PDE9 inhibitors with imidazo triazinone backbone

专利摘要:
This invention is directed to compounds, which are PDE9 enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides processes for the preparation of the compounds of formula (I). The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I). The present invention further provides a compound of formula(l) for use in a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I).
公开号:AU2013213603A1
申请号:U2013213603
申请日:2013-01-25
公开日:2014-07-24
发明作者:Karsten Juhl；Morten Langgard；Lars Kyhn Rasmussen；Klaus Baek Simonsen；Niels Svenstrup；Yazhou WANG；Kate Wen
申请人:H Lundbeck AS；
IPC主号:C07D487-04

专利说明:
WO 2013/110768 PCT/EP2013/051451 1 PDE9 inhibitors with imidazo triazinone backbone FIELD OF THE INVENTION The present invention relates to cyclic guanylate monophosphate (cGMP)-specific phos 5 phodiesterase type 9 inhibitors (hereinafter referred to as PDE9 inhibitors) of the form 3H imidazo[5,1-f][1,2,4]triazin-4-ones for the use as a medicament. Moreover the invention re lates to a pharmaceutical composition comprising 3H-imidazo[5,1-f][1,2,4]triazin-4-ones, as well as a process for preparation of the compounds. BACKGROUND OF THE INVENTION 10 The phosphodiesterases (PDEs) are a superfamily of enzymes that metabolically inactivate the ubiquitous intracellular messengers cAMP and cGMP. This function involves the PDEs in a broad range of important cellular functions, such as immune response, memory, and vision. The human genome encodes for 21 PDEs that are categorized into 11 families (Mehats C, Andersen CB, Filopanti M, Jin SL, Conti M. "Cyclic nucleotide phosphodiesterases and their 15 role in endocrine cell signaling." Trends Endocrinol Metab. 2002;13:29-35). These enzymes share a conserved catalytic domain of approximately 300 amino acids that is located in the C terminal region of the protein. The N-terminal regions, which vary among different PDEs, serve regulatory functions including autoinhibition of the catalytic domains or control of sub cellular localization (Mehats 2002). The PDEs have different substrate preferences: Cyclic 20 guanylate monophosphate (cGMP)-specific phosphodiesterase type 9 (PDE9) is a member of the PDE enzyme family that selectively hydrolyses cGMP over cAMP (D A Fisher et al., J. Biol. Chemistry, vol. 273, No. 25, 15559-15564 (1998)). The different substrate preferences, combined with different expression profiles, cellular compartmentalization, and regulation, al low the PDEs to play a very versatile role in cell signal transduction (Breer H, Boekhoff 1, 25 Tareilus E. "Rapid kinetics of second messenger formation in olfactory transduction." Nature. 1990;345:65-68). PDE9 inhibitors have been reported as useful to treat cardiovascular disorders (WO 03/037899), and insulin resistance syndrome, hypertension, and/or type 2 diabetes (WO 03/037432) as well as for treatment of obesity related conditions (WO/2005/041972). 30 Wunder F. et al (Mol. Pharmacol. 2005 Dec; 68(6):1775-81, 2005) report the in vitro characte rization of 1 -(2-chlorophenyl)-6-[(2 R)-3,3,3-trifluoro-2-methylpropyl]-1,5-d ihyd ro-4 H pyrazolo[3,4-d]pyrimidine-4-one, a selective inhibitor of phosphodiesterase 9 (PDE9), which is WO 2013/110768 PCT/EP2013/051451 2 under development for the treatment of Alzheimer's disease. This compound is reported to inhibit human (IC50 = 55 nM) and murine (IC50 = 100 nM) PDE9 activity in vitro. Over the years convincing experimental evidence has accumulated supporting the cognition enhancing properties of several classes of PDE-inhibitors (Blokland et al., 2006: "Improving 5 memory; a role for phosphordiesterases", Current Pharmacological Design 12, 2511-2523). In a later study van der Staay et al. (F. Josef van der Staay, Neuropharmacology Volume 55, Issue 5, October 2008, pages 908-918) concludes that the PDE9 inhibitor 1-(2-chlorophenyl) 6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one may act as a putative cognition enhancer. 10 WO 2012/040230 (Envivo Pharmaceuticals, Inc) is directed to imidazotriazinone compounds which ar claimed to be inhibitors of phosphordiesterease 9. Alzheimers disease is the most common form of dementia, it is incurable, degenerative, and terminal. The typical symptoms are cognitive difficulties, difficulties with executive functioning (such as planning, organization, mental flexibility and task coordination) as well as with per 15 ception (agnosia) and execution of movements (apraxia). Because AD cannot be cured and is degenerative, palliative treatment of patients is essential. SUMMARY OF THE INVENTION The present invention discloses novel PDE9 inhibitors for the use as a medicament, such as 20 in the treatment of patients suffering from cognitive impairments, in particular cognitive im pairments that relate to neurodegenerative diseases such as cortical dementia (e.g. Alz heimer's disease) or subcortical dementia, e.g. AIDS related dementia. The PDE9 inhibitors of the present invention have the structure I (i.e. a 3H-imidazo[5,1 f][1,2,4]triazin-4-one backbone): o R5 HN R1 N N R2,N',A R4 I R3 25 (I) WO 2013/110768 PCT/EP2013/051451 3 wherein R2 is cyclized with either R1 or R3. The invention relates to methods of improving conditions involving PDE9, such as cognition, 5 in particular the invention relates to a method of treating diseases involving cognitive difficul ties, difficulties with executive functioning (such as planning, organization, mental flexibility and task coordination) as well as with pereception (agnosia). The methods of improving con ditions involving PDE9 and/or treating diseases involving PDE9 comprises the administration of a compound of the present invention or a pharmaceutically acceptable salt, solvate or 10 prodrug thereof to a patient in need thereof. The compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof may be in the form of a pharma ceutical composition. In a further aspect the invention relates to an improved pharmaceutical composition compris ing a compound of the present invention particularly useful for the treatment of cognitive diffi 15 culties, difficulties with executive functioning (such as planning, organization, mental flexibility and task coordination) as well as with pereception (agnosia), in particular when associated neurodegenerative diseases, such as cortical or subcortical dementias, e.g. Alzheimer's dis ease (AD). DETAILED DESCRIPTION OF THE INVENTION 20 Cognitive impairment includes a decline in cognitive functions or cognitive domains, such as, e.g., difficulties with attention, learning, memory and executive function (relevant reactions to external stimuli). Cognitive impairment also may include: deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulty in expressing thoughts and/or integrating thoughts, feelings 25 and behaviour, and/or extinction of irrelevant thoughts, and difficulty in attention and vigi lance, verbal learning and memory, visual learning and memory, speed of processing, social cognition, reasoning and problem solving, e.g., executive functioning. There are presently no effective drugs for the treatment of cognitive disorders on the market and there is a great need and demand for drugs effective in the treatment of such disorders. 30 Without being limited to any specific theory it is believed that the mode of action of PDE9 in hibitors can be understood in the light of the following neurological processes: guanylyl cy clase (alt. guanylate cyclase) converts guanosine triphosphate (GTP) to cyclic guanosine WO 2013/110768 PCT/EP2013/051451 4 monophosphate (cGMP), which in turn activates cGMP-dependent protein kinase G (PKG). PKG is known to lower the threshold for the induction of long-term potentiation (LTP), i.e. the long-lasting improvement in communication between neurons (Zhou et al., 1994: "Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation", Nature 368, 5 635-639). The communication between neurons takes place via the chemical synapses (syn aptic transmission) and because memories are believed to be stored within these synapses, LTP is considered one of major cellular mechanisms that underlies cognition (Boron, W. F., 2005: Medical Physiology: A Cellular and Molecular Approach. Elsevier/Saunders, ISBN 1 4160-2328-3 and Cooke et al., 2006 "Plasticity in the human central nervous system". Brain 10 129, 1659-1673). As a result high levels of cGMP will eventually lead to improvement of cog nition via the activation of PKG. The level of cGMP can be increased by inhibition of PDE9, which - as mentioned above - has the highest affinity for cGMP of any of the PDEs. Accord ingly, PDE9 inhibitors will improve synaptic transmission and thereby enhance cognitive per formance as evidenced by the results presented in the experimental section. 15 The invention will be illustrated in the following non-limiting examples. Embodiments according to the invention In a first embodiment (El) the present invention relates to compounds having the structure (1) (also referred to as compounds of formula (1)) O R5 HN$N R2, NA R4 R3 20 () wherein R2 is cyclized with either R1 or R3, wherein R1, R2 and R3 are R1, when cyclized with R2, is WO 2013/110768 PCT/EP2013/051451 5 -C- R6 H wherein R6 is selected from the group consisting of H, -CH 3 , -C 2
H
5 , and -C 3
H
7 , wherein * denotes the cyclization point, and R1, when not cyclized, is selected from the group consisting of H C - R6 5 H and H wherein R6 is selected from the group consisting of H, -CH 3 , -C 2
H
5 , and -C 3
H
7 R2 is a compound selected from the group consisting of R-C C-R7 C-R7 H H and H wherein R7 and R1 1 independently are selected from the group consisting of H, -CH 3 , 10 -C 2
H
5 , and-C 3
H
7 wherein * denotes the cyclization point, and R3, when cyclized with R2, is H -CH2-C R8 wherein * denotes the cyclization point, and 15 wherein R8 is selected from the group consisting of H, C1-C6 alkyl, branched C3-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, substituted C6-C10 aryl, C3-C het eroaryl, substituted C3-C heteroaryl, C1-C6 alkoxy, branched C3-C6 alkoxy, C3-C6 cycloalkoxy, C6-C10 aryloxy, substituted C6-C10 aryloxy, C3-C heteroary loxy, substituted C3-C heteroaryloxy; and WO 2013/110768 PCT/EP2013/051451 6 R3, when not cyclized, is R9 H R10 wherein R9 is selected from the group consisting of H, -CH 3 , and -C 2
H
5 ; and 5 R10 is selected from the group consisting of C 6
-C
1 oaryl, substituted C6 C10 aryl, C3-C heteroaryl, substituted C3-C heteroaryl R4 is selected from the group consisting of C 6
-C
1 oaryl, substituted C6-C10 aryl, C3-C9 heteroaryl, substituted C3-C heteroaryl, C3-C6 heterocyclyl, substituted C3-C6 hetero cyclyl, C3-C6 cycloalkyl, and substituted C3-C cycloalkyl; 10 R5 is selected from the group consisting of hydrogen, F, Cl, CN, -CH 3 , -C 2
H
5 , -C 3
H
7 , and -CF 3 ; A is absent or -CH 2 and tautomers and pharmaceutically acceptable acid addition salts thereof, and poly morphic forms thereof, provided that the compound is not 2-[1-[(4 15 fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-(1 -benzyl-4-methyl-pyrrolid in-3-yl)-7-tetrahyd ropyran-4-yl-3 H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7 tetrahyd ropyran-4-yl-3 H-imidazo[5,1 -f][1 ,2,4]triazin-4-one; 2-(4-methylpyrrolidin-3-yl) 7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-[(6-methoxy-2 20 pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[(3S,4S)-1-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran 4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3R,4R)-1 -benzyl-4-methyl-pyrrolidin-3 yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3S,4S)-4 methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one 25 2-[(3R,4R)-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[(3S,4S)-4-methyl-1 -(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7 tetrahyd ropyran-4-yl-3 H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3R,4 R)-4-methyl-1 (pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 4-[3-methyl-4-(4-oxo-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 30 f][1,2,4]triazin-2-yl)pyrrolidin-1-yl]benzonitrile; 2-[(3S,4S)-1-[(4-fluorophenyl)methyl]-4- WO 2013/110768 PCT/EP2013/051451 7 methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; 2 [(3R,4R)-l -[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1-f][1,2,4]triazin-4-one or 2-[4-methyl-l-(pyrazin-2-ylmethyl)pyrrolidin-3 yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one. 5 In a further embodiment (E2) of (El) the one or more heteroaryls of R4, R8 and R10 inde pendently of each other comprise one or two nitrogen. In a further embodiment (E3) of (El) R8 is C1-C3 alkyl. In a further embodiment (E4) of (El) R8 is branched C1-C3 alkyl. In a further embodiment (E5) of (El) R8 is phenyl or napthyl. 10 In a further embodiment (E6) of (El) R8 is substituted phenyl or substituted napthyl. In a particular embodiment (E7) of any of embodiments (El) and E(6) the substituent is se lected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl. In a particular embodiment (E8) of (E7) the substituents are selected from the group consist 15 ing of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethyl amino. In an embodiment (E9) of any of embodiments (El) and (E2) R8 is a C4-C heteroaryl. In a particular embodiment (E10) of embodiment (E9) R8 is selected from the group consist ing of pyridyl, pyridazine, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, and quinoxalinyl. 20 In a further embodiment (El 1) of any of embodiments (El) and (E2) R8 is a substituted C4-C9 heteroaryl. In a particular embodiment (E12) of embodiment (El 1) R8 is selected from the group consist ing of substituted pyridyl, substituted pyridazine, substituted pyrimidinyl, substituted pyrazinyl, substituted quinolinyl, and substituted quinazolinyl, and substituted quinoxalinyl. 25 In a particular embodiment (E13) of embodiment (El0) R8 is selected from the group consist ing of 2-pyridyl, 3-pyridyl, 2-pyridazine, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-quinolinyl, 2-quinoxalinyl, 6-quinoxalinyl, and 2-quinazolinyl.
WO 2013/110768 PCT/EP2013/051451 8 In a particular embodiment (E14) embodiment (E12) R8 is selected from the group consisting of substituted 2-pyridyl, substituted 3-pyridyl, substituted 2-pyridazine, substituted 2-pyrimidinyl, substituted 4-pyrimidinyl, substituted 2-pyrazinyl, substituted 2-quinolinyl, sub stituted 2-quinoxalinyl, substituted 6-quinoxalinyl, and substituted 2-quinazolinyl. 5 In a particular embodiment (E15) of any of embodiments (El), (E2), (Eli), (E12) and (E14) the substituent of R8 is selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particu lar the substituents are selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino. 10 In an embodiment (E16) of embodiment (El) R8 is C1-C4 alkoxy. In a particular embodiment (E17) of (E16) R8 is methoxy or ethoxy. In an embodiment (E18) of embodiment (El) R8 is branched C3-C4 alkoxy. In a particular embodiment (E19) of (E18) R8 is isopropoxy or isobutoxy. In an embodiment (E20) of (El), when R8 is C6-C10 aryloxy, R8 is selected from the group 15 consisting of phenyloxy and naphtyloxy. In an embodiment (E21) of (El), when R8 is substituted C6-C10 aryloxy, R8 is selected from the group consisting of substituted phenyloxy and substituted naphtyloxy. In a particular embodiment (E22) of any of embodiments (El) and (E21) the substituents of R8, when R8 is a substituted C6-C10 aryloxy, is selected from the group consisting of F, Cl, 20 methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particular the substituents are selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino. In an embodiment (E23) of any of embodiments (El) and (E2) R8 is a C4-C heteroaryloxy. In an embodiment (E24) of embodiment (E23) R8 is selected from the group consisting of 25 pyridineoxy, pyridazineoxy, pyrimidineoxy and quinoxalineoxy In an embodiment (E25) of any of embodiments (El) and (E2) R8 is a substituted C4-C het eroaryloxy. In an embodiment (E26) of embodiment (E25) R8 is selected from the group consisting of substituted pyridineoxy, pyridazineoxy, substituted pyrimidineoxy and quinoxalineoxy WO 2013/110768 PCT/EP2013/051451 9 In an embodiment (E27) of any of embodiments (El), (E2), (E25) and (E26) the substituent is selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particular the substituents are se lected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, 5 cyano, ethyl, and dimethylamino. In an embodiment (E28) of embodiment (El) R10 is a C6-C10 aryl selected from the group consisting of phenyl and naphthyl. In a preferred embodiment (E29) of embodiment (E28) R10 is phenyl. In an embodiment (E30) of embodiment (El) R10 is a substituted C6-C10 aryl selected from 10 the group consisting of substituted phenyl and substituted naphthyl. In a preferred embodiment (E31) of embodiment (E28) R10 is substituted phenyl. In an embodiment (E32) of any of embodiments (El), E(30) and E(31) the substituent is se lected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particular the substituents are se 15 lected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino. In an embodiment (E33) of any of embodiments (El) and (E2) R10 is a C4-C heteroaryl. In a particular embodiment (E34) of embodiment (E33) R10 is selected from the group con sisting of pyridyl, pyridazine, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, and quinoxalinyl. 20 In a particular embodiment (E35) of embodiment (E34) R10 is selected from the group con sisting of 2-pyridyl, 3-pyridyl, 2-pyridazine, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2 quinolinyl, 2-quinoxalinyl, 6-quinoxalinyl, and 2-quinazolinyl. In a further embodiment (E36) of any of embodiments (El) and (E2) R10 is a substituted C4 C9 heteroaryl. 25 In a particular embodiment (E37) of embodiment (E36) R10 is selected from the group con sisting of substituted pyridyl, substituted pyridazine, substituted pyrimidinyl, substituted pyraz inyl, substituted quinolinyl, and substituted quinazolinyl, and substituted quinoxalinyl. In a particular embodiment (E38) of embodiment (E37) R10 is selected from the group con sisting of substituted 2-pyridyl, substituted 3-pyridyl, substituted 2-pyridazine, substituted WO 2013/110768 PCT/EP2013/051451 10 2-pyrimidinyl, substituted 4-pyrimidinyl, substituted 2-pyrazinyl, substituted 2-quinolinyl, sub stituted 2-quinoxalinyl, substituted 6-quinoxalinyl, and substituted 2-quinazolinyl. In a particular embodiment (E39) of any of embodiments (El), (E2), (E36), (E37) and (E38) the substituent of R10 is selected from the group consisting of F, Cl, methyl, trifluoromethyl, 5 methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particu lar the substituents are selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino. In an embodiment (E40) of embodiment of embodiment (El) R4 is selected from the group consisting of phenyl and naphthyl. 10 In an embodiment (E41) of embodiment (El) R4 is substituted phenyl. In an embodiment (E42) of embodiment (E41) the substituent is selected from the group con sisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethyl amino, cyclopropyl, and isopropyl; in particular the substituents are selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and di 15 methylamino. In an embodiment (E43) of embodiment of embodiment (El) R4 is pyridyl. In an embodiment (E44) of embodiment (El) R4 is substituted pyridyl. In an embodiment (E45) of embodiment (E44) the substituent is selected from the group con sisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethyl 20 amino, cyclopropyl, and isopropyl; in particular the substituents are selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and di methylamino. In an embodiment (E46) of embodiment (El) R4 is selected from the group consisting of tet rahydropyranyl, tetrahydrofuranyl and piperidyl. 25 In an embodiment (E47) of embodiment (El) R4 is selected from the group consisting of sub stituted tetrahydropyranyl, substituted tetrahyd rofuranyl and substituted piperidyl. In a particular embodiment (E48) of embodiment E(47) the substituent is selected from group consisting of F, Cl, methyl, cyano and methoxy. In an embodiment (E49) of embodiment (El) R4 is selected from the group consisting of 30 cyclobutyl, cyclopentyl and cyclohexyl.
WO 2013/110768 PCT/EP2013/051451 11 In a preferred embodiment (E50) of embodiment (E49) R4 is cyclopentyl or cyclohexyl. In an embodiment (E51) of embodiment (El) R4 is selected from the group consisting of sub stituted cyclobutyl, substituted cyclopentyl and substituted cyclohexyl. In a preferred embodiment (E52) of embodiment (E51) R4 is substituted cyclopentyl or substi 5 tuted cyclohexyl. In an embodiment (E53) of any of embodiments (E51) and (E52) substituent is selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particular the substituents are selected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and 10 dimethylamino. In an embodiment (E54) of embodiment (El), the compound of formula (1) is selected among the compounds listed in Table 1, in the form of the free base, one or more tautomers thereof or a pharmaceutically acceptable acid addition salt thereof. In an embodiment (E55) of any of embodiments (El) to (E54) the compound has an IC50 15 value, determined as described in the section "PDE9 inhibition assay", of 1 micro molar or less. In an embodiment (E56) of embodiment (El) the compound is selected from the compounds listed in Table 1. In an embodiment (E57) of any of embodiments (El) to (E56) the compound is for use as a 20 medicament. In an embodiment (E58) of any of embodiments (El) to (E56) the compound is for use in the treatment of a disease selected from the group consisting of Alzheimer's disease, mental re tardation; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive decline, substance-induced psychotic disorder, for example psychosis induced by alcohol, ampheta 25 mine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine. In an embodiment (E59) of any of embodiments (El) to (E56) the compound is for prepara tion of a medicament for use in the treatment of a disease selected from the group consisting of Alzheimer's disease, mental retardation; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive decline, substance-induced psychotic disorder, for example psychosis 30 induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine.
