Inhibition of type 9 phosphodiesterase enhances the efficacy of serotonergic hallucinogens in the treatment or prevention of certain neuropsychiatric disorders

Abstract

The present application provides compositions and methods for treating a disease or disorder with a therapeutically effective amount of a serotonergic hallucinogen and a therapeutically effective amount of a phosphodiesterase type 9 inhibitor.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[01] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 383,732, filed November 15, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002]

[02] Major depressive disorder (MDD), commonly known as depression, is a mental disorder characterized by a low mood and loss of pleasure, interest, and motivation lasting at least two weeks, often accompanied by decreased self-esteem, decreased energy, changes in sleep, appetite, and concentration, guilt rumination, preoccupation with death, and unexplained physical pain. MDD negatively impacts patients' social life, performance in work and other roles, and overall health, leading to suicide in 2–15% of adult patients. Up to 60% of suicides involve MDD or another mood disorder. Patients with MDD are often treated with counseling, structured psychotherapy, or antidepressants. Unfortunately, the effectiveness of currently available treatments is limited, and despite their active use, many patients continue to suffer. Furthermore, many patients do not receive evidence-based treatment due to inadequate healthcare system delivery and other structural flaws, or patients' reluctance to seek help.

[0003]

[03] Many other psychiatric conditions often coexist with major depressive disorder and / or may overlap in symptom patterns and even pathomechanisms. For example, other primary mood disorders include bipolar disorder types 1 and 2, cyclothymic disorder, and persistent depressive disorder (formerly known as dysthymia). Other related disorders include obsessive-compulsive disorder (OCD), OCD-related disorders (hoarding disorder, body dysmorphic disorder, trichotillomania, excoriation disorder, illness anxiety disorder, Tourette syndrome), and posttraumatic stress disorder (PTSD). Certain antidepressants and psychotherapies are used to treat these and related mental illnesses, but as with MDD, their effectiveness is limited for many patients, and new treatments are desperately needed.

[0004]

[04] Conventional antidepressants (ADs), such as SSRI antidepressants typified by fluoxetine, are used to treat a wide range of psychiatric disorders, including MDD, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), borderline personality disorder, and various other mood and anxiety disorders. However, these medications can take weeks to months to reach their full potential and are referred to herein as "slow-acting antidepressants (SAADs)." SAADs require daily treatment and are often associated with undesirable side effects. Furthermore, up to 50% of treated patients fail to achieve clinically significant improvement and continue to suffer. Improvements in the treatment of these psychiatric disorders are urgently needed.

[0005]

[05] A new class of rapid-acting antidepressants (RAADs) holds promise for revolutionizing treatment strategies for MDD, OCD, PTSD, and related psychiatric disorders. Ketamine, a representative RAAD, was discovered in the late 1990s to exhibit antidepressant effects within an hour in many patients, with effects lasting from several days to one to two weeks. Ketamine is currently used in clinical settings, with a typical administration protocol involving twice-weekly intravenous infusions for several weeks, followed by a gradual reduction in the frequency of administration. Esketamine, the purified S-enantiomer of racemic ketamine, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) and suicidal ideation. Like ketamine, it is administered repeatedly, but not daily. Furthermore, serotonergic hallucinogens such as psilocybin have recently demonstrated beneficial effects in small-scale controlled studies and ongoing pilot trials for MDD, addictive disorders, OCD, and other psychiatric disorders. Similarly, 3,4-methoxy-diaminodextroamphetamine (MDMA) and other drugs in the entactogen / empathogen class have been shown to have beneficial effects for PTSD and other conditions. Hallucinogens and entactogens / empathogens are not approved by the FDA, and many are regulated by the Drug Enforcement Administration as Schedule 1 substances, meaning they are not available for widespread clinical use, but are actively being investigated for a wide range of indications.

[0006]

[06] While these RAADs are transforming psychiatric practice, their clinical application remains limited. The beneficial effects of ketamine and esketamine are rapid in onset but may last only days to weeks, requiring repeated treatment in some cases. Early evidence suggests that psilocybin and other hallucinogens may have longer-lasting beneficial effects, but their efficacy has not yet been rigorously established. As a result, current implementations of these drugs in research settings require lengthy, labor-intensive interventions by teams of skilled clinicians, increasing costs and challenging the widespread adoption of these treatments (if they receive regulatory approval).

[0007] RAADs in general, and serotonergic hallucinogens in particular, are emerging as potential new therapeutic avenues for the treatment of MDD, other mood disorders, and other neuropsychiatric disorders such as PTSD, OCD, and addictive disorders. Ketamine and esketamine are already in clinical use, and serotonergic hallucinogens are currently under active investigation. However, these drugs still have inherent limitations. The effects of RAADs can be time-limited, and treatment is costly and burdensome, particularly for serotonergic hallucinogens, which are currently limited to research settings due to the long duration of acute psychological effects and the need for labor-intensive monitoring and support. These observations highlight the need for new strategies to extend the duration of efficacy following serotonergic hallucinogen treatment, reduce burdensome side effects (including, but not limited to, hallucinogenic effects, dissociation, and cardiovascular effects), and otherwise reduce the cost and burden of treatment, making it more widely available. Summary of the Invention [Means for solving the problem]

[0008]

[08] Provided herein is a method for treating or preventing a disorder in a subject, comprising administering a therapeutically effective amount of a serotonergic hallucinogen together with one or more inhibitors of brain phosphodiesterase type 9 (PDE9) to the subject.In some embodiments, the disorder includes a neuropsychiatric disorder, cluster headache, or migraine.In some embodiments, the PDE9 inhibitor enhances the therapeutic effect of the serotonergic hallucinogen on the disorder to be treated.In some embodiments, the PDE9 inhibitor prolongs at least one biological activity of the serotonergic hallucinogen in the subject.In some embodiments, the PDE9 inhibitor reduces at least one undesirable biological activity of the serotonergic hallucinogen in the subject.In some embodiments, the PDE9 inhibitor reduces the abuse potential of the serotonergic hallucinogen in the subject.

[0009]

[09] In some embodiments, the neuropsychiatric disorder is major depressive disorder (MDD, including major depressive episode), major depressive episode in bipolar disorder (bipolar depression), depressive episode associated with bipolar disorder I or II (bipolar depression), persistent depressive disorder (dysthymia), dysthymic disorder, premenstrual dysphoric disorder, substance / drug-induced depressive disorder, depressive disorder due to other medical conditions, other specified depressive disorder, not otherwise specified depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, addictive disorder, treatment-resistant depressive disorder, The treatment is selected from the group consisting of major depressive disorder (TRD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), adjunctive treatment of major depression, eating disorders (including anorexia and bulimia), depression associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, dementia, ALS, traumatic brain injury, suicidal ideation and behavior, chronic pain, persistent depressive disorder, seasonal affective disorder (SAD), psychotic depression, perinatal (postpartum) depression, premenstrual dysphoric disorder (PMDD), situational depression, and any combination thereof.

[0010]

[0010] In some embodiments, the serotonergic hallucinogen is selected from the following group: 1) classical hallucinogens (non-limiting examples include psilocybin, dimethyltryptamine (DMT), 5-methoxydimethyltryptamine (5-MeO-DMT), lysergic acid diamide (LSD), and lysergic acid amide (LSA)); 2) entactogens / empathogens (non-limiting examples include 3,4-methylenedioxymethamphetamine (MDMA)); 3) other phenethylamines (non-limiting examples include mescaline, 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), and 2,5-dimethoxy-4-bromophenethylamine (2C-B)).

[0011] In some embodiments, the serotonergic hallucinogen is tryptamine or ergoline. In some embodiments, the serotonergic hallucinogen comprises tryptamine, or a salt, solvate, enantiomer, or diastereomer thereof. In some embodiments, the serotonergic hallucinogen comprises ergoline, or a salt, solvate, enantiomer, or diastereomer thereof. In some embodiments, the serotonergic hallucinogen is psilocybin, or a salt, solvate, enantiomer, or diastereomer thereof.

[0012] In some embodiments, the phosphodiesterase inhibitor is selected from the following group: 1) non-selective phosphodiesterase inhibitors (non-limiting examples include aminophylline, pentoxifylline, and theobromine); 2) phosphodiesterase type 9 inhibitors (non-limiting examples include paraxanthine, PF-04447913, PF-04447943, PF-04447953, BAY 73-6691, E 2027, CRD 773, BI 409306, CRD 740, TT 00920, BAY 7081, FRM 16606, HUC1-288, WYQ-C36D, and any combination thereof). In some embodiments, the PDE9 inhibitor is PF-04447943, a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

[0013] In some embodiments, the hallucinogen and the PDE9 inhibitor are co-administered to a subject. In some embodiments, the PDE9 inhibitor is administered to a subject before the administration of the hallucinogen to the subject. In some embodiments, the hallucinogen is administered to a subject before the administration of the PDE9 inhibitor to the subject. In some embodiments, the hallucinogen and the PDE9 inhibitor are formulated together as a pharmaceutical composition. In some embodiments, the hallucinogen and the PDE9 inhibitor are independently administered to a subject via a route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, intrapleural, intraperitoneal, intravaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraaural, intraocular, intrathecal, intravenous, and any combination thereof. In some embodiments, the subject is administered a therapeutically effective amount of psilocybin and PF-04447943. In some embodiments, the subject is administered therapeutically effective amounts of psilocybin, or a derivative, salt, solvate, enantiomer, or diastereomer thereof, and PF-04447943, or a derivative, salt, solvate, enantiomer, or diastereomer thereof.

[0014]

[0014] Provided herein is a pharmaceutical composition comprising a serotonergic hallucinogen and a PDE9 inhibitor, wherein the serotonergic hallucinogen and the PDE9 inhibitor are present in amounts sufficient to treat or prevent a neuropsychiatric disorder when administered to a subject, and the PDE9 inhibitor reduces at least one side effect of the hallucinogen in the subject. In some embodiments, the pharmaceutical composition is formulated for administration via a route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, intrapleural, intraperitoneal, intravaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraaural, intraocular, intrathecal, and intravenous.

[0015] In some embodiments, the PDE9 inhibitor enhances the therapeutic effect of a serotonergic hallucinogen for the disorder being treated. In some embodiments, the PDE9 inhibitor prolongs at least one biological activity of the serotonergic hallucinogen in the subject. In some embodiments, the PDE9 inhibitor reduces at least one undesirable biological activity of the serotonergic hallucinogen in the subject. In some embodiments, the PDE9 inhibitor reduces the abuse potential of the serotonergic hallucinogen in the subject.

[0016] In some embodiments, the serotonergic hallucinogen is psilocin (4-hydroxy-N,N-dimethyltryptamine), psilocybin (4-phosphoryl-N,N-dimethyltryptamine), bufotenin (5-hydroxy-N,N-dimethyltryptamine), baeocystin (4-phosphoryloxy-N-methyltryptamine), aeruginacin (N,N,N-trimethyl-4-phosphoryloxytryptamine), 5-MeO-DMT (5-methoxy-N, N-dimethyltryptamine), N,N-dimethyltryptamine (DMT), 5-bromo-DMT (5-bromo-N,N-dimethyltryptamine), N-methyl-N-ethyltryptamine (MET), N-methyl-N-isopropyltryptamine (MiPT), N-methyl-N-propyltryptamine (MPT), N-diethyltryptamine (DET), N-ethyl-N-isopropyltryptamine (EiPT), N-methyl-N-butyltryptamine (MBT) , N-propyl-N-isopropyltryptamine (PiPT), N,N-dipropyltryptamine (DPT), N,N-diisopropyltryptamine (DiPT), N,N-diallyltryptamine (DALT), N,N-dibutyltryptamine (DBT), N-ethyltryptamine (NET), N-methyltryptamine (NMT), trimethyltryptamine (TMT) (N,N,N-trimethyltryptamine), α-methyltryptamine, α-ethyltryptamine , α,N-DMT (α,N-dimethyltryptamine), α,N,N-trimethyltryptamine, etosibin (4-phosphoryloxy-N,N-diethyltryptamine), 4-HO-MET, 4-HO-DET, 4-HO-MPT, 4-HO-MiPT, 4-HO-MALT, 4-HO-DPT, 4-HO-DiPT, 4-HO-DALT, 4-HO-DBT, 4-HO-DSBT, 4-HO-αMT, 4-HO-MPMI, 4-HO-TMT, 4-HO-1,N,N-TMT, 4-HO-5-MeO-DMT, 4-AcO-DMT, 4-AcO-MET, 4-AcO-MALT, 4-AcO-DET, 4-AcO-EiPT, 4-AcO-DPT, 4-AcO-DiPT, 4-A cO-DALT, 4-MeO-DMT, 4-MeO-MiPT, 5-MeO-NMT, 5-MeO-MET, 5-MeO-MPT, 5-MeO-MiPT, 5-MeO-DET, 5-MeO-EiPT, 5-MeO- EPT, 5-MeO-PiPT, 5-MeO-DPT, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-αMT, 5-MeO-2,N,N-TMT, 5-MeO-7,N,N-TMT, 5-MeO-a, N-DMT, 4-F-5-MeO-DMT, 5-Me-MiPT, 5-HO-DiPT, 2-α-DMT, 4-Me-αMT, 4-Me-αET, 7-Me-αET, 4,5-DHP-AMT, 4,5-DHP-DM T, 4,5-MDO-DMT, 4,5-MDO-DiPT, 5,6-MDO-DiPT, 5,6-MDO-MiPT, 5-fluoro-αMT (5-fluoro-α-methyltryptamine), 6-fluoro-αMT (6-fluoro-α-methyltryptamine), 6-fluoro-DMT (6-fluoro-N,N-dimethyltryptamine), N,N-tetramethyltriptamine (Pyr-T), 4-HO-pyr-T (4-hydroxy- Pyr-T), 5-MeO-pyr-T (5-methoxy-Pyr-T), RU-28306 (4,α-methylene-N,N-DMT), O-4310 (6-fluoro-1-isopropyl-4-HO-DMT), CP-132,484 (4,5-DHP-1-methyltryptamine), dimemebufe (5-MeO-BFE) (5-methoxy-benzofuranethaneamine), 5-MeO-DiBF, ibogaine ((2β,4β,5α,6β,18α)-12-Methoxyibogamine), Voacangin (12-Methoxyibogamine-18-carboxylic acid methyl ester), Lysergic acid diethylamide (LSD), Lysergic acid amide (LSA), Lysergic acid diamide, N1-methyl-lysergic acid diethylamide, 1-propionyl-lysergic acid diethylamide, 1-cyclopropanoyl-d-lysergic acid diethylamide, 1-valeryl-D-lysergic acid diethylamide, 6-allyl-6-nor-lysergic acid diethylamide, 6-butyl-6-nor-lysergic acid diethylamide, 6-Ethyl-6-nor-lysergic acid diethylamide, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 6-propyl-6-nor-lysergic acid diethylamide, 6-cyclopropyl-6-nor-lysergic acid diethylamide, 6-nor-lysergic acid diethylamide, lysergic acid ethylamide, lysergic acid α-hydroxyethylamide, lysergic acid 2-butylamide, lysergic acid 3-pentylamide, lysergic acid methyl ester, lysergic acid 2,4-dimethylazetidide, lysergic acid piperidine, N,N-dimethyl Tyl-lysergamid, methylisopropyl-lysergamid, N,N-diallyl-lysergamid, N-pyrrolidyl-lysergamid, N-morpholinyl-lysergamid, 1-methyl-lysergamid butanolamide, lysergamid β-propanolamide, lysergamid 1-butanolamide, mescaline (3,4,5-trimethoxyphenethylamine), lophophine (3-methoxy-4,5-methylenedioxyphenethylamine), isomescaline (2,3,4-trimethoxyphenethylamine), cyclopropylmescaline (4-( cyclopropylmethoxy)-3,5-dimethoxybenzeneethanamine), thioisomescaline (2-TIM, 3-TIM, and 4-TIM), 4-desoxymescaline, dimescaline ((1R)-2,3-dihydro-4,5,6-trimethoxy-1H-indene-1-methanamine), escaline (3,5-dimethoxy-4-ethoxyphenethylamine), metaescaline (3-methoxy-4,5-dimethoxyphenethylamine), thiometaescaline (3-TME, 4-TME, and 5-TME), trisescaline (3,4,5-triethoxyphenethylamine), thiotrysescaline (3-T-TRIS, and 4-T-TRIS), cinvescaline (3,5-diethoxy-4-methoxyphenethylamine), asymvescaline (3,4-diethoxy-5-methoxyphenethylamine), thiocinvescaline (3-TSB (3-ethylthio-4-methoxy-5-ethoxyphenethylamine) and 4-TSB (4-methylthio-3,5-diethoxyphenethylamine)), phenethylamine Scarin (3,5-dimethoxy-4-phenethoxyphenethylamine), allylescarin (4-allyloxy-3,5-dimethoxyphenethylamine), methallylscarin (4-methylallyloxy-3,5-dimethoxyphenethylamine), proscarin (4-propoxy-3,5-dimethoxyphenethylamine), isoproscarin (4-isopropoxy-3,5-dimethoxyphenethylamine), metaproscarin (3,4-dimethoxy-5-propoxyphenethylamine) 4-methyl-2,5-dimethoxy-α-ethylphenethylamine), thioproscaline (3,5-dimethoxy-4-propylthiophenethylamine), buscaline (3,5-dimethoxy-4-butoxyphenethylamine), thiobuscaline (3,5-dimethoxy-4-butylthiophenethylamine), α-ethylmescaline (3,4,5-trimethoxy-α-ethylphenethylamine), Ariadne (4-methyl-2,5-dimethoxy-α-ethylphenethylamine), macrometabolite (4-methyl-2,5-dimethoxy-α-ethylphenethylamine), Phosphorus (1-(3,4-dimethoxyphenyl)-2-(dimethylamino)ethanol), MEPEA, TOM (2-TOM and 5-TOM), Bis-TOM, TOMSO (2-methoxy-4-methyl-5-methylsulfinylamphetamine), TOET (2-TOET and 5-TOET), BOH, BOM (13-methoxy-mescaline), beta-D, 4-D, DME, F-2, F-22, FLEA, MDPH, MDMP, propynyl, 2C series (2,5-dimethoxy, 4-substituted phenethylamine), βk-2C-B, 2C-B, 2CB-2EtO, 2CB-5EtO, 2CB-diEtO, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-C, 2C-D, 2CD-2EtO, 2CD-diEtO, 2CD-5EtO, 2C-E, 2C-EF, 2C-F, 2C-G (2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, and 2C-GN), 2C-H, 2C-I, 2CI-2EtO, 2C-iP, 2C-N, 2C-O, 2C-O-4, 2C-P, 2C-SE, 2C-T, 2CT-5EtO, 2C-T-2, 2CT-2-2EtO, 2CT-2-5EtO, 2CT-2-diEtO, 2C-T-4 (2C-T-4 and Ψ-2C-T-4), 2CT-4-2EtO, 2C-T-7, 2CT-7-2EtO, 2C-T-8, 2C-T-9, 2C-T-13, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-19, 2C-T-21, 2C-TFM, 2C-YN, BOB(I3-methoxy-2C-B), BOD(I3-methoxy- 2C-D), BOHD (I3-hydroxy-2C-D), HOT-2, HOT-7, HOT-17, indane derivatives including 2CB-Ind., benzocyclobutene derivatives including 2C-BCB (TCB-2), NBOMe derivatives (NBOMe-mescaline, 2C-H-NBOMe, 2C-C-NBOMe, 2CBCB-NBOMe, 2CBFly-NBOMe, 2C-B-NBOMe, 2C-I-NBOMe, 2C-TFM-NBOMe, 2C-D-NBOMe, 2C-G-NBOMe, 2C-E-NBOMe, 2C-P -NBOMe, 2C-iP-NBOMe, 2C-CN-NBOMe, 2C-N-NBOMe, 2C-T-NBOMe, 2C-T-4-NBOMe, 2C-T-7-NBOMe, and DMBMPP), NBOH derivatives (2C-C-NBOH, 2C-B-NBOH, 2C-I-NBOH, and 2C-CN-NBOH), NBMD derivatives (2C-I-NBMD), NBF derivatives (2C-C-NBF, 2C-B-NBF, and 2C-I-NBF), 3C series including 3C-E, 3C-P, 3C-DFE, and 3C-BZ (3,DOx series (amphetamines with 2,5-dimethoxy and 4-substituents), including DOAM, DOB, Meta-DOB, Methyl-DOB, DOBU, DOC, DOEF, DOET, DOI, DOM, Ψ-DOM, DON, DOPR, SOiPR, DOT, Meta-DOT, Ortho-DOT, DOTFM, DMCPA, DMMDA, and DMMDA-2, 3,4-dimethyl-2 ,5-dimethoxyamphetamine, 4-methyl-2,5-dimethoxymethamphetamine, 2,N-dimethyl-4,5-methylenedioxyamphetamine, dimethoxyamphetamine (2,4-DMA, 2,5-DMA, and 3,4-DMA), trimethoxyamphetamine (TMA-2, TMA-6), tetramethoxyamphetamine, Br-DragonFLY, TFMFly, 2-bromo-4,5-methylenedioxyamphetamine, 4-bromo- 3,5-dimethoxyamphetamine, EEE, EEM, EME, EMM, EDMA, EIDA, Ethyl-J, Methyl-J, Ethyl-K, Methyl-K, IDNNA, Iris, MDAI, MDMAI, MDAT, MDMAT, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPK, MDPR, MEDA, MEM, Methyl-DMA, MMDA, MMDA-2,5-methyl Di-MDA, MEE, MME, MPM, DiFMDA, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB, 6-MAPDB, 6-MAPB, 6-EAPB, 5-EAPB, para-methoxyamphetamine, para-methoxymethamphetamine, 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, Substituted methylenedioxyphenethylamines including norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, benzoxazine, efavirenz, 3,4-methylenedioxymethamphetamine (MDMA), MDA, 2,3-MDA, 5-methyl-MDA, MMDA, MDEA, MBDB, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPM, MDPR, BDB, MMDA-2, DiFMDA, and EIDA (MDxx), Ethyl-K (3,4-methylenedioxy-N-ethyl-α-propylphenethylamine), lophophine, substituted amphetamines, EDMA (N-ethyl-3,4-methylenedioxyamphetamine), para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodo Doamphetamine, para-chloroamphetamine, substituted cathinones, methylone, ethylone, eutylone, butylone, pentylone, 4-ethylmethcathinone, 3-methylmethcathinone, substituted benzofurans, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB, 6-MAPDB, 6-MAPB, 5-EAPB, 6-EAPB, 5-MBPB, MDAT, MDMAT, 6-CAT, tetralinylaminopropane, trifluoromethylaminoindan, ethyltrifluoromethylaminoindan, 5-iodo-2-aminoindan, MMAI, MDAI, MDMAI, indanylaminopropane, naphthylaminopropane, 4-chlorophenylisobutylamine, 4-methylphenylisobutylamine, Ariadne, α-methyltryptamine, 5-MeO-αMT, α-ethyltryptamine, 4-Me-αET, 7-Me-αET, 5-MeO-αET, 5-MeO-MiPT, Δ 9-THC, CBD, CBN, THCV, (C6)-CP 47,497, (C9)-CP 47,497, 1-butyl-3-(2-methoxybenzoyl)indole, 1-butyl-3-(4-methoxybenzoyl)indole, 1-pentyl-3-(2-methoxybenzoyl)indole, 2-isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene, 4-HTMPIPO, 4-nonylphenylboronic acid, 5Br-UR-144, 5Cl-APINACA, 5Cl-UR-144, 5F-3- Pyridinoylindole, 5F-AB-FUPPYCA, 5F-ADB-PINACA, 5F-ADBICA, 5F-ADB, 5F-AMB, 5F-APINACA, 5F-CUMYL-PINACA, 5F-EMB-PINA CA, 5F-NNE1, 5F-PB-22, 5F-PCN, 5F-PY-PICA, 5F-PY-PINACA, 5F-SDB-006, HHC, A-796,260, A-834,735, A-836,339, A-955,840, A-40174, A-41988, A-42574, AB-001, AB-CHFUPYCA, AB-CHMFUPPYCA, AB-CHMINACA, AB-FUBICA, AB-FUBINACA 2-Fluorobenzyl Isomer, AB-FUBINACA, AB-PICA, AB-PINACA, Abnormal Cannabidiol, ADAMANTYL-THPINACA, ADB-CHMINACA, ADB-FUBICA, ADB-FUBINACA, ADB-PINACA, ADBICA, ADS B-FU B-187, Azulemic acid, AM-087, AM-411, AM-630, AM-679, AM-694, AM-855, AM-883, AM-905, AM-906, AM-919, AM-926, AM -938, AM-1220, AM-1221, AM-1235, AM-1241, AM-1248, AM-1346, AM-1387, AM-1714, AM-2201, AM-2232, AM-2233, AM-2389, AM-4030, AM-4113, AM-6527, AM-6545, AM-251, AM-281, AM-404, AMB-CHMINACA, AMB-FUBINACA, AMG-1, AMG-3, AMG-36, AMG-41, APICA, APINACA, APP-FUBINACA, Arachidonoyl Serotonin, ACEA, ACPA, Arvanil, AZ-11713908, BAY 38-7271, BAY 59-3074, BIM-018, Biochanin A, BML-190, Navidrox (Cambisol), cannabicyclohexanol, cannabipiperidiethanone, CAY-10401, CAY-10429, CAY-10508, CB-13, CB-25, CB-52, CB-86, CB-86, CBS-0550, CP47,497, CP55,244, CP55,940, cumyl-5f-pica, cumyl-bica, cumyl-pica, cumyl-pinaca, cumyl-thpinaca, dexanabinol, dimethylheptylpyran, drinabant, dronabinol, EAM-2201, emb-fubinaca, fab-144, fdu-nne1, fdu-pb-22, fub-144, fub-apinaca, fub-jwh-018, fub-pb-22, fubimina, genistein, gw-405,833, gw-842,166x, hemopressin, hv-210, hv-243, hv-308, hv-320, hv-331, hv-336, hv-345, hv-910, ibipinabant, ibid., jnj. 1661010, JNJ 1661010, JTE-907, JTE 7-31, JWH-007, JWH-015, JWH-018, JWH-019, JWH-030, JWH-051, JWH-073, JWH-081, JWH-098, JWH-116, JWH-122, JWH-133, JWH-139, JWH-14 7, JWH-149, JWH-161, JWH-164, JWH-167, JWH-175, JWH-176, JWH-182, JWH-184, JWH-185, JWH-192, JWH-193, JWH-194, JWH-195, JWH-196, J WH-197, JWH-198, JWH-199, JWH-200, JWH-203, JWH-210, JWH-229, JWH-249, JWH-250, JWH-251, JWH-302, JWH-307, JWH-359, JWH-369, JWH-370, JWH-398, JWH-424, JZL184, JZL195, kaempferol, KM-233, L-759,633, L-759,656, LASSBio-881, LBP-1, Leelamin, Levonantradol, LH-21, LY-320135, LY-2183240, NAM-2201, MDM-2201, MDA-7, MDA-19, MDA-77, MDMB-CHMICA, MDMB-CHMINACA, MDMB-FUBINACA, menabitan, MEPIRAPIM, methananandamide, MJ-15, MK-9470, MMB-2201, MN-18, MN-25, nabazenil, nabilone, nabitan, navoctate, NESS-0327, NESS-040C5, NIDA-41020, NM-2201, NMP-7, NNE1, nonavine O-224, O-581, O-585, O-606, O-689, O-774, O-806, O-823, O-889, O-1057, O -1125, O-1184, O-1191, O-1238, O-1248, O-1269, O-1270, O-1376, O-1399, O-1422, O-16 01, O-1602, O-1624, O-1656, O-1657, O-1660, O-1812, O-1860, O-1861, O-1871, O-1918, O -2048, O-2050, O-2093, O-2113, O-2220, O-2365, O-2372, O-2373, O-2383, O-2426, O-2484, O-2545, O-2654, O-2694, O-2715, O-2716, O-3223, O-3226, Oleoylethanolamide, Olvanil, Org 27569, Org 27759, Org 2831, Org 28611, Org 29647, Otenabant, Palmitoylethanolamide, Parahexyl, PF-03550096, PF-04457845, PF-622, PF-750, PF-3845, PF-514273, PHOP, PipISB, Pirunavine, Pravadrine, Pregnenolone, PSB-SB-487, PSB-SB-1202, PTI-1, PTI-2, PX-1, PX-2, PX-3, QUCHIC, QUPIC, RCS-4, RCS-8, Rimonabant, Lozonabant, RTI-371, S-444,823, SDB-006, SER-601, SPA-229, SR-144528, STS-135, Sulinabant, Taranabant, Tedarinab, THC-O-acetate, THC-O-phosphate, THJ-018, THJ-2201, Tinabinol, TM-38837, UR-144, URB-447, URB-447, URB-597, URB-602, URB-754, VCHSR, VDM-11, VSN-16, WIN 54,461, WIN 55,212-2, WIN 56,098, XLR-11, yangonine, harmaline, harmala alkaloids, other beta-carbolines, active ingredients of ayahuasca, salvinorin A, salvinorin B methoxymethyl ether, salvinorin B ethoxymethyl ether, piperazine, pFPP, TFMPP, myristicin, elemicin, cryogenin (vertine), atropine, scopolamine, hyoscyamine, ibotenic acid, muscimol, TiHKAL, 2-Me-D ET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-EPT, 4-HO-McPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPMI, 4-HO-MPT, 4-HO-αMT, 4 -Me-αMT, 4-MeO-MiPT, 4-PrO-DMT, 4,5-MDO-DiPT, 4,5-MDO-DMT, 5-ethoxy-αMT, 5-fluoro-AET, 5-fluoro-DET, 5-fluoro-DMT, 5 -Fluoro-EPT, 5-fluoro-MET, 5-MeO-AET, 5-MeO-aMT, 5-MeO-DALT, 5-MeO-DET, 5-MeO-DPT, 5-MeO-EiPT, 5-MeO-MALT, 5-Me O-MiPT, 5-MeO-MPMI, 5-MeO-pyr-T, 5-MeS-DMT, 5-MeO-2-TMT, 5-TFM-DMT, 5-TFMO-DMT, 5,6-MDO-DiPT, 5,6-MDO-DMT, 5 ,6-MDO-MiPT, 5,6-MeO-MiPT, 5,N,N-TMT, 5F-MPMI, 6-fluoro-DET, 6-fluoro-DMT, 6-MeO-THH, 7-chloro-AMT, 7-F-5-MeO-MET, 4-acetoxy-DET, 4-acetoxy-DiPT, 4-acetoxy-MET, 4-acetoxy-MiPT, O-acetylbufotenin, O-acetylpsilocin, aeruginacin, alpha,N-DMT, alpha,N,O-TMS, baeocystin, 5-bromo-DMT, bufotenin, 5-chloro-αMT, DALT, dibutyltryptamine, diethyltryptamine, diisopropyltryptamine, 5,N-dimethyl-N-isopropyltryptamine, dimethyltryptamine, N,N-dimethyltryptamine, dipropyltryptamine, 2,α-dimethyltryptamine, ethosybin, ethylisopropyltryptamine, A-ethyltryptamine, 5-fluoro-AMT, 4-fluoro-5-methoxy-DMT, FT-104, 5-MeO-DMT, 5-methoxy-N,N-diisopropyltryptamine, 4-methyl-α-ethyltryptamine, N-methyl-N-ethyltryptamine, methylbutyltryptamine, methylisopropyltryptamine, alpha-methylserotonin, alpha-methyltryptamine, N-methyltryptamine, MPMI, norbeocystine, propylisopropyltryptamine, 2,N,N-TMT, A,N,N-trimethyltryptamine, ketamine, esketamine, arketamine, mitragynine, yohimbine, and combinations thereof.

[0017] In some embodiments, the serotonergic hallucinogen is tryptamine or ergoline. In some embodiments, the serotonergic hallucinogen comprises tryptamine, or a salt, solvate, enantiomer, or diastereomer thereof. In some embodiments, the serotonergic hallucinogen comprises ergoline, or a salt, solvate, enantiomer, or diastereomer thereof. In some embodiments, the serotonergic hallucinogen is psilocybin, or a salt, solvate, enantiomer, or diastereomer thereof.

[0018] In some embodiments, the PDE9 inhibitor is selected from the group consisting of aminophylline, pentoxifylline, theobromine, paraxanthine, PF-04447913, PF-04447943, PF-04447953, BAY 73-6691, E 2027, CRD 773, BI 409306, CRD 740, TT 00920, BAY 7081, FRM 16606, HUC1-288, WYQ-C36D, and any combination thereof. In some embodiments, the PDE9 inhibitor is PF-04447943, a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

[0019]

