Ergolic acid derivatives with improved LSD-like action

Abstract

A composition of compounds generally represented by Figure 1A for use in substance adjuvant therapy. A method of altering neurotransmission by administering to a mammal a pharmaceutically effective amount of a compound of Figure 1A, interacting with the serotonin 5-HT2A receptor and inducing a psychoactive effect in the mammal, particularly in a human body. A method of treating a subject by administering to the subject a pharmaceutically effective amount of a compound of Figure 1A and treating the subject.

Description

Background of the Invention 1. Technical Field

[0002] The present invention relates to the substance definition and synthesis of lysergic acid derivatives with improved LSD-like effects for substance-assisted psychotherapy. 2. Background technology

[0003] Psychedelic drugs are substances that induce unique subjective effects, including dream-like alterations in consciousness, affective changes, increased introspection, visual imagery, pseudohallucinations, synesthesia, mystical experiences, dissociation, and ego-dissolution (Liechti, 2017; Passie, Halpern, Stichtenoth, Emrich, & Hintzen, 2008).

[0004] Psychedelic drugs, primarily lysergic acid diethylamide (LSD) and psilocybin, are currently being investigated as potential drugs. The first clinical trials have shown that LSD and psilocybin have potential efficacy in addiction (Bogenschutz, 2013; Bogenschutz et al., 2015; Garcia-Romeu et al., 2019; Garcia-Romeu, Griffiths, & Johnson, 2014; Johnson, Garcia-Romeu, Cosimano, & Griffiths, 2014; Johnson, Garcia-Romeu, & Griffiths, 2016; Krebs & Johansen, 2012), life-threatening diseases, and other disorders. Several trials investigating the therapeutic effects of LSD, psilocybin, and other psychedelics are also underway. There is also evidence that the psychedelic infusion Ayahuasca (Dominguez-Clave et al., 2016), which contains the active psychedelic substance N,N-dimethyltryptamine (DMT), can relieve depression (Dos Santos et al., 2016; Palhano-Fontes et al., 2019; Sanches et al., 2016). In contrast, there is currently no comparable therapeutic research or detailed concept on the use of psychedelic lysergic acid derivatives other than LSD to treat medical disorders.

[0005] Although no psychedelic drugs are currently licensed for medical use, psilocybin and LSD have been used in special programs for therapeutic use (Schmid, Gasser, Oehen, & Liechti, 2021). LSD is a serotonergic psychedelic similar to psilocybin, with comparable acute effects but significantly longer duration of action (8-12 hours for LSD compared to 6 hours for psilocybin) (Becker et al., 2022; Holze et al., 2022; Holze, Vizeli, et al., 2021).

[0006] A potentially important disadvantage of LSD is the long duration of its acute effects, which results in the need for prolonged patient monitoring and associated costs. On the other hand, LSD has advantages over psilocybin and other short-acting substances. Specifically, LSD has a long history of use (Nichols, 2016) and a wealth of information on its safety pharmacology (Holze, Caluori, Vizeli, & Liechti, 2021; Nichols & Grob, 2018). The pharmacology of LSD has been well studied (Holze, Caluori, et al., 2021; Holze et al., 2019; Holze, Vizeli, et al., 2021; Holze et al., 2020; Nichols, 2018b; Vizeli et al., 2021), and LSD is also one of the most potent psychedelics known in vivo, so only very low doses are required to produce the desired effects (Luethi & Liechti, 2018). Therefore, it might be desirable to design an LSD analog that has similar pharmacological properties to LSD in terms of potency, efficacy, and safety, and has a similar or preferably different and faster metabolism than classical LSD, and therefore a shorter duration of action.

[0007] Novel lysergic acid derivatives could be equally useful for treating medical conditions, or even more effectively. Specifically, existing psychedelic treatments such as LSD, psilocybin, and DMT may not be suitable for every patient considering psychedelic-assisted therapy. In general, it is important to have access to several substances with different properties, and the current lack of such substances is a treatment problem that will be further exacerbated as more and more patients require psychedelic-assisted therapy and as the demand for such treatments increases once the efficacy of first-time treatments is demonstrated in large clinical studies. For example, some patients may have strong adverse reactions to existing treatments (such as psilocybin), experiencing adverse effects including headache, nausea / vomiting, anxiety, cardiovascular stimulation, or significant dysphoria (Davis et al., 2021; R.R. Griffiths et al., 2016; Holze et al., 2022; Ross et al., 2016). On the other hand, the long duration of action of LSD may be a limiting factor in some cases, and the increased duration of treatment sessions may significantly increase medical costs. In addition, such long treatment sessions require cumbersome planning. Therefore, new compounds with psychedelic-like effects are needed.

[0008] Structurally, LSD is an ergoline derivative, distinct from psilocybin. Although they share some structural features, such as a tryptamine core, the primary pharmacophore of LSD is significantly different from psychedelic tryptamines such as psilocybin and DMT, and their binding modes and overall pharmacological profiles are also different (Cao et al., 2022; Rickli, Moning, Hoener, & Liechti, 2016; Wacker et al., 2017). Ergolines, tryptamines, and phenylethylamine psychedelics are all thought to induce acute psychedelic effects primarily through co-stimulation of the 5-HT2A receptor. All serotonergic psychedelics, including LSD, psilocybin, DMT, and mescaline, are 5-HT2A receptor agonists (Rickli et al., 2016) and are therefore likely to produce generally similar effects. However, there are differences in how the substances interact with the 5-HT2A receptor at the binding site, and some compounds even bind to the receptor without producing subjective effects (Cao et al., 2022). Furthermore, there are differences in the receptor activation profiles and subsequent activation patterns of signal transduction pathways between the substances, which may induce different subjective effects. In addition, LSD can potently stimulate not only 5-HT2A receptors, but also 5-HT2B / C, 5-HT1 and D1-3 receptors (Rickli et al., 2016). Dephosphopsilocybin, the active metabolite derived from the prodrug psilocybin present in humans, also stimulates 5-HT2A receptors, but additionally inhibits the 5-HT transporter (SERT) (Rickli et al., 2016). Mescaline binds to 5-HT2A, 5-HT2C, 5-HT1A and α2A receptors in a similar, but considerably lower, concentration range. In contrast to LSD, psilocybin and mescaline show no affinity for D2 receptors (Rickli et al., 2016). In summary, LSD may have stronger dopaminergic activity than psilocybin and mescaline, while psilocybin may produce additional effects at SERT. In contrast to psilocybin, mescaline and its derivatives do not interact with SERT. Overall, the pharmacological profiles of psychedelics may differ at the 5-HT2A receptor, but obviously also have additional effects at other receptors, which could then translate into different or even unique effect profiles for each substance.

[0009] In humans, the subjective effects of psychoactive doses of LSD appear within 15–60 minutes, peak at 2–4 hours, and persist in a dose-dependent manner for 8–12 hours. The plasma half-life is approximately 4 hours (Holze et al., 2019; Holze et al., 2022; Holze, Vizeli, et al., 2021). The long duration of action of LSD reflects the presence of LSD in plasma and is therefore related to the subject-specific concentration–time profile and plasma half-life (Holze et al., 2019). This is also true for psilocybin, where the presence of the active metabolite desphosphopsilin in its unconjugated form in plasma determines the duration of action of psilocybin in humans. The plasma half-life of unconjugated desphosphopsilin is an average of 2 hours (Becker et al., 2022), which is consistent with the shorter duration of action of psilocybin compared to LSD. It can therefore be expected that structurally related LSD compounds with shorter plasma half-lives would also have a similarly shorter duration of action.

[0010] The acute subjective effects of psychedelic drugs are mostly positive for most humans (RL Carhart-Harris, Kaelen, et al., 2016; Dolder, Schmid, Mueller, Borgwardt, & Liechti, 2016; Dolder et al., 2017; Holze et al., 2019; Schmid et al., 2015). However, there are negative subjective effects, such as anxiety in many people (Davis et al., 2021; R.R. Griffiths et al., 2016; Ross et al., 2016), which may depend on the dose used (Holze et al., 2022), personality traits (setting), environment (physical and social environment), and other factors (Studerus, Gamma, Kometer, & Vollenweider, 2012). An overall positive acute response to psychedelic drugs is crucial, as several studies have shown that more positive experiences predict stronger long-term therapeutic effects of psychedelic drugs (Garcia-Romeu et al., 2014; R. R. Griffiths et al., 2016; Ross et al., 2016). Even in healthy subjects, more positive acute responses to psychedelic drugs, including LSD, have been shown to be associated with more positive long-term effects on well-being (R. Griffiths, Richards, Johnson, McCann, & Jesse, 2008; Schmid & Liechti, 2018).

[0011] LSDs have associated acute side effects of varying degrees, depending on the subject being treated, including increased blood pressure, nausea and vomiting, increased temperature and blood glucose, numbness, tremors, negative body sensations, and dysphoria (Holze, Caluori et al., 2021). Such side effects of a substance are often related to its interaction with its pharmacological target. For example, interactions with adrenergic receptors can lead to adverse clinical cardiac excitatory properties. In addition, changes in the relative activation properties of serotonin 5-HT receptors and other targets can alter the quality of the psychoactive effect. Changes in binding potency, binding mode, potency of subsequent signaling pathways that activate 5-HT2A receptors, and lipophilicity of the molecule primarily determine the clinical dose that induces psychoactive effects. Changes that alter the metabolic stability of the compound can also significantly alter the duration of action of the substance.

[0012] There is a need for new LSD-based derivatives, ie, lysergic acid-based derivatives, to provide substances with an improved effect profile, such as, but not limited to, more positive effects, fewer adverse effects, different qualitative effects, and alterations in the duration of acute effects. Summary of the invention

[0013] The present invention provides a generally Figure 1A A composition of compounds denoted and named "lysergic acid amides" for use in substance-assisted therapy.

[0014] Therefore, the first category is Figures 2A to 2G , lysergic acid amides as shown in 3A to 3H, 4A to 4G, 5A to 5C and 6A to 6C, wherein R8' consists of the substituents shown in the subclasses designated as classes 1a to 1n, wherein R8 consists of:

[0015] a) R8',

[0016] b) any substituent of subclasses 1a to 1n and R8' = as defined in the specific classes 1a to 11,

[0017] c) hydrogen, C1-C5 alkyl, branched C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkylcycloalkyl, C2-C5 alkenyl, branched C3-C5 alkenyl, C2-C5 alkynyl, branched C4-C5 alkynyl, or

[0018] d) as specified in categories 1a to 1n;

[0019] Under the above definition,

[0020] In class 1a (as a subclass of class 1), the substituent R8' consists of: F1-F11 fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl, each optionally in combination with: D1-D10 deuterium, and / or hydroxyl and / or carbonyl,

[0021] In class 1b (as a subclass of class 1), the substituent R8' consists of: F1-F13 fluorine-substituted C3-C7 alkenyl, optionally in combination with: D1-D12 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the double bond is separated from the nitrogen,

[0022] In class 1c (as a subclass of class 1), the substituent R8' consists of: F1-F11 fluorine-substituted C3-C6 cycloalkyl, optionally in combination with: D1-D10 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl,

[0023] In class 1d (as a subclass of class 1), the substituent R8' consists of: F1-F17 fluorine-substituted C3-C6 cycloalkylalkyl, optionally in combination with: D1-D10 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl,

[0024] In class 1e (as a subclass of class 1), the substituent R8' consists of: F1-F11 fluorine-substituted C3-C7 alkynyl, optionally in combination with: D1-D12 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the triple bond is separated from the amide nitrogen,

[0025] In class 1f (as a subclass of class 1), the substituent R8' consists of: F0-F7 fluorine-substituted C2-C4 alkenyl, attached to the nitrogen with an unsaturated moiety to produce an enamide, optionally in combination with: D1-D7 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0026] In class 1g (as a subclass of class 1), the substituent R8' consists of: F1-F5 fluorine-substituted C2-C4 alkylalkynyl, attached to the nitrogen with an unsaturated moiety to produce an alkynamide, optionally in combination with: D1-D4 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0027] In class 1h (as a subclass of class 1), the substituent R8' consists of: F1-F13 fluorine-substituted C1-3-O-C1-3 alkoxyalkyl, optionally in combination with: D1-D12 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0028] In class 1i (as a subclass of class 1), the substituent R8' consists of: F0-F7 fluorine-substituted C1-C3 alkoxy or C3-C4 cycloalkoxy, each optionally in combination with: D1-D7 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0029] In class 1j (as a subclass of class 1), the substituent R8' consists of a nitrile attached to a C1-C3 alkyl group, optionally in combination with: F1-F7 fluorine and / or D1-D7 deuterium, and / or hydroxyl and / or carbonyl,

[0030] In class 1k (as a subclass of class 1), the substituent R8 consists of any D1-D6 deuteron in combination with a C1-C3 alkyl group containing F1-F6 fluorine, optionally in combination with a hydroxyl group and / or a carbonyl group, and R8' consists of hydrogen, C1-C6 alkyl or C3-C5 cycloalkyl or C4-C7 cycloalkylalkyl, optionally in combination with a hydroxyl group and / or a carbonyl group,

[0031] In class 11 (as a subclass of class 1), the substituent R8 consists of D1-D7 deuteron or F1-F7 fluorine, or any D1-D6 deuteron in combination with C1-C3 alkyl containing F1-F6 fluorine, optionally in combination with hydroxyl and / or carbonyl, and R8' consists of C2-C8 alkenyl or C2-C8 alkynyl, optionally in combination with nitrile, and / or hydroxyl and / or carbonyl,

[0032] In class 1m (as a subclass of class 1), substituents R8 and R8' are linked to each other to establish an azacycloalkane with the amide nitrogen and consist of: D1-D10 deuteron or F1-F10 fluorine, or any D1-D9 deuteron in combination with a C3-C6 alkylene containing F1-F9 fluorine, the C3-C6 alkylene containing F1-F9 fluorine optionally combined with: nitrile, and / or hydroxyl, and / or carbonyl and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl,

[0033] In class 1n (as a subclass of class 1), substituents R8 and R8' are linked to each other to establish an azacycloalkane with the amide nitrogen and consist of a C3-C6 alkylene group attached to an undeuterated or deuterated C1-C3 alkenyl group and / or an undeuterated or deuterated C2-C3 alkynyl group, the alkylene group forming the azacycloalkane being further and optionally combined with: nitrile, and / or hydroxyl, and / or carbonyl and / or deuterated and undeuterated C1-C3 alkyl group, and / or deuterated and undeuterated C1-C3 alkenyl group and / or deuterated and undeuterated C2-C3 alkynyl group.

[0034] The present invention provides a compound composition for use in substance-assisted therapy, wherein the compound is generally composed of Figure 1A is represented and named "lysergic acid amide" and is also represented by Class 2, which is represented by FIG. 4A to FIG. 5C The 6-substituted 6-demethyl-lysergic acid diethylamide shown in the embodiment, wherein R6 consists of the substituents shown in the subclasses designated as Class 2a to Class 2i, wherein R6 consists of:

[0035] In class 2a (as a subclass of class 2), the substituent R6 consists of: F1-F11 fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl, each optionally in combination with: D1-D10 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0036] In class 2b (as a subclass of class 2), the substituent R6 consists of: F1-F13 fluorine-substituted C3-C7 alkenyl, optionally in combination with: D1-D12 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the alkenyl double bond is separated from the nitrogen,

[0037] In class 2c (as a subclass of class 2), the substituent R6 consists of: C3-C7 alkynyl with F1-F11 fluorine substituted in which the triple bond is separated from the N6 nitrogen, optionally in combination with: D1-D10 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl. Provided that the substituent R6 contains at least one nitrile, one hydroxyl or one carbonyl, R6 can also consist of: C3-C7 alkynyl with the triple bond separated from the N6 nitrogen, optionally in combination with: D1-D10 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0038] In class 2d (as a subclass of class 2), the substituent R6 consists of: C3-C6 cycloalkyl, optionally in combination with: F1-F11 fluorine, and / or D1-D11 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl,

[0039] In class 2e (as a subclass of class 2), the substituent R6 consists of: F1-F17 fluorine-substituted C4-C9 cycloalkylalkyl, optionally in combination with: D1-D16 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl. Provided that the substituent R6 is not a cyclopropylmethyl group linked to the N6 nitrogen of the ergoline structure via an exocyclic methylene unit, or is a cyclopropylmethyl group linked to the N6 nitrogen of the ergoline structure via an exocyclic methylene unit and contains at least one nitrile, one hydroxyl group or one carbonyl group, R6 can also consist of: C4-C9 cycloalkylalkyl, optionally in combination with: D1-D17 deuteron, and / or nitrile, and / or hydroxyl group, and / or carbonyl group, and / or deuterated and undeuterated C1-C3 alkyl group and / or deuterated and undeuterated C1-C3 alkenyl group and / or deuterated and undeuterated C1-C3 alkynyl group,

[0040] In class 2f (as a subclass of class 2), the substituent R6 consists of: F0-F7 fluorine-substituted C2-C4 alkenyl, attached to the nitrogen with an unsaturated moiety to generate an enamine, optionally in combination with: D1-D7 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0041] In class 2g (as a subclass of class 2), the substituent R6 consists of: C3-C6 oxacycloalkyl, C3-C9 oxacycloalkylalkyl, C3-C6 thiacycloalkyl or C3-C9 thiacycloalkylalkyl, each optionally in combination with: F1-F19 fluorine, and / or D1-D19 deuterium, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl,

[0042] In class 2h (as a subclass of class 2), the substituent R6 consists of: F0-F11 fluorine-substituted C1-C5 alkoxy or C3-C6 cycloalkoxy or C2-C6 alkenyloxy, each optionally in combination with: D1-D11 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0043] In class 2i (as a subclass of class 2), the substituent R6 consists of: aryl, heteroaryl, arylmethyl or heteroarylmethyl, each optionally in combination with: F0-F7 fluorine, and / or D1-D7 deuterium, and / or one or more of the following substituents which may themselves be optionally fluorinated and / or deuterated: halogen, nitrile, nitro, hydroxy, carbonyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, methylenedioxy, C1-C4 alkylthio, C3-C6 alkenylthio, C3-C6 alkynylthio, C3-C6 cycloalkylthio. In addition, the R6 substituents as defined above in class 2i can further form a ring.

[0044] The present invention provides a composition of compounds for use in substance-assisted therapy, the compound generally consisting of Figure 1A It is indicated and named as "lysergic acid amide" and is also classified by Class 3 ( Fig. 6A ) indicates that from Class 1 and its subclasses 1a to 1n ( Figures 2A to 3H ) and the substituents R8 and R8' of class 2 and its subclasses 2a to 2i ( FIG. 4A to FIG. 5C ) is composed of any possible combination of substituents R6.

[0045] The present invention provides a compound composition for use in substance-assisted therapy, wherein the compound is generally composed of Figure 1A It is indicated and named "lysergic acid amide", and is also classified by Class 4 ( Figure 6B ) indicates that from Class 1 and its subclasses 1a to 1n ( Figures 2A to 3H ) and the substituents R8 and R8' of Class 2 and its subclasses 2a to 2i ( FIG. 4A to FIG. 5C ) and any possible combination of substituents R6 of the following groups on the ergoline substructure and the N1 nitrogen substituents of the following groups: a) any acyl group; b) unsubstituted and substituted carbamoyl groups; c) amide-bound amino acids; d) alkyl, alkenyl or alkynyl groups; e) alkoxy, alkenyloxy or alkynyloxy groups; f) any substituent described under a) to e) substituted with one or more fluorine atoms; g) any substituent described under a) to e) substituted with one or more deuterium atoms; h) any substituent described under a) to e) substituted with one or more fluorine atoms and one or more deuterium atoms.

[0046] The present invention provides a compound composition for use in substance-assisted therapy, wherein the compound is generally composed of Figure 1A It is indicated and named "lysergic acid amide", and is also classified by Class 5 ( Figure 6C ) represents, consisting of monodeuterated to fully deuterated ergoline core structures, and additionally consisting of Class 1 and its subclasses 1a to 1n ( Figures 2A to 3H ) and the substituents R8 and R8' of Class 2 and its subclasses 2a to 2i ( FIG. 4A to FIG. 5C ) and any possible combination of substituents R6 of the following groups on the N1 nitrogen substituent of the ergoline substructure: a) hydrogen; b) any acyl group; c) unsubstituted and substituted carbamoyl groups; d) amide-bonded amino acids; e) alkyl, alkenyl or alkynyl groups; f) alkoxy, alkenyloxy or alkynyloxy groups; g) any substituent described under a) to f) substituted with one or more fluorine atoms; h) any substituent described under a) to f) substituted with one or more deuterium atoms; i) any substituent described under a) to f) substituted with one or more fluorine atoms and one or more deuterium atoms.

[0047] The present invention provides a method of altering neurotransmission by administering to a mammal a pharmaceutically effective amount of Figure 1A Compounds that interact with the serotonin 5-HT2A receptor in mammals, and in particular humans, and induce psychoactive effects.

[0048] The present invention provides a method of treating an individual by administering to the individual a pharmaceutically effective amount of Figure 1A Compounds and treated individuals. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Other advantages of the present invention will be more readily appreciated, and become better understood, by reference to the following detailed description when considered in conjunction with the accompanying drawings, in which:

[0050] Figure 1A shows the general chemical structure of lysergic acid derivatives within the scope of the present invention, more specifically lysergic acid amides with different substituents at positions 1 (defined as R1), 6 (defined as R6) and the amide portion of the amide attached to position 8 (defined as R8 and R8'), Figure 1B The ergoline core structure and its numbering are shown, and Figure 1C The chemical structure of LSD and its stereochemical name are shown;

[0051] Figure 2A Compounds defined as Class 1 are shown, Figure 2B Compounds of subclass 1a are shown, Figure 2C Compounds of subclass 1b are shown, Figure 2D Compounds of subclass 1c are shown, Figure 2E Compounds of subclass 1d are shown, Figure 2F Compounds of subclass 1e are shown, and Figure 2G Compounds of subclass 1f are shown;

[0052] Figure 3ACompounds of subclass 1g are shown, Figure 3B Compounds of subclass 1h are shown, Figure 3C Compounds of subclass 1i are shown, Figure 3D Compounds of subclass 1j are shown, Figure 3E Compounds of subclass 1k are shown, Figure 3F Compounds of subclass 11 are shown, Figure 3G Compounds of subclass 1m are shown, and Figure 3H Compounds of subclass 1n are shown;

[0053] Figure 4A Compounds defined as class 2 are shown, Figure 4B Compounds of subclass 2a are shown, Figure 4C Compounds of subclass 2b are shown, Figure 4D Compounds of subclass 2c are shown, Figure 4E Compounds of subclass 2d are shown, Figure 4F Compounds of subclass 2e are shown, and Figure 4G Compounds of subclass 2f are shown;

[0054] Figure 5A Compounds of subclass 2g are shown, Figure 5B Compounds of subclass 2h are shown, and Figure 5C Compounds of subclass 2j are shown;

[0055] Fig. 6A Compounds of class 3 are shown, Figure 6B Compounds of class 4 are shown, and Figure 6C Compounds from class 5 are shown;

[0056] Figures 7A-7N An example of the preparation of a lysergic acid derivative represented by FIG1 is shown, Fig. 7A Compound 2a is shown, Figure 7B Compound 2b is shown, Figure 7C Compound 2c is shown, Fig.7D Compound 2d is shown, Fig. 7E Compound 2e is shown, Figure 7F Compound 2f is shown, Figure 7G Compound 2g is shown, Figure 7H Compound 2h is shown, Fig.7I Compound 2i is shown, Figure 7J Compound 2j is shown, Figure 7K Compound 2k is shown, Figure 7L Compound 21 is shown, Figure 7M Compound 2m is shown, and Figure 7N Compound 2n is shown;

[0057] Figures 8A-8N An example of the preparation of a lysergic acid derivative represented by FIG1 is shown, Fig. 8A Compound 12a is shown, Figure 8B Compound 12b is shown, Figure 8C Compound 12c is shown, Fig.8D Compound 12d is shown, Fig. 8E Compound 12e is shown, Fig.8F Compound 12f is shown, Figure 8G Compound 12g is shown, Figure 8H Compound 13 is shown, Figure 8I Compound 14a is shown, Figure 8J Compound 14b is shown, Figure 8K Compound 14c is shown, Figure 8L Compound 16a is shown, Figure 8M Compound 16b is shown, and Figure 8N Compound 16c is shown;

[0058] Fig. 9 The synthetic routes of lysergic acid derivatives 2a–2k, 2l, and 2m are summarized;

[0059] Fig.10 The synthetic route of lysergic acid derivative 2n is summarized;

[0060] Fig.11 The synthetic routes of lysergic acid derivatives 12a to 12g, 13, and 14a to 14c are generally described;

[0061] Fig.12 The synthetic routes of lysergic acid derivatives 16a to 16c are generally described;

[0062] Figures 13A-13J A diagram showing the metabolism of 10 novel lysergic acid derivatives, including Fig.13A Compound 2c is shown, Fig. 13B Compound 2d is shown, Fig. 13C Compound 2e is shown, Fig.13D Compound 2h is shown, Fig.13E Compound 2j is shown, Fig.13F Compound 21 is shown, Figure 13G Compound 2n is shown, Fig.13H Compound 12c is shown, Fig.13I Compound 16a is shown, and Fig.13J Compound 16b is shown; and

[0063] Fig.14 The receptor interactions of novel lysergic acid derivatives with LSD and dephosphorylated psilocybin as a control are described. DETAILED DESCRIPTION

[0064] The present invention provides a generally Figure 1A A composition of compounds represented and named "lysergic acid amides" for use in substance-assisted therapy. To better understand the problem, FIG. 2A to FIG. 6C Such compounds are represented in:

[0065] Therefore, the first category is Figures 2A to 3H Lysergic acid amide represented by wherein R8' consists of the substituents shown in the subclasses designated as Class 1a to Class 1n, wherein R8 consists of:

[0066] a) R8',

[0067] b) any substituent of subclasses 1a to 1n and R8' = as defined in the specific classes 1a to 11,

[0068] c) hydrogen, C1-C5 alkyl, branched C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkylcycloalkyl, C2-C5 alkenyl, branched C3-C5 alkenyl, C2-C5 alkynyl, branched C4-C5 alkynyl, or

[0069] d) as specified in categories 1a to 1n;

[0070] Under the above definition,

[0071] In class 1a (as a subclass of class 1), the substituent R8' consists of: F1-F11 fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl, each optionally in combination with: D1-D10 deuterium, and / or hydroxyl and / or carbonyl,

[0072] In class 1b (as a subclass of class 1), the substituent R8' consists of: F1-F13 fluorine-substituted C3-C7 alkenyl, optionally in combination with: D1-D12 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the double bond is separated from the nitrogen,

[0073] In class 1c (as a subclass of class 1), the substituent R8' consists of: F1-F11 fluorine-substituted C3-C6 cycloalkyl, optionally in combination with: D1-D10 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl,

[0074] In class 1d (as a subclass of class 1), the substituent R8' consists of: F1-F17 fluorine-substituted C3-C6 cycloalkylalkyl, optionally in combination with: D1-D10 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl,

[0075] In class 1e (as a subclass of class 1), the substituent R8' consists of: F1-F11 fluorine-substituted C3-C7 alkynyl, optionally in combination with: D1-D12 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the triple bond is separated from the amide nitrogen,

[0076] In class 1f (as a subclass of class 1), the substituent R8' consists of: F0-F7 fluorine-substituted C2-C4 alkenyl, attached to the nitrogen with an unsaturated moiety to produce an enamide, optionally in combination with: D1-D7 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0077] In class 1g (as a subclass of class 1), the substituent R8' consists of: F1-F5 fluorine-substituted C2-C4 alkylalkynyl, attached to the nitrogen with an unsaturated moiety to produce an alkynamide, optionally in combination with: D1-D4 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0078] In class 1h (as a subclass of class 1), the substituent R8' consists of: F1-F13 fluorine-substituted C1-3-O-C1-3 alkoxyalkyl, optionally in combination with: D1-D12 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0079] In class 1i (as a subclass of class 1), the substituent R8' consists of: F0-F7 fluorine-substituted C1-C3 alkoxy or C3-C4 cycloalkoxy, each optionally in combination with: D1-D7 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0080] In class 1j (as a subclass of class 1), the substituent R8' consists of a nitrile attached to a C1-C3 alkyl group, optionally in combination with: F1-F7 fluorine and / or D1-D7 deuterium, and / or hydroxyl and / or carbonyl,

[0081] In class 1k (as a subclass of class 1), the substituent R8 consists of any D1-D6 deuteron in combination with a C1-C3 alkyl group containing F1-F6 fluorine, optionally in combination with a hydroxyl group and / or a carbonyl group, and R8' consists of hydrogen, C1-C6 alkyl or C3-C5 cycloalkyl or C4-C7 cycloalkylalkyl, optionally in combination with a hydroxyl group and / or a carbonyl group,

[0082] In class 11 (as a subclass of class 1), the substituent R8 consists of D1-D7 deuteron or F1-F7 fluorine, or any D1-D6 deuteron in combination with C1-C3 alkyl containing F1-F6 fluorine, optionally in combination with hydroxyl and / or carbonyl, and R8' consists of C2-C8 alkenyl or C2-C8 alkynyl, optionally in combination with nitrile, and / or hydroxyl and / or carbonyl,

[0083] In class 1m (as a subclass of class 1), substituents R8 and R8' are linked to each other to establish an azacycloalkane with the amide nitrogen and consist of: D1-D10 deuteron or F1-F10 fluorine, or any D1-D9 deuteron in combination with a C3-C6 alkylene containing F1-F9 fluorine, the C3-C6 alkylene containing F1-F9 fluorine optionally combined with: nitrile, and / or hydroxyl, and / or carbonyl and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl,

[0084] In class 1n (as a subclass of class 1), substituents R8 and R8' are linked to each other to establish an azacycloalkane with the amide nitrogen and consist of a C3-C6 alkylene group attached to an undeuterated or deuterated C1-C3 alkenyl group and / or an undeuterated or deuterated C2-C3 alkynyl group, the alkylene group forming the azacycloalkane being further and optionally combined with: nitrile, and / or hydroxyl, and / or carbonyl and / or deuterated and undeuterated C1-C3 alkyl group, and / or deuterated and undeuterated C1-C3 alkenyl group and / or deuterated and undeuterated C2-C3 alkynyl group.

