WO2025202481A1

WO2025202481A1 - Prodrugs of lysergamides

Info

Publication number: WO2025202481A1
Application number: PCT/EP2025/058605
Authority: WO
Inventors: Matthias GRILL
Original assignee: Mihkal GmbH
Current assignee: Mihkal GmbH
Priority date: 2024-03-29
Filing date: 2025-03-28
Publication date: 2025-10-02
Anticipated expiration: 2026-09-29

Abstract

The present invention relates to compounds according to formula (I), which are prodrugs of psychoactive lysergamides or its derivatives. The prodrugs provided herein exhibit improved pharmacokinetic properties during uptake as compared to LSD, as well as reduced side effects resulting from the metabolites thus formed. Due to the affinity of the active lysergamide compound, inter alia, for the 5-HT_2A-receptor, these prodrugs are particularly advantageous for use in therapy, e.g., in the treatment of depression, posttraumatic stress disorder (PTSD), substance/alcohol use disorder (SUD/AUD).

Description

PRODRUGS OF LYSERGAMIDES

The present application claims the benefit of priority of European patent application EP24167939.8 filed on March 29, 2024, which is incorporated herein by reference in its entirety.

The present invention relates to compounds according to formula (I), which are prodrugs of psychoactive lysergamides. These prodrugs provided herein exhibit improved pharmacokinetic properties during uptake as compared to lysergic acid diethylamide (LSD), as well as reduced side effects resulting from the core drug as well as the metabolites thus formed. Due to the affinity of the active lysergamide compound, inter alia, for the 5-HT2A- receptor, these prodrugs are particularly advantageous for use in therapy, e.g., in the treatment of depression, posttraumatic stress disorder (PTSD) or substance/alcohol use disorder (SUD/AUD).

Since the discovery of LSD in 1943, further investigations of its weaker analogues like Lysergic acid mono ethylamide (LAE-32) have only been inadequately further investigated. Some studies like the "Project MKULTRA” - a covert CIA research program - have been conducted in the 1950s with less information in terms of medical usage.

Lysergic acid mono ethylamide (LAE-32) constituting the major natural metabolite of LSD, still exerts many of the unique effects of LSD, but with a much milder extent as well as a shorter duration. Subsequent clinical studies have revealed an equivalency ratio of approximately 0.4 equivalents compared to LSD. Due to these findings, the applied effective dose within these studies has been 500-750 microgram.

On a molecular level, this "lead compound” comprises additional advantages over LSD, since the mono ethyl amide group for the first time enables the conjugation of "fragile” pro-moieties to the drug compound. Also, this structure especially facilitates the linkage of pH-responsive self-immolative spacers to the lysergic amide group. On basis of these derivatization techniques, novel compounds with tunable pharmacokinetics have been invented. Additionally, the milder characteristics of the core drug with its altered pharmacologic profile facilitates drug-assisted therapy sessions, which have so far been unpredictable for patients with LSD whereby many have experienced acute adverse effects like panic attacks, nausea, hypertension, and dysphoria.

Caused on the same rationale, specific psychoactive compounds comprising shorter retention times in the human body promise a positive impact in psychedelic assisted therapies.

Especially, in the fields of depressive diseases like major depression and anxiety disorders as well as alcohol and substance use disorders, LSD-assisted therapies more and more prove to be a valuable tool [Fuentes J J, Front Psychiatry. 2020 Jan 21 ; 10:943], Unfortunately, some of the above-mentioned side effects of LSD make treatment complicated for sensitive patients or, even more severely, exclude a major group of patients from this therapy. To overcome or mitigate these issues, numerous prodrugs of known lysergic amides have been synthesized.

The molecular alterations within these novel prodrugs should mitigate these side effects while preserving the key characteristics of these compounds, which would be highly interesting for better tolerated therapies.

Novel active compounds, in particular those showing a modified (accelerated or retarded) activity in the human body due to their structure and consequently having a more favorable side-effect profile, are thus desired. Another important property of the thus designed "prodrugs” is a significantly decreased activity compared to LSD which enables the usage for therapy. In the context of the present invention, novel lysergamide prodrugs based on amide, carbamate, sulfonamide and aminal structures have been developed, which address the above-discussed issues.

Accordingly, in a first embodiment, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

RN is C1-5 alkyl;

Ri is selected from methyl and ethyl, and R2 is selected from -H, methyl, ethyl,

-(Co-3 alkylene)aryl , wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alky lene)ary I is optionally substituted with Rx, or R1 and R2 are taken together to form, together with the N atom to which they are attached, a heterocycloalkyl containing an S ring atom;

Rs is selected from -H, tetrahydropyranyl, -CH2-O-(CI-5 alkyl), each R4, R5 and Re is independently selected from C1-5 alkyl, C1-5 fluoroalkyl, -(C0-3 alkylene)cycloalkyl, -(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)aryl, and -(C0-3 alkylene)heteroaryl, wherein the cycloalkyl moiety in said -(C0-3 alkylene)cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)aryl, and the heteroaryl moiety in said -(C0-3 alkylene)heteroaryl are each optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with Rx; each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci.₅ alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.₅ alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 al ky lene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO- N(CI-5 alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-PO4H2, -(C0-3 alkyleneJ-POsH, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -(C0-3 al ky lene)-carbocyclyl and the heterocyclyl moiety in said -(C0-3 al ky lene)-heterocycly I are each optionally substituted with one or more groups independently selected from C1-5 alkyl, halogen, -CN, -NO2, -OH, -O-(Ci-5 alkyl), -SH, -S- (C1.5 alkyl), -NH₂, -NH(CI.₅ alkyl), -N(CI.₅ alkyl)(Ci.₅ alkyl), -COCH, -COO(Ci.₅ alkyl), -CONH₂, -CONH(CI.₅ alkyl), -CON(CI-₅ alkyl)(Ci.₅ alkyl), -NHCO(CI.₅ alkyl) and -N(CI.₅ alkyl)-CO(Ci.₅ alkyl);

Rx is selected from -CO-CH(-NH2)-Rz, -CO-R9 and O-glycosyl; Rz is selected from hydrogen, Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, -(C1-6 alkylenej-O-Rs, -(C1-6 alkylenej-S-Rs, -(C1-6 alkylene)-N(Rs)-R8, -(C1-6 alkylene)-CO-Rs, -(C1-6 alkylene)-COO-Rs, -(C1-6 alkylene)-O-CO-(Ci-6 alkyl), -(C1-6 alkylene)-CO-N(R8)-Rs, -(C1-6 alkylene)-N(R8)-CO-(Ci-6 alkyl), -(C1-6 alkylene)-CO-N(R8)-O-Rs, -(C1-6 alkylene)-O- CO-N(R₈)-R₈, -(C1.6 alkylene)-N(R₈)-CO-N(R₈)-R₈, -(Ci.₆ alkylene)-N(R₈)-C(=N-R₈)-N(R₈)-R8, -(Ci.₆ alkylene)-SO₃- Rs, -(Co-6 alkylene)-carbocyclyl, and -(Co-6 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(Co-6 alkylene)-carbocyclyl and the heterocyclyl group in said -(Co-6 alkylene)-heterocyclyl are each optionally substituted with one or more R^s, wherein said alkyl, said alkenyl, said alkynyl, and any alkylene group comprised in any of the aforementioned Rz groups are each optionally substituted with one or more -OH, and further wherein each Rs is independently selected from hydrogen and C1-6 alkyl; and

R9 is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R^s; provided that if R2 is -H, methyl or ethyl, then R3 is not -H.

In a further embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

In a further embodiment, the present invention relates to a compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, for use as a medicament.

In a further embodiment, the present invention relates to a compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, for use in the treatment of a serotonin 5-HT2A receptor associated disease/disorder.

In a further embodiment, the present invention relates to use of the compound of formula (I) or its pharmaceutically acceptable salt in the manufacture of a medicament for the treatment of a serotonin 5-HT2A receptor associated disease/disorder.

In a further embodiment, the present invention relates to a method of treating a serotonin 5-HT2A receptor associated disease/disorder in a subject in need thereof, the method comprising administering a compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, to a subject in need thereof. It is to be understood that a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, is to be administered in accordance with the method.

The present invention is illustrated by the appended figures.

Fig. 1 : LC-MS data obtained for the Preparative Example 1 Fig. 2: LC-MS data obtained for the Preparative Example 2.

Fig. 3: LC-MS data obtained for the Preparative Example 3.

Fig. 4: LC-MS data obtained for the Preparative Example 4.

Fig. 5: LC-MS data obtained for the Preparative Example 5.

Fig. 6: LC-MS data obtained for the Preparative Example 6.

Fig. 7: LC-MS data obtained for the Preparative Example 7.

Fig. 8: LC-MS data obtained for the Preparative Example 8.

Fig. 9: LC-MS data obtained for the Preparative Example 9.

Fig. 10: LC-MS data obtained for the Preparative Example 10.

Fig. 11 : LC-MS data obtained for the Preparative Example 11 .

Fig. 12: LC-MS data obtained for the Preparative Example 12.

Fig. 13: LC-MS data obtained for the Preparative Example 13.

Fig. 14: LC-MS data obtained for the Preparative Example 14.

Fig. 15: LC-MS data obtained for the Preparative Example 15.

Fig. 16: LC-MS data obtained for the Preparative Example 16.

Fig. 17: LC-MS data obtained for the Preparative Example 17.

Fig. 18: LC-MS data obtained for the Preparative Example 18.

Fig. 19: LC-MS data obtained for the Preparative Example 19.

Fig. 20: LC-MS data obtained for the Preparative Example 20. Accordingly, as mentioned before, in one embodiment, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof.

In formula (I), RN is C1-5 alkyl. Particularly preferred C1-5 alkyl are methyl and ethyl group. It is particularly preferred that RN is methyl.

In formula (I), R1 is selected from methyl and ethyl, and

R2 is selected from -H, methyl, ethyl,

-(C0-3 alkylene)aryl , wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alky lene)ary I is optionally substituted with Rx, or R1 and R2 are taken together to form, together with the N atom to which they are attached, a heterocycloalkyl containing an S ring atom.

Preferably, R1 is selected from methyl and ethyl, and

R2 is selected from -H, methyl, ethyl,

-(C0-3 alkylene)aryl , wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alky lene)ary I is optionally substituted with Rx.

Preferably, R1 is ethyl. However, alternatively, R1 may be methyl. Preferably, R2 is selected from alkylene)aryl , wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with Rx.

