Novel heterocyclic compounds and their use

Abstract

To provide novel compounds derived from substituted 1,2,3,6-tetrahydropyridines and 2,3-dihydropyridines, and pharmaceutical compositions comprising the compounds.SOLUTION: The present invention relates to: compounds of general formula (I), and stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising a compound of formula (I), and such compounds for use as a medicament and particularly in the treatment or prevention of drug addiction and CNS related diseases and conditions. Further, the invention relates to methods for the preparation of a compound of formula (I) or pharmaceutically acceptable salt or stereoisomer thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel compounds derived from substituted 1,2,3,6-tetrahydropyridines and 2,3-dihydropyridines, and pharmaceutical compositions containing the compounds. More specifically, the present invention relates to novel compounds derived from 1,2- or 2,3-disubstituted 1,2,3,4-tetrahydroisoquinolines and -2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles, as well as 1-methyl-4,9-dihydro-3H- and 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles. The present invention also relates to methods for preparing the derivatives, as well as to the compounds for use in the treatment or prevention of drug addiction and CNS-related disorders. [Background technology]

[0002] Background of the Invention Among endogenous tetrahydropyridine derivatives, tetrahydroharmane (1-methyl-1,2,3,4-tetrahydro-β-carboline) is an indole alkaloid that lowers blood pressure. Reserpine, another indole alkaloid with a tetrahydropyridine structure, is used as a hypertension treatment and has also been shown to alleviate psychotic symptoms. Furthermore, known tetrahydropyridine derivatives with a fused indole ring are tryptoline (tetrahydro-β-carboline, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole), pinoline (5-methoxytryptoline), tetrahydroharmine ((1R)-7-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole), harmaline (7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole), and tetrahydroharmine ((1R)-7-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole), which exhibit various activities such as psychoactive effects, monoamine oxidase inhibitory activity, serotonin reuptake inhibitory activity, central nervous system stimulating activity, and neurogenesis promoting activity. Among synthetic tetrahydropyridine derivatives, gevotroline (8-fluoro-2-(3-(pyridin-3-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole) is an atypical antipsychotic drug that was developed for the treatment of schizophrenia, but this compound was never marketed. Another tetrahydropyridine derivative, latrepirdine (dimebolin, 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole), is an antihistamine that failed phase III clinical trials for the treatment of both Alzheimer's disease and Huntington's disease.

[0003] Related endogenous isoquinolines exhibit a variety of effects, including sedative, psychotropic, and analgesic activities. Well-known examples of isoquinoline alkaloids are morphine and codeine. Endogenous isoquinolines are produced by the condensation of biogenic amines, such as phenethylamine, with simple aldehydes, such as formaldehyde and acetaldehyde. They are known to regulate neurotransmission, central metabolism, and motor activity. The endogenous tetrahydroisoquinoline (TIQ) derivative, salsolinol (SAL, 1-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol), is believed to be a causative agent of Parkinson's disease (PD), while (R)-1MeTIQ (1-methyl-1,2,3,4-tetrahydroisoquinoline) has been shown to have antiparkinsonian activity. Until recently, 1-MeTIQ was the only known TIQ derivative with neuroprotective / PD-preventive properties. In 2006, Katsuhiro OKUDA ​​et al. (Biological and Pharmaceutical Bulletin 29 (2006) pp. 1401-1403) discovered that 5- / 6- / 7-monohydroxylated 1MeTIQ derivatives have neuroprotective and PD-preventive effects greater than those of the parent compound.

[0004] The concentrations of many endogenous TIQ derivatives are significantly higher in the urine and cerebrospinal fluid of PD / ADHD (attention deficit hyperactivity disorder) patients compared to controls, whereas the content of 1MeTIQ has been shown to be significantly reduced in the cerebrospinal fluid and brains of PD patients.

[0005] SAL is formed enzymatically and non-enzymatically as a condensation product of acetaldehyde, a major metabolite of ethanol, and dopamine in the mammalian brain. SAL affects the uptake of catecholamines into nerve terminals, the release of stored catecholamines, and the activity of monoamine oxidase (MAO), catechol-O-methyltransferase (COMT), and tyrosine hydroxylase. Ethanol-induced elevation of salsolinol levels is known to be involved in the development of ethanol intoxication / alcoholism.

[0006] SAL is hypothesized to mediate some of the addictive properties of alcohol. Numerous studies have shown that primates can self-administer SAL at nanomolar concentrations following intracranial injection into specific brain regions. Acetaldehyde can also be self-administered via intracranial injection, but at much higher concentrations. Studies have confirmed that SAL is released during lactation in lactating sheep. It is clear that SAL mediates the reinforcing effects of many primate species. Studies have shown that controlled doses of ethanol intake have minimal effects on brain SAL concentrations. Nevertheless, it is clear that ethanol intake increases brain concentrations of dopamine and acetaldehyde, thereby increasing the concentrations of the starting materials for the Pictet-Spengler reaction, which forms SAL. Given this, it seems likely that alcoholics, who consume large amounts of ethanol and generally have high aldehyde dehydrogenase (ALDH) activity (see Alcohol Clin. Exp. Res. 2009 Nov.; 33(11):1935-44), will attempt to compensate for the decline in acetaldehyde and SAL levels by drinking more alcohol.

[0007] Most TIQs penetrate the brain in pharmacologically relevant amounts and produce a variety of effects. Most TIQs and 1MeTIQ are excreted from the brain (90.4% and 95.3%) and excreted unchanged in the urine (76% and 72%). Hydroxylated (C4 of the isoquinoline skeleton) derivatives of TIQs and 1MeTIQ were the most abundant metabolites in urine (2.7% and 8.7%).

[0008] European Journal of Medicinal Chemistry 41 (2006) pp. 241-252 reports 6-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline as a potential drug for Parkinson's disease.

[0009] EP 2090576 discloses certain 5,8- and 6,7-difluoro-substituted isoquinolines as intermediates in the preparation of pyrazolo[1,5-a]pyridines for use as metabotropic glutamate receptor modulators.

[0010] WO2002028865 discloses certain substituted 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles as selective inhibitors of cyclic guanosine 3',5'-monophosphate-specific phosphodiesterases.

[0011] European Patent Application Publication No. 3459950 discloses certain β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid compounds that have anti-plant viral activity, and are also disclosed to have fungicidal and insecticidal activity.

[0012] WO 2012 / 020170 discloses 6,7-disubstituted-1-methyl-1,2,3,4-tetrahydro- and -3,4-dihydroisoquinolines for use in the treatment of drug addiction and CNS-related disorders.

[0013] Mangalaraj, S. et al., J. Chem. Sci, 2015, Vol. 15, No. 5, pp. 811-819 (DOI:10.1007 / s12039-015-0836-8), disclose the synthesis of fused tetrahydro-β-carboline analogs via imide carbonyl activation using BBr3.

[0014] Raheem, IT et al., J. AM. CHEM. SOC. 2007, Vol. 129, pp. 13404-13405 (DOI:10.1021 / ja076179w), disclose an enantioselective Pictet-Spengler type cyclization of hydroxylactams.

[0015] It has now surprisingly been found that certain substituted 1,2,3,6-tetrahydropyridines and 2,3-dihydropyridines block the undesirable metabolic formation of dihydroxy compounds, thereby also improving the desired activity of the isoquinoline derivatives. Summary of the Invention

[0016] It is an object of the present invention to provide compounds useful in the treatment of disorders and diseases associated with drug addiction and CNS-related disorders.

[0017] One of the problems associated with known compounds is the pharmacokinetics of the compounds, in particular their metabolic stability. It is therefore a further object of the present invention to provide compounds with improved metabolic stability.

[0018] The present invention is based on the recognition that the compounds of the present invention bind to and / or affect the activity of proteins associated with drug addiction and CNS-related diseases.

[0019] The object of the present invention is achieved by a compound characterized in that it is set forth in the independent claims and by said compound for use as a pharmaceutical. Preferred embodiments of the invention are disclosed in the dependent claims.

[0020] The present invention relates to a compound of formula (I) [ka] [In the formula, Dotted lines represent optional bonds; R 1 and R 2 together with the carbon atoms to which they are attached form a group selected from 1H-indole and benzene groups, said 1H-indole and benzene groups being R 3 , R 4 , R 5 and R 6 and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: 3 , R 4, R 5 and R 6 are halogens, OH, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy; R a and R b together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; and R c is H; or R a is Me, and R b and R c together with the nitrogen and carbon atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; or R a is Me, R b is H, or R if the dotted line represents a bond b does not exist, and R c is H, except that R 1 and R 2 together with the carbon atom to which they are attached form said optionally substituted 1H-indole group; R 7 is halogen, OH, oxo, SH, NOR 8 , C 1~3 -(per)haloalkyl, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy, CN, C(O)N(R 8 )2 and N(R 8 )2, or R 7 is C 1~4 -alkyl, provided that the 1H-indole or benzene group is not substituted with halogen, OH, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C1~3 -alkoxy, C 1~3 -(per)haloalkoxy; or R 7 may be H, with the proviso that R a and R b together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; R c If is H, then R 4 and R 5 is a halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, or R a is Me and R b and R c together with the carbon and nitrogen atoms to which they are attached form a six-membered cyclic amide, R 1 and R 2 together with the carbon atom to which they are attached form said optionally substituted 1H-indole group, or R a is Me and R b and R c together with the carbon and nitrogen atoms to which they are attached form a five-membered cyclic amide, and R 1 and R 2 together with the carbon atom to which they are attached to form a 1H-indole or benzene group, said 1H-indole or benzene group may not contain halogen, OH, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy; or R a is Me and R c is H and R1 and R 2 together with the carbon atom to which they are attached form a substituted 1H-indole group, R of said substituted 1H-indole group 4 and R 5 is a halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy; Each R 8 is H, C 1~4 -Alkyl, C 1~4 -Alkenyl, C 1~4 -alkynyl and C 1~3 -(per)haloalkyl, or any N(R 8 )2, both R 8 may, together with the nitrogen to which they are attached, form a 3- to 6-membered aliphatic or aromatic heterocyclic ring containing 1 to 3 heteroatoms each independently selected from N, O, and S, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0021] The present invention also relates to pharmaceutical compositions comprising an effective amount of one or more compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable excipients.

[0022] Furthermore, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for use as a medicament.

[0023] Furthermore, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a CNS-related disease or condition.

[0024] The present invention also relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, depression, anxiety, hyperactivity, narcolepsy, drug addiction, alcoholism, anorexia nervosa, bulimia and mitochondrial disease.

[0025] Finally, the present invention provides a method for preparing compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description of the Invention The compounds of the present invention are derivatives of 1,2,3,6-tetrahydropyridine and 2,3-dihydropyridine fused at C4 and C5 to either an optionally substituted 1H-indole ring or an optionally substituted benzene ring, which, together with the specific substitution patterns of the 1,2,3,6-tetrahydropyridine and 2,3-dihydropyridine rings, provide the compounds with the properties in accordance with the present invention. The substitutions of the 1H-indole and benzene rings also further enhance the metabolic and / or inhibitory properties of the compounds of the present invention.

[0027] The term "halogen" as used herein and hereinafter by itself or as part of another group refers to Group VIIa elements and includes F, Cl, Br and I groups, preferably F.

[0028] As used herein and hereinafter, the term "alkyl" refers to an aliphatic linear, branched or cyclic, especially linear or branched, hydrocarbon group having the indicated number of carbon atoms, e.g., C 1~6 -Alkyl has 1 to 6 carbon atoms in the alkyl portion, thus e.g., C 1~4 -Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; C 1~6-Alkyl further includes branched and straight chain pentyl and hexyl. Preferably, alkyl is methyl or ethyl.

[0029] As used herein and hereinafter, the term "C 1~4 "-Alkenyl" refers to an unsaturated linear or branched hydrocarbon group having at least one olefinic double bond between any two carbon atoms, suitably having 1 to 4, preferably 1 to 3, carbon atoms in the alkenyl moiety, such as ethenyl, 1-propenyl, 2-propenyl, 3-propenyl, and butenyl. Preferred examples of alkenyl groups include, but are not limited to, linear alkenyl groups having a terminal double bond, such as vinyl and allyl groups.

[0030] As used herein and hereinafter, the term "C 1~4 "-Alkynyl" is an unsaturated linear or branched hydrocarbon group having at least one olefinic triple bond between any two carbon atoms and suitably having 1 to 4, preferably 1 to 2, carbon atoms in the alkenyl moiety, such as ethynyl, propynyl, and butynyl.

[0031] As used herein and hereinafter, the term "C 1~3 "-(Per)haloalkyl" refers to any of the above alkyl groups in which one or more hydrogen atoms have been replaced with a halogen, particularly I, Br, F, or Cl. Examples of haloalkyl groups include, but are not limited to, chloromethyl, fluoromethyl, and -CHCF. The term "perhaloalkyl" is understood to refer to an alkyl group in which all hydrogen atoms have been replaced with halogen atoms. Preferred examples include trifluoromethyl (-CF) and trichloromethyl (-CCl).

[0032] As used herein and hereinafter, the term "C 1~3 -alkoxy" is -O-(C 1~3 -alkyl) group, where "C 1~3-alkyl" has the meaning defined above. Examples of preferred alkoxy groups include, but are not limited to, methoxy, ethoxy and isopropyloxy.

