Methods for treating new cases of ergolin and mood disorders

Abstract

This disclosure provides ergoline compounds and their use in the treatment of mood disorders. Pharmaceutical compositions and methods for preparing various ergoline compounds are provided.

Description

[Technical Field]

[0001] This disclosure relates to ergoline compounds that can be reliably used for the treatment of mood disorders. [Background technology]

[0002] Ergoline is a diverse class of alkaloids containing a structural scaffold of the natural alkaloid ergoline.

[0003] [ka]

[0004] A considerable number of ergoline compounds exist, including naturally occurring compounds as well as synthetic and semi-synthetic chemical derivatives with similar structures. Ergoline compounds are known to have diverse psychoactive and physiological effects. Some ergoline compounds are found in serotonin 2a(5-HT). 2A Ergolines are receptor agonists and / or modulators of other serotonin receptors, and are known to be psychoactive and / or induce vasoconstriction. In some cases, such compounds induce long-lasting hallucinations. Other ergolines are dopamine receptor agonists. Perhaps the most well-known ergoline is the hallucinogenic compound lysergic acid diethylamide (LSD). This compound is known to have significant effects on thought, cognition, and behavior. However, it is currently classified as a Schedule I drug under the Controlled Substances Act due to its high potential for abuse, lack of medical use, and lack of established safety. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009 [Non-Patent Document 2] Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000 [Non-Patent Document 3] Fehr, T., Stadler, PA, Hofmann, A. Helvetica Chimica Acta, 1970, 53(8), pp. 2197~2201 [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, there is still a need for safe and effective ergoline compounds that can be reliably used to treat mood disorders. [Means for solving the problem]

[0007] This disclosure relates to compounds of formula (I):

[0008] [ka]

[0009] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 This includes [as defined herein] or a pharmaceutically acceptable salt thereof.

[0010] Furthermore, the present disclosure includes a method for treating a mood disorder, comprising the step of administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof. [Brief explanation of the drawing]

[0011] [Figure 1] This shows the effect of compound 1 in a mouse head unicontraction response (HTR) assay, quantified by the number of head unicontractions recorded during a 20-minute observation period. Data points represent the mean ± SEM. [Figure 2] This represents the immobility time in a forced swimming test in rats 23.5 hours after administration of compound 1. Data points represent the mean ± SEM. Comparison with vehicle: **p<0.01, ****p<0.0001. [Figure 3] This represents the total number of glass marbles obscured during a 30-minute observation period in a mouse glass marble obscuration test. Data points represent the mean ± SEM. Comparison with vehicle: *p<0.05, ****p<0.0001. [Figure 4] The effects of LSD, control, and representative compounds of this disclosure in a mouse head single contraction response (HTR) assay, quantified by the number of head single contractions recorded during a 20-minute observation period using an automated video tracking procedure, are shown. [Modes for carrying out the invention]

[0012] Features and other details of this disclosure are described more specifically here. Before further description of this disclosure, certain terms used in this specification, examples and appended claims are collected here. These definitions should be read in the context of the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0013] definition "To treat" includes any action that results in improvement of a condition, disease, disorder, etc., such as mitigating, reducing, modulating, or eliminating.

[0014] As used herein, the term "alkyl" refers to saturated linear or branched hydrocarbons having the number of carbon atoms specified herein, for example, 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, linear or branched hydrocarbons having 1 to 6, 1 to 4, or 1 to 3 carbon atoms, which are referred to herein as C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[0015] As used herein, the term "alkenyl" refers to a branched or unbranched hydrocarbon group having a specified number of carbon atoms and containing at least one double bond as defined herein, for example, having 2 to 6 carbon atoms and 1 to 3 carbon-carbon double bonds. In some embodiments, alkenyl refers to a branched or unbranched saturated hydrocarbon group having 3 carbon atoms (C3). In some embodiments, alkenyl refers to a branched or unbranched hydrocarbon group having 6 carbon atoms (C6). In some embodiments, the term "alkenyl" includes, but is not limited to, vinyl or allyl.

[0016] As used herein, the term "alkynyl" refers to a branched or unbranched hydrocarbon group having a specified number of carbon atoms and containing at least one triple bond as described below herein, for example, having 2 to 6 carbon atoms and 1 to 3 carbon-carbon triple bonds. In some embodiments, alkynyl refers to a branched or unbranched saturated hydrocarbon group having 3 carbon atoms (C3). In some embodiments, alkynyl refers to a branched or unbranched hydrocarbon group having 6 carbon atoms (C6). In some embodiments, the term "alkynyl" includes, but is not limited to, ethynyl or propargyl.

[0017] As used herein, the term "cyano" refers to the -CN group.

[0018] The terms “cycloalkyl,” “carbocyclic group,” or “carbocyclyl” are synonymous and, as used herein, refer to saturated or partially unsaturated hydrocarbon groups of, for example, 3-6 or 4-6 carbon atoms, which are referred herein as C3-C6 cycloalkyl or C4-C6 cycloalkyl, respectively. Exemplary cycloalkyl groups, but not limited to these, include cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0019] The terms "halo" or "halogen" as used herein refer to F, Cl, Br, or I.

[0020] The term “aryl,” used alone or as part of a larger term, such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic and bicyclic systems having a total of 5 to 14 membered rings, where at least one ring in the system is aromatic, and each ring in the system contains a 3 to 7 membered ring. The term “aryl” can be used interchangeably with the term “aryl ring.” In certain embodiments of this disclosure, “aryl” refers to an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthrasyl, etc., and may have one or more substituents. Also included in the scope of the term “aryl” are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl, as used herein.

[0021] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger term such as "heteroaralkyl" or "heteroaralkoxy", refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 π electrons shared in the cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Examples of heteroaryl groups, without limitation, include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-” also, as used herein, include groups in which an aromatic heterocycle is fused to one or more aryl, cyclic aliphatic, or heterocyclyl rings, wherein the group or bond is located on the aromatic heterocycle. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which may include a ring that is optionally substituted. The term "heteroaralkyl" refers to an alkyl group that is substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are optionally substituted independently.

[0022] The terms “heterocyclyl” or “heterocyclic group” are accepted in the art and refer to a saturated or partially unsaturated, 4- to 10-membered ring structure comprising a bridged or fused ring, wherein the ring structure contains 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring may be bonded to adjacent groups via carbon or nitrogen. Examples of heterocyclyl groups, but not limited to, include pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, or dihydrofuran.

[0023] As used herein, the terms "hydroxy" and "hydroxyl" refer to the -OH group.

[0024] As used herein, the term "linear C2-C6 alkyl" has the same meaning as "linear C2-C6 alkyl".

[0025] "Pharmacologically or pharmacologically acceptable" includes molecular entities and compositions that, when administered to animals or humans as needed, do not cause harmful, allergic, or other adverse reactions. For administration to humans, preparations should meet the sterility, pyrogenicity, overall safety, and purity standards required by the FDA Office of Biologies standards.

[0026] The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient,” as used herein, refer to any and all solvents, dispersions, coatings, isotonic agents, and absorption retarders, etc., that are suitable for the administration of a pharmacopoeia. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide auxiliary, additional, or enhanced therapeutic functions.

[0027] When used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein, which is formulated together with one or more pharmaceutically acceptable carriers.

[0028] "Individual," "patient," or "subject" is used interchangeably and includes any animal, preferably a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cattle, sheep, horse, or primate, and most preferably a human. The compounds of this disclosure can be administered to mammals, e.g., humans, but can also be administered to other mammals, e.g., animals requiring veterinary treatment, e.g., domestic animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Mammals treated by the methods of this disclosure are preferably mammals for which treatment of mental illness or disorder is desired. "Modulation" includes antagonistism (e.g., inhibition), agonism, partial antagonistism, and / or partial agonism.

[0029] In this specification, the term “therapeutic dose” means the amount of a compound of interest that elicits a biological or medical response in a tissue, system, or animal (e.g., mammal or human) being explored by researchers, veterinarians, medical doctors, or other clinicians. The compounds of this disclosure are administered in therapeutic doses to treat a disease. Instead, the therapeutic dose of a compound is the amount required to achieve the desired therapeutic and / or prophylactic effect, for example, the amount that results in a reduction of symptoms of a mental disorder. As used herein, the term “prophylactic effect” means preventing the worsening of a condition, disease, disorder, etc.

[0030] The term "pharmaceutically acceptable salt," as used herein, refers to a salt of an acidic or basic group that may be present in a compound used in a composition. Compounds included in the compositions of the present invention that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, which include, but are not limited to, salts of malic acid, oxalic acid, chloride, bromide, iodide, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, superphosphate, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid (i.e., salts of 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds contained in the compositions of the present invention, which are acidic in nature, can form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly salts of calcium, magnesium, sodium, lithium, zinc, potassium, and iron. Compounds contained in the compositions of the present invention, which include basic or acidic moieties, can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may also contain both acidic and basic groups, for example, one amino acid and one carboxylic acid group. In such cases, the compound can exist as an acid addition salt, an amphoteric ion, or a base salt. In some embodiments, the term “pharmaceutically acceptable salt” as used herein refers to hemi-tartrate. As used herein, the hemi-tartrate of the compound of formula (I) is a salt with a molar ratio of 2:1 to tartaric acid of the compound of formula (I). In some embodiments, the term “pharmaceutically acceptable salt” as used herein refers to tartrate. As used herein, the tartrate of the compound of formula (I) is a salt with a molar ratio of 1:1 to tartaric acid of the compound of formula (I).

[0031] The compounds of the present disclosure contain one or more chiral centers and can therefore exist as stereoisomers. As used herein, the term "stereoisomers" consists of all enantiomers or diastereomers. These compounds can also be designated by the symbols "(+)", "(-)", "R", or "S" according to the configuration of the substituents around the stereogenic carbon atoms, and those skilled in the art recognize that the structure can implicitly represent a chiral center. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. A mixture of enantiomers or diastereomers can be designated as "(±)" in the nomenclature, and those skilled in the art recognize that the structure can implicitly represent a chiral center.

[0032] The compounds of the present disclosure contain one or more double bonds and can therefore exist as geometric isomers generated from the arrangement of the substituents around the carbon-carbon double bond. The symbol

[0033]

Chemical formula

[0034] represents a bond that may be a single bond, double bond, or triple bond as described herein. The substituents around the carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used according to the IUPAC standards. Unless otherwise specified, a structure representing a double bond encompasses both the "E" and "Z" isomers. The substituents around the carbon-carbon double bond can also be called "cis" or "trans" instead, where "cis" means substituents on the same side of the double bond and "trans" means substituents on the opposite side of the double bond.

[0035] The compounds of this disclosure contain a carbocyclic or heterocyclic ring and can therefore exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents around a carbocyclic or heterocyclic ring can also be referred to as "cis" or "trans," where "cis" refers to substituents on the same side of the ring face and "trans" refers to substituents on the opposite side of the ring face. A mixture of compounds in which substituents are located on both the same side and the opposite side of the ring face is designated "cis / trans."

[0036] The individual enantiomers and diastereomers of the compounds of this disclosure can be prepared by synthesis from commercially available starting materials containing asymmetric or stereocenters, or by preparation of racemic mixtures, followed by separation methods well known to those skilled in the art. These separation methods are exemplified by: (1) separation of the mixture of diastereomers by attachment of the enantiomer mixture to chiral auxiliary groups, recrystallization, or chromatography, and liberation of the optically pure product from the auxiliary; (2) formation of salts using optically active decomposers; (3) direct separation of the mixture of optical enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. The racemic mixture can also be separated into its component enantiomers by well known methods, e.g., chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, chemical, or enzymatic reactions in which a single reactant forms an heterogeneous mixture of stereoisomers during the formation of a new stereocenter or the transformation of a pre-existing one are well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0037] The compounds disclosed herein can exist in solvated and non-solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and this disclosure is intended to encompass both solvated and non-solvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in crystalline form.

[0038] This disclosure also encompasses isotopically labeled compounds of the disclosure that are identical to those listed herein, except that one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. For example, one or more H atoms of the compounds of the disclosure may be replaced by deuterium.

[0039] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C labeled ones) are useful in compound and / or substrate tissue distribution assays. Tritium-labeled (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to the ease of their preparation and detectability. Further, heavier isotopes such as deuterium (i.e., 2Substitution with H) can result in certain therapeutic benefits (e.g., increased in vivo half-life or reduced dose required) arising from greater metabolic stability, and may therefore be preferable in some situations. The isotope-labeled compounds of this disclosure can generally be prepared by following procedures similar to those disclosed in the examples herein, by using isotope-labeled reagents instead of non-isotope-labeled reagents.

[0040] I. Compound In some embodiments, this disclosure relates to a compound of formula (I):

[0041] [ka]

[0042] [In the formula, R 1 R is a C1-C6 alkyl or 3-7 membered carbocyclyl, 1 It is optionally substituted with one or more halogens or C1-C6 alkyl groups. R 2 is hydrogen or C1-C6 alkyl, R 2 is substituted with one or more halogens or C1-C6 alkyls, or R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocyclines are optionally substituted with one or more fluoro or C1-C6 alkyl groups. R 3 R is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3-7 membered cycloalkyl groups. 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R3 R is selected from the group consisting of -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl, 3 The C1-C4 alkyl groups in the -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl compounds are optionally substituted with one or more fluoro, hydroxyl, or -OMe groups, and R 3 The aryl and heteroaryl in -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl are, independently, halogens, -OR 7 ,-OC(O)R 7 -CN, -NO2, -NR 7 R 8 , -CO2R 7 -C(O)NR 7 R 8 , C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and R 9 The molecule is optionally substituted with one or more substituents selected from the group consisting of the following, and each C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl molecule is optionally substituted with one or more fluoro, hydroxyl, or OMe groups. Each R 7 and R 8 These are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and R 10 Selected from the group consisting of the following, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl are optionally substituted with one or more fluoro, hydroxyl, or OMe. Each R 9 and R 10Each is an aryl or heteroaryl molecule that is optionally substituted with one or more substituents independently selected from the group consisting of halogens, -OH, -OC(O)(C1-C4 alkyl), -O(C1-C4 alkyl), -CN, -NO2, -NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl molecules are optionally substituted with one or more fluoro, hydroxyl, or OMe molecules. R 4 is hydrogen or -C(O)(C1~C8 alkyl), R 5 These are hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogens. R 6 [It is hydrogen or deuterium.] Or provide a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the compound of formula (I) above does not include the following: R 1 and R 2 Both are ethyl, and R 4 and R 5 If both are hydrogen, then R 3 It is not an unsubstituted linear C2-C6 alkyl, isopropyl, -CH2CH=CH2, -CH2CH2F, or -CH2CH2Ph. R 1 and R 2 Both are ethyl, and R 4 is -C(O)(C2 alkyl), and R 5 If R is hydrogen, 3 It is not unsubstituted ethyl. R 1 is ethyl, and R 2 If H, then R 3 It is not unsubstituted ethyl, unsubstituted n-propyl, or -CH2CH=CH2.

[0044] In the definitions herein, unless otherwise indicated, the phrase "and each C1-C8 and C1-C4 alkyl, C2-C8 and C2-C4 alkenyl, C2-C8 and C2-C4 alkynyl, and C3-C8 and C3-C5 cycloalkyl are optionally substituted with one or more fluoro, hydroxyl, or -OMe" in various embodiments means each C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl substituent in R3, and the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl substituents in R7 and R8, and R 9 and R 10 This refers to C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl groups, and includes R 9 and R 10 This also includes cases where the -OC(O)(C1~C4 alkyl) or -O(C1~C4 alkyl) is optionally substituted with one or more fluoro, hydroxyl, or OMe groups.

[0045] In the definitions herein, unless otherwise indicated, the terms "C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl" refer to C1-C4 alkyl, and -OC(O)(C1-C4 alkyl) C1-C4 alkyl, -O(C1-C4 alkyl), C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl which are optionally substituted with one or more fluoro, hydroxyl, or OMe R 9 and R 10 This refers to the definition.

[0046] In one embodiment, R 3 R is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3-7 membered cycloalkyl groups. 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe.

[0047] In another embodiment, R 3 is selected from the group consisting of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl, and the C1-C4 alkyl of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl is optionally substituted with one or more fluoros, hydroxyls, and -OMe, and the aryl and heteroaryl of aryl and heteroaryl-(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl are each independently halogen, -OR 7 , -OC(O)R 7 , -CN, -NO2, -NR 7 R 8 , -CO2R 7 , -C(O)NR 7 R 8 , C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and one or more substituents selected from the group consisting of R 9 are optionally substituted, and each R 7 and R 8 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and R 10 and each R 9 and R 10 are independently an aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -OC(O)(C1-C4 alkyl), -O(C1-C4 alkyl), -CN, -NO2, -NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl.

[0048] In one embodiment, the present disclosure provides a compound of formula I [wherein, R 1 is C1-C6 alkyl or 3-7 membered carbocyclic, R 1 is one or more fluoros or C1-C6 alkyl, optionally substituted, R2 is hydrogen or C1-C6 alkyl, R 2 is one or more fluoro or C1-C6 alkyl, optionally substituted, or R 1 and R 2 together with the atom to which they are attached can form an optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and the heterocyclyl is optionally substituted with one or more fluoro or C1-C6 alkyl, R 3 is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3- to 7-membered cycloalkyl, R 3 is each independently optionally substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R 3 is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), and the C1-C2 alkyl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluoro, hydroxyl, and -OMe, and the phenyl and 6-membered heteroaryl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C4 alkyl, C3-C5 cycloalkyl, and C1-C4 alkoxy, R 4 is hydrogen or -C(O)(C1-C8 alkyl), R 5 is hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogen, R 6 is hydrogen or deuterium].

[0049] In one embodiment, R 1 R is a C1-C6 alkyl or 3-5 membered carbocyclyl, 1 It is optionally substituted with one or more fluoro or C1-C4 alkyl groups. R 2 is hydrogen or C1-C3 alkyl, R 2 is optionally substituted with one or more fluoro or C1-C4 alkyl groups, or R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-6 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocyclines are optionally substituted with one or more fluoro or C1-C3 alkyl groups. R 3 R is selected from the group consisting of C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl), and 3-5 membered cycloalkyl. 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R 3 The molecule is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), where the C1-C2 alkyl is optionally substituted with one or more fluoropolymers, and the phenyl and 6-membered heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl, and C1-C3 alkoxy. R 4 is hydrogen or -C(O)(C1~C8 alkyl), R 5 These are hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogens. R6 It is hydrogen or deuterium.

[0050] In one embodiment, R 1 R is a C1-C6 alkyl or 3-5 membered carbocyclyl, 1 It is optionally substituted with one or more fluoro or C1-C4 alkyl groups. R 2 is hydrogen or C1-C3 alkyl, R 2 is optionally substituted with one or more fluoro or C1-C4 alkyl groups, or R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-6 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocyclines are optionally substituted with one or more fluoro or C1-C3 alkyl groups. R 3 R is selected from the group consisting of C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl), and 3-5 membered cycloalkyl. 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R 3 The compounds are selected from the group consisting of -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl), where the C1~C2 alkyl in (C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluoropolymers, and the phenyl and 6-membered heteroaryl in (C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl) are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1~C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1~C3 alkyl, cyclopropyl, and C1~C3 alkoxy. R4 is hydrogen or -C(O)(C1~C8 alkyl), R 5 These are hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogens. R 6 It is hydrogen or deuterium.

[0051] In one embodiment, in a compound of formula I, R 4 It is hydrogen.

[0052] In another embodiment, R 5 is hydrogen. In further embodiments, R 5 is Me, Et, -CH2F, CHF2, -CF3, or a halogen. In further embodiments, R 5 In further embodiments, R 6 is hydrogen. In another embodiment, R 4 , R 5 and R 6 Each of these is hydrogen.

[0053] In one embodiment, R 4 , R 5 , and R 6 Each of these is hydrogen. In another embodiment, R 4 and R 6 Each of them is hydrogen, and R 5 is Me, Et, -CH2F, -CHF2, -CF3, or a halogen. In further embodiments, R 5 It is Bromo.

[0054] In some embodiments, this disclosure relates to the compound of formula (II).

[0055] [ka]

[0056] [In the formula, R 1 R is a C1-C6 alkyl or 3-7 membered carbocyclyl, 1It is optionally substituted with one or more halogens or C1-C6 alkyl groups. R 2 is hydrogen or C1-C6 alkyl, R 2 is optionally substituted with one or more halogens or C1-C6 alkyl groups, or R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocyclines are optionally substituted with one or more fluoro or C1-C6 alkyl groups. R 4 is hydrogen or -C(O)(C1~C8 alkyl), R 5 is Me, Et, -CH2F, -CHF2, -CF3, or a halogen. R 6 This describes hydrogen or deuterium, or pharmaceutically acceptable salts.

[0057] In another embodiment, the present disclosure relates to a compound of formula II [wherein, R 1 R is a C1-C6 alkyl or 3-7 membered carbocyclyl, 1 It is optionally substituted with one or more halogens or C1-C6 alkyl groups. R 2 is hydrogen or C1-C6 alkyl, R 2 is optionally substituted with one or more halogens or C1-C6 alkyl groups, or R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocyclines are optionally substituted with one or more fluoro or C1-C6 alkyl groups. R 4is hydrogen or -C(O)(C1~C8 alkyl), R 5 is Me, Et, -CH2F, -CHF2, -CF3, or a halogen. R 6 This relates to hydrogen or deuterium or pharmaceutically acceptable salts thereof.

[0058] In some embodiments, the following compounds are excluded from formula (II): (a)R 1 and R 2 Both are ethyl, R 4 If R is hydrogen, 5 It is not chloro, bromo, iodine, or unsubstituted methyl. (b)R 2 is hydrogen, R 4 is hydrogen, R 5 If it is bromo, then R 1 is not ethyl, isopropyl, or propargyl, and (c)R 2 is methyl, and R 4 is hydrogen, R 5 If it is bromo, then R 1 It is not propargyl or cyclopropyl.

[0059] In some embodiments, this disclosure relates to compounds of formula (Ia) or (IIa):

[0060] [ka]

[0061] [In the formula, R 1 , R 2 , and R 3 This includes [as defined in the embodiments disclosed above and herein] or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, this disclosure relates to compounds of formula (Ib):

[0063] [ka]

[0064] [In the formula, R 3 and R 5 This includes [as defined in the embodiments disclosed above and herein] or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, this disclosure relates to compounds of formula (Ic):

[0066] [ka]

[0067] [In the formula, R 3 , and R 5 This includes [as defined in the embodiments disclosed above and herein] or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, this disclosure relates to compounds of formula (Id):

[0069] [ka]

[0070] [In the formula, R 3 , and R 5 This includes [as defined in the embodiments disclosed above and herein] or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, this disclosure relates to compounds of formula (Ie):

[0072] [ka]

[0073] [In the formula, R 3 and R 5This includes the [as defined above and in the classes and embodiments disclosed herein] or pharmaceutically acceptable salts thereof.

[0074] In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a linear C1-C6 alkyl group. In some embodiments, 1 R is a branched C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C5 alkyl group. In some embodiments, 1 The compound is selected from the group consisting of ethyl, sec-butyl, 2-pentyl, and 3-pentyl.

[0075] In some embodiments, R 1 R is a C1-C6 alkyl or 3-7 membered carbocyric, 1 R is optionally substituted with one or more halogens or C1-C6 alkyl groups. In some embodiments, 1 R is a C1-C6 alkyl or 3-5 membered carbocyric, 1 It is optionally substituted with one or more fluoro or C1-C4 alkyl groups.

[0076] In some embodiments, R 2 R is hydrogen or a C1-C6 alkyl group. 2 R is optionally substituted with one or more halogens or C1-C6 alkyl groups. In some embodiments, 2 R is hydrogen or a C1-C6 alkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 R is a linear C1-C6 alkyl group. In some embodiments, 2 R is a branched C1-C6 alkyl group. In some embodiments, R 2 R is a C2-C5 alkyl group. In some embodiments, 2 The element is selected from the group consisting of hydrogen, ethyl, sec-butyl, 2-pentyl, and 3-pentyl.

[0077] In some embodiments, R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted groups selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperidinyl, and morpholinyl. In some embodiments, R 1 and R 2 These can combine with the atoms to which they are bonded to form dimethylazetidinyl.

[0078] In some embodiments, R 3 R is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and 3-7 membered cycloalkyl, 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, 3- to 7-membered cycloalkyl, and phenyl, and each of the cycloalkyl or phenyl is optionally independently substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. In some embodiments, R 3 R is a C1-C6 alkyl or C2-C6 alkenyl, 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, 3- to 7-membered cycloalkyl, and phenyl, and each of the cycloalkyl or phenyl is optionally independently substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. In some embodiments, R 3 R is a C1-C3 alkyl or C2-C3 alkenyl, 3Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, 3- to 7-membered cycloalkyl, and phenyl, and each of the cycloalkyl or phenyl is optionally independently substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. In some embodiments, R 3 R is selected from the group consisting of methyl, ethyl, n-propyl, and allyl. 3 It may be substituted with one to three substituents selected from the group consisting of fluoro, 2-methoxyphenyl, and 2-hydroxyphenyl.

[0079] In one embodiment, R 3 R is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3-7 membered cycloalkyl groups. 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R 3 The substituent is selected from the group consisting of -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl), where the C1~C2 alkyl is optionally substituted with one or more fluoro, hydroxyl, and -OMe, and the phenyl and 6-membered heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1~C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1~C4 alkyl, C3~C5 cycloalkyl, and C1~C4 alkoxy. In some embodiments, R 3 R is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3-7 membered cycloalkyl groups. 3 R may be substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxyl, and -OMe. In some embodiments, R 3The substituent is selected from the group consisting of -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl), where the C1~C2 alkyl is optionally substituted with one or more fluoro, hydroxyl, and -OMe, and the phenyl and 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, -OC(O)(C1~C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1~C4 alkyl, C3~C5 cycloalkyl, and C1~C4 alkoxy.

[0080] In some embodiments, R 3 R is selected from the group consisting of C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl), and 3-5 membered cycloalkyl. 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R 3 R3 is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), where C1-C2 alkyl is optionally substituted with one or more fluoropolymers, and phenyl and 6-membered heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl, and C1-C3 alkoxy. In some embodiments, R3 is selected from the group consisting of C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl), and 3-5 membered cycloalkyl, R 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe. In some embodiments, R 3The substituent is selected from the group consisting of -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl), where the C1~C2 alkyl is optionally substituted with one or more fluoropolymers, and the phenyl and 6-membered heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1~C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1~C3 alkyl, cyclopropyl, and C1~C3 alkoxy.

[0081] In some embodiments, R 3 R is selected from the group consisting of ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, and -CH2-(cyclopropyl), 3 R may be substituted with fluoro in one to three cases. In some embodiments, 3 R is selected from the group consisting of ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, -CH2-(cyclopropyl), -CH2CF3, -CH2CH2CH2F, and -CH2CH2CF3. In some embodiments, R 3 is selected from the group consisting of -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl), where C1~C2 alkyl is optionally substituted with one or more fluoropolymers, and phenyl and 6-membered heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1~C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1~C3 alkyl, cyclopropyl, and C1~C3 alkoxy. In some embodiments, R 3 The substituent is selected from the group consisting of -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-pyridinyl, and each substituent is independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1~C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1~C3 alkyl, cyclopropyl, and C1~C3 alkoxy.

[0082] In further embodiments, R 3 R is selected from the group consisting of ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, and -CH2-(cyclopropyl), 3 It may be substituted with 1 to 3 fluoropolymers.

[0083] In further embodiments, R 3 These are ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, -CH2-(cyclopropyl), and -CH2CF 3、 The group is selected from -CH2CH2CH2F and -CH2CH2CF3.

[0084] In another embodiment, R 3 The compounds are selected from the group consisting of -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl, where the C1~C4 alkyl in -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl is optionally substituted with one or more fluoro, hydroxyl, and -OMe, and the aryl and heteroaryl in -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl are independently substituted with halogens, -OR 7 ,-OC(O)R 7 -CN, -NO2, -NR 7 R 8 , -CO2R 7 -C(O)NR 7 R 8 , C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and R 9 One or more substituents selected from the group consisting of the following, which are optionally substituted, and each R 7 and R 8 These are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and R 10Selected from the group consisting of the following, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl are optionally substituted with one or more fluoro, hydroxyl, or OMe. Each R 9 and R 10 Each of the substituents is an aryl or heteroaryl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -OC(O)(C1~C4 alkyl), -O(C1~C4 alkyl), -CN, -NO2, -NH2, C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, and C3~C5 cycloalkyl, wherein the -OC(O)(C1~C4 alkyl), -O(C1~C4 alkyl)-, C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, and C3~C5 cycloalkyl are optionally substituted with one or more fluoro, hydroxyl, or OMe.

[0085] In one embodiment, R 3 R is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3-7 membered cycloalkyl groups. 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R 3 R is selected from the group consisting of -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl, 3 The C1-C4 alkyl groups in the -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl compounds are optionally substituted with one or more fluoro, hydroxyl, and -OMe groups, R 3 The aryl and heteroaryl in -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl are, independently, halogens, -OR 7 ,-OC(O)R 7 -CN, -NO2, -NR 7 R 8 , -CO2R7 -C(O)NR 7 R 8 , C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and R 9 One or more substituents selected from the group consisting of the following are optionally substituted: Each R 7 and R 8 These are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and R 10 Selected from the group consisting of the following, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl are optionally substituted with one or more fluoro, hydroxyl, or OMe. Each R 9 and R 10 Each is an aryl or heteroaryl molecule that is optionally substituted with one or more substituents independently selected from the group consisting of halogens, -OH, -OC(O)(C1-C4 alkyl), -O(C1-C4 alkyl), -CN, -NO2, -NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl molecules are optionally substituted with one or more fluoro, hydroxyl, or OMe molecules.

[0086] In another embodiment, R 3 The compounds are selected from the group consisting of -(C1~C2 alkyl)-aryl and -(C1~C2 alkyl)-heteroaryl, where the C1~C2 alkyl in -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl is optionally substituted with one or more fluoro, hydroxyl, and -OMe, and the aryl and heteroaryl in -(C1~C4 alkyl)-aryl and -(C1~C4 alkyl)-heteroaryl are independently substituted with halogens, -OR 7 ,-OC(O)R 7 -CN, -NO2, -NR 7 R8 , -CO2R 7 -C(O)NR 7 R 8 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and R 9 One or more substituents selected from the group consisting of the following, which are optionally substituted, and each R 7 and R 8 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and R 10 Selected from the group consisting of each R 9 and R 10 This is an aryl or heteroaryl molecule that is optionally substituted with one or more substituents independently selected from the group consisting of halogens, -OH, -OC(O)(C1-C4 alkyl), -O(C1-C4 alkyl), -CN, -NO2, -NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl.

[0087] In some embodiments, R 3 teeth,

[0088] [ka]

[0089] It is selected from the group consisting of the following.

[0090] In some embodiments, R 3 teeth,

[0091] [ka]

[0092] It is selected from the group consisting of the following.

[0093] In some embodiments, R 3 teeth,

[0094] [ka]

[0095] It is selected from the group consisting of the following.

[0096] In some embodiments, R 4 R is hydrogen or -C(O)(C1~C8 alkyl). In some embodiments, 4 is hydrogen or -C(O)(C1~C3 alkyl). In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -C(O)(C1~C8 alkyl). In some embodiments, R 4 It is -C(O)(C1~C3 alkyl).

[0097] In some embodiments, R 5 is Me, Et, -CH2F, CHF2, -CF3, or a halogen. In some embodiments, R 5 is Me, Et, or a halogen. In some embodiments, R 5 is Me, Et, or Bromo. In some embodiments, R 5 is hydrogen or halogen. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is hydrogen or bromine. In some embodiments, R 5 is bromo. In some embodiments, R 5 is hydrogen, Me, or Et. In some embodiments, R 5 It is either Me or Et.

[0098] In some embodiments, this disclosure is,

[0099] [ka] [ka] [ka] [ka]

[0100] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, this disclosure is,

[0102] [ka] [ka] [ka] [ka]

[0103] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, this disclosure is,

[0105] [ka]

[0106] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, this disclosure is,

[0108] [ka]

[0109] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, this disclosure is,

[0111] [ka]

[0112] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0113] In other embodiments, for objects that require it,

[0114] [ka]

[0115] A method and composition for treating mood disorders are provided, which involve administering an effective amount of a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, this disclosure is,

[0117] [ka] [ka] [ka] [ka] [ka] [ka]

[0118] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, this disclosure is,

[0120] [ka] [ka] [ka]

[0121] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, this disclosure is,

[0123] [ka] [ka] [ka] [ka] [ka]

[0124] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, this disclosure is,

[0126] [ka]

[0127] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, this disclosure is,

[0129] [ka]

[0130] It comprises a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0131] Salts of the compounds of this disclosure can be prepared by reacting the compounds of this disclosure with a suitable acid or base in a suitable solvent or mixture of solvents (e.g., ether, e.g., diethyl ether, or alcohol, e.g., ethanol, or aqueous solvent) using conventional procedures. Salts of compounds of general formula I can be exchanged for other salts by processing using conventional ion exchange chromatography procedures. Preferred salts of the compounds of this disclosure include tartrates, fumarates, and maleates.

