Pharmaceutical compositions and methods

Abstract

The disclosure relates to the use of phosphodiesterase 1 (PDE1) inhibitors in combination with a Compound of Formula VIII or a Compound of Formula IX, as described herein, or in combination with an antiemetic agent, such as an antipsychotic agent, e.g., olanzapine, for preventing or treating nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting). In some embodiments, the Compound of Formula VIII or the Compound of Formula IX is used as mono-therapy (i.e., without a PDE1 inhibitor).

Description

IT-209-PCT / ICT1209WOPCT1PHARMACEUTICAL COMPOSITIONS AND METHODSCROSS-REFERENCE TO RELATED APPLICATIONSThe instant application is an international application which claims priority to, and the benefit of, U.S. Provisional Applications Ser. Nos. 63 / 722,779, 63 / 722,941, and 63 / 722,950, each filed on November 20. 2024, the contents of each of which are hereby incorporated by reference in their entireties.FIELD OF DISCLOSURE

[0001] The field relates to pharmaceutical compositions and methods for preventing or treating nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting), using a phosphodiesterase 1 (PDE1) inhibitor to slow cyclic nucleotide hydrolysis in combination with a Compound of Formula VIII, as described herein (e.g., lumateperone, or an analog or derivative thereof), or a Compound of Formula IX, as described herein, or using a PDE1 inhibitor in combination with an antiemetic agent, such as antipsychotic agents, e.g., olanzapine. In some embodiments, the Compound of Formula VIII or IX is used as mono-therapy (i.e., without a PDE1 inhibitor).BACKGROUND OF THE DISCLOSURE

[0002] Eleven families of phosphodiesterases (PDEs) have been identified but only PDEs in Family I, the Ca2+ / calmodulin-dependent phosphodiesterases (CaM-PDEs), which are activated by Ca2+ / calmodulin, have been shown to mediate the calcium dependent cyclic nucleotide (e.g., cGMP and cAMP) signaling pathways. The three known CaM-PDE genes. PDE1A, PDE1B, and PDE1C, are all expressed in central nervous system tissue. PDE1A is expressed in the brain, lung and heart. PDE1B is primarily expressed in the central nervous system, but it is also detected in monocytes and neutrophils and has been shown to be involved in inflammatory responses of these cells. PDE1C is expressed in olfactory epithelium, cerebellar granule cells, striatum, heart, vascular smooth muscle and tumor cells. PDE1C has been demonstrated to be a major regulator of smooth muscle proliferation in human smooth muscle. Cyclic nucleotide phosphodiesterases down-regulate intracellular cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to their respective 5’ -monophosphates (5’AMP and 5’GMP), which are inactive in terms of intra-cellular signaling pathways. Both cAMP and cGMP areIT-209-PCT / ICT1209WOPCT1 central intracellular second messengers and they play roles in regulating numerous cellular functions. PDE1A and PDE1B preferentially hydrolyze cGMP over cAMP, while PDE1C shows approximately equal cGMP and cAMP hydrolysis.

[0003] Cyclic nucleotide phosphodiesterases decrease intracellular cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to their respective inactive 5 '-monophosphates (5'AMP and 5'GMP). CaM-PDEs play a critical role in mediating signal transduction in brain cells. For example, NMDA-type glutamate receptor activation and / or dopamine D2 receptor activation result in increased intracellular calcium concentrations, leading to activation of effectors such as calmodulin-dependent kinase II (CaMKII) and calcineurin and to activation of CaM-PDEs, resulting in reduced cAMP and cGMP. Dopamine DI receptor activation, on the other hand, leads to activation of calcium dependent nucleotide cyclases, resulting in increased cAMP and cGMP. These cyclic nucleotides in turn activate protein kinase A (PKA; cAMP- dependent protein kinase) and / or protein kinase G (PKG; c AMP-dependent protein kinase) that phosphorylate downstream signal transduction pathway elements such as DARPP-32 (dopamine and cAMP-regulated phosphoprotein) and cAMP responsive element binding protein (CREB).

[0004] CaM-PDEs can therefore affect dopamine-regulated and other intracellular signaling pathways including but not limited to nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP) and endorphin intracellular signaling pathways.

[0005] PDE1 is a therapeutic target for regulation of intracellular signaling pathways, preferably in the nervous system, including but not limited to a dopamine DI receptor, dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP. CNP) or endorphin intracellular signaling pathway. For example, one on hand, inhibition of PDE1 can potentiate the effect of a dopamine DI agonist by protecting cGMP and cAMP from degradation, but on the other hand inhibition of PDE1 can inhibit dopamine D2 receptor signaling pathways.

[0006] The development of a wide range of chemotherapeutic drugs has significantly- improved cancer survival rate. However, chemotherapy causes several side effects. Chemotherapy-induced nausea and vomiting (CINV) is a common and distressing side effect ofIT-209-PCT / ICT1209WOPCT1 chemotherapy. Nausea is an unpleasant sensation experienced in the back of the throat and epigastrium, while vomiting is the motor reflex resulting in forceful upward expulsion of contents from the stomach. Although nausea and vomiting can result from other cancer treatments, such as surgery and radiation therapy, CINV is the most severe and most distressing. Severe symptoms of CINV decrease the patient’s quality of life and can potentially interfere with compliance with treatment, even leading to discontinuation of further treatment due to the fear of CINV.

[0007] The vomiting response is coordinated by the vomiting center (VC) of the brain, located in the medulla oblongata. The VC integrates a variety of peripheral and central inputs and elicits the emetic reflex as a response. Chemotherapeutic drugs can activate neurotransmitter receptors in the area postrema of the brain or stimulate vagal afferents near the enterochromaffin cells in the intestine. Multiple neurotransmitters, including serotonin (5-hydroxytryptamine or 5- HT), substance P (SP), dopamine, histamine, and their receptors are involved in CINV. Several antiemetic agents have been developed for CINV. Currently, the commonly used medications for CINV include 5-HT3 antagonists, corticosteroids, NK1 receptor antagonists, and dopamine receptor antagonists (e.g., promethazine, metoclopramide).

[0008] Various heterocycle fused gamma carbolines compounds have been disclosed as potential therapeutic agents based on their activity at one or more of the serotonin-2A (5-HT2A) receptors, dopamine DI or D2 receptors, and the serotonin transporter (SERT). These compounds have been suggested for use in the treatment of a variety of central nervous system disorders, such as psychosis, anxiety, depression, and other mood disorders. See, e.g., U.S. Pat. Nos. 6,548.49, 6,552,017. 6,713,471, 7,081.455, 7,183.282, 7,238,690, 8.309,722, 8,598,119. 8,648,077, 10,245,260, 10,906,906, 10,961,245, RE39,680, RE39.679, US 2021 / 006009.

[0009] One such substituted heterocycle fused gamma-carboline of the aforementioned art is lumateperone ((4-((6bR,10aS)-3-methyl-2,3,6b.9.10.10a-hexahydro-lH-pyrido[3',4': 4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)-l-(4-fluorophenyl)-l-butanone). Lumateperone is a drug with a novel mechanism of action, being an antagonist of the serotonin-2A (5-HT2A) receptor, as well as a modulator of dopamine receptor signaling at the level of key intra-cellular phosphoproteins, and an inhibitor of the serotonin transporter (SERT). Lumateperone, launched in the United States as CAPLYTA® (lumateperone tosylate), has been approved for the treatment of schizophrenia, depressive episodes associated with bipolar disorder (bipolarIT-209-PCT / ICT1209WOPCT1 depression) (both as monotherapy and adjunctive therapy), and as adjunctive treatment for major depressive disorder (MDD).

[0010] At dopamine D2 receptors, this compound has been shown to have dual properties and acts as both a post-synaptic antagonist and a pre-synaptic partial agonist of the D2 receptor. It also stimulates phosphorylation of glutamatergic NMDA NR2B, or GluN2B, receptors in a mesolimbic specific manner. It is believed that this regional selectivity in the brain areas thought to mediate the efficacy of antipsychotic drugs, together with the serotonergic, glutamatergic, and dopaminergic interactions, may result in antipsychotic efficacy for positive, negative, affective and cognitive symptoms associated with schizophrenia.

[0011] Lumateperone displays differential dose-dependent effects, selectively targeting the 5-HT2A receptor at low doses, while progressively interacting with the D2 receptor and serotonin transporter at higher doses. Lumateperone is believed to be particularly effective in treating acute depression owing to its rapid onset of action compared to existing antidepressants. This is believed to be due to signaling through a neurotransmitter system separate from the traditional monoamine signaling systems. Lumateperone provides a dopamine Di receptordependent enhancement of NMDA and AMPA currents coupled with activation of the mTOR (e.g„ mTORCl) signaling pathway.

[0012] While other D2 dopamine receptor antagonists, including second-generation antipsychotics such as olanzapine, have been reported to exert an antiemetic effect, including for CINV, this has not been previously reported for lumateperone. Unlike lumateperone, olanzapine has several significant off-target interactions, including antagonist activity at adrenergic receptors, histamine Hl receptors, acetylcholine muscarinic receptors, other dopamine receptors (DI, D3, D4), and numerous serotonin receptors (5-HT2A, 5-HT2C, 5-HTS, 5HTe), and it has not been clear which activities are responsible for the antiemetic efficacy of olanzapine.

[0013] While lumateperone is a potent antagonist of the 5-HT2A receptor, it has recently been discovered that the 5-HT2A receptor can operate using one of two distinct signaling pathways: a G-protein coupled pathway that is typical of monoamine receptors, as well as a betaarresting mediated signaling pathway. The functional effects of these two pathways are different, and it has been discovered that compound related in structure to lumateperone can have 5-HT2A agonist or antagonist activity, separately, or together, via the two distinct mechanisms of receptor signaling. When a compound binds to a receptor such as 5-HT2A and selectively activates (orIT-209-PCT / ICT1209WOPCT1 inhibits) signaling through one pathway but not the other, this is referred to as biased signaling, and such a compound can be a biased agonist (or biased antagonist), including biased partial agonists. The present inventors have developed a series of compounds having these properties, as well as varying levels of dopamine receptor and SERT inhibitory activity, similar to lumateperone and its analogs. These compounds are likely to also provide novel antiemetic effects.

[0014] Olanzapine is an atypical antipsychotic drug that is primarily used to treat schizophrenia and bipolar disorder. The term “atypical” refers to second-generation antipsychotic medications, which have somewhat improved side effect profiles compared to the first- generation antipsychotics, such as haloperidol. Atypical antipsychotics exert their antipsychotic efficacy through D2 dopamine receptor antagonism with additional effects on receptors for other neurotransmitters, e.g., serotonin. Olanzapine has been known to be an effective antiemetic drug for CINV. Olanzapine has antagonist activity at adrenergic receptors, histamine Hl receptors, acetylcholine muscarinic receptors, dopamine (DM) receptors and serotonin (5-HT2A, 5-HT2C, 5-HT?, 5HTfl) receptors. Olanzapine may exert an antiemetic effect through its antagonist activity at multiple receptors involved in CINV.

[0015] With the development of a wide range of cancer treatments, there is a need for the development of safe and efficacious pharmaceutical treatments for nausea and vomiting caused by cancer treatment, e.g., chemotherapy.SUMMARY OF THE DISCLOSURE

[0016] It was previously shown that the inhibition of PDE1 activity using the presently disclosed compounds can safely restore cAMP function in a wide spectrum of pathological conditions, including models of neurodegeneration and neuroinflammation, heart failure, cancers, pulmonary hypertension and peripheral inflammation and in humans with certain diseases.

[0017] Lumateperone is both a potent 5-HT2A receptor antagonist and a potent post- synaptic D2 receptor antagonist, and it is believed to have efficacy as an anti-emetic agent, such as for treating CINV. In the D2 and 5-HT2A receptor signaling pathways, receptor activation results in increased intracellular calcium concentrations, leading to activation of PDE- 1 and reduced concentrations of c MP and cGMP. A PDE1 inhibitor is expected to act in concert with a 5-HT2A / D2 receptor antagonist to increase or prolong the increased cAMP andIT-209-PCT / ICT1209WOPCT1 cGMP levels. Without being bound by any theory, it is believed that a PDE-1 inhibitor in combination with lumateperone may provide a strong antiemetic effect by protecting cAMP and / or cGMP from degradation. Therefore, a PDE1 inhibitor may be used in combination with lumateperone, and its analogs and derivatives, for the prevention or treatment of nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting) by enhancing the efficacy of the antiemetic effect. Alternatively, lumateperone, or an analog thereof, may be used without a PDE1 inhibitor for the prevention or treatment of nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting).

[0018] Unlike lumateperone, the compounds of Formula IX disclosed herein are biased agonists or antagonists of the 5-HT2A receptor and some are also potent post-synaptic D2 receptor antagonists. Preferably, these agents are biased, and provide agonism of the beta-arrestin signaling pathway, but weak agonism, inverse agonism, or antagonism of the G-protein coupled signaling pathway. It is believed that these compounds will have efficacy as anti-emetic agents, such as for treating CINV. In the D2 and 5-HT2A receptor signaling pathways, receptor activation results in increased intracellular calcium concentrations via the G-protein coupled mechanism, leading to activation of PDE-1 and reduced concentrations of cAMP and cGMP. A PDE1 inhibitor is expected to act in concert with the compound of Formula IX to increase or prolong the increased cAMP and cGMP levels. Without being bound by any theory, it is believed that a PDE-1 inhibitor in combination with the Compound of Formula IX may provide a strong antiemetic effect by protecting cAMP and / or cGMP from degradation. Therefore, a PDE1 inhibitor may be used in combination with Compounds of Formula IX, for the prevention or treatment of nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting) by enhancing the efficacy of the antiemetic effect. Alternatively, Compounds of Formula IX may be used without a PDE1 inhibitor for the prevention or treatment of nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting).

[0019] Olanzapine is mainly a 5-HT2A / D2 receptor antagonist. In the D2 and 5-HT2A receptor signaling pathways, receptor activation results in increased intracellular calcium concentrations, leading to activation of PDE-I and reduced concentrations of cAMP and cGMP. A PDE1 inhibitor is expected to act in concert with a 5-HT2A / D2 receptor antagonist to increase or prolong the increased cAMP and cGMP levels. Without being bound by any theory, it is believed that a PDE- 1 inhibitor can potentiate the antiemetic effect of olanzapine, or similarIT-209-PCT / ICT1209WOPCT1 antipsychotic agents, by protecting cAMP and / or cGMP from degradation. Therefore, a PDE1 inhibitor may be used in combination with an antiemetic agent such as olanzapine for the prevention or treatment of nausea and / or vomiting, e.g., CINV (chemotherapy-induced nausea and vomiting) by enhancing the efficacy of the antiemetic agent.

[0020] Thus, in a first aspect, the disclosure provides a method of preventing or treating nausea and / or vomiting (e.g., CINV), comprising administering a pharmaceutically effective amount of a Compound of Formula VIII (e.g., lumateperone), optionally in combination with a pharmaceutically effective amount of a PDE1 inhibitor (e.g.. a PDE1 inhibitor of Formulas I, la, II, III, IV, V, VI, and / or VII, described hereinbelow), to a subject in need thereof.

[0021] In another embodiment of the first aspect, the disclosure provides a method of preventing or treating nausea and / or vomiting (e.g.. CINV), comprising administering a pharmaceutically effective amount of a Compound of Formula IX, optionally in combination with a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a PDE1 inhibitor of Formulas I. la, II, III, IV, V, VI, and / or VII, described hereinbelow), to a subject in need thereof.

[0022] In another embodiment of the first aspect, the disclosure provides a method of preventing or treating nausea and / or vomiting (e.g., CINV), comprising administering a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a PDE1 inhibitor of Formulas I, la,II, III, IV, V, VI, and / or VII, described hereinbelow) in combination with a pharmaceutically effective amount of an antiemetic agent, to a subject in need thereof. In some embodiments, the antiemetic agent is an antipsychotic agent, e.g., an atypical antipsychotic agent. In some embodiments, the antiemetic agent is a D2 antagonist. In some embodiments, the antiemetic agent is a S-FEI Di antagonist. In some embodiments, the antiemetic agent is olanzapine.

[0023] In some embodiments, the nausea and / or vomiting is caused by chemotherapy, radiation therapy, surgery, advanced cancer, brain cancer, pregnancy, motion sickness, migraines, or food poisoning. In some embodiments, the nausea and / or vomiting is chemotherapy-induced nausea and vomiting (CINV). The CINV may be acute CINV, delayed CINV, anticipatory CINV, breakthrough CINV, or refractory CINV.

[0024] In some embodiments, the PDE1 inhibitor is a PDE1 inhibitor of Formulas I, la, II,III, IV, V, VI, and / or VII described hereinbelow in free or pharmaceutically acceptable salt form. In some embodiments, the PDE1 inhibitor is a selective PDE1 inhibitorIT-209-PCT / ICT1209WOPCT1

[0025] In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of PDE1 inhibitor, e.g., any of a Compound of Formulas I. la, II, III, IV, V, VI, and / or VII, and a pharmaceutically effective amount of a Compound of Formula VIII (e.g., lumateperone) or a Compound of Formula IX or an antiemetic agent.

[0026] In another aspect, the disclosure provides a combination therapy comprising a pharmaceutically effective amount of a PDE1 inhibitor (a PDE1 inhibitor of Formulas I, la, II, III, IV, V, VI, and / or VII described hereinbelow) and a pharmaceutically effective amount of a Compound of Formula VIII (e.g., lumateperone) or a Compound of Formula IX or an antiemetic agent.DETAILED DESCRIPTION OF THE DISCLOSURECompounds for use in the methods of the disclosure

[0027] In one embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are selective PDE1 inhibitors.PDE1 Inhibitors

[0028] In one embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula I:wherein(i) Ri is H or Ci-4 alkyl (e.g., methyl);IT-209-PCT / ICT1209WOPCT1(ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H, C1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl (e.g., R2 and R3 are both methyl, or R2 is H and R3 is isopropyl); orR2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge(pref, wherein the R3 and R4 together have the cis configuration, e.g., where the carbons carrying R3 and R4 have the R and S configurations, respectively);(iii) R5 is a substituted heteroarylalkyl, e.g., substituted with haloalkyl; or R5 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula AFormula A wherein X, Y, and Z are, independently, N or C, and Rs, R9, R11 and R12 are independently H or halogen (e.g., Cl or F), and Rio is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl) optionally substituted with halogen, thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl), diazolyl, triazolyl, tetrazolyl), arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, Rx. R or Rw, respectively, is not present;(iv) Re is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino. N,N-dialkylamino, N,N-diarylamino. or N-aryl-N-(arylalkyl)amino (e.g., N- phenyl-N -(1,1’ -biphen-4-ylmethyl)amino) ;(v) n=0 or 1 ;(vi) provided that when n=l, A is -C(Ri3Ri4)- wherein R13 and R14, are, independently, H, C1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl; in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.IT-209-PCT / ICT1209WOPCT1

[0029] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula la:Formula la wherein(i) R2 and R5 are independently H or hydroxy and R3 and R4 together form a tri- or tetramethylene bridge [pref, with the carbons carrying R3 and R4 having the R and S configuration respectively]; or R2 and R3 are each methyl and R4 and Rs are each H; or R2, R4 and Rs are H and R3 is isopropyl [pref, the carbon carrying R3 having the R configuration];(ii) Re is (optionally halo-substituted or hydroxy-substituted) phenylamino, (optionally halo- substituted or hydroxy-substituted) benzylamino, Ci-4alkyl, or Ci-4alkyl sulfide, for example, phenylamino or 4-fluorophenylamino;(iii) Rio is Ci-4alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy- substituted) pyridyl (for example 6-fluoropyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl), or Rw is -CH(CH3)-O- C(O)-RH, wherein Rn is C1-6 alkyl (e.g.. methyl, ethyl, or propyl), or Rio is saturated or unsaturated heterocycloalkyl comprising one or more oxygens or nitrogens (e.g., saturated or unsaturated 3-5 membered heterocycloalkyl comprising one or more oxygens or nitrogens, e.g., tetrahydrofuryl, dihydrofuryl, or aziridyl), or Rio is -C(=O)-Xi, wherein Xi is saturated or unsaturated heterocycloalkyl comprising one or more oxygens or nitrogens (e.g., saturated or unsaturated 3-5 membered heterocycloalkyl comprising one or more oxygens or nitrogens, e.g., tetrahydrofuryl, dihydrofuryl, or aziridyl); and(iv) X and Y are independently CH or N, in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers and racemates, thereof.IT-209-PCT / ICT1209WOPCT1

