Novel ergolins and methods of treating mood disorders

Abstract

The present disclosure provides ergoline compounds and their use in the treatment of mood disorders. Pharmaceutical compositions and methods of making various ergoline compounds are provided.

Description

[0001] Field of the Disclosure The present disclosure relates to ergot compounds that can be reliably used to treat mood disorders. BACKGROUND

[0002] Ergot compounds are a diverse class of alkaloids that contain the structural scaffold of the natural alkaloid ergotinine.

[0003] There are a large number of ergot compounds, including naturally occurring compounds, as well as synthetic and semi-synthetic chemical derivatives with similar structures. Ergot compounds are known to have a variety of psychoactive and physiological effects. Some ergot compounds are agonists of the serotonin 2a (5-HT 2A ) receptor and / or modulators of other serotonin receptors, and are known to be psychoactive and / or to induce vasoconstriction. In some cases, such compounds induce long-term hallucinations. Other ergot compounds are agonists of dopamine receptors. Perhaps the most well-known ergot compound is the hallucinogenic compound lysergic acid diethylamide (LSD). This compound is known to have significant effects on thought, perception, 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 accepted medical use, and lack of established safety.

[0004] Accordingly, there remains a need for safe and effective ergot compounds that can be reliably used to treat mood disorders. SUMMARY

[0005] The present disclosure includes compounds of Formula (I): (I) or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are defined herein.

[0006] Further, the present disclosure includes methods of treating mood disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).

[0007] BRIEF DESCRIPTION OF DRAWINGS Figure 1 The effects of Compound 1 in the mouse head twitch response (HTR) assay are depicted as quantified by the number of head twitches recorded during a 20-minute observation period. Data points represent mean ± SEM.

[0008] Figure 2 Depiction of immobility time in the rat forced swim test at 23.5 hours after administration of Compound 1. Data points represent mean ± SEM. Compared to vehicle: * p <0.01, p <0.0001.

[0009] Figure 3 Depiction of the total number of marbles buried during the 30-minute observation period in the mouse marble burying test. Data points represent mean ± SEM. Compared to vehicle: * p <0.05, p <0.0001.

[0010] Figure 4 Depiction of the effect of LSD, control, and representative compounds of the disclosure on the head twitch response (HTR) assay in mice, as quantified by the number of head twitches recorded during a 20-minute observation period using an automated video tracking program.

[0011] DETAILED DESCRIPTION The features and other details of the present disclosure will now be described more fully. Certain terms are used throughout the specification, examples, and appended claims to describe certain features of the present disclosure. These definitions should be read in light of the remainder of the disclosure and understood as by a person of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0012] DEFINITIONS “Treatment” includes any effect that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, modulation, or elimination.

[0013] As used herein, the term “alkyl” refers to a saturated straight-chain or branched- chain hydrocarbon having the number of carbon atoms specified herein, e.g., 1 to 6 carbon atoms. Exemplary alkyl groups include, but are not limited to, straight chain or branched chain hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-C6alkyl, C1-C4alkyl, and C1-C3alkyl, respectively. 1- C6alkyl, C 1- C4alkyl, and C 1- C3alkyl. Exemplary 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.

[0014] As used herein, the term "alkenyl" is a branched or unbranched hydrocarbon group having the number of carbon atoms specified and containing at least one double bond, as defined herein below, for example, having 2-6 carbon atoms and 1-3 carbon-carbon double bonds. In some embodiments, alkenyl refers to a branched or unbranched saturated hydrocarbon group having three carbon atoms (C3). In some embodiments, alkenyl refers to a branched or unbranched hydrocarbon group having six carbon atoms (C6). In some embodiments, the term "alkenyl" includes, but is not limited to, vinyl or allyl.

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

[0016] As used herein, the term "cyano" refers to the group -CN.

[0017] The terms "cycloalkyl" or "carbocyclic" or "carbocyclic group" are synonymous and, as used herein, refer to saturated or partially unsaturated hydrocarbon groups, for example, having 3-6 or 4-6 carbons, referred to herein as C3-C6cycloalkyl or C4-C6cycloalkyl, respectively. 3- C6cycloalkyl or C 4- C6cycloalkyl. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0018] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0019] The term "aryl" used alone or as part of a larger moiety, for example, in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic and bicyclic ring systems having from five to fourteen ring members in which at least one ring is aromatic, and in which each ring in the system contains from three to seven ring members. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the disclosure, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, biphenyl, naphthyl, anthryl, and the like, which can bear one or more substituent groups. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0020] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, e.g., "heteroaralkyl," or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-," also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is to the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, phenoxazine, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group can be mono- or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0021] The terms "heterocyclyl" or "heterocyclyl group" are art-recognized and refer to saturated or partially unsaturated 4-10 membered ring structures, including bridged or fused rings, and whose ring structure includes one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring can be attached to a neighboring group through a carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, or dihydrofuran, and the like.

[0022] As used herein, the terms "hydroxy" and "hydroxyl" refer to the group -OH.

[0023] As used herein, the term "linear C2-C6alkyl" is synonymous with straight chain C2-C6alkyl.

[0024] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other undesirable reactions when administered to animals or humans under appropriate conditions. For human administration, the preparation should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics standards.

[0025] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic agents, and absorption delay agents, etc., compatible with drug administration. 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 complementary, additional, or enhanced therapeutic functions.

[0026] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0027] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds of this disclosure can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., dairy cows, sheep, domestic pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammals treated in the methods of this disclosure are preferably mammals for which treatment of mental illness or disorder is desired. “Modulation” includes antagonism (e.g., inhibition), excitation, partial antagonism, and / or partial excitation.

[0028] In this specification, the term "therapeuticly effective amount" means the amount of the subject compound that will elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human) sought by a researcher, veterinarian, physician, or other clinician. The compounds of this disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, the therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventive effect, such as an amount resulting in a reduction of symptoms of a mental disorder. As used herein, the term "preventive effect" refers to the prevention of the worsening of a symptom, disease, disorder, etc.

[0029] As used herein, the term "pharmaceutically acceptable salt" refers to a salt containing acidic or basic groups that may be present in the compounds used in the composition. The basic compounds included in this composition are capable of forming a wide variety of salts with a variety of inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are acids that form non-toxic acid addition salts, which are salts containing pharmacologically acceptable anions, including but not limited to malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentisinates, fumarates, gluconates, glucuronides, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pyrates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthylcarbamate)). The acidic compounds included in this composition are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds comprising basic or acidic moieties in this composition may also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compound may exist as an acid addition salt, a zwitterion, or a basic salt. In some embodiments, as used herein, the term "pharmaceutically acceptable salt" refers to a hemitartaric acid salt. As used herein, the hemitartaric acid salt of a compound of formula (I) is a salt in which the molar ratio of the compound of formula (I) to tartaric acid is 2:1. In some embodiments, as used herein, the term "pharmaceutically acceptable salt" refers to a tartrate salt. As used herein, the tartrate acid salt of a compound of formula (I) is a salt in which the molar ratio of the compound of formula (I) to tartaric acid is 1:1.

[0030] The compounds disclosed herein may contain one or more chiral centers and thus exist as stereoisomers. The term "stereoisomer," as used herein, comprises all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the carbon atom of the stereoisomer source, these compounds may be indicated by the symbols "(+)", "(-)", "R", or "S," but those skilled in the art will recognize that the structure may implicitly indicate the chiral center. This disclosure covers various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated as "(±)" in nomenclature, but those skilled in the art will recognize that the structure may implicitly indicate the chiral center.

[0031] The compounds disclosed herein may contain one or more double bonds, and thus exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bonds. (Symbols) This indicates that the bond can be a single, double, or triple bond as described herein. Substituents around carbon-carbon double bonds are indicated as “…”. Z "or" E "Configuration, in which the term" Z "and" E "Used in accordance with IUPAC standards. Unless otherwise specified, the description of the double bond structure covers..." E” and" Z” Both areomers. The substituents around the carbon-carbon double bond can be alternatively referred to as "cis" or "trans", where "cis" means the substituent is on the same side of the double bond and "trans" means the substituent is on the opposite side of the double bond.

[0032] The compounds disclosed herein may contain a carbocyclic or heterocyclic ring, and thus exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents around the carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans," wherein the term "cis" indicates that the substituent is on the same side of the ring plane, and the term "trans" indicates that the substituent is on the opposite side of the ring plane. Mixtures of compounds in which the substituents are arranged on both the same and opposite sides of the ring plane are designated as "cis / trans."

[0033] The individual enantiomers and diastereomers of the compounds disclosed herein can be prepared synthetically from commercially available starting materials containing asymmetric or stereoisomeric source centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary agent, separating the resulting diastereomer mixture by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; or (4) kineticly resolving using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their constituent enantiomers by well-known methods, such as chiral liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective synthesis is well known in the art and is a chemical or enzymatic reaction in which individual reactants form unequal mixtures of stereoisomers during the creation of new stereocenters or during the transformation of existing stereocenters. Stereoselective synthesis encompasses both enantiomeric and diastereoselective stereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno. Classics in Stereoselective Synthesis (Classic Stereoselective Synthesis), Wiley-VCH: Weinheim, 2009.

[0034] The compounds disclosed herein can exist in both solvated and non-solvated forms using pharmaceutically acceptable solvents (such as water, ethanol, etc.), and this disclosure is intended to include 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 yet another embodiment, the compound is in crystalline form.

[0035] This disclosure also includes isotopically labeled compounds of this disclosure that are identical to the compounds described herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, […]. 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, compounds disclosed herein may have one or more H atoms replaced by deuterium.

[0036] The disclosed compounds labeled with certain isotopes (e.g., using) 3 H and 14 C-labeled compounds can be used for the determination of compound and / or substrate tissue distribution. Tritium-labeled compounds (i.e.,...) 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Further, heavier isotopes such as deuterium (i.e., 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and is therefore preferred in some cases. Isotopically labeled compounds of this disclosure can generally be prepared by following procedures similar to those disclosed in the embodiments herein, by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0037] I. Compounds In some embodiments, this disclosure provides compounds of formula (I). (I) Or its pharmaceutically acceptable salt. in R 1It is a C1-C6 alkyl or a 3-7 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more halogens or C1-C6 alkyl groups; R 2 It is hydrogen or C1-C6 alkyl, wherein R 2 Optionally substituted with one or more halogens or C1-C6 alkyl groups; or wherein R 1 and R 2 Together with the atoms to which they are attached, they can form 3-7 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or more fluorine or C1-C6 alkyl groups. R 3 Selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, --CH2-(cyclopropyl) and 3-7 membered cycloalkyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and -OMe; or R 3 Selected from -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl, wherein R 3 The C1-C4 alkyl group in the -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl groups is optionally replaced by one or more fluorine, hydroxyl, or -OMe groups, and wherein R 3 The aryl and heteroaryl groups in -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl are optionally substituted with one or more substituents, each of which is independently selected from 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 Each C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl group may optionally be replaced by one or more fluorine, hydroxyl, or OMe; Each R 7 and R 8 Independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl and R 10 The C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl groups are optionally substituted with one or more fluorine, hydroxyl, or OMe groups; and Each R 9 and R10 It is independently aryl or heteroaryl, optionally substituted with one or more substituents, said substituents being independently selected from 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 are optionally substituted with one or more fluorine, hydroxyl or OMe; R 4 It is hydrogen or -C(O)(C1-C8 alkyl); R 5 It can be hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogen; R 6 It is either hydrogen or deuterium.

[0038] In some embodiments, the compounds of formula (I) above do not include the following: Where R 1 and R 2 Both are ethyl, and R 4 and R 5 When all are hydrogen, R 3 It is not an unsubstituted straight-chain C2-C6 alkyl, isopropyl, -CH2CH=CH2, -CH2CH2F or -CH2CH2Ph; Where R 1 and R 2 All are ethyl, R 4 It is -C(O)(C2 alkyl), and R 5 When it is hydrogen, R 3 Not unsubstituted ethyl; and Where R 1 It is ethyl and R 2 When it is H, R 3 It is not an unsubstituted ethyl, unsubstituted n-propyl, or -CH2CH=CH2.

[0039] In the definitions herein, unless otherwise stated, in various embodiments, the term "and wherein 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 fluorine, hydroxyl, or -OMe" refers to each C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl substituent on R3, the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl substituent on R7 and R8, and R 9 and R 10C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C5 cycloalkyl groups, including R 9 and R 10 -OC(O) (C1-C4 alkyl), -O (C1-C4 alkyl), optionally substituted with one or more fluorine, hydroxyl or OMe.

[0040] In the definitions herein, unless otherwise stated, the terms "C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl and C3-C5 cycloalkyl" refer to R 9 and R 10 The definition of C1-C4 alkyl and -OC(O)(C1-C4 alkyl), -O(C1-C4 alkyl) C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C5 cycloalkyl may optionally be replaced with one or more fluorine, hydroxyl or OMe.

[0041] In the implementation plan, R 3 Selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl) and 3-7 membered cycloalkyl, wherein R 3 It can be substituted with one or more substituents, each independently selected from fluorine, hydroxyl and -OMe.

[0042] In another implementation, R 3 Selected from -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl, wherein the C1-C4 alkyl group of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl is optionally substituted with one or more fluorine, hydroxyl, and -OMe, and wherein the aryl and heteroaryl groups of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl are optionally substituted with one or more substituents, each of which is independently selected from 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 , where each R 7 and R 8 Independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl and R 10 And each of R 9 and R 10It is independently aryl or heteroaryl, optionally substituted with one or more substituents, said substituents being independently selected from 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.

[0043] In the embodiments, this disclosure relates to compounds of formula I, wherein R 1 It is a C1-C6 alkyl or a 3-7 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more fluorine or C1-C6 alkyl groups; R 2 It is hydrogen or C1-C6 alkyl, wherein R 2 Optionally substituted with one or more fluorine or C1-C6 alkyl groups; or Where R 1 and R 2 Together with the atoms to which they are attached, they can form 3-7 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or more fluorine or C1-C6 alkyl groups. R 3 Selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl) and 3-7 membered cycloalkyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and -OMe; or R 3 The group is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl group of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluorine, hydroxyl and -OMe, and wherein the phenyl and 6-membered heteroaryl groups of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) are optionally substituted with one or more substituents each independently selected from 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 It is hydrogen or -C(O)(C1-C8 alkyl); R 5 It can be hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogen; R 6 It is either hydrogen or deuterium.

[0044] In the implementation plan, R 1It is a C1-C6 alkyl or a 3-5 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more fluorine or C1-C4 alkyl groups; R 2 It is hydrogen or C1-C3 alkyl, wherein R 2 Optionally substituted with one or more fluorine or C1-C4 alkyl groups; or wherein R 1 and R 2 They can form optionally substituted 3-6 membered heterocyclic groups together with the atoms to which they are attached, the heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more fluorine or C1-C3 alkyl groups; R 3 Selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl) and 3-5 membered cycloalkyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and -OMe; or R 3 The group is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl group is optionally substituted with one or more fluorine groups, and wherein the phenyl group and the 6-membered heteroaryl group are optionally substituted with one or more substituents each independently selected from halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl and C1-C3 alkoxy groups; R 4 It is hydrogen or -C(O)(C1-C8 alkyl); R 5 It can be hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogen; R 6 It is either hydrogen or deuterium.

[0045] In the implementation plan, R 1 It is a C1-C6 alkyl or a 3-5 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more fluorine or C1-C4 alkyl groups; R 2 It is hydrogen or C1-C3 alkyl, wherein R 2 Optionally substituted with one or more fluorine or C1-C4 alkyl groups; or wherein R 1 and R 2 They can form optionally substituted 3-6 membered heterocyclic groups together with the atoms to which they are attached, the heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more fluorine or C1-C3 alkyl groups; R 3Selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl) and 3-5 membered cycloalkyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and -OMe; or R 3 The group is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl group of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluorine groups, and wherein the phenyl group of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more substituents, each independently selected from halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl and C1-C3 alkoxy groups; R 4 It is hydrogen or -C(O)(C1-C8 alkyl); R 5 It can be hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogen; R 6 It is either hydrogen or deuterium.

[0046] In the implementation scheme, in the compound of formula I, R 4 It is hydrogen.

[0047] In another implementation, R 5 It is hydrogen. In a further embodiment, R 5 It can be Me, Et, -CH2F, CHF2, -CF3, or a halogen. In a further embodiment, R 5 For Br. In a further embodiment, R 6 It is hydrogen. In another embodiment, R 4 R 5 and R 6 Each is hydrogen.

[0048] In the implementation plan, R 4 R 5 and R 6 Each is hydrogen. In another implementation, R 4 and R 6 Each is hydrogen, and R 5 It can be Me, Et, -CH2F, -CHF2, -CF3, or a halogen. In a further embodiment, R 5 It is bromine.

[0049] This disclosure describes compounds of formula (II) in some embodiments. (II) Or pharmaceutically acceptable salts; Where R 1 It is a C1-C6 alkyl or a 3-7 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more halogens or C1-C6 alkyl groups; R 2 It is hydrogen or C1-C6 alkyl, wherein R 2 Optionally substituted with one or more halogens or C1-C6 alkyl groups; or wherein R 1 and R 2 They can form optionally substituted 3-7 membered heterocyclic groups together with the atoms to which they are attached, the heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more fluorine or C1-C6 alkyl groups; R 4 It is hydrogen or -C(O)(C1-C8 alkyl); R 5 It can be Me, Et, -CH2F, -CHF2, -CF3, or a halogen; R 6 It is either hydrogen or deuterium.

[0050] In another embodiment, this disclosure relates to a compound of formula II or a pharmaceutically acceptable salt thereof, wherein R 1 It is a C1-C6 alkyl or a 3-7 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more halogens or C1-C6 alkyl groups; R 2 It is hydrogen or C1-C6 alkyl, wherein R 2 Optionally substituted with one or more halogens or C1-C6 alkyl groups; or wherein R 1 and R 2 They can form optionally substituted 3-7 membered heterocyclic groups together with the atoms to which they are attached, the heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more fluorine or C1-C6 alkyl groups; R 4 It is hydrogen or -C(O)(C1-C8 alkyl); R 5 It can be Me, Et, -CH2F, -CHF2, -CF3, or a halogen; R 6 It is either hydrogen or deuterium.

[0051] In some implementations, the following compounds are excluded from formula (II): (a) When R 1and R 2 Both are ethyl, and R 4 When it is hydrogen, then R 5 It is not chlorine, bromine, iodine, or an unsubstituted methyl group; (b) When R 2 For hydrogen, R 4 It is hydrogen, and R 5 When it is bromine, then R 1 Not ethyl, isopropyl, or propargyl; and (c) When R 2 It is methyl, R 4 It is hydrogen, and R 5 When it is bromine, then R 1 It is neither propargyl nor cyclopropyl.

[0052] In some embodiments, this disclosure includes compounds of formula (Ia) or (IIa): Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 and R 3 Defined in the foregoing and in the implementation schemes disclosed herein.

[0053] In some embodiments, this disclosure includes compounds of formula (Ib): Or a pharmaceutically acceptable salt thereof, wherein R 3 and R 5 Defined in the foregoing and in the implementation schemes disclosed herein.

[0054] In some embodiments, this disclosure includes compounds of formula (Ic): Or a pharmaceutically acceptable salt thereof, wherein R 3 and R 5 Defined in the foregoing and in the implementation schemes disclosed herein.

[0055] In some embodiments, this disclosure includes compounds of formula (Id): Or a pharmaceutically acceptable salt thereof, wherein R 3 and R 5 Defined in the foregoing and in the implementation schemes disclosed herein.

[0056] In some embodiments, this disclosure includes compounds of formula (Ie): Or a pharmaceutically acceptable salt thereof, wherein R3 and R 5 Defined in the foregoing and in the categories and implementation schemes disclosed herein.

[0057] In some implementation schemes, R 1 It is a C1-C6 alkyl group. In some embodiments, R 1 It is a straight-chain C1-C6 alkyl group. In some embodiments, R 1 It is a branched C1-C6 alkyl group. In some embodiments, R 1 It is a C2-C5 alkyl group. In some embodiments, R 1 It is selected from ethyl, sec-butyl, 2-pentyl and 3-pentyl.

[0058] In some implementation schemes, R 1 It is a C1-C6 alkyl or a 3-7 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more halogens or C1-C6 alkyl groups. In some embodiments, R 1 It is a C1-C6 alkyl or a 3-5 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more fluorine or C1-C4 alkyl groups.

[0059] In some implementation schemes, R 2 It is hydrogen or C1-C6 alkyl, wherein R 2 Optionally substituted with one or more halogens or C1-C6 alkyl groups. In some embodiments, R 2 It is hydrogen or a C1-C6 alkyl group. In some embodiments, R 2 It is hydrogen. In some implementations, R 2 It is a C1-C6 alkyl group. In some embodiments, R 2 It is a straight-chain C1-C6 alkyl group. In some embodiments, R 2 It is a branched C1-C6 alkyl group. In some embodiments, R 2 It is a C2-C5 alkyl group. In some embodiments, R 2 It is selected from hydrogen, ethyl, sec-butyl, 2-pentyl and 3-pentyl.

[0060] In some implementation schemes, R 1 and R 2 Together with the atoms to which they are attached, they can form 3-7 membered heterocyclic groups with optional substitutions of 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 1 and R 2 They can form optionally substituted groups selected from azircyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl groups together with the atoms to which they are attached. In some embodiments, R 1 and R 2They can form dimethylazonyl butyl with the atoms to which they are attached.

[0061] In some implementation schemes, R 3 Selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl and 3-7 membered cycloalkyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, 3-7 membered cycloalkyl, and phenyl, wherein the cycloalkyl or phenyl group is optionally substituted with one, two, or three substituents, each independently selected from halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. In some embodiments, R 3 It is a C1-C6 alkyl or C2-C6 alkenyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, 3-7 membered cycloalkyl, and phenyl, wherein the cycloalkyl or phenyl group is optionally substituted with one, two, or three substituents, each independently selected from halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. In some embodiments, R 3 It is a C1-C3 alkyl or C2-C3 alkenyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, 3-7 membered cycloalkyl, and phenyl, wherein the cycloalkyl or phenyl group is optionally substituted with one, two, or three substituents, each independently selected from halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. In some embodiments, R 3 Selected from methyl, ethyl, n-propyl and allyl, wherein R 3 It can be substituted with one to three substituents selected from fluorine, 2-methoxyphenyl and 2-hydroxyphenyl.

