Complex I regulators

Abstract

The present invention describes compounds having formula (I) that regulate the function of mitochondrial complex I (NADH-quinone oxidoreductase). TIFF2024506053000204.tif40170

Description

[Technical Field]

[0001] The present invention relates to a compound having the formula (I) [ka] , its pharmaceutical compositions, and its use in therapy. Unexpectedly, the compounds regulate the function of mitochondrial complex I (NADH-quinone oxidoreductase), allowing for the treatment or prevention of conditions associated with oxidative stress mediated by complex I NADH-quinone oxidoreductase. [Background technology]

[0002] Oxidative stress reflects an imbalance between the generation and detoxification of reactive oxygen species (ROS) and can cause toxic effects through increased ROS concentrations, disruption of intracellular signaling, and / or damage / oxidation of proteins, DNA, or lipids. Oxidative stress is thought to be important in many diseases. Various enzymes generate reactive oxygen species (ROS) within cells. One of the major sources of ROS is oxidative phosphorylation by complex I. This enzyme is a ubiquitously expressed protein complex encoded by 39 nuclear and 7 mitochondrial genes, which transfers electrons from NADH to ubiquinone, coupling it to the proton transport required for ATP synthesis. Because NADH oxidation is much faster than ubiquinone reduction, the enzyme is reduced under physiological conditions, resulting in electron leakage (i.e., the production of negatively charged superoxide O2) at the NADH binding site. ·- As a result, the reduction efficiency of UQ decreases due to the generation of radicals. ·- This leads to an increased occurrence and is observed in various diseases such as Leigh syndrome, LHON disease, AMD or Parkinson's disease. Cytotoxic O2 produced by Complex I ·-ROS are primarily detoxified by mitochondrial superoxide dismutase (SOD2), generating hydrogen peroxide, which is detoxified by various enzymes, including catalase, glutathione peroxidase, and thioredoxin. Given the central importance of complex I in oxidative phosphorylation and redox homeostasis, the identification of chemicals that can inhibit ROS formation is of great interest as potential therapeutic agents. Summary of the Invention

[0003] Terms not specifically defined herein should be given the meaning that would be given them by one of ordinary skill in the art in light of this disclosure and the context, except that as used herein, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, e.g., C 1-6 -Alkyl means an alkyl group or radical having 1 to 6 carbon atoms. Generally, for groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., the skilled artisan can determine the point of attachment of the radical to the molecule from the free valence of the group itself. For combined groups containing two or more subgroups, the last listed subgroup is the point of attachment of the radical; for example, the substituent "aryl-C1-3-alkyl" is C 1-3 -means an aryl group bonded to an alkyl group, C 1-3 The alkyl group is attached to a core or group to which the substituents are attached. When a compound of the invention is depicted by a chemical name and a chemical formula, the chemical formula shall prevail in the event of a conflict. An asterisk may be used in a sub-formula to indicate a bond that is connected to a defined core molecule.

[0004] As used herein, the term "substituted" means that any one or more hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.), as well as racemates thereof, as well as mixtures of different proportions of separate enantiomers, mixtures of diastereomers, or mixtures of any of the aforementioned forms in which such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and salts thereof, including solvates thereof, examples of which include, for example, hydrates, including solvates of the free compound or a salt of the free compound.

[0005] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of corresponding mixtures, by the use of stereochemically pure starting materials, and / or by stereoselective synthesis. Methods for preparing optically active forms are known in the art, for example, by resolution of racemates, or by synthesis starting from, for example, optically active starting materials and / or by the use of chiral reagents. Enantiomerically pure compounds or intermediates of the present invention may also be prepared via asymmetric synthesis, for example by the preparation and subsequent separation of suitable diastereomeric compounds or intermediates which may be separated by known methods (e.g., chromatographic separation or crystallization), and / or by the use of chiral reagents, such as chiral starting materials, chiral catalysts, or chiral auxiliaries. Furthermore, methods for preparing enantiomerically pure compounds from the corresponding racemic mixture are known to those skilled in the art, for example by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase; or by resolution of the racemic mixture using a suitable resolving agent, for example by formation of diastereomeric salts of the racemate with an optically active acid or base, followed by resolution of the salts and release of the desired compound from the salt; or by derivatization of the corresponding racemate with an optically active chiral auxiliary reagent, followed by diastereomeric separation and removal of the chiral auxiliary; or by kinetic resolution (e.g., enzymatic resolution) of the racemate; by enantioselective crystallization from a conglomerate of enantiomeric crystals under appropriate conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0006] The term "halogen" generally refers to fluorine, chlorine, bromine, and iodine. The term "alkyl," alone or in combination with other radical moieties, means an acyclic saturated branched or straight chain hydrocarbon radical containing 1 to 6 carbon atoms. For example, the term "C 1-5 "Alkyl" encompasses radicals represented by HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH-CH(CH)-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-, HC-CH-CH-CH(CH)-, HC-CH-CH(CH)-, HC-CH-CH(CH)-CH-, HC-CH(CH)-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH(CH)-, and HC-CH-CH(CHCH)-. The term "cycloalkyl," alone or in combination with other radical moieties, refers to a cyclic, unbranched, saturated hydrocarbon radical having 3 to 8 carbon atoms, preferably 3 to 5 carbon atoms. For example, the term C 3-8 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the term C 3-5Cycloalkyl includes cyclopropyl, cyclobutyl, and cyclopentyl.

[0007] The term "halo" appended to an "alkyl" or "cycloalkyl" group (saturated or unsaturated) means, for example, an alkyl or cycloalkyl group in which one or more hydrogen atoms have been replaced by a halogen atom selected from fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferably fluorine. Examples include: H2FC-, HF2C-, F3C- As used herein, the term "aryl," alone or in combination with other radical moieties, refers to a carbocyclic, aromatic, monocyclic group containing six carbon atoms, optionally fused to a second five- or six-membered carbocyclic group, which may be aromatic, saturated, or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, and dihydronaphthyl. The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic ring system, including aromatic ring systems containing one or more heteroatoms selected from N, O, or S(O)r (r=0, 1, or 2), consisting of 3 to 14 ring atoms, with no heteroatoms in the aromatic ring portion. The term "heterocyclyl" is intended to include all possible isomers.

[0008] Thus, the term "heterocyclyl" refers to the following exemplary structures not depicted as radicals, since each form is optionally covalently bonded to any atom as long as appropriate valences are maintained: [ka] [ka] Includes:

[0009] In particular, the term "heterocyclyl" includes the ring structures shown in exemplary compounds 1-175 and 1001-1178.

[0010] The term "heteroaryl" refers to a monocyclic aromatic ring system containing one or more heteroatoms selected from N, O, or S, consisting of 5 to 6 ring atoms, with at least one heteroatom in the aromatic ring. The term "heteroaryl" is intended to include all possible isomers. Thus, the term "heteroaryl" refers to the following exemplary structures that are not depicted as radicals, since each form is optionally covalently bonded to any atom as long as appropriate valences are maintained: [ka] Includes:

[0011] The expression "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds where the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. For example, such salts include those derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Additionally, pharmaceutically acceptable salts may be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glutamine, potassium, sodium, and tris(hydroxymethyl)-aminoethane.

