cooled to room temperature and the precipitate was filtered and washed with ethanol. The combined filtrate and washings were evaporated to dryness and the resultant gum was triturated with tetrahydrofuran and then ethanol to give a precipitate which was filtered and dried to give 0.660 g (3.95 mmol, 20% yield) of the title compound as a beige solid. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 12.73 (br s, 1H), 8.31 (br s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.62 (br s, 2H), 2.32 (s, 3H).
UPLC/MS (3 min) retention time 0.20 min.
LRMS: m/z 168 (M+1 ).
PREPARATION 40
7-Amino-5-methylpyrimido[4,5-d]pyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 39 and formamide following the method of PREPARATION 6. Yield : 77%. Purity 95%. H NMR (300 MHz, DMSO-d6) δ ppm 12.07 (br s, 1H), 8 .14 (s, 1H), 7.34 (br s, 2H), 2.69 (s, 3H).
UPLC/MS (3 min) retention time 0.44 min.
LRMS: m/z 178 (M+1 ).
PREPARATION 4 1 ferf-Butyl (5-methyl-4-oxoimidazo[5,1 - ][1,2,4]triazin-3(4H)-yl)acetate
The title compound of PREPARATION 6 (2.0 g , 13.3 mmol) was dissolved in dimethylformamide (35 ml). Potassium carbonate (3.7 g , 26.8 mmol) was added followed by the drop-wise addition of tert-butyl bromoacetate (2.2 ml, 14.9 mmol). The mixture was stirred at room temperature for 75 min. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organics were washed twice with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 3.52 g (0. 13 mmol, 100% yield) of the title compound as an amber solid. Purity 98%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.97 (s, 1H), 7.34 (s, 1H), 4.46 (s, 2H), 2.62 (s, 3H), 1.49 (s, 9H).
UPLC/MS (3 min) retention time 1.28 min.
LRMS: m/z 265 (M+1 ).
PREPARATION 42 ferf-Butyl (9-methyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetate
Synthesized from the title compound of PREPARATION 29 and tert-butyl bromoacetate following the method of PREPARATION 41. Yield : 40%. Purity 99%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.90 (br s, 1H), 7.82 (s, 1H), 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 43 ferf-Butyl (7,9-dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetate
The title compound of PREPARATION 42 (180 mg, 0.64 mmol) was dissolved in dimethylformamide (4 ml) and the solution was cooled to 0°C in an ice-bath. Sodium hydride (60% suspension in oil, 4 1 mg, 1.0 mmol) was added and the mixture was stirred for 30 min. Methyl iodide (42 µ Ι, 0.67 mmol) was added and the mixture was stirred overnight, warming to room temperature. The mixture was partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 190 mg (0.64 mmol, 100% yield) of the title compound as a yellow oil. Purity 96%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.80 (s, 1H), 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 44 ferf-Butyl (7-methoxy-5-methyl-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)acetate
Synthesized from the title compound of PREPARATION 34 and tert-butyl bromoacetate following the method of PREPARATION 4 1. Yield: 92%. Purity 93%.
UPLC/MS (3 min) retention time 1.52 min.
LRMS: m/z 306 (M+1 ).
PREPARATION 45 ferf-Butyl ( 1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)acetate
Synthesized from the title compound of PREPARATION 1 and ie/f-butyl bromoacetate following the method of PREPARATION 4 1. Yield: 100%. Purity 95%. H NMR (300 MHz, Chloroform-d) δ ppm 7.8 1 (s, 1H), 4.57 (s, 2H), 3.9 1 (s, 3H), 2.57 (s, 3H), 1.48 (s, 9H).
UPLC/MS (3 min) retention time 1.90 min.
LRMS: m/z 279 (M+1 ).
PREPARATION 46 ferf-Butyl ( 1 -methyl -7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5-d]pyrimidin-6- yl)acetate
Synthesized from the title compound of PREPARATION 17 and ie/f-butyl bromoacetate following the method of PREPARATION 41. Yield : 85%. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.95 (s, 1H), 4.65 (s, 2H), 4.47 (s, 3H), 1.51
(s, 9H).
UPLC/MS (3 min) retention time 1.15 min.
LRMS: m/z 266 (M+1 ).
PREPARATION 47
Methyl (7-methyl-6-oxo-6,7-dihydro-1 H-purin-1 -yl)acetate
7-Methyl-1 ,7-dihydro-6/-/-purin-6-one (0.50 g , 3.33 mmol) was dissolved in 3 ml anhydrous dimethylformamide under argon. Potassium carbonate (0.92 g, 4.0 mmol) was added followed by the drop-wise addition of methyl bromoacetate (0.38 ml, 4.0 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with 10 ml water and was extracted three times with dichloromethane. The combined organics were dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was re-evaporated three times from toluene, three times from dichloromethane and three times from ether to give 0.57 g (2.58 mmol, 77% yield) of the title compound as a pale brown semi-solid. Purity 95%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.2 1 (s, 1H), 4.84 (s, 2H), 3.96 (s, 3H), 3.70 (s, 3H). HPLC/MS (4.5 min) retention time 1.17 min.
LRMS: m/z 223 (M+1 ).
PREPARATION 48
(5-Methyl-4-oxoimidazo[5, 1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt
A solution of the title compound of PREPARATION 41 (3.52 g , 13.3 mmol) and hydrochloric acid (4M in dioxane, 87 ml) was stirred at room temperature. After 48 h, the precipitate was filtered , washed with ether and dried to give 3.00 g ( 12.26 mmol, 92% yield) of the title compound as a white solid. Purity 100%.
1H NMR (300 MHz, DMSO-d6) δ ppm 8.82 (s, 1H), 8.22 (s, 1H), 4 .6 1 (s, 2H), 2.52 (s,
3H).
UPLC/MS (3 min) retention time 0.47 min.
LRMS: m/z 209 (M+1 ).
PREPARATION 49
(7,9-Dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetic acid hydrochloride salt
Synthesized from the title compound of PREPARATION 43 following the method of PREPARATION 48. Yield : 99%. Purity 99%.
1H NMR (300 MHz, DMSO-d6) δ ppm 8.3 1 (s, 1H), 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 50
(7-Methoxy-5-methyl-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)acetic acid hydrochloride salt Synthesized from the title compound of PREPARATION 44 following the method of PREPARATION 48. Yield: 100%. Purity 92%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.48 (s, 1H), 6.79 (s, 1H), 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 5 1
( 1 ,3-Dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-c/lpyrimidin-5-yl)acetic acid hydrochloride salt
Synthesized from the title compound of PREPARATION 45 following the method of PREPARATION 48. Yield: 89%. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 8.32 (s, 1H), 4.68 (s, 2H), 3.83 (s, 3H), 2.42 (s, 3H).
UPLC/MS (3 min) retention time 0.63 min.
LRMS: m/z 223 (M+1 ).
PREPARATION 52
( 1 -Methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5-d]pyrimidin-6-yl)acetic acid hydrochloride salt
Synthesized from the title compound of PREPARATION 46 following the method of PREPARATION 48. Yield: 90%. Purity 95%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 4.80 (s, 2H), 4.35 (s, 3H).
UPLC/MS (3 min) retention time 0.32 min.
LRMS: m/z 2 0 (M+1 ). PREPARATION 53
(1,3-Dimethyl-4-oxo-1,4-dihydro-5H^yrazolo[3,4-<^pyrimidin-5-yl)acetonitrile
The title compound of PREPARATION 1 (50 mg, 0.30 mmol) was dissolved in 3 ml dimethylformamide. 2-Chloroacetonitrile (22 µ Ι_, 0.35 mmol) and potassium carbonate (85 mg, 0.62 mmol) were added and the mixture was stirred at room temperature for
1.5 h. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The organics were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 57 mg (0.28 mmol, 92% yield) of the title compound as a solid . Purity 100%.
UPLC/MS (3 min) retention time 0.71 min .
LRMS: m/z 204 (M+1 ).
PREPARATION 54
(5-Methyl-4-oxoimidazo[5,1-/][1,2,4]triazin-3(4H)-yl)acetonitrile
Synthesized from the title compound of PREPARATION 6 and chloroacetonitrile following the method of PREPARATION 53. Yield: 82%. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.02 (s, 1H), 7.63 (s, 1H), 4.8 1 (s, 2H), 2.69 (s, 3H)
HPLC/MS (3 min) retention time 0.60 min .
LRMS: m/z 190 (M+1 ).
PREPARATION 55
5-[(3-Bromo-1 ,2,4-oxadiazol-5-yl)methyl]-1 ,3-dimethyl-1 ,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one
The title compound of PREPARATION 53 ( 1 .12 g , 5.5 mmol) was suspended in 5 ml toluene. Sodium bicarbonate ( 1 .39 g , 16.55 mmol) was added and the mixture was warmed to 95 °C with stirring. Hydroxycarbonimidic dibromide (2.24 g, 11.0 mmol) was added in fractions over 35 min and the mixture was stirred at 95 °C overnight. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated . The residue was purified by reverse-phase chromatography using the Isolera Purification system (methanol-water gradient, 20:80 rising to 80:20) to give 740 mg (2.28 mmol , 4 1% yield) of the title compound as a white solid. Purity 100%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.98 (s, 1H), 5.35 (s, 2H), 3.92 (s, 3H), 2.55
(s, 3H).
UPLC/MS (3 min) retention time 1.11 min .
LRMS: m/z 325, 327 (M+ 1, 1* Br).
PREPARATION 56
Ethyl 5-[(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-cf]pyrimidin-5- yl)methyl]-1,2,4-oxadiazole-3-carboxylate
METHOD A
The title compound of PREPARATION 5 1 (250 mg, 0.97 mmol) was dissolved in 10 ml dichloroethane and 3 ml dimethylformamide. Ethyl (2Z)-amino(hydroxyimino)acetate
( 128 mg, 0.97 mmol) and /V-(3-dimethylaminopropyl)-/V'-ethylcarbodiimide hydrochloride (241 mg, 1.26 mmol) were added and the mixture was stirred at room temperature. After 1 h, the reaction was stirred at 120 °C for 1h under microwave irradiation . The mixture was allowed to cool and was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The organics were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 301 mg (0.96 mmol, 98% yield) of the title compound. Purity 100%.
METHOD B
A suspension of the title compound of PREPARATION 1 (263 mg, 1.60 mmol) and potassium carbonate (438 mg, 3.27 mmol) in 10 ml dimethylformamide was stirred at room temperature. After 10 min, ethyl 5-(chloromethyl)-1 ,2,4-oxadiazole-3-carboxylate
(332 mg, 1.74 mmol) was added and stirring was continued for 2 h. After this period, water was added and the mixture was extracted with ethyl acetate twice and the organic layer was washed with brine, dried and evaporated to give 370 mg of the crude title compound . Used as such without further purification. Purity 31% .
H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (s, 1H), 5.57 (s, 2H), 4.36 (q, J = 7 .1 Hz, 2H), 3.83 (s, 3H), 2.38 (s, 3H), 1.27 (t, J = 7 .1 Hz, 3H).
UPLC/MS (3 min) retention time 1.08 min.
LRMS: m/z 3 19 (M+1 ).
PREPARATION 57
5-[(1 ,3-Dimethyl-4-oxo-1 ,4-dihydro-5H^yrazolo[3,4-<^pyrimidin-5-yl)methyl]- 1,2,4-oxadiazole-3-carboxylic acid
The crude title compound of PREPARATION 56 method B (370 mg) was dissolved in 2 ml tetrahydrofuran and 2 ml water. Lithium hydroxide monohydrate (30.5 mg, 0.73 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and was acidified with 2N hydrochloric acid solution. The aqueous phase was extracted twice with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 145 mg (0.48 mmol, 31% yield over two steps) of the title compound. Purity 95%.
UPLC/MS (3 min) retention time 0.6 1 min.
LRMS: m/z 291 (M+1 ).
PREPARATION 58
2-[(1 ,3-Dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)acetyl]hydrazinecarboxamide
The title compound of PREPARATION 5 1 ( 100 mg, 0.39 mmol) was suspended in 3 ml dichloromethane. (Benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexa- fluorophosphate (BOP, 180 mg, 0.4 1 mmol) was added and the mixture was stirred for 5 min . Triethylamine (0. 14 ml, 1 mmol) was added, dissolving the suspension. Hydrazinecarboxamide (45 mg, 0.40 mmol) was added and the mixture was stirred overnight at room temperature forming a precipitate. The solid was collected by filtration to give 105 mg of the crude title compound. Purity 81% .
UPLC/MS (3 min) retention time 0.99 min.
LRMS: m/z 280 (M+1 ).
PREPARATION 59
1,3-Dimethyl-5-[(5-oxo-4,5-dihydro-1 ,3,4-oxadiazol-2-yl)methyl]-1 ,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one
The crude title compound of PREPARATION 58 ( 105 mg) was suspended in dioxane
(5 ml). Triethylamine (0.26 ml, 1.9 mmol) and trimethylsilyl trifluoromethanesulfonate (0.20 ml, 1.12 mmol) were added and the mixture was heated at 160 °C under microwave irradiation for 1 h. The mixture was evaporated under reduced pressure and the residue was re-suspended in water. The aqueous was extracted nine times with dichloromethane, the combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was partially purified by flash chromatography (isopropanol-dichloromethane gradient, 0 :100 rising to 15:85) to give 87 mg of the crude title compound as a hygroscopic solid. Purity 85%.
UPLC/MS (3 min) retention time 0.79 min.
LRMS: m/z 263 (M+1 ).
PREPARATION 60
3-(4-Chlorophenyl)propanamide
3-(4-Chlorophenyl)propionic acid (0.50 g , 2.71 mmol) was dissolved in 2.5 ml dimethylformamide. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.78 g , 4.06 mmol) and 1-hydroxybenzotriazole hydrate (0.55 g, 4.06 mmol) were added and the mixture was stirred at room temperature. Ammonium hydroxide (32% solution in water, 1.0 ml, 8 .13 mmol) was added and the mixture was stirred overnight at 50°C. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The organics were washed sequentially with water, saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 274 mg ( 1 .49 mmol, 55% yield) of the title compound as a white solid. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.23 - 7.34 (m , 2H), 7 .13 - 7.21 (m , 2H), 5.35 (br. s., 2H), 2.97 (t, J=7.3 Hz, 2H), 2.52 (t, J=7.3 Hz, 2H)
HPLC/MS (3 min) retention time 1.17 min .
LRMS: m/z 184 (M+ 1, 1*CI).
PREPARATION 6 1
5-[2-(4-Chlorophenyl)ethyl]-1 ,3,4-oxathiazol-2-one
The title compound of PREPARATION 60 (274 mg, 1.49 mmol) was dissolved in toluene (3 ml). Carbonochloridic hypochlorous thioanhydride ( 157 µ Ι_, 1.86 mmol) was added and the mixture was stirred at 100°C for 3 h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified using the Isolera Purification system (ether-hexane gradient, 0 :100 rising to 20:80) to give 230 mg (0.95 mmol, 64% yield) of the title compound as a yellow oil. Purity >95% by NMR. Compound unstable under UPLC conditions.
H NMR (300 MHz, Chloroform-d) δ ppm 7.29 - 7.33 (m , 2H), 7 .13 - 7 .19 (m , 2H), 3.02 - 3.09 (m , 2H), 2.90 - 2.97 (m, 2H).
UPLC/MS (3 min) retention time 1.76 min.
LRMS: m/z 242 (M+ 1, 1*CI).
PREPARATION 62
Methyl 3-[2-(4-chlorophenyl)ethyl]-1 ,2,4-thiadiazole-5-carboxylate
The title compound of PREPARATIO N 61 (229 mg, 0.95 mmol) was dissolved in 6 ml tetrahydrofuran . [(Cyanocarbonyl)oxy]methane (440 µ Ι_, 5.52 mmol) was added and the mixture was stirred at 140 °C for 2 h under microwave irradiation . The mixture was allowed to cool and was evaporated to dryness. The residue obtained was purified using the Isolera Purification system (ether-hexane gradient, 0 :100 rising to 20:80) to give 186 mg (0.62 mmol, 66% yield) of the title compound as a white solid. Purity 95%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.23 - 7.28 (m, 2H), 7 .13 - 7 .19 (m, 2H), 4.08 (s, 3H), 3.40 (t, J=7.9 Hz, 2H), 3 .19 (t, J=7.9 Hz, 2H)
UPLC/MS (3 min) retention time 1.79 min.
LRMS: m/z 283 (M+ 1, 1*CI).
PREPARATION 63
{3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-thiadiazol-5-yl}methanol
The title compound of PREPARATION 62 ( 184 mg, 0.65 mmol) was dissolved in ethanol (8 ml). Sodium borohydride (67 mg, 1.77 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness and partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane and the organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified using the Isolera Purification system (ether-hexane gradient, 30:70 rising to 70:30) to give 118 mg (0.46 mmol, 7 1% yield) of the title compound as a colorless oil . Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.27 (d, J=7.6 Hz, 2H), 7.16 (d, J=7.6 Hz, 2H), 5.11 (d , J=4.7 Hz, 2H), 3.28 (t, J=7.2 Hz, 2H), 3.15 (t, J=7.2 Hz, 2H), 2.62 (t, J=5.3 Hz, 1H)
UPLC/MS (3 min) retention time 1.52 min.
LRMS: m/z 255 (M+ 1, 1*CI).
PREPARATION 64
{3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-thiadiazol-5-yl}methyl methanesulfonate
The title compound of PREPARATION 63 ( 1 16 mg, 0.46 mmol) was dissolved in dichloromethane (3 ml) and cooled in an ice bath. Triethylamine (88 µ Ι_, 0.63 mmol) and methanesulfonyl chloride (42 µ Ι_, 0.54 mmol) were added and the mixture was slowly allowed to reach room temperature and stirred for 2 h. The mixture was partitioned between dichloromethane and a saturated sodium bicarbonate solution, extracted with dichloromethane and the organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified using the Isolera Purification system (ether-hexane gradient, 0 :100 rising to 70:30) to give 140 mg (0.42 mmol, 92% yield) of the title compound as a colorless oil. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.22 - 7.32 (m, 2H), 7 .11 - 7.20 (m, 2H), 5.60
(s, 2H), 3.31 (t, J=7.9 Hz, 2H), 3.11 - 3.22 (m, 5H)
HPLC/MS (3 min) retention time 1.67 min.
LRMS: m/z 333 (M+ 1, 1*CI).
PREPARATION 65
3-(4-Chlorophenyl)propanal
3-(4-Chlorophenyl)propan-1 -ol (2.0 g, 11.7 mmol) was dissolved in 35 ml dichloromethane. Pyridinium chlorochromate (3.8 g , 17.7 mmol) was added and the dark mixture was stirred overnight at room temperature. The mixture was filtered through a plug of Celite. The mixture was partitioned between water and dichloromethane, forming a dark residue. The organic phase was separated and was diluted with hexane to precipitate more dark oily residue. Anhydrous sodium sulphate was added to adsorb the dark oil and the mixture was filtered and evaporated under reduced pressure. The residue was partially purified by flash chromatography (dichloromethane-hexane gradient) to give 0.41 g of the crude title compound as a colourless oil. Purity 73%
H NMR (300 MHz, Chloroform-d) δ ppm 9.83 (s, 1H), 7.35 - 7.2 1 (m, 2H), 7.15 (d, J = 8.5 Hz, 2H), 3.03 - 2.88 (m, 2H), 2.87 - 2.72 (m, 2H).
UPLC/MS (3 min) retention time 1.3 1 min.
LRMS: m/z no ionization
PREPARATION 66
2-Amino-4-(4-chlorophenyl)butanoic acid The crude title compound of PREPARATION 65 (0.40 g) was dissolved in ethanol ( 15 ml) and water (4 ml). Sodium cyanide (0. 13 g, 2.65 mmol), ammonium chloride (0. 14 g , 2.62 mmol) and 2.5 ml concentrated ammonia solution were added and the mixture was stirred at room temperature for 24 h. The mixture was evaporated under reduced pressure. The residue was re-suspended in 5 N hydrochloric acid and was stirred at reflux for 6 h. The mixture was allowed to cool and was evaporated under reduced pressure. The solid residue was re-suspended in ether, filtered and the solid washed with a little water and then dried under reduced pressure to give 175 mg (0.82 mmol, 7% yield over two steps) of the title compound as a white solid . Purity 100%.
UPLC/MS (3 min) retention time 0.86 min.
LRMS: m/z 2 14 (M+ 1, 1*CI).
PREPARATION 67
2-Amino-4-(4-chlorophenyl)butan-1 -ol
The title compound of PREPARATION 66 ( 175 mg, 0.82 mmol) was dissolved in tetrahydrofuran (2 ml). Borane-dimethylsulphide complex ( 155 µ Ι, 1.63 mmol) was added drop-wise and the mixture was stirred for 3.5 h. The mixture was cooled to 0 °C and 1 ml methanol was added drop-wise and with stirring. The mixture was evaporated under reduced pressure to give 180 mg of the crude title compound as a yellow lacquer. Purity 84%.
UPLC/MS (3 min) retention time 0.75 min.
LRMS: m/z 200 (M+ 1, 1*CI).
PREPARATION 68
2-Chloro-yV-[3-(4-chlorophenyl)-1-(hydroxymethyl)propyl]acetamide
The crude title compound of PREPARATION 67 (90 mg) was dissolved in dichloromethane ( 10 ml) and the mixture was cooled to -78 °C under nitrogen. Triethylamine (0. 13 ml, 0.95 mmol) was added followed by chloroacetyl chloride (56 mg, 0.50 mmol). The mixture was stirred at -78 C for 15 min . Water was added and the mixture was allowed to warm to room temperature. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was re-dissolved in 5 ml tetrahydrofuran . Lithium hydroxide monohydrate (21 0 mg, 5 mmol) was added and the mixture was stirred for overnight. The mixture was evaporated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 90 mg (0.32 mmol, 79% yield over two steps) as a yellow lacquer. Purity 95%.
UPLC/MS (3 min) retention time 1.38 min.
LRMS: m/z 276 (M+ 1, 2*CI).
PREPARATION 69
2-Chloro-yV-[3-(4-chlorophenyl)-1-formylpropyl]acetamide
The title compound of PREPARATION 68 ( 125 mg, 0.45 mmol) was dissolved in dichloromethane (3 ml). Dess-Martin periodinane (2 11 mg, 0.50 mmol) was added and the mixture was stirred for 4 h at room temperature. The mixture was filtered and the filtrate was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 180 mg of the crude title compound as a yellow oil. Purity 40%.
UPLC/MS (3 min) retention time 1.89 min.
LRMS: m/z 274 (M+ 1, 2xCI).
PREPARATION 70
2-(Chloromethyl)-4-[2-(4-chlorophenyl)ethyl]-1,3-oxazole
The crude title compound of PREPARATION 69 ( 180 mg) was dissolved in phosphorus oxychloride (3 ml) and the mixture as stirred at 90 °C for 90 min. The mixture was allowed to cool and was evaporated under reduced pressure. The residue was was partitioned between dichloromethane and 4% sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 114 mg of the crude title compound as a brown oil. Purity 58%. UPLC/MS (3 min) retention time
LRMS: m/z 256 (M+ 1, 2*CI).
PREPARATION 7 1
( 1Z)-N'-{[3-(4-Chlorophenyl)propanoyl]oxy}-2-hydroxyethanimidamide
To a solution of 2-hydroxyacetonitrile solution (70 wt% in water, 300 mg, 3.68mmol) in 3 ml of water was added drop-wise hydroxylamine (50 wt% in water, 268 mg, 4.06 mmol). The mixture was stirred for 4 h at room temperature. The mixture was evaporated to dryness and was re-suspended in ethanol, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 331 mg of a crude preparation of ( 1Z)-/V',2-Dihydroxyethanimidamide. This preparation was immediately dissolved in 1 ml tetrahydrofuran and Λ/,/V-diisopropyethylamine (765 µ Ι, 4.4 1mmol) was added . The solution was cooled to 0 °C in an ice bath and 3-(4- chlorophenyl)propanoyl chloride (550 mg, 2.7 1 mmol) in 0.5 ml of tetrahydrofuran was added drop-wise. The mixture was stirred at 0 °C for 2 h. The mixture was partitioned between ethyl ether and saturated ammonium chloride solution. The aqueous phase was extracted with ethyl ether. The organics were dried over anhydrous sodium sulphate, filtered and evaporated to give 441 mg of the crude title compound. Purity 26%.
HPLC/MS (3 min) retention time 1.28 min .
LRMS: m/z 257 (M+ 1, 1*CI).
PREPARATION 72
{5-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-3-yl}methanol
Title crude title compound of PREPARATION 71 (44 1 mg) was dissolved in 5 ml ethanol and sodium acetate ( 1 10 mg, 1.34 mmol) was added. The mixture was stirred at reflux overnight. The mixture was evaporated to dryness. The resulting residue was partially purified using the Isolera Purification System (hexane-ethyl acetate gradient, 0 :100 rising to 100:0) to give 87 mg of the crude title compound . Purity 80%. H NMR (400 MHz, Chloroform-d) δ ppm 7.29 - 7.23 (m, 2H), 7 .17 - 7 .10 (m, 2H), 4.77 (s, 2H), 3.22 - 3 .16 (m, 2H), 3.15 - 3.09 (m, 2H).
HPLC/MS (3 min) retention time 1.45 min .
LRMS: m/z 239 (M+ 1, 1*CI).
PREPARATION 73
3-(Chloromethyl)-5-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazole
The crude title compound of PREPARATION 72 (87 mg) was dissolved in 4 ml chloroform and thionyl chloride (35 µ Ι, 0.48 mmol) was added . The mixture was stirred at reflux overnight. The mixture was allowed to cool, diluted with water and was basified with 8N sodium hydroxide solution. The aqueous phase was extracted twice with ethyl acetate. The organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using the Isolera Purification System (hexane-ethyl acetate gradient, 0 :100 rising to 40:60) to give 24 mg (0.093mmol, 2.5% yield over three steps) of the title compound. Purity 97%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.31 - 7.22 (m, 2H), 7 .18 - 7.08 (m, 2H), 4.57 (s, 2H), 3.24 - 3 .15 (m , 2H), 3.12 (dd , J = 8.5, 6.0 Hz, 2H).
HPLC/MS (3 min) retention time 1.74 min .
LRMS: m/z 257 (M+ 1, 2*CI).
PREPARATION 74
{5-[2-(4-Chlorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}methyl methanesulfonate
Synthesized from the crude title compound of PREPARATION 72 and methanesulfonyl chloride following the method of PREPARATION 64. Obtained as a colorless oil. Yield : 13% over three steps. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.30 (2H , d, J=8.2 Hz), 7 .15 (2H , d, J=8.2
Hz), 5.34 (2H , s), 3.25 (2H , t, J=7.0 Hz), 3.14 (3H , s), 3.12 - 3.20 (2H , m).
HPLC/MS (3 min) retention time 1.56 min. LRMS: m/z 3 17 (M+ 1, 1 CI).
PREPARATION 75
(1Z)-3-(4-Chlorophenyl)-yV'-hydroxypropanimidamide
A mixture of 3-(4-chlorophenyl)propanenitrile (2.00 g , 12 .1 mmol), hydroxylamine hydrochloride ( 1 .26 g , 18 .1 mmol) and sodium hydrogen carbonate (5. 10 g , 60.7 mmol) in methanol (2 1 ml) was stirred and heated to reflux. After 24 h, the mixture was cooled and filtered and the filtercake was washed with dichloromethane. The combined filtrate and washings were washed with water, brine, dried and evaporated to give a sticky solid which was absorbed onto silica gel and purified by flash chromatography (methanol-dichloromethane gradient, 0 :100 rising to 5:95) to give 1.34 g (6.75 mmol, 56% yield) of the title compound a white solid. Purity 95%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.28 (d , 2H, J = 8.6 Hz), 7 .16 (d , 2H, J = 8.6 Hz), 4.49 (br s, 2H), 2.88 (t, 2H, J = 7.4 Hz), 2.44 (t, 2H, J = 7.4 Hz).