[0062] In the implementation plan, R 3 Selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl) and 3-7 membered cycloalkyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and -OMe; or R 3 The radical is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl is optionally substituted with one or more fluorine, hydroxyl, and -OMe, and wherein the phenyl and 6-membered heteroaryl are optionally substituted with one or more substituents, each independently selected from 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 Selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl) and 3-7 membered cycloalkyl, wherein R 3It can be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and –OMe. In some embodiments, R 3 The group is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl group is optionally substituted with one or more fluorine, hydroxyl and -OMe groups, and wherein the phenyl and 6-membered heteroaryl groups are optionally substituted with one or more substituents each independently selected from halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C4 alkyl, C3-C5 cycloalkyl and C1-C4 alkoxy groups.

[0063] In some implementation schemes, R 3 Selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl) and 3-5 membered cycloalkyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and -OMe; or R 3 The radical is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl group is optionally substituted with one or more fluorine groups, and wherein the phenyl and 6-membered heteroaryl groups are optionally substituted with one or more substituents, each independently selected from halogen, hydroxyl, -OC(O) (C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl, and C1-C3 alkoxy groups. In some embodiments, R 3 Selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl) and 3-5 membered cycloalkyl, wherein R 3 It can be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and –OMe. In some embodiments, R 3 The group is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl group is optionally substituted with one or more fluorine groups, and wherein the phenyl group and the 6-membered heteroaryl group are optionally substituted with one or more substituents each independently selected from halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl and C1-C3 alkoxy groups.

[0064] In some implementation schemes, R 3 Selected from ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, and -CH2-(cyclopropyl), wherein R 3 One to three fluorine molecules can be substituted. In some implementations, R... 3Selected from ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, -CH2-(cyclopropyl), -CH2CF3, -CH2CH2CH2F, and -CH2CH2CF3. In some embodiments, R 3 The radical is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl group is optionally substituted with one or more fluorine groups, and wherein the phenyl and 6-membered heteroaryl groups are optionally substituted with one or more substituents, each independently selected from halogen, hydroxyl, -OC(O) (C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl, and C1-C3 alkoxy groups. In some embodiments, R 3 The group is selected from -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-pyridyl, wherein the phenyl and pyridyl groups are optionally substituted with one or more substituents, each independently selected from halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl and C1-C3 alkoxy.

[0065] In a further implementation scheme, R 3 Selected from ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, and -CH2-(cyclopropyl), wherein R 3 It can be replaced by one to three fluorides.

[0066] In a further implementation scheme, R 3 It is selected from ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, -CH2-(cyclopropyl), -CH2CF3, -CH2CH2CH2F and -CH2CH2CF3.

[0067] In another implementation, R 3 Selected from -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl, wherein the C1-C4 alkyl group of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl is optionally substituted with one or more fluorine, hydroxyl, and -OMe, and wherein the aryl and heteroaryl groups of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl are optionally substituted with one or more fluorine, hydroxyl, and -OMe, each independently selected from 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 R 9Substituents of R, wherein each R 7 and R 8 Independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl and R 10 The C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl groups are optionally substituted with one or more fluorine, hydroxyl, or OMe groups, and Each R 9 and R 10 It is independently aryl or heteroaryl, optionally substituted with one or more substituents, said substituents being independently selected from halogens, -OH, -OC(O)(C1-C4 alkyl), -O(C1-C4 alkyl), -CN, -NO2, -NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl and C3-C5 cycloalkyl, wherein -OC(O)(C1-C4 alkyl), -O(C1-C4 alkyl)-, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl and C3-C5 cycloalkyl are optionally substituted with one or more fluorine, hydroxyl or OMe.

[0068] In the implementation plan, R 3 Selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, --CH2-(cyclopropyl) and 3-7 membered cycloalkyl, wherein R 3 It may be substituted with one or more substituents, each independently selected from fluorine, hydroxyl, and -OMe; or R 3 Selected from -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl, wherein R 3 The C1-C4 alkyl group in the -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl groups is optionally replaced by one or more fluorine, hydroxyl, and -OMe, and wherein R 3 The aryl and heteroaryl groups in -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl are optionally composed of one or more elements each independently selected from 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 Substituents of the substituents; Each R 7 and R 8Independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl and R 10 The C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C3-C8 cycloalkyl groups are optionally substituted with one or more fluorine, hydroxyl, or OMe groups, and Each R 9 and R 10 It is independently aryl or heteroaryl, optionally substituted with one or more substituents, said substituents being independently selected from 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 are optionally substituted with one or more fluorine, hydroxyl or OMe.

[0069] In another implementation, R 3 Selected from -(C1-C2 alkyl)-aryl and -(C1-C2 alkyl)-heteroaryl, wherein the C1-C2 alkyl group of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl is optionally substituted with one or more fluorine, hydroxyl, and -OMe, and wherein the aryl and heteroaryl groups of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl are optionally substituted with one or more substituents, each of which is independently selected from halogens, -OR 7 -OC(O)R 7 -CN, -NO2, -NR 7 R 8 -CO2R 7 -C(O)NR 7 R 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and R 9 , where each R 7 and R 8 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and R 10 And each of R 9 and R 10 It is independently aryl or heteroaryl, optionally substituted with one or more substituents independently selected from 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.

[0070] In some implementation schemes, R 3Selected from .

[0071] In some implementation schemes, R 3 Selected from: .

[0072] In some implementation schemes, R 3 Selected from: .

[0073] In some implementation schemes, R 4 It is hydrogen or -C(O)(C1-C8 alkyl). In some embodiments, R 4 It is hydrogen or -C(O)(C1-C3 alkyl). In some embodiments, R 4 It is hydrogen. In some implementations, R 4 It is -C(O)(C1-C8 alkyl). In some embodiments, R 4 It is -C(O)(C1-C3 alkyl).

[0074] In some implementation schemes, R 5 It can be Me, Et, -CH2F, CHF2, -CF3, or a halogen. In some embodiments, R 5 For Me, Et, or halogen. In some implementations, R 5 It can be Me, Et, or bromine. In some implementations, R 5 It is hydrogen or halogen. In some implementations, R 5 It is hydrogen. In some implementations, R 5 It is a halogen. In some implementations, R 5 It is hydrogen or bromine. In some embodiments, R 5 It is bromine. In some implementations, R 5 It is hydrogen, Me, or Et. In some implementations, R 5 For Me or Et.

[0075] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0076] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0077] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0078] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0079] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0080] In other embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0081] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0082] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0083] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0084] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0085] In some embodiments, this disclosure includes compounds selected from the following: Or its pharmaceutically acceptable salt.

[0086] Salts of the compounds of this disclosure can be prepared by reacting the compounds of this disclosure with a suitable acid or base using conventional procedures in a suitable solvent or solvent mixture (such as an ether, e.g., diethyl ether, or an alcohol, e.g., ethanol, or an aqueous solvent). Salts of the compounds of general formula I can be exchanged for other salts by treatment using conventional ion-exchange chromatography procedures. Preferred salts of the compounds of this disclosure include tartrates, fumarates, and maleates.

[0087] In cases where a specific enantiomer of the disclosed compound is desired, this can be produced from the corresponding enantiomer mixture using any suitable conventional procedure for resolving enantiomers. For example, diastereomeric derivatives (such as salts) can be produced by reacting a mixture of enantiomers of the disclosed compound (such as racemates) with a suitable chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means (such as crystallization), and the desired enantiomers are recovered (e.g., by treatment with acid in the case where the diastereomers are salts). Alternatively, the racemic mixture of esters can be resolved by kinetic hydrolysis using various biocatalysts (see, for example, Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0088] In another resolution method, racemic derivatives of the disclosed compounds can be separated using chiral high-performance liquid chromatography. Alternatively, specific enantiomers can be obtained by using a suitable chiral intermediate in one of the methods described above. When a specific geometrical isomer of the disclosed compound is desired, chromatography, recrystallization, and other conventional separation procedures can also be used on the intermediate or final product.

[0089] II. Methods This document describes methods and compositions for treating mood disorders by administering the disclosed compounds to a patient in need of them. Pharmaceutical compositions comprising the disclosed compounds are also provided.

[0090] In the implementation scheme, the methods, compounds, and compositions can be used to treat mood disorders, including depressive disorders such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, disruptive mood disorder, substance / drug-induced depressive disorder, or depressive disorder caused by another medical condition.

[0091] In the embodiments, the methods, compounds, and compositions can treat mood disorders including bipolar disorder and related disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including substance-related disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including anxiety disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including obsessive-compulsive disorder and related disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including trauma and stressor-related disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including feeding and eating disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including neurocognitive disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including neurodevelopmental disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including personality disorders. In the embodiments, the methods, compounds, and compositions can treat mood disorders including sexual dysfunction. In the embodiments, the 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.

[0092] This article also provides methods for treating treatment-resistant depression, such as in patients with a depressive disorder that has not and / or has not responded to an adequate course of treatment with at least one or two other antidepressant compounds or treatments. As used herein, “depressive disorder” encompasses treatment-resistant depression.

[0093] In the implementation scheme, the methods, compounds, and compositions can be used to treat mood disorders, including bipolar disorder and related disorders, such as type I bipolar disorder, type II bipolar disorder, cyclothymia, substance / drug-induced bipolar disorder and related disorders, and bipolar disorder and related disorders caused by another medical condition. In the implementation methods, the methods, compounds, and compositions can be used to treat mood disorders, including substance-related disorders, such as preventing substance use cravings, reducing substance use cravings, and / or promoting substance use cessation or withdrawal. Substance use disorders involve the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, “substance” or “substances” refers to addictive psychoactive compounds such as alcohol, caffeine, cannabis, hallucinogens, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the methods, compounds, and compositions can be used to promote smoking cessation or cessation of opioid use.

[0094] In the implementation scheme, the methods, compounds, and compositions can be used to treat mood disorders, including anxiety disorders such as separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, or anxiety disorder caused by another medical condition.

[0095] In the implementation scheme, the methods, compounds, and compositions may be used to treat mood disorders, including obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), skin-picking disorder, substance / drug-induced obsessive-compulsive disorder and related disorders, or obsessive-compulsive disorder and related disorders caused by another medical condition.

[0096] In the implementation plan, the methods, compounds, and compositions can be used to treat mood disorders, including trauma and stressor-related disorders such as reactive attachment disorder, disinhibitory social engagement disorder, post-traumatic stress disorder, acute stress disorder, or adjustment disorder.

[0097] In the implementation scheme, the methods, compounds, and compositions can be used to treat mood disorders, including feeding and eating disorders such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, or avoidance / restrictive eating disorder.

[0098] In the implementation scheme, the methods, compounds, and compositions can be used to treat mood disorders, including neurocognitive disorders such as delirium, severe neurocognitive impairment, mild neurocognitive impairment, severe or mild neurocognitive impairment due to Alzheimer's disease, severe or mild frontotemporal neurocognitive impairment, severe or mild neurocognitive impairment with Lewy bodies, severe or mild vascular neurocognitive impairment, severe or mild neurocognitive impairment due to traumatic brain injury, substance / drug-induced severe or mild neurocognitive impairment, severe or mild neurocognitive impairment due to HIV infection, severe or mild neurocognitive impairment due to prion disease, severe or mild neurocognitive impairment due to Parkinson's disease, severe or mild neurocognitive impairment due to Huntington's disease, severe or mild neurocognitive impairment due to another medical condition, or severe or mild neurocognitive impairment due to multiple causes. In the implementation plan, the methods, compounds, and compositions can be used to treat mood disorders, including neurodevelopmental disorders such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotyped movement disorder, tic disorders, Tourette syndrome, persistent (chronic) motor or vocal tic disorders, or transient tic disorders. In the implementation scheme, the methods, compounds, and compositions can be used to treat mood disorders, including personality disorders such as borderline personality disorder.

[0099] In the implementation scheme, the methods, compounds, and compositions can be used to treat mood disorders, including sexual dysfunctions such as delayed ejaculation, erectile dysfunction, female orgasmic disorder, female libido / arousal disorder, genital-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, or substance / drug-induced sexual dysfunction.

[0100] In the implementation scheme, the methods, compounds, and compositions can be used to treat mood disorders, including gender dysphoria, for example, gender dysphoria.

[0101] The implementation plan provides a method for administering an effective amount (6a) to a subject in need of it. R 9 R )- N , N -Diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Methods and compositions for treating mood disorders using quinoline-9-carboxamide (1) or a pharmaceutically acceptable salt thereof. 1 In other embodiments, a method of treating mood disorders is provided, comprising administering to a patient in need of such a method a pharmaceutical composition comprising an effective amount of a compound according to formula I or II, as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of 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 of formula Ia or IIa, or Ib or IIb, or Ic or IIc, or Id or IId, or Ie or IIe.

[0103] In other embodiments, a method of treating mood disorders is provided, comprising administering a pharmaceutical composition to a patient in need of it, said pharmaceutical composition comprising an effective amount of a compound according to formula (I): (I), Or its pharmaceutically acceptable salt. in R 1 It is a C1-C6 alkyl or a 3-7 membered carbon cycloyl group, wherein R 1 Optionally substituted with one or more halogens or C1-C6 alkyl groups; R 2 It is hydrogen or C1-C6 alkyl, wherein R 2 Optionally substituted with one or more halogens or C1-C6 alkyl groups; or Where R 1 and R 2Together with the atoms to which they are attached, they can form 3-7 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or more fluorine or C1-C6 alkyl groups. R 3 Selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, --CH2-(cyclopropyl) and 3-7 membered cycloalkyl groups. Where R 3 It can be substituted with one or more substituents, each independently selected from fluorine, hydroxyl and -OMe; or R 3 The group is selected from –(C1-C2 alkyl)-phenyl and –(C1-C2 alkyl)-(6-membered heteroaryl), wherein the C1-C2 alkyl group of –(C1-C2 alkyl)-phenyl and –(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluorine, hydroxyl and -OMe groups, and wherein the phenyl and 6-membered heteroaryl groups of –(C1-C2 alkyl)-phenyl and –(C1-C2 alkyl)-(6-membered heteroaryl) are optionally substituted with one or more substituents each independently selected from 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 It is hydrogen or -C(O)(C1-C8 alkyl); R 5 It can be hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogen; R 6 It is either hydrogen or deuterium.

[0104] In other embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0105] In other embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0106] In other embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0107] In other embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0108] In other embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0109] In other embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0110] The compounds disclosed herein are found to be agonists of the 5-HT2A receptor. Furthermore, the compounds disclosed herein, particularly those having a substituent at the 2-position of the indole ring, are non-halogenated or less hallucinogenic 5-HT2A receptor agonists compared to other 5-HT2A receptor agonists. For example, compounds wherein the 2-substituent is halogenated or alkyl (such as Me, Et, -CH2F, CHF2, or -CF3) are non-halogenated or less hallucinogenic. In some embodiments, this reduced hallucinogenic effect can be demonstrated by a diminished maximum response in mouse head twitching assays compared to hallucinogenic 5-HT2A receptor agonists.

[0111] In other embodiments, methods and compositions are provided for treating migraines or cluster headaches by administering a therapeutically effective amount of the disclosed compound to a patient in need of it.

[0112] In one implementation, the method includes treating a mood disorder, such as a depressive disorder, by administering a pharmaceutical composition to a patient in need of it, said pharmaceutical composition comprising about 0.001 mg to about 20 mg of the compounds disclosed herein. In the embodiments, the dosage may be, for example, in the following ranges: 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 to 2 mg, 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0.25 mg, 0.01 to 0.15 mg, 0.01 to 0.1 mg, 0.01 to 0.075 mg. mg, 0.01 to 0.05 mg, 0.01 to 0.025 mg, 0.01 to 0.015 mg, 0.025 to 2 mg, 0.025 to 1 mg, 0.025 to 0.5 mg, 0.025 to 0.25 mg, 0.025 to 0.15 mg, 0.025 to 0.1 mg, 0.025 to 0.075 mg, 0.025 to 0.05 mg, 0.05 to 2 mg, 0.05 to 1 mg, 0.05 to 0.5 mg, 0.05 to 0.25 mg, 0.05 to 0.15 mg, 0.05 to 0.1 mg, 0.05 to 0.075 mg, 0.1 to 2 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.1 to 0.25 mg, 0.1 to 0.15 mg mg, of which, for example, doses of approximately 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, and 20 mg are examples.

[0113] In specific embodiments, the dosage may include amounts of the compounds disclosed herein within the range of approximately the following: for example, 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 to 2 mg, 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0.25 mg, 0.01 to 0.15 mg, 0.01 to 0.1 mg. mg, 0.01 to 0.075 mg, 0.01 to 0.05 mg, 0.01 to 0.025 mg, 0.01 to 0.015 mg, 0.025 to 2 mg, 0.025 to 1 mg, 0.025 to 0.5 mg, 0.025 to 0.25 mg, 0.025 to 0.15 mg, 0.025 to 0.1 mg, 0.025 to 0.075 mg, 0.025 to 0.05 mg, 0.05 to 2 mg, 0.05 to 1 mg, 0.05 to 0.5 mg, 0.05 to 0.25 mg, 0.05 to 0.15 mg, 0.05 to 0.1 mg, 0.05 to 0.075 mg, 0.1 to 2 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.1 to 0.25 mg mg, 0.1 to 0.15 mg, of which 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 and 20 mg are specific examples of dosage.

[0114] Typically, the compounds disclosed herein are administered to patients in need of them once, twice, three or four times daily, every other day, every three days, twice weekly, once weekly, twice monthly, or once monthly. In embodiments, the dosage is approximately, for example, 0.001-20 mg / day, or 0.001-10 mg / day, or 0.001-1 mg / day, or 0.001-0.25 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-described dosage ranges may be delivered at intervals longer than one day, for example, 0.001-20 mg / week.

[0115] In embodiments, pharmaceutical compositions for parenteral or inhalation (e.g., spray or aerosol) administration of the disclosed compounds have concentrations of about 0.001 mg / mL to about 100 mg / mL. In embodiments, the composition includes compounds disclosed herein at concentrations of, 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 mg / mL to about 0.05 mg / mL, about 0.005 mg / mL to about 0.025 mg / mL, about 0.001 mg / mL to about 0.05 mg / mL, about 0.001 mg / mL to about 0.025 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, or about 0.001 mg / mL to about 0.005 mg / mL.

[0116] In embodiments, the composition concentrations of the compounds disclosed herein are, 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 mg / mL to about 0.05 mg / mL, about 0.005 mg / mL to about 0.025 mg / mL, about 0.001 mg / mL to about 0.05 mg / mL, about 0.001 mg / mL to about 0.025 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, or about 0.001 mg / mL to about 0.005 mg / mL. In the embodiments, the pharmaceutical composition is formulated to a total volume of, for example, 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.

[0117] 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 12 months. In some embodiments, the compounds disclosed herein are administered to the subject once in the morning or once in the evening. In some embodiments, the compounds disclosed herein are administered to the subject once in the morning and once in the evening. In some embodiments, the compounds disclosed herein are administered to the subject three times a day (e.g., at breakfast, lunch, and dinner) at a dosage of, for example, 0.005 mg / administration (e.g., 0.015 mg / day).

[0118] In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.005 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.01 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.025 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.05 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.1 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.15 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.2 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.25 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.3 mg / day in one or more doses. In the embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.4 mg / day in one or more doses. In the implementation plan, the compounds disclosed herein are administered to the subject at a dose of 0.5 mg / day in one or more doses.

[0119] In the embodiments, the dosage of the compounds disclosed herein is 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 times, or four times daily. For example, in the embodiments, the dosage is 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, twice, three times, or four times daily. In the embodiments, the total daily dose of the compounds disclosed herein is administered to the subject once, twice, three times, or four times daily. In the implementation scheme, the total dose administered to the subject over a 24-hour period 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 the implementation scheme, the subject may start with a low dose and then increase that dose. In the implementation scheme, the subject may start with a high dose and then decrease that dose.

[0120] In the implementation plan, the compounds disclosed herein are administered to the patient under the supervision of a healthcare provider.

[0121] In the implementation scheme, the compounds disclosed herein are administered to patients under the supervision of a healthcare provider in clinics specializing in the delivery of psychoactive treatments.

[0122] In the implementation scheme, the compounds disclosed herein are administered to patients under the supervision of a healthcare provider at a high dose intended to induce hallucinatory experiences in subjects, such doses as 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.

[0123] In the implementation plan, high doses are administered to patients regularly under the supervision of a healthcare provider in order to maintain the therapeutic effect in the patient, such as once a week, twice a month, once a month, every 2 months, every 3 months, every 4 months, every 6 months, or every 12 months.

[0124] In the implementation plan, the compounds disclosed herein are administered by the patient at home or otherwise away from the supervision of a healthcare provider.

[0125] In the implementation, the compounds disclosed herein are administered by the patient at home or otherwise away from the supervision of a healthcare provider at low doses intended to induce subconscious or threshold psychoactive effects, such doses as 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.

[0126] In the implementation plan, patients administer low doses themselves regularly to maintain the therapeutic effect in the patient, such as daily, every other day, every three days, twice a week, once a week, twice a month, or once a month.

