Allobarbital

Example 21

• 7-Chloro-5-[3-(morpholine-4-carbonyl)-isoxazol-5-yl]-2-((S)-2,2,2-trifluoro-1-methyl-ethyl)-2,3-dihydro-isoindol-1-one.

The compounds described herein may be generally formulated into a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substance, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or table disintegrating agents. A solid carrier can also be an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized moulds and allowed to cool and solidify.

Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be made as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Exemplary compositions intended for oral use may contain one or more coloring, sweetening, flavoring and/or preservative agents.

Depending on the mode of administration, the pharmaceutical composition will include from about 0.05% w (percent by weight) to about 99% w, more particularly, from about 0.10% w to 50% w, of the compound of the invention, all percentages by weight being based on the total weight of the composition.

A therapeutically effective amount for the practice of the present invention can be determined by one of ordinary skill in the art using known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease that is being treated or being prevented.

Medical Uses

Compounds described herein exhibit activity as modulators of metabotropic glutamate receptors and more particularly exhibit activity as potentiators of the mGluR2 receptor. It is contemplated that the compounds will be useful in therapy as pharmaceuticals, in particular for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction in an animal and particularly in a human.

More specifically, the neurological and psychiatric disorders include, but are not limited to, disorders such as cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD)), mood disorders (including depression, mania, bipolar disorders), circadian rhythm disorders (including jet lag and shift work), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder.

The invention thus provides a use of any of the compounds according to Formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of any of the conditions discussed above.

Additionally, the invention provides a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in need of such treatment. The invention also provides a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The term “therapeutic” and “therapeutically” should be construed accordingly. The term “therapy” within the context of the present invention further encompasses the administration of an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or to mitigate a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.

In use for therapy in a warm-blooded animal such as a human, the compounds of the present invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. In preferred embodiments of the invention, the route of administration is oral, intravenous, or intramuscular.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, who determines the individual regimen and dosage level for a particular patient.

As mentioned above, the compounds described herein may be provided or delivered in a form suitable for oral use, for example, in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension. Alternatively, the compounds may be formulated into a topical administration, for example, as a cream, ointment, gel, spray, or aqueous solution, oily solution, emulsion or suspension. The compounds described herein also may be provided in a form that is suitable for nasal administration, for example, as a nasal spray, nasal drops, or dry powder. The compounds can be administered to the vagina or rectum in the form of a suppository. The compounds described herein also may be administered parentally, for example, by intravenous, intravesicular, subcutaneous, or intramuscular injection or infusion. The compounds can be administered by insufflation (for example as a finely divided powder). The compounds may also be administered transdermally or sublingually.

In addition to their use in therapeutic medicine, the compounds of Formula I, or salts thereof, are useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of mGluR-related activity in laboratory animals as part of the search for new therapeutics agents. Such animals include, for example, cats, dogs, rabbits, monkeys, rats and mice.

A compound of Formula I or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, or a pharmaceutical composition or formulation comprising a compound of Formula I may be administered concurrently, simultaneously, sequentially or separately with another pharmaceutically active compound or compounds selected from the following:

(i) antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(ii) atypical antipsychotics including for example quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof;
(iii) antipsychotics including for example amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(iv) anxiolytics including for example alnespirone, azapirones, benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(v) anticonvulsants including for example carbamazepine, valproate, lamotrogine, gabapentin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(vi) Alzheimer's therapies including for example donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(vii) Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(viii) migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(ix) stroke therapies including for example abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase, repinotan, traxoprodil and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(x) urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(xi) neuropathic pain therapies including for example gabapentin, lidoderm, pregablin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(xii) nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
(xiii) insomnia therapies including for example allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, roletamide, triclofos, secobarbital, zaleplon, zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof, or
(xiv) mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

Such combination products employ the compound of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.

Biological Assays

The pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity. Examples of glutamate receptor assays are well known in the art as described in, for example, Aramori et al., 1992, Neuron, 8:757; Tanabe et al., 1992, Neuron, 8:169; Miller et al., 1995, J. Neuroscience, 15:6103; Balazs, et al., 1997, J. Neurochemistry, 1997, 69:151. The methodology described in these publications is incorporated herein by reference. Conveniently, the compounds of the invention can be studied by means of an assay that measures the mobilization of intracellular calcium, [Ca²⁺], in cells expressing mGluR2.

hERG activity was assessed using the process described by Bridgland-Taylor, M. H., et al, J. Pharm. Tox. Methods 54 (2006) 189-199.

Solubility was determined in pH 7.4 phosphate buffer after equilibration for 24 h at 25° C. and HPLC-UV and LC-MSMS were used for quantitation.

A [³⁵S]-GTPγS binding assay was used to functionally assay mGluR2 receptor activation. The allosteric activator activity of compounds at the human mGluR2 receptor were measured using a [³⁵S]-GTPγS binding assay with membranes prepared from CHO cells that stably express the human mGluR2. The assay is based upon the principle that agonists bind to G-protein coupled receptors to stimulate GDP-GTP exchange at the G-protein. Since [³⁵S]-GTPγS is a non-hydrolyzable GTP analog, it can be used to provide an index of GDP-GTP exchange and, thus, receptor activation. The GTPγS binding assay therefore provides a quantitative measure of receptor activation.

Membranes were prepared from CHO cells stably transfected with human mGluR2. Membranes (30 μg protein) were incubated with test compound (3 nM to 300 μM) for 15 minutes at room temperature prior to the addition of 1 μM glutamate, and incubated for 30 min at 30° C. in 500 μl assay buffer (20 mM HEPES, 100 mM NaCl, 10 mM MgCl₂), containing 30 μM GDP and 0.1 nM [³⁵S]-GTPγS (1250 Ci/mmol). Reactions were carried out in triplicate in 2 ml polypropylene 96-well plates. Reactions were terminated by vacuum filtration using a Packard 96-well harvester and Unifilter-96, GF/B filter microplates. The filter plates were washed 4×1.5 ml with ice-cold wash buffer (10 mM sodium phosphate buffer, pH 7.4). The filter plates were dried and 35 μl of scintillation fluid (Microscint 20) was added to each well. The amount of radioactivity bound was determined by counting plates on the Packard TopCount. Data was analyzed using GraphPad Prism, and EC₅₀ and E_max values (relative to the maximum glutamate effect) were calculated using non-linear regression.

As illustrated in Table 2, below, generally, compounds described herein have favourable solubility, low capacity to activate the hERG ion channel and were highly active in assays described herein for mGluR2 modulator activity, having EC₅₀ values as shown.

Example 21

• 7-Chloro-5-[3-(morpholine-4-carbonyl)-isoxazol-5-yl]-2-((S)-2,2,2-trifluoro-1-methyl-ethyl)-2,3-dihydro-isoindol-1-one.

The compounds described herein may be generally formulated into a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substance, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or table disintegrating agents. A solid carrier can also be an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized moulds and allowed to cool and solidify.

Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be made as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Exemplary compositions intended for oral use may contain one or more coloring, sweetening, flavoring and/or preservative agents.

Depending on the mode of administration, the pharmaceutical composition will include from about 0.05% w (percent by weight) to about 99% w, more particularly, from about 0.10% w to 50% w, of the compound of the invention, all percentages by weight being based on the total weight of the composition.

A therapeutically effective amount for the practice of the present invention can be determined by one of ordinary skill in the art using known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease that is being treated or being prevented.

Medical Uses

Compounds described herein exhibit activity as modulators of metabotropic glutamate receptors and more particularly exhibit activity as potentiators of the mGluR2 receptor. It is contemplated that the compounds will be useful in therapy as pharmaceuticals, in particular for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction in an animal and particularly in a human.

More specifically, the neurological and psychiatric disorders include, but are not limited to, disorders such as cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD)), mood disorders (including depression, mania, bipolar disorders), circadian rhythm disorders (including jet lag and shift work), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder.

The invention thus provides a use of any of the compounds according to Formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of any of the conditions discussed above.

Additionally, the invention provides a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in need of such treatment. The invention also provides a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The term “therapeutic” and “therapeutically” should be construed accordingly. The term “therapy” within the context of the present invention further encompasses the administration of an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or to mitigate a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.

In use for therapy in a warm-blooded animal such as a human, the compounds of the present invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. In preferred embodiments of the invention, the route of administration is oral, intravenous, or intramuscular.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, who determines the individual regimen and dosage level for a particular patient.

As mentioned above, the compounds described herein may be provided or delivered in a form suitable for oral use, for example, in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension. Alternatively, the compounds may be formulated into a topical administration, for example, as a cream, ointment, gel, spray, or aqueous solution, oily solution, emulsion or suspension. The compounds described herein also may be provided in a form that is suitable for nasal administration, for example, as a nasal spray, nasal drops, or dry powder. The compounds can be administered to the vagina or rectum in the form of a suppository. The compounds described herein also may be administered parentally, for example, by intravenous, intravesicular, subcutaneous, or intramuscular injection or infusion. The compounds can be administered by insufflation (for example as a finely divided powder). The compounds may also be administered transdermally or sublingually.

In addition to their use in therapeutic medicine, the compounds of Formula I, or salts thereof, are useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of mGluR-related activity in laboratory animals as part of the search for new therapeutics agents. Such animals include, for example, cats, dogs, rabbits, monkeys, rats and mice.