UPLC/MS (3 min) retention time 0.82 min.
LRMS: m/z 199 (M+ 1, 1*CI).
PREPARATION 76
5-(Chloromethyl)-3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazole
A mixture of the title compound of PREPARATION 75 (2.95 g , 14.85 mol) and chloroacetic anhydride (2.80 g , 16.38 mol) in toluene (80 ml) were stirred and heated to reflux in a Dean-Stark apparatus. After 6.5 h, the toluene was removed in vacuo and the residue was purified using the Isolera Purification System (hexane-ethyl ether gradient, 0:100 rising to 100:0) to give 3.82 g ( 14.86 mols, 86% yield) of the title compound . Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.27 (d , 2H, J = 8.6 Hz), 7 .15 (d , 2H, J = 8.6 Hz), 4.67 (s, 2H), 3.07 (m , 4H).
UPLC/MS (3 min) retention time 1.86 min .
LRMS: m/z No ionization . PREPARATION 77
(1Z)-3-(3-Chlorophenyl)-N'-hydroxypropanimidamide
Synthesized from 3-(3-Chlorophenyl)propanenitrile and hydroxylamine hydrochloride following the method of PREPARATION 75. Yield : 52%. Purity 87%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.25 - 7 .17 (m, 3H), 7 .13 - 7.06 (m, 1H), 4.49 (s, 2H), 2.92 - 2.82 (m , 2H), 2.48 - 2.39 (m, 2H).
UPLC/MS (3 min) retention time 0.80 min .
LRMS: m/z 199 (M+ 1, 1*CI).
PREPARATION 78
5-(Chloromethyl)-3-[2-(3-chlorophenyl)ethyl]-1,2,4-oxadiazole
Synthesized from the title compound of PREPARATION 77 and chloroacetic anhydride following the method of PREPARATION 76. Yield : 76%. Purity 100%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.25 - 7 .17 (m , 3H), 7.09 (dt, J = 6.7, 1.7 Hz, 1H), 4.67 (s, 2H), 3.06 (s, 4H).
UPLC/MS (3 min) retention time 1.8 1 min.
LRMS: m/z No ionization .
PREPARATION 79
(1Z)-W'-Hydroxy-3-phenylpropanimidamide
Synthesized from 3-phenylpropanenitrile and hydroxylamine hydrochloride following the method of PREPARATION 75. To isolate the title compound the aqueous phase was evaporated to dryness and purified by reverse-phase chromatography using the Isolera Purification system. Yield : 64%. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (s, 1H), 7.31 - 7.08 (m, 5H), 5.40 (s, 2H), 2.84 - 2.7 1 (m, 2H), 2.28 - 2 .15 (m , 2H). UPLC/MS (3 min) retention time 0.65 min.
LRMS: m/z 165 (M+1 ).
PREPARATION 80
5-(Chloromethyl)-3-(2-phenylethyl)-1 ,2,4-oxadiazole
Synthesized from the title compound of PREPARATION 79 and Chloroacetic anhydride following the method of PREPARATION 76. Yield : 60%. Purity 82%.
UPLC/MS (3 min) retention time 1.64 min.
LRMS: m/z 223 (M+ 1, 1xCI).
PREPARATION 8 1
2-(3-Bromophenyl)ethyl methanesulfonate
Synthesized from 2-(3-bromophenyl)ethanol and methanesulfonyl chloride following the method of PREPARATION 64. Yield : 100%. Purity 100%.
UPLC/MS (3 min) retention time 1.48 min.
LRMS: m/z 296, 298 (M+N H4, 1* Br).
PREPARATION 82
3-(3-Bromophenyl)propanenitrile
The title compound of PREPARATION 8 1 (2.9 g, 10.4 mmol) was dissolved in 45 ml dimethylformamide. Sodium cyanide ( 1 .5 g , 30.6 mmol) was added and the mixture was stirred at 50 °C overnight. The residue was was partitioned between ether and water. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 2.06 g of the crude title compound as a pale pink oil. Purity 80%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.47 - 7.37 (m, 2H), 7.30 - 7 .16 (m, 2H),
2.95 (t, J = 7.4 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H). UPLC/MS (3 min) retention time 1.46 min.
LRMS: m/z No ionization
PREPARATION 83
( 1Z)-3-(3-Bromophenyl)-yV'-hydroxypropanimidamide
Synthesized from the crude title compound of PREPARATION 82 and hydroxylamine hydrochloride following the method of PREPARATION 75. Yield: 93% over two steps. Purity 97%.
UPLC/MS (3 min) retention time 0.79 min.
LRMS: m/z 243, 245 (M+ 1, 1* Br).
PREPARATION 84
3-[2-(3-Bromophenyl)ethyl]-5-(chloromethyl)-1 ,2,4-oxadiazole
Synthesized in crude form from the title compound of PREPARATION 83 and chloroacetic anhydride following the method of PREPARATION 76. Purity 72%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.37 (d , J = 8.9 Hz, 2H), 7.18 (d, J = 6 .1 Hz,
2H), 4.69 (s, 2H), 3.08 (m , 4H).
UPLC/MS (3 min) retention time 1.77 min.
LRMS: m/z 30 1,303 (M+ 1, 1xCI, 1* Br).
PREPARATION 85
(I ZJ^-^-ChlorophenylJthiol-yST-hydroxyethanimidamide
Synthesized from [(4-chlorophenyl)thio]acetonitrile and hydroxylamine hydrochloride following the method of PREPARATION 75. Yield : 77%. Purity 100%.
1H NMR (400 MHz, DMSO-d6) δ ppm 9 .14 (s, 1H), 7.43 - 7.35 (m, 2H), 7.35 - 7.27 (m , 2H), 5.48 (s, 2H), 3.53 (s, 2H). UPLC/MS (3 min) retention time 0.92
LRMS: m/z 2 17 (M+1, 1 CI).
PREPARATION 86
5-(Chloromethyl)-3-{[(4-chlorophenyl)thio]methyl}-1 ,2,4-oxadiazole
Synthesized from the title compound of PREPARATION 85 and chloroacetic anhydride following the method of PREPARATION 76. Yield : 30%. Purity 92%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.37 - 7.30 (m, 2H), 7.30 - 7.23 (m, 2H),
4.66 (s, 2H), 4 .12 (s, 2H).
UPLC/MS (3 min) retention time 1.73 min.
LRMS: m/z 275 (M+ 1, 2*CI).
PREPARATION 87
( 1Z)-Af-Hydroxy-3-phenoxypropanimidamide
Synthesized in crude form from 3-phenoxypropanenitrile and hydroxylamine hydrochloride following the method of PREPARATION 75. Purity 81% .
UPLC/MS (3 min) retention time 0.86 min.
LRMS: m/z 2 15 (M+ 1, 1xCI).
PREPARATION 88
5-(Chloromethyl)-3-[2-(4-chlorophenoxy)ethyl]-1 ,2,4-oxadiazole
Synthesized from the crude title compound of PREPARATION 87 and chloroacetic anhydride following the method of PREPARATION 76. The title compound was first partially purified by normal-phase chromatography and then purified by reverse-phase chromatography using the Isolera Purification system. Yield: 50% over two steps. Purity 100%. H NMR (400 MHz, Chloroform-d) δ ppm 7.24 - 7.18 (m, 2H), 6.88 - 6.76 (m, 2H), 4.67 (s, 2H), 4.34 (t, J = 6.5 Hz, 2H), 3.24 (t, J = 6.5 Hz, 2H).
UPLC/MS (3 min) retention time 1.82 min.
LRMS: m/z 273 (M+1 , 2*CI).
PREPARATION 89
3-(4-Chlorophenyl)-3-hydroxypropanenitrile
Sodium borohydride (0.40 g , 12.7 mmol) was added portion-wise to a stirred, cooled (ice-bath) suspension of 3-(4-chlorophenyl)-3-oxopropanenitrile (3.00 g, 16.7 mmol) in ethanol (70 ml). After 2h, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and evaporated to give 2.80 g (15.42 mmol, 92% yield) of the title compound as a yellow oil. Purity 97%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.35-7.50 (m, 4H), 5.02 (m, 1H), 2.75 (m, 2H), 2.40 (br s, 1H).
UPLC/MS (3 min) retention time 1.16 min.
LRMS: m/z No ionization.
PREPARATION 90
3-(4-Chlorophenyl)-3-methoxypropanenitrile
Methyl iodide (2.80 ml, 5.52 mmol) was added dropwise to a suspension of the title compound of PREPARATION 89 ( 1 .00 g, 5.51 mmol) and silver(l) oxide ( 1 .28 g , 5.52 mmol) in acetonitrile (10 ml) and the mixture was stirred at room temperature. After 24 h, further methyl iodide ( 1 .40 ml, 2.76 mmol) was added and stirring was continued.
After a further 24 h, the mixture was filtered and the filtrate was evaporated to give an oil that was purified by flash chromatography (ether-hexanes gradient, 0:100 rising to 50:50) to give 0.840 g (4.29 mmol, 75% yield) of the title compound as a clear oil. Purity 96%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.40 (d, 2H, J = 8.6 Hz), 7.30 (d, 2H, J = 8.6 Hz), 4.44 (m, 1H), 3.30 (s, 3H), 2.65-2.78 (m, 2H). UPLC/MS (3 min) retention time 1.53 min.
LRMS: m/z No ionization .
PREPARATION 9 1
(I ZJ-S^-ChlorophenylJ-yST-hydroxy-S-methoxypropanimidamide
Synthesized from the title compound of PREPARATION 90 and hydroxylamine hydrochloride following the method of PREPARATION 75. Yield : 28%. Purity 95%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.16 (s, 1H), 7.40 (d, 2H, J = 8.6 Hz), 7.3 1 (d,
2H, J = 8.6 Hz), 5.37 (br s, 2H), 4.52 (dd , 1H, J = 6.3, 7.8 Hz), 3 .10 (s, 3H), 2.24 (dd, 1H, J = 7.8, 14 .1 Hz), 2 .19 (dd, 1H, J = 6.3, 14 .1 Hz).
UPLC/MS (3 min) retention time 0.90 min .
LRMS: m/z 229 (M+ 1, 1*CI).
PREPARATION 92
5-(Chloromethyl)-3-[2-(4-chlorophenyl)-2-methoxyethyl]-1 ,2,4-oxadiazole
Synthesized from the title compound of PREPARATION 91 and chloroacetic anhydride following the method of PREPARATION 76. Yield : 6 1% . Purity 99%.
H NMR (300 MHz, DMSO-d6) δ ppm 7.44 (d , 2H, J = 8.6 Hz), 7.39 (d, 2H, J = 8.6 Hz), 5.09 (s, 2H), 4.68 (dd , 1H, J = 5 .1, 8.6 Hz), 3.20 (dd , 1H, J = 8.6, 15.2 Hz), 3.08 (s, 3H), 3.04 (dd , 1H, J = 5.1, 15.2 Hz).
UPLC/MS (3 min) retention time 1.73 min.
LRMS: m/z 287 (M+ 1, 2xCI).
PREPARATION 93
3-(4-Chlorophenyl)butanenitrile Copper ( I) acetate (0.01 2 g , 0.07 mmol), bis-[2-(diphenylphosphino)phenyl]ether (DPE- Phos, 0.036 g , 0.07 mmol) and poly(methylhydrosiloxane) (0.54 ml) were added to 2.5 ml degassed toluene and the blue mixture was stirred at room temperature. After 30 min, a solution of the title compound of PREPARATION 106 (0.400 g, 2.25 mmol) in degassed toluene (2.5 ml) and ie/f-butanol (0.86 ml) was added dropwise and the mixture was stirred overnight. After this period, water was added and the mixture was diluted with ether. 2M Aqueous sodium hydroxide solution (7 ml) was added and the biphasic mixture was stirred at room temperature. After 30 min, the organic layer was washed with brine, dried and evaporated and the residue was purified by flash chromatography (ether-hexanes gradient, 0 :100 rising to 20:80) to give 0.331 g ( 1 .84 mmol, 82% yield) of the title compound as a clear oil. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.33 (d , 2H, J = 8.6 Hz), 7 .19 (d , 2H, J = 8.6
Hz), 3 .12-3.20 (m, 1H), 2.52-2.63 (m, 2H), 1.45 (d , 3H, J = 7.0 Hz).
UPLC/MS (3 min) retention time 1.60 min .
LRMS: m/z No ionization .
PREPARATION 94
(I ZJ-S^-ChlorophenylJ-yST-hydroxybutanimidamide
Synthesized in crude form from the title compound of PREPARATION 93 and hydroxylamine hydrochloride following the method of PREPARATION 75. Purity 80%.
UPLC/MS (3 min) retention time 0.89 min.
LRMS: m/z 2 13 (M+ 1, 1xCI).
PREPARATION 95
5-(Chloromethyl)-3-[2-(4-chlorophenyl)propyl]-1 ,2,4-oxadiazole
Synthesized in crude from the crude title compound of PREPARATION 94 and chloroacetic anhydride following the method of PREPARATION 76. Purity 81% .
H NMR (300 MHz, Chloroform-d) δ ppm 7.27 (d , 2H, J = 8.6 Hz), 7 .16 (d , 2H, J = 8.6 Hz), 4.64 (s, 2H), 3.29-3.36 (m, 1H), 2.95-3.06 (m , 2H), 1.32 (d, 3H, J = 7.0 Hz). UPLC/MS (3 min) retention time 1.88
LRMS: m/z 271 (M+ 1, 2*CI).
PREPARATION 96
[2-(4-Chlorophenyl)-1 ,3-dioxolan-2-yl]acetonitrile
A mixture of 3-(4-chlorophenyl)-3-oxopropanenitrile (2.90 g , 16 .1 mmol), p-toluene sulphonic acid (0.29 g , 1.53 mmol) and ethylene glycol (25 ml) in toluene (20 ml) were stirred and heated to reflux in a Dean-Stark apparatus. After 5 h, the toluene was removed in vacuo and the residue was diluted with water and the mixture was basified with 2M aqueous sodium hydroxide solution and extracted with ether. The organic layer was washed with brine, dried and evaporated to give 3.40 g ( 15.2 mmol, 94% yield) of the title compound as a white solid . Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.46 (d , 2H, J = 8.6 Hz), 7.37 (d , 2H, J = 8.6
Hz), 4.20-4.24 (m, 2H), 3.88-3.9 1 (m , 2H), 2.92 (s, 2H).
UPLC/MS (3 min) retention time 1.49 min.
LRMS: m/z No ionization .
PREPARATION 97
( 1Z)-2-[2-(4-Chlorophenyl)-1 ,3-dioxolan-2-yl]-W'-hydroxyethanimidamide
Synthesized from the title compound of PREPARATION 96 and hydroxylamine hydrochloride following the method of PREPARATION 75. Yield : 100%. Purity 96%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.92 (s, 1H), 7.30-7.42 (m, 4H), 5.18 (br s, 2H),
4.02-4.06 (m, 2H), 3.70-3.74 (m, 2H), 2.55 (s, 2H).
UPLC/MS (3 min) retention time 0.89 min.
LRMS: m/z 257 (M+ 1, 1xCI).
PREPARATION 98 5-(Chloromethyl)-3-{[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]methyl}-1,2,4- oxadiazole
Synthesized from the title compound of PREPARATION 97 and chloroacetic anhydride following the method of PREPARATION 76. Yield : 65%. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 7.4 1 (m, 4H), 5.04 (s, 2H), 3.95 (m, 2H), 3.74
( , 21-1), 3.37 (s, 2H).
UPLC/MS (3 min) retention time 1.67 min.
LRMS: m/z 3 15 (M+ 1, 2xCI).
PREPARATION 99
6-[(3-{[2-(4-Chlorophenyl)-1,3-dioxolan-2-yl]methyl}-1,2,4-oxadiazol-5-yl)methyl]- 1-methyl-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
A solution of the title compound of PREPARATION 98 (0.66 g, 2.09 mmol) in 4 ml dimethylformamide was added dropwise to a suspension of the title compound of PREPARATION 17 (0.40 g , 2.65 mmol) and potassium carbonate (0.55 g , 3.97 mmol) in dimethylformamide (8 ml) and the mixture was stirred at room temperature. After 24 h, the mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with brine, dried and evaporated to give 0.97 g of the crude title compound as an orange oil which was used without further purification. Purity 73%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.54 (s, 1H), 7.35 (d, 2 H, J = 8.6 Hz), 7.3 1 (d,
2 H, J = 8.6 Hz), 5.55 (s, 2 H), 4.37 (s, 3H), 3.9 1 (m , 2 H), 3.71 (m, 2H), 3.28 (s, 2H).
HPLC/MS (5 min) retention time 2.27 min.
LRMS: m/z 430 (M+ 1, 1*CI).
PREPARATION 100
(3-{[2-(4-Chlorophenyl)-1,3-dioxolan-2-yl]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate 2-Chloro-2-oxoethyl acetate (0.406 ml, 3.78 mmol) was added dropwise to a solution of the title compound of PREPARATION 97 (0.923 g, 3.60 mmol) in pyridine (5 ml) and the mixture was stirred overnight. After this period, the mixture was stirred and heated to 115 °C for 3 h then cooled. The mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with brine, dried and evaporated . The residue was purified by flash chromatography (ether-hexanes gradient, 0 :100 rising to 50:50) to give 0.700 g (2.07 mmol , 58% yield) of the title compound as a colourless oil. Purity 95%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.43 (d , 2H, J = 8.6 Hz), 7.32 (d, 2H, J = 8.6 Hz), 5.27 (s, 2H), 4.00-4.03 (m, 2H), 3.78-3.82 (m , 2H), 3.39 (s, 2H), 2 .18 (s, 3H).
UPLC/MS (3 min) retention time 1.48 min.
LRMS: m/z No ionization .
PREPARATION 10 1
1-(4-Chlorophenyl)-2-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]ethanone
A mixture of the title compound of PREPARATION 100 (0.700 g, 2.07 mmol) and concentrated aqueous hydrochloric acid ( 1 .50 ml) in tetrahydrofuran ( 10 ml) was stirred at room temperature. After 72 h, the mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with brine, dried and evaporated to give 0.520 g (2.06 mmol, 100% yield) of the title compound as a white solid . Purity 95%.
UPLC/MS (3 min) retention time 1.22 min.
LRMS: m/z 253 (M+ 1, 1*CI).
PREPARATION 102
1-(4-Chlorophenyl)-2-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]ethanol
Sodium borohydride (0.039 g , 1.03 mmol) was added portion-wise to a stirred , cooled (ice-bath) suspension of the title compound of PREPARATION 101 (0.520 g , 2.06 mmol) in methanol ( 10 ml). After 20 min, the mixture was quenched with brine and extracted with dichloromethane. The organic layer was dried and evaporated and the residue was purified by flash chromatography (methanol-dichloromethane gradient,
0 :100 rising to 3:97) to give 0.4 10 g ( 1 .6 1 mmol, 78% yield) of the title compound as a white solid. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.36 (m, 4H), 5.15-5.20 (m, 1H), 4.90 (s, 2H), 3 .13-3. 16 (m , 2H).
UPLC/MS (3 min) retention time 1.12 min .
LRMS: m/z 255 (M+ 1, 1*CI).
PREPARATION 103
{3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl methanesulfonate
A solution of methanesulphonyl chloride (0.033 g , 0.29 mmol) in dichloromethane ( 1 ml) was added dropwise over 10 minutes to a stirred, cooled (-1 3 °C) solution of the title compound of PREPARATION 102 (0.069 g, 0.27 mmol) and triethylamine (0.076 ml, 0.55 mmol) in dichloromethane ( 1 ml). After 1 h, water was added and the mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried and evaporated to give 0.09 1 g (0.27 mmol, 100% yield) of the title compound as a colourless oil. Purity 93%.
UPLC/MS (3 min) retention time 1.3 1 min.
LRMS: m/z 333 (M+ 1, 1xCI).
PREPARATION 104
(2E)-3-(4-Chlorophenyl)acrylonitrile
Diethyl (cyanomethyl)phosphonate ( 13.9 g , 78 mmol) was dissolved in tetrahydrofuran (230 ml). Lithium hydroxide monohydrate (3.6 g , 86 mmol) was added and the mixture was stirred at reflux for 30 min. The mixture was allowed to cool and 4- chlorobenzaldehyde dissolved in tetrahydrofuran ( 100 ml) was added . The mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure. The residue was was partitioned between ether-hexane mixture and water. The organic phase was washed several times with water, decanting from the dark oily residue. The organic phase was evaporated under reduced pressure and the residue was re-suspended in cold heptane, forming a precipitate. The solid was collected by filtration and was dried in a stream of air to give 6 .17 g (37 mmol, 52% yield) of the title compound as a pale yellow solid. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.4 1 (s, 4H), 7.32 (d , J = 20.9 Hz, 1H), 5.88 (d , J = 16.7 Hz, 1H).
UPLC/MS (3 min) retention time 1.52 min.
LRMS: m/z 164 (M+ 1, 1*CI).
PREPARATION 105
(1Z,2E)-3-(4-Chlorophenyl)-yV'-hydroxyprop-2-enimidamide
Synthesized from the title compound of PREPARATION 104 and hydroxylamine hydrochloride following the method of PREPARATION 75. Yield : 83%. Purity 92%.
UPLC/MS (3 min) retention time 0.9 1 min.
LRMS: m/z 197 (M+ 1, 1*CI).
PREPARATION 106
(2E)-3-(4-Chlorophenyl)but-2-enenitrile
Diethyl cyanomethylphosphonate (0.91 ml, 5.64 mmol) was added dropwise to a stirred , cooled (ice bath) suspension of sodium hydride (60% in mineral oil, 0.280 g , 7.00 mmol) in dry tetrahydrofuran (20 ml). The mixture was warmed to room temperature over 60 min, then 1-(4-chlorophenyl)ethanone (0.750 g, 4.71 mmol) was added and stirring was continued overnight. After this period , water was added and the mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried and evaporated. The residue was purified by flash chromatography (ethyl acetate-hexanes gradient, 0 :100 rising to 10:90) to give 0.400 g (2.25 mmol, 48% yield) of the title compound as a white solid. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.42 (d , 2H, J = 8.6 Hz), 7.39 (d , 2H, J = 8.6 Hz), 5.62 (s, 1H), 2.46 (s, 3H). UPLC/MS (3 min) retention time 1.64 min.
LRMS: m/z No ionization.
PREPARATION 107
(1Z,2E)-3-(4-Chlorophenyl)-N'-hydroxybut-2-enimidamide
Synthesized from the title compound of PREPARATION 106 and hydroxylamine hydrochloride following the method of PREPARATION 75. Yield: 61%. Purity 95%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.43 - 7.23 (m, 4H), 6.02 (s, 1H), 4.69 (s, 2H), 2.36 (s, 3H).
UPLC/MS (3 min) retention time 0.91 min.
LRMS: m/z 2 1 1 (M+1 , 1*CI).
PREPARATION 108
5-(Chloromethyl)-3-[(1 E)-2-(4-chlorophenyl)prop-1 -en-1 -yl]-1 ,2,4-oxadiazole
Synthesized from the title compound of PREPARATION 107 and chloroacetic anhydride following the method of PREPARATION 76. Yield: 39%. Purity 96%.
UPLC/MS (3 min) retention time 1.95 min.
LRMS: m/z No ionization.
PREPARATION 109 trans 2-(4-Chlorophenyl)cyclopropanecarbonitrile
Dimethylsulfoxide (0.7 ml, 9.9 mmol) was diluted with 70 ml hexane. Sodium hydride (60% dispersion in oil, 0.30 g , 7.5 mmol) was added portion-wise and with stirring and the mixture was stirred until effervescence stopped. Tnmethyloxosulphonioum iodide
( 1 .53 g , 7.0 mmol) was added followed by the title compound of PREPARATION 104
( 1 .0 g , 6.1 mmol). The mixture was stirred overnight at room temperature. The residue was was partitioned between ether-hexane mixture and water. The organic phase was washed several times with water and was evaporated under reduced pressure. The residue was purified by flash chromatography (dichloromethane-hexane gradient) to give 0.15 g (0.86 mmol, 14% yield) of the title compound. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.36 (d, J = 7.0 Hz, 2H), 7.23 (d, J = 7.2 Hz, 2H), 2.54 (q, J = 8.0 Hz, 1H), 1.88 (q, J = 7.4, 6.7 Hz, 1H), 1.56 (m, 2H).
UPLC/MS (3 min) retention time 1.42 min.
LRMS: m/z 178 (M+1 , 1*CI).
PREPARATION 110 trans 2-(4-Chlorophenyl)-yS/'-hydroxycyclopropanecarboximidamide
Synthesized in crude form from the title compound of PREPARATION 109 and hydroxylamine hydrochloride following the method of PREPARATION 75. Purity 64%.
UPLC/MS (3 min) retention time 0.88 min.
LRMS: m/z 2 1 1 (M+1 , 1*CI).
PREPARATION 111 trans /^-[(Chloroacetyljoxyl^^-chlorophenyljcyclopropanecarboximidamide
The crude title compound of PREPARATION 110 (169 mg) was dissolved in dichloromethane (6 ml). Diisopropylethylamine (0.18 ml, 1.0 mmol) was added and the mixture was cooled to 0 °C. Chloroacetyl chloride (0.1 1 ml, 1.41 mmol) was added and the mixture was stirred for 2 h, warming to room temperature. The mixture was diluted with dichloromethane, was washed with water and the organic phase was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 160 mg of the crude title compound. Purity 57%.
UPLC/MS (3 min) retention time 1.48 min.
LRMS: m/z 287 (M+1 , 2*CI). PREPARATION 112 trans 5-(Chloromethyl)-3-[2-(4-chlorophenyl)cyclopropyl]-1,2,4-oxadiazole
The crude title compound of PREPARATION 111 ( 160 mg) was dissolved in toluene (2 ml) and the mixture was stirred at reflux for 2 h. The mixture was allowed to cool and was evaporated under reduced pressure. The residue was purified by preparative HPLC to give 50 mg (0. 19 mmol, 22% yield over three steps) of the title compound as a colourless oil . Purity 97%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.28 (m, 2H), 7 .15 - 7.02 (m, 2H), 4.66 (s,
2H), 2.57 (ddd , J = 9 .1, 6.3, 4.4 Hz, 1H), 2.38 (ddd , J = 8.8, 5.6, 4.4 Hz, 1H), 1.7 1 (dt, J = 9 .1, 5.3 Hz, 1H), 1.52 (ddd , J = 8.8, 6.3, 5 .1 Hz, 1H).
UPLC/MS (3 min) retention time 1.84 min.
LRMS: m/z No ionization .
PREPARATION 113
3-Hydroxy-3-[4-(trifluoromethyl)phenyl]propanenitrile
Lithium diisopropylamide (2M in tetrahydrofuran , 2.25 ml, 4.5 mmol) was diluted with 5 ml anhydrous tetrahydrofuran and cooled to -78 °C under argon atmosphere. Acetonitrile (0.22 ml, 4.2 mmol) diluted with 8 ml anhydrous tetrahydrofuran was added drop-wise and with the mixture was then stirred for 15 min. 4- (Trifluoromethyl)benzaldehyde (500 mg, 2.87 mmol) dissolved in 8 ml anhydrous tetrahydrofuran was added . The mixture was stirred at -78 °C for 30 min and was then allowed to warm to room temperature. The mixture was quenched with brine and was extracted three times with ethyl acetate. The combined organics were dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography (ether-hexane, gradient) to give 380 mg ( 1 .76 mmol , 75% yield) of the title compound as a colourless oil. Purity 98%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.67 (d , J = 8.1 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 5 .13 (t, J = 6.1 Hz, 1H), 2.79 (d , J = 6 .1 Hz, 2H).
