Piperidine carboxamide fatty acid prodrugs

Abstract

The present invention relates to compounds of Formula (I) and their use as prodrugs, in particular long-acting prodrugs. The compounds of Formula (I) are prodrugs of piperidine carboxamide medicaments, among which pipamperone.

Description

[0001] PIPERIDINE CARBOXAMIDE FATTY ACID PRODRUGS

[0002] Field of the invention

[0003] The present invention relates to the field of pharmacologically active compounds, in particular prodrugs of pharmacologically active compounds.

[0004] Background

[0005] Prodrugs of pharmaceutically active compounds typically undergo a biotransformation process in the body to release the active drug. The use of prodrugs offers several advantages in the field of drug development and therapy. Prodrugs can enhance the bioavailability of a drug by improving its solubility, stability, and absorption. This can lead to better therapeutic outcomes and more predictable drug delivery. Additionally, prodrugs can be designed to minimize side effects by targeting drug release to specific tissues or cells. This targeted delivery helps to reduce the exposure of non-target tissues to the active drug, resulting in fewer adverse effects. Further, prodrugs can improve the chemical stability of a drug, allowing for better formulation and storage.

[0006] An important aspect of prodrug development includes an extended duration of action: Prodrugs can be designed to have a prolonged or sustained release of the active drug, leading to a more sustained therapeutic effect and potentially reducing the frequency of dosing. An important beneficial consequence may be improved patient compliance or enhanced patient acceptance, leading to better compliance with medication regimens. In addition, medication regimes may be simplified and medication burden may be reduced.

[0007] Despite these advantages, the design and development of prodrugs require a thorough understanding of the pharmacokinetics, pharmacodynamics, and metabolism of the parent drug. Moreover, the chemical structure of the parent drug itself may pose serious restrictions on prodrug design and feasibility.

[0008] Pipamperone is a piperidine carboxamide drug originally described in US3041344. It belongs to the butyrophenone class of compounds. Several of the butyrophenone compounds, among which pipamperone, have been described as active ingredients in the treatment of various psychiatric disorders, among which psychotic disorders.

[0009] Summary

[0010] It is an object of the present invention to provide prodrugs of piperidine carboxamide drugs, such as pipamperone.

[0011] The present invention in particular relates to compounds of Formula I as well as stereoisomers, enantiomers, tautomers, solvates, hydrates, or pharmaceutically acceptable salt thereof: wherein, moiety A is selected from the group consisting of di-C1-4alkylamino, morpholinyl or a 4 to 7-membered nitrogen-containing heterocyclyl optionally substituted with one or more C1-4alkyl, preferably dimethylamino, pyrrolidinyl, di methylpyrrolidinyl , piperidyl, dimethylpiperidyl or morpholinyl;

[0012] L1is -(CR1aR1b)r~; r is an integer selected from 1, 2, and 3; each R1ais selected from the group consisting of hydrogen, halogen or Ci. ealkyl; each R1bis selected from the group consisting of hydrogen, halogen or C1- ealkyl;

[0013] R1is hydrogen or -C(O)R7;

[0014] R2is selected from R4is selected from phenyl or thienyl; wherein said phenyl or thienyl can be unsubstituted or substituted with one or more R4a; each R4ais selected from the group consisting of halogen, C1-6alkyl, and C1- ealkoxy;

[0015] R5is phenyl or thienyl; wherein said phenyl or thienyl can be unsubstituted or substituted with one or more R5a; each R5ais selected from the group consisting of halogen, C1-6alkyl and C1- ealkoxy;

[0016] R6is -C(O)R10;

[0017] R7is selected from the group consisting of C1-20alkyl, C2-20alkenyl, C3- locycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; wherein said C1- 2oalkyl, C2-20alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1- ealkyl can be unsubstituted or substituted with one, two or three R7a;

[0018] R10is selected from the group consisting of C1-20alkyl, C2-20alkenyl, C3- locycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; wherein said C1- 2oalkyl, C2-20alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylCi.6alkyl can be unsubstituted or substituted with one, two or three R10a; each R7ais selected from the group consisting of hydrogen, halogen, C1- ealkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, haloC1-6alkyloxy, cyanoC1-6alkyl, C1-6alkoxy, cyano, hydroxy, -NR13R14, -NR13S(O)2R15, -NR13C(O)2R15, -C(O)R15, - C(O)2R15, -S(O)nR15(wherein n = 0, 1 , or 2), C6-12aryl, and C1-6alkyl C6-12aryl; each R10ais selected from the group consisting of is selected from the group consisting of hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, haloC1-6alkyloxy, cyanoC1-6alkyl, C1-6alkoxy, cyano, hydroxy, -NR13R14, - NR13S(O)2R15, -NR13C(O)2R15, -C(O)R15, -C(O)2R15, -S(O)nR15(wherein n = 0, 1 , or 2), C6-12aryl, and C1-6alkylC6-12aryl; each R13is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or C1-6alkyl; each R14is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or C1-6alkyl; each R15is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or Ci -ealkyl ;

[0019] R4Y>' wherein when R1is hydrogen, then R2is not0, or wherein when

[0020] R1is hydrogen then R2is

[0021] The present inventors have surprisingly found that compounds of Formula I not only can be synthesised, in particular in sufficient purity, and having desired physicochemical, pharmacokinetic, and pharmacodynamic properties, including (chemical) stability and solubility, but advantageously function as (long acting) prodrugs, in particular (long acting) prodrugs of compounds of Formula II (including compounds of Formula IIA and I IB, as described herein elsewhere) wherein R2ais selected from and wherein moiety A, L1, R1,

[0022] R4and R5are as defined herein. Preferably, R4and R5are identical. Preferably, R4aand R5aare identical. Preferably, R4and R5are identical and R4aand R5aare identical.

[0023] In a preferred embodiment, the compounds of Formula I are prodrugs of pipamperone.

[0024] The present inventors have found that compounds of Formula I are slowly metabolized and hence can be used as bona fide long acting prodrugs. More importantly, and unexpectedly, metabolism of the compounds of Formula I effectively and predominantly results in compounds of Formula II. The regioselective hydrolysis of the compounds of Formula I into compounds of Formula II is a surprising finding, which could not have been expected a priori. Without wishing to be bound by theory, the backbone of the compounds of Formula II may provide sufficient steric hindrance to allow for the regioselective / regiospecific hydrolysis of the prodrug to specifically yield the active compound. Furthermore, the compounds of Formula I are primary amides (primary carboxamides), which are not typical moieties for designing prodrugs and the desired physicochemical, pharmacokinetic, and pharmacodynamic properties, including synthesis, (aqueous) stability, and solubility, but also the aforementioned stereoselective hydrolysis, are uncharted and cannot be reliably predicted, least of all in the context of long acting prodrugs.

[0025] The present invention further relates to pharmaceutical compositions comprising the compound of Formula I, as well as the compound of Formula I or the pharmaceutical composition comprising the compound of Formula I for use in therapy.

[0026] The present invention further relates to methods for producing the compound of Formula I.

[0027] Drawings

[0028] Figure 1 : Pipamperone prodrugs according to embodiments of the invention.

[0029] Figure 2: Metabolic pathways of a compound according to an embodiment of the invention.

[0030] Figure 3: Metabolic pathways of a compound according to an embodiment of the invention.

[0031] Detailed description

[0032] Before the aspects and embodiments of the present invention are described, it is to be understood that this invention is not limited to particular systems and methods or combinations described, since such systems and methods and combinations may, of course, vary. It is also to be understood that the terminology used herein is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.

[0033] The terms “comprising”, “comprises” and “comprised of’ as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. It will be appreciated that the terms “comprising”, “comprises” and “comprised of” as used herein comprise the terms “consisting of’, “consists” and “consists of”, as well as the terms “consisting essentially of”, “consists essentially” and “consists essentially of”.

[0034] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

[0035] The term “about” or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of + / -20% or less, preferably + / -10% or less, more preferably + / - 5% or less, and still more preferably + / -1 % or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier “about” or “approximately” refers is itself also specifically, and preferably, disclosed.

[0036] Whereas the terms “one or more” or “at least one”, such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members.

[0037] All references cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references herein specifically referred to are incorporated by reference.

[0038] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

[0039] In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0040] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some, but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

[0041] In the following detailed description of the invention, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration only of specific embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilised, and structural or logical changes may be made without departing from the scope of the present invention. The following detailed description, therefore, is not to be taken in a limiting sense, and the scope of the present invention is defined by the appended claims.

[0042] Preferred statements (features) and embodiments of this invention are set herein below. Each statements and embodiments of the invention so defined may be combined with any other statement and / or embodiments unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features or statements indicated as being preferred or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below numbered aspects and embodiments with any other statement and / or embodiments.

[0043] 1. A compound of Formula I, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof: wherein, moiety A is selected from the group consisting of di-C1-4alkylamino, morpholinyl or a 4 to 7-membered nitrogen-containing heterocyclyl optionally substituted with one or more C1-4alkyl, preferably dimethylamino, pyrrolidinyl, di methylpyrrolidinyl , piperidyl, dimethylpiperidyl or morpholinyl;

[0044] L1is -(CR1aR1b)r-; r is an integer selected from 1 , 2, and 3, each R1ais selected from the group consisting of hydrogen, halogen or C1- ealkyl; each R1bis selected from the group consisting of hydrogen, halogen or C1- ealkyl;

[0045] R1is hydrogen or -C(O)R7;

[0046] R2is selected from

[0047] R4is selected from phenyl or thiophenyl; wherein said phenyl or thienyl can be unsubstituted or substituted with one or more R4a; each R4ais selected from the group consisting of halogen, C1-6alkyl, and C1- ealkoxy; R5is phenyl or thienyl; wherein said phenyl or thienyl can be unsubstituted or substituted with one or more R5a; each R5ais selected from the group consisting of halogen, C1-6alkyl and C1- ealkoxy;

[0048] R6is -C(O)R10;

[0049] R7is selected from the group consisting of C1-20alkyl, C2-20alkenyl, C3- locycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; wherein said C1- 2oalkyl, C2-20alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1- ealkyl can be unsubstituted or substituted with one, two or three R7a;

[0050] R10is selected from the group consisting of C1-20alkyl, C2-20alkenyl, C3- locycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; wherein said C1- 2oalkyl, C2-20alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1- ealkyl can be unsubstituted or substituted with one, two or three R10a; each R7ais selected from the group consisting of hydrogen, halogen, C1- ealkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, haloC1-6alkyloxy, cyanoC1-6alkyl, C1-6alkoxy, cyano, hydroxy, -NR13R14, -NR13S(O)2R15, -NR13C(O)2R15, -C(O)R15, - C(O)2R15, -S(O)nR15(wherein n = 0, 1 , or 2), C6-12aryl, and C1-6alkylC6-12aryl; each R10ais selected from the group consisting of is selected from the group consisting of hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, haloC1-6alkyloxy, cyanoC1-6alkyl, C1-6alkoxy, cyano, hydroxy, -NR13R14, - NR13S(O)2R15, -NR13C(O)2R15, -C(O)R15, -C(O)2R15, -S(O)nR15(wherein n = 0, 1 , or 2), C6-12aryl, and C1-6alkylC6-12aryl; each R13is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or Ci -ealkyl ; each R14is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or C1-6alkyl ; each R15is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or C1-6alkyl ; wherein when R1is hydrogen, then R2is not The compound according to statement 1 , wherein the compound is a compound of formula IA or IB, wherein moiety A, L1, R1, R4, R5, and R6are as defined in statement 1. The compound according to statement 1 or 2, wherein moiety A is di-C1- salkylamino, morpholinyl or a 5-6 membered nitrogen-containing heterocyclyl optionally substituted with one or more Ci^alkyl; preferably moiety A is di-Ci.3alkylamino, morpholinyl or a 5-6 membered nitrogen-containing saturated heterocyclyl optionally substituted with one or more C1-4alkyl; preferably moiety A is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl pyrrolidin-3- yl, 2,3-dimethylpyrrolidin-1 -yl, 2,4-dimethylpyrrolidin-1 -yl, 3,4-dimethylpyrrolidin-1- yl, 3,4-dimethylpyrrolidin-2-yl, 4,5-dimethylpyrrolidin-2-yl, 3,5-dimethylpyrrolidin-2- yl, piperid-1-yl, piperid-2-yl, piperid-3-yl, piperid-4-yl, 2,3-dimethylpiperid-1 -yl, 2,4- dimethylpiperid-1 -yl, 2.5-dimethylpiperid-1-yl, 2.6-dimethylpiperid-1 -yl, 3.4- dimethylpiperid-1 -yl, 3.5-dimethylpiperid-1-yl, 3.6-dimethylpiperid-1 -yl, 2,3- dimethylpiperid-4-yl, 2.5-dimethylpiperid-4-yl, 2.6-dimethylpiperid-4-yl 3.5- dimethylpiperid-4-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The compound according to any of statements 1 to 3, wherein the compound is a compound of formula IC, or ID, wherein R1, R1a, R1b, R4, R5, and R6are as defined in any of statements 1 to 3.

[0051] 5. The compound according to any one of statements 1 to 4, wherein,

[0052] L1is -(CR1aR1b)r~; r is an integer selected from 1 , 2, and 3;

[0053] R4is phenyl; wherein said phenyl can be unsubstituted or substituted with one, two or three R4a; each R4ais selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, and methoxy;

[0054] R5is phenyl; wherein said phenyl, can be unsubstituted or substituted with one, two or three R5a; each R5ais selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, and methoxy.

[0055] 6. The compound according to any of statements 1 to 5, wherein R2is o and L1is -(CH2)2-.

[0056] 7. The compound according to any of statements 1 to 5, wherein R2is and L1is -(CH2)2-.

[0057] 8. The compound according to any of statements 1 to 7, wherein the compound is a compound of formula IE, IF, or IG,

[0058] wherein R1, R4a, R5a, and R6are as defined in any one of statements 1 to 7. 9. The compound according to any one of statements 1 to 8, wherein R4aand R5aare each independently a halogen.

[0059] 10. The compound according to any one of statements 1 to 9, wherein the compound wherein R1and R6are as defined in any one of statements 1 to 9. 11. The compound according to any of statements 1 to 10, wherein R1is selected from the group consisting of hydrogen and -C(O)R7.

[0060] 12. The compound according to any of statements 1 to 11 , wherein R6is -C(O)R10.

[0061] 13. The compound according to any of statements 1 to 12, wherein R7is C1-18alkyl, or C2-15alkenyl.

