US20210139479A1

US20210139479A1 - COMT Inhibiting Methods and Compositions

Info

Publication number: US20210139479A1
Application number: US17/155,371
Authority: US
Inventors: James Barrow; Glen Ernst; Dominique Swinnen; Florian Montel; Sabine Defays; Yifeng Huang; Pablo De Leon; Michael Steven Poslusney
Original assignee: Lieber Institute Inc
Current assignee: Lieber Institute Inc
Priority date: 2015-11-25
Filing date: 2021-01-22
Publication date: 2021-05-13
Also published as: PL3380471T3; WO2017091818A1; US20180305354A1; ES2893613T3; DK3380471T3; EP3380471A4; US10934283B2; CA3006189A1; EP3380471A1; EP3380471B1; HUE056356T2; EP3380471B8; CA3006189C

Abstract

This invention relates to compounds, pharmaceutical compositions and their use for treating neuropsychiatric and neurodegenerative disorders. In particular, the invention relates to inhibitors of catechol-O-methyltransferase and their use as therapeutics for central nervous system disease.

Description

NIH GRANT

This invention was made with government support under R01MH107126 awarded by National Institutes of Health. The government has certain rights in the invention.

FIELD OF THE INVENTION

BACKGROUND

Cognitive disorders are observed in many neurological and psychiatric disorders, be they neurodegenerative (e.g. Parkinson's disease, Alzheimer's disease), neurodevelopmental (e.g. schizophrenia, autism spectrum disorders) or the consequence of other etiology.
Parkinson's disease is a progressive neurodegenerative disorder (synucleopathy) diagnosed on the basis of characteristic motor disturbances, asymmetry of symptoms onset and response to levodopa (Litvan et al., 2003). Lewy bodies, neurofibrillary tangles and plaques are observed in nigral, limbic and neocortical regions. These degenerations are supposed to affect catecholaminergic (dopamine and norepinephrine) and cholinergic neurotransmission. In particular, an important part of cognitive deficits (executive function and working memory) have been related to a decreased prefrontal dopaminergic signaling in non-demented patients (Nandakumar et al., 2013).
Schizophrenia is the result of a complex series of neurodevelopmental or other changes that lead to impaired information processing in the brain (Marenco and Weinberger 2000). No single genetic change, aberrant protein function, or visible brain lesion has been demonstrated to lead to schizophrenia, and many different genetic and environmental changes are linked to increased disease risk (Fatemi and Folsom 2009). While many neurochemical signaling systems, such as the various monoamines, NMDA, and GABA, are likely to play a role in the etiology of schizophrenia (Pickard 2011), many pathways seem to converge on aberrant dopamine signaling as a final common pathway that leads to many of the observed symptoms (Howes and Kapur 2009).
With regard to the cognitive impairment, for which there is currently no treatment, patients with schizophrenia show significant deficits in specific cognitive domains, especially executive function, working memory, and episodic memory. Cognitive domains which are dysfunctioning in these two disorders are complex functions involving many neurotransmitters and brain regions; however, dopamine signaling in the dorsolateral prefrontal cortex (DLPFC) has been shown to play a critical role in these processes (Goldman-Rakic, Castner et al. 2004). One approach to rectifying cortical dopamine neurotransmission is to take advantage of the differential modes of clearance of dopamine from the different brain regions. In the midbrain, there is extensive expression of the dopamine transporter (DAT), which is thought to be primarily responsible for dopamine clearance from the synapse (Ciliax, Heilman et al. 1995). In contrast, cortical regions exhibit only low levels of DAT expression, and dopamine is cleared primarily by enzymatic catabolism of dopamine, with a contribution from the norepinephrine transporter (NET) (Yavich, Forsberg et al. 2007; Kaenmaki, Tammimaki et al. 2010). The primary enzymes responsible for dopamine catabolism in the prefrontal cortex (“PFC”) are monoamine oxidase (MAO) and catechol-O-methyltransferase (“COMT”).
Beyond Parkinson's and schizophrenia, inhibition of COMT may be useful in a number of neuro-psychiatric conditions, including ADHD, obsessive-compulsive disorder, alcoholism, depression, bipolar disorder (Lachman, Papolos et al. 1996), as well as age-associated cognitive symptoms, impulse control disorders, including compulsive gambling, sexual behavior, and other compulsive destructive behaviors. The role of COMT in dopamine metabolism in the brain make it an especially important target for improvement of cognition (Apud and Weinberger 2007).
Additionally, COMT inhibitors have shown utility in Parkinson's disease treatment, due to the role of COMT in metabolizing the dopamine precursor L-DOPA, which is given to Parkinson's disease patients to boost the levels of dopamine in the brain (Bonifacio, Palma et al. 2007). Since dopamine cannot cross the blood-brain barrier, L-DOPA is administered in its place and is transported into the brain and subsequently processed to dopamine. The percentage of exogenously administered L-DOPA that reaches the brain is 1%, and this low brain availability necessitates a high dose, which leads to peripheral side effects (Nutt and Fellman 1984). The primary enzymes responsible for dopamine metabolism are aromatic amino acid decarboxylase (AAAD) and COMT. Therefore, extensive efforts have been undertaken to develop potent and selective inhibitors of both enzymes. Carbidopa is an AAAD inhibitor now routinely given with L-DOPA, reducing the efficacious L-DOPA dose by 60-80% (Nutt, Woodward et al. 1985). Addition of a COMT inhibitor further decreases the variability of L-DOPA exposure, and a brain-penetrating COMT inhibitor could also increase brain dopamine levels.
Inhibitors of COMT have been developed for treatment of Parkinson's disease (Learmonth, Kiss et al. 2010). Notably, the nitrocatechol scaffold has been exploited to provide the clinically used drugs tolcapone and entacapone (Bonifacio, Palma et al. 2007). While they are effective in blocking peripheral COMT activity, entacapone has negligible brain penetration, and tolcapone has low but measurable levels in the brain (Russ, et al. 1999). Compounds with improved brain penetration should have greater efficacy for Parkinson's disease, as well as have utility for other psychiatric and neurological conditions such as cognitive impairment in schizophrenia. Despite the early clinical success achieved with tolcapone, the drug has been associated with serious liver injury, including three deaths, and requires strict liver function monitoring (Olanow and Watkins 2007). Thus, the risk-benefit profile for tolcapone prevents its widespread deployment, and new, inhibitors of COMT are needed, especially those that are active in the brain. Borchardt disclosed a series of non-nitrocatechol quinoline COMT inhibitors, but these compounds had weak potency (Borchardt, Thakker et al. 1976).
Accordingly, there remains a need for potent inhibitors of COMT and methods of using the same to treat central nervous system disorders.

SUMMARY OF THE INVENTION

The present invention provides compounds, pharmaceutical compositions and methods of treating or preventing neurological or psychiatric disorders for which inhibiting COMT provides a therapeutic effect.
The present invention also provides methods of treating or preventing a neurological or psychiatric disorder, or treating symptoms associated with a neurological or psychiatric disorder, and in particular such disorders for which inhibiting COMT provides a therapeutic effect. In a particular embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds according to formula I, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo; iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₅is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀alkyl or C₁-C₁₀cycloaklyl, optionally substituted with one or more groups selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄alkyl; and
Y is (CR₆R₇)_n, wherein n is from 0-3, and R₆and R₇are independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; or when R₅is phenyl, one of R₆or R₇comes together with R₅to form a bicycle.
Also provided herein are COMT-inhibiting compounds in accordance with formula I, or pharmaceutically acceptable salts thereof:
Also provided herein are pharmaceutical compositions comprising the COMT-inhibiting compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

The terms below, when used herein, have the following meanings unless indicated otherwise.
As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise.
When any variable (e.g. aryl, heterocycle, R¹, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence.
“Alkyl” refers to a saturated hydrocarbon chain. Such hydrocarbon chains may be branched or linear. “Alkyl” groups may be substituted by one or more substituents selected from halogen, amido, aryl or alkoxy. Particular alkyl groups according to the present invention include methyl, trifluoromethyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl, 1-ethylpropyl, 3-methylpentyl, octyl and the like.
The term “C₁-C₆” (for example), or “C_1-6”, includes, for this example, alkyls containing 6, 5, 4, 3, 2, or 1 carbon atom(s).
“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarbon radical, including bridged, fused, or spiro cyclic compounds, preferably having 3 to 8 carbon atoms. Nonlimiting examples of “C₃-C₆cycloalkyl” groups according to the present invention are cyclopropyl, cyclopentyl, cyclohexyl and the like.
The compounds of the present invention may contain one or more asymmetric centers and may thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or in other synthetic manipulations.
The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamme, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.
When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
A “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to an excipient that can be included in the compositions of the invention and that causes no significant adverse toxicological effects to the subject or patient to which the composition is administered. “Pharmacologically effective amount,” “physiologically effective amount,” and “therapeutically effective amount” are used interchangeably herein to mean the amount of an active agent present in a pharmaceutical preparation that is needed to provide a desired level of active agent and/or conjugate in the bloodstream or in the target tissue. The precise amount will depend upon numerous factors, e.g., the particular active agent, the components and physical characteristics of pharmaceutical preparation, intended patient population, patient considerations, and the like, and can readily be determined by one skilled in the art, based upon the information provided herein and available in the relevant literature.
The term “patient” refers to a living organism suffering from or prone to a condition that can be prevented or treated by administration of an active agent as described herein, and includes both humans and animals. In one embodiment, the patient is a human patient.
The term “mammal” “mammalian” or “mammals” includes humans, as well as animals, such as dogs, cats, horses, pigs and cattle.
Without being bound by theory, the administration of compounds according to the invention in an “effective amount” or “therapeutically effective amount” provides a concentration of the compound that functions as a COMT inhibitor sufficient to inhibit the effect of the COMT enzyme complex.
“Treating” or “treatment” of a disease state includes: 1) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; 2) attenuating the disease state, i.e. reducing the number or intensity of one or more symptoms associated with the disease state, such that one or more symptoms is reduced but may, or may not be completely eliminated; and/or 3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
“Prevent” or “preventing” a disease state includes: preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
All patents, patent applications and publications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

II. Methods

One aspect of the invention is a method of treating or preventing a neurological or psychiatric disorder, or treating symptoms associated with a neurological or psychiatric disorder, and in particular such disorders for which inhibiting COMT provides a therapeutic effect. Without being bound by theory, the therapeutic effect provided according to the invention is achieved by inhibiting the metabolism of catecholamines by COMT. Accordingly, in an aspect of the invention, the invention provides methods of treating and/or preventing disease for which inhibiting degradation of catecholamines such as, for example, dopamine, norepinephrine or L-dihydroxyphenylalanine (L-DOPA) provides a beneficial therapeutic effect.
In another aspect, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula I. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₅is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀alkyl or C₁-C₁₀cycloaklyl, optionally substituted with one or more groups selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄alkyl; and
Y is (CR₆R₇)_n, wherein n is from 0-3, and R₆and R₇are independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; or when R₅is phenyl, one of R₆or R₇comes together with R₅to form a bicycle.
In another aspect, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula Ia. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula Ia, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₅is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀alkyl or C₁-C₁₀cycloaklyl, optionally substituted with one or more groups selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄alkyl; and
Y is (CR₆R₇)_n, wherein n is from 0-3, and R₆and R₇are independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; or when R₅is phenyl, one of R₆or R₇comes together with R₅to form a bicycle.
In another embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula II. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula II, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
P, Q and R are each independently selected from CH and N;
R₁₀can be at one or more positions on the ring, and at each occurrence is independently selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl; or R₁₀comes together with P, Q or R to form a bicycle; and
R₆and R₇are each independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; or one of R₆or R₇comes together with P to form a bicycle.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In still another particular embodiment, three of R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆and R₇are each hydrogen.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇are hydrogen, and P, Q and R are all CH. In another preferred embodiment, X is H; three of R₁, R₂, R₃and R₄are hydrogen; R₆and R₇are each hydrogen and P, Q and R are all CH. In still another preferred embodiment, X is H; three of R₁, R₂, R₃and R₄are hydrogen; one of R₆or R₇is hydrogen; and P, Q and Rare all CH.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula IIa, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
P, Q and R are each independently selected from CH and N;
R₁₀can be at one more more positions on the ring, and at each occurrence is independently selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl, C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl; or R₁₀comes together with P, Q or R to form a bicycle; and
R₆and R₇are each independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; or one of R₆or R₇comes together with P to form a bicycle.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In still another particular embodiment, three of R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆and R₇are each hydrogen.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇are hydrogen, and P, Q and R are all CH. In another preferred embodiment, X is H; three of R₁, R₂, R₃, R₄, R₆and R₇are each hydrogen and P, Q and R are all CH. In still another preferred embodiment, X is H; three of R₁, R₂, R₃and R₄are hydrogen; one of R₆or R₇is hydrogen; and P, Q and R are all CH.
In another embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula IIb. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula IIa, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
P is CH;
R₁₀can be at one or more positions on the ring, and at each occurrence is independently selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl; or R₁₀comes together with P to form a bicycle; and
R₆and R₇are each independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; or one of R₆or R₇comes together with P to form a bicycle.
In a particular embodiment, Z is fluoro and X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇are each hydrogen.
In a preferred embodiment, Z is fluoro and X is H and R₁, R₂, R₃, R₄, R₆and R₇are hydrogen. In yet another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇and R₁₀is selected from optionally substituted phenyl or methyl.
In exemplary embodiments, a method of inhibiting COMT enzyme in a subject comprises administering one or more of the following compounds:
In another particular embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula III. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula III, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl; and
R₆, R₇, R₁₁and R₁₂are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇, R₁₁and R₁₂, R₆or R₇and R₁₁or R₁₂may also come together to form a C₃-C₆cycloalkyl.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇, R₁₁and R₁₂are each hydrogen.
In a preferred embodiment, X is H and R₁, R₂, R₃, R₄, R₆and R₇are hydrogen. In yet another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇and R₁₁are hydrogen and R₁₂is selected from phenyl or methyl.
In another particular embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula Ilia. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula IIIa, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl; and
R₆, R₇, R₁₁and R₁₂are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇, R₁₁and R₁₂are each hydrogen.
In a preferred embodiment, X is H and R₁, R₂, R₃, R₄, R₆and R₇are hydrogen. In yet another another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇and R₁₁are hydrogen and R₁₂is selected from phenyl or methyl. In exemplary embodiments, a method of inhibiting COMT enzyme in a subject comprises administering one or more of the following compounds:
In another embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula IV. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula IV, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylakyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆, R₇, R₁₁, R₁₂, R₁₃and R₁₄are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl and aryl; R₆and R₇, R₁₁and R₁₂, R₁₃and
R₁₄, R₆or R₇and R₁₁or R₁₂, R₆or R₇and R₁₃or R₁₄, R₁₁or R₁₂and R₁₃or R₁₄may also come together to form a C₃-C₆cycloalkyl; and
R₁₅and R₁₆are each hydrogen or come together to form a ring.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In still another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃and R₁₄are each hydrogen.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅and R₁₆are hydrogen. In yet another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₃and R₁₄are hydrogen; R₁₂is methyl; and R₁₅-R₁₆form a dioxolane.
In another embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula IVa. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula IVa, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylakyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆, R₇, R₁₁, R₁₂R₁₃and R₁₄are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl and aryl; and
R₁₅and R₁₆are each hydrogen or come together to form a ring.
In exemplary embodiments, a method of inhibiting COMT enzyme in a subject comprises administering one or more of the following compounds:
In another embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula V. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula V, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl; and
R₁₀can be at one or more positions on the ring, and at each occurrence is independently selected from the group consisting of hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl.
In a preferred embodiment, X is H; R₁, R₂, R₃, and R₄are hydrogen; and R₁₀is selected from hydrogen, C₁-C₄alkyl and mono-, di- or trihalomethyl. In a more specific embodiment, R₁₀is hydrogen. In an alternative specific embodiment, R₁₀is methyl. In yet another alternative specific embodiment, R₁₀is trifluoromethyl.
In another embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula Va. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula Va, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl; and
R₁₀can be at one or more positions on the ring, and at each occurrence is independently selected from from the group consisting of hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl.
In a preferred embodiment, X is H; R₁, R₂, R₃, and R₄are hydrogen; and R₁₀is selected from hydrogen, C₁-C₄alkyl and mono-, di- or trihalomethyl. In a more specific embodiment, R₁₀is hydrogen. In an alternative specific embodiment, R₁₀is methyl. In yet another alternative specific embodiment, R₁₀is trifluoromethyl. In exemplary embodiments, a method of inhibiting COMT enzyme in a subject comprises administering one or more of the following compounds:
In another embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula VI. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula VI or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
Y is (CR₆R₇)_n, wherein n is from 0-3, and R₆and R₇are independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl Het is a heterocycle. Het may be connected to the R₆/R₇carbon at any position of the heterocycle, provided it provides proper valency. In particular embodiments, the heterocycle is aromatic. Examples of heteroaromatics include, but are not limited to indole; 1H-pyrazole; benzothiazole; benzotriazole; quinoline; isoquinoline; quinoxaline; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole; 2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇, are hydrogen, and Het is selected from the group consisting of 1H-pyrazole; benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole; 2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.
In another embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula Via. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula Via or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆and R₇are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; and Het is a heterocycle. Het may be connected to the R₆/R₇carbon at any position of the heterocycle, provided it provides proper valency. In particular embodiments, the heterocycle is aromatic. Exemplary heteroaromatics include, but are not limited to indole; 1H-pyrazole; benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole; 2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇, are hydrogen, and Het is selected from the group consisting of 1H-pyrazole; benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole; 2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.
In exemplary embodiments, a method of inhibiting COMT enzyme in a subject comprises administering one or more of the following compounds:
In another particular embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula VII. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula VII, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆and R₇are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; and
R₁₇and R₁₈are selected from C₁-C₄alkyl or come together to form a 5-10 membered cycloalkane, which can optionally be further substituted with C₁-C₈alkyl or cycloalkyl.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇, are hydrogen, and R₁₇and R₁₈are methyl. In another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇, are hydrogen, and R₁₇and R₁₈come together to form a 6, 7 or 8 membered cycloalkane, which is further substituted with C₁-C₈alkyl or cycloalkyl.
In another particular embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds of formula Vila. These methods comprise administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula Vila, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆and R₇are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; and
R₁₇and R₁₈are selected from C₁-C₄alkyl or come together to form a 5-10 membered cycloalkane, which can optionally be further substituted with C₁-C₈alkyl or cycloalkyl.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇, are hydrogen, and R₁₇and R₁₈are methyl. In another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇, are hydrogen, and R₁₇and R₁₈come together to form a 6, 7 or 8 membered cycloalkane, which is further substituted with C₁-C₈alkyl or cycloalkyl.
In exemplary embodiments, a method of inhibiting COMT enzyme in a subject comprises administering one or more of the following compounds:
In another aspect, the invention provides a method of inhibiting COMT enzyme in a subject by administering to a subject in need thereof an effective amount of a compound selected from the following:

2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[4-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(4-fluorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[2-(benzotriazol-1-yl)ethyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[2-(benzotriazol-2-yl)ethyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-tert-butylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,4-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[4-(propan-2-yl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[4-(pyridin-3-yl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(4-ethylphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile
2-(4-ethyl-3-nitrobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-ethylbutyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(3,5-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(cyclohexylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-cyclopropylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(cyclooctylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,5-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-{[1-(phenylsulfonyl)-1H-indol-2-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(3-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(3,5-difluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-methylbenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[(5-phenyl-1H-pyrazol-3-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-{[6-chloro-4-(1H-imidazol-4-yl)-3,4-dihydro-2H-chromen-8-yl]methyl}-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,3-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(1,3-benzothiazol-2-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[(4-oxo-4H-chromen-3-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1H-indazol-3-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-{[3-(thiophen-2-yl)-1H-pyrazol-4-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[(3-phenyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dimethoxybenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(4-phenoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[3-(1,3-benzodioxol-5-yl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[4-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[3-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,1,3-benzothiadiazol-5-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[2-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-{[6-(4-methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-chloro-4-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-difluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(4-bromo-2-chloro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chloro-4-cyclopropyl-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chlorophenyl)methyl]-7-hydroxy-3,3-dimethyl-1,4-dihydropyrido[1,2-a]pyrazin-8-one
2-[(2,4-dichloro-5-nitro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[1-(2-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(4-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2,5-dichlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-{1-[4-(trifluoromethyl)phenyl]ethyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[1-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(3-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-chloro-2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2,6-dimethoxyphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[1-(2,3,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-{1-[2-(benzyloxy)phenyl]ethyl}-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylpentyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-phenyl-3,4-dihydro-2H-chromen-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(3-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[cyclopentyl(phenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[1-(3-methoxyphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(3-chloro-2,6-difluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2,5-dimethylphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(1,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylbutyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
4-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]benzonitrile
3-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]benzonitrile
N-{3-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]phenyl}acetamide
2-[1-(2,5-difluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(4-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-hydroxy-1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2,2,2-trifluoro-1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylcyclopropyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-(2-fluoro-1-phenyl-ethyl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-(2,2-difluoro-1-phenyl-ethyl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-(1,3-benzothiazol-2-yl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-phenylcyclopropyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(5-quinolyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(3-phenyloxetan-3-yl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(3-methylphenyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[2-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
1,2-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-benzyl-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dichlorobenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
(1R)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
(1S)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dimethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
1-(4-fluorophenyl)-7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1-[3-(pyridin-3-yl)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-benzyl-7-hydroxy-3-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2,3-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
3-benzyl-2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-3-methyl-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-benzyl-7-hydroxy-3-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-benzyl-7-hydroxy-3-(2-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
9-chloro-2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
6-fluoro-7-hydroxy-2-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chlorophenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
9-chloro-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
9-chloro-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
9-bromo-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
9-bromo-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chlorophenyl)methyl]-7-hydroxy-9-iodo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
9-cyclopropyl-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one.

