Substituted heterocycle fused gamma-carbolines

[0001] (Field of invention) The present invention is directed to a specific novel compound represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof: [0002] [Chemical 11]<img file="JP4916633B2_D0001.tif" />[0003] In the formula, R¹, R⁵, R^6a, R^6b, R⁷, R⁸, R⁹, X, b, k, m, and n, and dashed lines are as described below. The present invention also relates to pharmaceutical formulations containing these novel compounds as active ingredients and the use of novel compounds and formulations thereof in the treatment of specific diseases. The compounds of the invention are serotonin agonists and antagonists, including obesity, anxiety, depression, psychiatric disorders, schizophrenia, sleep disorders, sexual disorders, migraine headaches, headache-related conditions, social phobia, and gastrointestinal motility disorders. It is useful in the management or prevention of central nervous system disorders including gastrointestinal disorders. [0004] (Background of invention) There is a significant correlation between 5-HT2 receptor regulation and various diseases and treatments. To date, three subtypes of the 5-HT2 receptor class, 5-HT2A, 5-HT2B, and 5-HT2C have been identified. Prior to the early 1990s, 5-HT2C and 5-HT2A receptors were called 5-HT1C and 5-HT2, respectively. [0005] Selective or non-selective operability or antagonism of 5-HT2 receptors has been associated with the treatment of various central nervous system (CNS) disorders. Ligands that have an affinity for 5-HT2 receptors have been shown to have many physiological and behavioral effects (Trends in Pharmacological). Sciences, 11,181,1990). Recently, the contribution of serotoninergic activity to the mechanism of action of antidepressants has been demonstrated in detail. Compounds that enhance the general basal status of serotonin in the CNS have been successfully developed as antidepressants. Serotonin selective reuptake inhibitors (SSRIs) function by increasing the amount of serotonin present at nerve synapses. However, these breakthrough treatments are not without side effects and cause delayed onset of action (Leonard, J. Clin. Psychiatry, 54 (suppl), 3,1993). SSRIs affect the activity of many serotonin receptor subtypes by their mechanism of action. Non-specific regulation of the serotonin family of this receptor is thought to play an important role in the nature of side effects. In addition, these compounds often have high affinities for numerous serotonin receptors as well as numerous other monoamine neurotransmitters and interfering receptors. Elimination of some receptor cross-reactivity will allow the testing and development of potent therapeutic ligands with improved side effect properties. [0006] There is ample evidence to support the role of selective 5-HT2 receptor ligands in the treatment of some diseases. Regulation of 5-HT2 receptors has been associated with the treatment of schizophrenia and psychosis (Udego, L. et al., Psychopharmacology, 98, 45, 1989). Mood, behavior and hallucinations can be influenced by 5-HT2 receptors in the limbic system and cerebral cortex. Regulation of 5-HT2 receptors in the hypothalamus can affect appetite, thermoregulation, sleep, sexual behavior, motor activity, and neuroendocrine function (Hartig, P. et al., Annals New York Academy of Science, 149,159). There is also evidence that 5-HT2 receptors mediate hypoactivity, affect rat feeding, and mediate penile erection (Pyschopharmacology, 101, 57, 1990). [0007] Compounds that are selective for 5-HT2B receptors are used in the treatment of symptoms such as tachygastria, locomotor hyperactivity associated with irritant bowel disorders, constipation, dyspepsia, and other peripherally mediated symptoms. It is useful. [0008] 5-HT2A antagonists have been shown to be effective in the treatment of schizophrenia, anxiety, depression, and migraine (Koek, W., Neuroscience and Behavioral reviews, 16,95, 1996). Classical relaxants not only have beneficial antipsychotic effects, but are often responsible for inducing acute extrapyramidal side effects and neuroendocrine disorders. These compounds generally have significant dopamine D2 receptor affinity (as well as other interfering receptor affinity), which is often associated with extrapyramidal symptoms and tardive dyskinesia, and thus schizophrenia. It diminishes its effectiveness as a front-line treatment in diseases and related disorders. Compounds with more favorable selectivity will show the potential to improve the treatment of CNS disorders. [0009] U.S. Pat. Nos. 3,914,421, 4,013,652, 4,115,577, 4,183,936, and 4238607 disclose the pyridopyrrolobenz heterocycle of the following equation: [0010] [Chemical 12]<img file="JP4916633B2_D0002.tif" />[0011] In the formula, X is O, S, S (= O), or SO₂And n is 0 or 1 and R¹Is a variety of carbon substituents and Z is a mono-substituted group of H, methyl, or chloro. [0012] U.S. Pat. No. 4,219,550 discloses the pyridopyrrolobenz heterocycle of the following equation: [0013] [Chemical 13]<img file="JP4916633B2_D0003.tif" />[0014] In the formula, X is O or S and R¹Is C₁_~₄Alkyl or cyclopropyl, R²Is H, CH₃, OCH₃, Cl, Br, F, or CF₃And (A) is -CH₂-,-CH (CH₃)-Or-CH₂CH₂-. [0015] (Outline of the invention) One object of the present invention is to provide a novel compound useful as an agonist or antagonist of 5-HT2 receptor, particularly 5-HT2A and 5-HT2C receptor, or a pharmaceutically acceptable salt or prodrug thereof. is there. [0016] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the invention or a pharmaceutically acceptable salt or prodrug thereof. That is. [0017] Another object of the present invention is gastrointestinal such as obesity, anxiety, depression, psychiatric disorders, schizophrenia, sleep and sexual disorders, migraine and other conditions associated with headaches, social phobia, and gastrointestinal motility dysfunction. A method for treating central nervous system disorders, including disorders, which is therapeutically effective for at least one compound of the invention or a pharmaceutically acceptable salt or prodrug thereof for a host in need of such treatment. It is to provide a method comprising administering an amount. More specifically, the present invention provides methods for treating obesity, anxiety, depression or schizophrenia. [0018] These and other purposes, as will become apparent after reading the detailed description below, are the compounds of formula (I) below or pharmaceutically acceptable salts or prodrugs thereof: [0019] [Chemical 14]<img file="JP4916633B2_D0004.tif" />[0020] (In the formula, R¹, R⁵, R^6a, R^6b, R⁷, R⁸, R⁹, X, b, k, m, and n are defined below) was achieved by our findings that they are effective agonists or antagonists of 5-HT2 receptors. [0021] [0021] (Detailed description of the invention) Therefore, in the first embodiment, the present invention provides a novel compound of the following formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt: [0022] [Chemical 15]<img file="JP4916633B2_D0005.tif" />[0023] During the ceremony b is a single bond or a double bond; [0024] X is -CHR¹⁰-, -C (= O)-, -O-, -S-, -S (= O)-, -S (= O)₂-, -NR^10A-, -C (= O) NR^10A-Or -NR^10AC (= O)-is; [0025] R¹Is H, C (= O) R², C (= O) OR², C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₃_~₇Cycloalkyl, C replaced by Z₁_~₆Alkyl, C replaced by Z₂_~₆Alkenyl, C replaced by Z₂_~₆Alkyne, C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S. C replaced by Y₁_~₃Alkyl, C replaced by Y₂_~₃Alkenyl, C replaced by Y₂_~₃Alkyne, 0 ~ 2 R²C replaced by₁_~₆Alkyl, 0 ~ 2 R²C replaced by₂_~₆Alkenyl, 0 ~ 2 R²C replaced by₂_~₆Alkyne, 0 ~ 2 R²Aryl substituted with, as well Contains at least one heteroatom selected from the group consisting of N, O, and S, 0-2 R²Selected from 5- to 6-membered heterocyclic systems substituted with; [0026] Y is C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S. -(C₁_~₃Alkyl) -Z substituted C₃_~₆Cycloalkyl, -(C₁_~₃Alkyl) -Z-substituted aryl, as well Contains at least one heteroatom selected from the group consisting of N, O, and S,-(C₁_~₃Alkyl) -selected from Z-substituted 5- to 6-membered heterocyclic systems; [0027] Z is H, -CH (OH) R², -C (ethylenedioxy) R², -OR², -SR², -NR²R³, -C (O) R², -C (O) NR²R³, -NR³C (O) R², -C (O) OR², -OC (O) R², -CH (= NR)⁴) NR²R³, -NHC (= NR)⁴) NR²R³, -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0028] R²At each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0029] R³H, C at the time of each appearance₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0030] Alternatively, R²And R³Concatenate -O- or -N (R)⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0031] R⁴H and C at each appearance₁_~₄Selected independently of alkyl; [0032] R⁵Is H or C₁_~₄Alkyl; [0033] R^6aAnd R^6bH, -OH, -NR at each appearance⁴⁶R⁴⁷, -CF₃, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, and 0 to 3 Rs⁴⁴Selected independently of aryl substituted with; [0034] R⁷And R⁹At each appearance H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) R¹³, C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², As well as NR¹⁴S (O)₂R¹²Selected independently from; [0035] R⁸Is H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) R¹³, C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², As well as NR¹⁴S (O)₂R¹²Selected from; [0036] R¹⁰Is H, -OH, 0 to 1 R^10BC replaced by₁_~₆Alkyl, 0 to 1 R^10BC replaced by₂_~₆Alkenyl, 0 to 1 R^10BC replaced by₂_~₆Alkyne, and C₁_~₆Selected from alkoxy; [0037] R^10AIs H, 0 to 1 R^10BC replaced by₁_~₆Alkyl, 0 to 1 R^10BC replaced by₂_~₆Alkenyl, 0 to 1 R^10BC replaced by₂_~₆Alkyne, and C₁_~₆Selected from alkoxy; [0038] R^10BIs C₁_~₄Alkoxy, C₃_~₆Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0 ~ 3 R³³Phenyl substituted with, as well 0 ~ 2 R⁴⁴Selected from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with; [0039] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, C₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) R¹³, C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², As well as NR¹⁴S (O)₂R¹²Selected from; [0040] R¹²At each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0041] R¹³H, C at the time of each appearance₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0042] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0043] R¹⁴H and C at each appearance₁_~₄Selected independently of alkyl; [0044] R³¹H, OH, halo, CF at the time of each appearance₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, And C₁_~₄Selected independently of alkyl; [0045] R³³At each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-and C₁_~₄Selected independently of alkyl-C (= O) NH-; [0046] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0047] R⁴²At each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶SO₂R⁴⁵, NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0048] R⁴³Is 0 to 3 R⁴⁴C replaced by₃_~₆Cycloalkyl or aryl; [0049] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, C₁_~₄Alkyl, and C₁_~₄Selected independently of alkoxy; [0050] R⁴⁵Is C₁_~₄Alkyl; [0051] R⁴⁶H and C at each appearance₁_~₄Selected independently of alkyl; [0052] R⁴⁷H and C at each appearance₁_~₄Selected independently of alkyl; [0053] k is 1 or 2; m is 0, 1, 2, or 3; n is 0, 1, or 2; If m is 0, then k is 1; [0054] b is a double bond, n is 1 or 2, m is 1, k is 1, and X is -O-, -S-, -S (= O)-, or -SO.₂-And R⁷, R⁸, And R⁹If the three substituents are i) 3 hydrogens, ii) 2 hydrogens and 1 chloro, or iii) 2 hydrogens and 1 methyl, then R¹Must contain substituents Z or Y b is a double bond, n is 0 or 1, m is 1, k is 1, and X is -CH.₂-And R¹Is hydrogen, C₁_~₆R if alkyl or benzyl⁷, R⁸, And R⁹One of them is hydrogen, halo, C₁_~₆Alkyl, C₁_~₆Must be other than alkoxy or trifluoromethyl b is a single bond, n is 1 or 2, m is 1, k is 1, X is O or S, R¹Is C₁_~₄R if alkyl or cyclopropyl⁸Is a substituent other than H; [0055] R⁶Or R^6aIs NH₂If, then X is -CH (R)¹⁰) Not; If n = 0, then R⁶Or R^6aIs NH₂But it's not -OH. [0056] In another embodiment of the invention X is -CHR¹⁰-, -C (= O)-, -O-, -S-, -S (= O)-, -S (= O)₂-, -NH-, -C (= O) NH-, or -NHC (= O)-; [0057] R¹Is H, C (= O) R², C (= O) OR², C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₃_~₇Cycloalkyl, C replaced by Z₁_~₆Alkyl, C replaced by Z₂_~₆Alkenyl, C replaced by Z₂_~₆Alkyne, C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S; C replaced by Y₁_~₃Alkyl, C replaced by Y₂_~₃Alkenyl, C replaced by Y₂_~₃Alkyne, 0 ~ 2 R²C replaced by₁_~₆Alkyl, 0 ~ 2 R²C replaced by₂_~₆Alkenyl, 0 ~ 2 R²C replaced by₂_~₆Alkyne, 0 ~ 2 R²Aryl substituted with, as well Contains at least one heteroatom selected from the group consisting of N, O, and S, 0-2 R²Selected from 5- to 6-membered heterocyclic systems substituted with; [0058] [0058] Y is C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S; -(C₁_~₃Alkyl) -Z substituted C₃_~₆Cycloalkyl, -(C₁_~₃Alkyl) -Z-substituted aryl, as well Contains at least one heteroatom selected from the group consisting of N, O, and S,-(C₁_~₃Alkyl) -selected from Z-substituted 5- to 6-membered heterocyclic systems; [0059] Z is H, -CH (OH) R², -C (ethylenedioxy) R², -OR², -SR², -NR²R³, -C (O) R², -C (O) NR²R³, -NR³C (O) R², -C (O) OR², -OC (O) R², -CH (= NR)⁴) NR²R³, -NHC (= NR)⁴) NR²R³, -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0060] R²At each appearance Halo, C₁_~₃Haloalkyl, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Aryl substituted with, 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0061] R³H, C at the time of each appearance₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, and C₁_~₄Selected independently of alkoxy; [0062] Alternatively, R²And R³Concatenate -O- or -N (R)⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0063] R⁴H and C at each appearance₁_~₄Selected independently of alkyl; [0064] R⁵Is H or C₁_~₄Alkyl; [0065] R^6aAnd R^6bAt each appearance H, -OH, -NR⁴⁶R⁴⁷, -CF₃, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, and 0 ~ 3 R⁴⁴Selected independently of aryl substituted with; [0066] R⁷And R⁹At the time of each appearance H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, And NR¹²C (O) NHR¹⁵Selected independently from; [0067] R⁸Is H, Halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 2 R¹¹C replaced by₂_~₄Alkenyl, 0 to 1 R¹¹C replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0068] R¹¹Is H, Halo, -CF₃, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, C₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0069] R¹²At each appearance 0 to 1 R^12aC replaced by₁_~₄Alkyl, 0 to 1 R^12aC replaced by₂_~₄Alkenyl, 0 to 1 R^12aC replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0070] R^12aAt the time of each appearance 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0071] R¹³H, C at the time of each appearance₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0072] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0073] Alternatively, R¹²And R¹³Is a 9- or 10-membered bicyclic heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S, combined when attached to N, and not Saturated or partially saturated, 0 to 3 Rs¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0074] R¹⁴H and C at each appearance₁_~₄Selected independently of alkyl; [0075] R¹⁵H, C at the time of each appearance₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0076] R¹⁶H, OH, halo, CN, NO at each appearance₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₃Haloalkyl-oxy-, and C₁_~₃Alkyloxy-selected independently; [0077] R³¹H, OH, halo, CF at each appearance₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, And C₁_~₄Selected independently of alkyl; [0078] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-, C₁_~₄Alkyl-C (= O) NH-, C₁_~₄Alkyl-OC (= O)-, C₁_~₄Alkyl-C (= O) O-, C₃_~₆Cycloalkyl-oxy-, C₃_~₆Cycloalkylmethyl-oxy-; C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₁_~₆Alkyl, and C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₂_~₆Selected independently of alkenyl; [0079] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, = O, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0080] [0080] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵, NR⁴⁶SO₂R⁴⁵, NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0081] R⁴³Is 0 to 3 R⁴⁴C replaced by₃_~₆Cycloalkyl or aryl; [0082] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, C₁_~₄Alkyl, and C₁_~₄Selected independently of alkoxy; [0083] R⁴⁵Is C₁_~₄Alkyl; [0084] R⁴⁶At each appearance, H and C₁_~₄Selected independently of alkyl; [0085] R⁴⁷H, C at the time of each appearance₁_~₄Alkyl, -C (= O) NH (C₁_~₄Alkyl), -SO₂(C₁_~₄Alkyl), -C (= O) O (C₁_~₄Alkyl), -C (= O) (C₁_~₄Alkyl), and -C (= O) H are selected independently; [0086] k is 1 or 2; m is 0, 1, or 2; n is 1, 2, or 3; If m is 0 or 1, k is 1 or 2; If m is 2, then k is 1; [0087] b is a double bond, n is 1 or 2, m is 1, k is 1, and X is -O-, -S-, -S (= O)-, or -SO2- And R⁷, R⁸, And R⁹If the three substituents are i) 3 hydrogens, ii) 2 hydrogens and 1 chloro, or iii) 2 hydrogens and 1 methyl, then R¹Must contain substituents Z or Y b is a single bond, n is 1 or 2, m is 1, k is 1, X is O or S, R¹Is C₁_~₄R if alkyl or cyclopropyl⁸Is a substituent other than H; If n = 0, then R⁶Or R^6aIs NH₂But it's not -OH. [0088] [2] In a preferred embodiment of the present invention. X is -O-, -S-, -S (= O)-, or -S (= O)₂-And; [0089] R¹Is H, C (= O) R², C (= O) OR², C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₃_~₇Cycloalkyl, C replaced by Z₁_~₆Alkyl, C replaced by Z₂_~₆Alkenyl, C replaced by Z₂_~₆Alkyne, C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S. C replaced by Y₁_~₃Alkyl, C replaced by Y₂_~₃Alkenyl, C replaced by Y₂_~₃Alkyne, 0 ~ 2 R²C replaced by₁_~₆Alkyl, 0 ~ 2 R²C replaced by₂_~₆Alkenyl, 0 ~ 2 R²C replaced by₂_~₆Alkyne, 0 ~ 2 R²Aryl substituted with, as well Contains at least one heteroatom selected from the group consisting of N, O, and S, 0-2 R²Selected from 5- to 6-membered heterocyclic systems substituted with; [0090] Y is C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S; [0091] -(C₁_~₃Alkyl) -Z substituted C₃_~₆Cycloalkyl, -(C₁_~₃Alkyl) -Z-substituted aryl, as well Contains at least one heteroatom selected from the group consisting of N, O, and S,-(C₁_~₃Alkyl) -selected from Z-substituted 5- to 6-membered heterocyclic systems; [0092] Z is H, -CH (OH) R², -C (ethylenedioxy) R², -OR², -SR², -NR²R³, -C (O) R², -C (O) NR²R³, -NR³C (O) R², -C (O) OR², -OC (O) R², -CH (= NR)⁴) NR²R³, -NHC (= NR)⁴) NR²R³, -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0093] R²At the time of each appearance Halo, C₁_~₃Haloalkyl, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Aryl substituted with, 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0094] R³H, C at the time of each appearance₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, and C₁_~₄Selected independently of alkoxy; [0095] Alternatively, R²And R³Concatenate -O- or -N (R)⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0096] R⁴H and C at each appearance₁_~₄Selected independently of alkyl; [0097] R⁵Is H or C₁_~₄Alkyl; [0098] R^6aAnd R^6bH, -OH, -NR at each appearance⁴⁶R⁴⁷, -CF₃, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, and 0 ~ 3 R⁴⁴Selected independently of aryl substituted with; [0099] R⁷And R⁹At the time of each appearance H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected independently from; [0100] R⁸Is H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 2 R¹¹C replaced by₂_~₄Alkenyl, 0 to 1 R¹¹C replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0101] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, C₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0102] R¹²At the time of each appearance 0 to 1 R^12aC replaced by₁_~₄Alkyl, 0 to 1 R^12aC replaced by₂_~₄Alkenyl, 0 to 1 R^12aC replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0103] R^12aAt the time of each appearance 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0104] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0105] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0106] Alternatively, R¹²And R¹³Is a 9- or 10-membered bicyclic heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S, combined when attached to N, and not Saturated or partially saturated, 0 to 3 Rs¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0107] R¹⁴H and C at each appearance₁_~₄Selected independently of alkyl; [0108] R¹⁵At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0109] R¹⁶At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₃Haloalkyl-oxy-, and C₁_~₃Alkyloxy-selected independently; [0110] R³¹H, OH, halo, CF at the time of each appearance₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, And C₁_~₄Selected independently of alkyl; [0111] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-, C₁_~₄Alkyl-C (= O) NH-, C₁_~₄Alkyl-OC (= O)-, C₁_~₄Alkyl-C (= O) O-, C₃_~₆Cycloalkyl-oxy-, C₃_~₆Cycloalkylmethyl-oxy-, C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₁_~₆Alkyl, and C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₂_~₆Selected independently of alkenyl; [0112] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, = O, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0113] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵, NR⁴⁶SO₂R⁴⁵, NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0114] R⁴³Is 0 to 3 R⁴⁴C replaced by₃_~₆Cycloalkyl or aryl; [0115] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, C₁_~₄Alkyl, and C₁_~₄Selected independently of alkoxy; [0116] R⁴⁵Is C₁_~₄Alkyl; [0117] R⁴⁶At each appearance, H and C₁_~₄Selected independently of alkyl; [0118] R⁴⁷H, C at the time of each appearance₁_~₄Alkyl, -C (= O) NH (C₁_~₄Alkyl), -SO₂(C₁_~₄Alkyl), -C (= O) O (C₁_~₄Alkyl), -C (= O) (C₁_~₄Alkyl), and -C (= O) H are selected independently; [0119] k is 1 or 2; m is 0, 1, or 2; n is 1, 2, or 3; If m is 0 or 1, k is 1 or 2; If m is 2, then k is 1; [0120] b is a double bond, n is 1 or 2, m is 1, k is 1, and X is -O-, -S-, -S (= O)-, or -SO2- And R⁷, R⁸, And R⁹If the three substituents are i) 3 hydrogens, ii) 2 hydrogens and 1 chloro, or iii) 2 hydrogens and 1 methyl, then R¹Must contain substituents Z or Y b is a single bond, n is 1 or 2, m is 1, k is 1, X is O or S, R¹Is C₁_~₄R if alkyl or cyclopropyl⁸Is a substituent other than H; If n = 0, then R⁶Or R^6aIs NH₂But it's not -OH. [0121] [3] In a more preferred embodiment of the present invention. X is -O-, -S-, -S (= O)-, or -S (= O)₂-And; [0122] R¹Is H, C (= O) R², C (= O) OR², C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₃_~₇Cycloalkyl, 0 ~ 2 R²C replaced by₁_~₆Alkyl, 0 ~ 2 R²C replaced by₂_~₆Alkenyl, 0 ~ 2 R²C replaced by₂_~₆Alkyne, 0 ~ 2 R²Aryl substituted with, as well Contains at least one heteroatom selected from the group consisting of N, O, and S, 0-2 R²Selected from 5- to 6-membered heterocyclic systems substituted with; [0123] R²At the time of each appearance F, Cl, CH₂F, CHF₂, CF₃, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0124] R⁵Is H, methyl, ethyl, propyl, or butyl; [0125] R^6aIs H, -OH, -NR⁴⁶R⁴⁷, -CF₃, C₁_~₄Alkyl, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, and 0 ~ 3 R⁴⁴Selected from aryl substituted with; [0126] R^6bIs H; [0127] R⁷And R⁹At the time of each appearance H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected independently from; [0128] R⁸Is H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 2 R¹¹C replaced by₂_~₄Alkenyl, 0 to 1 R¹¹C replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0129] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, C₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0130] R¹²At