HPLC/MS (4.5 min) retention time 2.82 min.
LRMS: m/z No ionization . PREPARATION 114
(1Z)-AT,3-Dihydroxy-3-[4-(trifluoromethyl)phenyl]propanimidamide
The title compound of PREPARATION 113 (300 mg, 1.39 mmol) was dissolved in ethanol ( 10 ml). Hydroxylamine hydrochloride (386 mg, 5.55 mmol) and potassium carbonate (768 mg, 5.55 mmol) were added followed by several drops of water. The mixture was stirred at 60 °C for 24 h. The mixture was allowed to cool and was evaporated under reduced pressure. The residue was resuspended in water and the mixture was extracted 5 times with dichloromethane. The combined organics were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (methanol- dichloromethane gradient, 0 :100 rising to 10:90) to give 75 mg (0.30 mmol, 22% yield) of the title compound. Purity 99%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (s, 1H), 7.67 (d , J = 8 .1 Hz, 2H), 7.60 -
7.51 (m, 2H), 5.53 (d , J = 4.6 Hz, 1H), 5.42 (s, 2H), 5.03 - 4.89, (m, 1H), 2.44 - 2.20 (m , 2H)
HPLC/MS (4.5 min) retention time 1.40 min .
LRMS: m/z 249 (M+1 ).
PREPARATION 115
3-(4-Bromophenyl)-3-hydroxypropanenitrile
Synthesized from 4-Bromobenzaldehyde and acetonitrile following the method of PREPARATION 113. Yield : 59%. Purity 96%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.56-7.51 (m, 2H), 7.32-7.27 (m, 2H), 5.03
(td , J = 6 , 3.6 Hz, 1H), 2.75 (d, J = 6 Hz, 2H), 2.40 (d , J = 3.6 Hz, 1H)
HPLC/MS (4.5 min) retention time 2.67 min.
LRMS: m/z No ionization . PREPARATION 116
(IZJ-S^-BromophenylJ-yST.S-dihydroxypropanimidamide
Synthesized from the title compound of PREPARATION 115 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield : 29%. Purity 93%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (s, 1H), 7.47 (d , J = 8 Hz, 2H), 7.27 (d , J =
8 Hz, 2H), 5.40-5.36 (m, 3H), 4.85-4.80 (m , 1H), 2.28 (dd , J = 14 , 8 Hz, 1H), 2.20 (dd , J = 14 , 5.6 Hz, 1H).
HPLC/MS (4.5 min) retention time 1.27 min.
LRMS: m/z 259, 261 (M+ 1, 1* Br).
PREPARATION 117
3-Hydroxy-3-[4-(trifluoromethyl)phenyl]propanenitrile
Synthesized from 3-Bromobenzaldehyde and acetonitrile following the method of PREPARATION 113 to obtain 502 mg of the title compound . Yield: 41% . Purity 85%.
HPLC/MS (4.5 min) retention time 2.67 min.
LRMS: m/z no ionization (M+ 1, 1* Br).
PREPARATION 118
(1Z)-3-(3-Bromophenyl)-yV,3-dihydroxypropanimidamide
Synthesized from the title compound of PREPARATION 117 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield: 59%. Purity 98%.
H NMR (400 MHz, CD30D) δ ppm 7.57 (t, J = 2 Hz, 1H), 7.4 1-7.37 (m, 1H), 7.36-7.32
(m, 1H), 7.23 (t, J = 8 Hz, 1H), 4.9 1 (dd , J = 8, 5.2 Hz, 1H), 2.44 (dd, J = 14.4, 8 Hz, 1H), 2.38 (dd , J = 14.4, 4.8 Hz, 1H).
HPLC/MS (4.5 min) retention time 1.27 min.
LRMS: m/z 259, 261 (M+ 1, 1xBr). PREPARATION 119
3-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-hydroxypropanenitrile
Synthesized from 4-fluoro-3-(trifluoromethyl)benzaldehyde and acetonitrile following the method of PREPARATION 113. Yield: 41%. Purity 95%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.67 (dd, J = 6.6, 2.1 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.29 - 7.20 (m, 1H), 5.14 - 5.07 (m, 1H), 2.77 (d, J = 6.2 Hz, 2H).
HPLC/MS (4.5 min) retention time 2.88 min.
LRMS: m/z no ionization.
PREPARATION 120
(IZJ-S-^-Fluoro -S-itrifluoromethylJphenyll - s .S-dihydroxypropanimidamide
Synthesized from the title compound of PREPARATION 119 and hydroxylamine hydrochloride following the method of PREPARATION 114. Yield: 64%. Purity 90%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (s, 1H), 7.74 - 7.64 (m, 2H), 7.44 (dd, J = 10.8, 8.5 Hz, 1H), 5.58 (d, J = 4.7 Hz, 1H), 5.42 (s, 2H), 4.96 (q, J = 5.6 Hz, 1H), 2.35 (dd, J = 14.1 , 7.6 Hz, 1H), 2.26 (dd, J = 14.1 , 5.9 Hz, 1H).
HPLC/MS (4.5 min) retention time 1.55 min.
LRMS: m/z 267 (M+1).
PREPARATION 121
3-Hydroxy-3-[3-(trifluoromethoxy)phenyl]propanenitrile
Synthesized from 3-(trifluoromethoxy)benzaldehyde and acetonitrile following the method of PREPARATION 113. Yield: 21%. Purity 87%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.44 (t, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H),
7.29 (br s, 1H), 7.21 (d, J = 8 Hz, 1H), 5.09 (t, J = 6.4 Hz, 1H), 2.78 (d, J = 6.4 Hz, 2H), 2.53 (br s, 1H). HPLC/MS (4.5 min) retention time 2.87 min.
LRMS: m/z no ionization.
PREPARATION 122
( 1Z)-AT,3-Dihydroxy-3-[3-(trifluoromethoxy)phenyl]propanimidamide
Synthesized from the title compound of PREPARATION 12 1 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield : 5 1% . Purity 93%.
H NMR (400 MHz, CD30D) δ ppm 2.40 (dd , J = 14.4, 5.2 Hz, 1H), 2.45 (dd , J = 14.4, 8.2 Hz, 1H), 4.97 (dd, J = 8.2, 5.2 Hz, 1H), 7 .17-7. 13 (m, 1H), 7.32 (br s, 1H), 7.44- 7.35 (m , 2H)
HPLC/MS (4.5 min) retention time 1.48 min.
LRMS: m/z 265 (M+1 ).
PREPARATION 123
3-(3,4-Dichlorophenyl)-3-hydroxypropanenitrile
Synthesized from 3,4-dichlorobenzaldehyde and acetonitrile following the method of PREPARATION 113. Yield : 43%. Purity 89%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.52 (d, J = 2 Hz, 1H), 7.48 (d, J = 8.4 Hz,
1H), 7.27-7.24 (m, 1H), 5.03 (t, J = 5.6 Hz, 1H), 2.76 (d , J = 6.4 Hz, 2H), 2.54 (br s, 1H).
HPLC/MS (4.5 min) retention time 2.92 min.
LRMS: m/z no ionization .
PREPARATION 124
( 1Z)-3-(3,4-Dichlorophenyl)-yV',3-dihydroxypropanimidamide Synthesized from the title compound of PREPARATION 123 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield: 54%. Purity 95%.
H NMR (400 MHz, CD30D) δ ppm 7.54 (d , J = 2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H),
7.29 (dd , J = 8.4, 2 Hz, 1H), 4.92 (dd , J = 8, 5.2 Hz, 1H), 2.45 (dd , J = 14.4, 8 Hz, 1H), 2.38 (dd, J = 14.4, 5.2 Hz, 1H).
HPLC/MS (4.5 min) retention time 1.43 min.
LRMS: m/z 249 (M+ 1, 2*CI).
PREPARATION 125
3-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-hydroxypropanenitrile
Synthesized from 2-fluoro-4-(trifluoromethyl)benzaldehyde and acetonitrile following the method of PREPARATION 113. Yield : 52%. Purity 96%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.77 (t, J = 7.6 Hz, 1H), 7.52 (d , J = 8.5 Hz, 1H), 7.35 (d, J = 10.2 Hz, 1H), 5.47 - 5.38 (m, 1H), 2.91 (dd, J= 16.7, 4.4 Hz, 1H), 2.77 (dd, J = 16.7, 7 .1 Hz, 1H).
HPLC/MS (4.5 min) retention time 2.90 min .
LRMS: m/z no ionization.
PREPARATION 126
( 1Z)-3-[2-Fluoro-4-(trifluoromethyl)phenyl]-N\3-dihydroxypropanimidamide
Synthesized from the title compound of PREPARATION 125 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield : 30%. Purity 95%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.8 1 (s, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.57 (d , J =
9.0 Hz, 2H), 5.73 - 5.66 (m , 1H), 5.37 (s, 2H), 5.18 (q , J = 6.2 Hz, 1H), 2.40 - 2.3 1 (m, 2H)
HPLC/MS (4.5 min) retention time 1.47 min.
LRMS: m/z 267 (M+1 ). PREPARATION 127
3-(2-Chlorophenyl)-3-hydroxypropanenitrile
Synthesized from 2-chlorobenzaldehyde and acetonitrile following the method of PREPARATION 113. Yield : 82%. Purity 93%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.67 (m, 1H), 7.39-7.34 (m, 1H), 7.32-7.27
(m, 1H), 5.48-5.43 (m , 1H), 2.9 1 (dd, J = 16.8, 4.4 Hz, 1H), 2.72 (dd , J = 16.8, 7.2 Hz, 1H), 2.57 (d, J = 4 Hz, 1H).
HPLC/MS (4.5 min) retention time 2.52 min.
LRMS: m/z No ionization.
PREPARATION 128
(1Z)-3-(2-Chlorophenyl)-yV,3-dihydroxypropanimidamide
Synthesized from the title compound of PREPARATION 127 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield: 43%. Purity 99%.
H NMR (400 MHz, CD30D) δ ppm 7.64 (dd , J = 8 , 2 Hz, 1H), 7.35-7.29 (m , 2H), 7.60
(td , J = 8, 2 Hz, 1H), 5.32 (dd , J = 8.8, 3.6 Hz, 1H), 2.51 (dd, J = 14.8, 3.6 Hz, 1H), 2.36 (dd, J = 14.8, 8.8 Hz, 1H).
HPLC/MS (4.5 min) retention time 0.78 min .
LRMS: m/z 2 15 (M+ 1, 1xCI).
PREPARATION 129
3-Hydroxy-3-quinolin-2-ylpropanenitrile
Synthesized from quinoline-2-carbaldehyde and acetonitrile following the method of PREPARATION 113. Yield : 52%. Purity 94%.
H NMR (400 MHz, Chloroform-d) δ ppm 8.26 (d, J = 8.4 Hz, 1H), 8 .10 (d, J = 8 Hz,
1H), 7.87 (dd, J = 8 , 1.2 Hz, 1H), 7.78 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.60 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 5.29 (d, J = 4.8 Hz, 1H), 5.22-1 7 (m, 1H), 2.99-2.89 (m , 2H).
HPLC/MS (4.5 min) retention time 1.92 min.
LRMS: m/z 199 (M+1 ).
PREPARATION 130
(IZJ-yST^-Dihydroxy-S-quinolin^-ylpropanimidamide
Synthesized from the title compound of PREPARATION 129 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield : 42%. Purity 99%.
H NMR (400 MHz, CD30D) δ ppm 8.33 (d, J = 8.4 Hz, 1H), 8.01 (dd , J = 8.4, 0.8 Hz,
1H), 7.91 (dd, J = 8.4, 1.2 Hz, 1H), 7.74 (ddd , J = 8 , 6.4 , 1.2 Hz, 1H), 7.70 (d , J = 8.4
Hz, 1H), 7.57 (ddd, J = 8 , 6.8, 0.8 Hz, 1H), 5 .15 (dd , J = 8.4, 4 Hz, 1H), 2.68 (dd , J = 14.4, 4 Hz, 1H), 2.55 (dd , J = 14.4, 8.4 Hz, 1H).
HPLC/MS (4.5 min) retention time 0.80 min .
LRMS: m/z 232 (M+1 ).
PREPARATION 13 1
3-(2,4-Dichlorophenyl)-3-hydroxypropanenitrile
Synthesized from 2,4-dichlorobenzaldehyde and acetonitrile following the method of PREPARATION 113. Yield : 57%. Purity 91% .
H NMR (400 MHz, Chloroform-d) δ ppm 7.65 (d , J = 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 5.44-5.39 (m, 1H), 2.90 (dd, J = 16.4, 4 Hz, 1H), 2.70 (dd , J = 16.4, 7.2 Hz, 1H), 2.57 (d, J = 4 Hz, 1H).
HPLC/MS (4.5 min) retention time 2.97 min.
LRMS: m/z No ionization.
PREPARATION 132 (I ZJ-S^^-DichlorophenylJ-yST.S-dihydroxypropanimidamide
Synthesized in crude form from the title compound of PREPARATION 13 1 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Purity 80%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.59 (d , J = 8 Hz, 1H), 7.35 (d , J = 2 Hz, 1H),
7.28 (dd , J = 8 , 2 Hz, 1H), 5.32 (dd , J = 9.2, 2.4 Hz, 1H), 4.75 (br s, 2H), 3.49 (s, 2H), 2.58 (dd, J = 15.2, 2.4 Hz, 1H), 2.37 (dd , J = 15.2, 9.2 Hz, 1H).
HPLC/MS (4.5 min) retention time 1.40 min .
LRMS: m/z 249 (M+ 1, 2*CI).
PREPARATION 133
3-Hydroxy-3-[4-(trifluoromethoxy)phenyl]propanenitrile
Synthesized from 4-(trifluoromethoxy)benzaldehyde and acetonitrile following the method of PREPARATION 113. Yield : 67%. Purity 98%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.52 - 7.40 (m, 2H), 7.33 - 7 .17 (m, 2H),
5 .14 - 5.0 1 (m, 1H), 2.77 (d , J = 6.1 Hz, 2H), 2.44 (d , J = 3.6 Hz, 1H).
HPLC/MS (4.5 min) retention time 2.88 min.
LRMS: m/z No ionization .
PREPARATION 134
( 1Z)-yV',3-Dihydroxy-3-[4-(trifluoromethoxy)phenyl]propanimidamide
Synthesized from the title compound of PREPARATION 133 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield : 54%. Purity 90%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (s, 1H), 7.49 - 7.40 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.49 - 5.34 (m, 3H), 4.96 - 4.80 (m, 1H), 2.39 - 2 .19 (m , 2H).
HPLC/MS (4.5 min) retention time 1.52 min.
LRMS: m/z 265 (M+1 ). PREPARATION 135
3-Hydroxy-3-(4-isopropylphenyl)propanenitrile
Synthesized from 4-lsopropylbenzaldehyde and acetonitrile following the method of PREPARATION 113. Yield: 85%. Purity 98%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.35 - 7.30 (m, 2H), 7.29 - 7.23 (m, 2H), 5.07 - 4.98 (m, 1H), 2.92 (sept, J = 6.9 Hz, 1H), 2.77 (dd, J = 6.2, 2.3 Hz, 2H), 2.31 (d, J = 3.5 Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H).
HPLC/MS (4.5 min) retention time 2.95 min.
LRMS: m/z No ionization.
PREPARATION 136
(1Z)-yV,3-Dihydroxy-3-(4-isopropylphenyl)propanimidamide
Synthesized from the title compound of PREPARATION 135 and hydroxylamine hydrochloride following the method of PREPARATION 114. Yield: 22%. Purity 90%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (s, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 5.38 (s, 2H), 5.22 (d, J = 4.3 Hz, 1H), 4.86 - 4.75 (m, 1H), 2.85 (sept, J = 6.9 Hz, 1H), 2.33 - 2.18 (m, 2H), 1.18 (d, J = 6.9 Hz, 6H).
HPLC/MS (4.5 min) retention time 1.57 min.
LRMS: m/z 223 (M+1 ).
PREPARATION 137
3-[4-Chloro-3-(trifluoromethyl)phenyl]-3-hydroxypropanenitrile
Synthesized from 4-chloro-3-(trifluoromethyl)benzaldehyde and acetonitrile following the method of PREPARATION 113. Yield: 72%. Purity 98%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.74 (s, 1H), 7.62 - 7.51 (m, 2H), 5.1 1 (t, J =
6.1 Hz, 1H), 2.78 (d, J = 6.1 Hz, 2H). I l l HPLC/MS (4.5 min) retention time 3.08 min.
LRMS: m/z No ionization.
PREPARATION 138
(1Z)-3-[4-Chloro-3-(trifluoromethyl)phenyl]-W',3-dihydroxypropanimidamide
Synthesized from the title compound of PREPARATION 137 and hydroxylamine hydrochloride following the method of PREPARATION 114. Yield: 70%. Purity 98%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (s, 1H), 7.84 - 7.75 (m, 1H), 7.73 - 7.57
(m, 2H), 5.62 (d, J = 4.7 Hz, 1H), 5.42 (s, 2H), 5.02 - 4.91 (m, 1H), 2.35 (dd, J = 14.1 , 7.5 Hz, 1H), 2.26 (dd, J = 14.1 , 6.0 Hz, 1H).
HPLC/MS (4.5 min) retention time 1.70 min.
LRMS: m/z 283, 285 (M+1 , 1*CI).
PREPARATION 139
3-Hydroxy-3-(2-naphthyl)propanenitrile
Synthesized from 2-naphthaldehyde and acetonitrile following the method of PREPARATION 113. Yield: 76%. Purity 90%.
H NMR (400 MHz Chloroform-d) δ ppm 7.88 (t, J = 7.9 Hz, 4H), 7.60 - 7.44 (m, 3H), 5.22 (t, J = 6.2 Hz, 1H), 2.86 (d, J = 7.6 Hz, 2H).
HPLC/MS (4.5 min) retention time 2.80 min.
LRMS: m/z No ionization.
PREPARATION 140
(1Z)-Af,3-Dihydroxy-3-(2-naphthyl)propanimidamide
Synthesized from the title compound of PREPARATION 139 and hydroxylamine hydrochloride following the method of PREPARATION 114. Yield: 45%. Purity 98%. H NMR (400 MHz, DMSO-d6) δ ppm 8 .18 (s, 1H), 7.92 - 7.80 (m, 4H), 7.50 (ddd , J =
19.9, 8.9, 2.5 Hz, 3H), 5.45 (s, 2H), 5.09 - 4.97 (m, 1H), 3 .17 (s, 1H), 2.44 - 2.32 (m, 2H).
HPLC/MS (4.5 min) retention time 1.48 min.
LRMS: m/z 231 (M+1 ).
PREPARATION 14 1
3-Hydroxy-3-{4-[(trifluoromethyl)thio]phenyl}propanenitrile
Synthesized from 4-[(trifluoromethyl)thio]benzaldehyde and acetonitrile following the method of PREPARATION 113. Yield: 87%. Purity 98%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.70 (d , J = 8.2 Hz, 2H), 7.48 (d , J = 8 .1 Hz, 2H), 5.20 - 5.03 (m, 1H), 2.78 (d , J = 6 .1 Hz, 2H).
HPLC/MS (4.5 min) retention time 3 .12 min.
LRMS: m/z No ionization .
PREPARATION 142
(1Z)-N\3-Dihydroxy-3-{4-[(trifluoromethyl)thio]phenyl}propanimidamide
Synthesized from the title compound of PREPARATION 14 1 and hydroxylamine hydrochloride following the method of PREPARATION 114 . Yield : 31% . Purity 96%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (s, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.51 (d , J = 8.4 Hz, 2H), 5.55 - 5.47 (m, 1H), 5.43 (s, 2H), 5.0 1 - 4.86 (m, 1H), 2.30 (h, J = 8.6, 8.2 Hz, 2H).
HPLC/MS (4.5 min) retention time 1.72 min.
LRMS: m/z 281 (M+1 ).
PREPARATION 143 3-(5-Bromo-2-thienyl)-3-hydroxypropanenitrile
Synthesized from 5-bromothiophene-2-carbaldehyde and acetonitrile following the method of PREPARATION 113. Yield: 74%. Purity by NMR > 95%.
H NMR (400 MHz, Chloroform-d) δ ppm 6.96 (d, J = 4 Hz, 1H), 6.84 (d, J = 4 Hz, 1H), 5.21 (t, J = 6.4 Hz, 1H), 2.84 (dd, J = 6.4, 2 Hz, 2H).
UPLC/MS not recorded.
PREPARATION 144
(IZJ-S-iS-Bromo^-thienylJ-yST.S-dihydroxypropanimidamide
Synthesized from the title compound of PREPARATION 143 and hydroxylamine hydrochloride following the method of PREPARATION 114. Yield: 61%. Purity 99%.
H NMR (400 MHz, CD30D) δ ppm 6.92 (d, J = 3.2 Hz, 1H), 6.77 (dd, J = 4 , 0.8 Hz, 1H), 5.13-5.08 (m, 1H), 2.55-2.45 (m, 2H).
HPLC/MS (4.5 min) retention time 1.12 min.
LRMS: m/z 265, 267 (M+1 , 1*Br).
PREPARATION 145
(Tetrahydro-2H-pyran-2 -yIoxy)acetonitriIe
2-Hydroxyacetonitrile ( 1 .0 g , 17.5 mmol) was dissolved in dichloromethane (40 ml) and was cooled in an ice bath. 3,4-Dihydro-2/-/-pyran (2.4 ml, 26.3 mmol) and p- toluenesulfonic acid (20 mg, 0.1 1 mmol) were sequentially added and the mixture was stirred at room temperature for 20 min. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with dichloromethane. The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 770 mg (5.45 mmol, 31% yield) of the title compound as a colorless oil. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 4.74 - 4.90 (m, 1H), 4.23 - 4.50 (m, 2H), 3.75 - 3.92 (m, 1H), 3.53 - 3.68 (m, 1H), 1.55 - 1.93 (m, 6H).
UPLC/MS (3 min) retention time 1.84 min. LRMS: m/z No ionization.
PREPARATION 146
3-Bromo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,2,4-oxadiazole
Synthesized from the title compound of PREPARATION 145 and hydroxycarbonimidic dibromide following the method of PREPARATION 55. Obtained as a colorless oil. Yield: 22%. Purity 95%.
H NMR (300 MHz, Chloroform-d) δ ppm 4.77 - 4.96 (m, 3H), 3.80 - 3.92 (m, 1H), 3.53
- 3.63 (m, 1H), 1.55 - 1.91 (m, 6H)
UPLC/MS (3 min) retention time 1.48 min.
LRMS: m/z No ionization.
PREPARATION 147
2-{5-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-1,2,4-oxadiazol-3-yl}isoindoline
The title compound of PREPARATION 146 (60 mg, 0.23 mmol) was dissolved in ethanol (0.5 ml). Isoindoline (77 µ Ι_, 0.68 mmol) was added and the mixture was stirred at 80°C for 1 h. The mixture was evaporated to dryness and the residue was purified using the Isolera Purification system (methanol-dichloromethane gradient, 0:100 rising to 2:98) to give 52 mg (0.17 mmol, 76% yield) of the title compound as a pink solid. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.33 (s, 2H), 7.28 (s, 2H), 4.86 (t, J=3.2 Hz, 1H), 4.83 (s, 4H), 4.69 - 4.83 (m, 2H), 3.85 - 3.96 (m, 1H), 3.54 - 3.64 (m, 1H), 1.55 - 1.96 (m, 6H)
UPLC/MS (3 min) retention time 1.70 min.
LRMS: m/z 302 (M+1).
PREPARATION 148 [3-(1,3-Dihydro-2H-isoindol-2-yl)-1,2,4-oxadiazol-5-yl]methanol
The title compound of PREPARATION 147 (52 mg, 0.17 mmol) was dissolved in methanol ( 1 ml) and montmorillonite (50 mg) was added. The mixture was stirred at room temperature overnight and 2 h at 40 °C. The reaction mixture was filtered, the precipitate was washed with methanol and the combined filtrate was evaporated to dryness to give 37 mg of the crude title compound. Used as such without further purification. Purity: 69%.
UPLC/MS (3 min) retention time 1.12 min.
LRMS: m/z 218 (M+1).
PREPARATION 149
[3-(1 ,3-Dihydro-2H-isoindol-2-yl)-1 ,2,4-oxadiazol-5-yl]methyl methanesulfonate
Synthesized from the crude title compound of PREPARATION 148 and methanesulfonyl chloride following the method of PREPARATION 64. Obtained as a white solid. Yield: 36% over two steps. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.34 (s, 2H), 7.28 (s, 2H), 5.36 (s, 2H), 4.82 (s, 4H), 3.24 (s, 3H)
UPLC/MS (3 min) retention time 1.36 min.
LRMS: m/z 296 (M+1 ).
PREPARATION 150
3-(4-Chlorophenyl)propanohydrazide
3-(4-Chlorophenyl)propanoic acid (600 mg, 3.25 mmol) was dissolved in hydrazine monohydrate (4.74 ml, 97.5 mmol) and the mixture was heated at 150 °C under microwave irradiation for 1h. The mixture was allowed to cool and was partitioned between chloroform and 4N sodium bicarbonate solution. The organic phase was dried, filtered and evaporated to give 521 mg (2.62 mmol, 79% yield) of the title compound. Purity 90%. H NMR (300 MHz, Chloroform-d) δ ppm 7.24 - 7.31 (m, 2H), 7.12 - 7.18 (m, 2H), 6.61
(br. s., 1H), 3.89 (br. s., 2H), 2.97 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.6 Hz, 2H)
UPLC/MS (3 min) retention time 1.08 min.
LRMS: m/z 199 (M+1 , 1*CI).
PREPARATION 151
N'-(Chloroacetyl)-3-(4-chlorophenyl)propanohydrazide
The title compound of PREPARATION 150 (0.70 g , 3.55 mmol) was dissolved in 15 ml dichloromethane. Triethylamine (0.74 ml, 5.33 mmol) was added and the mixture was cooled to 0 °C. Chloroacetyl chloride (0.41 ml, 5.34 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane and was washed with water. The organics were evaporated under reduced pressure and the residue was triturated with 2 ml dichloromethane, filtered and the solid dried in a stream of air to give 0.63 g (2.29 mmol, 65% yield) of the title compound as a solid. Purity 100%.
HPLC/MS (3 min) retention time 1.27 min.
LRMS: m/z 275 (M+1 , 2*CI).
PREPARATION 152
2-(Chloromethyl)-5-[2-(4-chlorophenyl)ethyl]-1,3,4-oxadiazole
The title compound of PREPARATION 151 (200 mg, 0.73 mmol) was dissolved in 3 ml phosphorus oxychloride and the mixture was agitated at 100 °C for 25 min. The mixture was allowed to cool and was evaporated under reduced pressure. The residue was re-dissolved in dichloromethane and the organics were washed twice with 4% sodium bicarbonate solution and once with brine. The organics were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate-hexane gradient, 0:100 rising to 70:30) to give 134 mg (0.52 mmol, 72% yield) of the title compound as a white solid. Purity 100%. H NMR (400 MHz, Chloroform-d) δ ppm 7.27 (2H, d , J=8.2 Hz), 7.14 (2H, d , J=8.2 Hz), 4.66 (2H, s), 3.14 - 3.20 (2H, m), 3.07 - 3.14 (2H, m)
UPLC/MS (3 min) retention time 1.27 min.
LRMS: m/z 257 (M+1 , 2*CI).
