OA16957A

OA16957A - PDE9 inhibitors with imidazo triazinone backbone.

Info

Publication number: OA16957A
Application number: OA1201400323
Authority: OA
Inventors: Kate Wen; Yazhou WANG; Niels Svenstrup; Klaus Baek Simonsen; Lars Kyhn Rasmussen; Karsten Juhl; Morten LANGGÅRD
Original assignee: H Lundbeck A/S
Priority date: 2012-01-26
Filing date: 2013-01-25
Publication date: 2016-01-25

Abstract

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).

Description

The présent 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 présent invention further provides a compound of formula (I) for use in a method of treating a subject suffering from a psychiatrie disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

O.A.P.I. - B.P. 887, YAOUNDE (Cameroun) - Tel. (237) 22 20 57 00- Fax: (237) 22 20 57 27- Site web: http:/www.oapi.int - Email: oapi@oapi.int

PDE9 Inhibitors with imldazo trlazlnone backbone

FIELD OF THE INVENTION

The présent Invention relates to cyclic guanylate monophosphate (cGMP)-specific phosphodiesterase type 9 Inhibitors (hereinafter referred to as PDE9 Inhibitors) of the form 3Himidazo[5,1-f][1,2,4]triazin-4-ones for the use as a médicament. Moreover the invention relates to a pharmaceutical composition comprising 3H-imidazo[5,1-f][1,2,4]trlazin-4-ones, as well as a process for préparation of the compounds.

BACKGROUND OF THE INVENTION

The phosphodiesterases (PDEs) are a superfamily of enzymes that metabolically inactivate the ublquitous intracellular messengers cAMP and cGMP. This function involves the PDEs in a broad range of important cellular fonctions, 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 nucléotide phosphodiesterases and their rôle 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 région of the protein. The N-terminal régions, which vary among different PDEs, serve regulatory fonctions Including autoinhibition of the catalytic domains or control of subcellular localization (Mehats 2002). The PDEs hâve different substrate préférences: Cyclic 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 préférences, combined with different expression profiles, cellular compartmentalization, and régulation, allow the PDEs to play a very versatile rôle In cell signal transduction (Breer H, Boekhoff I, Tareilus E. Rapid kinetics of second messenger formation in olfactory transduction. Nature. 1990;345:65-68).

PDE9 Inhibitors hâve been reported as useful to treat cardiovascular disorders (WO 03/037899), and insulîn résistance syndrome, hypertension, and/or type 2 diabètes (WO 03/037432) as well as for treatment of obesity related conditions (WO/2005/041972).

Wunder F. et al (Mol. Pharmacol. 2005 Dec; 68(6):1775-81, 2005) report the In vitro characterization of 1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4Hpyrazolo[3,4-d]pyrimidine-4-one, a sélective inhibitor of phosphodiesterase 9 (PDE9), which is 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 cognitionenhancing properties of several classes of PDE-Inhibitors (Blokland et al., 2006: “Improving memory; a rôle 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-trifiuoro-2-methylpropyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimldine-4-one may act as a putative cognition enhancer.

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 perception (agnosia) and execution of movements (apraxia).

Because AD cannot be cured and Is degenerative, palliative treatment of patients Is essentiel.

SUMMARY OF THE INVENTION

The présent invention discioses novel PDE9 inhibitors for the use as a médicament, such as in the treatment of patients suffering from cognitive Impairments, in particular cognitive Impairments that relate to neurodegenerative diseases such as cortical dementia (e.g. Alzheimeris disease) or subcortlcal dementia, e.g. AIDS related dementia.

The PDE9 inhibitors of the présent invention hâve the structure I (I.e. a 3H-imidazo[5,1f][1,2,4]triazln-4-one backbone):

i R3 (D wherein R2 îs cyclized with either R1 or R3.

The Invention relates to methods of improving conditions involving PDE9, such as cognition, in particular the invention relates to a method of treating diseases Involving cognitive difficulties, difficulties with executive functioning (such as planning, organization, mental flexlbility and task coordination) as well as with pereception (agnosia). The methods of improving conditions involving PDE9 and/or treating diseases involving PDE9 comprises the administration of a compound of the présent invention or a pharmaceutically acceptable sait, solvaté or prodrug thereof to a patient in need thereof. The compound of the présent invention or a pharmaceutically acceptable sait, solvaté or prodrug thereof may be in the form of a pharmaceutical composition.

In a further aspect the invention relates to an Improved pharmaceutical composition comprising a compound of the présent invention particularly useful for the treatment of cognitive difficulties, difficulties with executive functioning (such as planning, organization, mental flexlbility and task coordination) as well as with pereception (agnosia), In particular when associated neurodegenerative diseases, such as cortical or subcortical dementias, e.g. Alzhelmeris disease (AD).

DETAILED DESCRIPTION OF THE INVENTION

Cognitive impairment includes a décliné In cognitive functions or cognitive domains, such as, e.g., difficulties with attention, leaming, memory and executive function (relevant reactions to extemal stimuli). Cognitive impairment also may include: déficits 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 and behaviour, and/or extinction of irrelevant thoughts, and difficulty in attention and vigilance, verbal leaming and memory, Visual leaming 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.

Without being limited to any spécifie theory It is believed that the mode of action of PDE9 Inhibitors can be understood in the light of the following neurological processes: guanylyl cyclase (ait. guanylate cyclase) converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which in turn activâtes 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: Rôle of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation, Nature 368, 635-639). The communication between neurons takes place via the chemical synapses (synaptic transmission) and because memories are believed to be stored within these synapses, LTP is considered one of major cellular mechanisms that underlles 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 129, 1659-1673). As a resuit high levels of cGMP will eventualiy lead to improvement of cognition 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. Accordingly, PDE9 inhibitors will Improve synaptic transmission and thereby enhance cognitive performance as evidenced by the results presented ln the experimental section.

The invention will be illustrated ln the following non-limiting examples.

Embodiments according to the invention ln a first embodiment (E1) the présent invention relates to compounds having the structure (I) (also referred to as compounds of formula (I))

wherein R2 Is cyclized with either R1 or R3, wherein R1, R2 and R3 are

R1, when cyclized with R2, Is *

I

--c--R6

I

H wherein R6 Is selected from the group consisting of H, -CH₃₁-C2H5, and -C3H7, wherein * dénotés the cyclization point, and

R1, when not cyclized, is selected from the group consisting of — c—Re

I

H and ^H wherein R6 is selected from the group consisting of H, -CH₃, -C2H5, and -C3H7

R2 is a compound selected from the group consisting of

R11—C — C—R7 — C—R7 and wherein R7 and R11 Independently are selected from the group consisting of H, -CH₃, •C2H5, and —C3H7 wherein * dénotés the cyclization point, and

R3, when cyclized with R2, Is

R8 wherein * dénotés the cyclization point, and wherein R8 is selected from the group consisting of H, CrCe alkyl, branched C₃Ce alkyl, CrCe cycloalkyl, C₆-C₁₀ aryl, substituted Ce-C₁₀ aryl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, CrCe alkoxy, branched Qj-Ce alkoxy, CrCe cycloalkoxy, Ce-C,₀ aryloxy, substituted Ce-C₁₀ aryloxy, C3-C9 heteroaryloxy, substituted C3-C9 heteroaryloxy, and

R3, when not cyclized, is

R9

I ^XH R10 wherein

R9 is selected from the group consisting of H, -CH₃, and -C2H5; and

R10 is selected from the group consisting of Ce-C_toaryl, substituted C₆·

Cio aryl, CrCg heteroaryl, substituted C3-C9 heteroaryl

R4 Is selected from the group consisting of Ce-C₁₀ aryl, substituted Ce-C₁₀ aryl, C3-C9 heteroaryl, substituted CyCg heteroaryl, CrCe heterocyclyl, substituted C3-Ce heterocyclyl, Ca-Ce cycloalkyl, and substituted C₃-Ce cycloalkyl;

R5 is selected from the group consisting of hydrogen, F, Cl, CN, -CH₃, -C2H5, -C3H7, and -CF₃;

A Is absent or-CH2and tautomers and pharmaceutically acceptable acid addition salts thereof, and polymorphie forms thereof, provided that the compound is not 2-[1-[(4-fluoropheny1)methy!]-

4-methy1-pyrrolidin-3-y1]-7-tetrahydropyran-4-yl-3H-lmidazo[5,1-f][1,2,4]triazin-4-one; 2(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-tetrahydropyran-4-y1-3H-lmidazo[5,1-f][1,2,4]triazin-

4-one; 2-[4-methyl-1-(pyrimidin-2-ylmethy1)pyrrolidin-3-yl]-7-tetrahydropyran-4-y1-3Himidazo[5,1-f][1,2,4]triazin-4-one; 2-{4-methylpyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3Himîdazo[5,1 -f][1,2,4]triazin-4-one; 2-[1 -[(6-methoxy-2-pyridy1)methy1]-4-methy1-pyrrolidin-

3- yl]-7-tetrahydropyran-4-y1-3H-imidazo[5,1-f][1,2,4]triaztn-4-one; 2-[(3S,4S)-1-benzyl-4methyl-pyrrolidin-3-y1]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f]Î1,2,4]triazin-4-one; 2[(3R,4R)-1-benzy!-4-methy1-pyrrolidin-3-y1]-7-tetrahydropyran-4-y1’3H4midazo[5,1f][1,2,4]triazin-4-one; 2-[(3S,4S)-4-methylpyrrolidin-3-y1]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1 -f] [1,2,4]triazin-4-one

2-I(3R,4R)-4-methy1pyrrolidin-3-y1]-7-tetrahydropyran-4-yl-3H-lmidazo[5,1-f][1,2,4]triazin-

4- one; 2-[(3S,4S}-4-methy1-1-(pyrimidin-2’y1methyl)pyrrolidin-3-y1]-7-tetrahydropyran-4- y1-3H-lmidazoI5,1-f][1,2,4]triazin-4-one; 2-[(3R,4R)-4-methyl-1-(pyrimidin-2y1methy1)pyrrolidin-3-y1]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; 4[3-methy1-4-(4-oxo-7-tetrahydropyran-4-y1-3H-imldazo[5,1-f][1,2,4]triazîn-2-y1)pyrrolidin-

1-y!]benzonitrile; 2-[(3S,4S)-1-[(4-fluoropheny1)methyl]-4-methy1-pyrrolidin-3-yl]-7- tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazln-4-one; 2-[(3R,4R)-1-K4fluoropheny1)methyl]-4-methyl-pyrrolldin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one or 2-[4-methyl-1-(pyrazin-2-y1methyl)pyrrolidin-3-y1]-7tetrahydropyran-4-y!-3H-imidazo[5,1-f][1,2,4]triazin-4-one.

In a further embodiment (E2) of (E1) the one or more heteroaryls of R4, R8 and R10 independently of each other comprise one or two nitrogen.

In a further embodiment (E3) of (E1 ) R8 Is C_rC₃ alkyl.

In a further embodiment (E4) of (El ) R8 is branched CrQj alkyl.

In a further embodiment (E5) of (E1) R8 is phenyl or napthyl.

In a further embodiment (E6) of (El ) R8 is substituted phenyl or substituted napthyl.

In a particular embodiment (E7) of any of embodiments (E1) and E(6) the substituent is selected 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 consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E9) of any of embodiments (E1 ) and (E2) R8 is a C4-C9 heteroaryl.

In a particular embodiment (E10) of embodiment (E9) R8 is selected from the group consisting of pyridyl, pyridazine, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, and quinoxalinyl.

In a further embodiment (E11) of any of embodiments (El ) and (E2) R8 is a substituted C4-C9 heteroaryl.

In a particular embodiment (E12) of embodiment (E11) R8 is selected from the group consisting of substituted pyridyl, substituted pyridazine, substituted pyrimidinyl, substituted pyrazinyl, substituted quinolinyl, and substituted quinazolinyl, and substituted quinoxalinyl.

In a particular embodiment (E13) of embodiment (E10) R8 Is selected from the group consisting of 2-pyridyl, 3-pyridyl, 2-pyridazine, 2-pyrimldinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-qulnolinyl, 2quinoxalinyl, 6-quinoxalinyl, and 2-quinazolinyl.

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-pyrimldinyl, substituted 4-pyrimidinyl, substituted 2-pyrazinyl, substituted 2-qulnolinyl, substituted 2qulnoxaiinyl, substituted 6-qulnoxalinyl, and substituted 2-qulnazolinyl.

In a particular embodiment (E15) of any of embodiments (E1 ), (E2), (E11), (E12) and (E14) the substituent of R8 is selected from the group consisting of F, Ci, 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 (E16) of embodiment (E1 ) R8 is C1-C4 alkoxy.

In a particular embodiment (E17) of (E16) R8 is methoxy or ethoxy.

In an embodiment (E18) of embodiment (E1) R8 is branched C3-C4 alkoxy.

In a particular embodiment (E19) of (E18) R8 ls Isopropoxy or Isobutoxy.

In an embodiment (E20) of (El ), when R8 ls Ce-C₁₀ aryloxy, R8 is selected from the group consisting of phenyloxy and naphtyloxy.

In an embodiment (E21) of (E1 ), when R8 ls substituted Ce-Cw aryloxy, R8 ls selected from the group consisting of substituted phenyloxy and substituted naphtyloxy.

In a particular embodiment (E22) of any of embodiments (E1)and (E21) the substituents of R8, when R8 ls a substituted Ce-C₁₀ aryloxy, ls selected from the group consisting of F, Cl, methyi, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particular the substituents are selected from the group consisting of F, Cl, methyi, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E23) of any of embodiments (E1 ) and (E2) R8 is a C4-C9 heteroaryloxy.

In an embodiment (E24) of embodiment (E23) R8 ls selected from the group consisting of pyridineoxy, pyridazineoxy, pyrimidineoxy and quinoxaiineoxy

In an embodiment (E25) of any of embodiments (E1) and (E2) R8 ls a substituted C4-C9 heteroaryloxy.

In an embodiment (E26) of embodiment (E25) R8 is selected from the group consisting of substituted pyridineoxy, pyridazineoxy, substituted pyrimidineoxy and quinoxaiineoxy

In an embodiment (E27) of any of embodiments (E1), (E2), (E25) and (E26) the substituent ls selected from the group consisting of F, Cl, methyi, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; In particular the substituents are selected from the group consisting of F, Ci, methyi, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E28) of embodiment (E1) R10 is a Ce-Cw 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 (E1) R10 ls a substituted Ce-Cio aryl selected from 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 (E1 ), E(30) and E(31) the substituent is seiected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cydopropyl, and isopropyl; In particular the substituents are seiected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E33) of any of embodiments (E1) and (E2) R10 is a C4-C9 heteroaryl.

In a particular embodiment (E34) of embodiment (E33) R10 is selected from the group consisting of pyridyl, pyridazine, pyrimidinyl, pyraztnyl, quinolinyl, quinazolinyl, and quinoxalinyl.

In a particular embodiment (E35) of embodiment (E34) R10 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 2-pyridazine, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-quinolinyl, 2quinoxalinyl, 6-quinoxalinyl, and 2-quinazolinyl.

In a further embodiment (E36) of any of embodiments (E1) and (E2) R10 Is a substituted C4-C9 heteroaryl.

In a particular embodiment (E37) of embodiment (E36) R10 Is selected from the group consisting of substituted pyridyl, substituted pyridazine, substituted pyrimidinyl, substituted pyrazinyl, substituted quinolinyl, and substituted quinazolinyl, and substituted quinoxalinyl.

In a particular embodiment (E38) of embodiment (E37) R10 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, substituted 2-qulnoxalinyl, substituted 6-quinoxalinyl, and substituted 2-quinazolinyl.

In a particular embodiment (E39) of any of embodiments (E1), (E2), (E36), (E37) and (E38) the substituent of R10 is seiected from the group consisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cydopropyl, 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 (E40) of embodiment of embodiment (E1) R4 is selected from the group consisting of phenyl and naphthyl.

In an embodiment (E41 ) of embodiment (E 1 ) R4 Is substituted phenyl.

In an embodiment (E42) of embodiment (E41) 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 selected from the group consisting of F, Cl, methyl, trifiuoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E43) of embodiment of embodiment (E1 ) R4 is pyridyl.

In an embodiment (E44) of embodiment (E1) R4 is substituted pyridyl.