[0127] The compounds disclosed herein can be administered to patients (animals and humans) requiring such treatment at doses that will provide optimal pharmaceutical efficacy. It will be understood that the dose required for use in any particular application will vary from patient to patient, not only depending on the specific compound or composition chosen, but also on the route of administration, the nature of the condition being treated, the patient's age and condition, any subsequent concomitant medications or special diet followed by the patient, and other factors that will be recognized by those skilled in the art; the appropriate dose is ultimately determined by the attending physician. For the treatment of the aforementioned clinical conditions and diseases, the compounds disclosed herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage units containing conventionally non-toxic, pharmaceutically acceptable carriers, adjuvants, and mediators. Parenterally administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0128] Treatment may last for as long or as short a period of time as desired. The composition may be administered, for example, once to four or more times daily. Suitable treatment periods may be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinite. The treatment period may be terminated when the desired outcome, such as a reduction in symptoms of the mental disorder, is achieved. The treatment regimen may include a correction phase, during which a dose sufficient to provide symptom relief is administered, and may subsequently be a maintenance phase, during which a lower dose sufficient to prevent relapse of symptoms is administered. Suitable maintenance doses may be found in the lower portion of the dose range provided herein, but correction and maintenance doses can be readily established by those skilled in the art on individual subjects based on the disclosure herein without excessive experimentation. Maintenance doses may be used to maintain relief in subjects whose symptoms have previously been controlled by other means, including treatment with other pharmacological agents.

[0129] III. Pharmaceutical Compositions and Kits Another aspect of this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and on the nature of the particular compound used. For example, the disclosed compositions may be formulated as unit doses and / or formulated for oral or subcutaneous administration.

[0130] The exemplary pharmaceutical compositions of this disclosure can be used in the form of pharmaceutical preparations, such as solid, semi-solid, or liquid forms, containing one or more compounds of this disclosure as active ingredients in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application. The active ingredient may be compounded with, for example, a pharmaceutically acceptable carrier that is generally non-toxic, for use in tablets, granules, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce a desired effect on the course or condition of a disease.

[0131] To prepare solid compositions such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformation composition containing a homogeneous mixture of the compounds of this disclosure or their non-toxic, pharmaceutically acceptable salts. When these preformation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equivalent unit dosage forms, such as tablets, pills, and capsules.

[0132] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) intended for oral administration, the subject 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 extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, the composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugars, and high molecular weight polyethylene glycol, etc.

[0133] Tablets can be made by compression or molding, optionally together with one or more excipients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the subject composition wetted with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as sugar-coated pills, capsules, pellets, and granules may optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings well known in the field of pharmaceutical formulation.

[0134] Compositions for inhalation or inhalation include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0135] In addition to the main composition, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0136] Formulations for rectal or vaginal administration may be presented as suppositories, which can be prepared by mixing a subject composition with one or more suitable, non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, and the suppository is solid at room temperature but liquid at body temperature, and thus will melt and release the active agent within the body cavity.

[0137] Dosage forms of the subject compositions for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient may be mixed under aseptic conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0138] In addition to the main composition, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0139] In addition to the main composition, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Sprays may additionally contain common propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0140] The compositions and compounds disclosed herein can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compound. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic atomizers can be used because they minimize the reagent's exposure to shear, which can lead to degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by formulation of an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the specific subject composition but typically include nonionic surfactants (Tween, Plannick, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared as isotonic solutions.

[0141] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0142] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Appropriate flowability may be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0143] In another aspect, this disclosure provides an enteric pharmaceutical formulation comprising the disclosed compound and an enteric-coated material; and a pharmaceutically acceptable carrier or excipient thereof. An enteric-coated material is a polymer that is substantially insoluble in the acidic environment of the stomach and soluble primarily in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5. Therefore, enteric materials are insoluble before reaching, for example, a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of vinyl methyl ether and maleic anhydride (GantrezES series), ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers, natural resins such as zein, shellac, and copal collophorium, and various commercially available enteric dispersion systems (e.g., Eudragit). L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be readily determined in vitro. The above is a list of possible materials, but those skilled in the art who benefit from this disclosure will recognize that it is not exhaustive, and that other enteric-coated materials exist that would satisfy the purposes of this disclosure.

[0144] Advantageously, this disclosure also provides kits for use by consumers, for example, those requiring treatment with the disclosed compounds. Such kits include suitable dosage forms (such as those described above) and instructions for use describing the method of using such dosage forms to treat medical conditions such as mental illnesses or disorders. The instructions will instruct the consumer or medical personnel to administer the dosage form according to administration methods known to those skilled in the art. Such kits can advantageously be packaged and sold in single or multiple kit units. One example of such kits is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packs typically consist of a relatively rigid sheet of material covered with a foil, preferably a transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The groove has 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 of material is sealed relative to the plastic foil on the side of the foil opposite to the direction in which the groove is formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the tablet is strong enough that it can be removed from the blister pack by manually applying pressure to the groove, thereby creating an opening in the tablet at the groove location. The tablet or capsule can then be removed through said opening.

[0145] It may be desirable to provide memory aids on the kit, for example, in the form of numbers corresponding to adjacent tablets or capsules, whereby the number corresponds to the number of days of the regimen in which the specified tablets or capsules should be taken. Another example of such memory aids is a calendar printed on a card, such as “Week 1, Monday, Tuesday, ... etc. Week 2, Monday, Tuesday, ... etc.” Other variations of memory aids will be apparent. “Daily dose” can be a single tablet or capsule to be taken on a given day, or multiple tablets or capsules. Furthermore, the daily dose of the first compound may consist of one tablet or capsule, while the daily dose of the second compound may consist of multiple tablets or capsules, and vice versa. The memory aid should reflect this.

[0146] This article also considers methods and compositions that include a second surfactant or the application of a second surfactant. Example

[0147] The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it will be understood that, unless otherwise specified, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and post-treatment procedures, are chosen as standard conditions for the reaction. Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods are therefore indicated. The starting materials used in the examples are commercially available or readily prepared from known materials by standard methods.

[0148] At least some of the compounds identified as "intermediates" in this article are considered to be compounds of this disclosure.

[0149] General Procedure The compounds disclosed herein can be prepared using 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.

[0150] abbreviation AcOH = Acetic acid DCM = dichloromethane DMF = dimethylformamide TEA = Triethylamine T3P = Propylphosphonic anhydride mCPBA = m-chloroperoxybenzoic acid HFBA = Heptafluorobutyric acid Example 1: Preparation of (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1) Reaction scheme (method 1): Synthesis experimental protocol (method 1): Under vigorous stirring, towards (6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-9-carboxylic acid (Int1, 2.01 g, 7.5 mmol) was suspended in anhydrous methanol (300 mL) and a solution of diazomethane in diethyl ether (0.5 M, 75.0 mmol, 150 mL) was added. The resulting mixture was stirred until it became 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 x 30 mL), and the filtrate was concentrated under vacuum to provide (6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg methyl quinoline-9-carboxylate (Int2) is a grayish-white foam.

[0151] Yield: 1.92 g (90%).

[0152] LC-MS purity: 98% (ELSD).

[0153] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA in 10 min): 6.82 min.

[0154] LC-MS m / z: 283.2 (M+H) + .

[0155] (6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg methyl quinoline-9-carboxylate (Int2, 564 mg, 2.0 mmol) was dissolved in anhydrous dichloromethane (30 mL) and purged with argon. Cyanogen bromide (1.14 g, 10.72 mmol) was added in a single addition, 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 rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 80:20 to 50:50) to give (6a) R 9 R )-7-cyano-4,6,6a,7,8,9-hexahydroindolo[4,3- fg methyl quinoline-9-carboxylate (Int3) is a colorless foam.

[0156] Yield: 300 mg (50%).

[0157] LC-MS purity: 98% (ELSD).

[0158] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA in 10 min): 8.63 min.

[0159] LC-MS m / z: 294.1 (M+H) + .

[0160] (6a) R 9 R )-7-cyano-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Methyl quinoline-9-carboxylate (Int3, 205 mg, 0.70 mmol) was dissolved in glacial acetic acid (5 mL), and zinc powder (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 which point LC / MS showed complete consumption of the starting material. The reaction was cooled to 0 °C, partitioned between saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL), and extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 95:5 to 90:10) to give (6a) R )-4,6,6a,7,8,9-hexahydroindolo[4,3- fg ] Quinoline-9-carboxylic acid methyl ester (Int4m) (a mixture of diastereomers; the epimer at position 9), is a grayish-white foam.

[0161] Yield: 51 mg (24%).

[0162] LC-MS purity: 85% (ELSD).

[0163] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA in 10 min): 2.87 min.

[0164] LC-MS m / z: 269.2 (M+H) + .

[0165] (6a) R )-4,6,6a,7,8,9-hexahydroindolo[4,3- fgA solution of methyl quinoline-9-carboxylate (Int4m, 75 mg, 0.280 mmol; a mixture of epimers at position 9) and propionaldehyde (88 µL, 1.40 mmol) in methanol (10 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (88.0 mg, 1.40 mmol) was added, the mixture was stirred for 5 min, and then acetic acid (300 µL) was added. After stirring at 0 °C for 1 hour, the solvent was evaporated, the residue was partitioned between dichloromethane (100 mL) and saturated sodium bicarbonate (100 mL), and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give (6a) R )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg ] Quinoline-9-carboxylate (Int5m) (a mixture of diastereomers; epimer at position 9), is a grayish-white foam.

[0166] Yield: 58 mg (67%).

[0167] LC-MS purity: 99% (ELSD), 95% (UV) 310 ).

[0168] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA in 10 min): 2.95 min.

[0169] LC-MS m / z: 311.2 (M+H) + .

[0170] (6a) R )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgmethyl quinoline-9-carboxylate (Int5m, 58.7 mg, 0.189 mmol; a 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 until complete conversion was observed by LC / MS. 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) (a mixture of diastereomers; epimers at position 9) was used in the next step without further purification.

[0171] Yield: 58 mg (crude product).

[0172] LC-MS purity: 100% (ELSD), 95% (UV) 310 ).

[0173] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA in 10 min): 7.08 min; 7.30 min.

[0174] LC-MS m / z: 297.2 (M+H) + .

[0175] crude product (6a) R )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxylic acid (Int6m, 55 mg; a mixture of epimers at position 9) dissolved in anhydrous water N,N- Dimethylformamide (3 mL) was added, and 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 x 30 mL). The combined organic layers were dried over 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 x 150 mm, acetonitrile / water 5:95 + 0.1% acetic acid) to give the title compound as a solution in acetonitrile / water. Lyophilization gave 10 mg (6a) R 9 R )-9-(diethylcarbamoyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-7-onium acetate (1) is a light yellow powder.

[0176] Yield: 10 mg (13% after two steps).

[0177] 1 1H NMR spectrum (acetate; acetate peak masked 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, 4.5Hz, 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).

[0178] LC-MS purity: 97% (ELSD), 96% (UV) 310 ).

[0179] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA in 10 min): 8.20 min.

[0180] LC-MS m / z: 352.2 (M+H) + .

[0181] Reaction scheme (method 2): Synthesis experimental protocol (method 2): (6a) R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide (Int7m, 45.0 mg, 0.145 mmol; a mixture of epimers at position 9) and propionaldehyde (52 µL, 0.72 mmol) in methanol (10 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (46.0 mg, 0.72 mmol) was added, the mixture was stirred for 5 min, and then acetic acid (160 µL) was added. The reaction mixture was stirred at 0 °C for 1 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane and 1% ammonium hydroxide solution. The aqueous phase was extracted with dichloromethane (3 x 50 mL), and the combined organic phases were dried over anhydrous sodium sulfate and evaporated. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give (6a) R 9 R )- N , N -Diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (1) is a colorless oil.

[0182] Yield: 6 mg (11%).

[0183] 1 1H NMR spectrum (acetate; acetate peak masked 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, 4.5Hz, 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).

[0184] LC-MS purity: 96% (ELSD), 93% (UV) 310 ).

[0185] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA in 10 min): 5.66 min.

[0186] LC-MS m / z: 352.2 (M+H) + .

[0187] Example 2: (6aR,9R)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- [fg] Quinoline-9-carboxamide (2) and (6aR,9S)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindole Preparation of [4,3-fg]quinoline-9-carboxamide (2a) reaction Reaction scheme (method 1): Synthesis experimental protocol (method 1): (6a) R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (Int7m, 60.0 mg, 0.194 mmol; a mixture of epimers at position 9), cesium carbonate (139 mg, 0.426 mmol), and 1-bromo-3-fluoropropane (30.2 mg, 0.214 mmol) were used in... N,NThe solution in 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 x 50 mL), and the combined organic phases were dried over magnesium sulfate and concentrated under vacuum. The crude product obtained was purified by silica gel chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6a) R 9 R )- N , N -Diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (2, a fast-moving fluorescent band) is a colorless foam.

[0188] Yield: 6 mg (10%).

[0189] 1 H 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).

[0190] LC-MS purity: 90% (ELSD), 81% (UV, 310 nm).

[0191] LC-MS Rt (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.68 min.

[0192] LC-MS m / z: 370.2 (M+H) + .

[0193] Reaction scheme (method 2): Synthesis experimental protocol (method 2): Under an argon atmosphere, towards (6a) R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of 1-bromo-3-fluoropropane (50 mg, 0.348 mmol) in methanol (1 mL) was added dropwise to a stirred solution of quinoline-9-carboxamide (Int7m, 45 mg, 0.145 mmol; a mixture of epimers at position 9) and potassium bicarbonate (30 mg, 0.29 mmol) in methanol (2 mL). Then, tetrabutylammonium iodide (53.5 mg, 0.145 mmol) was added in a single addition, and the reaction 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 added. The resulting suspension was desolventized under vacuum and subjected to silica gel chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia 98:2:0.1) to give (6a) R 9 R )- N , N -Diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (2, a fast-moving fluorescent band), is a colorless foam, and (6a) R 9 S )- N , N -Diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (2a, a slow-moving fluorescent band) appears as dark brown foam. 2: Yield: 13.9 mg (23%).

[0195] 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).

[0196] LC-MS purity: 97% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.47 min.

[0197] LC-MS m / z: 370.2 (M+H) + .

[0198] 2a: Yield: 7.8 mg (12%).

[0199] 1 1H NMR spectrum (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).

[0200] LC-MS purity: 100% (ELSD), 96% (UV, 310 nm).

[0201] LC-MS Rt (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.71 min.

[0202] LC-MS m / z: 370.2 (M+H) + .

[0203] Example 3: Preparation of (6aR,9R)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (3) and (6aR,9S)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (3a) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxylic acid (Int1, 805 mg, 3.00 mmol), triethylamine (1.69 mL, 12.0 mmol) and ( R )-But-2-amine (329 mg, 4.50 mmol) in anhydrous N , N The solution in 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 x 150 mL). The organic phase was discarded (the product was in the form of salts in the aqueous phase) and the aqueous phase was alkalized to pH = 12 by adding 30% ammonium hydroxide solution. The mixture was then extracted with dichloromethane (3 x 200 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 90:10) to give (6a) R 9 S )- N -(( R )-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-9-carboxamide (Int8a, a faster, less polar isomer), is a dark brown solid, and (6a) R 9 R )- N -(( R )-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (Int8, a slower, more polar isomer) is a colorless solid.

[0204] Int8a: Yield: 0.28 g (28%).

[0205] 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).

[0206] LC-MS purity: 100% (ELSD).

[0207] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 6.21 min.

[0208] LC-MS m / z: 324.2 (M+H) + .

[0209] Int8: Yield: 0.47 g (48%).

[0210] 1 1H NMR spectrum (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).

[0211] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.29 min.

[0212] LC-MS m / z: 324.2 (M+H) + .

[0213] A solution of 3-chloroperbenzoic acid (361 mg, 1.61 mmol) in anhydrous dichloromethane (20 mL) was added dropwise at 0 °C to (6a) R )- N -(( R )-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (Int8m, 526 mg, 1.63 mmol; a mixture of epimers at the 9-position) was dissolved in anhydrous dichloromethane (40 mL), and the resulting mixture was stirred for 1 hour. Then, 10% sodium hydroxide solution (50 mL) was added to separate the phase, and the aqueous phase was extracted with a solution of 10% isopropanol in dichloromethane (3 x 100 mL). The combined organic phases were dried and evaporated under vacuum to give (6a) R )-9-((( R )-sec-butyl)carbamoyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline 7-oxide (Int9m) (a mixture of diastereomers; the epimer at position 9), a dark brown solid, was used in the next step without further purification.

[0214] Yield: 0.52 g (100%).

[0215] LC-MS purity: 100% (UV, 310 nm).

[0216] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA in 10 min): 5.13 min.

[0217] LC-MS m / z: 340.2 (M+H) + .

[0218] crude product (6a) R )-9-((( R )-sec-butyl)carbamoyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline 7-oxide (Int9m, 520 mg; a mixture of epimers at position 9) was dissolved in methanol (20 mL), cooled to 0 °C, and purged with argon. Ferrous sulfate (II) heptahydrate (Fe₂SO₄·7H₂O, 895 mg, 3.22 mmol) was then added in portions to the 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 EDTA (10 g) with 30% ammonium hydroxide (10 mL) in water (100 mL). The aqueous phase was further extracted with dichloromethane (3 x 100 mL), and the combined organic phases were dried and evaporated. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2 to 85:15) to give (6a) R )- N -(( R )-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (Int10m) (a mixture of diastereomers; the epimer at position 9) is a dark brown solid.

[0219] Yield: 0.121 g (24% after 2 steps).

[0220] LC-MS purity: 100% (ELSD).

[0221] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA over 10 min): 4.78 min (diastereomer 1); 5.15 min (diastereomer 2).

[0222] LC-MS m / z: 340.2 (M+H) + .

[0223] (6a) R )- N -(( R )-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide (Int10m, 55.0 mg, 0.178 mmol; a mixture of epimers at the 9-position) and propanol (0.064 mL, 0.89 mmol) in methanol (10 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (56.0 mg, 0.89 mmol) was added, the mixture was stirred for 5 min, and then acetic acid (160 µL) was added. The reaction was then stirred at 0 °C for 1 h. The solvent was evaporated, and the residue was partitioned between dichloromethane (50 mL) and 1% ammonium hydroxide solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL), and the combined organic phases were dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give (6a) R 9 S )- N -(( R )-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (3a, the faster, less polar diastereomer), is a colorless oil, and (6a) R 9 R )- N -(( R )-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (3, a slower, more polar diastereomer) is a colorless oil.

[0224] 3a: Yield: 16 mg (26%).

[0225] 11H 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).

[0226] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.81 min.

[0227] LC-MS m / z: 352.1 (M+H) + . 3: Yield: 17 mg (27%).

[0229] 1 1H NMR spectrum (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).

[0230] LC-MS purity: 100% (ELSD).

[0231] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.00 min.

[0232] LC-MS m / z: 352.1 (M+H) + .

[0233] Example 4: Preparation of ((2S,4S)-2,4-dimethylazacyclobut-1-yl)((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-yl) methyl ketone (4) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxylic acid (Int1, 460 mg, 1.71 mmol), triethylamine (1.10 mL, 7.70 mmol), and (2... S 4 S 2,4-Dimethylazonium butane hydrochloride (250 mg, 2.05 mmol) in anhydrous N , NThe solution in dimethylformamide (10 mL) was cooled to 0 °C under an argon atmosphere. Propanephosphonic anhydride (T3P, 1.20 mL, 2.05 mmol, 50% solution in DMF) was then 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, it was quenched with ice-cold water (10 mL) and partitioned between 1 M ammonium hydroxide aqueous solution (100 mL) and ethyl acetate (100 mL). The aqueous phase was further extracted with ethyl acetate (2 x 50 mL), and the combined organic phases were washed with 5% lithium chloride solution (4 x 50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 100:0 to 98:2) to give ((2 S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R, 9R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl) methyl ketone (Int11, a fast-moving fluorescent band), is a grayish-white solid, and ((2) S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl) methyl ketone (Int11m; a mixture of diastereomers; the epimer at the 9-position) is a dark brown solid.

[0234] Yield: 368 mg (65%), combined isomers.

[0235] 1 1H NMR spectrum (Int11, pure β 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).

[0236] LC-MS purity: 100% (combined isomers, ELSD), 98% (combined isomers, UV) 310 ).

[0237] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA in 10 min): 3.59 min (diastereomer 1); 3.95 min (diastereomer 2).

[0238] LC-MS m / z: 336.0 (M+H) + .

[0239] A solution of 3-chloroperbenzoic acid (189 mg, 1.10 mmol) in anhydrous dichloromethane (5 mL) was added dropwise at 0 °C. S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-yl) methyl ketone (Int11m, 368 mg, 1.10 mmol; a mixture of epimers at the 9-position) was prepared in anhydrous dichloromethane (30 mL), and the resulting mixture was stirred at 0 °C for 1 hour. Then, a 10% sodium hydroxide solution (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with a 10% isopropanol solution in dichloromethane (3 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (6a) R )-9-((2 S 4 S )-2,4-dimethylazonylbutane-1-carbonyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinolone 7-oxide (Int12m) (a mixture of diastereomers; the epimer at position 9), is a grayish-white solid, which is used in the next step without further purification.

[0240] LC-MS purity: 100% (UV, 310 nm).

[0241] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA in 10 min): 1.92 min.

[0242] LC-MS m / z: 352.0 (M+H) + .

[0243] crude product (6a) R )-9-((2 S 4 S )-2,4-dimethylazonylbutane-1-carbonyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinolone 7-oxide (Int12m; a mixture of epimers at position 9) was dissolved in methanol (75 mL), cooled to 0 °C, and purged with argon. Ferrous sulfate (II) heptahydrate (609 mg, 2.20 mmol) was then 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 EDTA (10 g) with 30% ammonium hydroxide (10 mL) in water (100 mL). The aqueous phase was further extracted with dichloromethane (3 x 100 mL), and the combined organic phases were dried over magnesium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2 to 90:10) to give ((2 S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R )-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl) methyl ketone (Int13m) (a mixture of diastereomers; epimer at the 9-position), is a grayish-white amorphous solid.

[0244] Yield: 81.5 mg (23% after 2 steps).

[0245] LC-MS purity: 88% (ELSD), 86% (UV) 310 ).

[0246] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA in 10 min): 5.87 min.

[0247] LC-MS m / z: 322.2 (M+H) + .