the time of each appearance 0 to 1 R^12aC replaced by₁_~₄Alkyl, 0 to 1 R^12aC replaced by₂_~₄Alkenyl, 0 to 1 R^12aC replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0131] R^12aAt the time of each appearance 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0132] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0133] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0134] Alternatively, R¹²And R¹³Is a 9- or 10-membered bicyclic heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S, combined when attached to N, and not Saturated or partially saturated, 0 to 3 Rs¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0135] R¹⁴At each appearance, H and C₁_~₄Selected independently of alkyl; [0136] R¹⁵At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0137] R¹⁶At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₃Haloalkyl-oxy-, and C₁_~₃Alkyloxy-selected independently; [0138] R³¹At the time of each appearance H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, And C₁_~₄Selected independently of alkyl; [0139] R³³At each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-, C₁_~₄Alkyl-C (= O) NH-, C₁_~₄Alkyl-OC (= O)-, C₁_~₄Alkyl-C (= O) O-, C₃_~₆Cycloalkyl-oxy-, C₃_~₆Cycloalkylmethyl-oxy-, C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₁_~₆Alkyl, and C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₂_~₆Selected independently of alkenyl; [0140] R⁴¹At each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0141] R⁴²At each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0142] R⁴³Is 0 to 3 R⁴⁴C replaced by₃_~₆Cycloalkyl or aryl; [0143] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, C₁_~₄Alkyl, and C₁_~₄Selected independently of alkoxy; [0144] R⁴⁵Is C₁_~₄Alkyl; [0145] R⁴⁶H and C at each appearance₁_~₄Selected independently of alkyl; [0146] R⁴⁷H and C at each appearance₁_~₄Selected independently of alkyl; k is 1 or 2; m is 0, 1, or 2; and n is 1, 2, or 3. [0147] [4] In a more preferred embodiment of the present invention. X is -O- or -S-; [0148] R¹Is H, C (= O) R², C (= O) OR², C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, 0 ~ 2 R²C replaced by₁_~₄Alkyl, 0 ~ 2 R²C replaced by₂_~₄Alkenyl, and 0 ~ 2 R²C replaced by₂_~₄Selected from alkynyl; [0149] R²At each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0150] R⁵Is H, methyl, ethyl, propyl, or butyl; [0151] R^6aIs H, -OH, -NR⁴⁶R⁴⁷, -CF₃, C₁_~₃Alkyl, and C₁_~₃Selected independently of alkoxy; [0152] R^6bIs H; [0153] R⁷And R⁹At the time of each appearance H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₆Haloalkyl, C₁_~₆Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², As well as NR¹⁴S (O)₂R¹²Selected independently from; [0154] R⁸Is H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₆Haloalkyl, C₁_~₆Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 2 R¹¹C replaced by₂_~₄Alkenyl, 0 to 1 R¹¹C replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0155] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Haloalkyl, C₁_~₆Alkoxy, C₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², As well as NR¹⁴S (O)₂R¹²Selected from; [0156] R¹²At the time of each appearance 0 to 1 R^12aC replaced by₁_~₄Alkyl, 0 to 1 R^12aC replaced by₂_~₄Alkenyl, 0 to 1 R^12aC replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0157] R^12aAt the time of each appearance 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0158] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0159] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0160] Alternatively, R¹²And R¹³Is a 9- or 10-membered bicyclic heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S, combined when attached to N, and not Saturated or partially saturated, 0 to 3 Rs¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0161] R¹⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0162] R¹⁵H, C at the time of each appearance₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0163] R¹⁶At the time of each appearance H, OH, F, Cl, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy, independently selected; [0164] R³¹At the time of each appearance H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, And C₁_~₄Selected independently of alkyl; [0165] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-, C₁_~₄Alkyl-C (= O) NH-, C₁_~₄Alkyl-OC (= O)-, C₁_~₄Alkyl-C (= O) O-, C₃_~₆Cycloalkyl-oxy-, C₃_~₆Cycloalkylmethyl-oxy-, C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₁_~₆Alkyl, and C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₂_~₆Selected independently of alkenyl; [0166] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0167] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0168] R⁴³Is 0 to 3 R⁴⁴C replaced by₃_~₆Cycloalkyl or aryl; [0169] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, C₁_~₄Alkyl, and C₁_~₄Selected independently of alkoxy; [0170] R⁴⁵Is C₁_~₄Alkyl; [0171] R⁴⁶At each appearance, H and C₁_~₄Selected independently of alkyl; [0172] R⁴⁷At each appearance, H and C₁_~₄Selected independently of alkyl; [0173] k is 1 or 2; m is 0 or 1; and n is 1 or 2. [0174] [5] In an even more preferred embodiment of the present invention. X is -S-; [0175] R¹Is H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₄Cycloalkyl, 0 to 1 R²C replaced by₁_~₃Alkyl, 0 to 1 R²C replaced by₂_~₃Alkenyl, and 0 to 1 R²C replaced by₂_~₃Selected from alkynyl; [0176] R²At the time of each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₆Carbon ring residues, as well 0 ~ 3 R⁴¹Independently selected from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with; [0177] R⁵Is H, methyl, ethyl, propyl, or butyl; [0178] R^6aIs H, methyl, ethyl, methoxy, -OH, or -CF₃Is; [0179] R^6bIs H; [0180] R⁷And R⁹At the time of each appearance H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, as well 0 ~ 3 R³¹Selected independently from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with; [0181] R⁸Is H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 2 R¹¹C replaced by₂_~₄Alkenyl, 0 to 1 R¹¹C replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0182] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, as well 0 ~ 3 R³¹Selected from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms, selected from the group consisting of N, O, and S substituted with; [0183] R¹²At the time of each appearance 0 to 1 R^12aC replaced by₁_~₄Alkyl, 0 to 1 R^12aC replaced by₂_~₄Alkenyl, 0 to 1 R^12aC replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0184] R^12aAt the time of each appearance 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0185] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0186] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0187] Alternatively, R¹²And R¹³Combined when bound to N, consisting of 1 N, 2 N, 3 N, 1 N and 1 O, and 1 N and 1 S A 9- or 10-membered bicyclic heterocyclic system containing 1 to 3 heteroatoms selected from the group, unsaturated or partially saturated, with 0 to 2 Rs.¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0188] R¹⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0189] R¹⁵Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0190] R¹⁶At the time of each appearance H, OH, F, Cl, CN, NO₂, Methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; [0191] R³¹At the time of each appearance H, OH, halo, CF₃, Methyl, ethyl, and propyl independently selected; [0192] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-, C₁_~₄Alkyl-C (= O) NH-, C₁_~₄Alkyl-OC (= O)-, C₁_~₄Alkyl-C (= O) O-, C₃_~₆Cycloalkyl-oxy-, C₃_~₆Cycloalkylmethyl-oxy-, C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₁_~₆Alkyl, and C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₂_~₆Selected independently of alkenyl; [0193] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₃Alkoxy, C₁_~₃Haloalkyl, and C₁_~₃Selected independently of alkyl; [0194] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₃Alkoxy, C₁_~₃Haloalkyl, C₃_~₆Cycloalkyl, and C₁_~₃Selected independently of alkyl; [0195] R⁴³Are 0 to 3 Rs each⁴⁴Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl substituted with; [0196] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, Methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy; [0197] R⁴⁵Is methyl, ethyl, propyl, or butyl; [0198] R⁴⁶Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0199] R⁴⁷Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0200] k is 1; m is 1; n is 1 or 2. [0201] [6] In an even more preferred embodiment of the present invention. X is -S-; [0202] R¹Is H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₄Cycloalkyl, 0 to 1 R²C replaced by₁_~₃Alkyl, 0 to 1 R²C replaced by₂_~₃Alkenyl, and 0 to 1 R²C replaced by₂_~₃Selected from alkynyl; [0203] R²At the time of each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₆Carbon ring residues, as well 0 ~ 3 R⁴¹Selected independently from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with; [0204] R⁵Is H, methyl, ethyl, propyl, or butyl; [0205] R^6aIs H, methyl, ethyl, methoxy, -OH, or -CF₃Is; [0206] R^6bIs H; [0207] R⁷And R⁹At the time of each appearance H, F, Cl, -CH₃, -OCH₃, -CF₃, -OCF₃, -CN, and -NO₂Selected independently from; [0208] R⁸Is H, F, Cl, Br, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 2 R¹¹C replaced by₂_~₄Alkenyl, 0 to 1 R¹¹C replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O) 2R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0209] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, as well 0 ~ 3 R³¹Selected from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms, selected from the group consisting of N, O, and S substituted with; [0210] R¹²At the time of each appearance 0 to 1 R^12aC replaced by₁_~₄Alkyl, 0 to 1 R^12aC replaced by₂_~₄Alkenyl, 0 to 1 R^12aC replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0211] R^12aAt the time of each appearance 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0212] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently from alkynyl,; [0213] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0214] Alternatively, R¹²And R¹³Is a 9- or 10-membered bicyclic heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S, combined when attached to N, indrill. , Indolinyl, indazolyl, benzoimidazolyl, benzoimidazolinyl, and benztriazolyl, 0 to 1 R¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0215] R¹⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0216] R¹⁵Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0217] R¹⁶At the time of each appearance H, OH, F, Cl, CN, NO₂, Methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; [0218] R³¹At the time of each appearance H, OH, halo, CF₃, Methyl, ethyl, and propyl independently selected; [0219] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-, C₁_~₄Alkyl-C (= O) NH-, C₁_~₄Alkyl-OC (= O)-, C₁_~₄Alkyl-C (= O) O-, C₃_~₆Cycloalkyl-oxy-, C₃_~₆Cycloalkylmethyl-oxy-, C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₁_~₆Alkyl, and C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₂_~₆Selected independently of alkenyl; [0220] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₃Alkoxy, C₁_~₃Haloalkyl, and C₁_~₃Selected independently of alkyl; [0221] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₃Alkoxy, C₁_~₃Haloalkyl, C₃_~₆Cycloalkyl, and C₁_~₃Selected independently of alkyl; [0222] R⁴³Are 0 to 3 Rs each⁴⁴Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl substituted with; [0223] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, Methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy; [0224] R⁴⁵Is methyl, ethyl, propyl, or butyl; [0225] R⁴⁶Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0226] R⁴⁷Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0227] k is 1; m is 1; n is 1 or 2. [0228] [7] In an even more preferred embodiment of the present invention. X is -S-; [0229] R¹Is H, 0 to 1 R²C replaced by₁_~₅Alkyl, 0 to 1 R²C replaced by₂_~₅Alkenyl, and 0 to 1 R²C replaced by₂_~₃Selected from alkynyl; [0230] R²Is C₃_~₆Cycloalkyl; [0231] R⁵Is H, methyl, ethyl, or propyl; [0232] R^6aIs H, methyl, or ethyl; [0233] R^6bIs H; [0234] R⁷And R⁹H, F, Cl, -CH at each appearance₃, -OCH₃, -CF₃, -OCF₃, -CN, and -NO₂Selected independently from; [0235] R⁸Is R¹¹Methyl substituted with, R¹¹Etenil replaced with OR¹², SR¹², NR¹²R¹³, NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O) 2R¹⁵, And NR¹²C (O) NHR¹⁵Selected from; [0236] R¹¹Is Phenyl substituted with 0-5 fluoros, R³³Replaced by 2- (H₃CCH₂C (= O))-Phenyl-, R³³Replaced by 2- (H₃CC (= O))-Phenyl-, R³³2- (HC (= O))-Phenyl-, substituted with R³³Replaced by 2- (H₃CCH (OH))-Phenyl-, R³³Replaced by 2- (H₃CCH₂CH (OH))-Phenyl-, R³³Replaced by 2- (HOCH₂) -Fenil-, R³³Replaced by 2- (HOCH₂CH₂) -Fenil-, R³³Replaced by 2- (H₃COCH₂) -Fenil-, R³³Replaced by 2- (H₃COCH₂CH₂) -Fenil-, R³³Replaced by 2- (H₃CCH (OMe))-Fenil-, R³³Replaced by 2- (H₃COC (= O))-Fenil-, R³³Replaced by 2- (HOCH₂CH = CH) -Fenil-, R³³2-((MeOC = O) CH = CH) -phenil-, replaced by R³³2- (Methyl) -phenyl-, substituted with R³³2- (Ethyl) -phenyl-, substituted with R³³2- (i-propyl) -phenyl-, substituted with R³³Replaced by 2- (F₃C) -Fenil-, R³³2- (NC) -Phenil-, replaced by R³³Replaced by 2- (H₃CO) -Fenil-, R³³2- (Fluoro) -phenyl-, substituted with R³³2- (Chloro) -phenyl-, substituted with R³³3- (NC) -Phenil-, replaced by R³³3- (H) replaced by₃CO) -Fenil-, R³³3- (Fluoro) -phenyl-, substituted with R³³3- (Chloro) -phenyl-, substituted with R³³4- (NC) -Phenil-, replaced by R³³4- (Fluoro) -phenyl-, substituted with R³³4- (Chloro) -phenyl-, substituted with R³³4- (H) replaced by₃CS) -Fenil-, R³³4- (H) replaced by₃CO) -Fenil-, R³³4- (ethoxy) -phenyl-, substituted with R³³Replaced with 4- (i-propoxy) -phenyl-, R³³Replaced with 4- (i-butoxy) -phenyl-, R³³4- (H) replaced by₃CCH₂CH₂C (= O))-Fenil-, R³³Replaced by 4-((H₃C)₂CHC (= O))-Fenil-, R³³4- (H) replaced by₃CCH₂C (= O))-Fenil-, R³³4- (H) replaced by₃CC (= O))-Fenil-, R³³4- (H) replaced by₃CCH₂CH₂CH (OH))-Fenil-, R³³Replaced by 4-((H₃C)₂CHCH (OH)) -Fenil-, R³³4- (H) replaced by₃CCH₂CH (OH))-Fenil-, R³³4- (H) replaced by₃CCH (OH)) -Fenil-, R³³4- (Cyclopropyloxy) -phenyl-, substituted with R³³4- (Cyclobutyloxy) -phenyl-, substituted with, and R³³Selected from 4- (cyclopentyloxy) -phenyl-, substituted with; [0237] R¹²Is Phenyl substituted with 0-5 fluoros, R³³Replaced by 2- (H₃CCH₂C (= O))-Phenyl-, R³³Replaced by 2- (H₃CC (= O))-Phenyl-, R³³2- (HC (= O))-Phenyl-, substituted with R³³Replaced by 2- (H₃CCH (OH))-Phenyl-, R³³Replaced by 2- (H₃CCH₂CH (OH))-Phenyl-, R³³Replaced by 2- (HOCH₂) -Fenil-, R³³Replaced by 2- (HOCH₂CH₂) -Fenil-, R³³Replaced by 2- (H₃COCH₂) -Fenil-, R³³Replaced by 2- (H₃COCH₂CH₂) -Fenil-, R³³Replaced by 2- (H₃CCH (OMe))-Fenil-, R³³Replaced by 2- (H₃COC (= O))-Fenil-, R³³Replaced by 2- (HOCH₂CH = CH) -Fenil-, R³³2-((MeOC = O) CH = CH) -phenil-, replaced by R³³2- (Methyl) -phenyl-, substituted with R³³2- (Ethyl) -phenyl-, substituted with R³³2- (i-propyl) -phenyl-, substituted with R³³Replaced by 2- (F₃C) -Fenil-, R³³2- (NC) -Phenil-, replaced by R³³Replaced by 2- (H₃CO) -Fenil-, R³³2- (Fluoro) -phenyl-, substituted with R³³2- (Chloro) -phenyl-, substituted with R³³3- (NC) -Phenil-, replaced by R³³3- (H) replaced by₃CO) -Fenil-, R³³3- (Fluoro) -phenyl-, substituted with R³³3- (Chloro) -phenyl-, substituted with R³³4- (NC) -Phenil-, replaced by R³³4- (Fluoro) -phenyl-, substituted with R³³4- (Chloro) -phenyl-, substituted with R³³4- (H) replaced by₃CS) -Fenil-, R³³4- (H) replaced by₃CO) -Fenil-, R³³4- (ethoxy) -phenyl-, substituted with R³³Replaced with 4- (i-propoxy) -phenyl-, R³³Replaced with 4- (i-butoxy) -phenyl-, R³³4- (H) replaced by₃CCH₂CH₂C (= O))-Fenil-, R³³Replaced by 4-((H₃C)₂CHC (= O))-Fenil-, R³³4- (H) replaced by₃CCH₂C (= O))-Fenil-, R³³4- (H) replaced by₃CC (= O))-Fenil-, R³³4- (H) replaced by₃CCH₂CH₂CH (OH))-Fenil-, R³³Replaced by 4-((H₃C)₂CHCH (OH)) -Fenil-, R³³4- (H) replaced by₃CCH₂CH (OH))-Fenil-, R³³4- (H) replaced by₃CCH (OH)) -Fenil-, R³³4- (Cyclopropyloxy) -phenyl-, substituted with R³³4- (Cyclobutyloxy) -phenyl-, substituted with, and R³³Selected from 4- (cyclopentyloxy) -phenyl-, substituted with; [0238] R¹³Is H, methyl, or ethyl; [0239] Alternatively, R¹²And R¹³Link to form a 5- or 6-membered ring selected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl, piperidinyl, methylpiperidinyl, and morpholinyl; [0240] Alternatively, R¹²And R¹³Is a 9- or 10-membered bicyclic heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S, combined when attached to N, indrill. , Indolinyl, indazolyl, benzoimidazolyl, benzoimidazolinyl, and benztriazolyl, 0 to 1 R¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0241] R¹⁵Is H, methyl, ethyl, propyl, or butyl; [0242] R¹⁶At the time of each appearance H, OH, F, Cl, CN, NO₂, Methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; [0243] R³³At the time of each appearance H, F, Cl, -CH₃, -OCH₃, -CF₃, -OCF₃, -CN, and -NO₂Selected independently from; [0244] k is 1; m is 1; n is 1 or 2. [0245] [8] In another still more preferred embodiment of the invention. X is -O-; [0246] R¹Is H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₄Cycloalkyl, 0 to 1 R²C replaced by₁_~₃Alkyl, 0 to 1 R²C replaced by₂_~₃Alkenyl, and 0 to 1 R²C replaced by₂_~₃Selected from alkynyl; [0247] R²At the time of each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₆Carbon ring residues, as well 0 ~ 3 R⁴¹Selected independently from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with; [0248] R⁵Is H, methyl, ethyl, propyl, or butyl; [0249] R^6aIs H, methyl, ethyl, methoxy, -OH, or -CF₃Is; [0250] R^6bIs H; [0251] R⁷And R⁹At each appearance, H, Halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, as well 0 ~ 3 R³¹Selected independently from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with; [0252] R⁸Is H, halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 2 R¹¹C replaced by₂_~₄Alkenyl, 0 to 1 R¹¹C replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O) 2R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0253] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, as well 0 ~ 3 R³¹Selected from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms, selected from the group consisting of N, O, and S substituted with; [0254] R¹²At the time of each appearance 0 to 1 R^12aC replaced by₁_~₄Alkyl, 0 to 1 R^12aC replaced by₂_~₄Alkenyl, 0 to 1 R^12aC replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0255] R^12aAt the time of each appearance 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0256] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0257] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0258] Alternatively, R¹²And R¹³Combined when bound to N, consisting of 1 N, 2 N, 3 N, 1 N and 1 O, and 1 N and 1 S A 9- or 10-membered bicyclic heterocyclic system containing 1 to 3 heteroatoms selected from the group, unsaturated or partially saturated, with 0 to 2 Rs.¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0259] R¹⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0260] R¹⁵Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0261] R¹⁶At the time of each appearance H, OH, F, Cl, CN, NO₂, Methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; [0262] R³¹At the time of each appearance H, OH, halo, CF₃, Methyl, ethyl, and propyl independently selected; [0263] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-, C₁_~₄Alkyl-C (= O) NH-, C₁_~₄Alkyl-OC (= O)-, C₁_~₄Alkyl-C (= O) O-, C₃_~₆Cycloalkyl-oxy-, C₃_~₆Cycloalkylmethyl-oxy-, C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₁_~₆Alkyl, and C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₂_~₆Selected independently of alkenyl; [0264] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₃Alkoxy, C₁_~₃Haloalkyl, and C₁_~₃Selected independently of alkyl; [0265] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₃Alkoxy, C₁_~₃Haloalkyl, C₃_~₆Cycloalkyl, and C₁_~₃Selected independently of alkyl; [0266] R⁴³Are 0 to 3 Rs each⁴⁴Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl substituted with; [0267] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, Methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy; [0268] R⁴⁵Is methyl, ethyl, propyl, or butyl; [0269] R⁴⁶Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0270] R⁴⁷Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0271] k is 1; m is 1; n is 1 or 2. [0272] [9] In another further preferred embodiment of the invention. X is -O-; [0273] R¹Is H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₄Cycloalkyl, 0 to 1 R²C replaced by₁_~₃Alkyl, 0 to 1 R²C replaced by₂_~₃Alkenyl, and 0 to 1 R²C replaced by₂_~₃Selected from alkynyl; [0274] R²At the time of each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₆Carbon ring residues, as well 0 ~ 3 R⁴¹Selected independently from a 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with; [0275] R⁵Is H, methyl, ethyl, propyl, or butyl; [0276] R^6aIs H, methyl, ethyl, methoxy, -OH, or -CF₃Is; [0277] R^6bIs H; [0278] R⁷And R⁹H, F, Cl, -CH at each appearance₃, -OCH₃, -CF₃, -OCF₃, -CN, and -NO₂Selected independently from; [0279] R⁸Is H, F, Cl, Br, -CF₃, -OCF₃, -OH, -CN, -NO₂, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 2 R¹¹C replaced by₂_~₄Alkenyl, 0 to 1 R¹¹C replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O) 2R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0280] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R³³C replaced by₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, as well 0 ~ 3 R³¹A 5- to 6-membered heterocyclic system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected from; [0281] R¹²At the time of each appearance 0 to 1 R^12aC replaced by₁_~₄Alkyl, 0 to 1 R^12aC replaced by₂_~₄Alkenyl, 0 to 1 R^12aC replaced by₂_~₄Alkyne, 0 ~ 3 R³³C replaced by₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0282] R^12aAt the time of each appearance 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0283] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0284] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0285] Alternatively, R¹²And R¹³Is a 9- or 10-membered bicyclic heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S, combined when attached to N, indrill. , Indolinyl, indazolyl, benzoimidazolyl, benzoimidazolinyl, benztriazolyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl, from 0 to 1 R¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0286] R¹⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0287] R¹⁵Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0288] R¹⁶At the time of each appearance H, OH, F, Cl, CN, NO₂, Methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; [0289] R³¹At the time of each appearance H, OH, halo, CF₃, Methyl, ethyl, and propyl independently selected; [0290] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, -C (= O) H, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₃_~₆Cycloalkyl, C₁_~₄Haloalkyl, C₁_~₄Haloalkyl-oxy-, C₁_~₄Alkyloxy-, C₁_~₄Alkylthio-, C₁_~₄Alkyl-C (= O)-, C₁_~₄Alkyl-C (= O) NH-, C₁_~₄Alkyl-OC (= O)-, C₁_~₄Alkyl-C (= O) O-, C₃_~₆Cycloalkyl-oxy-, C₃_~₆Cycloalkylmethyl-oxy-, C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₁_~₆Alkyl, and C substituted with OH, methoxy, ethoxy, propoxy, or butoxy₂_~₆Selected independently of alkenyl; [0291] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₃Alkoxy, C₁_~₃Haloalkyl, and C₁_~₃Selected independently of alkyl; [0292] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₃Alkoxy, C₁_~₃Haloalkyl, C₃_~₆Cycloalkyl, and C₁_~₃Selected independently of alkyl; [0293] R⁴³Are 0 to 3 Rs each⁴⁴Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl substituted