Therapeutic combinations of drugs and methods of using them

Abstract

To provide therapeutic combinations of drugs and methods of using them.SOLUTION: Provided are methods for administering triple monoamine reuptake inhibitors (TRIs), melanin concentrating hormone receptor 1 (MCHR1) antagonists and diazoxide or diazoxide or its formulations, whose dosages are determined using a method as provided herein including empirical methods for safe and predictable titration and to determine the initial therapeutic dose; model -based methods for safe and predictable titration and to determine the initial therapeutic dose and to determine the lowest therapeutic dose or to determine an optimal effective dose, including use of Bayesian pharmacometrics models.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This Patent Cooperation Treaty (PCT) international application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Nos. 62 / 959,534, filed January 10, 2020, 62 / 959,769, filed January 10, 2020, 62 / 980,053, filed February 21, 2020, and 63 / 022,484, filed May 9, 2020. The foregoing applications are expressly incorporated by reference herein in their entirety for all purposes. All publications, patents, and patent applications cited herein are expressly incorporated by reference herein for all purposes.

[0002] The present invention relates generally to pharmacology and pharmacokinetics. In an alternative embodiment, therapeutic combinations or formulations of drugs are provided that include a triple monoamine reuptake inhibitor (TRI) (which inhibits the reuptake of serotonin, dopamine, and norepinephrine through blockade of the central serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET)), a melanin-concentrating hormone receptor 1 (MCHR1) antagonist, and diazoxide or formulations thereof, as well as various combinations thereof, and in combination with other drugs or active agents. In alternative embodiments, methods are provided for administering a triple monoamine reuptake inhibitor (TRI), a melanin-concentrating hormone receptor 1 (MCHR1) antagonist, or diazoxide, or a formulation thereof, where the dosage is determined using the methods provided herein, including empirical methods for stable and predictable titration and for determining the initial therapeutic dose; model-based methods, including the use of Bayesian pharmacometric models for stable and predictable titration and for determining the initial therapeutic dose and for determining the minimum therapeutic dose or determining the optimal effective dose. In alternative embodiments, methods are provided for treating various conditions, including genetically determined syndromes and diseases, using the therapeutic drug combinations and formulations provided herein. In an alternative embodiment, a PK-guided precision dosing method is provided that uses the pharmacokinetic modeling and simulation methods described above, or similar modeling and simulation methods, and a population PK / PD model of Formula I, for treating binge eating, binge eating in PWS, severe mood dysregulation disorder (DMDD), oppositional defiant disorder (ODD), obesity in hypothalamic lesion-induced obesity, and binge eating disorder (BED) by oral administration of Formula I or a deuterated form thereof. [Background technology]

[0003] Prader-Willi syndrome (PWS) is a rare, severe, complex, genetic neurodevelopmental disorder occurring in approximately 1 in 15,000–30,000 individuals. PWS is caused by a paternally expressed gene deletion on chromosome 15q11-13. In 70% of cases, PWS results from a paternally inherited deletion of 15q11-13. Approximately 25% of PWS cases result from maternal uniparental disomy (mUPD), i.e., when both copies of chromosome 15 are inherited from the mother, and 5% result from translocations or imprinting center mutations.

[0004] Today, the only treatment currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of PWS is human growth hormone, which is used to enhance linear growth. There are no approved treatments to treat the cardinal features of PWS, specifically the overeating, anxiety, and obsessive-compulsive symptoms. There are also no approved pharmaceutical treatments for the overeating or related behavioral symptoms associated with PWS.

[0005] Hypothalamic obesity or hypothalamic injury-induced obesity (HO or HIO) is caused by damage to the hypothalamus. The most common cause is related to a rare, noncancerous tumor called a craniopharyngioma. Removal of this tumor can damage the hypothalamus, resulting in symptoms of hypothalamic obesity, a disorder that shares many aspects of the PWS phenotype, including hyperphagia, excessive daytime sleepiness, ADHD, dysautonomia, and deficiencies of growth hormone, gonadotropins, and thyroid-stimulating hormone.

[0006] Narcolepsy is a chronic, disabling neurological disorder characterized by excessive sleepiness, affecting an estimated 20 to 67 people per 100,000 worldwide. Onset of narcolepsy most commonly occurs in the first decade of life, although diagnosis is often delayed for several years. Narcolepsy symptoms include excessive daytime sleepiness (EDS), which, while not specific to narcolepsy, is a diagnostic requirement and is therefore characteristic of the disorder present in all patients. Cataplexy, an involuntary loss of muscle tone during wakefulness, typically triggered by strong emotions, occurs in up to 60% of patients. Other symptoms include nocturnal sleep disturbances; hypnagogic and hypnagogic hallucinations (occurring when falling asleep and waking up, respectively); and sleep paralysis. There is no cure for narcolepsy. Symptom management involves the modulation of monoamine systems, such as serotonin, dopamine, norepinephrine, and histamine, as well as gamma-aminobutyric acid B (GABA). B Various drugs that modulate the orexin / hypocretin receptor are in clinical use. Narcolepsy, especially narcolepsy with cataplexy, is thought to be caused by a deficiency of orexin / hypocretin.

[0007] Obtaining the optimal dose for each patient is crucial for achieving clinical benefit and minimizing adverse events. It is difficult for physicians to prescribe the optimal dose for each patient due to individual differences in body weight, body composition, polymorphisms of metabolic enzymes (CYP P450), drug transporters (e.g., PGP polymorphisms), and drug-drug integration due to the use of multiple medications. Finding the optimal dose often involves inefficient empirical titration. It is even more difficult for pediatric patients, patients with intellectual disabilities, and clinically vulnerable patients.

[0008] The importance of dose to achieve clinical benefit and minimize adverse events has been emphasized in the case of tesofensine. Early clinical trials of tesofensine at standard doses showed some promise in managing weight in HIO and overeating in PWS (Saniona Corporation Presentation June 2020). However, published data also demonstrated that plasma drug concentrations can be highly variable in PWS patients (Saniona Corporation Presentation March 2019). Using only the standard mg / day dose, two-thirds of patients experienced plasma drug levels above safe levels, leading to treatment discontinuation due to adverse events (excessive dopamine increases due to DAT inhibition can cause CNS side effects or worsen existing CNS disorders in patients), whereas patients with adequate plasma drug levels achieved complete control of overeating. Similarly, dose reduction for all patients using the standard mg / day dose of tesofensine was ineffective. New paradigms are needed to ensure safe and effective dosing regimens for these high-risk patients. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Saniona Corporation Presentation June 2020 [Non-patent document 2] Saniona Corporation Presentation March 2019 Summary of the Invention [Means for solving the problem]

[0010] In an alternative embodiment, a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprising: (a)(i) triple monoamine reuptake inhibitors (TRIs) and melanin-concentrating hormone receptor 1 (MCHR1) antagonists or inhibitors; (ii) a triple monoamine reuptake inhibitor (TRI) and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation); (iii) a melanin-concentrating hormone receptor 1 (MCHR1) antagonist or inhibitor and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation); or (iv) a triple monoamine reuptake inhibitor (TRI) melanin-concentrating hormone receptor 1 (MCHR1) antagonist or inhibitor, and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation); or (b)(i) triple monoamine reuptake inhibitors (TRIs); (ii) melanin-concentrating hormone receptor 1 (MCHR1) antagonists or inhibitors; (iii) diazoxide choline controlled release (DCCR formulation); or (c): (a) or (b) formulated with any one or more of the following drugs or small molecules: (1) unacylated ghrelin (UAG) analogs and / or ribolitide (also known as AZP-531), (2) Carbetocin, or Duratocin™, Pabal™, or Lonactene™; (3) oxytocin and / or the precursor oxytocin-neurophysin, (4) liraglutide, or Victoza® or Saxenda®, (5) Exenatide, or Byetta™, Bydureon™, Bydureon™, or BCise™; (6) setomelanotide (also known as IMCIVREE™, RM-493, BIM-22493, IRC-022493, N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide); (7) rimonabant (also known as SR141716) and / or Acomplia™, Zimulti™, (8) a beta-adrenergic blocker (optionally, the beta-adrenergic blocker is or includes metoprolol (or Lopressor™, Metolar XR™, Toprol X™), atenolol (or Tenormin™), propranolol (or INDERAL™), and / or nadolol (or CORGARD™), or any combination thereof); (9) a melatonin receptor agonist (optionally, the melatonin receptor agonist is or includes melatonin or N-acetyl-5-methoxytryptamine, ramelteon (or Rozerem™) and / or tesimelteon (or Hetlioz™), or any combination thereof); (10) histamine receptor 1 antagonists (the histamine receptor 1 antagonist is or includes doxepin (or Sinequan™, Quitaxon™, or Aponal™), or low-dose doxepin (optionally the low dose is 3 mg or 6 mg per dose, trazadone (or Desyrel™, Desyrel Dividose™, or Oleptro™), amitriptyline (or ELAVIL™, Protanol™, Qualitriptine™, Redomex™, or Saroten™) or amitriptyline with chlordiazepoxide (Morelin™, Ristryl™, or Sedans™), and / or mirtazapine (or REMERON™), or any combination thereof); (11) a histamine H3 receptor antagonist or inverse agonist (optionally, the H3 receptor antagonist or inverse agonist is or includes pitolisant (or tiprolisant, ciproxidine, or WAKIX™), thioperamide, clobenpropit, ciproxifan, connessin (or nerin, locecine, lightin) and / or betahistine (or SERC™), SUVN-G3031 (Suven Life Sciences Ltd), or any combination thereof); (12) modafinil (or Provigil®, Alertec® or Modavigil®), and / or amodafonil (or Nuvigil®), (13) human growth hormone (hGH) (or somatotropin) or a recombinant form thereof (or Omnitrope™, Jintropin™, Nutropin™ or Nutropin DEPOT™, Humatrope™, Genotropin™, Norditropin™ or Saizen™), or any combination thereof; (14) testosterone and / or 17β-hydroxyandrost-4-en-3-one, (15) progesterone and / or pregn-4-ene-3,20-dione, (16) Estrogen, estrone, estradiol, or estriol, or any combination thereof; (17) a thyroid hormone or derivative thereof (optionally, the thyroid hormone or derivative thereof is or includes triiodothyronine (T3), thyroxine (T4), levothyroxine, or L-thyroxine, or any combination thereof); (18) Chorionic gonadotropin (hCG) hormone or its recombinant form, or Novarel™ or Pregnyl™, or any combination thereof, (19) metformin (or Glucophage™) and / or repaglinide (or PRANDIN™), (20) Insulin or human insulin or a recombinant form or analog thereof (or Actrapid™, Humalog™, NovoRapid™, Apidra™, Lantus™ or Levemir™) or any combination thereof; (21) glucocorticoid receptor antagonists or anticorticosteroids, or mifepristone (or RU-486, or Mifegyne™ or Mifeprex™), metyrapone (or Metopirone™), ketoconazole (or NIZORAL™) or aminoglutethimide (or Elipten™, Cytadren™ or Orimeten™), (22) a histamine receptor 2 antagonist (optionally, the histamine receptor 2 antagonist is or includes cimetidine (or TAGAMET™), ranitidine (or ZANTAC™), and / or famotidine (or PEPCID™), or any combination thereof); (23) mood stabilizers (optionally, the mood stabilizer is or includes gabapentin (or Neurontin™); clonazepam (or Klonopin™ or Rivotrilf™); valproate, valproic acid, sodium valproate, or valproic acid semisodium salt (or Convulex™, Depakote™, Epilim™, or Stavzor™); oxcarbazepine (or Trileptal™ or Oxtellar XR™); lithium or lithium carbonate (or Lithobid™ or LITHOMAX™); topiramate (or Topamax™, Trokendi XR™, or Qudexy XR™) and / or lamotrigine (or Lamictal™), or any combination thereof), (24) neuroleptics (optionally, the neuroleptics include risperidone (or Risperdal), aripiprazole (or Abilify™), quetiapine (or Seroquel™), olanzapine (or Zyprexa™), ziprasidone (or Geodon™) and / or haloperidol (or Haldol™ or Serenace™), or any combination thereof); (25) quetiapine, or Seroquel® or Temprolide®, (26) naltrexone (or FEBIA® or VIVITROL®), (27) γ-aminobutyric acid (GABA) B(GABA B ) receptor modulators, such as sodium oxybate (Xyrem™), or controlled-release sodium oxybate (or FT218), or low sodium oxybate, optionally JZP-258, or baclofen; (28) Solriamfetol or SUNOS (trademark), (29) a hypocretin / orexin 2 receptor selective agonist, optionally TAK-925, TAK-988, or TAK-994; (30) a selective norepinephrine reuptake inhibitor (NRI), or a selective serotonin reuptake inhibitor (SSRI), or a selective serotonin norepinephrine inhibitor (SNRI) (optionally, the SSRI or SNRI inhibitor is or includes reboxetine (or AXS-12, or Edronax™), atomoxetine (or Strattera™), venlafaxine (Effexor™ or EffexorXR™), fluoxetine (Prozac™), citalopram (Celexa™), escitalopram (Lexapro), paroxetine (Paxil™), sertraline (Zoloft™), or duloxetine (Cymbalta™)); (31) Amphetamine (optionally, amphetamine includes amphetamine, dextroamphetamine (or Adderall®), dextroamphetamine-amphetamine (Mydayis®), or lisdexamfetamine (or Vyvanse®)); (32) methylphenidate or Ritalin, Ritalin LA, Concerta, Metadate CD, Methylin, Methylin ER, Daytrana, Quillivant XR, Quillichew ER, Aptensio XR, Cotempla XR-ODT, Jornay PM, or Adhansia XR; (33) Tricyclic antidepressants (TCAs) (optionally, the TCA is or includes imipramine (Tofranil™), or amitriptyline (Elavil™), clomipramine (Anafranil™), or another TCA); (34) Monoamine oxidase inhibitors (MAOIs) (optionally, the MAOI is or includes selegiline (Emsam®), isocarboxazid (Marplan®), phenelzine (Nardil®), and tranylcypromine (Parnate®) or another MAOI); (35) THN102, or a combination of modafinil and flecainide; (36) an inhibitor of astroglial connexin inhibitors (optionally, the inhibitor of astroglial connexin inhibitors is or includes flecainide); (37) a prostaglandin DP1 receptor antagonist (optionally, the prostaglandin DP1 receptor antagonist is or comprises ONO-4127Na); (38) an opioid (optionally, the opioid comprises morphine); (39) antiobesity drugs (optionally, the antiobesity drugs include lorcaserin (Belviq™), orlistat (Alli™), phentermine and topiramate (Qsymia™), onaltrexone HCl, or bupropion HCl (Contrave™)); (40) a farnesoid X receptor (FXR) agonist (optionally, the FXR agonist comprises obeticholic acid (OCA), EYP001 (ENYO Pharma), TQA3526, Px-102, Px-104, or tropifexol); (41) PPAR agonists, optionally PPARα / δ agonists or PPAR-α / γ agonists (optionally PPAR-α / γ agonists include pioglitazone, elafibranor or lanifibranor (or IVA337, Inventiva)); (42) CC chemokine receptor CCR2 / CCR5 inhibitors (optionally, the CC chemokine receptor comprises tropifexor, a combination of tropifexor and cenicriviroc, or cenicriviroc); (43) mitochondrial pyruvate carrier (MPC) inhibitors (optionally, the MPC inhibitor includes MSDC-0602K (Cirius Therapeutics)); (44) Fibroblast Growth Factor 19 (FGF19) Analogues (Optionally, the FGF19 analogue comprises Aldafermin (or NGM282, NGM Biopharmaceuticals)) (45) Fibroblast growth factor 21 (FGF21) analogs (optionally, the FGF21 analogs include PEGylated fibroblast growth factor 21 analogs, optionally pegbelfermin); (46) thyroid hormone receptor beta (THR-β) agonists (optionally, the THR-β agonist includes resmetirom (MGL-3196, Magrigal Pharmaceuticals) or VK-2890); (47) Stearoyl-CoA desaturase-1 (SCD1) inhibitors (optionally, the SCD1 inhibitor comprises aramchol (Galmed Pharmaceuticals)); (48) Apoptosis signal-regulating kinase 1 (ASK1) inhibitors (optionally, the ASK1 inhibitors include selonsertib (Gilead Sciences)), (49) an acetyl-CoA carboxylase (ACC) inhibitor (optionally, the ACC inhibitor comprises filsocostat (GS-0976) or MK-4074), or (50) A therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture is provided that includes any one or more active agents or drugs comprising any combination of (1) through (49).

[0011] In an alternative embodiment, the triple monoamine reuptake inhibitor is: (a) Tesofensine, Tesomet, or Tesofen (Saniona, Ballerup, Denmark), (b) [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline or a salt, solvate, racemate, crystalline form or derivative thereof, optionally as described in U.S. Pat. No. 8,802,696, or 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline or a salt, solvate, racemate, crystalline form or derivative thereof, or a compound having the formula (Formula I): [ka] or a pharmaceutically acceptable salt thereof, or an S-enantiomer, (+)-stereoisomer or (-)-stereoisomer thereof, or a compound in the S or R configuration, or an (S)(+)-stereoisomer or (R)(-)-stereoisomer thereof, (c) is or contains a deuterated form of the compound or drug of (a) or (b), in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more hydrogen residues are deuterated.

[0012] In an alternative embodiment, the melanin-concentrating hormone receptor 1 (MCHR1) antagonist or inhibitor is (a) GW8564649 (GSK), AZD-1979 (AstraZeneca), AMG-076 (Amgen), BMS-830216 (BMS), ATC-0065 or ATC-0175 (see Chaki et al (2005) CNS Drug Reviews vol 11(4):341-52), GW-803430 or GW-3430 (see Gehlert et al (2009) J Pharm and Experimental Therapeutics, vol 329(2):429-38), NGD-4715 (Ligand Pharmaceuticals), SNAP-7941 (see Klemenhagen et al (2007) J Pharm and Experimental Therapeutics, vol 321(1):237-48), T-226 or T-296 (see Takekawa et al (2007) J Pharm and Experimental Therapeutics, vol 321(1):237-48), al(2002) Eur J Pharm vol 438(3):129-35), or any combination thereof; (b) a compound having the following formula (designated Formula II): [ka] or (1-azinone)-substituted pyridoindoles as described in USPN 8,716,308, or compounds having the formula: [ka] wherein R1 is H or optionally substituted alkyl; R2, R3, R4 are each independently selected from H, --O-alkyl, --S-alkyl, alkyl, halo, --CF3, and --CN; G is --CR 12 R 13 --NR 5 --or--NR 5 --CR12 R 13 and R 5 is H, optionally substituted alkyl, optionally substituted heterocycle, --C(=O)--R 6 , --C(=O)--O--R 7 , or --C(=O)--NR 19 R 20 and R 6 and R 7 are each optionally substituted alkyl or optionally substituted heterocycle; R8, R9, R 10 , R 11 , R 12 , R 13 , R 19 and R 20 are each independently selected from H or optionally substituted alkyl; R 14 and R 15 are each independently H or halogen; Y is CH; L is --CH2--O--, --CH2CH2--, --CH=CH-- or a bond; and B is aryl or heteroaryl or cycloalkyl, provided that when L is a direct bond, B cannot be unsubstituted heteroaryl or monofluorine-substituted heteroaryl); or (c) is or comprises a deuterated form of a compound or drug of (a) or (b), optionally a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture further comprising an N-acetyltransferase 2 (NAT2) or arylamine N-acetyltransferase inhibitor, optionally acetaminophen, N-acetyl-para-aminophenol (APAP), or paracetamol (or TYLENOL™ or PANADOL™), in combination with any compound of (b) or a deuterated form of a compound or drug of (b), optionally wherein (b) is of Formula II.

[0013] In alternative embodiments, the two or more drugs or active agents are formulated as separate compositions, or the two or more drugs or active agents are formulated in one composition or drug formulation (the two or more drugs or active agents are formulated together).

[0014] In alternative embodiments, the one or more drugs or active agents are individually packaged, packaged together, or packaged in any combination in a single package, multiple packages or packets, or blister packets, lidded blisters or blister cards or packets, or shrink wrap.

[0015] In alternative embodiments, one or more or all of the drugs or active agents are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a spray, a sachet, an inhalant, a powder, a lyophilized powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, nanoparticles, nanoliposomes, a microgel, a pellet, a suppository, or any combination thereof, and optionally the drug delivery device or product is or comprises an implant.

[0016] In alternative embodiments, one or more or all of the drugs or active agents are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one lyophilized powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one patch, one spray, one powder, one lyophilized powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel, or one suppository.

[0017] In an alternative embodiment, one or more or all of the drugs or active agents are packaged in dosages that correspond to optimal daily doses in accordance with a chrono-dosing administration regimen.

[0018] In an alternative embodiment, the drug or active agent is: (a) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and a histamine receptor 1 antagonist, optionally doxepin; (b) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and naltrexone; (c) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and a histamine receptor 1 antagonist, optionally doxepin, and naltrexone; (d) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation); (e) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of formula I, and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation), and a melatonin receptor agonist, optionally melatonin or N-acetyl-5-methoxytryptamine, ramelteon (or Rozerem™) and / or tesimelteon (or Hetlioz™), or any combination thereof; (f) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of formula I, and a melanin-concentrating hormone receptor 1 (MCHR1) antagonist or inhibitor, optionally a compound of formula II, or any combination thereof; (g) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and a beta-blocker, optionally atenolol (Tenormin™), bisoprolol (Cardicor™, Emcor™), or metoprolol (Betaloc™, Lopresor™, Toprol XL™), or any combination thereof; and / or (h) Any combination of (a) to (g) is included.