[0062] 14. The compound according to any of statements 1 to 13, wherein R7is C1-20alkyl.

[0063] 15. The compound according to any of statements 1 to 14, wherein R7is C5-20alkyl, preferably C5-15alkyl.

[0064] 16. The compound according to any of statements 1 to 15, wherein R7ais selected from halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, and hydroxy.

[0065] 17. The compound according to any of statements 1 to 16, wherein R10is C1 _18alkyl , or C2-15alkenyl.

[0066] 18. The compound according to any of statements 1 to 17, wherein R10is C1-20alkyl.

[0067] 19. The compound according to any of statements 1 to 18, wherein R10is C5-20alkyl, preferably C5-15alkyl.

[0068] 20. The compound according to any of statements 1 to 19, wherein R10ais selected from halogen, C1-salkyl, haloC1-6alkyl, C1-6alkoxy, and hydroxy.

[0069] 21. The compound according to any of statements 1 to 20, wherein R1is hydrogen and R6is -C(O)R10.

[0070] 22. The compound according to any of statements 1 to 21, wherein the compound is a compound of formula

[0071] 23. A pharmaceutical composition comprising a compound according to any one of statements 1 to 22.

[0072] 24. The compound according to any one of statements 1 to 22 or the pharmaceutical composition according to statement 23, for use as a medicament.

[0073] 25. The compound according to any one of statements 1 to 22 or the pharmaceutical composition according to statement 23, for use in the treatment of mood disorders, sleep disorders, psychotic disorders, excitement and agitation, including psychomotoric states of excitation disorders, behavioral disorders, including autistic behaviour, and / or disorders with impaired cognition.

[0074] 26. The compound for use or the pharmaceutical composition for use according to statement 25, wherein the mood disorder is selected from the group consisting of Major depressive disorder, Atypical depression, Melancholic depression, Psychotic depression, Depressive Disorder not otherwise specified, Postpartum depression, Dysthymia, Adjustment disorder with depressed mood, and Seasonal affective disorder.

[0075] 27. A method of treatment of mood disorders, sleep disorders, psychotic disorders, excitement and agitation, including psychomotoric states of excitation disorders, behavioural disorders, including autistic behaviour, and / or disorders with impaired cognition, comprising administering to a subject in need thereof an effective amount of a compound according to any one of statements 1 to 22 or a pharmaceutical composition according to statement 23.

[0076] 28. The method of treatment according to statement 27, wherein the mood disorder is selected from the group consisting of Major depressive disorder, Atypical depression, Melancholic depression, Psychotic depression, Depressive Disorder not otherwise specified, Postpartum depression, Dysthymia, Adjustment disorder with depressed mood, and Seasonal affective disorder.

[0077] In some embodiments moiety A is selected from the group comprising or consisting of di-C1-4alkylamino, pyrrolidin-1-yl, pyrrolidin-2-yl pyrrol idin-3-yl, 2,3-dimethylpyrrolidin-1 - yl, 2,4-dimethylpyrrolidin-1 -yl, 3,4-dimethylpyrrolidin-1 -yl, 3,4-dimethylpyrrolidin-2-yl,

[0078] 4.5-dimethylpyrrolidin-2-yl, 3,5-dimethylpyrrolidin-2-yl, 1 ,3-dimethylpyrrolidin-2-yl, 1 ,4- dimethylpyrrolidin-2-yl, 1 , 5-di methyl pyrrolidin-2-yl , 2.4-dimethylpyrrolidin-3-yl, 2.5- dimethylpyrrolidin-3-yl, 1 ,2-di methyl pyrrolidin-3-yl , 1.4-dimethylpyrrol idin-3-yl , 1.5- dimethylpyrrolidin-3-yl, 4,5-dimethylpyrrolidin-3-yl, piperid-1-yl, piperid-2-yl, piperid-3-yl, piperid-4-yl, 2,3-dimethylpiperid-1-yl, 2,4-dimethylpiperid-1 -yl, 2,5-dimethylpiperid-1-yl,

[0079] 2.6-dimethylpiperid-1 -yl, 3,4-dimethylpiperid-1-yl, 3,5-dimethylpiperid-1-yl, 3,6- dimethylpiperid-1 -yl, 3.4-dimethylpiperid-2-yl, 3.5-dimethylpiperid-2-yl, 3.6- dimethylpiperid-2-yl, 4.5-dimethylpiperid-2-yl, 4.6-dimethylpiperid-2-yl, 5.6- dimethylpiperid-2-yl, 2.4-dimethylpiperid-3-yl, 2.5-dimethylpiperid-3-yl, 2.6- dimethylpiperid-3-yl, 4.5-dimethylpiperid-3-yl, 4.6-dimethylpiperid-3-yl, 5.6- dimethylpiperid-3-yl, 2.5-dimethylpiperid-4-yl, 2.6-dimethylpiperid-4-yl 3,5- dimethylpiperid-4-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl; preferably moiety A is selected from di-C1-3alkylamino, pyrrolidin-1-yl, pyrrolidin-2-yl pyrrolidin-3-yl, 2,3-dimethylpyrrolidin-1-yl, 2,4-dimethylpyrrolidin-1-yl, 3,4-dimethylpyrrolidin-1 -yl, 3,4- dimethylpyrrolidin-2-yl, 4,5-dimethylpyrrolidin-2-yl, 3,5-dimethylpyrrolidin-2-yl, 2,4- dimethylpyrrolidin-3-yl, 2,5-dimethylpyrrolidin-3-yl, 4,5-dimethylpyrrolidin-3-yl, piperid-1- yl, piperid-2-yl, piperid-3-yl, piperid-4-yl, 2,3-dimethylpiperid-1-yl, 2,4-dimethylpiperid-1- yl, 2,5-dimethylpiperid-1-yl, 2,6-dimethylpiperid-1-yl, 3,4-dimethylpiperid-1-yl, 3,5- dimethylpiperid-1 -yl, 3,6-dimethylpiperid-1-yl, 1.3-dimethylpiperid-2-yl , 1.4- dimethylpiperid-2-yl, 1.5-dimethyl piperid-2-yl , 1.6-dimethylpiperid-2-yl , 3.4- dimethylpiperid-2-yl, 3.5-dimethylpiperid-2-yl, 3.6-dimethylpiperid-2-yl, 4.5- dimethylpiperid-2-yl, 4.6-dimethylpiperid-2-yl, 5.6-dimethylpiperid-2-yl, 1.2- dimethylpiperid-3-yl, 1.4-dimethyl piperid-3-yl , 1.5-dimethylpiperid-3-yl , 1.6- dimethylpiperid-3-yl, 2.4-dimethylpiperid-3-yl, 2.5-dimethylpiperid-3-yl, 2.6- dimethylpiperid-3-yl, 4.5-dimethylpiperid-3-yl, 4.6-dimethylpiperid-3-yl, 5.6- dimethylpiperid-3-yl, 1 ,2-dimethyl piperid-4-yl , 1.3-dimethylpiperid-4-yl , 2.3- dimethylpiperid-4-yl, 2.5-dimethylpiperid-4-yl, 2.6-dimethylpiperid-4-yl 3,5- dimethylpiperid-4-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl; preferably moiety A is selected from di-C1-3alkylamino, pyrrolidin-1-yl, pyrrolidin-2-yl pyrrolidin-3-yl, 2,3-dimethylpyrrolidin-1-yl, 2,4-dimethylpyrrolidin-1-yl, 3,4-dimethylpyrrolidin-1 -yl, 3,4- dimethylpyrrolidin-2-yl, 4,5-dimethylpyrrolidin-3-yl, piperid-1-yl, piperid-2-yl, piperid-3-yl, piperid-4-yl, 2,3-dimethylpiperid-1-yl, 2,4-dimethylpiperid-1 -yl, 2,5-dimethylpiperid-1-yl, 2,6-dimethylpiperid-1 -yl, 3,4-dimethylpiperid-1-yl, 3,5-dimethylpiperid-1-yl, 3,6- dimethylpiperid-1 -yl, 3.4-dimethylpiperid-2-yl, 3.5-dimethylpiperid-2-yl, 3.6- dimethylpiperid-2-yl, 4.5-dimethylpiperid-2-yl, 4.6-dimethylpiperid-2-yl, 5.6- dimethylpiperid-2-yl, 2.4-dimethylpiperid-3-yl, 2.5-dimethylpiperid-3-yl, 2.6- dimethylpiperid-3-yl, 4.5-dimethylpiperid-3-yl, 4.6-dimethylpiperid-3-yl, 5.6- dimethylpiperid-3-yl, 2,3-dimethylpiperid-4-yl, 2,5-dimethylpiperid-4-yl, 2.6- dimethylpiperid-4-yl 3,5-dimethylpiperid-4-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl; preferably moiety A is selected from dimethylamino, diethylamino, pyrrolidin-1 -yl, pyrrolidin-2-yl pyrrolidin-3-yl, piperid-1-yl, piperid-2-yl, piperid-3-yl, piperid-4-yl, 2,3-dimethylpiperid-1-yl, 2,4-dimethylpiperid-1 -yl, 2,5-dimethylpiperid-1-yl, 2,6-dimethylpiperid-1 -yl, 3,4-dimethylpiperid-1-yl, 3,5-dimethylpiperid-1-yl, 3.6- dimethylpiperid-1 -yl, 3.6-dimethylpiperid-2-yl, 4.6-dimethylpiperid-2-yl, 5.6- dimethylpiperid-2-yl, 2.6-dimethylpiperid-3-yl, 4.6-dimethylpiperid-3-yl, 5,6- dimethylpiperid-3-yl, 2,6-dimethylpiperid-4-yl 3,5-dimethylpiperid-4-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl; preferably moiety A is selected from dimethylamino, pyrrolidin-1 -yl, pyrrolidin-2-yl pyrrolidin-3-yl, piperid-1-yl, piperid-2-yl, piperid-3-yl, piperid-4-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl; preferably moiety A is selected from pyrrolidin-1 -yl, pyrrolidin-2-yl pyrrolidin-3-yl, piperid-1-yl, piperid-2-yl, piperid-3-yl, piperid-4-yl.

[0080] Preferably, when moiety A is a cycle, this group is attached to the compound of Formula I through a nitrogen atom.

[0081] In some embodiments L1is -(CR1aR1b)r-; preferably L1is -(CH2)r-; r is an integer selected from 1 , 2, and 3; preferably r is selected from 1 or2; each R1ais selected from the group comprising or consisting of hydrogen, halogen or C1- ealkyl; preferably R1ais hydrogen, halogen or C1-5alkyl; preferably R1ais hydrogen, halogen or C1-4alkyl; preferably R1ais hydrogen, halogen or C1-3alkyl; preferably R1ais hydrogen, fluoro, chloro, bromo, iodo or C1-6alkyl; preferably R1ais hydrogen, fluoro, chloro, bromo, iodo or C1-4alkyl; preferably R1ais hydrogen, fluoro, chloro, bromo, or iodo; each R1bis selected from the group comprising or consisting of hydrogen, halogen or C1- ealkyl; preferably R1bis hydrogen, halogen or C1-5alkyl; preferably R1bis hydrogen, halogen or C1-4alkyl; preferably R1 bis hydrogen, halogen or C1-3alkyl; preferably R1 bis hydrogen, fluoro, chloro, bromo, iodo or C1-6alkyl; preferably R1bis hydrogen, fluoro, chloro, bromo, iodo or C1-4alkyl; preferably R1bis hydrogen, fluoro, chloro, bromo, or iodo. In some embodiments R1is -C(O)R7.

[0082] In some embodiments R2is

[0083] In some embodiments R2is In some embodiments R4is selected from the group comprising or consisting of phenyl, thiophen-2-yl and thiophen-3-yl; preferably R4is phenyl or thiophen-2-yl; preferably R4is phenyl; wherein said groups can be unsubstituted or substituted with one or more R4a; preferably said groups can be unsubstituted or substituted with one, two, three or four R4a; preferably said groups can be unsubstituted or substituted with one, two, or three R4a; preferably said groups can be unsubstituted or substituted with one, or two R4a;

[0084] In some embodiments each R4ais selected from the group consisting of halogen, Cisalkyl, and C1-5alkoxy; preferably each R4ais halogen, C1-4alkyl, and C1-4alkoxy; preferably each R4ais halogen, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; preferably each R4ais fluoro, chloro, bromo, iodo, C1-4alkyl, and C1-4alkoxy; preferably each R4ais fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.

[0085] In some embodiments R5is selected from phenyl, thiophen-2-yl and thiophen-3-yl; preferably R5is phenyl and thiophen-2-yl; preferably R5is phenyl; wherein said groups can be unsubstituted or substituted with one or more R5a; preferably said groups can be unsubstituted or substituted with one, two, three or four R5a; preferably said groups can be unsubstituted or substituted with one, two, or three R5a; preferably said groups can be unsubstituted or substituted with one, or two R5a; in some embodiments each R5ais selected from the group consisting of halogen, C1- salkyl, and C1-5alkoxy; preferably each R5ais halogen, C1-4alkyl, and C1-4alkoxy; preferably each R5ais halogen, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; preferably each R5ais fluoro, chloro, bromo, iodo, C1-4alkyl, and C1-4alkoxy; preferably each R5ais fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.

[0086] Preferably, R4and R5are identical. Preferably, R4aand R5aare identical. Preferably, R4and R5are identical and R4aand R5aare identical.

[0087] In some embodiments R7is selected from the group consisting of C1-20alkyl, C2-20alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and Cs-^arylC1-salkyl; preferably R7is C1- i8alkyl, C2-i8alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; preferably R7is C1-16alkyl, C2-16alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; preferably R7is C1-16alkyl, C2-16alkenyl, C6-12aryl, and C6-12arylC1-6alkyl; preferably R7is C5-15alkyl, C5-15alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; wherein said groups can be unsubstituted or substituted with one, two or three R7a; preferably said groups can be unsubstituted or substituted with one or two R7a.