with; [0294] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, Methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy; [0295] R⁴⁵Is methyl, ethyl, propyl, or butyl; [0296] R⁴⁶Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0297] R⁴⁷Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0298] k is 1; m is 1; n is 1 or 2. [0299] [10] In another further preferred embodiment of the invention. X is -O-; [0300] R¹Is H, 0 to 1 R²C replaced by₁_~₅Alkyl, 0 to 1 R²C replaced by₂_~₅Alkenyl, and 0 to 1 R²C replaced by₂_~₃Selected from alkynyl; [0301] R²Is C₃_~₆Cycloalkyl; [0302] R⁵Is H, methyl, ethyl, or propyl; [0303] R^6aIs H, methyl, or ethyl; [0304] R^6bIs H; [0305] R⁷And R⁹H, F, Cl, -CH at each appearance₃, -OCH₃, -CF₃, -OCF₃, -CN, and -NO₂Selected independently from; [0306] R⁸Is R¹¹Methyl substituted with, R¹¹Etenil replaced with OR¹², SR¹², NR¹²R¹³, NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O) 2R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected from; [0307] R¹¹Is Phenyl substituted with 0-5 fluoros, R³³Replaced by 2- (H₃CCH₂C (= O))-Phenyl-, R³³Replaced by 2- (H₃CC (= O))-Phenyl-, R³³2- (HC (= O))-Phenyl-, substituted with R³³Replaced by 2- (H₃CCH (OH))-Phenyl-, R³³Replaced by 2- (H₃CCH₂CH (OH))-Phenyl-, R³³Replaced by 2- (HOCH₂) -Fenil-, R³³Replaced by 2- (HOCH₂CH₂) -Fenil-, R³³Replaced by 2- (H₃COCH₂) -Fenil-, R³³Replaced by 2- (H₃COCH₂CH₂) -Fenil-, R³³Replaced by 2- (H₃CCH (OMe))-Fenil-, R³³Replaced by 2- (H₃COC (= O))-Fenil-, R³³Replaced by 2- (HOCH₂CH = CH) -Fenil-, R³³2-((MeOC = O) CH = CH) -phenil-, replaced by R³³2- (Methyl) -phenyl-, substituted with R³³2- (Ethyl) -phenyl-, substituted with R³³2- (i-propyl) -phenyl-, substituted with R³³Replaced by 2- (F₃C) -Fenil-, R³³2- (NC) -Phenil-, replaced by R³³Replaced by 2- (H₃CO) -Fenil-, R³³2- (Fluoro) -phenyl-, substituted with R³³2- (Chloro) -phenyl-, substituted with R³³3- (NC) -Phenil-, replaced by R³³3- (H) replaced by₃CO) -Fenil-, R³³3- (Fluoro) -phenyl-, substituted with R³³3- (Chloro) -phenyl-, substituted with R³³4- (NC) -Phenil-, replaced by R³³4- (Fluoro) -phenyl-, substituted with R³³4- (Chloro) -phenyl-, substituted with R³³4- (H) replaced by₃CS) -Fenil-, R³³4- (H) replaced by₃CO) -Fenil-, R³³4- (ethoxy) -phenyl-, substituted with R³³Replaced with 4- (i-propoxy) -phenyl-, R³³Replaced with 4- (i-butoxy) -phenyl-, R³³4- (H) replaced by₃CCH₂CH₂C (= O))-Fenil-, R³³Replaced by 4-((H₃C)₂CHC (= O))-Fenil-, R³³4- (H) replaced by₃CCH₂C (= O))-Fenil-, R³³4- (H) replaced by₃CC (= O))-Fenil-, R³³4- (H) replaced by₃CCH₂CH₂CH (OH))-Fenil-, R³³Replaced by 4-((H₃C)₂CHCH (OH)) -Fenil-, R³³4- (H) replaced by₃CCH₂CH (OH))-Fenil-, R³³4- (H) replaced by₃CCH (OH)) -Fenil-, R³³4- (Cyclopropyloxy) -phenyl-, substituted with R³³4- (Cyclobutyloxy) -phenyl-, substituted with, and R³³4- (Cyclopentyloxy) -phenyl-replaced with Selected from; [0308] R¹²Is Phenyl substituted with 0-5 fluoros, R³³Replaced by 2- (H₃CCH₂C (= O))-Phenyl-, R³³Replaced by 2- (H₃CC (= O))-Phenyl-, R³³2- (HC (= O))-Phenyl-, substituted with R³³Replaced by 2- (H₃CCH (OH))-Phenyl-, R³³Replaced by 2- (H₃CCH₂CH (OH))-Phenyl-, R³³Replaced by 2- (HOCH₂) -Fenil-, R³³Replaced by 2- (HOCH₂CH₂) -Fenil-, R³³Replaced by 2- (H₃COCH₂) -Fenil-, R³³Replaced by 2- (H₃COCH₂CH₂) -Fenil-, R³³Replaced by 2- (H₃CCH (OMe))-Fenil-, R³³Replaced by 2- (H₃COC (= O))-Fenil-, R³³Replaced by 2- (HOCH₂CH = CH) -Fenil-, R³³2-((MeOC = O) CH = CH) -phenil-, replaced by R³³2- (Methyl) -phenyl-, substituted with R³³2- (Ethyl) -phenyl-, substituted with R³³2- (i-propyl) -phenyl-, substituted with R³³Replaced by 2- (F₃C) -Fenil-, R³³2- (NC) -Phenil-, replaced by R³³Replaced by 2- (H₃CO) -Fenil-, R³³2- (Fluoro) -phenyl-, substituted with R³³2- (Chloro) -phenyl-, substituted with R³³3- (NC) -Phenil-, replaced by R³³3- (H) replaced by₃CO) -Fenil-, R³³3- (Fluoro) -phenyl-, substituted with R³³3- (Chloro) -phenyl-, substituted with R³³4- (NC) -Phenil-, replaced by R³³4- (Fluoro) -phenyl-, substituted with R³³4- (Chloro) -phenyl-, substituted with R³³4- (H) replaced by₃CS) -Fenil-, R³³4- (H) replaced by₃CO) -Fenil-, R³³4- (ethoxy) -phenyl-, substituted with R³³Replaced with 4- (i-propoxy) -phenyl-, R³³Replaced with 4- (i-butoxy) -phenyl-, R³³4- (H) replaced by₃CCH₂CH₂C (= O))-Fenil-, R³³Replaced by 4-((H₃C)₂CHC (= O))-Fenil-, R³³4- (H) replaced by₃CCH₂C (= O))-Fenil-, R³³4- (H) replaced by₃CC (= O))-Fenil-, R³³4- (H) replaced by₃CCH₂CH₂CH (OH))-Fenil-, R³³Replaced by 4-((H₃C)₂CHCH (OH)) -Fenil-, R³³4- (H) replaced by₃CCH₂CH (OH))-Fenil-, R³³4- (H) replaced by₃CCH (OH)) -Fenil-, R³³4- (Cyclopropyloxy) -phenyl-, substituted with R³³4- (Cyclobutyloxy) -phenyl-, substituted with, and R³³4- (Cyclopentyloxy) -phenyl-replaced with Selected from; [0309] R¹³Is H, methyl, or ethyl; [0310] Alternatively, R¹²And R¹³Link to form a 5- or 6-membered ring selected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl, piperidinyl, methylpiperidinyl, and morpholinyl; [0311] Alternatively, R¹²And R¹³Is a 9- or 10-membered bicyclic heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S, combined when attached to N, indrill. , Indolinyl, indazolyl, benzoimidazolyl, benzoimidazolinyl, benztriazolyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl, from 0 to 1 R¹⁶Bicyclic heterocyclic systems substituted with may be formed; [0312] R¹⁵Is H, methyl, ethyl, propyl, or butyl; [0313] R¹⁶At the time of each appearance H, OH, F, Cl, CN, NO₂, Methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; [0314] R³³At the time of each appearance H, F, Cl, -CH₃, -OCH₃, -CF₃, -OCF₃, -CN, and -NO₂Selected independently from; [0315] k is 1; m is 1; n is 1 or 2. [0316] [11] In another further preferred embodiment of the invention, the compound of formula (I) is selected from the following formula (Ia). [0317] [Chemical 16]<img file="JP4916633B2_D0006.tif" />[0318] During the ceremony b is a single bond or a double bond; [0319] X is -S- or -O-; [0320] R¹Is Hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl , 3-Methylbutyl, 4-Methyl Pentyl, 2-Fluoroethyl, 2,2-Difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl, 3-Methyl-butenyl, 3-butenyl, trans-2-pentenyl, Sith-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, Benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,5-dimethylbenzyl, 2,4-dimethylbenzyl, 3,5-dimethylbenzyl, 2,4,6-trimethyl-benzyl, 3-methoxy-benzyl, 3,5-dimethoxy-benzyl, pentafluorobenzyl, 2-phenylethyl, 1-phenyl-2-propyl, 4-phenylbutyl, 4-phenylbenzyl, 2-phenylbenzyl, (2,3-dimethoxy-phenyl) C (= O)-, (2,5-dimethoxy-phenyl) C (= O)-, (3,4-dimethoxy-phenyl) C (= O)-, (3,5-dimethoxy-phenyl) C (= O)-, Cyclopropyl-C (= O)-, Isopropyl-C (= O)-, Ethyl-CO₂-, Propyl-CO₂-, T-Butyl-CO₂-, 2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl, 2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl, 2,4,5-trimethoxy-benzyl, 2,3,4-trimethoxy-benzyl, 3,4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl, (4-Fluoro-phenyl) ethyl, -CH = CH₂, -CH₂-CH = CH₂, -CH = CH-CH₃, -CCH, -CC-CH₃,and -CH₂-CCH Selected from; [0321] R⁷, R⁸And R⁹At the time of each appearance Hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, Methyl C (= O)-, Ethyl C (= O)-, Propyl C (= O)-, Isopropyl C (= O)-, Butyl C (= O)-, Phenyl C (= O)-, Methyl CO₂-, Ethyl CO₂-, Propyl CO₂-, Isopropyl CO₂-, Butyl CO₂-, Phenyl CO₂-, Dimethylamino-S (= O)-, diethylamino-S (= O)-, Dipropylamino-S (= O)-, Di-Isopropylamino-S (= O)-, Dibutylamino-S (= O)-, Diphenylamino-S (= O)-, Dimethylamino-SO₂-, Diethylamino-SO₂-, Dipropylamino-SO₂-, Di-isopropylamino-SO₂-, Dibutylamino-SO₂-, Diphenylamino-SO₂-, Dimethylamino-C (= O)-, diethylamino-C (= O)-, Dipropylamino-C (= O)-, Di-Isopropylamino-C (= O)-, Dibutylamino-C (= O)-, Diphenylamino-C (= O)-, 2-Chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 2-Methoxyphenyl, 2-trifluoromethoxyphenyl, 3-Chlorophenyl, 3-Fluorophenyl, 3-Bromophenyl, 3-Cyanophenyl, 3-Methylphenyl, 3-Ethylphenyl, 3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl, 3-Trifluoromethylphenyl, 3-methoxyphenyl, 3-Isopropoxyphenyl, 3-Trifluoromethoxyphenyl, 3-thiomethoxyphenyl, 4-Chlorophenyl, 4-Fluorophenyl, 4-Bromophenyl, 4-Cyanophenyl, 4-Methylphenyl, 4-Ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-Trifluoromethylphenyl, 4-methoxyphenyl, 4-Isopropoxyphenyl, 4-trifluoromethoxyphenyl, 4-thiomethoxyphenyl, 2,3-Dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl, 2,3-Ditrifluoromethylphenyl, 2,3-dimethoxyphenyl, 2,3-Ditrifluoromethoxyphenyl, 2,4-Dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2,4-Ditrifluoromethylphenyl, 2,4-dimethoxyphenyl, 2,4-Ditrifluoromethoxyphenyl, 2,5-Dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl, 2,5-Ditrifluoromethylphenyl, 2,5-dimethoxyphenyl, 2,5-Ditrifluoromethoxyphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl, 2,6-ditrifluoromethoxyphenyl, 3,4-Dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,4-Ditrifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,4-Ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl, 2-Chloro-4-CF₃-Fenil, 2-fluoro-3-chloro-Fenil, 2-Chloro-4-CF₃-Fenyl, 2-chloro-4-methoxy-Fenyl, 2-Methoxy-4-isopropyl-phenyl, 2-CF₃-4-Methoxy-phenyl, 2-Methyl-4-methoxy-5-fluoro-phenyl, 2-Methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-Fenil, 2, 4, 5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, Methyl-C (= O) NH-, Ethyl-C (= O) NH-, Propyl-C (= O) NH-, Isopropyl-C (= O) NH-, Butyl-C (= O) NH-, Phenyl-C (= O) NH-, 4-Acetylphenyl, 3-Acetamidephenyl, 4-Pyridyl, 2-Franyl, 2-thiophenyl, 2-naphthyl, 2-Me-5-F-Fenil, 2-F-5-Me-Fenil, 2-MeO-5-F-Fenil, 2-Me-3-Cl-Fenil, 3-NO₂-Fenil, 2-NO₂-Fenil, 2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl, 2-Cl-6-F-Fenil, 2-Cl-4- (CHF)₂) O-Fenil, 2,4-Di MeO-6-F-Fenil, 2-CF₃_~₆-F-Fenil, 2-MeS-Fenil, 2,6-Di Cl-4-MeO-Fenil, 2,3,4-tri F-phenyl, 2,6-di F-4-Cl-phenyl, 2, 3, 4, 6-Tetra F-Fenil, 2, 3, 4, 5, 6-Penta F-Fenil, 2-CF₃-4-EtO-Fenil, 2-CF₃-4-iPrO-Fenil, 2-CF₃-4-Cl-Fenil, 2-CF₃-4-F-Fenil, 2-Cl-4-EtO-Fenil, 2-Cl-4-iPrO-Fernil, 2-Et-4-MeO-Fenil, 2-CHO-4-MeO-Fenil, 2-CH (OH) Me-4-MeO-Fenil, 2-CH (OMe) Me-4-MeO-Fenil, 2-C (= O) Me-4-MeO-Fenil, 2-CH₂(OH) -4-MeO-Fenil, 2-CH₂(OMe) -4-MeO-Fenil, 2-CH (OH) Et-4-MeO-phenyl, 2-C (= O) Et-4-MeO-phenyl, (Z) -2-CH = CHCO₂Me-4-MeO-Fenil, 2-CH₂CH₂CO₂Me-4-MeO-Fenil, (Z) -2-CH = CHCH₂(OH) -4-MeO-Fenil, (E) -2-CH = CHCO₂Me-4-MeO-Fenil, (E) -2-CH = CHCH₂(OH) -4-MeO-Fenil, 2-CH₂CH₂OMe-4-MeO-Fenil, 2-F-4-MeO-Fenil, 2-Cl-4-F-Fenil, (2-Cl-phenyl) -CH = CH-, (3-Cl-phenyl) -CH = CH-, (2, 6-di F-Fenil) -CH = CH-, -CH₂CH = CH₂, Phenyl-CH = CH-, (2-Me-4-MeO-Phenyl) -CH = CH-, Cyclohexyl, cyclopentyl, cyclohexylmethyl, -CH₂CH₂CO₂Et,-(CH₂)₃CO₂Et,-(CH₂)₄CO₂Et, Benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl, 2-OH-benzyl, 2-CO₂Me-3-MeO-Fenil, 2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF₃-4-CN-Fenil, 3-CHO-Fenil, 3-CH₂(OH)-Fenil, 3-CH₂(OMe)-Fenil, 3-CH₂(NMe₂)-Fenil, 3-CN-4-F-Fenil, 3-CONH₂-4-F-Fenil, 2-CH₂(NH₂) -4-MeO-Fenil-, Phenyl-NH-, (4-F-phenyl) -NH-, (2,4-diCl-phenyl) -NH-, Phenyl-C (= O) NH-, benzyl-NH-, (2-Me-4-MeO-phenyl) -NH-, (2-F-4-MeO-Fenil) -NH-, (2-Me-4-F-Fenil) -NH-, Phenyl-S-, -NMe₂, 1-pyrrolidinyl, and -N (Tosilate)₂, Selected from; [0322] However, R⁷, R⁸And R⁹Two of them are independent of hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. Selected for; [0323] m is 1; n is 1 or 2. [0324] [12] In another further preferred embodiment of the invention, the compound of formula ( I) is selected from formula (II) below. [0325] [Chemical 17]<img file="JP4916633B2_D0007.tif" />[0326] During the ceremony b is a single bond and the crosslinked hydrogen is in the cis position; [0327] R¹Is Hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl , 3-Methylbutyl, 4-Methyl Pentyl, 2-Fluoroethyl, 2,2-Difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl, Trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-Methyl-3-pentenyl, 3,3-dichloro-2-propenyl, Trans-3-phenyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, -CH = CH₂, -CH₂-CH = CH₂, -CH = CH-CH₃, -CCH, -CC-CH₃, And -CH₂-Selected from CCH; [0328] R⁷And R⁹Are independently selected from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy at each appearance; [0329] R⁸Is Hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, Methyl C (= O)-, Ethyl C (= O)-, Propyl C (= O)-, Isopropyl C (= O)-, Butyl C (= O)-, Phenyl C (= O)-, Methyl CO₂-, Ethyl CO₂-, Propyl CO₂-, Isopropyl CO₂-, Butyl CO₂-, Phenyl CO₂-, Dimethylamino-S (= O)-, diethylamino-S (= O)-, Dipropylamino-S (= O)-, Di-Isopropylamino-S (= O)-, Dibutylamino-S (= O)-, Diphenylamino-S (= O)-, Dimethylamino-SO₂-, Diethylamino-SO₂-, Dipropylamino-SO₂-, Di-isopropylamino-SO₂-, Dibutylamino-SO₂-, Diphenylamino-SO₂-, Dimethylamino-C (= O)-, diethylamino-C (= O)-, Dipropylamino-C (= O)-, Di-Isopropylamino-C (= O)-, Dibutylamino-C (= O)-, Diphenylamino-C (= O)-, 2-Chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 2-Methoxyphenyl, 2-trifluoromethoxyphenyl, 3-Chlorophenyl, 3-Fluorophenyl, 3-Bromophenyl, 3-Cyanophenyl, 3-Methylphenyl, 3-Ethylphenyl, 3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl, 3-Trifluoromethylphenyl, 3-methoxyphenyl, 3-Isopropoxyphenyl, 3-Trifluoromethoxyphenyl, 3-thiomethoxyphenyl, 4-Chlorophenyl, 4-Fluorophenyl, 4-Bromophenyl, 4-Cyanophenyl, 4-Methylphenyl, 4-Ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-Trifluoromethylphenyl, 4-methoxyphenyl, 4-Isopropoxyphenyl, 4-trifluoromethoxyphenyl, 4-thiomethoxyphenyl, 2,3-Dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl, 2,3-Ditrifluoromethylphenyl, 2,3-dimethoxyphenyl, 2,3-Ditrifluoromethoxyphenyl, 2,4-Dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2,4-Ditrifluoromethylphenyl, 2,4-dimethoxyphenyl, 2,4-Ditrifluoromethoxyphenyl, 2,5-Dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl, 2,5-Ditrifluoromethylphenyl, 2,5-dimethoxyphenyl, 2,5-Ditrifluoromethoxyphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl, 2,6-ditrifluoromethoxyphenyl, 3,4-Dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,4-Ditrifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,4-Ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl, 2-Chloro-4-CF₃-Fenil, 2-fluoro-3-chloro-Fenil, 2-Chloro-4-CF₃-Fenyl, 2-chloro-4-methoxy-Fenyl, 2-Methoxy-4-isopropyl-phenyl, 2-CF₃-4-Methoxy-phenyl, 2-Methyl-4-methoxy-5-fluoro-phenyl, 2-Methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl, 2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, Methyl-C (= O) NH-, Ethyl-C (= O) NH-, Propyl-C (= O) NH-, Isopropyl-C (= O) NH-, Butyl-C (= O) NH-, Phenyl-C (= O) NH-, 4-Acetylphenyl, 3-Acetamidephenyl, 4-Pyridyl, 2-Franyl, 2-thiophenyl, 2-naphthyl, 2-Me-5-F-Fenil, 2-F-5-Me-Fenil, 2-MeO-5-F-Fenil, 2-Me-3-Cl-Fenil, 3-NO₂-Fenil, 2-NO₂-Fenil, 2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl, 2-Cl-6-F-Fenil, 2-Cl-4- (CHF)₂) O-Fenil, 2,4-Di MeO-6-F-Fenil, 2-CF₃_~₆-F-Fenil, 2-MeS-Fenil, 2,6-Di Cl-4-MeO-Fenil, 2,3,4-tri F-phenyl, 2,6-di F-4-Cl-phenyl, 2, 3, 4, 6-Tetra F-Fenil, 2, 3, 4, 5, 6-Penta F-Fenil, 2-CF₃-4-EtO-Fenil, 2-CF₃-4-iPrO-Fenil, 2-CF₃-4-Cl-Fenil, 2-CF₃-4-F-Fenil, 2-Cl-4-EtO-Fenil, 2-Cl-4-iPrO-Fernil, 2-Et-4-MeO-Fenil, 2-CHO-4-MeO-Fenil, 2-CH (OH) Me-4-MeO-Fenil, 2-CH (OMe) Me-4-MeO-Fenil, 2-C (= O) Me-4-MeO-Fenil, 2-CH₂(OH) -4-MeO-Fenil, 2-CH₂(OMe) -4-MeO-Fenil, 2-CH (OH) Et-4-MeO-phenyl, 2-C (= O) Et-4-MeO-phenyl, (Z) -2-CH = CHCO₂Me-4-MeO-Fenil, 2-CH₂CH₂CO₂Me-4-MeO-Fenil, (Z) -2-CH = CHCH₂(OH) -4-MeO-Fenil, (E) -2-CH = CHCO₂Me-4-MeO-Fenil, (E) -2-CH = CHCH₂(OH) -4-MeO-Fenil, 2-CH₂CH₂OMe-4-MeO-Fenil, 2-F-4-MeO-Fenil, 2-Cl-4-F-Fenil, (2-Cl-phenyl) -CH = CH-, (3-Cl-phenyl) -CH = CH-, (2, 6-di F-Fenil) -CH = CH-, -CH₂CH = CH₂, Phenyl-CH = CH-, (2-Me-4-MeO-Phenyl) -CH = CH-, Cyclohexyl, cyclopentyl, cyclohexylmethyl, -CH₂CH₂CO₂Et,-(CH₂)₃CO₂Et,-(CH₂)₄CO₂Et, Benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl, 2-OH-benzyl, 2-CO₂Me-3-MeO-Fenil, 2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF₃-4-CN-Fenil, 3-CHO-Fenil, 3-CH₂(OH)-Fenil, 3-CH₂(OMe)-Fenil, 3-CH₂(NMe₂)-Fenil, 3-CN-4-F-Fenil, 3-CONH₂-4-F-Fenil, 2-CH₂(NH₂) -4-MeO-Fenil-, Phenyl-NH-, (4-F-phenyl) -NH-, (2,4-diCl-phenyl) -NH-, Phenyl-C (= O) NH-, benzyl-NH-, (2-Me-4-MeO-phenyl) -NH-, (2-F-4-MeO-Fenil) -NH-, (2-Me-4-F-Fenil) -NH-, Phenyl-S-, -NMe₂, 1-pyrrolidinyl, and -N (Tosilate)₂Selected from; n is 1 or 2. [0330] [13] In another further preferred embodiment of the invention, the compound of formula (I) is selected from formula (III) below. [0331] [Chemical 18]<img file="JP4916633B2_D0008.tif" />[0332] During the ceremony b is a single bond and the crosslinked hydrogen is in the cis position; [0333] R¹Is Hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl , 3-Methylbutyl, 4-Methyl Pentyl, 2-Fluoroethyl, 2,2-Difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl, Trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-Methyl-3-pentenyl, 3,3-dichloro-2-propenyl, Trans-3-phenyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, -CH = CH₂, -CH₂-CH = CH₂, -CH = CH-CH₃, -CCH, -CC-CH₃, And -CH₂-Selected from CCH; [0334] R⁷And R⁹Are independently selected from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy at each appearance; R⁸Is Hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, Methyl C (= O)-, Ethyl C (= O)-, Propyl C (= O)-, Isopropyl C (= O)-, Butyl C (= O)-, Phenyl C (= O)-, Methyl CO₂-, Ethyl CO₂-, Propyl CO₂-, Isopropyl CO₂-, Butyl CO₂-, Phenyl CO₂-, Dimethylamino-S (= O)-, diethylamino-S (= O)-, Dipropylamino-S (= O)-, Di-Isopropylamino-S (= O)-, Dibutylamino-S (= O)-, Diphenylamino-S (= O)-, Dimethylamino-SO₂-, Diethylamino-SO₂-, Dipropylamino-SO₂-, Di-isopropylamino-SO₂-, Dibutylamino-SO₂-, Diphenylamino-SO₂-, Dimethylamino-C (= O)-, diethylamino-C (= O)-, Dipropylamino-C (= O)-, Di-Isopropylamino-C (= O)-, Dibutylamino-C (= O)-, Diphenylamino-C (= O)-, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-Cyanophenyl, 2-Methylphenyl, 2-Trifluoromethylphenyl, 2-Methoxyphenyl, 2-trifluoromethoxyphenyl, 3-Chlorophenyl, 3-Fluorophenyl, 3-Bromophenyl, 3-Cyanophenyl, 3-Methylphenyl, 3-Ethylphenyl, 3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl, 3-Trifluoromethylphenyl, 3-methoxyphenyl, 3-Isopropoxyphenyl, 3-Trifluoromethoxyphenyl, 3-thiomethoxyphenyl, 4-Chlorophenyl, 4-Fluorophenyl, 4-Bromophenyl, 4-Cyanophenyl, 4-Methylphenyl, 4-Ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-Trifluoromethylphenyl, 4-methoxyphenyl, 4-Isopropoxyphenyl, 4-trifluoromethoxyphenyl, 4-thiomethoxyphenyl, 2,3-Dichlorophenyl, 2,3-difluorophenyl, 2,3-Dimethylphenyl, 2,3-ditrifluoromethylphenyl, 2,3-Dimethoxyphenyl, 2,3-ditrifluoromethoxyphenyl, 2,4-Dichlorophenyl, 2,4-difluorophenyl, 2,4-Dimethylphenyl, 2,4-ditrifluoromethylphenyl, 2,4-Dimethoxyphenyl, 2,4-ditrifluoromethoxyphenyl, 2,5-Dichlorophenyl, 2,5-difluorophenyl, 2,5-Dimethylphenyl, 2,5-ditrifluoromethylphenyl, 2,5-Dimethoxyphenyl, 2,5-ditrifluoromethoxyphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-Dimethylphenyl, 2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl, 2,6-ditrifluoromethoxyphenyl, 3,4-Dichlorophenyl, 3,4-difluorophenyl, 3,4-Dimethylphenyl, 3,4-ditrifluoromethylphenyl, 3,4-Dimethoxyphenyl, 3,4-ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl, 2-Chloro-4-CF₃-Fenil, 2-fluoro-3-chloro-Fenil, 2-Chloro-4-CF₃-Fenyl, 2-chloro-4-methoxy-Fenyl, 2-Methoxy-4-isopropyl-phenyl, 2-CF₃-4-Methoxy-phenyl, 2-Methyl-4-methoxy-5-fluoro-phenyl, 2-Methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-Fenil, 2, 4, 5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, Methyl-C (= O) NH-, Ethyl-C (= O) NH-, Propyl-C (= O) NH-, Isopropyl-C (= O) NH-, Butyl-C (= O) NH-, Phenyl-C (= O) NH-, 4-Acetylphenyl, 3-Acetamidephenyl, 4-Pyridyl, 2-Franyl, 2-thiophenyl, 2-naphthyl, 2-Me-5-F-Fenil, 2-F-5-Me-Fenil, 2-MeO-5-F-Fenil, 2-Me-3-Cl-Fenil, 3-NO₂-Fenil, 2-NO₂-Fenil, 2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl, 2-Cl-6-F-Fenil, 2-Cl-4- (CHF)₂) O-Fenil, 2,4-Di MeO-6-F-Fenil, 2-CF₃_~₆-F-Fenil, 2-MeS-Fenil, 2,6-Di Cl-4-MeO-Fenil, 2,3,4-tri F-phenyl, 2,6-di F-4-Cl-phenyl, 2, 3, 4, 6-Tetra F-Fenil, 2, 3, 4, 5, 6-Penta F-Fenil, 2-CF₃-4-EtO-Fenil, 2-CF₃-4-iPrO-Fenil, 2-CF₃-4-Cl-Fenil, 2-CF₃-4-F-Fenil, 2-Cl-4-EtO-Fenil, 2-Cl-4-iPrO-Fernil, 2-Et-4-MeO-Fenil, 2-CHO-4-MeO-Fenil, 2-CH (OH) Me-4-MeO-Fenil, 2-CH (OMe) Me-4-MeO-Fenil, 2-C (= O) Me-4-MeO-Fenil, 2-CH₂(OH) -4-MeO-Fenil, 2-CH₂(OMe) -4-MeO-Fenil, 2-CH (OH) Et-4-MeO-phenyl, 2-C (= O) Et-4-MeO-phenyl, (Z) -2-CH = CHCO₂Me-4-MeO-Fenil, 2-CH₂CH₂CO₂Me-4-MeO-Fenil, (Z) -2-CH = CHCH₂(OH) -4-MeO-Fenil, (E) -2-CH = CHCO₂Me-4-MeO-Fenil, (E) -2-CH = CHCH₂(OH) -4-MeO-Fenil, 2-CH₂CH₂OMe-4-MeO-Fenil, 2-F-4-MeO-Fenil, 2-Cl-4-F-Fenil, (2-Cl-phenyl) -CH = CH-, (3-Cl-phenyl) -CH = CH-, (2, 6-di F-Fenil) -CH = CH-, -CH₂CH = CH₂, Phenyl-CH = CH-, (2-Me-4-MeO-Phenyl) -CH = CH-, Cyclohexyl, cyclopentyl, cyclohexylmethyl, -CH₂CH₂CO₂Et,-(CH₂)₃CO₂Et,-(CH₂)₄CO₂Et, Benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl, 2-OH-benzyl, 2-CO₂Me-3-MeO-Fenil, 2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF₃-4-CN-Fenil, 3-CHO-Fenil, 3-CH₂(OH)-Fenil, 3-CH₂(OMe)-Fenil, 3-CH₂(NMe₂)-Fenil, 3-CN-4-F-Fenil, 3-CONH₂-4-F-Fenil, 2-CH₂(NH₂) -4-MeO-Fenil-, Phenyl-NH-, (4-F-phenyl) -NH-, (2,4-diCl-phenyl) -NH-, Phenyl-C (= O) NH-, benzyl-NH-, (2-Me-4-MeO-phenyl) -NH-, (2-F-4-MeO-Fenil) -NH-, (2-Me-4-F-Fenil) -NH-, Phenyl-S-, -NMe₂, 1-pyrrolidinyl, and -N (Tosilate)₂Selected from; n is 1 or 2. [0335] [14] In another preferred embodiment of the invention. X is -O-, -S-, -S (= O)-, or -S (= O) 2-; [0336] R¹Is C replaced by Z₁_~₆Alkyl, C replaced by Z₂_~₆Alkenyl, C replaced by Z₂_~₆Alkyne, C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S. 0 ~ 2 R²C replaced by₁_~₆Alkyl, 0 ~ 2 R²C replaced by₂_~₆Alkenyl, 0 ~ 2 R²C replaced by₂_~₆Alkyne, 0 ~ 2 R²Aryl substituted with, as well Contains at least one heteroatom selected from the group consisting of N, O, and S, 0-2 R²5- to 6-membered heterocyclic system substituted with Selected from; [0337] Z is H, -CH (OH) R², -C (ethylenedioxy) R², -OR², -SR², -NR²R³, -C (O) R², -C (O) NR²R³, -NR³C (O) R², -C (O) OR², -OC (O) R², -CH (= NR)⁴) NR²R³, -NHC (= NR)⁴) NR²R³, -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0338] R²At the time of each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Aryl substituted with, 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0339] R³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, and C₁_~₄Selected independently of alkoxy; [0340] Alternatively, R²And R³Concatenate -O- or -N (R)⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0341] R⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0342] R⁵Is H, methyl, ethyl, propyl, or butyl; [0343] R^6aIs H, -OH, -NR⁴⁶R⁴⁷, -CF₃, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, and 0 ~ 3 R⁴⁴Selected from aryl substituted with; [0344] R^6bIs H; [0345] R⁷, R⁸And R⁹At each appearance, H, Halo, -CF₃, -OCF₃, -OH, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected independently from; [0346] R¹¹Is H, halo, -CF₃, -CN, -NO₂, C₁_~₈Alkyl, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Haloalkyl, C₁_~₈Alkoxy, C₃_~₁₀Cycloalkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², OC (O) OR¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O) NR¹²R¹³, S (O)₂NR¹²R¹³, NR¹⁴S (O) R¹², And NR¹⁴S (O)₂R¹²Selected from; [0347] R¹²At the time of each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0348] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0349] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0350] R¹⁴H and C at each appearance₁_~₄Selected independently of alkyl; [0351] R³¹At the time of each appearance