Novel ergolines and methods for treating mood disorders

Abstract

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

Description

[Technical field]

[0001] Ergolines are a diverse class of alkaloids that contain the structural scaffold of the natural alkaloid ergoline.

[0002] [ka] [Background technology]

[0003] There are a significant number of ergoline compounds, including naturally occurring compounds as well as synthetic and semisynthetic chemical derivatives with similar structures. Ergolines are known to have a variety of psychotropic and physiological actions. Some ergolines inhibit serotonin 2a (5-HT 2A ) receptor agonists and / or modulators of other serotonin receptors, are known to be psychotropic, and / or induce vasoconstriction. In some cases, such compounds induce long-lasting hallucinations. Other ergolines are agonists of dopamine receptors. Perhaps the best-known ergoline is the hallucinogenic compound lysergic acid diethylamide (LSD). This compound is known to have significant effects on thinking, cognition, and behavior. However, it is currently classified as a Schedule I drug under the Controlled Substances Act due to its high potential for abuse, lack of accepted medical use, and lack of established safety. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009 [Non-Patent Document 2] Patel Steroselective Biocatalysts, Marcel Decker; New York 2000 Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there remains a need for safe and effective ergoline compounds that can be reliably used for the treatment of mood disorders. [Means for solving the problem]

[0006] The present disclosure relates to a compound of formula (I):

[0007] [ka]

[0008] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is defined herein] or a pharma- ceutically acceptable salt thereof.

[0009] Further, the disclosure includes a method of treating a mood disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). [Brief description of the drawings]

[0010] [Figure 1] Figure 1 depicts the effect of Compound 1 in the mouse head twitch response assay as quantified by the number of head twitches recorded during a 20 minute observation period. Data points represent the mean ± SEM. [Diagram 2] Figure 1 represents the immobility time in the rat forced swimming test 23.5 hours after administration of Compound 1. Data points represent the mean ± SEM. Compared to vehicle: **p<0.01, ****p<0.0001. [Diagram 3] The total number of marbles buried during a 30-minute observation period in the mouse marble burying test is presented. Data points represent the mean ± SEM. Compared to vehicle: *p<0.05, ****p<0.0001. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The features and other details of the present disclosure will now be described more specifically.Before further description of the present disclosure, certain terms used in the specification, examples and appended claims are collected here.These definitions should be read in light of the remainder of the disclosure and as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0012] definition "Treating" includes any effect, eg, alleviating, reducing, modulating, or eliminating, that results in the improvement of a condition, disease, disorder, or the like.

[0013] The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched chain hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl, respectively. 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] The term "alkenyl" as used herein is a branched or unbranched hydrocarbon group having a specified number of carbon atoms and containing at least one double bond. 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] The term "alkynyl" as used herein is a branched or unbranched hydrocarbon group having a specified number of carbon atoms and containing at least one triple bond. 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] The term "cyano," as used herein, refers to a --CN group.

[0017] The term "cycloalkyl" or "carbocyclic group" as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3 to 6, or 4 to 6 carbons, which are referred to herein as C3-C6 cycloalkyl or C4-C6 cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0018] The term “halo” or “halogen” as used herein refers to F, Cl, Br, or I.

[0019] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and in which each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, and may bear one or more substituents. 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, for example, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[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, with 6, 10, or 14 p electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of 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, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which an aromatic heterocycle is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the group or point of attachment is on the aromatic heterocycle. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0021] The term "heterocyclyl" or "heterocyclic group" is art-recognized and refers to a saturated or partially unsaturated 4- to 10-membered ring structure, including bridged or fused rings, whose ring structure contains one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring may be attached to the adjacent 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] The terms "hydroxy" and "hydroxyl" as used herein refer to an --OH group.

[0023] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals, or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0024] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is well known in the art. The composition can also contain other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0025] The term "pharmaceutical composition," as used herein, refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable carriers.

[0026] "Individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. The compounds of the present 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 farm animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated by the method of the present disclosure is preferably a mammal for which treatment of a mental disease or disorder is desired. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0027] As used herein, the term "therapeutically effective amount" refers to an amount of a subject compound that induces a biological or medical response in a tissue, system or animal (e.g., a mammal or human) that is being sought by a researcher, veterinarian, medical doctor or other clinician. The compounds of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or prophylactic effect, e.g., the amount that results in a reduction in the symptoms of a psychiatric disorder.

[0028] The term "pharmaceutically acceptable salts" as used herein refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, the salts of malic acid, oxalic acid, chloride, bromide, iodide, nitric acid, sulfuric acid, bisulfate, phosphoric acid, superphosphate, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds included in the compositions of the present invention that are acidic in nature are capable of forming base 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 included in the compositions of the present invention that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure can also contain both acidic and basic groups, for example, one amino and one carboxylic acid group. In such cases, the compound can exist as an acid addition salt, a zwitterion, or a base salt. In some embodiments, the term "pharmaceutically acceptable salt" as used herein refers to a hemitartrate salt. As used herein, a hemitartrate salt of a compound of formula (I) is a salt of a compound of formula (I) with a molar ratio of 2:1 to tartaric acid. In some embodiments, the term "pharmaceutically acceptable salt" as used herein refers to a tartrate salt. As used herein, a tartrate salt of a compound of formula (I) is a salt of a compound of formula (I) with a molar ratio of 1:1 to tartaric acid.

[0029] The compounds of the present disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. The term "stereoisomers" as used herein consists of all enantiomers or diastereomers. These compounds may also be designated with the symbols "(+)", "(-)", "R" or "S" depending on the configuration of the substituents around the stereogenic carbon atom, and those of skill in the art will recognize that the structure may implicitly represent a chiral center. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated in the nomenclature as "(±)", and those of skill in the art will recognize that the structure may implicitly represent a chiral center.

[0030] The compounds of the present disclosure may contain one or more double bonds and therefore may exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.

[0031] [ka]

[0032] represents a bond which may be a single bond, double bond or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans", where "cis" refers to the substituent on the same side as the double bond and "trans" refers to the substituent on the opposite side of the double bond.

[0033] The compounds of the present disclosure contain carbocyclic or heterocyclic rings and therefore can exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents around a carbocyclic or heterocyclic ring can also be referred to as "cis" or "trans", with the term "cis" meaning the substituents on the same side of the plane of the ring and the term "trans" meaning the substituents on opposite sides of the plane of the ring. Mixtures of compounds in which the substituents are arranged on both the same and opposite sides of the plane of the ring are designated as "cis / trans".

[0034] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared by synthesis from commercially available starting materials containing asymmetric or stereocenters, or by preparation of racemic mixtures followed by separation methods well known to those skilled in the art. These separation methods are exemplified by: (1) binding of the mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure products from the auxiliary; (2) formation of salts utilizing optically active resolving agents; (3) direct separation of the mixture of optical enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be separated into their component enantiomers by well known methods, such as chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the generation of new stereocenters or during the conversion of pre-existing ones, are well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0035] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, etc., and the disclosure is intended to encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0036] The present disclosure also encompasses isotopically labeled compounds of the present disclosure identical to those enumerated herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 For example, the compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0037] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Additionally, heavier isotopes such as deuterium (i.e., 2H) may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability and may therefore be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures similar to those disclosed in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0038] I. Compound In some embodiments, the present disclosure provides a compound of formula (I):

[0039] [ka]

[0040] [In the formula, R 1 is C1-C6 alkyl or 3- to 7-membered carbocyclyl, R 1 is optionally substituted with one or more halogen or C1-C6 alkyl; R 2 is hydrogen or C1-C6 alkyl, R 2 is optionally substituted with one or more halogen or C1-C6 alkyl; or R 1 and R 2 can be taken together with the atom to which they are attached to form an optionally substituted 3-7 membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O, and S, the heterocyclyl being optionally substituted with one or more fluoro or C1-C6 alkyl; R 3 is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3- to 7-membered cycloalkyl; R 3 are each independently optionally substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe; or R 3 is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl); C1-C2 alkyl is optionally substituted with one or more of fluoro, hydroxyl, and -OMe; and phenyl and 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C4 alkyl, C3-C5 cycloalkyl, and C1-C4 alkoxy; R 4 is hydrogen or -C(O)(C1-C8 alkyl), R 5 is hydrogen or halogen, R 6 is hydrogen or deuterium, R 1 and R 2 are both ethyl, and R 4 and R 5 If both are hydrogen, R 3 is not an unsubstituted straight chain C2-C6 alkyl, isopropyl, -CH2CH=CH2, -CH2CH2F, or -CH2CH2Ph; R 1 and R 2 If both are ethyl, R 4 is -C(O)(C2 alkyl), and R 5 is hydrogen, but R 3 is not an unsubstituted ethyl, R 1 is ethyl, and R 2 If H, then R 3 is not unsubstituted ethyl, unsubstituted n-propyl, or -CHCH=CH. or a pharma- ceutically acceptable salt thereof.

[0041] In some embodiments, the present disclosure provides a compound of formula (Ia):

[0042] [ka]

[0043] [In the formula, R 1 , R 2 , and R 3 is defined above and in the classes and embodiments disclosed herein] or a pharma- ceutically acceptable salt thereof.

[0044] In some embodiments, the present disclosure provides a compound of formula (Ib):

[0045] [ka]

[0046] [In the formula, R 3 and R 5 is defined above and in the classes and embodiments disclosed herein] or a pharma- ceutically acceptable salt thereof.

[0047] In some embodiments, the present disclosure provides a compound of formula (Ic):

[0048] [ka]

[0049] [In the formula, R 3 and R 5 is defined above and in the classes and embodiments disclosed herein] or a pharma- ceutically acceptable salt thereof.

[0050] In some embodiments, the present disclosure provides a compound of formula (Id):

[0051] [ka]

[0052] [In the formula, R3 and R 5 is defined above and in the classes and embodiments disclosed herein] or a pharma- ceutically acceptable salt thereof.

[0053] In some embodiments, the present disclosure provides a compound of formula (Ie):

[0054] [ka]

[0055] [In the formula, R 3 and R 5 is defined above and in the classes and embodiments disclosed herein] or a pharma- ceutically acceptable salt thereof.

[0056] In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is a straight chain C1-C6 alkyl. In some embodiments, R 1 is a branched C1-C6 alkyl. In some embodiments, R 1 is C2-C5 alkyl. In some embodiments, R 1 is selected from the group consisting of ethyl, sec-butyl, 2-pentyl, and 3-pentyl.

[0057] In some embodiments, R 1 is C1-C6 alkyl or 3- to 7-membered carbocyclyl, R 1 is optionally substituted with one or more halogen or C1-C6 alkyl. 1 is C1-C6 alkyl or 3-5 membered carbocyclyl, R 1 is optionally substituted with one or more fluoro or C1-C4 alkyl.

[0058] In some embodiments, R 2 is hydrogen or C1-C6 alkyl, R 2is optionally substituted with one or more halogen or C1-C6 alkyl. 2 is hydrogen or C1-C6 alkyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is a straight chain C1-C6 alkyl. In some embodiments, R 2 is a branched C1-C6 alkyl. In some embodiments, R 2 is C2-C5 alkyl. In some embodiments, R 2 is selected from the group consisting of hydrogen, ethyl, sec-butyl, 2-pentyl, and 3-pentyl.

[0059] In some embodiments, R 1 and R 2 can be taken together with the atom to which they are attached to form an optionally substituted 3-7 membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, R 1 and R 2 can be taken together with the atom to which they are attached to form an optionally substituted group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperizinyl, and morpholinyl. 1 and R 2 can be taken together with the atom to which they are attached to form dimethylazetidinyl.

[0060] In some embodiments, R 3 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and 3- to 7-membered cycloalkyl; R 3are each independently substituted with one or more substituents selected from the group consisting of fluoro, 3- to 7-membered cycloalkyl, and phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. 3 is C1-C6 alkyl or C2-C6 alkenyl, R 3 are each independently substituted with one or more substituents selected from the group consisting of fluoro, 3- to 7-membered cycloalkyl, and phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. 3 is C1-C3 alkyl or C2-C3 alkenyl, R 3 are each independently substituted with one or more substituents selected from the group consisting of fluoro, 3- to 7-membered cycloalkyl, and phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy. 3 is selected from the group consisting of methyl, ethyl, n-propyl, and allyl; R 3 may be substituted with 1 to 3 substituents selected from the group consisting of fluoro, 2-methoxyphenyl, and 2-hydroxyphenyl.

[0061] R 3 is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3- to 7-membered cycloalkyl; R 3 are each independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R 3is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), where C1-C2 alkyl is optionally substituted with one or more fluoro, hydroxyl, and -OMe, and where phenyl and 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C4 alkyl, C3-C5 cycloalkyl, and C1-C4 alkoxy. 3 is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3- to 7-membered cycloalkyl; R 3 is optionally substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe. 3 is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), where C1-C2 alkyl is optionally substituted with one or more fluoro, hydroxyl, and -OMe, and where phenyl and the 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C4 alkyl, C3-C5 cycloalkyl, and C1-C4 alkoxy.

[0062] In some embodiments, R 3 is selected from the group consisting of C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl), and 3- to 5-membered cycloalkyl; R 3 are each independently substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe, or R 3is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), where C1-C2 alkyl is optionally substituted with one or more fluoro, and phenyl and 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl, and C1-C3 alkoxy. In some embodiments, R3 is selected from the group consisting of C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -CH2-(cyclopropyl), and 3-5 membered cycloalkyl, and R 3 is optionally substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe. 3 is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), where C1-C2 alkyl is optionally substituted with one or more fluoro, and where phenyl and the 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl, and C1-C3 alkoxy.

[0063] In some embodiments, R 3 is selected from the group consisting of ethyl, n-propyl, -CHCH=CH, cyclopropyl, and -CH-(cyclopropyl); R 3 is optionally substituted with 1 to 3 instances of fluoro. 3 is selected from the group consisting of ethyl, n-propyl, -CHCH=CH, cyclopropyl, -CH-(cyclopropyl), -CHCHCHF, and -CHCHCF. 3is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl), where C1-C2 alkyl is optionally substituted with one or more fluoro, and phenyl and 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl, and C1-C3 alkoxy. 3 is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-pyridinyl, wherein phenyl and pyridinyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C3 alkyl, cyclopropyl, and C1-C3 alkoxy.

[0064] In some embodiments, R 3 teeth,

[0065] [ka]

[0066] is selected from the group consisting of:

[0067] In some embodiments, R 4 is hydrogen or -C(O)(C1-C8 alkyl). In some embodiments, R 4 is hydrogen or -C(O)(C1-C8 alkyl). In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -C(O)(C1-C8 alkyl). In some embodiments, R 4 is -C(O)(C1-C3 alkyl).

[0068] In some embodiments, R 5is hydrogen or halogen. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is hydrogen or bromo. In some embodiments, R 5 is bromo.

[0069] In some embodiments, the present disclosure provides:

[0070] [ka] [ka] [ka]

[0071] or a pharma- ceutically acceptable salt thereof.

[0072] In some embodiments, the present disclosure provides:

[0073] [ka]

[0074] or a pharma- ceutically acceptable salt thereof.

[0075] In some embodiments, the present disclosure provides:

[0076] [ka] [ka]

[0077] or a pharma- ceutically acceptable salt thereof.

[0078] In some embodiments, the present disclosure provides:

[0079] [ka]

[0080] or a pharma- ceutically acceptable salt thereof.

[0081] In another embodiment, the subject in need thereof is

[0082] [ka]

[0083] Methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of:

[0084] In some embodiments, the present disclosure provides:

[0085] [ka] [ka]

[0086] or a pharma- ceutically acceptable salt thereof.

[0087] Salts of the compounds of the present disclosure can be prepared by reacting the compounds of the present disclosure with a suitable acid or base in a suitable solvent or mixture of solvents (e.g., ether, e.g., diethyl ether, or alcohol, e.g., ethanol, or aqueous solvent) using conventional procedures. Salts of the compounds of general formula I can be exchanged with other salts by treatment using conventional ion exchange chromatography procedures. Preferred salts of the compounds of the present disclosure include tartrates, fumarates, and maleates.

[0088] When it is desired to obtain a particular enantiomer of a compound of the present disclosure, it can be produced from the corresponding mixture of enantiomers by utilizing any suitable conventional procedure for separating enantiomers.For example, diastereomeric derivatives (e.g., salts) can be produced by reacting a mixture of enantiomers (e.g., racemates) of a compound of the present disclosure with a suitable chiral compound (e.g., chiral base).The diastereomers can then be separated by any conventional means, such as crystallization, and the desired enantiomer can be recovered (e.g., by treatment with acid if the diastereomer is a salt).Alternatively, racemic mixtures of esters can be separated by kinetic hydrolysis using various biocatalysts (see, for example, Patel Steroselective Biocatalysts, Marcel Decker; New York 2000).

[0089] In another separation process, the racemate of the compound of the present disclosure can be separated using chiral high performance liquid chromatography.Alternatively, specific enantiomers can be obtained by using suitable chiral intermediates in one of the methods described above.If it is desired to obtain specific geometric isomers of the present disclosure, chromatography, recrystallization and other conventional separation procedures can also be used on intermediates or final products.

[0090] II. Method Methods and compositions are described herein for treating mood disorders by administering the compounds of the present disclosure to a patient in need thereof. Pharmaceutical compositions comprising the compounds of the present disclosure are also provided.

[0091] In embodiments, the methods, compounds, and compositions can be used to treat depressive disorders, e.g., mood disorders including major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation disorder, substance / medication-induced depressive disorder, or depressive disorder due to another medical condition.

[0092] In embodiments, the methods, compounds, and compositions can treat mood disorders including bipolar disorder and related disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including substance-related disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including anxiety disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including obsessive-compulsive disorder and related disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including trauma and stressor-related disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including eating disorders and eating disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including cognitive disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including neurodevelopmental disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including personality disorders. In embodiments, the methods, compounds, and compositions can treat mood disorders including sexual dysfunction. In embodiments, the methods, compounds, and compositions can treat mood disorders including gender dysphoria. In embodiments, the methods, compounds and compositions can treat migraine or cluster headaches.

[0093] Also provided herein are methods of treating patients suffering from treatment-refractory depression, e.g., a depressive disorder that does not respond and / or has never responded to a sufficient course of at least one, or at least two, other antidepressant compounds or therapeutic agents. As used herein, "depressive disorder" includes treatment-refractory depression.

[0094] In embodiments, the methods, compounds, and compositions can be used to treat mood disorders including bipolar disorder and related disorders, I, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication induced bipolar disorder and related disorders, bipolar disorder and related disorders due to another medical condition.

[0095] In embodiments, the methods, compounds, and compositions can be used to treat mood disorders, including substance-related disorders, for example, to prevent substance use cravings, reduce substance use cravings, and / or promote substance use cessation or withdrawal. Substance use disorders include abuse of psychotropic compounds, such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, a "substance" is a psychotropic compound that may be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the methods, compounds, and compositions can be used to promote smoking cessation or withdrawal of opioid use.

[0096] In embodiments, the methods, compounds, and compositions can be used to treat mood disorders including anxiety disorders, e.g., separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication induced anxiety disorder, or anxiety disorder due to another medical condition.

[0097] In embodiments, the methods, compounds, and compositions can be used to treat mood disorders including obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation (skin picking) disorder, substance / medication-induced obsessive-compulsive disorder and related disorders, or obsessive-compulsive disorder and related disorders due to another medical condition.

[0098] In embodiments, the methods, compounds, and compositions can be used to treat trauma and stressor-related disorders, such as reactive attachment disorder, disinhibited interpersonal interaction disorder, post-traumatic stress disorder, acute stress disorder, or mood disorders, including adjustment disorder.

[0099] In embodiments, the methods, compounds, and compositions can be used to treat eating behavior disorders and eating disorders, such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, or mood disorders including avoidant / restrictive food intake disorder.