[0085] The present invention also provides a compound composition for use in substance-assisted therapy, wherein the compound is generally composed of Figure 1A It is indicated and named "lysergic acid amide", and is also indicated by Class 2, which is indicated by FIG. 4A to FIG. 5C The 6-substituted 6-demethyl-lysergic acid diethylamide shown in the embodiment, wherein R6 consists of the substituents shown in the subclasses designated as Class 2a to Class 2i, wherein R6 consists of:

[0086] In class 2a (as a subclass of class 2), the substituent R6 consists of: F1-F11 fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl, each optionally in combination with: D1-D10 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0087] In class 2b (as a subclass of class 2), the substituent R6 consists of: F1-F13 fluorine-substituted C3-C7 alkenyl, optionally in combination with: D1-D12 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the alkenyl double bond is separated from the nitrogen,

[0088] In class 2c (as a subclass of class 2), the substituent R6 consists of: C3-C7 alkynyl with F1-F11 fluorine substituted in which the triple bond is separated from the N6 nitrogen, optionally in combination with: D1-D10 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl. Provided that the substituent R6 contains at least one nitrile, one hydroxyl or one carbonyl, R6 can also consist of: C3-C7 alkynyl with the triple bond separated from the N6 nitrogen, optionally in combination with: D1-D10 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0089] In class 2d (as a subclass of class 2), the substituent R6 consists of: C3-C6 cycloalkyl, optionally in combination with: F1-F11 fluorine, and / or D1-D11 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl,

[0090] In class 2e (as a subclass of class 2), the substituent R6 consists of: F1-F17 fluorine-substituted C4-C9 cycloalkylalkyl, optionally in combination with: D1-D16 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl. Provided that the substituent R6 is not a cyclopropylmethyl group linked to the N6 nitrogen of the ergoline structure via an exocyclic methylene unit, or is a cyclopropylmethyl group linked to the N6 nitrogen of the ergoline structure via an exocyclic methylene unit and contains at least one nitrile, one hydroxyl group or one carbonyl group, R6 can also consist of: C4-C9 cycloalkylalkyl, optionally in combination with: D1-D17 deuteron, and / or nitrile, and / or hydroxyl group, and / or carbonyl group, and / or deuterated and undeuterated C1-C3 alkyl group and / or deuterated and undeuterated C1-C3 alkenyl group and / or deuterated and undeuterated C1-C3 alkynyl group,

[0091] In class 2f (as a subclass of class 2), the substituent R6 consists of: F0-F7 fluorine-substituted C2-C4 alkenyl, attached to the nitrogen with an unsaturated moiety to generate an enamine, optionally in combination with: D1-D7 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0092] In class 2g (as a subclass of class 2), the substituent R6 consists of: C3-C6 oxacycloalkyl, C3-C9 oxacycloalkylalkyl, C3-C6 thiacycloalkyl or C3-C9 thiacycloalkylalkyl, each optionally in combination with: F1-F19 fluorine, and / or D1-D19 deuterium, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl,

[0093] In class 2h (as a subclass of class 2), the substituent R6 consists of: F0-F11 fluorine-substituted C1-C5 alkoxy or C3-C6 cycloalkoxy or C2-C6 alkenyloxy, each optionally in combination with: D1-D11 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl,

[0094] In class 2i (as a subclass of class 2), the substituent R6 consists of: aryl, heteroaryl, arylmethyl or heteroarylmethyl, each optionally in combination with: F0-F7 fluorine, and / or D1-D7 deuterium, and / or one or more of the following substituents which may themselves be optionally fluorinated and / or deuterated: halogen, nitrile, nitro, hydroxy, carbonyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, methylenedioxy, C1-C4 alkylthio, C3-C6 alkenylthio, C3-C6 alkynylthio, C3-C6 cycloalkylthio. In addition, the R6 substituents as defined above in class 2i can further form a ring.

[0095] The present invention also provides a composition of compounds for use in substance-assisted therapy, wherein the compound is generally composed of Figure 1A It is indicated and named as "lysergic acid amide", and is also classified by Class 3 ( Fig. 6A ) indicates that from Class 1 and its subclasses 1a to 1n ( Figures 2A to 3H ) and the substituents R8 and R8' of class 2 and its subclasses 2a to 2i ( FIG. 4A to FIG. 5C ) is composed of any possible combination of substituents R6.

[0096] The present invention also provides a compound composition for use in substance-assisted therapy, wherein the compound is generally composed of Figure 1A It is indicated and named "lysergic acid amide", and is also classified by Class 4 ( Figure 6B ) indicates that from Class 1 and its subclasses 1a to 1n ( Figures 2A to 3H ) and the substituents R8 and R8' of Class 2 and its subclasses 2a to 2i ( FIG. 4A to FIG. 5C) and any possible combination of substituents R6 of the following groups on the ergoline substructure and the N1 nitrogen substituents of the following groups: a) any acyl group; b) unsubstituted and substituted carbamoyl groups; c) amide-bound amino acids; d) alkyl, alkenyl or alkynyl groups; e) alkoxy, alkenyloxy or alkynyloxy groups; f) any substituent described under a) to e) substituted with one or more fluorine atoms; g) any substituent described under a) to e) substituted with one or more deuterium atoms; h) any substituent described under a) to e) substituted with one or more fluorine atoms and one or more deuterium atoms.

[0097] The present invention provides a compound composition for use in substance-assisted therapy, wherein the compound is generally composed of Figure 1A It is indicated and named "lysergic acid amide", and is also classified by Class 5 ( Figure 6C ) represents, consisting of monodeuterated to fully deuterated ergoline core structures, and additionally consisting of Class 1 and its subclasses 1a to 1n ( Figures 2A to 3H ) and the substituents R8 and R8' of Class 2 and its subclasses 2a to 2i ( FIG. 4A to FIG. 5C ) and any possible combination of substituents R6 of the following groups on the N1 nitrogen substituent of the ergoline substructure: a) hydrogen; b) any acyl group; c) unsubstituted and substituted carbamoyl groups; d) amide-bonded amino acids; e) alkyl, alkenyl or alkynyl groups; f) alkoxy, alkenyloxy or alkynyloxy groups; g) any substituent described under a) to f) substituted with one or more fluorine atoms; h) any substituent described under a) to f) substituted with one or more deuterium atoms; i) any substituent described under a) to f) substituted with one or more fluorine atoms and one or more deuterium atoms.

[0098] Figure 1AThe compounds represented are basic compounds that form acid addition salts with inorganic or organic acids. Therefore, they form pharmaceutically acceptable inorganic and organic salts with pharmacologically acceptable inorganic or organic acids. The acid forming such salts can be selected from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as carbonic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, benzoic acid, etc. Thus, examples of such pharmaceutically acceptable salts are sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, formates, acetates, propionates, caprates, caprylates, acrylates, isobutyrates, caproates, heptanoates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, benzoates, phthalates, sulfonates, phenylacetates, citrates, lactates, glycolates, tartrates, methanesulfonates, propanesulfonates, mandelates, and the like. Figure 1A The compounds are represented in any hydrated form and in any ratio with pharmacologically acceptable inorganic or organic acids. Preferred pharmaceutically acceptable salts are those formed with tartaric acid and maleic acid.

[0099] Any pharmaceutically acceptable salt may also contain one or more deuterium or fluorine atoms and includes any stereoisomers.

[0100] Figures 1A to 12The general chemical terms used in have their usual meaning. The substituent of generic name can be connected to a molecule on any part of the substituent. For example, the term "alkyl" includes unbranched alkyl and branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. For another example, the term "cycloalkyl" includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, etc. For another example, the term "alkylcycloalkyl" is used as "cycloalkylalkyl" and includes groups such as the alkyl group as described above coupled to the cycloalkyl as described above. Some examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, (2-methylcyclopropyl)methyl, etc. The term "oxacycloalkyl" includes groups such as oxetanes, tetrahydrofuran, etc. In addition, the term "alkenyl" includes unbranched and branched alkenyl, and includes groups such as vinyl (vinyl / ethenyl), 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, etc., with cis, trans, E or Z configuration, and can exist in any combination or purity. In addition, the term "alkenyl" also includes alkylene, such as methine, ethylene, etc. Therefore, the number 1 in "C1-C3 alkenyl" or "C1-C3 alkenyl" can be used to represent methine, for example, when H2C= group is connected to ring. The term "alkyl alkenyl" is composed of any combination and branch of alkenyl and alkyl, with cis, trans, E or Z configuration, and can exist in any combination or purity. Examples of such terms include 1-prop-2-alkenyl, 2-prop-1-alkenyl, 1-but-2-alkenyl, 1-but-3-alkenyl, 1-methyl-1-prop-2-alkenyl, etc. The term "alkynyl" includes unbranched and branched alkynyl, and includes groups such as ethynyl, 1-propynyl-1-yl, 1-propynyl-3-yl, 3-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, phenylethynyl. The term "alkyl alkynyl" is composed of any combination and branch of alkynyl and alkyl. The term "alkylene" defines any unbranched or branched alkyl, as a connection between two molecular entities, substituents or groups, or as an entity that allows a ring to be constructed with a molecular entity, substituent or group. For some examples, methylene, ethylene, propylene or methylpropylene are included, and as a ring, for example, aziridine, azetidine, oxetane are some examples. Phenyl is defined as a substituent that can be without or with any number of substituents on a methylene or phenyl unit, such as deuteron, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, methylthio, hydroxyl, nitrile, methylenedioxy, etc. Such phenyl groups can be further cyclized. Aryl is defined as a substituent containing one or more aromatic (cyclic) homocyclic rings, such as phenyl or naphthyl. Heteroaryl is defined as any aromatic ring system containing a conjugated π electron system and having aromaticity, such as thiophene, furan, pyrrole, selenophene, pyrazole, oxazole, thiazole, isoxazole, isothiazole, benzothiophene, benzofuran, pyridine, pyrimidine, pyrazine, etc. Such heteroaryl groups can be further cyclized.The benzyl substituent defines a phenylmethyl group that may not or may not have any number of substituents on a methylene or phenyl unit, such as deuteron, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxyl, methylthio, hydroxyl, nitrile, methylenedioxy, etc. Such benzyl groups can further be cyclized. Heteroarylmethyl groups are composed of heteroaryls as defined above that are connected to a methylene unit, and may not or may not have any number of substituents on a methylene or phenyl unit, such as deuteron, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxyl, methylthio, hydroxyl, nitrile, methylenedioxy, etc. Such heteroarylmethyl groups can further be cyclized. The term "halogen" includes fluorine, chlorine, bromine and iodine substituents, and the number of halogens can be one to as many numbers as possible chemically, corresponding to fully halogenated substituents, also referred to as the term "polyhalogenation". The term "deuterated" includes the number of deuteron atoms, which can be one to as many numbers as possible chemically, corresponding to fully deuterated substituents, also referred to as the term "polydeuterated". Any ratios and additional stereoisomers resulting from the introduction of fluorine and / or deuterium atoms are included. Terms such as "F0 to F11 fluorinated" or "D0 to D5 deuterated" correspond to non-fluorinated to undefluorinated (eleven fluorine atoms) and non-deuterated to pentadeuterated (five deuterons), respectively. Similarly, this is given by a single term such as "F0–F. 11 fluorine", which means that the substituent may also contain zero fluorine and is therefore non-fluorinated. The term "A m –A n ” – m and n are numbers from 0 to 99 and indicate the number of atoms A – describes the total number of atoms A of a given group or substituent. An example of such a term is C3-C6 cycloalkylalkyl and means that it may include cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylethyl or any other cycloalkylalkyl consisting of three to six carbons. Similarly, for example, “C 1–3 -OC 1–3 " describes an alkoxyalkyl group consisting of an alkyl group with 1 to 3 carbons attached to an oxygen, which is itself attached to an alkyl group with 1 to 3 carbons. Such representative alkoxyalkyl groups are, for example, methoxymethyl, methoxyethyl, ethoxymethyl, and the like. Atom or substituent numbers may be shown in either normal characters or in subscript characters. Thus, for example, "C 1–3 -OC 1–3 The term "lysergic acid derivative" may be used interchangeably with the terms "lysergic acid amide", "lysergic acid amides", or "substituted lysergic acid amides" or "lysergic acid derivatives", and all of these terms are descriptive of the compounds of the present invention.

[0101] Those skilled in the art will appreciate that the compounds of the present invention have at least two chiral carbons and can therefore exist as racemates, individual enantiomers or diastereomers or epimers, and mixtures of individual enantiomers or diastereomers or epimers in any ratio. Those skilled in the art will also appreciate that Figure 1A The compounds of the present invention wherein R1, R6, R8 or R8' consists of chiral substituents will carry additional asymmetric centers, thereby producing additional optical isomers as described above, and such compounds are within the scope of the present invention. Although a preferred embodiment of the present invention is that the compounds of the present invention exist in the form of pure diastereoisomers with an absolute configuration of 5R, 8R within the ergoline core structure, the present invention also contemplates that the compounds of the present invention exist as racemates or mixtures of individual enantiomers or diastereoisomers in pure form.

[0102] Those skilled in the art will also appreciate that certain compounds of the present invention have at least one double bond, which, depending on the substituents on the double bond, produces cis / trans or E / Z configurational isomerism. Although a preferred embodiment of the present invention is to use the compounds of the present invention in pure configurational isomer form, the present invention also contemplates compounds of the present invention that exist in separate cis / trans or E / Z mixtures, respectively.

[0103] Individual enantiomers, diastereomers and epimers can be separated by Figure 1A The racemic or enantiomer or diastereomer or epimer mixture of the compound shown is prepared by achiral or chiral chromatography, or by fractional crystallization of a salt prepared from a racemic or enantiomer or diastereomer or epimer enriched compound of the invention and a chiral or achiral acid. Alternatively, the compound of the invention can be reacted with a chiral or achiral auxiliary and the enantiomer or diastereomer or epimer is separated by chromatography or crystallization, followed by removal of the chiral or achiral auxiliary to regenerate the compound of the invention. In addition, the separation of enantiomers or diastereomers or epimers can be carried out at any convenient point in the synthesis of the compound of the invention. The compound of the invention can also be prepared by applying chiral synthesis. The compound itself is a pharmacologically acceptable acid addition salt thereof.

[0104] Individual cis / trans or E / Z configurational isomers may be obtained by selective synthesis or separation techniques that account for the different physicochemical properties of the configurational isomers through the use of techniques such as chromatography, crystallization, distillation or extraction.

[0105] Lysergic acid derivatives may be used as an alternative treatment for patients who have adverse reactions to other psychedelic drugs. Lysergic acid derivatives may also be useful in some patients because an alternative experience different from phenylethylamine, psilocybin, or LSD is desired, or because the patient is not a priori suitable for treatment with these existing approaches. Figure 1A Lysergic acid derivatives may serve as alternative treatment options, with properties similar enough to other psychedelics to be therapeutic, but different enough to provide additional benefits or avoid the negative effects of other psychedelics.

[0106] Based on the structural relationship, it is expected that the present invention Figure 1A The compound has overall similar pharmacological properties to LSD.

[0107] This hypothesis is further supported by the few known and psychopharmacologically described lysergic acid derivatives, such as the N6-modified compounds ETH-LAD, PRO-LAD, ALL-LAD, the amide-modified compounds DAM-57, LPD-824 or LSM-775, and the N1-derived compounds ALD-52, OML-632 and MLD-41, which have shown psychoactive effects in humans (Abramson, 1959; A. Shulgin and Shulgin, 1991).

[0108] The present invention provides Figure 1A A compound that is pharmacologically active and allows to alter neurotransmission and / or generate neurogenesis. More particularly, but not exclusively, by administering to a mammal in need of such interaction a pharmaceutically effective amount of Figure 1A Compounds that interact with serotonin (5-HT, 5-hydroxytryptamine) 5-HT2A and 5-HT2C receptors in mammals.

[0109] Thus, the present invention provides a method of altering neurotransmission by administering to a mammal a pharmaceutically effective amount of Figure 1A Compounds that increase serotonin 5-HT2A receptor interactions in mammals and induce psychoactive effects.

[0110] The present invention also generally provides a method of treating an individual by administering to the individual a pharmaceutically effective amount of Figure 1A Compounds and treated individuals.

[0111] The conditions or diseases treated may include, but are not limited to, anxiety disorders (including anxiety disorders in advanced illnesses such as cancer, and generalized anxiety disorder), depression (including postpartum depression, major depressive disorder, and refractory depression), headache disorders (including cluster headaches and migraines), obsessive-compulsive disorder (OCD), personality disorders (including conduct disorders), stress disorders (including adjustment disorders and post-traumatic stress disorder), substance disorders (including alcohol dependence or withdrawal, nicotine dependence or withdrawal, opioid dependence or withdrawal, cocaine dependence or withdrawal, methamphetamine dependence or withdrawal), other addictions (including gambling disorder, eating disorders, and body dysmorphic disorder), pain, neurodegenerative disorders (such as dementia, Alzheimer's Disease, Parkinson's Disease), autism spectrum disorders, eating disorders, or neurological disorders (such as stroke).

[0112] Figure 1A The neuronal interactions of the compounds represented in can be used for substance-assisted psychotherapy in mammals, wherein the compounds induce psychoactive effects to enhance psychotherapy. The preferred mammal is a human.

[0113] The intensity and quality of psychoactive effects, including psychedelic or synaesthesia (also called restorative or MDMA-like) effects (Holze et al., 2020), the quality of perceptual alterations such as imagery, hallucinations, and visual effects with eyes closed or open, and changes in physical sensations, the pharmacologically active dose, and the duration of action may be different or similar to those of LSD.

[0114] LSD and some of its modified derivatives are known to interact with serotonin 5-HT2A, 5-HT2C, 5-HT1A, and dopamine receptors (Nichols, Frescas, Marona-Lewicka, & Kurrasch-Orbaugh, 2002; Rickli et al., 2016; Watts et al., 1995).

[0115] LSD and some of its modified derivatives are also known to replace LSD in two-rod drug discrimination assays (Nichols et al., 2002).

[0116] Among the known psychoactive lysergic acid derivatives, three structural regions of the original LSD molecule have been studied primarily.

[0117] One structural feature investigated early on was the substitution of N1 in the LSD molecule, resulting in N-acyl (e.g., N-acetyl, N-propionyl, N-butyryl), N-alkyl (e.g., N-methyl), or N-methoxy substituted LSD derivatives (Abramson, 1959; Halberstadt et al., 2020).

[0118] Some of these substituents are susceptible to rapid metabolism and the compounds were found to behave as prodrugs and only after N1 deprotection did the compounds become active at the target receptor and psychoactive.

[0119] The second structural feature of the original LSD molecule that was modified early to obtain the psychoactive compound was the N6-substituent. Thus, the N6-methyl group was replaced by an alkyl, allyl, propargyl, phenethyl, branched alkyl, alkylcycloalkyl group (Hoffman and Nichols, 1985; Huang, Marona-Lewicka, Pfaff, and Nichols, 1994; Nichols, 2018a; Nichols et al., 2002; Nichols, Monte, Huang, and Marona-Lewicka, 1996; Oberlender, Pfaff, Johnson, Huang, and Nichols, 1992; Pfaff, Huang, Marona-Lewicka, Oberlender, and Nichols, 1994; A. Shulgin and Shulgin, 1991) and WO2021019023A1, WO2021175816A1. Some compounds have been studied in humans and are only mentioned to have psychoactive properties, and at least in anecdotal reports, only three such compounds have been described as having psychedelic properties (A. Shulgin and Shulgin, 1991).

[0120] A third structural feature of the original LSD molecule that could be modified (or only mentioned in theory) to obtain potentially psychoactive compounds is the substituents attached to the amide group on the C8 atom of LSD. Thus, N-monoalkyl, branched N-monoalkyl, symmetrical and asymmetrical N,N-dialkyl, N-alkyl-N-alkenyl, N,N-dienyl, N,N-dialkynyl, N-ethyl-N-(2,2,2-trifluoroethyl), N-ethyl-N-(2-methoxyethyl), N-cycloalkyl, N-alkyl-N-cycloalkyl, N-alkyl-N-cycloalkyl or N-oxacycloalkyl derivatives have been described or mentioned as theoretical ideas. (Brandt et al., 2020; Huang et al., 1994; Nichols, 2018a; Nichols et al., 2002; Nichols et al., 1996; Oberlender et al., 1992; Pfaff et al., 1994; Watts et al., 1995) and WO2021019023A1, WO2021175816A1.

[0121] However, some of these compounds have only been described theoretically and have never been chemically prepared and studied biologically or even psychopharmacologically. Therefore, it remains unclear to what extent these compounds display psychoactive properties in general or, more specifically, psychedelic properties.

[0122] When it comes to the combination of modifications of the original LSD molecular structure mentioned above, namely N1, N6 and an amide functional group attached to C8, there are almost no known compounds, one of the few exceptions being the N1-propionyl form of ETH-LAD (Brandt et al., 2017). Other compounds have only been described in theory, for example in WO2021019023A1, WO2021175816A1, but their preparation and chemical characterization have never been described.

[0123] One of the main reasons is the relentless search for N,N-diethylamide substituted derivatives of lysergic acid, driven by the discovery that whenever a single ethyl group in the original LSD molecule undergoes a structural change, such as to a methyl, propyl, or isopropyl group, the subsequent compound loses significant potency at its psychoactive dose. Only minimal structural modifications of the N,N-diethylamide moiety are permitted to retain at least some of the psychoactive properties, and the nature of the retained psychoactive properties remains elusive and has not yet been described in detail.

[0124] Another reason for the extremely limited number of chemical preparations and biological studies of lysergic acid derivatives containing a combination of an amide other than N,N-diethylamide and an N6-substituent other than N-methyl is the difficulty in obtaining these compounds. From the existing, previously described structure-activity relationships, when N,N-diethylamide is not used as the amide substituent, there seems to be little interest in conducting synthetic efforts to obtain more examples of compounds with this extremely rare combination of pharmacophores.

[0125] One reason why the N6 substituents in the above compounds consist predominantly of methyl groups is the use of lysergic acid as a starting material; this acid is found in nature chemically bound to the ergot fungus primarily in the form of chemical substructures from which the compound ergotamine can be isolated. The hydrolysis of ergotamine and subsequent purification delivers pure lysergic acid, a compound that would otherwise require considerable effort to obtain chemically.

[0126] Another reason for the widespread retention of the "original" 6-methyl substituent may be the synthetic conditions used in the past to remove the methyl group. In this way, the classic Von-Braun reaction uses cyanogen bromide in boiling tetrachloromethane, both of which are extremely problematic to handle.

[0127] In general, almost all lysergic acid derivatives with known psychoactive properties contain an N,N-diethylamide pharmacophore in which the N6-substituent is changed, or the N6-substituent remains as N6-methyl and the amide moiety is changed.

[0128] The nature of the psychoactive properties of the psychoactive lysergic acid derivatives known to date are generally not described in detail, and it remains unclear whether they act as stimulants, desensitizers or hallucinogens (Holze et al., 2020) or a combination thereof.

[0129] As far as the psychedelic properties of lysergic acid derivatives are known to date, the psychopharmacological properties (e.g., subjective effect profiles compared to other substances) have only been described in detail and clinically for LSD (Holze et al., 2022; Holze, Vizeli et al., 2021; Holze et al., 2020). Therefore, it remains unclear whether any previously described lysergic acid derivatives are suitable for the scope of the invention referred to herein.

[0130] Figure 1A Some of the lysergic acid compounds of the present invention are shown to exhibit in vitro pharmacological activity at a relevant target (5-HT2A receptor; Liechti et al. on file) compared to LSD and are shown to possess psychedelic effects.

[0131] The introduction of a fluorine in one of the N-ethylamide substituents is expected to retain the psychedelic properties of the LSD molecule (for example in the compound TRALA-04).

[0132] The introduction of a fluorine in the N6 substituent of ET-LAD retains the psychedelic properties of the LSD molecule (such as the compound TRALA-15).

[0133] In conclusion, it is likely that the combination of these structural features will also give rise to lysergic acid derivatives with psychedelic properties.

[0134] The few lysergic acid derivatives known to date with psychedelic activity all show similar durations of action with only minor differences, mainly in the 8 to 12 hour range. The duration of action is primarily determined by the elimination half-life (Holze et al., 2019; Holze et al., 2022; Holze, Vizeli, et al., 2021), but receptor occupancy and kinetics may also play a role (Wacker et al., 2017).