[0012] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Other acid salts (eg, trifluoroacetates) that are useful, for example, in the purification or isolation of the compounds of the invention, also form part of this invention. Many of the above-mentioned terms may be used repeatedly in the chemical formulae and radical definitions and have in each case independently one of the above-mentioned meanings. DETAILED DESCRIPTION OF THE INVENTION

[0013] The compound of the present invention or a salt thereof is represented by formula (I) [ka] Shown below. (In the formula, R1 is unsubstituted or MeO-substituted C 1-4 - alkyl; unsubstituted tetrapyranyl, tetrahydrofuranyl, oxetanyl, dioxepanyl, pyrrolidinyl, or piperidinyl; or pyrrolidinyl or piperidinyl substituted on the nitrogen by methyl, isopropyl, oxetanyl, ethoxycarbonyl, acetyl, or trifluoroacetyl; R2 is an unsubstituted or substituted 5-, 6- or 7-membered ring having 1 or 2 heteroatoms selected from O or N, or an unsubstituted or substituted spirocyclic heterocyclyl group having 4 to 11 ring atoms and 1 to 3 heteroatoms selected from N or O, said cyclic or spirocyclic heterocyclyl group being bonded by a C=C double bond in formula (I), and In said cyclic or spirocyclic heterocyclyl group, one N atom may be substituted by methyl, isopropyl, acetyl, benzyloxycarbonyl, phenyl, oxetanyl or tetrahydropyranyl; and one or more C-atoms may be substituted by methyl or OH, R3 or R4 are each independently Hydrogen; unsubstituted or substituted with one or more F, methoxy, unsubstituted or substituted with one or more F 3-8 Cycloalkyl-substituted C 1-6 alkyl; aryl; heteroaryl having 5 to 6 ring atoms, such as unsubstituted or substituted 5-pyrazolyl, or a heterocyclyl ring having 3 to 6 ring atoms selected from the group consisting of oxetanyl, tetrahydropyranyl, and pyrrolidinyl, wherein the heterocyclyl ring is unsubstituted or C 1-6 alkyl, acetyl, tetrahydrofuranyl, oxetanyl substituted); or hydroxyethylacetyl; or R3 and R4 together with the N to which they are attached are unsubstituted or C 1-6 and forming a heterocyclyl ring selected from the group consisting of morpholinyl and pyrrolidinyl substituted with alkyl, F, or hydroxyl.

[0014] Representative examples of R1 in formula (I) include the following. unsubstituted or MeO group substituted, [ka] Unsubstituted or at the nitrogen site [ka] has been replaced [ka]

[0015] Structural elements in formula (I) [ka] Representative examples include the following: [ka] [ka]

[0016] Representative examples of the amino group containing R3 and R4 in formula (I) include the following: [ka] [ka]

[0017] Specific examples of R1 in formula (I) include the following. [ka] Preferred examples of R1 in formula (I) are tetrahydropyranyl and dioxepanyl.

[0018] In formula (I), the structural elements linked by a C=C double bond [ka] Specific examples of include 6- or 7-membered rings containing two heteroatoms selected from O or N, one or both N atoms of which may be substituted by methyl, isopropyl, acetyl, benzyloxycarbonyl, phenyl, oxetanyl, or tetrahydropropanyl, and one or more C atoms of which may be substituted by methyl or OH.

[0019] In formula (I), [ka] Other individual examples of [ka] Examples include: Specific examples of the amino group containing R3 and R4 in formula (I) include those having hydrogen at R3 and unsubstituted or fluorine (F)-substituted isopropyl, cyclobutyl, or cyclopentyl at R4. Other individual examples of amino groups comprising R3 and R4 in formula (I) are unsubstituted or substituted with one or more F groups. [ka] Examples include:

[0020] The compounds of the present invention can be obtained by the following methods. In the first step, the compound (2-fluoro-5-nitrophenyl)-acetic acid (compound ii) [ka] is reacted with an amine R1-NH2 using dimethylacetamide, dimethylformamide, N-methylpyrrolidone, acetonitrile, DMSO, dichloromethane, toluene, or other suitable solvent at elevated temperature to form the compound 5-nitro-2,3-dihydro-1H-indol-2-one (compound iii). [ka] In the next step, 5-nitro-2,3-dihydro-1H-indol-2-one (compound iii) is condensed with a suitable electrophile to give 5-nitro-3-ylidene-2,3-dihydro-1H-indol-2-one (compound iv) either neat or in a suitable solvent such as piperidine at elevated temperature using microwaves. [ka]

[0021] Suitable electrophiles include iminoethers, ketones, and acetals (e.g., 5-methoxy-3,6-dihydro-2H-oxazine, oxan-4-one, or 2,2-dimethoxy-1-methylpyrrolidine), which may be commercially available or easily prepared by one skilled in the art from commercially available materials (e.g., iminoethers can be obtained from the appropriate amide by O-methylation with trimethyloxonium tetrafluoroborate in a suitable solvent such as methylene chloride).

[0022] In the next step, the compound 5-nitro-3-ylidene-2,3-dihydro-1H-indol-2-one (compound iv) is reduced to 5-amino-3-ylidene-2,3-dihydro-1H-indol-2-one (compound v). [ka] The reduction can be carried out by catalytic hydrogenation using hydrogen gas under high pressure and a suitable catalyst such as Raney nickel in a suitable solvent such as methanol. To obtain the final compound of formula (I), the compound of formula (v) is reacted with an appropriate aldehyde or ketone and sodium cyanoborohydride, sodium triacetateborohydride or other reducing agent in a suitable solvent such as methanol with the addition of acetic acid, p-TosOH or other organic acid.

[0023] Alternatively, amine (v) may be reacted with a suitable electrophile bearing a Cl-, Br-, I-, methylsulfonyl ester, trifluorosulfonyl ester, tolylsulfonyl ester or other leaving group in the presence of a suitable base such as potassium carbonate in DMF or other suitable solvent. The compounds described above can be prepared in salt forms, particularly pharmaceutically acceptable salts, which are also a subject of the present invention. The medicaments thus obtained are also a further subject of the present invention.

[0024] The compounds of the present invention can be used in drugs or pharmaceutical compositions for human patients, such compositions can be applied to the human body for the treatment or diagnosis of disease. Similarly, the compounds of the present invention can be used in veterinary medicines or pharmaceutical compositions, which can be applied to the animal's body for the treatment or diagnosis of animal diseases.

[0025] In particular, the compounds of the present invention can be used in the manufacture of pharmaceutical compositions or medicaments for the treatment or prevention of the human conditions listed below. Suitable formulations for administering a compound of Formula I will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalants, and powders. Suitable tablets can be obtained, for example, by mixing one or more compounds of Formula I with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants. Such pharmaceutical compositions or medicaments contain a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, ranging from 0.1 to 2000 mg. In addition to the compounds in the present invention, such agents also include a pharmaceutically acceptable carrier.