[0030] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula II:Formula II wherein(i) X is Ci-ealkylene (e.g., methylene, ethylene or prop-2-yn-l-ylene);(ii) Y is a single bond, alkynylene (e.g., — C=C — ). arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene);(iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloCi-6alkyl (e.g., trifluoromethyl), — C(O) — R1, — N(R2)(R3), or C3-7cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);(iv) R1is Ci-ealkyl, haloCi-ealkyl, — OH or — OCi-ealkyl (e.g., — OCH3);(v) R2and R3are independently H or Ci-ealkyl;(vi) R4and R5are independently H, Ci-ealkyl, or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4- hydroxyphenyl or 2-hydroxyphenyl), or Ci-ealkoxy; and(vii) wherein X, Y and Z are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), Ci-ealkyl (e.g., methyl), or haloCi-ealkyl (e.g., trifluoromethyl), for example, Z is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6-fluoropyrid-2-yl, 5- fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2- yl), haloCi-ealkyl (e.g., 5-trifluoromethylpyrid-2-yl), or Ci-6-alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl),IT-209-PCT / ICT1209WOPCT1 in free, salt, or prodrug form e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

[0031] In yet another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula III:Formula III wherein(i) Ri is H or Ci-4 alkyl (e.g., methyl or ethyl);(ii) R2 and R3 are independently H or C1-6 alkyl (e.g., methyl or ethyl);(iii) R4 is H or C1-4 alkyl (e.g., methyl or ethyl);(iv) R5 is aryl (e.g.. phenyl) optionally substituted with one or more groups independently selected from -C(=O)-Ci-6 alkyl (e.g., -C(=O)-CH3) and C 1-6 -hydroxyalkyl (e.g., 1- hydroxy ethyl);(v) Re and R7 are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6 alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example, unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F), or phenyl substituted with one or more C1-6 alkyl and one or more halogen, or phenyl substituted with one C1-6 alkyl and one halogen, for example, 4-fluorophenyl or 3,4-difluorophenyl or 4- fluoro-3-methylphenyl; and(vi) n is 1, 2, 3, or 4, in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.IT-209-PCT / ICT1209WOPCT1

[0032] In yet another embodiment, the PDE1 inhibitors for use in the methods. compositions, and combination therapies, described herein are compounds of Formula IV:Formula IV in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof, wherein:(i) Ri is Ci-4alkyl (e.g., methyl or ethyl), or -NH(R2), wherein R2 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) X, Y and Z are, independently, N or C;(iii) R3, R4 and R5 are independently H or Ci-4alkyl (e.g., methyl); or R3 is H and R4 and R5 together form a tri-methylene bridge (pref, wherein the R4 and R5 together have the cis configuration, e.g., where the carbons carrying R4 and Rs have the R and S configurations, respectively);(iv) Re, R7 and Rs are independently H, Ci-4alkyl (e.g., methyl), pyrid-2-yl substituted with hydroxy, or -S(O)2-NH2;(v) provided that when X, Y and / or Z are N, then Re, R7 and / or Rs, respectively, are not present; and when X, Y and Z are all C, then at least one of Re, R7 or Rs is -S(O)2-NH2 or pyrid- 2-yl substituted with hydroxy.

[0033] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula V:IT-209-PCT / ICT1209WOPCT1wherein(i) Ri is -NH(R4), wherein R4 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) R2 is H or Ci-6alkyl (e.g., methyl, isobutyl or neopentyl); and(iii) R3is -SO2NH2 or -COOH; in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, or racemates, thereof.

[0034] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula VI:wherein(i) Ri is -NH(R4), wherein R4 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) R2 is H or Ci-6alkyl (e.g., methyl or ethyl); andIT-209-PCT / ICT1209WOPCT1(iii) R3 is H, halogen (e.g., bromo), Ci-ealkyl (e.g., methyl), aryl optionally substituted with halogen (e.g., 4-fluorophenyl), heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl), or acyl (e.g., acetyl); in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

[0035] In another embodiment, the PDE1 inhibitors for use in the methods, compositions, and combination therapies, described herein are compounds of Formula VII:wherein(i) Ri is H or C1-4 alkyl (e.g., methyl or ethyl);(ii) R2 and R3 are independently H or C1-6 alkyl (e.g.. methyl or ethyl);(iii) R4 is H or C1-4 alkyl (e.g., methyl or ethyl);(iv) R5 is aryl (e.g., phenyl) substituted with -C(=O)-CDs, wherein D is deuterium(2H);(v) Re and R7 are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6 alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F) or phenyl substituted with one or more C1-6 alkyl and one or more halogen or phenyl substituted with one C1-6 alkyl and one halogen, for example 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3- methylphenyl; and(vi) n is 1, 2, 3. or 4, in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.IT-209-PCT / ICT1209WOPCT1

[0036] In another embodiment, the PDE1 inhibitor for use in the methods, compositions, and combination therapies, described herein (e.g., the compound according to Formulas I, la, II, III, IV, V, VI, and / or VII), is a compound according to one or more of the following:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1each in free or salt form, e.g., pharmaceutically acceptable salt form.

[0037] In some embodiments, the PDE1 inhibitors of the any of the preceding formulae(e.g., Formulas I, la. II, III, IV, V, VI, and / or VII) inhibit phosphodiesterase-mediated (e.g..IT-209-PCT / ICT1209WOPCT1PDE1 -mediated, especially PDElB-mediated) hydrolysis of cGMP, e.g., with an TC50 of less than IpM, preferably less than 500 nM, preferably less than 50 nM, and preferably less than 5nM, such as in an immobilized-metal affinity particle reagent PDE assay.

[0038] In another embodiment, the PDE1 inhibitor for use in the methods, compositions, and combination therapies, described herein, is a compound according to one or more of the following:IT-209-PCT / ICT1209WOPCT1each in free or salt form, e.g., pharmaceutically acceptable salt form.

[0039] Further examples of PDE1 inhibitors suitable for use in the methods, compositions, and combination therapies, described herein can be found in International Publication WO2006133261A2; U.S. Patent 8,273.750; U.S. Patent 9,000,001; U.S. Patent 9,624,230; International Publication W02009075784A1; U.S. Patent 8,273,751; U.S. Patent 8,829,008; U.S. Patent 9,403,836; International Publication W02014151409A1, U.S. Patent 9,073,936; U.S. Patent 9,598,426; U.S. Patent 9,556,186; U.S. Publication 2017 / 0231994A1, International Publication WO2016022893A1, and U.S. Publication 2017 / 0226117A1, each of which are incorporated by reference in their entirety.

[0040] Still further examples of PDE1 inhibitors suitable for use in the methods, compositions, and combination therapies, described herein can be found in International Publication W02018007249A1; U.S. Publication 2018 / 0000786; International Publication W02015118097A1; U.S. Patent 9,718,832; International Publication W02015091805A1; U.S.IT-209-PCT / ICT1209WOPCT1Patent 9,701 ,665; U.S. Publication 2015 / 0175584A 1 ; U.S. Publication 2017 / 0267664A1 ; International Publication WO2016055618A1; U.S. Publication 2017 / 0298072A1; International Publication W02016170064A1; U.S. Publication 2016 / 0311831A1; International Publication WO2015150254A1; U.S. Publication 2017 / 0022186A1; International Publication WO2016174188A1; U.S. Publication 2016 / 0318939A1; U.S. Publication 2017 / 0291903A1;International Publication WO2018073251A1; International Publication WO2017178350A1; U.S. Publication 2017 / 0291901A1; International Publication WO2018 / 115067; U.S. Publication 2018 / 0179200A; U.S. Publication US20160318910A1; U.S. Patent 9.868,741; International Publication WO2017 / 139186A1; International Application WO2016 / 040083; U.S. Publication 2017 / 0240532; International Publication WO 2016033776A1; U.S. Publication 2017 / 0233373; International Publication WO2015130568; International Publication W02014159012; U.S. Patent 9,034,864; U.S. Patent 9,266,859; International Publication W02009085917; U.S. Patent 8,084,261; International Publication W02018039052; U.S. Publication US20180062729; and International Publication WO2019027783 each of which are incorporated by reference in their entirety. In any situation in which the statements of any documents incorporated by reference contradict or are incompatible with any statements made in the present disclosure, the statements of the present disclosure shall be understood as controlling.Compounds of Formula VIII

[0041] Without being bound by theory, it is believed that the unique pharmacological profile of the Compounds of Formula VIII, as described herein below, provide an unexpected synergistic effect when use with the PDE1 inhibitors of the disclosure for preventing or treating nausea and / or vomiting (e.g., CINV).

[0042] The present disclosure therefore provides for the use of a compound of Formula VIII:IT-209-PCT / ICT1209WOPCT1Formula VIII wherein:X is -N(H)-. -N(CH3)- or -O-;Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;Ri is -C(O)-Ci-2ialkyl (e.g., -C(O)-Ci-5alkyl, -C(O)-Ce-i5alkyl or -C(O)-Ci6-2ialkyl), preferably said alkyl is a straight chain, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or Ci-22alkoxy (e.g., ethoxy) groups, for example Ri is -C(O)-C6alkyl, -C(O)-C?alkyl, -C(O)-Cyalkyl, -C(O)-Cnalkyl, - C(O)-Ci3alkyl or -C(O)-Cisalkyl wherein such compound hydrolyzes to form the residue of a natural or unnatural, saturated or unsaturated fatty acid, e.g., the compound hydrolyzes to form the hydroxy compound on the one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand), optionally in deuterated form, in free, pharmaceutically acceptable salt, or prodrug form

[0043] In some embodiments, the compound of Formula VIII is a compound wherein X is -N(CHs)- and Y is -C(=O)- (i.e„ lumateperone), in free or pharmaceutically acceptable salt form. Preferably, the compound is in salt form, for example, toluenesulfonate, hydrochloride, bistosylate, besylate, naphthalenesulfonate, naphthalenedisulfonate, 4-octylbenzenesulfoate, 4- tert-butylbenzenesulfonate, 4-propylbenzenesulfonate, 4-ethylbenzenesulfonate, 2- naphthalenesulfonate, or a salt of another benzenesulfonic acid substituted by one, two, or three groups R, wherein each R is independently a Ci-nalkyl group. Such salts have been described, e.g., in U.S. 8,648,077, U.S. 11 ,440.91 1 , US 2020 / 0157100, WO 2018 / 031535, WOIT-209-PCT / ICT1209WOPCT12019 / 102240, WO 2020 / 182988, WO 2020 / 112941 , IN2017 / 41021763, and WO 2024 / 030835, the contents of each of which are hereby incorporated by reference in their entireties.

[0044] In some embodiments, the Compound of Formula VIII is a deuterated compound, for example, a compound as disclosed in any of U.S. Patents 10,077,267, 10,597,394, 10,688,097, 10,899,762, and 11,096,944, and patent publications US 2021 / 0008065 and WO 2022 / 051770, the contents of each of which are hereby incorporated by reference in their entireties.Compounds of Formula IX

[0045] Without being bound by theory, it is believed that the unique pharmacological profile of the Compounds of Formula IX, as described herein below, provide an unexpected synergistic effect when use with the PDE1 inhibitors of the disclosure for preventing or treating nausea and / or vomiting (e.g., CINV).

[0046] The present disclosure therefore provides for the use of a compound of FormulaIX:Formula IX wherein:X is S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N-C(O)-Ra, N- C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O~), a spiro-joined C3. ecycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-ecycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from Ci-ealkyl (e.g., methyl), haloCi-ealkyl (e.g., trifluoromethyl), Ci-ealkoxy (e.g., methoxy), C3. ecycloalkyl (e.g., cyclopropyl), C3-gcycloalkoxy (e.g., cyclopropoxy), and hydroxy;Y is CH2, CHRC, -C(O)-, C(RC)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from Ci-6alkyl (e.g., methyl), haloCi-ealkyl (e.g.,IT-209-PCT / ICT1209WOPCT1 trifluoromethyl), Ci-ealkoxy (e.g., methoxy), Cs-ecycloalkyl (e.g., cyclopropyl), C3- ecycloalkoxy (e.g., cyclopropoxy), and hydroxy;Z is a bond, -S-, S(O). S(O)2. -O-, -NH, N(Rd), -C(O)-. -C(OH)-, C(OCi-6alkyl), -C(=N- OH)-, -C(=N-OCi-6alkyl)-, a spiro-joined Cs ecycloalkyl (e.g., cyclopropane), a spirojoined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -0(CH2)P0- wherein p is 2, 3, or 4 (e.g.. p is 2), wherein said spiro-joined Ca-ecycloalkyl or 3-6- membered heterocycloalkyl is optionally substituted by one or more groups selected from Ci-6alkyl (e.g., methyl), haloCi-ealkyl (e.g., trifluoromethyl), Cnealkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), Cs-ecycloalkoxy (e.g., cyclopropoxy), and hydroxy;A is H, C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), aryl (e.g., phenyl) or heteroaryl, wherein said cycloalkyl, aryl or heteroaryl is substituted by 0-5 groups R; each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), Ci-ealkyl (e.g., methyl, ethyl), haloCi-ealkyl (e.g., trifluoromethyl), Cnealkylsulfonyl (e.g.. methylsulfonyl), Ci-ealkoxy (e.g.. methoxy, ethoxy), Ci-ealkylthio (e.g., methylthio), halo (e.g., F), cyano, Cs-ecycloalkyl (e.g., cyclopropyl), Cs-ecycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is optionally further substituted by one or more groups selected from aryl (optionally substituted with halo), halo, Ci-ealkyl (e.g., methyl), haloCi-ealkyl (e.g., trifluoromethyl), Ci-ealkylsulfonyl (e.g., methylsulfonyl), Ci-ealkoxy (e.g., methoxy), Ci- ealkylthio (e.g., methylthio), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), amino, Ci -ealkylamino (e.g., methylamino), di(Ci-ealkyl)amino (e.g., dimethylamino), (Ci-6alkyl)(Ci-ealkyl)amino (e.g., methylethylamino), and hydroxy;Raand Rd, are each independently selected from Ci-2oalkyl (e.g., methyl or tert-butyl), and Ci-2alkylaryl (e.g.. benzyl or phenethyl);Rband Rcare each independently selected from Ci-ealkyl (e.g., methyl, ethyl, tert-butyl), Ci-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl). C3-6cycloalkoxy (e.g., cyclopropoxy), and Ci-2alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2; and n is 1, 2, 3, 4, or 5 (e.g., 2 or 3); in free base, or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT1Definitions

[0047] If not otherwise specified or clear from context, the following terms herein have the following meanings: a. “Selective PDE1 inhibitor” as used herein refers to a PDE1 inhibitor with at least 100-fold selectivity for PDE1 inhibition over inhibition of any other PDE isoform; b. “Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably having one to six carbon atoms, which may be linear or branched, and may be optionally mono-, di- or tri- substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy; “alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, s- pentyl, isopentyl, neopentyl, isoamyl, n-hexyl, s-hexyl, isopentyl, and t-pentyl; c. “Cycloalkyl” as used herein is a saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to ten carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, and which may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy; when the cycloalkyl optionally contains one or more atoms selected from N and O and / or S, said cycloalkyl may also be a heterocycloalkyl; individual rings of bicyclic or polycyclic cycloalkyl groups can have different connectivities, e.g., fused, bridged, spiro, etc., in addition to covalent bond substitution; “cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomanyl, bicyclo[3.2.1]octanyl, octahydro-pentalenyl, spiro[4.5]decanyl, cyclopropyl, adamantyl. substituted with cyclobutyl, cyclobutyl substituted with cyclopentyl, cyclohexyl substituted with cyclopropyl; d. “Heterocycloalkyl” is, unless otherwise indicated, saturated or unsaturated nonaromatic moiety, preferably saturated, preferably comprising three to twelve, three to nine atoms, or three to six atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, wherein at least one ring atom is N, O or S, for example tetrahydrofuryl, dihydrofuryl, or aziridyl,IT-209-PCT / ICT1209WOPCT1 which heterocycloalkyl may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy; “heterocycloalkyl” includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl. l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, 1,2- pyrazolidin-2-yl, 1,3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl, 1,2- tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1 ,2-tetrahydrodiazin-2-yl, 1 ,3-tetrahydrodiazin- 1 -yl, tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2- pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8- azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8- diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[l ,2-a]pyrazinyl, 3- azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[4.4]nonanyl, 7- oxa-l-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, and octahydro- 1H- indolyl; e. “Aryl” as used herein is a mono or bicyclic aromatic hydrocarbon, preferably phenyl or naphthyl, optionally substituted, e.g., with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); “Aryl” includes 6- membered monocyclic aryl ring systems and 9-membered or 10-membered fused bicyclic aryl ring systems, and larger fused ring systems, as long as such ring systems comprise at least one 6-membered aromatic carbocyclic ring (i.e., a benzene ring) within the fused ring system, and as long as no ring-atoms are heteroatoms; the term “aryl” includes, but is not limited to, phenyl, naphthyl, phenanthryl, and anthracenyl; f. “Heteroaryl” as used herein is an aromatic moiety wherein one or more of the atoms making up the aromatic ring is oxygen, sulfur or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl, which may be optionally substituted, e.g., with alkyl, halogen, haloalkyl, hydroxy or carboxy; “heteroaryl” includes 5- membered and 6-membered monocyclic heteroaryl ring systems (e.g., azoles,IT-209-PCT / ICT1209WOPCT1 azines) and 9-membered or 10-membered fused bicyclic heteroaryl ring systems, and larger fused ring systems, as long as such ring systems comprise at least one aromatic carbocyclic or aromatic heterocyclic ring within the fused ring system and at least one heteroatom (e.g., N, S or O) ring-atom within the fused ring system (either in an aromatic ring or non-aromatic ring); “heteroaryl” therefore includes, but is not limited to, bicyclic fused ring systems selected from aromaticheteroaromatic, aromatic-heterocyclic, heteroaromatic-carbocyclic, heterocyclic- aromatic, and heteroaromatic-heteroaromatic, as well as larger fused ring systems comprising some combination of benzene, cycloalkane, heterocycloalkane and heteroaromatic rings, for example, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl. isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, 1,2,4- triazinyl. 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[l]pyridinyl, benzo [b] thiophenyl, 5, 6,7,8- tetrahydro-quinolin-3-yl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, benzothiadiazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolinyl, quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthyridyl, phenanthridinyl, acridinyl, carbazolyl, carbazolinyl, permidinyl, phenanthrolinyl, phenacenyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyridopyrimidinyl, theinopyrimidinyl, furopyrimidinyl, furopyridyl, furopyrrolyl, pyrazoloxazolyl, thienofuranyl, imidazothiazolyl, imidazopyridyl, imidazotriazyl, imidazopyrimidinyl, pyrazinopyridazinyl, phenothiazinyl, furazanyl, phenoxazinyl, pyrazo benzoxazinyl, azaindolizinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyridoxazinyl; g. “Bridged cyclic” as used herein means a 7-12 membered bicyclic cycloalkyl or heterocycloalkyl system formed by two rings wherein the bridgehead ring atoms are separated by bridges having at least one atom (either a carbon atom or aIT-209-PCT / ICT1209WOPCT1 heteroatom); the entire bicyclic system contains from 7 to 12 ring atom members, for example, wherein 1 to 4 of these atoms are heteroatoms (e.g., N, O, or S); bridged bicyclic systems include bridged morpholine rings, bridged piperidine rings, bridged piperazine rings, norbomane rings, and the like; preferably, at least one of the rings is a 5, 6, or 7-membered ring; h. “Substituted” or “optionally substituted” means that one or more hydrogen atoms of a group or radical is independently (i.e., where more than a single substitution occurs, each substituent is independent of another substituent) replaced by one or more non-hydrogen substituents, up to the maximum permissible number of substituents for the chemical structure, substructure, group or radical, for example, up to five substituents, preferably up to three substituents, often 1 or 2 substituents on a moiety. Substituents may themselves be further substituted. Optional substituents, unless otherwise indicated, include hydroxy (-OH), thiol (- SH), carboxy (-COOH), cyano (-CN), nitro (-NO2), halogen (preferably, F or Cl), Ci-C2oalkyl (e.g., Ci-Cioalkyl, Ci-Cealkyl), C2-C2oalkenyl (e.g., Ci-Cioalkenyl, C2-C6alkenyl), C2-C2oalkynyl (e.g., C2-Cioalkynyl, C2-C6alkynyl), aryl (e.g., phenyl, naphthyl), heteroaryl (e.g., 5- to 10-membered ring heteroaryls, such as azoles, diazoles, triazoles, pyridine, diazines, triazines, and benzo-fused derivatives thereof), 5-10 membered heterocycloalkyl (containing at least one heteroatom N, S, or O), Ci-C2oalkoxy (e.g., Ci-Cioalkoxy, Ci-Cealkoxy), C3- C2ocycloalkyl (e.g., C3-Ciocycloalkyl, C3-Cecycloalkyl), C3-C2ocycloalkoxy (e.g., Cs-Ciocycloalkoxy, Cs-Cecycloalkoxy), aryloxy (e.g., phenoxy), thioether (thioCi- G.alkyl or aryl), keto, acyl (preferably, Ci-Ce acyl), ester or thioester (preferably, Ci-Ce alkyl or aryl; including alkylene ester, such that attachment is on the alkylene group, rather than at the ester function which is preferably substituted with a Ci-Ce alkyl or aryl group), amine (including amino (-NH2), mono-Ci- Cealkylamino, di-Ci-Cealkylamino, five- or six-membered N-containing heterocycloalkyl), carbamate or urethane (such as optionally substituted N(Co-Ce alkyl)C(O)(OCi-Ce alkyl) group), hydrazine or hydrazide, amido (N-C(O), preferably substituted with one or two Ci-Ce alkyl groups; including a carboxamide which is optionally substituted with one or two Ci-Ce alkyl groups),IT-209-PCT / ICT1209WOPCT1 sulfone (SO2), sulfoxide (S(O)), sulfonamide, alkanol (preferably, Ci-Ce alkyl or aryl, such as (CH2)n0H), or alkanoic acid (preferably, Ci-Ce alkyl or aryl, such as (CH2)nCOOH), wherein n is an integer from 1-10, e.g., 1-6. Substituents according to the present invention may also include SiRiR^Ra groups wherein each of Ri and R2 is as otherwise described herein, and R3 is H or a Ci-Ce alkyl group, preferably Ri, R2, R3 in this context is a C1-C3 alkyl group (including an isopropyl or t-butyl group). Additional optional substituents include: NHC(O)NH, (CH2)nSH, ,(CH2)nO(Ci-C6alkyl), (CH2)nC(O)(Ci-C6alkyl), (CH2)nOC(O)(Ci-C6alkyl), (CH2)nC(O)O(Ci-C6alkyl), (CH2)nNHC(O)Ri, (CH2)nC(O)NRiR2, (OCH2)nOH, (CH20)nCOOH, Ci-C6alkyl, (OCH2)nO(Ci-C6alkyl), (CH2O)nC(O)(Ci-C6alkyl). (OCH2)nNHC(O)Ri, (CH2O)nC(O)NRiR2, S(O)2Rs, and S(O)Rs(Rsis Ci-Ce alkyl or a (CH2)mNRiR2group). Each of the abovedescribed groups may be linked directly to the substituted moiety or alternatively, the substituent may be linked to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) through an optionally substituted -(CH2)m- or, alternatively, an optionally substituted -(OCH2)m-, -(OCH2CH2)m- or - (CH2CH2O)m- group, which may be substituted with any one or more of the above-described substituents, wherein m is an integer from 1 to 20, e.g., 1 to 10 or 1 to 6. Alkylene groups -(CH2)m- or -(CH2)n- groups or other chains such as ethylene glycol chains, as identified above, may be substituted anywhere on the chain. As substituents can themselves be substituted, these groups also include, for example, such compound groups as arylCi-Cealkyl (e.g.. benzyl), haloCi- G.alkyl (e.g., trifluoromethyl), hydroxyCi-Cealkyl (e.g., 2-hydroxy-2- methylbutyl), and Ci-Cealkyl-aryl (e.g., tolyl).