[0248] ((2) S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R )-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-yl) methyl ketone (Int13m, 81.5 mg, 0.242 mmol; a 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 cyanoborohydride (76.0 mg, 1.21 mmol) was added, the mixture was stirred for 5 min, and 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 dichloromethane and 1% ammonium hydroxide solution. The aqueous phase was extracted with dichloromethane (3 x 50 mL), and the combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give ((2 S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R 9 R )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl) methyl ketone (4, a fast-moving fluorescent band), appears as grayish-white foam.

[0249] Yield: 35 mg (40%).

[0250] 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).

[0251] LC-MS purity: 99% (ELSD), 96% (UV, 310 nm).

[0252] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.51 min.

[0253] LC-MS m / z: 364.1 (M+H) + .

[0254] Example 5: Preparation of (6aR,9R)-N-((R)-sec-butyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (5) and (6aR,9S)-N-((R)-sec-butyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (5a) Reaction scheme: Synthesis experimental protocol: (6a) R )- N -(( RA solution of (-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int10m, 55.2 mg, 0.178 mmol; preparation described in Example 3; a mixture of epimers at the 9-position) and acetaldehyde (39.3 mg, 0.89 mmol) in methanol (10 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (56.1 mg, 0.89 mmol) was added, the mixture was stirred for 5 min, and then acetic acid (200 µL) was added. The reaction was stirred at 0 °C for 1 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (50 mL) and 1% ammonium hydroxide solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL), and the combined organic phases were dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give (6a) R 9 S )-N-(( R )-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (5a, the faster-moving, less polar diastereomer), is a colorless oil, and (6a) R 9 R )-N-(( R )-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (5, the slower-moving, more polar diastereomer), a colorless solid. The separated isomers were each dissolved in anhydrous methanol (500 µL) and treated with an equimolar amount of 1 M D-(-)-tartaric acid in anhydrous methanol. The resulting solutions were desolventized under a nitrogen stream and dried under high vacuum to produce (6a) R 9 S )-9-((( R )-sec-butyl)carbamoyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-7-onium (2 S ,3 S )-3-carboxy-2,3-dihydroxypropionate (5a tartrate), is a brown amorphous solid, and (6a R 9 R )-9-((( R )-sec-butyl)carbamoyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-7-onium (2 S ,3 S 3-Carboxy-2,3-dihydroxypropionate (5-tartrate) is a colorless solid.

[0255] 5a: Yield (free base): 12.0 mg (20%).

[0256] 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); 3.67-3.38 (m, 2 H); 3.33-3.01 (m, 3 H); 2.91-2.41 (m, 3 H); 1.52-1.38 (m, 2 H); 1.24-1.12 (m, 3 H); 1.09-0.97 (m, 3 H); 0.91 (t, J = 7.4 Hz, 3 H).

[0257] 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).

[0258] LC-MS purity (free base): 97% (ELSD), 91% (UV, 310 nm).

[0259] LC-MS purity (tartrate): 99% (ELSD).

[0260] LC-MS Rt (tartrate) (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.48 min.

[0261] LC-MS m / z: 338.1 (M+H) + . 5: Yield (of free base): 12.5 mg (21%).

[0263] 1 1H NMR spectrum (tartrate) (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).

[0264] LC-MS purity (tartrate): 91% (ELSD).

[0265] LC-MS Rt (tartrate) (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.65 min.

[0266] LC-MS m / z: 338.1 (M+H)+ .

[0267] Example 6: Preparation of (6aR,9R)-N-(pent-3-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (6) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxylic acid (Int1, 200 mg, 0.745 mmol), triethylamine (430 µL, 3.00 mmol), and 3-pentylamine (260 µL, 2.23 mmol) were dissolved in anhydrous water. N , N The solution in 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, and 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 rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 100:0 to 98:2) to give (6a) R 9 S )-7-methyl- N -(pentyl-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide (Int14a, a fast-moving, weakly polar diastereomer), is a dark brown solid, and (6a) R 9 R )-7-methyl- N -(pentyl-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide (Int14, a slower-moving, more polar diastereomer) is a dark brown solid.

[0268] Yield: 208 mg (83%, combined isomers).

[0269] 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); 3.71-3.51 (m, 2H); 3.11 (d, J = 11.7, 2H); 3.04-2.93 (m, 1H); 2.67 (dd, J = 11.8, 3.8, 1H); 2.56 (dd, J = 26.0, 1.6, 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).

[0270] LC-MS purity: 100% (ELSD), 100% (UV) 310 ).

[0271] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.27 min.

[0272] LC-MS m / z: 338.2 (M+H) + .

[0273] Int14: 1 1H NMR spectrum (300 MHz, CD3CN, δ) H ): 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 = 7.1, 1H); 6.40 (s, 1H); 3.67 (qd, J = 8.5, 4.2, 1H); 3.48 (dd, J = 14.6, 5.5, 1H); 3.37 (ddd, J = 8.2, 5.6, 3.0,1H); 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).

[0274] LC-MS purity: 100% (ELSD), 100% (UV) 310 ).

[0275] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 4.95 min.

[0276] LC-MS m / z: 338.2 (M+H) + .

[0277] A solution of 3-chloroperbenzoic acid (77%, 138 mg, 800 µmol) in anhydrous dichloromethane (5 mL) was added dropwise at 0 °C to (6a) R )-7-methyl- N -(pentyl-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide (Int14m, 208 mg, 616 µmol; a mixture of epimers at the 9-position) was dissolved in anhydrous dichloromethane (10 mL) and stirred for 1 hour under argon atmosphere. Then, 10% aqueous sodium hydroxide solution (100 mL) was added to the reaction mixture, and the mixture was extracted with a solution of 10% isopropanol in dichloromethane (3 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (6a) R )-7-methyl-9-(pent-3-ylcarbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline 7-oxide (Int15m) (a mixture of diastereomers; the epimer at position 9) is used in the next step without further purification.

[0278] LC-MS purity: 100% (UV, 310 nm).

[0279] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.09 min.

[0280] LC-MS m / z: 354.2 (M+H) + .

[0281] crude product (6a) R )-7-methyl-9-(pent-3-ylcarbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline 7-oxide (Int15m, the total amount obtained in 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. Ferrous sulfate (II) heptahydrate (343 mg, 1.23 mmol) was then 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 a solution of EDTA (10 g) with 30% ammonium hydroxide (10 mL) in water (100 mL). The aqueous phase was further extracted with dichloromethane (3 x 100 mL), and the combined organic phases were dried over magnesium sulfate and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2 to 90:10) to produce (6a) R )- N -(pentyl-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide (Int16m) (a mixture of diastereomers; epimer at position 9) is an amorphous, pale yellow solid.

[0282] Yield: 50.0 mg (25% from Int14m via 2 steps).

[0283] LC-MS purity: 95% (UV) 310 ).

[0284] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.77 min.

[0285] LC-MS m / z: 324.2 (M+H) + .

[0286] (6a) R )- N -(pentyl-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-] fgA solution of quinoline-9-carboxamide (Int16m, 50.0 mg, 0.154 mmol; a mixture of epimers at position 9) and propionaldehyde (55 µL, 0.771 mmol) in methanol (10 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (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), with the aqueous phase further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give (6a) R 9 R )- N -(pent-3-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide (6, a slow-moving fluorescent band) is a colorless foam.

[0287] Yield: 20 mg (30%).

[0288] 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).

[0289] LC-MS purity: 98% (ELSD), 97% (UV, 310 nm).

[0290] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.72 min.

[0291] LC-MS m / z: 366.2 (M+H) + .

[0292] Example 7: Preparation of (6aR,9R)-N-((R)-pent-2-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (7) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxylic acid (Int1, 200 mg, 0.745 mmol), triethylamine (430 µL, 3.00 mmol) and ( R 2-Pentane-2-amine hydrochloride (250 µg, 1.50 mmol) in anhydrous N , N The solution in dimethylformamide (10 mL) was cooled to 0 °C under an argon atmosphere. Propanephosphonic anhydride (T3P®, 875 µL, 1.50 mmol, 50% solution in DMF) was then added dropwise over 5 minutes. The resulting mixture was stirred at 0 °C for 3 hours and quenched with ice-cold water (1 mL). The resulting mixture was concentrated under vacuum with silica gel (10 g) and purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 100:0 to 98:2) to give (6a) R 9 S )-7-methyl- N -(( R )-pent-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (Int17a, faster fluorescent band), is a dark brown solid, and (6a) R 9 R )-7-methyl- N -(( R )-pent-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-9-carboxamide (Int17, slower fluorescent band) is a dark brown solid.

[0293] Int17a: Yield: 89 mg (35%).

[0294] 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).

[0295] LC-MS purity: 95% (ELSD), 100% (UV) 310 ).

[0296] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.317 min.

[0297] LC-MS m / z: 338.2 (M+H) + .

[0298] Int17: Yield: 102 mg (40%).

[0299] 1 1H NMR spectrum (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).

[0300] LC-MS purity: 91% (ELSD), 100% (UV) 310 ).

[0301] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.06 min.

[0302] LC-MS m / z: 338.2 (M+H) + .

[0303] A solution of 3-chloroperbenzoic acid (77%, 142.7 mg, 827 µmol) in anhydrous dichloromethane (5 mL) was added dropwise at 0 °C to (6a) R )-7-methyl- N -(( R )-pent-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide (Int17m, 215 mg, 630 µmol; a mixture of epimers at the 9-position) was prepared in anhydrous dichloromethane (10 mL), and the mixture was stirred for 1 hour at a given temperature under an argon atmosphere. Then, 10% aqueous sodium hydroxide solution (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with a solution of 10% isopropanol in dichloromethane (3 x 100 mL). The combined organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (6a) R ,)-7-methyl-9-((( R)-pent-2-yl)carbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline 7-oxide (Int18m) (a mixture of diastereomers, the epimer at position 9) was used in the next step without further purification.

[0304] LC-MS purity: 100% (UV, 310 nm).

[0305] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.23 min.

[0306] LC-MS m / z: 354.1 (M+H) + .

[0307] crude product (6a) R )-7-methyl-9-((( R )-pent-2-yl)carbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline 7-oxide (Int18m, the total amount obtained in the above procedure; a mixture of epimers at position 9) was dissolved in methanol (20 mL) and cooled to 0 °C under argon. Ferrous sulfate (II) heptahydrate (351 mg, 1.26 mmol) was then 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 EDTA (10 g) with 30% ammonium hydroxide (10 mL) in water (100 mL). The aqueous phase was further extracted with dichloromethane (3 x 100 mL), and the combined organic phases were dried over magnesium sulfate and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2 to 90:10) to produce (6a) R )- N -(( R )-pent-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (Int19m) (a mixture of diastereomers, the epimer at position 9) is an amorphous, light yellow solid.

[0308] Yield: 47.0 mg (23% from Int17m via 2 steps).

[0309] LC-MS purity: 97% (merged diastereomers, UV) 310 ).

[0310] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.94 min, 5.19 min.

[0311] LC-MS m / z: 324.2 (M+H) + .

[0312] (6a) R )- N -(pentyl-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg A solution of quinoline-9-carboxamide (Int19m, 47.0 mg, 0.145 mmol; a mixture of epimers at position 9) and propionaldehyde (53 µL, 0.74 mmol) in methanol (10 mL) was cooled to 0 °C under argon. Sodium cyanoborohydride (46.0 mg, 0.74 mmol) was added, and the resulting mixture was stirred for 5 min, 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 solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL), and the combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give (6a) R 9 R )-7-propyl- N -(( R )-pent-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (7, a slow-moving fluorescent band) appears as dark brown foam.

[0313] Yield: 20 mg.

[0314] LC-MS purity: 100% (ELSD), 89% (UV, 310 nm).

[0315] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.88 min.

[0316] LC-MS m / z: 366.2 (M+H) + .

[0317] Example 8: Preparation of (6aR,9R)-7-allyl-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (8) and (6aR,9S)-7-allyl-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (8a) Reaction scheme: Synthesis experimental protocol: To (6a) R )- N -(( R )-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide (Int10m, 35 mg, 0.113 mmol; preparation described in Example 3; a mixture of epimers at the 9-position) and potassium bicarbonate (23 mg, 0.226 mmol) in methanol (2 mL) under stirring was added dropwise under argon to a solution of allyl bromide (20 µL, 0.226 mmol) in methanol (1 mL). The resulting mixture was stirred at ambient temperature for 72 hours, diluted with dichloromethane (50 mL), and silica gel (10 g) was added. The resulting suspension was desolvated under vacuum and subjected to silica gel chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia 98:2:0.1) to give (6a) R 9 S )- N -(( R )-sec-butyl)-7-allyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (8a, a rapidly moving fluorescent band), is a brown amorphous solid, and (6a) R 9 R )- N -(( R )-sec-butyl)-7-allyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-9-carboxamide (8, slow-moving fluorescent band), as a brown foam. The separated isomers were each dissolved in anhydrous methanol (500 µL) and treated with an equimolar amount of 1 M D-(-)-tartaric acid in anhydrous methanol. The resulting solutions were desolventized under a nitrogen stream and dried under high vacuum to produce (6a) R 9 S )-7-Allyl-9-((( R )-sec-butyl)carbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-7-onium (2 S ,3 S )-3-carboxy-2,3-dihydroxypropionate (8a tartrate), a light brown solid, and (6a R 9 R )-7-Allyl-9-((( R )-sec-butyl)carbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-7-onium (2 S ,3 S )-3-carboxy-2,3-dihydroxypropionate (8-tartrate) is a light brown solid.

[0318] 8a: Yield (of free base): 14.1 mg (35%).

[0319] 1 1H NMR spectrum (tartrate) (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).

[0320] LC-MS purity (free base): 98% (ELSD), 97% (UV, 310 nm).

[0321] LC-MS purity (tartrate): 99% (ELSD).

[0322] LC-MS Rt (tartrate) (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 6.65 min.

[0323] LC-MS m / z: 350.1 (M+H) + . 8: Yield (free base): 12 mg (30%).

[0325] 1 1H NMR spectrum (tartrate) (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).

[0326] LC-MS purity (tartrate): 98% (ELSD).

[0327] LC-MS Rt (tartrate) (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.47 min.

[0328] LC-MS m / z: 350.1 (M+H) + .

[0329] Example 9: Preparation of (6aR,9R)-5-bromo-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (9) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R)-N , N- Diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindole[ 4,3-fg A solution of quinoline-9-carboxamide (1, 53.0 mg, 0.151 mmol) in anhydrous dioxane (2.0 mL) was purged with argon. A solution of 10% v / v bromine in dioxane (754 µL, 0.151 mmol) was added dropwise to this solution, and the resulting mixture was stirred for 48 h. The reaction mixture was filtered through a silica gel pad. The filtrate was concentrated under vacuum, and the residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6a) R 9 R )-5-bromo- N , N -Diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (9) is a dark-colored amorphous solid.

[0330] Yield: 28.4 mg (44%).

[0331] 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).

[0332] LC-MS purity: 100% (ELSD), 97% (UV, 310 nm).

[0333] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.20 min.

[0334] LC-MS m / z: 431.9 (M+H) + .

[0335] (6a) R, 9 R )-5-bromo- N , N -Diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3] -fg A solution of quinoline-9-carboxamide (9, 28.4 mg, 66 µmol) in a gradient of acetonitrile (5.0 mL) was treated with 1 M D-(-)-tartaric acid aqueous solution (33 µL, 66 µmol) and stirred for 5 min. The solvent was removed under vacuum, and the residue was redissolved in dioxane (5.0 mL) and then freeze-dried at 0 °C to produce (6a) R 9 R )-5-bromo- N , N -Diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (9-hemitartaric acid) is a fluffy light brown solid.

[0336] Yield: 33.2 mg (quantitative).

[0337] 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).

[0338] LC-MS purity: 100% (ELSD), 97% (UV, 310 nm).

[0339] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.20 min.

[0340] LC-MS m / z: 431.9 (M+H) + .

[0341] Example 10: Preparation of (6aR,9R)-N,N-diethyl-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (10) Reaction scheme: Synthesis experimental protocol: (6a) R )- N,N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgA solution of quinoline-9-carboxamide heptafluorobutyrate (Int7m, 40.0 mg, 0.077 mmol; a 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 cyanoborohydride (15.0 mg, 0.23 mmol) was added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (100 µL) and continued stirring at room temperature. After 48 hours, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (200 mL) and 1% ammonium hydroxide solution (150 mL), with the aqueous phase further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6a) R 9 R )- N , N -Diethyl-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (10) is a colorless solid.

[0342] Yield: 22 mg (66%).

[0343] 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).

[0344] LC-MS purity: 99% (ELSD), 100% (UV, 310 nm).

[0345] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 7.64 min.

[0346] LC-MS m / z: 430.2 (M+H) + .

[0347] Example 11: Preparation of (6aR,9R)-N,N-diethyl-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (11) Reaction scheme: Synthesis experimental protocol: 1.66 g (10.0 mmol) of 2-(2-methoxyphenyl)acetic acid was dissolved in anhydrous methanol (10 mL), 1.0 mL of 96% sulfuric acid was added, and 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 dried over anhydrous sodium sulfate and concentrated under vacuum to yield methyl 2-(2-methoxyphenyl)acetate (Int20), a colorless oil.

[0348] Yield: 1.80 g (100%).

[0349] 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).

[0350] 2-(2-methoxyphenyl)acetate (Int20, 1.80 g, 10.0 mmol) was dissolved in anhydrous toluene (20 mL) and cooled to -78 °C. A solution of diisobutylaluminum hydride (15.0 mL, 15 mmol, 1 M in hexane) was added dropwise, and the resulting mixture was stirred at -78 °C for 2 hours. The reaction was quenched by the slow addition of methanol (5 mL), followed by the addition of 10% potassium sodium tartrate solution (20 mL) and ethyl acetate (50 mL). The resulting mixture was then stirred at room temperature for 1 hour. The phases were separated, and the aqueous phase was further extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and evaporated. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 9:1) to give 2-(2-methoxyphenyl)acetaldehyde (Int21) as a colorless oil.

[0351] Yield: 1.11 g (74%).

[0352] 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, 2 H).

[0353] (6a R )- N,N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgA solution of quinoline-9-carboxamide hydrochloride (Int7m, 51.0 mg, 0.148 mmol; HCl salt; a mixture of epimers at the 9-position) and 2-(2-methoxyphenyl)acetaldehyde (Int21, 111 mg, 0.74 mmol) in methanol (10 mL) was cooled to 0 °C under argon. Sodium cyanoborohydride (46.0 mg, 0.74 mmol) was added, the mixture was stirred for 5 min, and then glacial acetic acid (100 µL) was added, with stirring continued at 0 °C. After 1 hour, the solvent was removed under vacuum, the residue was partitioned between dichloromethane (200 mL) and 1% ammonium hydroxide solution (150 mL), and the aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6a) R 9 R )- N,N -Diethyl-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (11) is a colorless foam.

[0354] Yield: 20 mg (30%).

[0355] 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).

[0356] LC-MS purity: 99% (ELSD), 97% (UV, 310 nm).

[0357] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.61 min.

[0358] LC-MS m / z: 444.3 (M+H) + .

[0359] Example 12: Preparation of (6aR,9R)-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (12) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide hemitartaric acid (Int7, 30.0 mg, 78.0 µmol; 2 mol Int7 / mol tartrate) and 3,3,3-trifluoropropionaldehyde (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 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 3 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and 1% ammonium hydroxide aqueous solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to provide (6a) R 9 R )- N,N -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (12) is a colorless foam.

[0360] Yield: 27.2 mg (86%).

[0361] 11H 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).

[0362] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0363] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.85 min.

[0364] LC-MS m / z: 406.0 (M+H) + .

[0365] (6a) R 9 R )- N , N -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-9-carboxamide (12, 27.2 mg, 67.1 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )- N,N -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (12-hemitartaric acid) is a fluffy white solid.

[0366] Yield: 32.2 mg (quantitative).

[0367] 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).

[0368] LC-MS purity: 97% (ELSD), 92% (UV, 310 nm).

[0369] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.85 min.

[0370] LC-MS m / z: 406.0 (M+H)+ .

[0371] Example 13: (6aR,9R)-N,N-diethyl-7-(cyclopropylmethyl)-4,6,6a,7,8,9-hexahydroindole Preparation of [4,3-fg]quinoline-9-carboxamide (13) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide hemitartaric acid (Int7, 30.0 mg, 78.0 µmol; 2 mol Int7 / mol tartrate) and cyclopropaneformaldehyde (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 min, followed by the addition of glacial acetic acid (20 μL). After stirring at 0 °C for 3 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and 1% ammonium hydroxide aqueous solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to provide (6a) R 9 R )-7-(cyclopropylmethyl)- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (13) is a colorless foam.

[0372] Yield: 19.0 mg (67%).

[0373] 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).

[0374] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0375] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.56 min.

[0376] LC-MS m / z: 364.1 (M+H) + (6a) R 9 R )-7-(cyclopropylmethyl)- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (13, 19.0 mg, 52.2 µmol) was dissolved in a gradient of 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 resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )-7-(cyclopropylmethyl)- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (13-hemitartaric acid) is a fluffy white solid.

[0377] 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).

[0378] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0379] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.56 min.

[0380] LC-MS m / z: 364.1 (M+H) + .

[0381] Example 14: ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-yl) Preparation of (pyrrolidine-1-yl)methyl ketone (14) Reaction scheme: Synthesis experimental protocol: (6a) R , 9 R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[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) were dissolved in anhydrous water. N , NThe solution in 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 h. The reaction was judged to be complete by LC-MS and then quenched with ice-cold water (10 mL). The mixture was partitioned between 1 M ammonium hydroxide aqueous solution (200 mL) and ethyl acetate (100 mL). The aqueous phase was re-extracted with ethyl acetate (2 x 150 mL). The organic phases were combined and washed with 10% lithium chloride aqueous solution (4 x 150 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 100:0 to 98:2) to give ((6a R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl)(pyrrolidine-1-yl) methyl ketone (Int22) is a dark brown solid.