[0132] If it is desired to obtain a specific enantiomer of a compound of the present disclosure, it can be produced from a corresponding mixture of enantiomers by utilizing any suitable conventional procedure for separating the enantiomers. For example, a diastereomer derivative (e.g., a salt) can be produced by reacting a mixture of enantiomers of a compound of the present disclosure (e.g., a racemate) with a suitable chiral compound (e.g., a chiral base). The diastereomer can then be separated by any conventional means, for example, crystallization, to recover the desired enantiomer (e.g., by treatment with acid if the diastereomer is a salt). Alternatively, a racemic mixture of esters can be separated by kinetic hydrolysis using various biocatalysts (see, for example, Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0133] In an alternative separation process, the racemic mixture of the compounds of this disclosure can be separated using chiral high-performance liquid chromatography. Alternatively, specific enantiomers can be obtained using a suitable chiral intermediate in one of the methods described above. If it is desired to obtain specific geometric isomers of this disclosure, chromatography, recrystallization, and other conventional separation procedures can also be used for intermediates or final products.

[0134] II. Method Methods and compositions for treating mood disorders by administering the compounds of the Disclosure to patients in need are described herein. Pharmaceutical compositions comprising the compounds of the Disclosure are also provided.

[0135] In embodiments, the methods, compounds, and compositions may be used to treat mood disorders, including, for example, major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal anxiety disorder, psychotic depression, severe mood dysregulation, substance / medication-induced depressive disorder, or depressive disorder due to another medical condition.

[0136] In embodiments, methods, compounds, and compositions can treat mood disorders, including bipolar disorder and related disorders. In embodiments, methods, compounds, and compositions can treat mood disorders, including substance-related disorders. In embodiments, methods, compounds, and compositions can treat mood disorders, including anxiety disorders. In embodiments, methods, compounds, and compositions can treat mood disorders, including obsessive-compulsive disorder and related disorders. In embodiments, methods, compounds, and compositions can treat mood disorders, including trauma and stressor-related disorders. In embodiments, methods, compounds, and compositions can treat mood disorders, including feeding behaviors and eating disorders. In embodiments, methods, compounds, and compositions can treat mood disorders, including cognitive impairments. In embodiments, methods, compounds, and compositions can treat mood disorders, including neurodevelopmental disorders. In embodiments, methods, compounds, and compositions can treat mood disorders, including personality disorders. In embodiments, methods, compounds, and compositions can treat mood disorders, including sexual dysfunction. In embodiments, methods, compounds, and compositions can treat mood disorders, including gender dysphoria. In the embodiments, the methods, compounds, and compositions can treat migraines or cluster headaches.

[0137] Methods for treating patients suffering from treatment-resistant depression, such as depressive disorders that do not respond to and / or have never responded to at least one or at least two other antidepressant compounds or therapeutic agents. As used herein, “depressive disorder” encompasses treatment-resistant depression.

[0138] In embodiments, methods, compounds, and compositions can be used to treat mood disorders, including bipolar disorder and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medicine-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to other medical conditions.

[0139] In embodiments, methods, compounds, and compositions can be used to treat mood disorders, including substance-related disorders, for example, to prevent substance use cravings, reduce substance use cravings, and / or to promote the cessation or discontinuation of substance use. Substance use disorders include the abuse of psychoactive compounds, such as alcohol, caffeine, hemp, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, “substance” refers to psychoactive compounds that may be addictive, such as alcohol, caffeine, hemp, hallucinogen, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the methods, compounds, and compositions can be used to promote smoking cessation or the cessation of opioid use.

[0140] In embodiments, methods, compounds, and compositions may be used to treat mood disorders, including, for example, separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, or anxiety disorders due to other medical conditions.

[0141] In embodiments, methods, compounds, and compositions can be used to treat mood disorders, including obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, abrasion disorder, substance / medication-induced obsessive-compulsive disorder and related disorders, or obsessive-compulsive disorder and related disorders due to another medical condition.

[0142] In embodiments, the methods, compounds, and compositions can be used to treat a group of trauma- and stressor-related disorders, including mood disorders such as reactive love disorder, disinhibited social interaction disorder, post-traumatic stress disorder, acute stress disorder, or adjustment disorder.

[0143] In embodiments, methods, compounds, and compositions can be used to treat eating behaviors and eating disorders, including mood disorders such as anorexia nervosa, bulimia nervosa, distractive eating disorder, pica, rumination disorder, or avoidant / restrictive food intake disorder.

[0144] In embodiments, the methods, compounds, and compositions can be used to treat mood disorders, including, for example, delirium, dementia, mild cognitive impairment, dementia or mild cognitive impairment due to Alzheimer's disease, frontotemporal dementia or mild frontotemporal cognitive impairment, dementia or mild cognitive impairment with Lewy body dementia, vascular dementia or mild vascular cognitive impairment, dementia or mild cognitive impairment due to traumatic brain injury, substance / medicine-induced dementia or mild cognitive impairment, dementia or mild cognitive impairment due to HIV infection, dementia or mild cognitive impairment due to prion disease, dementia or mild cognitive impairment due to Parkinson's disease, dementia or mild cognitive impairment due to Huntington's disease, dementia or mild cognitive impairment due to another medical condition, or dementia or mild cognitive impairment due to multiple etiologies.

[0145] In embodiments, methods, compounds, and compositions can be used to treat neurodevelopmental disorders, including mood disorders such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotyped movement disorder, tic disorder, Tourette syndrome, persistent (chronic) motor or vocal tic disorder, or provisional tic disorder.

[0146] In embodiments, the methods, compounds, and compositions can be used to treat personality disorders, such as mood disorders including borderline personality disorder.

[0147] In embodiments, methods, compounds, and compositions may be used to treat sexual dysfunction, such as delayed ejaculation, erectile dysfunction, female orgasm disorder, female sexual interest / arousal disorder, genital-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, or mood disorders including substance / pharmaceutical-induced sexual dysfunction.

[0148] In embodiments, the methods, compounds, and compositions can be used to treat gender dysphoria, for example, mood disorders including gender dysphoria.

[0149] In embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (1) or a pharmaceutically acceptable salt thereof to a subject requiring it.

[0150] [ka]

[0151] In other embodiments, a method for treating a mood disorder is provided, comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound according to formula I or II as defined herein above, or a pharmaceutically acceptable salt thereof, or formula Ia or IIa, or Ib or IIb, or Ic or IIc, or Id or IId, or Ie or IIe, or a pharmaceutically acceptable salt thereof.

[0152] In another embodiment, a method for treating a mood disorder, comprising administering a compound according to formula (I) to a patient in need:

[0153] [ka]

[0154] [In the formula, R 1 R is a C1-C6 alkyl or 3-7 membered carbocyclyl, 1 It is optionally substituted with one or more halogens or C1-C6 alkyl groups. R 2is hydrogen or C1-C6 alkyl, R 2 is optionally substituted with one or more halogens or C1-C6 alkyl groups, or R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocyclines are optionally substituted with one or more fluoro or C1-C6 alkyl groups. R 3 This is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3-7 membered cycloalkyl groups. R 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe. or R 3 The compounds are selected from the group consisting of -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl), where the C1~C2 alkyl in -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluoro, hydroxyl, and -OMe, and the phenyl and 6-membered heteroaryl in -(C1~C2 alkyl)-phenyl and -(C1~C2 alkyl)-(6-membered heteroaryl) are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1~C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1~C4 alkyl, C3~C5 cycloalkyl, and -O(C1~C4 alkyl). R 4 is hydrogen or -C(O)(C1~C8 alkyl), R 5 These are hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogens. R 6A method is provided which includes the step of administering a pharmaceutical composition comprising an effective amount of hydrogen or deuterium or a pharmaceutically acceptable salt thereof.

[0155] In other embodiments, for objects that require it,

[0156] [ka] [ka] [ka] [ka]

[0157] A method and composition for treating mood disorders are provided, which involve administering an effective amount of a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0158] In other embodiments, for objects that require it,

[0159] [ka]

[0160] A method and composition for treating mood disorders are provided, which involve administering an effective amount of a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0161] In other embodiments, for objects that require it,

[0162] [ka] [ka]

[0163] A method and composition for treating mood disorders are provided, which involve administering an effective amount of a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0164] In other embodiments, for objects that require it,

[0165] [ka]

[0166] A method and composition for treating mood disorders are provided, which involve administering an effective amount of a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0167] In other embodiments, for objects that require it,

[0168] [ka]

[0169] A method and composition for treating mood disorders are provided, which involve administering an effective amount of a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0170] In other embodiments, for objects that require it,

[0171] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0172] A method and composition for treating mood disorders are provided, which involve administering an effective amount of a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0173] The compounds of this disclosure have been found to be agonists of the 5-HT2A receptor. Furthermore, the compounds of this disclosure, particularly those having substituents at the 2-position of the indole ring, are non-hallucinogenic or less hallucinogenic than other 5-HT2A receptor agonists. For example, compounds in which the 2-substituent is halo or alkyl, e.g., Me, Et, -CH2F, CHF2, or -CF3, are non-hallucinogenic or less hallucinogenic. In some embodiments, this reduction in hallucinogenicity can be demonstrated by attenuated maximal response in a mouse head unicontraction assay compared to hallucinogenic 5-HT2A receptor agonists.

[0174] In other embodiments, methods and compositions for treating migraines or cluster headaches are provided, by administering a therapeutically effective dose of the compounds disclosed herein to a patient in need.

[0175] In embodiments, the method includes the step of treating a mood disorder, such as a depressive disorder, by administering to a patient in need a pharmaceutical composition containing about 0.001 mg to about 20 mg of a compound disclosed herein. In embodiments, the doses are, for example, about 0.001 to 20 mg, 0.001 to 10 mg, 0.001 to 5 mg, 0.001 to 2 mg, 0.001 to 1 mg, 0.001 to 0.5 mg, 0.001 to 0.25 mg, 0.001 to 0.15 mg, 0.001 to 0.1 mg, 0.001 to 0.075 mg, 0.001 to 0.05 mg, 0.001 to 0.025 mg, 0.001 to 0.015 mg, 0.001 to 0.01 mg, 0.01 to 5 mg, 0.01~2mg, 0.01~1mg, 0.01~0.5mg, 0.01~0.25mg, 0.01~0.15mg, 0.01~0.1mg, 0.01~0.075mg, 0.01~0.05mg, 0.01 ~0.025mg, 0.01~0.015mg, 0.025~2mg, 0.025~1mg, 0.025~0.5mg, 0.025~0.25mg, 0.025~0.15mg, 0.025~0.1mg, 0.025 The range may be ~0.075mg, 0.025~0.05mg, 0.05~2mg, 0.05~1mg, 0.05~0.5mg, 0.05~0.25mg, 0.05~0.15mg, 0.05~0.1mg, 0.05~0.075mg, 0.1~2mg, 0.1~1mg, 0.1~0.5mg, 0.1~0.25mg, 0.1~0.15mg, for example, approximately 0.001mg, 0.0025mg, 0.005mg, 0.007 Examples of dosages include 5 mg, 0.01 mg, 0.015 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg.

[0176] In certain embodiments, the doses are, for example, about 0.001-20 mg, 0.001-10 mg, 0.001-5 mg, 0.001-2 mg, 0.001-1 mg, 0.001-0.5 mg, 0.001-0.25 mg, 0.001-0.15 mg, 0.001-0.1 mg, 0.001-0.075 mg, 0.001-0.05 mg, 0.001-0.025 mg, 0.001-0.015 mg, 0.001-0.01 mg, 0.01-5 mg, 0.01~2mg, 0.01~1mg, 0.01~0.5mg, 0.01~0.25mg, 0.01~0.15mg, 0.01~0.1mg, 0.01~0.075mg, 0.01~0.05mg, 0.01~0.025 mg, 0.01~0.015mg, 0.025~2mg, 0.025~1mg, 0.025~0.5mg, 0.025~0.25mg, 0.025~0.15mg, 0.025~0.1mg, 0.025~0.075mg It may contain amounts of the compounds disclosed herein in the range of 0.025-0.05 mg, 0.05-2 mg, 0.05-1 mg, 0.05-0.5 mg, 0.05-0.25 mg, 0.05-0.15 mg, 0.05-0.1 mg, 0.05-0.075 mg, 0.1-2 mg, 0.1-1 mg, 0.1-0.5 mg, 0.1-0.25 mg, 0.1-0.15 mg, and may also contain amounts of 0.001 mg, 0.0025 mg, 0.005 mg, 0.007 Specific examples of dosages include 5 mg, 0.01 mg, 0.015 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg.

[0177] Typically, the doses of the compounds disclosed herein are administered to patients who require them once, twice, three or four times daily, every other day, every three days, twice a week, once a week, twice a month, or once a month. In embodiments, doses are, for example, about 0.001 to 20 mg / day, or 0.001 to 10 mg / day, or 0.001 to 1 mg / day, or 0.001 to 0.25 mg / day, such as 20 mg / day, 5 mg / day, 1 mg / day, 0.5 mg / day, 0.25 mg / day, 0.15 mg / day, 0.1 mg / day, 0.05 mg / day, 0.025 mg / day, 0.01 mg / day, 0.005 mg / day, or 0.001 mg / day. In embodiments, the above exemplary dose ranges may be delivered over intervals longer than one day, for example, 0.001 to 20 mg / week.

[0178] In embodiments, pharmaceutical compositions for parenteral or inhalation administration of the compounds disclosed herein, for example, as a spray or mist, have concentrations ranging from about 0.001 mg / mL to about 100 mg / mL. In embodiments, compositions contain the compounds disclosed herein in concentrations, for example, about 0.05 mg / mL to about 100 mg / mL, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.005 mg / mL to about 1 mg / mL, and about 0.005 mg / mL It contains the following concentrations: mL to approximately 0.25 mg / mL, approximately 0.005 mg / mL to approximately 0.05 mg / mL, approximately 0.005 mg / mL to approximately 0.025 mg / mL, approximately 0.001 mg / mL to approximately 0.05 mg / mL, approximately 0.001 mg / mL to approximately 0.025 mg / mL, approximately 0.001 mg / mL to approximately 0.01 mg / mL, or approximately 0.001 mg / mL to approximately 0.005 mg / mL.

[0179] In the embodiment, for example, about 0.05 mg / mL to about 100 mg / mL, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.005 mg / mL to about 1 mg / mL, about 0.005 mg / mL to about 0.25 mg / mL, about 0.005 Compositions of the compounds disclosed herein at concentrations of approximately mg / mL to about 0.05 mg / mL, approximately 0.005 mg / mL to about 0.025 mg / mL, approximately 0.001 mg / mL to about 0.05 mg / mL, approximately 0.001 mg / mL to about 0.025 mg / mL, approximately 0.001 mg / mL to about 0.01 mg / mL, or approximately 0.001 mg / mL to about 0.005 mg / mL. In embodiments, the pharmaceutical composition is formulated in total volume, for example, approximately 0.1 mL, 0.25 mL, 0.5 mL, 1 mL, 2 mL, 5 mL, 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0180] Typically, the dosage may be administered to the subject once, twice, three or four times daily, every other day, every three days, twice a week, once a week, twice a month, once a month, every two months, every three months, every four months, every six months, or every twelve months. In embodiments, the compounds disclosed herein are administered to the subject once in the morning or once in the evening. In embodiments, the compounds disclosed herein are administered to the subject once in the morning and once in the evening. In embodiments, the compounds disclosed herein are administered to the subject three times a day (e.g., at breakfast, lunch, and dinner) in a dose of, for example, 0.005 mg / dose (e.g., 0.015 mg / day).

[0181] In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.005 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.01 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.025 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.05 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.1 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.15 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.2 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.25 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.3 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.4 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.5 mg / day in one or more doses.

[0182] In embodiments, the doses of the compounds disclosed herein are 0.000025-0.25 mg / kg, 0.0001-0.1 mg / kg, 0.001-0.1 mg / kg, or 0.01-0.25 mg / kg once, twice, three, or four times a day. For example, in embodiments, the doses are 0.000025 mg / kg, 0.00005 mg / kg, 0.0001 mg / kg, 0.0005 mg / kg, 0.001 mg / kg, 0.002 mg / kg, 0.003 mg / kg, 0.004 mg / kg, 0.005 mg / kg, 0.01 mg / kg, or 0.05 mg / kg once, two, three, or four times a day. In the embodiments, the subject is administered a total daily dose of 0.001 mg to 20 mg of the compounds disclosed herein, once, twice, three times, or four times per day. In the embodiments, the total amount administered to the subject within 24 hours is, for example, 0.001 mg, 0.0025 mg, 0.005 mg, 0.0075 mg, 0.01 mg, 0.015 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg. In one embodiment, the subject may start with a low dose and gradually increase the dose. In another embodiment, the subject may start with a high dose and gradually decrease the dose.

[0183] In embodiments, the compounds disclosed herein are administered to patients under the supervision of a healthcare provider.

[0184] In embodiments, the compounds disclosed herein are administered to patients under the supervision of a healthcare provider in a hospital specializing in the provision of psychotropic treatments.

[0185] In embodiments, the compounds disclosed herein are administered to patients under the supervision of a healthcare provider in high doses intended to induce a hallucinatory experience in the subject, for example, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg.

[0186] In the embodiment, high-dose administration to the patient under the supervision of a healthcare provider is performed regularly, for example, once a week, twice a month, once a month, every two months, every three months, every four months, every six months, or every twelve months, in order to maintain the therapeutic effect in the patient.

[0187] In embodiments, the compounds disclosed herein are administered by the patient themselves at home or otherwise away from the supervision of a healthcare provider.

[0188] In embodiments, the compounds disclosed herein are administered by the patient themselves at home or away from the supervision of a healthcare provider in low doses intended to induce psychoactive effects below or above the perceptual threshold, for example, 0.001 mg, 0.0025 mg, 0.005 mg, 0.0075 mg, 0.01 mg, 0.015 mg, 0.02 mg, 0.025 mg, 0.03 mg, or 0.04 mg.

[0189] In this embodiment, the patient administers a low dose regularly to maintain the therapeutic effect in the patient, for example, daily, every other day, every three days, twice a week, once a week, twice a month, or once a month.

[0190] The compounds of this disclosure may be administered to patients (animals and humans) requiring such treatment in doses that provide optimal pharmacokinetic efficacy. It is understood that the dose required for any particular use will vary from patient to patient, depending not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the patient's age and condition, any concurrent drug therapies or special dietary therapies the patient is undergoing at that time, and other factors recognized by those skilled in the art, and that ultimately the appropriate dose will be at the discretion of the attending physician. To treat the conditions and diseases mentioned above, the compounds of this disclosure may be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in unit formulations containing conventional non-toxic, pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injection, intravenous or intramuscular injection, or intravenous infusion techniques.

[0191] Treatment can be continued for any desired duration, longer or shorter. The composition may be administered, for example, in regimens of 1 to 4 times per day or more. An appropriate treatment period may be, for example, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, at least about 1 year, or indefinite. The treatment period can be terminated when the desired outcome, for example, reduction of symptoms of the mental disorder, is achieved. The treatment regimen may include an adjustment phase, during which a dose sufficient to provide symptomatic relief is administered, followed by a maintenance phase, during which a lower dose sufficient to prevent symptom relapse is administered. An appropriate maintenance dose is likely to be found in the lower part of the dose range provided herein, but adjustment and maintenance doses can be readily established for individual subjects by those skilled in the art based on the disclosure herein, without excessive experimentation. The maintenance dose can be used to maintain remission in subjects whose symptoms have been previously controlled by other means, including treatment with other pharmacologically active substances.

[0192] III. Pharmaceutical Compositions and Kits Another aspect of this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, formulated with a pharmaceutically acceptable carrier. In particular, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, oral buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, but in any case, the most suitable mode of administration will depend on the degree and severity of the condition being treated and the properties of the specific compounds used. For example, the disclosed compositions may be formulated as unit doses and / or for oral or subcutaneous administration.

[0193] The exemplary pharmaceutical compositions of this disclosure may be used in the form of pharmaceutical preparations, for example, solid, semi-solid, or liquid, which contain one or more compounds of this disclosure as active ingredients, mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral application. The active ingredients may be formulated with ordinary non-toxic, pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other form suitable for use. The active compound of interest is included in the pharmaceutical composition in an amount sufficient to produce the desired effect in the course or state of the disease.

[0194] For the preparation of solid compositions, such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier, such as a conventional tableting agent, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and other pharmaceutical diluents, such as water, to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of this disclosure or a non-toxic, pharmaceutically acceptable salt thereof. When these preliminary formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0195] For solid dosage forms for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), the target composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants. , for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, for example, paraffin; (6) absorption enhancers, for example, quaternary ammonium compounds; (7) wetting agents, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, for example, kaolin and bentonite clay; (9) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the composition may also contain buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0196] Tablets may be prepared by compression or molding with one or more optional adjuncts. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or crosslinked sodium carboxymethylcellulose), a surfactant, or a dispersant. Molded tablets may be prepared by molding a mixture of the composition to be prepared, moistened with an inert liquid diluent, in appropriate equipment. Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, may optionally be slitted or prepared with coatings and shells, such as enteric coatings and other coatings known in pharmaceutical formulation technology.

[0197] Compositions for inhalation or inhalation include pharmaceutically acceptable solutions and suspensions in aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the composition in question, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0198] The suspension may contain, in addition to the target composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0199] Formulations for rectal or vaginal administration may be presented as suppositories, which can be prepared by mixing the composition with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the body cavity and release the activator.

[0200] Dosage forms for transdermal administration of the target composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or sprays.

[0201] Ointments, pastes, creams, and gels may contain, in addition to the target composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0202] The powder and spray formulations may contain, in addition to the target composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. The spray formulations may further contain conventional spraying agents such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0203] The compositions and compounds of this disclosure may be administered as aerosols instead. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon sprays) suspensions may also be used. Ultrasonic nebulizers may be used because they minimize drug shear, which can lead to the decomposition of compounds contained in the composition of interest. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the composition of interest together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the requirements of the particular composition of interest but usually include nonionic surfactants (Tweens, Pluronic®, or polyethylene glycol), harmless proteins, e.g., serum albumin, sorbitan esters, oleic acid, lecithin, amino acids, e.g., glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0204] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be restored to an injectable sterile solution or dispersion immediately before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes that impart an isotonic formulation with the blood of the recipient of the interest, or suspending agents or thickeners.

[0205] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and organic esters for injection (e.g., ethyl oleate and cyclodextrin). Appropriate fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0206] In another embodiment, the present disclosure provides enteral pharmaceutical formulations comprising disclosed compounds and enteric-coated materials; and pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials refer to polymers that are substantially insoluble in the acidic environment of the stomach but are primarily soluble in intestinal fluid at a specific pH. The small intestine is the part of the digestive tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the terminal ileum is approximately 7.5. Therefore, enteric-coated materials remain insoluble until the pH reaches, for example, approximately 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or 10.0. Exemplary enteric-coated materials include cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitic acetate, hydroxypropyl methylcellulose succinate, cellulose succinate acetate, cellulose hexahydrophthalate acetate, cellulose propionic acid phthalate, cellulose maleate acetate, cellulose butyrate acetate, cellulose propionic acid acetate, copolymer of methyl methacrylate and methyl methacrylate, copolymer of methyl acrylate, methyl methacrylate and methacrylic acid, copolymer of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal colophorum, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit Examples include FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is either known or readily determinable in vitro.The aforementioned materials are a list of possible materials, but those skilled in the art who would benefit from this disclosure will recognize that this is not exhaustive and that other enteric-coated materials exist that would satisfy the purposes of this disclosure.

[0207] Advantageously, this disclosure also provides kits for use by consumers requiring treatment with the disclosed compounds. Such kits include a suitable dosage form, e.g., one described above, and instructions describing how to use such dosage forms to treat a medical disorder, e.g., a mental illness or disorder. The instructions guide consumers or healthcare professionals to administer the dosage forms according to a mode of administration known to those skilled in the art. Such kits may be packaged and sold in single or multi-pack units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs typically consist of a relatively rigid sheet of a material, preferably a transparent plastic material, covered with foil. During the packaging process, grooves are formed in the plastic foil. The grooves have the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove, and the relatively rigid sheet is sealed against the plastic foil with the foil side opposite to the direction in which the grooves were formed. As a result, the tablets or capsules are sealed within the groove between the plastic foil and the sheet. Preferably, the sheet is strong enough so that pressure can be applied to the groove by hand, thereby forming an opening in the sheet at the location of the groove, allowing the tablets or capsules to be removed from the blister pack. The tablets or capsules can then be removed through the opening.

[0208] It may be desirable that the kit provide memory aids, for example, in the form of a number next to each tablet or capsule, where this number corresponds to the day of the regimen on which the identified tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on a card, such as "Week 1, Monday, Tuesday... etc., Week 2, Monday, Tuesday..." Other variations of memory aids are also readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules taken on a given day. Also, a daily dose of a first compound may consist of one tablet or capsule, while a daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0209] Methods and compositions comprising a second activator, or administration of a second activator, are also envisioned herein.

[0210] Example The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the descriptions of the synthetic methods below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures, can be selected to be standard conditions for the reaction unless otherwise noted. It is understood by those skilled in the art of organic synthesis that functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions are obvious to those skilled in the art, and therefore alternative methods are shown. Starting materials for the examples are commercially available or readily prepared from known materials by standard methods.

[0211] It is assumed that at least some of the compounds identified as “intermediates” in this specification are compounds of this disclosure.

[0212] General procedure The compounds of this disclosure can be prepared by techniques well known in organic synthesis and familiar to those skilled in the art. For example, the compounds can be prepared by the chemical transformations described in the following examples. However, these may not be the only means of synthesizing or obtaining the desired compounds.

[0213] Abbreviation Acetic acid (ACOH) DCM = Dichloromethane DMF = Dimethylformamide TEA = Triethylamine T3P = Propyl anhydride phosphonate mCPBA = Metachloroperbenzoic acid HFBA = Heptafluorobutyric acid [Examples]

[0214] Preparation of (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (1) Reaction scheme (Method 1):

[0215] [ka]

[0216] Synthesis protocol (Method 1): To a suspension of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylic acid (Int1, 2.01g, 7.5 mmol) in anhydrous methanol (300 mL), a solution of diazomethane in diethyl ether (0.5 M, 75.0 mmol, 150 mL) was added under vigorous stirring. The resulting mixture was stirred until clear, then concentrated under vacuum and suspended in dichloromethane (100 mL). The solid was removed by filtration, the filter cake was washed with dichloromethane (3 × 30 mL), and the filtrate was concentrated under vacuum to obtain methyl(6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylate (Int2) as an off-white foamy substance. Yield: 1.92g (90%). LC-MS purity: 98% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 20:80~100:0 + 0.1% FA, 10 min): 6.82 min LC-MS m / z:283.2(M+H) + .

[0217] Methyl(6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylate (Int2, 564 mg, 2.0 mmol) was dissolved in dry dichloromethane (30 mL) and purged with argon. Cyanogen bromide (1.14 g, 10.72 mmol) was added all at once, and the resulting solution was stirred for 4.5 hours, at which point LC / MS showed complete conversion. Silica gel (10 g) was added, and the resulting suspension was concentrated under vacuum. The product was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 80:20~50:50) to obtain methyl(6aR,9R)-7-cyano-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxylate (Int3) as a colorless foamy substance. Yield: 300 mg (50%). LC-MS purity: 98% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 05:95~100:0 + 0.1% FA, 10 min): 8.63 min LC-MS m / z:294.1(M+H) + .

[0218] Methyl(6aR,9R)-7-cyano-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylate (Int3, 205 mg, 0.70 mmol) was dissolved in glacial acetic acid (5 mL), and zinc dust (600 mg) and water (0.5 mL) were added. The resulting mixture was purged with argon, heated to 100°C, and stirred for 3 hours. At this point, LC / MS showed complete consumption of the starting material. The reaction mixture was cooled to 0°C and partitioned between saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL), and extracted with dichloromethane (2 × 50 mL). The combined organic extract was dehydrated with anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluate: dichloromethane / methanol 95:5-90:10) to obtain methyl(6aR)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylate (Int4m) (a mixture of diastereomers; epimer at position 9) as an off-white foamy substance. Yield: 51 mg (24%). LC-MS purity: 85% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 05:95~100:0 + 0.1% FA, 10 min): 2.87 min LC-MS m / z:269.2(M+H) + .

[0219] A solution of methyl(6aR)-4,6,6a,7,8,9-hexahydroindoro[4.,3-fg]quinoline-9-carboxylate (Int4m, 75 mg, 0.280 mmol; mixture of epimers at position 9) and propanal (88 μL, 1.40 mmol) in methanol (10 mL) was purged with argon and cooled to 0°C. Sodium borohydride cyanohydride (88.0 mg, 1.40 mmol) was added, and the mixture was stirred for 5 minutes, after which acetic acid (300 μL) was introduced. After stirring at 0°C for 1 hour, the solvent was evaporated, and the residue was partitioned between dichloromethane (100 mL) and saturated sodium bicarbonate (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain methyl(6aR)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylate (Int5m) (a mixture of diastereomers; epimer at position 9) as an off-white foamy substance. Yield: 58 mg (67%). LC-MS purity: 99% (ELSD), 95% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 05:95~100:0 + 0.1% FA, 10 min): 2.95 min LC-MS m / z:311.2(M+H) + .

[0220] Methyl(6aR)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylate (Int5m, 58.7 mg, 0.189 mmol; mixture of epimers at position 9) was dissolved in freshly distilled tetrahydrofuran (10 mL) and water (1 mL) and purged with argon. Lithium hydroxide (12.46 mg, 0.297 mmol) in water (500 μL) was added, and the resulting mixture was stirred overnight. At this point, LC / MS showed complete conversion. The reaction mixture was neutralized with ice-cold methanesulfonic acid (29.2 mg, 0.297 mmol) in water (1 mL), concentrated under vacuum, and the resulting off-white residue (Int6m) (mixture of diastereomers; epimer at position 9) was used in the next step without further purification. Yield: 58 mg (crude product). LC-MS purity: 100% (ELSD), 95% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 05:95~100:0 + 0.1% FA, 10 min): 7.08 min; 7.30 min LC-MS m / z:297.2(M+H) + .

