WO2014180556A1 - Arylpiperazines - Google Patents

Abstract

The present invention relates to arylpiperazines, and to the efficient treatment of an individual afflicted with L-DOPA-induced dyskinesia, which condition typically arises as a consequence of long-term treatment with L-DOPA therapy in Parkinson patients, or with anxiety, the instant treatments comprising administering to the individual an effective amount of an arylpiperazine or a pharmaceutically acceptable salt thereof.

Description

ARYLPIPERAZINES

FIELD OF THE INVENTION

[0001] The present invention relates to arylpiperazines, and to the efficient treatment of an individual afflicted with L-DOPA-induced dyskinesia, which condition typically arises as a consequence of long-term treatment with L- DOPA therapy in Parkinson patients, with ADHD, or with anxiety, the instant treatments comprising administering to the individual an effective amount of an arylpiperazine or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

[0002] This invention relates to arylpiperazines, particularly variants of Eltoprazine, and to an innovative method of treating patients afflicted with L- DOPA-induced dyskinesia, which condition may arise as a consequence of long-term treatment with L-DOPA therapy in Parkinson patients, of treating patients afflicted with ADHD, or of treating patients afflicted with anxiety.

[0003] Parkinsonian symptoms are characterized by slowness of movement (bradykinesia/akinesia), rigidity and/or tremor. These symptoms may have an idiopathic, toxic, traumatic or genetic origin (e.g., in Parkinson's disease (PD)) or may also occur as a consequence of treatment, e.g., with dopamine receptor antagonists in schizophrenia (Parkinson syndrome).

[0004] Currently, the principal symptomatic treatment for PD is based upon administration of dopamine-replacement therapy (e.g., levodopa (L-DOPA)) and/or therapy with dopamine receptor agonists (e.g., apomorphine). Long- term treatment with either therapy may lead to the development of dyskinesia, which is the most important motor complication that may arise in Parkinson patients. Although patients treated with dopamine receptor agonists are less prone to develop severe dyskinesia, other non-motor side effects such as somnolence, constipation, dizziness, nausea and hallucination have been reported to be increased with this treatment option. Concerning L-DOPA, long-term use of this treatment option leads to a reduction of its anti-parkinsonian efficacy and to the development of L- DOPA-induced dyskinesia (LID).

[0005] LID is characterised by a mixture of choreiform, dystonic or ballistic/myoclonic movements that are observed after L-DOPA administration. It is reported that about 30% of the Parkinson patients will experience dyskinesia after 4-6 years of treatment with L-DOPA while close to 90% will suffer from this complication after 9 years. Although the cause of dyskinesia remains unknown, the main risk factor for the development of LID is young age at PD onset, the disease severity and duration as well as a high initial dose of L-DOPA treatment. Ultimately, this complication severely impairs the quality of life and well-being of the patient and therefore limits the use of this drug as most important therapeutic agent.

[0006] According to the literature, LID may be related to the pulsatile and intermittent nature of L-DOPA therapy. Upon systemic administration of L- DOPA to Parkinson patients, dopamine is formed, stored and released by the remaining dopaminergic terminals as well as by other cellular components present in the striatum such as serotoninergic neurons. Since the striatal serotonin system remains relatively spared in most PD patients, it is believed to play an important role in determining the efficacy of L-DOPA therapy.

[0007] Many attempts have been made to develop serotonergic agents for the prevention or treatment of LID but these attempts have had limited success in patients. Based on the clinical results obtained with different 5- HTIA agonists such as buspirone, sarizotan and tandospirone, it becomes evident that the 5-HT _A component is not sufficient to treat the development of LID in Parkinson's patients in a way that makes a meaningful difference for patients. According to a recently published study, it is now suggested that the combination of a 5-HT_1A agonist with a 5-HTi_B agonist could prevent the dysregulated release of dopamine by serotonin neurons and therefore be beneficial for the treatment of LID (Carta M, Carlsson T, Kirik D and Bjorklund A. Dopamine released from 5-HT terminals is the cause of L- DOPA-induced dyskinesia in Parkinsonian rats, Brain 2007 130: 1819-1833). Although this combination has shown some positive results in the rat model of dyskinesia, the administration of Ru-24969, a substance acting through the joint stimulation of the 5-HTi_A and 5-HT _B receptors, was associated with worsening of motor symptoms and/or development of side effects in monkey studies (Iravani MM, Jackson MJ, Kuoppamaki M, Smith LA, Jenner P. 3,4- methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1 , 2,3,6- tetrahydropyridine-treated primates, J Neurosci. 2003 23:9107-9115). These observations have prohibited its further development for the treatment of Parkinson patients with LID.

[0008] WO 2010/063486 discloses the use of Eltoprazine for the treatment of LID. The peculiarity of the invention underlying WO 2010/063486 compared to former treatment approaches for L-DOPA-induced dyskinesia was the therapeutic efficiency of Eltoprazine unknown in the prior art, which was based on a unique receptor profile with several components potentiating each other in an unexpected way. Prior to WO 2010/063486, the pharmacological action of Eltoprazine had mainly been attributed to its agonistic effect on the 5-HT-_IA and 5-HTi_B receptors (see Schipper J, Tulp MTM, Sijbesma H. Neurochemical profile of Eltoprazine. Drug metabolism and Drug interactions 1990 8:85-114). In WO 2010/063486 it is described that Eltoprazine acts as an agonist at the 5-HT₂c receptor in human recombinant cell lines, in addition to its partial agonistic action on 5-HT2A and 5-HT_{I B} receptors as well as its weak agonistic action on the 5-HT _Aa receptor.

[0009] While this receptor profile is highly advantageous for the use in the treatment of LID, it has been reported as well in WO 2010/063486, that Eltoprazine additionally is a partial agonist on 5-HT₂B as well with an EC50 value of 0.464 μΜ (see Fig. 1 of WO 2010/063486).

[0010] 5-HT₂B receptors are involved in various functions of the CNS and cardiovascular system. Prolonged systemic exposure to 5-HT₂B agonists is considered to be the underlying cause of drug-induced valvular heart disease (VHD; Cosyns B, Drug-induced valvular heart disease. Heart, 99(1):7-12, 2013) In this pathology one or more heart valves don't function properly and blood pumping of the heart is compromised leading to regurgitation (backward leakage of blood) and finally heart failure, depending on the severity and duration of valve insufficiency. Treatment options for VHD are limited, mainly consisting of cardiac surgery, i.e. valve replacement.

[0011] VHD has been observed in patients treated with the weight-loss drugs fenfluramine and dexfenfluramine. Due to cardiac side effect these drugs were removed from the U.S. market in 1997 (Rothman & Baumann, Expert Opin Drug Saf. 2009 May;8(3):317-29). Dopamine agonists of the ergotamine type like pergolide and cabergoline were identified as 5-HT₂B receptor agonists and their valvulopathic activity is reflected by the higher incidence of VHD in patients treated with these compounds (Zanettini R et al. Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease. N Engl J Med 2007;356:39-46). Pergolide was removed from the US market in 2007 (Elangbam C Drug-induced Valvulopathy: An Update. Toxicologic Pathology, 38: 837-848, 2010).

[0012] Currently several strategies have been suggested to evaluate the agonistic potential of 5-HT_2B ligands (Huang X-P et al. Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine 2B Receptor Agonists: Implications for Drug Safety Assessment. Mol Pharmacol 76:710-722, 2009; Setola V et al. 3,4- Methylenedioxymethamphetamine (MDMA, "Ecstasy") Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro. Mol Pharmacol 63:1223-1229, 2003) in vitro. However, the validation of these models is difficult, because no accepted animal model for drug-induced VHD is available (Elangbam, loc. cit.). Due to the severity of this condition and the lack of reliable preclinical models the FDA recommends the inclusion of serial echocardiography measurements in the clinical development of weight loss drugs, which often target 5-HT₂ receptors (FDA Guidance for Industry: Developing Products for Weight Management, DRAFT GUIDANCE, February 2007)

[0013] Compounds with 5-HT₂B agonistic activity thus have a high risk to induce VHD in patients, which will usually be observed not before large late stage clinical trials or after market authorization. The only way to avoid this liability is developing compounds without agonistic activity at the 5-ΗΤ₂Β·

[0014] Thus, there is still a great need for pharmaceutical agents that are active in the treatment of disorders such as LID by having an agonistic effect on the 5-HTIA and 5-HTi_B receptors, while simultaneously not having an agonistic effect on the 5-HT₂B receptor.

[0015] Furthermore, while the agonistic activity of Eltoprazine at the 5-HT₂c receptor may advantageously be used in treating weight disorders, particularly obesity (see WO 201 1/000563), this activity may negatively impact the treatment of disorders and diseases where loss of weight is to be avoided, such as in the treatment of Parkinson's disease (see, for example, Aziz et al., Weight loss in neurodegenerative disorders. J Neurol. 255 (2008) 1872-80). Thus, there is a great need for pharmaceutical agents that are active in the treatment of disorders such as LID, but that do not have an agonistic activity on the 5-HT₂c receptor.

[0016] Recently, Eltoprazine has been studied in a phase lla clinical trial for the treatment of ADHD patients (see US 2009/0104261 ).

[0017] Anxiety in general is a feeling of unease. In more severe and excessive forms, anxiety can result in various anxiety disorders that require medical and/or psychological attention, such as phobias, obsessive- compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), or generalised anxiety disorder (GAD). Anxiety is closely related to the serotonergic system.

[0018] The present invention relates to Eltoprazine variants and their salts, which we have determined possesses a unique receptor profile, which lacks an an agonistic effect on the 5-HT₂B receptor, as well as to their use. Consequently, the present invention relates to the use of Eltoprazine variants for the treatment of Parkinson patients with motor complications. Besides the strong antidyskinetic efficacy, such Eltoprazine variants also provide surplus benefits by improving co-morbidities typically seen in PD patients, which could lead to a dramatic improvement of the quality-of-life of Parkinson patients. Furthermore, the present invention relates to the use of Eltoprazine variants for the treatment of patients with ADHD or with anxiety.

SUMMARY OF THE INVENTION

[0019] The present invention relates to Eltoprazine variants and to a method of treating or preventing L-DOPA-induced dyskinesia in a subject in need thereof, comprising administering an effective amount of an Eltoprazine variant or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to the use of Eltoprazine variants for the treatment of patients with ADHD or with anxiety.

[0020] In a first aspect, the present invention relates to a compound of Formula I

or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from -H and -F;

X is selected from -0-CR⁴R⁵-, -CH₂-0- and -CH₂-CR⁴R⁵-;

Y is (-CR⁶R⁷-)_n, wherein n is 0 or 1 ;

R² and R³ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R² and R³, together with the carbon atom they are attached to, form a cyclopropyl ring;

R⁴ and R⁵ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁴ and R⁵, together with the carbon atom they are attached to, form a cyclopropyl ring; and

R⁶ and R⁷ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁶ and R⁷, together with the carbon atom they are attached to, form a cyclopropyl ring,

provided that the following compounds 1 to 6 are excluded:

1 2 3

4 5 6

[0021] The disclaimed compounds are described in EP 0189612.

[0022] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, particularly a pharmaceutical composition for oral administration.

[0023] In a third aspect, the present invention relates to a compound of Formula I

I

or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from -H and -F;

X is selected from -O-CR⁴R⁵-, -CH₂-0- and -CH₂-CR⁴R⁵-;

Y is (-CR⁶R⁷-)n, wherein n is 0 or 1 ; R² and R³ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R² and R³, together with the carbon atom they are attached to, form a cyclopropyl ring;

R⁴ and R⁵ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁴ and R⁵, together with the carbon atom they are attached to, form a cyclopropyl ring; and

R⁶ and R⁷ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁶ and R⁷, together with the carbon atom they are attached to, form a cyclopropyl ring,

for use in the treatment or prevention of (i) L-DOPA-induced dyskinesia,

(ii) ADHD, or (iii) anxiety;

provided that the following compounds 1 , 3, and 6 are excluded:

1 3 6

[0024] In a fourth aspect, the present invention relates to a method of treating or preventing (i) L-DOPA-induced dyskinesia, (ii) ADHD, or (iii) anxiety, comprising the step of administering a compound of Formula I

I or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from -H and -F;

X is selected from -0-CR⁴R⁵-, -CH₂-0- and -CH₂-CR⁴R⁵-;

Y is (-CR⁶R⁷-)n, wherein n is 0 or 1 ;

R² and R³ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R² and R³, together with the carbon atom they are attached to, form a cyclopropyl ring;

R⁴ and R⁵ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁴ and R⁵, together with the carbon atom they are attached to, form a cyclopropyl ring; and

R⁶ and R⁷ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁶ and R⁷, together with the carbon atom they are attached to, form a cyclopropyl ring,

to a patient in need thereof;

xcluded:

1 3 6

[0025] In a fifth aspect, the present invention relates to a method of synthesizing a compound of the present invention, comprising the step of reacting (i) a compound of Formula II

II wherein Z is a leaving group, particularly a halogen atom, particularly - Br,

X¹ is selected from -O-CR⁴R⁵-, -CH₂-0- -CH₂-CR⁴R⁵-; and - CH=CR⁴; and

Y, R¹, R² and R³ are as defined above,

with (ii) a protected piperazine, particularly with N-Boc-piperazine.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 shows the effect of MRZ-6 on L-DOPA-induced dyskinesia in 6-OHDA-lesioned hemiparkinsonian rats (axial, limb and orolingual AIM scores): MRZ-6 was dissolved in PBS (5 ml/kg) and administered p.o. 30 min before the test; L-DOPA/benserazide were dissolved in saline (1 ml/kg) and administered i.p. 20 min before the test; ^* P < 0.021 vs L-DOPA - vehicle, Signed Rank test.