More preferably, R2 is selected from

Even more preferably, R2 is selected from

Still more preferably,

In formula (I), R3 is selected from -H, tetrahydropyranyl, -CH2-O-(CI-5 alkyl),

Preferably, R3 is selected from tetrahydropyranyl (e.g., tetrahydropyran-2-yl),

Even more preferably, R3 is selected from

Yet even more preferably, R3 is selected from

Still more preferably,

In formula (I), each R4, R5 and Re is independently selected from C1-5 alkyl, C1-5 fluoroalkyl, -(C0-3 alkylene)cycloalkyl, -(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)aryl, and -(C0-3 alkylene)heteroaryl, wherein the cycloalkyl moiety in said -(C0-3 alkylene)cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)aryl, and the heteroaryl moiety in said -(C0-3 alkylene)heteroaryl are each optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with Rx.

Preferably, in formula (I), R4 is selected from C1-5 alkyl, cycloalkyl, heterocycloalkyl, -(C0-3 alkylene)aryl, and heteroaryl, wherein said cycloalkyl, said heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)aryl, and said heteroaryl are each optionally substituted with one or more R^s.

More preferably R4 is selected from C1-5 alkyl, cycloalkyl, -(C2 alkylene)aryl, and heteroaryl, wherein said cycloalkyl, the aryl moiety in said -(C2 alkylene)aryl, and said heteroaryl are each optionally substituted with one or more R^s.

Even more preferably, R4 is selected from methyl, ethyl, cyclopropyl, phenylethyl and isoxazolyl.

Preferably, in formula (I), R5 is selected from C1-5 alkyl, C1-5 fluoroalkyl, -(C0-3 alkylene)cycloalkyl, and -(C0-3 alkylene)heterocycloalkyl, wherein the cycloalkyl moiety in said -(C0-3 alkylene)cycloalkyl, and the heterocycloalkyl moiety in said -(C0-3 alkylene)heterocycloalkyl are each optionally substituted with one or more R^s. More preferably, R5 is selected from C1-5 alkyl, C1-5 fluoroalkyl, cycloalkyl, and heterocycloalkyl, wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more R^s.

Even more preferably, R5 is selected from methyl, ethyl, fluoroethyl, ferf-butyl, cyclopropyl and 3-oxetanyl.

Preferably, in formula (I), Re is selected from C1-5 alkyl and -(C0-3 alkylene)cycloalkyl, wherein the cycloalkyl moiety in said -(C0-3 alkylene)cycloalkyl is optionally substituted with one or more R^s.

More preferably, Re is selected from C1-5 alkyl and cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more R^s.

Even more preferably, Re is selected from methyl, ethyl and cyclopropyl.

In formula (I), each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 al ky lene)-OH , -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci.₅ alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.₅ alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 al ky lene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO- N(CI-5 alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-PO4H2, -(C0-3 alkyleneJ-POabh, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -(C0-3 al ky lene)-carbocyclyl and the heterocyclyl moiety in said -(C0-3 al ky lene)-heterocycly I are each optionally substituted with one or more groups independently selected from C1-5 alkyl, halogen, -CN, -NO2, -OH, -O-(Ci-5 alkyl), -SH, -S- (C1.5 alkyl), -NH₂, -NH(CI.₅ alkyl), -N(CI.₅ alkyl)(Ci.₅ alkyl), -COCH, -COO(Ci.₅ alkyl), -CONH₂, -CONH(CI.₅ alkyl), -CON(CI-₅ alkyl)(Ci.₅ alkyl), -NHCO(CI.₅ alkyl) and -N(CI.₅ alkyl)-CO(Ci.₅ alkyl).

Preferably, each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci_₅ alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.₅ alkyl), -(C0-3 al ky lene)-N (C1-5 alkyl)-O(Ci-5 alkyl), -(C0-3 al ky lene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO- N(CI-5 alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl and the heterocyclyl moiety in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-5 alkyl, halogen, -CN, -NO2, -OH, -O-(Ci-5 alkyl), -SH, -S-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-₅ alkyl), -COCH, -COO(Ci.₅ alkyl), -CONH₂, -CONH(CI.₅ alkyl), -CON(CI.₅ alkyl)(Ci.₅ alkyl), -NHCO(CI.₅ alkyl) and -N(CI.₅ alkyl)-CO(Ci.₅ alkyl).

More preferably, each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-₅ alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci.₅ alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.₅ alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 al ky lene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO- N(CI-5 alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), and -(C0-3 alkylene)-SO-(Ci-5 alkyl).

Even more preferably, each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-₅ alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci.₅ alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.₅ alkyl), -(C0-3 al ky lene)-N (Ci-5 alkyl)-0(Ci-5 alkyl), -(C0-3 al ky lene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5 alkyl), and -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)-(Ci-5 alkyl).

Again more preferably, each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5 alkyl), and -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)-(Ci-5 alkyl).

Still again more preferably, each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -O(Ci-5 alkyl), -O(Ci-5 alkylene)-OH, -O(Ci-5 alkylene)-O(Ci-5 alkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5 alkylene)-SH, -S(Ci-5 alkylene)-S(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), halogen, -(C1-5 haloalkyl), -O-(Ci-5 haloalkyl), -ON, -NO₂, -COOH, -CO-O-(Ci.₅ alkyl), -O-CO-(Ci.₅ alkyl), -CO-NH₂, -CO-NH(CI.₅ alkyl), -CO-N(CI.₅ alkyl)(Ci-₅ alkyl), -NH-CO-(CI.₅ alkyl), -N(CI.₅ alkyl)-CO-(Ci.₅ alkyl), -NH-CO-O-(CI.₅ alkyl), -N(CI.₅ alkyl)-CO-O-(Ci.₅ alkyl), -O-CO-NH-(CI-₅ alkyl), and -O-CO-N(CI.₅ alkyl)-(Ci_₅ alkyl).

Even more preferably, each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -O(Ci-5 alkyl), -O(Ci-5 alkylene)-OH, -O(Ci-5 alkylene)-O(Ci-5 alkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5 alkylene)-SH, -S(Ci-5 alkylene)-S(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), halogen, -(C1-5 haloalkyl), -O-(Ci-5 haloalkyl), -ON, -NO₂, and -COOH.

Even more preferably, each R^s is independently selected from -OH, -SH, -NH2, halogen, -ON, -NO2, and -COOH.

Most preferably, each R^s is independently selected from -OH, -SH, -NH2, halogen, and -ON.

In formula (I), Rx is selected from -CO-CH(-NH2)-Rz, -CO-R9 and O-glycosyl. Preferably, Rx is selected from -CO-CH(-NH2)-Rz, and -CO-Rg.

More preferably, Rx is selected from -CO-CH(-NH2)-Rz. Alternatively, Rx may also be -CO-R9.

In formula (I), Rz is selected from hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -(C1-6 alkylene)-O-Rs, -(C1-6 alkylene)-S-R8, -(C1-6 alkylene)-N(R8)-R8, -(C1-6 alkylene)-CO-R8, -(C1-6 alkylene)-COO-R8, -(C1-6 alkylene)-O-CO- (C1-6 alkyl), -(C1-6 alkylene)-CO-N(R8)-R8, -(C1-6 alkylene)-N(R8)-CO-(Ci-6 alkyl), -(C1-6 alkylene)-CO-N(R8)-O-R8, -(C1.6 alkylene)-O-CO-N(R₈)-R₈, -(Ci.₆ alkylene)-N(R₈)-CO-N(R₈)-R8, -(Ci.₆ alkylene)-N(R8)-C(=N-R₈)-N(R₈)-R8, -(C1-6 alkyleneJ-SO -Rs, -(Co-6 alkylene)-carbocyclyl, and -(Co-6 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(Co-6 alkylene)-carbocyclyl and the heterocyclyl group in said -(Co-6 alkylene)-heterocyclyl are each optionally substituted with one or more R^s, wherein said alkyl, said alkenyl, said alkynyl, and any alkylene group comprised in any of the aforementioned Rz groups are each optionally substituted with one or more -OH, and further wherein each Rs is independently selected from hydrogen and C1-6 alkyl.

Preferably, Rz is selected from hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-O(Ci-6 alkyl), -(C1-6 alkylene)-SH, -(C1-6 alkylene)-S(Ci-6 alkyl), -(C1-6 alkylene)-NH2, -(C1-6 alkylene)-NH- CO-NH2, -(C1.6 alkylene)-NH-C(=NH)-NH₂, -(Ci.₆ alkylene)-O-CO-NH₂, -(Ci.₆ alkylene)-COOH, -(Ci.₆ alkylene)-CO- NH2, -(C1-6 alkylene)-CO-NH-OH, -(C1-6 alkyleneJ-SOsH, phenyl, -(C1-6 alkylene)-phenyl, cycloalkyl, -(C1-6 alkylene)- cycloalkyl, heteroaryl, -(C1-6 alkylene)-heteroaryl, heterocycloalkyl, and -(C1-6 alkylene)-heterocycloalkyl, wherein said phenyl, the phenyl group in said -(C1-6 alkylene)-phenyl, said cycloalkyl, the cycloalkyl group in said -(C1-6 alkylene)-cycloalkyl, said heteroaryl, the heteroaryl group in said -(C1-6 alkylene)-heteroaryl, said heterocycloalkyl, and the heterocycloalkyl group in said -(C1-6 alky lene)-heterocycloalkyl are each optionally substituted with one or more groups R^s, and further wherein said alkyl, said alkenyl, said alkynyl, and any alkylene group in any of the aforementioned groups are each optionally substituted with one or more -OH.

More preferably, Rz is selected from hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, phenyl, -(C1-6 alkylene)-phenyl, cycloalkyl, -(C1-6 alkylene)-cycloalkyl, heteroaryl, -(C1-6 alkylene)-heteroaryl, heterocycloalkyl, and -(C1-6 alkylene)- heterocycloalkyl, wherein said phenyl, the phenyl group in said -(C1-6 alkylene)-phenyl, said cycloalkyl, the cycloalkyl group in said -(C1-6 alkylene)-cycloalkyl, said heteroaryl, the heteroaryl group in said -(C1-6 alkylene)- heteroaryl, said heterocycloalkyl, and the heterocycloalkyl group in said -(C1-6 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups R^s, and further wherein said alkyl, said alkenyl, said alkynyl, and any alkylene group in any of the aforementioned groups are each optionally substituted with one or more -OH.