[0135] The metabolism of the original LSD molecule in human biological fluids has been studied (Canezin et al., 2001). The main metabolic attack was identified to occur at a) the diethylamide moiety to N-monodeethylation or monohydroxylation of one of the ethyl groups, b) N6-demethylation to form 6-Nor-LSD, and c) oxidation / hydroxylation of the indole moiety. Only recently, Vizeli et al. demonstrated that CYP2D6 has a genetic influence on the pharmacokinetics and acute subjective effects of LSD in healthy subjects (Vizeli et al., 2021). The main metabolite of LSD in humans is 2-oxo-3-hydroxy-LSD (Luethi, Hoener, Krahenbuhl, Liechti, & Duthaler, 2019), so the main metabolic attack occurs at the indole part of LSD.

[0136] Since the duration of the psychedelic effects of the original LSD molecule is quite long, and in some cases even disadvantageously long, the inventors have chosen an "anti-stabilization approach" as an option rather than a limitation, which is contrary to the usual approach to optimizing pharmacologically active molecules. In classical medicinal chemistry, one goal is to maintain or increase biological activity while / thereby also increasing metabolic stability. For some compounds of the present invention (e.g. Figure 1A Utilizing this metabolic enhancement strategy, destabilization and restabilization of substituents by adding specific atoms or groups allows for fine-tuning of metabolism while retaining the psychedelic properties of the original LSD molecule.

[0137] Since it is also within the scope of the present invention to obtain psychedelic lysergic acid derivatives having a shorter duration of action than the original LSD molecule, Figure 1A The structure represented identified two regions for modification, but was not limited thereto.

[0138] If psychedelic properties are the key property, then substitution at the N1 position of the original LSD molecule would require the attachment of a metabolically susceptible group to this position, thereby releasing the parent compound upon metabolism, since, based on existing SAR, it seems that almost no substitutions are tolerated at this position to obtain agonist serotonin 5-HT2A receptor ligands (Halberstadt et al., 2020), which is the main site for lysergic acid derivatives to produce psychedelic properties. Therefore, LSD or similar compounds substituted at N1 mostly act only as prodrugs and release the parent compound. As a result, the duration of action either remains unchanged or is prolonged rather than shortened. One of the few exceptions where N1 substituents can result in unchanged metabolism of the active compound is N1-substituted 1-methyl-LSD (Abramson, 1959), but this remains unclear at this point and this compound showed significantly lower potency in humans. Nevertheless, N1 substituents are still within the scope of the present invention as they can modify the physicochemical and potentially absorption, distribution, metabolism, and elimination (ADME) properties by jointly affecting the physicochemical and potentially absorption, distribution, metabolism, and elimination (ADME) properties. Figure 1A Duration and nature of action of the lysergic acid derivatives indicated.

[0139] The aforementioned “anti-stability method” is applied to Figure 1A on the N6 nitrogen of some lysergic acid derivatives represented. Metabolism can lead to, but is not limited to, polar conjugation and / or decomposition, up to a fully unsubstituted N6 nitrogen lysergic acid derivative structure (i.e., secondary amine). It is known that N6-demethylation of LSD (i.e., 6-Nor-LSD) leads to altered pharmacological properties in vivo (Fehr, Stadler, & Hofmann, 1970) and CH535236A and its loss of 5-HT2A binding affinity (factor 30) and ability to displace in LSD-trained rats, even at 20-fold the fully active dose of LSD (Hoffmann, 1987). However, in a recent binding assay, Nor-LSD retained highly efficient binding to the 5-HT2A receptor but not the 5-HT2C receptor (Luethi et al., 2019), suggesting that this molecule and the currently described analogs and prodrugs may have relevant psychoactive properties. Therefore, further studies of the currently designed and synthesized compounds are needed to elucidate their psychoactive properties. Figure 1A The formation of other metabolites besides N6-deprotection in the represented compounds can also lead to inactivation of the parent compound and thus affect the duration of action.

[0140] In addition, the above-mentioned “anti-stability method” is applied to Figure 1AThus, the amide substituents within the scope of the present invention may undergo or may result in different or faster metabolism than the diethylamide of the original LSD molecule, thereby resulting in inactivation of the psychoactive properties of the parent compound, thereby affecting the duration of action.

[0141] Different metabolism caused by N1, N6 or amide substituents different from the original LSD molecule may also occur Figure 1A Any portion of the chemical structure of the compounds of the present invention is represented, and is not limited to the substituents themselves being varied.

[0142] The "anti-stabilization method" in no way limits the scope of the present invention. Figure 1A The compounds represented do not necessarily require a different, faster, slower, or similar metabolism to the original LSD molecule, as other mechanisms on the compounds of the present invention may also result in different or similar duration of action, intensity and quality of psychoactive effects (including psychedelic or synaesthesia effects), quality of perceptual changes such as imagery, hallucinations, and closed-eye or open-eye visual effects, and changes in physical sensations and / or pharmacologically active doses.

[0143] The above modifications may occur at N6 or at the amide moiety, or any combination thereof.

[0144] Not only receptor interactions, receptor profiles, subsequent signal transduction cascades, receptor heterodimerization, overall psychological and psychedelic effects can be altered by structural modifications as represented in Figure 1, but metabolism can also be significantly altered by, for example, but not limited to, the formation of potentially rather unstable N-alkoxy compounds, enaminoether compounds, enaminoether (N-alkoxymethyl derivatives of amides) compounds, vinyl or ethynyl compounds (i.e., enamides, alkyneamides, enamines, alkyneamines) at N1, N6 or amide nitrogen, all of which are more or less prone to metabolism by the introduction of zero or one or several alkyl, fluorine or deuterium atoms, either independently or in any combination, at the vinyl, allyl or gamma position or at the ethynyl or propargyl position of these functional groups, as described above. In addition, nitrile groups can also be introduced at any of these positions of the above-mentioned substituents, and alkyl nitriles or alkenyl nitriles or alkynyl nitriles (each without or with any fluorine and / or deuterium substituents) are also an option. Additionally, independently fluorinated, deuterated or nitrile substituted N-allyl or N-propargyl groups are also within the scope of the invention. Thus, the present invention also allows for the synthesis of psychedelic compounds having a relatively shorter duration of action compared to more metabolically stable and longer acting compounds.

[0145] Any of the above substituents attached to N1, N6 or amide may also be combined with substituents attached to amide or N6 or N1, wherein the substituents are composed of alkyl, alkenyl or alkynyl, cycloalkyl, alkylcycloalkyl, benzyl, heteroarylmethyl, each substituent containing zero, one or more fluorine, deuterium atoms or nitrile groups.

[0146] In another embodiment, any of the above structural modifications can be combined with one or more fluorine and / or deuterium atoms in any combination on the entire lysergic acid core, i.e., the ergoline core structure. It is worth mentioning, but not limiting in any way, that a deuterium nucleus is introduced at C8 of the ergoline structure to make Figure 1A The lysergic acid derivatives represented are stable against epimerization. Epimerization can occur in a chemical / biological environment and is driven by factors such as pH and possibly by enzyme activity. Only the 5R,8R diastereomer of LSD is known to be psychoactive, and its 5R,8S diastereomer (also known as iso-LSD) is inactive at up to a few milligrams. The remaining two diastereomers (5S,8R and 5S,8S configurations) are also psychoactive.

[0147] The chemical stability of the above functional groups, such as enamides, alkynamides, alkoxyamides (also known as Weinreb amides), geminal N-amide ethers, enamines, alkynamines, alkoxyamines or geminal aminoethers under acidic, alkaline or any other chemical conditions depends on factors such as pH, solvent medium, temperature, surface, nucleophilicity or electrophilicity of the reaction partner or on the gas accommodation of the environment. Metabolic stability in biological environments such as the human body is additionally driven by factors such as absorption rate, enzyme exposure, enzyme activity, genetic polymorphisms, residence time in body media such as the gastrointestinal tract, body distribution rate or transit time. All of these aspects can be affected by changes introduced into the compound and produce the desired effect and duration of effect in the human body.

[0148] The stability of a functional group, a substituent, or a molecule in general, to the above factors can be significantly influenced and altered by the specific incorporation of stabilizing or destabilizing atoms or groups of atoms. In addition, the overall metabolic stability of a compound is also driven by overall lipophilicity, three-dimensional structure, dissociation constant, solubility, steric accessibility and steric bulk, among other characteristics.

[0149] Fluorine is a strong electron withdrawing atom and its incorporation into substituents can significantly reduce the electron richness. In addition, it changes the dipole moment, dissociation constants of acidic and basic groups, lipophilicity, pH, and to some extent also affects the steric properties of fluorinated molecules. Therefore, fluorine can change the physicochemical properties and incorporation into molecules can have a huge impact on the interaction with biological targets, chemical / metabolic stability and metabolic pathways. Fluorine atoms incorporated into molecules further allow so-called multipolar interactions with partially charged functional groups. This makes fluorine an excellent tool for medicinal chemistry.

[0150] Deuterium is a stable isotope of hydrogen. Since its metric is slightly different, its incorporation into molecules can affect the physicochemical properties. Thus, the kinetic isotope effect, the inverse kinetic isotope effect, and the steric isotope effect can be observed. Compared with protium (hydrogen), deuterium has stronger chemical bonds and different lengths, which makes such compounds have significant differences in biological reactions. Therefore, incorporating deuterium into molecules can greatly affect their biological stability.

[0151] Therefore, both fluorine and deuterium can be used to replace or add to the substituent to change the invented and Figure 1A He Ru FIG. 2A to FIG. 6C The overall stability and biological properties of the compounds represented by classes 1 to 5 are shown. The substitution may be by one or more fluorine atoms or one or more deuterium atoms or any combination of fluorine and deuterium atoms.

[0152] Analogous to these medicinal chemistry concepts, the biological properties of the compounds of the invention (ADME, target selectivity and target interaction, mode of action, duration of action, psychodynamic processes and qualitative perceptions, e.g. in terms of psychedelic or synaesthesia intensity compared to the original LSD molecule) can be influenced not only by the application of the above-mentioned fluorine or deuteron nuclei to functional groups such as enamides, alkynamides, alkoxyamides, geminal N-amide ethers, enamines, alkynamines, alkoxyamines or geminal aminoethers, but also by their introduction into the ergoline core structure ( Figure 1A ) is affected by simpler substituents of the C8 amide functional group, such as alkyl, alkenyl or alkynyl, cycloalkyl, oxacycloalkyl, alkylcycloalkyl, alkyloxacycloalkyl, benzyl or heteroarylmethyl substituents. Other atoms or groups of atoms, such as Figure 2A-6C Overview.

[0153] From earlier structure-activity relationships (Brandt et al., 2020; Huang et al., 1994; Nichols, 2018a; Nichols et al., 2002; Nichols et al., 1996; Oberlender et al., 1992; Pfaff et al., 1994; Watts et al., 1995), it is known that the amide functionality of lysergic acid amide cannot tolerate groups larger than the N,N-diethyl substituent without losing biological activity, such as receptor affinity for receptors associated with human psychoactive effects (e.g., the 5-HT2A receptor). Exceeding its size or using smaller groups (e.g., methyl) results in a fairly significant loss of 5-HT2A receptor binding properties as well as human potency. When modifying the N6-substituent, examples found in the literature (Hoffman and Nichols, 1985; Huang et al., 1994; Nichols, 2018a; Nichols et al., 2002; Nichols et al., 1996; Oberlender et al., 1992; Pfaff et al., 1994; A. Shulgin and Shulgin, 1991) show that enlarging the N6-methyl group to a certain extent is tolerated in order to retain in vivo potency, as shown, for example, in drug discrimination studies or anecdotal reports based on human administration. However, the inventors do not intend only to obtain compounds with in vitro or in vivo potency similar to or higher than that of the prototype LSD itself. In fact, a favorable overall profile may become more relevant and a lower potency will by no means limit the use of such compounds.

[0154] LSD is usually used by oral administration. Buccal or nasal absorption and intravenous or intramuscular application have also been used. Figure 1A The compounds represented can be used orally (i.e., absorbed in the gastrointestinal tract), but for certain compounds within the scope of the invention, the preferred route of administration may be buccal, nasal, enteral, intravenous or intramuscular application. These routes of administration may accelerate the onset of the drug effect in addition to changing the duration of action of the compound itself. It is expected that some compounds may also have significant differences between oral administration and parenteral administration. For example, after oral administration of a compound, it may be broken down or converted to LSD by gastric or intestinal fluids or enzymes, while it may be metabolized in a different manner when used parenterally. Therefore, any changes in structure will have different effects on oral versus parenteral administration.

[0155] Although Figure 1AAll lysergic acid derivatives represented in the are useful for optimizing the overall biological and clinical effect profile of psychedelics, but certain classes of compounds are preferred, such as where the compound is a free base, salt, hydrochloride, racemate (if applicable), single enantiomer, single diastereomer, single epimer, or a mixture of enantiomers or diastereomers or epimers in any ratio, or individual cis / trans or E / Z configurational isomers, or a mixture of these configurational isomers in any ratio. It should be understood that these classes can be combined to form additional preferred classes.

[0156] The synthetic route of the compounds of the present invention is as follows Figures 9 to 12 As shown in the figure, and given in detail in the "Preparation of compounds" section.

[0157] The groups presented in the preparation section (i.e. compounds 2a to 2m, 12a to 12g, 13, 14a to 14c and 16a to 16c (e.g. Figures 7A to 8N The present invention is considered within the scope of Figure 1A Description of the lysergic acid derivatives represented in.

[0158] Figures 9 and 10 A general route to some lysergic acid derivatives of class 1 is outlined. The lysergic acid derivatives are prepared using an amide coupling agent such as CDI, TBTU, TCFH, TFFH, T3P, COMU or any other suitable coupling agent ( Fig. 9 )) Commercially available and synthetic lysergic acid (1) or lysergic acid monohydrate is activated in a suitable solvent such as DMF, dimethylacetamide, DCM or THF, EtOAc, dioxane, acetonitrile or mixtures thereof. Alternatively, activation may be performed using reagents such as POCl3 or trifluoroacetic anhydride. Next, the activated intermediate is reacted with a primary or secondary amine. The amine may be used as a free base or a salt. In the case of a free base, the amine may be used in excess or in an equivalent amount compared to the activated lysergic acid together with a non-nucleophilic base such as triethylamine (NEt3), N-methylmorpholine (NMM) or N,N-diisopropylethylamine (DIPEA). When the amine to be coupled is applied in salt form (e.g., as its hydrochloride), it may be used in an equivalent or excess amount compared to the activated lysergic acid, and the amine may be released from its salt using a non-nucleophilic base as previously outlined. The reaction temperature may range from 0-120°C, more advantageously from 20-100°C. After a reaction time sufficient to allow the amide to form, the corresponding amide formed is then isolated from the reaction mixture by extractive methods, chromatographic methods or by crystallization of the compound itself or its salt, or by a combination of these methods.

[0159] Compounds of class 1 containing an enamide group (e.g., subclass 1f) Figures 2A to 3H ) can be obtained through different channels ( Fig. 9 In one embodiment, the corresponding primary or secondary 2-(benzenethiol)ethylamine is coupled with an activated lysergic acid derivative suitable for amide coupling. The 2-phenylthioethylamine may contain further substituents at any part of the molecule. The corresponding amide containing the 2-(benzenethiol)ethyl group is then oxidized to the corresponding sulfoxide, which is then reacted in a thermolysis to give the corresponding enamide (Taniguchi et al., 2005). The sulfoxide group is chiral and may have the R or S configuration, or be a mixture of any stereoisomers. The thermolysis is catalyzed by a suitable base such as NaHCO3, KHCO3, Na2CO3 or K2CO3 and carried out in a suitable solvent such as toluene or a dimethylated or trimethylated benzene such as o-xylene, m-xylene or p-xylene, but any other solvent that is chemically inert to the reaction being carried out may be used, most advantageously xylene. The temperature employed is 40-200°C, and more advantageously 100-150°C.

[0160] Sulfoxides can also be obtained as follows. Phenyl vinyl sulfoxide or substituted analogs are treated with primary amine R-NH2 in a suitable organic solvent (e.g., THF, dioxane, ethyl acetate or dichloromethane) to form the corresponding N-(2-phenylsulfinylethyl)-R-amine (Hu, Chan, He, Ho, and Wong, 2014). The obtained amine is then coupled with lysergic acid or lysergic acid hydrate as described above to obtain an amide suitable for thermal decomposition to form an enamide. As described above, the sulfoxide group is chiral and can have an R or S configuration, or be a mixture of any stereoisomers.

[0161] In another embodiment to obtain enamides (e.g., subclass 1f), an aldehyde can be coupled with a primary aldehyde to form an imine, which is then coupled with an activated lysergic acid derivative suitable for amide coupling and subsequent elimination (Golding and Wong, 1981; He, Zhao, Wang, and Wang, 2014; Kulyashova and M., 2016; Meuzelaar, van Vliet, Neeleman, Maat, and Sheldon, 1997). The coupled intermediate is then forced to eliminate to the corresponding enamide.

[0162] Another embodiment to obtain such enamides (eg, subclass 1f) is the formation of the oxazoline, followed by lithiation and alkylation, leading to ring opening and enamide formation (Xu, Xiao-Yu, Wang, & Tang, 2017).

[0163] Additionally, enamides (e.g., subclass 1f) can be accessed by direct elimination, for example using lithium bis(trimethylsilyl)amide (LiHMDS) (Spiess, Berger, Kaiser, & Maulide, 2021).

[0164] For example, Category 1 ( Figure 2G ) (e.g., subclass 1f) can also be accessed by applying an elimination procedure using a strong base (e.g., butyllithium (BuLi), lithium diisopropylamide (LDA), or LiHDMS) attached to the 2,2,2-trifluoroethyl or 2-bromo-2,2-difluoroethyl substituents attached to the amide group of the corresponding lysergic amide compounds (Meiresonne, Verniest, De Kimpe, & Mangelinckx, 2015; Riss & Aigbirhio, 2011).

[0165] Category 1( Figure 3A The formation of alkynamides (e.g., subclass 1g) as outlined in ) can be performed by, but not limited to, an elimination procedure using a strong base (e.g., LiHDMS) attached to a 2,2,2-trifluoroethyl or 2-bromo-2,2-difluoroethyl substituent attached to the amide group of the corresponding lysergic amide compound (Meiresonne et al., 2015).

[0166] Class 2 compounds ( FIG. 4A to FIG. 5C ) can be obtained by using the corresponding 6-Nor-LSD or any other 6-Nor compound as the starting material. 6-Nor-LSD ( Fig.11 The preparation of LSD is well documented, using the classic von Braun reaction, in which cyanogen bromide in boiling tetrachloromethane is used, both of which are extremely problematic to handle, and the aminonitrile formed is then reduced with elemental zinc in acetic acid (Fehr et al., 1970). Another approach is used here, as described in WO2006128658A1, in which the pyrrolidine analog of LSD is prepared. Similarly, LSD is treated with an oxidant such as meta-chloroperbenzoic acid (mCPBA) in dichloromethane under cooling, and the N-oxide formed is then reduced by adding FeSO4. This is quite safe, easy to handle and reacts very quickly. In addition, the yield is comparable to or even better than the von Braun reaction. Other oxidants, such as H2O2 or cumene hydroperoxide in an organic solvent such as an alcohol, ethyl acetate or dichloromethane, may also be used. After the separation step, which can be carried out by extraction, chromatography or crystallization of the compound itself or its salt or a combination of these methods, the obtained 6-Nor-LSD or any other 6-Nor compound (e.g. 6-Nor-TRALA-02) (e.g. Fig.12) is used in the reaction to obtain the compound represented by class 2 ( FIG. 4A to FIG. 5C ). The LSD or any other recovered lysergic acid derivative recovered from the above-described N-demethylation reaction can be reused in the N-demethylation reaction outlined above to further increase the amount of the desired 6-Nor-LSD or other 6-Nor compound. This cyclic process can be repeated as many times as the technology and / or the amount of the desired compound permit.

[0167] like FIG. 4A to FIG. 5C As indicated, some compounds represented by Class 2 can be obtained by reacting 6-Nor-LSD or another 6-Nor compound with a correspondingly substituted R6 containing a leaving group substituted by the basic N6 nitrogen of 6-Nor-LSD or another 6-Nor compound. The leaving group can be, for example, a halogen, a mesylate, a tosylate or a triflate. In addition, reductive amination can be applied using a suitable carbonyl compound and a reducing compound (e.g., NaBH4 or Na(OAc)3BH or NaBH3CN, also hydrogen) in the presence or absence of a catalyst in a suitable solvent.

[0168] For some R6 substituents to be introduced with strong electron withdrawing substituents, 6-Nor-LSD or the secondary N6 of other lysergic acid derivatives with NH at the 6-position, the nucleophilic character of the secondary amine may not be high enough to be used as a nucleophilic reagent. In this case, either the lysergic acid derivative must be fully protected to selectively deprotonate N6, or the electrophilic reagent must be activated. In this way, the use of transition metals or transition metal oxides or salts (such as silver salts) to accelerate the N-alkylation can be helpful. Advantageously, AgNO3 or AgOTf (AgCF3SO3) is added to the reaction mixture of the corresponding secondary N6 amine and the alkylating agent in an organic solvent (such as tetrahydrofuran (THF), dioxane, alcohols such as methanol (MeOH), ethanol (EtOH), isopropanol (iPrOH) or dichloromethane (DCM)). The mixture can be maintained at 0-100°C, more advantageously at 20-100°C.

[0169] It is well known that in some cases, 2,2,2-trifluoroethyl substituents cannot be simply introduced into amines by applying one of the above conditions due to extremely deactivating reactivity (i.e., due to the electron-withdrawing properties of fluorine), and even the compound 2,2,2-trifluoroethyl triflate, which is much more reactive than 2,2,2-trifluoroethyl iodide, exhibits extremely low reactivity in nucleophilic substitution with certain amines. Such substituents can be introduced onto amines by using synthetic equivalents, i.e., for example, 2,2,2-trifluoroacetaldehyde ethyl hemiacetal (alias: 1-ethoxy-2,2,2-trifluoroethanol) (Mimura, Kawada, Yamshita, Sakamato, and Kikugawa, 2010). The intermediate formed is then reduced with a suitable reducing agent (e.g., NaBH4 or Na(OAc)3BH or NaBH3CN).

[0170] like Figure 4G The enamine compounds represented by the second class (subclass 2f) represented in the above can be obtained by reacting the corresponding carbonyl compound with 6-Nor-LSD to form an imine, by removing or absorbing water, and applying an additional non-nucleophilic base if necessary. Alternatively, such enamines can also be obtained by direct halogen substitution reaction of fluorinated 1-halo-1-olefins with 6-Nor-LSD or another 6-Nor compound (WO2006046417A1).

[0171] In addition, if Figure 4G Enamine compounds represented by the represented class 2 (subclass 2f) can be obtained, for example, by reacting N6-substituted N6-2,2,2-trifluoroethyl-6-Nor-LSD with a strong base such as LDA or BuLi (Riss and Aigbirhio, 2011).

[0172] like Figure 5B The alkoxyamine compounds (also called N-hydroxy ethers) represented by the second class (subclass 2h) represented in the above can be obtained by reacting 6-Nor-LSD with an oxidant (e.g., H2O2 or mCPBA) in an organic solvent to form the corresponding 6-Nor-LSD-N6-hydroxylamine, followed by deprotonation of the N6-hydroxylamine with a base (e.g., LDA, KOtBU, BuLi or LiHDMS), and then reacting the deprotonated intermediate with a corresponding substituted R6 containing a leaving group to be replaced by the deprotonated oxygen of 6-Nor-LSD-N6-hydroxylamine. The leaving group can be, for example, a halogen, a mesylate, a tosylate or a triflate or other suitable leaving group.

[0173] like Figure 5CThe aryl or heteroaryl amines represented by class 2 (subclass 2i) can be obtained by reacting 6-Nor-LSD or another 6-Nor compound with the corresponding aryl or heteroaryl halide, triflate, as generally described, for example, by Buchwald-Hartwig amination.

[0174] like Figure 5C The benzylamines and (heteroarylmethyl)amines represented by class 2 (subclass 2i) represented in the above can be obtained by reacting 6-Nor-LSD or another 6-Nor compound with the corresponding aryl or (heteroarylmethyl) halide in a classical substitution reaction, or with the corresponding aldehyde in a reductive amination manner, wherein the reducing conditions applied are, for example, NaBH4 or Na(OAc)3BH or NaBH3CN, but also hydrogen, in the presence or absence of a catalyst in a suitable solvent.

[0175] The N6 substituent can also consist of cycloalkanes or oxacycloalkanes ( Figure 4E and Figure 5A These substituents can be introduced by reductive amination with 6-Nor-LSD or another 6-Nor compound and the corresponding oxo-cycloalkane or oxo-oxacycloalkane and a reducing compound (e.g. NaBH4 or Na(OAc)3BH or NaBH3CN) or also hydrogen in a suitable solvent in the presence or absence of a catalyst.

[0176] in addition, Figure 4E and Figure 5A These cycloalkane substituents represented by subclasses 2d and 2g in can also be introduced by substitution reactions, i.e., reacting 6-Nor-LSD or another 6-Nor compound with a correspondingly substituted R6 cycloalkane or oxacycloalkane containing a leaving group to be replaced by the basic N6 nitrogen of 6-Nor-LSD. The leaving group can be, for example, a halogen, a mesylate, a tosylate or a triflate.

[0177] get Figure 4E and Figure 5A Another way to produce compounds represented by subclasses 2d and 2g is by using 6-Nor-LSD or another 6-Nor compound and reacting it with a cycloalkane or oxacycloalkane containing geminal substituted alkoxy-(trialkylsilyloxy) in a suitable solvent in the presence or absence of a catalyst under acidic conditions, for example using acetic acid and using a reducing compound (e.g. NaBH4 or Na(OAc)3BH or NaBH3CN, which can also be hydrogen).

[0178] By combining any of the above synthetic routes, the third class of compounds ( Fig. 6A In addition to this, a suitable protecting group may first be introduced in N1, N6 or on the C8 carboxyl function of the ergoline structure attached to LSD, 6-Nor-LSD or any other Nor-derivative (e.g. N6-Nor-ergotamine, N6-deprotected intermediates, N6-deprotected lysergic acid, N6-deprotected lysergic acid esters or appropriately transformed compounds).

[0179] The fourth class of compounds ( Figure 6B ),vice versa.

[0180] The fifth class of compounds ( Figure 6C ), wherein there is at least one deuteron atom in the ergoline core structure, and vice versa.

[0181] Selected synthetic lysergic acid derivatives are being investigated for key targets of in vitro psychoactive effects (Liechti et al., on file). The primary target of psychedelic drugs is the 5-HT2A receptor (Holze, Vizeli, et al., 2021), and they generally bind to this receptor with high affinity (Rickli et al., 2016). Additionally, 5-HT2A receptor binding potency generally predicts the dose of psychoactive psychedelic drugs for many compounds in humans (Luethi and Liechti, 2018). Furthermore, psilocybin's psychedelic effects in humans have been shown to correlate with 5-HT2A receptor occupancy measured using positron emission tomography (Madsen et al., 2019). Therefore, an interaction with this target is relevant and has a high probability of predicting the psychedelic effects of most psychedelic drugs. However, this is not true for all substances in this class.