[0221] Crude (6aR)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylic acid (Int6m, 55 mg; mixture of epimers at position 9) was dissolved in dry N,N-dimethylformamide (3 mL), the solution was purged with argon, and cooled to 0°C. Triethylamine (106 μL, 0.760 mmol), diethylamine (60 μL, 0.570 mmol), and propanephosphonic anhydride (T3P, 332 μL, 0.570 mmol, 50% in DMF) were added, and the resulting mixture was stirred for 1 hour. Ice-cold water (50 mL) was added, followed by ice-cold 1% ammonium hydroxide solution (5 mL), and the aqueous phase was extracted with dichloromethane (5 × 30 mL). The combined organic layers were dehydrated with anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified by preparative LC / MS (Sinergy Polar RP C18, 5 μm, 21.2 mm × 150 mm, acetonitrile / water 5:95 + 0.1% acetic acid) to obtain the title compound as an acetonitrile / water solution. By freeze-drying, 10 mg of (6aR,9R)-9-(diethylcarbamoyl)-7-propyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-7-ium acetate (1) was obtained as a beige powder. Yield: 10 mg (13% in 2 steps). 1 1H NMR spectrum (acetate; acetate peak obscured by solvent peak) (300 MHz, CD3CN, δ H ): 9.00 (s, 1H), 7.22 (dd, J = 6.8, 1.9 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.98 - 6.84 (m, 2H), 6.30 (s, 1H), 3.78 - 3.68 (m, 1H), 3.56 - 3.30 (m, 6H), 3.13 (dd, J =10.9, 4.5 Hz, 1H), 2.93 - 2.82 (m, 1H), 2.69 - 2.42 (m, 4H), 1.67 - 1.43 (m, 2H), 1.21 (t, J =7.1 Hz, 3H), 1.11 (t, J =7.1 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). LC-MS purity: 97% (ELSD), 96% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 05:95~100:0 + 0.1% FA, 10 min): 8.20 min. LC-MS m / z: 352.2 (M+H) + . Reaction scheme (Method 2):

[0222] [ka]

[0223] Synthesis protocol (Method 2): A solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int7m, 45.0 mg, 0.145 mmol; mixture of epimers at position 9) and propanal (52 μL, 0.72 mmol) in methanol (10 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (46.0 mg, 0.72 mmol) was added, and the mixture was stirred for 5 minutes, then acetic acid (160 μL) was added. The reaction mixture was stirred at 0°C for 1 hour, the solvent was removed under vacuum, and the residue was partitioned between a 1% solution of dichloromethane and ammonium hydroxide. The aqueous phase was extracted with dichloromethane (3 × 50 mL), and the combined organic phase was dehydrated with anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (1) as a colorless oil. Yield: 6 mg (11%). 1 1H NMR spectrum (acetate; acetate peak obscured by solvent peak) (300 MHz, CD3CN, δ H): 9.00 (s, 1H), 7.22 (dd, J =6.8, 1.9 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.98 - 6.84 (m, 2H), 6.30 (s, 1H), 3.78 - 3.68 (m, 1H), 3.56 - 3.30 (m, 6H), 3.13 (dd, J =10.9, 4.5 Hz, 1H), 2.93 - 2.82 (m, 1H), 2.69 - 2.42 (m, 4H), 1.67 - 1.43 (m, 2H), 1.21 (t, J =7.1 Hz, 3H), 1.11 (t, J =7.1 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). LC-MS purity: 96% (ELSD), 93% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 20:80~100:0 + 0.1% FA, 10 min): 5.66 min. LC-MS m / z: 352.2 (M+H) + . [Examples]

[0224] Preparation of the reactions for (6aR,9R)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (2) and (6aR,9S)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (2a) Reaction scheme (Method 1):

[0225] [ka]

[0226] Synthesis protocol (Method 1): A solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int7m, 60.0 mg, 0.194 mmol; mixture of epimers at position 9), cesium carbonate (139 mg, 0.426 mmol), and 1-bromo-3-fluoropropane (30.2 mg, 0.214 mmol) in N,N-dimethylformamide (1 mL) was purged with argon and stirred at room temperature for 96 hours. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (3 × 50 mL), and the combined organic phase was dehydrated with magnesium sulfate and concentrated under vacuum. The crude product obtained was purified by silica gel chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (2, faster moving fluorescent band) as a colorless foamy substance. Yield: 6 mg (10%). 1 1H NMR (300 MHz, CDCl3, δ H ): 8.03 (s, 1H), 7.24 - 7.11 (m, 3H), 6.90 (s, 1H), 6.33 (s, 1H), 4.71 - 4.59 (m, 1H), 4.57 - 4.42 (m, 1H), 3.84 (s, 1H), 3.58 - 3.35 (m, 6H), 3.27 - 3.10 (m, 2H), 2.96 (t, J= 13.2 Hz, 1H), 2.85 - 2.64 (m, 2H), 2.13 - 1.86 (m, J= 23.6 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H), 1.18 (t, . J =7.1 Hz, 3H). LC-MS purity: 90% (ELSD), 81% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.68 min. LC-MS m / z: 370.2 (M+H) + . Reaction scheme (Method 2):

[0227] [ka]

[0228] Synthesis protocol (Method 2): (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int7m, 45 mg, 0.145 mmol; mixture of epimers at position 9) and potassium bicarbonate (30 mg, 0.29 mmol) were stirred in methanol (2 mL), to which a solution of 1-bromo-3-fluoropropane (50 mg, 0.348 mmol) in methanol (1 mL) was added dropwise under an argon atmosphere. Then, tetrabutylammonium iodide (53.5 mg, 0.145 mmol) was introduced all at once, and the reaction mixture was heated to 60 °C and stirred for 9 days. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (50 mL), and silica gel (10 g) was introduced. The solvent of the obtained suspension was evaporated under vacuum, and the mixture was subjected to silica gel chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9R)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (2, faster moving fluorescent band) as a colorless foamy substance, and (6aR,9S)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (2a, slower moving fluorescent band) as a dark brown foamy substance. 2: Yield: 13.9 mg (23%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 8.99 (s, 1H); 7.22 (dd, J = J = 6.9, 1.8, 1H); 7.14-7.03 (m, 2H); 6.95 (s, 1H); 6.30 (s, 1H); 4.75-4.58 (m, 1H); 4.57-4.41 (m, 1H); 3.79-3.65 (m, 1H); 3.57-3.29 (m, 6H); 3.18-3.01 (m, 2H); 2.71-2.45 (m, 3H); 2.02-1.82 (m, 2H); 1.20 (d, J = J = 7.1, 3H); 1.11 (t, J = J = 7.1, 3H). LC-MS purity: 97% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP 4.6 mm × 150 mm, アセトニトリル / water 30:70~100:0 + 0.1% HFBA, 10 points): 5.47 points. LC-MS m / z: 370.2 (M+H) + . 2a: Yield: 7.8 mg (12%). 1 H NMR スペクトル(300 MHz, CD3CN, δ H ): 8.98 (s, 1H); 7.20 (d, J = J = 7.3, 1H); 7.12-6.98 (m, 2H); 6.91 (s, 1H); 6.24 (s, 1H); 4.68-4.59 (m, 1H); 4.51-4.43 (m, 1H); 3.76-3.66 (m, 1H); 3.55-3.27 (m, 6H); 3.12 (dd, J = 14.6, 5.2, 1H); 3.07-2.75 (m, 5H); 1.92-1.77 (m, 2H); 1.23 (t, J = 7.1, 3H); 1.06 (t, J = 7.0, 3H). LC-MS purity: 100% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.71 min. LC-MS m / z: 370.2 (M+H) + . [Examples]

[0229] Preparation of (6aR,9R)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (3) and (6aR,9S)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (3a) Reaction scheme:

[0230] [ka]

[0231] Synthesis protocol: A solution of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylic acid (Int1, 805 mg, 3.00 mmol), triethylamine (1.69 mL, 12.0 mmol), and (R)-butane-2-amine (329 mg, 4.50 mmol) in dry N,N-dimethylformamide (30 mL) was cooled to 0°C, and propanephosphonic anhydride (T3P, 5.24 mL, 9.00 mmol, 50% solution in DMF) was added dropwise over 5 minutes. The resulting mixture was stirred at 0°C for 1 hour, then diluted with water (200 mL) and washed with ethyl acetate (3 × 150 mL). The organic phase was discarded (the product was in the form of a salt in the aqueous phase), and the aqueous phase was basicized to pH=12 by adding a 30% solution of ammonium hydroxide. The mixture was then extracted with dichloromethane (3 × 200 mL), the combined organic phase was dehydrated with anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~90:10) to obtain (6aR,9S)-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int8a, faster, less polar isomer) as a dark brown solid, and (6aR,9R)-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int8, slower, more polar isomer) as a colorless solid. Int8a: Yield: 0.28 g (28%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H): 8.28 (s, 1H); 8.01 (s, 1H); 7.25-7.10 (m, 3H); 6.93 (s, 1H); 6.60 (d, J = 5.7, 1H); 3.93-3.76 (m, 1H); 3.59 (dd, J = 14.5, 5.4, ​​1H); 3.27-3.04 (m, 2H); 2.78-2.61 (m, 2H); 2.58 (s, 3H); 1.56-1.33 (m, 2H); 1.01 (d, J = 6.6, 3H); 0.91 (d, J = 7.4, 3H). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HFBA, 10 minutes): 6.21 points. LC-MS m / z: 324.2 (M+H) + . Int8: Yield: 0.47 g (48%). 1 H NMR スペクトル (300 MHz, CDCl3, δ H ): 8.34 (s, 1H); 7.24-7.09 (m, 3H); 6.90 (s, 1H); 6.62 (d, J = 8.0, 1H); 6.42 (dd, J = 3.7, 1.9, 1H); 3.93 (dt, J = 14.8, 6.7, 1H); 3.54-3.48 (m, 1H); 3.44-3.34 (m, 2H); 3.10 (dd, J = 11.5, 4.7, 1H); 2.83-2.68 (m, 2H); 2.60 (s, 3H); 1.56-1.37 (m, 2H); 1.13 (d, J = 6.6, 3H); 0.90 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HFBA, 10 points): 5.29 points. LC-MS m / z: 324.2 (M+H) + .

[0232] A solution of 3-chloroperbenzoic acid (361 mg, 1.61 mmol) in dry dichloromethane (20 mL) was added dropwise at 0°C to a solution of (6aR)-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int8m, 526 mg, 1.63 mmol; mixture of epimers at position 9) in dry dichloromethane (40 mL), and the resulting mixture was stirred for 1 hour. Then, a 10% solution of sodium hydroxide (50 mL) was added to separate the phases, and the aqueous phase was extracted with a 10% solution of isopropanol in dichloromethane (3 × 100 mL). The combined organic phases were dried and evaporated under vacuum to obtain (6aR)-9-(((R)-sec-butyl)carbamoyl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline 7-oxide (Int9m) (a mixture of diastereomers; epimer at position 9) as a dark brown solid. This was used in the next step without further purification. Yield: 0.52g (100%). LC-MS purity: 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 50:50~100:0 + 0.1% FA, 10 min): 5.13 min LC-MS m / z:340.2(M+H) + .

[0233] Crude (6aR)-9-(((R)-sec-butyl)carbamoyl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline 7-oxide (Int9m, 520 mg; mixture of epimers at position 9) was dissolved in methanol (20 mL), cooled to 0°C, and purged with argon. Then, iron(II) sulfate heptahydrate (Fe2SO4·7H2O, 895 mg, 3.22 mmol) was gradually added to this solution, and the mixture was stirred at 0°C for 3 hours. The solvent was then removed under vacuum, and the residue was partitioned between dichloromethane (150 mL) and an aqueous solution (100 mL) of EDTA (10 g) and 30% ammonium hydroxide (10 mL). The aqueous phase was further extracted with dichloromethane (3 × 100 mL), and the combined organic phase was dried and evaporated. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2~85:15) to obtain (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int10m) (a mixture of diastereomers; epimer at position 9) as a dark brown solid. Yield: 0.121g (24% in 2 steps). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 50:50~100:0 + 0.1% FA, 10 min): 4.78 min (diastereomer 1); 5.15 min (diastereomer 2). LC-MS m / z:340.2(M+H) + .

[0234] A solution of (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int10m, 55.0 mg, 0.178 mmol; mixture of epimers at position 9) and propanol (0.064 mL, 0.89 mmol) in methanol (10 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (56.0 mg, 0.89 mmol) was added, and the mixture was stirred for 5 minutes, then acetic acid (160 μL) was added. The reaction was then stirred at 0°C for 1 hour. The solvent was evaporated, and the residue was partitioned between dichloromethane (50 mL) and a 1% solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL), and the combined organic phase was dehydrated with anhydrous magnesium sulfate and evaporated. The obtained residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain (6aR,9S)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (3a, faster, less polar diastereomer) as a colorless oil, and (6aR,9R)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (3, slower, more polar diastereomer) as a colorless oil. 3a: Yield: 16 mg (26%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H): 8.15 (br s, 1H); 7.99 (d, J = 5.9, 1H); 7.26-7.09 (m, 3H); 6.93 (s, 1H); 6.61 (d, J = 5.9, 1H); 3.85 (dt, J = 14.9, 6.6, 1H); 3.57 (dd, J = 14.5, 4.8, 1H); 3.46-3.34 (m, 1H); 3.27 (d, J = 11.7, 1H); 3.12 (br s, 1H); 2.92 (ddd, J = 13.3, 9.3, 4.6, 1H); 2.76-2.56 (m, 2H); 2.56-2.42 (m, 1H); 1.81-1.52 (m, 2H); 1.52-1.38 (m, 2H); 1.01 (d, J = 7.4, 3H); 1.00 (t, J = 7.4, 3H); 0.91 (t, J = 7.5, 3H). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HBFA, 10 points): 6.81 points. LC-MS m / z: 352.1 (M+H) + . 3: Yield: 17 mg (27%). 1 H NMR スペクトル (300 MHz, CDCl3, δ H): 8.15 (br s, 1H); 7.38 (br s, 1H); 7.23-7.12 (m, 2H); 7.08 (dd, J = 6.9, 0.9, 1H); 6.91 (s, 1H); 6.41 (dd, J = 5.3, 1.6, 1H); 4.03-3.80 (m, 2H); 3.26 (dd, J = 14.0, 4.8, 2H); 3.03 (dd, J = 11.9, 4.0, 1H); 2.97-2.79 (m, 3H); 2.76-2.59 (m, 1H); 1.75-1.55 (m, 2H); 1.54-1.34 (m, 2H); 1.13 (d, J = 6.6, 3H); 0.98 (t, J = 7.3, 3H); 0.88 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.00 min. LC-MS m / z: 352.1 (M+H) + [Examples]

[0235] Preparation of ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (4) Reaction scheme:

[0236] [ka]

[0237] Synthesis protocol: A solution of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxylic acid (Int1, 460 mg, 1.71 mmol), triethylamine (1.10 mL, 7.70 mmol), and (2S,4S)-2,4-dimethylazetidine hydrochloride (250 mg, 2.05 mmol) in dry N,N-dimethylformamide (10 mL) was cooled to 0°C under an argon atmosphere. Then, propanephosphonic anhydride (T3P, 1.20 mL, 2.05 mmol, 50% solution in DMF) was added dropwise over 5 minutes, and the resulting mixture was stirred at 0°C for 1 hour. After the reaction was completed by LC / MS, the mixture was quenched with ice-cold water (10 mL) and partitioned between 1 M aqueous ammonium hydroxide solution (100 mL) and ethyl acetate (100 mL). The aqueous phase was further extracted with ethyl acetate (2 × 50 mL), and the combined organic phase was washed with 5% lithium chloride solution (4 × 50 mL), dehydrated with anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 100:0~98:2) to obtain ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (Int11, faster-moving fluorescent band) as an off-white solid, and ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (Int11m; mixture of diastereomers; epimer at position 9) as a dark brown solid. Yield: 368 mg (65%), total of isomers. 1 1H NMR spectrum (Int11, pure beta isomer) (300 MHz, CDCl3, δ H): 8.24 (br s, 1H); 7.24-7.09 (m, 3H); 6.88 (s, 1H); 6.36 (s, 1H); 4.52 (dt, J = 7.5, 6.5, 2H); 3.60 (br s, 1H); 3.53 (dd, J = 14.5, 5.4, 1H); 3.31-3.17 (m, 1H); 3.07 (dd, J = 11.1, 4.9, 1H); 2.88 (t, J = 10.9, 1H); 2.70 (t, J = 12.0, 1H); 2.60 (s, 3H); 2.10-1.90 (m, 2H); 1.49 (t, J = 6.3, 6H). LC-MS purity: 100% (total isomers, ELSD), 98% (total isomers, UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 20:80~100:0 + 0.1% FA, 10 min): 3.59 min (diastereomer 1); 3.95 min (diastereomer 2). LC-MS m / z: 336.0 (M+H)+.

[0238] A solution of 3-chloroperbenzoic acid (189 mg, 1.10 mmol) in dry dichloromethane (5 mL) was added dropwise at 0°C to a solution of ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (Int11m, 368 mg, 1.10 mmol; mixture of epimers at position 9) in dry dichloromethane (30 mL), and the resulting mixture was stirred at 0°C for 1 hour. Then, a 10% solution of sodium hydroxide (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with a 10% solution of isopropanol in dichloromethane (3 × 100 mL). The organic phases were combined, dehydrated with anhydrous sodium sulfate, and concentrated under vacuum to obtain (6aR)-9-((2S,4S)-2,4-dimethylazetidine-1-carbonyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinolone 7-oxide (Int12m) (a mixture of diastereomers; epimer at position 9) as an off-white solid. This was used in the next step without further purification. LC-MS purity: 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 50:50~100:0 + 0.1% FA, 10 min): 1.92 min LC-MS m / z:352.0(M+H) + .

[0239] Crude (6aR)-9-((2S,4S)-2,4-dimethylazetidine-1-carbonyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinolone 7-oxide (Int12m; mixture of epimers at position 9) was dissolved in methanol (75 mL), cooled to 0°C, and purged with argon. Then, iron(II) sulfate heptahydrate (609 mg, 2.20 mmol) was added, and the mixture was stirred at 0°C for 3 hours. The solvent was removed under vacuum, and the residue was partitioned between dichloromethane (150 mL) and an aqueous solution (100 mL) of EDTA (10 g) and 30% ammonium hydroxide (10 mL). The aqueous phase was further extracted with dichloromethane (3 × 100 mL), and the combined organic phase was dehydrated with magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2~90:10) to obtain ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (Int13m) (a mixture of diastereomers; epimer at position 9) as an off-white amorphous solid. Yield: 81.5 mg (23% in 2 steps). LC-MS purity: 88% (ELSD), 86% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 05:95~100:0 + 0.1% FA, 10 min): 5.87 min LC-MS m / z:322.2(M+H) + .

[0240] A solution of ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (Intl 3m, 81.5 mg, 0.242 mmol; mixture of epimers at position 9) and propanol (87 μL, 1.21 mmol) in methanol (10 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (76.0 mg, 1.21 mmol) was added, and the mixture was stirred for 5 minutes, then acetic acid (300 μL) was added. After stirring at 0°C for 1 hour, the solvent was evaporated, and the residue was partitioned between a 1% solution of dichloromethane and ammonium hydroxide. The aqueous phase was extracted with dichloromethane (3 × 50 mL), and the combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (4, faster moving fluorescent band) as an off-white foamy substance. Yield: 35 mg (40%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H ): 8.22 (br s, 1H); 7.24 - 7.06 (m, 3H); 6.89 (s, 1H); 6.34 (s, 1H); 4.66 - 4.45 (m, J = 13.1, 6.2 Hz, 2H); 3.73 - 3.52 (m, J = 18.2 Hz, 2H); 3.50 - 3.40 (m, 1H); 3.20 (dd, J = 10.9, 4.4 Hz, 1H); 3.04 - 2.88 (m, J = 12.8, 10.6 Hz, 2H); 2.86 - 2.64 (m, 2H); 2.14 - 1.89 (m, 2H); 1.74 - 1.56 (m, 2H); 1.49 (dd, 6H); 0.96 (t, J = 7.3 Hz, 3H). LC-MS purity: 99% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.51 min. LC-MS m / z: 364.1 (M+H) + . [Examples]

[0241] Preparation of (6aR,9R)-N-((R)-sec-butyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (5) and (6aR,9S)-N-((R)-sec-butyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (5a) Reaction scheme:

[0242] [ka]

[0243] Synthesis protocol: A solution of (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int10m, 55.2 mg, 0.178 mmol; preparation described in Example 3; mixture of epimers at position 9) and acetaldehyde (39.3 mg, 0.89 mmol) in methanol (10 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (56.1 mg, 0.89 mmol) was added, and the mixture was stirred for 5 minutes, then acetic acid (200 μL) was added. The reaction was stirred at 0°C for 1 hour, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (50 mL) and a 1% solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL), and the combined organic phase was dehydrated with anhydrous sodium sulfate and evaporated. The obtained residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain (6aR,9S)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (5a, a faster-moving, less polar diastereomer) as a colorless oil, and (6aR,9R)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (5, a slower-moving, more polar diastereomer) as a colorless solid. The separated isomers were each dissolved in anhydrous methanol (500 μL) and treated with 1MD-(-)-tartaric acid in an equimolar volume of anhydrous methanol.The solvent of the obtained solution was volatilized in a nitrogen stream and dried under high vacuum to obtain (6aR,9S)-9-(((R)-sec-butyl)carbamoyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-7-ium(2S,3S)-3-carboxy-2,3-dihydroxypropanoate (5a tartrate) as a brown amorphous solid, and (6aR,9R)-9-(((R)-sec-butyl)carbamoyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-7-ium(2S,3S)-3-carboxy-2,3-dihydroxypropanoate (5 tartrate) as a colorless solid. 5a: Yield (free base): 12.0 mg (20%). 1 1H NMR spectrum (free base) (300 MHz, CDCl3, δ H ): 8.50-7.90 (m, 2 H); 7.26-7.21 (m, 1 H); 7.20-7.06 (m, 2 H); 6.92 (s, 1 H); 6.59 (d, J = 5.1 Hz, 1 H); 3.93-3.75 (m, 1 H); 0.91 (t, J = 7.4Hz, 3H). 1 1H NMR spectrum (tartrate) (300 MHz, MeOD, δ H): 7.29 (dd, J = 7.0, 1.6, 1H); 7.17 (t, J = 6.9, 2H); 7.09 (s, 1H); 6.62 (d, J = 5.7, 1H); 4.47 (s, 2H); 4.31 (dd, J = 11.9, 5.3, 1H); 3.82 (dd, J = 13.2, 6.4, 2H); 3.80-3.66 (m, 2H); 3.60-3.53 (m, 1H); 3.46-3.34 (m, 2H); 3.02 (t, J = 13.0, 1H); 1.55-1.42 (m, 2H); 1.47 (t, J = 7.3, 3H); 1.19 (d, J = 7.0, 3H); 0.87 (t, J = 7.4, 3H). LC-MS purity (free chlorohydrin): 97% (ELSD), 91% (UV, 310 nm). LC-MS purity (salt tartrate): 99% (ELSD). LC-MS Rt (tartaric acid) (Sinergy Polar RP, 4.6 mm × 150 mm, acrylic / water 30:70~100:0 + 0.1% HBFA, 10 points): 6.48 points. LC-MS m / z: 338.1 (M+H) + . 5: Yield (free salt): 12.5 mg (21%). 1 H NMR tartaric acid (300 MHz, MeOD, δ H): 7.27 (dd, J = 6.1, 2.5, 1H); 7.19-7.09 (m, 2H); 7.07 (s, 1H); 6.49 (s, 1H); 4.44 (s, 2H); 4.37-4.24 (m, 1H); 3.85 (dd, J = 13.3, 6.6, 2H); 3.74-3.61 (m, 2H); 3.60-3.42 (m, 1H); 3.61-3.40 (m, 2H); 3.37-3.33 (m, 1H); 3.08 (t, J = 12.9, 1H); 1.61-1.50 (m, 2H); 1.42 (t, J = 7.2, 3H); 1.16 (d, J = 7.0, 3H); 0.96 (t, J = 7.4, 3H). LC-MS purity (tartrate): 91% (ELSD). LC-MS Rt (tartrate) (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.65 min. LC-MS m / z: 338.1 (M+H) + . [Examples]

[0244] Preparation of (6aR,9R)-N-(pentan-3-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (6) Reaction scheme:

[0245] [ka]

[0246] Synthesis protocol: A solution of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylic acid (Int1, 200 mg, 0.745 mmol), triethylamine (430 μL, 3.00 mmol), and 3-pentanamine (260 μL, 2.23 mmol) in dry N,N-dimethylformamide (10 mL) was cooled to 0°C under an argon atmosphere. Propanephosphonic anhydride (T3P®, 1.30 mL, 2.23 mmol, 50% solution in DMF) was added dropwise over 5 minutes, the resulting mixture was stirred at 0°C for 3 hours, and then quenched with ice-cold water (10 mL). The reaction mixture was concentrated under vacuum with silica gel (10 g), and the resulting solid was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 100:0~98:2) to obtain (6aR,9S)-7-methyl-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int14a, a faster-moving, less polar diastereomer) as a dark brown solid, and (6aR,9R)-7-methyl-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int14, a slower-moving, more polar diastereomer) as a dark brown solid. Yield: 208 mg (83%, total of isomers). Int14a: 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.03 (br s, 1H); 7.87 (br d, J = 6.20 1H); 7.31-7.18 (m, 1H); 7.17-7.05 (m, 2H); 6.98 (s, 1H); 6.56 (d, J = 6.2, 1H); 2.55 (s, 3H); 1.59-1.20 (m, 4H); 0.89 (t, J = 7.4, 3H); 0.72 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD), 100% (UV) 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HFBA, 10 points): 5.27 points. LC-MS m / z: 338.2 (M+H) + . Int14: 1 H NMR スペクトル(300 MHz, CD3CN, δH): 9.03 (br s, 1H); 7.22 (dt, J = 7.2, 3.6, 1H); 7.14-7.05 (m, 2H); 6.95 (s, 1H); 6.49 (br d, J 3.24-3.14 (m, 1H); 3.07 (dd, J = 11.2, 5.0, 1H); 2.69-2.44 (m, 4H); 2.53 (s, 3H); 1.62-1.46 (m, 2H); 1.46-1.31 (m, 2H); 0.96-0.84 (m, 6H). LC-MS purity: 100% (ELSD), 100% (UV)310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 4.95 min. LC-MS m / z: 338.2 (M+H) + .

[0247] A solution of 3-chloroperbenzoic acid (77%, 138 mg, 800 μmol) in dry dichloromethane (5 mL) was added dropwise at 0°C to a solution of (6aR)-7-methyl-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int 14 m, 208 mg, 616 μmol; mixture of epimers at position 9) in dry dichloromethane (10 mL), and the mixture was stirred under an argon atmosphere for 1 hour. Then, a 10% aqueous solution of sodium hydroxide (100 mL) was added to the reaction mixture, and the mixture was extracted with a 10% solution of isopropanol in dichloromethane (3 × 100 mL). The organic phases were combined, dehydrated with anhydrous sodium sulfate, and concentrated under vacuum to obtain (6aR)-7-methyl-9-(pentan-3-ylcarbamoyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline 7-oxide (Int15m) (a mixture of diastereomers; the epimer at position 9). This was used in the next step without further purification. LC-MS purity: 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.09 min LC-MS m / z:354.2(M+H) + .

[0248] Crude (6aR)-7-methyl-9-(pentan-3-ylcarbamoyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline 7-oxide (Int 15m, the total amount obtained by the above procedure; a mixture of epimers at position 9) was dissolved in methanol (20 mL), and the solution was cooled to 0°C under argon. Then iron(II) sulfate heptahydrate (343 mg, 1.23 mmol) was added, and the resulting mixture was stirred at 0°C for 3 hours. At this point, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (150 mL) and an aqueous solution (100 mL) of EDTA (10 g) and 30% ammonium hydroxide (10 mL). The aqueous phase was further extracted with dichloromethane (3 × 100 mL), and the combined organic phase was dehydrated with magnesium sulfate and concentrated under vacuum. The crude residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2~90:10) to obtain (6aR)-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int16m) (a mixture of diastereomers; epimer at position 9) as an amorphous beige solid. Yield: 50.0 mg (25% from Int14m in 2 steps). LC-MS purity: 95% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.77 min LC-MS m / z:324.2(M+H) + .

[0249] A solution of (6aR)-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int16m, 50.0 mg, 0.154 mmol; mixture of epimers at position 9) and propanal (55 μL, 0.771 mmol) in methanol (10 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (48.0 mg, 0.77 mmol) was then added, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (100 μL). After stirring at 0°C for 1 hour, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (200 mL) and 1% ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain (6aR,9R)-N-(pentan-3-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (6, slower moving fluorescent band) as a colorless foamy substance. Yield: 20 mg (30%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H ): 9.00 (br s, 1H); 7.21 (dd, J = 7.6, 0.8, 1H); 7.14-7.00 (m, 2H); 6.99-6.84 (m, 2H); 6.37 (dd, J = 3.8, 1.7, 1H); 3.75-3.61 (m, 1H); 3.60-3.50 (m, 1H); 3.37 (dd, J = 14.4, 5.0, 1H); 3.23-3.13 (m, 1H); 3.07 (dd, J = 11.4, 4.5, 1H); 2.79-2.58 (m, 4H); 1.65-1.45 (m, 4H); 1.44-1.24 (m, 2H); 0.98-0.81 (m, 9H). LC-MS purity: 98% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.72 min. LC-MS m / z: 366.2 (M+H) + . [Examples]

[0250] Preparation of (6aR,9R)-N-((R)-pentan-2-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (7) Reaction scheme:

[0251] [ka]

[0252] Synthesis protocol: A solution of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylic acid (Int1, 200 mg, 0.745 mmol), triethylamine (430 μL, 3.00 mmol), and (R)-pentane-2-amine hydrochloride (250 μg, 1.50 mmol) in dry N,N-dimethylformamide (10 mL) was cooled to 0°C under an argon atmosphere. Then, propanephosphonic anhydride (T3P®, 875 μL, 1.50 mmol, 50% solution in DMF) was added dropwise over 5 minutes. The resulting mixture was stirred at 0°C for 3 hours and quenched with ice water (1 mL). The resulting mixture was concentrated under vacuum with silica gel (10 g) and purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 100:0~98:2) to obtain (6aR,9S)-7-methyl-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int17a, faster fluorescence band) as a dark brown solid, and (6aR,9R)-7-methyl-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int17, slower fluorescence band) as a dark brown solid. Int17a: Yield: 89 mg (35%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.07 (br s, 1H); 7.79 (br d, J = 6.10, 1H); 7.28-7.21 (m, 1H); 7.14-7.09 (m, 2H); 6.98 (s, 1H); 6.53 (d, J = 6.1, 1H); 3.89-3.73 (m, 1H); 3.61 (dd, J = 14.6, 5.5, 1H); 3.15 (br s, 1H); 3.12 (d, J = 12.0, 1H); 3.00 (br s, 1H); 2.69 (dd, J = 11.6, 3.4, 1H); 2.65-2.51 (m, 1H); 2.56 (s, 3H); 1.45-1.31 (m, 4H); 0.98 (d, J = 6.5, 3H); 0.90 (t, J = 6.94, H). LC-MS purity: 95% (ELSD), 100% (UV) 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, アセトニトリル / water 30:70~100:0 + 0.1% HFBA, 10 points): 5.317 points. LC-MS m / z: 338.2 (M+H) + . Int17: Yield: 102 mg (40%). 1 H NMR スペクトル(300 MHz, CD3CN, δ H): 9.02 (br s, 1H); 7.23 (p, J = 3.8, 1H); 7.13-7.07 (m, 2H); 6.95 (s, 1H); 6.53 (br d, J = 6.81, 1H); 6.38 (s, 1H); 3.89 (dt, J = 15.0, 6.6, 1H); 3.48 (dd, J = 14.6, 5.5, 1H); 3.38-3.27 (m, 1H); 3.21-3.11 (m, 1H); 3.05 (dd, J = 11.1, 5.0, 1H); 2.64-2.54 (m, 2H); 2.51 (s, 3H); 1.48–1.29 (m, 4H); 1.11 (d, J = 6.6, 3H); 0.91 (t, J = 7.1, 3H). LC-MS purity: 91% (ELSD), 100% (UV). 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HFBA, 10 points): 5.06 points. LC-MS m / z: 338.2 (M+H) + .

[0253] A solution of 3-chloroperbenzoic acid (77%, 142.7 mg, 827 μmol) in dry dichloromethane (5 mL) was added dropwise at 0°C to a solution of (6aR)-7-methyl-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int 17 m, 215 mg, 630 μmol; mixture of epimers at position 9) in dry dichloromethane (10 mL), and the mixture was stirred at 0°C under an argon atmosphere at a given temperature for 1 hour. Then, a 10% aqueous solution of sodium hydroxide (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with a 10% solution of isopropanol in dichloromethane (3 × 100 mL). The combined organic phases were dehydrated with anhydrous sodium sulfate and concentrated under vacuum to obtain (6aR,)-7-methyl-9-(((R)-pentan-2-yl)carbamoyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline 7-oxide (Int18m) (a mixture of diastereomers, with the epimer at position 9). This was used in the next step without further purification. LC-MS purity: 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.23 min LC-MS m / z:354.1(M+H) + .

[0254] Crude (6aR)-7-methyl-9-(((R)-pentan-2-yl)carbamoyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline 7-oxide (Int 18m, the total amount obtained by the above procedure; a mixture of epimers at position 9) was dissolved in methanol (20 mL) and cooled to 0°C under argon. Then iron(II) sulfate heptahydrate (351 mg, 1.26 mmol) was added, and the resulting mixture was stirred at 0°C for 3 hours. The solvent was removed under vacuum, and the residue was partitioned between dichloromethane (150 mL) and an aqueous solution (100 mL) of EDTA (10 g) and 30% ammonium hydroxide (10 mL). The aqueous phase was further extracted with dichloromethane (3 × 100 mL), and the combined organic phase was dehydrated with magnesium sulfate and concentrated under vacuum. The crude residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2~90:10) to obtain (6aR)-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int19m) (a mixture of diastereomers, epimer at position 9) as an amorphous beige solid. Yield: 47.0 mg (23% from Int17m in 2 steps). LC-MS purity: 97% (combined diastereomers, UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 mins): 4.94 mins, 5.19 mins. LC-MS m / z:324.2(M+H) + .