[0100] In embodiments, the methods, compounds, and compositions can be used to treat cognitive disorders, e.g., mood disorders including delirium, dementia, mild cognitive impairment, dementia or mild cognitive impairment due to Alzheimer's disease, frontotemporal dementia or mild frontotemporal cognitive impairment, dementia or mild cognitive impairment with Lewy bodies, vascular dementia or mild vascular cognitive impairment, dementia or mild cognitive impairment due to traumatic brain injury, substance / medication induced dementia or mild cognitive impairment, dementia or mild cognitive impairment due to HIV infection, dementia or mild cognitive impairment due to prion disease, dementia or mild cognitive impairment due to Parkinson's disease, dementia or mild cognitive impairment due to Huntington's disease, dementia or mild cognitive impairment due to another medical condition, or dementia or mild cognitive impairment due to multiple etiologies.

[0101] In embodiments, the methods, compounds, and compositions can be used to treat a neurodevelopmental disorder, e.g., mood disorders including autism spectrum disorder, attention deficit / hyperactivity disorder, stereotypic movement disorder, tic disorder, Tourette's disorder, persistent (chronic) motor or vocal tic disorder, or provisional tic disorder.

[0102] In embodiments, the methods, compounds and compositions can be used to treat personality disorders, e.g., mood disorders, including borderline personality disorder.

[0103] In embodiments, the methods, compounds, and compositions can be used to treat sexual dysfunction, e.g., delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genito-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation (early ejaculation), or mood disorders including substance / medication induced sexual dysfunction.

[0104] In embodiments, the methods, compounds, and compositions can be used to treat gender dysphoria, e.g., mood disorders involving gender dysphoria.

[0105] In embodiments, methods and compositions are provided for treating a mood disorder by administering to a subject in need thereof an effective amount of (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxamide (1), or a pharma- ceutically acceptable salt thereof.

[0106] [ka]

[0107] In another embodiment, there is provided a method of treating a mood disorder, comprising administering to a patient in need thereof a compound according to Formula (I):

[0108] [ka]

[0109] [In the formula, R 1 is C1-C6 alkyl or 3- to 7-membered carbocyclyl, R 1 is optionally substituted with one or more halogen or C1-C6 alkyl; R 2 is hydrogen or C1-C6 alkyl, R 2 is optionally substituted with one or more halogen or C1-C6 alkyl; or R 1 and R2 can be taken together with the atom to which they are attached to form an optionally substituted 3-7 membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O, and S, the heterocyclyl being optionally substituted with one or more fluoro or C1-C6 alkyl; R 3 is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-(cyclopropyl), and 3- to 7-membered cycloalkyl; R 3 are each independently optionally substituted with one or more substituents selected from the group consisting of fluoro, hydroxyl, and -OMe; or R 3 is selected from the group consisting of -(C1-C2 alkyl)-phenyl and -(C1-C2 alkyl)-(6-membered heteroaryl); C1-C2 alkyl is optionally substituted with one or more of fluoro, hydroxyl, and -OMe; and phenyl and 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -OC(O)(C1-C8 alkyl), -CN, -NO2, -NH2, -C(O)NH2, C1-C4 alkyl, C3-C5 cycloalkyl, and C1-C4 alkoxy; R 4 is hydrogen or -C(O)(C1-C8 alkyl), R 5 is hydrogen or halogen, R 6 is hydrogen or deuterium. or a pharma- ceutically acceptable salt thereof.

[0110] In another embodiment, the subject in need thereof is

[0111] [ka] [ka] [ka]

[0112] Methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of:

[0113] In another embodiment, the subject in need thereof is

[0114] [ka]

[0115] Methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of:

[0116] In another embodiment, the subject in need thereof is

[0117] [ka] [ka]

[0118] Methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of:

[0119] In another embodiment, the subject in need thereof is

[0120] [ka]

[0121] Methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of:

[0122] In another embodiment, the subject in need thereof is

[0123] [ka]

[0124] Methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of:

[0125] In another embodiment, the subject in need thereof is

[0126] [ka] [ka]

[0127] Methods and compositions are provided for treating mood disorders by administering an effective amount of a compound selected from the group consisting of:

[0128] In other embodiments, methods and compositions are provided for treating migraine or cluster headaches by administering a therapeutically effective amount of a compound disclosed herein to a patient in need thereof.

[0129] In embodiments, the method includes treating a mood disorder, e.g., a depressive disorder, by administering to a patient in need thereof a pharmaceutical composition comprising about 0.001 mg to about 20 mg of a compound disclosed herein. In embodiments, the dose may be, for example, about 0.001-20 mg, 0.001-10 mg, 0.001-5 mg, 0.001-2 mg, 0.001-1 mg, 0.001-0.5 mg, 0.001-0.25 mg, 0.001-0.15 mg, 0.001-0.1 mg, 0.001-0.075 mg, 0.001-0.05 mg, 0.001-0.025 mg, 0.001-0.015 mg, 0.001-0.01 mg, 0.01-5 mg, 0.0 ... mg, 0.01~2mg, 0.01~1mg, 0.01~0.5mg, 0.01~0.25mg, 0.01~0.15mg, 0.01~0.1mg, 0.01~0.075mg, 0.01~0.05mg, 0.01 ~0.025mg, 0.01~0.015mg, 0.025~2mg, 0.025~1mg, 0.025~0.5mg, 0.025~0.25mg, 0.025~0.15mg, 0.025~0.1mg, 0.025 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, for example, about 0.001 mg, 0.0025 mg, 0.005 mg, 0.007 Exemplary doses include 5 mg, 0.01 mg, 0.015 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg.

[0130] In certain embodiments, the dose may be, for example, about 0.001 to 20 mg, 0.001 to 10 mg, 0.001 to 5 mg, 0.001 to 2 mg, 0.001 to 1 mg, 0.001 to 0.5 mg, 0.001 to 0.25 mg, 0.001 to 0.15 mg, 0.001 to 0.1 mg, 0.001 to 0.075 mg, 0.001 to 0.05 mg, 0.001 to 0.025 mg, 0.001 to 0.015 mg, 0.001 to 0.01 mg, 0.01 to 5 mg, 0.01~2mg, 0.01~1mg, 0.01~0.5mg, 0.01~0.25mg, 0.01~0.15mg, 0.01~0.1mg, 0.01~0.075mg, 0.01~0.05mg, 0.01~0.025 mg, 0.01~0.015mg, 0.025~2mg, 0.025~1mg, 0.025~0.5mg, 0.025~0.25mg, 0.025~0.15mg, 0.025~0.1mg, 0.025~0.075mg , 0.025-0.05 mg, 0.05-2 mg, 0.05-1 mg, 0.05-0.5 mg, 0.05-0.25 mg, 0.05-0.15 mg, 0.05-0.1 mg, 0.05-0.075 mg, 0.1-2 mg, 0.1-1 mg, 0.1-0.5 mg, 0.1-0.25 mg, 0.1-0.15 mg, and the like. Doses of 5 mg, 0.01 mg, 0.015 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg are exemplary doses.

[0131] Typically, doses of the compounds disclosed herein are administered to a patient in need thereof once, twice, three or four times a day, every other day, every third day, twice a week, once a week, twice a month, or once a month. In embodiments, the dose is, for example, about 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 aforementioned exemplary dose ranges may be delivered over intervals of more than one day, for example, 0.001-20 mg / week.

[0132] In embodiments, pharmaceutical compositions for parenteral or inhalation administration of the compounds disclosed herein, e.g., as a spray or mist, have a concentration of about 0.001 mg / mL to about 100 mg / mL. In embodiments, the compositions contain the compounds disclosed herein at concentrations of, e.g., 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 ... The present invention is characterized in that the medicament is contained at a concentration of about 0.001 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.

[0133] In an embodiment, for example, about 0.05 mg / mL to about 100 mg / mL, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.005 mg / mL to about 1 mg / mL, about 0.005 mg / mL to about 0.25 mg / mL, about 0.005 A composition of a compound disclosed herein at a concentration of about 0.05 mg / mL, about 0.005 mg / mL, about 0.025 mg / mL, about 0.001 mg / mL, about 0.025 mg / mL, about 0.001 mg / mL, about 0.025 mg / mL, about 0.001 mg / mL, or about 0.001 mg / mL to about 0.005 mg / mL. In embodiments, the pharmaceutical composition is formulated in a total volume of, for example, about 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.

[0134] Typically, the dose may be administered to a subject once, twice, three or four times a day, every other day, every third day, twice a week, once a week, twice a month, once a month, every two months, every three months, every four months, every six months, or every twelve months. In an embodiment, the compounds disclosed herein are administered to a subject once in the morning or once in the evening. In an embodiment, the compounds disclosed herein are administered to a subject once in the morning and once in the evening. In an embodiment, the compounds disclosed herein are administered to a subject three times a day (e.g., at breakfast, lunch, and dinner) at a dose of, for example, 0.005 mg / dose (e.g., 0.015 mg / day).

[0135] In embodiments, the compound disclosed herein is administered to the subject in one or more doses at a dose of 0.005 mg / day. In embodiments, the compound disclosed herein is administered to the subject in one or more doses at a dose of 0.01 mg / day. In embodiments, the compound disclosed herein is administered to the subject in one or more doses at a dose of 0.025 mg / day. In embodiments, the compound disclosed herein is administered to the subject in one or more doses at a dose of 0.05 mg / day. In embodiments, the compound disclosed herein is administered to the subject in one or more doses at a dose of 0.1 mg / day. In embodiments, the compound disclosed herein is administered to the subject in one or more doses at a dose of 0.15 mg / day. In embodiments, the compound disclosed herein is administered to the subject in one or more doses at a dose of 0.2 mg / day. In embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.25 mg / day in one or more doses. In embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.3 mg / day in one or more doses. In embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.4 mg / day in one or more doses. In embodiments, the compounds disclosed herein are administered to a subject at a dose of 0.5 mg / day in one or more doses.

[0136] In embodiments, the dose 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 per day. For example, in embodiments, the dose 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 per day. In embodiments, a subject is administered a total daily dose of 0.001 mg to 20 mg of a compound disclosed herein, once, twice, three times, or four times daily. In embodiments, the total amount administered to a subject in 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 embodiments, subjects may be started on a low dose and the dose is gradually increased, In embodiments, subjects may be started on a high dose and the dose is gradually decreased.

[0137] In embodiments, the compounds disclosed herein are administered to a patient under the supervision of a health care provider.

[0138] In embodiments, the compounds disclosed herein are administered to a patient under the supervision of a health care provider in a hospital specialized in providing psychotropic treatment.

[0139] In embodiments, the compounds disclosed herein are administered to a patient under the supervision of a health care provider at a high dose intended to induce a hallucinatory experience in the subject, e.g., 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.

[0140] In embodiments, administration of the high dose to a patient under the supervision of a health care provider occurs periodically, for example, once weekly, twice monthly, monthly, every two months, every three months, every four months, every six months, or every twelve months, to maintain therapeutic benefit in the patient.

[0141] In embodiments, the compounds disclosed herein are administered by the patient themselves at home or otherwise away from the supervision of a health care provider.

[0142] In embodiments, the compounds disclosed herein are self-administered by the patient at home or otherwise away from the supervision of a health care provider at low doses intended to elicit sub- or threshold psychotropic effects of perception, e.g., 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.

[0143] In embodiments, self-administration of low doses is performed on a regular basis, for example daily, every other day, every third day, twice weekly, weekly, twice monthly, or monthly, to maintain therapeutic effect in the patient.

[0144] The compounds of the present disclosure may be administered to patients (animals and humans) in need of such treatment in dosages that provide optimal pharmaceutical efficacy. It is understood that the dosage required for any particular use will vary from patient to patient, depending not only on the particular compound or composition selected, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, any concurrent medications or special dietary regimens the patient is undergoing at the time, and other factors that will be recognized by those skilled in the art, and ultimately it will be recognized that the appropriate dosage is at the discretion of the attending physician. To treat the above-noted conditions and diseases, the compounds of the present disclosure may be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in unit dosage forms containing conventional non-toxic pharmacologic carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.

[0145] Treatment can continue for as long or as short as desired. The composition may be administered, for example, in a regimen of 1-4 times per day or more. A suitable treatment period can be, for example, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, at least about 1 year, or indefinite. The treatment period can be terminated when a desired result, for example, a reduction in the symptoms of a psychiatric disorder, is achieved. The treatment regimen can include an adjustment phase during which a dose sufficient to provide symptomatic relief is administered, followed by a maintenance phase during which a lower dose sufficient to prevent the return of symptoms is administered. Suitable maintenance doses will likely be found in the lower portion of the dosage ranges provided herein, but adjustment and maintenance doses can be readily established for an individual subject by one of skill in the art based on the disclosure herein without undue experimentation. Maintenance doses can be utilized to maintain remission in subjects whose symptoms have previously been controlled by other means, including treatment with other pharmacological agents.

[0146] III. Pharmaceutical Compositions and Kits Another aspect of the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, formulated together with a pharma- ceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, formulated together with one or more pharma- ceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intrabuccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although in any event the most suitable form of administration will depend on the extent and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions may be formulated as a unit dose and / or formulated for oral or subcutaneous administration.

[0147] The exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid or liquid form, which contain one or more compounds of the present disclosure as active ingredients mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. The active ingredients can be formulated with a conventional non-toxic, pharma-ceutically acceptable carrier, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other forms suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of the disease.

[0148] To prepare solid compositions, such as tablets, the primary active ingredient may be mixed with pharmaceutical carriers, such as conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, such as water, to form solid preformulation compositions containing a homogenous mixture of the compounds of the present disclosure or non-toxic pharma- ceutically acceptable salts thereof. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is uniformly dispersed throughout the composition such that the composition may be readily divided into equally effective unit dosage forms, such as tablets, pills, capsules, and the like.

[0149] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharma- ceutically 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 silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; and (4) disintegrants. Examples of suitable additives include, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, for example, paraffin; (6) absorption accelerators, for example, quaternary ammonium compounds; (7) wetting agents, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, for example, kaolin and bentonite clay; (9) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0150] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets can be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets, and other solid dosage forms such as dragees, capsules, pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.

[0151] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable, aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharma-ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0152] Suspensions may contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0153] Formulations for rectal or vaginal administration may be presented as suppositories, which can be prepared by mixing the subject compositions with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent.

[0154] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient can be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0155] The ointments, pastes, creams and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0156] Powders and sprays can contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powders, or mixtures of these substances. Sprays can additionally contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0157] The compositions and compounds of the present disclosure may alternatively be administered in an aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions may also be used. Sonic nebulizers may be used, as they minimize shearing of the drug, which may result in the degradation of the compound contained in the subject composition. Usually, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject composition together with conventional pharma- ceutically acceptable carriers and stabilizers. Carriers and stabilizers vary according to the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycols), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0158] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject compositions in combination with one or more pharma- ceutically 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 immediately prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0159] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0160] In another aspect, the present disclosure provides an enteral pharmaceutical formulation comprising the disclosed compound and an enteric material; and its pharma- ceutically acceptable carrier or excipient. Enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach, but is predominantly soluble in intestinal fluids at a particular pH. The small intestine is the part of the digestive tract (gut) 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 terminal ileum is about 7.5. Thus, the enteric material is not soluble until a pH of, for example, 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 acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac, and copal collophorium, and several commercially available enteric dispersions (e.g., Eudragit L30D55, Eudragit Examples of suitable materials include FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is either known or readily determinable in vitro.While the foregoing materials are a list of possible materials, one of ordinary skill in the art having the benefit of this disclosure will recognize that this is not comprehensive and that other enteric materials exist that would meet the objectives of this disclosure.

[0161] Advantageously, the disclosure also provides kits for use, for example, by consumers in need of treatment with the disclosed compounds. Such kits include suitable dosage forms, such as those described above, and instructions describing how to use such dosage forms to treat a medical disorder, such as a psychiatric disease or disorder. The instructions guide the consumer or medical personnel to administer the dosage forms according to modes of administration 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 a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material, preferably a transparent plastic material, covered with a foil. 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 packed. The tablet or capsule is then placed in the groove and the sheet of relatively stiff material is sealed against the plastic foil with the foil side opposite to the direction in which the groove was formed. As a result, the tablets or capsules are sealed in the grooves between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the grooves, thereby forming openings in the sheet at the locations of the grooves. The tablets or capsules can then be removed through said openings.

[0162] It may be desirable for the kit to be provided with a memory aid, for example in the form of a number next to the tablet or capsule, which number corresponds to the day of the regimen that the identified tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on a card, for example: "First week, Monday, Tuesday...etc., Second week, Monday, Tuesday...", etc. Other variations of memory aids are readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule, while a daily dose of a second compound can consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0163] Methods and compositions including or administering a second active agent are also contemplated herein.

[0164] Example The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures, can be selected to be standard conditions for the reaction, unless otherwise indicated. It is understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are not compatible with the reaction conditions will be clear to those skilled in the art, and therefore alternate methods are shown. Starting materials for the examples are commercially available or easily prepared by standard methods from known materials.

[0165] It is contemplated that at least some of the compounds identified herein as "intermediates" are compounds of the present disclosure.

[0166] General Procedure The compounds of the present disclosure can be prepared by techniques well known in organic synthesis and familiar to those skilled in the art. For example, the compounds can be prepared by the chemical transformations described in the examples below. However, these may not be the only means to synthesize or obtain the desired compounds.

[0167] Abbreviation AcOH = acetic acid DCM = dichloromethane DMF = Dimethylformamide TEA = triethylamine T3P = propyl phosphonate anhydride mCPBA = metachloroperbenzoic acid HFBA = Heptafluorobutyric acid EXAMPLES

[0168] 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):

[0169] [ka]

[0170] Synthesis Protocol (Method 1): To a suspension of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylic acid (Int1, 2.01 g, 7.5 mmol) in anhydrous methanol (300 mL) was added a solution of diazomethane in diethyl ether (0.5 M, 75.0 mmol, 150 mL) under vigorous stirring. The resulting mixture was stirred until clear, then concentrated in vacuo and suspended in dichloromethane (100 mL). The solids were removed by filtration, the filter cake was washed with dichloromethane (3×30 mL), and the filtrate was concentrated in vacuo to give methyl (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylate (Int2) as an off-white foam. Yield: 1.92g (90%). LC-MS purity: 98% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA, 10 min): 6.82 min LC-MS m / z: 283.2 (M+H) + .

[0171] Methyl (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylate (Int2, 564 mg, 2.0 mmol) was dissolved in dry dichloromethane (30 mL) and purged with argon. Cyanogen bromide (1.14 g, 10.72 mmol) was added in one portion and the resulting solution was stirred for 4.5 h, at which point LC / MS indicated complete conversion. Silica gel (10 g) was added and the resulting suspension was concentrated in vacuo. The product was purified by flash column chromatography (silica gel 60, 0.040–0.063 mm; eluent: cyclohexane / ethyl acetate 80:20–50:50) to give methyl (6aR.9R)-7-cyano-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylate (Int3) as a colorless foam. Yield: 300 mg (50%). LC-MS purity: 98% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95-100:0 + 0.1% FA, 10 min): 8.63 min LC-MS m / z: 294.1 (M+H) + .

[0172] Methyl (6aR,9R)-7-cyano-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylate (Int3, 205 mg, 0.70 mmol) was dissolved in glacial acetic acid (5 mL) and zinc dust (600 mg) and water (0.5 mL) were added. The resulting mixture was purged with argon, heated to 100° C., and stirred for 3 h, at which point LC / MS indicated complete consumption of starting material. The reaction was cooled to 0° C., partitioned between saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL), and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 95:5-90:10) to give methyl (6aR)-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylate (Int4m) (mixture of diastereomers; epimer at the 9-position) as an off-white foam. Yield: 51 mg (24%). LC-MS purity: 85% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95-100:0 + 0.1% FA, 10 min): 2.87 min LC-MS m / z: 269.2 (M+H) + .