[0019] The present disclosure also provides a pharmaceutical composition comprising a serotonergic hallucinogen and a PDE9 inhibitor, wherein the serotonergic hallucinogen is not mescaline. In some embodiments, the serotonergic hallucinogen and the PDE9 inhibitor are included in amounts sufficient to treat or prevent a neuropsychiatric disorder in a subject. In some embodiments, the PDE9 inhibitor prolongs at least one biological activity of the serotonergic hallucinogen in the subject. In some embodiments, the PDE9 inhibitor reduces at least one undesirable biological activity of the serotonergic hallucinogen in the subject. In some embodiments, the PDE9 inhibitor reduces the abuse potential of the serotonergic hallucinogen in the subject. In some embodiments, the pharmaceutical composition is formulated for administration via a route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, intrapleural, intraperitoneal, intravaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraauricular, intraocular, intrathecal, and intravenous. In some embodiments, the serotonergic hallucinogen is psilocin, psilocybin, bufotenin, baeocystin, aeruginasin, 5-MeO-DMT, N,N-dimethyltryptamine (DMT), 5-bromo-DMT, N-methyl-N-ethyltryptamine (MET), N-methyl-N-isopropyltryptamine (MiPT), N-methyl-N-propyltryptamine (MPT), N-N-diethyltryptamine (DET), N-ethyl-N-isopropyltryptamine (EiPT), N-methyl-N-isopropyltryptamine (Methyl ... N-butyltryptamine (MBT), N-propyl-N-isopropyltryptamine (PiPT), N,N-dipropyltryptamine (DPT), N,N-diisopropyltryptamine (DiPT), N,N-diallyltryptamine (DALT), N,N-dibutyltryptamine (DBT), N-ethyltryptamine (NET), N-methyltryptamine (NMT), trimethyltryptamine (TMT), α-methyltryptamine, α-ethyltryptamine, α,N-DMT, α,N,N- 4-HO-MET, 4-HO-DET, 4-HO-MPT 、4-HO-MiPT、4-HO-MALT、4-HO-DPT、4-HO-DiPT、4-HO-DA LT、4-HO-DBT、4-HO-DSBT、4-HO-αMT、4-HO-MPMI、4-HO-TMT、4-HO-1,N,N-TMT、4-HO-5-MeO-DMT、4-AcO-DMT、4-Ac O-MET, 4-AcO-MALT, 4-AcO-DET, 4-AcO-EiPT, 4-AcO-DPT, 4-AcO-DiPT, 4-AcO-DALT, 4-MeO-DMT, 4-MeO-MiPT, 5- MeO-NMT, 5-MeO-MET, 5-MeO-MPT, 5-MeO-MiPT, 5-MeO-DET, 5-MeO-EiPT, 5-MeO-EPT, 5-MeO-PiPT, 5-MeO-DPT, 5-M eO-DiPT, 5-MeO-DALT, 5-MeO-αMT, 5-MeO-2,N,N-TMT,5-MeO-7,N,N-TMT,5-MeO-α,N-DMT,4-F-5-MeO-DMT,5-Me -MiPT, 5-HO-DiPT, 2-α-DMT, 4-Me-αMT, 4-Me-αET, 7-Me-αET, 4,5-DHP-AMT, 4,5-DHP-DMT, 4,5-MDO-DMT, 4,5-MDO -DiPT、5,6-MDO-DiPT、5,6-MDO-MiPT、5-フルオロ-αMT、6-フルオロ-αMT、6-フルオロ-DMT、N,N-テトラメチルエントリプタミン(Pyr-T)チ4-DMT HO-pyr-T、5-MeO-pyr-T、RU-28306(4,a-メチレン-N,N-DMT) 、O-4310(6-フルオロ-1-イソプロピル-4-HO-DMT)、CP-132,484(4,5-DHP-1-methyltryptamine), dimemebufe (5-MeO-BFE), 5-MeO-DiBF, ibogaine, voacangine, lysergic acid diethylamide (LSD), lysergic acid amide (LSA), lysergic acid diamide, N1-methyl-lysergic acid diethylamide, 1-propionyl-lysergic acid diethylamide, 1-cyclopropanoyl-d-lysergic acid diethylamide, 1-valeryl-d-lysergic acid diethylamide, 6-allyl-6-nor-lysergic acid diethylamide, 6-butyl-6-nor-lysergic acid diethylamide, 6-ethyl-6-nor-lysergic acid diethylamide Lysergic acid diethylamide, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 6-propyl-6-nor-lysergic acid diethylamide, 6-cyclopropyl-6-nor-lysergic acid diethylamide, 6-nor-lysergic acid diethylamide, lysergic acid ethylamide, lysergic acid α-hydroxyethylamide, lysergic acid 2-butylamide, lysergic acid 3-pentylamide, lysergic acid methyl ester, lysergic acid 2,4-dimethylazetidide, lysergic acid piperidine, N,N-dimethyl-lysergamid, methylisopropyl-lysergamid, N,N-diallyl-lysergamide, N-pyrrolidyl-lysergamide, N-morpholinyl-lysergamide, 1-methyl-lysergic acid butanolamide, lysergic acid β-propanolamide, lysergic acid 1-butanolamide, mescaline, rofucaline, isomescaline, cyclopropylmescaline, thioisomescaline (2-TIM, 3-TIM, and 4-TIM), 4-desoxymescaline, dimescaline, escaline, metaescaline, thiometaescaline (3-TME, 4-TME, and 5-TME), trisescaline, thiotrisescaline (3-T-TRIS, and 4-T-TRIS), symbescaline, asymbescaline, thio Cymbescaline (3-TSB and 4-TSB), fenestrationscaline, allylescaline, methallylescaline, proscaline, isoproscaline, metaproscaline, thioproscaline, buscaline, thiobuscaline, α-ethylmescaline, ariadne, macromerine, MEPEA, TOM (2-TOM and 5-TOM), Bis-TOM, TOMSO (2-methoxy-4-methyl-5-methylsulfinylamphetamine), TOET (2-TOET and 5-TOET), BOH, BOM (13-methoxy-mescaline), beta-D, 4-D, DME, F-2, F-22, FLEA, MDPH, MDMP, propynyl, 2C series (2,5-dimethoxy, 4-substituted phenethylamine), βk-2C-B, 2C-B, 2CB-2EtO, 2CB-5EtO, 2CB-diEtO, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-C, 2C-D, 2CD-2EtO, 2CD-diEtO, 2CD-5EtO, 2C-E, 2C-EF, 2C-F, 2C-G (2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, and 2C-GN), 2C-H, 2C-I, 2CI-2EtO, 2C-iP, 2C-N, 2C-O, 2C-O-4, 2C-P, 2C-SE, 2C-T, 2CT-5EtO, 2C-T-2, 2CT-2-2EtO, 2CT-2-5EtO, 2CT-2-diEtO, 2C-T-4 (2C-T-4 and Ψ-2C-T-4), 2CT-4-2EtO, 2C-T-7, 2CT-7-2EtO, 2C-T-8, 2C-T-9, 2C-T-13, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-19, 2C-T-21, 2C-TFM, 2C-YN, BOB(I3-methoxy-2C-B), BOD(I3-methoxy- 2C-D), BOHD (I3-hydroxy-2C-D), HOT-2, HOT-7, HOT-17, indane derivatives including 2CB-Ind., benzocyclobutene derivatives including 2C-BCB (TCB-2), NBOMe derivatives (NBOMe-mescaline, 2C-H-NBOMe, 2C-C-NBOMe, 2CBCB-NBOMe, 2CBFly-NBOMe, 2C-B-NBOMe, 2C-I-NBOMe, 2C-TFM-NBOMe, 2C-D-NBOMe, 2C-G-NBOMe, 2C-E-NBOMe, 2C-P -NBOMe, 2C-iP-NBOMe, 2C-CN-NBOMe, 2C-N-NBOMe, 2C-T-NBOMe, 2C-T-4-NBOMe, 2C-T-7-NBOMe, and DMBMPP), NBOH derivatives (2C-C-NBOH, 2C-B-NBOH, 2C-I-NBOH, and 2C-CN-NBOH), NBMD derivatives (2C-I-NBMD), NBF derivatives (2C-C-NBF, 2C-B-NBF, and 2C-I-NBF), 3C series including 3C-E, 3C-P, 3C-DFE, and 3C-BZ (3,DOx series (2,5-dimethoxy and 4-substituted amphetamines), including DOAM, DOB, Meta-DOB, methyl-DOB, DOBU, DOC, DOEF, DOET, DOI, DOM, Ψ-DOM, DON, DOPR, SOiPR, DOT, Meta-DOT, Ortho-DOT, DOTFM, DMCPA, DMMDA, and DMMDA-2, 3,4-dimethyl-2,5-dimethoxyamphetamine, 4-methyl- 2,5-dimethoxymethamphetamine, 2,N-dimethyl-4,5-methylenedioxyamphetamine, dimethoxyamphetamine (2,4-DMA, 2,5-DMA, and 3,4-DMA), trimethoxyamphetamine (TMA-2, TMA-6), tetramethoxyamphetamine, Br-DragonFLY, TFMFly, 2-bromo-4,5-methylenedioxyamphetamine, 4-bromo-3,5-dimethoxyamphetamine, EEE, EEM, EME, EMM, EDMA, EIDA , Ethyl-J, Methyl-J, Ethyl-K, Methyl-K, IDNNA, Iris, MDAI, MDMAI, MDAT, MDMAT, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPK, MDPR, MEDA, MEM, Methyl-DMA, MMDA, MMDA-2, 5-Methyl-MDA, MEE, MME, MPM, DiFMDA, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB , 6-MAPDB, 6-MAPB, 6-EAPB, 5-EAPB, para-methoxyamphetamine, para-methoxymethamphetamine, 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, benzoxazine, efavirenz, 3,4-methylenedioxymethamphetamine (MDMA), MDA, 2,Substituted methylenedioxyphenethylamines (MDxx) including 3-MDA, 5-methyl-MDA, MMDA, MDEA, MBDB, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPM, MDPR, BDB, MMDA-2, DiFMDA, EIDA, ethyl-K, lophophine, substituted amphetamines, EDMA (N-ethyl-3,4-methylenedioxyamphetamine), para-methoxyamphetamine (PMA), para-methoxymethamphetamine Amphetamine (PMMA), 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, substituted cathinones, methylone, ethylone, eutrone, butylone, pentylone, 4-ethylmethcathinone, 3-methylmethcathinone, substituted benzofurans, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB, 6-MAPDB, 6-MAPB, 5-EAPB, 6-EAPB, 5-MBPB, MDAT, MDMAT, 6-CAT, tetralinylaminopropane, trifluoromethylaminoindan, ethyltrifluoromethylaminoindan, 5-iodo-2-aminoindan, MMAI, MDAI, MDMAI, indanylaminopropane, naphthylaminopropane, 4-chlorophenylisobutylamine, 4-methylphenylisobutylamine, Ariadne, α-methyltryptamine, 5-MeO-αMT, α-ethyltryptamine, 4-Me-αET, 7-Me-αET, 5-MeO-αET, 5-MeO-MiPT, Δ 9-THC, CBD, CBN, THCV, (C6)-CP 47,497, (C9)-CP 47,497, 1-butyl-3-(2-methoxybenzoyl)indole, 1-butyl-3-(4-methoxybenzoyl)indole, 1-pentyl-3-(2-methoxybenzoyl)indole, 2-isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene, 4-HTMPIPO, 4-nonylphenylboronic acid, 5Br-UR-144, 5Cl-APINACA, 5Cl-UR-144, 5F-3- Pyridinoylindole, 5F-AB-FUPPYCA, 5F-ADB-PINACA, 5F-ADBICA, 5F-ADB, 5F-AMB, 5F-APINACA, 5F-CUMYL-PINACA, 5F-EMB-PINA CA, 5F-NNE1, 5F-PB-22, 5F-PCN, 5F-PY-PICA, 5F-PY-PINACA, 5F-SDB-006, HHC, A-796,260, A-834,735, A-836,339, A-955,840, A-40174, A-41988, A-42574, AB-001, AB-CHFUPYCA, AB-CHMFUPPYCA, AB-CHMINACA, AB-FUBICA, AB-FUBINACA 2-Fluorobenzyl Isomer, AB-FUBINACA, AB-PICA, AB-PINACA, Abnormal Cannabidiol, ADAMANTYL-THPINACA, ADB-CHMINACA, ADB-FUBICA, ADB-FUBINACA, ADB-PINACA, ADBICA, ADS B-FU B-187, Azulemic acid, AM-087, AM-411, AM-630, AM-679, AM-694, AM-855, AM-883, AM-905, AM-906, AM-919, AM-926, AM -938, AM-1220, AM-1221, AM-1235, AM-1241, AM-1248, AM-1346, AM-1387, AM-1714, AM-2201, AM-2232, AM-2233, AM-2389, AM-4030, AM-4113, AM-6527, AM-6545, AM-251, AM-281, AM-404, AMB-CHMINACA, AMB-FUBINACA, AMG-1, AMG-3, AMG-36, AMG-41, APICA, APINACA, APP-FUBINACA, Arachidonoyl Serotonin, ACEA, ACPA, Arvanil, AZ-11713908, BAY 38-7271, BAY 59-3074, BIM-018, Biochanin A, BML-190, Navidrox (Cambisol), cannabicyclohexanol, cannabipiperidiethanone, CAY-10401, CAY-10429, CAY-10508, CB-13, CB-25, CB-52, CB-86, CB-86, CBS-0550, CP47,497, CP55,244, CP55,940, cumyl-5f-pica, cumyl-bica, cumyl-pica, cumyl-pinaca, cumyl-thpinaca, dexanabinol, dimethylheptylpyran, drinabant, dronabinol, EAM-2201, emb-fubinaca, fab-144, fdu-nne1, fdu-pb-22, fub-144, fub-apinaca, fub-jwh-018, fub-pb-22, fubimina, genistein, gw-405,833, gw-842,166x, hemopressin, hv-210, hv-243, hv-308, hv-320, hv-331, hv-336, hv-345, hv-910, ibipinabant, ibid., jnj. 1661010, JNJ 1661010, JTE-907, JTE 7-31, JWH-007, JWH-015, JWH-018, JWH-019, JWH-030, JWH-051, JWH-073, JWH-081, JWH-098, JWH-116, JWH-122, JWH-133, JWH-139, JWH-14 7, JWH-149, JWH-161, JWH-164, JWH-167, JWH-175, JWH-176, JWH-182, JWH-184, JWH-185, JWH-192, JWH-193, JWH-194, JWH-195, JWH-196, J WH-197, JWH-198, JWH-199, JWH-200, JWH-203, JWH-210, JWH-229, JWH-249, JWH-250, JWH-251, JWH-302, JWH-307, JWH-359, JWH-369, JWH-370, JWH-398, JWH-424, JZL184, JZL195, kaempferol, KM-233, L-759,633, L-759,656, LASSBio-881, LBP-1, Leelamin, Levonantradol, LH-21, LY-320135, LY-2183240, NAM-2201, MDM-2201, MDA-7, MDA-19, MDA-77, MDMB-CHMICA, MDMB-CHMINACA, MDMB-FUBINACA, menabitan, MEPIRAPIM, methananandamide, MJ-15, MK-9470, MMB-2201, MN-18, MN-25, nabazenil, nabilone, nabitan, navoctate, NESS-0327, NESS-040C5, NIDA-41020, NM-2201, NMP-7, NNE1, nonavine O-224, O-581, O-585, O-606, O-689, O-774, O-806, O-823, O-889, O-1057, O -1125, O-1184, O-1191, O-1238, O-1248, O-1269, O-1270, O-1376, O-1399, O-1422, O-16 01, O-1602, O-1624, O-1656, O-1657, O-1660, O-1812, O-1860, O-1861, O-1871, O-1918, O -2048, O-2050, O-2093, O-2113, O-2220, O-2365, O-2372, O-2373, O-2383, O-2426, O-2484, O-2545, O-2654, O-2694, O-2715, O-2716, O-3223, O-3226, Oleoylethanolamide, Olvanil, Org 27569, Org 27759, Org 2831, Org 28611, Org 29647, Otenabant, Palmitoylethanolamide, Parahexyl, PF-03550096, PF-04457845, PF-622, PF-750, PF-3845, PF-514273, PHOP, PipISB, Pirunavine, Pravadrine, Pregnenolone, PSB-SB-487, PSB-SB-1202, PTI-1, PTI-2, PX-1, PX-2, PX-3, QUCHIC, QUPIC, RCS-4, RCS-8, Rimonabant, Lozonabant, RTI-371, S-444,823, SDB-006, SER-601, SPA-229, SR-144528, STS-135, Sulinabant, Taranabant, Tedarinab, THC-O-acetate, THC-O-phosphate, THJ-018, THJ-2201, Tinabinol, TM-38837, UR-144, URB-447, URB-447, URB-597, URB-602, URB-754, VCHSR, VDM-11, VSN-16, WIN 54,461, WIN 55,212-2, WIN 56,098, XLR-11, yangonine, harmaline, harmala alkaloids, other beta-carbolines, active ingredients of ayahuasca, salvinorin A, salvinorin B methoxymethyl ether, salvinorin B ethoxymethyl ether, piperazine, pFPP, TFMPP, myristicin, elemicin, cryogenin (vertine), atropine, scopolamine, hyoscyamine, ibotenic acid, muscimol, TiHKAL, 2-Me-D ET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-EPT, 4-HO-McPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPMI, 4-HO-MPT, 4-HO-αMT, 4 -Me-αMT, 4-MeO-MiPT, 4-PrO-DMT, 4,5-MDO-DiPT, 4,5-MDO-DMT, 5-ethoxy-αMT, 5-fluoro-AET, 5-fluoro-DET, 5-fluoro-DMT, 5 -Fluoro-EPT, 5-Fluoro-MET, 5-MeO-AET, 5-MeO-αMT, 5-MeO-DALT, 5-MeO-DET, 5-MeO-DPT, 5-MeO-EiPT, 5-MeO-MALT, 5-Me O-MiPT, 5-MeO-MPMI, 5-MeO-pyr-T, 5-MeS-DMT, 5-MeO-2-TMT, 5-TFM-DMT, 5-TFMO-DMT, 5,6-MDO-DiPT, 5,6-MDO-DMT, 5 ,6-MDO-MiPT, 5,6-MeO-MiPT, 5,N,N-TMT, 5F-MPMI, 6-fluoro-DET, 6-fluoro-DMT, 6-MeO-THH, 7-chloro-AMT, 7-F-5-MeO-MET, 4-acetoxy-DET, 4-acetoxy-DiPT, 4-acetoxy-MET, 4-acetoxy-MiPT, O-acetylbufotenin, O-acetylpsilocin, aeruginacin, alpha,N-DMT, alpha,N,O-TMS, baeocystin, 5-bromo-DMT, bufotenin, 5-chloro-αMT, DALT, dibutyltryptamine, diethyltryptamine, diisopropyltryptamine, 5,N-dimethyl-N-isopropyltryptamine, dimethyltryptamine, N,N-dimethyltryptamine, dipropyltryptamine, 2,α-dimethyltryptamine, ethosybin, ethylisopropyltryptamine, α-ethyltryptamine, 5-fluoro-AMT, 4-fluoro-5-methoxy-DMT, FT-104, 5-MeO-DMT, 5-me The active ingredient is selected from the group consisting of thoxy-N,N-diisopropyltryptamine, 4-methyl-α-ethyltryptamine, N-methyl-N-ethyltryptamine, methylbutyltryptamine, methylisopropyltryptamine, alpha-methylserotonin, alpha-methyltryptamine, N-methyltryptamine, MPMI, norbeocystine, propylisopropyltryptamine, 2,N,N-TMT, A,N,N-trimethyltryptamine, ketamine, esketamine, arketamine, mitragynine, yohimbine, and combinations thereof.

[0020] In some embodiments, the serotonergic hallucinogen is tryptamine or ergoline. In some embodiments, the serotonergic hallucinogen comprises tryptamine, a derivative or a salt thereof. In some embodiments, the serotonergic hallucinogen comprises ergoline, a derivative or a salt thereof. In some embodiments, the serotonergic hallucinogen is psilocybin, a derivative or a salt thereof.

[0021] In some embodiments, the PDE9 inhibitor is selected from the group consisting of aminophylline, pentoxifylline, theobromine, paraxanthine, PF-04447913, PF-04447943, PF-04447953, BAY 73-6691, E 2027, CRD 773, BI 409306, CRD 740, TT 00920, BAY 7081, FRM 16606, HUC1-288, WYQ-C36D, and any combination thereof. In some embodiments, the PDE9 inhibitor is PF-04447943, a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

[0022]

[0022] Provided herein is a kit comprising the pharmaceutical composition described herein, the kit further comprising an applicator and instructions for its use.

[0023] Further aspects and advantages of the present disclosure will become readily apparent to those skilled in the art upon reference to the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be understood by those skilled in the art, the present disclosure is applicable to various other embodiments, and its details are capable of various changes in obvious respects without departing from the scope of the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative and not restrictive.

[0023] Incorporation by Reference

[0024] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference.

[0024]

[0025] The novel features of the present disclosure are set forth with distinctness in the following claims. For a fuller understanding of the features and advantages of the present disclosure, reference is made to the following detailed description and accompanying drawings (hereinafter referred to as "figures" or "drawings") that set forth illustrative embodiments, in which the principles of the present disclosure are utilized. [Brief explanation of the drawings]

[0025] [Figure 1]

[0026] FIG. 1 shows the dose-dependent suppression of psilocybin-induced head twitch response (HTR) by PDE9 inhibitors. [Figure 2]

[0027] Figure 2 shows psilocybin dose-dependent suppression of HTR by PDE9 inhibitors. DETAILED DESCRIPTION OF THE INVENTION

[0026] definition

[0028] Unless otherwise defined herein, all technical and scientific terms used herein shall have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In the practice or testing of this disclosure, any methods and materials similar or equivalent to those described herein can be used, but illustrative exemplary methods and materials are described below. Each of the following terms is used herein with the meaning defined in this section.

[0027]

[0029] Generally, the nomenclature used herein and the laboratory procedures in molecular biology, pharmacology and organic chemistry are those well known and commonly employed by those skilled in the art.

[0030] Standard techniques are used for biochemical and biological manipulations. These techniques and procedures are generally performed according to conventional methods well known in the art and described in references such as Sambrook & Russell, 2012, Molecular Cloning, A Laboratory Approach, Cold Spring Harbor Press, Cold Spring Harbor, NY, and Ausubel et al., 2002, Current Protocols in Molecular Biology, John Wiley & Sons, NY). These references are cited throughout this specification as appropriate.

[0028]

[0031] As used herein, "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0029]

[0032] Additionally, in this specification, the term "about" when used in reference to a measurable value such as an amount, length of time, etc., is meant to encompass variations from the specified value (±20% or ±10%, more preferably ±5%, even more preferably ±1%, and even more preferably ±0.1%) that are appropriate for carrying out the disclosed methods.

[0030]

[0033] The word "exemplary," as used herein, means serving as an example, instance, or illustration. Any embodiment described herein as "exemplary" is not to be construed as preferred or advantageous over other embodiments.

[0031]

[0034] The terms "identifying," "measuring," "assessing," "determining," "assay," and "analysis" are often used interchangeably herein to refer to a form of measurement. The group includes determining whether an element is present or not (e.g., detecting). These terms include quantitative, qualitative, or quantitative and qualitative determinations. The assessment can be a relative assessment or an absolute assessment. "Detecting the presence or absence of" can include identifying whether the substance is present or not, as well as the amount of it present, depending on the context.

[0032]

[0035] A disease or disorder is considered to be "alleviated" if the severity or frequency of at least one sign or symptom of the disease or disorder experienced by the patient is reduced.

[0036] "MDD" refers to major depressive disorder. "OCD" refers to obsessive-compulsive disorder. "PTSD" refers to post-traumatic stress disorder.

[0033]

[0037] An "effective amount" or "therapeutically effective amount" of a compound or composition refers to the amount of the compound or composition sufficient to provide a beneficial effect, e.g., a therapeutic effect, such as treatment of a particular disease or disorder, when administered to a subject. An "effective amount" of a delivery vehicle refers to an amount sufficient to effectively bind or deliver a compound or composition.

[0034]

[0038] A "therapeutic effect" can include reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system.

[0039] As used herein, the term "inhibit" means to reduce by a measurable amount the expression, stability, function, or activity of a molecule, reaction, interaction, gene, mRNA, and / or protein. Inhibitors are compounds that bind to, partially or completely block, reduce, prevent, delay activation, inactivate, desensitize, or downregulate the stability, expression, function, or activity of a protein, gene, or mRNA, for example, and include, for example, antagonists.

[0035]

[0040] "Naturally occurring" as applied to an object means that the object can be found in nature. For example, a polypeptide or polynucleotide sequence present in an organism (such as a virus) that can be isolated from a natural source and has not been modified by man is a naturally occurring sequence.

[0036]

[0041] As used herein, the terms "subject," "individual," or "patient" are often used interchangeably. "Subject" refers to a biological entity containing expressed genetic material. The biological entity may be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject may be tissues, cells, and their progeny of the organism, obtained in vivo or cultured in vitro. The subject may be a mammal. The mammal may be a human. The subject may have been diagnosed with or be suspected of being at high risk for a disease. In some embodiments, the subject may not necessarily have been diagnosed with or be suspected of being at high risk for the disease.

[0037]

[0042] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound or composition useful within the present disclosure into or to a patient so that it can perform its intended function. Typically, such a component is carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation containing a compound or composition useful in the present disclosure and not harmful to the patient. Examples of materials that can function as pharmaceutically acceptable carriers include the following: Sugars (e.g., lactose, glucose, sucrose), starches (e.g., corn starch, potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter, suppository wax), fats and oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil), glycols (e.g., propylene glycol), polyols (e.g., glycerin, sorbitol, mannitol, polyethylene glycol), esters (e.g., ethyl oleate, ethyl laurate), agar, buffers (e.g., magnesium hydroxide, aluminum hydroxide), surfactants, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffers, polyesters, polycarbonates, polyanhydrides, and other non-toxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" includes all coatings, antibacterial agents, antifungal agents, absorption delaying agents, and similar materials that are compatible with the activity of the compounds or compositions useful in the present disclosure and are physiologically acceptable to the patient. Additional active compounds may also be incorporated into the composition. Furthermore, "pharmaceutically acceptable carriers" can include pharmaceutically acceptable salts of the compounds useful in the present disclosure.Other additional ingredients that may be included in pharmaceutical compositions used in the practice of the present disclosure are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0038]

[0043] As used herein, "pharmaceutically acceptable salts" or "therapeutically acceptable salts" refer to salts of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids or bases, organic acids or bases, solvates, hydrates or clathrates thereof.

[0039]

[0044] As used herein, the terms "polypeptide," "protein," and "peptide" are used interchangeably and refer to polymers of amino acid residues, related naturally occurring structural variants, and synthetic non-natural analogues, joined through peptide bonds. Synthetic polypeptides can be synthesized, for example, using an automated polypeptide synthesizer.

[0040]

[0045] A "therapeutic" treatment refers to a treatment administered to a subject who exhibits symptoms of a pathological condition with the intent of reducing or eliminating those symptoms.

[0046] As used herein, "treating a disease or disorder" means reducing the frequency and / or intensity with which a patient experiences symptoms of the disease or disorder. The terms "disease" and "disorder" are used interchangeably herein. "Treatment" includes prophylaxis and / or therapy. Thus, the compositions and methods of the present disclosure are not limited to therapeutic applications, but can also be used for prophylactic purposes. Thus, "treatment" or "treating" a condition, disorder, or disease includes each of the following aspects: (i) preventing or delaying the onset of symptoms in a subject who may be suffering from or predisposed to the condition, disorder, or disease but who has not yet exhibited clinical or subclinical symptoms of the condition, disorder, or disease; (ii) inhibiting the condition, disorder, or disease, i.e., arresting or reducing the progression of the disease or the development of at least one clinical or subclinical symptom; or (iii) palliating the condition, disorder, or disease, i.e., reversing the condition, disorder, or disease, or at least one of its clinical or subclinical symptoms.

[0041]

[0047] Ranges: Throughout this specification, various aspects of the present disclosure may be presented in a range format. Descriptions in range format are merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range shall be deemed to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, description of a range "from 1 to 6" shall be deemed to have specifically disclosed subranges such as "1 to 3," "1 to 4," "1 to 5," "2 to 4," "2 to 6," "3 to 6," etc., as well as individual numerical values ​​within that range, e.g., "1," "2," "2.7," "3," "4," "5," "5.3," "6," etc. This concept applies regardless of the breadth of the range.

[0042]

[0048] As used herein, the terms "hallucinogen," "hallucinogen," or "psychedelic drug" refer to any of several pharmacological agents that, upon administration to humans, produce acute and dramatic alterations in sensation and consciousness. The term "serotonergic hallucinogen" refers to a hallucinogen that acts at least in part by binding to serotonin receptors, particularly the 5-HT2A serotonin receptor. Non-limiting examples of serotonergic hallucinogens include 5-MeO-DMT and psilocybin.

[0043]

[0049] As used herein, the term "NMDA" refers to N-methyl-D-aspartic acid.

[0050] As used herein, the term "NMDAR" or "NMDA-R" refers to NMDA receptor. As used herein, the terms "patient," "subject," "individual," and the like are used interchangeably and refer to any animal or cell thereof, in vitro or in situ, to which the methods described herein can be applied. In certain non-limiting embodiments, the patient, subject, or individual is a human.

[0044]

[0051] As used herein, "serotonin," "5-hydroxytryptamine," and "5-HT" are synonymous and used interchangeably and refer to the 5-hydroxytryptamine molecule, which, among other characteristics, is the primary regulatory neurotransmitter in the brain.

[0045]

[0052] As used herein, "5-HT receptor" or "5-HTR" refers to any of several proteins in the brain to which serotonin (5-HT) binds and exerts a regulatory effect on neurons, and the corresponding genes encoding these proteins. 5-HT receptors can be further specified, for example, as "5-HT1A" for serotonin type 1A receptor, "5-HT1B" for serotonin type 1B receptor, or "5-HT2A" for serotonin type 2A receptor. The 5-HT2A receptor is believed to play a role in the action of serotonergic hallucinogens.

[0046]

[0053] As used herein, "LSD" or "lysergic acid diamide" are synonymous and interchangeable and typically refer to the hallucinogen lysergic acid diamide. "DMT" or "dimethyltryptamine" are synonymous and interchangeable and typically refer to N,N-dimethyltryptamine, a relatively short-acting serotonergic hallucinogen. "5-MeO-DMT" or "5-methoxydimethyltryptamine" are synonymous and interchangeable and typically refer to the hallucinogen 5-methoxy-N,N-dimethyltryptamine, a relatively short-acting serotonergic hallucinogen.

[0047]

[0054] As used herein, "RAAD" refers to rapid acting antidepressants.

[0055] As used herein, "cyclic adenosine monophosphate," "cyclic AMP," and "cAMP" are synonymous and used interchangeably and refer to cyclic adenosine monophosphate, a small molecule often used to mediate signaling processes in nerve cells and other cells in the body. As used herein, "cyclic guanine monophosphate," "cyclic GMP," and "cGMP" are synonymous and used interchangeably and refer to cyclic guanine monophosphate, another small molecule often used to mediate signaling processes in nerve cells and other cells in the body.

[0048]

[0056] As used herein, "phosphodiesterase" or "PDE," which are synonymous and used interchangeably, refer to any of several proteins whose primary function is to modulate signaling processes in neurons or other cells in the body by breaking down cAMP and / or cGMP. These may be further identified as "phosphodiesterase type 1" or "PDE1," "phosphodiesterase 1A" or "PDE1A," "phosphodiesterase type 9" or "PDE9," or "phosphodiesterase type 9A" or "PDE9A" to indicate the specific subtype of phosphodiesterase protein or the genes that encode them.

[0049] Combination therapy

[0057] Provided herein is the use of serotonergic hallucinogens as RAAD.Non-limiting examples of serotonergic hallucinogens include psilocybin, mescaline, lysergic acid diamide (LSD), dimethyltryptamine (DMT), 3,4-methylenedioxy-N-methylamphetamine (MDMA) and 5-methoxydimethyltryptamine (5-MeO-DMT).In some cases, these serotonergic hallucinogens act as RAAD and may have beneficial effects on other neuropsychiatric disorders, such as (non-limiting examples) PTSD, OCD and addictive disorders.In some cases, these serotonergic hallucinogens cause profound changes in perception, thinking and emotion (" hallucinogenic effect"), and last much longer than ketamine.

[0050]

[0058] Inhibition of type 9 phosphodiesterase (PDE9) can reduce certain markers of the hallucinogenic effects of serotonergic hallucinogens in animal models.In some embodiments of the present disclosure, inhibition of PDE-9 blocks the hallucinogenic effects of these drugs without reducing their therapeutic effects.In certain embodiments, the PDE9 inhibitor reduces the undesirable hallucinogenic effects of the serotonergic hallucinogens, making them suitable for widespread use.In other embodiments, the PDE9 inhibitor prolongs the clinical effect of the serotonergic hallucinogens.In other embodiments, the phosphodiesterase inhibitor reduces the abuse liability of the serotonergic hallucinogens.

[0051]

[0059] The various studies presented herein (e.g., Example 1, Figures 1 and 2) reveal multiple mechanisms of action by which PDE inhibition alleviates the undesirable side effects of RAADs and exhibits synergistic and beneficial effects with respect to behavioral and neurophysiological effects. Without wishing to be bound by any particular theory, the ability to alleviate the undesirable side effects associated with serotonergic hallucinogen treatment without compromising or even enhancing some of the beneficial effects for conditions such as MDD, PTSD, and OCD suggests that combined use of PDE9 inhibition may improve the tolerability of the treatment, allow for administration with reduced oversight and monitoring, reduce the abuse potential of drugs where abuse potential is a limiting factor, and potentially allow for less frequent administration, thereby reducing costs, expanding the number of treatable patients, and reducing toxicity.

[0052] PDE9 inhibitors

[0060] Any PDE9 inhibitor known in the art is contemplated in this application.

[0053]

[0061] In some examples, non-limiting examples of PDE9 inhibitors include AKP-002 (ASP-4901), CRD-733, BAY-73-6691, osoresnontrine (BI-409306), irsenontrine (E-2027), tobinontrine (IMR-687), TT00920, and stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0054]

[0062] In some instances, as disclosed in WO2020 / 076752, examples of PDE9 inhibitors include, but are not limited to, the following compounds: 1-{[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetyl}-pyrrolidine-2-carboxylic acid; 1-{[2-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-acetyl}-pyrrolidine-2-carboxylic acid; Roridine-2(S)-carboxylic acid 3-isopropyl-5-[2-(2-oxo-2-piperazin-1-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;1-Cyclopentyl-6-[2-(2-oxo-2-piperazin-1-yl-ethoxy)-benzyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one 3-Isopropyl-5-[2-(2-morpholin-4-yl-2-oxo-ethoxy)-benzyl]-1,6-dihydro-pyrazolo [4,3-d]pyrimidin-7-one;3-Isopropyl-5-[2-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;5-{2-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethoxy]-benzyl}-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;N,N-Diethyl-2-[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[ 4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetamide;1-{[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetyl}-pyrrolidine-2-carboxylic acid methyl ester;4-{[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester;N-(2-Dimethylamino-ethyl)-2-[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetamide;1-{[2-(1-Cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-acetyl}-pyrrolidine-2-carboxylic acid methyl ester;4-{[2-(1-Cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl]-phenoxy]-acetyl}-pyrrolidine-2-carboxylic acid methyl ester )-phenoxy]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester;1-Cyclopentyl-6-[2-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Cyclopentyl-6-[2-(2-morpholin-4-yl-2-oxo-ethoxy)-benzyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;2-[2-(1-Cyclopentyl-4-oxo-4.5-dihydro-1H-pyrazolo[3,4-d]pyrimidine -6-ylmethyl)-phenoxy]-N-(2-dimethylamino-ethyl)-acetamide;1-Cyclopentyl-6-{2-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethoxy]-benzyl}-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;2-[2-(1-Cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-N,N-diethyl-acetamide;[2-(3-Isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[ 4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetic acid;[2-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-acetic acid;3-Isopropyl-5-[2-(5-chloro-2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;3-Isopropyl-5-[2-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;3-Isopropyl-5-[2-(2-morpholin-4-yl-ethoxy)-cyclohexylmethyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;5-[5-fluoro-2-(2-morpholin-4-yl-ethoxy)-benzyl]-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;3-Cyclopentyl-5-[5-fluoro-2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;3-Isopropyl-5-[ 2-(2-morpholin-4-yl-ethoxy-)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;9-(1,2-dimethyl-propyl)-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one;2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-9-(tetrahydro-furan-3-yl)-1,9-dihydro-purin-6-one;5-[2-(2-diethylamino-ethoxy)-benzyl]-3-isopropyl-1,6-dihydro-pyrazolo [4,3-d]pyrimidin-7-one;3-cyclopentyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;3-cyclobutyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[-4,3-d]pyrimidin-7-one;9-(1(R),2-dimethylpropyl)-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one;9-(2-methyl-butyl)-2-[ 2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one;9-cyclopentyl-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one;5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-3-pyridin-3-yl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;9-(1,2-dimethyl-propyl)-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one;9-Isopropyl-2-[2-(2-morpholin-4-yl-ethoxy)benzyl]-1,9-dihydro-purin-6-one;2-[2-(2-morpholin-4-yl-ethoxy)benzyl]-9-(tetrahydro-furan-2-ylmethyl)-1,9-dihydro-purin-6-one;9-(1-Isopropyl-2-methyl-propyl)-2-[-2-(2-morpholin-4-yl-ethoxy)benzyl]-1,9-dihydro-purin-6-one;9-(1-Ethyl-propyl)-2-[2-(2-morpholin-4-yl-ethoxy)benzyl]-1,9-dihydro-purin-6-one 9-Cyclopentyl-8-methyl-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one;3-Cyclopentyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one;1-Cyclopentyl-6-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,5-dihydro-pyrazolo-[3,4-d]pyrimidin-7-one;1-Cyclopentyl-6-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,5-dihydro-pyrazolo-[3,4-d]pyrimidin-7-one; 9-Cyclopentyl-2-[2-(3-morpholin-4-yl-propoxy)-benzyl]-1,9-dihydro-purin-6-one;N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-2-pyrrolidin-1-yl-acetamide;N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-cyclohex 1-{[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-acetamide; 1-{[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl-carbamoyl]-methyl}-pyrrolidine-2(S)-carboxylic acid methyl ester;2-Cyclobutylamino-N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[-4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-acetamide; or 2-cyclopropylamino-N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-acetamide; IMR-687; (a potent inhibitor of PDE9A); BAY73-6691; PF-04447943; PF-4181366; and stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, and any combination thereof.

[0055]

[0063] In some examples, as disclosed in US9573947 and WO2014163147, the PDE9 inhibitor may include one or more salts of the pyrazoloquinoline derivatives shown below.

[0056] [1] A salt of (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, malonic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; [2](S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one monomaleate; [3](S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one monobenzenesulfonate; [4] Crystals of the salt described in [1]; [5] A crystal of (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one monomaleate, which has a diffraction peak at a diffraction angle of 10.1° (2θ±0.2°) in powder X-ray diffraction; [6] A crystal of (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one monobenzenesulfonate, which has a diffraction peak at a diffraction angle of 9.9° (2θ±0.2°) in powder X-ray diffraction.

[0057]

[0064] In some instances, as disclosed in WO2017 / 070293, the PDE9 inhibitor is

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] or a pharmaceutically acceptable salt thereof.

[0065] In some examples, the PDE9 inhibitor is a compound represented by formula (I), as disclosed in WO2013051639 and US8563565.

[0065] [ka]

[0066] During the ceremony, R 1 is a hydrogen atom; R 2 is a group having an aromatic ring selected from the group consisting of a phenyl group, a pyridinyl group, and a pyrimidinyl group, wherein two atoms on the aromatic ring adjacent to the carbon atom bonded to the pyrazolo[4,3-c]quinoline ring each independently have a substituent selected from Group A1, and other atoms on the aromatic ring each independently may have a substituent selected from Group B1; R 3 is a hydrogen atom or a fluorine atom; R 4 is a hydrogen atom; R 5 is an oxepanyl group, a dioxepanyl group, a tetrahydropyranyl group, or a tetrahydrofuranyl group optionally bearing a methoxy group; R 6 The group is a hydrogen atom; Group A1 is a halogen atom, C optionally having 1 to 3 halogen atoms 1~6 Alkyl groups, and C 1~6 consisting of alkoxy groups; Group B1 is a halogen atom, a cyano group, a C group optionally having 1 to 3 halogen atoms 1~6 Alkyl group, C 1~6 Alkoxy-C 1~6 alkyl group, optionally containing 1 to 3 halogen atoms 1~6 an alkoxy group and a tetrahydropyranyl group; However, R 2 When the group is a 3-pyridinyl group, the substituent at the 4-position is a halogen atom or a C 1 -C 2 -C 3 -C 4 -C 2 -C 3 ... 1~6 It is an alkyl group.

[0067] In some embodiments, the PDE9 inhibitor is:

[0068] [ka]

[0069] In some embodiments, the PDE9 inhibitor is selected from the group consisting of:

[0070] [ka]

[0071] is. In some examples, as disclosed in CN106977518, the PDE9 inhibitor is an N-substituted pyrazolo[3,4-d]pyrimidinone compound having the structure of formula (II):

[0072] [ka]

[0073] wherein R is a cyclic or acyclic aliphatic alkyl group, a heterocyclic group, an acyl group, a hydroxy group, or a mercapto group; R is methoxy, halogen, trifluoromethyl, ethoxyacetyl, cyano, nitro, N,N-dimethyl, chloromethyl, benzyloxy, substituted or unsubstituted amino, substituted guanidino, substituted or unsubstituted phosphate, substituted or unsubstituted sulfonic acid base, long chain aliphatic alkyl, long chain aliphatic amino; provided that when R is cyclopentyl, R is not substituted or unsubstituted amino.

[0074]

[0068] In some examples, as disclosed in WO2003037899, the PDE9 inhibitor is a crystalline form of the compound represented by formula (III).

[0075] [ka]

[0076] During the ceremony, R 1 is H or C 1~6 alkyl, and R 1 is N 1 or N 2 R 2 is C optionally substituted with hydroxy or alkoxy 1~6 alkyl; C optionally substituted with alkyl, hydroxy or alkoxy 3~7 Cycloalkyl; saturated 5- to 6-membered heterocycles optionally substituted with alkyl, hydroxy or alkoxy (preferably tetrahydrofuran, tetrahydrothiophene, pyrrolidine or piperidine); het 1 or Ar 1 and;R 3 Ar 2 ;C 1~6 C optionally substituted with alkyl 3~7 Cycloalkyl;OAr 2 ;SAr 2 ;NHC(O)C 1~6 alkyl;het 2 C optionally substituted with one or two groups independently selected from: xanthene; and naphthalene. 1~6 alkyl; where Ar 1 and Ar 2 are independently expressed by the formula:

[0077] [ka]

[0078] where R 4 , R 5 and R 6 is hydrogen, halo, phenoxy, phenyl, CF3, OCF 3、 R 7 , S.R. 7 and OR 7 are independently selected from R7 het 3 By or halo, CF3, OCF3, C 1~6 Alkyl, C 1~6 C optionally substituted by phenyl groups optionally substituted by 1, 2 or 3 groups independently selected from alkoxy 1~6 alkyl; or R 4 and R 5 may be joined to form a linkage of 3 or 4 atoms, said linkage optionally containing 1 or 2 heteroatoms independently selected from O, S, or N; 1 , het 2 and het 3 are 5-6 membered aromatic heterocycles which may be the same or different and contain 1, 2 or 3 heteroatoms independently selected from O, S and N, and said heterocycles are C 1~6 Alkyl, C 1~6 Alkoxy, halo, and halo and C 1~6 optionally substituted with 1, 2, or 3 substituents independently selected from phenyl optionally substituted with 1, 2, or 3 groups independently selected from alkyl; with the proviso that a) R 1 N 1 Binds to R 1 C 1~3 alkyl, and R 2 is propyl, R 3 Ar 1 b) R 1 N 1 Binds to R 1 C 1~6 alkyl, and R 2 is methyl, R 3 Ar 1 C replaced with 1~4 Not alkyl.

[0079] In some examples, as disclosed in WO2020187165 and US20220194934, the PDE9 inhibitor is a compound represented by formula (IV), i.e., a crystalline form of 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-two:

[0080] [ka]

[0081] The naphthalene-3-carbonitrile of crystalline form I is characterized by exhibiting characteristic peaks at 7.3°, 13.6°, 14.5°, 18.0°, 19.1°, 22.0° and 23.4° in the range of 2θ±0.2° in powder X-ray diffraction using Cu-Kα radiation.

[0082] In some instances, as disclosed in US Pat. No. 7,964,607, the PDE9 inhibitor is a compound represented by formula (V):

[0083] [ka]

[0084] and pharmaceutically acceptable salts thereof, wherein: R is selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, halo, and (C1-C4) haloalkyl; R1 is selected from the group consisting of hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl, and cyclopropyl; R2 is selected from the group consisting of heteroaryl selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and ER5, wherein the heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4) alkyl, and (C1-C4) haloalkyl; R3 is selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, and (C1-C4) haloalkyl; E is selected from the group consisting of -CH2-, -CH2CH2-, -CH2CH2CH2- and -C(O)-; R5 is selected from the group consisting of (C3-C8)cycloalkyl, heterocycloalkyl, aryl, aryloxy, and heteroaryl, any of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3-C8)cycloalkyl, halo, cyano, phenyl, morpholinyl, (C1-C4)alkylamino, pyrazolyl, triazolyl, and imidazolyl.