A compound of Formula I or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, or a pharmaceutical composition or formulation comprising a compound of Formula I may be administered concurrently, simultaneously, sequentially or separately with another pharmaceutically active compound or compounds selected from the following:

• (i) antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (ii) atypical antipsychotics including for example quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (iii) antipsychotics including for example amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (iv) anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (v) anticonvulsants including for example carbamazepine, valproate, lamotrogine, gabapentin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (vi) Alzheimer's therapies including for example donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (vii) Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (viii) migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (ix) stroke therapies including for example abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase,repinotan, traxoprodil and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof,
• (x) urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (xi) neuropathic pain therapies including for example gabapentin, lidoderm, pregablin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (xii) nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
• (xiii) insomnia therapies including for example allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, roletamide, triclofos, secobarbital, zaleplon, zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof, or
• (xiv) mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

Such combination products employ the compound of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.

Biological Assays

The pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity. Examples of glutamate receptor assays are well known in the art as described in, for example, Aramori et al., 1992, Neuron, 8:757; Tanabe et al., 1992, Neuron, 8:169; Miller et al., 1995, J. Neuroscience, 15:6103; Balazs, et al., 1997, J. Neurochemistry, 1997,69:151. The methodology described in these publications is incorporated herein by reference. Conveniently, the compounds of the invention can be studied by means of an assay that measures the mobilization of intracellular calcium, [Ca²⁺]_i in cells expressing mGluR2.

hERG activity was assessed using the process described by Bridgland-Taylor, M. H., et al, J. Pharm. Tox. Methods 54 (2006) 189-199.

Solubility was determined in pH 7.4 phosphate buffer after equilibration for 24 h at 25° C. and HPLC-UV and LC-MSMS were used for quantitation.

A [³⁵S]-GTPγS binding assay was used to functionally assay mGluR2 receptor activation. The allosteric activator activity of compounds at the human mGluR2 receptor were measured using a [³⁵S]-GTPγS binding assay with membranes prepared from CHO cells that stably express the human mGluR2. The assay is based upon the principle that agonists bind to G-protein coupled receptors to stimulate GDP-GTP exchange at the G-protein. Since [³⁵S]-GTPγS is a non-hydrolyzable GTP analog, it can be used to provide an index of GDP-GTP exchange and, thus, receptor activation. The GTPγS binding assay therefore provides a quantitative measure of receptor activation.

Membranes were prepared from CHO cells stably transfected with human mGluR2. Membranes (30 82 g protein) were incubated with test compound (3 nM to 300 μM) for 15 minutes at room temperature prior to the addition of 1 μM glutamate, and incubated for 30 min at 30° C. in 500 μl assay buffer (20 mM HEPES, 100 mM NaCl, 10 mM MgCl₂), containing 30 μM GDP and 0.1 nM [³⁵S]-GTPγS (1250 Ci/mmol). Reactions were carried out in triplicate in 2 ml polypropylene 96-well plates. Reactions were terminated by vacuum filtration using a Packard 96-well harvester and Unifilter-96, GF/B filter microplates. The filter plates were washed 4×1.5 ml with ice-cold wash buffer (10 mM sodium phosphate buffer, pH 7.4). The filter plates were dried and 35 μl of scintillation fluid (Microscint 20) was added to each well. The amount of radioactivity bound was determined by counting plates on the Packard TopCount. Data was analyzed using GraphPad Prism, and EC₅₀ and E_max values (relative to the maximum glutamate effect) were calculated using non-linear regression.

As illustrated in Table 2, below, generally, compounds described herein have favourable solubility, low capacity to activate the hERG ion channel and were highly active in assays described herein for mGluR2 modulator activity, having EC₅₀ values as shown.

Example 2

[Figure (not displayed)]

To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μL). After stirring at RT for 5 min, (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 4.98 (quin, J=7.1 Hz, 1H), 5.09 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.93-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.29 (m, 2H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 393.9.

Example 5

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (21 mg, 88%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.86-4.94 (m, 1H), 5.01-5.11 (m, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.95 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.08-8.16 (m, 1H), 8.21-8.29 (m, 2H), 8.74 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 6

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-1-(p-tolyl)ethanamine to give the title compound as a white solid (39.3 mg, 83%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.28 (s, 3H), 4.86-4.95 (m, 1H), 5.01-5.11 (m, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.92-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.28 (m, 2H), 8.74 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 7

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (14 mg, 58%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.01-5.10 (m, 2H), 6.85-6.92 (m, 2H), 7.23-7.29 (m, 2H), 7.92-8.00 (m, 1H), 8.07-8.16 (m, 1H), 8.21-8.28 (m, 2H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 339.0.

Example 8

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-chlorophenyl)ethanamine to give the title compound as a white solid (10 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.38 (d, J=6.8 Hz, 3H), 4.93 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.33-7.42 (m, 4H), 7.92-7.98 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.83 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 342.9, 345.0.

Example 9

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethylphenyl)ethanamine, HCl to give the title compound as a white solid (16.3 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 4.98-5.08 (m, 3H), 6.94 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.92-7.96 (m, 1H), 8.08-8.14 (m, 1H), 8.20-8.27 (m, 2H), 8.74 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 337.0.

Example 10

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(o-tolyl)ethanamine to give the title compound as a white solid (1 mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.29 (s, 3H), 5.05 (d, J=2.4 Hz, 2H), 5.09 (t, J=7.3 Hz, 1H), 7.11-7.16 (m, 2H), 7.19-7.24 (m, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.92-7.98 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 8.80 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 11

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-ethoxyphenyl)ethanamine, HCl to give the title compound as a white solid (19.4 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29-1.33 (m, 3H), 1.37 (d, J=6.8 Hz, 3H), 3.96-4.04 (m, 2H), 4.84-4.93 (m, 1H), 5.01-5.10 (m, 2H), 6.85-6.90 (m, 2H), 7.21-7.28 (m, 2H), 7.92-7.99 (m, 1H), 8.08-8.16 (m, 1H), 8.21-8.29 (m, 2H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 12

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethoxyphenyl)ethanamine, HCl to give the title compound as a white solid (17.2 mg, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.28 (d, J=6.8 Hz, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 5.06 (s, 2H), 5.14 (quin, J=7.3 Hz, 1H), 6.49-6.53 (m, 2H), 6.49-6.52 (m, 1H), 6.52 (s, 2H), 7.22 (d, J=7.8 Hz, 1H), 7.95 (td, J=7.6, 1.5 Hz, 1H), 8.11 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.62 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]⁺ 390.9.

Example 13

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (81 mg, 88%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40-1.43 (m, 3H), 5.01 (quin, J=7.2 Hz, 1H), 5.10 (s, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.95 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.10-8.14 (m, 1H), 8.21-8.28 (m, 2H), 8.91 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+Na]⁺ 399.3.

Example 14

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (23.4 mg, 77%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.10-7.24 (m, 4H), 7.96-8.03 (m, 2H), 8.33-8.39 (m, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.0.

Example 15

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (18.6 mg, 58%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.1 Hz, 1H), 5.05 (d, J=1.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.29 (m, 2H), 7.96-8.03 (m, 2H), 8.33-8.39 (m, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 357.0.

Example 16

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (13.0 mg, 43%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.1 Hz, 1H), 5.06-5.09 (m, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.23 (m, 2H), 7.91-8.03 (m, 2H), 8.04-8.09 (m, 1H), 8.73 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.0.

Example 17

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (22.4 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.92-8.03 (m, 2H), 8.06 (dd, J=7.8, 1.5 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 357.0.

Example 18

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (18.1 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.32-1.40 (m, 3H), 2.27 (s, 3H), 3.97 (s, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.03 (d, J=1.5 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.58 (d, J=2.4 Hz, 1H), 7.63-7.68 (m, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 19

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (15.6 mg, 52%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.25-2.28 (m, 3H), 4.86-4.94 (m, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.24 (m, 2H), 8.13-8.18 (m, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 357.0, 358.9.

Example 20

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (20.4 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.70-3.75 (m, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.05 (d, J=1.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 8.13-8.18 (m, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 372.4, 374.9.

Example 21

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an white solid (15.3 mg, 51%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 7.98 (dd, J=8.5, 2.2 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 357.0, 358.9.

Example 22

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (18.6 mg, 63%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.26-2.29 (m, 3H), 4.91 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.24 (m, 2H), 7.91 (t, J=7.8 Hz, 1H), 8.17-8.26 (m, 2H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 357.0, 358.9.

Example 23

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (14.2 mg, 46%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 7.87-7.94 (m, 1H), 8.22 (ddd, J=18.4, 7.9, 1.5 Hz, 2H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 372.9, 374.9.

Example 24

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (8.0 mg, 26%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 2.77 (s, 3H), 4.90 (t, J=7.6 Hz, 1H), 5.05 (d, J=1.5 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.19-7.24 (m, 2H), 7.78-7.85 (m, 1H), 7.91-7.96 (m, 1H), 8.04-8.10 (m, 1H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 337.0.

Example 25

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (6.0 mg, 19%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.77 (s, 3H), 3.71-3.75 (m, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.04 (d, J=2.4 Hz, 2H), 6.86-6.92 (m, 2H), 7.21-7.28 (m, 2H), 7.78-7.85 (m, 1H), 7.94 (dt, J=7.1, 1.3 Hz, 1H), 8.07 (d, J=7.3 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 26

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (12.1 mg, 42%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.86-4.94 (m, 1H), 5.07 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.23 (m, 2H), 8.20 (d, J=2.0 Hz, 1H), 8.44-8.47 (m, 1H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 390.8, 392.9.