[0173] A solution of methyl (6aR)-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylate (Int4m, 75 mg, 0.280 mmol; mixture of epimers at 9-position) and propanal (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 introduced. After stirring at 0° C. for 1 h, 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 (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give methyl (6aR)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylate (Int5m) (mixture of diastereomers; epimer at the 9-position) as an off-white foam. Yield: 58 mg (67%). LC-MS purity: 99% (ELSD), 95% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA, 10 min): 2.95 min LC-MS m / z: 311.2 (M+H) + .

[0174] Methyl (6aR)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylate (Int5m, 58.7 mg, 0.189 mmol; mixture of epimers at 9-position) was dissolved in freshly distilled tetrahydrofuran (10 mL) and water (1 mL) and purged with argon. Lithium hydroxide (12.46 mg, 0.297 mmol) in water (500 μL) was added and the resulting mixture was stirred overnight, at which point LC / MS indicated complete conversion. The reaction mixture was neutralized with ice-cold methanesulfonic acid (29.2 mg, 0.297 mmol) in water (1 mL) and concentrated in vacuo to give an off-white residue (Int6m) (mixture of diastereomers; epimers at 9-position) that was used in the next step without further purification. Yield: 58 mg (crude product). LC-MS purity: 100% (ELSD), 95% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA, 10 min): 7.08 min; 7.30 min LC-MS m / z: 297.2 (M+H) + .

[0175] The crude (6aR)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxylic acid (Int6m, 55 mg; mixture of epimers at the 9-position) was dissolved in dry N,N-dimethylformamide (3 mL) 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 h. Ice-cold water (50 mL) was added, followed by ice-cold 1% ammonium hydroxide solution (5 mL) and the aqueous phase was extracted with dichloromethane (5×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was purified by preparative LC / MS (Sinergy Polar RP C18, 5 μm, 21.2 mm×150 mm, acetonitrile / water 5:95+0.1% acetic acid) to give the title compound as a solution in acetonitrile / water. Lyophilization gave 10 mg of (6aR,9R)-9-(diethylcarbamoyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinolin-7-ium acetate (1) as a beige powder. Yield: 10 mg (13% for two steps). 1 H NMR spectrum (acetate; acetate peaks obscured by solvent peaks) (300 MHz, CD3CN, δ H ): 9.00 (s, 1H), 7.22 (dd, J = 6.8, 1.9 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.98 - 6.84 (m, 2H), 6.30 (s, 1H), 3.78 - 3.68 (m, 1H), 3.56 - 3.30 (m, 6H), 3.13 (dd, J =10.9, 4.5 Hz, 1H), 2.93 - 2.82 (m, 1H), 2.69 - 2.42 (m, 4H), 1.67 - 1.43 (m, 2H), 1.21 (t, J =7.1 Hz, 3H), 1.11 (t, J =7.1 Hz, 3H), 0.94 (t, J =7.3 Hz, 3H). LC-MS purity: 97% (ELSD), 96% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mmx 150 mm, Acetonitrile / Water 05:95~100:0 + 0.1% FA, 10 min): 8.20 min. LC-MS m / z: 352.2 (M+H) + . Reaction scheme (method 2):

[0176] [ka]

[0177] Synthesis Protocol (Method 2): A solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int7m, 45.0 mg, 0.145 mmol; mixture of epimers at the 9-position) and propanal (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 in vacuo, and the residue was partitioned between dichloromethane and a 1% solution of ammonium hydroxide. The aqueous phase was extracted with dichloromethane (3×50 mL) and the combined organic phases were dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxamide (1) as a colorless oil. Yield: 6 mg (11%). 1 H NMR spectrum (acetate; acetate peaks obscured by solvent peaks) (300 MHz, CD3CN, δH ): 9.00 (s, 1H), 7.22 (dd, J =6.8, 1.9 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.98 - 6.84 (m, 2H), 6.30 (s, 1H), 3.78 - 3.68 (m, 1H), 3.56 - 3.30 (m, 6H), 3.13 (dd, J =10.9, 4.5 Hz, 1H), 2.93 - 2.82 (m, 1H), 2.69 - 2.42 (m, 4H), 1.67 - 1.43 (m, 2H), 1.21 (t, J =7.1 Hz, 3H), 1.11 (t, J =7.1 Hz, 3H), 0.94 (t, J =7.3 Hz, 3H). LC-MS purity: 96% (ELSD), 93% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mmx 150 mm, acetonitrile / water 20:80~100:0 + 0.1% FA, 10 min): 5.66 min. LC-MS m / z: 352.2 (M+H) + . EXAMPLES

[0178] Preparation of (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-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (2a) Reaction scheme (method 1):

[0179] [ka]

[0180] Synthesis Protocol (Method 1): A solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxamide (Int7m, 60.0 mg, 0.194 mmol; mixture of epimers at 9-position), cesium carbonate (139 mg, 0.426 mmol), and 1-bromo-3-fluoropropane (30.2 mg, 0.214 mmol) in N,N-dimethylformamide (1 mL) was purged with argon and stirred at room temperature for 96 h. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. 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 (6aR,9R)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxamide (2, faster migrating fluorescent band) as a colorless foam. Yield: 6 mg (10%). 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). LC-MS purity: 90% (ELSD), 81% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.68 min. LC-MS m / z: 370.2 (M+H) + . Reaction scheme (method 2):

[0181] [ka]

[0182] Synthesis Protocol (Method 2): To a stirred solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int7m, 45 mg, 0.145 mmol; mixture of epimers at the 9-position) and potassium bicarbonate (30 mg, 0.29 mmol) in methanol (2 mL) was added dropwise a solution of 1-bromo-3-fluoropropane (50 mg, 0.348 mmol) in methanol (1 mL) under an argon atmosphere. Tetrabutylammonium iodide (53.5 mg, 0.145 mmol) was then introduced in one portion 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 introduced. The resulting suspension was stripped of solvent 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 (6aR,9R)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxamide (2, faster moving fluorescent band) as a colorless foam and (6aR,9S)-N,N-diethyl-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinoline-9-carboxamide (2a, slower moving fluorescent band) as a dark brown foam. 2: Yield: 13.9 mg (23%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 8.99 (s, 1H); 7.22 (dd, J = J = 6.9, 1.8, 1H); 7.14-7.03 (m, 2H); 6.95 (s, 1H); 6.30 (s, 1H); 4.75-4.58 (m, 1H); 4.57-4.41 (m, 1H); 3.79-3.65 (m, 1H); 3.57-3.29 (m, 6H); 3.18-3.01 (m, 2H); 2.71-2.45 (m, 3H); 2.02-1.82 (m, 2H); 1.20 (d, J = J = 7.1, 3H); 1.11 (t, J = J = 7.1, 3H). LC-MS purity: 97% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP 4.6 mm x 150 mm, Asteril / Water 30:70~100:0 + 0.1% HFBA, 10 points): 5.47 points. LC-MS m / z: 370.2 (M+H) + . 2a: Yield: 7.8 mg (12%). 1 H NMR スペクトル(300 MHz, CD3CN, δ H ): 8.98 (s, 1H); 7.20 (d, J = J = 7.3, 1H); 7.12-6.98 (m, 2H); 6.91 (s, 1H); 6.24 (s, 1H); 4.68-4.59 (m, 1H); 4.51-4.43 (m, 1H); 3.76-3.66 (m, 1H); 3.55-3.27 (m, 6H); 3.12 (dd, J = 14.6, 5.2, 1H); 3.07-2.75 (m, 5H); 1.92-1.77 (m, 2H); 1.23 (t, J = 7.1, 3H); 1.06 (t, J = 7.0, 3H). LC-MS purity: 100% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.71 min. LC-MS m / z: 370.2 (M+H) + . EXAMPLES

[0183] 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:

[0184] [ka]

[0185] Synthesis protocol: A solution of (6aR,9R)-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)-butan-2-amine (329 mg, 4.50 mmol) in dry N,N-dimethylformamide (30 mL) was cooled to 0° C. and propanephosphonic anhydride (T3P, 5.24 mL, 9.00 mmol, 50% solution in DMF) was added dropwise over 5 min. The resulting mixture was stirred at 0° C. for 1 h, then diluted with water (200 mL) and washed with ethyl acetate (3×150 mL). The organic phase was discarded (product in the form of a salt in the aqueous phase) and the aqueous phase was basified to pH=12 by addition of a 30% solution of ammonium hydroxide. The mixture was then extracted with dichloromethane (3×200 mL) and the combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-90:10) to give (6aR,9S)-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int8a, the faster, less polar isomer) as a dark brown solid and (6aR,9R)-N-((R)-sec-butyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int8, the slower, more polar isomer) as a colorless solid. Int8a: Yield: 0.28 g (28%). 1 H NMR spectrum (300 MHz, CDCl3, δ H): 8.28 (s, 1H); 8.01 (s, 1H); 7.25-7.10 (m, 3H); 6.93 (s, 1H); 6.60 (d, J = 5.7, 1H); 3.93-3.76 (m, 1H); 3.59 (dd, J = 14.5, 5.4, ​​1H); 3.27-3.04 (m, 2H); 2.78-2.61 (m, 2H); 2.58 (s, 3H); 1.56-1.33 (m, 2H); 1.01 (d, J = 6.6, 3H); 0.91 (d, J = 7.4, 3H). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mmx 150 mm, Acrylic / Water 30:70~100:0 + 0.1% HFBA, 10 points): 6.21 points. LC-MS m / z: 324.2 (M+H) + . Int8: Yield: 0.47 g (48%). 1 H NMR スペクトル (300 MHz, CDCl3, δ H ): 8.34 (s, 1H); 7.24-7.09 (m, 3H); 6.90 (s, 1H); 6.62 (d, J = 8.0, 1H); 6.42 (dd, J = 3.7, 1.9, 1H); 3.93 (dt, J = 14.8, 6.7, 1H); 3.54-3.48 (m, 1H); 3.44-3.34 (m, 2H); 3.10 (dd, J = 11.5, 4.7, 1H); 2.83-2.68 (m, 2H); 2.60 (s, 3H); 1.56-1.37 (m, 2H); 1.13 (d, J = 6.6, 3H); 0.90 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mmx 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.29 min. LC-MS m / z: 324.2 (M+H) + .

[0186] A solution of 3-chloroperbenzoic acid (361 mg, 1.61 mmol) in dry dichloromethane (20 mL) was added dropwise to a solution of (6aR)-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; mixture of epimers at 9-position) in dry dichloromethane (40 mL) at 0° C., and the resulting mixture was stirred for 1 h. A 10% solution of sodium hydroxide (50 mL) was then added, the phases were separated, and the aqueous phase was extracted with a 10% solution of isopropanol in dichloromethane (3×100 mL). The combined organic phases were dried and evaporated under vacuum to give (6aR)-9-(((R)-sec-butyl)carbamoyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline 7-oxide (Int9m) (mixture of diastereomers; epimer at 9-position) as a dark brown solid, which was used in the next step without further purification. Yield: 0.52g (100%). LC-MS purity: 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA, 10 min): 5.13 min LC-MS m / z: 340.2 (M+H) + .

[0187] The crude (6aR)-9-(((R)-sec-butyl)carbamoyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline 7-oxide (Int9m, 520 mg; mixture of epimers at the 9-position) was dissolved in methanol (20 mL), cooled to 0 °C, and purged with argon. Iron(II) sulfate heptahydrate (Fe2SO4·7H2O, 895 mg, 3.22 mmol) was then added portionwise to the solution and the mixture was stirred at 0 °C for 3 h. The solvent was then removed in vacuo and the residue was partitioned between dichloromethane (150 mL) and a solution of EDTA (10 g) and 30% ammonium hydroxide (10 mL) in water (100 mL). The aqueous phase was further extracted with dichloromethane (3 × 100 mL) and the combined organic phases were dried and evaporated. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2-85:15) to give (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int10m) (mixture of diastereomers; epimer at the 9-position) as a dark brown solid. Yield: 0.121 g (24% for two steps). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA, 10 min): 4.78 min (diastereomer 1); 5.15 min (diastereomer 2). LC-MS m / z: 340.2 (M+H) + .

[0188] A solution of (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int10m, 55.0 mg, 0.178 mmol; mixture of epimers at the 9-position) and propanal (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 and the mixture was stirred for 5 min, followed by the addition of acetic acid (160 μL). 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 a 1% solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3×50 mL) and the combined organic phases were dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give (6aR,9S)-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) as a colorless oil and (6aR,9R)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (3, the slower, more polar diastereomer) as a colorless oil. 3a: Yield: 16 mg (26%). 1 H NMR spectrum (300 MHz, CDCl3, δ H): 8.15 (br s, 1H); 7.99 (d, J = 5.9, 1H); 7.26-7.09 (m, 3H); 6.93 (s, 1H); 6.61 (d, J = 5.9, 1H); 3.85 (dt, J = 14.9, 6.6, 1H); 3.57 (dd, J = 14.5, 4.8, 1H); 3.46-3.34 (m, 1H); 3.27 (d, J = 11.7, 1H); 3.12 (br s, 1H); 2.92 (ddd, J = 13.3, 9.3, 4.6, 1H); 2.76-2.56 (m, 2H); 2.56-2.42 (m, 1H); 1.81-1.52 (m, 2H); 1.52-1.38 (m, 2H); 1.01 (d, J = 7.4, 3H); 1.00 (t, J = 7.4, 3H); 0.91 (t, J = 7.5, 3H). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mmx 150 mm, Acrylic / Water 30:70~100:0 + 0.1% HBFA, 10 points): 6.81 points. LC-MS m / z: 352.1 (M+H) + . 3: Yield: 17 mg (27%). 1 H NMR スペクトル (300 MHz, CDCl3, δ H): 8.15 (br s, 1H); 7.38 (br s, 1H); 7.23-7.12 (m, 2H); 7.08 (dd, J = 6.9, 0.9, 1H); 6.91 (s, 1H); 6.41 (dd, J = 5.3, 1.6, 1H); 4.03-3.80 (m, 2H); 3.26 (dd, J = 14.0, 4.8, 2H); 3.03 (dd, J = 11.9, 4.0, 1H); 2.97-2.79 (m, 3H); 2.76-2.59 (m, 1H); 1.75-1.55 (m, 2H); 1.54-1.34 (m, 2H); 1.13 (d, J = 6.6, 3H); 0.98 (t, J = 7.3, 3H); 0.88 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD). LC-MS Rt (Sinergy Polar RP, 4.6 mmx 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 6.00 min. LC-MS m / z: 352.1 (M+H) + . EXAMPLES

[0189] Preparation of ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone (4) Reaction Scheme:

[0190] [ka]

[0191] Synthesis protocol: A solution of (6aR,9R)-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 (2S,4S)-2,4-dimethylazetidine hydrochloride (250 mg, 2.05 mmol) in dry N,N-dimethylformamide (10 mL) was cooled to 0° C. under an argon atmosphere. Propanephosphonic anhydride (T3P, 1.20 mL, 2.05 mmol, 50% solution in DMF) was then added dropwise over 5 min, and the resulting mixture was stirred at 0° C. for 1 h. After the reaction was complete by LC / MS, it was quenched with ice-cold water (10 mL) and partitioned between 1 M aqueous ammonium hydroxide solution (100 mL) and ethyl acetate (100 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with 5% lithium chloride solution (4×50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 100:0-98:2) to give ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone (Int11, the faster migrating fluorescent band) as an off-white solid and ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,7-methyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinolin-9-yl)methanone (Int11m; mixture of diastereomers; epimer at the 9-position) as a dark brown solid. Yield: 368 mg (65%), sum of isomers. 1 H NMR spectrum (Int11, pure beta isomer) (300 MHz, CDCl3, δ H): 8.24 (br s, 1H); 7.24-7.09 (m, 3H); 6.88 (s, 1H); 6.36 (s, 1H); 4.52 (dt, J = 7.5, 6.5, 2H); 3.60 (br s, 1H); 3.53 (dd, J = 14.5, 5.4, 1H); 3.31-3.17 (m, 1H); 3.07 (dd, J = 11.1, 4.9, 1H); 2.88 (t, J = 10.9, 1H); 2.70 (t, J = 12.0, 1H); 2.60 (s, 3H); 2.10-1.90 (m, 2H); 1.49 (t, J = 6.3, 6H). LC-MS Purity: 100% (total isomers, ELSD), 98% (total isomers, UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mmx 150 mm, acetonitrile / water 20:80~100:0 + 0.1% FA, 10 min): 3.59 min (diastereomer 1); 3.95 min (diastereomer 2). LC-MS m / z: 336.0 (M+H)+.

[0192] A solution of 3-chloroperbenzoic acid (189 mg, 1.10 mmol) in dry dichloromethane (5 mL) was added dropwise to a solution of ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinolin-9-yl)methanone (Int11m, 368 mg, 1.10 mmol; mixture of epimers at 9-position) in dry dichloromethane (30 mL) at 0° C., and the resulting mixture was stirred for 1 h at 0° C. Then, a 10% solution of sodium hydroxide (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with a 10% solution of isopropanol in dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give (6aR)-9-((2S,4S)-2.4-dimethylazetidine-1-carbonyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolone 7-oxide (Int12m) (mixture of diastereomers; epimer at the 9-position) as an off-white solid, which was used in the next step without further purification. LC-MS purity: 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA, 10 min): 1.92 min LC-MS m / z: 352.0 (M+H) + .

[0193] The crude (6aR)-9-((2S,4S)-2,4-dimethylazetidine-1-carbonyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolone 7-oxide (Int12m; mixture of epimers at the 9-position) was dissolved in methanol (75 mL), cooled to 0° C., and purged with argon. Iron(II) sulfate heptahydrate (609 mg, 2.20 mmol) was then added, and the mixture was stirred at 0° C. for 3 h. The solvent was removed in vacuo, and the residue was partitioned between dichloromethane (150 mL) and a solution (100 mL) of EDTA (10 g) and 30% ammonium hydroxide (10 mL) in water. The aqueous phase was further extracted with dichloromethane (3×100 mL), and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2-90:10) to give ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR)-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinolin-9-yl)methanone (Int13m) (mixture of diastereomers; epimer at the 9-position) as an off-white amorphous solid. Yield: 81.5 mg (23% for 2 steps) LC-MS purity: 88% (ELSD), 86% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 05:95-100:0 + 0.1% FA, 10 min): 5.87 min LC-MS m / z: 322.2 (M+H) + .