[0088] In some embodiments each R7ais independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, haloC1-6alkyloxy, cyanoC1-6alkyl, Ci^alkoxy, cyano, hydroxy, amino, mono-C1-6alkylamino, di-C1- ealkylamino, mono-C6-12arylamino, di-C6-12arylamino, -NR13S(O)2R15, -NR13C(O)2R15, - C(O)H, C1-6alkylcarbonyl, C6-12arylcarbonyl, -C(O)2H, C1-6alkyloxycarbonyl, C6-12aryloxycarbonyl, -S(O)2H, C1-6alkylsulfonyl, C6-12arylsulfonyl, C6-12aryl, and C1- ealkylC6-12aryl; preferably each R7ais selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyloxy, Ci^alkoxy, cyano, hydroxy, amino, mono-C1-6alkylamino, mono-C6-12arylamino, -NR13S(O)2R15, - NR13C(O)2R15, C1-6alkylcarbonyl, -C(O)2H, C1-6alkyloxycarbonyl, -S(O)2H, Ci.6alkylsulfonyl, C6-12aryl, and C1-6alkylC6-12aryl; preferably each R7ais selected from hydrogen, halogen, C1-4alkyl, C2-4alkynyl, haloC1-4alkyl, haloC1-4alkyloxy, cyanoC1-4alkyl, C1-4alkoxy, cyano, hydroxy, amino, mono-C1-4alkylamino, mono-C6-12arylamino, - NR13S(O)2R15, C1-4alkylcarbonyl, -C(O)2H, C1-4alkyloxycarbonyl, -S(O)2H, C1- 4alkylsulfonyl, C6-12aryl, and C1-4alkylC6-12aryl; preferably each R7ais selected from hydrogen, fluoro, chloro, bromo, iodo, C1-4alkyl, C2-4alkynyl, haloC1-4alkyl, cyanoC1-4alkyl, C1-4alkoxy, cyano, hydroxy, amino, mono-C1-4alkylamino, mono-C6-12arylamino, - NR13S(O)2R15, C6-12aryl, and C1-4alkylC6-12aryl.

[0089] In some embodiments R10is selected from the group consisting of Ci^alkyl, C2-20alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; preferably R10is C1- 18alkyl, C2-18alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; preferably R10is C1-16alkyl, C2-16alkenyl, C3-10cycloalkyl, C8.iocycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; preferably R10is C1-16alkyl , C2-iealkenyl, C6-12aryl, and C6-12arylC1-6alkyl; preferably R10is C5-15alkyl, Cs-isalkenyl, C3-10cycloalkyl, C3.10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; wherein said groups can be unsubstituted or substituted with one, two or three R10a; preferably said groups can be unsubstituted or substituted with one or two R10a.

[0090] In some embodiments each R10ais independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, haloC1-6alkyloxy, cyanoC1-6alkyl, C1-6alkoxy, cyano, hydroxy, amino, mono-C1-6alkylamino, di-C1- ealkylamino, mono-C6-12arylamino, di-C6-12arylamino, -NR13S(O)2R15, -NR13C(O)2R15, - C(O)H, C1-6alkylcarbonyl, C6-12arylcarbonyl, -C(O)2H, C1-6alkyloxycarbonyl, C6-12aryloxycarbonyl, -S(O)2H, C1-6alkylsulfonyl, C6-12arylsulfonyl, C6-12aryl, and C1- ealkylC6-12aryl; preferably each R10ais selected from hydrogen, halogen, C1-6alkyl, C2- ealkenyl, C2-6alkynyl, haloC1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyloxy, C1-6alkoxy, cyano, hydroxy, amino, mono-C1-6alkylamino, mono-C6-12arylamino, -NR13S(O)2R15, - NR13C(O)2R15, C1-6alkylcarbonyl, -C(O)2H, C1-6alkyloxycarbonyl, -S(O)2H, C1- ealkylsulfonyl, C6-12aryl, and C1-6alkylC6-12aryl; preferably each R10ais selected from hydrogen, halogen, C1-4alkyl, C2-4alkynyl, haloC1-4alkyl, haloC1-4alkyloxy, cyanoC1-4alkyl, C1-4alkoxy, cyano, hydroxy, amino, mono-C1-4alkylamino, mono-C6-12arylamino, - NR13S(O)2R15, C1-4alkylcarbonyl, -C(O)2H, C1-4alkyloxycarbonyl, -S(O)2H, Ci.4alkylsulfonyl, C6-12aryl, and C1-4alkylC6-12aryl; preferably each R10ais selected from hydrogen, fluoro, chloro, bromo, iodo, C1-4alkyl, C2-4alkynyl, haloC1-4alkyl, cyanoC1-4alkyl, C1-4alkoxy, cyano, hydroxy, amino, mono-C1-4alkylamino, mono-C6-12arylamino, - NR13S(O)2R15, C6-12aryl, and C1-4alkylC6-12aryl.

[0091] Preferably, R7and R10are identical. Preferably, R7aand R10aare identical. Preferably, R7and R10are identical and R7aand R10aare identical.

[0092] In some embodiments each R13is independently selected from the group consisting of hydrogen, C1-5alkyl, C2-5alkenyl, C2-5alkynyl, and C6-12aryl; preferably each R13is independently selected from the group consisting of hydrogen, C1-4alkyl, C6-12aryl.

[0093] In some embodiments each R14is independently selected from the group consisting of hydrogen, C1-5alkyl, C2-5alkenyl, C2-5alkynyl, and C6-12aryl; preferably each R14is independently selected from the group consisting of hydrogen, C1-4alkyl, C6-12aryl. In some embodiments each R15is independently selected from the group consisting of hydrogen, C1-5alkyl, C2-5alkenyl, C2-5alkynyl, and C6-12aryl; preferably each R15is independently selected from the group consisting of hydrogen, C1-4alkyl, C6-12aryl.

[0094] In some embodiments R1and R6are the same group.

[0095] The methods to produce a compound of formula II are described in US 3,041 ,344. The present invention also encompasses a method for the preparation of the compound of formula I as disclosed herein, said method comprising the step of: condensation of a compound of formula II in a non-reactive solvent and a base at a suitable temperature with a compound of formula R1X and / or a compound of formula R6X, wherein X is halogen; hydroxy, or OC1-4, preferably X is chlorine, bromine or iodine, wherein R1and / or R6are not hydrogen.

[0096] Suitable non-reactive solvents include aromatic solvents such as benzene, toluene, chlorobenzene; alcohols such as ethanol, iso-propanol; non-protic solvents such as DMF, NMP, DMA; ethers such as diethyl ether, THF, Me-THF. Suitable bases include Et3N, Hunigs base (Diisopropyl ethylamine), NaHMDS, LiHMDS, LDA, KOtBu, TBD.

[0097] When X is hydroxy an activating group is needed such as HOBt, EDC, T3P, PyBOP, COMU, FDPP, TCFH etc. wherein R2ais selected from and wherein moiety A, L1, R1,

[0098] R4and R5are as defined herein; thereby producing the compound of formula I.

[0099] The present invention also encompasses a method for the preparation of a compound of formula IA as disclosed herein, said method comprising the step of: condensation of a compound of formula IIA in a non-reactive solvent and a base at a suitable temperature with a compound of formula R1X and / or a compound of formula R6X, wherein X is halogen; hydroxy, or OC1-4, preferably X is chlorine, bromine or iodine, wherein R1and / or R6are not hydrogen. When X is hydroxy an activating group is needed such as HOBt, EDC, T3P, PyBOP, COMU, FDPP, TCFH etc. wherein moiety A, L1, R1, and R4, are as defined herein; thereby producing the compound of formula IA.

[0100] The present invention also encompasses a method for the preparation of a compound of formula IB as disclosed herein, said method comprising the step of: condensation of a compound of formula IIB in a non-reactive solvent and a base at a suitable temperature with a compound of formula R1X and / or a compound of formula R6X, wherein X is halogen, hydroxy, or OC1-4, preferably X is chlorine, bromine or iodine,

[0101] IIB, wherein A, L1, R1, R5, and R6, are as defined herein; or when X is hydroxy an activating group is needed such as HOBt, EDC, T3P, PyBOP,

[0102] COMII, FDPP, TCFH etc. thereby producing the compound of formula IB.

[0103] In preferred embodiments R1is -C(O)R7. In preferred embodiments R1is hydrogen and R6is -C(O)R10. In preferred embodiments R1is -C(O)R7and R6is -C(O)R10.

[0104] Whenever the term “substituted” is used herein, it is meant to indicate that one or more hydrogen atoms on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom’s normal valence is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation from a reaction mixture.

[0105] Where groups can be substituted, such groups may be substituted with one or more, and preferably one, two or three substituents. Preferred substituents may be selected from but not limited to, for example, the group comprising or consisting of halo, hydroxyl, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, cyano, amino, carboxyl, and mono- or dialkylamino.

[0106] The term “halo” or “halogen” as a group or part of a group is generic for fluoro, chloro, bromo, iodo.

[0107] The term “hydroxyl” or “hydroxy” as used herein refers to the group -OH.

[0108] The term “cyano” as used herein refers to the group -C=N.

[0109] The term “amino” as used herein refers to the -NH2group.

[0110] The term "alkyl", as a group or part of a group, refers to a hydrocarbyl group of formula -CnH2n+i wherein n is a number greater than or equal to 1. Alkyl groups may be linear or branched and may be substituted as indicated herein. Generally, alkyl groups of this invention comprise from 1 to 20 carbon atoms, preferably from 1 to 19 carbon atoms, preferably from 1 to 18 carbon atoms, preferably from 1 to 17 carbon atoms, preferably from 1 to 16 carbon atoms, preferably from 1 to 15 carbon atoms, preferably from 1 to 14 carbon atoms, preferably from 1 to 13 carbon atoms, preferably from 1 to 12 carbon atoms, preferably from 1 to 11 carbon atoms, preferably from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, preferably from 1 to 5 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, “C1-6alkyl” includes all linear or branched alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers. For example, “C1-5alkyl” includes all includes all linear or branched alkyl groups with between 1 and 5 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers. For example, “C1-4alkyl” includes all linear or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t- butyl). For example “C1-3alkyl” includes all linear or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl.

[0111] The term "haloalkyl" as a group or part of a group, refers to a alkyl group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1- trifluoroethyl, trichloromethyl, tribromomethyl, and the like.

[0112] The term “alkoxy" or “alkyloxy”, as a group or part of a group, refers to a group having the formula -ORbwherein Rbis alkyl as defined herein above. Non-limiting examples of suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secbutoxy, tert-butoxy, pentyloxy and hexyloxy.

[0113] The term "cyanoC1-6alkyl" as a group or part of a group, refers to a Ci _6alkyl group having the meaning as defined above wherein at least one hydrogen atom is replaced with at least one cyano group as defined herein. Non-limiting examples of such cyanoC1-6alkyl groups include cyanomethyl, 1-cyanoethyl, 1-cyanopropyl and the like.

[0114] The term “cycloalkyl”, as a group or part of a group, refers to a cyclic alkyl group, that is a monovalent, saturated, hydrocarbyl group having 1 or more cyclic structure, and comprising or consisting of from 3 to 10 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 7 carbon atoms; more preferably from 3 to 6 carbon atoms. Cycloalkyl includes all saturated hydrocarbon groups containing 1 or more rings, including monocyclic or bicyclic groups. The further rings of multi-ring cycloalkyls may be either fused, bridged and / or joined through one or more spiro atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “Cs-scycloalkyl”, a cyclic alkyl group comprising or consisting of from 3 to 8 carbon atoms. For example, the term “Cs-ecycloalkyl”, a cyclic alkyl group comprising or consisting of from 3 to 6 carbon atoms. Examples of C3-i2cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycle[2.2.1]heptan-2yl, (1S,4R)-norbornan-2-yl, (1 R,4R)-norbornan-2-yl, (1S,4S)- norbornan-2-yl, (1 R,4S)-norbornan-2-yl, 1-adamantyl.

[0115] The term “alkenyl” as a group or part of a group, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon-carbon double bonds. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “C2-6alkenyl” refers to an unsaturated hydrocarbyl group, which may be linear, or branched comprising one or more carbon-carbon double bonds and comprising or consisting of from 2 to 6 carbon atoms. For example, C2-4alkenyl includes all linear, or branched alkenyl groups having 2 to 4 carbon atoms. Examples of C2-6alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl. and the like.

[0116] The term “cycloalkenyl”, as a group or part of a group, refers to a cyclic alkenyl group, that is a monovalent, with at least one unsaturation, hydrocarbyl group having 1 or more cyclic structure, and comprising or consisting of from 5 to 12 carbon atoms, more preferably from 5 to 9 carbon atoms, more preferably from 5 to 7 carbon atoms; more preferably from 5 to 6 carbon atoms. Cycloalkenyl includes all unsaturated hydrocarbon groups containing 1 or more rings, including monocyclic or bicyclic groups. The further rings of multi-ring cycloalkenyls may be saturated or unsaturated. The further rings of multi-ring cycloalkyls may be either fused, bridged and / or joined through one or more spiro atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “Cs-i2cycloalkenyl”, a cyclic alkenyl group comprising or consisting of from 5 to 12 carbon atoms. For example, the term “Cs-ecycloalkenyl”, a cyclic alkenyl group comprising or consisting of from 5 to 6 carbon atoms.

[0117] The term "nitrogen-containg heterocyclyl" as a group or part of a group, refers to nonaromatic, fully saturated or partially unsaturated cyclic groups containing 4 to 7 members, and containing at least one nitrogen atom; preferably containing at most 2 nitrogen atoms; preferably containing at most 3 nitrogen atoms. Said ring may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. The N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized; and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one C=O. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. Preferably the heterocyclic group is attached via the nitrogen group. In some embodiments the heterocyclic group is saturated.

[0118] The term “pyrrolidinyl” as used herein includes pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl.

[0119] The term “dimethylpyrrolidinyl” as used herein includes 2,3-dimethylpyrrolidin-1-yl, 2,4- dimethylpyrrolidin-1-yl, 3,4-dimethylpyrrolidin-1-yl, 3,4-dimethylpyrrolidin-2-yl, 4,5- dimethylpyrrolidin-2-yl, 3,5-dimethylpyrrolidin-2-yl, 1 ,3-dimethylpyrrolidin-2-yl, 1 ,4- dimethylpyrrolidin-2-yl, 1 ,5-dimethylpyrrolidin-2-yl, 2,4-dimethylpyrrolidin-3-yl, 2,5- dimethylpyrrolidin-3-yl, 1 ,2-dimethylpyrrolidin-3-yl, 1 ,4-dimethylpyrrolidin-3-yl, 1 ,5- dimethylpyrrolidin-3-yl, and 4,5-dimethylpyrrolidin-3-yl.

[0120] The term “piperidyl” also known as “piperidinyl” as used herein includes piperid-1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl.