The compounds for use in the instant method may be selected from any one or any combination of compounds designated 1-142 herein.
For use in the method, the compound or compounds of the present invention, described above, is typically provided as a pharmaceutical composition wherein the compound or compounds is present in combination with a pharmaceutically acceptable carrier as described herein. Such pharmaceutical compositions are also provided by this disclosure.
For use in the method, the compound(s) of the present invention, described above, may also be used in combination with another additional therapeutic agent.
The methods of the present invention may be used to treat or prevent a neurological or psychiatric disorder. In particular, exemplary embodiments of the invention include methods of treating or preventing schizophrenia, major depression, a depressive phase of bipolar disorder, attention deficit disorder, attention deficit/hyperactivity disorder, substance dependency, or increased appetite associated with smoking cessation or antipsychotic use. Other significant indications include age-associated cognitive symptoms, impulse control disorders, including compulsive gambling, sexual behavior, and other compulsive destructive behaviors.
In addition to the psychiatric indications, the methods of the invention may also be used to treat neurological disorders. In one embodiment, the method of the present invention comprises administering an effective amount of a compound described herein above in combination with L-DOPA for treatment of Parkinson's disease. The compound can be administered in combination with L-DOPA, concurrently or separately, with or without an aromatic L-amino acid decarboxylase inhibitor (AADC) such as carbidopa, to prevent or inhibit COMT-mediated metabolism of L-DOPA.

III. Compounds

Also disclosed herein are the novel 7-hydroxy-tetrahydropyridopyrazinone derivatives described above which, preferably, are inhibitors of catechol O-methyltransferase (COMT) enzyme, and which are useful in the treatment or prevention of neurological or psychiatric disorders or diseases in which COMT is involved. The compounds of the invention are characterized by their activity to inhibit the enzyme COMT. In preferred embodiments, the compounds of the present invention are effective to inhibit the enzyme COMT, in an assay which determines the inhibitory concentration (IC₅₀) for the conversion of the methyl donor S-adenosyl methionine to S-adenosyl homocysteine (SAH) as described herein, with a pIC₅₀superior or equal to 4.5. In increasingly preferred embodiments, the pIC₅₀as so determined is superior or equal to 6.0. In a more preferred embodiment, the pIC₅₀as so determined is superior or equal to 7.0.
The ability of compounds within the scope of this invention to inhibit the activity of catechol-O-methyltransferase (COMT) may be determined by methods known to those in the art for measuring COMT inhibition. One method for measuring COMT activity uses a homogenous time-resolved fluorescent (HTRF) assay (Lina et al, 2012; kit from CisBio, Codolet, France). This assay measures the production of-S-adenosyl homocysteine (SAH) from the methyl donor S-adenosyl methionine. Using this assay preferred compounds of the invention have a pIC₅₀superior or equal to 4.5. In increasingly preferred embodiments, the pIC₅₀as so determined is superior or equal to 6.0. In a more preferred embodiment, the pIC₅₀as so determined is superior or equal to 7.0.
Provided herein are COMT-inhibiting compounds in accordance with formula I, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₅is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀alkyl or C₁-C₁₀cycloaklyl, optionally substituted with one or more groups selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄alkyl; and
Y is (CR₆R₇)_n, wherein n is from 0-3, and each R₆and R₇are independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl;
R₆and R₇may also come together to form a C₃-C₆cycloalkyl; or when R₅is phenyl, one of R₆or R₇comes together with R₅to form a bicycle.
In another embodiment are COMT-inhibiting compounds in accordance with formula Ia, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₅is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀alkyl or C₁-C₁₀cycloaklyl, optionally substituted with one or more groups selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄alkyl; and
Y is (CR₆R₇)_n, wherein n is from 0-3, and each R₆and R₇are independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; or when R₅is phenyl, one of R₆or R₇comes together with R₅to form a bicycle.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula II, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
P, Q and R are each independently selected from CH and N;
R₁₀can be at one more positions on the ring, and at each occurrence is independently selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl, C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl; or R₁₀comes together with P, Q or R to form a bicycle; and
R₆and R₇are each independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; or one of R₆or R₇comes together with P to form a bicycle.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In still another particular embodiment, three of R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆and R₇are each hydrogen.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇are hydrogen, and P, Q and R are all CH. In another preferred embodiment, X is H; three of R₁, R₂, R₃, R₄, R₆and R₇are each hydrogen and P, Q and R are all CH. In still another preferred embodiment, X is H; three of R₁, R₂, R₃and R₄are hydrogen; one of R₆or R₇is hydrogen; and P, Q and R are all CH.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula IIa, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
P, Q and R are each independently selected from CH and N;
R₁₀can be at one more more positions on the ring, and at each occurrence is independently selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl, C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl; or R₁₀comes together with P, Q or R to form a bicycle; and
R₆and R₇are each independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; or one of R₆or R₇comes together with P to form a bicycle.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In still another particular embodiment, three of R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆and R₇are each hydrogen.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇are hydrogen, and P, Q and R are all C. In another preferred embodiment, X is H; three of R₁, R₂, R₃, R₄, R₆and R₇are each hydrogen and P, Q and R are all C. In still another preferred embodiment, X is H; three of R₁, R₂, R₃and R₄are hydrogen; one of R₆or R₇is hydrogen; and P, Q and R are all CH.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula IIb, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
P is CH;
R₁₀can be at one more positions on the ring, and at each occurrence is independently selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl; or R₁₀comes together with P to form a bicycle; and
R₆and R₇are each independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; or one of R₆or R₇comes together with P to form a bicycle.
In a particular embodiment, Z is fluoro and X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇are each hydrogen.
In a preferred embodiment, Z is fluoro and X is H and R₁, R₂, R₃, R₄, R₆and R₇are hydrogen. In yet another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇and R₁₀is selected from optionally substituted phenyl or methyl.
In exemplary embodiments, a compound is selected from the following:
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula III, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl; and
R₆, R₇, R₁₁and R₁₂are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇; R₁₁and R₂; R₆or R₇and R₁₁or R₁₂may also come together to form a C₃-C₆cycloalkyl.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇, R₁₁and R₁₂are each hydrogen.
In a preferred embodiment, X is H and R₁, R₂, R₃, R₄, R₆and R₇are hydrogen. In yet another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇and R₁₁are hydrogen and R₁₂is selected from phenyl or methyl.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula IIIa, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl; and
R₆, R₇, R₁₁and R₁₂are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In yet another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇, R₁₁and R₁₂are each hydrogen.
In a preferred embodiment, X is H and R₁, R₂, R₃, R₄, R₆and R₇are hydrogen. In yet another another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇and R₁₁are hydrogen and R₁₂is selected from phenyl or methyl.
In exemplary embodiments, a compound is selected from the following:
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula IV, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆, R₇, R₁₁, R₁₂R₁₃and R₁₄are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl and aryl; R₆and R₇, R₁₁and R₁₂, R₁₃and R₁₄, R₆or R₇and R₁₁or R₁₂, R₆or R₇and R₁₃or R₁₄, R₁₁or R₁₂and R₁₃or R₁₄may also come together to form a C₃-C₆cycloalkyl; and
R₁₅and R₁₆are each hydrogen or come together to form a ring.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In still another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃and R₁₄are each hydrogen.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅and R₁₆are hydrogen. In yet another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₃and R₁₄are hydrogen; R₁₂is methyl; and R₁₅-R₁₆form a dioxolane.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula IVa, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆, R₇, R₁₁, R₁₂, R₁₃and R₁₄are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; and
R₁₅and R₁₆are each hydrogen or come together to form a ring.
In a particular embodiment, X is H. In another particular embodiment, R₁, R₂, R₃and R₄are hydrogen. In still another particular embodiment, R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃and R₁₄are each hydrogen.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅and R₁₆are hydrogen. In yet another another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₃and R₁₄are hydrogen; R₁₂is methyl; and R₁₅-R₁₆form a dioxolane.
In exemplary embodiments, a compound is selected from the following:
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula V, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl; and
R₁₀can be at one or more positions on the ring, and at each occurrence is independently selected from the group consisting of hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl.
In a preferred embodiment, X is H; R₁, R₂, R₃, and R₄are hydrogen; and R₁₀is selected from hydrogen, C₁-C₄alkyl and mono-, di- or trihalomethyl. In a more specific embodiment, R₁₀is hydrogen. In an alternative specific embodiment, R₁₀is methyl. In yet another alternative specific embodiment, R₁₀is trifluoromethyl.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula Va, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl; and
R₁₀can be at one or more positions on the ring, and at each occurrence is independently selected from from the group consisting of hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy; aryl; alkoxy; arylalkoxy and —NHC(O)R, wherein R is C₁-C₄alkyl.
In a preferred embodiment, X is H; R₁, R₂, R₃, and R₄are hydrogen; and R₁₀is selected from hydrogen, C₁-C₄alkyl and mono-, di- or trihalomethyl. In a more specific embodiment, R₁₀is hydrogen. In an alternative specific embodiment, R₁₀is methyl. In yet another alternative specific embodiment, R₁₀is trifluoromethyl.
In exemplary embodiments, a compound is selected from the following:
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula VI, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
Y is (CR₆R₇)_n, wherein n is from 0-3, and R₆and R₇are independently selected from hydrogen; C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl
Het is a heterocycle. Het may be connected to the R₆/R₇carbon at any position of the heterocycle, provided it provides proper valency. In particular embodiments, the heterocycle is aromatic. Examples of heteroaromatics include, but are not limited to indole; 1H-pyrazole; benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole 2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇, are hydrogen, and Het is selected from the group consisting of 1H-pyrazole; benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole 2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula Via, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆and R₇are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; and Het is a heterocycle. Het may be connected to the R₆/R₇carbon at any position of the heterocycle, provided it provides proper valency. In particular embodiments, the heterocycle is aromatic. Exemplary heteroaromatics include, but are not limited to indole; 1H-pyrazole; benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole 2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇, are hydrogen, and Het is selected from the group consisting of 1H-pyrazole; benzothiazole; 5-chloro-1,3-dimethyl-1H-pyrazole; 4H-chromen-4-one; 1H-indazole; 3-(thiophen-2-yl)-1H-pyrazole; 3-phenyl-1H-pyrazole; 6-(p-tolyl)imidazo[2,1-b]thiazole 2-phenylthiazole and 3,5-dimethyl-1-phenyl-1H-pyrazole.
In exemplary embodiments, a compound is selected from the following:
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula VII, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;
Z is selected from hydrogen and fluoro.
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆and R₇are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; and
R₁₇and R₁₈are selected from C₁-C₄alkyl or come together to form a 5-10 membered cycloalkane, which can optionally be further substituted with C₁-C₈alkyl or cycloalkyl.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇are hydrogen, and R₁₇and R₁₈are methyl. In another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇are hydrogen, and R₁₇and R₁₈come together to form a 6, 7 or 8 membered cycloalkane, which is further substituted with C₁-C₈alkyl or cycloalkyl.
In another embodiment, the invention provides COMT-inhibiting compounds in accordance with formula Vila, or pharmaceutically acceptable salts thereof:
wherein:
X is selected from hydrogen; chloride; bromide and cyclopropyl;
R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;
R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;
R₆and R₇are each independently selected from hydrogen; C₁-C₄alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono-, di-, or trihaloalkyl; and aryl; and
R₁₇and R₁₈are selected from C₁-C₄alkyl or come together to form a 5-10 membered cycloalkane, which can optionally be further substituted with C₁-C₈alkyl or cycloalkyl.
In a preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇are hydrogen, and R₁₇and R₁₈are methyl. In another preferred embodiment, X is H; R₁, R₂, R₃, R₄, R₆and R₇are hydrogen, and R₁₇and R₁₈come together to form a 6, 7 or 8 membered cycloalkane, which is further substituted with C₁-C₈alkyl or cycloalkyl.
In exemplary embodiments, a compound is selected from the following:
In particular embodiments, COMT-inhibiting compounds of the present invention are selected from the following:

2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[4-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(4-fluorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[2-(benzotriazol-1-yl)ethyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[2-(benzotriazol-2-yl)ethyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-tert-butylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,4-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[4-(propan-2-yl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[4-(pyridin-3-yl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(4-ethylphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile
2-(4-ethyl-3-nitrobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-ethylbutyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(3,5-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(cyclohexylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-cyclopropylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(cyclooctylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,5-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-{[1-(phenylsulfonyl)-1H-indol-2-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(3-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(3,5-difluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-methylbenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[(5-phenyl-1H-pyrazol-3-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-{[6-chloro-4-(1H-imidazol-4-yl)-3,4-dihydro-2H-chromen-8-yl]methyl}-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,3-dimethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(1,3-benzothiazol-2-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[(4-oxo-4H-chromen-3-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1H-indazol-3-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-{[3-(thiophen-2-yl)-1H-pyrazol-4-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[(3-phenyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dimethoxybenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(4-phenoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[3-(1,3-benzodioxol-5-yl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[4-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[3-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,1,3-benzothiadiazol-5-ylmethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[2-(benzyloxy)benzyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-{[6-(4-methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]methyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-chloro-4-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-difluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(4-bromo-2-chloro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chloro-4-cyclopropyl-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chlorophenyl)methyl]-7-hydroxy-3,3-dimethyl-1,4-dihydropyrido[1,2-a]pyrazin-8-one
2-[(2,4-dichloro-5-nitro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[1-(2-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(4-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2,5-dichlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-{1-[4-(trifluoromethyl)phenyl]ethyl}-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[1-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(3-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-chloro-2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2,6-dimethoxyphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[1-(2,3,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2-chlorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-{1-[2-(benzyloxy)phenyl]ethyl}-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylpentyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-phenyl-3,4-dihydro-2H-chromen-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(3-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[cyclopentyl(phenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[1-(3-methoxyphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,3-dihydro-1H-inden-1-yl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(3-chloro-2,6-difluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2,5-dimethylphenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(1,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylpropyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylbutyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
4-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]benzonitrile
3-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]benzonitrile
N-{3-[1-(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl]phenyl}acetamide
2-[1-(2,5-difluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[1-(4-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-hydroxy-1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2,2,2-trifluoro-1-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(1-phenylcyclopropyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-(2-fluoro-1-phenyl-ethyl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-(2,2-difluoro-1-phenyl-ethyl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-(1,3-benzothiazol-2-yl)-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(2-phenylcyclopropyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(5-quinolyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(3-phenyloxetan-3-yl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-(3-methylphenyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-2-[2-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
1,2-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-benzyl-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dichlorobenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
(1R)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
(1S)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dimethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
1-(4-fluorophenyl)-7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-(4-ethylbenzyl)-7-hydroxy-1-[3-(pyridin-3-yl)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-benzyl-7-hydroxy-3-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2,3-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
3-benzyl-2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
7-hydroxy-3-methyl-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-benzyl-7-hydroxy-3-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
2-benzyl-7-hydroxy-3-(2-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
9-chloro-2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
6-fluoro-7-hydroxy-2-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chlorophenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
9-chloro-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
9-chloro-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
9-bromo-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one
9-bromo-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
2-[(2-chlorophenyl)methyl]-7-hydroxy-9-iodo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one
9-cyclopropyl-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one and
2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one.

In some embodiments, the present invention provides prodrugs of the compounds described herein. The term “prodrug” refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated or dephosphorylated to produce the active compounds.
Prodrugs may be prepared by any variety of synthetic methods or appropriate adaptations presented in the chemical literature or as in synthetic or organic chemistry text books, such as those provide in Green's Protective Groups in Organic Synthesis, Wiley, 4^thEdition (2007) Peter G. M. Wuts and Theodora W. Green; March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith and Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze, hereby incorporated by reference. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association), also hereby incorporated by reference.
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds disclosed herein with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
Some non-limiting examples of prodrugs in accordance with the invention include: (i) where the exemplary compound contains a carboxylic acid functionality which is functionalized into a suitably metabolically labile group (esters, carbamates, etc.); (ii) where the exemplary compound contains an alcohol functionality which is functionalized into a suitably metabolically labile group (ethers, esters, carbamates, acetals, ketals, etc.); and (iii) where the exemplary compound contains a primary or secondary amino functionality, or an amide which are functionalized into a suitably metabolically labile group, e.g., a hydrolysable group (amides, carbamates, ureas, phosphonates, sulfonates, etc.). Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

IV. Indications

As discussed above, the COMT-inhibiting compounds of the present invention can be used for treating neuropsychiatric and neurological diseases for which inhibiting COMT provides a therapeutic benefit.
Significant psychiatric indications, as discussed above, include, but are not limited to ADHD, obsessive-compulsive disorder, alcoholism and other addictions, depression, bipolar disorder, age-associated cognitive symptoms, impulse control disorders, including compulsive gambling, sexual behavior, and other compulsive destructive behaviors, in particular, schizophrenia.
Among the preferred neurological diseases is treating Parkinson's disease, preferably when co-administered with L-DOPA, with or without an aromatic L-amino acid decarboxylase inhibitor (AADC) such as carbidopa, by preventing COMT-mediated metabolism of L-DOPA.
In one embodiment, a method for treating conditions in which inhibition of COMT enzyme is beneficial comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for use in the present methods. Such conditions include, but are not limited to, those provided in WO 2011/109254, the contents of which are incorporated herein by reference.
In a specific embodiment, a method for treating schizophrenia or psychosis comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for use in the present methods. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington, D.C.) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, conditions or diseases such as schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic, undifferentiated, or residual type), schizophreniform disorder, schizoaffective disorder, for example of the delusional type or the depressive type, delusional disorder, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine, ketamine and other dissociative anaesthetics, and other psychostimulants), psychosis/psychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, “schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, personality disorder of the paranoid type, personality disorder of the schizoid type, illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses.
In another specific embodiment, a method for treating cognitive disorders comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for use in the present methods. The DSM-IV-TR also provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline. As used herein, the term “cognitive disorders” includes the diagnosis and classification of these disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, disorders that comprise as a symptom a deficiency in attention and/or cognition, such as dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebral trauma, vascular problems or stroke, alcoholic dementia or other drug-related dementia, AIDS, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse), mild cognitive impairment, multi-infarct dementia, Lewy body dementia, AIDS-related dementia, and frontotemporal dementia, delirium, amnestic disorders or age related cognitive decline.
In another specific embodiment, a method for treating anxiety disorders comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for use in the present methods. The DSM-IV-TR also provides a diagnostic tool that includes anxiety disorders as generalized anxiety disorder, obsessive-compulsive disorder and panic attack. As used herein, the term “anxiety disorders” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, anxiety disorders such as, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition.
In another specific embodiment, a method for treating substance-related disorders and addictive behaviors comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for use in the present methods. The DSM-IV-TR also provides a diagnostic tool that includes persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse, and tolerance of, dependence on or withdrawal from substances of abuse. As used herein, the term “substance-related disorders and addictive behaviors” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, substance-related disorders and addictive behaviors, such as substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder, drug addiction, tolerance, and dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics.
In another specific embodiment, a method for treating obesity or eating disorders associated with excessive food intake, and complications associated therewith, comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for use in the present methods. At present, obesity is included in the tenth edition of the International Classification of Diseases and Related Health Problems (ICD-10) (1992 World Health Organization) as a general medical condition. The DSM-IV-TR also provides a diagnostic tool that includes obesity in the presence of psychological factors affecting medical condition. As used herein, the term “obesity or eating disorders associated with excessive food intake” includes the diagnosis and classification of these medical conditions and disorders described in ICD-10 and DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, obesity, bulimia nervosa and compulsive eating disorders.
In another specific embodiment, a method for treating mood and depressive disorders comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for use in the present methods. As used herein, the term “mood and depressive disorders” includes the diagnosis and classification of these medical conditions and disorders described in the DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, bipolar disorders, mood disorders including depressive disorders, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features, a depressive episode with melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression; major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders.
In another specific embodiment, a method for treating pain comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for use in the present methods. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain.
In other specific embodiments, the COMT-inhibiting compounds described hereinabove for use in the present methods can be used to treat other types of cognitive, learning and mental related disorders including, but not limited to, learning disorders, such as a reading disorder, a mathematics disorder, or a disorder of written expression, attention-deficit/hyperactivity disorder, age-related cognitive decline, pervasive developmental disorder including autistic disorder, attention disorders such as attention-deficit hyperactivity disorder (ADHD) and conduct disorder; an NMDA receptor-related disorder, such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury; a neurodegenerative disorder or condition, such as neurodegeneration associated with traumatic brain injury, stroke, cerebral infarct, epileptic seizure, neurotoxin poisoning, or hypoglycemia-induced neurodegeneration; multi-system atrophy; movement disorders, such as akinesias and akinetic-rigid syndromes (including, Parkinson's disease, drug-induced parkinsonism, post-encephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication-induced parkinsonism (such as, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Huntington's disease, dyskinesia associated with dopamine agonist therapy, Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias, including tremor (such as, rest tremor, postural tremor, intention tremor and essential tremor), restless leg syndrome, chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballismus), myoclonus (including, generalised myoclonus and focal myoclonus), tics (including, simple tics, complex tics and symptomatic tics), dystonia (including, generalised, idiopathic, drug-induced, symptomatic, paroxysmal, and focal (such as blepharospasm, oromandibular, spasmodic, spasmodic torticollis, axial dystonia, hemiplegic and dystonic writer's cramp)); urinary incontinence; neuronal damage (including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema); emesis; and sleep disorders, including insomnia and narcolepsy.
Of the disorders above, the treatment of schizophrenia, bipolar disorder, depression, including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning disorders, pervasive developmental disorders, including autistic disorder, attention disorders including Attention-Deficit Hyperactivity Disorder, autism, tic disorders including Tourette's disorder, anxiety disorders including phobia and post-traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance.
In particularly desirable embodiments, the COMT-inhibiting compounds, including the compounds of the present invention, are useful for treating Alzheimer's disease. Accordingly, a method for treating Alzheimer's disease comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for the present methods.
In other particularly desirable embodiments, the COMT-inhibiting compounds, including the compounds of the present invention, are useful for treating Parkinson's disease. Accordingly, a method for treating Parkinson's disease comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for the present methods.
In yet other particularly desirable embodiments, the COMT-inhibiting compounds, including the compounds of the present invention, are useful for treating mild cognitive impairment. Accordingly, a method for treating mild cognitive impairment comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for the present methods.
In still other particularly desirable embodiments, the COMT-inhibiting compounds, including the compounds of the present invention, are useful for treating cognitive, learning and mental related disorders in patients with neurodegeneration associated with traumatic brain injury. Accordingly, a method for treating cognitive, learning and mental related disorders in patients with neurodegeneration associated with traumatic brain injury comprises administering a COMT-inhibiting compound described hereinabove for the present methods.
In further particularly desirable embodiments, the COMT-inhibiting compounds, including the compounds of the present invention, are useful for treating schizophrenia. Accordingly, a method for treating schizophrenia comprises administering to a patient in need thereof a COMT-inhibiting compound described hereinabove for the present methods.
The subject COMT-inhibiting compounds, including the compounds of the present invention, are useful in methods for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.