[0194] A solution of ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR)-4,6,6a,7,8,9-hexahydroindolo[4.3-fg]quinolin-9-yl)methanone (Intl3m, 81.5 mg, 0.242 mmol; mixture of epimers at 9-position) and propanal (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 and the mixture was stirred for 5 min, followed by the addition of acetic acid (300 μL). After stirring at 0° C. for 1 h, the solvent was evaporated and the residue was partitioned between dichloromethane and a 1% solution of ammonium hydroxide. The aqueous phase was extracted with dichloromethane (3×50 mL) and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040–0.063 mm; eluent: dichloromethane / methanol 99:1–98:2) to give ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone (4, faster migrating fluorescent band) as an off-white foam. Yield: 35 mg (40%). 1 H 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 3.20 (dd, J = 10.9, 4.4 Hz, 1H); 3.04 - 2.88 (m, J = 12.8, 10.6 Hz, 2H); 2.86 -2.64 (m, 2H); 2.14 - 1.89 (m, 2H); 1.74 - 1.56 (m, 2H); 1.49 (dd, 6H); 0.96 (t, J = 7.3 Hz, 3H). LC-MS purity: 99% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mmx 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.51 min. LC-MS m / z: 364.1 (M+H) + . EXAMPLES

[0195] 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:

[0196] [ka]

[0197] Synthesis protocol: A solution of (6aR)-N-((R)-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; 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 and the mixture was stirred for 5 minutes, followed by the addition of acetic acid (200 μL). The reaction was stirred at 0° C. for 1 hour, the solvent removed in vacuo, and the residue partitioned between dichloromethane (50 mL) and a 1% solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3×50 mL) and the combined organic phases were dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give (6aR,9S)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (5a, the faster-running, less polar diastereomer) as a colorless oil and (6aR,9R)-N-((R)-sec-butyl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (5, the slower-running, more polar diastereomer) as a colorless solid. The separated isomers were each dissolved in anhydrous methanol (500 μL) and treated with an equimolar amount of 1M D-(-)-tartaric acid in anhydrous methanol.The resulting solution was stripped of solvent in a stream of nitrogen and dried under high vacuum to give (6aR,9S)-9-(((R)-sec-butyl)carbamoyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-7-ium(2S,3S)-3-carboxy-2,3-dihydroxypropanoate(5a tartrate) as a brown amorphous solid and (6aR,9R)-9-(((R)-sec-butyl)carbamoyl)-7-ethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-7-ium(2S,3S)-3-carboxy-2,3-dihydroxypropanoate(5 tartrate) as a colorless solid. 5a: Yield (free base): 12.0 mg (20%). 1 H NMR spectrum (free base) (300 MHz, CDCl3, δ H ): 8.50-7.90 (m, 2 H); 7.26-7.21 (m, 1 H); 7.20-7.06 (m, 2 H); 6.92 (s, 1 H); 6.59 (d, J = 5.1 Hz, 1 H); 3.93-3.75 (m, 1 H); 0.91 (t, J = 7.4Hz, 3H). 1 H NMR spectrum (tartrate salt) (300 MHz, MeOD, δ H): 7.29 (dd, J = 7.0, 1.6, 1H); 7.17 (t, J = 6.9, 2H); 7.09 (s, 1H); 6.62 (d, J = 5.7, 1H); 4.47 (s, 2H); 4.31 (dd, J = 11.9, 5.3, 1H); 3.82 (dd, J = 13.2, 6.4, 2H); 3.80-3.66 (m, 2H); 3.60-3.53 (m, 1H); 3.46-3.34 (m, 2H); 3.02 (t, J = 13.0, 1H); 1.55-1.42 (m, 2H); 1.47 (t, J = 7.3, 3H); 1.19 (d, J = 7.0, 3H); 0.87 (t, J = 7.4, 3H). LC-MS purity (free radical): 97% (ELSD), 91% (UV, 310 nm). LC-MS purity (tartrate): 99% (ELSD). LC-MS Rt (tartaric acid) (Sinergy Polar RP, 4.6 mm x 150 mm, Acrylic / Water 30:70~100:0 + 0.1% HBFA, 10 points): 6.48 points. LC-MS m / z: 338.1 (M+H) + . 5: Yield (free base): 12.5 mg (21%). 1 H NMR tartaric acid (300 MHz, MeOD, δ H): 7.27 (dd, J = 6.1, 2.5, 1H); 7.19-7.09 (m, 2H); 7.07 (s, 1H); 6.49 (s, 1H); 4.44 (s, 2H); 4.37-4.24 (m, 1H); 3.85 (dd, J = 13.3, 6.6, 2H); 3.74-3.61 (m, 2H); 3.60-3.42 (m, 1H); 3.61-3.40 (m, 2H); 3.37-3.33 (m, 1H); 3.08 (t, J = 12.9, 1H); 1.61-1.50 (m, 2H); 1.42 (t, J = 7.2, 3H); 1.16 (d, J = 7.0, 3H); 0.96 (t, J = 7.4, 3H). LC-MS purity (tartrate): 91% (ELSD). LC-MS Rt (tartrate) (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HBFA, 10 min): 5.65 min. LC-MS m / z: 338.1 (M+H) + . EXAMPLES

[0198] Preparation of (6aR,9R)-N-(pentan-3-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (6) Reaction Scheme:

[0199] [ka]

[0200] Synthesis protocol: A solution of (6aR,9R)-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-pentanamine (260 μL, 2.23 mmol) in dry N,N-dimethylformamide (10 mL) was cooled to 0° C. under an argon atmosphere. Propanephosphonic anhydride (T3P®, 1.30 mL, 2.23 mmol, 50% solution in DMF) was added dropwise over 5 min, and the resulting mixture was stirred at 0° C. for 3 h and then quenched with ice-cold water (10 mL). The reaction mixture was concentrated in vacuo with silica gel (10 g) and the resulting solid was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 100:0-98:2) to give (6aR,9S)-7-methyl-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int14a, the faster migrating, less polar diastereomer) as a dark brown solid and (6aR,9R)-7-methyl-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int14, the slower migrating, more polar diastereomer) as a dark brown solid. Yield: 208 mg (83%, sum of isomers). Int14a: 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.03 (br s, 1H); 7.87 (br d, J = 6.201H); 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). LC-MS purity: 100% (ELSD), 100% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Asteril / Water 30:70~100:0 + 0.1% HFBA, 10 points): 5.27 points. LC-MS m / z: 338.2 (M+H) + . Int14: 1 H NMR スペクトル(300 MHz, CD3CN, δH): 9.03 (br s, 1H); 7.22 (dt, J = 7.2, 3.6, 1H); 7.14-7.05 (m, 2H); 6.95 (s, 1H); 6.49 (br d, J 3.24-3.14 (m, 1H); 3.07 (dd, J = 11.2, 5.0, 1H); 2.69-2.44 (m, 4H); 2.53 (s, 3H); 1.62-1.46 (m, 2H); 1.46-1.31 (m, 2H); 0.96-0.84 (m, 6H). LC-MS purity: 100% (ELSD), 100% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HFBA, 10 min): 4.95 min. LC-MS m / z: 338.2 (M+H) + .

[0201] A solution of 3-chloroperbenzoic acid (77%, 138 mg, 800 μmol) in dry dichloromethane (5 mL) was added dropwise to a solution of (6aR)-7-methyl-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int14m, 208 mg, 616 μmol; mixture of epimers at 9-position) in dry dichloromethane (10 mL) at 0° C. and stirred for 1 h under argon atmosphere. A 10% aqueous solution of sodium hydroxide (100 mL) was then added to the reaction mixture and the mixture was extracted with a 10% solution of isopropanol in dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give (6aR)-7-methyl-9-(pentan-3-ylcarbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline 7-oxide (Int15m) (mixture of diastereomers; epimer at 9-position), which was used in the next step without further purification. LC-MS purity: 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 5.09 min LC-MS m / z: 354.2 (M+H) + .

[0202] The crude (6aR)-7-methyl-9-(pentan-3-ylcarbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline 7-oxide (Int15m, obtained in total as described above; mixture of epimers at the 9-position) was dissolved in methanol (20 mL) and the solution was cooled to 0° C. under argon. Iron(II) sulfate heptahydrate (343 mg, 1.23 mmol) was then added and the resulting mixture was stirred at 0° C. for 3 h. At this point, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (150 mL) and a solution (100 mL) of EDTA (10 g) and 30% ammonium hydroxide (10 mL) in water. The aqueous phase was further extracted with dichloromethane (3×100 mL) and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2-90:10) to give (6aR)-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int16m) (mixture of diastereomers; epimer at 9-position) as an amorphous beige solid. Yield: 50.0 mg (25% over two steps from Int14m). LC-MS purity: 95% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 4.77 min LC-MS m / z: 324.2 (M+H) + .

[0203] A solution of (6aR)-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int16m, 50.0 mg, 0.154 mmol; mixture of epimers at the 9-position) and propanal (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 uL). After stirring at 0° C. for 1 hour, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (200 mL) and 1% ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give (6aR,9R)-N-(pentan-3-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (6, slower migrating fluorescent band) as a colorless foam. Yield: 20 mg (30%). 1 H NMR spectrum (300 MHz, CD3CN, δ H ): 9.00 (br s, 1H); 7.21 (dd, J = 7.6, 0.8, 1H); 7.14-7.00 (m, 2H); 6.99-6.84 (m, 2H); 6.37 (dd, J = 3.8, 1.7, 1H); 3.75-3.61 (m, 1H); 3.60-3.50 (m, 1H); 3.37 (dd, J = 14.4, 5.0, 1H); 3.23-3.13 (m, 1H); 3.07 (dd, J = 11.4, 4.5, 1H); 2.79-2.58 (m, 4H); 1.65-1.45 (m, 4H); 1.44-1.24 (m, 2H); 0.98-0.81 (m, 9H). LC-MS purity: 98% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.72 min. LC-MS m / z: 366.2 (M+H) + . EXAMPLES

[0204] Preparation of (6aR,9R)-N-((R)-pentan-2-yl)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (7) Reaction Scheme:

[0205] [ka]

[0206] Synthesis protocol: A solution of (6aR,9R)-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)-pentan-2-amine hydrochloride (250 μg, 1.50 mmol) in dry N,N-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 min. The resulting mixture was stirred at 0° C. for 3 h and quenched with ice-cold water (1 mL). The resulting mixture was concentrated in vacuo with silica gel (10 g) and purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 100:0-98:2) to give (6aR,9S)-7-methyl-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int17a, faster fluorescent band) as a dark brown solid and (6aR,9R)-7-methyl-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int17, slower fluorescent band) as a dark brown solid. Int17a: Yield: 89 mg (35%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.07 (br s, 1H); 7.79 (br d, J = 6.10, 1H); 7.28-7.21 (m, 1H); 7.14-7.09 (m, 2H); 6.98 (s, 1H); 6.53 (d, J = 6.1, 1H); 3.89-3.73 (m, 1H); 3.61 (dd, J = 14.6, 5.5, 1H); 3.15 (br s, 1H); 3.12 (d, J = 12.0, 1H); 3.00 (br s, 1H); 2.69 (dd, J = 11.6, 3.4, 1H); 2.65-2.51 (m, 1H); 2.56 (s, 3H); 1.45-1.31 (m, 4H); 0.98 (d, J = 6.5, 3H); 0.90 (t, J = 6.94, H). LC-MS purity: 95% (ELSD), 100% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Acrylic / Water 30:70~100:0 + 0.1% HFBA, 10 minutes): 5.317 points. LC-MS m / z: 338.2 (M+H) + . Int17: Yield: 102 mg (40%). 1 H NMR スペクトル(300 MHz, CD3CN, δ H): 9.02 (br s, 1H); 7.23 (p, J = 3.8, 1H); 7.13-7.07 (m, 2H); 6.95 (s, 1H); 6.53 (br d, J = 6.81, 1H); 6.38 (s, 1H); 3.89 (dt, J = 15.0, 6.6, 1H); 3.48 (dd, J = 14.6, 5.5, 1H); 3.38-3.27 (m, 1H); 3.21-3.11 (m, 1H); 3.05 (dd, J = 11.1, 5.0, 1H); 2.64-2.54 (m, 2H); 2.51 (s, 3H); 1.48-1.29 (m, 4H); 1.11 (d, J = 6.6, 3H); 0.91 (t, J = 7.1, 3H). LC-MS purity: 91% (ELSD), 100% (UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Asteril / Water 30:70~100:0 + 0.1% HFBA, 10 minutes): 5.06 points. LC-MS m / z: 338.2 (M+H) + .

[0207] A solution of 3-chloroperbenzoic acid (77%, 142.7 mg, 827 μmol) in dry dichloromethane (5 mL) was added dropwise to a solution of (6aR)-7-methyl-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int17m, 215 mg, 630 μmol; mixture of epimers at 9-position) in dry dichloromethane (10 mL) at 0° C., and the mixture was stirred under argon atmosphere at the given temperature for 1 h. Then, a 10% aqueous solution of sodium hydroxide (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with a 10% solution of isopropanol in dichloromethane (3×100 mL). The combined organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give (6aR,)-7-methyl-9-(((R)-pentan-2-yl)carbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline 7-oxide (Int18m) (mixture of diastereomers, epimer at 9-position), which was used in the next step without further purification. LC-MS purity: 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 5.23 min LC-MS m / z: 354.1 (M+H) + .

[0208] The crude (6aR)-7-methyl-9-(((R)-pentan-2-yl)carbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline 7-oxide (Int18m, total amount obtained as above; mixture of epimers at 9-position) was dissolved in methanol (20 mL) and cooled to 0° C. under argon. Iron(II) sulfate heptahydrate (351 mg, 1.26 mmol) was then added and the resulting mixture was stirred at 0° C. for 3 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (150 mL) and a solution (100 mL) of EDTA (10 g) and 30% ammonium hydroxide (10 mL) in water. The aqueous phase was further extracted with dichloromethane (3×100 mL) and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2-90:10) to give (6aR)-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int19m) (mixture of diastereomers, epimer at 9-position) as an amorphous beige solid. Yield: 47.0 mg (23% over two steps from Int17m). LC-MS Purity: 97% (combined diastereomers, UV 310 ). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 4.94 min, 5.19 min. LC-MS m / z: 324.2 (M+H) + .

[0209] A solution of (6aR)-N-(pentan-3-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int19m, 47.0 mg, 0.145 mmol; mixture of epimers at the 9-position) and propanal (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 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (200 mL) and a 1% solution of ammonium hydroxide (150 mL). The aqueous phase was further extracted with dichloromethane (3 × 50 mL) and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give (6aR,9R)-7-propyl-N-((R)-pentan-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (7, slower moving fluorescent band) as a dark brown foam. Yield: 20mg. LC-MS purity: 100% (ELSD), 89% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 5.88 min LC-MS m / z: 366.2 (M+H) + . EXAMPLES

[0210] 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:

[0211] [ka]

[0212] Synthesis protocol: To a stirred solution of (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int10m, 35 mg, 0.113 mmol; preparation described in Example 3; mixture of epimers at the 9-position) and potassium bicarbonate (23 mg, 0.226 mmol) in methanol (2 mL) was added dropwise a solution of allyl bromide (20 μL, 0.226 mmol) in methanol (1 mL) under argon. The resulting mixture was stirred at ambient temperature for 72 hours, diluted with dichloromethane (50 mL) and silica gel (10 g) was introduced. The resulting suspension was stripped of solvent 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 (6aR,9S)-N-((R)-sec-butyl)-7-allyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (8a, faster moving fluorescent band) as a brownish amorphous solid and (6aR,9R)-N-((R)-sec-butyl)-7-allyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (8, slower moving fluorescent band) as a brownish 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 solution was stripped of solvent under a stream of nitrogen and dried under high vacuum to give (6aR,9S)-7-allyl-9-(((R)-sec-butyl)carbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-7-ium(2S,3S)-3-carboxy-2,3-dihydroxypropanoate (8a tartrate) as a light brown solid and (6aR,9R)-7-allyl-9-(((R)-sec-butyl)carbamoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-7-ium(2S,3S)-3-carboxy-2,3-dihydroxypropanoate (8 tartrate) as a light brown solid. 8a: Yield (free base): 14.1 mg (35%). 1 H NMR tartaric acid (300 MHz, MeOD, δ H ): 7.26 (dt, J = 7.3, 3.6, 1H); 7.18-7.08 (m, 2H); 7.05 (d, J = 1.1, 1H); 6.57 (d, J = 5.6, 1H); 6.18-5.99 (m, 1H); 5.63-5.46 (m, 2H); 4.47 (s, 2H); 4.14 (dd, J = 13.7, 5.6, 1H); 4.02 (d, J = 6.8, 1H); 3.87-3.62 (m, 4H); 3.40 (br s, 1H); 3.18 (dd, J = 12.1, 3.5, 1H); 2.93 (t, J = 13.0, 1H); 1.58-1.40 (m, 2H); 1.18 (t, J = 7.0, 1H); 1.13 (d, J = 6.6, 3H); 0.89 (t, J = 7.4, 3H). LC-MS purity (free radical): 98% (ELSD), 97% (UV, 310 nm). LC-MS purity (tartrate): 99% (ELSD). LC-MS Rt (tartaric acid) (Sinergy Polar RP 4.6 mm x 150 mm, Acrylic / Water 30:70~100:0 + 0.1% HFBA, 10 points): 6.65 points. LC-MS m / z: 350.1 (M+H) + . 8: Yield (free base): 12 mg (30%). 1 H NMR tartaric acid (300 MHz, MeOD, δ H): 7.25 (dd, J = 6.6, 2.0, 1H); 7.18-7.07 (m, 2H); 7.04 (s, 1H); 6.46 (s, 1H); 6.20-5.99 (m, 1H); 5.67-5.47 (m, 2H); 4.46 (s, 2H); 4.16-4.09 (m, 1H); 4.06 (dd, J = 21.2, 7.4, 1H); 3.91-3.64 (m, 4H); 3.57 (dd, J = 12.0, 4.8, 1H); 3.29 (t, J = 12.6, 1H); 3.00 (t, J = 12.6, 1H); 1.62-1.44 (m, 2H); 1.20 (t, J = 3.3, 1H); 1.17 (d, J = 7.0, 3H); 0.94 (t, J = 7.4, 3H). LC-MS purity (tartrate): 98% (ELSD). LC-MS Rt (tartrate) (Sinergy Polar RP 4.6 mm x 150 mm, acetonitrile / water 30:70~100:0 + 0.1% HFBA, 10 min): 5.47 min. LC-MS m / z: 350.1 (M+H) + . EXAMPLES

[0213] 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:

[0214] [ka]

[0215] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1, 53.0 mg, 0.151 mmol) in anhydrous dioxane (2.0 mL) was flushed with argon. To this solution was added a 10% v / v solution of bromine in dioxane (754 μL, 0.151 mmol) in a dropwise manner and the resulting mixture was stirred for 48 h. The reaction mixture was filtered through a pad of silica gel. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6aR,9R)-5-bromo-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (9) as a dark amorphous solid. Yield: 28.4 mg (44%). 1 H NMR spectrum (300 MHz, CD3CN, δ H ): 9.36 (s, 1H), 7.19 - 7.11 (m, 1H), 7.11 - 7.06 (m, 2H), 6.32 (s, 1H), 3.75 - 3.65 (m, 1H), 3.45 (dt, J = 10.8, 3.6, 2H), 3.41 - 3.29 (m, 4H), 3.13 (ddd, J = 11.2, 4.8, 1.0, 1H), 2.89 (ddd, J = 13.3, 9.0, 7.1, 1H), 2.61 (t, J = 10.8, 1H), 2.48 (ddd, J = 13.4, 8.7, 4.9, 1H), 2.40 (dd, J = 16.3, 12.6, 1H), 1.67 - 1.46 (m, 2H), 1.21 (t, J =7.1, 3H), 1.10 (t, J = 7.1, 3H), 0.94 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.20 min. LC-MS m / z: 431.9 (M+H) + .