[0027] Figure 2 shows the time course of the effect of MRZ-6 on L-DOPA- induced dyskinesia in 6-OHDA-lesioned hemiparkinsonian rats: MRZ-6 was dissolved in PBS (5 ml/kg) and administered p.o. 30 min before the test; L- DOPA/benserazide were dissolved in saline (1 ml/kg) and administered i.p. 20 min before the test; * P < 0.05 vs L-DOPA - vehicle, 2-way RM ANOVA followed by Holm-Sidak test.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The peculiarity of this invention compared to former treatment approaches for L-DOPA-induced dyskinesia is the identification of structural variants of Eltoprazine, which show an agonistic effect on the 5-HT-|_A and 5- HTI B receptors, while simultaneously showing no agonistic effect on the 5- HT₂B receptor.

[0029] Thus, in a first aspect, the present invention relates to a compound of Formula I

or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from -H and -F;

X is selected from -O-CR⁴R⁵-, -CH₂-O- and -CH₂-CR⁴R⁵-;

Y is (-CR⁶R⁷-)n, wherein n is 0 or 1 ;

R² and R³ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R² and R³, together with the carbon atom they are attached to, form a cyclopropyl ring;

R⁴ and R⁵ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁴ and R⁵, together with the carbon atom they are attached to, form a cyclopropyl ring; and

R⁶ and R⁷ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁶ and R⁷, together with the carbon atom they are attached to, form a cyclopropyl ring,

provided that the following compounds 1 to 6 are excluded:

[0030] The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). The term "pharmaceutically acceptable" may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[0031] The term "salt" is defined as a chemical containing different charged components. The term salt also includes hydrates and solvates. Contemplated in the instant description are pharmaceutically acceptable salts, which salts may include, but are not limited to, acid addition salts, such as those made with hydrochloric, sulphuric, nitric, phosphoric, acetic, maleic, fumaric, tartaric, citric, benzoic, methane sulphonic, naphthalene sulphonic, p-toluene sulphonic acid. All of these salts (or other similar salts) may be prepared by conventional means. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity. [0032] The compounds of the present invention may be used according to the invention in the form of any of pharmaceutically acceptable salts. Furthermore, the compounds may be used in the form of solvates, for example hydrates. The compounds may be in solid state, including in amorphous and crystalline form, including in one of several possible polymorphic forms, or may be in solution, particularly using a pharmaceutically acceptable solvent or mixture of solvents. Any references to a compound in the present invention in this description should be understood as also referring to such salts, solvates, solid state forms and solutions.

[0033] In a particular embodiment, at least one of R¹ to R⁷ is different from - H.

[0034] In a particular embodiment, no more than four substituents R¹ to R⁷ are different from -H, particularly wherein no more than two substituents R to R⁷ are different from -H, particularly wherein exactly two substituents R to R⁷ are different from -H, or wherein exactly one substituent R¹ to R⁷ is different from -H.

[0035] In a particular embodiment, R1 is -H.

[0036] In a particular embodiment, the compound is selected from the list of: MRZ-6, MRZ-71 , MRZ-85, MRZ-90, MRZ-91 , MRZ-94, MRZ-73, MRZ-80, MRZ-(-)87, MRZ-(+)88, and MRZ-93, particularly MRZ-6.

[0037] In a particular embodiment, the compound has an EC₅₀ value of greater than 0.25 μΜ in a cell-based in vitro 5-HT₂c activity measurements, particularly wherein the compound is selected from the list of: MRZ-6, MRZ- 71 , MRZ-90, MRZ-91 , MRZ-93, MRZ-(-)87, and MRZ-(+)88. [0038] In a particular embodiment, the compound has an EC₅o value of greater than 1.0 μΜ in a cell-based in vitro 5-HT₂c activity measurements, particularly wherein the compound is selected from the list of: MRZ-6, MRZ- 71 , and MRZ-91.

[0039] In a particular embodiment, the compound has an EC₅₀ value of greater than 2.0 μΜ in a cell-based in vitro 5-HT₂c activity measurements, particularly wherein the compound is selected from the list of: MRZ-6, and MRZ-91.

[0040] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, particularly a pharmaceutical composition for oral administration.

[0041] The pharmaceutical compositions comprise a therapeutically effective amount of a compound of the present invention. The pharmaceutical compositions of the invention may further comprise a solvent, a carrier, an excipient or other components commonly used, and well-known to one of ordinary skill in the art, in pharmaceutical compositions (all pharmaceutically acceptable).

[0042] The term "carrier" applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound (e.g., an Eltoprazine variant) is administered. Such pharmaceutical carriers may be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by A.R. Gennaro, 20^th Edition. [0043] The compositions may be formulated e.g. for once-a-day administration, twice-a-day administration, or three times a day administration.

[0044] The compound of the present invention may be used for the manufacture of a medicament for the treatment of at least one of the mentioned disorders, wherein the medicament is adapted to or appropriately prepared for a specific administration as disclosed herein (e.g., to once-a- day, twice-a-day, or three times a day administration). For this purpose the package leaflet and/or the patient information contains corresponding information.

[0045] According to the present invention, the dosage form of a compound of the present invention, or salt thereof, may be a solid, semisolid, or liquid formulation according to the following.

[0046] The compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. In another embodiment, a compound of the present invention may be formulated as a flavored liquid (e.g., peppermint flavor). A compound of the present invention may be administered orally in the form of a capsule, a tablet, granules, pellets or the like, or as a semi-solid, or liquid formulation (see Remington's Pharmaceutical Sciences, 20^th Edition, by A.R. Gennaro).

[0047] The formulations of the invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0048] In a third aspect, the present invention relates to a compound of Formula I

or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from -H and -F;

X is selected from -0-CR⁴R⁵- -CH₂-0- and -CH₂-CR⁴R⁵-;

Y is (-CR⁶R⁷-)_n, wherein n is 0 or 1 ;

R² and R³ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R² and R³, together with the carbon atom they are attached to, form a cyclopropyl ring;

R⁴ and R⁵ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii)R⁴ and R⁵, together with the carbon atom they are attached to, form a cyclopropyl ring; and

R⁶ and R⁷ (i) are independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁶ and R⁷, together with the carbon atom they are attached to, form a cyclopropyl ring,

for use in the treatment or prevention of (i) L-DOPA-induced dyskinesia,

(ii) ADHD, or (iii) anxiety;

provided that the following compounds 1 , 3, and 6 are excluded:

1 3 6

[0049] In a fourth aspect, the present invention relates to a method of treating or preventing (i) L-DOPA-induced dyskinesia, (ii) ADHD, or (iii) anxiety, comprising the step of administering a compound of Formula I

or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from -H and -F;

X is selected from -0-CR⁴R⁵-, -CH₂-O- and -CH₂-CR⁴R⁵-;

Y is (-CR⁶R⁷-)n, wherein n is 0 or 1 ;

R² and R³ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R² and R³, together with the carbon atom they are attached to, form a cyclopropyl ring;

R⁴ and R⁵ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁴ and R⁵, together with the carbon atom they are attached to, form a cyclopropyl ring; and R⁶ and R⁷ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁶ and R⁷, together with the carbon atom they are attached to, form a cyclopropyl ring,

to a patient in need thereof;

provided that the following compounds 1 , 3, and 6 are excluded:

1 3 6

[0050] The terms "treat" or "treatment" are used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Within the meaning of the present invention, the term "treat" also denotes to arrest the progress of a disease.

[0051] The terms "prevent" or "prevention" are used herein to mean to delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.

[0052] The term "dyskinesia" refers to involuntary movements similar to a tic or chorea, which interferes with the performance of voluntary movements. The term dyskinesia may be used in relation to Parkinson's disease and/or other extrapyramidal disorders. In the case of Parkinson's disease, dyskinesia may occur as a complication of dopaminomimetic therapy with L- DOPA (LID), or, in rare cases, after treatment with dopamine receptor agonists such as apomorphine. In LID, dyskinesia most commonly occurs in two forms: peak dose, also known as improvement-dyskinesia-improvement (IDI), which most commonly occur at the time of peak L-DOPA plasma concentrations, and diphasic dyskinesia also known as dyskinesia- improvement-dyskinesia (DID), which occur when the L-DOPA concentration rises or falls.

[0053] The term "levodopa" or "L-DOPA" refers to a therapeutic strategy use to treat PD. L-DOPA is defined as a dopamine precursor because L-DOPA needs to be decarboxylated to dopamine to be effective. On the other hand, the term "dopamine receptor agonist" refers to dopamine D1 , D2 or D3 receptor agonists, which bind directly to their respective receptors to induce an effect.

[0054] In a particular embodiment of the third aspect of the present invention, at least one of R¹ to R⁷ is different from -H.

[0055] In a particular such embodiment, no more than four substituents R¹ to R⁷ are different from -H, particularly wherein no more than two substituents R¹ to R⁷ are different from -H, particularly wherein exactly two substituents R¹ to R⁷ are different from -H, or wherein exactly one substituent R¹ to R⁷ is different from -H.

[0056] In a particular embodiment of the third aspect of the present invention, R¹ is -H.

[0057] In a particular embodiment of the third aspect of the present invention, the compound is selected from the list of: MRZ-6, MRZ-71 , MRZ-80, MRZ-(- )87, MRZ-(+)88, MRZ-93, MRZ-73, MRZ-90, MRZ-94, MRZ-85, MRZ-91 , and MRZ-D, particularly MRZ-6, MRZ-71 , MRZ-80, MRZ-(+)88, MRZ-93, MRZ-73, MRZ-90, MRZ-94, MRZ-85, and MRZ-91 , more particularly MRZ-6.

[0058] In a particular embodiment, the compound is for administration in a range from about 5 mg to about 75 mg/day, or in a range from about 5 mg to about 60 mg/day, or in a range from about 5 mg to about 50 mg/day, or in a range from about 5 mg to about 40 mg/day, or in a range from about 5 mg to about 20 mg/day, or in a range from about 5 mg to about 15 mg/day.

[0059] The term "about" or "approximately" usually means within 20%, alternatively within 10%, including within 5% of a given value or range. Alternatively, especially in biological systems, the term "about" means within about a log (i.e., an order of magnitude), including within a factor of two of a given value.

[0060] Suitable daily doses of the active ingredient of the invention in therapeutic treatment of humans are within the range from about 5 mg to about 150 mg per day, such as from about 5 mg to about 120 mg, from about 5 mg to about 100 mg, or from about 5 mg to about 75 mg, or from about 5 mg to about 60 mg, or from about 5 mg to about 50 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 15 mg, such as 10mg or 15 mg or 20 mg or 30 mg or 40 mg or 60mg or 80mg, per day. For example the daily dose may be body weight-adjusted such as 40 mg/day up to 80 kg body weight or 60 mg/day for patients with a body weight of > 80 kg. In modified release formulations the amounts of active ingredient per day could also be higher due to reduced bioavailability, e.g. up to 200 mg/day. An equimolar amount of another pharmaceutically acceptable salt, a solvate, a conjugate or a derivative thereof, such as a compound of the present invention as hydrochloride salt, is also suitable.

[0061] In particular embodiments, the daily dosage of a compound of the present invention is between about 10 and 20 mg/day.

[0062] The daily doses indicated herein may be administered, for example, as one or two dosing units once, twice or three times per day. Suitable doses per dosage unit may therefore be the daily dose divided (for example, equally) between the number of dosage units administered per day, and will thus typically be about equal to the daily dose or one half, one third, one quarter or one sixth thereof. Dosages per dosage unit may thus be calculated from each daily dosage indicated herein. A daily dose of 5 mg, for example may be seen as providing a dose per dosage unit of, for example, about 5 mg, 2.5 mg, 1.67 mg, 1.25 mg and 0.83 mg, depending upon the dosing regimen chosen. Correspondingly, a dosage of 50 mg per day corresponds to dosages per dosing unit of, for example, about 50 mg, 25 mg, 16.7 mg, 12.5 mg, and 8.33 mg for corresponding dosing regimens. In other embodiments, especially in cases where only two daily doses are administered, an unequal split of the first and the second dosage is envisaged. In such cases, for example, the first dosage comprises about 55 to 65% of the total daily dosage. For example, a daily dosage of 10 mg is split into a first dosage of 6 mg and a second dosage of 4 mg. In cases, in which more than two administrations per day are envisaged, the dosage might be split also unequally, wherein the second and further dosages are reduced in comparison to the dosage before. For example, if three dosages per day are administered, the first dosage could be about one half of the total daily dosage, i.e. between about 40% to 60%, the second dosage could be about one third of the total daily dosage, i.e. between about 20% to 40%, and the third dosage could be about one sixth of the total daily dosage, i.e. between about 5% to 20%. For example, a daily dosage of 10 mg could be split into a first dosage of 6 mg, a second dosage of 3 mg and a third dosage of 1 mg.

[0063] In certain such embodiments, the treatment is the treatment of diphasic dyskinesia (DID).

[0064] In a particular embodiment, the compound is for administration once a day, twice a day (b.i.d.), or three times a day.

[0065] In another embodiment, a therapeutically effective amount of e a compound of the present invention is administered twice a day. In particular, a compound of the present invention is administered once in the morning, particularly once prior to the first L-DOPA administration, and once in the middle of the day, particularly at about lunchtime, wherein the lunchtime treatment is between about 6 and 10, particularly between about 7 and 9 h before the patient wishes to go to bed, or, alternatively, prior to the mid-point of daily L-DOPA dosages (e.g. prior to the third L-DOPA dosage in a five- time-daily L-DOPA dosage regimen, or between the third and fourth L-DOPA dosages in a six-time-daily L-DOPA dosage regimen). Such an administration should allow for the plasma level of the compound of the present invention to ebb away during evening and at nighttime, reducing the risk of an impaired REM-(rapid eye movement)-ac.\v^'Ay.

[0066] In certain such embodiments, the treatment is the treatment of diphasic dyskinesia (DID).

[0067] In a particular embodiment, the daily dosage for said administration twice a day (b.i.d.) is split into a first dose of about 55 to 65% of the total daily dosage amount, and a second dose comprising the remaining total daily dosage amount.

[0068] In a particular embodiment, the second dosage is administered at about lunchtime.

[0069] In particular embodiments, the subject to be treated is not treated with an additional pharmaceutical agent(s) selected from the group of (i) a COX-2 inhibitor, particularly a COX-2 inhibitor listed in WO 2004/045509 or in WO 2005/048999; (ii) Pipamperone; (iii) an AMPA receptor antagonist, particularly an AMPA receptor antagonist listed in WO 2009/01 1412; and (iv) Flibanserin.