[0085] In some embodiments, the PDE9 inhibitor is 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-pyrimidin-2-ylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzoyl-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[3-(trifluoromethyl)benzyl]pyrrolidin-3-yl}1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinolin-2-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinolin-4-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinoxalin-2-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyrimidin-5-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1,4-dimethylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-(3,4-trans)-4-methyl-1-[(2-methylpyridin-3-yl)methyl]pyrrolidin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinolin-8-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(6-methylpyridin-3-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-isopropylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-cyclopentyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3S,4S)-4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(2-phenylethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(6-methoxypyridin-3-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(3-methylpyridin-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-ethylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-cyclopropylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl]-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[(3,4-trans)-4-methyl-1-(quinolin-2-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[(3,4-trans)-4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[(3,4-trans)-4-methyl-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-(trifluoromethyl)pyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[(3S,4S)-4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[(3S,4S)-4-methyl-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3S,4S)-4-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-ethylpyrrolidin-3-yl]-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-benzyl-4-ethylpyrrolidin-3-yl]-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-(1-benzylpyrrolidin-3-yl)-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-(3S,4S)-1-[(6-methoxypyridin-3-yl)methyl]-4-methylpyrrolidin-3-yl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-4-ethyl-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl]-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3,4-trans)-4-ethyl-1-[(6-methoxypyridin-3-yl)methyl]pyrrolidin-3-yl}-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-4-ethyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3S,4S)-1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3S,4S)-4-methyl-1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3S,4S)-4-methyl-1-[(1-methyl-1H-benzimidazol-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-{(3S,4S)-4-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(cinnolin-3-ylmethyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(quinoxalin-6-ylmethyl)-4-(trifluoromethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-4-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3S,4S)-1-{[2-(dimethylamino)pyrimidin-4-yl]methyl}-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-cyclopropyl-1-[(5-methylpyrazin-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-cyclopropyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-cyclopropyl-1-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-ethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3,4-trans)-4-ethyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[(3S,4S)-4-methyl-1-(1,5-naphthyridin-4-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[(3S,4S)-4-methyl-1-(1,8-naphthyridin-4-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[3S,4S)-4-methyl-1-(quinolin-4-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-[(3S,4S)-4-methyl-1-(pyrido[2,3-b]pyrazin-8-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-{(3,4-trans)-1-[(6-methoxy-1,5-naphthyridin-4-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3,4-trans)-1-[(8-fluoroquinolin-2-yl)methyl]-4-methylpyrrolidin-3-yl}-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Isopropyl-6-{(v)-1-[(6-methoxyquinolin-4-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3.4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-cyclobutyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3,4-trans)-4-ethyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-1-[(6-methoxypyridin-3-yl)methyl]-4-methylpyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-4-methyl-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-4-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[(6-methylpyridin-3-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-}([6-(trifluoromethyl)pyridin-3-yl]methyl}pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-methylpyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclobutyl-6-{(3,4-trans)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(2,1,3-benzothiadiazol-5-ylmethyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-4-methyl-1-(quinoxalin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-4-methyl-1-(quinolin-4-ylmethyl)pyrrolidin-3-yl]-1-tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl]-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(3-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(35-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[4-(trifluoromethyl)benzyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-benzyl-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-benzyl-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 3-methyl-6-[(3S,4S)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 3-methyl-6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-1-[(6-methoxypyridin-3-yl)methyl]-4-methylpyrrolidin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[(6-methylpyridin-2-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(2-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[2-(trifluoromethyl)benzyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(2,4-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(4-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(2-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(3-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-methyl-1-[3-(trifluoromethyl)benzyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-1-(26-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-ethyl-1-[(5-methylpyrazin-2-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3S,4S)-4-ethyl-1-[(6-methoxypyridin-3-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-4-ethyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-4-ethyl-1-(quinoxalin-2-ylcarbonyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 2-({(3S,4S)-3-ethyl-4-[4-oxo-1-(tetrahydro-2H-pyran-4-yl)-45-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidin-1-yl}methyl)benzonitrile; 3-({(3S,4S)-3-ethyl-4-[4-oxo-1-(tetrahydro-2H-pyran-4-yl)-45-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidin-1-yl}methyl)benzonitrile; 4-({(3S,4S)-3-ethyl-4-[4-oxo-1-(tetrahydro-2H-pyran-4-yl)-45-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidin-1-yl}methyl)benzonitrile; 1-Cyclopentyl-6-(3,4-trans)-4-methyl-1-[3-(1H-pyrazol-1-yl)benzyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(2-methylpyridin-4-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-(2-chloro-6-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,3-dimethylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[2-(difluoromethoxy)benzyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-]pyrimidin-4-one 1-Cyclopentyl-6-{(3,4-trans)-1-[(2-ethoxypyridin-3-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[4-(1H-imidazol-1-yl)benzyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,5-dichlorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(4-methoxy-3-methylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,3-dihydro-1-benzofuran-7-ylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,3-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(5-fluoro-2-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2-fluoro-4-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3-fluoro-4-methylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(4-isopropyl-1,3-thiazol-2-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,3-difluoro-4-methylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-{[6-(1H-pyrazol-1-yl)pyridin-2-yl]methyl}pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(4-methylbenzyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(2-naphthylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(2-methoxypyridin-3-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2-ethoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(1H-1,2,4-triazol-1-yl)benzyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3-methoxy-4-methylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(1-naphthylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3-fluoro-4-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,5-dimethoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(5-methylisoxazol-3-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2-fluoro-6-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,4-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(4-fluoro-3-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-(2-chloro-4-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,4-dimethylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3,5-dimethoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3-ethoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-(4-chloro-2-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 3-{[(3,4-trans)-3-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpyrrolidin-1-yl]methyl}benzonitrile; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,5-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 2-{[(3,4-trans)-3-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpyrrolidin-1-yl]methyl}benzonitrile; 6-[(3,4-trans)-1-(3-chloro-4-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[4-(difluoromethoxy)benzyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(3-methylbenzyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3,4-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,5-dimethylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-(3-chloro-2-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,3-dichlorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(1,3-thiazol-2-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3-fluoro-2-methylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(2-ethylpyrimidin-5-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(4-isopropylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(4-methoxypyridin-3-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(isoxazol-5-ylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(4-ethoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-{[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]methyl}-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3,4-dimethoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(2-phenyl-1,3-oxazol-4-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(2-methylbenzyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2-isopropoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-(cinnolin-3-ylmethyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[3-(difluoromethoxy)benzyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(4-fluoro-3-methylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(1H-pyrazol-1-yl)benzyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3,5-dichlorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(4-isopropoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-{[2-(1-hydroxy-1-methylethyl)pyridin-4-yl]methyl}-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(mesitylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,6-dichlorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 4-{[(3,4-trans)-3-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpyrrolidin-1-yl]methyl}benzonitrile; 1-Cyclopentyl-6-[(3,4-trans)-1-(2-fluoro-5-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,6-dimethylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3,5-dimethylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3,4-dimethylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(1-methyl-1H-benzimidazol-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(3-phenylpropyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[2-(trifluoromethyl)benzyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(4,4,4-trifluorobutyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(cyclopentylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,4-dimethoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(morpholin-4-ylmethyl)benzyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-(2,1,3-benzothiadiazol-5-ylmethyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-{(3,4-trans)-1-[2-(benzyloxy)ethyl]-4-methylpyrrolidin-3-yl}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,6-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2-methoxybenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(3,5,6-trimethylpyrazin-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,4-dichlorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-4-methyl-1-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2-methoxy-5-methylbenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(2-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-(2-chlorobenzyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3,4-dichlorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 6-[(3,4-trans)-1-(2,1,3-benzothiadiazol-4-ylmethyl)-4-methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(2-propylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-1-[(1-ethyl-1H-pyrazol-5-yl)methyl]-4-methylpyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[2-(trifluoromethoxy)benzyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(trifluoromethyl)benzyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[(3,4-trans)-1-(3,5-difluorobenzyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; and 1-Cyclopentyl-6-[(3,4-trans)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ylmethyl)-4-methylpyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one and pharmaceutically acceptable salts thereof.

[0086] In some embodiments, the PDE9 inhibitor is 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0087] [ka]

[0088] is.

[0073] In some examples, as disclosed in CN108218874, the PDE9 inhibitor is a compound represented by formula (VI), or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof:

[0089] [ka]

[0090] During the ceremony, m is optionally selected from 0, 1, 2, 3, or 4; n is arbitrarily selected from 0, 1, or 2; X, Y are independently selected from C, CH and N; Q and W are each independently selected from C, CH, N, NH, S, and O; E is -(CH2) z arbitrarily selected from -, -O-, -S-, -NH-, and -N(CH3)-, where z is independently selected from 0, 1, and 2; R1 is hydrogen, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 Cycloalkyl, halogenated C 1~4 alkyl, —C linked by —(CH2)m′ where m′=1 or 2 3~6 independently selected from cycloalkyl; R2 and R3 are hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyloxy, halogenated C 1~6 Alkoxy, halogenated C 1~6 Alkyl, halogenated C 3~6 Cycloalkyl, C 2~8 Alkenyl, C 2~8 Alkyne group, amino C 1~6Alkyl, C 3~6 Cycloalkylamino, C 1~6 Alkylsulfonyl, 3-8 membered cycloalkylsulfonyl, C 1~6 Alkyl carbonyl, C 3~6 Cycloalkylcarbonyl, C 1~6 independently selected from alkylthio, 5-14 membered cycloalkyl linked by -(CH2)n'-, 5-14 membered aromatic ring linked by -(CH2)n'- where n'=0, 1 or 2, 5-10 membered heterocyclic base linked by -(CH2)n'- and containing 1-3 O atoms, S atoms and / or N atoms, 5-10 membered heterocyclic group linked by -(CH2)n'- and containing 1-3 O atoms, S atoms and / or N atoms, and heteroaryl having 1-3 O atoms, S atoms and / or N atoms, wherein the cycloalkyl, aromatic ring, heteroaryl ring and heterocyclyl may be optionally substituted by 1-3 R4; R4 is hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen atom, C 1~4 C linked by —(CH2)m′, where m′=1 or 2, alkyl, trifluoromethyl, methoxy, cyclopropyl, 3~6 independently selected from cycloalkyl; Ring A is selected from an optionally selected 5-10-membered cycloalkyl, a 5-10-membered aromatic ring, a 5-10-membered heterocycloalkyl containing 1-3 O atoms, S atoms and / or N atoms, or a 5-10-membered heteroaromatic ring containing 1-3 O atoms, S atoms and / or N atoms, and Ring A is optionally substituted with 1-3 R5, a ring-constituting S atom is optionally oxidized to S(O) or S(O)2, and a ring-constituting carbon atom is optionally oxidized to C(O); R is hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen atom, C 1~6 Alkyl, C 1~6 Alkoxy, methoxy, trifluoromethyl, cyclopropyl, -C linked by -(CH2)m' where m'=1 or 2 3~6 cycloalkyl.

[0091]

[0074] In some examples, as disclosed in US20220160696 and WO2020182076, the PDE9 inhibitor is a compound represented by formula (VII).

[0092] [ka]

[0093] wherein X, X, X, and X are independently selected from CR or N, and the N heteroatom is

[0094] [ka]

[0095] may be optionally oxidized to; R3, each occurrence, is hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 Amino, Halo C 1~6 Alkyl, HaloC 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6 alkyl)2 aminocarbonyl, 4- to 6-membered heterocyclylcarbonyl, and 5- to 6-membered heteroaryloxy; 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 Amino, Halo C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6 alkyl)2 aminocarbonyl, 4- to 6-membered heterocyclylcarbonyl and 5- to 6-membered heteroaryloxy are unsubstituted or substituted with hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, C 1~6 Alkylcarbonyloxy, C 3~6 Cycloalkyl, C 2~8 Alkynyl, HaloC 1~6 Alkyl, C 2~8 Alkenyl, HaloC 1~6 substituted with one or more groups independently selected from alkoxy, unsubstituted or optionally substituted 4- to 6-membered heterocyclyl, and unsubstituted or optionally substituted heteroaryl; The substituents in the above-mentioned 4- to 6-membered heterocyclyl optionally substituted with a substituent and the heteroaryl optionally substituted with a substituent are hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl and C 1~6 selected from alkoxy; L is a single bond and -NH-(CH2) t - (wherein t is 0, 1, 2, or 3); The A ring is a 3- to 12-membered heterocyclyl, aryl, 5- to 10-membered heteroaryl, 3- to 12-membered cycloalkyl, and 3- to 12-membered cycloalkenyl, wherein the heteroatoms of the 3- to 12-membered heterocyclyl are selected from one of O, S, and N, or any combination thereof, and the S atom is optionally oxidized to S(O) or S(O)2, the C atom is optionally oxidized to C(O), and the N heteroatom is

[0096] [ka]

[0097] optionally oxidized to the heteroatoms of the 5- to 10-membered heteroaryl are selected from one of O, S, and N, or any combination thereof; Each R1 is hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 Amino, Halo C 1~6 Alkyl, HaloC 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 independently selected from alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 Amino, Halo C 1~6 Alkyl, HaloC 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6Alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl are unsubstituted or substituted with hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino and C 1~6 substituted with a group selected from alkylsulfonylamino; m is 0, 1, 2 or 3; R2 is hydrogen, C 1~6 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and HaloC 1~6 alkyl.

[0098]

[0075] In some examples, as disclosed in CN108341819, the PDE9 inhibitor is a compound represented by formula (VIII) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof:

[0099] [ka]

[0100] During the ceremony, n is selected from 0, 1 or 2; X is selected from N or CR1; R1 is hydrogen, C 1~6 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 3~6 Naphthene-based, halogenated C 1~6 alkyl, —C linked by —(CH2)m′ where m′=1 or 2 3~6 independently selected from naphthenes; R2 is hydrogen, C 1~6 Alkyl, C1~6 Alkoxy, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 3~6 Naphthene-based oxy group, C 3~6 Cycloalkylamino, halogenated C 3~6 Naphthene, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 3~8 The first naphthene-based sulfoacyl group (C 3-8 First naphthenic base sulfur Acyl group), C 1~6 Alkyl sulfenyl, C 2~8 Alkenyl (C 3~6 ) Naphthene, C 2~8 Alkynyl (C 3~6 ) Naphthene, C 1~6 Alkyl carbonyl, C 3~6 Naphthene-based carbonyls, where n' = 0, 1, or 2 -(CH2) n’ -linked 3 to 14-membered naphthenic base, -(CH2) n’ 5-14 membered aromatic rings linked by -, -(CH2) n’ -linked 5- to 10-membered heterocyclic base, -(CH2) n’ independently selected from 5-10 membered heteroaryl groups linked by -, wherein the heterocyclic ring and the heteroaryl group contain 1-3 O, S and / or N atoms, wherein the ring-forming sulfur atoms in the heterocyclic ring and the heteroaryl group are optionally oxidized to S(O) or S(O)2, and any ring-forming carbon atom is optionally oxidized to C(O), and the alkyl ring, heterocyclic ring, aromatic ring and heteroaromatic ring are optionally substituted with 1-3 R5; If X is CR1 and R1 is hydrogen, then R2 is

[0101] [ka]

[0102] It should not be, R3 is hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen atom, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyloxy, halogenated C 1~6 Alkoxy, halogenated C 1~6 Alkyl, halogenated C 3~6 Cycloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, Amino C 1~6 Alkyl, C 3~6 Cycloalkylamino, C 1~6 Alkylsulfonyl, 3-8 membered cycloalkylsulfonyl, C 1~6 Alkyl carbonyl, C 3~6 Cycloalkylcarbonyl, C 1~6 independently selected from alkylthio, 3- to 14-membered cycloalkyl, 5- to 14-membered aromatic ring, 5- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl, wherein the heterocyclic group and the heteroaryl contain 1 to 3 O atoms, S atoms, and / or N atoms, and any ring-membering sulfur atom in the heterocyclic group and the heteroaryl is optionally oxidized to S(O) or S(O)2, and any ring-membering carbon atom is optionally oxidized to C(O), and the cycloalkyl, aromatic ring, heteroaryl ring, and heterocyclyl are optionally substituted with 1 to 3 R6; R4 is hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen atom, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyloxy, halogenated C 1~6 Alkoxy, halogenated C 1~6 Alkyl, halogenated C 3~6 Naphthene, C 2~6 Alkenyl, C 2~6 Alkynyl, Amino C 1~6 Alkyl, C 3~6 Cycloalkylamino, C 1~6 Alkylsulfonyl, 3-8 membered alkylsulfonyl, C 1~6 Alkylcarbonyl or C3~6 Naphthene-based carbonyl group, C 1~6 Alkyl sulfenyl group or n'=0, 1 or 2, -(CH2) n’ -linked 3- to 7-membered ring naphthenic group, -(CH2) n’ 5-6 membered aromatic rings connected by -, -(CH2) n’ -linked 5- to 7-membered heterocyclic base, -(CH2) n’ Independently selected from 5-6 membered heteroaryls linked by -, wherein the heterocycle and the heteroaryl contain 1-3 O atoms, S atoms and / or N atoms, the ring-membered S atoms in the heterocycle and the heteroaryl are optionally oxidized to S(O) or S(O)2, any ring-membered carbon atom is optionally oxidized to C(O), and the ring alkyl, aromatic ring, heteroaromatic ring and heterocycle are optionally substituted by 1-3 R7; R5 is hydrogen, hydroxy, amino, carboxyl, cyano, nitro, a halogen atom, trifluoromethyl, a methoxyl group, -(CH2) n’ -linked 3 to 14-membered naphthenic base, -(CH2) n’ 5-14 membered aromatic rings linked by -, -(CH2) n’ 5-10 membered heterocycles linked by -, -(CH2) n’ -, wherein the heterocycle and the heteroaryl contain 0-3 O, S and / or N atoms, and n'=0, 1 or 2; R6 and R7 are hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen atoms, trifluoromethyl, C 1~6 Alkyl, C 1~4 Alkoxy, C 1~6 Alkylsulfonyl, C 1~6 Alkyl Sulfonyl C 1~6 Alkyl, C 1~6 Alkyl Sulfonyl C 1~6 Alkoxy, aminosulfonylamino C 1~6 Alkyl, methoxyl, cyclopropyl, m'=1 or 2 -(CH2) m’ -C3~6 naphthenes.

[0103]

[0076] In some examples, as disclosed in US10858362, US11472810, and WO2016174188, the PDE9 inhibitor is a compound represented by formula (X), its tautomers, and pharmaceutically acceptable addition salts.

[0104] [ka]

[0105] During the ceremony, n is 0 or 1; q is 0 or 1; R1 is selected from the group consisting of benzyl, indanyl, indoline, and 5-membered heteroaryl; all of which are optionally substituted with substituents selected from the group consisting of halogen and C1-C3 alkyl; or R1 is selected from the group consisting of saturated monocyclic rings containing 4 to 6 carbon atoms and 1 to 2 nitrogen atoms; all of which are optionally substituted one or more times with one or more substituents selected from the group consisting of methyl, fluorine, and sulfonamido; or R1 is selected from the group consisting of lactams containing 4 to 6 carbon atoms; all of which may be substituted one or more times with one or more substituents selected from the group consisting of methyl and fluorine; or R1 is selected from the group consisting of bicyclic ethers such as 7-oxabicyclo[2.2.1]heptane; all of which are optionally substituted one or more times with one or more substituents selected from the group consisting of methyl and fluorine; or R1 is selected from the group consisting of straight-chain or branched C1-C8 alkyl, saturated monocyclic C3-C5 cycloalkyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; all of which are optionally substituted one or more times with one or more substituents selected from the group consisting of methyl, fluorine, hydroxy, cyano, or methoxy; or R1 is a straight or branched C1-C3 alkyl substituted with a substituent selected from phenyl and a 5-membered heteroaryl, said 5-membered heteroaryl optionally being substituted with one or more C1-C3 alkyls; or R1 is selected from the group consisting of morpholine, tetrahydrofuran-3-amine, hexahydro-2H-furo[3,2-b]pyrrole, and morpholine; all of which are optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl; R2 is selected from the group consisting of hydrogen, straight or branched C1-C8 alkyl, phenyl, saturated monocyclic C3-C8 cycloalkyl, oxetanyl, benzo[d][1,3]dioxolyl, tetrahydrofuranyl, and tetrahydropyranyl; or R2 is phenyl or pyridyl substituted with one or more substituents selected from the group consisting of hydroxy, amino, cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C5 cycloalkoxy, C3-C5 cycloalkyl-methoxy, C1-C3 fluoroalkoxy, and —NC(O)CH3; or R2 is a 5-membered heteroaryl, optionally substituted one or more times with C1-C3 alkyl; R3 is selected from the group consisting of hydrogen, halogen, C1-C alkyl, C3-C5 cycloalkyl, and phenyl; or R3 is selected from the group consisting of phenyl substituted one or more times with C1-C3 alkyl; methyl substituted one, two or three times with fluorine; ethyl substituted one, two or three times with fluorine; R4 is hydrogen; provided that R2 and R3 cannot simultaneously be hydrogen; The compounds of formula (I) are the following three compounds: 3-methyl-7-(4-(trifluoromethoxy)benzyl)imidazo[1,5-a]pyrazin-8(7H)-one; 7-butyl-3-methylimidazo[1,5-a]pyrazin-8(7H)-one; and 7-(4-Methoxybenzyl)-3-methylimidazo[1,5-a]pyrazin-8(7H)-one It is not one of them.

[0106]

[0077] In some examples, the PDE9 inhibitor is a compound represented by formula (XI), as disclosed in US9725453, US9969742, and WO2013142269.

[0107] [ka]

[0108] During the ceremony, X is selected from the group consisting of a single bond, C(O) and S(O)2; R1 is independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyloxy, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl, and heterocycloalkyloxy, and each is selected from the group consisting of halogen, —S(O)2(C1-C4)alkyl, OH, —C(O)—(C1-C4)alkyl, oxo, CN, (C1- optionally substituted with one or more substituents selected from the group consisting of C6)alkyl, (C1-C4)alkoxy, (C3-C7)cycloalkyl, —C(O)NH(C1-C4)alkyl, —C(O)N[(C1-C4)alkyl(C1-C4)alkyl], (C1-C4 alkyl)-C(O)—, (C1-C4)alkylsulfonyl, —S(O)2NH(C1-C4)alkyl, and —S(O)2N[(C1-C4)alkyl(C1-C4)alkyl]; R2 is (C1-C6) alkyl, (C3-C 10 )cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4)alkyl, restricted phenyl, and restricted phenyl(C1-C4)alkyl, each independently selected from the group consisting of halogen, —S(O)2(C1-C4)alkyl, OH, —C(O)—(C1-C4)alkyl, oxo, CN, (C1-C6)alkyl, ( optionally substituted with one or more substituents selected from the group consisting of C1-C4)alkoxy, (C3-C7)cycloalkyl, —C(O)NH[(C1-C4)alkyl, —C(O)N[(C1-C4)alkyl(C1-C4)alkyl], (C1-C4 alkyl)-C(O)—, (C1-C4)alkylsulfonyl, —S(O)2NH(C1-C4)alkyl, and —S(O)2N[(C1-C4)alkyl(C1-C4)alkyl]; R3 is independently selected from the group consisting of (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4)alkyl, restricted phenyl, and restricted phenyl(C1-C4)alkyl, each of which is selected from the group consisting of halogen, —S(O)2(C1-C4)alkyl, OH, —C(O)—(C1-C4)alkyl, oxo, CN, It may be optionally substituted with one or more substituents selected from the group consisting of (C1-C6)alkyl, (C1-C4)alkoxy, (C3-C7)cycloalkyl, -C(O)NH(C1-C4)alkyl, -C(O)N[(C1-C4)alkyl(C1-C4)alkyl], (C1-C4 alkyl)-C(O)-, (C1-C4)alkylsulfonyl, -S(O)2NH(C1-C4)alkyl, and -S(O)2N[(C1-C4)alkyl(C1-C4)alkyl].

[0109]

[0078] In some examples, as disclosed in US20110212960 and WO2011018495, the PDE9 inhibitor is a compound represented by formula (XII) and its pharmaceutically acceptable salt forms or solvates:

[0110] [ka]

[0111] During the ceremony, R 1 is hydrogen, fluorine, chlorine, bromine, NC-, F3C-, HF2C-, FH2C-, F3C-CH2-, carboxy-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-S-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7-Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, heteroaryl-, heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, heterocyclyl-CO-, R 10 -O-, R 10 -OC 1~3 -alkyl-, (R 10 )2N-, R 10 O-CO-, (R 9 )2N-CO-, R 10 -CO-(R 10 )N-, R 10 -CO-, (R 9 )2N-CO-(R 10 )N-, (R 9 )2N-CO-O-, R 10 -O-CO-(R 10 )N-, R 10 -SO2-(R 10 )N-, and C 1~6 -alkyl-SO2- 1a From the group, each R 1 are selected independently for each Here, the above HF2C-, FH2C-, F3C-CH2-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, heteroaryl-, heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -OC 1~3 -alkyl-, heterocyclyl-CO-, and C 1~6 Each member of -alkyl-SO2- is fluorine, chlorine, bromine, OH-, NC-, O2N-, F3C-, HF2C-, FH2C-, F3C-CH2-, HO-C 1~6 -Alkyl-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-OC 1~6 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, (R 10 )2N-CO-, C 3~6 -cycloalkyl-, C 3~6 -Cycloalkyl-C 1~4 -alkyl-, and C 1~6 -alkyl-, and preferably fluorine, chlorine, bromine, OH—, NC—, O2N—, F3C—, HF2C—, FH2C—, F3C—CH2—, HO—C 1~6-Alkyl-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-OC 1~6 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, (R 10 )2N-CO-, C 3~6 -cycloalkyl-, and C 3~6 -Cycloalkyl-C 1~4 -alkyl-, L is selected from the integers 0, 1, 2, and 3; x is selected from the integers 0, 1, 2, 3 and 4; y is selected from 0, 1 and 2; D is a heterocyclyl 1a selected from the group Here, the above D 1a Each member of the group is independently R 2 and / or one R 3 optionally substituted with or D consists of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cycloheptatrienyl, cyclooctatrienyl, and cyclooctatetraenyl. 2a selected from the group Here, the above D 2a Each member of the group is independently R 4 optionally substituted with one or more substituents selected from the group D is C 1~8 - D consisting of alkyl 3a selected from the group Here, the above D 3a C of the group 1~8 Alkyl is R 5and optionally substituted with one or more substituents independently selected from the group or D is D consisting of aryl 4a selected from the group Here, the above D 4a The aryl group is R 6 and D 4a R with one or less 6 Preferred are those compounds substituted with or D is a heteroaryl 5a selected from the group Here, the above D 5a Each member of the group is independently R 6 and optionally substituted with one or more substituents selected from D 5a R with one or less 6 Preferred are those compounds substituted with R 2 teeth, H-, fluorine, NC-, F3C-, HF2C-, FH2C-, F3C-CH2-, carboxy-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-S-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6-Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, Heteroaryl, Heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -OC 2~3 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, R 10 O-CO-, (R 10 )2N-CO-, R 10 -CO-(R 10 )N-, R 10 -CO-, (R 10 )2N-CO-(R 10 )N-, R 10 -O-CO-(R 10 )N-, R 10 -SO2-(R 10 )N-, C 1~6 -alkyl-SO2-, and R consisting of oxo 2a selected from the group Here, the above HF2C-, FH2C-, F3C-CH2-, C 1~6 -alkyl-(preferably C 2~6- alkyl), C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6-alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, Heteroaryl, Heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -OC 2~3 -alkyl-, (R 10 )2N-C 1~3 -alkyl-, and C 1~6 -Alkyl-SO2- includes fluorine, chlorine, bromine, NC-, O2N-, F3C-, HF2C-, FH2C-, F3C-CH2-, HO-C 1~6 -Alkyl-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-OC 1~6 -Alkyl-, C 1~6 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, and (R 10 ) optionally substituted independently with one or more substituents independently selected from the group consisting of N—CO—; 1 NR as a ring member 2 When R is a heterocyclyl having 2 is any other R 2 Independently of H-, F3C-CH2-, HF2C-CH2-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7-Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Heteroaryl, Heteroaryl-C 1~6 -alkyl-, R 10 -OC 1~3 -alkyl-, R 10 O-CO-, (R 10 )2N-CO-, R 10 -CO-, R 10 -SO2-, and C 1~6 -alkyl-SO2-, Here, the above F3C-CH2-, HF2C-CH2-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Heteroaryl, Heteroaryl-C 1~6 -alkyl-, R 10 -OC 1~3 -alkyl-, and C 1~6-AlkylSO2-: fluorine, HO-, NC-, O2N-, F3C-, HF2C-, FH2C-, F3C-CH2-, HO-C 1~6 -alkyl-, R 10 -OC 1~6 -Alkyl-, C 1~6 -alkyl-, R 10 -O-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, and (R 10 ) optionally substituted independently with one or more substituents independently selected from the group consisting of N—CO—; R 3 H-, HO- and R 10 R consisting of -O- 3a is selected from R 4 is H-, fluorine, chlorine, bromine, HO-, NC-, F3C-, HF2C-, FH2C-, F3C-CH2-, carboxy-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-S-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6-Alkynyl-, heteroaryl-, heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -O-, R 10 -OC 1~3 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, R 10 O-CO-, (R 10 )2N-CO-, R 10 -CO-(R 10 )N-, R 10 -CO-, (R 10 )2N-CO-(R 10 )N-, R 10 -O-CO-(R 10 )N-, R 10 -SO2-(R 10 )N-, and C 1~6 -alkyl-SO2- 4a is selected from Here, the above HF2C-, FH2C-, F3C-CH2-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, heteroaryl-, heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -OC 1~3 -alkyl-, (R 10 )2N-C 1~3 -alkyl-, and C 1~6 -Alkyl-SO2- includes fluorine, chlorine, bromine, NC-, O2N-, F3C-, HF2C-, FH2C-, F3C-CH2-, HO-C 1~6 -Alkyl-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-OC 1~6 -Alkyl-, C 1~6 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, and (R 10 ) 2N—CO—, or R 4a The two substituents in C 2~6 - alkylene bridge, C 2~6 -One or two CH2 of the alkylene bridge may in each case be joined to an O atom, an S atom, SO, SO2, N(R) such that two O atoms or S atoms, or an O atom and an S atom, are not directly bonded together. 10 ) or NC(O)-R 10 may be substituted independently of each other by R 5 is H-, fluorine, chlorine, bromine, HO-, NC-, F3C-, HF2C-, FH2C-, F3C-CH2-, carboxy-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-S-, C 1~6 -Alkyl-SC1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, heteroaryl-, heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -O-, R 10 -OC 1~3 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, R 10 O-CO-, (R 10 )2N-CO-, R 10 -CO-(R 10 )N-, R 10 -CO-, (R 10 )2N-CO-(R 10 )N-, R 10 -O-CO-(R 10 )N-, R 10 -SO2-(R 10 )N-, and C 1~6 -alkyl-SO2- 5a is selected from The above HF2C-, FH2C-, F3C-CH2-, carboxy-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6-alkynyl-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, heteroaryl-, heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -OC 1~3 -alkyl-, (R 10 )2N-C 1~3 -alkyl-, and C 1~6 -Alkyl-SO2- includes fluorine, chlorine, bromine, NC-, O2N-, F3C-, HF2C-, FH2C-, F3C-CH2-, HO-C 1~6 -Alkyl-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-OC 1~6 -Alkyl-, C 1~6 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, and (R 10 ) 2N—CO—, R 6is H-, fluorine, chlorine, bromine, HO-, NC-, F3C-, HF2C-, FH2C-, F3C-CH2-, carboxy-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-S-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, heteroaryl-, heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -O-, R 10 -OC 1~3 -alkyl-, (R 10 )2N-, (R 10 )2N-C 1~3 -alkyl-, R 10 O-CO-, (R 10 )2N-CO-, R 10 -CO-(R 10 )N-, R 10 -CO-, (R 10 )2N-CO-(R 10 )N-, R 10 -O-CO-(R 10 )N-, R 10-SO2-(R 10 )N-, and C 1~6 -alkyl-SO2- 6a is selected from The above HF2C-, FH2C-, F3C-CH2-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 1~6 -Alkyl-SC 1~3 -Alkyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 2~6 -alkenyl-, C 3~7 -Cycloalkyl-C 2~6 -alkynyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, C 3~7 -heterocyclyl-C 2~6 -alkenyl-, C 3~7 -heterocyclyl-C 2~6 -Alkynyl-, aryl, aryl-C 1~6 -Alkyl-, Aryl-C 2~6 -Alkenyl-, aryl-C 2~6 -Alkynyl-, heteroaryl-, heteroaryl-C 1~6 -Alkyl-, Heteroaryl-C 2~6 -Alkenyl-, Heteroaryl-C 2~6 -alkynyl-, R 10 -OC 1~3 -alkyl-, (R 10 )2N-C 1~3 -Alkyl- and C 1~6 -Alkyl-SO2- includes fluorine, chlorine, bromine, NC-, O2N-, F3C-, HF2C-, FH2C-, F3C-CH2-, HO-C 1~6 -Alkyl-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-OC 1~6 -Alkyl-, C 1~6 -alkyl-, (R 10)2N-, (R 10 )2N-C 1~3 -alkyl-, and (R 10 ) 2N—CO—, optionally substituted independently with one or more substituents selected from the group consisting of: R 9 is H-, F3C-CH2-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~3 -Alkyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, aryl, aryl-C 1~3 -Alkyl-, Heteroaryl, Heteroaryl-C 1~3 -Alkyl- and C 1~6 -alkyl- 9a From each R 9 are independently selected for Above F3C-CH2-, C 2~6 -alkenyl-, C 2~6 -alkynyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~3 -Alkyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, aryl, aryl-C 1~3 -Alkyl-, Heteroaryl, Heteroaryl-C 1~3 -Alkyl- and C 1~6 Each member of -alkyl- is fluorine, chlorine, bromine, HO-, NC-, O2N-, F3C-, HF2C-, FH2C-, F3C-CH2-, HO-C 1~6 -Alkyl-, CH3-OC 1~6 -Alkyl-, C 1~6 -Alkyl-O- and C 1~6 -alkyl-, R 10is H-(where R 10 O-CO-, R 10 -SO2- or R 10 -CO-), F3C-CH2-, C 1~6 -Alkyl-, C 2~6 -alkenyl-, C 3~7 -cycloalkyl-, C 3~7 -Cycloalkyl-C 1~3 -Alkyl-, C 3~7 -heterocyclyl-, C 3~7 -heterocyclyl-C 1~6 -Alkyl-, aryl, aryl-C 1~3 -Alkyl-, heteroaryl, and heteroaryl-C 1~3 -alkyl- 10a From each R 10 are independently selected for The Two R's 10 If both are attached to the same nitrogen atom, R 10 may bond with the nitrogen atom to form a 3- to 12-membered heterocyclyl ring, and one of -CH2- in the formed heterocycle is -O-, -S-, -NH-, -N(C 3~6 -cycloalkyl)-, -N(C 3~6 -Cycloalkyl-C 1~4 -alkyl)- or -N(C 1~4 -alkyl)-, Each of the above members represents fluorine, chlorine, bromine, HO-, NC-, O2N-, F3C-, HF2C-, FH2C-, F3C-CH2-, HO-C 1~6 -Alkyl-, CH3-OC 1~6 -Alkyl-, C 1~6 -Alkyl- and C 1~6 -alkyl-O-.

[0112]

[0079] In some examples, as disclosed in US8809345 and WO2012110441, the PDE9 inhibitor is a compound represented by formula (XIII) and a salt thereof, preferably a pharmaceutically acceptable salt thereof, a solvate thereof and a solvate of the aforementioned salt.

[0113] [ka]

[0114] During the ceremony, X is N or CR e and R a , R b , R c , R e is H, C 1~6 Alkyl-, C 1~6 - independently selected from the group consisting of alkyl-O-, CF3-, CHF2-, CH2F-, NC- and halogen; C 1~6 Alkyl- and C 1~6 -alkyl-O- may be optionally substituted with halogen, preferably fluoro; Each R d is selected from the group consisting of fluorine, NC—, —CF3, —CHF2, —CH2F and methyl; D is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl; Cyclopentyl and cyclohexyl may be optionally substituted with one or two substituents, which may be independently selected from the group consisting of fluorine, NC—, F3C—, HF2C— and FH2C—; Tetrahydrofuranyl and tetrahydropyranyl may be optionally substituted with one or two substituents, which may be independently selected from the group consisting of fluorine, NC—, F3C—, FIF2C— and FH2C—; Pyridyl may be optionally substituted with 1, 2, 3 or 4 substituents, said substituents being fluorine, chlorine, bromine, NC—, F3C—, HF2C—, FH2C—, F3C—CH2—, C 1~6 -Alkyl- and C 3~7 -cycloalkyl; m is selected from 1 or 2, preferably 1; n is selected from 0, 1 or 2, preferably 0 or 1, more preferably 0; If n=2, two R d are selected independently of each other.

[0115]

[0080] In some examples, as disclosed in US Pat. No. 7,615,558, US Pat. No. 8,809,348, and WO2004099210, the PDE9 inhibitor is a compound represented by formula (XIV) or a salt, solvate, and / or solvate of the salt thereof:

[0116] [ka]

[0117] During the ceremony, R 1 is phenyl, pyridyl or thiophenyl, and the phenyl, pyridyl or thiophenyl is selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy, C1-C6 alkylamino, halogen, C6-C 10 -arylcarbonylamino, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C6-C 10 -optionally with up to three substituents independently selected from the group consisting of arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C1-C6-alkylsulfonylamino, C1-C6 alkylsulfonyl, and C1-C6 alkylthio; C1-C6-alkyl, C1-C6-alkoxy, C6-C10 -Alkylamino, C6-C 10 -Axylcarbonylamino, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C6-C 10 -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C1-C6-alkylsulfonylamino, C1-C6-alkylsulfonyl and C1-C6-alkylthio are hydroxy, cyano, halogen, hydroxycarbonyl and the group of the formula -NR 3 R 4 and optionally substituted with one or more substituents selected from the group consisting of: R 3 and R 4 are, independently of one another, hydrogen or C1-C6-alkyl, or R 3 and R 4 is the R 3 and R 4 together with the nitrogen atom to which it is attached form a 5- to 8-membered heterocyclyl, R 2 is phenyl or heteroaryl, the phenyl having 1 to 3 residues, the heteroaryl optionally having 1 to 3 residues, and is selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy, C1 to C6 alkylamino, halogen, C6 to C 10 Arylcarbonylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, C6-C 10 are independently selected from arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C1-C6 alkylsulfonylamino, and C1-C6 alkylthio; C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C6-C 10-arylcarbonylamino, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C6-C 10 -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C1-C6-alkylsulfonylamino, C1-C6-alkylsulfonyl and C1-C6-alkylthio are hydroxy, cyano, halogen, hydroxycarbonyl and the group of the formula -NR 3 R 4 and optionally substituted with one or more substituents selected from the group consisting of: R 3 and R 4 has the meaning given above.

[0118]

[0081] In some examples, as disclosed in US8158633, US20120165349, and WO2004018474, the PDE9 inhibitor is a compound represented by formula (XV) and salts, solvates and / or solvates of the salts thereof:

[0119] [ka]

[0120] During the ceremony, R 1 is phenyl, which is substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C6-alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro and C1-C6-alkoxy; R 2 is pentan-3-yl, C4-C6 cycloalkyl, X is oxygen or sulfur.

[0121]

[0082] In some examples, as disclosed in US8039477, US8741907, and WO2004026876, the PDE9 inhibitor is a compound represented by formula (XVI) and salts, solvates and / or solvates of the salts thereof:

[0122] [ka]

[0123] During the ceremony, R 1 is C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C6-alkoxy, -C(=O)OR 5 or -C(=O)NR 6 R 7 and C1-C6-alkyl is hydroxy, C1-C6-alkoxy, halogen, trifluoromethyl, trifluoromethoxy, -C(=O)OR 5 or -C(=O)NR 6 R 7 and optionally substituted with 1 to 3 groups, each independently selected from the group R 5 is C1-C6-alkyl, R 6 and R 7 are each independently hydrogen, C6 to C 10 -aryl, C1-C6-alkyl, or The R 6 and R 7 together with the nitrogen atom to which it is attached form a 4- to 10-membered heterocyclyl; R 2 is hydrogen, C1-C6-alkyl, trifluoromethyl, C1-C6-alkoxy, or R 1 and R 2 is the R 1 and R 2together with the carbon atom to which it is attached form a C3-C8-cycloalkyl, a C3-C8-cycloalkenyl or a 4- to 10-membered heterocyclyl, which are selected from C1-C6-alkyl, C1-C6-alkoxy, hydroxy, oxo, -C(=O)OR 8 and R is optionally substituted with up to two substituents selected from the group consisting of 8 is C1-C6-alkyl or benzyl, R 3 is hydrogen or C1-C6-alkyl; R 4 is pentan-3-yl, C3-C6 cycloalkyl, X is oxygen or sulfur.

[0124]

[0083] In some examples, the PDE9 inhibitor is a compound represented by formula (XVII), as disclosed in US8648085 and WO2009068617.

[0125] [ka]

[0126] During the ceremony, R 1 is phenyl or pyridyl, either of which is substituted with 1 to 4 substituents X; Further, phenyl and pyridyl can each be selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy, C1-C6 alkylamino, halogen, C6-C 10 -arylcarbonylamino, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C6-C 10-optionally optionally substituted independently with up to three groups selected from the group: arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C1-C6-alkylsulfonylamino, C1-C6-alkylsulfonyl, or C1-C6-alkylthio; C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C6-C 10 -arylcarbonylamino, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C6-C 10 -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C1-C6-alkylsulfonylamino, C1-C6-alkylsulfonyl and C1-C6-alkylthio are each independently selected from hydroxy, cyano, halogen, hydroxycarbonyl and the formula -NR 3 R 4 and optionally substituted with 1 to 3 radicals independently selected from the group X are, independently of one another, selected from C1-C6-alkoxy, which is substituted with 2 to 6 halogen substituents, which are selected from the group consisting of fluoro, chloro and bromo, and the C atom directly bonded to the O atom constitutes the beta position relative to the bond to the phenyl or pyridyl and is substituted with at least one halogen atom; R 2 is phenyl or heteroaryl, phenyl being substituted by 1 to 3 radicals, heteroaryl being, in each case independently of one another, C1-C6-alkyl, C1-C 6- Alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy, C1-C6-alkylamino, halogen, C6-C 10 -arylcarbonylamino, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C6-C 10-optionally substituted by 1 to 3 groups selected from the group consisting of arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C1-C6-alkylsulfonylamino, C1-C6-alkylsulfonyl and C1-C6-alkylthio, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C6-C 10 -arylcarbonylamino, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C6 alkoxycarbonyl, C6-C 10 -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C1-C6-alkylsulfonylamino, C1-C6-alkylsulfonyl and C1-C6-alkylthio are respectively hydroxy, cyano, halogen, hydroxycarbonyl and the group of the formula -NR 3 R 4 optionally substituted with 1 to 3 groups independently selected from the group R 3 is hydrogen or C1-C6-alkyl; R 4 is hydrogen or C1-C6-alkyl; or R 3 and R 4 is the R 3 and R 4 together with the nitrogen atom to which it is attached form a 5- to 8-membered heterocyclyl.