Example 27

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (16.2 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.86-4.93 (m, 1H), 5.07 (d, J=1.0 Hz, 2H), 6.87-6.91 (m, 2H), 7.22-7.28 (m, 2H), 8.18-8.22 (m, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 406.8, 408.8.

Example 28

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (9.1 mg, 30%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.55 (s, 3H), 4.90 (t, J=7.6 Hz, 1H), 5.04 (d, J=1.5 Hz, 2H), 7.11-7.16 (m, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.92 (dd, J=8.3, 1.5 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 337.1.

Example 29

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (7.0 mg, 22%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.54-2.57 (m, 3H), 3.73 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.03 (d, J=2.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.93 (dd, J=8.3, 1.5 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 30

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (12.3 mg, 41%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.26-2.28 (m, 3H), 4.04 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.03 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.72-7.76 (m, 1H), 7.85-7.90 (m, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 31

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (11.8 mg, 38%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.72-3.74 (m, 3H), 4.04 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 4.99-5.05 (m, 2H), 6.86-6.91 (m, 2H), 7.21-7.27 (m, 2H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.71-7.77 (m, 1H), 7.84-7.90 (m, 1H), 8.68 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 369.0.

Example 32

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (11.3 mg, 37%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.24-2.29 (m, 4H), 4.87-4.95 (m, 1H), 5.02 (s, 2H), 7.11-7.15 (m, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.71-7.78 (m, 1H), 8.03-8.14 (m, 2H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.0.

Example 33

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (8.4 mg, 26%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.84-4.95 (m, 1H), 5.01 (s, 2H), 6.86-6.92 (m, 2H), 7.22-7.28 (m, 2H), 7.71-7.79 (m, 1H), 8.04-8.08 (m, 1H), 8.08-8.15 (m, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 356.9.

Example 34

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (28.2 mg, 92%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.57 (s, 3H), 4.90 (t, J=7.3 Hz, 1H), 5.04 (d, J=1.0 Hz, 2H), 7.10-7.16 (m, 2H), 7.20-7.23 (m, 2H), 7.77 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+Na]⁺ 359.0.

Example 35

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (24.1 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.00-0.00 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 2.56-2.59 (m, 3H), 3.73 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.03 (d, J=2.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.75-7.80 (m, 1H), 8.04 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.66-8.73 (m, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 36

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (23.3 mg, 78%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.32-1.40 (m, 3H), 2.27 (s, 3H), 3.99 (s, 3H), 4.89 (quin, J=7.3 Hz, 1H), 5.03 (d, J=1.0 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 37

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (20.6 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 3.71-3.74 (m, 3H), 3.99 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.02 (d, J=1.5 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 8.11-8.18 (m, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 369.0.

Example 38

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (4.2 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.70-3.74 (m, 3H), 3.92 (s, 3H), 4.83-4.92 (m, 1H), 4.95 (d, J=2.0 Hz, 2H), 6.85-6.91 (m, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.67-7.71 (m, 1H), 7.96-8.04 (m, 1H), 8.65 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 369.0.

Example 39

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (1.2 mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.34-1.39 (m, 3H), 2.26-2.29 (m, 4H), 2.81 (s, 3H), 4.85-4.94 (m, 1H), 5.00 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.25 (m, 2H), 7.70 (d, J=7.3 Hz, 1H), 7.91-7.98 (m, 1H), 8.02 (d, J=8.3 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+Na]⁺ 359.0.

Example 40

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (0.5 mg, 2%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.81 (s, 3H), 3.72-3.75 (m, 3H), 4.86-4.94 (m, 1H), 4.99 (s, 2H), 6.85-6.93 (m, 2H), 7.23-7.29 (m, 2H), 7.68-7.74 (m, 1H), 7.91-7.97 (m, 1H), 7.99-8.05 (m, 1H), 8.68 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]⁺ 375.0.

Example 41

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (10.7 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.28 (s, 3H), 2.73 (s, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.03 (d, J=2.4 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.20-7.23 (m, 2H), 7.77 (s, 1H), 7.87 (s, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 351.1.

Example 42

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (9.0 mg, 29%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.29 (d, J=2.4 Hz, 1H), 2.73 (s, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.02 (d, J=2.9 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.75-7.79 (m, 1H), 7.88 (d, J=1.0 Hz, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 367.0.

Example 43

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (16.8 mg, 59%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.26-2.28 (m, 3H), 4.91 (t, J=7.6 Hz, 1H), 5.11 (s, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.20-7.25 (m, 2H), 8.41-8.53 (m, 3H), 8.75 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 391.0.

Example 44

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (20.3 mg, 68%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.86-4.95 (m, 1H), 5.10 (d, J=1.0 Hz, 2H), 6.84-6.93 (m, 2H), 7.23-7.27 (m, 2H), 8.41-8.54 (m, 3H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]⁺ 429.0.

Example 45

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (25.5 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.55 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.83-7.90 (m, 2H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 355.4.

Example 46

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-methoxy-4-methylphenyl)ethanamine, HCl to give the title compound as a tan solid (38.8 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29 (d, J=6.8 Hz, 3H), 2.28 (s, 3H), 3.77 (s, 3H), 5.03-5.08 (m, 2H), 5.16 (quin, J=7.2 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.78 (s, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.92-7.98 (m, 1H), 8.08-8.15 (m, 1H), 8.20-8.28 (m, 2H), 8.66 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.2.

Example 47

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-chloro-4-fluorophenyl)ethanamine, HCl to give the title compound as a white solid (30.1 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.19 (quin, J=7.1 Hz, 1H), 7.27 (td, J=8.5, 2.9 Hz, 1H), 7.39 (dd, J=8.8, 2.9 Hz, 1H), 7.54 (dd, J=8.8, 6.3 Hz, 1H), 7.90-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 8.97 (d, J=7.3 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 360.1, 362.1.

Example 48

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-bromo-4-fluorophenyl)ethanamine, HCl to give the title compound as a white solid (37.4 mg, 63%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35 (d, J=7.3 Hz, 3H), 5.09 (s, 2H), 5.11-5.19 (m, 1H), 7.32 (td, J=8.5, 2.4 Hz, 1H), 7.49-7.56 (m, 2H), 7.92-7.98 (m, 1H), 8.11 (td, 1.5 Hz, 1H), 8.20-8.28 (m, 2H), 9.00 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 405.1, 407.1.

Example 49

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-fluorophenyl)ethanamine to give the title compound as a white solid (27.9 mg, 59%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36-1.41 (m, 3H), 4.95 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 7.12-7.21 (m, 2H), 7.35-7.41 (m, 2H), 7.92-7.99 (m, 1H), 8.08-8.15 (m, 1H), 8.20-8.29 (m, 2H), 8.79 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 327.2.

Example 52

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethylphenyl)ethanamine, HCl to give the title compound as a white solid (23.6 mg, 74%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 4.99-5.08 (m, 3H), 6.94 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.97-8.03 (m, 2H), 8.35 (dd, J=8.8, 4.9 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 355.3.

Example 53

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-methylphenyl)ethanamine, HCl to give the title compound as a white solid (23.4 mg, 71%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.29 (s, 3H), 5.05-5.16 (m, 3H), 6.93-7.03 (m, 2H), 7.31 (t, J=8.1 Hz, 1H), 7.91-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.20-8.28 (m, 2H), 8.83 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.2.

Example 54

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-methylphenyl)ethanamine, HCl to give the title compound as a white solid (13.6 mg, 42%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.29 (s, 3H), 5.05-5.14 (m, 3H), 6.91-7.04 (m, 2H), 7.30 (t, J=8.1 Hz, 1H), 7.97-8.04 (m, 2H), 8.36 (dd, J=8.5, 5.1 Hz, 1H), 8.84 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 359.2.

Example 55

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (13.2 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37-1.42 (m, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.08 (s, 2H), 7.30-7.35 (m, 2H), 7.42-7.47 (m, 2H), 7.97-8.03 (m, 2H), 8.33-8.40 (m, 1H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 411.2.

Example 56

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (21.8 mg, 81%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 3.99 (s, 3H), 4.97 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.44-7.52 (m, 3H), 7.67 (d, J=2.4 Hz, 1H), 8.15 (d, J=9.3 Hz, 1H), 8.84 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.4.

Example 57

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (17.3 mg, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 3.98 (s, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.58 (d, J=2.9 Hz, 1H), 7.64-7.69 (m, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.83 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.3.

Example 58

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (16.2 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=7.3 Hz, 3H), 3.93 (s, 3H), 4.93-5.00 (m, 3H), 7.33 (d, J=8.3 Hz, 2H), 7.43-7.48 (m, 3H), 7.65-7.72 (m, 1H), 8.00 (t, J=8.3 Hz, 1H), 8.79 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.3.

Example 59

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (22.5 mg, 87%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41 (d, J=6.8 Hz, 3H), 3.99 (s, 3H), 5.00 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.49 (dd, J=8.8, 2.9 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.67 (d, J=2.9 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 8.15 (d, J=8.8 Hz, 1H), 8.91 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 407.4.

Example 60

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (19.9 mg, 77%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.42 (d, J=6.8 Hz, 3H), 3.97 (s, 3H), 4.97-5.03 (m, 1H), 5.07 (s, 2H), 7.54-7.58 (m, 3H), 7.65 (dd, J=9.0, 2.7 Hz, 1H), 7.70 (d, J=7.8 Hz, 2H), 8.17 (d, J=9.3 Hz, 1H), 8.90 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 407.4.