In an embodiment (E45) of embodiment (E44) the substituent is selected from the group consisting of F, Cl, methyl, trifiuoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particular the substituents are selected from the group consisting of F, Cl, methyl, trifiuoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E46) of embodiment (E1 ) R4 is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl and piperidyl.

In an embodiment (E47) of embodiment (E1) R4 is selected from the group consisting of substituted tetrahydropyranyf, substituted tetrahydrofuranyl and substituted piperidyl.

In a particular embodiment (Ε4Θ) of embodiment E(47) the substituent is selected from group consisting of F, Cl, methyl, cyano and methoxy.

In an embodiment (E49) of embodiment (E1 ) R4 is selected from the group consisting of cyclobutyl, cyclopenty! and cyclohexyl.

In a preferred embodiment (E50) of embodiment (E49) R4 is cyclopenty! or cyclohexyl.

In an embodiment (E51 ) of embodiment (E1) R4 is selected from the group consisting of substituted cyclobutyl, substituted cyclopentyl and substituted cyclohexyl.

In a preferred embodiment (E52) of embodiment (E51) R4 Is substituted cyclopenty! or substituted cyclohexyl.

In an embodiment (E53) of any of embodiments (E51) and (E52) substituent is selected from the group consisting of F, Cl, methyl, trifiuoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, and Isopropyl; In particular the substituents are selected from the group consisting of F, Cl, methyl, trifiuoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E54) of embodiment (E1 ), the compound of formula (I) 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 sait thereof.

ln an embodiment (E55) of any of embodiments (E1) to (E54) the compound has an IC50 value, determined as described in the section “PDE9 inhibition assay, of 1 micro molar or less.

ln an embodiment (E56) of embodiment (E1) the compound Is selected from the compounds listed ln Table 1.

In an embodiment (E57) of any of embodiments (E1) to (E56) the compound Is for use as a médicament.

ln an embodiment (E58) of any of embodiments (E1) to (E56) the compound is for use ln the treatment of a disease selected from the group consisting of Alzhelmeris disease, mental retardation; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive décliné, substance-lnduced psychotic disorder, for example psychosis Induced by alcohol, amphétamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine.

ln an embodiment (E59) of any of embodiments (E1) to (E56) the compound is for préparation of a médicament for use in the treatment of a disease selected from the group consisting of Alzhelmeris disease, mental retardation; CIAS, attention-deficit/hyperactivity disorder; and agerelated cognitive décliné, substance-lnduced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants, opioids, or phencyclidine.

Embodiment (E60) of the présent invention covers a method of treating a subject suffering from a disease selected from the group consisting of Alzhelmeris disease, mental retardation; CIAS, attention-deficit/hyperactivity disorder, and age-related cognitive décliné, substance-lnduced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaine, hallucinogens, Inhalants, opioids, or phencyclidine, which method comprises administering to said subject a compound of any of embodiments (E1HE56).

ln an embodiment (E61) the présent invention covers a pharmaceutical composition comprising a therapeutically effective amount of a compound of any of embodiments (E1) to (E56), and one or more pharmaceutically acceptable carriers, diluents and excipients.

ln an embodiment (E62) of embodiment (E61) the pharmaceutical composition Is for the treatment of a disease selected from the group consisting of Alzheimeris disease, mental retardation; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive décliné, substancelnduced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine.

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 présent invention:

Table 1: Compounds of the Invention and IC50 values

Compound	PDE9JC50 (nM)
7-(4-fluorophenyl)-2-[4-methyl-1 -[[6(trifluoromethyl )-3pyridyl]methyl]pyrrolidin-3-yl]-3HimldazofS, 1 -fjI1,2,4]triazin-4-one	86
2-[1-[(6-methoxy-3-pyridyl)methyl]-4methyl-pyrrolidin-3-yl]-7-tetrahydfopyran4-yl-3H-lmidazo[5,1 -f][1,2,4]triazin-4-one	67
2-[4-methyl-1-[[4- (trifluoromethyl)phenyl]methyl]pyrrolidin3-yl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one	12
2-(1 -benzyl-4-methyl-pyrrolidin-3-yl )-7(3,6-dihydro-2H-pyran-4-yl)-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one	281
7-(4-fluorophenyl)-2-[1-[(6-methoxy-3pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]3H-imidazo[5,1-f][1,2,4]triazin-4-one	372
2-( 1 -benzyl-4-methyl-pyrrolidin-3-yl )-7-(3pyridyl )-3H-imidazo[5, 1 -f][1,2,4]triazin-4one	656
2-[1-[(2,4-difluorophenyl)methyll-4methyl-pyrro!idin-3-yl]-7-tetrahydropyran4-yl-3H-lmidazo[5,1 -f][1,2,4]triazin-4-one	48
2-(1 -benzyl-4-methyl-pyrrolidin-3-yl >7(2,4-difluorophenyl)-3H-imIdazo[5₁1 -	201

Compound	PDE9JC50 (nM)
f][1,2,4]triazin-4-one
2-[4-methyl-1-[[4- (trifluoromethoxy)phenyl]methy1]pynOlidin- 3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one	19
2-[l3-(4-methoxyphenyl)azetidin-1 y!]methy1]-7-tetrahydropyran-4-yl-3Himidazo[5_I1-f][1,2,4]triazin-4-one	327
2-[1-[(2-chloro-4-methoxy-phenyl)methy1]4-methyl-pyrrolidin-3-y1]-7tetrahydropyran-4-y1-3H-imidazo[5,1 f][1,2,4]triazin-4-one	41
2-[4-methyl-1 -(qulnoxalin-6ylmethyl)pyrrolidin-3-y1]-7tetrahydropyran-4-yl-3H-lmidazo[5,1 f][ 1,2,4]triazin-4-one	24
2-[[3-(4-fluorophenyl)azetidin-1-yl]methy1]7-tetrahydropyran-4-yl-3H-lmldazo[5_I1f][1,2,4]triazîn-4-one	563
2-[1-[(4-mathoxyphenyl)methy1]-4-methylpyrroiidin-3-yl]-7-tetrahydropyran-4-y1-3HimldazoIS, 1 -f][1,2,4]triazin-4-one	49
2-[4-mathyl-1-(4-pyridylmethyl)pyrrolidin3-y1]-7-te trahyd ropyran-4-yl-3Hlmidazo[5,1-f]Î1,2,4]triazin-4-ona	52
2-[I3-(4-fluorophenoxy)azetidin-1 yl]methyl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one	80
2-[4-methyl-1-(pyrimidin-5-	135

Compound	PDE9JC50 (nM)
ylmethyl)pyrrolidin-3-yl]-7tetrahydropyran-4-yl-3H-lmidazo[5,1f][1,2,4]triazin-4-one
2-[1-[[4-(diethylamino)phenyl]methyl]-4methyl-pyrrolidin-3-yl]-7-tetrahydropyran4-yl-3H-lmldazo[5,1 -f][1,2,4]triazin-4-one	13
2-[1-(2-furylmethyl>-4-methyl-pyrrolidin-3yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one	25
7-(4-fluorophenyl)-2-[(3S_I4S)-4-methyl-1(pyrimldin-2-ylmethyl)pyrrolidin-3-yl]-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one	341
2-[1-[(2-chloro-4-fluoro-phenyl)methyl]-4methyl-pyrrolidin-3-yl]-7-tetrahydropyran4-yl-3H-lmidazo[5,1 -f] [1,2,4]triazin-4-one	21
2-[1-[(4-dîmethylaminophenyl)methyl]-4methyl-pyrrolidin-3-yl]-7-tetrahydropyran4-yl-3H-imîdazo[5,1 -f][1,2,4]triazin-4-one	27
2-[4-methyl-1-(p-tolylmethyl)pyrrolidin-3yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one	47
2-(benzyloxymethyl)-7-tetrahydropyran-4yl-3H-im1dazo[5,1 -f][1,2,4]triazln-4-one	384
2-[[3-(2,6-difluorophenoxy)azetidin-1yl]methyl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1-f][1,2,4]triazin-4-one	155
2-[1-(cyclohexylnnethyl)-4-nnethylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one	409

Compound	PDE9JC50 (nM)
7-tetrahydropyran-4-yl-2-[[3-[4(trifluoromethoxy)phenoxy]azetidin-1yl]methyl]-3H-imidazo[5,1 -f][1,2,4]triazin4-one	158
2-[[3-(4-dimethylamÎnophenyl)azetidÎn-1yl]methyl]-7-tetrahydropyran-4-yl-3Himldazo[5,1 -f][1,2,4]triazin-4-one	86
2-[4-methyl-1-(3-pyridylmethyl)pyrrolidin3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f] [1,2,4]triazin-4-one	37
2-[1-[(2,6-difluorophenyl)methyl]-4methyl-pyrrolidin-3-yl]-7-tetrahydropyran4-yl-3H-lmidazo[5,1 -f][1,2,4]triazin-4-one	62
2-[(3-phenoxyazetidi n-1 -yl)methyl]-7tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one	153
2-[[3-[(4-fluorophenyl)methoxy]azetidin-1yl]methyl]-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one	10
2-[1 -[3-(4-methoxyphenyl)azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3Hlmldazo[5,1-f][1,2,4]triazin-4-one	47
2-[4-methyl-1 -[(5-methyl-2furyl)methyl]pyrrolîdin-3-yl]-7tetrahydropyran-4-yl-3H-lmidazo[5,1 f][1,2,4]triazin-4-one	28
2-[1-[(5-chloro-2-furyl)methyl]-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H· imldazo[5,1-f][1,2,4]triazIn-4-one	63

Compound	PDE9JC50 (nM)
2-[1-[3-(4-fluoropheny1)azetidÎn-1-y1]ethyl]î-tetrahydropyran^yl-SH-imidazop, 1 f][1,2,4]triazin-4-one	128
2-[(3-phenylazetidin-1-y1)methyl]-7tetrahydropyran-4-yl-3H-imidazo[5,1f] [1,2,4]triazin-4-one	208
2-([3-(4-methy1phenoxy)azetidin-1y1]methy1]-7-tetrahydropyran-4-y1-3Hlmidazoî5,1 -f][1,2,4]triazin-4-on©	91
2-[1-[(5-fluoro-3-pyridyl)m©thyl]-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Hlmidazo[5_l1-f][1<2_l4]triazin-4-on©	25
2-H3-(4-isopropy1ph©noxy)azetidin-1yl]methyl]-7-tetrahydropyran-4-y1-3Himidazo[5,1-f][1,2₁4]triazin-4-on©	134
2-[1-[(3,4-difluoropheny1)m©thy1]-4m©thyl-pyrrolidin-3-y1]-7-tetrahydrapyran4-y1-3H-imidazo[5,1 -f][1,2,4]triazin-4-one	23
2-[1-[(4-chloropheny1)methyl]-4-m©thy1pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Himldazo[5,1-f][1,2,4]triazin-4-one	32
2-[1-([6-(dÎmethy1amino)-3-pyridy1]methyl]4-methy1-pyrrolidÎn-3-y1]-7t©trahydropyran-4-yl-3H-imidazo[5,1 f]î1,2,4]triazin-4-on©	36
methyl 5-[[3-methy1-4-(4-oxo-7tetrahydropyran^yl-SH-imidazolS, 1 - f] [ 1,2,4]triazin-2-yl)pynOiidin-1 y1]methy1]thiophene-2-carboxylate	8

Compound	PDE9JC50 (nM)
7-tetrahydropyran-4-yl-2-[[3-[5(trifluoromethyl)-2-pyridyl]azetidin-1yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin4-one	560
2-[[3-(3-pyridyloxy)azetidin-1-yl]methyl]-7tetrahydropyra n-4-yl-3H-imldazo[5,1f][1,2,4]triazin-4-one	350
2-[(3R,4R)-1-[(2_I4-difluorophenyl)methyl]4-methyl-pyrrolidin-3-yl]-7tetrahydropyran-4-yl-3H-imldazo[5,1 f][1,2,4]triazin-4-one	47
2-[(1 R)-1 -[3-(4-methoxyphenyl)azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3Himldazo[5,1 -f][1 ^^Jtriazin-^one	22
2-[1-[3-(4-fluorophenoxy)azetidin-1yl]ethyl]-7-tetrahydrapyran-4-yl-3H' imidazo[5,1 -f][1,2,4]triazln-4-one	57
2-[4-methyl-1 -[(5-methyl-2thienyl)methyl]pyrrolidin-3-yl]-7tetrahydropyra n-4-yl-3H-lmidazo[5,1 f][1,2,4]triazln-4-one	22
2-[1-[(5-chloro-2-thienyl)methyl]-4-methylpyirolidin-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f] [ 1,2,4]trlazin-4-one	13
2-[4-methyH -[(4-pyrroîidin-1 ylphenyl)methyl]pyrroîidin-3-yl]-7tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one	61
2-(1-benzyl-4-methoxy-pyrrolidin-3-yl)-7tetrahydropyran-4-yl-3H-lmidazo[5,1-	54

Compound	PDE9JC50 (nM)
f][1,2,4]triazin-4-one
2-[4-methyl-1 -(pyrimidin-4ylmethyl)pynOlidin-3-yl]-7tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one	Not determined
2-[1-[3-(4-hydroxyphenyl)azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f] [1,2,4]triazin-4-one	120
2-[1-[(4-fluorophenyl)methyl]-4-methoxypyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1 -f][1,2,4]triazln-4-one	94
2-[4-methoxy-1-(p-tolylmethyl)pyrrolidin-3yl]-7-tetra hydropyran-4-yl-3H-lmidazo[5,1f][1,2,4]triazin-4-one	90
2-[[3-(p-tolylmethoxy)azetidin-1 yl]methyl]-7-tetrahydropyran-4-yl-3Hlmldazo[5,1 -f][1,2,4]triazin-4-one	150
2-[(3-benzylazetidin-1-yl)methyl]-7tetrahydropyran-4-yl-3H-lmldazo[5,1f](1,2,4]triazin-4-one	Not determined
2-[(3S,4S}-1-benzyl-4-methoxy-pyrrolidin- 3-yl]-7-tetrahydropyran-4-yl-3H- lmidazo[5,1 -f] [1,2,4]triazin-4-one	Not determined
2-[1 -[3-(4-methylphenoxy)azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1-f][1,2,4]triazin-4-one	110
2-((3-((4- methoxyphenoxy)methyl]azetidin-1- yl]methyl]-7-tetrahydropyran-4-yl-3H-	82

Compound	PDE9JC50 (nM)
imidazo[5,1 -f][1,2,4]triazin-4-one
2-[(3-pyrimidin-2-ylazetidin-1-yl)methyl]-7tetrahydropyran-4-yl-3H-lmidazo[5,1 f][1,2,4]triazin-4-one	3400
2-[1-[3-(4-pyrrolidin-1-ylphenyl)azetidin-1yljethyl]-7-tetra hyd ro pyran-4-yl-3Hlmldazo[5,1 -f][1,2,4]triazin-4-one	110
2-[1-benzyl’4-(trifluoromethyl)pyrrolidin-3yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one	50
2-[[3-{5-pyrrolidin-1-ylpyrimidin-2yl)azetidin-1-yl]methy1]-7-tetrahydropyran4-yl-3H-imidazo[5,1 -f][1 _>2,4]triazin-4-one	120
2-[1-[3-(4-dim6thylaminophenyl)azetidin1-yf]ethyl]-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one	86
2-[4-methoxy-1-[(4methoxyphenyl)methyl]pyrrolidin-3-yl]-7tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one	83
2-[1-(3-phenylazetidin-1-yl)ethyl]-7tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one	360
2-[1-[3-(3-fluoro-4-methoxyphenyl)azetidin-1-yl]ethyl]-7tetrahydropyran-4-yl-3H-lmidazo[5,1f][1,2,4]triazin-4-one	240
2-[ 1 -[3-(2-fluoro-4-methoxyphenyl)azetidin-1 -yl]ethyl]-7-	300

Compound	PDE9JC50 (nM)
tetrahydropyran-4-yl-3H-imidazo[5,1 - f][ 1,2,4]triazin-4-one
2-[1-[3-(4-ethoxypheny!)azetidin-1 yl]ethyJ]-7-tetrahydropyran-4-yl-3Himldazo[5,1 -f][ 1,2,4]triazln-4-one	290
2-[1-[3-[(4- methoxyphenyJ)methyJ]azetidin-1 yl]ethyl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f][1,2,4Jtriazin-4-one	68
7-tetrahydropyran-4-yJ-2-[1 -(3-(4(trifluoromethoxy)pheny!]azetidin-1 yl]ethyl]-3H-imldazo[5,1 -f][1,2,4]triazin-4one	210
2-[ 1 -[3-(4-methy!phenoxy Jazetidin-1 yl]ethyJ]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f][ 1,2,4]triazin-4-one	110
2-[[3-[(4- methoxyphenoxy)methyl]azetidin-1yJ]methyJJ-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f][1,2,4]triazin-4-one	82
2-[(3-pyrimidin-2-yJazetidin-1-yl)methyl]-7tetrahydropyran-4-y!-3H-imldazo[5,1 f][1,2,4]triazin-4-one	3400
2-[1-[3-(4-pyrroîidin-1-yfphenyl)azetidin-1ylJethyl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f][1,2,4]triazin-4-one	110

Définition of substituents

As used in the context of the présent invention, the terms halo and “halogen are used interchangeably and refer to fluorine, chlorine, bromine or iodine.