[0182] Other receptors, such as serotonergic 5-HT1A and 5-HT2C or dopaminergic D2 receptors, are thought to moderate the effects of psychedelics (Rickli et al., 2016). Although some psychedelics (such as psilocybin) do not act directly on dopaminergic receptors, they still have some dopaminergic properties, namely releasing dopamine in the striatum (Vollenweider, Vontobel, Hell, & Leenders, 1999), possibly through 5-HT1A receptor activation (Ichikawa & Meltzer, 2000). In addition, LSD is active at D2 receptors (Rickli et al., 2016), and some of its behavioral effects in animals may be related to this target (Marona-Lewicka, Thisted, & Nichols, 2005), but its acute psychoactive effects in humans are mainly (if not entirely) mediated through 5-HT2 receptors (Holze, Vizeli et al., 2021; Preller et al., 2017).

[0183] The activity of compounds on monoamine transporters is thought to mediate MDMA-like synaesthesia (Hysek et al., 2012). Importantly, LSD is a high affinity 5-HT2A receptor ligand and only requires very low doses to induce psychoactive effects in humans. Even doses of 0.1 mg or less can produce very strong psychedelic effects in humans, and the substances developed in this invention may also be the case, but some lysergic acid compounds may also have higher or lower potency, which needs to be evaluated in detail in the clinic. The key results of the preliminary pharmacological analysis of the compounds described herein are as follows:

[0184] Figure 1A Some lysergic acid derivatives indicated in ongoing studies have shown higher binding affinity for the serotonin 5-HT2A receptor, suggesting psychedelic activity.

[0185] right Figure 1A Some of the lysergic acid derivatives presented in have been subjected to microsomal studies and revealed different metabolic stabilities compared to LSD, such as Figures 13A-13JSpecifically, in a 4-hour microsomal incubation, derivatives 21 (TRALA-12), 12c (TRALA-17), 16a (TRALA-26), and 16b (TRALA-27) were metabolized significantly faster than LSD. Substance 21 showed by far the fastest metabolism, with most of the substance being metabolized after only 30 minutes. Given its rapid metabolism, it may not be active when taken orally, but it could be a candidate for intravenous administration (particularly as an infusion), where a transient or sustained effect would be expected to ensue and terminate rapidly after cessation of the infusion. The metabolic profiles of 12c, 16a, and 16b all showed that their microsomal metabolism was significantly faster than that of LSD, and they appear promising among the orally administered test derivatives, and are expected to have a shorter duration of action than LSD. However, it is worth noting that in addition to the metabolic profile, other factors (such as 5-HT) are important in selecting promising drug candidates for therapeutic applications. 2A In addition, in vivo studies are needed to further evaluate the clinical pharmacokinetics of these substances.

[0186] The receptor interaction profiles of the novel substances at key targets were determined and compared with those of LSD and psilocybin dephosphate (the prodrug and active metabolite of the psychedelic drug psilocybin), and Fig.14 Many of the novel compounds exhibited higher binding affinity than LSD at the receptor responsible for the psychedelic effects of psychedelics (h5-HT2A), as evidenced by similar or lower Ki values ​​than LSD. Similarly, many of the novel compounds also exhibited similar or greater receptor activation potency than LSD at the 5-HT2A receptor responsible for their acute and therapeutic effects, as evidenced by lower or similar EC50 values ​​for h5-HT2A receptor activation compared to LSD. Several novel compounds had lower binding potency and / or receptor activation potency at the 5-HT2B receptor compared to LSD, suggesting similar or reduced risk of cardiotoxicity (heart valve fibrosis), as the 5-HT2B receptor is thought to mediate this adverse effect of serotonergic agents when used chronically at high doses.

[0187] In conclusion, Figure 1A Comparison of the in vitro profiles of lysergic acid derivatives presented in the literature with those of dephosphorylated psilocybin and LSD suggests that they possess overall psychedelic properties when used in humans. Thus, some lysergic acid derivatives may exert more beneficial acute psychedelic effects in some patients, including, but not limited to, more overall positive effects, different perceptual effects, more mood effects, less anxiety, less cardiac stimulant effects, less adverse effects, less nausea, longer and shorter effects, etc., compared to LSD.

[0188] There are several problems with the use of LSD that can be addressed using the compounds described herein. That is, in some cases, the long duration of the psychedelic experience may be limited. Figure 1A The derivatives represented in the formula can be more easily metabolized, thus resulting in a shorter duration of action. In addition, psychedelic drugs like psilocybin or LSD can produce adverse effects, including nausea and vomiting, cardiovascular stimulation, and increased body temperature. The new compounds can produce less nausea, less cardiac stimulation, less heat production, and / or other adverse reactions. The duration of action of LSD is very long. Substances currently in development are designed to have qualitative effects similar to those of LSD, but with a shorter duration of action, or to have a longer duration of action, but with structural changes and related pharmacological properties that reflect other qualitative effects. In particular, compounds that are less metabolically stable are created to shorten the human plasma half-life and duration of action. Other changes in chemical structure are designed to create substances that have qualitative effects different from LSD and produce subjective effects that are considered beneficial to assist psychotherapy (including empathy, openness, trust, insight, and feelings of interconnectedness) and are known by experts in the field.

[0189] Compared to the original LSD molecule, Figure 1A The indicated compound has a shorter, similar, or longer duration of action in the human body. Figure 1A caused by the modification of the molecular structure.

[0190] The group presented in the preparation section (i.e., compounds 2a to 2m, 12a to 12g, 13, 14a to 14c and 16a to 16c (see Figures 7A-7N and Figures 8A-8N )) is considered within the scope of the present invention Figure 1A Description of the lysergic acid derivatives represented in .

[0191] Compared to the original LSD molecule, Figure 1A The compounds of the invention represented allow to modify the mode of action, psychodynamic processes and qualitative perception, for example, in terms of the intensity of the psychedelic or synaesthesia.

[0192] Compared to the original LSD molecule, Figure 1A The compounds of the invention shown may produce imagery, hallucinations, and closed-eye or open-eye visual effects of similar or different qualities.

[0193] Compared to the original LSD molecule, Figure 1A The compounds of the invention represented may have similar, lower or higher efficacy at dosages.

[0194] Compared to the original LSD molecule, Figure 1A The compounds of the invention are shown to produce similar or more favorable physical sensations.

[0195] The modified properties can be tailored and applied individually to the needs of the patient. This can be achieved not only by changing the receptor profile of the compound, but also by greatly modifying the ADME (absorption, distribution, metabolism and excretion) by introducing more, similar or less susceptible substituents at the N1, N6 positions or at the carboxamide attached to C8 of the ergoline structure, as in Figure 1A In addition, the stability can be changed by introducing one or more deuterium nuclei into the ergoline core structure, such as Figure 6C As represented by the 5th category in .

[0196] Preparation of compounds

[0197] Figures 9 and 10 A general route to some lysergic acid derivatives of class 1 is outlined. The lysergic acid derivatives are prepared using an amide coupling agent such as CDI, TBTU, TCFH, TFFH, T3P, COMU or any other suitable coupling agent ( Fig. 9 )) Commercially available and synthetic lysergic acid (1) or lysergic acid monohydrate is activated in a suitable solvent such as DMF, dimethylacetamide, DCM or THF, EtOAc, dioxane, acetonitrile or mixtures thereof. Alternatively, activation may be performed using reagents such as POCl3 or trifluoroacetic anhydride. Next, the activated intermediate is reacted with a primary or secondary amine. The amine may be used as a free base or a salt. In the case of a free base, the amine may be used in excess or in an equivalent amount compared to the activated lysergic acid together with a non-nucleophilic base such as triethylamine (NEt3), N-methylmorpholine (NMM) or N,N-diisopropylethylamine (DIPEA). When the amine to be coupled is applied in salt form (e.g., as its hydrochloride), it may be used in an equivalent or excess amount compared to the activated lysergic acid, and the amine may be released from its salt using a non-nucleophilic base as previously outlined. The reaction temperature may range from 0-120°C, more advantageously from 20-100°C. After a reaction time sufficient to allow the amide to form, the corresponding amide formed is then isolated from the reaction mixture by extractive methods, chromatographic methods or by crystallization of the compound itself or its salt, or by a combination of these methods.

[0198] Compounds of class 1 containing an enamide group (e.g., subclass 1f) Figures 2A to 3H ) can be obtained through different channels ( Fig. 9In one embodiment, the corresponding primary or secondary 2-(benzenethiol)ethylamine is coupled with an activated lysergic acid derivative suitable for amide coupling. The 2-phenylthioethylamine may contain further substituents at any part of the molecule. The corresponding amide containing the 2-(benzenethiol)ethyl group is then oxidized to the corresponding sulfoxide, which is then reacted in a thermolysis to give the corresponding enamide (Taniguchi et al., 2005). The sulfoxide group is chiral and may have the R or S configuration, or be a mixture of any stereoisomers. The thermolysis is catalyzed by a suitable base such as NaHCO3, KHCO3, Na2CO3 or K2CO3 and carried out in a suitable solvent such as toluene or a dimethylated or trimethylated benzene such as o-xylene, m-xylene or p-xylene, but any other solvent that is chemically inert to the reaction being carried out may be used, most advantageously xylene. The temperature employed is 40-200°C, and more advantageously 100-150°C.

[0199] Sulfoxides can also be obtained as follows. Phenyl vinyl sulfoxide or substituted analogs are treated with primary amine R-NH2 in a suitable organic solvent such as THF, dioxane, ethyl acetate or dichloromethane to form the corresponding N-(2-phenylsulfinylethyl)-R-amine (Hu et al., 2014). The obtained amine is then coupled with lysergic acid or lysergic acid hydrate as described above to give an amide suitable for thermal decomposition to form an enamide. As described above, the sulfoxide group is chiral and can have the R or S configuration, or be a mixture of any stereoisomers.

[0200] In another embodiment to obtain enamides (e.g., subclass 1f), an aldehyde can be coupled with a primary aldehyde to form an imine, which is then coupled with an activated lysergic acid derivative suitable for amide coupling and subsequent elimination (Golding and Wong, 1981; He et al., 2014; Kulyashova and M., 2016; Meuzelaar et al., 1997). The coupled intermediate is then forced to eliminate to the corresponding enamide.

[0201] Another embodiment to obtain such enamides (eg, subclass 1f) is the formation of the oxazoline and subsequent lithiation and alkylation, leading to the ring opening and formation of the enamide (Xu et al., 2017).

[0202] Furthermore, enamides (e.g., subclass 1f) can be accessed by direct elimination using, for example, LiHMDS (Spiess et al., 2021).

[0203] For example, Category 1 ( Figures 2A to 3H) (e.g., subclass 1f) can also be accessed by applying an elimination procedure using a strong base (e.g., BuLi, LDA, or LiHDMS) attached to the 2,2,2-trifluoroethyl or 2-bromo-2,2-difluoroethyl substituents attached to the amide group of the corresponding lysergic amide compounds (Meiresonne et al., 2015; Riss and Aigbirhio, 2011).

[0204] Category 1( Figures 2A to 3H The formation of the alkyne amides (e.g., subclass 1g) as outlined in ) can be performed by an elimination procedure using a strong base (e.g., LiHDMS) attached to a 2,2,2-trifluoroethyl or 2-bromo-2,2-difluoroethyl substituent attached to the amide group of the corresponding lysergic amide compound (Meiresonne et al., 2015), but is not limited thereto.

[0205] Class 2 compounds ( FIG. 4A to FIG. 5C ) can be obtained by using the corresponding 6-Nor-LSD or any other 6-Nor compound as the starting material. 6-Nor-LSD ( Fig.11 The preparation of LSD is well documented, using the classic von Braun reaction, in which cyanogen bromide in boiling tetrachloromethane is used, both of which are extremely problematic to handle, and the aminonitrile formed is then reduced with elemental zinc in acetic acid (Fehr et al., 1970). Another approach is used here, as described in WO2006128658A1, in which the pyrrolidine analog of LSD is prepared. Similarly, LSD is treated with an oxidant (e.g. mCPBA) in dichloromethane under cooling, and the N-oxide formed is then reduced by adding FeSO4. This is quite safe, easy to handle and reacts very quickly. In addition, the yield is comparable to or even better than the von Braun reaction. Other oxidants, such as H2O2 or cumene hydroperoxide in an organic solvent (e.g. alcohol, ethyl acetate or dichloromethane) may also be used. After the separation step, which can be carried out by extraction, chromatography or crystallization of the compound itself or its salt or a combination of these methods, the obtained 6-Nor-LSD or any other 6-Nor compound (e.g. 6-Nor-TRALA-02) (e.g. Fig.12 ) is used in the reaction to obtain the compound represented by class 2 ( FIG. 4A to FIG. 5C ). The LSD or any other recovered lysergic acid derivative recovered from the above-described N-demethylation reaction can be reused in the N-demethylation reaction outlined above to further increase the amount of the desired 6-Nor-LSD or other 6-Nor compound. This cyclic process can be repeated as many times as the technology and / or the amount of the desired compound permit.

[0206] like FIG. 4A to FIG. 5C As indicated, some compounds represented by Class 2 can be obtained by reacting 6-Nor-LSD or another 6-Nor compound with a correspondingly substituted R6 containing a leaving group substituted by the basic N6 nitrogen of 6-Nor-LSD or another 6-Nor compound. The leaving group can be, for example, a halogen, a mesylate, a tosylate or a triflate. In addition, reductive amination can be applied using a suitable carbonyl compound and a reducing compound (e.g., NaBH4 or Na(OAc)3BH or NaBH3CN, also hydrogen) in the presence or absence of a catalyst in a suitable solvent.

[0207] For some R6 substituents to be introduced with strong electron withdrawing substituents, 6-Nor-LSD or the secondary N6 of other lysergic acid derivatives with NH at the 6-position, the nucleophilic character of the secondary amine may not be high enough to be used as a nucleophilic reagent. In this case, either the lysergic acid derivative must be fully protected to selectively deprotonate N6, or the electrophilic reagent must be activated. In this way, the use of transition metals or transition metal oxides or salts (such as silver salts) to accelerate the N-alkylation can be helpful. Advantageously, AgNO3 or AgOTf (AgCF3SO3) is added to the reaction mixture of the corresponding secondary N6 amine and the alkylating agent in an organic solvent (such as THF, dioxane, alcohol (such as MeOH, EtOH, iPrOH or DCM)). The mixture can be maintained at 0-100°C, more advantageously at 20-100°C.

[0208] It is well known that in some cases, 2,2,2-trifluoroethyl substituents cannot be introduced into amines simply by applying one of the above conditions due to extremely deactivating reactivity, i.e., due to the electron-withdrawing properties of fluorine, and even the compound 2,2,2-trifluoroethyl triflate, which is much more reactive than 2,2,2-trifluoroethyl iodide, shows extremely low reactivity in nucleophilic substitution with amines. Such substituents can be introduced onto amines by using synthetic equivalents, i.e., for example, 2,2,2-trifluoroacetaldehyde ethyl hemiacetal (alias: 1-ethoxy-2,2,2-trifluoro-ethanol) (Mimura et al., 2010). The intermediate formed is then reduced with a suitable reducing agent (e.g., NaBH4, Na(OAc)3BH or NaBH3CN).

[0209] like Figure 4GThe enamine compounds represented by the second class (subclass 2f) represented in the above can be obtained by reacting the corresponding carbonyl compound with 6-Nor-LSD to form an imine, by removing or absorbing water, and applying an additional non-nucleophilic base if necessary. Alternatively, such enamines can also be obtained by direct halogen substitution reaction of fluorinated 1-halo-1-olefins with 6-Nor-LSD or another 6-Nor compound (WO2006046417A1).

[0210] In addition, if Figure 4G Enamine compounds represented by the represented class 2 (subclass 2f) can be obtained, for example, by reacting N6-substituted N6-2,2,2-trifluoroethyl-6-Nor-LSD with a strong base such as LDA or BuLi (Riss and Aigbirhio, 2011).

[0211] like Figure 5B The alkoxyamine compounds (also called N-hydroxy ethers) represented by the second class (subclass 2h) represented in the above can be obtained by reacting 6-Nor-LSD with an oxidant (e.g., H2O2 or mCPBA) in an organic solvent to form the corresponding 6-Nor-LSD-N6-hydroxylamine, followed by deprotonation of the N6-hydroxylamine with a base (e.g., LDA, KOtBU, BuLi or LiHDMS), and then reacting the deprotonated intermediate with a corresponding substituted R6 containing a leaving group to be replaced by the deprotonated oxygen of 6-Nor-LSD-N6-hydroxylamine. The leaving group can be, for example, a halogen, a mesylate, a tosylate or a triflate or other suitable leaving group.

[0212] like Figure 5C The aryl or heteroaryl amines represented by class 2 (subclass 2i) can be obtained by reacting 6-Nor-LSD or another 6-Nor compound with the corresponding aryl or heteroaryl halide, triflate, as generally described, for example, by Buchwald-Hartwig amination.

[0213] like Figure 5C The benzylamines and (heteroarylmethyl)amines represented by class 2 (subclass 2i) represented in the above can be obtained by reacting 6-Nor-LSD or another 6-Nor compound with the corresponding aryl or (heteroarylmethyl) halide in a classical substitution reaction, or with the corresponding aldehyde in a reductive amination manner, wherein the reducing conditions applied are, for example, NaBH4, Na(OAc)3BH or NaBH3CN, but also hydrogen, in the presence or absence of a catalyst in a suitable solvent.

[0214] The N6 substituent can also consist of cycloalkanes or oxacycloalkanes ( Figure 4E and Figure 5A These substituents can be introduced by reductive amination with 6-Nor-LSD or another 6-Nor compound and the corresponding oxo-cycloalkane or oxo-oxacycloalkane and a reducing compound (e.g. NaBH4, Na(OAc)3BH or NaBH3CN, also hydrogen) in a suitable solvent in the presence or absence of a catalyst.

[0215] in addition, Figure 4E and Figure 5A These cycloalkane substituents represented by subclasses 2d and 2g in can also be introduced by substitution reactions, i.e., reacting 6-Nor-LSD or another 6-Nor compound with a correspondingly substituted R6 cycloalkane or oxacycloalkane containing a leaving group to be replaced by the basic N6 nitrogen of 6-Nor-LSD. The leaving group can be, for example, a halogen, a mesylate, a tosylate or a triflate.

[0216] get Figure 4E and Figure 5A Another way to produce compounds represented by subclasses 2d and 2g is by using 6-Nor-LSD or another 6-Nor compound and reacting it with a cycloalkane or oxacycloalkane containing geminal substituted alkoxy-(trialkylsilyloxy) in a suitable solvent in the presence or absence of a catalyst under acidic conditions, for example using acetic acid and using a reducing compound (e.g. NaBH4, Na(OAc)3BH or NaBH3CN, which can also be hydrogen).

[0217] By combining any of the above synthetic routes, the third class of compounds ( Fig. 6A In addition to this, a suitable protecting group may first be introduced in N1, N6 or on the C8 carboxyl function of the ergoline structure attached to LSD, 6-Nor-LSD or any other Nor-derivative (e.g. N6-Nor-ergotamine, N6-deprotected intermediates, N6-deprotected lysergic acid, N6-deprotected lysergic acid esters or appropriately transformed compounds).

[0218] The fourth class of compounds ( Figure 6B ),vice versa.

[0219] The fifth class of compounds ( Figure 6C), wherein there is at least one deuteron atom in the ergoline core structure, and vice versa.

[0220] Detailed description of the chemical preparation of the compound

[0221] General preparation and equipment information: NMR was performed at ambient temperature on a Bruker NMR ( 1 H: 300MHz and 19 The reaction was controlled by silica gel TLC (F 254 ; UV detection) and HPLC UV and MS (Agilent 1100, UV at 210nm and 313nm, Waters SQD, ESI+ mode) were performed under basic and acidic conditions (solvents: A: 0.02% NH4OH aqueous solution or 0.05% TFA aqueous solution, B: acetonitrile, gradient from 5% to 95% B, reversed phase C18 HPLC column). All reactions, treatments, drying steps and storage were performed in the absence of daylight and electric light (e.g., neon lamps or bulbs containing blue and / or UV spectral wavelengths). Work was performed in lightless laboratory vessels or under orange to red light (no UV LED). This helps prevent decomposition of the compounds. In addition, reactions and some purifications can be performed under protective gases such as nitrogen or argon to further protect the compounds from decomposition. Purification is carried out using silica gel column chromatography and an organic solvent such as a mixture of an alcohol (MeOH or EtOH) and dichloromethane, and in some cases, 0.1% to 1% NH4OH25% or 0.1% to 1% NEt3 is added. In a similar manner, preparative TLC (silica gel) using the above solvents is also applied. Work safety: Use appropriate personal protective equipment commonly used in laboratory work and a fume hood with a removable glass window. By using a long-wave UV lamp (e.g. 366 nm) on the hands, possible contamination, for example on gloves or surfaces, can be quickly detected, thereby preventing further diffusion of the active substance. In general, compounds with a complete lysergic acid amide substructure will show a strong, slightly bluish fluorescence even in trace amounts. A mixture of, for example, bleach and dilute alcohol can be used to quickly inactivate the potential central effect of these compounds.

[0222] Appropriate purity and identity check and determination of diastereomer identity are essential for evaluating the biological properties of the compounds of the present invention. The inventors did not rely on TLC or single HPLC analysis, but established a more in-depth analytical evaluation because for some compounds, TLC or single HPLC was not sufficient for judgment.

[0223] The purity of the final compounds was checked using two different HPLC systems, with different columns and different eluents at 195 nm and 313 nm (reaction controls: 210 nm and 313 nm). Very low absorption wavelengths reveal any organic contaminants, while longer wavelengths correspond roughly to the characteristic local maxima of these compounds and can reveal if there is any structure-related contamination. In addition, 1 H-NMR and (if applicable) 19 F-NMR can help to further determine the purity.

[0224] Using HPLC-MS and 1 H-NMR and (if applicable) 19 F-NMR was used to check the identity of the final compound. Please see the following note for important considerations regarding NMR analysis and interpretation.

[0225] General method for amide coupling. To a suspension of 286 mg (1 mmol) of lysergic acid monohydrate (note: anhydrous lysergic acid can be used similarly) in 4 mL of anhydrous DMF, 258 mg (1.59 mmol) of 1,1'-carbonyldiimidazole (CDI) was added in one portion. The suspension became clear after a few minutes, and after 30 min, an HPLC-UV and -MS-based activation check by dissolving a minimal sample of the reaction mixture in anhydrous MeOH (important) showed that the methyl ester was formed neat and completely (lysergic acid methyl ester appeared as two diastereomers). Therefore, the amine to be coupled (1.05 to 1.5 eq) was premixed as a free base or hydrochloride with diisopropylethylamine (DIPEA; 435 μL, 2.5 eq) in 2 mL of anhydrous DMF, and the clear amine solution was added in one portion to the above activated lysergic acid solution. Note: In some cases, a large excess of free amine (up to 10 eq without DIPEA) did force the reaction to produce the C8-epimer ratio more towards the desired and pharmacologically active 8R-carboxamide epimer. This method was used to force the epimer ratio depending on the availability of the amine used and economic reasons. Reaction control (by TLC: DCM / MeOH 9 / 1 and HPLC MS and UV at 210nm and 313nm) showed complete or nearly complete conversion (Note: in all cases, a mixture of C8-epimers was formed with ratios ranging from approximately 8R:8S = 8:2 to 4:6 based on interpretation of UV absorption at 313nm). For less nucleophilic amines (e.g., di(2,2-difluoroethyl)amine, which required reaction times of up to four days), the DMF was removed in vacuo using a strong vacuum pump at 40°C, followed by extraction as follows, or the reaction mixture was partitioned directly between water (40 mL) and 40 mL of heptane / EtOAc 1:1 (40 mL). The layers were separated and the very dark aqueous layer was further extracted with heptane / EtOAc 1:1 (2 x 20 mL). The combined brandy-colored organic layers were further washed with water (3 x 20 mL) and slowly filtered through a pad of Na2SO4 to dryness. A green to brown residue was obtained after evaporation of the organic volatiles as the crude product. This was purified by column chromatography or preparative TLC as described under the general section to give the corresponding lysergic acid amide derivative in free base form.As a general observation and in agreement with (Bailey, Verner, & Legault, 1973; Hoehn, Nichols, McCorvy, Neven, & Kais, 2017; Hoffman & Nichols, 1985; Stachulski, Nichols, & Scheinmann, 1996), under normal phase chromatography conditions, the first compound to elute from silica gel showing blue fluorescence under long-wave UV corresponds to the pharmacologically active compound with the 8R-carboxamide configuration and therefore to the desired C8 epimer. The second compound with blue fluorescence and always more polar corresponds to the 8S-carboxamide epimer, also called iso-compound. The mass was confirmed by LCMS and the structure was confirmed by NMR by comparing the isolated lysergic acid derivatives with the isolated isolysergic acid derivatives and with the existing exhaustive literature (e.g., Brandt et al., 2017; Hoehn et al., 2017; Hoffman and Nichols, 1985; Stachulski et al., 1996). Since not all lysergic acid derivatives can be separated well from their isolysergic acid derivatives under HPLC conditions, the inventors did not rely solely on TLC analysis (in rare cases, no clear separation occurred), but also used 1 H-NMR analysis is performed to check for proper diastereomeric separation. In general, there is hindered rotation at the amide CN junction, which results in a more complex spectrum. Of note, for the H9 proton, 1 H-NMR usually reveals only a single signal for symmetrically substituted amides (usually around 6.3-6.4 ppm, unimodal to multiplet). Most asymmetrically substituted amides show two signals for the H9 proton (usually around 6.3-6.4 ppm, unimodal to multiplet in some cases), with a non-1:1 ratio. In order to prove the absence of any 8S configuration impurities (iso-compounds) potentially contaminating the desired 8R configuration derivatives, in addition to HPLC UV and MS analysis (where 8R / 8S epimers are not always baseline separated), 1Different-compound was measured in H-NMR, and spectral comparison also shows that the ratio of H9 proton is non-1:1 two signals between 6.3ppm and 6.4ppm, but the chemical shift of these two signals is different from two signals of H9 of 8R configuration compound.Thus, the epimer purity of asymmetric amides was finally proved.Required free alkali product is dried under high vacuum, to remove any residual NH3 or NEt3, then obtain solid or foam with golden, slightly brown or beige outward appearance.Obtained different-compound (isolated compound with 8S-methane amide configuration) is also worth separating, and can easily carry out epimerization at C8 center, thereby obtain the mixture of 8R-and 8S-methane amide, apply alkali in suitable solvent by known procedure and realize (GB579484A).Then separate the epimer mixture obtained by above-mentioned purification step.Thus, easily increase the output of lysergic acid derivative with required 8R-methane amide configuration. For larger batches, it may be worth repeating this procedure several times to maximise your yield.

