Novel catecholamine prodrugs for use in the treatment of Parkinson's disease

Abstract

The present invention provides compounds of formula (Id) which are prodrugs of catecholamines for use in the treatment of neurodegenerative diseases and disorders. The present invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of treating neurodegenerative or neuropsychiatric diseases and disorders, particularly Parkinson's disease, using the compounds of the invention.

Description

[Technical field]

[0001] The present invention provides compounds that are prodrugs of the dopamine agonist (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol and their use in the treatment of Parkinson's disease and / or other conditions in which treatment with a dopamine agonist would be therapeutically beneficial, such as, but not limited to, restless legs syndrome, Huntington's disease and Alzheimer's disease, and also neuropsychiatric diseases and disorders, such as, but not limited to, schizophrenia, attention deficit hyperactivity disorder and drug addiction. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention. [Background technology]

[0002] Parkinson's disease (PD) is a common neurodegenerative disorder that becomes more prevalent with age and affects an estimated 7-10 million people worldwide. Parkinson's disease is a multifaceted disease characterized by both motor and non-motor symptoms. Motor symptoms include resting tremor, bradykinesia / akinesia (slowness and lack of movement), muscular rigidity, postural stability and gait dysfunction, and non-motor symptoms include neuropsychiatric disorders (e.g., depression, psychotic symptoms, anxiety, apathy, mild cognitive impairment and dementia) as well as autonomic and sleep disorders (Poewe et al., Nature Review, (2017) vol3 article 17013:1-21).

[0003] An important hallmark of the pathophysiology of Parkinson's disease is the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta, which provides dopaminergic innervation to the striatum and other brain regions. Such progressive neurodegeneration leads to a decline in striatal levels of dopamine, which ultimately results in a series of changes in the basal ganglia circuitry, ultimately resulting in the four cardinal motor features of Parkinson's disease. The primary targets of dopamine in the striatum consist of medium spiny GABAergic neurons (MSNs) with prominent topographic processes that selectively express D1 or D2 receptors. GABAergic MSNs projecting to the lateral pallidum, also called the striatopallidal "indirect pathway", express D2 receptors (MSN-2). GABAergic-MSNs projecting to the substantia nigra pars reticulata and medial pallidum, also called the striatopallidal "direct pathway", express D1 receptors (MSN-1). Lack of dopamine due to neuronal loss leads to an imbalance in the activity of the two pathways, resulting in a marked decrease in thalamic and cortical output activity and ultimately in motor dysfunction (Gerfen et al, Science (1990) 250:1429-32; Delong, (1990) Trends in Neuroscience 13:281-5; Alexander et Crutcher, (1990) Trends in Neuroscience 13:266-71 and for review Poewe et al., Nature Review (2017) vol.3 article 17013:1-21).

[0004] The most effective therapeutic strategies available for patients suffering from Parkinson's disease and aiming to control motor symptoms are mainly indirect and direct dopamine agonists. Classical and gold standard therapy includes chronic oral intake of L-3,4-dihydroxyphenylalanine (L-DOPA), which is decarboxylated in the brain to form dopamine. Other approaches include administration of dopamine receptor agonists such as apomorphine, which acts on both D1 and D2 receptor subtypes, or pramipexole, ropinirole, and other agonists that are predominantly directed against the D2 receptor subtype. Due to the activation of both D1 and D2 receptor subtypes and the holistic rebalancing of the indirect-direct pathway (i.e., only D2 agonists reverse the dysfunction of the indirect pathway), optimal MR (relief of symptoms with movement) is obtained with the use of both L-DOPA and apomorphine.

[0005] L-DOPA and apomorphine, whose structures are shown below, are currently the most effective PD drugs in clinical use. [ka]

[0006] L-DOPA is a prodrug of dopamine and remains the most effective drug in the treatment of motor Parkinson's disease. However, after several years of treatment (i.e., honeymoon period), complications occur due to the inherent progression of the disease (i.e., sustained loss of dopaminergic neurons) and the poor pharmacokinetic (PK) profile of L-DOPA. These complications include 1) dyskinesia, which is an abnormal involuntary movement that occurs during the optimal "timely effect" of the drug, and 2) out-of-phase periods during which the positive effects of L-DOPA gradually decrease and symptoms return or worsen (Sprenger and Poewe, CNS Drugs (2013), 27:259-272).

[0007] Direct dopamine receptor agonists can activate dopamine autoreceptors as well as postsynaptic dopamine receptors located on medium spiny neurons MSN-1 and MSN-2. Apomorphine belongs to a class of dopamine agonists that have a 1,2-dihydroxybenzene (catechol) moiety. When combined with a phenethylamine motif, catecholamines often have low or no oral bioavailability, as is the case with apomorphine. Clinically, apomorphine is used to treat PD, albeit with parenteral delivery (generally intermittent subcutaneous administration or continuous daytime parenteral infusion via pump). For apomorphine, animal studies have shown that transdermal delivery or implantation could provide a potential form of administration. However, when delivery of apomorphine from implants was studied in monkeys (Bibbiani et al., Chase Experimental Neurology (2005), 192:73-78), it was found that in most cases the animals had to be treated with the immunosuppressant dexamethasone to prevent local irritation and other complications after the implant procedure. Alternative delivery strategies for apomorphine therapy in PD, such as inhaled and sublingual formulations, have been extensively explored (see, for example, Grosset et al., Acta Neurol Scand. (2013), 128:166-171 and Hauser et al., Movement Disorders (2016), Vol. 32(9):1367-1372). However, these attempts have not yet been clinically implemented for the treatment of PD.

[0008] An alternative to parenteral formulation of catecholamines involves the use of prodrugs that mask the free catechol hydroxyl group to allow oral administration. However, a known problem with developing prodrugs for clinical use is the difficulty associated with predicting conversion to the parent compound in humans.

[0009] Various ester prodrugs of catecholamines have been reported in the literature, including fully coated N-propyl-noraporphine (NPA) and monopivaloyl esters of apomorphine for duodenal delivery (WO 02 / 100377) and the D1-like agonist adrogolide, a diacetyl prodrug of A-86929 (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305-316). Adrogolide undergoes extensive hepatic first-pass metabolism in men after oral administration, resulting in low oral bioavailability (about 4%). In PD patients, intravenous (IV) adrogolide has antiparkinsonian efficacy comparable to L-DOPA (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305-316).

[0010] In addition to ester prodrugs of catecholamines, an alternative prodrug approach involves masking the two catechol hydroxyl groups as the corresponding methylene-dioxy (MDO) derivatives or di-acetaryl derivatives. The principle of this prodrug is described, for example, in Campbell et al., Neuropharmacology (1982); 21(10): 953-961, as well as in U.S. Pat. No. 4,543,256, WO 2009 / 026934 and WO 2009 / 026935.

[0011] Another proposed approach to catecholamine prodrugs is the formation of enone derivatives as proposed, for example, in WO 2001 / 078713 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444. For further examples of catecholamine prodrugs, see, for example, Sozio et al., Exp. Opin. Drug Disc. (2012); 7(5): 385-406.

[0012] The compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, hereinafter referred to as Compound (I), is disclosed in WO 2009 / 026934. The trans isomer was previously disclosed in Liu et al., J. Med. Chem. (2006), 49:1494-1498, followed by Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444, with pharmacological data suggesting that the compound has low oral bioavailability in rats. The racemic compound was first disclosed in Cannon et al., J. Heterocyclic Chem. (1980); 17:1633-1636. [ka] Compound (I) is a dopamine receptor agonist with mixed D1 and D2 activity. Several prodrug derivatives of Compound (I) are known in the art.

[0013] Liu et al., J. Med. Chem. (2006), 49:1494-1498 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444 disclose an enone derivative of formula (Ia), shown below, which was shown to be converted to the active compound (I) in rats. [ka]

[0014] WO 2009 / 026934 and WO 2009 / 026935 disclose two prodrug derivatives of compound (I), including (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline, a methyldioxy (MDO) derivative having the following formula (Ib): [ka]

[0015] The conversion of compound (Ib) to compound (I) in rat and human hepatocytes has been demonstrated in WO 2010 / 097092. Furthermore, the in vivo pharmacology of compounds (Ia) and (Ib) and the active "parent compound" (I) has been tested in various animal models for Parkinson's disease (WO 2010 / 097092). Both compound (I) and compounds (Ia) and (Ib) have been found to be effective, and it has been shown that compounds (Ia) and (Ib) are converted to compound (I) in vivo. All three compounds have been reported to have a longer duration of action than that observed for L-dopa and apomorphine.

[0016] Other prodrugs of compound (I) disclosed in WO 2009 / 026934 and WO 2009 / 026935 are conventional ester prodrugs of formula (Ic): [ka]

[0017] Despite longstanding interest in this field, there remains a clear unmet need for the development of effective, well-tolerated and orally active drugs for the treatment of PD. Prodrug derivatives of mixed D1 / D2 agonists that provide a stable PK profile capable of providing continuous dopaminergic stimulation could fulfill this unmet need.

[0018] Masking the catechol hydroxy group of carbidopa derivatives with benzyl or lower alkyl to improve intestinal absorption was proposed in WO 2004 / 052841, but the potential for prodrugs of such compounds was not demonstrated. Summary of the Invention

[0019] The present invention relates to novel compounds for the treatment of Parkinson's disease, which are glucuronide derivatives of compound (I) or unsaturated glycosyl derivatives, ester derivatives, and ether derivatives of compound (I) further derivatized by esterification of the free hydroxyl and carboxylic acid groups in the molecule. More specifically, the present invention relates to novel prodrug derivatives of compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (compound (I)). The compounds of the present invention have been shown to be particularly useful for the oral delivery of compound (I).

[0020] Thus, the present invention relates to a compound of formula (Id) [ka] (In the formula, a) R1 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C3-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl, and R2 is selected from one of the following substituents (i) and (ii); or b) R1 is selected from one of the following substituents (i) and (ii) and R2 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C3-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl; or c) R1 and R2 are independently selected from the following substituents (i) and (ii): d) R1 and R2 are both represented by the following substituent (i); or e) R1 and R2 are both represented by the following substituent (ii): [ka] Where: * indicates the attachment point; The carbon atom at the point of attachment on substituent (i) is in the S configuration; R3 is selected from H, C1-C6 alkyl and benzyl; R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl; With the proviso that when R3 and R4 in substituent (i) are both H, R1 and R2 cannot both be substituent (i); and Provided that when one of R1 and R2 is a substituent (i) and both R3 and R4 in the substituent are H, the other of R1 and R2 cannot be H. or a pharma- ceutically acceptable salt thereof.

[0021] One aspect of the invention relates to a pharmaceutical composition comprising a compound according to formula (Id) or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0022] Another aspect of the invention relates to a compound according to formula (Id) for use as a medicament.

[0023] Another aspect of the invention relates to a compound according to formula (Id) or a pharma- ceutically acceptable salt thereof for use in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease, or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0024] Another aspect of the invention relates to a method of treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease, or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula (Id) or a pharma- ceutically acceptable salt thereof.

[0025] Another aspect of the invention relates to the use of a compound according to formula (Id) or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease, or for the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0026] definition connection point In the context of the present invention, it is understood that the carbon atom at the point of attachment on substituent (i) is at the anomeric position of (i). Similarly, the carbon atom at the point of attachment on substituent (ii) (as shown in embodiment 1) is at the anomeric position of (ii).

[0027] Compounds of the Invention Reference to a compound encompassed by the present invention includes the free substance (e.g., free base or zwitterion) of a compound of the present invention, pharma- ceutically acceptable salts, acid addition salts or base addition salts, etc. of a compound of the present invention, as well as polymorphic and amorphous forms of the compound of the present invention and its pharma- ceutically acceptable salts. Additionally, the compounds of the present invention and their pharma- ceutically acceptable salts can potentially exist in unsolvated as well as solvated forms with pharma- ceutical acceptable solvents such as water, ethanol, etc. Both solvated and unsolvated forms are encompassed by the present invention.

[0028] Pharmaceutically acceptable salts In the context of this invention, pharma- ceutically acceptable salts are intended to denote non-toxic, ie physiologically acceptable salts.

[0029] The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts, which are salts formed with inorganic and / or organic acids on a nitrogen atom in the parent molecule. The acids may be selected from, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, malonic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, gentisic acid, saccharin, and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalene-2-sulfonic acid, 2-hydroxyethanesulfonic acid, and benzenesulfonic acid.

[0030] The term "pharmaceutically acceptable salts" also includes pharmaceutically acceptable base addition salts, which are salts formed with inorganic and / or organic bases on acidic groups of the compounds of formula (Id), said bases may be selected, for example, from alkali metal bases such as zinc hydroxide and sodium hydroxide, lithium hydroxide, potassium hydroxide, and alkaline earth metal bases such as calcium hydroxide and magnesium hydroxide, and organic bases such as choline, diethylamine, trimethylamine and triethylamine.

[0031] Other examples of acids and bases useful for forming pharma- ceutically acceptable salts are described, for example, in Stahl and Wermuth (Eds), Handbook of Pharmaceutical salts. Properties, selection, and use, Wiley-VCH2008.

[0032] Prodrug In the context of the present invention, the term "prodrug" or "prodrug derivative" refers to a compound that is converted into a pharmacologically active site in the body after administration to a living subject, such as a mammal, preferably a human. The conversion preferably occurs in a mammal, such as a mouse, a rat, a dog, a miniature pig, a rabbit, a monkey and / or a human. In the context of the present invention, a "prodrug of the compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol" or a "prodrug of the compound of formula (I)" or a "prodrug of the compound (I)" is understood to be a compound that is converted into the compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol in the body after administration. The administration may be by conventional routes of administration of pharmaceutical compositions known in the art, preferably oral administration.

[0033] In the context of the present invention, the terms "parent compound" and "parent molecule" refer to the pharmacologically active moiety obtained upon conversion of the corresponding prodrug. For example, the "parent compound" of one of the compounds (Ia), (Ib), (Ic) or any of the compounds of the present invention is understood to be the compound of formula (I).

[0034] substituent In the context of the present invention, certain ranges are indicated indiscriminately by "-" (dash) or "~", for example, "C1-C6 alkyl" is equivalent to "C1 to C6 alkyl".

[0035] The term "alkyl" means a linear (i.e. unbranched) or branched saturated hydrocarbon having from 1 to 10 carbon atoms. Similarly, the term "C1-C6 alkyl" means a linear or branched hydrocarbon containing from 1 to 6 carbon atoms, unless otherwise specified. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, and n-hexyl. The term "linear C1-C6 alkyl" means a linear (i.e. unbranched) saturated hydrocarbon having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, 1-propyl, 1-butyl, n-pentyl, and n-hexyl.

[0036] The term "carbonyl" refers to the group -C(O)-.

[0037] The term "C3-C6 cycloalkyl" refers to a saturated, monovalent, monocyclic hydrocarbon ring containing 3, 4, 5 or 6 carbon atoms ("C3-C6 cycloalkyl"). The C3-C6 cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

[0038] The term "alkylcarbonyl" means an alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group. Similarly, the term "-C(O)C1-C6 alkyl" means a C1-C6 alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group.

[0039] Pharmacokinetic Definitions and Abbreviations As used herein, "PK profile" is an abbreviation for "pharmacokinetic profile." The pharmacokinetic profile and pharmacokinetic parameters described herein are based on plasma concentration-time data obtained for the compound of formula (I) following oral administration of the compounds of the invention using non-compartmental modeling. The omitted PK parameters are C max (maximum concentration);tmax (C max arrival time);t 1 / 2 (Half-life);AUC 0~24 (area under the curve from time of dosing to 24 hours post-dose) and "24 hour exposure" is the plasma concentration of a compound of formula (I) measured 24 hours post-dose.

[0040] Therapeutically Effective Dose In the context of the present invention, the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, prevent, partially prevent, eliminate or delay the clinical symptoms of a given disease and its complications in a therapeutic intervention involving the administration of said compound. An amount suitable for achieving this is defined as a "therapeutically effective amount". The amount effective for each purpose will vary depending, for example, on the severity of the disease or injury and the weight and general condition of the subject. It will be understood that the determination of the appropriate dosage is accomplished by constructing a matrix of values ​​and testing various points in the matrix, using routine experimentation that is all within the ordinary skill of the skilled physician.

[0041] In the context of the present invention, a "therapeutically effective amount" of a compound of the present invention means an amount of said compound of the present invention which, when administered, preferably by the oral route, to a mammal, preferably a human, is capable of providing an amount of compound (I) sufficient to alleviate, prevent, partially prevent, eliminate or delay the clinical symptoms of a given disease and its complications.

[0042] Treatment and Procedures In the context of the present invention, "treatment" or "treatment" is intended to indicate the management and care of the patient for the purpose of alleviating, preventing, partially preventing, eliminating or slowing the progression of the clinical symptoms of the disease. The patient to be treated is preferably a mammal, in particular a human being.

[0043] Symptoms for treatment The compounds of the present invention are intended for the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease and / or other conditions where treatment with a dopamine agonist is therapeutically beneficial.

[0044] Indications for treatment include various central nervous system disorders characterized by motor and / or non-motor disorders and part of the underlying pathophysiology is dysfunction of striatal-mediated circuitry. Such functional disorders are found in neurodegenerative disorders such as, but not limited to, Parkinson's disease (PD), restless legs syndrome, Huntington's disease, and Alzheimer's disease, as well as in neuropsychiatric disorders such as, but not limited to, schizophrenia, attention deficit hyperactivity disorder, and drug addiction.

[0045] In addition to neurodegenerative diseases and disorders, in other conditions where increasing dopaminergic turnover may be beneficial, mental function, including various aspects of cognition, is improved.It may also have a positive effect in depressed patients, and may be used as an appetite suppressant in the treatment of obesity and in the treatment of drug addiction.It may improve the potentially negative, positive and cognitive symptoms of microcerebrovascular disorder (MBD), narcolepsy, attention deficit hyperactivity disorder and schizophrenia.

[0046] Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are other indications that are clinically treated with dopamine agonists.In addition, impotence, erectile dysfunction, SSRI-induced sexual dysfunction, ovarian hyperstimulation syndrome (OHSS) and certain pituitary tumors (prolactinomas) may also be improved by treating with dopamine agonists.Dopamine is involved in the regulation of the circulatory and renal systems, therefore renal failure and hypertension may be considered as alternative indications for the compounds of the present invention.

[0047] The present invention encompasses the use of the compounds of the present invention to treat the diseases and disorders mentioned above.

[0048] combination In one embodiment of the present invention, the compound of formula (Id) is used in stand-alone therapy as the sole active compound. In another embodiment of the present invention, the compound of formula (Id) may be used in combination with other agents useful for the treatment of neurodegenerative diseases or disorders, such as Parkinson's disease. As used herein in connection with the method of the present invention, which comprises co-administering a compound of formula (Id) with another compound useful for the treatment of neurodegenerative diseases or disorders in therapeutically effective amounts, terms such as "concomitant use," "in combination with," and "combination of," are intended to mean simultaneous or sequential administration of the compound of formula (Id) with the other compound in any order.

[0049] The two compounds may be administered simultaneously or with a time interval between the administration of the two compounds. The two compounds may be administered as part of the same pharmaceutical formulation or composition or in separate pharmaceutical formulations or compositions. The two compounds may be administered on the same day or on different days. They may be administered by the same route, such as oral administration, subcutaneous injection, transdermal administration, depot, intramuscular injection or intravenous injection, or by different routes, such as one compound being administered, for example, orally or by depot, and the other compound being injected. The two compounds may be administered by the same dosing schedule or interval, such as once or twice a day, week or month, or by different dosing schedules, such as one being administered once a day and the other being administered twice a day, week or month.

[0050] In some cases, the patient being treated may already be undergoing treatment with one or more other compounds useful for treating a neurodegenerative disease or disorder when treatment with a compound of formula (Id) is initiated. In other cases, the patient may already be undergoing treatment with a compound of formula (Id) when treatment with one or more other compounds useful for treating a neurodegenerative disease or disorder is initiated. In other cases, treatment with a compound of formula (Id) and treatment with one or more other compounds useful for treating a neurodegenerative disease or disorder are initiated simultaneously.