The term “CpCe alkyi 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 limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methy1-2-propyl, 2-methy1-1-butyl, and nhexyl. The expression “C1-C6 hydroxyalkyi refers to a C_rCe alkyi group as defined above which is substituted with one hydroxy group.

The term halo(C₁-C_e)aiky1 refers to a C_rC_e alkyi group as defined above which is substituted with up to three halogen atoms, such as trifiuoromethyl.

The expression Ci-C_e 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. Examples of such groups Include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.

The term “C₃-C₈ cycloalkyl typically refers to cyclopropyl, cyclobutyl, cyclopenty!, cyclohexyl, cycloheptyl or cyclooctyl.

The expression CpCe alky1(C₃-C₈)cycloalkyl refers to a CrCe cycloalkyl as defined above which is substituted with a straight-chain or branched C_rCe alkyi. 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 and up to three N, O or S atoms, provided that the four to eight membered ring does not contain adjacent O 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, piperazinyl, morpholinyl, thiomorpholinyl and [1,4]diazepanyl.

The term “hydroxyheterocycloalkyl refers to a heterocycloalkyl as defined above which is substituted with one hydroxy group.

The term CrCe alkyl-heterocycloalkyl refers to a heterocycloalkyl as defined above which is substituted with a CrCe alkyi group. Examples of such groups include, but are not limited to, tetra hydropyran-4-yl-methyl and 2-morpholin-4-yl-ethyl.

The term “aryl refers to a phenyl ring, optionally substituted with halogen, C_rC₈ alkyi, C_rC₈ alkoxy or halo(CrCe)alkyl as defined above. Examples of such groups Include, but are not limited to, phenyl and 4-chlorophenyl.

The term “CpCearylalkyl refera to an aryl as defined above which is substituted with a stralghtchain or branched CrCe alkyl. Examples of such groups include, but are not iimited to, benzyl and 4-chlorobenzyl.

The term aryloxy refers to an univalent radicai of the form Ar-0 (such as phenoxy) composed of an aryl group (Ar) united with oxygen (O).

The term heteroaryloxy refers to an aryloxy where one or more carbon atoms hâve been substituted with one more hetero atoms, such as N, O, S.

In the context of the présent Invention the term ‘cyciization point’ ls understood to mean that connecting the atoms Indicated to be cyciization points by a bond results In a cyclic structure (a ring). The cyciization point is indicated with a * in the illustrative reaction scheme below:

* Dénotés cyciization points

Additionally, the présent invention further provides certain embodiments of the invention, which are described below. Additionally, the présent invention further provides certain embodiments of the invention that are described below.

Pharmaceutically Acceptable Salts

The présent invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts. Such salts Include pharmaceutically acceptable acid addition saits. Acid addition salts include salts of inorganic acids as well as organic acids.

Représentative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the iike. Représentative examples of suitable organic acids inciude formlc, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, malelc, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartane, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, giuconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzolc, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. Further examples of pharmaceutically acceptable Inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in 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, éthanol and the like. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of this Invention.

Pharmaceutical composition

The présent invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. The présent invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the spécifie compounds disclosed In the Experimental Section herein and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in 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), transdermal, intraclstemal, intraperitoneal, vaginal and parentéral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route wll! dépend on the general condition and âge of the subject to be treated, the nature of the condition to be treated and the active Ingrédient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingrédient such as sustalned or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, émulsions, suspensions, syrups and élixirs.

Pharmaceutical compositions for parentéral administration include stérile aqueous and nonaqueous injectable solutions, dispersions, suspensions or émulsions as well as stérile pow24 ders to be reconstituted In stérile injectable solutions or dispersions prior to use. Other suitable administration forms inciude, but are not iimited to, suppositories, sprays, ointments, creams, gels, inhalants, dermai patches and implants.

Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typlcal 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 dosages per day. The exact dosage will dépend upon the frequency and mode of administration, the sex, âge, 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 évident to those skilled in the art.

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 parentéral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration,

The présent invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula (I) and at least one pharmaceutically acceptable carrier or diluent. In an embodiment, of the présent invention, the compound utilized in the aforementioned process Is one of the spécifie compounds disclosed in the Experimental Section herein.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable sait thereof. One example Is an acid addition sait of a compound having the utility of a free base. When a compound of formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula (I) with a molar équivalent of a pharmaceutically acceptable acid. Représentative examples of suitable organic and Inorganic acids are described above.

For parentéral administration, solutions of the compounds of formula (I) in stérile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.

Such aqueous solutions should be sultably buffered if necessary and the liquid diluent first rendered isotonie with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula (I) may be readiiy incorporated into known stérile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers Include inert solid diluents or fillers, stérile aqueous solutions and various organic soivents. Examples of soiid carriers include iactose, terra alba, sucrose, cyciodextrin, taie, geiatin, agar, pectin, acacia, magnésium stéarate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers inciude, but are not limited to, syrup, peanut oii, olive oii, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustalned release material known In the art, such as giyceryl monostearate or glyceryl distearate, aione or mixed with a wax. The pharmaceutical compositions formed by combining the compounds of formula (I) and a pharmaceutically acceptable carrier are then readily administered In a variety of dosage forrns suitable for the disclosed routes of administration. The formulations may conveniently be presented In unit dosage form by methods known In the art of pharmacy.

Formulations of the présent Invention suitable for oral administration may be presented as discrète units such as capsules or tablets, each containing a predetermined amount of the active Ingrédient, and optionally a suitable excipient. Furthermore, the orally available formulations may be In the form of a powder or granules, a solution or suspension In an aqueous or nonaqueous liquid, or an oil-in-water orwater-in-oil liquid émulsion.

If a solid carrier is used for oral administration, the préparation may be tabietted, placed in a hard geiatin 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 wideiy but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the préparation may be in the form of a syrup, émulsion, soft gelatin capsule or stérile 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 ingrédient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine préparé tablets. Examples of adjuvants or diluents comprise: com starch, potato starch, talcum, magnésium stéarate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usuaily used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingrédients.

Diseases

In a particular embodiment the PDE9 Inhibitors of the présent 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 anse from a disorder affecting the cérébral cortex, the outer layers of the brain that play a critical rôle in cognitive processes such as memory and language. Partîcularly considered cortical dementias are Alzheimeris disease; vascular dementia (also known as multiinfarct dementia), including Binswangeris disease; Dementia with Lewy bodies (DLB); AlcoholInduced Perslstlng Dementia, including KorsakofTs syndrome and Wemicke's encephalopathy; frontotemporal lobar degeneration (FTLD), Including: Pick's disease, frontotemporai dementia (or frontal variant FTLD), semantic dementia (or temporal variant FTLD), and progressive nonfluent aphasia; Creutzfeldt-Jakob disease; dementia pugilistica; Moyamoya disease; and posterior cortical atrophy (an Alzhelmeris disease variant).

Subcortical dementias resuit from dysfunction in the parts of the brain that are beneath the cortex. Usually, the memory loss and language difficultés that are characteristic of cortical dementias are not présent. 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. Partîcularly considered subcortical dementias are dementia due to Huntington's disease, dementia due to hypothyroidism, dementia due to Parkinson's disease, dementia due to Vitamln B1 deficlency, dementia due to Vitamin B12 deficiency, dementia due to folate deficlency, dementia due to syphilis, dementia due to subdural hematoma, dementia due to hypercaicaemîa, dementia due to hypoglycaemia, AIDS dementia complex, pseudodementia (a major dépressive épisode with prominent cognitive symptoms), substance-lnduced perslsting dementia, dementia due to multiple étiologies, dementia due to other general medical conditions (Le. end stage rénal fallure, cardiovascular disease etc.), dementia not otherwise specifïed (used in cases where no spécifie criteria is met).

Experimental

General Description of pyrrolidlne-substituted 3H-imldazo[5,1-f][1,2,4]trlazin-4-ones

Compounds of formula I can be made by reductive amination of compounds of formula X, with aryl aldéhydes in the presence of NaBH₃CN or Na(OAc)₃BH, and a few drops of acetîc acid as catalyst in DME or MeOH, or by alkylation of compound X with aryl methyl halides, ln the presence of bases, such as K₂CO₃ or DIEA, in DMF or CH₃CN.

Ar-CHO, NaBHjCN, DME or Ar-CHjX, KjCOj, DMF

R' = Methyl, Trifluoromethyl, Methoxy!

Compounds of formula X can be prepared by deprotection with HCl in MeOH of compound of formula IX, which can be obtained by one-pot hydrogenolysis débenzylation and Boc protection with BOC2O of compounds with formula VIII. Compounds of formula VIII can be synthesized by 5 Suzuki reaction of compounds of formula VII, with a variety of organo boronic acids or boronic esters In the presence of Xantphos, and a palladium catalyst, such as Pd(dppf)CI₂, Pd(PPh₃)2Cl2, Pd(PPh₃)₄ and a base, such as KsPOx, K₂CO₃, 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 l₂, of compound VI, which can be made by 10 cyclization in the presence of NH₄OAc in MeOH with heating of compound V. Compound V can be made by coupling reaction of compound III, obtained from reaction between compound II with (aminooxy)diphenylphosphine oxide, with compound IV, which can be prepared from a known compound XI. Compound XI Is made according to the procedures In patent WO 2009/76387.

LUMDS.THF

III

NH.OAC

MeOH, HmI

II

XmthpO·, ΡιχίρρΟ,α, K, PO,.DMF

R-B(OH),

VIII

V!

r; hn\^_n rvBuLWHF (V

R MsUiyf, Trllluoromelhyl, Methoxyl

General Description of Azetldlne-substituted 3H-imldazo[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 chlorlde of formula X, with different amines In the presence of a base, such as DIEA. Compounds of formula X can be generated from the reaction between compounds of formula IX with thionyl chloride. Compounds of formula XI, when R Is an alkyl group, can be syntheslzed from reductive amination of ketones of formula XII with a variety of amines, in the presence of Na(CN)BH₃or Na(OAc)₃BH. Ketones of formula XII can be made from oxldation of the alcohol of formula IX with MnO₂ In DCM.

XII

xi

Alcohols of formula IX can be prepared from débenzylation, with Pd/C In 50 psi of H₂, of compounds of formula VIII, which can be syntheslzed by Suzuki coupling of compounds of formula Vil, with a variety of boronic acids or boronic esters, In the presence of a palladium catalyst, such as Pd(PPh₃)₄, Pd(dppf)CL₂, etc, with microwave heating. Compounds of formula VII can be generated from deprotonation of compounds of formula VI with a base, such as n-BuLI, followed by treatment with i₂.

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 from amlnolysis 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 III with 1-amino29

Imldazole II, 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.

nh₃.h₂o

Microwave

KOH(aq)

Microwave

V

OBn

VI

Part I (Pyrrolidine Sériés)

Préparation of Intermediates

2-(1«Benzyl-4-methyl-pyrrolldin-3-yl)-7-iodo-3H-lmIdazo[5,1-fJ[1,2,4]trlazin-4-one

Scheme 1

3-Amlno-3H-lmldazoie-4-carboxyllc 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^eC in N₂. The mixture was stirred at -78^eC for 2 hours. Then It was stirred at -30’C for 20 minutes. (Amlnooxyjdiphenylphosphine oxide (8.14 g, 31.7 mmol) was added In portions at -10’C. The reaction mixture was allowed to warm to r.t ovemight. 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]⁺. ¹H NMR (400 MHz, DMSO-d5): δ 7.82 (s. 1H), 7.54 (s, 1H). 6.20 (br. s, 2H). 3.79 (s, 3H).

3-[(1-Benzyl-4-methyl-pyrrolidlne-3-carbonyl)-amlno]-3H-lmidazole-4-carboxyllc 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 SOCI₂ was refluxed at 85^eC for 4 hours. The solvent was removed by concentration in vacuo to afford the acid chloride of 3.

The acid chloride was dissolved In 30 mL of CH₂CI₂. This resulting solution was added dropwise to a solution of compound 2 (3.5 g, 24.8 mmol) and EtjN (10 mL, 68.2 mmol) in 100 mL of CH₂Ci₂ at 0*C over 20 minutes. Then the reaction mixture was stirred at room température for 8 hours. The reaction mixture was washed with brine (100 mL x 2). The organic phase was dried over Na₂SO₄₁ filtered and concentrated to afford the crude residue, which was purified by column chromatography on silica gel (eluted with DCM/MeOH = 100:1 to 50:1) to afford compound 4 (5.0 g, 58.9% yield) as a red oil. LC-MS: m/z 343.11 [M+1 ]*. ¹H NMR (400 MHz, CDCI₃): δ

7.70 (s, 1H), 7.63 (s, 1H). 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), 2.56-2.50 (m, 2H), 1.92 (m, 1 H), 1.16 (d, J =7.2 Hz, 3H).

2-(1-Benzyl-4-methyi-pyrrolidin-3-yl)-3H-imldazo[5,1-f][1,2,4]triazln-4-one (5)

To a 300 mL sealed tube was added a mixture of compound 4 (4.7 g, 13.7 mmol), NH₄OAc (11 g, 14.3 mmol) and ammonium hydroxide (50 mL) in MeOH (120 mL). The reaction mixture was stirred at 130^eC for 2 days. After cooling down, the reaction mixture was concentrated in vacuo.

The residue was diluted with CH₂CI₂ (100 mL) and washed with water (50 mL χ 2). The organic phase was separated and dried over Na₂SO4. After filtering, the filtrate was 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+1J*. ’H NMR (400 MHz, CDCI₃): δ 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). 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, 1H), 1.95-1.91 (m, 1H), 1.20 (d, J= 6.4 Hz, 3H).

2-(1-Benzyl-4-methyl-pyrrolldln-3-yl)-7-lodo-3H-imldazo[5,1-f][1,2,4]triazln-4-one (6)

To a solution of compound 5 (1.0 g, 3.24 mmol) in dry THF (70 mL) was added n-BuU (2.5 M, 2 mL) dropwise at -78*C over 30 minutes. The reaction was stirred at -45*C for 30 minutes. Then a solution of iodine In THF (20 mL) was dropwise added at -78’C over 10 minutes. The resulting mixture was stirred at 0*C for 2 hours. The reaction was quenched with saturated aqueous Na₂S₂O₃ solution (10 mL). Then the reaction mixture was diluted with EtOAc (200 mL), and washed with brine (50 mL * 2). The separated organic phase was dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted by ΡΕ/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 f. Ή NMR (400 MHz, CDCI₃): δ 7.89 (s, 1H), 7.37-7.26 (m, 5H), 3.82 (d, 12.4 Hz, 1H), 3.59 (d, J= 12.4 Hz, 1H), 3.42-3.38 (m, 1H), 2.98 (d, J= 8.4

Hz, 1H), 2.82-2.81 (m, 1H), 2.55-2.51 (m, 1H), 2.45-2.42 (m, 1H), 1.96-1.92 (m, 1H), 1.22 (d, J =7.2 Hz, 3H).