[0226] General procedure for the formation of the hemitartrate or tartrate salt. Note: Only the desired 8R-carboxamide epimer is converted to its salt is described, and the C8 epimer (with the 8S configuration, the so-called iso-compound) is either kept as its free base or used for the purpose of 1 H-NMR spectrum is compared, and some diastereomers are also converted into salts.Prepare 10% (+)-tartaric acid in anhydrous methanol solution (accurately weighed to calculate the required volume).The purified lysergic acid amide derivative in the form of free alkali is dissolved in a minimum amount of anhydrous MeOH (if necessary) under slight heating, and neutralized with 0.5 (for half tartrate) to 1 molar equivalent (for tartrate) of the above-mentioned (+)-tartaric acid solution. Alternatively, it is also possible to neutralize by adding (+)-tartaric acid solution directly to the free alkali foam.Next, anhydrous ether (Et2O) is added until maximum precipitation is reached.The suspension formed is left to stand for the required time at ambient temperature or in a refrigerator, depending on the difficulty of the suspension formation.Carefully pour out or remove the liquid layer by using a Pasteur pipette (cotton wool or the like) blocked in the front, and rinse the residue with MeOH / Et2O 1:1, and finally rinse with Et2O, then dry overnight in a high vacuum. The residual crystalline lysergic acid amide hemi-tartrate or tartrate is white to off-white in appearance. 1 H-NMR determines the exact tartaric acid content (ratio of lysergic acid derivative to tartaric acid: can be 1:0.5 to 1:1, or even 1 to more than 1 when an excessive amount of tartaric acid is accidentally used and not properly removed). 1Comments on H-NMR spectroscopy (see also existing literature, e.g., (Bailey et al., 1973; Hoehn et al., 2017; Hoffman and Nichols, 1985; Stachulski et al., 1996): As observed on the free base of lysergic acid derivatives, for the H9 proton 1 H-NMR revealed only a single signal for symmetrically substituted amides (around 6.3-6.4 ppm, in some cases singlet to multiplets). Asymmetrically substituted amides showed two signals for the H9 proton (around 6.3-6.4 ppm, in some cases singlet to multiplets) in a non-1:1 ratio. In order to prove the absence of any 8S configuration impurities (iso-compounds), in addition to HPLC UV and MS analysis (where 8R / 8S diastereomers were not always baseline separated), 1 The iso-compound was measured in H-NMR and spectral comparison also showed that the ratio of the H9 protons was not 1:1, but the chemical shift was different from the two signals of H9 of the 8R-configured compound. Thus, the epimeric purity of the asymmetric amide was finally confirmed.

[0227] General procedure for N6 alkylation with alkyl halides was adapted from (Hoffman and Nichols, 1985). To a mixture of 97 μmol (for 6-Nor-LSD this corresponds to 30 mg) of the free base of the N6Nor-compound and 26.8 mg (2.0 eq) K2CO3 in 0.5 mL of anhydrous DMF under nitrogen was added 116 μmol (1.3 eq) of the corresponding alkyl halide. The reaction was controlled (TLC: DCM / MeOH 9 / 1, sometimes by adding 0.1% NEt3, or by HPLC After full conversion indicated by UV and MS (note: N6 alkylation is much faster than C8 epimerization, and thus, at ambient temperature and under the chosen reaction conditions, little epimerization occurs, as previously demonstrated (Stachulski et al., 1996), the mixture was worked up. When the N6 alkylation reaction was very slow (e.g., less than 20% conversion after one day), the reaction could be significantly forced to near completion by adding a second equivalent of alkylating agent after one, two, and three days, respectively, and in some cases a third equivalent of alkylating agent. Therefore, after stirring for the desired time, the reaction mixture was concentrated under high vacuum at 40°C to remove most of the volatiles (including DMF), and the residue was dissolved in the eluent for chromatography and purified by silica gel column chromatography as described in the General section. For most compounds In some embodiments, the free alkali product is dried under high vacuum to remove any residual NH or NEt, then obtain a solid or foam with a golden, slightly brown or beige outward appearance. If necessary, the product can be dissolved in a hot solvent (such as benzene) to be further purified, and filtered when necessary, then precipitated from filtered and cooled solution by adding some heptanes (Hoffman and Nichols, 1985). The precipitation is then collected by filtration and dried under high vacuum. When needed, the free alkali compound can be converted into a pharmaceutically acceptable salt. In some cases, the inventor has observed very weak salt characteristics, and with regard to some tartrates, tartaric acid can even be separated completely from lysergic acid amide derivatives by precipitating tartaric acid from solution.

[0228] Example - Amide coupling of lysergic acid with secondary amines and conversion into their salts: Preparation of lysergic acid derivatives 2a-1.

[0229] 9,10-Didehydro-N-methyl-N-propyn-3-yl-6-methylergoline-8R-carboxamide (TRALA-01), 2a. According to the general amide coupling method as described, from 286 mg of lysergic acid monohydrate (AT Shulgin and Shulgin, 1997), 258 mg of CDI and 276 mg of N-methyl-propargylamine (4 eq), without DIPEA. Yield: 77 mg (24%) of TRALA-01 as a beige amorphous solid and 75 mg (18%) of iso-TRALA-01 as a gray-green solid. The tartrate salt was formed according to the general method as described; yield: 62 mg of 2a tartrate salt product as an off-white solid. Analytical data of 2a as tartrate salt: 1 H-NMR (DMSO-d6): (for interpretation complexity: see section General; Amide coupling) ~2.50 (s, N(6)Me, superimposed by DMSO), 2.59 (m, 1H), 2.92 (s, 1H), 3.11 (m, 2H), 3.23 (t, 1H), 3.25-3.44 (m, ~2H), 3.51 (m, ~2H), 3.89-4.38 (m, ~3H), 4.23 (s, tartaric acid), 6.28 (about 60%) / 6.35 (about 40%) (2x s, total = H9; note; evidence for the diastereomeric purity of C9 of the ergoline structure: see section General; Amide coupling), 7.00-7.11 (m, 3 arom.H), 7.17-7.23 (m, 1 arom.H), 10.75 (bs, NH). LCMS (M+H): expected value for 2a: M=319.41; found: 320.3.

[0230] 9,10-Didehydro-N-ethyl-N-propyn-3-yl-6-methylergoline-8R-carboxamide (TRALA-02), 2b. According to the general amide coupling method described, from 286 mg lysergic acid monohydrate, 258 mg CDI, 180 mg N-ethyl-propargylamine hydrochloride (1.5 eq) and 435 μL DIPEA (2.5 eq). Yield: 110 mg (33%) TRALA-02 as a slightly brown amorphous solid and 116 mg (35%) iso-TRALA-02 as a brown solid. The tartrate salt was formed according to the general method described; yield: 104 mg of the product 2b tartrate salt as an off-white solid. Analytical data of 2b as tartrate salt: 1H-NMR (DMSO-d6): (for interpretation complexity: see section General; Amide coupling) 1.11 / 1.25 (2xt, total = 3H), 2.54 (s, N(6)Me, superimposed by DMSO), 2.69 (t, ~1H), 3.04-3.21 (m, ~3H), 3.35-3.65 (m, ~4H), 3.96 (m, ~1H), 4.21 (m, ~1H), 4.24 (s, tartaric acid), 4.35 (m, 1H), 6.25 (about 50%) / 6.36 (about 50%) (2x s, total = H9; Note: Evidence of epimeric purity of C9 of ergoline structure: see section General; Amide coupling), 7.00-7.11 (m, 3 arom.H), 7.17-7.23 (m, 1 arom.H), 10.74 (bs, NH). LCMS (M+H): 2b expected value: M = 333.43; found value: 334.2. Analytical data of iso-2b in tartrate form: 1 H-NMR (DMSO-d6): 1.10 / 1.26 (2x t, total = 3H), 2.64 (s, N(6)Me), 2.76 (t, ~1H), 2.98 (m, ~1H), 3.13 (m, ~1H), 3.27-3.67 (m, ~4H), 3.87 (m, ~1H), 4.16 (m, ~1H), 4.20 (s, tartaric acid), 4.39 (m, 1H), 6.32 (about 55%) / 6.39 (about 45%) (2x s, total = H9; note; evidence of diastereomeric purity of C9 of ergoline structure: see section General; Amide coupling), 7.07 (bs, 3arom.H), 7.14-7.23 (m, 1arom.H), 10.76 (bs, NH). LCMS (M+H): iso-2b expected: M=333.43; found: 334.2.

[0231] 9,10-Didehydro-N-(cyanomethyl)-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-03), 2c. According to the general amide coupling method as described, from 286 mg of lysergic acid monohydrate, 258 mg of CDI and 168 mg of 2-(ethylamino)acetonitrile (2 eq), without DIPEA. Yield: 30 mg (9%) of TRALA-03 as a beige amorphous solid and 104 mg (31%) of iso-TRALA-03 as slightly brown lumps. The tartrate salt was formed according to the general method as described; yield: 31 mg of the product 2c tartrate salt as an off-white solid. Analytical data of 2c as tartrate salt: 1H-NMR (DMSO-d6): (For interpretation of complexity: see section General; Amide coupling) 1.13 / 1.26 (2xt, total = 3H), 2.52 (m, ~1H, superimposed by DMSO), 2.56 (s, N(6)Me, superimposed by DMSO), 2.71 (t, ~1H), 3.15 (m, ~2H), 3.59 (m, ~3H), 3.96 (m, ~1H), 4.27 (s, tartaric acid), 4.41 (m, ~2H), 6.28 (s, H9), 7.03-7.10 (m, 3arom.H), 7.19-7.24 (m, 1arom.H), 10.74 (bs, NH). LCMS (M+H): 2c expected value: M = 334.42; found value: 335.2.

[0232] 9,10-Didehydro-N-ethyl-N-(2-fluoroethyl)-6-methylergoline-8R-carboxamide (TRA LA-04), 2d. According to the general amide coupling method as described, from 573 mg lysergic acid monohydrate, 517 mg CDI, 255 mg N-ethyl-(2-fluoroethyl)amine hydrochloride (1 eq) and 523 μL DIPEA (1.5 eq). Yield: 153 mg (22%) TRALA-04 as a beige foam and 156 mg (23%) iso-TRALA-04 as a brown foam. The tartrate salt was formed according to the general method as described; yield: 158 mg 2d tartrate salt as an off-white solid. Analytical data of 2d as tartrate salt: 1 H-NMR (DMSO-d6): (For interpretation of the complexity: see section General; Amide coupling) 1.07 / 1.21 (2xt, total = 3H), 2.52 (m, ~1H, superimposed by DM SO), 2.54 (s, N(6)Me, superimposed by DMSO), 2.69 (t, 1H), 3.01-3.19 (m, ~2.5H), 3.41 (m, ~1H), 3.53 (m, ~2.5H), 3.62-3.95 (m, ~2.5H), 4.23 (s, tartaric acid), 4.59 (txq, 2H), 6.27 (s, H9), 7.00-7.11 (m, 3arom.H), 7.17-7.23 (m, 1arom.H), 10.73 (bs, NH). 19 F-NMR (DMSO-d6): -221.29, -222.13. LCMS (M+H): 2d expected value: M=341.43; found value: 342.3.

[0233] 9,10-Didehydro-N-(2,2-difluoroethyl)-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-05), 2e. According to the general amide coupling method as described, from 492 mg lysergic acid monohydrate, 444 mg CDI, 250 mg N-(2,2-difluoroethyl)ethylamine hydrochloride (1 eq) and 448 μL DIPEA (1.5 eq). Yield: 202 mg (33%) TRALA-05 as a golden foam and 252 mg (41%) iso-TRALA-05 as a brown mass. The tartrate salt was formed according to the general method as described; yield: 204 mg 2e tartrate salt as an off-white solid. Analytical data of 2e as tartrate salt: 1 H-NMR (DMSO-d6): (for interpretation complexity: see section General; Amide coupling) 1.08 / 1.23 (2xt, total = 3H), 2.53 (s, N(6)Me, superimposed by DMSO), 2.62 (m, ~1.5H, superimposed by DMSO / N(6)Me), 3.02-3.19 (m, ~2.5H), 3.41 (m, ~1H), 3.54 (m, ~2.5H), 3.74 (txm , 1.5H), 3.93 (m, 1.5H), 4.25 (s, tartaric acid), 6.15 (txm, 1H), 6.24 (minor) / 6.26 (major) (2xs, total = H9; note; evidence of diastereomeric purity of C9 of ergoline structure: see section General; Amide coupling), 7.00-7.11 (m, 3 arom.H), 7.17-7.24 (m, 1 arom.H), 10.73 (bs, NH). 19 F-NMR (DMSO-d6): -120.46 (major), -122.04 (minor). LCMS (M+H): 2e expected value: M = 359.42; found value: 360.3. Analytical data of iso-2e in the form of tartrate salt: 1 H-NMR (DMSO-d6): (for interpretation complexity: see section General; Amide coupling) 1.05 / 1.23 (2xt, total = 3H), 2.64 (m, N(6)Me), 2.77 (m, 1H), 2.97 (m, 1H), 3.13 (m, 1H), 3.32 (m, ~2H), 3.48-3.78 (m, ~4H), 3.81-4.10 (m, ~1.8H), 4.22 (s, tartaric acid), 6.11 (txm, 1H), 6.30 (s, H9; note; evidence for diastereomeric purity of C9 of ergoline structure: see section General; Amide coupling), 7.07 (m, 3arom.H), 7.21 (m, 1arom.H), 10.76 (bs, NH). 19F-NMR (DMSO-d6): -120.42 (major), -121.87 (minor). LCMS (M+H): iso-2e expected value: M=359.42; found value: 360.3.

[0234] 9,10-Didehydro-N-ethyl-N-(2,2,2-trifluoroethyl)-6-methylergoline-8R-carboxamide (TRALA-06), 2f. According to the general amide coupling method as described, from 573 mg lysergic acid monohydrate, 517 mg CDI, 328 mg N-(2,2,2-trifluoroethyl)ethylamine hydrochloride (1 eq) and 522 μL DIPEA (1.5 eq). Yield: 128 mg (17%) TRALA-06 as a slightly yellowish foam and 170 mg (23%) iso-TRALA-06 as a brown mass. The tartrate salt was formed according to the general method as described; yield: 108 mg 2f tartrate salt as an off-white solid. Analytical data for 2f as tartrate salt: 1 H-NMR (DMSO-d6): (For interpretation complexity: see section General; Amide coupling) 1.09 / 1.23 (2xt, total = 3H), 2.54 (s, N(6)Me, superimposed by DMSO), 2.67 (m, ~1H, superimposed by DMSO / N(6)Me), 2.99-3.20 (m, ~3H), 3.54 (m, ~3H), 3.96 (m, 1H), 4.24 (m, ~1.5H, superimposed by tartaric acid), 4.26 (s, tartaric acid), 4.47 (m, ~0.5H), 6.21 (minor) / 6.24 (major) (2x s, total = H9; Note; Evidence for epimeric purity of C9 of ergoline structure: see section General; Amide coupling), 6.99-7.12 (m, 3 arom.H), 7.17-7.23 (m, 1 arom.H), 10.74 (bs, NH). 19 F-NMR (DMSO-d6): -68.27 (major), -69.38 (minor). LCMS (M+H): 2f expected value: M=377.41; found value: 378.3.

[0235] 9,10-Didehydro-N-methyl-N-(2,2,2-trifluoroethyl)-6-methylergoline-8R-carboxamide (TRALA-07), 2 g. According to the general amide coupling method as described, from 573 mg lysergic acid monohydrate, 517 mg CDI, 299 mg N-(2,2,2-trifluoroethyl)methylamine hydrochloride (1 eq) and 522 μL DIPEA (1.5 eq). Yield: 108 mg (15%) TRALA-07 as a yellow foam and 174 mg (24%) iso-TRALA-07 as a brown foam. The tartrate salt was formed according to the general method as described; yield: 86 mg 2 g tartrate salt as an off-white solid. Analytical data for 2 g as tartrate salt: 1 H-NMR (DMSO-d6): (For interpretation complexity: see section General; Amide coupling) 2.54 (s, N(6)Me, superimposed by DMSO), 2.63 (m, ~1.5H, superimposed by DMSO / N(6)Me), 2.97-3.20 (m, 3H), 3.28 (s, CONMe), 3.52 (dxd, 1H), 4.15 (m, 1H), 4.24 (m, 2H), 4.26 (s, tartaric acid), 4.53 (m, ~0.5H), 4.69 (dxt, 2H), 6.23 (minor) / 6.29 (major) (2x s, total = H9; Note; Evidence for epimeric purity of C9 of ergoline structure: see section General; Amide coupling), 7.01-7.12 (m, 3 arom.H), 7.17-7.23 (m, 1 arom.H), 10.73 (bs, NH). 19 F-NMR (DMSO-d6): -68.62 (major), -69.36 (minor). LCMS (M+H): 2g expected value: M = 363.39; found value: 364.3. Analytical data of iso-2g in tartrate form: 1 H-NMR (DMSO-d6): (for interpretation complexity: see section General; Amide coupling) 2.61 (s, N(6)Me), 2.73 (t, 1H), 2.94 (m, ~1.6H), 3.08 (dxd, ~1.3H), 3.29 (s, CONMe), 3.42 (m, ~1H), 3.94 (m, 1H), 4.21 (m, ~2H, superimposed by tartaric acid), 4.26 (s, tartaric acid), 6.27 (minor) / 6.33 (major) (2xs, total = H9; note; evidence for diastereomeric purity of C9 of ergoline structure: see section General; Amide coupling), 7.01-7.12 (m, 3 arom.H), 7.16-7.24 (m, 1 arom.H), 10.75 (bs, NH). 19F-NMR (DMSO-d6): -68.52 (major), -69.13 (minor). LCMS (M+H): iso-2g expected value: M=363.39; found value: 364.3.

[0236] 9,10-Didehydro-N,N-di(2-fluoroethyl)-6-methylergoline-8R-carboxamide (TRALA-08), 2h. According to the general amide coupling method as described, from 492 mg lysergic acid monohydrate, 444 mg CDI, 250 mg di(2-fluoroethyl)amine hydrochloride (1 eq) and 448 μL DIPEA (1.5 eq). Yield: 80 mg (13%) TRALA-08 as beige foam and 161 mg (26%) iso-TRALA-08 as beige foam. The tartrate salt was formed according to the general method as described; yield: 76 mg 2h tartrate salt as off-white solid. Analytical data of 2h as tartrate salt: 1 H-NMR (DMSO-d6): 2.57 (s, NMe, superimposed by DMSO), 2.68 (t, 1H), 3.03-3.21 (m, 3H), 3.52 (dxd, 1H), 3.70 (dxm, 2H), 3.87 (dxt, 2H), 3.98 (m, 1H), 4.24 (s, tartaric acid), 4.53 (dxt, 2H), 4.69 (dxt, 2H), 6.28 (s, H9), 7.01-7.12 (m, 3arom.H), 7.18-7.23 (m, 1arom.H), 10.73 (bs, NH). 19 F-NMR (DMSO-d6): -221.98, -222.95. LCMS (M+H): 2h expected value: M=359.42; found value: 360.3.

[0237] 9,10-Didehydro-N,N-bis(2,2-difluoroethyl)-6-methylergoline-8R-carboxamide (TRA LA-09), 2i. According to the general amide coupling method as described, from 394 mg lysergic acid monohydrate, 356 mg CDI, 250 mg bis(2,2-difluoroethyl)amine hydrochloride (1 eq) and 360 μL DIPEA (1.5 eq). Yield: 33 mg (6%) TRALA-09 as brown lumps and 44 mg (8%) iso-TRALA-09 as brown lumps. The tartrate salt was formed according to the general method as described; yield: 18 mg 2i tartrate salt as off-white solid. Analytical data of 2i as tartrate salt: 1H-NMR (DMSO-d6): (For interpretation of the complexity: see section General; Amide coupling) ~2.50 (NMe, superimposed by DMSO), 2.64 (t, 1H), 3.03-3.28 (m, 3H), 3.52 (dxd, 1H), 3.86 (txt, 2H), 3.97-4.15 (m, 3H), 4.27 (s, tartaric acid), 6.24 (s, H9), 6.25 (5.97-6.53: sharply separated txm; 2x CHF2), 7.02-7.14 (m, 3arom.H), 7.18-7.25 (m, 1arom.H), 10.74 (bs, NH). 19 F-NMR (DMSO-d6): -121.26, -121.29, -122.87. LCMS (M+H): 2i expected value: M=395.40; found value: 396.2.

[0238] 9,10-Didehydro-N-ethyl-N-(methoxy)-6-methylergoline-8R-carboxamide (TRALA-10), 2j. The general amide coupling procedure as described was from 1.14 g lysergic acid monohydrate, 1.04 g CDI, 0.51 g N-methoxy-ethylamine hydrochloride (1 eq) and 1.04 mL DIPE A (1.5 eq). Yield: 113 mg (17%) TRALA-10 as a yellow foam and 146 mg (22%) iso-TRALA-10 as a brown foam. The tartrate salt was formed according to the general procedure as described; yield: 74 mg 2j tartrate salt as an off-white solid. Analytical data for 2j as tartrate salt: 1 H-NMR (DMSO-d6): (For interpretation of complexity: see section General; Amide coupling): 1.13 (t, 3H), 2.56 (s, NMe, superimposed by DMSO), 2.62 (m, ~1H), 3.06-3.18 (m, 3H), 3.52 (dxd, 2H), 3.66 (q, 2H), 3.76 (s, OMe), 3.93 (m, 1H), 4.25 (s, tartaric acid), 6.30 (s, H9), 7.01-7.12 (m, 3arom.H), 7.18-7.23 (m, 1arom.H), 10.73 (bs, NH). LCMS (M+H): 2j expected value: M = 325.41; found value: 326.3.

[0239] 9,10-Didehydro-6-methylergoline-8R-((RS)-2-ethynylazetidine) (TRA LA-11), 2k. According to the general amide coupling method as described, from 243 mg lysergic acid monohydrate, 220 mg CDI, 100 mg (RS)-2-ethynylazetidine hydrochloride (1 eq) and 222 μL DIPEA (1.5 eq). Yield: 52 mg (19%) beige foamy TRALA-11 and 90 mg (32%) beige foamy iso-TRALA-11. The tartrate salt was formed according to the general method as described; yield: 45 mg 2k tartrate salt as off-white solid. Analytical data of 2k in tartrate form (for interpretation complexity: see section General; Amide coupling): 1 H-NMR (DMSO-d6): 2.24 (m, 1H), 2.48-2.62 (m, ca. 3H, superimposed by DMSO and NMe), 2.52 (s, NMe, superimposed by DMSO), 3.12 (m, 1H), 3.18 (s, CCH), 3.52 (m, 2H), 3.75 (m, 1H), 3.86 (m, ca. 1.5H), 4.25 (s, tartaric acid), 4.27 (m, ca. 0.5H), 4.83 (m, ca. 0.5H), 4.32 (m, ca. 0.5H), 6.26 (minor) / 6.35 (major) (2x s, total = H9; Note: the azetidine moiety contains a stereogenic center that is assumed to be racemic; Evidence of epimeric purity of C9 of the ergoline structure: see section General; Amide coupling) 7.01-7.11 (m, 3 arom.H), 7.21 (m, 1 arom.H), 10.73 (bs, NH). LCMS (M+H): 2k expected value: M = 331.42; found value: 332.2.

[0240] 9,10-Didehydro-N-(2-fluoroethyl)-N-(methyloxy)-6-methylergoline-8R-carboxamide (TRALA-14), 2n. 1.) Preparation of N-methoxy-2-fluoroethylamine hydrochloride (10; adapted from US20100029670A1). To a solution of 1.0 g (8.39 mmol) of ethyl N-methoxycarbamate (8) in 5 mL of anhydrous DMF was added 0.352 g (8.81 mmol) of 60% NaH dispersed in mineral oil under nitrogen and ice cooling. After stirring for 5 min, the mixture was stirred at ambient temperature for 1 h. Next, 1.46 g (8.39 mmol) of 1-fluoro-2-iodomethane was added and the mixture was heated to 75° C. for 6 h. The mixture was cooled to ambient temperature and mixed with water and EtOAc (70 mL each), and the layers were separated. The organic layer was further washed once with water (1×70 mL), dried over MgSO 4 , and concentrated in vacuo to afford 1.05 g (75%) of intermediate 9 as a yellow oil. 1 H-NMR(CDCl3):1.33(t,CH2CH3),3.75(s,OCH3),3.81(dxt,CH2CH2F),4.24(q,CH2CH3),4.59(dxt,CH2F). 19 F-NMR (CDCl3): -224.0. Intermediate 9 (1.03 g) was mixed with 1.5 mL EtOH, 1.5 mL water and 1.25 g KOH, and the mixture was heated to 75 ° C and kept for 5 h, wherein the flask (25 mL) was plugged with a diaphragm connected to a Teflon tube. The second end of the tube was placed in a small gas wash bottle containing a 2M HCl aqueous solution. After the reaction time, the mixture was heated to 90 ° C and any residual product was forced to be transferred to the gas wash bottle using a slow nitrogen stream (balloon, needle, over 1 h). The 2M HCl containing the product was concentrated in a vacuum, and the residual semi-solid was co-evaporated with MeOH, dried quickly in a high vacuum, and then ground with Et2O / hexane, and filtered off. After drying, 326 mg (40%) of rose-colored solid N-methoxy-2-fluoroethylamine hydrochloride (10) was obtained. 1 H-NMR (soluble in CDCl3): 3.66 (dxt, CH2CH2F) 4.12 (s, OCH3), 4.89 (dxt, CH2F). 19F-NMR (CDCl3): -223.2. 2.) Amide coupling reaction: According to the general amide coupling method described, from 248 mg of lysergic acid monohydrate, 155 mg (1.1 eq) of CDI, 123.5 mg of N-methoxy-2-fluoroethylamine hydrochloride (10; 1.1 eq) and 377 μL of DIPEA (2.5 eq); a solution of amine 10 and DIPEA in DMF was added dropwise under ice cooling and the reaction mixture was allowed to warm to ambient temperature over several hours. Yield: 21 mg (7%) of TRALA-14 as a golden-beige solid. Analytical data of 2n: 1 H-NMR(CDCl3):2.62(s,NMe),3.24(m,2H),3.57(dxd,1H),3.81(s,OMe),3.95(dxt,1H),4.04(dxt,1H),4.10(bm,1H),4.24(m,1H ),4.57(t,1H),4.73(t,1H),6.47(s,H9)6.92(m,1arom.H),7.14-7.26(m,3arom.H),7.55(m,0.5H),7.73(m,0.5H),7.98(bs,NH). 19 F-NMR (CDCl3): -222.5. LCMS (M+H): 2n expected value: M=343.40; found value: 344.2.

[0241] Example - Preparation of lysergic acid enamides, derivatives 21-m.

[0242] 1.) Amide formation

[0243] 9,10-Didehydro-N-ethyl-N-(2-(phenylthio)ethyl)-6-methylergoline-8R-carboxamide, 4. According to the general amide coupling method described, from 974 mg of lysergic acid monohydrate, 880 mg of CDI, 885 μL of N-ethyl-2-(benzenethiol)ethylamine (3; 1.1 eq) and 885 μL of DIPEA (1.5 eq). Yield: 550 mg (38%) of the title product as a golden foam. Analytical information for 4: 1 H-NMR (CDCl3): 1.12-1.32 (m, 3H), 2.59-2.78 (m, 4H), 2.92 (t, 1H), 3.04 (m, 1H), 3.10-3.32 (m, 3H), 3.40-3.68 (m, 5H), 3.89 (bm, 1H), 6.30 / 6.37 (2xs, H9) 6.93 (t, 1arom.H), 7.15-7.49 (m, 8arom.H), 8.00 (bs, NH). LCMS (M+H): 4 expected value: M = 431.60; found value: 432.3.