[0033] As used herein and hereinafter, the term "C 1~3 -(per)haloalkoxy" refers to -O-(C 1~3 -(per)haloalkyl) groups, where C 1~3 -(per)haloalkyl has the meaning defined above. Examples of preferred alkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trichloromethoxy and 1,1,1,3,3,3-hexafluoroisopropoxy.

[0034] The term "5- and 6-membered cyclic amide" as used herein and hereinafter refers to 5- and 6-membered lactams which may or may not contain other heteroatoms such as N, O, and S, or substituents such as methyl, hydroxy, amine, thiol, and methoxy. Examples of preferred 5- and 6-membered cyclic amide groups include, but are not limited to, 2-pyrrolidone, 2-piperidinone, imidazolidin-2-one, oxazolidin-2-one, oxazolidin-4-one, imidazolidin-4-one, tetrahydropyrimidin-2(1H)-one, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholin-3-one, 4-methylpiperidin-2-one, and 5-hydroxypiperidin-2-one.

[0035] As used herein and hereinafter, the term "oxo" refers to the functional group "=O" which, together with the carbon atom to which the oxygen of "oxo" is attached and the carbon-oxygen double bond between said carbon atom and said oxygen atom, forms a carbonyl group of the compounds disclosed herein. Thus, R 7 When is "oxo", it should be understood that the carbon atom to which the oxygen atom of the "oxo" is attached does not contain one or more hydrogen atoms.

[0036] As used herein and hereinafter, the term "NOR 8 " is NOR 8 a functional group which, together with the carbon atom to which the nitrogen of is attached and the carbon-nitrogen double bond between said carbon atom and said nitrogen atom, forms an oxime functional group of a ketoxime compound disclosed herein, said oxime functional group being either substituted or unsubstituted with an oxygen atom of the oxime functional group; 8 refers to a functional group that shall be as defined herein and hereinafter. Thus, R 7 NOR 8 If NOR 8 It should be understood that the carbon atom to which the nitrogen atom is attached does not include one or more hydrogen atoms. 8 is, for example, a carbonyl group (R 7 is oxo) with, for example, hydroxylamine, 7 The compound is formed where NOR is NOH. 8 Example groups include, but are not limited to, hydroxyimino, methoxyimino, (trifluoromethoxy)imino, and (2,2,2-trifluoroethoxy)imino, and their (E)- and (Z)-isomers.

[0037] As used herein and hereinafter, the term "a 3- to 6-membered aliphatic or aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S" refers to a saturated, partially unsaturated, unsaturated, or aromatic monocyclic ring having 3 to 6 ring atoms, which may or may not contain one or more double bonds between the ring atoms, wherein the monocyclic ring contains 1 to 3 heteroatoms independently selected from the group consisting of N, S, and O, while the remaining ring atoms are carbon atoms. The monocyclic ring may be substituted on any suitable ring atom, including N, with 1 to 4 substituents. Preferred substituents include, but are not limited to, halogen, particularly fluoro, CN, methoxy, hydroxy, amino, and methyl. Examples of heterocyclic rings include, but are not limited to, aziridinyl, azetidinyl, 1,3-diazetidinyl, pyrazolidinyl, imidazolidinyl, imidazolyl, piperidinyl, dihydrothiazolyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, thiomorpholinyl dioxide, and methoxymethylpyrrolidinyl.

[0038] As used herein and hereinafter, the term "optionally substituted" indicates that the group to which it refers is unsubstituted or independently substituted with one or more, preferably 1, 2, 3, or 4, substituents attached to any available atom to produce a stable compound. For example, phenyl may be substituted once with the indicated substituent attached to the o-, m-, or p-position of the phenyl ring. In general, "substituted" refers to a substituent defined herein in which one or more bonds to a hydrogen atom in the group are replaced with a bond to a non-hydrogen atom of the substituent, unless otherwise specified. Preferred substituents are halogens such as F, Cl, Br, and I, especially F and Cl; COH and its esters; C 1~4 -Alkyl, especially methyl; OH, C 1~3 -alkoxy, in particular OMe, OEt and OCHCH=CH2; NO2, N3, NOH and their ethers, in particular NOMe; CN, NH2 and their amides, in particular NHC(O)Me; NH(C 1~6 -alkyl), N(C1~6 -alkyl)2,N + (C 1~6 -alkyl)3, especially NHMe, N(Me)2, N + (Me)3 and its salts; C(O)N(C 1~6 -alkyl), especially C(O)NHMe; NHC(O)-C 1~6 -Alkyl, especially NHC(O)Me; SH and its thioethers; C 1~4 -Alkenyl, C 1~4 -alkynyl, C 1~3 -(per)haloalkyl, especially CF3 and CH2CF3;C 1~3 -(per)haloalkoxy, especially OCF3 and OCH2CF3; SC(O)-C 1~6 -Alkyl, OC(O)-C 1~6 -Alkyl, NHC(O)NH-C 1~6 -Alkyl, NHC(O)OC 1~6 -alkyl, preferably, the substituents are optionally substituted with OH, NH, COH, and halogen.

[0039] "Optional" or "optionally" indicates that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur. "Comprises" or "comprising" indicates that the subsequently described set may, but may not, include other elements.

[0040] As used herein and hereinafter, the term "stereoisomer" refers to a stereoisomer of a compound. Examples of stereoisomers include, but are not limited to, enantiomers, diastereomers, cis-trans isomers, and EZ isomers.

[0041] As used herein and hereinafter, the term "pharmaceutically acceptable salts" refers to salts that are known to be non-toxic and are commonly used in the pharmaceutical literature. Typically, these are acid addition salts or base addition salts of the compounds of the present invention.

[0042] The expression "acid addition salt" includes all non-toxic organic and inorganic acid addition salts that the compounds of Formulae (I)-(V), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (I') can form. Exemplary inorganic acids that form suitable acid addition salts include, but are not limited to, hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid. Exemplary organic acids that form suitable acid addition salts include, but are not limited to, acetic acid, lactic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, methanesulfonic acid, salicylic acid, and the like. As used herein, the term "acid addition salt" also includes solvates, such as hydrates, alcoholates, and the like, that the compounds and their salts can form. These salts also include salts useful for chiral resolution of racemates.

[0043] The expression "base addition salt" includes any non-toxic base addition salt that the compounds of Formulae (I)-(V), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (I') can form. Suitable base addition salts include, but are not limited to, those derived from inorganic bases such as aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, and zinc salts, particularly sodium and ammonium salts. Further examples of organic base addition salts include trialkylamines such as triethylamine and trimethylamine, other salts of organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, and choline salts.

[0044] The pharmaceutical composition of the present invention can be administered in an effective amount within the range of about 0.1 μg / kg body weight to about 300 mg / kg body weight, preferably 1.0 μg / kg body weight to 10 mg / kg body weight. The compound of the present invention may be administered once a day, or the total daily dose may be divided into two, three, or four doses per day.

[0045] The term "effective amount" refers to the amount of a composition or pharmaceutical composition that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of or feels an effect). Such treatment need not necessarily completely ameliorate the condition or disease. Furthermore, such treatment or prevention may be combined with other conventional treatments for alleviating the condition or disease known to those skilled in the art. The effective amount is typically determined by a physician and depends on the condition or disease being treated, the selected route of administration, the actual compound being administered, the age, sex, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0046] The skilled artisan has the knowledge and skill in the art to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. Moreover, there are many resources available to the skilled artisan that describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients.

[0047] Suitable pharmaceutically acceptable excipients include, but are not limited to, the following types of excipients: diluents (e.g., starch, mannitol), fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate), binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or methylcellulose), additives (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch), lubricants (e.g., sodium lauryl sulfate), flow agents (e.g., fumed silica, talc, magnesium carbonate), granulating agents (e.g., water, ethanol), coating agents (e.g., hydroxypropyl methylcellulose, gelatin, waxes, shellac, resins, vegetable fibers), wetting agents (e.g., sorbitan monopalmitate, poloxamer 407), solvents (e.g., water), cosolvents (e.g., ethanol, propylene glycol), suspending agents (e.g., sorbitol, cellulose derivatives, food hydrogenated fats and oils), emulsifiers (e.g., lecithin or acacia), sweeteners (e.g., sucrose), flavorings (e.g., cherry, lime), flavor masking agents (e.g., vanilla, citrus), coloring agents (e.g., titanium oxide), anti-caking agents (e.g., silicon dioxide), humectants (e.g., glycerin, sorbitol), chelating agents (e.g., EDTA salts, histidine, aspartic acid), plasticizers (e.g., tributyl citrate, diethyl phthalate), thickeners (e.g., methylcellulose), Antioxidants (e.g., ascorbic acid, cysteine), preservatives (e.g., methyl or propyl p-hydroxybenzoate, sorbic acid or ascorbic acid), stabilizers (e.g., polysorbate 20 and 80, poloxamer 407), surfactants (e.g., polyethylene glycol, polysorbate 80), and buffers (e.g., buffers of sodium and potassium salts of phosphate, citrate, acetate, carbonate, or glycine, depending on the desired pH range). Additives and / or adjuvants may facilitate processing of the active agent into a pharmaceutically usable formulation.The skilled artisan will recognize that a particular pharmaceutically acceptable excipient can serve more than one function and may perform alternative functions depending on how much of the excipient is present in the pharmaceutical composition and what other ingredients are present in the pharmaceutical composition.

[0048] The pharmaceutical compositions of the present invention are most preferably used alone or in combination, i.e., administered simultaneously, separately, or sequentially with other active ingredients, such as pharmaceutically active compounds or biological products. The amount of the pharmaceutical compositions of the present invention, particularly pharmaceutical compositions containing the compound of formula (I) or its pharmaceutically acceptable salt, as well as the other active ingredients and the relative timing of administration, can be selected to achieve the desired combined therapeutic effect. The pharmaceutical compositions of the present invention can be administered by various routes, for example, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, or topical administration, and can also be administered by intradermal injection, transdermal, rectal, buccal, mucosal, nasal, or ocular route, via inhalation, or via implants.

[0049] The pharmaceutical composition can be formulated into a suitable pharmaceutical preparation, and suitable dosage forms include, for example, solutions, dispersions, suspensions, powders, capsules, tablets, pills, controlled-release capsules, controlled-release tablets, and controlled-release pills. In addition to, or instead of, pharmaceutically acceptable additives and / or other active ingredients, the pharmaceutical preparation of the pharmaceutical composition can include one or more suitable pharmaceutically acceptable carriers.

[0050] In the present specification and the following, the term "pharmaceutically acceptable carrier" refers to a substrate contained in the pharmaceutical composition for drug delivery, which plays a role in improving the selectivity, efficacy and / or safety of drug administration.Examples of pharmaceutically acceptable carrier include, but are not limited to, pharmaceutically acceptable additives, liposomes, (polymeric) micelles, microspheres, nanoparticles and protein-drug conjugates.

[0051] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Pharmaceutical compositions of the present invention include, but are not limited to, compositions for parenteral administration and compositions for topical administration, including, but not limited to, sterile aqueous or non-aqueous solvents, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, fish oils, and injectable organic esters. Aqueous carriers include, but are not limited to, water, water-alcohol solutions, such as saline, and buffered internal parenteral vehicles, such as sodium chloride solution, Ringer's dextrose solution, glucose and sodium chloride solution, Ringer's lactose solution, or fixed oils. Intravenous vehicles include, but are not limited to, fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Depending on the desired pH range, aqueous pharmaceutical compositions according to the present invention may contain an appropriate buffer, such as sodium and potassium salts of phosphate, citrate, acetate, carbonate, or glycine. Sodium chloride may also be useful as an isotonicity agent. The pharmaceutical composition may contain other additives, such as stabilizers or preservatives. Useful stabilizing additives include surfactants (polysorbate 20 and 80, poloxamer 407), polymers (polyethylene glycol, povidone), carbohydrates (sucrose, mannitol, glucose, lactose), alcohols (sorbitol, glycerol propylene glycol, ethylene glycol), suitable proteins (albumin), suitable amino acids (glycine, glutamic acid), fatty acids (ethanolamine), antioxidants (ascorbic acid, cysteine, etc.), chelating agents (EDTA salts, histidine, aspartic acid), or metal ions (Ca, Ni, Mg, Mn). Useful preservatives include benzyl alcohol, chlorobutanol, benzalkonium chloride, and, in some cases, parabens. The pharmaceutical composition according to the present invention can be provided in a concentrated or powder form to be reconstituted as needed. In such cases, a powder formulation of the above-mentioned injection / infusion additive solution can be used.When freeze-drying, certain cryoprotectants are preferred, such as polymers (povidone, polyethylene glycol, dextran), sugars (sucrose, glucose, lactose), amino acids (glycine, arginine, glutamic acid), and albumin. If a reconstitution solution is added to the package, it can consist of, for example, purified water for injection, sodium chloride solution, dextrose solution, or glucose solution.

[0052] The term "treatment or prevention" as used herein and hereinafter includes the prevention or prophylaxis of the named disorders or conditions and the reduction of an individual's risk of suffering therefrom, or the alleviation, amelioration, elimination or cure of said disorders once established.

[0053] The term "administering" or "administered" to a subject or patient includes formulating a composition or pharmaceutical composition and delivering or applying it to a subject by any route suitable for delivering the composition or pharmaceutical composition to a desired internal site.

[0054] The compounds of formula (I) of the present invention may be useful in therapy, particularly in the treatment or prevention of CNS-related diseases and conditions in animals, particularly mammals and humans.In particular, the compounds of formula (I) have pharmacological properties for treating and / or preventing CNS-related diseases or conditions, including but not limited to Alzheimer's disease, Parkinson's disease, depression, anxiety, hyperactivity, narcolepsy, drug addiction, alcoholism, anorexia nervosa, bulimia, mitochondrial disease, obesity, and multiple sclerosis.