Even more preferably, Rz is selected from hydrogen, C1-8 alkyl, -(C1-6 alkylene)-phenyl, and -(C1-6 alkylene)- heteroaryl. Still more preferably, Rz is selected from hydrogen, methyl, benzyl, and -CH2-(indol-3-yl). Particularly preferred examples of Rz include hydrogen or -CH2-(1 H-indol-3-yl).

In formula (I), Rg is selected from Cvs alkyl, C2-8 alkenyl, C2-8 alkynyl, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R^s.

Preferably, R9 is a heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R^s.

More preferably, R9 is a heterocyclyl, wherein said heterocyclyl is attached via a ring carbon atom that is directly adjacent to a ring nitrogen atom, and further wherein said heterocyclyl is optionally substituted with one or more groups R^s.

Even more preferably, R9 is a heterocyclyl, wherein said heterocyclyl is attached via a ring carbon atom that is directly adjacent to a ring nitrogen atom, wherein said heterocyclyl is optionally substituted with one or more (e.g., one, two, three, four, or five) R^s, and wherein said heterocyclyl is a heterocycloalkyl, a heterocycloalkenyl, or a heteroaryl (wherein said heterocycloalkyl, said heterocycloalkenyl, or said heteroaryl may each be monocyclic or polycyclic, e.g., bicyclic or tricyclic).

Yet even more preferably, Rn is pyrrolidin-2-yl, 4-hydroxypyrrolidin-2-yl, 5-oxo-pyrrolidin-2-yl, or piperidin-2-yl.

Moreover, in the compound of formula (I), as provided herein, if R2 is -H, methyl or ethyl, then R3 is not -H.

In a first specific embodiment of the compound of formula (I), R1 and R2 are taken together to form, together with the N atom to which they are attached, a heterocycloalkyl containing an S ring atom. In this first specific embodiment, said heterocycloalkyl containing an S ring atom is thiomorpholin-4-yl. Further in this first specific embodiment, R3, R4, Rs, Re, Rz, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

As explained above, for psychoactive compounds to be used in therapy, shorter retention times in the human body would be desirable. In the context of the present invention, it has been found that the use of compounds containing an S ring atom (particularly in the heterocycloalkyl formed from R1 and R2, as described above; e.g., if R1 and R2 are taken together to form, together with the N atom to which they are attached, a thiomorpholin-4-yl) can lead to more hydrophilic metabolites with remarkable faster renal excretion rates due to the endogenous enzymatic conversion, as illustrated in the following:

The shorter retention time in the human body renders the corresponding compounds of formula (I) particularly advantageous for use in therapy.

In a second specific embodiment of the compound of formula (I), R2 is selected from -H, methyl, and ethyl. Further in this second specific embodiment, R1, R3, R4, R5, Re, R7, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In a third specific embodiment of the compound of formula preferred that in this third specific embodiment, R3 is H. In this third specific embodiment, it is further preferred that R4 (as comprised within R2) is selected from C1-5 alkyl, cycloalkyl, heterocycloalkyl, -(C0-3 alkylene)aryl, and heteroaryl, wherein said cycloalkyl, said heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)aryl, and said heteroaryl are each optionally substituted with one or more R^s. More preferably, R4 is selected from C1-5 alkyl, cycloalkyl, -(C2 alkylene)aryl, and heteroaryl, wherein said cycloalkyl, the aryl moiety in said -(C2 alkylene)aryl, and said heteroaryl are each optionally substituted with one or more R^s. Even more preferably, R4 is selected from methyl, ethyl, cyclopropyl, phenylethyl and isoxazolyl. Accordingly, R4 may be methyl. Alternatively, R4 may be ethyl. Alternatively, R4 may be cyclopropyl. Alternatively, R4 may be phenylethyl. Alternatively, R4 may be isoxazolyl. Further in this third specific embodiment, R1, R3, R5, Re, R7, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In a fourth specific embodiment, preferred that in this fourth specific embodiment, R3 is H. In this fourth specific embodiment, R5 (as comprised within R2) is preferably selected from C1-5 alkyl, C1-5 fluoroalkyl, -(C0-3 alkylene)cycloalkyl, and -(C0-3 alkylene)heterocycloalkyl, wherein the cycloalkyl moiety in said -(C0-3 alkylene)cycloalkyl, and the heterocycloalkyl moiety in said -(C0-3 alkylene)heterocycloalkyl are each optionally substituted with one or more R^s. More preferably, R5 is selected from C1-5 alkyl, C1-5 fluoroalkyl, cycloalkyl, and heterocycloalkyl, wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more R^s. Even more preferably, R5 is selected from methyl, ethyl, fluoroethyl, ferf-butyl, cyclopropyl and 3-oxetanyl. Accordingly, R5 may be methyl. Alternatively, R5 may be ethyl. Alternatively, R5 may be fluoroethyl. Alternatively, Re may be fert-butyl. Alternatively, R5 may be cyclopropyl. Alternatively, R5 may be 3-oxetanyl. Further in this fourth specific embodiment, R1, R3, R4, Re, Rz, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In a fifth specific embodiment, preferred that in this fifth specific embodiment, R3 is H. In this fourth specific embodiment, Re (as comprised within R2) is preferably selected from C1-5 alkyl and -(C0-3 alkylene)cycloalkyl, wherein the cycloalkyl moiety in said -(C0-3 al ky lene)cycloal ky I is optionally substituted with one or more R^s. More preferably, Re is selected from C1-5 alkyl and cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more R^s. Even more preferably, Re is selected from methyl, ethyl and cyclopropyl. Accordingly, Re may be methyl. Alternatively, Re may be ethyl. Alternatively, Re may be cyclopropyl. Further in this fifth specific embodiment, R1, R3, R4, R5, Rz, Rs, R9, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

H. Further in this sixth specific embodiment, R1, R3, R4, Rs, Re, Rz, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In a seventh specific embodiment, R2 is -(C0-3 alkylene)aryl, wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with Rx. Preferably, in this seventh specific embodiment, R2 is benzyl, wherein the phenyl moiety is optionally substituted with Rx. It is preferred that in this seventh specific embodiment, R3 is H. Further in this seventh specific embodiment, R1, R3, R4, R5, Re, Rz, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In an eighth specific embodiment of the compound of formula (I), R3 is -H. In this eighth specific embodiment, R1, R2, R4, R5, Re, Rz, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In a ninth specific embodiment of the compound of formula (I), R3 is tetrahydropyranyl. In this ninth specific embodiment, it is preferred that R2 is selected from -H, methyl, and ethyl, preferably from methyl and ethyl. Further in this ninth specific embodiment, R1, R2, R4, Rs, Re, Rz, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I). In a tenth specific embodiment of the compound of formula (I), R3 is tetrahydropyranyl. In this tenth specific embodiment, it is preferred that R2 is selected from -H, methyl, and ethyl, preferably from methyl and ethyl. Further in this tenth specific embodiment, R1, R2, R4, R5, Re, R7, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In an eleventh specific embodiment of the compound of formula this eleventh specific embodiment, it is preferred that R2 is selected from -H, methyl, and ethyl, preferably from methyl and ethyl. It is further preferred that R4 (as comprised within R3) in this eleventh specific is selected from C1-5 alkyl, cycloalkyl, heterocycloalkyl, -(C0-3 alkylene)aryl, and heteroaryl, wherein said cycloalkyl, said heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)aryl, and said heteroaryl are each optionally substituted with one or more R^s. More preferably, R4 is selected from C1-5 alkyl, cycloalkyl, -(C2 alkylene)aryl, and heteroaryl, wherein said cycloalkyl, the aryl moiety in said -(C2 alkylene)aryl, and said heteroaryl are each optionally substituted with one or more R^s. Even more preferably, R4 is selected from methyl, ethyl, cyclopropyl, phenylethyl and isoxazolyl. Accordingly, R4 may be methyl. Alternatively, R4 may be ethyl. Alternatively, R4 may be cyclopropyl. Alternatively, R4 may be phenylethyl. Alternatively, R4 may be isoxazolyl. Further in this eleventh specific embodiment, R1, R2, R5, Re, R7, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In a twelfth specific embodiment, this twelfth specific embodiment, it is preferred that R2 is selected from -H, methyl, and ethyl, preferably from methyl and ethyl. In this twelfth specific embodiment, R5 (as comprised within R3) is preferably selected from C1-5 alkyl, C1-5 fluoroalkyl, -(C0-3 alkylene)cycloalkyl, and -(C0-3 alkylene)heterocycloalkyl, wherein the cycloalkyl moiety in said -(C0-3 alkylene)cycloalkyl, and the heterocycloalkyl moiety in said -(C0-3 alky lene)heterocycloalky I are each optionally substituted with one or more R^s. More preferably, R5 is selected from C1-5 alkyl, C1-5 fluoroalkyl, cycloalkyl, and heterocycloalkyl, wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more R^s. Even more preferably, R5 is selected from methyl, ethyl, fluoroethyl, ferf-butyl, cyclopropyl and 3-oxetanyl. Accordingly, R5 may be methyl. Alternatively, R5 may be ethyl. Alternatively, R5 may be fluoroethyl. Alternatively, R5 may be fert-butyl. Alternatively, R5 may be cyclopropyl. Alternatively, R5 may be 3-oxetanyl. Further in this twelfth specific embodiment, R1, R2, R4, Re, R7, Rs, R9, R^s, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I). In a thirteenth specific embodiment, this thirteenth specific embodiment, it is preferred that R2 is selected from -H, methyl, and ethyl, preferably from methyl and ethyl. In this thirteenth specific embodiment. In this thirteenth specific embodiment, Re (as comprised within R3) is preferably selected from C1-5 alkyl and -(C0-3 alkylene)cycloalkyl, wherein the cycloalkyl moiety in said -(C0-3 al ky lene)cycloal ky I is optionally substituted with one or more R^s. More preferably, Re is selected from C1-5 alkyl and cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more R^s. Even more preferably, Re is selected from methyl, ethyl and cyclopropyl. Accordingly, Re may be methyl. Alternatively, Re may be ethyl. Alternatively, Re may be cyclopropyl. Further in this thirteenth specific embodiment, R1, R2, R4, R5, R7, Rs, R9, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

In a fourteenth specific embodiment, , wherein R5 is -CFh-aryl, wherein the aryl moiety in said -CF -aryl is optionally substituted with one or more R^s. Preferably, in this thirteenth embodiment, R5 is -CH2- phenyl, wherein the phenyl moiety in said -CF -phenyl is optionally substituted with one or more R^s, and wherein the phenyl moiety in said -CF -phenyl is optionally substituted with Rx. In this fourteenth specific embodiment, it is preferred that R2 is selected from -H, methyl, and ethyl, Further in this thirteenth specific embodiment, R1, R3, R4, R5, R7, Rs, R9, RN and Rx are as defined for formula (I), or for any of specific embodiments of the compound of formula (I).