[0051] Compounds for Combination Therapy In the context of the present invention, compounds used in conjunction with the compounds of formula (Id) may be selected from, for example, MAO-B inhibitors such as L-DOPA, droxidopa, foligrax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamic agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, and antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole.

[0052] In addition to small molecules, the combined compounds may also include emerging biologic approaches in the treatment of neurodegenerative diseases or disorders, such as, for example, antibodies targeting alpha-synuclein, Tau or A-beta proteins.

[0053] Route of administration Pharmaceutical compositions containing the compounds of formula (Id), either as the sole active compound or in combination with other active compounds, may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, buccal, sublingual, pulmonary, transdermal and parenteral (e.g. subcutaneous, intramuscular and intravenous) routes. In the context of the present invention, the oral route is the preferred route of administration.

[0054] It will be appreciated that the route will vary depending on the general condition and age of the subject being treated, the nature of the condition being treated and the active ingredient.

[0055] Pharmaceutical Formulations and Excipients Hereinafter, the term "excipient" or "pharmaceutical acceptable excipient" means pharmaceutical excipients such as, but not limited to, carriers, fillers, diluents, antiadherents, binders, coatings, colorants, disintegrants, flavors, glidants, lubricants, preservatives, adsorbents, sweeteners, solvents, vehicles and auxiliary agents.

[0056] The present invention also provides a pharmaceutical composition comprising a compound of formula (Id), such as one of the compounds disclosed in the experimental section herein. The present invention also provides a process for producing a pharmaceutical composition comprising a compound of formula (Id). The pharmaceutical composition according to the present invention can be formulated using pharma- ceutical acceptable excipients according to conventional techniques, such as those disclosed in Remington, The Science and Practice of Pharmacy, 22nd edition (2013), Edited by Allen, Loyd V., Jr.

[0057] The pharmaceutical composition comprising the compound of the present invention is preferably for oral administration.The pharmaceutical composition for oral administration includes solid oral dosage forms such as tablets, capsules, powders and granules, and liquid oral dosage forms such as liquids, emulsions, suspensions and syrups, and powders and granules that are dissolved or suspended in suitable liquids.

[0058] The solid oral dosage form can be provided as individual units (e.g., tablets or hard or soft capsules), each containing a predetermined amount of active ingredient, preferably one or more suitable excipients.If appropriate, the solid dosage form can be prepared with a coating, such as an enteric coating, or can be formulated to provide controlled release of the active ingredient, such as delayed or sustained release, according to methods well known in the art.If appropriate, the solid dosage form can also be a dosage form that disintegrates in saliva, such as, for example, an orodispersible tablet.

[0059] Examples of excipients suitable for solid oral dosage forms include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid formulations may contain excipients for delayed or sustained release formulations known in the art, such as glyceryl monostearate or hypromellose. When solid materials are used for oral administration, the formulations may be prepared, for example, by mixing the active ingredient with a solid excipient and then compressing the mixture with conventional tableting equipment, or the formulations may be placed in hard capsules, for example, in powder, pellet, or mini-tablet form. The amount of solid excipients may vary widely, but usually ranges from about 25 mg to about 1 g per dosage unit.

[0060] Liquid oral dosage forms can be provided, for example, as elixirs, syrups, oral drops, or liquid-filled capsules. Liquid oral dosage forms can also be provided as powders for solution or suspension in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral dosage forms include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamer, sorbitol, polysorbate, mono- and diglycerides, cyclodextrin, coconut oil, palm oil, and water. Liquid oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

[0061] Additional excipients such as colorants, flavors and preservatives may be used in both solid and liquid oral formulations.

[0062] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion, and sterile powders that are dissolved in a sterile solution or dispersion for injection or infusion before use. Examples of excipients suitable for parenteral formulations include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin solutions. Aqueous formulations should be appropriately buffered if necessary and rendered isotonic with sufficient saline or glucose.

[0063] Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, transdermal patches, implants, and formulations for buccal or sublingual administration.

[0064] Excipients used in pharmaceutical formulations should be compatible with the intended route of administration and with the active ingredient.

[0065] dose In one embodiment, the compound of the present invention is administered in an amount of about 0.0001 to about 5 mg / kg body weight per day. In particular, the daily dose may range from 0.001 to about 2 mg / kg body weight per day. The exact dosage will vary depending on the frequency and mode of administration of the subject to be treated, the sex, age, weight and general condition of the subject, the nature and severity of the condition to be treated, the associated disease to be treated, the desired effect of the treatment and other factors known to those skilled in the art.

[0066] A typical oral dosage for an adult is in the range of 0.1-100 mg / day of a compound of the invention, for example 0.05-50 mg / day, 0.1-10 mg / day or 0.1-5 mg / day. Conveniently, the compound of the invention is administered in a unit dosage form containing said compound in an amount of about 0.01-50 mg, for example 0.05 mg, 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg or up to 50 mg. [Brief description of the drawings]

[0067] [Figure 1a]Figure 1 illustrates the conversion of a compound of the invention to compound (Id). Solid arrow: conversion demonstrated in vitro and in vivo. Dotted arrow: conversion demonstrated in vitro. Striped arrow: conversion demonstrated in vivo. Open arrow: conversion not demonstrated. To provide a better overview, the figure is divided into Figures 1a to 1e. R is selected from methyl, ethyl and benzyl. [Figure 1b] Same as above. [Figure 1c] Same as above. [Figure 1d] Same as above. [Figure 1e] Same as above. [Figure 2a] PK profiles in Wistar rats obtained after oral administration according to Example 3. Profiles are based on average plasma concentrations from 3 subjects for each compound. X-axis: time (hours); Y-axis: plasma concentration of compound (I) (pg / mL). 2a: Profiles obtained after administration of the following compounds: ■: compound (Ia); ◆: compound (Ib); dotted ◆: compound (Id-ib); dotted X: compound (Id); dotted n: compound (Id-iab); ▲: compound (9); ●: compound (15); X: compound (27); and □: compound (2). 2b: Profiles obtained after administration of the following compounds: ■: compound (Ia); ◆: compound (Ib); ▲: A2; □: A7. [Figure 2b] Same as above. [Diagram 3]Figures 3 and 4: Locomotor activity time course (Figure 3) and total distance traveled (Figure 4) after treatment with vehicle (HO, orally) or compound (Id-ia) (10, 30, 100 or 300 μg / kg, orally) and compared to standard of care (SoC): apomorphine (APO, 3 mg / kg, subcutaneous), pramipexole (PPX, 0.3 mg / kg, subcutaneous). Animals were dosed at t = 60 min after a habituation period in the test chamber of 60 min and activity was then monitored for 350 min. Data were evaluated using Kruskal-Wallis tests with Dunn's multiple comparison test, giving an overall P value < 0.0001. Figure 3: X-axis: time (min); Y-axis: distance traveled (cm) ± SEM / 5 min-bins. Figure 4: Y-axis: total distance traveled (cm) ± SEM. Significance levels for post-hoc comparisons (vs. vehicle group) are indicated: *<0.05, **<0.01, ***<0.001, ****<0.0001. [Figure 4] Same as above. [Diagram 5] Figures 5 and 6: Relationship between plasma concentrations of compound (Id-ia) and compound (I) and hyperactivity induced by compound (Id-ia) (100 μg / kg, oral) (Figure 5) and the corresponding relationship between plasma apomorphine concentration and hyperactivity induced by apomorphine (3 mg / kg, subcutaneous) (Figure 6). X-axis time (min); Y-axis left: distance traveled (cm) ± SEM / 5-min-bins; Y-axis right (Figure 5): plasma concentration of compound (I) (pg / mL); Y-axis right (Figure 6): plasma concentration of apomorphine (ng / mL). □: distance traveled (cm) ● plasma concentration. [Figure 6] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0068] Detailed Description of the Invention The present inventors have identified novel compounds that are glucuronide derivatives, unsaturated glycosyl derivatives, and ester and ether derivatives of compound (I) that are further derivatized by esterification of the free hydroxyl and carboxylic acid groups. These compounds are prodrugs of the dual D1 / D2 agonist (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol [compound (I)] (see, e.g., WO 2009 / 026934).

[0069] The present inventors have determined that compound (I) is conjugated in rat and human hepatocytes with glucuronide derivatives (Id-ia) and (Id-ib) having the formulae shown below. [ka]

[0070] The conjugate has been shown to be converted to compound (I) by conjugation and deconjugation in vivo.

[0071] Glucuronide derivatives are generally known to be unstable in the intestine. The derivatives are formed as highly polar and soluble metabolites, facilitating the removal of the compound from the body, and are therefore easily excreted. For example, in bile duct-cannulated rats, glucuronide conjugates are often found in the bile, and the deconjugates (i.e., the parent compound) are found in the feces. Back-conversion of glucuronide conjugates in the intestine to the parent compound, which is sometimes subsequently reabsorbed, is known as part of the enterohepatic recycling process. As mentioned above, oral administration of phenethylcatecholamines such as apomorphine has generally proven unsuccessful due to low bioavailability. Similarly, compound (I) also has low oral bioavailability (Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444). With this in mind, and taking into account the instability of the glucuronide conjugate in the gastrointestinal tract, it would not be expected that oral administration of the glucuronide conjugate of Compound (I) would be able to achieve sufficient plasma exposure of the compound.

[0072] The principle of applying glucuronide derivatives as prodrugs for oral delivery has been discussed for retinoic acid (Goswami et al., J. Nutritional Biochem. (2003) 14:703-709) and for morphine (Stain-Texier et al., Drug Metab. and Disposition (1998) 26(5):383-387). Both studies showed very low levels of exposure to the parent compound after oral administration of the derivatives. Other studies have suggested the use of budesonide-β-D-glucuronide as a prodrug for local delivery of budesonide to the large intestine for the treatment of ulcerative colitis, based on poor absorption of the prodrug from the intestinal system itself (Nolen et al., J. Pharm Sci. (1995), 84(6):677-681).

[0073] Nevertheless, the following compounds of the formulae below have all been identified as metabolites of compound (I) in rats and minipigs: [ka] It has been observed that oral administration of glucuronide conjugates (Id-ia), (Id-ib) and (Id-iab) with provides systemic exposure of compound (I) in plasma, suggesting the utility of the glucuronide derivatives of compound (I) as orally active prodrugs of compound (I). The present invention provides glucuronide derivatives of compound (I) that are further derivatized by esterification of the free hydroxyl and carboxylic acid groups in the molecule. Unsaturated glycosyl derivatives, exemplified by compound (9), are also encompassed by the scope of the present invention. The scope of the present invention also encompasses ester and ether derivatives of compound (I).

[0074] According to Example 3, the plasma concentration profiles of compound (I) obtained from oral administration of compounds (Ia), (Ib), (Id-ia), (Id-ib) and (Id-iab) and exemplary compounds of the present invention to Wistar rats are shown in FIG. 2. For all compounds, the dose was corrected by molecular weight to be equivalent to a dose of 300 μg / kg of compound (Ib) corresponding to 287 μg / kg of compound (I). It was found that oral administration of compounds (Ia) and (Ib) to Wistar rats results in early and high peak plasma concentrations of compound (I). Such high peak concentrations may be associated with dopaminergic side effects in humans, such as nausea, vomiting and dizziness. In contrast, for the compounds of the present invention, the absorption rate is slowed with sustained exposure of compound (I) in plasma, preventing rapid peak plasma concentrations. Furthermore, the plasma exposure of compound (I) in Wistar rats is maintained throughout 24 hours, although the resulting AUC of compound (I) is generally lower than that obtained after administration of compounds (Ia) and (Ib). However, due to the lower peak concentrations of compound (I) expected to induce side effects, higher doses of the compounds of the present invention could potentially be administered to achieve higher total plasma concentrations of compound (I) compared to those achievable from administration of compounds (Ia) and (Ib). When investigating the PK properties of compound (Ic), the inventors found that the plasma concentrations of compound (I) were very low, leaving compound (Ic) unsuitable as a prodrug of compound (I) for oral administration, confirming that the oral bioavailability of the compounds of the present invention is very unpredictable. The PK parameters for the PK study in Wistar rats are listed in Table 4, and the PK profile is shown in Figure 2. All compounds evaluated in vivo showed conversion to compound (I).

[0075] The bioconversion of the compounds of the invention to compounds of formula (I) was also evaluated by incubation in human plasma and / or human hepatocytes as described in Example 1. For the parent compound (I) itself, a short half-life was observed in the plasma assay, which may explain why the appearance of compound (I) was sometimes difficult to detect or was only detected in very small amounts, since compound (I) may be metabolized as soon as it is formed. For compounds (15), (2) and (9), all showed conversion in vivo, and the appearance of compound (I) could not be detected in vitro. For some of the compounds, the direct appearance of compound (I) was not confirmed in the in vitro studies, but from the schematic diagram in Figure 1, it is reasonable to assume that these compounds are converted to compound (I). For example, compound (11), an acetylated glucuronide derivative, is converted to compound (Id-ia), which is then converted to compound (I). Another example is the acetylated bis-glucuronide derivative I2. No in vitro conversion could be demonstrated for this compound (the compound has not been tested in vivo). However, when the schematic in FIG. 1 is viewed as a whole, it is reasonable to assume that I2 is converted to compound (I) via compound (Id-iab). In general, when the schematic is viewed as a whole, it seems plausible that the esterified glucuronide derivatives are generally converted to compound (I) either directly or via the respective glucuronide derivatives ((Id-ia), (Id-ib) or (Id-iab).

[0076] Compounds of the invention were evaluated for conversion both in vitro or in vivo and in vitro, see Table 1 below and Figure 1.

[0077] [Table 1-1]

[0078] [Table 1-2]

[0079] [Table 1-3]

[0080] In conclusion, therefore, the compounds of the present invention are useful as orally active prodrugs of compound (I) and have the peak C activity observed in the known prodrugs (Ia) and (Ib). max It has been confirmed in rats that this provides a PK profile that avoids the above-mentioned problems and results in a significantly higher AUC for compound (I) than for compound (Ic).

[0081] Compound (Id-ia) was further investigated in a rat locomotor activity assay according to Example 4. The assay demonstrated a dopaminergic effect following oral administration of compound (Id-ia) (see Figures 3, 4 and 5). The fact that compound (Id-ia) does not retain in vitro dopaminergic activity (data not shown) further indicates that the effect of compound (Id-ia) in the rat locomotor activity assay is obtained by conversion of compound (Id-ia) to compound (I).

[0082] Finally, a key problem with the prior art compound (Ib) is that it is an agonist of the 5-HT2B receptor.The association of 5-HT2B receptor agonism with the pathogenesis of valvular heart disease (VHD) after long-term exposure makes such compounds unsuitable for use in the treatment of chronic diseases (Rothman et al., Circulation (2000), 102:2836-2841 and Cavero and Guillon, J. Pharmacol. Toxicol. Methods (2014), 69:150-161).Therefore, a further advantage of the compound of the present invention is that it is not a 5-HT2B agonist (see Example 2 and Table 3).

[0083] The compounds of the present invention are useful in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease and / or other conditions in which treatment with a dopamine agonist is therapeutically beneficial. Compounds suitable for oral administration have the potential to provide a novel treatment paradigm in Parkinson's disease.

[0084] In one embodiment of the invention, the compounds are used as a stand-alone treatment for neurodegenerative diseases or disorders. In another embodiment of the invention, the compounds are used in conjunction with other agents for the treatment of PD, such as compounds selected from the group consisting of MAO-B inhibitors such as L-DOPA, droxidopa, foligrax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamic agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, and antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole, or in conjunction with antibodies targeting alpha-synuclein, Tau or A-beta proteins.

[0085] EMBODIMENTS OF THE PRESENT DISCLOSURE In the following, embodiments of the present invention are disclosed, a first embodiment is denoted E1 and a second embodiment is denoted E2.

[0086] E1.Formula(Id) [ka] (In the formula, a) R1 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C2-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl, and R2 is selected from one of the following substituents (i) and (ii); or b) R1 is selected from one of the following substituents (i) and (ii) and R2 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C2-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl; or c) R1 and R2 are independently selected from the following substituents (i) and (ii): d) R1 and R2 are both represented by the following substituent (i); or e) R1 and R2 are both represented by the following substituent (ii): [ka] Where: * indicates the attachment point; The carbon atom at the point of attachment on substituent (i) is in the S configuration; R3 is selected from H, C1-C6 alkyl and benzyl; R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl; With the proviso that when R3 and R4 in substituent (i) are both H, R1 and R2 cannot both be substituent (i); and Provided that when one of R1 and R2 is a substituent (i) and both R3 and R4 in the substituent are H, the other of R1 and R2 cannot be H. or a pharma- ceutically acceptable salt thereof.

[0087] E2.Formula(Id) [ka] (In the formula, a) R1 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C2-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl, and R2 is selected from one of the following substituents (i) and (ii); or b) R1 is selected from one of the following substituents (i) and (ii) and R2 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C2-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl; or c) R1 and R2 are independently selected from the following substituents (i) and (ii): d) R1 and R2 are both represented by the following substituent (i); or e) R1 and R2 are both represented by the following substituent (ii): [ka] Where: * indicates the attachment point; The carbon atom at the point of attachment on substituent (i) is in the S configuration; R3 is selected from H, C1-C6 alkyl and benzyl; R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl; With the proviso that when R3 and R4 in substituent (i) are both H, R1 and R2 cannot both be substituent (i); and Provided that when one of R1 and R2 is a substituent (i) and both R3 and R4 in the substituent are H, the other of R1 and R2 cannot be H. or a pharma- ceutically acceptable salt thereof, However, the compound of formula (Id) is a compound selected from the following three compounds: (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate or a pharma- ceutically acceptable salt thereof, provided that the compound is not one of:

[0088] E3. R1 is H and R2 is the substituent (i); or R1 is a substituent (i) and R2 is H; or R1 and R2 are both represented by substituent (i); R3 is selected from H, C1-C6 alkyl and benzyl; R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl; A compound according to any of embodiments 1-2, or a pharma- ceutically acceptable salt thereof, with the proviso that R3 and R4 are not both H.

[0089] E4. R1 is H and R2 is the substituent (ii); or R1 is a substituent (ii) and R2 is H; or R1 and R2 are both represented by substituent (ii); R3 is selected from H, C1-C6 alkyl and benzyl; The compound according to any of Examples 1-2, or a pharma- ceutically acceptable salt thereof, wherein R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl.

[0090] E5. The compound according to any of Examples 1-4, wherein R1 is selected from the group consisting of H, C1-C4 alkyl, methyl substituted with C2-C6 cycloalkyl, benzyl and -C(O)C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof.

[0091] E6. The compound according to any of Examples 1-4, wherein R1 is selected from the group consisting of H, C1-C3 alkyl, benzyl, or a pharma- ceutically acceptable salt thereof.

[0092] E7. The compound according to any of Examples 1-4, wherein R1 is selected from the group consisting of H, methyl, ethyl and benzyl, or a pharma- ceutically acceptable salt thereof.

[0093] E8. The compound according to any of Examples 1-4, wherein R1 is H, or a pharma- ceutically acceptable salt thereof.

[0094] E9. The compound according to any of Examples 1-4, or a pharma- ceutically acceptable salt thereof, wherein R1 is selected from the group consisting of methyl and ethyl.

[0095] E10. The compound according to any of Examples 1-4, or a pharma- ceutically acceptable salt thereof, wherein R1 is benzyl.

[0096] E11. The compound according to any of Examples 1-4, wherein R2 is selected from the group consisting of H, C1-C4 alkyl, methyl substituted with C2-C6 cycloalkyl, benzyl and -C(O)C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof.

[0097] E12. The compound according to any of Examples 1-4, wherein R2 is selected from the group consisting of H, C1-C3 alkyl, benzyl, or a pharma- ceutically acceptable salt thereof.

[0098] E13. The compound according to any of Examples 1-4, wherein R2 is selected from the group consisting of H, methyl, ethyl and benzyl, or a pharma- ceutically acceptable salt thereof.