H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, Methyl, ethyl, and propyl independently selected; [0352] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, C₁_~₃Alkyl, C2 ~ 3 alkenyl, C2 ~ 3 alkynyl, C₃_~₅Cycloalkyl, C₁_~₃Haloalkyl, C₁_~₃Haloalkyl-oxy-, C₁_~₃Alkyloxy-, C₁_~₃Alkylthio-, C₁_~₃Alkyl-C (= O)-and C₁_~₃Selected independently of alkyl-C (= O) NH-; [0353] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, = O, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0354] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0355] R⁴³Is 0 to 3 R⁴⁴C replaced by₃_~₆Cycloalkyl or aryl; [0356] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, C₁_~₄Alkyl, and C₁_~₄Selected independently of alkoxy; [0357] R⁴⁵Is C₁_~₄Alkyl; [0358] R⁴⁶At each appearance, H and C₁_~₄Selected independently of alkyl; [0359] R⁴⁷H, C at the time of each appearance₁_~₄Alkyl, -C (= O) NH (C₁_~₄Alkyl), -SO₂(C₁_~₄Alkyl), -SO₂(Phenyl), -C (= O) O (C₁_~₄Alkyl), -C (= O) (C₁_~₄Alkyl), and -C (= O) H are selected independently; [0360] R⁴⁸H, C at the time of each appearance₁_~₄Alkyl, -C (= O) NH (C₁_~₄Alkyl), -C (= O) O (C₁_~₄Alkyl), -C (= O) (C₁_~₄Alkyl), and -C (= O) H are selected independently; [0361] k is 1 or 2; m is 0, 1, or 2; and n is 1 or 2. [0362] [15] In another more preferred embodiment of the invention. X is -O- or -S-; [0363] R¹Is C replaced by Z₂_~₅Alkyl, C replaced by Z₂_~₅Alkenyl, C replaced by Z₂_~₅Alkyne, C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S. 0 ~ 2 R²C replaced by₁_~₅Alkyl, 0 ~ 2 R²C replaced by₂_~₅Alkenyl, as well 0 ~ 2 R²C replaced by₂_~₅Alkyne Selected from; [0364] Z is H, -CH (OH) R², -C (ethylenedioxy) R², -OR², -SR², -NR²R³, -C (O) R², -C (O) NR²R³, -NR³C (O) R², -C (O) OR², -OC (O) R², -CH (= NR)⁴) NR²R³, -NHC (= NR)⁴) NR²R³, -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0365] R²At the time of each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R⁴²Aryl substituted with, 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0366] R³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, and C₁_~₄Selected independently of alkoxy; [0367] Alternatively, R²And R³Concatenate -O- or -N (R)⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0368] R⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0369] R⁵Is H, methyl or ethyl; [0370] R^6aIs H, -OH, -NR⁴⁶R⁴⁷, -CF₃, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, and C₃_~₆Selected from cycloalkyl; [0371] R^6bIs H; [0372] R⁷, R⁸And R⁹At the time of each appearance H, halo, -CF₃, -OCF₃, -OH, -OCH₃, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Haloalkyl, C₁_~₆Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O)₂NR¹²R¹³, NR¹⁴S (O)₂R¹², NR¹⁴S (O) R¹², NR¹⁴S (O)₂R¹², NR¹²C (O) R¹⁵, NR¹²C (O) OR¹⁵, NR¹²S (O)₂R¹⁵, As well as NR¹²C (O) NHR¹⁵Selected independently from; [0373] R¹¹Is H, halo, -CF₃, -OCF₃, -OH, -OCH₃, -CN, -NO₂, -NR⁴⁶R⁴⁷, C₁_~₆Alkyl, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Haloalkyl, C₁_~₆Alkoxy, (C₁_~₄Haloalkyl) oxy, 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residue, 0-5 R³³Aryl substituted with, 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. OR¹², SR¹², NR¹²R¹³, C (O) H, C (O) R¹², C (O) NR¹²R¹³, NR¹⁴C (O) R¹², C (O) OR¹², OC (O) R¹², CH (= NR)¹⁴) NR¹²R¹³, NHC (= NR)¹⁴) NR¹²R¹³, S (O) R¹², S (O)₂R¹², S (O)₂NR¹²R¹³, As well as NR¹⁴S (O)₂R¹²Selected from; [0374] R¹²At the time of each appearance C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, C₃_~₆Cycloalkyl, 0-5 R³³Phenyl, substituted with 0 ~ 3 R³³C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R³¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0375] R¹³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, and C₂_~₄Selected independently of alkynyl; [0376] Alternatively, R¹²And R¹³Concatenate -O- or -N (R)¹⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0377] R¹⁴H and C at each appearance₁_~₄Selected independently of alkyl; [0378] R³¹At the time of each appearance H, OH, halo, CF₃, Methyl, and ethyl are selected independently; [0379] R³³At the time of each appearance H, OH, halo, CN, NO₂, CF₃, Methyl, and ethyl are selected independently; [0380] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, = O, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0381] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0382] R⁴³Is 0 to 3 R⁴⁴C replaced by₃_~₆Cycloalkyl or aryl; [0383] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, C₁_~₄Alkyl, and C₁_~₄Selected independently of alkoxy; [0384] R⁴⁵Is C₁_~₄Alkyl; [0385] R⁴⁶At each appearance, H and C₁_~₃Selected independently of alkyl; [0386] R⁴⁷H, C at the time of each appearance₁_~₄Alkyl, -C (= O) NH (C₁_~₄Alkyl), -SO₂(C₁_~₄Alkyl), -SO₂(Phenyl), -C (= O) O (C₁_~₄Alkyl), -C (= O) (C₁_~₄Alkyl), and -C (= O) H are selected independently; [0387] R⁴⁸H, C at the time of each appearance₁_~₄Alkyl, -C (= O) NH (C₁_~₄Alkyl), -C (= O) O (C₁_~₄Alkyl), -C (= O) (C₁_~₄Alkyl), and -C (= O) H are selected independently; [0388] k is 1 or 2; m is 0, 1 or 2; and n is 1 or 2. [0389] [16] In another further preferred embodiment of the invention. X is -O-; [0390] R¹Is C replaced by Z₂_~₄Alkyl, C replaced by Z₂_~₄Alkenyl, C replaced by Z₂_~₄Alkyne, C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S. 0 ~ 2 R²C replaced by₂_~₄Alkyl, as well 0 ~ 2 R²C replaced by₂_~₄Alkenyl Selected from; [0391] Z is H, -CH (OH) R², -C (ethylenedioxy) R², -OR², -SR², -NR²R³, -C (O) R², -C (O) NR²R³, -NR³C (O) R², -C (O) OR², -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0392] R²At the time of each appearance 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0393] R³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, and C₁_~₄Selected independently of alkoxy; [0394] Alternatively, R²And R³Concatenate -O- or -N (R)⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0395] R⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0396] R⁵Is H; [0397] R^6aIs H, -OH, -CF₃, Methyl, ethyl, propyl, butyl, methoxy, and ethoxy; [0398] R^6bIs H; [0399] R⁷, R⁸And R⁹At the time of each appearance H, halo, -CF₃, -OCF₃, -OH, -OCH₃, -CN, -NO₂, C₁_~₄Alkyl, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₃Haloalkyl) oxy, and 0 ~ 2 R¹¹C replaced by₁_~₄Alkyl Selected independently from; [0400] R¹¹Is H, halo, -CF₃, -OCF₃, -OH, -OCH₃, -CN, -NO₂, C₁_~₄Alkyl, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, and (C₁_~₃Haloalkyl) Selected from Oxy; [0401] R³³At the time of each appearance H, OH, halo, CF₃, And selected independently of methyl; [0402] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, = O, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0403] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0404] R⁴³Are 0 to 3 Rs each⁴⁴Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl substituted with; [0405] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, Methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy; [0406] R⁴⁵Is methyl, ethyl, propyl, or butyl; [0407] R⁴⁶Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0408] R⁴⁷At the time of each appearance H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-Butyl, -C (= O) NH (Methyl), -C (= O) NH (Ethyl), -SO₂(Methyl), -SO₂(Ethyl), -SO₂(Phenyl), -C (= O) O (methyl), -C (= O) O (ethyl), -C (= O) (methyl), Selected independently of -C (= O) (ethyl) and -C (= O) H; [0409] R⁴⁸At the time of each appearance H, methyl, ethyl, n-propyl, i-propyl, -C (= O) NH (methyl), -C (= O) NH (ethyl), -C (= O) O (methyl), -C ( Selected independently from = O) O (ethyl), -C (= O) (methyl), -C (= O) (ethyl), and -C (= O) H; [0410] k is 1; m is 0, 1, or 2; and n is 1 or 2. [0411] [17] In another further preferred embodiment of the invention. X is -O-; [0412] R¹Is Z-substituted ethyl, Propyl substituted with Z, Butyl replaced with Z, Propenil replaced with Z, Butenyl replaced with Z, R²Ethyl substituted with R²Propyl substituted with R²Butyl substituted with R²Propenil replaced with, and R²Butenil replaced by Selected from; [0413] Z is H, -CH (OH) R², -OR², -SR², -NR²R³, -C (O) R², -C (O) NR²R³, -NR³C (O) R², -C (O) OR², -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0414] R²At the time of each appearance 0 ~ 3 R⁴²Phenyl, substituted with 0 ~ 3 R⁴²Naftil replaced with 0 ~ 3 R⁴¹Cyclopropyl substituted with 0 ~ 3 R⁴¹Cyclobutyl substituted with, 0 ~ 3 R⁴¹Cyclopentyl replaced with 0 ~ 3 R⁴¹Cyclohexyl replaced with 0 ~ 3 R⁴¹Pyridil replaced with 0 ~ 3 R⁴¹Indrill replaced by 0 ~ 3 R⁴¹Indolinyl replaced with 0 ~ 3 R⁴¹Benzoimidazolyl replaced with 0 ~ 3 R⁴¹Benztriazolyl replaced with 0 ~ 3 R⁴¹Benzothienyl replaced with, 0 ~ 3 R⁴¹Benzofuranyl substituted with 0 ~ 3 R⁴¹Phthalimide-1-yl substituted with 0 ~ 3 R⁴¹Inden-2-yl replaced with 0 ~ 3 R⁴¹2,3-Dihydro-1H-inden-2-yl, substituted with 0 ~ 3 R⁴¹Indazolyl replaced by 0 ~ 3 R⁴¹Tetrahydroquinolinyl substituted with, and 0 ~ 3 R⁴¹Tetrahydro-isoquinolinyl substituted with Selected independently from; [0415] R³At the time of each appearance Selected independently from H, methyl, and ethyl; [0416] R⁵Is H; [0417] R^6aIs selected from H, -OH, methyl, and methoxy; [0418] R^6bIs H; [0419] R⁷, R⁸And R⁹At each appearance, H, F, Cl, methyl, ethyl, methoxy, -CF₃, And -OCF₃Selected independently from; [0420] R⁴¹At the time of each appearance H, F, Cl, Br, OH, CF₃, NO₂, CN, = O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy independently selected; [0421] R⁴²At the time of each appearance H, F, Cl, Br, OH, CF₃, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, = O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy independently selected; [0422] R⁴⁵Is methyl, ethyl, propyl, or butyl; [0423] R⁴⁶Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0424] R⁴⁷At the time of each appearance H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-Butyl, -C (= O) NH (Methyl), -C (= O) NH (Ethyl), -SO₂(Methyl), -SO₂(Ethyl), -SO₂(Phenyl), -C (= O) O (methyl), -C (= O) O (ethyl), -C (= O) (methyl), Selected independently of -C (= O) (ethyl) and -C (= O) H; [0425] R⁴⁸At the time of each appearance H, methyl, ethyl, n-propyl, i-propyl, -C (= O) NH (methyl), -C (= O) NH (ethyl), -C (= O) O (methyl), -C ( Selected independently from = O) O (ethyl), -C (= O) (methyl), -C (= O) (ethyl), and -C (= O) H; [0426] k is 1; m is 0, 1, or 2; and n is 1 or 2. [0427] [18] In another further preferred embodiment of the invention. X is -S-; [0428] R¹Is C replaced by Z₂_~₄Alkyl, C replaced by Z₂_~₄Alkenyl, C replaced by Z₂_~₄Alkyne, C replaced by Z₃_~₆Cycloalkyl, Z-substituted aryl, A Z-substituted 5- to 6-membered heterocyclic system containing at least one heteroatom selected from the group consisting of N, O, and S; 0 ~ 2 R²C replaced by₂_~₄Alkyl, as well 0 ~ 2 R²C replaced by₂_~₄Selected from alkenyl; [0429] Z is H, -CH (OH) R², -C (ethylenedioxy) R², -OR², -SR², -NR²R³, -C (O) R², -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0430] R²At the time of each appearance 0-5 R⁴²Phenyl, substituted with 0 ~ 3 R⁴¹C replaced by₃_~₁₀Carbon ring residues, as well 0 ~ 3 R⁴¹Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0431] R³At the time of each appearance H, C₁_~₄Alkyl, C₂_~₄Alkenyl, C₂_~₄Alkyne, and C₁_~₄Selected independently of alkoxy; [0432] Alternatively, R²And R³Concatenate -O- or -N (R)⁴)-Forms an arbitrarily substituted 5- or 6-membered ring; [0433] R⁴Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0434] R⁵Is H; [0435] R^6aIs H, -OH, -CF₃, Methyl, ethyl, propyl, butyl, methoxy, and ethoxy; [0436] R^6bIs H; [0437] R⁷, R⁸And R⁹At each appearance, H, Halo, -CF₃, -OCF₃, -OH, -OCH₃, -CN, -NO₂, C₁_~₄Alkyl, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, (C₁_~₃Haloalkyl) oxy, and 0 ~ 2 R¹¹C replaced by₁_~₄Selected independently of alkyl; [0438] R¹¹Is H, halo, -CF₃, -OCF₃, -OH, -OCH₃, -CN, -NO₂, C₁_~₄Alkyl, C₁_~₄Haloalkyl, C₁_~₄Alkoxy, and (C₁_~₃Haloalkyl) Selected from Oxy; [0439] R³³At the time of each appearance H, OH, halo, CF₃, And selected independently of methyl; [0440] R⁴¹At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, = O, C₂_~₈Alkenyl, C₂_~₈Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴²Aryl substituted with, as well 0 ~ 3 R⁴⁴A 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with. Selected independently from; [0441] R⁴²At the time of each appearance H, CF₃, Haro, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH (= NH) NH₂, NHC (= NH) NH₂, C₂_~₆Alkenyl, C₂_~₆Alkyne, C₁_~₄Alkoxy, C₁_~₄Haloalkyl, C₃_~₆Cycloalkyl, 0 to 1 R⁴³C replaced by₁_~₄Alkyl, 0 ~ 3 R⁴⁴Aryl substituted with, as well 0 ~ 3 R⁴⁴Independently selected from a 5- to 10-membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with; [0442] R⁴³Are 0 to 3 Rs each⁴⁴Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl substituted with; [0443] R⁴⁴H, halo, -OH, NR at each appearance⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, -CF₃, -OCF₃, -CN, -NO₂, Methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy; [0444] R⁴⁵Is methyl, ethyl, propyl, or butyl; [0445] R⁴⁶Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0446] R⁴⁷At the time of each appearance H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-Butyl, -C (= O) NH (Methyl), -C (= O) NH (Ethyl), -SO₂(Methyl), -SO₂(Ethyl), -SO₂(Phenyl), -C (= O) O (methyl), -C (= O) O (ethyl), -C (= O) (methyl), Selected independently of -C (= O) (ethyl) and -C (= O) H; [0447] R⁴⁸At the time of each appearance H, methyl, ethyl, n-propyl, i-propyl, -C (= O) NH (methyl), -C (= O) NH (ethyl), -C (= O) O (methyl), -C ( Selected independently from = O) O (ethyl), -C (= O) (methyl), -C (= O) (ethyl), and -C (= O) H; [0448] k is 1; m is 0, 1, or 2; and n is 1 or 2. [0449] [19] In another further preferred embodiment of the invention. X is -O-; [0450] R¹Is Z-substituted ethyl, Propyl substituted with Z, Butyl replaced with Z, Propenil replaced with Z, Butenyl replaced with Z, R²Ethyl substituted with R²Propyl substituted with R²Butyl substituted with R²Propenil replaced with, and R²Butenil replaced with Selected from; [0451] Z is H, -CH (OH) R², -OR², -SR², -NR²R³, -C (O) R², -C (O) NR²R³, -NR³C (O) R², -C (O) OR², -S (O) R², -S (O)₂R², -S (O)₂NR²R³, And -NR³S (O)₂R²Selected from; [0452] R²At the time of each appearance 0 ~ 3 R⁴²Phenyl substituted with; 0 ~ 3 R⁴²Naftil replaced with; 0 ~ 3 R⁴¹Cyclopropyl substituted with 0 ~ 3 R⁴¹Cyclobutyl substituted with, 0 ~ 3 R⁴¹Cyclopentyl replaced with 0 ~ 3 R⁴¹Cyclohexyl replaced with 0 ~ 3 R⁴¹Pyridil replaced with 0 ~ 3 R⁴¹Indrill replaced by 0 ~ 3 R⁴¹Indolinyl replaced with 0 ~ 3 R⁴¹Benzoimidazolyl replaced with 0 ~ 3 R⁴¹Benztriazolyl replaced with 0 ~ 3 R⁴¹Benzothienyl replaced with, 0 ~ 3 R⁴¹Benzofuranyl substituted with 0 ~ 3 R⁴¹Phthalimide-1-yl substituted with 0 ~ 3 R⁴¹Inden-2-yl replaced with 0 ~ 3 R⁴¹2,3-Dihydro-1H-inden-2-yl, substituted with 0 ~ 3 R⁴¹Indazolyl replaced by 0 ~ 3 R⁴¹Tetrahydroquinolinyl substituted with, and 0 ~ 3 R⁴¹Tetrahydro-isoquinolinyl substituted with Selected independently from; [0453] R³Are selected independently of H, methyl, and ethyl at each appearance; [0454] R⁵Is H; [0455] R^6aIs selected from H, -OH, methyl, and methoxy; [0456] R^6bIs H; [0457] R⁷, R⁸And R⁹H, F, Cl, Methyl, Ethyl, Methoxy, -CF at the time of each appearance₃, And -OCF₃Selected independently from; [0458] R⁴¹At the time of each appearance H, F, Cl, Br, OH, CF₃, NO₂, CN, = O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy independently selected; [0459] R⁴²H, F, Cl, Br, OH, CF at the time of each appearance₃, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, = O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy independently selected; [0460] R⁴⁵Is methyl, ethyl, propyl, or butyl; [0461] R⁴⁶Are independently selected from H, methyl, ethyl, propyl, and butyl at each appearance; [0462] R⁴⁷At the time of each appearance H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-Butyl, -C (= O) NH (Methyl), -C (= O) NH (Ethyl), -SO₂(Methyl), -SO₂(Ethyl), -SO₂(Phenyl), -C (= O) O (methyl), -C (= O) O (ethyl), -C (= O) (methyl), Selected independently of -C (= O) (ethyl) and -C (= O) H; [0463] R⁴⁸At the time of each appearance H, methyl, ethyl, n-propyl, i-propyl, -C (= O) NH (methyl), -C (= O) NH (ethyl), -C (= O) O (methyl), -C ( Selected independently from = O) O (ethyl), -C (= O) (methyl), -C (= O) (ethyl), and -C (= O) H; [0464] k is 1; m is 0, 1, or 2; and n is 1 or 2. [0465] [20] In another further preferred embodiment of the invention, the compound of formula (I) is selected from formula (Ia) below. [0466] [Chemical 19]<img file="JP4916633B2_D0009.tif" />[0467] During the ceremony b is a single bond or a double bond; [0468] X is -S- or -O-; [0469] R¹Is -(CH₂)₃C (= O) (4-fluoro-phenyl), -(CH₂)₃C (= O) (4-bromo-phenyl), -(CH₂)₃C (= O) (4-methyl-phenyl), -(CH₂)₃C (= O) (4-methoxy-phenyl), -(CH₂)₃C (= O) (4- (3,4-dichloro-phenyl) phenyl), -(CH₂)₃C (= O) (3-methyl-4-fluoro-phenyl), -(CH₂)₃C (= O) (2,3-dimethoxy-phenyl), -(CH₂)₃C (= O) (phenyl), -(CH₂)₃C (= O) (4-chloro-phenyl), -(CH₂)₃C (= O) (3-methyl-phenyl), -(CH₂)₃C (= O) (4-t-butyl-phenyl), -(CH₂)₃C (= O) (3,4-difluoro-phenyl), -(CH₂)₃C (= O) (2-methoxy-5-fluoro-phenyl), -(CH₂)₃C (= O) (4-fluoro-1-naphthyl), -(CH₂)₃C (= O) (benzyl), -(CH₂)₃C (= O) (4-pyridyl), -(CH₂)₃C (= O) (3-pyridyl), -(CH₂)₃CH (OH) (4-fluoro-phenyl), -(CH₂)₃CH (OH) (4-pyridyl), -(CH₂)₃CH (OH) (2,3-dimethoxy-phenyl), -(CH₂)₃S (3-fluoro-phenyl), -(CH₂)₃S (4-fluoro-phenyl), -(CH₂)₃S (= O) (4-fluoro-phenyl), -(CH₂)₃SO₂(3-Fluoro-phenyl), -(CH₂)₃SO₂(4-Fluoro-phenyl), -(CH₂)₃O (4-fluoro-phenyl), -(CH₂)₃O (phenyl), -(CH₂)₃O (3-pyridyl), -(CH₂)₃O (4-pyridyl), -(CH₂)₃O (2-NH₂-Fenil), -(CH₂)₃O (2-NH₂-5-F-Fenil), -(CH₂)₃O (2-NH₂-4-F-Fenil), -(CH₂)₃O (2-NH₂-3-F-Fenil), -(CH₂)₃O (2-NH₂-4-Cl-Fenil), -(CH₂)₃O (2-NH₂-4-OH-Fenil), -(CH₂)₃O (2-NH₂-4-Br-Fenil), -(CH₂)₃O (2-NHC (= O) Me-4-F-Fenil), -(CH₂)₃O (2-NHC (= O) Me-Fenil), -(CH₂)₃NH (4-fluoro-phenyl), -(CH₂)₃N (methyl) (4-fluoro-phenyl), -(CH₂)₃CO₂(ethyl), -(CH₂)₃C (= O) N (methyl) (methoxy), -(CH₂)₃C (= O) NH (4-fluoro-phenyl), -(CH₂)₂NHC (= O) (Phenyl), -(CH₂)₂NMeC (= O) (Phenyl), -(CH₂)₂NHC (= O) (2-fluoro-phenyl), -(CH₂)₂NMeC (= O) (2-fluoro-phenyl), -(CH₂)₂NHC (= O) (4-fluoro-phenyl), -(CH₂)₂NMeC (= O) (4-fluoro-phenyl), -(CH₂)₂NHC (= O) (2,4-difluoro-phenyl), -(CH₂)₂NMeC (= O) (2,4-difluoro-phenyl), -(CH₂)₃(3-Indrill), -(CH₂)₃(1-Methyl-3-indrill), -(CH₂)₃(1-Indrill), -(CH₂)₃(1-Indolinil), -(CH₂)₃(1-Benzoimidazolyl), -(CH₂)₃(1H-1,2,3-benzotriazol-1-yl), -(CH₂)₃(1H-1,2,3-benzotriazol-2-yl), -(CH₂)₂(1H-1,2,3-benzotriazol-1-yl), -(CH₂)₂(1H-1,2,3-benzotriazol-2-yl), -(CH₂)₃(3,4 dihydro-1 (2H) -quinolinyl), -(CH₂)₂C (= O) (4-fluoro-phenyl), -(CH₂)₂C (= O) NH (4-fluoro-phenyl), -CH₂CH₂(3-Indrill), -CH₂CH₂(1-phthalimidil), -(CH₂)₄C (= O) N (methyl) (methoxy), -(CH₂)₄CO₂(ethyl), -(CH₂)₄C (= O) (phenyl), -(CH₂)₄(Cyclohexyl), -(CH₂)₃CH (Phenyl)₂, -CH₂CH₂CH = C (Phenyl)₂, -CH₂CH₂CH = CMe (4-F-Fenil), -(CH₂)₃CH (4-fluoro-phenyl)₂, -CH₂CH₂CH = C (4-fluoro-phenyl)₂, -(CH₂)₂(2,3-dihydro-1H-inden-2-yl), -(CH₂)₃C (= O) (2-NH₂-Fenil), -(CH₂)₃C (= O) (2-NH₂-5-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-3-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-Cl-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-OH-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-Br-Fenil), -(CH₂)₃(1H-Indazol-3-yl), -(CH₂)₃(5-F-1H-Indazol-3-yl), -(CH₂)₃(7-F-1H-Indazol-3-yl), -(CH₂)₃(6-Cl-1H-Indazol-3-yl), -(CH₂)₃(6-Br-1H-Indazol-3-yl), -(CH₂)₃C (= O) (2-NHMe-Fenil), -(CH₂)₃(1-benzothien-3-yl), -(CH₂)₃(6-F-1H-Indoru-1-Il), -(CH₂)₃(5-F-1H-Indoru-1-yl), -(CH₂)₃(6-F-2, 3-dihydro-1H-indol-1-yl), -(CH₂)₃(5-F-2, 3-dihydro-1H-indol-1-yl), -(CH₂)₃(6-F-1H-Indoru-3-Il), -(CH₂)₃(5-F-1H-Indoru-3-Il), -(CH₂)₃(5-F-1H-Indoru-3-Il), -(CH₂)₃(9H-Purin-9-Il), -(CH₂)₃(7H-Purin-7-Il), -(CH₂)₃(6-F-1H-Indazol-3-yl), -(CH₂)₃C (= O) (2-NHSO₂Me-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) Me-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) Me-Fenil), -(CH₂)₃C (= O) (2-NHCO₂Et-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) NHEt-4-F-Fenil), -(CH₂)₃C (= O) (2-NHCHO-4-F-Fenil), -(CH₂)₃C (= O) (2-OH-4-F-phenyl), -(CH₂)₃C (= O) (2-MeS-4-F-Fenil), -(CH₂)₃C (= O) (2-NHSO₂Me-4-F-Fenil), -(CH₂)₂C (Me) CO₂Me, -(CH₂)₂C (Me) CH (OH) (4-F-Fenil)₂, -(CH₂)₂C (Me) CH (OH) (4-Cl-Fenil)₂, -(CH₂)₂C (Me) C (= O) (4-F-Fenil), -(CH₂)₂C (Me) C (= O) (2-MeO-4-F-Fenil), -(CH₂)₂C (Me) C (= O) (3-Me-4-F-Fenil), -(CH₂)₂C (Me) C (= O) (2-Me-phenyl), -(CH₂)₂C (Me) C (= O) Phenyl, [0470] [Chemical 20]<img file="JP4916633B2_D0010.tif" />[0471] Selected from; R⁷, R⁸And R⁹At the time of each appearance Hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, benzyl, HC (= O)-, Methyl C (= O)-, Ethyl C (= O)-, Propyl C (= O)-, Isopropyl C (= O)-, n-Butyl C (= O)-, Isobutyl C (= O)-, sec Butyl C (= O)-, tert Butyl C (= O)-, Phenyl C (= O)-, Methyl C (= O) NH-, Ethyl C (= O) NH-, Propyl C (= O) NH-, Isopropyl C (= O) NH-, n-Butyl C (= O) NH-, Isobutyl C ( = O) NH-, sec Butyl C (= O) NH-, tert Butyl C (= O) NH-, Phenyl C (= O) NH-, Methylamino-, ethylamino-, propylamino-, isopropylamino-, n-butylamino-, isobutylamino-, sec butylamino-, tertbutylamino-, phenylamino-, Selected from; [0472] However, the substituent R⁷, R⁸And R⁹Two of them are independent of hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. Selected for; [0473] k is 1 or 2; m is 1 or 2; n is 1 or 2. [0474] [21] In another further preferred embodiment of the invention, the compound of formula (I) is selected from formula (II-a) below. [0475] [Chemical 21]<img file="JP4916633B2_D0011.tif" />[0476] During the ceremony b is a single bond and the crosslinked hydrogen is in the cis position; [0477] R¹Is -(CH₂)₃C (= O) (4-fluoro-phenyl), -(CH₂)₃C (= O) (4-bromo-phenyl), -(CH₂)₃C (= O) (4-methyl-phenyl), -(CH₂)₃C (= O) (4-methoxy-phenyl), -(CH₂)₃C (= O) (4- (3,4-dichloro-phenyl) phenyl), -(CH₂)₃C (= O) (3-methyl-4-fluoro-phenyl), -(CH₂)₃C (= O) (2,3-dimethoxy-phenyl), -(CH₂)₃C (= O) (phenyl), -(CH₂)₃C (= O) (4-chloro-phenyl), -(CH₂)₃C (= O) (3-methyl-phenyl), -(CH₂)₃C (= O) (4-t-butyl-phenyl), -(CH₂)₃C (= O) (3,4-difluoro-phenyl), -(CH₂)₃C (= O) (2-methoxy-5-fluoro-phenyl), -(CH₂)₃C (= O) (4-fluoro-1-naphthyl), -(CH₂)₃C (= O) (benzyl), -(CH₂)₃C (= O) (4-pyridyl), -(CH₂)₃C (= O) (3-pyridyl), -(CH₂)₃CH (OH) (4-fluoro-phenyl), -(CH₂)₃CH (OH) (4-pyridyl), -(CH₂)₃CH (OH) (2,3-dimethoxy-phenyl), -(CH₂)₃S (3-fluoro-phenyl), -(CH₂)₃S (4-fluoro-phenyl), -(CH₂)₃S (= O) (4-fluoro-phenyl), -(CH₂)₃SO₂(3-Fluoro-phenyl), -(CH₂)₃SO₂(4-Fluoro-phenyl), -(CH₂)₃O (4-fluoro-phenyl), -(CH₂)₃O (phenyl), -(CH₂)₃NH (4-fluoro-phenyl), -(CH₂)₃N (methyl) (4-fluoro-phenyl), -(CH₂)₃CO₂(ethyl), -(CH₂)₃C (= O) N (methyl) (methoxy), -(CH₂)₃C (= O) NH (4-fluoro-phenyl), -(CH₂)₂NHC (= O) (Phenyl), -(CH₂)₂NMeC (= O) (Phenyl), -(CH₂)₂NHC (= O) (2-fluoro-phenyl), -(CH₂)₂NMeC (= O) (2-fluoro-phenyl), -(CH₂)₂NHC (= O) (4-fluoro-phenyl), -(CH₂)₂NMeC (= O) (4-fluoro-phenyl), -(CH₂)₂NHC (= O) (2,4-difluoro-phenyl), -(CH₂)₂NMeC (= O) (2,4-difluoro-phenyl), -(CH₂)₃(3-Indrill), -(CH₂)₃(1-Methyl-3-indrill), -(CH₂)₃(1-Indrill), -(CH₂)₃(1-Indolinil), -(CH₂)₃(1-Benzoimidazolyl), -(CH₂)₃(1H-1,2,3-benzotriazol-1-yl), -(CH₂)₃(1H-1,2,3-benzotriazol-2-yl), -(CH₂)₂(1H-1,2,3-benzotriazol-1-yl), -(CH₂)₂(1H-1,2,3-benzotriazol-2-yl), -(CH₂)₃(3,4 dihydro-1 (2H) -quinolinyl), -(CH₂)₂C (= O) (4-fluoro-phenyl), -(CH₂)₂C (= O) NH (4-fluoro-phenyl), -CH₂CH₂(3-Indrill), -CH₂CH₂(1-phthalimidil), -(CH₂)₄C (= O) N (methyl) (methoxy), -(CH₂)₄CO₂(ethyl), -(CH₂)₄C (= O) (phenyl), -(CH₂)₄(Cyclohexyl), -(CH₂)₃CH (Phenyl)₂, -CH₂CH₂CH = C (Phenyl)₂, -CH₂CH₂CH = CMe (4-F-Fenil), -(CH₂)₃CH (4-fluoro-phenyl)₂, -CH₂CH₂CH = C (4-fluoro-phenyl)₂, -(CH₂)₂(2,3-dihydro-1H-inden-2-yl), -(CH₂)₃C (= O) (2-NH₂-Fenil), -(CH₂)₃C (= O) (2-NH₂-5-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-3-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-Cl-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-OH-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-Br-Fenil), -(CH₂)₃(1H-Indazol-3-yl), -(CH₂)₃(5-F-1H-Indazol-3-yl), -(CH₂)₃(7-F-1H-Indazol-3-yl), -(CH₂)₃(6-Cl-1H-Indazol-3-yl), -(CH₂)₃(6-Br-1H-Indazol-3-yl), -(CH₂)₃C (= O) (2-NHMe-Fenil), -(CH₂)₃(1-benzothien-3-yl), -(CH₂)₃(6-F-1H-Indoru-1-Il), -(CH₂)₃(5-F-1H-Indoru-1-yl), -(CH₂)₃(6-F-2,3-dihydro-1H-indol-1-yl), -(CH₂)₃(5-F-2,3-dihydro-1H-indol-1-yl), -(CH₂)₃(6-F-1H-Indoru-3-Il), -(CH₂)₃(5-F-1H-Indoru-3-Il), -(CH₂)₃(5-F-1H-Indoru-3-Il), -(CH₂)₃(9H-Purin-9-Il), -(CH₂)₃(7H-Purin-7-Il), -(CH₂)₃(6-F-1H-Indazol-3-yl), -(CH₂)₃C (= O) (2-NHSO₂Me-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) Me-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) Me-4-F-Fenil), -(CH₂)₃C (= O) (2-NHCO₂Et-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) NHEt-4-F-Fenil),-(CH₂)₃C (= O) (2-NHCHO-4-F-Fenil), -(CH₂)₃C (= O) (2-OH-4-F-phenyl), -(CH₂)₃C (= O) (2-MeS-4-F-Fenil), -(CH₂)₃C (= O) (2-NHSO₂Me-4-F-Fenil), -(CH₂)₂C (Me) CO₂Me, -(CH₂)₂C (Me) CH (OH) (4-F-Fenil)₂, -(CH₂)₂C (Me) CH (OH) (4-Cl-Fenil)₂, -(CH₂)₂C (Me) C (= O) (4-F-Fenil), -(CH₂)₂C (Me) C (= O) (2-MeO-4-F-Fenil), -(CH₂)₂C (Me) C (= O) (3-Me-4-F-Fenil), -(CH₂)₂C (Me) C (= O) (2-Me-phenyl), -(CH₂)₂C (Me) C (= O) Phenyl, [0478] [Chemical 22]<img file="JP4916633B2_D0012.tif" />[0479] Selected from; R⁷, R⁸And R⁹At each appearance, hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methyl C (= O)-, Ethyl C (= O)-, Propyl C (= O)-, Isopropyl C (= O)-, Methyl C (= O) NH-, Ethyl C (= O) NH-, Propyl C Selected independently from (= O) NH-, isopropyl C (= O) NH, methylamino-, ethylamino-, propylamino-, and isopropylamino-; [0480] However, the substituent R⁷, R⁸And R⁹Two of them are independently selected from hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; [0481] m is 1 or 2; n is 1 or 2. [0482] [22] In another further preferred embodiment of the invention, the compound of formula (I) is selected from formula (III-a) below. [0483] [Chemical 23]<img file="JP4916633B2_D0013.tif" />[0484] During the ceremony b is a single bond and the crosslinked hydrogen is in the cis position; [0485] R¹Is -(CH₂)₃C (= O) (4-fluoro-phenyl), -(CH₂)₃C (= O) (4-bromo-phenyl), -(CH₂)₃C (= O) (4-methyl-phenyl), -(CH₂)₃C (= O) (4-methoxy-phenyl), -(CH₂)₃C (= O) (4- (3,4-dichloro-phenyl) phenyl), -(CH₂)₃C (= O) (3-methyl-4-fluoro-phenyl), -(CH₂)₃C (= O) (2,3-dimethoxy-phenyl), -(CH₂)₃C (= O) (phenyl), -(CH₂)₃C (= O) (4-chloro-phenyl), -(CH₂)₃C (= O) (3-methyl-phenyl), -(CH₂)₃C (= O) (4-t-butyl-phenyl), -(CH₂)₃C (= O) (3,4-difluoro-phenyl), -(CH₂)₃C (= O) (2-methoxy-5-fluoro-phenyl), -(CH₂)₃C (= O) (4-fluoro-1-naphthyl), -(CH₂)₃C (= O) (benzyl), -(CH₂)₃C (= O) (4-pyridyl), -(CH₂)₃C (= O) (3-pyridyl), -(CH₂)₃CH (OH) (4-fluoro-phenyl), -(CH₂)₃CH (OH) (4-pyridyl), -(CH₂)₃CH (OH) (2,3-dimethoxy-phenyl), -(CH₂)₃S (3-fluoro-phenyl), -(CH₂)₃S (4-fluoro-phenyl), -(CH₂)₃S (= O) (4-fluoro-phenyl), -(CH₂)₃SO₂(3-Fluoro-phenyl), -(CH₂)₃SO₂(4-Fluoro-phenyl), -(CH₂)₃O (4-fluoro-phenyl), -(CH₂)₃O (phenyl), -(CH₂)₃NH (4-fluoro-phenyl), -(CH₂)₃N (methyl) (4-fluoro-phenyl), -(CH₂)₃CO₂(ethyl), -(CH₂)₃C (= O) N (methyl) (methoxy), -(CH₂)₃C (= O) NH (4-fluoro-phenyl), -(CH₂)₂NHC (= O) (Phenyl), -(CH₂)₂NMeC (= O) (Phenyl), -(CH₂)₂NHC (= O) (2-fluoro-phenyl), -(CH₂)₂NMeC (= O) (2-fluoro-phenyl), -(CH₂)₂NHC (= O) (4-fluoro-phenyl), -(CH₂)₂NMeC (= O) (4-fluoro-phenyl), -(CH₂)₂NHC (= O) (2,4-difluoro-phenyl), -(CH₂)₂NMeC (= O) (2,4-difluoro-phenyl), -(CH₂)₃(3-Indrill), -(CH₂)₃(1-Methyl-3-indrill), -(CH₂)₃(1-Indrill), -(CH₂)₃(1-Indolinil), -(CH₂)₃(1-Benzoimidazolyl), -(CH₂)₃(1H-1,2,3-benzotriazol-1-yl), -(CH₂)₃(1H-1,2,3-benzotriazol-2-yl), -(CH₂)₂(1H-1,2,3-benzotriazol-1-yl), -(CH₂)₂(1H-1,2,3-benzotriazol-2-yl), -(CH₂)₃(3,4 dihydro-1 (2H) -quinolinyl), -(CH₂)₂C (= O) (4-fluoro-phenyl), -(CH₂)₂C (= O) NH (4-fluoro-phenyl), -CH₂CH₂(3-Indrill), -CH₂CH₂(1-phthalimidil), -(CH₂)₄C (= O) N (methyl) (methoxy), -(CH₂)₄CO₂(ethyl), -(CH₂)₄C (= O) (phenyl), -(CH₂)₄(Cyclohexyl), -(CH₂)₃CH (Phenyl)₂, -CH₂CH₂CH = C (Phenyl)₂, -CH₂CH₂CH = CMe (4-F-Fenil), -(CH₂)₃CH (4-fluoro-phenyl)₂, -CH₂CH₂CH = C (4-fluoro-phenyl)₂, -(CH₂)₂(2,3-dihydro-1H-inden-2-yl), -(CH₂)₃C (= O) (2-NH₂-Fenil), -(CH₂)₃C (= O) (2-NH₂-5-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-3-F-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-Cl-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-OH-Fenil), -(CH₂)₃C (= O) (2-NH₂-4-Br-Fenil), -(CH₂)₃(1H-Indazol-3-yl), -(CH₂)₃(5-F-1H-Indazol-3-yl), -(CH₂)₃(7-F-1H-Indazol-3-yl), -(CH₂)₃(6-Cl-1H-Indazol-3-yl), -(CH₂)₃(6-Br-1H-Indazol-3-yl), -(CH₂)₃C (= O) (2-NHMe-Fenil), -(CH₂)₃(1-benzothien-3-yl), -(CH₂)₃(6-F-1H-Indoru-1-Il), -(CH₂)₃(5-F-1H-Indoru-1-yl), -(CH₂)₃(6-F-2, 3-dihydro-1H-indol-1-yl), -(CH₂)₃(5-F-2, 3-dihydro-1H-indol-1-yl), -(CH₂)₃(6-F-1H-Indoru-3-Il), -(CH₂)₃(5-F-1H-Indoru-3-Il), -(CH₂)₃(5-F-1H-Indoru-3-Il), -(CH₂)₃(9H-Purin-9-Il), -(CH₂)₃(7H-Purin-7-Il), -(CH₂)₃(6-F-1H-Indazol-3-yl), -(CH₂)₃C (= O) (2-NHSO₂Me-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) Me-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) Me-4-F-Fenil), -(CH₂)₃C (= O) (2-NHCO₂Et-4-F-Fenil), -(CH₂)₃C (= O) (2-NHC (= O) NHEt-4-F-Fenil),-(CH₂)₃C (= O) (2-NHCHO-4-F-Fenil), -(CH₂)₃C (= O) (2-OH-4-F-phenyl), -(CH₂)₃C (= O) (2-MeS-4-F-Fenil), -(CH₂)₃C (= O) (2-NHSO₂Me-4-F-Fenil), -(CH₂)₂C (Me) CO₂Me, -(CH₂)₂C (Me) CH (OH) (4-F-Fenil)₂, -(CH₂)₂C (Me) CH (OH) (4-Cl-Fenil)₂, -(CH₂)₂C (Me) C (= O) (4-F-Fenil), -(CH₂)₂C (Me) C (= O) (2-MeO-4-F-Fenil), -(CH₂)₂C (Me) C (= O) (3-Me-4-F-Fenil), -(CH₂)₂C (Me) C (= O) (2-Me-phenyl), -(CH₂)₂C (Me) C (= O) Phenyl, [0486] [Chemical 24]<img file="JP4916633B2_D0014.tif" />[0487] Selected from; R⁷, R⁸And R⁹At each appearance, hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methyl C (= O)-, Ethyl C (= O)-, Propyl C (= O)-, Isopropyl C (= O)-, Methyl C (= O) NH-, Ethyl C (= O) NH-, Propyl C Selected independently from (= O) NH-, isopropyl C (= O) NH, methylamino-, ethylamino-, propylamino-, and isopropylamino-; [0488] However, the substituent R⁷, R⁸And R⁹Two of them are independently selected from hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; [0489] m is 1 or 2; n is 1 or 2. [0490] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 1. [0491] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 1A. [0492] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 2. [0493] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 2A. [0494] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 3. [0495] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 3A. [0496] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 4. [0497] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 4A. [0498] In an even more preferred embodiment of the invention, the compound of formula (I) is selected from Table 5. [0499] In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. [0500] In a third embodiment, the present invention is a method of treating a central nervous system disorder, wherein a therapeutically effective amount of a compound of formula (I) or a compound thereof is used for a host in need of such treatment. Provided is a method of administering a pharmaceutically acceptable salt, wherein the compound is a 5HT2a antagonist or a 5HT2c agonist. [0501] In a preferred embodiment, the compound is a 5HT2a antagonist. [0502] In another preferred embodiment, the compound is a 5HT2c agonist. [0503] In a more preferred embodiment, the present invention provides gastrointestinal disorders such as obesity, anxiety, depression, psychiatric disorders, schizophrenia, sleep disorders, sexual disorders, migraine headaches, headache-related conditions, social phobia and gastrointestinal motility disorders. Provided is a method for treating a central nervous system disorder including, which comprises a step of administering a therapeutically effective amount of a compound of formula (I) to a host in need of such treatment. [0504] In a more preferred embodiment, CNS disorders include obesity. [0505] In yet another preferred embodiment, CNS disorders include schizophrenia. [0506] In yet another preferred embodiment, CNS disorders include depression. [0507] In yet another preferred embodiment, CNS disorders include anxiety. [0508] In a fourth embodiment, the present invention provides a novel compound of formula (I) used therapeutically or a pharmaceutically acceptable salt of the compound. [0509] In a fifth embodiment, the invention relates to central nerves such as obesity, anxiety, depression, psychiatric disorders, schizophrenia, sleep disorders, sexual disorders, migraine, other conditions associated with headaches, social phobia, and gastrointestinal disorders. Provided is the use of a novel compound of formula (I) or a pharmaceutically acceptable salt of the compound in the manufacture of a pharmaceutical product for the treatment of a system disorder. [0510] Definition The compounds described herein may have an asymmetric center. The compounds of the invention having asymmetrically substituted atoms can be isolated in optically active or racemic forms. Methods for producing optically active substances are known in the art, and include, for example, division of racemates or synthesis from optically active raw materials. Many geometric isomers such as olefins, C = N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the invention are described and can be isolated as a mixture of isomers or as a separated isomer. Unless a specific stereochemistry or isomer is specifically indicated, all chiral, diastereomeric, racemic and all geometric isomers of a structure are intended. [0511] The numbering of the tetracyclic system present in the compound of formula (I) defined by a nomenclature known to those skilled in the art is that of formula (I) when k is 1, m is 1, and n is 1. Two examples are shown with equation (I ) when ) and k are 1, m is 1 and n is 2. [0512] [Chemical 25]<img file="JP4916633B2_D0015.tif" />[0513] The tetracyclic system present in the compound of formula (I) occurs as a "cis" isomer or a "trans" isomer when the carbon-carbon bond b in formula (I) is a single bond. Thus, the terms "cis" and "trans" in combination with the tetracyclic structure are on carbon atoms 7a and 11a in formula (I'), or, for example, on carbon atoms 8a and 12a in formula (I') above. Refers to the arrangement of hydrogen atoms. If both hydrogens are on the same side of the mean plane determined by the octahydro tetracyclic moiety, the arrangement is referred to as "cis", otherwise the arrangement is referred to as "trans". It is understood that the above examples are for illustration purposes only and do not limit the range of the tetracyclic system present in the compound of formula (I). Therefore, those skilled in the art of organic chemistry can apply the above numbering system to other values of k, m and n in the range of compounds of formula (I) to determine appropriate numbering. it is obvious. Further examples of tetracyclic numbering are in the following synthetic examples. Finally, it is clear that the use of "cis" or "trans" in the identification of tetracyclics does not explain the arrangement of other cis or trans geometric isomers in molecules such as cis or transbutene. .. [0514] As used herein, the term "substitution" means that one or more hydrogens on a specified atom have replaced those selected from the indicated groups. However, it does not exceed the normal valence of the specified atom, and a stable compound can be obtained by substitution. If the substituent is a keto (ie = O), the two hydrogens on that atom have been replaced. [0515] One of the variables (eg R) in a component or formula of a compound²If there are more than one), the definition for each case is independent of that definition for any other case. So, for example, a group has 0 to 2 Rs.²If indicated as being replaced by, the group is up to two Rs.²May be substituted with a group, R in each case²Is independently R²Selected from the definition of. Moreover, combinations of substituents and / or variables are only allowed if such combinations result in stable compounds. [0516] Such substituents can be attached to any atom on the ring if the bond to the substituent is shown to intersect the bond connecting the two atoms in the ring. If a substituent is listed without an intervening atom in binding to the rest of the compound of a given formula, then such substituent is one of those substituents. Can be bonded through the atoms of. Substituent and / or variable combinations are only allowed if such combinations result in stable compounds. [0517] As used herein, the term "alkyl" or "alkylene" includes both branched and linear saturated aliphatic hydrocarbon groups with a specified number of carbon atoms. For example, "C₁~ C₆"Alkyl" refers to an alkyl having 1 to 6 carbon atoms. Examples of alkyls are methyl, ethyl, npropyl, ipropyl, nbutyl, ibutyl, secbutyl, tbutyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3 -Methylpentyl, 4-methylpentyl, etc., but are not limited to these. [0518] An "alkenyl" or "alkenylene" is a linear or branched having one or more unsaturated carbon-carbon bonds that have a specified number of carbon atoms and can be at any stable location in the longitudinal direction of the chain. It contains an arrangement of hydrocarbon groups. Examples of alkenyl are ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl. , 5-Hexenyl, 2-Methyl-2-propenyl, 4-Methyl-3-pentenyl, etc. [0519] "Alkynyl" or "alkynylene" comprises a linear or branched hydrocarbon chain having one or more carbon-carbon triple bonds that can be at any stable location in the longitudinal direction of the chain. For example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. [0520] The "cycloalkyl" includes a saturated ring group having a specified number of carbon atoms. For example, "C₃~ C₆"Cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. [0521] "Alkoxy" or "alkyloxy" represents an alkyl group as defined above having a specified number of carbon atoms bonded via an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy and s-pentoxy. .. Similarly, "alkylthio" represents an alkyl group as defined above having a specified number of carbon atoms bonded via a sulfur bridge. [0522] As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo and iodine, and "counterion" is a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate. It is used to represent the chemical species that have been produced. [0523] A "haloalkyl" is one that contains both branched and linear saturated aliphatic hydrocarbon groups with a specified number of carbon atoms substituted with one or more halogens (eg, -C)._vF_w(V = 1 to 3 and w = 1 to (2v + 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Absent. [0524] As used herein, "carbon ring" can be saturated, partially unsaturated or aromatic, any stable 3- to 7-membered monocyclic or bicyclic compound, or 7 It means a 13-membered bicyclic or tricyclic compound. Examples of such carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane ( Decalin), [2.2.2] Bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthyl (tetralin), but not limited to these. [0525] As used herein, a "heterocycle" or "heterocyclic ring" can be saturated, partially unsaturated or unsaturated (aromatic) from carbon atoms and N, O and S. A stable 5- to 7-membered monocyclic or bicyclic heterocycle consisting of 1, 2, 3 or 4 heteroatoms independently selected from the group, or a 7 to 14-membered bicyclic heterocycle. Means that any of the heterocycles defined above comprises a bicyclic group fused to a benzene ring. The nitrogen heteroatom and the sulfur heteroatom may be optionally oxidized. The heterocycle may be attached to its pendant group at any heteroatom or carbon atom that produces a stable structure. The heterocycles described herein may be substituted on carbon or nitrogen atoms as long as the resulting compound is stable. When specifically stated, the nitrogen in the heterocycle may be quaternized. When the total number of S and O atoms in the heterocycle exceeds 1, it is preferable that these heteroatoms are not adjacent to each other. The total number of S and O atoms in the heterocycle is preferably 1 or less. [0526] 4 There are, but are not limited to, triazolyl, xanthenyl, and the like. Preferred heterocycles include pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indrill, benzoimidazolyl, 1H indazolyl, oxazolidinyl, benztriazolyl, benzoisooxazolyl, benzoxazolyl, oxoindrill. , Benzoxazolinyl, benzthiazolyl, benzoisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridini However, it is not limited to these. Preferred 5- or 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, and oxazolidinyl. Further, for example, a condensed ring having the above heterocycle and a spiro compound are also included. [0527] As used herein, the term "bicyclic heterocyclic system" refers to the substituent NR.¹²R¹³A stable 9-10 membered bicyclic heterocycle formed from, partially unsaturated or unsaturated (aromatic), a group consisting of a carbon atom, a nitrogen atom and N, O and S. Means one or two different heteroatoms that are independently selected from. Another nitrogen or sulfur heteroatom may optionally be oxidized. Heterocycle is NR¹²R¹³The nitrogen atom of the group binds to the pendant group, giving it a stable structure. The heterocycles described herein may be substituted on carbon or nitrogen atoms as long as the resulting compound is stable. When specifically stated, the nitrogen in the heterocycle may optionally be quaternized. When the total number of S and O atoms in the heterocycle exceeds 1, it is preferable that these heteroatoms are not adjacent to each other. The total number of S and O atoms in the heterocycle is preferably 1 or less. The term "bicyclic heterocyclic system" is a subgroup of the term "heterocyclic system". Preferred examples of 9- or 10-membered bicyclic heterocyclic systems are benzoimidazolyl, benzoimidazolinyl, benzoxazolinyl, dihydrobenzthiazolyl, dihydrodioxobenzthiazolyl, benzoisooxazolinyl, 1H. Indazolyl, indyl, indolinyl, isoindolinyl, tetrahydro-isoquinolinyl, tetrahydro-quinolinyl, and benztriazolyl. [0528] In addition, the preferred heterocyclic subgroup is -CH.₂-C (= O) -A heterocyclic ring such as phenyl that functions as an homocyclic of a non-heterocyclic substituent. Preferred examples of such heterocycles are benzoimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzoisoxazolyl, furanyl, imidazolinyl, 1H indazolyl, indolinyl, isoindolinyl, isoquinolinyl, oxazolyl, piperidinyl, pyrazinyl. , Pyridinyl, pyrimidinyl, quinolinyl, thiazolyl, thiophenyl, and 1,2,3-triazolyl, but are not limited to these. [0529] As used herein, the term "aryl" or aromatic residue means an aromatic moiety having a specified number of carbon atoms, such as phenyl, pyridinyl and naphthyl. [0530] The expression "acceptable as a pharmaceutical product" herein is suitable for use in contact with human and animal tissues within reasonable medical judgment, and is overly toxic, irritating, allergic response, It is used to refer to compounds, materials, compositions and / or dosage forms that do not cause any other problems or complications and have a reasonable benefit / risk ratio. [0531] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by producing its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are limited to, inorganic salts or organic acid salts of basic residues such as amines; alkalis or organic salts of acidic residues such as carboxylic acids. is not it. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitrate; as well as acetic acid, propionic acid, succinic acid, glycolic acid, Stealic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamate, benzoic acid, salicylic acid, sulfanic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfone There are salts made from organic acids such as acids, methanesulfonic acids, ethanedisulfonic acids, oxalic acids and isetionic acids. [0532] The pharmaceutically acceptable salt of the present invention can be synthesized from a parent compound having a basic or acidic moiety by conventional chemical methods. Generally, such salts are those in which the free acid or base form of the compound is reacted with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. Can be manufactured in. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418; its disclosures are cited herein by reference. Included in). [0533] A "prodrug" includes a covalently bound carrier that releases the active parent drug according to formula (I) in vivo when such a prodrug is administered to a mammalian subject. The prodrug of the compound of formula (I) is a normal operation on the parent compound or in It is produced by modifying the functional groups present in the compound in such a way that the modified moiety is cleaved in vivo. Prodrugs include hydroxy, amino or or groups that are cleaved when the prodrug or compound of formula (I) is administered to a mammalian patient to form a free hydroxy group, a free amino group or a free sulfhydryl group, respectively. Includes compounds of formula (I) to which sulfhydryl groups are attached. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I). [0534] "Stable compound" and "stable structure" refer to a compound that is robust enough not to be degraded by isolation from the reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent. [0535] Synthetic Throughout the detailed description of the present invention, the following abbreviations are used with the following meanings. [0536] reagent: MCPBA: m-chloroperbenzoic acid DIBAL: Diisobutylaluminum hydride Et₃N: Triethylamine TFA: Trifluoroacetic acid LAH: Lithium aluminum hydride NBS: N-bromosuccinimide Red-Al: Sodium hydride bis (2-methoxyethoxy) aluminum Pd₂dba₃: Tris (dibenzylideneacetone) dipallad (0) ACE-Cl: 2-chloroethyl chloroformate [0537] solvent: THF: tetrahydrofuran MeOH: Methanol EtOH: Ethanol EtOAc: ethyl acetate HOAc: Acetic acid DMF: Dimethylformamide DMSO: Dimethyl sulfoxide DME: dimethoxyethane Et₂O: Diethyl ether iPrOH: isopropanol MEK: Methyl ethyl ketone [0538] Other: Ar: Aryl Ph: Phenyl Me: Methyl Et: Ethyl NMR: Nuclear Magnetic Resonance MHz: Megahertz BOC: tert-butoxycarbonyl CBZ: benzyloxycarbonyl Bn: benzyl Bu: Butyl Pr: Propyl cat .: catalyst mL: milliliter nM: nanometer ppm: parts per million mmol: mmol mg: milligram g: gram kg: kilogram TLC: Thin Layer Chromatography HPLC: High Performance Liquid Chromatography RPM: Number of revolutions per minute rt: room temperature aq .: Water system sat .: saturated [0539] The compounds of the present invention can be produced by several methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the synthetic organic chemistry industry or modifications of those methods that can be understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated by reference in their entirety. [0540] The novel compounds of the invention can be prepared using the reactions and techniques described in this section. These reactions are carried out in a solvent suitable for the reagents and materials used, and are suitable for performing conversion. In addition, all of the presented reaction conditions, such as solvent, reaction atmosphere, reaction temperature, duration of experiment and selection of post-treatment procedures, should be understood by those skilled in the art as described below in the description of the synthesis method. It was selected to be a standard of conditions for the reaction, which would be easily understood if any. It will be apparent to those skilled in the art of organic synthesis that the functional groups present in the various parts of the molecule must be compatible with the reagents and reactions presented. Such restrictions on substituents that are compatible with the reaction conditions are well understood by those of skill in the art and therefore a separate method must be used. [0541] The compound of formula (I) of the present invention can be produced by an intensive or sequential synthetic method. The detailed synthetic production of the compound of formula (I) is shown in the reaction scheme below. Techniques required for the production and purification of compounds of formula (I) and intermediates leading to such compounds are known in the art. Purification procedures include, but are not limited to, normal or reverse phase chromatography, crystallization and distillation. [0542] Several methods of making the compounds of the invention are shown in the schemes and examples shown below. The substitutions are as described and defined above. [0543] The compound of formula (I) of the present invention can be prepared according to the method shown in Scheme 1. Therefore, in the production of aryl hydrazine (III), for example, the corresponding substituted aniline (II) is NaNO.