[0070] Treatment duration may be short-term, e.g., several weeks (for example 8-14 weeks), or long-term until the attending physician deems further administration no longer is necessary. [0071] In a particular embodiment, the subject to be treated suffers from a movement disorder.

[0072] As used herein, the term "subject" encompasses mammals including animals and humans.

[0073] In a particular embodiment, the movement disorder is selected from parkinsonism, restless legs syndrome (RLS), and Chorea Huntington, particularly parkinsonism.

[0074] In a particular embodiment, the parkinsonism is idiopathic (Parkinson's disease, PD).

[0075] In a particular embodiment, the subject is undergoing long-term treatment with L-DOPA therapy indicated for the treatment of PD.

[0076] In a particular embodiment, the subject is undergoing treatment with dopamine receptor agonists.

[0077] The term "agonist" refers to a substance that binds to a receptor and mimics the cellular effect of the native or endogenous ligand for the same receptor. The term agonist includes the class of agents called full agonists, which bind and display full efficacy at the receptor, and partial agonists, which have only partial efficacy at the receptor. Partial agonists may also be seen as competitive antagonists, competing away the endogenous ligand when it is in excess or give a sub maximal response when inadequate amount of endogenous ligand is present. The term "activation" refers to the state of a receptor when an agonist is bound to it. [0078] In a particular embodiment, the compound is in the form of an oral formulation.

[0079] In a particular embodiment, the treatment or prevention comprises the additional administration with at least one additional pharmaceutical agent.

[0080] The compound of the present invention may be administered as a single antidyskinetic agent in combination with dopamine replacement therapy (e.g. L-DOPA) and/or therapy with dopamine receptor agonists (e.g. apomorphine) for the treatment of L-DOPA-induced dyskinesias. In particular embodiments, L-DOPA is administered together with a decarboxylase inhibitor, including but not limited to benserazide (e.g. in Levodopa comp. B STADA^®, Levopar^® Madopar^®, PK-Levo^®, or Restex^®), or carbidopa (e.g. in Nacom®, Dopadura C^®, Levobeta C^®, or Stalevo^®).

[0081] The term "combination" applied to active ingredients is used herein to define two separate pharmaceutical compositions, each comprising an active agent (e.g. a compound of the present invention, and another pharmaceutical composition comprising another agent prescribed for the treatment of motor disorders such as Parkinson disease), to be administered conjointly.

[0082] Within the meaning of the present invention, the term "conjoint administration" is used to refer to administration of a compound of the present invention, and a second active agent simultaneously in different compositions, or sequentially. For the sequential administration to be considered "conjoint", however, a compound of the present invention and the second active agent must be administered separated by a time interval, which still permits the resultant beneficial effect for treating L-DOPA-induced dyskinesias in a mammal. [0083] Thus, in a particular embodiment, the additional pharmaceutical agent(s) is/are selected from the group of (i) an agent which has been shown to be effective for the treatment of PD, and (ii) a decarboxylase inhibitor such as benserazide and carbidopa.

[0084] In a particular embodiment, the compound is for administration at least about 10 minutes before the administration of a therapeutically effective amount of L-DOPA.

[0085] In one embodiment, a therapeutically effective amount of a compound of the present invention is administered before the administration of a therapeutically effective amount of L-DOPA, for example at least about 10, 15, 20, 25, 30, 35, or 40 minutes before the administration of a therapeutically effective amount of L-DOPA. In particular embodiments, a therapeutically effective amount of a compound of the present invention is administered between about 10 and 25 minutes before the administration of a therapeutically effective amount of L-DOPA. This administration scheme should allow synchronizing the peak plasma level of L-DOPA with the plasma levels of a compound of the present invention, due to the faster uptake of L-DOPA in comparison to a compound of the present invention. In doing so, the brain-activity of both substances should occur during the same time period.

[0086] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition sufficient to result in a desired activity upon administration to a subject in need thereof.

[0087] Therapeutic efficacy and toxicity and of the compositions of the invention may be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD₅o (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD₅o/ED₅o. Compositions that exhibit large therapeutic indices are preferred.

[0088] In a particular embodiment, the compound is for use in the prevention of L-DOPA-induced dyskinesia, wherein said compound is for administration to a subject receiving L-DOPA, wherein said subject is still free of symptoms of L-DOPA induced dyskinesia, and wherein the treatment with said compound is started at the latest 9 years after the beginning of said L-DOPA treatment.

[0089] In one such embodiment, the compound of the present invention is for administration to a patient, who receives L-DOPA as first-line treatment of PD, particularly within about 9, about 6, about 4, about 3 years or about 2 years from start of L-DOPA treatment. In a particular embodiment, the patient is at the age of at least 60, 65 or 70 years.

[0090] In a particular embodiment, the subject receives L-DOPA as first-line treatment of Parkinson's disease.

[0091] In a particular embodiment, the subject receives L-DOPA either in combination with a dopamine agonist or as a second-line treatment of Parkinson's disease.

[0092] In particular such embodiment, the compound of the present invention is for administration to a patient, who either receives L-DOPA in combination with one or more dopamine receptor agonists, or as second-line treatment of PD after prior treatment with one or more dopamine receptor agonists, particularly within about 9, about 6, about 4, about 3 years or about 2 years from start of L-DOPA treatment. Alternatively, the patient is treated with a compound of the present invention from the point in time on, where such L- DOPA combination or second-line treatment is started. [0093] In a particular embodiment, the treatment comprises administration of an increased dosage of L-DOPA compared to the dosage used by said subject without the administration of said compound.

[0094] In a particular embodiment, the compound is for administration of an effective amount of said compound to said subject; and the effective amount is selected such that the L-DOPA induced dyskinesia caused by said increased dosage of L-DOPA is kept at, or below, the level which was present in said subject without the administration of said effective amount.

[0095] Sometimes a patient is more interested in reducing the periods of insufficient motility ("off-phase") than in the reduction of dyskinesia ("on- phase"). The dosage of a treatment with L-DOPA and/or dopamine agonists, however, can only be increased as long as the occurrence of LID is still bearable. Therefore, in another embodiment, the compound of the present invention is used to keep the LID symptoms at a stable level (rather than reducing them), thereby enabling to increase the dosage of a treatment with L-DOPA and/or dopamine agonists and as such decreasing the off-phase. Thus, this embodiment relates to a method of using the compound of the present invention or a pharmaceutically acceptable salt thereof for, or the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for, maintaining the level of L-DOPA-induced dyskinesia in a patient that is treated with an increased amount of L-DOPA and/or dopamine receptor agonists. In the context of the present invention, the term "maintaining the level" has the meaning that dyskinetic events are kept at a level that shows about the same grade and/or frequency of dyskinetic events as at beginning of treatment using a compound of the present invention, and the term "increased amount of L-DOPA and/or dopamine receptor agonists" has the meaning that the patient is treated with a higher amount of L-DOPA when compared with the amount at the beginning of treatment using a compound of the present invention.

[0096] In addition to this strong antidyskinetic effect, the compounds of the present invention

- improve the primary symptoms of PD (bradykinesia, OFF time etc.),

- improve depression and anxiety, which are one of the most challenging co-morbidities in Parkinson's disease

- reduce pain, which is an extremely inconvenient consequence of dystonic dyskinesia as well as of muscular rigidity

- improve the "on / off phenomenon"

[0097] Thus, in a particular embodiment the present invention relates to a method for administering an effective amount of eltoprazine or a pharmaceutically acceptable salt thereof for improving the primary symptoms of PD, such as bradykinesia and/or OFF time, in a subject having Parkinson's disease, particularly to a subject suffering from L-DOPA induced dyskinesia, and to compositions comprising eltoprazine or a pharmaceutically acceptable salt thereof for use in such methods.

[0098] The active ingredient (e.g., an Eltoprazine variant) or the composition of the present invention may be used for the treatment of at least one of the mentioned disorders, wherein the treatment is adapted to or appropriately prepared for a specific administration as disclosed herein (e.g., to once-a- day, twice-a-day, or three times a day administration). For this purpose the package leaflet and/or the patient information contains corresponding information.

[0099] In a fifth aspect, the present invention relates to a method of synthesizing a compound of the present invention, comprising the step of reacting (i) a compound of Formula II

II

wherein Z is a leaving group, particularly a halogen atom, particularly - Br,

X¹ is selected from -O-CR R⁵-, -CH₂-0- -CH₂-CR⁴R⁵-; and - CH=CR⁴; and

Y, R¹, R² and R³ are as defined above,

With (ii) a protected piperazine, particularly with N-Boc-piperazine.

[00100] In particular embodiments, the synthesis step is performed by palladium catalysis, particularly by using Pd₂(dba)₃, particularly in the presence of BINAP and sodium tert-butoxide.

[00101] In particular embodiments, wherein X¹ is -CH=CR⁴, the method further comprises the step of hydrogenating the double bond in X¹, particularly by using Pd/C and H_2.

EXAMPLES

[00102] The following examples illustrate the invention without limiting its scope.

Part A. Synthesis of the Compounds of the Present Invention

General experimental methods

[00103] H NMR spectra were recorded on Bruker Avance III, 400 MHz and TMS was used as an internal standard.

[00104] LCMS was taken on a quadrupole Mass Spectrometer on Agilent LC/MSD 1200 Series (Column: Welchrom XB-C18 (50 χ 4.6 mm, 5 pm) operating in ES (+) or (-) ionization mode; T = 30 DC; flow rate = 1.5 ml/min.

[00105] Preparative HPLC was performed at conditions: Column: Welchrom C18 (150 * 20); Wavelength 214 nm; Mobile phase: A acetonitrile; B water; Flow rate: 25 ml/min; Injection volume: 2 ml; Run time: 30 min; Equilibration: 5 min.

[00106] The synthesis of MRZ-A, MRZ-B; MRZ-C and MRZ-D is described in EP 0189612. Abbreviations

Example 1 : Synthesis of 1-(2,2-Dimethylchroman-5-yl)piperazine (MRZ- 6)

Scheme 1. Synthesis of Compound MRZ-6

1.1 Synthesis of 1-Bromo-3-((2-methylbut-3-yn-2-yl)oxy)benzene (61):

[00107] Compound 46 (800 mg, 4.7 mmol), 3-chloro-3-methylbut-1-yne (1.0 g, 9.7 mmol) and DBU (1.5 g, 9.9 mmol) were dissolved in acetonitrile (10 ml), and the solution was stirred at room temperature overnight under nitrogen atmosphere. Acetonitrile was removed under vacuum, and the residual was dissolved in water (50 ml), extracted with ethyl acetate (50 ml ^χ 2), the combined organic phase was washed with water, 2N HCI, brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum) to give 1.1 g of compound 61 as brown oil (yield 99%).

[00108] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.64 (s, 6H), 2.60 (s, 1 H), 7.13- 7.20 (m, 3H), 7.38-7.39 (m, 1 H).

1.2 Synthesis of 5-Bromo-2,2-dimethyl-2H-chromene (62):

[00109] Compound 61 (1.2 g, 5.0 mmol) was dissolved in N,N- diethylphenylamine (20 ml) and heated to 220°C for 8 h under nitrogen atmosphere. After the reaction was complete indicated by TLC, the mixture was poured into ice-water (40 ml), extracted with ethyl acetate (30 ml ^χ 2), and the combined organic layer was washed with 5N HCI (80 ml ^χ 2), and brine. The solution was dried and concentrated, purified by column chromatography on silica gel (ethyl acetate/petroleum = 1 :12) to give 1.2 g of compound 62 and 63 as pale yellow oil (yield 100%).

1.3 Synthesis of terf-Butyl 4-(2,2-dimethyl-2H-chromen-5-yl)piperazine-1- carboxylate (64):

[001 10] A mixture of compound 62 and 63 (1.0 g, 4.2 mmol), N-tert- butyl piperazinecarboxylate (920 mg, 5 mmol), BINAP (105 mg, 0.17 mmol), Pd₂(dba)₃ (82 mg, 0.09 mmol) and sodium terf-butoxide (560 mg, 5.9 mmol) in toluene (25 ml) was stirred at 100°C under nitrogen atmosphere overnight and then cooled to room temperature. The mixture was poured into water (50 ml), and extracted with ethyl acetate (40 ml ^χ 2), washed with brine, dried over anhydrous Na₂SO₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (ethyl acetate/petroleum = 1 :8) to give 890 mg of compound 64 as yellow oil (yield 62%). [00111] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.42 (s, 6H), 1.46 (s, 9H), 2.89 (t, J = 4.8 Hz, 4H), 3.57 (br s, 4H), 5.59-5.63 (m, 1 H), 6.48-6.60 (m, 3H), 7.06 (t, J = 8.0 Hz, 1 H).

1.4 Synthesis of terf-Butyl 4-(2,2-dimethylchroman-5-yl)piperazine-1- carboxylate (65):

[00112] Compound 64 (550 mg, 1.6 mmol) and 10% Pd/C (80 mg) were dissolved in methanol (30 ml), and this mixture was stirred at room temperature for 18 h under H₂ atmosphere. The mixture was filtered and the filtrate was concentrated, dried under vacuum to give 550 mg of crude compound 65 as colorless oil (yield 99%).

1.5 Synthesis of 1-(2,2-Dimethylchroman-5-yl)piperazine (MRZ-6):

[00113] A solution of 4M HCI in ethyl acetate (10 ml) was added to a solution of compound 65 (550 mg, 1.6 mmol) in ethyl acetate (10 ml). The mixture was stirred at room temperature overnight. Then filtered, the solid was collected and dissolved in water (30 ml), 10% NaOH solution was added to adjusted pH over 10, dichloromethane (30 ml ^χ 2) was added and extracted, the combined organic layer was washed with brine and dried over anhydrous Na₂SO₄, concentrated to give 160 mg of compound MRZ-6 as a white solid (yield 41%).