[0055] The compounds of formula (I) of the present invention bind to one or more proteins involved in CNS-related diseases or conditions, some examples of which include, but are not limited to, trace amine receptors, dopamine and serotonin receptors, their respective transporters and acyl and methyltransferases, norpinephrine transporter, monoaminooxidase, catecholine-O-methyltransferase, adrenergic receptors, tyrosine hydroxylase, histamine receptors, orexin receptors, NMDA receptors, sigma-1 receptors, muscarinic and nicotinic acetylcholine receptors, opioid receptors, neuropeptide receptors, melanocortin receptors (excluding MC3R), neurokinin receptors and type 1 corticotropin-releasing factor receptor.

[0056] As used herein and hereinafter, the term "protected by a protecting group" refers to an atom or functional group that is covalently bonded to or modified with a protecting group. The protecting group allows for chemoselectivity in the reaction, and thus these protecting groups protect the atom or functional group from reacting during the reaction. It should be understood that a protecting group completely or partially protects the atom or functional group, i.e., an atom or functional group protected by a protecting group may partially react during the reaction. A skilled artisan has the knowledge and skill in the art to select a suitable protecting group for the atom or functional group to be protected. Furthermore, there are many resources available to the skilled artisan that describe protecting groups and may be useful in selecting a suitable protecting group for the atom or functional group to be protected. For information on suitable protecting groups and methods for protecting compounds with suitable protecting groups, see, for example, Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Inc., Hoboken, New Jersey. Examples of atoms and functional groups that can be protected with protecting groups include, but are not limited to, optionally substituted 1H-indole, preferably the nitrogen of 1H-indole, O, S, N, OH, SH, NH, carbonyls such as aldehydes and ketones, ethers, esters, and amides.Examples of protecting groups include, but are not limited to, carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl, BOC, Fmoc, acetyl, benzoyl, phenyl, benzyl, trityl, sulfonyl such as phenylsulfonyl, tosyl (Ts), mesyl, and trifyl; tosylate, silyl ether such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ether; tetrahydropyranyl (THP), p-methoxyphenyl ether (PMP), p-methoxybenzyl ether (PMB), β-methoxyethoxymethyl ether (MEM), pivaloyl, thioether, acetal, ketal, dithiane, benzyl ester, tert-butyl ester, orthoester, and photolabile groups.

[0057] As used herein and hereinafter, the term "the 1H-indole nitrogen is optionally protected with a protecting group" means any protecting group replacing the hydrogen of the 1H-indole nitrogen; [ka] where R 3 , R 4 , R 5 and R 6 is as defined above and below, and thus the protecting group protects the nitrogen from reaction and the 1H-indole is R 1 and R 2 and the carbon atoms to which they are attached (the 2- and 3-positions (indicated by an asterisk) of said 1H-indole are fused with the 4- and 5-positions of a substituted 1,2,3,6-tetrahydropyridine and 2,3-dihydropyridine to form the compounds of the present invention). Similarly, "the oxygen or sulfur of said OH or SH is optionally protected by a protecting group" means herein and hereinafter any protecting group that replaces the hydrogen of said OH or SH, and thus said protecting group protects said oxygen or sulfur.

[0058] As used herein and hereinafter, the term "activating group" refers to a functional group of a compound that facilitates a reaction to occur and / or favorably influences the overall reaction rate and / or has a directing effect on the positional isomerism of the product formed. The activating group may or may not be part of the product formed, i.e., the activating group may be present in the product or may be present in the product, e.g., S N 2. S N It should be understood that the activating group may be a leaving group or part of a leaving group in addition-elimination reactions. The compounds disclosed herein can have one or more activating groups, which may be the same or different. Examples of activating groups include, but are not limited to, sulfonyl, such as phenylsulfonyl, tosyl (Ts), mesyl, and trifyl; halogen, (substituted) amino group, amide, ester, hydroxy, alkoxy, acyloxy, thiol, alkyl, (per)haloalkyl, and photolabile groups.

[0059] In this specification and the following, the term "aldehyde" refers to a compound having an aldehyde functional group or a compound having a functional group that forms an aldehyde functional group. Examples of aldehydes include, but are not limited to, acetaldehyde, esters and anhydrides of 4-oxobutanoic acid and 5-oxopentanoic acid, such as methyl 4-oxobutanoate, methyl 5-oxopentanoate, and 1,1-diethoxyethane (acetaldehyde diethyl acetal). It should be understood that 1,1-diethoxyethane and other masked aldehydes that can be used in the method of the present invention form acetaldehyde in situ in the ring-forming reaction of the process of the present invention.

[0060] As used herein and hereinafter, the term "activating group reactant" refers to a reactant containing an activating group that reacts with a compound in a reaction to form a compound or intermediate containing the activating group. It should be understood that different activating group reactants containing the same activating group can exist. A reaction can include one or more activating group reactants, which can be the same or different. Examples of activating group reactants (with examples of the corresponding activating group shown in parentheses) include, but are not limited to, sulfinic acids (sulfonyl), such as phenylsulfinic acid (phenylsulfonyl) and p-toluenesulfinic acid (tosyl); mesyl halides (mesyl), such as methanesulfonyl chloride (mesyl); trifyl azide (trifyl), trifluoromethanesulfonyl chloride (trifyl); halogens (X), such as BR (Br); trifluoroacetyl chloride (TFA) and trifluoroacetic anhydride (TFA).

[0061] As used herein and hereinafter, the term "activator" refers to a substance or compound added to a reaction to cause a chemical reaction. The activator may or may not be a catalyst. It should be understood that the activator may or may not be consumed in the reaction. Examples of activators include, but are not limited to, Lewis acids such as TiCl4, boron trifluoride, and boron trifluoride diethyl etherate.

[0062] As used herein and hereinafter, the term "ring formation" refers to a reaction in which one or more cyclic structures of a compound are formed, and the compound formed has more (e.g., one, two, three, or four or more) cyclic structures than the starting compound (e.g., a compound of formula (I')). It should be understood that a ring formation reaction can include one or more reactions (steps), i.e., the reaction may or may not first produce an intermediate compound, which may or may not be isolated, that is further reacted to form a compound having one or more cyclic structures, e.g., a compound of formula (I). Alternatively, a compound having one or more cyclic structures, e.g., a compound of formula (I), is formed by one or more ring formation reactions in a one-pot reaction. Additionally or alternatively, a temporary intermediate compound is formed that generates a compound having one or more cyclic structures (e.g., a compound of formula (I)).

[0063] As used herein and hereinafter, the term "deprotection reaction" refers to a reaction that removes a protecting group from a compound. A skilled artisan has the knowledge and skill in the art to select suitable reactants or reagents for a deprotection reaction. Furthermore, there are many resources available to the skilled artisan that describe suitable reagents and reactants and can be useful in selecting suitable reagents and reactants for the protecting group to be deprotected. For suitable deprotection reactions, reactants, and reagents, see, for example, Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Inc., Hoboken, New Jersey. Examples of reactants and reagents that can be used in a deprotection reaction (with an example of the protecting group to be deprotected shown in parentheses) include, but are not limited to, tetra-n-butylammonium fluoride (TMS), H2 (benzyl), bases such as NaOH (acetyl), acids such as pyridinium p-toluenesulfonate and EtOH (THP), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (PMB).

[0064] The present invention relates to a compound of formula (I) [ka] [In the formula, Dotted lines represent optional bonds; R 1 and R 2 together with the carbon atoms to which they are attached form a group selected from 1H-indole and benzene groups, said 1H-indole and benzene groups being R 3 , R 4 , R 5 and R 6 and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: 3 , R 4 , R 5 and R 6 are halogens, OH, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy; R a and R b together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; and R c is H; or R a is Me, and R b and R c together with the nitrogen and carbon atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; or R a is Me, R b is H, or R if the dotted line represents a bond b does not exist, and R c is H, except that R 1 and R 2together with the carbon atom to which they are attached form said optionally substituted 1H-indole group; R 7 is halogen, OH, oxo, SH, NOR 8 , C 1~3 -(per)haloalkyl, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy, CN, C(O)N(R 8 )2 and N(R 8 )2, or R 7 is C 1~4 -alkyl, provided that the 1H-indole or benzene group is not substituted with halogen, OH, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy; or R 7 may be H, with the proviso that R a and R b together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; R c If is H, then R 4 and R 5 is a halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, or R a is Me and R b and R c together with the carbon and nitrogen atoms to which they are attached form a six-membered cyclic amide, R 1 and R 2 together with the carbon atom to which they are attached form said optionally substituted 1H-indole group, or R ais Me and R b and R c together with the carbon and nitrogen atoms to which they are attached form a five-membered cyclic amide, and R 1 and R 2 together with the carbon atom to which they are attached to form a 1H-indole or benzene group, said 1H-indole or benzene group may not contain halogen, OH, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy; or R a is Me and R c is H and R 1 and R 2 together with the carbon atom to which they are attached form a substituted 1H-indole group, R of said substituted 1H-indole group 4 and R 5 is a halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy; Each R 8 is H, C 1~4 -Alkyl, C 1~4 -Alkenyl, C 1~4 -alkynyl and C 1~3 -(per)haloalkyl, or any N(R 8 )2, both R 8 may, together with the nitrogen to which they are attached, form a 3- to 6-membered aliphatic or aromatic heterocyclic ring containing 1 to 3 heteroatoms each independently selected from N, O, and S, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0065] In the present specification and the following, the term "dotted line represents an optional bond" means a bond that may or may not be present. When a dotted line is present, the dotted line forms a double bond together with the single bond next to it, and therefore, the compound of formula (I) is a compound of formula (II) [ka] and if the dotted line is absent, then the compound of formula (I) is equivalent to a compound of formula (III) [ka] It should be understood that this is equivalent to a compound of the formula:

[0066] As used herein and hereinafter, the term "1H-indole group" refers to the R 1 and R 2 As used herein and hereinafter, the term "benzene group" refers to a 1H-indole fused at the 2- and 3-positions with the carbon to which R is attached in a compound of formula (I). 1 and R 2 Therefore, the term "R" as used herein and hereinafter refers to a benzene ring fused to a carbon atom to which R is attached. 1 and R 2 together with the carbon atoms to which they are attached form a group selected from 1H-indole and benzene groups" refers to 1H-indole and benzene rings fused with the 1,2,3,6-tetrahydropyridine and 2,3-dihydropyridine derivatives of the present invention. 1 and R 2 together with the carbon atom to which they are attached to form a 1H-indole group, the compound of formula (I) has the formula (IV) [ka] [In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Ra , R b , R c and the dotted line is as defined above], and R 1 and R 2 together with the carbon atom to which they are attached to form a benzene group, the compound of formula (I) is [ka] [In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , R c and the dotted line is as defined above].

[0067] Thus, in embodiments, the compound has formula (Ia), (Ib) or (Ic) [ka] [In the formula, R a and R b together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; and R c is H; or R a is Me, and R b and R c together with the nitrogen and carbon atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; R d is H, or R if the dotted line represents a bond d does not exist; and R 3 , R 4 , R 5 , R 6 , R 7, R 8 and the dotted line is as defined above], or a stereoisomer or pharmaceutically acceptable salt thereof.

[0068] Furthermore, the substituent R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The selection of is particularly important to achieve the desired properties of the compounds of the present invention.

[0069] Additionally or alternatively, the substituent R a , R b , R c and R d The selection of is particularly important to achieve the desired properties of the compounds of the present invention.

[0070] In embodiments, the compound has formula (Ic), (Id), (Ie), (If) or (Ig): [ka] [In the formula, m is 1 or 2; n is 1 or 2; R d is H, or R if the dotted line represents a bond d does not exist; and Dotted line, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0071] Furthermore, the substituent R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The selection of is particularly important to achieve the desired properties of the compounds of the present invention.

[0072] Additionally or alternatively, m, n and the substituent R a , R b , R c and R d The selection of is particularly important to achieve the desired properties of the compounds of the present invention.

[0073] In embodiments, the compound has formula (Id), (Ie), (If) or (Ig): [ka] [In the formula, m is 1 or 2; n is 1 or 2; and R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0074] Furthermore, the substituent R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The selection of m and n is particularly important for achieving the desired properties of the compounds of the present invention. Additionally or alternatively, the selection of m and n is particularly important for achieving the desired properties of the compounds of the present invention.

[0075] In an embodiment, the compound has formula (Id) or (If), preferably (Id) [In the formula, n is 1 or 2, preferably 1; and R 3 , R 4 , R 5 , R 6 , R 7 and R 8is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof. In one preferred embodiment, the compound has formula (Id) and n is 1. Furthermore, the substituent R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The selection of is particularly important to achieve the desired properties of the compounds of the present invention.

[0076] In an embodiment, the compound has formula (Ie) or (Ig), preferably (Ig) [In the formula, m is 1 or 2, preferably 1; and R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is as defined above], or a stereoisomer or pharmaceutically acceptable salt thereof. In one preferred embodiment, the compound has formula (Ig) and m is 1. Furthermore, the substituent R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The selection of is particularly important to achieve the desired properties of the compounds of the present invention.

[0077] In an embodiment, the compound has formula (Ic) [In the formula, R d is H, or R if the dotted line represents a bond d does not exist; and Dotted line, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is as defined above, or a stereoisomer or pharmaceutically acceptable salt thereof. 3 , R4 , R 5 , R 6 , R 7 and R 8 The selection of is particularly important to achieve the desired properties of the compounds of the present invention.