V. Combination Therapies

The subject COMT-inhibiting compounds, including the compounds of the present invention, are further useful in a method for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other agents. In many instances, the combination of the drugs together is safer or more effective than either drug alone; the compounds of the present invention and the other active ingredients may often be used in lower doses than when each is used singly. The drug(s) in the combination may be administered contemporaneously or sequentially (i.e. one preceding or following the other, at any appropriate time interval). When administered contemporaneously, the drugs may be administered separately, or a single dosage form may contain both active agents.
Accordingly, the subject compounds may be used in combination with other agents which are known to be beneficial in the subject indications, or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention. It will be appreciated that any of the drugs listed herein may be in the form of a pharmaceutically acceptable salt.
In a particularly preferred embodiment, the subject compound is employed in combination with levodopa, with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide. In other embodiments, the COMT inhibitor of the invention is administered in combination with anticholinergics such as biperiden and trihexyphenidyl (benzhexol) hydrochloride, other COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.
In another embodiment, the subject compound may be employed in combination with a neuroleptic or antipsychotic agent, or pharmaceutically acceptable salts thereof. Classes of neuroleptic agents include phenothiazines; thioxanthenes; heterocyclic dibenzazepines; butyrophenones; diphenylbutylpiperidines; indolones, such as acepromazine, amisulpride, amoxapine, aripiprazole, asenapine, benperidol, bifeprunox, blonanserin, brexpiprazole, bromperidol, bupropion, busprione, capuride, cariprazine, carpipramine, chlorpromazine, chlorprothixene, clocapramine, clopenthixol, cloperidone, clotiapine, clozapine, cyamemazine, dexclamol, divalproex, dixyrazine, droperidol, flupentixol tiotixene, flupentixol, fluphenazine, fluphenazine, fluspirilene, haloperidol, hydroxyzine, iloperidone, levomepromazine, loxapine, lurasidone, melperone, mesoridazine, molindone, moperone, mosapramine, nefazodone, nemonapride, olanzapine, paliperidone, penfluridol, perazine, pericyazine, perlapine, perospirone, perphenazine, perphenazine, phenelzine, pimavanserin, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, quetiapine, remoxipride, risperidone, roletamide, sertindole, sulpiride, sultopride, thioproperazine, thioridazine, thiothixene, timiperone, tranylcypromaine, trazodone, trepipam, trifluoperazine, triflupromazine, trimipramine, veralipride, zicronapine, ziprasidone, zotepine, or zuclopenthixol.
In one embodiment, the subject compound may be employed in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, and anti-amyloid antibodies.
In another embodiment, the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clonazepam, clorazepate, chlordiazepoxide, clorethate, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flupentixol, fiurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, phenelzine, phenobarbital, prazepam, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, or zolpidem.
In another embodiment, the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, β-adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide; venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

VI. Formulation and Administration

The invention provides a method for administering a COMT inhibiting compound as provided herein to a patient suffering from a condition, or prone to a condition, that is responsive to treatment or prevention with the compound. The method comprises administering, e.g. orally or parenterally, a therapeutically effective amount of the compound, preferably provided as part of a pharmaceutical preparation.
In some embodiments, a prodrug of the COMT inhibiting compound is administered.
The invention also provides pharmaceutical preparations comprising a COMT-inhibiting compound as provided herein in combination with a pharmaceutical excipient.
Modes of administration include administration by injection, e.g. parenteral, intravenous, intraarterial, intramuscular, subcutaneous, and intrathecal, as well as pulmonary, rectal, transdermal, transmucosal, and oral delivery.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, or other bovine, ovine, equine, canine, feline, or rodent, such as mouse, species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
Suitable formulation types for parenteral administration include ready-for-injection solutions, dry powders for combination with a solvent prior to use, suspensions ready for injection, dry insoluble compositions for combination with a vehicle prior to use, emulsions and liquid concentrates for dilution prior to administration.
The pharmaceutical carrier(s) employed may be solid or liquid. Liquid carriers can be used in the preparation of solutions, emulsions, suspensions and pressurized compositions. The compounds are dissolved or suspended in a pharmaceutically acceptable liquid excipient. Suitable examples of liquid carriers for parenteral administration include, but are not limited to, water (which may contain additives, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), phosphate buffered saline solution (PBS), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). The liquid carrier can contain other suitable pharmaceutical additives including, but not limited to, the following: solubilizers, suspending agents, emulsifiers, buffers, thickening agents, colors, viscosity regulators, preservatives, stabilizers and osmolarity regulators.
Exemplary excipients include, without limitation, carbohydrates, inorganic salts, antimicrobial agents, antioxidants, surfactants, buffers, acids, bases, and combinations thereof. A carbohydrate such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer may be present as an excipient. Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.
The excipient can also include an inorganic salt or buffer including, but not limited to, citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.
A surfactant may be present as an excipient. Exemplary surfactants include, but are not limited to, polysorbates such as Tween 20 and Tween 80 and pluronics such as F68 and F88 (both available from BASF, Mount Olive, N.J.); sorbitan esters; lipids, such as phospholipids such as lecithin and other phosphatidyl cholines, phosphatidyl ethanolamines (although preferably not in liposomal form), and fatty acids and fatty esters.
Acids or bases may be present as an excipient in the preparation. Nonlimiting examples of acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Examples of suitable bases include, without limitation, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.
For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile carriers are useful in sterile liquid form compositions for parenteral administration. Sterile liquid pharmaceutical compositions, solutions or suspensions can be utilized by, for example, intraperitoneal injection, subcutaneous injection, intravenously, or topically. The compositions can also be administered intravascularly or via a vascular stent.
For pressurized compositions, the liquid carrier can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. Such pressurized compositions may also be lipid encapsulated for delivery via inhalation. For administration by intranasal or intrabronchial inhalation or insufflation, the compositions may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
The compositions may be administered topically, as a solution, cream, or lotion, by formulation with pharmaceutically acceptable vehicles containing the active compound. The compositions can be in a form suitable for use in transdermal devices.
The compositions of this invention may be orally administered, in formulations such as capsules, tablets, powders or granules, or as suspensions or solutions in water or non-aqueous media. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
The amount of the compound in the composition will vary depending on a number of factors, but will optimally be a therapeutically effective dose when the composition is stored in a unit dose container (e.g., a vial). In addition, the pharmaceutical preparation can be housed in a syringe. A therapeutically effective dose can be determined experimentally by repeated administration of increasing amounts of the COMT-inhibiting compound in order to determine which amount produces a clinically desired endpoint.
The amount of any individual excipient in the composition will vary depending on the activity of the excipient and particular needs of the composition. Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then further exploring the range at which optimal performance is attained with no significant adverse effects. Generally, however, the excipient will be present in the composition in an amount of about 1% to about 99% by weight, preferably from about 5%-98% by weight, more preferably from about 15-95% by weight of the excipient, with concentrations less than 30% by weight most preferred.
The foregoing pharmaceutical excipients, along with other excipients, are described in “Remington: The Science & Practice of Pharmacy”, 21st ed., Williams & Williams, (2005), the “Physician's Desk Reference”, 67th ed., PDR Network, Montvale, N.J. (2013), and Kibbe, A. H., “Handbook of Pharmaceutical Excipients”, 7th Edition, Pharmaceutical Press, Washington, D.C., 2012.
The dose of the compounds according to the invention to be administered, both unit dosage and dosing schedule, will vary depend upon the age, weight, and general condition of the subject, as well as the desired therapeutic effect, the route of administration, and the duration of the treatment. The compounds of the invention are administered to the patient in therapeutically effective amounts. Methods are known to those skilled in the art to adjust the dose to obtain maximal benefit. Generally, dosage levels of between 0.001 to 10 mg/kg of body weight daily are administered to the patient. The dosage range will generally be about 0.5 mg to 1.0 g per patient per day, which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; and in yet another embodiment about 5 mg to 50 mg per patient per day. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
These and other aspects of the invention will be realized upon closer inspection of the specification as a whole.

EXAMPLES

The present compounds can be prepared and evaluated according to procedures provided in the following Examples. The following Examples further describe, but do not limit, the scope of the invention.
COMT Inhibition Assay Procedure
The ability of compounds to inhibit the activity of catechol-O-methyltransferase (COMT) was determined by a homogenous time-resolved fluorescent (HTRF) assay (Lina et al, 2012; kit from CisBio, Codolet, France). This assay measures the production of S-adenosyl homocysteine (SAH) from the methyl donor S-adenosyl methionine. Recombinant human membrane bound COMT (MB-COMT; M51A variant) was expressed in HEK 293F cells using 293Fectin (Life Technologies, Gent, Belgium) and membranes prepared. The membranes were re-suspended in buffer (20 mM Tris/HCl pH 7; 10 mM glycerol; 2 mM MgCl₂; 10 mM NaCl), aliquoted and stored at −80° C.
Recombinant human soluble COMT(S-COMT), Val58 variant and a hexa-His tag on the N-terminus, was purified using Ni-NTA chromatography, the His tag removed and stored in buffer as above.
For the human MB-COMT assay, membranes (62 ng/well) were incubated with SAM (20 μM final, CisBio) and dopamine (1.5 μM final; Sigma H8502, Diegem, Belgium) in the presence or absence of varying concentrations (typically 10 concentrations ranging from 10
M to 0.1 nM) of compound for 40 min at 37° C. in 384-well microtiter plates (10
l per well final volume). The reaction was terminated by the addition of acylation buffer and the amount of SAH produced determined according to manufacturer's instructions. Specific inhibition as that inhibited by a high concentration of tolcapone and all experiments were validated using a control curve to tolcapone.
The human S-COMT assay was performed as above except that 0.15 ng enzyme/well was incubated with SAM (20 μM final) and dopamine (100 μM final) for 15 min at 37° C. and SAH production determined.
HTRF readings were performed using a Perkin Elmer Envision and results expressed as concentration of SAH produced using a standard curve. Results were analyzed using non-linear regression to the 4-parameter logistic equation and pIC50 (−log 10 concentration of drug which inhibits enzyme activity/SAH production by 50%) determined.
As the data herein indicate, a broad variety of compounds of formula I were found effective as COMT inhibitors at low concentrations. pIC₅₀values for exemplary compounds of formula I (see below for compound names and structures) are provided in Table 1 below. Any compound with a pIC₅₀superior or equal to 4.5 in this assay, as described above, is deemed a COMT inhibitor. In the Table 1 below, a single plus (+) is associated with a pIC₅₀of from about 4.5 to 6; two plus signs (++) is associated with a pIC₅₀of from about 6 to 7; and three plus signs (+++) is associated with a pIC₅₀of above about 7.

	TABLE 1

	Example	Activity range

	1	++
	2	++
	3	+
	4	+
	5	+
	6	+++
	7	+++
	8	+++
	9	+++
	10	+++
	11	++
	12	++
	13	+++
	14	+++
	15	++
	16	+++
	17	++
	18	+++
	19	++
	20	++
	21	+++
	22	++
	23	+++
	24	+++
	25	+++
	26	++
	27	+++
	28	+++
	29	+++
	30	++
	31	++
	32	++
	33	+++
	34	++
	35	++
	36	+++
	37	+++
	38	++
	39	+++
	40	++
	41	++
	42	++
	43	++
	44	+++
	45	++
	46	++
	47	+++
	48	++
	49	++
	50	++
	51	++
	52	+++
	53	+++
	54	++
	55	++
	56	++
	57	+++
	58	+++
	59	+++
	60	+++
	61	+++
	62	+++
	63	+++
	64	+++
	65	++
	66	+++
	67	+++
	68	++
	69	+++
	70	++
	71	++
	72	++
	73	+++
	74	++
	75	+++
	76	+++
	77	+++
	78	+++
	79	+++
	80	++
	81	++
	82	+++
	83	++
	84	++
	85	+++
	86	+++
	87	+++
	88	+++
	89	++
	90	+++
	91	+++
	92	+++
	93	++
	94	++
	95	++
	96	++
	97	+++
	98	++
	99	++
	100	+
	101	+++
	102	++
	103	++
	104	+++
	105	+++
	106	+++
	107	+++
	108	++
	109	++
	110	+
	111	++
	112	+++
	113	++
	114	++
	115	++
	116	+++
	117	+++
	118	+++
	119	+++
	120	+++
	121	+++
	122	+++
	123	+++
	124	+++
	125	+++
	126	+++
	127	+++
	128	++
	129	++
	130	++
	131	++
	132	+++
	133	+++
	134	++
	135	++
	136	+++
	137	+++
	138	+++
	139	+++
	140	+
	141	++
	142	+++

Synthetic Procedures
Exemplary compounds were prepared via several general synthetic routes set forth in the Examples below. Any of the disclosed compounds of the present invention can be prepared according to one or more of these synthetic routes or specific examples, or via modifications thereof accessible to the person of ordinary skill in the art.

Intermediate 1: 7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step1: Preparation of 1-(2-aminoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

Ethylenediamine (45.3 g, 754 mmol, 50.9 mL) was added to a suspension of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (35 g, 151 mmol) in ethanol (350 mL). The mixture was heated at 90° C. for 1.5 h. The reaction mixture was concentrated to yield the title intermediate as a brown viscous oil (46.4 g, quant.) used as such in the next experiment without further purification. MS, ES⁺ m/z 275.2 [M+H]⁺.

Method A

Step 2a: Preparation of 7-benzyloxy-3,4-dihydropyrido[1,2-a]pyrazin-8-one

1-(2-aminoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one (49 g, 179 mmol) was dissolved in CHCl₃(400 mL) and MnO₂(78 g, 893 mmol) was added to the mixture and heated overnight at 60° C. The reaction mixture was filtered and the residue was concentrated to yield the title intermediate used in the next step without further purification. MS, ES⁺ m/z 255.5 [M+H]⁺.

Step 2b: Preparation of 7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

7-benzyloxy-3,4-dihydropyrido[1,2-a]pyrazin-8-one (46.4 g, 182 mmol) was dissolved in MeOH (500 mL). NaBH4 (20.71 g, 547 mmol) was added portionwise to the mixture and the mixture was stirred over 48 h at rt. The reaction mixture was then concentrated to give a residue (10 g) that was purified by chromatography (SiO₂, DCM:MeOH:NH₃(7 N) (90:9:1) to yield the title intermediate as a yellow solid (23.4 g, 50%). MS, ES⁺ m/z 257.2 [M+H]⁺.
¹H-NMR (300 MHz, DMSO-d₆)
7.45-7.22 (m, 6H), 5.90 (s, 1H), 4.96 (s, 2H), 3.74 (t, J=5.6 Hz, 2H), 3.70 (br. s., 2H), 3.00 (t, J=5.6 Hz, 2H), 2.57 (br. s., 1H), 1H-NMR (300 MHz, MeOD)
7.48-7.42 (m, 3H), 7.38-7.26 (m, 3H), 6.25 (s, 1H), 5.06 (s, 1H), 3.97-3.81 (m, 4H), 3.28 (t, J=5.6 Hz, 2H).

Intermediate 2: 7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)-4Hpyran-4-one

To a suspension of Kojic acid (25.4 g, 179 mmol) in anhydrous DMF (450 mL) was added potassium carbonate (29.6 g, 214 mmol) and alpha-chloro-4-methoxytoluene (30.8 g, 197 mmol, 26.7 mL) and the resulting suspension was stirred at 80° C. for 4 h. The reaction mixture was evaporated in vacuo (oil pump, high vacuum) and water (500 mL) was added. The resulting suspension was stirred for 30 minutes. The solids were filtered off and dried under air current for 30 minutes, then triturated from heptane:diethyl ether (1:1, 300 mL) and dried in a vacuum oven (40° C.) overnight to yield 38.44 g of the title intermediate as a brown solid used in the next step without any further purification.

Step 2: Preparation of 1-(2-aminoethyl)-2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)pyridin-4(1H)-one

Ethylenediamine (38.2 g, 635 mmol, 42.9 mL) was added to a suspension of 2-hydroxymethyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (33.3 g, 127 mmol) in Ethanol (400 mL). The reaction mixture was stirred for 4 h at 90° C. and then stirred overnight at rt. The reaction mixture was concentrated to yield the title intermediate (50.3 g) as a brown viscous oil used in the next step without any further purification. MS, ES⁺ m/z 305.2 [M+H]⁺.

Step 3: Preparation of 7-((4-methoxybenzyl)oxy)-3H-pyrido[1,2-a]pyrazin-8(4H)-one

1-(2-aminoethyl)-2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)pyridin-4(1H)-one (38.6 g, 127 mmol) was dissolved in chloroform (400 mL) and stirred for a few minutes. MnO₂(55.1 g, 634 mmol) was added to the mixture was stirred at 60° C. overnight. The reaction mixture was filtered and the residue was concentrated to yield the title intermediate (47.5 g). MS, ES⁺ m/z 285.2 [M+H]⁺.

Step 4: Preparation of 7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

To a cooled (ice bath) solution of 7-[(4-methoxyphenyl)methoxy]-3,4-dihydropyrido[1,2-a]pyrazin-8-one (5.0 g, 17.59 mmol) in MeOH (100 mL) was added NaBH₄(672 mg, 1 eq.) and the resulting mixture was stirred at rt for 14 h. The reaction mixture was filtered on a bed of celite/silicagel/celite and rinsed with MeOH (3×10 mL). The solvent was evaporated to give a pale yellow solid (6.1 g). This solid was then dissolved in a DCM/MeOH (9:1). The mixture was then washed with an aq. saturated solution of NaCl. The organic layers were dried on MgSO₄and concentrated under vacuum to yield the title intermediate as a yellow solid (4.6 g, 90%). MS, ES⁺ m/z 287.2 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d₆)
7.35 (s, 1H), 7.31 (d, J=4.3 Hz, 2H), 6.91 (d, J=4.3 Hz, 2H), 5.88 (s, 1H), 4.89 (s 2H), 3.75-3.71 (m, 4H), 3.73 (s, 3H), 3.01 (t, J=5.9, 2H), 1H-NMR (300 MHz, MeOD) O 7.42 (s, 1H), 7.36 (d, J=4.3 Hz, 2H), 6.90 (d, J=4.3 Hz, 2H), 6.25 (s, 1H), 5.05 (s 2H), 3.97-3.92 (m, 4H), 3.78 (s, 3H), 3.19 (t, J=5.9, 2H).

Intermediate 3: 5-benzyloxy-1-(2-chloroethyl)-2-(chloromethyl)pyridin-4-one

Step 1: Preparation of 5-benzyloxy-1-(2-hydroxyethyl)-2-(hydroxymethyl)pyridin-4-one

To a suspension of 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (9.90 g, 42.7 mmol) in EtOH (20 mL) was added ethanolamine (3.0 mL, 49.2 mmol). The resulting mixture was stirred at reflux (bath oil heated at 110° C.) for 4.5 h and then at room temperature overnight. Ethanolamine (0.5 mL) was added and the mixture was stirred at reflux for another 1 h. The mixture was cooled to rt, then filtered. The collected solid was washed with Et₂O (3×15 mL) to yield the title intermediate as a beige solid (9.7 g, 83%). This intermediate is used in the next step without further purification. MS, ES⁺ m/z 275 [M+H]⁺.

Step 2: Preparation of 5-benzyloxy-1-(2-chloroethyl)-2-(chloromethyl)pyridin-4-one

Method B

A mixture of 5-benzyloxy-1-(2-hydroxyethyl)-2-(hydroxymethyl)pyridin-4-one (980 mg, 3.56 mmol) in CHCl₃(6 mL) with SOCl₂(2 mL) was stirred at 50° C. for 2 h. Evaporation of the solvents under vacuum (40° C. overnight) gave 1.1 g of a beige brown solid (quant.). MS, ES⁺ m/z 312 (M+H)⁺. This intermediate is used in the next step without further purification.