WO 2013/110768 PCT/EP2013/051451 12 Embodiment (E60) of the present invention covers a method of treating a subject suffering from a disease selected from the group consisting of Alzheimer's disease, mental retarda tion; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive decline, sub stance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, 5 cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine, which method com prises administering to said subject a compound of any of embodiments (El)-(E56). In an embodiment (E61) the present invention covers a pharmaceutical composition compris ing a therapeutically effective amount of a compound of any of embodiments (El) to (E56), and one or more pharmaceutically acceptable carriers, diluents and excipients. 10 In an embodiment (E62) of embodiment (E61) the pharmaceutical composition is for the treat ment of a disease selected from the group consisting of Alzheimer's disease, mental retarda tion; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive decline, sub stance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine. 15 Table 1 lists compounds of the invention and the corresponding IC50 values (nM) determined as described in the section "PDE9 inhibition assay". Each of the compounds constitutes an individual embodiment of the present invention: Table 1: Compounds of the invention and IC50 values Compound PDE9_C50 (nM) 7-(4-fluorophenyl)-2-[4-methyl- 1 -[[6 (trifluoromethyl)-3-pyridyl] methyl]pyrrolid in-3- 86 yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[(6-methoxy-3-pyridyl)methyl]-4-m ethyl pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 67 imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methyl-1 -[[4 (trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]- 12 7-tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3,6 dihydro-2H-pyran-4-yl)-3H-imidazo[5,1- 281 f][1,2,4]triazin-4-one 7-(4-fluorophenyl)-2-[1-[(6-methoxy-3 pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-3H- 372 imidazo[5,1-f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 13 Compound PDE9_IC50 (nM) 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3- 656 pyridyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[(2,4-difluorophenyl)methyl]-4-methyl pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 48 imidazo[5,1-f][1,2,4]triazin-4-one 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(2,4 difluorophenyl)-3H-imidazo[5,1- 201 f][1,2,4]triazin-4-one 2-[4-methyl-1 -[[4 (trifluoromethoxy)phenyl]methyl]pyrrolidin-3- 19 yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one 2-[[3-(4-methoxyphenyl)azetid in- 1-yl] methyl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 327 f][1,2,4]triazin-4-one 2-[1-[(2-chloro-4-methoxy-phenyl)methyl]-4 methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4- 41 yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methyl-1-(quinoxalin-6 ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4- 24 yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 563 f][1,2,4]triazin-4-one 2-[1-[(4-methoxyphenyl)methyl]-4-methyl pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 49 imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methyl- 1 -(4-pyridylmethyl)pyrrolid in-3 yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- 52 f][1,2,4]triazin-4-one 2-[[3-(4-fluorophenoxy)azetid in-1 -yl]methyl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 80 f][1,2,4]triazin-4-one 2-[4-methyl-1-(pyrimidin-5 ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4- 135 yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[[4-(diethylamino)phenyl]methyl]-4 methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4- 13 yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-(2-furylmethyl)-4-methyl-pyrrolidin-3-yl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 25 f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 14 Compound PDE9_IC50 (nM) 7-(4-fluorophenyl)-2-[(3S,4S)-4-methyl-1 (pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3H- 341 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[(2-chloro-4-fluoro-phenyl)methyl]-4 methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4- 21 yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[(4-dimethylaminophenyl)methyl]-4 methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4- 27 yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methyl- 1 -(p-tolylmethyl)pyrrol id i n-3-yl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 47 f][1,2,4]triazin-4-one 2-(benzyloxymethyl)-7-tetrahydropyran-4-yl- 384 3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[[3-(2,6-difluorophenoxy)azetidin-1 yl]methyl]-7-tetrahydropyran-4-yl-3H- 155 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-(cyclohexylmethyl)-4-methyl-pyrrolidin 3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- 409 f][1,2,4]triazin-4-one 7-tetrahyd ropyran-4-yl-2-[[3-[4 (trifluoromethoxy)phenoxy]azetid in-1- 158 yl]methyl]-3H-imidazo[5, 1 -f][1,2,4]triazin-4 one 2-[[3-(4-dimethylaminophenyl)azetidin-1 yl] methyl]-7-tetrahyd ropyran-4-yl-3H- 86 imidazo[5, 1 -f][1,2,4]triazin-4-one 2-[4-methyl-1 -(3-pyridylmethyl)pyrrolidin-3 yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1- 37 f][1,2,4]triazin-4-one 2-[1-[(2,6-difluorophenyl)methyl]-4-methyl pyrrolid in-3-yl]-7-tetrahyd ropyran-4-yl-3H- 62 imidazo[5, 1 -f][1,2,4]triazin-4-one 2-[(3-phenoxyazetidin-1 -yl)methyl]-7 tetrahydropyran-4-yl-3H-imidazo[5, 1- 153 f][1,2,4]triazin-4-one 2-[[3-[(4-fluorophenyl)methoxy]azetid in-1 yl] methyl]-7-tetrahyd ropyran-4-yl-3H- 10 imidazo[5, 1 -f][1,2,4]triazin-4-one 2-[1-[3-(4-methoxyphenyl)azetid in-1 -yl]ethyl] 7-tetrahydropyran-4-yl-3H-imidazo[5, 1- 47 f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 15 Compound PDE9_IC50 (nM) 2-[4-methyl-1 -[(5-rn ethyl-2 furyl)methyl]pyrrolid in-3-yl]-7- 28 tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one 2-[1-[(5-chloro-2-fu ryl)methyl]-4-methyl pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 63 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[3-(4-fluorophenyl)azetidin-1-yl]ethyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 128 f][1,2,4]triazin-4-one 2-[(3-phenylazetidin-1-yl)methyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 208 f][1,2,4]triazin-4-one 2-[[3-(4-methylphenoxy)azetid in- 1-yl] methyl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 91 f][1,2,4]triazin-4-one 2-[1-[(5-fluoro-3-pyridyl)methyl]-4-methyl pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 25 imidazo[5,1-f][1,2,4]triazin-4-one 2-[[3-(4-isopropylphenoxy)azetidin-1 yl]methyl]-7-tetrahydropyran-4-yl-3H- 134 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[(3,4-difluorophenyl)methyl]-4-methyl pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 23 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[(4-chlorophenyl)methyl]-4-methyl pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 32 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[[6-(dimethylamino)-3-pyridyl]methyl]-4 methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4- 36 yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one methyl 5-[[3-methyl-4-(4-oxo-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 8 f][1,2,4]triazin-2-yl)pyrrolidin-1 yl]methyl]thiophene-2-carboxylate 7-tetrahyd ropyran-4-yl-2-[[3-[5 (trifluoromethyl)-2-pyridyl]azetid in-1- 560 yl]methyl]-3H-imidazo[5, 1 -f][1,2,4]triazin-4 one 2-[[3-(3-pyridyloxy)azetid in- 1-yl] methyl]-7 tetrahydropyran-4-yl-3H-imidazo[5, 1- 350 f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 16 Compound PDE9_IC50 (nM) 2-[(3R,4R)-1-[(2,4-difluorophenyl)methyl]-4 methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4- 47 yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[(1 R)-1-[3-(4-methoxyphenyl)azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3H- 22 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[3-(4-fluorophenoxy)azetidin-1-yl]ethyl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 57 f][1,2,4]triazin-4-one 2-[4-methyl-1 -[(5-m ethyl-2 thienyl)methyl] pyrrolid in-3-yl]-7- 22 tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one 2-[1-[(5-chloro-2-thienyl)methyl]-4-m ethyl pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 13 imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methyl-1-[(4-pyrrolidin-1 ylphenyl)methyl] pyrrolid in-3-yl]-7- 61 tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one 2-(1-benzyl-4-methoxy-pyrrolidin-3-yl)-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 54 f][1,2,4]triazin-4-one 2-[4-methyl-1-(pyrimidin-4 ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4- Not determined yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[3-(4-hydroxyphenyl)azetidin-1-yl]ethyl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 120 f][1,2,4]triazin-4-one 2-[1-[(4-fluorophenyl)methyl]-4-methoxy pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H- 94 imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methoxy-1-(p-tolylmethyl)pyrrolidin-3-yl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 90 f][1,2,4]triazin-4-one 2-[[3-(p-tolylmethoxy)azetidin-1-yl]methyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 150 f][1,2,4]triazin-4-one 2-[(3-benzylazetidin-1-yl)methyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- Not determined f][1,2,4]triazin-4-one 2-[(3S,4S)-1-benzyl-4-methoxy-pyrrolidin-3- Not determined yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- WO 2013/110768 PCT/EP2013/051451 17 Compound PDE9_IC50 (nM) f][1,2,4]triazin-4-one 2-[1-[3-(4-methylphenoxy)azetid in-1 -yl]ethyl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 110 f][1,2,4]triazin-4-one 2-[[3-[(4-methoxyphenoxy)methyl]azetidin-i yl]methyl]-7-tetrahydropyran-4-yl-3H- 82 imidazo[5,1-f][1,2,4]triazin-4-one 2-[(3-pyrimidin-2-ylazetidin-1-yl)methyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 3400 f][1,2,4]triazin-4-one 2-[1-[3-(4-pyrrolidin-1-ylphenyl)azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3H- 110 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-benzyl-4-(trifluoromethyl)pyrrolidin-3-yl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 50 f][1,2,4]triazin-4-one 2-[[3-(5-pyrrolidin-1-ylpyrimidin-2-yl)azetidin 1-yl]methyl]-7-tetrahydropyran-4-yl-3H- 120 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[3-(4-dimethylaminophenyl)azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3H- 86 imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methoxy-1-[(4 methoxyphenyl)methyl]pyrrolidin-3-yl]-7- 83 tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one 2-[1-(3-phenylazetidin-1-yl)ethyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 360 f][1,2,4]triazin-4-one 2-[1-[3-(3-fluoro-4-methoxy-phenyl)azetidin 1-yl]ethyl]-7-tetrahydropyran-4-y-3H- 240 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[3-(2-fluoro-4-methoxy-phenyl)azetidin 1-yl]ethyl]-7-tetrahydropyran-4-yl-3H- 300 imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[3-(4-ethoxyphenyl)azetidin-1-yl]ethyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 290 f][1,2,4]triazin-4-one 2-[1-[3-[(4-methoxyphenyl)methyl]azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3H- 68 imidazo[5,1-f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 18 Compound PDE9_IC50 (nM) 7-tetrahydropyran-4-yl-2-[1-[3-[4 (trifluoromethoxy)phenyl]azetidin-1-yl]ethyl]- 210 3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[1-[3-(4-methylphenoxy)azetid in-1 -yl]ethyl] 7-tetrahydropyran-4-yl-3H-imidazo[5,1- 110 f][1,2,4]triazin-4-one 2-[[3-[(4-methoxyphenoxy)methyl]azetidin-1 yl]methyl]-7-tetrahydropyran-4-yl-3H- 82 imidazo[5,1-f][1,2,4]triazin-4-one 2-[(3-pyrimidin-2-ylazetidin-1-yl)methyl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1- 3400 f][1,2,4]triazin-4-one 2-[1-[3-(4-pyrrolidin-1-ylphenyl)azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3H- 110 imidazo[5,1-f][1,2,4]triazin-4-one Definition of substituents As used in the context of the present invention, the terms "halo" and "halogen" are used inter changeably and refer to fluorine, chlorine, bromine or iodine. 5 The term "C1-C6 alkyl" refers to a straight-chain or branched saturated hydrocarbon having from one to six carbon atoms, inclusive. Examples of such groups include, but are not lim ited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, and n-hexyl. The expression "C1-C6 hydroxyalkyl" refers to a C1-C6 alkyl group as defined above which is substituted with one hydroxy group. 10 The term "halo(C 1
-C
6 )alkyl" refers to a C1-C6 alkyl group as defined above which is substi tuted with up to three halogen atoms, such as trifluoromethyl. The expression "C1-C6 alkoxy" refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Ex amples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl 15 pentoxy and n-hexyloxy. The term "C3-C8 cycloalkyl" typically refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
WO 2013/110768 PCT/EP2013/051451 19 The expression "C1-C6 alkyl(C 3
-C
8 )cycloalkyl" refers to a C3-C8 cycloalkyl as defined above which is substituted with a straight-chain or branched C1-C6 alkyl. Examples of such groups include, but are not limited to, cyclopropylmethyl. The term "heterocycloalkyl" refers to a four to eight membered ring containing carbon atoms 5 and up to three N, 0 or S atoms, provided that the four to eight membered ring does not con tain adjacent 0 or adjacent S atoms. The open valency is on either the heteroatom or carbon atom. Examples of such groups include, but are not limited to, azetidinyl, oxetanyl, piperaz inyl, morpholinyl, thiomorpholinyl and [1,4]diazepanyl. The term "hydroxyheterocycloalkyl" refers to a heterocycloalkyl as defined above which is 10 substituted with one hydroxy group. The term "C1-C6 alkyl-heterocycloalkyl" refers to a heterocycloalkyl as defined above which is substituted with a C1-C6 alkyl group. Examples of such groups include, but are not limited to, tetrahyd ropyran-4-yl-methyl and 2-morpholin-4-yl-ethyl. The term "aryl" refers to a phenyl ring, optionally substituted with halogen, C1-C6 alkyl, C1-C6 15 alkoxy or halo(C1-C 6 )alkyl as defined above. Examples of such groups include, but are not limited to, phenyl and 4-chlorophenyl. The term "C 1 -Cearylalkyl" refers to an aryl as defined above which is substituted with a straight-chain or branched C1-C6 alkyl. Examples of such groups include, but are not limited to, benzyl and 4-chlorobenzyl. 20 The term aryloxy refers to an univalent radical of the form Ar-O (such as phenoxy) composed of an aryl group (Ar) united with oxygen (0). The term heteroaryloxy refers to an aryloxy where one or more carbon atoms have been sub stituted with one more hetero atoms, such as N, 0, S. In the context of the present invention the term 'cyclization point' is understood to mean that 25 connecting the atoms indicated to be cyclization points by a bond results in a cyclic structure (a ring). The cyclization point is indicated with a * in the illustrative reaction scheme below: WO 2013/110768 PCT/EP2013/051451 20 * Ry Ry * N ) N RxRx * Denotes cyclization points Additionally, the present invention further provides certain embodiments of the invention, which are described below. Additionally, the present invention further provides certain em 5 bodiments of the invention that are described below. Pharmaceutically Acceptable Salts The present invention also comprises salts of the compounds, typically, pharmaceutically ac ceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addi tion salts include salts of inorganic acids as well as organic acids. 10 Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hy droiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, 15 ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for exam ple 8-bromotheophylline and the like. Further examples of pharmaceutically acceptable inor ganic or organic acid addition salts include the pharmaceutically acceptable salts listed in 20 Berge, S.M. et al., J. Pharm. Sci. 1977, 66, 2, the contents of which are hereby incorporated by reference. Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In gen eral, the solvated forms are considered equivalent to the unsolvated forms for the purposes of 25 this invention. Pharmaceutical composition WO 2013/110768 PCT/EP2013/051451 21 The present invention further provides a pharmaceutical composition comprising a therapeu tically effective amount of a compound of formula (1) and a pharmaceutically acceptable car rier or diluent. The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experi 5 mental Section herein and a pharmaceutically acceptable carrier or diluent. The compounds of the invention may be administered alone or in combination with pharma ceutically acceptable carriers, diluents or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceuti cally acceptable carriers or diluents as well as any other known adjuvants and excipients in 10 accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), 15 transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient. Pharmaceutical compositions for oral administration include solid dosage forms such as cap 20 sules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the com positions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administra tion include solutions, emulsions, suspensions, syrups and elixirs. 25 Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants. 30 Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dos- WO 2013/110768 PCT/EP2013/051451 22 ages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. 5 The formulations may also be presented in a unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg. For parenteral routes such as intravenous, intrathecal, intramuscular and similar administra 10 tion, typical doses are in the order of half the dose employed for oral administration. The present invention also provides a process for making a pharmaceutical composition com prising admixing a therapeutically effective amount of a compound of formula (1) and at least one pharmaceutically acceptable carrier or diluent. In an embodiment, of the present inven tion, the compound utilized in the aforementioned process is one of the specific compounds 15 disclosed in the Experimental Section herein. The compounds of this invention are generally utilized as the free substance or as a pharma ceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of formula (1) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of for 20 mula (1) with a molar equivalent of a pharmaceutically acceptable acid. Representative exam ples of suitable organic and inorganic acids are described above. For parenteral administration, solutions of the compounds of formula (1) in sterile aqueous so lution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be em ployed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent 25 first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula (1) may be readily incorporated into known sterile aqueous media us ing standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions 30 and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, pea nut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