[0216] A solution of (6aR,9R)-5-bromo-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (9, 28.4 mg, 66 μmol) in a gradient grade of acetonitrile (5.0 mL) was treated with 1 M aqueous D-(-)-tartaric acid (33 μL, 66 μmol) and stirred for 5 min. The solvent was removed in vacuo and the residue was redissolved in dioxane (5.0 mL) and then freeze-dried at 0° C. to give (6aR,9R)-5-bromo-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (9 hemitartrate) as a fluffy light brown solid. Yield: 33.2 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.18 (dd, J = 7.0, 1.9, 1H), 7.16 - 7.06 (m, 2H), 6.39 (s, 1H), 4.40 (s, 1H), 4.07 - 3.99 (m, 1H), 3.99 - 3.86 (m, 1H), 3.58 (dt, J = 14.1, 7.2, 2H), 3.51 - 3.36 (m, 5H), 3.27 - 3.12 (m, 2H), 3.09 - 2.93 (m, 1H), 2.77 (t, J = 12.4, 1H), 1.89 - 1.69 (m, 2H), 1.31 (t, J = 7.1, 3H), 1.19 (t, J = 7.1, 3H), 1.06 (t, J = 7.3, 3H). LC-MS purity: 100% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.20 min. LC-MS m / z: 431.9 (M+H) + . EXAMPLES

[0217] 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:

[0218] [ka]

[0219] Synthesis protocol: A solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamidoheptafluorobutanoate (Int7m, 40.0 mg, 0.077 mmol; mixture of epimers at the 9-position) 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, then glacial acetic acid (100 μL) was added and stirring was continued at room temperature. After 48 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (200 mL) and a 1% solution of ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6aR,9R)-N,N-diethyl-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (10) as a colorless solid. Yield: 22 mg (66%). 1 H NMR spectrum (300 MHz, CD3CN, δ H ): 8.99 (br s, 1H); 7.48 (d, J = 7.4, 1H); 7.30-7.19 (m, 2H); 7.14-7.05 (m, 2H); 7.00-6.90 (m, 3H); 6.32 (s, 1H); 4.14 (d, J = 14.6, 1H); 3.80 (s, 3H); 3.75-3.63 (m, 3H); 3.47-3.26 (m, 5H); 3.05 (dd, J = 11.1, 4.4, 1H); 2.70-2.47 (m, 2H); 1.08 (dt, J = 9.4, 7.1, 6H). LC-MS purity: 99% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HFBA, 10 min): 7.64 min. LC-MS m / z: 430.2 (M+H) + . EXAMPLES

[0220] 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:

[0221] [ka]

[0222] Synthesis protocol: 2-(2-Methoxyphenyl)acetic acid (1.66 g, 10.0 mmol) was dissolved in dry methanol (10 mL), sulfuric acid 96% (1.0 mL) was added and the mixture was refluxed for 3 h. The solvent was then evaporated and the residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl 2-(2-methoxyphenyl)acetate (Int20) as a colorless oil. Yield: 1.80 g (100%). 1 H 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).

[0223] 2-(2-Methoxyphenyl)acetate (Int20, 1.80 g, 10.0 mmol) was dissolved in dry toluene (20 mL) and cooled to -78°C. A solution of diisobutylaluminium hydride (15.0 mL, 15 mmol, 1 M solution in hexane) was introduced dropwise and the resulting mixture was stirred at -78°C for 2 h. The reaction was quenched by slow addition of methanol (5 mL), followed by a 10% solution of sodium potassium tartrate (20 mL) and ethyl acetate (50 mL). The resulting mixture was then stirred at room temperature for 1 h. The phases were separated, the aqueous phase was further extracted with ethyl acetate (2 x 50 mL) and the combined organic phases were dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash 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. Yield: 1.11 g (74%). 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 9.68 (t, J = 2.1 Hz, 1 H); 7.30 (td, J = 8.1, 1.6 Hz, 1 H); 7.15 (dd, J = 7.3, 1.2 Hz, 1 H); 7.01-6.87 (m, 2 H); 3.83 (s, 3 H); 3.65 (d, J = 2.0 Hz, 2H).

[0224] A solution of (6aR)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hydrochloride (Int7m, 51.0 mg, 0.148 mmol; HCl salt; mixture of epimers at the 9-position) and 2-(2-methoxyphenyl)acetaldehyde (Int21, 111 mg, 0.74 mmol) in methanol (10 mL) under argon was cooled to 0° C. Sodium cyanoborohydride (46.0 mg, 0.74 mmol) was added and the mixture was stirred for 5 min, then glacial acetic acid (100 μL) was added and stirring was continued at 0° C. After 1 h, the solvent was removed in vacuo, the residue was partitioned between dichloromethane (200 mL) and a 1% solution of ammonium hydroxide (150 mL), and the aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6aR,9R)-N,N-diethyl-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (11) as a colorless foam. Yield: 20 mg (30%). 1 H NMR spectrum (300 MHz, CD3CN, δ H ): 9.01 (br s, 1H); 7.25-7.15 (m, 3H); 7.13-7.06 (m, 2H); 6.99-6.83 (m, 3H); 6.31 (s, 1H); 3.85 (s, 3H); 3.76-3.67 (m, 1H); 3.60 (dd, J = 14.4, 5.4, 1H); 3.53-3.33 (m, 4H); 3.18 (dd, J = 11.1, 4.1, 1H); 3.13-3.02 (m, 1H); 2.97-2.69 (m, 4H); 2.46 (ddd, J = 14.2, 11.1, 1.5, 1H); 1.22 (t, J = 7.1, 3H); 1.12 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.61 min. LC-MS m / z: 444.3 (M+H) + . EXAMPLES

[0225] 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:

[0226] [ka]

[0227] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 30.0 mg, 78.0 μmol; 2 moles of Int7 per mole of tartrate) and 3,3,3-trifluoropropanal (27.0 μL, 0.31 mmol) in methanol (2 mL) was purged with argon and cooled to 0° C. Sodium cyanoborohydride (20.0 mg, 0.32 mmol) was added and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 μL). After stirring at 0 °C for 3 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and 1% aqueous ammonium hydroxide solution (150 mL) and the aqueous phase was further extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6aR,9R)-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (12) as a colorless foam. Yield: 27.2 mg (86%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.01 (s, 1H), 7.23 (dd, J = 6.8, 1.9, 1H), 7.15 - 7.03 (m, 2H), 6.96 (t, J = 1.8, 1H), 6.31 (s, 1H), 3.79 - 3.66 (m, 1H), 3.51 (dd, J = 14.5, 5.5, 1H), 3.46 (dd, J = 7.3, 3.2, 1H), 3.37 (m, 4H), 3.22 (ddd, J = 14.0, 9.1, 6.8, 1H), 3.09 (ddd, J = 11.1, 4.8, 1.0, 1H), 2.86 (ddd, J = 14.0, 8.9, 5.3, 1H), 2.73 (t, 1H), 2.57 (dd, J = 11.1, 1.7, 1H), 2.54 - 2.40 (m, 2H), 1.22 (t, J = 7.1, 3H), 1.11 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.85 min. LC-MS m / z: 406.0 (M+H) + .

[0228] (6aR,9R)-N,N-Diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (12, 27.2 mg, 67.1 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (33.6 μL, 33.6 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-(3,3,3-trifluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (12 hemitartrate) as a fluffy white solid. Yield: 32.2 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.20 (dd, J = 6.3, 2.4, 1H), 7.14 - 7.05 (m, 2H), 6.98 (d, J = 1.2, 1H), 6.31 (s, 1H), 4.50 (s, 1H), 3.99 - 3.88 (m, 1H), 3.63 - 3.40 (m, 7H), 3.20 (dd, J = 11.1, 4.5, 1H), 3.11 - 2.99 (m, 1H), 2.94 (t, J = 10.3, 1H), 2.73 (t, J = 12.0, 1H), 2.58 (ddd, J = 16.1, 10.2, 5.5, 2H), 1.30 (t, J = 7.1, 3H), 1.18 (t, J = 7.1, 3H). LC-MS purity: 97% (ELSD), 92% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.85 min. LC-MS m / z: 406.0 (M+H) + . EXAMPLES

[0229] Preparation of (6aR,9R)-N,N-diethyl-7-(cyclopropylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (13) Reaction Scheme:

[0230] [ka]

[0231] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 30.0 mg, 78.0 μmol; 2 moles of Int7 per mole of tartrate) and cyclopropanecarbaldehyde (23.0 μL, 0.31 mmol) in methanol (2 mL) was purged with argon and cooled to 0° C. Sodium cyanoborohydride (20.0 mg, 0.32 mmol) was added and the resulting mixture was stirred for 5 minutes, followed by the addition of glacial acetic acid (20 uL). After stirring at 0° C. for 3 hours, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and a 1% aqueous solution of ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6aR,9R)-7-(cyclopropylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (13) as a colorless foam. Yield: 19.0 mg (67%). 1 H NMR spectrum (300 MHz, CD3CN, δ H ): 9.17 (s, 1H), 7.27 (dd, J = 6.8, 1.9, 1H), 7.17 - 7.05 (m, 2H), 7.00 (s, 1H), 6.37 (s, 1H), 3.98 - 3.79 (m, 2H), 3.62 - 3.30 (m, 6H), 3.18 (dd, J = 11.3, 7.7, 1H), 3.01 - 2.84 (m, 2H), 2.78 (t, J = 13.1, 1H), 1.24 (t, J = 7.1, 3H), 1.13 (t, J = 7.1, 3H), 1.15 - 1.00 (m, 1H), 0.65 - 0.56 (m, 2H), 0.34 - 0.26 (m, 2H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.56 min. LC-MS m / z: 364.1 (M+H) + .

[0232] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M aqueous D-(-)-tartaric acid (26.2 μL, 26.2 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0° C. to give (6aR,9R)-7-(cyclopropylmethyl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (13 hemitartrate) as a fluffy white solid. Yield: 22.9 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.27 (p, J = 3.8, 1H), 7.17 - 7.10 (m, 2H), 7.07 (d, J = 0.8, 1H), 6.43 (dd, J = 2.8, 1.7, 1H), 4.40 (s, 1H), 4.36 - 4.24 (m, 1H), 4.15 (s, 1H), 3.77 - 3.36 (m, 8H), 3.31 - 3.22 (m, 1H), 3.02 (t, J = 12.9, 1H), 1.34 (t, J = 7.1, 3H), 1.34 - 1.16 (m, 1H), 1.20 (t, J = 7.1, 3H), 0.78 (q, J = 5.4, ​​2H), 0.48 (d, J = 4.3, 2H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.56 min. LC-MS m / z: 364.1 (M+H) + . EXAMPLES

[0233] Preparation of ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone (14) Reaction Scheme:

[0234] [ka]

[0235] Synthesis protocol: A solution of (6aR,9R)-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) in dry N,N-dimethylformamide (10 mL) was cooled to 0° C. under an argon atmosphere. Propanephosphonic anhydride (T3P®, 3.26 mL, 5.59 mmol, 50% solution in DMF) was added dropwise over 5 min. The resulting mixture was stirred at 0° C. for 1 h. The reaction was determined to be complete by LC-MS and was then quenched with ice-cold water (10 mL). The mixture was partitioned between 1 M aqueous ammonium hydroxide solution (200 mL) and ethyl acetate (100 mL). The aqueous phase was re-extracted with ethyl acetate (2×150 mL). The organic phases were combined, then washed with 10% aqueous lithium chloride solution (4×150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 100:0-98:2) to give ((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone (Int22) as a dark brown solid. Yield: 255 mg (43%). LC-MS purity: 100% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 4.59 min LC-MS m / z: 322.0 (M+H) + .

[0236] A solution of ((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone (Int22, 52.7 mg, 0.164 mmol) in gradient grade acetonitrile (5.0 mL) was treated with 1 M aqueous D-(-)-tartaric acid (81.4 μL, 0.081 mmol) and stirred at room temperature for 5 min. The solvent was removed in vacuo. The residue was redissolved in dioxane (5.0 mL) and lyophilized at 0° C. to give ((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone hemitartrate (Int22 hemitartrate) as a fluffy white solid. Yield: 69.0 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.24 (d, J = 7.7, 1H), 7.20 - 7.07 (m, 2H), 7.03 (s, 1H), 6.46 (s, 1H), 4.40 (s, 1H), 4.07 (dd, J = 6.5, 4.0, 1H), 3.90 - 3.79 (m, 1H), 3.76 - 3.67 (m, 1H), 3.71 (dd, J = 13.8, 6.3, 2H), 3.54 - 3.44 (m, 1H), 3.49 (dd, J = 12.7, 5.9, 2H), 3.28 - 3.16 (m, 1H), 2.94 (s, 3H), 2.95 - 2.83 (m, 1H), 2.10 - 1.90 (m, 4H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 4.59 min. LC-MS m / z: 322.0 (M+H) + .

[0237] To a solution of cyanogen bromide (380 mg, 3.60 mmol) in carbon tetrachloride (30 mL) under reflux was added a solution of ((6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone (Int22, 255 mg, 0.795 mmol) in chloroform (10 mL) and carbon tetrachloride (70 mL) at a rate sufficient to maintain reflux. The reaction mixture was then heated under reflux for an additional 4 hours. The mixture was then allowed to cool to room temperature and silica gel (silica gel 0.063-0.200 mm, 10 g) was added. The mixture was concentrated in vacuo. The resulting powder was added to the top of a flash chromatography column pre-packed with silica gel and the product was eluted as follows (silica gel 60, 0.040-0.063 mm; eluent: cyclohexane / ethyl acetate 100:0-50:50) to give (6aR,9R)-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7(4H)-carbonitrile (Int23) as a colorless amorphous solid. Yield: 200 mg (75%). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 8.10 (s, 1H), 7.33 - 7.23 (m, 1H), 7.22 - 7.13 (m, 2H), 6.98 (s, 1H), 6.36 (s, 1H), 4.32 - 4.17 (m, 1H), 3.92 - 3.80 (m, 1H), 3.76 - 3.69 (m, 2H), 3.68 - 3.50 (m, 5H), 3.11 - 2.98 (m, 1H), 2.11 - 1.89 (m, 4H). LC-MS purity: 98% (ELSD), 98% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.87 min. LC-MS m / z: 333.0 (M+H) + .

[0238] A solution of (6aR,9R)-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7(4H)-carbonitrile (Int23, 200 mg, 0.601 mmol) in acetic acid (15 mL) and water (1.5 mL) was treated with zinc dust (1000 mg). The resulting suspension was heated under reflux for 1 h. After cooling, the mixture was filtered through cotton and the solution was basified with 10% aqueous ethylenediamine (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 (silica gel 0.063-0.200 mm, 10 g) and evaporated under vacuum. The powder was added to the top of a flash chromatography column prepacked with silica gel and the product was eluted as follows (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 100:0-98:2) to give ((6aR,9R)-4,6,6a,7,8,9 hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone (Int24) as a dark amorphous solid. Yield: 125 mg (68%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.08 (s, 1H), 7.28 - 7.17 (m, 1H), 7.16 - 7.06 (m, 2H), 6.95 (s, 1H), 6.39 (s, 1H), 3.71 (ddd, J = 11.4, 5.7, 2.4, 1H), 3.66 - 3.50 (m, 3H), 3.39 (td, J = 6.8, 3.7, 2H), 3.25 (dd, J = 12.9, 4.8, 1H), 3.14 (dd, J = 14.8, 5.8, 1H), 2.99 (dd, J = 12.5, 9.3, 1H), 2.67 - 2.53 (m, 1H), 2.14 (s, 1H), 1.98 - 1.91 (m, 2H), 1.90 - 1.77 (m, 2H). LC-MS purity: 95% (ELSD), 95% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Acrylic / Water 30:70~100:0 + 0.1% HBFA, 10 points): 4.22 points. LC-MS m / z: 308.0 (M+H) + .

[0239] A solution of ((6aR,9R)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone hemitartrate (Int24, 40 mg, 105 μmol; 2 moles of Int24 per mole of tartrate; salt prepared as described for other hemitartrates) and propanal (15 μL, 210 μmol) in methanol (2 mL) was purged with argon gas and cooled to 0 °C. Sodium cyanoborohydride (14 mg, 210 μmol) was added. The resulting mixture was stirred for 5 min, then acetic acid (50 μL) was introduced. After stirring at 0 °C for 1 h, silica gel (silica gel 0.063-0.200 mm, 10 g) was added and the mixture was concentrated in vacuo. The powder was added to the top of a flash chromatography column prepacked with silica gel and the product was eluted as follows (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone (14) as a colorless foam. Yield: 20.5 mg (56%). LC-MS purity: 100% (ELSD), 100% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 5.28 min LC-MS m / z: 350.1 (M+H) + .

[0240] A gradient graded solution of ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone (14, 20.5 mg, 58.7 μmol) in acetonitrile (5.0 mL) was treated with 1 M aqueous D-(-)-tartaric acid (29 μL, 29 μmol). After stirring at room temperature for 5 min, the solvent was removed in vacuo. The residue was redissolved in dioxane (5.0 mL) and lyophilized at 0° C. to give ((6aR,9R)-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)(pyrrolidin-1-yl)methanone hemitartrate (14 hemitartrate) as a fluffy white solid. Yield: 23.2 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.26 (dd, J = 7.2, 1.4, 1H), 7.19 - 7.09 (m, 2H), 7.06 (d, J = 1.1, 1H), 6.47 (s, 1H), 4.39 (s, 1H), 4.25 - 4.10 (m, 1H), 4.08 - 3.95 (m, 1H), 3.74 (dd, J = 6.3, 4.7, 2H), 3.70 - 3.63 (m, 2H), 3.59 - 3.47 (m, 3H), 3.47 - 3.38 (m, 1H), 3.25 - 3.11 (m, 1H), 2.99 (t, J = 12.0, 1H), 2.07 (dt, J = 11.5, 5.8, 2H), 1.97 (dt, J = 9.0, 4.6, 2H), 1.90 - 1.77 (m, 2H), 1.07 (t, J = 7.4, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.28 min. LC-MS m / z: 350.1 (M+H) +. EXAMPLES

[0241] 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:

[0242] [ka]

[0243] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 2-hydroxybenzaldehyde (22.0 μL, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0° C. Sodium cyanoborohydride (13.0 mg, 0.208 mmol) was introduced and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 μL). After stirring at 0° C. for 3 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and 1% aqueous ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3×50 mL), basified with 24% aqueous ammonium hydroxide and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give (6aR,9R)-N,N-diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (16) as a colorless solid. Yield: 9.2 mg (43%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.03 (s, 1H), 7.25 (dd, J = 6.1, 2.6, 1H), 7.20 - 7.06 (m, 3H), 6.96 (t, J = 1.7, 1H), 6.87 - 6.71 (m, 3H), 6.37 (s, 1H), 4.61 (d, J = 14.2, 1H), 3.79 - 3.73 (m, 1H), 3.68 (dd, J = 14.3, 5.1, 1H), 3.57 (d, J = 14.3, 1H), 3.49 (ddd, J = 11.5, 4.6, 2.5, 1H), 3.41 (dd, J = 15.0, 7.4, 1H), 3.36 - 3.25 (m, 4H), 3.08 (dd, J = 11.5, 4.4, 1H), 2.79 (dd, J = 12.0, 2.2, 1H), 2.72 (dd, J = 11.6, 9.2, 1H), 1.08 (dt, J = 14.3, 7.1, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.85 min. LC-MS m / z: 416.1 (M+H) + .

[0244] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (11.0 μL, 11.0 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-(2-hydroxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (16 hemitartrate) as a fluffy off-white solid. Yield: 13.3 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.33 - 7.18 (m, 3H), 7.16 - 7.07 (m, 2H), 7.03 (d, J = 1.0, 1H), 6.87 (t, J = 7.7, 2H), 6.37 (s, 1H), 4.67 (d, J = 13.6, 1H), 4.42 (s, 1H), 4.05 (d, J = 13.6, 1H), 4.00 - 3.91 (m, 2H), 3.86 (dd, J = 13.8, 5.0, 1H), 3.66 - 3.33 (m, J = 7.9, 1.9, 6H), 3.12 - 2.91 (m, 2H), 1.18 (t, J = 7.1, 3H), 1.12 (t, J = 7.1, 3H). LC-MS purity: 97% (ELSD), 90% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.84 min. LC-MS m / z: 416.1 (M+H) + . EXAMPLES

[0245] 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:

[0246] [ka]

[0247] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and 3-methoxybenzaldehyde (28.3 μL, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0° C. Sodium cyanoborohydride (13.0 mg, 0.208 mmol) was introduced and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 μL). After stirring at 0° C. for 3 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and 1% aqueous ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give material that still contained impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3×50 mL), basified with 24% aqueous ammonium hydroxide and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give (6aR,9R)-N,N-diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (18) as a colorless solid. Yield: 14.2 mg (64%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.02 (s, 1H), 7.33 - 7.21 (m, 2H), 7.18 - 7.08 (m, 2H), 7.06 - 7.00 (m, 2H), 6.98 (t, J = 1.7, 1H), 6.88 - 6.81 (m, 1H), 6.37 (s, 1H), 4.33 (d, J = 14.1, 1H), 3.81 (s, 3H), 3.74 - 3.68 (m, 1H), 3.68 (dd, J = 14.6, 5.4, 1H), 3.49 - 3.25 (m, 6H), 3.02 (ddd, J = 11.1, 4.7, 1.0, 1H), 2.69 (ddd, J = 14.6, 11.3, 1.7, 1H), 2.56 (t, J = 10.5, 1H), 1.08 (td, J = 7.1, 2.5, 6H). LC-MS purity: 97% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.31 min. LC-MS m / z: 430.1 (M+H) + .