2·(4-Μθ^γΙ-ργτΓθΙΙάΙη·3-γΙ)-7-(1βΐΓ3ίψάΓθ-ργΓ3η-4-γΙ)-3Η-ΐΓηΙά3ζο[5,1·ί](1,2,4]ίιΐ3ζΙη··4-οπβ Hydrochloric acid sait

Scheme 2

2- {1-Benzyl-4-methyl-pyrrolldln-3-yi)-7-(3,6-dlhydro-2H-pyran-4-yl)-3H-lmidazo[5₍1f][1,2,4]trlazln-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 added potassium phosphate (146 mg, dissolved In 1 mL of H₂O). The reaction mixture was degassed by purglng with N₂ for 15 min, before Pdidppf^Ch (28 mg, 0.035 mmol) and Xantphos (40 mg, 0.069 mmol) were added. The resulting suspension was bubbled with nitrogen for 10 minutes. The reaction mixture was heated to 150°C under microwave Irradiation for one hour. After cooling down, the reaction mixture was diluted with EtOAc (50 mL), and the precipîtate was filtered off. The filtrate was washed with brine (50 mL), dried over Na₂SO4, filtered and the filtrate was concentrated. The crude product was purified by column chromatography 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, CDCI₃): δ 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 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-yl)-3,4-dlhydro-lmldazo(5,1-1)(1,2,4]trlazln-2-yl]pyrrolidlne-1*carboxylic acid tert-butyl ester (8)

To a 75 mL flask was added compound 7 (0.3 g, 0.76 mmol), di-tert-butyl dlcarbonate (1.6 g, 7.6 mmol), potassium acetate (0.75 g, 7.6 mmol), 10% Pd/C (300 mg, 0.28 mmol) and méthanol (40 mL). The reaction mixture was stirred with hydrogen (50 psi) at 50°C 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. 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+1f. ’H NMR (400 MHz, CDCI₃): δ 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 Hz. 3H).

2-(4-Methyl-pyrrolldln-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-lmidazo[5,1-f][1,2_l4]trlazln-4-one

Hydrochlorlc acid sait (9)

To a solution of compound 8 (130 mg, 0.32 mmol) In CH₂CI₂ (10 mL) was added a saturated solution of HCl in diethytether (20 mL). The resulting mixture was stirred at room température 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]*. ¹H NMR (400 MHz, D₂O-d2): δ 8.02 (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-phenyi)>2-(4-methyl-pyrroiidin-3-yi)-3H-imidazo[5,1-f][1,2,4]triazln-4-one Hydrochlorlc acid sait

Scheme 3

2-(1-Benzyl-4-methyl-pyrroildin-3-yi)-7-(4-fluoro-phenyl)-3H-lmldazo[5,1-f][1,2,4]trlazln-4one (10)

To a solution of compound 6 (500 mg, 1.14 mmol) and 4-fluorophenytboronic acid (300 mg, 2.14 mmol) In 30 mL of toluene was added K₂CO₃ (1.0 g, 7.24 mmol). The resulting mixture was degassed by purging with nitrogen for 15 min, before Pd(PPh₃)4 (120 mg, 0.10 mmol) was added. The resulting suspension was bubbled with nitrogen for 10 minutes. The reaction mixture was heated to 100°C for 18 hours and then cooled to room température. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with ΡΕ/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+1f. ¹H NMR (400 MHz, CDCI₃): δ 8.34-8.31 (m, 2H), 7.95 (s, 1H), 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), 1.99 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H).

3-[7-(4-Fluoro-phenyi)-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yi]-4-methylpyrroHdlne-1-carboxylic acid tert-butyl ester (11)

Compound 11 was prepared in the same method as described for préparation of compound 8. 46% yield. LC-MS: m/z 414.08 [M+1]*. ’H NMR (400 MHz. DMSO-d6): δ 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).

7-(4-Fluoro-phenyl)-2-(4-methy1-pyrrol1din-3-yl)-3H-lmidazo[5,1-f][1,2,4]triazin-4-one Hydrochloric acid sait (12)

Compound 12 was prepared in the same way as described for préparation for compound 9. 95% yield. LC-MS: m/z 314.31 [M+1]*. ’H NMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H),

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

3-[(1-Benzyl-4-trlfluoromethy1-pyrroHdine-3-carbonyl)-amlno]-3H-lmldazole-4-carboxylic acid methyl ester (13)

To a solution of compound 2 (2.0 g, 14.1 mmol), 1-Benzyl-4-trifluoromethyi-pyrrolidine-3carboxylic 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 reaction was monitored by LC-MS. The reaction was quenched with water (100 mL) when it was complété. The aqueous solution was extracted with EtOAc (80 mL * 3). The combined organic phase was washed with brine and concentrated to afford the crude product. The residue 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]*. ¹H NMR (400 MHz, CDCI₃): δ 8.00 (br. s, 1 H),

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, 1H).

2-(1-Benzyl-4-trifluoromethyl-pyrrolldln-3-yl)-3H-lmidazo[5,1-f][1,2_l4]triazln-4-one (14) o

The procedure for the préparation ofcompound 14 was similar to that of compound 5.

28.8% yield. LC-MS: m/z 364 [M+1f. ’H NMR (400 MHz, CDCI₃): 5 8.06 (s, 1H), 7.88 (s, 1H),

7.41-7.30 (m, 5H), 3.88 (d, J - 12.8 Hz. 1 H), 3.67 (d, J = 12.4 Hz, 1H), 3.45-3.40 (m, 1H),

3.35-3.33 (m, 1H). 3.08-3.06 (m, 2H), 2.65-2.61 (m, 1H), 2.52-2.48 (m. 1H).

2-(1-Benzyl-4-trifluoromethyl-pyrrolidin-3-yl)-7-lodo-3H-lmldazo[5,1-f][1,2,4]triazln-4-one (15)

The procedure for the préparation ofcompound 15 was similar to that of compound 6.

38.7% yield. LC-MS: m/z 490 [M+1]*. ¹H NMR (400 MHz, CDCI₃): 57.91 (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 (m, 2H),

2.67-2.62 (m, 1H), 2.54-2.49 (m, 1H).

2-(1-Benzyl-4-trifluoromethyi-pyrrolidin-3-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3Hlmldazo[5,1-f][1,2,4]triazln-4-one (16)

The procedure for the préparation ofcompound 16 was similar to that of compound 7.

91% yield. LC-MS: m/z 446 [M+1J*. ’HNMR (400 MHz, CDCI₃): δ 7.87 (s, 1H), 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), 5 3.41 -3.36 (m, 2H), 3.09-3.04 (m, 2H), 2.76 (m, 2H), 2.65-2.60 (m, 1 H), 2.52-2.47 (m, 1 H).

3-[4-Oxo-7-(tetrahydro-pyran-4-yl)-3,4-dihydro-imidazo[5,1-f][1_I2_I4]triazin-2-yl]-4trlfluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (17)

The procedure for the préparation ofcompound 17 was similar to that of compound 8.

27% yield. LC-MS: m/z 458 [M+1J*. ¹H NMR (400 MHz, CDCI₃): δ 7.89 (s, 1H), 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 (m, 2H), 1.77-1.59 (m, 3H), 1.47 (s, 9H).

7-(T etrahydro-pyran-4-yl)-2-(4-trifluoromethyl-pyrro1idin-3-y1)-3H-imidazo[5,1f][1,2,4]trlazln-4-one Hydrochloric acid sait (18)

The procedure for the préparation of compound 18 was similar to that of compound 9.

100% yield. LC-MS: m/z 358 [M+1]*. ¹H NMR (400 MHz, DMSO-cf6): δ 7.90 (br. s, 1H). 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

3-[(1-Benzyl-4-methoxy-pyrrol!dlne-3-carbonyl)-amlno]-3H-imidazoie-4-carboxy!lc acid methyl ester (19)

The procedure for the préparation ofcompound 19 was similar to that of compound 4.

77% yield. LC-MS (ESI): m/z = 359.1 [M+1]*. ¹H NMR (400 MHz, CDCI₃): δ 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, 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, 1H).

2-(1.Benzyi-4-methoxy-pyrrol1din-3-yl)-3H-1mlda2o[5,1-f][1,2,4]triazin-4-one (20)

Ο

The procedure for the préparation ofcompound 20 was similar to that of compound 5.

32% yield. LC-MS (ESI): m/z = 325.3 [M+1]*. ¹H NMR (300 MHz, CDCI₃): δ 8.05 (s, 1H), 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, 5 1H), 3.57-3.53 (m, 1H), 3.38 (s, 3H), 3.14-3.12 (m, 1 H), 3.02-2.99 (m, 1 H), 2.74-2.68 (m, 1H),

2.36-2.31 (m, 1 H).

2-(1-Benzyl-4-methoxy-pyrrolldin-3-yl)-7-iodo-3H-lmidazo[5,1-f](1,2,4]trlazin-4-one (21) o

The procedure for the préparation ofcompound 21 was similar to that of compound 6.

38% yield. LC-MS (ESI): m/z = 452.2 [M+1f. ’H NMR (300 MHz, CDCI₃): δ 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),

3.24-3.22 (m. 1H), 3.03-2.99 (m, 1 H). 2.74-2.69 (m, 1 H), 2.37-2.32 (m, 1H).

2-( 1 -Benzyl-4-methoxy-pyrrolidin-3-yi)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5₁1 f][1,2,4]triazin-4-one (22)

O

The procedure for the préparation ofcompound 22 was similar to that of compound 7.

85% yield. LC-MS (ESI): m/z = 408 [M+1J*. Ή NMR (400 MHz, CDCI₃): δ 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),

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, 1H), 2.78-2.70 (m, 2H), 2.36-2.32 (m, 1H).

3-Methoxy-4-[4-oxo-7-(tetrahydro-pyran-4-yl)-3₁4-dihydro-imidazo[5,1 -f][1,2,4]triazin-2-y1]pyrrolidine-1-carboxylic acid tert-butyl ester (23)

The procedure for the préparation ofcompound 23 was similar to that ofcompound 8.

46% yield. LC-MS (ESI): m/z = 420 [M+1J*. *H NMR (400 MHz, CDC|₃): δ 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).

2-{4-Methoxy-pyrrolidln-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5,1-f][1,2,4]trlazin-4one Hydrochloric acid sait (24)

The procedure for the préparation of compound 24 was similar to that of compound 9.

100% yield. LC-MS (ESI): m/z = 320.2 [M+1 J*. ¹H NMR (400 MHz, DMSO-c/6): δ 9.77-9.62 (br.

s, 2H), 7.88 (s, 1H), 4.40-4.35 (m, 1 H), 3.95-3.91 (m, 2H), 3.69-3.49 (m, 6H), 3.36 (s, 3H),

1.85-1.79 (m, 4H), 1.30-1.23 (m, 1H), 1.11-1.05 (m, 1H).

Préparation of target compounds:

Example 1

2-[1-(4-Fluoro-benzyl)-4-methyl-pyrrolidln-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5,1· f][1,2,4]triazln-4-one

To a solution of compound 9 (80 mg, 0.263 mmol) and 4-fluorobenza!dehyde (326 mg, 2.63 mmol) !n 1,2-dichloroethane (15 mL) was added 2 drops of acetic acid, The resulting solution was stirred at room température for one hour. Then NaBH₃CN (178 mg, 2.63 mmol) was added to the reaction in portions. The resulting mixture was stirred at room température for 16 hours. LC-MS showed that the starting material was almost consumed. The réaction mixture was quenched with water (40 mL), and extracted with CH2CI2 (30 mL ^x 3). The combined organic phases were washed with brine (30 mL), and dried over Na₂SO₄. After fiitered, the filtrate was concentrated In vacuum. The residue was purified by préparative TLC to afford the desired product (20 mg, 21% yield) as a white solid. LC*MS: m/z 412.2 [M+1J*. ’H NMR (400 MHz, CD₃OD-d4): 5 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).

The racemic mixture of 2-[1-(4-Fluoro-benzyl)*4-methyl-pyrrolldin-3-yl]-7*(tetrahydro-pyran-

4-yl)-3H-lmldazo[5,1-f][1,2_l4]trlazln-4-one was submitted for préparative chiral HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate =12 mL/min; UV: 230 nm;

mg/inj ln) and give two enantiomers:

2-((3S,4S)-1-(4-fluorobenzyl)-4-methylpyrrolldln-3-yl)-7-(tetrahydro-2H-pyran-4y1)lmidazo[1,5-f][1,2,4]triazin-4(3H)-one

30% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase - n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): T_R = 7.03. LC-MS: m/z 412.2 [M+1]*. Ή NMR (400 MHz, CDCI3): 5 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).

2-((3R,4R)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-y1)-7-(tetrahydro-2H-pyran-4yl)lmldazo[1,5-f][1,2,4]triazln-4(3H)-one

30% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): T_R = 9.03. LC-MS: m/z 412.2 [M+1]*. ’H NMR (400 MHz, CDCI3): δ 7.78 (s, 1 H), 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).

The following compounds were prepared In a similar way:

7-(4-fluorophenyi)-2-(1-(4-methoxybenzyl)-4-methylpyrrolidin-3-yl)imldazo[1,5f] [1,2,4]trlazi n-4(3H)-one

F

42% yield. LC-MS: m/z 434.2 [M+1f. ¹H NMR (400 MHz, CD₃OD-d4): δ 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, 1 H), 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).

7-(4-Fluoro-phenyl)-2-[4-methyl-1-(6-trifluoromethyi-pyridin-3-ylmethyl)-pyrrolidin-3-yl]3H-lmldazo[5,1-f][1,2,4]trlazin-4-one

29% yield. LC-MS: m/z 473.2 [M+1J*. ¹H NMR (400 MHz, CDCI₃): δ 8.67 (br. s, 1H), 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, 1 H), 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, 1H),

2.68-2.64 (m, 1H), 2.51-2.49 (m, 1H), 2.01-1.97 (dd, J = 8.4, 9.2 Hz, 1H), 1.25 (d, J = 6.8 Hz, 3H).

2-[1-(6-Methoxy*pyridin-3*ylmethyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3Himldazo[5,1-f][1,2,4]triazln-4-one

23% yield, LC-MS: m/z 425.2 [M+1]*. Ή NMR (400 MHz, CD₃OD-d4): δ 8.22 (br. s, 1H), 7.92 (s, 1H), 7.78 (dd, J = 2.4, 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 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),

2.85-2.82 (m, 1 H), 1.98-1.85 (m,4H), 1.18 (d, J =6.4 Hz,3H).

2-[4-Methyl-1-(6-trlfluoromethyl-pyrldin-3-ylmethyl)-pyrrolidln-3-yl]-7-(tetrahydro-pyran-4yi)-3H-imldazo[5,1-f][1,2,4]trlazln-4-one

18% yield, LC-MS. m/z 463.2 [M+1J*. ¹H NMR (400 MHz. CDCI₃): 58.66 (s, 1H), 7.98 (d, J =8.0 Hz, 1H), 7.81 (s. 1H), 7.76 (d, J = 8.0 Hz. 1 H). 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).

2-[1-(6-Methoxy-pyrldln-2-ylmethyl)-4-methyl-pyrrolldln-3-yl]-7-(tetrahydro-pyran-4-yl)-3Himldazo[5,1-f][1,2,4]triazln-4-one

9% yield. LC-MS: m/z 425.2 [M+1]*. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.59 (s. 1H), 7.53-7.51 (m. 1H), 6.89 (d, J = 7.2 Hz. 1H). 6.58 (d, J = 8.0 Hz. 1H), 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), 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-Fiuoro-phenyi)-2-[1-(6-methoxy-pyridln-2-ylmethyi)-4-methyl-pyrroiidin-3-yl]-3HI ml dazo(5,1 -f] [1,2,4]trl azi n-4-one

47% yield. LC-MS: m/z 435.2 [M+1]*. ¹H NMR (400 MHz. CDCI₃): δ 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), 1.95 (m. 1 H), 1.09 (d. J - 6.8 Hz, 3H).

7-(4-Fluoro-phenyl)-2-[1-(6-methoxy-pyridin-3-y1methy1)-4-methyl-pyrro1ldin-3-yl]-3H· lmidazo[5,1-f][1,2_l4]trlazin-4-one

22% yield. LC-MS: m/z 435.2 [M+1]*. ¹H NMR (400 MHz, CDCI₃): 58.36-8.33 (m, 2H), 8.07 (d, J = 1.2 Hz, 1H), 7.95 (s, 1 H), 7.68-7.65 (dd, J = 2.4. 8.4 Hz, 1 H). 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).