[0255] A solution of (6aR)-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int19m, 47.0 mg, 0.145 mmol; mixture of epimers at position 9) and propanal (53 μL, 0.74 mmol) in methanol (10 mL) was cooled to 0°C under argon. Sodium borocyanohydride (46.0 mg, 0.74 mmol) was added, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (100 μL). After stirring at 0°C for 1 hour, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (200 mL) and a 1% solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL), and the combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain (6aR,9R)-7-propyl-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (7, slower moving fluorescent band) as a dark brown foamy substance. Yield: 20 mg. LC-MS purity: 100% (ELSD), 89% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.88 min LC-MS m / z:366.2(M+H) + . [Examples]

[0256] Preparation of (6aR,9R)-7-allyl-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (8) and (6aR,9S)-7-allyl-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (8a) Reaction scheme:

[0257] [ka]

[0258] Synthesis protocol: (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int10m, 35mg, 0.113 mmol; preparation described in Example 3; mixture of epimers at position 9) and potassium bicarbonate (23mg, 0.226 mmol) were stirred in methanol (2mL), to which allyl bromide (20μL, 0.226 mmol) in methanol (1mL) was added dropwise under argon. The resulting mixture was stirred at ambient temperature for 72 hours, diluted with dichloromethane (50mL), and silica gel (10g) was introduced. The solvent of the obtained suspension was volatilized under vacuum, and the mixture was subjected to silica gel chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9S)-N-((R)-sec-butyl)-7-allyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (8a, faster moving fluorescent band) as a brownish amorphous solid, and (6aR,9R)-N-((R)-sec-butyl)-7-allyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (8, slower moving fluorescent band) as a brownish foamy substance. The separated isomers were each dissolved in anhydrous methanol (500 μL) and treated with 1 M D-(-)-tartaric acid in an equimolar volume of anhydrous methanol. The solvent of the obtained solution was volatilized under a nitrogen stream and dried under high vacuum to obtain (6aR,9S)-7-allyl-9-(((R)-sec-butyl)carbamoyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-7-ium(2S,3S)-3-carboxy-2,3-dihydroxypropanoate (8a tartrate) as a light brown solid, and (6aR,9R)-7-allyl-9-(((R)-sec-butyl)carbamoyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-7-ium(2S,3S)-3-carboxy-2,3-dihydroxypropanoate (8 tartrate) as a light brown solid. 8a: Yield (free base): 14.1 mg (35%). 1 H NMR tartaric acid (300 MHz, MeOD, δ H ): 7.26 (dt, J = 7.3, 3.6, 1H); 7.18-7.08 (m, 2H); 7.05 (d, J = 1.1, 1H); 6.57 (d, J = 5.6, 1H); 6.18-5.99 (m, 1H); 5.63-5.46 (m, 2H); 4.47 (s, 2H); 4.14 (dd, J = 13.7, 5.6, 1H); 4.02 (d, J = 6.8, 1H); 3.87-3.62 (m, 4H); 3.40 (br s, 1H); 3.18 (dd, J = 12.1, 3.5, 1H); 2.93 (t, J = 13.0, 1H); 1.58-1.40 (m, 2H); 1.18 (t, J = 7.0, 1H); 1.13 (d, J = 6.6, 3H); 0.89 (t, J = 7.4, 3H). LC-MS purity (free saturates): 98% (ELSD), 97% (UV, 310 nm). LC-MS purity (salt tartrate): 99% (ELSD). LC-MS Rt (tartaric acid) (Sinergy Polar RP 4.6 mm × 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HFBA, 10 minutes): 6.65 points. LC-MS m / z: 350.1 (M+H) + . 8: Yield (free salt): 12 mg (30%). 1 H NMR tartaric acid (300 MHz, MeOD, δ H): 7.25 (dd, J = 6.6, 2.0, 1H); 7.18-7.07 (m, 2H); 7.04 (s, 1H); 6.46 (s, 1H); 6.20-5.99 (m, 1H); 5.67-5.47 (m, 2H); 4.46 (s, 2H); 4.16-4.09 (m, 1H); 4.06 (dd, J = 21.2, 7.4, 1H); 3.91-3.64 (m, 4H); 3.57 (dd, J = 12.0, 4.8, 1H); 3.29 (t, J = 12.6, 1H); 3.00 (t, J = 12.6, 1H); 1.62-1.44 (m, 2H); 1.20 (t, J = 3.3, 1H); 1.17 (d, J = 7.0, 3H); 0.94 (t, J = 7.4, 3H). LC-MS purity (tartrate): 98% (ELSD). LC-MS Rt (tartrate) (Sinergy Polar RP 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.47 min. LC-MS m / z: 350.1 (M+H) + . [Examples]

[0259] Preparation of (6aR,9R)-5-bromo-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (9) Reaction scheme:

[0260] [ka]

[0261] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (1, 53.0 mg, 0.151 mmol) in anhydrous dioxane (2.0 mL) was flushed with argon. To this solution, a 10% v / v solution of bromine in dioxane (754 μL, 0.151 mmol) was added dropwise, and the resulting mixture was stirred for 48 hours. The reaction mixture was filtered through a silica gel pad. The filtrate was concentrated under vacuum, and the residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-5-bromo-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (9) as a dark amorphous solid. Yield: 28.4 mg (44%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H ): 9.36 (s, 1H), 7.19 - 7.11 (m, 1H), 7.11 - 7.06 (m, 2H), 6.32 (s, 1H), 3.75 - 3.65 (m, 1H), 3.45 (dt, J = 10.8, 3.6, 2H), 3.41 - 3.29 (m, 4H), 3.13 (ddd, J = 11.2, 4.8, 1.0, 1H), 2.89 (ddd, J = 13.3, 9.0, 7.1, 1H), 2.61 (t, J = 10.8, 1H), 2.48 (ddd, J = 13.4, 8.7, 4.9, 1H), 2.40 (dd, J = 16.3, 12.6, 1H), 1.67 - 1.46 (m, 2H), 1.21 (t, J =7.1, 3H), 1.10 (t, J = 7.1, 3H), 0.94 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.20 min. LC-MS m / z: 431.9 (M+H) + .

[0262] A solution of (6aR,9R)-5-bromo-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (9, 28.4 mg, 66 μmol) in gradient grade acetonitrile (5.0 mL) was treated with 1 M D-(-)-tartaric acid aqueous solution (33 μL, 66 μmol) and stirred for 5 minutes. The solvent was removed under vacuum, the residue was redissolved in dioxane (5.0 mL), and then lyophilized at 0°C to obtain (6aR,9R)-5-bromo-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemitartrate (9 hemitartrate) as a flaky light brown solid. Yield: 33.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.18 (dd, J = 7.0, 1.9, 1H), 7.16 - 7.06 (m, 2H), 6.39 (s, 1H), 4.40 (s, 1H), 4.07 - 3.99 (m, 1H), 3.99 - 3.86 (m, 1H), 3.58 (dt, J = 14.1, 7.2, 2H), 3.51 - 3.36 (m, 5H), 3.27 - 3.12 (m, 2H), 3.09 - 2.93 (m, 1H), 2.77 (t, J = 12.4, 1H), 1.89 - 1.69 (m, 2H), 1.31 (t, J = 7.1, 3H), 1.19 (t, J = 7.1, 3H), 1.06 (t, J = 7.3, 3H). LC-MS purity: 100% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.20 min. LC-MS m / z: 431.9 (M+H) + . [Examples]

[0263] Preparation of (6aR,9R)-N,N-diethyl-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (10) Reaction scheme:

[0264] [ka]

[0265] Synthesis protocol: A solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamideheptafluorobutanoate (Int7m, 40.0 mg, 0.077 mmol; mixture of epimers at position 9) and 2-methoxybenzaldehyde (32.0 mg, 0.23 mmol) in methanol (10 mL) was cooled to 0°C under argon. Sodium borocyanohydride (15.0 mg, 0.23 mmol) was added, and the resulting mixture was stirred for 5 minutes, then glacial acetic acid (100 μL) was added, and stirring was continued at room temperature. After 48 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (200 mL) and a 1% solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phases were dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-N,N-diethyl-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (10) as a colorless solid. Yield: 22 mg (66%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H ): 8.99 (br s, 1H); 7.48 (d, J = 7.4, 1H); 7.30-7.19 (m, 2H); 7.14-7.05 (m, 2H); 7.00-6.90 (m, 3H); 6.32 (s, 1H); 4.14 (d, J = 14.6, 1H); 3.80 (s, 3H); 3.75-3.63 (m, 3H); 3.47-3.26 (m, 5H); 3.05 (dd, J = 11.1, 4.4, 1H); 2.70-2.47 (m, 2H); 1.08 (dt, J = 9.4, 7.1, 6H). LC-MS purity: 99% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 7.64 min. LC-MS m / z: 430.2 (M+H) + . [Examples]

[0266] Preparation of (6aR,9R)-N,N-diethyl-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (11) Reaction scheme:

[0267] [ka]

[0268] Synthesis protocol: 2-(2-methoxyphenyl)acetic acid (1.66 g, 10.0 mmol) was dissolved in dry methanol (10 mL), and 96% sulfuric acid (1.0 mL) was added. The mixture was refluxed for 3 hours. The solvent was then evaporated, and the residue was partitioned between ethyl acetate (50 mL) and a saturated sodium bicarbonate solution (50 mL). The organic phase was dehydrated with anhydrous sodium sulfate and concentrated under vacuum to obtain methyl 2-(2-methoxyphenyl)acetate (Int20) as a colorless oil. Yield: 1.80 g (100%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H ): 7.30-7.14 (m, 2 H); 6.96-6.84 (m, 2 H); 3.82 (s, 3 H); 3.69 (s, 3 H); 3.64 (s, 2 H).

[0269] 2-(2-methoxyphenyl)acetate (Int20, 1.80 g, 10.0 mmol) was dissolved in dry toluene (20 mL) and cooled to -78°C. A solution of diisobutylaluminum hydride (15.0 mL, 15 mmol, 1 M solution in hexane) was added dropwise, and the resulting mixture was stirred at -78°C for 2 hours. The reaction product was quenched by the slow addition of methanol (5 mL), followed by the addition of 10% solutions of sodium potassium tartrate (20 mL) and ethyl acetate (50 mL). The resulting mixture was then stirred at room temperature for 1 hour. The phases were separated, the aqueous phase was further extracted with ethyl acetate (2 × 50 mL), and the combined organic phase was dehydrated with anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluate: cyclohexane / ethyl acetate 9:1) to obtain 2-(2-methoxyphenyl)acetaldehyde (Int21) as a colorless oil. Yield: 1.11 g (74%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H): 9.68 (t, J = 2.1 Hz, 1 H); 7.30 (td, J = 8.1, 1.6 Hz, 1 H); 7.15 (dd, J = 7.3, 1.2 Hz, 1 H); 7.01-6.87 (m, 2 H); 3.83 (s, 3 H); 3.65 (d, J = 2.0 Hz, 2H).

[0270] A solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hydrochloride (Int7m, 51.0 mg, 0.148 mmol; HCl salt; mixture of epimers at position 9) and 2-(2-methoxyphenyl)acetaldehyde (Int21, 111 mg, 0.74 mmol) in methanol (10 mL) was cooled to 0°C under argon. Sodium borocyanohydride (46.0 mg, 0.74 mmol) was added, and the mixture was stirred for 5 minutes, then glacial acetic acid (100 μL) was added, and stirring was continued at 0°C. After 1 hour, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (200 mL) and a 1% solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-N,N-diethyl-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (11) as a colorless foamy substance. Yield: 20 mg (30%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.01 (br s, 1H); 7.25-7.15 (m, 3H); 7.13-7.06 (m, 2H); 6.99-6.83 (m, 3H); 6.31 (s, 1H); 3.85 (s, 3H); 3.76-3.67 (m, 1H); 3.60 (dd, J = 14.4, 5.4, 1H); 3.53-3.33 (m, 4H); 3.18 (dd, J = 11.1, 4.1, 1H); 3.13-3.02 (m, 1H); 2.97-2.69 (m, 4H); 2.46 (ddd, J = 14.2, 11.1, 1.5, 1H); 1.22 (t, J = 7.1, 3H); 1.12 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.61 min. LC-MS m / z: 444.3 (M+H) + . [Examples]

[0271] Preparation of (6aR,9R)-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (12) Reaction scheme:

[0272] [ka]

[0273] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 30.0 mg, 78.0 μmol; 2 moles of Int7 per mole of tartrate) and 3,3,3-trifluoropropanal (27.0 μL, 0.31 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (20.0 mg, 0.32 mmol) was added, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 3 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (12) as a colorless foamy substance. Yield: 27.2 mg (86%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.01 (s, 1H), 7.23 (dd, J = 6.8, 1.9, 1H), 7.15 - 7.03 (m, 2H), 6.96 (t, J = 1.8, 1H), 6.31 (s, 1H), 3.79 - 3.66 (m, 1H), 3.51 (dd, J = 14.5, 5.5, 1H), 3.46 (dd, J = 7.3, 3.2, 1H), 3.37 (m, 4H), 3.22 (ddd, J = 14.0, 9.1, 6.8, 1H), 3.09 (ddd, J = 11.1, 4.8, 1.0, 1H), 2.86 (ddd, J = 14.0, 8.9, 5.3, 1H), 2.73 (t, 1H), 2.57 (dd, J = 11.1, 1.7, 1H), 2.54 - 2.40 (m, 2H), 1.22 (t, J = 7.1, 3H), 1.11 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.85 min. LC-MS m / z: 406.0 (M+H) + .

[0274] (6aR,9R)-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (12, 27.2 mg, 67.1 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (33.6 μL, 33.6 μmol). The solvent was removed under vacuum, the obtained material was dissolved again in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (12-hemitartrate) as a splashable white solid. Yield: 32.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.20 (dd, J = 6.3, 2.4, 1H), 7.14 - 7.05 (m, 2H), 6.98 (d, J = 1.2, 1H), 6.31 (s, 1H), 4.50 (s, 1H), 3.99 - 3.88 (m, 1H), 3.63 - 3.40 (m, 7H), 3.20 (dd, J = 11.1, 4.5, 1H), 3.11 - 2.99 (m, 1H), 2.94 (t, J = 10.3, 1H), 2.73 (t, J = 12.0, 1H), 2.58 (ddd, J = 16.1, 10.2, 5.5, 2H), 1.30 (t, J = 7.1, 3H), 1.18 (t, J = 7.1, 3H). LC-MS purity: 97% (ELSD), 92% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.85 min. LC-MS m / z: 406.0 (M+H) + . [Examples]

[0275] Preparation of (6aR,9R)-N,N-diethyl-7-(cyclopropylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (13) Reaction scheme:

[0276] [ka]

[0277] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 30.0 mg, 78.0 μmol; 2 moles of Int7 per mole of tartrate) and cyclopropanecarboldehyde (23.0 μL, 0.31 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (20.0 mg, 0.32 mmol) was added, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 3 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phases were dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-7-(cyclopropylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (13) as a colorless foamy substance. Yield: 19.0 mg (67%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H ): 9.17 (s, 1H), 7.27 (dd, J = 6.8, 1.9, 1H), 7.17 - 7.05 (m, 2H), 7.00 (s, 1H), 6.37 (s, 1H), 3.98 - 3.79 (m, 2H), 3.62 - 3.30 (m, 6H), 3.18 (dd, J = 11.3, 7.7, 1H), 3.01 - 2.84 (m, 2H), 2.78 (t, J = 13.1, 1H), 1.24 (t, J = 7.1, 3H), 1.13 (t, J = 7.1, 3H), 1.15 - 1.00 (m, 1H), 0.65 - 0.56 (m, 2H), 0.34 - 0.26 (m, 2H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.56 min. LC-MS m / z: 364.1 (M+H) + .

[0278] (6aR,9R)-7-(cyclopropylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (13, 19.0 mg, 52.2 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (26.2 μL, 26.2 μmol). The solvent was removed under vacuum, and the obtained material was dissolved again in dioxane (5.0 mL) and freeze-dried at 0°C to obtain (6aR,9R)-7-(cyclopropylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemi-tartrate (13-hemi-tartrate) as a splashable white solid. Yield: 22.9 mg (quantitative). δ 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.27 (p, J = 3.8, 1H), 7.17 - 7.10 (m, 2H), 7.07 (d, J = 0.8, 1H), 6.43 (dd, J = 2.8, 1.7, 1H), 4.40 (s, 1H), 4.36 - 4.24 (m, 1H), 4.15 (s, 1H), 3.77 - 3.36 (m, 8H), 3.31 - 3.22 (m, 1H), 3.02 (t, J = 12.9, 1H), 1.34 (t, J = 7.1, 3H), 1.34 - 1.16 (m, 1H), 1.20 (t, J = 7.1, 3H), 0.78 (q, J = 5.4, ​​2H), 0.48 (d, J = 4.3, 2H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.56 min. LC-MS m / z: 364.1 (M+H) + . [Examples]

[0279] Preparation of ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanone (14) Reaction scheme:

[0280] [ka]

[0281] Synthesis protocol: A solution of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylic acid (Int1, 500 mg, 1.86 mmol), triethylamine (1.05 mL, 7.44 mmol), and pyrrolidine (460 μl, 5.59 mmol) in dry N,N-dimethylformamide (10 mL) was cooled to 0°C under an argon atmosphere. Propanephosphonic anhydride (T3P®, 3.26 mL, 5.59 mmol, 50% solution in DMF) was added dropwise over 5 minutes. The resulting mixture was stirred at 0°C for 1 hour. The reaction was determined to be complete by LC-MS, and then the mixture was quenched with ice-cold water (10 mL). The mixture was partitioned between 1 M aqueous ammonium hydroxide solution (200 mL) and ethyl acetate (100 mL). The aqueous phase was re-extracted with ethyl acetate (2 × 150 mL). The organic phase was combined and then washed with a 10% aqueous solution of lithium chloride (4 × 150 mL), dehydrated with anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 100:0~98:2) to obtain ((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanone (Int22) as a dark brown solid. Yield: 255 mg (43%). LC-MS purity: 100% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.59 min LC-MS m / z:322.0(M+H) + .

[0282] A solution of ((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanone (Int22, 52.7 mg, 0.164 mmol) in gradient grade acetonitrile (5.0 mL) was treated with 1 M D-(-)-tartaric acid aqueous solution (81.4 μL, 0.081 mmol) and stirred at room temperature for 5 minutes. The solvent was removed under vacuum. The residue was redissolved in dioxane (5.0 mL) and freeze-dried at 0°C to obtain ((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanonehemitartrate (Int22hemitartrate) as a splashable white solid. Yield: 69.0 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.24 (d, J = 7.7, 1H), 7.20 - 7.07 (m, 2H), 7.03 (s, 1H), 6.46 (s, 1H), 4.40 (s, 1H), 4.07 (dd, J = 6.5, 4.0, 1H), 3.90 - 3.79 (m, 1H), 3.76 - 3.67 (m, 1H), 3.71 (dd, J = 13.8, 6.3, 2H), 3.54 - 3.44 (m, 1H), 3.49 (dd, J = 12.7, 5.9, 2H), 3.28 - 3.16 (m, 1H), 2.94 (s, 3H), 2.95 - 2.83 (m, 1H), 2.10 - 1.90 (m, 4H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.59 min. LC-MS m / z: 322.0 (M+H) + .

[0283] To a solution of cyanogen bromide (380 mg, 3.60 mmol) in carbon tetrachloride (30 mL), ((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanone (Int22, 255 mg, 0.795 mmol) in chloroform (10 mL) and carbon tetrachloride (70 mL) were added under reflux at a rate sufficient to maintain reflux. The reaction mixture was then heated under reflux for an additional 4 hours. The mixture was then allowed to cool to room temperature, and silica gel (silica gel 0.063-0.200 mm, 10 g) was added. The mixture was concentrated under vacuum. The obtained powder was added to the upper side of a flash chromatography column pre-packed with silica gel, and the product was eluted as follows (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 100:0~50:50) to obtain (6aR,9R)-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindoro[4,3-fg]quinoline-7(4H)-carbonitrile (Int23) as a colorless amorphous solid. Yield: 200 mg (75%). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 8.10 (s, 1H), 7.33 - 7.23 (m, 1H), 7.22 - 7.13 (m, 2H), 6.98 (s, 1H), 6.36 (s, 1H), 4.32 - 4.17 (m, 1H), 3.92 - 3.80 (m, 1H), 3.76 - 3.69 (m, 2H), 3.68 - 3.50 (m, 5H), 3.11 - 2.98 (m, 1H), 2.11 - 1.89 (m, 4H). LC-MS purity: 98% (ELSD), 98% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.87 min. LC-MS m / z: 333.0 (M+H) + .

[0284] A solution of (6aR,9R)-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindoro[4,3-fg]quinoline-7(4H)-carbonitrile (Int23, 200 mg, 0.601 mmol) in acetic acid (15 mL) and water (1.5 mL) was treated with zinc dust (1000 mg). The resulting suspension was heated under reflux for 1 hour. After cooling, the mixture was filtered through cotton, and the solution was basicized with 10% aqueous ethylenediamine (100 mL) and stirred for 1 hour. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic extracts were dehydrated with anhydrous sodium sulfate and then filtered. The filtrate was treated with silica gel (silica gel 0.063~0.200 mm, 10 g) and evaporated under vacuum. The powder was added to the upper side of a flash chromatography column pre-packed with silica gel, and the product was eluted as follows (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 100:0~98:2) to obtain ((6aR,9R)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanone (Int24) as a dark amorphous solid. Yield: 125 mg (68%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.08 (s, 1H), 7.28 - 7.17 (m, 1H), 7.16 - 7.06 (m, 2H), 6.95 (s, 1H), 6.39 (s, 1H), 3.71 (ddd, J = 11.4, 5.7, 2.4, 1H), 3.66 - 3.50 (m, 3H), 3.39 (td, J = 6.8, 3.7, 2H), 3.25 (dd, J = 12.9, 4.8, 1H), 3.14 (dd, J = 14.8, 5.8, 1H), 2.99 (dd, J = 12.5, 9.3, 1H), 2.67 - 2.53 (m, 1H), 2.14 (s, 1H), 1.98 - 1.91 (m, 2H), 1.90 - 1.77 (m, 2H). LC-MS purity: 95% (ELSD), 95% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HBFA, 10 points): 4.22 points. LC-MS m / z: 308.0 (M+H) + .

[0285] A solution of ((6aR,9R)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanonehemitartrate (Int24, 40 mg, 105 μmol; 2 moles of Int24 per mole of tartrate; salt prepared as described for other hemitartrates) and propanal (15 μL, 210 μmol) in methanol (2 mL) was purged with argon gas and cooled to 0°C. Sodium borocyanohydride (14 mg, 210 μmol) was added. The resulting mixture was stirred for 5 minutes, then acetic acid (50 μL) was introduced. After stirring at 0°C for 1 hour, silica gel (silica gel 0.063~0.200 mm, 10 g) was added, and the mixture was concentrated under vacuum. The powder was added to the upper side of a flash chromatography column pre-packed with silica gel, and the product was eluted as follows (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanone (14) as a colorless foamy substance. Yield: 20.5 mg (56%). LC-MS purity: 100% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.28 min LC-MS m / z:350.1(M+H) + .

[0286] A solution of ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanone (14, 20.5 mg, 58.7 μmol) in gradient grade acetonitrile (5.0 mL) was treated with 1 M D-(-)-tartaric acid aqueous solution (29 μL, 29 μmol). After stirring at room temperature for 5 minutes, the solvent was removed under vacuum. The residue was redissolved in dioxane (5.0 mL) and freeze-dried at 0°C to obtain ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrrolidine-1-yl)methanone hemitartrate (14 hemitartrate) as a splashable white solid. Yield: 23.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.26 (dd, J = 7.2, 1.4, 1H), 7.19 - 7.09 (m, 2H), 7.06 (d, J = 1.1, 1H), 6.47 (s, 1H), 4.39 (s, 1H), 4.25 - 4.10 (m, 1H), 4.08 - 3.95 (m, 1H), 3.74 (dd, J = 6.3, 4.7, 2H), 3.70 - 3.63 (m, 2H), 3.59 - 3.47 (m, 3H), 3.47 - 3.38 (m, 1H), 3.25 - 3.11 (m, 1H), 2.99 (t, J = 12.0, 1H), 2.07 (dt, J = 11.5, 5.8, 2H), 1.97 (dt, J = 9.0, 4.6, 2H), 1.90 - 1.77 (m, 2H), 1.07 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.28 min. LC-MS m / z: 350.1 (M+H) + . [Examples]

[0287] Preparation of (6aR,9R)-N,N-diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (16) Reaction scheme:

[0288] [ka]

[0289] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 2-hydroxybenzaldehyde (22.0 μL, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (13.0 mg, 0.208 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 3 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain a material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 × 50 mL), basicized with 24% aqueous ammonium hydroxide, and extracted with dichloromethane (3 × 50 mL). The combined organic extracts were dehydrated with anhydrous sodium sulfate and concentrated under vacuum to obtain (6aR,9R)-N,N-diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (16) as a colorless solid. Yield: 9.2 mg (43%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.03 (s, 1H), 7.25 (dd, J = 6.1, 2.6, 1H), 7.20 - 7.06 (m, 3H), 6.96 (t, J = 1.7, 1H), 6.87 - 6.71 (m, 3H), 6.37 (s, 1H), 4.61 (d, J = 14.2, 1H), 3.79 - 3.73 (m, 1H), 3.68 (dd, J = 14.3, 5.1, 1H), 3.57 (d, J = 14.3, 1H), 3.49 (ddd, J = 11.5, 4.6, 2.5, 1H), 3.41 (dd, J = 15.0, 7.4, 1H), 3.36 - 3.25 (m, 4H), 3.08 (dd, J = 11.5, 4.4, 1H), 2.79 (dd, J = 12.0, 2.2, 1H), 2.72 (dd, J = 11.6, 9.2, 1H), 1.08 (dt, J = 14.3, 7.1, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.85 min. LC-MS m / z: 416.1 (M+H) + .

[0290] (6aR,9R)-N,N-diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (16 mg, 9.20 mg, 22.1 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (11.0 μL, 11.0 μmol). The solvent was removed under vacuum, the obtained material was dissolved again in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (16-hemitartrate) as a splashable off-white solid. Yield: 13.3 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.33 - 7.18 (m, 3H), 7.16 - 7.07 (m, 2H), 7.03 (d, J = 1.0, 1H), 6.87 (t, J = 7.7, 2H), 6.37 (s, 1H), 4.67 (d, J = 13.6, 1H), 4.42 (s, 1H), 4.05 (d, J = 13.6, 1H), 4.00 - 3.91 (m, 2H), 3.86 (dd, J = 13.8, 5.0, 1H), 3.66 - 3.33 (m, J = 7.9, 1.9, 6H), 3.12 - 2.91 (m, 2H), 1.18 (t, J = 7.1, 3H), 1.12 (t, J = 7.1, 3H). LC-MS purity: 97% (ELSD), 90% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.84 min. LC-MS m / z: 416.1 (M+H) + . [Examples]

[0291] Preparation of (6aR,9R)-N,N-diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (18) Reaction scheme:

[0292] [ka]

[0293] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 3-methoxybenzaldehyde (28.3 μL, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (13.0 mg, 0.208 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 3 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain a material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 × 50 mL), basicized with 24% aqueous ammonium hydroxide, and extracted with dichloromethane (3 × 50 mL). The combined organic extracts were dehydrated with anhydrous sodium sulfate and concentrated under vacuum to obtain (6aR,9R)-N,N-diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (18) as a colorless solid. Yield: 14.2 mg (64%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.02 (s, 1H), 7.33 - 7.21 (m, 2H), 7.18 - 7.08 (m, 2H), 7.06 - 7.00 (m, 2H), 6.98 (t, J = 1.7, 1H), 6.88 - 6.81 (m, 1H), 6.37 (s, 1H), 4.33 (d, J = 14.1, 1H), 3.81 (s, 3H), 3.74 - 3.68 (m, 1H), 3.68 (dd, J = 14.6, 5.4, 1H), 3.49 - 3.25 (m, 6H), 3.02 (ddd, J = 11.1, 4.7, 1.0, 1H), 2.69 (ddd, J = 14.6, 11.3, 1.7, 1H), 2.56 (t, J = 10.5, 1H), 1.08 (td, J = 7.1, 2.5, 6H). LC-MS purity: 97% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.31 min. LC-MS m / z: 430.1 (M+H) + .

[0294] (6aR,9R)-N,N-diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (18 mg, 14.2 mg, 33.0 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (16.4 μL, 16.4 μmol). The solvent was removed under vacuum, the obtained material was dissolved again in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (18-hemitartrate) as a splashable white solid. Yield: 16.8 mg (quantitative). 11H NMR spectrum (300 MHz, MeOD, δ H ): 7.30 (t, J = 7.9, 1H), 7.22 (dd, J = 6.5, 2.2, 1H), 7.15 - 7.00 (m, 5H), 6.91 (dd, J = 8.2, 1.9, 1H), 6.35 (s, 1H), 4.46 (d, J = 13.1, 1H), 4.44 (s, 1H), 3.91 - 3.84 (m, 2H), 3.81 (s, 3H), 3.83 - 3.78 (m, 2H), 3.51 - 3.33 (m, 4H), 3.21 (dd, J = 11.4, 4.2, 1H), 2.92 (t, J = 13.8, 1H), 2.82 (t, J = 10.2, 1H), 1.13 (dt, J = 14.4, 7.2, 6H). LC-MS purity: 99% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.31 min. LC-MS m / z: 430.1 (M+H) + . [Examples]

[0295] Preparation of (6aR,9R)-N,N-diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (19) Reaction scheme:

[0296] [ka]

[0297] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and p-anisaldehyde (22.0 μL, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (13.0 mg, 0.208 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 3 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain a material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 × 50 mL), basicized with 24% aqueous ammonium hydroxide, and extracted with dichloromethane (3 × 50 mL). The combined organic extracts were dehydrated with anhydrous sodium sulfate and concentrated under vacuum to obtain (6aR,9R)-N,N-diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (19) as a colorless solid. Yield: 15.6 mg (70%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.01 (s, 1H), 7.31 (d, J = 8.6, 2H), 7.23 (dd, J = 6.7, 1.9, 1H), 7.14 - 7.05 (m, 2H), 6.96 (t, J = 1.7, 1H), 6.89 (d, J = 10.9, 2H), 6.32 (s, 1H), 4.24 (d, J = 13.7, 1H), 3.77 (s, 3H), 3.69 (dd, J = 14.7, 5.3, 1H), 3.63 - 3.58 (m, 1H), 3.45 - 3.18 (m, 6H), 2.99 (ddd, J = 11.1, 4.7, 0.9, 1H), 2.66 (ddd, J = 14.5, 11.3, 1.6, 1H), 2.49 (t, J = 10.6, 1H), 1.05 (t, J = 7.1, 6H). LC-MS purity: 97% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.24 min. LC-MS m / z: 430.1 (M+H) + .

[0298] (6aR,9R)-N,N-diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (19 mg, 15.6 mg, 36.3 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (18.2 μL, 18.2 μmol). The solvent was removed under vacuum, the obtained material was dissolved again in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (19-hemitartrate) as a splashable white solid. Yield: 18.4 mg (quantitative). 11H NMR spectrum (300 MHz, MeOD, δ H ): 7.44 (d, J = 8.6, 2H), 7.25 (dd, J = 5.4, 3.4, 1H), 7.17 - 7.10 (m, 2H), 7.07 (d, J = 1.1, 1H), 6.98 (d, J = 8.7, 2H), 6.36 (s, 1H), 4.48 (d, J = 13.5, 1H), 4.45 (s, 1H), 4.02 - 3.97 (m, 1H), 3.97 - 3.88 (m, 3H), 3.81 (s, 3H), 3.48 (dd, J = 14.8, 7.6, 2H), 3.45 (ddd, J = 14.6, 13.5, 7.4, 2H), 3.30 - 3.27 (m, 1H), 3.09 - 2.83 (m, 2H), 1.17 (dt, J = 14.2, 7.1, 6H). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.24 min. LC-MS m / z: 430.1 (M+H) + . [Examples]

[0299] Preparation of (6aR,9R)-N,N-diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (20) Reaction scheme:

[0300] [ka]

[0301] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 30.0 mg, 78.0 μmol; 2 moles of Int7 per mole of tartrate) and 2-(3-methoxyphenyl)acetaldehyde (50.0 mg, 0.33 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (20.0 mg, 0.32 mmol) was added, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 3 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain a material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 × 50 mL), basicized with 24% aqueous ammonium hydroxide, and extracted with dichloromethane (3 × 50 mL). The combined organic extracts were dehydrated with anhydrous sodium sulfate and concentrated under vacuum to obtain (6aR,9R)-N,N-diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (20) as a colorless foamy substance. Yield: 14.9 mg (43%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 8.99 (s, 1H), 7.27 - 7.16 (m, 2H), 7.14 - 7.05 (m, 2H), 6.95 (t, J = 1.7, 1H), 6.87 (dd, J = 4.0, 2.2, 2H), 6.76 (ddd, J = 8.3, 2.5, 0.9, 1H), 6.30 (s, 1H), 3.77 (s, 3H), 3.74 - 3.65 (m, 1H), 3.55 (dd, J = 14.5, 5.3, 1H), 3.50 - 3.29 (m, 5H), 3.22 - 3.10 (m, 2H), 2.92 - 2.69 (m, 4H), 2.48 (ddd, J = 14.3, 11.0, 1.6, 1H), 1.21 (t, J = 7.1, 3H), 1.11 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.58 min. LC-MS m / z: 444.2 (M+H) + .