Particularly preferred compound of formula (I) is a compound selected from: or a pharmaceutically acceptable salt thereof.

Due to their specific molecular structure as a "prodrug”, i.e. as an active compound to be converted into its active form only within the body, the compounds of formula (I) presented herein have advantageous pharmacological properties. Accordingly, the lysergamide prodrugs according to the present invention are pharmacologically released, taken up and metabolized in the human body with different pharmacokinetics (as compared to LSD and LAE-32). The potential for side effect of psychotropic substances is often related to a rapid increase of their concentration upon uptake of the substances and the affinities of the corresponding drug to target receptors. Therefore, active compounds leading only to a slow increase in initial concentrations and/or comprise lower affinities to on/off target areas are beneficial from a pharmaceutical point of view.

The compounds of formula (I) according to the invention exert their effect on the organism only after endogenous metabolization into the actual active lysergamide (such as LSD or LAE-32), whereby delayed pharmacokinetics and a longer-lasting effect are obtained. The steadier and more uniform release of the active compound in the organism furthermore contributes to reducing side effects. A "smoothening effect” resulting from such delayed release is therefore a particular advantage of the present invention. It is further noted that the compounds of the present invention are particularly advantageous with respect to their ability to cross the blood-brain-barrier due to their enhanced nonpolar characteristics while still remaining easily degradable by endogenous enzymes. Furthermore, the effective dose of these high-potency drugs like LSD known for its noticeable side effects in microgram quantities needs to be elevated. As a result, an enhanced dosage controllability of these prodrugs is advantageous for a better drug safety.

Another key feature of the present invention is the implemented technology of "self-immolative” pro-moieties that facilitates an explicit release of the drug upon endogenous trigger-systems like pH-values or specific enzymes only. By the linking of protecting groups like esters, phosphates or gylcosides within the "self-immolative” pro-moiety, the drugs release can be guided selectively towards a specific body periphery where the endogenous conditions enable the split-off [Angew Chem Int Ed Engl. 2015 Jun 22;54(26):7492-509.]. Consequently, this invention provides prodrugs with novel techniques of targeted release. The compounds of formula (I) can be prepared in accordance with, or in analogy to, the synthetic routes described in the examples section. General synthesis routes and considerations regarding the synthesis of the compounds of formula (II), (III) and (IV) are discussed in the following. Specific examples of preparation of the compounds of formula (V) and (VI) are shown in the Examples.

The compounds of the formulas (I I) - (IV) can be prepared according to the general method comprising the following steps: a. Preparing a solution of the lysergamide starting material (e.g. LAE-32) in solvent I b. Cooling of the resulting solution to -78°C c. Adding an organic base (e.g. LDA) under protective gas atmosphere d. Stirring of the mixture for at least 15 min at -78 °C e. Adding a chloroformate or a dicarbonate (e.g. Boc-Anhydrid) under protective gas atmosphere f. Stirring of the mixture under protective gas atmosphere for at least 1 h at ambient temperature g. Extracting with water and saturated saline solution h. Drying the organic phase over a desiccant at 40 - 60 °C under vacuum (or reduced pressure) i. Purifying the crude product mixture by column chromatography j. Obtaining the lysergamide carbamate prodrugs of formula (II) - (IV) according to the invention

In step (a), between 0.5 mmol and 1.7 mmol of lysergamide starting material are dissolved in 10 ml to 25 ml of solvent I, wherein solvent I is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, chloroform and dichloromethane.

In step (b), the reaction is cooled to the required temperature. This can be done at a temperature between -78 °C and 0 °C, with strong organo-metal bases (e.g. lithiumdiisopropylamide) preferably at a temperature between -10 °C and -80 °C, with weaker nitrogen bases (e.g. triethylamine) more preferably at room temperature (293.15 Kelvin; In step (c), between 1 mmol and 9 mmol of an activating agent are added, such as, e.g., a nitrogen base or a organo-metal base. In this case, the organo-metal base is selected from n-butyllithium (n-BuLi), lithiumdiisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS) , potassium bis(trimethylsilyl)amide (KHMDS) and sodium bis(trimethylsilyl)amide (NaHMDS). It is also possible to use a deprotonating agent such as nitrogen bases like triethylamine, diisopropyl ethylamine, pyridine, diazabicyloundecene, diazabicyclononene and 4-dimethyl aminopyridine.

In step (d), the mixture is stirred between 15 and 90 min at - 78 °C under protective gas atmosphere.

In step (e), between 0.6 mmol and 2.3 mmol of a derivatization agent are added dropwise through a septum, wherein the derivatization agent is selected from methyl chloroformate, di-tert-butyl pyrocarbonate and 2-fluoroethy I chloroformate.

In step (f), the reaction is stirred under protective gas atmosphere for at least 1 h at ambient temperature. Based on the basicity of the applied base (nitrogen base or organo-metal base), the reaction time varies between minutes up to 24h.

In step (g), extraction is performed with between 30 ml and 150 ml of water. Subsequent extraction with between 30 ml and 150 ml saturated saline solution may be performed. In case of usage of tetrahydrofuran or dioxane, the reaction mixture was evaporated and resuspended before the extraction procedure could be accomplished.

In step (h), the mixture is dried. Particularly preferred is drying with a desiccant at a temperature between 35 °C and 60 °C and a vacuum (reduced pressure) of 30 - 60 mbar. Preferred desiccants are anhydrous calcium chloride, anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous magnesium sulphate, or anhydrous calcium sulfate. Particularly preferred desiccant is anhydrous MgSCh, the temperature is 45 °C and the vacuum is 40 mbar.

In step (i), the crude product is further purified. The purification can be conducted, e. g. by column purification over silica using the eluents dichloromethane/methanol in one embodiment. Other column materials and eluents known in the art can also be used.

The products obtained in steps (a) to (i) contain the compounds of formula (II) to (IV) according to the invention.

With this method, in step (j), the products can be obtained in yields of more than 55 wt-% (gravimetric determination of the amount of the end product, relative to the intermediate product). Further details on the method of production are provided in the examples and will be apparent to the person skilled in the art.

The compounds of the formulas (V) - (VII) can be prepared according to the general method comprising the following steps: a. Preparing a solution of the lysergamide starting material (e.g. LAE-32) in solvent I b. Cooling of the resulting solution to -78°C c. Adding an organic base (e.g. LDA) under protective gas atmosphere d. Stirring of the mixture for at least 15 min at -78 °C e. Adding an acyl-chloride (e.g. acetylchloride) under protective gas atmosphere f. Stirring of the mixture under protective gas atmosphere for at least 1 h at ambient temperature g. Extracting with water and saturated saline solution h. Drying the organic phase over a desiccant at 40 - 60 °C under vacuum (or reduced pressure) i. Purifying the crude product mixture by column chromatography j. Obtaining the lysergamide prodrugs of formula (V) - (VII) according to the invention

In step (a), between 0.7 mmol and 2.4 mmol of lysergamide starting material are dissolved in 10 ml to 25 ml of solvent I, wherein solvent I is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, chloroform and dichloromethane.

In step (b), the reaction is cooled to the required temperature. This can be done at a temperature between -78 °C and 0 °C, with strong organo-metal bases (e.g. lithiumdiisopropylamide) preferably at a temperature between -10 °C and -80 °C, with weaker nitrogen bases (e.g. triethylamine) more preferably at room temperature (293.15 Kelvin; 20 °C).

In step (c), between 1 mmol and 3.1 mmol of an activating agent are added, such as, e.g., a nitrogen base or a organo-metal base. In this case, the organo-metal base is selected from n-butyllithium (n-BuLi), lithiumdiisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS) , potassium bis(trimethylsilyl)amide (KHMDS) and sodium bis(trimethylsilyl)amide (NaHMDS). It is also possible to use a deprotonating agent such as nitrogen bases like triethylamine, diisopropyl ethylamine, pyridine, diazabicyloundecene, diazabicyclononene and 4-dimethyl aminopyridine.

In step (e), between 0.9 mmol and 4.8 mmol of a derivatization agent are added dropwise through a septum, wherein the derivatization agent is selected from acetyl chloride, cyclopropanecarboxylic acid chloride, phenylpropionyl chloride and isoxazole-5-carbonyl-chloride.

The products obtained in steps (a) to (I) contain the compounds of formula (V) to (VII) according to the invention.

With this method, in step (j), the products can be obtained in yields of more than 29 wt-% (gravimetric determination of the amount of the end product, relative to the intermediate product).

Further details on the method of production are provided in the examples and will be apparent to the person skilled in the art.

The compounds of the formula (VII I) can be prepared according to the general method comprising the following steps: a. Preparing a solution of the lysergamide starting material (e.g. LAE-32) in solvent I b. Cooling of the resulting solution to -78°C c. Adding an organic base (e.g. n-BuLi) under protective gas atmosphere d. Stirring of the mixture for at least 15 min at -78 °C e. Adding a sulfonylchloride (e.g. mesylchloride) under protective gas atmosphere f. Stirring of the mixture under protective gas atmosphere for at least 1 h at ambient temperature g. Extracting with water and saturated saline solution h. Drying the organic phase over a desiccant at 40 - 60 °C under vacuum (or reduced pressure) i. Purifying the crude product mixture by column chromatography j. Obtaining the lysergamide prodrugs of formula (VIII) according to the invention

In step (a), between 0.3 mmol and 0.9 mmol of lysergamide starting material are dissolved in 8 ml to 15 ml of solvent I, wherein solvent I is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, chloroform and dichloromethane.

In step (b), the reaction is cooled to the required temperature. This can be done at a temperature between -78 °C and 0 °C, with strong organo-metal bases (e.g. n-butyllithium) preferably at a temperature between -10 °C and -80 °C, with weaker nitrogen bases (e.g. triethylamine) more preferably at room temperature (293.15 Kelvin; 20 °C).