[0127]

[0084] In some examples, as disclosed in US9096603, US8623879, and WO2009121919, the PDE9 inhibitor is a compound represented by formula (XVIII) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0128] [ka]

[0129] Hc is selected from the group of tetrahydropyranyl, tetrahydrofuranyl, piperidinyl and pyrrolidinyl; R 1 is selected from the group phenyl, 2-, 3- and 4-pyridyl-, pyrimidinyl, pyrazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclopentylmethyl, cyclohexyl, ethyl, 1- and 2-propyl-, 1- and 2-butyl-, 1-, 2- and 3-pentyl-, tetrahydrofuranyl and tetrahydropyranyl, These R 1 The groups are fluorine, chlorine, bromine, iodine, HO-, oxo, NC-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-, C 3~7 -cycloalkyl-O-, C 3~7 Cycloalkyl-C 1~3 -optionally substituted with one or more substituents independently selected from the group consisting of alkyl-O-, CF3O- and CF3; R 2 is any other R 2 Independently of H-, C 1~6 -alkyl- and oxo; R 2 is bonded to a nitrogen atom that is a ring member of Hc, 2 is any other R 2 Independently of H-, C 1~6 -Alkyl-CO-, C 1~6 -Alkyl-O-CO-, C 1~6 -alkyl-, phenyl-CO-, phenyl-O-CO- and (C 1~6 -alkyl)N—CO—; Above R 2 each member of which, independently of one another, may be optionally substituted with one or more fluorine substituents; R 3 H-, hydroxy and C 1~6 -alkyl-O-, C 1~6 -alkyl-O- may be optionally substituted with one or more fluorine, chlorine, bromine and HO-; R4 and R 5 are independently selected from the group consisting of H, fluorine and methyl; x is 0, 1, 2, 3 or 4; y is 0 or 1.

[0130] In some embodiments, the PDE9 inhibitor is:

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] [ka]

[0135] [ka]

[0136] [ka]

[0137] [ka]

[0138] [ka]

[0139] [ka]

[0140] [ka]

[0141] [ka]

[0142] [ka]

[0143] [ka]

[0144] [ka]

[0145] In some embodiments, the PDE9 inhibitor is selected from the group consisting of:

[0146] [ka]

[0147] is.

[0086] In some examples, the PDE9 inhibitor is a compound represented by formula (XIX) and salts thereof, as disclosed in US9079905 and WO2010026214.

[0148] [ka]

[0149] During the ceremony, A is cyclohexyl; R 1is selected from the group consisting of phenyl, 2-, 3- and 4-pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethyl, 1- and 2-propyl, 1- and 2-butyl, 1-, 2- and 3-pentyl, tetrahydrofuranyl and tetrahydropyranyl, These R 1 The groups are fluorine, chlorine, bromine, iodine, NC-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-, CF3O-, F3C-, pyridyl, (R 10 )2N-CO-CH2-, N-morpholinyl-C 1~6 -alkyl-, pyrazolyl, and phenyl 1.1 optionally substituted with one or more substituents selected from the group R 1 When is tetrahydrofuranyl or tetrahydropyranyl, it may be substituted by oxo; Above R 1.1 The pyridyl, pyrazolyl and phenyl groups of the group may optionally be substituted with groups selected from fluorine, chlorine, H3C-, F3C-, CHO-, H2NCO- and NC-; R 2 is fluorine; R 3 is fluorine; R 4 and R 5 are independently selected from H and fluorine; R 10 is any other R 10 Independently of H-, C 1~6 -alkyl-, phenyl and pyridyl; x is 1.

[0150]

[0087] In some examples, as disclosed in U.S. Patent Nos. 8,912,201 and 9,328,120 and WO2012020022 and WO2012 / 110440, the PDE9 inhibitor is a compound represented by formula (XX) and a salt thereof, preferably a pharmaceutically acceptable salt thereof, a solvate thereof and a solvate of the aforementioned salt.

[0151] [ka]

[0152] During the ceremony, R 1 is a 5- or 6-membered heteroaryl, in which 1, 2, 3 or 4, preferably 1, 2 or 3, ring atoms are heteroatoms independently selected from N, O or S, and the 5- or 6-membered aromatic heteroaryl may be optionally substituted with 1, 2, 3 or 4, preferably 1 or 2, substituents independently selected from the group consisting of fluorine, chlorine, bromine, HO—, NC—, F3C—, HF2C—, FH2C—, methyl, H2N— and (CH3)2N—; R 2 is selected from the group consisting of fluorine, NC—, F3C—, HF2C—, FH2C— and methyl, preferably fluorine, NC—, F3C— and methyl; D is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, wherein cyclopentyl and cyclohexyl may be optionally substituted with one or two substituents, which may be independently selected from the group consisting of fluorine, NC—, F3C—, HF2C— and FH2C—; Tetrahydrofuranyl and tetrahydropyranyl may be optionally substituted with one or two substituents, which may be independently selected from the group consisting of fluorine, NC—, F3C—, FIF2C— and FH2C—; Pyridyl may be optionally substituted with 1, 2, 3 or 4 substituents, said substituents being fluorine, chlorine, bromine, NC—, F3C—, HF2C—, FH2C—; F3C—CH2—, C 1~6 -Alkyl- and C 3~7 -cycloalkyl; m is selected from 1 or 2, preferably 1; n is selected from 0, 1 or 2, preferably 0 or 1, more preferably 0; When n=2, these two R 2 are selected independently of each other, with the proviso that the compound is not an oxadiazolyl derivative of

[0153] [ka]

[0154] It is in the form of any possible stereoisomer, a mixture of all or part thereof, a salt thereof, a solvate thereof or a solvate of a salt thereof.

[0088] In some examples, as disclosed in U.S. Patent Nos. 8,623,879 and 9,096,603, the PDE9 inhibitor is a compound represented by formula (XXI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0155] [ka]

[0156] During the ceremony, Hc is selected from the group of tetrahydropyranyl, tetrahydrofuranyl, piperidinyl and pyrrolidinyl; R 1 is selected from the group phenyl, 2-, 3- and 4-pyridyl-, pyrimidinyl, pyrazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclopentylmethyl, cyclohexyl, ethyl, 1- and 2-propyl-, 1- and 2-butyl-, 1-, 2- and 3-pentyl-, tetrahydrofuranyl and tetrahydropyranyl, These R 1 The groups are fluorine, chlorine, bromine, iodine, HO-, oxo, NC-, C 1~6 -Alkyl-O-, C 1~6 -Alkyl-, C 3~7 -cycloalkyl-O-, C 3~7 Cycloalkyl-C 1~3-optionally substituted with one or more substituents independently selected from the group consisting of alkyl-O-, CF3O- and CF3; R 2 is any other R 2 Independently of H-, C 1~6 -alkyl- and oxo; R 2 When R is bonded to a nitrogen atom that is a ring member of Hc, 2 is any other R 2 Independently of H-, C 1~6 -Alkyl-CO-, C 1~6 -Alkyl-O-CO-, C 1~6 -alkyl-, phenyl-CO-, phenyl-O-CO- and (C 1~6 -alkyl)N—CO—; Above R 2 each member of which, independently of one another, may be optionally substituted with one or more fluorine substituents; R 3 H-, hydroxy and C 1~6 -alkyl-O-, C 1~6 -alkyl-O- may be optionally substituted with one or more fluorine, chlorine, bromine and HO-; R 4 and R 5 are independently selected from the group consisting of H, fluorine and methyl; x is 0, 1, 2, 3 or 4; y is 0 or 1.

[0157]

[0089] In some examples, the PDE9 inhibitor is a compound represented by formula (XXII), as disclosed in US Pat. Nos. 8,623,901 and 9,102,679.

[0158] [ka]

[0159] During the ceremony, Hc is tetrahydropyranyl, One or more of the ring carbon atoms may be fluorine, NC-, F3C-, HF2C-, FH2C-, F3C-CH2-, C 1~6 -Alkyl-, C 1~6 -alkyl-O-, optionally substituted with 1 or 2 substituents independently selected from the group, and up to one ring carbon atom may be substituted with oxo; R 1 is VW- * It is the basis, During the ceremony, W is phenyl; V is selected from the group of phenyl or heteroaryl, said heteroaryl being selected from the group of oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl; - * In formula (I), W is CR 2 R 3 is the point of attachment to; W and V are independently fluorine, chlorine, bromine, C 1~6 -Alkyl-, F3C-, HF2C-, FH2C-, F3C-CH2-, F3C-O-, HF2C-O-, C 3~7 -heterocycloalkyl-, HOC 1~6 -Alkyl-, C 1~6 -Alkyl-OC 1~6 -Alkyl-, C 3~7 -Cycloalkyl-OC 1~6 -Alkyl-, C 3~7 -Cycloalkyl-C 1~3 -Alkyl-OC 1~6 -Alkyl-, phenyl-OC 1~6 -Alkyl-, benzyl-OC 1~6 -Alkyl-, HO-, C 1~6 -Alkyl-O-, C 3~7 -cycloalkyl-O-, C 3~7 -Cycloalkyl-C 1~3 -optionally substituted with one or more substituents selected from the group consisting of alkyl-O-, phenyl-O-, benzyl-O-, N-morpholinyl, and N-C-; R 2are H-, fluorine, F3C-, HF2C-, FH2C-, and C 1~3 - selected from the group of alkyl; R 3 are H-, fluorine, F3C-, HF2C-, FH2C-, and C 1~3 -alkyl.

[0160] In some examples, as disclosed in PCT International Publication No. WO2019204298 and U.S. Patent No. 10,822,346, the PDE9 inhibitor is a compound represented by formula (XXIII):

[0161] [ka]

[0162] or a stereoisomer, tautomer or hydrate thereof. During the ceremony, R 1 is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy or (C1-C6) haloalkyl containing 1 to 6 halogen atoms; R 2 is hydrogen, (C1-C6) alkyl, [(C1-C6) alkylene] aryl or amino; R 3 is hydrogen, (C1-C6) alkyl, (C1-C6) alkenyl, [(C1-C6) alkylene]N(R 4 )(R 5 ), [(C1-C6) alkylene]S(R 4 ) or -XY, or R 2 and R 3 is the R 2 and R 3 together with the atom to which it is attached form a heterocyclyl; R 4 and R 5 are independently H or (C1-C6) alkyl; X is a chemical bond, -CH2-, -CH(OH)-, -CH(C6H5)-, -CO-, -CH2CH2-, CH2CO-, -COCH2-, S, O or NH; Y is cycloalkyl, heterocyclyl, aryl, or heteroaryl; Z is S or O; N is 0, 1, 2, 3 or 4; M + teeth,

[0163] [ka]

[0164] and; Any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one, two or three groups selected from OH, CN, halogen, (C1-C6)alkyl, O(C1-C6)alkyl, (C2-C6)alkenyl, haloalkyl, amino, oxo and nitro.

[0165]

[0091] In some examples, as disclosed in WO2018009899, ​​the PDE9 inhibitor is a compound represented by formula (XXIV) and pharmaceutically acceptable salts thereof:

[0166] [ka]

[0167] During the ceremony, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 C containing alkyl or 1 to 6 halogen atoms 1~6 is haloalkyl, R 2 is hydrogen, C 1~6 alkyl, phenyl C1-C6 alkyl or amino; R 3 is C2~6 Alkyl, C 2~6 Alkenyl, Carbamoyl C 1~6 Alkyl, Amino C 1~6 Alkyl, C 1~6 Alkylamino C 1~6 Alkyl, di(C 1~6 Alkyl)amino C 1~6 Alkyl, C 1~6 alkylthio or YX, or R 2 and R 3 may together form tetramethylene, X is a chemical bond or CH2, CH(OH), CH(C6H5), CO, CH2CH2, CH2CO, COCH2, S, O, or NH; Y is an aromatic carbocyclic group, benzyl, an aromatic heterocyclic group, a 4- to 7-membered cycloalkyl, a 4- to 7-membered cycloalkenyl, a 5- to 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms, or a 5- to 7-membered saturated heterocyclic group which forms a condensed ring with a 5- or 6-membered saturated cyclic group and contains 1 or 2 nitrogen atoms, and all of these groups are free from halogen atoms, C 1~6 Alkyl, C containing 1-6 halogen atoms 1~6 Haloalkyl, C containing 1-6 halogen atoms 1~6 Haloalkyloxy, C containing 1-6 halogen atoms 1~6 Haloalkylthio, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~4 Alkylenedioxy, carboxyl, C 1~6 optionally containing 1 to 3 substituents selected from alkoxycarbonyl, oxo, amino, nitro and phenyl; Z is S or O, and n is 0 or an integer of 1-4.

[0168]

[0092] In some examples, the PDE9 inhibitor is a compound represented by formula (XXV) or a salt thereof, as disclosed in WO2006135080, US8293754, and US8377944.

[0169] [ka]

[0170] During the ceremony, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 C containing alkyl or 1 to 6 halogen atoms 1~6 is haloalkyl, R 2 is hydrogen, C 1~6 Alkyl, Phenyl C 1~6 alkyl or amino, R 3 is C 2~6 Alkyl, C 2~6 Alkenyl, Carbamoyl C 1~6 Alkyl, Amino C 1~6 Alkyl, C 1~6 Alkylamino C 1~6 Alkyl, di(C 1~6 Alkyl)amino C 1~6 Alkyl, C 1~6 alkylthio or YX-, or R 2 and R 3 may together form tetramethylene, X is a direct bond or CH2, CH(OH), CH(C6H5), CO, CH2CH2, CH2CO, COCH2, S, O or NH; Y is an aromatic carbocyclic group, an aromatic heterocyclic group, a 4- to 7-membered cycloalkyl, a 4- to 7-membered cycloalkenyl, a 5- to 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms, or a 5- to 7-membered saturated heterocyclic group which forms a condensed ring with a 5- or 6-membered saturated cyclic group and contains 1 or 2 nitrogen atoms, and all of these groups are free from halogen atoms, C 1~6 Alkyl, C containing 1-6 halogen atoms 1~6 Haloalkyl, C containing 1-6 halogen atoms 1~6 Haloalkyloxy, C containing 1-6 halogen atoms 1~6 Haloalkylthio, C 1~6 Alkoxy, C 1~6Alkylthio, C 1~4 Alkylenedioxy, carboxyl, C 1~6 optionally containing 1 to 3 substituents selected from the group consisting of alkoxycarbonyl, oxo, amino, nitro, and phenyl; Z is S or O; n is 0 or an integer from 1 to 4, However, R 1 is methyl and R 2 is hydrogen and R 3 Except when is benzyl, Z is O, and n is 0.

[0171] In some embodiments, the PDE9 inhibitor is:

[0172] [ka]

[0173] [ka]

[0174] [ka]

[0175] In some embodiments, the PDE9 inhibitor is selected from the group consisting of compounds having the structure:

[0176] [ka]

[0177] is. In some examples, as disclosed in WO2012004900, the PDE9 inhibitor is a compound represented by formula (XXVI):

[0178] [ka]

[0179] During the ceremony, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 C containing alkyl or 1 to 6 halogen atoms 1~6 represents haloalkyl, R 2 is hydrogen, C 1~6 Alkyl, Phenyl C 1~6 represents alkyl or amino, R 3 is C 1~6 Alkyl, C 2~6 Alkenyl, Carbamoyl C 1~6 Alkyl, Amino C 1~6 Alkyl, C 1~6 Alkylamino C 1~6 Alkyl, di(C 1~6 Alkyl)amino C 1~6 Alkyl, C 1~6 represents alkylthio or YX-, or R 2 and R 3 may together form tetramethylene, R 4 represents a carboxylic acid or its equivalent, X represents a direct bond or CH2, CH(OH), CH(C6H5), CO, CH2CH2, CH2CO, COCH2, S, O or NH; Y represents an aromatic carbocyclic group, an aromatic heterocyclic group, a 4- to 7-membered cycloalkyl group, a 4- to 7-membered cycloalkenyl group, a 5- to 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms, or a 5- to 7-membered saturated heterocyclic group which forms a condensed ring with a 5- or 6-membered saturated cyclic group and contains 1 or 2 nitrogen atoms, and all of these groups are free from halogen atoms, C 1~6 Alkyl, C containing 1-6 halogen atoms 1~6 Haloalkyl, C containing 1-6 halogen atoms 1~6 Haloalkyloxy, C containing 1-6 halogen atoms 1~6 Haloalkylthio, C 1~6 Alkoxy, C1~6 Alkylthio, C 1~4 Alkylenedioxy, carboxyl, C 1~6 optionally containing 1 to 3 substituents selected from alkoxycarbonyl, oxo, amino, nitro and phenyl; Z represents S or O; n is 0 or an integer from 1 to 4, A 1 and A 2 one of which represents a carbon atom and the other represents a sulfur atom; R 1 is A 1 or A 2 It is bonded to a carbon atom represented by either However, A 1 is a carbon atom, and A 2 is a sulfur atom, and R 4 Unless is hydroxy Alternatively, a salt of the compound is provided.

[0180]

[0095] In some examples, as disclosed in JPWO2008072778 and US20100113484, the PDE9 inhibitor is represented by the compounds of the following formulae (XXVII) to (XXXII) and can be named as follows:

[0181] Thienopyrimidine derivatives represented by formula (XXVII)

[0182] [ka]

[0183] [In the formula, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl or C with 1 to 9 halogen atoms 1~6 represents haloalkyl, R 2 is hydrogen, C 1~6 Alkyl, Phenyl C 1~6represents alkyl or amino, R 3 is C 2~6 Alkyl, C 2~6 Alkenyl, Carbamoyl C 1~6 Alkyl, Amino C 1~6 Alkyl, C 1~6 Alkylamino C 1~6 Alkyl, di(C 1~6 Alkyl)amino C 1~6 Alkyl, C 1~6 represents alkylthio or YX-, or R 2 and R 3 may together form tetramethylene, X represents a direct bond or CH2, CH(OH), CH(C6H5), CO, CH2CH2, CH2CO, COCH2, S, O or NH; Y is an aromatic carbocyclic group, an aromatic heterocyclic group, C 4~7 Cycloalkyl, C 4~7 cycloalkenyl, a 5- to 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms, or a 5- to 7-membered saturated heterocyclic group which forms a condensed ring with a 5- to 6-membered saturated cyclic group and contains 1 or 2 nitrogen atoms, each of which is selected from the group consisting of halogen, C 1~6 Alkyl, C with 1-9 halogen atoms 1~6 Haloalkyl, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, C 1~6 Alkylthio, C with 1-9 halogen atoms 1~6 Haloalkylthio, C 1~4 Alkylenedioxy, Carboxy, C 1~6 optionally substituted with 1 to 3 substituents selected from alkoxycarbonyl, oxo, amino, nitro and phenyl; Z 1 represents S or O, n is 0 or an integer from 1 to 4; or its salts; A quinazoline derivative represented by formula (XXVIII)

[0184] [ka]

[0185] [In the formula, R 4 is a halogen, C 1~6 Alkyl, C with 1-9 halogen atoms 1~6 Haloalkyl and C 1~6 represents a phenyl or aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from alkoxy; m is an integer from 1 to 3]; or its salts; A quinoxaline derivative represented by formula (XXIX)

[0186] [ka]

[0187] [In the formula, R 5 and R 6 are each independently hydrogen; halogen; hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, C 1~6 C optionally substituted with alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic or heterocyclic groups 1~6 Alkyl or C 1~6 Alkoxy; Hydroxy, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 Haloalkyl, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Acyl optionally substituted with haloalkoxy, amino, carbocyclic or heterocyclic groups; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6amino optionally substituted with 1 to 2 substituents selected from alkynyl, alkanoyl, carbocyclic and heterocyclic groups; hydroxy; or halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 pyrimidinyl optionally substituted with haloalkoxy, nitro or amino; R 7 is hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, alkanoyl, amino (wherein the amino group is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group, each of which may be further optionally substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 C substituted with (optionally further substituted with alkoxycarbonyl, amino, amido or carbamoyl) 1~9 Alkyl, C 2~9 Alkenyl or C 2~9 Alkynyl; halogen, hydroxy, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy (wherein the C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Alkoxy is independently selected from halogen, hydroxy, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6Haloalkoxy, Carboxy, C 1~6 alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl, carbocyclic or heterocyclic group), C having 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Aryl, saturated carbocyclic or saturated heterocyclic groups optionally substituted with alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl, carbocyclic or heterocyclic groups; carboxy; C 1~6 Alkoxycarbonyl (wherein the C 1~6 The C in the alkoxycarbonyl 1~6 The alkoxy moiety can be hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 alkoxycarbonyl, amino, amido, carbamoyl, carbocyclic or heterocyclic groups; amide (wherein the amino moiety in the amide is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 and optionally further substituted with 1 to 2 substituents selected from haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group; or carbamoyl (wherein the amino moiety in the carbamoyl is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 which may be further optionally substituted with 1 to 2 substituents selected from haloalkyl, alkanoyl, carbocyclic groups, and heterocyclic groups; R 8 is hydrogen; hydroxy; hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 C optionally substituted with alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl or oxo 1~6Alkyl; or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 represents an amino optionally substituted by 1 to 2 substituents selected from a haloalkyl, an alkanoyl, a carbocyclic group, and a heterocyclic group; R 9 and R 12 are each independently hydrogen; halogen; hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 C optionally substituted with alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl or oxo 1~6 Alkyl, C 2~6 Alkenyl or C 1~6 represents alkoxy; cyano; or nitro; R 10 and R 11 are each independently hydrogen; halogen; hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, alkanoyl, amino (wherein the amino is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group, each of which may be further substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 optionally substituted with alkoxycarbonyl, amino, amido or carbamoyl; 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl or C 1~6 Alkoxy; Cyano; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (wherein the C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl can be, independently of each other, hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, C 1~6 alkanoyl, amino, amido, carbamoyl, oxo, a carbocyclic group, and a heterocyclic group (which may be optionally substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 amino optionally substituted by 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy (wherein the C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Alkoxy is independently selected from the group consisting of hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, C 1~6 alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic or heterocyclic group), C having 1 to 9 halogen atoms 1~6Haloalkoxy, Carboxy, C 1~6 Carbocyclic or heterocyclic groups optionally substituted with alkoxycarbonyl, amino, amido or carbamoyl; COR 13 ; or SO2R 13 represents; R 13 are hydrogen; hydroxy; hydroxy, halogen, and C, respectively. 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, alkanoyl, amino (wherein the amino is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group, each of which may be further substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 optionally substituted with alkoxycarbonyl, amino, amido or carbamoyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl or C 1~6 Alkoxy;C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, wherein the C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl can be, independently of each other, hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic or heterocyclic group), C having 1 to 9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic and heterocyclic groups, wherein the carbocyclic and heterocyclic groups are each independently selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 amino optionally substituted by 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy (wherein the C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Alkoxy is independently selected from the group consisting of hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 C having 1 to 9 halogen atoms), which may be further optionally substituted with alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic or heterocyclic groups 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, alkanoyl, amino (wherein the amino is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic and heterocyclic groups, each of which may be further substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-1-yl or pyrazol-1-yl optionally substituted by 1 to 2 substituents selected from (which may be further substituted by alkoxycarbonyl, amino, amido or carbamoyl); Z 2 represents S or O, A 1 , A 2 and A 3 represent, independently of one another, N or C, with the proviso that R 5 , R 6 and R 12 does not exist, and A 1 , A 2 and A 3 Each represents N] or its salts; A pyrazolopyrimidine derivative represented by formula (XXX)

[0188] [ka]

[0189] [In the formula, R 14 is a halogen, C 1~6 Alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro and C 1~6 phenyl substituted by 1 to 5 substituents selected from alkoxy; R 15 is pentan-3-yl, or C 4~6 represents cycloalkyl, Z 3 represents S or O] or a salt thereof; and A pyrazolopyrimidine derivative represented by formula (XXXI)

[0190] [ka]

[0191] [In the formula, R 16 is hydrogen or C 1~6 represents alkyl, and the R 16 is N 1 or N 2 is bound to R 17 is C optionally substituted with hydroxy or alkoxy 1~6 alkyl; C optionally substituted with alkyl, hydroxy or alkoxy 3~7 Cycloalkyl; saturated 5- to 6-membered heterocycle optionally substituted with alkyl, hydroxy, or alkoxy; het 1 ; or Ar 1 represents; R 18 Ar 2 or C substituted with 1~6 Alkyl-substituted C 3~7 Cycloalkyl, OAr 2 , SAr 2 , NHC(O)C 1~6 Alkyl, het 2 C optionally substituted with 1 to 2 substituents selected from xanthine and naphthalene 1~6 represents alkyl; where Ar 1 and Ar 2 each independently represents a group represented by the following formula (XXXII):

[0192] [ka]

[0193] In the formula, R 19 , R 20 and R 21 are independently hydrogen, halogen, phenoxy, phenyl, CF3, OCF3, R 22 , S.R. 22 and OR 22 (where R 22is a phenyl optionally substituted het 3 or C 1~6 alkyl, and the phenyl is selected from halogen, CF3, OCF3, C 1~6 Alkyl and C 1~6 alkoxy), or R 19 and R 20 together form a 3 or 4 atom linker optionally containing 1 to 2 heteroatoms selected from O, S and N; het 1 , het 2 and het 3 represent a 5- to 6-membered aromatic heterocycle containing 1 to 3 heteroatoms independently selected from O, S, and N, which may be the same or different, and the heterocycle is 1~6 Alkyl, C 1~6 Optionally substituted with 1 to 3 substituents selected from alkoxy, halogen, and phenyl, wherein the phenyl is selected from halogen and C 1~6 further substituted with 1 to 3 substituents selected from alkyl], or a salt thereof.

[0194] In some examples, as disclosed in WO2004096811, the PDE9 inhibitor is a compound represented by formula (XXXIII):

[0195] [ka]

[0196] a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, wherein: A is,

[0197] [ka]

[0198] and P is (C-C)cycloalkyl, (C-C)heterocycloalkyl, aryl, or heteroaryl, including the carbon atom to which said P is attached, optionally independently substituted with 1 to 3 substituents independently selected from halogen, (C-C)alkyl, (C-C)alkoxy, and trifluoromethyl; J is O, S, -N(R 15 )-, -N(R 15 )CO-, -CON(R 15 )-, -SO2N(R 15 )-, or -N(R 15 ) SO2-; x is 0, 1, 2, 3, 4, 5 or 6; R 10 -CO2H, -CONR 30 R 31 , -NR 30 R 31 , or -N(R 15 )SO2R 40 and; R and R 2 are independently H or (C1-C3) alkyl; R 3 is (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl-methyl, (C3-C8)heterocycloalkyl, (C3-C8)heterocycloalkyl-methyl, aryl, or heteroaryl optionally independently substituted with 1 to 3 substituents independently selected from halogen atoms, hydroxy, oxo, (C1-C5)alkyl, and (C1-C5)alkoxy; R 5 is H or (C1-C5) alkyl; R 30 and R 31 are each taken separately and independently H, (C1-C5) alkyl, (C3-C8) cycloalkyl, (C3-C8) heterocycloalkyl, aryl, or heteroaryl, and said R 30 and R 31 is halogen, oxo, (C1-C5) alkyl, -CO2R 40 , -COR 40 , -OR 40 , -CONR 50 R51 , -NR 50 R 51 , and -SO2R 40 optionally independently substituted with 1 to 3 substituents independently selected from R 30 and R 31 is the R 30 and R 31 together with the nitrogen atom to which it is attached to form a 5- to 8-membered heterocycloalkyl ring, said ring optionally having one additional heteroatom independently selected from N, O and S, said 5- to 8-membered heterocycloalkyl ring being free of halogen, oxo, (C1-C5) alkyl, -COR 40 , -COR 40 , -OR 40 , -CONR 50 R 51 , -NR 50 R 51 , and -SO2R 40 optionally independently substituted with 1 to 3 substituents independently selected from: R 40 is H, (C1-C5)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl; R 50 and R 51 are each taken separately and independently H, (C1-C5)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl; or R 50 and R 51 is the R 50 and R 51 together with the nitrogen atom to which it is attached to form a 5- to 8-membered heterocycloalkyl ring, which optionally has one additional heteroatom independently selected from N, O, and S.

[0199]

[0097] In some examples, the PDE9 inhibitor is a compound represented by formula (XXXIV) or a salt thereof, as disclosed in US Pat. No. 8,901,126 and WO 2012 / 033101.

[0200] [ka]

[0201] During the ceremony, A is N or CH; R 1 is 2,3-dihydroisoindolyl, 1,3-dihydroisoindolyl or dihydropyrrolopyridyl, each of which may be substituted; R 2 is halogen, or lower alkyl, —O-lower alkyl, or cycloalkyl, each of which may be substituted; R 3 is lower alkyl, cycloalkyl or saturated heterocycle, each of which may be substituted.

[0202]

[0098] In some examples, as disclosed in U.S. Patent Publication No. 20030195205, the PDE9 inhibitor is a compound represented by formula (XXXV) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0203] [ka]

[0204] During the ceremony, R 1 is H or C 1~6 alkyl, and R 1 is N 1 or N 2 is bound to one of the following; R 2 is C optionally substituted with hydroxy or alkoxy 1~6 alkyl; C optionally substituted with alkyl, hydroxy or alkoxy 3~7Cycloalkyl; saturated 5- to 6-membered heterocycles optionally substituted with alkyl, hydroxy or alkoxy (preferably tetrahydrofuran, tetrahydrothiophene, pyrrolidine or piperidine); het 1 or Ar 1 and; R 3 Ar 2 ;C 1~6 C optionally substituted with alkyl 3~7 Cycloalkyl;OAr 2 ;SAr 2 ;NHC(O)C 1~6 alkyl;het 2 C optionally substituted with one or two groups independently selected from: xanthene; and naphthalene. 1~6 is alkyl; Ar 1 and Ar 2 are independently expressed by the formula:

[0205] [ka]

[0206] wherein R4, R5 and R6 are hydrogen, halo, phenoxy, phenyl, CF3, OCF 3、 R 7 , S.R. 7 and OR 7 are independently selected from R 7 het 3 By or halo, CF3, OCF3, C 1~6 Alkyl, and C 1~6 C optionally substituted by phenyl groups optionally substituted by 1, 2 or 3 groups independently selected from alkoxy 1~6 alkyl; or R 4 and R 5 may be linked to form a linkage of 3 or 4 atoms, said linkage optionally containing 1 or 2 heteroatoms independently selected from O, S, or N; het 1 , het 2 and het 3are 5-6 membered aromatic heterocycles containing 1, 2 or 3 heteroatoms independently selected from O, S and N, which may be the same or different, and said heterocycles are 1~6 Alkyl, C 1~6 Alkoxy, halo, and halo and C 1~6 optionally substituted with 1, 2, or 3 substituents independently selected from phenyl optionally substituted with 1, 2, or 3 groups independently selected from alkyl; however, a)R 1 N 1 Attached to atom, R 1 C 1~3 alkyl, and R 2 is propyl, R 3 Ar 1 Instead of methyl substituted with b)R 1 N 1 Attached to atom, R 1 C 1~6 alkyl, and R 2 is methyl, R 3 Ar 1 C replaced with 1~4 Not alkyl.

[0207] In some instances, as disclosed in WO2003037432, the PDE9 inhibitor is a compound represented by formula (XXXVI):

[0208] [ka]

[0209] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 1 is H or (C 1~6 ) alkyl; R 2 is (C1-C6) alkyl, straight or branched chain, (C3-C7) cycloalkyl or heteroaryl; R 3is a straight-chain or branched (C1-C6)alkyl optionally substituted with 1 to 2 groups independently selected from Ar, (C3-C7)cycloalkyl, OAr, SAr, NC(O)(C1-C6)alkyl, heteroaryl, xanthene, and naphthalene; Ar is a compound of the formula

[0210] [ka]

[0211] is the basis of In the formula, R 4 , R 5 and R 6 are independently selected from H, halo, phenoxy, phenyl, CF, OCF, S(C-C)alkyl, (C-C)alkyl, O(C-C)alkyl, wherein the alkyl is optionally substituted with heteroaryl or phenyl, and the phenyl group is optionally substituted with 1 to 3 groups selected from halo, CF, OCF, and (C-C)alkyl; or R 4 and R 5 may be joined to form a linkage consisting of (C2-C3)alkyl, said linkage optionally incorporating a heteroatom selected from O, S and N; heteroaryl is a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms independently selected from O, S and N, said heterocycle optionally being substituted with 1-3 substituents independently selected from (C1-C6)alkyl, halogen atoms and phenyl, said phenyl optionally being substituted with 1-3 groups independently selected from halogen atoms and (C1-C6)alkyl; with the proviso that R 1 is -CH3, R 2 must not be -CH2CH2CH3.

[0212]

[0100] In some examples, the PDE9 inhibitor is a compound represented by formula (XXXVII), as disclosed in US Pat. Nos. 10,889,591 and 1,1434,248.

[0213] [ka]

[0214] wherein X1, X2, X3, and X4 are, independently of one another, CR3 or N, and X1, X2, X3, and X4 are not simultaneously CR3; R3, each occurrence, is hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6 alkyl)2 aminocarbonyl, 4- to 6-membered heterocyclylcarbonyl, and 5- to 6-membered heteroaryloxy; C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6alkyl)2 aminocarbonyl, 4- to 6-membered heterocyclylcarbonyl and 5- to 6-membered heteroaryloxy are unsubstituted or substituted with hydroxy, amino, carboxyl, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, C 1~6 Alkylcarbonyloxy, C 3~6 Cycloalkyl, C 2~8 Alkynyl, halogenated C 1~6 Alkyl, C 2~8 Alkenyl, halogenated C 1~6 optionally substituted with one or more groups independently selected from the group consisting of alkoxy, unsubstituted or optionally substituted 4- to 6-membered heterocyclyl, and unsubstituted or optionally substituted heteroaryl; The substituents in the above-mentioned 4- to 6-membered heterocyclyl optionally substituted with a substituent and the heteroaryl optionally substituted with a substituent are hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl and C 1~6 selected from the group consisting of alkoxy; L is a single bond and -NH-(CH2) t - (wherein t is 0, 1, 2, or 3); The A ring is selected from the group consisting of 3-12 membered heterocyclyl, aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl, and 3-12 membered cycloalkenyl, wherein the 3-12 membered heterocyclyl has a heteroatom selected from one of O, S, N, or any combination thereof, and the S atom is optionally oxidized to S(O) or S(O)2, and the 5-10 membered heteroaryl has a heteroatom selected from one of O, S, and N, or any combination thereof; Each R1 is hydrogen, hydroxy, amino, carboxyl, cyano, nitro, a halogen atom, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 independently selected from the group consisting of alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclyl, aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with hydroxy, amino, carboxyl, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino and C 1~6 optionally substituted with a group selected from the group consisting of alkylsulfonylamino; m is 0, 1, 2 or 3; R2 is hydrogen, C 1~6 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and halogenated C 1~6alkyl.

[0215] In some embodiments, the PDE9 inhibitor is

[0216] [ka]

[0217] is selected from the group consisting of: In some embodiments, the PDE9 inhibitor is

[0218] [ka]

[0219] [ka]

[0220] [ka]

[0221] [ka]

[0222] [ka]

[0223] In some embodiments, the PDE9 inhibitor is selected from the group consisting of:

[0224] [ka]

[0225] In some embodiments, the PDE9 inhibitor is:

[0226] [ka]

[0227] In some embodiments, the PDE9 inhibitor is:

[0228] [ka]

[0229] is.

[0103] In some examples, as disclosed in WO2020 / 151636, the PDE9 inhibitor is a compound represented by formula (XXXVIII) or a pharmaceutically acceptable salt, isomer, deuterated compound, metabolite, or prodrug thereof.

[0230] [ka]

[0231] wherein X1, X2, X4 are independently selected from CR' or an N atom, X3 is selected from CR3 or an N atom, and X1, X2, X3, X4 are at least one N heteroatom, and the N heteroatom is

[0232] [ka]

[0233] may be optionally oxidized to; R' and R3 are hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1~6 Alkane Carbonyl, Amino Carbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6 alkyl)2 aminocarbonyl, 4- to 6-membered heterocyclylcarbonyl, and 5- to 6-membered heteroaryloxy; 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6 alkyl)2 aminocarbonyl, 4- to 6-membered heterocyclic carbonyl and 5- to 6-membered heteroaryloxy are unsubstituted or substituted with hydroxy, amino, carboxy, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, C 1~6 Alkylcarbonyloxy, C 3~6 Cycloalkyl, C 3~6 Cycloalkylcarbonyloxy, C 2~8 Alkynyl, halogenated C 1~6 Alkyl, C 2~8 Alkenyl, halogenated C 1~6 Alkoxy,

[0234] [ka]

[0235] optionally substituted with one or more independently selected from a 4- to 6-membered heterocyclic group which is unsubstituted or optionally substituted with one or more independent substituents, or heteroaryl which is unsubstituted or optionally substituted with one or more independent substituents; The substituents of the above 4- to 6-membered heterocyclic group optionally substituted with one or more independent substituents and the heteroaryl group optionally substituted with one or more independent substituents are hydroxy, amino, carboxy, cyano, nitro, halogen atoms, C 1~6 Alkyl and C 1~6 selected from alkoxy; Y is selected from metal ions or organic ammonium ions; preferably Na + , K. + , NH4 + and; L is a single bond, -NH-(CH2) t - where t is 0, 1, 2 or 3; Ring A is a 3- to 12-membered heterocyclic group, a 5- to 10-membered heteroaryl group, a 3- to 12-membered cycloalkyl group, or a 3- to 12-membered cycloalkenyl group, wherein the heteroatoms of the 3- to 12-membered heterocyclic group are selected from one of O, S, and N, or any combination thereof, and the S atom is optionally oxidized to S(O) or S(O)2, the C atom is optionally oxidized to C(O), and the N heteroatom is

[0236] [ka]

[0237] optionally oxidized to the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one of O, S, and N, or any combination thereof; Each R1 is hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, a halogen atom, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 independently selected from alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclic group, aryl, and 5- to 10-membered heteroaryl, wherein C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkanoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclyl, aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with hydroxy, amino, carboxy, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino and C 1~6 optionally selected from alkylsulfonylamino group substitutions; m is 0, 1, 2 or 3; R2 is hydrogen, C 1~6 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, halogenated C 1~6 alkyl; The requirements are: (1) When X2 is N, X1 is CH, X3 is CR3, and X4 is CH, ring A is

[0238] [ka]

[0239] and (i)

[0240] [ka]

[0241] but,

[0242] [ka]

[0243] If R3 is not H; (ii)

[0244] [ka]

[0245] but,

[0246] [ka]

[0247] If R3 is not Cl; (iii)

[0248] [ka]

[0249] but,

[0250] [ka]

[0251] When R3 is H,

[0252] [ka]

[0253] rather than; (2) X2 and X4 are N, X1 is CH, X3 is CR3, and the A ring is

[0254] [ka]

[0255] and when m is 0, R3 is not a methylthio group; (3) X4 is N, X1 and X2 are each CH, X3 is CR3, and ring A is

[0256] [ka]

[0257] and when m is 0, R3 is not hydrogen; (4) X1 is N, X2 and X4 are CR', X3 is CR3, and ring A is pyrrolidinyl,

[0258] [ka]

[0259] When m is 0, R2 is either H or C 1~6 Not alkyl, Preferably, X2 is N, X1 is CH, X3 is CR3, and X4 is CH;

[0260] [ka]

[0261] but,

[0262] [ka]

[0263] When R3 is isopropyl, cyclopropyl, hydroxymethyl,

[0264] [ka]

[0265] C 1~6 Alkyl carbonyl, C 1~6 Alkylcarbonyloxy C 1~6 Alkyl,

[0266] [ka]

[0267] C replaced with 1~6 Alkyl, C 3~6 Cycloalkylcarbonyloxy C 1~6 Alkyl, deuterated C 1~6 alkyl; Preferably, when X2 is N, X1 is CH, X3 is CR3, and X4 is CH, the A ring is

[0268] [ka]

[0269] is.