[0302] (6aR,9R)-N,N-diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (20 mg, 14.9 mg, 33.6 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (16.8 μL, 16.8 μmol). The solvent was removed under vacuum, the obtained material was dissolved again in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (20-hemitartrate) as a splashable off-white solid. Yield: 17.4 mg (quantitative). 11H NMR spectrum (300 MHz, MeOD, δ H ): 7.28 - 7.20 (m, 2H), 7.14 - 7.08 (m, 2H), 7.02 (d, J = 1.0, 1H), 6.92 - 6.87 (m, 2H), 6.80 (dd, J = 8.3, 1.5, 1H), 6.37 (s, 1H), 4.41 (s, 1H), 4.08 - 3.96 (m, 2H), 3.79 (s, 3H), 3.68 - 3.49 (m, 5H), 3.49 - 3.38 (m, 4H), 3.10 - 2.98 (m, 2H), 2.91 (t, J = 12.9, 1H), 1.32 (t, J = 7.2, 3H), 1.19 (t, J = 7.1, 3H). LC-MS purity: 96% (ELSD), 90% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.58 min. LC-MS m / z: 444.1 (M+H) + . [Examples]

[0303] Preparation of (6aR,9R)-N,N-diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (21) Reaction scheme:

[0304] [ka]

[0305] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 33.0 mg, 86.0 μmol; 2 moles of Int7 per mole of tartrate) and 2-(4-methoxyphenyl)acetaldehyde (50.0 mg, 0.33 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (20.0 mg, 0.32 mmol) was added, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 3 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain a material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 × 50 mL), basicized with 24% aqueous ammonium hydroxide, and extracted with dichloromethane (3 × 50 mL). The combined organic extracts were dehydrated with anhydrous sodium sulfate and concentrated under vacuum to obtain (6aR,9R)-N,N-diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (21) as a colorless foamy substance. Yield: 36.2 mg (95%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.04 (s, 1H), 7.25 - 7.17 (m, 3H), 7.13 - 7.05 (m, 2H), 6.95 (t, J = 1.6, 1H), 6.90 - 6.81 (m, 2H), 6.32 (s, 1H), 3.80 - 3.75 (m, 1H), 3.75 (s, J = 3.0, 3H), 3.53 (dd, J = 15.8, 5.4, 1H), 3.48 - 3.32 (m, 5H), 3.23 - 3.07 (m, 2H), 2.93 - 2.74 (m, 4H), 2.55 (ddd, J = 15.6, 12.6, 1.6, 1H), 1.21 (t, J = 7.1, 3H), 1.11 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.55 min. LC-MS m / z: 444.2 (M+H) + .

[0306] (6aR,9R)-N,N-diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (21 mg, 36.2 mg, 81.6 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (40.8 μL, 40.80 μmol). The solvent was removed under vacuum, and the obtained material was dissolved again in dioxane (5.0 mL). It was then freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (21-hemitartrate) as a splashable white solid. Yield: 42.3 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H): 7.28 - 7.19 (m, 3H), 7.16 - 7.08 (m, 2H), 7.03 (d, J = 0.8, 2H), 6.89 (d, J = 8.6, 2H), 6.39 (s, 1H), 4.42 (s, 1H), 4.18 - 4.03 (m, 2H), 3.77 (s, 3H), 3.68 - 3.54 (m, 2H), 3.54 - 3.40 (m, 4H), 3.10 - 2.89 (m, 3H), 1.32 (t, J = 7.2, 3H), 1.20 (t, J = 7.1, 3H). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.57 min. LC-MS m / z: 444.1 (M+H) + . [Examples]

[0307] Preparation of (6aR,9R)-N,N-diethyl-7-(pyridine-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (22) Reaction scheme:

[0308] [ka]

[0309] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and pyridine-2-carboldehyde (20.0 μL, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (13.0 mg, 0.208 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 3 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phase was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain a material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 × 50 mL), basicized with 24% aqueous ammonium hydroxide, and extracted with dichloromethane (3 × 50 mL). The combined organic extracts were dehydrated with anhydrous sodium sulfate and concentrated under vacuum to obtain (6aR,9R)-N,N-diethyl-7-(pyridine-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (22) as a dark amorphous solid. Yield: 15.8 mg (76%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.02 (s, 1H), 8.51 (ddd, J = 4.8, 1.6, 0.8, 1H), 7.73 (td, J = 7.7, 1.8, 1H), 7.57 (d, J = 7.8, 1H), 7.22 (dt, J = 7.7, 3.9, 2H), 7.15 - 7.05 (m, 2H), 6.94 (t, J = 1.7, 1H), 6.33 (s, 1H), 4.31 (d, J = 14.8, 1H), 3.76 - 3.68 (m, 1H), 3.72 (d, J = 14.8, 1H), 3.66 (dd, J = 14.4, 5.1, 1H), 3.57 - 3.46 (m, 1H), 3.44 - 3.27 (m, 4H), 3.05 (dd, J = 10.8, 4.3, 1H), 2.69 (t, J = 10.5, 1H), 2.63 (ddd, J = 14.4, 11.2, 1.7, 1H), 1.08 (dt, J = 12.3, 7.1, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, Atomizer / water 30:70~100:0 + 0.1% HBFA, 10 points): 5.74 points. LC-MS m / z: 401.1 (M+H) + .

[0310] (6aR,9R)-N,N-diethyl-7-(pyridine-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (22 mg, 15.8 mg, 39.5 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (39.4 μL, 39.4 μmol). The solvent was removed under vacuum, the obtained material was dissolved again in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(pyridine-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide tartrate (22-tartrate) as a splashable off-white solid. Yield: 21.8 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 8.60 (d, J = 4.2, 1H), 7.91 (td, J = 7.7, 1.7, 1H), 7.67 (d, J = 7.8, 1H), 7.41 (dd, J = 7.0, 5.5, 1H), 7.23 (dd, J = 6.8, 1.9, 1H), 7.16 - 7.07 (m, 2H), 7.00 (d, J = 1.2, 1H), 6.39 (s, 1H), 4.63 (d, J = 14.7, 1H), 4.49 (s, 2H), 4.21 (d, J = 14.6, 1H), 4.08 - 3.93 (m, 2H), 3.73 (dd, J = 14.0, 5.2, 1H), 3.57 - 3.34 (m, 5H), 3.13 (dd, J = 11.6, 8.9, 1H), 3.03 - 2.90 (m, 1H), 1.22 (t, J = 7.1, 3H), 1.15 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.74 min. LC-MS m / z: 401.1 (M+H) + . [Examples]

[0311] Preparation of (6aR,9R)-N,N-diethyl-7-(2-(pyridine-2-yl)ethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (23) Reaction scheme:

[0312] [ka]

[0313] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 53.0 μmol; 2 moles of Int7 per mole of tartrate), potassium bicarbonate (32 mg, 0.32 mmol), and 2-(2-bromoethyl)pyridine-1-ium bromide (28.0 mg, 0.33 mmol) in methanol (2 mL) was purged with argon and stirred at 80°C for 4 days. After LC-MS analysis showed complete consumption of the starting materials, the reaction mixture was concentrated on silica gel and subjected to flash column chromatography (silica gel 60, 0.040-0.063 mm; eluate: dichloromethane / methanol 98:2). The solvent of the combined product fraction was evaporated under vacuum to obtain (6aR,9R)-N,N-diethyl-7-(2-(pyridine-2-yl)ethyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (23) as a dark amorphous solid. Yield: 3.8 mg (18%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 8.97 (s, 1H), 8.53 - 8.49 (m, 1H), 7.65 (td, J = 7.7, 1.9, 1H), 7.29 (d, J = 7.8, 1H), 7.22 (dd, J = 6.7, 2.0, 1H), 7.18 - 7.13 (m, 1H), 7.11 - 7.07 (m, 2H), 6.95 (t, J = 1.8, 1H), 6.29 (s, 1H), 3.71 - 3.62 (m, 1H), 3.53 (dd, J = 14.4, 5.3, 1H), 3.48 - 3.26 (m, 6H), 3.19 (dd, J = 11.1, 3.8, 1H), 3.06 - 2.93 (m, 3H), 2.73 (t, J = 10.7, 1H), 2.41 (ddd, J = 14.3, 11.0, 1.6, 1H), 1.22 (t, J = 7.1, 3H), 1.11 (t, J = 7.1, 3H). LC-MS purity: 98% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.88 min. LC-MS m / z: 415.1 (M+H) + .

[0314] (6aR,9R)-N,N-diethyl-7-(2-(pyridine-2-yl)ethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (23 mg, 3.8 mg, 9.17 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (9.2 μL, 9.2 μmol). The solvent was removed under vacuum, the obtained material was dissolved again in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(2-(pyridine-2-yl)ethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide tartrate (23-tartrate) as a splashable light brown solid. Yield: 5.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 8.52 (dd, J = 4.9, 0.8, 1H), 7.80 (td, J = 7.7, 1.8, 1H), 7.43 (d, J = 7.8, 1H), 7.31 (ddd, J = 7.5, 5.0, 0.9, 1H), 7.28 - 7.21 (m, 1H), 7.13 (dd, J = 6.7, 5.6, 2H), 7.05 (d, J = 1.0, 1H), 6.41 (dd, J = 3.6, 1.7, 1H), 4.45 (s, 2H), 4.29 - 4.18 (m, 1H), 4.13 - 4.03 (m, 1H), 3.81 - 3.35 (m, 9H), 3.01 (t, J = 12.9, 1H), 1.33 (t, J = 7.1, 3H), 1.19 (t, J = 7.1, 3H). LC-MS purity: 95% (ELSD), 92% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.88 min. LC-MS m / z: 415.1 (M+H) + . [Examples]

[0315] Preparation of (6aR)-N-((R)-sec-butyl)-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (24m) Reaction scheme:

[0316] [ka]

[0317] Synthesis protocol: A solution of (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int10m, 20mg, 46.7μmol; mixture of epimers at position 9) and 2-methoxybenzaldehyde (27mg, 194μmol) in methanol (0.5mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (12mg, 194μmol) was added, and the resulting mixture was stirred for 5 minutes. Acetic acid (20μL) was then introduced, and the reaction mixture was stirred at 0°C for 24 hours. As confirmed by LC-MS analysis, a diastereomer mixture of (6aR)-N-((R)-sec-butyl)-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (24m; mixture of diastereomers; epimer at position 9) was obtained. Composition determined by LC-MS: 87% (ELSD, faster-moving isomer), 13% (ELSD, slower-moving isomer). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.54 min (isomer A), 6.57 min (isomer B). LC-MS m / z: 430.2 (M+H) + . [Examples]

[0318] Preparation of (6aR)-N-((R)-sec-butyl)-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (25m) Reaction scheme:

[0319] [ka]

[0320] Synthesis protocol: A solution of (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int10m, 20mg, 46.7μmol; mixture of epimers at position 9) and 2-(2-methoxyphenyl)acetaldehyde (29mg, 194μmol) in methanol (0.5mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (12mg, 194μmol) was added, and the resulting mixture was stirred for 5 minutes. Acetic acid (20μL) was introduced, and the reaction mixture was then stirred at 0°C for 24 hours. As confirmed by LC-MS analysis, a diastereomer mixture (25m; mixture of diastereomers; epimer at position 9) of (6aR)-N-((R)-sec-butyl)-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide was obtained. Composition determined by LC-MS: 87% (ELSD, faster-moving isomer), 13% (ELSD, slower-moving isomer). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.49 min (isomer A), 6.79 min (isomer B). LC-MS m / z: 444.2 (M+H) + . [Examples]

[0321] Preparation of ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-yl)methanone (26) Reaction scheme:

[0322] [ka]

[0323] Synthesis protocol: A solution of ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (Int13, 40 mg, 0.117 mmol), potassium bicarbonate (47 mg, 0.468 mg), and 1-bromo-3-fluoropropane (33 mg, 0.234 mmol) in isopropanol (1.0 mL) was purged with argon and heated to 90°C in a sealed glass vial. The reaction mixture was stirred for 20 hours. The vial was opened, the solvent was removed, and the mixture was evaporated under vacuum. The crude material was redissolved in dichloromethane (25 mL), treated with silica gel (silica gel 0.063-0.200 mm, 10 g), and concentrated. The obtained powder was added to a flash column and purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (26) as a colorless foamy substance. Yield: 15.6 mg (35%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H ): 8.99 (s, 1H), 7.22 (dd, J = 6.6, 2.1, 1H), 7.16 - 7.03 (m, 2H), 6.94 (t, J = 1.7, 1H), 6.30 (s, 1H), 4.73 - 4.55 (m, 2H), 4.55 - 4.44 (m, 1H), 4.43 - 4.33 (m, 1H), 3.50 (dd, J = 14.6, 5.1, 1H), 3.41 - 3.29 (m, 2H), 3.18 - 3.02 (m, 2H), 2.66 - 2.43 (m, 3H), 2.01 - 1.91 (m, 2H), 2.05 - 1.86 (m, 2H), 1.46 (d, J = 6.3, 3H), 1.39 (d, J = 6.3, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.53 min. LC-MS m / z: 382.1 (M+H) + .

[0324] ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (26 mg, 15.6 mg, 40.9 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (19.6 μL, 19.6 μmol). The resulting solution was stirred for 5 minutes. The solvent was removed under vacuum, the residue was redissolved in dioxane (5.0 mL), and freeze-dried at 0°C to obtain ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanonehemitartrate (26hemitartrate) as a splashable white solid. Yield: 18.6 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H): 7.22 (dd, J = 6.9, 1.8, 1H), 7.16 - 7.06 (m, 2H), 7.00 (d, J = 1.2, 1H), 6.32 (s, 1H), 4.73 (dd, J = 13.2, 6.2, 1H), 4.70 - 4.61 (m, 1H), 4.50 (dd, J = 12.7, 6.3, 2H), 4.43 (s, 1H), 3.88 - 3.74 (m, 1H), 3.70 - 3.64 (m, 2H), 3.62 (dd, J = 14.7, 5.4, 1H), 3.38 (dd, J = 15.3, 4.2, 1H), 3.38 - 3.28 (m, 2H), 3.05 (t, J = 9.8, 1H), 2.81 (t, J = 12.6, 1H), 2.16 - 2.06 (m, 2H), 2.22 - 1.95 (m, 2H), 1.57 (d, J = 6.3, 3H), 1.47 (d, J = 6.3, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.53 min. LC-MS m / z: 382.1 (M+H) + . [Examples]

[0325] Preparation of ((6aR,9R)-7-allyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanone (27) Reaction scheme:

[0326] [ka]

[0327] Synthesis protocol: A solution of ((2S,4S)-2,4-dimethylazetidine-1-yl)((6aR,9R)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)methanone (4, 40.0 mg, 0.117 mmol), potassium bicarbonate (47 mg, 0.468 mg), and allyl bromide (20 μL, 0.234 mmol) in isopropanol (1.0 mL) was purged with argon and heated to 90°C. The reaction mixture was stirred for 20 hours. The solvent was removed under vacuum, and the crude material was dissolved again in dichloromethane (25 mL). Silica gel (silica gel 0.063~0.200 mm, 10 g) was added, and the solvent was removed under vacuum. The obtained powder was placed on a pre-packed silica gel flash column and eluted (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain ((6aR,9R)-7-allyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanone (27) as a colorless foamy substance. Yield: 14.2 mg (33%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H): 9.03 (s, 1H), 7.29 - 7.20 (m, 1H), 7.17 - 7.08 (m, 2H), 6.97 (t, J = 1.8, 1H), 6.33 (s, 1H), 6.11 - 5.93 (m, 1H), 5.32 (dd, J = 17.2, 1.1, 1H), 5.21 (d, J = 10.1, 1H), 4.68 - 4.53 (m, 1H), 4.41 (dq, J = 12.8, 6.2, 1H), 3.74 - 3.63 (m, 1H), 3.57 (dd, J = 14.7, 5.2, 1H), 3.45 - 3.34 (m, 2H), 3.23 - 3.12 (m, 2H), 2.62 (t, J = 12.0, 1H), 2.59 - 2.47 (m, 1H), 2.09 - 1.99 (m, 2H), 1.48 (d, J = 6.3, 3H), 1.41 (d, J = 6.3, 3H). LC-MS purity: 98% (ELSD), 91% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, Atomizer / water 30:70~100:0 + 0.1% HBFA, 10 points): 5.42 points. LC-MS m / z: 362.1 (M+H) + .

[0328] ((6aR,9R)-7-allyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanone (27 mg, 14.2 mg, 39.3 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (19.6 μL, 19.6 μmol). The resulting solution was stirred for 5 minutes, and then the solvent was removed under vacuum. The residue was redissolved in dioxane (5.0 mL) and freeze-dried at 0°C to obtain ((6aR,9R)-7-allyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanonehemitartrate (27hemitartrate) as a splashable off-white solid. Yield: 17.1 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.23 (dd, J = 7.2, 1.5, 1H), 7.16 - 7.07 (m, 2H), 7.01 (d, J = 1.2, 1H), 6.33 (s, 1H), 6.14 - 5.96 (m, 1H), 5.49 (d, J = 17.0, 1H), 5.42 (d, J = 10.3, 1H), 4.77 - 4.63 (m, 1H), 4.56 - 4.44 (m, 1H), 4.44 (s, 1H), 3.92 (dd, J = 14.1, 5.5, 1H), 3.86 - 3.76 (m, 1H), 3.73 - 3.53 (m, 4H), 3.40 (dd, J = 11.5, 4.5, 1H), 3.00 (t, J = 10.8, 1H), 2.82 (t, J = 10.8, 1H), 2.20 - 2.01 (m, 2H), 1.57 (d, J = 6.3, 3H), 1.46 (d, J = 6.3, 3H). LC-MS purity: 98% (ELSD), 91% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.42 min. LC-MS m / z: 362.1 (M+H) + . [Examples]

[0329] Preparation of (6aR,9R)-5-bromo-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (35) Reaction scheme:

[0330] [ka]

[0331] Synthesis protocol: (6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (54.0 mg, 0.167 mmol) was dissolved in anhydrous dioxane (2.0 mL) and flushed with argon. Bromine solution in dioxane (10% v / v, 834 μL, 0.151 mmol) was added dropwise, and the resulting mixture was stirred for 2 hours. The mixture was then treated with silica gel (silica gel 0.063-0.200 mm, 10 g) and evaporated under vacuum. The obtained powder was added to the upper side of a flash chromatography column pre-packed with silica gel, and the product was eluted as follows (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-5-bromo-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (35) as a dark amorphous solid. Yield: 32.8 mg (49%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.48 (s, 1H), 7.21 - 7.05 (m, 3H), 6.33 (s, 1H), 3.88 - 3.73 (m, 1H), 3.45 (q, J = 7.1, 2H), 3.36 (ddd, J = 9.0, 6.4, 2.2, 3H), 3.11 - 3.05 (m, 1H), 3.02 (dd, J = 11.7, 4.4, 1H), 2.64 (t, J = 10.8, 1H), 2.51 (s, 3H), 2.41 (dd, J = 14.9, 11.3, 1H), 1.20 (t, J = 7.0, 3H), 1.10 (t, J = 7.1, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.37 min. LC-MS m / z: 403.9 (M+H) + .

[0332] (6aR,9R)-5-bromo-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (35 mg, 32.8 mg, 81.5 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (40.8 μL, 40.8 μmol). The mixture was stirred at room temperature and then evaporated under vacuum. The residue was redissolved in dioxane (5.0 mL) and freeze-dried at 0°C to obtain (6aR,9R)-5-bromo-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (35-hemitartrate) as a flaky, light brown solid. Yield: 38.8 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H): 7.21 - 7.06 (m, 3H), 6.39 (s, 1H), 4.42 (s, 1H), 4.16 - 4.04 (m, 1H), 3.76 - 3.66 (m, 1H), 3.62 - 3.41 (m, 5H), 3.41 - 3.33 LC-MS purity: 100% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.37 min. LC-MS m / z: 403.9 (M+H) + . [Examples]

[0333] (6aR,9R)-N,N-diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindro[4,3-fg]quinoline-9-carboxamide(36) Reaction scheme:

[0334] [ka]

[0335] Synthesis protocol: (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (1,200 mg, 0.567 mmol) was dissolved in anhydrous dioxane (10 mL), followed by the addition of triethylsilane (1 mL) and trifluic acid (500 μL). The resulting mixture was stirred at 40°C for 96 hours. The mixture was then allowed to cool to room temperature, and silica gel (silica gel 0.063-0.200 mm, 10 g) was added. The mixture was concentrated under vacuum, and the resulting powder was added to the upper side of a flash chromatography column pre-packed with silica gel. The product was eluted as follows (silica gel 60, 0.040-0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-N,N-diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindoro[4,3-fg]quinoline-9-carboxamide (36; mixture of diastereomers; epimer at position 5a) as a dark amorphous solid. Yield: 97.6 mg (49%). LC-MS purity: 100% (ELSD), 98% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 mins): 3.85 mins. LC-MS m / z:354.2(M+H) + .

[0336] (6aR,9R)-N,N-diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindro[4,3-fg]quinoline-9-carboxamide (36, 16.3 mg, 46.1 μmol; mixture of epimers at position 5a) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (50 μL, 50.0 μmol). The solvent was removed under vacuum. The residue was redissolved in dioxane (5.0 mL) and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindoro[4,3-fg]quinoline-9-carboxamide tartrate (36 tartrate; mixture of diastereomers; epimer at position 5a) as a spatterable brown solid. Yield: 24.0 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.11 - 6.94 (m, 2H), 6.57 (dd, J = 5.3, 2.9, 1H), 6.37 (s, 1H), 4.42 (s, 2H), 4.22 - 4.06 (m, 2H), 3.75 - 3.67 (m, 1H), 3.66 - 3.61 (m, 2H), 3.56 (dd, J = 14.8, 7.4, 2H), 3.50 - 3.40 (m, 1H), 3.44 (dt, J = 11.5, 6.3, 2H), 3.31 - 3.22 (m, 2H), 3.21 - 3.06 (m, 2H), 2.81 - 2.67 (m, 1H), 1.93 - 1.73 (m, 2H), 1.65 (dd, J = 23.6, 11.7, 1H), 1.31 (t, J = 7.1, 3H), 1.17 (t, J = 7.1, 3H), 1.05 (t, J = 7.3, 3H). LC-MS purity: 100% (ELSD), 98% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 3.85 min. LC-MS m / z: 354.2 (M+H) + . [Examples]

[0337] Preparation of (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindro[4,3-fg]quinoline-9-carboxamide (37) Reaction scheme:

[0338] [ka]

[0339] Synthesis protocol: (6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (108 mg, 0.334 mmol) was dissolved in trifluoroacetic acid (10 mL), followed by the addition of triethylsilane (1 mL). The resulting mixture was stirred at 40°C for 72 hours. The mixture was then allowed to cool to room temperature, and silica gel (silica gel 0.063-0.200 mm, 10 g) was added. The mixture was concentrated under vacuum. The obtained powder was added to the upper side of a flash chromatography column pre-packed with silica gel, and the product was eluted as follows (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindro[4,3-fg]quinoline-9-carboxamide (37; mixture of diastereomers; epimer at position 5a) as a dark amorphous solid. Yield: 16.3 mg (15%). LC-MS purity: 92% (ELSD), 77% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 3.46 min LC-MS m / z:326.1(M+H) + .

[0340] (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindro[4,3-fg]quinoline-9-carboxamide (37 mg, 16.3 mg, 50.0 μmol; mixture of epimers at position 5a) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (50 μL, 50.0 μmol). The solvent was removed under vacuum, the material was redissolved in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindoro[4,3-fg]quinoline-9-carboxamide tartrate (37 tartrate; mixture of diastereomers; epimer at position 5a) as a splashable brown solid. Yield: 24.0 mg (quantitative). LC-MS purity: 92% (ELSD), 77% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 3.46 min LC-MS m / z:326.1(M+H) + . [Examples]

[0341] Preparation of (6aR,9R)-N,N-bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (38) Reaction scheme:

[0342] [ka]

[0343] Synthesis protocol: A solution of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylic acid (Int1, 384 mg, 1.43 mmol), triethylamine (0.93 mL, 6.43 mmol), and bis(2-fluoroethyl)amine hydrochloride (250 mg, 1.71 mmol) in dry N,N-dimethylformamide (10 mL) was cooled to 0°C under an argon atmosphere. Propanephosphonic anhydride (T3P®, 0.998 mL, 1.71 mmol, 50% solution in DMF) was added dropwise over 5 minutes. The resulting mixture was stirred at 0°C for 3 hours. The reaction was determined to be complete by LC-MS, and then quenched with ice-cold water (10 mL). The mixture was partitioned between 1 M ammonium hydroxide solution (250 mL) and ethyl acetate (200 mL). The aqueous phase was re-extracted with ethyl acetate (2 × 200 mL), and the combined organic phase was washed with 10% lithium chloride aqueous solution (4 × 150 mL) and dehydrated with anhydrous magnesium sulfate. The solvent was filtered and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 100:0~98:2). The main fraction was excised, and after evaporation of the solvent, (6aR,9R)-N,N-bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (38) was obtained as a colorless amorphous solid. Yield: 25 mg (5%). 1 1H NMR spectrum (300 MHz, CD3CN, δ H): 9.01 (s, 1H), 7.23 (dd, J = 6.0, 2.7, 1H), 7.14 - 7.06 (m, 2H), 6.95 (t, J = 1.7, 1H), 6.32 (s, 1H), 4.74 - 4.62 (m, 2H), 4.59 - 4.47 (m, 2H), 3.98 - 3.86 (m, 2H), 3.80 (dd, J = 9.2, 4.6, 1H), 3.75 (td, J = 4.9, 1.9, 1H), 3.70 - 3.63 (m, 1H), 3.53 (dd, J = 14.7, 5.6, 1H), 3.12 - 3.07 (m, 1H), 3.07 - 2.98 (m, 1H), 2.63 (t, J = 10.7, 1H), 2.58 - 2.47 (m, 1H), 2.48 (s, 3H). LC-MS purity: 100% (ELSD), 95% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.90 min. LC-MS m / z: 360.1 (M+H) + .

[0344] (6aR,9R)-N,N-bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (38 mg, 25.0 mg, 69.6 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (34.8 μL, 34.8 μmol). The resulting mixture was stirred for an additional 5 minutes. The solvent was removed under vacuum, and the remaining material was redissolved in dioxane (5.0 mL) and freeze-dried at 0°C. This yielded (6aR,9R)-N,N-bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (38 hemitartrate) as a splashable white solid. Yield: 30.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.24 (dd, J = 6.8, 1.9, 1H), 7.16 - 7.07 (m, 2H), 7.02 (d, J = 1.3, 1H), 6.42 (s, 1H), 4.77 (t, J = 4.6, 1H), 4.70 (t, J = 4.9, 1H), 4.61 (t, J = 4.6, 1H), 4.55 (t, J = 4.9, 1H), 4.40 (s, 1H), 4.34 - 4.24 (m, 1H), 4.02 (dd, J = 9.7, 4.7, 1H), 3.93 (dd, J = 10.2, 4.8, 1H), 3.84 (t, J = 4.9, 1H), 3.81 - 3.73 (m, 2H), 3.72 - 3.63 (m, 2H), 3.43 (dd, J = 11.7, 4.8, 1H), 3.19 (t, J = 10.4, 1H), 2.89 (s, 3H), 2.93 - 2.82 (m, 1H). LC-MS purity: 100% (ELSD), 95% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.90 min. LC-MS m / z: 360.1 (M+H) + . [Examples]

[0345] Preparation of (6aR,9R)-N,N-diethyl-7-(2-fluoroethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (39) Reaction scheme:

[0346] [ka]

[0347] Synthesis protocol: (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (Int7, 30 mg, 96.0 μmol), potassium bicarbonate (33 mg, 323 μmol), and 1-iodo-2-fluoroethane (53 mg, 323 μmol) were mixed in 2-propanol (1 mL) under an argon atmosphere in a sealed pressure vessel. The reaction mixture was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (20 mL) and silica gel (4 g) was added. The solvent in this suspension was evaporated under vacuum, and the mixture was subjected to silica gel chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9R)-N,N-diethyl-7-(2-fluoroethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (39, upper fluorescent band on TLC) as a colorless foamy substance. Yield: 30.8 mg (23%). LC-MS purity: 99% (ELSD), 99% (UV, 310nm). LC-MS Rt (Sinergy Polar RP 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.21 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 356.1 (M+H) + .

[0348] (6aR,9R)-N,N-diethyl-7-(2-fluoroethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (39, 30.8 mg, 86.6 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (43.3 μL, 43.3 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and the solvent was removed under vacuum to obtain (6aR,9R)-N,N-diethyl-7-(2-fluoroethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemi-tartrate (39-hemi-tartrate) as an amorphous off-white solid. Yield: 37.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.21 (dd, J=6.7, 1.9, 1H), 7.16 - 7.05 (m, 2H), 6.98 (s, 1H), 6.34 (s, 1H), 4.84 - 4.76 (m, 1H), 4.75 - 4.62 (m, 1H), 4.46 (s, 1H), 4.07 - 3.95 (m, 1H), 3.86 - 3.72 (m, 1H), 3.57 (dt, J=11.4, 7.4, 3H), 3.45 (dd, J=14.1, 7.0, 3H), 3.42 - 3.35 (m, 1H), 3.28 - 3.17 (m, 1H), 3.11 (t, J=10.5, 1H), 2.79 (t, J=12.8, 1H), 1.30 (t, J=7.1, 3H), 1.18 (t, J=7.1, 3H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.21 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 356.1 (M+H) + . [Examples]

[0349] Preparation of (6aR,9R)-N-((R)-sec-butyl)-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (40) Reaction scheme:

[0350] [ka]

[0351] Synthesis protocol: A solution of (6aR,9R)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (Int10, 15.0 mg, 48.5 μmol) and 3,3,3-trifluoropropanal (21.8 μL, 194 μmol) in methanol (2.0 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (12.2 mg, 194 μmol) was added, and the mixture was stirred for 5 minutes. Then, acetic acid (50 μL) was added, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with dichloromethane (10 mL), and then silica gel (4 g) was added, and the solvent of the resulting suspension was evaporated under vacuum. This residue was purified via flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 99:1~98:2) to obtain (6aR,9R)-N-((R)-sec-butyl)-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (40, a spot that moves faster on TLC, a less polar diastereomer) as a colorless oily substance. Yield: 18.8 mg (96%) LC-MS purity: 99% (ELSD), 100% (UV, 310nm) LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.78 min LC-MS m / z (ESI+, cone voltage 30V, Centroid): 406.1 (M+H) +

[0352] (6aR,9R)-5-bromo-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (40, 18.8 mg, 46.5 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (23.2 μL, 23.2 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and then the solvent was removed under vacuum to obtain (6aR,9R)-5-bromo-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemi-tartrate (40 hemi-tartrate) as an off-white solid. Yield: 22.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.19 (dd, J=6.7, 1.9, 1H), 7.14 - 7.04 (m, 2H), 6.97 (s, 1H), 6.38 (s, 1H), 4.51 (s, 1H), 3.93 - 3.79 (m, 1H), 3.68 - 3.58 (m, 1H), 3.48 (dd, J=14.0, 5.3, 2H), 3.28 - 3.17 (m, 2H), 3.11 - 2.98 (m, 1H), 2.90 (dd, J=11.0, 8.9, 1H), 2.81 - 2.67 (m, 2H), 2.55 (ddd, J=16.3, 10.7, 5.7, 2H), 1.59 - 1.46 (m, 2H), 1.18 (d, J=6.6, 3H), 0.94 (t, J=7.4, 3H). LC-MS purity: 99% (ELSD), 100% (UV, 310 nm) LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.78 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 406.1 (M+H) + [Examples]

[0353] Preparation of (6aR,9R)-5-bromo-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (41) Reaction scheme:

[0354] [ka]

[0355] Synthesis protocol: (6aR,9R)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (2, 30.0 mg, 0.081 mmol) was dissolved in anhydrous dioxane (3.0 mL) and flushed with argon. Bromine solution in dioxane (28.5 mg / mL, 455.2 μL, 0.081 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was basicized with triethylamine (100 μL), injected into silica gel (4 g), and concentrated under vacuum. Flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 100:0~70:30 + 0.5%) v / vPurification via triethylamine yielded (6aR,9R)-5-bromo-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (41) as an off-white amorphous solid. Yield: 16.5 mg (45%). LC-MS purity: 100% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.91 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 448.1( 79 Br, M+1), 450.0( 81 Br, M+1)

[0356] (6aR,9R)-5-bromo-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (41, 16.5 mg, 37.0 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (18.5 μL, 18.5 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and the solvent was removed under vacuum to obtain (6aR,9R)-5-bromo-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemi-tartrate (41 hemi-tartrate) as an off-white solid. Yield: 19.25 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H): 7.24 - 7.02 (m, 1H), 6.37 (s, 1H), 4.74 - 4.63 (m, 1H), 4.58 - 4.48 (m, 1H), 4.44 (s, 1H), 4.05 - 3.94 (m, 1H), 3.89 - 3.74 (m, 1H), 3.63 - 3.51 (m, 2H), 3.46 (q, J=7.4, 3H), 3.40 - 3.33 (m, 2H), 3.18 - 2.92 (m, 2H), 2.70 (t, J=12.0, 1H), 2.23 - 1.99 (m, 2H), 1.31 (t, J=7.0, 3H), 1.18 (t, J=7.1, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.91 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 448.1 ( 79 Br, M+1), 450.0 ( 81 Br, M+1). [Examples]

[0357] Preparation of (6aR,9R)-5-bromo-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (42) Reaction scheme:

[0358] [ka]

[0359] Synthesis protocol: (6aR,9R)-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (12, 35.8 mg, 0.088 mmol) was dissolved in anhydrous dioxane (3.0 mL) and flushed with argon. Bromine solution in dioxane (28.5 mg / mL, 495.1 μL, 0.081 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basicized with triethylamine (100 μL), injected into silica gel (4.0 g), and concentrated under vacuum. Flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 100:0~70:30 + 0.5%) v / v Purification via triethylamine yielded (6aR,9R)-5-bromo-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (42) as an off-white amorphous solid. Yield: 19.3 mg (45%). LC-MS purity: 100% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.28 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 484.1( 79 Br, M+1), 486.0( 81 Br, M+1).