[0382] Yield: 255 mg (43%).

[0383] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0384] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.59 min.

[0385] LC-MS m / z: 322.0 (M+H) + .

[0386] ((6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-yl)(pyrrolidone-1-yl) methyl ketone (Int22, 52.7 mg, 0.164 mmol) in a gradient of 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 min. The solvent was removed under vacuum. The residue was redissolved in dioxane (5.0 mL) and subjected to freeze-drying at 0 °C to produce ((6a) R 9 R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl)(pyrrolidone-1-yl)methyl ketone hemitartarate (Int22 hemitartarate) is a fluffy white solid.

[0387] Yield: 69.0 mg (quantitative).

[0388] 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).

[0389] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0390] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.59 min.

[0391] LC-MS m / z: 322.0 (M+H) + .

[0392] A solution of cyanogen bromide (380 mg, 3.60 mmol) in carbon tetrachloride (30 mL) was added under reflux at a rate sufficient to maintain reflux (6a). R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgA solution of quinoline-9-yl)(pyrrolidine-1-yl) methyl ketone (Int22, 255 mg, 0.795 mmol) in chloroform (10 mL) and carbon tetrachloride (70 mL) was prepared. The reaction mixture was then heated under reflux for an additional 4 h. The mixture was then allowed to cool to room temperature and silica gel (0.063–0.200 mm, 10 g) was added. The mixture was concentrated under vacuum. The resulting powder was added to the top of a pre-packed silica gel column and eluted with the product as follows (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 100:0 to 50:50) to give (6a) R 9 R )-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3- fg Quinoline-7(4H)-formonitrile (Int23) is a colorless amorphous solid.

[0393] Yield: 200 mg (75%).

[0394] 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).

[0395] LC-MS purity: 98% (ELSD), 98% (UV, 310 nm).

[0396] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.87 min.

[0397] LC-MS m / z: 333.0 (M+H) + .

[0398] (6a) R 9 R )-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3- fgA solution of quinoline-7(4H)-formonitrile (Int23, 200 mg, 0.601 mmol) in acetic acid (15 mL) and water (1.5 mL) was treated with zinc powder (1000 mg). The resulting suspension was heated under reflux for 1 h. After cooling, the mixture was filtered through cotton, and the solution was alkalized with 10% ethylenediamine aqueous solution (100 mL) and stirred for 1 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then filtered. The filtrate was treated with silica gel (0.063–0.200 mm, 10 g) and evaporated under vacuum. The powder was added to the top of a pre-packed silica gel rapid chromatography column and the product was eluted as follows (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 100:0 to 98:2) to give ((6a) R,9R )-4,6,6a,7,8,9 hexahydroindole[4,3- fg Quinoline-9-yl)(pyrrolidine-1-yl) methyl ketone (Int24) is a dark-colored amorphous solid.

[0399] Yield: 125 mg (68%).

[0400] 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).

[0401] LC-MS purity: 95% (ELSD), 95% (UV, 310 nm).

[0402] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.22 min.

[0403] LC-MS m / z: 308.0 (M+H) + .

[0404] ((6a) R 9 R )-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-yl)(pyrrolidone-1-yl) methyl ketone hemitartarate (Int24, 40 mg, 105 µmol; 2 mol Int24 / mol tartrate; salt prepared as described for other hemitartarates) and propionaldehyde (15 µL, 210 µmol) in methanol (2 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (14 mg, 210 µmol) was added. The resulting mixture was stirred for 5 minutes, and then acetic acid (50 µL) was added. After stirring at 0 °C for 1 hour, silica gel (0.063–0.200 mm, 10 g) was added, and the mixture was concentrated under vacuum. The powder was added to the top of a pre-packed silica gel column, and the product was eluted as follows (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give ((6a) R 9 R )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl)(pyrrolidone-1-yl) methyl ketone (14) is a colorless foam.

[0405] Yield: 20.5 mg (56%).

[0406] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0407] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.28 min.

[0408] LC-MS m / z: 350.1 (M+H) + .

[0409] ((6a) R 9 R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-yl)(pyrrolidone-1-yl) methyl ketone (14, 20.5 mg, 58.7 µmol) in a gradient of 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 lyophilized at 0 °C to give ((6a) R 9 R )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl)(pyrrolidone-1-yl)methyl ketone hemitartarate (14-hemitartarate) is a fluffy white solid.

[0410] Yield: 23.2 mg (quantitative).

[0411] 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).

[0412] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0413] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.28 min.

[0414] LC-MS m / z: 350.1 (M+H) + .

[0415] Example 15: Preparation of (6aR,9R)-N,N-diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (16) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol 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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 3 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and 1% ammonium hydroxide aqueous solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to obtain a material still containing impurities. The crude material was dissolved in 1M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 x 50 mL), alkalized with 24% ammonium hydroxide aqueous solution, and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to provide (6a) R 9 R )- N , N -Diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-9-carboxamide (16) is a colorless solid.

[0416] Yield: 9.2 mg (43%).

[0417] 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).

[0418] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0419] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.85 min.

[0420] LC-MS m / z: 416.1 (M+H) + .

[0421] (6a) R 9 R )- N,N -Diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (16, 9.20 mg, 22.1 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )- N,N -Diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (16-hemitartaric acid) is a fluffy grayish-white solid.

[0422] Yield: 13.3 mg (quantitative).

[0423] 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).

[0424] LC-MS purity: 97% (ELSD), 90% (UV, 310 nm).

[0425] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.84 min.

[0426] LC-MS m / z: 416.1 (M+H)+ .

[0427] Example 16: Preparation of (6aR,9R)-N,N-diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (18) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol 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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 3 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and 1% ammonium hydroxide aqueous solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to provide material still containing impurities. The crude material was dissolved in 1M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 x 50 mL), alkalized with 24% ammonium hydroxide aqueous solution, and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to give (6a) R 9 R )- N , N -Diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (18) is a colorless solid.

[0428] Yield: 14.2 mg (64%).

[0429] 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).

[0430] LC-MS purity: 97% (ELSD), 99% (UV, 310 nm).

[0431] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.31 min.

[0432] LC-MS m / z: 430.1 (M+H) + .

[0433] (6a) R 9 R )- N , N -Diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (18, 14.2 mg, 33.0 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )- N , N-Diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (18-hemitartaric acid) is a fluffy white solid.

[0434] Yield: 16.8 mg (quantitative).

[0435] 1 1H 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).

[0436] LC-MS purity: 99% (ELSD), 96% (UV, 310 nm).

[0437] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.31 min.

[0438] LC-MS m / z: 430.1 (M+H) + .

[0439] Example 17: Preparation of (6aR,9R)-N,N-diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (19) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol 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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 3 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and 1% ammonium hydroxide aqueous solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to provide material still containing impurities. The crude material was dissolved in 1M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 x 50 mL), alkalized with 24% ammonium hydroxide aqueous solution, and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to provide (6a) R 9 R )- N , N -Diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (19) is a colorless solid.

[0440] Yield: 15.6 mg (70%).

[0441] 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).

[0442] LC-MS purity: 97% (ELSD), 99% (UV, 310 nm).

[0443] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.24 min.

[0444] LC-MS m / z: 430.1 (M+H) + .

[0445] (6a) R 9 R )- N , N -Diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (19, 15.6 mg, 36.3 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )- N , N -Diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (19-hemitartaric acid) is a fluffy white solid.

[0446] Yield: 18.4 mg (quantitative).

[0447] 1 1H 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).

[0448] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.24 min.

[0449] LC-MS m / z: 430.1 (M+H) + .

[0450] Example 18: Preparation of (6aR,9R)-N,N-diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (20) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgA solution of quinoline-9-carboxamide hemitartaric acid (Int7, 30.0 mg, 78.0 µmol; 2 mol Int7 / mol 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 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 3 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and 1% ammonium hydroxide aqueous solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to provide material still containing impurities. The crude material was dissolved in 1M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 x 50 mL), alkalized with 24% ammonium hydroxide aqueous solution, and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to provide (6a) R 9 R )- N,N -Diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (20) is a colorless foam.

[0451] Yield: 14.9 mg (43%).

[0452] 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).

[0453] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0454] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.58 min.

[0455] LC-MS m / z: 444.2 (M+H) + .

[0456] (6a) R 9 R )- N , N -Diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (20, 14.9 mg, 33.6 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )- N , N -Diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (20 hemitartaric acid) is a fluffy grayish-white solid.

[0457] Yield: 17.4 mg (quantitative).

[0458] 1 1H 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).

[0459] LC-MS purity: 96% (ELSD), 90% (UV, 310 nm).

[0460] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.58 min.

[0461] LC-MS m / z: 444.1 (M+H) + .

[0462] Example 19: Preparation of (6aR,9R)-N,N-diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (21) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgA solution of quinoline-9-carboxamide hemitartaric acid (Int7, 33.0 mg, 86.0 µmol; 2 mol Int7 / mol 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 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 3 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and 1% ammonium hydroxide aqueous solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to provide material still containing impurities. The crude material was dissolved in 1M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 x 50 mL), alkalized with 24% ammonium hydroxide aqueous solution, and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to provide (6a) R 9 R )- N , N -Diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (21) is a colorless foam.

[0463] Yield: 36.2 mg (95%).

[0464] 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).

[0465] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0466] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.55 min.

[0467] LC-MS m / z: 444.2 (M+H) + .

[0468] (6a) R 9 R )- N , N -Diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (21, 36.2 mg, 81.6 µmol) was dissolved in a gradient of 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 resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )- N , N -Diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (21-hemitartaric acid) is a fluffy white solid.

[0469] Yield: 42.3 mg (quantitative).

[0470] 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).

[0471] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.57 min.

[0472] LC-MS m / z: 444.1 (M+H) + .

[0473] Example 20: Preparation of (6aR,9R)-N,N-diethyl-7-(pyridin-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (22) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgA solution of quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol tartrate) and pyridine-2-carboxaldehyde (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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 3 h, the solvent was removed under vacuum, and the residue was partitioned between dichloromethane (100 mL) and 1% ammonium hydroxide aqueous solution (150 mL). The aqueous phase was further extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to obtain a material still containing impurities. The crude material was dissolved in 1M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3 x 50 mL), alkalized with 24% ammonium hydroxide aqueous solution, and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to provide (6a) R 9 R )- N,N -Diethyl-7-(pyridin-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (22) is a dark-colored amorphous solid.

[0474] Yield: 15.8 mg (76%).

[0475] 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).

[0476] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0477] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.74 min.

[0478] LC-MS m / z: 401.1 (M+H) + .

[0479] (6a) R 9 R )- N,N -Diethyl-7-(pyridin-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (22, 15.8 mg, 39.5 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )- N,N -Diethyl-7-(pyridin-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide tartrate (22-tartrate) is a fluffy grayish-white solid.

[0480] Yield: 21.8 mg (quantitative).

[0481] 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).

[0482] LC-MS purity: 99% (ELSD), 96% (UV, 310 nm) LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.74 min.

[0483] LC-MS m / z: 401.1 (M+H) + .

[0484] Example 21: Preparation of (6aR,9R)-N,N-diethyl-7-(2-(pyridin-2-yl)ethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (23) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N , N-Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 53.0 µmol; 2 mol Int7 / mol tartrate), potassium bicarbonate (32 mg, 0.32 mmol), and 2-(2-bromoethyl)pyridin-1-onium 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 material, the reaction mixture was concentrated on silica gel and subjected to rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2). The combined product fractions were desolventized under vacuum to produce (6a) R 9 R )- N , N -Diethyl-7-(2-(pyridin-2-yl)ethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (23) is a dark-colored amorphous solid.

[0485] Yield: 3.8 mg (18%).

[0486] 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).

[0487] LC-MS purity: 98% (ELSD), 97% (UV, 310 nm).

[0488] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.88 min.

[0489] LC-MS m / z: 415.1 (M+H) + .

[0490] (6a) R 9 R )- N , N -Diethyl-7-(2-(pyridin-2-yl)ethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (23, 3.8 mg, 9.17 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6a) R 9 R )- N , N -Diethyl-7-(2-(pyridin-2-yl)ethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide tartrate (23-tartrate) is a fluffy, light brown solid.

[0491] Yield: 5.2 mg (quantitative).

[0492] 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).

[0493] LC-MS purity: 95% (ELSD), 92% (UV, 310 nm).

[0494] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.88 min.

[0495] LC-MS m / z: 415.1 (M+H) + .

[0496] Example 22: Preparation of (6aR)-N-((R)-sec-butyl)-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (24m) Reaction scheme: Synthesis experimental protocol: (6) aR )- N -(( R )-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide (Int10m, 20 mg, 46.7 µmol; a mixture of epimers at the 9-position) and 2-methoxybenzaldehyde (27 mg, 194 µmol) in methanol (0.5 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (12 mg, 194 µmol) was added, and the resulting mixture was stirred for 5 min. Acetic acid (20 µL) was then added, and the reaction mixture was stirred at 0 °C for 24 h. As confirmed by LC-MS analysis, (6...) aR )-N -(( R )-sec-butyl)-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A mixture of diastereomers of quinoline-9-carboxamide (24m; a mixture of diastereomers; an epimer at position 9).

[0497] Composition confirmed by LC-MS: 87% (ELSD, faster-moving isomer), 13% (ELSD, slower-moving isomer).

[0498] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.54 min (isomer A), 6.57 min (isomer B).

[0499] LC-MS m / z: 430.2 (M+H) + .

[0500] Example 23: Preparation of (6aR)-N-((R)-sec-butyl)-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (25m) Reaction scheme: Synthesis experimental protocol: (6) aR )- N -(( R )-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-carboxamide (Int10m, 20 mg, 46.7 µmol; a mixture of epimers at the 9-position) and 2-(2-methoxyphenyl)acetaldehyde (29 mg, 194 µmol) in methanol (0.5 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (12 mg, 194 µmol) was added, and the resulting mixture was stirred for 5 min. Acetic acid (20 µL) was added, and the reaction mixture was then stirred at 0 °C for 24 h. As confirmed by LC-MS analysis, (6... aR )- N -(( R )-sec-butyl)-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fgA mixture of diastereomers of quinoline-9-carboxamide (25m; a mixture of diastereomers; an epimer at position 9).

[0501] Composition confirmed by LC-MS: 87% (ELSD, faster-moving isomer), 13% (ELSD, slower-moving isomer).

[0502] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.49 min (isomer A), 6.79 min (isomer B).

[0503] LC-MS m / z: 444.2 (M+H) + .

[0504] Example 24: Preparation of ((2S,4S)-2,4-dimethylazacyclobut-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-yl) methyl ketone (26) Reaction scheme: Synthesis experimental protocol: ((2) S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R 9 R )-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-yl) methyl ketone (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 solution was evaporated under vacuum. The crude material was redissolved in dichloromethane (25 mL), treated with silica gel (0.063–0.200 mm, 10 g), and concentrated. The resulting powder was added to a rapid column and purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give ((2 S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R 9R )-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl) methyl ketone (26) is a colorless foam.

[0505] Yield: 15.6 mg (35%).

[0506] 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).

[0507] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0508] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.53 min.

[0509] LC-MS m / z: 382.1 (M+H) + .

[0510] ((2) S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R 9 R )-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-9-yl) methyl ketone (26, 15.6 mg, 40.9 µmol) was dissolved in a gradient of 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 min. The solvent was removed under vacuum, and the residue was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to give ((2) S 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R 9 R )-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl) methyl ketone hemitartarate (26 hemitartarate) is a fluffy white solid.

[0511] Yield: 18.6 mg (quantitative).

[0512] 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).

[0513] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0514] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.53 min.

[0515] LC-MS m / z: 382.1 (M+H) + .

[0516] Example 25: Preparation of ((6aR,9R)-7-allyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazacyclobut-1-yl)methyl ketone (27) Reaction scheme: Synthesis experimental protocol: ((2) S, 4 S )-2,4-Dimethylazacyclobut-1-yl)((6a R 9 R )-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of quinoline-9-yl) methyl ketone (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 h. The solvent was removed under vacuum, and the crude material was redissolved in dichloromethane (25 mL). Silica gel (0.063–0.200 mm, 10 g) was added, and the solvent was removed under vacuum. The resulting powder was placed on a pre-loaded silica gel fast column and eluted (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give ((6a) R 9 R )-7-Allyl-4,6,6a,7,8,9-Hexahydroindolo[4,3- fg Quinoline-9-yl)((2 S 4 S )-2,4-dimethylazazene-1-yl)methyl ketone (27) is a colorless foam.

[0517] Yield: 14.2 mg (33%).

[0518] 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).

[0519] LC-MS purity: 98% (ELSD), 91% (UV, 310 nm).

[0520] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.42 min.

[0521] LC-MS m / z: 362.1 (M+H) + .

[0522] ((6a) R 9 R )-7-Allyl-4,6,6a,7,8,9-Hexahydroindolo[4,3- fg Quinoline-9-yl)((2 S 4 S2,4-Dimethylazazole-1-yl)methyl ketone (27, 14.2 mg, 39.3 µmol) was dissolved in a gradient of 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 min and then the solvent was removed under vacuum. The residue was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give ((6a) R 9 R )-7-Allyl-4,6,6a,7,8,9-Hexahydroindolo[4,3- fg Quinoline-9-yl)((2 S 4 S 2,4-Dimethylazonylbutan-1-yl)methyl ketone hemitartaric acid salt (27 hemitartaric acid salt) is a fluffy grayish-white solid.

[0523] Yield: 17.1 mg (quantitative).

[0524] 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).

[0525] LC-MS purity: 98% (ELSD), 91% (UV, 310 nm).

[0526] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.42 min.

[0527] LC-MS m / z: 362.1 (M+H) + .

[0528] Example 26: Preparation of (6aR,9R)-5-bromo-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (35) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- fg -Diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (54.0 mg, 0.167 mmol) was dissolved in anhydrous dioxane (2.0 mL) and washed with argon. A solution of bromine in dioxane (10% v / v, 834 µL, 0.151 mmol) was added dropwise, and the resulting mixture was stirred for 2 h. The mixture was then treated with silica gel (0.063–0.200 mm, 10 g) and evaporated under vacuum. The resulting powder was added to the top of a pre-packed silica gel column and eluted with the product as follows (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6a) R 9 R )-5-bromo- N , N -Diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (35) is a dark-colored amorphous solid.

[0529] Yield: 32.8 mg (49%).

[0530] 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).

[0531] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0532] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.37 min.

[0533] LC-MS m / z: 403.9 (M+H) + .

[0534] (6a) R 9 R )-5-bromo- N , N -Diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (35, 32.8 mg, 81.5 µmol) was dissolved in a gradient of 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 lyophilized at 0 °C to give (6a) R 9 R )-5-bromo- N , N -Diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- Reaction scheme:Quinoline-9-carboxamide hemitartaric acid (35 hemitartaric acid) is a fluffy light brown solid.

[0535] Yield: 38.8 mg (quantitative).

[0536] 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 (m, 1H), 3.20 – 3.09 (m, 1H), 2.87 (s, 3H), 2.72 (dd, J = 14.5, 11.6, 1H), 1.31 (t, J = 7.1, 3H), 1.18 (t, J = 7.1, 3H).

[0537] LC-MS purity: 100% (ELSD), 97% (UV, 310 nm).

[0538] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.37 min.

[0539] LC-MS m / z: 403.9 (M+H) + .

[0540] Example 27: (6aR,9R)-N,N-diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (36) Synthesis experimental protocol: fg (6a) R 9 R )- N , N -Diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-9-carboxamide (1,200 mg, 0.567 mmol) was dissolved in anhydrous dioxane (10 mL), followed by the addition of triethylsilane (1 mL) and trifluoromethanesulfonic acid (500 µL), and the resulting mixture was stirred at 40 °C for 96 h. The mixture was then allowed to cool to room temperature, and 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 top of a pre-packed silica gel column, and the product was eluted as follows (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6a) R 9 R )- N , N -Diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- fg Quinoline-9-carboxamide (36; a mixture of diastereomers; epimer at the 5a position) is a dark-colored amorphous solid.

[0541] Yield: 97.6 mg (49%).

[0542] LC-MS purity: 100% (ELSD), 98% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 3.85 min.

[0543] LC-MS m / z: 354.2 (M+H) + .

[0544] (6a) R 9 R )- N , N -Diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- fg Quinoline-9-carboxamide (36, 16.3 mg, 46.1 µmol; a mixture of epimers at the 5a position) was dissolved in a gradient of 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 lyophilized at 0 °C to produce (6a) R 9 R )- N , N-Diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- Reaction scheme: Quinoline-9-carboxamide tartrate (36-tartrate; a mixture of diastereomers; epimer at the 5a position) is a fluffy brown solid.

[0545] Yield: 24.0 mg (quantitative).

[0546] 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).

[0547] LC-MS purity: 100% (ELSD), 98% (UV, 310 nm).

[0548] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 3.85 min.

[0549] LC-MS m / z: 354.2 (M+H) + .

[0550] Example 28: Preparation of (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (37) Synthesis experimental protocol: fg (6a) R 9 R )- N , N -Diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[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 h. The mixture was then allowed to cool to room temperature, and silica gel (0.063–0.200 mm, 10 g) was added. The mixture was concentrated under vacuum. The resulting powder was added to the top of a pre-packed silica gel column and eluted with the following eluent (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6a) R 9 R )- N , N -Diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- fg Quinoline-9-carboxamide (37; a mixture of diastereomers; epimer at the 5a position) is a dark-colored amorphous solid.

[0551] Yield: 16.3 mg (15%).

[0552] LC-MS purity: 92% (ELSD), 77% (UV, 310 nm).

[0553] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 3.46 min.

[0554] LC-MS m / z: 326.1 (M+H) + .

[0555] (6a) R 9 R )- N , N-Diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- fg Quinoline-9-carboxamide (37, 16.3 mg, 50.0 µmol; a mixture of epimers at the 5a position) was dissolved in a gradient of 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, and the material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to give (6a) R 9 R )- N , N -Diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- Reaction scheme: Quinoline-9-carboxamide tartrate (37 tartrate; a mixture of diastereomers; epimer at the 5a position) is a fluffy brown solid.