[0026] The present invention is directed to compounds useful for the treatment of diseases, disorders and conditions in which the suppression of oxidative stress as a result of the reduction of ROS generated by complex I is therapeutically beneficial, including, but not limited to, the treatment and / or prevention of neurological or neurodegenerative or psychiatric conditions, and non-neurological conditions such as cardiovascular disease, ischemia-reperfusion injury, cancer and pulmonary disease, and mitochondrial diseases. Neurological or neurodegenerative conditions include, for example, Parkinson's disease, Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis (ALS), diseases associated with retinal dysfunction such as retinopathies and age-related macular degeneration (AMD), and other brain dysfunctions caused by trauma or other injuries, including aging. Mitochondrial diseases include, for example, Lever's hereditary optic neuropathy (LHON), Leigh's syndrome, myoclonic epilepsy associated with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, encephalomyopathy, lactic acidosis, stroke (MELAS) or diabetes and hearing loss (DAD). Psychiatric conditions include depressive disorders such as major depression, major depressive disorder, psychiatric depression, dysthymia, and postpartum depression, and bipolar disorder, and fear-related disorders (such as post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety), chronic fatigue syndrome, and autism. Pain disorders include nociceptive pain, inflammatory pain, cancer pain, and neuropathic pain (e.g., cancer pain, osteoarthritis pain, rheumatoid arthritis pain, post-herpetic neuralgia, burn pain, and other conditions). Pain can be chronic or acute. Non-neurological conditions include disorders and other conditions such as pulmonary diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and other fibrotic diseases, liver diseases such as nephropathy, proteinuric kidney disease, hepatic dyslipidemia associated with cholestasis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pruritus, diseases associated with abnormalities of the cardiovascular system or vascular permeability (e.g., heart failure, pulmonary arterial hypertension, acute respiratory distress syndrome (ARDS), maladaptive cardiac remodeling, diseases associated with maladaptive blood pressure regulation such as hypertension or hypotension, infectious diseases such as viral hepatitis and parasitic infections (including malaria, African sleeping sickness and Chagas disease), sarcopenia and other musculoskeletal diseases, diabetes, insulin resistance, metabolic syndrome and obesity.

[0027] The daily allowable dose of the compound of the present invention can vary within the range of 0.1 to 2000 mg. The actual therapeutic amount or dosage will depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease, etc. In any case, the drug must be administered in a dosage and manner that delivers a pharmaceutically effective amount appropriate to the patient's health condition.

[0028] Compositions suitable for administering the compounds of the present invention can be prepared by those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalants, and powders. The content of the pharmaceutically active compound can vary from 0.1 to 95 wt%, preferably from 5.0 to 90 wt%, of the total composition. Suitable tablets can be obtained by mixing the compounds of the present invention with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants, and compressing the resulting mixture into tablet form. The compounds of the present invention may be used as the sole active ingredient or in combination with other commonly used active ingredients in connection with the treatment of any of the indications focused on in this invention.

[0029] The compounds and their characteristics in the following table are presented to illustrate the invention but not to define its scope. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 [Table 1-44] [Table 1-45] [Example]

[0030] The following examples are intended to illustrate the present invention but not to limit its scope.

[0031] Principles, melting point, IR, 1 H-NMR and / or mass spectra were obtained for prepared compounds. Unless otherwise stated, Rf values ​​were obtained using ready-made silica gel 60 F254 TLC plates (E. Merck, Darmstadt, item no. 1.05714) without chamber saturation. The ratios given for eluents refer to the volume units of the solvents. Chromatographic purification was performed using silica gel provided by E. Merck, Darmstadt (Silica gel 60, 0.040-0.063 mm, item no. 1.09385.2500).

[0032] The following abbreviations are used in the examples below: BOC tBuOCO CH Cyclohexane CM dichloromethane DIPEA Diisopropylamine DMSO dimethyl sulfoxide DMF N,N-dimethoxyformamide EA Ethyl acetate ESI electrospray ionization h time HPLC High-Performance Liquid Chromatography M molar concentration MeOH Methanol EtOH ethanol min mL milliliter μL microliter mmol millimolar μmol micromol MPLC Medium Pressure Liquid Chromatography MS mass spectrum NMP N-methyl-pyrrolidinone Pd / C Palladium activated carbon PE Petroleum Ether Rf retention factor Rt retention time sat. saturated Tert. Third grade TLC thin layer chromatography TFA trifluoroacetic acid THF tetrahydrofuran TBME tert-butyl methyl ether UPLC Ultra High Performance Liquid Chromatography

[0033] Brine refers to a saturated aqueous solution of sodium chloride. All temperatures are in °C (degrees Celsius) unless otherwise noted. All reactions are not under an inert atmosphere and are conducted at room temperature unless otherwise noted.

[0034] example: Example 1: HPLC / UPLC measurement method Method A [Table 2] Method B [Table 3] Method C [Table 4] Method D [Table 5] Method E Table 6 Method F Table 7 Method G Table 8 Method H Table 9 Method I Table 10 Method J Table 11 Method K Table 12 Method L Table 13 Method M Table 14 Method N Table 15 Method O Table 16 Method P Table 17

[0035] Example 2: Synthesis of intermediates A1, A2, A4, A5, A7-9 and A11 Intermediate A1: [ka] (2-Fluoro-5-nitrophenyl)acetic acid (4.60 g; 23.10 mmol) and tetrahydrofuran-3-ylamine (10.0 g; 114.78 mmol) in DMSO (20 mL) are stirred overnight at 45° C. HCl (aqueous; 2 M; 92.4 mL; 184.80 mmol) is added. After stirring at 45° C. for 1.5 h, the resulting precipitate is filtered off, washed with water, and dried. MS(ESI + ): m / z=249[M+H] + HPLC (Method B): Rt=1.0 min

[0036] The following intermediates were prepared in a similar manner to intermediate A1: [Table 18-1] [Table 18-2]

[0037] Example 3: Synthesis of intermediate A3 [ka] Step 1: (2-Fluoro-5-nitrophenyl)-acetic acid (500 mg; 2.51 mmol) and oxetan-3-ylamine (936 mg; 12.81 mmol) in DMSO (2 mL) are stirred overnight at 45° C. The mixture is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: methanol). MS(ESI + ): m / z=251[MH] - HPLC (Method A): Rt=0.66 min Step 2: Intermediate A3 Step 1 (462 mg; 0.92 mmol) and TBTU (0.71 g; 2.20 mmol) in DMF (8 mL) are stirred at room temperature overnight. The resulting precipitate is filtered off and dried. MS(ESI + ): m / z=235[M+H] + HPLC (Method A): Rt=0.95 min