₂The N-nitroso intermediate obtained is then reduced with a reducing agent such as LAH or zinc and an organic acid such as acetic acid or trifluoroacetic acid at low temperature. The assembly of the core tetracyclic intermediate Indole (V) is by Sandberg (RJ Sundberg, Indoles, Best Synthetic Methods , 1996, Academic Press, San Diego, CA) (limited to this). It is carried out by Fischer indole cyclization of a ketone (ie, (IV)) suitably substituted with the aryl hydrazine by the method described in (not). For example, in the presence of an inorganic acid, the arylhydrazine (III) as a free base or an equivalent inorganic acid salt is added to a ketone (IV) (R) in an alcohol solvent.¹= H, Bn, CBZ, CO₂By treating with (Et, etc.), the indole compound (V) is obtained as a free base (after treatment with an aqueous NaOH solution). Reduction of indol compounds to corresponding cis or trans-substituted dihydroindole compounds by treatment with hydrogen in the presence of a catalyst such as platinum oxide or palladium / carbon, or with metals such as zinc and inorganic acids such as hydrochloric acid. Or by treatment with a borane-amine complex such as borane-triethylamine in tetrahydrofuran, or preferably NaCNBH in an acid such as acetic acid or trifluoroacetic acid.₃It is done by processing with. [0544] The corresponding enantiomers can be isolated by separation of the racemic mixture of (I) on a chiral stationary phase column utilizing normal or reverse phase HPLC methods. The details will be described in Examples. Alternatively, (I, R¹Treatment of = H) with a suitable chiral acid (or a preferably activated derivative), such as dibenzoyl tartrate, can produce a diastereomeric mixture of (I) (eg, Kinbara, K. et al.). , Et al., J. Chem. Soc., Perkin Trans. 2, 1996, 2615 and Tomori, H., et al., Bull. Chem. Soc. Jpn., 1996, 3581). The diastereomers were then separated by conventional techniques (ie, silica chromatography, crystallization, HPLC, etc.) followed by elimination of the chiral auxiliary to give enantiomeric pure (I). It is considered to be. [0545] When carboline nitrogen is protected (VI) (ie, R¹= Boc, Bn, CBZ, CO₂R), it is in the work of Greene et al. (Greene, TW, Wuts, PGW, Protective Groups in Organic Synthesis, 2nd Edition , John Wiley and Sons, Inc., New York, pp.309-405, 1991). It can be desorbed under the various conditions described. Next, for example, according to the method described in the report of Glennon et al. (Glennon, RA, et al., Med. Chem. Res., 1996, 197), the free secondary amine was replaced with, for example, a suitably substituted alkyl halide. (R¹Cl or R¹It is believed that treatment with I) and a base can result in alkylation to give another compound of type (I). [0546] [Chemical 26]<img file="JP4916633B2_D0016.tif" />[0547] Alternatively, the compound of formula (I) can be prepared according to the method shown in Scheme 2. Nucleophilic alkyl halides (X = OH, SH, NHR, (VIII)) according to the method described in the report of Kharasch, N., Langford, RB, J. Org. Chem., 1963, 1903. ) And a suitable base to treat the orthohalonitrobenzene compound (VII) and then reduce the corresponding nitroaryl derivative to an aniline compound (IX), for example LAH, SnCl.₂, NaBH₄, N₂H₄It can be done by various reducing agents such as, or by hydrogen in the presence of suitable catalysts such as palladium / carbon or platinum oxide (Hudlicky, M., Reductions in Organic Chemistry , Ellis Horwood, Ltd., Chichester. , UK, 1984). The formation of aryl hydrazine (X) is carried out according to the method described in Scheme 1 or more directly at room temperature with aqueous hydrochloric acid solution, stannous chloride and NaNO.₂This can be done by treating the aniline compound (IX) in (see Buck, JS, Ide, WS, Org.Syn., Coll.Vol., 2, 1943, 130). The primary aryl hydrazine (X) can then be cyclized with respect to compound (V) under Fischer's indole cyclization conditions detailed above to give indole compound (XI) as the corresponding salt. Treatment of the indole compound (XI) with a base such as potassium hydroxide or potassium t-butoxide in a solvent such as DME or THF gives a tetracyclic indole intermediate (V). These indoles can also be reduced to the corresponding cis- or trans-indolins (I) according to the method described above in Scheme 1. [0548] [Chemical 27]<img file="JP4916633B2_D0017.tif" />[0549] Yet another related pathway to the compound of formula (I) is shown in Scheme 3. Since the synthesis is initiated using a nitrobenzene derivative such as (XII), this approach enables various inductions. More highly substituted nitrobenzenes can be obtained by conventional synthetic procedures (ie, aromatic substitutions), which are known to those of skill in the art (Larock, RC, Comprehensive Organic Transformations, VCH Publishers, New York, See 1989). [0550] The method described above (Hudlicky, et The corresponding aniline intermediate is obtained by treating the nitrobenzene derivative with a reducing agent such as LAH according to al.). Hydrazine formation is then performed, followed by Fischer indole cyclization with suitably functionalized ketones according to the methods described above (ie, Schemes 1, (III)-(V)) to g-carboline indole. Obtain (XIII). At this point, the fused ring can be suspended by condensation of a haloalkylcarboxylic acid such as (XIV) or a related activated carboxylic acid (ie, acid chloride, hybrid anhydride, etc.). The resulting heterocyclic carbonyl is reduced by using various reducing agents such as sodium borohydride, diisobutylaluminum hydride, etc. (Larock, RC, Comprehensive Organic Transformations, VCH Publishers, New York, 1989 and / or Hudlicky, M., Reductions in Organic Chemistry , Ellis Horwood, Ltd., Chichester, UK, 1984), a tetracyclic indole compound (V) can be obtained. Further reduction of indole compound (V) to indoline compound (I) is as described above in Scheme 1. [0551] [Chemical 28]<img file="JP4916633B2_D0018.tif" />[0552] The production of aniline precursor (II) for Fischer indole cyclization is shown in Scheme 4. A preferably orthofunctionalized aniline (XVI) was treated with a chloroalkylcarboxylic acid or ester (or equivalent material, i.e. acrylic acid, acryloyl chloride, etc.) and simultaneously condensed to give the resulting heterocyclic carbonyl. Is reduced with a reducing agent such as LAH, DIBAL or Red-Al to obtain a condensed heterocyclic benzene derivative (II). More diverse intermediates (II) can be obtained by forming ortho-substituted anilines from the corresponding ortho-substituted nitrobenzenes and at the same time reducing the nitro moiety according to the method described above. In addition, aromatic substitutions of the fluoro (or other halogenated nitrobenzene) functional groups of (XV) with oxygen or sulfur moieties are performed by treating (XV) with a nucleophile such as sodium sulfide or alcohol. Then, using standard techniques known in the art, form the required thiophenols or phenols, respectively (Larock, RC, Comprehensive Organic Transformations, VCH). Publishers, New York, 1989, p.481). Substituted aniline (XVI) is obtained by reducing nitro according to the method described above. [0553] [Chemical 29]<img file="JP4916633B2_D0019.tif" />[0554] Scheme 5 shows another way to produce substituted condensed aniline (II). Phenol (X = OH), thiophenol (X = SH), or other nucleophilic aromatic substitution derivative (XVII), eg, haloalkylcarboxylic acid (or equivalent activated haloalkylcarboxylic acid (ie, acid halide, mixed) Derivatives (XVIII) are obtained by treatment with anhydrides, acrylic acids, acryloyl chloride, etc.)). Friedel-Crafts acylation conditions (for various conditions and protocols, Ed. GAOlah, Friedel-Crafts and Related Reactions , J. Wiley and Sons, New York, 1964, Vol.3, Pts 1 and 2 or Chem. Rev., 1955,229, or Olah, GA, Friedel-Crafts Chemistry , Wiley Interscience, New York, 1973), ie strong Lewis acid (AlCl)₃, FeCl₃By treating with (etc.), cyclic alkylphenylone (XIX) can be obtained. Incorporation of nitrogen functional groups can be carried out in several ways. For example, Schmidt rearrangement (according to the method described in Smith's report (Smith, PAS, J.Am.Chem.Soc., 1948,320)), carbonyl derivative (XIX) to NaN.₃And treatment with methanesulfonic acid to give bicyclic lactam (XX). Alternatively, under the Hofmann rearrangement protocol (see, eg, Dike, SY, et al., Bioorg. Med. Chem. Lett., 1991, 383), the oxime derivative of (XXI) was first treated with hydroxylamine hydrochloride. This transformation can be performed by forming. The rearrangement to lactam is then efficiently carried out by heating in polyphosphoric acid to give lactam (XX). Aniline (II) can be obtained by reducing lactam (XX) with various reducing agents such as DIBAL and Red-Al. [0555] [Chemical 30]<img file="JP4916633B2_D0020.tif" />[0556] The production of compounds of formula (I) having another type of functional group on the aromatic A ring of the four-ring moiety is shown in Scheme 6 and Scheme 7 and will be described herein. Due to the nature of the synthetic route of Scheme 1 to the derivative of formula (I), it is difficult to produce a compound having a halogen substituent on the A ring. However, indoline (I, R) when protecting amines, for example with NBS in DMF, for example with Boc or CBZ protecting groups.⁸When = H) is brominated, R⁸A brominated derivative (XXII) is obtained. These activated aryl derivatives (XXII) serve as excellent counterparts in a number of important synthetic transformations. [0557] For example, under the Suzuki coupling protocol, biaryl coupling is performed. For a review and key references on the palladium-catalyzed cross-coupling reaction, see the report by Miyaura et al. (Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457). In one such procedure, Pd (PPH) in a suitable solvent such as DMF, toluene, THF, DME, etc.₃)₄, Pd (PPH)₃)₂Cl₂, Pd (OAc)₂, Pd₂(dba)₃Catalysts such as Pd (0) species and PPH₃, AsPH₃Suitable coordinating species such as, or other such Pd (0) catalysts, as well as Na₂CO₃Or Et₃Indoline (XXIV) is obtained by treating aryl bromide (XXII) with functionalized arylboronic acid (XXIII) in the presence of a base such as N. Alternatively, a bromine derivative (XXII) (ie, (I, R)⁸= B (OH)₂By forming indole boronic acid from)), a more diverse subsequent coupling of the commercially available halo aromatic derivative with the indole boronic acid is performed in a similar Suzuki coupling strategy according to the method described above. , Indole (XXIV) can be obtained. [0558] [Chemical 31]<img file="JP4916633B2_D0021.tif" />[0559] Similarly, scheme 7 shows a biaryl coupling of a bromine derivative (XXV), which is readily obtained by the synthetic procedure exemplified in Scheme 2, from a preferably functionalized bromonitrobenzene (II) source. By this method, biarylindole and the corresponding indoline derivative can be produced. R¹If = H, protection of amine functional groups must be performed (see the work of Green et al. For protection of amines). This includes, for example, bromine derivative (XXV) in aqueous sodium hydroxide solution and dioxane (Boc).₂It is easily done by processing with O. Subsequently, Suzuki coupling with various arylboronic acids is performed according to the method described above in Scheme 6 to obtain a biaryl adduct (XXVI). This protocol is R⁷, R⁸And R⁹Is applicable to bromide, iodide, triflates, and / or diazo derivatives (see Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457 for a review of aryl coupling). .. [0560] [Chemical 32]<img file="JP4916633B2_D0022.tif" />[0561] In addition, as an extension of this way to the rapid production of a large number of biarylindole and indoline derivatives, these bromine derivatives (XXV) can be attached to the solid support according to the method shown in Scheme 8. Suzuki coupling can be performed on a solid support (see XXVIII). To that end, CH indoline compound (XXV)₂Cl₂Free amine (XXXVII) is obtained by treatment with medium TFA to remove Boc protecting groups and then extraction from aqueous base solution. Free amines are attached onto suitable solid supports such as (XXVIII) using conditions known to those of skill in the art. Then, the p-nitrophenyl one (Wang) resin (XXVIII) commercially available from sources such as Novabiochem, Inc. is swollen in a suitable solvent such as N-methylpyrrolidinone. Treat with 1.5 equivalents of amine to give a functionalized resin (XXIX). Then Pd (PPH) with an excess amount (typically 5 equivalents) of arylboronic acid₃)₄Or Pd (dppf) Cl₂Suitable palladium sources such as and 2M aqueous K₂CO₃Or Na₂CO₃Alternatively, the Suzuki coupling is carried out in an array by treating the resin (XXIX) with a suitable base such as triethylamine (procedures for solid phase Suzuki coupling and other palladium couplings are known to those of skill in the art and are known to those skilled in the art. See, for example, LAThompson and JAEllman, Chem. Rev., 1996,96, (1), 555-600). The coupling can be repeated to ensure complete conversion to the desired coupling product. Cleavage from the solid support by TFA treatment yields the corresponding indole and indoline (XXX) as their TFA salts. [0562] [Chemical 33]<img file="JP4916633B2_D0023.tif" />[0563] In addition, there are a wide variety of procedures and protocols for functionalizing haloaromatic compounds, aryldiazonium compounds and aryltriflate compounds. These procedures are known to those of skill in the art, such as Stanforth, SP, Tetrahedron, 1998, 263, Buchwald, SL, et al., J. Am. Chem. Soc. , 1998,9722), and reported by Still et al. (Stille, JK, et al., J.Am. Chem. Soc., 1984, 7500). These procedures include biaryl coupling, alkylation, and acyl. , amination and amidation. The power of palladium-catalyzed functionalization of aromatic nuclei has been investigated in detail over the last decade. An excellent review in this area is in Tsuji's book (J. Tsuji, Palladium Reagents and Catalysts, Innovations in Organic Synthesis , J. Wiley and Sons, New. York, 1995). [0564] Substitution R¹Scheme 9 shows one such method for more directly producing compounds of formula (I) with side chains. NaI or KI and K in dioxane or THF or other such solvents while heating₂CO₃, Na₂CO₃In the presence of bases such as ClCH₂(CH₂)_pCO₂Indole derivative or indoline derivative (I, R) with haloalkyl ester such as Me¹By alkylating = H) (see Glennon, RA, et al., Med. Chem. Res., 1996, 197), R¹Obtain an alkylated ester. The ester is then treated with N, O-dimethylhydroxylamine hydrochloride and a Lewis acid such as trimethylaluminum or triethylaluminum at 0 ° C. in toluene to form the activated amide (XXXI) (eg Golec). , JMC, et al., Tetrahedron, 1994, 809). Grignard reagent R at low temperatures in suitable solvents such as THF and ether^1aBy treating the amide (XXXI) with various organometallic agents such as MgBr, alkyl and aryllithium reagents (Sibi, MP, et al., Tetrahedron Lett., 1992, 1941, more generally House, HO, Modern. Synthetic Reactions, WABenjamin, Inc., Menlo Park, CA., 1972), obtained substituted ketone (XXXII). [0565] [Chemical 34]<img file="JP4916633B2_D0024.tif" />[0566] The production of the compound of formula (I) with m = 0 and k = 1 is shown in Scheme 10 and will be described below. Under various typical cyclization conditions, Fisher Indol cyclization with known protection 2,3-dioxopyrrolidine of hydrazine (III) (Carlson, EH, et al., J.Org.Chem., 1956, 1087) ) To obtain a 4-ring indole (XXXIII). For example, pyrrol condensed indole (XXXIV) can be obtained by performing reduction using various reducing agents such as LAH and DIBAL. The derivative is then deprotected and then alkylated according to the method described above (Greene, TW, Wuts, PGW, Protective Groups in Organic Synthesis, 2nd Edition , John Wiley and Sons, Inc. ., New York, 1991 and Scheme 1), R¹Alkylated indole analogs (XXXV) can be obtained. Alternatively, the indole is reduced to indoline according to the method described above (see Scheme 1), then deprotection of the benzyl group is performed (XXXVI) to obtain the corresponding R by alkylation.¹Obtain an alkylated indoline derivative (XXXVII). Functional groups of aromatic rings, various R¹All of the aforementioned methods for obtaining side chain derivatives can be applied to these nuclei. [0567] [Chemical 35]<img file="JP4916633B2_D0025.tif" />[0568] (Example) The chemical abbreviations used in the examples are as defined above. The following examples illustrate the detailed procedure for preparing the compound of formula (I). However, it will be understood that the present invention is not limited to the specific details of these examples. The examples shown below are intended to clarify the scope of the invention and are not intended to limit the scope of the invention. Proton nuclear magnetic resonance spectrum (¹1 H NMR) is chloroform-d (CDCl) unless otherwise specified.₃), The peak is reported from tetramethylsilane (TMS) to a low magnetic field at parts per million (ppm). Coupling patterns are reported as follows: s, single line; d, double line; dd, double line double line; t, triple line; q, quadruple line; m, multiple line; bs, Wide single line; bm, wide multiple lines. [0569] (Example 4) 1-Fluoro-6,7,9,12-Tetrahydro-5H-Pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (10H) -Ethyl carbonate [0570] (Step A) P-fluorothiophenol (5 g, 40 mmol) and β-propiolactone (2.8 g, 40 mmol) were dissolved in THF (newly distilled 36 mL) and then placed in an ice bath. Over an hour, 95% sodium hydride (1 g, 42.9 mmol) was added in small portions. The reaction was stirred at 0 ° C. for 2 hours and then placed in the refrigerator overnight. The reaction was quenched with ice pieces and then acidified to pH 2 with concentrated hydrochloric acid. The product was extracted with ethyl acetate (1 x 200 mL) and dichloromethane (2 x 200 mL), dried (sodium sulfate) and concentrated to give 3- (4-fluorophenylthio) propanoic acid (7.08 g, 89%). Obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.42-7.35 (m, 2H), 7.02 (t, 2H, J = 8.6Hz), 4.35 (t, 1H, J = 6.2Hz), 3.10 (t, 2H, J = 7.3MHz) , 2.63 (t, 2H, J = 7.3Hz) ppm. [0571] (Step B) 3- (4-Fluorophenylthio) propanoic acid (3 g, 15 mmol) was dissolved in dichloromethane (30 mL) and cooled to 0 ° C. in an ice bath. Oxalyl chloride (10 mL) was added slowly, dimethylformamide (1 drop) was added and the reaction mixture was stirred at 0 ° C. for 0.5 hours. At that point, the reaction was concentrated under reduced pressure to a residue, then resuspended in dichloromethane and cooled to 0 ° C. in an ice bath. Cs₂(1mL) and AlCl₃(4 g, 15 mmol) was added slowly. The reaction mixture was then warmed to room temperature and stirred overnight. Ice pieces and water (250 mL) were added and stirred. Concentrated hydrochloric acid was added to pH 2 and extracted with dichloromethane (3 x 150 mL). The organics were combined, washed with saline (1 x 100 mL) and water (1 x 100 mL), dried (sodium sulfate) and concentrated to give a yellow solid. Purification of the solid by flash column chromatography eluting with 10% ethyl acetate in hexanes on 100 g of silica gel reveals 6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (2.55 g, 93%). )was gotten.¹1 H NMR (CDCl₃, 300MHz): δ7.80-7.76 (m, 1H), 7.27-7.23 (m, 2H), 7.15-7.09 (m, 1H), 3.23 (t, 2H, J = 6.4Hz), 2.97 (t, 2H) , J = 6.4Hz) ppm. [0572] (Step C) 6-Fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (100 mg, 0.54 mmol) is dissolved in acetic acid (0.5 mL, 1.1 eq) and sodium azide (71.2 mg, 1.1 mmol) is added. , The mixture was heated to 50 ° C. Sulfuric acid (0.13 mL, 4.3 eq) was added slowly and stirred at 50 ° C. for 1.5 hours. Add ice pieces (150 mg) to precipitate a green solid, which is filtered, washed with water and dried, 7-fluoro-2,3-dihydro-1,5-benzothiazepine-4 (5H). -On (80 mg, 24%).¹1 H NMR (CDCl₃, 300MHz): δ7.77 (s-broad, 1H), 7.69 (t, 1H, J = 7.3Hz), 6.94-6.82 (m, 2H), 3.42 (t, 2H, J = 7Hz), 2.63 (t) , 2H, J = 6.7Hz) ppm. [0573] (Step D) 7-Fluoro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one (76 mg, 0.38 mmol) was dissolved in toluene (1 mL) and cooled to 0 ° C. in an ice bath. Red-Al (275 mL, 0.91 mmol) was added and then the reaction was warmed to room temperature. The reaction was heated to reflux for 1.5 hours. 1N sodium hydroxide was added slowly until the pH was above 10 and this was stirred for 10 minutes, extracted with dichloromethane (3 x 25 mL), washed with water and dried (sodium sulphate). The concentrated organic matter was purified by preparative thin layer chromatography on silica gel, eluted with 50% ethyl acetate in hexanes, and 7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (30.8 mg). , 93%).¹1 H NMR (CDCl₃, 300MHz): δ7.32 (t, 1H, J = 7.5Hz), 6.53-6.42 (m, 2H), 4.09 (s-broad, 1H), 3.31-3.27 (m, 2H), 2.83-2.79 (m) , 2H), 2.11-2.04 (m, 2H) ppm. [0574] (Step E) 7-Fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (423 mg, 2.3 mmol) was dissolved in acetic acid (1.15 mL) at 0 ° C. in an ice bath. 2.7 M aqueous sodium nitrite solution (1 mL) was added and the mixture was stirred overnight. Add water (100 mL), extract with dichloromethane (3 x 50 mL), combine and concentrate organic matter, 7-fluoro-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine ( 449 mg, 92%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.43 (t, 1H, J = 7.1Hz), 7.30 (dd, 1H, J = 9.1Hz, J = 9.2MHz), 7.26-7.00 (m, 1H), 4.18 (t, 2H, J = 5.8Hz), 2.86 (t, 2H, J = 7.2Hz), 2.17-2.04 (m, 2H) ppm. [0575] (Step F) 7-Fluoro-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (449 mg, 2.11 mmol) was suspended in THF (newly distilled 1 mL) at 0 ° C. in an ice bath. Cooled to C. Lithium aluminum hydride (80 mg, 2.11 mmol) was added in small portions. The flask was removed from the ice bath, warmed to room temperature and stirred for 2 hours. Water (0.08 mL) was added and the mixture was stirred for 10 minutes. 