[0099] E14. The compound according to any of Examples 1-4, wherein R2 is H, or a pharma- ceutically acceptable salt thereof.

[0100] E15. The compound according to any of Examples 1-4, or a pharma- ceutically acceptable salt thereof, wherein R2 is selected from the group consisting of methyl and ethyl.

[0101] E16. The compound according to any of Examples 1-4, or a pharma- ceutically acceptable salt thereof, wherein R2 is benzyl.

[0102] E17. The compound according to any of Examples 1-4, wherein R3 is selected from H, C1-C4 alkyl and benzyl, or a pharma- ceutically acceptable salt thereof.

[0103] E18. The compound according to example 5, wherein R3 is selected from H and C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof.

[0104] E19. The compound according to Example 6, wherein R3 is selected from H, methyl and ethyl; or a pharma- ceutically acceptable salt thereof.

[0105] E20. The compound according to Example 6, wherein R3 is H, or a pharma- ceutically acceptable salt thereof.

[0106] E21. The compound according to example 6, wherein R3 is selected from methyl and ethyl, or a pharma- ceutically acceptable salt thereof.

[0107] E22. The compound according to any of Examples 1-7, wherein R4 is selected from H, -C(O)C1-C4 alkyl and -C(O)phenyl, or a pharma- ceutically acceptable salt thereof.

[0108] E23. The compound according to example 8, wherein R4 is selected from H and -C(O)C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof.

[0109] E24. The compound according to example 9, wherein R4 is selected from H, acetyl, propionyl and pivaloyl, or a pharma- ceutically acceptable salt thereof.

[0110] E25. The compound according to example 10, wherein R4 is selected from H, acetyl and pivaloyl, or a pharma- ceutically acceptable salt thereof.

[0111] E26. The compound according to Example 11, wherein R4 is H, or a pharma- ceutically acceptable salt thereof.

[0112] E27. The compound according to example 11, wherein R4 is selected from acetyl and pivaloyl, or a pharma- ceutically acceptable salt thereof.

[0113] E28. The compound according to example 11, wherein R1 and R2 are both represented by substituent (i), or R1 and R2 are both represented by substituent (ii), or a pharma- ceutically acceptable salt thereof.

[0114] E29. The compound according to example 11, wherein R1 and R2 are both represented by substituent (i), or a pharma- ceutically acceptable salt thereof.

[0115] E30. The compound according to example 11, wherein R1 and R2 are both represented by the substituent (ii), or a pharma- ceutically acceptable salt thereof.

[0116] E31. (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2R,3R,4S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate; (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2R,3R,4S)-3,4-dihydroxy-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4-dihydro-2H-pyran-6-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; Ethyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-2-((methoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-((ethoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); and (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate or a pharma- ceutically acceptable salt of any of these compounds.

[0117] E32. A compound according to any of embodiments 1-23 or a pharma- ceutically acceptable salt thereof for use in therapy.

[0118] E33. A compound according to any of embodiments 1-23 or a pharma- ceutically acceptable salt thereof for use as a medicament.

[0119] E34. A compound or a pharma- ceutically acceptable salt for use as a medicament according to embodiment 25, wherein said medicament is an oral medicament, such as a tablet or capsule for oral administration.

[0120] E35. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of embodiments 1-23 or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0121] E36. The pharmaceutical composition according to embodiment 27, which is for oral administration.

[0122] E37. A pharmaceutical composition according to any of embodiments 27-28, which is an oral pharmaceutical composition.

[0123] E38. The pharmaceutical composition according to any of embodiments 27-29, which is a solid oral dosage form.

[0124] E39. A pharmaceutical composition according to any of embodiments 27-30, which is a tablet or capsule for oral administration.

[0125] E40. A pharmaceutical composition according to any of embodiments 27-31, further comprising another agent useful in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease.

[0126] E41. A pharmaceutical composition according to any of embodiments 27-31, further comprising a compound selected from the group consisting of an MAO-B inhibitor such as L-DOPA, droxidopa, foligrax, selegiline or rasagiline, a COMT inhibitor such as entacapone or tolcapone, an adenosine 2a antagonist such as istradefylline, an antiglutamate such as amantadine or memantine, an acetylcholinesterase inhibitor such as rivastigmine, donepezil or galantamine, and an antipsychotic such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole, or an antibody targeted alpha-synuclein, Tau or A-beta protein.

[0127] E42. The compound is (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate 24. The compound or a pharma- ceutically acceptable salt thereof according to any of embodiments 1-23, for use in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or in the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or dimethylaminobutyric acid (DMPA), selected from the group consisting of:

[0128] E43. A compound or a pharma- ceutically acceptable salt thereof according to any of embodiments 1-23, for use in treatment according to embodiment 34, wherein said neurodegenerative disease or disorder is Parkinson's disease.

[0129] E44. A compound according to any of embodiments 1-23 or a pharma- ceutically acceptable salt thereof, for use in therapy according to any of embodiments 34-35, wherein the compound is used in conjunction with another agent that is useful in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease.

[0130] E45. For use in treatment according to any of embodiments 34-35, wherein the compound is in combination with a compound selected from the group consisting of MAO-B inhibitors such as L-DOPA, droxidopa, foligrax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine and antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole, or in combination with an antibody targeting alpha-synuclein, Tau or A-beta protein, or a pharmaceutically acceptable salt thereof according to any of embodiments 1-23.

[0131] E46. A compound according to any of embodiments 1-23 or a pharma- ceutically acceptable salt thereof, for use in treatment according to any of embodiments 34-37, wherein said treatment is carried out by oral administration of said compound.

[0132] E47. A compound according to any of embodiments 1-23 or a pharma- ceutically acceptable salt thereof, for use in treatment according to any of embodiments 34-38, wherein the compound is comprised in a pharmaceutical composition, such as a tablet or capsule for oral administration.

[0133] E48. A method of treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease, or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any of Examples 1-23 or a pharma- ceutically acceptable salt thereof.

[0134] E49. The method according to embodiment 40, wherein said neurodegenerative disease or disorder is Parkinson's disease.

[0135] E50. The method according to any of embodiments 40-41, wherein the compound or a pharma- ceutically acceptable salt thereof according to any of embodiments 1-23 is used in conjunction with another agent useful in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease.

[0136] E51. The use according to any of embodiments 40-41, wherein the compound or a pharma- ceutically acceptable salt thereof according to any of embodiments 1-23 is used in conjunction with a compound selected from the group consisting of MAO-B inhibitors such as L-DOPA, droxidopa, foligrax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamic agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, and antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole, or in conjunction with an antibody targeting α-synuclein, Tau or A-β protein.

[0137] E52. The method according to any of embodiments 40-43, wherein said administration is by oral route.

[0138] E53. The method according to any of embodiments 40-44, wherein the compound according to any of embodiments 1-23 or a pharma- ceutically acceptable salt thereof is comprised in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

[0139] E54. Use of a compound according to any of embodiments 1-23 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease, or for the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0140] E55. The use according to embodiment 46, wherein said neurodegenerative disease or disorder is Parkinson's disease.

[0141] E56. The use according to any of embodiments 46-47, wherein said medicament is used in conjunction with another agent useful in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease.

[0142] E57. The use according to any of embodiments 46-47, wherein the agent is used in conjunction with a compound selected from the group consisting of MAO-B inhibitors such as L-DOPA, droxidopa, foliglalax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamic agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole, or in conjunction with an antibody targeting alpha-synuclein, Tau or A-beta protein.

[0143] E58. The use according to any of embodiments 46-49, wherein the medicament is an oral medicament, such as a tablet or capsule for oral administration.

[0144] E59. A compound according to any of embodiments 1-13 or a pharma- ceutically acceptable salt thereof for use in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0145] E60. The compound or pharma- ceutically acceptable salt thereof according to any of embodiments 59, wherein said neurodegenerative disease or disorder is Parkinson's disease.

[0146] E61. A compound according to any of embodiments 59-60, for use in conjunction with other agents useful in the treatment of neurodegenerative diseases or disorders, such as Parkinson's disease.

[0147] E62. The compound according to any of embodiments 61, wherein said agent is used in combination with a compound selected from the group consisting of MAO-B inhibitors such as L-DOPA, droxidopa, foliglalax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamic agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole, or in combination with an antibody targeting alpha-synuclein, Tau or A-beta proteins.

[0148] item The following list of items further describes embodiments and aspects of the present invention, and are listed as EE1, EE2, etc.

[0149] EE1.Formula(Id) [ka] (In the formula, a) R1 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C3-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl, and R2 is selected from one of the following substituents (i) and (ii); or b) R1 is selected from one of the following substituents (i) and (ii) and R2 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C3-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl; or c) R1 and R2 are independently selected from the following substituents (i) and (ii): d) R1 and R2 are both represented by the following substituent (i); or e) R1 and R2 are both represented by the following substituent (ii): [ka] Where: * indicates the attachment point; The carbon atom at the point of attachment on substituent (i) is in the S configuration; R3 is selected from H, C1-C6 alkyl and benzyl; R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl; With the proviso that when R3 and R4 in substituent (i) are both H, R1 and R2 cannot both be substituent (i); and Provided that when one of R1 and R2 is a substituent (i) and both R3 and R4 in the substituent are H, the other of R1 and R2 cannot be H. or a pharma- ceutically acceptable salt thereof.

[0150] EE2.Formula(Id) [ka] (In the formula, a) R1 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C3-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl, and R2 is selected from one of the following substituents (i) and (ii); or b) R1 is selected from one of the following substituents (i) and (ii) and R2 is selected from the group consisting of H, C1-C6 alkyl, methyl substituted with C3-C6 cycloalkyl, benzyl, and -C(O)C1-C6 alkyl; or c) R1 and R2 are independently selected from the following substituents (i) and (ii): d) R1 and R2 are both represented by the following substituent (i); or e) R1 and R2 are both represented by the following substituent (ii): [ka] Where:* indicates the attachment point; The carbon atom at the point of attachment on substituent (i) is in the S configuration; R3 is selected from H, C1-C6 alkyl and benzyl; R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl; With the proviso that when R3 and R4 in substituent (i) are both H, R1 and R2 cannot both be substituent (i); and Provided that when one of R1 and R2 is a substituent (i) and both R3 and R4 in the substituent are H, the other of R1 and R2 cannot be H. or a pharma- ceutically acceptable salt thereof, However, the compound of formula (Id) is the following three compounds: (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate or a pharma- ceutically acceptable salt thereof, provided that the compound is not one of:

[0151] EE3. R1 is H and R2 is the substituent (i); or R1 is a substituent (i) and R2 is H; or R1 and R2 are both represented by substituent (i); and R3 is selected from H, C1-C6 alkyl and benzyl; R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl; A compound according to any one of items EE1-EE2, or a pharma- ceutically acceptable salt thereof, with the proviso that R3 and R4 are not both H.

[0152] EE4. R1 is H and R2 is the substituent (i); or R1 is a substituent (ii) and R2 is H; or R1 and R2 are both represented by substituent (ii); R3 is selected from H, C1-C6 alkyl and benzyl; The compound according to any one of items EE1-EE2, or a pharma- ceutically acceptable salt thereof, wherein R4 is selected from H, -C(O)C1-C6 alkyl, and -C(O)phenyl.

[0153] EE5.R1 is selected from the group consisting of H, C1-C4 alkyl, methyl substituted with C3-C6 cycloalkyl, benzyl and -C(O)C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof, according to any one of items EE1-EE4.

[0154] EE6.R1 is selected from the group consisting of H, C1-C3 alkyl, benzyl; or a pharma- ceutically acceptable salt thereof, according to any one of items EE1-EE5.

[0155] EE7.R1 is selected from the group consisting of H, methyl, ethyl and benzyl, or a pharma- ceutically acceptable salt thereof, according to any one of items EE1 to EE6.

[0156] EE8. The compound according to any one of items EE1 to EE7, wherein R1 is H, or a pharma- ceutically acceptable salt thereof.

[0157] EE9.R1 is selected from the group consisting of methyl and ethyl, a compound according to any one of items EE1-EE2, or a pharma- ceutically acceptable salt thereof.

[0158] EE10.R1 is benzyl, or a pharma- ceutically acceptable salt thereof, according to any one of items EE1-EE2.

[0159] EE11.R1 is a compound according to any one of items EE1-EE3, or a pharma- ceutically acceptable salt thereof, which is (i).

[0160] EE12.R1 is (ii), a compound or a pharma- ceutically acceptable salt thereof according to any one of items EE1-EE2 and EE4.

[0161] EE13.R2 is selected from the group consisting of H, C1-C4 alkyl, methyl substituted with C3-C6 cycloalkyl, benzyl and -C(O)C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof.

[0162] EE14.R2 is selected from the group consisting of H, C1-C3 alkyl, benzyl; or a pharma- ceutically acceptable salt thereof; according to any one of items EE1-EE13.

[0163] EE15.R2 is selected from the group consisting of H, methyl, ethyl and benzyl, or a pharma- ceutically acceptable salt thereof, according to any of items EE1 to EE14.

[0164] EE16. A compound according to any of items EE1 to EE15, or a pharma- ceutically acceptable salt thereof, wherein R2 is H.

[0165] EE17.R2 is selected from the group consisting of methyl and ethyl, a compound according to any of items EE1 to EE15, or a pharma- ceutically acceptable salt thereof.

[0166] EE18.R2 is benzyl, or a pharma- ceutically acceptable salt thereof, according to any of items EE1 to EE15.

[0167] EE19.R2 is a compound according to any one of items EE1 to EE3 and EE5 to EE12, or a pharma- ceutically acceptable salt thereof, wherein R2 is substituent (i).

[0168] EE20. A compound according to any one of items EE1-EE3 and EE5-EE10, or a pharma- ceutically acceptable salt thereof, wherein R2 is a substituent (i) and R1 is selected from H, methyl or benzyl.

[0169] EE21. A compound according to any one of items EE1-EE3 and EE5-EE8, wherein R2 is substituent (i) and R1 is H; or a pharma- ceutically acceptable salt thereof.

[0170] EE22. A compound according to any one of items EE1-EE3 and EE5-EE7, or a pharma- ceutically acceptable salt thereof, wherein R2 is substituent (i) and R1 is methyl.

[0171] EE23. A compound according to any one of items EE1-EE3 and EE5-EE7, or a pharma- ceutically acceptable salt thereof, wherein R2 is substituent (i) and R1 is benzyl.

[0172] EE24. A compound according to any one of items EE1-EE2 and EE4-EE12, wherein R2 is substituent (ii) and R1 is H; or a pharma- ceutically acceptable salt thereof.

[0173] EE25. A compound according to any one of items EE1-EE2 and EE12, wherein R2 is substituent (ii) and R1 is H; or a pharma- ceutically acceptable salt thereof.

[0174] EE26.R3 is selected from H, C1-C4 alkyl and benzyl; or a pharma- ceutically acceptable salt thereof; according to any of items EE1-EE25.

[0175] EE27.R3 is selected from H and C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof, according to any one of items EE1-EE26.

[0176] EE28. A compound according to any one of items EE1 to EE27, wherein R3 is selected from H, methyl and ethyl, or a pharma- ceutically acceptable salt thereof.

[0177] EE29. The compound according to any one of items EE1 to EE28, wherein R3 is H, or a pharma- ceutically acceptable salt thereof.

[0178] EE30.R3 is selected from methyl and ethyl, a compound according to any one of items EE1 to EE29, or a pharma- ceutically acceptable salt thereof.

[0179] EE31.R4 is selected from H, -C(O)C1-C4 alkyl, and -C(O)phenyl; or a pharma- ceutically acceptable salt thereof; according to any one of items EE1-EE30.

[0180] EE32.R4 is selected from H and -C(O)C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof, according to any one of items EE1-EE31.

[0181] EE33.R4 is a compound according to any one of items EE1 to EE32 selected from H, acetyl, propionyl and pivaloyl, or a pharma- ceutically acceptable salt thereof.

[0182] EE34. A compound according to any one of items EE1 to EE33, wherein R4 is selected from H, acetyl and pivaloyl, or a pharma- ceutically acceptable salt thereof.

[0183] EE35. The compound according to any one of items EE1 to EE34, wherein R4 is H; or a pharma- ceutically acceptable salt thereof.

[0184] EE36.R4 is a compound according to any one of items EE1 to EE34, or a pharma- ceutically acceptable salt thereof, selected from acetyl and pivaloyl.

[0185] EE37. A compound according to any one of items EE1 to EE4, EE27 to EE36, or a pharma- ceutically acceptable salt thereof, wherein R1 and R2 are both represented by substituent (i), or R1 and R2 are both represented by substituent (ii).

[0186] EE38. A compound according to any one of items EE1-EE2 and EE27-EE36, or a pharma- ceutically acceptable salt thereof, wherein R1 and R2 are both represented by substituent (i).

[0187] EE39. A compound according to any one of items EE1-EE2 and EE27-EE36, or a pharma- ceutically acceptable salt thereof, wherein R1 and R2 are both represented by substituent (i).

[0188] EE40.(2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2R,3R,4S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate; (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2R,3R,4S)-3,4-dihydroxy-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4-dihydro-2H-pyran-6-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; Ethyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-2-((methoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-((ethoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); and (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate or a pharma- ceutically acceptable salt of any of these compounds.

[0189] EE41. Compound (2): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; Compound (9): (2R,3R,4S)-3,4-dihydroxy-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4-dihydro-2H-pyran-6-carboxylic acid; Compound (11): (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; Compound (12): ethyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylate; Compound (15): (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; and Compound (27): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate or a pharma- ceutically acceptable salt of any of these compounds.

[0190] EE42. Compound (2): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; Compound (9): (2R,3R,4S)-3,4-dihydroxy-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4-dihydro-2H-pyran-6-carboxylic acid; Compound (15): (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; and Compound (27): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate or a pharma- ceutically acceptable salt of any of these compounds.

[0191] EE43.The following formula [ka] or a pharma- ceutically acceptable salt thereof.

[0192] EE44.The following formula [ka] or a pharma- ceutically acceptable salt thereof.

[0193] EE45.The following formula [ka] or a pharma- ceutically acceptable salt thereof.

[0194] EE46.The following formula [ka] or a pharma- ceutically acceptable salt thereof.

[0195] EE47.The following formula [ka] or a pharma- ceutically acceptable salt thereof.

[0196] EE48.The following formula [ka] or a pharma- ceutically acceptable salt thereof.

[0197] EE49. A compound or a pharma- ceutically acceptable salt thereof according to any of items EE1 to EE48 for use in therapy.

[0198] EE50. A compound or a pharma- ceutically acceptable salt thereof according to any of items EE1 to EE48 for use as a medicament.

[0199] EE51. A compound or a pharma- ceutically acceptable salt for use as a medicament according to item EE50, wherein said medicament is an oral medicament, such as a tablet or capsule for oral administration.

[0200] EE52. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof according to any of items EE1-EE48, and one or more pharma- ceutically acceptable excipients.

[0201] EE53. A pharmaceutical composition according to item EE52, for oral administration.

[0202] EE54. A pharmaceutical composition according to any of items EE52-EE53 which is an oral pharmaceutical composition.

[0203] EE55. A pharmaceutical composition according to any of items EE52-EE54 which is a solid oral dosage form.

[0204] EE56. A pharmaceutical composition according to any of items EE52 to EE55 which is a tablet or capsule for oral administration.

[0205] EE57. A pharmaceutical composition according to any of items EE52-EE56 further comprising another agent which is useful in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease.

[0206] EE58. The pharmaceutical composition according to any of items EE52 to EE57, further comprising a compound selected from the group consisting of: an MAO-B inhibitor such as L-DOPA, droxidopa, foliglalax, selegiline or rasagiline, a COMT inhibitor such as entacapone or tolcapone, an adenosine 2a antagonist such as istradefylline, an antiglutamate such as amantadine or memantine, an acetylcholinesterase inhibitor such as rivastigmine, donepezil or galantamine, an antipsychotic such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole; or an antibody targeting alpha-synuclein, Tau or A-beta protein.