[0038] Example 4: Synthesis of intermediate A6 [ka] Step 1: 1,3-Dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one (5.51 g; 25.49 mmol) and TEA (7.16 mL; 50.99 mmol) in DCM (30 mL) are cooled in an ice bath. Trifluoroacetic anhydride (4.25 mL; 30.59 mmol) is added dropwise. The mixture is stirred at room temperature for 2 h. The mixture is diluted with NaHCO3 (9% aqueous solution; 20 mL). After gas evolution has ceased, the mixture is further diluted with DCM and water. The organic layer is separated, dried, and evaporated. The residue is purified by MPLC (DCM / MeOH; 1 / 0 to 97 / 3). MS(ESI + ): m / z=313[M+H] + HPLC (Method A): Rt=1.25 min Step 2: Intermediate A6 Step 1 (8.02 g; 25.68 mmol) is dissolved in concentrated sulfuric acid (45 mL) and cooled to -5°C. A cooled mixture of concentrated sulfuric acid (15 mL) and concentrated nitric acid (1.80 mL; 28.25 mmol) is added dropwise. After stirring at -5°C for 1 h, the mixture is poured into ice water. The resulting precipitate is filtered off and dried. The residue is dissolved in DCM. The organic layer is washed with NaHCO3 (9% aqueous solution), separated, dried and evaporated. MS(ESI + ): m / z=358[M+H] + HPLC (Method A): Rt=1.22 min

[0039] Example 5: Synthesis of intermediate A10 [ka] To a cooled mixture of sodium nitrite (12.71 g; 149.48 mmol) and concentrated sulfuric acid (22.9 mL; 407.68 mmol) is added additional concentrated sulfuric acid (40 mL) dropwise. 1-Methyl-1,3-dihydroindol-2-one (20.0 g; 135.89 mmol) is dissolved in concentrated sulfuric acid (120 mL) and added dropwise to the cooled nitrosulfuric acid. The mixture is allowed to warm to room temperature overnight. The mixture is poured into ice water. The resulting precipitate is filtered off, washed with water, and dried. The residue is dissolved in DCM, washed with water and brine, separated, dried, and evaporated. MS(ESI + ): m / z=193[M+H] + HPLC (Method H): Rt=0.90 min

[0040] Example 6: Synthesis of Intermediates B1, B2, B4, B6, B7, B9 and B10 The following intermediates can be prepared according to the references given in the table or are commercially available: [Table 19-1] [Table 19-2]

[0041] Example 7: Synthesis of Intermediates B3, B5 and B8 Intermediate B3: [ka] 2-Oxa-6-aza-spiro[3.4]octan-7-one (1.00 g; 7.87 mmol) and trimethyloxonium tetrafluoroborate (1.28 g; 8.65 mmol) in DCM (120 mL) are stirred overnight at room temperature. The mixture is diluted with saturated NaHCO3 solution until gas evolution ceases. The organic layer is separated, dried, and evaporated. MS(ESI+ ): m / z=142[M+H] +

[0042] The following intermediates are prepared in a similar manner to intermediate B3: [Table 20]

[0043] Example 8: Synthesis of intermediates C1-C3, C5-C8, C10-C12, C14, C16, C18, C20-C25, C27-C29, C32-C36 Intermediate C1: [ka] Intermediate A1 (700 mg; 2.82 mmol) and intermediate B1 (714 mg; 6.20 mmol) are stirred in a microwave for 20 min at 130° C. The resulting precipitate is suspended in MeOH, filtered off and dried. MS(ESI + ): m / z=332[M+H] + HPLC (Method B): Rt=1.29 min

[0044] The following intermediates were prepared in a similar manner to intermediate C1: [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5] [Table 21-6] [Table 21-7] [Table 21-8] [Table 21-9]

[0045] Example 9: Synthesis of intermediates C4 and C31 Intermediate C4: [ka] Intermediate A4 (1.50 g; 6.81 mmol) and tetrahydro-4H-pyran-4-one (13.0 mL; 140.76 mmol) in piperidine (1.36 mL; 13.62 mmol) are stirred in a microwave at 100°C for 15 min. The solvent is evaporated. The residue is stirred in TBME. The precipitate is filtered off and dried. MS(ESI + ): m / z=303[M+H] + HPLC (Method A): Rt=1.40 min

[0046] The following intermediates were prepared in a similar manner to intermediate C4: [Table 22]

[0047] Example 10: Synthesis of intermediates C9 and C13 Intermediate C9: [ka] The following reaction is carried out under a nitrogen atmosphere. Intermediate A2 (225 mg; 1.24 mmol) and 2,2-dimethoxy-1-methylpyrrolidine (450 mg; 3.10 mmol) in chloroform (2.5 mL) are stirred at reflux for 3 h. Additional 2,2-dimethoxy-1-methylpyrrolidine (1.2 equiv.) is added and the mixture is stirred at 65 °C overnight. The mixture is washed with saturated NaHCO3 solution. The organic layer is separated, washed with brine, dried, and evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=344[M+H] + HPLC (Method A): Rt=1.26 min

[0048] The following intermediates were prepared in a similar manner to intermediate C9: [Table 23]

[0049] Example 11: Synthesis of intermediates C15 and C37 Intermediate C15: [ka] Intermediate C14 (81 mg; 0.16 mmol) in THF (5 mL) and potassium carbonate (51 mg; 0.37 mmol) in water (1.5 mL) are stirred at 40° C. for 2 h. The mixture is diluted with brine and EA. The organic layer is separated, dried and evaporated. MS(ESI + ): m / z=345[M+H] + HPLC (Method B): Rt=0.9 min

[0050] The following intermediates were prepared in a similar manner to intermediate C15: [Table 24]

[0051] Example 12: Synthesis of intermediate C17 [ka] Intermediate C16 (800 mg; 1.86 mmol) in DCM / TFA (1 / 1; 15 mL) is stirred at room temperature for 1 h. The solvent is evaporated. The residue is dissolved in DCM and washed with NaOH (aq; 1 M). The organic layer is separated, dried and evaporated. MS(ESI + ): m / z=331[M+H] + HPLC (Method B): Rt=0.91 min

[0052] Example 13: Synthesis of intermediate C19 [ka] Step 1: Intermediate C18 (2.70 g; 5.71 mmol) in DCM / TFA (1 / 1; 30 mL) is stirred at room temperature for 1 hour. The solvent is evaporated. MS(ESI + ): m / z=373[M+H] + HPLC (Method B): Rt=1.15 min Step 2: Intermediate C19 Step 1 (600 mg; 1.23 mmol), acetone (448 μL; 6.17 mmol), and glacial acetic acid (182 μL; 3.33 mmol) in MeOH (20 mL) are stirred at room temperature for 1 h. Sodium cyanoborohydride (155 mg; 2.47 mmol) is stirred at room temperature for 2 h. Additional acetone (2 mL) is added. After stirring overnight, the mixture is diluted with saturated NaHCO3 solution. The organic layer is separated, dried, and evaporated. MS(ESI + ): m / z=415[M+H] + HPLC (Method B): Rt=1.12 min