[0104] In some examples, as disclosed in WO2020 / 143626, the PDE9 inhibitor is a compound represented by formula (XXXIX), or a pharmaceutically acceptable salt or isomer thereof.

[0270] [ka]

[0271] Each R2 is hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4- to 6-membered heterocyclic group, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6 alkyl)2 aminocarbonyl, aryl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclylcarbonyl, and 5- to 6-membered heteroaryloxy; 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4- to 6-membered heterocyclic group, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6alkyl)2 aminocarbonyl, aryl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclylcarbonyl, and 5- to 6-membered heteroaryloxy groups are unsubstituted or optionally substituted with hydroxy, amino, carboxy, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, C 1~6 Alkylcarbonyloxy, C 3~6 Cycloalkyl, C 2~8 Alkynyl, halogenated C 1~6 Alkyl, C 2~8 Alkenyl, halogenated C 1~6 one or more independently selected from alkoxy, an unsubstituted or optionally substituted 4- to 6-membered heterocyclic group, and an unsubstituted or substituted heteroaryl group; The substituents of the 4- to 6-membered heterocyclic group optionally substituted with a substituent and the heteroaryl optionally substituted with a substituent are hydroxy, amino, carboxy, cyano, nitro, halogen, C 1~6 Alkyl and C 1~6 selected from the group consisting of alkoxy; L is a single bond, -NH-(CH2) t - where t is 0, 1, 2 or 3; Ring A is a 3-8 membered monoheterocyclic group, a 6-12 membered bridged heterocyclic group, a 6-12 membered spiroheterocyclic group, a 6-12 membered heterocyclic group, an aryl group, a 5-10 membered heteroaryl group, a 3-12 membered cycloalkyl, a 3-12 membered cycloalkenyl, wherein the heteroatoms of the heterocyclic group are selected from one of O, S and N, or any combination thereof, and the S atom is optionally oxidized to S(O) or S(O)2, the C atom is optionally oxidized to C(O), and the heteroatom of the 5-10 membered heteroaryl is selected from one of O, S and N, or any combination thereof; Each R1 is hydrogen, hydroxy, amino, carboxy, cyano, nitro, a halogen atom, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 independently selected from alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclic group, aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with hydroxy, amino, carboxy, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino and C 1~6 optionally selected from alkylsulfonylamino-substituted; m and n are independently 0, 1, 2, or 3; When ring A is a 3- to 8-membered monoheterocycle, R2 is not hydrogen; When ring A is phenyl, L is not a bond; The A ring is

[0272] [ka]

[0273] When R2 is not hydrogen.

[0105] In some examples, the PDE9 inhibitor is a compound represented by formula (XXXX) or a pharmaceutically acceptable salt thereof, as disclosed in US Pat. No. 10,370,336.

[0274] [ka]

[0275] During the ceremony, R 3 teeth, (1)-CN, (2)-CH3, and (3)-CF3 selected from the group consisting of: R 5 , R 6 and R 7 teeth, (1) Hydrogen, (2) C 1~6 alkyl, and (3) Fluoro are independently selected from the group consisting of: or R 5 and R 6 is the R 5 and R 6 together with the carbon atom to which it is attached form a fused phenyl ring.

[0276]

[0106] In some examples, the PDE9 inhibitor is a compound represented by formula (XXXXI) or a pharmaceutically acceptable salt thereof, as disclosed in US Pat. Nos. 10,934,294 and 11,028,092.

[0277] [ka]

[0278] During the ceremony, A is a cyclobutyl ring, which is unsubstituted or substituted with a substituent selected from fluoro and methyl; R 1 , R 2 and R 3 teeth, (1) Hydrogen, (2) halogens, (3) hydroxy, (4) C which is unsubstituted or substituted with a substituent selected from hydroxy and fluoro. 1~6 Alkyl, (5) —OC, which is unsubstituted or substituted with a substituent selected from fluoro 1~6 Alkyl, (6) C 3~6 cycloalkyl, (7) C 2~6 alkynyl, and (8)-CN are independently selected from; R 4 teeth, (1) Hydrogen, (2)-CH3, (3)-CF3, (4)-CH2OH, (5)-CO2H, and (6)-CH2CH3 Selected from; R 5 is a phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring, and the phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring is a , R 1b and R 1c is replaced by R 1a , R 1b and R 1c teeth, (1) Hydrogen, (2) halogens, (3) hydroxy, (4) C which is unsubstituted or substituted with a substituent selected from hydroxy and fluoro. 1~6 Alkyl, (5) —OC, which is unsubstituted or substituted with a substituent selected from fluoro 1~6 Alkyl, (6) C 3~6 cycloalkyl, and (7)-CN are independently selected from

[0279]

[0107] In some examples, the PDE9 inhibitor is a compound represented by formula (XXXXII) or a pharmaceutically acceptable salt thereof, as disclosed in US Pat. No. 10,370,337.

[0280] [ka]

[0281] During the ceremony, R 5 teeth, (1) -C, which is unsubstituted or substituted with hydroxy, oxetane, or allyl 1~6 Alkyl, (2)-tetrahydropyranyl, and (3)-C 6~7 cycloalkyl is selected from the group consisting of:

[0282] In one embodiment herein, R 5 But C 1~6 alkyl, 1~6 Includes compounds where the alkyl is unsubstituted or substituted with hydroxy, oxetane, or allyl.

[0283]

[0108] In some examples, as disclosed in US Patent Publication No. 20220017526, the PDE9 inhibitor is a compound represented by Formula (XXXXIII) or a pharmaceutically acceptable salt thereof:

[0284] [ka]

[0285] During the ceremony, X is -N(R 6 )- or -C(R 8 R 9 )-and; Y is -N= or -CH=; Z is -N= or -CH=; R 1 , R 2 and R 3 teeth, (1) Hydrogen, (2) halogens, (3) hydroxy, (4) C which is unsubstituted or substituted with a substituent selected from hydroxy and fluoro. 1~6 Alkyl, (5) —OC, which is unsubstituted or substituted with a substituent selected from fluoro 1~6 Alkyl, (6) C 3~6 cycloalkyl, (7) C 2~6 alkynyl, and (8)-CN are independently selected from; R 4 teeth, (1) Hydrogen, (2)-CH3, (3)-CF3, (4)-CH2OH, (5)-CO2H, and (6)-CH2CH3 Selected from; R 5 is a phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring, and the phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring is R 1a , R1b and R 1c is replaced by R 1a , R 1b and R 1c teeth, (1) Hydrogen, (2) halogens, (3) hydroxy, (4) C which is unsubstituted or substituted with a substituent selected from hydroxy and fluoro. 1~6 Alkyl, (5) —OC, which is unsubstituted or substituted with a substituent selected from fluoro 1~6 Alkyl, (6) C 3~6 cycloalkyl, (7) azetidine, morpholine, piperidine, or pyrrolidine, and (8)-CN are independently selected from; R 6 teeth, (1) hydrogen, and (2) C 1~6 Alkyl is selected from R 7 teeth, (1) Hydrogen, (2) C which is unsubstituted or substituted with a substituent selected from hydroxy and fluoro 1~6 Alkyl, (3) C 2~6 alkenyl, (4) C which is unsubstituted or substituted with a substituent selected from hydroxy and fluoro. 3~6 cycloalkyl, (5) Azetidine, morpholine, piperidine, or pyrrolidine Selected from; or R 6 and R 7 is the R 6 and R 7 together with the -CH-N- to which it is attached to form an azetidine or pyrrolidine ring; R 8 and R 9 teeth, (1) hydrogen, and (2) C 1~6 Alkyl are independently selected from

[0286]

[0109] In some examples, the PDE9 inhibitor is a compound represented by formula (XXXXIV) or a pharmaceutically acceptable salt thereof, as disclosed in US Pat. No. 10,376,504.

[0287] [ka]

[0288] During the ceremony, R 5 teeth, (1) hydrogen, and (2)-C 1~6 Alkyl selected from the group consisting of: R 6 is unsubstituted or oxetane-substituted -C 1~6 is alkyl, or R 5 and R 6 is the R 5 and R 6 -C through the nitrogen atom to which it is bonded 3~6 Together with the alkyl, they form an azetidine, pyrrolidine, piperidine or azepane ring, which is unsubstituted or contains one or two -C 1~6 It is substituted with alkyl.

[0289]

[0110] In some examples, as disclosed in US Patent Publication No. 20220017525, the PDE9 inhibitor is a compound represented by Formula (XXXXV) or a pharmaceutically acceptable salt thereof:

[0290] [ka]

[0291] During the ceremony, A is a pyrazinyl, pyrazolyl, pyridyl, pyridyl-N-oxide, 5-pyrimidinyl, pyridazinyl, pyrrolopyrazolyl, dihydropyrrolopyrazolyl, morpholinyl, oxomorpholinyl, or oxadiazolyl ring; R 1 , R 2 and R 3 If exists, (1) Hydrogen, (2) halogens, (3) hydroxy, (4) C which is unsubstituted or substituted with a substituent selected from hydroxy and fluoro. 1~6 Alkyl, (5) —OC, which is unsubstituted or substituted with a substituent selected from fluoro 1~6 Alkyl, (6) C 3~6 cycloalkyl, (7) C 2~6 alkynyl, and (8)-CN are independently selected from; R 4 teeth, (1) Hydrogen, (2)-CH3, (3)-CF3, (4)-CH2OH, (5)-CO2H, and (6)-CH2CH3 Selected from; R 5 is a phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring, and the phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring is a , R 1b and R 1c is replaced by R 1a , R 1b and R 1c If exists, (1) Hydrogen, (2) halogens, (3) hydroxy, (4) C which is unsubstituted or substituted with a substituent selected from hydroxy and fluoro. 1~6 Alkyl, (5) —OC, which is unsubstituted or substituted with a substituent selected from fluoro 1~6 Alkyl, (6) C 3~6 cycloalkyl, and (7)-CN are independently selected from

[0292]

[0111] In some examples, as disclosed in PCT / EP2015 / 062140, the PDE9 inhibitor is a 1-benzyl-2,5,6,8-tetrahydro-3-oxo-2,7-naphthyridine-4-carbonitrile compound represented by formula (XXXXVI) and its pharmaceutically acceptable acid addition salts.

[0293] [ka]

[0294] During the ceremony, R is -COCH2R 2 , COO-C 1~6 -Alkyl, CH2CONR 3 R 4 , pyridinyl, pyrimidinyl or C 1~6 -C optionally substituted with alkoxy 1~6 -alkyl, and R 2 is C 1~6 -morpholinyl or piperazinyl optionally substituted with alkyl; R 3 and R 4 is C 1~6 -independently selected from alkyl and benzyl, or R 3 and R 4 together with the nitrogen to which they are attached, C 1~6 -forming morpholinyl or piperazinyl optionally substituted with alkyl.

[0295]

[0112] In some examples, the PDE9 inhibitor is a compound represented by formula (XXXXVII), or a pharmaceutically acceptable salt thereof, as disclosed in US Patent No. 8,822,448 and WO2012 / 033144.

[0296] [ka]

[0297] During the ceremony, R 1 and R 2 one of which is hydrogen, halogen, halogeno lower alkyl, lower alkyl, -O-lower alkyl or cycloalkyl, each of which may be substituted, and the other is a group of formula (II):

[0298] [ka]

[0299] ) and R 3 is lower alkyl, cycloalkyl or saturated heterocycle, each of which may be substituted; R 4 , R 5 and R 6 are the same or different and each is a hydrogen atom or a lower alkyl; R a and R b are the same or different and each is hydrogen, or lower alkyl, cycloalkyl, aryl, or a heterocycle, any of which may each be substituted; or R a and R b is bonded to the adjacent nitrogen atom to form an optionally substituted monocyclic nitrogen-containing heterocycle or polycyclic nitrogen-containing heterocycle.

[0300]

[0113] In some examples, the PDE9 inhibitor is a compound represented by formula (I-1), or a pharmaceutically acceptable salt thereof, as disclosed in US Pat. No. 8,822,448 and WO2012 / 033144.

[0301] [ka]

[0302] During the ceremony, R 11 and R 21 is hydrogen, halogen, lower alkyl, -O-lower alkyl or cycloalkyl, each of which may be substituted, and the other is a group of formula (II-1):

[0303] [ka]

[0304] and R 31 is lower alkyl, cycloalkyl or saturated heterocycle, each of which may be substituted; R 41 , R 51 and R 61 are the same or different and each is hydrogen or lower alkyl; R a1 and R b1 are the same or different and each is hydrogen, or lower alkyl, cycloalkyl, aryl, or a heterocycle, any of which may each be substituted; or R a1 and R b1 is bonded to the adjacent nitrogen atom to form a monocyclic nitrogen-containing heterocycle or a polycyclic nitrogen-containing heterocycle, each of which may be substituted.

[0305]

[0114] In some examples, the PDE9 inhibitor is a compound represented by formula (XXXVIII), or a pharmaceutically acceptable salt thereof, as disclosed in US Pat. No. 9,550,776.

[0306] [ka]

[0307] In the formula, R 1 is expressed as follows:

[0308] [ka]

[0309] a group represented by The following formula:

[0310] [ka]

[0311] A group represented by or the following formula:

[0312] [ka]

[0313] and R 2 is a 3-methyltetrahydro-2H-pyran-4-yl group or a 4-methoxycyclohexyl group.

[0115] In some instances, the PDE9 inhibitor is a compound represented by formula (XXXXIX), as disclosed in US Pat. No. 9,550,776.

[0314] [ka]

[0315] In the formula, R 3is expressed as follows:

[0316] [ka]

[0317] a group represented by or the following formula:

[0318] [ka]

[0319] is a group represented by In some examples, as disclosed in US9540380 and WO2012 / 040230, the PDE9 inhibitor is a compound represented by formula (L):

[0320] [ka]

[0321] or a pharmaceutically acceptable salt thereof. During the ceremony, X is selected from a single bond, C(O) or S(O)2; R1 is independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyloxy, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl, and heterocycloalkyloxy, each of which is selected from the group consisting of halogen (e.g., F or Cl), —S(O)2(C1-C4)alkyl, OH, —C(O)—(C1-C4)alkyl, oxo, CN , (C1-C6)alkyl, (C1-C4)alkoxy, (C3-C7)cycloalkyl, —C(O)NH(C1-C4)alkyl, —C(O)N[(C1-C4)alkyl(C1-C4)alkyl], (C1-C4 alkyl)-C(O)—, (C1-C4)alkylsulfonyl-, —S(O)2NH(C1-C4)alkyl, and —S(O)2N[(C1-C4)alkyl(C1-C4)alkyl]; R2 is (C1-C6) alkyl, (C3-C 10 )cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4)alkyl, restricted phenyl, and restricted phenyl(C1-C4)alkyl, each of which is independently selected from the group consisting of halogen (e.g., F or Cl), —S(O)2(C1-C4)alkyl, OH, —C(O)—(C1-C4)alkyl, oxo, CN, (C1-C6) optionally substituted with one or more substituents selected from the group consisting of alkyl, (C1-C4)alkoxy, (C3-C7)cycloalkyl, -C(O)NH(C1-C4)alkyl, -C(O)N[(C1-C4)alkyl(C1-C4)alkyl], (C1-C4 alkyl)-C(O)-, (C1-C4)alkylsulfonyl-, -S(O)2NH(C1-C4)alkyl, and -S(O)2N[(C1-C4)alkyl(C1-C4)alkyl]; R3 is independently selected from the group consisting of (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4)alkyl, restricted phenyl, and restricted phenyl(C1-C4)alkyl, each of which is selected from the group consisting of halogen (e.g., F or Cl), —S(O)2(C1-C4)alkyl, OH, —C(O)—(C1-C4)alkyl, oxo , CN, (C1-C6)alkyl, (C1-C4)alkoxy, (C3-C7)cycloalkyl, —C(O)NH(C1-C4)alkyl, —C(O)N[(C1-C4)alkyl(C1-C4)alkyl], (C1-C4 alkyl)-C(O)—, (C1-C4)alkylsulfonyl-, —S(O)NH(C1-C4)alkyl, and —S(O)N[(C1-C4)alkyl(C1-C4)alkyl].

[0322] In some instances, as disclosed in WO2008 / 139293, the PDE9 inhibitor is a compound represented by formula (LI):

[0323] [ka]

[0324] and pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, halo, and (C1-C4) haloalkyl; R1 is selected from the group consisting of hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl, and cyclopropyl; R2 is selected from the group consisting of heteroaryl selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and ER5, wherein the heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4) alkyl, and (C1-C4) haloalkyl; R3 is selected from the group consisting of hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, and (C1-C4) haloalkyl; E is selected from the group consisting of -CH2-, -CH2CH2-, -CH2CH2CH2- and -C(O)-; R 5 is selected from the group consisting of (C3-C8)cycloalkyl, heterocycloalkyl, aryl, aryloxy, and heteroaryl, any of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3-C8)cycloalkyl, halo, cyano, phenyl, morpholinyl, (C1-C4)alkylamino, pyrazolyl, triazolyl, and imidazolyl; Preferably, R is selected from the group consisting of ethyl, isopropyl, trifluoroethyl, cyclobutyl, cyclopentyl, difluorocyclohexyl, methoxyphenyl, and tetrahydro-2H-pyran-4-yl; R is hydrogen or methyl; R is methyl, trifluoroethyl, trifluorobutyl, pyrimidinyl, trifluoromethylpyrimidinyl, or ER; R is methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, or cyclopropyl; E is -CH or -C(O)-; R is substituted or unsubstituted cyclopentyl, morpholinyl, phenyl, naphthyl, benzyloxy, pyrimidinyl, selected from pindinyl, quinolinyl, quinoxalinyl, pyrazinyl, pyrazolyl, benzimidazolyl, cinnolinyl, naphthyridinyl, pyrido[2,3-b]pyrazinyl, imidazo[4,5-c]pyridinyl, benzothiadiazolyl, tetrahydropyrazolo[1,5-a]pyridinyl, dihydrobenzodioxinyl, imidazolyl, dihydrobenzofuranyl, triazolyl, oxazolyl, isoxazolyl, benzodioxinyl, thiazolyl, imidazo[1,2-a]pyridinyl, tetrahydrobenzothiazolyl, dihydrobenzoxazinyl, tetrahydropyranyl, tetrahydropyrazolo[1,5-a]azeptanyl, dihydropyrrolo[1,2-b]pyrazolyl; More preferably, R is selected from the group consisting of isopropyl, cyclobutyl, cyclopentyl, and tetrahydro-2H-pyranyl, R is hydrogen, R is ER, R is methyl or ethyl, E is -CH, and R is selected from the group consisting of phenyl, pyrimidin-2-yl, pyridin-2-yl, pyrazin-2-yl, and 5-methylpyrazin-2-yl.

[0325] In some examples, as disclosed in WO2010 / 084438, the PDE9 inhibitor is a compound represented by formula (LII):

[0326] [ka]

[0327] and pharmaceutically acceptable salts thereof, wherein: R 1 is (i) hydrogen, (ii) (C1-C4) alkyl, (iii) (C2-C4) alkenyl, (iv) (C2-C4) alkynyl, (v) (C1-C4) alkoxy, (vi) (C1-C4) haloalkyl, (vii) (C3-C6) cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, cyano, carboxy, and carbamoyl; (viii) (C1-C4) alkyl, (C1-C4) alkoxy, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, cyano, carboxy, and carbamoyl; (ix) aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, cyano, carboxy, and carbamoyl; and (x) heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, cyano, carboxy, and carbamoyl; R 2 is selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, and (C3-C6) cycloalkyl; R 3 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halo, and (C1-C4)haloalkyl; n is 1 or 2; A is -CR4 R 5 -or- CHR a -CHR b - and; R 4 is (i) hydrogen, (ii) (C1-C7) alkyl, (iii) (C3-C8) cycloalkyl, (iv) 4- to 10-membered heterocycloalkyl, (v) aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, (C3-C6) cycloalkyl, cyano, carboxy, and carbamoyl, (vi) heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, (C3-C6) cycloalkyl, cyano, carboxy, and carbamoyl, and (vii) LR 6 is selected from the group consisting of where: L is -CH2-, -NR 7 - and -O-; R 6 is aryl, heteroaryl, (C1-C8)alkyl, (C3-C8)cycloalkyl, 4- to 10-membered heterocycloalkyl, or (C1-C8)alkoxy, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, halo, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C3-C6)cycloalkyl, cyano, carboxy, and carbamoyl; R 7 is hydrogen, methyl or ethyl; R 5 is selected from the group consisting of hydrogen, hydroxy, (C1-C4)alkoxy, halogen, and (C1-C6)alkyl; or R 4 and R 5 is R 4 and R 5together with the carbon to which is attached form a cycloalkyl or heterocycloalkyl ring optionally incorporating an oxo group, further optionally substituted with (C1-C8)alkyl, (C3-C8)cycloalkyl, halo, (C1-C8)alkoxy, or (C1-C3)haloalkyl; R a is (C1-C4)alkoxy or R 8 -OC(O)- and R 8 is (C1-C4) alkyl; R b is aryl, heteroaryl, or heterocycloalkyl optionally substituted with halo, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C1-C8)alkoxy, or (C1-C3)haloalkyl; or R a and R b is R a and R b together with the carbon to which it is attached form a cycloalkyl or heterocycloalkyl ring, optionally incorporating an oxo group, further optionally substituted with (C1-C8)alkyl, (C3-C8)cycloalkyl, halo, (C1-C8)alkoxy, or (C1-C3)haloalkyl.

[0328]

[0119] In some examples, as disclosed in WO2014024125, the PDE9 inhibitor is a compound represented by formula (LIII), and salts thereof, including pharmaceutically acceptable salts, as well as optically active diastereoisomers and mixtures thereof.

[0329] [ka]

[0330] During the ceremony, R 1 represents a hydrogen atom or methyl; R 1 If represents a hydrogen atom, R 2 represents cyclopentyl, tetrahydropyranyl, cyclohexyl, or cyclohexyl substituted by one or two halogen atoms; R1 If represents methyl, R 2 represents cyclopentyl; R 3 is - phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from F, CI, Br, I and OCH3; - 6-10 membered heteroaryl, wherein the 6-10 membered heteroaryl has 1-3 heteroatoms independently selected from O, N and S. and Q represents C1-C3-alkylene which is unsubstituted or substituted with 1 to 3 C1-C3-alkyl.

[0331] In some instances, as disclosed in US2004220186, the PDE9 inhibitor is a compound represented by formula (LIV):

[0332] [ka]

[0333] or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, wherein A is,

[0334] [ka]

[0335] and P is (C-C)cycloalkyl, (C-C)heterocycloalkyl, aryl, or heteroaryl, including the carbon atom to which said P is attached, optionally independently substituted with 1 to 3 substituents independently selected from halogen, (C-C)alkyl, (C-C)alkoxy, and trifluoromethyl; J is O, S, -N(R 15 )-, -N(R 15 )CO-, -CON(R 15 )-, -SO2N(R15 )-, or -N(R 15 )SO2-; x is 0, 1, 2, 3, 4, 5 or 6; R 10 -CO2H, -CONR 30 R 31 , -NR 30 R 31 , or -N(R 15 )SO2R 40 and; R 1 and R 2 are independently H or (C1-C3) alkyl; R 3 is (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl-methyl, (C3-C8)heterocycloalkyl, (C3-C8)heterocycloalkyl-methyl, aryl, or heteroaryl, optionally independently substituted with 1 to 3 substituents independently selected from halogen, hydroxy, oxo, (C1-C5)alkyl, and (C1-C5)alkoxy; R 15 is H or (C1-C5) alkyl; R 30 and R 31 are each taken separately and independently selected from H, (C1-C5) alkyl, (C3-C8) cycloalkyl, (C3-C8) heterocycloalkyl, aryl, or heteroaryl, and said R 30 and R 31 is halogen, oxo, (C1-C5) alkyl, -CO2R 40 , -COR 40 , -OR 40 , -CONR 50 R 51 , -NR 50 R 51 , and -SO2R 40 optionally independently substituted with 1 to 3 substituents independently selected from R 30 and R 31 is the R 30 and R 31together with the nitrogen atom to which it is attached to form a 5- to 8-membered heterocyclyl ring which optionally further contains one additional heteroatom independently selected from N, O, and S, and the 5- to 8-membered heterocycloalkyl ring is optionally substituted with a halogen atom, oxo, (C1-C5) alkyl, -COR 40 , -COR 40 , -OR 40 , -CONR 50 R 51 , -NR 50 R 51 , and -SO2R 40 optionally independently substituted with 1 to 3 substituents independently selected from: R 40 is H, (C1-C5)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl; R 50 and R 51 are each taken separately and independently selected from H, (C1-C5)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl; or R 50 and R 51 is the R 50 and R 51 together with the nitrogen atom to which it is attached to form a 5- to 8-membered heterocycloalkyl ring, which may optionally further contain one additional heteroatom independently selected from N, O, and S.

[0336] In some instances, as disclosed in WO2003037432, the PDE9 inhibitor is a compound represented by formula (LV):

[0337] [ka]

[0338] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 1is H or (C 1~6 ) alkyl; R 2 is (C1-C6) alkyl, straight or branched chain, (C3-C7) cycloalkyl or heteroaryl; R 3 is a straight-chain or branched (C1-C6)alkyl optionally substituted with 1 to 2 groups independently selected from Ar, (C3-C7)cycloalkyl, OAr, SAr, NC(O)(C1-C6)alkyl, heteroaryl, xanthene, and naphthalene; Ar is a compound of the formula

[0339] [ka]

[0340] where R 4 , R 5 and R 6 are independently selected from H, halo, phenoxy, phenyl, CF3, OCF3, S(C1-C6)alkyl, (C1-C6)alkyl, O(C1-C6)alkyl, where the alkyl is optionally substituted with a heteroaryl group or a phenyl group, where the phenyl group is optionally substituted with 1 to 3 groups selected from halo, CF3, OCF3, and (C1-C6)alkyl; or R 4 and R 5 may be joined to form a linkage consisting of (C2-C3)alkyl, which may optionally incorporate a heteroatom selected from O, S, and N; heteroaryl is a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms independently selected from O, S, and N, which heterocycle may optionally be substituted with 1-3 substituents independently selected from (C1-C6)alkyl, halogen atoms, and phenyl, which may optionally be substituted with 1-3 groups independently selected from halo and (C1-C6)alkyl; with the proviso that R 1 is -CH3, R 2 must not be -CH2CH2CH3.

[0341]

[0122] In some cases, as disclosed in U.S. Patent Application Publication No. 20220089593, the PDE9 inhibitor is a compound represented by formula (LVI) or a pharmaceutically acceptable salt, isomer, deuterated compound, metabolite or prodrug thereof.

[0342] [ka]

[0343] During the ceremony, X1, X2, and X4 are independently selected from CR' and N; X3 is selected from CR3 and N, and at least one of X1, X2, X3, and X4 is N; The N heteroatom is

[0344] [ka]

[0345] optionally oxidized to; R' and R3 each occurrence are hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6alkyl)2 aminocarbonyl, 4- to 6-membered heterocyclylcarbonyl, and 5- to 6-membered heteroaryloxy; 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1~6 Alkylcarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, (C 1~6 alkyl)2 aminocarbonyl, 4- to 6-membered heterocyclylcarbonyl and 5- to 6-membered heteroaryloxy are unsubstituted or substituted with hydroxy, amino, carboxyl, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, C 1~6 Alkylcarbonyloxy, C 3~6 Cycloalkyl, C 3~6 Cycloalkylcarbonyloxy, C 2~8 Alkynyl, halogenated C 1~6 Alkyl, C 2~8 Alkenyl, halogenated C 1~6 Alkoxy,

[0346] [ka]

[0347] optionally substituted with one or more groups independently selected from 4- to 6-membered heterocyclyl which is unsubstituted or optionally substituted with one or more independent substituents and heteroaryl which is unsubstituted or optionally substituted with one or more independent substituents; The substituents of the above 4- to 6-membered heterocyclyl optionally substituted by one or more independent substituents and the heteroaryl optionally substituted by one or more independent substituents are hydroxy, amino, carboxyl, cyano, nitro, halogen atoms, C 1~6 Alkyl and C 1~6 selected from alkoxy; Y is selected from metal ions or organic ammonium ions, preferably Na + Ion, K + ion, NH4 + ions; L is a single bond, -NH-(CH2) t - where t is 0, 1, 2 or 3; The A ring is a 3- to 12-membered heterocyclyl, a 5- to 10-membered heteroaryl, a 3- to 12-membered cycloalkyl, or a 3- to 12-membered cycloalkenyl, wherein the 3- to 12-membered heterocyclyl has a heteroatom selected from one of O, S, and N, or any combination thereof, wherein the S atom is optionally oxidized to S(O) or S(O)2, the C atom is optionally oxidized to C(O), and the N heteroatom is

[0348] [ka]

[0349] optionally oxidized to The 5- to 10-membered heteroaryl has heteroatoms selected from one of O, S, and N, or any combination thereof; Each R1 is hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 independently selected from alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclyl, aryl, and 5- to 10-membered heteroaryl; 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl) 2 amino, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclyl, aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with hydroxy, amino, carboxyl, cyano, nitro, halogen atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 1~6 Alkylamino, (C 1~6 Alkyl)2amino, C 1~6 Alkylcarbonylamino and C 1~6 optionally substituted with the group selected from alkylsulfonylamino; m is 0, 1, 2 or 3; R2 is hydrogen, C 1~6 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and halogenated C 1~6 alkyl; however, (1) When X2 is N, X1 is CH, X3 is CR3, and X4 is CH, ring A is

[0350] [ka]

[0351] and (i)

[0352] [ka]

[0353] but,

[0354] [ka]

[0355] If R3 is not H;

[0356] [ka]

[0357] teeth,

[0358] [ka]

[0359] and (ii)

[0360] [ka]

[0361] but,

[0362] [ka]

[0363] If R3 is not Cl; (iii)

[0364] [ka]

[0365] If R3 is not H, (2) X2 and X4 are each N, X1 is CH, X3 is CR3, and ring A is

[0366] [ka]

[0367] and when m is 0, R3 is not methylthio; (3) X4 is N, X1 and X2 are each CH, X3 is CR3, and ring A is

[0368] [ka]

[0369] and when m is 0, R3 is not hydrogen; (4) X1 is N, X2 and X4 are each CR', X3 is CR3, and ring A is pyrrolidinyl or

[0370] [ka]

[0371] When m is 0, R2 is either H or C 1~6 Not alkyl, Preferably, X2 is N, X1 is CH, X3 is CR3, and X4 is CH;

[0372] [ka]

[0373] but,

[0374] [ka]

[0375] When R3 is isopropyl, cyclopropyl, hydroxymethyl,

[0376] [ka]

[0377] C 1~6 Alkyl carbonyl, C 1~6 Alkylcarbonyloxy C 1~6 Alkyl,

[0378] [ka]

[0379] C replaced with 1~6 Alkyl, C 3~6 Cycloalkylcarbonyloxy C 1~6 Alkyl and deuterated C 1~6 alkyl; Preferably, when X2 is N, X1 is CH, X3 is CR3, and X4 is CH, the A ring is

[0380] [ka]

[0381] is.

[0123] In some examples, as disclosed in U.S. Patent Nos. 9,643,970 and 9,993,477, the PDE9 inhibitor is a compound represented by formula (LVII) (i.e., a 7H-imidazo[1,5-a]pyrazin-8-one skeleton) and its tautomers, pharmaceutically acceptable acid addition salts, and polymorphs thereof.

[0382] [ka]

[0383] During the ceremony, R2 may be cyclized with R1 or R3; R1, R2 and R3 are as follows: When R1 cyclizes with R2,

[0384] [ka]

[0385] and R7 is selected from the group consisting of H, -CH3, -C2H5 and -C3H7; * indicates the cyclization position, When not cyclized, R1 is H and

[0386] [ka]

[0387] is selected from the group consisting of R7 is selected from the group consisting of H, -CH3, -C2H5 and -C3H7; R2 is

[0388] [ka]

[0389] is a compound selected from the group consisting of R8 and R12 are independently selected from the group consisting of H, -CH3, -C2H5 and -C3H7; * indicates the cyclization position, When R3 is cyclized with R2, R3 is

[0390] [ka]

[0391] and * indicates the cyclization position, R9 is H, C1-C6 alkyl, branched C3-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, substituted C6-C 10 Aryl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, C1-C6 alkoxy, branched C3-C6 alkoxy, C3-C6 cycloalkoxy, C6-C 10 Aryloxy, substituted C6-C 10 selected from the group consisting of aryloxy, C3-C9 heteroaryloxy, and substituted C3-C9 heteroaryloxy; When not cyclized, R3 is

[0392] [ka]

[0393] and During the ceremony, R10 is selected from the group consisting of H, -CH3, and -C2H5; R11 is C6~C 10 Aryl, substituted C6-C 10 selected from the group consisting of aryl, C3-C9 heteroaryl, and substituted C3-C9 heteroaryl; R4 is selected from the group consisting of hydrogen, -CH3, -C2H5, -C3H7, -CF3, -CN, an F atom, and a Cl atom; R5 is C6~C 10 Aryl, substituted C6-C 10 selected from the group consisting of aryl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, C3-C6 heterocyclyl, substituted C3-C6 heterocyclyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl; R6 is selected from the group consisting of hydrogen, F, Cl, CN, —CH3, —C2H5, —C3H7, and —CF3; A is absent or -CH2-.

[0394]

[0124] In some examples, as disclosed in U.S. Patent Application Publication Nos. 20190307754, 20210085684, 20220047589, and 20220023302 and U.S. Patent No. 11,370,795, the PDE9 inhibitor is a compound represented by formula (LVIII) or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

[0395] [ka]

[0396] R 2 is R 1 or R 3 may be cyclized with R 1 , R 2 and R 3 is as follows: R 1 is R 2 When cyclizing with

[0397] [ka]

[0398] and R 7 is selected from the group consisting of H, -CEE, -C2H5, and C3H7; * indicates the cyclization position; If not cyclized, R 1 is H and

[0399] [ka]

[0400] is selected from the group consisting of R 7is selected from the group consisting of H, —CH3, —C2H5 and —C3H7; R 2 teeth,

[0401] [ka]

[0402] is a compound selected from R 8 and R 12 are independently selected from the group consisting of H, —CH3, —C2H6, and —C3H7; * indicates the cyclization position; R 3 R 2 When cyclizing with R 3 teeth,

[0403] [ka]

[0404] and * indicates the cyclization position, R 9 is H, C1-C6 alkyl, substituted C1-C6 alkyl, branched C3-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C6-C 10 Aryl, substituted C6-C 10 Aryl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, C1-C6 alkoxy, substituted C1-C6 alkoxy, branched C3-C6 alkoxy, C3-C6 cycloalkoxy, substituted C3-C6 cycloalkoxy, C6-C 10 Aryloxy, substituted C6-C 10 selected from the group consisting of aryloxy, C3-C9 heteroaryloxy, and substituted C3-C9 heteroaryloxy; If not cyclized, R 3 teeth,

[0405] [ka]

[0406] and During the ceremony, R 10 is selected from the group consisting of H, —CH3, and —C2H5; R 11 is C6~C 19 Aryl, substituted C6-C 10 selected from the group consisting of aryl, C3-C9 heteroaryl, and substituted C3-C9 heteroaryl; R 4 is selected from the group consisting of hydrogen, —CH3, —C2H5, —C3H7, —CF3, —CN, an F atom, and a Cl atom; R 5 is C6~C 10 Aryl, substituted C6-C 10 selected from the group consisting of aryl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, C3-C6 heterocyclyl, substituted C3-C6 heterocyclyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl; R 6 is selected from the group consisting of hydrogen, F, Cl, CN, —CH3, —C2H5, —C3H7, and —CF3; A is absent or -CH2.

[0407] In some embodiments, the PDE9 inhibitor is

[0408] [ka]

[0409] In some embodiments, the PDE9 inhibitor is selected from:

[0410] [ka]

[0411] is.

[0126] In some examples, as disclosed in U.S. Patent No. 7,488,733, the PDE9 inhibitor is a compound represented by formula (LIX) and salts, solvates and / or solvates of the salts thereof:

[0412] [ka]

[0413] During the ceremony, A is C1-C8-alkyl, C3-C8-cycloalkyl, tetrahydrofuryl or tetrahydropyranyl, which is optionally substituted by up to three groups independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, amino, hydroxy, C1-C6-alkylamino, halogen atoms, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and C1-C6-alkylthio, C1-C6-Alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and C1-C6-alkylthio are hydroxy, cyano, halogen, hydroxycarbonyl and the group of the formula -NR 3 R 4 and optionally substituted with one or more groups selected from the group consisting of R 3 and R 4 are, independently of one another, hydrogen or C1-C6-alkyl, or R 3 and R 4 is the R 3 and R 4 together with the nitrogen atom to which it is attached form a 5- to 8-membered heterocyclyl, B is phenyl or heteroaryl, which is optionally substituted with up to three groups independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, amino, nitro, hydroxy, C1-C6-alkylamino, halogen atoms, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and C1-C6-alkylthio, C1-C6-Alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and C1-C6-alkylthio are hydroxy, cyano, halogen atoms, hydroxycarbonyl and the group of the formula -NR 3 R 4 and optionally substituted with a group selected from the group consisting of R 3 and R 4 has the meaning given above.

[0414]

[0127] In some examples, the PDE9 inhibitor is a compound represented by formula (LX) or a pharmaceutically acceptable salt thereof, as disclosed in US Pat. Nos. 8,357,688 and 8,674,096.

[0415] [ka]

[0416] During the ceremony, A 1 is N and A 2 is CR 6 and R 1 and R 2one of which is hydrogen; halogen; lower alkyl, -O-lower alkyl or cycloalkyl, each of which may be substituted with one or more substituents selected from the group consisting of OH, -O-lower alkyl, -NH, -NH-lower alkyl, -N(lower alkyl) and monocyclic nitrogen-containing heterocycles optionally substituted with lower alkyl; and the other is a group of formula (LXI),

[0417] [ka]

[0418] R 3 is lower alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or saturated heterocycle, each optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, —OH, oxo, —O-lower alkyl, —COOH, —CO—O-lower alkyl, —CO—O-lower alkenyl, —CO—O-lower alkynyl, —CO—O-lower alkylene-O-lower alkyl, —CO—O-lower alkylene-aryl, —CO—O-lower alkylene-O-aryl, —CO—NH, —CO—NH-lower alkyl, —CO—N(lower alkyl), —CO—N(lower alkyl)-aryl, —CO—N(lower alkyl)-(lower alkylene-aryl), —CO—NH-lower alkylene-OH, —CO—NH-lower alkylene-COH, and monocyclic sulfur-containing saturated heterocycle; R 4 and R 5 are the same or different and each is hydrogen or lower alkyl; R 6 is hydrogen or lower alkyl, R a and R b R is bonded to the adjacent nitrogen atom to form a polycyclic nitrogen-containing heterocycle, a and R bis halogen; -OH; oxo; -O-lower alkyl; cyano; nitro; halogeno-lower alkyl; cycloalkyl; aryl which may be further substituted with a group selected from the group G1; G 2 a heterocycle optionally further substituted with a group selected from the group G1; a lower alkylene-(aryl optionally further substituted with a group selected from the group G1); a lower alkylene-SO2-NR 7 R 8 ;Lower alkylene-heterocycle;Lower alkyl optionally further substituted by OH, -O-lower alkyl, cyano or cycloalkyl;-COOH;-CO-O-lower alkyl;-CO-O-lower alkenyl;-CO-O-lower alkynyl;-CO-O-lower alkylene-O-lower alkyl;-CO-O-lower alkylene-aryl;-CO-O-lower alkylene-O-aryl;-CO-NH2;-CO-NH-lower alkyl;-CO-N(lower alkyl)2;-CO-N(lower alkyl)-aryl;-CO-N(lower alkyl)-(lower alkylene-aryl);-CO-NH-lower alkylene-OH;-CO-NH-lower alkylene-CO2H;-NH-SO2-R 9 ;-SO2-NR 7 R 8 and monocyclic sulfur-containing saturated heterocycles; wherein R 7 and R 8 are the same or different and each is hydrogen or lower alkyl; R 9 is lower alkyl, or aryl (the aryl may be substituted with lower alkyl); the G1 group includes a halogen atom, lower alkyl, halogeno-lower alkyl, -OH, -O-lower alkyl, -O-lower alkylene-aryl, -O-lower alkylene-heterocycle, -O-halogeno-lower alkyl, aryl, and heterocycle; and the G2 group includes a halogen atom, lower alkyl, halogeno-lower alkyl, -OH, -O-lower alkyl, -O-lower alkylene-aryl, -O-lower alkylene-heterocycle, -O-halogeno-lower alkyl, aryl, and heterocycle.