[0019] In an alternative embodiment, a compound having the formula: [ka] (In the formula, R1~R 15 At least one of R1 to R2 is -D (deuterium) or 15 All of are -D, Optionally, the carbon atom marked with *, if it is a stereogenic center, is in the R or S configuration. or a pharmaceutically acceptable salt thereof.

[0020] In an alternative embodiment, provided herein is a compound having the formula: (a) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4,8-d6 compound having the formula: [ka] (b) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5 compound having the formula: [ka] (c) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 compound having the formula: [ka] (d) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3-d2 compound having the formula: [ka] (e) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-4-d compound having the formula: [ka] (f) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-8-d compound having the formula: [ka] or (g) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3 compound having the formula: [ka]

[0021] In an alternative embodiment, a compound having the formula: [ka] (In the formula, R1~R 18 At least one of R1 to R2 is -D (deuterium) or 18 (All of the are -D) or a pharmaceutically acceptable salt thereof.

[0022] In an alternative embodiment, there is provided a pharmaceutical composition, medicament, or formulation comprising a compound having the formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0023] In an alternative embodiment, a method for treating, ameliorating, delaying progression of, alleviating symptoms of, reducing adverse events associated with, or preventing a disease or condition comprising or associated with: Binge eating (optionally assessed by HQ-CT), Moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity (optionally further including weight loss management and weight loss maintenance, or optionally further including increased physical activity as an adjunct to a reduced calorie diet or for long-term weight management); early-onset morbid obesity, Nonalcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), Primary biliary cholangitis of the liver (PBC), Inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), type II diabetes, hypothalamic damage-induced obesity, Obsessive-compulsive disorder (OCD), Disorders of mood dysregulation (DMDD), Oppositional Defiant Disorder (ODD), Skin picking, trichotillomania, Intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, Narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders, Third Edition (ICSD-3), narcolepsy with cataplexy, Narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, Cataplexy, idiopathic hypersomnia, Rapid eye movement (REM) sleep behavior disorder, seizures, epilepsy, addiction, or addictive disorder or behavior (optionally, the addiction, addictive disorder, or addictive behavior is or includes Internet Gaming Disorder (IGD) or drug addiction, and optionally, the drug addiction is or includes cocaine addiction or alcohol addiction); Major depressive disorder (MDD), Treatment-resistant depression (TRD), Negative symptoms of schizophrenia, Parkinson's disease, MDD associated with Parkinson's disease, generalized anxiety, Social anxiety disorder (social phobia), fibromyalgia (FM), diabetic neuropathy, lower back pain, chronic fatigue syndrome, Attention Deficit Hyperactivity Disorder (ADHD), autism, Asperger's spectrum disorder, genetically determined disease or syndrome (optionally, the genetically determined disease or syndrome is Prader-Willi syndrome, Bardet-Biedl syndrome, Smith-Maginnis syndrome, 1p36 deletion syndrome, 16p11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, melanocortin 4 receptor (MC4R) pathway heterozygous obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked inheritance) is or includes: a genetic disorder, Angelman syndrome, Scharf-Yang syndrome, Albright hereditary osteodystrophy, Silver-Russell syndrome, maternal disomy, Alström syndrome, Wilms tumor, aniridia, genitourinary abnormalities, mental retardation, i.e., WAGR or WAGRO syndrome; Dravet syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Dawes syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick disease type C, or Norrie disease, or Coffin-Lowry disease, wherein optionally, reducing adverse events includes alleviating psychiatric disorders, serotonin syndrome, tachycardia, or postural tachycardia syndrome; (a)(i) providing or having provided a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture provided herein, or a pharmaceutical composition provided herein; and (ii) administering or implanting a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture to an individual in need thereof; or (b) A method is provided, comprising administering to or implanting in an individual in need thereof a therapeutically effective dose of a therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture provided herein.

[0024] In an alternative embodiment of the methods provided herein, the drug, or therapeutic combination, pharmaceutical dosage form is administered orally, parenterally, by inhalation spray, intranasally, topically, intrathecally, intracranially, epidurally, intracranially or rectally, optionally parenteral administration including intrathecal, intracranial or epidural administration (administration into the intrathecal, intracranial or epidural space), subcutaneously, intravenously, intramuscularly and / or intra-arterially; - the drug, or therapeutic combination, pharmaceutical dosage form is administered to achieve a therapeutic range of plasma concentrations at steady state, wherein The therapeutic range of plasma concentrations of the [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, or compound of Formula I, is about 50-4000 ng / ml; 100-3000 ng / ml; 250-1600 ng / ml; 500-1400 ng / ml, 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, 1250-1500 ng / ml, 1500-2000 ng / ml, 2000-2500 ng / ml; 2500-3000 ng / ml; 3000-3500 ng / ml; or 3500-4000 ng / ml. the therapeutic range of plasma concentrations of the (1-azinone)-substituted pyridoindole, or compound of formula II, is about 5-4000 ng / ml, 10-1000 ng / ml, 10-500 ng / ml, 25-500 ng / ml, 25-250 ng / ml, 50-500 ng / ml, 50-1000 ng / ml, 50-500 ng / ml, 100-1000 ng / ml, 100-500 ng / ml, 200-1000 ng / ml, 500-1000 ng / ml, 1000-2000 ng / ml, 2000-3000 ng / ml, or 3000-4000 ng / ml; The therapeutic range of plasma concentrations of tesofensine is about 2 ng to 50 ng / ml, 5 to 20 ng / ml, 6.5 to 15 ng / ml, 8 to 12 ng / ml, or about 10 ng / ml; The therapeutic range of plasma concentrations of diazoxide is about 10 ng / ml to 100 ng / ml, 20 ng / ml to 80 ng / ml, 30 to 50 ng / ml, or about 40 ng / ml; In an alternative embodiment of the methods provided herein, the steady state concentration is the time over which the concentration of the drug in the body remains constant, and for most drugs, the time to reach steady state is 3 to 5 half-lives of the drug when administered at regular intervals; In an alternative embodiment of the methods provided herein, the plasma concentration of the drug, or therapeutic combination, or pharmaceutical dosage form is (a) Trough level or trough concentration (C トラフ ), or the lowest concentration of the drug, or therapeutic combination, or pharmaceutical dosage form reached before a second or subsequent dose is administered; (b) determined from a blood sample taken between 0.5 hours and 24 hours, or between 4 and 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours or more after the last dose or administration of a drug, or therapeutic combination, or pharmaceutical dosage form; - the drug, therapeutic combination, or pharmaceutical dosage form is administered to achieve a therapeutic level range of plasma concentrations (optionally human plasma concentrations) at steady state, wherein (a) the therapeutic plasma concentration range of the compound of Formula I is about 250-1600 ng / ml; 500-1400 ng / ml, 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, 1250-1500 ng / ml, 1500-2000 ng / ml, 2000-2500 ng / ml; or 2500-3000 ng / ml; (b) the therapeutic plasma concentration range of the compound of Formula I is about 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, 1250-1500 ng / ml, 1500-2000 ng / ml, or 2000-2500 ng / ml; (c) the therapeutic plasma concentration range of the compound of Formula I is about 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, or 1250-1500 ng / ml; In an alternative embodiment, the drug, or therapeutic combination, pharmaceutical dosage form is administered to achieve a daytime therapeutic range of about 8 to 12 hours of time-averaged plasma concentration, wherein the plasma concentration is measured after achieving steady state; the therapeutic range of the daytime 12-hour hourly average plasma concentration of the [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, or compound of Formula I, is about 50-4000 ng / ml; 100-3000 ng / ml; 250-1600 ng / ml; 500-1400 ng / ml, 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, 1250-1500 ng / ml, 1500-2000 ng / ml, 2000-2500 ng / ml; 2500-3000 ng / ml; 3000-3500 ng / ml; or 3500-4000 ng / ml; the therapeutic level range of a 12-hour daytime average plasma concentration of the (1-azinone)-substituted pyridoindole, or compound of formula II, is about 5-4000 ng / ml, 10-1000 ng / ml, 10-500 ng / ml, 25-500 ng / ml, 25-250 ng / ml, 50-500 ng / ml, 50-1000 ng / ml, 50-500 ng / ml, 100-1000 ng / ml, 100-500 ng / ml, 200-1000 ng / ml, 500-1000 ng / ml, 1000-2000 ng / ml, 2000-3000 ng / ml, or 3000-4000 ng / ml; The therapeutic range of 12-hour daytime average plasma concentrations of tesofensine is about 2 ng to 50 ng / ml, 5 to 20 ng / ml, 6.5 to 15 ng / ml, 8 to 12 ng / ml, or about 10 ng / ml; The therapeutic range of diazoxide's 12-hour daytime mean plasma concentration is about 10 ng / ml to 100 ng / ml, 20 to 80 ng / ml, 30 to 50 ng / ml, or about 40 ng / ml; - each drug or active agent of the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture is delivered to the individual simultaneously or separately, optionally wherein one or each drug or active agent of the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture is administered in a timed regimen, and / or - the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprises Formula I, or a deuterated derivative of Formula I.

[0025] In an alternative embodiment, there is provided a use of a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture provided herein to treat, ameliorate, delay progression of, alleviate symptoms of, reduce adverse events associated with, or prevent a disease or condition including or associated with: Binge eating (optionally assessed by HQ-CT), Moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity (optionally further including weight loss management and weight loss maintenance, or optionally further including increased physical activity as an adjunct to a reduced calorie diet or for long-term weight management); early-onset morbid obesity, Non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), Primary biliary cholangitis (PBC), inflammatory bowel disease (IBD), or irritable bowel syndrome (IBS), type II diabetes, hypothalamic damage-induced obesity, Obsessive-compulsive disorder (OCD), Disorders of mood dysregulation (DMDD), Oppositional Defiant Disorder (ODD), Skin picking, trichotillomania, Intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, Narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders, Third Edition (ICSD-3), narcolepsy with cataplexy, Narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, Cataplexy, idiopathic hypersomnia, Rapid eye movement (REM) sleep behavior disorder, convulsions, epilepsy, addiction, or addictive disorder or behavior (optionally, the addiction, addictive disorder, or addictive behavior is or includes Internet Gaming Disorder (IGD) or drug addiction, and optionally, the drug addiction is or includes cocaine addiction or alcohol addiction); Major depressive disorder (MDD), Treatment-resistant depression (TRD), Negative symptoms of schizophrenia, Parkinson's disease, MDD associated with Parkinson's disease, generalized anxiety, Social anxiety disorder (social phobia), Fibromyalgia (FM), diabetic neuropathy, lower back pain, chronic fatigue syndrome, Attention Deficit Hyperactivity Disorder (ADHD), autism, Asperger's spectrum, A genetically determined disease or syndrome (optionally, the genetically determined disease or syndrome is Prader-Willi syndrome, Bardet-Biedl syndrome, Smith-Maginis syndrome, 1p36 deletion syndrome, 16p11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, melanocortin 4 receptor (MC4R) pathway heterozygous obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, and Angiopathy being or including Fellman syndrome, Scharf-Yang syndrome, Albright hereditary osteodystrophy, Silver-Russell syndrome, maternal disomy 14, Alström syndrome, Wilms tumor, aniridia, genitourinary abnormalities, mental retardation, i.e., WAGR or WAGRO syndrome; Dravet syndrome, Lennox-Gastaut syndrome, Gillespie syndrome, or cerebellar ataxia; Dawes syndrome, or myoclonic atonic epilepsy (MAE); Niemann-Pick disease type C; Norrie disease; or Coffin-Lowry disease), Here, optionally, uses are provided wherein the reduction in adverse events includes alleviating psychiatric disorders, serotonin syndrome, tachycardia, or postural tachycardia syndrome.

[0026] In an alternative embodiment, the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprises Formula I, or a deuterated derivative of Formula I.

[0027] In alternative embodiments, a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture provided herein for use in treating, ameliorating, delaying progression of, alleviating symptoms of, reducing adverse events associated with, or preventing a disease or condition comprising or associated with: Binge eating (optionally assessed by HQ-CT), Moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity (optionally further including weight loss management and weight loss maintenance, or optionally further including increased physical activity as an adjunct to a reduced calorie diet or for long-term weight management); early-onset morbid obesity, Non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), Primary biliary cholangitis of the liver (PBC), Inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), type II diabetes, hypothalamic damage-induced obesity, Obsessive-compulsive disorder (OCD), Disorders of mood dysregulation (DMDD), Oppositional Defiant Disorder (ODD), Skin picking, trichotillomania, Intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), Excessive daytime sleepiness associated with narcolepsy and sleep apnea, Excessive daytime sleepiness associated with narcolepsy, Excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, Narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders, Third Edition (ICSD-3) Narcolepsy with cataplexy Narcolepsy type 2 (NT2) according to ICSD-3, Narcolepsy without cataplexy Cataplexy convulsions, epilepsy, an addiction or addictive disorder or behavior (optionally, the addiction, addictive disorder or addictive behavior is or includes Internet Gaming Disorder (IGD) or drug addiction, and optionally, the drug addiction is or includes cocaine addiction or alcohol addiction); Major depressive disorder (MDD), Treatment-resistant depression (TRD), Negative symptoms of schizophrenia, Parkinson's disease, MDD associated with Parkinson's disease, generalized anxiety, Social anxiety disorder (social phobia), fibromyalgia (FM), diabetic neuropathy, lower back pain, chronic fatigue syndrome, Attention Deficit Hyperactivity Disorder (ADHD), autism, Asperger's spectrum, A genetically determined disease or syndrome (optionally, the genetically determined disease or syndrome is Prader-Willi syndrome, Bardet-Biedl syndrome, Smith-Maginis syndrome, 1p36 deletion syndrome, 16p11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, melanocortin 4 receptor (MC4R) pathway heterozygous obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, and Angiopathy being or including Fellman syndrome, Scharf-Yang syndrome, Albright hereditary osteodystrophy, Silver-Russell syndrome, maternal disomy 14, Alström syndrome, Wilms tumor, aniridia, genitourinary abnormalities, mental retardation, i.e., WAGR or WAGRO syndrome; Dravet syndrome, Lennox-Gastaut syndrome, Gillespie syndrome, or cerebellar ataxia; Dawes syndrome, or myoclonic atonic epilepsy (MAE); Niemann-Pick disease type C; Norrie disease; or Coffin-Lowry disease), Provided herein is a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture, wherein optionally the reduction in adverse events comprises alleviating psychiatric disorders, serotonin syndrome, tachycardia or postural tachycardia syndrome.

[0028] In an alternative embodiment, (i) Triple monoamine reuptake inhibitors (TRIs), (ii) melanin-concentrating hormone receptor 1 (MCHR1) antagonists or inhibitors, (iii) diazoxide or diazoxide formulations, (iv) any therapeutic combination of (i) to (iii); (iv) a therapeutic combination used in the methods provided herein; or (v) A method for administering a pharmaceutical composition, drug, or formulation provided herein, comprising a deuterated compound or composition provided herein, comprising: The dosage is (a) an empirical method for stable and predictable titration and for determining the initial therapeutic dose, or for determining the minimum therapeutic dose, or for determining the optimal effective dose, 1. Administering a test dose (e.g., a dose at which no adverse events or minimal adverse events are observed or a safe dose) daily until the patient achieves a steady-state plasma drug concentration; 2. Obtaining a blood sample and assessing test plasma drug concentrations prior to the next scheduled dose; 3. Calculating the initial treatment dose / day, A. For drugs that are dose-linear with respect to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiply the divided value by the test dose; B. For drugs that are dose-nonlinear with respect to plasma concentration, dividing the initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiplying the divided value by the test dose, and then multiplying the product by a nonlinear exponential coefficient, optionally calculating the initial target therapeutic plasma drug concentration as follows: (i) a concentration corresponding to a particular pharmacodynamic efficacy marker level, e.g., serotonin transporter (SERT or 5-HTT), dopamine transporter (DAT), or norepinephrine transporter (NET), as determined by an imaging method such as positron emission tomography (PET), or (ii) a concentration corresponding to the lowest effective therapeutic dose as determined by clinical trials; 4. Optionally, i. administering the initial therapeutic dose daily until the patient achieves steady-state plasma drug concentrations; ii. Obtaining a blood sample prior to the next scheduled dose to assess the current therapeutic plasma drug concentration; iii. Calculating the next treatment target dose / day, A. For drugs that are dose-linear with respect to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiply the divided value by the current therapeutic dose; B. For drugs with non-linear dose to plasma concentration, calculating the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiplying the divided value by the current therapeutic dose, and then multiplying the product by a non-linear exponential coefficient; iv. Optionally, achieving steady state after two subsequent plasma drug concentration results separated by at least one week and within the next therapeutic plasma drug concentration target range; v. An empirical method, optionally including continuing the process until the lowest therapeutic dose or the optimal effective dose is achieved; or (b) a model-based method for determining the initial therapeutic dose for stable and predictable titration, and for determining the minimum therapeutic dose or determining the optimal effective dose, 1. administering the test dose daily for approximately 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or approximately 1 day; 2. Obtaining the first blood sample between about 1 hour and 3 days, 6 hours and 2 days, or about 1 day after administering the first test dose; 3. Collecting a second or subsequent blood sample between about 1 hour and 28 days, 6 hours and 14 days, 1 day and 7 days, or about 2 days after collecting the first or subsequent blood sample; 4. Calculating the initial treatment starting dose / day, i. using the initial target therapeutic plasma drug concentration, test dose, time of administration of the test dose(s), plasma concentration of the blood sample and time of collection of the blood sample and the pharmacometric model; ii. optionally, calculating an initial target therapeutic plasma drug concentration, the test dose, the time of administration of the test dose(s), the plasma concentration of the blood sample, the time of collection of the blood sample, human PK data, and a Bayesian pharmacometrics model; i. administering an initial treatment starting dose daily until the individual or patient achieves a steady-state plasma drug concentration; ii. Obtaining a blood sample prior to the next scheduled dose to assess the current therapeutic plasma drug concentration; iii. Calculating the next treatment target dose / day, A. For drugs that are dose-linear with respect to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiply the divided value by the current therapeutic dose; B. For drugs with nonlinear dose to plasma concentration, calculating the next target therapeutic plasma drug concentration by dividing the current therapeutic plasma drug concentration, then multiplying the divided value by the current therapeutic dose, and then multiplying the product by a nonlinear exponential coefficient; and iv. A model-based method, which involves continuing the process until the lowest therapeutic dose or the optimal effective dose is achieved; or (c) a model-based Bayesian adaptive control method for stable and predictable titration and for determining the initial therapeutic dose, and for determining the minimum therapeutic dose, or for determining the optimal effective dose, 1. Administering the test dose once or twice daily for approximately 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or approximately 1 day; 2. Collecting initial blood samples at approximately 1 / 2 hour to 28 days, 1 hour to 3 days, 6 hours to 2 days, and 1 day after administering the first test dose; 3. Optionally, collecting a second or subsequent blood sample between about 1 hour and 28 days, 6 hours and 14 days, 1 day and 7 days, or about 2 days after collecting the first or subsequent blood sample; 4. Calculating the initial treatment starting dose / day, i. selecting an initial target trough plasma drug concentration or other corresponding PK parameter, such as CMAX and other pre-trough plasma concentration(s), AUC, among others; ii. Recording information that may include, but is not limited to, the test dose, the time of administration of the test dose (recorded on the patient's paper or electronic planner), the measured plasma drug concentration and time of blood sample collection, patient information (e.g., age, weight, height, sex, patient genetic information such as CYP450 profile, patient non-genetic information, patient medications, patient health status, among other factors), available dose strengths; iii. Developing a population PK model, A. Use data from PK studies in human populations; B. Using nonlinear mixed-effects modeling software (e.g., NONMEM (version 7.2, ICON, Ellicott City, MD), Phoenix NLME (version 8.1, CERTARA, St. Louis, MO), or other modeling software); C. Applying estimation methods such as first-order conditional approximation with interactions (FOCE-I), Bayesian estimation, and other similar estimation methods; D. Exploring different structural models, allometric models and other types of models; E. Selecting a model that adequately describes the data, defining goodness-of-fit diagnostic plots, comparisons based on minimum objective function values ​​(OFVs), and evaluation of population fixed and random effect parameter estimates; F. Developing a PK model by parametrizing it with values ​​of clearance (CL), volume of distribution (V), and absorption rate constant (Ka); iv. Entering the information in i, ii, and iii into the appropriate sections of pharmacokinetic clinical decision support software such as MWPharm++ (Mediware, Prague, Czech Republic), InsightRx (InsightRx, San Francisco, CA), DoseMeRx (DoseMe, Queensland, Australia), among other software systems; v. using a Bayesian estimator to generate individual parameter estimates and select an available dose strength that most closely achieves the initial trough plasma drug concentration target, or optionally, other PK parameter targets that characterize the target therapeutic plasma drug concentration target; vi. Optionally, calculating by reaching steady state at the current dose, as defined by two subsequent plasma drug concentration results measured approximately one week apart being within the current target plasma concentration range; 5. Optionally, calculating the next and subsequent doses, i. Selecting the next target trough plasma drug concentration or other corresponding PK parameter, such as CMAX and other pre-trough plasma concentration(s), AUC, among others; ii. Recording information that may include, but is not limited to, the current dose, the time of administration of the test dose (recorded on the patient's paper or electronic planner), the measured plasma drug concentration and time of blood sample collection, patient information (e.g., age, weight, height, sex, patient genetic information such as CYP450 profile, patient non-genetic information, patient medications, patient health status, and available active ingredient strength; iii. entering i and ii above into the appropriate sections of pharmacokinetic clinical decision support software such as MWPharm++ (Mediware, Prague, Czech Republic), InsightRx (InsightRx, San Francisco, CA), DoseMeRx (DoseMe, Queensland, Australia), among other software systems, and using a Bayesian estimator to generate individual parameter estimates and select the available dose intensity that most closely reaches the next trough plasma drug concentration target, or optionally, other PK parameter targets that characterize the target therapeutic plasma drug concentration; iv. Optionally, steady state is reached after two subsequent plasma drug concentration results, measured approximately one week apart, are within the target range; v. Optionally, a method is provided in which the minimum therapeutic dose or optimal effective dose at steady state is determined by a model-based Bayesian adaptive control method, including calculating by continuing the process until the minimum therapeutic dose or optimal effective dose at steady state is achieved.