In step (c), between 0.5 mmol and 1.8 mmol of an activating agent are added, such as, e.g., a nitrogen base or a organo-metal base. In this case, the organo-metal base is selected from n-butyllithium (n-BuLi), lithiumdiisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS) , potassium bis(trimethylsilyl)amide (KHMDS) and sodium bis(trimethylsilyl)amide (NaHMDS). It is also possible to use a deprotonating agent such as nitrogen bases like triethylamine, diisopropyl ethylamine, pyridine, diazabicyloundecene, diazabicyclononene and 4-dimethyl aminopyridine.

In step (e), between 0.6 mmol and 1.8 mmol of a derivatization agent are added dropwise through a septum, wherein the derivatization agent is selected from methanesulfonyl chloride and ethanesulfonyl chloride.

In step (f), the reaction is stirred under protective gas atmosphere for at least 0.5 h at ambient temperature. Based on the basicity of the applied base (nitrogen base or organo-metal base), the reaction time varies between minutes up to 24h.

In step (g), extraction is performed with between 30 ml and 70 ml of water. Subsequent extraction with between 30 ml and 70 ml saturated saline solution may be performed. In case of usage of tetrahydrofuran or dioxane, the reaction mixture was evaporated and resuspended before the extraction procedure could be accomplished.

The products obtained in steps (a) to (I) contain the compounds of formula (VIII) according to the invention.

With this method, in step (j), the products can be obtained in yields of more than 60 wt-% (gravimetric determination of the amount of the end product, relative to the intermediate product).

The compounds of the formulas (IX)/(X) can be prepared according to the general method comprising the following steps: a. Preparing a solution of lysergamide in solvent I (DCE) b. Adding the derivatization agent - 3,4-dihydropyran c. Adding a catalyst (e.g. PTSA) under protective gas atmosphere d. Stirring of the mixture for at least 24 hours at 78 °C with a condensing cooler e. Stopping the reaction by dilution with solvent (e.g., solvent I) f. Extracting with water and saturated saline solution g. Drying the organic phase over a desiccant at 40 - 60 °C under vacuum (or reduced pressure) h. Purifying the crude product mixture by column chromatography i. Obtaining the lysergamide prodrugs of formula (IX) I (X) according to the invention

In step (a), between 0.8 mmol and 1 .2 mmol of lysergamide starting material are dissolved in 4 ml to 6 ml of solvent I, wherein solvent I is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, chloroform and dichloroethane.

In step (b), between 52 mmol and 66 mmol of a derivatization agent is added through a septum, wherein the derivatization agent is selected as 3,4-dihydropyran.

In step (c), between 0.1 mmol and 0.4 mmol of a catalyst is added, wherein the catalyst is selected from pyridinium p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid or oxalic acid.

In step (d), the reaction is stirred with mounted reflux condenser under protective gas atmosphere for at least 24 h at 85°C.

In step (e), the reaction is stopped by dilution with solvent I. In step (f), extraction is performed with between 5 ml and 10 ml of water. Subsequent extraction with between 5 ml and 10 ml saturated saline solution may be performed.

In step (g), the mixture is dried. Particularly preferred is drying with a desiccant at a temperature between 35 °C and 60 °C and a vacuum (reduced pressure) of 30 - 60 mbar. Preferred desiccants are anhydrous calcium chloride, anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous magnesium sulphate, or anhydrous calcium sulfate. Particularly preferred desiccant is anhydrous MgSCh, the temperature is 45 °C and the vacuum is 40 mbar.

In step (h), the crude product is further purified. The purification can be conducted, e. g. by column purification over silica using the eluents dichloromethane/methanol in one embodiment. Other column materials and eluents known in the art can also be used.

The products obtained in steps (a) to (h) contain the compounds of formula (IX) to (X) according to the invention.

With this method, in step (i), the products can be obtained in yields of more than 53 wt-% (gravimetric determination of the amount of the end product, relative to the intermediate product).

The compound of the formula (XI) can be prepared according to the general method comprising the following steps: a. Preparing a suspension of lysergic acid in solvent I at room temperature under argon atmosphere b. Adding an organic base (e.g. DiPEA) under protective gas atmosphere c. Adding of an amine compound, particularly an N-(4-substituted benzyl)-ethylamine, under protective gas atmosphere d. Adding of a coupling reagent (e.g. propane-phosphonic acid anhydride solution [T3P]) in solvent I e. Stirring of the mixture under protective gas atmosphere for at least 24 h f. Stopping of the reaction by dilution with solvent I g. Extracting with water and saturated saline solution h. Drying the organic phase over a desiccant at 40 - 60 °C under vacuum (or reduced pressure)

I. Purifying the crude product mixture by column chromatography j. Obtaining the lysergamide prodrugs of formula (XI) according to the invention

In one embodiment, in step (a), between 4 mmol and 11 mmol lysergic acid hydrate are suspended in 60 ml up to 180 ml in solvent I, wherein solvent I is selected from tetrahydrofuran, dioxane, 2-methy Itetrahydrofuran, chloroform and dichloroethane and preferably ethyl acetate.

In one embodiment, in step (b), 32 mmol to 88 mmol of an organic non-nucleophilic base are added. This base is selected from diisopropylethylamine or trimethylamine. The suspension is aerated with protective gas.

In step (c), between 8 mmol and 23 mmol of a derivatization agent are added dropwise to the reaction suspension, wherein the derivatization agent is selected as N-benzylacetylmethylester-ethylamine.

In one embodiment, in step (d), between 30 wt.% and 65 wt.% propane-phosphonic acid anhydride solution (T3P) in ethyl acetate, between 12 mmol to 33 mmol are added, preferably dropwise through a septum. T3P dissolved in other solvents (e.g. DMF) can also be used (instead of T3P dissolved in ethyl acetate), but the ethyl acetate solution is preferred as it is nontoxic and environmentally compatible, and as undesired impurities can be avoided in synthesis. The drip rate is preferably adjusted such that the addition takes between 15 and 60 minutes.

In step (e), the reaction is stirred under protective gas atmosphere for at least 24 h at ambient temperature.

In step (f), the reaction is stopped by dilution (between 100 ml and 300 ml) with solvent I.

In step (g), extraction is performed with between 40 ml and 80 ml of water. Subsequent extraction with between 40 ml and 80 ml saturated saline solution may be performed.

In step (h), the mixture is dried. Particularly preferred is drying with a desiccant at a temperature between 35 °C and 60 °C and a vacuum (reduced pressure) of 30 - 60 mbar. Preferred desiccants are anhydrous calcium chloride, anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous magnesium sulphate, or anhydrous calcium sulfate. Particularly preferred desiccant is anhydrous MgSCh, the temperature is 45 °C and the vacuum is 40 mbar. In step (i), the crude product is further purified. The purification can be conducted, e. g. by column purification over silica using the eluents dichloromethane/ethanol in one embodiment. Other column materials and eluents known in the art can also be used.

The products obtained in steps (a) to (i) contain the compounds of formula (XI) according to the invention.

With this method, in step (j), the products can be obtained in yields of more than 70 wt-% (gravimetric determination of the amount of the end product, relative to the intermediate product).

The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

The term "hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

As used herein, the term "alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an "alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A “C1-6 alkyl” denotes an alkyl group having 1 to 6 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term "alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

As used herein, the term "alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term "C2-6 alkenyl” denotes an alkenyl group having 2 to 6 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1 -en-2-yl, or prop-2- en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term "alkenyl” preferably refers to C2-4 alkenyl.

As used herein, the term “alkynyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. The term "C2-6 alkynyl” denotes an alkynyl group having 2 to 6 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term "alkynyl” preferably refers to C2-4 alkynyl. As used herein, the term "alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “C1-6 alkylene” denotes an alkylene group having 1 to 6 carbon atoms, and the term "Co-6 alkylene” indicates that a covalent bond (corresponding to the option "Co alkylene”) or a C1-6 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH₃)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH₂-CH₃)-, -CH₂-CH(-CH₃)-, or -CH(-CH₃)-CH₂-), or butylene (e.g., -CH₂- CH2-CH2-CH2-). Unless defined otherwise, the term "alkylene” preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

As used herein, the term "carbocyclyl” refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless defined otherwise, "carbocyclyl” preferably refers to aryl, cycloalkenyl or cycloalkyl.

As used herein, the term “heterocyclyl” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, "heterocyclyl” preferably refers to heteroaryl, heterocycloalkenyl or heterocycloalkyl.

As used herein, the term "aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). "Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an "aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

As used herein, the term "heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1 -benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 , 10]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4- oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1,2,4-triazolyl, or 4H-1 ,2,4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2- a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4, 5,6,7- tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1 ,3-benzodioxanyl or 1,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term "heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a "heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

As used herein, the term "cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). "Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, "cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred "cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1 ,3-dithiolanyl, thianyl, 1 ,1-dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept- 5-yl. Unless defined otherwise, "heterocycloalkyl” preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

As used herein, the term "cycloal kenyl” refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond. "Cycloal kenyl” may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless defined otherwise, “cycloalkenyl” preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl. A particularly preferred "cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.

As used herein, the term "heterocycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkenyl” may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5- dihydro-1 H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1 ,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1 ,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1 ,2,3,4,4a,5,6,7-octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1 ,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless defined otherwise,

"heterocycloalkenyl” preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, "heterocycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. As used herein, the term "glycosyl” is a monovalent radical structure obtained by removing the -OH group from the cyclic form of a monosaccharide. Preferably, the -OH group of the hemiacetal group (i.e., -CH(OH)-O-) present in said monosaccharide is removed. An example of glycosyl is beta-D-glucopyranosyl, according to the formula:

A "monosaccharide” is preferably defined as a simple sugar, that is a compound of a linear and unbranched carbon skeleton with one carbonyl functional group and one hydroxyl functional group on each of the remaining carbon atoms. For certain carbon atoms, the hydroxy group may be absent. Accordingly, a monosaccharide is a compound of the formula

H-(CHX)_n-(C=O)-(CHX)_m-H, wherein n+m+1 is preferably selected from 3, 4, 5, 6 and 7, wherein each X is independently H or -OH, provided that at least two instances of X are OH and not more than 2 instances of X are H, preferably wherein not more than 1 instance of X is H, more preferably wherein each X is -OH. Preferably, the monosaccharide is a hexose or a pentose. A hexose is a monosaccharide as defined hereinabove wherein n+m+1 = 6, and preferably wherein each instance of X is -OH. A pentose is a monosaccharide as defined hereinabove, wherein n+m+1 = 5 and preferably wherein each instance of X is -OH). More preferably, the monosaccharide is a hexose. Even more preferably, the monosaccharide is glucose or fructose. Still more preferably, the monosaccharide is glucose. The definition of monosaccharide, as referred to herein, further encompasses compounds in which a -CH2OH group has been replaced with -COOH group. Such compounds may be referred to as uronic acids. Thus, an exemplary glycosyl derived from uronic acid is a glycosyl derived from glucuronic acid, as shown in the following formula:

As used herein, the term "halogen” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).