[0419] In some examples, the PDE9 inhibitor is a quinoxaline derivative or a salt thereof, as disclosed in U.S. Patent Nos. 8,299,080, 8,829,000, and 9,040,536. In some examples, the quinoxaline derivative is a compound represented by formula (LXII) or a salt thereof:

[0420] [ka]

[0421] During the ceremony, R 1 and R 2 are each independently hydrogen; halogen; hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, C 1~6 C optionally substituted with alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic or heterocyclic groups 1~6 Alkyl or C 1~6 Alkoxy; Hydroxy, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 Haloalkyl, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Acyl optionally substituted with haloalkoxy, amino, carbocyclic or heterocyclic groups; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 amino optionally substituted with 1 to 2 substituents selected from alkynyl, alkanoyl, carbocyclic and heterocyclic groups; hydroxy; or halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 pyrimidinyl optionally substituted with haloalkoxy, nitro or amino; R 3 is hydroxy, halogen, C1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, alkanoyl, amino (wherein the amino group is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group, each of which may be further substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 C substituted with (optionally further substituted with alkoxycarbonyl, amino, amido or carbamoyl) 1~9 Alkyl, C 2~9 Alkenyl or C 2~9 Alkynyl; halogen, hydroxy, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy (wherein the C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Alkoxy is independently selected from halogen, hydroxy, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl, carbocyclic or heterocyclic group), C having 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6Aryl, saturated carbocyclic or saturated heterocyclic groups optionally substituted with alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl, carbocyclic or heterocyclic groups; carboxy; C 1~6 Alkoxycarbonyl (wherein the C 1~6 The C in the alkoxycarbonyl 1~6 The alkoxy moiety can be hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 alkoxycarbonyl, amino, amido, carbamoyl, carbocyclic or heterocyclic group; amide (wherein the amino moiety in the amide is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 and optionally further substituted with 1 to 2 substituents selected from haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group; or carbamoyl (wherein the amino moiety in the carbamoyl is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 which may be further substituted by 1 to 2 substituents selected from haloalkyl, alkanoyl, carbocyclic groups, and heterocyclic groups; R 4 is hydrogen; hydroxy; hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 C optionally substituted with alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl or oxo 1~6 Alkyl; or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 represents an amino optionally substituted by 1 to 2 substituents selected from a haloalkyl, an alkanoyl, a carbocyclic group, and a heterocyclic group; R 5 and R 8 are each independently hydrogen; halogen; hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 C optionally substituted with alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl or oxo 1~6 Alkyl, C 2~6 Alkenyl or C 1~6 represents alkoxy; cyano; or nitro; R 6 and R 7 are each independently hydrogen; halogen; hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, alkanoyl, amino (wherein the amino is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group, each of which may be further substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 optionally substituted with alkoxycarbonyl, amino, amido or carbamoyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl or C 1~6 Alkoxy; Cyano; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (wherein the C 1~6 Alkyl, C2~6 Alkenyl and C 2~6 Alkynyl is independently selected from the group consisting of hydroxy, halogen atoms, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, C 1~6 alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic and heterocyclic groups, wherein the carbocyclic and heterocyclic groups are each substituted with hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 amino optionally substituted by 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy (wherein the C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Alkoxy is independently selected from the group consisting of hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, C 1~6 alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic or heterocyclic group), C having 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 a carbocyclic or heterocyclic group optionally substituted with alkoxycarbonyl, amino, amido or carbamoyl; COR 9 ; or SO2R 9 represents; R 9are hydrogen; hydroxy; hydroxy, halogen, and C, respectively. 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, alkanoyl, amino (wherein the amino is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group, each of which may be further substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 optionally substituted with alkoxycarbonyl, amino, amido or carbamoyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl or C 1~6 Alkoxy;C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy (wherein the C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Alkoxy is independently selected from the group consisting of hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic or heterocyclic group), C having 1 to 9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic and heterocyclic groups, wherein the carbocyclic and heterocyclic groups are each independently selected from hydroxy, halogen, C 1~6Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6 hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy (wherein the C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Alkoxy is independently selected from the group consisting of hydroxy, halogen, C 1~6 Alkoxy, C with 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 alkoxycarbonyl, alkanoyl, amino, amido, carbamoyl, oxo, carbocyclic or heterocyclic group), C having 1 to 9 halogen atoms 1~6 Haloalkoxy, Carboxy, C 1~6 Alkoxycarbonyl, alkanoyl, amino (wherein the amino is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with 1-9 halogen atoms 1~6 haloalkyl, alkanoyl, carbocyclic group, and heterocyclic group, each of which may be further substituted with 1 to 2 substituents selected from hydroxy, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, carboxy, C 1~6aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-1-yl or pyrazol-1-yl optionally substituted by 1 to 2 substituents selected from (which may be further substituted by alkoxycarbonyl, amino, amido or carbamoyl); X represents S or O; A 1 , A 2 and A 3 are each independently N or C, provided that R 1 , R 2 and R 8 does not exist, and A 1 , A 2 and A 3 respectively represent N.

[0422] In some examples, the PDE9 inhibitor is a quinazoline derivative or a salt thereof, as disclosed in U.S. Patent No. 8,101,624. In some examples, the quinazoline derivative is a compound represented by formula (LXIII) or a salt thereof:

[0423] [ka]

[0424] During the ceremony, R 1 is a halogen, C 1~6 Alkyl, C containing 1-6 halogen atoms 1~6 Haloalkyl and C 1~6 phenyl or an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from alkoxy; n is an integer of 1 to 3.

[0425]

[0130] In some examples, the PDE9 inhibitor is a compound represented by formula (LXIV), as disclosed in CN105669680.

[0426] [ka]

[0427] In the formula, R 1 H,

[0428] [ka]

[0429] represents; Ar is

[0430] [ka]

[0431] Represents.

[0131] In some examples, as disclosed in WO201424125, the PDE9 inhibitor is a compound represented by formula (LXV), and salts thereof, including pharmaceutically acceptable salts, as well as optically active diastereoisomers and mixtures thereof.

[0432] [ka]

[0433] During the ceremony, R 1 represents a hydrogen atom or methyl; R 1 If represents a hydrogen atom, R 2 represents cyclopentyl, tetrahydropyranyl, cyclohexyl, or cyclohexyl substituted by one or two halogen atoms; R 1 If represents methyl, R 2 represents cyclopentyl; R 3is selected from the group consisting of: phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from F, CI, Br, I and OCH3; 6-10 membered heteroaryl, having 1 to 3 heteroatoms independently selected from O, N and S; Q represents C1-C3-alkylene, which is unsubstituted or substituted with 1 to 3 C1-C3-alkyl.

[0434] In some examples, the PDE9 inhibitor is 5-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-3-cyclopentyl-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; 5-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-3-cyclopentyl-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; 5-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-3-cyclopentyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; (-)-5-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-3-cyclopentyl-1H-pyrazolo-[4,3-d]pyrimidin-7(6H)-one; (+)-5-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-3-cyclopentyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; 5-[(3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; (-)-5-[(3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; (+)-5-[(3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; 3-Cyclopentyl-5-[(3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; 5-[1-(3-fluorobenzyl)-4-methylpyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; (-)-5-[1-(3-fluorobenzyl)-4-methylpyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; (+)-5-[1-(3-fluorobenzyl)-4-methylpyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; 3-(4,4-difluorocyclohexyl)-5-[(3,4-trans)-1-(3-fluorobenzyl)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; (-)-3-(4,4-difluorocyclohexyl)-5-[(3,4-trans)-1-(3-fluorobenzyl)-4-methyl-pyrrolidin-3-yl]-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; (+)-3-(4,4-difluorocyclohexyl)-5-[(3,4-trans)-1-(3-fluorobenzyl)-4-methyl-pyrrolidin-3-yl]-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; and 3-(4,4-Difluorocyclohexyl)-5-[(3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)-pyrrolidin-3-yl]-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one; and salts thereof, in particular pharmaceutically acceptable salts, their optically active diastereoisomers and mixtures thereof, including racemic mixtures.

[0435]

[0133] In some examples, as disclosed in WO2014016789, the PDE9 inhibitor is a compound represented by formula (LXVI) or a salt thereof:

[0436] [ka]

[0437] During the ceremony, R 1 teeth, - unsubstituted or F, Cl, Br, I, CN, -O-C1-C3-alkyl, fluorinated -O-C1-C3-alkyl, -(CH2) m phenyl substituted with 1 to 3 substituents selected from OH and a 5-membered heterocyclic group having 1 or 2 heteroatoms selected from N, O and S; and 6 to 10-membered heteroaryl having 1 to 3 heteroatoms selected from O, N and S; R 2 and R 3 are each independently an H atom or a linear or branched C1-C3 alkyl; R 4 wherein one of the carbon atoms may be replaced by an O atom, and the 4-6 membered cycloalkyl is unsubstituted or substituted by 1 or 2 halogen atoms; and linear or branched C1-C4 alkyl; Q represents a single bond or C1-C3-alkylene, which may be optionally substituted with 1 to 3 C1-C3-alkyl; X is O, NR 5 , and S(O) p selected from the group consisting of: R 5 represents a H atom or a C1-C3 alkyl; m is 1, 2, or 3; and p is 0, 1, or 2.

[0438] In some examples, the PDE9 inhibitor is 1-Cyclopentyl-6-(phenoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(phenylthio)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclohexyl-6-(phenoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 6-(phenoxymethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Isopropyl-6-(phenoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Tert-butyl-6-(phenoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(quinolin-8-yloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Isopropyl-6-[(quinolin-8-yloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(2-methoxyphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 6-[(2-bromophenoxy)methyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(2,4-difluorophenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(2-fluorophenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 6-[(2-chlorophenoxy)methyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 3-[(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methoxy]-benzonitrile; 4-[(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methoxy]-benzonitrile; 6-[(3-chlorophenoxy)methyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 6-{[(4-chlorophenyl)thio]methyl}-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(phenylamino)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-{[methyl(phenyl)amino]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 6-[(2-chlorophenoxy)methyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]-pyrimidin-4(5H)-one; 1-Cyclopentyl-6-{[2-(trifluoromethoxy)phenoxy]methyl}-1H-pyrazolo[3,4-d]-pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(2-iodophenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;6-[(benzyloxy)methyl]-1 -cyclopentyl-1 H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-{[(2,6-dichlorobenzyl)oxy]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-{[2-(hydroxymethyl)phenoxy]methyl}-1H-pyrazolo[3,4-d]-pyrimidin-4(5H)-one; 1-Cyclopentyl-6-{[3-(hydroxymethyl)phenoxy]methyl}-1H-pyrazolo[3,4-d]-pyrimidin-4(5H)-one; 6-{[1-(2-chlorophenyl)ethoxy]methyl}-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 6-{[(2-chlorophenyl)amino]methyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 6-{[2-(1H-imidazol-1-yl)phenoxy]methyl}-1-cyclopentyl-1H-pyrazolo[3,4-d]-pyrimidin-4(5H)-one; 1-Cyclopentyl-6-{[2-(pyrrolidin-1-yl)phenoxy]methyl}-1H-pyrazolo[3,4-d]-pyrimidin-4(5H)-one; 6-{[2-(1H-pyrrol-1-yl)phenoxy]methyl}-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(pyridin-4-yloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-(phenethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 1-Cyclopentyl-6-[(phenylsulfinyl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; and 1-Cyclopentyl-6-[(phenylsulfonyl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one is selected from the group consisting of:

[0439] In some embodiments, the PDE9 inhibitor is 6-[(2-chlorophenoxy)methyl]-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one or a salt thereof.

[0440]

[0136] In some examples, the PDE9 inhibitor is a compound represented by formula (LXVII) or a salt thereof, as disclosed in US Pat. No. 7,488,733.

[0441] [ka]

[0442] During the ceremony, A is C1-C8-alkyl, C3-C8-cycloalkyl, tetrahydrofuryl or tetrahydropyranyl, which is optionally substituted by up to three groups independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, amino, hydroxy, C1-C6-alkylamino, halogen, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and C1-C6-alkylthio, where C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and C1-C6-alkylthio are also understood to mean hydroxy, cyano, halogen, hydroxycarbonyl and groups of the formula -NR 3 R 4 and optionally substituted with one or more groups selected from the group consisting of where: R 3 and R 4 are, independently of one another, hydrogen or C1-C6-alkyl, or R 3 and R 4 is the R 3 and R 4 together with the nitrogen atom to which it is attached form a 5- to 8-membered heterocyclyl, B is phenyl or heteroaryl, which is optionally substituted with up to three groups independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, amino, nitro, hydroxy, C1-C6-alkylamino, halogen, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and C1-C6-alkylthio, where C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and C1-C6-alkylthio are also understood to mean hydroxy, cyano, halogen, hydroxycarbonyl and groups of the formula -NR 3 R 4 and optionally substituted with a group selected from the group consisting of where: R 3 and R 4 has the meaning given above.

[0443] In some instances, the PDE9 inhibitor is

[0444] [ka]

[0445] It is a compound having the structure: In some examples, the PDE9 inhibitor is

[0446] [ka]

[0447] It is a compound having the structure:

[0139] In some examples, the PDE9 inhibitor is a compound represented by formula (LXVIII) or a salt thereof, as disclosed in US Pat. No. 8,088,769 and US Pat. No. 8,431,573.

[0448] [ka]

[0449] During the ceremony, A is phenyl; heteroaryl, which is a monocyclic aromatic group having 5-6 ring atoms and 1-3 heteroatoms selected from S, O and N; or a group of formula

[0450] [ka]

[0451] is the basis of When A is phenyl, A is substituted with 1 to 2 groups, and when A is heteroaryl, A is optionally substituted with up to 2 groups, each of which is independently selected from the group consisting of heteroaryl, a monocyclic aromatic group having 5 to 6 ring atoms and 1 to 3 heteroatoms selected from S, O, and N; halogen; C1-C6-alkyl; C1-C6-alkoxy; trifluoromethyl; trifluoromethoxy; benzyloxy, and benzyl; where C1-C6-alkyl is a group of the formula -NR 3 R 4 and R 3 is C1-C6-alkyl, and R 4 is hydrogen or C1-C6-alkoxy(C1-C6)-alkyl; heteroaryl is optionally substituted with C1-C6-alkoxy, R 1 is C3-C8-cycloalkyl, C1-C6-alkyl, C1-C6-alkoxy(C1-C6)alkyl, benzyl or of the formula

[0452] [ka]

[0453] is the basis of wherein C3-C8-cycloalkyl is optionally substituted by hydroxy, C1-C6-alkyl or trifluoromethyl, C1-C6-alkyl is optionally substituted by heteroaryl, C3-C8-cycloalkyl or hydroxy, and benzyl is optionally substituted by C1-C6-alkoxy or halogen; R 2 is hydrogen, or R 1 and R 2 is the R 1 and R 2 is a 5- or 6-membered heterocyclyl group which, together with the nitrogen atom to which it is attached, is a monocyclic, saturated or partially unsaturated heterocyclic group having 5 or 6 ring atoms and 1 to 2 heteroatoms selected from N, O and S, including C1-C6 alkyl; hydroxy; cyano; oxo; heteroaryl, which is a monocyclic aromatic group having 5 to 6 ring atoms and 1 to 3 heteroatoms selected from S, O and N; benzyl; formyl; C1-C6 alkylcarbonyl; and the following groups:

[0454] [ka]

[0455] (which group is attached to one of the carbon atoms in the heterocycle via two oxygen atoms), forming a 5- to 6-membered heterocyclyl group, optionally substituted with at most two substituents independently selected from The C1-C6-cycloalkyl may be optionally substituted by hydroxy or heteroaryl, which is a monocyclic aromatic group having 5 to 6 ring atoms and 1 to 3 heteroatoms selected from S, O and N.

[0456] In some examples, as disclosed in WO2013142269, the PDE9 inhibitor is a compound represented by formula (AA-I):

[0457] [ka]

[0458] or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of a single bond, C(O) and S(O)2; R1 is (i) (C1-C6) alkyl (the (C1-C6) alkyl is one or more R a optionally replaced by ); (ii) (C1-C6) haloalkyl (the (C1-C6) haloalkyl is one or more R a optionally replaced by ); (iii) (C1-C6) alkoxy (the (C1-C6) alkoxy is one or more R a optionally replaced by ); (iv) (C3-C7) cycloalkyl (the (C1-C6) cycloalkyl is one or more R b optionally replaced by ); (v) (C3-C7)cycloalkyl(C1-C4)alkyl, wherein the alkyl portion is one or more R a and the cycloalkyl moiety is optionally substituted with one or more R b optionally replaced by ); (vi) (C3-C7)cycloalkyloxy, (the (C3-C7)cycloalkyloxy is optionally substituted with one or more R); (vii) heterocycloalkyl, wherein the heterocycloalkyl is one or more R b optionally replaced by ); (viii) heterocycloalkyl(C1-C4)alkyl, wherein the alkyl portion is one or more R a and the cycloalkyl moiety is optionally substituted with one or more R boptionally replaced by ); (ix) heterocycloalkyloxy (the heterocycloalkyloxy may be one or more R b (optionally replaced by selected from the group consisting of: R2 is (i) heterocycloalkyl (the heterocycloalkyl may be one or more R c optionally replaced by ); (ii) heterocycloalkyl(C1-C4)alkyl (the alkyl portion may be one or more R d and the cycloalkyl moiety is optionally substituted with one or more R c optionally replaced by ); (iii) (C3-C7) cycloalkyl (the C3-C7) cycloalkyl is one or more R c optionally replaced by ); (iv) (C3-C7)cycloalkyl(C1-C4)alkyl (the alkyl portion may be one or more R d and the cycloalkyl moiety is optionally substituted with one or more R c optionally replaced by ); (v) phenyl (the phenyl may be one or more R e optionally replaced by ); (vi) phenyl(C1-C4) alkyl (the alkyl portion may be one or more R d and the phenyl moiety is optionally substituted with one or more R e optionally replaced by ); (vii) heteroaryl, wherein the heteroaryl is selected from one or more R e optionally replaced by ); (viii) heteroaryl(C1-C4) alkyl (the alkyl portion may be one or more R d and the heteroaryl moiety is optionally substituted with one or more R e optionally replaced by ); (ix) (C1-C6) alkyl (the (C1-C6) alkyl is one or more R d optionally substituted with ); (x) (C1-C6) haloalkyl (the (C1-C6) haloalkyl is one or more R d (optionally substituted with); R3 is (i) heteroaryl, wherein the heteroaryl is optionally substituted with one or more R; (ii) heteroaryl(C1-C4) alkyl (the alkyl portion may be one or more R g wherein the heteroaryl moiety is optionally substituted with one or more R; (iii) phenyl, wherein the phenyl is optionally substituted with one or more R; (iv) phenyl(C1-C4) alkyl (the alkyl portion may be one or more R g and the phenyl moiety is optionally substituted with one or more R f optionally replaced by ); (v) (C-C)cycloalkyl, wherein the C-C)cycloalkyl is optionally substituted with one or more R; (vi) (C3-C7)cycloalkyl(C1-C4)alkyl, wherein the alkyl portion is one or more R g and the cycloalkyl moiety is optionally substituted with one or more R h optionally replaced by ); (vii) heterocycloalkyl (the heterocycloalkyl may be one or more R h optionally replaced by ); (viii) heterocycloalkyl(C1-C4)alkyl, wherein the alkyl portion is one or more R g and the cycloalkyl moiety is optionally substituted with one or more R h optionally replaced by ); (ix) (C1-C6) alkyl (the (C1-C6) alkyl is one or more R g optionally replaced by ); (x) (C1-C6) haloalkyl (the (C1-C6) haloalkyl is one or more R g (optionally replaced by selected from the group consisting of: R a , R d , and R g each occurrence is independently selected from the group consisting of: -S(O)2(C1-C4)alkyl, -OH, -C(O)-(C1-C4)alkyl, oxo, -CN, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3-C8)cycloalkyl, (C3-C6)cycloalkyloxy, (C1-C4)alkylthio, (C3-C6)cycloalkylthio-, -C(O)NH2, -C(O)NH(C1-C4)alkyl, -C(O)N[(C1-C4)alkyl]2, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -S(O)2NH(C1-C4)alkyl, and -S(O)2N[(C1-C4)alkyl]2; R a , R d and R g is independently selected from the group consisting of halo, -S(O)2(C1-C4)alkyl, -OH, -C(O)-(C1-C4)alkyl, oxo, -CN, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3-C7)cycloalkyl, (C3-C6)cycloalkyloxy, (C1-C4)alkylthio, (C3-C6)cycloalkylthio-, -C(O)NH2, -C(O)NH(C1-C4)alkyl, -C(O)N[(C1-C4)alkyl]2, -S(O)2NH(C1-C4)alkyl, and -S(O)2N[(C1-C4)alkyl]2; R b , R c and R h Each occurrence of represents halo, -S(O)2(C1-C4)alkyl, -OH, -C(O)-(C1-C4)alkyl, -C(O)-O-(C1-C6)alkyl, -CN, (C1-C6)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3-C y)cycloalkyl, (C3-C6)cycloalkyloxy, (C1-C4)alkylthio, (C3-C6)cycloalkylthio-, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N[(C1-C4)alkyl]2, —S(O)2NH(C1-C4)alkyl, and —S(O)2N[(C1-C4)alkyl]2; R e and R f each occurrence represents (C3-C alkyl) optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo; -S(O)2(C1-C4)alkyl; -OH; -C(O)-(C1-C4)alkyl; -C(O)-O-(C1-C6)alkyl; -CN; -C(O)OH; (C1-C6)alkyl optionally substituted with -OH or -OCH3; (C1-C4)haloalkyl; (C1-C4)alkoxy; (C1-C4)haloalkoxykyl; and (C1-C4)alkyl. y )cycloalkyl; (C3-C6)cycloalkyloxy; (C1-C4)alkylthio; (C3-C6)cycloalkylthio-; -C(O)NH2; -C(O)NH(C1-C4)alkyl; -C(O)N[(C1-C4)alkyl]2; -NH2; -NH(C1-C4)alkyl; -N[(C1-C4)alkyl]2; -NH-C(O)-(C1-C4)alkyl; -S(O)2NH(C1-C4)alkyl; -S(O)2N[(C1-C4)alkyl]2; (C1-C4)alkyl Independently selected from the group consisting of heterocycloalkyl optionally substituted with 1 to 3 independently selected substituents; phenyl optionally substituted with 1 to 3 independently selected from the group consisting of F, -Cl, (C1-C4)alkyl, -CF3, -OCH3, and -CN; and heteroaryl containing 5 to 6 ring atoms independently selected from the group consisting of N, O, and S, and optionally substituted with 1 to 3 independently selected from the group consisting of (C1-C4)alkyl, -CF3, and -OCH3.

[0459] In some instances, the PDE9 inhibitor is (−)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydrofuran-3-yl)imidazo[5,1-fJ[1,2,4]triazin-4(3H)-one; (-)-tert-butyl 4-(2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate; (+)-tert-butyl 4-(2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(5-fluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(5-fluoro-2-methylphenyl)imidazo[1,5-fJ[1,2,4]triazin-4(3H)-one; (+)-7-(5-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (-)-7-(5-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(piperidin-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(piperidin-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydrofuran-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-(1-(3,4-trans)-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydrofuran-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-3-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)benzonitrile; (+)-4-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)benzonitrile; (-)-2-((3,4-trans)-1-((6-methoxypyridin-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(2-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(3-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)benzonitrile; (-)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(furan-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(furan-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; 2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(1-methylpiperidin-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((R)-1-phenylethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-((S)-1-phenylethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(3-(trifluoromethyl)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2,4-difluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(2-(trifluoromethyl)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2-fluoro-5-methoxybenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(isoquinolin-7-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(quinolin-6-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2,5-difluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2,3-difluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(o-tolyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(quinolin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(isoquinolin-6-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-(quinolin-7-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridazin-3-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridazin-4-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(quinazolin-6-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(quinoxalin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-benzoyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(2-fluorobenzoyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(3-fluorobenzoyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(4-fluorobenzoyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-nicotinoylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-fluorobenzoyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzoyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((2-methylpyrimidin-4-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrimidin-4-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((2-fluorophenyl)sulfonyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)sulfonyl)benzonitrile; (-)-2-((3,4-trans)-4-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)sulfonyl)benzonitrile; (+)-2-((3,4-trans)-4-methyl-1-(pyrimidin-5-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidine-1-carbonyl)benzonitrile; (+)-2-((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidine-1-carbonyl)benzonitrile; (-)-2-((3,4-trans)-4-methyl-1-(pyrimidine-2-carbonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrimidine-2-carbonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-isonicotinoyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-4-((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidine-1-carbonyl)benzonitrile; (-)-2-((3,4-trans)-4-methyl-1-(pyrimidine-5-carbonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-(pyrazine-2-carbonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((3-fluorophenyl)sulfonyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-4-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)sulfonyl)benzonitrile; (+)-2-((3,4-trans)-4-methyl-1-(quinolin-7-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-picolinoylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-(quinoline-2-carbonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-(pyrimidine-4-carbonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylsulfonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2-methoxybenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3-methoxybenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-methoxybenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-(quinazoline-2-carbonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(2-methylbenzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(3-methylbenzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(4-methylbenzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(ethylsulfonyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(ethylsulfonyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(cyclohexylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-4-methyl-1-(4-(pyrrolidin-1-yl)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(2-(pyrrolidin-1-yl)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2-(dimethylamino)benzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3-(dimethylamino)benzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-(dimethylamino)benzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-phenethylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((6-methoxypyridin-3-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-yl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2,6-difluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3-cyclopropylbenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-cyclopropylbenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-((3,4-trans)-1,4-dimethylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (-)-2-((3,4-trans)-1-(2-cyclopropylbenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3-(1H-pyrazol-1-yl)benzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(quinolin-4-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((2-methylpyrimidin-5-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((2-methylthiazol-5-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((6-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((5-methylpyrazin-2-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((5-methylpyrazin-2-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(3-(pyrrolidin-1-yl)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((2-ethylpyrimidin-5-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3-bromobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2,4-dichlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-bromobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3,5-dichlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(3-(trifluoromethoxy)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2-chloro-4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2-bromobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(4,4-difluorocyclohexyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chloro-3-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-fluoro-3-(trifluoromethyl)benzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2,5-dichlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3,5-difluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3,4-dichlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-(4,4-difluorocyclohexyl)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4,4-difluorocyclohexyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,4-difluorocyclohexyl)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((3aH-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(4,4-difluorocyclohexyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,4-difluorocyclohexyl)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,4-difluorocyclohexyl)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,4-difluorocyclohexyl)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(5-fluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(5-fluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(5-fluoro-2-^4(3H)-one; (+)-7-(5-fluoro-2-methylphenyl)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(5-fluoro-2-methylphenyl)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(5-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(5-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-(+)-7-(5-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorocyclohexyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorocyclohexyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorocyclohexyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorocyclohexyl)imidazo[1,5-f][1,2,4]triazin-4(3H))-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4-fluorocyclohexyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4-fluorocyclohexyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorocyclohexyl)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorocyclohexyl)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorocyclohexyl)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorocyclohexyl)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorocyclohexyl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorophenyl)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorophenyl)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorophenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorophenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluorophenyl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(3-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(3-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(3-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(3-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(3-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(3-fluorophenyl)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(3-fluorophenyl)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(3-fluorophenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(3-fluorophenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(3-fluorophenyl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)-7-o-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(4,5-difluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4,5-difluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(4,5-difluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4,5-difluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,5-difluoro-2-methylphenyl)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,5-difluoro-2-methylphenyl)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,5-difluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,5-difluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,5-difluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4,5-difluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-phenylimidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(4-fluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(4-chlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4-fluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(4-fluoro-2-methylphenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluoro-2-methylphenyl)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluoro-2-methylphenyl)-2-((3,4-trans)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-7-(4-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((2-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(quinolin-8-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((2-methylpyridin-4-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((2-propylpyrimidin-5-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(2-(pyrimidin-2-yl)ethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1,5-naphthyridin-4-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1,8-naphthyridin-4-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((2-(dimethylamino)pyrimidin-4-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(cinnolin-3-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)methyl)pyrrolidin-3-yl)-7-(teta^4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(2-(pyrimidin-5-yl)ethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((8-fluoroquinolin-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((1-methyl-1H-imidazol-5-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(thiazol-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(quinuclidin-4-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((1,3,5-triazin-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-Fluoro-5-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)benzonitrile; (+)-2-((3,4-trans)-1-((4,6-dimethylpyrimidin-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((5-chloropyrimidin-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(2,3-dichlorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(3-chloro-4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrido[2,3-d]pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-4-methyl-1-(pyrido[3,2-b]pyrazin-3-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-tert-butyl 4-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)piperidine-1-carboxylate; (+)-2-((3,4-trans)-1-((1,2,4-oxadiazol-5-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((4,4-difluorocyclohexyl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((5-chlorofuran-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((5-chlorofuran-3-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((5-chlorothiophen-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-((5-chlorothiophen-3-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one (+)-2-((3,4-trans)-1-(cyclopentylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(cyclopropylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-1-(furan-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one; (+)-2-((3,4-trans)-...

Claims

1. A method for treating or preventing a disorder in a subject, comprising administering to the subject a therapeutically effective amount of a serotonergic hallucinogen and a therapeutically effective amount of a PDE9 inhibitor, wherein the disorder comprises a neuropsychiatric disorder, cluster headache, or migraine.

2. 10. The method of claim 1, wherein the PDE9 inhibitor enhances the therapeutic effect of the serotonergic hallucinogen on the disorder being treated.

3. 10. The method of claim 1, wherein the PDE9 inhibitor reduces at least one undesirable biological activity of a serotonergic hallucinogen in the subject.

4. 10. The method of claim 1, wherein the PDE9 inhibitor reduces the abuse potential of the serotonergic hallucinogen in the subject.

5. Neuropsychiatric disorders include major depressive disorder (MDD, including major depressive episode), major depressive episode in bipolar disorder (bipolar depression), depressive episode associated with bipolar disorder type I or type II (bipolar depression), persistent depressive disorder (dysthymia), dysthymic disorder, premenstrual dysphoric disorder, substance / drug-induced depressive disorder, depressive disorder due to other medical conditions, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, addictive disorder, treatment-resistant depression (TRD), generalized anxiety disorder 5. The method of any one of claims 1 to 4, wherein the treatment is selected from the group consisting of: generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), adjunctive treatment of major depression, eating disorders including anorexia and bulimia, depression associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, dementia, ALS, traumatic brain injury, suicidal ideation and behavior, chronic pain, persistent depressive disorder, seasonal affective disorder (SAD), psychotic depression, perinatal (postpartum) depression, premenstrual dysphoric disorder (PMDD), situational depression, and any combination thereof.

6. 6. The method of any one of claims 1 to 5, wherein the serotonergic hallucinogen and the PDE9 inhibitor are co-administered to the subject.

7. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the PDE9 inhibitor is administered to the subject prior to administration of the serotonergic hallucinogen to the subject.

8. 6. The method of any one of claims 1 to 5, wherein the serotonergic hallucinogen is administered to the subject prior to administration of the PDE9 inhibitor to the subject.

9. 6. The method of any one of claims 1 to 5, wherein the serotonergic hallucinogen and the PDE9 inhibitor are formulated together as a pharmaceutical composition.

10. 6. The method of any one of claims 1 to 5, wherein the serotonergic hallucinogen and the PDE9 inhibitor are independently administered to the subject via a route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, intrapleural, intraperitoneal, intravaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraaural, intraocular, intrathecal, intravenous, and any combination thereof.