[00114] ¹H NMR δ_Η (400 MHz; CDCI₃):1.34 (s, 6H), 1.76 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.86-2.89 (m, 4H), 3.00-3.03 (m, 4H), 6.54-6.59 (m, 2H), 7.07 (t, J = 8.0 Hz, 1 H).

[00115] HPLC-UV: method [mobile phase: from 95% water (0.02% ammonium acetate) and 5% acetonitrile to 40% water (0.02% ammonium acetate) and 60% acetonitrile in 6.5 min], Rt = 3.23 min, purity 99.7% (214 nm).

[00116] MS: 247.2 ([M+H]\ 100%). Example 2: Synthesis of 1-(2,2-Dimethyl-2,3- dihydrobenzo[J ][1 ,4]dioxin-5-yl)piperazine (MRZ

Scheme 2. Synthesis of Compound MRZ-71

2.1 Synthesis of 3-Bromo-2-((2-methylallyl)oxy)phenol (71-1):

[001 17] A solution of compound 1-3 (1.0 g, 5.3 mmol), 3-chloro-2- methylprop-1 -ene (479 mg, 5.3 mmol) and potassium carbonate (803 mg, 5.8 mmol) in A/-methyl-2-pyrrolidone (3 ml) was stirred at 40°C for 10 h. The mixture was poured into water (40 ml), and extracted with ethyl acetate (30 ml x 2), washed with brine, dried over anhydrous Na₂S0₄. The solvent was removed under vacuum and the crude product was purified by prep-TLC (ethyl acetate/petroleum ether = 1 :5) to give 400 mg of compound 71-1 as yellow oil (yield 31 %).

[001 18] ¹H NMR δ_Η (400 MHz; CDCI₃):1.91 (s, 3H), 4.43 (s, 2H), 5.05 (s, 1 H), 5.20 (s, 1 H), 5.78 (s, 1 H), 6.87-6.92 (m, 2H), 7.05-7.07 (m, 1 H).

2.2 Synthesis of 5-Bromo-2,2-dimethyl-2,3-dihydrobenzo[fc][1 ,4]dioxin (71-2):

[00119] A solution of compound 71-1 (400 mg, 1 .65 mmol) in formic acid (2 ml) was heated to reflux for 2 h. The mixture was evaporated under reduced pressure, the residue was treated with water (10 ml), extracted with ethyl acetate (20 ml * 3), washed with brine, dried over anhydrous Na₂SO₄. The solvent was removed under vacuum and the crude product was purified by prep-TLC (ethyl acetate/petroleum ether = 1 :20) to give 110 mg of compound 71-2 as yellow oil (yield 27%).

[00120] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.36 (s, 6H), 3.98 (s, 2H), 6.73 (t, J = 8.0 Hz, 1 H), 6.78 (dd, J = 8.0, 1.2 Hz, 1 H), 7.07 (dd, J = 8.0, 1.2 Hz, 1 H).

2.3 Synthesis of tert-Butyl 4-(2,2-dimethyl-2,3-dihydrobenzo[b][1 ,4]dioxin-5- yl)piperazine-1-carboxylate (71-3):

[00121] A mixture of compound 71-2 (320 mg, 1.3 mmol), /V-ferf-butyl piperazinecarboxylate (368 mg, 2.0 mmol), BINAP (164 mg, 0.26 mmol), Pd₂(dba)₃ (121 mg, 0.13 mmol) and sodium ferf-butoxide (253 mg, 2.6 mmol) in toluene (15 ml) was stirred at 100°C under nitrogen atmosphere overnight and then cooled to room temperature. The mixture was poured into water (20 ml), and extracted with ethyl acetate (30 ml χ 3). The organic layer was washed with brine, and dried over anhydrous Na₂SO₄. The solvent was removed under vacuum and the crude product was purified by prep-TLC (ethyl acetate/petroleum ether = 1 :3) to give 60 mg of compound 71-3 as yellow oil (yield 18%).

[00122] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.35 (s, 6H), 1.48 (s, 9H), 2.98- 3.00 (m, 4H), 3.60-3.62 (m, 4H), 3.94 (s, 2H), 6.48 (dd, J = 8.0, 1.2 Hz, 1 H), 6.57 (dd, J = 8.0, 1.2 Hz, 1 H), 6.79 (t, J = 8.0 Hz, 1 H).

2.4 Synthesis of 1-(2,2-Dimethyl-2,3-dihydrobenzo[jb][1 ,4]dioxin-5- yl)piperazine (71):

[00123] A solution of 4M hydrochloride in ethyl acetate (10 ml) was added to a solution of compound 71-3 (160 mg, 0.46 mmol) in ethyl acetate (2 ml). The reaction mixture was stirred at room temperature overnight, then filtered, the solid was collected and dissolved in water (5 ml), 10% sodium hydroxide solution was added to adjusted pH over 12, dichloromethane (30 ml x 2) was added and extracted, the combined organic layer was washed with brine and dried over anhydrous Na₂SO₄, and concentrated to give 110 mg of compound 71 as yellow oil (yield 96%).

[00124] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.34 (s, 6H), 3.03-3.07 (m, 8H), 3.93 (s, 2H), 6.51-6.57 (m, 2H), 6.79 (t, J = 8.0 Hz, 1 H).

[00125] HPLC-UV: method [mobile phase: from 90% water (0.05% trifluoroacetic acid) and 10% acetonitrile to 5% water (0.05% trifluoroacetic acid) and 95% acetonitrile in 6.5 min], Rt = 2.40 min, purity 99.3% (214 nm).

[00126] MS: 249.1 ([M+H]⁺, 100%).

Example 3: Synthesis of 1-(6-Fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperazine (MRZ-80)

Scheme 3. Synthesis of Compound MRZ-80

t

3.1 Synthesis of 2-Bromo-1-fluoro-3,4-dimethoxybenzene (80-2)

[00127] n-Butyllithium (2.5 M in hexane, 39 ml, 97.5 mmol) was added dropwise at -78 °C to a solution of compound 80-1 (10.1 g, 65.0 mmol) and tetramethylethylenediamine (7.5 g, 65 mmol) in anhydrous ethyl ether (67 ml) under nitrogen atmosphere and stirred at -78°C for 1.5 h. Then 1 ,2- dibromo-1 ,1 ,2,2-tetrachloroethane (27.5 g, 84.5 mmol) was added, after stirring for a further 10 min, the cooling bath was removed and the reaction vessel allowed to warm to room temperature. The reaction mixture was diluted with ether (200 ml), washed with water (200 ml), 1 N HCI (67 ml ^χ 2), brine (67 ml) and dried over anhydrous Na₂S0₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (petroleum ether/dichloromethane = 2:1) to afford compound 80- 2 (12.5 g, 82%) as yellow oil.

[00128] ¹H NMR δ_Η (400 MHz; CDCI₃): 3.85 (s, 3H), 3.89 (s, 3H), 6.80- 6.88 (m, 2H).

3.2 Synthesis of 3-Bromo-4-fluorobenzene-1 ,2-diol (80-3):

[00129] Compound 80-2 (12.5 g, 53.1 mmol) was dissolved in dichloromethane (320 ml) and treated with 1.0 M boron tribromide/dichloromethane solution (80 ml, 80 mmol) at 0°C and then allowed to warm to room temperature. After stirring for 3 h, the reaction mixture was cooled to 0°C, 11 ml of methanol was added, and the solvent was removed under vacuum. The residue was dissolved in 150 ml of ethyl acetate and washed with 1 N HCI (150 ml ^χ 2), water, brine and dried over anhydrous Na₂SO₄, concentrated to afford crude compound 80-3 (12.8 g, 100%) as red oil.

[00130] ¹H NMR δ_Η (400 MHz; CDCI₃):5.32 (s, 1 H), 5.66 (s, 1 H), 6.66 (t, J = 8.8 Hz, 1 H), 6.82-6.85 (m, 1 H).

3.3 Synthesis of 5-Bromo-6-fluoro-2,3-dihydrobenzo[ ?][1 ,4]dioxin (80-4):

[00131] A mixture of compound 80-3 (5.5 g, 26.6 mmol), 1 ,2- dibromoethane (10.0 g, 53.1 mmol), caesium carbonate (17.3 g, 53.1 mmol) in DMF (45 ml) was stirred at 80°C under nitrogen atmosphere overnight and then cooled to room temperature. The mixture was poured into water (450 ml), and extracted with ethyl acetate (400 ml ^χ 2), washed with brine, dried over anhydrous Na₂SO₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to afford compound 80-4 (4.87 g, 79%) as a white solid.

[00132] ¹H NMR δ_Η (400 MHz; CDCI₃): 4.23-4.25 (m, 2H), 4.36-4.38 (m, 2H), 6.65 (t, J = 8.4 Hz, 1 H), 6.77-6.81 (m, 1 H).

3.4 Synthesis of ferf-Butyl 4-(6-fluoro-2,3-dihydrobenzo[b][1 ,4]dioxin-5- yl)piperazine-1 -carboxylate (80-5):

[00133] A mixture of compound 80-4 (932 mg, 4.0 mmol), /V-tert-butyl piperazinecarboxylate (968 mg, 5.2 mmol), BINAP (498 mg, 0.8 mmol), Pd₂(dba)₃ (367 mg, 0.4 mmol) and sodium terf-butoxide (768 mg, 8.0 mmol) in toluene (40 ml) was stirred at 100°C under nitrogen atmosphere overnight and then cooled to room temperature. The mixture was poured into water (100 ml), and extracted with ethyl acetate (100 ml ^χ 2), washed with brine, dried over Na₂SO₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to afford compound 80-5 (1.2 g, 89%) as a yellow solid.

[00134] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.48 (s, 9H), 3.10-3.12 (m, 4H), 3.51-3.53 (m, 4H), 4.19-4.28 (m, 4H), 6.49-6.55 (m, 2H).

3.5 Synthesis of 1-(6-Fluoro-2,3-dihydrobenzo[jb][1 ,4]dioxin-5-yl)piperazine (80):

[00135] To a solution of compound 80-5 (1.2 g, 3.6 mmol) in ethyl acetate (10 ml) was added 4M HCI in ethyl acetate (15 ml). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (25 ml), extracted with ethyl acetate (abandoned), the water layer was basified with 10% sodium hydroxide solution to pH > 10, then extracted with dichloromethane (30 ml ^χ 2), the combined organic layer was washed with brine and dried over anhydrous Na₂SO , concentrated to afford compound 80 (675 mg, 80%) as yellow oil.

[00136] ¹H NMR δ_Η (400 MHz; CDCI₃): 2.96-2.98 (m, 4H), 3.13-3.14 (m, 4H), 4.18-4.28 (m, 4H), 6.51-6.53 (m, 2H).

[00137] HPLC-UV: method [mobile phase: from 90% water (0.05% trifluoroacetic acid) and 10% acetonitrile to 5% water (0.05% trifluoroacetic acid) and 95% acetonitrile in 6.5 min], Rt = 2.28 min, purity 99.2% (214 nm).

[00138] MS: 239.0 ([M+H]⁺, 100%).

Example 4: Synthesis of (-)-1-(2-Methyl-2,3-dihydrobenzo[6][1 ,4]dioxin- 5-yl)piperazine (MRZ-(-)87) and (+)-1-(2-Methyl-2,3- dihydrobenzo[b][1 ,4]dioxin-5-yl)piperazine (MRZ-(+)88)

Scheme 4. Synthesis of Compound MRZ-(-)87 and MRZ-(+)88

4.1 Synthesis of 5-Bromo-2-methyl-2,3-dihydrobenzo[fo][1 ,4]dioxin (87-1):

[00139] A solution of compound 1-3 (1.89 g, 10 mmol), 1 ,2- dibromopropane (4.0 g, 20 mmol), potassium iodide (0.33 g, 2 mmol) and potassium carbonate (2.76 g, 20 mmol) in DMSO (20 ml) was stirred at 120°C under nitrogen atmosphere overnight. The mixture was cooled, diluted with water (200 ml) and extracted with ethyl acetate (200 ml 2), the combined ethyl acetate was washed by brine, dried over Na₂SO₄, concentrated and purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 40:1) to give the mixture of compound 87-1 and 87-1 B (230 mg, 10%) as colorless oil, and the ratio of compound 87-1 and 87-1 B = 2/1 showed by ¹H NMR.

[00140] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.38 (d, J = 6.4 Hz, 2H), 1.43 (d, J = 6.4 Hz, 1 H), 3.82-3.87 (m, 0.33H), 3.88-3.93 (m, 0.67H), 4.20-4.37 (m, 2H), 6.69-6.74 (m, 1 H), 6.80-6.84 (m, 1 H), 7.07-7.11 (m, 1 H).

4.2 Synthesis of (-)-terf-Butyl 4-(2-methyl-2,3-dihydrobenzo[b][1 ,4]dioxin-5- yl)piperazine-1-carboxylate (Boc-87) and (+)-ferf-Butyl 4-(2-methyl-2,3- dihydrobenzo[6][1 ,4]dioxin-5-yl)piperazine-1 -carboxylate (Boc-88):

[00141] A mixture of compound 87-1 and 87-1 B (440 mg, 1.9 mmol), /V-ferf-butyl piperazinecarboxylate (530 mg, 2.9 mmol), BINAP (250 mg, 0.4 mmol), Pd₂(dba)3 (185 mg, 0.2 mmol) and sodium terf-butoxide (360 mg, 3.8 mmol) in toluene (10 ml) was stirred at 100°C under nitrogen atmosphere overnight and then cooled to room temperature. The mixture was poured into water (50 ml), and extracted with ethyl acetate (30 ml * 2). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (ethyl acetate/petroleum ether = 15:100) to give the crude product (610 mg, 96%) as a yellow solid.