As used herein, the term "nitro” refers to a group -NO2.

The terms "bond” and "covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context. As used herein, the terms "optional”, "optionally” and "may” denote that the indicated feature may be present but can also be absent. Whenever the term "optional”, "optionally” or "may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression "X is optionally substituted with Y” (or "X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be "optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

Various groups are referred to as being "optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the "optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.

A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.

As used herein, unless explicitly indicated otherwise or contradicted by context, the terms "a”, "an” and "the” are used interchangeably with "one or more” and "at least one”. Thus, for example, a composition comprising "a” compound of formula (I) can be interpreted as referring to a composition comprising "one or more” compounds of formula (I).

It is to be understood that wherever numerical ranges are provided/disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

As used herein, the term "about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term "about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint. As used herein, the term "comprising” (or "comprise”, "comprises”, "contain”, "contains”, or "containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of "containing, inter alia”, i.e., "containing, among further optional elements, In addition thereto, this term also includes the narrower meanings of "consisting essentially of” and "consisting of'. For example, the term "A comprising B and C” has the meaning of "A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., "A containing B, C and D” would also be encompassed), but this term also includes the meaning of "A consisting essentially of B and C” and the meaning of "A consisting of B and C” (i.e., no other components than B and C are comprised in A).

The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a fumarate salt, a maleate salt, an oxalate salt, a malate salt, a tartrate salt, and a mesylate salt. The present invention also specifically relates to the compound of formula (I), including any one of the specific compounds of formula (I) described herein, in non-salt form.

Moreover, the scope of the invention embraces the compounds of formula (I) in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of formula (I) are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the formula (I) are likewise embraced by the invention.

Furthermore, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis/trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto/enol tautomers or thione/thiol tautomers). All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures/racemates and non-racemic mixtures). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.

The scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., ²H; also referred to as “D”). Accordingly, the invention also embraces compounds of formula (I) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (¹H) and about 0.0156 mol-% deuterium (²H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or ¹H hydrogen atoms in the compounds of formula (I) is preferred.

The present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., ¹⁸F, ¹¹C, ¹³N, ¹⁵0, ⁷⁶Br, ⁷⁷Br, ¹²⁰l and/or ¹²⁴l. Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET). The invention thus includes (I) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by ¹⁸F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by ¹¹C atoms, (ill) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by ¹³N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by ¹⁵O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by ⁷⁶Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by ⁷⁷Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by ¹²⁰l atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by ¹²⁴l atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.

The present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention as defined herein, and a pharmaceutically acceptable excipient. The present invention further relates to the said pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention, and a pharmaceutically acceptable excipient for use in therapy.

The compounds and/or chemical entities provided herein may be administered as compounds per se or may be formulated as medicaments. The medicaments/pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers.

The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., polyethylene glycol), including poly (ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, o-cyclodextrin, p-cyclodextrin, y-cyclodextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p- cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-p-cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-p-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-p- cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

The pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22^nd edition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

The compounds of formula (I) or the pharmaceutically acceptable salts thereof or the above described pharmaceutical compositions comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof may be administered to a subject by any convenient route of administration, whether systemical ly/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration. If said compounds or pharmaceutically acceptable salts or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecal ly, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and/or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

Said compounds or pharmaceutically acceptable salts or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

For oral administration, the compounds, the pharmaceutically acceptable salts or the pharmaceutical compositions are preferably administered by oral ingestion, particularly by swallowing. The compounds or pharmaceutical compositions can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as "oral-gastrointestinal” administration.

Alternatively, said compounds, pharmaceutically acceptable salts or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention may also be dermal ly or transdermally administered, for example, by the use of a skin patch.

Said compounds, pharmaceutically acceptable salts or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(— )-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention or a pharmaceutically acceptable salt thereof.

Said compounds, pharmaceutically acceptable salts or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

It is also envisaged to prepare dry powder formulations of the compounds of formula (I) or the pharmaceutically acceptable salt thereof for pulmonary administration, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification/spray drying process.

For topical application to the skin, said compounds, pharmaceutically acceptable salts or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.

The present invention thus relates to the compounds, pharmaceutically acceptable salts or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route. Preferred routes of administration are oral administration or parenteral administration. For each of the compounds, salts or pharmaceutical compositions provided herein, it is particularly preferred that the respective compound or pharmaceutical composition is to be administered orally (particularly by oral ingestion). Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.

A proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose. The unit dose may be administered, e.g., 1 to 3 times per day. The unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

The invention further relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof or to the for use as a medicament. As understood herein the use as a medicament is meant as the use in the treatment of a disease.

As used herein, the term "treatment” (or "treating”) in relation to a disease or disorder refers to the management and care of a patient for the purpose of combating the disease or disorder, such as to reverse, alleviate, inhibit or delay the disease or disorder, or one or more symptoms of such disease or disorder. It also refers to the administration of a compound or a composition for the purpose of preventing the onset of symptoms of the disease or disorder, alleviating such symptoms, or eliminating the disease or disorder. Preferably, the "treatment” is curative, ameliorating or palliative.

The compounds of formula (I) or the pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present invention are useful in the treatment of a serotonin 5-HT2A receptor associated disease/disorder.

A serotonin 5-HT2A receptor associated disease/disorder as described herein, is preferably selected from an anxiety disorder, depression (e.g., major depression), posttraumatic stress disorder (PTSD), substance use disorder (SUD), alcohol use disorder (AUD), cluster headache, migraine, Parkinson's disease, and an eating disorder (e.g., anorexia).

The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal). Preferably, the subject/patient is a mammal. More preferably, the subject/patient is a human (e.g., a male human or a female human) or a non-human mammal. Most preferably, the subject/patient to be treated in accordance with the invention is a human.

The invention further provides the following compounds: ds. It is to be understood that the invention provides each of these compounds individually.

It is to be understood that these compounds can be formulated in an analogous way as the compounds of formula (I), and they are provided for the same medical/therapeutic uses as the compounds of formula (I).

The invention is illustrated by the following examples, which serve merely illustrative purpose and are not meant to be construed as limiting in any way. EXAMPLES

Preparative example 1 : methyl ethyl (7-methyl-4,6,6a,7, 8,9-hexahydroindolo[4, 3-fglqui nol ine-9-carbonvDcarbamate

Lysergic acid mono ethylamide (1.7 mmol/500 mg) was dissolved in tetrahydrofuran (17 ml) at -78 °C and aerated with argon. Lithiumdiisopropylamide 2 M in THF (4 mmol/2.0 ml) was added through septum. This results in a yellow suspension. After stirring for 30min, methyl chloroformate (2.21 mmol/0.20 ml) was added dropwise through septum. Upon addition of chloroformate, the dry ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 2 h under argon at 25 °C.

In-process-control via HPLC shows 26% conversion to the desired N-amide product.

The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was dissolved in dichloromethane (150 ml) and extracted with 50 ml water and 50 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.86 g).

The crude product was treated on a column over 200 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100: 1. This yielded 330 mg the N-amide product as a yellowish oil (55 %).

LC-MS measurement for the obtained compound is shown in Figure 1 .

The LC-MS measurements for this as well as other examples described herein have been performed as in the following.

LC-system:

Running time: 9.0 min

Column: Shimadzu Shim-pack Scepter C18 1.9 micrometer; dimension 100 x 2.1 mm

Oven temperature: 40°C

UV-detection: 215 - 400 nm

Gradient: solvent A = water; solvent B = acetonitrile

MS-system:

Running time: 9.0 min

Acqusition mode: Scan positive

Start m/z: 90 End m/z: 900

Scan speed: 10000 u/sec

Event time: 0.1 sec

Preparative example 2: methyl 9-(ethylcarbamoyl)-7-methyl-6a,7,8,9-tetrahvdroindolo[4,3-fg]quinoline-4(6H)- carboxylate

In-process-control via HPLC shows 13% conversion to the requested N-indole product.

The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (150 ml) and extracted with 50 ml water and 50 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.86 g). The crude product was treated on a column over 200 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100:1. This yielded 110 mg the N-indole carbamate compound as a yellowish oil (18 %).

LC-MS measurement for the obtained compound is shown in Figure 2.

Preparative example 3: methyl 9-(ethyl(methoxycarbonyl)carbamoyl)-7-methyl-6a,7,8,9-tetrahydroindolo[4,3- fg]quinoline-4(6H)-carboxylate

In-process-control via HPLC shows 44% conversion to the requested dicarbamate product.

The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (150 ml) and extracted with 50 ml water and 50 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.86 g).

The crude product was treated on a column over 200 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100:1. This yielded 300 mg the dicarbamate compound as a yellowish oil (43 %).

LC-MS measurement for the obtained compound is shown in Figure 3.

Lysergic acid mono methylamide (0.72 mmol/200 mg) was dissolved in chloroform (10 ml) at 0 °C and aerated with argon. Triethylamine (1 mmol/0.14 ml) and dimethylaminopyridine (0.036 mmol/5mg) was added. After stirring for 30min, 2-fluoroethyl chloroformate (0.86 mmol/0.08 ml) diluted in 2 ml chloroform was added dropwise through septum. Upon addition of chloroformate, the ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 7 h under argon at 25 °C.

In-process-control via HPLC shows 31% conversion to the requested N-amide product.

The reaction mixture was diluted with dichloromethane (40 ml) and extracted with 40 ml water and 40 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.280 g).

The crude product was treated on a column over 50 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100:1. This yielded 40 mg the N-carbamate compound as an oily residue (15 %).

LC-MS measurement for the obtained compound is shown in Figure 4.

Preparative example 5: 2-fluoroethyl 7-methyl-9-(methylcarbamoyl)-6a,7,8,9-tetrahvdroindolo[4,3-fg]quinoline- Lysergic acid mono methylamide (0.72 mmol/200 mg) was dissolved in chloroform (10 ml) at 0 °C and aerated with argon. Triethylamine (1 mmol/0.14 ml) and dimethylaminopyridine (0.036 mmol/5mg) was added. After stirring for 30min, 2-fluoroethyl chloroformate (0.86 mmol/0.08 ml) diluted in 2 ml chloroform was added dropwise through septum. Upon addition of chloroformate, the ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 7 h under argon at 25 °C.