15% sodium hydroxide (0.08 mL) was added and the mixture was stirred for 10 minutes. Water (0.024 mL) was added and the mixture was stirred for 10 minutes. The reaction was extracted with dichloromethane (2 x 25 mL). The organics are concentrated to a residue, then dissolved in a minimum amount of dichloromethane, then hydrogen chloride (1M) in ether is added until the precipitate is purified and the precipitate is filtered to 7-fluoro-3,4-. Dihydro-1,5-benzothiazepine-5 (2H) -amine (471 mg, 95%) was used.¹H NMR (CD)₃OD, 300MHz): δ7.59 (t, 1H, J = 7.5Hz), 7.28 (d, 1H, J = 9.9Hz), 7.00 (t, 1H, J = 8.2Hz), 3.52 (t, 1H, J = 7.5Hz), 2.92-2.86 (m, 1H), 2.72-2.70 (m, 2H), 2.40-2.31 (m, 1H), 2.2-2.18 (m, 2H) ppm. [0576] (Step G) 7-Fluoro-3,4-dihydro-1,5-benzothiazepine-5 (2H) -amine (470 mg, 2 mmol), 1-carboethoxy-4-piperidinone (0.3 mL, 2 mmol), and ethanol (11 mL) Was mixed and heated to reflux overnight. The reaction was concentrated to a residue and purified by flash column chromatography on 20 g of silica eluting with methanol (1%, 2%, 3% and 10%) in dichloromethane to give the title compound (115 mg, 54%). Obtained.¹1 H NMR (CDCl₃, 300MHz): δ6.84 (t, 1H, J = 6.4Hz), 6.50 (t, 1H, J = 6Hz), 4.72 (s-broad, 2H), 4.47 (t, 2H, J = 5.8Hz), 4.20-4.13 (m, 2H), 3.82 (s-broad, 2H), 3.27 (t, 2H, J = 6.7Hz), 2.69 (s-broad, 2H), 2.27 (q, 2H, J = 6.1Hz) , 1.36 (t, 3H, J = 6.9Hz) ppm. Mass spectrometry (ESI): 335 (base, M + H). [0577] (Example 5) 1-Fluoro-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0578] 1-Fluoro-6,7,9,12-Tetrahydro-5H-Pyrid [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (10H) -Ethylene glycol (26mg) , 0.079 mmol), ethylene glycol (0.7 mL), hydrazine hydrate (19.5 mg, 0.39 mmol), and potassium hydroxide (11.2 mg, 0.2 mmol) were mixed and heated to reflux for 1.5 hours. Water (15 mL) was added, then extracted with dichloromethane (2 x 15 mL), dried (sodium sulfate) and concentrated to make a residue. The residue was dissolved in ether (2 mL) and 1 M hydrogen chloride (0.1 mL) in ether was added until the solid precipitated. Filtration of the solid gave the title compound (5.6 mg, 26.7%).¹H NMR (CD)₃OD, 300MHz): δ6.92 (q, 1H, J = 4.8Hz), 6.57 (q, 1H, J = 6.1Hz), 5.46 (s, 2H), 4.69 (t, 2H, J = 5.9Hz), 4.46 (s, 2H), 3.59 (t, 2H, J = 6.2Hz), 3.07 (t, 2H, J = 6.2Hz), 2.33 (q, 2H, J = 5.8Hz) ppm. [0579] (Example 6) 1-Methyl-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0580] (Step A) The corresponding acid, 3-[(4-methylphenyl) sulfanyl] propanoic acid, was prepared by the method of Example 4 Step A and obtained with P-thiocresol (7.84 g, 43.9%).¹1 H NMR (CDCl₃, 300MHz): δ7.30 (d, 2H, J = 8.1Hz), 7.11 (d, 2H, J = 7.7Hz), 3.10 (t, 2H, J = 7.3Hz), 2.64 (t, 2H, J = 7.3Hz), 2.32 (s, 3H) ppm. [0581] (Step B) 6-Methyl-2,3-dihydro-4H-1-benzothiopyran-4-one was prepared and obtained by the method of Example 4 Step B (3.44 g, 100%).¹1 H NMR (CDCl₃, 300MHz): δ7.92 (s, 1H), 7.26-7.18 (m, 2H), 3.23 (t, 2H, J = 6.4Hz), 2.96 (m, 2H, J = 6.4Hz), 2.32 (s, 3H) ppm. [0582] (Step C) 6-Methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (2 g, 10.9 mmol) was dissolved in 80% ethanol (73 mL), to which hydroxylamine hydrochloride (840 mg, 12.05 mmol) and acetate Sodium (990 mg, 12.03 mmol) was added. The mixture was heated to reflux for 3 hours. Water (150 mL) was added, then extracted with dichloromethane (3 x 100 mL), washed with brine (75 mL) and water (75 mL), dried (sodium sulfate) and concentrated to give a residue. The residue was dissolved in polyphosphoric acid (10 mL) and heated to reflux for 1 hour. The ice pieces were dissolved in water (100 mL) and stirred for 1 hour. The solids are formed, filtered and purified by flash column chromatography on 20 g of silica gel eluting with ethyl acetate (50%, 60% and 70%) in hexanes to 7-methyl-2,3,4,5. -Tetrahydrobenzo [b] 1,4-thiazepine-4-one (500 mg, 30%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.87 (s-broad, 1H), 7.47 (d, 1H, J = 7.7Hz), 6.98 (d, 1H, J = 8.1Hz), 6.91 (s, 1H), 3.42 (t, 2H, J = 6.9Hz), 2.62 (t, 2H, J = 6.9Hz), 2.35 (s, 3H) ppm. [0583] (Step D) 7-Methyl-2,3,4,5-tetrahydro-1,5-benzothiazepine was prepared and obtained by the method of Example 4 Step D (939 mg, 100%).¹1 H NMR (CDCl₃, 300MHz): δ7.26 (d, 1H, J = 4.8Hz), 6.44 (d, 1H, J = 8.4Hz), 6.58 (s, 1H), 4.00-3.75 (s-broad, 1H), 3.22 ( t, 2H, J = 5.3Hz), 2.77 (t, 2H, J = 5.8Hz), 2.25 (s, 3H), 2.09-2.03 (m, 2H) ppm. [0584] (Step E) 7-Methyl-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine was prepared and obtained by the method of Example 4 Step E (1.06 g, 98%).¹1 H NMR (CDCl₃, 300MHz): δ7.37-7.34 (m, 2H), 7.12-7.10 (d, 1H, 9.2Hz), 4.17-4.14 (t, 2H, 5.9Hz), 2.87-2.83 (t, 2H, 6Hz), 2.38 (s, 3H), 2.17-2.10 (m, 2H) ppm. Mass Spectrometry (ESI): U / A (base, M + H). [0585] (Step F) 7-Methyl-3,4-dihydro-1,5-benzothiazepine-5 (2H) -amine was prepared and obtained by the method of Example 4 Step F (292 mg, 30%).¹1 H NMR (CDCl₃, 300MHz): δ7.68 (d, 1H, J = 7.7Hz), 7.31-7.26 (m, 2H), 3.46 (t, 2H, J = 5.6Hz), 2.88 (t, 2H, J = 5.7Hz) , 2.38 (s, 3H) ppm. [0586] (Step G) 7-Methyl-3,4-dihydro-1,5-benzothiazepine-5 (2H) -amine (50 mg, 0.24 mmol) and 4-piperidone monohydrate (37 mg, 0.24 mmol) in 1 of ethanol / acetic acid 1 Dissolved in a mixture (0.4 mL) and cooled to 0 ° C in an ice bath. Zinc powder (94 mg, 1.44 mmol) was slowly added to this while monitoring the rate of addition to keep the internal temperature below 20 ° C. The reaction was stirred at 0 ° C for 1 hour. The reaction was warmed to room temperature and stirred for an additional 0.5 hour. The reaction was then filtered and the filtered cake was washed with ethanol. The filtrate was heated to reflux for 2 hours and then concentrated to give a residue. The residue was dissolved in a minimum amount of water and cold ammonium hydroxide was added to it until pH 11 was higher. This was extracted with dichloromethane (2 x 50 mL), dried (sodium sulfate) and then concentrated to give a residue. The residue was dissolved in a minimal amount of dichloromethane and a hydrochloride prepared with hydrogen chloride (1M) in ether. The salt was then refluxed in 2-propanol (10 mL) for 24 hours. The product was purified by preparative thin layer chromatography on silica gel and eluted with dichloromethane / methanol (9: 1) to give the title compound (18 mg, 50%).¹H NMR (CD)₃OD, 300MHz): δ7.14 (d, 1H, J = 7.7Hz), 6.77 (d, 1H, J = 7.7Hz), 4.66 (s, 2H), 3.57 (t, 2H, J = 6.2Hz), 3.00 (t, 2H, J = 7.7Hz), 2.90 (t, 2H, J = 6.95Hz), 2.54 (s, 3H) ppm. [0587] (Example 7) 1-Methyl-6,7,9,12-Tetrahydro-5H-Pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (10H) -tert-Butyl Carbonate [0588] 1-Methyl-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole (47 mg, 0.18 mmol) Was heated at 90 ° C for 4 hours with di-tert-butyl bicarbonate (90 mg, 0.9 mmol). It was then purified by preparative thin layer chromatography on silica gel and eluted with hexane / ethyl acetate (3: 1) to give the title compound (18.7 mg, 29%).¹1 H NMR (CDCl₃, 300MHz): δ6.91-6.89 (m, 1H), 6.63-6.61 (m, 1H), 4.77 (s, 2H), 4.46 (t, 2H, J = 5.8Hz), 3.71 (s, 1H), 3.33 (t, 2H, J = 5.7Hz), 2.76-2.71 (m, 2H), 2.53 (s, 3H), 2.44-2.30 (m, 2H): 2.28-2.26 (m, 2H), 1.49 (s, 12H) ppm. [0589] (Example 8) cis- (8a, 12a) -1-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0590] 1-Methyl-6,7,9,12-Tetrahydro-5H-Pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (10H) -tert-Butyl Carbonate (59 mg, 0.23 mmol) was dissolved in trifluoroacetic acid (1.6 mL) and cooled to 0 ° C. in an ice bath. Sodium cyanoborohydride (45 m, 0.72 mmol) was added slowly over 10 minutes and this was stirred at 0 ° C. for 1.5 hours. Then 6N hydrogen chloride (0.5 mL) was added and the reaction was heated to reflux for 1 hour. 1N sodium hydroxide was added until the pH was above 12, extracted with dichloromethane (2 x 25 mL), dried (sodium sulfate) and concentrated to give the title compound.¹1 H NMR (CDCl₃, 300MHz): δ6.84 (d, 1H, J = 8.1Hz), 6.43 (d, 1H, J = 7.9Hz), 3.96-3.83 (m, 1H), 3.62-3.57 (m, 1H), 3.31- 3.20 (m, 1H), 3.11-2.83 (m, 4H), 2.80-2.63 (m, 2H), 2.41-2.38 (m, 1H), 2.168 (s, 3H), 1.97-1.91 (m, 1H), 1.80-1.75 (m, 1H), 1.63-1.58 (s-broad, 2H) ppm. Mass spectrometry (ESI): 261 (base, M + H). [0591] (Example 9) trans- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole [0592] Example 128 Step B 6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (90 mg, 0.37) Excess borane-THF (3 mL) was added to the solution of mmol) at 0 ° C in an ice bath. The solution was carefully diluted with water (29 mL), followed by the addition of trifluoroacetic acid (4.3 mL). The reaction was stirred at 0 ° C. and TLC (10% methanol in dichloromethane) was run until the starting material was exhausted. The reaction was basicized with ammonium hydroxide until pH 12 and extracted with dichloromethane (3 x 20 mL). Extracts were collected, washed with saline (1 x 20 mL), water and dried (magnesium sulphate). Then concentration gave the title compound (78 mg, 84%).¹1 H NMR (CDCl₃, 300MHz): δ7.10 (dd, 1H, J = 8Hz, J = 7.7Hz), 7.00 (dd, 1H, J = 7.7Hz, J = 7.3Hz), 6.85 (t, 1H, J = 7.7Hz) , 4.59-4.50 (m, 1H), 4.39-4.34 (m, 1H), 4.24 (dd, 1H, J = 15.4Hz, J = 15.4Hz), 3.83 (t, 1H, J = 10.6Hz, J = 13.2 Hz), 3.79-3.60 (m, 2H), 3.42-3.2 (m, 2H), 3.07-2.92 (m, 1H), 2.87-2.73 (m, 2H), 2.30-2.19 (m, 2H) ppm. [0593] (Example 10) 1-Nitro-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0594] (Step A) 2-Amino-4-nitro-fluorobenzene (500 mg, 3.2 mmol), 3-chloro-1-propanethiol (354 mg, 3.2 mmol), and potassium hydroxide (269 mg, 4.8 mmol) in ethylene glycol dimethyl ether (6.4 mL) They were mixed together and heated to reflux for 72 hours. The reaction was filtered and the filtered cake was washed with chloroform. The filtrate is concentrated, purified by flash column chromatography on 10 g of silica gel, and eluted with 3% methanol in chloroform to give 2-[(3-chloropropyl) sulfanyl] -5-nitrophenylamine (130 mg, 17%). was gotten.¹1 H NMR (CDCl₃, 300MHz): δ7.49-7.48 (m, 2H), 7.38 (dd, 1H, J = 7.7Hz, J = 7.7Hz), 4.55 (s-broad, 2H), 3.64 (t, 2H, J = 6.2) Hz), 3.03 (t, 2H, J = 7Hz), 2.00 (q, 2H, J = 7Hz) ppm. Mass spectrometry (ESI): 264 (base, M + H). [0595] (Step B) 2-[(3-Chloropropyl) sulfanyl] -5-nitrophenylamine (100 mg, 0.44 mmol) was dissolved in hydrochloric acid (1.8 mL) in an ice bath, and a 1 M aqueous sodium nitrate solution (0.5 mL) was added dropwise. This was stirred at 0 ° C for 1.5 hours. 0.25 M tin (II) chloride (3.28 mL) in hydrogen chloride was added dropwise. After the addition, the reaction was warmed to room temperature and stirred for 1.5 hours. The reaction was basicized with 50% sodium hydroxide to pH 14 and extracted with ethyl acetate (3 x 50 mL). The solution was concentrated to a residue, dissolved in a minimum amount of chloroform, and 1M hydrogen chloride in ether was added until precipitated. The solution was filtered and dried to give 1-{2-[(3-chloropropyl) sulfanyl] -5-nitrophenyl} hydrazine (100 mg, 85%).¹1 H NMR (CDCl₃, 300MHz): δ7.94 (d, 1H, J = 2.5Hz), 7.3 (dd, 1H, J = 8.5Hz, J = 8.4Hz), 7.38 (d, 1H, J = 8.4Hz), 6.28 (s -broad, 1H), 3.73 (s-broad, 2H), 3.63 (t, 2H, J = 6.3Hz), 3.00 (t, 2H, J = 7Hz), 2.01 (q, 2H, J = 6.5Hz) ppm .. [0596] (Step C) 1-{2-[(3-Chloropropyl) sulfanyl] -5-nitrophenyl} hydrazine (100 mg, 0.38 mmol) and 4-piperidone monohydrate (58 mg, 0.38 mmol) dissolved in trifluoroethanol (1 mL) Then, the mixture was heated under reflux for 1 hour. To this was added 12N HCl (3 mL) and the reaction was heated to reflux for 2 hours. When cooled to room temperature, the product precipitates, which is filtered and washed with cold 2-propanol to give 3-chloropropyl 9-nitro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]. ] Indol-6-ylsulfide (120 mg, 75.4%) was obtained.¹H NMR (CD)₃OD, 300MHz): δ8.00 (d, 1H, J = 8.4Hz), 7.30 (d, 1H, J = 8.4Hz), 4.68 (s, 2H), 3.69 (t, 2H, J = 6.2Hz), 3.60 (t, 2H, J = 6Hz), 3.23 (t, 2H, J = 6.2Hz), 2.08 (q, 2H, J = 6.2Hz) ppm. [0597] (Step D) 3-Chloropropyl 9-nitro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-6-ylsulfide (100 mg, 0.38 mmol) and 4-piperidone monohydrate (58 mg) , 0.38 mmol) was dissolved in trifluoroethanol (1 mL), and the mixture was heated under reflux for 1 hour. To this was added 12N HCl (3 mL) and the reaction was heated to reflux for 2 hours. Cooling to room temperature settled the product, which was filtered and washed with cold 2-propanol to give the title compound (160 mg, 63%).¹H NMR (CD)₃OD, 300MHz): δ7.79 (d, 1H, J = 8.4Hz), 7.11 (d, 1H, J = 8.4Hz), 4.65 (t, 2H, J = 6.1Hz), 4.58 (s, 2H), 3.61 (t, 2H, J = 6.3Hz), 3.17 (t, 2H, J = 6.3Hz), 2.36 (q, 2H, J = 6.2Hz) ppm. [0598] (Example 11) cis- (8a, 12a) -1-nitro-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0599] 1-Nitro-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole (0.04 mg, 0.13 mmol) ) Was dissolved in trifluoroacetic acid (0.86 mL) at 0 ° C. Sodium cyanoborohydride (40.1 mg, 0.66 mmol) was added slowly at an internal temperature of less than 8 ° C. After the addition, the reaction was stirred at 0 ° C. for 5 hours. Then, sodium hydroxide (50%) was used to make it basic to pH 12-14. The solution was extracted with dichloromethane (3 x 10 mL) and concentrated to give a residue. Concentrated hydrogen chloride (0.5 mL) was added to this residue, and the mixture was heated under reflux for 1.5 hours. It was then basicized with ammonium hydroxide to pH 12-14 and then extracted with dichloromethane (3 x 10 mL) and concentrated. Purification of the residue by preparative thin layer chromatography eluting with 10% methanol in dichloromethane gave the title compound (5 mg, 13%).¹H NMR (CD)₃OD, 300MHz): δ7.40 (d, 1H, J = 8.4Hz), 7.04 (d, 1H, J = 8.4Hz), 4.09-3.70 (m, 5H), 3.51-3.48 (m, 2H), 3.12. -2.92 (m, 2H), 2.83-2.78 (m, 1H), 2.20-2.18 (m, 1H), 2.02-1.89 (m, 3H) ppm. [0600] (Example 12) 3-Chloro-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0601] (Step A) KOH pellets were added in one portion to a dry THF (Aldrich anhydrous grade, 70 mL) solution of 2,3-dichloronitrobenzene (9.61 g, 50.1 mmol) and 3-chloropropanethiol (5.0 g, 45.5 mmol) at 23 ° C. The resulting mixture was vigorously stirred at 23 ° C for 3.5 hours. The reaction mixture was filtered through a Celite filler to remove residual KOH. The filler was washed with THF (2 x 50 mL). Concentration of the filtrate in vacuo gave crude 1-chloro-2-[(3-chloropropyl) sulfanyl] -3-nitrobenzene (12 g, about 100%). [0602] (Step B) Crude 1-chloro-2-[(3-chloropropyl) sulfanyl] -3-nitrobenzene was dissolved in MeOH (150 mL) and N₂I degassed. Palladium hydroxide (1.8 g) was added in 4 portions to this solution in the Parr apparatus. The resulting heterogeneous solution was shaken at room temperature for 18 hours under hydrogenation conditions (55 psi (about 3.7 atm)). The catalyst was removed by filtration in the same manner as above, and the filtrate was concentrated in vacuo to give 3-chloro-2-[(3-chloropropyl) sulfanyl] aniline (9.94 g, 93%) as a dark oil.¹1 H NMR (CHCl 3,300MHz) δ7.03 (t, 1H, J = 8.1Hz), 6.82 (t, 1H, J = 8.1Hz), 6.63 (t, 1H, J = 8.0Hz), 4.62 (brs, 1H) ), 3.68 (t, 2H, J = 6.4Hz), 2.92 (t, 2H, J = 6.9Hz), 1.98 (quintet, 2H, J = 6.6Hz) ppm. [0603] (Step C) 3-Chloro-2-[(3-chloropropyl) sulfanyl] aniline (4.2 g, 15.4 mmol) was dissolved in TFA (24 mL) at 23 ° C. Concentrated HCl (24 mL) was added with stirring. The mixture was cooled in an ice bath. NaNO₂A solution of (1.17 g, 10 mmol) in water (6 mL) was added dropwise over 10 minutes. During this addition, the internal temperature of the reactants was maintained below 5 ° C, then at 0 ° C for 1 hour, and then SnCl cooled in an ice bath.₂ 2H₂Transferred to O (7.65 g, 34 mmol) concentrated HCl stirred solution (8 mL) over 10 minutes by cannula. The cooling bath was then removed and the reaction was warmed to 23 ° C in 1 hour. This was recooled in an ice bath. Addition of aqueous sodium hydroxide solution (50%) until the pH is above 12 gives a heterogeneous product, which is CH.₂Cl₂-Treatment with MeOH (20: 1, 250 mL). The mixture was filtered and the resulting two-phase filtrate was CH.₂Cl₂Extracted with (2 x 200 mL). Dry the combined organic extracts (DDL₄), Concentrated in vacuo to give 3-chloro-2- (3'-chloropropylthio) phenylhydrazine (4.0 g, 90%) as a brown oil. CH the obtained oil₂Cl₂Dissolved in (100 mL), flow of HCl gas was aerated in this solution for 5 minutes. Separation of the purple solid obtained after evaporation of the solvent gave 1-{3-chloro-2-[(3-chloropropyl) sulfanyl] phenyl} hydrazine hydrochloride, which was used without further purification.¹H NMR (CD)₃OD, 300MHz) δ7.37 (t, 1H, J = 8.0Hz), 7.15 (dd, 1H, J = 8.1, 1.1Hz), 6.95 (dd, 1H, J = 8.5, 1.1Hz), 3.67 (t, 2H, J = 6.3Hz), 2.95 (t, 2H, J = 7.0Hz), 1.90 (quintet, 2H, J = 6.6Hz) ppm [0604] (Step D) 1-{3-Chloro-2-[(3-chloropropyl) sulfanyl] phenyl} hydrazine hydrochloride (700 mg, 2.4 mmol) and 4-piperidone monohydrate hydrochloride (373 mg, 2.4 mmol) at 23 ° C. It was added to 2,2,2-trifluoroethanol (6 mL). The suspension was heated to reflux for 18 hours to form a solid. After cooling to 23 ° C, the solids were collected by vacuum filtration. When this is dried for 12 hours, it is 7-chloro-6-[(3-chloropropyl) sulfanyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole as a brown powder. It became hydrochloride (506 mg, 59%). Concentration of the filtrate gave a different yield of product (140 mg, 16%).¹H NMR (CD)₃OD, 300MHz) δ11.09 (brs, 1H), 7.41 (t, 1H, J = 8.4Hz), 7.17 (d, 1H, J = 8.4Hz), 4.40 (brs, 2H), 3.67-3.59 (m, 4H), 3.17 (t, 2H, J = 5.9Hz), 3.00 (t, 2H, J = 7.0Hz), 1.84 (quintet, 2H, J = 6.9Hz) ppm. [0605] (Step E) 7-Chloro-6-[(3-chloropropyl) sulfanyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (2.0 g, 5.7 mmol) and KI (850 mg) ) Was suspended in anhydrous DME (200 mL). With stirring, KOH powder (3.2 g, 57 mmol) was added in 4 portions. The mixture was heated to reflux for 3 hours. The reaction mixture was cooled and filtered. Concentration of the filtrate gave the title compound (1.13 g, 71%) as an oil.¹1 H NMR (CHCl 3,300MHz) δ7.07 (d, 1H, J = 8.4Hz), 6.99 (d, 1H, J = 8.4Hz), 4.50 (t, 2H, J = 5.9Hz), 3.92 (brs, 2H) ), 3.40 (t, 2H, J = 6.6Hz), 3.24 (t, 2H, J = 5.7Hz), 2.65 (t, 2H, J = 5.5Hz), 1.28 (quintet, 2H, J = 6.3Hz) ppm .. [0606] (Example 13) cis- (8a, 12a) -3-chloro-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0607] 3-Chloro-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole cooled in an ice bath NaBH in (1.0 g, 3.6 mmol) TFA solution (40 mL) for 20 minutes₄(684 mg, 18.0 mmol) was added in 10 portions. During this addition, the internal temperature of the reaction mixture was maintained below 8 ° C. The heterogeneous solution was stirred at 2 ° C for an additional 1.5 hours. It was then poured onto ice pieces and an aqueous NaOH solution (50%) was added (by pH paper) until the pH was above 12. CH the resulting mixture₂Cl₂Extracted with (3 x 200 mL). Combine the extracts and dry (EDTA)₄) Concentrated in vacuum. The title compound was isolated as a yellowish brown powder (350 mg, 35%).¹1 H NMR (CHCl 3,300MHz) δ6.72 (s, 2H), 4.01-3.91 (m, 1H), 3.72-3.62 (m, 2H), 3.38-3.33 (m, 1H), 3.14-3.30 (m, 4H) ), 2.91 (dd, 1H, J = 8.3, 4.4Hz), 2.56 (dd, 1H, J = 12.1, 2.2Hz), 2.17-1.79 (m, 4H) ppm. MS (CI, NH₃): 281 (base, M + H). [0608] (Example 14) 3-Methyl-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0609] (Step A) A solution of acetonitrile (30 mL) and o-thiocresol (5.0 g, 40 mmol) was heated to reflux. Pure β-propiolactone (2.8 mL, 40 mmol) was added dropwise over 5 minutes. Heating reflux was continued for 20 hours, at which point additional β-propiolactone (2.8 mL, 40 mmol) was added in one portion. After heating for an additional 24 hours, the reaction mixture was concentrated in vacuo. The resulting solid and oil mixture was treated with 2N aqueous NaOH solution (150 mL) at 23 ° C. Et this basic solution₂Washed with O (2 x 200 mL). The separated aqueous layer was acidified with concentrated HCl aqueous solution to pH 1. This heterogeneous solution was concentrated in vacuo to half its original volume. Then, it was left at 23 ° C for 2 hours. Collect solid products by vacuum filtration, H₂Washing with O (20 mL) and drying in vacuum at 65 ° C. for 2 hours gave 3-[(2-methylphenyl) sulfanyl] propanoic acid (4.62 g, 59%) as a white powder.¹1 H NMR (CHCl 3,300MHz) δ7.31 (d, 1H, J = 7.0Hz), 7.20-7.15 (m, 3H), 3.14 (t, 2H, J = 7.3Hz), 2.69 (t, 2H, J = 7.4Hz), 2.39 (s, 3H) ppm. [0610] (Step B) To polyphosphoric acid (PPA, 7.5 g) heated (at 105 ° C), 3-[(2-methylphenyl) sulfanyl] propanoic acid (4.5 g, 23.0 mmol) was added at once. Keep this mixture at 105 ° C for 1.5 hours, ice-H₂When poured into O (250 mL), a heterogeneous mixture was obtained. Reactor H₂Washed with O (3 x 50 mL) and combined with the washing solution. After the PPA was completely dissolved in water, the reaction mixture was filtered by vacuum. Separated solid H₂Wash with O (3 x 50 mL) and dry in vacuum for 18 hours to give 8-methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (3.52 g, 86%) as a pink solid. Was done.¹1 H NMR (CHCl 3,300MHz) δ8.00 (d, 1H, J = 8.0Hz), 7.28 (d, 1H, J = 8.0Hz), 7.09 (t, 1H, J = 8.0Hz), 3.22 (t, 2H) , J = 6.6Hz), 2.95 (t, 2H, J = 6.6Hz), 2.30 (s, 3H) ppm. [0611] (Step C) 8-Methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (2.24 g, 12.6 mmol) and NaN₃Concentrated H at 50 ° C in (1.64 g, 25.2 mmol) AcOH (7.6 mL) solution₂SO₄(1.9 mL) was added dropwise. The reaction was maintained at 50 ° C for 2 hours and poured into ice pieces. Solids were collected by vacuum filtration and dried in vacuum at 23 ° C. This crude sample has a ratio of 1: 11: 7 (¹It was a mixture of starting material (by 1 H NMR), desired product and position isomer product. 20: 1CHCl₃-When the crude solid is purified by column silica gel chromatography eluting with MeOH, a mixture of 9-methyl-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one and its positional isomers (500 mg, 4: 1,¹(By 1 H NMR) was obtained. This sample was used without further purification.¹H NMR (CHCl)₃, 300MHz) δ7.22 (t, 1H, J = 7.7Hz), 7.15 (d, 1H, J = 7.3Hz), 6.94 (d, 1H, J = 7.4Hz), 3.39 (t, 2H, J = 7.3) Hz), 2.59 (t, 2H, J = 7.0Hz), 2.54 (s, 3H) ppm. [0612] (Step D) Red-Al in a toluene (10 mL) suspension of 9-methyl-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one (4: 1 position isomer, 500 mg, 2.6 mmol). (65 wt% toluene solution, 1.6 mL) was added dropwise over 3 minutes. The solution was heated at 85 ° C for 1.5 hours. After cooling to 23 ° C, 1N aqueous NaOH solution (2 mL) was carefully added. Then CHCl₃(50 mL) and saturated aqueous Rochelle salt solution (50 mL) were added sequentially. The two-phase mixture was vigorously stirred at 23 ° C for 1 hour. Separate the layers and CHCl the aqueous layer₃Back extraction was performed with (2 x 50 mL). Combine the extracts and dry (EDTA)₄) Concentration in vacuo gave 9-methyl-2,3,4,5-tetrahydro-1,5-benzothiazepine (500 mg,&gt; 100%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): δ6.92 (t, 1H, J = 7.3Hz), 6.75 (d, 1H, J = 7.4Hz), 6.58 (d, 1H, J = 8.1Hz), 3.34 (t, 1H, J = 5.2Hz), 2.92 (t, 2H, J = 5.8Hz), 2.48 (s, 3H), 2.25 (s, 3H), 2.04 (quintet, 2H, J = 3.0Hz) ppm. [0613] (Step E) NaNO in a solution of 9-methyl-2,3,4,5-tetrahydro-1,5-benzothiazepine (500 mg, 2.6 mmol) and AcOH (2 mL) cooled to about 9 ° C.