[0360] (6aR,9R)-5-bromo-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (42, 19.3 mg, 39.8 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (19.9 μL, 19.9 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and then the solvent was removed under vacuum to obtain (6aR,9R)-5-bromo-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemi-tartrate (42 hemi-tartrate) as an off-white solid. Yield: 22.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.22 - 7.00 (m, 3H), 6.31 (s, 1H), 4.51 (s, 1H), 3.97 - 3.83 (m, 1H), 3.55 (q, J=7.1, 3H), 3.45 (ddd, J=14.0, 7.0, 3.7, 2H), 3.38 (dd, J=5.8, 2.8, 1H), 3.28 (dd, J=12.5, 6.5, 1H), 3.19 (dd, J=11.2, 4.1, 1H), 3.05 - 2.92 (m, 1H), 2.86 (t, J=9.0, 1H), 2.56 (ddt, J=15.9, 10.5, 5.2, 3H), 1.29 (t, J=7.1, 3H), 1.18 (t, J=7.1, 3H) LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.28 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 484.1 ( 79 Br, M+1), 486.0 ( 81Br, M+1). [Examples]

[0361] Preparation of (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (43) Reaction scheme:

[0362] [ka]

[0363] Synthesis protocol: (6aR,9R)-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int8, 56.3 mg, 174 μmol) was dissolved in anhydrous dioxane (5.0 mL), and the container was flushed with argon. Bromine solution in dioxane (28.5 mg / mL, 976 μL, 174 μmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basicized with trimethylamine (100 μL), injected into silica gel (4 g), and concentrated under vacuum. Flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 100:0~70:30 + 0.5%) v / v Purification via triethylamine yielded (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (43) as an off-white amorphous solid. Yield: 15.1 mg (45%). LC-MS purity: 100% (ELSD), 98% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.16 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 402.9( 79 Br, M+1), 403.9( 81 Br, M+1).

[0364] (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (43, 15.1 mg, 37.6 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (18.8 μL, 18.8 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and then the solvent was removed under vacuum to obtain (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemi-tartrate (43 hemi-tartrate) as an off-white solid. Yield: 18.0 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.23 - 7.05 (m, 3H), 6.46 (s, 1H), 4.43 (s, 1H), 3.85 (dd, J=13.3, 6.7, 1H), 3.79 - 3.67 (m, 2H), 3.49 (dd, J=14.5, 5.3, 1H), 3.44 (dd, J=14.4, 4.6, 1H), 3.14 (t, J=11.0, 1H), 2.89 (s, 3H), 2.73 (dd, J=14.1, 11.7, 1H), 1.60 - 1.46 (m, 2H), 1.20 (d, J=6.6, 3H), 0.94 (t, J=7.4, 3H). LC-MS purity: 100% (ELSD), 98% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.16 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 402.9 ( 79 Br, M+1), 403.9 ( 81 Br, M+1). [Examples]

[0365] Preparation of (6aR,9R)-5-bromo-N-(pentan-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (44) Reaction scheme:

[0366] [ka]

[0367] Synthesis protocol: (6aR,9R)-N-(pentan-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int14, 58.7 mg, 174 μmol) was dissolved in anhydrous dioxane (6.0 mL) and flushed with argon. Bromine solution in dioxane (28.5 mg / mL, 976 μL, 174 μmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basicized with trimethylamine (100 μL), injected into silica gel (4 g), and concentrated under vacuum. Flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 100:0~70:30 + 0.5%) v / v Purification via triethylamine yielded (6aR,9R)-5-bromo-N-(pentan-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (44) as an off-white amorphous solid. Yield: 29.1 mg (40%). LC-MS purity: 99% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.43 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 416.0( 79 Br, M+1), 418.0( 81 Br, M+1).

[0368] (6aR,9R)-5-bromo-N-(pentan-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (44, 29,1 mg, 69.8 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (34.9 μL, 34.9 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and then the solvent was removed under vacuum to obtain (6aR,9R)-5-bromo-N-(pentan-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide hemi-tartrate (44-hemi-tartrate) as an off-white solid. Yield: 34.2 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.22 - 7.06 (m, 3H), 6.48 (s, 1H), 4.43 (s, 1H), 3.86 - 3.75 (m, 2H), 3.75 - 3.67 (m, 1H), 3.50 (dd, J=15.0, 5.2, 2H), 3.21 (t, J=11.1, 1H), 2.92 (s, 3H), 2.77 (dd, J=14.3, 11.8, 1H), 1.62 (dt, J=13.5, 7.7, 2H), 1.46 (dt, J=14.1, 7.8, 2H), 0.96 (dt, J=15.1, 7.4, 6H). LC-MS purity: 99% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.43 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 416.0 ( 79 Br, M+1), 418.0 ( 81 Br, M+1). [Examples]

[0369] Preparation of (6aR,9R)-5-bromo-N-((R)-pentan-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (45) Reaction scheme:

[0370] [ka]

[0371] Synthesis protocol: (6aR,9R)-N-((R)-pentan-2-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int17, 39.3 mg, 116 μmol) was dissolved in anhydrous dioxane (5.0 mL) and flushed with argon. Bromine solution in dioxane (28.5 mg / mL, 653 μL, 116 μmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basicized with trimethylamine (100 μL), injected into silica gel (4 g), and concentrated under vacuum. Flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 100:0~70:30 + 0.5%) v / v Purification via triethylamine yielded (6aR,9R)-5-bromo-N-((R)-pentan-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (45) as an off-white amorphous solid. Yield: 12.8 mg (61%). LC-MS purity: 100% (ELSD), 98% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.54 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 416.0( 79 Br, M+1), 418.0( 81 Br, M+1).

[0372] (6aR,9R)-5-bromo-N-((R)-pentan-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (45, 12.8 mg, 30.9 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (15.4 μL, 15.4 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and then the solvent was removed under vacuum to obtain (6aR,9R)-5-bromo-N-((R)-pentan-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemi-tartrate (45 hemi-tartrate) as an off-white solid. Yield: 15.3 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.24 - 7.06 (m, 3H), 6.46 (s, 1H), 4.43 (s, 1H), 3.95 (dd, J=13.1, 6.4, 1H), 3.75 - 3.63 (m, 2H), 3.49 (dd, J=14.3, 5.3, 1H), 3.40 (dd, J=11.7, 3.7, 1H), 3.10 (t, J=10.8, 1H), 2.86 (s, 3H), 2.70 (dd, J=14.2, 11.9, 1H), 1.55 - 1.32 (m, 4H), 1.19 (d, J=6.6, 3H), 0.95 (t, J=7.1, 3H). LC-MS purity: 100% (ELSD), 98% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.54 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 416.0 ( 79 Br, M+1), 418.0 ( 81 Br, M+1). [Examples]

[0373] Preparation of (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (46) Reaction scheme:

[0374] [ka]

[0375] Synthesis protocol: (6aR,9R)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (3, 22.5 mg, 64.0 μmol) was dissolved in anhydrous dioxane (3.0 mL) and flushed with argon. Bromine solution in dioxane (26.43 mg / mL, 359.8 μL, 64.0 μmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basicized with trimethylamine (100 μL), injected into silica gel (4 g), and concentrated under vacuum. Flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 100:0~70:30 + 0.5%) v / vPurification via triethylamine yielded (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide free base (46) as an off-white amorphous solid. Yield: 16.7 mg (61%). LC-MS purity: 100% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.86 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 430.1( 79 Br, M+1), 432.0( 81 Br, M+1).

[0376] (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (46, 16.7 mg, 38.8 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (19.4 μL, 19.4 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and then the solvent was removed under vacuum to obtain (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide hemitartrate (46 hemitartrate) as an off-white solid. Yield: 19.6 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H): 7.23 - 7.05 (m, 3H), 6.45 (s, 1H), 4.41 (s, 1H), 4.01 - 3.90 (m, 1H), 3.85 (dd, J=13.4, 6.7, 1H), 3.66 - 3.56 (m, 1H), 3.50 - 3.41 (m, 1H), 3.41 (dd, J=14.6, 5.2, 1H), 3.25 - 3.12 (m, 1H), 3.25 - 3.11 (m, 1H), 3.09 - 2.95 (m, 1H), 2.77 (dd, J=14.2, 11.9, 1H), 1.87 - 1.67 (m, 2H), 1.61 - 1.46 (m, 2H), 1.19 (d, J=6.6, 3H), 1.05 (t, J=7.3, 3H), 0.94 (t, J=7.4, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.86 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 430.1 ( 79 Br, M+1), 432.0 ( 81 Br, M+1). [Examples]

[0377] Preparation of ((6aR,9R)-5-bromo-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanone (47) Reaction scheme:

[0378] [ka]

[0379] Synthesis protocol: ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanone (4, 46.3 mg, 127 μmol) was dissolved in anhydrous dioxane (6.0 mL) and flushed with argon. Bromine solution in dioxane (28.5 mg / mL, 715 μL, 127 μmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basicized with trimethylamine (100 μL), injected into silica gel (4 g), and concentrated under vacuum. Flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: cyclohexane / ethyl acetate 100:0~80:20 + 0.5%) v / v Purification via triethylamine yielded ((6aR,9R)-5-bromo-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanone (47) as an off-white amorphous solid. Yield: 5.2 mg (61%). LC-MS purity: 100% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.99 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 442.0( 79 Br, M+1), 444.0( 81 Br, M+1).

[0380] ((6aR,9R)-5-bromo-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanone (47 mg, 5.2 mg, 11.7 μmol) was dissolved in gradient-grade methanol (5.0 mL) and treated with 2N d-tartaric acid aqueous solution (5.9 μL, 5.9 μmol). The resulting mixture was stirred at room temperature for 5 minutes, and then the solvent was removed under vacuum to obtain ((6aR,9R)-5-bromo-7-propyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidine-1-yl)methanonehemitartrate (47hemitartrate) as an off-white solid. Yield: 6.05 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.24 - 7.05 (m, 3H), 6.35 (s, 1H), 4.81 - 4.64 (m, 1H), 4.57 - 4.43 (m, 1H), 4.42 (s, 1H), 3.99 - 3.76 (m, 1H), 3.69 - 3.59 (m, 1H), 3.51 - 3.38 (m, 2H), 3.25 - 3.12 (m, 1H), 3.01 - 2.87 (m, 2H), 2.69 (t, J=13.2, 1H), 2.20 - 2.05 (m, 2H), 1.88 - 1.66 (m, 2H), 1.58 (d, J=6.2, 3H), 1.47 (d, J=6.3, 3H), 1.05 (t, J=7.3, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.99 min. LC-MS m / z (ESI+, cone voltage 30V, Centroid): 442.0 ( 79 Br, M+1), 444.0 (81 Br, M+1). [Examples]

[0381] Preparation of (6aR,9R)-N,N-diethyl-7-(4-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (49) Reaction scheme:

[0382] [ka]

[0383] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 4-fluorobenzaldehyde (11.2 μL, 0.104 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (6.53 mg, 0.104 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 4 days. Silica gel (4.0 g) and trimethylamine (100 μL) were introduced, and the solvent was removed under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol 98:2) to obtain (6aR,9R)-N,N-diethyl-7-(4-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (49) as a colorless glassy solid. Yield: 17.3 mg (80%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H): 8.08 (s, 1H), 7.46 - 7.32 (m, 2H), 7.23 - 7.11 (m, 3H), 7.03 (t, J=8.6, 2H), 6.91 (s, 1H), 6.34 (s, 1H), 4.32 (d, J=13.4, 1H), 3.67 (s, 1H), 3.66 (dd, J=14.4, 5.0, 1H), 3.55 (s, 1H), 3.43 - 3.33 (m, 1H), 3.38 (ttd, J=21.7, 14.3, 7.1, 4H), 3.13 - 2.98 (m, 1H), 2.77 (s, 1H), 2.77 (s, 1H), 1.14 (t, J=7.1, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.26 min. LC-MS m / z: 418.1 (M+H) + .

[0384] (6aR,9R)-N,N-diethyl-7-(4-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (49 mg, 17.3 mg, 41.4 μmol) was dissolved in gradient methanol (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (20.7 μL, 20.7 μmol). The solvent was removed under vacuum, the obtained material was redissolved in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(4-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (49-hemitartrate) as a splashable white solid. Yield: 20.4 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H): 7.52 (dd, J=8.3, 5.5, 2H), 7.27 - 7.19 (m, 1H), 7.18 - 7.06 (m, 4H), 7.03 (s, 1H), 6.34 (s, 1H), 4.47 (s, 1H), 4.47 (d, J=13.4, 1H), 3.94 - 3.84 (m, 1H), 3.86 - 3.74 (m, 3H), 3.55 - 3.43 (m, 1H), 3.43 - 3.33 (m, J=6.7, 4H), 3.20 (dd, J=11.4, 3.9, 1H), 3.02 - 2.89 (m, 1H), 2.92 - 2.79 (m, 1H), 1.14 (dt, J=11.4, 7.1, 6H). LC-MS purity: 98% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.26 min. LC-MS m / z: 418.1 (M+H) + . [Examples]

[0385] Preparation of (6aR,9R)-7-(4-chlorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (50) Reaction scheme:

[0386] [ka]

[0387] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 4-chlorobenzaldehyde (14.6 mg, 0.104 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (6.53 mg, 0.104 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 4 days. Silica gel (4.0 g) and trimethylamine (100 μL) were introduced, and the solvent was removed under vacuum. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9R)-7-(4-chlorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (50) as a colorless glassy solid. Yield: 19.2 mg (85%). 1 1H NMR spectrum (300 MHz, CDCl3, δ H ): 8.08 (s, 1H), 7.34 (dd, J=18.5, 8.2, 4H), 7.24 - 7.08 (m, 3H), 6.90 (s, 1H), 6.34 (s, 1H), 4.31 (d, J=13.9, 1H), 3.87 - 3.68 (m, 1H), 3.68 - 3.50 (m, 1H), 3.62 (d, J=14.1, 1H), 3.38 (ddt, J=21.4, 14.4, 7.2, 4H), 3.49 - 3.25 (m, 1H), 3.02 (s, 1H), 2.91 - 2.68 (m, 2H), 1.14 (t, J=6.9, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.49 min. LC-MS m / z: 434.1 (M+H) + .

[0388] (6aR,9R)-7-(4-chlorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (50 mg, 19.2 mg, 44.2 μmol) was dissolved in gradient methanol (5.0 mL) and treated with 1 M D-(-)-tartaric acid aqueous solution (22.1 μL, 22.1 μmol). The solvent was removed under vacuum, the obtained material was redissolved in dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-7-(4-chlorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (50 hemitartrate) as a splashable white solid. Yield: 22.4 mg (quantitative). 1 1H NMR spectrum (300 MHz, MeOD, δ H ): 7.49 (d, J=8.3, 2H), 7.40 (d, J=8.4, 2H), 7.22 (dd, J=6.0, 2.7, 1H), 7.16 - 7.06 (m, 2H), 7.01 (s, 1H), 6.34 (s, 1H), 4.48 (s, 1H), 4.44 (d, J=13.7, 1H), 3.90 - 3.82 (m, 1H), 3.87 - 3.76 (m, 1H), 3.77 (d, J=10.8, 1H), 3.81 - 3.71 (m, 1H), 3.52 - 3.33 (m, 1H), 3.42 - 3.32 (ddt, J=21.4, 14.4, 7.2, 4H), 3.16 (dd, J=11.2, 4.1, 1H), 2.98 - 2.85 (m, 1H), 2.87 - 2.77 (m, 1H), 1.13 (dd, J=16.4, 7.1, 6H). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.49 min. LC-MS m / z: 434.1 (M+H) + . [Examples]

[0389] Preparation of (6aR,9R)-N,N-diethyl-7-(pyridine-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (51) Reaction scheme:

[0390] [ka]

[0391] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 30.0 mg, 78.0 μmol; 2 moles of Int7 per mole of tartrate) and isonicotinaldehyde (29.3 mg, 0.312 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (19.6 mg, 0.312 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 4 days. Silica gel (4.0 g) and triethylamine (100 μL) were introduced, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9R)-N,N-diethyl-7-(pyridine-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (51) as a colorless glassy solid (yield: 27.2 mg, 87%). LC-MS purity: 95.5% (ELSD), 92.5% (UV, 310nm) LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.54 min LC-MS m / z: 401.1 (M+H) + .

[0392] (6aR,9R)-N,N-diethyl-7-(pyridine-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (51 mg, 27.2 mg, 68.0 μmol) was dissolved in gradient methanol (5.0 mL) and treated with D-(-)-tartaric acid aqueous solution (1.0 M, 68.0 μL, 68.0 μmol). The solvent was removed under reduced pressure, and the obtained material was redissolved in 1,4-dioxane (5.0 mL). It was then freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(pyridine-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide tartrate (51 tartrate) as a splashable off-white solid (yield: 37.4 mg, quantitative). 1 1H NMR (500 MHz, MeOD, δ H): 7.96 (bs, 4H), 7.20 (dd, J = 7.6, 0.8 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.95 (d, J = 1.2 Hz, 1H), 6.32 (s, 1H), 4.54 (s, 2H), 4.37 (d, J = 14.4 Hz, 1H), 3.92 - 3.80 (m, 1H), 3.65 (d, J = 12.6 Hz, 1H), 3.69 - 3.56 (m, 2H), 3.52 - 3.35 (m, 4H), 2.99 (dd, J = 11.2, 4.5 Hz, 1H), 2.78 (t, J = 11.3 Hz, 1H), 2.73 (t, J = 10.5 Hz, 1H), 1.15 (t, J = 6.0 Hz, 3H), 1.12 (t, J = 6.0 Hz, 3H). LC-MS purity: 95.5% (ELSD), 92.5% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.54 min. LC-MS m / z: 401.1 (M+H) + . [Examples]

[0393] Preparation of (6aR,9R)-N,N-diethyl-7-(pyridine-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (55) Reaction scheme:

[0394] [ka]

[0395] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 30.0 mg, 78.0 μmol; 2 moles of Int7 per mole of tartrate) and nicotinaldehyde (29.3 mg, 0.312 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (19.6 mg, 0.312 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 4 days. Silica gel (4.0 g) and triethylamine (100 μL) were introduced, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9R)-N,N-diethyl-7-(pyridine-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (55) as a colorless glassy solid (yield: 7.1 mg, 23%). LC-MS purity: 96% (ELSD), 95% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.49 min LC-MS m / z: 401.1 (M+H) + .

[0396] (6aR,9R)-N,N-diethyl-7-(pyridine-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (55 mg, 7.1 mg, 17.7 μmol) was dissolved in gradient methanol (5.0 mL) and treated with D-(-)-tartaric acid aqueous solution (1.0 M, 17.8 μL, 17.8 μmol). The solvent was removed under reduced pressure, and the obtained material was redissolved in 1,4-dioxane (5.0 mL). It was then freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(pyridine-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide tartrate (55 tartrate) as a splashable off-white solid (yield: 9.7 mg, quantitative). 1 1H NMR (500 MHz, MeOD, δ H ): 8.66 (d, J = 1.1 Hz, 1H), 8.50 (dd, J = 4.8, 1.2 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.48 (dd, J = 7.8, 5.0 Hz, 1H), 7.21 (dd, J = 7.0, 1.6 Hz, 1H), 7.13 - 7.07 (m, 2H), 7.00 (d, J = 1.4 Hz, 1H), 6.32 (s, 1H), 4.51 (s, 2H), 4.47 (d, J = 14.1 Hz, 1H), 3.86 - 3.81 (m, 1H), 3.75 (dd, J = 14.1, 5.2 Hz, 1H), 3.72 - 3.67 (m, 1H), 3.49 - 3.34 (m, 4H), 3.37 (d, J = 7.0 Hz, 1H), 3.09 (dd, J = 11.4, 4.5 Hz, 1H), 2.87 (t, J = 12.3 Hz, 1H), 2.78 (t, J = 10.2 Hz, 1H), 1.14 (t, J = 5.8 Hz, 3H), 1.12 (t, J = 5.8 Hz, 3H). LC-MS purity: 96% (ELSD), 95% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.49 min. LC-MS m / z: 401.1 (M+H) + . [Examples]

[0397] Preparation of (6aR,9R)-N,N-diethyl-7-(3-(methoxy-d3)benzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (56) Reaction scheme:

[0398] [ka]

[0399] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 3-(methoxy-d3)benzaldehyde (29.0 mg, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (13.1 mg, 0.208 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. Silica gel (4.0 g) and triethylamine (100 μL) were introduced, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9R)-N,N-diethyl-7-(3-(methoxy-d3)benzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (56) as a colorless glassy solid (yield: 10.0 mg, 45%). 1 1H NMR (300 MHz, MeOD, δ H): 7.25 (t, J = 8.0 Hz, 1H), 7.18 (dd, J = 7.8, 0.5 Hz, 1H), 7.13 - 7.05 (m, 2H), 7.02 - 6.95 (m, 3H), 6.83 (dd, J = 8.2, 1.9 Hz, 1H), 6.30 (s, 1H), 4.34 (d, J = 13.6 Hz, 1H), 3.82 - 3.75 (m, 1H), 3.72 (dd, J = 14.5, 5.3 Hz, 1H), 3.49 - 3.43 (m, 1H), 3.44 (dd, J = 12.0, 6.5Hz, 1H), 3.43 - 3.32 (m, 5H), 3.10 - 3.03 (m, 1H), 2.77 (ddd, J = 14.3, 11.4, 1.7 Hz, 1H), 2.53 (t, J = 10.8 Hz, 1H), 1.11 (dd, J = 13.2, 7.1 Hz, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.21 min. LC-MS m / z: 433.2 (M+H) + .

[0400] (6aR,9R)-N,N-diethyl-7-(3-(methoxy-d3)benzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (56 mg, 10.0 mg, 23.1 μmol) was dissolved in gradient methanol (5.0 mL) and treated with D-(-)-tartaric acid aqueous solution (1 M, 11.5 μL, 11.5 μmol) at room temperature. The solvent was removed under reduced pressure, the obtained material was redissolved in 1,4-dioxane (5.0 mL), and freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(3-(methoxy-d3)benzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (56 hemitartrate) as a splashable white solid. Yield: 11.6 mg (quantitative) LC-MS purity: 99% (ELSD), 99% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.21 min LC-MS m / z: 433.2 (M+H) + . [Examples]

[0401] Preparation of (6aR,9R)-N,N-diethyl-7-(4-fluoro-3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (60) Reaction scheme:

[0402] [ka]

[0403] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 4-fluoro-3-methoxybenzaldehyde (32.0 mg, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (13.1 mg, 0.208 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. Silica gel (4.0 g) and triethylamine (100 μL) were introduced, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9R)-N,N-diethyl-7-(4-fluoro-3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (60) as a colorless glassy solid (yield: 14.8 mg, 64%). 1 1H NMR (300 MHz, MeOD, δ H): 7.18 (t, J = 7.7 Hz, 2H), 7.10 (dd, J = 15.9, 7.1 Hz, 2H), 7.04 (dd, J = 11.4, 8.3 Hz, 1H), 6.96 (d, J = 1.4 Hz, 1H), 6.96 - 6.92 (m, 1H), 6.30 (s, 1H), 4.30 (d, J = 13.6 Hz, 1H), 3.87 (s, 3H), 3.80 - 3.74 (m, 1H), 3.69 (dd, J = 14.5, 5.3 Hz, 1H), 3.48 - 3.44 (m, 1H), 3.39 (d, J = 13.6 Hz, 1H), 3.37 (dq, J = 21.3, 7.1 Hz, 4H), 3.35 (d, J = 7.1 Hz, 1H), 3.03 (ddd, J = 11.1, 4.6, 0.8 Hz, 1H), 2.76 (ddd, J = 14.3, 11.4, 1.6 Hz, 1H), 2.53 (t, J = 10.7 Hz, 1H), 1.14 - 1.07 (m, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HBFA, 10 points): 6.25 points. LC-MS m / z: 448.1 (M+H) + .

[0404] (6aR,9R)-N,N-diethyl-7-(4-fluoro-3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (60 mg, 14.8 mg, 33.0 μmol) was dissolved in gradient methanol (5.0 mL) and treated with D-(-)-tartaric acid aqueous solution (1 M, 16.5 μL, 16.5 μmol). The solvent was removed under reduced pressure, and the obtained material was redissolved in 1,4-dioxane (5.0 mL). It was then freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(4-fluoro-3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (60-hemitartrate) as a splashable white solid (yield: 17.3 mg, quantitative). LC-MS purity: 99% (ELSD), 99% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.25 min LC-MS m / z: 448.1 (M+H) + . [Examples]

[0405] Preparation of (6aR,9R)-N,N-diethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (62) Reaction scheme:

[0406] [ka]

[0407] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 3-hydroxybenzaldehyde (25.4 mg, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (13.1 mg, 0.208 mmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. Silica gel (4.0 g) and triethylamine (100 μL) were introduced, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel 60, 0.040~0.063 mm; eluate: dichloromethane / methanol / ammonia 98:2:0.1) to obtain (6aR,9R)-N,N-diethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (62) as a colorless glassy solid (yield: 16.5 mg, 76%). 1 1H NMR (300 MHz, MeOD, δ H ): 7.22 - 7.04 (m, 4H), 6.96 (d, J = 1.5 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.70 (ddd, J = 8.1, 2.4, 0.7 Hz, 1H), 6.31 (s, 1H), 4.30 (d, J = 13.5 Hz, 1H), 3.84 - 3.76 (m, 1H), 3.73 (dd, J = 14.5, 5.3 Hz, 1H), 3.50 - 3.44 (m, 1H), 3.41 (d, J = 13.5 Hz, 1H), 3.43 - 3.32 (m, 4H), 3.09 (ddd, J = 11.0, 4.6, 0.9 Hz, 1H), 2.77 (ddd, J = 14.3, 11.4, 1.7 Hz, 1H), 2.53 (t, J = 10.8 Hz, 1H), 1.12 (t, J = 7.1 Hz, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.54 min. LC-MS m / z: 416.1 (M+H) + .

[0408] (6aR,9R)-N,N-diethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (16.5 mg, 39.7 μmol) was dissolved in gradient methanol (5.0 mL) and treated with D-(-)-tartaric acid aqueous solution (1 M, 19.9 μL, 19.9 μmol). The solvent was removed under reduced pressure, and the obtained material was redissolved in 1,4-dioxane (5.0 mL). It was then freeze-dried at 0°C to obtain (6aR,9R)-N,N-diethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide hemitartrate (62) as a splashable white solid (yield: 19.5 mg, quantitative). LC-MS purity: 99% (ELSD), 99% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6mm x 150mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.54 min LC-MS m / z: 416.1 (M+H) + . [Examples]

[0409] Preparation of (6aR,9R)-N-ethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (63) Reaction scheme:

[0410] [ka]

[0411] Synthesis protocol: (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylic acid (Int1, 520 mg, 1.94 mmol) was suspended in dimethylformamide (50 mL). Ethylammonium chloride (629 mg, 7.75 mmol), triethylamine (1.62 mL, 11.6 mmol), and propanephosphonic acid anhydride (T3P®, 50% solution, 4.74 mL, 7.75 mmol) in 2-MeTHF were subsequently added to the reaction mixture. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was evaporated and partitioned between 2-MeTHF (100 mL) and 5% Na2CO3 aqueous solution (100 mL). The aqueous layer was extracted with 2-MeTHF (50 mL). The combined organic phases were washed with 5% LiCl aqueous solution (100 mL x 3) and concentrated on silica gel (0.2 mm, 3 g). The crude product was purified by flash column chromatography (SiliaSphere silica gel 60 Å, 50 μm, eluate: dichlormethane / methanol + 0.1% ammonia 100:0~95:5) to obtain (6aR,9R)-N-ethyl-7-methyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (Int25) as a colorless foamy substance (yield: 330 mg, 58%). 1 1H NMR (500 MHz, MeOD, δ H): 7.19 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.39 (s, 1H), 3.63 - 3.49 (m, 1H), 3.27 (q, J = 7.3 Hz, 2H), 3.23 - 3.16 (m, 1H), 3.13 (dd, J = 11.2, 5.3 Hz, 1H), 2.71 (t, J = 11.0 Hz, 1H), 2.65 (t, J = 12.1 Hz, 1H), 2.59 (s, 1H), 1.17 (t, J = 7.3 Hz, 2H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HBFA, 10 points): 3.89 points. LC-MS m / z: 296.1 (M+H) + .

[0412] (6aR,9R)-N-ethyl-7-methyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int25, 290 mg, 0.949 mmol) was dissolved in dichloromethane (27 mL) and cooled to 0°C. Metachloroperbenzoic acid (77% purity, 213 mg, 0.949 mmol) was added, and the reaction mixture was stirred at 0°C for 1 hour. This mixture was then evaporated, and the crude residue was redissolved in 90% methanol aqueous solution (50 mL). Iron sulfate heptahydrate was added, and the reaction mixture was stirred for 1 hour, then concentrated under reduced pressure. The resulting material was partitioned between 2-MeTHF (100 mL) and 1 M EDTA aqueous solution. The phases were separated, the aqueous phase was basicized with ethylenediamine, and extracted with additional 2-MeTHF (3 × 100 mL). The combined organic extracts were evaporated and purified via flash column chromatography (SiliaSphere silica gel 60 Å, 50 μm, eluate: dichloromethane / methanol + 0.1% ammonia 100:0~90:10) to obtain (6aR,9R)-N-ethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int26) as a colorless film (yield: 36 mg, 13%). 1 1H NMR (500 MHz, MeOD, δ H ): 7.19 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.1 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 6.39 (s, 1H), 3.78 (tdd, J = 5.7, 4.5, 2.8 Hz, 1H), 3.42 (ddd, J = 12.8, 5.8, 3.0 Hz, 1H), 3.36 - 3.32 (m, J = 11.5, 5.4, 3.8 Hz, 1H), 3.27 (q, J = 7.3 Hz, 3H), 3.24 - 3.20 (m, 1H), 3.06 (dd, J = 12.4, 10.0 Hz, 1H), 2.72 (ddd, J = 14.3, 11.8, 1.7 Hz, 1H), 1.17 (t, J = 7.3 Hz, 3H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS m / z: 182.1 (M+H) + . LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 3.76 min.