WO 2013/110768 PCT/EP2013/051451 23 Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The phar maceutical compositions formed by combining the compounds of formula (1) and a pharma ceutically acceptable carrier are then readily administered in a variety of dosage forms suit 5 able for the disclosed routes of administration. The formulations may conveniently be pre sented in unit dosage form by methods known in the art of pharmacy. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient. Furthermore, the orally available formu 10 lations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per 15 dosage unit. If a liquid carrier is used, the preparation may be in the form of a syrup, emul sion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordi 20 nary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preserva tives etc. may be used provided that they are compatible with the active ingredients. 25 Diseases In a particular embodiment the PDE9 inhibitors of the present invention may be used in the treatment of cognition deficiencies related to neurodegenerative disorders, such dementia, such as cortical dementia or subcortical dementia. Cortical dementias arise from a disorder affecting the cerebral cortex, the outer layers of the 30 brain that play a critical role in cognitive processes such as memory and language. Particu larly considered cortical dementias are Alzheimer's disease; vascular dementia (also known as multi-infarct dementia), including Binswanger's disease; Dementia with Lewy bodies (DLB); Alcohol-Induced Persisting Dementia, including Korsakoff's syndrome and Wernicke's WO 2013/110768 PCT/EP2013/051451 24 encephalopathy; frontotemporal lobar degeneration (FTLD), including: Pick's disease, fronto temporal dementia (or frontal variant FTLD), semantic dementia (or temporal variant FTLD), and progressive non-fluent aphasia; Creutzfeldt-Jakob disease; dementia pugilistica; Moya moya disease; and posterior cortical atrophy (an Alzheimer's disease variant). 5 Subcortical dementias result from dysfunction in the parts of the brain that are beneath the cortex. Usually, the memory loss and language difficulties that are characteristic of cortical dementias are not present. Rather, people with subcortical dementias, such as Huntington's disease, Parkinson's Disease, and AIDS dementia complex, tend to show changes in their personality and attention span, and their thinking slows down. Particularly considered subcor 10 tical dementias are dementia due to Huntington's disease, dementia due to hypothyroidism, dementia due to Parkinson's disease, dementia due to Vitamin B1 deficiency, dementia due to Vitamin B12 deficiency, dementia due to folate deficiency, dementia due to syphilis, de mentia due to subdural hematoma, dementia due to hypercalcaemia, dementia due to hypo glycaemia, AIDS dementia complex, pseudodementia (a major depressive episode with 15 prominent cognitive symptoms), substance-induced persisting dementia, dementia due to multiple etiologies, dementia due to other general medical conditions (i.e. end stage renal failure, cardiovascular disease etc.), dementia not otherwise specified (used in cases where no specific criteria is met). Experimental 20 General Description of pyrrolidine-substituted 3H-imidazo[5,1-f][1,2,4]triazin-4-ones Compounds of formula I can be made by reductive amination of compounds of formula X, with aryl aldehydes in the presence of NaBH 3 CN or Na(OAc) 3 BH, and a few drops of acetic acid as catalyst in DME or MeOH, or by alkylation of compound X with aryl methyl halides, in 25 the presence of bases, such as K 2
CO
3 or DIEA, in DMF or CH 3 CN. 0 R' HN N Ar-CHO, NaBH 3 CN, DME R' HN N' orAr-CH 2 X, K 2 C0 3 , DMF N N RR H N X ArUI R'= Methyl, Trifluoromethyl, Methoxyl WO 2013/110768 PCT/EP2013/051451 25 Compounds of formula X can be prepared by deprotection with HCI in MeOH of compound of formula IX, which can be obtained by one-pot hydrogenolysis debenzylation and Boc protec tion with Boc 2 0 of compounds with formula VIII. Compounds of formula VIII can be synthe sized by Suzuki reaction of compounds of formula VII, with a variety of organo boronic acids 5 or boronic esters in the presence of Xantphos, and a palladium catalyst, such as Pd(dppf)C1 2 , Pd(PPh 3
)
2 Cl 2 , Pd(PPh 3
)
4 and a base, such as K 3
PO
4 , K 2
CO
3 , or Cs2CO3, with conventional heating or microwave heating in DMF or Toluene. Compounds of formula VII can be prepared by deprotonation with n-BuLi, followed by treatment with 12, of compound VI, which can be made by cyclization in the presence of NH 4 0Ac in MeOH with heating of compound V. Com 10 pound V can be made by coupling reaction of compound Ill, obtained from reaction between compound II with (aminooxy)diphenylphosphine oxide, with compound IV, which can be pre pared from a known compound XI. Compound XI is made according to the procedures in pat ent WO 2009/76387. 0 O NH 2 0 0 0 00 O O DCM Et N H AC R' HN N n-BuLi/THF HN <N LiHMDS,THF H2N'N N IV N N N MeOH, Heat 12 HNU IIS H 21- N N 0N II III N V VI 0 0 0 0 R' HN N R-B(OH) 2 R HN Hd HN N R HN N N_ N H N HCI/MeOHN I Xanthpos, Pd(dPPf) 2 C1 2 N Boo VII 3POVIII OH SOC 2 CI N O N 0 XI IV 15 R' = Methyl, Trifluoromethyl, Methoxyl General Description of Azetidine-substituted 3H-imidazo[5,1-f][1,2,4]triazin-4-ones Compounds of formula XI, when R is proton, can be made from direct displacement of a chlo ride of formula X, with different amines in the presence of a base, such as DIEA. Compounds 20 of formula X can be generated from the reaction between compounds of formula IX with thio nyl chloride. Compounds of formula XI, when R is an alkyl group, can be synthesized from reductive amination of ketones of formula XII with a variety of amines, in the presence of WO 2013/110768 PCT/EP2013/051451 26 Na(CN)BH 3 or Na(OAc) 3 BH. Ketones of formula XII can be made from oxidation of the alco hol of formula IX with MnO 2 in DCM. 0 HN N RNHR
SOC
2 R N'N DiEA O 0 DCM CI R' R=H HN HN R N R N X R N'N OH R' 0 RI' R2 xMn 0 2 H~ -xi IX CM HN R NN N
R,NHR
2 O ' R' Na(CN)BH 3 R = Me XII 5 Alcohols of formula IX can be prepared from debenzylation, with Pd/C in 50 psi of H 2 , of com pounds of formula VIII, which can be synthesized by Suzuki coupling of compounds of for mula VII, with a variety of boronic acids or boronic esters, in the presence of a palladium cata lyst, such as Pd(PPh 3
)
4 , Pd(dppf)CL 2 , etc, with microwave heating. Compounds of formula VII can be generated from deprotonation of compounds of formula VI with a base, such as n 10 BuLi, followed by treatment with 12. 0 0 0 0 HN 12 HN - N R'B(OH) 2 , Pd(PPh 3
)
4 HN H 2 , Pd/C HN N R N /' N n-BuLi NR N Dioxane, Microwave R N, N heating R N OBn OBn OBn R' OH R VI VII VIII IX Compounds of formula VI can be made from microwave heating of amide of formula V in the presence of aqueous solution of a base, such as KOH. Amide of formula V can be generated 15 from aminolysis of esters of formula IV with aqueous solution of ammonia. Esters of formula IV can be prepared by coupling in the presence of HATU of carboxylic acid Ill with 1-amino imidazole 1l, which was made from the reaction of methyl 1H-imidazole-5-carboxylate (1) with (aminooxy)diphenylphosphine oxide in the presence of a base, such as LiHMDS.
WO 2013/110768 PCT/EP2013/051451 27 0 0 O Phs'/ NH O OBn O O" H ~ NHH0 N Ph' 'O' 2 HO n N OBn 3.2 N / LiHMDS N, HATU, Et3N N=/ R Microwave H
NH
2 3 || IV O NH O H OBn KOH (aq) HN ___R N N- R Microwave N OBn V VI Part I (Pyrrolidine Series) 5 Preparation of intermediates 2-(1 -Benzyl-4-methyl-pyrrolidin-3-yI)-7-iodo-3H-imidazo[5,1 -f][1,2,4]triazin-4-one Scheme 1 N 3 -o 3HO-O
SOC
2 H P h - N 0 Ph 'O'NH2 0 0 0 0 N N CI NH 4 0Ac LiHMDS N Et3N DCM NNO N MeOH H NH 2 N-J //o NMO 1 2 4 0 0 HN HN N n-BuLi/THF N N N12 N 1056 WO 2013/110768 PCT/EP2013/051451 28 3-Amino-3H-imidazole-4-carboxylic acid methyl ester (2) To a suspension of compound 1 (4.0 g, 31.7 mmol) in dry THF was dropwise added LiHMDS (38 mL, 38 mmol) at -78'C in N 2 . The mixture was stirred at -78'C for 2 hours. Then it was stirred at -30'C for 20 minutes. (Aminooxy)diphenylphosphine oxide (8.14 g, 31.7 mmol) was 5 added in portions at -10'C. The reaction mixture was allowed to warm to r.t overnight. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (eluted with DCM/MeOH = 150:1 to 100:1) to afford the desired product 2 (2.4 g, 53% yield) as a white powder. LC-MS: m/z 142.50 [M+1]*. 'H NMR (400 MHz, DMSO-d6): 6 7.82 (s, 1H), 7.54 (s, 10 1H), 6.20 (br. s, 2H), 3.79 (s, 3H). 3-[(1 -Benzyl-4-methyl-pyrrolidine-3-carbonyl)-amino]-3H-imidazole-4-carboxylic acid methyl ester (4) A mixture of compound 3 (prepared according to procedures in patent WO 2009/76387) (13 g, 59.4 mmol) in 30 mL of SOC 2 was refluxed at 85'C for 4 hours. The solvent was removed 15 by concentration in vacuo to afford the acid chloride of 3. The acid chloride was dissolved in 30 mL of CH 2
CI
2 . This resulting solution was added drop wise to a solution of compound 2 (3.5 g, 24.8 mmol) and Et 3 N (10 mL, 68.2 mmol) in 100 mL of CH 2 Cl 2 at 00C over 20 minutes. Then the reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was washed with brine (100 mL x 2). The organic phase 20 was dried over Na 2
SO
4 , filtered and concentrated to afford the crude residue, which was puri fied by column chromatography on silica gel (eluted with DCM/MeOH = 100:1 to 50:1) to af ford compound 4 (5.0 g, 58.9% yield) as a red oil. LC-MS: m/z 343.11 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.70 (s, 1 H), 7.63 (s, 1 H), 7.33-7.25 (m, 5H), 3.78 (s, 3H), 3.80-3.77 (d, J = 12.4 Hz, 1H), 3.68-3.65 (d, J = 12.4 Hz, 1H), 3.36-3.28 (m, 2H), 2.70-2.65 (m, 1H), 25 2.56-2.50 (m, 2H), 1.92 (m, 1H), 1.16 (d, J = 7.2 Hz, 3H). 2-(1-Benzyl-4-methyl-pyrrolidin-3-yI)-3H-imidazo[5,1-f][1,2,4]triazin-4-one (5) To a 300 mL sealed tube was added a mixture of compound 4 (4.7 g, 13.7 mmol), NH 4 0Ac (11 g, 14.3 mmol) and ammonium hydroxide (50 mL) in MeOH (120 mL). The reaction mix 30 ture was stirred at 130'C for 2 days. After cooling down, the reaction mixture was concen trated in vacuo. The residue was diluted with CH 2 Cl 2 (100 mL) and washed with water (50 mL x 2). The organic phase was separated and dried over Na 2
SO
4 . After filtering, the filtrate was WO 2013/110768 PCT/EP2013/051451 29 concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted with DCM/MeOH = 50:1 to 30:1) to afford compound 5 (1.8 g, 40.6% yield) as a white solid. LC-MS: m/z 310.17 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.02 (s, 1 H), 7.85 (s, 1H), 7.39-7.28 (m, 5H), 3.82 (d, J = 12.4 Hz, 1H), 3.58 (d, J = 12.4 Hz, 1H), 5 3.41-3.37 (m, 1H), 2.99 (d, J = 6.4 Hz, 1H), 2.72-2.70 (m, 1H), 2.54-2.50 (m, 1H), 2.44-2.40 (m, 1 H), 1.95-1.91 (m, 1 H), 1.20 (d, J = 6.4 Hz, 3H). 2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one (6) To a solution of compound 5 (1.0 g, 3.24 mmol) in dry THF (70 mL) was added n-BuLi (2.5 M, 10 2 mL) dropwise at -780C over 30 minutes. The reaction was stirred at -450C for 30 minutes. Then a solution of iodine in THF (20 mL) was dropwise added at -780C over 10 minutes. The resulting mixture was stirred at 0 C for 2 hours. The reaction was quenched with saturated aqueous Na 2
S
2 0 3 solution (10 mL). Then the reaction mixture was diluted with EtOAc (200 mL), and washed with brine (50 mL x 2). The separated organic phase was dried over 15 Na 2
SO
4 , filtered and concentrated under reduced pressure. The residue was purified by col umn chromatography on silica gel (eluted by PE/EtOAc = 10:1 to 2:1) to afford compound 6 (930 mg, 66% yield) as a white solid. LC-MS: m/z 435.99 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.89 (s, 1H), 7.37-7.26 (m, 5H), 3.82 (d, J = 12.4 Hz, 1H), 3.59 (d, J = 12.4 Hz, 1H), 3.42-3.38 (m, 1 H), 2.98 (d, J = 8.4 Hz, 1 H), 2.82-2.81 (m, 1 H), 2.55-2.51 (m, 1 H), 2.45-2.42 20 (m, 1 H), 1.96-1.92 (m, 1 H), 1.22 (d, J = 7.2 Hz, 3H). 2-(4-Methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4 one Hydrochloric acid salt 25 Scheme 2 00 0 0 0 HN N BO HN N HN HN N I Pd(dppf) 2 CI, Xantphos N' B c O tN N N HCI/MeOH N'N N O M F H O N b c H C IH 6 Mrwae7 0 bc 8 0 9 0 WO 2013/110768 PCT/EP2013/051451 30 2-(1 -Benzyl-4-methyl-pyrrolidin-3-yI)-7-(3,6-dihydro-2H-pyran-4-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one (7) To a mixture of compound 6 (100 mg, 0.23 mmol) and 4-(4,4,5,5-Tetramethyl [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (145 mg, 0.69 mmol) in DMF (10 mL) was 5 added potassium phosphate (146 mg, dissolved in 1 mL of H 2 0). The reaction mixture was degassed by purging with N 2 for 15 min, before Pd(dppf) 2 Cl 2 (28 mg, 0.035 mmol) and Xant phos (40 mg, 0.069 mmol) were added. The resulting suspension was bubbled with nitrogen for 10 minutes. The reaction mixture was heated to 1500C under microwave irradiation for one hour. After cooling down, the reaction mixture was diluted with EtOAc (50 mL), and the pre 10 cipitate was filtered off. The filtrate was washed with brine (50 mL), dried over Na 2
SO
4 , fil tered and the filtrate was concentrated. The crude product was purified by column chromatog raphy on silica gel (eluting with EtOAc) to afford 7 (50 mg, 55% yield) as a white solid. LC MS: m/z 393.03 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.85 (s, 1H), 7.37-7.22 (m, 6H), 4.40 (d, J = 2.8 Hz, 2H), 3.95-3.92 (m, 2H), 3.82-3.79 (d, J = 12.6 Hz, 1H), 3.61-3.58 (d, J = 12.6 15 Hz, 1H), 3.39-3.37 (m, 1H), 3.00-2.98 (d, J = 10.0 Hz, 1H), 2.76-2.73 (m, 3H), 2.54-2.52 (m, 1H), 2.44-2.42 (m, 1H), 1.95-1.90 (m, 2H), 1.21 (d, J = 7.2 Hz, 3H). 3-Methyl-4-[4-oxo-7-(tetrahydro-pyran-4-y)-3,4-dihydro-imidazo[5,1 -f][1,2,4]triazin-2-yl] pyrrolidine-1 -carboxylic acid tert-butyl ester (8) 20 To a 75 mL flask was added compound 7 (0.3 g, 0.76 mmol), di-tert-butyl dicarbonate (1.6 g, 7.6 mmol), potassium acetate (0.75 g, 7.6 mmol), 10% Pd/C (300 mg, 0.28 mmol) and methanol (40 mL). The reaction mixture was stirred with hydrogen (50 psi) at 500C until LC MS showed that the starting material was almost consumed. After cooling down, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. 25 The crude product was purified by column chromatography on silica gel (eluting with EtOAc) to afford compound 8 (50 mg, 42% yield) as a white solid. LC-MS: m/z 404.35 [M+1]*. 'H NMR (400 MHz, CDC13): 6 10.49 (br. s, 1H), 7.86 (s, 1H), 4.11-4.08 (m, 2H), 3.91 (m, 1H), 3.76 (m, 1H), 3.63-3.57 (m, 3H), 3.46 -3.41 (m, 1H), 3.11-3.06 (m, 1H), 2.91-2.89 (m, 1H), 2.69-2.65 (m, 1H), 2.11-2.05 (m, 2H), 1.93-1.90 (m, 2H), 1.48 (s, 9H), 1.20-1.18 (d, J = 6.8 30 Hz, 3H). 2-(4-Methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4 one Hydrochloric acid salt (9) WO 2013/110768 PCT/EP2013/051451 31 To a solution of compound 8 (130 mg, 0.32 mmol) in CH 2
CI
2 (10 mL) was added a saturated solution of HCI in diethylether (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to dryness to afford compound 9 (110 mg, 100% yield). LC-MS (free base): m/z 304.37 [M+1]*. 'H NMR (400 MHz, D 2 0-d2): 6 8.02 5 (s, 1H), 3.98-3.95 (dd, J = 2.8, 8.8 Hz, 2H), 3.64-3.60 (m, 3H), 3.56-3.50 (m, 3H), 3.15-3.09 (m, 1H), 3.01-2.96 (m, 1H), 2.72-2.67 (m, 1H), 1.92-1.87 (m, 4H), 1.09 (d, J = 6.8 Hz ,3H). 7-(4-Fluoro-phenyl)-2-(4-methyl-pyrrolidin-3-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one Hydrochloric acid salt 10 Scheme 3 O OH 0 HN' r- , BOH HN1 - -,1 I N OHH N HN HN N F N H2/Pd/C NN N HCI/MeOH HN N N N I Pd(PPH3)4, Toluene, K2CO3 N Boc20, Et 3 N N boc H CIH 6 10 F 11 12 F F 2-(1 -Benzyl-4-methyl-pyrrolidin-3-yl)-7-(4-fluoro-phenyl)-3H-imidazo[5,1 -f][1,2,4]triazin 4-one (10) 15 To a solution of compound 6 (500 mg, 1.14 mmol) and 4-fluorophenylboronic acid (300 mg, 2.14 mmol) in 30 mL of toluene was added K 2
CO
3 (1.0 g, 7.24 mmol). The resulting mixture was degassed by purging with nitrogen for 15 min, before Pd(PPh 3
)
4 (120 mg, 0.10 mmol) was added. The resulting suspension was bubbled with nitrogen for 10 minutes. The reaction mixture was heated to 1000C for 18 hours and then cooled to room temperature. After re 20 moval of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc = 5:1 to 1:2) to afford compound 10 (398 mg, 86% yield) as a white solid. LC MS: m/z 404.31 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.34-8.31 (m, 2H), 7.95 (s, 1 H), 7.38 (m, 4H), 7.31 (m, 1H), 7.16 (m, 2H), 3.85 (d, J = 12.4 Hz, 1H), 3.63 (d, J = 12.4 Hz, 1H), 3.44-3.40 (m, 1H). 3.05 (d, J = 10 Hz, 1H), 2.84 (m, 1H), 2.61 (m, 1H), 2.50-2.47 (m, 1H), 25 1.99 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H). 3-[7-(4-Fluoro-phenyl)-4-oxo-3,4-dihydro-imidazo[5,1 -f][1,2,4]triazin-2-yl]-4-methyl pyrrolidine-1 -carboxylic acid tert-butyl ester (11) WO 2013/110768 PCT/EP2013/051451 32 Compound 11 was prepared in the same method as described for preparation of compound 8. 46% yield. LC-MS: m/z 414.08 [M+1]*. 'H NMR (400 MHz, DMSO-d6): 6 12.01 (br. s, 1H), 8.36 (m, 2H), 7.88 (s, 1H), 7.35 (m, 2H), 3.75 (m, 1H), 3.56 (m, 2H). 2.95 (m, 2H), 2.64 (m, 1H), 1.39 (s, 9H), 1.10 (d, J = 6.4 Hz, 3H). 5 7-(4-Fluoro-phenyl)-2-(4-methyl-pyrrolidin-3-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one Hydrochloric acid salt (12) Compound 12 was prepared in the same way as described for preparation for compound 9. 95% yield. LC-MS: m/z 314.31 [M+1]*. 'H NMR (400 MHz, DMSO-d6): 6 12.19 (s, 1H), 10 9.47-9.49 (br. s, 2H), 8.37 (dd, J = 5.6, 8.4 Hz, 2H), 7.93 (s, 1H), 7.39 (m, 2H), 3.67 (m, 1H), 3.48 (m, 2H). 3.09 (m, 1H), 2.91 (m, 1H), 2.71 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H). Scheme 4 F N F 0 F FF 0 SF F F F HN F F F HOAc N F- HN N N HOHF NH40Ac___ _NN n-BuLi/THFN' N 0F N HATU, DiEA NN N MeOH N 2 N 2 O 13 14 15 0 0 0 0 F F F F F FU BF F HN F- F HN N F F HN ON HCI/MeOH N N 0 _N H 2 IPd/C N N______ N Pd(dppf),C, Xanthpos N AcOK, BocO N N
K
3 P0 4 , DMF/H,0 16 02 o 00 H CIH 0 16 17 18 3-[(1 -Benzyl-4-trifluoromethyl-pyrrolidine-3-carbonyl)-amino]-3H-imidazole-4-carboxylic 15 acid methyl ester (13) | FF F N 0 To a solution of compound 2 (2.0 g, 14.1 mmol), 1-Benzyl-4-trifluoromethyl-pyrrolidine-3 carboxylic acid (4.06 g, 14.9 mmol) and DIEA (10 mL, 42.5 mmol) in DMF (30 mL) was added HATU (8.1 g, 21.2 mmol). The resulting reaction mixture was stirred at r.t. overnight. The re 20 action was monitored by LC-MS. The reaction was quenched with water (100 mL) when it was complete. The aqueous solution was extracted with EtOAc (80 mL x 3). The combined organic phase was washed with brine and concentrated to afford the crude product. The resi- WO 2013/110768 PCT/EP2013/051451 33 due was purified by silica gel column (eluted with PE/EA = 5:1 to 1:2) to afford compound 13 (4.8 g, 85.6% yield) as white oil. LC-MS: m/z 397 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.00 (br. s, 1H), 7.70 (s, 1H), 7.65(s, 1H), 7.34-7.28 (m, 5H), 3.81 (s, 3H), 3.78-3.72 (m, 2H), 3.41-3.38 (m, 1H), 3.30-3.24 (m, 2H), 3.14-3.12 (m, 1H), 2.71-2.67 (m, 1H), 2.58-2.53 (m, 5 1H). 2-(1-Benzyl-4-trifluoromethyl-pyrrolidin-3-y)-3H-imidazo[5,1-f][1,2,4]triazin-4-one (14) 0 FEF F HN N N' N N The procedure for the preparation ofcompound 14 was similar to that of compound 5. 10 28.8% yield. LC-MS: m/z 364 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.06 (s, 1H), 7.88 (s, 1H), 7.41-7.30 (m, 5H), 3.88 (d, J = 12.8 Hz, 1H), 3.67 (d, J = 12.4 Hz, 1H), 3.45-3.40 (m, 1H), 3.35-3.33 (m, 1 H), 3.08-3.06 (m, 2H), 2.65-2.61 (m, 1 H), 2.52-2.48 (m, 1 H). 2-(1 -Benzyl-4-trifluoromethyl-pyrrolidin-3-y)-7-iodo-3H-imidazo[5,1 -f][1,2,4]triazin-4 15 one (15) 0 F HN N'N N The procedure for the preparation ofcompound 15 was similar to that of compound 6. 38.7% yield. LC-MS: m/z 490 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.91 (s, 1H), 7.40-7.29 (m, 5H), 3.87 (d, J = 12.8 Hz, 1H), 3.66 (d, J = 12.4 Hz, 1H), 3.46-3.41 (m, 2H), 3.08-3.05 20 (m, 2H), 2.67-2.62 (m, 1 H), 2.54-2.49 (m, 1 H).
WO 2013/110768 PCT/EP2013/051451 34 2-(1 -Benzyl-4-trifluoromethyl-pyrrolidin-3-y)-7-(3,6-dihydro-2H-pyran-4-yl)-3H imidazo[5,1-f][1,2,4]triazin-4-one (16) 0 F F HN N'N N N 0 The procedure for the preparation ofcompound 16 was similar to that of compound 7. 5 91% yield. LC-MS: m/z 446 [M+1]*. 1 HNMR (400 MHz, CDC13): 6 7.87 (s, 1 H), 7.37-7.27 (m, 5H), 7.18 (m, 1H), 4.39 (m, 2H), 3.94-3.91 (m, 2H), 3.88-3.85 (m, 1H), 3.68-3.65 (m, 1H), 3.41-3.36 (m, 2H), 3.09-3.04 (m, 2H), 2.76 (m, 2H), 2.65-2.60 (m, 1H), 2.52-2.47 (m, 1H). 3-[4-Oxo-7-(tetrahydro-pyran-4-yl)-3,4-dihydro-imidazo[5,1 -f][1,2,4]triazin-2-yl]-4 10 trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (17) 0 FEF F HN N N' N N o= 0 0 The procedure for the preparation ofcompound 17 was similar to that of compound 8. 27% yield. LC-MS: m/z 458 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.89 (s, 1 H), 4.13-4.03 (m, 3H), 3.89-3.87 (m, 1H), 3.68-3.58 (m, 3H), 3.46-3.39 (m, 1H), 2.14-2.05 (m, 2H), 1.92-1.89 15 (m, 2H), 1.77-1.59 (m, 3H), 1.47 (s, 9H). 7-(Tetrahydro-pyran-4-y)-2-(4-trifluoromethyl-pyrrolidin-3-yl)-3H-imidazo[5, 1 f][1,2,4]triazin-4-one Hydrochloric acid salt (18) WO 2013/110768 PCT/EP2013/051451 35 0 FEF F HN N N' N N H CIH 0 The procedure for the preparation of compound 18 was similar to that of compound 9. 100% yield. LC-MS: m/z 358 [M+1]*. 'H NMR (400 MHz, DMSO-d6): 6 7.90 (br. s, 1H), 5 3.96-3.93 (m, 3H), 3.75-3.70 (m, 3H), 3.56-3.50 (m, 5H), 1.87-1.82 (m, 4H). Scheme 5 N 0 00 Nc N N O N 0 00 O N 0 N N HO O NH 4 OAc N n-BuLi/THF N N N EtaN,DCM N N MeOH N N N 2 N-- 0 19 20 21 0 0 0 0 0 ONO N H 2 /Pd/C N HCI/EtO N N N N N N Pd(PPh3)4/CsCO3 N (Boc) 2 0/KOAc N N Dioxane/MicroWave 22 0 23 0 24 0 3-[(1-Benzyl-4-methoxy-pyrrolidine-3-carbonyl)-amino]-3H-imidazole-4-carboxylic acid 10 methyl ester (19) 0 0 NI 0 H SN_ N N 0 The procedure for the preparation ofcompound 19 was similar to that of compound 4. 77% yield. LC-MS (ESI): m/z = 359.1 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.70 (d, J = 0.4 Hz, 1H), 7.64 (d, J = 0.8 Hz, 1H), 7.33-7.27 (m, 5H), 4.22-4.19 (m, 1H), 3.80 (s, 3H), 3.76 (d, 15 J = 6.8 Hz, 2H), 3.45-3.41 (m, 1H), 3.37 (s, 3H), 3.25-3.22 (m, 1H), 2.98-2.95 (m, 1H), 2.74-2.69 (m, 1H), 2.40-2.37 (m, 1 H).
WO 2013/110768 PCT/EP2013/051451 36 2-(1-Benzyl-4-methoxy-pyrrolidin-3-y)-3H-imidazo[5,1-f][1,2,4]triazin-4-one (20) 0 -O HN N'N J O-j N The procedure for the preparation ofcompound 20 was similar to that of compound 5. 5 32% yield. LC-MS (ESI): m/z = 325.3 [M+1]*. 'H NMR (300 MHz, CDC13): 6 8.05 (s, 1 H), 7.87 (s, 1H), 7.38-7.30 (m, 5H), 4.00-3.96 (m, 1H), 3.86 (d, J = 12.6 Hz, 1H), 3.62 (d, J = 12.6 Hz, 1H), 3.57-3.53 (m, 1H), 3.38 (s, 3H), 3.14-3.12 (m, 1H), 3.02-2.99 (m, 1H), 2.74-2.68 (m, 1 H), 2.36-2.31 (m, 1 H). 10 2-(1-Benzyl-4-methoxy-pyrrolidin-3-yI)-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one (21) 0 O HN N N'N The procedure for the preparation ofcompound 21 was similar to that of compound 6. 38% yield. LC-MS (ESI): m/z = 452.2 [M+1]*. 'H NMR (300 MHz, CDC13): 6 7.91 (s, 1 H), 7.40-7.30 (m, 5H), 4.00-3.96 (m, 1H), 3.88-3.84 (m, 1H), 3.66-3.49 (m, 2H), 3.40 (s, 3H), 15 3.24-3.22 (m, 1H), 3.03-2.99 (m, 1H), 2.74-2.69 (m, 1H), 2.37-2.32 (m, 1H). 2-(1 -Benzyl-4-methoxy-pyrrolidin-3-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5, 1 f][1,2,4]triazin-4-one (22) WO 2013/110768 PCT/EP2013/051451 37 0