Example 61

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (12.9 mg, 50%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41 (d, J=7.3 Hz, 3H), 3.93 (s, 3H), 4.96-5.04 (m, 3H), 7.41-7.47 (m, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.66-7.73 (m, 3H), 7.99 (t, J=8.3 Hz, 1H), 8.86 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 407.4.

Example 62

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (4.8 mg, 18%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.39 (d, J=7.3 Hz, 3H), 4.04 (s, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.43-7.49 (m, 2H), 7.62-7.67 (m, 1H), 7.74 (dd, J=7.8, 1.0 Hz, 1H), 7.84-7.91 (m, 1H), 8.82 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.3.

Example 64

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (10.6 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41 (d, J=7.3 Hz, 3H), 4.97-5.05 (m, 1H), 5.10 (s, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.97-8.02 (m, 2H), 8.36 (ddq, J=8.2, 4.9, 1.5, 1.5, 1.5 Hz, 1H), 8.92 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 395.3.

Example 65

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (11.3 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.42 (d, J=6.8 Hz, 3H), 5.10 (s, 2H), 5.14-5.21 (m, 1H), 7.59-7.70 (m, 3H), 7.92-7.98 (m, 1H), 8.11 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 9.02 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 395.6.

Example 66

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (19.2 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35-1.40 (m, 3H), 4.88-4.99 (m, 1H), 5.03-5.09 (m, 2H), 7.03-7.36 (m, 3H), 7.14 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.95-7.98 (m, 1H), 8.08-8.15 (m, 1H), 8.21-8.28 (m, 2H), 8.81 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 375.7.

Example 67

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (15.0 mg, 73%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.42 (d, J=6.8 Hz, 3H), 3.92 (s, 3H), 4.97-5.02 (m, 2H), 5.16 (quin, J=7.1 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.57-7.72 (m, 4H), 7.99 (t, J=8.1 Hz, 1H), 8.97 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 425.4.

Example 68

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (12.1 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.38 (d, J=6.8 Hz, 3H), 4.89-4.99 (m, 1H), 5.07 (s, 2H), 7.03-7.41 (m, 5H), 7.95-8.05 (m, 2H), 8.33-8.40 (m, 1H), 8.77-8.84 (m, 1H); ESI-MS m/z [M+H]⁺ 393.4.

Example 69

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (17.5 mg, 78%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.38 (d, J=6.8 Hz, 3H), 3.93 (s, 3H), 4.89-5.00 (m, 3H), 7.01-7.41 (m, 2H), 7.11-7.16 (m, 1H), 7.42-7.47 (m, 1H), 7.67-7.72 (m, 1H), 7.99 (t, J=8.3 Hz, 1H), 8.75 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 405.4.

Example 70

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (6.0 mg, 27%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.13 (quin, J=7.1 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.36 (dd, J=10.5, 1.7 Hz, 1H), 7.56 (t, J=8.5 Hz, 1H), 7.92-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.95 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 411.3.

Example 71

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (7.8 mg, 33%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.10-5.17 (m, 1H), 7.27 (d, J=9.8 Hz, 1H), 7.36 (d, J=10.7 Hz, 1H), 7.55 (t, J=8.5 Hz, 1H), 7.95-8.04 (m, 2H), 8.36 (dd, J=8.5, 5.1 Hz, 1H), 8.95 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 429.2.

Example 72

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (11.8 mg, 49%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37-1.42 (m, 3H), 3.92 (s, 3H), 4.99 (s, 2H), 5.13 (quin, J=7.2 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.33-7.39 (m, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.56 (t, J=8.5 Hz, 1H), 7.69 (dd, J=7.8, 1.0 Hz, 1H), 7.97-8.03 (m, 1H), 8.90 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 441.2.

Example 73

[Figure (not displayed)]

To a solution of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (25 mg, 0.122 mmol) in DCM (406 μL) was added 1 drop DMF and oxalyl chloride (21 μL, 0.244 mmol). The mixture was allowed to stir at RT for 45 min, and was then added to a solution of 2-phenylethanamine (15 μL, 0.122 mmol) and triethylamine (19 μL, 0.134 mmol) in 400 μL DCM. The reaction mixture was stirred at RT for 18 h. Purification by HPLC Method A provided the title compound as a white solid (11.1 mg, 30%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.73 (t, J=7.6 Hz, 2H), 3.29-3.34 (m, 2H), 5.00 (s, 2H), 7.20-7.33 (m, 5H), 7.93-7.99 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.41 (t, J=5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 309.9.

Example 74

[Figure (not displayed)]

To a solution of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (25 mg, 0.122 mmol) in DCM (406 μL) was added 1 drop DMF and oxalyl chloride (21 μL, 0.244 mmol). The mixture was stirred at RT for 45 min, then added to a solution of 2-(4-chlorophenyl)ethanamine (17 μL, 0.122 mmol) and triethylamine (19 μL, 0.134 mmol) in 400 μL DCM. The reaction mixture was stirred at RT for 18 h. Purification by flash silica gel chromatography, eluting with 0-70% EtOAc in heptanes provided the title compound as a white solid (5.2 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.73 (t, J=7.1 Hz, 2H), 3.28-3.32 (m, 2H), 4.99 (s, 2H), 7.24-7.29 (m, 2H), 7.33-7.37 (m, 2H), 7.93-8.00 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.39 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 342.9, 344.9.

Example 75

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 74 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(3-chlorophenyl)ethanamine to give the title compound as a white solid (8.4 mg, 20%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.75 (t, J=7.1 Hz, 2H), 3.32-3.36 (m, 2H), 4.99 (s, 2H), 7.18-7.35 (m, 4H), 7.96 (td, J=7.6, 1.5 Hz, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.41 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 342.9, 344.9.

Example 76

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 73 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(p-tolyl)ethanamine to give the title compound as a white solid (5.5 mg, 14%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H), 2.68 (t, J=7.6 Hz, 2H), 3.25-3.31 (m, 2H), 4.99 (s, 2H), 7.10 (s, 4H), 7.92-8.00 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.37-8.42 (m, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 79

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-2-phenylpropan-1-amine to give the title compound as a white solid (12.5 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3H), 2.89 (sxt, J=7.1 Hz, 1H), 3.24 (dd, J=7.1, 6.1 Hz, 2H), 4.99 (s, 2H), 7.17-7.34 (m, 5H), 7.92-7.99 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.29 (m, 2H), 8.36 (t, J=5.9 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 80

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-2-phenylpropan-1-amine to give the title compound as a white solid (13.1 mg, 56%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3H), 2.86-2.93 (m, 1H), 3.22-3.26 (m, 2H), 4.99 (s, 2H), 7.17-7.34 (m, 5H), 7.96 (td, J=7.6, 1.5 Hz, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.29 (m, 2H), 8.36 (t, J=5.9 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 81

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(2-chloro-4-methoxyphenyl)ethanamine to give the title compound as a white solid (16.6 mg, 61%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.78 (t, J=7.3 Hz, 2H), 3.25-3.30 (m, 2H), 3.31 (s, 2H), 3.75 (s, 3H), 4.99 (s, 2H), 6.87 (dd, J=8.5, 2.7 Hz, 1H), 7.01 (d, J=2.9 Hz, 1H), 7.21-7.27 (m, 1H), 7.93-8.00 (m, 1H), 8.09-8.16 (m, 1H), 8.22-8.30 (m, 2H), 8.42 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 373.0, 374.9.

Example 82

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-1-(4-methoxyphenyl)propan-2-amine to give the title compound as a white solid (17.9 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.53-2.72 (m, 2H), 3.70-3.74 (m, 3H), 3.91 (spt, J=6.8 Hz, 1H), 4.92-5.02 (m, 2H), 4.97 (d, J=4.9 Hz, 2H), 6.79-6.88 (m, 2H), 7.09-7.15 (m, 2H), 7.92-8.00 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.30 (m, 3H); ESI-MS m/z [M+H]⁺ 354.0.

Example 83

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)propan-2-amine to give the title compound as a white solid (14.1 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.53-2.74 (m, 2H), 3.70-3.74 (m, 3H), 3.88-3.96 (m, 1H), 4.92-5.02 (m, 2H), 6.81-6.88 (m, 2H), 7.08-7.16 (m, 2H), 7.96 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.22-8.30 (m, 3H); ESI-MS m/z [M+H]⁺ 353.9.

Example 84

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-chloro-2-methoxyphenyl)propan-2-amine to give the title compound as a white solid (19.7 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.67 (d, J=6.8 Hz, 2H), 3.78-3.82 (m, 3H), 3.97-4.07 (m, 1H), 4.89-4.99 (m, 2H), 6.92 (dd, J=7.8, 2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.93-7.99 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.22-8.28 (m, 2H); ESI-MS m/z [M, M+2]⁺ 386.9, 389.0.

Example 85

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-chloro-4-methoxyphenyl)propan-2-amine, HCl to give the title compound as a tan solid (32.5 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.8 Hz, 3H), 2.75-2.78 (m, 2H), 3.75 (s, 3H), 3.99-4.09 (m, 1H), 4.89-5.02 (m, 2H), 6.86 (dd, J=8.5, 2.7 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 7.22-7.27 (m, 1H), 7.96-7.99 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.31 (m, 3H); ESI-MS m/z [M, M+2]⁺ 386.9, 388.9.