[0048] It is understood that when describing the substituents attached in various positions to the core structure described herein, including substituents attached to substituents, in some cases, the substituent may be referred to using the name of the corresponding chemical compound, especially in the case of rings, whereas in some cases the same substituent may be referred to using the name of the corresponding chemical radical (e.g., having an “-yl” suffix), but these terms are interchangeable. For example, when referring to a heteroaryl ring substituent, the terms “pyridine” and “pyridyl” are equivalent, as are the terms “morpholine” andIT-209-PCT / ICT1209WOPCT1“morpholinyl.” The skilled artisan will recognize that such terms are used to denote attachment of, for example, pyridine or morpholine ring at the designated position, thus converting said ring to a pyridyl or morpholinyl substituent (radical) respectively. Absent an indication otherwise, such attachments may be made at any chemically permissible location of the attached ring.

[0049] Compounds of the Disclosure, e.g., PDE1 inhibitors or Compounds of Formula VIII or IX or antiemetic agents, as described herein, may exist in free or salt form, e.g., as acid addition salts. In this specification unless otherwise indicated, language such as “Compounds of the Disclosure” is to be understood as embracing the compounds in any form, for example, free base or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form. The Compounds of the Disclosure are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Disclosure or their pharmaceutically acceptable salts, and are therefore also included.

[0050] Compounds of the Disclosure may in some cases also exist in prodrug form. A prodrug form is compound which converts in the body to a Compound of the Disclosure. For example, when the Compounds of the Disclosure contain hydroxy or carboxy substituents, these substituents may form physiologically hydrolysable and acceptable esters. As used herein, “physiologically hydrolysable and acceptable ester” means esters of Compounds of the Disclosure which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Disclosure which have hydroxy substituents) or alcohols (in the case of Compounds of the Disclosure which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered. Therefore, wherein the Compound of the Disclosure contains a hydroxy group, for example, Compound-OH, the acyl ester prodrug of such compound, i.e., Compound-0-C(0)-Ci-4alkyl, can hydrolyze in the body to form physiologically hydrolysable alcohol (Compound-OH) on the one hand and acid on the other (e.g., HOC(O)-Ci-4alkyl). Alternatively, wherein the Compound of the Disclosure contains a carboxylic acid, for example, Compound-C(0)OH, the acid ester prodrug of such compound, Compound-C(O)O-Ci-4alkyl can hydrolyze to form Compound-C(O)OH and HO-Ci-4alkyl. As will be appreciated the term thus embraces conventional pharmaceutical prodrug forms.IT-209-PCT / ICT1209WOPCT1

[0051] The Compounds of the Disclosure (PDE1 inhibitors and Compounds of Formula VIII or IX and antiemetic agents) include their enantiomers, diastereomers and racemates, as well as their polymorphs, hydrates, solvates and complexes. Some individual compounds within the scope of this disclosure may contain double bonds. Representations of double bonds in this disclosure are meant to include both the E and the Z isomer of the double bond. In addition, some compounds within the scope of this disclosure may contain one or more asymmetric centers. This disclosure includes the use of any of the optically pure stereoisomers as well as any combination of stereoisomers.

[0052] It is also intended that the Compounds of the Disclosure (PDE1 inhibitors and Compounds of Formula VIII or IX and antiemetic agents) encompass their stable and unstable isotopes. Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non-isotopic analogs. For example, the hydrogen atom at a certain position on the Compounds of the Disclosure may be replaced with deuterium (a stable isotope which is non-radioactive). Examples of known stable isotopes include, but not limited to, deuterium,13C,15N,18O. Alternatively, unstable isotopes, which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g.,1231,1311,125I,nC,18F, may replace the corresponding abundant species of I, C and F. Another example of useful isotope of the compound of the disclosure is theUC isotope. These radioisotopes are useful for radio-imaging and / or pharmacokinetic studies of the compounds of the disclosure.

[0053] The terms “treatment” and “treating” are to be understood as embracing treatment or amelioration of one or more symptoms of nausea and vomiting. For methods of treatment, the term “effective amount” is intended to encompass a therapeutically effective amount to treat or mitigate symptoms of nausea and vomiting.

[0054] The terms “prevention” and “preventing” are to be understood as embracing inhibition of one or more symptoms of nausea and vomiting and reduction of the likelihood of nausea and vomiting. For methods of prevention, the term “effective amount” is intended to encompass a therapeutically effective amount to inhibit one or more symptoms of nausea and vomiting.IT-209-PCT / ICT1209WOPCT1

[0055] The terms “patient” and “subject” include human or non-human (i.e., animal) patient, and are understood to be interchangeable within the context of this disclosure. In particular embodiment, the disclosure encompasses both human and nonhuman. In another embodiment, the disclosure encompasses nonhuman. In other embodiment, the term encompasses human.

[0056] The term “comprising” as used in this disclosure is intended to be open-ended and does not exclude additional, un-recited elements or method steps.

[0057] The terms “purified,” “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof. Thus, the term “purified.” “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization, LC-MS and LC-MS / MS techniques and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.Methods of Using Compounds of the Disclosure

[0058] In a first aspect, the present disclosure provides a method (Method 1.0) of preventing or treating nausea and / or vomiting (e.g., CINV), comprising administering a pharmaceutically effective amount of a Compound of Formula VIII (e.g., lumateperone), optionally in combination with a pharmaceutically effective amount of a PDE1 inhibitor, to a subject in need thereof. In further embodiments of the first aspect, the present disclosure provides:1.1 Method 1.0, wherein the nausea and / or vomiting is caused by cancer treatment (e.g., chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy, bone marrow or stem cell transplant), advanced cancer, brain cancer, pregnancy, motion sickness, migraines, or food poisoning.1.2 Method 1.0 or 1.1, wherein the subject is a cancer patient, optionally wherein the cancer is selected from Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma, osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Leiomyosarcoma, Myxosarcoma, Fibrocartilaginous mesenchymoma, Astrocytoma, Brainstem glioma,IT-209-PCT / ICT1209WOPCT1Pilocytic astrocytoma. Ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioblastoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma. Pineal astrocytoma, Pituitary adenoma. Visual pathway and hypothalamic glioma, Breast cancer, Inflammatory breast cancer, Invasive lobular carcinoma. Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma. Male breast cancer. Phyllodes tumor, Mammary secretory carcinoma, Papillary carcinomas of the breast, Adrenocortical carcinoma, Islet cell carcinoma, Multiple endocrine neoplasia syndrome, Pancreatic Cancer, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Optic nerve glioma, Anal cancer. Appendix cancer. Cholangiocarcinoma. Carcinoid tumor, Colon cancer, Duodenal cancer. Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, Rectal cancer, Small intestine cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Penile cancer, Kidney cancer, Renal cell carcinoma, Prostate cancer Testicular cancer, Gestational trophoblastic tumor, Urothelial carcinoma, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer. Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia. Acute myeloid leukemia. Acute myeloid dendritic cell leukemia, AIDS -related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma. Chronic lymphocytic leukemia. Chronic myelogenous leukemia. Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma. Intravascular large B- cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma / plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma,IT-209-PCT / ICT1209WOPCT1Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, Basal cell carcinoma, Squamous cell carcinoma. Squamous cell skin cancer, Skin adnexal tumors (e.g. sebaceous carcinoma), Melanoma, Merkel cell carcinoma, Keratoacanthoma, Sarcomas of primary cutaneous origin (e.g. dermatofibrosarcoma protuberans), Lymphomas of primary cutaneous origin (e.g. mycosis fungoides), Lung cancer, Adenocarcinoma of the lung, Basaloid squamous cell lung carcinoma, Bronchial adenomas / carcinoids Small cell lung cancer, Mesothelioma Non-small cell lung cancer, Non-small cell lung carcinoma, Pleuropulmonary blastoma Laryngeal cancer, Thymoma and thymic carcinoma, Squamous-cell carcinoma of the lung, AIDS-related cancers, Kaposi sarcoma Epithelioid hemangioendothelioma (EHE), Desmoplastic small round cell tumor, and Liposarcoma.1.3 Any preceding method, wherein the nausea and / or vomiting is chemotherapy- induced nausea and vomiting (CINV), radiation therapy- induced nausea and vomiting (RINV), or postoperative nausea and vomiting (PONV).1.4 Method 1.3, wherein the nausea and / or vomiting is CINV, optionally wherein the chemotherapeutic agent is selected from Alkylating agents (e.g., Altretamine, Bendamustine, Busulfan, Carboquone, Carmustine, Chlorambucil, Chlormethine, Chlorozotocin, Cyclophosphamide, Dacarbazine, Fotemustine, Ifosfamide, Lomustine, Melphalan, Melphalan flufenamide, Mitobronitol, Nimustine, Nitrosoureas, Pipobroman, Ranimustine, Semustine, Streptozotocin, Temozolomide, Thiotepa, Treosulfan, Triaziquone, Triethylenemelamine, Trofosfamide, Uramustine), Anthracyclines (e.g., Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pirarubicin, Valrubicin, Zorubicin), Cytoskeletal disruptors (taxanes) (e.g., Abraxane, Cabazitaxel, Docetaxel, Larotaxel, Paclitaxel, Taxotere, Tesetaxel), Epothilones (e.g., Ixabepilone), Histone deacetylase inhibitors (e.g., Entinostat, Romidepsin, Vorinostat, Zabadinostat), Inhibitors of topoisomerase I (Belotecan, Camptothecin, Exatecan, Gimatecan, Irinotecan, Topotecan), Inhibitors of topoisomerase II (e.g.. Etoposide, Teniposide, Tafluposide), Kinase inhibitors (Bortezomib, Erlotinib, Gefitinib, Imatinib,IT-209-PCT / ICT1209WOPCT1Vemurafenib, Vismodegib), Nucleotide analogs (e.g., Azacitidine, Azathioprine, Capecitabine, Cytarabine, Doxifluridine, Fluorouracil, Gemcitabine, Hydroxyurea, Mercaptopurine. Methotrexate. Tioguanine), Peptide antibiotics (e.g.. Actinomycin, Bleomycin), Platinum-based agents (e.g., Carboplatin, Cisplatin, Dicycloplatin, Oxaliplatin, Nedaplatin, Satraplatin), Retinoids (e.g., Alitretinoin, Bexarotene, Tretinoin), Vinca alkaloids and derivatives (e.g., Vinblastine, Vincristine. Vindesine, Vinorelbine). and combinations thereof.1.5 Method 1.3 or 1.4, wherein the CINV is acute CINV, delayed CINV, anticipatory CINV, breakthrough CINV, or refractory CINV.1.6 Method 1.3, wherein the nausea and / or vomiting is radiation therapy-induced nausea and vomiting (RINV).1.7 Method 1.3, wherein the nausea and / or vomiting is postoperative nausea and vomiting (PONV).1.8 Method 1.0 or any of 1.1-1.7, wherein the subject is an advanced cancer patient, optionally wherein the nausea and / or vomiting is caused by advanced cancer.1.9 Method 1.0 or any of 1.1-1.8, wherein the cancer is brain cancer.1.10 Method 1.0, wherein the nausea and / or vomiting is caused by pregnancy, i.e., the nausea and / or vomiting is morning sickness.1.11 Method 1.0, wherein the nausea and / or vomiting is caused by motion sickness.1.12 Method 1.0, wherein the nausea and / or vomiting is caused by migraines.1.13 Method 1.0, wherein the nausea and / or vomiting is caused by food poisoning.1.14 Any preceding method, wherein the Compound formula VIII is a compound wherein:(a) X is -N(H)- or -N(CH3)-, and Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;(b) X is -N(H)- and Y is -C(=O)-. -C(H)(OH)- or -C(H)(ORi)-;(c) X is-N(CH3)- and Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;(d) X is -N(H)- or -N(CH3)-, and Y is -C(=O)-, or -C(H)(OH)-;(e) X is -N(H)- and Y is -C(=O)-, or -C(H)(OH)-;(f) X is -N(CH3)- and Y is -C(=O)-, or -C(H)(OH)-;(g) X is -N(H)- and Y is -C(=O)-;(h) X is -N(CH3)- and Y is -C(=O)-;IT-209-PCT / ICT1209WOPCT1(i) X is -N(CH3)- and Y is -C(H)(OH)-;(j) X is -N(CH3)- and Y is -C(H)(ORi)-;(k) X is -N(H)- or -N(CH3)-, and Y is -O-;(l) X is -N(H)- and Y is -O-; or(m)X is-N(CH3)- and Y is -O-; each in in free base or pharmaceutically acceptable salt form, and optionally in deuterated form.1.15 Any preceding method, wherein the Compound formula VIII is the compound:in free base or pharmaceutically acceptable salt form, e.g. toluenesulfonic acid addition salt form.1.16 Any preceding method, wherein the Compound of Formula VIII is selected from:IT-209-PCT / ICT1209WOPCT1wherein D represents a hydrogen position with substantially greater than natural deuterium incorporation (i.e., substantially greater than 0.0156%), e.g., greater than 60%, or greater than 70%. or greater than 80%, or greater than 90% or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%, each in free base or pharmaceutically acceptable salt form, e.g. toluenesulfonic acid addition salt form.1.17 Any preceding method, wherein the Compound formula VIII is in free base form.1.18 Any preceding method, wherein the Compound formula VIII is in pharmaceutically acceptable salt form, e.g., selected from toluenesulfonate, hydrochloride, bistosylate, besylate, 1 -naphthalenesulfonate, naphthalenedisulfonate, 4- octylbenzenesulfoate, 4-tert-butylbenzenesulfonate, 4-propylbenzenesulfonate, 4- ethylbenzenesulfonate, or 2-naphthalenesulfonate salt form, or another benzenesulfonate salt form wherein the benzenesulfonate is substituted by one, two, or three groups R, wherein each R is independently a Ci-nalkyl group, preferably wherein the compound of Formula VIII is in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).IT-209-PCT / ICT1209WOPCT11.19 Method 1.18, wherein the Compound of Formula VTIT is in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).1.20 Any preceding method, wherein the PDE1 inhibitor and / or the Compound of Formula VIII are administered orally, optionally wherein the PDE1 inhibitor and / or the Compound of Formula VIII are administered as a tablet or capsule.1.21 Any of Methods 1.0-1.19, wherein the PDE1 inhibitor and / or the Compound of Formula VIII are administered by inhalation, optionally wherein the PDE1 inhibitor and / or the Compound of Formula VIII are administered as a nasal spray or inhaler.1.22 Any of Methods 1.0-1.19, wherein the PDE1 inhibitor and / or the Compound of Formula VIII are administered by injection, optionally wherein the PDE1 inhibitor and / or the Compound of Formula VIII are administered as a form of a long-acting depot for administration by injection to provide sustained release.1.23 Any preceding method, wherein the PDE1 inhibitor and the Compound of Formula VIII are in a single dosage form, e.g., an oral dosage form (such as a tablet or capsule), an intranasal dosage form (e.g., a nasal spray or mister), a pulmonary dosage form (e.g., an inhaler), or an injectable dosage form (e.g., an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection), in combination or association with a pharmaceutically acceptable diluent or carrier.1.24 Any of Methods 1.0-1.22, wherein the PDE1 inhibitor and the Compound of Formula VIII are in two distinct dosage forms (i.e., one dosage form comprising the PDE1 inhibitor and a separate dosage form comprising the Compound of Formula VIII), optionally wherein the two dosage forms are administered separately, simultaneously, or sequentially.1.25 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II. III. IV, V. VI. and / or VII.1.26 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.1.27 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound according to the following:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1, or in free or pharmaceutically acceptable salt form.1.28 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.1.29 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.30 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.31 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.32 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.33 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.34 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.35 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.36 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.37 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.38 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.39 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.40 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.41 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.42 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.43 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.44 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.45 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.46 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.47 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.48 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.49 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.50 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.51 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.52 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.53 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.54 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.55 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.56 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.57 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.58 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.59 Any of Methods 1.0-1.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.60 Any preceding methods, wherein the subject is a human, e.g., a patient, such as a cancer patient.1.61 Any preceding method, wherein the composition does not comprise administration of aa PDE1 inhibitor to the subject.1.62 Any preceding method, wherein the method does not comprise administration any other antiemetic agents, e.g., any antipsychotic agents or D2 receptor antagonists, other than the Compound of Formula VIII (e.g., lumateperone).1.63 Any preceding method, wherein the method further comprises administration of an additional antiemetic agent, such as an antipsychotic agent (e.g., an atypical antipsychotic agent).1.64 Method 1.63, wherein the additional antiemetic agent is selected from amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil,IT-209-PCT / ICT1209WOPCT1 brexpiprazole, brilaroxazine, and cariprazine. Other suitable antiemetic agents include D2 receptor antagonists, such as promethazine, metoclopramide, benperidol, bromperidol, droperidol. haloperidol, moperone. pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl. thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol, thiothixene, zuclopenthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine, and molindone.1.65 Method 1.63, wherein the additional antiemetic agent is selected from asenapine, clozapine, olanzapine, quetiapine, and zotepine. e.g., olanzapine.1.66 Any preceding method, wherein the method comprises administering the Compound of Formula VIII (e.g., lumateperone) with the additional antiemetic agent, and without a PDE1 inhibitor.1.67 Any preceding method, wherein the method further comprises administration of a 5-HT3 receptor antagonist (e.g., ondansetron, dolasetron, granisetron, polanosetron, tropisetron, alosetron, batanopride, renzapride, zacopride, mosapride, bupropion, mianserin, mirtazapine, or vortioxine).