[0121] The term “dimethylpiperidyl” as used herein includes 2,3-dimethylpiperid-1 -yl, 2,4- dimethylpiperid-1 -yl, 2.5-dimethylpiperid-1-yl, 2.6-dimethylpiperid-1 -yl, 3,4- dimethylpiperid-1 -yl, 3.5-dimethylpiperid-1-yl, 3.6-dimethylpiperid-1 -yl, 1 ,3- dimethylpiperid-2-yl, 1.4-dimethyl piperid-2-yl , 1.5-dimethylpiperid-2-yl, 1 ,6- dimethylpiperid-2-yl, 3.4-dimethylpiperid-2-yl, 3.5-dimethylpiperid-2-yl, 3,6- dimethylpiperid-2-yl, 4.5-dimethylpiperid-2-yl, 4.6-dimethylpiperid-2-yl, 5,6- dimethylpiperid-2-yl, 1.2-dimethyl piperid-3-yl , 1.4-dimethylpiperid-3-yl, 1 ,5- dimethylpiperid-3-yl, 1.6-dimethyl piperid-3-yl , 2.4-dimethylpiperid-3-yl, 2,5- dimethylpiperid-3-yl, 2.6-dimethylpiperid-3-yl, 4.5-dimethylpiperid-3-yl, 4,6- dimethylpiperid-3-yl, 5.6-dimethylpiperid-3-yl, 1 ,2-dimethylpiperid-4-yl, 1 ,3- dimethylpiperid-4-yl, 2.3-dimethylpiperid-4-yl, 2.5-dimethylpiperid-4-yl, 2,6- dimethylpiperid-4-yl and 3,5-dimethylpiperid-4-yl.

[0122] The term “morpholinyl” as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term “thiophenyl” (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl).

[0123] The term “alkynyl” by itself or as part of another substituent, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carboncarbon triple bonds. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “C2-6alkynyl” refers to an unsaturated hydrocarbyl group, which may be linear, or branched comprising one or more carbon-carbon triple bonds and comprising or consisting of from 2 to 6 carbon atoms. For example, C2-4alkynyl includes all linear, or branched alkynyl groups having 2 to 4 carbon atoms. Non limiting examples of C2-6alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its chain isomers, 2-hexynyl and its chain isomers, and the like.

[0124] The term “aryl”, as a group or part of a group, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), or linked covalently, typically comprising or consisting of 6 to 12 carbon atoms; wherein at least one ring is aromatic, preferably comprising or consisting of 6 to 10 carbon atoms, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Examples of suitable aryl include C6-12aryl, preferably Ce-waryl, more preferably Ce-saryl. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, or 1-or 2-naphthanelyl; 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- azulenyl, 4-, 5-, 6 or 7-indenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1 , 2,3,4- tetrahydronaphthyl, and 1 ,4-dihydronaphthyl; 1-, 2-, 3-, 4- or 5-pyrenyl. A “substituted aryl” refers to an aryl group having one or more substituent(s) (for example 1 , 2 or 3 substituent(s), or 1 to 2 substituent(s)), at any available point of attachment.

[0125] The term "C6-12arylC1-6alkyl", as a group or part of a group, means a C1-6alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-12aryl as defined herein. Non-limiting examples of C6-12arylC1-6alkyl group include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like. The term “mono- or di-alkylamino”, as a group or part of a group, refers to a group of formula -N(R°)(RP) wherein R° and RP are each independently selected from hydrogen, or alkyl, wherein at least one of R° or Rpis alkyl. Thus, alkylamino include mono-alkyl amino group (e.g. mono-C1-6alkylamino group such as methylamino and ethylamino), and di-alkylamino group (e.g. di-C1-6alkylamino group such as dimethylamino and diethylamino). Non-limiting examples of suitable mono- or di-alkylamino groups include n-propylamino, isopropylamino, n-butylamino, / -butylamino, sec-butylamino, t- butylamino, pentylamino, n-hexylamino, di-n-propylamino, di- / -propylamino, ethylmethylamino, methyl-n-propylamino, methyl- / -propylamino, n-butylmethylamino, / - butylmethylamino, f-butylmethylamino, ethyl-n-propylamino, ethyl- / -propylamino, n- butylethylamino, i-butylethylamino, f-butylethylamino, di-n-butylamino, di- / -butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.

[0126] The term “mono- or di-C6-12arylamino”, as a group or part of a group, refers to a group of formula -N(Rp)(Rr) wherein RP and Rrare each independently selected from hydrogen, aryl, or alkyl, wherein at least one of RP or Rris C6-12aryl.

[0127] The term “alkylcarbonyl”, as a group or part of a group, refers to a group of formula - CO-Rb, wherein Rbis alkyl as defined herein.

[0128] The term “C6-12arylcarbonyl”, as a group or part of a group, refers to a group of formula -CO-Rb, wherein Rbis C6-12aryl as defined herein.

[0129] The term “alkyloxycarbonyl”, as a group or part of a group, refers to a group of formula -COO-Rb, wherein Rbis alkyl as defined herein.

[0130] The term “C6-12aryloxycarbonyl”, as a group or part of a group, refers to a group of formula -COO-Rb, wherein Rbis C6-12aryl as defined herein.

[0131] The term “C1-6alkylsulfonyl”, as a group or part of a group, refers to a group of formula - S(O)2-Rb, wherein Rbis C1-6alkylas defined herein. The term “C6-12arylsulfonyl”, as a group or part of a group, refers to a group of formula - S(O)2-Rb, wherein Rbis C6-12aryl as defined herein.

[0132] Whenever used in the present invention the term “compounds of the invention” or a similar term is meant to include the compounds of general formula I, IA, IB, IC, ID, IE, IF, IG, IH, IJ IK, IL, IM, and IN and any subgroup thereof. This term also refers to the compounds as described herein and their derivatives, N-oxides, salts, solvates, hydrates, tautomeric forms, analogues, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues.

[0133] As used herein and unless otherwise stated, the term "stereoisomer" refers to all possible different isomeric as well as conformational forms which the compounds of structural formula herein may possess, in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and / or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.

[0134] The present invention includes all possible stereoisomers of compounds of formula I or II and any subgroup thereof. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry. A structural isomer is a type of isomer in which molecules with the same molecular formula have different bonding patterns and atomic organization. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. The term “prodrug” as used herein means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p 13-15) describing pro-drugs generally is hereby incorporated. Prodrugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component. Typical examples of prodrugs are described for instance in WO 99 / 33795, WO 99 / 33815, WO 99 / 33793 and WO 99 / 33792 all incorporated herein by reference. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active inhibitors in vivo. The term “prodrug”, as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the pre-drug reaches the area of the body where administration of the drug is indicated.

[0135] The compounds of the invention may be in the form of salts, preferably pharmaceutically acceptable salts, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and / or inorganic acids are as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the prior art referred to below).

[0136] When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH), the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

[0137] Pharmaceutically acceptable salts of the compounds of formula (I) and any subgroup thereof include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference.

[0138] The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ('melting point').

[0139] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods:

[0140] (i) by reacting the compound of formula (I) with the desired acid;

[0141] (ii) by reacting the compound of formula (I) with the desired base;

[0142] (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or (iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

[0143] All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost nonionized.

[0144] The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

[0145] A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Britain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0146] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0147] Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.

[0148] The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO'Na+, -COO'K+, or -SC>3'Na+) or non-ionic (such as -N’N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970), incorporated herein by reference.

[0149] All references to compounds of formula (I) or any subgroups thereof include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.

[0150] The compounds of the invention include compounds of formula (I) or any subgroups thereof as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I).

[0151] In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and / or purification of the compounds of the invention. Pipamperone (T-[3-(p-fluorobenzoyl)propyl]-[1 ,4'-bipiperidine]-4'-carboxamide) or 1-[4- (4-fluorophenyl)-4-oxobutyl]-4-piperidin-1-ylpiperidine-4-carboxamide), also known as carpiperone and floropipamide or fluoropipamide, and as floropipamide hydrochloride, is a typical antipsychotic of the butyrophenone family used in the treatment of schizophrenia. It is or has been marketed under brand names including Dipiperon, Dipiperal, Piperonil, Piperonyl, and Propitan. The chemical formula of pipamperone is provided below (Formula A).

[0152] Formula A

[0153] It will be understood that pharmaceutically acceptable derivatives, such as salts are also included. In certain embodiments, pipamperone is pipamperone (di)hydrochloride (pipamperone HCI). In will be understood that when pipamperone is formulated as a pharmaceutically acceptable derivative, such as a salt, such as pipamperone HCI, the dose may be adjusted to the equivalent of pipamperone.

[0154] In certain preferred embodiments, R1is -C(O)R7wherein R7is C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is linear C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unbranched C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted linear C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted unbranched C5-20 alkyl.

[0155] In certain preferred embodiments, R6is -C(O)R10wherein R10is C5-20 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is linear C5-20 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is unbranched C5-20 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is unsubstituted C5-20 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is unsubstituted linear C5-20 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is unsubstituted unbranched C5-20 alkyl.

[0156] In certain preferred embodiments, R1is -C(O)R7wherein R7is C5-20 alkyl and R6is - C(O)R10wherein R10is C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is linear C5-20 alkyl and R6is -C(O)R10wherein R10is linear C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unbranched C5-20 alkyl and R6is -C(O)R10wherein R10is unbranched C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted C5-20 alkyl and R6is -C(O)R10wherein R10is unsubstituted C5-20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted linear C5-20 alkyl and R6is -C(O)R10wherein R10is unsubstituted linear C5- 20 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted unbranched C5-20 alkyl and R6is -C(O)R10wherein R10is unsubstituted unbranched C5-20 alkyl.

[0157] In certain preferred embodiments, R1is -C(O)R7wherein R7is C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is linear C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unbranched C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted linear C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted unbranched Cs-is alkyl.

[0158] In certain preferred embodiments, R6is -C(O)R10wherein R10is C8-18 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is linear C8-18 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is unbranched C8-18 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is unsubstituted C8-18 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is unsubstituted linear C8-18 alkyl. In certain preferred embodiments, R6is -C(O)R10wherein R10is unsubstituted unbranched Cs-18 alkyl.

[0159] In certain preferred embodiments, R1is -C(O)R7wherein R7is C8-18 alkyl and R6is - C(O)R10wherein R10is C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is linear C8-18 alkyl and R6is -C(O)R10wherein R10is linear C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unbranched C8-18 alkyl and R6is -C(O)R10wherein R10is unbranched C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted C8-18 alkyl and R6is -C(O)R10wherein R10is unsubstituted C8-18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted linear C8-18 alkyl and R6is -C(O)R10wherein R10is unsubstituted linear Cs- 18 alkyl. In certain preferred embodiments, R1is -C(O)R7wherein R7is unsubstituted unbranched C8-18 alkyl and R6is -C(O)R10wherein R10is unsubstituted unbranched Cs-is alkyl.

[0160] In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof: wherein, R1is -C(O)R7wherein R7is C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is linear C5- 20 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unbranched C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is - C(O)R7wherein R7is unsubstituted C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted linear C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted unbranched C5-20 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof:

[0161] IJ wherein, R6is -C(O)R10wherein R10is C5-20 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is -C(O)R10wherein R10is linear C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IJ, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is -C(O)R10wherein R10is unbranched C5-20 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is - C(O)R10wherein R10is unsubstituted C5-20 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is -C(O)R10wherein R10is unsubstituted linear C5-20 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is -C(O)R10wherein R10is unsubstituted unbranched C5-20 alkyl.

[0162] In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof: wherein, R1is -C(O)R7wherein R7is C5-20 alkyl and wherein R6is -C(O)R10wherein R10is C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is linear C5-20 alkyl and wherein R6is - C(O)R10wherein R10is linear C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unbranched C5-20 alkyl and wherein R6is -C(O)R10wherein R10is unbranched C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted C5-20 alkyl and wherein R6is -C(O)R10wherein R10is unsubstituted C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted linear C5-20 alkyl and wherein R6is -C(O)R10wherein R10is unsubstituted linear C5-20 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted unbranched C5-20 alkyl and wherein R6is -C(O)R10wherein R10is unsubstituted unbranched C5-20 alkyl.

[0163] In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof: wherein, R1is -C(O)R7wherein R7is C8-18 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is linear C8- 18 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unbranched C8-18 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is - C(O)R7wherein R7is unsubstituted C8-18 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted linear C8-18 alkyl. In an aspect, the invention relates to a compound of Formula IH, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted unbranched C8-18 alkyl.

[0164] In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof:

[0165] IJ wherein, R6is -C(O)R10wherein R10is C8-18 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is -C(O)R10wherein R10is linear Cs-18 alkyl. In an aspect, the invention relates to a compound of Formula IJ, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is -C(O)R10wherein R10is unbranched C8-18 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is - C(O)R10wherein R10is unsubstituted C8-18 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is -C(O)R10wherein R10is unsubstituted linear C8-18 alkyl. In an aspect, the invention relates to a compound of Formula I J, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R6is -C(O)R10wherein R10is unsubstituted unbranched C8-18 alkyl.

[0166] In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof: wherein, R1is -C(O)R7wherein R7is C8-18 alkyl and wherein R6is -C(O)R10wherein R10is Cs-18 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is linear C8-18 alkyl and wherein R6is - C(O)R10wherein R10is linear C8-18 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unbranched C8-18 alkyl and wherein R6is -C(O)R10wherein R10is unbranched Cs-is alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted C8-18 alkyl and wherein R6is -C(O)R10wherein R10is unsubstituted C8-18 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted linear C8-18 alkyl and wherein R6is -C(O)R10wherein R10is unsubstituted linear C8-18 alkyl. In an aspect, the invention relates to a compound of Formula IK, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein R1is -C(O)R7wherein R7is unsubstituted unbranched C8-18 alkyl and wherein R6is -C(O)R10wherein R10is unsubstituted unbranched C8-18 alkyl. A further aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0167] The term “pharmaceutically acceptable” as used herein is consistent with the art and means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.

[0168] As used herein, “carrier” or “excipient” includes any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline or phosphate buffered saline), solubilisers, colloids, dispersion media, vehicles, fillers, chelating agents (such as, e.g., EDTA or glutathione), amino acids (such as, e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavourings, aromatisers, thickeners, agents for achieving a depot effect, coatings, antifungal agents, preservatives, antioxidants, tonicity controlling agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active substance, its use in the therapeutic compositions may be contemplated.

[0169] Illustrative, non-limiting carriers for use in formulating the pharmaceutical compositions include, for example, oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for intravenous (IV) use, liposomes or surfactant-containing vesicles, microspheres, microbeads and microsomes, powders, tablets, capsules, suppositories, aqueous suspensions, aerosols, and other carriers apparent to one of ordinary skill in the art.