[0078] In an embodiment, the compound has formula (I) [In the formula, R 1 and R 2 together with the carbon atom to which they are attached form a group selected from a 1H-indole group, said 1H-indole group being selected from R 3 , R 4 , R 5 and R 6 and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: 3 , R 4 , R 5 and R 6 are halogens, OH, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy; R a is Me; R b is H, or R if the dotted line represents a bond b is absent, and preferably R b is H; R c is H; and Dotted line, R 7 and R 8 is as defined above, or a stereoisomer or pharmaceutically acceptable salt thereof. 3 , R 4 , R 5 , R 6 , R 7 and R 8 The selection of is particularly important to achieve the desired properties of the compounds of the present invention.

[0079] In embodiments, the compound has formula (I), (Ic), (Id), (Ie), (If) or (Ig): [In the formula, R 3 and R 6 H, halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, each independently selected from the group consisting of: H and F; R 4 and R 5 are both halogen, preferably F, or R 4 and R 5 One of the groups is a halogen, preferably F, and the other is C 1~4 -Alkyl, C 1~3 -(per)haloalkyl or C 1~3 -(per)haloalkoxy, preferably methoxy, methyl or trifluoromethyl; R 7 is H, halogen, OH, oxo, NOR 8 , C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy, preferably H, F, OH or methoxy, most preferably F; and Dotted line, R 1 , R 2 , R a , R b , R c , R d and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0080] In embodiments, the compound has formula (I), (Ic), (Id), (Ie), (If) or (Ig): [In the formula, R 3 and R 6 H, halogen, C 1~4-Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, each independently selected from the group consisting of, preferably, H and F, and most preferably, H; R 4 and R 5 are both F or R 4 and R 5 One of them is F and the other is C 1~4 -Alkyl or C 1~3 -(per)haloalkyl, preferably both are F; R 7 is H, halogen, OH, oxo, NOR 8 , C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy, preferably H, F, OH or methoxy, most preferably F; and Dotted line, R 1 , R 2 , R a , R b , R c , R d and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0081] In embodiments, the compound has formula (I), (Ic), (Id), (Ie), (If) or (Ig): [In the formula, R 3 and R 6 H, halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, each independently selected from the group consisting of, preferably, H and F, and most preferably, H; R 4 and R 5 are both F or R4 and R 5 One of the groups is a halogen, preferably F, and the other is H, C 1~4 -Alkyl or C 1~3 -(per)haloalkyl, preferably R 4 and R 5 one of which is halogen and the other is H; R 7 are halogens, OH, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy, preferably selected from the group consisting of F, OH, methoxy and ethoxy, most preferably F; and Dotted line, R 1 , R 2 , R a , R b , R c , R d and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, R 4 and R 5 are both halogen, preferably F. In another embodiment, R 4 is H and R 5 is a halogen, preferably F, and R 7 is selected from the group consisting of halogen, preferably F and OH. 4 is a halogen, preferably F, and R 5 is H and R 7 is selected from the group consisting of halogens, preferably F and OH.

[0083] In embodiments, the compound has formula (I), (Ic), (Id), (Ie), (If) or (Ig): [In the formula, R 3 and R 6 are each independently selected from H and halogen, preferably each independently selected from H and F; R 4and R 5 are both F or R 4 and R 5 One of them is F and the other is C 1~4 -Alkyl or C 1~3 -(per)haloalkyl, preferably both are F; and R 7 are H, F, OH, and C. 1~4 - selected from the group consisting of alkyl and methoxy, preferably H, F, OH or methoxy, more preferably H or F, most preferably F; and Dotted line, R 1 , R 2 , R a , R b , R c , R d and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0084] In embodiments, the compound has formula (Ic), (Id), (Ie), (If) or (Ig): [In the formula, m is 1 or 2, preferably 1; n is 1 or 2, preferably 1; R 3 and R 6 H, halogen, OH, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy, each independently selected from the group consisting of: (per)haloalkoxy, preferably each independently selected from H, F, peroxy, ethoxy, more preferably each independently selected from H and F; R 4 and R 5 are both halogen, preferably F, or R 4 and R 5 One of the groups is a halogen, preferably F, and the other is H, C 1~3 -alkoxy, C 1~4 -Alkyl, C1~3 -(per)haloalkyl or C 1~3 -(per)haloalkoxy, preferably H, methoxy, methyl or trifluoromethyl, most preferably H; R 7 is halogen, OH, oxo, NOR 8 , C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy, preferably H, F, OH or methoxy, most preferably F; and R 8 , R d and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0085] In embodiments, the compound has formula (Ie) or (Ig) [In the formula, m is 1; R 3 and R 6 H, halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, each independently selected from the group consisting of: H and F; R 4 and R 5 are both halogen, preferably F, or R 4 and R 5 One of the groups is a halogen, preferably F, and the other is H, C 1~3 -alkoxy, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl or C 1~3 -(per)haloalkoxy, preferably H, methoxy, methyl or trifluoromethyl, most preferably H; R 7 is H, halogen, OH, oxo, NOR8 , C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy, preferably H, F, OH or methoxy, most preferably F; and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0086] In an embodiment, the compound has formula (Id) or (If) [In the formula, n is 1 or 2, preferably 1; R 3 and R 6 H, halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, each independently selected from the group consisting of: H and F; R 4 and R 5 are both halogen, preferably F, or R 4 and R 5 One of the groups is a halogen, preferably F, and the other is C 1~4 -Alkyl, C 1~3 -(per)haloalkyl or C 1~3 -(per)haloalkoxy, preferably methyl, trifluoromethyl or trifluoromethoxy, most preferably trifluoromethyl; R 7 is H, halogen, OH, oxo, NOR 8 , C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy, preferably H, F, OH or methoxy, most preferably F; and R 8is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0087] In an embodiment, the compound has formula (Ic) [In the formula, R 3 and R 6 H, halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, each independently selected from the group consisting of: H and F; R 4 and R 5 are both halogen, preferably F, or R 4 and R 5 One of the groups is a halogen, preferably F, and the other is C 1~4 -Alkyl, C 1~3 -(per)haloalkyl or C 1~3 -(per)haloalkoxy, preferably methyl, trifluoromethyl or trifluoromethoxy, most preferably trifluoromethyl; R 7 is H, halogen, OH, oxo, NOR 8 , C 1~4 -Alkyl, C 1~3 -(per)haloalkyl, C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy, preferably H, F, OH or methoxy, most preferably F; R b is H, or R if the dotted line represents a bond b is absent, and preferably R b is H; and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0088] In an embodiment, the compound has formula (Ic) [In the formula, R 3 and R 6 H, halogen, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl and C 1~3 -(per)haloalkoxy, each independently selected from the group consisting of: H and F; R 4 and R 5 are both halogen, preferably F, or R 4 and R 5 One of the groups is a halogen, preferably F, and the other is H, C 1~4 -Alkyl, C 1~3 -(per)haloalkyl or C 1~3 -(per)haloalkoxy, preferably H, methyl, trifluoromethyl or trifluoromethoxy, most preferably H; R 7 is halogen, OH, oxo, NOR 8 , C 1~3 -alkoxy and C 1~3 -(per)haloalkoxy, preferably H, F, OH or methoxy, most preferably F; R b is H, or R if the dotted line represents a bond b is absent, and preferably R b is H; and R 8 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0089] In embodiments, the compound has formula (I), (Ic), (Id), (Ie), (If) or (Ig): [In the formula, R 3 , R 6 and R 7 is H; R 4 and R 5 is F; and Dotted line, R 1 , R2 , R a , R b , R c and R d is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0090] In a preferred embodiment, the compound has formula (Id), (Ie), (If) or (Ig), more preferably (Ie) or (Ig), most preferably (Ig) [In the formula, R 3 , R 6 and R 7 is H; and R 4 and R 5 is F], or a stereoisomer or pharmaceutically acceptable salt thereof.

[0091] 10. In an embodiment, the compound has formula (I), (Ic), (Id), (Ie), (If) or (Ig): [In the formula, R 3 and R 6 is H; R 4 , R 5 and R 7 is F; and Dotted line, R 1 , R 2 , R a , R b , R c and R d is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0092] In embodiments, the compound has formula (I), (Id), (Ie), (If) or (Ig): [In the formula, R 3 and R 6 is H; R 4 , R 5 and R 7 is F; R a is Me; R b and R c together with the nitrogen and carbon atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; and R 1 and R 2 is as defined above], or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0093] In a preferred embodiment, the compound has formula (Id), (Ie), (If) or (Ig), more preferably (Ie) or (Ig), most preferably (Ig) [In the formula, R 3 and R 6 is H; R 4 , R 5 and R 7 is F; m is 1 or 2, preferably 1; and n is 1 or 2, preferably 1; or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0094] In one preferred embodiment, the compound has formula (Ig) [In the formula, m is 1; R 3 and R 6 is H; and R 4 , R 5 and R 7 is F], or a stereoisomer or pharmaceutically acceptable salt thereof.

[0095] In embodiments, the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) is 5-Fluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-Fluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4,6-Difluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 7-Fluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; 7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bS)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7S,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; 7,9-Difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; 7,8,10-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; 4,5,6,7-tetrafluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5,6-Difluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole; 5,6,7-trifluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole; 4,5,6,7-tetrafluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole; 7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (5S,10R,10aR)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (5S,10R,10aS)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (5S,10S,10aR)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; 7,10-Difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; 9,10-Difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; 7,8-Difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (5R,11S)-10,11-difluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one; (6R,12S)-12-fluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one; (5R,11S)-11-Fluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one; (6R,12S)-1,12-difluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one; (5R)-9-Fluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one; (6R)-2-Fluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one; (4S)-4,6-Difluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole; (5S,6S,10bS)-6,9-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; (5R,6R,10bS)-6,9-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; (5R,6S,10bR)-6,8,9-trifluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; (12bS)-8,9-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (not part of the present invention); (7R,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7S,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (12bS)-9,10-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7S,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (5S,6R,10bS)-6,8-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; (5S,10S,10aR)-8,10-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (1R,4R)-4,6,7-trifluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (7R,12bS)-7,9,10-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bR)-7,8-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (5R,6R,10bS)-6,9-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; and 6-fluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0096] In one aspect of the present invention, there is provided a pharmaceutical composition comprising an effective amount of one or more compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable excipients.

[0097] In addition to or alternatively to pharmaceutically acceptable additives, the pharmaceutical composition of the present disclosure comprises an effective amount of one or more compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable carriers. Thus, in an embodiment, the pharmaceutical composition comprises an effective amount of one or more compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable additives and / or one or more pharmaceutically acceptable carriers, or any combination thereof. Preferably, the pharmaceutical composition comprises one compound of formula (I) or its stereoisomers or pharmaceutically acceptable salts, preferably a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable additives and one pharmaceutically acceptable carrier.

[0098] In addition to or alternatively to pharmaceutically acceptable excipients and / or pharmaceutically acceptable carriers, the pharmaceutical compositions of the present disclosure comprise an effective amount of one or more compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof in combination with one or more other active ingredients. Thus, in embodiments, the pharmaceutical compositions comprise an effective amount of one or more compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable excipients and / or one or more pharmaceutically acceptable carriers and / or one or more other active ingredients, or any combination thereof.

[0099] In an embodiment, the pharmaceutical composition consists of an effective amount of one or more compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, preferably a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, preferably one, two or three pharmaceutically acceptable excipients, more preferably one pharmaceutically acceptable excipient.

[0100] In an embodiment, the pharmaceutical composition consists of an effective amount of one or more compounds of formula (I), preferably an effective amount of one or two compounds of formula (I), more preferably one compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, preferably a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, preferably one, two or three pharmaceutically acceptable excipients and / or one or more pharmaceutically acceptable carriers, preferably one, two or three pharmaceutically acceptable carriers, more preferably one pharmaceutically acceptable carrier.

[0101] In an embodiment, the pharmaceutical composition comprises an effective amount of one or more compounds of formula (I), preferably an effective amount of one or two compounds of formula (I), more preferably one compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, preferably a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients, preferably one, two or three pharmaceutically acceptable excipients and / or one or more pharmaceutically acceptable carriers, preferably one, two or three pharmaceutically acceptable carriers, more preferably one pharmaceutically acceptable carrier and / or one or more other active ingredients, preferably one other active ingredient.

[0102] In one aspect of the invention there is provided a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0103] In one aspect of the invention there is provided a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a CNS-related disease or condition.

[0104] In an embodiment of the present invention there is provided a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease or condition selected from the group consisting of Alzheimer's disease, Parkinson's disease, depression, anxiety, hyperactivity, narcolepsy, drug addiction, alcoholism, anorexia nervosa, bulimia and mitochondrial disease.