[0029] In an alternative embodiment, the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprises Formula I, or a deuterated derivative of Formula I.

[0030] In an alternative embodiment, a method is provided for delivering or administering a triple monoamine reuptake inhibitor (TRI) to an individual in need thereof, wherein the TRI comprises Formula I, or a deuterated derivative of Formula I, and optionally the TRI comprises tesofensine.

[0031] In an alternative embodiment, the effective dose is: (i) Triple monoamine reuptake inhibitors (TRIs), (ii) melanin-concentrating hormone receptor 1 (MCHR1) antagonists or inhibitors, (iii) diazoxide or diazoxide formulations, (iv) any therapeutic combination of (i) to (iii); or (iv) a therapeutic combination used in the methods provided herein; or (v) A method for administering and maintaining a pharmaceutical composition, drug, or formulation provided herein, comprising a deuterated compound or composition provided herein, comprising: The dosage is (a) recording the maintenance dose and maintenance therapeutic plasma drug concentrations associated with the lowest effective therapeutic dose or optimal therapeutic dose; and (b) Between about 1 and 12 months, 3 and 9 months, 4 and 8 months, or early 6 months, or when there is a change in weight, medication, or health status. Prior to the next scheduled dose, a blood sample is taken to assess the current therapeutic plasma drug concentration; Optionally, if the current plasma drug concentration differs from the maintenance therapeutic plasma drug concentration by more than about 20%, and optionally, by more than about 50%, calculate the new therapeutic dose / day by a method including: i. for drugs that are dose-linear with respect to plasma concentration, dividing the maintenance treatment plasma drug concentration by the current plasma drug concentration and then multiplying the divided value by the maintenance dose; A. Optionally, attainment of steady state after two subsequent plasma drug concentration results separated by at least one week and within about 20% of the maintenance therapeutic plasma concentration; or B. Optionally, continuing the process until a steady-state maintenance therapeutic dose is achieved; ii. For drugs with nonlinear dose to plasma concentration, dividing the maintenance treatment plasma drug concentration by the current plasma drug concentration, then multiplying the divided value by the maintenance dose, and then multiplying the product by a nonlinear exponential coefficient; or iii. Optionally, using Bayesian adaptive model-based methods, including: (A) Recording the maintenance treatment trough plasma drug concentration, the actual dose, the time of administration of the dose(s), the current trough plasma concentration of the measured blood sample and / or the time of blood sample collection, and patient factors; (B) Entering the above into the appropriate section of the pharmacokinetic clinical software; and (C) using a Bayesian estimator to generate the individual parameter(s) and select the dose that most closely achieves the maintenance therapeutic trough plasma drug concentration; or D. Optionally, attainment of steady state after two subsequent plasma drug concentration results separated by at least one week and within about 20% of the maintenance therapeutic plasma concentration; or E. Optionally, a method is provided in which the method is determined by continuing the process until a maintenance therapeutic dose at steady state is achieved.

[0032] In alternative embodiments, the TRI comprises Formula I, or a deuterated derivative of Formula I, or the TRI comprises tesofensine.

[0033] In an alternative embodiment, a method is provided for treating overeating, overeating in PWS, Disorderly Mood Dysregulation Disorder (DMDD), Oppositional Defiant Disorder (ODD), obesity in hypothalamic lesion-induced obesity, or Binge Eating Disorder (BED), comprising administering to an individual in need thereof Formula I, or a deuterated derivative of Formula I.

[0034] In alternative embodiments, methods are provided for administering Formula I, or a deuterated derivative of Formula I, to treat overeating, overeating in PWS, severe mood dysregulation disorder (DMDD), oppositional defiant disorder (ODD), obesity in hypothalamic injury-induced obesity, or binge eating disorder (BED).

[0035] In alternative embodiments, there is provided a method for treating binge eating, binge eating in PWS, Disorderly Mood Dysregulation Disorder (DMDD), Oppositional Defiant Disorder (ODD), obesity in hypothalamic lesion-induced obesity, and Binge Eating Disorder (BED) with an oral dosage form of Formula I, or a deuterated derivative of Formula I, as defined in the preceding claims, the method comprising administering the oral dosage form once daily or twice daily to provide a trough plasma level, a 24 hour hourly average plasma level, or a 12 hour daytime hourly average plasma level of Formula I, or a deuterated derivative of Formula I, as defined in the preceding claims, of 250 ng / mL to 500 ng / mL, 500 to 1000 ng / mL, 1000 to 1500 ng / mL, 1500 to 2000 ng / mL, or 1500 to 2500 ng / mL, when measured for about 1 week, about 2 weeks, or at steady state.

[0036] In alternative embodiments, there is provided a method for treating binge eating, binge eating in PWS, Disruptive Mood Dysregulation Disorder (DMDD), Oppositional Defiant Disorder (ODD), obesity in hypothalamic lesion-induced obesity, and Binge Eating Disorder (BED) with an oral dosage form of Formula I, or a deuterated derivative of Formula I, as defined in the preceding claims, the method comprising administering the oral dosage form once daily or twice daily to provide a trough plasma level, a 24 hour hourly average plasma level, or a 12 hour daytime hourly average plasma level of Formula I, or a deuterated derivative of Formula I, as defined in the preceding claims, of 150 to 3000 ng / ml when measured for about 1 week, about 2 weeks, or at steady state.

[0037] The details of one or more exemplary embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0038] All publications, patents, and patent applications cited herein are expressly incorporated herein by reference in their entirety for all purposes.

[0039] This patent and this application document contains at least one drawing executed in color. Copies of this patent or this patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0040] The drawings described herein are illustrative of the exemplary embodiments provided herein and are not meant to limit the scope of the invention as encompassed by the claims.

[0041] The figures will now be described in detail. [Brief explanation of the drawings]

[0042] [Figure 1] An exemplary protocol is provided for synthesizing the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5, which is discussed in Example 2 below. [Figure 2] An exemplary protocol is provided for synthesizing the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2, which is discussed in Example 3 below. [Figure 3] An exemplary protocol is provided for synthesizing the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3, which is discussed in Example 4 below. [Figure 4] An exemplary protocol is provided for synthesizing the exemplary compound 4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-1,1-d2)pyridin-2(1H)-one, which is discussed in Example 5 below. [Figure 5]An exemplary protocol is provided for synthesizing the exemplary compound 4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-1,1,3,3-d4)pyridin-2(1H)-one, which is discussed in Example 6 below. [Figure 6] An exemplary protocol is provided for synthesizing the exemplary compound 4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-3,3-d2)pyridin-2(1H)-one, which is discussed in Example 7 below. [Figure 7] 1 shows the relationship between plasma concentrations of the compound of Formula I and striatal occupancy of the dopamine transporter (DAT) following repeated administration of 10-60 mg of the compound of Formula I. [Figure 8] 1 shows the relationship between plasma concentration of the compound of Formula I and striatal serotonin transporter (SERT) occupancy after repeated administration of 3-60 mg of the compound of Formula I. Like reference symbols in the drawings refer to like elements. [Figure 9] 1 shows the relationship between plasma concentration of the compound of Formula I and thalamic serotonin transporter (SERT) occupancy after repeated administration of 3-60 mg of the compound of Formula I. Like reference symbols in the drawings refer to like elements. [Figure 10] 1 illustrates schematically an exemplary alternative protocol for synthesizing the exemplary compound 4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-1,1,3,3-d4)pyridin-2(1H)-one. [Figure 11] Schematic diagram of an exemplary alternative protocol for synthesizing exemplary compound P, which is discussed in detail in Example 8 below. [Figure 12] 1 shows a schematic representation of the proton NMR spectrum of Compound P, which is discussed in detail in Example 8 below. [Figure 13] 1 shows a schematic representation of the LCMS spectrum of compound P, which is discussed in detail in Example 8 below. [Figure 14]

[0033] An exemplary protocol is provided for synthesizing 8A and 8B of the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5, discussed in Example 4.1 below. [Figure 15] 1 shows a schematic representation of the proton NMR spectrum of compound 8-Boc, which is discussed in detail in Example 4.1 below. [Figure 16] Schematic representation of the proton NMR spectrum of compound 8A, discussed in detail in Example 4.1 below. [Figure 17-1]

[0033] An exemplary protocol is provided for synthesizing 12A and 12B of the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2, which is discussed in Example 5.1 below. [Figure 17-2]

[0033] An exemplary protocol is provided for synthesizing 12A and 12B of the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2, which is discussed in Example 5.1 below. [Figure 18] Schematic representation of the proton NMR spectrum of compound 12, discussed in detail in Example 5.1 below. [Figure 19] Schematic representation of the proton NMR spectrum of compound 12A, discussed in detail in Example 5.1 below. [Figure 20]

[0033] An exemplary protocol is provided for synthesizing 16A and 16B of 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3, an exemplary compound discussed in Example 6.1 below. [Figure 21] Schematic representation of the proton NMR spectrum of compound 16B, discussed in detail in Example 6.1 below. [Figure 22] 1 shows summary statistics of pharmacokinetic parameters of Formula I from a single ascending dose PK study in healthy humans. [Figure 23] 1 shows a dose proportionality plot of Cmax. of Formula I from a single ascending dose PK study in healthy humans. [Figure 24] 1 shows a dose proportionality plot of AUC(0-T) of Formula I from a single ascending dose PK study in healthy humans. [Figure 25] 1 shows the PK profile of Formula I in a Phase I single ascending dose study. [Figure 26] 1 shows a three-compartment PK model of Equation I. [Figure 27] 1 shows a goodness-of-fit plot for the population PK model of Formula I. [Figure 28] 1 shows the consistency of the PK results from the PK model with those determined by data from a human SAD study of Formula I. [Figure 29] 1 shows visual posterior predictive performance (VPC) stratified by dose panel of Formula I. [Figure 30] 1 shows the Emax model fitting using PK-PD data from Example 12. [Figure 31] PK / PD model parameters for simulation of Equation I are shown. [Figure 32] As discussed in Example 16 below, the C trough levels of Formula I required for 30, 45, and 60% DAT receptor occupancy are shown. [Figure 33] As discussed in Example 16 below, a simulation of Equation I is provided for the relationship between receptor occupancy and time (in hours) after administration. [Figure 34] As discussed in Example 16 below, dose changes at day 14 are extrapolated based on C trough at day 7, providing a simulation of individualized dosing to achieve 30% DAT receptor occupancy. [Figure 35] As discussed in Example 16 below, a simulation of individualized dosing to achieve 60% DAT receptor occupancy for a 160 kg patient is shown. DETAILED DESCRIPTION OF THE INVENTION

[0043] Like reference symbols in the various drawings refer to like elements.

[0044] In alternative embodiments, there are provided triple monoamine reuptake inhibitors that are novel deuterated [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivatives. In alternative embodiments, there are provided melanin-concentrating hormone receptor 1 (MCHR1) antagonists or inhibitors that are novel deuterated (1-azinone)-substituted pyridoindoles.

[0045] In alternative embodiments, therapeutic drug combinations or formulations are provided that include a triple monoamine reuptake antagonist or inhibitor, a melanin-concentrating hormone receptor 1 (MCHR1) antagonist or inhibitor, and diazoxide or a diazoxide choline controlled-release (DCCR) formulation, in combination with other drugs or active agents. In alternative embodiments, methods are provided for treating various conditions, including genetically determined syndromes and diseases, using the therapeutic drug combinations and formulations provided herein.

[0046] Although the embodiments provided herein are not limited to any particular mechanism of action, evidence shows that TRIs, MCHR1 antagonists, and diazoxide target different regions and pharmacological targets in the brain, yet their actions are complementary, and thus, for the first time, the discovery is described herein that administering a combination of a TRI, an MCHR1 antagonist, and diazoxide, or all three, can provide synergistic benefit to individuals in need thereof, for example, in the treatment of binge eating and / or related eating disorders.

[0047] Pharmaceutical Compositions and Formulations In alternative embodiments, drugs or compounds provided herein or drugs or compounds used in practicing the methods provided herein are provided and are formulated for administration by any or a variety of means, including oral, parenteral, inhalation spray, intranasal, topical, intrathecal, intracranial, intracerebral, epidural, intracranial, or rectal. Drugs or compounds provided herein or drugs or compounds used in practicing the methods provided herein may further comprise pharmaceutically acceptable carriers, adjuvants, and vehicles. In alternative embodiments, drugs or compounds provided herein or compositions used in practicing the methods provided herein are formulated for parenteral administration, including intrathecal, intracerebral, or epidural administration (administration into the intrathecal, intracerebral, or epidural space), subcutaneous, intravenous, intramuscular, and / or intraarterial administration, e.g., by injection route, but also including various infusion techniques. Intra-arterial, intrathecal, intracranial, epidural, intravenous, and other injections used in some embodiments may include administration via a catheter or pump, e.g., an intrathecal pump, or an implantable medical device (which may be an intrathecal pump or catheter).

[0048] In alternative embodiments, drugs or compounds provided herein, or compositions used to practice the methods provided herein, can be formulated according to routine procedure(s) compatible with the desired route of administration. In alternative embodiments, drugs or compounds provided herein, or compositions used to practice the methods provided herein, can be formulated or produced as lyophilizates, powders, lozenges, liposomes, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0049] In alternative embodiments, the drugs or compounds provided herein, or the compositions used in carrying out the methods provided herein, can be formulated as preparations for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Alternative and exemplary formulations suitable for each of these administration methods can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

[0050] In alternative embodiments, the drugs or compounds provided herein, or compositions used to practice the methods provided herein, may be formulated for parenteral administration containing any common excipient, for example, sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of synthetic or plant origin, hydrogenated naphthalenes, etc. In alternative embodiments, the drugs or compounds provided herein, or compositions used to practice the methods provided herein, may be biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.

[0051] In alternative embodiments, the drugs or compounds provided herein, or the compositions used in the methods provided herein, are administered using a parenteral delivery system, such as ethylene vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, intrathecal catheters, pumps and implants, and / or liposomes. Formulations for parenteral administration may also contain glycocholate for oral mucosal administration, methoxysalicylic acid for rectal administration, or citric acid for vaginal administration. Formulations for inhalation administration may contain, for example, lactose as an excipient, or may be an aqueous solution containing, for example, polyoxyethylene-9-auryl ether, glycocholate, and deoxycholate, or an oily solution for administration in the form of nasal drops, or a gel for application to the nasal cavity.

[0052] In alternative embodiments, the drugs or compounds provided herein or the compositions used in the methods provided herein are administered intranasally.When administered via this route, suitable dosage forms include nasal sprays or dry powders, as known to those skilled in the art.For example, nasal formulations can contain conventional surfactants, generally nonionic surfactants.When nasal formulations contain surfactants, their amount can vary depending on the specific surfactant selected, the specific mode of administration (e.g., drop or spray) and the desired effect.

[0053] In an alternative embodiment, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, are in the form of a sterile injectable preparation, such as an aqueous or oily sterile injectable suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or can be prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In an alternative embodiment, sterile, fixed oils are typically used as solvents or suspending media. Any non-irritating, fixed oil, including synthetic mono- or diglycerides, can be used for this purpose. In an alternative embodiment, fatty acids such as oleic acid can also be used in the preparation of injectables. Formulations for intravenous administration can include solutions in sterile, isotonic aqueous buffer solutions. If necessary, the formulation may also include a solubilizing agent and a local anesthetic to reduce pain at the injection site. Generally, each ingredient is supplied either separately or mixed together in a unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent. When the compound is administered by infusion, the compound can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical-grade water, saline, or dextrose / water. When the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0054] In alternative embodiments, the drugs or compounds provided herein, or compositions used to practice the methods provided herein, further comprise aqueous and non-aqueous sterile injection solutions which may contain (or may contain) antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the body fluids of the intended recipient, and / or aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0055] In alternative embodiments, the drugs or compounds provided herein or the compositions used in the methods provided herein are formulated for topical administration, for example, in the form of liquid, lotion, cream or gel.Topical administration can be achieved by directly applying to the treatment area.For example, this application can be achieved by rubbing the formulation (such as lotion or gel) into the skin of the treatment area, or by spraying the liquid formulation onto the application area or treatment area.

[0056] In an alternative embodiment, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, comprise a bioimplant or bioimplant material, and may be coated with a compound of the invention or other compounds to improve the interaction between cells and the implant.

[0057] In alternative embodiments, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0058] In an alternative embodiment, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, are formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0059] In alternative embodiments, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, comprise oral formulations such as tablets, pills, troches, lozenges (see, e.g., those described in U.S. Pat. No. 5,780,055), aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or gel tabs, gels, jellies, syrups, and / or elixirs. Compositions intended for oral use can be prepared according to any method known to those skilled in the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents, including sweeteners, flavoring agents, flavorings, coloring agents, and preservatives, to provide a palatable preparation. Oral formulations may include standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinylpyrrolidone, sodium saccharin, cellulose, magnesium carbonate, and the like. Tablets containing the active ingredient in admixture with pharmaceutically acceptable, non-toxic excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate, alone or with a wax, may be employed.

[0060] In an alternative embodiment, formulations for oral use are hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0061] In an alternative embodiment, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, comprise aqueous suspensions containing the active agent in admixture with excipients suitable for the manufacture of aqueous suspensions. Exemplary excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic, as well as dispersing or wetting agents such as natural phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl benzoate or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0062] In an alternative embodiment, the compositions for use in carrying out the drugs or compounds provided herein or the methods provided herein include oily suspensions, which can be formulated by suspending the active ingredient (e.g., the compound of the present invention) in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents, such as those described above, can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0063] In alternative embodiments, the drugs or compounds provided herein, or compositions used to practice the methods provided herein, include an agent that controls the release of the compound, thereby providing a sustained or extended release compound.

[0064] In alternative embodiments, a drug or compound provided herein, or a composition used in practicing a method provided herein, is formulated or manufactured as a multiparticulate and / or solid dispersion formulation, e.g., as described in U.S. Patent Application Publication No. 20080118560, comprising a hydrophobic matrix-forming agent that is an insoluble, non-swelling amphiphilic lipid, and a hydrophilic matrix-forming agent that is a meltable, water-soluble excipient. In one embodiment, the drug or compound provided herein, or the composition used in carrying out the method provided herein, is contained in a tablet, pill, capsule, lozenge, etc., containing any combination of, for example, a binder such as starch, polyvinylpyrrolidone, tragacanth gum, or gelatin; a filler such as microcrystalline cellulose or lactose; a disintegrating agent such as crospovidone, sodium starch glycolate, or corn starch; a lubricant such as magnesium stearate, stearic acid, or glyceryl behenate; a flow agent such as colloidal silicon dioxide and talc; a sweetener such as sucrose or saccharin, aspartame, or acesulfame-K; and / or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.When the dosage unit form is a capsule, it may contain a liquid carrier such as fatty oil.

[0065] In an alternative embodiment, a drug or compound provided herein, or a composition used to practice a method provided herein, comprises (or is contained or packaged in) a unit dosage formulation having a coating, such as sugar, shellac, sustained-release and / or other enteric coating, or a coating comprising any pharmaceutically pure and / or non-toxic agent.

[0066] In an alternative embodiment, a drug or compound provided herein, or a composition used in practicing a method provided herein, comprises (or is contained or packaged within) a unit dosage formulation, and each different compound of the composition or article of manufacture is contained in a different layer of a pill, tablet, or capsule, e.g., having an outer base-soluble layer and an inner acid-soluble layer, as described, for example, in U.S. Pat. No. 7,384,653. In an alternative embodiment, a drug or compound provided herein, or a composition used in practicing a method provided herein, comprises (or is contained or packaged within) a unit dosage formulation, and each different compound of the composition or article of manufacture is contained in a liquid or gel of different viscosity, as described, for example, in U.S. Patent Application Publication No. 20050214223. In alternative embodiments, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, comprise (or are contained or packaged in) unit dose formulations with reduced abuse potential, including, for example, bittering agents, gloss suppressants / indicator dyes, or fine insoluble particulates, e.g., as described in U.S. Patent Application Publication No. 20040228802.

[0067] Carrier In alternative embodiments, the drugs or compounds provided herein or compositions used in practicing the methods provided herein comprise, are formulated with, or are formulated as, aqueous or non-aqueous solutions, suspensions, emulsions, and solids. Examples of non-aqueous solvents suitable for use as disclosed herein include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. In alternative embodiments, aqueous carriers may include water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions, and / or suspensions, including saline and buffered media. Oral carriers may be elixirs, syrups, capsules, tablets, and the like.

[0068] In alternative embodiments, liquid carriers are used in the manufacture or formulation of the drugs or compounds provided herein or compositions used in practicing the methods provided herein, including carriers for preparing solutions, suspensions, emulsions, syrups, elixirs, and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or lipid. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, dyes, viscosity adjusters, stabilizers, or osmolarity adjusters.