[0170] Pharmaceutical compositions as intended herein may be formulated for essentially any route of administration, such as without limitation, oral administration (such as, e.g., oral ingestion or inhalation), intranasal administration (such as, e.g., intranasal inhalation or intranasal mucosal application), parenteral administration (such as, e.g., subcutaneous, intravenous (I.V.), intramuscular, intraperitoneal or intrasternal injection or infusion), transdermal or transmucosal (such as, e.g., oral, sublingual, intranasal) administration, topical administration, rectal, vaginal or intra-tracheal instillation, and the like. In this way, the therapeutic effects attainable by the methods and compositions can be, for example, systemic, local, tissue-specific, etc., depending of the specific needs of a given application. In a preferred embodiment, the pharmaceutical compositions as described herein are formulated for parenteral administration, such as preferably intramuscular, subdermal, or subcutaneous administration. The pharmaceutical compositions as described herein may be delivered as or function as depot injections.

[0171] Overall, the requirements for effective pharmaceutical carriers for parenteral compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250, (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).

[0172] The dosage or amount of the agent as taught herein, optionally in combination with one or more other active compounds to be administered, depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, the unit dose and regimen depend on the nature and the severity of the disorder to be treated, and also on factors such as the species of the subject, the sex, age, body weight, general health, diet, mode and time of administration, immune status, and individual responsiveness of the human or animal to be treated, efficacy, metabolic stability and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to the agent of the invention. In order to optimize therapeutic efficacy, the compound or the pharmaceutical composition as taught herein can be first administered at different dosing regimens. Typically, levels of the agent in a tissue can be monitored using appropriate screening assays as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. The frequency of dosing is within the skills and clinical judgement of medical practitioners (e.g., doctors, veterinarians or nurses). Typically, the administration regime is established by clinical trials which may establish optimal administration parameters. However, the practitioner may vary such administration regimes according to the one or more of the aforementioned factors, e.g., subject’s age, health, weight, sex and medical status. The frequency of dosing can be varied depending on whether the treatment is prophylactic or therapeutic. It will be understood that in general, the dose to be administered to a subject in need thereof corresponds to an effective dose, i.e. a dose achieving the desired therapeutic effect. Toxicity and therapeutic efficacy of the agent as described herein or pharmaceutical compositions comprising the same can be determined by known pharmaceutical procedures in, for example, cell cultures or experimental animals. These procedures can be used, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions that exhibit high therapeutic indices are preferred. While pharmaceutical compositions that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to normal cells (e.g., non-target cells) and, thereby, reduce side effects.

[0173] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in appropriate subjects. The dosage of such pharmaceutical compositions lies generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilised. For a pharmaceutical composition used as described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e. , the concentration of the pharmaceutical composition which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

[0174] In certain embodiments, 1-360 mg / day of the compound as taught herein is to be administered, such as 1-15 mg / day, 1-20 mg / day, 1-40 mg / day, 1-60 mg / day, 1-80 mg / day, 1-100 mg / day, 1-120 mg / day, 1-140 mg / day, 5-15 mg / day, 5-20 mg / day, 5-40 mg / day, 5-60 mg / day, 5-80 mg / day, 5-100 mg / day, 5-120 mg / day, 5-140 mg / day, 5-200 mg / day, 5-250 mg / day, 5-300 mg / day, 5-350 mg / day, 10-20 mg / day, 10-40 mg / day, IQ- 60 mg / day, 10-80 mg / day, 10-100 mg / day, 10-120 mg / day, 10-140 mg / day, 10-200 mg / day, 10-250 mg / day, 10-300 mg / day, 10-350 mg / day, 20-40 mg / day, 20-60 mg / day, 20-80 mg / day, 20-100 mg / day, 20-120 mg / day, 20-140 mg / day, 20-200 mg / day, 20-250 mg / day, 20-300 mg / day, 20-350 mg / day, 40-60 mg / day, 40-80 mg / day, 40-100 mg / day, 40-120 mg / day, 40-140 mg / day, 40-200 mg / day, 40-250 mg / day, 40-300 mg / day, 40- 350 mg / day, 60-80 mg / day, 60-100 mg / day, 60-120 mg / day, 60-140 mg / day, 60-200 mg / day, 60-250 mg / day, 60-300 mg / day, 60-350 mg / day, 100-120 mg / day, 100-140 mg / day, 100-200 mg / day, 100-250 mg / day, 100-300 mg / day, 100-350 mg / day, 150-200 mg / day, 150-250 mg / day, 150-300 mg / day, or 150-350 mg / day. In certain embodiments, 0.01-10 mg / kg / day (i.e. mg per kg bodyweight per day) of the compound as taught herein is to be administered, such as 0.01-8 mg / kg / day, 0.01-6 mg / kg / day, 0.01-4 mg / kg / day, 0.01-3 mg / kg / day, 0.01-2 mg / kg / day, 0.01-1 mg / kg / day, 0.01-0.8 mg / kg / day, 0.01-0.5 mg / kg / day, 0.01-0.25 mg / kg / day, 0.01-0.1 mg / kg / day, 0.02-8 mg / kg / day, 0.02-6 mg / kg / day, 0.02-4 mg / kg / day, 0.02-3 mg / kg / day, 0.02-2 mg / kg / day, 0.02-1 mg / kg / day, 0.02-0.8 mg / kg / day, 0.02-0.5 mg / kg / day, 0.02-0.25 mg / kg / day, 0.02-0.1 mg / kg / day, 0.05-8 mg / kg / day, 0.05-6 mg / kg / day, 0.05-4 mg / kg / day, 0.05-3 mg / kg / day, 0.05-2 mg / kg / day, 0.05-1 mg / kg / day, 0.05-0.8 mg / kg / day, 0.05-0.5 mg / kg / day, 0.05-0.25 mg / kg / day, 0.05-0.1 mg / kg / day, 0.1-8 mg / kg / day, 0.1-6 mg / kg / day, 0.1-4 mg / kg / day, 0.1-

[0175] 3 mg / kg / day, 0.1-2 mg / kg / day, 0.1-1 mg / kg / day, 0.1 -0.8 mg / kg / day, 0.1 -0.5 mg / kg / day, 0.1-0.25, 0.5-8 mg / kg / day, 0.5-6 mg / kg / day, 0.5-4 mg / kg / day, 0.5-3 mg / kg / day, 0.5-2 mg / kg / day, 0.5-1 mg / kg / day, 0.5-0.8 mg / kg / day, 0.8-8 mg / kg / day, 0.8-6 mg / kg / day, 0.8-

[0176] 4 mg / kg / day, 0.8-3 mg / kg / day, 0.8-2 mg / kg / day, 0.8-1 mg / kg / day, 1-8 mg / kg / day, 1-6 mg / kg / day, 1-4 mg / kg / day, 1-3 mg / kg / day, or 1-2 mg / kg / day. In certain embodiments, a dose corresponding to 1-360 mg / day (or any of the above dosages, including those expressed in mg / kg / day) of active ingredient of the compound as taught herein (i.e. the active metabolite, such as for instance pipamperone) is to be administered. As the compounds of the invention as described herein are (long acting) prodrugs, they need not necessarily be administered daily. The skilled person will understand that if the compound is administered less than daily (e.g. weekly), the dose may need to be adapted accordingly (and for instance be provided by depot injection), such as for instance corresponding to a daily dose of 1-360 mg (or any of the above dosages, including those expressed in mg / kg / day) of active ingredient, e.g. pipamperone (for instance as determined in blood or serum). The skilled person will understand that the dose or dose range (of active ingredient) may depend on the disease or disorder to be (therapeutically of prophylactical ly) treated. For instance, for the treatment of affective disorders, a dose of 1-20 mg / day may apply and for instance for the treatment of psychotic disorders a dose of 40-360 mg / day may apply. In some embodiments, the compound as taught herein is the main or only active ingredient of the pharmaceutical composition.

[0177] In some embodiments the compound as taught herein is or is to be administered simultaneously with or subsequent to, in either order, one or more further active ingredient(s). It will be understood that multiple active ingredients may be administered as a single (i.e. combined) or multiple (pharmaceutical) compositions. For instance the compound of the invention may be administered parenteral and additional active ingredients, such as described below, may be administered orally. It will be understood that dosage regimes may be the same or different, such as less than daily administration of the compound of the invention (e.g. weekly) and daily (or bidaily) administration of additional active ingredients, such as those described below.

[0178] In some embodiments the compound as taught herein is or is to be administered as an adjuvant or adjunctive therapy simultaneously with or subsequent to, in either order, one or more further active ingredient(s).

[0179] In some embodiments the compound as taught herein is or is to be administered as a maintenance therapy.

[0180] In some embodiments, the or more further active ingredient(s) are selected from selective serotonin reuptake inhibitors (SSRI) (such as citalopram (e.g. Celexa), escitalopram (e.g. Lexapro), fluoxetine (e.g. Prozac), fluvoxamine (e.g. Luvox), paroxetine (e.g. Paxil), sertraline (e.g. Zoloft), dapoxetine (e.g. Prilligy), indalpine (e.g.Upstene), zimelidine (e.g. Zelmid), alaproclate (GEA-654), centpropazine, cericlamine (JO-1017), femoxetine (Malexil; FG-4963), ifoxetine (CGP-15210), omiloxetine, panuramine (WY-26002), pirandamine (AY-23713), seproxetine ((S)- norfluoxetine)), serotonin-norepinephrine reuptake inhibitors (SNRI) (such as atomoxetine (e.g. Strattera), desvenlafaxine (e.g. Pristiq, Khedezla), duloxetine (e.g. Cymbalta, Irenka), levomilnacipran (e.g. Fetzima), milnacipran (e.g. Ixel, Savella, Impulsor), sibutramine (e.g. Meridia), tramadol (e.g. Ultrarn), venlafaxine (e.g. Effexor)), serotonin modulators and stimulators (SMS) (such as vortioxetine, vilazodone), serotonin antagonists and reuptake inhibitors (SARI) (such as etoperidone (e.g. Axiomin, Etonin), lorpiprazole (e.g. Normarex), mepiprazole (e.g. Psigodal), nefazodone (e.g. Serzone, Nefadar), trazodone (e.g. Desyrel), vilazodone (e.g. Viibryd), vortioxetine (e.g. Trintellix), niaprazine (e.g. Nopron), medifoxamine (e.g.Cledial, Gerdaxyl), lubazodone), norepinephrine reuptake inhibitors (NRI or NERI) (such as amedalin (UK-3540-1), atomoxetine (e.g. Strattera), CP-39,332, daledalin (UK-3557-15), edivoxetine (LY- 2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (e.g. Edronax, Vestra), talopram (e.g. tasulopram) (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), viloxazine (Vivalan), including NRIs with activity at other sites such as bupropion (e.g. Wellbutrin, Zyban), ciclazindol (Wy-23,409), duloxetine, manifaxine (GW-320,659), maprotiline (e.g. Deprilept, Ludiomil, Psymion), radafaxine (GW-353,162), tapentadol (e.g. Nucynta), teniloxazine (e.g. Lucelan, Metatone), protriptyline (e.g. Vivactil), nortriptyline (e.g. Pamelor), desipramine (e.g. Norpramin)), norepinephrine-dopamine reuptake inhibitors (NDRI) (such as bupropion), tricyclic antidepressants (TCA) (such as butriptyline (e.g. Evadyne), clomipramine (e.g. Anafranil), imipramine (e.g. Tofranil, Janimine, Praminil), trimipramine (e.g. Surmontil), desipramine (e.g. Norpramin, Pertofrane), dibenzepin (e.g. Noveril, Victoril), lofepramine (e.g. Lomont, Gamanil), maprotiline (e.g. Ludiomil), nortriptyline (e.g. Pamelor, Aventyl, Norpress), protriptyline (e.g. Vivactil), amitriptyline (e.g. Elavil, Endep), amitriptylinoxide (e.g.Amioxid, Ambivalon, Equilibrin), amoxapine (e.g. Asendin), demexiptiline (e.g. Deparon, Tinoran), dimetacrine (e.g. Istonil, Istonyl, Miroistonil), dosulepin (e.g. Prothiaden), doxepin (e.g. Adapin, Sinequan), fluacizine (e.g. Phtorazisin), imipraminoxide (e.g. Imiprex, Elepsin), melitracen (e.g. Deanxit, Dixeran, Melixeran, Trausabun), metapramine (e.g. Timaxel), nitroxazepine (e.g. Sintamil), noxiptiline (e.g. Agedal, Elronon, Nogedal), pipofezine (e.g. Azafen / Azaphen), propizepine (e.g. Depressin, Vagran), quinupramine (e.g. Kevopril, Kinupril, Adeprim, Quinuprine), amineptine (e.g. Survector, Maneon, Directim), iprindole (e.g. Prondol, Galatur, Tetran), opipramol (e.g. Insidon, Pramolan, Ensidon, Oprimol), tianeptine), tetracyclic antidepressants (TeCA) (such as maprotiline (e.g. Ludiomil), mianserin (e.g. Tolvon), mirtazapine (e.g. Remeron), setiptiline (e.g. Tecipul), amoxapine (e.g. Asendin), benzoctamine (e.g. Tacitin), loxapine (e.g. Adasuve, Loxitane), mazindol (e.g. Mazanor, Sanorex, aptazapine (CGS-7525A), esmirtazapine (ORG-50,081), oxaprotiline (C 49- 802 BDA), ciclazindol (WY-23,409)), monoamine oxidase inhibitors (MAGI) (such as isocarboxazid (e.g. Marplan), nialamide (e.g. Niamid), phenelzine (e.g. Nardil, Nardelzine), hydracarbazine, tranylcypromine (e.g. Parnate, Jatrosom), bifemelane (e.g. Alnert, Celeport), moclobemide (e.g. Aurorix, Manerix), pirlindole (e.g. Pirazidol, toloxatone (e.g. Humoryl), rasagiline (e.g. Azilect), selegiline (e.g. Deprenyl, Eldepryl, Emsam, Zelapar), safinamide (e.g. Xadago), linezolid, benmoxin (e.g. Nerusil, Neuralex), iproclozide (e.g. Sursum), iproniazid (e.g. Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida), mebanazine (e.g. Actomol), octamoxin (e.g. Ximaol, Nimaol), pheniprazine (e.g. Catron), phenoxypropazine (e.g. Drazine), pivalylbenzhydrazine (e.g. Tersavid), safrazine (e.g. Safra), caroxazone (e.g. Surodil, Timostenil), minaprine (e.g. Cantor), brofaromine (e.g. Consonar), caroxazone (e.g. Surodil, Timostenil), eprobemide (e.g. Befol), methylene blue, metralindole (e.g. Inkazan), minaprine (e.g. Cantor), moclobemide (e.g. Aurorix, Manerix), pirlindole (e.g. Pirazidol), toloxatone (e.g. Humoryl), curcumin, harmaline, harmine, amiflamine (FLA-336), befloxatone (MD- 370,503), cimoxatone (MD-780,515), esuprone, sercloremine (CGP-4718-A), tetrindole, CX157 (TriRima)), and NMDA receptor antagonists (e.g. ketamine, esketamine), preferably said medicament is a selective serotonin reuptake inhibitors (SSRI), preferably citalopram or escitalopram.