[0105] In one aspect of the invention there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, said method comprising: Formula (I') [ka] [In the formula, R 1 , R 2 and R 7 is as defined herein and hereinafter, R 1 and R 2 together with the carbon atom to which they are attached form an 1H-indole group, the nitrogen of said 1H-indole group is optionally protected with a protecting group; R 7 is OH or SH, the oxygen or sulfur of said OH or SH is optionally protected with a protecting group; R b’ and R c’’ together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; or R b’ is H or an activating group, and R c’’ is H; - reacting said compound of formula (I') with an aldehyde, optionally in the presence of one or more activating group reactants, which optionally together with one or more activating agents promote ring formation; - optionally performing one or more deprotection reactions. It includes Formula (I) [ka] [In the formula, R 1 , R 2 , R 7 , R a , R b , Rc and the dotted line are as defined herein and hereinafter], and said method comprises: - optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof. A method is provided which includes:

[0106] Additionally or alternatively, to the step of converting a compound of formula (I) into a pharmaceutically acceptable salt thereof, the process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof may comprise: - converting the compound of formula (I) into another stereoisomer thereof, said step being carried out before or after optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof. Further includes:

[0107] In an embodiment, in the process for preparing a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, one or more activating group reactants, preferably one activating group reactant, optionally together with one or more activating agents, preferably one activating agent, promote said ring formation.

[0108] In an embodiment, in the process for preparing a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, one or more activating group reactants, preferably one activating group reactant, are combined with one or more activating agents, preferably one activating group reactant, to promote said ring formation.

[0109] In an embodiment, in the process for preparing a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, the aldehyde is selected from the group consisting of acetaldehyde, methyl 4-oxobutanoate, methyl 5-oxopentanoate, and 1,1-diethoxyethane.

[0110] In embodiments, in the process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, the step of reacting a compound of formula (I') with an aldehyde optionally further comprises one or more steps of isolating and / or purifying one or more aldehydes, and optionally one or more compounds of formula (I).

[0111] The compounds of the present invention can be synthesized using well-documented reactions and commercially available starting materials. We have explored a series of novel TIQ analogs aimed primarily at mimicking the effects of 1MeTIQ and, to some extent, SAL. These novel compounds can be used to achieve many desirable pharmacological responses. Fluorination can alter binding strength, lipophilicity, conformation, electrostatic potential, dipole, and pKa.

[0112] Substitutions, especially fluorinations, at metabolically attacking positions, mainly the substituents R of compounds having formulae (Ia), (Ib) and (Ic) 4 , R 5 and R 7 Substitutions, particularly fluorination, at positions corresponding to are used to alter the pathway and rate of metabolic degradation. Fluorination can also alter the tissue distribution, pharmacodynamics, and toxicity of a compound. It can be generalized that substituting hydrogen for fluorine minimizes steric effects at the receptor.

[0113] By specifically substituting both catechol hydroxyls of SAL with fluorine, better targeting of drug distribution and a lower active dose are achieved. Unlike SAL, the compounds of the present invention are actively transported across the blood-brain barrier by organic cation transporters and are concentrated in the brain. Most of the compounds of the present invention cannot be oxidized to form epoxides, and therefore are less likely to cause oxidative stress. Instead of the neurotoxicity and neurodegeneration seen in SAL, the compounds of the present invention have neuroprotective and neuroregenerative properties. Furthermore, the novel compounds mimic the desirable effects of SAL and are superior to, for example, 6-monofluoro-TIQ in treating alcoholism and Parkinson's disease.

[0114] The novel compounds of the present invention show structural similarity to 1MeTIQ. Therefore, the novel compounds can be used to treat or prevent addiction in general, from alcohol to cocaine to heroin, in addition to treating, for example, Alzheimer's disease and Parkinson's disease. Many positive pharmacological responses are simultaneously achieved. These compounds can act as general mood stabilizers and general neuroprotective agents with significant antiparkinsonian and antiepileptic properties, while reducing the likelihood of relapse and onset of addiction.

[0115] These compounds exhibit a number of pharmacological responses, including - Extends the duration of morphine without increasing peak effect; - antagonizes the development of morphine tolerance; - Relieves withdrawal symptoms induced by naloxone; - Inhibits relapse to cocaine self-administration; - Inhibits the activity of monoamine oxidase (MAO), reducing cravings; - Inhibits the activity of acetylcholinesterase (ACE); - affecting the activity and metabolic redirection of one or more of the following: trace amine receptors, dopamine receptors and transporters, serotonin receptors and transporters, serotonin acyl- and methyltransferase, norepinephrine transporter, monoaminooxidase, catecholine-O-methyltransferase; adrenergic receptors, tyrosine hydroxylase, histamine receptors, orexin receptors, NMDA receptors, sigma-1 receptors, muscarinic and nicotinic acetylcholine receptors, opioid receptors, neuropeptide receptors, melanocortin receptors (except MC3R), neurokinin receptors, corticotropin release; - Protects nerves; - Shifting catabolism of catecholamine neurotransmitters towards catechol-O-methyltransferase (COMT)-dependent methylation; - Suppressing or enhancing prolactin release; - Releases norepinephrine; - Induce or inhibit neuron-associated apoptosis and / or necrosis; - Reversing the inhibition of noradrenaline metabolism induced by cocaine; - Improve mitochondrial disease / dysfunction.

[0116] Additionally, the present invention may be used to treat or prevent diseases or conditions associated with HIV transcriptase.

[0117] Furthermore, the compounds of formula (I) can be used as synthetic intermediates for producing other compounds, particularly other pharmaceutically active compositions, obtained from the compounds of formula (I) by, for example, introducing a substituent or modifying a functional group moiety.

[0118] The compounds and pharmaceutical compositions of the present invention may also be useful in medical devices and kits.

[0119] General manufacturing method The compounds according to the present invention can be prepared by processes known per se as follows.

[0120] The following examples illustrate the preparation of compounds of formula (I).

[0121] General Procedure for the Preparation of Optionally Substituted Phenethylamines, General Procedure A [ka]

[0122] Step 1. 1.0 molar equivalent of optionally substituted benzaldehyde, 1.2 molar equivalents of nitromethane, 0.47 molar equivalents of ammonium acetate, and 0.35 molar equivalents of glacial acetic acid (GAA) were sonicated (40 kHz) at RT for 3 hours. After removal of the nitromethane, the crude product was obtained by partitioning between dichloromethane and water, followed by brine, which was then recrystallized from aqueous (meth)ethanol or AcOH; or 1.0 molar equivalent of optionally substituted benzaldehyde, 1.2 molar equivalents of nitromethane, and 0.1 molar equivalents of cyclohexylamine were mixed and stored in the dark for 4 weeks or until HO formation ceased. The crude product was ground, washed with brine, and recrystallized from aqueous (meth)ethanol or AcOH; or R 7 In the case of halogen substitution (preferably fluorine), the synthesis proceeds via the nitroalcohol intermediate, otherwise skip to step 4: 1.0 molar equivalent of optionally substituted benzaldehyde with 1.0 molar equivalent of triethylamine and 1.2 molar equivalents of nitromethane was stirred in methanol at -12°C for 2.5 hours. While still below freezing, the amine was quenched with 1.0 molar equivalent of GAA. Most of the solvent was stripped under vacuum, and the residue was dissolved in dichloromethane (DCM) and washed twice with water and once with brine. The DCM was stripped, leaving the crude nitroalcohol.

[0123] Process 2.(R 7 Aliphatic OH groups were sulfonated to the appropriate sulfonyl esters by stirring 1.0 molar equivalent of the substituted nitroalcohol in DCM with 1.2 molar equivalents of triethylamine (or using pyridine as the solvent) and slowly adding 1.1 molar equivalents of p-toluenesulfonyl chloride while maintaining the temperature at -5°C until conversion was complete. The product was washed several times with brine, dried over anhydrous MgSO4, and concentrated in vacuo.

[0124] Process 3.(R 7-Halogen substitution) The modified Finkelstein reaction to sulfonate esters using potassium halide (KF in this case) proceeded by dissolving 1 molar equivalent of the sulfonyl intermediate from step 2 in 6 ml of acetonitrile, 0.5 molar equivalents of 1-butyl-3-methylimidazolium tetrafluoroborate, and 5 molar equivalents of HO per gram of substrate. Then, 1.05 molar equivalents of KF were added, and the solution was mixed and sonicated at RT for 180 minutes or until TLC showed completion. The reaction was then carried out in the presence of potassium halide (KF in this case). 7 The -halogen substituted compound was extracted with DCM, washed several times with brine, dried over anhydrous MgSO4, and concentrated in vacuo before proceeding.

[0125] Step 4. Protected R 7 In the case of the -OH group, the synthesis proceeds via a nitroalcohol intermediate: Following procedures well known in the art, the aliphatic OH group is protected with a suitable protecting group, for example as a silyl ether, by stirring 1.0 molar equivalent of an optionally substituted nitroalcohol in DCM with 1.2 molar equivalents of pyridine (or using pyridine as the solvent) and slowly adding 1.1 molar equivalents of trimethylsilyl chloride, maintaining the temperature at 0° C. until conversion is complete. The product is washed several times with brine, dried over anhydrous MgSO4, and concentrated in vacuo; or R 7 In the case of -alkoxy or -(per)haloalkoxy substitution, the synthesis proceeds via a nitroalcohol intermediate: Following procedures well known in the art, the aliphatic OH group is O-alkylated with a suitable alkyl or (per)haloalkyl group, for example as an O-methyl ether, by stirring 1.0 molar equivalent of an optionally substituted nitroalcohol in DCM (or THF) with 1.05 molar equivalents of diazomethane and 1.0 molar equivalent of boron trifluoride diethyl etherate at 0° C. until conversion is complete. The product is washed several times with brine, dried over anhydrous MgSO4, and concentrated in vacuo; or Skip to step 5.

[0126] Step 5. Any C=C bonds and nitro groups present are reduced to form amino groups according to procedures well known in the art, for example, by catalytic hydrogenation using platinum(IV) oxide (PtO), Raney nickel, and / or platinum on carbon (Pt / C).

[0127] General Procedure for the Preparation of Optionally Substituted 2-(1H-indol-3-yl)ethan-1-amines, General Procedure B [ka]

[0128] General procedure A was followed, except that an optionally substituted 1H-indole-3-carbaldehyde or an N-protected 1H-indole-3-carboxaldehyde (e.g., 1-benzyl-1H-indole-3-carboxaldehyde or 1-(triisopropylsilyl)-1H-indole-3-carbaldehyde) was used instead of the optionally substituted benzaldehyde.

[0129] General Procedure for the Preparation of Optionally Substituted N-Tosyl-Phenethylamines, General Procedure C [ka]

[0130] To 1.0 molar equivalent of the product obtained in step 5 of General Procedure A in DCM was added 1.2 molar equivalents of triethylamine (or pyridine was used as the solvent), and 1.1 molar equivalents of p-toluenesulfonyl chloride was added slowly, maintaining the temperature at −5° C. until complete conversion. The product was washed several times with brine, dried over anhydrous MgSO4, and concentrated in vacuo.

[0131] General Procedure for the Preparation of Substituted N-Tosyl-2-(1H-indol-3-yl)ethylamines, General Procedure C' [ka]

[0132] To 1.0 molar equivalent of the product of General Procedure B in DCM was added 1.2 molar equivalents of triethylamine (or pyridine was used as the solvent), and 1.1 molar equivalents of p-toluenesulfonyl chloride was added slowly, maintaining the temperature at −5° C. until complete conversion. The product was washed several times with brine, dried over anhydrous MgSO4, and concentrated in vacuo.

[0133] General procedure for the preparation of optionally substituted 5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-ones and 6-methyl-1,2,3,6,11,11a-hexahydro-4H-pyrido[1,2-b]isoquinolin-4-ones (compounds of formula (Ig)), General Procedure D: [ka]

[0134] Step 1. Tetrahedron synthesis: Adapted from Asymmetry 14 (2003) 1171-1178; 1.0 molar equivalent of optionally substituted 5-benzylpyrrolidin-2-one (m=1) or 6-benzylpiperidin-2-one (m=2) (protected R 7 -OH groups (e.g., R 7 In the case of (m = silyl ether), 1.0 molar equivalent of the respective protected compound (m = 1 or 2) was dissolved in dichloromethane (3 mL / mmol of optionally substituted 5-benzylpyrrolidin-2-one (m = 1) or 6-benzylpiperidin-2-one), followed by the sequential addition of 2.0 molar equivalents of benzenesulfinic acid, 1.5 molar equivalents of acetaldehyde, and anhydrous MgSO (0.1 g / mmol of optionally substituted 5-benzylpyrrolidin-2-one (m = 1) or 6-benzylpiperidin-2-one) at room temperature. The mixture was stirred at room temperature for 36 hours and then filtered through a short pad of Florisil. Removal of the solvent gave the crude sulfone, which was purified by column chromatography (7:3 hexane-ethyl acetate).

[0135] Step 2. 1.0 molar equivalent of the above sulfone (2 mmol) was dissolved in CHCl (10 mL / mmol sulfone) and the solution was cooled to −78°C. Then, 1.5 molar equivalents of TiCl was added dropwise over 5 min. After 45 min at −78°C, the reaction mixture was quenched with brine. The separated aqueous phase was extracted three times with CHCl, and the collected organic phase was dried over MgSO. After removing the solvent under reduced pressure, the resulting optionally substituted 5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one or 6-methyl-1,2,3,6,11,11a-hexahydro-4H-pyrido[1,2-b]isoquinolin-4-one was purified by column chromatography (7:3 hexane-ethyl acetate).