PREPARATION 153
Ethyl 2-[2-(4-chlorophenyl)ethyl]-2H-tetrazole-5-carboxylate
Ethyl 2H-tetrazole-5-carboxylate (300 mg, 1.83 mmol) was dissolved in dimethylformamide (4 ml). Potassium carbonate (378 mg, 2.73 mmol) and 1-(2- bromoethyl)-4-chlorobenzene (398 µ Ι_, 2.74 mmol) were added and the mixture was stirred at 80°C for 4.5 h. The mixture was partitioned between ethyl acetate water, extracted with ethyl acetate and the organics were sequentially washed with water and brine, dried over anhydrous sodium sulphate, filtered and evaporated. The residue was partially purified using the Isolera Purification system (ether-hexane gradient, 0:100 rising to 50:50) to give 415 mg of the crude title compound. Purity 61%.
UPLC/MS (3 min) retention time 1.62 min.
LRMS: m/z 281 (M+1 , 1*CI).
PREPARATION 154
{2-[2-(4-Chlorophenyl)ethyl]-2H-tetrazol-5-yl}methanol
Synthesized from the crude title compound of PREPARATION 153 following the method of PREPARATION 63. Obtained as a white solid. Yield: 38% over two steps. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.28 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 4.96 (d, J=4.7 Hz, 2H), 4.83 (t, J=7.5 Hz, 2H), 3.32 (t, J=7.5 Hz, 2H), 2.70 (br. s., 1H)
UPLC/MS (3 min) retention time 1.28 min.
LRMS: m/z 239 (M+1 , 1*CI). PREPARATION 155
{2-[2-(4-Chlorophenyl)ethyl]-2H-tetrazol-5-yl}methyl methanesulfonate
Synthesized from the title compound of PREPARATION 154 and methanesulfonyl chloride following the method of PREPARATION 64. Purity by NMR >90%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.24 - 7.35 (m, 2H), 7.09 (d, J=7.6 Hz, 2H),
5.50 (s, 2H), 4.88 (t, J=7.3 Hz, 2H), 3.34 (t, J=7.3 Hz, 2H), 3.1 1 (s, 3H).
UPLC/MS (3 min) retention time 1.46 min.
LRMS: m/z 317 (M+1 , 1*CI).
PREPARATION 156
{ 1-[2-(4-Chlorophenyl)ethyl]-1 H-1 ,2,4-triazol-3-yl}methanol
Synthesized in crude form from 1/-/-1 ,2,4-Triazol-3-ylmethanol and 1-(2-bromoethyl)-4- chlorobenzene following the method of PREPARATION 153. Purity 52%.
H NMR (300 MHz, Chloroform-d) δ ppm 7.75 (s, 1H), 7.27 (d, J=8.2 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 4.78 (s, 2H), 4.34 (t, J=7.0 Hz, 2H), 3.16 (t, J=6.7 Hz, 2H)
UPLC/MS (3 min) retention time 1.14 min.
LRMS: m/z 238 (M+1 , 1xCI).
PREPARATION 157
{ 1-[2-(4-Chlorophenyl)ethyl]-1 H-1 ,2,4-triazol-3-yl}methyl methanesulfonate
Synthesized in crude form from the crude title compound of PREPARATION 156 and methanesulfonyl chloride following the method of PREPARATION 64. Purity 75%.
UPLC/MS (3 min) retention time 1.34 min.
LRMS: m/z 316 (M+1 , 1xCI). PREPARATION 158
Methyl 1-amino-1 H-pyrazole-5-carboxylate
Synthesized from methyl 1H-pyrazole-5-carboxylate following the method of PREPARATION 5 . The crude product (yellow oil) was isolated as a 4:1 mixture of regioisomers in quantitative yield and was used in the next synthetic step without further purification.
HPLC/MS (3 min) retention times 0.54 min (minor isomer), 0.62 min (major isomer).
LRMS: m/z 142 (M+1).
PREPARATION 159
Pyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the crude title compound (5.1 g) of PREPARATION 158 and formamide following the method of PREPARATION 6 . After cooling the reaction mixture, the solid precipitate was filtered, washed with several portions of methyl ethyl ketone and finally with methanol and dried to give the title compound ( 1 .40 g , 33%) as a white solid. The filtrate was evaporated and the residue was purified by reverse phase chromatography to give a further 0.70 g (18%) of the title compound as a white solid. Total yield: 51%. Purity 95%.
1H NMR (400 MHz, DMSO-d6) δ ppm 7.05 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 12.29 (br s, 1H).
HPLC/MS (3 min) retention time 0.44 min.
LRMS: m/z 137 (M+1).
PREPARATION 160
5-Chloropyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
N-Chlorosuccinimide ( 1 .42 g, 10.6 mmol) was added portionwise over 5 minutes to a stirred solution of the title compound of PREPARATION 159 ( 1 .37 g, 10.1 mmol) in N,N-dimethylformamide (18 mL). After 3 days, the mixture was diluted with water and stirred for 2 hours at room temperature. The resulting suspension was filtered and the product was washed with water and dried in vacuo to give the title compound ( 1 .44 g, 84%) as a white solid. Purity 98%.
1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (s, 1H), 8.10 (s, 1H), 12.48 (br s, 1H).
HPLC/MS (3 min) retention time 0.69 min.
LRMS: m/z 171 (M+1 ).
PREPARATION 161
5-Bromopyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
N-Bromosuccinimide (0.29 g, 1.63 mmol) was added portionwise over 5 minutes to a stirred solution of the title compound of PREPARATION 159 (0.202 g , 1.48 mmol) in N,N-dimethylformamide (5 ml_). After 24 hours, the mixture was diluted with water and stirred for 2 hours at room temperature. The resulting suspension was filtered and the product was washed with water and dried in vacuo to give the title compound (0.295 g , 93%) as a white solid. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H).
LRMS: m/z 215/217 (M+1).
PREPARATION 162
5-Bromo-3-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[5J-f][1,2,4]triazin-4(3H)-on
N,N-Diisopropylethylamine (0.12 ml_, 0.7 mmol) was added to a stirred suspension of the title compound of PREPARATION 161 (100 mg, 0.47 mmol) in dichloromethane (2 ml_). After 5 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (0.099 ml_, 0.56 mmol) was added and stirring was continued at ambient temperature. After 2 hours, the solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and evaporated to give the title compound (0.150 g, 93%) as an oil which slowly crystallized to give a solid. 1H NMR (400 MHz, Chloroform-d) δ ppm -0.1 1 (s, 9H), 0.71 - 1.13 (m, 2H), 3.59 - 3.79 (m, 2H), 5.35 (s, 2H), 7.78 (s, 1H), 7.83 (s, 1H).
LRMS: m/z 345/347 (M+1).
HPLC/MS (3 min) retention time 1.80 min.
PREPARATION 163
5-Ethylpyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
The title compound of PREPARATION 162 (75 mg, 0.22 mmol), potassium ethyltrifluoroborate (73 mg, 0.54 mmol), palladium acetate (4.9 mg, 0.02 mmol) and cesium carbonate (212 mg, 0.65 mmol) were combined and suspended in a mixture of toluene (4ml_) and water (0.4 mL) in a Shlenck tube and the mixture was evacuated and then argon was introduced. Di(1-adamantyl)-n-butylphosphine ( 1 1.7 mg, 0.03 mmol) was introduced and the evacuation/introduction of argon procedure was repeated several times and the tube was then sealed and stirred and heated to 100 °C. After 5 hours, the mixture was diluted with ethyl acetate and the organic solution was washed with water, brine, dried and evaporated to give an orange oil. The oil was taken up in a solution of 4M hydrochloric acid in dioxane (4 mL) and the mixture was stirred for 7 days. The solvent was evaporated and the residue was purified by reverse-phase chromatography using the Isolera purification system (methanol-water gradient, 0:100 rising to 100: 0) to give the title compound (13 mg, 37%) as a white solid. Purity 98%.
LRMS: m/z 165 (M+1).
HPLC/MS (3 min) retention time 0.87 min.
PREPARATION 164
5-Fluoropyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
A suspension of the title compound of PREPARATION 159 (0.075 g, 0.55 mmol) and 1-(chloromethyl)-4-fluoro-1 ,4- diazabicyclo[2.2.2]octane-1 ,4-diium tetrafluoroborate (0.390 g , 1.10 mmol) in acetonitrile was stirred and heated to 100 °C. After 3 hours, further 1-(chloromethyl)-4-fluoro-1 ,4- diazabicyclo[2.2.2]octane-1 ,4-diium tetrafluoroborate (0.188 g , 0.53 mmol) was added and heating was continued. After a further 3 hours, the reaction was quenched with water and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated in vacuo and the residue was purified by reverse-phase chromatography using the Isolera purification system to give the title compound (0.054 g , 63%) as a white solid. Purity 95%.
1H NMR (400 MHz, DMSO-d) δ ppm 8.05 (s, 1H), 7.91 (d, J = 3.6 Hz, 1H).
LRMS: m/z 155 (M+1 ).
PREPARATION 165
5-lodopyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Iodine (0.31 g, 1.22 mmol) was added to a solution of the title compound of PREPARATION 159 (0.233 g, 1.71 mmol) and ammonium cerium (IV) nitrate (0.671 g ,
1.22 mmol) in acetonitrile and the mixture was stirred and heated to 70 °C. After 1 hour, the mixture was diluted with ethyl acetate and the organic extract was washed with a saturated aqueous solution of sodium thiosulphate, brine, dried and evaporated to give the title compound (0.350 g, 75%) as a yellow solid. Purity: 95%
1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1H), 7.94 (s, 1H).
LRMS: m/z 263 (M+1 ).
PREPARATION 166
5-lodo-3-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[5J-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 165 and 2- (trimethylsilyl)ethoxymethyl chloride following the method of PREPARATION 162. Yield: 92%. Purity 96%.
1H NMR (400 MHz, Chloroform-d) δ ppm 7.85 (s, 2H), 5.35 (s, 2H), 3.69-3.63 (m, 2H), 0.99-0.95 (m, 2H), 0.02 (s, 9H).
LRMS: m/z 393 (M+1 ). PREPARATION 167
5-(Trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[5,1- q[1,2,4]triazin-4(3H)-one
Argon was bubbled through a solution of the title compound of PREPARATION 166 (0.151 g, 0.38 mmol), copper(l) iodide (0.088 g, 0.46 mmol), hexamethylphosphoramide (0.333 ml_, 1.92 mmol) and methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (0.368 g, 1.92 mmol) in N,N-dimethylformamide and the mixture was stirred and heated to 80 °C. After 20 hours, the reaction mixture was filtered and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and evaporated and the residue was purified by reverse phase chromatography to give the title compound (0.084 g, 66%) as a white solid.
1H NMR (400 MHz, Chloroform-d) δ ppm 8.06 (s, 1H), 7.96 (s, 1H), 5.41 (s, 2H), 3.72- 3.67 (m, 2H), 1.01-0.96 (m, 2H), 0.01 (s, 9H).
LRMS: m/z 335 (M+1 ).
PREPARATION 168
5-(Trifluoromethyl)pyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 167 following the deprotection method used in PREPARATION 163. Yield: 67%. Purity 96%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (s, 1H), 8.00 (s, 1H),
LRMS: m/z 205 (M+1 ).
PREPARATION 169
8-Bromo-7-methyl-1 H-purin-6(7H)-one
A suspension of the 7-methyl-1 H-purin-6(7H)-one (0.200 g , 1.33 mmol) in acetic acid
( 1 . 1 ml) was stirred and heated to 50 °C. After 30 minutes, bromine (0.072 ml_, 1.41 mmol) was added and the reaction mixture was heated to 70 °C. After a further 1.5 hours, additional bromine (0.072 ml_, 1.41 mmol) was added and heating was continued for a further 2 hours. Subsequently the mixture was evaporated to dryness in vacuo and the residue purified by flash chromatography (dichloromethane/methanol) to give the title compound (0.030 g , 10%) as a white solid. Purity 75%.
1H NMR (400 MHz, Chloroform-d) δ 4.06 ppm (s, 3H), 8.03 (s, 1H).
LRMS: m/z 229/231 (M+1).
PREPARATION 170 tert-Butyl 2-(7-bromo-5-methyl-4-oxoimidazo[5,1-f][1,2,4]triazin-3(4H)-yl)acetate
Synthesized from the title compound of PREPARATION 7 and tert-butyl bromoacetate following the method of PREPARATION 4 1. Yield: 100%. Purity 98%.
1H NMR (400 MHz, Chloroform-d) δ ppm 1.49 (s, 9H), 2.61 (s, 3H), 4.47 (s, 2H), 7.42 (s, 1H).
LRMS: m/z 343/345 (M+1).
PREPARATION 171 tert-Butyl 2-(7-cyclopropyl-5-methyl-4-oxoimidazo[5,1-f][1,2,4]triazin-3(4H)- yl)acetate
Synthesized from the title compound of PREPARATION 170 and potassium cyclopropyltrifluoroborate following the method of PREPARATION 163. Yield: 68%. Purity 96%.
1H NMR (400 MHz, Chloroform-d) δ ppm 1.05 - 1. 1 1 (m, 2H), 1.14 - 1.20 (m, 2H), 1.49 (s, 9H), 2.35 (m, 1H), 2.55 (s, 3H), 4.44 (s, 2H), 7.31 (s, 1H).
LRMS: m/z 305 (M+1 ).
PREPARATION 172
2-(7-Cyclopropyl-5-methyl-4-oxoimidazo[5,1-f][1,2,4]triazin-3(4H)-yl)acetic acid
Synthesized from the title compound of PREPARATION 171 following the method of PREPARATION 48. Yield: 81%. Purity 99%. LRMS: m/z 249 (M+1).
PREPARATION 173
(Z)-3-(4-Chlorophenyl)-N ',3-dihydroxypropanimidamide
Synthesized from the title compound of PREPARATION 89 and hydroxylamine following the method of PREPARATION 114. The crude product was purified by reverse-phase chromatography using the Isolera purification system (methanol-water gradient, 0:100 rising to 100: 0) to give the title compound as a white solid. Yield: 34%. Purity 95%.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 - 2.42 (m, 2H), 4.86 (dd, J = 7.8, 5.5 Hz, 1H), 5.42 (br s, 2H), 7.28 - 7.42 (m, 4H).
LRMS: m/z 215 (M+1).
PREPARATION 174 tert-Butyl 2-(7-ethyl-5-methyl-4-oxoimidazo[5,1-f][1,2,4]triazin -3(4H)-yl)acetate
Synthesized from the title compound of PREPARATION 170 and potassium ethyltrifluoroborate following the method of PREPARATION 163. Yield: 43%. Purity 96%.
LRMS: m/z 293 (M+1 ).
PREPARATION 175
2-(7-Ethyl-5-methyl-4-oxoimidazo[5,1-f][1,2,4]triazin -3(4H)-yl)acetic acid
Synthesized from the title compound of PREPARATION 174 following the method of PREPARATION 48. Yield: 99%. Purity 99%.
LRMS: m/z 237 (M+1 ).
PREPARATION 176 2,6-Diamino-4-methylnicotinonitrile
A suspension of 2,6-dichloro-4-methylnicotinonitrile (0.340g, 2 mmol) in dimethyl sulfoxide ( 1 mL) and concentrated aqueous ammonia solution ( 1 1 mL) was heated and stirred to 130 °C under microwave irradiation. After 3 hours, the reaction mixture was concentrated in vacuo. The reaction was repeated two more times and the combined crude products were purified by reverse-phase chromatography using the Isolera purification system to give the title compound (0.596 g , 67%) as a white solid. Purity 95%.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.1 1 (s, 3H), 5.65 (s, 1H), 6.10 (br s, 2H), 6.36 (br s, 2H).
LRMS: m/z 149 (M+1 ).
PREPARATION 177
2,6-Diamino-4-methylnicotinamide
Synthesized from the title compound of PREPARATION 176 following the method of PREPARATION 33. Yield: 76%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 3H), 5.53 (s, 1H), 5.64 (br s, 2H), 5.71 (br s, 2H), 7.12 (br s, 2H).
LRMS: m/z 167 (M+1).
PREPARATION 178
7-Amino-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 177 and formamide following the method of PREPARATION 6. Yield: 83%. Purity 96%.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (s, 3H), 6.29 (s, 1H), 6.82 (br s, 2H), 7.99 (s, 1H), 8.47 (s, 1H).
LRMS: m/z 177 (M+1 ). PREPARATION 179
2-Amino-6-(dimethylamino)-4-methylnicotinonitrile and 6-amino-2- (dimethylamino)-4-methylnicotinonitrile
A suspension of the title compounds of PREPARATION 35 (0.200 g, 1.20 mmol) in
40% aqueous dimethylamine solution ( 1 1 mL) was heated and stirred to 130 °C under microwave irradiation. After 2 hours, the reaction mixture was cooled. The reaction was repeated four more times and the combined reactions mixtures were evaporated to dryness. The mixture was partitioned between water and ethyl acetate and the aqueous layer was further extracted several times with ethyl acetate. The combined organic extract was washed with brine, dried and evaporated to give a mixture of the title compounds ( 1 .05 g , 99%) as a yellow solid.
LRMS: m/z 177 (M+1 ).
PREPARATION 180
2-Amino-6-(dimethylamino)-4-methylnicotinamide and 6-amino-2- (dimethylamino)-4-methylnicotinamide
A mixture of the title compounds of PREPARATION 179 ( 1 .50 g , 8.5 mmol) in concentrated aqueous sulphuric acid (6 mL) was heated and stirred to 40 °C. After 6 days, The mixture was poured onto ice and neutralized with solid sodium bicarbonate. The mixture was filtered and the filtrate was evaporated to dryness. The residue was stirred overnight with a 1: 1 mixture of dichloromethane/methanol, then filtered and the filtrate was concentrated to give mixture of the title compounds ( 1 .26 g , 73%) as a white solid. Purity 95%.
LRMS: m/z 195 (M+1 ).
PREPARATION 181
7-(Dimethylamino)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one
Synthesized from a mixture of the title compounds of PREPARATION 180 and formamide following the method of EXAMPLE 1. Yield: 10%. Purity 98%. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.65 (s, 3H), 3.1 1 (s, 6H), 6.58 (s, 1H), 8.00 (s, 1H), 8.53 (s, 1H).
LRMS: m/z 205 (M+1).
PREPARATION 182
6-Chloro-N-ethylpyrimidin-4-amine
Synthesized from 4,6-dichloropyrimidine and ethylamine following the method of PREPARATION 24. Yield: 87%. Purity 98%.
LRMS: m/z 158 (M+1).
PREPARATION 183
N-Ethyl-6-methoxypyrimidin-4-amine
Synthesized from the title compound of PREPARATION 182 and sodium methoxide following the method of PREPARATION 25. Yield: 81%. Purity 98%.
LRMS: m/z 154 (M+1).
PREPARATION 184
6-(Ethylamino)pyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 183 and concentrated hydrochloric acid following the method of PREPARATION 26. Yield: 99%. Purity 99%.
LRMS: m/z 140 (M+1).
PREPARATION 185
6-(Ethylamino)pyrimidin-4(3H)-one Synthesized from the title compound of PREPARATION 184 and nitric acid following the method of PREPARATION 27. Yield: 27%. Purity 99%.
1H NMR (DMSO-d6) δ ppm 9.53 (s, 1H), 8.06 (s, 1H), 3.56 (q, J = 7 Hz, 2H), 1.14 (t, J
= 7 Hz, 3H).
LRMS: m/z 171 (M+ 1).
PREPARATION 186
5-Amino-6-(ethylamino)pyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 185 following the method of PREPARATION 28. Yield: 87%. Purity 97%.
1H NMR (DMSO-D6, 400 MHz) δ ppm 11.66 (br s, 1H), 7.48 (s, 1H), 5.59 (s, 1H), 3.67 (q , J = 7 Hz, 2H), 3.14 (s, 2H), 1.08 (t, J = 7 Hz, 3H).
LRMS: m/z 155 (M+ 1).
PREPARATION 187
9-Ethyl-1 H-purine-6,8(7H,9H)-dione
Synthesized from the title compound of PREPARATION 186 and urea following the method of PREPARATION 29. Yield : 72%. Purity 98%.
1H-N MR (DMSO-d6, 400 MHz) δ ppm 12.41 (br s, 1H), 11.22 (br s, 1H), 7.94 (s, 1H), 3.73 (q, J = 7 Hz, 2H), 1.18 (t, J = 7 Hz, 3H)
LRMS: m/z 181 (M+ 1).
PREPARATION 188
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-9-ethyl-1 H- purine-6,8(7H,9H)-dione Synthesized from the title compound of PREPARATION 187 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield : 42%. Purity 99%.
1H NMR (DMSO, 400 MHz) δ ppm 11.37 (s, 1H), 8.46 (s, 1H), 7.32 (s, 4H), 5.59 (d , J = 5 Hz, 1H), 5.50 (s, 2H), 4.94-4.89 (m, 1H), 3.78 (q , J = 7 Hz, 2H), 2.98 (dd , J = 14.4,
8 Hz, 1H), 2.92 (dd, J = 14.4, 5.4 Hz, 1H), 1.23 (t, J = 7 Hz, 3H).
LRMS: m/z 4 17 (M+1 ).
PREPARATION 189
Ethyl 3-amino-1 ,5-dimethyl-1 H-pyrazole-4-carboxylate
Benzaldehyde methylhydrazone (2.0 g , 14.9 mmol) and (E)-ethyl 2-cyano-3-ethoxybut-
2-enoate (2.82 g , 15.4 mmol) were dissolved in toluene ( 15 ml), and the reaction mixture was stirred and heated to reflux. After 2 hours, the mixture was evaporated and the residue triturated with light petroleum (b.p. 60-80 °C) and filtered . The resultant solid was suspended in ethyl alcohol ( 16 ml) and concentrated hydrochloric acid ( 1 .1 mL) was added and the mixture was stirred and heated to reflux. After 30 minutes, the mixture was evaporated , 2M aqueous hydrochloric acid (24 mL) was added and the mixture was extracted with ether. The pH of the aqueous layer was then adjusted to pH 8 with 2M aqueous sodium hydroxide solution and extracted with chloroform (3 x 50 mL). The combined extracts were dried and evaporated to afford the title compound (0.845 g , 31%) as an oil.
1H NMR (400 MHz, Chloroform-d) δ ppm 1.35 (t, J = 7.1 Hz, 3H), 2.42 (s, 3H), 3.60 (s, 3H), 4.28 (q, J = 7.1 Hz, 2H), 4.65 (br s, 2H).
LRMS: m/z 184 (M+ 1).
PREPARATION 190
2,3-Dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
Synthesized from the title compound of PREPARATION 189 and formamide following the method of PREPARATION 6. Yield : 64%. Purity 98%. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.57 (s, 3H), 3.85 (s, 3H), 7.84 (s, 1H), 11.38
(br s, 1H).
LRMS: m/z 165 (M+ 1).
PREPARATION 191
Ethyl 3-amino-1 -ethyl-5-methyl-1 H-pyrazole-4-carboxylate
Sodium hydride (60% dispersion in mineral oil, 0.047 g , 1.18 mmol) was added to a stirred solution of ethyl 3-amino-5-methyl-1 H-pyrazole-4-carboxylate (0.202 g , 1.19 mmol) in acetonitrile ( 12 mL) under an inert atmosphere of nitrogen. Subsequently iodoethane (0. 10 mL, 1.00 mmol) was added dropwise and the mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The organic layer was washed with brine, dried and evaporated to 0.242 g of a 1:1 mixture of the title compound and the regioisomeric product ethyl 5-amino-1 -ethyl-3-methyl-1 H-pyrazole-4-carboxylate. The crude mixture was used as such in the subsequent reaction without further purification .
LRMS: m/z 198 (M+ 1).
PREPARATION 192
2-Ethyl-3-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
Synthesized from the title compound of PREPARATION 191 and formamide following the method of PREPARATION 6 . Yield: 91% (based on 50% purity of staring material). Purity 100%.
1H NMR (400 MHz, Chloroform-d) δ ppm 1.51 (t, J = 7.3 Hz, 3H), 2.7 1 (s, 3H), 4.25 (q , J = 7.3 Hz, 2H), 7.95 (s, 1H), 10.46 (s, 1H).
LRMS: m/z 179 (M+1 ).
PREPARATION 193
Ethyl 3-amino-1 -isopropyl-5-methyl-1 H-pyrazole-4-carboxylate Synthesized from ethyl 3-amino-5-methyl-1 H-pyrazole-4-carboxylate and 2- iodopropane following the method of PREPARATION 191. Yield : 17%. Purity 96%.
1H NMR (400 MHz, Chloroform-d) δ 1.25 ppm 1.34 (t, J = 7.1 Hz, 3H), 1.40 (d, J = 6.6
Hz, 6H), 2.45 (s, 3H), 4 .18 - 4.39 (m , 3H), 4.68 (br s, 2H).
LRMS: m/z 2 12 (M+ 1).
PREPARATION 194
2-lsopropyl-3-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
Synthesized from the title compound of PREPARATION 193 and formamide following the method of PREPARATION 6. Yield: 70%. Purity 100%.
1H NMR (400 MHz, Chloroform-d) δ 1.56 (d , J = 6.6 Hz, 6H), 2.7 1 (s, 3H), 4.60 (p, J = 6.6 Hz, 1H), 7.90 (d, J = 3 .1 Hz, 1H), 9.90 (s, 1H).
LRMS: m/z 193 (M+ 1).
PREPARATION 195
3-(3,4-Dichlorophenyl)propanamide
1-Hydroxybenzotriazole hydrate (0. 185 g, 1.37 mmol) and N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (0.263 g , 1.37 mmol) were added to a stirred solution of 3-(3,4-dichlorophenyl)propanoic acid (0.250 g, 1.14 mmol) in N,N- dimethylformamide (3 mL). After 20 minutes, concentrated aqueous ammonia solution (0.090 mL, 2.29 mmol) was added and the reaction mixture was stirred overnight. Subsequently, the mixture was diluted with dichloromethane and the organic layer was washed with 4% aqueous sodium hydrogen carbonate solution, brine, dried and evaporated to give the title compound (0.248 g, 82%) as a beige solid. Purity 82%.
1H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.27 (s, 1H), 7 .19 (dd , J = 8.2, 2.0 Hz, 1H), 6.78 (s, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H).
LRMS: m/z 2 18 (M+1 ). HPLC/MS (3 min) retention time 1.36 min.
PREPARATION 196
3-(3,4-Dichlorophenyl)propanenitrile
Pyridine (0.23 ml_, 2.85 mmol) was added to a stirred solution of the title compound of
PREPARATION 195 (0.248 g, 1.14 mmol) in dry dichloromethane ( 1 1 mL) under an inert atmosphere of nitrogen. The mixture was cooled in an ice-bath and a solution of trifluoroacetic anhydride (0.396 mL, 2.85 mmol) in dry dichloromethane ( 1 mL) was added dropwise. After stirring for 1 hour in the ice bath, the mixture was warmed to ambient temperature and stirring was continued for a further 30 minutes. Subsequently, the mixture was diluted with dichloromethane and the organic layer was washed with 4% aqueous sodium hydrogen carbonate solution, brine, dried and evaporated to give the title compound (0.213 g, 94%) as a beige solid.
1H NMR (400 MHz, Chloroform-d) δ ppm 7.42 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.13 - 7.06 (m, 1H), 2.92 (t, J = 7.3 Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H).
LRMS: m/z 218 (M+1 ).
HPLC/MS (3 min) retention time 1.58 min.
PREPARATION 197
(Z)-3-(3,4-Dichlorophenyl)-N'-hydroxypropanimidamide
Synthesized from the title compound of PREPARATION 196 and hydroxylamine hydrochloride following the method of PREPARATION 114. Yield: 53%. Purity 65%.
LRMS: m/z 233 (M+1 ).
HPLC/MS (3 min) retention time 1.00 min.