-
HN N N'N / N D N The procedure for the preparation ofcompound 22 was similar to that of compound 7. 85% yield. LC-MS (ESI): m/z = 408 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.91 (s, 1H), 7.40-7.29 (m, 5H), 7.21 (m, 1H), 4.39-4.38 (m, 2H), 4.00-3.97 (m, 1H), 3.95-3.92 (m, 2H), 5 3.87-3.84 (m, 1H), 3.65-3.62 (m, 1H), 3.55-3.49 (m, 2H), 3.40-3.37 (s, 3H), 3.17-3.14 (m, 1 H), 3.03-3.00 (m, 1 H), 2.78-2.70 (m, 2H), 2.36-2.32 (m, 1 H). 3-Methoxy-4-[4-oxo-7-(tetrahydro-pyran-4-yl)-3,4-dihydro-imidazo[5,1 -f][1,2,4]triazin-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester (23) 0 0 HN N NN'N N 0 0 10 The procedure for the preparation ofcompound 23 was similar to that of compound 8. 46% yield. LC-MS (ESI): m/z = 420 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 4.10-4.06 (m, 2H), 3.96-3.80 (m, 2H), 3.61-3.54 (m, 2H), 3.48 (s, 3H), 3.42-3.31 (m, 1H), 3.31-3.22 (m, 2H), 2.09-2.03 (m, 2H), 2.02-1.89 (m, 2H), 1.62-1.58 (m, 2H), 1.49 (s, 9H). 15 2-(4-Methoxy-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4 one Hydrochloric acid salt (24) WO 2013/110768 PCT/EP2013/051451 38 0 0 H N N NN / N N H CIH 0 The procedure for the preparation of compound 24 was similar to that of compound 9. 100% yield. LC-MS (ESI): m/z = 320.2 [M+1]*. 'H NMR (400 MHz, DMSO-d6): 6 9.77-9.62 (br. s, 2H), 7.88 (s, 1H), 4.40-4.35 (m, 1H), 3.95-3.91 (m, 2H), 3.69-3.49 (m, 6H), 3.36 (s, 5 3H), 1.85-1.79 (m, 4H), 1.30-1.23 (m, 1H), 1.11-1.05 (m, 1H). Preparation of target compounds: Example 1 2-[1-(4-Fluoro-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-y)-3 H 10 imidazo[5,1 -f][1,2,4]triazin-4-one 0 0 0 HN H HN N N1 N N'N F NN NaBH 3 CN, DME N N H CIH 9 0 F0 To a solution of compound 9 (80 mg, 0.263 mmol) and 4-fluorobenzaldehyde (326 mg, 2.63 mmol) in 1,2-dichloroethane (15 mL) was added 2 drops of acetic acid. The resulting solution was stirred at room temperature for one hour. Then NaBH 3 CN (178 mg, 2.63 mmol) was 15 added to the reaction in portions. The resulting mixture was stirred at room temperature for 16 hours. LC-MS showed that the starting material was almost consumed. The reaction mixture was quenched with water (40 mL), and extracted with CH 2
CI
2 (30 mL x 3). The combined or ganic phases were washed with brine (30 mL), and dried over Na 2
SO
4 . After filtered, the fil trate was concentrated in vacuum. The residue was purified by preparative TLC to afford the 20 desired product (20 mg, 21% yield) as a white solid. LC-MS: m/z 412.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.27 (s, 1H), 7.61 (s, 1H), 7.35-7.31 (m, 2H), 7.02-6.98 (m, 2H), 3.96-3.93 (m, 2H), 3.79-3.70 (m, 2H), 3.51-3.39 (m, 3H), 3.15-3.11 (m, 1H), 3.05-2.95 (m, 2H), 2.84-2.79 (m, 1H), 2.61-2.57 (m, 1H), 2.33-2.29 (m, 1H), 1.93-1.87 (m, 2H), 1.80-1.77 (m, 2H), 1.09 (d, J = 6.8 Hz ,3H).
WO 2013/110768 PCT/EP2013/051451 39 The racemic mixture of 2-[1-(4-Fluoro-benzyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro pyran-4-yi)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one was submitted for preparative chiral HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 12 mL/min; UV: 230 nm; 30 mg/inj in) and give two enantiomers: 5 2-((3S,4S)-1 -(4-fluorobenzyl)-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN --- -- HN N N F 0 30% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 10 70/30; Flow rate = 1.0 mL/min): TR = 7.03. LC-MS: m/z 412.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.79 (s, 1H), 7.34-7.31 (m, 2H), 7.07-7.03 (m, 2H), 4.11-4.05 (m, 2H), 3.79-3.76 (d, J = 12.8 Hz, 1H), 3.62-3.53 (m, 3H), 3.41-3.35 (m, 2H), 2.97-2.95 (d, J = 10.4 Hz, 1H), 2.76-2.74 (m, 1H), 2.52-2.48 (m, 1H), 2.43-2.41 (m, 1H), 2.10-2.02 (m, 2H), 1.93-1.86 (m, 3H), 1.09 (d, J = 6.8 Hz, 3H). 15 2-((3R,4R)-1 -(4-fluorobenzyl)-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN -N N N F 0 30% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 20 70/30; Flow rate = 1.0 mL/min): TR = 9.03. LC-MS: m/z 412.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.78 (s, 1H), 7.33-7.30 (m, 2H), 7.06-7.02 (m, 2H), 4.10-4.05 (m, 2H), 3.78-3.74 (d, J = 12.8 Hz, 1H), 3.60-3.52 (m, 3H), 3.41-3.36 (m, 2H), 2.98-2.95 (d, J = 10.0 Hz, 1H), 2.76-2.73 (m, 1H), 2.52-2.49 (m, 1H), 2.43-2.41 (m, 1H), 2.08-2.01 (m, 2H), 1.93-1.85 (m, 3H), 1.09 (d, J = 6.4 Hz, 3H). 25 WO 2013/110768 PCT/EP2013/051451 40 The following compounds were prepared in a similar way: 7-(4-fluorophenyl)-2-(1-(4-methoxybenzyl)-4-methylpyrrolidin-3-y)imidazo[1,5 f][1,2,4]triazin-4(3H)-one 0 HN N' N N 0 F 5 42% yield. LC-MS: m/z 434.2 [M+1]*. 1H NMR (400 MHz, CD 3 0D-d4): 6 8.25-8.22 (m, 2H), 7.78 (s, 1H), 7.23-7.15 (m, 4H), 6.85-6.82 (m, 2H), 3.72 (s, 3H), 3.69 (m, 2H), 3.13 (m, 1H), 3.06-3.02 (m, 1H), 2.98-2.88 (m, 1H), 2.86-2.84 (m, 1H), 2.62-2.59 (m, 1H), 2.30-2.26 (m, 1H), 1.12 (d , J = 6.8 Hz, 3H). 10 7-(4-Fluoro-phenyl)-2-[4-methyl-1 -(6-trifluoromethyl-pyridin-3-ylmethyl)-pyrrolidin-3-yl] 3H-imidazo[5,1 -f][1,2,4]triazin-4-one 0 N L N N N N F
F
F N_ F 29% yield. LC-MS: m/z 473.2 [M+1]*. 1H NMR (400 MHz, CDC13): 6 8.67 (br. s, 1H), 15 8.36-8.32 (m, 2H), 8.00-7.96 (m, 1H), 7.96 (s, 1H), 7.77-7.75 (d, J = 8.0 Hz, 1H), 7.19-7.15 (m, 2H), 3.87-3.79 (m, 2H), 3.42-3.48 (m, 1H), 3.09-3.06 (d, J = 10.0 Hz, 1H), 2.90-2.87 (m, 1 H), 2.68~2.64 (m, 1 H), 2.51~2.49 (m, 1 H), 2.01~1.97 (dd, J = 8.4, 9.2 Hz, 1 H), 1.25 (d, J= 6.8 Hz, 3H). 20 2-[1-(6-Methoxy-pyridin-3-ylmethyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-y) 3H-imidazo[5,1 -f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 41 0 HN N' N N N N 0 0 23% yield, LC-MS: m/z 425.2 [M+1]. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.22 (br. s, 1H), 7.92 (s, 1 H), 7.78 (dd, J = 2.4, 8.4 Hz, 1 H), 6.80 (d, J = 8.4 Hz, 1 H), 4.42-4.27 (m, 2H), 3.96-3.94 (m, 2H), 3.89 (s, 3H), 3.84-3.81 (m, 2H), 3.68-3.64 (m, 2H), 3.64-3.56 (m, 2H), 3.20 (m, 2H), 5 2.85-2.82 (m, 1H), 1.98-1.85 (m, 4H), 1.18 (d, J = 6.4 Hz ,3H). 2-[4-Methyl-1 -(6-trifluoromethyl-pyridin-3-ylmethyl)-pyrrolidin-3-yI]-7-(tetrahydro-pyran 4-yi)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N v N N F N N F 0 F 10 18% yield, LC-MS: m/z 463.2 [M+1]*. 1H NMR (400 MHz, CDC13): 6 8.66 (s, 1H), 7.98 (d, J 8.0 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 4.11-4.06 (m, 2H), 3.87-3.84 (d, J = 13.2 Hz, 1H), 3.78-3.74 (d, J = 13.2 Hz, 1H), 3.62-3.54 (m, 2H), 3.36-3.41 (m, 2H), 3.04-3.02 (d, J = 9.6 Hz, 1H), 2.83-2.81 (m, 1H), 2.63 (m, 1H), 2.54 (m, 1H), 2.11-2.09 (m, 1H), 2.07-1.98 (m, 2H), 1.90-1.88 (m, 2H), 1.25 (d, J = 6.8 Hz ,3H). 15 2-[1-(6-Methoxy-pyridin-2-ylmethyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y) 3H-imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N~ NN N 0/N N N 0 9% yield, LC-MS: m/z 425.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.59 (s, 1H), 20 7.53-7.51 (m, 1 H), 6.89 (d, J = 7.2 Hz, 1 H), 6.58 (d, J = 8.0 Hz, 1 H), 3.95-3.92 (m, 2H), 3.82 (s, 3H), 3.73-3.62 (m, 2H), 3.52-3.46 (m, 3H), 3.19-3.15 (m, 1H), 3.05-3.03 (m, 1H), WO 2013/110768 PCT/EP2013/051451 42 2.93-2.91 (m, 1H), 2.78 (m, 1H), 2.54 (m, 1H), 2.25-2.23 (m, 1H), 1.92-1.87 (m, 2H), 1.81-1.78 (m, 2H), 1.09 (d, J = 6.8 Hz, 3H). 7-(4-Fluoro-phenyl)-2-[1-(6-methoxy-pyridin-2-ylmethyl)-4-methyl-pyrrolidin-3-yl]-3H 5 imidazo[5,1 -f][1,2,4]triazin-4-one 0 N NN N N F -0 47% yield. LC-MS: m/z 435.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.29 (m, 2H), 7.87 (s, 1H), 7.48 (m, 1H), 7.09 (m, 2H), 6.81 (m, 1H), 6.58 (m, 1H), 3.91 (s, 3H), 3.85-3.77 (m, 1H), 3.62-3.59 (m, 1H), 3.42-3.38 (m, 1H), 3.07 (m, 1H), 2.77 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 10 1.95 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H). 7-(4-Fluoro-phenyl)-2-[1-(6-methoxy-pyridin-3-ylmethyl)-4-methyl-pyrrolidin-3-yl]-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N N N N N 15 22% yield. LC-MS: m/z 435.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.36-8.33 (m, 2H), 8.07 (d, J = 1.2 Hz, 1H), 7.95 (s, 1H), 7.68-7.65 (dd, J = 2.4, 8.4 Hz, 1H), 7.18-7.14 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.74-3.70 (d, J = 12.8 Hz, 1H), 3.60-3.57 (d, J = 12.8 Hz, 1H), 3.40-3.36 (m, 1H), 3.05-3.02 (d, J = 10.4 Hz, 1H), 2.82 (m, 1H), 2.56 (m, 1H), 1.95-1.91 (m, 2H), 1.14 (d, J = 6.8 Hz, 3H). 20 7-(4-Fluoro-phenyl)-2-(4-methyl-1 -pyridin-2-ylmethyl-pyrrolidin-3-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 43 0 N 'N N N N N F 49% yield. LC-MS: m/z 405.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.44 (d, J = 4.4 Hz, 1 H), 8.24-8.22 (m, 2H), 7.77 (s, 1 H), 7.73-7.69 (m, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.24-7.21 (m, 1H), 7.17-7.12 (m, 2H), 3.84-3.73 (m, 2H), 3.12-3.10 (m, 1H), 3.04-3.00 (m, 1H), 5 2.94-2.89 (m, 1H), 2.85-2.81 (m, 1H), 2.61-2.59 (m, 1H), 2.26-2.22 (t, J = 8.4 Hz, 1H), 1.10 (d, J = 6.8 Hz, 3H). 2-[1-(2,4-Difluoro-benzyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N N N F 0 10 F 88% yield. LC-MS: m/z 387.1 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.73 (s, 1H), 7.52-7.46 (m, 1H), 6.96-7.01 (m, 2H), 4.08-4.05 (m, 2H), 3.79 (s, 2H), 3.65-3.55 (m, 3H), 3.18-3.14 (m, 1H), 3.03-2.97 (m, 2H), 2.88 (m, 1H), 2.69-2.62 (m, 1H), 2.29 (m, 1H), 2.06-1.97 (m, 2H), 1.93-1.90 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). 15 2-(3S,4S)-[1 -(2,4-Difluoro-benzyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 HN N' N N F 0 F 16% yield. Chiral analytical HPLC (Column = chiralcel AD; Mobile phase = C0 2 /MeOH/DEA 80/20/0.02 (v/v/v); Flow rate = 2.5 mL/min): TR = 1.43. LC-MS: m/z 430.2 [M+1]*. 'H NMR 20 (400 MHz, CDC13): 6 7.79 (s, 1H), 7.34-7.30 (m, 1H), 6.91-6.83 (m, 2H), 4.11-4.05 (m, 2H), 3.75-3.62 (m, 2H), 3.62-3.55 (m, 2H), 3.41-3.33 (m, 2H), 3.01 (d, J = 9.6 Hz, 1H), 2.76-2.74 WO 2013/110768 PCT/EP2013/051451 44 (m, 1H), 2.59-2.55 (m, 1H), 2.42-2.40 (m, 1H), 2.12-2.02 (m, 2H), 1.95-1.86 (m, 3H), 1.21 (d, J = 6.8 Hz, 3H). 5 2-(3R,4R)-[1 -(2,4-Difluoro-benzyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 HNN N'N -iN F 0 F 16% yield. Chiral analytical HPLC (Column = chiralcel AD; Mobile phase = C0 2 /IPA/DEA 60/40/0.04 (v/v/v); Flow rate = 2.4 mL/min): TR = 3.81. LC-MS: m/z 430.2 [M+1]*. 'H NMR 10 (300 MHz, CDC13): 6 7.80 (s, 1H), 7.36-7.27 (m, 1H), 6.93-6.84 (m, 2H), 4.11-4.08 (m, 2H), 3.77-3.76 (m, 2H), 3.63-3.56 (m, 2H), 3.43-3.34 (m, 2H), 3.01 (d, J = 10.2 Hz, 1H), 2.77-2.76 (m, 1H), 2.61-2.58 (m, 1H), 2.44-2.40 (m, 1H), 2.15-2.03 (m, 2H), 1.97-1.87 (m, 3H), 1.22 (d, J = 10.0 Hz, 3H). 15 2-(1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yI)-7-(4-fluorophenyl)imidazo[1,5 f][1,2,4]triazin-4(3H)-one 0 HN -N N N N F F 39% yield. LC-MS: m/z 422.1 [M+1]*. 'H NMR (400 MHz, DMSO-d6): 6 8.41-8.38 (m, 2H), 20 7.87 (s, 1H), 7.40-7.32 (m, 4H), 7.15-7.10 (m, 2H), 3.62 (s, 2H), 2.98 (m, 1H), 2.88-2.78 (m, 2H), 2.71-2.67 (m, 1H), 2.30-2.26 (m, 1H), 2.01-1.97 (m, 1H), 1.12 (d , J= 6.8 Hz, 3H).
WO 2013/110768 PCT/EP2013/051451 45 2-(4-methyl-1 -(4-(trifluoromethoxy)benzyl)pyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN N F F N FE N
F
0- 0 36% yield. LC-MS: m/z 478 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.74 (s, 1H), 7.32 (d, J = 5 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.00 (m, 2H), 3.73 (d, J = 12.8 Hz, 1H), 3.57-3.48 (m, 3H), 3.35-3.30 (m, 2H), 2.95 (d, J = 10.0 Hz, 1H), 2.73-2.71 (m, 1H), 2.40 (m, 1H), 2.38 (m, 1H), 1.89-1.82 (m, 5H), 1.15 (d, J= 6.8 Hz, 3H). 2-(1-(2-chloro-4-methoxybenzyl)-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 10 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN N CI N 0 0 27% yield. LC-MS: m/z 458.2 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.77 (s, 1H), 7.25 (d, J 8.4 Hz, 1 H), 6.97 (d, J = 2.8 Hz, 1 H), 6.82-6.79 (dd, J = 8.4, 2.8 Hz, 1 H), 4.08-4.05 (m, 2H), 3.79 (s, 3H), 3.79-3.61 (m, 2H), 3.61-3.55 (m, 2H), 3.44-3.00 (m, 2H), 3.02 (m, 1H), 15 2.76-2.74 (m, 1H), 2.62-2.58 (m, 1H), 2.42-2.37 (m, 1H), 2.15-2.00 (m, 2H), 1.99-1.86 (m, 3H), 1.26 (d, J= 12.4 Hz, 3H). 2-(4-methyl-1 -(quinoxalin-6-ylmethyl)pyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN N N N N 0 20 c-zN WO 2013/110768 PCT/EP2013/051451 46 30% yield. LC-MS: m/z 446 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.10 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 4.02-3.88 (m, 3H), 3.88-3.86 (m, 1H), 3.53-3.46 (m, 2H), 3.43-3.29 (m, 2H), 3.05 (m, 1H), 2.77 (m, 1H), 2.67 (m, 1H), 2.46 (m, 1H), 2.09-1.91 (m, 3H), 1.83-1.78 (m, 2H), 1.19 (d, J = 6.8 Hz, 3H). 5 2-[1-(5-Methoxy-2-methyl-penta-2,4-dienyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro pyran-4-yi)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N N N N N 0- 0 20% yield. LC-MS: m/z 424.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.79 (s, 1 H), 7.27 (d, J = 10 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.11-4.05 (m, 2H), 3.79 (s, 3H), 3.78 (m, 1H), 3.61-3.55 (m, 2H), 3.50-3.36 (m, 3H), 2.97-2.94 (d, J = 10.0 Hz, 1H), 2.73 (m, 1H), 2.49-2.41 (m, 2H), 2.13-2.02 (m, 3H), 1.92-1.86 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). 2-(4-methyl-1 -(pyridin-4-ylmethyl)pyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 15 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 N N' N N 0 12% yield. LC-MS: m/z 395.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.60 (d, J = 5.2 Hz, 2H), 7.82 (s, 1H), 7.29 (d, J = 5.2 Hz, 2H), 4.11 (m, 2H), 3.81 (d, J = 13.6 Hz, 1H), 3.65-3.55 (m, 3H), 3.44-3.38 (m, 2H), 3.03 (d, J = 10.0 Hz, 1H), 2.81-2.79 (m, 1H), 2.60-2.55 (m, 1H), 20 2.48-2.45 (m, 1H), 2.16-2.03 (m, 2H), 1.97-1.74 (m, 3H), 1.24 (d, J = 6.0 Hz, 3H) 2-(4-Methyl-1 -pyridin-2-ylmethyl-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-yl)-3H imidazo[5,1 -f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 47 0 HN N N N 7% yield. LC-MS: m/z 395.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.43 (d, J = 4.8 Hz, 1H), 7.75-7.70 (m, 1H), 7.60 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.24-7.21 (m, 1H), 3.93 (m, 2H), 3.82-3.71(m, 2H), 3.52-3.46 (m, 2H), 3.10-3.05 (m, 1H), 2.98-2.94 (m, 1H), 2.87-2.76 5 (m, 2H), 2.56-2.53 (m, 1H), 2.21-2.17 (m, 1H), 1.93-1.87 (m, 2H), 1.81-1.78 (m, 2H), 1.07 (d, J = 7.2 Hz, 3H),. 2-(4-methyl-1 -(pyrimidin-5-ylmethyl)pyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN I N N N N N 10 N O 44% yield. LC-MS: m/z 396.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 9.17 (br. s, 1 H), 8.75 (s, 2 H), 7.79 (s, 1H), 4.09-4.05 (m, 2H), 3.73 (s, 2H), 3.61-3.54 (m, 2H), 3.47-3.31 (m, 2H), 3.06 (d, J = 6.0 Hz, 1H), 2.83-2.80 (m, 1H), 2.66-2.61 (dd, J = 10.0, 7.2 Hz, 1H), 2.47-2.44 (m, 1H), 2.12-1.96 (m, 2H), 1.94-1.74 (m, 3H), 1.25 (d, J = 6.8 Hz, 3H). 15 2-[1-(4-Diethylamino-benzyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-yl)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N N'N N N NN Nj 0 35% yield. LC-MS: m/z 465.3 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.78 (s, 1H), 7.17 (d, J= 20 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.11-4.05 (m, 2H), 3.76-3.73 (d, J = 12.4 Hz, 1H), 3.62-3.55 (m, 2H), 3.49-3.30 (m, 7H), 2.98 (d, J = 10.0 Hz, 1H), 2.70 (m, 1H), 2.46-2.39 (m, 2H), 2.15-1.81 (m, 5H), 1.19 (d, J = 7.2 Hz, 3H), 1.16-1.13 (t, J= 7.2 Hz, 6H).
WO 2013/110768 PCT/EP2013/051451 48 2-(1 -(furan-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5 f][1,2,4]triazin-4(3H)-one 0 HN N~ NN 0 N Gk-j 0 5 35% yield. LC-MS: m/z 384.2 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.80 (s, 1 H), 7.41 (d, J = 2.0 Hz, 1H), 6.34 (dd, J = 2.0, 2.8 Hz, 1H), 6.26 (d, J = 2.8 Hz, 1H ), 4.11-4.07 (m, 2H), 3.88-3.84 (d, J = 14.0 Hz, 1H), 3.67-3.56 (m, 3H), 3.45-3.37 (m, 2H), 3.03 (d, J = 10.0 Hz, 1H), 2.77-2.74 (m, 1H), 2.61-2.58 (m, 1H), 2.45-2.42 (m, 1H), 2.14-1.98 (m, 3H), 1.92-1.88 (m, 2H), 1.21 (d, J = 7.2 Hz, 3H) 10 2-(1 -((1 H-imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN N N 5% yield. LC-MS: m/z 384.2 [M+1]*. 1H NMR (400 MHz, CD 3 0D-d4): 6 8.44 (br. s, 2H), 7.75 15 (s, 1H), 7.11 (s, 1H), 4.08-4.06 (m, 2H), 3.87 (s, 2H), 3.65-3.53 (m, 3H), 3.18-3.14 (dd, J = 7.6, 8.8 Hz, 1H), 3.07-3.00 (m, 2H), 2.93-2.88 (m, 1H), 2.73-2.69 (m, 1H), 2.38-2.34 (dd, J = 7.6, 9.2 Hz, 1 H), 2.07-1.91 (m, 4H), 1.09 (d, J = 6.8 Hz, 3H). 2-((3S,4S)-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5 20 f][1,2,4]triazin-4(3H)-one WO 2013/110768 PCT/EP2013/051451 49 0 HN H 0 45% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n Hexane/EtOH/DEA 80/20:0.3; Flow rate = 1.0 mL/min): TR = 7.44. LC-MS: m/z = 304.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.49 (s, 1H), 3.96-3.93 (m, 2H), 3.53-3.31 (m, 5 6H), 2.82-2.77 (m, 1H), 2.69-2.66 (m, 1H), 2.64-2.53 (m, 1H), 1.95-1.88 (m, 2H), 1.82-1.78 (m, 2H), 1.10 (d, J = 6.8 Hz, 3H). 2-((3R,4R)-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5 fl[1,2,4]triazin-4(3H)-one 0 HN N N N H 10 0 45% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase =n Hexane/EtOH/DEA 80/20:0.3; Flow rate = 1.0 mL/min): TR = 9.93. LC-MS: m/z 304.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.42 (br. s, 2H), 7.63 (s, 1 H), 3.97-3.93 (m, 2H), 3.68-3.41 (m, 6H), 3.05-2.99 (m, 1H), 2.96-2.91 (m, 1H), 2.70-2.66 (m, 1H), 1.95-1.90 (m, 2H), 15 1.82-1.78 (m, 2H), 1.10 (d, J = 6.8 Hz, 3H). 4-((3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-y)-3,4-dihydroimidazo[l,5 fl[1,2,4]triazin-2-yl)pyrrolidin-1 -yl)methyl)benzonitrile 0 HN NC N 36% yield. LC-MS: m/z 419.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.63 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J = 7.6 Hz, 2H), 3.96-3.93 (m, 2H), 3.76-3.72 (d, J = 13.6 Hz, 1H), WO 2013/110768 PCT/EP2013/051451 50 3.70-3.66 (d, J = 13.6 Hz, 1H), 3.53-3.40 (m, 3H), 3.05-3.00 (dd, J = 8.0, 8.8 Hz, 1H), 2.91-2.84 (m, 2H), 2.80-2.75 (m, 1H), 2.60-2.57 (m, 1H), 2.21-2.17 (m, 1H), 1.95-1.90 (m, 2H), 1.81-1.78 (m, 2H), 1.10 (d, J = 6.8 Hz, 3H). 5 2-(1 -(2-ch Ioro-4-fl uorobenzyl)-4-methyl pyrrol idi n-3-yl)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN C N'N N F 0 72% yield. LC-MS: m/z 446 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.77 (s, 1H), 7.35-7.31 (m, 10 1H), 7.19-7.16 (m, 1H), 7.01-6.99 (m, 1H), 4.10-4.05 (m, 2H), 3.83 (d, J = 12.8 Hz, 1H), 3.72 (d, J = 12.8 Hz, 1H), 3.61-3.55 (m, 2H), 3.40-3.30 (m, 2H), 3.03 (d, J = 10.0 Hz, 1H), 2.77 (m, 1H), 2.65-2.61 (m, 1H), 2.41-2.39 (m, 1H), 2.10-2.03 (m, 2H), 1.95-1.88 (m, 3H), 1.22 (d, J = 8.8 Hz, 3H). 15 2-(1-(4-(dimethylamino)benzyl)-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN N SN' N N N N- 0 25% yield. LC-MS: m/z 437 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.78 (s, 1H), 7.22 (d, J = 20 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.10-4.05 (m, 2H), 3.79 (d, J = 12.8 Hz, 1H), 3.61-3.55 (m, 2H), 3.45-3.36 (m, 3H), 2.97 (d, J = 8.0 Hz, 1 H), 2.93 (s, 6H), 2.88 (m, 1 H), 2.72 (m, 1 H), 2.48-2.40 (m, 2H), 2.12-2.01 (m, 2H), 1.91-1.85 (m, 2H), 1.19 (d, J = 6.8 Hz, 3H).
WO 2013/110768 PCT/EP2013/051451 51 2-(4-methyl-1 -(4-methylbenzyl)pyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4-yI)imidazo[1,5 f][1,2,4]triazin-4(3H)-one 0 HN N N NYN -/N 0 62% yield. LC-MS: m/z 408 [M+1]*. 1H NMR (400 MHz, CDC13): 6 8.05 (br. s, 1H), 7.79 (s, 5 1H), 7.24 (d, J = 7.2 Hz, 2H), 7.17 (d, J = 7.2 Hz, 2H), 4.10-4.05 (m, 2H), 3.82 (d, J = 12.4 Hz, 1H), 3.61-3.55 (m, 2H), 3.51 (d, J = 12.8 Hz, 1H), 3.41-3.37 (m, 2H), 2.99 (d, J = 10.0 Hz, 1H), 2.74 (d, J = 4.4 Hz, 1H), 2.52-2.42 (m, 2H), 2.32 (s, 3H), 2.13-2.01 (m, 2H), 1.95-1.85 (m, 3H), 1.20 (d, J = 6.4 Hz, 3H). 10 2-(1 -Cyclohexylmethyl-4-methyl-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N N N N C -j 0 37% yield. LC-MS: m/z 400.2 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.79 (s, 1 H), 4.09-4.05 (m, 2H), 3.63-3.59 (m, 2H), 3.43-3.41 (m, 2H), 3.09-3.06 (d, J = 11.6 Hz, 1 H), 2.75 (m, 1 H), 15 2.41-2.44 (m, 1H), 2.37-2.34 (m, 3H), 2.17-2.01 (m, 2H), 1.90-1.93 (m, 3H), 1.80-1.76 (m, 5H), 1.68-1.65 (m, 1H), 1.46-1.43 (m, 1H), 1.24 (m, 2H), 1.21 (d, J = 7.2 Hz, 3H), 0.98 (m, 2H). 2-(4-Methyl-1 -pyridin-3-ylmethyl-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-yl)-3H 20 imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N' N N
NN
WO 2013/110768 PCT/EP2013/051451 52 60% yield. LC-MS: m/z 395.2 [M+1]*. 'HNMR (400 MHz, CDC13): 6 8.55 (m, 2H), 7.80 (s, 1H), 7.78 (m, 1H), 7.37-7.35 (m, 1H), 4.08 (m, 2H), 3.81-3.78 (d, J = 12.8 Hz, 1H), 3.67-3.64 (d, J = 12.8 Hz, 1H), 3.62-3.58 (m, 2H), 3.41-3.38 (m, 2H), 2.99 (d, J = 10.0 Hz, 1H), 2.79-2.77 (m, 1H), 2.59-2.57 (m, 1H), 2.50-2.40 (m, 1H), 1.99-1.89 (m, 5H), 1.22 (d, J = 7.2 Hz, 3H). 5 2-[1-(2,6-Difluoro-benzyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 N N N F N 0 F 9% yield. LC-MS: m/z 430.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.78 (s, 1H), 7.28 (m, 1H), 10 6.97-6.94 (t, J = 8.0 Hz, 2H), 4.10-4.06 (m, 2H), 3.91 (s, 2H), 3.61-3.55 (m, 2H), 3.40-3.38 (m, 2H), 3.15 (m, 1H), 2.74-2.62 (m, 2H), 2.42 (m, 1H), 2.10-2.02 (m, 3H), 1.90-1.87 (m, 2H), 1.19 (d, J= 7.2 Hz, 3H). 2-[4-Methyl-1 -(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H imidazo[5,1-f][1,2,4]triazin-4-one 0 HN N' N /N N ND 15 S 15% yield. LC-MS: m/z = 414.2 [M+1]*. 'H NMR (300 MHz, CDC13): 6 7.81 (s, 1H), 6.73 (d, J = 3.3 Hz, 1H), 6.58-6.57 (m, 1H), 4.13-4.06 (m, 2H), 3.97 (d, J = 13.5 Hz, 1H), 3.67 (d, J= 13.5 Hz, 1H), 3.64-3.55 (m, 2H), 3.48-3.38 (m, 2H), 3.08 (d, J = 9.9 Hz, 1H), 2.78-2.75 (m, 1H), 2.53-2.43 (m, 5H), 2.16-1.88 (m, 5H), 1.22 (d, J = 7.2 Hz, 3H). 20 2-[1-(5-Chloro-thiophen-2-ylmethyl)-4-methyl-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y) 3H-imidazo[5,1 -f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 53 0 HN I 'N N N N CI S0 20% yield. LC-MS: m/z = 434.1 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.81 (s, 1 H), 6.77-6.75 (m, 2H), 4.11-4.06 (m, 2H), 3.94 (d, J = 14.4 Hz, 1H), 3.69 (d, J = 13.2 Hz, 1H), 3.62-3.56 (m 2H), 3.47-3.42 (m, 2H), 3.10 (d, J = 10.0 Hz, 1H), 2.79-2.78 (m, 1H), 2.55-2.43 (m, 2H), 5 2.15-1.96 (m, 2H), 1.92-1.90 (m, 3H), 1.22 (d, J = 6.8 Hz, 3H). 2-[4-Methyl-1 -(4-pyrrolidin-1 -yI-benzyl)-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 HN N N cN 0 10 10% yield. LC-MS: m/z = 463.3 [M+1]*. 'H NMR (300 MHz, CDC13): 6 7.80 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 8.7 Hz, 2H), 4.11-4.03 (m, 2H), 3.78 (d, J = 12.9 Hz, 1H), 3.62-3.54 (m 2H), 3.44-3.35 (m, 3H), 3.28-3.23 (m, 4H), 2.98-2.95 (m, 1H), 2.72-2.70 (m, 1H), 2.47-2.42 (m, 2H), 2.17-1.85 (m, 9H), 1.19 (d, J = 6.9 Hz, 3H). 15 2-[1-(4-Fluoro-benzyl)-4-methoxy-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 0' HN N F 0 19% yield. LC-MS: m/z = 428.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.81 (s, 1H), 7.34-7.31 (m, 2H), 7.08-7.04 (m, 2H), 4.10-4.07 (m, 2H), 3.99-3.97 (m, 1H), 3.84 (d, J = 12.4 Hz, 1H), 20 3.61-3.50 (m, 4H), 3.39 (s, 3H), 3.16 (d, J = 6.4 Hz, 1H), 3.99 (d, J = 9.6 Hz, 1H), 2.72-2.69 (m, 1H), 2.35-2.30 (m, 1H), 2.15-2.01 (m, 2H), 1.90-1.88 (m, 2H), 1.25-1.24 (m, 1H).