[0059] In another embodiment of the first aspect, the present disclosure provides a method (Method 2.0) of preventing or treating nausea and / or vomiting (e.g., CINV), comprising administering a pharmaceutically effective amount of a Compound of Formula IX, optionally in combination with a pharmaceutically effective amount of a PDE1 inhibitor, to a subject in need thereof. In further embodiments of the first aspect, the present disclosure provides:2.1 Method 2.0, wherein the nausea and / or vomiting is caused by cancer treatment (e.g., chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy, bone marrow or stem cell transplant), advanced cancer, brain cancer, pregnancy, motion sickness, migraines, or food poisoning.2.2 Method 2.0 or 2.1, wherein the subject is a cancer patient, optionally wherein the cancer is selected from Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma, osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Leiomyosarcoma. Myxosarcoma, Fibrocartilaginous mesenchymoma, Astrocytoma, Brainstem glioma,IT-209-PCT / ICT1209WOPCT1Pilocytic astrocytoma. Ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioblastoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma. Pineal astrocytoma, Pituitary adenoma. Visual pathway and hypothalamic glioma, Breast cancer, Inflammatory breast cancer, Invasive lobular carcinoma. Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma. Male breast cancer. Phyllodes tumor, Mammary secretory carcinoma, Papillary carcinomas of the breast, Adrenocortical carcinoma, Islet cell carcinoma, Multiple endocrine neoplasia syndrome, Pancreatic Cancer, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Optic nerve glioma, Anal cancer. Appendix cancer. Cholangiocarcinoma. Carcinoid tumor, Colon cancer, Duodenal cancer. Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, Rectal cancer, Small intestine cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Penile cancer, Kidney cancer, Renal cell carcinoma, Prostate cancer Testicular cancer, Gestational trophoblastic tumor, Urothelial carcinoma, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer. Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia. Acute myeloid leukemia. Acute myeloid dendritic cell leukemia, AIDS -related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma. Chronic lymphocytic leukemia. Chronic myelogenous leukemia. Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma. Intravascular large B- cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma / plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma,IT-209-PCT / ICT1209WOPCT1Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, Basal cell carcinoma, Squamous cell carcinoma. Squamous cell skin cancer, Skin adnexal tumors (e.g. sebaceous carcinoma), Melanoma, Merkel cell carcinoma, Keratoacanthoma, Sarcomas of primary cutaneous origin (e.g. dermatofibrosarcoma protuberans), Lymphomas of primary cutaneous origin (e.g. mycosis fungoides), Lung cancer, Adenocarcinoma of the lung, Basaloid squamous cell lung carcinoma, Bronchial adenomas / carcinoids Small cell lung cancer, Mesothelioma Non-small cell lung cancer, Non-small cell lung carcinoma, Pleuropulmonary blastoma Laryngeal cancer, Thymoma and thymic carcinoma, Squamous-cell carcinoma of the lung, AIDS-related cancers, Kaposi sarcoma Epithelioid hemangioendothelioma (EHE), Desmoplastic small round cell tumor, and Liposarcoma.2.3 Any preceding method, wherein the nausea and / or vomiting is chemotherapy- induced nausea and vomiting (CINV), radiation therapy- induced nausea and vomiting (RINV), or postoperative nausea and vomiting (PONV).2.4 Method 2.3, wherein the nausea and / or vomiting is CINV, optionally wherein the chemotherapeutic agent is selected from Alkylating agents (e.g., Altretamine, Bendamustine, Busulfan, Carboquone, Carmustine, Chlorambucil, Chlormethine, Chlorozotocin, Cyclophosphamide, Dacarbazine, Fotemustine, Ifosfamide, Lomustine, Melphalan, Melphalan flufenamide, Mitobronitol, Nimustine, Nitrosoureas, Pipobroman, Ranimustine, Semustine, Streptozotocin, Temozolomide, Thiotepa, Treosulfan, Triaziquone, Triethylenemelamine, Trofosfamide, Uramustine), Anthracyclines (e.g., Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pirarubicin, Valrubicin, Zorubicin), Cytoskeletal disruptors (taxanes) (e.g., Abraxane, Cabazitaxel, Docetaxel, Larotaxel, Paclitaxel, Taxotere, Tesetaxel), Epothilones (e.g., Ixabepilone), Histone deacetylase inhibitors (e.g., Entinostat, Romidepsin, Vorinostat, Zabadinostat), Inhibitors of topoisomerase I (Belotecan, Camptothecin, Exatecan, Gimatecan, Irinotecan, Topotecan), Inhibitors of topoisomerase II (e.g.. Etoposide, Teniposide, Tafluposide), Kinase inhibitors (Bortezomib, Erlotinib, Gefitinib, Imatinib,IT-209-PCT / ICT1209WOPCT1Vemurafenib, Vismodegib), Nucleotide analogs (e.g., Azacitidine, Azathioprine, Capecitabine, Cytarabine, Doxifluridine, Fluorouracil, Gemcitabine, Hydroxyurea, Mercaptopurine. Methotrexate. Tioguanine), Peptide antibiotics (e.g.. Actinomycin, Bleomycin), Platinum-based agents (e.g., Carboplatin, Cisplatin, Dicycloplatin, Oxaliplatin, Nedaplatin, Satraplatin), Retinoids (e.g., Alitretinoin, Bexarotene, Tretinoin), Vinca alkaloids and derivatives (e.g., Vinblastine, Vincristine. Vindesine, Vinorelbine). and combinations thereof.2.5 Method 2.3 or 2.4, wherein the CINV is acute CINV, delayed CINV, anticipatory CINV, breakthrough CINV, or refractory CINV.2.6 Method 2.3, wherein the nausea and / or vomiting is radiation therapy-induced nausea and vomiting (RINV).2.7 Method 2.3, wherein the nausea and / or vomiting is postoperative nausea and vomiting (PONV).2.8 Method 2.0 or any of 2.1-2.7, wherein the subject is an advanced cancer patient, optionally wherein the nausea and / or vomiting is caused by advanced cancer.2.9 Method 2.0 or any of 2.1-2.8, wherein the cancer is brain cancer.2.10 Method 2.0, wherein the nausea and / or vomiting is caused by pregnancy, i.e., the nausea and / or vomiting is morning sickness.2.11 Method 2.0, wherein the nausea and / or vomiting is caused by motion sickness.2.12 Method 2.0, wherein the nausea and / or vomiting is caused by migraines.2.13 Method 2.0, wherein the nausea and / or vomiting is caused by food poisoning.2.14 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is S, S(O), or S(O)2.2.15 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is O.2.16 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is CH2. CHRb, or C(Rb)2.2.17 Method 2.16, wherein Rbis independently Ci-ealkyl (e.g., methyl).2.18 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is CH2.IT-209-PCT / ICT1209WOPCT12.19 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is NH.2.20 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is N-C(O)-Ra.2.21 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is N-C(O)-O-Ra.2.22 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is N-C(O)-O-CH2-O-Ra.2.23 Any one of methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is N-CH2-O-C(O)-Ra.2.24 Method 2.0, or any of 2.20-2.23, wherein Rais Ci-2alkylaryl (e.g., benzyl or phenethyl).2.25 Method 2.0, or any of 2.20-2.23, wherein Rais Ci-2oalkyl (e.g., methyl or tertbutyl).2.26 Method 2.0, or any of 2.20-2.23, wherein Rais Cio-2oalkyl (e.g., decyl or dodecyl).2.27 Method 2.0, or any of 2.20-2.23, wherein Rais Ci-isalkyl (e.g., hexyl or octyl).2.28 Method 2.0, or any of 2.20-2.23, wherein Rais Cv-isalkyl (e.g., heptyl or nonyl).2.29 Method 2.0, or any of 2.20-2.23, wherein Rais Ci-6alkyl (e.g., butyl or hexyl).2.30 Method 2.0, or any of 2.20-2.23, wherein Rais Ci-4alkyl (e.g., n-butyl or tertbutyl).2.31 Method 2.0, or any of 2.20-2.23, wherein Rais Ci-3alkyl (e.g., propyl or isopropyl).2.32 Method 2.0, or any of 2.20-2.23, wherein Rais Ci-2alkyl (e.g., methyl or ethyl).2.33 Any one of Methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is N(Ra).2.34 Method 2.33, wherein Rais Ci-2alkylaryl (e.g., benzyl or phenethyl).2.35 Method 2.33, wherein Rais Ci-2oalkyl (e.g., methyl or tert-butyl).2.36 Method 2.33, wherein Rais Cio-2oalkyl (e.g., decyl or dodecyl).2.37 Method 2.33, wherein Rais Ci-isalkyl (e.g., hexyl or octyl).2.38 Method 2.33, wherein Rais Cv-isalkyl (e.g., heptyl or nonyl).2.39 Method 2.33, wherein Rais Ci-6alkyl (e.g., butyl or hexyl).2.40 Method 2.33, wherein Rais Ci.galkyl (e.g., n-butyl or tert-butyl)).IT-209-PCT / ICT1209WOPCT12.41 Method 2.33, wherein Rais Ci^alkyl (e.g., n-butyl or tert-butyl).2.42 Method 2.33, wherein Rais Cualkyl (e.g., propyl or isopropyl).2.43 Method 2.33, Rais Ci-2alkyl (e.g., methyl or ethyl).2.44 Method 2.33, wherein Rais selected from methyl, ethyl, isopropyl, and tert-butyl.2.45 Method 2.33, Rais methyl (i.e.. X is N(CH3)).2.46 Any one of Methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is a spiro-joined Cs-ecycloalkyl (e.g., cyclopropane).2.47 Method 2.46, wherein the spiro-joined Cs ecycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane.2.48 Method 2.46, wherein the spiro-joined Cs ecycloalkyl is cyclopropane.2.49 Any one of Methods 2.0-2.13, wherein the Compound of Formula IX is a compound wherein X is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane).2.50 Method 2.49, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine.2.51 Method 2.49, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine.2.52 Any one of Methods 2.46-2.51, wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is unsubstituted.2.53 Any one of Methods 2.46-2.51, wherein said spiro-joined C.3-6cycloalkyl or 3-6- membered heterocycloalkyl is substituted by one or more groups selected from Cnealkyl (e.g., methyl), haloCi ealkyl (e.g., trifluoromethyl), Ci ealkoxy (e.g., methoxy), C3 ecycloalkyl (e.g., cyclopropyl), C3-ecycloalkoxy (e.g., cyclopropoxy), and hydroxy.2.54 Any one of Methods 2.0-2.53, wherein the Compound of Formula IX is a compound wherein Y is -C(O)-.2.55 Any one of Methods 2.0-2.53, wherein the Compound of Formula IX is a compound wherein Y is CHRCor C(RC)2.2.56 Method 2.55, wherein each Rcis independently Ci-ealkyl.2.57 Method 2.55, wherein each Rcis independently selected from methyl, ethyl and propyl.IT-209-PCT / ICT1209WOPCT12.58 Any one of Methods 2.0-2.53, wherein the Compound of Formula IX is a compound wherein Y is a spiro-joined Cs-ecycloalkyl (e.g., cyclopropane).2.59 Method 2.58, wherein the spiro-joined Cs ecycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane.2.60 Method 2.58, wherein the spiro-joined C3-6cycloalkyl is cyclopropane.2.61 Any one of Methods 2.0-2.53, wherein the Compound of Formula IX is a compound wherein Y is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane).2.62 Method 2.61, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine.2.63 Method 2.61, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine.2.64 Any one of Methods 2.58-2.63, wherein said spiro-joined Cs-ecycloalkyl or 3-6- membered heterocycloalkyl is unsubstituted.2.65 Any one of Methods 2.58-2.63, wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is substituted by one or more groups selected from Ci-6alkyl (e.g., methyl), haloCi-ealkyl (e.g., trifluoromethyl), Ci-ealkoxy (e.g., methoxy), C3- ecycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy.2.66 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is a bond.2.67 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is S, S(O), or S(O)2.2.68 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is O.2.69 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is NH.2.70 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is N(Rd), optionally wherein Rdis Ci-6alkyl (e.g., methyl).2.71 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is -C(O)-.IT-209-PCT / ICT1209WOPCT12.72 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is -C(OH)-.2.73 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is -C(OH)-, -C(OCi-ealkyl), -C(=N-OH)-, -C(=N-OCi-ealkyl)-, optionally wherein said Ci-6alkyl is methyl.2.74 Any one of methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is a spiro-joined Ca-ecycloalkyl (e.g., cyclopropane).2.75 Method 2.74, wherein the spiro-joined Cs ecycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane.2.76 Method 2.74, wherein the spiro-joined Cs ecycloalkyl is cyclopropane.2.77 Any one of Methods 2.0-2.65, wherein the Compound of Formula IX is a compound wherein Z is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane).2.78 Method 2.77, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine.2.79 Method 2.77, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine.2.80 Any one of methods 2.74-2.79, wherein said spiro-joined C?-6cycloalkyl or 3-6- membered heterocycloalkyl is unsubstituted.2.81 Any one of methods 2.74-2.79, wherein said spiro-joined C -ecycloalkyl or 3-6- membered heterocycloalkyl is substituted by one or more groups selected from Ci-ealkyl (e.g., methyl), haloCi ealkyl (e.g., trifluoromethyl), Ci ealkoxy (e.g., methoxy), C3 ecycloalkyl (e.g., cyclopropyl), C3-ecycloalkoxy (e.g., cyclopropoxy), and hydroxy.2.82 Any one of methods 2.0-2.81, wherein the Compound of Formula IX is a compound wherein A is H.2.83 Any one of methods 2.0-2.81, wherein the Compound of Formula IX is a compound wherein A is a 6-10 membered aryl ring, e.g., selected from phenyl and naphthyl, substituted by 0-5 groups R.2.84 Any one of methods 2.0-2.81, wherein the Compound of Formula IX is a compound wherein A is a 5-10 membered heteroaryl ring, substituted by 0-5 groups R.IT-209-PCT / ICT1209WOPCT12.85 Method 2.84, wherein A is selected from furan, thiophene (e.g., thiophen-2-yl), pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyridine (e.g., pyrid-4-yl), 2-oxopyridine (e.g., 2-oxopyridin-l(2H)-yl), pyrimidine, pyridazine, pyrazine, benzofuran (e.g., benzofuran-4-yl, or benzofuran-7-yl, or 2-methylbenzofuran- 4-yl), dihydrobenzofuran (e.g., 2,3-dihydrobenzofuran-7-yl), benzothiophene, indole (e.g., indol-l-yl, indol-3-yl. or indol-5-yl). benzoxazole, benzothiazole, benzimidazole (e.g., benzo[d]imidazol-l-yl), benzisoxazole (e.g., benzo[d]isoxazol-3-yl, or benzo[d]isoxazol- 4-yl), benzisothiazole (e.g., benzo[d]isothiazol-3-yl), benzotriazole (e.g., benzo[d][l,2,3- triazol-l-yl), indazole (e.g., indazol-l-yl, indazol-3-yl, or indazol-7-yl), quinoline (e.g., quinolin- 8 -yl), isoquinoline (e.g., isoquinolin-7-yl), quinazoline (e.g., quinazolin-7-yl), and quinoxaline (e.g., quinoxalin-5-yl).2.86 Method 2.85, wherein A is substituted by 0 groups R.2.87 Method 2.85, wherein A is substituted by 1 groups R.2.88 Method 2.85, wherein A is substituted by 2 groups R.2.89 Method 2.83, wherein A is a phenyl ring, substituted by 0-5 groups R.2.90 Method 2.89, wherein A is substituted by one group R.2.91 Method 2.90, wherein the one group R is positioned at the para position of the phenyl ring.2.92 Method 2.90, wherein the one group R is positioned at the meta position of the phenyl ring.2.93 Method 2.90, wherein the one group R is positioned at the ortho position of the phenyl ring.2.94 Method 2.89, wherein A is substituted by two groups R.2.95 Method 2.94, wherein the two groups R are positioned at the ortho and para positions of the phenyl ring.2.96 Method 2.94, wherein the two groups R are positioned at the meta and para positions of the phenyl ring.2.97 Method 2.94, wherein the two groups R are positioned at the ortho and meta positions on the same side of the phenyl ring.2.98 Method 2.94, wherein the two groups R are positioned at the ortho and meta positions on opposite sides of the phenyl ring.IT-209-PCT / ICT1209WOPCT12.99 Method 2.94, wherein the two groups R are positioned at the two ortho positions of the phenyl ring.2.100 Method 2.94, wherein the two groups R are positioned at the two meta positions of the phenyl ring.2.101 Method 2.89, wherein A is substituted by three groups R.2.102 Method 2.101. wherein the three groups R are positioned at the two ortho positions and the para position of the phenyl ring.2.103 Method 2.89, wherein A is substituted by four groups R.2.104 Method 2.89, wherein A is substituted by five groups R.2.105 Any one of methods 2.0-2.105, wherein the Compound of Formula IX is a compound wherein each group R is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, 2-methoxyethoxy, methylsulfonyl, methylthio, cyclopropoxy, cyclopropylmethoxy, methylamino, 4- fluorophenoxy, and (4-fluorobenzyl)oxy.2.106 Any one of methods 2.0-2.105, wherein the Compound of Formula IX is a compound wherein A is selected from the group consisting of: phenyl, 2-cyanophenyl, 3- cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4- ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 3-chloro-4-fluorophenyl, 2- cyano-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-methyl-4-fluorophenyl, 3-methyl-4- fluorophenyl, 2-methoxy-4-fluorophenyl, 2-methoxy-5 -fluorophenyl, 2-fluoro-4- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 2-hydroxyphenyl, 2,5-dimethoxyphenyl, 2-trifluoromethyoxyphenyl, 3- trifluoromethylphenyl, 2-(methylsulfonyl)phenyl, 3-(methylthio)phenyl, 4- (methoxyethoxy)phenyl, 4-(4-fluorobenzyloxy)phenyl, 4-(4-fluorophenoxy)phenyl, 3- cyclopropoxyphenyl, 3-(cyclopropylmethoxy)phenyl, and 2-(methylamino)phenyl.2.107 Any one of methods 2.0-2.105, wherein the Compound of Formula IX is a compound wherein A is selected from the group consisting of: pyrid-4-yl, thiophen-2-yl, indol-l-yl, indol-3-yl, 5-fluoroindol-3-yl, indazol-l-yl, indazol-3-yl, indazol-7-yl, benzofuran-4-yl, benzofuran-7-yl, 2,3-dihydrobenzofuran-7-yl, 2-methylbenzofuran-7-yl, benzo[d]isoxazol-3-yl, benzo[d]isoxazol-4-yl, benzo[d]isoxazol-7-yl, 6- fluorobenzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, benzo [d] imidazole- 1-yl,IT-209-PCT / ICT1209WOPCT1 benzo[d][l ,2,3]triazol-l-yl, isoquinolin-7-yl, quinolin-8-yl, quinoxaline-5-yl, quinazolin- 7-yl, and 2-oxopyridin-l(2H)-yl.2.108 Any one of Methods 2.0-2.105, wherein the Compound of Formula IX is a compound wherein A is selected from the group consisting of: phenyl, 2-ethylphenyl, 4- fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, benzofuran-7-yl, benzo[d]isoxazol-3- yl, and benzo[d]isothiazol-3-yl.2.109 Any one of Methods 2.0-2.108, wherein the Compound of Formula IX is a compound wherein m is 1.2.110 Any one of Methods 2.0-2.108, wherein the Compound of Formula IX is a compound wherein m is 2.2.111 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound wherein n is 2.2.112 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound wherein n is 3.2.113 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound wherein n is 4.2.114 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound wherein n is 5.2.115 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound wherein X is S, O, CH2, NH, N(CH3), or spiro-joined cyclopropyl; Y is CH2, C(O), or spiro-joined cyclopropyl, and Z is a bond, -O-, -C(O)-, -O(CH2)2O-, or - C(=NOCH3)-.2.116 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound wherein X is N(CH3) or spiro-joined cyclopropyl; Y is CH2, C(O), or spiro- joined cyclopropyl, and Z is a bond, -O-, or -C(O)-.2.117 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound of Formula IXa:wherein n, Z, and A are defined as in any preceding embodiment.IT-209-PCT / ICT1209WOPCT12.118 Any one of Methods 2.0-2.110, wherein the Compound of Formula TX is a compound of Formula IXb:wherein n, Z, and A are defined as in any preceding embodiment.2.119 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound of Formula IXc:wherein n, Z, and A are defined as in any preceding embodiment.2.120 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound of Formula IXd:wherein n, Z, and A are defined as in any preceding embodiment.2.121 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound of Formula IXe:wherein n, Z, and A are defined as in any preceding embodiment.2.122 Any one of Methods 2.0-2.122, wherein the Compound of Formula IX is a compound wherein n is 4 and Z is a bond.2.123 Any one of Methods 2.0-2.122, wherein the Compound of Formula IX is a compound wherein n is 3 and Z is -O- or -C(O)-.IT-209-PCT / ICT1209WOPCT12.124 Any one of Methods 2.0-2.122, wherein the Compound of Formula TX is a compound wherein n is 3 and Z is a bond.2.125 Any one of Methods 2.0-2.122, wherein the Compound of Formula IX is a compound wherein n is 2 and Z is -O- or -C(O)-.2.126 Any one of Methods 2.0-2.122, wherein the Compound of Formula IX is a compound wherein n is 2 and Z is a bond.2.127 Any one of Methods 2.0-2.122, wherein the Compound of Formula IX is a compound wherein n is 1 and Z is -O- or -C(O)-.2.128 Any one of Methods 2.0-2.122, wherein the Compound of Formula IX is a compound wherein n is 1 and Z is a bond.2.129 Any one of Methods 2.0-2.110, wherein the Compound of Formula IX is a compound wherein X is N(Ra) (e.g., N(CHs)); Y is -C(O)-; Z is a bond, -O-, -C(O)-, - C(OH)-, a spiro-joined C -ecycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6- membered heterocycloalkyl (e.g., aziridine or oxetane); A is aryl (e.g., phenyl) or heteroaryl, wherein said aryl or heteroaryl is substituted by 0-5 groups R, m is 1, and n is 2 or 3.2.130 Method 2.129, wherein the Compound of Formula IX is a compound wherein X is N(CHs), Y is C(O), Z is -O-, m is 1, and n is 2 or 3.2.131 Method 2.130, wherein the Compound of Formula IX is a compound wherein A is phenyl substituted by 2 or 3 groups R, wherein each group R is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, F, Cl, cyano, and hydroxy.2.132 Method 2.130. wherein the Compound of Formula IX is a compound wherein A is phenyl substituted by 2 or 3 groups R, wherein each group R is independently selected from F, Cl, cyano, and hydroxy.2.133 Method 2.131 or 2.132, wherein the Compound of Formula IX is a compound wherein the 2 or 3 groups R are positioned with at least one group R in the para position, and at least one R group in the ortho position.2.134 Any one of Methods 2.129-2.133, wherein the Compound of Formula IX is a compound wherein n is 3.2.135 Any preceding method, wherein the Compound of Formula IX is a compound selected from the group consisting of:IT-209-PCT / ICT1209WOPCT1each independently in free or pharmaceutically acceptable salt or form.2.136 Any preceding method, wherein the Compound of formula IX is a compound defined by any of the following embodiments:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT12.137 Any preceding method, wherein the Compound of Formula IX is a compound defined by any of the following embodiments:2.138 Any preceding method, wherein the Compound of Formula IX is a compound selected from the group consisting of:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1 each independently in free or pharmaceutically acceptable salt or form.2.139 Any preceding method, wherein the Compound of formula IX is a compound defined by any of the following embodiments:2.140 Any preceding method, wherein the Compound of formula IX is defined as provided in any embodiment of U.S. Provisional Application No. 63 / 667,517, filed on July 3, 2024, or PCT / US2025 / 36531 , filed on July 3, 2025, the contents of each of which are hereby incorporated by reference in their entireties.2.141 Any preceding method, wherein the Compound of formula IX is defined as provided in any embodiment of WO 2024 / 145659, the contents of which are hereby incorporated by reference in its entirety.2.142 Any preceding method, wherein the Compound of Formula IX is not a compound wherein:(a) n is 3. Z is -C(O)-, X is CH2 or O, and m is 2;(b) n is 3, Z is -C(O)-, X is CH2, and m is 1;(c) n is 3, Z is -C(O)- or -O-, X is NH or N(Ra), and m is 1; and / or(d) n is 3, Z is O, X is NCH3, Y is -C(O)-, and m is 1.2.143 Any preceding method, wherein the Compound of Formula IX is not a compound defined by any one or more of the following embodiments:IT-209-PCT / ICT1209WOPCT12.144 Any preceding method, wherein the Compound formula IX is in free base form.2.145 Any preceding method, wherein the Compound formula IX is in pharmaceutically acceptable salt form, e.g., selected from toluenesulfonate, or hydrochloride preferably wherein the compound of Formula IX is in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).2.146 Method 2.145. wherein the Compound of Formula IX is in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).2.147 Any preceding method, wherein the Compound formula IX is in in substantially pure diastereomeric form (i.e„ substantially free from other diastereomers).2.148 Any preceding method, wherein the Compound formula IX has a diastereomeric excess of greater than 70%, preferably greater than 80%. more preferably greater than 90% and most preferably greater than 95%.2.149 Any preceding method, wherein the Compound formula IX is in solid form, e.g., in crystal form.2.150 Any preceding method, wherein the Compound formula IX is in isolated or purified form (e.g., in at least 90% pure form, or at least 95% or at least 98% or at least 99%).2.151 Any preceding method, wherein the Compound formula IX is a compound characterized by one or more of:IT-209-PCT / ICT1209WOPCT1(a) 5-HT2A receptor binding affinity of at least 60% at 100 nM concentration, e.g., at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%. or at least 98%. at 100 nM concentration;(b) a 5-HT2A receptor dissociation constant (Kd) of less than 250 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM. or less than 30 nM. or less than 20 nM, or less than 10 nM;(c) agonism of beta-arrestin signaling via the 5-HT2A receptor, e.g., a partial agonist or a full agonist, for example:(c)(1) partial agonism of beta-arrestin signaling having an Emaxof less than 90%, or less than 80%, or less than 70%, or less than 60%, or less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10%, relative to a full agonist (e.g., alpha-methylserotonin);(c)(2) an EC50 for 5-HT A receptor beta-arrestin agonism of less than 500 nM, or less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM;(c)(3) a beta-arrestin signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0. or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9. or 0.6 to 0.8;(c)(4) a beta-arrestin signaling relative intrinsic activity (RAi) of greater than 1.0 compared to the reference compound alpha-methylserotonin, e.g.. a relative intrinsic activity of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6;(d) antagonism of beta-arrestin signaling via the 5-HT2A receptor, for example:(d)(1) an IC50 for 5-HT2A receptor beta-arrestin antagonism of less than 300 nM, or less than 200 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM;IT-209-PCT / ICT1209WOPCT1(e) non-antagonism of beta-arrestin signaling via the 5-HT2A receptor, for example, an IC50 for 5-HT2A receptor beta-arrestin antagonism of greater than 10 nM, or greater than 50 nM, or greater than 100 nM, or greater than 250 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 5000 nM, or greater than 10,000 nM;(f) non-agonism of G-q signaling via the 5-HT2A receptor, for example, an EC50 for 5-HT2A receptor G-q agonism of greater than 10 nM, or greater than 25 nM, or greater than 50 nM, or greater than 100 nM, or greater than 150 nM, or greater than 200 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 2000 nM, or greater than 5000 nM, or greater than 10,000 nM;(g) weak agonism of G-q signaling via the 5-HT2A receptor, for example, partial agonism of G-q signaling with an Emaxof less than 90%, or less than 80%, or less than 70%, or less than 60%, or less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10%, relative to a full agonist (e.g., alphamethylserotonin), preferably an Emaxof less than 50% or less than 30% or less than 10%;(h) a G-q signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8;(i) antagonism of G-q signaling via the 5-HT2A receptor, for example, has an IC50 for 5-HT2A receptor G-q antagonism of less than 10 nM, or less than 25 nM, or less than 50 nM, or less than 100 nM, or less than 150 nM, or less than 200 nM, or less than 500 nM;(j) a bias ratio (beta-an'estin / G-q) for agonism 5-HT2A receptor of at least 2, or at least 5, or at least 10, or at least 25, or at least 50, or at least 100, or at least 150, or at least 200 or at least 500, or at least 1000, or at least 10,000, or undefined (i.e., where the compound has any degree of beta-arrestin agonism and zero G-q agonism);IT-209-PCT / ICT1209WOPCT1(k) antagonism or agonism of DI and / or D2 dopamine receptor (e.g., having at least 70% receptor affinity at 100 nM concentration or an IC50 of less than 100 nM);(l) inactivity at the DI and / or D2 dopamine receptor (e.g., having less than 50% receptor affinity at 100 nM concentration and / or an ECso or IC50 of more than 500 nM);(m) antagonism of the serotonin transporter (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an IC50 of less than 100 nM);(n) inactivity at the serotonin transporter (e.g., having less than 50% receptor binding affinity at 100 nM concentration and / or an EC50 or IC50 of more than 500 nM);(0) agonist, antagonist, or partial agonist activity at the mu-opioid receptor (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an EC50 or IC50 of less than 100 nM);(p) inactivity at the mu-opioid receptor (e.g., having at less than 50% receptor binding affinity at 100 nM concentration and / or an EC50 or ICsoof more than 500 nM);2.152 Any preceding method, wherein the Compound formula DC is a compound which is non-hallucinogenic. e.g., at therapeutic doses for the treatment of preventing or treating nausea and / or vomiting (e.g., CINV) the compound does not cause visual or auditory hallucinations, visual distortions (such as drifting, morphing, breathing or melting of objects and surfaces in the field of view), detachment from reality, dissociation, delirium, undesired altered states of consciousness.2.153 Any preceding method, wherein the Compound formula DC is a compound which does not stimulate head twitch response in an animal test model, or is antagonist of DOI- induced head twitch response.2.154 Any preceding method, wherein the Compound formula DC is a compound which does not cause one or more of psychosis, self-harm, harm to others, heart valvulopathy, pulmonary arterial hypertension, abuse or dependence, in a patient treated with the Compound at therapeutic doses for the preventing or treatment of nausea and / or vomiting (e.g., CINV);IT-209-PCT / ICT1209WOPCT12.155 Any preceding method, wherein the PDE1 inhibitor and / or the Compound of Formula IX are administered orally, optionally wherein the PDE1 inhibitor and / or the Compound of Formula IX are administered as a tablet or capsule.2.156 Any of Methods 2.0-2.154, wherein the PDE1 inhibitor and / or the Compound of Formula IX are administered by inhalation, optionally wherein the PDE1 inhibitor and / or the Compound of Formula IX are administered as a nasal spray or inhaler.2.157 Any of Methods 2.0-2.154, wherein the PDE1 inhibitor and / or the Compound of Formula IX are administered by injection, optionally wherein the PDE1 inhibitor and / or the Compound of Formula IX are administered as a form of a long-acting depot for administration by injection to provide sustained release.2.158 Any preceding method, wherein the PDE1 inhibitor and the Compound of Formula IX are in a single dosage form, e.g., an oral dosage form (such as a tablet or capsule), an intranasal dosage form (e.g., a nasal spray or mister), a pulmonary dosage form (e.g., an inhaler), or an injectable dosage form (e.g., an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection), in combination or association with a pharmaceutically acceptable diluent or carrier.2.159 Any of Methods 2.0-2.159, wherein the PDE1 inhibitor and the Compound of Formula IX are in two distinct dosage forms (i.e., one dosage form comprising the PDE1 inhibitor and a separate dosage form comprising the Compound of Formula IX), optionally wherein the two dosage forms are administered separately, simultaneously, or sequentially.2.160 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII.2.161 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.2.162 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound according to the following:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1, or in free or pharmaceutically acceptable salt form.2.163 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.2.164 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.165 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.166 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.167 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.168 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.169 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.170 Any of Methods 2.0-2.160. wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.171 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.172 Any of Methods 2.0-2.160. wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.173 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.174 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.175 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.176 Any of Methods 2.0-2.160. wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.177 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.178 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.179 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.180 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.181 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.182 Any of Methods 2.0-2.160. wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.183 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.184 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.185 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.186 Any of Methods 2.0-2.160. wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.187 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.188 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.189 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.190 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.191 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.192 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.193 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.194 Any of Methods 2.0-2.160, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.195 Any preceding methods, wherein the subject is a human, e.g., a patient, such as a cancer patient.2.196 Any preceding method, wherein the composition does not comprise administration of aa PDE1 inhibitor to the subject.2.197 Any preceding method, wherein the method does not comprise administration of any other antiemetic agents, e.g., any antipsychotic agents or D2 receptor antagonists, other than the Compound of Formula IX.2.198 Any preceding method, wherein the method further comprises administration of an additional antiemetic agent, such as an antipsychotic agent (e.g., an atypical antipsychotic agent).2.199 Method 2.198, wherein the additional antiemetic agent is selected from amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole,IT-209-PCT / ICT1209WOPCT1 aripiprazole lauroxil, brexpiprazole, brilaroxazine, cariprazine, promethazine, metoclopramide, benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone. fluspirilene. penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl. thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol, thiothixene, zuclopenthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine, and molindone, or a combination thereof.2.200 Method 2.198, wherein the additional antiemetic agent is selected from asenapine, clozapine, olanzapine, quetiapine, and zotepine, e.g., olanzapine.2.201 Any preceding method, wherein the method comprises administering the Compound of Formula IX with the additional antiemetic agent, and without a PDE1 inhibitor.2.202 Any preceding method, wherein the method further comprises administration of a 5-HT3 receptor antagonist (e.g., ondansetron, dolasetron, granisetron, polanosetron, tropisetron, alosetron, batanopride, renzapride, zacopride, mosapride, bupropion, mianserin, mirtazapine, or vortioxine).