[0181] In an aspect, the invention relates to a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I as described herein for use in therapy or prophylaxis of a disease or disorder, or for use as a medicament, for instance as adjuvant or maintenance therapy, optionally simultaneously with or subsequent to, in either order, with one or more further active ingredient(s).

[0182] In an aspect, the invention relates to the use of a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I for the manufacture of a (therapeutic of prophylactic) medicament, for instance for adjuvant or maintenance therapy, optionally simultaneously with or subsequent to, in either order, with one or more further active ingredient(s).

[0183] In an aspect, the invention relates to a method of (therapeutic of prophylactic) treatment (of a disease or disorder), for instance adjuvant or maintenance therapy, optionally simultaneously with or subsequent to, in either order, with one or more further active ingredient(s), comprising administering a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I to a subject in need thereof. In certain embodiments, the invention relates to a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I as described herein for use in therapy or for use in the (therapeutic or prophylactic) treatment of mood disorders, sleep disorders, psychotic disorders, excitement and agitation, including psychomotoric states of excitation disorders, behavioural disorders, including autistic behaviour, and / or disorders with impaired cognition, for instance as adjuvant or maintenance therapy, optionally simultaneously with or subsequent to, in either order, with one or more further active ingredient(s).

[0184] In certain embodiments, the invention relates to the use of a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I as described herein for the manufacture of a medicament for (therapeutically or prophylactically) treating mood disorders, sleep disorders, psychotic disorders, excitement and agitation, including psychomotoric states of excitation disorders, behavioural disorders, including autistic behaviour, and / or disorders with impaired cognition, for instance as adjuvant or maintenance therapy, optionally simultaneously with or subsequent to, in either order, with one or more further active ingredient(s).

[0185] In certain embodiments, the invention relates to a method of (therapeutically or prophylactically) treating mood disorders, sleep disorders, psychotic disorders, excitement and agitation, including psychomotoric states of excitation disorders, behavioural disorders, including autistic behaviour, and / or disorders with impaired cognition, comprising administering a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I as described herein to a subject in need thereof, for instance as adjuvant or maintenance therapy, optionally simultaneously with or subsequent to, in either order, with one or more further active ingredient(s).

[0186] In certain embodiments, mood disorders are selected from Major depressive disorder, Atypical depression, Melancholic depression, Psychotic depression, Depressive Disorder not otherwise specified, Postpartum depression, Dysthymia, Adjustment disorder with depressed mood, and Seasonal affective disorder. In certain embodiments, the invention relates to a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I as described herein for use in (therapeutic or prophylactic) therapy or for use in the (therapeutic or prophylactic) treatment of cognitive disorders, such as cognitive disorders in a subject having a mood disorder or mood disorder in remission, in particular major depressive disorder or major depressive order in remission.

[0187] In certain embodiments, the invention relates to the use of a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I as described herein for the manufacture of a medicament for (therapeutically or prophylactical ly) treating cognitive disorders, such as cognitive disorders in a subject having a mood disorder or mood disorder in remission, in particular major depressive disorder or major depressive order in remission.

[0188] In certain embodiments, the invention relates to a method of (therapeutically or prophylactically) treating cognitive disorders, such as cognitive disorders in a subject having a mood disorder or mood disorder in remission, in particular major depressive disorder or major depressive order in remission, comprising administering a compound of Formula I as described herein or the pharmaceutical composition comprising the compound of Formula I as described herein to a subject in need thereof.

[0189] In certain embodiments, the cognitive disorder is subjective cognitive decline, (pre-)mild cognitive disorder or impairment, (pre-)prodomal neurodegenerative disorder, or pre- clinical or asymptomatic neurodegenerative disorder.

[0190] In certain embodiments, the subject to be treated according to the invention has subjective cognitive decline (SCD).

[0191] In certain embodiments, the cognitive disorder as described herein elsewhere is subjective cognitive decline (SCD).

[0192] As used herein, the term “cognitive disorder” also known as “neurocognitive disorder” refers to a category of mental health disorders that primarily affect cognitive abilities including learning, memory, perception, and problem solving. Neurocognitive disorders include delirium and mild and major neurocognitive disorder (also known as dementia). They are defined by deficits in cognitive ability that are acquired (as opposed to developmental), typically represent decline, and may have an underlying brain pathology. The DSM-5 defines six key domains of cognitive function: executive function, learning and memory, perceptual-motor function, language, complex attention, and social cognition. Neurocognitive disorders are described in DSM-5 as those with “a significant impairment of cognition or memory that represents a marked deterioration from a previous level of function”.

[0193] Although Alzheimer's disease accounts for the majority of cases of neurocognitive disorders, there are various medical conditions that affect mental functions such as memory, thinking, and the ability to reason, including frontotemporal degeneration, Huntington’s disease, Lewy body disease, traumatic brain injury (TBI), Parkinson’s disease, prion disease, and dementia / neurocognitive issues due to HIV infection. Neurocognitive disorders are diagnosed as mild and major based on the severity of their symptoms. While anxiety disorders, mood disorders, and psychotic disorders can also have an effect on cognitive and memory functions, the DSM-5 does not consider these cognitive disorders, because loss of cognitive function is not the primary (causal) symptom. Additionally, developmental disorders such as Autism spectrum disorder are typically developed at birth or early in life as opposed to the acquired nature of neurocognitive disorders.

[0194] A prodrome is an early sign or symptom (or set of signs and symptoms), which often indicate the onset of a disease before more diagnostically specific signs and symptoms develop. The prodrome is a period during which an individual experiences some symptoms and / or a change in functioning, which can signal the impending onset of a disease or disorder. It is otherwise known as the prodromal phase when referring to the subsyndromal stage or the early abnormalities, for instance in behaviour, mood, and / or cognition before illness onset. In the very early stages, for instance in the case of neurodegenerative disorders such as Alzheimer’s disease, when the neuropathology is confined, the neuropsychological symptoms may not be apparent at all (latent phase), but as the pathology cumulates over time early symptoms emerge (prodrome stage) followed later by fully manifest clinical disease (dementia stage). Prodromal AD can be defined as the symptomatic predementia phase of AD, generally included in the MCI category; this stage is characterised by symptoms not severe enough to meet currently accepted diagnostic criteria for AD. Typically, prodromal Alzheimer’s disease is the very early form of Alzheimer’s when memory is deteriorating but a person remains functionally independent. MCI can be considered a (symptom of) prodromal neurodegenerative disease such as pre-prodromal Alzheimer’s disease, in particular if positive for the relevant biomarkers, such as in the case of Alzheimer’s disease amyloidosis or neurodegeneration, and where deterioration in cognitive performance can detected objectively through formal neuropsychological testing, but not severe enough to be classified as dementia. Subjectively perceived memory problems (such as SCD) can be an indicator of a pre-prodromal stage of a neurodegenerative disease such as Alzheimer's disease. SCD can be considered (a symptom of) a pre-prodromal neurodegenerative disease such as pre-prodromal Alzheimer’s disease, in particular if positive for the relevant biomarkers, such as in the case of Alzheimer’s disease amyloidosis (neuropathologic p-amyloid plaque and tau accumulation) or neurodegeneration, but in the absence of any objective cognitive deficits such as with detection through formal neuropsychological testing or where deterioration in cognitive performance cannot detected objectively through formal neuropsychological testing.

[0195] Subjects having a pre-clinical or asymptomatic neurodegenerative disease, such as Alzheimer’s disease, are characterized by the presence of biomarkers for the disease, without being impaired by the disease of without showing the characteristic symptoms of the disease. In particular, individuals with preclinical or asymptomatic AD have AD pathology without clinical symptoms yet. Accordingly, preclinical or asymptomatic AD is characterised by positive biomarkers, such as amyloidosis (neuropathologic p-amyloid plaque and tau accumulation) and neurodegeneration, without cognitive impairment or in the absence of any objective cognitive deficits such as with detection through formal neuropsychological testing or if deterioration in cognitive performance cannot detected objectively through formal neuropsychological testing, such as for instance in subjects with SCD, pre-MCI, and / or pre-prodromal AD. Vice versa, subjects with SCD, pre-MCI, and / or pre-prodromal AD may be characterized as having preclinical or asymptomatic AD.

[0196] Subjective cognitive decline (SCD), also known as subjective cognitive impairment or subjective cognitive concerns, is characterized by a person’s subjective experience of worsening in cognition (in particular in, though not limited to, the memory domain), in the absence of any objective cognitive deficits such as with detection through formal neuropsychological testing (e.g. through MMSE, where a score of at least 26, such as at least 27, at least 28, at least 29, or 30 may be obtained). SCD can also be considered as pre-mild cognitive impairment (pre-MCI) in the absence of any objective cognitive deficits such as with detection through formal neuropsychological testing or in cases where deterioration in cognitive performance cannot be detected objectively through formal neuropsychological testing. The rationale and meaning of the term of subjective cognitive decline are the following (Jenssen et al. (2014), Alzheimers Dement, 10(6):844- 52). “Subjective” refers to the self-perception or self-experience of cognitive performance. It is conceptually independent of performance on a cognitive test. No “validation” of the subjective experience of cognitive capability by means of cognitive testing is required. In the context of SCD in preclinical AD, cognitive testing is required to establish a normal objective performance level, which defines preclinical AD. If SCD is studied in other conditions than preclinical AD, the respective criteria set for these conditions (e.g. MCI) need to be applied. “Cognitive” refers to any cognitive domain. It includes, but is not restricted to memory. Cognitive as opposed to memory was chosen for the following reasons: (1) the first symptoms of for instance AD are not limited to memory decline and (2) lay people may report memory decline when they actually experience decline in other cognitive domains such as executive function and vice versa (e.g., reporting a “speech problem” when the difficulty is really memory retrieval). This notwithstanding, SCD is sometimes also referred to as subjective memory impairment, complaint, or disorder. “Decline” refers to a subjectively experienced worsening of cognitive capacities. It reflects the progressive nature of cognitive deterioration, such as for instance in AD. It refers to the idea of progressive deterioration or a change from the previous level of functioning and not just an isolated complaint. The criteria for SCD can be (Net and Nitrini (2016), Dement Neuropsychol, 10(3): 170-77): (1) self-experienced persistent decline in cognitive abilities compared with previously normal status and not related to an acute event; and (2) normal performance on standardized cognitive tests (for age, gender and education); while exclusion criteria are: (1) mild cognitive impairment or dementia diagnosis; and (2) decline explained by psychiatric disorders, neurological diseases (except (pre-clinical) Alzheimer's disease), other medical disorders, medication or other substance use. Additional criteria can be onset of decline within the last five years, age at onset above 60 years, associated concerns about decline and confirmation by an informant (such as a relative). Epidemiological data have shown that individuals with subjective cognitive decline are at increased risk of progression to (AD) dementia. SCD may or may not be associated with the prevalence of positive biomarkers for instance for amyloidosis (neuropathologic p-amyloid plaque and tau accumulation) and neurodegeneration. Furthermore, individuals with subjective cognitive decline in combination with major depressive disorder even have a higher increased risk of progression to (AD) dementia (Liew (2019), Alzheimers Res Ther, 11(1):70; doi 10.1186 / s13195-019-0527-7).

[0197] In certain embodiments, the subject to be treated according to the invention has mild cognitive impairment (MCI) or pre-mild cognitive impairment (pre-MCI).

[0198] Mild cognitive impairment (MCI), also known as incipient dementia and isolated memory impairment, is the stage between the expected cognitive decline of normal aging and the more serious decline of dementia. It is a neurological disorder that occurs in older adults which involves cognitive impairments with minimal impairment in instrumental activities of daily living. It can involve problems with memory, language, thinking and judgment that are greater than normal age-related changes. When having mild cognitive impairment, a subject may be aware that his memory or mental function has "slipped." Family and close friends also may notice a change. But these changes aren't severe enough to significantly interfere with daily life and usual activities. Mild cognitive impairment may increase the risk of later developing dementia caused by Alzheimer's disease or other neurological conditions. But some people with mild cognitive impairment never get worse, and a few eventually get better. There's no single cause of mild cognitive impairment (MCI), just as there's no single outcome for the disorder. Symptoms of MCI may remain stable for years, progress to Alzheimer's disease or another type of dementia, or improve over time. Current evidence indicates that MCI often, but not always, develops from a lesser degree of the same types of brain changes seen in Alzheimer's disease or other forms of dementia. Some of these changes have been identified in autopsy studies of people with MCI. These changes include: abnormal clumps of beta-amyloid protein (plaques) and microscopic protein clumps of tau characteristic of Alzheimer's disease (tangles); Lewy bodies, which are microscopic clumps of another protein associated with Parkinson's disease, dementia with Lewy bodies and some cases of Alzheimer's disease; Small strokes or reduced blood flow through brain blood vessels. Pre-MCI can be considered as an intermediate stage between no cognitive impairment (NCI) and mild cognitive impairment (MCI), and can be characterized by cognitive, functional, motor, behavioural and / or imaging features that are intermediate between NCI and MCI states. Pre-MCI can be SCD in the absence of any objective cognitive deficits such as with detection through formal neuropsychological testing or if deterioration in cognitive performance cannot be detected objectively through formal neuropsychological testing (e.g. only imaging or biomarkers reveal impairment).

[0199] As used herein, the terms “treatment”, “treating”, and the like relate to amelioration or elimination of a developed cognitive disorder once it has been established or alleviation of the characteristic symptoms of such disorder. It is to be understood that compete elimination of the disorder need not be achieved for the term treatment to apply. Partial treatment is hence also encompassed by the term treatment. Also a future recurrence of the disease or disorder does not preclude the term treatment to apply if at one point at least the disease is eliminated or ameliorated.