PREPARATION 198
3-(4-Chlorophenyl)-3-hydroxybutanenitrile Acetonitrile (7.1 mmol) was added dropwise to a cooled (-78 °C), stirred solution of lithium diisopropylamide (2M in tetrahydrofuran, 7.8 mmol). After 10 minutes, a solution of 1-(4-chlorophenyl)ethanone (6.5 mmol) in tetrahydrofuran was added dropwise and the mixture was stirred at -78 °C for and further 25 minutes. After warming to room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate. The combined organic phases were washed with brine, dried and concentrated under reduced pressure and the residue was purified by flash chromatography (hexanes/ether) to give the title compound (0.59 g , 47%) as a white solid. Purity 95%.
H NMR (400 MHz, Chloroform-d) δ ppm 7.45-4.41 (m, 2H), 7.38-7.35 (m, 2H), 2.82 (d, J = 16.6 Hz, 1H), 2.77 (d, J = 16.6 Hz, 1H), 1.76 (s, 3H).
PREPARATION 199
(Z)-3-(4-Chlorophenyl)-N',3-dihydroxybutanimidamide
Synthesized from the title compound of PREPARATION 198 and hydroxylamine following the method of PREPARATION 114.
The crude product was purified by flash chromatography (dichloromethane/methanol) to give 0.46 g (66%) of the title compound as a white solid. Purity 99%.
H NMR (CDsOD, 400 MHz) δ ppm 7.48-7.42 (m, 1H), 7.31-7.26 (m, 1H), 3.34 (s, 1H), 2.51 (d, J = 14.4 Hz, 1H), 2.46 (d, J = 14.4 Hz, 1H), 1.53 (s, 3H).
LRMS: m/z 229 (M+1 ).
PREPARATION 200 tert-Butyl 2-(5-chloro-4-oxopyrazolo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate
Synthesized from the title compound of PREPARATION 160 and tert-butyl bromoacetate following the method of PREPARATION 4 1. Yield: 100%. Purity 99%.
1H NMR (400 MHz, Chloroform-d) δ 1.50 (s, 9H), 4.55 (s, 2H), 7.62 (s, 1H), 7.73 (s, 1H). LRMS: m/z 285 (M+1).
PREPARATION 201
2-(5-Chloro-4-oxopyrazolo[5,1-f][1,2,4]triazin-3(4H)-yl)acetic acid
Synthesized from the title compound of PREPARATION 200 following the method of PREPARATION 48. Yield: 100%. Purity 99%.
LRMS: m/z 229 (M+1).
PREPARATION 202
2-(4-Chlorophenyl)acetaldehyde
2-(4-Chlorophenyl)ethanol ( 1 .00 g, 6.30 mmol) was added dropwise to a stirred solution of Dess-Martin periodinane (3.25 g, 7.66 mol) in dichloromethane (79 mL). After 2 hours, saturated aqueous sodium thiosulphate solution (63 mL) was added and stirring was continued for 15 minutes. The organic phase was separated and the aqueous phase was extracted with further dichloromethane. The combined organic extracts were washed with brine, dried and evaporated and the residue was purified by flash chromatography (hexanes/ethyl acetate) to give 0.708 g (73%) of the title compound as a white solid. Purity 100%.
1H NMR (400 MHz, Chloroform-d) δ 9.74 ppm (t, J = 2.1 Hz, 1H), 7.32- 7.37 (m, 2H), 7.13- 7.18 (m, 2H), 3.68 (d, J =2.1 Hz, 2H). HPLC/MS (3 min) retention time 1.33 min.
LRMS: m/z No ionization.
PREPARATION 203
3-(4-Chlorophenyl)-2-hydroxypropanenitrile
Zinc chloride (0.002 g, 0.01 mmol) was added to a stirred solution of the title compound of PREPARATION 202 (0.605 g, 3.91 mmol) in dichloromethane (2 mL) under an inert atmosphere. The mixture was cooled in an ice bath and trimethylsilyl cyanide (0.58 mL, 4.60 mmol) was added dropwise and the reaction was then warmed to ambient temperature. After 4 hours, the reaction mixture was concentrated in vacuo and the residue was taken up in tetrahydrofuran (2 mL) and 20% aqueous hydrochloric acid solution (4 mL) was added. After stirring for a further 2 hours, the mixture was partitioned between ether and water. The organic extract was dried and evaporated and the residue was purified by flash chromatography (hexanes/ethyl acetate) to give 0.396 g (56%) of the title compound as a clear colourless oil. Purity 100%.
1H NMR (400 MHz, Chloroform-d) δ ppm 2.4 1 (d, J = 6.8 Hz, 1H), 3.11 (d, J = 6.3 Hz, 2H), 4.66 (m, 1H), 7.26 - 7.38 (m , 4H). HPLC/MS (3 min) retention time 1.32 min. LRMS: m/z No ionization .
PREPARATION 204
3-(4-chlorophenyl)-N',2-dihydroxypropanimidamide
A mixture of the title compound of PREPARATION 203 (0.396 g, 2 .18 mmol), hydroxylamine hydrochloride (0. 167 g , 2.40 mmol) and triethylamine (0.34 mL, 2.40 mmol) in ethanol (3 mL) was stirred at ambient temperature overnight. The mixture was evaporated and the residue was purified by reverse-phase chromatography using the Isolera purification system (methanol-water gradient, 0 :100 rising to 100: 0) to give the title compound (0.263 g , 47%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 - 2.9 1 (m, 2H), 3.99 (m , 1H), 5.23 (d, J = 5.5 Hz, 1H), 5.30 (s, 2H), 7.18 - 7.25 (m, 2H), 7.27 - 7.33 (m , 2H), 8.93 (s, 1H).
LRMS: m/z 229 (M+1 ). HPLC/MS (3 min) retention time 0.78 min.
PREPARATION 205
(S)-3-((tert-Butyldimethylsilyl)oxy)-3-(4-chlorophenyl)propanoic acid
Imidazole (0.783 g , 11.50 mmol) was added to a stirred , cooled (ice bath) solution of tert-butylchlorodimethylsilane (0.606 g , 4.03 mmol) in N,N-dimethylformamide (4 mL). After 15 minutes, a solution of (S)-3-hydroxy-3-phenylpropanoic acid (0.230 g , 1.15 mmol) in N,N-dimethylformamide (2 mL) was added and the mixture was stirred at ambient temperature overnight. The mixture was then partitioned between ethyl acetate and water and the organic extract was washed with brine, dried and evaporated. The residue was taken up in a mixture of tetrahydrofuran ( 1 .5 mL) and methanol (3 mL) and aqueous potassium carbonate solution was added . After 2 hours, the mixture was diluted with brine and the pH was adjusted to 3 with 2M aqueous sulfuric acid solution. The mixture was extracted with ethyl acetate and the organic layer was dried and evaporated to give the title compound (0.373 g , > 00%) as an oil which was used without further purification
1H NMR (Chloroform-d , 400 MHz) δ ppm 7.48-7.41 (m , 4H), 5.11 (dd, J = 8.5, 4.4 Hz, 1H), 2.72 (dd, J = 15 .1, 8.5 Hz, 1H), 2.61 (dd , J = 15 .1, 4.4 Hz, 1H), 0.86 (s, 9H), - 0.045 (s, 3H), -0. 15 (s, 3H).
LRMS: m/z 3 15 (M+ 1).
PREPARATION 206
(S)-3-((tert-Butyldimethylsilyl)oxy)-3-(4-chlorophenyl)propanoyl chloride
Oxalyl chloride (2M in dichloromethane, 0.862 mL, 1.72 mmol) was added to a stirred, cooled (ice bath) solution of the title compound of PREPARATION 205 (0.362 g , 1.15 mmol) and N,N-dimethylformamide (5 drops) in dichloromethane ( 10 mL). After 1 hour, the reaction mixture was evaporated and the residue was used without further purification .
PREPARATION 207
(S)-(5-(2-((tert-Butyldimethylsilyl)oxy)-2-(4-chlorophenyl)ethyl)-1 ,2,4-oxadiazol-3- yl)methanol
The crude title compound of PREPARATION 206 ( 1 .15 mmol) in tetrahydrofuran was added to a cooled (ice bath), stirred suspension of (Z)-N',2-dihydroxyacetimidamide (0. 114 g, 1.25 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.44 mmol) in acetonitrile (5 mL). After 1 hour, the mixture diluted with ether and washed with saturated ammonium chloride solution . The organic phase was dried and evaporated and the residue was purified by flash chromatography (dichloromethane/methanol) to give 0.158 g of (S,Z)-N'-((3-((tert-butyldimethylsilyl)oxy)-3-(4- chlorophenyl)propanoyl)oxy)-2-hydroxyacetimidamide as a white solid which was taken up in toluene (6 mL) and stirred and heated to 120 °C. After stirring overnight, the solvent was removed in vacuo and the residue was purified by flash chromatography (dichloromethane/hexane) to give the title compound (0.095 g , 22% over 2 synthetic steps) as a white solid .
1H NMR (Chloroform-d , 400 MHz) δ ppm 7.35-7.28 (m, 4H), 5.17 (dd , J = 9 and 4.2 Hz, 1H), 4.77 (s, 2H), 3.28 (dd, J = 14.6 and 9.0 Hz, 1H), 3 .10 (dd , J = 14.6 and 4.2
Hz, 1H), 0.77 (s, 9H), -0. 11 (s, 3H), -0.20 (s, 3H).
LRMS: m/z 387 (M+1 ).
PREPARATION 208
(S)-(5-(2-((tert-Butyldimethylsilyl)oxy)-2-(4-chlorophenyl)ethyl)-1 ,2,4-oxadiazol-3- yl)methyl methanesulfonate
Synthesized from the title compound of PREPARATION 207 and methanesulphonyl chloride following the method of PREPARATION 103. The title compound was obtained in quantitative yield and was used without further purification.
LRMS: m/z 447 (M+ 1).
PREPARATION 209
(S)-3-((5-(2-((tert-Butyldimethylsilyl)oxy)-2-(4-chlorophenyl)ethyl)-1 ,2,4-oxadiazol- 3-yl)methyl)-5-chloropyrazolo[5, 1-f][1 ,2,4]triazin-4(3H)-one
Synthesized from the title compounds of PREPARATIONS 160 and 208 following the method of EXAMPLE 1. Yield : 38%. Purity 98%.
1H NMR (Chloroform-d , 400 MHz) δ ppm 7.80 (s, 1H), 7.75 (s, 1H), 7.33-7.26 (m , 4H),
5.23 (s, 2H), 5.12 (dd , J = 9.0, 4.0 Hz, 1H), 3.27 (dd, J = 14.7, 9.0 Hz, 1H), 3.08 (dd , J = 14.7 , 4.0 Hz, 1H), 0.72 (s, 9H), -0. 19 (s, 3H), -0.25 (s, 3H).
LRMS: m/z 521 (M+ 1). EXAMPLES
EXAMPLE 1
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylquinazolin- 4(3H)-one
A suspension of 5-methylquinazolin-4(3H)-one (0.040 g , 0.25 mmol) and potassium carbonate (0.069 g , 0.50 mmol) in dimethylformamide ( 1 .0 ml) was stirred at room temperature. After 10 min, a solution of the title compound of PREPARATION 76
(0.071 g, 0.28 mmol) in dimethylformamide (0.5 ml) was added and stirring was continued for 3 h. After this period, water was added and the mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried and evaporated. The residue was purified by flash chromatography (methanol-dichloromethane gradient, 0 :100 rising to 5:95) to give 0.070 g (0. 18 mmol, 72% yield) of the title compound as a white solid . Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.48 (s, 1H), 7.72 (m, 1H), 7.56 (d, 1H, J = 7.8 Hz), 7.35 (d , 1H, J = 7.4 Hz), 7.26 (d , 2H, J = 8.6 Hz), 7.2 1 (d, 2H, J = 8.6 Hz), 5.47 (s, 2H), 2.91 -3.00 (m , 4H), 2.75 (s, 3H).
HPLC/MS (5 min) retention time 3.25 min .
LRMS: m/z 38 1 (M+ 1, 1*CI).
EXAMPLE 2
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)imidazo[5, 1- ,2,4]triazin-4(3H)-one
Synthesized from lmidazo[5, 1-f][1 ,2,4]triazin-4(3H)-one and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield : 77%. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (d, J = 0.8 Hz, 1H), 8.32 (s, 1H), 7.89 (d, J
= 0.8 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.25 - 7 .17 (m, 2H), 5.41 (s, 2H), 3.03 - 2.86 (m, 4H).
UPLC/MS (3 min) retention time 1.50 min . LRMS: m/z 357 (M+ 1, 1 CI).
EXAMPLE 3
3-({3-[2-(4-Chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- /][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 6 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield: 68%. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 8.22 (s, 1H), 7.28 (d, 2H, J = 8.6 Hz), 7.23 (d, 2H, J = 8.6 Hz), 5.37 (s, 2H), 2.92-3.01 (m, 4H), 2.47 (s, 3H).
HPLC/MS (5 min) retention time 2.68 min.
LRMS: m/z 371 (M+1 , 1*CI).
EXAMPLE 4
3-({3-[2-(3-Chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- fl[1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 6 and the title compound of PREPARATION 78 following the method of EXAMPLE 1. The title compound was obtained after reverse-phase chromatography using the Isolera Purification system . Yield: 24%. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (s, 1H), 8.20 (s, 1H), 7.35 - 7.09 (m, 4H), 5.35 (s, 2H), 3.06 - 2.89 (m, 4H), 2.45 (s, 3H).
UPLC/MS (3 min) retention time 1.62 min.
LRMS: m/z 371 (M+1 , 1 CI).
EXAMPLE 5
3-({3-[2-(4-Chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-5,7- dimethylimidazo[5,1 - ][1,2,4]triazin-4(3H)-one Synthesized from the title compound of PREPARATION 12 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield: 56%. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (s, 1H), 7.33 - 7.09 (m, 4H), 5.33 (s, 2H), 3.02 - 2.84 (m, 4H), 2.46 (s, 3H), 2.41 (s, 3H).
UPLC/MS (3 min) retention time 1.70 min.
LRMS: m/z 385 (M+1 , 1*CI).
EXAMPLE 6
3-({3-[2-(4-Chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-4-oxo-3,4- dihydroimidazo[5,1-/][1,2,4]triazine-5-carbonitrile
Synthesized from the title compound of PREPARATION 19 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. The title compound was obtained after reverse-phase chromatography using the Isolera Purification system. Yield: 16%. Purity 95%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (s, 1H), 8.53 (s, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 5.46 (s, 2H), 3.06 - 2.88 (m, 4H).
UPLC/MS (3 min) retention time 1.59 min.
LRMS: m/z 382 (M+1 , 1*CI).
EXAMPLE 7
3-({3-[2-(4-Chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-5-methyl-7- (methylamino)imidazo[5,1-/][1,2,4]triazin-4(3H)-one
Synthesized from the crude title compound of PREPARATION 9 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield: 56% over two steps. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.70 (q, J = 4.5 Hz, 1H), 5.29 (s, 2H), 3.01 (apparent dq, J = 11.3, 5.7 Hz, 4H), 2.92 (d, J = 4.8 Hz, 3H), 2.40 (s, 3H). UPLC/MS (3 min) retention time 1.39 min.
LRMS: m/z 400 (M+1 , 1*CI).
EXAMPLE 8
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylpyrazolo[5,1 - f ,2,4]triazin-4(3W)-one
Synthesized from the title compound of PREPARATION 23 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. To isolate the title compound was purified by flash chromatography (ethyl acetate-hexane gradient, 0:100 rising to 100:0) to give 60 mg of the title compound (0.162 mmol, 77% yield). Purity 96%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 7.75 (s, 1H), 7.29 - 7.24 (m, 2H), 7.24 - 7.19 (m, 2H), 5.43 (s, 2H), 3.01 - 2.89 (m, 4H), 2.34 (d, 3H).
UPLC/MS (3 min) retention time 1.71 min.
LRMS: m/z 371 (M+1 , 1 ).
EXAMPLE 9
6-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
Synthesized from the title compound of PREPARATION 2 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. The title compound was obtained after reverse-phase chromatography using the SP1 Purification system. Yield: 55%. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 7.29 - 7.23 (m, 2H), 7.23 - 7.17 (m, 2H), 5.52 (s, 2H), 4.09 (s, 3H), 3.01 - 2.85 (m, 4H), 2.37 (s, 3H).
UPLC/MS (3 min) retention time 1.66 min.
LRMS: m/z 385 (M+1 , 1*CI). EXAMPLE 10
5-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,5-dihydro- 4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from 1-Methyl-1 H-pyrazolo[3,4-c/]pyrimidin-4(5/-/)-one and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield: 60%. Purity 100%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.13 (s, H), 7.30 - 7.25 (m, 2H), 7.25 - 7.18 (m, 2H), 5.50 (s, 2H), 3.94 (s, 3H), 3.00 - 2.86 (m, 4H).
UPLC/MS (3 min) retention time 1.55 min.
LRMS: m/z 371 (M+1 , 1xCI).
EXAMPLE 11
5-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-1 ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 1 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield: 70%. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (s, 1H), 7.31 - 7.23 (m, 2H), 7.23 - 7.15 (m, 2H), 5.46 (s, 2H), 3.84 (s, 3H), 3.02 - 2.85 (m, 4H), 2.40 (s, 3H).
UPLC/MS (3 min) retention time 1.63 min.
LRMS: m/z 385 (M+1 , 1xCI).
EXAMPLE 12
1,3-Dimethyl-5-{[3-(2-phenylethyl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 1 and the title compound of PREPARATION 80 following the method of EXAMPLE 1. Yield: 62%. Purity 100%. H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (s, 1H), 7.32 - 7.07 (m, 5H), 5.46 (s, 2H), 3.83 (s, 3H), 3.05 - 2.87 (m , 4H), 2.39 (s, 3H).
UPLC/MS (3 min) retention time 1.48 min.
LRMS: m/z 351 (M+1 ).
EXAMPLE 13
6-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro- 7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one
Synthesized from the title compound of PREPARATION 17 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield : 56%. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.58 (s, 1H), 7.29 (d, 2H, J = 8.2 Hz), 7.23 (d,
2H, J = 8.2 Hz), 5.59 (s, 2H), 4.36 (s, 3H), 2.90-3.02 (m , 4H).
HPLC/MS (5 min) retention time 2.62 min.
LRMS: m/z 372 (M+ 1, 1*CI).
EXAMPLE 14
1-({3-[2-(4-Chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-7,9-dimethyl-7,9- dihydro-1 H-purine-6,8-dione
/V-(3-Dimethylaminopropyl)-/V -ethylcarbodiimide hydrochloride (EDC- HCI, 0.054 g, 0.28 mmol) and the title compound of PREPARATION 75 (0.043 g , 0.22 mmol) were added sequentially to a stirred suspension of the title compound of PREPARATION 49 (0.060 g , 0.22 mmol) in 1,2-dichloroethane (2.0 ml) and dimethylformamide (0.5 ml) and the mixture was stirred at room temperature. After 4 h, the mixture was warmed to 85 °C and stirred overnight. After this period , the mixture was diluted with ethyl acetate and washed with water, brine, dried and evaporated and the residue was purified by reverse phase chromatography to give 0.020 g (0.05 mmol, 23% yield) of the title compound as a white solid . Purity 98%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.29 (d, 2H, J = 8.6 Hz), 7.23 (d,
2H, J = 8.6 Hz), 5.52 (s, 2H), 3.45 (s, 3H), 3.30 (s, 3H), 2.92-3.02 (m , 4H). HPLC/MS (5 min) retention time 2.38
LRMS: m/z 401 (M+ 1, 1xCI).
EXAMPLE 15
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5, 1- [1,2,4]triazine-4,7(3H,6H)-dione
Synthesized from the crude title compound of PREPARATION 8 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield: 16% over two steps. Purity 96%.
H NMR (400 MHz, CD30D) δ ppm 7.62 (s, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7 .15 (d , J = 8.5 Hz, 2H), 5.19 (s, 2H), 3.09 - 2.87 (m , 4H), 2.44 (s, 3H).
UPLC/MS (3 min) retention time 1.45 min.
LRMS: m/z 387 (M+1 , 1*CI).
EXAMPLE 16
7-Chloro-3-({3-[2-(4-chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 37 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield : 72%. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.36 (s, 1H), 7.29 (s, 1H), 7.24 (d, 2H, J = 8.6
Hz), 7.11 (d, 2H, J = 8.6 Hz), 5.33 (s, 2H), 3.01 (m, 4H), 2.86 (s, 3H).
UPLC/MS (3 min) retention time 1.82 min.
LRMS: m/z 4 16 (M+ 1, 2*CI).
EXAMPLE 17
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methoxy-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one Synthesized from the title compound of PREPARATION 34 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield 64%. Purity 97%.
H NMR (400 MHz, Chloroform-d) δ ppm 8.31 (s, 1H), 7.24 - 7 .19 (m, 2H), 7 .12 - 7.05 (m, 2H), 6.67 (d, J = 0.9 Hz, 1H), 5.30 (s, 2H), 4.07 (d, J = 0.6 Hz, 3H), 2.99 (s, 4H), 2.77 (d , J = 0.9 Hz, 3H).
UPLC/MS (3 min) retention time 1.83 min.
LRMS: m/z 4 12 (M+ 1, 1*CI).
EXAMPLE 18
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione
The title compound of EXAMPLE 17 (35 mg, 0.085 mmol) was dissolved in 2 ml acetonitrile. Sodium iodide (64 mg, 0.427 mmol) and trimethylchlorosilane (54 µ Ι, 0.427 mmol) were added and the mixture was stirred at 70 °C for 1 h. The mixture was then evaporated under reduced pressure and water and saturated sodium thiosulfate solution were added. The mixture was agitated at room temperature for 2h. The mixture was extracted with ethyl acetate twice, the organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC chromatography to give 7 mg (0.0 17 mmol , 2 1% yield) of the title compound . Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (s, 1H), 8.60 (s, 1H), 7.26 (d , J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6 .18 (s, 1H), 5.39 (s, 2H), 3.04 - 2.85 (m, 4H), 2.44 (s, 3H).
UPLC/MS (3 min) retention time 1.52 min.
LRMS: m/z 398 (M+ 1, 1xCI).
EXAMPLE 19
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5,8- dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione Synthesized from the title compound of PREPARATION 2 1 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield: 37%. Purity 100%.
H NMR (400 MHz, Chloroform-d) δ ppm 8.21 (s, 1H), 7.25 - 7.21 (m, 2H), 7.12 - 7.08
(m, 2H), 6.43 (d, J = 1. 1 Hz, 1H), 5.29 (s, 2H), 3.72 (s, 3H), 3.01 (s, 4H), 2.60 (d, J =
1. 1 Hz, 3H).
UPLC/MS (3 min) retention time 1.62 min.
LRMS: m/z 412 (M+1 , 1xCI).
EXAMPLE 20
7-Amino-3-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-5- methylpyrimido[4,5-c/lpyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 40 and the title compound of PREPARATION 76 following the method of EXAMPLE 1. Yield: 71%. Purity 99%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.62 (s, 1H), 7.54 (br s, 2H), 7.28 (d, 2H, J = 8.6 Hz), 7.23 (d, 2H, J = 8.6 Hz), 5.40 (s, 2H), 2.92-3.00 (m, 4H), 2.68 (s, 3H).
UPLC/MS (3 min) retention time 1.49 min.
LRMS: m/z 398 (M+1 , 1xCI).
EXAMPLE 2 1
1-({3-[2-(3-Bromophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7-dihydro- 6H-purin-6-one
Synthesized from 7-Methyl-1 ,7-dihydro-6H-purin-6-one and the crude title compound of PREPARATION 84 following the method of EXAMPLE 1. Yield: 36% over two steps. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.14 (s, 1H), 7.87 (s, 1H), 7.36 (m, 2H), 7.14
(m, 2H), 5.41 (s, 2H), 4.1 1 (s, 3H), 3.03 (s, 4H).
UPLC/MS (3 min) retention time 1.44 min. LRMS: m/z 4 15, 4 17 (M+ 1, 1* Br).
EXAMPLE 22
3-({5-[2-(4-Chlorophenyl)ethyl]-1 ,3,4-oxadiazol-2-yl}methyl)-5-methylimidazo[5, 1- ][1,2,4]triazin-4(3W)-one
Synthesized from the title compound of PREPARATION 6 and the title compound of PREPARATION 152 following the method of EXAM PLE 1. Yield : 70%. Purity 95%.
H NMR (400 MHz, Chloroform-d) δ ppm 8.0 1 (s, 1H), 7.54 (s, 1H), 7.24 (d , 2H, J=8.2
Hz), 7.12 (d, 2H, J=8.2 Hz), 5.23 (s, 2H), 3.13 - 3 .19 (m , 2H), 3.06 - 3 .12 (m, 2H), 2.66 (s, 3H)
UPLC/MS (3 min) retention time 1.45 min.
LRMS: m/z 37 1 (M+ 1, 1xCI).
EXAMPLE 23
5-({5-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-3-yl}methyl)-1 ,3-dimethyl-1 ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 1 and the title compound of PREPARATION 73 following the method of EXAMPLE 1. Yield : 91% . Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 7.31 - 7.18 (m, 4H), 5.27 (s, 2H), 3.82 (s, 3H), 3.20 (t, J = 7.6 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.38 (s, 3H).
UPLC/MS (3 min) retention time 1.60 min .
LRMS: m/z 385 (M+ 1, 1*CI).
EXAMPLE 24
6-({5-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-3-yl}methyl)-1 -methyl-1 ,6-dihydro- 7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one Synthesized from the title compound of PREPARATION 17 and the title compound of PREPARATION 74 following the method of EXAM PLE 1. Obtained as a white solid. Yield: 26%. Purity 99%.
H NMR (300 MHz, Chloroform-d) δ ppm 8 .18 (s, 1H), 7.25 (d , J=8.2 Hz, 2H), 7 .11 (d ,
J=8.2 Hz, 2H), 5.34 (s, 2H), 4.49 (s, 3H), 3.13 - 3.24 (m , 2H), 3.04 - 3 .13 (m , 2H)
UPLC/MS (3 min) retention time 1.48 min.
LRMS: m/z 372 (M+ 1, 1*CI).
EXAMPLE 25
5-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-thiadiazol-5-yl}methyl)-1 ,3-dimethyl-1 ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 1 and the title compound of PREPARATION 64 following the method of EXAM PLE 1. Obtained as a white solid. Yield : 49%. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 8 .12 (s, 1H), 7.24 (d , J=7.5 Hz, 2H), 7 .14 (d ,
J=7.5 Hz, 2H), 5.47 (s, 2H), 3.95 (s, 3H), 3.26 (d, J=7.9 Hz, 2H), 3 .12 (t, J=7.9 Hz, 2H), 2.62 (s, 3H)
UPLC/MS (3 min) retention time 1.7 1 min.
LRMS: m/z 401 (M+ 1, 1*CI).
EXAMPLE 26
5-({1 -[2-(4-Chlorophenyl)ethyl]-1 -1,2,4-triazol-3-yl}methyl)-1 ,3-dimethyl-1 ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 1 and the crude title compound of PREPARATION 157 following the method of EXAMPLE 1. Obtained as a colorless film. Yield : 11% over three steps. Purity 96%. H NMR (300 MHz, Chloroform-d) δ ppm 8.1 1 (s, 1H), 7.71 (s, 1H), 7.24 (d, J=8.2 Hz,
2H), 6.97 (d, J=8.2 Hz, 2H), 5.28 (s, 2H), 4.32 (t, J=7.0 Hz, 2H), 3.94 (s, 3H), 3.13 (t, J=7.0 Hz, 2H), 2.61 (s, 3H)
HPLC/MS (5 min) retention time 2.13 min.
LRMS: m/z 384 (M+1 , 1xCI).