[0060] In another embodiment of the first aspect, the present disclosure provides a method (Method 3.0) of preventing or treating nausea and / or vomiting (e.g., CINV), comprising administering a pharmaceutically effective amount of a PDE1 inhibitor in combination with a pharmaceutically effective amount of an antiemetic agent to a subject in need thereof. In further embodiments of the first aspect, the present disclosure provides:3.1 Method 3.0, wherein the nausea and / or vomiting is caused by cancer treatment (e.g., chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy, bone marrow or stem cell transplant), advanced cancer, brain cancer, pregnancy, motion sickness, migraines, or food poisoning.3.2 Method 3.0 or 3.1 , wherein the subject is a cancer patient, optionally wherein the cancer is selected from Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma, osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Leiomyosarcoma, Myxosarcoma, Fibrocartilaginous mesenchymoma, Astrocytoma, Brainstem glioma,IT-209-PCT / ICT1209WOPCT1Pilocytic astrocytoma. Ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioblastoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma. Pineal astrocytoma. Pituitary adenoma. Visual pathway and hypothalamic glioma, Breast cancer, Inflammatory breast cancer, Invasive lobular carcinoma. Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma. Male breast cancer. Phyllodes tumor, Mammary secretory carcinoma, Papillary carcinomas of the breast, Adrenocortical carcinoma, Islet cell carcinoma, Multiple endocrine neoplasia syndrome, Pancreatic Cancer, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Optic nerve glioma, Anal cancer. Appendix cancer. Cholangiocarcinoma. Carcinoid tumor, Colon cancer. Duodenal cancer. Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, Rectal cancer, Small intestine cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Penile cancer, Kidney cancer, Renal cell carcinoma, Prostate cancer Testicular cancer, Gestational trophoblastic tumor, Urothelial carcinoma, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer. Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia. Acute myeloid leukemia. Acute myeloid dendritic cell leukemia, AIDS -related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma. Chronic lymphocytic leukemia. Chronic myelogenous leukemia. Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma. Intravascular large B- cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma / plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma,IT-209-PCT / ICT1209WOPCT1Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, Basal cell carcinoma, Squamous cell carcinoma. Squamous cell skin cancer, Skin adnexal tumors (e.g. sebaceous carcinoma), Melanoma, Merkel cell carcinoma, Keratoacanthoma, Sarcomas of primary cutaneous origin (e.g. dermatofibrosarcoma protuberans), Lymphomas of primary cutaneous origin (e.g. mycosis fungoides), Lung cancer, Adenocarcinoma of the lung, Basaloid squamous cell lung carcinoma, Bronchial adenomas / carcinoids Small cell lung cancer, Mesothelioma Non-small cell lung cancer, Non-small cell lung carcinoma, Pleuropulmonary blastoma Laryngeal cancer, Thymoma and thymic carcinoma, Squamous-cell carcinoma of the lung, AIDS-related cancers, Kaposi sarcoma Epithelioid hemangioendothelioma (EHE), Desmoplastic small round cell tumor, and Liposarcoma.3.3 Any preceding method, wherein the nausea and / or vomiting is chemotherapy- induced nausea and vomiting (CINV), radiation therapy- induced nausea and vomiting (RINV), or postoperative nausea and vomiting (PONV).3.4 Method 3.3, wherein the nausea and / or vomiting is CINV, optionally wherein the chemotherapeutic agent is selected from Alkylating agents (e.g., Altretamine, Bendamustine, Busulfan, Carboquone, Carmustine, Chlorambucil, Chlormethine, Chlorozotocin, Cyclophosphamide, Dacarbazine, Fotemustine, Ifosfamide, Lomustine, Melphalan, Melphalan flufenamide, Mitobronitol, Nimustine, Nitrosoureas, Pipobroman, Ranimustine, Semustine, Streptozotocin, Temozolomide, Thiotepa, Treosulfan, Triaziquone, Triethylenemelamine, Trofosfamide, Uramustine), Anthracyclines (e.g., Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pirarubicin, Valrubicin, Zorubicin), Cytoskeletal disruptors (taxanes) (e.g., Abraxane, Cabazitaxel, Docetaxel, Larotaxel, Paclitaxel, Taxotere, Tesetaxel), Epothilones (e.g., Ixabepilone), Histone deacetylase inhibitors (e.g., Entinostat, Romidepsin, Vorinostat, Zabadinostat), Inhibitors of topoisomerase I (Belotecan, Camptothecin, Exatecan, Gimatecan, Irinotecan, Topotecan), Inhibitors of topoisomerase II (e.g.. Etoposide, Teniposide, Tafluposide), Kinase inhibitors (Bortezomib, Erlotinib, Gefitinib, Imatinib,IT-209-PCT / ICT1209WOPCT1Vemurafenib, Vismodegib), Nucleotide analogs (e.g., Azacitidine, Azathioprine, Capecitabine, Cytarabine, Doxifluridine, Fluorouracil, Gemcitabine, Hydroxyurea, Mercaptopurine. Methotrexate. Tioguanine), Peptide antibiotics (e.g.. Actinomycin, Bleomycin), Platinum-based agents (e.g., Carboplatin, Cisplatin, Dicycloplatin, Oxaliplatin, Nedaplatin, Satraplatin), Retinoids (e.g., Alitretinoin, Bexarotene, Tretinoin), Vinca alkaloids and derivatives (e.g., Vinblastine, Vincristine. Vindesine, Vinorelbine). and combinations thereof.3.5 Method 3.3 or 3.4, wherein the CINV is acute CINV, delayed CINV, anticipatory CINV, breakthrough CINV, or refractory CINV.3.6 Method 3.3, wherein the nausea and / or vomiting is radiation therapy-induced nausea and vomiting (RINV).3.7 Method 3.3, wherein the nausea and / or vomiting is postoperative nausea and vomiting (PONV).3.8 Method 3.0 or any of 3.1-3.7, wherein the subject is an advanced cancer patient, optionally wherein the nausea and / or vomiting is caused by advanced cancer.3.9 Method 3.0 or any of 3.1-3.8, wherein the cancer is brain cancer.3.10 Method 3.0, wherein the nausea and / or vomiting is caused by pregnancy, i.e., the nausea and / or vomiting is morning sickness.3.11 Method 3.0, wherein the nausea and / or vomiting is caused by motion sickness.3.12 Method 3.0, wherein the nausea and / or vomiting is caused by migraines.3.13 Method 3.0, wherein the nausea and / or vomiting is caused by food poisoning.3.14 Any preceding method, wherein the antiemetic agent is an antipsychotic agent, optionally wherein the antiemetic agent is an atypical antipsychotic agent.3.15 Any preceding method, wherein the antiemetic agent is a D2 antagonist, optionally wherein the antiemetic agent is a 5-HT2A / D2 antagonist.3.16 Any preceding method, wherein the antiemetic agent is selected from the group consisting of promethazine, metoclopramide, benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine. mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine,IT-209-PCT / ICT1209WOPCT1 trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol, thiothixene, zuclopenthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine. mosapramine. molindone, amisulpride, nemonapride, remoxipride. suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole. aripiprazole lauroxil, brexpiprazole. brilaroxazine. and cariprazine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.17 Any preceding method, wherein the antiemetic agent is selected from the group consisting of amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone. perospirone, risperidone, ziprasidone. lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.18 Any preceding method, wherein the antiemetic agent is selected from asenapine, clozapine, olanzapine, quetiapine, and zotepine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.19 Any preceding method, wherein the antiemetic agent is olanzapine, in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.20 Any preceding method, wherein the PDE1 inhibitor and / or the antiemetic agents are administered orally, optionally wherein the PDE1 inhibitor and / or the antiemetic agents are administered as a tablet or capsule.3.21 Any of Methods 3.0-3.19, wherein the PDE1 inhibitor and / or the antiemetic agents are administered by inhalation, optionally wherein the PDE1 inhibitor and / or the antiemetic agents are administered as a nasal spray or inhaler.3.22 Any of Methods 3.0-3.19, wherein the PDE1 inhibitor and / or the antiemetic agents are administered by injection, optionally wherein the PDE1 inhibitor and / or the antiemetic agents are administered as a form of a long-acting depot for administration by injection to provide sustained release.3.23 Any preceding method, wherein the PDE1 inhibitor and the antiemetic agents are in a single dosage form, e.g., an oral dosage form (such as a tablet or capsule), anIT-209-PCT / ICT1209WOPCT1 intranasal dosage form (e.g., a nasal spray or mister), a pulmonary dosage form (e.g., an inhaler), or an injectable dosage form (e.g., an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection), in combination or association with a pharmaceutically acceptable diluent or carrier.3.24 Any of Methods 3.0-3.22, wherein the PDE1 inhibitor and the antiemetic agents are in two distinct dosage forms (i.e., one dosage form comprising the PDE1 inhibitor and a separate dosage form comprising the antiemetic agent), optionally wherein the two dosage forms are administered separately, simultaneously, or sequentially.3.25 Any preceding method, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII.3.26 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.3.27 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound according to the following:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1, or in free or pharmaceutically acceptable salt form.3.28 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.3.29 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.30 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.31 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.32 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.33 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.34 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.35 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.36 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.37 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.38 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1 in free or pharmaceutically acceptable salt form.3.39 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.40 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.41 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.42 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.43 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.44 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.45 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.46 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.47 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.48 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.49 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.50 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.51 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.52 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.53 Any of Methods 3.0-3.25, wherein the PDEl inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.54 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.55 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.56 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.57 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.58 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.59 Any of Methods 3.0-3.25, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.60 Any preceding methods, wherein the subject is a human, e.g., a patient, such as a cancer patient.3.61 Any preceding method, wherein the method does not comprise administering lumateperone, in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.62 Any preceding method, wherein the method further comprises administration of a 5-HT3 receptor antagonist (e.g., ondansetron, dolasetron, granisetron, polanosetron, tropisetron. alosetron, batanopride, renzapride, zacopride, mosapride, bupropion, mianserin, mirtazapine, or vortioxine).