[0069] In an alternative embodiment, the liquid carrier used to manufacture or formulate the compounds of the present invention includes water (partially containing the above-mentioned additives, e.g., cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also include oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful for sterile liquid forms containing compounds for parenteral administration. Liquid carriers for pressurized compounds disclosed herein can be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0070] In alternative embodiments, solid carriers are used in the manufacture or formulation of the drugs or compounds provided herein or compositions used in practicing the methods provided herein, and include solid carriers containing substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, and the like. Solid carriers may further include one or more substances that act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow agents, compression aids, binders, or tablet disintegrants, and may also be encapsulating materials. In the case of powders, the carrier may be a finely divided solid mixed with the finely divided active compound. In the case of tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted into the desired shape and size. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low-melting waxes, and ion exchange resins. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surfactant, or dispersing agent. Molded tablets can be produced by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. Tablets can optionally be coated or scored and can be formulated to provide sustained or controlled release of the active ingredient therein, using, for example, hydroxypropyl methylcellulose in various proportions to provide the desired release profile. Tablets can optionally be enteric coated to provide release in parts of the intestine other than the stomach.

[0071] In alternative embodiments, parenteral carriers are used in the manufacture or formulation of drugs or compounds provided herein or compositions used in practicing the methods provided herein; suitable parenteral carriers for use as disclosed herein include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Intravenous carriers may include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may include, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like.

[0072] In alternative embodiments, carriers used in manufacturing or formulating the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, may be mixed, as needed, with disintegrants, diluents, granulating agents, lubricants, binders, etc. using conventional techniques known in the art. Carriers may also be sterilized using methods that do not dramatically react with the compounds, as is generally known in the art.

[0073] The present invention also provides articles of manufacture and kits containing (including) drugs or compounds provided herein or compositions used in practicing the methods provided herein, including pharmaceutical compositions and formulations. By way of example only, a kit or article of manufacture may include a container (e.g., a bottle) containing a desired amount of a compound (or pharmaceutical composition of a compound) described herein. Such a kit or article of manufacture may further include instructions for using the compound (or pharmaceutical composition of a compound) described herein. The instructions may be affixed to the container or may be included in the packaging (e.g., a box or plastic or foil bag) that houses the container.

[0074] The drugs or compounds provided herein, or compositions used in practicing the methods provided herein, can be delivered to the body or targeted to a particular tissue or organ (e.g., muscle or brain) by any method or protocol, including, for example, ex vivo "cell loading" of drugs or compounds provided herein, or compositions used in practicing the methods provided herein, where the "loaded cells" are administered intramuscularly, or intrathecally, intracerebrally, or epidurally to the central nervous system (CNS), for example, as described in U.S. Patent Application Publication No. 20050048002.

[0075] In an alternative embodiment, a drug or compound provided herein, or a composition used in practicing a method provided herein, is first lyophilized and then suspended in a hydrophobic medium containing, for example, an aliphatic, cyclic, or aromatic molecule, as described, for example, in U.S. Patent Application Publication No. 20080159984.

[0076] In an alternative embodiment, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, comprise or are formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts may include suitable acid addition salts or base or basic salts thereof. In an alternative embodiment, the compounds are Berge et al., J Pharm Sci, 66, 1-19 (1977).

[0077] In alternative embodiments, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, may be prepared using a solvent such as a strong inorganic acid, e.g., a mineral acid, e.g., a hydrohalic acid, such as hydrochloric acid, hydrobromic acid, and hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen sulfate, hemisulfate, thiocyanate, persulfate, and sulfonic acid; a strong organic carboxylic acid, e.g., an unsubstituted or substituted (e.g., substituted by a halogen) alkane-carboxylic acid of 1 to 4 carbon atoms, such as acetic acid; a saturated or unsaturated dicarboxylic acid, e.g., The compound of the present invention can be formulated as the salt formed with oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid; hydroxycarboxylic acid such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acid such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid, unsubstituted or substituted (for example, by halogen) (C1-C4)-alkyl-sulfonic acid or aryl-sulfonic acid.The compound of the present invention also includes pharmaceutically unacceptable salts, for example, salts can still be useful as intermediates in synthesis or analysis process or protocol.

[0078] In alternative embodiments, the compounds, active agents, or drugs provided herein, or used in the practice of the methods provided herein, may be any acceptable salt, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptanoate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropioate, or the like. Acid salts include phosphates, picrates, pivalates, propionates, tartrates, lactobionates, pivalates, camphorates, undecanoates, and succinates, organic sulfonic acids such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates, and p-toluenesulfonates; and inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, hydrogensulfates, hemisulfates, thiocyanates, persulfates, phosphoric acids, and sulfonic acids. The pharmaceutical compositions disclosed herein can be prepared according to methods well known and routinely practiced in the art. See, e.g., Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000; and Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0079] In some embodiments, the compounds, active agents, or drugs provided herein, or used in practicing the methods provided herein, are provided in the form of pharmaceutically acceptable salts that contain amines that are basic in nature and can react with inorganic or organic acids to form pharmaceutically acceptable acid addition salts; for example, such salts can be obtained with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as para-toluenesulfonic acid, methanesulfonic acid, oxalic acid, para -bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids, or optionally such pharmaceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, Oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dionate, hexyne-1,6-dionate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, Includes tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, hippurate, gluconate, lactobionate, methylene-bis-b-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinatetraurylsulfonate and similar salts.

[0080] In alternative embodiments, the compounds, active agents or drugs provided herein, or those used in practicing the methods provided herein, include compositions manufactured in accordance with "Good Manufacturing Practice" or GMP, or "current Good Manufacturing Practice" (cGMP) requirements.

[0081] Derivatized and deuterated compounds In alternative embodiments, the compounds, active agents, or drugs provided herein, or used in practicing the methods provided herein, are derivatized analogs, e.g., metabolically blocked or otherwise modified derivatives, including deuterated, hydroxylated, fluorinated, or methylated analogs or derivatives, or any combination thereof.

[0082] With respect to the deuterated compounds provided herein or used in practicing the methods provided herein, it is recognized that synthesized compounds will have some variation in natural isotopic abundance depending on the origin of the chemical materials used in their synthesis. Thus, preparations of compounds may inherently contain small amounts of deuterated isotopologues. With respect to the compounds provided herein or those used in practicing the methods provided herein, including pharmaceutical preparations and formulations, when a particular position is designated as having deuterium ("-D"), it is understood that the abundance of deuterium at that position is greater than or substantially greater than the natural abundance of deuterium, which is 0.015%. For example, alternative embodiments of the present invention include drugs or compounds provided herein, or analogs of drugs or compounds used in practicing the methods provided herein, having greater than 0.02% or greater than about 0.1% deuterium. In one embodiment, deuterium substitution, or "enrichment," occurs at one or more specific positions. In one embodiment, the deuterium enrichment is greater than about 1%, 10%, 20%, 50%, 70%, 80%, 90%, or 95%, or between about 1% and 100%.

[0083] In one embodiment, the deuterated (or otherwise substituted) compounds provided herein, or used in practicing the methods provided herein, have a slower metabolic rate, e.g., a slower hydroxylation rate, than the corresponding protonated (non-deuterated, unsubstituted) compound.

[0084] With respect to providing new sites for deuteration of Formula II, it has been found that a key metabolic pathway for Formula II is N-acetylation via N-acetyltransferase 2 (NAT-2), which produces 1-(2-acetyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one, i.e., the following structure: [ka] The amount of this metabolite was found to be highly significant compared to the parent compound, Formula II, in healthy volunteers in a Phase I clinical trial. This metabolite does not contribute to the pharmacology of MCHR1 antagonism. Combining Formula II with an NAT-2 inhibitor, such as acetaminophen, is expected to reduce this metabolite and increase the effective concentration of Formula II in patients, thereby reducing the required dose. Substituting deuterium for the hydrogen on the carbon(s) adjacent to the acetylated nitrogen (see, e.g., Examples 5-7) can slow the acetylation process and reduce the formation of this metabolite.

[0085] stereoisomer In alternative embodiments, the compounds, active agents, or drugs provided herein, or those used in practicing the methods provided herein, exist as (include) each individual stereoisomer substantially free of other possible stereoisomers. In alternative embodiments, the term "substantially free of other stereoisomers" as used herein means that there is less than about 15%, 20%, 25%, 30%, 35%, 40%, 50%, or 55% of other stereoisomers, or less than about 10%, or less than about 5%, or less than about 2%, or less than about 1%, or less than "X"% of other stereoisomers (where X is a number between 0 and 100). Methods for obtaining or synthesizing individual enantiomers of a given compound are known in the art and can be applied to final compounds or starting materials or intermediates.

[0086] Administration method In alternative embodiments, drugs or compounds provided herein or drugs or compounds used in practicing the methods are provided and are administered by any or a variety of means, including orally, parenterally, by inhalation spray, intranasally, topically, intrathecally, intracranially, epidurally, intracranially, or rectally. Drugs or compounds provided herein or drugs or compounds used in practicing the methods are provided herein and are administered with pharmaceutically acceptable carriers, adjuvants, and vehicles. In alternative embodiments, drugs or compounds provided herein or compositions used in practicing the methods provided herein are administered intrathecally, intracranially, or epidurally (administration into the intrathecal, intracerebral, or epidural space), subcutaneously, intravenously, intramuscularly, and / or intraarterially, e.g., via injection routes, but also including various infusion techniques. Intraarterial, intrathecal, intracranial, epidural, intravenous, and other injections can include administration via a catheter or pump, e.g., an intrathecal pump, or an implantable medical device (which may be an intrathecal pump or catheter).

[0087] In alternative embodiments, the drug therapeutic combinations, pharmaceutical compositions, preparations and kits may be administered by any known method or route, including intranasal, intramuscular, intravenous, topical or oral routes, or a combination thereof.

[0088] One embodiment includes an article of manufacture comprising a pharmaceutical composition or formulation, a blister pack, a blister with lid or a blister card or packet, a clamshell, a tray or shrink wrap or a kit containing a drug therapeutic combination, pharmaceutical composition or preparation provided herein for oral administration.

[0089] In alternative embodiments, all components may be contained in a single blister pack, lidded blister or blister card or packet, clamshell, tray or shrink wrap, or kit, but the separate components may be formulated, for example, for topical, oral, or local application. Each component may be packaged separately or formulated as a unit dose, for example, in a tube (e.g., a gel, lotion, etc.), ampoule, blister packet, etc.

[0090] Dosage In alternative embodiments, the drugs or compounds provided herein, or compositions used in practicing the methods provided herein, are formulated and administered in a variety of different dosages and treatment regimens depending on the disease or condition to be improved, the condition of the individual being treated, the therapeutic goals, etc., as routinely determined by a clinician. See, e.g., the latest edition of Remington: The Science and Practice of Pharmacy, Mack Publishing Co. (supra).

[0091] In alternative embodiments, an effective amount of a drug or compound provided herein, including a stereoisomer, salt, hydrate, or solvate, or a composition used in practicing a method provided herein, is about 0.1 mg to about 20.0 mg per kg of body weight of an individual or subject (e.g., patient). In another variation, the effective amount is about 0.1 mg to about 10.0 mg per kg of body weight of an individual or subject (e.g., patient), or about 0.1 mg to about 5.0 mg per kg of body weight of a patient. Alternatively, the effective amount is about 0.2 mg to about 2 mg per kg of body weight of an individual or subject (e.g., patient).

[0092] In alternative embodiments, an effective amount of a drug or compound provided herein, or a composition used to practice a method provided herein (e.g., as a solid dosage form such as a pill, tablet, or lozenge) of the individual, subject, or patient is about 0.1 mg / kg to about 2.0 mg / kg of body weight, or about 0.1 mg / kg to about 1.0 mg / kg of body weight, or about 0.1 mg / kg, about 0.15 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, or about 0.5 mg / kg of body weight. , about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, or about 1.0 mg, or an effective amount of a drug or compound provided herein, or a composition used in practicing a method provided herein, is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, or about 0.3 mg per kg of body weight.

[0093] In alternative embodiments, an effective amount of a drug or compound provided herein, or a composition used in practicing a method provided herein (e.g., as a solid dosage form such as a pill, tablet, or lozenge) is from about 1 mg to about 400 mg, or a solid dosage form comprising from about 1 mg to about 250 mg, or a solid dosage form comprising from about 5 mg to about 150, or a solid dosage form (e.g., as a pill, tablet, or lozenge) comprising from about 1 mg to about 75, or a solid dosage form comprising about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg.

[0094] Safe and predictable dose titration In an alternative embodiment, an empirical method is provided for stable and predictable titration and for determining the initial therapeutic dose, or for determining the minimum therapeutic dose, or for determining the optimal effective dose for any individual drug used in the methods provided herein (e.g., when the drug is used alone), or for any combination of drugs provided herein, the method comprising: a. administering a test dose (e.g., a dose at which no adverse events or minimal adverse events are observed or a safe dose) daily until the patient achieves a steady-state plasma drug concentration; b. taking a blood sample and assessing the test plasma drug concentration prior to the next scheduled dose; c. calculating the initial therapeutic dose / day; 1. For drugs that are dose-linear with respect to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiply the divided value by the test dose; 2. For drugs that are dose-nonlinear with respect to plasma concentration, dividing the initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiplying the divided value by the test dose, and then multiplying the product by a nonlinear exponential coefficient, optionally calculating the initial target therapeutic plasma drug concentration as follows: (i) a concentration corresponding to a particular pharmacodynamic efficacy marker level, e.g., serotonin transporter (SERT or 5-HTT), dopamine transporter (DAT), or norepinephrine transporter (NET) occupancy, as determined by an imaging method such as positron emission tomography (PET), or (ii) a concentration corresponding to the lowest effective therapeutic dose as determined by clinical trials; d. Optionally, i. administering the initial therapeutic dose daily until the patient achieves steady-state plasma drug concentrations; ii. Obtaining a blood sample prior to the next scheduled dose to assess the current therapeutic plasma drug concentration; iii. Calculating the next treatment target dose / day, 1. For drugs that are dose-linear with respect to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiply the divided value by the current therapeutic dose; 2. For drugs with nonlinear dose to plasma concentration, calculating the next target therapeutic plasma drug concentration by dividing the current therapeutic plasma drug concentration, then multiplying the divided value by the current therapeutic dose, and then multiplying the product by a nonlinear exponential coefficient; and iv. A method is provided which includes continuing the process until the lowest therapeutic dose or the optimal effective dose is achieved.

[0095] In an alternative embodiment, a model-based method for stable and predictable titration and for determining the initial therapeutic dose, and for determining the minimum therapeutic dose, or for determining the optimal effective dose, is provided, the method comprising: a. administering the test dose daily for about 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or about 1 day; b. Obtaining the first blood sample between about 1 hour and 3 days, 6 hours and 2 days, or about 1 day after administering the first test dose; c. collecting a second or subsequent blood sample between about 1 hour and 28 days, 6 hours and 14 days, 1 day and 7 days, or about 2 days after the first or subsequent blood sample is collected; d. Calculating the initial treatment starting dose / day, i. using the initial target therapeutic plasma drug concentration, test dose, time of administration of the test dose(s), plasma concentration of the blood sample and time of collection of the blood sample and the pharmacometric model; ii. optionally using initial target therapeutic plasma drug concentrations, test doses, time of administration of test dose(s), plasma concentrations of blood samples, time of blood sample collection, human PK data and a Bayesian pharmacometric model; iii. optionally, calculating an initial target therapeutic plasma drug concentration, by using the test dose, the time of administration of the test dose, the plasma concentration of the blood sample, the time of collection of the blood sample, human PK data, the patient's genetic information, the patient's non-genetic host factors, the patient's other medications, and a Bayesian pharmacometrics model; e. Optionally, i. administering the initial treatment starting dose daily until the patient achieves steady-state plasma drug concentrations; ii. Obtaining a blood sample prior to the next scheduled dose to assess the current therapeutic plasma drug concentration; iii. Calculating the next treatment target dose / day, 1. For drugs that are dose-linear with respect to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiply the divided value by the current therapeutic dose; 2. For drugs with nonlinear dose to plasma concentration, calculating the next target therapeutic plasma drug concentration by dividing the current therapeutic plasma drug concentration, then multiplying the divided value by the current therapeutic dose, and then multiplying the product by a nonlinear exponential coefficient; and iv. A method is provided which includes continuing the process until the lowest therapeutic dose or the optimal effective dose is achieved.

[0096] In an alternative embodiment, a method for maintaining an effective dose is provided, the method comprising: (a) recording a maintenance dose and maintenance therapeutic plasma drug concentration associated with a minimum effective therapeutic dose or an optimal therapeutic dose; (b) Between about 1 and 12 months, 3 and 9 months, 4 and 8 months, or early 6 months, or when there is a change in weight, medication, or health status. 1. Prior to the next scheduled dose, a blood sample is drawn to assess the current therapeutic plasma drug concentration; 2. If the current plasma drug concentration differs from the maintenance therapeutic plasma drug concentration by more than about 20%, and optionally, by more than about 50%, calculate the new therapeutic dose / day by a method that includes: i. for drugs that are dose-linear with respect to plasma concentration, divide the maintenance treatment plasma drug concentration by the current plasma drug concentration, then multiply the divided value by the maintenance dose; ii. For drugs with nonlinear dose to plasma concentration, divide the maintenance treatment plasma drug concentration by the current plasma drug concentration, then multiply the divided value by the maintenance dose, and then multiply the product by a nonlinear exponential coefficient; or iii. Optionally, steady state is reached after two subsequent plasma drug concentration results separated by at least one week and within about 20% of the maintenance therapeutic plasma concentration; or iv. Optionally, a method is provided that includes continuing the process until a maintenance therapeutic dose is achieved at steady state.

[0097] In alternative embodiments, it may be necessary to round the lowest therapeutic dose or optimally effective dose to the nearest available dose. For example, a calculation may determine that the optimally effective dose is 23 mg / day, but the nearest available dose may be only 20 mg. Thus, the patient is only administered 20 mg / day.

[0098] In an alternative embodiment, a pharmacokinetic modeling and simulation method of Formula I is provided, comprising using the human PK data set forth sequentially in Figures 25-29. A three-compartment model best described the human PK data. The inter-patient variability in healthy volunteers was 20.2%. Visual posterior predictive performance (VPC) plots indicated that the final model was unbiased. In an alternative embodiment, a population PK / PD model of Formula I using the human PK data set forth in Figures 30 and 31 is provided.

[0099] In an alternative embodiment, a PK-guided precision dosing method is provided that uses the pharmacokinetic modeling and simulation methods described above, or similar modeling and simulation methods, and a population PK / PD model of Formula I to treat binge eating, binge eating in PWS, Disordered Mood Dysfunction Disorder (DMDD), Oppositional Defiant Disorder (ODD), obesity in hypothalamic lesion-induced obesity, and Binge Eating Disorder (BED) by oral administration of Formula I.

[0100] Packaging and Drug Delivery Systems In alternative embodiments, therapeutic combinations, preparations, formulations, and / or kits are provided that include a combination of ingredients as described herein. In one aspect, each member of the combination of ingredients is manufactured in a separate package, kit, or container; alternatively, all or a subset of the combination of ingredients is manufactured in a separate package or container. In alternative aspects, the package, kit, or container comprises a blister pack, clamshell, tray, shrink wrap, or the like.

[0101] In one aspect, the package, kit, or container comprises a "blister pack" (also called a blister pack, or bubble pack). In an alternative embodiment, there is provided a therapeutic combination, preparation, formulation, and / or kit manufactured as a "blister pack" or as multiple small pouches, including a lidded blister pack, a lidded blister, or a blister card, or a packet, or a small packet, or shrink wrap.

[0102] In one embodiment, a blister package is comprised of two separate elements: a clear or occlusive plastic cavity shaped to fit the product and its blister foil backing. These two elements are then sealed together to form a blister strip of one or more blisters, each blister being an environmentally protected (e.g., moisture, pathogen, light) unit dose. One or more blister strips may be further joined together with a cardboard material, which allows the product to be packaged, handled, hung, displayed, or shipped without damaging the blister seal and may also provide child-resistant features. Exemplary types of "blister packages" include surface seal blister packages, gang run blister packages, mock blister packages, two-way blister packages, and slide blister packages.

[0103] A blister pack, clamshell, or tray is a form of packaging used for an article; thus, a blister pack, clamshell, or tray containing a composition provided herein (e.g., a combination of active ingredients (multi-component drug combinations provided herein)) is provided. The blister pack, clamshell, or tray can be designed to be non-reclosable, allowing the consumer to tell if the package has been opened. The blister pack, clamshell, or tray is used in packaging for sales items where tampering of products, such as pharmaceutical products provided herein, is a concern. In one embodiment, the blister pack provided herein comprises a molded PVC substrate with raised portions ("blisters") for receiving tablets, pills, etc., containing the combination provided herein, and is covered with a laminated foil. The tablets, pills, etc. are removed from the pack by either peeling the foil or by pressing the blister to break the foil with the tablet. In one embodiment, a specialized form of blister pack is a strip pack. In one embodiment, in the UK, the blister pack adheres to British Standard 8404.

[0104] In an alternative embodiment, laminated aluminum foil blister packs are used, for example, for drug preparations designed to dissolve immediately in a patient's mouth. This exemplary process involves preparing the drug combinations, therapeutic combinations, and pharmaceutical dosage forms provided herein as aqueous solution(s) that are dispensed (e.g., in measured doses) into an aluminum (e.g., Alfoil) laminated tray portion of a blister pack. The tray is then freeze-dried to form tablets that take the shape of the blister pockets. The Alfoil laminate on both the tray and lid provides complete protection for highly hygroscopic and / or delicate individual medications. In one aspect, the pack incorporates a child-resistant peel-open safety laminate. In one aspect, this system provides an identifying mark on the tablet by embossing a design into the Alfoil pocket that is incorporated into the tablet as it transitions from an aqueous to a solid state. In one aspect, individual "push-through" blister packs / sachets are used, for example, using a hard-tempered aluminum (e.g., Alfoil) lid material. In one embodiment, a hermetically sealed high barrier aluminum (e.g., aluminum foil) laminate is used. In one embodiment, any article of manufacture provided herein, including kits or blister packs, uses peelable and non-peelable laminations in combination with foil laminations and strip packs, strip packs, sachets and pouches, foils, papers, and films for high barrier packaging.