[0136] Step 3. Protected R 7 In the case of -OH groups, e.g., in the case of O-trimethylsilyl protected compounds, R 7 Remove the -OH protecting group, otherwise skip this step: To a cold (0 °C) solution of 1.0 molar equivalent of the silyl ether in tetrahydrofuran (THF, 10 mL / mol silyl ether) was added 1.1 molar equivalents of tetra-n-butylammonium fluoride (TBAF) (1 M solution in THF), and the resulting solution was stirred for 45 min. The mixture was then warmed to room temperature and continued stirring until conversion was complete. The resulting solution was diluted with DCM and quenched with water. The organic layer was extracted with brine, dried over magnesium sulfate, and the solvent was then removed under reduced pressure in vacuo. The crude product was purified by column chromatography (hexane / ethyl acetate, 7:3 to 1:10) to give the alcohol.

[0137] Process 4.R 7 For -SH groups, otherwise skip this step: The product obtained in step 3 was converted to the tosylate according to step 2 of general procedure A. The resulting tosylate was treated with excess sodium hydrogen sulfide in acetone to give the crude thiol product (R 7The crude product was purified by column chromatography (hexane / ethyl acetate, 7:3 to 1:10) to obtain the thiol.

[0138] General procedure for the preparation of optionally substituted 5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-ones and 6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-ones (compounds of formula (Ie)), General Procedure E: [ka]

[0139] According to general procedure D, optionally substituted 5-((1H-indol-3-yl)methyl)pyrrolidin-2-one (m=1, R=H, Bn or TIPS) or 6-((1H-indol-3-yl)methyl)piperidin-2-one (m=2, R=H, Bn or TIPS) (protected R 7 -OH groups (e.g., R 7 In the case of R and / or R (m = silyl ether), 1.0 molar equivalent of the respective protected compound (m = 1 or 2) was used as starting material. 7 If R has a protecting group, the protecting group was removed according to procedures well known in the art, for example, step 3 of general procedure D (where R = TIPS and R 7 = For silyl ethers, 2.2 molar equivalents of (TBAF) (1 M solution in THF) were used). 7 -SH group; deprotected R 7 Step 4 of general procedure D was followed using the -OH compound.

[0140] General Procedure for the Preparation of Optionally Substituted 1,5,6,10b-Tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-ones and 1,2,3,6,7,11b-Hexahydro-4H-pyrido[2,1-a]isoquinolin-4-ones (Compounds of Formula (If), General Procedure F: [ka]

[0141] Optionally substituted 1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one and 1,2,3,6,7,11b-hexahydro-4H-pyrido[2,1-a]isoquinolin-4-one are prepared according to the method described in ChemComm., 2018, 54(11), Briefly, 1.0 molar equivalent of the optionally substituted phenethylamine obtained in step 5 of General Procedure A and 1.5 molar equivalents of an aldehyde (e.g., methyl 4-oxobutanoate or methyl 5-oxopentanoate) in aqueous potassium phosphate KPi buffer (0.3 M) in acetonitrile (1:1) were stirred at 60°C under argon at pH 6 in the presence of 1.0 molar equivalent of ascorbic acid for 18 hours. Sodium carbonate (1 M) was then added, the pH was adjusted to 7.5, and the mixture was stirred for 4 hours to give the lactam. The lactam was purified by a basic, then acidic, extraction procedure using EtOAc and then MeOCOMe as described in Tetrahedron Lett., 2014, 55, 5047 and Nat. Commun., 2017, 8, 14883.

[0142] Protected R 7 In the case of an -OH group, R 7 The -OH protecting group was removed, e.g., in the case of O-trimethylsilyl protected compounds, by following step 3 of general procedure D. 7 -SH group; deprotected R 7 Step 4 of general procedure D was followed using the -OH compound.

[0143] General Procedure for the Preparation of Optionally Substituted 1,2,5,6,11,11b-Hexahydro-3H-Indolizino[8,7-b]indol-3-ones and 2,3,6,7,12,12b-Hexahydroindolo[2,3-a]quinolizin-4(1H)-ones (Compounds of Formula (Id), General Procedure G: [ka]

[0144] General procedure F was followed, except that the optionally substituted phenethylamine was replaced by an optionally substituted 2-(1H-indol-3-yl)ethan-1-amine (R=H) obtained in general procedure B or an N-protected 1H-indole-3-carboxaldehyde (e.g., 1-benzyl-1H-indole-3-carboxaldehyde (R=Bn) or 1-(triisopropylsilyl)-1H-indole-3-carbaldehyde (R=TIPS)). R and / or R 7 If R has a protecting group, the protecting group was removed according to procedures well known in the art, for example, step 3 of general procedure D (where R = TIPS and R 7 = For silyl ethers, 2.2 molar equivalents of (TBAF) (1 M solution in THF) were used). 7 -SH group; deprotected R 7 Step 4 of general procedure D was followed using the -OH compound.

[0145] General procedure for the preparation of optionally substituted 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles and 1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indoles (compounds of formula (Ic), General Procedure H: [ka]

[0146] Step 1. Industrial-scale Pictet-Spengler reaction (EP 0929527) was adapted: 1.0 molar equivalent of optionally substituted N-tosyl-2-(1H-indol-3-yl)ethylamine (R = H or a protecting group, e.g., Bn or TIPS, R''' = Ts) obtained in General Procedure C' and 3.0 molar equivalents of boron trifluoride diethyl etherate were refluxed with 21.0 molar equivalents of 1,1-diethoxyethane under N2 atmosphere for 12 hours or until TLC showed completion. Tosyl removal was performed, e.g., using sodium, naphthalene, and dimethoxyethane, or using KOH and MeOH; or 1.0 molar equivalent of optionally substituted 2-(1H-indol-3-yl)ethan-1-amine obtained in General Procedure B was refluxed with 3.0 molar equivalents of acetaldehyde for 1 hour, after which 1.2 molar equivalents of hydrochloric acid 37% was added and refluxing continued until TLC showed completion.

[0147] Step 2. The reaction mixture was partitioned between ethyl acetate (10 mL / 1 g substrate) and water (10 mL / 1 g substrate), separated, and the organic layer was washed twice with saturated sodium bicarbonate and dried over sodium sulfate (Na2SO4). The drying agent was removed by filtration, and the filtrate was distilled under reduced pressure to give the desired compound. R and / or R 7 If R and / or R have protecting groups, remove the protecting groups according to procedures well known in the art. 7 The protecting group of was removed, for example, according to step 3 of general procedure D (R = TIPS and R 7 = For silyl ethers, 2.2 molar equivalents of (TBAF) (1 M solution in THF) were used). 7 -SH group; deprotected R 7 Step 4 of general procedure D was followed using the -OH compound.

[0148] General procedure for the preparation of compounds of the present invention using a one-pot chemo-enzymatic cascade methodology, as an example, the preparation of optionally substituted 1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one: [ka]

[0149] In a one-pot chemoenzymatic synthesis of the compounds of the invention, acetolactate synthase (ALS) converts an optionally substituted benzaldehyde (e.g., 3,4-difluorobenzaldehyde) to an optionally substituted 2-hydroxy-2-phenylacetaldehyde (e.g., (2R)-(3,4-difluorophenyl)(hydroxyl)acetaldehyde). A transaminase (EC 2.6.1) then converts the formed optionally substituted (R)-2-hydroxy-2-phenylacetaldehyde to the respective optionally substituted phenethylamine, which is then converted by norcoclaurine synthase ((S)-norcoclaurine synthase (EC 4.2.1.78)) to an optionally substituted 1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (e.g., 8,9-difluoro-6-hydroxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one). Optionally, the product can be purified according to procedures well known in the art. Optionally, R 7 -OH can be converted to halogen, OH, oxo, SH, NOR, by the synthetic methods described herein or by conventional processes known to those skilled in the art. 8 , C 1~3 -(per)haloalkyl, C 1~3 -alkoxy, C 1~3 -(per)haloalkoxy, CN, C(O)N(R 8 )2 or N(R 8 )2.

[0150] The one-pot chemo-enzymatic reaction cascade method can also be used to synthesize other compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig) of the present invention. Thus, for example, optionally substituted 1H-indole-3-carbaldehydes or optionally substituted N-protected 1H-indole-3-carboxaldehydes (e.g., 1-benzyl-1H-indole-3-carboxaldehyde or 1-(triisopropylsilyl)-1H-indole-3-carbaldehyde) can be used as starting materials in a one-pot chemoenzymatic synthesis to provide optionally substituted 1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-b]indol-3-ones and 2,3,6,7,12,12b-hexahydroindolo[2,3-a]quinolizin-4(1H)-ones: [ka]

[0151] The one-pot chemoenzymatic synthesis method can also include other enzymes depending on the compound being synthesized. Also, one or more intermediate products (e.g., optionally substituted phenethylamine or optionally substituted 2-(1H-indol-3-yl)ethan-1-amine) may be used in the one-pot chemoenzymatic synthesis method, or the reaction products of one or more of the chemical methods disclosed above for producing the compound may be used in the one-pot chemoenzymatic synthesis method.

[0152] Alternatively or additionally, chemical reactions can be carried out on any of the above products. For example, the optionally substituted 2-hydroxy-2-phenylacetaldehyde produced by the enzymatic reaction can be isolated, optionally purified, and converted to 2-fluoro-2-phenylacetaldehyde according to the general procedure A described above. The formed 2-fluoro-2-phenylacetaldehyde can then be subjected to a one-pot chemoenzymatic synthesis to obtain 6-fluoro-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one.

[0153] Additionally or alternatively, protecting groups can be introduced by chemical reaction into the product that has been produced, optionally isolated, and then subjected to a one-pot chemo-enzymatic synthesis.Furthermore, protecting groups can be removed from the compound after the final enzymatic reaction, or before, during, or after any step of the enzymatic reaction.

[0154] In one-pot chemical-enzymatic synthesis, one or more expression plasmids can be used, each containing a gene encoding the required enzymatic activity, operably linked to the required regulatory sequences. A single plasmid containing all the genes for the required enzymatic activity represents a particularly advantageous embodiment. A suitable plasmid for use in such a method is exemplified by SEQ ID NO: 1, which is shown in the sequence protocol that forms part of this disclosure.

[0155] As exemplified by SEQ ID NO:1, the one or more plasmids may contain acetolactate synthase activity (e.g., AHAS 1, which is further exemplified by nucleotides 1142 to 3097 of SEQ ID NO:1); an enzyme having activity in EC 2.6.1 (e.g., a suitable transaminase, such as transaminase E1V913_HALED, in particular as further exemplified by nucleotides 4603 to 5985 of SEQ ID NO: 1); Enzymes having salsolinol synthase activity (particularly those further exemplified in nucleotides 6779 to 7009 of SEQ ID NO: 1), an enzyme having activity in EC 4.2.1.78 (e.g., a suitable norcolaurin synthase, e.g., a norcolaurin synthase as exemplified by nucleotides 10117-10689 of SEQ ID NO: 1); and An enzyme having activity in EC 2.1.1.28 (e.g., a suitable phenylethanolamine N-methyltransferase (PNMT), such as P11086 PNMT, further exemplified at nucleotides 14784-15335 of SEQ ID NO: 1) Code the following.

[0156] Regulatory sequences include sequences necessary to effect expression, translation, and secretion of the enzyme, such as enhancers, promoters, sequences encoding signal peptides (e.g., AmyE signal peptide, sortase cleavage signal, or PrsA), terminators, 5' untranslated regions (5'UTR), 3' untranslated regions (3'UTR), and transcription control sequences (e.g., those of the arabinose operon or CUP operon). Plasmids usually also contain additional sequences necessary for plasmid maintenance, such as an origin of replication (e.g., oriU) and / or a reporter or selection gene (e.g., mRaspberry reporter). An example of such a sequence is shown in SEQ ID NO: 1. However, those skilled in the art will be aware of alternatives that form part of their general knowledge, and whose sequences are publicly available in sequence databases.

[0157] Any suitable host compatible with the selected sequence and codon usage of the plasmid can be used. For example, for the plasmid exemplified in SEQ ID NO: 1, a suitable Bacillus strain, e.g., a suitable Bacillus subtilis strain, can be used as the host. For example, Bacillus subtilis (WB-600) can be used as an electrocompetent host. Methods for introducing plasmids into host cells are widely known to those skilled in the art and are provided in references. Host cells containing the plasmid, such that the enzymatic activity is expressed and secreted into the host cell environment, can then be used in a one-pot chemoenzymatic synthesis method. The host cells can be used directly in the synthesis method, or only the supernatant of the fermentation of the host cells can be used. Suitable fermentation procedures are also known to those skilled in the art and are publicly available, for example, from catalogs of cell culture collections, and depend on the host cell selected.

[0158] Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by conventional processes well known to those skilled in the art. For the preparation of pharmaceutical compositions and dosage forms, and for the carriers, diluents and other materials used in the preparation thereof, see, for example, Remington's Pharmaceutical Sciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pennsylvania.

[0159] The pharmacological activity of the compounds of the present invention can be confirmed by methods known in the art. For example, the inhibitory effect on alcohol-seeking behavior can be confirmed using the procedure described in Heidbreder, CA, et al., Addict Biol. 2007 March;12(1):35-50. The preventive activity against Parkinsonism is described, for example, in Okuda, K., et al., Biol Pharm Bull. 2006 July;29(7):1401-1403.

[0160] The compounds of the present invention are further defined by the following specific, non-limiting examples.

[0161] compound 1 5-Fluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole [ka]

[0162] Starting from 4-fluoro-1H-indole-3-carbaldehyde, general procedure B was used, followed by general procedures C' and H.

[0163] [ka]

[0164] compound 2 6-Fluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole [ka]

[0165] Starting from 5-fluoro-1H-indole-3-carbaldehyde, general procedure B was used, followed by general procedures C' and H.