[0200] As used herein the terms “prophylaxis”, and the like relate to preventing the onset of a disease or disorder or of symptoms associated with a disorder, including partial prevention by reducing the severity of the disorder or symptoms associated therewith by treatment prior to affliction with said disease or condition. Such prevention or reduction prior to affliction refers to administration of the compound or composition or applying the methods of the invention to a patient that is not at the time of administration afflicted with the disease or disorder. “Prophylaxis” also encompasses (partially) preventing the recurrence or relapse-prevention of a disease or disorder or of symptoms associated therewith, for instance after a period of improvement.

[0201] Prophylaxis and treatment also encompass delaying or preventing the onset and / or progression of a disease or disorder.

[0202] As used herein the terms “delaying the onset” and the like relate to postponement of the onset of a disease or disorder or of symptoms associated with the disorder. The onset of the disorder may for instance be postponed by at least half a year, such as at least one year. The exact time of the onset of the disease may possibly not be unequivocally determined. However, the time of diagnosis of the disease or disorder may serve as a proxy.

[0203] As used herein the terms “delaying the progression” or “preventing the progression” and the like relate to delaying or preventing the disease or disorder (once it has been established) or the characteristic symptoms of such disorder from getting more severe over time. It will be understood that delay or prevention may not need to be indefinite. It will be further understood that such delay or prevention need not be complete, but may also be partial.

[0204] It should be clear that disease or disorder may be responsible for physical complaints. In this respect, the terms specified above also include prevention, delaying the onset and / or progression, or treatment of a physical disease or condition or amelioration or elimination of the developed physical disease, characteristic, or condition once it has been established or alleviation of the characteristic symptoms of such conditions.

[0205] As used herein, the term “medicament” also encompasses the terms “drug”, “therapeutic”, “potion” or other terms which are used in the field of medicine to indicate a preparation with therapeutic or prophylactic effect.

[0206] As used herein, the term “subject” preferably refers to a subject, preferably human, in need of the prophylactic or therapeutic treatments of the invention as described herein or which will benefit from the prophylactic or therapeutic treatments of the invention as described herein.

[0207] In certain embodiments, the subject to be treated has a medical history of a mood disorder, such as major depressive disorder.

[0208] It will be understood that “medical history of mood disorder” refers to the occurrence of such mood disorder (such as major depressive disorder) during the lifetime of the subject, preferably during adult life of the subject (such as from 16, 17, or 18 years of age onward). Included are recurrent or remittent mood disorders. In certain embodiments, a subject having a medical history of mood disorder has an mood disorder, i.e. at the time of initiating the treatment according to the invention as described herein the subject is afflicted with an mood disorder. In certain embodiments, a subject having a medical history of mood disorder does not have an mood disorder, i.e. at the time of initiating the treatment according to the invention as described herein the subject is not afflicted with an mood disorder or is in (full or partial) remission. In certain embodiments, a subject having an mood disorder does not have a medical history of an mood disorder, i.e. at the time of initiating the treatment according to the invention as described herein the subject does not have a medical history of an mood disorder, i.e. the mood disorder is not recurrent (at the time of diagnosis). In certain embodiments, a subject having an mood disorder has a medical history of an mood disorder, i.e. at the time of initiating the treatment according to the invention as described herein the subject also has a medical history of an mood disorder. In certain embodiments, the subjects to be treated according to the invention have an mood disorder in remission. In certain embodiments, the subjects to be treated according to the invention have major depressive disorder in remission. It will be understood that the subjects to be treated according to the invention, when having (a medical history of) an mood disorder (such as major depressive disorder), may simultaneously receive therapy for an mood disorder (such as major depressive disorder). In certain embodiments, the subjects to be treated according to the invention receive a combination of an effective amount of an antidepressant and a compound or Formula I as described herein.

[0209] In certain embodiments, the subject to be treated has a partially responsive mood disorder or a mood disorder which is partially responsive to (first line) therapy, such as partially responsive major depressive disorder or major depressive disorder which is partially responsive to (first line) therapy.

[0210] In certain embodiments, the compounds of Formula I of the invention are or are to be administered as adjunctive therapy to (first line) antidepressant therapy.

[0211] As used herein, “partially / partial responsive” mood disorder, such as partially / partial responsive depression (e.g. MDD), refers to an mood disorder, such as depression (e.g. MDD), which is partially responsive to anti-mood disorder treatment, such as antidepressant treatment (e.g. anti-MDD treatment). The term can be used interchangeably with partially refractive mood disorder, such as partially refractive depression (e.g. partially refractive MDD). It is to be understood that subjects with partially responsive mood disorder, such as partially responsive depression (e.g. MDD), do not achieve (full) remission upon or after treatment, such as after treatment with antimood disorder medication, such as antidepressants. It is to be understood that partially responsive mood disorder, such as partially responsive depression (e.g. MDD) is to be distinguished from treatment refractory mood disorder, such as treatment refractory depression (e.g. MDD), in which no significant improvement is observed. Treatment refractory subjects can also be classified as non-responders. Preferably, non-responders are classified as having an improvement of less than 25%, preferably less than 10%, more preferably less than 5% of the symptoms as determined according to the appropriate criteria, as described herein elsewhere (e.g. according to MADRS for evaluation of depression), preferably after 4 to 8 weeks of treatment, such as after 6 weeks of treatment. Partially responsive mood disorder, such as partially responsive depression (e.g. MDD), may be characterized by an improvement of at least 20%, more preferably at least 25% and less than 40%, more preferably less than 50% of the symptoms as determined according to the appropriate criteria, as described herein elsewhere (e.g. according to MADRS for evaluation of depression), preferably after 4 to 8 weeks of treatment, such as after 6 weeks of treatment. Partially responsive mood disorder, such as partially responsive depression (e.g. MDD), may be characterized by an improvement of at least 10% and less than 50% of the symptoms as determined according to the appropriate criteria, as described herein elsewhere (e.g. according to MADRS for evaluation of depression), preferably after 4 to 8 weeks of treatment, such as after 6 weeks of treatment. It is to be understood that subjects classified as having partially responsive mood disorder, such as partially responsive depression (e.g. MDD), must have undergone prior or undergo current anti-mood disorder treatment, such as antidepressant treatment, in order to establish partial responsiveness. Accordingly, the subjects classified as having partially responsive mood disorder, such as partially responsive depression (e.g. MDD), are known to be partially responsive. In certain embodiments, the subjects have received or are receiving adjunctive treatment (other than pipamperone), such as described herein elsewhere. In certain embodiments, the subjects to be treated according to the invention which have partially responsive depression (e.g. MDD) have a MADRS total score of at least 20, preferably at least 24, more preferably at least 26. In certain embodiments, the subjects to be treated according to the invention which have partially responsive depression (e.g. MDD) have a MADRS total score of at least 20, preferably at least 24, more preferably at least 26 after first-line treatment. In certain embodiments, the subjects according to the invention are partially responsive to at least 1 antidepressant medication. In certain embodiments, the subjects according to the invention are partially responsive to at least 2 antidepressant medications. In certain embodiments, the subjects according to the invention are partially responsive to at most 4 antidepressant medications. In certain embodiments, the subjects according to the invention are partially responsive to at most 3 antidepressant medications. In certain embodiments, the subjects according to the invention are partially responsive to at least 1 antidepressant medication, such as . at least 2 antidepressant medications and at most 4 antidepressant medications, such as at most 3 antidepressant medications.

[0212] As used herein “adjunctive treatment, “adjunctive therapy”, and the like generally refers to treatment or therapy aiming at increasing therapeutic efficacy of a particular therapeutic. Typically, adjunctive treatment is initiated in cases where a therapeutic fails to achieve a desired clinical outcome. For instance, in the case of depression (such as MDD), adjunctive treatment is initiated in case (full) remission of depression or depressive symptoms is not achieved. Accordingly, adjunctive treatment may be initiated in subjects partially responsive to antidepressant therapy.

[0213] In certain embodiments, the compounds of Formula I of the invention are or are to be administered as maintenance treatment.

[0214] In certain embodiments, the compounds of Formula I of the invention are or are to be administered (as maintenance treatment) for maintaining remission of a mood disorder, such as major depressive disorder.

[0215] In certain embodiments, the compounds of Formula I of the invention are or are to be administered (as maintenance treatment) for preventing relapse of a mood disorder, such as major depressive disorder.

[0216] In certain embodiments, remission (of depression) is achieved. In certain embodiments, remission (of depression) is maintained or prolonged or relapse (of depression) is prevented or postponed. In certain embodiments, remission (of depression) is maintained / prolonged or relapse (of depression) is prevented / postponed for at least 6 months, preferably at least 12 months, more preferably at least 18 months, such as at least 6 months, preferably at least 12 months, more preferably at least 18 months longer than compared to a subject not receiving or having received said dopamine D4 and 5- HT2A receptor antagonist, reverse agonist, or partial agonist.

[0217] In an aspect, the invention relates to a compound of Formula I for use in maintaining or prolonging remission or preventing or postponing relapse of a mood disorder, such as major depressive disorder, after mood disorder (such as antidepressant) therapy in a subject.

[0218] The skilled person will understand that typically once remission (of depression) is achieved, the (first line) (antidepressant) medication is discontinued. The compounds of the invention can therefore be considered to be a maintenance treatment in certain embodiments. In certain embodiments, remission (of depression) is maintained or prolonged or relapse is prevented or postponed for at least 6 months, preferably at least 12 months, more preferably at least 18 months, such as at least 6 months, preferably at least 12 months, more preferably at least 18 months longer than a subject not receiving or having received the compound of Formula I of the invention. The skilled person will understand that the compound of Formula I of the invention may be administered indefinitely, or alternatively may be administered for a fixed or variable period in time, such as for instance (at least) 1 year, 2 years, 3 years, 4 years, 5 years, or more, such as ad vitam.

[0219] In certain embodiments, the compounds of Formula I of the invention are or are to be administered to improve treatment adherence, in particular treatment adherence during mood disorder therapy, such as major depressive disorder therapy.

[0220] In certain embodiments, treatment adherence is improved. The skilled person will understand that improvement of treatment adherence refers to a diminished incidence of antidepressant treatment discontinuation. In certain embodiments, treatment adherence is improved by at least 20%, for instance less than 20% of subjects discontinue antidepressant therapy (compared to treatment without the dopamine D4 and 5-HT2A receptor antagonist, reverse agonist, or partial agonist), or for instance at least 20% less subjects discontinue the treatment (compared to treatment without the dopamine D4 and 5-HT2A receptor antagonist, reverse agonist, or partial agonist).

[0221] In an aspect, the invention relates to a compound of Formula I for use in improving treatment adherence during mood disorder therapy, such as antidepressant therapy, such as treatment adherence compared to a subject not receiving or having received a compound of Formula I or relative to treatment adherence in the subject prior to receiving a compound of Formula I. The skilled person will understand that improvement of treatment adherence refers to a diminished incidence of mood disorder, such as antidepressant, treatment discontinuation. In certain embodiments, treatment adherence is improved by at least 20%, i.e. less than 20% of subjects discontinue therapy (compared to treatment without the compound of Formula I).

[0222] The skilled person will understand that whenever reference is made herein to a compound of Formula I, this explicitly includes a reference to any of compounds IA to IN, as described herein elsewhere. Accordingly, all aspects and embodiments referring to a compound of Formula I explicitly read on any of compounds of Formula IA to IN.

[0223] Examples

[0224] Example 1 : Synthesis of pipamperone prodrugs

[0225] Analytical methods

[0226] LCMS

[0227] Method A

[0228] Instrument: Agilent 1260 Infinity II, 1260 G7112B Bin. Pump, 1260 G7167A Multisampler, 1260 MCT G7116A Column Comp. 1260 G7115A DAD (210, 220 and 210-320 nm), PDA (210-320 nm), G6130B MSD (ESI pos / neg) mass range 90-1800, Alltech 3300 ELSD (Neb temp. 50°C, gas flow 1.3 ml / min), Column: XTerra MS C8 (50x2.1 mm 3.5p) Flow: 1 ml / min, Column temp.: 50°C, Eluent A: 0.1% Formic acid in Water, Eluent B: 0.1% Formic acid in Acetonitrile, Gradient: t=0 min 5% B, t=4.5 min 98%B, t=6 min 98% B, Post run: 2 min. MS Parameters: source API-ES, Capillary voltage: 3000 V, Drying gas flow: 13 L / min, Nebulizer Pressure 60 psig, Drying Gas Temp: 350 °C, Fragmentor 70.

[0229] SFC

[0230] Method B

[0231] Instrument: Waters Acquity LIPC2: Waters ACQ-ccBSM Binary Pump; Waters ACQ- CCM Convergence Manager; Waters ACQ-SM Sample Manager - Fixed Loop; Waters ACQ-CM Column Manager - 30S; Waters ACQ-PDA Photodiode Array Detector (210- 320 nm); Waters ACQ-ISM Make Up Pump, Waters Acquity QDa MS Detector (ESI pos, mass range 300-1000); Column: Waters Acquity UPC2 Torus 2-PIC (100x3.0mm 1.7pm); Column temp: 40°C; Flow: 1.0 ml / min; BPR: 170 bar; Eluent A: CO2, Eluent B: (MeOH + 20 mM Ammonia); Gradient: t=0 min 2% B, t=4 min 50% B, t=6 min 50% B; Postrun: 0.5 min

[0232] Free base of pipamperone

[0233] 1'-(4-(4-fluorophenyl)-4-oxobutyl)-[1 ,4'-bipiperidine]-4'-carboxamide.

[0234] Comp. 1 was obtained by treating pipamperone dihydrochloride with a saturated aqueous solution of NaHCOs at room temperature for 1 h.

[0235] Pipamperone dihydrochloride (886 mg, 1 Eq, 1.98 mmol) was dissolved in an aqueous saturated solution of NaHCOs (150 mL) and then stirred at room temperature for 1 hour. Then, EtOAc was added (100 mL) and the aqueous layer was extracted with EtOAc twice. Combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1'-(4-(4-fluorophenyl)-4-oxobutyl)- [1 ,4'-bipiperidine]-4'-carboxamide (723 mg, 97%) as white solid. LCMS: >97% (Method B); m / z [M+H]+ = 376.2. 1 H NMR (400 MHz, CDCI3) δ 8.04 - 7.95 (m, 2H), 7.12 (t, J = 8.6 Hz, 2H), 6.65 (s, 1 H), 5.26 - 4.98 (m, 1 H), 2.94 (t, J = 7.1 Hz, 2H), 2.83 - 2.65 (m, 2H), 2.43 (dt, J = 22.0, 6.0 Hz, 8H), 1 .93 (p, J = 7.2 Hz, 2H), 1.75 (t, J = 4.8 Hz, 4H), 1 .53 (p, J = 5.6 Hz, 4H), 1.43 (q, J = 5.7 Hz, 2H).