[0105] In an alternative embodiment, any article of manufacture provided herein, including a kit or blister pack, includes a memory aid to help remind the patient when and how to take their medication, protecting each pill until taken to ensure efficacy of the medication, and providing portability to the product or kit, facilitating taking medication anytime or anywhere.

[0106] In alternative embodiments, the drug combinations, therapeutic combinations, pharmaceutical dosage forms, drug delivery devices, and products provided herein use child-resistant and elderly-friendly packaging, e.g., packaging that complies with U.S. government child-resistant packaging regulations requiring minimal fingertip and grip strength. For example, in alternative embodiments, foil-only enclosed pills are used.

[0107] In alternative embodiments, the drug combinations, therapeutic combinations, pharmaceutical dosage forms, drug delivery devices, and articles of manufacture provided herein are preferably tablets, capsules, pills, or the like, on a blister card or the like that tracks usage. In tracking usage, a blister card monitor can remind the patient and / or primary caregiver to take (or have taken) medication at the correct time, e.g., morning and / or afternoon, facilitating discussions with healthcare professionals and identifying and overcoming barriers to adherence.

[0108] In an alternative embodiment, patient use is monitored through the use of customized blister cards or equivalents using an Electronic Compliance Monitor (ECM) system (Intelligent Devices SEZC Inc. (IDI), Grand Cayman, Cayman Islands) or equivalent. For example, in an alternative embodiment, the blister card or equivalent includes electronic components that detect, record, protect, and / or transmit when medication is removed from the blister card or equivalent. For example, a sensor detects when medication is removed from the blister card or equivalent, and this information can be transmitted remotely, for example, for verification by the medication provider and / or primary care institution or individual. Data transmission can be by hard-contact download of data to a transmitting and / or storage device, or can be remotely scanned and data downloaded using a radio frequency identification (RFID) chip, tag, or device or equivalent that can be operably connected to a computer and / or cell phone or other device. Radio frequency identification uses electromagnetic fields to automatically identify and track tags attached to objects, which contain electronically stored information, in this embodiment, transmitted as to whether and / or when medication has been removed from each compartment of a blister card or equivalent, or transmitted via near field communication (NFC) to an NFC-enabled mobile device or cell phone. NFC is a type of communications protocol that allows two electronic devices (one of which is typically a mobile device such as a smartphone) to establish communication when brought within 4 cm (1.6 inches) of each other.

[0109] In an alternative embodiment, the multi-drug delivery system used in the methods provided herein may further include the use of a box contained or enclosed within a drug delivery device or package, blister pack, clamshell, or tray provided herein; in this exemplary delivery system, a week's supply of pharmaceutical dosage forms (e.g., one, two, or three or more tablets, pills, capsules, gel tabs, or the like) are contained in four columns, with two columns for morning or breakfast, or AM administration and two columns for evening, dinner, or PM administration, for administration (opening and self-administration by a user, e.g., a patient), the columns for morning or breakfast, or AM administration being clearly separated from the columns for evening, dinner, or PM administration, and each day's and backup doses being arranged in a vertical column. In an alternative embodiment, the blister packs, clamshells, or trays are physically coupled to the storage box, and the blister packs, clamshells, or trays slide in and out of the storage box, and in an alternative embodiment, the set of PM rows can be folded over the set of AM rows to reinsert the blister packs, clamshells, or trays into the storage box as needed. In an alternative embodiment, the storage box includes sensors that detect when medication is removed from each compartment (e.g., which compartment was opened and when), and this information can be transmitted remotely, e.g., by near field communication (NFC) to an NFC-enabled mobile device or cell phone, for verification, e.g., by the medication provider and / or primary care institution or individual.

[0110] In any embodiment of the methods provided herein, the plasma concentration of the drug, or therapeutic combination, pharmaceutical dosage form, is determined by: (a) a trough level or concentration (C トラフ ), or the lowest concentration reached by the drug, or therapeutic combination, or pharmaceutical dosage form before the second or subsequent dose is administered, or (b) as determined from a blood sample taken between 0.5 hours and 24 hours, or between 4 and 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more hours after the last dose or administration of the drug, or therapeutic combination, or pharmaceutical dosage form.

[0111] In an alternative embodiment, "individualized dosing" and "PK-guided dosing" and "precision dosing" are interchangeable terms and refer to dosing to each patient based on the PK properties of the drug in that patient.

[0112] In alternative embodiments, the terms "plasma concentration", "plasma drug concentration", "serum concentration", "serum drug concentration", "plasma level", "level" in the context of drug concentration are interchangeable and refer to drug concentrations in humans or animals, measurement and interpretation by one of skill in the art see Loftsson T. Essential Pharmacokinetics - 1st Edition. Elsevier. 2015.

[0113] In alternative embodiments, a "target therapeutic plasma drug concentration," or similar term, is within a therapeutic plasma range, optionally about the midpoint of the therapeutic range of plasma concentrations. For example, if the therapeutic, i.e., effective, or efficacious, plasma concentration range for treating PWS is 1000 ng / ml to 1400 ng / ml, then the target therapeutic plasma drug concentration can be about 1000 ng / ml, about 1300 ng / ml, or optionally the midpoint of about 1200 ng / ml.

[0114] In an alternative embodiment, treatment in the context of plasma concentrations means effective or effective in treating a medical condition(s).

[0115] Any of the above aspects and embodiments may be combined with any other aspect or embodiment disclosed in the Summary, Drawings and / or Detailed Description sections herein.

[0116] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0117] Unless specifically stated or clear from context, the term "or," as used herein, is understood to be inclusive and include both "or" and "and."

[0118] Unless specifically stated or clear from the context, the term "about" as used herein is understood to mean within a normal range of tolerance in the art, for example, within two standard deviations of the mean. About (use of the term "about") can be understood to mean within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term "about."

[0119] Unless specifically stated or clear from context, the terms "substantially all," "substantially a majority of," "substantially all of," or "the majority of," as used herein, include at least about 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 99.5% or more of a reference amount of a composition. For example, in alternative embodiments, the term "substantially pure" refers to chemical purity, e.g., a compound that is "substantially pure" provided or used in a therapeutic formulation or combination provided herein (e.g., comprising Formula I) is at least about 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 99.5% pure or free from contaminants or other forms, e.g., free from any form other than the S-enantiomer of Formula I.

[0120] Each patent, patent application, publication, and document referred to herein is incorporated herein by reference in its entirety. Citation of the above patents, patent applications, publications, and documents is not an admission that any of the foregoing is relevant prior art, nor does it constitute any admission as to the content or date of such publications or documents. It should be understood that the incorporation by reference of these documents alone does not assert or admit that any part of the contents of any document shall be deemed essential material to satisfy any national or local statutory disclosure requirements for patent applications. The right, however, to rely on any such documents, where appropriate, to provide material deemed essential to the claimed subject matter by an examining authority or court is reserved.

[0121] Various modifications may be made to the foregoing without departing from the essential aspects of the invention. While the present invention has been described in substantial detail with reference to one or more specific embodiments, those skilled in the art will recognize that changes can be made to the embodiments specifically disclosed herein, and that such modifications and improvements are within the spirit and scope of the present invention. The invention illustratively described herein may suitably be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each example herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced by either of the other two terms. Thus, the terms and expressions employed are used as terms of description rather than limitation, and equivalents of the features shown and described, or portions thereof, are not to be excluded, recognizing that various modifications are possible within the scope of the invention. Embodiments of the invention are set forth in the following claims.

[0122] While the present invention will be further described with reference to the examples described herein, it will be understood that the invention is not limited to such examples. [Example]

[0123] Example 1: Exemplary Method for Treating Prader-Willi Syndrome by Administering Formula I or a Deuterated Analogue This example describes exemplary methods and compositions for the treatment of Prader-Willi syndrome by administering a pharmaceutical composition comprising Formula I, or 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline.

[0124] Male and female patients (age 4 years or older) with a medically recorded history of PWS confirmed by genetic testing are selected for treatment.

[0125] Patients receive a daily (optionally subtherapeutic) dose of 1 mg to 20 mg of the pharmaceutical composition for one day, one week, two weeks, three weeks, or four weeks. Blood samples are collected periodically to determine steady-state drug concentrations, and the nearest target dose required to achieve 15% to 75% dopamine transporter (DAT) occupancy is determined, with or without the aid of pharmacometric modeling methods that also utilize pharmacokinetic / pharmacodynamic (PK / PD) data. Optionally, the nearest target dose is determined by achieving a plasma drug concentration value of 100 ng / ml to 4000 ng / ml at steady state; optionally, the nearest target dose is determined by achieving a plasma drug concentration value of 200 ng / ml to 2000 ng / ml at steady state; and optionally, the nearest target dose is determined by achieving a plasma drug concentration value of 400 ng / ml to 2000 ng / ml at steady state. Every three or six months, or if there are significant changes in the patient's medication, weight and other physical changes may affect drug absorption and metabolism, so blood levels should be retested and the dose adjusted as needed. Optionally, patients may begin at a low dose of 5 mg to 20 mg per day and gradually increase the dose in 5 mg, 10 mg, or 20 mg increments until efficacy against overeating and / or neuropsychiatric and behavioral symptoms is safely achieved. Clinicians can accelerate the titration, slow it down as needed, and then re-accelerate it later based on the patient's tolerance.

[0126] Example 2: Exemplary Method for Treating Hypothalamic Obesity or Hypothalamic Damage-Induced Obesity by Administering Formula I or Any Deuterated Analogues thereof This example describes exemplary methods and compositions for the treatment of hypothalamic obesity, or hypothalamic injury-induced obesity, by administering a pharmaceutical composition comprising Formula I, or 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline.

[0127] Male and female patients (age 4 and older) diagnosed with hypothalamic lesion-induced obesity are selected for treatment.

[0128] Patients receive a low (optionally subtherapeutic) dose of 1 mg to 20 mg of the pharmaceutical composition daily for 1 day, 1 week, 2 weeks, 3 weeks, or 4 weeks. Blood samples are collected periodically to determine steady-state drug concentrations, and the nearest target dose required to achieve 15% to 75% DAT occupancy is determined with or without the aid of pharmacometric modeling methods that also utilize PK / PD data. Optionally, the nearest target dose is determined by achieving a steady-state plasma drug concentration value of 100 ng / ml to 4000 ng / ml; optionally, the nearest target dose is determined by achieving a steady-state plasma drug concentration value of 200 ng / ml to 2000 ng / ml; optionally, the nearest target dose is determined by achieving a steady-state plasma drug concentration value of 400 ng / ml to 2000 ng / ml; optionally, the nearest target dose is determined by achieving a steady-state plasma drug concentration value of about 400 ng / ml to 2000 ng / ml. Every three or six months, or whenever there are significant changes in the patient's medication, weight and other physical changes may affect drug absorption and metabolism, and blood drug levels are retested and the dose adjusted as needed. Optionally, the patient is started on a low dose of 5 mg to 20 mg per day and gradually increased in 5 mg, 10 mg, or 20 mg increments until efficacy against overeating and / or neuropsychiatric and behavioral symptoms is safely achieved. Clinicians can accelerate titration, slow titration if necessary, and then re-accelerate titration later based on patient tolerance.

[0129] Example 3: Exemplary Methods for the Treatment of Binge Eating Disorder (BED) by Administering Formula I or Any Deuterated Analogues Thereof This example describes exemplary methods and compositions for the treatment of binge eating disorder (BED).

[0130] Male and female patients diagnosed with BED according to DCM-IV (DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), optionally male and female patients diagnosed with BED according to DCM-IV and with major depressive disorder (MDD) according to DCM-IV, optionally BED is treatment-refractory BED, optionally MDD is treatment-refractory MDD, and optionally the diagnosis of MDD includes a video-recorded interview.

[0131] Patients receive a low (optionally subtherapeutic) dose of 1 mg to 20 mg of the pharmaceutical composition daily for one, one, two, three, or four weeks. Blood samples are collected periodically to determine steady-state drug concentrations, and the nearest target dose required to achieve 15% to 75% DAT occupancy is determined, with or without the aid of pharmacometric modeling methods that also utilize PK / PD data. Optionally, the nearest target dose is determined by achieving a plasma drug concentration value of 100 ng / ml to 4000 ng / ml at steady state; optionally, the nearest target dose is determined by achieving a plasma drug concentration value of 200 ng / ml to 2000 ng / ml at steady state; and optionally, the nearest target dose is determined by achieving a plasma drug concentration value of 400 ng / ml to 2000 ng / ml at steady state. Every three or six months, or if there are significant changes in the patient's medication, weight and other physical changes may affect drug absorption and metabolism, so blood levels should be retested and the dose adjusted as needed. Optionally, patients may begin at a low dose of 5 mg to 20 mg per day and gradually increase the dose in 5 mg, 10 mg, or 20 mg increments until efficacy against BED is safely achieved. Clinicians can accelerate the titration, slow it down as needed, and then re-accelerate it later, based on the patient's tolerance.

[0132] Example 4: This example describes an exemplary protocol for synthesizing the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5, as shown schematically in Figure 1.

[0133] The ketone 4, 2-amino-1-(3,4-dichlorophenyl)ethan-1-one hydrochloride, is converted to intermediate 5 under active proton deuteration conditions. Reduction of intermediate 5 with sodium borodeuteride forms alcohol 6. The deuterated aldehyde 3, 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-α-d1, prepared by reduction of intermediate 2, 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzonitrile, with DIBAL-D (diisobutylaluminum hydride), undergoes reductive amination with deuterated amine 6 and sodium borodeuteride to give intermediate 7. Cyclization of intermediate 7 under acidic conditions affords the target molecule 8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5. Example 4.1: Preparation of 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5 8A and 8B

[0134] Preparation of 2-(amino-d2)-1-(3,4-dichlorophenyl)ethan-1-one-2,2-d2DCl salt 5: A mixture of 2-amino-1-(3,4-dichlorophenyl)ethan-1-one hydrochloride 4 (3.0 g, 12.5 mmol), DO (20 mL), THF (20 mL), and DCl (20%, 8 mL) in a sealed tube was stirred at 95 °C for 24 h. The isotopic purity was determined by mass spectrometry (91% D). The volatiles were removed under vacuum. The procedure was repeated. Vacuum concentration afforded the product as an off-white solid (>99% D). ESI-MS (M+1) m / z: 206

[0135] Preparation of 2-(amino-d2)-1-(3,4-dichlorophenyl)ethan-1,2,2-d3-1-ol-d 6: To a solution of 2-(amino-d)-1-(3,4-dichlorophenyl)ethan-1-one-2,2-dDC1 salt 5 (367 mg, 1.50 mmol) in CH3OD (2.8 mL) at 0 °C was added NaBD4 (61 mg, 1.46 mmol). The mixture was stirred at room temperature overnight. A few drops of DO were added to quench the reaction. The mixture was concentrated to dryness in vacuo to give the crude title compound 6.

[0136] Preparation of 2-(((3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methyl-d2)amino-d)-1-(3,4-dichlorophenyl)ethan-1,2,2-d3-1-ol-d7: To a solution of the residue 6 (1.50 mmol) in CH3OD (2.8 mL) was added (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-□-d1 3 (336 mg, 1.50 mmol) and DCM (1.5 mL) were added. The mixture was stirred at room temperature for 2 h, and then NaBD (61 mg, 1.46 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was partitioned between DCM and 4N NH OH. The aqueous phase was extracted with DCM (2×). The combined extracts were dried over Na SO , filtered, and concentrated in vacuo to give the crude product (610 mg).

[0137] Preparation of tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-1,1,3,3,4-d5 8-Boc: To cold sulfuric acid (2.15 mL) at 0 °C was added dropwise a solution of 2-(((3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methyl-d2)amino-d)-1-(3,4-dichlorophenyl)ethan-1,2,2-d3-1-ol-d7 (610 mg) in DCM (1.9 mL). The mixture was stirred and allowed to warm to room temperature overnight. Ice water was added to the reaction, and the pH was adjusted to 9-10 by adding 20% ​​NaOH. The mixture was extracted with DCM (3×), and the combined extracts were dried over NaSO, filtered, and concentrated in vacuo to give a crude residue containing 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5 8. The crude residue containing 8 was dissolved in DCM (20 mL). To the solution was added di-t-butyl dicarbonate (360 mg, 1.65 mmol). The resulting mixture was stirred at room temperature overnight and then purified by column chromatography (2:1 to 1:2 H:EtOAc) to give tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-1,1,3,3,4-d5 8-Boc (180 mg, 24% over three steps). ESI-MS (M+1) m / z: 500; 1 HNMR(400 MHZ, CDCl3)δ 8.80(s, 1H), 8.39(s, 1H), 7.93-7.69(m, 2H), 7.47-7.30(m, 3H), 7.20(s, 1H), 7.12-6.77(m, 2H?), 1.64-1.14(m, 9H).

[0138] Chiral SFC separation: Racemic tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-1,1,3,3,4-d5 8-Boc (165 mg) was dissolved in 5 mL of MeOH and 5 mL of dichloromethane and then separated by chiral SFC (Regis Whelk-O1(S,S)2 1X250 mm; mobile phase: 45% 2-propanol + 0.25 DEA / CO2; 254 nM) to give enantiomer A 8A-Boc (88 mg, RT = 2.35 min, 100% ee) and enantiomer B 8B-Boc (69 mg, RT = 2.77 min, 100% ee).

[0139] Preparation of enantiomer 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5 HCl salt 8A: A mixture of 8A-Boc and 4N HCl in dioxane (1 mL) was stirred at room temperature for 1 hour. After removing the volatiles, the residue was triturated with EtOAc (2 mL). The enantiomer of the product, 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5 HCl salt 8B (60 mg) was obtained; ESI-MS (M+1) m / z: 400; 1 HNMR(400 MHZ, DMSO)δ 9.8(bs, 2H), 9.34(s, 1H), 8.56(s, 1H), 7.68(m, 4H), 7.37-7.27(m, 1H), 6.90(d, J=7.80 Hz, 1H).

[0140] Preparation of enantiomer 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5 HCl salt 8B: A mixture of 8B-Boc and 4N HCl in dioxane (1 mL) was stirred at room temperature for 1 hour. After removing the volatiles, the residue was triturated with EtOAc (2 mL). The enantiomer of the product, 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5 HCl salt 8B (50 mg) was obtained; ESI-MS (M+1) m / z: 400; 1 HNMR: Identical to 8A.

[0141] Example 5: This example describes an exemplary protocol for synthesizing the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2, as shown schematically in FIG. 2. Compound 5 is reduced with sodium borohydride to compound alcohol 9, which is then converted to deuterated amine 10. Deuterated aldehyde 3, 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-□-d1, prepared by reducing intermediate 2, 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzonitrile, with DIBAL-D (diisobutylaluminum hydride), is subjected to reductive amination with deuterated amine 10 and sodium borodeuteride to afford intermediate 11. Cyclization of intermediate 11 under acidic conditions affords target molecule 12, 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2.

[0142] Example 5.1: Preparation of 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 12A and 12B Preparation of 2-(amino-d2)-1-(3,4-dichlorophenyl)ethan-1-ol-d 10: To a solution of 2-amino-1-(3,4-dichlorophenyl)ethan-1-one hydrochloride 4 (288 mg, 1.2 mmol) in 2 mL of methanol at 0 °C was added NaBH (33 mg, 0.79 mmol). The mixture was stirred at 0 °C for 30 min and then concentrated in vacuo. The residue was treated with DO / MeOD (0.5 mL / 1.5 mL). After stirring at room temperature for 20 min, the mixture was concentrated in vacuo. The residue was used directly in the next reaction.

[0143] Preparation of (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methan-d-ol 3b: To a solution of 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde 3a (2.51 g, 11.2 mmol) in CH3OD (22 mL) at 0 °C was added NaBD4 (265 mg, 6.33 mmol). The mixture was stirred at 0 °C for 30 min, and then water (40 mL) was added. Filtration gave (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methane-d-ol 3b as a white solid (1.65 g, 65% yield).

[0144] Preparation of 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-a-d1 3: To a solution of (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methan-d-ol 3b (1.65 g, 7.37 mmol) in CHCl (30 mL) at room temperature, Dess-Martin periodinane (3.75 g, 8.84 mmol) was added. The mixture was stirred at room temperature overnight. Column chromatography purification afforded (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-α-d1. 3 (1.64 g, 99%, 74% D) was obtained as an off-white solid. ESI-MS (M+1) m / z: 225.

[0145] Preparation of (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methan-d2-ol 3c: To a solution of 3(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-a-d1 3 (1.64 g, 7.37 mmol) in CH3OD (20 mL) at 0 °C was added NaBD4 (310 mg, 7.37 mmol). The mixture was stirred at 0 °C for 30 min, and then water (30 mL) was added. Filtration gave (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methan-d2-ol 3c as a white solid (1.40 g, 84% yield, 95% D).

[0146] Preparation of 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-a-d1 3: To a solution of (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methan-d2-ol 3c (1.40 g, 6.25 mmol) in CHCl (30 mL) at room temperature was added Dess-Martin periodinane (3.18 g, 7.50 mmol). The mixture was stirred at room temperature overnight. Column chromatography purification afforded (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-□-d1 3 (1.39 g, 99%, 92% D) as an off-white solid. ESI-MS (M+1) m / z: 225

[0147] 2-(((3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methyl-d2)amino)-1-(3,4-dichlorophenyl)ethan-1-ol Preparation of 11: A mixture of 2-(amino-d2)-1-(3,4-dichlorophenyl)ethan-1-ol-d10 (210 mg, 0.99 mmol), (3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde-□-d13 (220 mg, 0.99 mmol), DCM (1 mL), and CH3OD (1.4 mL) was stirred at room temperature for 4 h. NaBD4 (41 mg, 0.90 mmol) was added, and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and the residue was partitioned between DCM and 4 N NH4OH. The aqueous phase was extracted with DCM (2×). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product (approximately 440 mg, >99% D).