11. Serotonergic hallucinogens include psilocin, psilocybin, bufotenin, baeocystin, aeruginacin, 5-MeO-DMT, N,N-dimethyltryptamine (DMT), 5-bromo-DMT, N-methyl-N-ethyltryptamine (MET), N-methyl-N-isopropyltryptamine (MiPT), N-methyl-N-propyltryptamine (MPT), N. N-Diethyltryptamine (DET), N-Ethyl-N-isopropyltryptamine (EiPT), N-Methyl-N-butyltryptamine (MBT), N-Propyl-N-isopropyltryptamine (PiPT), N,N-Dipropyltryptamine (DPT), N,N-Diisopropyltryptamine (DiPT), N,N-Diallyltryptamine (DALT), N,N-Dibutyltryptamine (DBT), N-Ethyltryptamine (NET), N-Methyltryptamine NMT, trimethyltryptamine (TMT), α-methyltryptamine, α-ethyltryptamine, α,N-DMT, α,N,N-trimethyltryptamine, ethosybin, 4-HO-MET, 4-HO-DET, 4-HO-MPT, 4-HO-MiPT, 4-HO-MALT, 4-HO-DPT, 4-HO-DiPT, 4-HO-DALT, 4-HO-DBT, 4-HO-DSBT, 4-HO-αMT, 4-HO-MPMI, 4-HO-TMT, 4-HO-1, N,N-TMT, 4-HO-5-MeO-DMT, 4-AcO-DMT, 4-AcO-MET, 4-AcO-MALT, 4-AcO-DET, 4-AcO-EiPT, 4-AcO-DPT, 4-AcO-DiPT, 4-AcO-DA LT, 4-MeO-DMT, 4-MeO-MiPT, 5-MeO-NMT, 5-MeO-MET, 5-MeO-MPT, 5-MeO-MiPT, 5-MeO-DET, 5-MeO-EiPT, 5-MeO-EPT, 5-MeO-PiP T, 5-MeO-DPT, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-αMT, 5-MeO-2,N,N-TMT, 5-MeO-7,N,N-TMT, 5-MeO-α,N-DMT, 4-F-5-MeO-DMT, 5 -Me-MiPT, 5-HO-DiPT, 2-α-DMT, 4-Me-αMT, 4-Me-αET, 7-Me-αET, 4,5-DHP-AMT, 4,5-DHP-DMT, 4,5-MDO-DMT, 4,5-MDO-DiPT, 5,6-MDO-DiPT, 5,6-MDO-MiPT, 5-fluoro-αMT, 6-fluoro-αMT, 6-fluoro-DMT, N,N-tetramethyltributamine (Pyr-T), 4-HO-pyr-T, 5-MeO-pyr-T, RU-28306 (4,α-methylene-N,N-DMT), O-4310 (6-fluoro-1-isopropyl-4-HO-DMT), CP-13 2,484 (4,5-DHP-1-methyltryptamine), dimemebufe (5-MeO-BFE), 5-MeO-DiBF, ibogaine, voacangine, lysergic acid diethylamide (LSD), lysergic acid amide (LSA), lysergic acid diamide, N1-methyl-lysergic acid diethylamide, 1-propionyl-lysergic acid diethylamide, 1-cyclopropanoyl-d-lysergic acid Diethylamide, 1-valeryl-D-lysergic acid diethylamide, 6-allyl-6-nor-lysergic acid diethylamide, 6-butyl-6-nor-lysergic acid diethylamide, 6-ethyl-6-nor-lysergic acid diethylamide, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 6-propyl-6-nor-lysergic acid diethylamide, 6-cyclopropyl-6-nor-lysergic acid diethylamide, 6-nor-lysergic acid diethylamide, lysergic acid ethylamide, lysergic acid α-hydroxyethylamide, lysergic acid 2-butylamide, lysergic acid 3-pentylamide, lysergic acid methyl ester, lysergic acid 2,4-dimethylazetidide, lysergic acid piperidine, N,N-dimethyl-lysergamide, methylisopropyl-lysergamide, N,N-diallyl-lysergamide, N-pyrrolidyl-lysergamide, N-morpholinyl-lysergamide, 1-methyl-lysergic acid butanolamide, lysergic acid β-propanolamide, lysergic acid 1-butanolamide, mescaline, lophophine, isomescaline, cyclopropylmescaline, thioisomescaline (2-TIM, 3-TIM, and 4-TIM), 4-desoxymescaline, dimescaline, escaline, metaescaline, thiometaescaline (3-TME, 4-TME, and 5-TME), trisescaline, thiotrisescaline (3-T-TRIS and 4-T-TRIS), symbescaline, asymbescaline, thio Cymbescaline (3-TSB and 4-TSB), fenestrationscaline, allylescaline, methallylescaline, proscaline, isoproscaline, metaproscaline, thioproscaline, buscaline, thiobuscaline, α-ethylmescaline, ariadne, macromerine, MEPEA, TOM (2-TOM and 5-TOM), Bis-TOM, TOMSO (2-methoxy-4-methyl-5-methylsulfinylamphetamine), TOET (2-TOET and 5-TOET), BOH, BOM (13-methoxy-mescaline), beta-D, 4-D, DME, F-2, F-22, FLEA, MDPH, MDMP, propynyl, 2C series (2,5-dimethoxy, 4-substituted phenethylamine), βk-2C-B, 2C-B, 2CB-2EtO, 2CB-5EtO, 2CB-diEtO, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-C, 2C-D, 2CD-2EtO, 2CD-diEtO, 2CD-5EtO, 2C-E, 2C-EF, 2C-F, 2C-G (2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, and 2C-G-N), 2C-H, 2C-I, 2CI-2EtO, 2C-iP, 2C-N, 2C-O, 2C-O-4, 2C-P, 2C-SE, 2C-T, 2CT -5EtO, 2C-T-2, 2CT-2-2EtO, 2CT-2-5EtO, 2CT-2-diEtO, 2C-T-4 (2C-T-4 and Ψ-2C-T-4), 2CT-4-2EtO, 2C-T-7, 2CT-7-2EtO, 2C-T-8, 2C-T-9, 2C-T-13, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-19, 2C-T-21, 2C-TFM, 2C-YN, BOB (I3-methoxy-2C-B), BOD (I3-methoxy-2C-D), BOHD (I3-hydroxy-2C-D), HOT-2, HOT-7, HOT-17, 2CB-Ind. Indane derivatives including 2C-BCB (TCB-2), benzocyclobutene derivatives including 2C-BCB (TCB-2), NBOMe derivatives (NBOMe-mescaline, 2C-H-NBOMe, 2C-C-NBOMe, 2CBCB-NBOMe, 2CBFly-NBOMe, 2C-B-NBOMe, 2C-I-NBOMe, 2C-TFM-NBOMe, 2C-D-NBOMe, 2C-G-NBOMe, 2C-E-NBOMe, 2C-P-NBOMe, 2C-iP-NBOMe, 2C-CN-NB OMe, 2C-N-NBOMe, 2C-T-NBOMe, 2C-T-4-NBOMe, 2C-T-7-NBOMe, and DMBMPP), NBOH derivatives (2C-C-NBOH, 2C-B-NBOH, 2C-I-NBOH, and 2C-CN-NBOH), NBMD derivatives (2C-I-NBMD), NBF derivatives (2C-C-NBF, 2C-B-NBF, and 2C-I-NBF), 3C series (3, including 3C-E, 3C-P, 3C-DFE, and 3C-BZ)DOx series (2,5-dimethoxy and 4-substituted amphetamines), including DOAM, DOB, Meta-DOB, methyl-DOB, DOBU, DOC, DOEF, DOET, DOI, DOM, Ψ-DOM, DON, DOPR, SOiPR, DOT, Meta-DOT, Ortho-DOT, DOTFM, DMCPA, DMMDA, and DMMDA-2, 3,4-dimethyl-2,5-dimethoxyamphetamine, 4-methyl- 2,5-dimethoxymethamphetamine, 2,N-dimethyl-4,5-methylenedioxyamphetamine, dimethoxyamphetamine (2,4-DMA, 2,5-DMA, and 3,4-DMA), trimethoxyamphetamine (TMA-2, TMA-6), tetramethoxyamphetamine, Br-DragonFLY, TFMFly, 2-bromo-4,5-methylenedioxyamphetamine, 4-bromo-3,5-dimethoxyamphetamine, EEE, EEM, EME, EMM, EDMA, EIDA , ethyl-J, methyl-J, ethyl-K, methyl-K, IDNNA, Iris, MDAI, MDMAI, MDAT, MDMAT, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPK, MDPR, MEDA, MEM, methyl-DMA, MMDA, MMDA-2, 5-methyl-MDA, MEE, MME, MPM, DiFMDA, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB , 6-MAPDB, 6-MAPB, 6-EAPB, 5-EAPB, para-methoxyamphetamine, para-methoxymethamphetamine, 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, benzoxazine, efavirenz, 3,4-methylenedioxymethamphetamine (MDMA), MDA, 2,Substituted methylenedioxyphenethylamines (MDxx) including 3-MDA, 5-methyl-MDA, MMDA, MDEA, MBDB, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPM, MDPR, BDB, MMDA-2, DiFMDA, EIDA, ethyl-K, lophophine, substituted amphetamines, EDMA (N-ethyl-3,4- methylenedioxyamphetamine), para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, substituted cathinones, methylone, ethylone, eutrone, butylone, pentylone, 4-ethylmethcathinone, 3-methylmethcathinone, substituted benzofurans, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB, 6-MAPB, 6-MAPB, 5-EAPB, 6-EAPB, 5-MBPB, MDAT, MDMAT, 6-CAT, tetralinylaminopropane, trifluoromethylaminoindan, ethyltriflate Iodomethylaminoindan, 5-iodo-2-aminoindan, MMAI, MDAI, MDMAI, indanylaminopropane, naphthylaminopropane, 4-chlorophenylisobutylamine, 4-methylphenylisobutylamine, Ariadne, α-methyltryptamine, 5-MeO-αMT, α-ethyltryptamine, 4-Me-αET, 7-Me-αET, 5-MeO-αET, 5-MeO-MiPT, Δ, ９ -THC, CBD, CBN, THCV, (C6)-CP 47,497, (C9)-CP 47,497, 1-butyl-3-(2-methoxybenzoyl)indole, 1-butyl-3-(4-methoxybenzoyl)indole, 1-pentyl-3-(2-methoxybenzoyl)indole, 2-isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene, 4-HTMPIPO, 4-nonylphenylboronic acid, 5Br-UR-144, 5Cl-APINACA, 5C1-UR-144, 5F-3-pyridinoylindole, 5F-AB-FUPPYCA, 5F-AD B-PINACA, 5F-ADBICA, 5F-ADB, 5F-AMB, 5F-APINACA, 5F-CUMYL-PINACA, 5F-EMB -PINACA, 5F-NNE1, 5F-PB-22, 5F-PCN, 5F-PY-PICA, 5F-PY-PINACA, 5F-SDB-006, HHC, A-796,260, A-834,735, A-836,339, A-955,840, A-40174, A-41988, A-42574 , AB-001, AB-CHFUPYCA, AB-CHMFUPPYCA, AB-CHMINACA, AB-FUBICA, AB-FUBINACA 2-Fluorobenzyl isomers, AB-FUBINACA, AB-PICA, AB-PINACA, abnormal cannabidiol, ADAMANTYL-THPINACA, ADB-CHMINACA, ADB-FUBICA, ADB-FUBINACA, ADB-PINACA, ADBICA, ADS B-FU B-187, adulemic acid, AM-087, AM-411, AM-630, AM-679, AM-694, AM-855, AM-883, AM-905, AM-906, AM-919, AM-926, AM -938, AM-1220, AM-1221, AM-1235, AM-1241, AM-1248, AM-1346, AM-1387, AM-1714, AM-2201, AM-2232, AM-2233, AM-2389, AM-4030, AM-4113, AM-6527, AM-6545, AM-251, AM-281, AM-404, AMB-CHMINACA, AMB-FUBINACA, AMG-1, AMG-3, AMG-36, AMG-41, APICA, APINACA, APP-FUBINACA, arachidonoyl serotonin, ACEA, ACPA, Arvanil, AZ-11713908, BAY 38-7271, BAY 59-3074, BIM-018, Biochanin A, BML-190, Navidrox (Cambisol), cannabicyclohexanol, cannabipiperidiethanone, CAY-10401, CAY-10429, CAY-10508, CB-13, CB-25, CB-52, CB-86, CB-86, CBS-0550, CP47,497, CP55,244, CP55,940, CUMYL-5F-PICA, CUMYL-BICA, CUMYL-PICA, CUMYL-PINACA, CUMYL-THPINACA, dexanabinol, dimethylheptylpyran, drinabant, dronabinol, EAM-2201, EMB-FUBINACA, FAB-144, FDU-NNE1, FDU-PB-22, FUB -144, FUB-APINACA, FUB-JWH-018, FUB-PB-22, FUBIMINA, genistein, GW-405,833, GW-842,166X, hemopressin, HU-210, HU-243, HU-308, HU-320, HU-331, HU-336, HU-345, HU-910, ibipinabant, IDFP, JNJ 1661010, JNJ 1661010, JTE-907, JTE 7-31, JWH-007, JWH-015, JWH-018, JWH-019, JWH-030, JWH-051, JWH-073, JWH-081, JWH-098, JWH-116, JWH-122, JWH-133, JWH-139, JWH-14 7, JWH-149, JWH-161, JWH-164, JWH-167, JWH-175, JWH-176, JWH-182, JWH-184, JWH-185, JWH-192, JWH-193, JWH-194, JWH-195, JWH-196, J WH-197, JWH-198, JWH-199, JWH-200, JWH-203, JWH-210, JWH-229, JWH-249, JWH-250, JWH-251, JWH-302, JWH-307, JWH-359, JWH-369, JWH-370, JWH-398, JWH-424, JZL184, JZL195, kaempferol, KM-233, L-759,633, L-759,656, LASSBio-881, LBP-1, Leelamin, levonantradol, LH-21, LY-320,135, LY-2183240, NAM-2201, MDM-2201, MDA-7, MDA-19, MDA-77, MDMB-CHMICA, MDMB-CHMINACA, MDMB-FUBINACA, Menabitan, MEPIRAPIM, Methaneanandamide, MJ-15, MK-9470, MMB-2201, MN-18 , MN-25, Nabazenil, Nabilone, Nabitan, Navoctate, NESS-0327, NESS-040C5, NIDA-41020, NM-2201, NMP-7, NNE1, Nonavine O-224, O-581, O-585, O-606, O-689, O-774, O-806, O-823, O-889, O-1057, O -1125, O-1184, O-1191, O-1238, O-1248, O-1269, O-1270, O-1376, O-1399, O-1422, O-16 01, O-1602, O-1624, O-1656, O-1657, O-1660, O-1812, O-1860, O-1861, O-1871, O-1918, O -2048, O-2050, O-2093, O-2113, O-2220, O-2365, O-2372, O-2373, O-2383, O-2426, O-2484, O-2545, O-2654, O-2694, O-2715, O-2716, O-3223, O-3226, oleoylethanolamide, Olvanil, Org 27569, Org 27759, Org 2831, Org 28611, Org 29647, Otenabant, Palmitoylethanolamide, Parahexyl, PF-03550096, PF-04457845, PF-622, PF-750, PF-3845, PF-514273, PHOP, PipISB, Pirunavine, Pravadrine, Pregnenolone, PSB-SB-487, PSB-SB-1202, PTI-1, PTI-2, PX-1, PX-2, PX-3, QUCHIC. QUPIC, RCS-4, RCS-8, rimonabant, lozonabant, RTI-371, S-444,823, SDB-006, SER-601, SPA-229, SR-144,528, STS-135, surinabant, taranabant, tedarinab, THC-O-acetate, THC-O-phosphate, THJ-018, THJ-2201, tinabinol, TM-38837, UR-144, URB-447, URB-447, URB-597, URB-602, URB-754, VCHSR, VDM-11, VSN-16, WIN 54,461, WIN 55,212-2, WIN 56,098, XLR-11, yangonin, harmaline, harmala alkaloids, other beta-carbolines, active ingredients of ayahuasca, salvinorin A, salvinorin B methoxymethyl ether, salvinorin B ethoxymethyl ether, piperazine, pFPP, TFMPP, myristicin, elemicin, cryogenin (vertine), atropine, scopolamine, hyoscyamine, ibotenic acid, muscimol, TiHKAL, 2-Me-D ET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-EPT, 4-HO-McPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPMI, 4-HO-MPT, 4-HO-αMT, 4 -Me-αMT, 4-MeO-MiPT, 4-PrO-DMT, 4,5-MDO-DiPT, 4,5-MDO-DMT, 5-ethoxy-αMT, 5-fluoro-AET, 5-fluoro-DET, 5-fluoro-DMT, 5 -Fluoro-EPT, 5-fluoro-MET, 5-MeO-AET, 5-MeO-αMT, 5-MeO-DALT, 5-MeO-DET, 5-MeO-DPT, 5-MeO-EiPT, 5-MeO-MALT, 5-Me O-MiPT, 5-MeO-MPMI, 5-MeO-pyr-T, 5-MeS-DMT, 5-MeO-2-TMT, 5-TFM-DMT, 5-TFMO-DMT, 5,6-MDO-DiPT, 5,6-MDO-DMT, 5 , 6-MDO-MiPT, 5,6-MeO-MiPT, 5,N,N-TMT, 5F-MPMI, 6-fluoro-DET, 6-fluoro-DMT, 6-MeO-THH, 7-chloro-AMT, 7-F-5-MeO-MET, 4-acetoxy-DET, 4-acetoxy-DiPT, 4-acetoxy-MET, 4-acetoxy-MiPT, O-acetylbufotenin, O-acetylpsirosin, aeruginasin, alpha,N-DMT, alpha,N,O-TMS, baeocystin, 5-bromo-DMT, bufotenin, 5-chloro-αMT, DALT, dibutyltryptamine, diethyltryptamine, diisopropyltryptamine, 5,N-dimethyl-N-isopropyltryptamine, dimethyltryptamine, N,N-dimethyltryptamine, dipropyltryptamine, 2,α-dimethyltryptamine, ethosybin, ethylisopropyltryptamine, A-ethyltryptamine, 5-fluoro-AMT, 4-fluoro-5-methoxy-DMT, FT-104, 5-MeO-DMT, 5-methoxy-N,N-diisopropyltryptamine The method of any one of claims 1 to 10, wherein the active ingredient is selected from the group consisting of propyltryptamine, 4-methyl-α-ethyltryptamine, N-methyl-N-ethyltryptamine, methylbutyltryptamine, methylisopropyltryptamine, alpha-methylserotonin, alpha-methyltryptamine, N-methyltryptamine, MPMI, norbeocystin, propylisopropyltryptamine, 2,N,N-TMT, A,N,N-trimethyltryptamine, ketamine, esketamine, arketamine, mitragynine, yohimbine, and combinations thereof.

12. 11. The method of any one of claims 1 to 10, wherein the serotonergic hallucinogen is a tryptamine or an ergoline.

13. 13. The method of claim 12, wherein the serotonergic hallucinogen is tryptamine, or a salt, solvate, enantiomer, or diastereomer thereof.

14. 13. The method of claim 12, wherein the serotonergic hallucinogen comprises ergoline, or a salt, solvate, enantiomer, or diastereomer thereof.

15. 12. The method of claim 11, wherein the serotonergic hallucinogen is psilocybin, or a salt, solvate, enantiomer, or diastereomer thereof.

16. 13. The method of any one of claims 1 to 12, wherein the PDE9 inhibitor is selected from the group consisting of aminophylline, pentoxifylline, theobromine, paraxanthine, PF-04447913, PF-04447943, PF-04447953, BAY 73-6691, E 2027, CRD 773, BI 409306, CRD 740, TT 00920, BAY 7081, FRM 16606, HUC1-288, WYQ-C36D, and any combination thereof.

17. 13. The method of any one of claims 1 to 12, wherein the PDE9 inhibitor is PF-04447943, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof.

18. 18. The method of any one of claims 1 to 17, wherein the subject is administered therapeutically effective amounts of psilocybin and PF-04447943.

19. 19. The method of any one of claims 1 to 18, wherein the subject is administered therapeutically effective amounts of psilocybin, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof, and PF-04447943, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof.

20. PDE9 inhibitors include 1-{[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetyl}-pyrrolidine-2-carboxylic acid; 1-{[2-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-acetyl}-pyrrolidine-2(S)-carboxylic acid 3-isopropyl-5-[2-(2-oxo-2-piperazin-1-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 1-cyclopentyl-6-[2-(2-oxo-2-piperazin-1-yl-ethoxy)-benzyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one 3-isopropyl-5-[2-(2-morpholin-4-yl-2-oxo-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 3-Isopropyl-5-[2-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethoxy]-benzyl}-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; N,N-diethyl-2-[2-(3-isopropyl-7-oxo-6,7-dihydro -1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetamide; 1-{[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetyl}-pyrrolidine-2-carboxylic acid methyl ester; 4-{[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetamide 1-{[2-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester; N-(2-dimethylamino-ethyl)-2-[2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetamide; 1-{[2-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-acetyl}-pyrrolidine-2-carboxylic acid methyl ester; 4-{[2-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester; 1-cyclopentyl-6-[2-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one; 1-Cyclopentyl-6-[2-(2-morpholin-4-yl-2-oxo-ethoxy)-benzyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one; 2-[2-(1-cyclopentyl-4-oxo-4.5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-N-(2-dimethylamino-ethyl)-acetamide; 1-Cyclopentyl-6-{2-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethoxy]-benzyl}-1,5-dihydro-pyrazo 2-[2-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-N,N-diethyl-acetamide; [2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-phenoxy]-acetic acid; [2-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-phenoxy]-acetic acid; 3-Isopropyl-5-[2-(5-chloro-2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 3-Isopropyl-5-[2-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 3-Isopropyl-5-[2-(2-morpholin-4-yl-ethoxy)-cyclohexylmethyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-fluoro-2-(2-morpholin-4-yl-ethoxy)-benzyl]-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 3-Cyclopentyl-5-[5-fluoro-2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 3-Isopropyl-5-[2-(2-morpholin-4-yl-ethoxy-)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 9-(1,2-dimethyl-propyl)-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one; 2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-9-(tetrahydro-furan-3-yl)-1,9-dihydro-purin-6-one; 5-[2-(2-diethylamino-ethoxy)-benzyl]-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 3-Cyclopentyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 3-cyclobutyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[-4,3-d]pyrimidin-7-one; 9-(1(R),2-dimethylpropyl)-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one; 9-(2-methyl-butyl)-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one; 9-Cyclopentyl-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one; 5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-3-pyridin-3-yl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one; 9-(1,2-dimethyl-propyl)-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one; 9-Isopropyl-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one; 2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-9-(tetrahydro-furan-2-ylmethyl)-1,9-dihydro-purin-6-one; 9-(1-Isopropyl-2-methyl-propyl)-2-[-2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one; 9-(1-ethyl-propyl)-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,9-dihydro-purin-6-one; 9-Cyclopentyl-8-methyl-2-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,-9-dihydro-purin-6-one; 3-Cyclopentyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl-]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one; 1-Cyclopentyl-6-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,5-dihydro-pyrazolo-[3,4-d]pyrimidin-4-one; 9-Cyclopentyl-2-[2-(3-morpholin-4-yl-propoxy)-benzyl]-1,9-dihydro-purin-6-one; N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-2-pyrrolidin-1-yl-acetamide; N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-2-morpholin-4-yl-acetamide; 2-Diethylamino-N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-acetamide; 1-{[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl-carbamoyl]-methyl}-pyrrolidine-2(S)-carboxylic acid methyl ester; 2-Cyclobutylamino-N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[-4,3-d]pyrimidin-5-ylmethyl]- 13. The method of any one of claims 1 to 12, wherein the compound is selected from the group consisting of: 2-cyclopropylamino-N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-acetamide; or 2-cyclopropylamino-N-[(1R,2S)2-(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethyl)-cyclohex-1-yl]-acetamide; IMR-687; (a potent inhibitor of PDE9A); BAY 73-6691; PF-04447943; PF-4181366; and stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, and any combination thereof.

21. PDE9 inhibitors, a salt of (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, malonic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one monomaleate; (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one monobenzenesulfonate; Crystals of said salt; A crystal of (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one monomaleate, which has a diffraction peak at a diffraction angle (2θ±0.2°) of 10.1° in powder X-ray diffraction; A crystal of (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one monobenzenesulfonate, which has a diffraction peak at a diffraction angle (2θ±0.2°) of 9.9° in powder X-ray diffraction.

13. The method of any one of claims 1 to 12, selected from the group consisting of:

22. 1. A pharmaceutical composition comprising a serotonergic hallucinogen and a PDE9 inhibitor, wherein the serotonergic hallucinogen and the PDE9 inhibitor are present in amounts sufficient to treat or prevent a disorder in a subject, wherein the disorder comprises a neuropsychiatric disorder, cluster headache, or migraine.

23. 23. The pharmaceutical composition of claim 22, wherein the PDE9 inhibitor enhances the therapeutic effect of the serotonergic hallucinogen on the disorder being treated.

24. 23. The pharmaceutical composition of claim 22, wherein the PDE9 inhibitor reduces at least one undesirable biological activity of a serotonergic hallucinogen in a subject.

25. 23. The pharmaceutical composition of claim 22, wherein the PDE9 inhibitor reduces the abuse potential of the serotonergic hallucinogen in a subject.

26. 26. The pharmaceutical composition of any one of claims 22 to 25, formulated for administration via a route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, intrapleural, intraperitoneal, intravaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraaural, intraocular, intrathecal, and intravenous.

27. Serotonergic hallucinogens include psilocin, psilocybin, bufotenin, baeocystin, aeruginacin, 5-MeO-DMT, N,N-dimethyltryptamine (DMT), 5-bromo-DMT, N-methyl-N-ethyltryptamine (MET), N-methyl-N-isopropyltryptamine (MiPT), N-methyl-N-propyltryptamine (MPT), N. N-Diethyltryptamine (DET), N-Ethyl-N-isopropyltryptamine (EiPT), N-Methyl-N-butyltryptamine (MBT), N-Propyl-N-isopropyltryptamine (PiPT), N,N-Dipropyltryptamine (DPT), N,N-Diisopropyltryptamine (DiPT), N,N-Diallyltryptamine (DALT), N,N-Dibutyltryptamine (DBT), N-Ethyltryptamine (NET), N-Methyltryptamine NMT, trimethyltryptamine (TMT), α-methyltryptamine, α-ethyltryptamine, α,N-DMT, α,N,N-trimethyltryptamine, ethosybin, 4-HO-MET, 4-HO-DET, 4-HO-MPT, 4-HO-MiPT, 4-HO-MALT, 4-HO-DPT, 4-HO-DiPT, 4-HO-DALT, 4-HO-DBT, 4-HO-DSBT, 4-HO-αMT, 4-HO-MPMI, 4-HO-TMT, 4-HO-1, N,N-TMT, 4-HO-5-MeO-DMT, 4-AcO-DMT, 4-AcO-MET, 4-AcO-MALT, 4-AcO-DET, 4-AcO-EiPT, 4-AcO-DPT, 4-AcO-DiPT, 4-AcO-DA LT, 4-MeO-DMT, 4-MeO-MiPT, 5-MeO-NMT, 5-MeO-MET, 5-MeO-MPT, 5-MeO-MiPT, 5-MeO-DET, 5-MeO-EiPT, 5-MeO-EPT, 5-MeO-PiP T, 5-MeO-DPT, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-αMT, 5-MeO-2,N,N-TMT, 5-MeO-7,N,N-TMT, 5-MeO-α,N-DMT, 4-F-5-MeO-DMT, 5 -Me-MiPT, 5-HO-DiPT, 2-α-DMT, 4-Me-αMT, 4-Me-αET, 7-Me-αET, 4,5-DHP-AMT, 4,5-DHP-DMT, 4,5-MDO-DMT, 4,5-MDO-DiPT, 5,6-MDO-DiPT, 5,6-MDO-MiPT, 5-fluoro-αMT, 6-fluoro-αMT, 6-fluoro-DMT, N,N-tetramethyltributamine (Pyr-T), 4-HO-pyr-T, 5-MeO-pyr-T, RU-28306 (4,α-methylene-N,N-DMT), O-4310 (6-fluoro-1-isopropyl-4-HO-DMT), CP-13 2,484 (4,5-DHP-1-methyltryptamine), dimemebufe (5-MeO-BFE), 5-MeO-DiBF, ibogaine, voacangine, lysergic acid diethylamide (LSD), lysergic acid amide (LSA), lysergic acid diamide, N1-methyl-lysergic acid diethylamide, 1-propionyl-lysergic acid diethylamide, 1-cyclopropanoyl-d-lysergic acid Diethylamide, 1-valeryl-D-lysergic acid diethylamide, 6-allyl-6-nor-lysergic acid diethylamide, 6-butyl-6-nor-lysergic acid diethylamide, 6-ethyl-6-nor-lysergic acid diethylamide, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 6-propyl-6-nor-lysergic acid diethylamide, 6-cyclopropyl-6-nor-lysergic acid diethylamide, 6-nor-lysergic acid diethylamide, lysergic acid ethylamide, lysergic acid α-hydroxyethylamide, lysergic acid 2-butylamide, lysergic acid 3-pentylamide, lysergic acid methyl ester, lysergic acid 2,4-dimethylazetidide, lysergic acid piperidine, N,N-dimethyl-lysergamide, methylisopropyl-lysergamide, N,N-diallyl-lysergamide, N-pyrrolidyl-lysergamide, N-morpholinyl-lysergamide, 1-methyl-lysergic acid butanolamide, lysergic acid β-propanolamide, lysergic acid 1-butanolamide, mescaline, lophophine, isomescaline, cyclopropylmescaline, thioisomescaline (2-TIM, 3-TIM, and 4-TIM), 4-desoxymescaline, dimescaline, escaline, metaescaline, thiometaescaline (3-TME, 4-TME, and 5-TME), trisescaline, thiotrisescaline (3-T-TRIS and 4-T-TRIS), symbescaline, asymbescaline, thio Cymbescaline (3-TSB and 4-TSB), fenestrationscaline, allylescaline, methallylescaline, proscaline, isoproscaline, metaproscaline, thioproscaline, buscaline, thiobuscaline, α-ethylmescaline, ariadne, macromerine, MEPEA, TOM (2-TOM and 5-TOM), Bis-TOM, TOMSO (2-methoxy-4-methyl-5-methylsulfinylamphetamine), TOET (2-TOET and 5-TOET), BOH, BOM (13-methoxy-mescaline), beta-D, 4-D, DME, F-2, F-22, FLEA, MDPH, MDMP, propynyl, 2C series (2,5-dimethoxy, 4-substituted phenethylamine), βk-2C-B, 2C-B, 2CB-2EtO, 2CB-5EtO, 2CB-diEtO, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-C, 2C-D, 2CD-2EtO, 2CD-diEtO, 2CD-5EtO, 2C-E, 2C-EF, 2C-F, 2C-G (2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, and 2C-G-N), 2C-H, 2C-I, 2CI-2EtO, 2C-iP, 2C-N, 2C-O, 2C-O-4, 2C-P, 2C-SE, 2C-T, 2CT -5EtO, 2C-T-2, 2CT-2-2EtO, 2CT-2-5EtO, 2CT-2-diEtO, 2C-T-4 (2C-T-4 and Ψ-2C-T-4), 2CT-4-2EtO, 2C-T-7, 2CT-7-2EtO, 2C-T-8, 2C-T-9, 2C-T-13, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-19, 2C-T-21, 2C-TFM, 2C-YN, BOB (I3-methoxy-2C-B), BOD (I3-methoxy-2C-D), BOHD (I3-hydroxy-2C-D), HOT-2, HOT-7, HOT-17, 2CB-Ind. Indane derivatives including 2C-BCB (TCB-2), benzocyclobutene derivatives including 2C-BCB (TCB-2), NBOMe derivatives (NBOMe-mescaline, 2C-H-NBOMe, 2C-C-NBOMe, 2CBCB-NBOMe, 2CBFly-NBOMe, 2C-B-NBOMe, 2C-I-NBOMe, 2C-TFM-NBOMe, 2C-D-NBOMe, 2C-G-NBOMe, 2C-E-NBOMe, 2C-P-NBOMe, 2C-iP-NBOMe, 2C-CN-NB OMe, 2C-N-NBOMe, 2C-T-NBOMe, 2C-T-4-NBOMe, 2C-T-7-NBOMe, and DMBMPP), NBOH derivatives (2C-C-NBOH, 2C-B-NBOH, 2C-I-NBOH, and 2C-CN-NBOH), NBMD derivatives (2C-I-NBMD), NBF derivatives (2C-C-NBF, 2C-B-NBF, and 2C-I-NBF), 3C series (3, including 3C-E, 3C-P, 3C-DFE, and 3C-BZ)DOx series (2,5-dimethoxy and 4-substituted amphetamines), including DOAM, DOB, Meta-DOB, methyl-DOB, DOBU, DOC, DOEF, DOET, DOI, DOM, Ψ-DOM, DON, DOPR, SOiPR, DOT, Meta-DOT, Ortho-DOT, DOTFM, DMCPA, DMMDA, and DMMDA-2, 3,4-dimethyl-2,5-dimethoxyamphetamine, 4-methyl- 2,5-dimethoxymethamphetamine, 2,N-dimethyl-4,5-methylenedioxyamphetamine, dimethoxyamphetamine (2,4-DMA, 2,5-DMA, and 3,4-DMA), trimethoxyamphetamine (TMA-2, TMA-6), tetramethoxyamphetamine, Br-DragonFLY, TFMFly, 2-bromo-4,5-methylenedioxyamphetamine, 4-bromo-3,5-dimethoxyamphetamine, EEE, EEM, EME, EMM, EDMA, EIDA , ethyl-J, methyl-J, ethyl-K, methyl-K, IDNNA, Iris, MDAI, MDMAI, MDAT, MDMAT, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPK, MDPR, MEDA, MEM, methyl-DMA, MMDA, MMDA-2, 5-methyl-MDA, MEE, MME, MPM, DiFMDA, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB , 6-MAPDB, 6-MAPB, 6-EAPB, 5-EAPB, para-methoxyamphetamine, para-methoxymethamphetamine, 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, benzoxazine, efavirenz, 3,4-methylenedioxymethamphetamine (MDMA), MDA, 2,Substituted methylenedioxyphenethylamines (MDxx) including 3-MDA, 5-methyl-MDA, MMDA, MDEA, MBDB, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPM, MDPR, BDB, MMDA-2, DiFMDA, EIDA, ethyl-K, lophophine, substituted amphetamines, EDMA (N-ethyl-3,4- methylenedioxyamphetamine), para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, substituted cathinones, methylone, ethylone, eutrone, butylone, pentylone, 4-ethylmethcathinone, 3-methylmethcathinone, substituted benzofurans, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB, 6-MAPB, 6-MAPB, 5-EAPB, 6-EAPB, 5-MBPB, MDAT, MDMAT, 6-CAT, tetralinylaminopropane, trifluoromethylaminoindan, ethyltriflate Iodomethylaminoindan, 5-iodo-2-aminoindan, MMAI, MDAI, MDMAI, indanylaminopropane, naphthylaminopropane, 4-chlorophenylisobutylamine, 4-methylphenylisobutylamine, Ariadne, α-methyltryptamine, 5-MeO-αMT, α-ethyltryptamine, 4-Me-αET, 7-Me-αET, 5-MeO-αET, 5-MeO-MiPT, Δ, ９ -THC, CBD, CBN, THCV, (C6)-CP 47,497, (C9)-CP 47,497, 1-butyl-3-(2-methoxybenzoyl)indole, 1-butyl-3-(4-methoxybenzoyl)indole, 1-pentyl-3-(2-methoxybenzoyl)indole, 2-isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene, 4-HTMPIPO, 4-nonylphenylboronic acid, 5Br-UR-144, 5Cl-APINACA, 5Cl-UR-144, 5F-3-pyridinoylindole, 5F-AB-FUPPYCA, 5F-AD B-PINACA, 5F-ADBICA, 5F-ADB, 5F-AMB, 5F-APINACA, 5F-CUMYL-PINACA, 5F-EMB-PINACA, 5F-NNE1, 5F-PB-22, 5F-PCN, 5F-PY-PICA, 5F-PY-P INACA, 5F-SDB-006, HHC, A-796,260, A-834,735, A-836,339, A-955,840, A-40174, A-41988, A-42574, AB-001, AB-CH FU PYCA, AB-CHMFUPPYCA, AB-CHMINACA, AB-FUBICA, AB-FUBINACA 2-fluorobenzyl isomer, AB-FUBINACA, AB-PICA, AB-PINACA, abnormal cannabidiol, ADAMANTYL-THPINACA, ADB-CHMINACA, ADB-FUBICA, ADB-FUBICA, ADB-PINACA, ADBICA, ADS B-FU B-187, adulemic acid, AM-087, AM-411, AM-630, AM-679, AM-694, AM-855, AM-883, AM-905, AM-906, AM-919, AM-926, AM -938, AM-1220, AM-1221, AM-1235, AM-1241, AM-1248, AM-1346, AM-1387, AM-1714, AM-2201, AM-2232, AM-2233, AM-2389, AM-4030, AM-4113, AM-6527, AM-6545, AM-251, AM-281, AM-404, AMB-CHMINACA, AMB-FUBINACA, AMG-1, AMG-3, AMG-36, AMG-41, APICA, APINACA, APP-FUBINACA, arachidonoyl serotonin, ACEA, ACPA, Arvanil, AZ-11713908, BAY 38-7271, BAY 59-3074, BIM-018, Biochanin A, BML-190, Navidrox (Cambisol), cannabicyclohexanol, cannabipiperidiethanone, CAY-10401, CAY-10429, CAY-10508, CB-13, CB-25, CB-52, CB-86, CB-86, CBS-0550, CP47,497, CP55,244, CP55,940, CUMYL-5F-PICA, CUMYL-BICA, CUMYL-PICA, CUMYL-PINACA, CUMYL-THPINACA, dexanabinol, dimethylheptylpyran, drinabant, dronabinol, EAM-2201, EMB-FUBINACA, FAB-144, FDU-NNE1, FDU-PB-22, FUB -144, FUB-APINACA, FUB-JWH-018, FUB-PB-22, FUBIMINA, genistein, GW-405,833, GW-842,166X, hemopressin, HU-210, HU-243, HU-308, HU-320, HU-331, HU-336, HU-345, HU-910, ibipinabant, IDFP, JNJ 1661010, JNJ 1661010, JTE-907, JTE 7-31, JWH-007, JWH-015, JWH-018, JWH-019, JWH-030, JWH-051, JWH-073, JWH-081, JWH-098, JWH-116, JWH-122, JWH-133, JWH-139, JWH-14 7, JWH-149, JWH-161, JWH-164, JWH-167, JWH-175, JWH-176, JWH-182, JWH-184, JWH-185, JWH-192, JWH-193, JWH-194, JWH-195, JWH-196, J WH-197, JWH-198, JWH-199, JWH-200, JWH-203, JWH-210, JWH-229, JWH-249, JWH-250, JWH-251, JWH-302, JWH-307, JWH-359, JWH-369, JWH-370, JWH-398, JWH-424, JZL184, JZL195, kaempferol, KM-233, L-759,633, L-759,656, LASSBio-881, LBP-1, Leelamin, levonantradol, LH-21, LY-320,135, LY-2183240, NAM-2201, MDM-2201, MDA-7, MDA-19, MDA-77, MDMB-CHMICA, MDMB-CHMINACA, MDMB-FUBINACA, Menabitan, MEPIRAPIM, Methaneanandamide, MJ-15, MK-9470, MMB-2201, MN-18 , MN-25, Nabazenil, Nabilone, Nabitan, Navoctate, NESS-0327, NESS-040C5, NIDA-41020, NM-2201, NMP-7, NNE1, Nonavine O-224, O-581, O-585, O-606, O-689, O-774, O-806, O-823, O-889, O-1057, O -1125, O-1184, O-1191, O-1238, O-1248, O-1269, O-1270, O-1376, O-1399, O-1422, O-16 01, O-1602, O-1624, O-1656, O-1657, O-1660, O-1812, O-1860, O-1861, O-1871, O-1918, O -2048, O-2050, O-2093, O-2113, O-2220, O-2365, O-2372, O-2373, O-2383, O-2426, O-2484, O-2545, O-2654, O-2694, O-2715, O-2716, O-3223, O-3226, oleoylethanolamide, Olvanil, Org 27569, Org 27759, Org 2831, Org 28611, Org 29647, Otenabant, Palmitoylethanolamide, Parahexyl, PF-03550096, PF-04457845, PF-622, PF-750, PF-3845, PF-514273, PHOP, PipISB, Pirunavine, Pravadrine, Pregnenolone, PSB-SB-487, PSB-SB-1202, PTI-1, PTI-2, PX-1, PX-2, PX-3, QUCHIC. QUPIC, RCS-4, RCS-8, rimonabant, lozonabant, RTI-371, S-444,823, SDB-006, SER-601, SPA-229, SR-144,528, STS-135, surinabant, taranabant, tedarinab, THC-O-acetate, THC-O-phosphate, THJ-018, THJ-2201, tinabinol, TM-38837, UR-144, URB-447, URB-447, URB-597, URB-602, URB-754, VCHSR, VDM-11, VSN-16, WIN 54,461, WIN 55,212-2, WIN 56,098, XLR-11, yangonin, harmaline, harmala alkaloids, other beta-carbolines, active ingredients of ayahuasca, salvinorin A, salvinorin B methoxymethyl ether, salvinorin B ethoxymethyl ether, piperazine, pFPP, TFMPP, myristicin, elemicin, cryogenin (vertine), atropine, scopolamine, hyoscyamine, ibotenic acid, muscimol, TiHKAL, 2-Me-D ET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-EPT, 4-HO-McPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPMI, 4-HO-MPT, 4-HO-αMT, 4 -Me-αMT, 4-MeO-MiPT, 4-PrO-DMT, 4,5-MDO-DiPT, 4,5-MDO-DMT, 5-ethoxy-αMT, 5-fluoro-AET, 5-fluoro-DET, 5-fluoro-DMT, 5 -Fluoro-EPT, 5-fluoro-MET, 5-MeO-AET, 5-MeO-αMT, 5-MeO-DALT, 5-MeO-DET, 5-MeO-DPT, 5-MeO-EiPT, 5-MeO-MALT, 5-Me O-MiPT, 5-MeO-MPMI, 5-MeO-pyr-T, 5-MeS-DMT, 5-MeO-2-TMT, 5-TFM-DMT, 5-TFMO-DMT, 5,6-MDO-DiPT, 5,6-MDO-DMT, 5 , 6-MDO-MiPT, 5,6-MeO-MiPT, 5,N,N-TMT, 5F-MPMI, 6-fluoro-DET, 6-fluoro-DMT, 6-MeO-THH, 7-chloro-AMT, 7-F-5-MeO-MET, 4-acetoxy-DET, 4-acetoxy-DiPT, 4-acetoxy-MET, 4-acetoxy-MiPT, O-acetylbufotenin, O-acetylpsirosin, aeruginasin, alpha,N-DMT, alpha,N,O-TMS, baeocystin, 5-bromo-DMT, bufotenin, 5-chloro-αMT, DALT, dibutyltryptamine, diethyltryptamine, diisopropyltryptamine, 5,N-dimethyl-N-isopropyltryptamine, dimethyltryptamine, N,N-dimethyltryptamine, dipropyltryptamine, 2,α-dimethyltryptamine, ethosybin, ethylisopropyltryptamine, A-ethyltryptamine, 5-fluoro-AMT, 4-fluoro-5-methoxy-DMT, FT-104, 5-MeO-DMT, 5-methoxy-N,N-diisopropyl The pharmaceutical composition according to any one of claims 22 to 26, wherein the active ingredient is selected from the group consisting of pirtryptamine, 4-methyl-α-ethyltryptamine, N-methyl-N-ethyltryptamine, methylbutyltryptamine, methylisopropyltryptamine, alpha-methylserotonin, alpha-methyltryptamine, N-methyltryptamine, MPMI, norbeocystin, propylisopropyltryptamine, 2,N,N-TMT, A,N,N-trimethyltryptamine, ketamine, esketamine, arketamine, mitragynine, yohimbine, and combinations thereof.

28. 28. A pharmaceutical composition according to any one of claims 22 to 27, wherein the serotonergic hallucinogen is a tryptamine or ergoline, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof.

29. 29. The pharmaceutical composition of claim 28, wherein the serotonergic hallucinogen comprises tryptamine, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

30. 29. The pharmaceutical composition of claim 28, wherein the serotonergic hallucinogen is an ergoline, a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

31. 28. The pharmaceutical composition of claim 27, wherein the serotonergic hallucinogen is psilocybin, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof.

32. 32. The pharmaceutical composition of any one of claims 22 to 31, wherein the PDE9 inhibitor is selected from the group consisting of aminophylline, pentoxifylline, theobromine, paraxanthine, PF-04447913, PF-04447943, PF-04447953, BAY 73-6691, E 2027, CRD 773, BI 409306, CRD 740, TT 00920, BAY 7081, FRM 16606, HUC1-288, WYQ-C36D, and any combination thereof.

33. 33. The pharmaceutical composition of any one of claims 22 to 32, wherein the PDE9 inhibitor is PF-04447943, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof.

34. 34. The pharmaceutical composition of any one of claims 22 to 33, wherein the serotonergic hallucinogen is psilocybin, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof, or the PDE9 inhibitor is PF-04447943, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof.

35. A composition comprising a serotonergic hallucinogen and a PDE9 inhibitor, wherein the serotonergic hallucinogen is not mescaline.

36. 36. A pharmaceutical composition comprising the composition of claim 35, wherein the serotonergic hallucinogen and PDE9 inhibitor are present in amounts sufficient to treat or prevent a disorder in a subject, wherein the disorder comprises a neuropsychiatric disorder, cluster headache, or migraine.

37. 37. The pharmaceutical composition of claim 36, wherein the PDE9 inhibitor enhances the therapeutic effect of the serotonergic hallucinogen on the disorder being treated.

38. 38. The pharmaceutical composition of claim 36 or 37, wherein the PDE9 inhibitor reduces at least one undesirable biological activity of a serotonergic hallucinogen in a subject.

39. 39. The pharmaceutical composition of any one of claims 36 to 38, wherein the PDE9 inhibitor reduces the abuse potential of the serotonergic hallucinogen in a subject.

40. 40. The pharmaceutical composition of any one of claims 36 to 39, formulated for administration via a route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, intrapleural, intraperitoneal, intravaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraaural, intraocular, intrathecal, and intravenous.