WO 2013/110768 PCT/EP2013/051451 54 2-[4-Methoxy-1 -(4-methyl-benzyl)-pyrrolidin-3-yI]-7-(tetrahydro-pyran-4-y)-3 H imidazo[5,1 -f][1,2,4]triazin-4-one 0 o HN IN N N N 0 5 13% yield. LC-MS: m/z = 424.3 [M+1]*. 1H NMR (300 MHz, CDC13): 6 7.80 (s, 1H), 7.25 (d, J = 6.6 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 4.09-4.00 (m, 3H), 3.88 (d, J = 12.6 Hz, 1H), 3.61-3.53 (m, 4H), 3.44-3.40 (m, 1H), 3.37 (s, 3H), 3.19-3.17 (m, 1H), 3.07-3.03 (m, 1H), 2.77-2.76 (m, 1H), 2.41-2.37 (m, 1H), 2.33 (s, 3H), 2.13-1.99 (m, 2H), 1.90-1.96 (m, 2H). 10 2-[4-Methoxy-1 -(4-methoxy-benzyl)-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 o HN N N-N N 00 0 25% yield. LC-MS: m/z = 440.1 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.81 (s, 1 H), 7.27 (d, J = 6.0 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.09-4.07 (m, 2H), 3.99-3.96 (m, 1 H), 3.79 (s, 3H), 15 3.61-3.51 (m, 4H), 3.38 (s, 3H), 3.15-3.13 (m, 1H), 3.00-2.97 (m, 1H), 2.69-2.65 (m, 1H), 2.34-2.30 (m, 1H), 2.13-2.00 (m, 3H), 1.90-1.87 (m, 3H). Example 2 20 2-(1 -Benzyl-4-methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5, 1 f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 55 0 N Br N NN N NN N CI K 2
CO
3 , CH 3 CN N 9 0 To a solution of compound 6 (70 mg, 0.296 mmol) and potassium carbonate (70 mg, 0.296 mmol) in acetonitrile (10 mL) was added benzyl bromide (70 mg, 0.296 mmol). The resulting solution was stirred at room temperature for 2 h. LC-MS showed that the reaction was com 5 plete. The reaction was quenched with water (40 mL), and the reaction mixture was extracted with CH 2
CI
2 (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na 2
SO
4 and concentrated in vacuum. The residue was purified by preparative TLC
(CH
2
CI
2 /MeOH = 10:1) to afford the desired product (28.6 mg, 25% yield) as a white solid. LC-MS: m/z 394.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.60 (s, 1 H), 7.29-7.22 (m, 4H), 10 7.19-7.17 (m, 1H), 3.95-3.92 (m, 2H), 3.69-3.58 (m, 2H), 3.52-3.46 (m, 3H), 3.21 (m, 1H), 3.06-3.04 (m, 1H), 2.91-2.76 (m, 2H), 2.58-2.56 (m, 1H), 2.16 (m, 1H), 1.89-1.81 (m, 2H), 1.78 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). The racemic mixture of 2-(1-Benzyl-4-methyl-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-y) 15 3H-imidazo[5,1-f][1,2,4]triazin-4-one was submitted for preparative chiral HPLC (Column = chiralpak OD-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 25 mL/min; UV: 230 nm; 30 mg/inj in) and gave two enantiomers: 2-((3S,4S)-1 -benzyl-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5 20 f][1,2,4]triazin-4(3H)-one 0 N N N N N 0 80% yield. Chiral analytical HPLC (Column = chiralpak OD-H; Mobile phase =n Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): TR = 5.85. LC-MS: m/z 394.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.79 (s, 1H), 7.37-7.35 (m, 4H), 7.31-7.29 (m, 1H), 4.11-4.05 (m, 25 2H), 3.84-3.81 (d, J = 12.4 Hz, 1H), 3.62-3.55 (m, 3H), 3.43-3.38 (m, 2H), 2.99-2.96 (d, J = WO 2013/110768 PCT/EP2013/051451 56 10.4 Hz, 1H), 2.75-2.73 (m, 1H), 2.53-2.48 (m, 1H), 2.43-2.41 (m, 1H), 2.13-2.02 (m, 2H), 1.95-1.86 (m, 3H), 1.21 (d, J = 7.2 Hz, 3H). 2-((3R,4R)-1 -benzyl-4-methylpyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4-yI)imidazo[1,5 5 f][1,2,4]triazin-4(3H)-one 0 N N N N 0 80% yield. Chiral analytical HPLC (Column = chiralpak OD-H; Mobile phase =n Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): TR = 7.57. LC-MS: m/z 394.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.79 (s, 1H), 7.37-7.35 (m, 4H), 7.31-7.26 (m, 1H), 4.11-4.05 (m, 10 2H), 3.84-3.81 (d, J = 12.4 Hz, 1H), 3.62-3.55 (m, 3H), 3.43-3.37 (m, 2H), 2.99-2.96 (d, J = 10.0 Hz, 1H), 2.75-2.73 (m, 1H), 2.53-2.48 (m, 1H), 2.43-2.41 (m, 1H), 2.13-2.02 (m, 2H), 1.95-1.85 (m, 3H), 1.21 (d, J = 7.2 Hz, 3H). The following compounds were prepared in a similar way: 15 7-(4-Fluoro-phenyl)-2-(4-methyl-1 -pyrimidin-2-ylmethyl-pyrrolidin-3-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one 0 N N N N N N N F 40 % yield. LC-MS: m/z 405.9 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.76 (d, J = 4.8 Hz, 20 2H), 8.15 (m, 2H), 7.84 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.20-7.16 (d, J = 8.8 Hz, 2H), 4.62-4.47 (m, 3H), 4.01-3.91 (m, 3H), 3.30-3.20 (m, 1H), 2.94-2.86 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H).
WO 2013/110768 PCT/EP2013/051451 57 7-(4-fluorophenyl)-2-((3S,4S)-4-methyl-1 -(pyrimidin-2-ylmethyl)pyrrolidin-3 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN N N N N' N F 30% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 5 70/30; Flow rate = 1.0 mL/min): TR = 7.68. LC-MS: m/z 406.2 [M+1]*. 'H NMR (400 MHz, MeOH-d4): 6 8.74 (d, J = 5.2 Hz, 2H), 8.28-8.25 (m, 2H), 7.78 (s, 1H), 7.32 (m, 1H), 7.18 (m, 2H), 4.04 (d, J = 15.2 Hz, 1H), 4.87 (d, J = 15.2 Hz, 1H), 3.19 (m, 2H), 2.89-2.82 (m, 3H), 2.31 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H). 10 7-(4-fluorophenyl)-2-((3R,4R)-4-methyl-1 -(pyrimidin-2-ylmethyl)pyrrolidin-3 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HNN NN N CN
N
N F 30% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): TR = 9.39. LC-MS: m/z 406.2 [M+1]*. 'H NMR (400 MHz, 15 MeOH-d4): 6 8.74 (d, J =4.8 Hz, 2H), 8.28-8.25 (m, 2H), 7.78 (s, 1H), 7.32 (m, 1H), 7.18 (m, 2H), 4.04 (d, J = 15.6 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), 3.19 (m, 2H), 2.89-2.82 (m, 3H), 2.31 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H). 2-(4-Methyl-1 -pyrimidin-2-ylmethyl-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-y)-3H 20 imidazo[5,1 -f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 58 0 H N N' N N N CN 33% yield. LC-MS: m/z 396.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.73 (d, J = 5.2 Hz, 2H), 7.62 (s, 1H), 7.30 (t, J = 4.8 Hz, 1H), 4.08-4.04 (d, J = 15.6 Hz, 1H), 3.96-3.86 (m, 3H), 3.54-3.44 (m, 3H), 3.26-3.15 (m, 2H), 2.85-2.82 (m, 2H), 2.52 (m, 1H), 2.30-2.28 (m, 1H), 5 1.92-1.89 (m, 2H), 1.88-1.79 (m, 2H), 1.11 (d, J = 7.2 Hz, 3H). 2-((3S,4S)-4-methyl-1 -(pyrimidin-2-ylmethyl)pyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN I NN N N -j 0 NO 10 29% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): TR = 6.63. LC-MS: m/z 396 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.84 (d, J= 4.8 Hz, 2H), 7.81 (s, 1H), 7.23 (t, J = 4.8 Hz, 1H), 4.30 (d, J = 16.8 Hz, 1H), 4.07 (m, 2H), 3.87 (d, J = 16.8 Hz, 1H), 3.64-3.57 (m, 2H), 3.51-3.44 (m, 2H), 3.26 (d, J = 10.0 Hz, 1H), 2.83-2.81 (m, 1H), 2.63-2.60 (m, 1H), 2.51-2.48 (m, 1H), 2.30-2.26 (m, 1H), 15 2.12-2.05 (m, 2H), 1.95-1.89 (m, 2H), 1.27 (d, J = 7.2 Hz, 3H). 2-((3R,4R)-4-methyl-1 -(pyrimidin-2-ylmethyl)pyrrolidin-3-yI)-7-(tetrahydro-2H-pyran-4 yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one 0 HN N N N N 20 29% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): TR = 8.13. LC-MS: m/z 396 [M+1]*. 'H NMR (400 MHz, WO 2013/110768 PCT/EP2013/051451 59 CDC13): 6 8.84 (d, J= 4.8 Hz, 2H), 7.81 (s, 1H), 7.23 (t, J = 4.8 Hz, 1H), 4.30 (d, J = 16.8 Hz, 1H), 4.07 (m, 2H), 3.87 (d, J = 16.8 Hz, 1H), 3.64-3.57 (m, 2H), 3.51-3.44 (m, 2H), 3.26 (d, J = 10.0 Hz, 1H), 2.83-2.81 (m, 1H), 2.62-2.58 (m, 1H), 2.49-2.47 (m, 1H), 2.29-2.25 (m, 1H), 2.12-2.05 (m, 2H), 1.95-1.89 (m, 2H), 1.27 (d, J = 7.2 Hz, 3H). 5 2-(1 -Benzyl-4-methoxy-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5, 1 f][1,2,4]triazin-4-one 0 o HN N N'.N / N O-j 0 32% yield. LC-MS: m/z = 410.2 [M+1]*. 'H NMR (300 MHz, CDC13): 6 7.86 (s, 1 H), 7.46-7.43 (m, 5H), 4.77-4.71 (m, 1H), 4.53-4.35 (m, 2H), 4.23-4.18 (m, 1H), 4.07-4.04 (m, 2H), 10 3.81-3.71 (m, 3H), 3.56-3.46 (m, 2H), 3.42 (s, 3H), 3.38-3.31 (m, 2H), 2.10-2.01 (m, 2H), 1.88-1.83 (m, 2H). 2-(3S,4S)-(1 -Benzyl-4-methoxy-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5, 1 f][1,2,4]triazin-4-one 0 O HN N N 'N N 15 40% yield. Chiral analytical HPLC (Column = chiralcel AD-H; Mobile phase = n-Hexane/EtOH 60/40; Flow rate = 0.6 mL/min): TR = 10.8. LC-MS m/z = 410.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.81 (s, 1H), 7.40-7.34 (m, 5H), 4.10-4.07 (m, 2H), 4.00-3.97 (m, 1H), 3.88 (d, J = 12.4 Hz, 1H), 3.62-3.53 (m, 4H), 3.44-3.37 (m, 4H), 3.15 (d, J = 6.4 Hz, 1H), 2.99 (d, J = 20 10.0 Hz, 1H), 2.72-2.68 (m, 1H), 2.36-2.32 (m, 1H), 2.13-2.03 (m, 2H), 1.91-1.87 (m, 2H).
WO 2013/110768 PCT/EP2013/051451 60 2-(3R,4R)-(1 -Benzyl-4-methoxy-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 HN N NN O-j 0 40% yield. Chiral analytical HPLC (Column = chiralcel AD-H; Mobile phase = n-Hexane/EtOH 5 60/40; Flow rate = 0.6 mL/min): TR = 11.9. LC-MS: m/z = 410.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.81 (s, 1H), 7.39-7.29 (m, 5H), 4.10-4.07 (m, 2H), 3.99-3.96 (m, 1H), 3.88 (d, J = 12.4 Hz, 1H), 3.62-3.52 (m, 4H), 3.41-3.38 (m, 4H), 3.15 (d, J = 6.0 Hz, 1H), 2.99 (d, J = 10.0 Hz, 1H), 2.72-2.68 (m, 1H), 2.36-2.32 (m, 1H), 2.13-2.03 (m, 2H), 1.91-1.87 (m, 2H). 10 2-(4-Methyl-1 -pyrimidin-4-ylmethyl-pyrrolidin-3-yI)-7-(tetrahydro-pyran-4-yl)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 HN N'N N' N /N NN N NN 0 5% yield. LC-MS: m/z = 396.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 9.15 (s, 1H), 8.74 (d, J = 5.2 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J = 6.0 Hz, 1H), 4.07-4.04 (m, 2H), 3.98 (d, J = 15.2 15 Hz, 1H), 3.87 (d, J = 15.2 Hz, 1H), 3.64-3.55 (m, 3H), 3.24-3.20 (m, 1H), 3.13-3.12 (m, 1H), 3.01-2.97 (m, 1H), 2.93-2.88 (m, 1H), 2.70-2.66 (m, 1H), 2.38-2.34 (m, 1H), 2.06-1.99 (m, 2H), 1.92-1.89 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H). Example 3 20 2-(1 -Benzyl-4-methyl-pyrrolidin-3-yI)-7-pyridin-3-yI-3H-imidazo[5,1 -f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 61 0 OH
B
HN N N OH HN N N N N N N, - - N N Pd(dppf) 2 Cl 2 , Xantphos, K 3
PO
4 N DMF/H20, Microwave N 6 The procedure for the preparation of this compound was similar to that of compound 7. 60% yield. LC-MS: m/z 387.1 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 9.37 (br. s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.51 (m, 1H), 7.97 (br. s, 1H), 7.89 (m, 1H), 7.81 (s, 1H), 7.50-7.47 (m, 5 1H), 7.30-7.14 (m, 4H), 3.74-3.65 (m, 2H), 3.12-3.09 (m, 1H), 3.01-2.92 (m, 2H), 2.85-2.81 (m, 1H), 2.63-2.60 (m, 1H), 2.26-2.23 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H). 2-(1 -benzyl-4-methylpyrrolidin-3-yI)-7-(4-(trifluoromethoxy)phenyl)imidazo[1,5 f][1,2,4]triazin-4(3H)-one 0 HN NN N N N F 0 F 10 F 47% yield. LC-MS: m/z 470.2 [M+H]*. 'H NMR (400 MHz, DMSO-d6): 6 8.49 (d, J = 9.2 Hz, 2H), 7.90 (s, 1H), 7.54-7.52 (d, J = 8.0 Hz, 2H), 7.34-7.28 (m, 3H), 7.25-7.23 (m, 1H), 3.64 (s, 2H), 2.99-2.87 (m, 3H), 2.85-2.82 (m, 1H), 2.28 (m, 1H), 2.00 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H). 15 2-(1 -Benzyl-4-methyl-pyrrolidin-3-y)-7-pyridin-4-y-3H-imidazo[5,1 -f][1,2,4]triazin-4-one 0 HN N N N N (: -jN WO 2013/110768 PCT/EP2013/051451 62 20% yield. 'H NMR (400 MHz ,CDC13): 6 8.72 (d, J = 7.2 Hz, 2H), 8.29 (d, J = 3.6 Hz, 2H), 8.01 (s, 1H), 7.39-7.31 (m, 5H), 3.87 (m, 1H), 3.65 (m, 1H), 3.49-3.43 (m, 1H), 3.08 (m, 1H), 2.88 (m, 1 H), 2.53 (m, 1 H), 2.24 (m, 2H), 1.27 (d, J = 7.2 Hz, 3H). 5 2-(1 -benzyl-4-methylpyrrolidin-3-yI)-7-(2,4-difluorophenyl)imidazo[1,5-f][1,2,4]triazin 4(3H)-one 0 HN N N F N F 31% yield. LC-MS: m/z 422 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.99 (s, 1H), 7.78-7.72 (m, 1H), 7.40-7.28 (m, 5H), 7.03-6.93 (m, 2H), 3.82 (d, J = 12.4 Hz, 1H), 3.57 (d, J = 12.4 Hz, 10 1H), 3.39 (t, J = 8.4 Hz, 1H), 2.99 (d, J = 10.0 Hz, 1H), 2.72-2.70 (m, 1H), 2.52-2.40 (m, 2H), 1.92 (dd, J = 8.0, 9.2 Hz, 1H), 1.17 (d, J = 6.8 Hz, 3H). Part II (Azetidine Series) 15 Preparation of intermediates 2-Chloromethyl-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one Scheme 6 WO 2013/110768 PCT/EP2013/051451 63 00 O o 0 NH, 0 N HO H OBn NH3-H 2 O H OBn KOH (aq) HN 2 HATU,EtaN N Microwave N N N N n-BuLi NH, N_ 0 IN J N OBn 1 2 3 4 0 0B 0 0 0 HN N 0 HN H 2 /Pd/C HN SOCl 2 HN N IN IN IN DMN NN Pd(PPh3A, dioxane N N N DCM N N OBn OH CI 5 6 7 o 8 o 00 3-(2-Benzyloxy-acetylamino)-3H-imidazole-4-carboxylic acid methyl ester (2) To a solution of compound 1 (5.0 g, 35.4 mmol), benzyloxy-acetic acid (6.5 g, 39.0 mmol) and 5 DIEA (19ml, 106.3mmol) in DMF (50 mL) on an ice-water bath was added HATU (20.2 g, 53.1 mmol). The mixture was stirred at ambient temperature overnight. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc = 10:1 to 2:1) to afford compound 2 (8.7 g, 85% yield) as an oil. LC-MS: m/z 290.2 [M+H]*. 10 3-(2-Benzyloxy-acetylamino)-3H-imidazole-4-carboxylic acid amide (3) Compound 2 (8.7 g, 30.1 mmol) and ammonium hydroxide (15 ml) were combined in a sealed tube and heated to 70'C under microwave irradiation for 2 hours. The mixture was concen trated in vacuo to afford compound 3 (7.3 g, 88% yield) as a white solid. LC-MS: m/z 275.1 15 [M+H]*. 2-Benzyloxymethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (4) A solution of KOH (4.4 g, 78.5 mmol) in water (50 mL) was added dropwise to a solution of compound 3 (7.3 g, 26.6 mmol) in EtOH (60 mL) at room temperature. The resulting solution 20 was heated to 110'C for 3 hours. After removal of the organic solvent, the mixture was poured into ice water and the pH was adjusted to 7.0 with 1M aqueous HCI solution. The suspension was filtered and the filtrate was dried to afford compound 4 (4.9 g, 71% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6): 6 12.05 (s, 1H), 8.45 (s, 1H), 7.74 (s, 1H), 7.39-7.29 (m, 5H), 4.59 (s, 2H), 4.36 (s, 2H). LC-MS: m/z 257.2 [M+H]*.
WO 2013/110768 PCT/EP2013/051451 64 2-Benzyloxymethyl-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one (5) To a solution of compound 4 (4.9 g, 19.1 mmol) in THF (120 mL) was added n-BuLi (23 mL) dropwise at -78'C and the resulting reaction mixture was stirred below -70'C for one hour, 5 followed by dropwise addition of iodine (19.4 g, 76.3 mmol) in THF (60 mL) at the same tem perature. The reaction was allowed to warm to room temperature slowly. The reaction was quenched with saturated aqueous Na 2
SO
3 solution (60 mL), and it was then extracted with EtOAc (60 mL x 3). The organic phases were combined and dried over Na 2
SO
4 . The solid was filtered and the filtrate was concentrated in vacuo to give the crude product, which was 10 purified by chromatography on silica gel column (eluted with PE/EtOAc = 10:1 to 2:1) to afford compound 5 (4.1 g, 56% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6): 6 12.16 (s, 1 H), 7.84 (s, 1 H), 7.42-7.29 (m, 5H), 4.62 (s, 2H), 4.40 (s, 2H). LC-MS: m/z 383.2 [M+H]*. 2-Benzyloxymethyl-7-(3,6-dihydro-2H-pyran-4-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one 15 (6) To a solution of compound 5 (1.0 g, 2.61 mmol) in dioxane (12 mL) at room temperature was added dropwise a solution of Cs2CO3 (2.5 g, 7.66 mmol) in water (3 mL), followed by addition of Pd(PPh 3
)
4 (300 mg, 0.26 mmol) and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6 dihydro-2H-pyran (636 mg, 3.0 mmol). The reaction mixture was degassed by purging with N 2 20 for 15 min. Then the mixture was heated to 125'C under microwave irradiation for 40 min. After removal the solvent, the residue was purified by chromatography on silica gel column eluted with PE/EtOAc = 10:1 to 1:5) to afford compound 6 (680 mg, 76% yield) as a white solid. LC-MS: m/z 339.1 [M+H]*. 25 2-Hydroxymethyl-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1-f][1,2,4]triazin-4-one (7) To a solution of compound 6 (650 mg, 1.14 mmol) in MeOH (30 mL) was added Pd(OH) 2 /C (120 mg). The reaction mixture was stirred under 50 psi of hydrogen at 70 'C until LC-MS showed that the starting material was almost consumed. The suspension was filtered through celite and washed with MeOH (20 mL x 2) and the filtrate was concentrated in vacuo to afford 30 compound 7 (410 mg, 85% yield) as a white solid. LC-MS: m/z 251.3 [M+H]*.
WO 2013/110768 PCT/EP2013/051451 65 2-Chloromethyl-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1-f][1,2,4]triazin-4-one (8) To a solution of compound 7 (400 mg, 1.6 mmol) in CH 2
CI
2 (50 mL) in ice-water bath was added SOCl 2 (10 mL) dropwise. The resulting mixture was then stirred at ambient tempera ture overnight. The reaction mixture was concentrated in vacuo to afford compound 8 (370 5 mg, 86% yield) as a white solid. LC-MS: m/z 269.1 [M+H]*. 'H NMR (400 MHz, DMSO-d6): 6 12.50 (s, 1H), 8.02 (s, 1H), 4.57 (s, 2H), 3.95 (m, 2H), 3.48 (m, 3H), 1.88 (m, 4H). 2-Acetyl-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one 10 Scheme 7 0 0 0 HO OBn 0>0O N O>,' N H 2 J' HO H ONHHOBn KOH a HN N N N -N 320 H-N OJ OH(q), -N HATU, Et 3 NNN Miroav N NH2 N0 0 OBn n-BuLi 2 9 10 11 0 0 B, 0 0 0 HN N 0 HN N H 2 /Pd/C HN -I N MnO 2 HN N Pd(PPh 3 )N, Dioxane NN NN DCM N OBnNNN OBn -OH 0 12 13 0H 14 OO 15 0 3-(2-Benzyloxy-propionylamino)-3H-imidazole-4-carboxylic acid methyl ester (9) To a solution of compound 2 (4.2 g, 29.7 mmol), 2-Benzyloxy-propionic acid (5.5 g, 29.7 15 mmol) and DIEA (10 mL) in a mixture of DMF (1 mL) and THF (50 mL) in ice-water bath was added HATU (13.5 g, 35.7 mmol). The resulting mixture was then stirred at ambient tempera ture overnight. Water (100 mL) was added. The mixture was extracted with ethyl acetate (300 mL x 2). The combined organic phases were concentrated to give a crude residue, which was purified by chromatography on silica gel column (eluted with PE/EtOAc = 1:1 to 1:3) to afford 20 compound 9 (8.2 g, 91% yield) as brown oil. LC-MS: m/z 304 [M+H]*. 3-(2-Benzyloxy-propionylamino)-3H-imidazole-4-carboxylic acid amide (10) WO 2013/110768 PCT/EP2013/051451 66 Compound 9 (8.2 g, 27 mmol) and ammonium hydroxide (100 mL) were mixed and heated to 60'C for two hours. The reaction mixture was concentrated in vacuo to give compound 10 (7.8 g, 100% yield) as white solid. LC-MS: m/z 289 [M+H]*. 5 2-(l-Benzyloxy-ethyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one (11) To a solution of compound 10 (1.5 g, 5.2 mmol) in EtOH (10 mL) was added a solution of KOH (870 mg, 15.6 mmol) in H 2 0 (4 mL). Then the resulting mixture was heated at 1000C under microwave heating for one hour. After removal of the solvent, the mixture was poured into ice water and pH was adjusted to 7 with 1 M aqueous HCI solution. The suspension was 10 filtered and the solid was dried to give compound 11 (1.06 g, 75% yield) as a white solid. LC MS: m/z 271 [M+H]*. 'H NMR (400 MHz, CDC13): 6 8.70 (br. s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.39-7.32 (m, 5H), 4.60 (m, 2H), 4.46 (q, J = 6.4 Hz, 1 H), 1.57 (d, J = 6.4 Hz, 3H). 2-(1-Benzyloxy-ethyl)-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one (12) 15 To a solution of compound 11 (1.2 g, 4.4 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 3.5 ml) dropwise at -780C over 30 minutes and the resulting reaction mixture was stirred be low -70'C for another one hour. Then a solution of iodine (2.2 g, 8.8 mmol) in THF (20 mL) was added dropwise and the dark brown mixture was allowed to warm up to room tempera ture slowly over one hour. The reaction was quenched with saturated aqueous solution of 20 Na 2
SO
3 (60 mL), and then the mixture was extracted with EtOAc (200 mL x 2). The organic layers were combined and dried over Na 2
SO
4 , filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel column (eluted with PE/EtOAc = 10:1 to 2:1) to afford compound 12 (450 mg, 25% yield) as a yellow solid. LC MS: m/z 397 [M+H]*. 'H NMR (400 MHz, CDC13): 6 8.82 (br. s, 1H), 7.94 (s, 1H), 7.36-7.32 25 (m, 5H), 4.65-4.55 (m, 3H), 1.60 (d, J = 6.4 Hz, 3H). 2-(1 -Benzyloxy-ethyl)-7-(3,6-dihydro-2H-pyran-4-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one (13) To a solution of compound 12 (300 mg, 0.75 mmol) in dioxane (2 mL) was added a solution of 30 Cs 2
CO
3 (492 mg, 1.51 mmol) in H 2 0 (0.5 mL) dropwise, followed by addition of 4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (318 mg, 1.5 mmol) and WO 2013/110768 PCT/EP2013/051451 67 Pd(PPh 3
)