7-(4-Fluoro-phenyi)-2-(4-methy1-1-pyr1din-2-ylmethyl-pyrrolidin-3-yi)-3H-imidazo[5,1* f][1,2,4]triazin-4-one

49% yield. LC-MS: m/z 405.2 [M+1]*. Ή NMR (400 MHz, CD₃OD-d4): δ 8.44 (d, J = 4.4 Hz,

H), 8.24-8.22 (m, 2H), 7.77 (s, 1H). 7.73-7.69 (m. 1H), 7.41 (d. J= 8.0 Hz, 1H), 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), 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-ΟίΑυοΓθ-όθηζγΙ)-4-ηΐθΙήγΙ-ργπ·οΠΰίη-3-γΙ]-7-(ΙθΐΓ3ΐιγ(ΐΓθ-ργΓ3η-4-γΙ)-3Ηimidazo[5,1-f][1,2,4]triazin-4-one

88% yield. LC-MS: m/z 387.1 [M+1]*. Ή NMR (400 MHz, CD₃OD-d4): δ 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).

2-(3S,4S)-[1-(2,4-Dlf1uoro-benzyl)-4-methyl-pyrrolldln-3-yl]-7-(tetrahydro-pyran-4-yl)-3Himidazo[5,1-f][1,2,4]triazin-4-one

F

16% yield. Chiral analytical HPLC (Column = chiralcel AD; Mobile phase = CO₂/MeOH/DEA 80/20/0.02 (v/v/v); Flow rate = 2.5 mUmin): T_R = 1.43. LC-MS: m/z 430.2 [M+1]*. ’H NMR (400 MHz. CDCh): δ 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. 9.6 Hz. 1H). 2.76-2.74 (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).

2-(3R,4R)-[1-(2,4-Dlf1uoro-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3Himldazo[5,1-f][1,2,4]triazln-4-one

Ο

F

16% yield. Chiral analytical HPLC (Column = chiralcel AD; Mobile phase = CO₂/IPA/DEA 60/40/0.04 (v/v/v); Flow rate = 2.4 mL/min): T_R = 3,81. LC-MS: m/z 430.2 [M+1]*. ’H NMR (300 MHz, CDCI₃): δ 7.80 (s, 1H), 7.36-7.27 (m, 1H), 6.93-6.84 (m, 2H), 4.11-4.08 (m, 2H), 5 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, 1 H), 2.77-2.76 (m, 1H), 2.61-2.58 (m, 1H), 2.44-2.40 (m, 1 H), 2.15-2.03 (m, 2H), 1.97-1.87 (m, 3H), 1.22 (d, J =10.0 Hz, 3H).

2-(1-(4-fluorobenzyl)-4-methylpynOlldln-3-yl)-7-(4-f1uorophenyl)lmldazo[1,5-f][1,2,4]triazin4(3H)-one o

39% yield. LC-MS: m/z 422.1 [M+1]*. ¹H NMR (400 MHz, DMSO-d6): δ 8.41-8.38 (m, 2H), 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, 1 H), 2.01-1.97 (m, 1H), 1.12 (d , J~ 6.8 Hz, 3H).

2-(4-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4yi)imldazo[1,5-f][1,2,4]triazin-4(3H)-one

36% yield. LC-MS: m/z 478 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 7.74 (s, 1H), 7.32 (d, J = 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-methylpyrrolldin-3-yl)-7-(tetrahydro-2H-pyran-4yl)imldazo[1,5-f][1.2,4]trlazln-4(3H)-one

27% yield. LC-MS: m/z 458.2 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 7.77 (s, 1H), 7.25 (d, J =

8.4 Hz, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.82-6.79 (dd, J = 8.4, 2.8 Hz, 1H), 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),

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-(qulnoxalin-6-ylmethyl)pyrrolldln-3-yl)-7-(tetrahydro-2H-pyran-4yl)lmldazo[1,5-f][1,2,4]trlazln-4(3H)-one

30% yield. LC-MS: m/z 446 [M+1]*. ¹H NMR (400 MHz, CDCI₃): δ 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, 1 H). 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).

2-[1-(5-Methoxy-2-methy1-penta-2_l4-dienyl)-4-methyl-pyrrolidln-3-yl]-7-(tetrahydro-pyran-

4-yl)-3H-lmldazo[5,1-f][1,2,4]triazin-4-one

20% yield. LC-MS: m/z 424.2 [M+1f. ’H NMR (400 MHz, CDCI₃): 57.79 (s, 1H), 7.27 (d, J = 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, 10.0 Hz, 1 H), 2.73 (m, 1H), 2.49-2.41 (m, 2H), 2.132.02 (m, 3H), 1.92-1.86 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H).

2-(4-methyl-1-(pyridin-4-ylmethyl)pyrrolidln-3-yl)-7-(tetrahydro-2H-pyran-4-yl)lmldazo[1,5f][1,2,4]trlazln-4(3H)-one

12% yield. LC-MS: m/z 395.2 [M+1]*. ¹H NMR (400 MHz, CDCI₃): 5 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, 1 H). 2.81-2.79 (m, 1H), 2.60-2.55 (m, 1 H),

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-pyrldin-2-ylnwthyl-pyrrolidln-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imldazo[5,1· f][1,2,4]trlazin-4-one

7% yield. LC-MS: m/z 395.2 [M+1]⁺. Ή NMR (400 MHz, CD₃OD-cf4): δ 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, 1 H), 2.98-2.94 (m. 1H), 2.87-2.76 (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-(pyrimidln-5-ylmethyl)pyrrolidin-3-yi)-7-(tetrahydro-2H-pyran-4yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

44% yield. LC-MS: m/z 396.2 [M+1]⁺. Ή NMR (400 MHz, CDCI₃): 5 9.17 (br. s, 1H), 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, 1 H), 2.12-1.96 (m, 2H), 1.94-1.74 (m, 3H), 1.25 (d, J= 6.8 Hz, 3H).

2-[1-(4-Diethylamino-benzyi)-4-methyl-pyrrolldin-3-yl]-7-(tetrahydro-pyran-4-yi)-3HimldazolS.I-fJlI.Z.AJtriazin^one

35% yield. LC-MS: m/z 465.3 [M+1J*. Ή NMR (400 MHz, CDCI₃): δ 7.78 (s, 1H), 7.17 (d, J = 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).

2-(1-(furan-2-yimethyl)-4-methylpyrroiidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imldazo[1,5f][1,2,4]triazin-4(3H)-one o

35% yield. LC-MS: m/z 384.2 [M+1J*. ¹H NMR (400 MHz, CDCI₃): δ 7.80 (s, 1H), 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, 1 H), 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)

2-(1-((1H-lmldazol-2-yl)methyi)-4-methylpyrrol1dln-3-y1)-7-(tetrahydro-2H-pyran-4yl)lmldazo[1,5-f][1,2,4]trlazin-4(3H)-one

5% yield. LC-MS: m/z 384.2 [M+1J*. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.44 (br. s, 2H), 7.75 (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, 1 H), 2.73-2.69 (m, 1H), 2.38-2.34 (dd, J - 7.6,

9.2 Hz. 1H). 2.07-1.91 (m, 4H), 1.09 (d, J= 6.8 Hz, 3H).

2-((3S,4S)-4-methylpyrrolidln-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imldazo[1,5-f][1,2,4]trlazin4(3H)-one

45% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = nHexane/EtOH/DEA 80/20:0.3; Flow rate = 1.0 mL/min): T_R = 7.44. LC-MS: m/z = 304.2 [M+1]*. ¹H NMR (400 MHz, CD₃OD-</4): δ 7.49 (s, 1H), 3.96-3.93 (m, 2H). 3.53-3.31 (m, 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-methyipyrrolidln-3-yi)-7-(tetrahydro-2H-pyran-4-yl)imldazo[1,5-f][1_l2,4]trlazln4(3H)-one

45% yield. Chiral analytical HPLC (Column - chiralcel OJ-H; Mobile phase = nHexane/EtOH/DEA 80/20:0.3; Flow rate = 1.0 mL/min): T_R = 9,93. LC-MS: m/z 304.2 [M+1]*. ’H

NMR (400 MHz, CD₃OD-d4): δ 8.42 (br. s, 2H), 7.63 (s, 1H), 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), 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-yl)-3_t4-dihydroimidazo[1,5-f][1,2,4]trlazin2-yi)pyrrolidin-1-yl)methyl)benzonitrile

36% yield. LC-MS: m/z 419.2 [M+1]*. ’H NMR (400 MHz, CD₃OD-d4): δ 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),

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).

2-(1-(2-chloro-4-fluorobenzyl)-4-methyipyrrolldin-3-yl)-7-(tetrahydro-2H-pyran-420 yl)lmldazo[1,5-f][1,2,4]triazin-4(3H)-one

72% yield. LC-MS: m/z 446 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 7.77 (s, 1H), 7.35-7.31 (m,

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).

2-(1-(4-(dimethylam!no)benzy!)-4-methylpyrro!idin-3-y!)-7-{tetrahydro-2H-pyran-4y!)!mldazo[1,5-f][1,2,4]trlazin-4(3H)-one

25% yield. LC-MS: m/z 437 [M+1f. ’H NMR (400 MHz, CDCI₃): δ 7.78 (s, 1H), 7.22 (d, J= 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, 1H), 2.93 (s, 6H), 2.88 (m, 1H), 2.72 (m, 1H),

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).

2-{4-methyl-1-(4-methylbenzy!)pyrro!idin-3-y!)-7-(tetrahydro-2H-pyran-4-y!)imidazo[1,5f][1,2,4]tr!azin-4(3H)-one

62% yield. LC-MS: m/z 408 [M+1]*. Ή NMR (400 MHz, CDCI₃): 58.05 (br. s, 1H), 7.79 (s, 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).

2-(1-Cyc!ohexylmethy!-4-methyl-pyrrolidin-3-y!)-7-(tetrahydro-pyran-4-yl)-3H-!midazo[5,1f] [1,2,4]trlazln-4-one

37% yield. LC-MS: m/z 400.2 [M+1]*. ’H NMR (400 MHz, CDCI₃): δ 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, 1H), 2.75(m. 1H), 2.412.44 (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, 1 H), 1.46-1.43 (m, 1 H), 1.24 (m, 2H), 1.21 (d, J = 7.2 Hz, 3H), 0.98 (m, 2H).

2-(4-Methyl-1-pyridln-3-ylmethy1-pyrrolldln-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imldazo[5,1f][1,2,4]triazln-4-one

60% yield. LC-MS: m/z 395.2 [M+1]*. ’HNMR (400 MHz, CDCI₃): δ 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, 12.8 Hz, 1H), 3.67-3.64 (d, J =

12.8 Hz, 1 H), 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).

2-[1-(2,6-Difluoro-benzyl)-4-methyl-pyrrolidln-3-yl]-7-(tetrahydro-pyran-4-y1)-3Hlmldazo[5,1-f][1_l2,4]triazln-4-one

9% yield. LC-MS: m/z 430.2 [M+1]*. ¹H NMR (400 MHz, CDCI₃): 5 7.78 (s, 1H), 7.28 (m, 1H),

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-methyI-thiophen-2-ylmethyl)-pynOlîdin-3-yl]-7-(tetrahydro-pyran-4-yl)-3Himidazo[5,1 -f][1,2,4]triazin-4-one

15% yield. LC-MS: m/z = 414.2 [M+1J*. ’H NMR (300 MHz, CDCI₃): δ 7.81 (s, 1H), 6.73 (d, J =

3.3 Hz, 1 H), 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).

2-[1-(5-Chloro-thlophen-2-ylmethyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3Himldazo[5,1-f][1,2,4]trlazin-4-one

20% yield. LC-MS: m/z - 434.1 [M+1f. Ή NMR (400 MHz, CDCI₃): δ 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), 2.15-1.96 (m, 2H), 1.92-1.90 (m, 3H), 1.22 (d, J = 6.8 Hz, 3H).

2-[4-ΜθίΚγΙ-1-(4·ργΓΓθΙΜΙη-1-γΙ-ΒθηζγΙ)-ργΓΓθΙΜΙη-3-γΙ]-7·(ίθίΓ3ΐ^Γθ-ργΓ3η-4-γΙ)-3Ηlmidazo[5,1-f][1,2,4]trlazin-4-one

10% yield. LC-MS: m/z = 463.3 [M+1]*. ’H NMR (300 MHz, CDCI₃): δ 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).

2-[1-(4-Fluoro-benzyl)-4-methoxy-pyrrolldin-3-yl]-7-(tetrahydro-pyran-4-yl)-3Hlmldazo[5,1-f][1,2,4]trlazin-4-one

19% yield. LC-MS: m/z = 428.2 [M+1J*. ’H NMR (400 MHz, CDCI₃): δ 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),

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, 1 H). 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).

2-[4-Methoxy-1-(4-methyl-benzyl)-pyrrolldln-3-yl]-7-(tetrahydro-pyran-4-yl)-3H' lmidazo[5,1-f][1,2,4]trlazln-4-one

13% yield. LC-MS: m/z = 424.3 [M+1J*. ’H NMR (300 MHz, CDCI₃): 5 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).

2-[4-Methoxy-1-(4-methoxy-benzyl)-pyrroildln-3-yl]-7-(tetrahydro-pyran-4-yl)-3HIml dazo[5,1 -f] [1,2,4]trlazi π-4-one

25% yield. LC-MS: m/z = 440.1 [M+1]*. *H NMR (400 MHz, CDCI₃): 57.81 (s, 1H), 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, 1H), 3.79 (s, 3H),

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

2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-inildazo[5,1f] [1,2,4]trlazln-4-one

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 température for 2 h. LC-MS showed that the reaction was complété. The reaction was quenched with water (40 mL), and the reaction mixture was extracted with CH₂CI₂ (30 mL χ 3). The combined organic phases were washed with brine (30 mL), dried over Na₂SO< and concentrated In vacuum. The residue was purified by préparative TLC (CH₂CI₂/MeOH = 10:1) to afford the desired product (28.6 mg, 25% yield) as a white solid. LCMS: m/z 394.2 [M+1]*. Ή NMR (400 MHz, CD₃OD-d4): δ 7.60 (s, 1H), 7.29-7.22 (m, 4H), 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-ΒβηζγΙ-4-ΠΊθΙήγΙ-ργτΓθΙΙύΙη-3-γΙ)-7-(ΙβΐΓ8ή7ύΓθ-ργΓ3η-4-7ΐ)- 3Himldazo[5,1-f][1,2,4]trtazln-4-one was submitted for préparative chiral HPLC (Column = chiralpak OD-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 25 mL/min; UV: 230 nm; 30 mg/inj ln) and gave two enantiomers:

2-((3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5f][1,2,4]triazln-4(3H)-one

80% yield. Chiral analytical HPLC (Column = chiralpak OD-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): T_R = 5.85. LC-MS: m/z 394.2 [M+1f. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.79 (s, 1H), 7.37-7.35 (m, 4H), 7.31-7.29 (m, 1H). 4.11-4.05 (m, 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 = 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-methylpyrrolldln-3-yl)-7-(tetrahydro-2H-pyran-4-yl)lmldazo[1,5f][1,2,4]trlazln-4(3H)-one

80% yield. Chiral analytical HPLC (Column = chiralpak OD-H; Mobile phase = n-Hexane/EtOH

70/30; Flow rate = 1.0 mL/min): T_R = 7.57. LC-MS: m/z 394.2 [M+1J*. ’H NMR (400 MHz,

CD₃OD-d4): δ 7.79 (s, 1H), 7.37-7.35 (m, 4H), 7.31-7.26 (m, 1H), 4.11-4.05 (m, 2H),

3.84-3.81 (d, J - 12.4 Hz, 1 H), 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:

7-(4-Fiuoro-phenyl)-2-(4-methy!-1-pyrimidln-2-ylmethyl-pyrro!ldln-3-yl)-3H-!midazo[5,1f] [1,2,4]triazln-4-one % yield. LC-MS: m/z 405.9 [M+1]*. *H NMR (400 MHz, CD₃OD-d4): δ 8.76 (d, J - 4.8 Hz, 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).