41. Serotonergic hallucinogens include psilocin, psilocybin, bufotenin, baeocystin, aeruginacin, 5-MeO-DMT, N,N-dimethyltryptamine (DMT), 5-bromo-DMT, N-methyl-N-ethyltryptamine (MET), N-methyl-N-isopropyltryptamine (MiPT), N-methyl-N-propyltryptamine (MPT), N. N-Diethyltryptamine (DET), N-Ethyl-N-isopropyltryptamine (EiPT), N-Methyl-N-butyltryptamine (MBT), N-Propyl-N-isopropyltryptamine (PiPT), N,N-Dipropyltryptamine (DPT), N,N-Diisopropyltryptamine (DiPT), N,N-Diallyltryptamine (DALT), N,N-Dibutyltryptamine (DBT), N-Ethyltryptamine (NET), N-Methyltryptamine NMT, trimethyltryptamine (TMT), α-methyltryptamine, α-ethyltryptamine, α,N-DMT, α,N,N-trimethyltryptamine, ethosybin, 4-HO-MET, 4-HO-DET, 4-HO-MPT, 4-HO-MiPT, 4-HO-MALT, 4-HO-DPT, 4-HO-DiPT, 4-HO-DALT, 4-HO-DBT, 4-HO-DSBT, 4-HO-αMT, 4-HO-MPMI, 4-HO-TMT, 4-HO-1, N,N-TMT, 4-HO-5-MeO-DMT, 4-AcO-DMT, 4-AcO-MET, 4-AcO-MALT, 4-AcO-DET, 4-AcO-EiPT, 4-AcO-DPT, 4-AcO-DiPT, 4-AcO-DA LT, 4-MeO-DMT, 4-MeO-MiPT, 5-MeO-NMT, 5-MeO-MET, 5-MeO-MPT, 5-MeO-MiPT, 5-MeO-DET, 5-MeO-EiPT, 5-MeO-EPT, 5-MeO-PiP T, 5-MeO-DPT, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-αMT, 5-MeO-2,N,N-TMT, 5-MeO-7,N,N-TMT, 5-MeO-α,N-DMT, 4-F-5-MeO-DMT, 5 -Me-MiPT, 5-HO-DiPT, 2-α-DMT, 4-Me-αMT, 4-Me-αET, 7-Me-αET, 4,5-DHP-AMT, 4,5-DHP-DMT, 4,5-MDO-DMT, 4,5-MDO-DiPT, 5,6-MDO-DiPT, 5,6-MDO-MiPT, 5-fluoro-αMT, 6-fluoro-αMT, 6-fluoro-DMT, N,N-tetramethyltributamine (Pyr-T), 4-HO-pyr-T, 5-MeO-pyr-T, RU-28306 (4,α-methylene-N,N-DMT), O-4310 (6-fluoro-1-isopropyl-4-HO-DMT), CP-13 2,484 (4,5-DHP-1-methyltryptamine), dimemebufe (5-MeO-BFE), 5-MeO-DiBF, ibogaine, voacangine, lysergic acid diethylamide (LSD), lysergic acid amide (LSA), lysergic acid diamide, N1-methyl-lysergic acid diethylamide, 1-propionyl-lysergic acid diethylamide, 1-cyclopropanoyl-d-lysergic acid Diethylamide, 1-valeryl-D-lysergic acid diethylamide, 6-allyl-6-nor-lysergic acid diethylamide, 6-butyl-6-nor-lysergic acid diethylamide, 6-ethyl-6-nor-lysergic acid diethylamide, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 6-propyl-6-nor-lysergic acid diethylamide, 6-cyclopropyl-6-nor-lysergic acid diethylamide, 6-nor-lysergic acid diethylamide, lysergic acid ethylamide, lysergic acid α-hydroxyethylamide, lysergic acid 2-butylamide, lysergic acid 3-pentylamide, lysergic acid methyl ester, lysergic acid 2,4-dimethylazetidide, lysergic acid piperidine, N,N-dimethyl-lysergamide, methylisopropyl-lysergamide, N,N-diallyl-lysergamide, N-pyrrolidyl-lysergamide, N-morpholinyl-lysergamide, 1-methyl-lysergic acid butanolamide, lysergic acid β-propanolamide, lysergic acid 1-butanolamide, mescaline, lophophine, isomescaline, cyclopropylmescaline, thioisomescaline (2-TIM, 3-TIM, and 4-TIM), 4-desoxymescaline, dimescaline, escaline, metaescaline, thiometaescaline (3-TME, 4-TME, and 5-TME), trisescaline, thiotrisescaline (3-T-TRIS and 4-T-TRIS), symbescaline, asymbescaline, thio Cymbescaline (3-TSB, 4 and -TSB), fenestrationscaline, allylescaline, methallylescaline, proscaline, isoproscaline, metaproscaline, thioproscaline, buscaline, thiobuscaline, α-ethylmescaline, ariadne, macromerine, MEPEA, TOM (2-TOM and 5-TOM), Bis-TOM, TOMSO (2-methoxy-4-methyl-5-methylsulfinylamphetamine), TOET (2-TOET and 5-TOET), BOH, BOM (13-methoxy-mescaline), beta-D, 4-D, DME, F-2, F-22, FLEA, MDPH, MDMP, propynyl, 2C series (2,5-dimethoxy, 4-substituted phenethylamine), βk-2C-B, 2C-B, 2CB-2EtO, 2CB-5EtO, 2CB-diEtO, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-C, 2C-D, 2CD-2EtO, 2CD-diEtO, 2CD-5EtO, 2C-E, 2C-EF, 2C-F, 2C-G (2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, and 2C-G-N), 2C-H, 2C-I, 2CI-2EtO, 2C-iP, 2C-N, 2C-O, 2C-O-4, 2C-P, 2C-SE, 2C-T, 2CT -5EtO, 2C-T-2, 2CT-2-2EtO, 2CT-2-5EtO, 2CT-2-diEtO, 2C-T-4 (2C-T-4 and Ψ-2C-T-4), 2CT-4-2EtO, 2C-T-7, 2CT-7-2EtO, 2C-T-8, 2C-T-9, 2C-T-13, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-19, 2C-T-21, 2C-TFM, 2C-YN, BOB (I3-methoxy-2C-B), BOD (I3-methoxy-2C-D), BOHD (I3-hydroxy-2C-D), HOT-2, HOT-7, HOT-17, 2CB-Ind. Indane derivatives including 2C-BCB (TCB-2), benzocyclobutene derivatives including 2C-BCB (TCB-2), NBOMe derivatives (NBOMe-mescaline, 2C-H-NBOMe, 2C-C-NBOMe, 2CBCB-NBOMe, 2CBFly-NBOMe, 2C-B-NBOMe, 2C-I-NBOMe, 2C-TFM-NBOMe, 2C-D-NBOMe, 2C-G-NBOMe, 2C-E-NBOMe, 2C-P-NBOMe, 2C-iP-NBOMe, 2C-CN-NB OMe, 2C-N-NBOMe, 2C-T-NBOMe, 2C-T-4-NBOMe, 2C-T-7-NBOMe, and DMBMPP), NBOH derivatives (2C-C-NBOH, 2C-B-NBOH, 2C-I-NBOH, and 2C-CN-NBOH), NBMD derivatives (2C-I-NBMD), NBF derivatives (2C-C-NBF, 2C-B-NBF, and 2C-I-NBF), 3C series (3, including 3C-E, 3C-P, 3C-DFE, and 3C-BZ)DOx series (2,5-dimethoxy and 4-substituted amphetamines), including DOAM, DOB, Meta-DOB, methyl-DOB, DOBU, DOC, DOEF, DOET, DOI, DOM, Ψ-DOM, DON, DOPR, SOiPR, DOT, Meta-DOT, Ortho-DOT, DOTFM, DMCPA, DMMDA, and DMMDA-2, 3,4-dimethyl-2,5-dimethoxyamphetamine, 4-methyl- 2,5-dimethoxymethamphetamine, 2,N-dimethyl-4,5-methylenedioxyamphetamine, dimethoxyamphetamine (2,4-DMA, 2,5-DMA, and 3,4-DMA), trimethoxyamphetamine (TMA-2, TMA-6), tetramethoxyamphetamine, Br-DragonFLY, TFMFly, 2-bromo-4,5-methylenedioxyamphetamine, 4-bromo-3,5-dimethoxyamphetamine, EEE, EEM, EME, EMM, EDMA, EIDA , ethyl-J, methyl-J, ethyl-K, methyl-K, IDNNA, Iris, MDAI, MDMAI, MDAT, MDMAT, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPK, MDPR, MEDA, MEM, methyl-DMA, MMDA, MMDA-2, 5-methyl-MDA, MEE, MME, MPM, DiFMDA, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB , 6-MAPDB, 6-MAPB, 6-EAPB, 5-EAPB, para-methoxyamphetamine, para-methoxymethamphetamine, 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, benzoxazine, efavirenz, 3,4-methylenedioxymethamphetamine (MDMA), MDA, 2,Substituted methylenedioxyphenethylamines (MDxx) including 3-MDA, 5-methyl-MDA, MMDA, MDEA, MBDB, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPM, MDPR, BDB, MMDA-2, DiFMDA, EIDA, ethyl-K, lephophine, substituted amphetamines, EDMA (N-ethyl-3,4-methyl- dioxyamphetamine), para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, substituted cathinones, methylone, ethylone, eutrone, butylone, pentylone, 4-ethylmethcathinone, 3-methylmethcathinone, substituted benzofurans, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB, 6-MAPB, 6-MAPB, 5-EAPB, 6-EAPB, 5-MBPB, MDAT, MDMAT, 6-CAT, tetralinylaminopropane, trifluoromethylaminoindan, ethyltrifluoromethylaminoindan, methyl ... Noindan, 5-iodo-2-aminoindan, MMAI, MDAI, MDMAI, indanylaminopropane, naphthylaminopropane, 4-chlorophenylisobutylamine, 4-methylphenylisobutylamine, Ariadne, α-methyltryptamine, 5-MeO-αMT, α-ethyltryptamine, 4-Me-αET, 7-Me-αET, 5-MeO-αET, 5-MeO-MiPT, Δ, ９ -THC, CBD, CBN, THCV, (C6)-CP 47,497, (C9)-CP 47,497, 1-butyl-3-(2-methoxybenzoyl)indole, 1-butyl-3-(4-methoxybenzoyl)indole, 1-pentyl-3-(2-methoxybenzoyl)indole, 2-isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene, 4-HTMPIPO, 4-nonylphenylboronic acid, 5Br-UR-144, 5Cl-APINACA, 5Cl-UR-144, 5F-3-pyridinoylindole, 5F-AB-FUPP YCA, 5F-ADB-PINACA, 5F-ADBICA, 5F-ADB, 5F-AMB, 5F-APINACA, 5F-CUMYL-PINACA, 5F-EMB-PINACA, 5F-NNE1, 5F-PB-22, 5F-PCN, 5F-PY-PICA, 5F-PY-PINACA, 5F-SDB- 006, HHC, A-796,260, A-834,735, A-836,339, A-955,840, A-40174, A-41988, A-42574, AB-001, AB-CHFUPYCA, AB-CHMFUPPYCA, AB-CHMINACA, AB-FUBICA, AB-FUBINACA 2-fluorobenzyl isomer, AB-FUBINACA, AB-PICA, AB-PINACA, abnormal cannabidiol, ADAMANTYL-THPINACA, ADB-CHMINACA, ADB-FUBICA, ADB-FUBINACA, ADB-PINACA, ADBICA, ADS B-FU B-187, adulemic acid, AM-087, AM-411, AM-630, AM-679, AM-694, AM-855, AM-883, AM-905, AM-906, AM-919, AM-926, AM -938, AM-1220, AM-1221, AM-1235, AM-1241, AM-1248, AM-1346, AM-1387, AM-1714, AM-2201, AM-2232, AM-2233, AM-2389, AM-4030, AM-4113, AM-6527, AM-6545, AM-251, AM-281, AM-404, AMB-CHMINACA, AMB-FUBINACA, AMG-1, AMG-3, AMG-36, AMG-41, APICA, APINACA, APP-FUBINACA, arachidonoyl serotonin, ACEA, ACPA, Arvanil, AZ-11713908, BAY 38-7271, BAY 59-3074, BIM-018, Biochanin A, BML-190, Navidrox (Cambisol), cannabicyclohexanol, cannabipiperidiethanone, CAY-10401, CAY-10429, CAY-10508, CB-13, CB-25, CB-52, CB-86, CB-86, CBS-0550, CP47,497, CP55,244, CP55,940, CUMYL-5F-PICA, CUMYL-BICA, CUMYL-PICA, CUMYL-PINACA, CUMYL-THPINACA, dexanabinol, dimethylheptylpyran, drinabant, dronabinol, EAM-2201, EMB-FUBINACA, FAB-144, FDU-NNE1, FDU-PB-22, FUB -144, FUB-APINACA, FUB-JWH-018, FUB-PB-22, FUBIMINA, genistein, GW-405,833, GW-842,166X, hemopressin, HU-210, HU-243, HU-308, HU-320, HU-331, HU-336, HU-345, HU-910, ibipinabant, IDFP, JNJ 1661010, JNJ 1661010, JTE-907, JTE 7-31, JWH-007, JWH-015, JWH-018, JWH-019, JWH-030, JWH-051, JWH-073, JWH-081, JWH-098, JWH-116, JWH-122, JWH-133, JWH-139, JWH-14 7, JWH-149, JWH-161, JWH-164, JWH-167, JWH-175, JWH-176, JWH-182, JWH-184, JWH-185, JWH-192, JWH-193, JWH-194, JWH-195, JWH-196, J WH-197, JWH-198, JWH-199, JWH-200, JWH-203, JWH-210, JWH-229, JWH-249, JWH-250, JWH-251, JWH-302, JWH-307, JWH-359, JWH-369, JWH-370, JWH-398, JWH-424, JZL184, JZL195, kaempferol, KM-233, L-759,633, L-759,656, LASSBio-881, LBP-1, Leelamin, levonantradol, LH-21, LY-320,135, LY-2183240, NAM-2201, MDM-2201, MDA-7, MDA-19, MDA-77, MDMB-CHMICA, MDMB-CHMINACA, MDMB-FUBINACA, Menabitan, MEPIRAPIM, Methaneanandamide, MJ-15, MK-9470, MMB-2201, MN-18 , MN-25, Nabazenil, Nabilone, Nabitan, Navoctate, NESS-0327, NESS-040C5, NIDA-41020, NM-2201, NMP-7, NNE1, Nonavine O-224, O-581, O-585, O-606, O-689, O-774, O-806, O-823, O-889, O-1057, O -1125, O-1184, O-1191, O-1238, O-1248, O-1269, O-1270, O-1376, O-1399, O-1422, O-16 01, O-1602, O-1624, O-1656, O-1657, O-1660, O-1812, O-1860, O-1861, O-1871, O-1918, O -2048, O-2050, O-2093, O-2113, O-2220, O-2365, O-2372, O-2373, O-2383, O-2426, O-2484, O-2545, O-2654, O-2694, O-2715, O-2716, O-3223, O-3226, oleoylethanolamide, Olvanil, Org 27569, Org 27759, Org 2831, Org 28611, Org 29647, Otenabant, Palmitoylethanolamide, Parahexyl, PF-03550096, PF-04457845, PF-622, PF-750, PF-3845, PF-514273, PHOP, PipISB, Pirunavine, Pravadrine, Pregnenolone, PSB-SB-487, PSB-SB-1202, PTI-1, PTI-2, PX-1, PX-2, PX-3, QUCHIC. QUPIC, RCS-4, RCS-8, rimonabant, lozonabant, RTI-371, S-444,823, SDB-006, SER-601, SPA-229, SR-144,528, STS-135, surinabant, taranabant, tedarinab, THC-O-acetate, THC-O-phosphate, THJ-018, THJ-2201, tinabinol, TM-38837, UR-144, URB-447, URB-447, URB-597, URB-602, URB-754, VCHSR, VDM-11, VSN-16, WIN 54,461, WIN 55,212-2, WIN 56,098, XLR-11, yangonin, harmaline, harmala alkaloids, other beta-carbolines, active ingredients of ayahuasca, salvinorin A, salvinorin B methoxymethyl ether, salvinorin B ethoxymethyl ether, piperazine, pFPP, TFMPP, myristicin, elemicin, cryogenin (vertine), atropine, scopolamine, hyoscyamine, ibotenic acid, muscimol, TiHKAL, 2-Me-D ET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-EPT, 4-HO-McPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPMI, 4-HO-MPT, 4-HO-αMT, 4 -Me-αMT, 4-MeO-MiPT, 4-PrO-DMT, 4,5-MDO-DiPT, 4,5-MDO-DMT, 5-ethoxy-αMT, 5-fluoro-AET, 5-fluoro-DET, 5-fluoro-DMT, 5 -Fluoro-EPT, 5-fluoro-MET, 5-MeO-AET, 5-MeO-αMT, 5-MeO-DALT, 5-MeO-DET, 5-MeO-DPT, 5-MeO-EiPT, 5-MeO-MALT, 5-Me O-MiPT, 5-MeO-MPMI, 5-MeO-pyr-T, 5-MeS-DMT, 5-MeO-2-TMT, 5-TFM-DMT, 5-TFMO-DMT, 5,6-MDO-DiPT, 5,6-MDO-DMT, 5 , 6-MDO-MiPT, 5,6-MeO-MiPT, 5,N,N-TMT, 5F-MPMI, 6-fluoro-DET, 6-fluoro-DMT, 6-MeO-THH, 7-chloro-AMT, 7-F-5-MeO-MET, 4-acetoxy-DET, 4-acetoxy-DiPT, 4-acetoxy-MET, 4-acetoxy-MiPT, O-acetylbufotenin, O-acetylpsirosin, aeruginasin, alpha,N-DMT, alpha,N,O-TMS, baeocystin, 5-bromo-DMT, bufotenin, 5-chloro-αMT, DALT, dibutyltryptamine, diethyltryptamine, diisopropyltryptamine, 5,N-dimethyl-N-isopropyltryptamine, dimethyltryptamine, N,N-dimethyltryptamine, dipropyltryptamine, 2,α-dimethyltryptamine, ethosybin, ethylisopropyltryptamine, A-ethyltryptamine, 5-fluoro-AMT, 4-fluoro-5-methoxy-DMT, FT-104, 5-MeO-DMT, 5-methoxy-N,N-diisopropyltryptamine 41. The composition of claim 35 or the pharmaceutical composition of any one of claims 36 to 40, wherein the benzodiazepine is selected from the group consisting of 4-methyl-α-ethyltryptamine, N-methyl-N-ethyltryptamine, methylbutyltryptamine, methylisopropyltryptamine, alpha-methylserotonin, alpha-methyltryptamine, N-methyltryptamine, MPMI, norbeocystin, propylisopropyltryptamine, 2,N,N-TMT, A,N,N-trimethyltryptamine, ketamine, esketamine, arketamine, mitragynine, yohimbine, and combinations thereof.

42. 41. The composition of claim 35, or the pharmaceutical composition of any one of claims 36 to 40, wherein the serotonergic hallucinogen is a tryptamine or an ergoline.

43. 41. The composition of claim 35, or the pharmaceutical composition of any one of claims 36 to 40, wherein the serotonergic hallucinogen is tryptamine, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

44. 41. The composition of claim 35 or the pharmaceutical composition of any one of claims 36 to 40, wherein the serotonergic hallucinogen is ergoline, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

45. 41. The composition of claim 35, or the pharmaceutical composition of any one of claims 36 to 40, wherein the serotonergic hallucinogen is psilocybin, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

46. 41. The composition as defined in claim 35, or the pharmaceutical composition of any one of claims 36 to 40, wherein the PDE9 inhibitor is selected from the group consisting of aminophylline, pentoxifylline, theobromine, paraxanthine, PF-04447913, PF-04447943, PF-04447953, BAY 73-6691, E 2027, CRD 773, BI 409306, CRD 740, TT 00920, BAY 7081, FRM 16606, HUC1-288, WYQ-C36D, and any combination thereof.

47. 41. The composition of claim 35, or the pharmaceutical composition of any one of claims 36 to 40, wherein the PDE9 inhibitor is PF-04447943, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

48. 41. The composition of claim 35, or the pharmaceutical composition of any one of claims 36 to 40, wherein the serotonergic hallucinogen is psilocybin, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof, or the PDE9 inhibitor is PF-04447943, or a derivative thereof, or a salt, solvate, enantiomer or diastereomer thereof.

49. 41. A kit comprising the composition of claim 35 or the pharmaceutical composition of any one of claims 36 to 40, further comprising instructions for its use.

50. 41. A kit comprising the composition of claim 35 or the pharmaceutical composition of any one of claims 36-40, wherein the serotonergic hallucinogen and PDE9 inhibitor are present in the kit in amounts sufficient to treat or prevent a disorder in a subject, wherein the disorder comprises a neuropsychiatric disorder, cluster headache, or migraine.

51. 51. The kit of claim 49 or 50, wherein the PDE9 inhibitor enhances the therapeutic effect of the serotonergic hallucinogen on the disorder being treated.

52. 51. The kit of claim 49 or 50, wherein the PDE9 inhibitor reduces at least one undesirable biological activity of a serotonergic hallucinogen in a subject.

53. 51. The kit of claim 49 or 50, wherein the PDE9 inhibitor reduces the abuse potential of the serotonergic hallucinogen in the subject.

54. 54. The kit of any one of claims 49 to 53, wherein the pharmaceutical composition is formulated for administration via a route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, intrapleural, intraperitoneal, intravaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraaural, intraocular, intrathecal, and intravenous.

55. The serotonergic hallucinogens include psilocin, psilocybin, bufotenin, baeocystin, aeruginacin, 5-MeO-DMT, N,N-dimethyltryptamine (DMT), 5-bromo-DMT, N-methyl-N-ethyltryptamine (MET), N-methyl-N-isopropyltryptamine (MiPT), N-methyl-N-propyltryptamine (MPT), N. N-Diethyltryptamine (DET), N-Ethyl-N-isopropyltryptamine (EiPT), N-Methyl-N-butyltryptamine (MBT), N-Propyl-N-isopropyltryptamine (PiPT), N,N-Dipropyltryptamine (DPT), N,N-Diisopropyltryptamine (DiPT), N,N-Diallyltryptamine (DALT), N,N-Dibutyltryptamine (DBT), N-Ethyltryptamine (NET), N-Methyltryptamine tryptamine (NMT), trimethyltryptamine (TMT), α-methyltryptamine, α-ethyltryptamine, α,N-DMT, α,N,N-trimethyltryptamine, ethosybin, 4-HO-MET, 4-HO-DET, 4-HO-MPT, 4-HO-MiPT, 4-HO-MALT, 4-HO-DPT, 4-HO-DiPT, 4-HO-DALT, 4-HO-DBT, 4-HO-DSBT, 4-HO-αMT, 4-HO-MPMI, 4-HO-TMT, 4-HO-1,N,N-TMT, 4-HO-5-MeO-DMT, 4-AcO-DMT, 4-AcO-MET, 4-AcO-MALT, 4-AcO-DET, 4-AcO-EiPT, 4-AcO-DPT, 4-AcO-DiPT, 4-AcO-DALT, 4-MeO-DMT, 4-MeO-MiPT, 5-MeO-NMT, 5-MeO-MET, 5-MeO-MPT, 5-MeO-MiPT, 5-MeO-DET, 5-MeO-EiPT, 5-MeO-EPT , 5-MeO-PiPT, 5-MeO-DPT, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-αMT, 5-MeO-2,N,N-TMT, 5-MeO-7,N,N-TMT, 5-MeO-α,N-DMT, 4-F -5-MeO-DMT, 5-Me-MiPT, 5-HO-DiPT, 2-α-DMT, 4-Me-αMT, 4-Me-αET, 7-Me-αET, 4,5-DHP-AMT, 4,5-DHP-DMT, 4,5-MDO-DMT, 4,5-MDO-DiPT, 5,6-MDO-DiPT, 5,6-MDO-MiPT, 5-fluoro-αMT, 6-fluoro-αMT, 6-fluoro-DMT, N,N-tetramethyltributamine (Pyr-T), 4-HO-pyr-T, 5-MeO-pyr-T, RU-28306 (4,α-methylene-N,N-DMT), O-4310 (6-fluoro-1-isopropyl-4-HO-D MT), CP-132,484 (4,5-DHP-1-methyltryptamine), dimemebufe (5-MeO-BFE), 5-MeO-DiBF, ibogaine, voacangine, lysergic acid diethylamide (LSD), lysergic acid amide (LSA), lysergic acid diamide, N1-methyl-lysergic acid diethylamide, 1-propionyl-lysergic acid diethylamide, 1-cyclopropanoyl-d -lysergic acid diethylamide, 1-valeryl-D-lysergic acid diethylamide, 6-allyl-6-nor-lysergic acid diethylamide, 6-butyl-6-nor-lysergic acid diethylamide, 6-ethyl-6-nor-lysergic acid diethylamide, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 6-propyl-6-nor-lysergic acid diethylamide, 6-cyclopropyl-6-nor-lysergic acid diethylamide, 6-nor-lysergic acid diethylamide, lysergic acid ethylamide, lysergic acid α-hydroxyethylamide, lysergic acid 2-butylamide, lysergic acid 3-pentylamide, lysergic acid methyl ester, lysergic acid 2,4-dimethylazetidide, lysergic acid piperidine, N,N-dimethyl-lysergamide, methylisopropyl-lysergamide, N,N-diallyl-lysergamide, N-pyrrolidyl-lysergamide, N-morpholinyl-lysergamide, 1-methyl-lysergic acid butanolamide, lysergic acid β-propanolamide, lysergic acid 1-butanolamide, mescaline, lophophine, isomescaline, cyclopropylmescaline, thioisomescaline (2-TIM, 3-TIM, and 4-TIM), 4-desoxymescaline, dimescaline, escaline, metaescaline, thiometaescaline (3-TME, 4-TME, and 5-TME), trisescaline, thiotrisescaline (3-T-TRIS and 4-T-TRIS), symbescaline, asymbescaline, thio Cymbescaline (3-TSB and b4-TSB), fenestrationscaline, allylescaline, methallylescaline, proscaline, isoproscaline, metaproscaline, thioproscaline, buscaline, thiobuscaline, α-ethylmescaline, ariadne, macromelin, MEPEA, TOM (2-TOM and 5-TOM), Bis-TOM, TOMSO (2-methoxy-4-methyl-5-methylsulfinylamphetamine), TOET (2-TOET and 5-TOET), BOH, BOM (13-methoxy-mescaline), beta-D, 4-D, DME, F-2, F-22, FLEA, MDPH, MDMP, propynyl, 2C series (2,5-dimethoxy, 4-substituted phenethylamine), βk-2C-B, 2C-B, 2CB-2EtO, 2CB-5EtO, 2CB-diEtO, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-C, 2C-D, 2CD-2EtO, 2CD-diEtO, 2CD-5EtO, 2C-E, 2C-EF, 2C-F, 2C-G (2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, and 2C-G-N), 2C-H, 2C-I, 2CI-2EtO, 2C-iP, 2C-N, 2C-O, 2C-O-4, 2C-P, 2C-SE, 2C-T, 2CT -5EtO, 2C-T-2, 2CT-2-2EtO, 2CT-2-5EtO, 2CT-2-diEtO, 2C-T-4 (2C-T-4 and Ψ-2C-T-4), 2CT-4-2EtO, 2C-T-7, 2CT-7-2EtO, 2C-T-8, 2C-T-9, 2C-T-13, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-19, 2C-T-21, 2C-TFM, 2C-YN, BOB (I3-methoxy-2C-B), BOD (I3-methoxy-2C-D), BOHD (I3-hydroxy-2C-D), HOT-2, HOT-7, HOT-17, 2CB-Ind. Indane derivatives including 2C-BCB (TCB-2), benzocyclobutene derivatives including 2C-BCB (TCB-2), NBOMe derivatives (NBOMe-mescaline, 2C-H-NBOMe, 2C-C-NBOMe, 2CBCB-NBOMe, 2CBFly-NBOMe, 2C-B-NBOMe, 2C-I-NBOMe, 2C-TFM-NBOMe, 2C-D-NBOMe, 2C-G-NBOMe, 2C-E-NBOMe, 2C-P-NBOMe, 2C-iP-NBOMe, 2C-CN-NB OMe, 2C-N-NBOMe, 2C-T-NBOMe, 2C-T-4-NBOMe, 2C-T-7-NBOMe, and DMBMPP), NBOH derivatives (2C-C-NBOH, 2C-B-NBOH, 2C-I-NBOH, and 2C-CN-NBOH), NBMD derivatives (2C-I-NBMD), NBF derivatives (2C-C-NBF, 2C-B-NBF, and 2C-I-NBF), 3C series (3, including 3C-E, 3C-P, 3C-DFE, and 3C-BZ)DOx series (2,5-dimethoxy and 4-substituted amphetamines), including DOAM, DOB, Meta-DOB, methyl-DOB, DOBU, DOC, DOEF, DOET, DOI, DOM, Ψ-DOM, DON, DOPR, SOiPR, DOT, Meta-DOT, Ortho-DOT, DOTFM, DMCPA, DMMDA, and DMMDA-2, 3,4-dimethyl-2,5-dimethoxyamphetamine, 4-methyl- 2,5-dimethoxymethamphetamine, 2,N-dimethyl-4,5-methylenedioxyamphetamine, dimethoxyamphetamine (2,4-DMA, 2,5-DMA, and 3,4-DMA), trimethoxyamphetamine (TMA-2, TMA-6), tetramethoxyamphetamine, Br-DragonFLY, TFMFly, 2-bromo-4,5-methylenedioxyamphetamine, 4-bromo-3,5-dimethoxyamphetamine, EEE, EEM, EME, EMM, EDMA, EIDA , ethyl-J, methyl-J, ethyl-K, methyl-K, IDNNA, Iris, MDAI, MDMAI, MDAT, MDMAT, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPK, MDPR, MEDA, MEM, methyl-DMA, MMDA, MMDA-2, 5-methyl-MDA, MEE, MME, MPM, DiFMDA, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB , 6-MAPDB, 6-MAPB, 6-EAPB, 5-EAPB, para-methoxyamphetamine, para-methoxymethamphetamine, 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, benzoxazine, efavirenz, 3,4-methylenedioxymethamphetamine (MDMA), MDA, 2,Substituted methylenedioxyphenethylamines (MDxx) including 3-MDA, 5-methyl-MDA, MMDA, MDEA, MBDB, MDAL, MDBU, MDBZ, MDDM, MDIP, MDMEOET, MDMEO, MDOH, MDHOET, MDPL, MDCPM, MDPR, BDB, MMDA-2, DiFMDA, EIDA, ethyl-K, lophophine, substituted amphetamines, EDMA (N-ethyl-3,4- methylenedioxyamphetamine), para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), 4-ethylamphetamine, 3-methoxy-4-methylamphetamine, 4-methylmethamphetamine, 4-methylthioamphetamine, 4-fluoroamphetamine, norfenfluramine, para-iodoamphetamine, para-chloroamphetamine, substituted cathinones, methylone, ethylone, eutrone, butylone, pentylone, 4-ethylmethcathinone, 3-methylmethcathinone, substituted benzofurans, 5-APB, 6-APB, 5-APDB, 6-APDB, 5-MAPB, 5-MAPDB, 6-MAPB, 6-MAPB, 5-EAPB, 6-EAPB, 5-MBPB, MDAT, MDMAT, 6-CAT, tetralinylaminopropane, trifluoromethylaminoindan, ethyltriflate Iodomethylaminoindan, 5-iodo-2-aminoindan, MMAI, MDAI, MDMAI, indanylaminopropane, naphthylaminopropane, 4-chlorophenylisobutylamine, 4-methylphenylisobutylamine, Ariadne, α-methyltryptamine, 5-MeO-αMT, α-ethyltryptamine, 4-Me-αET, 7-Me-αET, 5-MeO-αET, 5-MeO-MiPT, Δ, ９ -THC, CBD, CBN, THCV, (C6)-CP 47,497, (C9)-CP 47,497, 1-butyl-3-(2-methoxybenzoyl)indole, 1-butyl-3-(4-methoxybenzoyl)indole, 1-pentyl-3-(2-methoxybenzoyl)indole, 2-isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene, 4-HTMPIPO, 4-nonylphenylboronic acid, 5Br-UR-144, 5Cl-APINACA, 5Cl-UR-144, 5F-3-pyridinoylindole, 5F-AB-FUPPYCA, 5F- ADB-PINACA, 5F-ADBICA, 5F-ADB, 5F-AMB, 5F-APINACA, 5F-CUMYL-PINA CA, 5F-EMB-PINACA, 5F-NNE1, 5F-PB-22, 5F-PCN, 5F-PY-PICA, 5F-PY-P INACA, 5F-SDB-006, HHC, A-796,260, A-834,735, A-836,339, A-955,840, A-40174, A-41988, A-42574, AB-001, AB-CH FU PYCA, AB-CHMFUPPYCA, AB-CHMINACA, AB-FUBICA, AB-FUBINACA 2-fluorobenzyl isomer, AB-FUBINACA, AB-PICA, AB-PINACA, abnormal cannabidiol, ADAMANTYL-THPINACA, ADB-CHMINACA, ADB-FUBICA, ADB-FUBICA, ADB-PINACA, ADBICA, ADS B-FU B-187, adulemic acid, AM-087, AM-411, AM-630, AM-679, AM-694, AM-855, AM-883, AM-905, AM-906, AM-919, AM-926, AM -938, AM-1220, AM-1221, AM-1235, AM-1241, AM-1248, AM-1346, AM-1387, AM-1714, AM-2201, AM-2232, AM-2233, AM-2389, AM-4030, AM-4113, AM-6527, AM-6545, AM-251, AM-281, AM-404, AMB-CHMINACA, AMB-FUBINACA, AMG-1, AMG-3, AMG-36, AMG-41, APICA, APINACA, APP-FUBINACA, arachidonoyl serotonin, ACEA, ACPA, Arvanil, AZ-11713908, BAY 38-7271, BAY 59-3074, BIM-018, Biochanin A, BML-190, Navidrox (Cambisol), cannabicyclohexanol, cannabipiperidiethanone, CAY-10401, CAY-10429, CAY-10508, CB-13, CB-25, CB-52, CB-86, CB-86, CBS-0550, CP47,497, CP55,244, CP55,940, CUMYL-5F-PICA, CUMYL-BICA, CUMYL-PICA, CUMYL-PINACA, CUMYL-THPINACA, dexanabinol, dimethylheptylpyran, drinabant, dronabinol, EAM-2201, EMB-FUBINACA, FAB-144, FDU-NNE1, FDU-PB-22, FUB -144, FUB-APINACA, FUB-JWH-018, FUB-PB-22, FUBIMINA, genistein, GW-405,833, GW-842,166X, hemopressin, HU-210, HU-243, HU-308, HU-320, HU-331, HU-336, HU-345, HU-910, ibipinabant, IDFP, JNJ 1661010, JNJ 1661010, JTE-907, JTE 7-31, JWH-007, JWH-015, JWH-018, JWH-019, JWH-030, JWH-051, JWH-073, JWH-081, JWH-098, JWH-116, JWH-122, JWH-133, JWH-139, JWH-14 7, JWH-149, JWH-161, JWH-164, JWH-167, JWH-175, JWH-176, JWH-182, JWH-184, JWH-185, JWH-192, JWH-193, JWH-194, JWH-195, JWH-196, J WH-197, JWH-198, JWH-199, JWH-200, JWH-203, JWH-210, JWH-229, JWH-249, JWH-250, JWH-251, JWH-302, JWH-307, JWH-359, JWH-369, JWH-370, JWH-398, JWH-424, JZL184, JZL195, kaempferol, KM-233, L-759,633, L-759,656, LASSBio-881, LBP-1, Leelamin, levonantradol, LH-21, LY-320,135, LY-2183240, NAM-2201, MDM-2201, MDA-7, MDA-19, MDA-77, MDMB-CHMICA, MDMB-CHMINACA, MDMB-FUBINACA, Menabitan, MEPIRAPIM, Methaneanandamide, MJ-15, MK-9470, MMB-2201, MN-18 , MN-25, Nabazenil, Nabilone, Nabitan, Navoctate, NESS-0327, NESS-040C5, NIDA-41020, NM-2201, NMP-7, NNE1, Nonavine O-224, O-581, O-585, O-606, O-689, O-774, O-806, O-823, O-889, O-1057, O -1125, O-1184, O-1191, O-1238, O-1248, O-1269, O-1270, O-1376, O-1399, O-1422, O-16 01, O-1602, O-1624, O-1656, O-1657, O-1660, O-1812, O-1860, O-1861, O-1871, O-1918, O -2048, O-2050, O-2093, O-2113, O-2220, O-2365, O-2372, O-2373, O-2383, O-2426, O-2484, O-2545, O-2654, O-2694, O-2715, O-2716, O-3223, O-3226, oleoylethanolamide, Olvanil, Org 27569, Org 27759, Org 2831, Org 28611, Org 29647, Otenabant, Palmitoylethanolamide, Parahexyl, PF-03550096, PF-04457845, PF-622, PF-750, PF-3845, PF-514273, PHOP, PipISB, Pirunavine, Pravadrine, Pregnenolone, PSB-SB-487, PSB-SB-1202, PTI-1, PTI-2, PX-1, PX-2, PX-3, QUCHIC. QUPIC, RCS-4, RCS-8, rimonabant, lozonabant, RTI-371, S-444,823, SDB-006, SER-601, SPA-229, SR-144,528, STS-135, surinabant, taranabant, tedarinab, THC-O-acetate, THC-O-phosphate, THJ-018, THJ-2201, tinabinol, TM-38837, UR-144, URB-447, URB-447, URB-597, URB-602, URB-754, VCHSR, VDM-11, VSN-16, WIN 54,461, WIN 55,212-2, WIN 56,098, XLR-11, yangonin, harmaline, harmala alkaloids, other beta-carbolines, active ingredients of ayahuasca, salvinorin A, salvinorin B methoxymethyl ether, salvinorin B ethoxymethyl ether, piperazine, pFPP, TFMPP, myristicin, elemicin, cryogenin (vertine), atropine, scopolamine, hyoscyamine, ibotenic acid, muscimol, TiHKAL, 2-Me-D ET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-EPT, 4-HO-McPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPMI, 4-HO-MPT, 4-HO-αMT, 4 -Me-αMT, 4-MeO-MiPT, 4-PrO-DMT, 4,5-MDO-DiPT, 4,5-MDO-DMT, 5-ethoxy-αMT, 5-fluoro-AET, 5-fluoro-DET, 5-fluoro-DMT, 5 -Fluoro-EPT, 5-fluoro-MET, 5-MeO-AET, 5-MeO-αMT, 5-MeO-DALT, 5-MeO-DET, 5-MeO-DPT, 5-MeO-EiPT, 5-MeO-MALT, 5-Me O-MiPT, 5-MeO-MPMI, 5-MeO-pyr-T, 5-MeS-DMT, 5-MeO-2-TMT, 5-TFM-DMT, 5-TFMO-DMT, 5,6-MDO-DiPT, 5,6-MDO-DMT, 5 , 6-MDO-MiPT, 5,6-MeO-MiPT, 5,N,N-TMT, 5F-MPMI, 6-fluoro-DET, 6-fluoro-DMT, 6-MeO-THH, 7-chloro-AMT, 7-F-5-MeO-MET, 4-acetoxy-DET, 4-acetoxy-DiPT, 4-acetoxy-MET, 4-acetoxy-MiPT, O-acetylbufotenin, O-acetylpsirosin, aeruginasin, alpha,N-DMT, alpha,N,O-TMS, baeocystin, 5-bromo-DMT, bufotenin, 5-chloro-αMT, DALT, dibutyltryptamine, diethyltryptamine, diisopropyltryptamine, 5,N-dimethyl-N-isopropyltryptamine, dimethyltryptamine, N,N-dimethyltryptamine, dipropyltryptamine, 2,α-dimethyltryptamine, ethosybin, ethylisopropyltryptamine, A-ethyltryptamine, 5-fluoro-AMT, 4-fluoro-5-methoxy-DMT, FT-104, 5-MeO-DMT, 5-methoxy-N,N-diisopropyl The kit according to any one of claims 49 to 54, wherein the active ingredient is selected from the group consisting of propyltryptamine, 4-methyl-α-ethyltryptamine, N-methyl-N-ethyltryptamine, methylbutyltryptamine, methylisopropyltryptamine, alpha-methylserotonin, alpha-methyltryptamine, N-methyltryptamine, MPMI, norbeocystin, propylisopropyltryptamine, 2,N,N-TMT, A,N,N-trimethyltryptamine, ketamine, esketamine, arketamine, mitragynine, yohimbine, and combinations thereof.

56. 56. The kit of any one of claims 49 to 55, wherein the serotonergic hallucinogen is a tryptamine or ergoline, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

57. 57. The kit of claim 56, wherein the serotonergic hallucinogen is tryptamine, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

58. 57. The kit of claim 56, wherein the serotonergic hallucinogen is ergoline, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

59. 56. The kit of claim 55, wherein the serotonergic hallucinogen is psilocybin, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

60. 60. The kit of any one of claims 49-59, wherein the PDE9 inhibitor is selected from the group consisting of aminophylline, pentoxifylline, theobromine, paraxanthine, PF-04447913, PF-04447943, PF-04447953, BAY 73-6691, E 2027, CRD 773, BI 409306, CRD 740, TT 00920, BAY 7081, FRM 16606, HUC1-288, WYQ-C36D, and any combination thereof.

61. 57. The kit of any one of claims 45 to 56, wherein the PDE9 inhibitor is PF-04447943, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

62. 61. The kit of any one of claims 49 to 60, wherein the serotonergic hallucinogen is psilocybin, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof, and the PDE9 inhibitor is PF-04447943, or a derivative thereof, or a salt, solvate, enantiomer, or diastereomer thereof.

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