[0248] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (16.4 μL, 16.4 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-(3-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (18 hemitartrate) as a fluffy white solid. Yield: 16.8 mg (quantitative). 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). LC-MS purity: 99% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.31 min. LC-MS m / z: 430.1 (M+H) + . EXAMPLES

[0249] 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:

[0250] [ka]

[0251] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and p-anisaldehyde (22.0 μL, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0° C. Sodium cyanoborohydride (13.0 mg, 0.208 mmol) was introduced and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 μL). After stirring at 0° C. for 3 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and 1% aqueous ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3×50 mL), basified with 24% aqueous ammonium hydroxide and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give (6aR,9R)-N,N-diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (19) as a colorless solid. Yield: 15.6 mg (70%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.01 (s, 1H), 7.31 (d, J = 8.6, 2H), 7.23 (dd, J = 6.7, 1.9, 1H), 7.14 - 7.05 (m, 2H), 6.96 (t, J = 1.7, 1H), 6.89 (d, J = 10.9, 2H), 6.32 (s, 1H), 4.24 (d, J = 13.7, 1H), 3.77 (s, 3H), 3.69 (dd, J = 14.7, 5.3, 1H), 3.63 - 3.58 (m, 1H), 3.45 - 3.18 (m, 6H), 2.99 (ddd, J = 11.1, 4.7, 0.9, 1H), 2.66 (ddd, J = 14.5, 11.3, 1.6, 1H), 2.49 (t, J = 10.6, 1H), 1.05 (t, J = 7.1, 6H). LC-MS purity: 97% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.24 min. LC-MS m / z: 430.1 (M+H) + .

[0252] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (18.2 μL, 18.2 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-(4-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (19 hemitartrate) as a fluffy white solid. Yield: 18.4 mg (quantitative). 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). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.24 min. LC-MS m / z: 430.1 (M+H) + . EXAMPLES

[0253] 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:

[0254] [ka]

[0255] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 30.0 mg, 78.0 μmol; 2 moles of Int7 per mole of tartrate) and 2-(3-methoxyphenyl)acetaldehyde (50.0 mg, 0.33 mmol) in methanol (2 mL) was purged with argon and cooled to 0° C. Sodium cyanoborohydride (20.0 mg, 0.32 mmol) was added and the resulting mixture was stirred for 5 min followed by the addition of glacial acetic acid (20 μL). After stirring at 0° C. for 3 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and 1% aqueous ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give material that still contained impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3×50 mL), basified with 24% aqueous ammonium hydroxide and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give (6aR,9R)-N,N-diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (20) as a colorless foam. Yield: 14.9 mg (43%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 8.99 (s, 1H), 7.27 - 7.16 (m, 2H), 7.14 - 7.05 (m, 2H), 6.95 (t, J = 1.7, 1H), 6.87 (dd, J = 4.0, 2.2, 2H), 6.76 (ddd, J = 8.3, 2.5, 0.9, 1H), 6.30 (s, 1H), 3.77 (s, 3H), 3.74 - 3.65 (m, 1H), 3.55 (dd, J = 14.5, 5.3, 1H), 3.50 - 3.29 (m, 5H), 3.22 - 3.10 (m, 2H), 2.92 - 2.69 (m, 4H), 2.48 (ddd, J = 14.3, 11.0, 1.6, 1H), 1.21 (t, J = 7.1, 3H), 1.11 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.58 min. LC-MS m / z: 444.2 (M+H) + .

[0256] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (16.8 μL, 16.8 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-(3-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (20 hemitartrate) as a fluffy off-white solid. Yield: 17.4 mg (quantitative). 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). LC-MS purity: 96% (ELSD), 90% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.58 min. LC-MS m / z: 444.1 (M+H) + . EXAMPLES

[0257] 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:

[0258] [ka]

[0259] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 33.0 mg, 86.0 μmol; 2 moles of Int7 per mole of tartrate) and 2-(4-methoxyphenyl)acetaldehyde (50.0 mg, 0.33 mmol) in methanol (2 mL) was purged with argon and cooled to 0° C. Sodium cyanoborohydride (20.0 mg, 0.32 mmol) was added and the resulting mixture was stirred for 5 min followed by the addition of glacial acetic acid (20 μL). After stirring at 0° C. for 3 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and 1% aqueous ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3×50 mL), basified with 24% aqueous ammonium hydroxide and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give (6aR,9R)-N,N-diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (21) as a colorless foam. Yield: 36.2 mg (95%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.04 (s, 1H), 7.25 - 7.17 (m, 3H), 7.13 - 7.05 (m, 2H), 6.95 (t, J = 1.6, 1H), 6.90 - 6.81 (m, 2H), 6.32 (s, 1H), 3.80 - 3.75 (m, 1H), 3.75 (s, J = 3.0, 3H), 3.53 (dd, J = 15.8, 5.4, 1H), 3.48 - 3.32 (m, 5H), 3.23 - 3.07 (m, 2H), 2.93 - 2.74 (m, 4H), 2.55 (ddd, J = 15.6, 12.6, 1.6, 1H), 1.21 (t, J = 7.1, 3H), 1.11 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.55 min. LC-MS m / z: 444.2 (M+H) + .

[0260] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (40.8 μL, 40.80 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-(4-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (21 hemitartrate) as a fluffy white solid. Yield: 42.3 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H): 7.28 - 7.19 (m, 3H), 7.16 - 7.08 (m, 2H), 7.03 (d, J = 0.8, 2H), 6.89 (d, J = 8.6, 2H), 6.39 (s, 1H), 4.42 (s, 1H), 4.18 - 4.03 (m, 2H), 3.77 (s, 3H), 3.68 - 3.54 (m, 2H), 3.54 - 3.40 (m, 4H), 3.10 - 2.89 (m, 3H), 1.32 (t, J = 7.2, 3H), 1.20 (t, J = 7.1, 3H). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 6.57 min. LC-MS m / z: 444.1 (M+H) + . EXAMPLES

[0261] 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:

[0262] [ka]

[0263] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 52.0 μmol; 2 moles of Int7 per mole of tartrate) and pyridine-2-carbaldehyde (20.0 μL, 0.208 mmol) in methanol (2 mL) was purged with argon and cooled to 0° C. Sodium cyanoborohydride (13.0 mg, 0.208 mmol) was introduced and the resulting mixture was stirred for 5 min, followed by the addition of glacial acetic acid (20 μL). After stirring at 0° C. for 3 h, the solvent was removed in vacuo and the residue was partitioned between dichloromethane (100 mL) and 1% aqueous ammonium hydroxide (150 mL) and the aqueous phase was further extracted with dichloromethane (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give material still containing impurities. This crude material was dissolved in 1 M hydrochloric acid (25 mL) and methanol (5 mL), washed with diethyl ether (3×50 mL), basified with 24% aqueous ammonium hydroxide and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give (6aR,9R)-N,N-diethyl-7-(pyridin-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (22) as a dark amorphous solid. Yield: 15.8 mg (76%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.02 (s, 1H), 8.51 (ddd, J = 4.8, 1.6, 0.8, 1H), 7.73 (td, J = 7.7, 1.8, 1H), 7.57 (d, J = 7.8, 1H), 7.22 (dt, J = 7.7, 3.9, 2H), 7.15 - 7.05 (m, 2H), 6.94 (t, J = 1.7, 1H), 6.33 (s, 1H), 4.31 (d, J = 14.8, 1H), 3.76 - 3.68 (m, 1H), 3.72 (d, J = 14.8, 1H), 3.66 (dd, J = 14.4, 5.1, 1H), 3.57 - 3.46 (m, 1H), 3.44 - 3.27 (m, 4H), 3.05 (dd, J = 10.8, 4.3, 1H), 2.69 (t, J = 10.5, 1H), 2.63 (ddd, J = 14.4, 11.2, 1.7, 1H), 1.08 (dt, J = 12.3, 7.1, 6H). LC-MS purity: 99% (ELSD), 99% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Asteril / Water 30:70~100:0 + 0.1% HBFA, 10 points): 5.74 points. LC-MS m / z: 401.1 (M+H) + .

[0264] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (39.4 μL, 39.4 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-(pyridin-2-ylmethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide tartrate (22 tartrate) as a fluffy off-white solid. Yield: 21.8 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 8.60 (d, J = 4.2, 1H), 7.91 (td, J = 7.7, 1.7, 1H), 7.67 (d, J = 7.8, 1H), 7.41 (dd, J = 7.0, 5.5, 1H), 7.23 (dd, J = 6.8, 1.9, 1H), 7.16 - 7.07 (m, 2H), 7.00 (d, J = 1.2, 1H), 6.39 (s, 1H), 4.63 (d, J = 14.7, 1H), 4.49 (s, 2H), 4.21 (d, J = 14.6, 1H), 4.08 - 3.93 (m, 2H), 3.73 (dd, J = 14.0, 5.2, 1H), 3.57 - 3.34 (m, 5H), 3.13 (dd, J = 11.6, 8.9, 1H), 3.03 - 2.90 (m, 1H), 1.22 (t, J = 7.1, 3H), 1.15 (t, J = 7.1, 3H). LC-MS purity: 99% (ELSD), 96% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.74 min. LC-MS m / z: 401.1 (M+H) + . EXAMPLES

[0265] 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:

[0266] [ka]

[0267] Synthesis protocol: A solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (Int7, 20.0 mg, 53.0 μmol; 2 moles of Int7 per mole of tartrate), potassium bicarbonate (32 mg, 0.32 mmol), and 2-(2-bromoethyl)pyridin-1-ium bromide (28.0 mg, 0.33 mmol) in methanol (2 mL) was purged with argon and stirred at 80 °C for 4 days. After LC-MS analysis showed complete consumption of starting material, the reaction mixture was concentrated onto silica gel and subjected to flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2). The solvent of the combined product fractions was stripped under vacuum to give (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) as a dark amorphous solid. Yield: 3.8 mg (18%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 8.97 (s, 1H), 8.53 - 8.49 (m, 1H), 7.65 (td, J = 7.7, 1.9, 1H), 7.29 (d, J = 7.8, 1H), 7.22 (dd, J = 6.7, 2.0, 1H), 7.18 - 7.13 (m, 1H), 7.11 - 7.07 (m, 2H), 6.95 (t, J = 1.8, 1H), 6.29 (s, 1H), 3.71 - 3.62 (m, 1H), 3.53 (dd, J = 14.4, 5.3, 1H), 3.48 - 3.26 (m, 6H), 3.19 (dd, J = 11.1, 3.8, 1H), 3.06 - 2.93 (m, 3H), 2.73 (t, J = 10.7, 1H), 2.41 (ddd, J = 14.3, 11.0, 1.6, 1H), 1.22 (t, J = 7.1, 3H), 1.11 (t, J = 7.1, 3H). LC-MS purity: 98% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 4.88 min. LC-MS m / z: 415.1 (M+H) + .

[0268] (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, 3.8 mg, 9.17 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M aqueous D-(-)-tartaric acid (9.2 μL, 9.2 μmol). The solvent was removed in vacuo and the resulting material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-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) as a fluffy light brown solid. Yield: 5.2 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 8.52 (dd, J = 4.9, 0.8, 1H), 7.80 (td, J = 7.7, 1.8, 1H), 7.43 (d, J = 7.8, 1H), 7.31 (ddd, J = 7.5, 5.0, 0.9, 1H), 7.28 - 7.21 (m, 1H), 7.13 (dd, J = 6.7, 5.6, 2H), 7.05 (d, J = 1.0, 1H), 6.41 (dd, J = 3.6, 1.7, 1H), 4.45 (s, 2H), 4.29 - 4.18 (m, 1H), 4.13 - 4.03 (m, 1H), 3.81 - 3.35 (m, 9H), 3.01 (t, J = 12.9, 1H), 1.33 (t, J = 7.1, 3H), 1.19 (t, J = 7.1, 3H). LC-MS purity: 95% (ELSD), 92% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 4.88 min. LC-MS m / z: 415.1 (M+H) + . EXAMPLES

[0269] 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:

[0270] [ka]

[0271] Synthesis protocol: A solution of (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int10m, 20 mg, 46.7 μmol; 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 introduced and the reaction mixture was stirred at 0° C. for 24 h. A diastereomeric mixture of (6aR)-N-((R)-sec-butyl)-7-(2-methoxybenzyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (24m; mixture of diastereomers; epimer at the 9-position) was obtained, as confirmed via LC-MS analysis. Composition by LC-MS: 87% (ELSD, faster running isomer), 13% (ELSD, slower running isomer). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 6.54 min (isomer A), 6.57 min (isomer B). LC-MS m / z: 430.2 (M+H) + . EXAMPLES

[0272] 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:

[0273] [ka]

[0274] Synthesis protocol: A solution of (6aR)-N-((R)-sec-butyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Int10m, 20 mg, 46.7 μmol; 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 introduced and the reaction mixture was then stirred at 0° C. for 24 h. A diastereomeric mixture of (6aR)-N-((R)-sec-butyl)-7-(2-methoxyphenethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (25m; mixture of diastereomers; epimer at the 9-position) was obtained as confirmed via LC-MS analysis. Composition by LC-MS: 87% (ELSD, faster running isomer), 13% (ELSD, slower running isomer). LC-MS Rt (Sinergy Polar RP, 4.6 mm × 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 6.49 min (isomer A), 6.79 min (isomer B). LC-MS m / z: 444.2 (M+H) + . EXAMPLES

[0275] Preparation of ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone (26) Reaction Scheme:

[0276] [ka]

[0277] Synthesis protocol: A solution of ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,9R)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone (Int13, 40 mg, 0.117 mmol), potassium bicarbonate (47 mg, 0.468 mg), and 1-bromo-3-fluoropropane (33 mg, 0.234 mmol) in isopropanol (1.0 mL) was purged with argon and heated to 90 °C in a sealed glass vial. The reaction mixture was stirred for 20 h. The vial was opened and the solvent was removed and evaporated under vacuum. The crude material was redissolved in dichloromethane (25 mL), treated with silica gel (silica gel 0.063-0.200 mm, 10 g), and concentrated. The resulting powder was added to a flash column and purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone (26) as a colorless foam. Yield: 15.6 mg (35%). 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.99 (s, 1H), 7.22 (dd, J = 6.6, 2.1, 1H), 7.16 - 7.03 (m, 2H), 6.94 (t, J = 1.7, 1H), 6.30 (s, 1H), 4.73 - 4.55 (m, 2H), 4.55 - 4.44 (m, 1H), 4.43 - 4.33 (m, 1H), 3.50 (dd, J = 14.6, 5.1, 1H), 3.41 - 3.29 (m, 2H), 3.18 - 3.02 (m, 2H), 2.66 - 2.43 (m, 3H), 2.01 - 1.91 (m, 2H), 2.05 - 1.86 (m, 2H), 1.46 (d, J = 6.3, 3H), 1.39 (d, J = 6.3, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.53 min. LC-MS m / z: 382.1 (M+H) + .

[0278] ((2S,4S)-2,4-Dimethylazetidin-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone (26, 15.6 mg, 40.9 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (19.6 μL, 19.6 μmol). The resulting solution was stirred for 5 min. The solvent was removed in vacuo and the residue was redissolved in dioxane (5.0 mL) and lyophilized at 0° C. to give ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,9R)-7-(3-fluoropropyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone hemitartrate (26 hemitartrate) as a fluffy white solid. Yield: 18.6 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H): 7.22 (dd, J = 6.9, 1.8, 1H), 7.16 - 7.06 (m, 2H), 7.00 (d, J = 1.2, 1H), 6.32 (s, 1H), 4.73 (dd, J = 13.2, 6.2, 1H), 4.70 - 4.61 (m, 1H), 4.50 (dd, J = 12.7, 6.3, 2H), 4.43 (s, 1H), 3.88 - 3.74 (m, 1H), 3.70 - 3.64 (m, 2H), 3.62 (dd, J = 14.7, 5.4, 1H), 3.38 (dd, J = 15.3, 4.2, 1H), 3.38 - 3.28 (m, 2H), 3.05 (t, J = 9.8, 1H), 2.81 (t, J = 12.6, 1H), 2.16 - 2.06 (m, 2H), 2.22 - 1.95 (m, 2H), 1.57 (d, J = 6.3, 3H), 1.47 (d, J = 6.3, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.53 min. LC-MS m / z: 382.1 (M+H) + . EXAMPLES

[0279] Preparation of ((6aR,9R)-7-allyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)((2S,4S)-2,4-dimethylazetidin-1-yl)methanone (27) Reaction Scheme:

[0280] [ka]

[0281] Synthesis protocol: A solution of ((2S,4S)-2,4-dimethylazetidin-1-yl)((6aR,9R)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)methanone (4, 40.0 mg, 0.117 mmol), potassium bicarbonate (47 mg, 0.468 mg), and allyl bromide (20 μL, 0.234 mmol) in isopropanol (1.0 mL) was purged with argon and heated to 90 °C. The reaction mixture was stirred for 20 h. The solvent was removed in vacuo and the crude material was redissolved in dichloromethane (25 mL). Silica gel (silica gel 0.063-0.200 mm, 10 g) was added and the solvent was removed in vacuo. The resulting powder was placed onto a pre-packed silica gel flash column and eluted (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1-98:2) to give ((6aR,9R)-7-allyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)((2S,4S)-2,4-dimethylazetidin-1-yl)methanone (27) as a colorless foam. Yield: 14.2 mg (33%). 1 H NMR spectrum (300 MHz, CDCl3, δ H): 9.03 (s, 1H), 7.29 - 7.20 (m, 1H), 7.17 - 7.08 (m, 2H), 6.97 (t, J = 1.8, 1H), 6.33 (s, 1H), 6.11 - 5.93 (m, 1H), 5.32 (dd, J = 17.2, 1.1, 1H), 5.21 (d, J = 10.1, 1H), 4.68 - 4.53 (m, 1H), 4.41 (dq, J = 12.8, 6.2, 1H), 3.74 - 3.63 (m, 1H), 3.57 (dd, J = 14.7, 5.2, 1H), 3.45 - 3.34 (m, 2H), 3.23 - 3.12 (m, 2H), 2.62 (t, J = 12.0, 1H), 2.59 - 2.47 (m, 1H), 2.09 - 1.99 (m, 2H), 1.48 (d, J = 6.3, 3H), 1.41 (d, J = 6.3, 3H). LC-MS purity: 98% (ELSD), 91% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, Asteril / Water 30:70~100:0 + 0.1% HBFA, 10 points): 5.42 points. LC-MS m / z: 362.1 (M+H) + .