[0061] The nausea and / or vomiting may be caused by various health conditions. In some embodiments, the nausea and / or vomiting is caused by cancer treatment (e.g., chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, bone marrow or stem cell transplant), advanced cancer, brain cancer, pregnancy, motion sickness, migraines, or food poisoning.IT-209-PCT / ICT1209WOPCT1

[0062] In some embodiments, the subject is a cancer patient. As used herein, cancer refers to a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Non-limiting examples of cancers include Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma, osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Leiomyosarcoma, Myxosarcoma, Fibrocartilaginous mesenchymoma. Astrocytoma, Brainstem glioma, Pilocytic astrocytoma. Ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioblastoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma. Visual pathway and hypothalamic glioma, Breast cancer, Inflammatory breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Mammary secretory carcinoma. Papillary carcinomas of the breast, Adrenocortical carcinoma, Islet cell carcinoma, Multiple endocrine neoplasia syndrome, Pancreatic Cancer, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma. Uveal melanoma. Retinoblastoma, Optic nerve glioma, Anal cancer. Appendix cancer. Cholangiocarcinoma. Carcinoid tumor, Colon cancer, Duodenal cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, Rectal cancer, Small intestine cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Penile cancer, Kidney cancer, Renal cell carcinoma, Prostate cancer Testicular cancer, Gestational trophoblastic tumor, Urothelial carcinoma, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer. Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Acute biphenotypic leukemia, Acute eosinophilic leukemia. Acute lymphoblastic leukemia, Acute myeloid leukemia. Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cellIT-209-PCT / ICT1209WOPCT1 lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma / plasma cell neoplasm, Myelodysplastic syndromes, Mucosa- associated lymphoid tissue lymphoma. Mycosis fungoides. Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma. Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, Basal cell carcinoma, Squamous cell carcinoma, Squamous cell skin cancer, Skin adnexal tumors (e.g. sebaceous carcinoma), Melanoma, Merkel cell carcinoma, Keratoacanthoma, Sarcomas of primary cutaneous origin (e.g. dermatofibrosarcoma protuberans), Lymphomas of primary cutaneous origin (e.g. mycosis fungoides), Lung cancer, Adenocarcinoma of the lung. Basaloid squamous cell lung carcinoma, Bronchial adenomas / carcinoids Small cell lung cancer, Mesothelioma Nonsmall cell lung cancer, Non-small cell lung carcinoma, Pleuropulmonary blastoma Laryngeal cancer, Thymoma and thymic carcinoma, Squamous-cell carcinoma of the lung, AIDS-related cancers, Kaposi sarcoma Epithelioid hemangioendothelioma (EHE), Desmoplastic small round cell tumor, and Liposarcoma.

[0063] In some embodiments, the nausea and / or vomiting is caused by cancer treatment (e.g., chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, bone marrow or stem cell transplant). In some embodiments, the nausea and / or vomiting is chemotherapy- induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), or postoperative nausea and vomiting (PONV).

[0064] In some embodiments, the nausea and / or vomiting is chemotherapy-induced nausea and vomiting (CINV). Nausea and vomiting are common side effects of chemotherapy treatment for cancer. Non-limiting examples of chemotherapeutic agents include Alkylating agents (e.g., Altretamine, Bendamustine, Busulfan, Carboquone, Carmustine, Chlorambucil, Chlormethine, Chlorozotocin, Cyclophosphamide, Dacarbazine, Fotemustine, Ifosfamide, Lomustine, Melphalan, Melphalan flufenamide, Mitobronitol, Nimustine, Nitrosoureas, Pipobroman, Ranimustine, Semustine, Streptozotocin, Temozolomide, Thiotepa, Treosulfan, Triaziquone, Triethylenemelamine, Trofosfamide, Uramustine), Anthracyclines (e.g., Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pirarubicin, Valrubicin, Zorubicin), Cytoskeletal disruptors (taxanes) (e.g., Abraxane, Cabazitaxel, Docetaxel,IT-209-PCT / ICT1209WOPCT1Larotaxel, Paclitaxel, Taxotere, Tesetaxel), Epothilones (e.g., Txabepilone), Histone deacetylase inhibitors (e.g., Entinostat, Romidepsin, Vorinostat, Zabadinostat), Inhibitors of topoisomerase I (Belotecan, Camptothecin, Exatecan, Gimatecan, Irinotecan, Topotecan), Inhibitors of topoisomerase II (e.g., Etoposide, Teniposide, Tafluposide), Kinase inhibitors (Bortezomib, Erlotinib, Gefitinib, Imatinib, Vemurafenib, Vismodegib), Nucleotide analogs (e.g., Azacitidine, Azathioprine, Capecitabine, Cytarabine. Doxifluridine. Fluorouracil, Gemcitabine, Hydroxyurea. Mercaptopurine, Methotrexate, Tioguanine), Peptide antibiotics (e.g., Actinomycin, Bleomycin), Platinum-based agents (e.g., Carboplatin, Cisplatin, Dicycloplatin, Oxaliplatin. Nedaplatin, Satraplatin), Retinoids (e.g., Alitretinoin, Bexarotene, Tretinoin), and Vinca alkaloids and derivatives (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine).

[0065] In some embodiments, the CINV is acute CINV, delayed CINV, anticipatory CINV, breakthrough CINV, or refractory CINV. As used herein, acute CINV refers to vomiting and / or nausea occurring in the first 24 hours after chemotherapy. Delayed CINV refers to vomiting and / or nausea occurring 24 h to 5 days after chemotherapy. Anticipatory CINV refers to nausea and vomiting occurring before chemotherapy treatment as a conditioned response due to the occurrence of CINV in previous cycles. Anticipatory CINV is likely mediated by a combination of physiological and psychological mechanisms. Breakthrough CINV refers to vomiting and / or nausea that occurs within five days of chemotherapy administration after the use of guideline directed prophylactic antiemetic agents. Refractory CINV refers to vomiting and / or nausea occurring after chemotherapy in subsequent chemotherapy cycles after guideline directed prophylactic antiemetic agents have failed in earlier cycles.

[0066] In some embodiments, the nausea and / or vomiting is radiation therapy-induced nausea and vomiting (RINV). Radiation therapy can cause nausea and vomiting, especially when radiation is directed at the brain, upper abdomen, or whole body.

[0067] In some embodiments, the nausea and / or vomiting is postoperative nausea and vomiting (PONV). PONV is a common occurrence following anesthesia and leads to patient dissatisfaction and discomfort.

[0068] In some embodiments, the nausea and / or vomiting is caused by advanced cancer. As used herein, advanced cancer refers to cancer that is unlikely to be cured or cancer that has spread from where it first started to nearby tissue, lymph nodes, or other parts of the body (i.e., metastatic cancer). Nausea and vomiting are common in advanced cancer patients. Sometimes,IT-209-PCT / ICT1209WOPCT1 the nausea and vomiting in advanced cancer patients are not caused by cancer treatment (e.g., chemotherapy) but caused by the advanced cancer itself.

[0069] In some embodiments, the nausea and / or vomiting is caused by brain cancer.

[0070] In some embodiments, the nausea and / or vomiting is caused by pregnancy, motion sickness, migraines, or food poisoning. In some embodiments, the nausea and / or vomiting is morning sickness. Morning sickness is nausea and vomiting during pregnancy. It is a common condition affecting up to 70% of pregnant women in the first trimester of pregnancy.

[0071] The PDE1 inhibitors described in this disclosure may be administered in combination with the Compound of Formula VIII or the Compound of Formula IX for preventing or treating nausea and / or vomiting. In some embodiments, the Compound of Formula VIII is lumateperone, e.g., lumateperone tosylate.

[0072] In some embodiments pertaining to the administration of a PDE1 inhibitor in combination with the Compound of Formula VIII or the Compound of Formula IX, the methods described herein may further comprise administration of third agent, an antiemetic agent, such as an antipsychotic agent (e.g., an atypical antipsychotic agent). Suitable antipsychotic agents include amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine. Other suitable antiemetic agents include D2 receptor antagonists, such as promethazine, metoclopramide, benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine. mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol. thiothixene, zuclopenthixol, sulpiride, veralipride. carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine, and molindone. In some embodiments, the antiemetic agent is selected from asenapine, clozapine, olanzapine, quetiapine, and zotepine, e.g., olanzapine.

[0073] In some embodiments pertaining to the administration of a PDE1 inhibitor in combination with the Compound of Formula VIII or the Compound of Formula IX, the methods described herein do not comprise the administration of any other antiemetic agents, e.g., anyIT-209-PCT / ICT1209WOPCT1 antipsychotic agents or D2 receptor antagonists, other than the Compound of Formula VTTI (e.g., lumateperone) or the Compound of Formula IX. For example, the methods do not comprise the administration of any agent selected from amisulpride, nemonapride, remoxipride. suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, cariprazine, promethazine, metoclopramide, benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene. clopenthixol, flupentixol, thiothixene, zuclopenthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine, and molindone.

[0074] The PDE1 inhibitors described in this disclosure may be administered in combination with the antiemetic agent for preventing or treating nausea and / or vomiting, i.e., without a Compound of Formula VIII and without a Compound of Formula IX. In some embodiments, the antiemetic agent is an antipsychotic agent. In some embodiments, the antiemetic agent is an atypical antipsychotic agent. Non-limiting examples of atypical antipsychotic agents include amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.

[0075] In some embodiments, the antiemetic agent is a D2 receptor antagonist. In some embodiments, the antiemetic agent is a 5-HT2A / D2 receptor antagonist.

[0076] In some embodiment, the antiemetic agent is selected from the group consisting of promethazine, metoclopramide, benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol, thiothixene, zuclopenthixol, sulpiride, veralipride, carpipramine, clocapramine,IT-209-PCT / ICT1209WOPCT1 clorotepine, clotiapine, loxapine, mosapramine, molindone, amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.

[0077] In some embodiments, the antiemetic agent is selected from the group consisting of amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine.

[0078] In some embodiments, the antiemetic agent is selected from asenapine, clozapine, olanzapine, quetiapine, and zotepine.

[0079] In some embodiments, the antiemetic agent is olanzapine. In some embodiments the antiemetic agent is not lumateperone, and the methods described herein do not comprise the administration of lumateperone.

[0080] In some embodiments, the antiemetic agent is selected from antipsychotic agents, 5-HT? receptor antagonists, corticosteroids, NK1 receptor antagonists, and dopamine receptor antagonists. In some embodiments, the antiemetic agent is a 5-HT3 receptor antagonist. In some embodiments, the antiemetic agent is selected from ondansetron, dolasetron, granisetron, polanosetron, tropisetron, alosetron, batanopride, renzapride, zacopride, mosapride, bupropion, mianserin, mirtazapine, and vortioxine.

[0081] The term “combination,” or “combination therapy,” as used herein, embraces simultaneous, sequential, or contemporaneous administration of the PDE1 inhibitor and the Compound of Formula VIII, or the PDE1 inhibitor and the Compound of Formula IX, or the PDE1 inhibitor and the antiemetic agent. The combination therapy may be achieved by administering a single composition or pharmacological formulation that includes the PDE1 inhibitor and the Compound of Formula VIII, or the PDE1 inhibitor and the Compound of Formula IX, or the PDE1 inhibitor and the antiemetic agent, or by administration of two distinct compositions or formulations, separately, simultaneously or sequentially, wherein one composition includes the PDE1 inhibitor and the other includes the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent. The term “simultaneously” whenIT-209-PCT / ICT1209WOPCT1 referring to a therapeutic use means administration of two or more active ingredients at or about the same time by the same route of administration. The term “separately” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by different route of administration.

[0082] In some embodiments, the PDE1 inhibitor and / or the Compound of Formula VIII and / or the Compound of Formula IX and / or the antiemetic agent may be provided in the form of a pharmaceutical composition (e.g., a dosage form), for example for oral administration, e.g., in the form of pills (tablets or capsules), or for parenteral administration. In some embodiments, the PDE1 inhibitor and / or the Compound of Formula VIII and / or the Compound of Formula IX and / or the antiemetic agent are provided in the form of a long-acting depot for administration by injection to provide sustained release (e.g., intramuscular or subcutaneous injection). In some embodiments, the solid drug for oral administration or as a depot may be embedded, dissolved, dispersed, or suspended, in a suitable polymer matrix to provide delayed release of the active compound, for example, in polymeric microspheres or in a solvent-based earner. In some embodiments, the PDE1 inhibitor and / or the Compound of Formula VIII and / or the Compound of Formula IX and / or the antiemetic agent are provided in the form of nasal spray or inhaler. In some embodiments, the PDE1 inhibitor and the Compound of Formula VIII and / or the Compound of Formula IX and / or the antiemetic agent are in a single dosage form in combination or association with a pharmaceutically acceptable diluent or carrier.

[0083] As used herein, the term “spiro-joined” is meant to clarify that the stated C3- ecycloalkyl group or 3-6-membered heterocycloalkyl is present in a spiro-junction, meaning that one atom of said cyclic group is an atom of the ring to which the group is attached. For example, the follow are examples of compounds of Formula EX having spiro-joined cyclic groups within the scope of the present disclosure:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1

[0084] In each of the above examples, the cyclopropane, cyclobutane, aziridine, azetidine, or oxetane, may be replaced by any other C?-6cycloalkyl or 3-6-membered heterocycloalkyl, including, but not limited to, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, or morpholine.

[0085] In some embodiments, the Compound of Formula IX is a biased agonist of the serotonin 5-HTIA receptor (e.g., biased towards beta-arrestin mediated agonism). Without being bound by theory, it is believed that biased agonism of this receptor will provide the benefits of rapid and / or potent anti-depressant activity comparable to or better than the hallucinogenic psychedelics, but without the hallucinogenic side effects of such compounds. Nevertheless, in some embodiments, the Compounds of the Invention may be slightly or mildly hallucinogenic and / or may be non-biased agonists, or antagonists, of the serotonin 5-HT2A receptor. Preferably, the Compounds of Formula IX are non-hallucinogenic.

[0086] The term “biased agonist” as used herein, is used in reference to a compound having activity at the serotonin 5-HT2A receptor with either partial or full agonism for beta-arrestin signaling via the receptor, but with either antagonism or weak partial agonism for G-q mediated signaling. A useful measure of bias is the “bias ratio”, which is calculated as the ratio of the intrinsic relative activity (RAi) for beta-arrestin signaling over the RAi for G-q signaling. A nonbiased agonist has a bias ratio of 1.0. A biased agonist has a non-zero bias ratio. In some embodiments, compounds of the present disclosure are preferably biased towards beta-arrestin signaling, and thus have a bias ratio greater than 1.0. More preferably, the bias ratio towards beta-arrestin signaling is greater than 10, or greater than 100, or greater than 1000. or 10,000 or more.