Example 87

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 87 using (S)-1-(4-(trifluoromethyl)phenyl)propan-1-amine hydrochloride to give the title compound as an off-white solid (19 mg, 56%). ¹H NMR (500 MHz, chloroform-d) δ ppm 0.92 (t, J=7.1 Hz, 3H) 1.86 (t, J=7.3 Hz, 2H) 4.95 (d, J=7.3 Hz, 1H) 5.13 (s, 2H) 6.31 (d, J=7.8 Hz, 1H) 7.40 (d, J=7.8 Hz, 2H) 7.59 (d, J=7.8 Hz, 2H) 7.86 (d, J=8.3 Hz, 1H) 8.00 (s, 1H) 8.21 (d, J=8.3 Hz, 1H) 8.38 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 391.

The compounds of the invention can be administered alone or in the form of a pharmaceutical composition. In practice, the compounds of the invention are usually administered in the form of pharmaceutical compositions, that is, in admixture with at least one pharmaceutically acceptable excipient. The proportion and nature of any pharmaceutically acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.

In another embodiment, the present invention provides pharmaceutical compositions comprising: a compound of invention and at least one pharmaceutically acceptable excipient.

In effecting treatment of a patient in need of such treatment, a compound of the invention can be administered in any form and route which makes the compound bioavailable. The compounds of the invention can be administered by a variety of routes, including orally, in particularly by tablets and capsules. The compounds of the invention can be administered by parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.

One skilled in the art can readily select the proper form and route of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the invention may be administered to the patient, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, and suspensions.

The pharmaceutical compositions of the present invention are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient. The amount of a compound of the invention may be varied depending upon its particular form and may conveniently be between 1% to about 50% of the weight of the unit dose form. The term “pharmaceutically acceptable excipient” refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which in the aggregate can serve as a vehicle or medium for the active ingredient. Some examples of pharmaceutically acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.

The present pharmaceutical compositions are preferably formulated in a unit dose form, each dose typically containing from about 0.5 mg to about 100 mg of a compounds of the invention. The term “unit dose form” refers to a physically discrete unit containing a predetermined quantity of active ingredient, in association with a suitable pharmaceutical excipient, by which one or more is used throughout the dosing regimen to produce the desired therapeutic effect. One or more “unit dose form” may be taken to affect the treatment dosage, typically on a daily schedule.

In one particular variation, the composition is a pharmaceutical composition adapted for oral administration, such as a tablet or a capsule or a liquid formulation, for example, a solution or suspension, adapted for oral administration. In still another particular variation, the pharmaceutical composition is a liquid formulation adapted for parenteral administration.

In another embodiment, the invention provides a method of treating a disease, disorder or condition associated with GPR139, comprising: administering to a patient in need thereof an effective amount of a compound of the invention. In another embodiment, a compound of the invention is provided for use as a medicament. The invention also provides the use of a compound of the invention, including the use for the manufacture of a medicament, to treat a disease, disorder or condition associated with GPR139 described herein. The compounds of the invention are GPR139 agonists for treating a variety of subjects (e.g., humans, non-human mammals and non-mammals).

As used herein terms “condition,” “disorder,” and “disease” relate to any unhealthy or abnormal state. The compounds of the invention are GPR139 agonists and may be useful for treating a variety of conditions. The term “disease, disorder or condition associated with GPR139” includes conditions, disorders, and diseases in which an agonist of GPR139 may provide a therapeutic benefit, such as CNS disorders, disorders of the pancreas, such as pancreatitis, phenylketonuria, and pituitary disorders.

The term “disease, disorder or condition associated with GPR139” includes specifically, but is not limited to, CNS disorders such as schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, including mild cognitive impairment, Alzheimer's Disease, disorders affecting short term memory, disorders affecting long term memory, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, including generalized anxiety disorder and social anxiety disorder, pain, fibromyalgia and other disorders mentioned herein, among others.

Schizophrenia is a chronic, severe, and disabling disorder characterized, in part, by negative symptoms, such as blunted affect, deficits in social functioning, anhedonia, avolition and poverty of speech, and by congnitive impairment associated with schizophrenia (CIAS), such as impairment in attention, working memory, executive function and social cognition. Autism spectrum disorder is a group of developmental disabilities that can cause significant social, communication and behavioral challenges (repetitive and stereotyped behavior). Because of the pro-social effects expected from GPR139 agonists, the present compounds may treat schizophrenia and autism spectrum disorder.

In particular, the term “disease, disorder or condition associated with GPR139” includes schizophrenia.

In particular, the term “disease, disorder or condition associated with GPR139” includes autism spectrum disorder.

In particular, the term “disease, disorder or condition associated with GPR139” includes addiction. Examples include addiction to nicotine, alcohol, and/or cocaine.

In particular, the term “disease, disorder or condition associated with GPR139” includes attention deficit hyperactivity disorder.

In particular, the term “disease, disorder or condition associated with GPR139” includes bipolar disorder.

In particular, the term “disease, disorder or condition associated with GPR139” includes depression, such as major depressive disorder.

The terms “treat,” “treatment,” and “treating” include improvement of the conditions described herein. The terms “treat,” “treatment,” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition. The terms “treat,” “treatment,” and “treating” are intended to include therapeutic treatment of such disorders. The terms “treat,” “treatment,” and “treating” are intended to include prophylactic treatment of such disorders.

As used herein the terms “patient” and “subject” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs.

As used herein, the term “effective amount” refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, the dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of the present invention, the treatment dosage, is expected to range from 1 mg to 100 mg. Specific amounts can be determined by the skilled person. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient having a mass that falls outside of this weight range.

The compounds of the invention may be combined with one or more other pharmacologically active compounds or therapies for the treatment of one or more disorders, diseases or conditions for which GPR139 is indicated may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating a particular disease, disorder or condition associated with GPR139.

For example, in the treatment of schizophrenia the compounds of the invention may be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, mGlu2/3 agonists, 5HT-2 antagonists, PDE10 antagonists, GlyT1 inhibitors, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazopam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazopam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazopam, thioridazine, thiothixene, tracazolate, kanylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and the like.

Also for example, in the treatment of depression the compounds of the invention may be administered 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 (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazopines, 5-HTA agonists or antagonists, especially 5-HTA 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, clonazopam, chlorazepate, diazopam, halazepam, lorazepam, oxazopam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and the like.

In yet another example, in the treatment of Alzheimer's disease or mild cognitive impairment the compounds of the invention may be administered in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, anti-amyloid antibodies, also sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, and tranquilizers, and such other medications as are used in the treatment of Alzheimer's disease or mild cognitive impairment.

The activity of compounds as GPR139 agonists may be determined by a variety of methods, including in vitro and in vivo methods.

Example 2

[Figure (not displayed)]

To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μL). After stirring at RT for 5 min, (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 4.98 (quin, J=7.1 Hz, 1H), 5.09 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.93-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.29 (m, 2H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 393.9.

Example 5

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (21 mg, 88%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.86-4.94 (m, 1H), 5.01-5.11 (m, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.95 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.08-8.16 (m, 1H), 8.21-8.29 (m, 2H), 8.74 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 6

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-1-(p-tolyl)ethanamine to give the title compound as a white solid (39.3 mg, 83%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.28 (s, 3H), 4.86-4.95 (m, 1H), 5.01-5.11 (m, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.92-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.28 (m, 2H), 8.74 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 7

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (14 mg, 58%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.01-5.10 (m, 2H), 6.85-6.92 (m, 2H), 7.23-7.29 (m, 2H), 7.92-8.00 (m, 1H), 8.07-8.16 (m, 1H), 8.21-8.28 (m, 2H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 339.0.

Example 8

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-chlorophenyl)ethanamine to give the title compound as a white solid (10 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.38 (d, J=6.8 Hz, 3H), 4.93 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.33-7.42 (m, 4H), 7.92-7.98 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.83 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 342.9, 345.0.

Example 9

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethylphenyl)ethanamine, HCl to give the title compound as a white solid (16.3 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 4.98-5.08 (m, 3H), 6.94 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.92-7.96 (m, 1H), 8.08-8.14 (m, 1H), 8.20-8.27 (m, 2H), 8.74 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 337.0.

Example 10

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(o-tolyl)ethanamine to give the title compound as a white solid (1 mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.29 (s, 3H), 5.05 (d, J=2.4 Hz, 2H), 5.09 (t, J=7.3 Hz, 1H), 7.11-7.16 (m, 2H), 7.19-7.24 (m, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.92-7.98 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 8.80 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 11

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-ethoxyphenyl)ethanamine, HCl to give the title compound as a white solid (19.4 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29-1.33 (m, 3H), 1.37 (d, J=6.8 Hz, 3H), 3.96-4.04 (m, 2H), 4.84-4.93 (m, 1H), 5.01-5.10 (m, 2H), 6.85-6.90 (m, 2H), 7.21-7.28 (m, 2H), 7.92-7.99 (m, 1H), 8.08-8.16 (m, 1H), 8.21-8.29 (m, 2H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 12

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethoxyphenyl)ethanamine, HCl to give the title compound as a white solid (17.2 mg, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.28 (d, J=6.8 Hz, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 5.06 (s, 2H), 5.14 (quin, J=7.3 Hz, 1H), 6.49-6.53 (m, 2H), 6.49-6.52 (m, 1H), 6.52 (s, 2H), 7.22 (d, J=7.8 Hz, 1H), 7.95 (td, J=7.6, 1.5 Hz, 1H), 8.11 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.62 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]⁺ 390.9.

Example 13

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (81 mg, 88%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40-1.43 (m, 3H), 5.01 (quin, J=7.2 Hz, 1H), 5.10 (s, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.95 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.10-8.14 (m, 1H), 8.21-8.28 (m, 2H), 8.91 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+Na]⁺ 399.3.