[0053] Example 14: Synthesis of intermediate C26 [ka] Step 1: Intermediate C18 (2.70 g; 5.71 mmol) in DCM / TFA (1 / 1; 30 mL) is stirred at room temperature for 1 hour. The solvent is evaporated. MS(ESI + ): m / z=373[M+H] + HPLC (Method B): Rt=1.15 min Step 2: Intermediate C26 Step 1 (300 mg; 0.62 mmol), acetic anhydride (87 μL; 0.93 mmol), and TEA (316 μL; 1.85 mmol) in DCM (7 mL) are stirred at room temperature for 1 h. The mixture is diluted with saturated NaHCO3 solution and DCM. The organic layer is separated, dried, and evaporated. MS(ESI + ): m / z=415[M+H] + HPLC (Method B): Rt=1.40 min

[0054] Example 15: Synthesis of intermediate C30 [ka] Step 1: Intermediate C29 (500 mg; 0.87 mmol) in THF (17 mL) and potassium carbonate (157 mg; 1.13 mmol) in water (12 mL) are stirred at 40 °C for 5 h. The mixture is diluted with NaHCO3 (9% aqueous solution) and extracted with EA. The organic layer is washed with brine, separated, dried and evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=478[M+H] + HPLC (Method A): Rt=1.46 min Step 2: Intermediate C30 Step 1 (118 mg; 0.25 mmol), acetone (90 μL; 1.24 mmol), and glacial acetic acid (36 μL; 0.67 mmol) in MeOH (8 mL) are stirred at room temperature for 2 hours. Sodium cyanoborohydride (31 mg; 0.49 mmol) is added, and the mixture is stirred at 40 °C for 2 days. The mixture is diluted with NaHCO3 (9% saturated aqueous solution) and DCM. The organic layer is separated, dried, and evaporated. The residue is stirred in MeOH, filtered, and dried. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=520[M+H] + HPLC (Method A): Rt=1.58 min

[0055] Example 16: Synthesis of intermediate C38 [ka] Intermediate C29 (203 mg; 0.35 mmol) in THF (7 mL) and potassium carbonate (64 mg; 0.46 mmol) in water (5 mL) are stirred at 40 °C for 3 days. The mixture is diluted with NaHCO3 (9% aqueous solution) and extracted with EA. The organic layer is washed with brine, separated, dried and evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=494[M+H] + HPLC (Method A): Rt=1.38 min

[0056] Example 17: Synthesis of intermediates D1-D12, D15-D26 and D28-D31 Intermediate D1: [ka] Intermediate C1 (862 mg; 2.60 mmol) and Raney-Nickel (150 mg) in MeOH (25 mL) and THF (50 mL) are hydrogenated in a Parr apparatus (rt; 50 psi; 4.5 h). The catalyst is removed by filtration and the solvent is evaporated. MS(ESI + ): m / z=302[M+H] + HPLC (Method B): Rt=0.67 min

[0057] The following intermediates were prepared in a similar manner to intermediate D1: [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4] [Table 25-5] [Table 25-6] [Table 25-7] [Table 25-8] [Table 25-9]

[0058] Example 18: Synthesis of intermediate D13 [ka] Step 1: Intermediate C17 (270 mg; 0.82 mmol), acetic anhydride (85 μL; 0.90 mmol) and DIPEA (423 μL; 2.46 mmol) in DCM (5 mL) are stirred at room temperature for 15 min. The solvent is evaporated. MS(ESI + ): m / z=373[M+H] + HPLC (Method A): Rt=1.17 min Step 2: Intermediate D13 Step 1 (430 mg; 0.58 mmol) and Raney-Nickel (50 mg) in MeOH (5 mL) and THF (10 mL) are hydrogenated in a Parr apparatus (rt; 50 psi; 17 h). The catalyst is removed by filtration and the solvent is evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=343[M+H] +

[0059] Example 19: Synthesis of intermediate D14 [ka] Step 1: Intermediate C17 (489 mg; 1.48 mmol), oxetan-3-one (160 mg; 2.22 mmol), and glacial acetic acid (218 μL; 4.00 mmol) in MeOH (20 mL) are stirred at room temperature for 1 h. Sodium cyanoborohydride (186 mg; 2.96 mmol) is added, and the mixture is stirred at room temperature for 1 h. THF (5 mL) is added. After stirring overnight, additional sodium cyanoborohydride (186 mg; 2.96 mmol) is added. The mixture is diluted with water. The organic solvent is evaporated and the aqueous layer is extracted with DCM. The organic layer is separated, dried, and evaporated. The residue is stirred in MeOH, filtered off, and dried. The residue is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=387[M+H] + HPLC (Method A): Rt=1.24 min Step 2: Intermediate D14 Step 1 (164 mg; 0.42 mmol) and Raney-Nickel (50 mg) in MeOH (5 mL) and THF (10 mL) are hydrogenated in a Parr apparatus (rt; 50 psi; 4 h). The catalyst is removed by filtration and the solvent is evaporated. MS(ESI + ): m / z=357[M+H] + HPLC (Method B): Rt=0.43 min

[0060] Example 20: Synthesis of intermediate D27 [ka] Intermediate C31 (448 mg; 1.30 mmol) and iron powder (392 mg; 7.02 mmol) in water (14 mL) and ethanol (29 mL) are heated to reflux. Glacial acetic acid (0.79 mL; 13.78 mmol) is added dropwise and the mixture is stirred for 1 h. The organic solvent is evaporated and the residue is dissolved in DCM and water. The mixture is alkalized with NaOH (aq; 5 mL). The mixture is filtered through Celite. The organic layer is separated, dried and evaporated. The residue is stirred in MeOH / ACN, filtered and dried. MS(ESI + ): m / z=315[M+H] + HPLC (Method A): Rt=1.07 min

[0061] Example 21: Synthesis of intermediate E1 [ka] Intermediate A10 (11.0 g; 57.24 mmol) and Pd / C (10%; 1.0 g) in DCM (200 mL) are hydrogenated in a Parr apparatus (rt; 50 psi; 5 h). Additional Pd / C (10%; 1.0 g) and MeOH (100 mL) are added, and the mixture is hydrogenated for 3 h. Formaldehyde (aqueous; 37%; 22.70 mL; 304.90 mmol) is added, and the mixture is stirred for 10 min without H2 pressure and for an additional 3 h under H2 pressure. The catalyst is removed by filtration, and the solvent is evaporated. The residue is dissolved in NaOH (aqueous; 1 M) and extracted with DCM. The organic layer is separated, dried, and evaporated. The residue is purified by MPLC (DCM / MeOH = 98 / 2). MS(ESI + ): m / z=191[M+H] + HPLC (Method P): Rt=0.25 min

[0062] Example 22: Synthesis of intermediates F1, F2 and F4 Intermediate F1: [ka] Step 1: Intermediate D19 (430 mg; 1.10 mmol), 1,4-diiodobutane (145 μL; 1.10 mmol), and potassium carbonate (303 mg; 2.19 mmol) in DMF (12 mL) are stirred at 70 °C for 2 h. After stirring overnight at room temperature, the mixture is diluted with NaHCO3 (9% aqueous solution) and extracted with EA. The organic layer is washed with brine, separated, and evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=447[M+H] + HPLC (Method A): Rt=1.57 min Step 2: Intermediate F1 Step 1 (203 mg; 0.46 mmol) and Pd / C (10%; 20 mg) in MeOH (20 mL) and THF (10 mL) are hydrogenated in a Parr apparatus (rt; 50 psi; 1 h). Additional Pd / C (10%) is added and the mixture is hydrogenated. The catalyst is removed by filtration and the solvent is evaporated. MS(ESI + ): m / z=313[M+H] + HPLC (Method A): Rt=1.33 min