In-process-control via HPLC shows 5% conversion to the requested N-indole product.

The reaction mixture was diluted with dichloromethane (40 ml) and extracted with 40 ml water and 40 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSO4. Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.280 g).

The crude product was treated on a column over 50 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100: 1. This yielded 10 mg the N-carbamate compound as an oily residue (3 %).

LC-MS measurement for the obtained compound is shown in Figure 5. tert-butyl 9-(ethylcarbamovl)-7-methyl-6a,7,8,9-1 ,3-fq]quinoline-4(6H)-

Lysergic acid mono ethylamide (0.68 mmol/200 mg) was dissolved in tetrahydrofuran (6 ml) at -78 °C and aerated with argon. Lithiumdiisopropylamide 2 M in THF (0.88 mmol/0.44 ml) was added through septum. This results in a yellow suspension. After stirring for 15 min, di-tert.-butyl-pyrocarbonate solution 30% in THF (1.7 mmol/320 mg) was added dropwise through septum. Upon addition of pyrocarbonate, the dry ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 7 h under argon at 25 °C.

In-process-control via HPLC shows 60% conversion to the requested N-indole product. The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (40 ml) and extracted with 40 ml water and 40 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product (0.19 g).

The crude product was treated on a column over 70 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100: 1. This yielded 60 mg the N-indole carbamate compound as a greenish foam (22 %).

LC-MS measurement for the obtained compound is shown in Figure 6.

Preparative example 7: tert-butyl 7-methyl-9-(methylcarbamoyl)-6a,7,8,9-tetrahvdroindolo[4,3-fg]quinoline-4(6H)- carboxylate

Lysergic acid mono methylamide (1 .77 mmol/500 mg) was dissolved in tetrahydrofuran (20 ml) at -78 °C and aerated with argon. Lithium-bis-(trimethylsilyl)-amid 1 M in THF (4.14 mmol/4.1 ml) was added through septum. This results in a yellow suspension. After stirring for 30 min, di-tert.-butyl-pyrocarbonate solution 30% in THF (2.35 mmol/1 .70 g) was added dropwise through septum. Upon addition of pyrocarbonate, the dry ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 7 h under argon at 25 °C.

In-process-control via HPLC shows 27% conversion to the requested N-indole product.

The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (40 ml) and extracted with 40 ml water and 40 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product (0.51 g).

The crude product was treated on a column over 200 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100: 1. This yielded 144 mg the N-indole carbamate compound as a yellowish oil (21 %). LC-MS measurement for the obtained compound is shown in Figure 7. ,3-fq]quinoline-9-carbonyl) carbamate

Lysergic acid mono methylamide (1.3 mmol/365 mg) was dissolved in tetrahydrofuran (13 ml) at -78 °C and aerated with argon. N-Butyllithium 2.5 M in hexane (1.56 mmol/0.63 ml) was added through septum. This results in an orange suspension. After stirring for 15 min, methyl chloroformate (1.7 mmol/0.13 ml) was added dropwise through septum. Two hours after addition of methyl chloroformate, the dry ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 20 h under argon at 25 °C.

In-process-control via HPLC shows 34% conversion to the requested N-amide product.

The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (25 ml) and extracted with 15 ml water and 15 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSO4. Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.18 g).

The crude product was treated on a column over 70 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100: 1. This yielded 67 mg the N-amide carbamate compound as a yellowish oil (15 %).

LC-MS measurement for the obtained compound is shown in Figure 8. Preparative example 9: methyl 7-methyl-9-(methylcarbamoyl)-6a,7,8,9-tetrahvdroindolo[4,3-fg]quinoline-4(6H)- carboxylate

In-process-control via HPLC shows 34% conversion to the requested N-indole product.

The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (25 ml) and extracted with 15 ml water and 15 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.18 g).

The crude product was treated on a column over 70 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100: 1. This yielded 49 mg the N-indole carbamate compound as a brownish oil (11 %).

LC-MS measurement for the obtained compound is shown in Figure 9.

,3-fq]quinoline-9-carboxamide Lysergic acid mono ethylamide (2.4 mmol/700 mg) was dissolved in tetrahydrofuran (23 ml) at -78 °C and aerated with argon. Lithiumdiisopropylamide 2 M in THF (3.1 mmol/1.55 ml) was added through septum. This results in a yellow-greenish suspension. After stirring for 60 min, acetyl chloride (4.8 mmol/0.34 ml/ diluted in 2 ml THF) was added dropwise through septum. Upon addition of acetyl chloride, the dry ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 1 h under argon at 25 °C.

In-process-control via HPLC shows 45% conversion to the requested N-indole amide.

The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (50 ml) and extracted with 70 ml water and 70 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a yellow oil (1 .00 g).

The crude product was treated on a column over 250 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100: 1. This yielded 320 mg the N-indole amide as a brown oil (39%).

LC-MS measurement for the obtained compound is shown in Figure 10.

Preparative example 11 : 4-(cvclopropanecarbonyl)-N-ethyl-7-methyl-4, 6,6a, 7,8, 9-hexahydroindolo[4,3-1qui noline- 9-carboxamide

Lysergic acid mono ethylamide (0.68 mmol/200 mg) was dissolved in tetrahydrofuran (12 ml) at -78 °C and aerated with argon. N-Butyllithium 2.5 M in hexane (0.88 mmol/0.35 ml) was added through septum. This results in an orange suspension. After stirring for 15 min, cyclopropane carboxylic acid chloride (0.81 mmol/0.07 ml/ diluted in THF) was added dropwise through septum. Two hours after addition of the acid chloride, the dry ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 23 h under argon at 25 °C.

In-process-control via HPLC shows 50% conversion to the requested N-indole product. The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (70 ml) and extracted with 70 ml water and 70 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.21 g).

The crude product was treated on a column over 50 g silica using the eluent mixture dichloromethane/methanol in a ratio of 100: 1. This yielded 70 mg the N-indole amide as a greenish oil (28%).

LC-MS measurement for the obtained compound is shown in Figure 11 . ,3-fqlquinoline-9- carboxamide

Lysergic acid mono methylamide (0.72 mmol/200 mg) was dissolved in chloroform (10 ml) at 0 °C and aerated with argon. Triethylamine (0.99 mmol/0.14 ml) was added. After stirring for 60 min, lsoxazole-5-carbonylchloride (0.85 mmol/0.08 ml) diluted in 1 ml chloroform was added dropwise through septum. Upon addition of acid chloride, the ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 2 h under argon at 25 °C.

In-process-control via HPLC shows 20% conversion to the requested N-indole product.

The reaction mixture was diluted with dichloromethane (50 ml) and extracted with 50 ml water and 50 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.130 g).

The crude product was treated on a column over 50 g silica using the eluent mixture dichloromethane/ethanol in a ratio of 20: 1 . This yielded 30 mg of the N-indole amide as an oily residue (11 %). LC-MS measurement for the obtained compound is shown in Figure 12.

Preparative example 13: N,7-dimethyl-N-(3-phenylpropanoyl)-4,6,6a,7,8,9-hexahvdroindolo[4,3-fg]quinoline-9- carboxamide

Lysergic acid mono methylamide (0.89 mmol/250 mg) was dissolved in chloroform (5 ml) at 25°C and aerated with argon. Triethylamine (1.33 mmol/0.18 ml) was added. After stirring for 30 min, phenylpropionyl chloride (0.98 mmol/0.15 ml) diluted in 1 ml chloroform was added dropwise through septum. The stirring was continued for 45 min under argon at 25 °C.

In-process-control via HPLC shows 20% conversion to the requested N-amide product.

The reaction mixture was diluted with dichloromethane (50 ml) and extracted with 50 ml water and 50 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.110 g).

The crude product was treated on a column over 50 g silica using the eluent mixture dichloromethane/ethanol in a ratio of 20:1. This yielded 40 mg of the N-amide as an oily residue (10 %).

LC-MS measurement for the obtained compound is shown in Figure 13.

Preparative example 14: N,7-dimethyl-N,4-bis(3-phenylpropanoyl)-4,6,6a,7,8,9-hexahvdroindolo[4,3-fg]quinoline- 9-carboxamide

In-process-control via HPLC shows 25% conversion to the double-reacted N-amide.

The crude product was treated on a column over 50 g silica using the eluent mixture dichloromethane/ethanol in a ratio of 20:1. This yielded 50 mg of the N,N-diamide as an oily residue (10 %).

LC-MS measurement for the obtained compound is shown in Figure 14. Lysergic acid mono ethylamide (0.85 mmol/250 mg) was dissolved in tetrahydrofuran (10 ml) at -78 °C and aerated with argon. N-Butyllithium 2.5 M in hexane (1.02 mmol/0.40 ml) was added through septum. This results in an orange suspension. After stirring for 15 min, methanesulfonyl chloride (1.02 mmol/0.08 ml/ diluted in THF) was added dropwise through septum. Two hours after addition of the sulfonyl chloride, the dry ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 18 h under argon at 25 °C.

In-process-control via HPLC shows 30% conversion to the requested N-indole product.

The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (70 ml) and extracted with 70 ml water and 70 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.63 g).

The crude product was purified on a column over 100 g silica using the eluent mixture dichloromethane/ethanol in a ratio of 100: 1. This yielded 200 mg the N-indole amide as a yellow oil (60%).

LC-MS measurement for the obtained compound is shown in Figure 15.

Preparative example 16: N-ethyl-4-(ethylsulfonyl)-7-methyl-4,6,6a,7,8,9-hexahvdroindolo[4,3-fg]quinoline-9- carboxamide

Lysergic acid mono ethylamide (0.85 mmol/250 mg) was dissolved in tetrahydrofuran (10 ml) at -78 °C and aerated with argon. N-Butyllithium 2.5 M in hexane (1.02 mmol/0.40 ml) was added through septum. This results in an orange suspension. After stirring for 15 min, ethanesulfonyl chloride (1.1 mmol/0.07 ml/ diluted in THF) was added dropwise through septum. Two hours after addition of the sulfonyl chloride, the dry ice bath has been removed and the reaction has allowed to come to 25°C. The stirring was continued for 2 h under argon at 25 °C.