Example 14

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (23.4 mg, 77%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.10-7.24 (m, 4H), 7.96-8.03 (m, 2H), 8.33-8.39 (m, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.0.

Example 15

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (18.6 mg, 58%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.1 Hz, 1H), 5.05 (d, J=1.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.29 (m, 2H), 7.96-8.03 (m, 2H), 8.33-8.39 (m, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 357.0.

Example 16

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (13.0 mg, 43%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.1 Hz, 1H), 5.06-5.09 (m, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.23 (m, 2H), 7.91-8.03 (m, 2H), 8.04-8.09 (m, 1H), 8.73 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.0.

Example 17

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (22.4 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.92-8.03 (m, 2H), 8.06 (dd, J=7.8, 1.5 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 357.0.

Example 18

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (18.1 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.32-1.40 (m, 3H), 2.27 (s, 3H), 3.97 (s, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.03 (d, J=1.5 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.58 (d, J=2.4 Hz, 1H), 7.63-7.68 (m, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 19

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (15.6 mg, 52%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.25-2.28 (m, 3H), 4.86-4.94 (m, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.24 (m, 2H), 8.13-8.18 (m, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 357.0, 358.9.

Example 20

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (20.4 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.70-3.75 (m, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.05 (d, J=1.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 8.13-8.18 (m, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 372.4, 374.9.

Example 21

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an white solid (15.3 mg, 51%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 7.98 (dd, J=8.5, 2.2 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 357.0, 358.9.

Example 22

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (18.6 mg, 63%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.26-2.29 (m, 3H), 4.91 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.24 (m, 2H), 7.91 (t, J=7.8 Hz, 1H), 8.17-8.26 (m, 2H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 357.0, 358.9.

Example 23

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (14.2 mg, 46%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 7.87-7.94 (m, 1H), 8.22 (ddd, J=18.4, 7.9, 1.5 Hz, 2H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 372.9, 374.9.

Example 24

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (8.0 mg, 26%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 2.77 (s, 3H), 4.90 (t, J=7.6 Hz, 1H), 5.05 (d, J=1.5 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.19-7.24 (m, 2H), 7.78-7.85 (m, 1H), 7.91-7.96 (m, 1H), 8.04-8.10 (m, 1H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 337.0.

Example 25

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (6.0 mg, 19%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.77 (s, 3H), 3.71-3.75 (m, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.04 (d, J=2.4 Hz, 2H), 6.86-6.92 (m, 2H), 7.21-7.28 (m, 2H), 7.78-7.85 (m, 1H), 7.94 (dt, J=7.1, 1.3 Hz, 1H), 8.07 (d, J=7.3 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 26

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (12.1 mg, 42%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.86-4.94 (m, 1H), 5.07 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.23 (m, 2H), 8.20 (d, J=2.0 Hz, 1H), 8.44-8.47 (m, 1H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 390.8, 392.9.

Example 27

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (16.2 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.86-4.93 (m, 1H), 5.07 (d, J=1.0 Hz, 2H), 6.87-6.91 (m, 2H), 7.22-7.28 (m, 2H), 8.18-8.22 (m, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 406.8, 408.8.

Example 28

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (9.1 mg, 30%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.55 (s, 3H), 4.90 (t, J=7.6 Hz, 1H), 5.04 (d, J=1.5 Hz, 2H), 7.11-7.16 (m, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.92 (dd, J=8.3, 1.5 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 337.1.

Example 29

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (7.0 mg, 22%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.54-2.57 (m, 3H), 3.73 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.03 (d, J=2.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.93 (dd, J=8.3, 1.5 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 30

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (12.3 mg, 41%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.26-2.28 (m, 3H), 4.04 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.03 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.72-7.76 (m, 1H), 7.85-7.90 (m, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 31

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (11.8 mg, 38%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.72-3.74 (m, 3H), 4.04 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 4.99-5.05 (m, 2H), 6.86-6.91 (m, 2H), 7.21-7.27 (m, 2H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.71-7.77 (m, 1H), 7.84-7.90 (m, 1H), 8.68 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 369.0.

Example 32

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (11.3 mg, 37%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.24-2.29 (m, 4H), 4.87-4.95 (m, 1H), 5.02 (s, 2H), 7.11-7.15 (m, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.71-7.78 (m, 1H), 8.03-8.14 (m, 2H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.0.

Example 33

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (8.4 mg, 26%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.84-4.95 (m, 1H), 5.01 (s, 2H), 6.86-6.92 (m, 2H), 7.22-7.28 (m, 2H), 7.71-7.79 (m, 1H), 8.04-8.08 (m, 1H), 8.08-8.15 (m, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 356.9.

Example 34

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (28.2 mg, 92%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.57 (s, 3H), 4.90 (t, J=7.3 Hz, 1H), 5.04 (d, J=1.0 Hz, 2H), 7.10-7.16 (m, 2H), 7.20-7.23 (m, 2H), 7.77 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+Na]⁺ 359.0.

Example 35

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (24.1 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.00-0.00 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 2.56-2.59 (m, 3H), 3.73 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.03 (d, J=2.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.75-7.80 (m, 1H), 8.04 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.66-8.73 (m, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 36

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (23.3 mg, 78%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.32-1.40 (m, 3H), 2.27 (s, 3H), 3.99 (s, 3H), 4.89 (quin, J=7.3 Hz, 1H), 5.03 (d, J=1.0 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.0.

Example 37

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (20.6 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3H), 3.71-3.74 (m, 3H), 3.99 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.02 (d, J=1.5 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 8.11-8.18 (m, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 369.0.

Example 38

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (4.2 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.70-3.74 (m, 3H), 3.92 (s, 3H), 4.83-4.92 (m, 1H), 4.95 (d, J=2.0 Hz, 2H), 6.85-6.91 (m, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.67-7.71 (m, 1H), 7.96-8.04 (m, 1H), 8.65 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 369.0.

Example 39

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (1.2 mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.34-1.39 (m, 3H), 2.26-2.29 (m, 4H), 2.81 (s, 3H), 4.85-4.94 (m, 1H), 5.00 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.25 (m, 2H), 7.70 (d, J=7.3 Hz, 1H), 7.91-7.98 (m, 1H), 8.02 (d, J=8.3 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+Na]⁺ 359.0.

Example 40

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (0.5 mg, 2%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.81 (s, 3H), 3.72-3.75 (m, 3H), 4.86-4.94 (m, 1H), 4.99 (s, 2H), 6.85-6.93 (m, 2H), 7.23-7.29 (m, 2H), 7.68-7.74 (m, 1H), 7.91-7.97 (m, 1H), 7.99-8.05 (m, 1H), 8.68 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]⁺ 375.0.

Example 41

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (10.7 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.28 (s, 3H), 2.73 (s, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.03 (d, J=2.4 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.20-7.23 (m, 2H), 7.77 (s, 1H), 7.87 (s, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 351.1.

Example 42

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (9.0 mg, 29%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.29 (d, J=2.4 Hz, 1H), 2.73 (s, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.02 (d, J=2.9 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.75-7.79 (m, 1H), 7.88 (d, J=1.0 Hz, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 367.0.

Example 43

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (16.8 mg, 59%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.26-2.28 (m, 3H), 4.91 (t, J=7.6 Hz, 1H), 5.11 (s, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.20-7.25 (m, 2H), 8.41-8.53 (m, 3H), 8.75 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 391.0.

Example 44

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (20.3 mg, 68%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.86-4.95 (m, 1H), 5.10 (d, J=1.0 Hz, 2H), 6.84-6.93 (m, 2H), 7.23-7.27 (m, 2H), 8.41-8.54 (m, 3H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]⁺ 429.0.

Example 45

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (25.5 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.55 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.83-7.90 (m, 2H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 355.4.

Example 46

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-methoxy-4-methylphenyl)ethanamine, HCl to give the title compound as a tan solid (38.8 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29 (d, J=6.8 Hz, 3H), 2.28 (s, 3H), 3.77 (s, 3H), 5.03-5.08 (m, 2H), 5.16 (quin, J=7.2 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.78 (s, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.92-7.98 (m, 1H), 8.08-8.15 (m, 1H), 8.20-8.28 (m, 2H), 8.66 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 353.2.

Example 47

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-chloro-4-fluorophenyl)ethanamine, HCl to give the title compound as a white solid (30.1 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.19 (quin, J=7.1 Hz, 1H), 7.27 (td, J=8.5, 2.9 Hz, 1H), 7.39 (dd, J=8.8, 2.9 Hz, 1H), 7.54 (dd, J=8.8, 6.3 Hz, 1H), 7.90-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 8.97 (d, J=7.3 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 360.1, 362.1.

Example 48

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-bromo-4-fluorophenyl)ethanamine, HCl to give the title compound as a white solid (37.4 mg, 63%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35 (d, J=7.3 Hz, 3H), 5.09 (s, 2H), 5.11-5.19 (m, 1H), 7.32 (td, J=8.5, 2.4 Hz, 1H), 7.49-7.56 (m, 2H), 7.92-7.98 (m, 1H), 8.11 (td, 1.5 Hz, 1H), 8.20-8.28 (m, 2H), 9.00 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 405.1, 407.1.

Example 49

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-fluorophenyl)ethanamine to give the title compound as a white solid (27.9 mg, 59%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36-1.41 (m, 3H), 4.95 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 7.12-7.21 (m, 2H), 7.35-7.41 (m, 2H), 7.92-7.99 (m, 1H), 8.08-8.15 (m, 1H), 8.20-8.29 (m, 2H), 8.79 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 327.2.