4 (86 mg, 0.075 mmol). The reaction mixture was degassed by purging with N 2 for 15 min. Then the reaction was heated to 125'C under microwave heating for 40 min. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc = 10:1 to 1:5) to afford compound 13 (200 mg, 75% yield) as white 5 solid. LC-MS: m/z 353 [M+H]*. 'H NMR (400 MHz, CDC13): 6 8.82 (br. s, 1H), 7.91 (s, 1H), 7.37-7.32 (m, 5H), 7.19 (br. s, 1H) , 4.61 (m, 2H), 4.49 (q, J = 6.8 Hz, 1H), 4.40 (m, 2H), 3.95 (t, J = 5.2 Hz, 2H), 2.78 (m, 2H), 1.58 (d, J = 6.4 Hz, 3H). 2-(1 -Hydroxy-ethyl)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 -f][1,2,4]triazin-4 10 one (14) To a solution of compound 13 (900 mg, 2.55 mmol) in MeOH (30 mL) was added Pd(OH) 2 /C (120 mg). The mixture was stirred at 75'C under H 2 (50 psi) overnight. The suspension was filtered through Celite, washed with MeOH (20 mL x 2). The combined organic phases were concentrated in vacuo to afford compound 14 (540 mg, 80% yield) as a white solid. LC-MS: 15 m/z 265 [M+H]*. 'H NMR (400 MHz, CDC13): 6 9.07 (br. s, 1H), 7.85 (s, 1H), 4.84 (q, J = 6.4 Hz, 1H), 4.11 (m, 2H), 3.59 (m, 2H), 3.44-3.39 (m, 1H), 2.14-2.06 (m, 3H), 1.92-1.88 (m, 2H), 1.64 (d, J = 6.4 Hz, 3H). 2-Acetyl-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1-f][1,2,4]triazin-4-one (15) 20 To a solution of compound 14 (400 mg, 1.6 mmol) in CH 2 Cl 2 (50 mL) was added MnO 2 (520 mg, 6 mmol). The mixture was heated at 500C overnight. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford compound 15 (370 mg, 86% yield) as a white solid. LC-MS: m/z 263 [M+H]*. 'H NMR (300 MHz, CDC13): 6 8.99 (br. s, 1H), 7.93 (s, 1H), 4.16-4.12 (m, 2H), 3.67-3.59 (m, 2H), 3.54-3.48 (m, 1H), 2.72 25 (s, 3H), 2.19-2.11 (m, 2H), 2.00-1.96 (m, 2H). Preparation of target compounds: Example 4 2-[3-(4-Fluoro-phenoxy)-azetidin-1 -ylmethyl]-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 68 0 0 N 0DiEA 0 N N N + F O NH D F O N N N ci 8 Al 00 To a solution of compound 15 (40 mg, 0.15 mmol) and compound Al (50 mg, 0.30 mmol) in
CH
3 CN (40 mL) was added DiEA (0.5 mL, 3.0 mmol). The resulting solution was heated to 70'C for 2 h. The reaction was found to be complete by monitoring with TLC. The reaction 5 was concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluted with EtOAc/MeOH 100:1 to 30:1) to afford the desired product (25 mg, 42% yield) as a white solid. LC-MS: m/z 400.1 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.44 (br. s, 1 H), 7.65 (s, 1H), 6.93 (m, 2H), 6.73 (m, 2H), 3.98-3.95 (m, 2H), 3.90-3.86 (m, 2H), 3.59 (s, 2H), 3.54-3.46 (m, 3H), 3.32 (m, 2H), 1.95-1.81 (m, 5H). 10 The following compounds were prepared in a similar way: 2-[3-(4-Methoxy-phenyl)-azetidin-1 -ylmethyl]-7-(tetrahydro-pyran-4-y)-3H-imidazo[5, 1 f][1,2,4]triazin-4-one 0 0 N N N 15 0 31% yield. LC-MS: m/z 396.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.23-7.21 (d, J = 8.4 Hz, 2H), 6.90-6.88 (d, J = 8.4 Hz, 2H), 4.11-4.08 (m, 2H), 3.88-3.86 (m, 2H), 3.84 (s, 3H), 3.81-3.72 (m, 1H), 3.62 (s, 2H), 3.59-3.56 (m, 2H), 3.45-3.41 (m, 1H), 3.38-3.35 (m, 2H), 2.11-2.04 (m, 2H), 1.89-1.82 (m, 2H). 20 7-(4-Fluoro-phenyl)-2-[3-(4-methoxy-phenyl)-azetidin-1 -ylmethyl]-3H-imidazo[5,1 f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 69 O o N N N F 20% yield. LC-MS: m/z 406.1[M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.38-8.34 (m, 2H), 7.91 (s, 1H), 7.32-7.29 (m, 4H), 6.92-6.90 (d, J = 8.8 Hz, 2H), 3.97-3.94 (m, 2H), 3.82 (s, 3H), 3.80-3.77 (m, 1H), 3.75 (s, 2H), 3.51-3.47 (m, 2H). 5 7-(4-Fluoro-phenyl)-2-[3-(4-fluoro-phenyl)-azetidin-1 -ylmethyl]-3H-imidazo[5,1 f][1,2,4]triazin-4-one F N N ' N N N N F 14% yield. LC-MS: m/z 394.1[M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 8.19-8.16 (m, 2H), 10 7.94 (s, 1H), 7.46-7.42 (m, 2H), 7.33-7.29 (m, 2H), 7.17-7.13 (m, 2H), 4.73-4.65 (m, 2H), 4.61 (s, 2H), 4.50-4.45 (m, 2H), 4.36-4.29 (m, 1 H). 2-[3-(4-Fluoro-phenyl)-azetidin-1 -ylmethyl]-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one F 0 N N N N 15 0 18 mg, 20% yield. LC-MS: m/z 384.1[M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.62 (s, 1H), 7.30-7.26 (m, 2H), 6.97-6.93 (m, 2H), 3.96-3.93 (m, 2H), 3.83-3.79 (m, 2H), 3.71-3.67 (m, 1H), 3.55 (s, 2H), 3.53-3.45 (m, 2H), 3.38 (m, 1H), 3.33-3.30 (m, 2H), 1.93-1.87 (m, 2H), 1.82-1.78 (m, 2H). 20 WO 2013/110768 PCT/EP2013/051451 70 2-[3-(2,6-Difluoro-phenoxy)-azetidin-1 -ylmethyl]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one F O N N 'N -N /N F N 0 36% yield. LC-MS: m/z 418.1 [M+1]*. H NMR (400 MHz, DMSO-d6): 6 12.20 (br. s, 1 H), 7.70 5 (s, 1H), 7.23-7.19 (m, 3H), 5.08 (m, 1H), 4.70 (m, 2H), 4.56 (s, 2H), 4.52-4.48 (m, 2H), 3.97 (d, J= 10.7 Hz, 2H), 3.52-3.40 (m, 3H), 1.85 (m, 4H). 7-(Tetrahydro-pyran-4-y)-2-[3-(4-trifluoromethoxy-phenoxy)-azetidin-1 -ylmethyl]-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 00e NN
F
3 CON 10 0 35% yield. LC-MS: m/z 466.1 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.16-7.14 (d, J = 8.8 Hz, 2H), 6.77-6.74 (d, J = 8.8 Hz, 2H), 4.84-4.81 (m, 1H), 4.11-4.07 (m, 2H), 3.97-3.93 (m, 2H), 3.67 (s, 2H), 3.61-3.55 (m, 2H), 3.44-3.38 (m, 3H), 2.11-2.04 (m, 2H), 1.91-1.87 (m, 2H). 15 2-[3-(4-Dimethylamino-phenyl)-azetidin-1 -ylmethyl]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one Nn 0 NN N N xN 0 26% yield. LC-MS: m/z 409.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.19-7.17 20 (d, J = 8.8 Hz, 2H), 6.74-6.72 (d, J = 8.8 Hz, 2H), 4.11-4.08 (m, 2H), 3.86-3.82 (m, 2H), WO 2013/110768 PCT/EP2013/051451 71 3.72-3.68 (m, 1H), 3.62-3.56 (m, 4H), 3.42-3.37 (m, 1H), 3.35-3.33 (m, 2H), 2.94 (s, 6 H), 2.11-2.05 (m, 2H), 1.92-1.89 (m, 2H). 2-(3-Phenoxy-azetidin-1 -ylmethyl)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one 0 0 N N/ 5 0 32% yield. LC-MS: m/z 382.1 [M+H]*. 1H NMR (400 MHz, DMSO-d6): 6 11.73 (br. s, 1H), 7.67 (s, 1H), 7.27 (m, 2H), 6.95 (m, 1H), 6.82 (m, 2H), 4.83 (m, 1H), 3.93-3.84 (m, 4H), 3.54 (s, 2H), 3.47 (m, 2H), 3.32 (m, 1H), 3.24 (m, 2H), 1.85 (m, 4H). 2-(3-Pyrimidin-2-yi-azetidin-1 -ylmethyl)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 10 f][1,2,4]triazin-4-one N0 HN N N N 0 12% yield. LC-MS: m/z = 368.2 [M+1]*. 1H NMR (400 MHz, CD 3 0D-d6): 6 8.76-8.75 (m, 2H), 7.65-7.63 (m, 1H), 7.37-7.35 (m, 1H), 3.98-3.80 (m, 5H), 3.58-3.38 (m, 7H), 1.87-1.81 (m, 4H). 15 2-[3-(4-Methyl-benzyloxy)-azetidin-1 -ylmethyl]-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one 0 O HN N N'N -C N 0 9% yield. LC-MS: m/z = 410.2 [M+1]*. 'H NMR (300 MHz, CD 3 0D-d4): 6 7.93 (s, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 4.57-4.60 (m, 7H), 4.23-4.26 (m, 2H), 4.05-4.10 20 (m, 2H), 3.58-3.66 (m, 3H), 2.34 (s, 3H), 1.92-2.00 (m, 4H).
WO 2013/110768 PCT/EP2013/051451 72 2-(3-Benzyl-azetidin-1 -ylmethyl)-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one 0 HN N N 0 23% yield. LC-MS: m/z = 380.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.82 (s, 1H), 7.31-7.27 5 (m, 2H), 7.23-7.21 (m, 1H), 7.14-7.12 (m, 2H), 4.10-4.07 (m, 2H), 3.61-3.50 (m, 6H), 3.43-3.37 (m, 1H), 3.12-3.09 (m, 2H), 2.91-2.89 (m, 2H), 2.84-2.83 (m, 1H), 2.11-2.083 (m, 2H), 1.91-1.87 (m, 2H). 2 -[3 -(4-Methoxy-phenoxymethyl) -azetid in-1 -ylmethyl]-7-(tetrahydro-pyran-4-yI)-3H 10 imidazo[5,1 -f][1,2,4]triazin-4-one 0 0 0 N N N'N 0 15% yield. LC-MS: m/z = 426.2 [M+1]*. 1H NMR (400 MHz, CD 3 0D-d4): 6 7.84 (s, 1H), 7.04 (d, J = 12.0 Hz, 2H), 6.92 (d, J = 12.0 Hz, 2H), 4.62 (m, 4H), 4.46 (m, 2H), 4.13-4.15 (m, 2H), 4.02-4.07 (m, 2H), 3.78 (s, 3H), 3.54-3.60 (m, 3H), 3.37 (m, 1 H), 1.89-2.06 (m, 4H). 15 2-[3-(4-Pyrrolidin-1 -yi-phenyl)-azetidin-1 -ylmethyl]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one N 0 HN N' N N N O 0 WO 2013/110768 PCT/EP2013/051451 73 23% yield. LC-MS: m/z = 435.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 4.11-4.08 (m, 2H), 3.86-3.84 (m, 2H), 3.71-3.67 (m, 1H), 3.62-3.56 (m, 4H), 3.45-3.39 (m, 1H), 3.36-3.33 (m, 2H), 3.29-3.26 (m, 4H), 2.17-2.10 (m, 2H), 2.08-1.99 (m, 4H), 1.92-1.89 (m, 2H). 5 Example 5 2-{1 -[3-(4-Methoxy-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 00 HN H N _ Ti(Oi-Pr) 3 HN N N HN oN N NHN NaBH(OAc) 3 N N 0 4_ 10 15 0 A2 0 To a solution of compound 15 (57 mg, 0.21 mmol) and compound A2 (43 mg, 0.21 mmol) in THF (50 mL) was added Ti(Oi-Pr) 3 (1 mL). The mixture was then stirred at ambient tempera ture overnight. Then NaBH(OAc) 3 (200 mg, 0.95 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was poured into 10 ml of water 15 and the pH of the solution was adjusted to 7 with a saturated aqueous solution of NaHCO 3 . The reaction mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over Na 2
SO
4 , and the solid was filtered off. The filtrate was concentrated in vacuo to give a crude residue which was subjected to Prep-HPLC to afford the desired com pound (7 mg, 7.8% yield) as a white solid. LC-MS: m/z 410.2 [M+H]*. 'H NMR (400 MHz, 20 CD 3 0D-d4): 6 7.63 (s, 1H), 7.18 (dd, J = 2.0, 7.2 Hz, 2H), 6.80 (dd, J = 2.0, 7.2 Hz, 2H), 3.98-3.95 (m, 2H), 3.83-3.73 (m, 2H), 3.68 (s, 3H), 3.67-3.63 (m, 1H), 3.56-3.47 (m, 1H), 3.32-3.22 (m, 2H), 1.96-1.80 (m, 4H), 1.31 (d, J = 6.4 Hz, 3H). The racemic mixture of 2-{1-[3-(4-Methoxy-phenyl)-azetidin-1-yI]-ethyl}-7-(tetrahydro pyran-4-yi)-3H-imidazo[5,1 -f][1,2,4]triazin-4-one was submitted for preparative chiral H PLC 25 (Column = chiralpak IA; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 12 mL/min; UV: 230 nm; 30 mg/inj in) and gave two enantiomers: WO 2013/110768 PCT/EP2013/051451 74 2-{1 -[3-(4-Methoxy-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 'O 0 HN N N ' ' N N 0 40% yield. Chiral analytical HPLC (Column = chiralpak IA; Mobile phase = n-Hexane/EtOH 5 70/30; Flow rate = 1.0 mL/min): TR = 9.98. LC-MS (ESI) m/z = 410.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.88 (dd, J =1.6 Hz, J = 6.4 Hz, 2H), 4.12-4.08 (m, 2H), 3.81 (s, 3H), 3.77-3.68 (m, 3H), 3.63-3.57(m, 2H), 3.46-3.40 (m, 2H), 3.31-3.28 (m, 1H), 3.23-3.20 (m, 1H), 2.11-2.07 (m, 2H), 1.93-1.89 (m, 2H), 1.33 (d, J = 6.4 Hz, 3H). 10 2-{1 -[3-(4-Methoxy-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 'O 0 HN N N N'N 0 40% yield. Chiral analytical HPLC (Column = chiralpak IA; Mobile phase = n-Hexane/EtOH 15 70/30; Flow rate = 1.0 mL/min): TR = 14.7. LC-MS (ESI) m/z = 410.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.12-4.08 (m, 2H), 3.80 (s, 3H), 3.77-3.74 (m, 1H), 3.72-3.68 (m, 2H), 3.62-3.57(m, 2H), 3.46-3.40 (m, 2H), 3.31-3.28 (m, 1H), 3.23-3.20 (m, 1H), 2.11-2.07 (m, 2H), 1.93-1.90 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H). 20 The following compound was prepared in a similar way: WO 2013/110768 PCT/EP2013/051451 75 2-{1 -[3-(4-Fluoro-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one F N N '-N N N' N 0 15% yield. LC-MS: m/z 398.2 [M+H]*. 1H NMR (400 MHz, MeOD-d4): 6 7.85 (s, 1H), 5 7.26-7.23 (m, 2H), 7.05-7.01 (m, 2H), 4.12-4.09 (m, 2H), 3.80-3.72 (m, 3H), 3.63-3.57 (m, 2H), 3.47-3.40 (m, 2H), 3.33-3.29 (m, 1H), 3.25-3.22 (m, 1H), 2.12-2.06 (m, 2H), 1.93-1.90 (m, 2H), 1.31 (d, J = 7.2 Hz, 3H). 2-{1 -[3-(4-Fluoro-phenoxy)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H 10 imidazo[5,1 -f][1,2,4]triazin-4-one 0 0 ~ HN . N F N 0 10% yield. LC-MS: (ESI) m/z = 414.1 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.83 (s, 1H), 6.99-6.94 (m, 2H), 6.71-6.69 (m, 2H), 4.77-4.74 (m, 1H), 4.10-4.08 (m, 2H), 3.86-3.77 (m, 2H), 3.61-3.56 (m, 2H), 3.49-3.46 (m, 1H), 3.42-3.33 (m, 2H), 3.25-3.21 (m, 1H), 2.11-2.04 15 (m, 2H), 1.92-1.88 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H). 7-(Tetrahydro-pyran-4-y)-2-[1-(3-p-tolyloxy-azetidin-1 -yl)-ethyl]-3H-imidazo[5,1 f][1,2,4]triazin-4-one 0 HN N N N O 0 WO 2013/110768 PCT/EP2013/051451 76 35% yield. LC-MS: m/z = 410 [M+1]*. 'H NMR (300 MHz, CDC13): 6 7.84 (s, 1H), 7.07 (d, J 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.80-4.76 (m, 1H), 4.12-4.07 (m, 2H), 3.87-3.77 (m, 2H), 3.63-3.55 (m, 2H), 3.49-3.32 (m, 3H), 3.24-3.20 (m, 1H), 2.28 (s, 3H), 2.11-2.06 (m, 2H), 1.93-1.88 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H). 5 2-[1-(3-Phenyl-azetidin-1 -yl)-ethyl]-7-(tetrahydro-pyran-4-y)-3H-i midazo[5,1 f][1,2,4]triazin-4-one 0 HN -N N N / 0 62% yield. LC-MS: m/z = 380.1 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.37-7.33 10 (m, 2H), 7.29-7.24 (m, 3H), 4.11-4.09 (m, 2H), 3.80-3.73 (m, 3H), 3.63-3.57 (m, 2H), 3.47-3.40 (m, 2H), 3.37-3.34 (m, 1H), 3.30-3.25 (m, 1H), 2.16-2.05 (m, 2H), 1.93-1.90 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H). 2-{1 -[3-(3-Fluoro-4-methoxy-phenyl)-azetidin-1 -y] -ethyl}-7-(tetrahydro-pyran-4-yl)-3 H 15 imidazo[5,1 -f][1,2,4]triazin-4-one 0 HN N FN N'N 0 25% yield. LC-MS: m/z = 428.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.04-6.90 (m, 3H), 4.11-4.09 (m, 2H), 3.89 (s, 3H), 3.76-3.57 (m, 5H), 3.46-3.40 (m, 2H), 3.29-3.26 (m, 1H), 3.22-3.19 (m, 1H), 2.11-2.04 (m, 2H), 1.93-1.90 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H). 20 2-{1 -[3-(2-Fluoro-4-methoxy-phenyl)-azetidin-1 -y] -ethyl}-7-(tetrahydro-pyran-4-yl)-3 H imidazo[5,1 -f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 77 0 HN N F N N' N 0 36% yield. LC-MS: m/z= 428.2 [M+1]*. 'H NMR (400 MHz, CDC13): 67.84 (s, 1H), 7.16 (dd, J = 8.8 Hz, J = 8.8 Hz, 1 H), 6.68 (dd, J = 2.4 Hz, J = 6.8 Hz, 1 H), 6.59 (dd, J = 2.4 Hz, J = 12.0 Hz, 1H), 4.11-4.08 (m, 2H), 3.88-3.81 (m, 2H), 3.79 (s, 3H), 3.75-3.72 (m, 1H), 3.62-3.57 5 (m, 2H), 3.46-3.39 (m, 2H), 3.36-3.33 (m, 1H), 3.27-3.23 (m, 1H), 2.14-2.04 (m, 2H), 1.93-1.90 (m, 2H), 1.32 (d, J = 6.4 Hz, 3H). 2-{1 -[3-(4-Ethoxy-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H-imidazo[5,1 f][1,2,4]triazin-4-one o 0 H I N N -N N N 10 0 18% yield. LC-MS: m/z = 424.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.11-4.09 (m, 2H), 4.05-4.00 (m, 2H), 3.78-3.66 (m, 3H), 3.63-3.57 (m, 2H), 3.46-3.40 (m, 2H), 3.32-3.29 (m, 1H), 3.24-3.20 (m, 1H), 2.11-2.05 (m, 2H), 1.93-1.90 (m, 2H), 1.41 (t, J = 6.8 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H). 15 2-{1 -[3-(4-Hydroxy-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-yI)-3H imidazo[5,1 -f][1,2,4]triazin-4-one HN N N
-
N N / D 0 WO 2013/110768 PCT/EP2013/051451 78 10% yield. LC-MS (ESI): m/z = 396.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.91 (s, 1H), 7.27 (d, J = 11.2 Hz, 2H), 6.84 (d, J =11.2 Hz, 2H), 4.72-4.65 (m, 3H), 4.44-4.41 (m, 2H), 4.22-4.19 (m, 1H), 4.11-4.06 (m, 2H), 3.69-3.60 (m, 3H), 2.05-1.92 (m, 4H), 1.70 (d, J = 8.8 Hz, 3H). 5 2-{1 -[3-(4-Pyrrolidin-1 -yi-phenyl)-azetidin-1 -yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-4a,7 dihydro-3H-imidazo[5,1 -f][1,2,4]triazin-4-one N0 HN N '0--N T N' N / 0 28% yield. LC-MS: m/z = 449.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.15 (d, J 10 = 8.4 Hz, 2H), 6.54 (d, J = 8.4 Hz, 2H), 4.11-4.08 (m, 2H), 3.74-3.57 (m, 5H), 3.46-3.40 (m, 2H), 3.27-3.25 (m, 5H), 3.20-3.17 (m, 1H), 2.11-2.08 (m, 2H), 2.05-2.00 (m, 4H), 1.93-1.90 (m, 2H), 1.32 (d, J= 6.8 Hz, 3H). 2-{1 -[3-(4-Dimethylamino-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H 15 imidazo[5,1 -f][1,2,4]triazin-4-one NN 1N N N"N' 0 23% yield. LC-MS: m/z = 423.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.83 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.11-4.08 (m, 2H), 3.74-3.69 (m, 1H), 3.68-3.57 (m, 4H), 3.45-3.40 (m, 2H), 3.30-3.27 (m, 1H), 3.21-3.17 (m, 1H), 2.94 (s, 6H), 2.11-2.08 (m, 20 2H), 1.93-1.90 (m, 2H), 1.32 (d, J= 6.8 Hz, 3H).
WO 2013/110768 PCT/EP2013/051451 79 7-(Tetrahydro-pyran-4-yl)-2-{1 -[3-(4-trifluoromethoxy-phenyl)-azetidin-1 -yl]-ethyl}-3 H imidazo[5,1-f][1,2,4]triazin-4-one F N N N'N/ 0 36% yield. LC-MS: m/z = 464.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 8.92 (br. s, 1 H), 7.84 (s, 5 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.19 (d, J= 8.0 Hz, 2H), 4.11-4.08 (m, 2H), 3.81-3.72 (m, 3H), 3.62-3.57 (m, 2H), 3.47-3.40 (m, 2H), 3.34-3.31 (m, 1H), 3.29-3.26 (m, 1H), 2.14-2.04 (m, 2H), 1.93-1.89 (m, 2H), 1.29 (d, J = 8.8 Hz, 3H). 2-{1 -[3-(4-Methoxy-benzyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-yI)-3H 10 imidazo[5,1 -f][1,2,4]triazin-4-one 0 SN N 0 CrrN 0 18% yield. LC-MS: m/z = 424.2 [M+1]*. 'H NMR (400 MHz, CD 3 0D-d4): 6 7.59 (s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 3.97-3.94 (m, 2H), 3.65 (s, 3H), 3.54-3.43 (m, 6H), 3.10-3.07 (m, 2H), 2.72 (m, 3H), 1.94-1.88 (m, 2H), 1.85-1.77 (m, 2H), 1.25 (d, J = 6.8 15 Hz, 3H). 2-{1 -[3-(3-Chloro-4-methoxy-phenyl)-azetidin-1 -yl] -ethyl}-7-(tetrahydro-pyran-4-yl)-3 H imidazo[5,1 -f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 80 o 0 CI HN N N NN'N 0 26% yield. LC-MS: m/z = 444.1 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.29 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.12-4.09 (m, 2H), 3.94 (s, 3H), 3.76-3.57 (m, 5H), 3.45-3.43 (m, 2H), 3.28 (t, J = 6.4 Hz, 1H), 3.21 (t, J = 6.4 Hz, 1H), 5 2.17-2.05 (m, 2H), 1.93-1.90 (m, 2H), 1.33 (d, J = 6.4 Hz, 3H). 2-{1 -[3-(3,4-Dimethoxy-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one ox 0 oHN N N /N' 0 10 18% yield. LC-MS: m/z = 440.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 6.85 (m, 2H), 6.74 (s, 1H), 4.12-4.09 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.80-3.68 (m, 3H), 3.63-3.57 (m, 2H), 3.49-3.41 (m, 2H), 3.32 (t, J = 6.4 Hz, 1H), 3.23 (t, J = 6.0 Hz, 1H), 2.13-2.06 (m, 2H), 1.93-1.90 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H). 15 2-{1 -[3-(4-Fluoro-3-methoxy-phenyl)-azetidin-1 -yl] -ethyl}-7-(tetrahydro-pyran-4-yl)-3 H imidazo[5,1 -f][1,2,4]triazin-4-one F O O Ci HN N N N'N 0 WO 2013/110768 PCT/EP2013/051451 81 15% yield. LC-MS: m/z = 428.2 [M+1]*. 'H NMR (300 MHz, CDC13): 6 7.85 (s, 1H), 7.06 (dd, J = 8.4 Hz, J = 10.5 Hz, 1H), 6.85-6.81 (m, 2H), 4.14-4.09 (m, 2H), 3.92 (s, 3H), 3.81-3.71 (m, 3H), 3.65-3.57 (m, 2H), 3.47-3.42 (m, 2H), 3.35-3.33 (m, 1H), 3.24 (m, 1H), 2.14-2.10 (m, 2H), 1.95-1.90 (m, 2H), 1.35 (d, J = 6.6 Hz, 3H). 5 2-{1 -[3-(3,5-Difluoro-4-methoxy-phenyl)-azetidin-1 -yl] -ethyl}-7-(tetrahydro-pyran-4-yl) 3H-imidazo[5,1 -f][1,2,4]triazin-4-one | F 0 0 HN - N N N'N 0 15% yield. LC-MS: m/z = 446.2 [M+1]*. 1H NMR (400 MHz, CDC13): 6 7.85 (s, 1H), 6.86-6.83 10 (m, 2H), 4.13-4.09 (m, 2H), 3.99 (s, 3H), 3.77-3.71 (m, 2H), 3.67-3.57 (m, 3H), 3.48-3.41 (m, 2H), 3.29-3.20 (m, 2H), 2.13-2.08 (m, 2H), 1.95-1.90 (m, 2H), 1.34 (d, J = 8.8 Hz, 3H). 2-{1 -[3-(3-Methoxy-phenyl)-azetidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one HN Ojo"N xrIN 15 0 5% yield. LC-MS: m/z = 410.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.13 (s, 1 H), 6.86 (d, J = 7.6 Hz, 1 H), 6.82-6.89 (m, 2H), 4.11-4.09 (m, 2H), 3.82 (s, 3H), 3.79-3.70 (m, 2H), 3.63-3.57 (m, 2H), 3.46-3.40 (m, 2H), 3.36-3.34 (m, 1H), 3.33-3.26 (m, 1H), 2.23 (s, 1 H), 2.12-2.05 (m, 2H), 1.93-1.90 (m, 2H), 1.33 (d, J = 6.4 Hz, 3H). 20 2-{1 -[3-(4-Methoxy-3-methyl-phenyl)-azetidin-1 -yl] -ethyl}-7-(tetrahydro-pyran-4-yl)-3 H imidazo[5,1 -f][1,2,4]triazin-4-one WO 2013/110768 PCT/EP2013/051451 82 0 0 HN N N
N
0 21% yield. LC-MS: m/z = 424.2 [M+1]*. 'H NMR (300 MHz, CDC13): 6 7.85 (s, 1H), 7.09-7.06 (m, 2H), 6.80 (d, J = 7.8 Hz, 1H), 4.14-4.09 (m, 2H), 3.84 (s, 3H), 3.78-3.67 (m, 3H), 3.66-3.57 (m, 2H), 3.49-3.42 (m, 2H), 3.34-3.29 (m, 1H), 3.24-3.22 (m, 1H), 2.24 (s, 3H), 5 2.14-2.08 (m, 2H), 1.96-1.91 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H). 2-[1-(3-Benzo[1,3]dioxol-5-yI-azetidin-1 -yI)-ethyl]-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 HN N N N 0 10 10% yield. LC-MS: m/z = 424.2 [M+1]*. 'H NMR (300 MHz, CDC13): 6 7.85 (s, 1H), 6.81-6.70 (m, 3H), 5.97 (s, 2H), 4.14-4.10 (m, 2H), 3.77-3.70 (m, 3H), 3.68-3.58 (m, 2H), 3.49-3.41 (m, 2H), 3.29 (t, J = 6.6 Hz, 1H), 3.22 (t, J = 6.0 Hz, 1H), 2.13-2.09 (m, 2H), 1.95-1.91 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H). 15 2-{1 -[3-(4-Methoxy-phenyl)-pyrrolidin-1 -yI]-ethyl}-7-(tetrahydro-pyran-4-y)-3H imidazo[5,1 -f][1,2,4]triazin-4-one 0 HNI 0 N N 0 6% yield. LC-MS: m/z = 424.2 [M+1]*. 'H NMR (400 MHz, CDC13): 6 7.84 (s, 1H), 7.17-7.15 (d, J = 7.6 Hz, 2H), 6.87-6.84 (dd, J = 2.4, 8.4 Hz, 2H), 4.11-4.08 (m, 2H), 3.79 (s, 3H), WO 2013/110768 PCT/EP2013/051451 83 3.62-3.42 (m, 3H), 3.33-3.39 (m, 2H), 3.11-3.04 (m, 1H), 2.90-2.78 (m, 2H), 2.62-2.57 (m, 1H), 2.35-2.31 (m, 1H), 2.11-2.04 (m, 2H), 1.93-1.90 (m, 3H), 1.25 (d, J = 6.6 Hz, 3H). IN VITRO TESTING PDE9 inhibition assay 5 A PDE9 assay may for example, be performed as follows: The assay is performed in 60 uL samples containing a fixed amount of the relevant PDE enzyme (sufficient to convert 20-25% of the cyclic nucleotide substrate), a buffer (50 mM HEPES7.6; 10mM MgCl 2 ; 0.02% Tween20), 0.1mg/ml BSA, 225 pCi of 3 H-labelled cyclic nucleotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors. Reactions are initi 10 ated by addition of the cyclic nucleotide substrate, and reactions are allowed to proceed for one hr at room temperature before being terminated through mixing with 15 uL 8 mg/mL yt trium silicate SPA beads (Amersham). The beads are allowed to settle for one hr in the dark before the plates are counted in a Wallac 1450 Microbeta counter. The measured signal can be converted to activity relative to an uninhibited control (100 %) and IC50 values can be cal 15 culated using the Xlfit extension to EXCEL. In the context of the present invention the assay was performed in 60 uL assay buffer (50 mM HEPES pH 7.6; 10mM MgCl 2 ; 0.02% Tween20) containing enough PDE9 to convert 20-25% of 10 nM 3 H-cAMP and varying amounts of inhibitors. Following a 1 hour incubation the re actions were terminated by addition of 15 uL 8 mg/mL yttrium silicate SPA beads (Amer 20 sham). The beads were allowed to settle for one hr in the dark before the plates were counted in a Wallac 1450 Microbeta counter. IC50 values were calculated by non linear regression us ing XLfit (IDBS). Results of the experiments showed that the tested compounds of the invention inhibit the PDE9 enzyme with IC50 values below 250 nM.