[0207] EE59. A compound or a pharma- ceutically acceptable salt thereof according to any of items EE1-EE48 for use in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0208] EE60. The compound is (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate 5. The compound or a pharma- ceutically acceptable salt thereof according to any of items EE1-EE2, for use in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0209] EE61. A compound or a pharma- ceutically acceptable salt thereof according to any one of items EE1 to EE48 and EE60 for use in the treatment of Parkinson's disease.

[0210] EE62. A compound or a pharma- ceutically acceptable salt thereof according to any one of items EE1 to EE48 and EE60 for use in treatment according to any of items EE59 to EE61, wherein the compound is used in conjunction with another agent that is useful in the treatment of a neurodegenerative disease or disorder such as Parkinson's disease.

[0211] EE63. A compound according to any one of items EE1 to EE48 and EE60 or a pharma- ceutically acceptable salt thereof for use in treatment according to any of items EE59 to EE62, wherein the compound is used in conjunction with a compound selected from the group consisting of an MAO-B inhibitor such as L-DOPA, droxidopa, foliglalax, selegiline or rasagiline, a COMT inhibitor such as entacapone or tolcapone, an adenosine 2a antagonist such as istradefylline, an antiglutamate such as amantadine or memantine, an acetylcholinesterase inhibitor such as rivastigmine, donepezil or galantamine, an antipsychotic such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole; or in conjunction with an antibody targeting alpha-synuclein, Tau or A-beta protein.

[0212] EE64. A compound or a pharma- ceutically acceptable salt thereof according to any of items EE1 to EE48 and EE60 for use in a treatment according to any of items EE59 to EE63, wherein said treatment is effected by oral administration of the compound or a pharma-ceutically acceptable salt thereof.

[0213] EE65. A compound or a pharma- ceutically acceptable salt thereof according to any of items EE1 to EE48 for use in the treatment according to any of items EE59 to EE64, said compound or a pharma- ceutically acceptable salt thereof being comprised in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

[0214] EE66. A method of treating a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any of items EE1-EE48 or a pharma- ceutically acceptable salt thereof.

[0215] EE67. The method according to item EE66, wherein said neurodegenerative disease or disorder is Parkinson's disease.

[0216] EE68. A method according to any of items EE66-EE67, wherein the compound or a pharma- ceutically acceptable salt thereof according to any of items EE1-EE48 is used in conjunction with another agent useful in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease.

[0217] EE69. The method according to any of items EE66-EE68, wherein the compound or a pharma- ceutically acceptable salt thereof according to any of items EE1-EE48 is used in conjunction with a compound selected from the group consisting of: MAO-B inhibitors such as L-DOPA, droxidopa, foliglalax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole; or in conjunction with an antibody targeting α-synuclein, Tau or A-β protein.

[0218] EE70. The method according to any of paragraphs EE66-EE69, wherein said administration is by oral route.

[0219] EE71. The method according to any of items EE66 to EE70, wherein the compound or a pharma- ceutically acceptable salt thereof according to any of items EE1 to EE48 is comprised in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

[0220] EE72. Use of a compound according to any of items EE1-EE48, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0221] EE73. Use according to item EE72, wherein said neurodegenerative disease or disorder is Parkinson's disease.

[0222] EE74. Use according to any of items EE72-EE73, wherein the medicament is used in conjunction with another agent useful in treating a neurodegenerative disease or disorder such as Parkinson's disease.

[0223] EE75. Use according to any of items EE72-EE74, wherein the medicament is used in conjunction with a compound selected from the group consisting of: an MAO-B inhibitor such as L-DOPA, droxidopa, foliglalax, selegiline or rasagiline, a COMT inhibitor such as entacapone or tolcapone, an adenosine 2a antagonist such as istradefylline, an antiglutamate agent such as amantadine or memantine, an acetylcholinesterase inhibitor such as rivastigmine, donepezil or galantamine, an antipsychotic such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole; or in conjunction with an antibody targeting alpha-synuclein, Tau or A-beta protein.

[0224] EE76. Use according to any of items EE72 to EE75, wherein the medicament is an oral medicament, such as a tablet or capsule for oral administration.

[0225] In the context of the present invention, it is understood that the carbon atom of the point of attachment on substituent (i) (as shown in embodiment 1) is at the anomeric position of (i). Similarly, the carbon atom of the point of attachment on substituent (ii) (as shown in embodiment 1) is at the anomeric position of (ii).

[0226] All references mentioned in this specification, including publications, patent applications, and patents, are incorporated by reference herein in their entirety and to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety (to the fullest extent permitted by law).

[0227] Headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0228] Description herein of any aspect or embodiments of the invention using terms such as "comprising," "having," "including," or "containing" when referring to one or more elements is intended to provide support for similar aspects or embodiments of the invention that "consist," "consist essentially of," or "substantially comprise" that particular element or elements, unless otherwise specified or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise specified or clearly contradicted by context).

[0229] The use of any and all examples or exemplary terms in this specification (such as "for instance," "for example," "for example," "such as," and "per se") is intended merely to make the invention more clear and does not limit the scope of the invention unless otherwise specified.

[0230] It should be understood that the various aspects, embodiments, implementations, and features of the invention described herein may be claimed separately or in any combination.

[0231] This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. The present invention may include the following aspects. [1] Formula (Id)

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[10] R4 is H, -C(O)C 1 ~C 4 10. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the alkyl group is selected from alkyl and -C(O)phenyl.

[11] R4 is H or -C(O)C 1 ~C 4 11. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of aryl, aryl, aryl and alkyl.

[12] The compound according to any one of claims 1 to 11, wherein R1 and R2 are both represented by substituent (i), or R1 and R2 are both represented by substituent (ii), or a pharma- ceutically acceptable salt thereof.

[13] (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2R,3R,4S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate; (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2R,3R,4S)-3,4-dihydroxy-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4-dihydro-2H-pyran-6-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; Ethyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-2-((methoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-((ethoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); and (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 2. The compound of claim 1, selected from the group consisting of:

[14] 14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable carriers or diluents.

[15] 14. A compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a psychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction, wherein the compound is (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate or a pharma- ceutically acceptable salt thereof, selected from:

[16] 15. A method for treating a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a psychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharma- ceutical acceptable salt thereof, wherein the compound is (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate A method selected from the group consisting of

[17] 14. A compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[18] 14. The compound or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 13 for use in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[19] 14. A method for treating a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a psychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharma- ceutical acceptable salt thereof.

[20] 14. Use of a compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0232] Compounds of the Invention

[0233] [Table 2-1]

[0234] [Table 2-2]

[0235] [Table 2-3]

[0236] [Table 2-4]

[0237] [Table 2-5]

[0238] [Table 2-6]

[0239] [Table 2-7]

[0240] [Table 2-8]

[0241] [Table 2-9]

[0242] [Table 2-10]

[0243] [Table 2-11]

[0244] [Table 2-12]

[0245] [Table 2-13]

[0246] Experimental Section General method The compound of formula (Id) or its salts are prepared by the methods described below, together with synthetic methods known in the art of organic chemistry or modifications familiar to those skilled in the art. The starting materials used herein are commercially available or can be prepared by conventional methods known in the art, for example, methods described in standard reference books such as "Compendium of Organic Synthetic Methods, Vol. I-XII" (published by Wiley-Interscience). Preferred methods include, but are not limited to, the following methods.

[0247] The schemes represent methods useful for synthesizing compounds of the invention. They are not intended to limit the scope of the invention in any way.

[0248] LC-MS method LC-MS analytical data was obtained using the methods identified below. Method 25: MS: Ion source (APPI), temperature 450℃ OR / RNG 20 / 200V OR / RNG 5 / 100V Mass: 100~1000amu HPLC: Column: dC-18 4.6×30mm 3μm Atlantis (Waters) Column temperature: 40°C, gradient, reversed phase with ion pair Solvent A: 100% HO 0.05% FA Solvent B: 95% ACN 5% H2O 0.035% TFA Flow rate: 3.3ml / min, injection volume: 15μl Gradient: 2% B to 100% B in 2.4 min, 2% B 0.4 min, Total run time: 2.8 min, UV: 254 nm ELSD: Glass tube: 21°C, Evaporation chamber: 40°C, Pressure: 2.3 bar

[0249] Method 550: LC-MS was performed on a Waters Aquity UPLC-MS consisting of a Waters Aquity containing a column manager, a binary solvent manager, a sample organizer, a PDA detector (operating at 254 nM), an ELS detector and a TQ-MS equipped with an APPI source operated in positive ion mode. LC conditions: The column was an Acquity UPLC BEH C18 1.7 μm; 2.1×50 mm operated at 60° C. using a binary gradient of 1.2 ml / min consisting of water+0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5)+0.05% trifluoroacetic acid. gradient: 0.00 minutes 10%B 1.00 minutes 100%B 1.01 minutes 10%B 1.15 minutes 10%B Total execution time: 1.15 minutes

[0250] Method 551: LC-MS was performed on a Waters Aquity UPLC-MS consisting of a Waters Aquity containing a column manager, a binary solvent manager, a sample organizer, a PDA detector (operating at 254 nM), an ELS detector and a TQ-MS equipped with an APPI source operated in positive ion mode. LC conditions: The column was an Acquity UPLC HSS T3 1.8 μm; 2.1×50 mm operated at 60° C. using a binary gradient of 1.2 ml / min consisting of water+0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5)+0.05% trifluoroacetic acid. gradient: 0.00 min 2%B 1.00 minutes 100%B 1.15 minutes 2%B Total execution time: 1.15 minutes

[0251] Method 555: LC-MS was performed on a Waters Aquity UPLC-MS consisting of a Waters Aquity containing a column manager, a binary solvent manager, a sample organizer, a PDA detector (operating at 254 nM), an ELS detector and a TQ-MS equipped with an APPI source operated in positive ion mode. LC conditions: The column was an Acquity UPLC BEH C18 1.7 μm; 2.1×150 mm operated at 60° C. using a binary gradient of 0.6 ml / min consisting of water+0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5)+0.05% trifluoroacetic acid. gradient: 0.00 minutes 10%B 3.00 minutes 100%B 3.60 minutes 10%B Total execution time: 3.6 minutes

[0252] Method 111: LC-MS was performed on a Shimadzu LCMS-2020 consisting of a PDA detector operating at 190-800 nM and an MS equipped with an ESI source operating in positive mode. LC conditions: The column was a Phenomenex Kinetex EVO C18 2.6 μm; 2.1×100 mm operated at 25° C. using a gradient of 0.5 ml / min consisting of water+0.1% formic acid (A) and acetonitrile+0.1% formic acid (B). gradient: 0.00 min 2%B 1.00 minutes 2%B 10.00 minutes 90%B 13.00 minutes 90%B 13.10 minutes 2%B 18.00 minutes 2%B Total execution time: 18 minutes

[0253] Preparative LCMS was performed using the methods identified below. Waters AutoPurification system with combined mass / UV detection. Column: Sunfire 30×100 mm, 5 μm particles, operated at 40° C. with a binary gradient of 90 ml / min consisting of water+0.05% trifluoroacetic acid (A) and acetonitrile / water (3:5)+0.05% trifluoroacetic acid. gradient: 0.00min 98%A 5.00 min 50%A 5.50 min 98%A 6.00 min 98%A

[0254] Method AB01 (Agilent 1200&6120): Equipment: Agilent 1200&MS6120 MS mode: Positive MS range: 100~1000 MS Fragmentor 70V Drying gas flow rate: 12L / min Nebulizer pressure 40psig Drying gas temperature 350℃ Capillary voltage 3500V LC conditions: The column was a Luna-C18(2) 2.0×50 mm, 5 μm operated at 40° C. with a gradient of 0.8 ml / min of water+0.037% TFA (A) and MeCN+0.018% TFA (B). gradient: 0.00 min 1%B 0.01~0.40 min 1%B 0.40~3.40 minutes 1~90%B 3.40~3.85 minutes 90~100%B 3.85~3.86 minutes 100~1%B 3.86~4.50 minutes 1%B Total execution time: 4.50 minutes

[0255] Method 0-30AB-HPLC (Agilent XDB): Equipment: Agilent 1260&MS6120 MS mode: Positive MS range: 100~1000 MS Fragmenter 70V Drying gas flow rate: 12L / min Nebulizer pressure 40psig Drying gas temperature 350℃ Capillary voltage 2500V 0-30AB-HPLC-Conditions: The column was an Agilent XDB-C18 4.6×50 mm column (1.8 μm particles) operated at 40° C. with a binary gradient of 0.6 ml / min consisting of water+0.037% trifluoroacetic acid (A) and acetonitrile+0.018% trifluoroacetic acid (B). gradient: 0.01~2.00 minutes 0~30%B 2.00~4.00 minutes 30%B 4.00~4.01 minutes 30~0%B Total execution time: 4.00 minutes

[0256] Method 10-90AB (Shimadzu LC-20AD&MS2010): Method name: 10-90AB Equipment: Shimadzu LC-20AD&MS2020 MS mode: Positive MS range: 100~1000 CDL temperature 250℃ Heat block temperature 28℃ Atomizing gas flow rate: 1.5L / min LC-Conditions: The column was a Luna-C18(2) 2.0 x 30 mm (3 micron particles) operated at 40°C with a gradient of 0.8 ml / min (0.01-1.51 min) and 1.2 ml / min (1.52-2.00 min) of water + 0.037% TFA (A) and MeCN + 0.018% TFA (B). gradient: 0.01 min 10%B 0.01~1.15 minutes 10~90%B 1.15~1.65 minutes 90%B 1.65~1.66 minutes 90~10%B 1.66~2.00 minutes 10%B Total execution time: 2.00 minutes

[0257] Method DELIVER-K-1 (Agilent 1200&6110): Equipment: Agilent 1200&MS6110 MS mode: Positive MS range: 100~1000 MS Fragmenter 70V Drying gas flow rate: 12L / min Nebulizer pressure 40psig Drying gas temperature 350℃ Capillary voltage 2500V LC-conditions: The column was a Kromasil Eternity-C18 3.0×30 mm, 2.5 μm operated at 40° C. with a gradient of 0.8 ml / min of water+0.037% TFA (A) and MeCN+0.018% TFA (B). gradient: 0.01 min 5%B 0.01~1.60 minutes 5~95%B 1.60~2.50 minutes 95~100%B 2.50~2.52 minutes 100~5%B 2.52~3.00 minutes 5%B Total execution time: 3.00 minutes

[0258] Method AB10 (Agilent 1200&1956A): Equipment: Agilent 1200&MS1956A MS mode: Positive MS range: 100~1000 MS Fragmenter 70V Drying gas flow rate: 12L / min Nebulizer pressure 55psig Drying gas temperature 350℃ Capillary voltage 2500V LC-conditions: The column was a Luna-C18(2) 2.0×50 mm, 5 μm operated at 40° C. with a gradient of 0.8 ml / min of water+0.037% TFA (A) and MeCN+0.018% TFA (B). gradient: 0.00 minutes 10%B 0.01~0.40 minutes 10%B 0.40~3.40 minutes 10~100%B 3.40~3.85 minutes 100%B 3.85~3.86 minutes 100~10%B 3.86~4.50 minutes 10%B Total execution time: 4.50 minutes

[0259] Method AB25 (Agilent 1200&1956A): Equipment: Agilent 1200&MS1956A MS mode: Positive MS range: 100~1000 MS Fragmenter 70V Drying gas flow rate: 12L / min Nebulizer pressure 55psig Drying gas temperature 350℃ Capillary voltage 2500V LC-conditions: The column was a Luna-C18(2) 2.0×50 mm, 5 μm operated at 40° C. with a gradient of 0.8 ml / min of water+0.037% TFA (A) and MeCN+0.018% TFA (B). gradient: 0.00 min 25%B 0.01~0.40min 25%B 0.40~3.40 minutes 25~100%B 3.40~3.85 minutes 100%B 3.85~3.86 minutes 100~25%B 3.86~4.50 minutes 25%B Total execution time: 4.50 minutes

[0260] Method DELIVER-K (Agilent 1200&6110): Equipment: Agilent 1200&MS6110 MS mode: Positive MS range: 100~1000 MS Fragmenter 70V Drying gas flow rate: 12L / min Nebulizer pressure 40psig Drying gas temperature 350℃ Capillary voltage 2500V LC-conditions: The column was a Halo-C18 3.0×30 mm, 2.7 μm operated at 40° C. with a gradient of 0.8 ml / min of water+0.037% TFA (A) and MeCN+0.018% TFA (B). gradient: 0.01 min 5%B 0.01~1.60 minutes 5~95%B 1.60~2.50 minutes 95~100%B 2.50~2.52 minutes 100~5%B 2.52~3.00 minutes 5%B Total execution time: 3.00 minutes

[0261] Method AB25-MS1500 (Agilent 1200&1956A): Equipment: Agilent 1200&MS1956A MS mode: Positive MS range: 100~1500 MS Fragmenter 70V Drying gas flow rate: 12L / min Nebulizer pressure 55psig Drying gas temperature 350℃ Capillary voltage 2500V LC-conditions: The column was a Luna-C18(2) 2.0×50 mm, 5 μm operated at 40° C. with a gradient of 0.8 ml / min of water+0.037% TFA (A) and MeCN+0.018% TFA (B). gradient: 0.00 min 25%B 0.01~0.40min 25%B 0.40~3.40 minutes 25~100%B 3.40~3.85 minutes 100%B 3.85~3.86 minutes 100~25%B 3.86~4.50 minutes 25%B Total execution time: 4.50 minutes HighRes MS was performed on a Bruker Compact qTOF equipped with electrospray operated in positive or negative ion mode. Direct infusion was used and calibration was performed with sodium formate.

[0262] Chemical composition abbreviations Ac: Acetyl AcCl: acetyl chloride AcOH: acetic acid BF3-OEt2: Boron trifluoride diethyl etherate BnCl: benzyl chloride DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DMF: Dimethylformamide EtOAc: ethyl acetate EtOH: Ethanol MeI: Methyl iodide MeOH: Methanol MeCN: Acetonitrile MOMCl: Methoxymethyl chloride MS: molecular sieve MTBE: Methyl t-butyl ether Pd / C: Palladium on carbon Piv: Pivaloil TFA: Trifluoroacetic acid THF: tetrahydrofuran

[0263] Preparation of Compounds of the Invention - General Methods For example, the compounds of the present invention were synthesized using (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride [compound (I)] as a precursor, which can be prepared as disclosed in WO 2009 / 026934. WO 2019 / 101917 further describes a method for preparing a gluconate-conjugated derivative of compound (I).

[0264] Treatment of compound (I) with an appropriate excess of a glucuronyl donor, such as (2S,3R,4S,5S,6S)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate or (2S,3S,4S,5R,6R)-2-((benzyloxy)carbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate), in the presence of a Lewis acid, such as BF3-OEt2, affords the corresponding bis-glucuronide. Such compounds can be deprotected by saponification. This chemical action is methyl(2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran Examples are exemplified herein for (2S,2'S,3S,3'S,4S,4'S,5R,5'R,6S,6'S)-6,6'-(((4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl)bis(oxy))bis(3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid). For analogs containing benzyl esters, selective deprotection can be achieved by hydrogenolysis. [ka]

[0265] Compounds in which the catechol 6-hydroxyl group is a gluconated group can be prepared in several ways, for example from (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol as shown below: Briefly, glucuronidation of the free catechol hydroxyl group gives a prodrug in which the catechol 7-hydroxyl group is benzylated. Subsequent saponification affords the 7-benzylated compound with a free glucuronide attached to the 6-position of the catechol (exemplified by the synthesis of (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid). By hydrogenolysis instead of saponification, the catechol 7-hydroxyl group is selectively deprotected and, in the case of R=benzyl, the carboxyl group of the glucuronide is also deprotected as exemplified herein for (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate. If R' is the only benzyl group after the glucuronidation step, it can then be selectively cleaved and subsequent esterification introduces an acyl group onto the catechol 7-hydroxyl group. Similar chemistry applies to (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol, except for the selective debenzylation step mentioned immediately above. [ka]

[0266] Application of the above chemistry to regioisomeric O-benzyl / methyl substrates gives the corresponding products shown below. [ka]

[0267] Treatment of the glucuronide with a strong base such as DBU can result in the formation of the corresponding α,β-unsaturated compounds, as exemplified by the synthesis of (2R,3R,4S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate. [ka]

[0268] Mono-glucuronidation of compound (I) followed by esterification of the catechol 6-hydroxyl group gives up to three different ester prodrug groups (i.e. R, Pg and R'). The synthesis of (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate is an example of this chemistry. As already mentioned, hydrogenolysis can be applied to selectively cleave the glucaric acid benzyl ester. [ka]

[0269] Treatment of compound (I) with BnCl and a base such as triethylamine or K2CO3 gives a mixture of (4aR,10aR)-6-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol and (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; these regioisomers can be separated. Using MeI instead of BnCl gives a mixture of the corresponding methyl ethers, which can be separated. [ka]

[0270] Provided herein are alternative routes to (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol and (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol.