[00142] The crude product (1.2 g, 3.6 mmol) was separated twice by chiral preparative HPLC [step I: Chiralpak AY-H column, mobile phase: hexane/ethanol/diethylamine (98/2/0.1 , v/v/v); step II: Chiralpak AY-H column, mobile phase: hexane/isopropylamine/diethylamine (80/20/0.1 , v/v/v)] to give two isomers Boc-87 (peak 1 , 334 mg) and Boc-88 (peak 2, 373 mg). Boc-87 (peak 1):

[00143] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.36 (d, J = 6.8 Hz, 3H), 1.48 (s, 9H), 2.99 (t, J = 4.8 Hz, 4H), 3.60 (t, J = 4.8 Hz, 4H), 3.86 (dd, J = 10.8, 8.0 Hz, 1 H), 4.23-4.28 (m, 1 H), 4.31 (dd, J = 10.8, 2.0 Hz, 1 H), 6.50 (dd, J = 8.4, 1.6 Hz, 1 H), 6.61 (dd, J = 8.4, 1.6 Hz, 1 H), 6.78 (t, J = 8.4 Hz, 1 H).

[00144] Chiral HPLC-UV: method [Column: Chiralpak AYH (0.46 cm I.D. x 15 cm L); Wavelength: 254 nm; Mobile phase: hexane/ethanol/diethylamine = 95/5/0.1 (v/v/v); T = 35°C; Flow rate: 1.0 ml/min; Injection volume: 10 μΙ; Run time: 15 min], Rt = 8.32 min, Optical purity 99.8% (254 nm).

Boc-88 (peak 2):

[00145] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.36 (d, J = 6.8 Hz, 3H), 1.48 (s, 9H), 2.99 (t, J = 4.8 Hz, 4H), 3.60 (t, J = 4.8 Hz, 4H), 3.86 (dd, J = 10.8, 8.0 Hz, 1 H), 4.23-4.28 (m, 1 H), 4.31 (dd, J = 10.8, 2.0 Hz, 1 H), 6.50 (dd, J = 8.4, 1.6 Hz, 1 H), 6.61 (dd, J = 8.4, 1.6 Hz, 1 H), 6.78 (t, J = 8.4 Hz, 1 H).

[00146] Chiral HPLC-UV: method [Column: Chiralpak AYH (0.46 cm I.D. x 15 cm L); Wavelength: 254 nm; Mobile phase: hexane/ethanol/diethylamine = 95/5/0.1 (v/v/v); T = 35°C; Flow rate: 1.0 ml/min; Injection volume: 10 μΙ; Run time: 15 min.], Rt = 9.98 min, Optical purity 98.8% (254 nm).

4.3 Synthesis of (-)-1-(2-Methyl-2,3-dihydrobenzo[b][1 ,4]dioxin-5- yl)piperazine ((-)87):

[00147] A solution of 4M hydrochloride in ethyl acetate (2 ml) was added to a solution of compound Boc-87 (200 mg, 0.6 mmol) in ethyl acetate (2 ml). The reaction mixture was stirred at room temperature for 3 h, then filtered, the solid was collected and dissolved in water (15 ml), this solution was basified with 10% sodium hydroxide to pH > 10, then extracted with dichloromethane (10 ml χ 2), the combined dichloromethane was dried over anhydrous Na₂SO₄, then concentrated to give compound (-)87 (120 mg, 86%) as yellow oil.

[00148] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.36 (d, J = 6.4 Hz, 3H), 3.00- 3.08 (m, 8H), 3.86 (dd, J = 10.8, 8.4 Hz, 1 H), 4.22-4.32 (m, 2H), 6.53 (dd, J = 8.0, 1.2 Hz, 1 H), 6.59 (dd, J = 8.0, 1.2 Hz, 1 H), 6.78 (t, J = 8.0 Hz, 1 H).

[00149] Chiral HPLC-UV: method [Column: Chiralpak AY-H (250 ^χ 4.6 mm, 5 pm); Wavelength: 230 nm; Mobile phase: hexane/ethanol = 80/20 (v/v); T = 30 °C; Flow rate: 1.0 ml/min; Injection volume: 5 pi; Run time: 30 min.], Rt = 8.88 min, Optical purity 100.0% (230 nm).

[00150] HPLC-UV: method [mobile phase: from 95% water (0.05% trifluoroacetic acid) and 5% acetonitrile to 5% water (0.05% trifluoroacetic acid) and 95% acetonitrile in 6.5 min], Rt = 2.48 min, purity 99.0% (214 nm).

[00151] MS: 231.1 ([M+H]⁺, 100%).

[00152] Optical rotation value: [a]_D = -0.125 (0.86 g in 100 ml of methanol, Sodium D-Line light, temperature: 20-25°C, polarimeter tube length: 10 cm).

Example 5: Synthesis of (+)-1-(2-Methyl-2,3-dihydrobenzo[ ][1,4]dioxin- 5-yl)piperazine (MRZ-(+)88)

Boc-88 (+)88 [00153] A solution of 4M hydrochloride in ethyl acetate (2 ml) was added to a solution of compound Boc-88 (363 mg, 1.1 mmol) in ethyl acetate (3 ml). The reaction mixture was stirred at room temperature for 3 h, then filtered, the solid was collected and dissolved in water (20 ml), this solution was basified with 10% sodium hydroxide to pH > 10, then extracted with dichloromethane (15 ml ^χ 2), the combined dichloromethane was washed with brine, dried over anhydrous Na₂SO₄, then concentrated to give compound (+)88 (133 mg, 53%) as a white solid.

[00154] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.36 (d, J = 6.4 Hz, 3H), 3.00- 3.08 (m, 8H), 3.86 (dd, J = 10.8, 8.4 Hz, 1 H), 4.22-4.32 (m, 2H), 6.53 (d, J = 8.0 Hz, 1 H), 6.59 (dd, J = 8.0, 1.2 Hz, 1 H), 6.78 (t, J = 8.0 Hz, 1 H).

[00155] Chiral HPLC-UV: method [Column: Chiralpak AY-H (250 ^χ 4.6 mm, 5 pm); Wavelength: 230 nm; Mobile phase: hexane/ethanol = 80/20 (v/v); T = 30°C; Flow rate: 1.0 ml/min; Injection volume: 5 pi; Run time: 20 min.], Rt = 6.46 min, Optical purity 100.0% (230 nm).

[00156] HPLC-UV: method [mobile phase: from 95% water (0.05% trifluoroacetic acid) and 5% acetonitrile to 5% water (0.05% trifluoroacetic acid) and 95% acetonitrile in 6.5 min], Rt = 2.49 min, purity 97.8% (214 nm).

[00157] MS: 231.1 ([M+Hf, 100%).

[00158] Optical rotation value: [a]_D = +0.322 (0.88 g in 100 ml of methanol, Sodium D-Line light, temperature: 20-25°C, polarimeter tube length: 10 cm). Example 6: Synthesis of 1-(Spiro[chroman-2,1'-cyclopropan]-5- yl)piperazine (MRZ-93)

Scheme 5. Synthesis of Compound MRZ-93

1) MeMgCI, Toluene

2) NH4CI solution

Cp₂Ti Cl₂ ·- Cp₂Ti Me₂

78%

6.1 Synthesis of Ethyl 3-(2-bromo-6-hydroxyphenyl)acrylate (93-2):

[00159] To a solution of compound 93-1 (3.0 g, 15 mmol) and ethyl 2- (diethoxyphosphoryl)acetate (6.7 g, 30 mmol) in DMF (30 ml) was added sodium hydride (60% in mineral oil, 1.20 g, 30 mmol) at room temperature under nitrogen atmosphere, and then stirred at 40°C overnight. The mixture was cooled to room temperature, diluted with saturated ammonium chloride aqueous solution and extracted with ethyl acetate (100 ml * 3). The combined organic phase was washed with water and brine, dried over anhydrous Na₂S0₄, concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to afford compound 93-2 (3.6 g, 88%) as a white solid.

[00160] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.36 (t, J = 6.8 Hz, 3H), 2.69 (q, J = 6.8 Hz, 2H), 6.17 (s, 1 H), 6.79-6.85 (m, 2H), 7.05 (t, J = 8.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H). 6.2 Synthesis of Ethyl 3-(2-bromo-6-hydroxyphenyl)propanoate (93-3):

[00161] A mixture of compound 93-2 (3.81 g, 14 mmol), p- toluenesulfonyl hydrazide (5.23 g, 28 mmol) and sodium acetate (3.46 g, 42 mmol) in THF (50 ml) and water (50 ml) was heated to reflux overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the combined ethyl acetate was washed with water and brine, dried over anhydrous Na₂S0 . The solvent was removed under vacuum to afford crude compound 93-3 (4.85 g, 100%) as yellow oil.

[00162] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.25 (t, J = 7.2 Hz, 3H), 2.80- 2.83 (m, 2H), 3.04-3.07 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1 H), 6.98 (t, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1 H).

6.3 Synthesis of 5-Bromochroman-2-one (93-4):

[00163] A mixture of compound 93-3 (3.84 g, 14 mmol) and amberlyst- 15 ion exchange resin (1.4 g) in toluene (150 ml) was heated to reflux for 4 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated, the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to afford compound 93-4 (3.03 g, 95%) as yellow oil.

[00164] ¹H NMR δ_Η (400 MHz; CDCI₃): 2.80 (t, J = 7.6 Hz, 2H), 3.11 (t, J = 7.6 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H).

6.4 Synthesis of 5-Bromo-2-methylenechroman (93-5):

[00165] To a solution of titanocene dichloride (Cp₂TiCI₂, 9.96 g, 40 mmol) in anhydrous toluene (108 ml) was added methylmagnesium chloride (3.0 M in tetrahydrofuran, 32 ml, 96 mmol) dropwise at -5°C under nitrogen atmosphere, and then the reaction mixture was stirred at 5°C for 2 h. The reaction mixture was cooled to -10°C and 6% ammonium chloride solution in water (28 ml) was added, after stirring for a further 1 h at 5°C, the mixture was extracted with toluene (100 ml χ 3), and the combined toluene was washed with water and brine, dried over anhydrous Na₂S0₄, concentrated at a bath temperature of no more than 35°C to give a solution of dimethyltitanocene (Cp₂TiMe₂) in toluene as a red liquid (36.7 g, w/w% = 17.7%, 78% yield).

[00166] A mixture of compound 93-4 (1.65 g, 7.3 mmol) and dimethyltitanocene in toluene (36.7 g, w/w% = 17.7%, 31.0 mmol) was stirred under nitrogen atmosphere in the dark at 60°C overnight. The reaction mixture was cooled to room temperature, diluted with petroleum ether, filtered and the filtrate was concentrated, the residue was purified by flash chromatography on basic aluminum oxide (eluted by petroleum ether) to afford compound 93-5 (816 mg, 50%) as yellow oil.

[00167] ¹H NMR δ_Η (400 MHz; CDCI₃):2.58 (t, J = 6.8 Hz, 2H), 2.86 (t, J = 6.8 Hz, 2H), 4.20 (s, 1 H), 4.59 (s, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 7.02 (t, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H)

6.5 Synthesis of 5-Bromospiro[chroman-2,1 '-cyclopropane] (93-6):

[00168] To a solution of compound 93-5 (866 mg, 3.9 mmol) in dichloromethane (50 ml) was added diethylzinc (1.0 M in hexane, 4.3 ml, 4.3 mmol) and diiodomethane (1.18 g, 4.4 mmol) at 25°C under nitrogen atmosphere, and then stirred at 30°C for 4 h. The reaction was cooled to room temperature and quenched with a saturated ammonium chloride aqueous solution (10 ml), the mixture was extracted with dichloromethane (50 ml x 3), and the combined dichloromethane was washed with brine, dried over anhydrous Na₂SO₄, concentrated and purified by flash chromatography on basic aluminum oxide (eluted by petroleum ether) to afford compound 93-6 (910 mg, 99%) as colorless oil. [00169] ¹H NMR δ_Η (400 MHz; CDCI₃): 0.59 (t, J = 5.6 Hz, 2H), 0.97 (t, J = 5.6 Hz, 2H), 1.96 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 6.70 (d, J = 8.0 Hz, 1 H), 6.94 (t, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1H).

6.6 Synthesis of 1-(Spiro[chroman-2,1'-cyclopropan]-5-yl)piperazine (93):

[00170] A mixture of compound 93-6 (478 mg, 2.0 mmol), piperazine (1.72 g, 20.0 mmol), BINAP (249 mg, 0.4 mmol), sodium ferf-butoxide (384 mg, 4.0mmol) and Pd₂(dba)₃ (183 mg, 0.2 mmol) in toluene (25 ml) was stirred under nitrogen atmosphere at 100°C overnight. The mixture was cooled to room temperature, evaporated to dry, and then purified by preparative TLC (dichloromethane/methanol = 15:1) to afford compound 93 (25.9 mg, 5%) as a yellow solid.

[00171] H NMR δ_Η (400 MHz; CDCI₃): 0.59 (t, J = 5.6 Hz, 2H), 1.00 (t, J = 5.6 Hz, 2H), 1.89 (t, J = 6.0 Hz, 2H), 2.81 (t, J = 6.0 Hz, 2H), 3.22-3.38 (m, 8H), 6.58 (d, J = 8.0 Hz, 1 H), 6.64 (d, J = 8.0 Hz, 1 H), 7.07 (t, J = 8.0 Hz, 1 H).

[00172] HPLC-UV: method [mobile phase: from 90% water (0.05% trifluoroacetic acid) and 10% acetonitrile to 5% water (0.05% trifluoroacetic acid) and 95% acetonitrile in 6.5 min], Rt = 2.90 min, purity 97.7% (214 nm).

[00173] MS: 245.1 ([M+H]\ 100%).

Example 7: Synthesis of 1-(3,3-Dimethyl-2,3- dihydrobenzo[6][1 ,4]dioxin-5-yl)piperazine (MRZ-73)

Scheme 6. Synthesis of Compound MRZ-73

7.1 Synthesis of 3-Bromo-2-((4-methoxybenzyl)oxy)phenol (73-1)

[00174] To a solution of compound 1-3 (1.0 g, 5.3 mmol) in DMF (10 ml) was added sodium hydride (60% in mineral oil, 212 mg, 5.3 mmol) at room temperature, after 30 min, a solution of 1-(chloromethyl)-4- methoxybenzene (828 mg, 5.3 mmol) in DMF (5 ml) was added by syringe pump at 80°C and stirred at 80°C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (30 ml ^χ 3). The combined organic phase was dried over anhydrous Na₂SO₄, concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to give compound 73-1 (490 mg, 31 %) as yellow oil.