[0166] [ka]

[0167] compound 3 1-Methyl-4,9-dihydro-3H-pyrido[3,4-b]indole [ka]

[0168] Starting from 1H-indole-3-carbaldehyde, general procedure B was used, followed by general procedures C' and H.

[0169] [ka]

[0170] compound 4 4,6-Difluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole [ka]

[0171] Starting from 5-fluoro-1H-indole-3-carbaldehyde, general procedure B was used, followed by general procedures C' and H.

[0172] [ka]

[0173] compound 5 7-Fluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0174] General procedure B was used starting from 1H-indole-3-carbaldehyde, followed by general procedure G.

[0175] [ka]

[0176] Compound 6 (not part of the present invention) 10-Fluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0177] General procedure B was used starting from 6-fluoro-1H-indole-3-carbaldehyde, followed by general procedure G.

[0178] [ka]

[0179] compound 7 7,8,9,10-Tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0180] General procedure B was used starting from 4,5,6-trifluoro-1H-indole-3-carbaldehyde, followed by general procedure G.

[0181] [ka]

[0182] compound 8 7,9-Difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0183] General procedure B was used starting from 5-fluoro-1H-indole-3-carbaldehyde, followed by general procedure G.

[0184] [ka]

[0185] compound 9 7,8,10-Trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0186] General procedure B was used starting from 4,6-difluoro-1H-indole-3-carbaldehyde, followed by general procedure G.

[0187] [ka]

[0188] compound 10 4,5,6,7-tetrafluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole [ka]

[0189] Starting from 4,5,6-trifluoro-1H-indole-3-carbaldehyde, general procedure B was used, followed by general procedures C' and H.

[0190] [ka]

[0191] compound 11 5,6-Difluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole [ka]

[0192] Starting from 5,6-difluoro-1H-indole-3-carbaldehyde, general procedure B was used, followed by general procedures C' and H.

[0193] [ka]

[0194] compound 12 5,6,7-trifluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole [ka]

[0195] Starting from 4,5,6-trifluoro-1H-indole-3-carbaldehyde, general procedure B was used, followed by general procedures C' and H.

[0196] [ka]

[0197] compound 13 4,5,6,7-Tetrafluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole [ka]

[0198] Starting from 4,5,6-trifluoro-1H-indole-3-carbaldehyde, general procedure B was used, followed by general procedures C' and H.

[0199] [ka]

[0200] compound 14 7,8,10-Trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one [ka]

[0201] General procedure D was used starting from 5-((3,4-difluorophenyl)fluoromethyl)pyrrolidin-2-one.

[0202] [ka]

[0203] compound 15 7,10-Difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one [ka]

[0204] General procedure D was used starting from 5-(fluoro(4-fluorophenyl)methyl)pyrrolidin-2-one.

[0205] [ka]

[0206] compound 16 9,10-Difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one [ka]

[0207] 2 General procedure D was used starting from 5-(fluoro(2-fluorophenyl)methyl)pyrrolidin-2-one.

[0208] [ka]

[0209] compound 17 7,8-Difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one [ka]

[0210] General procedure D was used starting from 5-(3,4-difluorobenzyl)pyrrolidin-2-one.

[0211] [ka]

[0212] compound 18 (5R,11S)-10,11-Difluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one [ka]

[0213] General procedure E was used starting from 5-((S)-fluoro(4-fluoro-1-(triisopropylsilyl)-1H-indol-3-yl)methyl)pyrrolidin-2-one or 5-((S)-(1-benzyl-4-fluoro-1H-indol-3-yl)fluoromethyl)pyrrolidin-2-one.

[0214] [ka]

[0215] compound 19 (6R,12S)-12-Fluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one [ka]

[0216] General procedure E was used starting from 6-((S)-fluoro(1-(triisopropylsilyl)-1H-indol-3-yl)methyl)piperidin-2-one or 6-((S)-(1-benzyl-1H-indol-3-yl)fluoromethyl)piperidin-2-one.

[0217] [ka]

[0218] compound 20 (5R,11S)-11-Fluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one [ka]

[0219] General procedure E was used starting from 5-((S)-fluoro(1-(triisopropylsilyl)-1H-indol-3-yl)methyl)pyrrolidin-2-one or 5-((S)-(1-benzyl-1H-indol-3-yl)fluoromethyl)pyrrolidin-2-one.

[0220] [ka]

[0221] compound 21 (6R,12S)-1,12-Difluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one [ka]

[0222] General procedure E was used starting from (S)-6-((S)-fluoro(4-fluoro-1-(triisopropylsilyl)-1H-indol-3-yl)methyl)piperidin-2-one or 6-((S)-(1-benzyl-4-fluoro-1H-indol-3-yl)fluoromethyl)piperidin-2-one.

[0223] [ka]

[0224] compound 22 (5R,11aS)-9-Fluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one [ka]

[0225] General procedure E was used starting from 5-((5-fluoro-1-(triisopropylsilyl)-1H-indol-3-yl)methyl)pyrrolidin-2-one or 5-((1-benzyl-6-fluoro-1H-indol-3-yl)methyl)pyrrolidin-2-one.

[0226] [ka]

[0227] compound 23 (6R,11aS)-2-Fluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one [ka]

[0228] General procedure E was used starting from 6-((5-fluoro-1-(triisopropylsilyl)-1H-indol-3-yl)methyl)piperidin-2-one or 6-((1-benzyl-5-fluoro-1H-indol-3-yl)methyl)piperidin-2-one.

[0229] [ka]

[0230] compound 24 (4S)-4,6-Difluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole [ka]

[0231] General procedure H was used starting from (2S)-2-fluoro-2-(5-fluoro-1H-indol-3-yl)ethanamine.

[0232] [ka]

[0233] compound 25 (5S,6S,10bS)-6,9-Difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one [ka]

[0234] General procedure A was used starting from 4-fluorobenzaldehyde, followed by procedure F.

[0235] [ka]

[0236] compound 26 (5R,6S,10bR)-6,8,9-trifluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one [ka]

[0237] General procedure F was used starting from 3,4-difluorobenzaldehyde.

[0238] [ka]

[0239] Compound 27 (not part of the present invention) (12bS)-8,9-Difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0240] General procedure G was used starting from 4,5-difluoro-1H-indole-3-carbaldehyde.

[0241] [ka]

[0242] compound 28 7,8,9-Trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0243] General procedure G was used starting from 4,5-difluoro-1H-indole-3-carbaldehyde.

[0244] [ka]

[0245] compound 29 (7R,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0246] General procedure G was used starting from 4,5-difluoro-1H-indole-3-carbaldehyde.

[0247] [ka]

[0248] compound 30 (7S,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0249] General procedure G was used starting from 4,5-difluoro-1H-indole-3-carbaldehyde.

[0250] [ka]

[0251] compound 31 (7R,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0252] General procedure G was used starting from 4,5-difluoro-1H-indole-3-carbaldehyde.

[0253] [ka]

[0254] compound 32 (5S,6R,10bS)-6,8-Difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one [ka]

[0255] General procedure F was used starting from 3-fluorobenzaldehyde.

[0256] [ka]

[0257] compound 33 (5S,10S,10aR)-8,10-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one [ka]

[0258] General procedure D was used starting from 3-fluorobenzaldehyde.

[0259] [ka]

[0260] compound 34 (1R,4R)-4,6,7-trifluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole [ka]

[0261] General procedure H was used starting from 5,6-difluoro-1H-indole-3-carbaldehyde.

[0262] [ka]

[0263] compound 35 (7R,12bS)-7,9,10-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0264] General procedure G was used starting from 5,6-difluoro-1H-indole-3-carbaldehyde.

[0265] [ka]

[0266] compound 36 (7R,12bR)-7,8-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0267] General procedure G was used starting from 4-fluoro-1H-indole-3-carbaldehyde.

[0268] [ka]

[0269] compound 37 (5R,6R,10bS)-6,9-Difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one [ka]

[0270] General procedure F was used starting from 4-fluorobenzaldehyde.

[0271] [ka]

[0272] compound 38 6-Fluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole [ka]

[0273] General procedure H was used starting from 5-fluoro-1H-indole-3-carbaldehyde.

[0274] [ka]

[0275] compound 39 (7R,12bS)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0276] General procedure G was used starting from 4,5,6-trifluoro-1H-indole-3-carbaldehyde.

[0277] [ka]

[0278] compound 40 (7R,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0279] General procedure G was used starting from 4,5,6-trifluoro-1H-indole-3-carbaldehyde.

[0280] [ka]

[0281] compound 41 (7S,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0282] General procedure G was used starting from 4,5,6-trifluoro-1H-indole-3-carbaldehyde.

[0283] [ka]

[0284] compound 42 (5S,10R,10aR)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one [ka]

[0285] General procedure D was used starting from 5-[(R)-(3,4-difluorophenyl)(fluoro)methyl]pyrrolidin-2-one.

[0286] [ka]

[0287] compound 43 (5S,10R,10aS)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one [ka]

[0288] General procedure D was used starting from (5S)-5-[(R)-(3,4-difluorophenyl)(fluoro)methyl]pyrrolidin-2-one.

[0289] [ka]

[0290] compound 44 (5S,10S,10aR)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one [ka]

[0291] General procedure D was used starting from (5R)-5-[(S)-(3,4-difluorophenyl)(fluoro)methyl]pyrrolidin-2-one.

[0292] [ka]

[0293] compound 45 (12bS)-9,10-Difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one [ka]

[0294] General procedure B was used starting from 5,6-difluoro-1H-indole-3-carbaldehyde, followed by general procedure G.

[0295] [ka]

[0296] Experiments on the binding affinity of the compounds of the present inventionBinding affinity calculations for compounds of the invention were performed using Qvina2 with an explicitly random seed value of 5061982. The coverage was 100. Methods for performing binding affinity calculations for the compounds of the present invention are well known in the art, and are described in Alhossary A. et al. Fast, Accurate, and Reliable Molecular Docking with QuickVina 2 Bioinformatics (2015) 31 (13) 2214-2216, O. Trott, AJ Olson, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, Journal of Computational Chemistry 31 (2010) 455-461, Feinstein WP, Brylinski M. Calculating an optimal box size for ligand docking and virtual screening against experimental and predicted binding pockets. J. Cheminform. (2015), 7 (1): 18, Tetko, IV et al. Virtual computational chemistry laboratory - design and description, J. Comput. Aid. Mol. Des., 2005, 19, 453-63, Also described in VCCLAB, Virtual Computational Chemistry Laboratory, http: / / www.vcclab.org, 2005. The search space (X,Y,Z) coordinates of the center for binding affinity calculations can be obtained by methods well known in the art.For example, the search space (X, Y, Z) coordinates for PDB ID 1bp3 and protein homolog ClassA_5ht1a_human_Active_6G79_2018-07-10_GPCRDB were (13.730, 30.880, 13.170) and (91.84457623, 54.99481, 63.31365), respectively. The PDB IDs and protein homolog codes of the proteins used in the calculation of the compounds of the present invention are listed in Table 1, and the calculation results are shown in Table 2.

[0297] [Table 1(1)] [Table 1(2)] [Table 1(3)]

[0298] [Table 2(1)] [Table 2(2)] [Table 2(3)] [Table 2(4)] [Table 2(5)] [Table 2(6)] [Table 2(7)] [Table 2(8)]

[0299] The compound with the strongest binding affinity to the dopamine transporter is (7R,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (40).

[0300] The compound with the strongest binding affinity to dopamine type 1 receptors is (5S,6S,10bS)-6,9-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (25).

[0301] The compound with the strongest binding affinity to the dopamine type 2 receptor is (5R,6S,10bR)-6,8,9-trifluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (26).

[0302] The compound with the strongest binding affinity to the dopamine type 3 receptor is (5S,10R,10aR)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (42).

[0303] The compound with the strongest binding affinity to the dopamine type 4 receptor is (7R,12bS)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (39).

[0304] The compound with the strongest binding affinity for the norepinephrine transporter is (12bS)-8,9-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (27).

[0305] The compound with the strongest binding affinity to phenylethanolamine N-methyltransferase is 7,8-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (17), preferably the (5S,10aR)-7,8-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one isomer.

[0306] The compound with the strongest binding affinity to the serotonin transporter is (7S,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (30).

[0307] The compound with the strongest binding affinity to serotonin N-acetyltransferase is (7R,12bS)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (39).

[0308] The compound with the strongest binding affinity to N-acetylserotonin methyltransferase is (5S,10R,10aS)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (43).

[0309] The compound with the strongest binding affinity to the 5-HT1A receptor is (7R,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (29).

[0310] The compound with the strongest binding affinity to the 5-HT2A receptor is 7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (7), preferably the (7S,12bS)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one isomer.

[0311] The compound with the strongest binding affinity to the 5-HT1B receptor is (12bS)-8,9-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (27).

[0312] The compound with the strongest binding affinity to the 5-HT2B receptor is (7R,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (31).

[0313] The compound with the strongest binding affinity to the 5-HT2C receptor is (5S,10S,10aR)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (44).

[0314] The compound with the strongest binding affinity to the 5-HT3 receptor is (4S)-4,6-difluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (24).

[0315] The compound with the strongest binding affinity to monoamino oxidase A is 7,10-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (15), preferably the (5R,10R,10aS)-7,10-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one isomer.

[0316] The compound with the strongest binding affinity to monoaminooxidase B is (1S,4S)-4,6-difluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4).