[0271] Intermediates for the preparation of (Id-ia), (Id-ib) and (Id-iab) Intermediates: (4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol and (4aR,10aR)-1-propyl-6-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol. [ka] (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (2.21 g, 7.4 mmol) was suspended in dichloromethane (80 ml) at room temperature under a nitrogen atmosphere and N,N-diisopropylethylamine (4.44 g, 6.0 ml, 34.4 mmol) was added followed by triisopropylsilyl chloride (2.73 g, 3.0 ml, 14.2 mmol) and the mixture was stirred at room temperature for 92 hours. 10 mL of MeOH was added, the crude mixture evaporated, coevaporated twice with dichloromethane / heptane, redissolved in dichloromethane, evaporated directly onto filter aid, and purified by column chromatography (eluent: n-heptane / ethyl acetate / triethylamine, 100:0:0 to 35:60:5) to give 3.14 g of a mixture of (4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol and (4aR,10aR)-1-propyl-6-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol, which was shown by NMR (CDCl3) to be a >30:1 mixture of silylated isomers.

[0272] Intermediates: t-butyl ((4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)carbonate and t-butyl ((4aR,10aR)-1-propyl-6-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)carbonate. [ka] The mixture of (4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol from the previous step and (4aR,10aR)-1-propyl-6-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol (2.94 g, 7.0 mmol) was dissolved in dichloromethane (30 ml) under a nitrogen atmosphere and cooled to 0° C. Pyridine (6.00 ml) was added followed by di-t-butyl dicarbonate (6.30 g) and the reaction mixture was allowed to warm to room temperature for 3-4 hours and then stirred at room temperature overnight. 10 mL of MeOH was added, the reaction mixture was evaporated, coevaporated twice with dichloromethane / n-heptane, dissolved in dichloromethane and evaporated onto filter aid. Purification by column chromatography (eluent: n-heptane / ethyl acetate / triethylamine, 100:0:0 to 75:20:5) afforded a mixture of t-butyl ((4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)carbonate and t-butyl ((4aR,10aR)-1-propyl-6-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)carbonate (3.6 g). After drying, NMR (CDCl3) showed a mixture of regioisomers.

[0273] Intermediates: (4aR,10aR)-6-((t-butoxycarbonyl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl acetate and (4aR,10aR)-7-((t-butoxycarbonyl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl acetate. [ka] t-Butyl ((4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)carbonate (3.60 g, 7.0 mmol) (mixture from previous step) was dissolved in THF (150 ml) under nitrogen atmosphere at 0° C., triethylamine trihydrofluoride (2.97 g, 3.00 ml, 18.4 mmol) was added and the mixture was stirred at 0° C. After 3 hours at 0° C., pyridine (10.0 ml, 124 mmol) and acetic anhydride (4.33 g, 4.00 ml, 42.4 mmol) were added directly to the reaction mixture at 0° C. and the reaction mixture was allowed to warm to room temperature. After 16 hours, 20 mL of MeOH was added and the reaction mixture was evaporated, redissolved in dichloromethane / heptane, evaporated onto filter aid and subsequently purified by dry column vacuum chromatography to give (4aR,10aR)-6-((t-butoxycarbonyl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl acetate and (4aR,10aR)-7-((t-butoxycarbonyl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl acetate. LCMS (Method 550) Retention time = 0.56 min, [M+H] + =404m / z.

[0274] Intermediate I1: (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; and A3: (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ka] (4aR,10aR)-6-((t-butoxycarbonyl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl acetate and (4aR,10aR)-7-((t-butoxycarbonyl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl acetate (2.49 g, 6.2 mmol) A mixture of 2S,3R,4S,5S,6S)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate (7.53 g, 20.0 mmol) was added at room temperature under nitrogen, followed by boron trifluoride diethyl etherate (6.72 g, 6.0 ml, 47.3 mmol) and the mixture was stirred at room temperature for 5 days. The mixture was diluted with dichloromethane and MeOH and evaporated onto a filter aid. Purification by dry column vacuum chromatography gave a mixture of (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate and (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (4.37 g). LC-MS (Method 555) rt=1.94 min, [M+H] + =620m / z.

[0275] Intermediate 12: Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate [ka] (2S,3S,4S,5R,6R)-2-(Methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.29 g, 2.7 mmol) and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (0.4 g, 1.3 mmol) were dissolved in dichloromethane (4.00 ml), and then boron trifluoride diethyl etherate (0.38 g, 0.34 ml, 2.7 mmol) was added under a nitrogen atmosphere and the mixture was stirred in an 8 mL vial under nitrogen for 3 days. Further (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.286 g, 2.69 mmol), and Boron trifluoride diethyl etherate (0.38 g, 0.340 ml, 2.7 mmol) was added and the mixture was stirred for 4 h, then the mixture was poured into saturated aqueous NaHCO3 (30 mL) and then extracted with dichloromethane (2 x 20 mL), the combined organic phases were dried (Na2SO4), filtered and evaporated to dryness in vacuo. The crude foam was suspended in heptane / ethyl acetate (1:1) and stirred overnight. Subsequently, HCl in ether (0.67 ml, 1.3 mmol, 2 moles) was added, the mixture was stirred for 1 hour, evaporated to dryness in vacuo, MTBE (40 mL) was added, the mixture was heated to reflux, cooled to room temperature, the mixture was then filtered, and the solid was dried in a vacuum oven at 40° C. for 1 day to give methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate hydrochloride (1.09 g). LC-MS (Method 550) Retention time = 63 minutes, [M+H] + =895.7m / z.

[0276] (Id-ib): (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid, and (Id-ia): (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid. [ka] (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate and (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2 A mixture of 1,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3.82 g, 6.2 mmol) was dissolved in MeOH (100 ml) and water (20 ml), cooled to 0°C, potassium cyanide (7.295 g, 112 mmol) was added, and the suspension was allowed to slowly warm to room temperature for 17.5 h. The crude mixture was evaporated to dryness over filter aid. The crude mixture was purified by silica gel column chromatography (eluent: ethyl acetate / MeOH / water 100:0:0 to 0:50:50) to give a ratio of (Id-ib) and (Id-ia) of 5 to 6:1. The mixture was separated by preparative LCMS. The collected peak 1 fractions containing (Id-ib) were pooled, evaporated, and combined with another batch of 186 mg (Id-ib)-TFA prepared in a similar manner, evaporated with MeOH, and dried to give (Id-ib). (Id-ib) was resuspended in 10 mL EtOH, 100 mL MTBE was added, the resulting suspension was stirred at room temperature for 8 hours, the suspension was filtered, the precipitate was washed with 2×10 mL MTBE, and dried overnight in a vacuum oven to give 1.601 g of (Id-ib), corresponding to (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid. The two collected peak fractions containing (Id-ia) were pooled, evaporated, transferred to a small flask with MeOH, evaporated, redissolved in approximately 12 mL MeOH, repurified by preparative LCMS, and evaporated to give (Id-ia).The appropriate fractions were pooled, evaporated, transferred to a small flask with MeOH, evaporated, and combined with another batch of 40.7 mg (Id-ia) prepared in a similar manner. The combined batches were dissolved in 2.5 mL EtOH, 25 mL MTBE was added, and the suspension was stirred at room temperature. After 8 h, the suspension was filtered and the precipitate was washed with 2×2.5 mL MTBE and dried overnight in a vacuum oven to give 362.2 mg (Id-ia). (Id-ia) was suspended in approximately 10 mL EtOH, 50 mL MTBE was added, the suspension was stirred at room temperature and after 19 hours was filtered, the precipitate was washed with 2×10 mL MTBE and dried in a vacuum oven at 40° C. to give 0.279 g of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid (Id-ia).

[0277] (Id-ib) LCMS (Method 551) Retention time = 0.37 min. 1 H NMR(600MHz, methanol-d4)δ 7.02(d,J=8.4Hz,1H),6.65(d,J=8.4Hz,1H),4.73(d,J=7.7Hz,1H),3.89(d,J=9.7Hz,1H),3.68-3.5 8(m,2H),3.54(dd,J=9.3,7.7Hz,1H),3.49(t,J=9.1Hz,1H),3.47-3.36(m,2H),3.30(dt,J=11.2,5. 6Hz,1H),3.21-3.11(m,3H),2.85(dd,J=15.4,11.3Hz,1H),2.35(dd,J=17.6,11.5Hz,1H),2.12-2.0 2(m,2H),2.02-1.84(m,3H),1.81-1.71(m,1H),1.49(qd,J=13.0,3.7Hz,1H),1.09(t,J=7.3Hz,3H).

[0278] (Id-ia) LCMS (Method 551) Retention time = 0.39 min. 1 H NMR(600MHz, methanol-d4)δ 6.87(d,J=8.3Hz,1H),6.74(d,J=8.4Hz,1H),4.62(d,J=7.9Hz,1H),3.75(dd,J=17.7,4.9Hz,1H),3 .66-3.62(m,2H),3.61-3.51(m,2H),3.50-3.35(m,3H),3.31-3.22(m,1H),3.14(qd,J=12.7,4.0Hz, 2H),2.83(dd,J=15.2,11.3Hz,1H),2.37(dd,J=17.7,11.7Hz,1H),2.12(d,J=13.4Hz,1H),2.08-2.0 0(m,1H),1.98-1.83(m,3H),1.81-1.71(m,1H),1.44(qd,J=13.2,3.9Hz,1H),1.09(t,J=7.3Hz,3H).

[0279] (Id-iab): (2S,2'S,3S,3'S,4S,4'S,5R,5'R,6S,6'S)-6,6'-(((4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl)bis(oxy))bis(3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid) [ka] Synthesis A: (1S,4aR,10aR)-1-propyl-6,7-bis(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (0.25 g, 0.27 mmol) was dissolved in water (1.21 g, 1.21 ml, 67.1 mmol) and MeOH (3.83 g, 4.84 ml, 120 mmol) and aqueous KOH (0.393 g, 0.270 ml, 3.2 mmol, 46%) were added and stirred overnight at room temperature in a sealed vial. A precipitate formed overnight which was isolated by filtration. The compound was washed with MeOH (1.5 mL) to give (2S,2'S,3S,3'S,4S,4'S,5R,5'R,6S,6'S)-6,6'-(((4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl)bis(oxy))bis(3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate), dipotassium (0.096 g). LC-MS (Method 551) Retention time = 0.31 min, [M+H] + =614.2m / z.

[0280] Synthesis B: (1S,4aR,10aR)-1-Propyl-6,7-bis(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (0.26 g, 0.29 mmol) was dissolved in water (1.250 g, 1.25 ml, 69.4 mmol) and MeOH (3.96 g, 5 ml, 124 mmol) and KCN (0.34 g, 5.3 mmol) were added and stirred overnight at room temperature in a sealed vial. A precipitate formed overnight and was isolated by filtration. The compound was washed with MeOH (1.5 mL) to give (2S,2'S,3S,3'S,4S,4'S,5R,5'R,6S,6'S)-6,6'-(((4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl)bis(oxy))bis(3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate), dipotassium (0.096 g). LC-MS (Method 551) Retention time = 0.34 min, [M+H] + =614.6m / z. 1H NMR(600MHz,DMSO-d6)δ 7.09(d,J=8.5Hz,1H),6.84(d,J=8.5Hz,1H),4.91-4.79(m,1H),4.78-4.66(m,1H),3.93(bs,22H(OH / water)),3.42(d, J=9.8Hz,1H),3.37-3.21(m,7H),3.19(s,1H),3.11(dd,J=16.2,4.9Hz,1H),2.90(d,J=11.0Hz,1H),2.67(ddd,J=1 2.9,10.7,5.6Hz,1H),2.49(dd,J=15.9,10.9Hz,1H),2.39-2.27(m,1H),2.15(dt,J=17.5,11.5Hz,2H),2.05(td,J =10.4,4.9Hz,1H),1.86(d,J=11.7Hz,1H),1.67-1.38(m,5H),1.03(qd,J=12.3,5.1Hz,1H),0.85(t,J=7.3Hz,3H).

[0281] Intermediates of the compounds of the present invention [ka] A1: (4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (10.75 g) and K2CO3 (17.5 g) were added to a flask, degassed under vacuum and purged with N2 before DMF (107 mL) and benzyl chloride (8.55 mL) were added and the mixture was stirred at room temperature for 18 h, then at 100° C. for 5 h and at room temperature for 19 h. K2CO3 (7.48 g) and benzyl chloride (6.29 mL) were added and the mixture was stirred at 100° C. for 5 h. After cooling to room temperature, the mixture was partitioned between water (500 mL) and heptane (250 mL). The aqueous phase was washed with heptane (3×100 mL) and the combined organic phases were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound (14.6 g).

[0282] A2: (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (4aR,10aR)-6,7-Bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline) (11.9 g) was added to the flask and evaporated before adding MeCN (180 mL) and purging with N2. The mixture was stirred until homogeneous before adding trimethylsilyl iodide (10.0 mL) and the mixture was stirred at room temperature under N2 for 2 h. MeOH (5.5 mL) was added and the mixture was stirred for 1 h. Isopropyl acetate / heptane (10 / 150 mL) was added and the mixture was cooled to 0° C. and stirred for 1 h. The compound was collected, washed with isopropyl acetate / heptane (3 / 47 mL) and dried to give the title compound (7.6 g). 1H NMR(600MHz,CDCl3)δ 10.42(bs,1H),7.43-7.33(m,4H),7.26(d,J=1.0Hz,1H),6.78(d,J=8.3Hz,1H),6.58(d,J=8.3Hz,1H),5.72(s,1H),5.08(s,2H),3.71( dd,J=11.70,15.0Hz,1H),3.58(d,J=11.70,1H),3.25-3.11(m,4H),2.94-2.86(m,1H),2.77-2.57(m,2H),2.26(dd,J=11.70Hz,17.0Hz 1H),2.19(d,J=13.80,1H),2.01-1.92(m,2H),1.80-1.69(m,1H),1.56-1.53(m,1H),1.39(qd,J=3.60Hz,13.30Hz,1H),1.06(t,J=7.2Hz,3H). LCMS (Method 550), retention time = 0.55 min, [M+H] + =352.5m / z. [ka]

[0283] A3: (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2S,3R,4S,5S,6S)-6-(Methoxycarbonyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate (9.51 g) and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (1.10 g) were dissolved in DCM (17 mL) at 0° C. BF3-OEt2 (5.3 mL) was added at room temperature under N2. The mixture was stirred for 3 days before BF3-OEt2 (0.94 mL) was added. AcCl (0.59 mL) was added and the mixture was stirred for 2 h before being quenched by dropwise addition into saturated aqueous NaHCO3 (20 mL). The mixture was extracted with DCM (2 x 15 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (n-heptane: EtOAc: MeOH 100:0:0 to 0:100:0 to 0:0:100) to give the compound (3.06 g). This material was dissolved in MeOH (4.3 mL) before water (4.3 mL) was added dropwise at 40-50 °C, causing a solid to precipitate. The mixture was cooled to room temperature and the compound was collected and dried to give the title compound (0.62 g). 1 H NMR(600MHz,CDCl3)δ 6.95(d,J=8.5Hz,1H),6.81(d,J=8.5Hz,1H),5.34-5.27(m,2H),5.09(d,J=6.0Hz,1H),4.20- 4.15(m,1H),3.74(s,3H),3.14(dd,J=4.80Hz,16.30Hz,1H),3.01-2.97(m,1H),2.79-2.68(m, 2H),2.64-2.56(m,1H),2.50-2.43(m,1H),2.30-2.22(m,3H),2.19-2.02(m,9H),1.87(d,J=1 0.50Hz,1H),1.72-1.63(m,2H),1.63-1.45(m,7H),1.12-0.99(m,1H),0.89(t,J=12.7Hz,3H). LCMS (Method 555), retention time = 1.84 min, [M+H] + =621.4m / z. [ka]

[0284] A4: (4aR,10aR)-7-(benzyloxy)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline To a mixture of (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (20 g) in DMF (400 mL) was added NaH (4.17 g, 60% dispersion) slowly at 0 °C under N2. The mixture was stirred at 0 °C for 30 min before MOMCl (3.5 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 h before it was poured into water (400 mL), stirred for 20 min, and then extracted with EtOAc (300 mL x 3). The combined organic phase was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (20 g).

[0285] A5: (4aR,10aR)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol To a solution of (4aR,10aR)-7-(benzyloxy)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (20 g) in MeOH (140 mL) was added Pd / C (10%, 30 g) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (50 psi) for 12 h before the catalyst was removed by filtration. The filtrate was concentrated to give the title compound (15.4 g).

[0286] A6: (4aR,10aR)-7-methoxy-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline To a solution of (4aR,10aR)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol (15 g) in MeOH (150 mL) was added (trimethylsilyl)diazomethane (2 M in ether, 246 mL) dropwise over 0.5 h at room temperature. The mixture was concentrated to give the title compound (15 g).

[0287] A7: (4aR,10aR)-7-Methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol A solution of (4aR,10aR)-7-methoxy-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (15 g) in 4M HCl solution in MeOH (150 mL) was stirred at room temperature for 1 h before concentrating. The residue was dissolved in water (100 mL) and the aqueous layer was basified to pH 7-8 with NaHCO3. The aqueous layer was extracted with EtOAc (100 mL and 50 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound (7 g). 1 H NMR(400MHz,CDCl3)δ 6.70(d,J=8.4Hz,1H),6.62(d,J=8.0Hz,1H),5.71(br s,1H),3.86(s,3H),3.07-3.18(m,2H),3.01(dd,J=5.2,17.6Hz,1H),2.72-2.89(m,2H),2.58-2.68(m,1H),2.29-2.44(m,2H),2.2 4(dd,J=12.0,17.6Hz,1H),1.97(d,J=13.2Hz,1H),1.70-1.92(m,3H),1.54-1.63(m,2H),1.10-1.23(m,1H),0.93(t,J=7.2Hz,3H). LCMS (Method 25), retention time = 0.95 min, [M+H] + =276.1m / z.

[0288] Exemplary Compounds of the Invention [ka] Compound (1): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a solution of (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (4 g) and (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (T-1; prepared as described in Advances in Chemical Engineering and Science, 2012, 2, 379-383, 7.99 g) in DCM (400 mL) was added BF3-OEt2 (4.12 mL) dropwise at -10 °C. The mixture was stirred at -10 °C to room temperature for 12 h before being washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250 x 80 mm, 10 μm particle column operated at room temperature with a gradient of 150 ml / min: water + formic acid (A) and MeCN (B): 0-25 min 22% B to 52% B; 25.1-30 min 95% B; 30.1-35 min 22% B) to give the title compound (1.8 g). 1H NMR (400MHz, CDCl3) δ 7.32-7.46(m,5H),6.85(d,J=8.0Hz,1H),6.80(d,J=8.4Hz,1H),5.01-5.38(m ,7H),3.87(d,J=9.6Hz,1H),3.69(s,3H),3.51(s,2H),3.13(d,J=10.0Hz,2H), 2.29-2.13(m,1H),2.06(d,J=4.4Hz,1H),2.04(s,3H),2.03(s,3H),1.87(bs, 2H),1.76(s,3H),1.75-1.5(bs,5H),1.13-1.31(m,2H),0.98(t,J=7.2Hz,3H). QC-LCMS (method AB01), retention time = 3.00 minutes, [M+H] + =668.3m / z.