[00175] ¹H NMR δ_Η (400 MHz; CDCI₃): 3.83 (s, 3H), 5.01 (s, 2H), 6.84- 6.94 (m, 4H), 7.09 (dd, J = 8.0, 1.6 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 2H).

7.2 Synthesis of 1-Bromo-2-((4-methoxybenzyl)oxy)-3-((2- methylallyl)oxy)benzene (73-2)

[00176] To a solution of compound 73-1 (5.9 g, 19.1 mmol) in DMF (50 ml) was added sodium hydride (60% in mineral oil, 763 mg, 19.1 mmol) at room temperature, after 30 min, 3-chloro-2-methylprop-1-ene (1.7 g, 19.1 mmol) was added by syringe at room temperature and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml * 3). The combined organic phase was dried over anhydrous Na₂S0 , concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give compound 73-2 (6.0 g, 87%) as colorless oil.

[00177] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.86 (s, 3H), 3.83 (s, 3H), 4.48 (s, 2H), 4.99-5.01 (m, 3H), 5.13 (s, 1 H), 6.83-6.97 (m, 4H), 7.14 (dd, J = 8.0, 1.6 Hz, 1 H), 7.44-7.48 (m, 2H).

7.3 Synthesis of 2-Bromo-6-((2-methylallyl)oxy)phenol (73-3)

[00178] To a solution of compound 73-2 (4.6 g, 12.7 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (1.5 g, 12.7 mmol) at room temperature, the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane (20 ml x 3). The combined organic phase was dried over anhydrous Na₂S0₄, concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to give compound 73-3 (800 mg, 26%) as colorless oil.

[00179] ¹H NMR δ_Η (400 MHz; CDCI₃):1.83 (s, 3H), 4.52 (s, 2H), 5.03 (s, 1 H), 5.07 (s, 1 H), 6.71 (t, J = 8.0 Hz, 1 H), 6.80 (dd, J = 8.0, 1.2 Hz, 1 H), 7.08-7.10 (m, 1 H).

7.4 Synthesis of 8-Bromo-2,2-dimethyl-2,3-dihydrobenzo[j ][1 ,4]dioxin (73-4)

[00180] A solution of compound 73-3 (800 mg, 3.3 mmol) in formic acid (5 ml) was heated to reflux for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (20 ml * 3). The combined organic phase was dried over anhydrous Na₂S0₄, concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give compound 73-4 (200 mg, 25%) as colorless oil. [00181] ¹H NMR δ_Η (400 MHz; CDCI₃):1.39 (s, 6H), 3.89 (s, 2H), 6.70 (t, J = 8.0 Hz, 1 H), 6.84 (dd, J = 8.0, 1.6 Hz, 1 H), 7.10 (dd, J = 8.0, 1.6 Hz, 1 H).

7.5 Synthesis of 1-(3,3-Dimethyl-2,3-dihydrobenzo[jb][1 ,4]dioxin-5- yl)piperazine (73)

[00182] A mixture of compound 73-4 (200 mg, 0.8 mmol), piperazine (708 mg, 8.2 mmol), 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl (102 mg, 0.16 mmol), sodium fe/f-butoxide (158 mg, 1.6 mmol) and tris(dibenzylideneacetone)dipalladium(0) (76 mg, 0.08 mmol) in toluene (10 ml) was stirred under nitrogen atmosphere at 100°C overnight. The reaction mixture was cooled to room temperature. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (dichloromethane/methanol = 20:1) and preparative TLC (dichloromethane/methanol = 10:1) to give compound 73 (43.5 mg, 25%) as a white solid.

[00183] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.37 (s, 6H), 3.37-3.39 (m, 8H), 3.88 (s, 2H), 6.51 (d, J = 7.6 Hz, 1 H), 6.65 (d, J = 7.6 Hz, 1 H), 6.77 (t, J =

7.6 Hz, 1 H).

[00184] HPLC-UV: method [mobile phase: from 95% water (0.05% trifluoroacetic acid) and 5% acetonitrile to 5% water (0.05% trifluoroacetic acid) and 95% acetonitrile in 6.5 min], Rt = 2.53 min, purity 98.8% (214 nm).

[00185] MS: 249.1 ([M+H]⁺, 100%). Example 8: Synthesis of 1-(3,3-Dimethyl-3,4-dihyd

benzo[fo][1 ,4]dioxepin-6-yl)piperazine (MRZ-90)

Scheme 7. Synthesis of Compound MRZ-90

8.1 Synthesis of 6-Bromo-3,3-dimethyl-3,4-dihydro-2 -/-benzo[£)][1 ,4]dioxepin (90-1):

[00186] A solution of compound 1-3 (500 mg, 2.65 mmol) and potassium hydroxide (326 mg, 5.82 mmol) in DMSO (5 ml_) was stirred under nitrogen atmosphere at room temperature for 30 min, then 2,2- dimethyl-1 ,3-dichloropropane (746 mg, 5.3 mmol) was added at room temperature. The reaction mixture was stirred at 100°C overnight, cooled, diluted with water and extracted with ethyl acetate, the combined ethyl acetate was dried over anhydrous Na₂SO₄, concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate from 100 to 20:1) to give 100 mg of compound 90-1 as yellow oil (yield 14%).

[00187] ¹H NMR δ_Η (400 MHz; CDCI₃):1.07 (s, 6H), 3.85 (s, 2H), 3.92 (s, 2H), 6.70 (t, J = 8.0 Hz, 1 H), 6.90 (dd, J = 8.0, 1.2 Hz, 1 H). 7.18 (dd, J = 8.0, 1.2 Hz, 1 H).

8.2 Synthesis of 1-(3,3-Dimethyl-3,4-dihydro-2H-benzo[b][1 ,4]dioxepin-6- yl)piperazine (90):

[00188] A mixture of compound 90-1 (200 mg, 0.78 mmol), piperazine (669 mg, 7.8 mmol), BINAP (97 mg, 0.16mmol), sodium te/f-butoxide (149 mg, 1.56 mmol) and Pd₂(dba)3 (72 mg, 0.08 mmol) in toluene (8 ml) was stirred under nitrogen atmosphere at 100°C overnight. The mixture was cooled to room temperature, evaporated to dry, and then purified by prep- TLC (dichloromethane/methanol = 12:1) to afford 58 mg of compound 90 as a yellow solid (yield 28%).

[00189] H NMR δ_Η (400 MHz; CDCI₃): 1 .05 (s, 6H), 3.35-3.36 (m, 8H), 3.83-3.85 (m, 4H), 6.56 (d, J = 8.0 Hz, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 6.82 (t, J = 8.0 Hz, 1 H).

[00190] HPLC-UV: method [mobile phase: from 90% water (0.02% ammonium acetate) and 10% acetonitrile to 5% water (0.02% ammonium acetate) and 95% acetonitrile in 6.5 min], Rt = 3.00 min, purity 97.4% (214 nm).

[00191] MS: 263.1 ([M+H]⁺, 100%).

Example 9: Synthesis of 1-(2,3,4,5-Tetrahydrobenzo[ ]oxepin-6- yl)piperazine (MRZ-94)

Scheme 8. Synthesis of Compound MRZ-94

9.1 Synthesis of 1-(Allyloxy)-3-bromobenzene (94-2):

[00192] To a mixture of compound 94-1 (10 g, 57.8 mmol) in acetonitrile (100 ml), potassium carbonate (16.0 g, 115.6 mmol) was added. The mixture was stirred at room temperature for 30 min, and then ally! bromide (14.0 g, 115.6 mmol) was added and stirred at 60°C for 3 h. The mixture was cooled to room temperature and filtered, concentrated to give 12 g of compound 94-2 as colorless oil (yield 98%).

[00193] ¹H NMR δ_Η (400 MHz; CDCI₃): 4.45-4.52 (m, 2H), 5.28-5.31 (m, 1 H), 5.38-5.43 (m, 1 H), 5.99-6.06 (m, 1 H), 6.83-6.86 (m, 1 H), 7.06-7.15 (m, 3H).

9.2 Synthesis of 2-Allyl-3-bromophenol (94-3):

[00194] A mixture of compound 94-2 (12 g, 56.3 mmol) in N,N- diethylphenyiamine (25 ml) was stirred under nitrogen atmosphere at 220°C for 5 h and then cooled to room temperature. The mixture was poured into 1 N hydrochloric acid solution, extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to give 4.0 g of compound 94-3 as colorless oil (yield 33%).

[00195] ¹H NMR δ_Η (400 MHz; CDCI₃): 3.62-3.63 (m, 2H), 5.01-5.13 (m, 2H), 5.65 (s, 1 H), 5.92-6.02 (m, 1 H), 6.76 (d, J = 8.0 Hz, 1 H), 6.96 (t, J = 8.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H).

9.3 Synthesis of 2-Allyl-1-(allyloxy)-3-bromobenzene (94-4):

[00196] To a mixture of compound 94-3 (4.0 g, 18.8 mmol) in acetonitrile (40 ml), potassium carbonate (5.2 g, 37.5 mmol) was added. The mixture was stirred at room temperature for 30 min, and then allyl bromide (2.27 g, 8.8 mmol) was added and stirred at 60°C for 3 h. The mixture was cooled to room temperature and filtered, concentrated to give 4.0 g of compound 94-4 as colorless oil (yield 84%).

[00197] ¹H NMR δ_Η (400 MHz; CDCI₃): 3.62 (d, J = 6.4 Hz, 2H), 4.53- 4.55 (m, 2H), 5.00-5.08 (m, 2H), 5.26-5.29 (m, 1 H), 5.39-5.44 (m, 1 H), 5.90- 6.07 (m, 2H), 6.79 (d, J = 8.4 Hz, 1 H), 7.02 (t, J = 8.4 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H).

9.4 Synthesis of 6-Bromo-2,5-dihydrobenzo[j ]oxepin (94-5):

[00198] A mixture of compound 94-4 (2.53 g, 10 mmol) and 2nd Generation Grubbs' Catalyst (425 mg, 0.5 mmol) in toluene (30 ml) was stirred under nitrogen atmosphere at 80°C overnight, filtered, concentrated and purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to give 1.44 g of compound 94-5 as yellow oil (yield 64%).

[00199] ¹H NMR δ_Η (400 MHz; CDCI₃): 3.71-3.74 (m, 2H), 4.58-4.61 (m, 2H), 5.44-5.48 (m, 1 H), 5.82-5.88 (m, 1 H), 6.91-6.97 (m, 1 H), 7.01-7.05 (m, 1 H), 7.30-7.33 (m, 1 H).

9.5 Synthesis of 6-Bromo-2,3,4,5-tetrahydrobenzo[b]oxepin (94-6):

[00200] A mixture of compound 94-5 (1.44 g, 6.4 mmol) and Rhodium on alumina (5%, 500 mg) in methanol (20 ml) was stirred under hydrogen atmosphere at room temperature overnight, filtered, concentrated to give 1.2 g of compound 94-6 as yellow oil (yield 83%).

[00201] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.68-1.74 (m, 2H), 1.92-1.98 (m, 2H), 3.06 (t, J = 6.0 Hz, 2H), 4.02 (t, J = 5.2 Hz, 2H), 6.94-6.97 (m, 1 H), 7.27-7.31 (m, 2H).

9.6 Synthesis of ferf-Butyl 4-(2,3,4,5-tetrahydrobenzo[j£>]oxepin-6- yl)piperazine-1 -carboxylate (94-7): [00202] A mixture of compound 94-6 (800 mg, 3.52 mmol), fe/f-butyl piperazine-1-carboxylate (1.32 g, 7.11 mmol), BINAP (442 mg, 0.71 mmol), sodium terf-butoxide (683 mg, 7.11 mmol) and Pd₂(dba)₃ (326 mg, 0.36 mmol) in toluene (20 ml) was stirred under nitrogen atmosphere at 100°C overnight. The mixture was cooled to room temperature, filtered and concentrated, then diluted with water, extracted with ethyl acetate, the combined ethyl acetate was washed with brine, dried over anhydrous Na₂S0₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give 166 mg of compound 94-7 as yellow oil (yield 14%).

[00203] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.48 (s, 9H), 1.68-1.72 (m, 2H), 1.94-2.00 (m, 2H), 2.76-2.82 (m, 4H), 2.91-2.94 (m, 2H), 3.49-3.59 (m, 4H), 4.00-4.03 (m, 2H), 6.71-6.77 (m, 2H), 7.06 (t, J = 8.0 Hz, 1 H).

9.7 Synthesis of 1-(2,3,4,5-Tetrahydrobenzo[/?]oxepin-6-yl)piperazine (94):

[00204] To a solution of compound 94-7 (166 mg, 0.5 mmol) in ethyl acetate (2 ml) was added 4M hydrochloride in ethyl acetate (3 ml), and then stirred at room temperature overnight. The mixture was filtered to give a solid. The solid was dissolved in water, added 10% sodium hydroxide to pH > 10, extracted with dichloromethane, dried over Na₂S0₄, concentrated to give 100 mg of compound 94 as yellow oil (yield 86%).

[00205] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.69-1.71 (m, 2H), 1.95-1.98 (m, 2H), 2.84 (brs, 4H), 2.91-2.94 (m, 2H), 3.00-3.03 (m, 4H), 4.00-4.03 (m, 2H), 6.73-6.78 (m, 2H), 7.06 (t, J = 8.0 Hz, 1 H).

[00206] HPLC-UV: method [mobile phase: from 90% water (0.05% trifluoroacetic acid) and 10% acetonitrile to 5% water (0.05% trifluoroacetic acid) and 95% acetonitrile in 6.5 min], Rt = 2.36 min, purity 96.3% (214 nm).