7-(4-fluorophenyl)-2-((3S,4S)-4-methyl-1-(pyrimldln-2-ylmethyl)pyrro!ldin-3-y!)lmidazo[1_l5f] [1,2,4]triazin-4(3H)-one

30% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): T_R = 7.68. LC-MS: m/z 406.2 [M+1]*. ¹H NMR (400 MHz, MeOH-d4): δ 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).

7-{4-fluoropheny!)-2-((3R,4R)-4-methyi-1-(pyr!midin-2-y!methy!)pyrrolidln-3-y!)lmidazo[1₍5f][1,2,4]triazln-4(3H)-one

30% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH

70/30; Flow rate = 1.0 mL/min): T_R = 9.39. LC-MS: m/z 406.2 [M+1]*. Ή NMR (400 MHz,

MeOH-d4): δ 8.74 (d, J =4.8 Hz, 2H). 8.28-8.25 (m, 2H). 7.78 (s, 1H), 7.32 (m, 1 H), 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-pyrlmldln-2-ylmethyl-pyrrolidin-3-yi)-7-(tetrahydro-pyran-4-yl)-3Hlmldazo[5,1-f][1,2,4]trlazln-4-one

33% yield. LC-MS: m/z 396.2 [M+1J*. Ή NMR (400 MHz, CD₃OD-d4): δ 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, 1 H). 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).

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-(pyrlmldin-2-ylmethyl)pyrrolidln-3-yl)-7-(tetrahydro-2H-pyran-4yl)imidazo[1,5-f][1,2,4]triazln-4(3H)-one

29% yield. Chiral analytical HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH

70/30; Flow rate = 1.0 mL/min): T_R = 6.63. LC-MS: m/z 396 [M+1]*. ’H NMR (400 MHz. CDCI₃):

δ 8.84 (d. J = 4.8 Hz, 2H), 7.81 (s, 1H), 7.23 (t, J = 4.8 Hz. 1 H). 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), 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-(pyrlmldln-2-ylmethyl)pyrrolldln-3-yl)-7-(tetrahydro-2H-pyran-4* yl)imldazo[1,5-f][1,2,4]trlazln-4(3H)-one

29% yield. Chiral analytlcal HPLC (Column = chiralcel OJ-H; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): T_R = 8.13. LC-MS: m/z 396 [M+1J*. ¹H NMR (400 MHz, CDCI₃): δ 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).

2-(1-Benzyi-4*methoxy-pynOlidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5,1f][1,2,4]trlazln-4*one

32% yield. LC-MS: m/z = 410.2 [M+1J*. ¹H NMR (300 MHz, CDCI₃): δ 7.86 (s, 1H), 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), 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-yl)-7-(tetrahydro-pyran-4-yl)-3H-lmidazo[5,1· f][1,2,4]triazin-4-one

40% yield. Chiral analytical HPLC (Column = chiralcel AD-H; Mobile phase = n-Hexane/EtOH

60/40; Flow rate = 0.6 mL/min): T_R = 10.8. LC-MS m/z = 410.2 [M+1]*. ’H NMR (400 MHz.

CDCh): 5 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 = 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).

2-(3R,4R)-(1-Benzyl-4-methoxy-pyrrolldin-3-y!)-7-(tetrahydro-pyran-4-yl)-3H-imldazo[5,1f][1,2.4]tr1azin-4-one o

40% yield. Chiral analytical HPLC (Column = chiralcel AD-H; Mobile phase » n-Hexane/EtOH 60/40; Flow rate = 0.6 mL/min): T_R =11.9. LC-MS: m/z - 410.2 [M+1]*. ’H NMR (400 MHz, CDCI₃): δ 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, 1 H), 2.72-2.68 (m, 1H), 2.36-2.32 (m. 1H). 2.13-2.03 (m, 2H), 1.91-1.87 (m. 2H).

2-(4-Methyl-1-pyrlmidin-4-y!methyl-pyrrolldln-3-yl)-7-(tetrahydro-pyran-4-y!)-3HIm1dazo[5,1 -f][1,2,4]triazln-4-one

5% yield. LC-MS: m/z = 396.2 [M+1]*. Ή NMR (400 MHz, CD₃OD-d4): δ 9.15 (s, 1H), 8.74 (d, J - 5.2 Hz, 1 H), 7.73 (s, 1H), 7.60 (d, J= 6.0 Hz. 1H). 4.07-4.04 (m, 2H). 3.98 (d, J = 15.2 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, 1 H), 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

2-(1-Benzyl-4-methyl-pyrrolidln-3-yl)-7*pyiidln-3-yl-3H-lmidazo[5,1-f][1_l2,4]triazln-4-one

ÇH

Pd(cfppn₂Clj, Xantpbos, K,PO₄

DMF/HjO, Microwave

The procedure for the préparation of this compound was similar to that of compound 7.

60% yield. LC-MS: m/z 387.1 [M+1]*. Ή NMR (400 MHz. CD₃OD-cf4): δ 9.37 (br. s, 1 H), 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, 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-yl)-7*(4-(trlfluoromethoxy)phenyl)imidazo[1,5f][1,2,4]trlazln-4(3H)-one

47% yield. LC-MS: m/z 470.2 [M+H]*. Ή NMR (400 MHz, DMS0-c6): δ 8.49 (d. J = 9.2 Hz, 2H),

7.90 (s, 1 H), 7.54-7.52 (d, J = 8.0 Hz, 2H), 7.34-7.28 (m, 3H), 7.25-7.23 (m, 1 H), 3.64 (s, 2H),

2.99-2.87 (m, 3H), 2.85-2.82 (m, 1 H), 2.28 (m, 1 H), 2.00 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H).

2-(1-Benzyl-4-methyl-pyrrolidin-3-yi)-7-pyridin-4-yl-3H-imidazo[5,1-f][1,2,4]trlazin-4-one

20% yield. Ή NMR (400 MHz ,CDCI₃): δ 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, 1H), 2.53 (m, 1H), 2.24 (m, 2H). 1.27 (d, J = 7.2 Hz, 3H).

2-(1-benzyl-4-methyipyrroiidin-3-yl)-7’(2,4-difluorophenyi)imidazo[1,5-f][1,2,4]trlazln4(3H)-one

31% yield. LC-MS: m/z 422 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 7.99 (s, 1 H). 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,

1H), 3.39 (t, J = 8.4 Hz, 1H), 2.99 (d, J = 10.0 Hz, 1H), 2.72-2.70 (m, 1 H). 2.52-2.40 (m, 2H),

1.92 (dd, J - 8.0, 9.2 Hz, 1 H), 1.17 (d, J = 6.8 Hz, 3H).

Part ii (Azetidine Sériés)

Préparation of Intermediates

2-Chioromethyi-7-(tetrahydro-pyran-4-yi)-3H-imidazo[5_l1-f][1,2,4]triazin-4-one

Scheme 6

KOH(aq)

OBn

n-BuU

t

Pd(PPty₄, dioxane

ΝΗ, Η,Ο Microwave

3-(2-Benzyloxy-acetylamino)-3H-lmidazole-4-carboxylÎc 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 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 température ovemight. 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]*.

3-(2-Benzyloxy-acetylamlno)-3H-imldazole-4-carboxylic acid amide (3)

Compound 2 (8.7 g, 30.1 mmol) and ammonium hydroxide (15 m!) were combined in a sealed tube and heated to 70C under microwave irradiation for 2 hours. The mixture was concentrated in vacuo to afford compound 3 (7.3 g, 88% yield) as a white solid. LC-MS: m/z 275.1 [M+H]*.

Z-Benzyloxymethyl-SH-lmidazoISJ-fni^^ltriazin^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 température. The resulting solution 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 HCl solution. The suspension was filtered and the filtrate was dried to afford compound 4 (4.9 g, 71% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 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]*.

2-Benzyloxymethyl-7-iodo-3H-lmidazo[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, followed by dropwise addition of iodine (19.4 g, 76.3 mmol) in THF (60 mL) at the same température. The reaction was allowed to warm to room température slowly. The reaction was quenched with saturated aqueous Na₂SO₃ solution (60 mL), and it was then extracted with EtOAc (60 mL χ 3). The organic phases were combined and dried over Na₂SO₄. The solid was filtered and the filtrate was concentrated In vacuo to give the crude product, which was purified by chromatography on silica gel coiumn (eluted with ΡΕ/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): δ 12.16 (s, 1H), 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+Hf.

2-Benzyloxymethyl-7-(3,6-dlhydro-2H-pyran-4-yl)-3H-lmldazo[5,1-f][1,2,4]triazin-4-one (6)

To a solution of compound 5 (1.0 g, 2.61 mmol) In dioxane (12 mL) at room température was added dropwise a solution of CS2CO3 (2.5 g, 7.66 mmoi) In water (3 mL), followed by addition of Pd(PPh₃)₄ (300 mg, 0.26 mmoi) and 4-(4,4,5,5-Tetramethy1-[1,3_l2ldioxaborolan-2-yl)-3_l6dihydro-2H-pyran (636 mg, 3.0 mmol). The reaction mixture was degassed by purging with N₂for 15 min. Then the mixture was heated to 125^eC under microwave irradiation for 40 min. After removal the solvent, the residue was purified by chromatography on silica gei column eluted with PE/EtOAc = 10:1 to 1:5) to afford compound 6 (680 mg, 76% yield) as a white solid. LCMS: m/z 339.1 [M+H]*.

2-Hydroxymethyl-7-(tetrahydro-pyran-4-yl)-3H-lmidazo[5,1 -f][1,2,4]trlazin-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 réaction mixture was stirred under 50 psi of hydrogen at 70 ^eC until LC-MS showed that the starting material was almost consumed. The suspension was filtered through celite and washed with MeOH (20 mL χ 2) and the filtrate was concentrated in vacuo to afford compound 7 (410 mg, 85% yield) as a white solid. LC-MS: m/z 251.3 [M+H]*.

2-Chloromethyl-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5,1-f][1,2,4]triazln-4-one (8)

To a solution of compound 7 (400 mg, 1.6 mmol) in CH₂CI₂ (50 mL) in Ice-water bath was added SOCI₂ (10 mL) dropwise. The resulting mixture was then stirred at ambient température overnight. The reaction mixture was concentrated in vacuo to afford compound 8 (370 mg, 86% yield) as a white solid. LC-MS: m/z 269.1 [M+H]*. Ή NMR (400 MHz, DMSO-d6): δ 12.50 (s, 1H), 8.02 (s, 1 H). 4.57 (s, 2H), 3.95 (m, 2H), 3.48 (m, 3H), 1.88 (m, 4H).

2-Acetyl-7-(tetrahydro-pyran-4-yl)-3H-lmidazo[5,1-f][1,2,4]triazin-4-one

Scheme 7

K0H(l}

MIcrmirM

3-(2-Benzyloxy-propionylamlno)-3H-lmidazole-4-carboxyllc acid methyl ester (9)

To a solution of compound 2 (4.2 g, 29.7 mmol), 2-Benzyloxy-proplonic acid (5.5 g, 29.7 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 température 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 compound 9 (8.2 g, 91% yield) as brown oil. LC-MS: m/z 304 [M+H]*.

3-(2-Benzyloxy-proplonylamino)-3H-lmldazole-4-carboxylic acid amide (10)

Compound 9 (8.2 g, 27 mmol) and ammonium hydroxide (100 mL) were mixed and heated to

60^eC 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/z289 [M+H]*.

2-( 1 -Benzyloxy-ethyl)-3H-imidazo[5,1 -f] [1,2,4]trlazl n-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 H₂O (4 mL). Then the resulting mixture was heated at 100’C 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 1M aqueous HCl solution. The suspension was 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]*. Ή NMR (400 MHz, CDCI₃): δ 8.70 (br. s, 1 H), 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-lodo-3H-lmldazo[5,1-f][1,2,4]trlazln-4-one (12)

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 -78*C over 30 minutes and the resulting reaction mixture was stirred below 70°C for another one hour. Then a solution of lodine (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 température slowiy over one hour. The reaction was quenched with saturated aqueous solution of Na₂SO₃ (60 mL), and then the mixture was extracted with EtOAc (200 mL x 2). The organic layers were combined and dried over Na₂SO₄, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel column (eluted with ΡΕ/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, CDCI₃): δ 8.82 (br. s, 1H). 7.94 (s, 1H), 7.36-7.32 (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-yl)-3H-lmldazo[5,1-f][1,2,4]trlazln-4-one (13)

To a solution of compound 12 (300 mg, 0.75 mmol) in dioxane (2 mL) was added a solution of Cs₂CO₃ (492 mg, 1.51 mmol) in H₂O (0.5 mL) dropwise, followed by addition of 4-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (318 mg, 1.5 mmol) and Pd(PPh₃)₄(86 mg, 0.075 mmol). The reaction mixture was degassed by purging with N₂ for 15 min. Then the reaction was heated to 125^eC under microwave heating for 40 min. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with ΡΕ/EtOAc = 10:1 to 1:5) to afford compound 13 (200 mg, 75% yield) as white solid. LC-MS: m/z 353 [M+H]*. ’H NMR (400 MHz, CDCI₃): δ 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, 1 H). 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-ethyi)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4one (14)

To a solution of compound 13 (900 mg, 2.55 mmol) in MeOH (30 mL) was added Pd(OH)î/C (120 mg). The mixture was stirred at 75°C under H₂ (50 psi) ovemight, The suspension was filtered through Ceiite, washed with MeOH (20 mL χ 2). The combined organic phases were concentrated ln vacuo to afford compound 14 (540 mg, 80% yield) as a white solid. LC-MS: m/z 265 [M+H]*. *H NMR (400 MHz, CDCI₃): δ 9.07 (br. s, 1H), 7.85 (s, 1H), 4.84 (q, J = 6.4 Hz, 1 H), 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-yl)-3H-lmidazo[5,1-f][1,2,4]trlazin-4-one (15)

To a solution of compound 14 (400 mg, 1.6 mmol) ln CH₂CI₂ (50 mL) was added MnO₂ (520 mg, 6 mmol). The mixture was heated at 50°C ovemight. 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, CDCI₃): δ 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 (s, 3H), 2.19-2.11 (m, 2H), 2.00-1.96 (m, 2H).

Préparation of target compounds:

Example 4

2-[3-(4-Fluoro-phenoxy)-azetldin-1-ylmethyl]-7-(tetrahydro-pyran-4-yi)-3H-lmidazo[5,1f][1,2,4]triazln-4-one

To a solution of compound 15 (40 mg, 0.15 mmol) and compound A1 (50 mg, 0.30 mmol) in

CH₃CN (40 mL) was added DiEA (0.5 mL, 3.0 mmol). The resulting solution was heated to

70^eC for 2 h. The reaction was found to be complété by monitoring with TLC. The reaction 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, CD₃OD-d4): 5 8.44 (br. s, 1H), 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).

The following compounds were prepared In a similar way:

2-[3-(4-Methoxy-phenyl)-azetldln-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5,1· f] [1,2,4]trlazl n-4-one

31% yield. LC-MS: m/z 396.2 [M+1]*. <H NMR (400 MHz, CDCI₃): 57.84 (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).

7-(4-Fluoro-phenyl)-2-[3-(4-methoxy-phenyl)-azetldln-1-ylmethyl]-3H-lmldazo[5,1f][1»2,4]trlazln-4-one

20% yield. LC-MS: m/z 406.1[M+1]*. NMR (400 MHz, CD₃OD-d4): 5 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).

7-(4-Fluoro-phenyl)-2-[3-(4-fluoro-phenyl)-azetidin-1-ylmethyl]-3H-lmidazo[5,1fj[1,2,4]trlazln-4-one

14% yield. LC-MS: m/z 394.1 [M+1J*. Ή NMR (400 MHz, CD₃OD-d4): 58.19-8.16 (m, 2H). 7.94 (s, 1 H), 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, 1H).

2-[3-(4-Fluoro-phenyl)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1f] [ 1,2,4] triazi n-4-o ne

mg, 20% yield. LC-MS: m/z 384.1[Μ+1Γ. ¹H NMR (400 MHz, CD₃OD-d4): δ 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).