权利要求:
Claims (3)
[1] 1. A compound having the structure (1) O R5 HN$ N R1 R2, NA R4 R3 5 (I) wherein R2 is cyclized with either R1 or R3, wherein R1, R2 and R3 are: R1, when cyclized with R2, is I -o R6 10 H wherein R6 is selected from the group consisting of H, -CH 3 , -C 2 H 5 , and -C 3 H 7 , wherein * denotes the cyclization point, and R1, when not cyclized, is selected from the group consisting of H C - R6 H and H 15 wherein R6 is selected from the group consisting of H, -CH 3 , -C 2 H 5 , and -C 3 H 7 R2 is a compound selected from the group consisting of R-C C-R7 C-R7 H H and H WO 2013/110768 PCT/EP2013/051451 85 wherein R7 and R1 1 independently are selected from the group consisting of H, -CH 3 , -C 2 H 5 , and -C 3 H 7 wherein * denotes the cyclization point, and R3, when cyclized with R2, is 5 -CH -C -C2 C R8 wherein * denotes the cyclization point, and wherein R8 is selected from the group consisting of H, C1-C6 alkyl, branched C3-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, substituted C6-C10 aryl, C3-C het 10 eroaryl, substituted C3-C heteroaryl, C1-C alkoxy, branched C3-C6 alkoxy, C3 C cycloalkoxy, C6-C10 aryloxy, substituted C6-C10 aryloxy, C3-C heteroaryloxy, substituted C3-C heteroaryloxy; and R3, when not cyclized, is R9 C H R10 15 wherein R9 is selected from the group consisting of H, -CH 3 , and -C 2 H 5 ; and R10 is selected from the group consisting of C6-C10 aryl, substituted C6-C10 aryl, C3-C heteroaryl, substituted C3-C heteroaryl R4 is selected from the group consisting of C6-C10aryl, substituted C6-C10 aryl, C3-C9 20 heteroaryl, substituted C3-C heteroaryl, C3-C6 heterocyclyl, substituted C3-C6 hetero cyclyl, C3-C6 cycloalkyl, and substituted C3-C cycloalkyl; R5 is selected from the group consisting of hydrogen, F, Cl, CN, -CH 3 , -C 2 H 5 , -C 3 H 7 , and -CF 3 ; A is absent or -CH 2 - WO 2013/110768 PCT/EP2013/051451 86 and tautomers and pharmaceutically acceptable acid addition salts thereof, and poly morphic forms thereof provided that the compound is not 2-[1-[(4 fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-(1 -benzyl-4-methyl-pyrrolid in-3-yl)-7-tetrahyd ropyran-4-yl-3 H 5 imidazo[5,1-f][1,2,4]triazin-4-one; 2-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7 tetrahyd ropyran-4-yl-3 H-imidazo[5,1 -f][1 ,2,4]triazin-4-one; 2-(4-methylpyrrolidin-3-yl)
[2] 7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-[(6-methoxy-2 pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[(3S,4S)-1-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran 10 4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3R,4R)-1 -benzyl-4-methyl-pyrrolidin-3 yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3S,4S)-4 methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one 2-[(3R,4R)-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[(3S,4S)-4-methyl-1 -(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7 15 tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3R,4R)-4-methyl-1 (pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 4-[3-methyl-4-(4-oxo-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-2-yl)pyrrolidin-1-yl]benzonitrile; 2-[(3S,4S)-1-[(4-fluorophenyl)methyl]-4 methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; 2 20 [(3R,4R)-1 -[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1-f][1,2,4]triazin-4-one or 2-[4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3 yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one. 2. The compound of claim 1 wherein the one or more heteroaryls of R4, R8 and R10 in dependently of each other comprise one or two nitrogen. 25 3. The compound of claim 1, wherein the compound is selected from the group consisting of 7-(4-fluorophenyl)-2-[4-methyl-1-[[6-(trifluoromethyl)-3 pyridyl]methyl]pyrrolidin-3-yl]-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-[(6-methoxy-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4 30 yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[4-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-(1 -benzyl-4-methyl-pyrrolidin-3-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H imidazo[5,1-f][1,2,4]triazin-4-one; WO 2013/110768 PCT/EP2013/051451 87 7-(4-fluorophenyl)-2-[1 -[(6-methoxy-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl] 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 7-(4-fluorophenyl)-2-[4-methyl-1 -(2-pyridylmethyl)pyrrolidin-3-yl]-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 5 2-(1 -benzyl-4-methyl-pyrrolidin-3-yl)-7-(3-pyridyl)-3H-imidazo[5,1 -f][1,2,4]triazin 4-one 2-[1-[(2,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-(1 -benzyl-4-methyl-pyrrolidin-3-yl)-7-[4-(trifluoromethoxy)phenyl]-3H 10 imidazo[5,1-f][1,2,4]triazin-4-one; 7-(4-fluorophenyl)-2-[1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-(1 -benzyl-4-methyl-pyrrolidin-3-yl)-7-(2,4-difluorophenyl)-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 15 2-[4-methyl-1 -[[4-(trifluoromethoxy)phenyl]methyl]pyrrolidin-3-yl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-(1 -benzyl-4-methyl-pyrrolidin-3-yl)-7-(4-pyridyl)-3H-imidazo[5,1 -f][1,2,4]triazin 4-one 2-[[3-(4-methoxyphenyl)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H 20 imidazo[5,1-f][1,2,4]triazin-4-one; 7-(4-fluorophenyl)-2-[[3-(4-methoxyphenyl)azetidin-1 -yl]methyl]-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 7-(4-fluorophenyl)-2-[[3-(4-fluorophenyl)azetidin-1 -yl]methyl]-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 25 2-[1 -[(2-chloro-4-methoxy-phenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[4-methyl-1 -(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[[3-(4-fluorophenyl)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H 30 imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1-[(4-methoxyphenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[4-methyl-1 -(4-pyridylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; WO 2013/110768 PCT/EP2013/051451 88 2-[4-methyl-1 -(2-pyridylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[[3-(4-fluorophenoxy)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 5 2-[4-methyl-1 -(pyrimidin-5-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1 -[[4-(diethylamino)phenyl]methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran 4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-(2-furylmethyl)-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H 10 imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1 -(1 H-imidazol-2-ylmethyl)-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 7-(4-fluorophenyl)-2-[(3S,4S)-4-methyl-1 -(pyrimidin-2-ylmethyl)pyrrolidin-3-yl] 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 15 7-(4-fluorophenyl)-2-[(3R,4R)-4-methyl-1 -(pyrimidin-2-ylmethyl)pyrrolidin-3-yl] 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-[(2-chloro-4-fluoro-phenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-[(4-dimethylaminophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7 20 tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[4-methyl-1 -(p-tolylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-(benzyloxymethyl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4 one; 25 2-[[3-(2,6-difluorophenoxy)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1 -(cyclohexylmethyl)-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one 7-tetrahydropyran-4-yl-2-[[3-[4-(trifluoromethoxy)phenoxy]azetidin-1 -yl]methyl] 30 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[[3-(4-dimethylaminophenyl)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[4-methyl-1 -(3-pyridylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; WO 2013/110768 PCT/EP2013/051451 89 2-[1 -[(2,6-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3-phenoxyazetidin-1 -yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 5 2-(1 -ethyl-4-methyl-pyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[[3-[(4-fluorophenyl)methoxy]azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1-[3-(4-methoxyphenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H 10 imidazo[5,1-f][1,2,4]triazin-4-one; 2-[4-methyl-1 -[(5-methyl -2-fu ryl)methyl] pyrrol id in-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1 -[(5-chloro-2-furyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 15 2-[1-[3-(4-fluorophenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[(3-phenylazetidin-1 -yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[[3-(4-methylphenoxy)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H 20 imidazo[5,1-f][1,2,4]triazin-4-one; 2-(1 -benzyl-4-methyl-pyrrolidin-3-yl)-7-(4-piperidyl)-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[1-[(5-fluoro-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 25 2-[[3-(2-pyridyl)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[[3-(4-isopropylphenoxy)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1-[(3,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 30 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-[(4-chlorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3S,4S)-1 -[(2,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7 tetrahydropyran-4-y-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; WO 2013/110768 PCT/EP2013/051451 90 2-[1 -[[6-(dimethylamino)-3-pyridyl]methyl]-4-methyl-pyrrolidin-3-yl]-7 tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; methyl 5-[[3-methyl-4-(4-oxo-7-tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-2-yl)pyrrolidin-1 -yl]methyl]thiophene-2-carboxylate; 5 7-tetrahydropyran-4-yl-2-[[3-[5-(trifluoromethyl)-2-pyridyl]azetidin-1 -yl]methyl] 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[[3-(3-pyridyloxy)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[(3R,4R)-1 -[(2,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7 10 tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(1 R)-1 -[3-(4-methoxyphenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1-[3-(4-fluorophenoxy)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 15 2-[4-methyl-1 -[(5-methyl-2-thienyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1 -[(5-chloro-2-thienyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[4-methyl-1 -[(4-pyrrolidin-1 -ylphenyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran 20 4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-(1 -benzyl-4-methoxy-pyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[4-methyl-1 -(pyrimidin-4-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 25 2-[1-[3-(4-hydroxyphenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1-[(4-fluorophenyl)methyl]-4-methoxy-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[4-methoxy-1 -(p-tolylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H 30 imidazo[5,1-f][1,2,4]triazin-4-one; 2-[[3-(p-tolylmethoxy)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[(3-benzylazetidin-1 -yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; WO 2013/110768 PCT/EP2013/051451 91 2-[(3S,4S)-1 -benzyl-4-methoxy-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1-[3-(4-methylphenoxy)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 5 2-[[3-[(4-methoxyphenoxy)methyl]azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[(3-pyrimidin-2-ylazetidin-1 -yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 f][1,2,4]triazin-4-one; 2-[1-[3-(4-pyrrolidin-1 -ylphenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H 10 imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1 -benzyl-4-(trifluoromethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[[3-(5-pyrrolidin-1 -ylpyrimidin-2-yl)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 15 2-[1-[3-(4-dimethylaminophenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[4-methoxy-1 -[(4-methoxyphenyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-(3-phenylazetidin-1 -yl)ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1 20 f][1,2,4]triazin-4-one; 2-[1-[3-(3-fluoro-4-methoxy-phenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 2-[1-[3-(2-fluoro-4-methoxy-phenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl 3H-imidazo[5,1 -f][1,2,4]triazin-4-one; 25 2-[1-[3-(4-ethoxyphenyl)azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; 2-[1-[3-[(4-methoxyphenyl)methyl]azetidin-1 -yl]ethyl]-7-tetrahydropyran-4-yl-3H imidazo[5,1-f][1,2,4]triazin-4-one; and 7-tetrahydropyran-4-yl-2-[1-[3-[4-(trifluoromethoxy)phenyl]azetidin-1 -yl]ethyl]-3H 30 imidazo[5,1-f][1,2,4]triazin-4-one and pharmaceutically acceptable acid addition salts thereof. 4. A compound of any one of claims 1 to 4 for use as a medicament. WO 2013/110768 PCT/EP2013/051451 92 5. A compound of any one of claims 1 to 4 for use in the treatment of a disorder, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, mental retardation; CIAS, attention-deficit/hyperactivity disorder; and age related cognitive decline, substance-induced psychotic disorder, for example psychosis 5 induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine. 6. A compound of any one of claims 1 to 4 for the preparation of a medicament for use in the treatment of a disorder selected from the group consisting of Alzheimer's disease, 10 mental retardation; CIAS, attention-deficit/hyperactivity disorder; and age-related cog nitive decline, substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine. 15 7. A method of treating a subject suffering from a disorder, wherein the neurodegenera tive disorder is selected from the group consisting of Alzheimer's disease, mental re tardation; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive de cline, substance-induced psychotic disorder, for example psychosis induced by alco hol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencycli 20 dine.
[3] 8. A pharmaceutical composition comprising a therapeutically effective amount of a com pound of any one of claims 1 to 4, and one or more pharmaceutically acceptable carri ers, diluents and excipients. 25