EXAMPLE 27
3-({3-[2-(4-Chlorophenyl)ethyl]-1 H-1 ,2,4-triazol-5-yl}methyl)-5-methylimidazo[5,1 - ,2,4]triazin-4(3H)-one
The title compound of PREPARATION 54 (50 mg, 0.26 mmol) was dissolved in ethanol (0.5 ml). The title compound of PREPARATION 150 (52 mg, 0.26 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added and the mixture was submitted to microwave irradiation for 15 h at 140 °C. The mixture was evaporated to dryness and the residue was purified using the Isolera Purification system (methanol- dichloromethane gradient, 0:100 rising to 10:90) to give 39 mg (0.1 1 mmol, 40% yield) of the title compound as a white solid. Purity 97%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.00 (s, 1H), 7.65 (s, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 5.13 (s, 2H), 3.04 - 3.09 (m, 4H), 2.66 (s, 3H)
UPLC/MS (3 min) retention time 1.28 min.
LRMS: m/z 370 (M+1 , 1xCI).
EXAMPLE 28
5-({2-[2-(4-Chlorophenyl)ethyl]-2H-tetrazol-5-yl}methyl)-1,3-dimethyl-1,5-dihydro- 4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 1 and the title compound of PREPARATION 155 following the method of EXAMPLE 1. Obtained as a white solid. Yield: 87%. Purity 100%. H NMR (300 MHz, Chloroform-d) δ ppm 8.09 (s, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.05 (d,
J=7.0 Hz, 2H), 5.43 (s, 2H), 4.81 (t, J=7.3 Hz, 2H), 3.95 (s, 3H), 3.29 (t, J=7.3 Hz, 2H), 2.60 (s, 3H)
UPLC/MS (3 min) retention time 1.47 min.
LRMS: m/z 385 (M+1 , 1*CI).
EXAMPLE 29
6-({2-[2-(4-Chlorophenyl)ethyl]-2H-tetrazol-5-yl}methyl)-1-methyl-1,6-dihydro-7H- [1,2,3]triazolo[4,5-d]pyrimidin-7-one
Synthesized from the title compound of PREPARATION 17 and the title compound of PREPARATION 155 following the method of EXAMPLE 1. Obtained as a colorless oil. Yield: 29%. Purity 100%.
Ή NMR (300 MHz, Chloroform-d) δ ppm 8.23 (s, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 5.50 (s, 2H), 4.82 (t, J=7.6 Hz, 2H), 4.48 (s, 3H), 3.29 (t, J=7.3 Hz, 2H)
UPLC/MS (3 min) retention time 1.37 min.
LRMS: m/z 372 (M+1 , 1 C I).
EXAMPLE 30
1-({4-[2-(4-Chlorophenyl)ethyl]-1 ,3-oxazol-2-yl}methyl)-7-methyl-1 ,7-dihydro-6H- purin-6-one
Synthesized from 7-Methyl-1 ,7-dihydro-6H-purin-6-one and the crude title compound of PREPARATION 70 following the method of EXAMPLE 1. The title compound was obtained after preparative reverse-phase HPLC. Yield: 1% over three steps. Purity 97%.
UPLC/MS (3 min) retention time 1.44 min.
LRMS: m/z 370 (M+1 , 1xCI). EXAMPLE 3 1
5-({4-[2-(4-Chlorophenyl)ethyl]-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl}methyl)- 1,3-dimethyl-1 ,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the crude title compound of PREPARATION 59 and 1-(2- bromoethyl)-4-chlorobenzene. Yield: 14% over three steps. Purity 96%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 7.30 (d, J = 7.7 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.20 (s, 2H), 3.99 - 3.76 (m, 5H), 2.94 (t, J = 6.3 Hz, 2H), 2.49 (s, 3H).
UPLC/MS (3 min) retention time 1.57 min.
LRMS: m/z 401 (M+1 , 1*CI).
EXAMPLE 32
1-[(3-{[(4-Chlorophenyl)thio]methyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7-methyl-1 ,7- dihydro-6H-purin-6-one
Synthesized from 7-Methyl-1 ,7-dihydro-6H-purin-6-one and the title compound of PREPARATION 86 following the method of EXAMPLE 1. The title compound was obtained after purification by preparative HPLC. Yield: 44%. Purity 99%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (s, 1H), 8.23 (s, 1H), 7.41 - 7.28 (m, 4H), 5.52 (s, 2H), 4.33 (s, 2H), 3.93 (s, 3H).
HPLC/MS (5 min) retention time 2.18 min.
LRMS: m/z 389 (M+1 , 1xCI).
EXAMPLE 33
5-[(3-{[(4-Chlorophenyl)thio]methyl}-1,2,4-oxadiazol-5-yl)methyl]-1,3-dimethyl- 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 1 and the title compound of PREPARATION 86 following the method of EXAMPLE 1. Yield: 97%. Purity 100%. H NMR (400 MHz, DMSO-d6) d ppm 8.46 ( 1 H, s), 7.35 (2H , d, J=8.2 Hz), 7.29 (2H , d, J=8.2 Hz), 5.45 (2H , s), 4.30 (2H , s), 3.83 (3H , s), 2.39 (3H , s).
UPLC/MS (3 min) retention time 1.62 min .
LRMS: m/z 403 (M+ 1, 1*CI).
EXAMPLE 34
5-[(3-{[(4-Chlorophenyl)sulfinyl]methyl}-1,2,4-oxadiazol-5-yl)methyl]-1,3- dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Sodium periodate (4 1 mg, 0 .190 mmol) in water (2 ml) was added to a solution of the title compound of EXAMPLE 33 (74 mg, 0 .180 mmol) in methanol (20 ml) and the mixture was stirred at room temperature. After 48 h, further sodium periodate (4 1 mg, 0 .190 mmol) in water (2 ml) was added and stirring was continued. After a further 24 h, further sodium periodate (41 mg, 0 .190 mmol) in water (2 ml) was added and stirring was continued. After a further 24 h, the mixture was evaporated to dryness and the residue was partitioned between chloroform and water. The organic layer was washed with brine, dried and evaporated to give a solid that was purified by preparative HPLC chromatography to give 28 mg of the title compound (0.067 mmol, 38% yield). Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 7.64 - 7.54 (m, 2H), 7.54 - 7.46
(m , 2H), 5.46 (s, 2H), 4.54 (d, J = 13.8 Hz, 1H), 4.33 (d , J = 13.8 Hz, 1H), 3.85 (s, 3H), 2.4 1 (s, 3H).
UPLC/MS (3 min) retention time 1.22 min.
LRMS: m/z 4 19 (M+ 1, 1*CI).
EXAMPLE 35
6-({3-[(E)-2-(4-Chlorophenyl)vinyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one
Synthesized from the title compound of PREPARATION 52 and the title compound of PREPARATION 105 following the method of EXAMPLE 14 . Yield : 2%. Purity 97%. H NMR (300 MHz, Chloroform-d) δ ppm 8.23 (s, 1H), 7.60 (d, J = 16.2 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.42 - 7.34 (m, 2H), 7.00 (d, J = 16.2 Hz, 1H), 5.48 (s, 2H), 4.50 (s, 3H).
HPLC/MS (5 min) retention time 2.61 min.
LRMS: m/z 370 (M+1 , 1*CI).
EXAMPLE 36
6-({3-[(1 E)-2-(4-Chlorophenyl)prop-1 -en-1 -yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 - methyl-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
Synthesized from the title compound of PREPARATION 17 and the title compound of PREPARATION 108 following the method of EXAMPLE 1. Yield: 23%. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.22 (s, 1H), 7.56 - 7.32 (m, 4H), 6.60 (s, 1H), 5.49 (s, 2H), 4.50 (s, 3H), 2.54 (s, 3H).
UPLC/MS (3 min) retention time 1.70 min.
LRMS: m/z 384 (M+1 , 1xCI).
EXAMPLE 37
trans 6-({3-[2-(4-Chlorophenyl)cyclopropyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 - methyl-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-cflpyrimidin-7-one
Synthesized from the title compound of PREPARATION 17 and the title compound of PREPARATION 112 following the method of EXAMPLE 1. Yield: 31%. Purity 97%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.18 (s, 1H), 7.26 (m, 2H), 7.07 (d, J = 8.2 Hz, 2H), 5.42 (s, 2H), 4.50 (s, 3H), 2.61 - 2.40 (m, 1H), 2.44 - 2.22 (m, 1H), 1.68 - 1.62 (m, 1H), 1.55 - 1.40 (m, 1H).
UPLC/MS (3 min) retention time 1.61 min.
LRMS: m/z 384 (M+ 1, 1xCI).
EXAMPLE 38 3-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylimidazo[5, 1- ][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 6 and the title compound of PREPARATION 88 following the method of EXAM PLE 1. Yield : 60%. Purity 100%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (s, 1H), 8.20 (s, 1H), 7.26 (d, J = 8.9 Hz,
2H), 6.90 (d , J = 8.9 Hz, 2H), 5.36 (s, 2H), 4.27 (t, J = 6.0 Hz, 2H), 3 .14 (t, J = 6.0 Hz,
2H), 2.43 (s, 3H).
UPLC/MS (3 min) retention time 1.65 min.
LRMS: m/z 387 (M+ 1, 1*CI).
EXAMPLE 39
6-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2 ,4-oxadiazol -5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1,2,3]triazolo [4,5-cf]pyrimidin-7-one
Synthesized from the title compound of PREPARATION 17 and the title compound of PREPARATION 88 following the method of EXAMPLE 1. Obtained as a white solid. Yield: 32%. Purity 97%.
H NMR (300 MHz, Chloroform-d) δ ppm 8 .17 (s, 1H), 7.20 - 7.27 (m , 2H), 6.78 - 6.85
(m , 2H), 5.44 (s, 2H), 4.48 (s, 3H), 4.31 (t, J=6.5 Hz, 2H), 3.22 (t, J=6.5 Hz, 2H)
UPLC/MS (3 min) retention time 1.48 min .
LRMS: m/z 388 (M+ 1, 1xCI).
EXAMPLE 40
1-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
Synthesized from 7-Methyl-1 ,7-dihydro-6H-purin-6-one and the title compound of PREPARATION 88 following the method of EXAM PLE 1. Obtained as a white solid.
Yield: 8 1% . Purity 98%. H NMR (300 MHz, Chloroform-d) δ ppm 8.15 (s, 1H), 7.87 (s, 1H), 7.20 - 7.27 (m,
2H), 6.79 - 6.86 (m, 2H), 5.43 (s, 2H), 4.31 (t, J=6.5 Hz, 2H), 4.09 (s, 3H), 3.22 (t, J=6.5 Hz, 2H)
UPLC/MS (3 min) retention time 1.40 min .
LRMS: m/z 387 (M+ 1, 1xCI).
EXAMPLE 4 1
5-{[3-(1 ,3-Dihydro-2H-isoindol-2-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,3-dimethyl-1 ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 55 and Isoindoline following the method of PREPARATION 147. Obtained as a pale green solid . Yield: 88%. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.07 (s, 1H), 7.32 (s, 4H), 5.30 (s, 2H), 4.78 (s, 4H), 3.98 (s, 3H), 2.61 (s, 3H)
UPLC/MS (3 min) retention time 1.44 min.
LRMS: m/z 364 (M+1 ).
EXAMPLE 42
1-{[3-(1 ,3-Dihydro-2H-isoindol-2-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-7-methyl-1 ,7- dihydro-6H-purin-6-one
Synthesized from 7-Methyl-1 ,7-dihydro-6H-purin-6-one and the title compound of PREPARATION 149 following the method of EXAMPLE 1. Obtained as a white solid. Yield : 71% . Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 8 .17 (s, 1H), 7.86 (s, 1H), 7.3 1 (s, 2H), 7.28
(s, 2H), 5.33 (s, 2H), 4.77 (s, 4H), 4 .10 (s, 3H)
UPLC/MS (3 min) retention time 1.18 min.
LRMS: m/z 350 (M+1 ). EXAMPLE 43
5-{[3-(3,4-Dihydroisoquinolin-2(1 H)-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,3-dimethyl- 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 55 and 1,2,3,4- Tetrahydroisoquinoline following the method of PREPARATION 147. Obtained as a white solid. Yield : 63%. Purity 100%.
H NMR (400 MHz, Chloroform-d) δ ppm 8.02 (s, 1H), 7 .16 - 7.21 (m, 2H), 7 .10 - 7.16
(m, 2H), 5.24 (s, 2H), 4.57 (s, 2H), 3.94 (s, 3H), 3.7 1 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.9 Hz, 2H), 2.58 (s, 3H)
UPLC/MS (3 min) retention time 1.54 min.
LRMS: m/z 378 (M+1 ).
EXAMPLE 44
5-({3-[3-(4-Chlorophenyl)azetidin-1 -yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl- 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Synthesized from the title compound of PREPARATION 55 and 3-(4- chlorophenyl)azetidine following the method of PREPARATION 147. Obtained as a white solid . Yield : 37%. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.03 (s, 1H), 7.27 - 7.38 (m, 4H), 5.27 (s, 2H), 4.46 (t, J=8.2 Hz, 2H), 4.05 (t, J=8.2 Hz, 2H), 3.96 (s, 3H), 3.90-4.00 (m, 1H), 2.6 1 (s, 3H).
UPLC/MS (3 min) retention time 1.64 min.
LRMS: m/z 4 12 (M+ 1, 1xCI).
EXAMPLE 45
5-({3-[3-(4-Chlorophenyl)pyrrolidin-1 -yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3- dimethyl-1 ,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Synthesized from the title compound of PREPARATION 55 and 3-(4- chlorophenyl)pyrrolidine following the method of PREPARATION 147. Obtained as a white solid. Yield : 64%. Purity 100%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.04 (s, 1H), 7.29 - 7.34 (m, 2H), 7 .16 - 7.2 1 (m, 2H), 5.26 (s, 2H), 3.96 (s, 3H), 3.87 (dd , J=9. 1, 6.7 Hz, 1H), 3.66 (ddd , J=9.2, 3.2 Hz, 1H), 3.33 - 3.58 (m, 3H), 2.60 (s, 3H), 2.33 - 2.46 (m, 1H), 1.97 - 2 .16 (m, 1H)
UPLC/MS (3 min) retention time 1.7 1 min.
LRMS: m/z 426 (M+ 1, 1*CI).
EXAMPLE 46 yV-(4-Chlorophenyl)-5-[(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4- d]pyrimidin-5-yl)methyl]-1,2,4-oxadiazole-3-carboxamide
A mixture of title compound of PREPARATION 57 (40. 1 mg, 0.14 mmol), /V-Ethyl-/V'- (3-dimethylaminopropyl)carbodiimide hydrochloride (32. 1 mg, 0.17 mmol) and 1- hydroxybenzotriazole hydrate (28.2 mg, 0.2 1 mmol) in dichloromethane ( 1 ml) was stirred at room temperature. After 30 minutes, 4-Chloroaniline (20. 1 mg, 0 .16mmol) was added and stirring was continued for 2 days. The mixture was partitioned between dichloromethane and 4% sodium bicarbonate solution. The organic layer was washed with 4% sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative HPLC chromatography to give 7 mg (0.0 17 mmol , 13% yield) of the title compound. Purity 100%.
H NMR (400 MHz, Chloroform-d) δ ppm 8.52 (s, 1H), 8.05 (s, 1H), 7.6 1 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 5.43 (s, 2H), 3.96 (s, 3H), 2.57 (s, 3H).
UPLC/MS (3 min) retention time 1.43 min.
LRMS: m/z 400 (M+ 1, 1*CI).
EXAMPLE 47 6-({3-[2-(4-Chlorophenyl)propyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1,2,3]triazolo[4,5-rflpyrimidin-7-one
Synthesized from the title compound of PREPARATION 17 and the crude title compound of PREPARATION 95 following the method of EXAMPLE 1. Yield: 14% over three steps. Purity 98%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 7.23-7.29 (m, 4H), 5.56 (s, 2H), 4.36 (s, 3H), 3.19 (m, 1H), 2.95 (m, 2H), 1.20 (d, 3H, J = 7.0 Hz).
UPLC/MS (3 min) retention time 1.66 min.
LRMS: m/z 386 (M+1 , 1*CI).
EXAMPLE 48
6-({3-[2-(4-Chlorophenyl)-2-fluoroethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one
Deoxofluor (0.015 ml, 0.08 mmol) in dichloromethane (0.5 ml) was added dropwise to a stirred, cooled (-78 °C) suspension of the title compound of EXAMPLE 5 1 (0.027 g,
0.07 mmol) in dichloromethane ( 1 ml) under a nitrogen atmosphere. After 15 min, the mixture was warmed to 0 °C and stirring was continued for 2 h. Further deoxofluor (0.010 ml, 0.05 mmol) in dichloromethane (0.3 ml) was added and stirring was continued at 0 °C. After stirring further 2 h, the mixture was diluted with dichloromethane and washed with 4% aqueous sodium hydrogencarbonate solution and brine and the organic extract was dried and evaporated. The residue was purified by reverse phase chromatography to give 0.01 1 g (0.03 mmol, 41% yield) of the title compound as a white solid. Purity 98%.
H NMR (300 MHz, Chloroform-d) δ ppm 8.16 (s, 1H), 7.37 (d, 2H, J = 8.6 Hz), 7.30 (d,
2H, J = 8.6 Hz), 5.85 (ddd, 1H, J = 4.3, 9.0, 46.9 Hz), 5.44 (s, 2H), 4.48 (s, 3H), 3.42 (m, 1H), 3.18 (ddd, 1H, J = 4.7, 15.6, 30.1 Hz).
UPLC/MS (3 min) retention time 1.47 min.
LRMS: m/z 390 (M+1 , 1*CI). EXAMPLE 49
6-({3-[2-(4-Chlorophenyl)-2-methoxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-1-methyl- 1,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
Synthesized from the title compound of PREPARATION 17 and the title compound of PREPARATION 92 following the method of EXAMPLE 1. Yield: 36%. Purity 98%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 7.38 (d, 2H, J = 8.6 Hz), 7.34 (d,
2H, J = 8.6 Hz), 5.60 (s, 2H), 4.61 (dd, 1H, J = 5.5, 8.2 Hz), 4.37 (s, 3H), 3.15 (dd, 1H, J = 8.2, 14.9 Hz), 3.06 (s, 3H), 2.99 (dd, 1H, J = 5.5, 14.9 Hz).
HPLC/MS (5 min) retention time 2.40 min.
LRMS: m/z 402 (M+1 , 1xCI).
EXAMPLE 50
6-({3-[2-(4-Chlorophenyl)-2-oxoethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one
A mixture of the crude title compound of PREPARATION 99 (0.050 g) and concentrated aqueous hydrochloric acid (0.4 ml) in tetrahydrofuran ( 1 ml) was stirred at room temperature for 96 h. After this period, water was added and the mixture was neutralized with solid sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated and the residue was purified by chromatography (methanol-dichloromethane gradient, 0:100 rising to 5:95) to give 0.01 6 g (0.04 mmol, 38% yield over two steps) of the title compound as a white solid. Purity 97%.
Mixture of Keto/Enol Tautomers: H NMR (300 MHz, DMSO-d6) δ ppm . KETO TAUTOMER: 8.60 (s, 1H), 8.02 (d, 2H, J = 8.6 Hz), 7.63 (d, 2H, J = 8.6 Hz), 5.64 (s, 2H), 4.71 (s, 2H), 4.35 (s, 3H). ENOL TAUTOMER: 11.69 (s, 1H), 8.42 (s, 1H), 7.91 (d, 2H, J = 8.6 Hz), 7.59 (d, 2H, J = 8.6 Hz), 7.37 (s, 1H), 4.99 (s, 2H), 4.37 (s, 3H).
HPLC/MS (5 min) retention time 2.07 min.
LRMS: m/z 386 (M+1 , 1*CI). EXAMPLE 5 1
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-1-methyl- 1,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
Synthesized from the title compound of PREPARATION 17 and the title compound of PREPARATION 103 following the method of EXAMPLE 1. Yield: 48%. Purity 99%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 7.32-7.39 (m, 4H), 5.60 (m, 3H), 4.92-4.96 (m, 1H), 4.37 (s, 3H), 2.95-3.01 (m, 2H).
UPLC/MS (3 min) retention time 1.23 min.
LRMS: m/z 388 (M+1 , 1*CI).
The enantiomers of EXAMPLE 5 1 were separated by preparative HPLC on an Agilent 1200 Series (AE-0010) using a Chiralpak IA column (5 mm, 30x250 mm) using the following conditions: mobile phase: 60% heptane (0.2% diethylamine) / 40% isopropanol, run time: 120 min, flow: 20 ml/min, Injection: sample dissolved in ethanol (2 ml) and DMSO (4 drops).
EXAMPLE 5 1. 1
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-1-methyl- 1,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one Ent 1
Recovery: 96%. Purity 99%. Enantiomeric excess > 99.5%.
HPLC (60 min, chiral column) retention time 26.4 min.
EXAMPLE 5 1.2
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-1-methyl- 1,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one Ent 2
Recovery 73%. Purity 99%. Enantiomeric excess > 99.5%.
HPLC (60 min, chiral column) retention time 35.4 min.
EXAMPLE 52 3-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrazolo[5,1- ][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 23 and the title compound of PREPARATION 103 following the method of EXAM PLE 1. Yield: 54%. Purity 100%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.4 1 (s, 1H), 7.77 (s, 1H), 7.36 (d, 2H, J = 8.6 Hz), 7.32 (d, 2H, J = 8.6 Hz), 5.6 1 (d, 1H, J = 4.7 Hz), 5.45 (s, 2H), 4.92-4.97 (m, 1H), 2.94-3.02 (m , 2H), 2.37 (s, 3H).
HPLC/MS (5 min) retention time 2.42 min .
LRMS: m/z 387 (M+ 1, 1*CI).
The enantiomers of EXAMPLE 52 were separated by preparative HPLC on an Agilent 1200 Series (AE-001 0) using a Chiralpak IA column (5 mm, 30x250 mm) using the following conditions: mobile phase: 60% heptane (0.2% diethylamine) / 40% isopropanol, run time: 120 min , flow: 20 ml/min , Injection: sample dissolved in ethanol and DMSO.
EXAMPLE 52. 1
(S)-3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
Purity 99%. Enantiomeric excess > 99.5 % .
HPLC retention time 12.48 min. (Chiralpak IA (4.6mm x 250mm, δµηι ) - Waters Alliance 2795, Flow rate: 1.0 mL/min , mobile phase: 60% heptane (0.2% diethylamine) / 40% isopropanol)
EXAMPLE 52.2
(R)-3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
Purity 99%. Enantiomeric excess > 99.5 % .
HPLC retention time 15.48 min. (Chiralpak IA (4.6mm x 250mm, µη ) - Waters
Alliance 2795, Flow rate: 1.0 mL/min , mobile phase: 60% heptane (0.2% diethylamine) / 40% isopropanol) EXAMPLE 53
1-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-7-methyl- 1,7-dihydro-6H-purin-6-one
Synthesized from 7-Methyl-1 ,7-dihydro-6H-purin-6-one and the title compound of PREPARATION 103 following the method of EXAM PLE 1. Yield : 89%. Purity 97%.
H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 8.24 (s, 1H), 7.32-7.37 (m, 4H),
5.62 (d , 1H, J = 4.7 Hz), 5.54 (s, 2H), 4.9 1-4.96 (m, 1H), 3.96 (s, 3H), 2.92-3.01 (m, 2H).
HPLC/MS (5 min) retention time 1.87 min.
LRMS: m/z 387 (M+ 1, 1*CI).
EXAMPLE 54
1-[(3-{2-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
The title compound of PREPARATION 47 (50 mg, 0.225 mmol) was suspended in 2 ml anhydrous toluene under argon. The title compound of PREPARATION 120 (60 mg, 0.225 mmol) and potassium carbonate (622 mg, 4.5 mmol) were added and the mixture was stirred at 110 °C for 40 min. The mixture was allowed to cool and was partitioned between water and dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organics were washed with brine, dried over anhydrous magnesium sulphate, filtetered and evaporated. The residue was purified by flash chromatography using the Biotage purification system (methanol- dichloromethane gradient, 0:100 rising to 10:90) to give 40 mg (0.91 mmol, 41% yield) of the title compound as a white solid. Purity 97%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 8.24 (s, 1H), 7.76 (dd, J = 7 .1, 2.0 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.4 1 (dd, J = 10.7, 8.8 Hz, 1H), 5.79 - 5.75 (m, 1H), 5.54
(s, 2H), 5.04 (q, J = 5.7 Hz, 1H), 3.95 (s, 3H), 3.06 - 3.00 (m, 2H).
HPLC/MS (4.5 min) retention time 2.55 min. LRMS: m/z 439 (M+1 ).
EXAMPLE 55
1-({3-[2-(3-Bromophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl- 1,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 118 following the method of EXAMPLE 54. Yield : 24%. Purity 99%.
H NMR (400MHz, CD30D) δ ppm 8.37 (s, 1H), 8.14 (s, 1H), 7.53 (br s, 1H), 7.38-7.34
(m, 1H), 7.28 (d , J = 7.6 Hz, 1H), 7 .19 (t, J = 8 Hz, 1H), 5.53 (s, 2H), 5.03 (dd , J = 8 ,
5.2 Hz, 1H), 4.06 (s, 3H), 3.09 (dd, J = 14.6, 8 Hz, 1H), 3.0 1 (dd, J = 14.6, 5.2 Hz, 1H).
HPLC/MS (4.5 min) retention time 2.32 min.
LRMS: m/z 431 , 433 (M+ 1, 1xBr).
EXAMPLE 56
1-[(3-{2-Hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl}-1 ,2,4-oxadiazol-5-yl)methyl]- 7-methyl-1 ,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 114 following the method of EXAMPLE 54. Yield : 41% . Purity 96%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 8.24 (s, 1H), 7.65 (d, J = 8 .1 Hz,
2H), 7.57 (d, J = 8.3 Hz, 2H), 5.74 (d, J = 4.9 Hz, 1H), 5.55 (s, 2H), 5.04 (q , J = 6.4 Hz, 1H), 3.96 (s, 3H), 3.02 (d , J = 6.8 Hz, 2H)
HPLC/MS (4.5 min) retention time 2.48 min.
LRMS: m/z 42 1 (M+1 ).
EXAMPLE 57
1-({3-[2-(4-Bromophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl- 1,7-dihydro-6H-purin-6-one Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 116 following the method of EXAMPLE 54. Yield: 13%. Purity 98%.
H NMR (400MHz, CD30D) δ ppm 8.37 (s, 1H), 8.14 (s, 1H), 7.44-7.39 (m, 2H), 7.27- 7.22 (m, 2H), 5.53 (s, 2H), 5.03 (dd, J = 8 , 5.2 Hz, 1H), 4.06 (s, 3H), 3.09 (dd, J = 14.6, 8 Hz, 1H), 3.00 (dd, J = 14.6, 5.6 Hz, 1H)
HPLC/MS (4.5 min) retention time 2.32 min.
LRMS: m/z 431 , 433 (M+1 , 1*Br).
EXAMPLE 58
1-[(3-{2-Hydroxy-2-[3-(trifluoromethoxy)phenyl]ethyl}-1,2,4-oxadiazol-5- yl)methyl]-7-methyl-1,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 122 following the method of EXAMPLE 54. Yield: 37%. Purity 99%.
1H NMR (400MHz, CD30D) δ ppm 8.37 (s, 1H), 8.14 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.27 (br s, 1H), 7.14-7.10 (m, 1H), 5.53 (s, 2H), 5.10 (dd, J = 8.4, 5.2 Hz, 1H), 4.06 (s, 3H), 3.10 (dd, J = 14.6, 8.4 Hz, 1H), 3.03 (dd, J = 14.6, 5.2 Hz, 1H).
HPLC/MS (4.5 min) retention time 2.53 min.
LRMS: m/z 437 (M+1 ).