[00207] MS: 233.1 ([M+H]⁺, 100%). Example 10: Synthesis of 1-(3,5-Dihydro-2H-benzo[e][1,4]dioxepin-6- yl)piperazine (MRZ-85)

Scheme 9. Synthesis of Compound MRZ-85

10.1 Synthesis of 3-Bromo-2-((2-hydroxyethoxy)methyl)phenol (85-1):

[00208] A mixture of compound 51-2 (101 mg, 0.5 mmol) and p- toluenesulfonic acid (95 mg, 0.5 mmol) in ethylene glycol (2 ml) was stirred under nitrogen atmosphere at 80°C for 3 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the combined ethyl acetate was washed with brine, dried over anhydrous Na₂SO₄. The solvent was removed under vacuum to give 107 mg of compound 85-1 as yellow oil (yield 86%).

[00209] ¹H NMR δ_Η (400 MHz; CDCI₃): 2.01 (br s, 1 H), 3.73-3.74 (m, 2H), 3.81-3.85 (m, 2H), 4.93 (s, 2H), 6.83 (d, J = 8.0 Hz, 1 H), 7.00-7.09 (m, 2H), 8.17 (br s, 1 H). 10.2 Synthesis of 3-Bromo-2-((2-chloroethoxy)methyl)phenol (85-2):

[00210] To a solution of compound 85-1 (499 mg, 2.02 mmol) in dry dichloromethane (4 ml) was added pyridine (240 mg, 3.03 mmol) and thionyl chloride (265 mg, 2.22 mmol) at 0°C, then stirred at room temperature for 3 h. More pyridine (239 mg, 3.03 mmol) and thionyl chloride (265 mg, 2.22 mmol) was added and stirred at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate, the combined ethyl acetate was washed with brine, dried over anhydrous Na₂S0₄ and concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give 353 mg of compound 85-2 (yield 66%).

[00211] ¹H NMR δ_Η (400 MHz; CDCI₃): 3.69-3.72 (m, 2H), 3.84-3.87 (m, 2H), 4.99 (s, 2H), 6.86 (d, J = 8.0 Hz, 1 H), 7.03-7.10 (m, 2H), 7.98 (s, 1 H).

10.3 Synthesis of 6-Bromo-3,5-dihydro-2H-benzo[e][1 ,4]dioxepin (85-3):

[00212] A mixture of compound 85-2 (346 mg, 1.3 mmol) and potassium carbonate (216 mg, 1.6 mmol) and potassium iodide (108 mg, 0.7 mmol) in /V,/V-diethylphenylamine (5 ml) was stirred under nitrogen atmosphere at 45°C for 2 days. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the combined ethyl acetate was washed with brine, dried over anhydrous Na₂S0₄. The solvent was removed under vacuum to give 298 mg of compound 85-3 as a yellow solid (yield 100%).

[00213] ¹H NMR δ_Η (400 MHz; CDCI₃): 4.00-4.02 (m, 2H), 4.11-4.13 (m, 2H), 4.96 (s, 2H), 6.98-7.07 (m, 2H), 7.28 (d, J = 8.0 Hz, 1 H). 10.4 Synthesis of 1-(3,5-Dihydro-2/- -benzo[e][1 ,4]dioxepin-6-yl)piperazine (85):

[00214] A mixture of compound 85-3 (298 mg, 1.3 mmol), piperazine (1.12 g, 13.0 mmol), BINAP (162 mg, 0.26 mmol), sodium terf-butoxide (250 mg, 2.6 mmol) and Pd₂(dba)3 (119 mg, 0.13 mmol) in toluene (10 ml) was stirred under nitrogen atmosphere at 100°C overnight. The mixture was cooled to room temperature, evaporated to dry, then purified by prep-TLC (dichloromethane/methanol = 10:1) to afford 68 mg of compound 85 as a yellow solid (yield 22%).

[00215] ¹H NMR δ_Η (400 MHz; CDCI₃): 3.25 (br s, 4H), 3.37 (br s, 4H), 3.98-4.00 (m, 2H), 4.08-4.10 (m, 2H), 4.79 (s, 2H), 6.80-6.87 (m, 2H), 7.17 (t, J = 8.0 Hz, 1 H).

[00216] HPLC-UV: method [mobile phase: from 95% water (0.05% trifluoroacetic acid) and 5% acetonitrile to 40% water (0.05% trifluoroacetic acid) and 60% acetonitrile in 6.5 min], Rt = 2.56 min, purity 99.6% (214 nm).

[00217] MS: 235.1 ([M+H]⁺, 100%).

Example 11 : Synthesis of 1-(2,2-Dimethyl-3,4-dihyd

benzo[6][1,4]dioxepin-6-yl)piperazine (MRZ-91)

Scheme 10. Synthesis of Compound MRZ-91 (= compound 91 in Scheme

10)

11.1 Synthesis of 3-Methylbut-3-en-1-yl methanesulfonate (91-2):

[00218] To a solution of compound 91-1 (3.0 g, 34.88 mmol) and triethylamine (7.05 g, 69.76 mmol) in dichloromethane (30 ml) was added methanesulfonyl chloride (4.8 g, 41.86 mmol) at 0°C, then stirred at room temperature for 3 h. The mixture was quenched with water, two phases were separated. The dichloromethane layer was washed with water and brine, dried over anhydrous Na₂S0₄. The solvent was removed under vacuum to give 5.0 g of compound 91-2 as a white solid (yield 88%).

[00219] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.77 (s, 3H), 2.46 (t, J = 6.8 Hz, 2H), 3.00 (s, 3H), 4.33 (t, J = 6.8 Hz, 2H), 4.79 (s, 1 H), 4.87 (s, 1 H).

11.2 Synthesis of 3-Bromo-2-((3-methylbut-3-en-1-yl)oxy)phenol (91-3):

[00220] A mixture of compound 1-3 (3.0 g, 15.87 mmol), compound 91- 2 (2.6 g, 15.87 mmol), potassium carbonate (2.2 g, 15.87 mmol) and potassium iodide (266 mg, 1.6 mmol) in DMF (50 ml) was stirred at 60°C overnight. After concentration, the residue was dissolved in water (25 ml) and acidified with 6 N hydrochloric acid to pH = 2. The mixture was extracted with dichloromethane (20 ml ^χ 3), and the combined dichloromethane was washed with water and brine, dried over anhydrous Na₂S0₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to give

I .48 g of the mixture of compound 91-3 and 91-3B as colorless oil (yield 36%).

[00221] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.80-1.84 (m, 3H), 2.49-2.54 (m, 2H), 4.10-4.22 (m, 2H), 4.82-5.00 (m, 2H), 6.03-6.07 (m, 1 H), 6.72-6.88 (m, 2H), 7.02-7.11 (m, 1 H).

I I .3 Synthesis of 6-Bromo-2,2-dimethyl-3,4-dihydro-2/-/- benzo[£>][1 ,4]dioxepin (91-4):

[00222] A mixture of compound 91-3 and 91-3B (1.38 g, 5.37 mmol) in formic acid (10 ml) was stirred at 90°C for 10 min. The mixture was quenched with water, extracted with ethyl acetate (20 ml ^χ 3), and the combined ethyl acetate was washed with a saturated NaHCO₃ aqueous solution, water and brine, dried over anhydrous Na₂SO₄. The solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 100:1) to give 392 mg of the mixture of compound 91-4 and 91-4B (trace) as yellow oil (yield 28%).

[00223] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.35 (s, 6H), 2.09 (t, J = 5.2 Hz, 2H), 4. 34 (m, 2H), 6.76 (t, J = 8.4 Hz, 1 H), 6.87 (dd, J = 8.0, 1.6 Hz, 1 H), 7.24 (m, 1 H). 11.4 Synthesis of ferf-Butyl 4-(2,2-dimethyl-3,4-dihydro-2/-/- benzo[6][1 ,4]dioxepin-6-yl)piperazine-1-carboxylate (91-5):

[00224] A mixture of compound 91-4 and 91-4B (390 mg, 1.52 mmol), terf-butyl piperazinecarboxylate (423 mg, 2.27 mmol), Pd₂(dba)₃ (104 mg, 0.15 mmol), BINAP (187 mg, 0.3 mmol) and sodium terf-butoxide (289 mg, 0.3 mmol) in toluene (10 ml) was stirred at 100°C under nitrogen atmosphere overnight. After cooling, the mixture was diluted with ethyl acetate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to give 375 mg of compound 91-5 as yellow oil (yield 68%).

[00225] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.36 (s, 6H), 1.48 (s, 9H), 2.06 (t, J = 5.2, Hz, 2H), 2.95-2.98 (m, 4H), 3.56-3.59 (m, 4H), 4.30 (t, J = 5.2 Hz, 2H), 6.61-6.65 (m, 2H), 6.82 (t, J = 8.0 Hz, 1 H).

11.5 Synthesis of 1-(2,2-Dimethyl-3,4-dihydro-2H-benzo[ib][1 ,4]dioxepin-6- yl)piperazine (91):

[00226] A mixture of compound 91-5 (375 mg, 1.03 mmol) in 2M hydrochloride/ethyl acetate solution (5 ml) was stirred at room temperature for 3 h. After concentration, the residue was dissolved in water, extracted with ethyl acetate (abandoned). The water phase was basified with 2N sodium hydroxide to pH = 10, then extracted with dichloromethane (20 ml 3). The combined dichloromethane was washed with water and brine, dried over anhydrous Na₂S0₄. The solvent was removed under vacuum and the crude product was purified by prep-TLC (dichloromethane/methanol = 10:1) to give 103 mg of compound 91 as a white solid (yield 38%).

[00227] ¹H NMR δ_Η (400 MHz; CDCI₃): 1.35 (s, 6H), 2.06 (d, J = 5.2, Hz, 2H), 3.36-3.37 (m, 8H), 4.28 (t, J = 4.8 Hz, 2H), 6.63-6.70 (m, 2H), 6.83 (t, J = 8.0 Hz, 1 H). [00228] HPLC-UV: method [mobile phase: from 95% water (0.05% trifluoroacetic acid) and 5% acetonitrile to 40% water (0.05% trifluoroacetic acid) and 60% acetonitrile in 6.5 min], Rt = 2.98 min, purity 96.0% (214 nm).

[00229] MS: 263.1 ([M+H]⁺, 100%).

Part B. Biochemical Assays

Example 12: In vitro 5-HT _A/B and 5-HT₂A_/2B Activity Measurements:

A. 5-HT_1A/B SPA GTPyS assay

(performed at Euroscreen, order no.: 5-HTi_A:FAST-0500G, 5-HTi_B: FAST-0501G):

[00230] SPA ³⁵S-GTPyS experiments were conducted with Euroscreen membrane preparations (see Table 1). Membranes were mixed with GDP (volume:volume) and incubated for at least 15 min on ice. In parallel, GTPy[³⁵S] was mixed with the beads (volume:volume) just before starting the reaction.

[00231] For agonist testing, the following reagents were successively added in the wells of an Optiplate (Perkin Elmer): 50μΙ of test compound or reference ligand, 20μΙ of the membranes:GDP mix, 10μΙ of assay buffer and 20μΙ of the GTPy [³⁵S]:beads mix.

[00232] The plates were covered with a top seal, shaken on an orbital shaker for 2 min, and then incubated for 1 h at room temperature. Then the plates were centrifuged for 10 min at 2000 rpm, incubated at room temperature 1 h and counted for 1min/well with a PerkinElmer TopCount reader. [00233] Material:

- Assay Buffer: 20mM HEPES pH 7.4; 100 mM NaCI, 10 pg/ml saponin, 3 mM MgCI₂

- Membranes: recombinant CHO-K1 membrane extracts (see Table 1) thawed on ice and diluted in assay buffer to give 500 Mg/ml (5 pg/10 μΙ) and kept on ice.

- GDP: diluted in assay buffer to give 3 μΜ final concentration.

- Beads: PVT-WGA (Amersham, RPNQ0001), diluted in assay buffer at 50mg/ml (0.5mg/10 μΙ).

- GTPy³⁵S: (Perkin Elmer, NEG030X), diluted in assay buffer to give 0.1 nM final concentration

- Ligand: 5-CT (Tocris, 458) diluted in assay buffer

B. 5-HT_2B Aequorin assay

(performed at Euroscreen, order no.: FAST-0506A):

[00234] The Aequorin assay was conducted with recombinant cell lines. Receptor accession numbers, cellular background and reference compounds are shown in Table 1.

[00235] Recombinant cells co-expressing mitochondrial apoaequorin and recombinant human 5-HT_2B receptor grown to mid-log phase in culture media without antibiotics were detached with PBS-EDTA, centrifuged and resuspended in assay buffer (DMEM/HAM's F12 with HEPES, without phenol red + 0.1 % BSA protease free) at a concentration of 1 x 10⁶ cells/ml. Cells were incubated at room temperature for at least 4h with coelenterazine h.

[00236] The reference agonist was tested to evaluate the performance of the assay on each day of the test and determine EC₅₀.

[00237] For agonist testing, 50 μΙ of cell suspension was mixed with 50μΙ of test or reference agonist in a 96-well plate. The resulting emission of light was recorded using a Hamamatsu Functional Drug Screening System 6000 (FDSS 6000) luminometer.

[00238] To standardize the emission of recorded light (determination of the "100% signal") across plates and across different experiments, some of the wells contained 100 μΜ digitonin or a saturating concentration of ATP (20 μΜ).

C. 5-HT₂A assay

[00239] An aequorin cell line expressing the 5-HT₂c non-edited (ne) receptor can be used to evaluate the functional activity of the compounds of the present invention. Aequorin cells grown 18 h prior to the test in media without antibiotics are detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in "assay buffer" (DMEM/HAM's F12 with HEPES + 0.1 % BSA protease free). Cells are incubated at room temperature for at least 4 h with Coelenterazine h (Molecular Probes). The reference agonist used is 5-HT and a-methyl-5-HT. For agonist testing, 50 μΙ of cell suspension are injected on 50 μΙ of test compound or reference agonist plated in a 96-well plate. The resulting emission of light is recorded using the Hamamatsu Functional Drug Screening System 6000 (FDSS 6000).