[0556] Yield: 24.0 mg (quantitative).

[0557] LC-MS purity: 92% (ELSD), 77% (UV, 310 nm).

[0558] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 3.46 min.

[0559] LC-MS m / z: 326.1 (M+H) + .

[0560] Example 29: Preparation of (6aR,9R)-N,N-bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (38) Synthesis experimental protocol: fg (6a) R 9 R )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[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 anhydrous... N, N The solution in 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 h. The reaction was judged 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 rediscovered with ethyl acetate (2 x 200 mL), and the combined organic phases were washed with 10% lithium chloride aqueous solution (4 x 150 mL) and dried over anhydrous magnesium sulfate. The solvent was filtered and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 100:0 to 98:2). The pilot fraction was cut to obtain (6a) after solvent evaporation. R 9 R )- N , N -bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (38) is a colorless amorphous solid.

[0561] Yield: 25 mg (5%).

[0562] 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).

[0563] LC-MS purity: 100% (ELSD), 95% (UV, 310 nm).

[0564] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.90 min.

[0565] LC-MS m / z: 360.1 (M+H) + .

[0566] (6a) R 9 R )- N , N -bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (38, 25.0 mg, 69.6 µmol) was dissolved in a gradient of 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 another 5 minutes. The solvent was removed under vacuum, and the remaining material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C. This yielded (6a) R 9 R )- N , N -bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- Example 30. Preparation of (6aR,9R)-N,N-diethyl-7-(2-fluoroethyl)-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (39) Quinoline-9-carboxamide hemitartaric acid (38 hemitartaric acid) is a fluffy white solid.

[0567] Yield: 30.2 mg (quantitative).

[0568] 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).

[0569] LC-MS purity: 100% (ELSD), 95% (UV, 310 nm).

[0570] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.90 min.

[0571] LC-MS m / z: 360.1 (M+H) + .

[0572] Reaction scheme: Synthesis experimental protocol: fg N,N (6a) R 9 R )- N , N -Diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fgQuinoline-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 was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction was diluted with dichloromethane (20 mL) and silica gel (4 g) was added. The suspension was desolventized under vacuum and subjected to silica gel chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia 98:2:0.1) to give (6a) R 9 R )- N,N -Diethyl-7-(2-fluoroethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (39, upper fluorescent band on TLC) is a colorless foam.

[0573] Yield: 30.8 mg (23%).

[0574] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0575] LC-MS Rt (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.21 min.

[0576] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 356.1 (M+H) + .

[0577] (6a) R 9 R )- N,N -Diethyl-7-(2-fluoroethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (39, 30.8 mg, 86.6 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d -Tartrate aqueous solution (43.3 µL, 43.3 µmol) was used for treatment. The resulting mixture was stirred at room temperature for 5 min, and the solvent was removed under vacuum to produce (6a) R 9 R )- Example 31. Preparation of (6aR,9R)-N-((R)-sec-butyl)-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (40) -Diethyl-7-(2-fluoroethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-Reaction scheme: Quinoline-9-carboxamide hemitartaric acid (39 hemitartaric acid) is an amorphous grayish-white solid.

[0578] Yield: 37.2 mg (quantitative).

[0579] 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).

[0580] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0581] LC-MS Rt (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HFBA in 10 min): 5.21 min.

[0582] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 356.1 (M+H) + .

[0583] Synthesis experimental protocol: fg fg N,N (6a)R 9 R )- N -(( R )-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg A solution of 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 cyanoborohydride (12.2 mg, 194 µmol) was added, and the mixture was stirred for 5 min. Acetic acid (50 µL) was then added, and the mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with dichloromethane (10 mL), then with silica gel (4 g), and the solvent was removed from the resulting suspension under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to give (6a) R 9 R )-N-(( R )-sec-butyl)-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- N,N Quinoline-9-carboxamide (40, the fastest-moving point on TLC, the weakest polar diastereomer), is a colorless oil.

[0584] Yield: 18.8 mg (96%) LC-MS purity: 99% (ELSD), 100% (UV, 310 nm) LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.78 min LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 406.1 (M+H) + (6a) R 9 R )-5-bromo- fg -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- Example 32. Preparation of (6aR,9R)-5-bromo-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (41) Quinoline-9-carboxamide (40, 18.8 mg, 46.5 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d-Tartrate aqueous solution (23.2 µL, 23.2 µmol). The resulting mixture was stirred at room temperature for 5 min, and then the solvent was removed under vacuum to produce (6a) R 9 R )-5-bromo- Reaction scheme: -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- Synthesis experimental protocol: Quinoline-9-carboxamide hemitartaric acid (40 hemitartaric acid) is a grayish-white solid.

[0585] Yield: 22.2 mg (quantitative).

[0586] 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).

[0587] LC-MS purity: 99% (ELSD), 100% (UV, 310 nm) LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.78 min LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 406.1 (M+H) + N,N fg N,N fg (6a) R 9 R )- N,N -Diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (2, 30.0 mg, 0.081 mmol) was dissolved in anhydrous dioxane (3.0 mL) and washed with argon. A solution of bromine 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 h. The reaction mixture was alkalized with triethylamine (100 µL), poured onto silica gel (4 g), and concentrated under vacuum. Purification was achieved by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 100:0 to 70:30 + 0.5%). v / v Triethylamine provides (6a) R 9 R )-5-bromo- N,N -Diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (41) is a grayish-white amorphous solid.

[0588] Yield: 16.5 mg (45%).

[0589] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0590] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.91 min.

[0591] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 448.1 ( 79 Br, M+1), 450.0 ( 81 Br, M+1) (6a) R 9 R )-5-bromo- Example 33. Preparation of (6aR,9R)-5-bromo-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (42) -Diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- Reaction scheme:Quinoline-9-carboxamide (41, 16.5 mg, 37.0 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d -Tartrate aqueous solution (18.5 µL, 18.5 µmol). The resulting mixture was stirred at room temperature for 5 min, and the solvent was removed under vacuum to produce (6a) R 9 R )-5-bromo- Synthesis experimental protocol: -Diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- N,N Quinoline-9-carboxamide hemitartaric acid salt (41 hemitartaric acid salt) is a grayish-white solid.

[0592] Yield: 19.25 mg (quantitative).

[0593] 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).

[0594] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0595] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA over 10 min): 5.91 min. LC-MS m / z (ESI+, cone voltage 30 V, centroid mode): 448.1 ( 79 Br, M+1), 450.0 ( 81 Br, M+1).

[0596] fg N,N fg N,N (6a) R 9 R )- fg -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- N,N Quinoline-9-carboxamide (12, 35.8 mg, 0.088 mmol) was dissolved in anhydrous dioxane (3.0 mL) and washed with argon. A solution of bromine 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 h. The reaction mixture was alkalized with triethylamine (100 µL), poured onto silica gel (4.0 g), and concentrated under vacuum. Purification was achieved by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 100:0 to 70:30 + 0.5%). v / v Triethylamine provides (6a) R 9 R )-5-bromo- fg -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- Example 34. Preparation of (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (43) Quinoline-9-carboxamide (42) is a grayish-white amorphous solid.

[0597] Yield: 19.3 mg (45%).

[0598] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0599] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.28 min.

[0600] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 484.1 ( 79 Br, M+1), 486.0 ( 81 Br, M+1).

[0601] (6a) R 9 R )-5-bromo-Reaction scheme: -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- Synthesis experimental protocol: Quinoline-9-carboxamide (42, 19.3 mg, 39.8 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d -Tartrate aqueous solution (19.9 µL, 19.9 µmol) was used for treatment. The resulting mixture was stirred at room temperature for 5 min, and then the solvent was removed under vacuum to produce (6a) R 9 R )-5-bromo- sec-butyl -Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (42 hemitartaric acid) is a grayish-white solid.

[0602] Yield: 22.2 mg (quantitative).

[0603] 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).

[0604] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0605] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.28 min.

[0606] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 484.1 ( 79 Br, M+1), 486.0 ( 81 Br, M+1).

[0607] sec-butyl fg sec-butyl fg (6a) R 9 R )- N -(( R )- sec-butyl )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (Int8, 56.3 mg, 174 µmol) was dissolved in anhydrous dioxane (5.0 mL), and the container was rinsed with argon. A solution of bromine in dioxane (28.5 mg / mL, 976 µL, 174 µmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was alkalized with trimethylamine (100 µL), poured onto silica gel (4 g), and concentrated under vacuum. Purification was achieved by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 100:0 to 70:30 +0.5%). v / v Triethylamine provides (6a) R 9 R )-5-bromo- N -(( R )- Example 35. Preparation of (6aR,9R)-5-bromo-N-(pentan-3-yl)-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (44) )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- Reaction scheme: Quinoline-9-carboxamide (43) is a grayish-white amorphous solid.

[0608] Yield: 15.1 mg (45%).

[0609] LC-MS purity: 100% (ELSD), 98% (UV, 310 nm).

[0610] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.16 min.

[0611] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 402.9 ( 79 Br, M+1), 403.9 ( 81 Br, M+1).

[0612] (6a) R 9 R )-5-bromo- N -(( R )- Synthesis experimental protocol: )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (43, 15.1 mg, 37.6 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d -Tartrate aqueous solution (18.8 µL, 18.8 µmol) was used for treatment. The resulting mixture was stirred at room temperature for 5 min, and then the solvent was removed under vacuum to produce (6a) R 9 R )-5-bromo- N -(( R )- fg )-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide hemitartaric acid (43 hemitartaric acid) is a grayish-white solid.

[0613] Yield: 18.0 mg (quantitative).

[0614] 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).

[0615] LC-MS purity: 100% (ELSD), 98% (UV, 310 nm).

[0616] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.16 min.

[0617] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 402.9 ( 79 Br, M+1), 403.9 ( 81 Br, M+1).

[0618] fg Example 36. Preparation of (6aR,9R)-5-bromo-N-((R)-pentan-2-yl)-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (45) Reaction scheme: Synthesis experimental protocol: (6a) R 9 R )- N -(pent-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide (Int14, 58.7 mg, 174 µmol) was dissolved in anhydrous dioxane (6.0 mL) and washed with argon. A solution of bromine in dioxane (28.5 mg / mL, 976 µL, 174 µmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was alkalized with trimethylamine (100 µL), poured onto silica gel (4 g), and concentrated under vacuum. Purification was achieved by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 100:0 to 70:30 + 0.5%). v / v Triethylamine provides (6a) R 9 R )-5-bromo- N -(pent-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide (44) is a grayish-white amorphous solid.

[0619] Yield: 29.1 mg (40%).

[0620] LC-MS purity: 99% (ELSD), 100% (UV, 310 nm).

[0621] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.43 min.

[0622] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 416.0 ( 79 Br, M+1), 418.0 ( 81 Br, M+1).

[0623] (6a) R 9 R )-5-bromo- N -(pent-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide (44, 29, 1 mg, 69.8 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d - The mixture was treated with an aqueous tartaric acid solution (34.9 µL, 34.9 µmol). The resulting mixture was stirred at room temperature for 5 min, and then the solvent was removed under vacuum to produce (6a) R 9 R )-5-bromo- N -(pent-3-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-] fg Quinoline-9-carboxamide hemitartaric acid (44 hemitartaric acid) is a grayish-white solid.

[0624] Yield: 34.2 mg (quantitative).

[0625] 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).

[0626] LC-MS purity: 99% (ELSD), 100% (UV, 310 nm).

[0627] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.43 min.

[0628] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 416.0 ( 79 Br, M+1), 418.0 ( 81 Br, M+1).

[0629] Example 37. Preparation of (6aR,9R)-5-bromo-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (46) Reaction scheme: Synthesis experimental protocol: sec-butyl (6a) R 9 R )- N -(( R )-pent-2-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (Int17, 39.3 mg, 116 µmol) was dissolved in anhydrous dioxane (5.0 mL) and washed with argon. A solution of bromine in dioxane (28.5 mg / mL, 653 µL, 116 µmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was alkalized with trimethylamine (100 µL), poured onto silica gel (4 g), and concentrated under vacuum. Purification was achieved by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 100:0 to 70:30 +0.5%). v / v Triethylamine provides (6a) R 9 R)-5-bromo- N -(( R )-pent-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- sec-butyl Quinoline-9-carboxamide (45) is a grayish-white amorphous solid.

[0630] Yield: 12.8 mg (61%).

[0631] LC-MS purity: 100% (ELSD), 98% (UV, 310 nm).

[0632] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.54 min.

[0633] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 416.0 ( 79 Br, M+1), 418.0 ( 81 Br, M+1).

[0634] (6a) R 9 R )-5-bromo- N -(( R )-pent-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-carboxamide (45, 12.8 mg, 30.9 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d -Tartrate aqueous solution (15.4 µL, 15.4 µmol) was used for treatment. The resulting mixture was stirred at room temperature for 5 min, and then the solvent was removed under vacuum to produce (6a) R 9 R )-5-bromo- N -(( R )-pent-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- sec-butyl Quinoline-9-carboxamide hemitartaric acid (45 hemitartaric acid) is a grayish-white solid.

[0635] Yield: 15.3 mg (quantitative).

[0636] 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).

[0637] LC-MS purity: 100% (ELSD), 98% (UV, 310 nm).

[0638] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.54 min.

[0639] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 416.0 ( 79 Br, M+1), 418.0 ( 81 Br, M+1).

[0640] fg sec-butyl fg ​ (6a) R 9 R )- N -(( R )- ​ )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- ​Quinoline-9-carboxamide (3, 22.5 mg, 64.0 µmol) was dissolved in anhydrous dioxane (3.0 mL) and washed with argon. A solution of bromine 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 h. The reaction mixture was alkalized with trimethylamine (100 µL), poured onto silica gel (4 g), and concentrated under vacuum. Purification was achieved by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 100:0 to 70:30 + 0.5%). v / v Triethylamine provides (6a) R 9 R )-5-bromo- N -(( R )- ​ )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- ​ Quinoline-9-carboxamide free base (46) is a grayish-white amorphous solid.

[0641] Yield: 16.7 mg (61%).

[0642] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0643] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.86 min.

[0644] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 430.1 ( 79 Br, M+1), 432.0 ( 81 Br, M+1).

[0645] (6a) R 9 R )-5-bromo- N -(( R )- ​ )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- ​ Quinoline-9-carboxamide (46, 16.7 mg, 38.8 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d -Tartrate aqueous solution (19.4 µL, 19.4 µmol) was used for treatment. The resulting mixture was stirred at room temperature for 5 min, and then the solvent was removed under vacuum to produce (6a)R 9 R )-5-bromo- N -(( R )- ​ )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- ​ Quinoline-9-carboxamide hemitartaric acid (46 hemitartaric acid) is a grayish-white solid.

[0646] Yield: 19.6 mg (quantitative).

[0647] 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).

[0648] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0649] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.86 min.

[0650] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 430.1 ( 79 Br, M+1), 432.0 ( 81 Br, M+1).

[0651] Example 38. Preparation of ((6aR,9R)-5-bromo-7-propyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidin-1-yl)methanone (47) Example 38. Preparation of ((6aR,9R)-5-bromo-7-propyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-yl)((2S,4S)-2,4-dimethylazetidin-1-yl)methanone (47) Reaction scheme: Synthetic experimental protocol: ((6a) R 9 R )-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl)((2 S 4 S 2,4-Dimethylazazole-1-yl)methyl ketone (4, 46.3 mg, 127 µmol) was dissolved in anhydrous dioxane (6.0 mL) and washed with argon. A solution of bromine in dioxane (28.5 mg / mL, 715 µL, 127 µmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was alkalized with trimethylamine (100 µL), poured onto silica gel (4 g), and concentrated under vacuum. Purification was achieved by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 100:0 to 80:20 + 0.5%). v / v Triethylamine provides ((6a) R 9 R )-5-bromo-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl)((2 S 4 S )-2,4-dimethylazazole-1-yl)methyl ketone (47) is a grayish-white amorphous solid.

[0652] Yield: 5.2 mg (61%).

[0653] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0654] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.99 min.

[0655] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 442.0 ( 79 Br, M+1), 444.0 ( 81 Br, M+1).

[0656] ((6a) R 9 R )-5-bromo-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl)((2 S 4 S 2,4-Dimethylazonylbut-1-yl) methyl ketone (47, 5.2 mg, 11.7 µmol) was dissolved in a gradient of methanol (5.0 mL) and precipitated with 2N... d -Tartrate aqueous solution (5.9 µL, 5.9 µmol) was used for treatment. The resulting mixture was stirred at room temperature for 5 min, and then the solvent was removed under vacuum to produce ((6a) R 9 R )-5-bromo-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg Quinoline-9-yl)((2 S 4 S 2,4-Dimethylazonylbutan-1-yl)methyl ketone hemitartaric acid salt (47 hemitartaric acid salt) is a grayish-white solid.

[0657] Yield: 6.05 mg (quantitative).

[0658] 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).

[0659] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0660] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.99 min.

[0661] LC-MS m / z (ESI+, cone voltage 30V, centroid mode): 442.0 ( 79 Br, M+1), 444.0 ( 81 Br, M+1).

[0662] Example 39: Preparation of (6aR,9R)-N,N-diethyl-7-(4-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (49) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol tartrate) with 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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 1 hour, the reaction was allowed to rise to room temperature and stirred for another 4 days. Silica gel (4.0 g) and trimethylamine (100 µL) were added, and the solvent was removed under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol = 98:2) to provide (6aR,9R)-N,N-diethyl-7-(4-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (49), as a colorless, glassy solid.

[0663] Yield: 17.3 mg (80%).

[0664] 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).

[0665] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0666] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.26 min.

[0667] LC-MS m / z: 418.1 (M+H) + .

[0668] (6aR,9R)-N,N-diethyl-7-(4-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (49, 17.3 mg, 41.4 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6aR,9R)-N,N-diethyl-7-(4-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartarate (49 hemitartarate), a fluffy white solid.

[0669] Yield: 20.4 mg (quantitative).

[0670] 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).

[0671] LC-MS purity: 98% (ELSD), 96% (UV, 310 nm).

[0672] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.26 min.

[0673] LC-MS m / z: 418.1 (M+H) + .

[0674] Example 40: Preparation of (6aR,9R)-7-(4-chlorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (50) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol 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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 1 hour, the reaction was allowed to rise to room temperature and stirred for another 4 days. Silica gel (4.0 g) and trimethylamine (100 µL) were added, and the solvent was removed under vacuum. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia = 98:2:0.1) to provide (6aR,9R)-7-(4-chlorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (50), as a colorless, glassy solid.

[0675] Yield: 19.2 mg (85%).

[0676] 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).

[0677] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0678] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.49 min.

[0679] LC-MS m / z: 434.1 (M+H) + .

[0680] (6aR,9R)-7-(4-chlorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (50, 19.2 mg, 44.2 µmol) was dissolved in a gradient of 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, and the resulting material was redissolved in dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6aR,9R)-7-(4-chlorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartarate (50 hemitartarate), a fluffy white solid.

[0681] Yield: 22.4 mg (quantitative).

[0682] 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).

[0683] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.49 min.

[0684] LC-MS m / z: 434.1 (M+H) + .

[0685] Example 41: Preparation of (6aR,9R)-N,N-diethyl-7-(pyridin-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (51) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 30.0 mg, 78.0 µmol; 2 mol Int7 / mol tartrate) with isonicoaldehyde (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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 1 hour, the reaction was allowed to rise to room temperature and stirred for another 4 days. Silica gel (4.0 g) and triethylamine (100 µL) were added, and the solvent was removed under reduced pressure. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia = 98:2:0.1) to provide (6aR,9R)-N,N-diethyl-7-(pyridin-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (51) as a colorless, glassy solid (yield: 27.2 mg, 87%).

[0686] LC-MS purity: 95.5% (ELSD), 92.5% (UV, 310 nm).

[0687] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.54 min.

[0688] LC-MS m / z: 401.1 (M+H) + .

[0689] (6aR,9R)-N,N-diethyl-7-(pyridin-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (51, 27.2 mg, 68.0 µmol) was dissolved in a gradient of methanol (5.0 mL) and treated with an aqueous solution of D-(-)-tartaric acid (1.0 M, 68.0 µL, 68.0 µmol). The solvent was removed under reduced pressure, and the resulting material was redissolved in 1,4-dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6aR,9R)-N,N-diethyl-7-(pyridin-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide tartrate (51 tartrate), a fluffy grayish-white solid (yield: 37.4 mg, quantified).

[0690] 1 H 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).

[0691] LC-MS purity: 95.5% (ELSD), 92.5% (UV, 310 nm).

[0692] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.54 min.

[0693] LC-MS m / z: 401.1 (M+H) + .

[0694] Example 42: Preparation of (6aR,9R)-N,N-diethyl-7-(pyridin-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (55) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 30.0 mg, 78.0 µmol; 2 mol Int7 / mol tartrate) and nicotinic acid (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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 1 hour, the reaction was allowed to rise to room temperature and stirred for another 4 days. Silica gel (4.0 g) and triethylamine (100 µL) were added, and the solvent was removed under reduced pressure. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia = 98:2:0.1) to provide (6aR,9R)-N,N-diethyl-7-(pyridin-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (55) as a colorless, glassy solid (yield: 7.1 mg, 23%).

[0695] LC-MS purity: 96% (ELSD), 95% (UV, 310 nm).

[0696] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.49 min.

[0697] LC-MS m / z: 401.1 (M+H) + .

[0698] (6aR,9R)-N,N-diethyl-7-(pyridin-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (55, 7.1 mg, 17.7 µmol) was dissolved in a gradient of methanol (5.0 mL) and treated with an aqueous solution of D-(-)-tartaric acid (1.0 M, 17.8 µL, 17.8 µmol). The solvent was removed under reduced pressure, and the resulting material was redissolved in 1,4-dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6aR,9R)-N,N-diethyl-7-(pyridin-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide tartrate (55 tartrate), a fluffy grayish-white solid (yield: 9.7 mg, quantified).