[0087] As used herein, the term “partial agonist” is understood to refer to a compound having agonism to any extent that is lesser than that of a reference standard full agonist. For example, the reference compound for 5-HT2A receptor agonism is alpha-methylserotonin. A compound which has a maximum efficacy (Emax) that is less than 100% of the maximum efficacy for alpha-methylserotonin is a partial agonist.IT-209-PCT / ICT1209WOPCT1

[0088] The term “hallucinogen” refers to a compound which causes hallucinogenic symptoms, which are any one or more symptoms selected from visual hallucinations, auditory hallucinations, visual distortions (such as drifting, morphing, breathing or melting of objects and surfaces in the field of view), detachment from reality, dissociation, delirium, and undesired altered states of consciousness. A compound of the present disclosure is considered “non- hallucinogenic” if at doses which are therapeutically effective for the treatment of neuropsychiatric disorders described herein (e.g., depression, anxiety, etc.) the compound does not cause hallucinogenic symptoms.

[0089] It is understood that the terms “opiate” and “opioid” are distinct, in that “opiate” refers to natural products derived from the opium poppy, such as morphine, codeine and heroin, but “opioid” refers to these natural compounds as well as semi-synthetic and synthetic derivatives thereof, such as fentanyl and its analogs.

[0090] In a second aspect, the present disclosure provides a pharmaceutical composition (Composition 1.0) comprising a pharmaceutically effective amount of PDE1 inhibitor, e.g., any of a Compound of Formulas I, la, II, III, IV, V, VI and / or VII, and a pharmaceutically effective amount of a Compound of Formula VIII. For example, the present disclosure provides the following Compositions:1.1 Composition 1.0, wherein the Compound of Formula VIII is a compound wherein:(a) X is -N(H)- or -N(CH3)-, and Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;(b) X is -N(H)- and Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;(c) X is-N(CH3)- and Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;(d) X is -N(H)- or -N(CH3)-, and Y is -C(=O)-, or -C(H)(OH)-;(e) X is -N(H)- and Y is -C(=O)-, or -C(H)(OH)-;(f) X is -N(CH3)- and Y is -C(=O)-. or -C(H)(OH)-;(g) X is -N(H)- and Y is -C(=O)-;(h) X is -N(CH3)- and Y is -C(=O)-;(i) X is -N(CH3)- and Y is -C(H)(OH)-;(j) X is -N(CH3)- and Y is -C(H)(ORi)-;(k) X is -N(H)- or -N(CH3)-, and Y is -O-;(l) X is -N(H)- and Y is -O-; orIT-209-PCT / ICT1209WOPCT1(m)X is-N(CH3)- and Y is -0-; each in in free base or pharmaceutically acceptable salt form, and optionally in deuterated form.1.2 Any preceding composition, wherein the Compound formula VIII is the compoundin free base or pharmaceutically acceptable salt form, e.g. toluenesulfonic acid addition salt form.1.3 Any preceding composition, wherein the Compound formula VIII is selected from:IT-209-PCT / ICT1209WOPCT1wherein D represents a hydrogen position with substantially greater than natural deuterium incorporation (i.e., substantially greater than 0.0156%), e.g., greater than 60%, or greater than 70%. or greater than 80%, or greater than 90% or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%, each in free base or pharmaceutically acceptable salt form, e.g. toluenesulfonic acid addition salt form.1.4 Any preceding composition, wherein the Compound of Formula VIII is in free base form.1.5 Any preceding composition, wherein the Compound formula VIII is in pharmaceutically acceptable salt form, e.g., selected from toluenesulfonate, hydrochloride, bistosylate, besylate, 1 -naphthalenesulfonate, naphthalenedisulfonate, 4- octylbenzenesulfoate, 4-tert-butylbenzenesulfonate, 4-propylbenzenesulfonate, 4- ethylbenzenesulfonate, or 2-naphthalenesulfonate salt form, or another benzenesulfonate salt form wherein the benzenesulfonate is substituted by one, two, or three groups R,IT-209-PCT / ICT1209WOPCT1 wherein each R is independently a Ci-nalkyl group, preferably wherein the compound of Formula VIII is in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).1.6 Any preceding composition, wherein the Compound formula VIII in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).1.7 Any of Compositions 1.0-1.6, wherein the composition is in the form of a tablet.1.8 Any of Compositions 1.0- 1.6, wherein the composition is in the form of a capsule.1.9 Any of Compositions 1.0- 1.6, wherein the composition is in the form of an injectable composition (e.g., for intravenous, intramuscular, or subcutaneous injection).1.10 Any of Compositions 1.0-1.6, wherein the composition is in the form of a long- acting depot (e.g., a long-acting injectable composition, e.g., for intramuscular or subcutaneous injection).1.11 Any of Compositions 1.0- 1.6, wherein the composition is an intranasal formulation, e.g., in the form of a nasal spray or mister), or a pulmonary formulation, e.g., an inhaler).1.12 Any preceding composition, wherein the composition further comprises a pharmaceutically acceptable diluent or carrier.1.13 Any preceding composition, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII.1.14 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.1.15 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound according to the following:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1, or in free or pharmaceutically acceptable salt form.1.16 Any of Compositions 1.0-1.11, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.1.17 Any of Compositions 1.0-1.11, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.18 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT11.19 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.20 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.21 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.22 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.23 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT11.24 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.25 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.26 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.27 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.28 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.29 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.30 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.31 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.32 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.33 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.34 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1 in free or pharmaceutically acceptable salt form.1.35 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.36 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.37 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.38 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.39 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT11.40 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.41 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.42 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT11.43 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.44 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.45 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.46 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.1.47 Any of Compositions 1.0-1.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.1.46 Any preceding Composition, wherein the composition does not comprise any other antiemetic agents, e.g., any antipsychotic agents or D2 receptor antagonists, other than the Compound of Formula VIII (e.g., lumateperone).1.47 Any preceding Composition for use in a method of preventing or treating nausea and / or vomiting, e.g., in accordance with any of Method 1.0, et seq.

[0091] In another embodiment of the second aspect, the present disclosure provides a pharmaceutical composition (Composition 2.0) comprising a pharmaceutically effective amount of PDE1 inhibitor, e.g., any of a Compound of Formulas I, la, II, III, IV, V, VI and / or VII, and a pharmaceutically effective amount of a Compound of Formula IX. For example, the present disclosure provides the following Compositions:2.1 Composition 2.0, wherein the Compound of Formula IX is a compound wherein the compound is as described in any one of embodiments 2.0 or 2.14 to 2.154 above.IT-209-PCT / ICT1209WOPCT12.2 Any preceding composition, wherein the Compound of Formula IX is in free base form.2.3 Any preceding composition, wherein the Compound formula IX is in pharmaceutically acceptable salt form, e.g., selected from toluenesulfonate, and hydrochloride, preferably wherein the compound of Formula IX is in toluenesulfonate salt form (e.g.. monotosylate or bistosylate salt form).2.4 Any preceding composition, wherein the Compound formula IX in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).2.5 Any of Compositions 2.0-2.4, wherein the composition is in the form of a tablet.2.6 Any of Compositions 2.0-2.4, wherein the composition is in the form of a capsule.2.7 Any of Compositions 2.0-2.4, wherein the composition is in the form of an injectable composition (e.g., for intravenous, intramuscular, or subcutaneous injection).2.8 Any of Compositions 2.0-2.4, wherein the composition is in the form of a long- acting depot (e.g., a long-acting injectable composition, e.g., for intramuscular or subcutaneous injection).2.9 Any of Compositions 2.0-2.4, wherein the composition is an intranasal formulation, e.g., in the form of a nasal spray or mister), or a pulmonary formulation, e.g., an inhaler).2.10 Any preceding composition, wherein the composition further comprises a pharmaceutically acceptable diluent or carrier.2.11 Any preceding composition, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII.2.12 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.2.13 Any of Compositions 2.0-2.10. wherein the PDE1 inhibitor is a compound according to the following:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1, or in free or pharmaceutically acceptable salt form.2.14 Any of Compositions 2.0-2.9, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form, e.g., in monophosphate salt form.2.15 Any of Compositions 2.0-2.9, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.16 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT12.17 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.18 Any of Compositions 2.0-2.10. wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.19 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.20 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.21 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT12.22 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.23 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.24 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.25 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.26 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.27 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.28 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.29 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.30 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.31 Any of Compositions 2.0-2.10. wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.32 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1 in free or pharmaceutically acceptable salt form.2.33 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.34 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.35 Any of Compositions 2.0-2.10. wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.36 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.37 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT12.38 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.39 Any of Compositions 2.0-2.10. wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.40 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT12.41 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.42 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.43 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.44 Any of Compositions 2.0-2.10. wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.2.45 Any of Compositions 2.0-2.10, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.2.46 Any preceding Composition, wherein the composition does not comprise any other antiemetic agents, e.g., any antipsychotic agents or D2 receptor antagonists, other than the Compound of Formula IX.2.47 Any preceding Composition for use in a method of preventing or treating nausea and / or vomiting, e.g., in accordance with any of Method 2.0, et seq.

[0092] In another embodiment of the second aspect, the present disclosure provides a pharmaceutical composition (Composition 3.0) comprising a pharmaceutically effective amount of PDE1 inhibitor, e.g., any of a Compound of Formulas I, la, II, III, IV, V, VI and / or VII, and a pharmaceutically effective amount of an antiemetic agent. For example, the present disclosure provides the following Compositions:3.1 Composition 3.0, wherein the antiemetic agent is an antipsychotic agent, optionally wherein the antiemetic agent is an atypical antipsychotic agent.IT-209-PCT / ICT1209WOPCT13.2 Any preceding composition, wherein the antiemetic agent is a D2 antagonist, optionally wherein the antiemetic agent is a 5-HT2A / D2 antagonist.3.3 Any preceding composition, wherein the antiemetic agent is selected from the group consisting of promethazine, metoclopramide, benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine. chlorpromazine, cyamemazine, dixyrazine. fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol, thiothixene, zuclopenthixol, sulpiride, veralipride, carpipramine, clocapramine, clorotepine, clotiapine, loxapine, mosapramine. molindone, amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole. aripiprazole lauroxil, brexpiprazole. brilaroxazine. and cariprazine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.4 Any preceding composition, wherein the antiemetic agent is selected from the group consisting of amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone. perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.5 Any preceding composition, wherein the antiemetic agent is selected from asenapine, clozapine, olanzapine, quetiapine, and zotepine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.6 Any preceding composition, wherein the antiemetic agent is olanzapine, in free or pharmaceutically acceptable salt form, or a prodrug thereof.3.7 Any of Compositions 3.0-3.6, wherein the composition is in the form of a tablet.3.8 Any of Compositions 3.0-3.6, wherein the composition is in the form of a capsule.3.9 Any of Compositions 3.0-3.6, wherein the composition is in the form of an injectable composition (e.g., for intravenous, intramuscular, or subcutaneous injection).IT-209-PCT / ICT1209WOPCT13.10 Any of Compositions 3.0-3.6, wherein the composition is in the form of a long- acting depot (e.g., a long-acting injectable composition, e.g., for intramuscular or subcutaneous injection).3.11 Any of Compositions 3.0-3.6, wherein the composition is an intranasal formulation, e.g., in the form of a nasal spray or mister, or a pulmonary formulation, e.g., an inhaler).3.12 Any preceding composition, wherein the composition further comprises a pharmaceutically acceptable diluent or carrier.3.13 Any preceding composition, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formulas I, la, II, III, IV, V, VI, and / or VII.3.14 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a PDE1 inhibitor according to Formula la.3.15 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound according to the following:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1, or in free or pharmaceutically acceptable salt form.3.16 Any of Compositions 3.0-3.11, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form, e.g.. in monophosphate salt form.3.17 Any of Compositions 3.0-3.11, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1 in free or pharmaceutically acceptable salt form.3.18 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.19 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.20 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.21 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.22 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT13.23 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.24 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.25 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.26 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.27 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.28 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.29 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.30 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.31 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.32 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.33 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1 in free or pharmaceutically acceptable salt form.3.34 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.35 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.36 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1in free or pharmaceutically acceptable salt form.3.37 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.38 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT13.39 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.40 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.41 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:IT-209-PCT / ICT1209WOPCT1 in free or pharmaceutically acceptable salt form.3.42 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.43 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.44 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT13.45 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.46 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.3.47 Any of Compositions 3.0-3.12, wherein the PDE1 inhibitor is a compound as follows:in free or pharmaceutically acceptable salt form.IT-209-PCT / ICT1209WOPCT13.46 Any preceding Composition, wherein the composition does not comprise lumateperone, in free or pharmaceutically acceptable salt form, or a prodrug or analog thereof.3.47 Any preceding Composition for use in a method of preventing or treating nausea and / or vomiting, e.g., in accordance with any of Method 3.0, el seq.Combination Therapies with PDE1 Inhibitors

[0093] In the present disclosure, the PDE1 inhibitor may be administered in combination with the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent. For example, a patient may be administered the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent in combination with any of the disclosed PDE1 inhibitors.

[0094] Combinations may be achieved by administering a single composition or pharmacological formulation (e.g., dosage form) that includes the PDE1 inhibitor and the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent, or by administration of two distinct compositions or formulations (e.g., dosage forms), separately, simultaneously or sequentially, wherein one composition, formulation, or dosage form comprises the PDE1 inhibitor and the other composition, formulation, or dosage form comprises the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent. The therapy using a PDE1 inhibitor may precede or follow administration of the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent by intervals ranging from minutes to weeks. In embodiments where the PDE1 inhibitor and the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent are applied separately to the subject or patient, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the PDE1 inhibitor and the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent would still be able to exert an advantageously combined effect on the subject or patient. In some embodiments, it is contemplated that one would typically administer both the PDE1 inhibitor and the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent within about 12-24 hours of each other and, more preferably, within about 6-12 hours of each other, with a delay time of only about 12 hours being most preferred. In some situations, it may be desirable to extend the time period forIT-209-PCT / ICT1209WOPCT1 treatment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1 , 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.

[0095] It also is conceivable that more than one administration of either the PDE1 inhibitor, or the Compound of Formula VIII or the Compound of Formula IX will be desired. In this regard, various combinations may be employed. By way of illustration, where the PDE1 inhibitor is “A” and the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent is “B,” the following permutations based on 3 and 4 total administrations are exemplary:

[0096] Accordingly, in various embodiments, the present disclosure also provides a pharmaceutical combination therapy comprising a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a compound according to any of Formula I, II, III, IV, V, VI and / or VII) and a pharmaceutically effective amount of the Compound of Formula VIII or the Compound of Formula IX or the antiemetic agent for administration in a method of preventing or treating nausea and / or vomiting, e.g., in accordance with any of Method 1.0, et seq., or Method 2.0, et seq., or Method 3.0, et seq.Methods of Making Compounds of the Disclosure

[0097] Methods of synthesizing lumateperone and related compounds, and salts and cocrystals thereof, are known in art. and include the methods disclosed in U.S. Patents Nos. 6,552,017, 6,548,493, 7,071,186, 7,183,282, 7,238,690, 8,309,722, 8,779,139; 9,315,504, 9,751,883, 10,077,267, 10,221,176, 10,464,938, 10,597,394, 10,597,395, 10,654,854, 10,688,097, 10,899,762, 11,014,925. 11.066,407, 11,096,944, RE39,679. and U.S. RE39,680; and US 2020 / 0102309, US 2020 / 0157100, and US 2020 / 0247805, the contents of each of which are incorporated by reference in their entirety.

[0098] Methods of synthesizing fused heterocycle gamma carboline compounds, such as the Compounds of Formula IX, and salts and co-crystals thereof, are known in art, and include the methods disclosed in U.S. Patents Nos. 6,552,017, 6,548,493, 7,071,186, 7,183,282,IT-209-PCT / ICT1209WOPCT17,238,690, 8,309,722, 8,779,139; 9,315,504, 9,751 ,883, 10,077,267, 10,221 ,176, 10,464,938, 10,597,394, 10,597,395, 10,654,854, 10,688,097, 10,899,762, 11,014,925, 11,066,407, 11,096.944, RE39.679, and U.S. RE39.680; and US 2020 / 0102309, US 2020 / 0157100, and US 2020 / 0247805, the contents of each of which are incorporated by reference in their entirety. Compounds of Formula IX of the present disclosure may also be prepared using the methods described in WO 2024 / 145659. in U.S. Provisional Application No. 63 / 667,517. filed on July 3, 2024, and in PCT / US2025 / 36531, filed on July 2, 2025, the contents of each of which are hereby incorporated by reference in their entireties.

[0099] The PDE1 inhibitors of the Disclosure and their pharmaceutically acceptable salts may be made using the methods as described and exemplified in U.S. 8,273,750, US 2006 / 0173878. U.S. 8,273,751. US 2010 / 0273753, U.S. 8,697,710, U.S. 8,664,207, U.S.8,633,180, U.S. 8,536,159, US 2012 / 0136013, US 2011 / 0281832, US 2013 / 0085123, US 2013 / 0324565, US 2013 / 0338124, US 2013 / 0331363, WO 2012 / 171016, and WO 2013 / 192556, and by methods similar thereto and by methods known in the chemical art. Such methods include, but are not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.

[0100] Various PDE1 inhibitors and starting materials therefor may be prepared using methods described in US 2008-0188492 Al, US 2010-0173878 Al. US 2010-0273754 Al, US 2010-0273753 Al, WO 2010 / 065153, WO 2010 / 065151, WO 2010 / 065151, WO 2010 / 065149, WO 2010 / 065147, WO 2010 / 065152, WO 2011 / 153129, WO 2011 / 133224, WO 2011 / 153135, WO 2011 / 153136. WO 2011 / 153138. All references cited herein are hereby incorporated by reference in their entirety.Dosages

[0101] The PDE1 inhibitors may be administered by any suitable route, including orally, parenterally (intravenously, intramuscular or subcutaneous), transdermally, or by inhalation (e.g., nasal spray or inhaler), preferably administered orally. In certain embodiments, PDE1 inhibitors, e.g., in depot formulation, are preferably administered parenterally, e.g., by injection.

[0102] In general, satisfactory results, e.g., for preventing or treating nausea and / or vomiting, may be obtained on administration (e.g., oral administration) of a PDE1 inhibitor at dosages of from about 0.01 to 2.0 mg / kg. In larger mammals, for example humans, an indicatedIT-209-PCT / ICT1209WOPCT1 daily dosage for oral administration of a PDE1 inhibitor will accordingly be in the range of from about 0.50 to 300 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for administration (e.g., oral administration) thus, for example, may comprise from about 0.2 to 150 or 300 mg, e.g., from about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, or 200 mg, from about 1 to 100 mg, from about 1 to 50 mg, from about 1 to 10 mg, from about 5 to 10 mg, from about 10 to 50 mg, 1 mg, 3 mg, 5 mg, 10 mg, 30 mg, or 90 mg, of a PDE1 inhibitor, together with a pharmaceutically acceptable diluent or carrier therefor.

[0103] The Compounds of Formula VIII and IX may be administered by any suitable route, including orally, parenterally (intravenously, intramuscular or subcutaneous), transdermally, or by inhalation (e.g., nasal spray or inhaler), preferably administered orally. In certain embodiments, the Compounds of Formula VIII and IX, e.g., in depot formulation, are preferably administered parenterally, e.g., by injection.

[0104] In general, satisfactory results, e.g., for preventing or treating nausea and / or vomiting, are indicated to be obtained on administration (e.g., oral administration) of Compounds of Formula VIII, e.g., lumateperone (e.g., lumateperone tosylate), at dosages of the order from about 0.01 to 2.0 mg / kg. In larger mammals, for example humans, an indicated daily dosage for oral administration of the Compound of Formula VIII will accordingly be in the range of from about 0.50 to 300 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for administration (e.g., oral administration) thus for example may comprise from about 0.2 to 150 or 300 mg, e.g., from about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, or 200 mg, from about 1 to 100 mg, from about 1 to 50 mg, from about 1 to 10 mg, from about 5 to 10 mg, from about 10 to 50 mg, 1 mg, 3 mg, 5 mg, 10 mg, 30 mg, or 90 mg, of Compounds of Formula VIII, together with a pharmaceutically acceptable diluent or carrier therefor. Preferably, Compounds of Formula VIII, e.g., lumateperone (e.g., lumateperone tosylate), for treatment of a human patient, are administered using daily administration of an oral dosage form (e.g., capsule or tablet) comprising 5 to 50 mg of the Compound of Formula VIII (e.g., lumateperone), measured as the free base equivalent, e.g., 5-15 mg, or 15-25 mg, or 25-45 mg, or about 10.5 mg, or about 21 mg, or about 42 mg.