Intermediate 4: 5-benzyloxy-4-oxo-pyran-2-carbaldehyde

MnO₂(18.7 g, 216 mmol) was added to a suspension of 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (43.1 mmol, 10 g) in toluene (150 mL). The mixture was heated at 100° C. for 14 h. The mixture was cooled to rt, filtered on a bed of celite then concentrated to yield the title intermediate as a colorless oil (6.0 g, 60%). This intermediate is used in the next step without further purification

Intermediate 5: N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]methylene]-2-methyl-propane-2-sulfinamide

Step 1: Preparation of 5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(hydroxymethyl)pyridin-4-one

5-benzyloxy-2-(hydroxymethyl)pyran-4-one (55.2 g, 238 mmol) was suspended in water (180 ml). 2-[tert-butyl(dimethyl)silyl]oxyethanamine (50 g, 285 mmol) and an aq. solution of NaOH (23.8 ml, 23.8 mmol, 1N) was added and the mixture was stirred at 60° C. for 2 h, then an additional amount of 2-[tert-butyl(dimethyl)silyl]oxyethanamine (50 g, 285 mmol) was added and the mixture was stirred at 60° C. for 14 h. Water was added, the mixture decanted and iPrOH (100 mL) was added. Ether was added (100 mL), until a beige precipitate was formed. The precipitate was filtered off, washed with ether and dried. The mother liquor was concentrated and ether was added. The precipitate was filtered off, washed with ether and combined with the first batch to afford the title intermediate as an off-white solid (43.5 g). MS, ES⁺ m/z, 390.2 (M+H)⁺.

Step 2: Preparation of 5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-pyridine-2-carbaldehyde

5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(hydroxymethyl)pyridin-4-one (43.8 g, 112 mmol) was dissolved in DCM (700 ml). Dess-Martin periodinane (52.5 g, 124 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was washed with an aq. sat. solution of sodium bicarbonate (2×). The organic layer was dried with sodium sulfate and concentrated to afford a yellow solid (56.5 g). Purification by chromatography (SiO₂, gradient up to 5% MeOH in DCM) gave the title intermediate as a yellow oil (51 g). MS, ES⁺ m/z, 388.2 (M+H)⁺.

Step 3: Preparation of N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]methylene]-2-methyl-propane-2-sulfinamide

5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(hydroxymethyl)pyridin-4-one (51 g, 132 mmol) and 2-methylpropane-2-sulfinamide (19.14 g, 158 mmol) were dissolved in DCM (1 L). Titanium (IV) isopropoxide (46.3 mL, 158 mmol) was added and the mixture was stirred overnight. The reaction mixture was concentrated (87 g crude) and filtered over a plug of silica (10% MeOH in DCM) to afford the title intermediate as a yellow solid/oil (65.95 g, 95%). MS, ES⁺ m/z, 491.2 (M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆)
8.51 (s, 1H), 7.75 (s, 1H), 7.44-7.27 (m, 5H), 6.73 (s, 1H), 5.04 (s, 2H), 4.44-4.23 (m, 2H), 3.91-3.71 (m, 2H), 1.18 (s, 9H), 0.73 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H).

Intermediate 6: 7-benzyloxy-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of N-[1-[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide

N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]methylene]-2-methyl-propane-2-sulfinamide (Intermediate 5, 20 g, 40.8 mmol) was dissolved in THF (dry) (500 mL), the mixture was cooled to −15° C. under a nitrogen atmosphere. Methylmagnesium bromide (1 N in THF, 122 mmol, 122 mL) was added and the mixture was stirred 1 h and slowly warmed to 12° C. The mixture was added to aq. sat. solution of ammonium chloride, extracted with EtOAc. The combined organic layers were dried with Na₂SO₄filtered and concentrated under reduced pressure to give a white solid. Purification by chromatography (SiO₂, 5-10% MeOH in DCM) yielded the title intermediate (9.98 g, 48%). MS, ES⁺ m/z, 507.4 (M+H)⁺.

Step 2: Preparation of N-[1-[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide

N-[1-[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide (9.98 g, 19.69 mmol) was dissolved in anhydrous DMF (100 mL). Cesium fluoride (5.98 g, 39.4 mmol) was added to the stirred mixture and stirring was continued at room temperature for 20 h. The reaction mixture was added to a water/aq. sat. solution of NH₄Cl (1:1) and extracted with EtOAc. The organic phase was evaporated under vacuum. The remaining aqueous phase were evaporated to dryness under reduced pressure (0.5 Torr) and stripped with toluene (100 mL), affording a yellow oil batch combined with the evaporated organic phase. This material was taken up in DCM:MeOH (1:1) and filtered over SiO₂(eluting with DCM:MeOH (1:1)) to yield the title intermediate (6.86 g, 89%). MS, ES⁺ m/z, 393.2 (M+H)⁺.

Step 3: Preparation of 7-benzyloxy-2-tert-butylsulfinyl-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

A solution of N-[1-[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide (6.68 g, 17.02 mmol) and triphenylphosphine (4.46 g, 17.02 mmol) in anhydrous THF (100 mL) was cooled to 0° C. The reaction mixture was stirred and DIAD (4.16 g, 20.57 mmol, 4 mL) was added in 100 μL portions, until an orange color persisted. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was then cooled to 0° C. and another portion of triphenylphosphine (4 g, 15.25 mmol) and DIAD (4.16 g, 20.57 mmol, 4 ml) were added. Reaction mixture was stirred for 1 h while slowly warming to room temperature. The reaction mixture was evaporated to dryness to obtain a red oil (23.5 g). Material was taken up in 50 mL MeOH and purified by automated reversed phase chromatography (8 runs of 8 mL MeOH solution, 120 g C₁₈, water:CH3CN). The collected fractions were freeze-dried to yield the title intermediate (4.32 g, 68%). MS, ES⁺ m/z, 375.2 (M+H)⁺.

Step 4: Preparation of 7-benzyloxy-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

A solution of 7-benzyloxy-2-tert-butylsulfinyl-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (4.23 g, 11.30 mmol) in MeOH (50 mL) was cooled in an ice bath. A solution of HCl (4 N in dioxane, 13.55 mmol, 3.39 mL) was added dropwise and the stirring was continued for 15 min, while keeping the flask in the ice bath. Diethyl ether (50 mL) was added to the reaction mixture and the stirring continued for 30 minutes. The white precipitate was collected by filtration. The filtrates were then evaporated to dryness and the residue was combined with the collected solid. The material was taken up in MeOH:DCM (1:9, 50 mL). A solution of NH₃in MeOH (7 N, 2.3 mL) was added and hydromatrix (50 g) was added. The mixture was evaporated to dryness under reduced pressure and charged on a SiO₂column (100 g silica, DCM:MeOH (95:5)) until molybdate staining revealed no side products anymore. Subsequently, the product was eluted with DCM:MeOH:NH₃/MeOH (8:2:0.1) to give the title intermediate (1.95 g, 65%). MS, ES⁺ m/z, 271.2 (M+H)⁺. ¹H-NMR (300 MHz, MeOD)
7.46 (m, 3H), 7.38-7.24 (m, 3H), 6.62 (s, 1H), 5.09 (s, 2H), 4.12-3.95 (m, 3H), 3.36-3.31 (m, 1H, coincides with solvent residual peak), 3.23-3.14 (m, 1H), 1.49 (d, J=3.8 Hz).

Intermediate 7: 7-benzyloxy-1-tetrahydropyran-4-yl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide

Under nitrogen atmosphere, magnesium (6.05 g, 249 mmol) was suspended in THF (30 ml). A catalytic amount of iodine and dibromoethane (0.4 ml) were added. The mixture was heated to 60° C. and 4-chlorotetrahydro-2H-pyran (5 g, 41.5 mmol) in THF (5 ml) was added dropwise. The mixture was stirred at 60° C. for 2.5 h. The mixture was cooled to 0° C. and N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]methylene]-2-methyl-propane-2-sulfinamide (Intermediate 5, 6.78 g, 13.82 mmol) in THF (20 ml) was added. The resulting mixture was stirred at rt for 45 min. The reaction was quenched with ammonium chloride solution and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried with sodium sulfate and concentrated to afford the title intermediate as an orange gum (8.7 g). Purification by chromatography (SiO₂, 10% MeOH in DCM) gave the title intermediate as an orange oil (7.3 g, 56%). MS, ES⁺ m/z, 577 (M+H)⁺.

Step 2: Preparation of N-[[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide

N-[[5-benzyloxy-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide (7.3 g, 7.59 mmol) was dissolved in DMF (50 mL). Cesium fluoride (3.5 g, 22.78 mmol) was added and the mixture was stirred at rt for 3 h. Additional Cesium fluoride (5 g) was added and the mixture was stirred over the weekend at rt. The mixture was concentrated and stripped with toluene to afford a yellow oil (8.3 g). Purification by chromatography (SiO₂, 5% MeOH in DCM) afforded the title intermediate (2.12 g, 48%). MS, ES⁺ m/z, 463.2 (M+H)⁺.

Step 3: Preparation of 7-benzyloxy-2-tert-butylsulfinyl-1-tetrahydropyran-4-yl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-[[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide (2.1 g, 3.63 mmol) and triphenylphosphine (1.1 g, 4.19 mmol) were dissolved in THF (30 mL). The mixture was cooled to 0° C. and DIAD (0.8 ml, 4.11 mmol) was added until an orange color persisted. The mixture was allowed to reach rt and stirred overnight. Additional triphenylphosphine (1.1 g, 4.19 mmol) and DIAD (0.8 mL, 4.11 mmol) were added and the mixture was stirred at rt for 2 h. The mixture was concentrated to afford an orange oil. Purification by chromatography (SiO₂, 5% MeOH in DCM) afforded an orange gum (1.95 g, 90%). MS, ES⁺ m/z, 445.2 (M+H)⁺.

Step 4: Preparation of 7-benzyloxy-1-tetrahydropyran-4-yl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

N-[[5-benzyloxy-1-(2-hydroxyethyl)-4-oxo-2-pyridyl]-tetrahydropyran-4-yl-methyl]-2-methyl-propane-2-sulfinamide (1.95 g, 3.27 mmol) was dissolved in MeOH (4 mL). HCl (4 N in dioxane, 1.2 ml, 4.9 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was concentrated, dissolved in MeOH (4 mL)/7N ammonia in MeOH (2 ml) and stirred for 15 min.
The resulting mixture was coated onto silica and purified with flash column chromatography (7.5% MeOH in DCM) to afford the title intermediate as a white foam (492 mg, 42%). MS, ES⁺ m/z, 341.2 (M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆)
7.43-7.28 (m, 6H), 6.05 (s, 1H), 4.95 (s, 2H), 3.87-3.74 (m, 4H), 3.61 (d, J=2.7 Hz, 1H), 3.29-3.19 (m, 1H, overlap with solvent residual peak), 3.14-3.07 (m, 1H), 2.94-2.85 (m, 1H), 2.61 (bs, 1H), 2.04-1.90 (m, 1H), 1.50 (qd, J1=6.2 Hz, J2=2.1 Hz, 1H), 1.41-1.28 (m, 3H),

Intermediate 8: 7-benzyloxy-3-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 1-(2-amino-2-phenyl-ethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

Method C

1-phenyl-ethane-1,2-diamine (10.34 mmol, 1.482 g, 1.2 eq.) was added to a solution of 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (8.6 mmol, 2.0 g) in EtOH (15 mL) and the mixture was heated at 90° C. for 14 h. 1-phenyl-ethane-1,2-diamine (0.2 g) was added and the mixture was stirred for another 14 h. Water was added, then the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to give a residue (3.4 g). Purification by chromatography (gradient from 3% methanolic ammonia in DCM up to 10%) gave the title intermediate (1.33 g, 45%). MS, ES⁺ m/z, 351.3 (M+H)⁺.

Step 2: Preparation of 7-benzyloxy-3-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using 1-(2-amino-2-phenyl-ethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one as a yellow oil. (77%). MS, ES⁺ m/z, 333.3 (M+H)⁺.

Intermediate 9: 3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 1-(2-amino-3-phenyl-propyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

The title intermediate was prepared according to Method C using 3-phenylpropane-1,2-diamine, and isolated as a brown oil (used in the next step without purification). MS, ES⁺ m/z, 365.3 (M+H)⁺.

Step 2: Preparation of 3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using 3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one involving a purification of the crude product by chromatography (SiO₂, 7% methanolic ammonia in DCM) (45%). MS, ES⁺ m/z, 347.3 (M+H)⁺.

Intermediate 10: 7-benzyloxy-3-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 1-(2-aminopropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

The title intermediate was prepared according to Method C using 1,2-diaminopropane as a brown oil (56%). The crude product was purified by chromatography (SiO₂, DCM-MeOH—NH4OH 88-10.8-1.2). MS, ES⁺ m/z, 289.2 (M+H)⁺.

Step 2: Preparation of 7-benzyloxy-3-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using 1-(2-aminopropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one as a yellow solid (77%), used in the next step without any further purification.

Intermediate 11: 7-benzyloxy-3,3-dimethyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 1-(2-amino-2-methylpropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

The title intermediate was prepared according to Method C using 1,2-diamino-2-methylpropane. The crude product was purified by chromatography (SiO₂, 0-50% MeOH/DCM) to give 1-(2-amino-2-methylpropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one as a tan gum (27%). MS, ES⁺ m/z, 303.2 (M+H)⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.53 (s, 1H) 7.30-7.42 (m, 5H) 6.23 (s, 1H) 5.01 (s, 2H) 4.42 (s, 2H) 3.75 (s, 2H) 0.96 (s, 6H)

Step 2: Preparation of 7-benzyloxy-3,3-dimethyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using 1-(2-amino-2-methylpropyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one. The crude product was purified by chromatography (SiO₂, 0-50% MeOH/DCM) to give 7-benzyloxy-3,3-dimethyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one as a yellow solid (49%). MS, ES⁺ m/z, 285.2 (M+H)⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.30-7.44 (m, 6H) 5.98 (s, 1H) 4.97 (s, 2H) 3.75 (s, 2H) 3.58 (s, 2H) 1.06 (s, 6H).

Example 1: 2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method D

7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 1, 55 mg, 0.22 mmol) was dissolved in EtOH (1 mL). Benzyl bromide (30 μL, 0.25 mmol) and an aq. solution of NaOH (0.25 mL, 0.25 mmol, 1 N) were added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to rt, then extracted with DCM (10 mL). The combined org. layers were washed with an aq. sat. solution of NaCl, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, gradient up to 10% methanolic ammonia in DCM) to yield the title intermediate as a light yellow oil (62 mg, 83%). MS, ES⁺ m/z, 347.4 (M+H)⁺.

Step 2: Preparation of 2-benzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method E

2-benzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (99 mg, 0.27 mmol) was dissolved in an aq. solution of HCl (7 mL, 5 N) and heated 1 h at 100° C. The mixture was cooled to rt, then washed with CHCl₃(2×3 mL). The aq. phase was evaporated under vacuum to yield the title intermediate as a white solid (12 mg, 22%). High-Res MS, ES⁺ m/z, 257.1276 (M+H)+(obs.), 257.129 (M+H)⁺ (calc.).
The following compound 2 has been synthesized according to Methods D followed by Method E:

				Preparation
Example	Name	R	Analytical data	Information

2	7-hydroxy-2-[4- (trifluoromethyl) benzyl]-1,2,3,4- tetrahydro-8H- pyrido[1,2-a]pyrazin- 8-one	High-Res MS ES⁺, 325.1144 (M + H)⁺ (obs.), 325.1164 (M + H)⁺ (calc.)	Method D using 4- (trifluoromethyl)benzyl bromide, followed by Method E.

3	2-[(4- fluorophenyl)methyl]- 7-hydroxy-3,4- dihydro-1H- pyrido[1,2-a]pyrazin- 8-one	MS, ES⁺ m/z, 275.2 (M + H)⁺. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (s, 1 H) 7.44 (dd, J = 8.59, 5.81 Hz, 2 H) 7.17-7.27 (m, 2 H) 7.02 (s, 1 H) 4.38 (t, J = 5.43 Hz, 2 H) 3.93 (s, 2 H) 3.83 (s, 2 H) 3.03 (t, J = 5.31 Hz, 2 H)	Method D using 4- fluoromethylbenzyl bromide, followed by Method E.

4	2-[2-(benzotriazol-1- yl)ethyl]-7-hydroxy- 3,4-dihydro-1H- pyrido[1,2-a]pyrazin- 8-one	MS, ES⁺ m/z, 312.2 (M + H)⁺. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02- 8.08 (m, 2 H) 7.97 (d, 1 H) 7.53-7.59 (m, 1 H) 7.38-7.44 (m, 1 H) 7.09 (s, 1 H) 4.99 (t, 2 H) 4.30 (t, 2 H) 4.08 (br. s., 2 H) 3.20 (br. s., 2 H) 3.14 (br. s., 2 H)	Method D using 1-(2- bromoethyl)benzo- triazole, followed by Method E.

5	2-[2-(benzotriazol-2- yl)ethyl]-7-hydroxy- 3,4-dihydro-1H- pyrido[1,2-a]pyrazin- 8-one	MS, ES⁺ m/z, 312.2 (M + H)⁺. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (s, 1 H) 7.90-7.96 (m, 2 H) 7.42-7.47 (m, 2 H) 7.15 (s, 1 H) 5.06 (t, 2 H) 4.35 (d, 2 H) 4.15 (br. s., 2 H) 3.41 (br. s., 2 H) 3.18 (br. s., 2 H)	Method D using 2-(2- bromoethyl)benzo- triazole, followed by Method E.

Example 6: 7-hydroxy-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-2-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Method F

7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 1, 150 mg, 0.59 mmol), 3-(trifluoromethoxy)benzaldehyde (130 μL, 0.86 mmol), 4A molecular sieve (<5 μm, 72 mg), Si—BH₃CN (Silicycle, 1.81 g, 1.6 mmol, 0.89 mmol/g) in EtOH (4 mL, 68.5 mmol) were dispersed in THF (2 mL). The mixture was stirred for 1 h at 40° C. before addition of HOAc (0.5 mL, 9 mmol). The mixture was stirred again for an additional 2.5 h at 40° C. Filtration on a bed of Celite (rinse with EtOAc, 3×20 mL). The liquors were evaporated under vacuum to give a yellow oil (306 mg). Purification by column chromatography (SiO₂, gradient 5% methanolic ammonia in up to 10%) yielded the title intermediate as a white solid (87 mg, 35%). MS, ES⁺ m/z, 431.3 (M+H)⁺.

Step 2: Preparation of 7-hydroxy-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared using 7-benzyloxy-2-[[4-(trifuoromethyl)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one following to Method E, as a white solid (86%). High-Res MS, ES⁺, 341.1116 (M+H)⁺ (obs.), 341.1113 (M+H)⁺ (calc.).
The following compounds 4-17 have been synthesized according to Method F followed by Method E

				Preparation
Ex.	Name	R	Analytical data	Information

7	2-(4-tert- butylbenzyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 313.1917 (M + H)⁺(obs.), 313.1916 (M + H)⁺(calc.).	Method F using 4- tert- butylbenzaldehyde, followed by Method E

8	7-hydroxy-2-[4- (trifluorometh- oxy)benzyl]- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 341.1118 (M + H)⁺(obs.), 341.1113 (M + H)⁺(calc.).	Method F using 4- (trifluoromethyl) benzaldehyde, followed by Method E

9	2-(2,4- dimethylbenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS ES⁺, 285.1597 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.).	Method F using 2,4- dimethylbenzaldehyde, followed by Method E

10	7-hydroxy-2-[4- (propan-2- yl)benzyl]- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS ES⁺, 299.1755 (M + H)⁺(obs.), 299.1759 (M + H)⁺(calc.).	Method F using 4- isopropylbenzaldehyde, followed by Method E

11	7-hydroxy-2- (pyridin-2- ylmethyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 258.1242 (M + H)⁺(obs.), 258.1242 (M + H)⁺(calc.).	Method F using pyridine-2- carbaldehyde, followed by Method E

12	7-hydroxy-2-[4- (pyridin-3- yl)benzyl]- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 334.1541 (M + H)⁺(obs.), 334.1555 (M + H)⁺(calc.).	Method F using 4- (pyridine-3- yl)benzaldehyde, followed by Method E

13	2-(4- ethylbenzyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 285.1612 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.).	Method F using 4- ethylbenzaldehyde, followed by Method E

14	7-hydroxy-2- (quinolin-8- ylmethyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 308.1383 (M + H)⁺(obs.), 308.1399 (M + H)⁺(calc.)	Method F using Intermediate 2 and quinoline-8- carbaldehyde, followed by Method E

15	7-hydroxy-2-(1- phenylethyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 271.1434 (M + H)⁺(obs.), 271.1447 (M + H)⁺(calc.)	Method F using acetophenone, purification by chromatography (SiO₂, 10% methanolic ammonia in DCM),
			followed by
			Method E

16	2-[1-(4- ethylphenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 299.1747 (M + H)⁺(obs.), 299.1759 (M + H)⁺(calc.).	Method F using 4′- ethylacetophenone, purification by chromatography (SiO₂, 10% methanolic ammonia in DCM), followed by Method E

Example 17: 2-[(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile

Step 1: Preparation of 2-[[7-[(4-methoxyphenyl)methoxy]-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2-yl]methyl]benzonitrile

The title intermediate was prepared following to Method C starting from intermediate 2 and 2-cyanobenzaldehyde (yield: 44%). MS, ES⁺, 402.1 (M+H)⁺.

Step 2: Preparation of 2-[(7-hydroxy-8-oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile

TFA (0.4 mL) was added to a solution of 2-[[7-[(4-methoxyphenyl)methoxy]-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2-yl]methyl]benzonitrile (185 mg, 0.46 mmol) in DCM (2 mL). The mixture was stirred at rt for 1 h. Evaporation of the solvent under vacuum gave a residue that was purified by reverse phase chromatography to yield the title compound as a beige solid (65 mg, 35%). MS, ES⁺, 282 (M+H)⁺.