[0413] (6aR,9R)-N-ethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (Int26, 18 mg, 64.0 μmol) was dissolved in methanol (1 mL) at room temperature, and then 3-methoxybenzaldehyde (30 μL, 196 μmol) and sodium borohydride cyanohydride (15 mg, 238 μmol) were added. After 5 minutes, acetic acid (25 μL) was added. After stirring for 3 hours, the remaining portion of 3-methoxybenzaldehyde (15 μL, 98.4 μmol) was added, and the reaction mixture was stirred overnight at room temperature. Volatile substances were removed under reduced pressure, and the resulting residue was redissolved in aqueous hydrochloric acid solution (1 M, 20 mL). The aqueous phase was washed with diethyl ether (3 × 20 mL). Next, the aqueous phase was basicized with a 20% sodium hydroxide aqueous solution and extracted with 2-MeTHF (3 × 50 mL). The combined organic extracts were dehydrated with magnesium sulfate, evaporated to dryness, and the residue was purified by flash column chromatography (SiliaSphere silica gel 60 Å, 50 μm, eluate: dichloromethane / methanol + 0.1% ammonia 100:0~97:3). The obtained material was further purified by preparative HPLC (Synergi 4μm Polar-RP 80Å, LC column 100×21.2mm, acetonitrile / water 30:70~100:0 + 0.1% acetic acid), the solvent of the combined fraction was evaporated under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to obtain (6aR,9R)-N-ethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (63) as a white, swollen foamy substance (yield: 13.0 mg, 51%). 11H NMR (500 MHz, MeOD, δ H ): 7.25 (t, 1H), 7.18 (dd, J = 7.7, 0.8 Hz, 1H), 7.13 - 7.05 (m, 2H), 7.02 - 6.96 (m, 2H), 6.96 (d, J = 1.5 Hz, 1H), 6.83 (dd, J = 7.9, 2.2 Hz, 1H), 6.34 (s, J = 2.3 Hz, 1H), 4.21 (d, J = 13.5 Hz, 1H), 3.79 (s, 3H), 3.64 (dd, J = 14.3, 5.3 Hz, 1H), 3.59 (d, J = 13.5 Hz, 1H), 3.57 - 3.52 (m, J = 10.1, 5.2, 2.6 Hz, 1H), 3.19 (q, J = 7.3 Hz, 2H), 3.10 (dd, J = 11.3, 4.8 Hz, 1H), 2.80 (ddd, J = 14.1, 11.4, 1.7 Hz, 1H), 2.64 (dd, J = 11.3, 8.6 Hz, 1H), 1.10 (t, J = 7.3 Hz, 3H). LC-MS purity: 98.5% (ELSD), 100.0% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.96 min. LC-MS m / z: 401.51 (M+H) + . [Examples]

[0414] Preparation of (6aR,9R)-N-ethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (64) Reaction scheme:

[0415] [ka]

[0416] Synthesis protocol: (6aR,9R)-N-ethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (Int26, 18 mg, 64.0 μmol) was dissolved in methanol (1 mL) at room temperature, and then 3-hydroxybenzaldehyde (30 μL, 169 μmol) and sodium borohydride cyanohydride (15 mg, 238 μmol) were added. After 5 minutes, acetic acid (25 μL) was added. After stirring for 3 hours, the remaining portion of 3-hydroxybenzaldehyde (15 μL, 98.3 μmol) was added, and the reaction mixture was stirred overnight. Volatile substances were removed under reduced pressure, and the residue was redissolved in aqueous hydrochloric acid (1 M, 20 mL) and washed with diethyl ether (3 × 20 mL). Next, the aqueous phase was basicized to pH 8 with a 20% sodium hydroxide aqueous solution and extracted with 2-MeTHF (3 × 50 mL). The combined 2-MeTHF phase was dehydrated with magnesium sulfate, evaporated to dryness, and the residue was purified via preparative HPLC (Synergi 4 μm Polar-RP 80 Å, LC column 100 × 21.2 mm, acetonitrile / water 30:70~100:0 + 0.1% acetic acid). The resulting fractions were combined and concentrated, and the resulting material was lyophilized from tert-butanol to obtain (6aR,9R)-N-ethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (64) as a white, swollen foamy substance (yield: 10.0 mg, 40%). 1 1H NMR (500 MHz, MeOD, δ H): 7.18 (dd, J = 7.6, 0.9 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.96 (d, J = 1.4 Hz, 1H), 6.89 - 6.86 (m, 2H), 6.70 (dd, J = 8.1, 1.6 Hz, 1H), 6.34 (s, 1H), 4.17 (d, J = 13.4 Hz, 1H), 3.65 (dd, J = 14.2, 5.2 Hz, 1H), 3.58 (d, J = 13.1 Hz, 2H), 3.19 (q, J = 7.2 Hz, 2H), 3.13 (dd, J = 11.3, 4.8 Hz, 1H), 2.81 (t, J = 12.7 Hz, 1H), 2.65 (t, J = 10.1 Hz, 1H), 1.10 (t, J = 7.3 Hz, 1H). LC-MS purity: 93.0% (ELSD), 100.0% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.41 min. LC-MS m / z: 388.3 (M+H) + . [Examples]

[0417] Preparation of (6aR,9R)-N,N-diethyl-7-(isoxazole-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (70) Reaction scheme:

[0418] [ka]

[0419] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int7, 19.0 mg, 61.5 μmol) and isoxazole-3-carboldehyde (25.4 mg, 185 μmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (11.6 mg, 185 μmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of 2% aqueous acetic acid solution. The residue was purified by preparative HPLC (Synergi 4 μm Polar-RP80, LC column 100 × 21.2 mm, acetonitrile / water 30:70~100:0 + 0.1% acetic acid). The solvent of the combined fraction was evaporated under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to obtain (6aR,9R)-N,N-diethyl-7-(isoxazole-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (70) as an off-white, splashable solid (yield: 21.2 mg, 88%). 1 1H NMR (300 MHz, MeOD, δ H): 8.64 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 7.7, 0.8 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.97 (d, J = 1.5 Hz, 1H), 6.58 (d, J = 1.7 Hz, 1H), 6.29 (s, 1H), 4.27 (d, J = 14.8 Hz, 1H), 4.03 (d, J = 14.8 Hz, 1H), 3.93 - 3.87 (m, 1H), 3.73 (dd, J = 14.4, 5.5 Hz, 1H), 3.56 - 3.45 (m, 1H), 3.45 - 3.39 (m, 4H), 3.15 (ddd, J = 11.1, 4.9, 1.2 Hz, 1H), 2.79 (t, J = 11.0 Hz, 1H), 2.73 (ddd, J = 14.3, 11.4, 1.7 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). LC-MS purity: 99,9% (ELSD), 99,9% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.27 min. LC-MS m / z: 391.2 (M+H) + . [Examples]

[0420] Preparation of (6aR,9R)-N,N-diethyl-7-(oxazole-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (73) Reaction scheme:

[0421] [ka]

[0422] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int7, 19.0 mg, 61.5 μmol) and oxazole-4-carbornehyde (25.4 mg, 185 μmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (11.6 mg, 185 μmol) was added, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of 2% aqueous acetic acid solution. The residue was purified by preparative HPLC (Synergi 4 μm Polar-RP 80 Å, LC column 100 × 21.2 mm, acetonitrile / water 30:70~100:0 + 0.1% acetic acid). The solvent of the combined fraction was evaporated under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to obtain (6aR,9R)-N,N-diethyl-7-(oxazole-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (73) as an off-white, splashable solid (yield: 13.0 mg, 54%). 1 1H NMR (300 MHz, MeOD, δ H): 8.14 (d, J = 0.7 Hz, 1H), 7.93 (s, 1H), 7.18 (dd, J = 7.6, 0.8 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.96 (d, J = 1.4 Hz, 1H), 6.28 (d, J = 0.8 Hz, 1H), 4.08 (d, J = 15.0 Hz, 1H), 3.93 (d, J = 14.9 Hz, 1H), 3.93 - 3.88 (m, 1H), 3.76 (dd, J = 14.4, 5.5 Hz, 1H), 3.52 - 3.44 (m, 3H), 3.44 - 3.36 (m, 2H), 3.20 (ddd, J = 11.2, 4.8, 1.0 Hz, 1H), 2.77 (t, J = 10.9 Hz, 1H), 2.72 (ddd, J = 14.3, 11.4, 1.7 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). LC-MS purity: 98% (ELSD), 98% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 4.95 min. LC-MS m / z: 391.1 (M+H) + . [Examples]

[0423] Preparation of (6aR,9R)-N,N-diethyl-7-(3-cyanobenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (76) Reaction scheme:

[0424] [ka]

[0425] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 3-cyanobenzaldehyde (27.3 mg, 208 μmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium cyanoborohydride (13.1 mg, 208 μmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of 2% aqueous acetic acid solution. The residue was purified by preparative HPLC (Synergi 4 μm Polar-RP 80 Å, LC column 100 × 21.2 mm, acetonitrile / water 30:70~100:0 + 0.1% acetic acid). The solvent of the combined fraction was evaporated under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to obtain (6aR,9R)-N,N-diethyl-7-(3-cyanobenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (76) as an off-white, splashable solid (yield: 21.2 mg, 88%). 1 1H NMR (300 MHz, MeOD, δ H): 7.84 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.19 (dd, J = 7.7, 0.8 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.96 (d, J = 1.5 Hz, 1H), 6.31 (s, 1H), 4.42 (d, J = 14.3 Hz, 1H), 3.82 (dt, J = 10.0, 4.9 Hz, 1H), 3.69 (dd, J = 14.5, 5.3 Hz, 1H), 3.55 (d, J = 14.3 Hz, 1H), 3.53 - 3.33 (m, 5H), 2.97 (dd, J = 11.1, 3.7 Hz, 1H), 2.77 (ddd, J = 14.3, 11.4, 1.7 Hz, 1H), 2.62 (t, J = 10.5 Hz, 1H), 1.13 (td, J = 7.1, 2.5 Hz, 6H). LC-MS purity: 99,9% (ELSD), 99,9% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.91 min. LC-MS m / z: 425.2 (M+H) + . [Examples]

[0426] Preparation of (6aR,9R)-N,N-diethyl-7-((2-methoxypyridine-4-yl)methyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (79) Reaction scheme:

[0427] [ka]

[0428] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (Int7, 19.0 mg, 61.5 μmol) and 2-methoxyisonicotinaldehyde (25.0 mg, 185 μmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (11.6 mg, 185 μmol) was added, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of 2% aqueous acetic acid solution. The residue was purified by preparative HPLC (Synergi 4 μm Polar-RP 80 Å, LC column 100 × 21.2 mm, acetonitrile / water 30:70~100:0 + 0.1% acetic acid). The solvent of the combined fraction was evaporated under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to obtain (6aR,9R)-N,N-diethyl-7-((2-methoxypyridine-4-yl)methyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (79) as an off-white, splashable solid (yield: 18.2 mg, 69%). 1 1H NMR (300 MHz, MeOD, δ H): 8.08 (d, J = 5.3 Hz, 1H), 7.19 (dd, J = 7.7, 0.7 Hz, 1H), 7.14 - 7.05 (m, 3H), 6.95 (d, J = 1.5 Hz, 1H), 6.92 (s, 1H), 6.31 (s, 1H), 4.34 (d, J = 14.8 Hz, 1H), 3.91 (s, 3H), 3.88 - 3.81 (m, 1H), 3.63 (dd, J = 14.5, 5.3 Hz, 1H), 3.48 (d, J = 14.9 Hz, 1H), 3.54 - 3.34 (m, 4H), 3.33 - 3.30 (m, 1H), 2.99 (ddd, J = 11.0, 4.6, 0.9 Hz, 1H), 2.74 (ddd, J = 14.3, 11.3, 1.7 Hz, 1H), 2.63 (t, J = 11.0 Hz, 1H), 1.15 (t, J = 6.0 Hz, 3H), 1.13 (t, J = 6.0 Hz, 3H). LC-MS purity: 99.9% (ELSD), 99.9% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.60 min. LC-MS m / z: 431.2 (M+H) + . [Examples]

[0429] Preparation of (6aR,9R)-7-benzyl-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (82) Reaction scheme:

[0430] [ka]

[0431] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 16.0 mg, 42.0 μmol; 2 moles of Int7 per mole of tartrate) and benzaldehyde (19 μL, 185 μmol) in methanol (2 mL) was purged with argon and cooled to 0°C. Sodium borocyanohydride (11.6 mg, 185 μmol) was introduced, and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 μL). After stirring at 0°C for 1 hour, the reaction mixture was allowed to warm to room temperature and stirred for an additional 20 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of 2% aqueous acetic acid solution. The residue was purified by preparative HPLC (Synergi 4 μm Polar-RP 80 Å, LC column 100 × 21.2 mm, acetonitrile / water 30:70~100:0 + 0.1% acetic acid). The solvent of the combined fraction was evaporated under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to obtain (6aR,9R)-7-benzyl-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (82) as an off-white, splashable solid (yield: 12.2 mg, 71%). 1 1H NMR (300 MHz, MeOD, δ H): 7.42 (d, J = 7.1 Hz, 2H), 7.35 (dd, J = 10.3, 4.7 Hz, 2H), 7.30 - 7.24 (m, 1H), 7.19 (dd, J = 7.7, 0.6 Hz, 1H), 7.13 - 7.04 (m, 2H), 6.97 (d, J = 1.5 Hz, 1H), 6.30 (d, J = 0.9 Hz, 1H), 4.37 (d, J = 13.5 Hz, 1H), 3.80 - 3.78 (m, 1H), 3.75 (dd, J = 14.4, 5.2 Hz, 1H), 3.49 (d, J = 13.5 Hz, 1H), 3.51 - 3.44 (m, 1H), 3.44 - 3.29 (m, 4H), 3.06 (ddd, J = 11.1, 4.6, 0.9 Hz, 1H), 2.78 (ddd, J = 14.3, 11.4, 1.6 Hz, 1H), 2.54 (t, J = 10.7 Hz, 1H), 1.11 (t, J = 5.2 Hz, 3H), 1.09 (t, J = 5.2 Hz, 3H). LC-MS purity: 99.9% (ELSD), 99.9% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Atomizer / Water 30:70~100:0 + 0.1% HBFA, 10 points): 6.06 points. LC-MS m / z: 400.2 (M+H) + .

Example

[0432] General synthetic compounds General synthesis スキーム1:

[0433]

change

[0434] General synthetic プロトコル1: Step 1 - Preparation of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (83m) and pure diastereomer (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (83)

[0435] [ka]

[0436] To a stirred solution of sodium (6aR)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylate (Int27m; 5.0g, 18.16 mmol, dr1:1; Fehr, T., Stadler, PA, Hofmann, A. Helvetica Chimica Acta, 1970, 53(8), pp. 2197-2201) in anhydrous DMF (80 mL) at 0°C, diethylamine (3.99 g, 54.49 mmol) was added, followed by propyl phosphonate anhydride (T3P; 50% in ethyl acetate, 34.68 g, 54.49 mmol) and triethylamine (8.94 mL, 63.58 mmol). The reaction mixture was stirred at 0°C for 10 minutes, slowly warmed to room temperature, and stirred for 5 hours. The reaction products were analyzed by LC-MS and TLC(R f The reaction was monitored by (0.5; 10% MeOH / DCM). After completion, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (silica gel 60-120, eluate: 5-10% MeOH in DCM (0.1% methanol ammonia additive)) to obtain (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (83m) as a reddish-brown solid (3g, 89% LC-MS purity). This was approximately a 1:1 mixture of diastereomers. LC-MS: 310.10[M+1] +The pure diastereomer (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (83) was separated from the mixture by column chromatography (SiliCycle Silia Sphere PC60A, 50 μm; eluate: dichloromethane / methanol / ammonia aqueous solution 99:1:0.01~90:10:0.1) to obtain an off-white solid. 1 H NMR (500 MHz, MeOD): δ = 7.19 (dd, J = 7.8, 0.7 Hz, 1H), 7.12 (dd, J = 7.2, 0.7 Hz, 1H), 7.10 - 7.06 (m, 1H), 6.93 (d, J = 1.5 Hz, 1H), 3.87 - 3.81 (m, 1H), 3.81 - 3.76 (m, 1H), 3.53 (q, J = 7.1 Hz, 2H), 3.42 (qd, J = 13.4, 6.9 Hz, 2H), 3.26 (ddd, J = 12.8, 5.3, 1.4 Hz, 1H), 3.23 (dd, J = 15.0, 5.6 Hz, 1H), 3.07 (dd, J = 12.5, 9.8 Hz, 1H), 2.70 (ddd, J = 14.4, 11.8, 1.7 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0437] Step 2 - 83m is reductively aminated to obtain diastereomer 1 and diastereomer 2.

[0438] [ka]

[0439] To a stirred solution of the crude product (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxamide (83 m; 1 equivalent) in methanol (30 mL), a suitable aldehyde (2 equivalents) was added. The reaction mixture was purged with nitrogen for 5 minutes. The reaction mixture was cooled to 0°C, sodium borohydride (3 equivalents) was added, followed by acetic acid (2 equivalents). The reaction mixture was warmed to room temperature and stirred until complete. The reaction products were analyzed by LC-MS and TLC(R f The reaction was monitored with (0.5; 10% MeOH / DCM). After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product as a mixture of diastereomers. This was purified by preparative HPLC to obtain diastereomers 1 and 2.

[0440] Compound: Preparation of (6aR,9R)-N,N-diethyl-7-(3-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (52) and (6aR,9S)-N,N-diethyl-7-(3-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (52a)

[0441] [ka]

[0442] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 300mg, 0.97 mmol) according to general procedure (Step 2); diastereomers were separated by preparative HPLC: column: X Bridge C8 (19mm × 250mm, 5μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 30-98% gradient, run for 18 minutes; flow rate: 18mL / min.

[0443] (6aR,9R)-N,N-diethyl-7-(3-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(52) Yield: 65 mg, 16%, off-white solid. LC-MS: m / z: 418.20 [M+H] + ; 1 ¹H NMR (400 MHz, CD3CN): δ = 8.99 (s, 1H), 7.38-7.24 (m, 4H), 7.18-7.09 (m, 2H), 7.02-6.97 (m, 2H), 6.35 (s, 1H), 4.34 (d, J = 14.0 Hz, 1H), 3.71-3.61 (m, 2H), 3.45-3.24 (m, 6H), 3.00-2.96 (m, 1H), 2.67-2.60 (m, 2H), 1.10-1.03 (m, 6H). Enantiomeric excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm x 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 2.29 min (minor components), 3.39 min (major components).

[0444] (6aR,9S)-N,N-diethyl-7-(3-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(52a) Yield: 20 mg, 5%, off-white solid. LC-MS: m / z: 418.20 [M+H] + ; 1¹H NMR (400 MHz, CD3CN): δ = 9.00 (s, 1H), 7.27-6.95 (m, 8H), 6.35 (s, 1H), 4.10-3.80 (m, 2H), 3.77-3.75 (m, 1H), 3.38-2.91 (m, 9H), 1.14 (t, J = 7.0 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H). Enantio-excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm × 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35°C. Rt=2.22 minutes (main component), 3.41 minutes (minor component).

[0445] Preparation of (6aR,9R)-7-(3,4-difluorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (54) and (6aR,9S)-7-(3,4-difluorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (54a)

[0446] [ka]

[0447] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 200mg, 0.65 mmol) according to general procedure (Step 2); diastereomers were separated by preparative HPLC: column: X Bridge C8 (19mm × 250mm, 5μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 47-98% gradient, run for 21 minutes; flow rate: 18mL / min.

[0448] (6aR,9R)-7-(3,4-difluorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(54) Yield: 21 mg, 7.46%, off-white solid. LC-MS: m / z: 436.40 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.99 (s, 1H), 7.42-7.37 (m, 1H), 7.28-7.22 (m, 3H), 7.15-7.09 (m, 2H), 6.97 (s, 1H), 6.34 (s, 1H), 4.29 (d, J = 14.3 Hz, 1H), 3.72-3.66 (m, 1H), 3.62 (dd, J = 14.6, 5.2 Hz, 1H), 3.47-3.28 (m, 6H), 2.95 (dd, J = 11.0, 4.9 Hz, 1H), 2.70-2.60 (m, 1H), 2.57 (t, J = 10.4 Hz, 1H), 1.11-1.05 (m, 6H). Enantiomeric excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 2.16 min (minor components), 4.06 min (major components).

[0449] (6aR,9S)-7-(3,4-difluorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(54a) Yield: 4 mg, 1.42%, off-white solid. LC-MS: m / z: 436.40 [M+H] + ; 1H NMR (400 MHz, CD3CN): δ = 8.95 (s, 1H), 7.42-7.37 (m, 1H), 7.23-7.17 (m, 3H), 7.12-7.05 (m, 2H), 6.91 (s, 1H), 6.28 (s, 1H), 3.85-3.82 (m, 2H), 3.75-3.71 (m, 1H), 3.51-3.48 (m, 1H), 3.38-3.29 (m, 4H), 3.16 (dd, J = 14.5, 5.2 Hz, 1H), 3.03-2.97 (m, 1H), 2.92-2.86 (m, 2H), 1.14 (t, J = 7.0 Hz, 3H), 1.04 (t, J = 7.0 Hz, 3H). Enantiomeric excess (98.2%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm × 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35°C. Rt = 2.32 min (main component), 4.07 min (minor component).

[0450] Preparation of (6aR,9R)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d2)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (68) and (6aR,9S)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d2)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (68a)

[0451] [ka]

[0452] (Step 2) (m-methoxybenzene ( ) was synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (83mg; 140mg, 0.45mmol) according to a general procedure. 2H) Carboaldehyde, NaCNBD3, CH3COOD, and CH3OD were used; diastereomers were separated by preparative HPLC: Column: X Bridge C8 (19 mm × 250 mm, 5 μM); Mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 20-98% gradient, run for 25 minutes; Flow rate: 18 ml / min.

[0453] (6aR,9R)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d2)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(68) Yield: 36 mg, 18.44%, off-white solid. LC-MS: m / z: 432.5 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.97 (s, 1H), 7.28-7.23 (m, 2H), 7.13-7.08 (m, 2H), 7.01-6.99 (m, 2H), 6.96 (s, 1H), 6.96 (m, 1H), 6.34 (s, 1H), 3.78 (s, 3H), 3.69-3.64 (m, 2H), 3.44-3.26 (m, 5H), 2.99 (dd, J = 11.1, 3.9 Hz, 1H), 2.70-2.63 (m, 1H), 2.53 (t, J = 10.8 Hz, 1H), 1.09-1.03 (m, 6H). Enantio-excess (98.7%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 2.65 min (minor components), 3.51 min (major components).

[0454] (6aR,9S)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d2)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(68a) Yield: 25 mg, 12.8%, off-white solid. LC-MS: m / z: 432.5 [M+H] +; 1 H NMR (400 MHz, CD3CN): δ = 8.92 (s, 1H), 7.25-7.19 (m, 2H), 7.11-6.99 (m, 4H), 6.89 (s, 1H), 6.80 (dd, J = 7.8, 2.6 Hz, 1H), 6.27 (s, 1H), 3.77-3.72 (m, 4H), 3.50-3.47 (m, 1H), 3.36-3.26 (m, 4H), 3.14 (dd, J = 14.6, 5.2 Hz, 1H), 3.02-2.14 (m, 3H), 1.12 (t, J = 7.0 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H). The enantiomeric excess (94.34%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. t = 2.54 minutes (main component), 3.50 minutes (minor component).

[0455] Preparation of (6aR,9R)-N,N-diethyl-7-(oxazole-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (74)

[0456] [ka]

[0457] Synthesized from (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (83) according to a general procedure (Step 2) (Yield: 28.1 mg, 75%, splashable white solid). LC-MS: m / z: 391.4 [M+H] + ; 1H NMR (500 MHz, MeOD): δ = 7.90 (d, J = 0.8 Hz, 1H), 7.20 - 7.13 (m, 2H), 7.12 - 7.04 (m, 2H), 6.97 (d, J = 1.4 Hz, 1H), 6.28 (s, 1H), 4.24 (q, J = 15.5 Hz, 2H), 3.99 - 3.92 (m, 1H), 3.76 (dd, J = 14.3, 5.5 Hz, 1H), 3.54 (q, J = 7.1 Hz, 2H), 3.48 - 3.42 (m, 1H), 3.49 - 3.37 (m, 2H), 3.24 (ddd, J = 11.2, 4.9, 1.1 Hz, 1H), 2.92 (t, J = 10.8 Hz, 1H), 2.71 (ddd, J = 14.2, 11.4, 1.7 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). Column name: X Bridge C18 (4.6 mm x 100 mm, 5 μM); Mobile phase: A = acetonitrile, B = 0.1% TFA in water; 5-100% gradient. R t =5.40 minutes

[0458] Preparation of (6aR,9R)-N,N-diethyl-7-(oxazole-5-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (75)

[0459] [ka]

[0460] Synthesized from (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (83) according to a general procedure (Step 2) (Yield: 29.1 mg, 77%, splashable white solid). LC-MS: m / z: 391.4 [M+H] + ; 1H NMR (500 MHz, MeOD): δ = 8.18 (s, 1H), 7.21 - 7.15 (m, 2H), 7.11 - 7.04 (m, 2H), 6.99 (d, J = 1.4 Hz, 1H), 6.27 (s, 1H), 4.20 (s, 2H), 3.93 (dt, J = 10.4, 5.1 Hz, 1H), 3.75 (dd, J = 14.4, 5.5 Hz, 1H), 3.53 (qd, J = 15.1, 7.7 Hz, 2H), 3.46 - 3.39 (m, 3H), 3.22 - 3.15 (m, 1H), 2.83 (t, J = 10.8 Hz, Column name: X Bridge C18 (4.6 mm x 100 mm, 5 μM); Mobile phase: A = acetonitrile, B = 0.1% TFA in water; 5-100% gradient. R t =5.21 minutes

[0461] Preparation of (6aR,9R)-7-(cyclohexylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (89) and (6aR,9S)-7-(cyclohexylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (89a)

[0462] [ka]

[0463] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 100mg, 0.32 mmol) according to general procedure (Step 2); diastereomers were separated by preparative HPLC: column: X Select CSH phenylhexyl (19mm × 250mm, 5μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 40-98% gradient, run for 16 minutes; flow rate: 18ml / min.

[0464] (6aR,9R)-7-(cyclohexylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(89) Yield: 31 mg, 23.65%, off-white solid. LC-MS: m / z: 406.25 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.94 (s, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.12-7.06 (m, 2H), 6.94 (s, 1H), 6.30 (s, 1H), 3.52-3.50 (m, 1H), 3.7 (m, 1H), 3.48-3.37 (m, 4H), 3.26-3.14 (m, 1H), 3.11 (dd, J = 4.7, 11.0 Hz, 1H), 2.72-2.69 (m, 1H), 2.55-2.49 (m, 2H), 1.77-1.50 (m, 5H), 1.39-1.20 (m, 6H), 1.10 (t, J = 7.0 Hz, 3H), 0.99-0.93 (m, 2H). Enantiomeric excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 1.69 min (minor components), 2.13 min (major components).

[0465] (6aR,9S)-7-(cyclohexylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(89a) Yield: 40 mg, 30.52%, off-white solid. LC-MS: m / z: 406.25 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.94 (s, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.92 (s, 1H), 6.24 (s, 1H), 3.69 (s, 1H), 3.46-3.27 (m, 5H), 3.12 (m, 1H), 2.98 (m, 1H), 2.89-2.81 (m, 2H), 2.60 (m, 1H), 2.46-2.43 (m, 1H), 1.74-1.67 (m, 5H), 1.52 (s, 1H), 1.27-1.16 (m, 6H), 1.06 (t, J = 7.0 Hz, 3H), 0.90 (d, J = 12.4 Hz, 2H). Enantiomeric excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 1.63 min (major component), 2.13 min (minor component).

[0466] Preparation of (6aR,9R)-7-(cyclopentylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (90) and (6aR,9S)-7-(cyclopentylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (90a)

[0467] [ka]

[0468] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 200mg, 0.65 mmol) according to general procedure (Step 2); diastereomers were separated by preparative HPLC: column: X Select CSH phenylhexyl (19mm × 250mm, 5μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 40-98% gradient, run for 16 minutes; flow rate: 18ml / min.

[0469] (6aR,9R)-7-(cyclopentylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(90) Yield: 35 mg, 13.83%, off-white solid. LC-MS: m / z: 392.30 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.95 (s, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.12-7.06 (m, 2H), 6.94 (s, 1H), 6.30 (s, 1H), 3.73-3.65 (m, 1H), 3.55-3.43 (m, 3H), 3.43-3.34 (m, 2H), 3.22-3.18 (m, 2H), 2.77 (t, J = 10.2 Hz, 1H), 2.54-2.51 (m, 2H), 2.40-2.30 (m, 1H), 2.14 (m, 1H), 1.80-1.77 (m, 2H), 1.65-1.57 (m, 4H), 1.39 (m, 1H), 1.22 (t, J = 7.0 Hz, 4H), 1.10 (t, J = 7.0 Hz, 3H). Enantio-excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 1.69 min (minor components), 2.04 min (major components).

[0470] (6aR,9S)-7-(cyclopentylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(90a) Yield: 41 mg, 16.20%, off-white solid. LC-MS: m / z: 392.35 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.95 (s, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.92 (s, 1H), 6.23 (s, 1H), 3.71 (s, 1H), 3.49-3.44 (m, 3H), 3.37-3.29 (m, 2H), 3.20-3.10 (m, 1H), 2.99-2.95 (m, 2H), 2.97 (t, J = 4.8 Hz, 1H), 2.82 (t, 1H), 2.69 (m, 1H), 2.55 (m, 1H), 1.78-1.69 (m, 2H), 1.60-1.52 (m, 4H), 1.31-1.21 (m, 6H), 1.06 (t, J = 7.0 Hz, 3H). Enantio-excess (91.56%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 1.65 min (main component), 2.05 min (minor component).

[0471] Preparation of (6aR,9R)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (96) and (6aR,9S)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (96a)

[0472] [ka]

[0473] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 100mg, 0.32 mmol) according to a general procedure (Step 2) (using NaCNBD3, CH3COOD and CH3OD); diastereomers were separated by preparative HPLC: column: X Bridge C8 (19mm × 250mm, 5μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 30-98% gradient, run for 19 minutes; flow rate: 18ml / min.

[0474] (6aR,9R)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(96) Yield: 30 mg, 21.56%, off-white solid. LC-MS: m / z: 431.3 [M+H] + ; 1H NMR (400 MHz, CD3CN): δ = 8.98 (s, 1H), 7.28-7.24 (m, 2H), 7.13-7.08 (m, 2H), 7.01-6.99 (m, 2H), 6.96 (s, 1H), 6.84-6.81 (m, 1H), 6.34 (s, 1H), 4.28 (s, 1H), 3.78 (s, 3H), 3.69-3.64 (m, 2H), 3.41-3.26 (m, 5H), 2.99 (dd, J = 4.6, 11.1 Hz, 1H), 2.70-2.64 (m, 1H), 2.56-2.51 (m, 1H), 1.09-1.03 (m, 6H). Enantio-excess (98.58%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=MeOH with 0.2% diethylamine (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. R t = 2.70 minutes (minor component), 3.60 minutes (principal component).

[0475] (6aR,9S)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(96a) Yield: 20 mg, 14.37%, off-white solid. LC-MS: m / z: 431.3 [M+H] + ; 1H NMR (400 MHz, CD3CN): δ = 8.93 (s, 1H), 7.25-7.19 (m, 2H), 7.11-6.99 (m, 4H), 6.89 (s, 1H), 6.80 (dd, J = 2.2, 8.1 Hz, 1H), 6.28 (s, 1H), 3.92-3.83 (m, 1H), 3.78 (s, 4H), 3.50-3.47 (m, 1H), 3.36-3.30 (m, 4H), 3.13 (dd, J = 5.0, 14.5 Hz, 1H), 3.02-2.86 (m, 3H), 1.12 (t, J = 7.1Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H). The enantiomeric excess (95.18%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. t = 2.58 minutes (main component), 3.60 minutes (minor component).

[0476] Preparation of (6aR,9R)-N,N-diethyl-7-(4-methylbenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (97) and (6aR,9S)-N,N-diethyl-7-(4-methylbenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (97a)

[0477] [ka]

[0478] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 300mg, 0.97mmol) according to general procedure (Step 2); diastereomers were separated by preparative HPLC: column: Gemini NX C18 (21.1mm × 150mm, 5μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 10-98% gradient, run for 18 minutes; flow rate: 18ml / min.

[0479] (6aR,9R)-N,N-diethyl-7-(4-methylbenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(97) Yield: 25 mg, 6.23%, off-white solid. LC-MS: m / z: 414.2 [M+H] + ; 1 ¹H NMR (400 MHz, CD3CN): δ = 8.98 (s, 1H), 7.41-7.32 (m, 2H), 7.23-7.07 (m, 5H), 6.92 (s, 1H), 6.31 (s, 1H), 3.89 (s, 2H), 3.76 (s, 1H), 3.50-3.29 (m, 5H), 3.14-2.92 (m, 4H), 2.32 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H). The enantiomeric excess (96%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm x 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. t = 2.50 minutes (main component), 3.20 minutes (minor component).

[0480] (6aR,9S)-N,N-diethyl-7-(4-methylbenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(97a) Yield: 44 mg, 11%, off-white solid. LC-MS: m / z: 414.2 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.98 (s, 1H), 7.31 (d, J = 7.8 Hz, 2H), 7.25-7.16 (m, 3H), 7.13-7.08 (m, 2H), 6.97 (s, 1H), 6.33 (s, 1H), 4.29 (d, J = 13.9 Hz, 1H), 3.72-3.63 (m, 2H), 3.41-3.35 (m, 3H), 3.33-3.22 (m, 2H), 2.99 (dd, J = 11.1, 4.0 Hz, 1H), 2.70-2.63 (m, 1H), 2.51 (t, J = 10.7 Hz, 1H), 2.32 (s, 3H), 1.08-1.04 (m, 6H). Enantiomeric excess (96%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. R t = 2.36 minutes (minor component), 3.10 minutes (principal component).

[0481] Preparation of (6aR,9R)-N,N-diethyl-7-(3-methylbenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (98) and (6aR,9S)-N,N-diethyl-7-(3-methylbenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (98a)

[0482] [ka]

[0483] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 300mg, 0.97mmol) according to general procedure (Step 2); diastereomers were separated by preparative HPLC: column: Gemini NX C18 (21.1mm × 150mm, 5μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 10-98% gradient, run for 18 minutes; flow rate: 18ml / min.