[0105] In general, satisfactory results, e.g., for preventing or treating nausea and / or vomiting, are indicated to be obtained on administration (e.g., oral administration) of Compounds of Formula IX, at dosages of the order from about 0.01 to 2.0 mg / kg. In largerIT-209-PCT / ICT1209WOPCT1 mammals, for example humans, an indicated daily dosage for oral administration of the Compound of Formula IX will accordingly be in the range of from about 0.50 to 300 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for administration (e.g., oral administration) thus for example may comprise from about 0.2 to 150 or 300 mg, e.g., from about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, or 200 mg, from about 1 to 100 mg, from about 1 to 50 mg, from about 1 to 10 mg, from about 5 to 10 mg, from about 10 to 50 mg, 1 mg, 3 mg, 5 mg, 10 mg, 30 mg, or 90 mg, of Compounds of Formula IX, together with a pharmaceutically acceptable diluent or carrier therefor. Preferably, Compounds of Formula IX, for treatment of a human patient, are administered using daily administration of an oral dosage form (e.g., capsule or tablet) comprising 5 to 50 mg of the Compound of Formula IX, measured as the free base equivalent, e.g., 5-15 mg, or 15-25 mg, or 25-45 mg, or about 10.5 mg, or about 21 mg, or about 42 mg.

[0106] In general, satisfactory results, e.g., for preventing or treating nausea and / or vomiting, are indicated to be obtained on administration (e.g., oral administration) of antiemetic agents, e.g., olanzapine, at dosages of the order from about 0.01 to 2.0 mg / kg. In larger mammals, for example humans, an indicated daily dosage for oral administration of antiemetic agents will accordingly be in the range of from about 0.50 to 300 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for administration (e.g., oral administration) thus for example may comprise from about 0.2 to 150 or 300 mg, e.g., from about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, or 200 mg, from about 1 to 100 mg, from about 1 to 50 mg, from about 1 to 10 mg, from about 5 to 10 mg, from about 10 to 50 mg, 1 mg, 3 mg, 5 mg, 10 mg, 30 mg, or 90 mg, of antiemetic agents, together with a pharmaceutically acceptable diluent or carrier therefor.

[0107] Pharmaceutical compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions and the like.

[0108] The term “pharmaceutically acceptable diluent or carrier” is intended to mean diluents and carriers that are useful in pharmaceutical preparations, and that are free of substances that are allergenic, pyrogenic or pathogenic, and that are known to potentially cause or promote illness. Pharmaceutically acceptable diluents or earners thus exclude bodily fluids such as example blood, urine, spinal fluid, saliva, and the like, as well as their constituentIT-209-PCT / ICT1209WOPCT1 components such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in any of several well-known treatises on pharmaceutical formulations, for example Anderson, Philip O.; Knoben, James E.; Troutman, William G. eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed.. Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s Pharmaceutical Sciences, 20thEd., Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

Claims

IT-209-PCT / ICT1209WOPCT1CLAIMS1. A method of preventing or treating nausea and / or vomiting (e.g. CINV), comprising administering a Compound of Formula VIII (e.g., lumateperone), optionally in combination with a pharmaceutically effective amount of a PDE1 inhibitor to a subject in need thereof.

2. A method of preventing or treating nausea and / or vomiting (e.g. CINV), comprising administering a Compound of Formula IX, optionally in combination with a pharmaceutically effective amount of a PDE1 inhibitor to a subject in need thereof.

3. A method of preventing or treating nausea and / or vomiting (e.g. CINV), comprising administering a pharmaceutically effective amount of a PDE1 inhibitor in combination with a pharmaceutically effective amount of an antiemetic agent to a subject in need thereof.

4. The method of claim 1, wherein the Compound formula VIII is a compound wherein:(a) X is -N(H)- or -N(CH3)-, and Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;(b) X is -N(H)- and Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;(c) X is-N(CH3)- and Y is -C(=O)-, -C(H)(OH)- or -C(H)(ORi)-;(d) X is -N(H)- or -N(CH3)-, and Y is -C(=O)-, or -C(H)(OH)-;(e) X is -N(H)- and Y is -C(=O)-, or -C(H)(OH)-;(f) X is -N(CH3)- and Y is -C(=O)-, or -C(H)(OH)-;(g) X is -N(H)- and Y is -C(=O)-;(h) X is -N(CH3)- and Y is -C(=O)-;(i) X is -N(CH3)- and Y is -C(H)(OH)-;(j) X is -N(CH3)- and Y is -C(H)(ORi)-;(k) X is -N(H)- or -N(CH3)-, and Y is -O-;(l) X is -N(H)- and Y is -O-; or(m)X is-N(CH3)- and Y is -O-; each in in free base or pharmaceutically acceptable salt form, and optionally in deuterated form.

5. The method of claim 1, wherein the Compound of Formula VIII is the compound:IT-209-PCT / ICT1209WOPCT1in free base or pharmaceutically acceptable salt form, e.g. toluenesulfonic acid addition salt form.

6. The method of claim 1, wherein the Compound of Formula VIII is selected from:IT-209-PCT / ICT1209WOPCT1wherein D represents a hydrogen position with substantially greater than natural deuterium incorporation (i.e., substantially greater than 0.0156%), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90% or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%, each in free base or pharmaceutically acceptable salt form, e.g. toluenesulfonic acid addition salt form.

7. The method of claim 2, wherein the Compound formula IX is a compound wherein:Formula IX wherein:X is S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N-C(O)-Ra, N- C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O~), a spiro-joined C3. ecycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from Ci ealkyl (e.g., methyl), haloCi-ealkyl (e.g., trifluoromethyl), Ci-ealkoxy (e.g., methoxy), C3. ecycloalkyl (e.g., cyclopropyl), C3-ecycloalkoxy (e.g., cyclopropoxy), and hydroxy;IT-209-PCT / ICT1209WOPCT1Y is CH2, CHRC, -C(0)-, C(RC)2, a spiro-joined Cs-ecycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined Cs-ecycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from Ci ealkyl (e.g., methyl), haloCi ealkyl (e.g., trifluoromethyl), Ci-6alkoxy (e.g., methoxy), Cs-ecycloalkyl (e.g., cyclopropyl), C3- ecycloalkoxy (e.g., cyclopropoxy), and hydroxy;Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(Rd), -C(O)-, -C(OH)-, C(OCi-6alkyl), -C(=N- OH)-, -C(=N-OCi-6alkyl)-, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), a spiro- joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -0(CH2)P0- wherein p is 2, 3, or 4 (e.g., p is 2), wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is optionally substituted by one or more groups selected from Ci-ealkyl (e.g., methyl), haloCi-ealkyl (e.g., trifluoromethyl), Ci-ealkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy;A is H, C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), aryl (e.g., phenyl) or heteroaryl, wherein said cycloalkyl, aryl or heteroaryl is substituted by 0-5 groups R; each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), Ci-6alkyl (e.g., methyl, ethyl), haloCi-6alkyl (e.g., trifluoromethyl), Ci-ealkylsulfonyl (e.g., methylsulfonyl), Ci-ealkoxy (e.g., methoxy, ethoxy), Ci-6alkylthio (e.g., methylthio), halo (e.g., F), cyano. Cs-ecycloalkyl (e.g., cyclopropyl), Cs-ecycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is optionally further substituted by one or more groups selected from aryl (optionally substituted with halo), halo, Ci ealkyl (e.g., methyl), haloCi ealkyl (e.g., trifluoromethyl), Ci-ealkylsulfonyl (e.g., methylsulfonyl), Ci-ealkoxy (e.g., methoxy), Ci- ealkylthio (e.g., methylthio), C3-ecycloalkyl (e.g., cyclopropyl), C3-ecycloalkoxy (e.g., cyclopropoxy), amino, Ci -ealkylamino (e.g., methylamino), di(Ci-ealkyl)amino (e.g., dimethylamino), (Ci-6alkyl)(Ci-ealkyl)amino (e.g., methylethylamino), and hydroxy;Raand Rd, are each independently selected from Ci-2oalkyl (e.g., methyl or tert-butyl), and Ci-2alkylaryl (e.g., benzyl or phenethyl);IT-209-PCT / ICT1209WOPCT1Rband Rcare each independently selected from Ci-ealkyl (e.g., methyl, ethyl, tert-butyl), Ci-6alkoxy, Cs ecycloalkyl (e.g., cyclopropyl), Cs ecycloalkoxy (e.g., cyclopropoxy), and Ci-2alkylaryl (e.g.. benzyl or phenethyl); m is 1 or 2; and n is 1, 2, 3, 4, or 5 (e.g., 2 or 3); each in in free base or pharmaceutically acceptable salt form.

8. The method of any one of claims 1-7, wherein the Compound of Formula VIII or the Compound of Formula IX is in free base form.

9. The method of any one of claims 1-7, wherein the Compound of Formula VIII or the Compound of Formula IX is in pharmaceutically acceptable salt form, e.g., wherein the Compound of Formula VIII is in salt form selected from toluenesulfonate, hydrochloride, bistosylate. besylate, 1 -naphthalenesulfonate, naphthalenedisulfonate. 4- octylbenzenesulfoate, 4-tert-butylbenzenesulfonate, 4-propylbenzenesulfonate, 4- ethylbenzenesulfonate, or 2-naphthalenesulfonate salt form, or another benzenesulfonate salt form wherein the benzenesulfonate is substituted by one, two, or three groups R, wherein each R is independently a Ci-i2alkyl group, preferably wherein the compound of Formula VIII is in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).

10. The method of claim 9, wherein the Compound of Formula VIII or the Compound of Formula IX is in toluenesulfonate salt form (e.g., monotosylate or bistosylate salt form).

11. The method of claim 1, wherein the Compound of Formula VIII is the compound:in toluenesulfonic acid addition salt form.IT-209-PCT / ICT1209WOPCT112. The method of claim 3, wherein the antiemetic agent is an antipsychotic agent, e.g., an atypical antipsychotic agent.

13. The method of claim 3, wherein the antiemetic agent is a D2 antagonist or wherein the antiemetic agent is a 5-HT2A / D2 antagonist, optionally wherein the antiemetic agent is selected from the group consisting of promethazine, metoclopramide, benperidol, bromperidol. droperidol, haloperidol, moperone, pipamperone, timiperone. fluspirilene. penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol, thiothixene, zuclopenthixol, sulpiride, veralipride, carpipramine. clocapramine, clorotepine, clotiapine, loxapine, mosapramine, molindone, amisulpride, nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone. melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof.

14. The method of claim 3, wherein the antiemetic agent is selected from the group consisting of amisulpride. nemonapride, remoxipride, suitopride, iloperidone, paliperidone, perospirone, risperidone, ziprasidone, lurasidone, melperone, lumateperone, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin, sertindole, aripiprazole, aripiprazole lauroxil, brexpiprazole, brilaroxazine, and cariprazine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof, optionally wherein the antiemetic agent is selected from asenapine, clozapine, olanzapine, quetiapine, and zotepine, each in free or pharmaceutically acceptable salt form, or a prodrug thereof; and further optionally wherein the antiemetic agent is olanzapine, in free or pharmaceutically acceptable salt form, or a prodrug thereof.

15. The method of any of the preceding claims, wherein the nausea and / or vomiting is caused by cancer treatment (e.g., chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy, bone marrow or stem cell transplant), advanced cancer, brain cancer, pregnancy, motion sickness, migraines, or food poisoning.IT-209-PCT / ICT1209WOPCT116. The method of any of the preceding claims, wherein the nausea and / or vomiting is chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), or postoperative nausea and vomiting (PONV).

17. The method of any of claims 1, 2, or 4-11, wherein the method does not comprise administration of a PDE1 inhibitor.

18. The method according to any of claims 1-16, wherein the method comprises administration of a PDE1 inhibitor, and wherein the PDE1 inhibitor is a compound selected from:(A) Formula I:Formula I wherein(i) Ri is H or Ci-4 alkyl (e.g.. methyl);(ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H, C1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl (e.g., R2 and R3 are both methyl, or R2 is H and R3 is isopropyl); orR2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge(pref, wherein the R3 and R4 together have the cis configuration, e.g., where the carbons carrying R3 and R4 have the R and S configurations, respectively);(iii) R5 is a substituted heteroarylalkyl, e.g., substituted with haloalkyl; or R5 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula AIT-209-PCT / ICT1209WOPCT1Formula A wherein X, Y and Z are, independently, N or C, and Rs, R9, R11 and R12 are independently H or halogen (e.g., Cl or F), and Rio is halogen, alkyl, cycloalkyl, haloalkyl (e.g.. trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl) optionally substituted with halogen, thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl), diazolyl, triazolyl, tetrazolyl), arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, Rs, R9, or Rio, respectively, is not present;(iv) Re is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N- (arylalkyl)amino (e.g., N-phenyl-N-(l,l’-biphen-4-ylmethyl)amino); and(v) n=0 or 1 ;(vi) provided that when n=l, A is -C(RI3RM)- wherein R13 and RM, are, independently, H, C1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl; in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;IT-209-PCT / ICT1209WOPCT1(B) Formula IT:wherein(i) X is Ci-6alkylene (e.g., methylene, ethylene or prop-2-yn-l-ylene);(ii) Y is a single bond, alkynylene (e.g., — C=C — ), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene);(iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloCi-ealkyl (e.g., trifluoromethyl), — C(O) — R1, — N(R2)(R3), or Cs-vcycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);(iv) R1is Ci-ealkyl, haloCi-ealkyl, — OH or — OCi-ealkyl (e.g., — OCH3);(v) R2and R3are independently H or Ci-ealkyl;(vi) R4and R5are independently H, Ci-ealkyl, or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl), or Ci-ealkoxy; and(vii) wherein X, Y and Z are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), Ci-ealkyl (e.g., methyl), or haloCi-ealkyl (e.g., trifluoromethyl), for example, Z is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6- fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4- fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloCi-ealkyl (e.g., 5-trifluoromethylpyrid-2-yl), or Ci-6-alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl),IT-209-PCT / ICT1209WOPCT1 in free, salt, or prodrug form e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(C) Formula III:Formula III wherein(i) Ri is H or C1-4 alkyl (e.g., methyl or ethyl);(ii) R2 and R3 are independently H or C1-6 alkyl (e.g., methyl or ethyl);(iii) R4 is H or C1-4 alkyl (e.g., methyl or ethyl);(iv) R5 is aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from -C(=O)-Ci-6 alkyl (e.g., -C(=O)-CH3) and C1-6 -hydroxyalkyl (e.g., 1- hydroxy ethyl);(v) Re and R7 are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6 alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F), or phenyl substituted with one or more C1-6 alkyl and one or more halogen, or phenyl substituted with one C1-6 alkyl and one halogen, for example. 4- fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and(vi) n is 1, 2, 3, or 4,IT-209-PCT / ICT1209WOPCT1 in free, salt, or prodrug form e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(D) Formula IVFormula IV in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof, wherein:(i) Ri is Ci-4alkyl (e.g., methyl or ethyl), or -NH(R2), wherein R2 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) X, Y and Z are, independently, N or C;(iii) R3, R4 and R5 are independently H or Ci-4alkyl (e.g., methyl); or R3 is H and R4 and R5 together form a tri-methylene bridge (pref, wherein the R4 and R5 together have the cis configuration, e.g., where the carbons carrying R4 and R5 have the R and S configurations, respectively),(iv) Re, R7 and Rs are independently H, Ci-4alkyl (e.g., methyl), pyrid-2-yl substituted with hydroxy, or -S(O)2-NH2; provided that when X, Y and / or Z are N, then Re, R7 and / or Rs, respectively, are not present; and when X, Y and Z are all C, then at least one of Re, R7 or Rs is -S(O)2-NH2 or pyrid-2-yl substituted with hydroxy;IT-209-PCT / ICT1209WOPCT1(E) Formula la:wherein(i) R2 and R5 are independently H or hydroxy and R3 and R4 together form a tri- or tetramethylene bridge [pref, with the carbons carrying R3 and R4 having the R and S configuration respectively]; or R2 and R3 are each methyl and R4 and R5 are each H; or R2, R4 and R5 are H and R3 is isopropyl [pref, the carbon carrying R having the R configuration];(ii) Re is (optionally halo-substituted or hydroxy-substituted) phenylamino, (optionally halo- substituted or hydroxy-substituted) benzylamino, Ci-4alkyl, or Ci-4alkyl sulfide, for example, phenylamino or 4-fluorophenylamino;(iii) Rio is Ci-4alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl (for example 6-fluoropyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl), or Rio is -CH(CH3)-0- C(O)-Rn, wherein Rn is C1-6 alkyl (e.g., methyl, ethyl, or propyl), or Rio is saturated or unsaturated heterocycloalkyl comprising one or more oxygens or nitrogens (e.g.. saturated or unsaturated 3-5 membered heterocycloalkyl comprising one or more oxygens or nitrogens, e.g., tetrahydrofuryl, dihydrofuryl, or aziridyl), or Rio is -C(=O)-Xi, wherein Xi is saturated or unsaturated heterocycloalkyl comprising one or more oxygens or nitrogens (e.g., saturated or unsaturated 3-5 membered heterocycloalkyl comprising one or more oxygens or nitrogens, e.g., tetrahydrofuryl, dihydrofuryl, or aziridyl); and(iv) X and Y are independently CH or N,IT-209-PCT / ICT1209WOPCT1 in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(F) Formula Vwherein(i) Ri is -NH(R.4), wherein R4 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) R2 is H or Ci-6alkyl (e.g., methyl, isobutyl or neopentyl); and(iii) R3is -SO2NH2 or -COOH; in free, salt, or prodrug form e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof;(G) Formula VIwhereinIT-209-PCT / ICT1209WOPCT1(i) Ri is -NH(R4), wherein R4 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;(ii) R2 is H or Ci-ealkyl (e.g., methyl or ethyl); and(iii) R3 is H, halogen (e.g., bromo), Ci ealkyl (e.g., methyl), aryl optionally substituted with halogen (e.g., 4-fluorophenyl), heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl), or acyl (e.g., acetyl); in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof, and(H) Formula VIIwherein(i) Ri is H or C1-4 alkyl (e.g., methyl or ethyl);(ii) R2 and R3 are independently H or C1-6 alkyl (e.g., methyl or ethyl);(iii) R4 is H or C1-4 alkyl (e.g., methyl or ethyl);(iv) Rs is aryl (e.g., phenyl) substituted with -C(=O)-CD3, wherein D is deuterium(2H);(v) Re and R7 are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from C1-6 alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F) or phenyl substituted with one or more C1-6 alkyl and one or more halogen or phenyl substituted with one C1-6 alkyl and one halogen, for example 4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3- methylphenyl; and(vi) n is 1, 2, 3, or 4,IT-209-PCT / ICT1209WOPCT1 in free, salt, or prodrug form, e.g., pharmaceutically acceptable salt form, including enantiomers, diastereomers, and racemates, thereof.

19. The method according to any of claims 1-18, wherein the PDE1 inhibitor is selected from any of the following:IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1IT-209-PCT / ICT1209WOPCT1, or in free or pharmaceutically acceptable salt form.

20. A pharmaceutical combination therapy comprising a pharmaceutically effective amount of a PDE1 inhibitor and a pharmaceutically effective amount of a Compound of Formula VIII or a Compound of Formula IX or an antiemetic agent for administration in a method according to any of claims 1-19; orIT-209-PCT / ICT1209WOPCT1 a pharmaceutical composition comprising a pharmaceutically effective amount of PDE1 inhibitor and a pharmaceutically effective amount of a Compound of Formula VIII or a Compound of Formula IX or an antiemetic agent, optionally wherein the composition is in the form of an oral dosage form (such as a tablet or capsule), an intranasal dosage form (e.g., a nasal spray or mister), a pulmonary dosage form (e.g., an inhaler), or an injectable dosage form (e.g.. an intravenous, intramuscular or subcutaneous injection, such as a long-acting depot injection)

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