[0282] ((6aR,9R)-7-Allyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)((2S,4S)-2,4-dimethylazetidin-1-yl)methanone (27, 14.2 mg, 39.3 μmol) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M aqueous D-(-)-tartaric acid (19.6 μL, 19.6 μmol). The resulting solution was stirred for 5 min and then the solvent was removed in vacuo. The residue was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give ((6aR,9R)-7-allyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl)((2S,4S)-2,4-dimethylazetidin-1-yl)methanone hemitartrate (27 hemitartrate) as a fluffy off-white solid. Yield: 17.1 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.23 (dd, J = 7.2, 1.5, 1H), 7.16 - 7.07 (m, 2H), 7.01 (d, J = 1.2, 1H), 6.33 (s, 1H), 6.14 - 5.96 (m, 1H), 5.49 (d, J = 17.0, 1H), 5.42 (d, J = 10.3, 1H), 4.77 - 4.63 (m, 1H), 4.56 - 4.44 (m, 1H), 4.44 (s, 1H), 3.92 (dd, J = 14.1, 5.5, 1H), 3.86 - 3.76 (m, 1H), 3.73 - 3.53 (m, 4H), 3.40 (dd, J = 11.5, 4.5, 1H), 3.00 (t, J = 10.8, 1H), 2.82 (t, J = 10.8, 1H), 2.20 - 2.01 (m, 2H), 1.57 (d, J = 6.3, 3H), 1.46 (d, J = 6.3, 3H). LC-MS purity: 98% (ELSD), 91% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.42 min. LC-MS m / z: 362.1 (M+H) + . EXAMPLES

[0283] 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:

[0284] [ka]

[0285] Synthesis protocol: (6aR,9R)-N,N-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 flushed 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 (silica gel 0.063-0.200 mm, 10 g) and evaporated under vacuum. The resulting powder was added to the top of a flash chromatography column prepacked with silica gel and the product was eluted as follows (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6aR,9R)-5-bromo-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (35) as a dark amorphous solid. Yield: 32.8 mg (49%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.48 (s, 1H), 7.21 - 7.05 (m, 3H), 6.33 (s, 1H), 3.88 - 3.73 (m, 1H), 3.45 (q, J = 7.1, 2H), 3.36 (ddd, J = 9.0, 6.4, 2.2, 3H), 3.11 - 3.05 (m, 1H), 3.02 (dd, J = 11.7, 4.4, 1H), 2.64 (t, J = 10.8, 1H), 2.51 (s, 3H), 2.41 (dd, J = 14.9, 11.3, 1H), 1.20 (t, J = 7.0, 3H), 1.10 (t, J = 7.1, 3H). LC-MS purity: 100% (ELSD), 100% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.37 min. LC-MS m / z: 403.9 (M+H) + .

[0286] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M aqueous D-(-)-tartaric acid (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 (6aR,9R)-5-bromo-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (35 hemitartrate) as a fluffy light brown solid. Yield: 38.8 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H): 7.21 - 7.06 (m, 3H), 6.39 (s, 1H), 4.42 (s, 1H), 4.16 - 4.04 (m, 1H), 3.76 - 3.66 (m, 1H), 3.62 - 3.41 (m, 5H), 3.41 - 3.33 LC-MS purity: 100% (ELSD), 97% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 5.37 min. LC-MS m / z: 403.9 (M+H) + . EXAMPLES

[0287] (6aR,9R)-N,N-Diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (36) Reaction Scheme:

[0288] [ka]

[0289] Synthesis protocol: (6aR,9R)-N,N-diethyl-7-propyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1, 200 mg, 0.567 mmol) was dissolved in anhydrous dioxane (10 mL), followed by triethylsilane (1 mL) and triflic acid (500 μL) and the resulting mixture was stirred for 96 h at 40° C. The mixture was then allowed to cool to room temperature and silica gel (silica gel 0.063-0.200 mm, 10 g) was added. The mixture was concentrated in vacuo, the resulting powder was added to the top of a flash chromatography column prepacked with silica gel, and the product was eluted as follows (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6aR,9R)-N,N-diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (36; mixture of diastereomers; epimer at the 5a position) as a dark amorphous solid. Yield: 97.6 mg (49%). 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, 10 min): 3.85 min. LC-MS m / z: 354.2 (M+H) + .

[0290] (6aR,9R)-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; mixture of epimers at the 5a position) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M aqueous D-(-)-tartaric acid (50 μL, 50.0 μmol). The solvent was removed in vacuo. The residue was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-propyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide tartrate (36 tartrate; mixture of diastereomers; epimer at the 5a position) as a fluffy brown solid. Yield: 24.0 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.11 - 6.94 (m, 2H), 6.57 (dd, J = 5.3, 2.9, 1H), 6.37 (s, 1H), 4.42 (s, 2H), 4.22 - 4.06 (m, 2H), 3.75 - 3.67 (m, 1H), 3.66 - 3.61 (m, 2H), 3.56 (dd, J = 14.8, 7.4, 2H), 3.50 - 3.40 (m, 1H), 3.44 (dt, J = 11.5, 6.3, 2H), 3.31 - 3.22 (m, 2H), 3.21 - 3.06 (m, 2H), 2.81 - 2.67 (m, 1H), 1.93 - 1.73 (m, 2H), 1.65 (dd, J = 23.6, 11.7, 1H), 1.31 (t, J = 7.1, 3H), 1.17 (t, J = 7.1, 3H), 1.05 (t, J = 7.3, 3H). LC-MS purity: 100% (ELSD), 98% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 3.85 min. LC-MS m / z: 354.2 (M+H) + . EXAMPLES

[0291] 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) Reaction Scheme:

[0292] [ka]

[0293] Synthesis protocol: (6aR,9R)-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 (silica gel 0.063-0.200 mm, 10 g) was added. The mixture was concentrated in vacuo. The resulting powder was added to the top of a flash chromatography column prepacked with silica gel and the product was eluted as follows (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 98:2) to give (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (37; mixture of diastereomers; epimer at the 5a position) as a dark amorphous solid. Yield: 16.3 mg (15%). LC-MS purity: 92% (ELSD), 77% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 3.46 min LC-MS m / z: 326.1 (M+H) + .

[0294] (6aR,9R)-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; mixture of epimers at the 5a position) was dissolved in gradient grade acetonitrile (5.0 mL) and treated with 1 M aqueous D-(-)-tartaric acid (50 μL, 50.0 μmol). The solvent was removed in vacuo and the material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C to give (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide tartrate (37 tartrate; mixture of diastereomers; epimer at the 5a position) as a fluffy brown solid. Yield: 24.0 mg (quantitative). LC-MS purity: 92% (ELSD), 77% (UV, 310nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70 to 100:0 + 0.1% HBFA, 10 min): 3.46 min LC-MS m / z: 326.1 (M+H) + . EXAMPLES

[0295] 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) Reaction Scheme:

[0296] [ka]

[0297] Synthesis protocol: A solution of (6aR,9R)-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 dry N,N-dimethylformamide (10 mL) was cooled to 0° C. under an argon atmosphere. Propanephosphonic anhydride (T3P®, 0.998 mL, 1.71 mmol, 50% solution in DMF) was added dropwise over 5 minutes. The resulting mixture was stirred at 0° C. for 3 hours. The reaction was determined to be complete by LC-MS and was then quenched with ice-cold water (10 mL). The mixture was partitioned between 1 M ammonium hydroxide solution (250 mL) and ethyl acetate (200 mL). The aqueous phase was re-extracted with ethyl acetate (2 × 200 mL) and the combined organic phases were washed with 10% aqueous lithium chloride solution (4 × 150 mL) and dried over anhydrous magnesium sulfate. The solvent was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 100:0-98:2). The main fraction was cut off and after evaporation of the solvent, (6aR,9R)-N,N-bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (38) was obtained as a colorless amorphous solid. Yield: 25 mg (5%). 1 H NMR spectrum (300 MHz, CD3CN, δ H): 9.01 (s, 1H), 7.23 (dd, J = 6.0, 2.7, 1H), 7.14 - 7.06 (m, 2H), 6.95 (t, J = 1.7, 1H), 6.32 (s, 1H), 4.74 - 4.62 (m, 2H), 4.59 - 4.47 (m, 2H), 3.98 - 3.86 (m, 2H), 3.80 (dd, J = 9.2, 4.6, 1H), 3.75 (td, J = 4.9, 1.9, 1H), 3.70 - 3.63 (m, 1H), 3.53 (dd, J = 14.7, 5.6, 1H), 3.12 - 3.07 (m, 1H), 3.07 - 2.98 (m, 1H), 2.63 (t, J = 10.7, 1H), 2.58 - 2.47 (m, 1H), 2.48 (s, 3H). LC-MS purity: 100% (ELSD), 95% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 4.90 min. LC-MS m / z: 360.1 (M+H) + .

[0298] (6aR,9R)-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 gradient grade acetonitrile (5.0 mL) and treated with 1 M D-(-)-tartaric acid in water (34.8 μL, 34.8 μmol). The resulting mixture was stirred for an additional 5 min. The solvent was removed in vacuo and the remaining material was redissolved in dioxane (5.0 mL) and lyophilized at 0 °C. This gave (6aR,9R)-N,N-bis(2-fluoroethyl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide hemitartrate (38 hemitartrate) as a fluffy white solid. Yield: 30.2 mg (quantitative). 1 H NMR spectrum (300 MHz, MeOD, δ H ): 7.24 (dd, J = 6.8, 1.9, 1H), 7.16 - 7.07 (m, 2H), 7.02 (d, J = 1.3, 1H), 6.42 (s, 1H), 4.77 (t, J = 4.6, 1H), 4.70 (t, J = 4.9, 1H), 4.61 (t, J = 4.6, 1H), 4.55 (t, J = 4.9, 1H), 4.40 (s, 1H), 4.34 - 4.24 (m, 1H), 4.02 (dd, J = 9.7, 4.7, 1H), 3.93 (dd, J = 10.2, 4.8, 1H), 3.84 (t, J = 4.9, 1H), 3.81 - 3.73 (m, 2H), 3.72 - 3.63 (m, 2H), 3.43 (dd, J = 11.7, 4.8, 1H), 3.19 (t, J = 10.4, 1H), 2.89 (s, 3H), 2.93 - 2.82 (m, 1H). LC-MS purity: 100% (ELSD), 95% (UV, 310 nm). LC-MS Rt (Sinergy Polar RP, 4.6 mm x 150 mm, acetonitrile / water 30:70-100:0 + 0.1% HBFA, 10 min): 4.90 min. LC-MS m / z: 360.1 (M+H) + . EXAMPLES

[0299] 5-HT2A and 5-HT2B receptor binding In radioligand binding experiments, the binding affinities of the disclosed compounds at the ketanserin binding site of the 5-HT2A receptor and at the LSD binding site of the 5-HT2B receptor were determined.

[0300] method: WuXi AppTec (HongKong) Limited 3The affinity of the test compounds for the 5-HT2A receptor was determined in radioligand binding experiments with [H]ketanserin by using a method adapted from the literature and under the conditions described in Table 1.

[0301] [Table 1]

[0302] WuXi AppTec (Hong Kong) Limited 3 The affinity of the test compounds for the 5-HT2B receptor was determined in radioligand binding experiments with [H]LSD by using a method adapted from the literature and under the conditions described in Table 2.

[0303] [Table 2]

[0304] result: The results of the radioligand binding assay are shown in Table 3. The tested compounds showed appreciable binding affinity to the 5-HT2A and 5-HT2B receptors. Compounds with an R configuration at position 9 were much more potent at the 5-HT2A receptor than compounds with an S configuration at this position. The tested compounds were more selective for the 5-HT2A receptor over the 5-HT2B receptor compared to the reference compound LSD. Compounds bearing an arylalkyl or heteroarylalkyl substituent at the amine nitrogen (position 7) were significantly more selective for Ca 2+ Binding at the 5-HT2A receptor tended to be much stronger than in the signal transduction assay (see Table 4).

[0305] [Table 3] EXAMPLES

[0306] Functional activity at serotonin receptors Ca 2+ The disclosed compounds were tested for agonist activity at several serotonin receptor subtypes (5-HT2A, 2-HT2B, 5-HT2C, and 5-HT1A) using a flux functional assay, and for agonist activity at the 5-HT1B receptor using a cAMP accumulation assay. The results are summarized in Table 4. Most compounds showed potent agonist activity at the 5-HT2A receptor, suggesting potential hallucinogenic activity as well as possible therapeutic effects. Compounds with an R configuration at position 9 were much more potent at the 5-HT2A receptor than compounds with an S configuration at this position. Potent agonist activity was also observed at other serotonin receptors tested, although the selectivity profile differed by receptor across all compounds. For example, compounds with longer alkyl chains on the amine nitrogen (e.g., 2, 3, 4, and 6) tended to show higher selectivity for 5-HT2A over 5-HT1B compared to the N-methyl prototype LSD. Similarly, compounds with longer N-alkyl chains (e.g., N-propyl compounds 3, 4, and 7) tended to have higher selectivity for 5-HT2A over 5-HT2B compared to their closest N-methyl counterparts (e.g., Int8, Int11, and Int17, respectively). At the same time, however, the N-propyl compounds were more effective agonists at 5-HT2B than the corresponding N-methyl compounds. The selectivity of the disclosed compounds for 5-HT2A over 5-HT2C and 5-HT1A was less predictable and varied widely across all compounds, ranging from about 1:6 to about 20:1 (2C / 2A) for 5-HT2C and from about 1:4 to >100:1 (1A / 2A) for 5-HT1A. Compounds bearing an arylalkyl or heteroarylalkyl substituent at the amine nitrogen (position 7) tend to be more selective for the 5-HT2A receptor in terms of agonist activity and show no substantial agonist activity at other serotonin receptors.

[0307] Functional assays for 5-HT2A, 5-HT2B, and 5-HT1A. FLIPRCa was developed by WuXi AppTec (Hong Kong). 2+ Flow assays were used to determine agonist activity at 5-HT2A, 5-HT2B, and 5-HT1A receptors following these standard protocols. Briefly, stably transfected cells expressing the receptors of interest (HEK293 for 5-HT2A and 5-HT2B; CHO cells for 5-HT1A) were cultured and plated into 384-well plates and incubated overnight at 37°C and 5% CO2. A solution of 250 mM probenecid in 1 mL FLIPR assay buffer was freshly prepared. This was combined with a fluorescent dye (Fluo-4 Direct™) to produce a final assay concentration of 2.5 mM. Compounds were diluted 1:3.16 for 10 points and 750 nL was added to a 384-well compound plate using an ECHO with 30 μL assay buffer. The fluorescent dye was then added to the assay plate with assay buffer to a final volume of 40 μL. The cell plate was incubated at 37° C. and 5% CO2 for 50 minutes and placed in the FLIPR Tetra along with the compound plate. 10 μL of reference compounds and compounds were then transferred from the compound plate to the cell plate and the fluorescent signal was read.

[0308] Functional assay for 5-HT2C. FLIPR Ca was used in Eurofins DiscoverX (Fremont, CA). 2+A flow assay was used to determine agonist activity at 5-HT2C following these standard protocols. Briefly, stably transfected cells expressing human 5-HT2C receptors were cultured, plated in 384-well plates, and incubated overnight at 37°C and 5% CO2. Assays were performed in 1x Dye Loading Buffer consisting of 1x dye, 1x Additive A, and 2.5mM probenecid in HBSS / 20mM Hepes. Probenecid was freshly prepared. Prior to testing, cells were loaded with dye and incubated at 37°C for 30-60 minutes. After dye loading, cells were removed from the incubator and 10μL of HBSS / 20mM Hepes was added. 3x vehicle was included in the assay buffer. Cells were incubated in the dark at room temperature for 30 minutes to equilibrate to plate temperature. Intermediate dilutions of sample stocks were performed to generate 4x samples in assay buffer. Compound agonist activity was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and assayed by adding 10 μL of 4× sample in HBSS / 20 mM Hepes to cells for 5 seconds.

[0309] Functional assay in 5-HT1B. The cAMP accumulation protocol was used to determine the agonist activity in 5-HT1B according to the standard protocol at WuXi AppTec (HongKong) Limited. Briefly, stably transfected cells were plated on OptiPlate-384 well plate, incubated at room temperature for 60 minutes, and cAMP standard (800nM, 10μL) was added to empty wells. Then, 10μL of detection reagent was added to each well, the plate was incubated at room temperature for 60 minutes, and the plate was read using EnVision.

[0310] [Table 4A]

[0311] [Table 4B] EXAMPLES

[0312] Functional activity at the 5-HT2A receptor in a beta-arrestin recruitment assay The disclosed compounds were tested for agonist activity at the 5-HT2A receptor using a beta-arrestin (arrestin) recruitment functional assay. The results are summarized in Table 5. All compounds tested were agonists in this assay, and many were highly potent. Compounds with an R configuration at position 9 were much more potent at the 5-HT2A receptor than compounds with an S configuration at this position. The size and nature of the substituent at the amine nitrogen (position 7) was found to be an important determinant of maximal efficacy in this assay. Compounds with longer alkyl chains at this position (e.g., 1, 2, 3, 4, 5, 6, 7, and 8) were all full agonists, whereas compounds with a methyl substituent on the amine (e.g., LSD, Int11, Int8, Int14, and Int17) all showed E max Interestingly, compounds 10 and 11, which have much larger aryl substituents at this position, were also partial agonists. These compounds (10 and 11) also inhibited G protein-dependent Ca 2+ It was also unique in that it was much more potent (>50-fold) in this assay compared to the signaling assay, thus demonstrating a significant arrestin bias in signaling (see Table 4). The degree of arrestin bias varied widely across all other compounds tested.

[0313] Arrestin Functional Assay in 5-HT2A. Recruitment of beta-arrestin was determined using the PathHunter assay at Eurofins DiscoverX (Fremont, CA) following their standard protocol. The PathHunter GPCR beta-arrestin assay utilizes DiscoverX's proprietary Enzyme Fragment Complementation technology. The GPCR is fused in frame with a small enzyme donor fragment, ProLink™ (PK), and co-expressed in cells stably expressing a fusion protein of beta-arrestin and a larger, N-terminal deletion mutant of beta-galactosidase. Activation of the GPCR (in this case the 5-HT2A receptor) stimulates the binding of beta-arrestin to the PK-tagged GPCR, driving complementation of the two enzyme fragments resulting in the formation of active beta-galactosidase enzyme. This interaction results in an increase in enzyme activity that can be measured using the chemiluminescent PathHunter Detection Reagents. Briefly, PathHunter cells expressing the 5-HT2A receptor were seeded in 384-well plates in a volume of 20 μL and incubated at 37° C. for an appropriate time prior to testing. For determination of agonist activity, cells were incubated with 5 μL of 5× sample in assay buffer, with a vehicle concentration of 1%, for 90-180 min at 37° C. Plates were then imaged on a microplate reader and agonist activity was calculated using the following formula: % activity = 100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control), where RLU = relative light units.

[0314] [Table 5] EXAMPLES

[0315] Functional activity at other monoamine receptors Ca 2+Using the flux functional assay, the disclosed compounds were tested for agonist activity at several adrenergic (Alpha1A and Alpha2A) and dopamine (D1 and D2) receptor subtypes. The results are summarized in Table 6. Selectivity for the 5-HT2A receptor over these other targets varies depending on the specific target and compound. In many cases, the disclosed compounds were more selective than LSD for the 5-HT2A receptor over the adrenergic and dopamine receptors tested. In particular, compound 3 showed exceptional selectivity. It was also found that the size and nature of the substituent on the amine nitrogen (position 7) was an important determinant of maximal efficacy at these receptors. Compounds with longer alkyl chains at this position (e.g., 1, 2, 3, 4, and 6) showed significantly higher maximal efficacy at alpha1A, alpha2A, and D2 compared to the N-methyl compound LSD. Interestingly, compounds 10 and 11, which have much larger aryl substituents at this position, were much less potent agonists at alpha 1A and alpha 2A.

[0316] Functional assays for adrenergic and dopamine receptors. WuXi AppTec (Hong Kong) Limited uses FLIPR Ca 2+A flux assay was used to determine agonist activity at alpha1A, alpha2A, D1, and D2 receptors according to its standard protocol. Briefly, stably transfected cells expressing the receptor of interest were cultured and plated in 384-well plates and incubated overnight at 37°C and 5% CO2. A solution of 250 mM probenecid in 1 mL FLIPR assay buffer was freshly prepared. This was combined with a fluorescent dye (Fluo-4 Direct™) to produce a final assay concentration of 2.5 mM. Compounds were diluted 1:3.16 for 10 points and 750 nL was added to a 384-well compound plate using an ECHO with 30 μL assay buffer. The fluorescent dye was then added to the assay plate with assay buffer to a final volume of 40 μL. The cell plate was incubated for 50 minutes at 37°C and 5% CO2 and placed in the FLIPR Tetra with the compound plate. 10 μL of reference compound and compound were then transferred from the compound plate to the cell plate and the fluorescent signal was read.