[0063] The following intermediates were prepared in a similar manner to intermediate F1: [Table 26]

[0064] Example 23: Synthesis of Intermediates F3 and F5 Intermediate F3 [ka] Step 1: Intermediate D29 (0.78 g; 1.74 mmol), acetone (631 μL; 8.70 mmol), and glacial acetic acid (256 μL; 4.70 mmol) in MeOH (20 mL) are stirred at room temperature for 2 h. Sodium cyanoborohydride (219 mg; 3.48 mmol) is added, and the mixture is stirred at room temperature overnight. The mixture is diluted with NaHCO3 (aq; 9%) and extracted with DCM. The organic layer is separated, dried, and evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=491[M+H] + HPLC (Method A): Rt=1.49 min Step 2: Intermediate F3 Step 1 (348 mg; 0.71 mmol) and Pd / C (10%; 35 mg) in MeOH (14 mL) and THF (10 mL) are hydrogenated in a Parr apparatus (rt; 50 psi; 1.25 h). The catalyst is removed by filtration and the solvent is evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=357[M+H] + HPLC (Method A): Rt=1.19 min

[0065] The following intermediates were prepared in a similar manner to intermediate F3: [Table 27]

[0066] Example 24: Synthesis of intermediate G1 [ka] The following reactions are carried out under an argon atmosphere. Intermediate E1 (700 mg; 3.68 mmol) and carbon disulfide (0.24 mL; 4.05 mmol) in DMF (15 mL) are cooled in an ice bath. Sodium hydride (55% in mineral oil; 0.32 g; 7.36 mmol) is added and the mixture is stirred for 20 minutes. The mixture is allowed to warm to room temperature. After stirring at room temperature for 1 hour, the mixture is poured into ice water. The resulting precipitate is filtered off, washed with water, and dried. MS(ESI + ): m / z=295[M+H] + HPLC (Method H): Rt=1.05 min

[0067] Example 25: Synthesis of compounds 1001-1123 Compound 1001: [ka] Intermediate D1 (150 mg; 0.50 mmol), dihydrofuran-3-one (58 μL; 0.75 mmol), and glacial acetic acid (73 μL; 1.34 mmol) in MeOH (3 mL) are stirred at room temperature for 1 h. Sodium cyanoborohydride (63 mg; 1.00 mmol) is added, and the mixture is stirred at room temperature for 1 h. The mixture is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=372[M+H] + HPLC (Method A): Rt=1.11 min

[0068] Analogously to the preparation of compound 1001, the following compounds are obtained: [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4] [Table 28-5] [Table 28-6] [Table 28-7] [Table 28-8] [Table 28-9] [Table 28-10] [Table 28-11] [Table 28-12] [Table 28-13] [Table 28-14] [Table 28-15] [Table 28-16] [Table 28-17] [Table 28-18] [Table 28-19] [Table 28-20] [Table 28-21] [Table 28-22] [Table 28-23] [Table 28-24] [Table 28-25] [Table 28-26]

[0069] example 26: Synthesis of compounds 1124-1147 Compound 1124: [ka] Compound 1173 (70 mg; 0.22 mmol), 2-iodo-2-(-2-iodo-ethoxy)-ethane (32 μL; 0.22 mmol), and potassium carbonate (61 mg; 0.44 mmol) in DMF (3 mL) are stirred at 70 °C for 2 h. Additional 2-iodo-2-(2-ethoxy)-ethane (0.22 mmol) and potassium carbonate (0.44 mmol) are added. The mixture is stirred at 70 °C for 1.5 h and then at room temperature for 3 days. The mixture is diluted with NaHCO3 (9% aqueous solution) and extracted with EA. The organic layer is washed with brine, separated, and evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=386[M+H] + HPLC (Method A): Rt=1.19 min

[0070] The following compounds are obtained analogously to the preparation method of Example 1124: [Table 29-1] [Table 29-2] [Table 29-3] [Table 29-4] [Table 29-5] [Table 29-6]

[0071] Example 27: Synthesis of compounds 1148-1151 Compound 1148: [ka] Intermediate E1 (200 mg; 1.05 mmol) and 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (134 mg; 1.05 mmol) are stirred in a microwave oven for 20 min at 170 °C. The residue is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=286[M+H] + HPLC (Method H): Rt=1.05 min

[0072] The following compounds are obtained analogously to the preparation method of Example 27: [Table 30]

[0073] Example 28: Synthesis of compounds 1152-1163 Compound 1152: [ka] Intermediate F1 (30 mg; 0.10 mmol), 3-(2H)-furanone dihydrochloride (9 μL; 0.12 mmol), and glacial acetic acid (13 μL; 0.24 mmol) in MeOH (2 mL) are stirred at 50 °C for 1 h. Sodium cyanoborohydride (12 mg; 0.19 mmol) is added and the mixture is stirred at room temperature overnight. The mixture is diluted with NaHCO3 (9% aqueous solution) and extracted with DCM. The organic layer is separated, dried, and evaporated. The residue is purified by preparative HPLC (free solution A: water with 0.1% ammonia, free solution B: MeOH). MS(ESI + ): m / z=383[M+H] + HPLC (Method A): Rt=1.42 min

[0074] The following compounds are obtained analogously to the preparation method of Example 1152: [Table 31-1] [Table 31-2] [Table 31-3]

[0075] Example 29: Synthesis of Compound 1164 [ka] Intermediate F4 (100 mg; 0.26 mmol), acetic anhydride (37 μL; 0.39 mmol), and DIPEA (134 μL; 0.78 mmol) in DCM (3 mL) are stirred at room temperature for 1 h. The mixture is diluted with NaHCO3 (9% aqueous solution) and extracted with DCM. The organic layer is separated, dried, and evaporated. The residue is dissolved in MeOH, and the precipitate is filtered off. The residue is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=425[M+H] + HPLC (Method B): Rt=0.84 min

[0076] Example 30: Synthesis of compounds 1165-1166 Compound 1165: [ka] Intermediate F5 (30 mg; 0.10 mmol), acetyl chloride (6 μL; 0.09 mmol) and TEA (20 μL; 0.14 mmol) in THF (3 mL) are stirred at room temperature for 10 min. Additional acetyl chloride is added. The mixture is diluted with water and extracted with DCM. The organic layer is separated, dried and evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.1% TFA, eluent B: MeOH). MS(ESI + ): m / z=357[M+H] + HPLC (Method D): Rt=0.62 min

[0077] The following compounds are obtained in a similar manner to the preparation of compound 1165: [Table 32]