EXAMPLE 59
1-({3-[2-(3,4-Dichlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-7- methyl-1,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 124 following the method of EXAMPLE 54. Yield: 20%. Purity 98%.
H NMR (400MHz, CD30D) δ ppm 8.37 (s, 1H), 8.14 (s, 1H), 7.51 (t, J = 2 Hz, 1H),
7.1 1 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 8.4, 2 Hz, 1H), 5.53 (s, 2H), 5.04 (dd, J = 8 , 6 Hz, 1H), 4.06 (s, 3H), 3.09 (dd, J = 14.4, 8 Hz, 1H), 3.02 (dd, J = 14.4, 6 Hz, 1H). HPLC/MS (4.5 min) retention time 2.52 min.
LRMS: m/z 421 (M+ 1, 2*CI).
EXAMPLE 60
1-[(3-{2-[2-Fluoro-4-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1 ,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 126 following the method of EXAMPLE 54. Yield : 40%. Purity 98%.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 ( 1 H, s), 8.22 ( 1 H, s), 7.73 ( 1 H, t, J=7.8 Hz),
7.50 - 7.61 (2H , m), 5.86 ( 1 H, d, J=5. 1 Hz), 5.53 (2H , s), 5.25 ( 1 H, q, J=6.3 Hz), 3.94 (3H , s), 3.03 (2H , d, J=6.6 Hz)
HPLC/MS (4.5 min) retention time 2.53 min.
LRMS: m/z 439 (M+1 ).
EXAMPLE 61
1-[(3-{2-Hydroxy-2-[4-(trifluoromethoxy)phenyl]ethyl}-1,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 134 following the method of EXAMPLE 54. Yield : 44%. Purity 98%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.43 ( 1 H, s), 8.22 ( 1 H, s), 7.45 (2H , d, J=8.6
Hz), 7.26 (2H , d, J=8.2 Hz), 5.63 ( 1 H, d, J=4.7 Hz), 5.53 (2H , s), 4.92 - 5.00 ( 1 H, m),
3.94 (3H , s), 2.99 ( 1 H, dd, J=15.0, 7.8 Hz), 2.95 ( 1 H, dd, J=1 5.0, 6.0 Hz)
HPLC/MS (4.5 min ) retention time 2.55 min.
LRMS: m/z 437 (M+1 ).
EXAMPLE 62 1-({3-[2-Hydroxy-2-(4-isopropylphenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-7- methyl-1,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 136 following the method of EXAMPLE 54. Yield: 45%. Purity 98%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.44 ( 1 H, s), 8.22 ( 1 H, s), 7.24 (2H, d , J=8.2
Hz), 7.14 (2H, d , J=8.2 Hz), 5.53 (2H, s), 5.40 ( 1 H, d , J=4.7 Hz), 4.88 ( 1 H, ddd, J=8.8,
4.7, 4.5 Hz), 3.94 (3H, s), 2.96 ( 1 H, dd, J=15.0, 8.8 Hz), 2.90 ( 1 H, dd, J=15.0, 4.5 Hz),
2.82 ( 1 H, sept, J=7.0 Hz), 1.15 (6H, d, J=7.0 Hz)
HPLC/MS (4.5 min) retention time 2.57 min.
LRMS: m/z 395 (M+1 ).
EXAMPLE 63
1-[(3-{2-[4-Chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1,2,4-oxadiazol-5- yl)methyl]-7-methyl-1,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 138 following the method of EXAMPLE 54. Yield: 33%. Purity 97%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.42 ( 1 H, s), 8.22 ( 1 H, s), 7.82 ( 1 H, s), 7.60 -
7.64 (2H, m), 5.79 ( 1 H, d , J=5.1 Hz), 5.53 (2H, s), 5.01 - 5.07 ( 1 H, m), 3.94 (3H, s),
3.05 ( 1 H, dd, J=15.0, 4.8 Hz), 3.00 ( 1 H, dd, J=15.0, 8.2 Hz)
HPLC/MS (4.5 min) retention time 2.67 min.
LRMS: m/z 455 (M+1 , 1xCI).
EXAMPLE 64
1-({3-[2-(2-Chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-7-methyl- 1,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 128 following the method of EXAMPLE 54. Yield: 57%. Purity 94%. H NMR (400 MHz, CD30D) δ ppm 8.37 ( 1 H, s), 8.14 ( 1 H, s), 7.59 ( 1 H, d, J=7.4 Hz),
7.25 - 7.32 (2H , m), 7.20 ( 1 H, t, J=7.5 Hz), 5.54 (3H , s), 5.47 ( 1 H, dd, J=8.4, 4.5 Hz),
4.06 (3H , s), 3.10 ( 1 H, dd, J=15.0, 4.5 Hz), 3.0 1 ( 1 H, dd, J=1 5.0, 8.4 Hz)
HPLC/MS (4.5 min) retention time 2.52 min.
LRMS: m/z 4 15 (M+ 1, 1xCI).
EXAMPLE 65
1-{[3-(2-Hydroxy-2-quinolin-2-ylethyl)-1 ,2,4-oxadiazol-5-yl]methyl}-7-methyl-1 ,7- dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 130 following the method of EXAMPLE 54. Yield : 25%. Purity 98%.
H NMR (400 MHz, CD30D) δ ppm 8.33 ( 1 H, s), 8.26 ( 1 H, d, J=8.6 Hz), 8.13 ( 1 H, s),
7.96 ( 1 H, d, J=8.2 Hz), 7.86 ( 1 H, d, J=7.8 Hz), 7.71 ( 1 H, t, J=7.6 Hz), 7.66 ( 1 H, d,
J=8.0 Hz), 7.55 ( 1 H, t, J=7.5 Hz), 5.51 (2H , s), 5.29 ( 1 H, dd, J=8.0, 4.9 Hz), 4.03 (3H , s), 3.28 - 3.37 (2H , m), 3.22 ( 1 H, dd, J=15.0, 8.0 Hz)
HPLC/MS (4.5 min) retention time 1.48 min.
LRMS: m/z 404 (M+1 ).
EXAMPLE 66
1-({3-[2-(2,4-Dichlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7- methyl-1 ,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the crude title compound of PREPARATION 132 following the method of EXAMPLE 54. Yield: 22% over two steps. Purity 99%.
H NMR (400 MHz, CD30D) δ ppm 8.37 ( 1 H, s), 8.14 ( 1 H, s), 7.56 ( 1 H, d, J=8.6 Hz),
7.34 ( 1 H, d, J=2.0 Hz), 7.30 ( 1 H, dd, J=8.2, 2.0 Hz), 5.53 (2H , s), 5.42 ( 1 H, dd, J=8.2,
4.7 Hz), 4.06 (3H , s), 3.09 ( 1 H, dd, J=1 5.0, 4.7 Hz), 3.02 ( 1 H, dd, J=15.0, 8.2 Hz)
HPLC/MS (4.5 min) retention time 2.52 min. LRMS: m/z 421 (M+1 , 2xCI).
EXAMPLE 67
1-({3-[2-Hydroxy-2-(2-naphthyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 140 following the method of EXAMPLE 54. Yield: 13%. Purity 98%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.45 ( 1 H, s), 8.23 ( 1 H, s), 7.77 - 7.89 (4H, m),
7.51 ( 1 H, d , J=8.6 Hz), 7.42 - 7.48 (2H, m), 5.65 ( 1 H, d , J=4.3 Hz), 5.54 (2H, s), 5.06 -
5.15 ( 1 H, m), 3.94 (3H, s), 2.99 - 3.14 (2H, m)
HPLC/MS (4.5 min) retention time 2.17 min.
LRMS: m/z 403 (M+1 ).
EXAMPLE 68
1-{[3-(2-Hydroxy-2-{4-[(trifluoromethyl)thio]phenyl}ethyl)-1,2,4-oxadiazol-5- yl]methyl}-7-methyl-1,7-dihydro-6H-purin-6-one
Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 142 following the method of EXAMPLE 54. Yield: 54%. Purity 95%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.43 ( 1 H, s), 8.22 ( 1 H, s), 7.62 ( 1 H, d , J=8.2
Hz), 7.50 ( 1 H, d , J=8.2 Hz), 5.69 ( 1 H, d , J=4.7 Hz), 5.53 (2H, s), 4.96 - 5.03 ( 1 H, m), 3.94 (3H, s), 2.99 (2H, d, J=7.0 Hz)
HPLC/MS (4.5 min) retention time 2.25 min.
LRMS: m/z 453 (M+1 ).
EXAMPLE 69
1-({3-[2-(5-Bromo-2-thienyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-7- methyl-1,7-dihydro-6H-purin-6-one Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 144 following the method of EXAMPLE 54. Yield: 15%. Purity 99%.
H NMR (400 MHz, DMSO-d6) δ ppm 8.43 ( 1 H, s), 8.22 ( 1 H, s), 7.62 (2H, d , J=8.2
Hz), 7.50 (2H, d , J=8.2 Hz), 5.69 ( 1 H, d , J=4.7 Hz), 5.53 (2H, s), 4.96 - 5.03 ( 1 H, m), 3.94 (3H, s), 2.99 (2H, d, J=7.0 Hz)
HPLC/MS (4.5 min) retention time 2.32 min.
LRMS: m/z 437, 439 (M+1 , 1*Br).
EXAMPLE 70
5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)- pyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 160 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 75%. Purity 98%.
1H NMR (400 MHz, DMSO-d6) δ 2.88 - 3.06 (m, 2H), 4.93 (m, 1H), 5.45 (s, 2H), 5.60 (d, J = 4.8 Hz, 1H), 7.09 - 7.50 (m, 4H), 8.1 1 (s, 1H), 8.53 (s, 1H).
LRMS: m/z 407 (M+1).
The enantiomers of EXAMPLE 70 were separated by preparative HPLC on an Agilent 1200 Series (AE-0010) using a Chiralpak IA column (5 mm, 30x250 mm) using the following conditions: mobile phase: 60% heptane (0.2% diethylamine) / 40% isopropanol, run time: 120 min, flow: 20 ml/min, Injection: sample dissolved in ethanol and DMSO.
EXAMPLE 70.1
(S)-5-chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Recovery: 93%. Purity 99%. Enantiomeric excess > 99%. HPLC retention time 16.2 min. (Chiralpak IA (4.6mm x 250mm, µη ) - Waters Alliance
2795, Flow rate: 1.0 mL/min, mobile phase: 60% heptane (0.2% diethylamine) / 40% isopropanol)
EXAMPLE 70.2
(R)-5-chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Recovery: 91%. Purity 99%. Enantiomeric excess > 99 % .
HPLC retention time 2 1.3 min. (Chiralpak IA (4.6mm x 250mm, µη ) - Waters Alliance
2795, Flow rate: 1.0 mL/min, mobile phase: 60% heptane (0.2% diethylamine) / 40% isopropanol)
EXAMPLE 7 1
7-Amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5- methylpyrimido[4,5-d]pyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 40 and (3-(2-(4-chlorophenyl)- 2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 50%. Purity 98%.
H NMR (400 MHz, DMSO-d6) δ 2.67 (s, 3H), 2.88 - 3.08 (m, 2H), 4.94 (m, 1H), 5.40 (s, 2H), 5.62 (d, J = 4.8 Hz, 1H), 7.1 6 - 7.42 (m, 4H), 7.55 (br s, 2H), 8.62 (s, 1H).
LRMS: m/z 414 (M+1 ).
EXAMPLE 72
7-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5- methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 7 and (3-(2-(4-chlorophenyl)- 2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 57%. Purity 97%. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.60 (s, 3H), 2.97 (d, J = 3.7 Hz, 1H), 3.00 - 3.19 (m, 2H), 5.13 (m, 1H), 5.25 (s, 2H), 7.31 (s, 4H), 7.63 (s, 1H).
LRMS: m/z 467/465 (M+1 ).
EXAMPLE 73
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5,7- dimethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 12 and (3-(2-(4-chlorophenyl)- 2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 88%. Purity 98%.
1H NMR (400 MHz, Chloroform-d) δ ppm 2.58 (s, 3H), 2.59 (s, 3H), 3.03 - 3.16 (m, 2H), 5.14 (m, 1H), 5.23 (s, 2H), 7.29 - 7.33 (m, 4H), 7.49 (s, 1H).
LRMS: m/z 401 (M+1 ).
EXAMPLE 74
5-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 161 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 61%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.91 - 3.08 (m, 2H), 4.95 (s, 1H), 5.47 (s, 2H), 5.62 (d, J = 4.2 Hz, 1H), 7.10 - 7.45 (m, 4H), 8.13 (s, 1H), 8.56 (s, 1H).
LRMS: m/z 453/455 (M+1 ).
HPLC/MS (3 min) retention time 1.50 min.
EXAMPLE 75 3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5- ethylpyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 163 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 50%. Purity 98%.
1H NMR (400 MHz, DMSO-d6) δ 1.21 (t, J = 7.5 Hz, 3H), 2.80 (q, J = 7.5 Hz, 2H), 2.89 - 3.07 (m, 2H), 4.94 (m, 1H), 5.46 (s, 2H), 5.61 (s, 1H), 7.22 - 7.39 (m, 4H), 7.83 (s, 1H), 8.42 (s, 1H).
LRMS: m/z 401 (M+1 ).
HPLC/MS (3 min) retention time 1.56 min.
EXAMPLE 76
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5- fluoropyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 164 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 15%. Purity 98%.
1H NMR (Chloroform-d, 400 MHz) δ ppm 7.77 (s, 1H), 7.68 (d, J = 4 Hz, 1H), 7.33 (s, 4H), 5.34 (s, 2H), 5.14 (m, 1H), 3.17 (dd, J = 15.6, 8.8 Hz, 1H), 3.09 (dd, J = 15.6, 4 Hz, 1H), 2.69 (d, J = 4 Hz, 1H).
LRMS: m/z 155 (M+1 ).
EXAMPLE 77
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5- (trifluoromethyl)pyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 168 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 35%. Purity 98%. 1H NMR (400 MHz, Chloroform-d) δ ppm 8.09 (s, 1H), 7.98 (s, 1H), 7.32 (s, 4H), 5.40 (s, 2H), 5 .14 (dd , J = 8.8, 4.4 Hz, 1H), 3.17 (dd, J = 15.2, 8.8 Hz, 1H), 3.09 (dd, J = 15.2, 4.4 Hz, 1H).
LRMS: m/z 44 1 (M+ 1).
EXAMPLE 78
8-Bromo-1 -((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7- methyl-1 H-purin-6(7H)-one
Synthesized from the title compound of PREPARATION 169 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield : 39%. Purity 97%.
1H NMR (400 MHz, Chloroform-d) δ ppm 3.0 1 - 3 .18 (m, 2H), 4.02 (s, 3H), 5 .11 (dd , J = 8.7, 4.2 Hz, 1H), 5.41 (d, J = 1.2 Hz, 2H), 7.27 - 7.32 (m , 4H), 8 .12 (s, 1H).
LRMS: m/z 465/467 (M+ 1).
EXAMPLE 79
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7- cyclopropyl-5-methylimidazo[5, 1-f][1 ,2,4]triazin-4(3H)-one
Synthesized from the title compound of PREPARATION 172 and the title compound of PREPARATION 173 following the method of EXAMPLE 14 . Yield : 28%. Purity 99%.
1H NMR (400 MHz, Chloroform-d) δ ppm 1.07 - 1- 13 (m, 2H), 1.16 - 1.22 (m, 2H),
2.36 (m, 1H), 2.54 (s, 3H), 3.04 - 3 .18 (m, 2H), 5 .13 (dd , J = 8.6, 4.4 Hz, 1H), 5.22 (s, 2H), 7.31 (s, 4H), 7.48 (s, 1H).
LRMS: m/z 427 (M+1 ).
EXAMPLE 80
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-ethyl-5- methylimidazo[5, 1-f][1 ,2,4]triazin-4(3H)-one Synthesized from the title compound of PREPARATION 175 and the title compound of PREPARATION 173 following the method of EXAMPLE 14. Yield: 27%. Purity 98%.
1H NMR (400 MHz, Chloroform-d) δ ppm 1.36 (t, J = 7.6 Hz, 3H), 2.59 (s, 3H), 2.96 (q, J = 7.6 Hz, 2H), 3.05 - 3.20 (m, 2H), 5.14 (dd, J = 8.5, 4.3 Hz, 1H), 5.22 (s, 2H), 7.31 (s, 4H), 7.48 (s, 1H).
LRMS: m/z 415 (M+1 ).
EXAMPLE 8 1
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-7,8- dimethyl-1H-purin-6(7H)-one
The title compound of EXAMPLE 78 (16 mg, 0.034 mmol), 2,4,6-trimethyl-1 ,3,5,2,4, 6- trioxatriborinane (24 µ , 0.172 mmol), [ 1 , 1 '-bis(diphenylphosphino)ferrocene]dichloro- palladium(ll), complex with dichloromethane (6 mg, 0.008 mmol) and potassium carbonate (15 mg, 0.190 mmol) were combined and suspended in dioxane ( 1 mL) in a Shienck tube, the mixture was evacuated and argon was introduced. The tube was then sealed and stirred and heated to 100 °C. After 24 hours, further 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (24 µ , 0.172 mmol) was added and stirring was continued for a further 24 hours. Subsequently, the mixture was diluted with ethyl acetate and the organic solution was washed with water, brine, dried and evaporated to give an oil. The oil was purified by reverse-phase chromatography using the Isolera purification system (methanol-water gradient, 0:100 rising to 100: 0) to give the title compound (2 mg, 15%) as a white solid. Purity 90%.
1H NMR (400 MHz, Chloroform-d) δ ppm 2.56 (s, 3H), 3.05 - 3.18 (m, 2H), 3.99 (s, 3H), 5.13 (dd, J = 8.2, 4.5 Hz, 1H), 5.39 (s, 2H), 7.31 (s, 4H), 8.08 (s, 1H).
LRMS: m/z 401 (M+1 ).
EXAMPLE 82
7-Amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one Synthesized from the title compound of PREPARATION 178 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield : 28%. Purity 99%.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (s, 3H), 2.89 - 3.05 (m, 2H), 4.94 (dt, J =
8.0, 5.3 Hz, 1H), 5.39 (s, 2H), 5.62 (d , J = 4.8 Hz, 1H), 6.36 (s, 1H), 6.98 (s, 2H), 7.27 - 7.42 (m, 4H), 8.47 (s, 1H).
LRMS: m/z 4 13 (M+1 ).
EXAMPLE 83
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-7- (dimethylamino)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one
Synthesized from the title compound of PREPARATION 181 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield : 43%. Purity 95%.
1H NMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H), 2.86 - 3.09 (m, 8H), 4.91 (m, 1H), 5.59 (s, 2H), 6.59 (s, 1H), 7.27 (s, 4H), 8.55 (s, 1H).
LRMS: m/z 44 1 (M+1 ).
EXAMPLE 84
5-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5- yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
Synthesized from 5-bromopyrido[3,4-d]pyrimidin-4(3H)-one (WO20 15/1 55306 Preparation 59) and (3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 12%. Purity 95%.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (s, 1H), 8.87 (s, 1H), 8.72 (s, 1H), 7.30-7.35
(m , 4H), 5.62 (d, 1H, J = 4.3 Hz), 5.52 (s, 2H), 4.93 (m , 1H), 2.96-3.03 (m , 2H).
HPLC/MS (3 min) retention time 1.50 min . LRMS: m/z 462/464 (M+1 , 1xBr).
EXAMPLE 85
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-9-ethyl-7- methyl-1 H-purine-6,8(7H,9H)-dione
Synthesized from the title compound of PREPARATION 188 and methyl iodide following the method of PREPARATION 43. Yield: 83%. Purity 99%.
1H NMR (DMSO-d6, 400 MHz) δ ppm 8.48 (s, 1H), 7.36-7.28 (m, 4H), 5.60 (d, J = 5.2 Hz, 1H), 5.50 (s, 2H), 4.95-4.90 (m, 1H), 3.82 (q, J = 7.2 Hz, 2H), 3.43 (s, 3H), 2.99 (dd, J = 14.8, 8.4 Hz, 1H), 2.94 (dd, J = 14.8, 5.6 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H).
LRMS: m/z 431 (M+1 ).
EXAMPLE 86
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-7,9- dimethyl-1H-purine-6,8(7H,9H)-dione
Synthesized from the title compounds of PREPARATIONS 49 and 173 following the method of EXAMPLE 14. The crude product was purified by reverse-phase chromatography using the Isolera purification system (methanol-water gradient, 0:100 rising to 100: 0) to give the title compound as a white solid. Yield: 17%. Purity 96%.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.92 - 3.04 (m, 2H), 3.31 (s, 3H), 3.45 (s, 3H), 4.94 (m, 1H), 5.53 (s, 2H), 5.64 (d, J = 4.8 Hz, 1H), 7.26 - 7.45 (m, 4H), 8.51 (s, 1H).
HPLC/MS (3 min) retention time 1.21 min.
LRMS: m/z 4 17 (M+1 ).
EXAMPLE 87
5-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)-2,3-dimethyl-2H- pyrazolo[3,4-d]pyrimidin-4(5H)-one Synthesized from the title compounds of PREPARATIONS 76 and 190 following the method of EXAMPLE 1. Yield: 43%. Purity 98%.
1H NMR (400 MHz, Chloroform-d) δ ppm 2.68 (s, 3H), 2.99 (s, 4H), 3.95 (s, 3H), 5.28 (s, 2H), 7.07 - 7.13 (m, 2H), 7.19 - 7.25 (m, 2H), 7.99 (s, 1H).
LRMS: m/z 385 (M+1).
EXAMPLE 88
5-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-2,3- dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
Synthesized from the title compound of PREPARATION 190 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 80%. Purity 98%.
1H NMR (400 MHz, Chloroform-d) δ ppm 2.65 (s, 3H), 2.97 - 3.19 (m, 2H), 3.93 (s, 3H), 5.1 1 (dd, J = 8.5, 4.4 Hz, 1H), 5.31 (s, 2H), 7.28 (m, 4H), 8.05 (s, 1H).
LRMS: m/z 401 (M+1 ).
EXAMPLE 89
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-2-ethyl-3- methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
Synthesized from the title compound of PREPARATION 192 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield: 66%. Purity 98%.
1H NMR (400 MHz, Chloroform-d) δ ppm 1.52 (t, J = 7.3 Hz, 3H), 2.68 (s, 3H), 2.96 (d, J = 3.7 Hz, 1H), 3.02 - 3.20 (m, 2H), 4.24 (q, J = 7.3 Hz, 2H), 5.12 (ddd, J = 8.1 , 4.9, 3.6 Hz, 1H), 5.33 (s, 2H), 7.32 (s, 4H), 7.99 (s, 1H).
LRMS: m/z 415 (M+1 ).
EXAMPLE 90 5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2- isopropyl-3-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
Synthesized from the title compound of PREPARATION 194 and (3-(2-(4- chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl methanesulfonate (PREPARATION 103) following the method of EXAMPLE 1. Yield : 71% . Purity 95%.
1H NMR (400 MHz, Chloroform-d) δ 1.56 (d , J = 6.6 Hz, 6H), 2.69 (s, 3H), 3.01 (s, 1H), 3.05 - 3 .16 (m, 2H), 4.59 (p, J = 6.6 Hz, 1H), 5.09 - 5 .16 (m, 1H), 5.30 (s, 2H),
7.3 1 (s, 4H), 7.99 (s, 1H).
LRMS: m/z 429 (M+1 ).
EXAMPLE 9 1
1-((3-(3,4-Dichlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H-purin- 6(7H)-one
Synthesized from the title compound of PREPARATION 197 and the title compound of PREPARATION 47 following the method of EXAMPLE 54. Yield : 10%. Purity 98%.
1H NMR (400 MHz, Chloroform-d) δ ppm 8 .12 (s, 1H), 7.85 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.0 1 (dd, J = 8.2, 2 .1 Hz, 1H), 5.39 (s, 2H), 4.08 (s, 3H), 3.00 (s, 4H).
LRMS: m/z 405 (M+ 1).
HPLC/MS (5 min) retention time 2.65 min .
EXAMPLE 92
6-((3-(3,4-Dichlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-1 -methyl-1 H-
[ ,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one
Synthesized from the title compound of PREPARATION 197 and the title compound of PREPARATION 52 following the method of EXAMPLE 14 . Yield : 14%. Purity 96%.
1H NMR (400 MHz, Chloroform-d) δ ppm 8 .14 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.26 (d ,
J = 2 .1 Hz, 1H), 7.00 (dd, J = 8.2, 2 .1 Hz, 1H), 5.4 1 (s, 2H), 4.47 (s, 3H), 3.00 (s, 4H). LRMS: m/z 406 (M+ 1).
HPLC/MS (3 min) retention time 1
EXAMPLE 93
1-((3-(2-(4-Chlorophenyl)-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)methyl)-7-methyl- 1H-purin-6(7H)-one
A mixture of methyl 2-(7-methyl-6-oxo-6,7-dihydro-1 H-purin-1 -yl)acetate (PREPARATION 47, 0.27 mmol), the title compound of PREPARATION 199 (0.27 mmol) and potassium carbonate (5.4 mmol) in toluene were stirred and heated to 110 °C. After 1 hour, the mixture was cooled and partitioned between dichloromethane and water and the aqueous phase was extracted with further dichloromethane. The combined organic phases were dried and concentrated in vacuo and the residue was purified by flash chromatography (dichloromethane/methanol) to give 44 mg (4 1%) of the title compound as a white solid. Purity 99%.
H NMR (CDsOD, 400 MHz) δ ppm 8.32 (s, 1H), 8 .14 (s, 1H), 7.37-7.33 (m, 2H), 7.2 1- 7 .16 (m , 2H), 5.47 (s, 2H), 4.05 (s, 3H), 3.15 (2H), 1.57 (s, 3H).
LRMS: m/z 401 (M+1 ).
EXAMPLE 94
5-Chloro-3-((3-(2-(4-chlorophenyl)-1-hydroxyethyl)-1,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-f][1,2,4]triazin-4(3H)-one
Synthesized from the title compounds of PREPARATIONS 201 and 204 following the method of EXAMPLE 14 . Yield : 6%. Purity 98%.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.0 1 (d , J = 7.0 Hz, 2H), 4.84 - 4.90 (m, 1H),
5.49 (s, 2H), 5.97 (d , J = 6 .1 Hz, 1H), 7.08 - 7.23 (m , 2H), 7.23 - 7.3 1 (m, 2H), 8 .13 (s, 1H), 8.57 (s, 1H).
LRMS: m/z 407 (M+1 ). HPLC/MS (5 min) retention time 2.48 min.
EXAM PLE 95
(S)-5-Chloro-3-((5-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-3- yl)methyl)pyrazolo[5, 1-f][1 ,2,4]triazin-4(3H)-one
Trifluoroacetic acid (0.25 mL) and water (0.05 mL) were added to a solution of the title compound of PREPARATION 209 (0.0 15 g , 0.03 mmol) in dichloromethane (0.2 mL) and the mixture was stirred at ambient temperature. After 5 hours the mixture was concentrated to dryness and the residue was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The organic extract was dried and evaporated in vacuo and the residue was purified by reverse-phase chromatography using the Isolera purification system to give the title compound (0.009 g , 77%) as a white solid .
1H NMR (400 MHz, Chloroform-d) δ ppm 7.82 (s, 1H), 7.75 (s, 1H), 7.36-7-30 (m, 4H), 5.25 (s, 2H), 5.23 (dd, J = 9.0, 4.0 Hz, 1H), 3.31 (dd , J = 16.0, 9.0 Hz, 1H), 3.22 (dd , J = 16.0, 4.0 Hz, 1H).