Example 52

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethylphenyl)ethanamine, HCl to give the title compound as a white solid (23.6 mg, 74%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 4.99-5.08 (m, 3H), 6.94 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.97-8.03 (m, 2H), 8.35 (dd, J=8.8, 4.9 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 355.3.

Example 53

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-methylphenyl)ethanamine, HCl to give the title compound as a white solid (23.4 mg, 71%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.29 (s, 3H), 5.05-5.16 (m, 3H), 6.93-7.03 (m, 2H), 7.31 (t, J=8.1 Hz, 1H), 7.91-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.20-8.28 (m, 2H), 8.83 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.2.

Example 54

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-methylphenyl)ethanamine, HCl to give the title compound as a white solid (13.6 mg, 42%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.29 (s, 3H), 5.05-5.14 (m, 3H), 6.91-7.04 (m, 2H), 7.30 (t, J=8.1 Hz, 1H), 7.97-8.04 (m, 2H), 8.36 (dd, J=8.5, 5.1 Hz, 1H), 8.84 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 359.2.

Example 55

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (13.2 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37-1.42 (m, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.08 (s, 2H), 7.30-7.35 (m, 2H), 7.42-7.47 (m, 2H), 7.97-8.03 (m, 2H), 8.33-8.40 (m, 1H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 411.2.

Example 56

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (21.8 mg, 81%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 3.99 (s, 3H), 4.97 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.44-7.52 (m, 3H), 7.67 (d, J=2.4 Hz, 1H), 8.15 (d, J=9.3 Hz, 1H), 8.84 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.4.

Example 57

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (17.3 mg, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 3.98 (s, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.58 (d, J=2.9 Hz, 1H), 7.64-7.69 (m, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.83 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.3.

Example 58

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (16.2 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=7.3 Hz, 3H), 3.93 (s, 3H), 4.93-5.00 (m, 3H), 7.33 (d, J=8.3 Hz, 2H), 7.43-7.48 (m, 3H), 7.65-7.72 (m, 1H), 8.00 (t, J=8.3 Hz, 1H), 8.79 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.3.

Example 59

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (22.5 mg, 87%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41 (d, J=6.8 Hz, 3H), 3.99 (s, 3H), 5.00 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.49 (dd, J=8.8, 2.9 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.67 (d, J=2.9 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 8.15 (d, J=8.8 Hz, 1H), 8.91 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 407.4.

Example 60

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (19.9 mg, 77%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.42 (d, J=6.8 Hz, 3H), 3.97 (s, 3H), 4.97-5.03 (m, 1H), 5.07 (s, 2H), 7.54-7.58 (m, 3H), 7.65 (dd, J=9.0, 2.7 Hz, 1H), 7.70 (d, J=7.8 Hz, 2H), 8.17 (d, J=9.3 Hz, 1H), 8.90 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 407.4.

Example 61

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (12.9 mg, 50%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41 (d, J=7.3 Hz, 3H), 3.93 (s, 3H), 4.96-5.04 (m, 3H), 7.41-7.47 (m, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.66-7.73 (m, 3H), 7.99 (t, J=8.3 Hz, 1H), 8.86 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 407.4.

Example 62

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (4.8 mg, 18%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.39 (d, J=7.3 Hz, 3H), 4.04 (s, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.43-7.49 (m, 2H), 7.62-7.67 (m, 1H), 7.74 (dd, J=7.8, 1.0 Hz, 1H), 7.84-7.91 (m, 1H), 8.82 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.3.

Example 64

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (10.6 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41 (d, J=7.3 Hz, 3H), 4.97-5.05 (m, 1H), 5.10 (s, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.97-8.02 (m, 2H), 8.36 (ddq, J=8.2, 4.9, 1.5, 1.5, 1.5 Hz, 1H), 8.92 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 395.3.

Example 65

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (11.3 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.42 (d, J=6.8 Hz, 3H), 5.10 (s, 2H), 5.14-5.21 (m, 1H), 7.59-7.70 (m, 3H), 7.92-7.98 (m, 1H), 8.11 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 9.02 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 395.6.

Example 66

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (19.2 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35-1.40 (m, 3H), 4.88-4.99 (m, 1H), 5.03-5.09 (m, 2H), 7.03-7.36 (m, 3H), 7.14 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.95-7.98 (m, 1H), 8.08-8.15 (m, 1H), 8.21-8.28 (m, 2H), 8.81 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 375.7.

Example 67

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (15.0 mg, 73%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.42 (d, J=6.8 Hz, 3H), 3.92 (s, 3H), 4.97-5.02 (m, 2H), 5.16 (quin, J=7.1 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.57-7.72 (m, 4H), 7.99 (t, J=8.1 Hz, 1H), 8.97 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 425.4.

Example 68

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (12.1 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.38 (d, J=6.8 Hz, 3H), 4.89-4.99 (m, 1H), 5.07 (s, 2H), 7.03-7.41 (m, 5H), 7.95-8.05 (m, 2H), 8.33-8.40 (m, 1H), 8.77-8.84 (m, 1H); ESI-MS m/z [M+H]⁺ 393.4.

Example 69

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (17.5 mg, 78%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.38 (d, J=6.8 Hz, 3H), 3.93 (s, 3H), 4.89-5.00 (m, 3H), 7.01-7.41 (m, 2H), 7.11-7.16 (m, 1H), 7.42-7.47 (m, 1H), 7.67-7.72 (m, 1H), 7.99 (t, J=8.3 Hz, 1H), 8.75 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 405.4.

Example 70

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (6.0 mg, 27%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.13 (quin, J=7.1 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.36 (dd, J=10.5, 1.7 Hz, 1H), 7.56 (t, J=8.5 Hz, 1H), 7.92-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.95 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 411.3.

Example 71

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (7.8 mg, 33%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.10-5.17 (m, 1H), 7.27 (d, J=9.8 Hz, 1H), 7.36 (d, J=10.7 Hz, 1H), 7.55 (t, J=8.5 Hz, 1H), 7.95-8.04 (m, 2H), 8.36 (dd, J=8.5, 5.1 Hz, 1H), 8.95 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 429.2.

Example 72

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (11.8 mg, 49%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37-1.42 (m, 3H), 3.92 (s, 3H), 4.99 (s, 2H), 5.13 (quin, J=7.2 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.33-7.39 (m, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.56 (t, J=8.5 Hz, 1H), 7.69 (dd, J=7.8, 1.0 Hz, 1H), 7.97-8.03 (m, 1H), 8.90 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 441.2.

Example 73

[Figure (not displayed)]

To a solution of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (25 mg, 0.122 mmol) in DCM (406 μL) was added 1 drop DMF and oxalyl chloride (21 μL, 0.244 mmol). The mixture was allowed to stir at RT for 45 min, and was then added to a solution of 2-phenylethanamine (15 μL, 0.122 mmol) and triethylamine (19 μL, 0.134 mmol) in 400 μL DCM. The reaction mixture was stirred at RT for 18 h. Purification by HPLC Method A provided the title compound as a white solid (11.1 mg, 30%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.73 (t, J=7.6 Hz, 2H), 3.29-3.34 (m, 2H), 5.00 (s, 2H), 7.20-7.33 (m, 5H), 7.93-7.99 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.41 (t, J=5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 309.9.

Example 74

[Figure (not displayed)]

To a solution of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (25 mg, 0.122 mmol) in DCM (406 μL) was added 1 drop DMF and oxalyl chloride (21 μL, 0.244 mmol). The mixture was stirred at RT for 45 min, then added to a solution of 2-(4-chlorophenyl)ethanamine (17 μL, 0.122 mmol) and triethylamine (19 μL, 0.134 mmol) in 400 μL DCM. The reaction mixture was stirred at RT for 18 h. Purification by flash silica gel chromatography, eluting with 0-70% EtOAc in heptanes provided the title compound as a white solid (5.2 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.73 (t, J=7.1 Hz, 2H), 3.28-3.32 (m, 2H), 4.99 (s, 2H), 7.24-7.29 (m, 2H), 7.33-7.37 (m, 2H), 7.93-8.00 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.39 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 342.9, 344.9.

Example 75

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 74 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(3-chlorophenyl)ethanamine to give the title compound as a white solid (8.4 mg, 20%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.75 (t, J=7.1 Hz, 2H), 3.32-3.36 (m, 2H), 4.99 (s, 2H), 7.18-7.35 (m, 4H), 7.96 (td, J=7.6, 1.5 Hz, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.41 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 342.9, 344.9.

Example 76

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 73 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(p-tolyl)ethanamine to give the title compound as a white solid (5.5 mg, 14%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H), 2.68 (t, J=7.6 Hz, 2H), 3.25-3.31 (m, 2H), 4.99 (s, 2H), 7.10 (s, 4H), 7.92-8.00 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.37-8.42 (m, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 79

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-2-phenylpropan-1-amine to give the title compound as a white solid (12.5 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3H), 2.89 (sxt, J=7.1 Hz, 1H), 3.24 (dd, J=7.1, 6.1 Hz, 2H), 4.99 (s, 2H), 7.17-7.34 (m, 5H), 7.92-7.99 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.29 (m, 2H), 8.36 (t, J=5.9 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 80

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-2-phenylpropan-1-amine to give the title compound as a white solid (13.1 mg, 56%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3H), 2.86-2.93 (m, 1H), 3.22-3.26 (m, 2H), 4.99 (s, 2H), 7.17-7.34 (m, 5H), 7.96 (td, J=7.6, 1.5 Hz, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.29 (m, 2H), 8.36 (t, J=5.9 Hz, 1H); ESI-MS m/z [M+H]⁺ 323.0.