Example 18: 2-(4-ethyl-3-nitrobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

2-[(4-ethylphenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Example 13, 0.25 mmol, 70 mg) was poured in sulfuric acid (0.5 mL). Fuming nitric acid (0.26 mmol, 17 mg, 1.1 eq., 11 μL) was added and the resulting mixture stirred at rt for 10 min. Water (2 mL) was added and the mixture was neutralized to pH 7 by the addition of an aq. solution of K₂CO₃, then NaHCO₃. The precipitate was filtered, dried under vacuum to yield the title compound as an orange solid (38 mg, 47%). MS, ES⁺, 330.29 (M+H)⁺.

Example 19: 2-(2,2-diphenylethyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method G

0.6 mL of THF, 0.3 mL of EtOH and 0.1 mL of HOAc were added to 7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 1, 19.2 mg, 0.075 mmol). 2,2-diphenylacetaldehyde (22 mg, 1.5 eq.) followed by Si—BH₃CN (Silicycle, 250 mg, 0.223 mmol, 3 eq.) were added. The resulting reaction mixture was stirred overnight at rt. The mixture was filtered, evaporated. The residue was then dissolved in CH₃CN (2 mL) and purified by reverse phase preparative chromatography.
An aq. solution of HCl (1 mL, 6 N) was added to the purified and evaporated fractions and the mixture was heated at 100° C. for 1.5 h. The solvent was evaporated under vacuum. The residue was dissolved in CH₃CN/H₂O 75:25 (2 mL) and the solvents evaporated under vacuum to yield the title compound as a colorless film (28.4 mg). High-Res MS, ES⁺, 347.1765 (M+H)⁺ (obs.), 347.1759 (M+H)⁺ (calc.).
The following compounds 21-52 have been synthesized according to Methods G

				Preparation
Ex.	Name	R	Analytical data	Information

20	2-(2- ethylbutyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-	High-Res MS, ES⁺, 251.1755 (M + H)⁺(obs.), 251.1759 (M + H)⁺(calc.).	Method G using 2- ethylbutyraldehyde
	a]pyrazin-8-one

21	2-(3,5- dichlorobenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 325.0521 (M + H)⁺(obs.), 325.0511 (M + H)⁺(calc.).	Method G using 3,5- dichlorobenzalde- hyde

22	2- (cyclohexylmeth- yl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 263.1747 (M + H)⁺(obs.), 263.1759 (M + H)⁺(calc.).	Method G using cyclohexane- carboxaldehyde

23	2-(4- cyclopropylben- zyl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 297.1603 (M + H)⁺(obs.), 297.1603 (M + H)⁺(calc.).	Method G using 4- cyclopropyl- benzaldehyde

24	2-[(8,8- dimethyl- 1,2,3,4,5,6,7,8- octahydronaph- thalen-2- yl)methyl]-7- hydroxy-	High-Res MS, ES⁺, 343.2372 (M + H)⁺(obs.), 343.2386 (M + H)⁺(calc.).	Method G using 1,2,3,4,5,6,7,8- octahydro-8,8- dimethyl-2- naphthaldehyde
	1,2,3,4-
	tetrahydro-8H-
	pyrido[1,2-
	a]pyrazin-8-one

25	2-(3,4- dichlorobenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 325.0516 (M + H)⁺(obs.), 325.0511 (M + H)⁺(calc.).	Method G using 3,4- dichlorobenzalde- hyde

26	2- (cyclooctylmeth- yl)-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	LCMS (Method D, ES⁺) RT, (M + H)⁺, 98.8% purity.	Method G using cyclooctane- carbaldehyde

27	2-(2,6- dimethylbenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 285.1591 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.)	Method G using 2,6- dimethylbenzalde- hyde

28	2-(2,5- dimethylbenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 285.1595 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.).	Method G using 2,5- dimethylbenzalde- hyde

29	7-hydroxy-2- {[1- (phenylsulfonyl)- 1H-indol-2- yl]methyl}- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 436.1325 (M + H)⁺(obs.), 436.1331 (M + H)⁺(calc.).	Method G using 1- (phenylsulfonyl)- 1h-indole-2- carbaldehyde

30	7-hydroxy-2-(3- phenylpropyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 285.1593 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.).	Method G using 3- phenylpropional- dehdye

31	7-hydroxy-2-(2- phenylpropyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 285.1587 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.).	Method G using 2- phenylpropional- dehyde

32	2-(3,5- difluorobenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 293.1098 (M + H)⁺(obs.), 293.1101 (M + H)⁺(calc.).	Method G using 2,6- difluorobenzalde- hyde

33	7-hydroxy-2-(2- methylbenzyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 271.1434 (M + H)⁺(obs.), 271.1447 (M + H)⁺(calc.).	Method G using 2- methylbenzaldehyde

34	7-hydroxy-2- [(5-phenyl-1H- pyrazol-3- yl)methyl]- 1,2,3,4- tetrahydro-8H-	High-Res MS, ES⁺, 323.1483 (M + H)⁺(obs.), 323.1508 (M + H)⁺(calc.).	Method G using 5-phenyl-1h- pyrazole-3- carbaldehyde
	pyrido[1,2-
	a]pyrazin-8-one

35	2-{[6-chloro-4- (1H-imidazol-4- yl)-3,4-dihydro- 2H-chromen-8- yl]methyl}-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 413.1355 (M + H)⁺(obs.), 413.138 (M + H)⁺(calc.).	Method G using 6-chloro-4-(1h- imidazol-4- yl)chromane-8- carbaldehyde

36	7-hydroxy-2-(3- phenoxybenzyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 349.1562 (M + H)⁺(obs.), 349.1552 (M + H)⁺(calc.).	Method G using 4- phenoxybenzalde- hyde

37	2-(2,3- dimethylbenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 285.1581 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.).	Method G using 2,3- dimethylbenzalde- hyde

38	2-(1,3- benzothiazol-2- ylmethyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺), 314.0943 (M + H)⁺(obs.), 314.0963 (M + H)⁺(calc.)	Method G using 1,3- benzothiazole-2- carbaldehyde

39	2-(2- fluorobenzyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 275.1202 (M + H)⁺(obs.), 275.1196 (M + H)⁺(calc.)	Method G using 2- fluorobenzaldehyde

40	2-[(5-chloro- 1,3-dimethyl- 1H-pyrazol-4- yl)methyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-	High-Res MS, ES⁺, 309.1111 (M + H)⁺(obs.), 309.1118 (M + H)⁺(calc.).	Method G using 5-chloro-1,3- dimethyl-1h- pyrazole-4- carbaldehyde
	a]pyrazin-8-one

41	7-hydroxy-2- [(4-oxo-4H- chromen-3- yl)methyl]- 1,2,3,4- tetrahydro-8H- pyrido[1,2-	High-Res MS, ES⁺, 325.1214 (M + H)⁺(obs.), 325.1188 (M + H)⁺(calc.).	Method G using chromone-3- carboxaldehyde
	a]pyrazin-8-one

42	7-hydroxy-2- (1H-indazol-3- ylmethyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 297.1372 (M + H)⁺(obs.), 297.1351 (M + H)⁺(calc.).	Method G using 1h-indazole-3- carbaldehyde

43	7-hydroxy-2- {[3-(thiophen-2- yl)-1H-pyrazol- 4-yl]methyl}- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 329.1059 (M + H)⁺(obs.), 329.1072 (M + H)⁺(calc.).	Method G using 3-(2-thienyl)-1h- pyrazole-4- carbaldehyde

44	7-hydroxy-2-[2- (trifluoromethyl) benzyl]- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 325.1154 (M + H)⁺(obs.), 325.1164 (M + H)⁺(calc.).	Method G using 2- (trifluoromethyl) benzaldehyde

45	7-hydroxy-2- [(3-phenyl-1H- pyrazol-4- yl)methyl]- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 323.1494 (M + H)⁺(obs.), 323.1508 (M + H)⁺(calc.).	Method G using 3-phenyl-1h- pyrazole-4- carbaldehyde

46	2-(2,6- dimethoxybenzyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 317.1486 (M + H)⁺(obs.), 317.1501 (M + H)⁺(calc.).	Method G using 2,6- dimethoxybenzal- dehyde.

47	7-hydroxy-2-(4- phenoxybenzyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺), 349.1549 (M + H)⁺(obs.), 349.1552 (M + H)⁺(calc.).	Method G using 4- phenoxybenzalde- hyde

48	2-(2,3-dihydro- 1,4- benzodioxin-6- ylmethyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one	High-Res MS, ES⁺, 315.1329 (M + H)⁺(obs.), 315.1345 (M + H)⁺(calc.).	Method G using 2,3-dihydro-1,4- benzodioxine-6- carbaldehyde

49	2-[3-(1,3- benzodioxol-5- yl)-2- methylpropyl]- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-	High-Res MS, ES⁺, 343.1656 (M + H)⁺(obs.), 343.1658 (M + H)⁺(calc.).	Method G using 3-(1,3- benzodioxol-5- yl)-2-methyl- propanal
	a]pyrazin-8-one

Example 50: 7-hydroxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method H

0.6 mL of THF, 0.3 mL of EtOH and 0.1 mL of HOAc were added to 7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 2, 21.5 mg, 0.075 mmol). 4-methoxybenzaldehyde (22.1 mg, 1.5 eq.) followed by MP-BH₃CN (SOPACHEM, 35 mg, 0.1851 mmol, 2.5 eq.) were added. The resulting reaction mixture was stirred overnight at rt. The mixture was filtered, evaporated. The residue was then dissolved in CH₃CN (2 mL) and purified by reverse phase preparative chromatography. DCM (0.5 mL) and TFA (0.5 mL) were added to the purified and evaporated fractions and the mixture was stirred at rt for 2 h. The solvent was evaporated under vacuum. The residue was dissolved in CH₃CN/H₂O 90:10 (2 mL), filtered and the solvents evaporated under vacuum to yield the title compound as a colorless film (32.8 mg). High-Res MS, ES⁺287.1391 (M+H)⁺ (obs.), 287.1396 (M+H)⁺ (calc.).
The following compounds 54-59 have been synthesized according to Method H

				Preparation
Ex.	Name	R	Analytical data	Information

51	7-hydroxy-2-(2- methoxybenzyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 287.1399 (M + H)⁺(obs.), 287.1396 (M + H)⁺(calc.).	Method H using 4- methoxybenzalde- hyde

52	2-[4- (benzyloxy)benzyl]- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 363.1693 (M + H)⁺(obs.), 363.1709 (M + H)⁺(calc.).	Method H using 4- benzyloxybenzal- dehyde

53	2-[3- (benzyloxy)benzyl]- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺), 363.169 (M + H)⁺(obs.), 363.1709 (M + H)⁺(calc.).	Method H using 3- benzyloxybenzal- dehyde

54	2-(2,1,3- benzothiadiazol- 5-ylmethyl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 315.09 (M + H)⁺(obs.), 315.0916 (M + H)⁺(calc.).	Method H using 2,1,3- benzothiadiazole- 5-carbaldehyde

55	2-[2- (benzyloxy)benzyl]- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 363.1703 (M + H)⁺(obs.), 363.1709 (M + H)⁺(calc.).	Method H using 2- benzyloxybenzal- dehyde

56	7-hydroxy-2- {[6-(4- methylphenyl)imi- dazo[2,1- b][1,3]thiazol-5- yl]methyl}- 1,2,3,4- tetrahydro-8H- pyrido[1,2-		High-Res MS, ES⁺, 393.137 (M + H)⁺(obs.), 393.1385 (M + H)⁺(calc.).	Method H using 6-(4- methylphenyl)imi- dazo[2,1- b][1,3]thiazole-5- carbaldehyde
	a]pyrazin-8-one

Example 57: 7-hydroxy-2-[(2,4-dichlorophenyl)methyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method I

Step 1

To a suspension of 7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 2, 150 mg, 0.52 mmol) in DCE (10 mL) was added 2,4-dichlorobenzaldehyde (101 mg, 0.58 mmol) and sodium triacetoxyborohydride (333 mg, 1.57 mmol). The resulting mixture was stirred at room temperature for 18 h. The contents were treated with 1 N NaOH, added 10% Na₂CO₃and extracted with CHCl₃(3×). The organic layers were combined, dried over Na₂SO₄, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal-phase chromatography (0-40% MeOH/DCM, silica gel) to give 2-[(2,4-dichlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (166 mg, 0.373 mmol, 71% yield) as an off-white foam. MS, ES⁺ m/z 445.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64 (d, 1H) 7.55 (d, 1H) 7.42-7.47 (m, 2H) 7.32-7.36 (m, 2H) 6.92-6.96 (m, 2H) 5.95 (s, 1H) 4.89 (s, 2H) 3.92 (t, 2H) 3.76 (s, 3H) 3.71 (s, 2H) 3.59 (s, 2H) 2.85 (t, 2H)

Step 2

To a solution of 2-[(2-chloro-4-fluorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (160 mg, 0.36 mmol) in EtOH (5 mL) was added 6 M HCl (3.27 mL, 19.6 mmol). The resulting mixture was stirred at 100° C. for 3 h, then allowed to reach room temperature with stirring overnight (for convenience). The solvent was removed in vacuo and the residue was triturated with Et2O (3×) and the triturants removed by decantation. The solid was dried under vacuum to give 2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one hydrochloride (121 mg, 0.33 mmol, 93% yield) as an off-white solid. MS, ES⁺ m/z 325.0 [M+H]⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.26 (br. s., 1H) 8.12 (s, 1H) 7.68 (d, 1H) 7.63 (d, 1H) 7.49 (dd, 1H) 7.17 (s, 1H) 4.44 (t, 2H) 4.04 (br. s., 2H) 3.94 (br. s., 2H) 3.12 (br. s., 2H)
The following compounds 58-65 have been synthesized according to Method I


				Preparation
Ex.	Name	Structure	Analytical data	Information

58	2-[(2- chlorophenyl)meth- yl]-7- hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 291.2 (M + H)⁺, ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.34 (br. s., 1 H) 8.17 (s, 1H) 7.68 (br. s., 1 H) 7.50-7.56 (m, 1 H) 7.38-7.45 (m, 2 H) 7.24 (s, 1 H) 4.50 (br. s., 2 H) 4.19 (br. s., 2 H) 4.10 (br. s., 2 H) 3.26 (br. s., 2 H)	Method I using 2- chlorobenzaldehyde and Intermediate 2

59	2-[(2-chloro-6- fluoro- phenyl)methyl]- 7-hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺309.0 (M + H)⁺, ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.21 (br. s., 1 H) 8.07 (s, 1 H) 7.38-7.50 (m, 2 H) 7.27-7.33 (m, 1 H) 7.17 (s, 1 H) 4.36 (t,, 2 H) 4.00 (s, 2 H) 3.90 (s, 2 H) 3.06 (br. s., 2 H)	Method I using 2- chloro-4- fluorobenzaldehyde and Intermediate 2

60	2-[(2,6- dichlorophenyl) methyl]-7- hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 325.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.21 (br. s., 1 H) 8.06 (s, 1 H) 7.51-7.55 (m, 2 H) 7.37-7.43 (m, 1 H) 7.16 (s, 1 H) 4.33 (t, 2 H) 4.00 (s, 2 H) 3.95 (s, 2 H) 3.06 (t, 2 H)	Method I using 2,6- dichlorobenzaldehyde and Intermediate 2

61	2-[(2-chloro-4- fluorophenyl)meth- yl)]-7- hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 309.0 (M + H)⁺, ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.09-11.38 (m, 1 H) 8.10 (s, 1H) 7.61- 7.67 (m, 1 H) 7.51 (dd, 1 H) 7.29 (td, 1 H) 7.15 (s, 1 H) 4.43 (t, 2 H) 4.02 (br. s., 2H) 3.91 (br. s., 2 H) 3.10 (br. s., 2 H)	Method I using 2- chloro-4- fluorobenzaldehyde and Intermediate 2

62	2-[(2,6- difluorophenyl) methyl]-7- hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 293.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.20 (br. s., 1 H) 8.06 (s, 1 H) 7.45-7.55 (m, 1 H) 7.12-7.22 (m, 3 H) 4.38 (t, 2 H) 3.97 (s, 2 H) 3.88 (s, 2 H) 3.04 (br. s., 2 H)	Method I using 2,6- difluorobenzaldehyde and Intermediate 2

63	2-[(4-bromo-2- chloro- phenyl)methyl]- 7-hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one hydrochloride		MS, ES⁺, 368.9 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.16 (br. s., 1 H) 8.07 (s, 1 H) 7.78 (d, 1 H) 7.58-7.62 (m, 1 H) 7.49- 7.53 (m, 1 H) 7.10 (s, 1 H) 4.40 (t, 2 H) 3.96 (s, 2 H) 3.83 (s, 2 H) 3.04 (br. s., 2 H)	Method I using 4- bromo-2- chlorobenzaldehyde and Intermediate 2

64	2-[(2-chloro-4- cyclopropyl- phenyl)methyl]- 7-hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one hydrochloride		MS, ES⁺, 331.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.14 (br. s., 2 H) 8.06 (s, 1 H) 7.43 (d, 1 H) 7.21 (d, 1 H) 7.11 (s, 1 H) 7.07 (dd, 1 H) 4.40 (br. s., 2 H) 3.99 (br. s., 2 H) 3.86 (br. s., 2 H) 3.06 (br. s., 2 H) 1.90-1.99 (m, 1 H) 0.95-1.01 (m, 2 H) 0.68- 0.74 (m, 2 H)	Method I using 2- chloro-4- cyclopropylbenzalde- hyde and Intermediate 2

65	2-[(2- chlorophenyl)meth- yl]-7- hydroxy-3,3- dimethyl-1,4- dihydropyrido[1,2- a]pyrazin-8- one		MS, ES⁺, 319.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.28 (br. s., 1 H) 8.06 (s, 1 H) 7.63 (br. s., 1 H) 7.47 (d, 1 H) 7.31- 7.41 (m, 2 H) 7.14 (s, 1 H) 4.30 (br. s., 2 H) 3.91 (br. s., 4 H) 1.22-1.31 (br. s., 6 H)	Method I using 2- chlorobenzaldehyde and Intermediate 11

Example 66: 2-[(2,4-dichloro-5-nitro-phenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

To a solution of 2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Example 61, 30 mg, 0.083 mmol) in sulfuric acid (1 mL) was added potassium nitrate (16.8 mg, 0.17 mmol) in portions over 5 min. The resulting mixture was stirred for 30 min at 0° C., then quenched by adding cold water (3 mL) followed by careful addition of sat'd. NaHCO₃. The aqueous phase was extracted with CHCl₃(3×). The organic layers were combined, dried over Na₂SO₄, filtered, and 0.5 mL 6N HCl was added to the filtrate. The solvent was removed in vacuo to give to yield the hydrochloride salt of the title compound as a yellow solid (25 mg, 74%). MS, ES⁺, 370.0 (M+H)⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.19 (br. s., 1H) 8.22 (s, 1H) 8.06-8.10 (m, 2H) 7.06 (s, 1H) 4.41 (br. s., 2H) 3.97 (br. s., 2H) 3.88 (br. s., 2H) 3.05 (br. s., 2H)

Example 67: 7-hydroxy-2-[1-(2-methylphenyl)ethyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method J

7-[(4-methoxyphenyl)methoxy]-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 2, 0.1 mmol, 0.1 mmol), 2′-methylacetophenone (14.8 mg, 0.110 mmol), MP-BH₃CN (Sopachem, 80 mg, 0.199 mmol) were poured in a mixture EtOH (0.6 mL): THF (0.3 mL): HOAc (0.1 mL) and stirred overnight at rt, then at 60° C. for 14 h. MP-BH₃CN (Sopachem, 40 mg, 0.050 mmol) and 2′-methylacetophenone (8 mg) was added. The mixture was heated at 70° C. overnight. The reaction mixture was filtered, evaporated. The residue was purified by reverse phase chromatography to yield the PMB protected intermediate (18 mg). This intermediate was dissolved in DCM (0.4 mL), TFA (0.4 mL) was added and the resulting mixture was stirred at rt for 30 min. The solvents were evaporated to yield the title compound as a brown oil (20 mg). High-Res MS, ES⁺, 285.1597 (M+H)⁺ (obs.), 285.1603 (M+H)⁺ (calc.).
The following compounds 68-97 have been synthesized according to Methods J. Examples 94-97 were repurified by reverse phase chromatography.