Table 1 :

Receptor Accession Cell line Reference

Number agonist

5-HTIA NP 000515.2 CHO-K1 5-CT

5-HT-i B NP 000854.1 CHO-K1 5-CT

5-HT_2B NP 00858.2 CHO-mt Aeq a-methyl-5HT

+Ga16

Results

Quality Control

[00240] On each day of experimentation, reference compounds were tested at several concentrations in duplicate (n = 2) to obtain a dose- response curve and an estimated EC₅₀ value.

[00241] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session. A session was considered as valid only if the reference value was found to be within a 0.5 logs interval from the historical value. For replicate determinations, the maximum variability tolerated in the test was of +/-20% around the average of the replicates.

[00242] Dose-response data from test compounds were analyzed with XLfit (IDBS) software using nonlinear regression applied to a sigmoidal dose-response model (4 Parameter Fit).

[00243] Agonist activity of test compounds is expressed as a percentage of the activity of the reference agonist at its EC₁₀₀ concentration. Part C. In vivo Experiments

EXAMPLE 13 Effect of MRZ-6 on L-DOPA Induced Dyskinesia in the 6- hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease

Materials and Methods

Animals

[00244] Male Sprague Dawley rats (Elevage Janvier, Le Genest Saint Isle, France) weighing between 220 and 250 g at the beginning of the study are used in these experiments. They are housed under a 12-h light/dark cycle with free access to standard pelleted food and tap water. Animal treatment and experimental procedures are in accordance with Animal Health regulations and are approved by local ethical committees.

Dopamine-denervating lesions

[00245] Dopamine-denervating lesions are performed on rats anaesthetized with a 5:1 mixture of ketamine and xylazine (1 ml/kg, i.p.). All rats receive unilateral injection of 6-hydroxydopamine (6-OHDA-HCI) (4 pg/pl in 0.02% ascorbate-saline, in total 16pg/4 μΙ) into the right ascending DA fibre bundle at the following coordinates (in mm relative to bregma and the dural surface): A = - 4.4, L = -1.2, V = -8.3, tooth bar -2.3. Injections are performed at the rate of 1 μΙ/min (allowing an additional 3 min before retracting the needle) using a 10-μΙ Hamilton microsyringe with a 26-gauge steel cannula.

Experimental Design and Drug Treatment

[00246] At 4 weeks post-lesion, rats are treated for 3 weeks (15 days in total, weekends excluded) with a single daily i.p. injection of 6 mg/kg of L- DOPA mixed with 15 mg/kg of the peripheral DOPA-decarboxylase inhibitor benserazide hydrochloride or with saline (vehicle controls). L-DOPA and benserazide are dissolved in a physiological saline solution. Chronic treatment with this dose of L-DOPA has been shown to induce gradual development of dyskinetic-like movements in 6-OHDA-lesioned rats. After ca. 3 weeks of the daily treatment, rats are administered 30 min before the evaluation of abnormal involuntary movement (AIM)s with MRZ-6 (3 mg/kg, dissolved in 20% HP BCD/distil led water, p.o.), followed by L- DOPA/benserazide (L-DOPA 6 mg/kg, benserazide 15 mg/kg), i.p., 20 min before the beginning of the test.

Behavioral Test

[00247] In order to evaluate the severity of LID, AIMs are recorded every second day as described by Cenci et al. (1998). Cenci MA, Lee CS, Bjorklund A. L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. Eur J Neurosci 1998 10:2694-2706. Repetitive movements affecting the side of the body contralateral to the lesion that could not be ascribed to any normal behavioural pattern are classified into four different subtypes: locomotive AIMs, i.e., increased locomotion with contralateral side bias; axial dystonia, i.e., contralateral twisted posturing of the neck and upper body; orolingual AIMs, i.e., stereotyped jaw movements and contralateral tongue protrusion; and forelimb dyskinesia, i.e., repetitive jerks of the contralateral forelimb, sometimes combined with grabbing movements of the paw. Each rat is scored on a severity scale from 0 to 4 based on its frequency and persistence (1 = occasional; 2 = frequent; 3 = continuous but interrupted by sensory distraction; 4 = continuous, severe and not interrupted by sensory distraction). The axial, orolingual and forelimb (AOL) AIMs are presented together as a mean (mean AIM score) per time point. Only rats with a dyskinesia severity > grade 2 in two of the abnormal involuntary movements (axial and /or limb and /or orolingual), resulting in a cumulative abnormal involuntary movement (AIM) score > 40 over the two consecutive selection sessions, are included in further experiments. In this experiment, L-DOPA (6 mg/kg + Benserazide 15mg/kg) is injected with vehicle or in combination with MRZ-6 at 3 and 10 mg/kg. Statistical Analysis

[00248] A signed-rank test is used for the evaluation of within-subject comparison of the cumulative data over the total time of 3 h. A two-way ANOVA is used to evaluate the significance of the time course of LID. A Post hoc Tukey test is performed where appropriate.

Results

[00249] Figure 1 shows the cumulative ALO AIM score over 180 min. ^* indicates a significant difference with p<0.021 vs L-DOPA - vehicle treated animals (signed rank test). Figure 2 illustrates the time course of the effect of MRZ-6 on AIM scores in 6-OHDA-lesioned rats. The data are expressed as number of AIMs. * indicates a significant difference with p<0.05 between L- DOPA - vehicle-treated animals (2-way RM ANOVA followed by Holm-Sidak test).

[00250] This result demonstrates that MRZ-6 (3 mg/kg) strongly reduced LID.

Part D. EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL

COMPOSITIONS

[00251] With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions follow.

(a) Tablets suitable for oral administration, which contain the active ingredient, may be prepared by conventional tableting techniques.

(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.

(c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.

[00252] Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.

[00253] The following examples are again given by way of illustration only and are not to be construed as limiting.

EXAMPLE 14: Tablet Formulation

[00254] A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:

mg

Active Ingredient 10

Lactose 61

Microcrystalline Cellulose 25

Talcum 2

Magnesium stearate 1

Colloidal silicon dioxide 1

EXAMPLE 15: Tablet Formulation

[00255] Another suitable formulation for a tablet containing 100 mg is as follows:

mg

Active Ingredient 100

Polyvinylpyrrolidone, crosslinked 10 Potato starch 20

Polyvinylpyrrolidone 19

Magnesium stearate 1

Microcrystalline Cellulose 50

Film coated and colored.

The film coating material consists of:

Hypromellose 10

Microcryst. Cellulose 5

Talcum 5

Polyethylene glycol 2

Color pigments 5

EXAMPLE 16: Capsule Formulation

[00256] A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:

mg

Active Ingredient 50

Com starch 26

Dibasic calcium phosphate 50

Talcum 2

Colloidal silicon dioxide 2 filled in a gelatin capsule.

EXAMPLE 17: Solution for injection

[00257] A suitable formulation for an injectable solution is as follows:

Active Ingredient mg 10

Sodium chloride mg q.s.

Water for Injection ml ad 1.0

EXAMPLE 18:Liquid oral formulation

[00258] A suitable formulation for 1 liter of an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: mg

Active Ingredient 2

Saccharose 250

Glucose 300

Sorbitol 150

Orange flavor 10

Colorant q.s.

Purified water ad 1000 ml

EXAMPLE 19: Liquid oral formulation

[00259] Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:

9

Active Ingredient 20.00

Tragacanth 7.00

Glycerol 50.00

Saccharose 400.00

Methylparaben 0.50

Propylparaben 0.05

Black currant-flavor 10.00

Soluble Red color 0.02

Purified water ad 1000 ml

EXAMPLE 20: Liquid oral formulation

[00260] Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: g

Active Ingredient 2

Saccharose 400 Bitter orange peel tincture 20

Sweet orange peel tincture 15

Purified water ad 1000 ml

EXAMPLE 21 : Aerosol formulation

[00261] 180 g aerosol solution contain:

9

Active Ingredient 0

Oleic acid 5

Ethanol 81

Purified Water 9

Tetrafluoroethane 75

[00262] 15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.

EXAMPLE 22: TPS formulation

[00263] 100 g solution contain:

Active Ingredient 10.0

Ethanol 57.5

Propyleneglycol 7.5

Dimethylsulfoxide 5.0

Hydroxyethylcellulose 0.4

Purified water 19.6

[00264] 1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use.

EXAMPLE 23: Nanoparticle formulation

[00265] 10 g of polybutylcyanoacrylate nanoparticles contain: g

Active Ingredient 1.00

Poloxamer 0.10

Butylcyanoacrylate 8.75

Mannitol 0.10

Sodium chloride 0.05

[00266] Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.

* * * * *

[00267] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[00268] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference to the extent permitted under the respective patent law and patent regulations.

Claims

1. A compound of Formula I

I

or a pharmaceutically acceptable salt thereof,

wherein R is selected from -H and -F, particularly wherein R¹ is -H; X is selected from -0-CR⁴R⁵-, -CH₂-0- and -CH₂-CR⁴R⁵-; Y is (-CR⁶R⁷-)n, wherein n is 0 or 1 ;

R² and R³ (i) are independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R² and R³, together with the carbon atom they are attached to, form a cyclopropyl ring;

R⁴ and R⁵ (i) are independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁴ and R⁵, together with the carbon atom they are attached to, form a cyclopropyl ring; and

R⁶ and R⁷ (i) are independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁶ and R⁷, together with the carbon atom they are attached to, form a cyclopropyl ring,

provided that the following compounds 1 to 6 are excluded:

The compound of claim 1 , wherein at least one of R¹ to R⁷ is different from -H, particularly wherein no more than four substituents R¹ to R⁷ are different from -H, particularly wherein no more than two substituents R¹ to R⁷ are different from -H, particularly wherein exactly two substituents R¹ to R⁷ are different from -H, or wherein exactly one substituent R¹ to R⁷ is different from -H.

The compound of claim 1 , which is selected from the list of: MRZ-6, MRZ-71 , MRZ-80, MRZ-93, MRZ-73, MRZ-90, MRZ-94, MRZ-85, and MRZ-91 , particularly MRZ-6.

The compound of any one of claims 1 to 3, wherein said compound has an EC₅₀ value of greater than 0.5 μΜ in a cell-based in vitro 5-HT2C activity measurements, particularly wherein the compound is selected from the list of: MRZ-6, MRZ-71 , MRZ-90, MRZ-91 , MRZ-(-)87, and MRZ-(+)88.

A pharmaceutical composition comprising a compound of any one of claims 1 to 4, particularly a pharmaceutical composition for oral administration.

6. A compound of Formula I

or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from -H and -F, particularly wherein R¹ is -H; X is selected from -0-CR⁴R⁵-, -CH₂-0- and -CH₂-CR⁴R⁵-; Y is (-CR⁶R⁷-)n, wherein n is 0 or 1 ;

R² and R³ are (i) independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R² and R³, together with the carbon atom they are attached to, form a cyclopropyl ring;

R⁴ and R⁵ (i) are independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁴ and R⁵, together with the carbon atom they are attached to, form a cyclopropyl ring; and

R⁶ and R⁷ (i) are independently selected from H and Me, (ii) one of R² and R³ is ethyl and the other is H; or (iii) R⁶ and R⁷, together with the carbon atom they are attached to, form a cyclopropyl ring,

for use in the treatment or prevention of (i) L-DOPA-induced dyskinesia, (ii) ADHD, or (iii) anxiety;

rovided that the following compounds 1 , 3, and 6 are excluded:

1 3 6

7. The compound of claim 6, wherein at least one of R¹ to R⁷ is different from -H, particularly wherein no more than four substituents R to R⁷ are different from -H, particularly wherein no more than two substituents R¹ to R⁷ are different from -H, particularly wherein exactly two substituents R¹ to R⁷ are different from -H.

8. The compound of claim 6, which is selected from the list of: MRZ-6,

MRZ-7171 , MRZ-80, MRZ-(-)87, MRZ-(+)88, MRZ-93, MRZ-73, MRZ-90, MRZ-94, MRZ-85, and MRZ-91 , particularly MRZ-6, MRZ-71 , MRZ-80, MRZ-93, MRZ-73, MRZ-90, MRZ-94, MRZ-85, MRZ-91 , and MRZ-D, more particularly MRZ-6.

9. The compound of any one of claims 6 to 8, wherein said compound has an EC₅₀ value of greater than 0.25 μΜ in a cell-based in vitro 5-HT₂c activity measurements, particularly wherein the compound is selected from the list of: MRZ-6, MRZ-71 , MRZ-90, MRZ-91 , MRZ-(-)87, MRZ- (+)88, and MRZ-93.

10. The compounds of any one of claims 6 to 9, wherein the subject to be treated suffers from a movement disorder, particularly wherein the movement disorder is selected from parkinsonism, restless legs syndrome (RLS), and Chorea Huntington, particularly parkinsonism, particularly wherein the parkinsonism is idiopathic (PD), particularly wherein the subject is undergoing long-term treatment with L-DOPA therapy indicated for the treatment of PD.

11. The compound of any one of claims 6 to 10 in the form of an oral formulation.

12. The compound of any one of claims 6 to 11 , wherein said treatment or prevention comprises the additional administration with at least one additional pharmaceutical agent, particularly wherein the additional pharmaceutical agent(s) is/are selected from the group of (i) an agent which has been shown to be effective for the treatment of PD, and (ii) a decarboxylase inhibitor such as benserazide and carbidopa.

13. A method of synthesizing a compound of anyone of claims 1 to 4 and 6 to

12, comprising the step of reacting (i) a compound of Formula II

II

wherein Z is a leaving group, particularly a halogen atom, particularly - Br,

X¹ is selected from -0-CR⁴R⁵-, -CH₂-O- -CH₂-CR⁴R⁵-; and - CH=CR⁴; and

Y, R¹, R² and R³ are as defined in claim 1 ,

with (ii) a protected piperazine, particularly with N-Boc-piperazine; particularly, wherein said step is performed by palladium catalysis, particularly by using Pd₂(dba)₃, particularly in the presence of BINAP and sodium tert-butoxide.

The method of claim 13, wherein X¹ is -CH=CR⁴, further comprising the step of hydrogenating the double bond in X¹, particularly by using Pd/C and H₂.