[0148] Preparation of 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 12: To cold sulfuric acid (1.72 mL) at 0 °C was added dropwise a solution of 2-(((3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methyl-d2)amino)-1-(3,4-dichlorophenyl)ethan-1-ol 11 in DCM (1.5 mL). The mixture was stirred and allowed to warm to room temperature overnight. Ice water was added to the reaction and the pH was brought to 9-10 by adding 20% ​​NaOH. The mixture was extracted with DCM (3X) and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound 12 (177 mg, 45% over two steps). ESI-MS (M+1) m / z: 397; 1 HNMR(400 MHZ, CDCl3)δ 8.79(s, 1H), 8.39(s, 1H), 7.88-7.73(m, 2H), 7.47-7.27(m, 3H), 7.25-7.22(s, 1H), 7.05-6.97(m, 2H), 4.32-4.25(m, 1H), 3.58-3.50(m, 1H), 3.18-3.10(m, 1H).

[0149] Preparation of tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-1,1-d2 12-Boc: To a solution of 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 12 (177 mg, 0.446 mmol) in DCM (4 mL) at room temperature was added BocO (107 mg, 0.490 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by column chromatography to give the title compound 12-Boc (160 mg).

[0150] Chiral SFC (Supercritical Fluid Chromatography) Separation: Racemic tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-1,1-d2 12-Boc (139 mg) was dissolved in 5 mL of MeOH and 5 mL of dichloromethane and then separated by chiral SFC (Regis Whelk-O1(S,S)2 1X250 mm; mobile phase: 45% 2-propanol + 0.25 DEA / CO2; 254 nM) to give enantiomer A 12A-Boc (56 mg, RT = 2.35 min, 100% ee) and enantiomer B 12B-Boc (56 mg, RT = 2.77 min, 100% ee).

[0151] Preparation of enantiomer (7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 HCl salt 12A: A mixture of 12A-Boc and 4N HCl in dioxane (1 mL) was stirred at room temperature (rt) for 1 hour. After removing the volatiles, the residue was triturated with EtOAc (2 mL). The product enantiomer (7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 HCl salt 12A (50 mg) was obtained; ESI-MS (M+1) m / z: 397; 1 HNMR(400 MHZ, DMSO)δ 9.8(bs, 2H), 9.34(s, 1H), 8.56(s, 1H), 7.68(m, 4H), 7.37-7.27(m, 1H), 6.90(d, J=7.80Hz, 1H), 4.61-4.39(m, 1H), 3.76-3.62(m, 1H), 3.50-3.45(m, 1H).

[0152] Preparation of enantiomer (7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 HCl salt 12B: A mixture of 12B-Boc and 4N HCl in dioxane (1 mL) was stirred at room temperature for 1 hour. After removing the volatiles, the residue was triturated with EtOAc (2 mL). The enantiomer of the product (7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 HCl salt 12B (50 mg) was obtained; ESI-MS (M+1) m / z: 397; 1 HNMR: Identical to 12A.

[0153] Example 6: This example describes an exemplary protocol for synthesizing the exemplary compound 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3, as shown schematically in Figure 3.

[0154] The ketone 5, 2-amino-1-(3,4-dichlorophenyl)ethan-1-one hydrochloride, was converted to intermediate 13 under active proton deuteration conditions. Reduction of intermediate 13 with sodium borodeuteride gave alcohol 14. The aldehyde 3a, 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde, prepared by reduction of intermediate 2, 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzonitrile, with DIBAL-D (diisobutylaluminum hydride), was then subjected to reductive amination with deuterated intermediate 14 and sodium borodeuteride to give intermediate 15. Cyclization of intermediate 15 under acidic conditions afforded the target molecule 16, 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3.

[0155] Example 6.1: Preparation of 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3 16A and 16B: Preparation of 2-((3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzyl)amino)-1-(3,4-dichlorophenyl)ethan-1,2,2-d3-1-ol 15: To a solution of the above residue 14 (1.50 mmol) in CHOH (2.2 mL) was added aldehyde 3a (336 mg, 1.50 mmol) and DCM (1.5 mL). The mixture was stirred at room temperature for 2 h, and then NaBH (57 mg, 1.50 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and 4N NHOH. The aqueous phase was extracted with DCM (2×). The combined extracts were dried over NaSO, filtered, and concentrated in vacuo to give the crude product (580 mg).

[0156] Preparation of tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-3,3,4-d3 16-Boc: To cold sulfuric acid (2.15 mL) at 0 °C was added dropwise a solution of 2-((3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzyl)amino)-1-(3,4-dichlorophenyl)ethan-1,2,2-d3-1-ol 15 (580 mg) in DCM (1.9 mL). The mixture was stirred and allowed to warm to room temperature overnight. Ice water was added to the reaction, and the pH was adjusted to 9-10 by adding 20% ​​NaOH. The mixture was extracted with DCM (3×), and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue containing 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3 16. The residue containing 16 was dissolved in DCM (20 mL). Di-t-butyl dicarbonate (360 mg, 1.65 mmol) was added to the solution. The resulting mixture was stirred at room temperature overnight and then purified by column chromatography (2:1 to 1:2 H:EtOAc) to give 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-3,3,4-d3 16-Boc (168 mg, 22% over three steps). ESI-MS (M+1) m / z: 498;

[0157] Chiral SFC separation: Racemic tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-3,3,4-d3 16-Boc (101 mg) was dissolved in 5 mL of MeOH and 5 mL of dichloromethane and then subjected to chiral SFC (Regis Separation by Whelk-O1 (S,S) 21×250 mm; mobile phase: 45% 2-propanol + 0.25 DEA / CO2; 254 nM) gave enantiomer A 16A-Boc (30 mg, RT = 2.35 min, 100% ee) and enantiomer B 16B-Boc (33 mg, RT = 2.77 min, 100% ee).

[0158] Preparation of enantiomer 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3 HCl salt 16A: A mixture of 16A-Boc and 4N HCl in dioxane (1 mL) was stirred at room temperature for 1 hour. After removing the volatiles, the residue was triturated with EtOAc (2 mL). The enantiomer of the product, 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3 HCl salt 16A (26 mg) was obtained; ESI-MS (M+1) m / z: 398; 1 HNMR: Identical to 16B.

[0159] Preparation of enantiomer 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3 HCl salt 16B: A mixture of 16B-Boc and 4N HCl in dioxane (1 mL) was stirred at room temperature for 1 hour. After removing the volatiles, the residue was triturated with EtOAc (2 mL). The enantiomer of the product, 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3 HCl salt 16B (27 mg) was obtained; ESI-MS (M+1) m / z: 398; 1HNMR(400 MHZ, DMSO)δ 9.8(bs, 2H), 9.34(s, 1H), 8.56(s, 1H), 7.68(m, 4H), 7.37-7.27(m, 1H), 6.90(d, J=7.80 Hz, 1H), 4.58-4.50(m, 1H), 4.41-3.99(m, 1H).

[0160] Example 7: This example describes an exemplary protocol for synthesizing the exemplary compound 4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-1,1-d2)pyridin-2(1H)-one, as shown schematically in FIG.

[0161] Indole amine A is cyclized with deuterated formaldehyde to form intermediate B, which is Boc-protected to give intermediate C. Methylation of indole C gives compound D. Ullmann coupling of bromide D with pyridine F gives compound G, which is subsequently deprotected under acidic conditions to give the target compound H as the HCl salt.

[0162] Example 8: This example describes an exemplary protocol for synthesizing the exemplary compound 4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-1,1,3,3-d4)pyridin-2(1H)-one, as shown schematically in FIG.

[0163] Indole acid I is converted to indole amide J. Pictet-Spengler reaction of indole amide J with CD2O affords lactam K. Reduction of lactam K with deuterated borane gives amine L, which is then Boc-protected to give indole M. Methylation of indole M gives compound N. Compound E gives pyridone F by treatment with ammonium formate acetate. Ullmann coupling of bromide N with F gives compound O. Deprotection of O under acidic conditions affords the target compound P as the HCl salt.

[0164] As shown schematically in Figure 10, an alternative protocol is described for synthesizing the exemplary compound 4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-1,1,3,3-d4)pyridin-2(1H)-one.

[0165] Reaction of benzylamine W with allyltrimethylsilane X in the presence of deuterated formaldehyde forms 1-benzylpiperidin-2,2,6,6-d4-4-ol Y. Debenzylation of Y followed by Boc protection affords alcohol Z. After oxidation of alcohol Z with N-methylmorpholine N-oxide (NMO) and tetrapropylammonium perruthenate (TPAP), ketone AA is then reacted with (3-bromophenyl)hydrazine AB to give deuterated indole L, which is then Boc-protected to give indole M. Methylation of indole M affords compound N. Treatment of compound E with formic acid and ammonium acetate affords compound F. Ullmann coupling of bromide N with pyridine F affords compound O, followed by deprotection of O under acidic conditions to give the target compound P.

[0166] Compound P was synthesized according to the route described in Figure 11. Treatment of nitrosamine AD, obtained from hydroxylpiperidine AC, with sodium deuterium oxide in deuterium oxide formed 2,2,6,6-d4N-nitrosopiperidine AE. Removal of the N-nitroso group by Ni / Al reduction gave piperidine AF, which was then Boc-protected to give compound Z. Oxidation of hydroxylpiperidine Z gave ketone AA. Fischer indole synthesis from ketone AA and 3-bromophenylhydrazine gave indole L, which was then Boc-protected to form compound M. Methylation of indole M gave compound N. Ullmann coupling of bromide N with pyridone F gave compound O, followed by deprotection under acidic conditions afforded over 50 mg of the target compound P as the HCl salt. Proton NMR and LCMS spectra are included in Figures 12 and 13, respectively.

[0167] Example 9: This example describes an exemplary protocol for synthesizing the exemplary compound 4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-3,3-d2)pyridin-2(1H)-one, as shown schematically in FIG.

[0168] Indole acid I is converted to indole amide J. Pictet-Spengler reaction of indole amide J with formaldehyde gives lactam Q. Reduction of lactam Q with deuterated borane gives amine R, which is Boc-protected to give indole S. Methylation of indole S gives compound T. Compound E gives pyridone F by treatment with ammonium formate acetate. Ullmann coupling of bromide T with F gives compound U. Deprotection of U under acidic conditions gives the target compound V as the HCl salt.

[0169] Example 10: This example describes a novel algorithm provided herein for calculating initial doses, followed by safe titration and maintaining an effective dose. Central transporter occupancy is a powerful pharmacodynamic marker for assessing target binding of transporter inhibitors and guiding doses in efficacy clinical trials. Occupancy rates measured by positron emission tomography (PET) have been reported for several reuptake inhibitors. Effective doses of SSRIs and SSNRIs have been reported to have SERT occupancy rates of 65-85% (Meyer JH et al., Am J Psychiatry. 2004 May;161(5):826-35; Herold N et al., J Neural Transm (Vienna). 2006 May;113(5):659-70; Klein N et al., Psychopharmacology (Berl). 2007 Apr;191(2):333-9). Interestingly, SERT occupancy by clinical doses of sibutramine is modest, ranging from 25 to 46%, suggesting that inhibition of serotonin reuptake may be necessary, but not sufficient, for sibutramine efficacy in humans, supporting preclinical data that co-inhibition of both SERT and NET is required for anorectic action (Talbot PS et al, Neuropsychopharmacology. 2010 Feb;35(3):741-51). DAT occupancy has been reported for bupropion (14-26%), modafinil (51-57%), and methylphenidate (40-74%) at various approved doses ( Volkow ND et al, Am J Psychiatry. 1998 Oct;155(10):1325-31; Kim W et al, Int J Neuropsychopharmacol. 2014 May;17(5):697-703, Kim W et al, Int J Neuropsychopharmacol. 2014 May;17(5):697-703. Tesofensine has been reported to produce DAT occupancy rates of 50%-70%, suggesting an optimal weight loss dose (Appel L et al, Eur Neuropsychopharmacol. 2014 Feb;24(2):251-61). Radioligands for NETs have recently been developed, enabling assessment of NET occupancy. At effective doses, NET occupancy ranges from approximately 30-50% with duloxetine (Moriguchi S et al, Int J Neuropsychopharmacol.2017 Dec 1;20(12):957-962) and a range of 8-61% for venlafaxine (Arakawa 2014). The reported transporter occupancy ranges for the approved monoamine reuptake inhibitors referenced above are summarized in Table 9 for ease of viewing. [Table 1]

[0170] PET studies have been part of the strategy to evaluate the safety, tolerability and pharmacokinetics of compounds of formula I, as well as DAT and SERT occupancy, in healthy male volunteers during their previous clinical development.

[0171] In this study, repeated administration of 30-60 mg of the compound of Formula I at steady state achieved a SERT occupancy of 65-75%. A significant, dose-dependent DAT occupancy was achieved after repeated administration of 60 mg of the compound of Formula I, up to approximately 60%. The approximately linear relationship between plasma concentrations of the compound of Formula I and DAT occupancy, using individual values, is shown in Figure 7. The relationship between plasma concentrations of the compound of Formula I and SERT occupancy, using individual values, is shown in Figures 8 and 9. Individual SERT and DAT occupancy values ​​and corresponding plasma concentrations are tabulated in Example 12.

[0172] As can be seen in Figures 5 and 6, significant variability in plasma concentrations of the compound of Formula I as a function of dose was observed in a small number of cohorts, but generally the magnitude of plasma concentrations corresponded well to the magnitude of estimated occupancy. This established PK / PD relationship will be used to guide dosing in future studies.

[0173] At the time PET studies were initiated, no suitable methods were available for estimating NET occupancy in the human brain. However, based on ex vivo occupancy data in mouse brain, NET occupancy is expected to closely match DAT occupancy after administration of a compound of Formula I.

[0174] Taking the results of this PET study together with preclinical data, we conclude that Formula I is a potent, competitive, and selective triple reuptake inhibitor of the DAT, SERT, and NET in humans. Furthermore, Formula I's unique triple reuptake inhibition profile allows it to be administered at effective doses within the therapeutic range of approved single- and dual-agent SERT, DAT, and NET inhibitors. Notably, Formula I can achieve SERT occupancy levels approaching those seen with SSRIs within a safe dose range, while achieving DAT occupancy of approximately 60% in PET studies conducted in healthy men. Formula I's unique TRI profile provides flexibility for gradual titration, resulting in well-tailored tolerability and efficacy.

[0175] Given the near-linear relationship between plasma concentration and DAT occupancy, and the large variability expected in dose and plasma drug concentration, using a concentration-controlled dosing approach that exploits the PK / PD relationship established in PET studies of Formula I can provide precision dosing with optimal outcomes for individual patients.

[0176] Example 1 above describes exemplary methods and compositions for the treatment of Prader-Willi syndrome and related disorders, and Example 2 above describes methods and compositions for the treatment of hypothalamic injury-induced obesity (HO) and related disorders, using compounds of Formula I and deuterated analogs thereof, e.g., those described herein.

[0177] Patients receive a subtherapeutic dose of 1 mg to 20 mg per day for one, one, two, three, or four weeks. Blood samples are collected periodically to determine steady-state drug concentrations, and the nearest target dose required to achieve 15% to 75% DAT occupancy is determined, with or without the aid of pharmacometric modeling methods that also utilize PK / PD data. Optionally, the approximate target dose is determined by achieving a steady-state plasma drug concentration value of 100 ng / ml to 4000 ng / ml; optionally, the approximate target dose is determined by achieving a steady-state plasma drug concentration value of 200 ng / ml to 2000 ng / ml; and optionally, the approximate target dose is determined by achieving a steady-state plasma drug concentration value of 400 ng / ml to 2000 ng / ml. Every three or six months, or whenever there is a significant change in the patient's medication, weight and other physical changes may affect drug absorption and metabolism, and blood drug levels are retested and the dose adjusted as needed. Optionally, patients start on a low dose of 5 mg to 20 mg per day and gradually increase the dose in 5 mg, 10 mg, or 20 mg increments until efficacy against overeating and / or neuropsychiatric and behavioral symptoms is safely achieved. Based on patient tolerability, clinicians can accelerate the titration, slow the titration as needed, and then re-accelerate the titration later.

[0178] Example 11: In an alternative embodiment, a method is provided that includes administering a drug in an amount sufficient to achieve a plasma concentration (optionally a human plasma concentration) in the therapeutic range at steady state, and this example describes an exemplary analytical method for determining the concentration of Formula I in human plasma using LC-MS-MS methods known to those skilled in the art, and an exemplary bioanalytical method for determining the concentration of Formula I in human EDTA plasma.

[0179] An LC-MS / MS method was developed and validated seven times to quantify Formula I in 0.250 mL of human EDTA plasma, with one failure. This method used stably labeled Formula I as the internal standard. After adding the internal standard (equivalent to 285.4 ng / mL in human EDTA plasma) and 0.250 mL of each quality control (QC) sample and calibration standard, 0.525 mL of methyl t-butyl ether (MTBE) was added to a 96-well sample tube. The organic layer was removed and evaporated to dryness using liquid-liquid extraction (LLE). The residue was reconstituted and injected into the LC-MS / MS system. Chromatographic separation was performed using Acquity UPLC was performed using gradient elution on a BEH Shield RP18™, 50 x 2.1 mm, 1.7 μm particle size column. The mobile phase contained water, acetonitrile, ammonium formate, and formic acid. Detection was performed using a Sciex API 4000 tandem mass spectrometer in positive ion electrospray SRM mode. A standard curve of Formula I ranging from 1.00 to 1000 ng / mL was fitted to a 1 / ×2 weighted linear regression model. The intra-assay precision based on four analytical QC levels (low, medium, GM, and high) was within 4.2% CV, and the intra-assay precision for the analyte was within 7.2% CV. The assay accuracy, expressed as %DEV, was within 6.4% of the nominal analyte concentration. At a lower limit of quantitation (LLOQ) of 1.00 ng / mL for Formula I, the deviation of the predicted concentration from the nominal value was within 14.1% for all LLOQ samples across six different matrix lots. The LLOQ response ratio, compared to the QC0 response ratio, was 5 or greater for all matrix lots. The analyte was stable in human EDTA plasma for at least 24 hours at room temperature, at least 14 days at -20°C, and after at least three freeze-thaw cycles. Processed samples were stable for 72 hours (h) at room temperature.

[0180] Based on the results of this validation, the acceptance criteria for sample analysis are as follows: 1) The predicted concentrations of at least three-quarters of all calibration standards should be within ±15.0% of their nominal concentration, except for the LLOQ, which is within ±20.0%. Standards that do not meet these criteria are excluded from the regression. At least three-quarters of all standards will meet the acceptance criteria and be included in the final regression. 2) At least one repeat of the lowest concentration in the standard curve meets the above criteria and is included in the final regression for that level to qualify as the LLOQ. If this criterion is not met, the next standard level is subjected to the same test and the LLOQ is increased accordingly. 3) The predicted concentrations of at least two-thirds of all analytical quality control samples are within ±15.0% of their nominal concentrations, and at least 50% of the QC samples meet the acceptance criteria at each level. 4) When a single dilution QC is used, the predicted concentration of at least 50% of the diluted QC samples at a particular dilution shall be within ±15.0% of their nominal concentration for results of diluted samples at the same or lower dilution to be acceptable.

[0181] If Dilution QCs of different dilutions are used, the predicted concentrations of at least 50% of the Dilution QC samples at each dilution shall be within ±15.0% of their nominal concentration for the results of the Dilution QC samples at the same dilution to be acceptable. The results of the Dilution QC samples shall not be used to determine the acceptability of the assay.

[0182] The HPLC parameters used are shown in the table below: [Table 2] Mobile phase A - 10 mM ammonium formate and 0.1% formic acid in water and acetonitrile (90 / 10). 0.63 g of ammonium formate was dissolved in 900 mL of water and 100 mL of acetonitrile, and 1.0 mL of formic acid was added. Mobile Phase D - 10 mM ammonium formate and 0.1% formic acid in water and acetonitrile (10 / 90). 0.63 grams (g) of ammonium formate was dissolved in 100 mL of water and 900 mL of acetonitrile, and 1.0 mL of formic acid was added.

[0183] The mass spectrometric parameters used are shown in the table below: [Table 3] [ka]

[0184] Example 12: Plasma concentrations of Formula I and striatal receptor occupancy of dopamine transporter (DAT) and serotonin transporter (SERT) at midpoints of post-dose PET (positron emission tomography) scans (T=4 and 24) following repeated daily administration of 3-60 mg and 10-60 mg to a cohort of healthy men with SERT and DAT, respectively (RO stands for receptor occupancy in the table below). Post-dose PET scans were performed to measure the specific DAT and SERT tracers. 11 C-PE2I and 11 Steady-state measurements were performed on days 10 (4 hours after the last dose) and 14 (24 hours after the last dose) using C-MADAM, respectively. In the 45 mg and 60 mg cohorts, 30 mg was administered for 3 days, then titrated to the designated dose starting on day 4. Representative reports on the use of these two tracers are Learned-Coughlin SM et al., Biol Psychiatry. 2003, 54(8):800-5; Jucaite A et al., Eur J Nucl Med Mol Imaging. 2006, 33(6):657-68; and Lundberg J et al., Int J Neuropsychopharmacol. 2007, 10(6):777-85. [Table 4-1] [Table 4-2]

[0185] Example 13 This example describes methods for determining the inhibitory potency of compounds of Formula I, 8A, 8B, 12A, 12B, 16A, and 16B against the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT or 5-HTT) and using these methods (Eurofin Discovery Taiwan Category #s 220320, 204410, 274030), as well as methods for determining the inhibitory potency against the dopamine transporter (DAT) (Giros et al., Trends Pharmacol Sci. 14(2):43-49, 1993; Gu et al., J Biol Chem. 269(10):7124-7130, 1994).