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公开号 | 公开日

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HK1199879A1|2015-07-24|

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US9533992B2|2017-01-03|

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AP2014007820A0|2014-07-31|

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MX351582B|2017-10-20|

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US20150045348A1|2015-02-12|

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AU2017200886B2|2018-01-18|

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EP3178820B1|2017-12-20|

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CN104093720B|2017-04-12|

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CN107082783B|2019-03-22|

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WO2013110768A1|2013-08-01|

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EP2807163A1|2014-12-03|

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MX2014008912A|2014-08-26|

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AU2013213603B2|2017-02-02|

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US20160213674A1|2016-07-28|

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SG11201403909RA|2014-10-30|

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AU2017200886A1|2017-03-02|

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US20170081333A1|2017-03-23|

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US9850249B2|2017-12-26|

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DOP2014000175A|2014-08-31|

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PH12014501695A1|2014-10-20|

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CR20140361A|2014-11-11|

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EP3178820A1|2017-06-14|

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CN104093720A|2014-10-08|

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US9434733B2|2016-09-06|

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ECSP14015609A|2015-12-31|

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PH12014501695B1|2014-10-20|

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CN107082783A|2017-08-22|

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EP2807163B1|2017-03-22|

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BR112014018199A8|2021-03-02|

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法律状态:
2017-06-01| FGA| Letters patent sealed or granted (standard patent)|

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CN2012070718||2012-01-26||

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CNPCT/CN2012/070718||2012-01-26||

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