[0289] Compound (2): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a solution of (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1 g) in THF (30 mL) and water (6 mL) was added dPd / C (0.4 g, 50% (w / w)) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 for 12 h before the catalyst was removed by filtration. The filtrate was concentrated to give the title compound (1 g). LCMS (Method 10-90AB), retention time = 0.99 min, [M+H] + =578.4m / z.

[0290] Compound (3): (2R,3R,4S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate To a solution of (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1 g) in DCM (20 mL) was added DBU (0.52 mL) and the mixture was stirred at room temperature for 12 h. The mixture was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a GX281 apparatus (Phenomenex Luna C18 100×30 mm, 5 μm particle column operated at room temperature with a gradient of 25 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-15 min 1% B-30% B; 15.1-17 min 100% B; 17.1-20 min 1% B) to give the title compound (0.2 g). 1 H NMR(400MHz,CDCl3)δ 6.80-6.83(m,2H),6.29(d,J=4.0Hz,1H),5.51(d,J=3.6Hz,1H),5.38-5.44(m,2H),3 .85(s,3H),3.37(d,J=9.2Hz,1H),2.97-3.17(m,4H),2.80-2.92(m,1H),2.51-2.71( m,3H),2.26-2.33(m,2H),2.15(s,3H),2.14(s,3H),2.01(d,J=12.4Hz,2H),1.82(d, J=14.0Hz,1H),1.60-1.72(m,J=4.8Hz,2H),1.33-1.15(m,1H),0.99(t,J=7.2Hz,3H). QC-LCMS (method DELIVER-K-1), retention time = 1.49 min, [M+H] + =518.2m / z.

[0291] Compound (4): (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid NaOH (150 mg) was dissolved in water / MeOH (3 / 12 mL) at 0° C. and (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.5 g) was added. The mixture was stirred at 0° C. for 1 h before lyophilization. The residue was purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250×50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-20 min 1% B-30% B; 20.1-25 min 100% B; 25.1-30 min 1% B) to give the title compound (200 m). 1 H NMR(400MHz,DMSO-d6)δ 7.50(d,J=7.2Hz,2H),7.24-7.38(m,3H),6.92(d,J=8.8Hz,1H),6.82(d, J=8.4Hz,1H),4.98-5.25(m,3H),4.83(d,J=7.2Hz,1H),3.51(d,J=13.6H z,2H),3.08-3.44(m,10H),2.75-3.03(m,3H),2.10-2.20(m,1H),1.78-1 .88(m,4H),1.54-1.70(m,2H),1.25-1.31(m,1H),0.91(t,J=7.2Hz,3H). QC-LCMS (method AB01), retention time = 2.37 minutes, [M+H] + =528.2m / z. [ka]

[0292] Compound (5): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) To a solution of (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (1.0 g) and (2S,3S,4S,5R,6R)-2-((benzyloxy)carbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (T-16; prepared in a similar manner to T-1 described in Advances in Chemical Engineering and Science, 2012, 2, 379-383; 3.88 g) in DCM (100 mL) was added BF3-OEt2 (0.7 mL) at -10 °C under N2. The mixture was stirred at room temperature for 1 h before partitioning it between saturated aqueous NaHCO3 (100 mL) and DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250 x 100, 10 μm particle column operated at room temperature with a gradient of 250 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-20 min 55% B-75% B; 20.1-25 min 100% B; 25.1-30 min 55% B) to give the title compound (1.20 g). 0.2 g of this material was combined with 0.4 g of product from a previous batch made under similar conditions and purified by preparative HPLC using a GX281 apparatus (Waters Xbridge C18 150×25 mm, 5 μm particle column operated at room temperature with a 25 ml / min gradient of water+0.225% formic acid (A) and MeCN (B): 0-13 min 45% B-75% B; 13.1-16 min 100% B; 16.1-19 min 75% B) to give the title compound (300 mg). 1H NMR(400MHz,CDCl3)δ 7.33-7.44(m,10H),6.78-6.84(m,2H),5.29-5.32(m,4H),5.14-5.18(d,J=12.4Hz,2H),5.07-5.15(d,J=12.4Hz,2H),4 .98(d,J=12.0Hz,1H),3.78-3.80(m,1H),3.24-3.30(m,2H),3.10(d,J=10.8Hz,1H),2.95(s,1H),2.79(s,1H),2.52(br s,2H),2.14-2.21(m,1H),1.86-2.07(m,2H),1.74-1.77(d,J=12Hz,3H),1 .62(m,2H),1.13(s,9H),1.08(s,9H),1.06(s,9H),0.96(t,J=7.2Hz,3H). QC-LCMS (method DELIVER-K-1), retention time = 2.17 minutes, [M+H] + =870.4m / z.

[0293] Compound (6): (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid To a mixture of Pd / C (50% (w / w), 4.0 g) in THF (20 mL) and H2O (4.0 mL) was added (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (1.00 g) and AcOH (0.066 mL) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (30 psi) for 12 h before the catalyst was removed by filtration. The filtrate was purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250×50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-20 min 30% B-60% B; 20.1-25 min 100% B; 25.1-30 min 30% B) to give the title compound (200 mg). 1H NMR(400MHz,DMSO)δ 9.44(br s,1H),6.69-6.75(m,2H),5.37(d,J=18.0Hz,2H),5.07-5.12(m,2H),3.78-3.98(m,1H),3.37-3.43(m,4H),2.99-3.32(m,4 H),2.12-2.19(m,1H),1.59-1.84(m,6H),1.28-1.35(m,1H),1.14(s,9H),1.07(s,9H),1.07(s,9H),0.88(t,J=7.2Hz,3H). LCMS (Method 550), retention time = 0.78 min, [M+H] + =690.7m / z. [ka]

[0294] Compound (7): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a solution of (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (1.00 g), (2S,3S,4S,5R,6R)-2-((benzyloxy)carbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (T-3; prepared as described in Bioorg. Med. Chem. 16 (2008) 6312-6318, 2.37 g), and 4 Å MS (1.00 g) in DCM (100 mL) was added BF3-OEt2 (0.53 mL) at -40 to -20 °C. The mixture was stirred at -40°C for 1 h and at room temperature for 2 h. The reaction mixture was poured into saturated aqueous NaHCO3 (250 mL) and stirred for 20 min, then extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250 x 100 mm, 10 μm particle column operated at room temperature with a gradient of 250 ml / min of water + 0.225% formic acid (A) and MeCN (B): 0-30 min 15-45% B; 30.1-35 min 100% B; 35.1-40 min 15% B) to give the title compound (0.66 g). 1H NMR(400MHz,CDCl3)δ 7.29-7.45(m,10H),6.83-6.88(m,1H),6.76-6.80(m,1H),5.28(s,3H),4.99-5.18(m,4H),3.92( d,J=8.8Hz,1H),3.32(d,J=16.0Hz,1H),3.11(dd,J=4.4,15.6Hz,2H),2.51-2.89(m,4H),2.34(br s,1H),2.19(dd,J=12.0,17.4,Hz,2H),2.02(s,3H),1.83(s,4H),1.77(s,4H),1.72(br s,2H),1.56(br s,2H),1.06(d,J=11.6Hz,1H),0.92(t,J=7.2Hz,3H). LC-MS (Method 10-90AB), retention time = 1.02 min, [M+H] + =744.4m / z.

[0295] Compound (8): (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid To a mixture of Pd / C (1.00 g, 10% Pd) in THF (66 mL) was added (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.66 g) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (30 psi) for 12 h before the catalyst was removed by filtration. The filtrate was concentrated and purified by preparative HPLC using a Shimadzu LC20AP instrument (Agela Durashell C18 250×50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-20 min 2-35% B; 20.1-25 min 100% B; 25.1-30 min 2% B) to give the title compound (0.45 g). 1 H NMR(400MHz,CDCl3)δ 12.40(br s,1H),6.42(d,J=8.4Hz,1H),6.31(d,J=8.4Hz,1H),5.99(d,J=5.0Hz,1H),5.48(dd,J=7.2,11.6Hz,1H ),5.04(dd,J=5.2,11.6Hz,1H),4.73(d,J=7.2Hz,1H),4.36(s,1H),3.75(d,J=11.2Hz,1H),3.22-3.44( m,2H),2.86-2.99(m,2H),2.69-2.86(m,2H),2.30-2.53(m,3H),2.23(d,J=10.8Hz,1H),2.15(s,3H),2. 06(s,3H),2.02(s,3H),1.95-1.99(m,1H),1.76-1.94(m,4H),1.09-1.18(m,1H),1.05(t,J=7.2Hz,3H). QC-LCMS (method AB01), retention time=2.34 min, [M+H]+=564.2 m / z. [ka]

[0296] Compound (9): (2R,3R,4S)-3,4-dihydroxy-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4-dihydro-2H-pyran-6-carboxylic acid To a mixture of K2CO3 (1.12 g) in HO (4 mL) and MeOH (24 mL) was added (2R,3R,4S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate (0.7 g) at 0 °C under N2. The mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The mixture was dissolved in HO (20 mL) and lyophilized. The residue was purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250×50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-20 min 1-20% B; 20.1-25 min 100% B; 25.1-30 min 1% B) to give the title compound (0.39 g). 1 H NMR(400MHz,D2O)δ 6.77-6.91(m,2H),6.08(d,J=4.0Hz,1H),5.65(s,1H),4.11-4.28(m,2H),3.55(d,J=12.0Hz,1H),2.94-3.4 3(m,6H),2.72-2.84(m,1H),2.14-2.30(m,1H),1.57-2.05(m,6H),1.22-1.41(m,1H),0.95(t,J=7.2Hz,3H). QC-LCMS (Method 0-30AB-HPLC), retention time = 4.44 minutes, [M+H] + =420.2m / z. [ka]

[0297] Compound (10): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a mixture of (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (2.0 g) and (2S,3S,4S,5R,6R)-2-(ethoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (T-2; prepared in a similar manner to T-1 described in Advances in Chemical Engineering and Science, 2012, 2,379-383; 4.77 g) and 4Å MS (1 g) in DCM (200 mL) was added BF3-OEt2 (1.1 mL) at -20 to -10 °C. The mixture was stirred at -10 °C for 1 h and at room temperature for 2 h. The reaction mixture was poured into saturated aqueous NaHCO3 (200 mL) and stirred for 20 min before being extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250 x 100 mm, 10 μm particle column operated at room temperature with a gradient of 250 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-30 min 15-50% B; 30.1-35 min 100% B; 35.1-40 min 15% B) to give the title compound (2.38 g). 1H NMR(400MHz,CDCl3)δ 7.38-7.45(m,4H),7.31-7.37(m,1H),6.85(d,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),5.22-5.30(m,4H),5.07(q,J =12.0Hz,2H),4.07-4.16(m,2H),3.86(d,J=9.2Hz,1H),3.37(dd,J=17.6,4.6Hz,1H),3.04-3.14(m,2H),2.81(br s,1H),2.70(br s,1H),2.58(br s,1H),2.35(br s,1H),2.16-2.27(m,2H),2.03(s,3H),2.02(s,3H),1.76(s,3H),1.60-1.6 5(bs,6H),1.22(t,J=7.5Hz,3H),1.09-1.18(m,1H),0.91(t,J=7.2Hz,3H). LC-MS (method: 550) retention time=0.68 min, [M+H]+=682.6m / z.

[0298] Compound (11): (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a mixture of Pd / C (10 g) in THF (200 mL) was added (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2.0 g) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at 20 °C under H2 (30 psi) for 12 h before the catalyst was removed by filtration. The filtrate was concentrated and combined with another residue prepared in a similar manner. This material was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250×100 mm, 10 μm particle column operated at room temperature using a gradient of 250 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-25 min 10-40% B; 25.1-30 min 100% B; 30.1-35 min 10% B) to give the title compound (1.0 g). QC-LC-MS (method AB01), retention time=2.60 min, [M+H]+=592.2 m / z. 1 H NMR(400MHz,CDCl3)δ 8.50(s,1H),6.80-6.88(m,2H),5.26-5.37(m,3H),4.79-4.85(m,1H),4.18-4.27(m,2H),4.01-4.05(m,1H),3.53(br d,J=11.6Hz,1H),2.95-3.24(m,6H),2.74-2.77(m,2H),2.19-2.28(m,2H),2.14(s,3H),2.07(s,3H),2.06(s,3H),2.00(br s,1H),1.88(d,J=14.4Hz,1H),1.64-1.81(m,2H),1.29(t,J=7.2Hz,3H),1.26-1.27(m,1H),1.02(t,J=7.2Hz,3H).

[0299] Compound (12): Ethyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylate To a solution of (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.68 g) in EtOH (33 mL) was added EtONa (155 mg) at room temperature under N2. The mixture was stirred for 3 h before purifying it by preparative HPLC using a GX281 apparatus (Phenomenex Luna C18 100×30 mm, 5 μm particle column operated at room temperature with a gradient of 25 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-15 min 1-30% B; 15.1-17 min 100% B; 17.1-20 min 1% B) to give the title compound (127 mg). 1 H NMR(400MHz,MeOD)δ 8.54(s,1H),6.85(d,J=8.4Hz,1H),6.72(d,J=8.4Hz,1H),5.49(s,1H),4.70(d,J=8.0Hz ,1H),4.23(q,J=6.8Hz,2H),3.82(d,J=10.0Hz,1H),3.43-3.63(m,6H),3.36(d,J=5.2Hz ,1H),3.21-3.28(m,1H),2.92-3.11(m,3H),2.74-2.81(m,1H),2.32(dd,J=17.6,11.8Hz ,1H),1.64-2.02(m,7H),1.36-1.46(m,1H),1.29(t,J=7.2Hz,3H),1.04(t,J=7.2Hz,3H). QC-LCMS (method AB01), retention time = 2.17 min, [M+H] + =466.2m / z. [ka]

[0300] Compound (13): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) To a solution of (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (1.00 g), (2S,3S,4S,5R,6R)-2-(ethoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (T-15; prepared in a similar manner to T-1 described in Advances in Chemical Engineering and Science, 2012, 2,379-383; 2.58 g) and 4Å MS (1.00 g) in DCM (100 mL) was added BF3-OEt2 (0.39 mL) under N2 at -20 °C. The mixture was allowed to warm to room temperature over 3 h before partitioning between saturated aqueous NaHCO3 (30 mL) and DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250 x 100 mm, 10 μm particle column operated at room temperature with a gradient of 250 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-25 min 50-80% B; 25.1-30 min 100% B; 30.1-35 min 50% B) to give the title compound (1.00 g). 1H NMR(400MHz,CDCl3)δ δ 7.37-7.45(m,5H),6.82(s,2H),5.27-5.33(m,4H),5.17(d,J=12.0Hz,1H),5.09(d,J=12.4 Hz,1H),4.17-4.22(m,1H),4.05-4.10(m,1H),3.72(d,J=9.2Hz,1H),3.41(d,J=14.0Hz,2H ),3.08-3.12(m,3H),2.68(s,2H),2.21-2.28(m,2H),2.09(d,J=11.2Hz,1H),1.66-1.87(m ,5H),1.25(t,J=7.2Hz,4H),1.15(s,9H),1.13(s,9H),1.07(s,9H),1.01(t,J=6.8Hz,3H). LC-MS (Method 10-90AB), retention time = 1.28 min, [M+H] + =808.6m / z

[0301] Compound (14): (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) To a solution of (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (1.00 g) in THF (20 mL) and H2O (4 mL) was added Pd / C (50%, 2.50 g) and AcOH (0.07 mL) under N2. The suspension was degassed under vacuum and purged with H2. The catalyst was removed by filtration and the mixture was stirred under H2 (30 psi) at room temperature for 12 h before the filtrate was concentrated. The residue was purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250×50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-20 min 30-60% B; 20.1-25 min 100% B; 25.1-30 min 30% B) to give the title compound (0.10 g). 1 H NMR(400MHz,CDCl3)δ 6.82-6.89(m,2H),5.44(d,J=8.8Hz,3H),4.98(d,J=5.2Hz,1H),4.24-4.28(m,1H),4. 16(d,J=8.0Hz,1H),4.04(d,J=7.6Hz,1H),3.27(d,J=10.0Hz,1H),3.13-3.17(m,2H),2 .94(s,2H),2.77(s,1H),2.51(s,2H),2.21-2.28(m,3H),1.79-1.98(m,4H),1.64(s,2H) ),1.30(t,J=7.2Hz,3H),1.25(s,9H),1.15(s,9H),1.14(s,9H),0.98(t,J=7.2Hz,3H). QC-LCMS (method AB10), retention time=2.92 min, [M+H]+=718.4 m / z. [ka]

[0302] Compound (15): (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid To a mixture of (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid methyl ester (500 mg) in MeOH (6 mL) was added NaOH (568 mg) in HO (3 mL). The resulting mixture was then cooled to room temperature using a Shimadzu LC20AP instrument (water + 0.225% formic acid (A) and MeCN (B): 0-20 min 2-20% B; 20.1-25 min 100% B; 25.1-30 min 2% B) operated at room temperature using a Phenomenex The mixture was stirred at room temperature for 2 days for purification by preparative HPLC using a Luna C18 250×50 mm, 10 μm particle column) to give the title compound (390 mg). 1 H NMR(400MHz,D2O)δ 6.98(d,J=8.4Hz,2H),5.00(d,J=7.6Hz,1H),3.81(s,3H),3.50-3.59(m,5H),3.35-3.43(m,2H),3.17-3.30(m,2H),3.02-3.13 (m,2H),2.73-2.80(m,1H),2.24-2.28(m,1H),1.90-2.05(m,2H),1.60-1.90(m,4H),1.28-1.38(m,1H),0.98(t,J=7.2Hz,3H). QC-LCMS (method DELIVER-K), retention time = 1.18 min, [M+H] + =452.2m / z. [ka]

[0303] Compound (16): (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a stirred solution of (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (1.0 g) in DCM (100 mL) was added (2S,3S,4S,5R,6R)-2-((benzyloxy)carbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (T-3; prepared as described in Bioorg. Med. Chem. 16 (2008) 6312-6318, 4.03 g) and BF3-OEt2 (0.90 mL) at -10 °C under N2. The reaction mixture was allowed to warm to room temperature over 3 h before partitioning between saturated aqueous NaHCO3 (100 mL) and EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250 x 50 mm, 10 μm particle column operated at room temperature with 80 ml / min of two components: water + 0.225% formic acid (A) and MeCN (B): 0-20 min 20-45% B; 20.1-25 min 100% B; 25.1-30 min 20% B) to give the title compound (800 mg). 1H NMR(400MHz,DMSO-d6)δ 7.27-7.40(m,5H),6.81-6.93(m,2H),5.36-5.45(m,1H),5.26(d,J=7.6Hz,1H),4.98-5.1 4(m,4H),4.50(m,1H),3.72(m,3H),3.08-3.23(m,3H),2.91(m,1H),2.63-2.74(m,1H),2.2 3-2.43(m,2H),2.06-2.16(m,2H),2.04(s,3H),1.99(s,3H),1.81(s,3H),1.68(m,1H),1. 56-1.64(m,1H),1.37-1.55(m,3H),1.30(m,1H),0.94-1.07(m,1H),0.85(t,J=7.2Hz,3H). QC-LCMS (method AB10), retention time = 2.67 minutes, [M+H] + =668.2m / z.