[0236] 723 mg with a purity >97% was obtained.

[0237] Pipamperone prodrugs

[0238] Different pipamperone prodrugs (Comp. 2, Comp. 3, and Comp. 4; Figure 1) were produced as follows.

[0239] To a cooled (-5°C) suspension of Pipamperone dihydrochloride (1.00 g, 2.23 mmol) in anhydrous THF (40 mL) was added NaHMDS 2M in THF (3.68 mL, 7.36 mmol) dropwise, keeping the temperature at -5°C. After 10 minutes, a solution of lauroyl chloride (677 pL, 2.90 mmol) in THF (3.5 mb) was added dropwise keeping the temperature at -5°C. The reaction mixture was stirred at -5°C for 5 minutes then at room temperature for 1 h. The reaction mixture was poured into a 0.5M HCI aqueous solution, then rapidly basified using a saturated aqueous solution of NaHCOs. Separated aqueous layer was extracted three times with EtOAc. The combined organic solvents were washed with brine, dried over anhydrous Na2SC>4 and concentrated in vacuo to give 1.49 g of crude material. The regio-isomers were separated using SFC (Method B) affording three fractions, comp. 4, comp.2 and comp. 3 respectively.

[0240] The first fraction containing Comp.4 was purified on silica gel using a EtOAc / Heptane 5% to 25% gradient affording (Z)-4-(4'-(dodecanoylcarbamoyl)-[1 ,4'-bipiperidin]-1'-yl)-1- (4-fluorophenyl)but-1-en-1-yl dodecanoate (Comp. 4, 140 mg, 8%; Figure 1) as an oil. LCMS: >97% (Method A); m / z [M+H]+ = 740.8. 1 H NMR (400 MHz, CDCI3) δ 9.59 (s, 1 H), 7.39 - 7.29 (m, 2H), 7.04 - 6.95 (m, 2H), 5.71 (t, J = 7.2 Hz, 1 H), 2.88 (d, J = 11 .6 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.63 - 2.06 (m, 12H), 1.96 (td, J = 12.9, 4.5 Hz, 2H), 1.80 - 1.52 (m, 8H), 1.51 - 1.18 (m, 36H), 0.88 (td, J = 6.9, 2.0 Hz, 6H). 1 H NMR (400 MHz, MeOD) δ 7.57 - 7.33 (m, 2H), 7.18 - 6.94 (m, 2H), 5.85 (t, J = 7.3 Hz, 1 H), 2.94 (d, J = 11.6 Hz, 2H), 2.74 - 2.38 (m, 10H), 2.32 (q, J = 7.6 Hz, 2H), 2.12 - 1.86 (m, 4H), 1.72 (p, J = 7.3 Hz, 2H), 1.62 (q, J = 5.9 Hz, 6H), 1 .54 - 1 .21 (m, 36H), 0.89 (td, J = 6.8, 2.6 Hz, 6H).

[0241] The second fraction containing Comp. 2 was further purified using flash chromatography on silica gel using EtOAc / Heptane 5%-40% gradient elution affording N-dodecanoyl-1'- (4-(4-fluorophenyl)-4-oxobutyl)-[1 ,4'-bipiperidine]-4'-carboxamide as a solid (Comp. 2, 120 mg, 9% yield, melting point of 78.9°C; Figure 1). LCMS: >97% (Method A); m / z [M+H]+ = 558.6. 1 H NMR (400 MHz, MeOD) δ 8.15 - 7.99 (m, 2H), 7.21 (t, J = 8.7 Hz, 2H), 3.01 (t, J = 6.9 Hz, 2H), 2.85 (dd, J = 9.6, 5.9 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H), 2.41 (dq, J = 35.9, 5.9 Hz, 8H), 1.93 (p, J = 7.0 Hz, 2H), 1 .88 - 1.75 (m, 4H), 1 .68 - 1 .54 (m, 6H), 1.47 (d, J = 7.2 Hz, 2H), 1.31 (d, J = 16.1 Hz, 16H), 0.94 - 0.84 (m, 3H). 1 H NMR (400 MHz, CDCI3) δ 9.55 (s, 1 H), 8.04 - 7.95 (m, 2H), 7.17 - 7.06 (m, 2H), 2.93 (t, J = 7.0 Hz, 2H), 2.77 (t, J = 7.6 Hz, 4H), 2.47 - 2.29 (m, 8H), 1.93 (p, J = 7.1 Hz, 2H), 1.83 - 1.51 (m, 10H), 1.44 (d, J = 6.4 Hz, 2H), 1.39 - 1.20 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H).

[0242] The third fraction containing Comp. 3 was purified on silica gel using a EtOAc / Heptane gradient 10%-80% as eluent affording (Z)-4-(4'-carbamoyl-[1 ,4'-bipiperidin]-1'-yl)-1-(4- fluorophenyl)but-1-en-1-yl dodecanoate as a solid (Comp. 3, 159 mg, 13%, melting point of 63.2°C; Figure 1).LCMS: >97% (Method A); m / z [M+H]+ = 558.6. 1 H NMR (400 MHz, CDCI3) δ 7.39 - 7.30 (m, 2H), 7.04 - 6.95 (m, 2H), 6.68 (s, 1 H), 5.72 (t, J = 7.2 Hz, 1 H), 5.13 (s, 1 H), 2.81 (d, J = 11.0 Hz, 2H), 2.58 - 2.39 (m, 10H), 2.29 (q, J = 7.4 Hz, 2H), 1.96 - 1.66 (m, 6H), 1.55 (p, J = 5.5 Hz, 4H), 1.49 - 1.18 (m, 18H), 0.93 - 0.84 (m, 3H). 1 H NMR (400 MHz, MeOD) δ 7.48 - 7.40 (m, 2H), 7.11 - 7.01 (m, 2H), 5.85 (t, J = 7.3 Hz, 1 H), 2.83 (dt, J = 10.2, 4.2 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.51 (q, J = 7.3 Hz, 6H), 2.42 - 2.26 (m, 4H), 2.04 (d, J = 13.8 Hz, 2H), 1.94 - 1.81 (m, 2H), 1.72 (p, J = 7.3 Hz, 2H), 1.57 (t, J = 5.7 Hz, 4H), 1.50 - 1.22 (m, 18H), 0.99 - 0.81 (m, 3H).

[0243] Example 2: Metabolite identification and metabolite profile of pipamperone prodrugs

[0244] Materials and methods

[0245] Chemicals and suppliers HPLC grade acetonitrile: Merck (Darmstadt, Germany). HPLC grade formic acid: BDH Laboratory Supplies (Poole, UK). Other chemicals: Sigma Aldrich (Helsinki, Finland), the highest purity available. Water was in-house freshly prepared with a Direct-Q3 (Millipore Oy, Espoo, Finland) purification system and UP grade (ultra pure, 18.2 MQ).

[0246] Incubation material & procedures

[0247] Enzyme source I supplier: Frozen plasma (heparin) I Bioreclamation IVT

[0248] Species: Dog (beagle, male, lot: BGL134397) Human (mixed gender, lot: HMN950213)

[0249] Table A: Conditions in the final incubation:

[0250] Sample preparation for analysis

[0251] The samples were thawed at room temperature (RT), shaken and centrifuged for 20 min at 2272 x g (Thermo SL16 centrifuge, room temperature), and pipetted to Waters 96- well UPLC-plate for analysis.

[0252] Liquid chromatography-mass spectrometry

[0253] Instrumentation and settings are provided in Table B.

[0254] Table B

[0255] Gradient Elution; A = 1 % formic acid, B = acetonitrile

[0256] Elution conditions are provided in Table C

[0257] Table C

[0258] Column oven temperature was 40 (°C). Injection volume was 4 (pl). Ion chromatograms were extracted from the total ion chromatograms using calculated monoisotopic accurate masses with 5 mDa window. The metabolites were mined from the data using software- aided data processing (Thermo Compound Discoverer 2.1 including structure-intelligent dealkylation tool & mass defect filter) with manual confirmation. Results

[0259] For each of Comp.2 and Comp.3, metabolite profiles after incubation with human or dog plasma was determined for different time points.

[0260] Comp.2

[0261] For Comp. 2, observed metabolites and expected metabolic pathways are provided respectively in Table D and Figure 2.

[0262] Table D: UPLC / QE-orbitrap / MS-data obtained for Comp.2 and its metabolites. The metabolite profiles of Comp.2, expressed as a percentage of each metabolite from the total LC / MS peak area at different time points, are shown in Table E.

[0263] Table E

[0264] From Table E it is clear that pipamperone (M2) is the main metabolite formed and that the metabolic profile over time is in line with expectations for a long acting prodrug.

[0265] Comp.3

[0266] For Comp. 3, observed metabolites and expected metabolic pathways are provided respectively in Table F and Figure 3.

[0267] Table F: UPLC / QE-orbitrap / MS-data obtained for Comp.3 and its metabolites.

[0268] The metabolite profiles of Comp.3, expressed as a percentage of each metabolite from the total LC / MS peak area at different time points, are shown in Table G. Table G

[0269] From Table G it is clear that pipamperone (M3) is the main metabolite formed and that the metabolic profile over time is in line with expectations for a long acting prodrug. Example 3: Embodiments of compounds of the invention

[0270] Table H provides embodiments of compounds according to the invention. These compounds can for instance be obtained according to the method of Example 1 by reacting Pipamperone dihydrochloride with the respective fatty acid chloride.

Claims

Claims1. A compound of Formula I, or a stereoisomer, enantiomer, tautomer, solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof:wherein, moiety A is selected from the group consisting of di-C1-4alkylamino, morpholinyl or a 4 to 7-membered nitrogen-containing heterocyclyl optionally substituted with one or more C1-4alkyl, preferably dimethylamino, pyrrolidinyl, dimethylpyrrolidinyl, piperidyl, dimethylpiperidyl or morpholinyl;L1is -(CR1aR1b)r-; r is an integer selected from 1 , 2, and 3; each R1ais selected from the group or consisting of hydrogen, halogen or C1- ealkyl; each R1bis selected from the group consisting of hydrogen, halogen or C1- ealkyl;R1is selected from the group consisting of hydrogen and -C(O)R7;R2is selected fromR4is selected from phenyl or thienyl; wherein said phenyl or thienyl can be unsubstituted or substituted with one or more R4a; each R4ais selected from the group consisting of halogen, C1-6alkyl, and C1- ealkoxy;R5is phenyl or thienyl; wherein said phenyl or thienyl can be unsubstituted or substituted with one or more R5a; each R5ais selected from the group consisting of halogen, C1-6alkyl and C1- ealkoxy;R6is -C(O)R10;R7is selected from the group consisting of C1-20alkyl, C2-20alkenyl, C3- wcycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; wherein said Ci. 2oalkyl, C2-20alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1- ealkyl can be unsubstituted or substituted with one, two or three R7a;R10is selected from the group consisting of C1-20alkyl, C2-20alkenyl, C3- locycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1-6alkyl; wherein said C1- 2oalkyl, C2-20alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-12aryl, and C6-12arylC1- ealkyl can be unsubstituted or substituted with one, two or three R10a; each R7ais selected from the group consisting of hydrogen, halogen, C1- ealkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, haloC1-6alkyloxy, cyanoC1-6alkyl, C1-6alkoxy, cyano, hydroxy, -NR13R14, -NR13S(O)2R15, -NR13C(O)2R15, -C(O)R15, - C(O)2R15, -S(O)nR15(wherein n = 0, 1 , or 2), C6-12aryl, and C1-6alkylC6-12aryl; each R10ais selected from the group consisting of is selected from the group consisting of hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, haloC1-6alkyloxy, cyanoC1-6alkyl, C1-6alkoxy, cyano, hydroxy, -NR13R14, - NR13S(O)2R15, -NR13C(O)2R15, -C(O)R15, -C(O)2R15, -S(O)nR15(wherein n = 0, 1 , or 2), C6-i2aryl, and C1-6alkylC6-i2aryl; each R13is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or Ci -ealkyl ; each R14is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or C1-6alkyl ; each R15is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C6-12aryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C6-12aryl can be unsubstituted or substituted with one, two or three halogen, hydroxy or C1-6alkyl ;wherein when R1is hydrogen, then R2is not2. The compound according to claim 1 , wherein the compound is a compound of formula IA or IB,wherein moiety A, L1, R1, R4, R5, and R6are as defined in claim 1.The compound according to claim 1 , wherein the compound is a compound of formula IC, or ID,wherein R1, R1a, R1b, R4, R5, and R6are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, wherein,L1is -(CR1aR1b)r-; r is an integer selected from 1 , 2, and 3;R4is phenyl; wherein said phenyl can be unsubstituted or substituted with one, two or three R4a; each R4ais selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, and methoxy;R5is phenyl; wherein said phenyl, can be unsubstituted or substituted with one, two or three R5a; each R5ais selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, and methoxy.

5. The compound according to any of claims 1 to 4, wherein the compound is a compound of formula IE, IF, or IG,wherein R1, R4a, R5a, and R6are as defined in any one of claims 1 to 4.

6. The compound according to claim 5, wherein each R4aand R5aindependently are halogen.

7. The compound according to claim 5 or 6, wherein the compound is a compound of formula IH, I J, or IK,wherein R1and R6are as defined in any one of claims 1 to 4.

8. The compound according to any of claims 5 to 7, wherein R1is -C(O)R7or hydrogen, wherein R7is as defined in claim 1.

9. The compound according to any of claims 5 to 7, wherein R6is -C(O)R10; wherein R10is as defined in claim 1.

10. The compound according to any of claim 8, wherein R7and / or R10are C5-2oalkyl, preferably C5-15alkyl or C8-18alkyl.

11. The compound according to any of claims 5 to 10, wherein the compound is a compound of formulaoror12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11.

13. The compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, for use as a medicament.

14. The compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, for use in the treatment of mood disorders, sleep disorders, psychotic disorders, excitement and agitation, including psychomotoric states of excitation disorders, behavioural disorders, including autistic behaviour, and / or disorders with impaired cognition.

15. The compound for use or the pharmaceutical composition for use according to claim 14, wherein the mood disorder is selected from the group consisting of Major depressive disorder, Atypical depression, Melancholic depression, Psychotic depression, Depressive Disorder not otherwise specified, Postpartum depression, Dysthymia, Adjustment disorder with depressed mood, and Seasonal affective disorder.

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