[0244] 2.) Sulfoxide formation

[0245] 9,10-Didehydro-N-ethyl-N-(2-(phenylsulfinyl)ethyl)-6-methylergoline-8R-carboxamide, 5. To an ice-cooled solution of 405 mg (0.94 mmol) of 4 in 20 mL of DCM was added 81 μL of aqueous HCl 37% (1.05 eq). Next, a solution of 211 mg (1.0 eq) of meta-chloroperbenzoic acid (mCPBA) in 20 mL of DCM was added over the course of 5 min. After 20 min, LCMS analysis indicated the formation of the sulfoxide (50%; a small second peak with the same mass corresponds to the N-oxide, the identity of which was determined by separation and 1 H-NMR to prove), and double oxidation product (20%), together with starting material (30%), and quenched by adding 20mL 10% Na2S2O3 aqueous solution. After vigorous stirring for 5min, separate the layers and further extract the aqueous layer with DCM (2x20mL), and the combined organic layers are dried over Na2SO4 and concentrated in vacuo. The light green-black residue (547mg) is purified by silica gel chromatography (DCM / MeOH / NEt3). Yield: 54mg (13%) off-white foamy title product, together with 258mg recovered starting material. Analytical information of 5: 1 H-NMR (CDCl 3； Note: sulfoxide carries additional chiral center and increases complexity): 1.15-1.36 (m, 3H), 2.58-2.78 (m, 4H), 2.80-2.95 (bm, 1H), 2.95-3.20 (m, ~2.5H), 3.25-3.38 (m, ~2.5H), 3.5-3.8 (m, 5H), 3.93 (bm, 1H), 6.23 / 6.27 (both minor) and 6.32 / 6.38 (both major) (each as s, H9; total = 1H) 6.94 (m, 1 arom.H), 7.15-7.27 (m, 3 arom.H), 7.50-7.61 (m, 3 arom.H), 7.65-7.72 (m, 2 arom.H), 7.95 (bs, NH). LCMS (M+H): 5 expected: M=447.60; found: 448.2.

[0246] 3.) Pyrolysis

[0247] 9,10-Didehydro-N-vinyl-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-12), 21. A mixture of 54 mg (0.121 mmol) 9,10-didehydro-N-ethyl-N-(2-(phenylsulfinyl)ethyl)-6-methylergoline-8R-carboxamide (5) and 51 mg (5 eq.) NaHCO3 in 8 mL of m-xylene was heated to 130-140° C. under nitrogen. After a total of 2 days, about 25% conversion (LCMS) was observed in the starting material and some decomposition products. The volatiles were removed at 50° C. in a high vacuum and the residue was purified by first dissolving it in 1 mL of DCM / MeOH / NEt3=90 / 10 / 0.2 and filtering it through a silica gel pad (height 1 cm) using 70 mL of the same solvent system. This removed most of the dark color. The eluent was concentrated in vacuo and the residue was further purified by silica gel chromatography using the same solvent system starting with 98% DCM. About 2 mg of the title product was obtained. Analysis of basic or acidic HPLC MS (see section General) indicated the same purity (about 85%), revealing the stability of the product under these conditions. LCMS (M+H): 21 expected value: M = 321.43; found value: 322.2. 1 H-NMR (CDCl3): Signals are consistent with spectra obtained by alternative pathways (e.g., 6 to 7 to 5 to 2l; Fig. 9 LCMS retention time is also consistent), but 1 H-NMR also indicated the presence of a large amount of impurities.

[0248] 4.) Enamides obtained by base-promoted elimination (microscale)

[0249] 9,10-Didehydro-N-(2,2-difluorovinyl)-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-13), 2m. The reaction can be carried out using LDA or BuLi, and no epimerization is observed. A solution of 7 mg (18.5 μmol) of TRALA-06 (2f) in 0.2 mL of anhydrous THF was cooled to -100 °C under nitrogen (liquid nitrogen, acetone / THF 4:1 mixture as cooling bath). Next, 2.0 eq of 1.6 M BuLi or in a second experiment 2.0 eq. of a freshly prepared THF solution of lithium diisopropylamide (from BuLi and diisopropylamine in THF) was added within 30 s. Basic and acidic HPLC MS from samples hydrolyzed in dripping water and diluted with MeOH indicated 30% product formation in the intact starting material (integrated by UV absorption at 313 nm, and by integration of e / z=358, relative to the starting material); no significant decomposition was observed, and the product remained intact. To further test the chemical stability, a hydrolyzed sample stored overnight at ambient temperature (thus, under basic conditions) remained intact. Another hydrolyzed sample was made acidic by adding excess tartaric acid, and after storage for 24 h, reanalysis indicated the same product distribution as after the initial hydrolysis of the reaction. LCMS (M+H): 2m expected value: M=357.41; found value: 358.3.

[0250] Example - Alternative route to the enamides of lysergic acid: Preparation of derivative 21.

[0251] 1.) Hydroamination

[0252] N-ethyl-2-(phenylsulfinyl)ethylamine, 7. Procedure adapted from (Hu et al., 2014). To ethylamine 2M (6 mL; 12 mmol) in anhydrous THF was added 1.33 mL (10 mmol) of phenyl vinyl sulfoxide (6) and the clear solution was stirred under nitrogen for 18 h. The volatiles were removed in vacuo at 50 °C and the residual viscous slightly orange oil was purified by silica gel chromatography (DCM / MeOH / NEt3=100 / 0 / 0.5 to 95 / 5 / 0.5). Yield: 1.72 g (72%) of the title product as a colorless oil. Analytical information for 7: 1 H-NMR (CDCl3; note: sulfoxide with chiral center; enantiomeric ratio not determined): 1.11 (t, CH3), 2.67 (q, NHCH2), 2.96 (m, CH2), 3.13 (m, CH2), 7.48-7.57 (m, 3arom.H), 7.62-7.67 (m, 2arom.H). LCMS (M+H): 7 expected value: 197.30; found value: 198.1.

[0253] 2.) Amide formation

[0254] 9,10-Didehydro-N-ethyl-N-(2-(phenysulfinyl)ethyl)-6-methylergoline-8R-carboxamide, 5. According to the general amide coupling method described, from 394 mg of lysergic acid monohydrate, 356 mg of CDI, 272 mg of N-ethyl-2-(phenylsulfinyl)ethylamine (7; 1.0 eq) and 356 μL of DIPEA (1.5 eq). Yield: 191 mg (31%) of the title product as a beige solid. Analytical information for 5: 1 H-NMR (CDCl 3； Note: sulfoxide carries an additional chiral center and adds complexity; due to its synthetic route, it is likely racemic here): 1.15-1.36 (m, 3H), 2.58-2.78 (m, 4H), 2.80-2.95 (bm, 1H), 2.95-3.20 (m, ~2.5H), 3.25-3.38 (m, ~2.5H), 3.5-3.8 (m, 5H), 3.93 (bm, 1H), 3.97 (m, 2H), 4.10 (m, 5H), 4.69 (m, 6H), 4.91 (m, 7H), 4.85 (m, 8H), 4.94 (m, 9H), 4.82 (m, 10H), 4.98 (m, 20H), 4.84 (m, 21H), 4.86 (m, 31H), 4.90 (m, 41H), 4.81 (m, 51H), 4.80 (m, 61H), 4.81 (m, 71H), 4.83 (m, 71H), 4.91 (m, 8H), 4.82 (m, 9H), 4.83 (m, 10H), 4.83 (m, 10H), 4.83 (m, 10H), 4.91 (m, 10H), 4.83 (m, m, 1H), 6.23 / 6.27 (all minor; the first one is more dominant) and 6.32 / 6.38 (all major) (H9; total = 1H) 6.92 / 6.94 (m, 1 arom.H), 7.15-7.27 (m, 3 arom.H), 7.50-7.61 (m, 3 arom.H), 7.65-7.72 (m, 2 arom.H), 7.95 (bs, NH). LCMS (Note: The retention time obtained is the same as that of sulfoxide 5 obtained by an alternative route, see section "2.) Sulfoxide formation;" M+H): 5 expected value: 447.60; found value: 448.2.

[0255] 3.) Pyrolysis

[0256] 9,10-Didehydro-N-vinyl-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-12), 21. A mixture of 180 mg (0.402 mmol) of 9,10-didehydro-N-ethyl-N-(2-(phenylsulfinyl)ethyl)-6-methylergoline-8R-carboxamide (5) and 283 mg (5 eq.) of K2CO3 in 26 mL of m-xylene was heated to 130-140° C. under nitrogen. After a total of 22 hours, a conversion of about 40% was observed in the starting material and only minor decomposition products (LCMS). Longer heating would have resulted in a gradual decomposition. The volatiles were removed at 50° C. in a high vacuum and the residue was purified by first dissolving it in 5 mL of DCM / MeOH / NEt3=90 / 10 / 0.1 and filtering it through a silica gel pad (height 1 cm) using 150 mL of the same solvent system. This removed most of the dark color. iv. The eluent was concentrated and the residue was further purified by silica gel chromatography using DCM / MeOH / NEt3=98 / 2 / 0.1 to 90 / 10 / 0.1 as eluent. The crude product (24 mg) eluted first (followed by the starting material; recovered: 89 mg) and was further purified by silica gel preparative TLC using DCM / MeOH / NEt3=98 / 2 / 0.1 as eluent. Finally, 9 mg (7%) of the title product 21 were obtained. Analysis of basic or acidic HPLCMS indicated the same purity (approximately 90%), revealing the stability of the product under these conditions. 1 H-NMR (CDCl3): (for interpretation complexity: see section General; Amide coupling) 1.3 (m; superimposed by some Et2O and impurities, CH2CH3), 2.63 (s, NMe), 2.74 (txm, 1H), 2.87 (m, 1H), 3.16 (dxd, 1H), 3.28 (bm, 1H), 3.56 (dxd, 1H), 3.78 (m, 2H), 4.10 (bm, 1H), 4.43 (d, 1H), 4.62 (d, 1H), 6.34-6.44 (two superimposed s, H9; total = 1H; note: evidence of epimeric purity of C9 of ergoline structure: see section General; Amide coupling) 6.93 (m, 1 arom.H), 7.03 (dxd, 1H), 7.15-7.27 (m, 3 arom.H), 7.95 (bs, NH). LCMS (M+H): 2l expected value: M = 321.43; found value: 322.2.

[0257] Example - Preparation of N6-substituted derivatives of 6-nor-lysergic acid diethylamide, derivatives 12a-g.

[0258] 1.) Synthesis of LSD

[0259] 9,10-Didehydro-N,N-diethyl-6-methylergoline-8R-carboxamide (LSD), 2o. From 3.52 g of lysergic acid monohydrate, 3.18 g of CDI and 13.4 mL of diethylamine (10 eq; DIPEA was not used) according to the general amide coupling method described. Yield: 1.64 g (41%) of LSD as a beige foam and 0.65 g (16%) of iso-LSD as a brown sticky mass. The analytical data of the free base form of 2o (LSD) are consistent with the reference: 1 H-NMR (CDCl3): 1.19 (t, 1x CH2CH3), 1.26 (t, 1x CH2CH3), 2.63 (s, NMe), 2.72 (txm, 1H), 2.93 (t, 1H), 3.08 (dxd, 1H), 3.26 (bm, 1H), 3.47 superimposed with 3.57 (m and dxd, total 5H), 3.92 (bm, 1H), 6.37 (s (suggestive triplet), H9. Note: separated diastereomers iso-LSD showed this signal as t at 6.31), 6.93 (t, 1arom.H), 7.14-7.27 (m, 3arom.H), 7.99 (bs, NH). LCMS (M+H): 2o expected value: M = 323.41; found value: 324.3.

[0260] 2.) N6-demethylation of LSD: Preparation of 6-Nor-LSD.

[0261] 9,10-Didehydro-N,N-diethylergoline-8R-carboxamide (6-Nor-LSD), 11. This is adapted from (WO2006128658A1). To an ice-cold solution of 1.35 g (4.17 mmol) LSD (2o) in 40 mL DCM was added 1.13 g (1.2 eq) mCPBA 77% (wet). After stirring for 10 min (note: LCMS analysis showed that the N-oxide intermediate was formed cleanly and completely as two well-chromatographically separated diastereomers, e / z=340; reason: the N-oxide group carries an additional chiral center), a solution of 580 mg (0.5 eq) FeSO4 heptahydrate just prepared in 3.0 mL MeOH p.A. was quickly added. The cooling bath was removed and stirring was continued at ambient temperature until the N-oxide completely disappeared (note: the reason why the N-oxide was not completely converted to the desired product is because one of the N-oxide diastereomers converts back to the starting material LSD faster than the rate of N-demethylation, see for example (McCamley, Ripper, Singer, and Scammells, 2003). By changing the reaction conditions for the formation of N-oxides such as LSD, the diastereomer ratio of the N-oxide can be influenced, which will lead to a higher rate of N-demethylation; archived, unpublished results). After 3.5 h, the reaction mixture was poured into 50 mL of 0.1 M ethylenediaminetetraacetic acid (EDTA) solution (pH = 9 (adjusted with NH4OH 25% aqueous solution)). After vigorous shaking, the layers were filtered through a small celite pad and then separated, and the aqueous layer was further extracted with DCM (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The dark brown residue was purified by silica gel chromatography (DCM / MeOH / NH3=95 / 5 / 0.1 to 90 / 10 / 0.1). 449 mg of recovered LSD (2o; eluted first) and 587 mg (46%) of 6-Nor-LSD (11) as a tan solid were obtained. The recovered LSD (2o) can be easily reused in the same reaction, each time producing the desired 6-Nor-LSD (11) in essentially the same yield (the reaction was repeated twice from the recovered LSD). 1 H-NMR (CDCl3): 1.20 (t, 1x CH2CH3), 1.30 (t, 1x CH2CH3), 2.81 (txm, 1H), 3.23-3.58 (m, 8H), 3.69 (m, 1H), 3.96 (m, 1H), 6.38 (t, H9), 6.92 (t, 1arom.H), 7.15-7.26 (m, 3arom.H), 7.97 (bs, N1H). LCMS (M+H): 11 expected value: M = 309.41; found value: 310.3.

[0262] 3.) N6-Alkylation of 6-Nor-LSD: Preparation of compounds 12a-g.

[0263] 9,10-Didehydro-N,N-diethyl-6-(2-fluoroethyl)ergoline-8R-carboxamide (TRALA-15), 12a. According to the general procedure for N6 alkylation as described, from a total of 28.5 μL (3x9.5 μL, 2nd addition on day 2, 3rd addition on day 3) 1-fluoro-2-iodoethane iodide 30 mg 6-Nor-LSD (11), reaction time: 3 days. Yield: 9 mg (26%) beige foamy TRALA-15. Analytical information of 12a as free base: 1 H-NMR(CDCl3):1.20(t,1x CH2CH3),1.27(t,1x CH2CH3),2.73(t,1H),2.85-3.11(m,2H),3.18-3.63(m,8H),3.87(bm,1H),4.68(dx m,CH2F,2H),6.36(s,H9),6.91(t,1arom.H),7.14-7.25(m,3arom.H),8.04(bs,NH). 19 F-NMR (CDCl3): -219.0 (s). LCMS (M+H): Expected value of 12a: M = 355.46; Found: 356.3.

[0264] 9,10-Didehydro-N,N-diethyl-6-(3-fluoropropyl)ergoline-8R-carboxamide (TRALA-16), 12b. According to the general procedure described for N6 alkylation, from a total of 35.4 μL (2 x 17.7 μL, 2nd addition on day 2) 1-bromo-3-fluoropropane and 50 mg 6-Nor-LSD (11), reaction time: 2 days. Yield: 12 mg (20%) TRALA-16 as a yellow solid. Analytical information of 12b as free base: 1 H-NMR(CDCl3):1.20(t,1x CH2CH3),1.27(t,1x CH2CH3),1.9-2.1(bm,2H),2.60-2.84(m,2H),2.84-2.98(m,2H),3.14(bm,2H),3.4-3.6(m,6H),3.82 (bm,1H),4.61(dxm,CH2F,2H),6.35(s,H9),6.93(s,1arom.H),7.15-7.26(m,3arom.H),7.94(bs,NH). 19F-NMR (CDCl3): -220.3 (s). LCMS (M+H): 12b expected value: M = 369.49; found value: 370.4.

[0265] 9,10-Didehydro-N,N-diethyl-6-(2-fluoro-1-propan-3-yl)ergoline-8R-carboxamide (TRALA-17), 12c. According to the general procedure described for N6 alkylation, from a total of 33.9 μL (3 x 11.3 μL, 2nd addition on day 2, 3rd addition on day 3) 3-bromo-2-fluoro-1-propene and 30 mg 6-Nor-LSD (11), reaction time: 3 days. Yield: 20 mg (56%) TRALA-17 as a yellow foam. Analytical information of 12c as free base: 1 H-NMR(CDCl3):1.21(t,1xCH2CH3),1.27(t,1x CH2CH3),2.75(t,1H),2.99(t,1H),3.22-3.62(m,8H),3.72(dxd,1H),3.85(bm,1H),4.58(dx d,1H),4.77(dxd,1H),6.37(s,H9),6.91(t,1arom.H),7.14-7.26(m,3arom.H),8.09(bs,NH). 19 F-NMR (CDCl3): -97.7 (s). LCMS (M+H): 12c expected value: M = 367.47; found value: 368.3.

[0266] 9,10-Didehydro-N,N-diethyl-6-((RS)-(2,2-difluorocyclopropyl)methyl)ergoline-8R-carboxamide (TRALA-18), 12d. According to the general procedure described for N6 alkylation, from a total of 60 mg (3x20 mg, 2nd addition on day 2, 3rd addition on day 3) racemic 2-(bromomethyl)-1,1-difluorocyclopropane and 30 mg 6-Nor-LSD (11), reaction time: 3 days. Yield: 11 mg (28%) TRALA-18 as a slightly yellowish solid. Analytical information of 12d as free base: 1 H-NMR(CDCl3):1.11(m,1H),1.21(t,1xCH2CH3),1.28(t,1x CH2CH3),1.53,(m,1H),1.84(m,1H),2.62-3.28(m,5H),3.38-3.68(m,6H),3.87 (bm,1H),6.37(s,H9),6.92(s,1arom.H),7.14-7.25(m,3arom.H),8.05(bs,NH).19 F-NMR (CDCl3): -128.7 (m: -128.15; -128.71; -128.75; -129.31), -142.4 (m: -141.63; -142.18; -142.58; -143.14). LCMS (M+H): 12d expected value: M = 399.49; found value: 400.3.

[0267] 9,10-Didehydro-N,N-diethyl-6-(cyanomethyl)ergoline-8R-carboxamide (TRALA-19), 12e. According to the general procedure for N6 alkylation as described, from a total of 24.4 μL (2x12.4 μL, 2nd addition on day 2) chloroacetonitrile and 50 mg 6-Nor-LSD (11), reaction time: 2 days. Yield: 33 mg yellow foam, which still contained some impurities (approximately 15%) based on NMR analysis. Therefore, the product was further purified by preparative TLC (DCM / MeOH / NEt3=98 / 2 / 0.2) to give 7 mg (13%) of TRALA-19 as a yellow foam. Analytical information of 12e in free base form: 1 H-NMR (CDCl3): 1.21 (t, 1x CH2CH3), 1.27 (t, 1x CH2CH3), 2.71 (txm, 1H), 3.08 (dxd, 1H), 3.30 (t, 1H), 3.37-3.57 (m, 5H), 3.72 (bm, 1H), 3.76 (d, 1H), 3.91 (bm, 1H), 4.07 (d, 1H), 6.37 (s, H9), 6.94 (t, 1arom.H), 7.15-7.26 (m, 3arom.H), 8.06 (bs, NH). LCMS (M+H): 12e expected value: M = 348.45; found value: 349.2.

[0268] 9,10-Didehydro-N,N-diethyl-6-(2-oxopropyl)ergoline-8R-carboxamide (TRALA-20), 12f. According to the general procedure described for N6 alkylation, a total of 27.9 μL (3 x 9.3 μL, 2nd addition on day 2, 3rd addition on day 3) chloroacetone and 30 mg 6-Nor-LSD (11), reaction time: 2 days. Yield: 18 mg (51%) TRALA-20 as a yellow-beige foam. Analytical information of 12f as free base: 1H-NMR (CDCl3): 1.19 (t, 1x CH2CH3), 1.27 (t, 1xCH2CH3), 2.26 (s, 3H), 2.78 (t, 1H), 2.95 (t, 1H), 3.09 (dxd, 1H), 3.28-3.60 (m, 7H), 3.81-3.95 (m, 2H), 6.39 (s, H9), 6.90 (t, 1arom.H), 7.13-7.25 (m, 3arom.H), 8.12 (bs, NH). LCMS (M+H): 12f expected value: M = 365.48; found value: 366.3.

[0269] 9,10-Didehydro-N,N-diethyl-6-benzylergoline-8R-carboxamide (TRALA-21), 12 g. According to the general procedure described for N6 alkylation, from 13.8 μL benzyl bromide and 30 mg 6-Nor-LSD (11), reaction time: 2.5 h. Yield: 16 mg (41%) beige foamy TRALA-21. Analytical data of 12 g in free base form: 1 H-NMR (CDCl3): 1.14 (m, 2xCH2CH3), 2.83 (m, 2H), 3.10 (dxd, 1H), 3.25-3.52 (m, 5H), 3.57 (m, 1H), 3.73 (m, 2H), 4.36 (d, 1H), 6.38 (s, H9), 6.92 (t, 1arom.H), 7.13-7.23 (m, 3arom.H), 7.24-7.38 (m, 3arom.H), 7.44 (m, 2arom.H), 8.14 (bs, NH). LCMS (M+H): 12g expected value: M = 399.54; found value: 400.3.

[0270] 9,10-Didehydro-N,N-diethyl-6-cyclopropylergoline-8R-carboxamide (TRALA-22), 13. The procedure was adapted from WO2009068214. To a solution of 42.2 mg (136.2 μmol) 6-Nor-LSD (11) in 0.45 mL anhydrous MeOH was then added 41.1 μL (1.5 eq) 1-ethoxy-1-trimethylsilyloxycyclopropane, 8.7 μL (1.1 eq) glacial acetic acid and 18 mg (2 eq) NaBH3CN (be careful of HCN vapors when opening the bottle) and the mixture was heated to 60°C under nitrogen for 4 h. The mixture was cooled to ambient temperature, the volatiles were stripped off and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residual crude product was purified by silica gel chromatography using DCM / MeOH / NEt3=98 / 2 / 0.1 as eluent. Yield: 20 mg (42%) of TRALA-22 as beige foam. Analytical information of 13 in free base form: 1 H-NMR (CDCl3): 0.51 (m, 1H), 0.62 (m, 1H), 0.82 (m, ~2H), 1.24 (m, 2x CH2CH3), 1.87 (m, 1H), 2.72 (m, 1H), 3.01 (t, 1H), 3.36 (dxd, 1H), 3.42-3.56 (m, 4H), 3.63 (m, 1H), 3.76-3.93 (m, 2H), 6.39 (s, H9), 6.92 (t, 1arom.H), 7.13-7.25 (m, 3arom.H), 8.15 (bs, NH). LCMS (M+H): 13 expected value: M = 349.48; found value: 350.3.

[0271] 9,10-Didehydro-N,N-diethyl-6-cyclobutylergoline-8R-carboxamide (TRALA-23), 14a. To a solution of 42.2 mg (136.2 μmol) 6-Nor-LSD (11) and 15.2 μL (1.5 eq) cyclobutanone in 0.45 mL anhydrous dichloromethane was added 57.6 mg (2 eq) NaBH(OAc)3 and the mixture was stirred under nitrogen at ambient temperature for 2 h. The mixture was diluted with water, stirred for 10 min, diluted with DCM and NaOH 1 M was added to a final pH of 8-9. The layers were separated and the aqueous layer was further extracted with 2x DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residual crude product was purified by silica gel chromatography using DCM / MeOH / NEt3=98 / 2 / 0.1 as eluent. Yield: 13 mg (26%) TRALA-23 as a yellow foam. Analytical data of the free base form of 14a: 1H-NMR (CDCl3): 1.24 (m, 2x CH2CH3), 1.72 (m, 2H), 2.11 (m, 2H), 2.31 (m, 2H), 2.73 (m, 2H), 3.23 (dxd, 1H), 3.36-3.60 (m, 7H), 3.80 (m, 1H), 6.36 (s, H9), 6.90 (t, 1arom.H), 7.13-7.24 (m, 3arom.H), 8.06 (bs, NH). LCMS (M+H): expected value of 14a: M = 363.51; found value: 364.4.

[0272] 9,10-Didehydro-N,N-diethyl-6-(3-oxetanyl)ergoline-8R-carboxamide (TRALA-24), 14b. As described for compound X, from 42.2 mg (136.2 μmol) 6-Nor-LSD (11) and 12 μL (1.5 eq) 3-oxetanone and 57.6 mg (2 eq) NaBH(OAc)3 in 0.45 mL anhydrous dichloromethane. Yield: 23 mg (46%) TRALA-24 as a beige foam. Analytical information of 14b as free base: 1 H-NMR (CDCl3): 1.20 (t, CH2CH3), 1.29 (t, CH2CH3), 2.79 (m, 2H), 2.97 (m, 2H), 3.38-3.63 (m, 5H), 3.83 (m, 1H), 4.13 (p, 1H), 4.70 (t, 1H), 4.86 (m, 3H), 6.38 (s, H9), 6.87 (t, 1arom.H), 7.13-7.23 (m, 3arom.H), 8.16 (bs, NH). LCMS (M+H): 14b expected value: M = 365.48; found value: 366.4.

[0273] 9,10-Didehydro-N,N-diethyl-6-((oxetan-3-yl)methyl)ergoline-8R-carboxamide (TRALA-25), 14c. As described for compound X, from 42.2 mg (136.2 μmol) 6-Nor-LSD (11) and 17.6 mg (1.5 eq) oxetane-3-carboxaldehyde and 57.6 mg (2 eq) NaBH(OAc)3 in 0.45 mL anhydrous dichloromethane. Yield: 25 mg (48%) beige foamy TRALA-25. Analytical information of 14c as free base: 1H-NMR (CDCl3): 1.20 (t, CH2CH3), 1.29 (t, CH2CH3), 2.79 (m, 2H), 2.97 (m, 2H), 3.38-3.63 (m, 5H), 3.83 (m, 1H), 4.13 (p, 1H), 4.70 (t, 1H), 4.86 (m, 3H), 6.38 (s, H9), 6.87 (t, 1arom.H), 7.13-7.23 (m, 3arom.H), 8.16 (bs, NH). LCMS (M+H): 14c expected value: M = 379.51; found value: 380.4.

[0274] Example -6 - Preparation of N6-substituted derivatives of Nor-TRALA-02, derivatives 16a-c.

[0275] 1.) N6-Demethylation of TRALA-02: Preparation of 6-Nor-TRALA-02.