[0699] 1 H 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).

[0700] LC-MS purity: 96% (ELSD), 95% (UV, 310 nm).

[0701] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.49 min.

[0702] LC-MS m / z: 401.1 (M+H) + .

[0703] Example 43: Preparation of (6aR,9R)-N,N-diethyl-7-(3-(methoxy-d3)benzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (56) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol 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 cyanoborohydride (13.1 mg, 0.208 mmol) was added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 1 hour, the reaction was allowed to rise to room temperature and stirred for another 20 hours. Silica gel (4.0 g) and triethylamine (100 µL) were added, and the solvent was removed under reduced pressure. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia = 98:2:0.1) to provide (6aR,9R)-N,N-diethyl-7-(3-(methoxy-d3)benzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (56) as a colorless, glassy solid (yield: 10.0 mg, 45%).

[0704] 1 H 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, 6.5 Hz, 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, 7.1Hz, 6H).

[0705] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0706] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.21 min.

[0707] LC-MS m / z: 433.2 (M+H) + .

[0708] (6aR,9R)-N,N-diethyl-7-(3-(methoxy-d3)benzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (56, 10.0 mg, 23.1 µmol) was dissolved in a gradient of methanol (5.0 mL) and treated with an aqueous solution of D-(-)-tartaric acid (1 M, 11.5 µL, 11.5 µmol) at room temperature. The solvent was removed under reduced pressure, and the resulting material was redissolved in 1,4-dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6aR,9R)-N,N-diethyl-7-(3-(methoxy-d3)benzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartarate (56 hemitartarate), a fluffy white solid.

[0709] Yield: 11.6 mg (quantitative).

[0710] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0711] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.21 min.

[0712] LC-MS m / z: 433.2 (M+H) + .

[0713] Example 44: Preparation of (6aR,9R)-N,N-diethyl-7-(4-fluoro-3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (60) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol 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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 1 hour, the reaction was allowed to rise to room temperature and stirred for another 20 hours. Silica gel (4.0 g) and triethylamine (100 µL) were added, and the solvent was removed under reduced pressure. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia = 98:2:0.1) to provide (6aR,9R)-N,N-diethyl-7-(4-fluoro-3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (60) as a colorless, glassy solid (yield: 14.8 mg, 64%).

[0714] 1 H 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 = 7.1Hz, 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).

[0715] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0716] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.25 min.

[0717] LC-MS m / z: 448.1 (M+H) + .

[0718] (6aR,9R)-N,N-diethyl-7-(4-fluoro-3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (60, 14.8 mg, 33.0 µmol) was dissolved in a gradient of methanol (5.0 mL) and treated with an aqueous solution of D-(-)-tartaric acid (1 M, 16.5 µL, 16.5 µmol). The solvent was removed under reduced pressure, and the resulting material was redissolved in 1,4-dioxane (5.0 mL) and freeze-dried at 0 °C to produce (6aR,9R)-N,N-diethyl-7-(4-fluoro-3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartarate (60 hemitartarate), a fluffy white solid (yield: 17.3 mg, quantified).

[0719] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0720] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.25 min.

[0721] LC-MS m / z: 448.1 (M+H) + .

[0722] Example 45: Preparation of (6aR,9R)-N,N-diethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (62) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol 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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 1 hour, the reaction was allowed to rise to room temperature and stirred for another 20 hours. Silica gel (4.0 g) and triethylamine (100 µL) were added, and the solvent was removed under reduced pressure. The residue was purified by rapid column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol / ammonia = 98:2:0.1) to provide (6aR,9R)-N,N-diethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (62) as a colorless, glassy solid (yield: 16.5 mg, 76%).

[0723] 1 H 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).

[0724] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0725] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.54 min.

[0726] LC-MS m / z: 416.1 (M+H) + .

[0727] (6aR,9R)-N,N-diethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (16.5 mg, 39.7 µmol) was dissolved in a gradient of methanol (5.0 mL) and treated with an aqueous solution of D-(-)-tartaric acid (1 M, 19.9 µL, 19.9 µmol). The solvent was removed under reduced pressure, and the resulting material was redissolved in 1,4-dioxane (5.0 mL) and lyophilized at 0 °C to produce (6aR,9R)-N,N-diethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartarate (62), a fluffy white solid (yield: 19.5 mg, quantified).

[0728] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0729] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.54 min.

[0730] LC-MS m / z: 416.1 (M+H) + .

[0731] Example 46: Preparation of (6aR,9R)-N-ethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (63) Reaction scheme: Synthesis experimental protocol: (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylic acid (Int 1,520 mg, 1.94 mmol) was suspended in dimethylformamide (50 mL). Then, ethylammonium chloride (629 mg, 7.75 mmol), triethylamine (1.62 mL, 11.6 mmol), and propanephosphonic anhydride / 2-MeTHF (T3P) were added to the reaction mixture. ® (50% solution, 4.74 mL, 7.75 mmol). 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% sodium carbonate aqueous solution (100 mL). The aqueous layer was extracted with 2-MeTHF (50 mL). The combined organic phases were washed with 5% lithium chloride aqueous solution (100 mL × 3) and concentrated with silica gel (0.2 mm, 3 g). The crude product was purified by rapid column chromatography (SiliaSphere silica gel 60 Å, 50 μm, eluent: dichloromethane / methanol + 0.1% ammonia 100:0 to 95:5) to provide (6aR,9R)-N-ethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int25) as a colorless foam (yield: 330 mg, 58%).

[0732] 1 H NMR (500 MHz, MeOD, δ H ): 7.19 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.2Hz, 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).

[0733] LC-MS purity: 100% (ELSD), 100% (UV, 310 nm).

[0734] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 3.89 min.

[0735] LC-MS m / z: 296.1 (M+H) + .

[0736] (6aR,9R)-N-ethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int25, 290 mg, 0.949 mmol) was dissolved in dichloromethane (27 mL) and cooled to 0 °C. m-chloroperoxybenzoic acid (77% purity, 213 mg, 0.949 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour. The mixture was then evaporated, and the crude residue was redissolved in 90% methanol aqueous solution (50 mL). Ferric sulfate heptahydrate was added, and the reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The resulting material was partitioned between 2-MeTHF (100 mL) and 1M EDTA aqueous solution. The separated phase was basified with ethylenediamine and extracted with additional 2-MeTHF (3 × 100 mL). The combined organic extracts were evaporated and purified by rapid column chromatography (SiliaSphere silica gel 60 Å, 50 μm, eluent: dichloromethane / methanol + 0.1% ammonia 100:0 to 90:10) to provide (6aR,9R)-N-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int26) as a colorless film (yield: 36 mg, 13%).

[0737] 1 H NMR (500 MHz, MeOD, δ H): 7.19 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.1Hz, 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).

[0738] LC-MS purity: 99% (ELSD), 99% (UV, 310 nm).

[0739] LC-MS m / z: 182.1 (M+H) + .

[0740] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 3.76 min.

[0741] (6aR,9R)-N-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int26, 18 mg, 64.0 µmol) was dissolved in methanol (1 mL) at room temperature, followed by the addition of 3-methoxybenzaldehyde (30 μL, 196 µmol) and sodium cyanoborohydride (15 mg, 238 µmol). Acetic acid (25 μL) was added after 5 minutes. After stirring for 3 hours, another portion of 3-methoxybenzaldehyde (15 μL, 98.4 µmol) was added, and the reaction mixture was stirred overnight at room temperature. Volatiles were removed under reduced pressure, and the resulting residue was redissolved in aqueous hydrochloric acid (1 M, 20 mL). The aqueous phase was washed with diethyl ether (3 × 20 mL). The aqueous phase was then alkalized with 20% sodium hydroxide aqueous solution and extracted with 2-MeTHF (3 × 50 mL). The combined organic extracts were dried over magnesium sulfate and evaporated to dryness. The residues were purified by rapid column chromatography (SiliaSphere silica gel 60 Å, 50 μm, eluent: dichloromethane / methanol + 0.1% ammonia 100:0 to 97:3). The resulting material was further purified by preparative high-performance liquid chromatography (Synergi 4 µm Polar-RP 80 Å, LC column 100 x 21.2 mm, acetonitrile / water 30:70 to 100:0 + 0.1% acetic acid). The combined fractions were desolventized under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to produce (6aR,9R)-N-ethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (63), as a white, fluffy foam (yield: 13.0 mg, 51%).

[0742] 1 H 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).

[0743] LC-MS purity: 98.5% (ELSD), 100.0% (UV, 310 nm).

[0744] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.96 min.

[0745] LC-MS m / z: 401.51 (M+H) + .

[0746] Example 47: Preparation of (6aR,9R)-N-ethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (64) Reaction scheme: Synthesis experimental protocol: (6aR,9R)-N-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int26, 18 mg, 64.0 µmol) was dissolved in methanol (1 mL) at room temperature, followed by the addition of 3-hydroxybenzaldehyde (30 μL, 169 µmol) and sodium cyanoborohydride (15 mg, 238 µmol). Acetic acid (25 μL) was added after 5 minutes. After stirring for 3 hours, another portion of 3-hydroxybenzaldehyde (15 μL, 98.3 µmol) was added, and the reaction mixture was stirred overnight. Volatiles 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). The aqueous phase was then alkalized to pH 8 with 20% sodium hydroxide solution and extracted with 2-MeTHF (3 × 50 mL). The combined 2-MeTHF phases were dried over magnesium sulfate and evaporated to dryness. The residues were purified by preparative high-performance liquid chromatography (Synergi 4 µm Polar-RP 80 Å, LC column 100 x 21.2 mm, acetonitrile / water 30:70 to 100:0 + 0.1% acetic acid). The resulting fractions were combined, concentrated, and the material was lyophilized from tert-butanol to provide (6aR,9R)-N-ethyl-7-(3-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (64), as a white, fluffy foam (yield: 10.0 mg, 40%).

[0747] 1 H 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 = 7.2Hz, 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).

[0748] LC-MS purity: 93.0% (ELSD), 100.0% (UV, 310 nm).

[0749] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.41 min.

[0750] LC-MS m / z: 388.3 (M+H) + .

[0751] Example 48: Preparation of (6aR,9R)-N,N-diethyl-7-(isoxazo-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (70) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int7, 19.0 mg, 61.5 µmol) and isoxazol-3-carboxaldehyde (25.4 mg, 185 µmol) in methanol (2 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (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 was allowed to rise to room temperature and stirred for another 20 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 2% aqueous acetic acid (100 mL) and purified by preparative high-performance liquid chromatography (Synergi 4 µm Polar-RP 80 Å, LC column 100 x 21.2 mm, acetonitrile / water 30:70 to 100:0 + 0.1% acetic acid). The combined fractions were solvent removed under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to produce (6aR,9R)-N,N-diethyl-7-(isoxazo-3-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (70), as a grayish-white, fluffy solid (yield: 21.2 mg, 88%).

[0752] 1 H 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).

[0753] LC-MS purity: 99.9% (ELSD), 99.9% (UV, 310 nm).

[0754] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.27 min.

[0755] LC-MS m / z: 391.2 (M+H) + .

[0756] Example 49: Preparation of (6aR,9R)-N,N-diethyl-7-(oxazol-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (73) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int7, 19.0 mg, 61.5 µmol) and oxazol-4-carboxaldehyde (25.4 mg, 185 µmol) in methanol (2 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (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 was allowed to rise to room temperature and stirred for another 20 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 2% aqueous acetic acid (100 mL) and purified by preparative high-performance liquid chromatography (Synergi 4 µm Polar-RP 80 Å, LC column 100 x 21.2 mm, acetonitrile / water 30:70 to 100:0 + 0.1% acetic acid). The combined fractions were solvent removed under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to produce (6aR,9R)-N,N-diethyl-7-(oxazol-4-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (73), as a grayish-white, fluffy solid (yield: 13.0 mg, 54%).

[0757] 1 H 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 = 14.9Hz, 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 = 7.1Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).

[0758] LC-MS purity: 98% (ELSD), 98% (UV, 310 nm).

[0759] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 4.95 min.

[0760] LC-MS m / z: 391.1 (M+H) + .

[0761] Example 50: Preparation of (6aR,9R)-N,N-diethyl-7-(3-cyanobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (76) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 20.0 mg, 52.0 µmol; 2 mol Int7 / mol 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 added, and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 µL). After stirring at 0 °C for 1 hour, the reaction was allowed to rise to room temperature and stirred for another 20 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 2% aqueous acetic acid (100 mL) and purified by preparative high-performance liquid chromatography (Synergi 4 µm Polar-RP 80 Å, LC column 100 x 21.2 mm, acetonitrile / water 30:70 to 100:0 + 0.1% acetic acid). The combined fractions were solvent removed under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to produce (6aR,9R)-N,N-diethyl-7-(3-cyanobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (76), as a grayish-white, fluffy solid (yield: 21.2 mg, 88%).

[0762] 1 H 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, 0.8Hz, 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 = 10.5Hz, 1H), 1.13 (td, J = 7.1, 2.5 Hz, 6H).

[0763] LC-MS purity: 99.9% (ELSD), 99.9% (UV, 310 nm).

[0764] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.91 min.

[0765] LC-MS m / z: 425.2 (M+H) + .

[0766] Example 51: Preparation of (6aR,9R)-N,N-diethyl-7-((2-methoxypyridin-4-yl)methyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (79) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int7, 19.0 mg, 61.5 µmol) and 2-methoxyisononial (25.0 mg, 185 µmol) in methanol (2 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (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 was allowed to rise to room temperature and stirred for another 20 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 2% aqueous acetic acid (100 mL) and purified by preparative high-performance liquid chromatography (Synergi 4 µm Polar-RP 80 Å, LC column 100 x 21.2 mm, acetonitrile / water 30:70 to 100:0 + 0.1% acetic acid). The combined fractions were then removed from the solvent under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to produce (6aR,9R)-N,N-diethyl-7-((2-methoxypyridin-4-yl)methyl)-4,6,6a,7,8,9-hexahydroindololo[4,3-fg]quinoline-9-carboxamide (79), as a grayish-white, fluffy solid (yield: 18.2 mg, 69%).

[0767] 1 H 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).

[0768] LC-MS purity: 99.9% (ELSD), 99.9% (UV, 310 nm).

[0769] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 5.60 min.

[0770] LC-MS m / z: 431.2 (M+H) + .

[0771] Example 52: Preparation of (6aR,9R)-7-benzyl-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (82) Reaction scheme: Synthesis experimental protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartaric acid (Int7, 16.0 mg, 42.0 µmol; 2 mol Int7 / mol tartrate) and benzaldehyde (19 µL, 185 µmol) in methanol (2 mL) was purged with argon and cooled to 0 °C. Sodium cyanoborohydride (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 was allowed to rise to room temperature and stirred for another 20 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 2% aqueous acetic acid (100 mL) and purified by preparative high-performance liquid chromatography (Synergi 4 µm Polar-RP 80 Å, LC column 100 x 21.2 mm, acetonitrile / water 30:70 to 100:0 + 0.1% acetic acid). The combined fractions were then removed from the solvent under reduced pressure, redissolved in tert-butanol, and lyophilized under reduced pressure to produce (6aR,9R)-7-benzyl-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (82), as a grayish-white, fluffy solid (yield: 12.2 mg, 71%).

[0772] 1 H 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).

[0773] LC-MS purity: 99.9% (ELSD), 99.9% (UV, 310 nm).

[0774] LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA in 10 min): 6.06 min.

[0775] LC-MS m / z: 400.2 (M+H) + .

[0776] Example 53: Compound prepared according to general synthetic scheme 1 General synthesis scheme 1: General Synthesis Experimental Scheme 1: Step 1 – Preparation of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m) and the pure diastereomer (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83) At 0 °C, diethylamine (3.99 g, 54.49 mmol) was added to a stirred solution of (6aR)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylate (Int27m; 5.0 g, 18.16 mmol, dr 1:1; Fehr, T., Stadler, PA, Hofmann, A. HelveticaChimica Acta, 1970, 53(8), 2197-2201) in anhydrous DMF (80 mL), followed by propylphosphonic 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 min, slowly heated to room temperature, and stirred for 5 h. Through LC-MS and TLC(R) f = 0.5; 10% MeOH / DCM) to monitor the reaction. After completion, the reaction mixture was concentrated under reduced pressure and purified by rapid column chromatography (silica gel 60-120, eluent: 5-10% MeOH / DCM (0.1% methanol-ammonia additive)) to provide (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m), a pale reddish-brown solid (3 g, 89% LC-MS purity), 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-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83) was separated from the mixture by column chromatography (SiliCycle Silia Sphere PC60A, 50 µm; eluent: dichloromethane / methanol / ammonia 99:1:0.01 to 90:10:0.1) to obtain a grayish-white solid. 1HNMR (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, 6.9Hz, 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).

[0777] Step 2 – Reductive amination at 83m to provide diastereomer 1 and diastereomer 2 A suitable aldehyde (2 equivalents) was added to a stirred solution of crude (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 1 eq) in methanol (30 mL). The reaction mixture was purged with nitrogen for 5 min. The reaction mixture was cooled to 0 °C, and sodium cyanoborohydride (3 equivalents) was added, followed by acetic acid (2 equivalents). The reaction mixture was heated to room temperature and stirred until complete. The final product was analyzed by LC-MS and TLC (R f = 0.5; 10% MeOH / DCM) to monitor the reaction. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude product in the form of a mixture of diastereomers, which was purified by preparative high performance liquid chromatography to provide diastereomer 1 and diastereomer 2.

[0778] Preparation of compounds: (6aR,9R)-N,N-diethyl-7-(3-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (52) & (6aR,9S)-N,N-diethyl-7-(3-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (52a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 300 mg, 0.97 mmol) according to the general procedure (step 2); the diastereomers were separated by preparative high performance liquid chromatography: column: X Bridge C8 (19 mm x 250 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; gradient of 30-98%, run for 18 minutes; flow rate: 18 mL / min.

[0779] (6aR,9R)-N,N-diethyl-7-(3-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (52) Yield: 65 mg, 16%, grayish-white solid.

[0780] 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35 ℃. Rt = 2.29 min (minor), 3.39 min (major).

[0781] (6aR,9S)-N,N-Diethyl-7-(3-fluorobenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide(52a) Yield: 20 mg, 5%, grayish-white solid.

[0782] 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO₂, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35 ℃. Rt = 2.22 min (primary), 3.41 min (secondary).

[0783] Preparation of (6aR,9R)-7-(3,4-difluorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (54) & (6aR,9S)-7-(3,4-difluorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (54a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 200 mg, 0.65 mmol) according to the general procedure (step 2); the diastereomers were separated by preparative high performance liquid chromatography: column: X Bridge C8 (19 mm x 250 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 47-98% gradient, 21 min run; flow rate: 18 mL / min.

[0784] (6aR,9R)-7-(3,4-difluorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (54) Yield: 21 mg, 7.46%, grayish-white solid.

[0785] LC-MS: m / z: 436.40 [M+H] + ; 1H 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35 ℃. Rt = 2.16 min (minor), 4.06 min (major).

[0786] (6aR,9S)-7-(3,4-difluorobenzyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide(54a) Yield: 4 mg, 1.42%, grayish-white solid.

[0787] 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 1.04 (t, J = 7.0 Hz, 3H). Enantiomer excess (98.2%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35 ℃. Rt = 2.32 min (major), 4.07 min (minor).

[0788] Preparation of (6aR,9R)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d2)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (68) & (6aR,9S)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d2)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (68a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 140 mg, 0.45 mmol) according to a general procedure (step 2) using m-methoxybenzaldehyde, NaCNBD3, CH3COOD, and CH3OD. The diastereomers were separated by preparative high-performance liquid chromatography: column: X Bridge C8 (19 mm x 250 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 20-98% gradient, 25 min run; flow rate: 18 mL / min.

[0789] (6aR,9R)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d2)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (68) Yield: 36 mg, 18.44%, grayish-white solid.

[0790] 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). Enantiomer excess (98.7%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35 ℃. Rt = 2.65 min (minor), 3.51 min (major).

[0791] (6aR,9S)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d2)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide(68a) Yield: 25 mg, 12.8%, grayish-white solid.

[0792] LC-MS: m / z: 432.5 [M+H] +; 1H 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, 2.6Hz, 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). Enantiomer excess (94.34%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35 ℃. t =2.54 min (primary), 3.50 min (secondary).

[0793] Preparation of (6aR,9R)-N,N-diethyl-7-(oxazol-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (74) Synthesized from (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83) according to the general procedure (step 2) (yield: 28.1 mg, 75%, fluffy white solid).

[0794] LC-MS: m / z: 391.4 [M+H] + ; 1H NMR (500 MHz, MeOD): δ = 7.90 (d, J = 0.8Hz, 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 (t, J = 10.8 Hz, 1H), 2.92 (t, J = 10.8 Hz, 1H), 2.71 (tdd, 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: XBridge C18 (4.6 mm x 100 mm, 5 µM); Mobile phase: A = acetonitrile, B = 0.1% TFA / water; 5-100% gradient. R t = 5.40 min.

[0795] Preparation of (6aR,9R)-N,N-diethyl-7-(oxazol-5-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (75) Synthesized from (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83) according to the general procedure (step 2) (yield: 29.1 mg, 77%, fluffy white solid).

[0796] 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, 5.5Hz, 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, 1H), 2.73 (ddd, J = 14.3, 11.4, 1.7 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). Column name: XBridge C18 (4.6 mm x 100 mm, 5 µM); Mobile phase: A = acetonitrile, B = 0.1% TFA / water; 5-100% gradient. R t = 5.21 min.

[0797] Preparation of (6aR,9R)-7-(cyclohexylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (89) & (6aR,9S)-7-(cyclohexylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (89a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 100 mg, 0.32 mmol) according to the general procedure (step 2); the diastereomers were separated by preparative high performance liquid chromatography: column: X Select CSH Phenyl-Hexyl (19 mm x 250 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 40-98% gradient, 16 min run; flow rate: 18 mL / min.