[0078] Example 31: Synthesis of compounds 1167-1168 Compound 1167: [ka] Intermediate G1 (90 mg; 0.31 mmol) and N1-phenylethane-1,2-diamine (42 mg; 0.31 mmol) in n-butanol (2 mL) are stirred in a microwave oven for 15 min at 220 °C. The solvent is evaporated and the residue is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=335[M+H] + HPLC (Method H): Rt=1.02 min

[0079] The following compounds are obtained in a similar manner to the preparation of compound 1167: [Table 33]

[0080] Example 32: Synthesis of compounds 1169-1171 Compound 1169: [ka] Intermediate C35 (100 mg; 0.26 mmol), formaldehyde (aqueous; 37%; 0.19 mL; 2.58 mmol) and Raney-Nickel (50 mg) in MeOH (10 mL) are hydrogenated in a Parr apparatus (rt; 1.1 bar; 8 h). The catalyst is removed by filtration and the solvent is evaporated. The residue is stirred in MeOH, filtered and dried. MS(ESI +): m / z=328[M+H] + HPLC (method?): Rt=0.72 min

[0081] The following compounds are obtained in a similar manner to the preparation of compound 1169: [Table 34]

[0082] Example 33 Synthesis of compounds 1172-1174 Compound 1172: [ka] Intermediate C35 (200 mg; 0.52 mmol) and Raney-Nickel (50 mg) in MeOH (10 mL) are hydrogenated in a Parr apparatus (rt; 1.1 bar; 8 h). The catalyst is removed by filtration and the solvent is evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=300[M+H] + HPLC (Method L): Rt=0.63 min

[0083] The following compounds are obtained in a similar manner to the preparation of compound 1172: [Table 35]

[0084] Example 34 Synthesis of Compound 1175 [ka] Intermediate C35 (200 mg; 0.52 mmol) and Raney-Nickel (50 mg) in MeOH (10 mL) are hydrogenated in a Parr apparatus (rt; 1.1 bar; 8 h). The catalyst is removed by filtration and the solvent is evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.1% ammonia, eluent B: MeOH). MS(ESI + ): m / z=314[M+H] + HPLC (Method M): Rt=1.12 min

[0085] Example 35 Synthesis of Compound 1176 [ka] Intermediate C4 (1.78 g; 5.90 mmol) and iron powder (1.78 g; 31.87 mmol) are stirred in water (56.5 mL) and ethanol (116 mL) at 80 °C. Glacial acetic acid (3.58 mL; 62.55 mmol) is added dropwise and the mixture is stirred at 80 °C for 1 h. The organic solvent is evaporated, the aqueous layer is alkalized with NaOH (7 mL) and extracted with DCM. The iron is removed by filtration through Celite. The organic layer is separated, dried and evaporated. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=273[M+H] + HPLC (Method A): Rt=1.16 min

[0086] Example 36 :Synthesis of Compound 1177 [ka] Intermediate D1 (150 mg; 0.50 mmol), bromocyclobutane (101 mg; 0.75 mmol), and potassium carbonate (138 mg; 1.00 mmol) in DMF (3 mL) are stirred at 70 °C for 4 h. Additional bromocyclobutane (101 mg; 0.75 mmol) is added, and the mixture is stirred at 80 °C overnight. Additional bromocyclobutane (101 mg; 0.75 mmol) is added. After stirring at 90 °C for 4 h, the mixture is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=356[M+H] + HPLC (Method B): Rt=0.89 min

[0087] Example 37: Synthesis of compound 1178 [ka] In MeOH (5 mL), Example 146 (65 mg; 0.15 mmol) and Pd / C (10%; 10 mg) are hydrogenated in a Parr apparatus (rt; 50 psi; 1 h). The catalyst is filtered off and the solvent is removed. The residue is purified by preparative HPLC (eluent A: water with 0.15% ammonia, eluent B: MeOH). MS(ESI + ): m / z=313[M+H] + HPLC (Method A): Rt=1.34 min

[0088] Example 38: Biological Assay The biological activity of the compounds is assessed by the following methods:

[0089] Assay A: Assessment of Complex I-mediated ROS inhibition rate (CI) Enzyme kinetic experiments can detect ROS generated via complex I. Herein, complex I was purified from bovine heart (Sharpley et al. 2006 Biochemistry.45(1):241-8.) First, intracellular fractionation was performed to obtain a crude mitochondrial fraction, followed by hypotonic lysis and differential centrifugation to obtain mitochondrial membranes. Solubilization of the mitochondrial membranes was followed by ion exchange and size exclusion chromatography to obtain enzyme preparations containing complex I but largely free of complex IV. These preparations were used to assess ROS generation in the presence of complex I, the substrate NADH (1 μM), and atmospheric oxygen. Generated ROS was detected via the oxidation of amplex red in a coupled reaction involving amplex red and horseradish peroxidase. The IC50 of the compounds of the invention was calculated by testing the compounds using an eight-point concentration-response experiment.

[0090] In a 384-well microtiter plate, 5 μL of test compound (final concentrations ranging from 0.01 nM to 30 μM, final dilution in assay buffer and 1% DMSO) or control was mixed with 5 μL of substrate mixture (3 μM NADH, 10 μM Amplex Red, 1 mM fructose 1,6-bisphosphate, and 1 mM AsO). The enzymatic reaction was initiated by adding 15 μL of enzyme mixture (20 μg / ml complex I, 2 U / ml horseradish peroxidase, 1 U / ml aldolase, 1 U / ml triose isomerase, and 1 U / ml glyceraldehyde-3-phosphate dehydrogenase). ROS generation was assessed by measuring the increase in absorbance at 557 nm every 53 seconds for 12 minutes at room temperature, followed by linear regression (slope analysis). To assess compound potency, IC50 values ​​were calculated as 50% activity of complex I by nonlinear regression curve fitting using a four-parameter sigmoidal dose-response model.

[0091] Assay B : Evaluation of cell protection (HT22) To demonstrate the involvement of selective pathways in cellular contexts, mouse neuroblastoma (HT-22) cells were depleted of the endogenous antioxidant glutathione, resulting in oxidative stress and cell death at the mitochondrial and cellular levels (Tan S, Sagara Y, Liu Y, Maher P, Schubert D. The regulation of reactive oxygen species production during programmed cell death. J Cell Biol. 1998; 141: 1423-1432.). By culturing these cells with a high concentration of glutamate (5 mM), intracellular glutathione was depleted by inhibiting cystine uptake, leading to the accumulation of mitochondrially derived ROS and ultimately to cell death. 2000HT-22 cells were seeded in 50 μl of cell culture medium (DMEM containing 10% calf serum and 1% penicillin / streptomycin) in a 384-well plate and cultured for 24 hours. Subsequently, they were incubated with glutamate (to induce cell death) or vehicle (100% viable cells) in the presence of test compounds (final concentrations of 0.01-30 μM) for 16 hours. Cell viability was calculated by measuring fluorescence (excitation wavelength 530 nm, emission wavelength 590 nm) after incubation at 37°C for 1 hour with 10% Alamar Blue reagent.

[0092] To assess compound potency, EC50 values ​​were calculated by non-linear regression curve fitting using a four-parameter sigmoidal dose-response model (see Complex I assay).