2-(3-(2,6-Difluoro-phenoxy)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yi)-3H-lmldazo[5,1f] [1,2.4] tri azin-4-one

36% yield. LC-MS: m/z 418.1 [M+lf. ¹H NMR (400 MHz, DMSO-d6): δ 12.20 (br. s, 1H), 7.70 (s, 1H), 7.23-7.19 (m, 3H), 5.08 (m, 1 H>, 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-yl)-2-[3-(4-trlfIuoromethoxy-phenoxy)-azetldln-1-ylmethyl]-3H* imidazo[5,1-f][1,2,4]triazln-4-one

35% yield. LC-MS: m/z 466.1 [M+1]*. ’H NMR (400 MHz, CDC!₃): 57.84 (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).

2-[3-(4-Dimethylamlno-phenyl)-azetldln-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)>3Himidazo[5,1 -f][1,2,4]trlazl n-4-o ne

26% yield.LC-MS: m/z409.2 [M+1]*. Ή NMR(400 MHz, CDCI₃): 57.84(s, 1H), 7.19-7.17(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), 3.72-3.68 (m, 1 H). 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-azetldin-1-yimethyl)-7-(tetrahydro-pyran-4-yl)-3H-lmÎdazo[5,1-f][1,2,4]triazin-

4-one

32% yield. LC-MS: m/z 382.1 [M+H]*. Ή NMR (400 MHz, DMSO-56): 511.73 (br. s, 1H). 7.67 (s, 1 H). 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-yl-azetldin-1-ylmethyl)-7-(tetrahydro-pyran-4-yi)-3H-lmldazo[5,1 f][1,2,4]trlazin-4-one

12% yield. LC-MS: m/z = 368.2 [M+1]*. *H NMR (400 MHz, CD₃OD-d6): δ 8.76-8.75 (m, 2H),

7.65-7.63 (m, 1H), 7.37-7.35 (m, 1 H), 3.98-3.80 (m, 5H), 3.58-3.38 (m, 7H), 1.87-1.81 (m, 4H).

2-[3-(4-Methyi-benzyloxy)-azetidln-1-yimethyi]-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5,1f][1,2,4]trlazln-4-one

9% yield. LC-MS: m/z = 410.2 [M+1]*. ¹H NMR (300 MHz, CD₃OD-d4): δ 7.93 (s, 1 H), 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 (m, 2H), 3.58-3.66 (m, 3H), 2.34 (s, 3H), 1.92-2.00 (m, 4H).

2-(3-Benzyl-azetldln-1-ylmethyl)-7-(tetrahydro-pyran-4-yl)-3H-lmidazo[5,1-f][1,2,4]trlazin-4one

23% yield. LC-MS: m/z - 380.2 [M+1]*. ¹H NMR (400 MHz, CDCI₃): δ 7.82 (s, 1 H), 7.31-7.27 (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)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3HIml dazo[5,1 -f][1,2,4]triazi n-4-one

I

15% yield. LC-MS: m/z = 426.2 [M+1]⁺. ’H NMR (400 MHz, CD₃OD-d4): δ 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).

2-[3-(4-Pyrrolidln-1-yl-pheny1)-azetldln-1-ylmethyl]-7-(tetrahydro-pyran-4-y1)-3Himldazo[5,1-f][1,2,4]trlazin-4-one

23% yield. LC-MS: m/z = 435.2 [M+1]*. ¹H NMR (400 MHz, CDCI₃): δ 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).

Example 5

2-{1-[3-(4-Methoxy-phenyi)-azetldln’1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imldazo[5,1· f] [1,2,4]triazi π-4-one

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 température overnight. Then NaBH(OAc)₃ (200 mg, 0,95 mmol) was added and the reaction was stirred at room température overnight. The reaction mixture was poured into 10 ml of water and the pH of the solution was adjusted to 7 with a saturated aqueous solution of NaHCO₃. The reaction mixture was extracted with ethyl acetate (100 mL * 2). The combined organic layers were dried over Na₂SO₄, 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 compound (7 mg, 7.8% yield) as a white solid. LC-MS: m/z 410.2 [M+H]*. Ή NMR (400 MHz, CD₃OD-cf4): δ 7.63 (s, 1 H), 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)-azetldin-1-yl]-ethyl}-7-(tetrahydro-pyran4-yl)-3H-ImIdazo[5,1-f][1,2,4]triazin-4-one was submitted for préparative chiral HPLC (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:

2-{1-[3-(4-Methoxy-phenyl)-azetidin-1-yl]-ethyl)-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5,1· f] [1,2,4] tri azl n-4-o ne

40% yield. Chiral analytical HPLC (Column = chiralpak IA; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): T_R - 9.98. LC-MS (ESI) m/z = 410.2 [M+1]*. ’H NMR (400 MHz, CDCI₃): δ 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, 1 H), 3.23-3.20 (m, 1 H), 2.11 -2.07 (m, 2H), 1.93-1.89 (m, 2H), 1.33 (d, J = 6.4 Hz, 3H).

2-{1-[3-(4-Methoxy-phenyl)-azetidin-1-yi]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imldaz^o[5,1f] [1,2,4]trlazIn-4-one

40% yield. Chiral analytical HPLC (Column = chiralpak IA; Mobile phase = n-Hexane/EtOH 70/30; Flow rate = 1.0 mL/min): T_R = 14.7. LC-MS (ESI) m/z = 410.2 [M+1 f. ’H NMR (400 MHz, CDCI₃): 57.84 (s, 1 H). 7.21 (d, 8.4 Hz, 2H), 6.88 (d, 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).

The following compound was prepared in a similar way:

2-{1-[3-(4-Fluoro-phenyl)-azetidln-1-yi]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5_t1 f][1,2,4]trlazln-4-one

15% yield. LC-MS: m/z 398.2 (M+Hf. Ή NMR (400 MHz, MeOD-c/4): 5 7.85 (s, 1H), 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)-azetidln-1*yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1f][1,2,4]triazln-4-one

o

10% yield. LC-MS: (ESI) m/z = 414.1 [M+1]*. ¹H NMR (400 MHz, CDCI₃): δ 7.83 (s. 1H). 6.99-6.94 (m, 2H), 6.71-6.69 (m, 2H), 4.77-4.74 (m, 1 H), 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 (m, 2H), 1.92-1.88 (m, 2H), 1.34 (d, J - 6.4 Hz, 3H).

7-(Tetrahydro-pyran-4-yl)-2-[1-(3-p-tolyloxy-azetldln-1-yl)-ethyl]-3H-lmldazo[5,1f] [1,2,4]trlazln-4-one

35% yield. LC-MS: m/z = 410 [M+1]*. Ή NMR (300 MHz, CDCI₃): δ 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).

2-[1-(3-Phenyl-azetldln-1-yl)-ethyl]-7-(tetrahydro-pyran-4-yl)-3H-lmldazo[5,1f][1,2,4]triazln-4-one

62% yield. LC-MS: m/z - 380.1 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 7.84 (s, 1 H), 7.37-7.33 (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-Fiuoro-4-methoxy-phenyl)-azetldin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3Hlmidazo[5,1 -f][1,2,4]triaztn-4-one ι

25% yield. LC-MS: m/z - 428.2 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 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, 1 H). 3.22-3.19 (m, 1 H), 2.11 -2.04 (m, 2H), 1.93-1.90 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H).

2-{1-[3-(2-Fluoro-4-methoxy-phenyl)-azetldln-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3Hlmldazo[5,1-f][1,2,4]triazÎn-4-one

36% yield. LC-MS: m/z - 428.2 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 7.84 (s, 1H), 7.16 (dd, J = 10 8.8 Hz, J = 8.8 Hz, 1H), 6.68 (dd, J = 2.4 Hz, J - 6.8 Hz, 1H), 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 (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)-azetldin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1f][1,2,4]triazin-4-one r

18% yield. LC-MS: m/z =424.2 [M+1]*. Ή NMR (400 MHz, CDCI₃): 5 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).

2-{1-[3-(4-Hydroxy-phanyl)-azetidin-1-yi]-ethyi}-7-(tetrahydro-pyran-4-yl)-3H-lmidazo[5,1·

f][1,2,4]trlazln-4-one

10% yield. LC-MS (ESI): m/z - 396.2 [M+1f. ’H NMR (400 MHz, CD₃OD-d4): δ 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 10 Hz, 3H).

2-{1-[3-(4-Pyrrolldin-1-yi-phenyi)-azetldin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-4a,7> dlhydro-3H-lmldazo[5,1-f][1,2,4]trlazln-4-ona

28% yield. LC-MS: m/z - 449.2 [M+1 ]⁺. ⁵H NMR (400 MHz, CDCI₃): δ 7.84 (s, 1 H). 7.15 (d, J =

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-Dlmethylamlno-phenyl)-azetldln-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3Hlmldazo[5,1-f][1,2,4]triazln-4-one

23% yield. LC-MS: m/z = 423.2 [M+1]*. ³H NMR (400 MHz, CDCI₃): δ 7.83 (s, 1 H>, 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, 2H),

1.93-1.90 (m, 2H), 1.32 (d, J= 6.8 Hz, 3H).

7-(Tetrahydro-pyran-4-yî)-2-{1-[3-{4-trifluoromethoxy-pheny!)-azetidin-1-y!]-ethyî}-3H10 imidazo[5,1-f][1,2,4]triazin-4-one

36% yield. LC-MS: m/z = 464.2 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 8.92 (br. s, 1H), 7.84 (s,

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, 15 2H). 1.93-1.89 (m, 2H), 1.29 (d. J= 8.8 Hz, 3H).

2-{1-[3-(4-Methoxy-benzyl)-azetidln-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imldazo[5,1f] [1.2,4] tr iazi n-4-one

O

18% yield. LC-MS: m/z - 424.2 [M+1]*. Ή NMR (400 MHz, CD₃OD-d4): δ 7.59 (s, 1H), 6.98 (d,

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 Hz, 3H).

2-{1-[3-(3-Chloro-4-methoxy-phenyl)-azetldin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl}-3Hlmldazo[5,1 -f] [1,2,4]triazin-4-one

26% yield. LC-MS: m/z = 444.1 [M+1]*. Ή NMR (400 MHz, CDCI₃): δ 7.84 (s, 1H), 7.29 (s, IH), 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), 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-Di methoxy-p henyl)-azetidi n-1 -yl]-ethyl}-7-(tetra hydro-pyra n-4-yl)-3Himidazo[5,1 -f] [1,2,4]triazin-4-one

18% yield. LC-MS: m/z = 440.2 [M+1]*. Ή NMR (400 MHz, CDCl₃): δ 7.84 (s, 1 H), 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).

2-{1-[3-(4-Fluoro-3-methoxy*phenyl)-azetldln-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H· lmldazo[5,1-f][1,2,4]trlazin-4-one

15% yield. LC-MS: m/z - 428.2 [M+1 ]⁺. ’H NMR (300 MHz, CDCI₃): δ 7.85 (s, 1 H), 7.06 (dd, J =

8.4 Hz, J = 10.5 Hz, 1 H>. 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, 1 H), 3.24 (m, 1H>, 2.14-2.10 (m, 2H), 1.95-1.90 (m, 2H). 1.35 (d, J= 6.6 Hz, 3H).

2-{1-[3-(3,5-Dlfluoro-4-methoxy-phenyl)-azetldin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3Himidazo[5,1-f][1,2,4]triazln-4-one

15% yield. LC-MS: m/z = 446.2 [M+1]*. ¹H NMR (400 MHz, CDCI₃): δ 7.85 (s. 1 H), 6.86-6.83 (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-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1f][1,2,4]triazin-4-one

5% yield. LC-MS: m/z - 410.2 [M+1]*. ’H NMR (400 MHz, CDCI₃): 5 7.84 (s. 1H), 7.13 (s, 1H>.

6.86 (d, 7.6 Hz, 1H), 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, 1H),

2.12-2.05 (m, 2H), 1.93-1.90 (m, 2H), 1.33 (d, J= 6.4 Hz, 3H).

2-{1-[3-{4-Methoxy-3-methyl-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3Himldazo[5,1-f][1,2,4]trlazln-4-one

21% yield. LC-MS: m/z = 424.2 [M+1f. ¹H NMR (300 MHz, CDCI₃): δ 7.85 (s, 1 H), 7.09-7.06 (m, 2H), 6.80 (d, J = 7.8 Hz, 1 H). 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, 1 H), 2.24 (s, 3H), 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-yl-azetidin-1 -yl)-ethyl]-7-(tetrahydro-pyran-4-yl)-3H-lmidazo[5,1f][1,2,4]triazln-4-one

10% yield. LC-MS: m/z = 424.2 [M+1]*. ’H NMR (300 MHz, CDCI₃): δ 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).

2-{1-[3-(4-Methoxy-phenyl)-pyrrolidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3Hlmldazo[5,1-f][1,2,4]trlazin-4-one

6% yield. LC-MS: m/z = 424.2 [M+1f. ’H NMR (400 MHz, CDCI₃): δ 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), 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, 1 H), 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

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 nucléotide substrate), a buffer (50 mM HEPES7.6; 10mM MgCI₂; 0.02% Tween20), 0.1mg/ml BSA, 225 pCI of ³H-labelled cyclic nucléotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors. Reactions are Initiated by addition of the cyclic nucleotîde substrate, and reactions are allowed to proceed for one hr at room température before being termînated through mixing with 15 uL 8 mg/mL yttrium 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 calculated using the Xlflt extension to EXCEL

In the context of the présent invention the assay was performed In 60 uL assay buffer (50 mM HEPES pH 7.6; 10mM MgCI₂; 0.02% Tween20) containing enough PDE9 to convert 20-25% of 10 nM ³H-cAMP and varying amounts of Inhibitors. Following a 1 hour incubation the reactions were termînated by addition of 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). The beads were allowed to settle for one hr in the dark before the plates were counted in a Wallac 1450 Microbeta counter. IC» values were calculated by non linear régression using XLfit (IDBS).

Results of the experiments showed that the tested compounds of the invention inhibit the PDE9 enzyme with IC50 values below 250 nM.

Claims

Claims

1. A compound having the structure (I) wherein R2 is cyclized with either R1 or R3, wherein R1, R2 and R3 are:

R1, when cyclized with R2, Is

I

--C--R6

I

H wherein R6 Is selected from the group consisting of H, -CH₃₁-C2H5, and -CsHr, wherein * dénotés the cyclization point, and

R1, when not cyclized, Is selected from the group consisting of

H

I

-—C—R6

I

Hand ^H wherein R6 is selected from the group consisting of H, -CH₃₁-C2H5, and -C^Hr

R2 is a compound selected from the group consisting of

R11—C — C—R7 -—C—R7

I I I

H H and H wherein R7 and R11 Independently are selected from the group consisting of H, -CH₃, •CzHs, and — C3H7 wherein * dénotés the cyclization point, and

R3, when cyclized with R2, is wherein * dénotés the cyclization point, and wherein R8 is selected from the group consisting of H, CrCe alkyl, branched C3Ce alkyl, C₃-Ce cycioalkyl, Ce-C₁₀ aryl, substituted Ce-Cw aryl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, CrCe alkoxy, branched C3-Ce alkoxy, C₃-Ce cycloaikoxy, Ce-Cto aryloxy, substituted Ce-C₁₀ aryloxy, C₃-C9 heteroaryloxy, substituted CrCe heteroaryloxy; and

R3, when not cyclized, is wherein

R9 Is selected from the group consisting of H, -CH₃, and -C2H5; and

R10 is selected from the group consisting of Ce-Cio aryl, substituted Ce-Cioaryl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl

R4 is selected from the group consisting of C₆-Cw aryl, substituted Ce-Cw aryl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, C₃-Ce heterocyclyl, substituted Cs-Ce heterocyciyl, Cs-Ce cycioalkyl, and substituted C₃-Ce cycioalkyl;

R5 is selected from the group consisting of hydrogen, F, Cl, CN, -CH₃, -CîHs, -C3H7, and

A is absent or -CHr and tautomers and pharmaceutically acceptable acid addition salts thereof, and polymorphie forms thereof provided that the compound is not 2-[1-[(4-fluorophenyl)methyl]-4methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; 2-(1benzyl-4-methyl-pyrrolîdin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1 -f][1,2,4]triazin-4one; 2-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one; 2-(4-methylpyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3Himidazo[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]triazîn-4-one; 2-[(3S,4S)-1 -benzyl-4methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazoI5,1-f][1,2,4]triazin-4-one; 2[(3R,4R)-l-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f]I1,2,4]triazin-4-one; 2-[(3S,4S)-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f] [1,2,4]triazin-4-one
2-[(3R,4R)-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5₁1-f]I1,2,4]triazin-

4- one; 2-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4- yl-3H-imidazoI5,1 -f]I1,2,4]triazin-4-one; 2-I(3R,4R)-4-methyl-1 -(pyrimidin-2ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f]I1,2_l4]triazin-4-one; 4[3-methyl-4-(4-oxo-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin1 -yljbenzon itrile; 2-[(3S,4S)-1 -[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2_l4]triazin-4-one; 2-[(3R,4R)-1-[(4fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1.2,4]triazin-4-one or 2-[4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl]-7tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2_l4]triazin-4-one.