[0304] Compound (17): (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid To a mixture of Pd / C (0.5 g) in THF (20 mL) was added (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.40 g) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (30 psi) for 12 h before the catalyst was removed by filtration. The filtrate was concentrated and purified by preparative HPLC using a GX281 apparatus (Waters Xbridge C18 150×25 mm, 5 μm particle column operated at room temperature with a gradient of 25 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-13 min 10-45% B; 13.1-16 min 100% B; 16.1-19 min 10% B) to give the title compound (0.2 g). 1 H NMR(400MHz,DMSO-d6)δ 6.88(s,2H),5.24(d,J=4.4Hz,1H),5.04(t,J=9.6Hz,1H),4.98(d,J=5.6Hz,2H) ,3.74(s,4H),3.52(m,1H),3.20(m,1H),3.17(m,2H),2.96(m,2H),2.62-2.85(m, 2H),2.33-2.34(m,1H),2.10-2.14(m,1H),2.04(s,3H),1.96(s,3H),1.91(s,3H) ,1.70-1.78(m,2H),1.45-1.55(m,3H),1.20-1.28(m,1H),0.85(t,J=7.2Hz,3H). QC-LCMS (method AB01), retention time = 2.47 minutes, [M+H] + =578.2m / z. [ka]

[0305] Compound (18): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a mixture of (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (1.30 g), (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (T-1; prepared as described in Advances in Chemical Engineering and Science, 2012, 2, 379-383, 4.52 g), and 4AMS (1.00 g) in DCM (130 mL) was added BF3-Et2O (0.87 mL) at -10 to 0 °C. The mixture was stirred at room temperature for 2 h before being partitioned between saturated aqueous NaHCO3 (200 mL) and DCM (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250 x 80 mm, 10 μm particle column operated at room temperature with a gradient of 160 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-20 min 20-80% B; 20.1-25 min 100% B; 25.1-30 min 20% B) to give the title compound (1.40 g). 1H NMR:(400MHz CDCl3)δ 6.87(d,J=8.4Hz,1H),6.74(d,J=8.4Hz,1H),5.36(d,J=9.4Hz,1H),5.22-5.31(m,2H),5.10(d, J=7.6Hz,1H),3.93(d,J=10Hz,1H),3.81(s,3H),3.70(s,3H),3.41-3.53(m,1H),3.28(m,1H),3. 08-3.18(m,1H),2.99(m,2H),2.80(m,1H),2.54(m,4H),2.16-2.27(m,2H),2.10(s,3H),2.06(s ,3H),2.03(s,3H),1.81(m,J=14.4Hz,1H),1.65(m,2H),1.13-1.27(m,1H),0.97(t,J=7.2Hz,3H) QC-LCMS: (Method DELIVER-K-1), Retention time = 1.59 minutes, [M+H] + =592.2m / z. [ka]

[0306] Compound (19): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a stirred solution of (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (1 g) in DCM (100 mL) was added (2S,3S,4S,5R,6R)-2-(ethoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (T-2; prepared in a similar manner to T-1 described in Advances in Chemical Engineering and Science, 2012, 2, 379-383; 3.58 g) and BF3-Et2O (0.9 mL) at -10 °C. The reaction mixture was stirred at room temperature for 3 h before being partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250×100 mm, 10 μm particle column operated at room temperature with a gradient of 250 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-30 min 20-35% B; 30.1-35 min 100% B; 35.1-40 min 20% B) to give the title compound (0.2 g). 1 H NMR:(400MHz DMSO)δ 6.92-6.84(m,2H),5.41(t,J=9.6Hz,1H),5.23(d,J=7.6Hz,1H),5.08-5.00(m,2H),4.43(d,J=10.0Hz, 1H),4.11-4.00(m,2H),3.74(s,3H),3.22-3.26(m,2H),3.13(dd,J=4.8,15.6Hz,1H),2.91(d,J=11.2Hz ,1H),2.44-2.34(m,1H),2.23-2.34(m,2H),2.18-2.08(m,1H),2.05(s,4H),2.00(s,3H),1.97(s,3H), 1.78(d,J=10.0Hz,1H),1.58-1.70(m,1H),1.27-1.57(m,4H),1.02-1.18(m,4H),0.84(t,J=7.2Hz,3H). QC-LCMS: (Method DELIVER-K-1), retention time=1.62 min, [M+H]+=606.2 m / z. [ka]

[0307] Compound (20): (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) To a solution of (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (1.00 g) and (2S,3S,4S,5R,6R)-2-((benzyloxy)carbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (T-16; prepared in a similar manner to T-1 described in Advances in Chemical Engineering and Science, 2012, 2, 379-383; 4.95 g) in DCM (100 mL) was added BF3-Et2O (0.9 mL) at -10 °C. The mixture was stirred at room temperature for 1 h before being partitioned between saturated aqueous NaHCO3 (100 mL) and DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250 x 50 mm, 10 μm particles operated at room temperature with a gradient of 80 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-20 min 50-80% B; 20.1-25 min 100% B; 25.1-30 min 50% B) to give 1.6 g of the title compound. 0.6 g of this material was purified by preparative HPLC using a GX281 apparatus (Waters Xbridge C18 150×25 mm, 5 μm particle column operated at room temperature using a gradient of 25 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-13 min 45-75% B; 13.1-16 min 100% B; 16.1-19 min 45% B) to give the title compound (0.3 g). 1H NMR:(400MHz CDCl3)δ 7.23-7.32(m,5H),6.78(d,J=8.4Hz,1H),6.65(d,J=8.4Hz,1H),5.38(t,J =8.8Hz,1H),5.2-5.29(m,3H),5.10(d,J=12.0Hz,1H),4.92(d,J=12.0Hz, 1H),3.92(d,J=10.0Hz,1H),3.71(s,3H),3.26(d,J=13.2Hz,2H),3.02(d, J=10.4Hz,2H),2.80-2.94(m,2H),2.51(s,2H),2.08-2.16(m,2H),1.95(br d,J=16.0Hz,2H),1.43-1.70(m,4H),1.18(s,9H),1.13(s,9H),1.06(s,9H),0.90(t,J=7.2Hz,3H). QC-LCMS: (Method AB25), retention time = 2.91 min, [M+H] + =794.4m / z.

[0308] Compound (21): (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid To a solution of (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (1.00 g) in THF (20 mL) and H2O (4 mL) was added Pd / C (50%, 4.00 g) and AcOH (0.07 mL) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (30 psi) for 12 h before the catalyst was removed by filtration. The filtrate was concentrated and purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250×50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-20 min 30-60% B; 20.1-25 min 100% B; 25.1-30 min 30% B) to give the title compound (850 mg). 1 H NMR:(400MHz CDCl3)δ 6.87(d,J=8.8Hz,1H),6.72(d,J=8.4Hz,1H),5.44(t,J=9.2Hz,1H),5.33-5.38(m ,2H),5.21(d,J=7.6Hz,1H),4.82(s,1H),3.79(s,3H),3.64-3.70(m,1H),3.45(br d,J=11.6Hz,1H),3.29-3.38(m,2H),3.00-3.11(m,2H),2.76-2.87(m,2H),2.25-2.33(m,3H),2.08(d,J=10.4H) z,2H),1.93(d,J=14.0Hz,1H),1.59-1.70(m,2H),1.19(s,9H),1.14(s,9H),1.14(s,9H),1.00(t,J=7.2Hz,3H) QC-LCMS: (Method DELIVER-K-1), Retention time = 1.93 minutes, [M+H] + =704.3m / z. [ka]

[0309] Compound (22): (2S,3S,4S,5R,6S)-2-((methoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) To a stirred solution of (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (1 g) in DCM (100 mL) was added (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (T-7; prepared as described in Bioorg. Med. Chem. Lett. 9 (1999) 659-662; 4.39 g) and BF3-Et2O (0.9 mL) at -10°C. The crude mixture was stirred at room temperature for 3 h. The crude mixture was partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250 x 50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-20 min 40-70% B; 20.1-25 min 100% B; 25.1-30 min 40% B) to give the title compound (0.2 g). 1H NMR:(400MHz d6-DMSO)δ 6.80-6.92(m,2H),5.42-5.57(m,2H),4.96-5.14(m,2H),4.50(d,J=10.0Hz,1H),3.74(s,3H),3 .55(s,3H),3.24(d,J=4.8Hz,1H),3.20(d,J=4.4Hz,1H),3.12(dd,J=4.4,16.0Hz,1H),2.92(d,J =10.8Hz,1H), 2.67(d,J=4.4Hz,1H), 2.24-2.46(m,2H), 1.97-2.21(m,3H), 1.80(d,J=10.2Hz,1H), 1.60-1.69(m,1H), 1.27-1.59(m,4H), 1.12(s,9H), 1.06(broad s,18H), 0.84(t,J=7.2Hz,3H). QC-LCMS: (Method AB10), retention time = 3.20 minutes, [M+H] + =718.4m / z. [ka]

[0310] Compound (23): (2S,3S,4S,5R,6S)-2-((ethoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) To a solution of (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (1.00 g,) and (2S,3S,4S,5R,6R)-2-(ethoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (T-15; prepared in a similar manner to T-1 described in Advances in Chemical Engineering and Science, 2012, 2, 379-383; 4.49 g) in DCM (100 mL) was added BF3-Et2O (0.9 mL) at -10 °C. The mixture was stirred at room temperature for 1 h before being partitioned between saturated aqueous NaHCO3 (100 mL) and DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using an Agela FL-H600G instrument (Phenomenex Luna C18 250 x 100 mm, 10 μm particle column operated at room temperature with a gradient of 250 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-20 min 50-70% B; 20.1-25 min 100% B; 25.1-30 min 50% B) to give 1.2 g of the title compound. 0.5 g of this material was purified by preparative HPLC using a GX281 apparatus (Waters Xbridge C18 150×25 mm, 5 μm particle column operated at room temperature with a gradient of 25 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-13 min 40-75% B; 13.1-16 min 100% B; 16.1-19 min 40% B) to give the title compound (250 mg). 1H NMR:(400MHz CDCl3)δ 6.79(d,J=8.4Hz,1H),6.67(d,J=8.4Hz,1H),5.37(t,J=9.2Hz,1H),5.20-5.27(m,3H),4.08-4.16(m,1H),3.96-4.03(m,1H),3 .86(d,J=9.6Hz,1H),3.72(s,3H),3.34-3.39(m,1H),3.24(d,J=10.8Hz,1H),3.06(d,J=4.4Hz,2H),2.90-2.95(m,1H),2.78(br s,1H),2.52(d,J=10.0Hz,2H),2.13-2.20(m,1H),1.97-2.08(m,3H),1.75(br d,J=14.0Hz,1H),1.54-1.69(m,2H),1.17(t,J=7.2Hz,4H),1.12(s,9H),1.06(s,9H),1.05(s,9H),0.90(t,J=7.2Hz,3H) QC-LCMS: (Method DELIVER-K-1), Retention time = 2.02 minutes, [M+H] + =732.4m / z, purity 98.5%. [ka]

[0311] Compound (24): (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid To a solution of (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (compound 13) (1.00 g) in MeOH (20 mL) was added 20% aqueous KCO (5 mL). The mixture was stirred at room temperature for 2 hours before being purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250×50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-20 min 30-65% B; 20.1-25 min 100% B; 25.1-30 min 30% B) to give the title compound (0.50 g). 1 H NMR:(400MHz CDCl3)δ 7.27-7.45(m,5H),6.83(d,J=8.8Hz,1H),6.74(d,J=8.4Hz,1H),5.23-5.33(m,3H),5.06-5.05(m,3H),3.47-3.6 3(m,1H),3.20-3.43(m,4H),2.92-2.97(m,1H),2.60-2.87(m,4H),2.12-2.25(m,2H),1.86-2.01(m,2H),1.81(br d,J=14.0Hz,1H),1.36-1.60(m,2H),1.12-1.22(m,1H),1.09(s,9H)1.06(s,9H),0.96(s,9H),0.95(t,J=7.2Hz,3H). QC-LC-MS: (Method: AB25), Retention time = 2.79 minutes, [M+H] + =780.3m / z. [ka]

[0312] Compound (25): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) To a stirred mixture of (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (2 g), 4 Å MS (2 g), and (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (T-7; prepared as described in Bioorg. Med. Chem. Lett. 9 (1999) 659-662; 5.16 g) in DCM (200 mL) was added BF3-Et2O (1.05 mL) dropwise at -10 °C. The mixture was stirred at room temperature for 2 h before partitioning between saturated aqueous NaHCO3 (200 mL) and DCM (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250 x 50 mm, 10 μm particle column operated at room temperature with a gradient of 80 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-20 min 45-75% B; 20.1-25 min 100% B; 25.1-30 min 45% B) gave the title compound (1.25 g). 1 H NMR:(400MHz CDCl3)δ 7.34-7.48(m,5H),6.83(s,2H),5.09-5.32(m,6H),3.64-3.75(m,4H),3.22-3.31(m,3H),3.01-3.31(m,3H),2.73-2.97 (m,2H),2.12-2.43(m,3H),1.41-1.98(m,4H),1.19-1.34(m,1H),1.13-1.15(m,18H),1.08(s,9H),1.03(t,J=7.2Hz,3H) QC-LC-MS: (Method DELIVER-K-1), Retention time = 2.09 minutes, [M+H] + =794.4m / z.

[0313] Compound (26): (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) To a mixture of Pd / C (4 g, 50%) in THF (20 mL) was added (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (1 g) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (30 psi) for 12 h before the catalyst was removed by filtration. The filtrate was concentrated and purified by preparative HPLC using a GX281 apparatus (Phenomenex Luna C18 100×30 mm, 5 μm particle column operated at room temperature with a gradient of 25 ml / min: water+0.225% formic acid (A) and MeCN (B): 0-15 min 30-60% B; 15.1-17 min 100% B; 17.1-20 min 30% B) to give the title compound (200 mg). 1H NMR:(400MHz d6-DMSO)δ 9.27(s,1H),6.65-6.78(m,2H),5.47-5.58(m,2H),5.14(dd,J=9.6,8.0Hz,1H),5.0 4(t,J=9.6Hz,1H),4.55(d,J=10.0Hz,1H),3.57(s,3H),3.24(dd,J=4.8,17.6Hz,2H) ,3.15(d,J=10.4Hz,2H),2.90(s,1H),2.67(s,2H),2.12(dd,J=11.6,17.2Hz,1H),1. 44-1.89(m,6H),1.17-1.30(m,2H),1.14(s,9H),1.07(m,18H),0.89(t,J=7.2Hz,3H) QC-LC-MS: (Method AB01), retention time = 3.33 minutes, [M+H] + =704.3m / z. [ka]

[0314] Compound (27): (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate To a solution of (4aR,10aR)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol (1.0 g), (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminomethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (T-1; prepared as described in Advances in Chemical Engineering and Science, 2012, 2, 379-383, 3.13 g) and 4 Å MS (1.0 g) in DCM (100 mL) was added BF3-Et2O (0.81 mL) dropwise at -10 to 0 °C. The mixture was stirred at room temperature for 2 h before partitioning between saturated aqueous NaHCO3 (200 mL) and DCM (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using an Agela Fl-H600G apparatus (Phenomenex Luna C18 250*100 mm, 10 μm particle column operated at room temperature with a gradient of 250 ml / min: water + 0.225% formic acid (A) and MeCN (B): 0-25 min 50-80% B; 25.1-30 min 100% B; 30.1-35 min 50% B) to give the title compound (0.2 g). 1 H NMR:400MHz CDCl3:δ6.77(d,J=8.4Hz,1H),6.60(d,J=8.4Hz,1H),5.24-5.38(m,3H),4.96(d,J=7.2Hz) ,1H),4.14(d,J=9.2Hz,1H),3.77(s,3H),3.33(d,J=10.4Hz,1H),2.94-3.18(m,4H),2.85 -2.87(m,1H),2.59(s,2H),2.19-2.27(m,3H),2.12(s,3H),2.06(d,J=3.2Hz,6H),2.02(s ,1H),1.81(d,J=12.4Hz,1H),1.61-1.71(m,3H),1.23-1.26(m,1H),0.98(t,J=7.2Hz,3H) QC-LCMS: (Method DELIVER-K), Retention time = 1.54 min, [M+H] +=578.2m / z.

[0315] In vitro and in vivo characterization of the present invention Example 1: Conversion of the compounds of the invention in human plasma and hepatocytes Example 1a: Conversion of the compounds of the invention in human plasma Frozen human plasma was thawed and then centrifuged at 3200×g for 5 min to remove debris. The pH value of the supernatant was then measured and the pH was adjusted to 7.4±0.1 by adding 1% phosphoric acid or 1N sodium hydroxide. 2 μL of dosing solution (50 μM for test compounds and 100 μM for positive control (propantheline bromide)) was mixed with 98 μL of blank plasma to achieve a final concentration of 1 μM test compound and 2 μM positive control. The mixture was incubated and samples were taken (in duplicate) from the incubation at 37° C. in a water bath at predefined time points of 0, 0.5, 1, 2, 4 and 6 hours. At each corresponding time point, 10 μL inhibitor and 20 μL ascorbic acid and 2 μL formic acid (20%) were added, followed by the addition of 400 μL of “stop solution” (200 ng / mL tolbutamide+200 ng / mL labetalol in 50% ACN / MeOH) to precipitate proteins. The material was mixed thoroughly and then centrifuged at 4,000 rpm for 20 min. An aliquot of the supernatant (50 μL) was then transferred from each well to a sample plate and mixed with 100 μL ultrapure water. The plate was shaken at 800 rpm for approximately 10 min before being subjected to LC-MS / MS analysis.

[0316] Example 1b: Conversion of the compounds of the invention in human hepatocytes Incubations were performed in duplicate at 1 μM compound concentration in 96-well plates. The cell concentration of hepatocytes used for the final incubation at 37°C in an incubator with 5% CO2 and 95% relative humidity was 0.5 × 10 6The concentrations were in cells / mL. Control samples of medium were included in the absence of cells at 0 and 60 min. Total organic concentration in the final incubation was ≦1% (DMSO≦0.1%). Controls (7-ethoxycoumarin and 7-hydroxycoumarin) were incubated in parallel at 3 μM. 2 μL of dosing solution (50 μM for test compounds, 100 μM for positive control) was mixed with 98 μL of 100 mM PBS to achieve a final concentration of 1 μM test compound and 2 μM positive control. The mixtures were incubated and samples were taken (in duplicate) from the incubation at 37° C. in a water bath at the designated time points of 0, 0.5, 1, 2, 4 and 6 h. To each sample, 10 μL inhibitor and 20 μL ascorbic acid and 2 μL formic acid (20%) were added, followed by 400 μL of stop solution (200 ng / mL tolbutamide + 200 ng / mL labetalol in 50% ACN / MeOH). The material was mixed thoroughly and then centrifuged at 4,000 rpm for 20 min. An aliquot of the supernatant (50 μL) was transferred from each well to a sample plate and mixed with 100 μL ultrapure water. The plate was shaken at 800 rpm for approximately 10 min before being subjected to LC-MS / MS analysis.

[0317] Instruments used for analysis of plasma and hepatocyte incubation samples Mass spectrometer (LC-MS / MS): Shimadzu LC 20-AD Shimadzu UHPLC API 4000. Analytical column: ACQUITY UPLC® BEH Phenyl 1.7 μm 2.1×50 mm. Mobile phase A: 0.1% formic acid in water. Mobile phase B: 0.1% formic acid in acetonitrile. Gradient moving from 95 / 5% to 5 / 95% in 2.0 min. Flow rate: 0.7 mL / min. MRM monitoring (multiple reaction monitoring) of test items and added analytical standards (labetalol or tolbutamide).

[0318] Example 1c: Conversion of compounds (Id-ia), (Id-ib) and (Id-iab) in rat and human hepatocytes Compounds were incubated at 1 μg / mL with human or rat hepatocytes suspended in DMEM (Dulbecco's modified Eagle's medium) (pH 7.4) containing HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid). The cell concentration at incubation was 1 × 10 6 The viable cells / mL. Incubations were performed in glass tubes at 37°C with a total incubation volume of 3.5mL, with duplicate incubations performed for each test item. 3.5mL of hepatocyte suspension was equilibrated for 10 minutes in a water bath set at 37°C, after which incubation was initiated by adding 3.5μL of the test item stock solution in DMSO (dimethyl sulfoxide) and gently inverting the tube. The final solvent concentration in the incubation was 0.1% DMSO. After homogeneity of the hepatocyte suspension was ensured, 600μL samples were taken from the incubation at predefined time points of 0.25, 5, 15, 30 and 60 minutes. The taken volume was added to a 1mL Nunc cryotube on wet ice containing 60μL of ice-cold ascorbic acid (100mg / mL) in 0.5M citric acid and 30μL of ice-cold 100mM sugar acid 1.4-lactone. The tubes were mixed and 35 μL of ice-cold 20% formic acid solution was added. The tubes were mixed thoroughly and stored at −80° C. pending analysis. The analytical method and apparatus used for the analysis of (I) from administration of (Id-ia), (Id-ib) and (Id-iab) were the methods and apparatus described in Example 3 in the section “Apparatus used for the analysis of compound (I) from administration of compounds (Ic), (Id-ia), (Id-ib), (Id-iab), compound (2), compound (9), compound (15), compound (27), A2 and A7”.