LRMS: m/z 407 (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 F 12 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 µ Ι of dye solution (FLI PR
Calcium 5 Express Kit, Molecular Devices) for 1 h at room temperature in the presence of 250 µ Μ 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 µ Ι of compound plate content were added by the FLI PR 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 µ Ι of AITC were added by the FLIPR into the plates to reach a concentration of 1 µΜ (approximately AITC EC80) and fluorescence intensity recorded for 3 extra minutes to assess compound inhibition. Peak and base line were taken for the calculation of the ratio (Peak/Base Line). Percentage activation or Inhibition for each compound was calculated by normalizing compound ratios to maximal and minimal ratios obtained for 100 µΜ and 1 µΜ of AITC, for agonist and antagonist mode respectively, as total response and vehicle (0.1% DMSO) for basal response.
In the following table, IC50 values are represented by letters according to the value:
A : < 100 nM
B: 100 - 1000 nM
C: > 1000 nM 18 A
19 A 20 A
2 1 B 32 B 33 A 34 C 35 B 36 B 37 B 38 B 39 A 40 A
4 1 A 42 B 43 B 44 B 45 C 46 A 47 B 48 A 49 C 50 C
5 1 A
5 1. 1 A
5 1.2 B 52 A 52.1 A 52.2 B 53 A 54 B 55 B 56 B 57 A 58 B 59 B 60 B
6 1 B 62 B 63 B 64 B 65 C 66 B 67 A 68 B 69 B 70 A 70.1 A 70.2 B
7 1 A 72 A 73 A 74 A 75 B 76 A 77 B 78 A 79 A 80 A
8 1 B 82 A 83 B 84 A 85 A 86 A 87 B 88 A 89 A 90 A
9 1 A Without being bound by theory, it seems that when L group represents an ethylene group substituted by a hydroxyl group, the compounds of the present invention show better metabolic profile.
COMBINATIONS
The compounds of the invention may also be combined with other active compounds in the treatment of diseases indicated above. For example the compounds of the present invention can be combined with active substances which are known to be useful in the treatment of these diseases.
Examples of such active substances are:
a . Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone;
b. Calcineurin inhibitors, such as cyclosporine A , tacrolimus, pimecrolimus or voclosporin;
c. Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR- 845;
d . Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant;
e. Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine;
f. Histamine 1 (H1 ) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine or cetirizine;
g . Antiinflammatory agents, such as anti-l L31 , Phosphodiesterase IV inhibitors NSAIDs, JAK inhibitors or Syk inhibitors; h. Analgesics, such as paracetamol or opioids; i. Leukotriene receptor antagonists, such as 5-lipoxygenase inhibitors, 5- lipoxygenase activating protein inhibitors; j . Dihydrofolate reductase inhibitors, such as methotrexate or pralatrexate; k. Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or ASLAN-003 or LAS1 86323;
I. Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; m. Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine; n. Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin or mizoribine; o. Fumaric acid esters, such as dimethyl fumarate; p. Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol; q . Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin; r. Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab; s. Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC-1 1050; t. Anti-lnterleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061 ; u. Anti-lnterleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) antibody, such as ustekinumab; v. Anti-lnterleukin 17 Receptor (IL-17R) antibody, such as brodalumab; w. Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; x . Anti-lnterleukin 5 (IL-5) antibody, such as mepolizumab; y. Anti-lnterleukin 5 Receptor (IL-5R) antibody, such as benralizumab; z . Anti-lnterleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab; aa. Anti-lnterleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody, such as dupilumab;
bb. Anti-lnterleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab;
cc. Anti-lnterleukin 1 Receptor ( IL-1 R) antibody
dd. Anti-lnmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab;
ee. Anti-B-cell activating factor (BAFF), such as belimumab or atacicept;
ff. Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as blinatumomab, MEDI-551 or MOR-208;
gg. Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast, masilukast;
hh. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981 , ADC-3680, ARRY-502 or setipripant;
ii. Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths.
Accordingly, another embodiment of the invention is a combination product comprising (i) at least a bicyclic heterocycle derivative as defined previously, and (ii) one or more active ingredients as described above, for simultaneous, separate or sequential use in the treatment of the human or animal body.
The combinations of the invention may be used in the treatment of disorders which are susceptible to amelioration by TRPA1 inhibition or antagonism. Thus, the present application encompasses methods of treatment of these disorders, as well as the use of the combinations of the invention in the manufacture of a medicament for the treatment of these disorders.
The amount of each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disease or disorder being treated. However, an effective dosage is typically in the range of 0.01-3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day.
The active ingredients may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. Preferably, the active ingredients are administered once or twice a day, most preferably once a day.
The active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
PHARMACEUTICAL COMPOSITIONS
Pharmaceutical compositions according to the present invention comprise the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier.
As used herein, the term pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, /V-oxides, tautomers, stereoisomers, or isotopically-labelled derivatives thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
As used herein, a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
A pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
The invention further provides pharmaceutical compositions comprising the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents such as the previously described for use in the treatment of a pathological condition or disease susceptible to amelioration by TRPA1 antagonists or inhibitors, in particular wherein the pathological condition or disease is selected from acute and/or chronic pain, acute and/or chronic pruritus, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
The invention is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological disease or disorder susceptible to amelioration by TRPA1 antagonists or inhibitors, in particular wherein the pathological disease or disorder is as described above.
The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by TRPA1 receptor antagonists in particular wherein the pathological condition or disease is as described above, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a compound of Formula (I) or a pharmaceutically acceptable salts, solvates, /V-oxides, tautomers, stereoisomers, or isotopically-labelled derivatives thereof, in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001% to 99% by weight, preferably 0.01% to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application. Preferably the compositions are made up in a form suitable for oral, oral mucosa, inhaled, topical, nasal mucosa, rectal/intravaginal, percutaneous, parenteral, ocular or aural administration. More preferably the compositions are made up in a form suitable for oral administration.
Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001 .
The pharmaceutically acceptable excipients which are admixed with the active compound or a pharmaceutically acceptable salts, solvates, /V-oxides, tautomers, stereoisomers, or isotopically-labelled derivatives thereof, to form the compositions of this invention are well-known perse 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, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001 .
i) Oral Administration
The compounds of the invention may be administered orally (peroral administration; peros (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 mucosa administration
The compounds of the invention can also be administered via the oral mucosa administration. Within the oral mucosa cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosa membranes lining the floor of the mouth, (b) buccal delivery, which is drug administration through the mucosa membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.
Pharmaceutical products to be administered via the oral mucosa can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, polyisobutylene or polyisoprene); and oral mucosa permeation enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulphate and others)
iii) Inhaled administration
The compounds of the invention can also be administered by inhalation, typically in the form of a dry powder from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
iv) Nasal mucosa administration
The compounds of the invention may also be administered via the nasal mucosa.
Typical compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents.
v) Parenteral Administration
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
vi) Topical Administration
The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection.
vii) Rectal/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 and aural Administration
Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysacchande polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
ix) Other Technologies
Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
The following preparations forms are cited as formulation examples:
Formulation Example 1 (Oral suspension) Dye 0,5 mg
Distilled water q.s. to 100 ml
Formulation Example 2 (Hard gelatine capsule for oral administration)
Modifications, which do not affect, alter, change or modify the essential aspects of the compounds, combinations or pharmaceutical compositions described, are included within the scope of the present invention. CLAIMS
1. A bicyclic heterocycle derivative for use in the treatment of the human or animal body, which bicyclic heterocycle derivative is a compound of Formula ( I), or a pharmaceutically acceptable salt, or a solvate, or a /V-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:
Formula ( I)
wherein :
G is selected from the group consisting of a C atom and a N atom;
G2, G ,G4 and G5 are each independently selected from the group consisting of a C(R a) group, a N(R ) group and N atom;
G6 is a N atom, G7 is a C atom, G8 is a N atom and G9 is a O atom;
Ra is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a linear or branched Ci-4alkoxy group, a linear or branched Ci-4haloalkyl group, a linear or branched Ci-4haloalkoxy group, an
oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a C1-4 monoalkylamino group, a Ci-4dialkylamino group and a hydroxyl group;
R is selected from the group consisting of a H atom and a linear or branched
C1-4 alkyl group;
L represents a linear or branched C2-4 alkylene group unsubstituted or substituted by one or more substituents selected from a halogen atom, a
hydroxyl group, a linear or branched C1-4 alkyl group, a linear or branched C1-4
alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched Ci- 4 haloalkoxy group and a -NR'R" group; a -C(R )=C(R )- group; a C3-7
cycloalkylene group of formula (i); a -(CH2)2-3 -0- group; a -(CH2)i-2-C(0)- group; a -(CH2)i-2-S- group; a -(CH2)i-2-S(0)- group; a -CONH- group; a -CF2O- group; and a 4- to 6-membered N-containing heterocyclylene group, wherein at least one nitrogen atom is linked the G7 group;
(1)
wherein R' and R" each independently represent a hydrogen atom, a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 haloalkyl group;
• Q is selected from the group consisting of a monocyclic or bicyclic C 6-i4aryl group and a monocyclic or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N, O and S;
wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, a linear or branched C1-4 thioalkyl group, a linear or branched C1-4 halothioalkyl group and a cyano group;
• or when Q represents a phenyl group, L together with Q form a 5- to 7- membered N-containing heterocyclyl fused to the phenyl group;
• n is 0 or 1; and
• represents a single or a double bond;
wherein the bicyclic heterocycle derivative is other than:
• 3-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)pyrimido[4,5-d]pyrimidin- 4(3H)-one • 6-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-1 -methyl-1 H- pyrazolo[4,3-d]pyrimidin-7(6H)-one • 1-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H-purin- 6(7H)-one 2 . A bicyclic heterocycle derivative for use according to claim 1 wherein
• G4 is selected from the group consisting of a C-H group and a N atom; and/or
• G5 is selected from the group consisting of a C(R a) group and a N(R ) group.
3 . A bicyclic heterocycle derivative for use according to claims 1 or 2 , wherein the compound of Formula (I) is represented by compounds from Formula (la) to Formula
(ig):
Formula (la) Formula (lb) Formula (lc)
Formula (Id) Formula (le) Formula (If)
4 . A bicyclic heterocycle derivative for use according to any one of the preceding claims wherein Ra is selected from the group consisting of a H atom, a linear or branched Ci-3 alkyl group, a halogen atom, a linear or branched Ci-2 alkoxy group, an oxo group, a cyano group, an amino group, a Ci-2 rmonoalkylamino group and a hydroxyl group; preferably Ra is selected from the group consisting of a H atom, a linear or branched C1-2 alkyl group, a chlorine atom, a methoxy group, an oxo group, a cyano group, an amino group, a methylamino group and a hydroxyl group. 5 . A bicyclic heterocycle derivative for use according to any one of the preceding claims wherein R is selected from the group consisting of a H atom and a linear or branched Ci-3 alkyl group, preferably R is a H atom or a linear or branched Ci-2 alkyl group.
6 . A bicyclic heterocycle derivative for use according to any one of the preceding claims wherein L represents an ethylene group unsubstituted or substituted by one or more substituents selected from a fluorine atom, a methyl group, a hydroxyl group and a methoxy group; a-C(H)=C(H)- group; a-C(H)=C(Me)- group; a cyclopropylene group according to formula (i); a -(CH2)2-0- group; a -(CH2)-C(0)- group; a -(CH2)-S- group; a -(CH2)-S(0)- group; a -CONH- group; an azetidinylene group of formula (ii) and a pyrrolidylene group of formula (iii) wherein the nitrogen atom is linked to the G7 group.
(ii) (iii)
7 . A bicyclic heterocycle derivative for use according to any one of the preceding claims wherein Q is selected from the group consisting of a phenyl group, a naphthyl group, a quinolinyl group and a thienyl group;
wherein the phenyl, naphthyl, quinolinyl and thienyl groups are unsubstituted or substituted by one or more substituents selected from a chlorine atom, a bromine atom, a -CF3 group, a -OCF3 group, a -SCF3 group and an isopropyl group; or when Q represents a phenyl group, L together with Q form a pyrrolidinyi and piperidinyi fused to the phenyl group, forming a ring of formula (viii) or (ix).
(viii) (ix)
8 . A bicyclic heterocycle derivative for use according to any of the preceding claims, wherein the compound of Formula (I) is represented by compounds from Formula (Ip) to Formula (Iv): Formula (lp) Formula (Iq) Formula (Ir)
Formula (Is) Formula (It) Formula (lu)
Formula (Iv)
wherein:
• Ra is selected from the group consisting of a H atom, a linear or branched C1-2 alkyl group or an oxo group;
• R is independently selected from the group consisting of a H atom or a linear
or branched C1-2 alkyl group;
• L represents an ethylene group substituted by a hydroxyl group; and • Q is selected from the group consisting of a phenyl group, a naphthyl group, a quinolinyl group and a thienyl group;
wherein the phenyl, naphthyl, quinolinyl and thienyl groups are unsubstituted or substituted by one or more substituents selected from a chlorine atom, a bromine atom, a -CF3 group, a -OCF3 group, a -SCF3 group and an isopropyl group.
9 . A bicyclic heterocycle derivative for use according to claim 1 which is one of
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylquinazolin-4(3H)- one 3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2 4-oxadiazol-5-yl}methyl)imidazo[5 1-f][1 2,4]triazin- 4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2 4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(3-Chlorophenyl)ethyl]-1 ,2,4K)xadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5,7-dimethylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2 4-oxadiazol-5-yl}methyl)-4-oxo-3,4- dihydroimidazo[5,1-f][1 ,2,4]triazine-5-carbonitrile
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-5-methyl-7- (methylamino)imidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2 4-oxadiazol-5-yl}methyl)-5-methylpyrazolo[5,1- f][1 ,2,4]triazin-4(3H)-one
6-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one
5-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one
5-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,5-dihydro- 4H-pyrazolo[3,4-d]pyrimidin-4-one
1,3-Dimethyl-5-{[3-(2-phenylethyl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one
6-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
1-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-7 9-dimethyl-7,9-dihydro- 1H-purine-6,8-dione
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazine-4,7(3H,6H)-dione
7-Chloro-3-({3-[2-(4-chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one
3-({3-[2-(4-Chlorophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methoxy-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one 3-({3-[2-(4-Chlorophenyl)ethyl]-1 2 4-oxadiazol-5-yl}methyl)-5-methylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione
3-({3-[2-(4-Chlorophenyl)ethyl]-1 2 4-oxadiazol-5-yl}methyl)-5 8-dimethylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione
7-Amino-3-({3-[2-(4-chlorophenyl)ethyl]-1 2,4-oxadiazol-5-yl}methyl)-5- methylpyrimido[4,5-d]pyrimidin-4(3H)-one
1-({3-[2-(3-Bromophenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7-dihydro-6H- purin-6-one
1-[(3-{[(4-Chlorophenyl)thio]methyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7-methyl-1 ,7-dihydro- 6H-purin-6-one
5-[(3-{[(4-Chlorophenyl)thio]methyl}-1 ,2,4-oxadiazol-5-yl)methyl]-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
5-[(3-{[(4-Chlorophenyl)sulfinyl]methyl}-1 ,2,4-oxadiazol-5-yl)methyl]-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
6-({3-[(E)-2-(4-Chlorophenyl)vinyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro- 7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[(1 E)-2-(4-Chlorophenyl)prop-1 -en-1 -yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl- 1,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one trans 6-({3-[2-(4-Chlorophenyl)cyclopropyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
3-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5-methylimidazo[5,1- f][1 ,2,4]triazin-4(3H)-one
6-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
1-({3-[2-(4-Chlorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7-dihydro-6H- purin-6-one
5-{[3-(1 ,3-Dihydro-2H-isoindol-2-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
1-{[3-(1 ,3-Dihydro-2H-isoindol-2-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-7-methyl-1 ,7-dihydro- 6H-purin-6-one
5-{[3-(3,4-Dihydroisoquinolin-2(1 H)-yl)-1 ,2,4-oxadiazol-5-yl]methyl}-1 ,3-dimethyl-1 ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 5-({3-[3-(4-Chlorophenyl)azetidin-1-yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
5-({3-[3-(4-Chlorophenyl)pyrrolidin-1 -yl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 ,3-dimethyl-l ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
N-(4-Chlorophenyl)-5-[(1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)methyl]-1 ,2,4-oxadiazole-3-carboxamide
6-({3-[2-(4-Chlorophenyl)propyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6-dihydro-7H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-fluoroethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-methoxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-oxoethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one Ent 1
6-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one Ent 2
3-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
(S)-3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
(R)-3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
1-({3-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-[(3-{2-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1 ,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(3-Bromophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one 1-[(3-{2-Hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7- methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(4-Bromophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-[(3-{2-Hydroxy-2-[3-(trifluoromethoxy)phenyl]ethyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7- methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(3,4-Dichlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-[(3-{2-[2-Fluoro-4-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1 ,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
1-[(3-{2-Hydroxy-2-[4-(trifluoromethoxy)phenyl]ethyl}-1 ,2,4-oxadiazol-5-yl)methyl]-7- methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-Hydroxy-2-(4-isopropylphenyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-[(3-{2-[4-Chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethyl}-1 ,2,4-oxadiazol-5- yl)methyl]-7-methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(2-Chlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-{[3-(2-Hydroxy-2-quinolin-2-ylethyl)-1 ,2,4-oxadiazol-5-yl]methyl}-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-({3-[2-(2,4-Dichlorophenyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-({3-[2-Hydroxy-2-(2-naphthyl)ethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
1-{[3-(2-Hydroxy-2-{4-[(trifluoromethyl)thio]phenyl}ethyl)-1 2,4-oxadiazol-5-yl]methyl}-7- methyl-1 ,7-dihydro-6H-purin-6-one
1-({3-[2-(5-Bromo-2-thienyl)-2-hydroxyethyl]-1 ,2,4-oxadiazol-5-yl}methyl)-7-methyl-1 ,7- dihydro-6H-purin-6-one
5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-fl[1 ,2,4]triazin-4(3H)-one
(S)-5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-fl[1 ,2,4]triazin-4(3H)-one (R)-5-Chloro-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-1][1 ,2,4]triazin-4(3H)-one
7-Amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrimido[4,5-d]pyrimidin-4(3H)-one
7-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2 4-oxadiazol-5-yl)methyl)-5,7- dimethylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
5-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-1][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- ethylpyrazolo[5,1-fl[1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- fluoropyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- (trifluoromethyl)pyrazolo[5,1-f][1 ,2,4]triazin-4(3H)-one
8-Bromo-1-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7- methyl-1 H-purin-6(7H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-cyclopropyl-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-ethyl-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 2 4-oxadiazol-5-yl)methyl)-7,8-dimethyl- 1H-purin-6(7H)-one
7-Amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one
3-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7- (dimethylamino)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one
5-Bromo-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-9-ethyl-7- methyl-1 H-purine-6 8(7H,9H)-dione 1-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 2,4-oxadiazol-5-yl)methyl)-7,9-dimethy 1H-purine-6,8(7H,9H)-dione
5-((3-(4-Chlorophenethyl)-1 2 4-oxadiazol-5-yl)methyl)-2 3-dimethyl-2H-pyrazolo[3,4- d]pyrimidin-4(5H)-one
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 2 4-oxadiazol-5-yl)methyl)-2,3-dimethyl- 2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-ethyl-3- methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
5-((3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-isopropyl-3- methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
1-((3-(3,4-Dichlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H-purin-6(7H)- one
6-((3-(3,4-Dichlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-1 -methyl-1 H-
[ 1 ,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one
1-((3-(2-(4-Chlorophenyl)-2-hydroxypropyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H- purin-6(7H)-one
5-Chloro-3-((3-(2-(4-chlorophenyl)-1-hydroxyethyl)-1 ,2,4-oxadiazol-5- yl)methyl)pyrazolo[5,1-fl[1 ,2,4]triazin-4(3H)-one or a pharmaceutically acceptable salt, solvate, /V-oxide, tautomer, stereoisomer, isotopically-labelled derivative thereof.
10. A bicyclic heterocycle derivative as defined in any one of claims 1 to 9 , for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition or antagonism of TRPA1 .
11. A bicyclic heterocycle derivative for use according to any one of claims 1 to 10, wherein the treatment is of a pathological condition or disease selected from acute and/or chronic pruritus, acute and/or chronic pain, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
12. A pharmaceutical composition comprising a bicyclic heterocycle derivative as defined in any one of claims 1 to 9 in association with a pharmaceutically acceptable diluent or carrier. 13. Use of a bicyclic heterocycle derivative as defined in any one of claims 1 to 9, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claim 10 or 11.
14. A method for treating a subject afflicted with a pathological condition or disease as defined in claim 10 or 11, which comprises administering to said subject a therapeutically effective amount of a bicyclic heterocycle derivative as defined in any one of claims 1 to 9 , or a pharmaceutical composition as defined in claim 12.
15. A combination product comprising (i) at least one bicyclic heterocycle derivative as defined in any one of claims 1 to 9 , and (ii) one or more active ingredients selected from:
a . Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone;
b. Calcineurin inhibitors, such as cyclosporine A , tacrolimus, pimecrolimus or voclosporin;
c. Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR- 845;
d . Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant;
e. Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine;
f. Histamine 1 (H1 ) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine or cetirizine;
g . Antiinflammatory agents (such as anti-l L31 , Phosphodiesterase IV inhibitors NSAIDs, JAK inhibitors or Syk inhibitors);
h. Analgesics (such as paracetamol or opioids);
i. Leukotriene receptor antagonists (such as 5-lipoxygenase inhibitors, 5- lipoxygenase activating protein inhibitors) j . Dihydrofolate reductase inhibitors, such as methotrexate or pralatrexate; k. Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or ASLAN-003 or LAS1 86323;
I. Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; m. Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine; n. Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin or mizoribine; o. Fumaric acid esters, such as dimethyl fumarate; p. Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol; q . Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin; r. Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab; s. Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC-1 1050; t. Anti-lnterleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061 ; u. Anti-lnterleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) antibody, such as ustekinumab; v. Anti-lnterleukin 17 Receptor (IL-17R) antibody, such as brodalumab; w. Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; x . Anti-lnterleukin 5 (IL-5) antibody, such as mepolizumab; y. Anti-lnterleukin 5 Receptor (IL-5R) antibody, such as benralizumab; z . Anti-lnterleukin 13 (IL-1 3) antibody, such as lebrikizumab or tralokinumab; aa. Anti-lnterleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody, such as dupilumab; bb. Anti-lnterleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab;
cc. Anti-lnterleukin 1 Receptor ( IL-1 R) antibody
dd. Anti-lnmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab;
ee. Anti-B-cell activating factor (BAFF), such as belimumab or atacicept;
ff. Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as blinatumomab, MEDI-551 or MOR-208;
gg. Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast, masilukast;
hh. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981 , ADC-3680, ARRY-502 or setipripant; or
ii. Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths. for simultaneous, separate or sequential use in the treatment of the human or animal body.
16. A bicyclic heterocycle derivative, which bicyclic heterocycle derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a N- oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof :
Formula (I) wherein:
• G is selected from the group consisting of a C atom and a N atom;
• G2, G ,G4 and G5 are each independently selected from the group consisting of a C(Ra) group, a N(R ) group and N atom; • G6 is a N atom, G7 is a C atom, G8 is a N atom and G9 is a O atom;
• Ra is selected from the group consisting of a H atom, a linear or branched C1-4
alkyl group, a halogen atom, a linear or branched Ci-4alkoxy group, a linear or
branched Ci-4 haloalkyl group, a linear or branched Ci-4 haloalkoxy group, an
oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a C1-4
monoalkylamino group, a Ci-4dialkylamino group and a hydroxyl group;
• R is selected from the group consisting of a H atom and a linear or branched
C1-4 alkyl group;
• L represents a linear or branched C2-4 alkylene group unsubstituted or substituted by one or more substituents selected from a halogen atom, a
hydroxyl group, a linear or branched C1-4 alkyl group, a linear or branched C1-4
alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched Ci-
4 haloalkoxy group and a -NR'R" group; a -C(R )=C(R )- group; a C3-7
cycloalkylene group of formula (i); a -(CH2)2 -3 -0- group; a -(CH2)i-2-C(0)- group;
a -(CH2)i-2-S- group; a -(CH2)i-2-S(0)- group; a -CONH- group; a -CF2O- group; and a 4- to 6-membered N-containing heterocyclylene group, wherein at least one nitrogen atom is linked to the G7 group;
(1)
wherein R' and R" each independently represent a hydrogen atom, a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 haloalkyl group;
• Q is selected from the group consisting of a monocyclic or bicyclic C 6-i4 aryl group and a monocyclic or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N, O and S;
wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, a linear or branched C1-4 thioalkyl group, a linear or branched C1-4 halothioalkyl group and a cyano group; • or when Q represents a phenyl group, L together with Q form a 5- to 7- membered N-containing heterocyclyi fused to the phenyl group;
• n is 0 or 1; and
represents a single or a double bond;
wherein the bicyclic heterocycle derivative is other than:
• 3-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)pyrimido[4,5-d]pyrimidin- 4(3H)-one • 6-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-1 -methyl-1 H- pyrazolo[4,3-d]pyrimidin-7(6H)-one • 1-((3-(4-Chlorophenethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-7-methyl-1 H-purin- 6(7H)-one
17. A bicyclic heterocycle derivative according to claim 16, which bicyclic heterocycle derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or solvate, or /V-oxide, or tautomer or an isotopically-labelled derivative thereof, as defined in any one of claims 2 to 9 . A . CLASSIFICATION O F SUBJECT MATTER INV. A61K31/522 A61P13/00 A61P17/00 A61P29/00 ADD.
According to International Patent Classification (IPC) o r t o both national classification and IPC
B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
EPO-Internal , BIOSIS, EMBASE, WPI Data
C . DOCUMENTS CONSIDERED TO B E RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
KURUMURTHY C ET AL: "Synthesi s of novel 1-17 al kyl tri azol e tagged pyri o [2 ,3-d] pyrimi i ne deri vati ves and thei r anti cancer acti vi ty" , EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCI ENTI FIQUE ELSEVI ER, PARIS, FR, vol . 46, no. 8 , 4 May 2011 (2011-05-04) , pages 3462-3468, XP028377969 , ISSN : 0223-5234, D0I : 10. 1016/J . EJMECH .2011 .05 .011 [retri eved on 2011-05-12] page 3463 - page 3465
0 03/042214 A2 (CV THERAPEUTICS INC [US] ) 1-17 22 May 2003 (2003-05-22) the whol e document
□ Further documents are listed in the continuation of Box C . See patent family annex.
* Special categories of cited documents : "T" later document published after the international filing date o r priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle o r theory underlying the invention to be of particular relevance "E" earlier application o r patent but published o n o r after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel o r cannot b e considered to involve a n inventive "L" documentwhich may throw doubts o n priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation o r other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve a n inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition o r other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family
Date of the actual completion of the international search Date of mailing of the international search report
8 December 2016 16/12/2016
Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Al bayrak, Timur Patent document Publication Patent family Publication cited in search report date member(s) date
WO 03042214 A2 22-05-2003 AT 520694 T 15- 09 2011 AU 2002359365 A2 26-05 2003 CA 2466477 Al 22- 05 2003 CN 1585769 A 23- 02 2005 CY 1112459 Tl 09- 12 2015 DK 1444233 T3 17-10 2011 EP 1444233 A2 11- 08 2004 HK 1071127 Al 25-11 2011 HU 0401925 A2 28- 0 1 2005 I L 161867 A 29- 0 1 2015 P 4350517 B2 21- 10 2009 P 2005509036 A 07-04 2005 KR 20050044361 A 12- 05 2005 MX PA04004388 A 16- 05 2005 NO 329692 Bl 06-12 2010 NZ 532816 A 25-11 2005 PT 1444233 E 29-09 2011 RU 2318824 C2 10- 03 2008 US 2003139428 Al 24- 07 2003 US 2005038045 Al 17- 02 2005 O 03042214 A2 22- 05 2003