Example 81

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(2-chloro-4-methoxyphenyl)ethanamine to give the title compound as a white solid (16.6 mg, 61%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.78 (t, J=7.3 Hz, 2H), 3.25-3.30 (m, 2H), 3.31 (s, 2H), 3.75 (s, 3H), 4.99 (s, 2H), 6.87 (dd, J=8.5, 2.7 Hz, 1H), 7.01 (d, J=2.9 Hz, 1H), 7.21-7.27 (m, 1H), 7.93-8.00 (m, 1H), 8.09-8.16 (m, 1H), 8.22-8.30 (m, 2H), 8.42 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]⁺ 373.0, 374.9.

Example 82

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-1-(4-methoxyphenyl)propan-2-amine to give the title compound as a white solid (17.9 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.53-2.72 (m, 2H), 3.70-3.74 (m, 3H), 3.91 (spt, J=6.8 Hz, 1H), 4.92-5.02 (m, 2H), 4.97 (d, J=4.9 Hz, 2H), 6.79-6.88 (m, 2H), 7.09-7.15 (m, 2H), 7.92-8.00 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.30 (m, 3H); ESI-MS m/z [M+H]⁺ 354.0.

Example 83

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)propan-2-amine to give the title compound as a white solid (14.1 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.53-2.74 (m, 2H), 3.70-3.74 (m, 3H), 3.88-3.96 (m, 1H), 4.92-5.02 (m, 2H), 6.81-6.88 (m, 2H), 7.08-7.16 (m, 2H), 7.96 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.22-8.30 (m, 3H); ESI-MS m/z [M+H]⁺ 353.9.

Example 84

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-chloro-2-methoxyphenyl)propan-2-amine to give the title compound as a white solid (19.7 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.67 (d, J=6.8 Hz, 2H), 3.78-3.82 (m, 3H), 3.97-4.07 (m, 1H), 4.89-4.99 (m, 2H), 6.92 (dd, J=7.8, 2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.93-7.99 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.22-8.28 (m, 2H); ESI-MS m/z [M, M+2]⁺ 386.9, 389.0.

Example 85

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-chloro-4-methoxyphenyl)propan-2-amine, HCl to give the title compound as a tan solid (32.5 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.8 Hz, 3H), 2.75-2.78 (m, 2H), 3.75 (s, 3H), 3.99-4.09 (m, 1H), 4.89-5.02 (m, 2H), 6.86 (dd, J=8.5, 2.7 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 7.22-7.27 (m, 1H), 7.96-7.99 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.31 (m, 3H); ESI-MS m/z [M, M+2]⁺ 386.9, 388.9.

Example 87

[Figure (not displayed)]

The title compound was prepared in a manner similar to Example 87 using (S)-1-(4-(trifluoromethyl)phenyl)propan-1-amine hydrochloride to give the title compound as an off-white solid (19 mg, 56%). ¹H NMR (500 MHz, chloroform-d) δ ppm 0.92 (t, J=7.1 Hz, 3H) 1.86 (t, J=7.3 Hz, 2H) 4.95 (d, J=7.3 Hz, 1H) 5.13 (s, 2H) 6.31 (d, J=7.8 Hz, 1H) 7.40 (d, J=7.8 Hz, 2H) 7.59 (d, J=7.8 Hz, 2H) 7.86 (d, J=8.3 Hz, 1H) 8.00 (s, 1H) 8.21 (d, J=8.3 Hz, 1H) 8.38 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 391.

The compounds of the invention can be administered alone or in the form of a pharmaceutical composition. In practice, the compounds of the invention are usually administered in the form of pharmaceutical compositions, that is, in admixture with at least one pharmaceutically acceptable excipient. The proportion and nature of any pharmaceutically acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.

In another embodiment, the present invention provides pharmaceutical compositions comprising: a compound of invention and at least one pharmaceutically acceptable excipient.

In effecting treatment of a patient in need of such treatment, a compound of the invention can be administered in any form and route which makes the compound bioavailable. The compounds of the invention can be administered by a variety of routes, including orally, in particularly by tablets and capsules. The compounds of the invention can be administered by parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.

One skilled in the art can readily select the proper form and route of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the invention may be administered to the patient, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, and suspensions.

The pharmaceutical compositions of the present invention are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient. The amount of a compound of the invention may be varied depending upon its particular form and may conveniently be between 1% to about 50% of the weight of the unit dose form. The term “pharmaceutically acceptable excipient” refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which in the aggregate can serve as a vehicle or medium for the active ingredient. Some examples of pharmaceutically acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.

The present pharmaceutical compositions are preferably formulated in a unit dose form, each dose typically containing from about 0.5 mg to about 100 mg of a compounds of the invention. The term “unit dose form” refers to a physically discrete unit containing a predetermined quantity of active ingredient, in association with a suitable pharmaceutical excipient, by which one or more is used throughout the dosing regimen to produce the desired therapeutic effect. One or more “unit dose form” may be taken to affect the treatment dosage, typically on a daily schedule.

In one particular variation, the composition is a pharmaceutical composition adapted for oral administration, such as a tablet or a capsule or a liquid formulation, for example, a solution or suspension, adapted for oral administration. In still another particular variation, the pharmaceutical composition is a liquid formulation adapted for parenteral administration.

In another embodiment, the invention provides a method of treating a disease, disorder or condition associated with GPR139, comprising: administering to a patient in need thereof an effective amount of a compound of the invention. In another embodiment, a compound of the invention is provided for use as a medicament. The invention also provides the use of a compound of the invention, including the use for the manufacture of a medicament, to treat a disease, disorder or condition associated with GPR139 described herein. The compounds of the invention are GPR139 agonists for treating a variety of subjects (e.g., humans, non-human mammals and non-mammals).

As used herein terms “condition,” “disorder,” and “disease” relate to any unhealthy or abnormal state. The compounds of the invention are GPR139 agonists and may be useful for treating a variety of conditions. The term “disease, disorder or condition associated with GPR139” includes conditions, disorders, and diseases in which an agonist of GPR139 may provide a therapeutic benefit, such as CNS disorders, disorders of the pancreas, such as pancreatitis, phenylketonuria, and pituitary disorders.

The term “disease, disorder or condition associated with GPR139” includes specifically, but is not limited to, CNS disorders such as schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, including mild cognitive impairment, Alzheimer's Disease, disorders affecting short term memory, disorders affecting long term memory, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, including generalized anxiety disorder and social anxiety disorder, pain, fibromyalgia and other disorders mentioned herein, among others.

Schizophrenia is a chronic, severe, and disabling disorder characterized, in part, by negative symptoms, such as blunted affect, deficits in social functioning, anhedonia, avolition and poverty of speech, and by congnitive impairment associated with schizophrenia (CIAS), such as impairment in attention, working memory, executive function and social cognition. Autism spectrum disorder is a group of developmental disabilities that can cause significant social, communication and behavioral challenges (repetitive and stereotyped behavior). Because of the pro-social effects expected from GPR139 agonists, the present compounds may treat schizophrenia and autism spectrum disorder.

In particular, the term “disease, disorder or condition associated with GPR139” includes schizophrenia.

In particular, the term “disease, disorder or condition associated with GPR139” includes autism spectrum disorder.

In particular, the term “disease, disorder or condition associated with GPR139” includes addiction. Examples include addiction to nicotine, alcohol, and/or cocaine.

In particular, the term “disease, disorder or condition associated with GPR139” includes attention deficit hyperactivity disorder.

In particular, the term “disease, disorder or condition associated with GPR139” includes bipolar disorder.

In particular, the term “disease, disorder or condition associated with GPR139” includes depression, such as major depressive disorder.

The terms “treat,” “treatment,” and “treating” include improvement of the conditions described herein. The terms “treat,” “treatment,” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition. The terms “treat,” “treatment,” and “treating” are intended to include therapeutic treatment of such disorders. The terms “treat,” “treatment,” and “treating” are intended to include prophylactic treatment of such disorders.

As used herein the terms “patient” and “subject” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs.

As used herein, the term “effective amount” refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, the dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of the present invention, the treatment dosage, is expected to range from 1 mg to 100 mg. Specific amounts can be determined by the skilled person. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient having a mass that falls outside of this weight range.

The compounds of the invention may be combined with one or more other pharmacologically active compounds or therapies for the treatment of one or more disorders, diseases or conditions for which GPR139 is indicated may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating a particular disease, disorder or condition associated with GPR139.

For example, in the treatment of schizophrenia the compounds of the invention may be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, mGlu2/3 agonists, 5HT-2 antagonists, PDE10 antagonists, GlyT1 inhibitors, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazopam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazopam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazopam, thioridazine, thiothixene, tracazolate, kanylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and the like.

Also for example, in the treatment of depression the compounds of the invention may be administered 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 (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazopines, 5-HTA agonists or antagonists, especially 5-HTA 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, clonazopam, chlorazepate, diazopam, halazepam, lorazepam, oxazopam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and the like.

In yet another example, in the treatment of Alzheimer's disease or mild cognitive impairment the compounds of the invention may be administered in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, anti-amyloid antibodies, also sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, and tranquilizers, and such other medications as are used in the treatment of Alzheimer's disease or mild cognitive impairment.

The activity of compounds as GPR139 agonists may be determined by a variety of methods, including in vitro and in vivo methods.