[0319] The analytical method and equipment used for the analysis of (I) from the administration of (Id-iab) consisted of mixing equal aliquots of the sample and precipitation solution (10% methanol (MeOH) and 1% formic acid in acetonitrile (MeCN)), followed by centrifugation at 16000g for 10 min at 4°C. The supernatant was collected and analyzed by LC-MS / MS. Mass spectrometer: Waters Acquity-Waters Xevo TQ-MS. Analytical column: Acquity UPLC HSS T3, 100 x 2.1 mm, 1.8 μm. Mobile phase A: 0.2% formic acid in water. Mobile phase B: 0.2% formic acid in acetonitrile. Gradient moving from 95 / 5% to 60 / 40 in 5 min. Flow rate 0.3 mL / min. MRM monitoring of (I) in the study samples and analytical standards.

[0320] Example 1d: Conversion of compounds (Id-ia) and (Id-ib) in fresh rat and human blood The conversion of (Id-ia) and (Id-ib) to (I) in human blood (average of 3 donors) and rat blood (average of 45 donors) was demonstrated in fresh blood spiked with 1 μg / mL of (Id-ia), (Id-ib) and (Id-iab), respectively, at 37° C., and (I) was measured in isolated plasma at 0, 5, 15, 30 and 60 minutes. The analytical method and apparatus are described in Example 3 below in the section "Apparatus used for the analysis of Compound (I) from administration of Compound (Ic), (Id-ia), (Id-ib), (Id-iab), Compound (2), Compound (9), Compound (15), Compound (27), A2 and A7".

[0321] Example 2: 5-HT2B agonist activity and binding assays 5-HT2B agonist activity assay The agonist activity of compounds (I), (Ia), (Ib), (Ic), (Ia-iab), compound (2), compound (9), compound (15), compound (27), A2, A3 and A7 at the human 5-HT2B receptor was evaluated by Eurofins / Cerep (France) using HTRF detection to measure the effect of the compounds on inositol monophosphate (IP1) production. Briefly, the human 5-HT2B receptor was expressed in transfected CHO cells. Cells were suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCl, 146 mM NaCl, 1 mM CaCl2, 0.5 mM MgCl2, 5.5 mM glucose and 50 mM LiCl, then distributed into microplates at a density of 4100 cells / well and incubated for 30 min at 37° C. in the presence of buffer (basal control), test compound or reference agonist. For measurements of stimulated controls, individual assay wells contained 1 μM 5-HT. After incubation, cells were lysed and a fluorescent acceptor (fluorophen D2-labeled IP1) and a fluorescent donor (anti-IP1 antibody labeled with europium cryptate) were added. After 60 min at room temperature, the fluorescence transfer was measured using a microplate reader (Rubystar, BMG) at λ(Ex) 337 nm and λ(Em) 620 and 665 nm. IP1 concentrations were determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio). The results were expressed as a percentage of the control response to 1 μM 5-HT. The standard reference agonist was 5-HT, which was tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value was calculated as described above for the dopamine functional assay.

[0322] 5-HT2B binding assay The affinity of the compounds for human 5-HT2B receptors was evaluated in a radioligand binding assay at Eurofins / Cerep (France). Membrane homogenates prepared from CHO cells expressing human 5HT2B receptors were incubated with 0.2 nM [125I] (±) DOI (1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine) at room temperature for 60 min in the absence or presence of test compounds in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM pargyline and 0.1% ascorbic acid. Non-specific binding is determined in the presence of 1 μM (±) DOI. After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% polyethyleneimine (PEI) and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). Filters were dried and counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). Results are expressed as percent inhibition of control radioligand-specific binding. A standard reference compound was (±) DOI, which was tested in each experiment at several concentrations to obtain a competition curve from which its IC 50 is calculated.

[0323] [Table 3]

[0324] Example 3: PK studies in rats For all experiments, approximately 0.68 mL blood samples were collected from the tail or sublingual vein and placed in K3EDTA tubes that had been pre-chilled and prepared with a stabilizing solution consisting of 80 μL ascorbic acid and 40 μL 100 mM D-glyceric acid 1,4 lactone in water. The tubes were gently inverted 6-8 times to mix thoroughly and then placed on wet ice. Collection tubes were placed on wet ice for up to 30 min until centrifugation. Centrifugation was started immediately after removal from the wet ice. Samples were placed back on wet ice immediately after centrifugation was completed. Three subsamples of 130 μL plasma were transferred to each of three appropriately labeled cryotubes containing pre-chilled formic acid (20%) (tubes had been previously spiked and kept refrigerated prior to use). The tube caps were immediately replaced and the plasma solution was thoroughly mixed by gently inverting 6-8 times. Samples were stored frozen at nominally -70°C within 60 min after sampling. Centrifugation conditions were 3000G for 10 minutes at 4° C. After collection, plasma was placed on ice water. Final storage at approximately −70° C.

[0325] Plasma samples were analyzed by UPLC-MS / MS following solid phase extraction or direct protein precipitation. MS detection using electrospray in positive ion mode by monitoring the specific mass / charge transition of compound (I) using an internal standard to correct the response. Concentration-time data were analyzed using standard software with appropriate non-compartmental techniques to obtain estimates of derived PK parameters.

[0326] Equipment used for the analysis of compound (I) from administering compound (Ia): Mass spectrometer (LC-MS / MS): Waters Acquity-Sciex API 5000. Analytical column: Waters BEH UPLC Phenyl 100 x 2.1 mm column, particle size 1.7 μm. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient moving from 95 / 5% to 2 / 98% in 6.1 min. Flow rate: 0.5 mL / min. MRM monitoring (multiple reaction monitoring) of test items and added analytical standards. Dosing and blood sampling: Han Wistar rats were provided by Charles River Laboratories, Sulzfeld, Germany. An automatically controlled artificial 12-hour light and dark cycle was maintained. Rats were fed a standard laboratory diet (Altromin 1324 pellets) obtained from Brogaarden. Rats had free access to food. During the study (4-week toxicity study), rats were orally administered a dose of (Ia) once a day by gavage. From rats administered 300 μg / kg (Ia), blood samples from 3 male satellite animals were taken at the following time points on day 29: 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dosing.

[0327] Equipment used for the analysis of compound (I) from the administration of compound (Ib): Mass spectrometer (LC-MS / MS): Waters Acquity-Sciex API5000. Analytical column: Waters BEH UPLC Phenyl 100 x 2.1 mm column, particle size 1.7 μm. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient moving from 95 / 5% to 2 / 98 in 6.1 min. Flow rate: 0.5 mL / min. MRM monitoring of test items and added analytical standards. Dosing and blood sampling: Han Wistar rats were provided by Charles River Laboratories (UK). An automated artificial 12-hour light and dark cycle was maintained. Rats were fed a standard laboratory diet (Teklad 2014C Diet). Rats had free access to food. During the study (26-week toxicity study), rats were orally administered a dose of (Ib) once daily by gavage. From rats dosed with 300 μg / kg of (Ib), blood samples from three male satellite animals were taken at the following time points on day 182: 0.5, 1, 2, 4, 8 and 24 hours post-dose.

[0328] Equipment used for the analysis of compound (I) from doses of compounds (Ic), (Id-ia), (Id-ib), (Id-iab), compound (2), compound (9), compound (15), compound (27), A2 and A7: Mass spectrometer (LC-MS / MS): Waters Acquity-Waters Xevo TQ-S. Analytical column: Acquity BEH C18 100 x 2.1 mm, 1.7 μm. Mobile phase A: 20 mM ammonium formate + 0.2% formic acid. Mobile phase B: acetonitrile + 0.2% formic acid. Gradient moving from 95 / 5% to 5 / 95% in 11.0 min. Flow rate: 0.3 mL / min. MRM monitoring of test items and added analytical standards. Administration of compounds (Id-ia) and (Id-ib) and blood sampling: Han Wistar rats were provided by Charles River Laboratories, Wiga GmbH, German. An automatically controlled artificial 12-hour light and dark cycle was maintained. Rats were fed with standard laboratory chow (Altromin 1324 pellets) obtained from Brogaarden. Rats had free access to food. (Id-ia) and (Id-ib) were each administered orally by gavage to male Han Wistar rats in a single oral gavage dose. From rats administered 633 μg / kg of (Id-ia) or (Id-ib), blood samples from three male animals were taken on day 1 at the following time points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. Administration of Compound (Ic), (Id-iab), Compound (2), Compound (9), Compound (15), Compound (27), A2, and A7, and Blood Sampling: Han Wistar rats were provided by Envigo, UK. An automated artificial 12-hour light and dark cycle was maintained. Rats were fed a standard laboratory diet Teklad 2014C. Rats had free access to food. Each of Compound (Ic), (Id-iab), Compound (9), Compound (2), Compound (27), A2, A7, or Compound (15) was administered orally by gavage to male Han Wistar rats in a single dose. Rats were dosed with (Id-iab) 793 μg / kg, (Ic) 494 μg / kg, compound (2) 664 μg / kg, compound (9) 483 μg / kg, compound (27) 665 μg / kg, compound (15) 519 μg / kg, A7 359 μg / kg and A2 551 μg / kg. Blood samples from 3 male animals were taken on day 1 at the following time points: 1, 0.25, 0.5, 2, 4, 8 and 24 hours post-dose.

[0329] Equipment used for the analysis of apomorphine from administered apomorphine: Mass spectrometer (UPCLC-MS / MS) Waters Acquity I-Class - Waters Xevo TQ-S. Analytical column Acquity HSS T3 C18 50 x 2.1 mm, 1.8 μm. Mobile phase A: 10 mM ammonium formate 0.2% formic acid:acetonitrile (95:5). Mobile phase B: 10 mM ammonium formate 0.2% formic acid:acetonitrile (5:95). Gradient moving from 95 / 5% to 5 / 95% in 2.40 min. Flow rate 0.3 mL / min. MRM detection of test items and added analytical standards. Dosing and blood sampling: Han Wistar rats were provided by Charles River Laboratories, Wiga GmbH, Germany. An automatically controlled artificial 12-hour light and dark cycle was maintained. Rats were fed with standard laboratory chow (Altromin 1324 pellets) obtained from Brogaarden. Rats had free access to food. Male Han Wistar rats were administered a single dose of apomorphine subcutaneously or orally by gavage. From rats administered 3000 μg / kg apomorphine, blood samples from 3 male animals were taken on day 1 at the following time points: 0.25, 0.5, 1, 2, 4 and 6 hours after subcutaneous administration.

[0330] [Table 4]

[0331] Example 4: PK / PD of Compound (Id-ia) / Compound (I) in the Hyperactivity Assay in Rat animal A total of 206 male CD rats (Charles River, Germany) weighing 200-250 grams (165-190 grams on arrival) were used in the study. The animals were housed at standard temperature (22±1°C) and in a light-controlled environment (lights on from 7 am to 8 pm) with free access to food and water. The experiments described below were carried out in accordance with the standard operating procedures of Charles River Discovery Research Services Finland Ltd. and in accordance with The National Animal Experiment Board of Finland (Elainkoelautakunta, ELLA) authority for animal testing.

[0332] Locomotor activity test, open field The test device is a square Plexiglas area (measuring 40x40x40cm) within which the rat's travel path is recorded by an activity monitor (Med. Associates Inc.). Rats are allowed to habituate to their test cage for 60 minutes before the test period begins. Once habituation is complete, animals are treated with either compound or vehicle and placed back into the open field apparatus. The primary test parameter measured is distance traveled (recorded in 5 minute intervals). The overall measurement time after receiving the first treatment was 360 minutes. The total follow-up time for the study was 420 minutes, including 60 minutes of habituation.

[0333] Blood samples were collected, processed and analyzed as described in Example 3 under the PK study in rats.

[0334] result Oral administration of compound (Id-ia) was evaluated in a rat locomotor activity assay, and this functional readout was then correlated with the plasma concentration of compound (I). Apomorphine and pramipexole were also tested simultaneously in this assay as a comparison (i.e., standard of care (SoC) known in the Parkinson's field), and plasma concentrations were analyzed for apomorphine.

[0335] As shown in Figure 3, compound Id-ia (10-300 μg / kg, p.o.) increased locomotor activity, with the effect beginning approximately 2 hours after administration (at approximately 180 minutes) and continuing until the end of the recording (at 415 minutes). In contrast, the hyperactivity induced by apomorphine (3 mg / kg, s.c.) was immediate but only lasted a short time, as the effect disappeared 1.5 hours after administration (at 150 minutes). Pramipexole (0.3 mg / kg, s.c.) also induced an increase in activity, but the effect appeared approximately 1 hour after administration and disappeared after 2.5 hours (at 270 minutes). The total distance traveled, seen in Figure 4, demonstrates a significant increase in activity for both the tested compound Id-ia and the two comparators, an effect that is expected from a dopamine agonist.

[0336] In parallel with the locomotor activity assessment, plasma samples were taken from satellite animals at six different time points (0.5, 1, 2, 3, 4 and 6 hours post-dose for animals treated with compound (Id-ia)). Pharmacokinetic analysis demonstrated that the behavioral effects of compound (Id-ia) (100 μg / kg, oral) correlated with the plasma concentration of compound (I) (see FIG. 5), demonstrating that the behavioral effects of compound (Id-ia) were induced by compound (I) and not by compound (Id-ia) itself. Corresponding exposure analysis of apomorphine (at 0.25, 0.5, 1, 2, 4 and 6 hours post-dose) yielded a correlation between apomorphine plasma concentrations and hyperactivity behavior (see FIG. 6).

Claims

1. Formula (Id) 【Chemistry 1】 (In the formula, a) R1 is H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl-substituted methyl, benzyl and -C(O)C １ ~C ６ alkyl, and R2 is selected from one of the following substituents (i) and (ii); or b) R1 is selected from one of the following substituents (i) and (ii) and R2 is H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl-substituted methyl, benzyl and -C(O)C １ ~C ６ alkyl; or c) R1 and R2 are independently selected from the following substituents (i) and (ii): d) R1 and R2 are both represented by the following substituent (i): e) R1 and R2 are both represented by the following substituent (ii): 【Chemistry 2】 Where: ＊ indicates the point of attachment; The carbon atom at the point of attachment on substituent (i) is in the S configuration; R3 is H, C １ ~C ６ selected from alkyl and benzyl; R4 is H, -C(O)C １ ~C ６ selected from alkyl and —C(O)phenyl; With the proviso that when R and R in substituent (i) are both H, then R and R cannot both be substituent (i); and With the proviso that when one of R1 and R2 is a substituent (i) and both R3 and R4 in the substituent are H, the other of R1 and R2 cannot be H. or a pharma- ceutically acceptable salt thereof.

2. Formula (Id) 【Chemistry 3】 (In the formula, a) R1 is H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl-substituted methyl, benzyl and -C(O)C １ ~C ６ alkyl, and R2 is selected from one of the following substituents (i) and (ii); or b) R1 is selected from one of the following substituents (i) and (ii) and R2 is H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl-substituted methyl, benzyl and -C(O)C １ ~C ６ alkyl; or c) R1 and R2 are independently selected from the following substituents (i) and (ii): d) R1 and R2 are both represented by the following substituent (i): e) R1 and R2 are both represented by the following substituent (ii): 【Chemistry 4】 Where: ＊ indicates the point of attachment; The carbon atom at the point of attachment on substituent (i) is in the S configuration; R3 is H, C １ ~C ６ selected from alkyl and benzyl; R4 is H, -C(O)C １ ~C ６ alkyl and -C(O)phenyl. or a pharma- ceutically acceptable salt thereof; With the proviso that when R and R in substituent (i) are both H, then R and R cannot both be substituent (i); and provided that if one of R1 and R2 is a substituent (i) and both R3 and R4 in the substituent are H, then the other of R1 and R2 cannot be H; and The compound of formula (Id) is (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate or a pharma- ceutically acceptable salt thereof, provided that the compound is not one of:

3. R1 is H and R2 is substituent (i); or R1 is a substituent (i) and R2 is H; or R1 and R2 are both represented by substituent (i); where R3 is H, C １ ~C ６ alkyl and benzyl; and R4 is H, -C(O)C １ ~C ６ selected from alkyl and —C(O)phenyl; 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, provided that R3 and R4 are not both H.

4. R1 is H and R2 is substituent (ii); or R1 is a substituent (ii) and R2 is H; or R1 and R2 are both represented by substituent (ii); where R3 is H, C １ ~C ６ alkyl and benzyl; and R4 is H, -C(O)C １ ~C ６ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, selected from alkyl and -C(O)phenyl.

5. R1 is H, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl-substituted methyl, benzyl and -C(O)C １ ~C ４ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl.

6. R1 is H, C １ ~C ３ The compound according to any one of claims 1 to 5, wherein the compound is selected from the group consisting of alkyl and benzyl, or a pharma- ceutically acceptable salt thereof.

7. R2 is H, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl-substituted methyl, benzyl and -C(O)C １ ~C ４ The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl.

8. R2 is H, C １ ~C ３ The compound according to any one of claims 1 to 6, wherein the compound is selected from the group consisting of alkyl and benzyl, or a pharma- ceutically acceptable salt thereof.

9. R3 is H, C １ ~C ４ The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein said alkyl is selected from alkyl and benzyl.

10. R4 is H, -C(O)C １ ~C ４ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, selected from alkyl and -C(O)phenyl.

11. R4 is H or -C(O)C １ ~C ４ 11. The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

12. 12. The compound according to any one of claims 1 to 11, wherein R1 and R2 are both represented by substituent (i), or R1 and R2 are both represented by substituent (ii), or a pharma- ceutically acceptable salt thereof.

13. (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2R,3R,4S)-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate; (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2R,3R,4S)-3,4-dihydroxy-2-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4-dihydro-2H-pyran-6-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; Ethyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-(ethoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (2S,3S,4S,5R,6S)-2-((benzyloxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-2-((methoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-((ethoxy)carbonyl)-6-(((4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-6-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-3,4,5-tris(pivaloyloxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate); and (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 2. The compound of claim 1 selected from the group consisting of:

14. The formula:

2. The compound of claim 1 having the formula:

15. The formula:

2. The compound of claim 1 having the formula:

16. The formula:

2. The compound of claim 1 having the formula:

17. The formula:

2. The compound of claim 1 having the formula:

18. The formula:

2. The compound of claim 1 having the formula:

19. The formula:

2. The compound of claim 1 having the formula:

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers or diluents.

21. (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate A pharmaceutical composition comprising a compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

22. 1. A pharmaceutical composition for treating a neurodegenerative disease or disorder, including Parkinson's disease, Huntington's disease, restless legs syndrome, or Alzheimer's disease; or a neuropsychiatric disease or disorder, including schizophrenia, attention deficit hyperactivity disorder, or drug addiction, comprising a compound or a pharma- ceutical acceptable salt thereof, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and Methyl (2S,3S,4S,5R,6S)-6-[[(4aR,10aR)-1-propyl-6-[(2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl]oxy-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-7-yl]oxy]-3,4,5-triacetoxy-tetrahydropyran-2-carboxylate A pharmaceutical composition selected from the group consisting of

23. 20. A compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, for use in therapy.

24. 20. A pharmaceutical composition for treating a neurodegenerative disease or disorder, including Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a psychiatric disease or disorder, including schizophrenia, attention deficit hyperactivity disorder or drug addiction, comprising a compound according to any one of claims 1 to 19 or a pharma- ceutical composition comprising a compound or a pharma- ceutical acceptable salt thereof.

25. 20. Use of a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, including Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder, including schizophrenia, attention deficit hyperactivity disorder or drug addiction.

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