[0186] Protocol Overview: Source: human recombinant CHO-S cells; Vehicle: 1.0% DMSO; Incubation time / temperature: 3 hours @ 4°C; Incubation buffer: 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 μM ipeptin, 10 μM PMSF; Kd: 0.58 nM (historical value); Ligand: 0.15 nM 125 I]RTI-55; Nonspecific ligand: 10.0 μM nomifensine; Specific binding: 90% (historical value); Quantitative methods: radioligand binding; Significance criteria: ≥50% maximal stimulation or inhibition; Bmax: 0.047 pmole / mg protein Measurement of inhibitory potency against the norepinephrine transporter (NET) (Galli et al., J Exp Biol. 198(Pt 10):2197-2212, 1995) Protocol Overview: Source: human recombinant MDCK cells; Vehicle: 1.0% DMSO; Incubation time / temperature: 3 hours @ 4°C; Incubation buffer: 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 μM ipeptin, 10 μM PMSF; Kd: 0.024 μM (historical value); Ligand: 0.2nM 125 I]RTI-55; Nonspecific ligand: 10.0 μM desipramine; Specific binding: 75% (historical value); Quantitative methods: radioligand binding; Significance criteria: ≥50% maximal stimulation or inhibition; Bmax: 2.50 pmole / mg protein Measurement of inhibitory potency against the serotonin (5-hydroxytryptamine) transporter (SERT) (Shearman et al., Am J Physiol. 275(6 Pt 1):C1621-1629, 1998; Wolf et al., J Biol Chem. 267(29):20820-20825, 1992) Protocol Overview: Source: human recombinant HEK-293 cells; Vehicle: 1.0% DMSO; Incubation time / temperature: 60 min @ 25°C; Incubation buffer: 50 mM Tris-HCl, pH 7.4, 120 mM NaCl, 5 mM KCl; Kd: 0.078 nM (historical value); Ligand: 0.4 nM [3H]paroxetine; Nonspecific ligand: 10.0 μM imipramine; Specific binding: 95% (historical value); Quantitative methods: radioligand binding; Significance criteria: (≥) 50% or greater maximal stimulation or inhibition; Bmax: 4.40 pmole / mg protein (previous value)

[0187] Potency data are expressed in the table below as % inhibition at compound concentrations of 10 nM and 100 nM. [Table 5]

[0188] Example 14 This example describes a method for measuring the inhibitory potency against MCHR1 and the inhibitory potency of compounds of formula II using this method (Eurofin Discovery Taiwan) Category # 251010). Protocol Overview: Source: human recombinant CHO-K1 cells; Vehicle: 1.00% DMSO; Incubation time / temperature: 2 hours @ 25°C; Incubation buffer: 25 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM EDTA, 0.2% BSA; Kd: 0.10 nM (historical value); Ligand: 0.050nM 125 I]Tyr-S36057; Nonspecific ligand: 1.0 μM MCH (human, mouse, rat); Specific binding: 85% (historical value); Quantitative methods: radioligand binding; Significance criteria: ≥50% maximal stimulation or inhibition; Bmax: 26.0 pmole / mg protein (previous value)

[0189] Potency data are expressed as IC50 and Ki in the table below. [Table 6]

[0190] Example 16: Individualized Dosing of a Compound of Formula I Using PK-Guided Dosing for Patients with PWS or Hypothalamic Damage-Induced Obesity: Patients receive an initial low dose of 10 mg / day of a compound of Formula I for two weeks, followed by an optional additional titration step. The titration step involves individualized dose escalation with the goal of achieving a target trough plasma concentration of approximately 375 ng / mL (equivalent to approximately 30% DAT occupancy in a healthy human) over two weeks. Patients are then titrated up to the dose required to achieve a target trough plasma concentration of approximately 700 ng / mL for the low dose (equivalent to approximately 45% DAT occupancy in a healthy human) or approximately 1295 ng / mL (equivalent to approximately 60% DAT occupancy in a healthy human). Figure 32 shows a simulation based on PK / PD model information of the plasma levels required to achieve the target receptor occupancy. The target plasma concentration is calculated using the PK-PD model described for Formula I in the embodiments.

[0191] PK-guided dosing is based on drug plasma concentrations, not the actual dose in mg administered to an individual. In other words, depending on age, size, ability to metabolize the drug, and other factors, two patients may receive entirely different doses even if they are randomly assigned to the same "dose" group, as described below.

[0192] The drug is formulated as tablets or capsules and is available in appropriate increments from 5 to 240 mg, allowing all participants to reach target plasma levels as close as possible. All patients take one or two tablets / capsules daily in the morning.

[0193] The C trough required for each target DAT occupancy level was selected to achieve or slightly exceed the target DAT receptor occupancy for 12 daytime hours after morning drug administration, corresponding to fluctuations in plasma levels throughout the day, as shown in the simulation below. Pk-guided dosing provides each patient with the best chance of achieving the desired effect without unnecessary drug exposure. Figure 25 shows plasma levels over 24 hours at a dose optimized to provide the desired 30% DAT receptor occupancy range during the 12-hour daytime period. For an illustration, see Figure 33.

[0194] Example 17: This example describes simulated individualized dosing to achieve 30% DAT receptor occupancy, extrapolating dose changes at day 14 based on C trough at day 7. See diagram in Figure 34.

[0195] Example 18: This example describes a simulation of individualized dosing to achieve 60% DAT receptor occupancy for a 160 kg patient. See diagram in Figure 35.

[0196] Example 19: This example describes individualized dosing of a compound of Formula I using PK-guided dosing following initial PK evaluation in patients with PWS or hypothalamic injury-induced obesity.

[0197] Patients undergo an initial PK assessment to determine the subject's individual PK parameters in order to adjust the initial starting dose of Formula I. During the initial PK assessment, subjects receive a single low dose, such as a 10 mg dose, of the compound of Formula I. PK is obtained pre-dose and at 1 hour, 2 hours, 4 hours, 24 hours, 3 days, and 7 days post-dose.

[0198] Patients are then individually dosed to achieve target trough plasma concentrations of about 375 ng / mL (or equivalent to about 30% DAT occupancy in a healthy human), about 700 ng / mL (equivalent to about 45% DAT occupancy in a healthy human), or approximately 1300 ng / mL (equivalent to 60% DAT occupancy in a healthy human) using the PK simulation methods described in the embodiments. Optional repeat PK at steady state is performed after 3-12 months of treatment, if desired.

[0199] PK-guided dosing is based on drug plasma concentrations, not the actual dose in mg administered to an individual. In other words, depending on age, size, ability to metabolize the drug, and other factors, two patients may receive entirely different doses even if they are randomly assigned to the same "dose" group, as described below.

[0200] The drug is formulated as tablets or capsules and is available in appropriate increments from 5 to 240 mg, allowing all participants to reach target plasma levels as close as possible. All patients take one or two tablets / capsules daily in the morning.

[0201] The C trough required for each target DAT occupancy level was selected to achieve or slightly exceed the target DAT receptor occupancy for 12 daytime hours after morning drug administration, corresponding to fluctuations in plasma levels throughout the day, as shown in the simulation below. PK-guided dosing provides each patient with the best chance of achieving the desired effect without unnecessary drug exposure.