[0317] [Table 6] EXAMPLES

[0318] Effects of Compound 1 on the Head Twitch Response (HTR) in Mice Compound 1 was tested for its ability to induce a head twitch response (HTR) in mice. The results are summarized in Figure 1. Agonists of the 5-HT2A receptor are well known to induce this effect in rodents, and the potency of this HTR correlates with hallucinogenic potency in humans. Compound 1 induced a strong, dose-dependent HTR.

[0319] method: Animals. Adult male C57BL / 6 mice, 6-8 weeks of age (body weight 20-25 g) were used in this study. The animals were housed under controlled temperature and a 12-h light / dark cycle (lights on between 07:00 and 19:00) with food and water available ad libitum. The study was carried out in strict accordance with the requirements of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India. All efforts were made to minimize suffering.

[0320] Drugs and Drug Administration. Compound 1 was synthesized as described above. It was dissolved in saline vehicle at a volume of 10 mL / kg and administered subcutaneously (SC). Five doses were tested with n=6 animals / group. Doses were calculated based on the free base.

[0321] Procedure. Mice were administered a single dose of drug and immediately placed in a small open field for behavioral observation. Animals were continuously observed for 20 min and the number of head twitches (HT) was counted by an observer blinded to the treatment conditions.

[0322] Statistical analysis. Data points shown are mean ± standard error of the mean (SEM). Analysis was performed using GraphPad Prism6. ED 50 To calculate Emax values, curves were fitted using a nonlinear Gaussian distribution. EXAMPLES

[0323] Effects of Compound 1 in the Forced Swim Test in Rats In the forced swim test (FST), Compound 1 induced antidepressant-like effects in rats receiving a 23.5-h pretreatment period (Figure 2). Specifically, at the highest dose, the compound reduced immobility time compared to vehicle controls, indicating an antidepressant-like effect. This effect on immobility was observed 23.5 hours after single compound administration, at which point most or all of the drug had been cleared from the systemic circulation.

[0324] method: Animals. Male Sprague Dawley rats, 9-10 weeks of age, were used in this study. The animals were housed in two groups under controlled temperature (22±3°C) and relative humidity (30-70%) conditions, with a 12-h light / dark cycle and free access to food and water. The study was carried out in strict accordance with the requirements of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India. All efforts were made to minimize suffering.

[0325] Drugs and Drug Administration. Compound 1 was synthesized as described above. Desipramine HCl was obtained commercially. Test compounds, saline vehicle, and the positive control, desipramine, were administered subcutaneously (SC) with doses calculated based on the free base. Saline was used as the vehicle. All compounds were administered in a volume of 5 mL / kg. Test compounds and vehicle were administered 0.5 hours after the start of the training swim (swim 1) and 23.5 hours before the test swim (swim 2). Desipramine was administered three times before the test swim (swim 2), at 23.5 hours, 5 hours, and 1 hour, each time at a dose of 20 mg / kg. Group size was n=10 per treatment.

[0326] Forced Swim Test (FST). Animals were randomized based on body weight to ensure that variation between groups was minimal and did not exceed ±20% of the mean body weight across groups. Rats were habituated by handling for approximately 2 min per day starting 5 days before the start of the experimental procedure. On the first day of the experiment (i.e., day 0), a post-randomization, training swim session (Swim 1) was performed for all animals between 12:00 and 18:00, in which rats were placed in individual glass cylinders (46 cm high x 20 cm diameter) containing water at 23-25°C and a depth of 30 cm for 15 min. At the end of Swim 1, animals were dried using paper towels and placed in heated drying cages for 15 min and then returned to their home cages. Animals were then administered the appropriate drug or vehicle treatment as described above. For clarity, the time of compound administration 23.5 hours prior to swim 2 means 0.5 hours from the start of swim 1 and 0.25 hours from the completion of swim 1 (i.e., immediately after returning to the home cage). On day 1 (i.e., 24 hours after the start of swim 1), animals performed a test swim (swim 2) for a 5 minute period, otherwise under the same conditions as swim 1. Water was changed between each animal during all swim sessions.

[0327] Behavioral scoring was performed by an observer blinded to the treatment groups. Animals were continuously observed during swim 2 and the total time spent in the following behaviors was recorded: immobile, swimming, and climbing. Rats were scored as immobile if they remained floating in the water without struggling and only made movements necessary to keep their head above water. Rats were scored as swimming if they made more vigorous swimming movements than those required simply to keep their head above water (e.g., moving around in the cylinder). Rats were scored as climbing if they made vigorous movements by moving their forelimbs in and out of the water, usually against the wall.

[0328] Statistical analysis. Data points shown represent the mean ± standard error of the mean (SEM). Analysis was performed using GraphPad Prism 9. Comparisons between groups were performed using one-way analysis of variance (ANOVA), followed by Dunnett's test for comparisons with vehicle. EXAMPLES

[0329] Effects of Compound 1 on marble burying in mice Compound 1 produced anxiolytic-like effects in the marble burying test (MBT) in C57BL / 6 mice ( FIG. 3 ). Specifically, Compound 1 reduced the number of marbles buried over a 30-minute period compared to vehicle.

[0330] method: Animals. Adult male C57BL / 6 mice, 8-10 weeks of age (body weight 20-25 g) were used for these experiments. The animals were housed under controlled temperature and a 12-h light / dark cycle (lights on between 07:00 and 19:00) with food and water available ad libitum. The study was performed in strict accordance with the requirements of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India. All efforts were made to minimize suffering.

[0331] Drugs and Drug Administration. Compound 1 was synthesized as described above. Desipramine HCl was obtained commercially. Test compounds, vehicle, and the positive control desipramine were administered subcutaneously (SC) with doses calculated based on the free base. Saline was used as the vehicle. All compounds were administered in a volume of 10 mL / kg. All treatments were administered 30 min prior to the start of behavioral testing. Group size was n=9-10 per treatment.

[0332] Marble burying test (MBT). Animals were randomized based on body weight to ensure minimal variation between groups and did not exceed ±20% of the mean body weight across groups. Mice were habituated by handling for approximately 2 min per day, beginning 3 days prior to the start of the experimental procedure. Twenty marbles (16 mm diameter) were placed at equal distances in a 5 × 4 pattern in a 5 cm layer of corncob bedding, with the marbles spaced at least 2 cm from the cage edge. The total number of buried marbles was counted in three 10 min time bins (30 min total). A marble was considered buried if it was >2 / 3 covered by the bedding material.

[0333] Statistical analysis. Data points shown are the mean ± standard error of the mean (SEM). Analysis was performed using GraphPad Prism 9. Comparisons between groups were performed using one-way analysis of variance (ANOVA), followed by Dunnett's test for comparisons with vehicle. EXAMPLES

[0334] Effects of additional compounds in the mouse head twitch assay Additional disclosed compounds were tested in the mouse head twitch response (HTR) assay according to the procedure described in Example 34. The compounds induced HTR. The results are summarized in Table 7. Interestingly, the maximum effect (E max) varied widely, and the size and nature of the substituent on the amine nitrogen (position 7) and the amide substituent, as quantified by the number of HTRs induced at the most effective dose, were found to be important determinants of efficacy in this assay. For example, compounds with larger alkyl substituents on the amine (e.g., 1, 2, 3, 5, 6, 7, and 8; all >15 HTR at the most effective dose) tended to be more effective at inducing HTRs compared with compounds with a methyl group at this position (e.g., Int8, Int14, and Int17; all <15 HTR at the most effective dose). However, some compounds showed the opposite trend. For example, the N-propyl derivative 4 was less effective than its N-methyl equivalent, compound Int11. Furthermore, both of these azetidinyl amide compounds (4 and Int11) were less effective than similar compounds bearing other amide substituents, suggesting that they may be less prone to induce hallucinogenic effects. Finally, compounds with larger benzyl and phenethyl substituents on the amine nitrogen (e.g., 10 and 11) were less effective in this assay. This was consistent with their lower maximal effects in arrestin functional assays (see Example 32).

[0335] [Table 7] EXAMPLES

[0336] Effects of additional compounds in the forced swimming test in rats Additional disclosed compounds were tested in the forced swimming test (FST) in rats following the procedure described in Example 35. The compounds reduced immobility time in a dose-dependent manner, indicating antidepressant-like effects. The results are summarized in Table 8. All compounds tested reduced immobility time in a dose-dependent manner 23.5 hours after a single dose, suggesting that the compounds rapidly induce long-lasting antidepressant-like effects. Compounds 2 and 4 were the most potent tested in this assay, being as effective as the positive control desipramine at a dose of 0.032 mg / kg, SC.

[0337] [Table 8] EXAMPLES

[0338] Effects of additional compounds in the mouse marble burying assay Additional compounds of the invention were tested in the mouse marble burying test (MBT) according to the procedures described in Example 36. The compounds reduced the number of buried marbles in a dose-dependent manner, indicating anxiolytic-like activity. EXAMPLES

[0339] Metabolic stability in human liver microsomes The disclosed compounds were tested for stability in human liver microsomes (HLM). The results are summarized in Table 9. The stability of the compounds varied in this assay. The size and nature of the substituent on the amine nitrogen (position 7) was found to be an important determinant of stability in this assay. Among the compounds with the R configuration at position 9, those with longer alkyl chains or bulkier substituents on the amine (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, and 11) showed much lower stability (higher clearance) than those with a methyl substituent at this position (e.g., LSD, Int11, Int8, Int14, and Int17), suggesting that the former may exhibit shorter half-lives in vivo.

[0340] method: HLM stability. Pooled HLM (Corning 452117) from adult male and female donors were used. Microsome incubations were performed in multiwell plates. Liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM) with 0.50 mg liver microsomal protein per mL. Control incubations were performed replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with microsomes at 37° C. with constant shaking. Six time points over 60 min were analyzed, with 60 μL aliquots of reaction mixture withdrawn at each time point. Reaction aliquots were stopped by the addition of 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 min and then precipitation of proteins by centrifugation at 4000 rpm for 20 min at 4° C. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography tandem mass spectrometry (LC-MS / MS) method.

[0341] Data analysis. Linear regression analysis was used to determine the desorption constant (k el ), half-life (t 1 / 2 ), and intrinsic clearance (CL int ) was determined by plotting ln(AUC) versus time.

[0342] [Table 9] EXAMPLES

[0343] Metabolic stability in mouse liver microsomes The disclosed compounds were tested for stability in mouse liver microsomes (MLM). The results are summarized in Table 10. The stability of the compounds varied in this assay. The size and nature of the substituent on the amine nitrogen (position 7) was found to be an important determinant of stability in this assay. Among the compounds with the R configuration at position 9, those with longer alkyl chains or bulkier substituents on the amine (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, and 11) showed much lower stability (higher clearance) than those with a methyl substituent at this position (e.g., LSD, Int11, Int8, Int14, and Int17), suggesting that the former may exhibit shorter half-lives in vivo.

[0344] method: MLM stability. Pooled MLM (BIOIVT M00501) from CD-1 mice was used. Microsomal incubations were performed in multiwell plates. Liver microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM) with 0.50 mg liver microsomal protein per mL. Control incubations were performed substituting PBS for the NADPH cofactor system. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with microsomes at 37° C. with constant shaking. Six time points were analyzed over a 60 min period, with 60 μL aliquots of reaction mixture withdrawn at each time point. Reaction aliquots were stopped by the addition of 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 min and then precipitation of proteins by centrifugation at 4000 rpm for 20 min at 4° C. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0345] Data analysis. Linear regression analysis was used to determine the desorption constant (k el ), half-life (t 1 / 2 ) and intrinsic clearance (Cl int ) was determined by plotting ln(AUC) versus time.

[0346] [Table 10] EXAMPLES

[0347] Metabolic stability in rat liver microsomes The disclosed compounds were tested for stability in rat liver microsomes (RLM). The results are summarized in Table 11. The stability of the compounds varied in this assay. The size and nature of the substituent on the amine nitrogen (position 7) was found to be an important determinant of stability in this assay. Among the compounds with the R configuration at position 9, those with longer alkyl chains or bulkier substituents on the amine (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, and 11) showed much lower stability (higher clearance) than those with a methyl substituent at this position (e.g., LSD, Int11, Int8, Int14, and Int17), suggesting that the former may exhibit shorter half-lives in vivo.

[0348] method: RLM stability. Pooled RLM (Xenotech R1000) from adult male and female donors were used. Microsomal incubations were performed in multiwell plates. Liver microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM) with 0.50 mg of liver microsomal protein per mL. Control incubations were performed replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with microsomes at 37° C. with constant shaking. Six time points over 60 min were analyzed, with 60 μL aliquots of reaction mixture withdrawn at each time point. Reaction aliquots were stopped by the addition of 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 min and then precipitation of proteins by centrifugation at 4000 rpm for 20 min at 4° C. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography tandem mass spectrometry (LC-MS / MS) method.

[0349] Data analysis. Linear regression analysis was used to determine the desorption constant (k el ), half-life (t 1 / 2 ) and intrinsic clearance (Cl int ) was determined by plotting ln(AUC) versus time.

[0350] [Table 11]

[0351] Incorporation by Reference All publications and patents mentioned herein, including but not limited to the items listed below, are hereby incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0352] Equivalent Although specific embodiments of the present disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will be apparent to those skilled in the art upon review of the specification. The full scope of the present disclosure should be determined by reference to the claims, together with such variations, their full scope of equivalents, and the specification.

[0353] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless specifically indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. Compounds of formula (I): 【Chemistry 1】 [In the formula, R 1 is C 1 ~C 6 alkyl or 3- to 7-membered carbocyclyl; R 1 is one or more halogens or C 1 ~C 6 alkyl, optionally substituted; R 2 is hydrogen or C 1 ~C 6 is alkyl, R 2 is one or more halogens or C 1 ~C 6 alkyl, optionally substituted; or R 1 and R 2 can be taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, said heterocyclyl containing one or more fluoro or C 1 ~C 6 alkyl, optionally substituted; R3 is -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 (alkyl)-(6-membered heteroaryl); C 1 ~C 2 The alkyl is optionally substituted with one or more of fluoro, hydroxyl, and -OMe, and the phenyl and 6-membered heteroaryl are each independently substituted with halogen, hydroxyl, -OC(O)(C 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 , -C(O)NH 2 , C 1 ~C 4 Alkyl, C 3 ~C 5 Cycloalkyl and C 1 ~C 4 optionally substituted with one or more substituents selected from the group consisting of alkoxy; R 4 is hydrogen or -C(O)(C 1 ~C 8 alkyl), R 5 is hydrogen or halogen, R 6 is hydrogen or deuterium, R 1 and R 2 are both ethyl, and R 4 and R 5 If both are hydrogen, R 3 Ha-CH 2 CH 2 nor Ph, wherein Ph is unsubstituted. or a pharma- ceutically acceptable salt thereof.

2. R 1 C 1 ~C 6 alkyl or 3- to 5-membered carbocyclyl; R 1 One or more fluoro or C 1 ~C 4 alkyl, optionally substituted; R 2 is hydrogen or C 1 ~C 3 is alkyl, R 2 One or more fluoro or C 1 ~C 4 alkyl, optionally substituted; or R 1 and R 2 can be taken together with the atom to which they are attached to form an optionally substituted 3-6 membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O, and S, said heterocyclyl containing one or more fluoro or C 1 ~C 3 alkyl, optionally substituted; R3 is -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 (alkyl)-(6-membered heteroaryl); C 1 ~C 2 The alkyl is optionally substituted with one or more fluoro, and the phenyl and 6-membered heteroaryl are each independently halogen, hydroxyl, -OC(O)(C 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 , -C(O)NH 2 , C 1 ~C 3 Alkyl, cyclopropyl, and C 1 ~C 3 optionally substituted with one or more substituents selected from the group consisting of alkoxy; R 4 is hydrogen or -C(O)(C 1 ~C 8 alkyl), R 5 is hydrogen or halogen, R 6 The compound of claim 1, wherein is hydrogen or deuterium.

3. R 4 3. The compound according to claim 1 or 2, wherein is hydrogen.

4. Compounds of formula (Ia): 【Chemistry 2】 3. The compound according to claim 1 or 2,

5. Compounds of formula (Ib), (Ic), (Id) or (Ie): 【Chemistry 3】 3. The compound according to claim 1 or 2,

6. R 5 6. The compound according to any one of claims 1 to 3 or 5, wherein is hydrogen.

7. R 3 But-(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 (alkyl)-(6-membered heteroaryl); C 1 ~C 2 The alkyl is optionally substituted with one or more fluoro, and the phenyl and 6-membered heteroaryl are each independently selected from halogen, hydroxyl, -OC(O)(C 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 , -C(O)NH 2 , C 1 ~C 3 Alkyl, cyclopropyl, and C 1 ~C 3 7. The compound of any one of claims 1 to 6, optionally substituted with one or more substituents selected from the group consisting of alkoxy.

8. R 3 But -(C 1 ~C 2 Alkyl)-phenyl and -(C 1 ~C 2 (alkyl)-pyridinyl; Phenyl and pyridinyl are each independently a halogen, a hydroxyl, -OC(O)(C 1 ~C 8 Alkyl), -CN, -NO 2 , -NH 2 , -C(O)NH 2 , C 1 ~C 3 Alkyl, cyclopropyl, and C 1 ~C 3 8. The compound of any one of claims 1 to 7, optionally substituted with one or more substituents selected from the group consisting of alkoxy.

9. R 3 is selected from the group consisting of -(C 1 -C 2 alkyl)-phenyl and -(C 1 -C 2 alkyl)-pyridinyl; 9. The compound of any one of claims 1 to 8, wherein phenyl and pyridinyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -CN, methyl, ethyl, and -OMe.

10. R 3 is selected from the group consisting of -(C 1 -C 2 alkyl)-phenyl and -(C 1 -C 2 alkyl)-pyridinyl; 10. The compound of any one of claims 1 to 9, wherein phenyl and pyridinyl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxyl, and -OMe.

11. R 3 is selected from the group consisting of -(C 1 -C 2 alkyl)-phenyl and -(C 1 -C 2 alkyl)-pyridinyl; 11. The compound according to any one of claims 1 to 10, wherein the phenyl and pyridinyl are optionally substituted with one hydroxyl or -OMe.

12. The compound according to any one of claims 1 to 11, wherein R 3 is -(C 1 -C 2 alkyl)-phenyl.

13. The compound of any one of claims 1 to 11, wherein R 3 is -(C 1 alkyl)-phenyl.

14. R 3 but, 【Chemistry 4】 12. The compound according to any one of claims 1 to 11, selected from the group consisting of:

15. 【Chemical 5】 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

16. 【Chemical 7】 or a pharma- ceutically acceptable salt thereof.

17. 【Chemical 8】 or a pharma- ceutically acceptable salt thereof.

18. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharma- ceutically acceptable adjuvant or carrier.

19. 20. A compound according to any one of claims 1 to 17 for use in the treatment of a mood disorder.

20. 20. The compound of claim 19, wherein the mood disorder is a depressive disorder.

21. 20. The compound of claim 19, wherein the mood disorder is bipolar disorder.

22. 20. The compound of claim 19, wherein the mood disorder is an anxiety disorder.

23. 20. The compound of claim 19, wherein the mood disorder is selected from the group consisting of substance-related disorders, substance use disorders, obsessive-compulsive disorders and related disorders, trauma- and stress-related disorders, eating disorders and eating disorders, borderline personality disorder, attention-deficit / hyperactivity disorder, and autism spectrum disorder.

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