2. The compound of claim 1 wherein the one or more heteroaryls of R4, R8 and R10 independently of each other comprise one or two nitrogen.
3. The compound of claim 1, wherein the compound Is selected from the group consisting of 7-(4-fluorophenyl)-2-[4-methyl-1-n6-(trifluoromethyl)-3-pyridyl]methyl]pyrroiidin-3-yl]-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one;

2-[1-I(6-methoxy-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f](1,2,4]triazin-4-one;

2-(4-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1 -f](1,2,4]triazin-4-one;

2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3₁6-dihydro-2H-pyran-4-yl)-3H-imidazo[5,1f][1,2,4]triazin-4-one;

7*(4-fluorophenyl)-2-[1-[(6-methoxy-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-3Hlmidazo[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;

2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3-pyridyl)-3H-imidazo[5,1-f][1,2_l4]triazin-4-one

2-[1-[(2,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f] [1,2,4]triazln-4-one;

2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-[4-(trifluoromethoxy)phenyl]-3H-lmidazo[5_l1f][1,2,4]triazin-4-one;

7-(4-fluorophenyl)-2-[1-[(4-nuorophenyl)methyl]-4-rnethyl-pyrrolidin-3-yl]-3H-lmidazo[5,1f][1,2,4]triazin-4-one;

2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(2_l4-dinuoraphenyl)-3H-imidazo[5,1-f][1_I2,4]triazÎn-
4-one;

2-[4-methyl-1-[[4-(trinuoromethoxy)phenyl]methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl3H-imidazo[5,1-f][1,2,4]triazin-4-€ne;

2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(4-pyridyl)-3H-lmidazo[5,1-f][1,2_I4]triazin-4-one

2-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-lmidazo[5,1f][1,2,4]triazin-4-one;

7-(4-fluorophenyl)-2-[[3-(4-rnethoxyphenyl)azetÎdin-1-yl]methyl]-3H-imidazo[5,1f][1,2,4]triazin-4-one;

7-(4-fluorophenyl)-2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-3H-lmidazo[5,1f][1,2,4]triazin-4-one;

2-[1-[(2-chloro-4-methoxy-phenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl3H-imidazo[5,1 -f][1,2,4]triazin-4-one;

2-[4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Hlmldazo[5,1 -f][1,2,4]triazin-4-one;

2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5_l1f][1,2,4]triazin-4-one;

2-[1-[(4-methoxypheny1)methyl]-4-methy1-pyrrolidin-3-y1]-7-tetrahydropyran-4-y1’3H’ lmidazo[5,1-f][1,2,4]triazin-4-one;

2-[4-methy1-1-(4-pyridy1methyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-lmidazo[5,1f][1,2,4]triazin-4-one:

2-[4-methy1-1-(2-pyridylmethyl)pynOlidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one;

2-Q3-(4-fluorophenoxy)azetidin-1-yl]methy1]-7-tetrahydropyran-4-y1-3H-imidazo[5,1f][1,2,4]triazin-4-one;

2-[4-methyl-1-(pyrimidin-5-y1methy1)pyrrolidin-3-y1]-7-tetrahydropyran-4-yl-3H-imidazo[5,1 f][1,2,4]triazin-4-one;

2-[1-R4-(diethy1amino)phenyl]methy1]-4-methy1-pyrrolidin-3-y1]-7-tetrahydiOpyran-4-yl-3Himidazo[5,1 -f][1,2,4]triazin-4-one;

2-[1-(2-furylmethy1)-4-methy1-pyrrolîdin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one;

2-[1-( 1 H-lmldazol-2-y1methy1)-4-methyl-pyrrolidin-3-y1]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f][1,2,4]triazin-4-one;

7-(4-fluorophenyl)-2-[(3S,4S)-4-methyl-1-(pyrîmidin-2-ylmethy1)pyrrolidin-3-yl]-3Himldazo[5,1 -f] [1,2,4]triazin-4-one;

7-(4-fluoropheny1)-2-[(3R,4R)-4-methyl-1-(pyrimidin-2-ylmethy1)pyrrolidin-3-yl]-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one;

2-[1-[(2-chloro-4-fluoro-pheny1)methy1]-4-methy1-pyrrolidin-3-yl]-7-tetrahydropyran-4-y1-3Hlmidazo[5,1-f][1,2,4]triazin-4-one;

2-[l-[(4-dimethy1amlnophenyl)methyl]-4-methy1-pyrrolidin-3-yl]-7-tetrahydropyran-4-y1-3Himidazo[5,1-f][1,2,4]triazin-4-one;

2-[4-methyl-1-(p-toly1methyl)pyrîOlidin-3-y1]-7-tetrahydropyran-4-yl-3H-imldazo[5_l1f][1,2,4]triazin-4-one;

2-(benzyloxymethyl)-7-tetrahydropyran-4-yt-3H-lmîdazo[5,1-f][1,2₍4îtriazin-4-one;

2-[[3-(2_l6-difluorophenoxy)azetidin-1 -yl]methyl]-7-tetrahydropyran-4-y1-3H-imidazo[5.1 f][1,2,4]triazin-4-one;

2-[1-(cyclohexylmethyl)-4*methyl-py!Tolidin-3-y1]-7-tetrahydropyran-4-yl-3H-lmÎdazo[5,1f][1,2,4]triazin-4-one

7-tetrahydropyran-4-yl-2-[[3-[4-(trifluoromethoxy)phenoxy]azetidin-1-ylImethyî]-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one;

2-Q3-(4-dimethyîaminophenyl)azetidin*1-yl]methyl]-7-tetrahydropyran-4-yî-3H-lmidazo[5,1 f][1,2,4]triazîn-4-one;

2-[4-methy1-1-(3-pyridyîmethyî)pyrrolidin-3-yî]-7-tetrahydropyran-4-yî-3H-lmidazo[5,1f][1,2,4]triazin-4-one;

2-[1-[(2,6-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one;

2-[(3-phenoxyazetidin-1-yl)methyl]-7-tetrahydropyran-4-yl-3H-imldazo[5,1-f][1_I2,4]triazin-4one;

2-(1-ethyl-4-methyî-pyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triaz!n-4one;

2-n3-[(4-fluorophenyl)methoxy]azetidin-1-yl]methy1]-7-tetrahydropyran-4-y1-3Hlmidazo[5,1 -f][1,2,4]triazin-4-one;

2-[1-[3-(4-methoxyphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yî-3H-lmidazo[5,1f][1,2,4]triazin-4-one;

2-[4-methyM-[(5-methyl-2-furyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f][1,2,4]triazin-4-one;

2-[1-[(5-chloro-2-fury1)methyî]-4-methyî-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f][1,2,4]triazin-4-one;

2-[l-[3-(4-fluorophenyl)azetidin-1-yî]ethyî]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one;

2-[(3-pheny1azetidin-1-yl)methyî]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4one;

2-[[3-(4-methylphenoxy)azetidin-1-yl]methyî]-7-tetrahydropyran-4-yî-3H-imidazo[5_l1f][1,2,4]triazin-4-one;

2-(1-benzyl-4-methyl-pyrrolidin-3-y1)-7-(4-piperidyl)-3H-imidazo[5,1-f][1_l2,4]triazin-4-one;

2-[1-[(5-fluoro-3-pyridy1)methyl]-4-methyl-pyrrolidÎn-3’y1]-7-tetrahydropyran-4-yî’3H’ lmidazo[5,1-f][1,2,4]triazin-4-one;

2-[[3-{2-pyridy1)azet(dÎn-1-yl]methyl]-7-tetrahydropyran-4-y!-3H-imidazo[5_l1’f][1,2,4]triazin-

4-one;

2-[[3-(4-lsopropyIphenoxy)azetidin-1-yl]methyn-7-tetrahydropyran-4-yl-3H-lmidazo[5_l1f][1,2,4]triazin-4-one;

2-[1-[(3,4-difluorophenyl)methy1]-4-methy1-pynOlidin-3-yl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1-f][1,2,4]triazin-4-one;

2-[1-[(4-chloropheny1)methyl]-4-methy1-pyrro1idin-3-yl]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1-f][1,2,4]triazln-4-one;

2-[(3S,4S)-1-[(2,4-difluorophenyl)methyl]-4-methyl-pyrro1idin-3-y1]-7-tetrahydropyran-4-y13H-1mldazo[5,1-f][1,2,4]triazin-4-one;

2-[1-[(6-(dimethyIamino)-3-pyridy1]methyl]-4-methyl-pynOlidin-3-yl]-7-tetrahydropyran-4-yl3H-lmidazo[5,1 -f][1,2,4]triazin-4-one;

methyi 5-[[3-methy!-4-(4-oxo-7-tetrahydropyran-4-yl’3H’1mîdazo[5_l 1 -f][1,2,4]triazin-2y1)pyrrolidin-1-yl]methy1]thlophene-2-carboxylate;

7-tetrahydropyran-4-y1-2-[[3-[5-(trifluoromethy1)-2-pyridyl]azetidin-1-y1]methyll-3H1midazo[5,1-f][1,2,4]triazin-4-one;

2-[[3-(3-pyridy1oxy)azetÎdÎn-1-y1]methyll-7-tetrahydropyran-4-y1-3H-lmidazo[5,1’

f][1,2,4]triazin-4-one;

2-[(3R,4R)-1-[(2,4-dÎfluorophenyl)methy1]-4-methy1-pyrrolidin-3-yl]-7-tetrahydropyran-4-y13H-lmidazo[5,1-f][1,2,4]triazin-4-one;

2-[(1R)-1-[3-(4-methoxyphenyl)azetidin-1-yl]ethy1]-7-tetrahydropyran-4-y1-3H-lmidazo[5_I1f][1,2,4]triazin-4-one;

2-[1 -[3-(4-fluorophenoxy)azetidin-1 -yl]ethy!]-7-tetrahydropyran-4-y1-3H-lmldazo[5,1 f][1,2,4]triazin-4-one;

2-[4-methy1-1-[(5-methyl-2-thienyt)methyl]pyrroiidin-3-yl]-7-tetrahydropyran-4-y1-3Hlmldazo[5,1-f][1,2,4]triazln-4-one;

2-[1-[(5-chîoro-2-thienyl)methyt]-4-methyt-pyrroîidin-3-yt]-7-tetrahydropyran-4-yt-3HimidazoI5,1 -f][ 1,2,4]triazln-4-one;

2-[4-methyl-1*[(4-pyrrolidin-1-ylphenyl)methy!]pyrTolidin-3-y!]-7-tetrahydropyran’4-yl-3HimîdazoI5,1 -f][1,2,4]triazln-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-methy1-14pyrimidin-4-y!methyl)pyrrolidin-3-y!]-7-tetrahydropyran-4-y!-3l-l-imidazo[5,1 f][1,2,4]triazin-4-one;

2-[1-[3-(4’hydroxypheny1)azetidin-1-y!]ethy1]-7-tetrahydropyran’4’y1-3H-imidazo[5,1f][1,2,4]triazin-4-one;

2-[1-[(4-f!uorophenyl)methyl]-4-methoxy-pyrTolidin-3-y!]-7-tetrahydropyran-4-y!-3Himidazo[5,1 -f] [ 1,2,4]triazin-4-one;

2-I4-methoxy-1 -(p-tolylmethyl)pyiTolidin-3-yl]-7-tetrahydropyran-4-y!-3H-imidazoI5,1 f][1,2,4]triazin-4-one;

2-[[3-(p-toly!methoxy)azetidin-1-y!]methy!]-7-tetrahydropyran-4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one;

2-[(3-benzylazetidin-1 -yl)rïiethy!]-7-tetrahydropyran-4-yl-3H-lmldazo[5,1 -f][1,2,4]triazin-4one;

2-[(3S,4S)-1 -benzyM-methoxy-pyrroîidin-3-yt]-7-tetrahydropyran-4-yt-3H-imidazo[5,1 f][1,2,4]triazin-4-one;

2-(1-(3-(4-methylphenoxy)azetidin*1*yl]ethyl]-74etrahydropyran’4-yl-3H-imidazo[5,1f] [1,2,4]triazin-4-one;

2-([3-[(4-methoxyphenoxy)methy!]azetidin-1-yl]methyn-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one;

2-[(3-pyrimidin-2-y!azetidin-1-yl)methy!]-7-tetrahydropyran’4-yl-3H-imidazo[5,1f][1,2,4]triazin-4-one:

2-il-i3-(4-pyrrolidin-1-ylphenyl)azetidin-1-yl]ethy!]-7-tetrahydropyran-4-yl-3H-imidazoI5₍1·

f][1,2,4]triazin-4-one;

2-[1 ’benzyl-4-(trifluoromethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-irTiidazo[5₁1 f][1,2,4]triazin-4-one;

2-[[3-(5-pyrrolidin-1-ylpyrimidin-2-yl)azetidin-1-y!]methyl]-7-tetrahydropyran-4-yl-3Himidazo[5,1 -f][1,2,4]triazin-4-one;

2-[1-[3-(4-dimethylaminophenyl)azetidin-1-yi]ethyl]-7-tetrahydropyran-4-y!-3H-imidazo[5,1f][1,2₁4]triazin-4-one;

2-[4-methoxy-1-i(4-methoxyphenyl)methyl]pyrrolidîn-3-yl]-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one;

2-[1-(3-phenylazetidin-1-y!)ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5_I1-f][1,2,4]triazin-4one;

2-[1-[3-(3-fluoro-4-methoxy-phenyl)azetîdin-1-yl]ethyt]-7-tetrahydropyran-4-yl-3Hlmidazo[5,1-f][1,2,4]triazin-4-one;

2-[1-[3-(2-fluoro-4-methoxy-phenyl)azetidin-1-yl]ethylI-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one;

2-[1-[3-(4-ethoxyphenyi)azetidin-1-yi]ethy!]-7-tetrahydropyran-4-yl-3H-imidazo[5_l1f]i1,2,4]triazin-4-one;

2-[1-[3-[(4-methoxyphenyl)methyl]azetidin-1-yl]ethy!]-7-tetrahydropyran-4-yl-3Himidazo[5,1-f][1,2,4]triazin-4-one; and

7-tetrahydropyran-4-yl-2-[1-[3-[4-(trifluoromethoxy)phenyl]azetidin-1-ynethyl]-3Himidazo[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 médicament.
5. A compound of any one of claims 1 to 4 for use in the treatment of a disorder, wherein the neurodegenerative disorder ls seiected from the group consisting of Alzheimer’s disease, mental retardation; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive décliné, substance-induced psychotic disorder, for example psychosis Induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants, opioids, or phencyclidine.
6. A compound of any one of claims 1 to 4 for the préparation of a médicament for use ln the treatment of a disorder selected from the group consisting of Alzheimeris disease, mental retardation: CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive décliné, substance-lnduced psychotic disorder, for example psychosis induced by al-

5 cohol, amphétamine, cannabis, cocaine, hallucinogens, Inhalants, opioids, or phencyclidine.
7. A method of treating a subject suffering from a disorder, wherein the neurodegenerative disorder is selected from the group consisting of Aizheimeris disease, mental retardait) tion; CIAS, attention-deficit/hyperactivity disorder; and age-related cognitive décliné, substance-induced psychotic disorder, for example psychosis Induced by alcohol, amphétamine, cannabis, cocaine, hallucinogens, Inhalants, opioids, or phencyclidine.
8. A pharmaceutical composition comprising a therapeutically effective amount of a com-

15 pound of any one of claims 1 to 4, and one or more pharmaceutically acceptable carriers, diluents and excipients.