[0202] Example 20 PK data (Cmax, Ctrough and AUC) at day 14 in healthy humans in a 14-day, multiple ascending dose study of the compound of Formula I administered orally once daily are tabulated. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0203] Although numerous embodiments of the present invention have been described, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. The present invention provides, for example, the following items. (Item 1) A therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprising: (a) (i) triple monoamine reuptake inhibitors (TRIs) and melanin-concentrating hormone receptor 1 (MCHR1) antagonists, (ii) a triple monoamine reuptake inhibitor (TRI) and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation); (iii) a melanin-concentrating hormone receptor 1 (MCHR1) antagonist and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation); or (iv) a triple monoamine reuptake inhibitor (TRI) melanin-concentrating hormone receptor 1 (MCHR1) antagonist and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation); or (b) (i) Triple monoamine reuptake inhibitors (TRIs), (ii) melanin-concentrating hormone receptor 1 (MCHR1) antagonists; (iii) diazoxide choline controlled release (DCCR formulation); or (c) (a) or (b) formulated with one or more of the following drugs or small molecules: (1) unacylated ghrelin (UAG) analogs and / or ribolitide (also known as AZP-531), (2) Carbetocin, or Duratocin™, Pabal™, or Lonactene™; (3) oxytocin and / or the precursor oxytocin-neurophysin, (4) liraglutide, or Victoza® or Saxenda®, (5) Exenatide, or Byetta™, Bydureon™, Bydureon™, or BCise™; (6) setomelanotide (also known as IMCIVREE™, RM-493, BIM-22493, IRC-022493, N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide); (7) rimonabant (also known as SR141716) and / or Acomplia™, Zimulti™, (8) a beta-adrenergic blocker (optionally, the beta-adrenergic blocker is or includes metoprolol (or Lopressor™, Metolar XR™, Toprol X™), atenolol (or Tenormin™), propranolol (or INDERAL™), and / or nadolol (or CORGARD™), or any combination thereof); (9) a melatonin receptor agonist (optionally, the melatonin receptor agonist is or comprises melatonin or N-acetyl-5-methoxytryptamine, ramelteon (or Rozerem™) and / or tesimelteon (or Hetlioz™), or any combination thereof); (10) histamine receptor 1 antagonists (the histamine receptor 1 antagonist is or includes doxepin (or Sinequan™, Quitaxon™, or Aponal™), or low-dose doxepin (optionally, the low dose is 3 mg or 6 mg per dose, trazadone (or Desyrel™, Desyrel Dividose™, or Oleptro™), amitriptyline (or ELAVIL™, Protanol™, Qualitriptine™, Redomex™, or Saroten™) or amitriptyline with chlordiazepoxide (Morelin™, Ristryl™, or Sedans™), and / or mirtazapine (or REMERON™), or any combination thereof); (11) a histamine H3 receptor antagonist or inverse agonist (optionally, the H3 receptor antagonist or inverse agonist is or includes pitolisant (or tiprolisant, ciproxidine, or WAKIX™), thioperamide, clobenpropit, ciproxifan, connessin (or nerin, locecine, lightin), and / or betahistine (or SERC™), SUVN-G3031 (Suven Life Sciences Ltd), or any combination thereof); (12) modafinil (or Provigil®, Alertec® or Modavigil®), and / or amodafonil (or Nuvigil®), (13) human growth hormone (hGH) (or somatotropin) or a recombinant form thereof (or Omnitrope™, Jintropin™, Nutropin™ or Nutropin DEPOT™, Humatrope™, Genotropin™, Norditropin™ or Saizen™), or any combination thereof; (14) testosterone and / or 17β-hydroxyandrost-4-en-3-one, (15) progesterone and / or pregn-4-ene-3,20-dione, (16) Estrogen, estrone, estradiol, or estriol, or any combination thereof; (17) a thyroid hormone or a derivative thereof (optionally, the thyroid hormone or a derivative thereof is or comprises triiodothyronine (T3), thyroxine (T4), levothyroxine, or L-thyroxine, or any combination thereof); (18) chorionic gonadotropin (hCG) hormone or its recombinant form, or Novarel™ or Pregnyl™, or any combination thereof; (19) metformin (or Glucophage™) and / or repaglinide (or PRANDIN™), (20) Insulin or human insulin or a recombinant form or analog thereof (or Actrapid™, Humalog™, NovoRapid™, Apidra™, Lantus™ or Levemir™) or any combination thereof; (21) glucocorticoid receptor antagonists or anticorticosteroids, or mifepristone (or RU-486, or Mifegyne™ or Mifeprex™), metyrapone (or Metopirone™), ketoconazole (or NIZORAL™) or aminoglutethimide (or Elipten™, Cytadren™ or Orimeten™), (22) a histamine receptor 2 antagonist (optionally, the histamine receptor 2 antagonist is or includes cimetidine (or TAGAMET™), ranitidine (or ZANTAC™), and / or famotidine (or PEPCID™), or any combination thereof); (23) mood stabilizers (optionally, the mood stabilizer is or comprises gabapentin (or Neurontin™); clonazepam (or Klonopin™ or Rivotrilf™); valproate, valproic acid, sodium valproate or valproic acid semisodium salt (or Convulex™, Depakote™, Epilim™ or Stavzor™); oxcarbazepine (or Trileptal™ or Oxtellar XR™); lithium or lithium carbonate (or Lithobid™ or LITHOMAX™); topiramate (or Topamax™, Trokendi XR™ or Qudexy XR™) and / or lamotrigine (or Lamictal™), or any combination thereof), (24) neuroleptics (optionally, the neuroleptics include risperidone (or Risperdal), aripiprazole (or Abilify™), quetiapine (or Seroquel™), olanzapine (or Zyprexa™), ziprasidone (or Geodon™) and / or haloperidol (or Haldol™ or Serenace™), or any combination thereof); (25) quetiapine, or Seroquel® or Temprolide®, (26) naltrexone (or FEBIA® or VIVITROL®), (27) γ-aminobutyric acid (GABA) B(GABA B ) receptor modulators, such as sodium oxybate (Xyrem™), or controlled-release sodium oxybate (or FT218), or low sodium oxybate, optionally JZP-258, or baclofen; (28) Solriamfetol or SUNOS (trademark), (29) a hypocretin / orexin 2 receptor selective agonist, optionally TAK-925, TAK-988, or TAK-994; (30) a selective norepinephrine reuptake inhibitor (NRI), or a selective serotonin reuptake inhibitor (SSRI), or a selective serotonin norepinephrine inhibitor (SNRI), optionally wherein the SSRI or SNRI inhibitor is or includes reboxetine (or AXS-12, or Edronax™), atomoxetine (or Strattera™), venlafaxine (Effexor™ or EffexorXR™), fluoxetine (Prozac™), citalopram (Celexa™), escitalopram (Lexapro), paroxetine (Paxil™), sertraline (Zoloft™), or duloxetine (Cymbalta™); (31) Amphetamines (optionally, the amphetamines include amphetamine, dextroamphetamine (or Adderall®), dextroamphetamine-amphetamine (Mydayis®), or lisdexamfetamine (or Vyvanse®)); (32) methylphenidate or Ritalin, Ritalin LA, Concerta, Metadate CD, Methylin, Methylin ER, Daytrana, Quillivant XR, Quillichew ER, Aptensio XR, Cotempla XR-ODT, Jornay PM, or Adhansia XR; (33) Tricyclic antidepressants (TCAs), optionally the TCA is or comprises imipramine (Tofranil™), or amitriptyline (Elavil™), clomipramine (Anafranil™), or another TCA; (34) Monoamine oxidase inhibitors (MAOIs), optionally the MAOI is or includes selegiline (Emsam™), isocarboxazid (Marplan™), phenelzine (Nardil™), and tranylcypromine (Parnate™) or another MAOI; (35) THN102, or a combination of modafinil and flecainide; (36) an inhibitor of astroglial connexin inhibitors (optionally, the inhibitor of astroglial connexin inhibitors is or includes flecainide); (37) a prostaglandin DP1 receptor antagonist (optionally, the prostaglandin DP1 receptor antagonist is or comprises ONO-4127Na); (38) an opioid (optionally, the opioid comprises morphine); (39) antiobesity drugs (optionally, the antiobesity drugs include lorcaserin (Belviq™), orlistat (Alli™), phentermine and topiramate (Qsymia™), onaltrexone HCl, or bupropion HCl (Contrave™)); (40) Farnesoid X receptor (FXR) agonists (optionally, the FXR agonists include obeticholic acid (OCA), EYP001 (ENYO Pharma), TQA3526, Px-102, Px-104, or tropifexol); (41) PPAR agonists, optionally PPARα / δ agonists or PPAR-α / γ agonists (optionally, the PPAR-α / γ agonists include pioglitazone, elafibranor, or lanifibranor (or IVA337, Inventiva)); (42) CC chemokine receptor CCR2 / CCR5 inhibitors (optionally, the CC chemokine receptors include tropifexor, a combination of tropifexor and cenicriviroc, or cenicriviroc); (43) a mitochondrial pyruvate carrier (MPC) inhibitor (optionally, the MPC inhibitor comprises MSDC-0602K (Cirius Therapeutics)); (44) Fibroblast Growth Factor 19 (FGF19) Analogues (Optionally, the FGF19 analogue comprises aldafermin (or NGM282, NGM Biopharmaceuticals)) (45) Fibroblast growth factor 21 (FGF21) analogs (optionally, the FGF21 analogs comprise PEGylated fibroblast growth factor 21 analogs, optionally pegbelfermin); (46) Thyroid hormone receptor beta (THR-β) agonists (optionally, the THR-β agonists include resmetirom (MGL-3196, Magrigal Pharmaceuticals) or VK-2890); (47) Stearoyl-CoA desaturase-1 (SCD1) inhibitors (optionally, the SCD1 inhibitor comprises aramchol (Galmed Pharmaceuticals)); (48) Apoptosis signal-regulating kinase 1 (ASK1) inhibitor (optionally, the ASK1 inhibitor comprises selonsertib (Gilead Sciences)); (49) an acetyl-CoA carboxylase (ACC) inhibitor (optionally, the ACC inhibitor comprises filsocostat (GS-0976) or MK-4074); or (50) Any combination of (1) to (49) any one or more of said therapeutic combinations, pharmaceutical dosage forms, drug delivery devices or articles of manufacture comprising an active agent or drug comprising: (Item 2) The triple monoamine reuptake inhibitor is (a) Tesofensine, Tesomet, or Tesofen (Saniona, Ballerup, Denmark), (b) [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivatives or 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline, as described in U.S. Pat. No. 8,802,696, or compounds having the formula (Formula I): [ka] or a pharmaceutically acceptable salt thereof, or a (+)-stereoisomer or a (-)-stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)-stereoisomer or a (R)(-)-stereoisomer thereof, (c) a deuterated form of the compound or drug of (a) or (b). 2. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture according to item 1, which is or comprises: (Item 3) The melanin-concentrating hormone receptor 1 (MCHR1) antagonist is (a) GW8564649 (GSK), AZD-1979 (AstraZeneca), AMG-076 (Amgen), BMS-830216 (BMS), ATC-0065 or ATC-0175 (see Chaki et al (2005) CNS Drug Reviews vol 11(4):341-52), GW-803430 or GW-3430 (see Gehlert et al (2009) J Pharm and Experimental Therapeutics, vol 329(2):429-38), NGD-4715 (Ligand Pharmaceuticals), SNAP-7941 (see Klemenhagen et al (2007) J Pharm and Experimental Therapeutics, vol 321(1):237-48), T-226 or T-296 (see Takekawa et al (2007) J Pharm and Experimental Therapeutics, vol 321(1):237-48), al(2002) Eur J Pharm vol 438(3):129-35), or any combination thereof; (b) a compound having the following formula (designated Formula II): [ka] or (1-azinone)-substituted pyridoindoles as described in USPN 8,716,308, or compounds having the formula: [ka] wherein R1 is H or optionally substituted alkyl; R2, R3, R4 are each independently selected from H, --O-alkyl, --S-alkyl, alkyl, halo, --CF3, and --CN; G is --CR 12 R 13 --NR 5 --or--NR 5 --CR 12 R 13 and R 5 is H, optionally substituted alkyl, optionally substituted heterocycle, --C(=O)--R 6 , --C(=O)--O--R 7 , or --C(=O)--NR 19 R 20 and R 6 and R 7 are each optionally substituted alkyl or optionally substituted heterocycle; R8, R9, R 10 , R 11 , R 12 , R 13 , R 19 and R 20 is H or optional and R is independently selected from alkyl substituted with 14 and R 15are each independently H or halogen; Y is CH; L is --CH2--O--, --CH2CH2--, --CH=CH-- or a bond; and B is aryl or heteroaryl or cycloalkyl, provided that when L is a direct bond, B cannot be unsubstituted heteroaryl or monofluorine-substituted heteroaryl); or (c) a deuterated form of the compound or drug of (a) or (b). is or contains Optionally, the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture further comprises an N-acetyltransferase 2 (NAT2) or arylamine N-acetyltransferase inhibitor, optionally acetaminophen, N-acetyl-para-aminophenol (APAP), or paracetamol (or TYLENOL™ or PANADOL™), in combination with any compound of (b) or a deuterated form of a compound or drug of (b), optionally in which combination (b) is of Formula II: Item 1. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture according to item 1. (Item 4) 4. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture according to any one of items 1 to 3, wherein two or more of said drugs or active agents are formulated as separate compositions or wherein two or more of said drugs or active agents are formulated in one composition or drug formulation (two or more drugs or active agents are formulated together). (Item 5) 5. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of any one of items 1 to 4 or any one of the preceding items, wherein the one or more drugs or active agents are individually packaged, packaged together, or packaged in any combination, in a single package, multiple packages or packets, or blister packets, lidded blisters or blister cards or packets, or shrink wrap. (Item 6) one or more or all of said drugs or active agents are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a spray, a sachet, an inhalant, a powder, a lyophilized powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository, or any combination thereof; Optionally, the drug delivery device or article of manufacture is or comprises an implant; 10. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture according to any one of items 1 to 5 or any one of the preceding items. (Item 7) 7. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of item 6, wherein the one or more or all of the drugs or active agents are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one lyophilized powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one patch, one spray, one powder, one lyophilized powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel, or one suppository. (Item 8) 8. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of any one of items 1 to 7 or any one of the preceding items, wherein the one or more or all of the drugs or active agents are packaged in dosages that correspond to a time-adjusted dosing regimen and that correspond to optimal daily doses. (Item 9) the drug or active agent is (a) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and a histamine receptor 1 antagonist, optionally doxepin; (b) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and naltrexone; (c) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and a histamine receptor 1 antagonist, optionally doxepin, and naltrexone; (d) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation); (e) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of formula I, and diazoxide (or Proglycem™) or diazoxide choline controlled-release (DCCR formulation), and a melatonin receptor agonist, optionally melatonin or N-acetyl-5-methoxytryptamine, ramelteon (or Rozerem™) and / or tesimelteon (or Hetlioz™), or any combination thereof; (f) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of formula I, and a melanin-concentrating hormone receptor 1 (MCHR1) antagonist, optionally a compound of formula II, or any combination thereof; (g) a triple monoamine reuptake inhibitor or a [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and a beta-blocker, optionally atenolol (Tenormin™), bisoprolol (Cardicor™, Emcor™), or metoprolol (Betaloc™, Lopresor™, Toprol XL™), or any combination thereof; and / or (h) Any combination of (a) to (g) 9. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of any one of items 1 to 8 or any one of the preceding items, comprising: (Item 10) A compound having the formula: [ka] (In the formula, R1~R 15 At least one of R1 to R2 is -D (deuterium) or 15 All of are -D, Optionally, the carbon atom marked with *, if it is a stereogenic center, is in the R or S configuration. or a pharmaceutically acceptable salt thereof 10. A pharmaceutical composition, drug or formulation comprising: (Item 11) The compound is (a) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4,8-d6 compound having the formula: [ka] (b) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1,3,3,4-d5 compound having the formula: [ka] (c) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,1-d2 compound having the formula: [ka] (d) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3-d2 compound having the formula: [ka] (e) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-4-d compound having the formula: [ka] (f) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-8-d compound having the formula: [ka] or (g) a 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-3,3,4-d3 compound having the formula: [ka] Item 11. The pharmaceutical composition, drug or formulation according to Item 10, wherein (Item 12) A compound having the formula: [ka] (In the formula, R1~R 18 At least one of R1 to R2 is -D (deuterium) or 18 (All of the are -D) or a pharmaceutically acceptable salt thereof. (Item 13) The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Item 13. The pharmaceutical composition, drug or formulation according to Item 12, wherein (Item 14) A method for treating, ameliorating, delaying progression of, alleviating symptoms of, reducing adverse events associated with, or preventing a disease or condition comprising or associated with: Binge eating (optionally assessed by HQ-CT), Moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity (optionally further including weight loss management and weight loss maintenance, or optionally further including increased physical activity as an adjunct to a reduced calorie diet or for long-term weight management); early-onset morbid obesity, Nonalcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), Primary biliary cholangitis of the liver (PBC), Inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), type II diabetes, hypothalamic damage-induced obesity, Obsessive-compulsive disorder (OCD), Disorders of mood dysregulation (DMDD), Oppositional Defiant Disorder (ODD), Skin picking, trichotillomania, Intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, Narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders, Third Edition (ICSD-3), narcolepsy with cataplexy, Narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, Cataplexy, idiopathic hypersomnia, Rapid eye movement (REM) sleep behavior disorder, convulsions, epilepsy, an addiction, or an addictive disorder or behavior (optionally, said addiction, addictive disorder, or addictive behavior is or includes Internet Gaming Disorder (IGD) or drug addiction, and optionally, said drug addiction is or includes cocaine addiction or alcohol addiction); Major depressive disorder (MDD), Treatment-resistant depression (TRD), Negative symptoms of schizophrenia, MDD associated with Parkinson's disease, Parkinson's disease, generalized anxiety, Social anxiety disorder (social phobia), fibromyalgia (FM), diabetic neuropathy, lower back pain, chronic fatigue syndrome, Attention Deficit Hyperactivity Disorder (ADHD), autism, Asperger's spectrum disorder, a genetically determined disease or syndrome (optionally, said genetically determined disease or syndrome is Prader-Willi syndrome, Bardet-Biedl syndrome, Smith-MaGinnis syndrome, 1p36 deletion syndrome, 16p11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, melanocortin 4 receptor (MC4R) pathway heterozygous obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, Angelman syndrome, Scharf-Yang syndrome, Orb-like syndrome, Wright hereditary osteodystrophy, Silver-Russell syndrome, maternal disomy, Alström syndrome, Wilms' tumor, aniridia, genitourinary abnormalities, mental retardation, i.e., WAGR or WAGRO syndrome; Dravet syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Doze syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick disease type C, or Norrie disease, or Coffin-Lowry disease), wherein, optionally, the reduction in adverse events includes alleviating psychiatric disorders, serotonin syndrome, tachycardia or postural tachycardia syndrome; (a)(i) providing or having provided a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture according to any one of the preceding paragraphs, or a pharmaceutical composition according to any one of the preceding paragraphs; and (ii) administering or implanting said therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture to an individual in need thereof; or (b) administering to or implanting in an individual in need thereof a therapeutically effective dose of the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of any one of the preceding items. (Item 15) the drug, or therapeutic combination, pharmaceutical dosage form is administered orally, parenterally, by inhalation spray, intranasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially, or rectally; Optionally, parenteral administration includes intrathecal, intracerebral, or epidural administration (administration into the intrathecal, intracerebral, or epidural space), subcutaneous, intravenous, intramuscular, and / or intra-arterial administration; Item 15. The method according to item 14. (Item 16) The drug, or therapeutic combination, pharmaceutical dosage form is administered to achieve a therapeutic range of steady-state plasma concentrations, wherein: The therapeutic plasma concentration range of the [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative or compound of Formula I is about 50-4000 ng / ml; 100-3000 ng / ml; 250-1600 ng / ml; 500-1400 ng / ml, 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, 1250-1500 ng / ml, 1500-2000 ng / ml, 2000-2500 ng / ml; 2500-3000 ng / ml; 3000-3500 ng / ml; or 3500-4000 ng / ml; the therapeutic plasma concentration range of the (1-azinone)-substituted pyridoindole or compound of Formula II is about 5-4000 ng / ml, 10-1000 ng / ml, 10-500 ng / ml, 25-500 ng / ml, 25-250 ng / ml, 50-500 ng / ml, 50-1000 ng / ml, 50-500 ng / ml, 100-1000 ng / ml, 100-500 ng / ml, 200-1000 ng / ml, 500-1000 ng / ml, 1000-2000 ng / ml, 2000-3000 ng / ml, or 3000-4000 ng / ml; the therapeutic plasma concentration range of tesofensine is about 2 ng to 50 ng / ml, 5 to 20 ng / ml, 6.5 to 15 ng / ml, 8 to 12 ng / ml, or about 10 ng / ml; The therapeutic plasma concentration range of diazoxide is about 10 ng / ml to 100 ng / ml, 20 to 80 ng / ml, 30 to 50 ng / ml, or about 40 ng / ml. The method according to item 14 or 15. (Item 17) The drug, therapeutic combination, or pharmaceutical dosage form is administered to achieve a therapeutic level range of plasma concentrations (optionally human plasma concentrations) at steady state, wherein: (a) the therapeutic plasma concentration range of the compound of Formula I is about 250-1600 ng / ml; 500-1400 ng / ml, 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, 1250-1500 ng / ml, 1500-2000 ng / ml, 2000-2500 ng / ml; or 2500-3000 ng / ml; (b) the therapeutic plasma concentration range of the compound of Formula I is about 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, 1250-1500 ng / ml, 1500-2000 ng / ml, or 2000-2500 ng / ml; (c) the therapeutic plasma concentration range of the compound of Formula I is about 600-1300 ng / ml, 800-1250 ng / ml, 1000 ng / ml-1250 ng / ml, or 1250-1500 ng / ml; Item 17. The method according to item 16. (Item 18) The steady state is (a) the elimination half-life (T 1 / 2 ) for approximately 3 to 5 times the (b) periodic or regular administration of said drug, or therapeutic combination, or pharmaceutical dosage form, optionally once daily for about 7 to 14 days after administration; The method according to items 16 to 17, wherein the method is carried out after (Item 19) The plasma concentration of the drug, or therapeutic combination, pharmaceutical dosage form is (a) Trough level or trough concentration (C トラフ ), or the lowest concentration reached by the drug, therapeutic combination, or pharmaceutical dosage form before a second or subsequent dose is administered; (b) determined from a blood sample taken between 2 hours and 24 hours, or between 4 and 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours or more after the last dose or administration of said drug, or therapeutic combination, or pharmaceutical dosage form; The method according to items 16 to 18. (Item 20) 20. The method of any one of items 14 to 19, wherein each drug or active agent of the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture is delivered to the individual simultaneously or separately, and optionally wherein one or each or several drugs or active agents of the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture are administered in a timed regimen. 21. The method of any one of items 14 to 20, or the method of any one of the preceding items, wherein the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprises Formula I, or a deuterated derivative of Formula I. (Item 21) 10. Use of a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture according to any one of the preceding paragraphs to treat, ameliorate, delay progression of, alleviate symptoms of, reduce adverse events associated with, or prevent a disease or condition including or related to: Binge eating (optionally assessed by HQ-CT), Moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity (optionally further including weight loss management and weight loss maintenance, or optionally further including increased physical activity as an adjunct to a reduced calorie diet or for long-term weight management); early-onset morbid obesity, Non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), Primary biliary cholangitis of the liver (PBC), Inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), type II diabetes, hypothalamic damage-induced obesity, Obsessive-compulsive disorder (OCD), Disorders of mood dysregulation (DMDD), Oppositional Defiant Disorder (ODD), skin picking, trichotillomania, Intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, Narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders, Third Edition (ICSD-3), narcolepsy with cataplexy, Narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, Cataplexy, idiopathic hypersomnia, Rapid eye movement (REM) sleep behavior disorder, convulsions, epilepsy, an addiction, or an addictive disorder or behavior (optionally, said addiction, addictive disorder, or addictive behavior is or includes Internet Gaming Disorder (IGD) or drug addiction, and optionally, said drug addiction is or includes cocaine addiction or alcohol addiction); Major depressive disorder (MDD), Treatment-resistant depression (TRD), Negative symptoms of schizophrenia, MDD associated with Parkinson's disease, Parkinson's disease, generalized anxiety, Social anxiety disorder (social phobia), fibromyalgia (FM), diabetic neuropathy, lower back pain, chronic fatigue syndrome, Attention Deficit Hyperactivity Disorder (ADHD), autism, Asperger's spectrum disorder, a genetically determined disease or syndrome (optionally, said genetically determined disease or syndrome is Prader-Willi syndrome, Bardet-Biedl syndrome, Smith-MaGinnis syndrome, 1p36 deletion syndrome, 16p11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, melanocortin 4 receptor (MC4R) pathway heterozygous obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, Angelman syndrome, Scharf-Yang syndrome, Orb-like syndrome, Wright hereditary osteodystrophy, Silver-Russell syndrome, maternal disomy, Alström syndrome, Wilms' tumor, aniridia, genitourinary abnormalities, mental retardation, i.e., WAGR or WAGRO syndrome; Dravet syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Dawes syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick disease type C, or Norrie disease, or Coffin-Lowry disease), wherein, optionally, the reduction in adverse events includes alleviating psychiatric disorders, serotonin syndrome, tachycardia, or postural tachycardia syndrome, The above use. (Item 22) 22. The method of claim 21, wherein the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprises Formula I, or a deuterated derivative of Formula I. (Item 23) 10. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of any one of the preceding items for use in treating, ameliorating, delaying progression of, alleviating symptoms of, reducing adverse events associated with, or preventing a disease or condition comprising or associated with: Binge eating (optionally assessed by HQ-CT), Moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity (optionally further including weight loss management and weight loss maintenance, or optionally further including increased physical activity as an adjunct to a reduced calorie diet or for long-term weight management); early-onset morbid obesity, Nonalcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), Primary biliary cholangitis of the liver (PBC), Inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), type II diabetes, hypothalamic damage-induced obesity, Obsessive-compulsive disorder (OCD), Disorders of mood dysregulation (DMDD), Oppositional Defiant Disorder (ODD), Skin picking, trichotillomania, Intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, Narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders, Third Edition (ICSD-3), narcolepsy with cataplexy, Narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, Cataplexy, idiopathic hypersomnia, Rapid eye movement (REM) sleep behavior disorder, convulsions, epilepsy, an addiction or addictive disorder or behavior (optionally, the addiction, addictive disorder or addictive behavior is or includes Internet Gaming Disorder (IGD) or drug addiction, and optionally, the drug addiction is or includes cocaine addiction or alcohol addiction); Major depressive disorder (MDD), Treatment-resistant depression (TRD), Negative symptoms of schizophrenia, MDD associated with Parkinson's disease, Parkinson's disease, generalized anxiety, Social anxiety disorder (social phobia), fibromyalgia (FM), diabetic neuropathy, lower back pain, chronic fatigue syndrome, Attention Deficit Hyperactivity Disorder (ADHD), autism, Asperger's spectrum disorder, genetically determined disease or syndrome (optionally, the genetically determined disease or syndrome is Prader-Willi syndrome, Bardet-Biedl syndrome, Smith-Maginnis syndrome, 1p36 deletion syndrome, 16p11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, melanocortin 4 receptor (MC4R) pathway heterozygous obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked inheritance) is or includes: a genetic disorder, Angelman syndrome, Scharf-Yang syndrome, Albright hereditary osteodystrophy, Silver-Russell syndrome, maternal disomy, Alström syndrome, Wilms tumor, aniridia, genitourinary abnormalities, mental retardation, i.e., WAGR or WAGRO syndrome; Dravet syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Dawes syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick disease type C, or Norrie disease, or Coffin-Lowry disease, wherein, optionally, the reduction in adverse events includes alleviating psychiatric disorders, serotonin syndrome, tachycardia, or postural tachycardia syndrome. said therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture. (Item 24) 24. The method of claim 23, wherein the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprises Formula I, or a deuterated derivative of Formula I. (Item 25) (i) Triple monoamine reuptake inhibitors (TRIs), (ii) melanin-concentrating hormone receptor 1 (MCHR1) antagonists; (iii) diazoxide or a diazoxide preparation; (iv) any therapeutic combination of (i) to (iii); (iv) a therapeutic combination used in a method according to any one of the preceding items or a therapeutic combination used in any one of items 13 to 17; or (v) A method for administering the pharmaceutical composition, drug or formulation according to any one of items 10 to 13, The dosage is (a) an empirical method for stable and predictable titration and for determining the initial therapeutic dose, or for determining the minimum therapeutic dose, or for determining the optimal effective dose, 1. Administering a test dose (e.g., a dose at which no adverse events or minimal adverse events are observed or a safe dose) daily until the patient achieves a steady-state plasma drug concentration; 2. Obtaining a blood sample and assessing test plasma drug concentrations prior to the next scheduled dose; 3. Calculating the initial treatment dose / day, A. For drugs that are dose-linear with respect to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiply the divided value by the test dose; B. For drugs that are dose-nonlinear with respect to plasma concentration, dividing an initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiplying the divided value by the test dose, and then multiplying the product by a nonlinear exponential coefficient, optionally wherein the initial target therapeutic plasma drug concentration is (i) a concentration corresponding to a particular pharmacodynamic efficacy marker level, e.g., serotonin transporter (SERT or 5-HTT), dopamine transporter (DAT), or norepinephrine transporter (NET) occupancy, as determined by an imaging method such as positron emission tomography (PET), or (ii) a concentration corresponding to a minimum effective therapeutic dose as determined by a clinical trial; 4. Optionally, i. administering the initial therapeutic dose daily until the patient achieves steady-state plasma drug concentrations; ii. Obtaining a blood sample prior to the next scheduled dose to assess the current therapeutic plasma drug concentration; iii. Calculating the next treatment target dose / day, A. For drugs that are dose-linear with respect to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, and then multiply the divided value by the current therapeutic dose; B. For drugs with non-linear dose to plasma concentration, calculating the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiplying the divided value by the current therapeutic dose, and then multiplying the product by a non-linear exponential coefficient; iv. the empirical method, which includes continuing the process until the minimum therapeutic dose or optimal effective dose is achieved; or (b) a model-based method for determining the initial therapeutic dose for stable and predictable titration, and for determining the minimum therapeutic dose or determining the optimal effective dose, 1. administering the test dose daily for approximately 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or approximately 1 day; 2. Obtaining the first blood sample between about 1 hour and 3 days, 6 hours and 2 days, or about 1 day after administering the first test dose; 3. Collecting a second or subsequent blood sample between about 1 hour and 28 days, 6 hours and 14 days, 1 day and 7 days, or about 2 days after collecting the first or subsequent blood sample; 4. Calculating the initial treatment starting dose / day, i. using an initial target therapeutic plasma drug concentration, the test dose, the time of administration of the test dose(s), the plasma concentration of the blood sample and the time of collection of the blood sample, and a pharmacometric model; ii. optionally using an initial target therapeutic plasma drug concentration, said test dose, the time of administration of said test dose(s), the plasma concentration of said blood sample, the time of collection of said blood sample, human PK data and a Bayesian pharmacometrics model; iii. optionally, calculating by using an initial target therapeutic plasma drug concentration, the test dose, the time of administration of the test dose, the plasma concentration of the blood sample, the time of collection of the blood sample, human PK data, the patient's genetic information, the patient's non-genetic host factors, the patient's other medications, and a Bayesian pharmacometrics model; 5. Optionally, i. administering said initial treatment starting dose daily until the patient achieves a steady-state plasma drug concentration; ii. Obtaining a blood sample prior to the next scheduled dose to assess the current therapeutic plasma drug concentration; iii. Calculating the next treatment target dose / day, A. For drugs that are dose-linear with respect to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, and then multiply the divided value by the current therapeutic dose; B. For drugs with nonlinear dose to plasma concentration, calculating the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiplying the divided value by the current therapeutic dose, and then multiplying the product by a nonlinear exponential coefficient; and iv. The method as determined by the model-based method, comprising continuing the process until the minimum therapeutic dose or optimal effective dose is achieved. (Item 26) 26. The method of claim 25, wherein the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprises Formula I, or a deuterated derivative of Formula I. (Item 27) 1. A method for delivering or administering a triple monoamine reuptake inhibitor (TRI) to an individual in need thereof, wherein the TRI comprises Formula I, or a deuterated derivative of Formula I. (Item 28) 28. The method of claim 27, wherein the TRI comprises tesofensine. (Item 29) Effective doses of: (i) Triple monoamine reuptake inhibitors (TRIs), (ii) melanin-concentrating hormone receptor 1 (MCHR1) antagonists; (iii) diazoxide or a diazoxide preparation; (iv) any therapeutic combination of (i) to (iii); or (iv) a therapeutic combination used in a method according to any one of the preceding items or a therapeutic combination used in any one of items 13 to 17; or (v) A method for administering and maintaining the pharmaceutical composition, drug or formulation according to any one of items 10 to 13, comprising: Dosage should be determined by (a) recording the maintenance dose and maintenance therapeutic plasma drug concentrations associated with the lowest effective therapeutic dose or optimal therapeutic dose; and (b) Between about 1 and 12 months, 3 and 9 months, 4 and 8 months, or early 6 months, or when there is a change in weight, medication, or health status. Prior to the next scheduled dose, a blood sample is taken to assess the current therapeutic plasma drug concentration; Optionally, if said current plasma drug concentration differs from said maintenance treatment plasma drug concentration by more than about 20%, optionally by more than about 50%, determining a new treatment dose / day by a method comprising: Calculate: i. for drugs that are dose-linear with respect to plasma concentration, dividing the maintenance treatment plasma drug concentration by the current plasma drug concentration and then multiplying the divided value by the maintenance dose; ii. for drugs with a non-linear dose to plasma concentration, dividing the maintenance treatment plasma drug concentration by the current plasma drug concentration, then multiplying the divided value by the maintenance dose, and then multiplying the product by a non-linear exponential coefficient; or iii. optionally, reaching steady state after two subsequent plasma drug concentration results separated by at least one week and within about 20% of said maintenance therapeutic plasma concentration; or iv. Optionally, the method is determined by continuing the process until a maintenance therapeutic dose is achieved at steady state. (Item 30) 30. The method of claim 29, wherein the TRI comprises Formula I, or a deuterated derivative of Formula I. (Item 31) 31. The method of claim 30, wherein the TRI comprises tesofensine. (Item 32) 1. A method for treating overeating, overeating in PWS, Disorderly Mood Dysregulation Disorder (DMDD), Oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, or Binge Eating Disorder (BED), comprising administering to an individual in need thereof Formula I, or a deuterated derivative of Formula I. (Item 33) A method for administering Formula I, or a deuterated derivative of Formula I, to treat overeating, overeating in PWS, Disorders of Mood Dysfunction (DMDD), Oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, or Binge Eating Disorder (BED). (Item 34) 1. A method for treating binge eating, binge eating in PWS, Disruptive Mood Dysregulation Disorder (DMDD), Oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, and Binge Eating Disorder (BED) with an oral dosage form of Formula I, or a deuterated derivative of Formula I, as described in the preceding paragraphs, which is administered once daily or twice daily and results in a trough plasma concentration, a 24-hour hourly average plasma concentration, or a 12-hour daytime hourly average plasma concentration of Formula I, or a deuterated derivative of Formula I, as described in the preceding paragraphs, of 250 ng / mL to 500 ng / mL, 500 to 1000 ng / mL, 1000 to 1500 ng / mL, 1500 to 2000 ng / mL, or 1500 to 2500 ng / mL, when measured for about 1 week, about 2 weeks, or at steady state.

Claims

[Claim 1] The invention as described in the drawings of this application.

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