Claims

1. A compound having the formula (I) or a salt thereof: 【Chemistry 1】 (In the formula, R1 is unsubstituted or MeO-substituted C 1-4 - alkyl; tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, dioxepanyl or piperidinyl; or pyrrolidinyl or piperidinyl substituted on the nitrogen by methyl, isopropyl, oxetanyl, ethoxycarbonyl, acetyl, or trifluoroacetyl; R2 is an unsubstituted or substituted 5-, 6-, or 7-membered ring having 1 or 2 heteroatoms selected from O or N, or an unsubstituted or substituted spirocyclic heterocyclyl group having 8 to 11 ring atoms and 2 to 3 heteroatoms selected from N or O; The ring or spirocyclic heterocyclyl group is attached in formula (I) by a C═C double bond, and In said ring or spirocyclic heterocyclyl group, one N atom may be substituted by methyl, isopropyl, acetyl, benzyloxycarbonyl, phenyl, oxetanyl or tetrahydropyranyl, and one or more C-atoms may be substituted by methyl or OH, R3 or R4 are each independently Hydrogen; unsubstituted or multiple F, methoxy, unsubstituted C 3-5 Cycloalkyl-substituted C 1-6 alkyl; or heterocyclyl selected from the group consisting of oxetanyl and tetrahydropyranyl, wherein the heterocyclyl is unsubstituted; or R3 and R4 together with the N to which they are attached are unsubstituted or C 1 The alkyl or hydroxyl forms a heterocyclyl ring selected from the group consisting of substituted morpholinyl and pyrrolidinyl.

2. R1 is unsubstituted or substituted with a MeO group 【Chemistry 2】 Unsubstituted or nitrogen 【Transformation 3】 has been replaced 【Chemistry 4】 2. The compound according to claim 1, or a salt thereof,

3. R1 is, 【Transformation 5】 【change】 【change】 2. The compound according to claim 1, or a salt thereof,

4. The compound or salt thereof according to claim 2, wherein R1 is a tetrahydropyranyl group or a dioxepanyl group.

5. The compound or salt thereof according to claim 1, wherein R2 is a 5-, 6-, or 7-membered ring bonded to the C=C double bond in formula (I), containing one or two heteroatoms selected from O or N, one or both N atoms being optionally substituted with methyl, isopropyl, acetyl, benzyloxycarbonyl, phenyl, oxetanyl, or tetrahydropyranyl, and one or more C atoms being optionally substituted with methyl or OH.

6. Structural Elements 【Transformation 6】 but, 【Chemistry 7-1】 【change】 【change】 【Chemistry 7-2】 【change】 【change】 【change】 【Transformation 7-3】 【change】 2. The compound according to claim 1, or a salt thereof,

7. In formula (I), the amino group including R3 and R4 is 【Chemistry 8-1】 【change】 【Chemistry 8-2】 【change】 【change】 【change】 【change】 【change】 2. The compound according to claim 1, or a salt thereof,

8. 2. The compound or salt thereof according to claim 1, wherein in the amino group containing R3 and R4 in formula (I), R3 is hydrogen and R4 is unsubstituted isopropyl, cyclobutyl or cyclopentyl.

9. In formula (I), the amino group including R3 and R4 is unsubstituted 【Chemistry 9】 2. The compound according to claim 1, or a salt thereof,

10. A salt of the compound according to any one of claims 1 to 9.

11. The compound or salt thereof according to claim 1, wherein formula (I) is any one of the formulae of compounds 1 to 175 and 1001 to 1178 shown below. 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] 【Transformation 10-5】 【Chemistry 10-6】 【Chemistry 10-7】 [Transformation 10-8] 【Chemistry 10-9】 【Chemistry 10-10】 【Chemistry 10-11】 [Chemistry 10-12] [Chemistry 10-13] [Chemistry 10-14] [Chemistry 10-15] [Chemistry 10-16] 【Chemistry 10-17】 [Chemistry 10-18] [Chemistry 10-19] [Chemistry 10-20] 【Chemistry 10-21】 [Chemistry 10-22] [Chemistry 10-23] [Chemistry 10-24] [Chemistry 10-25] [Chemistry 10-26] [Chemistry 10-27] [Chemistry 10-28] [Chemistry 10-29] [Chemistry 10-30] 【Chemistry 10-31】 【Chemistry 10-32】 【Chemistry 10-33】 【Chemistry 10-34】 [Chemistry 10-35] 【Chemistry 10-36】 【Chemistry 10-37】 [Chemistry 10-38] [Chemistry 10-39] [Chemistry 10-40] 【Chemistry 10-41】 【Chemistry 10-42】 [Chemistry 10-43] [Chemistry 10-44] [Chemistry 10-45] [Chemistry 10-46] [Chemistry 10-47] [Chemistry 10-48] [Chemistry 10-49] [Chemistry 10-50] 【Chemistry 10-51】 【Chemistry 10-52】 【Chemistry 10-53】 [Chemistry 10-54] 【Chemistry 10-55】 [Chemistry 10-56] 【Chemistry 10-57】 [Chemistry 10-58] [Chemistry 10-59] [Chemistry 10-60] 【Chemistry 10-61】 【Chemistry 10-62】 【Chemistry 10-63】 [Chemistry 10-64] 【Chemistry 10-65】 【Chemistry 10-66】 【Chemistry 10-67】 【Chemistry 10-68】 [Chemistry 10-69] [Chemistry 10-70] 【Chemistry 10-71】 【Chemistry 10-72】 【Chemistry 10-73】 [Chemistry 10-74] 【Chemistry 10-75】 【Chemistry 10-76】 【Chemistry 10-77】 【Chemistry 10-78】 【Chemistry 10-79】 [Chemistry 10-80] 【Chemistry 10-81】 【Chemistry 10-82】 【Chemistry 10-83】 [Chemistry 10-84] 【Chemistry 10-85】 【Chemistry 10-86】 【Chemistry 10-87】 【Chemistry 10-88】 [Chemistry 10-89] [Chemistry 10-90] 【Chemistry 10-91】 【Chemistry 10-92】 【Chemistry 10-93】 【Chemistry 10-94】 【Chemistry 10-95】 【Chemistry 10-96】 【Chemistry 10-97】 【Chemistry 10-98】 【Chemistry 10-99】 [Chemistry 10-100] 【Chemistry 10-101】 【Chemistry 10-102】 【Chemistry 10-103】 【Chemistry 10-104】 【Chemistry 10-105】 【Chemistry 10-106】 【Chemistry 10-107】 【Chemistry 10-108】 【Chemistry 10-109】 【Chemistry 10-110】 【Chemistry 10-111】 【Chemistry 10-112】 【Chemistry 10-113】

12. A medicament prepared using the compound or salt thereof according to any one of claims 1 to 11.

13. 12. A pharmaceutical composition for the treatment or prevention of a neurological or neurodegenerative or psychiatric condition in humans, comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. 14. The pharmaceutical composition of claim 13, comprising a therapeutically effective amount of 0.1 to 2000 mg of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

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