				Preparation
Ex.	Name	R	Analytical data	Information

68	2-[1-(4- chlorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 305.1053 (M + H)⁺(obs.), 3.05.1057 (M + H)⁺(calc.).	Method J using 4′- chloroaceto- phenone

69	2-[1-(2,5- dichlorophenyl) ethyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 399.0656 (M + H)⁺(obs.), 339.0667 (M + H)⁺(calc.).	Method J using 2′,5′- dichloroaceto- phenone

70	7-hydroxy-2-{1- [4- (trifluoromethyl) phenyl]ethyl}- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 339.1321 (M + H)⁺(obs.), 339.132 (M + H)⁺(calc.).	Method J using 4′- (trifluoromethyl) acetophenone

71	7-hydroxy-2-[1- (3- methylphenyl)eth- yl]-1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 285.1599 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.).	Method J using 3′- methylaceto- phenone

72	2-[1-(3- chlorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 305.1041 (M + H)⁺(obs.), 3.05.1057 (M + H)⁺(calc.).	Method J using 3′- chloroaceto- phenone

73	2-(4-chloro-2,3- dihydro-1H- inden-1-yl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 317.1044 (M + H)⁺(obs.), 317.1057 (M + H)⁺(calc.).	Method J using 4-chloro-1- indanone

74	2-[1-(2,6- dimethoxyphenyl) ethyl]-7- hydroxy- 1,2,3,4- tetrahdyro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 331.1638 (M + H)⁺(obs.), 331.1658 (M + H)⁺(calc.).	Method J using 2′,6′- dimethoxyaceto- phenone

75	7-hydroxy-2-[1- (2,3,5- trifluorophenyl) ethyl]-1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 325.1161 (M + H)⁺(obs.), 325.1164 (M + H)⁺(calc.).	Method J using 2′,3′,5′- trifluoroacetophe- none

76	2-[1-(2- chlorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 305.1039 (M + H)⁺(obs.), 305.1057 (M + H)⁺(calc.).	Method J using 2- chloroacetophe- none

77	2-{1-[2- (benzyloxy)phe- nyl]-ethyl}-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 377.1847 (M + H)⁺(obs.), 3.77.1865 (M + H)⁺(calc.).	Method J using 2′- benzyloxyacetophe- none

78	7-hydroxy-2-(1- phenylpentyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 313.1911 (M + H)⁺(obs.), 313.1916 (M + H)⁺(calc.).	Method J using valerophenone

79	2-(7-fluoro-2,3- dihydro-1H- inden-1-yl)-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-		High-Res MS, ES⁺, 301.1338 (M + H)⁺(obs.), 301.1352 (M + H)⁺(calc.).	Method J using 7-fluoro-1- indanone
	a]pyrazin-8-one

80	7-hydroxy-2-(2- phenyl-3,4- dihydro-2H- chromen-4-yl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		LCMS (Method D, ES⁺) RT, (M + H)⁺, 95% purity.	Method J using flavanone

81	2-[1-(3- fluorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 289.1344 (M + H)⁺(obs.), 289.1352 (M + H)⁺(calc.).	Method J using 3′- fluoroacetophenone

82	2- cyclopentyl(phe- nyl)methyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2-		High-Res MS, ES⁺, 325.1905 (M + H)⁺(obs.), 325.1916 (M + H)⁺(calc.).	Method J using cyclopentyl phenyl ketone
	a]pyrazin-8-one

83	7-hydroxy-2-[1- (3- methoxyphenyl) ethyl]-1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 301.1534 (M + H)⁺(obs.), 301.1552 (M + H)⁺(calc.).	Method J using 3′- methoxyacetophe- none

84	2-(2,3-dihydro- 1H-inden-1-yl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 283.1427 (M + H)⁺(obs.), 283.1447 (M + H)⁺(calc.).	Method J using 1-indanone

85	2-[1-(3-chloro- 2,6- difluorophenyl) ethyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 341.0881 (M + H)⁺(obs.), 341.0868 (M + H)⁺(calc.).	Method J using 3′-chloro-2′,6′- difluoroacetophe- none

86	7-hydroxy-2- (6,7,8,9- tetrahydro-5H- benzo[7]annulen- 5-yl)-1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 311.1765 (M + H)⁺(obs.), 311.1759 (M + H)⁺(calc.).	Method J using 1-benzosuberone

87	2-[1-(2,5- dimethylphenyl) ethyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 299.1744 (M + H)⁺(obs.), 2991.759 (M + H)⁺(calc.).	Method J using 2′,5′- dimethylacetophe- none

88	2-(1,2- diphenylethyl)- 7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 347.1757 (M + H)⁺(obs.), 347.1759 (M + H)⁺(calc.).	Method J using deoxybenzoin

89	7-hydroxy-2-(1- phenylpropyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 285.1589 (M + H)⁺(obs.), 285.1603 (M + H)⁺(calc.).	Method J using propiophenone

90	7-hydroxy-2- (1,2,3,4- tetrahydronaph- thalen-1-yl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 297.1606 (M + H)⁺(obs.), 297.1603 (M + H)⁺(calc.).	Method J using 1-tetralone

91	7-hydroxy-2-(7- methoxy- 1,2,3,4- tetrahydronaph- thalen-1-yl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 327.1693 (M + H)⁺(obs.), 327.1709 (M + H)⁺ (calc.).	Method J using 7-methoxy-1- tetralone

92	7-hydroxy-2-(4- methyl-2,3- dihydro-1H- inden-1-yl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 297.1601 (M + H)⁺(obs.), 297.1603 (M + H)⁺(calc.).	Method J using 4-methyl-1- indanone

93	7-hydroxy-2-(1- phenylbutyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 299.1752 (M + H)⁺(obs.), 299.1759 (M + H)⁺(calc.).	Method J using butyrophenone

94	4-[1-(7- hydroxy-8-oxo- 1,3,4,8- tetrahydro-2H- pyrido[1,2- a]pyrazin-2- yl)ethyl]benzoni- trile		High-Res MS, ES⁺, 296.1386 (M + H)⁺(obs.), 296.1399 (M + H)⁺(calc.)	Method J using 4- acetylbenzonitrile

95	3-[1-(7- hydroxy-8-oxo- 1,3,4,8- tetrahydro-2H- pyrido[1,2- a]pyrazin-2- yl)ethyl]benzoni- trile		High-Res MS, ES⁺, 296.1383 (M + H)⁺(obs.), 296.1399 (M + H)⁺(calc.).	Method J using 3- acetylbenzonitrile

96	N-{3-[1-(7- hydroxy-8-oxo- 1,3,4,8- tetrahydro-2H- pyrido[1,2- a]pyrazin-2- yl)ethyl]phenyl} acetamide		High-Res MS, ES⁺, 328.1646 (M + H)⁺(obs.), 328.1661 (M + H)⁺(calc.)	Method J using 3′- acetamidoacetophe- none

97	2-[1-(2,5- difluorophenyl) ethyl]-7- hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		High-Res MS, ES⁺, 307.1252 (M + H)⁺(obs.), 307.1258 (M + H)⁺(calc.)	Method J using 2′,5′- difluoroacetophe- none

Example 98: 2-[1-(2-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method K

Step1: Preparation of 7-benzyloxy-2-[1-(2-fluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

5-benzyloxy-1-(2-chloroethyl)-2-(chloromethyl)pyridin-4-one (Intermediate 3, 0.32 mmol, 101 mg), sodium iodide (0.16 mmol, 24 mg, 0.50 eq.), NEt₃(4 eq., 1.32 mmol, 135 mg), (1-(2-fluorophenyl)ethanamine, 2.0 eq., 0.660 mmol) were placed in CH₃CN (2 mL). The reaction mixture was heated at 125° C. for 2.5 h. Addition of water (2 mL) and extraction with DCM (2 mL). The organic phase was evaporated under vacuum and purified by reverse phase preparative chromatography to yield the title intermediate (101 mg as a yellow oil (83%). MS, ES⁺, 379.2 (M+H)⁺.

Step 2: Preparation of 2-[1-(2-fluorophenyl)ethyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

An aq. solution of HCl (2 mL, 5 N) was added to 7-benzyloxy-2-[1-(2-fluorophenyl)ethyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (101 mg, 0.27 mmol) and the mixture was heated for 2 h at 95° C. The mixture was then evaporated under vacuum. The residue was then triturated with ether, filtered then dried under vacuum.
MS, ES⁺, 289.3 (M+H)⁺.
The following compounds 92-96 have been synthesized according to Methods K

				Preparation
Ex.	Name	R	Analytical data	Information

99	2-[1-(4- fluorophenyl)eth- yl]-7-hydroxy- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 289.2 (M + H)⁺,	Method K using 1-(4- fluorophenyl)eth- anamine

100	7-hydroxy-2-(2- hydroxy-1- phenylethyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺287.2 (M + H)⁺,	Method K using dl-2- phenylglycinol

101	7-hydroxy-2- (2,2,2-trifluoro- 1-phenylethyl)- 1,2,3,4- tetrahydro-8H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 325.2 (M + H)⁺	Method K using 2,2,2-trifluoro-1- phenyl- ethylamine

102	7-hydroxy-2- [(2-phenyl-1,3- thiazol-4- yl)methyl]- 1,2,3,4- tetrahydro-8H- pyrido[1,2-		MS, ES⁺, 340.3 (M + H)⁺,	Method K using (2-phenyl-1,3- thiazol-4- yl)methylamine
	a]pyrazin-8-one

103	2-[(3,5- dimethyl-1- phenyl-1H- pyrazol-4- yl)methyl]-7- hydroxy- 1,2,3,4-		MS, ES⁺, 351.3 (M + H)⁺	Method K using c-(3,5-dimethyl- 1-phenyl-1h- pyrazol-4-yl)- methylamine
	tetrahydro-8H-
	pyrido[1,2-
	a]pyrazin-8-one

104	7-hydroxy-2-(1- phenylcyclopro- pyl)-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 283.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.08 (br. s., 1 H) 7.99 (s, 1 H) 7.37-7.44 (m, 4 H) 7.30-7.36 (m, 1 H) 7.11 (s, 1 H) 4.30 (t, 2 H) 3.88 (s, 2 H) 2.95-3.01 (m,	Method K using 1- phenylcyclopropyl- amine
			2 H) 1.03-1.08 (m, 2 H)
			0.86-0.90 (m, 2 H)

105	2-(2-fluoro-1- phenyl-ethyl)-7- hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 289.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 7.9 (s, 1H) 7.44- 7.39 (m, 5H) 6.86 (s, 1H) 4.96-4.67 (m, 3H) 4.31-4.25 (m, 2H) 4.02-3.80 (m, 2H) 3.01-2.86 (m, 2H)	Method K using 2-fluoro-1- phenyl- ethylamine

106	2-[1-(2- chlorophenyl)cy- clopropyl]-7- hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 317.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 7.99 (s, 1 H) 7.56 (dd, 1 H) 7.47-7.51 (m, 1 H) 7.34-7.43 (m, 2 H) 7.10 (s, 1 H) 4.29 (t, 2 H) 3.95 (s, 2 H) 3.09 (t, 2 H) 1.18-1.22	Method K using 1-(2- chlorophenyl)cyclo- propylamine
			(m, 2 H) 0.94-0.99 (m, 2 H)

107	2-(2,2-difluoro- 1-phenyl-ethyl)- 7-hydroxy-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 307.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 7.9 (s, 1H) 7.54- 7.40 (m, 5H) 7.33-7.08 (m, 1H) 6.87 (s, 1H) 6.83-6.54 (m, 1H) 4.35-4.15 (m, 2H) 3.92 (quart., 2H) 3.11-3.03	Method K using 2,2-difluoro-1- phenyl- ethylamine
			(m, 1H) 2.92-2.83 (m, 1H).

108	2-(1,3- benzothiazol-2- yl)-7-hydroxy- 3,4-dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 300.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.27 (br. s., 1 H) 8.30 (s, 1 H) 7.87 (d, 1 H) 7.55 (d, 1 H) 7.42 (s, 1 H) 7.31-7.38 (m, 1 H) 7.12- 7.18 (m, 1 H) 5.05 (s, 2 H) 4.66 (t, 2 H) 3.97-4.02 (m, 2 H)	Method K using 1,3-benzothiazol- 2-amine

109	7-hydroxy-2-(2- phenylcyclopro- pyl)-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 283.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 8.03 (s, 1H) 7.26- 7.24 (m, 2H) 7.20-7.17 (m, 3H) 7.06 (s, 1H) 4.38-4.30 (m, 2H) 4.11-3.95 (m, 2H) 3.20-3.05 (m, 2H) 2.22 (s, 1H), 2.11-2.03 (m, 2H) 1.17- 1.04 (m, 2H).	Method K using 2- phenylcyclopropyl- amine

110	7-hydroxy-2-(5- quinolyl)-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8- one		MS, ES⁺, 294.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 11.31 (br. s., 1 H) 9.20 (d, 1 H) 9.07 (d, 1 H) 8.28 (s, 1 H) 8.07 (d, 1 H) 7.97-8.04 (m, 1 H) 7.92 (dd, 1 H) 7.53 (d, 1 H) 7.29 (s, 1	Method K using 5- aminoquinoline
			H) 4.67 (s, 4 H) 3.71 (d, 2 H)

111	7-hydroxy-2-(3- phenyloxetan- 3-yl)-3,4- dihydro-1H- pyrido[1,2- a]pyrazin-8-one		MS, ES⁺, 299.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d₆) δ ppm 8.09 (s, 1H) 7.81- 7.35 (m, 5H) 7.15 (s, 1H) 5.12 (br. s., 4H) 4.36 (t, 2H) 3.64 (s, 2H) 2.70 (t, 2H).	Method K using 3-phenyloxetan- 3-amine

Example 112: 7-hydroxy-2-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 1-(2-anilinoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one

A suspension of 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (100 mg, 0.43 mmol) and N′-phenylethane-1,2-diamine (84.5 μL, 0.65 mmol) in water (2 mL) was heated under microwave conditions at 150° C. for 90 min. The solvent was removed in vacuo and the residue treated with 10% Na₂CO₃and CHCl₃and passed through a phase separator tube. After removing the organic solvent in vacuo, the residue was purified by automated normal-phase chromatography (0-20% MeOH/DCM, 4 g silica gel cartridge). The product-containing fractions were combined and the solvent removed in vacuo to give 1-(2-anilinoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one (58 mg, 38% yield) as a tan solid. MS, ES⁺, 351 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (s, 1H), 7.31-7.40 (m, 5H), 7.08 (t, 2H, J=7.7 Hz), 6.52-6.60 (m, 3H), 6.20 (s, 1H), 5.80 (t, 1H, J=6.1 Hz), 5.62 (t, 1H, J=5.7 Hz), 4.92 (s, 2H), 4.36 (d, 2H, J=5.8 Hz), 4.03 (t, 2H, J=6.2 Hz), 3.38 (m, 2H).

Step 2: Preparation of 7-benzyloxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

To a solution of 1-(2-anilinoethyl)-5-benzyloxy-2-(hydroxymethyl)pyridin-4-one (55.mg, 0.16 mmol) in DME (5 mL) and chloroform (100 mL) was added thionyl chloride (500 μL, 6.9 mmol) in chloroform (100 mL) over 45 min at ambient temperature. The contents were allowed to stir for 3 days (for convenience), then 10 mL of 1M NaOH was added. The resulting mixture was allowed to stir for 24 h at ambient temperature, then at 50° C. for 24 h. The contents were transferred to a separatory funnel, the CHCl₃layer removed and the aqueous layer washed with CHCl₃(2×). The organic layers were combined, dried over MgSO₄, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal-phase chromatography (0-20% MeOH/DCM, 4 g silica gel cartridge). The product-containing fractions were combined and the solvent removed in vacuo to give 7-benzyloxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (32 mg, 61% yield) as a colorless glass. MS, ES⁺, 333 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.64 (s, 1H), 7.32-7.46 (m, 5H), 7.23-7.29 (m, 2H), 6.95 (d, 2H, J=8.8 Hz), 6.80 (t, 1H, J=7.3 Hz), 6.22 (s, 1H), 4.99 (s, 2H), 4.38 (s, 2H), 4.09-4.14 (m, 2H), 3.65 (t, 2H, J=5.6 Hz).

Step 3: Preparation of 7-hydroxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (29.mg, 0.090 mmol) was stirred in 6M HCl (2.mL, 12 mmol) at 100° C. for 2 h. The solvents were removed in vacuo to give 7-hydroxy-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one hydrochloride (24.5 mg, 0.089 mmol, 98% yield) as a brown solid. MS, ES⁺, 243 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H), 7.25-7.34 (m, 4H), 6.99-7.03 (m, 2H), 6.84 (t, 1H, J=7.3 Hz), 4.68 (s, 2H), 4.51-4.56 (m, 2H), 3.71-3.76 (m, 2H).

Example 113: 7-hydroxy-2-(3-methylphenyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Method L

Step 1: Preparation of 7-benzyloxy-2-(o-tolyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one Xantphos (45 mg, 0.078 mmol), Pd₂(dba)₃(13 mg, 0.038 mmol) and potassium tert-butoxide (0.135 g, 1.17 mmol) were added to a suspension of 7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 1, 0.1 g, 0.39 mmol) and 3-bromotoluene (0.14 g, 0.78 mmol) in 1,4-dioxane (1 mL). The mixture was heated at 130° C. for 14 h, then cooled to rt and filtered. The filtered solid was washed with EtOAc and the combined filtrates were evaporated under vacuum. The residue was purified by chromatography (SiO₂, gradient from 100% DCM up to 7% methanolic ammonia in DCM) to yield the title intermediate as a yellow solid (83 mg, 61%). MS, ES⁺, 347 (M+H)⁺.

Step 2: Preparation of 7-hydroxy-2-(3-methylphenyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

An aq. solution of HCl (2 mL, 5 N) was added to 7-benzyloxy-2-(m-tolyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (83 mg, 0.24 mmol) and the mixture heated at 100° C. for 30 min., then cooled to rt. The reaction mixture was washed with CH₃Cl, treated with Norite®, filtered and evaporated to give a residue (30 mg, brown solid). Purification by reverse phase preparative chromatography yielded the title compound as a brown solid (22 mg, 24%). MS, ES⁺, 257 (M+H)⁺.

Example 114: 7-hydroxy-2-[2-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound has been prepared according to Method L, but using 1-bromo-2-(trifluoromethoxy)benzene. Purification of the intermediate by chromatography (SiO₂, gradient from 100% DCM up to 7% methanolic ammonia in DCM) yielded the intermediate as a yellow solid (127 mg) used in the next step without any further purification. MS, ES⁺, 417.3 (M+H)⁺. HCl treatment (Method E) gave the title compound. MS, ES⁺, 327.2 (M+H)⁺. ¹H NMR (400 MHz, D₂O) δ 7.97 (s, 1H), 7.38 (m, 1H), 7.31 (t, 1H, J=7.6 Hz), 7.19 (m, 2H), 7.08 (s, 0H), 4.50 (s, 2H), 4.43 (m, 2H), 3.65 (m, 2H).

Example 115: 1,2-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 5-benzyloxy-2-(1-hydroxy-2-phenyl-ethyl)pyran-4-one

A solution of benzylmagnesium bromide (0.6 M, 1.2 eq., 10.4 mmol, 17.4 mL) in THF was added dropwise (in ca. 20 min) to a solution of 5-benzyloxy-4-oxo-pyran-2-carbaldehyde (Intermediate 4, 8.7 mmol, 2.0 g) in THF (20 mL) cooled at −70° C. The mixture was warmed to rt. Water was added, then the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered and concentrated under vacuum to give a brown oil (3.27 g). Purification by chromatography (SiO₂, 5% methanolic ammonia in DCM) gave the title intermediate (1.47 g, 52%). MS, ES⁺, 323.3 (M+H)⁺.

Step 2: Preparation of 1-(2-aminoethyl)-5-benzyloxy-2-(1-hydroxy-2-phenyl-ethyl)pyridin-4-one

Ethylenediamine (13.7 mmol, 0.830 g, 3 eq.) was added to a solution of 5-benzyloxy-2-(1-hydroxy-2-phenyl-ethyl)pyran-4-one (4.56 mmol, 1.47 g, 1 eq.) in EtOH (5 mL) and the mixture was heated to 90° C. for 15.5 h. The reaction mixture was concentrated under vacuum. The residue was taken up in a mixture of EtOAc/MeOH 90/10, washed with H₂O. The aqueous layer was extracted with n-BuOH. The combined org. layers were dried over MgSO₄, filtered and concentrated to yield a brown oil (1.83 g, quant.) used in the next step without any further purification.

Step 3: Preparation of 1-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

Method M

SOCl₂(15 mmol, 1.8 g, 3.1 eq.) was added to a solution of 1-(2-aminoethyl)-5-benzyloxy-2-(1-hydroxy-2-phenyl-ethyl)pyridin-4-one (4.9 mmol, 1.8 g, 1.0 eq.) in DCM (10 mL). The mixture was stirred at rt for 1 h. then evaporated under vacuum to yield a brown oil. This residue was taken up in n-BuOH and an aq. solution of NaHCO₃was added until the pH is 9. The mixture was then stirred for 14 h. at rt.
The reaction mixture was decanted, and the aq. layer was extracted with n-BuOH. The org, phase was dried over MgSO₄, filtered and concentrated to yield a black oil (1.5 g). Purification by chromatography (SiO₂, 10% methanolic ammonia in DCM) yielded the title intermediate as a brown oil (0.7 g) MS, ES⁺, 347.3 (M+H)⁺.

Step 4: Preparation of 1,2-dibenzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Method N

Benzaldehyde (0.58 mmol, 0.061 g, 2.0 eq.) and molecular sieve 4A (<5 μm, 0.3 g) were added to a solution of 1-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (0.29 mmol, 0.1 g, 1.0 eq.) in MeOH (4 mL). The mixture was stirred 1 h at rt, then HOAc (0.58 mmol, 0.035 g, 2.0 eq.) followed by sodium cyanoborohydride (0.87 mmol, 0.054 g, 3.0 eq.). The mixture was then stirred 14 h at rt. The mixture was filtered and concentrated. The residue was taken up in DCM, washed with H2O then dried over MgSO₄, filtered and concentrated under vacuum to give a residue. Purification by chromatography (SiO₂, from 3% methanolic ammonia up to 10% in DCM) yielded the title intermediate (30 mg). MS, ES⁺, 337.4 (M+H)+

Step 5: Preparation of: 1,2-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

An aq. solution of HCl (2 mL, 5 N) was added to a solution of 1,2-dibenzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (0.034 mmol, 0.015 g, 1.0 eq.) in dioxane (1 mL). The mixture was stirred at 90° C. for 1 h then cooled to rt. The reaction mixture was washed with CHCl₃(2×2 mL). The aq. phase was filtered on Celite, then concentrated under vacuum to give a brown solid. Purification by reverse phase preparative chromatography yielded the title compound (9 mg). High-Res MS, ES⁺, 347.1764 (M+H)⁺ (obs.), 347.1759 (M+H)⁺ (calc.).