[0317] The compound with the strongest binding affinity to catechol-O-methyltransferase is 7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (28), preferably the (7S,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one isomer.

[0318] The compound with the strongest binding affinity to the α-1A adrenergic receptor is (7S,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (43).

[0319] The compound with the strongest binding affinity to the α-1B adrenergic receptor is (12bS)-9,10-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (45).

[0320] The compound with the strongest binding affinity to the α-2A adrenergic receptor is (12bS)-8,9-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (27).

[0321] The compound with the strongest binding affinity to the α-2B adrenergic receptor is (5S,6R,10bS)-6,8-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (32).

[0322] The compound with the strongest binding affinity to the α-2C adrenergic receptor is 5,6,7-trifluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (12).

[0323] The compound with the strongest binding affinity to the β-1 adrenergic receptor is (5S,10S,10aR)-8,10-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (33).

[0324] The compound with the strongest binding affinity to the β-2 adrenergic receptor is (1R,4R)-4,6,7-trifluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (34).

[0325] The compound with the strongest binding affinity to phenylalanine hydroxylase is (7R,12bS)-7,9,10-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (35).

[0326] The compound with the strongest binding affinity for tyrosine hydroxylase is (7S,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (30).

[0327] The compound with the strongest binding affinity to the H1 histamine receptor is (7R,12bR)-7,8-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (36).

[0328] The compound with the strongest binding affinity to the H3 histamine receptor is (7S,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (41).

[0329] The compound with the strongest binding affinity to the OX1 orexin receptor is (7R,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (31).

[0330] The compound with the strongest binding affinity to the OX2 orexin receptor is (7R,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (31).

[0331] The compound with the strongest binding affinity to the prolactin receptor is (7R,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (29).

[0332] The compound with the strongest binding affinity to the NMDA receptor GluN1 is (5R,6R,10bS)-6,9-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (37).

[0333] The compound with the strongest binding affinity to the NMDA receptor Glu2B is 4,5,6,7-tetrafluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (10), preferably the (1S,4R)-4,5,6,7-tetrafluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole isomer.

[0334] The compound with the strongest binding affinity to the α4β2 nicotinic receptor is 6-fluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (38).

[0335] The compound with the strongest binding affinity to the σ1 receptor is (7S,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (30).

[0336] The compound with the strongest binding affinity to the nociceptin / orphanin receptor is (7R,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (40).

[0337] The compound with the strongest binding affinity to the μ-opioid receptor is (7S,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (41).

[0338] The compound with the strongest binding affinity to the δ opioid receptor is 7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one (7), preferably the (7S,12bS)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one isomer.

[0339] It will be apparent to those skilled in the art that with the advancement of technology, the concept of the present invention can be implemented in various ways. The present invention and its embodiments are not limited to the above-described examples, but can be modified in various ways within the scope of the claims.

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, The dotted line represents an optional bond; R １ and R ２ together with the carbon atoms to which they are attached form a group selected from 1H-indole and benzene groups, said 1H-indole and benzene groups being R ３ , R ４ , R ５ and R ６ and optionally substituted with 1 to 4 substituents each independently selected from the group consisting of: ３ , R ４ , R ５ and R ６ is halogen, OH, C １～４ -Alkyl, C １～３ -(per)haloalkyl, C １～３ -alkoxy, C １～３ -(per)haloalkoxy; R ａ and R ｂ together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; and R ｃ is H; or R ａ is Me, and R ｂ and R ｃ together with the nitrogen and carbon atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; or R ａ is Me, R ｂ is H, or R if the dotted line represents a bond. ｂ does not exist, and R ｃ is H, except that R １ and R ２ taken together with the carbon atom to which they are attached form said optionally substituted 1H-indole group; R ７ is halogen, OH, SH, NOR ８ , C １～３ -(per)haloalkoxy, CN, C(O)N(R ８ ) ２ and N(R ８ ) ２ or is selected from the group consisting of R ７ is C １～４ -alkyl, provided that the 1H-indole or benzene group is not substituted with halogen, OH, C １～４ -Alkyl, C １～３ -(per)haloalkyl, C １～３ -alkoxy, C １～３ -(per)haloalkoxy; or R ７ may be H, with the proviso that R ａ and R ｂ together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides, R ｃ is H, then R ４ and R ５ is a halogen, C １～４ -Alkyl, C １～３ -(per)haloalkyl and C １～３ -(per)haloalkoxy; R ａ is Me and R ｂ and R ｃ together with the carbon atom and nitrogen atom to which they are attached form a 6-membered cyclic amide, R １ and R ２ together with the carbon atom to which they are attached form said optionally substituted 1H-indole group, or R ａ is Me and R ｂ and R ｃ together with the carbon and nitrogen atoms to which they are attached form a five-membered cyclic amide, and R １ and R ２ together with the carbon atom to which they are attached to form a 1H-indole group or a benzene group, said 1H-indole group or benzene group is not １～４ -Alkyl, C １～３ -(per)haloalkyl, C １～３ -alkoxy and C １～３ -substituted with 1 to 4 substituents each independently selected from the group consisting of (per)haloalkoxy; R ａ is Me and R ｃ is H and R １ and R ２ together with the carbon atom to which they are attached to form a substituted 1H-indole group, R of said substituted 1H-indole group ４ and R ５ is a halogen, C １～４ -Alkyl, C １～３ -(per)haloalkyl and C １～３ -(per)haloalkoxy; Each R ８ is H, C １～４ -Alkyl, C １～４ -alkenyl, C １～４ -alkynyl and C １～３ -(per)haloalkyl, or any N(R ８ ) ２ If it is part of both R ８ may be taken together with the nitrogen to which they are attached to form a 3-6 membered aliphatic or aromatic heterocyclic ring containing 1-3 heteroatoms each independently selected from N, O and S, or a stereoisomer or pharmaceutically acceptable salt thereof.

2. The compound has formula (Ia), (Ib) or (Ic) 【Chemistry 2】 [In the formula, R ａ and R ｂ together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; and R ｃ is H; or R ａ is Me, and R ｂ and R ｃ together with the nitrogen and carbon atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; R ｄ is H, or R if the dotted line represents a bond. ｄ does not exist; and R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and the dotted line is as defined in claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

3. The compound has formula (Ic), (Id), (Ie), (If) or (Ig): 【Transformation 3】 [In the formula, m is 1 or 2; n is 1 or 2; R ｄ is H, or R if the dotted line represents a bond. ｄ does not exist; and The dotted line, R ３ , R ４ , R ５ , R ６ , R ７ and R ８ is as defined in claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

4. The compound has formula (Id), (Ie), (If) or (Ig) [In the formula, m is 1 or 2; n is 1 or 2; R ３ , R ４ , R ５ , R ６ , R ７ and R ８ is as defined in claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

5. The compound has the formula (Ic) [In the formula, R ｄ is H, or R if the dotted line represents a bond. ｄ does not exist; and The dotted line, R ３ , R ４ , R ５ , R ６ , R ７ and R ８ is as defined in claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

6. R ３ and R ６ is H, halogen, C １～４ -Alkyl, C １～３ -(per)haloalkyl and C １～３ -(per)haloalkoxy; R ４ and R ５ are both halogens or R ４ and R ５ One of them is halogen and the other is C １～４ -Alkyl, C １～３ -(per)haloalkyl or C １～３ -(per)haloalkoxy; and R ７ is H, halogen, OH, NOR ８ , C １～４ -Alkyl and C １～３ 6. The compound of any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from the group consisting of -(per)haloalkoxy.

7. R ３ and R ６ is H, halogen, C １～４ -Alkyl, C １～３ -(per)haloalkyl and C １～３ -(per)haloalkoxy; R ４ and R ５ are both F or R ４ and R ５ One of them is F and the other is C １～４ -Alkyl or C １～３ -(per)haloalkyl; and R ７ is H, halogen, OH, NOR ８ , C １～４ -Alkyl and C １～３ 7. The compound of any one of claims 1 to 6, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of -(per)haloalkoxy.

8. R ３ and R ６ are each independently selected from H and halogen; R ４ and R ５ are both F or R ４ and R ５ One of them is F and the other is C １～４ -Alkyl or C １～３ -(per)haloalkyl; and R ７ are H, F, OH and C １～４ 8. The compound of any one of claims 1 to 7, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: -alkyl.

9. R ３ , R ６ and R ７ is H; and R ４ and R ５ 9. The compound of claim 1, wherein R is F, or a stereoisomer or pharmaceutically acceptable salt thereof.

10. R ３ and R ６ is H; and R ４ , R ５ and R ７ 9. The compound of claim 1, wherein R is F, or a stereoisomer or pharmaceutically acceptable salt thereof.

11. R ａ is Me; and R ｂ and R ｃ 11. The compound of claim 10, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: taken together with the nitrogen atom and carbon atom to which they are attached, form a group selected from 5- and 6-membered cyclic amides.

12. R ３ and R ６ is H, halogen, C １～４ -Alkyl, C １～３ -(per)haloalkyl and C １～３ -(per)haloalkoxy; R ４ and R ５ are both F or R ４ and R ５ One of the groups is a halogen and the other is H, C １～４ -Alkyl or C １～３ -(per)haloalkyl; and R ７ is halogen, OH, C １～３ 6. The compound of any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of -(per)haloalkoxy.

13. R ３ and R ６ are each independently selected from the group consisting of H and F; R ４ and R ５ are both F or R ４ and R ５ One of them is F and the other is H, C １～４ -Alkyl or C １～３ -(per)haloalkyl; and R ７ 13. The compound of any one of claims 1 to 5 or claim 12, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: is selected from the group consisting of F and OH.

14. The compound is 5-fluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-fluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4,6-difluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 7-Fluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; 7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bS)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7S,12bR)-7,8,9,10-tetrafluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; 7,9-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; 7,8,10-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; 4,5,6,7-tetrafluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5,6-difluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole; 5,6,7-trifluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole; 4,5,6,7-tetrafluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole; 7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (5S,10R,10aR)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (5S,10R,10aS)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (5S,10S,10aR)-7,8,10-trifluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; 7,10-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; 9,10-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; 7,8-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (5R,11S)-10,11-difluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one; (6R,12S)-12-fluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one; (5R,11S)-11-fluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one; (6R,12S)-1,12-difluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one; (5R)-9-fluoro-5-methyl-1,2,5,6,11,11a-hexahydro-3H-indolizino[6,7-b]indol-3-one; (6R)-2-fluoro-6-methyl-6,9,10,11,11a,12-hexahydroindolo[3,2-b]quinolizin-8(5H)-one; (4S)-4,6-difluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole; (5S,6S,10bS)-6,9-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; (5R,6R,10bS)-6,9-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; (5R,6S,10bR)-6,8,9-trifluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; (7R,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7S,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (12bS)-9,10-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bR)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7S,12bS)-7,8,9-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (5S,6R,10bS)-6,8-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; (5S,10S,10aR)-8,10-difluoro-5-methyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one; (1R,4R)-4,6,7-trifluoro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (7R,12bS)-7,9,10-trifluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (7R,12bR)-7,8-difluoro-1H,2H,3H,4H,6H,7H,12H,12bH-indolo[2,3-a]quinolizin-4-one; (5R,6R,10bS)-6,9-difluoro-5-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one; and 6-fluoro-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole 14. The compound of any one of claims 1 to 13, selected from the group consisting of: or a stereoisomer or pharmaceutically acceptable salt thereof.

15. 15. A pharmaceutical composition comprising an effective amount of one or more compounds according to any one of claims 1 to 14, or stereoisomers or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable excipients.

16. 16. The pharmaceutical composition of claim 15, comprising one or more compounds according to any one of claims 1 to 14, or stereoisomers or pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable carriers.

17. 17. A pharmaceutical composition according to claim 15 or 16, comprising one or more compounds according to any one of claims 1 to 14, or stereoisomers or pharmaceutically acceptable salts thereof, in combination with one or more other active ingredients.

18. 15. A compound according to any one of claims 1 to 14, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

19. 15. A compound according to any one of claims 1 to 14, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a CNS-related disease or condition.

20. 20. A compound according to any one of claims 1 to 14, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition according to claim 19, wherein the disease or condition is selected from the group consisting of Alzheimer's disease, Parkinson's disease, depression, anxiety, hyperactivity, narcolepsy, drug addiction, alcoholism, anorexia nervosa, bulimia and mitochondrial disease.

21. 10. A process for preparing a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, said process comprising: Formula (I') 【Chemistry 4】 [In the formula, R １ , R ２ and R ７ is as defined in claim 1, R １ and R ２ together with the carbon atom to which they are attached form a 1H-indole group, the nitrogen of said 1H-indole group is optionally protected with a protecting group; R ７ is OH or SH, the oxygen or sulfur of said OH or SH is optionally protected with a protecting group; R ｂ’ and R ｃ’’ together with the carbon and nitrogen atoms to which they are attached form a group selected from 5- and 6-membered cyclic amides; or R ｂ’ is H or an activating group, and R ｃ’’ is H; reacting said compound of formula (I') with an aldehyde, optionally in the presence of one or more activating group reactants, wherein said one or more activating group reactants, optionally together with one or more activating agents, promote ring formation; - optionally carrying out one or more deprotection reactions; It includes Formula (I) 【Transformation 5】 [In the formula, R １ , R ２ , R ７ , R ａ , R ｂ , R ｃ and the dotted line is as defined in claim 1 , and the method comprises: - optionally converting said compound of formula (I) into a pharmaceutically acceptable salt thereof. The method shall include:

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