[0484] (6aR,9R)-N,N-diethyl-7-(3-methylbenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(98) Yield: 42 mg, 10.47%, off-white solid. LC-MS: m / z: 414.20 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.97 (s, 1H), 7.26-7.20 (m, 4H), 7.12-7.08 (m, 3H), 6.97-6.96 (m, 1H), 6.34 (s, 1H), 4.32 (d, J = 13.9 Hz, 1H), 3.71-3.66 (m, 2H), 3.40-3.27 (m, 6H), 2.97 (dd, J = 3.7, 6.1 Hz, 1H), 2.70-2.66 (m, 1H), 2.50 (t, J = 10.8 Hz, 1H), 2.34 (s, 3H), 1.08-1.03 (m, 6H). Column name: Chiralpak IJ (250mm x 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 2.29 min (minor components), 3.06 min (major components).

[0485] (6aR,9S)-N,N-diethyl-7-(3-methylbenzyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(98a) Yield: 15 mg, 3.74%, off-white solid. LC-MS: m / z: 414.30 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.92 (s, 1H), 7.25-7.18 (m, 4H), 7.11-7.03 (m, 3H), 6.89-6.88 (m, 1H), 6.27 (s, 1H), 3.95-3.83 (m, 2H), 3.76-3.73 (m, 1H), 3.48 (m, 1H), 3.36-3.28 (m, 4H), 3.12 (dd, J = 5.2, 14.5 Hz, 1H), 2.98-2.85 (m, 3H), 2.31 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.0 (Hz, 3H). Enantio-excess (96.36%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 2.21 min (main component), 3.05 min (minor component).

[0486] Preparation of (6aR,9R)-N,N-diethyl-7-(naphthalene-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(100) and (6aR,9S)-N,N-diethyl-7-(naphthalene-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(100a)

[0487] [ka]

[0488] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 300mg, 0.97mmol) according to a general procedure (Step 2); diastereomers were separated by preparative HPLC: column: X Bridge C8 (19mm × 250mm, 5μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 40-98% gradient, run for 23 minutes; flow rate: 18ml / min.

[0489] (6aR,9R)-N,N-diethyl-7-(naphthalene-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(100) Yield: 27 mg, 6.19%, off-white solid. LC-MS: m / z: 450.30 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.98 (s, 1H), 7.90-7.87 (m, 4H), 7.88 (dd, J = 3.9, 8.5 Hz, 1H), 7.52-7.46 (m, 2H), 7.26-7.22 (m, 1H), 7.14-7.10 (m, 2H), 6.98 (s, 1H), 6.36 (s, 1H), 4.52 (d, J = 14.0 Hz, 1H), 3.76-3.71 (m, 2H), 3.56-3.49 (m, 2H), 3.31-3.20 (m, 4H), 3.04 (dd, J = 3.9, 11.2 Hz, 1H), 2.77-2.73 (m, 1H), 2.57 (t, J = 10.7 Hz, 1H), 1.03-0.95 (m, 6H). Enantio-excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 6.43 min (minor components), 8.03 min (major components).

[0490] (6aR,9S)-N,N-diethyl-7-(naphthalene-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(100a) Yield: 9 mg, 2%, off-white solid. LC-MS: m / z: 450.25 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.92 (s, 1H), 7.87-7.82 (m, 4H), 7.64 (dd, J = 1.4, 8.5 Hz, 1H), 7.50-7.44 (m, 2H), 7.2 (m, 1H), 7.1-7.04 (m, 2H), 6.87 (t, J = 1.7 Hz, 1H), 6.30 (s, 1H), 4.09 (m, 2H), 3.81-3.79 (m, 1H), 3.58-3.55 (m, 1H), 3.31-3.25 (m, 4H), 3.15 (dd, J = 5.2, 14.5 Hz, 1H), 3.04-2.89 (m, 3H), 1.06-0.98 (m, 6H). Enantiomeric excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 6.50 min (main component), 8.13 min (minor component).

[0491] Preparation of (6aR,9R)-N,N-diethyl-7-(naphthalene-1-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (101) and (6aR,9S)-N,N-diethyl-7-(naphthalene-1-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (101a)

[0492] [ka]

[0493] Synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxamide (83m; 300mg, 0.97mmol) according to general procedure (Step 2); diastereomers were separated by preparative HPLC: column: X Bridge C8 (19mm × 250mm, 10μM); mobile phase: 5mM ammonium bicarbonate aqueous solution / acetonitrile; 15-98% gradient, run for 16.5 minutes; flow rate: 18ml / min.

[0494] (6aR,9R)-N,N-diethyl-7-(naphthalene-1-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(101) Yield: 12 mg, 2.75%, off-white solid. LC-MS: m / z: 450.20 [M+H] + ; 1H NMR (400 MHz, CD3CN): δ = 9.01 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 5.1 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.84-7.55 (m, 2H), 7.53-7.47 (m, 1H), 7.29-7.17 (m, 1H), 7.15-7.12 (m, 2H), 7.01 (t, J = 1.6 Hz, 1H), 6.37 (s, 1H), 4.95 (d, J = 13.6 Hz, 1H), 3.87 (dd, J = 5.0, 13.5 Hz, 1H), 3.72 (d, J = 13.6 Hz, 1H), 3.56-3.53 (m, 2H), 3.26-3.17 (m, 3H), 3.16-3.09 (m, 1H), 2.94-2.89 (m, 2H), 2.53 (t, J = 11.0 Hz, 1H), 0.99 (t, J = 7.0 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H). Enantiomeric excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm x 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt = 4.89 min (minor components), 7.14 min (major components).

[0495] (6aR,9S)-N,N-diethyl-7-(naphthalene-1-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide(101a) Yield: 15 mg, 3.44%, off-white solid. LC-MS: m / z: 450.20 [M+H] + ; 1H NMR (400 MHz, CD3CN): δ = 8.95 (s, 1H), 8.48 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.60-7.52 (m, 3H), 7.47-7.43 (m, 1H), 7.23 (dd, J = 0.9, 7.6 Hz, 1H), 7.15-7.11 (m, 1H), 7.10-7.08 (m, 1H), 6.90 (s, 1H), 6.33 (s, 1H), 4.45 (d, J = 13.2 Hz, 1H), 4.35 (d, J = 13.2 Hz, 1H), 3.85-3.82 (m, 1H), 3.69-3.66 (m, 1H), 3.33-3.24 (m, 4H), 3.16-3.11 (m, 1H), 3.04-2.91 (m, 3H), 1.10 (t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.0 Hz, 3H). Enantio-excess (95.9%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250mm × 4.6mm, 5μM); Mobile phase: A=CO2, B=0.2% diethylamine in MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35℃. Rt=4.91 min (main component), 7.17 min (minor component).

[0496] Preparation of (6aR,9R)-N,N-diethyl-7-(oxazole-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (104)

[0497] [ka]

[0498] Synthesized from (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide (83) according to a general procedure (Step 2) (Yield: 21.4 mg, 55%, splashable white solid). LC-MS: m / z: 406.4 [M+H] + ; 1 H NMR (500 MHz, MeOD): δ = 7.33 (dd, J = 5.1, 1.0 Hz, 1H), 7.19 (dd, J = 7.7, 0.8 Hz, 1H), 7.12 - 7.05 (m, 2H), 7.01 - 6.96 (m, 2H), 6.30 (s, 1H), 4.41 (d, J = 14.7 Hz, 1H), 4.07 (d, J = 14.7 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.74 (dd, J = 14.4, 5.4 Hz, 1H), 3.55 - 3.49 (m, 1H), 3.54 - 3.43 (m, 3H), 3.40 (q, J = 7.1 Hz, 2H), 3.18 (dd, J = 11.1, 3.7 Hz, 1H), 2.76 (ddd, J = 14.0, 11.4, 1.6 Hz, 1H), 2.72 (t, J = 10.6 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H). Column name: X Bridge C18 (4.6 mm x 100 mm, 5 μM); Mobile phase: A = acetonitrile, B = 0.1% TFA in water; 5-100% gradient. R t =5.96 minutes [Examples]

[0499] Compounds prepared according to General Synthesis Scheme 2 General synthesis scheme 2:

[0500] [ka]

[0501] General synthesis protocol 2: Step 1 - Preparation of (6aR)-7-(alkyl)-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxylic acid

[0502] [ka]

[0503] To a stirred solution of the crude product sodium (6aR)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylate (Int27m; 1g, approx. 3.5 mmol, dr1:1; Fehr, T., Stadler, PA, Hofmann, A. Helvetica Chimica Acta, 1970, 53(8), pp. 2197-2201) in methanol (20 mL), aldehyde (7 mmol, 2 equivalents) was added, and the reaction mixture was sparged with nitrogen for 5 minutes. The reaction mixture was then cooled to 0°C, sodium borocyanohydride (0.627 g, 10.5 mmol, 3 equivalents) was added, followed by acetic acid (0.4 mL, 7 mmol, 2 equivalents). The reaction mixture was warmed to room temperature and stirred for 30 hours. The progress of the reaction was monitored by LC-MS and TLC. After completion, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (silica gel 60-120, eluate: 0-15% MeOH in DCM). Subsequently, it was ground with diethyl ether to obtain (6aR)-7-(alkyl)-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylic acid as a diastereomer mixture.

[0504] Step 2 - Form amides to obtain diastereomer 1 and diastereomer 2.

[0505] [ka]

[0506] (6aR)-7-(alkyl)-4,6,6a,7,8,9-hexahydroindo[4,3-fg]quinoline-9-carboxylic acid (1 equivalent) was stirred in anhydrous DMF (10 vol) and amine (3 equivalents) was added at 0°C, followed by propyl phosphonate anhydride (T3P, 50% in ethyl acetate; 3 equivalents) and triethylamine (3.5 equivalents). The reaction mixture was stirred at 0°C for 10 minutes, then slowly warmed to room temperature and stirred until complete. The progress of the reaction was monitored by LC-MS and TLC. After completion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to obtain diastereomers 1 and 2.

[0507] Compound: Preparation of ((6aR,9R)-7-benzyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-yl)(pyrroridine-1-yl)methanone(84) & ((6aR,9S)-7-benzyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-yl)(pyrroridine-1-yl)methanone(84a)

[0508] [ka]

[0509] Synthesized from (6aR)-7-benzyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-carboxylic acid (200 mg, 0.58 mmol) according to general procedure (Step 2); diastereomers were separated by preparative HPLC: column: X Select CSH C18 (19 mm × 250 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 20-98% gradient, run for 20 minutes; flow rate: 18 ml / min.

[0510] ((6aR,9R)-7-benzyl-4,6,6a,7,8,9-hexahydroindoro[4,3-fg]quinoline-9-yl)(pyrroridine-1-yl)methanone(84) Yield: 22 mg, 9.53%, off-white solid. LC-MS: m / z: 398.4 [M+H] + ; 1 H NMR (400 MHz, CD3CN): δ = 8.99 (s, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.29-7.22 (m, 2H), 7.14-7.09 (m, 2H), 6.97 (s, 1H), 6.38 (s, 1H), 4.34 (d, J = 14.0 Hz, 1H), 3.69 (dd, J = 5.2, 14.6 Hz, 1H), 3.58-3.52 (m, 2H), 3.46-3.41 (m, 2H), 3.39-3.29 (m, 3H), 3.02 (dd, J = 4.7, 11.2 Hz, 1H), 2.71-2.64 (m, 1H), 2.54 (t, J = 10.6 Hz, 1H), 1.90-1.77 (m, 4H). Enantiomeric excess (95.6%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm × 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine i...

Claims

1. Compound of formula (I): 【Chemistry 1】 [In the formula, R 1 C 1 ~C 6 Alkyl or 3-7 membered carbocyric, R 1 is one or more halogens or C 1 ~C 6 Alkyl is optionally substituted, R 2 is hydrogen or C 1 to C 6 alkyl, and R 2 is one or more halogens or C 1 to C 6 alkyl, optionally substituted, or R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocycline may contain one or more fluoro or C atoms. 1 ~C 6 Alkyl is optionally substituted, R 3 C 2 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, -CH 2 -(cyclopropyl) and selected from the group consisting of 3- to 7-membered cycloalkyl groups, R 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe. or R 3 is, -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 Selected from the group consisting of alkyl)-heteroaryl compounds, -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 C of alkyl)-heteroaryl 1 ~C 4 The alkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups. -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 The aryl and heteroaryl in alkyl)-heteroaryl are, independently, halogens, -OR 7 ,-OC(O)R 7 -CN, -NO 2 , -NR 7 R 8 , -CO 2 R 7 -C(O)NR 7 R 8 , C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl, C 3 ~C 8 Cycloalkyl, and R 9 One or more substituents selected from the group consisting of the above, which are optionally substituted, and each C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl, C 3 ~C 8 The cycloalkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups, and each R 7 and R 8 H and C are independent of each other. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl, C 3 ~C 8 Cycloalkyl, and R 10 Selected from the group consisting of C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl, C 3 ~C 8 The cycloalkyl is optionally substituted with one or more fluoro, hydroxyl, or -OMe, each R 9 and R 10 is independently selected from the group consisting of halogen, -OH, -OC(O)(C 1 to C 4 alkyl), -O(C 1 to C 4 alkyl), -CN, -NO 2 , -NH 2 , C 1 to C 4 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, and C 3 to C 5 cycloalkyl, and is an aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group, each C 1 to C 4 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, C 3 to C 5 The cycloalkyl is optionally substituted with one or more fluoro, hydroxyl, or -OMe, R 4 is hydrogen or -C(O)(C 1 ~C 8 It is alkyl, R 5 These are hydrogen, Me, Et, and -CH 2 F, -CHF 2 ,-CF 3 , or halogen, R 6 is hydrogen or deuterium, however, (a)R 1 and R 2 Both are ethyl, R 4 and R 5 If both are hydrogen, then R 3 is an unsubstituted linear C 2 ~C 6 Alkyl, isopropyl, -CH 2 CH=CH 2 ,-CH 2 CH 2 F, or -CH 2 CH 2 It is not considered a false statement. (b)R 1 and R 2 Both are ethyl, R 4 is -C(O)(C 2 Alkyl) and R 5 If R is hydrogen, 3 This is not unsubstituted ethyl, and (c)R 1 is ethyl, and R 2 If H, then R 3 is unsubstituted ethyl, unsubstituted n-propyl, or -CH 2 CH=CH 2 [It shall not be assumed] or a pharmaceutically acceptable salt thereof.

2. R 1 However, C 1 ~C 6 Alkyl or 3-7 membered carbocyric, R 1 However, one or more fluorocarbons or C atoms 1 ~C 6 Alkyl is optionally substituted, R 2 However, hydrogen or C 1 ~C 6 It is alkyl, R 2 However, one or more fluorocarbons or C atoms 1 ~C 6 Alkyl, optionally substituted, R 1 and R 2 However, together with the atoms to which they are bonded, they can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocycline may contain one or more fluoro or C atoms. 1 ~C 6 Alkyl is optionally substituted, R 3 However, C 2 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, -CH 2 -(cyclopropyl) and selected from the group consisting of 3- to 7-membered cycloalkyl groups, R 3 However, each may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe. or R 3 However, -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 Selected from the group consisting of alkyl)-(6-membered heteroaryl), -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 C of alkyl)-(6-membered heteroaryl) 1 ~C 2 The alkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups. -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 The alkyl)-(6-membered heteroaryl) phenyl and 6-membered heteroaryl groups are independently halogens, hydroxyls, and -OC(O)(C) 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 -C(O)NH 2 , C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, C 3 ~C 5 Cycloalkyl, and -O(C 1 ~C 4 One or more substituents selected from the group consisting of alkyls are optionally substituted, and each C 1 ~C 8 and C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl and C 3 ~C 5 The compound according to claim 1, wherein the cycloalkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups.

3. R 1 However, C 1 ~C 6 Alkyl or 3-5 membered carbocyric, R 1 However, one or more fluorocarbons or C atoms 1 ~C 4 Alkyl is optionally substituted, R 2 However, hydrogen or C 1 ~C 3 It is alkyl, R 2 However, one or more fluorocarbons or C atoms 1 ~C 4 Alkyl, optionally substituted, R 1 and R 2 However, together with the atoms to which they are bonded, they can form optionally substituted 3-6 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocyclines may contain one or more fluoro or C atoms. 1 ~C 3 Alkyl is optionally substituted, R 3 However, C 2 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, -CH 2 -(cyclopropyl) and selected from the group consisting of 3- to 5-membered cycloalkyl groups, R 3 However, each may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe. or R 3 However, -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 Selected from the group consisting of alkyl)-(6-membered heteroaryl), -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 C of alkyl)-(6-membered heteroaryl) 1 ~C 2 The alkyl group is optionally substituted with one or more fluoro groups. -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 The alkyl)-(6-membered heteroaryl) phenyl and 6-membered heteroaryl groups are independently halogens, hydroxyls, and -OC(O)(C) 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 -C(O)NH 2 , C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 Alkynyl, cyclopropyl, and -O(C 1 ~C 3 One or more substituents selected from the group consisting of alkyls are optionally substituted, and each C 1 ~C 8 and C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 The compound according to claim 2, wherein the alkynyl and cyclopropyl are optionally substituted with one or more fluoropolymers.

4. R 4 A compound according to any one of claims 1 to 3, wherein is hydrogen.

5. R 5 A compound according to any one of claims 1 to 3, wherein is hydrogen.

6. R 5 Me, Et, -CH 2 F, -CHF 2 ,-CF 3 The compound according to any one of claims 1 to 3, which is either a halogen or a halogen.

7. R 5 The compound according to claim 6, wherein is bromo.

8. R 6 A compound according to any one of claims 1 to 3, wherein is hydrogen.

9. R 3 However, C 2 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, -CH 2 -(cyclopropyl) and selected from the group consisting of 3- to 7-membered cycloalkyl groups, R 3 The compound according to claim 1, wherein each of these substituents may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe.

10. R 3 However, -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 Selected from the group consisting of alkyl)-heteroaryl compounds, -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 C of alkyl)-heteroaryl 1 ~C 4 The alkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups. -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 The aryl and heteroaryl in alkyl)-heteroaryl are, independently, halogens, -OR 7 ,-OC(O)R 7 -CN, -NO 2 , -NR 7 R 8 , -CO 2 R 7 -C(O)NR 7 R 8 , C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl, C 3 ~C 8 Cycloalkyl, and R 9 One or more substituents selected from the group consisting of the following, which are optionally substituted, and each R 7 and R 8 However, independently, H, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl, C 3 ~C 8 Cycloalkyl, and R 10 Selected from the group consisting of each R 9 and R 10 However, independently, halogen, -OH, -OC(O)(C 1 ~C 4 Alkyl), -O(C 1 ~C 4 Alkyl), -CN, -NO 2 , -NH 2 , C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl and C 3 ~C 5 An aryl or heteroaryl compound that is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl compounds, and each C 1 ~C 8 and C 1 ~C 4 Alkyl, C 2 ~C 8 and C 2 ~C 4 Alkenil, C 2 ~C 8 and C 2 ~C 4 Alkinyl, and C 3 ~C 8 and C 3 ~C 5 The compound according to claim 1, wherein the cycloalkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups.

11. R 3 However, -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 Selected from the group consisting of alkyl)-(6-membered heteroaryl), -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 C of alkyl)-(6-membered heteroaryl) 1 ~C 2 The alkyl group is optionally substituted with one or more fluoro groups. -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 The alkyl)-(6-membered heteroaryl) phenyl and 6-membered heteroaryl groups are independently halogens, hydroxyls, and -OC(O)(C) 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 -C(O)NH 2 , C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 Alkynyl, cyclopropyl, and -O(C 1 ~C 3 One or more substituents selected from the group consisting of alkyls are optionally substituted, and each C 1 ~C 8 and C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 The compound according to claim 1, wherein the alkynyl and cyclopropyl are optionally substituted with one or more fluoropolymers.

12. R 4 , R 5 , and R 6 The compound according to any one of claims 9 to 11, wherein each of them is hydrogen.

13. R 4 and R 6 Each of them is hydrogen, and R 5 Me, Et, -CH 2 F, -CHF 2 ,-CF 3 The compound according to any one of claims 9 to 11, which is either a halogen or a halogen.

14. R 5 The compound according to claim 13, wherein is bromo.

15. Compound of formula (Ia): 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. Compounds of formula (Ib), formula (Ic), formula (Id), or formula (Ie): 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. R 5 The compound according to claim 16, wherein is hydrogen.

18. R 5 The compound according to claim 16, wherein is Me, Et, or a halogen.

19. R 5 The compound according to claim 16, wherein is Me, Et, or bromo.

20. R 5 The compound according to claim 16, wherein is bromo.

21. R 3 However, ethyl, n-propyl, -CH 2 CH=CH 2 cyclopropyl and -CH 2 Selected from the group consisting of -(cyclopropyl), R 3 The compound according to any one of claims 15 to 20, which may be substituted with 1 to 3 fluoropolymers.

22. R 3 However, ethyl, n-propyl, -CH 2 CH=CH 2 , cyclopropyl, -CH 2 -(cyclopropyl), -CH 2 CF 3、 -CH 2 CH 2 CH 2 F and -CH 2 CH 2 CF 3 A compound according to any one of claims 15 to 20, selected from the group consisting of the following.

23. R 3 However, -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 Selected from the group consisting of alkyl)-heteroaryl compounds, -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 C of alkyl)-heteroaryl 1 ~C 4 The alkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups. -(C 1 ~C 4 Alkyl)-aryl and -(C 1 ~C 4 The aryl and heteroaryl in alkyl)-heteroaryl are, independently, halogens, -OR 7 ,-OC(O)R 7 -CN, -NO 2 , -NR 7 R 8 , -CO 2 R 7 -C(O)NR 7 R 8 , C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl, C 3 ~C 8 Cycloalkyl, and R 9 One or more substituents selected from the group consisting of the following, which are optionally substituted, and each R 7 and R 8 However, independently, H, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl, C 3 ~C 8 Cycloalkyl, and R 10 Selected from the group consisting of each R 9 and R 10 However, independently, halogen, -OH, -OC(O)(C 1 ~C 4 Alkyl), -O(C 1 ~C 4 Alkyl), -CN, -NO 2 , -NH 2 , C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl and C 3 ~C 5 An aryl or heteroaryl compound that is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl compounds, and each C 1 ~C 8 and C 1 ~C 4 Alkyl, C 2 ~C 8 and C 2 ~C 4 Alkenil, C 2 ~C 8 and C 2 ~C 4 Alkinyl, and C 3 ~C 8 and C 3 ~C 5 The compound according to any one of claims 15 to 20, wherein the cycloalkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups.

24. R 3 However, -(C 1 ~C 2 Alkyl)-aryl and -(C 1 ~C 2 Selected from the group consisting of alkyl)-heteroaryl compounds, -(C 1 ~C 2 Alkyl)-aryl and -(C 1 ~C 2 C of alkyl)-heteroaryl 1 ~C 2 The alkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups. -(C 1 ~C 2 Alkyl)-aryl and -(C 1 ~C 2 The aryl and heteroaryl in alkyl)-heteroaryl are, independently, halogens, -OR 7 ,-OC(O)R 7 -CN, -NO 2 , -NR 7 R 8 , -CO 2 R 7 -C(O)NR 7 R 8 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 3 ~C 6 Cycloalkyl, and R 9 One or more substituents selected from the group consisting of the following, which are optionally substituted, and each R 7 and R 8 However, independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 3 ~C 6 Cycloalkyl, and R 10 Selected from the group consisting of each R 9 and R 10 However, independently, halogen, -OH, -OC(O)(C 1 ~C 4 Alkyl), -O(C 1 ~C 4 Alkyl), -CN, -NO 2 , -NH 2 , C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl and C 3 ~C 5 An aryl or heteroaryl compound that is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl compounds, and each C 1 ~C 6 and C 1 ~C 4 Alkyl, C 2 ~C 6 and C 2 ~C 4 Alkenil, C 2 ~C 6 and C 2 ~C 4 Alkinyl, and C 3 ~C 6 and C 3 ~C 5 The compound according to any one of claims 15 to 20, wherein the cycloalkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups.

25. R 3 However, -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 Selected from the group consisting of alkyl)-(6-membered heteroaryl), -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 C of alkyl)-(6-membered heteroaryl) 1 ~C 2 The alkyl group is optionally substituted with one or more fluoro groups. -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 The alkyl)-(6-membered heteroaryl) phenyl and 6-membered heteroaryl groups are independently halogens, hydroxyls, and -OC(O)(C) 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 -C(O)NH 2 , C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 Alkynyl, cyclopropyl, and -O(C 1 ~C 3 One or more substituents selected from the group consisting of alkyls are optionally substituted, and each C 1 ~C 8 and C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 The compound according to any one of claims 15 to 20, wherein the alkynyl and cyclopropyl are optionally substituted with one or more fluoropolymers.

26. R 3 However, -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 Selected from the group consisting of alkyl)-pyridinyl, -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 The phenyl and pyridinyl in alkyl)-pyridinyl are, independently, halogen, hydroxyl, and -OC(O)(C) 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 -C(O)NH 2 , C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 Alkynyl, cyclopropyl, and -O(C 1 ~C 3 One or more substituents selected from the group consisting of alkyls are optionally substituted, and each C 1 ~C 8 and C 1 ~C 3 Alkyl, C 2 ~C 3 Alkenil, C 2 ~C 3 The compound according to any one of claims 15 to 20, wherein the alkynyl and cyclopropyl are optionally substituted with one or more fluoropolymers.

27. R 3 but, 【Chemistry 4】 A compound according to any one of claims 15 to 20, selected from the group consisting of the following.

28. R 3 but, 【Transformation 5】 A compound according to any one of claims 15 to 20, selected from the group consisting of the following.

29. R 3 but, 【Transformation 6】 A compound according to any one of claims 15 to 20, selected from the group consisting of the following. 【Request Item 30】 【Chemistry 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof. 【Request Item 31】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 A compound according to claim 30 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following. 【Request Item 32】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 A compound according to claim 30 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

33. Compound of formula (II): 【Chemistry 21】 [In the formula, R 1 C 1 ~C 6 Alkyl or 3-7 membered carbocyric, R 1 is one or more halogens or C 1 ~C 6 Alkyl is optionally substituted, R 2 is hydrogen or C 1 ~C 6 It is alkyl, R 2 is one or more halogens or C 1 ~C 6 Alkyl, optionally substituted, R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocycline may contain one or more fluoro or C atoms. 1 ~C 6 Alkyl is optionally substituted, R 4 is hydrogen or -C(O)(C 1 ~C 8 It is alkyl, R 5 is Me, Et, -CH 2 F, -CHF 2 ,-CF 3 , or halogen, R 6 is hydrogen or deuterium, however, (a)R 1 and R 2 Both are ethyl, R 4 If R is hydrogen, 5 This shall not be chloro, bromo, iodine, or unsubstituted methyl, (b)R 2 is hydrogen, R 4 is hydrogen, R 5 If it is bromo, then R 1 This shall not be ethyl, isopropyl, or propargyl, and (c)R 2 is methyl, and R 4 is hydrogen, R 5 If it is bromo, then R 1 [This shall not be propargyl or cyclopropyl.] or a pharmaceutically acceptable salt thereof.

34. R 1 However, C 1 ~C 6 Alkyl or 3-5 membered carbocyric, R 1 However, one or more fluorocarbons or C atoms 1 ~C 4 Alkyl is optionally substituted, R 2 However, hydrogen or C 1 ~C 3 It is alkyl, R 2 However, one or more fluorocarbons or C atoms 1 ~C 4 Alkyl, optionally substituted, or R 1 and R 2 However, together with the atoms to which they are bonded, they can form optionally substituted 3-6 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocycline may contain one or more fluoro or C atoms. 1 ~C 3 The compound according to claim 33, wherein the alkyl group is optionally substituted.

35. R 4 and R 6 The compound according to claim 33 or 34, wherein each of these is hydrogen.

36. Compounds of formula (IIb), formula (IIc), formula (IId), or formula (IIe): 【Chemistry 22】 The compound according to claim 33, or a pharmaceutically acceptable salt thereof.

37. R 5 The compound according to claim 36, wherein is Me, Et, or a halogen.

38. R 5 The compound according to claim 36, wherein is Me, Et, or bromo.

39. R 5 The compound according to claim 36, wherein is bromo. 【Request Item 40】 【Chemistry 23】 A compound according to claim 36 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

41. structure: 【Chemistry 24】 A compound having [a certain characteristic], or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising the compound described in claim 1, 30, 33, or 41 and a pharmaceutically acceptable adjuvant or carrier.

43. A method for treating a mood disorder, comprising the step of administering to a patient in need thereof a pharmaceutical composition containing an effective amount of the compound described in claim 1, 30, 33, or 41.

44. The method according to claim 43, wherein the mood disorder is selected from the group consisting of depressive disorders and bipolar disorders.

45. The method according to claim 43, wherein the mood disorder is a depressive disorder.

46. The method according to claim 43, wherein the mood disorder is a treatment-resistant depressive disorder.

47. The method according to claim 43, wherein the mood disorder is selected from the group consisting of major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal anxiety disorder, psychotic depression, severe mood dysregulation, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

48. The method according to claim 43, wherein the mood disorder is selected from the group consisting of bipolar disorder I, bipolar disorder II, cyclothymic disorder, substance / medicine-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to another medical condition.

49. The method according to claim 43, wherein the mood disorder is a substance-related disorder.

50. The method according to claim 43, wherein the mood disorder is a substance use disorder.

51. The method according to claim 43, wherein the mood disorder is an anxiety disorder.

52. The method according to claim 43, wherein the mood disorder is selected from the group consisting of obsessive-compulsive disorder and related disorders, trauma and stressor-related disorders, eating behavior and feeding disorders, borderline personality disorder, attention deficit / hyperactivity disorder, and autism spectrum disorder.

53. The method according to claim 43, wherein the mood disorder is a cognitive disorder.

54. A method for treating mood disorders, wherein a compound according to formula (I) is administered to a patient in need. 【Chemistry 25】 [In the formula, R 1 C 1 ~C 6 Alkyl or 3-7 membered carbocyric, R 1 is one or more halogens or C 1 ~C 6 Alkyl is optionally substituted, R 2 is hydrogen or C 1 ~C 6 It is alkyl, R 2 is one or more halogens or C 1 ~C 6 Alkyl, optionally substituted, R 1 and R 2 These, together with the atoms to which they are bonded, can form optionally substituted 3-7 membered heterocyclines containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and the heterocycline may contain one or more fluoro or C atoms. 1 ~C 6 Alkyl is optionally substituted, R 3 C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, -CH 2 -(cyclopropyl) and selected from the group consisting of 3- to 7-membered cycloalkyl groups, R 3 Each of these may be independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe. or R 3 is, -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 Selected from the group consisting of alkyl)-(6-membered heteroaryl), -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 C of alkyl)-(6-membered heteroaryl) 1 ~C 2 The alkyl group is optionally substituted with one or more fluoro, hydroxyl, or -OMe groups. -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 Phenyl and 6-membered heteroaryl groups of alkyl)-(6-membered heteroaryl are independently halogenated, hydroxylated, and -OC(O)(C) 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 -C(O)NH 2 , C 1 ~C 4 Alkyl, C 3 ~C 5 Cycloalkyl, and -O(C 1 ~C 4 Optionally substituted with one or more substituents selected from the group consisting of alkyl groups, R 4 is hydrogen or -C(O)(C 1 ~C 8 It is alkyl, R 5 These are hydrogen, Me, Et, and -CH 2 F, CHF 2 ,-CF 3 , or halogen, R 6 A method comprising the step of administering a pharmaceutical composition containing an effective amount of hydrogen or deuterium or a pharmaceutically acceptable salt thereof.

55. The method according to claim 54, wherein the mood disorder is selected from the group consisting of depressive disorders and bipolar disorders.

56. The method according to claim 54, wherein the mood disorder is a depressive disorder.

57. The method according to claim 54, wherein the mood disorder is a treatment-resistant depressive disorder.

58. The method according to claim 54, wherein the mood disorder is selected from the group consisting of major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal anxiety disorder, psychotic depression, severe mood dysregulation, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

59. The method according to claim 54, wherein the mood disorder is selected from the group consisting of bipolar disorder I, bipolar disorder II, cyclothymic disorder, substance / medicine-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to another medical condition.

60. The method according to claim 54, wherein the mood disorder is a substance-related disorder.

61. The method according to claim 54, wherein the mood disorder is a substance use disorder.

62. The method according to claim 54, wherein the mood disorder is an anxiety disorder.

63. The method according to claim 54, wherein the mood disorder is selected from the group consisting of obsessive-compulsive disorder and related disorders, trauma and stressor-related disorders, eating behavior and feeding disorders, borderline personality disorder, attention deficit / hyperactivity disorder, and autism spectrum disorder.

64. The method according to claim 54, wherein the mood disorder is a cognitive disorder.

65. The compound has the following structure: 【Chemistry 26】 The method according to claim 54, or the method comprising a pharmaceutically acceptable salt thereof.

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