[0276] 9,10-Didehydro-N-ethyl-N-propyn-3-ylergoline-8R-carboxamide (6-Nor-TRALA-02), 15. It was carried out exactly following the procedure described for 6-Nor-LSD (11) by using 366 mg (1.1 mmol) TRALA-02 (2b) in 11 mL DCM, 295 mg (1.2 eq) mCPBA in 0.8 mL MeOH and 153 mg (0.5 eq) FeSO4 heptahydrate. The crude product was purified by silica gel chromatography using DCM / MeOH / NEt3=95 / 5 / 0.1 as eluent. The recovered starting material (2b; 67 mg; 18%) eluted first, followed by the title compound 15, yield: 172 mg (49%) tan solid. Analytical information of 15 in free base form: 1 H-NMR (CDCl3): 1.21 (2x t, total = 3H), 2.31 (m, 1H), 2.84 (txm, 1H), 3.28-3.43 (m, ~3H), 3.55-3.87 (m, ~4H), 3.99 (m, 1H), 4.28 (m, 2H), 6.38 (about 60%) / 6.48 (about 40%) (2x s, total = H9; note; evidence of epimeric purity of C9 of ergoline structure: see section General; Amide coupling), 6.93 (s, 1arom.H), 7.15-7.27 (m, 3arom.H), 7.96 (bs, N1H). LCMS (M+H): 15 expected value: M = 319.41; found value: 320.3.

[0277] 2.) N6-Alkylation of 6-Nor-TRALA-02: Preparation of compounds 16a-c.

[0278] 9,10-Didehydro-N-ethyl-N-propyn-3-yl-6-(2-fluoroethyl)ergoline-8R-carboxamide (TRALA-26), 16a. According to the general procedure described for N6 alkylation, from a total of 28.5 μL (3 x 9.5 μL, 2nd addition on day 2, 3rd addition after 8 h on day 2) 1-fluoro-2-iodoethane and 31 mg 6-Nor-TRALA-02 (15), reaction time: 6 days. Yield: 15 mg (42%) TRALA-26 as a yellow-beige foam. Analytical information of 16a in free base form: 1 H-NMR (CDCl3): 1.32 (m, 3H), 2.31 (m, 1H), 2.73 (t, 1H), 2.99 (m, 2H), 3.28 (m, 2H), 3.45-3.75 (m, 4H), 3.92 (m, 1H), 4.26 (m, 2H), 4.59 (m, 1H), 4.75 (m, 1H), 6.36 (about 55%) / 6.45 (about 45%) (2xs, total = H9; note; evidence of the diastereomeric purity of C9 of the ergoline structure: see section General; Amide coupling), 6.91 (t, 1arom.H), 7.14-7.26 (m, 3arom.H), 8.03 (bs, NH). 19 F-NMR (CDCl3): -218.99, -219.03. LCMS (M+H): Expected value of 16a: M=365.45; Found: 366.2.

[0279] 9,10-Didehydro-N-ethyl-N-propyn-3-yl-6-(2-fluoro-1-propan-3-yl)ergoline-8R-carboxamide (TRALA-27), 16b. According to the general procedure described for N6 alkylation, from a total of 33.9 μL (3 x 11.3 μL, 2nd addition on day 2, 3rd addition after 8 h on day 3) 3-bromo-2-fluoro-1-propene and 31 mg 6-Nor-TRALA-02 (15), reaction time: 6 days. Yield: 12 mg (33%) TRALA-27 as a yellow foam. Analytical information of 16b as free base: 1H-NMR (CDCl3): 1.31 (m, 3H), 2.31 (m, 1H), 2.74 (txm, 1H), 3.01 (m, 1H), 3.31 (m, 2H), 3.48-3.78 (m, 5H), 3.89 (m, 1H), 4.27 (m, 2H), 4.59 (dxd, 1H), 4.78 (dxd, 1H), 6.37 (about 60%) / 6.45 (about 40%) (2x s, total = H9; note; evidence of the diastereomeric purity of C9 of the ergoline structure: see section General; Amide coupling), 6.92 (t, 1arom.H), 7.14-7.26 (m, 3arom.H), 7.99 (bs, NH). 19 F-NMR (CDCl3): -97.77, -97.85. LCMS (M+H): 16b expected value: M=377.47; found value: 378.3.

[0280] 9,10-Didehydro-N-ethyl-N-propyn-3-yl-6-((RS)-(2,2-difluorocyclopropyl)methyl)ergoline-8R-carboxamide (TRALA-28), 16c. According to the general procedure described for N6 alkylation, from a total of 59.4 μL (3 x 19.8 μL, 2nd addition on day 2, 3rd addition after 8 h on day 3) racemic 2-(bromomethyl)-1,1-difluorocyclopropane and 31 mg 6-Nor-TRALA-02 (15), reaction time: 6 days. Yield: 13 mg (33%) TRALA-28 as a yellow foam. Analytical information of 16c as free base: 1 H-NMR (CDCl3): 1.11 (m, 1H), 1.31 (m, 3H), 1.52 (m, 1H), 1.84 (m, 1H), 2.31 (m, 1H), 2.61-3.35 (m, 5H), 3.47-3.78 (m, 4H), 3.91 (m, 1H), 4.29 (m, 2H), 6.37 (about 50%) / 6.45 (about 50%) (2xs, total = H9; note; evidence of the diastereomeric purity of C9 of the ergoline structure: see section General; Amide coupling), 6.92 (s, 1arom.H), 7.14-7.26 (m, 3arom.H), 8.00 (bs, NH). 19 F-NMR (CDCl3): -141.65, -141.73, -142.20, -142.28, -142.57, -142.60, -143.13, -143.16. LCMS (M+H): 16c expected value: M = 409.48; found value: 410.3.

[0281] Microsomal assay: The purpose of this study was to investigate the effects of 10 novel lysergic acid amides ( Figures 13A-13J ) to predict whether any of the derivatives would be metabolized faster than lysergic acid diethylamide (LSD) in the clinic. The test substances were incubated with human liver microsomes for 4 hours, followed by measurement of metabolic degradation using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Briefly, LSD and derivatives (10 nM) were incubated in the presence of pooled human liver microsomes for 4 hours. The microsomal reaction mixture contained 464.5 μL of phosphate buffered saline, 25 μL of nicotinamide adenine dinucleotide phosphate (NADPH) solution A (1:20 dilution, #451220, batch number: 0344003; Corning Life Sciences BV) and 5 μL of solution B (1:100 dilution, #451200, batch number: 0342002; Corning Life Sciences B.V), 5 μL of liver microsomes (150 donors, 20 mg / mL, #452117, batch number: 38296; Corning Life Sciences BV, Amsterdam, The Netherlands) and 0.5 μL of the test drug (10 μM). Samples (50 μL) were collected 2 minutes before microsomal incubation (t0) and 0.5, 1, 2, 3 and 4 hours after the start of the microsomal reaction. A total of five measurements were performed for each substance. The amount of test substances (peak area) exposed to human liver microsomes for 4 hours was compared relative to a concentration of 10 nM (t0, 100% peak area). Linear regression slopes were plotted to compare the degradation of the derivatives and LSD. None of the TRALA derivatives were metabolized to LSD (data not shown).

[0282] Throughout this application, various publications (including U.S. Patents) are cited by author and year, and patents are cited by number. The complete citations of publications are listed herein. The disclosures of these publications and patents are hereby incorporated into this application in their entirety by reference to more fully describe the state of the art in the field to which the invention belongs.

[0283] The present invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation.

[0284] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings.It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

[0285] References

[0286] 1.Abramson,H.A.(1959).Lysergic acid diethylamide(LSD-25):XXIX.TheResponse Index as a Measure of Threshold Activity of Psychotropic Drugs inMan.J Psychol,48(1),65-78.

[0287] 2.Bailey,K.,Verner,D.,&Legault,D.(1973).Distinction of Some DialkylAmides of Lysergic and iso-Lysergic Acids from LSD.J Assoc Off Anal Chem,56,88-99.

[0288] 3.Becker,A.M.,Holze,F.,Grandinetti,T.,Klaiber,A.,Toedtli,V.E.,Kolaczynska,K.E.,Liechti,M.E.(2022).Acute effects of psilocybin afterescitalopram or placebo pretreatment in a randomized,double-blind,placebo-controlled,crossover study in healthy subjects.Clin Pharmacol Ther,111,886-895.doi:v 0.1002 / cpt.2487

[0289] 4.Bogenschutz,M.P.(2013).Studying the effects of classichallucinogens in the treatment of alcoholism:rationale,methodology,andcurrent research with psilocybin.Curr Drug Abuse Rev,6(1),17-29.Retrievedfrom http: / / www,ncbi.nlm.nih.gov / pubmed / 23627783

[0290] 5.Bogenschutz,M.P.,Forcehimes,A.A.,Pommy,J.A.,Wilcox,C.E.,Barbosa,P.C.,&Strassman,R.J.(2015).Psilocybin-assisted treatment for alcoholdependence:a proof-of-concept study.J Psychopharmacol,29(3),289-299.doi:10.1177 / 0269881114565144

[0291] 6.Brandt,S.D.,Kavanagh,P.V.,Westphal,F.,Elliott,S.P.,Wallach,J.,Colestock,T.,Halberstadt,A.L.(2017).Return of the lysergamides.Part I1:Analytical and behavioural characterization of N(6)-allyl-6-norlysergic aciddiethylamide(AL-LAD)and(2'S,4'S)-lysergic acid 2,4-dimethylazetidide(LSZ).Drug Test Anal,9(1),38-50.doi:10.1002 / dta.1985

[0292] 7.Brandt,S.D.,Kavanagh,P.V.,Westphal,F.,Stratford,A.,Odland,A.U.,Klein,A.K.,Halberstadt,A.L.(2020).Return of the lysergamides.Part VI:Analytical and behavioural characterization of 1-cyclopropanoyl-d-lysergicacid diethylamide(1CP-LSD).Drug Test Anal,12(6),812-826.doi:10.1002 / dta.2789

[0293] 8.Canezin,J.,Cailleux,A.,Turcant,A.,Le Bouil.A.,Harry,P.,&Allain,P.(2001).Determination of LSD and its metabolites in human biological fluids byhigh-performance liquid chromatography with electrospray tandem massspectrometry.J Chromatogr B Biomed Sci Appl,765(1),15-27.Retrieved from http: / / www,ncbi.nlm.nih.gov / pubmed / 11817305

[0294] 9.Cao,D.,Yu,J.,Wang,H.,Luo,Z.,Liu,X.,He,L.,Wang,S.(2022).Structure-based discovery of nonhallucinogenic psychedelic analogs.Science,375(6579),403-411.doi:10.1126 / science.ab18615

[0295] 10.Carhart-Harris,R.,Giribaldi,B.,Watts,R.,Baker-Jones,M.,Murphy-Beiner,A.,Murphy,R.,...Nutt,D.J.(2021).Trial of psilocybin versusescitalopram for depression.N Engl J Med,384(15),1402-1411.doi:10.1056 / NEJMoa2032994

[0296] 11.Carhart-Harris,R.L.,Bolstridge,M.,Rucker,J.,Day,C.M.,Erritzoe,D.,Kaelen,M.,Nutt,D.J.(2016).Psilocybin with psychological support fortreatment-resistant depression:an open-label feasibility study.LancetPsychiatry,3,619-627.doi:10.1016 / S2215-0366(16)30065-7

[0297] 12.Carhart-Harris,R.L.,Kaelen,M.,Bolstridge,M.,Williams,T.M.,Williams,L.T.,Underwood,R.,Nutt,D.J.(2016).The paradoxical psychologicaleffects of lysergic aciddiethylamide(LSD).Psychol Med,46,1379-1390.doi:10.1017 / S0033291715002901

[0298] 13.Davis,A.K.,Barrett,F.S.,May,D.G.,Cosimano,M.P.,Sepeda,N.D.,Johnson,M.W.,Griffiths,R.R.(2021).Effects of psilocybin-assisted therapy onmajor depressive disorder:a randomized clinical trial.JAMA Psychiatry,78(5),481-489.doi:10.1001 / jamapsychiatry.2020.3285

[0299] 14.Dolder,P.C.,Schmid,Y.,Mueller,F.,Borgwardt,S.,&Liechti,M.E.(2016).LSD acutely impairs fear recognition and enhances emotional empathy and sociality.Neuropsychopharmacology,41,2638-2646.

[0300] 15.Dolder,P.C.,Schmid,Y.,Steuer,A.E.,Kraemer,T.,Rentsch,K.M.,Hammann,F.,&Liechti,M.E.(2017).Pharmacokinetics and pharmacodynamics of lysergic aciddiethylamide in healthy subjects.Clin Pharmacokinetics,56,1219-1230.

[0301] 16.Dominguez-Clave,E.,Soler,J.,Elices,M.,Pascual,J.C.,Alvarez,E.,dela Fuente Revenga,M.,Riba,J.(2016).Ayahuasca:Pharmacology,neuroscience andtherapeutic potential.Brain Res Bull,126(Pt 1),89-101.doi:10.1016 / j.brainresbull.2016.03.002

[0302] 17.Dos Santos,R.G.,Osorio,F.L.,Crippa,J.A.,Riba,J.,Zuardi,A.W.,&Hallak,J.E.(2016).Antidepressive,anxiolytic,and antiaddictive effects ofayahuasca,psilocybin and lysergic acid diethylamide(LSD):a systematic reviewof clinical trials published in the last 25 years.Ther Adv Psychopharmacol,6(3),193-213.doi:10.1177 / 204512531663800818.Fehr,T.,Stadler,P.A.,&Hofmann,A.(1970).[Demethylation of lysergic acid skeleton].Helv Chim Acta,53(8),2197-2201.doi:l 0.1002 / hlca.19700530832

[0303] 19.Garcia-Romeu,A.,Davis,A.K.,Erowid,F.,Erowid,E.,Griffiths,R.R.,&Johnson,M.W.(2019).Cessation and reduction in alcohol consumption and misuseafter psychedelic use.J Psychopharmacol,33(9),1088-1101.doi:10.1177 / 0269881119845793

[0304] 20.Garcia-Romeu,A.,Griffiths,R.R.,&Johnson,M.W.(2014).Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction.CurrDrug Abuse Rev,7(3),157-164.Retrieved from http: / / www,ncbi.nlm.nih.gov / pubmed / 25563443

[0305] 21.Gasser,P.,Holstein,D.,Michel,Y.,Doblin,R.,Yazar-Klosinski,B.,Passie,T.,&Brenneisen,R.(2014).Safety and efficacy of lysergic aciddiethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases.J Nerv Ment Dis,202(7),513-520.doi:10.1097 / NMD.0000000000000113

[0306] 22.Gasser,P.,Kirchner,K.,&Passie,T.(2015).LSD-assisted psychotherapyfor anxiety associated with a life-threatening disease:a qualitative study ofacute and sustained subjective effects.J Psychopharmacol,29(1),57-68.doi:10.1177 / 0269881114555249

[0307] 23.Golding,B.T.,&Wong,A.K.(1981).Preparation of labeled aldehydes andketones from enamides.Angewandte Chemie,20,89-90.

[0308] 24.Griffiths,R.,Richards,W.,Johnson,M.,McCann,U.,&Jesse,R.(2008).Mystical-type experiences occasioned by psilocybin mediate the attributionof personal meaning and spiritual significance 14 months later.JPsychopharmacol,22(6),621-632.doi:10.1177 / 0269881108094300

[0309] 25.Griffiths,R.R.,Johnson,M.W.,Carducci,M.A.,Umbricht,A.,Richards,W.A.,Richards,B.D.,Klinedinst,M.A.(2016).Psilocybin produces substantial andsustained decreases in depression and anxiety in patients with life-threatening cancer:a randomized double-blind trial.J Psychopharmacol,30(12),1181-1197.doi:10.1177 / 0269881116675513

[0310] 26.Grob,C.S.,Danforth,A.L.,Chopra,G.S.,Hagerty,M.,McKay,C.R.,Halberstadt,A.L.,&Greer,G.R.(2011).Pilot study of psilocybin treatment foranxiety in patients with advanced-stage cancer.Arch Gen Psychiatry,68(1),71-78.doi:10.1001 / archgenpsychiatry.2010.116

[0311] 27.Halberstadt,A.L.,Chatha,M.,Klein,A.K.,McCorvy,J.D.,Meyer,M.R.,Wagmann,L.,Brandt,S.D.(2020).Pharmacological and biotransformation studies of1-acyl-substituted derivatives of d-lysergic acid diethylamide(LSD).Neuropharmacology,t72,107856.doi:10.1016 / j.neuropharm.2019.107856

[0312] 28.He,L.,Zhao,L.,Wang,D.X.,&Wang,M.X.(2014).Catalytic asymmetricdifunctionalization of stable tertiary enamides with salicylaldehydes:highlyefficient,enantioselective,and diastereoselective synthesis of diverse 4-chromanol derivatives.Org Lett,16(22),5972-5975.doi:10.1021 / ol5029964

[0313] 29.Hoehn,R.D.,Nichols,D.E.,McCorvy,J.D.,Neven,H.,&Kais,S.(2017).Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation.Proc Natl Acad Sci U S A,114(22),5595-5600.doi:10.1073 / pnas.1618422114

[0314] 30.Hoffman,A.J.,&Nichols,D.E.(1985).Synthesis and LSD-likediscriminative stimulus properties in a series of N(6)-alkyl norlysergic acidN,N-diethylamide derivatives.J Med Chem,28(9),1252-1255.doi:10.1021 / jm00147a022

[0315] 31.Hoffmann,A.J.(1987).Synthesis and pharmacological evaluation of N(6)-alkyl norlyergic acid N,N-diethylamide derivatives.In Department ofPharmacology:Perdue University.

[0316] 32.Holze,F.,Caluori,T.V.,Vizeli,P.,&Liechti,M.E.(2021).Safetypharmacology of acute LSD administration in healthysubjects.Psychopharmacology(Berl)doi:10.1007 / s00213-021-05978-6

[0317] 33.Holze,F.,Duthaler,U.,Vizeli,P.,Muller,F.,Borgwardt,S.,&Liechti,M.E.(2019).Pharmacokinetics and subjective effects of a novel oral LSDformulation in healthy subjects.Br J Clin Pharmacol,85,1474-1483.doi:10.1111 / bcp.13918

[0318] 34.Holze,F.,Ley,L.,Muller,F.,Becker,A.M.,Straumann,I.,Vizeli,P.,Liechti,M.E.(2022).Direct comparison of the acute effects of lysergic aciddiethylamide and psilocybin in a double-blind placebo-controlled study inhealthy subjects.Neuropsychopharmacology,doi.org / 10.1038 / s41386-022-01297-2.

[0319] 35.Holze,F.,Vizeli,P.,Ley,L.,Muller,F.,Dolder,P.,Stocker,M.,Liechti,M.E.(2021).Acute dose-dependent effects of lysergic acid diethylamide in adouble-blind placebo-controlled study in healthy subjects.Neuropsychopharmacology,46(3),537-544.doi:10.1038 / s41386-020-00883-6

[0320] 36.Holze,F.,Vizeli,P.,Muller,F.,Ley,L.,Duerig,R.,Varghese,N.,Liechti,M.E.(2020).Distinct acute effects of LSD,MDMA,and D-amphetamine in healthy subjects.Neuropsychopharmacology,45(3),462-471.doi:10.1038 / s41386-019-0569-3

[0321] 37.Hu,Y.,Chan,K.H.,He,X.,Ho,M.K.,&Wong,Y.H.(2014).Synthesis andfunctional characterization of substituted isoquinolinones as MT2-selectivemelatoninergic ligands.PLoS One,9(12),e1 13638.doi:10.1371 / journal.pone.0113638

[0322] 38.Huang,X.,Marona-Lewicka,D.,Pfaff,R.C.,&Nichols,D.E.(1994).Drugdiscrimination and receptor binding studies of N-isopropyl lysergamidederivatives.Pharmacol Biochem Behav,47(3),667-673.doi:10.1016 / 0091-3057(94)90172-4

[0323] 39.Hysek,C.M.,Simmler,L.D.,Nicola,V.,Vischer,N.,Donzelli,M., S.,Liechti,M.E.(2012).Duloxetine inhibits effects of MDMA("ecstasy")in vitroand in humans in a randomized placebo-controlled laboratory study.PLoS One,7,e36476.

[0324] 40.Ichikawa,J.,&Meltzer,H.Y.(2000).The effect of serotonin(1A)receptor agonism on antipsychotic drug-induced dopamine release in ratstriatum and nucleus accumbens.Brain Res,858(2),252-263.doi:10.1016 / s0006-8993(99)02346-x

[0325] 41.Johnson,M.W.,Garcia-Romeu,A.,Cosimano,M.P.,&Griffiths,R.R.(2014).Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobaccoaddiction.J Psychopharmacol,28(11),983-992.doi:10.1177 / 0269881114548296

[0326] 42.Johnson,M.W.,Garcia-Romeu,A.,&Griffiths,R.R.(2016).Long-termfollow-up of psilocybin-facilitated smoking cessation.Am J Drug AlcoholAbuse,43,55-60.doi:10.3109 / 00952990.2016.1170135

[0327] 43.Krebs,T.S.,&Johansen,P.O.(2012).Lysergic acid diethylamide(LSD)foralcoholism:meta-analysis of randomized controlled trials.J Psychopharmacol,26(7),994-1002.doi:10.1177 / 0269881112439253

[0328] 44.Kulyashova,A.,&M.,K.(2016).Convenient modular construction ofmedicinally important5-acylamino-4,5-dihydroisoxazoles featuring fourelements of diversity.Tetrahedron Lett,57,4395-4397.

[0329] 45.Liechti,M.E.(2017).Modern clinical research onLSD.Neuropsychopharmacology,42,2114-2127.

[0330] 46.Luethi,D.,Hoener,M.C.,Krahenbuhl,S.,Liechti,M.E.,&Duthaler,U.(2019).Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSDand 2-oxo-3-hydroxy-LSD:Implications for clinical LSD use.Biochern Pharmacol,164,129-138.doi:10.1016 / j.bcp.2019.04.013

[0331] 47.Luethi,D.,&Liechti,M.E.(2018).Monoamine transporter and receptorinteraction profiles in vitro predict reported human doses of novelpsychoactive stimulants and psychedelics.Int J Neuropsychopharmacol,21(10),926-931.doi:10.1093 / ijnp / pyy047

[0332] 48.Madsen,M.K.,Fisher,P.M.,Burmester,D.,Dyssegaard,A.,Stenbaek,D.S.,Kristiansen,S.,Knudsen,G.M.(2019).Correction:Psychedelic effects ofpsilocybin correlate with serotonin 2A receptor occupancy and plasma psilocinlevels.Neuropsychopharmacology,44(7),1328-1334.doi:10.1038 / s41386-019-0360-5

[0333] 49.Marona-Lewicka,D.,Thisted,R.A.,&Nichols,D.E.(2005).Distincttemporal phases in the behavioral pharmacology of LSD:dopamine D2 receptor-mediated effects in the rat and implications for psychosis.Psychopharmacology(Berl),180(3),427-435.doi:10.1007 / s00213-005-2183-9

[0334] 50.McCamley,K.,Ripper,J.A.,Singer,R.D.,&Scammells,P.J.(2003).Efficient N-demethylation of opiate alkaloids using a modified nonclassicalPolonovski reaction.J Org Chem,68(25),9847-9850.doi:10.1021 / jo035243z

[0335] 51.Meiresonne,T.,Verniest,G.,De Kimpe,N.,&Mangelinckx,S.(2015).Synthesis of 2-Fluoro-1,4-benzoxazines and 2-Fluoro-1,4-benzoxazepin-5-onesby Exploring the Nucleophilic Vinylic Substitution(S(N)V)Reaction of gem-Difluoroenamides.J Org Chem,80(10),5111-5124.doi:10.1021 / acs.joc.5b00507

[0336] 52.Meuzelaar,G.J.,van Vliet,C.A.,Neeleman,E.,Maat,L.,&Sheldon,R.A.(1997).Synthesis of gamma-unsaturated enamides by N-acylation of iminesderived from gamma-unsaturated amines.Liebigs Ann Recueil,1159-1163.

[0337] 53.Mimura,H.,Kawada,K.,Yamshita,T.,Sakamato,T.,&Kikugawa,Y.(2010).Trifluoroacetaldehyde:A useful industrial bulk material for the synthesis oftrifluoromethylated amino compounds.J Fluor Chem,131,477-486.

[0338] 54.Nichols,D.E.(2016).Psychedelics.Pharmacol Rev,68(2),264-355.doi:10.1124 / pr.115.011478

[0339] 55.Nichols,D.E.(2018a).Chemistry and Structure-Activity Relationshipsof Psychedelics.Curr Top Behav Neurosci,36,1-43.doi:l 0.1007 / 7854_2017_475

[0340] 56.Nichols,D.E.(2018b).Dark classics in chemical neuroscience:lysergic acid diethylamide(LSD).ACS Chem Neurosci,9,2331-2343.doi:10.1021 / acschemneuro.8b00043

[0341] 57.Nichols,D.E.,Frescas,S.,Marona-Lewicka,D.,&Kurrasch-Orbaugh,D.M.(2002).Lysergamides of isomeric 2,4-dimethylazetidines map the bindingorientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide(LSD).J Med Chem,45(19),4344-4349.Retrieved from http: / / www.ncbi.nlm.nih.gov / pubmed / 12213075

[0342] 58.Nichols,D.E.,&Grob,C.S.(2018).Is LSD toxic?Forensic Sci Int,284,141-145.doi:10.1016 / j.forsciint.2018.01.006

[0343] 59.Nichols,D.E.,Monte,A.,Huang,X.,&Marona-Lewicka,D.(1996).Stereoselective pharmacological effects of lysergic acid amides possessingchirality in the amide substituent.Behav Brain Res,73(1-2),117-119.doi:10.1016 / 0166-4328(96)00080-0

[0344] 60.Oberlender,R.,Pfaff,R.C.,Johnson,M.P.,Huang,X.M.,&Nichols,D.E.(1992).Stereoselective LSD-like activity in d-lysergic acid amides of(R)-and(S)-2-aminobutane.J Med Chem,35(2),203-211.doi:10.1021 / jm00080a001

[0345] 61.Palhano-Fontes,F.,Barreto,D.,Onias,H.,Andrade,K.C.,Novaes,M.M.,Pessoa,J.A.,Araujo,D.B.(2019).Rapid antidepressant effects of the psychedelicayahuasca in treatment-resistant depression:a randomized placebo-controlledtrial.Psychol Med,49(4),655-663.doi:10.1017 / S0033291718001356

[0346] 62.Passie,T.,Halpern,J.H.,Stichtenoth,D.O.,Emrich,H.M.,&Hintzen,A.(2008).The pharmacology of lysergic acid diethylamide:a review.CNS NeurosciTher,14(4),295-314.doi:10.1111 / j.1755-5949.2008.00059.x

[0347] 63.Pfaff,R.C.,Huang,X.,Marona-Lewicka,D.,Oberlender,R.,&Nichols,D.E.(1994).Lysergamides revisited.NIDA Res Monogr,146,52-73.Retrieved fromhttp: / / www,ncbi.nlm.nih.gov / pubmed / 8742796

[0348] 64.Preller,K.H.,Herdener,M.,Pokorny,T.,Planzer,A.,Kraehenmann,R., P.,Vollenweider,F.X.(2017).The fabric of meaning and subjective effectsin LSD-induced states depend on serotonin 2A receptor activation Curr Biol,27,451-457.

[0349] 65.Rickli,A.,Moning,O.D.,Hoener,M.C.,&Liechti,M.E.(2016).Receptorinteraction profiles of novel psychoactive tryptamines compared with classichallucinogens.Eur Neuropsychopharmacol,26,1327-1337.