Example 116: 2-benzyl-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 5-benzyloxy-2-[hydroxy(phenyl)methyl]pyran-4-one

Method O

A solution of phenylmagnesium chloride (2 M in THF, 6.53 mL, 13.0 mmol, 1.5 eq.) was added dropwise to a cold (−70° C.) solution of 5-benzyloxy-4-oxo-pyran-2-carbaldehyde (Intermediate 4, 8.7 mmol, 2.0 g, 1.0 eq.) in THF (20 mL). The mixture was stirred and the temperature allowed to warm up to −30° C. H₂O was then added (10 mL), the mixture allowed to reach rt. The mixture was extracted with EtOAc. The combined org. layers were washed with H₂O, then dried over MgSO₄, filtered and evaporated to give an oil (4.0 g). This residue was triturated with Et₂O and the precipitate formed filtered to yield the title intermediate (1.44 g, 54%) used in the next step without any further purification. MS, ES⁺, 309.2 (M+H)⁺.

Step 2: Preparation of 1-(2-aminoethyl)-5-benzyloxy-2-[hydroxy(phenyl)methyl]pyridin-4-one

Method P

Ethylenediamine (0.84 g, 3 eq.) and 5-benzyloxy-2-[hydroxy(phenyl)methyl]pyran-4-one (4.61 mmol, 1.42 g, 1.0 eq.) were heated at 70° C. for 4 h. The mixture was cooled to rt, concentrated and the residue was purified by chromatography (SiO₂, 10% methanolic ammonia in DCM) to yield the title intermediate as a brown oil (0.9 g, 60%). MS, ES⁺, 351.3 (M+H)⁺.

Step 3: Preparation of 7-benzyloxy-1-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A, using 1-(2-aminoethyl)-5-benzyloxy-2-[hydroxy(phenyl)methyl]pyridin-4-one (0.9 g, 2.6 mmol) and longer reaction time (heated 48 h at 60° C.).
The residue obtained was dissolved in MeOH (12 mL) and sodium borohydride (100 mg, 3 mmol) were added and the mixture stirred at rt for 1 h. Another portion of sodium borohydride (100 mg) were added and the mixture stirred at rt for 14 h. The reaction mixture was concentrated to give a residue (700 mg). Purification by chromatography (SiO₂, 10% methanolic ammonia in DCM) yielded the title intermediate (417 mg). MS, ES⁺, 333.3 (M+H)⁺.

Step 4: Preparation of 2-benzyl-7-benzyloxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Method Q

7-benzyloxy-1-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (0.42 mmol, 140 mg), potassium carbonate (0.87 mmol, 121 mg, 2.05 eq.), sodium iodide (ca. 1 mg) and benzyl bromide (0.35 mmol, 59 mg, 0.8 eq., dissolved in CH₃CN 1 mL) were stirred 14 h at rt in CH₃CN (1.5 mL). Then DMF (2 mL) were added and the resulting reaction mixture stirred another 14 h at rt.
H₂O was then added, the mixture was extracted with EtOAc. The combined org. layers were washed with H₂O, then dried over MgSO₄, filtered and evaporated to give a residue (100 mg). Purification by chromatography (SiO₂, gradient from DCM up to 10% methanolic ammonia in DCM) yielded the title intermediate (120 mg). MS, ES⁺, 423.3 (M+H)⁺.

Step 5: Preparation of 2-benzyl-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

An aq. solution of HCl (3 mL, 5 N) was added to 2-benzyl-7-benzyloxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (0.28 mmol, 120 mg) and the mixture heated at 90° C. for 2 h, then cooled to rt. The precipitate was filtered, washed with Et₂O, dried under vacuum to yield the title compound (62 mg) High-Res MS, ES⁺, 333.1613 (M+H)⁺ (obs.), 333.1603 (M+H)⁺ (calc.).

Example 117: 2-(2,6-dichlorobenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to method Q, but using 2,6-dichlorobenzyl bromide.
High-Res MS, ES⁺, 401.0815 (M+H)⁺ (obs.), 401.0823 (M+H)⁺ (calc.).

Example 118: (1R)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate (240 mg) was prepared according to Method N, using 7-benzyloxy-1-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (200 mg, 0.60 mmol), 4-ethylbenzyldehyde (205 mg, 1.5 mmol, 2.5. eq.) and Si—BH₃CN (Silicycle, 1.5 g, 1.3 mmol, 2.2 eq.). MS, ES⁺, 451.3 (M+H)⁺.

Step 2: Preparation of (1R)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (240 mg) was purified by chiral chromatography (SFC conditions on ChiralCel OD (50×266 mm, 360 mL/min, 25° C., CO₂+40% EtOH, conc: 20 g/), to give 100 mg of the first eluting enantiomer (RT 7.13 min) as a brown oil, attributed to (1R)-2-[(4-ethylphenyl)methyl]-7-hydroxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one and 110 mg of the second eluting enantiomer, attributed to (1S)-2-[(4-ethylphenyl)methyl]-7-hydroxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (RT 11.5 min) as a brown oil. ChiralCel OD-H, 50% EtOH in n-heptane (5 um, 240×4.6 mm, 1.0 mL/min) RT 6.4 min (100% purity). ChiralCel OD-H, 50% EtOH in n-heptane (5 um, 240×4.6 mm, 1.0 mL/min) RT 10.2 min (100% purity).
(1R)-2-[(4-ethylphenyl)methyl]-7-hydroxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (100 mg, 0.22 mmol) was reacted following Method E to yield the title compound (25 mg). High-Res MS, ES⁺, 361.1903 (M+H)⁺ (obs.), 361.1916 (M+H)⁺ (calc.).

Example 119: (1S)-2-(4-ethylbenzyl)-7-hydroxy-1-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

(1S)-2-[(4-ethylphenyl)methyl]-7-hydroxy-1-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (100 mg, 0.22 mmol) was reacted following Method E to yield the title compound (31 mg, 38%). High-Res MS, ES⁺, 361.1933 (M+H)⁺ (obs.), 361.1916 (M+H)⁺ (calc.).

Example 120: 2-(4-ethylbenzyl)-7-hydroxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of tert-butyl 7-benzyloxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate

Di-tert-butyl dicarbonate (258 mg, 1.5 eq., 1.2 mmol) was added to a suspension of 7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (200 mg, 0.78 mmol) and DMAP (0.1 eq., 0.078 mmol) in THF (10 mL) and the reaction mixture was stirred 2 days at rt. H₂O was added, the mixture was extracted with EtOAc. The combined org. layers were washed with H₂O, then dried over MgSO₄, filtered and evaporated. The residue was purified by reverse phase chromatography to yield the title intermediate (100 mg). MS, ES⁺), 357.1 (M+H)⁺.

Step 2: Preparation of tert-butyl 7-benzyloxy-1-isopropyl-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate

sec-butyllithium (1.2 eq., 0.33 mmol, 1.4 M, 0.240 mL) was added dropwise to a cold (−78° C.) solution of tert-butyl 7-benzyloxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (100 mg, 0.28 mmol) in anhydrous THF (5 mL) and the resulting reaction mixture was stirred 30 min at −78° C. 2-iodopropane (143 mg, 3 eq., 0.84 mmol) was then added dropwise and the mixture was allowed to reach rt and stirred for 14 h. An aq. solution of NaHCO₃was added and the mixture extracted with EtOAc. The combined org. phases were dried over MgSO₄, filtered and evaporated under vacuum to give a yellow oil (80 mg). The residue was purified by reverse phase chromatography to yield the title intermediate (20 mg). MS, ES⁺, 399.2 (M+H)⁺.

Step 3: Preparation of 7-benzyloxy-1-isopropyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

TFA (3 mL) was added to a solution of tert-butyl 7-benzyloxy-1-isopropyl-8-oxo-3,4-dihydro-H-pyrido[1,2-a]pyrazine-2-carboxylate (300 mg, 0.75 mmol) in DCM (3 mL). The mixture was stirred at rt for 2 h. The solvents were evaporated to yield the title intermediate as a brown oil (350 mg) used in the next step without further purification. MS, ES⁺, 299.1 (M+H)⁺.

Step 4: Preparation of 7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-isopropyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method C using 7-benzyloxy-1-isopropyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one and 4-ethylbenzaldehyde. The crude product was purified by reverse phase chromatography (SiO2, DCM-MeOH—NH₄OH 97-2.7-0.3) to yield the title intermediate as a yellow oil (57%).

Step 5: Preparation of 2-(4-ethylbenzyl)-7-hydroxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E, using 7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-isopropyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one, affording the title compound as a yellow solid MS, ES⁺), 327 (M+H)⁺.

Example 121: 2-(2,6-dimethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-2-[(2,6-dimethylphenyl)methyl]-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method F using 7-benzyloxy-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one and 2,6-dimethylbenzaldehyde (Intermediate 5), reaction at 40° C. for 40 h. The crude product was purified by chromatography (SiO₂, gradient from 100% DCM up to 6% methanolic ammonia in DCM) to give the title intermediate as a colorless oil (60 mg). MS, ES⁺, 389.3 (M+H)⁺.

Step 2: Preparation of 2-(2,6-dimethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E from 7-benzyloxy-2-[(2,6-dimethylphenyl)methyl]-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one to give the title compound as a yellow solid.
MS, ES⁺, 299.27 (M+H)⁺.

Example 122: 2-(4-ethylbenzyl)-7-hydroxy-1-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method F using 7-benzyloxy-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 5) and 4-ethylbenzaldehyde (quant.) followed by Method E using 7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one.
MS, ES⁺, 299.2 (M+H)⁺.

Example 123: 1-(4-fluorophenyl)-7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 5-benzyloxy-2-[(4-fluorophenyl)-hydroxy-methyl]pyran-4-one

The title intermediate was prepared according to Method O using 4-fluorophenylmagnesium bromide. MS, ES⁺, 327.2 (M+H)⁺.

Step 2: Preparation of 1-(2-aminoethyl)-5-benzyloxy-2-[(4-fluorophenyl)-hydroxy-methyl]pyridin-4-one

The title intermediate was prepared according to Method P using 5-benzyloxy-2-[(4-fluorophenyl)-hydroxy-methyl]pyran-4-one as a brown oil. MS, ES⁺, 369.3 (M+H)⁺.

Step 3: Preparation of 7-benzyloxy-1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using 1-(2-aminoethyl)-5-benzyloxy-2-[(4-fluorophenyl)-hydroxy-methyl]pyridin-4-one as a brown oil. MS, ES⁺, 349.3 (M+H)⁺.

Step 4: Preparation of 7-benzyloxy-1-(4-fluorophenyl)-2-(8-quinolylmethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using 7-benzyloxy-1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one and quinoline-8-carbaldehyde as a yellow oil. MS, ES⁺, 492.3 (M+H)⁺.

Step 5: Preparation of 1-(4-fluorophenyl)-7-hydroxy-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E from 7-benzyloxy-1-(4-fluorophenyl)-2-(8-quinolylmethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one to give the title compound as an orange solid.
MS, ES⁺, 402.3 (M+H)⁺.

Example 124: 2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-2-[(2,6-dimethylphenyl)methyl]-1-(4-fluorophenyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using 7-benzyloxy-1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one and 2,6-dimethylbenzaldehyde. MS, ES⁺, 469.3 (M+H)⁺,

Step 2: Preparation of 2-(2,6-dimethylbenzyl)-1-(4-fluorophenyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 7-benzyloxy-2-[(2,6-dimethylphenyl)methyl]-1-(4-fluorophenyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (57%). MS, ES⁺, 379.3 (M+H)⁺.

Example 125: 2-(4-ethylbenzyl)-7-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-tetrahydropyran-4-yl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using 7-benzyloxy-1-tetrahydropyran-4-yl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 6) as a white solid (65%). MS, ES⁺, 459.4 (M+H)⁺.

Step 2: Preparation of 2-(4-ethylbenzyl)-7-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-tetrahydropyran-4-yl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as a pale yellow solid (93%).
MS, ES⁺, 369.32 (M+H)⁺.

Example 126: 2-(4-ethylbenzyl)-7-hydroxy-1-[3-(pyridin-3-yl)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step1: Preparation of 5-benzyloxy-2-[(3-bromophenyl)-hydroxy-methyl]pyran-4-one
I₂(ca. 5 mg) was added to a suspension of magnesium (26.1 mmol, 633 mg, 1.2 eq.) in anhydrous THF (5 mL). A solution of 1,3-dibromobenzene (26.1 mmol, 6.33 g, 1.2 eq.) in THF (10 mL) was added dropwise. The mixture was stirred at rt for 3 h then 1 h at reflux.
This solution was added dropwise onto a solution of 5-benzyloxy-4-oxo-pyran-2-carbaldehyde (21.7 mmol, 5.0 g, 1.0 eq.) in THF (100 mL) and the mixture was stirred 1 h at rt. An aq. solution of HCl (20 mL, 1 N) was added. The resulting reaction mixture was extracted with EtOAc. The combined org. layers were dried over MgSO₄, filtered and evaporated to give a residue (13 g).
Purification by chromatography (SiO₂, DCM-MeOH—NH₄OH 98-1.8-0.2) yielded the title intermediate (1.3 g). MS, ES⁺, 487.2 (M+H)⁺.

Step 2: Preparation of 1-(2-aminoethyl)-5-benzyloxy-2-[(3-bromophenyl)-hydroxy-methyl]pyridin-4-one

Ethylenediamine (5.1 mmol, 0.3 g, 1.5 eq.) was added to a solution of 5-benzyloxy-2-[(3-bromophenyl)-hydroxy-methyl]pyran-4-one (3.4 mmol, 1.3 g) in EtOH (10 mL). The mixture was stirred at 40° C. for 48 h. The solvent was evaporated under vacuum to give a residue used in the next step without any further purification. MS, ES⁺, 429.2/431.2 (M+H)⁺.

Step 3: Preparation of 7-benzyloxy-1-(3-bromophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method A using 1-(2-aminoethyl)-5-benzyloxy-2-[(3-bromophenyl)-hydroxy-methyl]pyridin-4-one, involving a purification by reverse phase chromatography.

Step 4: Preparation of 7-benzyloxy-1-(3-bromophenyl)-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using 7-benzyloxy-1-(3-bromophenyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (43%) involving a purification by chromatography (SiO2, gradient from DCM up to 10% methanolic ammonia in DCM). MS, ES⁺, 529.2/531.2 (M+H)⁺.

Step 5: Preparation of 7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-[3-(3-pyridyl)phenyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-1-(3-bromophenyl)-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (0.19 mmol, 100 mg), pyridine-3-boronic acid (0.23 mmol, 29 mg, 1.2 eq.), cesium carbonate (2.29 mmol, 745 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.009 mmol, 7 mg, 0.05 eq.) were placed in a mixture 10:1 dioxane:H₂O (2 mL). The mixture was degassed then heated 3 h at 100° C. The reaction mixture was then cooled to rt. H₂O was added and the mixture extracted with EtOAc. The combined org. layers were washed with a sat. solution of NaCl, dried over MgSO₄, filtered and evaporated to give a residue (100 mg). Purification by chromatography (SiO₂, gradient from DCM up to 10% methanolic ammonia) yielded the title intermediate as a brown oil (89 mg, 89%). MS, ES⁺, 528.2 (M+H)⁺.

Step 6: Preparation of 2-(4-ethylbenzyl)-7-hydroxy-1-[3-(pyridin-3-yl)phenyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 7-benzyloxy-2-[(4-ethylphenyl)methyl]-1-[3-(3-pyridyl)phenyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as a pale yellow solid.
MS, ES⁺, 438.2 (M+H)⁺.

Example 127: 2-benzyl-7-hydroxy-3-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 2-benzyl-7-benzyloxy-3-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method Q using 7-benzyloxy-3-phenyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 7) and benzyl bromide as a yellow oil. MS, ES⁺, 423.3 (M+H)⁺.

Step 2: Preparation of 2-benzyl-7-hydroxy-3-phenyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using of 2-benzyl-7-benzyloxy-3-phenyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (26%). High-Res MS, ES⁺, 333.1604 (M+H)+(obs.), 333.1603 (M+H)⁺ (calc.).

Example 128: 2,3-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 2,3-dibenzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using 3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 8) and benzaldehyde involving a purification of the crude product by chromatography (SiO₂, gradient from DCM up to 10% methanolic ammonia in DCM) (48%). MS, ES⁺, 437.3 (M+H)⁺.

Step 2: Preparation of 2,3-dibenzyl-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 2,3-dibenzyl-7-benzyloxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as an orange solid (quant.). High-Res MS, ES⁺, 347.175 (M+H)⁺ (obs.), 347.1759 (M+H)⁺ (calc.).

Example 129: 3-benzyl-2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 3-benzyl-7-benzyloxy-2-[(2,6-dichlorophenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using 3-benzyl-7-benzyloxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 8) and 2,6-dichlorobenzaldehyde involving a purification of the crude product by chromatography (SiO₂, gradient from DCM up to 10% methanolic ammonia in DCM) as a colorless oil. MS, ES⁺, 505.3 (M+H)⁺.

Step 2: Preparation of 3-benzyl-2-(2,6-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 3-benzyl-7-benzyloxy-2-[(2,6-dichlorophenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (18%). High-Res MS, ES⁺, 415.0984 (M+H)⁺ (obs.), 415.098 (M+H)⁺ (calc.).

Example 130: 7-hydroxy-3-methyl-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-3-methyl-2-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using 7-benzyloxy-3-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 9) and 4-(trifluoromethoxy)benzaldehyde involving a purification of the crude product by chromatography (SiO₂, gradient from DCM up to 10% methanolic ammonia in DCM) as a colorless oil (61%). MS, ES⁺, 445.3 (M+H)⁺.

Step 2: Preparation of 7-hydroxy-3-methyl-2-[4-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 7-benzyloxy-3-methyl-2-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as a light yellow solid (66%).
High-Res MS, ES⁺, 355.1269 (M+H)⁺ (obs.), 355.127 (M+H)⁺ (calc.).

Example 131: 2-benzyl-7-hydroxy-3-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 2-benzyl-7-benzyloxy-3-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method F using 7-benzyloxy-3-methyl-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one (Intermediate 9) and benzaldehyde involving a purification of the crude product by chromatography (SiO₂, gradient from DCM up to 10% methanolic ammonia in DCM) as a colorless oil (90%). MS, ES⁺, 361.3 (M+H)⁺.

Step 2: Preparation of 2-benzyl-7-hydroxy-3-methyl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 2-benzyl-7-benzyloxy-3-methyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as a light yellow solid (71%).
High-Res MS, ES⁺, 271.1454 (M+H)⁺ (obs.), 271.1447 (M+H)⁺ (calc.).

Example 132: 2-benzyl-7-hydroxy-3-(2-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 5-benzyloxy-2-(chloromethyl)-1-(2-chloro-4-phenyl-butyl)pyridin-4-one

The title intermediate was prepared according to Method C using 1-amino-4-phenylbutan-2-ol involving a purification of the crude product by chromatography (SiO₂, gradient from DCM up to 15% methanolic ammonia in DCM) as a yellow oil. MS, ES⁺, 380.3 (M+H)⁺.

Step 2: Preparation of 5-benzyloxy-2-(chloromethyl)-1-(2-chloro-4-phenyl-butyl)pyridin-4-one

The title intermediate was prepared according to Method B using 5-benzyloxy-2-(chloromethyl)-1-(2-chloro-4-phenyl-butyl)pyridin-4-one at 60° C. as a dark beige powder used in the next step without any further purification. MS, ES⁺, 416.1/418.1 (M+H)⁺.

Step 3: Preparation of 2-benzyl-7-benzyloxy-3-phenethyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title intermediate was prepared according to Method K using 5-benzyloxy-2-(chloromethyl)-1-(2-chloro-4-phenyl-butyl)pyridin-4-one, benzylamine and triethylamine, involving a purification of the crude product by chromatography (SiO₂, gradient from DCM up to 15% methanolic ammonia in DCM) as a dark yellow oil. MS, ES⁺, 451.2 (M+H)⁺.

Step 4: Preparation of: 2-benzyl-7-hydroxy-3-(2-phenylethyl)-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 2-benzyl-7-benzyloxy-3-phenethyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as a yellow solid (42%).
High-Res MS, ES⁺, 361.1907 (M+H)⁺ (obs.), 361.1916 (M+H)⁺ (calc.).

Example 133: 9-chloro-2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-9-chloro-2-[(2-chloro-6-fluoro-phenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-2-[(2-chloro-6-fluoro-phenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Intermediate prepared for the Example 7, 63 mg, 0.16 mmol) and N-chlorosuccinimide (22 mg, 0.16 mmol) were poured in CH₃CN (1 mL). The solution was degassed for 2 min, then heated overnight at 50° C. DCM (1 mL) was added and the suspension filtered on a 5 um filter. The solvent was evaporated to yield a light yellow oil (45 mg) used in the next step without any further purification. MS, ES⁺, 433.2/435.2 (M+H)⁺.

Step 2: Preparation of 9-chloro-2-(2-chloro-6-fluorobenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 7-benzyloxy-9-chloro-2-[(2-chloro-6-fluoro-phenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as an off white powder (quant.).
High-Res MS, ES⁺, 343.0398 (M+H)⁺ (obs.), 343.0416 (M+H)⁺ (calc.).