In-process-control via HPLC shows 80% conversion to the requested N-indole amide. The reaction mixture was completely dried to remove all tetrahydrofuran and the residue was solved in dichloromethane (70 ml) and extracted with 70 ml water and 70 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (0.26 g).

The crude product was purified via column over 50 g silica using the eluent mixture dichloromethane/ethanol in a ratio of 100: 1. This yielded 120 mg the N-indole amide as a yellowish oil (36%).

LC-MS measurement for the obtained compound is shown in Figure 16.

Preparative example 17: N-ethyl-7-methyl-4-(tetrahvdro-2H-pyran-2-yl)-4,6,6a,7,8,9-hexahydroindolo- [4,3-fg]quinoline-9-carboxamide

Lysergic acid mono ethylamide (0.85 mmol/250 mg) was dissolved in chloroform (5 ml) at 25°C and aerated with argon. 3,4-Dihydropyran (44 mmol/ 4.0 ml) have been added to this reaction solution. Pyridinium p-toluenesulfonate (0.1 mmol/ 25 mg) have been added and the reaction mixture was stirred at 70°C.

After stirring for 18 h, the reaction mixture was diluted with dichloromethane (50 ml) and washed with 50 ml water and 50 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a black oil (0.283 g). The crude product was chromatographed on a column over 50 g silica using the eluent mixture dichloromethane/methanol in a ratio of 20:1. This yielded 200 mg the N-indole compound as a brown wax (62%).

LC-MS measurement for the obtained compound is shown in Figure 17. Preparative example 18: N,N-diethyl-7-methyl-4-(tetrahydro-2H-pyran-2-yl)-4,6,6a,7,8,9-hexahydroindolo- [4,3-fg]quinoline-9-carboxamide

Lysergic acid diethylamide (1.4 mmol/454 mg) was dissolved in dichloroethane (6 ml) at 25°C and aerated with argon. 3,4-Dihydropyran (64 mmol/ 5.0 ml) have been added to this reaction solution. Pyridinium p-toluenesulfonate (0.9 mmol/ 226 mg) have been added and the reaction mixture was stirred at 78°C.

After stirring for 24 h, the reaction mixture was diluted with dichloromethane (50 ml) and washed with 50 ml water and 50 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a black oil (0.958 g). The crude product was chromatographed on a column over 50 g silica using the eluent mixture dichloromethane/methanol in a ratio of 20: 1. This yielded 404 mg the N-indole protected compound as a brown wax (71 %).

LC-MS measurement for the obtained compound is shown in Figure 18.

3-fq]quinoline-9-

Lysergic acid hydrate (11 mmol/3.15g) was suspended in ethyl acetate (180 ml) at 25 °C and aerated with argon.

Diisopropylamine (88 mmol/14.95 ml) was added through septum. This results in a fawn suspension. N-Benzylacetylmethylester-ethylamine (23 mmol/4.50 g/diluted in ethyl acetate) was added dropwise through septum. Subsequently, propane-phosphonic acid anhydride 50% solution in ethyl acetate [T3P] (21.1 ml) was added dropwise through the septum over a period of 1 h. The reaction mixture was stirred for 24 h at 25°C.

In-process-control via HPLC shows more than 80% conversion to the requested lysergamide.

The reaction mixture was diluted with in ethyl acetate (300 ml) and extracted with 80 ml water and 70 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSC Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a brown oil (7.40 g).

The crude product was purified on a column over 250 g silica using the eluent mixture dichloromethane/ethanol in a ratio of 30: 1 . This yielded 3.56 g the requested lysergamide as a brown oil (73%).

LC-MS measurement for the obtained compound is shown in Figure 19.

Preparative example 20: (7-methyl-4,6,6a,7,8,9-hexahvdroindolo[4,3-fg]59uinoline-9-yl)(thiomorpholino)methanone

Lysergic acid hydrate (4 mmol/1.14 g) was suspended in ethyl acetate (60 ml) at 25 °C and aerated with argon. Diisopropylethylamine (32 mmol/5.47 ml) was added through septum. This results in a fawn suspension.

Thiomorpholine (8 mmol/ 0.8 ml) was added dropwise through septum. Subsequently, propane-phosphonic acid anhydride 50% solution in ethyl acetate [T3P] (7.6 ml) was added dropwise through the septum over a period of 15 min. The reaction mixture was stirred for 1 h at 25°C.

In-process-control via HPLC shows quantitative conversion to the requested lysergamide.

The reaction mixture was diluted with ethyl acetate (100 ml) and extracted with 40 ml water and 40 ml saturated saline solution. Subsequently, the organic phase was dried over some MgSO4. Subsequently, the organic phase was slowly concentrated on the rotary evaporator, yielding the crude product as a beige foam (1.50 g). The crude product was purified on a column over 130 g silica using the eluent mixture dichloromethane/ethanol in a ratio of 30: 1 . This yielded 0.57 g the requested lysergamide as a colorless oil (40%).

LC-MS measurement for the obtained compound is shown in Figure 20.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

RN is C1-5 alkyl;

Ri is selected from methyl and ethyl, and and -(Co-3 al ky lene)ary I , wherein the aryl moiety in said -(C0-3 alky lene)ary I is optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with Rx, or R1 and R2 are taken together to form, together with the N atom to which they are attached, a heterocycloalkyl containing an S ring atom;

R3 is selected from -H, tetrahydropyranyl, -CH2-O-(CI-5 alkyl), , , and each R4, R5 and Re is independently selected from C1-5 alkyl, C1-5 fluoroalkyl, -(C0-3 alkylene)cycloalkyl, -(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)aryl, and -(C0-3 alkylene)heteroaryl, wherein the cycloalkyl moiety in said -(C0-3 alkylene)cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)aryl, and the heteroaryl moiety in said -(C0-3 alkylene)heteroaryl are each optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alkylene)aryl is optionally substituted with Rx; each R^s is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5 alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-PO4H2, -(C0-3 alkyleneJ-POaH, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl and the heterocyclyl moiety in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-5 alkyl, halogen, -CN, -NO2, -OH, -0- (C1.5 alkyl), -SH, -S-(Ci.₅ alkyl), -NH₂, -NH(CI.₅ alkyl), -N(CI.₅ alkyl)(Ci.₅ alkyl), -COCH, -C00(Ci.₅ alkyl), -CONH2, -CONH(CI-₅ alkyl), -CON(CI.₅ alkyl)(Ci.₅ alkyl), -NHCO(CI.₅ alkyl) and -N(CI.₅ alkyl)-CO(Ci.₅ alkyl);

Rx is selected from -C0-CH(-NH2)-Rz, -CO-R9 and O-glycosyl;

R? is selected from hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -(C1-6 alkyleneJ-O-Rs, -(C1-6 alkylene)-S- Rs, -(C1-6 alkylene)-N(Rs)-R8, -(C1-6 alkylene)-C0-R8, -(C1-6 alkylene)-C00-R8, -(C1-6 alkylene)-0-C0-(Ci-6 alkyl), -(C1-6 alkylene)-CO-N(R8)-R8, -(C1-6 alkylene)-N(R8)-CO-(Ci-6 alkyl), -(C1-6 alkylene)-CO-N(R8)-O-R8, -(C1.6 alkylene)-O-CO-N(R₈)-R8, -(Ci.₆ alkylene)-N(R₈)-CO-N(R₈)-R8, -(Ci.₆ alkylene)-N(R₈)-C(=N-R₈)-N(R₈)- Rs, -(C1-6 alkyleneJ-SO -Rs, -(Co-6 alkylene)-carbocyclyl, and -(Co-6 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(Co-6 alkylene)-carbocyclyl and the heterocyclyl group in said -(Co-6 alkylene)- heterocyclyl are each optionally substituted with one or more R^s, wherein said alkyl, said alkenyl, said alkynyl, and any alkylene group comprised in any of the aforementioned Rz groups are each optionally substituted with one or more -OH, and further wherein each Rs is independently selected from hydrogen and C1-6 alkyl; and

2. The compound of claim 1 , wherein R1 is selected from methyl and ethyl, and and -(C0-3 al ky lene)ary I , wherein the aryl moiety in said -(C0-3 alky lene)ary I is optionally substituted with one or more R^s, and wherein the aryl moiety in said -(C0-3 alky lene)ary I is optionally substituted with Rx.

3. The compound of claim 1 or 2, wherein R2 is selected from -H and ethyl.

4. The compound of claim 1 or 2, wherein R3 is -H.

5. The compound of any one of claims 1 , 2 or 4, wherein R2 is selected from preferably wherein R2 is selected from

6. The compound of any one of claims 1 to 3 or 5, wherein R3 is selected from , preferably wherein R3 is selected from

7. The compound of any one of claims 1 or 4 to 6, wherein Ri and R2 are taken together to form, together with the N atom to which they are attached, a heterocycloalkyl containing an S ring atom, preferably wherein said heterocycloalkyl containing an S ring atom is thiomorpholin-4-yl.

8. The compound of any one of claims 1 to 7, wherein R4 is selected from methyl, ethyl, cyclopropyl, phenylethyl and isoxazolyl.

9. The compound of any one of claims 1 to 8, wherein R5 is selected from methyl, ethyl, fluoroethyl, ferf-butyl, cyclopropyl and 3-oxetanyl.

10. The compound of any one of claims 1 to 9, wherein Re is selected from methyl, ethyl and cyclopropyl.

11. The compound of any one of claims 1 , 2, 4 to 6, 8 or 10, wherein is -CH2-aryl, wherein the aryl moiety in said -CFh-aryl is optionally substituted with one or more R^s; preferably wherein R5 is -CF phenyl, wherein the phenyl moiety in said -CH2-phenyl is optionally substituted with one or more R^s, and wherein the phenyl moiety in said -CH2-phenyl is optionally substituted with Rx.

12. The compound of claim 1 , wherein the compound is a compound selected from:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12 and a pharmaceutically acceptable excipient.

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

15. The compound of any one of claims 1 to 12 or the pharmaceutical composition of claim 13 for use in the treatment of a serotonin 5-HT2A receptor associated disease/disorder.

16. The compound for use of claim 15 or the pharmaceutical composition for use of claim 15, wherein said serotonin 5-HT2A receptor associated disease/disorder is selected from an anxiety disorder, depression, major depression, posttraumatic stress disorder (PTSD), substance use disorder (SUD), alcohol use disorder (AUD), cluster headache, migraine, Parkinson's disease, an eating disorder, and anorexia.