[0350] 66.Riss,P.J.,&Aigbirhio,F.I.(2011).A simple,rapid procedure fornucleophilicradiosynthesis of aliphatic[18F]trifluoromethyl groups.ChemCommun(Camb),47(43),11873-11875.doi:10.1039 / c1cc15342k

[0351] 67.Roseman,L.,Nutt,D.J.,&Carhart-Harris,R.L.(2017).Quality of acutepsychedelic experience predicts therapeutic efficacy of psilocybin fortreatment-resistant depression.Front Pharmacol,8,974.doi:10.3389 / fphar.2017.00974

[0352] 68.Ross,S.,Bossis,A.,Guss,J.,Agin-Liebes,G.,Malone,T.,Cohen,B.,Schmidt,B.L.(2016).Rapid and sustained symptom reduction following psilocybintreatment for anxiety and depression in patients with life-threateningcancer:a randomized controlled trial.J Psychopharmacol,30(12),1165-1180.doi:10.1177 / 0269881116675512

[0353] 69.Sanches,R.F.,de Lima Osorio,F.,Dos Santos,R.G.,Macedo,L.R., -de-Oliveira,J.P.,Wichert-Ana,L.,Hallak,J.E.(2016).Antidepressant Effects of aSingle Dose of Ayahuasca in Patients With Recurrent Depression:ASPECT Study.JClin Psychopharmacol,36(1),77-81.doi:10.1097 / jcp.0000000000000436

[0354] 70.Schmid,Y.,Enzler,F.,Gasser,P.,Grouzmann,E.,Preller,K.H.,Vollenweider,F.X.,Liechti,M.E.(2015).Acute effects of lysergic aciddiethylamide in healthy subjects.Biol Psychiatry,78(8),544-553.doi:10.1016 / j.biopsych.2014.11.015

[0355] 71.Schmid,Y.,Gasser,P.,Oehen,P.,&Liechti,M.E.(2021).Acute subjectiveeffects in LSD-and MDMA-assisted psychotherapy.J Psychopharmacol,35(4),362-374.doi:10.1177 / 0269881120959604

[0356] 72.Schmid,Y.,&Liechti,M.E.(2018).Long-lasting subjective effects ofLSD in normal subjects.Psychopharmacology(Berl),235(2),535-545.doi:10.1007 / s00213-017-4733-3

[0357] 73.Shulgin,A.,&Shulgin,A.(1991).PiHKAL:a chemicallove story(1 edn).

[0358] 74.Shulgin,A.T.,&Shulgin,A.(1997).TiHKAL the continuation:Berkeley:Transform Press.

[0359] Direct Synthesisof Enamides via Electrophilic Activation of Amides.J Am Chem Soc,143(28),10524-10529.doi:10.1021 / jacs.1c04363

[0360] Stereochemical and NMR Reassignment of 6-Norlysergic Acid Diethylamide and 6-Nor-6-allylysergic Acid Diethylamide.J Chem Res,S1,30-31.

[0361] PLoS One, 7(2), e30800.doi:10.1371 / journal.pone.0030800 77.Studerus,E.,Gamma,A.,Kometer,M.,&Vollenweider,FX(2012).Prediction of psilocybin response in healthy volunteers

[0362] 78.Taniguchi,T.,Ishita,A.,Uchiyama,M.,Tamura,O.,Muraoka,O.,Tanabe,G,&Ishibashi,H.(2005).7-endo selective aryl radical cyclization onto enamidesleading to 3-benzazepines:concise construction of a cephalotaxine skeleton.JOrg Chem,70(5),1922-1925.doi:10.1021 / jo040264u

[0363] 79.Vizeli,P.,Straumann,I.,Holze,F.,Schmid,Y.,Dolder,P.C.,&Liechti,M.E.(2021).Genetic influence of CYP2D6 on pharmacokinetics and acutesubjective effects of LSD in a pooled analysis.Sci Rep,11(1),10851.doi:10.1038 / s41598-021-90343-y

[0364] 80.Vollenweider,F.X.,Vontobel,P.,Hell,D.,&Leenders,K.L.(1999).5-HTmodulation of dopamine release in basal ganglia in psilocybin-inducedpsychosis in man--a PET study with[11C]raclopride.Neuropsychopharmacology,20(5),424-433.doi:10.1016 / S0893-133X(98)00108-0

[0365] 81.Wacker,D.,Wang,S.,McCorvy,J.D.,Betz,R.M.,Venkatakrishnan,A.J.,Levit,A.,Roth,B.L.(2017).Crystal structure of an LSD-bound human serotoninreceptor.Cell,168(3),377-389.e312.doi:10.1016 / j.cell.2016.12.033

[0366] 82.Watts,V.J.,Lawler,C.P.,Fox,D.R.,Neve,K.A.,Nichols,D.E.,&Mailman,R.B.(1995).LSD and structural analogs:pharmacological evaluation at D1dopamine receptors.Psychopharmacology(Berl),118(4),401-409.Retrieved fromhttp: / / www,ncbi.nlm.nih.gov / pubmed / 7568626

[0367] 83.Xu,Y.,Xiao-Yu,L.,Wang,Z.,&Tang,L.(2017).A convenient synthesis ofN-vinyl enamides via the lithiation and ring-openingreaction of 2-phenyl-2-oxazolines Tetrahedron Lett,58,1788-1791.

Claims

1. A pharmacologically active compound, Features It is shown as consisting of the structure shown in FIG1A , is further characterised in that it is part of categories 1 to 5; And such compounds are represented as shown in Figures 2A to 6C, wherein: Class 1 is lysergic acid amides as represented in Figures 2A-2G and Figures 3A-3H, wherein R8' consists of the substituents shown in the subclasses designated as Subclass 1a to Subclass 1n, wherein R8 consists of a) R8', b) any substituent of said subclasses 1a to 1n and R8' = as defined in the specific classes 1a to 11, c) hydrogen, C1-C5 alkyl, branched C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkylcycloalkyl, C2-C5 alkenyl, branched C3-C5 alkenyl, C2-C5 alkynyl, branched C4-C5 alkynyl, or d) as specified in subcategories 1a to 1n; Under the above definition, In subclass 1a, the substituent R8' consists of: F1-F 11 Fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl, each optionally in combination with: D1-D 10 deuterium, and / or hydroxyl and / or carbonyl, In subclass 1b, the substituent R8' consists of: F1-F13 fluorine-substituted C3-C7 alkenyl, optionally in combination with: D1-D12 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the double bond is separated from the nitrogen, In subclass 1c, the substituent R8' consists of: F1-F11 fluorine-substituted C3-C6 cycloalkyl, optionally in combination with: D1-D10 deuterium, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl, In subclass 1d, the substituent R8' consists of: F1-F17 fluorine-substituted C3-C6 cycloalkylalkyl, optionally in combination with: D1-D10 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl, In subclass 1e, the substituent R8' consists of: F1-F11 fluorine-substituted C3-C7 alkynyl, optionally in combination with: D1-D12 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the triple bond is separated from the amide nitrogen, In subclass 1f, the substituent R8' consists of: F0-F7 fluorine-substituted C2-C4 alkenyl, attached to the nitrogen with an unsaturated moiety to produce an enamide, optionally in combination with: D1-D7 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 1g, the substituent R8' consists of: F1-F5 fluorine-substituted C2-C4 alkyl alkynyl, attached to the nitrogen with an unsaturated moiety to produce an alkynamide, optionally in combination with: D1-D4 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl, In class 1h which is a subclass of class 1, the substituent R8' consists of: F1-F13 fluorine-substituted C1-3-O-C1-3 alkoxyalkyl, optionally in combination with: D1-D12 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 1i, the substituent R8' consists of: F0-F7 fluorine-substituted C1-C3 alkoxy or C3-C4 cycloalkoxy, each optionally in combination with: D1-D7 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 1j, the substituent R8' consists of: a nitrile attached to a C1-C3 alkyl group, optionally in combination with: F1-F7 fluorine, and / or D1-D7 deuterium, and / or hydroxyl and / or carbonyl, In subclass 1k, the substituent R8 consists of any D1-D6 deuteron in combination with a C1-C3 alkyl group containing F1-F6 fluorine, optionally in combination with a hydroxyl group and / or a carbonyl group, and R8' consists of hydrogen, C1-C6 alkyl, or C3-C5 cycloalkyl or C4-C7 cycloalkylalkyl, optionally in combination with a hydroxyl group and / or a carbonyl group, In subclass 11, the substituent R8 consists of D1-D7 deuterium or F1-F7 fluorine, or any D1-D6 deuterium in combination with C1-C3 alkyl containing F1-F6 fluorine, optionally in combination with hydroxyl and / or carbonyl, and R8' consists of C2-C8 alkenyl or C2-C8 alkynyl, optionally in combination with nitrile, and / or hydroxyl and / or carbonyl, In subclass 1m, the substituents R8 and R8' are linked to each other to form an azacycloalkane with the amide nitrogen and consist of: D1-D10 deuteron or F1-F10 fluorine, or any D1-D9 deuteron in combination with a C3-C6 alkylene containing F1-F9 fluorine, the C3-C6 alkylene containing F1-F9 fluorine optionally combined with: nitrile, and / or hydroxyl, and / or carbonyl and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl, and In subclass 1n, the substituents R8 and R8' are linked to each other to establish an azacycloalkane with the amide nitrogen and consist of a C3-C6 alkylene group attached to an undeuterated or deuterated C1-C3 alkenyl group and / or an undeuterated or deuterated C2-C3 alkynyl group, the alkylene group forming the azacycloalkane being further and optionally combined with: a nitrile, and / or a hydroxyl group, and / or a carbonyl group and / or a deuterated and undeuterated C1-C3 alkyl group, and / or a deuterated and undeuterated C1-C3 alkenyl group and / or a deuterated and undeuterated C2-C3 alkynyl group; Class 2 is lysergic acid amides as represented in Figures 4A-4G and Figures 5A-5C, further characterized in that they consist of: 6-substituted 6-nor-lysergic acid diethylamides, wherein R6 consists of the substituents shown in the subclasses designated as Subclass 2a to Subclass 2i, wherein R6 is characterized as follows: In subclass 2a, the substituent R6 consists of: F1-F 11 Fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl, each optionally in combination with: D1-D 10 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 2b which is a subclass of class 2, the substituent R6 consists of: F1-F13 fluorine-substituted C3-C7 alkenyl, optionally in combination with: D1-D12 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the alkenyl double bond is separated from the nitrogen, In subclass 2c, the substituent R6 consists of: C3-C7 alkynyl substituted with F1-F11 fluorine in which the triple bond is separated from the N6 nitrogen, optionally in combination with: D1-D10 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl, provided that the substituent R6 contains at least one nitrile, one hydroxyl or one carbonyl, R6 can also consist of: C3-C7 alkynyl in which the triple bond is separated from the N6 nitrogen, optionally in combination with: D1-D10 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 2d, the substituent R6 consists of: C3-C6 cycloalkyl, optionally in combination with: F1-F11 fluorine, and / or D1-D11 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl, In subclass 2e, the substituent R6 consists of: F1-F17 fluorine-substituted C4-C9 cycloalkylalkyl, optionally in combination with: D1-D16 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl, provided that the substituent R6 is not a ring attached to the N6 nitrogen of the ergoline structure via an exocyclic methylene unit. propylmethyl, or cyclopropylmethyl which is linked to the N6 nitrogen of the ergoline structure via the exocyclic methylene unit and contains at least one nitrile, one hydroxyl or one carbonyl group, R6 can also consist of: C4-C9 cycloalkylalkyl, optionally in combination with: D1-D17 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C1-C3 alkynyl, In subclass 2f, the substituent R6 consists of: F0-F7 fluorine-substituted C2-C4 alkenyl, attached to the nitrogen with an unsaturated moiety to generate an enamine, optionally in combination with: D1-D7 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 2g, the substituent R6 consists of: C3-C6 oxacycloalkyl, C3-C9 oxacycloalkylalkyl, C3-C6 thiacycloalkyl or C3-C9 thiacycloalkylalkyl, each optionally in combination with: F1-F19 fluorine, and / or D1-D19 deuterium, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl, In subclass 2h, the substituent R6 consists of: F0-F11 fluorine-substituted C1-C5 alkoxy or C3-C6 cycloalkoxy or C2-C6 alkenyloxy, each optionally in combination with: D1-D11 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 2i, the substituent R6 consists of: aryl, heteroaryl, arylmethyl or heteroarylmethyl, each optionally in combination with: F0-F7 fluorine, and / or D1-D7 deuterium, and / or one or more of the following substituents which can themselves be optionally fluorinated and / or deuterated: halogen, nitrile, nitro, hydroxy, carbonyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, methylenedioxy, C1-C4 alkylthio, C3-C6 alkenylthio, C3-C6 alkynylthio, C3-C6 cycloalkylthio, and the R6 substituents as defined above in class 2i can further form a ring; Class 3 is lysergic acid amide as represented in FIG6A , which is further characterized in that it consists of: any possible combination of the substituents R8 and R8′ of Class 1 and its subclasses 1a to 1n ( FIGS. 2A to 3H ) and the substituents R6 of Class 2 and its subclasses 2a to 2i ( FIGS. 4A to 5C ); Class 4 is lysergic acid amide as represented in FIG6B , further characterized in that it consists of any possible combination of the substituents R8 and R8′ of Class 1 and its subclasses 1a to 1n ( FIGS. 2A to 3H ) and the substituents R6 of Class 2 and its subclasses 2a to 2i ( FIGS. 4A to 5C ) and the N1 nitrogen substituents of the following groups on the ergoline substructure: a) any acyl group; b) unsubstituted and substituted carbamoyl; c) amine-bound amino acids; d) alkyl, alkenyl or alkynyl; e) alkoxy, alkenyloxy or alkynyloxy; f) any of the substituents described under a) to e), which is substituted with one or more fluorine atoms; g) any substituent described under a) to e) substituted with one or more deuterium atoms; h) any substituent described under a) to e) substituted with one or more fluorine atoms and one or more deuterium atoms; and Class 5 ( FIG. 6C ) consists of monodeuterated to fully deuterated ergoline core structures and is additionally composed of any possible combination of substituents R8 and R8′ of Class 1 and its subclasses 1a to 1n ( FIGS. 2A to 3H ) and substituents R6 of Class 2 and its subclasses 2a to 2i ( FIGS. 4A to 5C ) and combinations of N1 nitrogen substituents of the following groups on the ergoline substructure: a) hydrogen; b) any acyl group; c) unsubstituted and substituted carbamoyl groups; d) amide-bonded amino acids; e) alkyl, alkenyl or alkynyl groups; f) alkoxy, alkenyloxy or alkynyloxy groups; g) any substituent described under a) to f) substituted with one or more fluorine atoms; h) any substituent described under a) to f) substituted with one or more deuterium atoms; i) any substituent described under a) to f) substituted with one or more fluorine atoms and one or more deuterium atoms.

2. The pharmacologically active compound of claim 1, further characterized in that The compound is a free base.

3. The pharmacologically active compound of claim 1, further characterized in that The compound is a salt thereof.

4. The pharmacologically active compound of claim 3, further characterized in that The compound is in the form of a tartrate or hemi-tartrate salt.

5. The pharmacologically active compound of claim 4, further characterized in that The compounds are in the form of pharmacologically acceptable acid addition salts.

6. The pharmacologically active compound of claim 1, further characterized in that The compound is selected from the group consisting of: racemates, single enantiomers, diastereomers, epimers and mixtures of enantiomers or diastereomers or epimers in any ratio, single E or Z configuration isomers and mixtures thereof in any ratio, single cis or trans configuration isomers and mixtures thereof in any ratio, and any combination thereof.

7. A method of altering neurotransmission comprising the steps of: Compositions for administering a pharmaceutically effective amount of a pharmacologically active compound to a mammal The compound is characterized in that the compound exhibits a structural composition as represented by FIG. 1A , is further characterised in that it is part of categories 1 to 5; And such compounds are represented as shown in Figures 2A to 6C, wherein: Class 1 is lysergic acid amides as represented in Figures 2A-2G and Figures 3A-3H, wherein R8' consists of the substituents shown in the subclasses designated as Subclass 1a to Subclass 1n, wherein R8 consists of a) R8', b) any substituent of said subclasses 1a to 1n and R8' = as defined in the specific classes 1a to 11, c) hydrogen, C1-C5 alkyl, branched C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkylcycloalkyl, C2-C5 alkenyl, branched C3-C5 alkenyl, C2-C5 alkynyl, branched C4-C5 alkynyl, or d) as specified in subcategories 1a to 1n; Under the above definition, In subclass 1a, the substituent R8' consists of: F1-F 11 Fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl, each optionally in combination with: D1-D 10 deuterium, and / or hydroxyl and / or carbonyl, In subclass 1b, the substituent R8' consists of: F1-F13 fluorine-substituted C3-C7 alkenyl, optionally in combination with: D1-D12 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the double bond is separated from the nitrogen, In subclass 1c, the substituent R8' consists of: F1-F11 fluorine-substituted C3-C6 cycloalkyl, optionally in combination with: D1-D10 deuterium, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl, In subclass 1d, the substituent R8' consists of: F1-F17 fluorine-substituted C3-C6 cycloalkylalkyl, optionally in combination with: D1-D10 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl, In subclass 1e, the substituent R8' consists of: F1-F11 fluorine-substituted C3-C7 alkynyl, optionally in combination with: D1-D12 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the triple bond is separated from the amide nitrogen, In subclass 1f, the substituent R8' consists of: F0-F7 fluorine-substituted C2-C4 alkenyl, attached to the nitrogen with an unsaturated moiety to produce an enamide, optionally in combination with: D1-D7 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 1g, the substituent R8' consists of: F1-F5 fluorine-substituted C2-C4 alkyl alkynyl, attached to the nitrogen with an unsaturated moiety to produce an alkynamide, optionally in combination with: D1-D4 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl, In class 1h which is a subclass of class 1, the substituent R8' consists of: F1-F13 fluorine-substituted C1-3-O-C1-3 alkoxyalkyl, optionally in combination with: D1-D12 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 1i, the substituent R8' consists of: F0-F7 fluorine-substituted C1-C3 alkoxy or C3-C4 cycloalkoxy, each optionally in combination with: D1-D7 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 1j, the substituent R8' consists of: a nitrile attached to a C1-C3 alkyl group, optionally in combination with: F1-F7 fluorine, and / or D1-D7 deuterium, and / or hydroxyl and / or carbonyl, In subclass 1k, the substituent R8 consists of any D1-D6 deuteron in combination with a C1-C3 alkyl group containing F1-F6 fluorine, optionally in combination with a hydroxyl group and / or a carbonyl group, and R8' consists of hydrogen, C1-C6 alkyl, or C3-C5 cycloalkyl or C4-C7 cycloalkylalkyl, optionally in combination with a hydroxyl group and / or a carbonyl group, In subclass 11, the substituent R8 consists of D1-D7 deuterium or F1-F7 fluorine, or any D1-D6 deuterium in combination with C1-C3 alkyl containing F1-F6 fluorine, optionally in combination with hydroxyl and / or carbonyl, and R8' consists of C2-C8 alkenyl or C2-C8 alkynyl, optionally in combination with nitrile, and / or hydroxyl and / or carbonyl, In subclass 1m, the substituents R8 and R8' are linked to each other to establish an azacycloalkane with the amide nitrogen and consist of: D1-D10 deuteron or F1-F10 fluorine, or any D1-D9 deuteron in combination with a C3-C6 alkylene group containing F1-F9 fluorine, optionally in combination with: nitrile, and / or hydroxyl, and / or carbonyl and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl, In subclass 1n, the substituents R8 and R8' are linked to each other to establish an azacycloalkane with the amide nitrogen and consist of a C3-C6 alkylene group attached to an undeuterated or deuterated C1-C3 alkenyl group and / or an undeuterated or deuterated C2-C3 alkynyl group, the alkylene group forming the azacycloalkane being further and optionally combined with: a nitrile, and / or a hydroxyl group, and / or a carbonyl group and / or a deuterated and undeuterated C1-C3 alkyl group, and / or a deuterated and undeuterated C1-C3 alkenyl group and / or a deuterated and undeuterated C2-C3 alkynyl group; Class 2 is lysergic acid amides as represented in Figures 4A-4G and Figures 5A-5C, further characterized in that they consist of: 6-substituted 6-nor-lysergic acid diethylamides, wherein R6 consists of the substituents shown in the subclasses designated as Subclass 2a to Subclass 2i, wherein R6 is characterized as follows: In subclass 2a, the substituent R6 consists of: F1-F 11 Fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl, each optionally in combination with: D1-D 10 deuteron, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 2b which is a subclass of class 2, the substituent R6 consists of: F1-F13 fluorine-substituted C3-C7 alkenyl, optionally in combination with: D1-D12 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, wherein the alkenyl double bond is separated from the nitrogen, In subclass 2c, the substituent R6 consists of: C3-C7 alkynyl substituted with F1-F11 fluorine in which the triple bond is separated from the N6 nitrogen, optionally in combination with: D1-D10 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl, provided that the substituent R6 contains at least one nitrile, one hydroxyl or one carbonyl, R6 can also consist of: C3-C7 alkynyl in which the triple bond is separated from the N6 nitrogen, optionally in combination with: D1-D10 deuterons, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 2d, the substituent R6 consists of: C3-C6 cycloalkyl, optionally in combination with: F1-F11 fluorine, and / or D1-D11 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl, In subclass 2e, the substituent R6 consists of: F1-F17 fluorine-substituted C4-C9 cycloalkylalkyl, optionally in combination with: D1-D16 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl, provided that the substituent R6 is not a ring attached to the N6 nitrogen of the ergoline structure via an exocyclic methylene unit. propylmethyl, or cyclopropylmethyl which is linked to the N6 nitrogen of the ergoline structure via the exocyclic methylene unit and contains at least one nitrile, one hydroxyl or one carbonyl group, R6 can also consist of: C4-C9 cycloalkylalkyl, optionally in combination with: D1-D17 deuteron, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C1-C3 alkynyl, In subclass 2f, the substituent R6 consists of: F0-F7 fluorine-substituted C2-C4 alkenyl, attached to the nitrogen with an unsaturated moiety to generate an enamine, optionally in combination with: D1-D7 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 2g, the substituent R6 consists of: C3-C6 oxacycloalkyl, C3-C9 oxacycloalkylalkyl, C3-C6 thiacycloalkyl or C3-C9 thiacycloalkylalkyl, each optionally in combination with: F1-F19 fluorine, and / or D1-D19 deuterium, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and undeuterated C1-C3 alkyl, and / or deuterated and undeuterated C1-C3 alkenyl and / or deuterated and undeuterated C2-C3 alkynyl, In subclass 2h, the substituent R6 consists of: F0-F11 fluorine-substituted C1-C5 alkoxy or C3-C6 cycloalkoxy or C2-C6 alkenyloxy, each optionally in combination with: D1-D11 deuterium, and / or nitrile, and / or hydroxyl and / or carbonyl, In subclass 2i, the substituent R6 consists of: aryl, heteroaryl, arylmethyl or heteroarylmethyl, each optionally in combination with: F0-F7 fluorine, and / or D1-D7 deuterium, and / or one or more of the following substituents which can themselves be optionally fluorinated and / or deuterated: halogen, nitrile, nitro, hydroxy, carbonyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, methylenedioxy, C1-C4 alkylthio, C3-C6 alkenylthio, C3-C6 alkynylthio, C3-C6 cycloalkylthio, and the R6 substituents as defined above in class 2i can further form a ring; Class 3 is lysergic acid amide as represented in FIG6A , which is further characterized in that it consists of: any possible combination of the substituents R8 and R8′ of Class 1 and its subclasses 1a to 1n ( FIGS. 2A to 3H ) and the substituents R6 of Class 2 and its subclasses 2a to 2i ( FIGS. 4A to 5C ); Class 4 is lysergic acid amide as represented in FIG6B , further characterized in that it consists of any possible combination of the substituents R8 and R8′ of Class 1 and its subclasses 1a to 1n ( FIGS. 2A to 3H ) and the substituents R6 of Class 2 and its subclasses 2a to 2i ( FIGS. 4A to 5C ) and the N1 nitrogen substituents of the following groups on the ergoline substructure: a) any acyl group; b) unsubstituted and substituted carbamoyl; c) amine-bound amino acids; d) alkyl, alkenyl or alkynyl; e) alkoxy, alkenyloxy or alkynyloxy; f) any of the substituents described under a) to e), which is substituted with one or more fluorine atoms; g) any of the substituents described under a) to e), which is substituted with one or more deuterium atoms; h) any of the substituents described under a) to e), which is substituted with one or more fluorine atoms and one or more deuterium atoms; and Class 5 ( FIG. 6C ) consists of a monodeuterated to fully deuterated ergoline core structure and is additionally composed of any possible combination of substituents R8 and R8′ of Class 1 and its subclasses 1a to 1n ( FIGS. 2A to 3H ) and substituents R6 of Class 2 and its subclasses 2a to 2i ( FIGS. 4A to 5C ) and combinations of N1 nitrogen substituents of the following groups on the ergoline substructure: a) hydrogen; b) any acyl group; c) unsubstituted and substituted carbamoyl groups; d) amide-bonded amino acids; e) alkyl, alkenyl or alkynyl groups; f) alkoxy, alkenyloxy or alkynyloxy groups; g) any substituent described under a) to f) substituted with one or more fluorine atoms; h) any substituent described under a) to f) substituted with one or more deuterium atoms; i) any substituent described under a) to f) substituted with one or more fluorine atoms and one or more deuterium atoms; increasing serotonin 5-HT2A and 5-HT2C receptor interactions in said mammal; and Induces psychoactive effects.

8. The method of claim 7, wherein the compound is selected from the group consisting of a racemate, a single enantiomer, a diastereomer, or a mixture of enantiomers or diastereomers or epimers in any ratio, a single E or Z configuration isomer and a mixture in any ratio thereof, a single cis or trans configuration isomer and a mixture in any ratio thereof, and any combination thereof.

9. The method of claim 7, wherein the psychoactive effect comprises a psychedelic or synaesthesia effect in a mammal that is similar or different in intensity, quality of effect, or duration of effect than LSD.

10. The method of claim 7, wherein the compound is administered to a mammal for substance-assisted psychotherapy.

11. The method of claim 7, wherein the compound is administered to allow for altered dose efficacy compared to LSD.

12. The method of claim 7, wherein the compound is administered to allow customization and individualization of treatment to the mammal's therapeutic needs.

13. The method of claim 7, wherein the mammal is a human.

14. A method of treating an individual comprising the steps of: administering to the individual a pharmaceutically effective amount of the compound of FIG. 1A ; and Treating the individual.

15. The pharmacologically active compound of claim 1, wherein the compound is selected from the group consisting of Compound 21, Compound 12c, Compound 16a and Compound 16b, and is further characterized in that The compound is metabolized more rapidly than LSD resulting in a shorter duration of acute effects.

16. The pharmacologically active compound of claim 1, wherein the compound is selected from the group consisting of Compounds 2a-2n, Compounds 12a-12g, Compound 13, Compounds 14a-c, and Compounds 16a-c, and is further characterized in that The compound's potency is similar to that of LSD, allowing similarly small doses to have psychoactive and therapeutic activity.

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