[0798] (6aR,9R)-7-(cyclohexylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (89) Yield: 31 mg, 23.65%, grayish-white solid.

[0799] 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 1.69 min (minor), 2.13 min (major).

[0800] (6aR,9S)-7-(cyclohexylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (89a) Yield: 40 mg, 30.52%, grayish-white solid.

[0801] LC-MS: m / z: 406.25 [M+H] + ; 1H 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 1.63 min (major), 2.13 min (minor).

[0802] Preparation of (6aR,9R)-7-(cyclopentylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (90) & (6aR,9S)-7-(cyclopentylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (90a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 200 mg, 0.65 mmol) according to the general procedure (step 2); the diastereomers were separated by preparative high performance liquid chromatography: column: X Select CSH Phenyl-Hexyl (19 mm x 250 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 40-98% gradient, 16 min run; flow rate: 18 mL / min.

[0803] (6aR,9R)-7-(cyclopentylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (90) Yield: 35 mg, 13.83%, grayish-white solid.

[0804] 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), 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 1.69 min (minor), 2.04 min (major).

[0805] (6aR,9S)-7-(cyclopentylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (90a) Yield: 41 mg, 16.20%, grayish-white solid.

[0806] LC-MS: m / z: 392.35 [M+H] + ; 1H 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). Enantiomeric excess (91.56%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 1.65 min (major), 2.05 min (minor).

[0807] Preparation of (6aR,9R)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (96) & (6aR,9S)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (96a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 100 mg, 0.32 mmol) according to the general procedure (step 2) (using NaCNBD3, CH3COOD and CH3OD); the diastereomers were separated by preparative high performance liquid chromatography: column: X Bridge C8 (19 mm x 250 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 30-98% gradient, 19 min run; flow rate: 18 mL / min.

[0808] (6aR,9R)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (96) Yield: 30 mg, 21.56%, grayish-white solid.

[0809] LC-MS: m / z: 431.3 [M+H] + ; 1 H 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). Enantiomer excess (98.58%) was determined by chiral SFC analysis. Column: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 ml / min; Column temperature: 35 ℃. t =2.70 min (minor), 3.60 min (major).

[0810] (6aR,9S)-N,N-diethyl-7-((3-methoxyphenyl)methyl-d)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide(96a) Yield: 20 mg, 14.37%, grayish-white solid.

[0811] 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, 8.1Hz, 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). Enantiomer excess (95.18%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. R t =2.58 min (primary), 3.60 min (secondary).

[0812] Preparation of (6aR,9R)-N,N-diethyl-7-(4-methylbenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (97) & (6aR,9S)-N,N-diethyl-7-(4-methylbenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (97a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 300 mg, 0.97 mmol) according to the general procedure (step 2); the diastereomers were separated by preparative high performance liquid chromatography: column: Gemini NX C18 (21.1 mm x 150 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 10-98% gradient, 18 min run; flow rate: 18 mL / min.

[0813] (6aR,9R)-N,N-diethyl-7-(4-methylbenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (97) Yield: 25 mg, 6.23%, grayish-white solid.

[0814] 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). Enantiomer excess (96%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. t =2.50 min (primary), 3.20 min (secondary).

[0815] (6aR,9S)-N,N-diethyl-7-(4-methylbenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (97a) Yield: 44 mg, 11%, grayish-white solid.

[0816] LC-MS: m / z: 414.2 [M+H] + ; 1H 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). Enantiomer excess (96%) was determined by chiral SFC analysis. Column: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. t =2.36 min (minor), 3.10 min (major).

[0817] Preparation of (6aR,9R)-N,N-diethyl-7-(3-methylbenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (98) & (6aR,9S)-N,N-diethyl-7-(3-methylbenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (98a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 300 mg, 0.97 mmol) according to the general procedure (step 2); the diastereomers were separated by preparative high performance liquid chromatography: column: Gemini NX C18 (21.1 mm x 150 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 10-98% gradient, 18 min run; flow rate: 18 mL / min.

[0818] (6aR,9R)-N,N-diethyl-7-(3-methylbenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (98) Yield: 42 mg, 10.47%, grayish-white solid.

[0819] 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 (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 2.29 min (minor), 3.06 min (major).

[0820] (6aR,9S)-N,N-diethyl-7-(3-methylbenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (98a) Yield: 15 mg, 3.74%, grayish-white solid.

[0821] LC-MS: m / z: 414.30 [M+H] + ; 1H 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). Enantiomer excess (96.36%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 2.21 min (major), 3.05 min (minor).

[0822] Preparation of (6aR,9R)-N,N-diethyl-7-(naphth-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (100) & (6aR,9S)-N,N-diethyl-7-(naphth-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (100a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 300 mg, 0.97 mmol) according to the general procedure (step 2); the diastereomers were separated by preparative high performance liquid chromatography: column: X Bridge C8 (19 mm x 250 mm, 5 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 40-98% gradient, 23 min run; flow rate: 18 mL / min.

[0823] (6aR,9R)-N,N-diethyl-7-(naphth-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide(100) Yield: 27 mg, 6.19%, grayish-white solid.

[0824] 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 6.43 min (minor), 8.03 min (major).

[0825] (6aR,9S)-N,N-Diethyl-7-(naphth-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide(100a) Yield: 9 mg, 2%, grayish-white solid.

[0826] LC-MS: m / z: 450.25 [M+H] + ; 1H 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 6.50 min (major), 8.13 min (minor).

[0827] Preparation of (6aR,9R)-N,N-diethyl-7-(naphth-1-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (101) & (6aR,9S)-N,N-diethyl-7-(naphth-1-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (101a) The diastereomers were synthesized from (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (83m; 300 mg, 0.97 mmol) according to the general procedure (step 2); the diastereomers were separated by preparative high performance liquid chromatography: column: X Bridge C8 (19 mm x 250 mm, 10 μM); mobile phase: 5 mM ammonium bicarbonate aqueous solution / acetonitrile; 15-98% gradient, 16.5 min run; flow rate: 18 mL / min.

[0828] (6aR,9R)-N,N-diethyl-7-(naphth-1-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (101) Yield: 12 mg, 2.75%, grayish-white solid.

[0829] LC-MS: m / z: 450.20 [M+H] + ; 1 H 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 (d, J = 13.6 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). Enantiomer excess (>99%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35℃. Rt = 4.89 min (minor), 7.14 min (major).

[0830] (6aR,9S)-N,N-diethyl-7-(naphth-1-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (101a) Yield: 15 mg, 3.44%, grayish-white solid.

[0831] 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). Enantiomer excess (95.9%) was determined by chiral SFC analysis. Column name: Chiralpak IJ (250 mm x 4.6 mm, 5 μM); Mobile phase: A = CO2, B = 0.2% diethylamine / MeOH (60:40); Flow rate: 3.0 mL / min; Column temperature: 35 ℃. Rt = 4.91 min (primary), 7.17 min (secondary). [...

Claims

1. A compound of Formula (I): ###0001### or a pharmaceutically acceptable salt thereof, wherein (I)， wherein the C1-C4 alkyl in -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl is optionally substituted with one or more fluoro, hydroxy, or -OMe, and 2. The compound of claim 1, wherein R 1 is Ci-C6alkyl or 3-7 membered carbocyclyl, wherein R 1 is optionally substituted with one or more halogen or Ci-C6alkyl; R 2 is hydrogen or Ci-C6alkyl, wherein R 2 optionally substituted with one or more halogen or Ci-C6alkyl; or wherein R 1 and R 2 may form, together with the atom to which they are attached, an optionally substituted 3-7 membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more fluoro or Ci-C6alkyl; R 3 selected from C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CH2- (cyclopropyl), and 3- to 7-membered cycloalkyl, wherein R 3 optionally substituted with one or more substituents each independently selected from the group consisting of fluoro, hydroxy, and -OMe; or R 3 selected from -(Ci-C4alkyl)-aryl and -(Ci-C4alkyl)-heteroaryl, or wherein the aryl and heteroaryl groups in -(C1-C4alkyl)-aryl and -(C1-C4alkyl)- heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OR 7 , -OC(O)R 7 , -CN, -NO2, -NR 7 R 8 , -CO2R 7 , -C(O)NR 7 R 8 , C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, and R 9 , wherein each C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl is optionally substituted with one or more fluoro, hydroxy, or -OMe; wherein each R 7 and R 8 is independently selected from the group consisting of H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, and R 10 , wherein C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl is optionally substituted with one or more fluoro, hydroxy, or -OMe; and wherein each R 9 and R 10 is independently aryl or heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -OC(O)(C1-C4alkyl), -O(C1-C4alkyl), -CN, -NO2, -NH2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, and C3-C5cycloalkyl, and wherein each C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C5cycloalkyl is optionally substituted with one or more fluoro, hydroxy, or -OMe; R 4 is hydrogen or -C(O)(C1-C8alkyl); R 5 is hydrogen, Me, Et, -CH2F, -CHF2, -CF3, or halogen; R 6 is hydrogen or deuterium; provided that (a) when R 1 and R 2 are both ethyl, and R 4 and R 5 are both hydrogen, R 3 is not unsubstituted straight chain C2-C6alkyl, isopropyl, -CH2CH=CH2, -CH2CH2F, or -CH2CH2Ph; (b) When R 1 and R 2 All are ethyl, R 4 It is -C(O)(C2 alkyl), and R 5 When it is hydrogen, R 3 Not unsubstituted ethyl; and (c) when R 1 is ethyl and R 2 is H, R 3 is not unsubstituted ethyl, unsubstituted n-propyl or -CH2CH=CH2. wherein the C1-C2 alkyl in -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluoro, hydroxy, or -OMe, and R 1 is Ci-C6alkyl or 3-7 membered carbocyclyl, wherein R 1 is optionally substituted with one or more fluoro or Ci-C6alkyl; R 2 is hydrogen or Ci-C6alkyl, wherein R 2 is optionally substituted with one or more fluorine or Ci-C6alkyl; or wherein R 1 and R 2 may form, together with the atom to which they are attached, an optionally substituted 3-7 membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more fluoro or Ci-C6alkyl; R 3 selected from C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CH2- (cyclopropyl), and 3- to 7-membered cycloalkyl, wherein R 3 may be substituted with one or more substituents each independently selected from fluoro, hydroxy, and -OMe; wherein the phenyl and 6-membered heteroaryl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, and -O(C1-C3 alkyl), wherein each C1-C8 and C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and cyclopropyl is optionally substituted with one or more fluoro. R 3 selected from -(Ci-C2alkyl)-phenyl and -(Ci-C2alkyl)-(6-membered heteroaryl), 3. The compound of claim 2, wherein wherein the C1-C2 alkyl in -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluoro, and wherein the phenyl and 6-membered heteroaryl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, and -O(C1-C3 alkyl), wherein each C1-C8 and C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and cyclopropyl is optionally substituted with one or more fluoro. R 1 is Ci-C6alkyl or 3-5 membered carbocyclyl, wherein R 1 is optionally substituted with one or more fluoro or Ci-C4alkyl; R 2 is hydrogen or C1-C3alkyl, wherein R 2 is optionally substituted with one or more fluorine or C1-C4alkyl; or wherein R 1 and R 2 may form, together with the atom to which they are attached, an optionally substituted 3-6 membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more fluoro or C1-C3alkyl; R 3 selected from C2-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -CH2- (cyclopropyl), and 3- to 5-membered cycloalkyl, wherein R 3 may be substituted with one or more substituents each independently selected from the group consisting of fluoro, hydroxy, and -OMe; or R 3 selected from -(Ci-C2alkyl)-phenyl and -(Ci-C2alkyl)-(6-membered heteroaryl), wherein the C1-C4 alkyl in -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl is optionally substituted with one or more fluoro, hydroxy, or -OMe, and and 4. The compound of any one of claims 1-3, wherein R 4 is hydrogen.

5. The compound of any one of claims 1-3, wherein R 5 is hydrogen.

6. The compound according to any one of claims 1-3, wherein R 5 is Me, Et, -CH2F, -CHF2, -CF3, or halogen.

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

8. The compound of any one of claims 1-3, wherein R 6 is hydrogen.

9. The compound according to claim 1, wherein R 3 is selected from C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CH2-(cyclopropyl), and 3-7 membered cycloalkyl, wherein R 3 may be substituted with one or more substituents each independently selected from fluoro, hydroxy, and -OMe.

10. The compound of claim 1, wherein R 3 is selected from -(Ci-C4alkyl)-aryl and -(Ci-C4alkyl)-heteroaryl, wherein the C1-C2 alkyl in -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluoro, and and The aryl and heteroaryl groups in -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl are optionally substituted with one or more substituents, each of which is independently selected from 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 , where each R 7 and R 8 Independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl and R 10 And each of R 9 and R 10 It is independently aryl or heteroaryl, optionally substituted with one or more substituents selected independently from 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 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 is optionally substituted with one or more fluorine, hydroxyl or -OMe.

11. The compound of claim 1, wherein R 3 is selected from -(Ci-C2alkyl)-phenyl and -(Ci-C2alkyl)-(6-membered heteroaryl), wherein the phenyl and 6-membered heteroaryl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, and -O(C1-C3 alkyl), wherein each C1-C8 and C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and cyclopropyl is optionally substituted with one or more fluoro. ​ ​ 12. The compound of any one of claims 9-11, wherein R 4 , R 5 , and R 6 are each hydrogen.

13. The compound according to any one of claims 9-11, wherein R 4 and R 6 are each hydrogen, and R 5 is Me, Et, -CH2F, -CHF2, -CF3, or halogen.

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

15. The compound of claim 1, wherein the compound is a compound of Formula (la): (la) or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein the compound is a compound of Formula (lb), Formula (lc), Formula (Id), or Formula (le): (lb) (lc) (Id) (le) or a pharmaceutically acceptable salt thereof. wherein the C1-C4 alkyl of -(C1-C4 alkyl)-aryl and -(C1-C4 alkyl)-heteroaryl is optionally substituted with one or more fluoro, hydroxyl, or -OMe, and wherein the C1-C2 alkyl of -(C1-C2 alkyl)-aryl and -(C1-C2 alkyl)-heteroaryl is optionally substituted with one or more fluoro, hydroxyl, or -OMe, and wherein the C1-C2 alkyl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more fluoro, and 17. The compound of claim 16, wherein R 5 is hydrogen.

18. The compound of claim 16, wherein R 5 is Me, Et, or halo.

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

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

21. The compound according to any one of claims 15-20, wherein R 3 is selected from ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, and -CH2- (cyclopropyl), wherein R 3 may be substituted with one to three fluorines.

22. The compound of any one of claims 15-20, wherein R 3 is selected from ethyl, n-propyl, -CH2CH=CH2, cyclopropyl, -CH2-(cyclopropyl), -CH2CF3, -CH2CH2CH2F, and -CH2CH2CF3.

23. The compound of any one of claims 15-20, wherein R 3 is selected from -(Ci-C4alkyl)-aryl and -(Ci-C4alkyl)-heteroaryl, wherein the phenyl and 6-membered heteroaryl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, and -O(C1-C3 alkyl), wherein each C1-C8 and C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and cyclopropyl is optionally substituted with one or more fluoro. wherein the aryl and heteroaryl groups in -(C1-C4alkyl)-aryl and -(C1-C4alkyl)- heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OR 7 , -OC(O)R 7 , -CN, -NO2, -NR 7 R 8 , -CO2R 7 , -C(O)NR 7 R 8 , C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, and R 9 , wherein each R 7 and R 8 is independently selected from the group consisting of H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, and R 10 , and wherein each R 9 and R 10 is independently aryl or heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -OC(O)(C1-C4alkyl), -O(C1-C4alkyl), -CN, -NO2, -NH2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, and C3-C5cycloalkyl, and wherein each C1-C8and C1-C4alkyl, C2-C8and C2-C4alkenyl, C2-C8and C2-C4alkynyl, and C3-C8and C3-C5cycloalkyl is optionally substituted with one or more fluorine, hydroxyl, or -OMe.

24. The compound of any one of claims 15-20, wherein R 3 is selected from -(Ci-C2alkyl)-aryl and -(Ci-C2alkyl)-heteroaryl, wherein the phenyl and pyridyl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-pyridyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, and -O(C1-C3 alkyl), wherein each C1-C8 and C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, and cyclopropyl is optionally substituted with one or more fluoro.

30. A compound selected from the group consisting of: wherein the aryl and heteroaryl of -(Ci-C2alkyl)-aryl and -(Ci-C2alkyl)-heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OR 7 , -OC(O)R 7 , -CN, -NO2, -NR 7 R 8 , -CO2R 7 , -C(O)NR 7 R 8 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and R 9 wherein each R 7 and R 8 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and R 10 , and wherein each R 9 and R 10 is independently aryl or heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -OC(O)(Ci-C4 alkyl), -O(Ci-C4 alkyl), -CN, -NO2, -NH2, Ci-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C5 cycloalkyl, and wherein each Ci-C6 and Ci-C4 alkyl, C2-C6 and C2-C4 alkenyl, C2-C6 and C2-C4 alkynyl, and C3-C6 and C3-C5 cycloalkyl is optionally substituted with one or more fluorine, hydroxyl, or -OMe.

25. The compound according to any one of claims 15-20, wherein R 3 is selected from -(Ci-C2alkyl)-phenyl and -(Ci-C2alkyl)-(6-membered heteroaryl), or a pharmaceutically acceptable salt thereof.

31. The compound of claim 30, selected from the group consisting of:

26. The compound of any one of claims 15-20, wherein R 3 is selected from -(Ci-C2alkyl)-phenyl and -(Ci-C2alkyl)-pyridyl, or a pharmaceutically acceptable salt thereof.

27. The compound according to any one of claims 15-20, wherein R 3 is selected from 。 28. The compound according to any one of claims 15-20, wherein R 3 is selected from 。 29. The compound according to any one of claims 15-20, wherein R 3 is selected from 。 32. The compound of claim 30, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

33. A compound of Formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein 34. The compound of claim 33, wherein 36. The compound of claim 33, wherein the compound is a compound of Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe): or a pharmaceutically acceptable salt thereof.

40. The compound of claim 36, selected from the group consisting of: R 1 is Ci-C6alkyl or 3-7 membered carbocyclyl, wherein R 1 is optionally substituted with one or more halogen or Ci-C6alkyl; R 2 is hydrogen or Ci-C6alkyl, wherein R 2 is optionally substituted with one or more halogen or Ci-C6alkyl; or wherein R 1 and R 2 may form, together with the atom to which they are attached, an optionally substituted 3-7 membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more fluoro or Ci-C6alkyl; R 4 is hydrogen or -C(O)(C1-C8alkyl); R 5 Me, Et, -CH2F, -CHF2, -CF3, or halogen; R 6 is hydrogen or deuterium; provided that (a) when R 1 and R 2 are both ethyl, and R 4 is hydrogen, then R 5 is not chloro, bromo, iodo or unsubstituted methyl; (b) when R 2 is hydrogen, R 4 is hydrogen, and R 5 is bromo, then R 1 is not ethyl, isopropyl, or propargyl; and (c) when R 2 is methyl, R 4 is hydrogen, and R 5 is bromo, then R 1 is not propargyl or cyclopropyl. or a pharmaceutically acceptable salt thereof. R 1 is Ci-C6alkyl or 3-5 membered carbocyclyl, wherein R 1 is optionally substituted with one or more fluoro or Ci-C4alkyl; R 2 is hydrogen or C1-C3alkyl, wherein R 2 is optionally substituted with one or more fluorine or C1-C4alkyl; or wherein R 1 and R 2 may form, together with the atom to which they are attached, an optionally substituted 3-6 membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more fluoro or C1-C3alkyl.

35. The compound of claim 33 or 34, wherein R 4 and R 6 are each hydrogen.

41. A compound having the structure: or a pharmaceutically acceptable salt thereof.

37. The compound of claim 36, wherein R 5 is Me, Et, or halo.

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

39. The compound of claim 36, wherein R 5 is bromo. ​ ​ ​ ​ 42. A pharmaceutical composition comprising a compound according to claim 1, 30, 33, or 41 and a pharmaceutically acceptable adjuvant or carrier.

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

44. The method according to claim 43, wherein the mood disorder is selected from depressive disorders and bipolar and related 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 major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, disruptive mood dysregulation disorder, 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 bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar and related disorder, and bipolar and related disorder 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 obsessive-compulsive and related disorders, trauma- and stressor-related disorders, feeding and eating 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 neurocognitive disorder.

54. A method of treating a mood disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof (I) wherein R 1 is Ci-C6alkyl or 3-7 membered carbocyclyl, wherein R 1 is optionally substituted with one or more halogen or Ci-C6alkyl; R 2 is hydrogen or Ci-C6alkyl, wherein R 2 is optionally substituted with one or more halogen or Ci-C6alkyl; or wherein R 1 and R 2 may form, together with the atom to which they are attached, an optionally substituted 3-7 membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more fluoro or Ci-C6alkyl; R 3 selected from the group consisting of Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, - CH2-(cyclopropyl), and 3- to 7-membered cycloalkyl, wherein R 3 substituted with one or more substituents each independently selected from fluoro, hydroxy, and -OMe; or R 3 selected from -(Ci-C2alkyl)-phenyl and -(Ci-C2alkyl)-(6-membered heteroaryl), wherein 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, or -OMe, and wherein the phenyl and 6-membered heteroaryl of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from 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-C8alkyl); R 5 is hydrogen, Me, Et, -CH2F, CHF2, -CF3, or halogen; R 6 is hydrogen or deuterium.

55. The method according to claim 54, wherein the mood disorder is selected from depressive disorders and bipolar and related 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 of claim 54, wherein the mood disorder is selected from major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, disruptive mood dysregulation disorder, substance / drug-induced depressive disorder, and depressive disorder due to another medical condition.

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

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

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

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

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

64. The method of claim 54, wherein the mood disorder is a neurocognitive disorder.

65. The method of claim 54, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof. ​

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