Example 134: 6-fluoro-7-hydroxy-2-[[2-chlorophenyl]methyl]-3,4-dihydro-1H-pyrido[l, 2-a]pyrazin-8-one

Step 1: Preparation of 6-bromo-2-fluoropyridin-3-ol

To a stirring solution of 2-fluoropyridin-3-ol (8.00 g, 70.7 mmol) in acetic acid (70 mL), potassium acetate (4.25 g, 70.7 mmol) was added. The solution was cooled to 0° C. after the potassium acetate had dissolved. Bromine (3.65 mL, 70.7 mmol) in acetic acid (10 mL) was added dropwise and the resulting mixture was stirred at room temperature for 1 h. Sodium sulfite (5 g) was added, followed by 1 N NaOH (30 mL). After the brown color of the solution disappeared, the solution was extracted with EtOAc (2×100 mL). The EtOAc extracts were combined, washed with water (100 mL), saturated NaHCO₃(100 mL), brine (100 mL), dried over Na₂SO₄, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal-phase chromatography (0-40% EtOAc/heptane) to give 6-bromo-2-fluoropyridin-3-ol (8.80 g, 45.8 mmol, 65% yield) as a white solid. MS (ES⁺) m/z 191.9 [M+H]⁺.
¹H NMR (400 MHz, CDCl₃) ppm 7.24-7.34 (m, 2H), 5.75 (br. s., 1H).

Step 2: Preparation of 6-bromo-2-fluoro-3-methoxypyridine

To a stirring solution of 6-bromo-2-fluoropyridin-3-ol (8.80 g, 45.8 mmol) in acetone (150 mL), potassium carbonate (12.67 g, 91.67 mmol) and iodomethane (5.71 mL, 91.7 mmol) were added. The resulting mixture was stirred under reflux overnight. The contents were filtered and the solvent removed in vacuo to give a residue which was purified by automated normal-phase chromatography (0-30% EtOAc/heptane) to give 6-bromo-2-fluoro-3-methoxypyridine (7.00 g, 34.0 mmol, 74% yield) as a white solid. MS (ES⁺) m/z 206.0 [M+H]⁺.
¹H NMR (400 MHz, CDCl₃) ppm 7.27-7.34 (m, 1H), 7.20 (dd, 1H), 3.88-3.95 (m, 3H).

Step 3: Preparation of 6-bromo-2-fluoro-3-methoxypyridin-4-ol

To a stirring solution of 6-bromo-2-fluoro-3-methoxypyridine (2.70 g, 13.1 mmol) in THF (50 mL) at −78° C., LDA (2 M in THF, 7.86 mL, 15.7 mmol) was added slowly. The resulting mixture was stirred at −78° C. for 1 h, then trimethyl borate (1.75 mL, 15.7 mmol) was added portionwise. The resulting mixture was stirred at −78° C. for 1 h then allowed to reach room temperature with stirring over 1 h. Hydrogen peroxide (30%, 2.49 mL, 15.7 mmol) was added slowly to the contents, and the resulting mixture was stirred at room temperature for 1 h. Sodium sulfite (5 g) was added, followed by water (50 mL) and 1 N HCl (50 mL) and stirring continued for 1 h. The contents were extracted with EtOAc (2×150 mL). The EtOAc extracts were combined, washed with brine (200 mL), dried over Na₂SO₄, filtered and the solvent removed in vacuo to give an off-white solid, which was used without further purification.

Step 4: Preparation of 4-benzyloxy-6-bromo-2-fluoro-3-methoxypyridine

To a stirring solution of crude 6-bromo-2-fluoro-3-methoxypyridin-4-ol (2.91 g, 13.1 mmol) in acetonitrile (50 mL), benzyl bromide (1.87 mL, 15.7 mmol) and potassium carbonate (3.98 g, 28.8 mmol) were added and the resulting mixture stirred at reflux overnight. After cooling to room temperature, the contents were filtered and washed with EtOAc. The filtrate was concentrated in vacuo to give a residue which was purified by automated normal-phase chromatography (0-20% EtOAc/heptane) to give 4-benzyloxy-6-bromo-2-fluoro-3-methoxy-pyridine (3.22 g, 10.3 mmol, 79% yield, two steps) as a white solid. MS (ES⁺) m/z 312.0 [M+H]⁺.
¹H NMR (400 MHz, CDCl₃) ppm 7.36-7.49 (m, 5H), 6.96-7.02 (m, 1H), 5.19 (s, 2H), 3.88-3.96 (m, 3H).

Step 5: Preparation of 4-benzyloxy-6-fluoro-5-methoxypyridine-2-carbaldehyde

To a stirring solution of 4-benzyloxy-6-bromo-2-fluoro-3-methoxypyridine (4.10 g, 13.1 mmol) in Et₂O (60 mL) at −78° C., nBuLi (1.6 M in hexanes, 9.85 mL, 15.8 mmol) was added dropwise. After the resulting mixture was stirred at −78° C. for 40 min, DMF (1.52 mL, 19.7 mmol) was added and stirring continued for 2 h at −78° C. Saturated NH₄Cl (50 mL) was added and the resulting mixture extracted with EtOAc (2×150 mL). The EtOAc extracts were combined. washed with water (100 mL), brine (100 mL), dried over Na₂SO₄, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal-phase chromatography (0-30% EtOAc/heptane) to give 4-benzyloxy-6-fluoro-5-methoxypyridine-2-carbaldehyde (1.85 g, 7.06 mmol, 54% yield) as an off-white solid. MS (ES⁺) m/z 262.0 [M+H]⁺.
¹H NMR (400 MHz, CDCl₃) ppm 9.77-9.84 (m, 1H), 7.52-7.58 (m, 1H), 7.35-7.49 (m, 5H), 5.22-5.30 (m, 2H), 4.03-4.10 (m, 3H).

Step 6: Preparation of 2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methylamino]ethanol

To a stirring solution of 4-benzyloxy-6-fluoro-5-methoxypyridine-2-carbaldehyde (1.85 g, 7.06 mmol) in MeOH (30 mL) at room temperature was added ethanolamine (0.52 g, 8.47 mmol). The contents were stirred at room temperature for 30 min, then NaBH₄(0.40 g, 10.6 mmol) was added. After stirring 1 h, the reaction was complete and the solvent was removed in vacuo. Ethyl acetate (150 mL) was added then washed with 0.1 N NaOH (20 mL), brine (20 mL), dried over Na₂SO₄, filtered and the solvent removed in vacuo to give 2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methylamino]ethanol (1.75 g, 5.71 mmol, 81% yield) as a colorless oil which was used without further purification.

Step 7: Preparation of tert-butyl N-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl]-N-(2-hydroxyethyl)carbamate

To a stirring solution of 2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methylamino]ethanol (2.16 g, 7.06 mmol) in DCM (50 mL), was added triethylamine (1.96 mL, 14.1 mmol), followed by di-tert-butydicarbonate (2.00.g, 9.18 mmol). The resulting mixture was stirred at room temperature overnight, diluted with DCM (30 mL) and washed with 1 N HCl (2×30 mL), brine (20 mL), dried over Na₂SO₄, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal-phase chromatography (0-60% EtOAc/heptane) to give tert-butyl N-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl]-N-(2-hydroxyethyl)carbamate (2.32 g, 5.72 mmol, 81% yield) as a colorless oil. MS (ES⁺) m/z 407.2 [M+H]⁺.
¹H NMR (400 MHz, CDCl₃) ppm 7.33-7.46 (m, 5H), 6.69-6.90 (m, 1H), 5.20 (br. s., 2H), 4.32 (d, 2H), 3.93 (d, 3H), 3.78 (br. s., 2H), 3.46-3.55 (m, 2H).

Step 8: Preparation of 2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl-tert-butoxycarbonyl-amino]ethyl Methanesulfonate

To a stirring solution of tert-butyl N-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl]-N-(2-hydroxyethyl)carbamate (2.32 g, 5.71 mmol) in DCM (50 mL) at 0° C. was added triethylamine (1.19 mL, 8.56 mmol) and methanesulfonyl chloride (0.53 mL, 6.85 mmol). The resulting mixture was stirred at 0° C. for 1 h, diluted with DCM (20 mL) and washed with 1 N HCl (3×20 mL), water (5 mL), brine (10 mL), dried over Na₂SO₄, filtered and the solvent removed in vacuo to give 2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl-tert-butoxycarbonyl-amino]ethyl methanesulfonate (2.63 g, 5.43 mmol, 95% yield) as a colorless oil which was used without further purification.

Step 9: Preparation of 2-[tert-butoxycarbonyl-[(6-fluoro-4-hydroxy-5-methoxy-2-pyridyl)methyl]amino]ethyl Methanesulfonate

To a stirring solution of 2-[(4-benzyloxy-6-fluoro-5-methoxy-2-pyridyl)methyl-tert-butoxycarbonyl-amino]ethyl methanesulfonate (2.63 g, 5.43 mmol) in EtOAc (60 mL), was added 10% Pd/C (1.5 g, 1.42 mmol). After purging under vacuum, the contents were reacted for 2 h under H₂at atmospheric pressure. The contents were filtered and the solvent removed in vacuo to give a residue which was used without further purification. MS (ES⁺) m/z 395.0 [M+H]⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.75 (s, 1H), 4.25-4.32 (s, 3H), 3.73-3.78 (s, 3H), 3.48-3.58 (m, 4H), 3.14-3.18 (m, 2H), 2.31-2.37 (m, 9H).

Step 10: Preparation of tert-butyl 6-fluoro-7-methoxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate

To a stirring solution of 2-[tert-butoxycarbonyl-[(6-fluoro-4-hydroxy-5-methoxy-2-pyridyl)methyl]amino]ethyl methanesulfonate (2.10 g, 5.32 mmol) in acetonitrile (30 mL), was added potassium carbonate (1.10 g, 7.99 mmol). The resulting mixture was stirred at room temperature overnight, diluted with ethyl acetate (60 mL), filtered through a pad of Celite and the solvent removed in vacuo to give a residue which was purified by automated normal-phase chromatography (0-5% MeOH/DCM) to give tert-butyl 6-fluoro-7-methoxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (1.60 g, 5.36 mmol, 100% yield) as a colorless oil. MS (ES⁺) m/z 299.2 [M+H]⁺.
¹H NMR (400 MHz, CDCl₃) ppm 6.29 (s, 1H), 4.51 (s, 2H), 4.02-4.10 (m, 2H), 3.92-3.98 (m, 3H), 3.77-3.86 (m, 2H), 1.51 (s, 9H).

Step 11: Preparation of 6-fluoro-7-methoxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one

To a stirring solution of tert-butyl 6-fluoro-7-methoxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (1.61 g, 5.40 mmol) in DCM (25 mL) was added TFA (25.mL). The resulting mixture was stirred at room temperature for 1 h and the solvent removed in vacuo to give 6-fluoro-7-methoxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one trifluoroacetate as a colorless oil which was used without further purification.

Method R

Step 12a: Preparation of 2-[(2-chlorophenyl)methyl]-6-fluoro-7-methoxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

To a stirring solution of 6-fluoro-7-methoxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one trifluoroacetate (290 mg, 0.58 mmol) in DCM (5 mL) was added 2-chlorobenzaldehyde (80 μL, 0.69 mmol) and two drops of acetic acid, followed by sodium triacetoxyborohydride (244 mg, 1.15 mmol). The resulting mixture was stirred at room temperature overnight, diluted with DCM (20 mL), washed with saturated NaHCO₃(3×20 mL), brine (20 mL), dried over Na₂SO₄, filtered the solvent removed in vacuo to give a residue which was purified by automated normal-phase chromatography (0-5% MeOH/DCM) to give 2-[(2-chlorophenyl)methyl]-6-fluoro-7-methoxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (83.0 mg, 0.257 mmol, 45% yield) as colorless oil. MS (ES⁺) m/z 323.0 [M+H]⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.46-7.59 (m, 2H), 7.34-7.43 (m, 2H), 6.89 (s, 1H), 4.28 (br. s., 2H), 3.96 (s, 2H), 3.87 (s, 2H), 3.01-3.11 (m, 2H).

Step 12b: Preparation of 2-[(2-chlorophenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

To a stirring solution of 2-[(2-chlorophenyl)methyl]-6-fluoro-7-methoxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (78 mg, 0.24 mmol) in DCM (10 mL) at 0° C., was slowly added boron tribromide (1 M in DCM, 0.97 mL, 0.97 mmol). The resulting mixture was stirred at 0° C. for 1 h, allowed to reach room temperature and stirred for 3 h, then quenched with the addition of MeOH (3 mL). The solvent was removed in vacuo and the residue which was purified by automated normal-phase chromatography [0-10% (5% HOAc in MeOH)/DCM] to give the purified free base, was converted to its HCl salt by treating with HCl (2 M in Et2O, 20 mL) and evaporated to dryness under vacuum to give 2-[(2-chlorophenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one hydrochloride (65.0 mg, 0.188 mmol, 78% yield) as a pale purple solid. MS (ES⁺) m/z 309.0 [M+H]⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.52 (dd, 3H), 7.44-7.49 (m, 1H), 7.29-7.40 (m, 2H), 6.02 (s, 1H), 3.94 (t, 2H), 3.71-3.77 (m, 5H), 3.62 (s, 2H), 2.89 (t, 2H).

Example 135: 2-[(4-(trifluoromethoxy)phenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method R using 6-fluoro-7-methoxy-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-8-one trifluoroacetate and 4-(trifluoromethoxy)benzaldehyde, followed by demethylation with BBr₃to give 2-[(4-(trifluoromethoxy)phenyl)methyl]-6-fluoro-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one hydrochloride (53%). MS, ES⁺, 359.0 (M+H)⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.54-7.70 (m, 2H), 7.32-7.49 (m, 2H), 6.98 (s, 1H), 4.41 (br. s., 2H), 4.13-4.30 (m, 4H), 3.35 (br. s., 2H).

Example 136: 9-chloro-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-9-chloro-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-chlorosuccinimide (1 equiv., 0.2670 mmol, 37.14 mg) was added to a solution of 7-benzyloxy-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Intermediate prepared for the Example 13, 100 mg, 0.27 mmol) in CH₃CN (1 mL). The mixture was degassed and stirred 14 h at 50° C. The reaction mixture was allowed to cool to rt. The precipitate was filtered and the filtrates were evaporated to give the title intermediate as a brown oil (113 mg) used in the next step without further purification. MS, ES⁺, 409.3 (M+H)⁺.

Step 2: Preparation of 9-chloro-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 7-benzyloxy-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (63%).
MS, ES⁺, 319 (M+H)⁺.

Example 137: 9-chloro-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 9-chloro-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-chlorosuccinimide (68.2 mg, 0.511 mmol) was added to a solution of 2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Intermediate prepared for the Example 58, 200 mg, 0.487 mmol) in CH₃CN (1 mL). The mixture was degassed and stirred 1 h at room temperature. The contents were poured into brine, extracted with DCM, dried over Na₂SO₄, filtered and the solvent removed in vacuo to give a residue which was purified by normal-phase chromatography to give the title intermediate as a yellow oil (50 mg). MS, ES⁺, 446.3 (M+H)⁺.

Step 2: Preparation of 9-chloro-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 9-chloro-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (30%).
MS, ES⁺, 326.2 (M+H)⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.54-7.60 (m, 1H), 7.45-7.53 (m, 2H), 7.32-7.44 (m, 2H), 4.07 (t, 2H), 3.92 (s, 2H), 3.82 (s, 2H), 2.97 (br. s., 2H)

Example 138: 9-bromo-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-9-bromo-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-bromosuccinimide (428 mg, 1 eq., 2.4 mmol) was added to a solution of 7-benzyloxy-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Intermediate prepared for the Example 13, 900 mg, 2.4 mmol) in CH₃CN (3 mL) and the mixture was stirred 1 h at 40° C. An aq. solution of NaHCO₃was added and the mixture was extracted with DCM. The combined organic layers were dried over MgSO₄, filtered and evaporated to give a yellow oil (1.2 g). Purification by chromatography (SiO₂, DCM-MeOH—NH₄OH 97-2.7-0.3) to yield the title intermediate as a yellow solid (86%). MS, ES⁺, 451.3/453.2 (M+H)⁺.

Step 2: Preparation of 9-bromo-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 7-benzyloxy-9-bromo-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one as a yellow solid (94%). MS, ES⁺, 363.2 (M+H)⁺.

Example 139: 9-bromo-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 9-bromo-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-bromosuccinimide (0.91 g, 5.11 mmol) was added to a solution of 2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Intermediate prepared for the Example 58, 200 mg, 0.487 mmol) in CHCl₃(75 mL). The mixture was stirred 1 h at room temperature. The contents were poured into brine, extracted with DCM, dried over Na₂SO₄, filtered and the solvent removed in vacuo to give a residue which was purified by normal-phase chromatography to give the title intermediate as a yellow solid (1.5 g). MS, ES⁺, 490.0 (M+H)⁺.

Step 2: Preparation of 9-bromo-2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 9-bromo-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (80%).
MS, ES⁺, 370.1 (M+H)⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.49-7.63 (m, 3H), 7.40 (dd, 2H), 4.09-4.21 (m, 2H), 4.03 (s, 2H), 3.91 (s, 2H), 3.08 (d, 2H)

Example 140: 2-[(2-chlorophenyl)methyl]-7-hydroxy-9-iodo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 2-[(2-chlorophenyl)methyl]-9-iodo-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

N-iodosuccinimide (152 mg, 0.678 mmol) was added to a solution of 2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Intermediate prepared for the Example 58, 265 mg, 0.645 mmol) in HOAc (5 mL). The solvent was removed in vacuo to give a residue which was purified by normal-phase chromatography to give the title intermediate as a yellow solid (155 mg). MS, ES⁺, 537.3 (M+H)⁺.

Step 2: Preparation of 2-[(2-chlorophenyl)methyl]-7-hydroxy-9-iodo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 2-[(2-chlorophenyl)methyl]-9-iodo-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (74%).
MS, ES⁺, 417.2 (M+H)⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.75 (br. s., 2H), 7.41-7.63 (m, 3H), 4.28-4.44 (m, 4H), 4.14 (br. s., 2H), 3.32 (br. s., 2H)

Example 141: 9-cyclopropyl-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 7-benzyloxy-9-cyclopropyl-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

7-benzyloxy-9-bromo-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Intermediate formed for the preparation of Example 120, 100 mg, 0.22 mmol), cyclopropylboronic acid (5 eq., 1.10 mmol, 99.7 mg), [bis(diphenylphosphino)ferrocene]dichloropalladium (II) (3 eq., 0.66 mmol, 484 mg) and cesium carbonate (0.5 eq., 0.110 mmol, 35.9 mg) were placed in a mixture 1,4-dioxane (3 mL) and H₂O (1 mL). The mixture was degassed for 10 min. then heated 20 min. at 110° C. under microwave irradiation followed by 14 h at 100° C. (oil bath). The solvents were evaporated and the residue purified by chromatography (SiO₂, gradient from EtOAc up to 20% methanolic ammonia in EtOAc) to yield the title intermediate (30 mg, 33%). MS, ES⁺, 415.4 (M+H)⁺.

Step 2: Preparation of 9-cyclopropyl-2-(4-ethylbenzyl)-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 7-benzyloxy-9-cyclopropyl-2-[(4-ethylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (69%).
MS, ES⁺, 325.3 (M+H)⁺.

Example 142: 2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

Step 1: Preparation of 2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

9-bromo-2-[(2-chlorophenyl)methyl]-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one (Intermediate prepared for Example 139, 100 mg, 0.204 mmol), cyclopropylboronic acid (26.3 mg, 0.306 mmol), palladium (II) acetate (4.6 mg, 0.02 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25.4 mg, 0.04 mmol) and cesium carbonate (200 mg, 0.61 mmol) were suspended in 1,4-dioxane (4 mL). The mixture was degassed for 10 min. then heated 18 h at 95° C. The solvents were evaporated and the residue purified by to give the title intermediate as a colorless oil. MS, ES⁺, 451.3 (M+H)⁺.

Step 2: Preparation of 2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one

The title compound was prepared according to Method E using 2-[(2-chlorophenyl)methyl]-9-cyclopropyl-7-[(4-methoxyphenyl)methoxy]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one and the crude product purified by HPLC (5%). MS, ES⁺, 331.2 (M+H)⁺.
¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.90 (s, 1H), 7.48-7.64 (m, 2H), 7.38 (dd, 2H), 7.34-7.45 (m, 2H), 4.31-4.51 (m, 2H), 4.07 (s, 2H), 3.85-4.00 (m, 2H), 3.00 (d, 2H), 1.46-1.62 (m, 1H), 0.89-1.07 (m, 2H), 0.57-0.74 (m, 2H)

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Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein:

X is selected from hydrogen; chloro; bromo, iodo and cyclopropyl;

Z is selected from hydrogen and fluoro;

R₁and R₂are each independently selected from hydrogen; C_1-4alkyl; aryl; substituted aryl; arylalkyl and heterocycle;

R₃and R₄are each independently selected from hydrogen; C₁-C₄alkyl; aryl and arylalkyl;

R₅is selected from aryl, heteroaryl, heterocycle, C₁-C₁₀alkyl or C₁-C₁₀cycloaklyl, optionally substituted with one or more groups selected from hydrogen; mono-, di-, or trihalomethyl; C₁-C₄alkyl; C₃-C₁₀cycloalkyl; halo; heteroaryl; cyano; nitro; aryloxy;

aryl; alkoxy; arylalkoxy and NHC(O)R, wherein R is C₁-C₄alkyl; and

Y is (CR₆R₇)_n, wherein n is from 0-3, and R₆and R₇are independently selected from hydrogen;

C₁-C₆alkyl; C₃-C₅cycloalkyl; C₁-C₄alkylhydroxyl; mono- di-, or trihaloalkyl; and aryl; R₆and R₇may also come together to form a C₃-C₆cycloalkyl; or

when R₅is phenyl, one of R₆or R₇comes together with R₅to form a bicycle