₂A solution of (212 mg, 3.1 mmol) and water (1 mL) was added dropwise over 4 minutes (internal temperature &lt;12 ° C). The cooling bath was removed and the reaction was maintained at 23 ° C for 2 hours. H₂Diluted with O (50 mL). After collecting by vacuum filtration and air drying at 23 ° C, 9-methyl-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (470 mg, 87%) was added as a yellow solid. Obtained. [0614] (Step F) LiAlH₄9-Methyl-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (crude, 470 mg,) in 1.0 MTHF solution (2.3 mL, 2.3 mmol) cooled to about 10 ° C. A 2.3 mmol) THF solution (2.3 mL) was cannulated over 3 minutes (internal temperature &lt;25 ° C). When the addition was complete, the cooling bath was removed and the reaction was maintained at 25 ° C to 32 ° C for 1.5 hours. H₂Carefully add O (0.1 mL) over 5 minutes, followed by THF (40 mL), NaOH aqueous solution (15%, 0.1 mL), and H again.₂O (0.3 mL) was added. The resulting mixture was vigorously stirred at 23 ° C for 1 hour and dried (DDL).₄). The desiccant was removed by filtration and the filtrate was concentrated to give a residue, which was dissolved in EtOAc (4 mL). In this solution, 1MHCl · Et₂O solution was added dropwise over 1 minute. Separation of the solid by concentration in vacuo yields 9-methyl-3,4-dihydro-1,5-benzothiazepine-5 (2H) -amine hydrochloride (477 mg, 80%) as a brown powder. Was done.¹1 H NMR (CDCl₃, 300MHz): δ7.13 (m, 2H), 6.91 (m, 1H), 4.00-3.80 (brs, 2H), 3.36 (t, 2H, J = 5.7Hz), 2.87 (t, 2H, J = 5.7) Hz), 2.42 (s, 3H), 2.05 (m, 2H) ppm. [0615] (Step G) 9-Methyl-3,4-dihydro-1,5-benzothiazepine-5 (2H) -amine hydrochloride (477 mg, 2.1 mmol) and 4-piperidone monohydrate hydrochloride (307 mg, 2.1 mmol) 23 Suspended in 2,2,2-trifluoroethanol (5 mL) at ° C. The suspension was heated at 70 ° C. for 1.5 hours. After cooling the reaction mixture to 23 ° C., the product was collected by vacuum filtration to give the title compound (312 mg, 35%) as a pale yellow powder.¹H NMR (CD)₃OD, 300MHz): δ7.09 (d, 1H, J = 8.0Hz), 6.83 (d, 1H, J = 8.0Hz), 4.56 (t, 2H, J = 6.1Hz), 4.33 (brs, 2H), 3.60 (t, 2H, J = 6.2Hz), 3.18 (t, 2H, J = 5.9Hz), 3.06 (t, 2H, J = 6.0Hz), 2.34 (s, 3H), 2.29 (m, 2H) ppm .. [0616] (Example 15) cis- (8a, 12a) -3-methyl-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0617] 3-Methyl-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole cooled in an ice bath NaBH in (295 mg, 1.0 mmol) TFA solution (10 mL) for 4 minutes₄(122 mg, 3.2 mmol) was added in 4 portions. After the addition, the cooling bath was removed and the heterogeneous solution was stirred at 23 ° C for 24 hours. It was then poured onto ice pieces and slowly added 50% aqueous NaOH solution (with pH paper) until the pH was above 12 (internal temperature less than 8 ° C). The resulting mixture is CHCl₃Extracted with (6 x 100 mL). Combine the extracts and dry (EDTA)₄) Concentration in vacuo gave the crude title compound (225 mg, 87%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): δ6.75 (d, 1H, J = 8.1Hz), 6.59 (d, 1H, J = 7.9Hz), 4.08-3.92 (m, 1H), 3.72-3.60 (m, 1H), 3.39- 3.30 (m, 1H), 3.20-2.92 (m, 6H), 2.64-2.52 (m, 1H), 2.25 (s, 3H), 2.19-1.90 (m, 4H) ppm. Recrystallization of this oil as fumarate gave the title compound. [0618] (Example 18) 1-Bromo-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0619] (Step A) 2,5-Dibromonitrobenzene (6.32 g, 22.5 mmol) and 3-bromopropane-1-thiol (2 mL, 20 mmol) were dissolved in THF (35 mL) at room temperature. The reaction flask was cooled to 0 ° C. Powdered KOH (1.72 g, 30.7 mmol) was added at once. The reaction was then warmed to room temperature and stirred for 4 hours. Water (20 mL) and EtOAc (20 mL) were added. The layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried and concentrated. 5.40 g of a crude yellow oily solid was isolated. When the crude product is purified by column chromatography (10-30% acetone-hexane), it is 4-bromo-1-[(3-chloropropyl) sulfanyl] -2-nitrobenzene (3.56 g, 64%) as a pale yellow solid. was gotten.¹1 H NMR (CDCl₃, 300Mhz) δ8.35 (d, 1H, 2.2Hz), 7.67 (dd, 1H, 2.2, 8.5HzHz), 7.32 (d, 1H, 8.0Hz), 3.70 (t, 2H, 5.9Hz), 3.13 (t) , 2H, 7.3Hz), 2.14-2.21 (m, 2H) ppm. [0620] (Step B) 4-Bromo-1-[(3-chloropropyl) sulfanyl] -2-nitrobenzene (1.97 g, 7.1 mmol) was dissolved in MeOH (25 mL). Exhaust the reaction flask with nitrogen and Pd (OH)₂-Carbon (Pd (OH)₂ on carbon) (400 mg) was added. After evacuating the reaction flask with nitrogen several times, H₂The atmosphere was (50 psi (about 3.4 atm)). The flask was shaken on the parr device for 72 hours. The reaction was filtered through a layer of Celite and the residue was washed with MeOH (5 mL). The supernatant is concentrated and the crude black residue is column chromatographed (50-20% hexane-CH).₂Cl₂), 5-Bromo-2-[(3-chloropropyl) sulfanyl] aniline (1.28 g, 73%) was obtained as a clear oil.¹1 H NMR (CDCl₃, 300Mhz) δ7.20 (d, 1H, 8.0Hz), 6.88 (d, 1H, 2.0Hz), 6.79 (dd, 1H, 2.0Hz, 8.0Hz), 4.41 (s, 2H), 3.64 (t, 2H) , 6.6Hz), 2.86 (t, 2H, 7.0Hz), 1.94-1.99 (m, 2H) ppm. [0621] (Step C) 5-Bromo-2-[(3-chloropropyl) sulfanyl] aniline (0.938 g, 3.3 mmol) was dissolved in TFA (4 mL). The reaction flask was cooled to 0 ° C. and HCl (15 mL) was added. In the resulting suspension, NaNO₂(0.25g, 3.7 mmol, 3mLH₂The aqueous solution of O) was added slowly. The flask was warmed to room temperature and stirred for 2 hours. Recool the flask to 0 ° C and SnCl₂ 2H₂O (1.49g, 6.6mmol, H₂Transferred to an aqueous solution of O3 mL) by cannula. The solution was stirred for 3 hours. The precipitate was collected by filtration and the residue was air dried overnight. 1- {5-Bromo-2-[(3-chloropropyl) sulfanyl] phenyl} hydrazine hydrochloride (0.800 g, 73%) was isolated as a light brown powder.¹H NMR (CD)₃OD, 300Mhz) δ7.42 (d, 1H, 8.0Hz), 7.14-7.21 (m, 2H), 3.66 (t, 2H, 6.2Hz), 2.97 (t, 2H, 6.9Hz), 1.90-1.99 (m , 2H) ppm. MS (CI, NH₃): 297 (base, M + H). [0622] (Step D) 1-{5-Bromo-2-[(3-chloropropyl) sulfanyl] phenyl} hydrazine hydrochloride (784 mg, 2.4 mmol) and 4-piperidone monohydrate-HCl (398 mg, 2.6) in EtOH (5 mL) Dissolved. Concentrated HCl (0.2 mL, 2.4 mmol) was added. The reaction was refluxed for 18 hours and then cooled to room temperature. The precipitate was collected by filtration and the residue was washed with EtOH (3 mL). 9-Bromo-6-[(3-chloropropyl) sulfanyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (500.4 mg, 58%) as a white powder Isolated.¹H NMR (CD)₃OD, 300Mhz) δ7.18 (d, 1H, 8.0Hz), 7.12 (d, 1H, 8.0Hz), 4.73 (s, 2H), 3.64 (t, 2H, 6.6Hz), 3.58 (t, 2H, 6.3 Hz), 3.16 (t, 2H, 6.3Hz), 3.02 (t, 2H, 6.6Hz), 1.87-1.96 (m, 2H) ppm. [0623] (Step E) 9-Bromo-6-[(3-chloropropyl) sulfanyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (297 mg, 0.82 mmol) in DME (50 mL) Dissolved in. KOH (460 mg, 8.2 mmol) and KI (1360 mg, 0.82 mmol) were added. The solution was refluxed for 18 hours and then cooled to room temperature. The reaction was concentrated. Water (20 mL) and CH₂Cl₂(20 mL) was added. Separate the layers and CH the aqueous solution₂Cl₂Extracted with (2 x 20 mL). The combined organic layers were washed with saline, dried and concentrated to give 5 (209 mg, 92%) as a pale white amorphous solid.¹1 H NMR (CDCl₃, 300Mhz) δ6.97 (d, 1H, 7.9Hz), 6.82 (d, 1H, 7.9Hz), 4.55 (t, 2H, 5.9Hz), 4.37 (s, 2H), 3.34 (t, 2H, 7.0Hz) ), 3.21 (t, 2H, 5.9Hz), 2.65 (t, 2H, 5.8Hz), 2.25-2.33 (m, 2H) ppm. [0624] (Example 19) (8aS, 12aR) -1-Bromo-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indole [0625] 1-Bromo-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole (53.0 mg, 0.17 mmol) ) Was dissolved in TFA (2 mL). The reaction was cooled to 0 ° C. NaCNBH₃(32.3 mg, 0.51 mmol) was added. The reaction was stirred at 0 ° C for 2 hours. Ice (2 pieces) was added. The reaction was basicized to pH 14 with 50% NaOH while keeping the temperature below 7 ° C. CH reaction mixture₂Cl₂Extracted with (3 x 10 mL). The combined organic layers were washed with saline, dried and concentrated to give the title compound (53 mg, 100%) as a pure white amorphous solid. Enantiomers were separated by preparative HPLC on a Chiracelle OD column using non-gradient 10% IPA / hexane as the eluate.¹1 H NMR (CDCl₃, 300Mhz) δ6.79 (d, 1H, 8.4Hz), 6.72 (d, 1H, 8.4Hz), 3.89-3.99 (m, 1H), 3.55-3.65 (m, 1H), 3.30-3.40 (m, 1H) ), 3.10-3.30 (m, 2H), 2.80-3.10 (m, 3H), 3.34 (t, 1H, 11.7Hz), 1.60-2.30 (m, 5H) ppm. MS (CI, NH₃): 325 (base, M + H). [0626] (Example 25) cis- (8a, 12a) -11- (3,4-dimethoxybenzoyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0627] cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2,3,4-hi ] CH indole (44mg, 0.16)₂Cl₂Dissolved in (3 mL). Et₃N (0.067 mL, 0.48 mmol) and 3,4-dimethoxybenzoyl chloride (47 mg, 0.23 mmol) were added. The reaction was stirred for 18 hours. Saline (5 mL) was added. The layers were separated. CH the aqueous phase₂Cl₂(2 x 5 mL) was extracted. The combined organic layers were washed with saline, dried and concentrated to give a crude brown amorphous solid (138 mg). Residue column chromatography (1-5% MeOH / CH)₂Cl₂), The title compound (691 mg, 100%) was obtained as a white amorphous solid.¹1 H NMR (CDCl₃ 300MHz) δ6.80-7.10 (m, 5H), 6.62 (m, 1H), 3.75-4.10 (m, 8H), 3.42-3.70 (M, 4H), 2.80-3.40 (m, 4H), 1.80-2.25 (m, 4H) ppm. MS (ESI): 411 (base, M + H). [0628] (Example 26) cis- (8a, 12a) -11- (2,5-dimethoxybenzoyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0629] The title compound was cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] by the method of Example 25. ] Thiazepino [2,3,4-hi] indole (44 mg, 0.16 mmol), 2,5-dimethoxybenzoyl chloride (47 mg, 0.23 mmol), and Et.₃Prepared from N (0.067 mL, 0.48 mmol) and purified by chromatography to give the title compound (32 mg, 49%) as a white amorphous solid.¹1 H NMR (CDCl₃ 300MHz) δ6.90-7.05 (m, 1H), 6.75-6.90 (m, 2H), 6.60-6.75 (m, 1H), 6.50-6.60 (m, 1H), 4.20-4.60 (m, 1H), 3.95 -4.10 (m, 1H), 3.65-3.94 (m, 6H), 3.20-3.60 (M, 4H), 2.80-3.25 (m, 4H), 1.60-2.20 (m, 4H) ppm. MS (ESI): 411 (base, M + H). [0630] (Example 27) cis- (8a, 12a) -11- (3,5-dimethoxybenzoyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0631] The title compound was cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] by the method of Example 25. ] Thiazepino [2,3,4-hi] indole (44 mg, 0.16 mmol), 3,5-dimethoxybenzoyl chloride (47 mg, 0.23 mmol), and Et.₃Prepared from N (0.067 mL, 0.48 mmol) and purified by chromatography to give the title compound (44 mg, 99%) as a white amorphous solid.¹1 H NMR (CDCl₃ 300MHz) δ6.90-7.10 (m, 1H), 6.30-6.80 (m, 4H), 3.80-4.20 (m, 2H), 3.79 (s, 6H), 3.25-3.90 (M, 4H), 2.80-3.20 (m, 4H), 1.70-2.20 (m, 4H) ppm. MS (ESI): 411 (base, M + H). [0632] (Example 28) (8aS, 12aR) -11- (2,6-dimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0633] cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole was dissolved in 1: 1 THF / MeOH (4 mL). 2,6-dimethoxybenzaldehyde (34 mg, 0.20 mmol), molecular sieve (20 mg), and 2 drops of acetic acid were added. The solution was stirred at room temperature for 4 hours. NaCNBH₃Was added (45 mg, 0.72 mmol) and the reaction was stirred for 18 hours. The suspension was filtered through a packing of Celite and the residue was washed with EtOAc. Saturated in supernatant LVDS₃An aqueous solution (5 ml) was added. The two-phase mixture was stirred for 10 minutes. The layers were separated. The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine, dried and concentrated. A crude brown amorphous solid 94 mg was isolated. Column chromatography of residue (5-10% MeOH-CH₂Cl₂). The title compound (56 mg, 78%) was obtained as an amorphous white solid.¹1 H NMR (CDCl₃, 300MHz) δ7.22 (t, 1H, 8.4Hz), 6.93 (dd, 1H, 1.1Hz, 7.7Hz), 6.83 (d, 1H, 6.6Hz), 6.60 (t, 1H, 7.3Hz), 6.56 ( d, 2H, 8.4Hz), 3.80 (s, 6H), 3.69 (s, 2H), 3.47-3.62 (m, 2H), 3.18-3.38 (m, 2H), 2.77-3.10 (m, 4H), 2.30 -2.60 (m, 1H), 1.80-2.20 (m, 5H) ppm. MS (ESI): 397.3 (base, M + H). [0634] (Example 29) (8aS, 12aR) -11- (2,4-dimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0635] The title compound was cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1, by the method of Example 28. 4] Thiazepino [2,3,4-hi] indole (63 mg, 0.22 mmol), 2,4-dimethoxybenzaldehyde (41 mg, 0.25 mmol), and NaCNBH₃Prepared from (56 mg, 0.89 mmol) and purified by column chromatography to give the title compound (49 mg, 56%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.23 (d, 1H, 7.7Hz), 6.93 (dd, 1H, 1.1Hz, 7.7Hz), 6.81 (d, 1H, 7.3Hz), 6.60 (t, 1H, 7.5Hz), 3.81 ( s, 3H), 3.78 (s, 3H), 3.51-3.61 (m, 2H), 3.43 (d, 2H, 5.1Hz), 3.21-3.35 (m, 1H), 3.01-3.20 (m, 1H), 2.85 -3.00 (m, 1H), 2.72-2.81 (m, 1H), 2.60-2.70 (m, 1H), 2.22-2.38 (m, 1H), 1.92-2.20 (m, 3H), 1.82-1.90 (m, 2H) ppm. MS (ESI): 397.3 (base, M + H). [0636] (Example 30) (8aS, 12aR) -11- (2,4,6-trimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [0637] The title compound was cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1, by the method of Example 28. 4] Thiazepino [2,3,4-hi] indole (48 mg, 0.17 mmol), 2,3,6-trimethoxybenzaldehyde (37 mg, 0.19 mmol), and NaCNBH₃Prepared from (43 mg, 0.68 mmol) and purified by column chromatography to give the title compound (60 mg, 83%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ6.93 (dd, 1H, 1.1Hz, 7.7Hz), 6.83 (dd, 1H, 1.1Hz, 7.0Hz), 6.60 (t, 1H, 7.6Hz), 6.12 (s, 2H), 3.81 ( s, 3H), 3.78 (s, 6H), 3.42-3.70 (m, 4H), 3.10-3.40 (m, 2H), 2.92-3.08 (m, 1H), 2.70-2.90 (m, 3H), 2.30- 2.50 (m, 1H), 1.70-2.20 (m, 5H) ppm. MS (ESI): 427.3 (base, M + H). [0638] (Example 31) (8aS, 12aR) -11- (2,3-dimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0639] The title compound was cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1, by the method of Example 28. 4] Thiazepino [2,3,4-hi] indole (57 mg, 0.20 mmol), 2,3-dimethoxybenzaldehyde (37 mg, 0.22 mmol), and NaCNBH₃Prepared from (50 mg, 0.80 mmol) and purified by column chromatography to give the title compound (47 mg, 59%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ6.99-7.07 (m, 2H), 6.93 (dd, 1H, 1.1Hz, 7.0Hz), 6.80-6.86 (m, 2H), 6.59 (t, 1H, 7.7Hz), 3.87 (s, 3H), 3.81 (s, 3H), 3.41-3.70 (m, 4H), 3.21-3.35 (m, 1H), 3.01-3.21 (m, 2H), 2.87-3.01 (m, 1H), 2.75-2.82 ( m, 1H), 2.60-2.72 (m, 1H), 2.24-2.42 (m, 1H), 1.80-2.20 (m, 5H) ppm. MS (ESI): 397.3 (base, M + H). [0640] (Example 32) cis- (8a, 12a) -11- (2,4,5-trimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0641] The title compound was cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1, by the method of Example 28. 4] Thiazepino [2,3,4-hi] indole (56 mg, 0.20 mmol), 2,4,5-trimethoxybenzaldehyde (47 mg, 0.23 mmol), and NaCNBH₃Prepared from (50 mg, 0.80 mmol) and purified by column chromatography to give the title compound (18 mg, 41%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.02 (s, 1H), 6.94 (d, 1H, 7.7Hz), 6.81 (d, 1H, 7.0Hz), 6.60 (t, 1H, 7.7Hz), 6.51 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 3.40-3.70 (m, 4H), 3.15-3.35 (m, 2H), 3.05-3.15 (m, 1H), 2.90-3.05 (m, 1H), 2.60-2.90 (m, 2H), 2.25-2.50 (m, 1H), 1.80-2.20 (m, 5H) .MS (ESI): 427.3 (base, M + H). [0642] (Example 33) cis- (8a, 12a) -11- (cyclohexylmethyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole [0643] cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Cyclohexanecarboxyaldehyde (19.8 mg, 0.18 mmol) and 3 Å molecular sieves were added to a solution of indole (50 mg, 0.18 mmol) in MeOH (2 mL) and the mixture was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (45.2 mg, 0.72 mmol) was added and the reaction was stirred overnight. The reaction mixture was filtered through Celite, the filtrate was extracted with EtOAc (3 x 50 mL), washed with saturated potassium carbonate (1 x 50 mL) and brine (1 x 50 mL) and dried (sodium sulfate). Concentrate to residue and column chromatography (gradient: CH₂Cl₂Purification with 1%, 2.5%, and 5% MeOH) in the title compound (35 mg, 58%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ6.93 (dd, H, J = 7.7Hz, J = 7.6Hz), 6.85 (d, 1H, J = 7.3Hz), 6.61 (t, 1H, J = 7.3Hz), 3.81-3.77 (m, 1H), 3.61-3.48 (m, 1H), 3.31-3.3.22 (m, 1H), 3.21-3.11 (m, 1H), 3.10-3.02 (m, 1H), 2.98-2.88 (m, 1H), 2.79-2.70 (m, 1H), 2.69-2.59 (m, 1H), 2.25-2.17 (m, 1H), 2.12-1.97 (m, 3H), 1.93-182 (m, 2H), 1.80- 1.61 (m, 4H), 1.58-1.43 (m, 1H), 1.33-1.09 (m, 3H), 0.94-0.81 (m, 2H) ppm. Mass spectrometry (ESI): 343 (base, M + H). [0644] (Example 34) cis- (8a, 12a) -11- (2,3,4-trimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0645] The above compound was prepared by the method of Example 33 using 2,3,4-trimethoxybenzaldehyde. Column chromatography (gradient: CH₂Cl₂Purification with 1%, 2.5%, and 5% MeOH) in the title compound (15.7 mg, 42%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.03 (d, 1H, J = 8.4Hz), 6.93 (dd, 1H, J = 8Hz, J = 8.1Hz), 6.81 (d, 1H, J = 6.6Hz), 6.8-6.6 ( m, 3H), 4.16 (q, 1H, J = 7.1Hz), 3.93-3.90 (m, 1H), 3.8-3.75 (m, 1H), 3.6-3.53 (m, 1H), 3.4 (m, 2H) , 3.3-3.25 (m, 1H), 3.2-3.12 (m, 2H), 3.1-2.9 (m, 1H), 2.7-2.59 (m, 2H), 2.3-2.22 (m, 1H), 2.1-2.07 ( m, 1H), 2.04 (s, 2H), 2.01 (s, 1H), 1.98-1.88 (m, 3H), 1.25 (t, 1H, J = 7.1Hz) ppm. [0646] (Example 35) cis- (8a, 12a) -11- (3,4-dimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0647] The above compound was prepared by the method of Example 33 using 4,5-dimethoxybenzaldehyde. Column chromatography (gradient: CH₂Cl₂Purification with 1%, 2.5%, and 5% MeOH) in the title compound (26 mg, 37%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ6.97-6.87 (m, 2H), 6.82-6.79 (m, 2H), 6.91 (t, 1H, J = 7.4Hz), 4.15 (q, 1H, J = 7.1Hz), 3.8- 3.75 (m, 1H), 3.6-3.48 (m, 1H), 3.4 (s, 2H), 3.37-3.25 (m, 2H), 3.2-3.3.08 (m, 1H), 2.73-2.67 (m, 1H) ), 2.63-2.59 (m, 1H), 2.32-2.23 (m, 1H), 2.17-2.07 (m, 1H), 2.04 (s, 2H), 1.95-1.88 (m, 3H), 1.25 (t, 1H) , J = 7.1Hz) ppm. [0648] (Example 36) cis- (8a, 12a) -11- (3,4,5-trimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0649] The above compound was prepared by the method of Example 33 using 3,4,5-trimethoxybenzaldehyde. Column chromatography (gradient: CH₂Cl₂Purification with 1%, 2.5%, and 5% MeOH) in the title compound (30 mg, 49%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ6.95 (dd, 1H, J = 7.7Hz, J = 7.7Hz), 6.80 (d, 1H, J = 6.6Hz), 6.63-6.56 (m, 3H), 4.15 (q, 1H, J = 8Hz), 3.92 (d, 1H, J = 2.2Hz), 3.8-3.75 (m, 1H), 3.6-3.53 (m, 1H), 3.39 (d, 2H, J = 2.2Hz), 3.3-3.25 (m, 1H), 3.2-3.12 (m, 2H), 3.1-2.9 (m, 1H), 2.7-2.59 (m, 2H), 2.3-2.22 (m, 1H), 2.1-2.07 (m, 1H) , 2.04 (s, 2H), 2.01 (s, 1H), 1.98-1.88 (m, 3H), 1.25 (t, 1H, J = 7.1Hz) ppm. Mass spectrometry (ESI): 427 (base, M + H). [0650] (Example 39) cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH)-carboxylate [0651] cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole (0.320g, 1.3mmol), 1M K₂CO₃CH at 0 ° C with aqueous solution (15.6 mL)₂Cl₂Dissolved in (15 mL). Ethyl chloroformate (0.423 g, 3.92 mmol) was then added slowly and the reaction was allowed to warm to room temperature over 2 hours. Separate the aqueous layer and the organic layer. CHCl the water layer₃Extracted with (3 x 15 mL). Wash the combined extracts with water and dry (Na₂SO₄), When evaporated, the title compound (0.480 g, 100%) was obtained.¹H NMR (CD)₃OD, 300MHz) δ6.87 (d, 2H, J = 7.3Hz), 6.58 (t, 1H, J = 7.3Hz), 4.0-4.17 (m, 2H), 3.55-3.82 (m, 3H), 3.28- 3.47 (m, 4H), 3.15-3.28 (m, 3H), 2.81-1.93 (m, 1H), 1.92-2.19 (m, 2H), 1.82-1.9 (m, 2H), 1.19 (t, 3H, J = 6.6Hz) ppm. [0652] (Example 40) cis- (8a, 12a) -2-acetyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole-11 (8aH) -Ethyl Carbonate [0653] AlCl₃(0.359g, 2.7 mmol) CH₂Cl₂Add acetyl chloride (0.133 g, 1.78 mmol) to the (1.7 mL) solution and stir for 30 minutes. This solution was then applied to Example 39 cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2]. , 3,4-hi] Indole-11 (8aH) -ethyl carbonate (0.285g, 0.89 mmol) CH₂Cl₂It was added to the (0.8 mL) solution and refluxed for 2 hours. Ice was added to separate the aqueous and organic layers. CHCl the water layer₃Extracted with (3 x 20 mL). The combined extracts were washed with saline and dried (Na).₂SO₄) When evaporated, oil remains, which is preparative silica gel TLC (2% MeOH / CH)₂Cl₂). The title compound was obtained in a yield of 27% (87 mg).¹H NMR (CD)₃OD, 300MHz) δ7.56 (d, 1H, J = 1.5Hz), 7.51 (d, 1H, J = 1.5Hz), 3.92-4.16 (m, 3H), 3.52-3.81 (m, 4H), 3.29- 3.52 (m, 4H), 2.98-3.08 (m, 1H), 2.21 (s, 3H), 2.02-2.18 (m, 2H), 1.83-1.95 (m, 2H), 1.12-1.20 (m, 3H) ppm .. [0654] (Example 41) cis- (8a, 12a) -2- (acetylamino) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indole-11 (8aH) -Ethyl Carbonate [0655] cis- (8a, 12a) -2-acetyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole-11 (8aH) -ethyl carbonate (0.088 g, 0.24 mmol) was dissolved in methanesulfonate (1.2 mL). NaN₃(0.031 g, 0.48 mmol) was added slowly. The reaction was stirred at room temperature for 1 hour. Add ice and CHCl the aqueous layer₃Extracted with (3 x 10 mL). The combined extracts are washed with saline and water and dried (Na).₂SO₄) Evaporation gave the title compound (0.063 g, 69%).¹H NMR (CD)₃OD, 300MHz) δ6.95-7.19 (m, 2H), 4.0-4.13 (m, 2H), 3.95 (br.s, 1H), 3.56-3.65 (m, 2H), 3.32-3.48 (m, 4H) , 3.10-3.23 (m3H), 2.82-2.92 (m, 1H), 2.0-2.18 (m, 2H), 2.03 (s, 3H), 2.84-2.96 (m, 2H), 1.98 (t, 3H, J = 6.5Hz) ppm. [0656] (Example 42) cis- (8a, 12a) -11- [2- (4-fluorophenyl) ethyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0657] (Step A) CH 4-fluorophenethyl alcohol (2.0 g, 14.2 mmol) with catalytic amounts of DMAP and triethylamine (2.2 g, 21.3 mmol)₂Cl₂Dissolved in (12 mL). The reaction was cooled to 0 ° C. and methanesulfonyl chloride (1.9 g, 17.0 mmol) was added slowly. The reaction was brought to room temperature and stirred for 2 hours. The reaction was partitioned between water and EtOAC. The aqueous layer was extracted with EtOAc (3 x 50 mL), the combined extracts were washed with saline and water and dried (Na).₂SO₄) Evaporation gave 4-fluorophenethylmethane sulfonate (2.5 g, 89%) as a pale yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ7.21 (d, 1H, J = 5.2Hz), 7.18 (d, 1H, J = 5.1Hz), 7.01 (t, 2H, J = 8.8Hz), 4.41 (t, 2H, J = 6.6) Hz), 3.03 (t, 2H, J = 6.7Hz), 2.88 (s, 3H) ppm. [0658] (Step B) cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole (0.100 g, 0.408 mmol), 4-fluorophenethylmethane sulfonate (0.106 g, 0.489 mmol) and K₂CO₃It was dissolved in 1,4 dioxane (3 mL) with (0.281 g, 2.04 mmol) and refluxed overnight. The reaction was cooled and the inorganic material was filtered. CHCl the filtrate₃Dilute with (10 mL), wash with saline and water, and dry (Na)₂SO₄) Evaporated. Separation of residue Silica gel TLC (10% MeOH / CHCl)₃), The title compound (0.047 g, 31%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ7.14 (m, 2H), 6.95-7.02 (m, 3H), 6.87 (d, 1H, J = 7Hz), 6.63 (t, 1H, J = 7.3Hz), 3.78-3.92 (m, 1H), 3.56-3.63 (m, 1H), 3.25-3.33 (m, 1H), 3.17-3.22 (m, 1H), 3.03-3.17 (m, 1H), 2.89-3.0 (m, 1H), 2.65- 2.90 (m, 4H), 2.45-2.63 (m, 2H), 2.32 (dt, 1H, J = 6.6, 4.4Hz), 1.91-2.20 (m, 5H) ppm. [0659] (Example 43) (General procedure) cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole (1.0 molar equivalent) in a 1,4-dioxane solution with alkyl halide or mesylate (1.3-2.0 molar equivalent), KI (catalytic equivalent) and K₂CO₃(1.5 molar equivalents) was added. The reaction mixture was heated at 100 ° C. for 1.5-2.5 days. Cool the reaction mixture to 20 ° C, then CHCl₃Diluted with. Filter the solution for excess K₂CO₃Remove, concentrate the filtrate in vacuo, CHCl₃Chromatography on a silica gel column by eluting with / MeOH gave the title compound. [0660] (General procedure for mesylation) CH of alcohol (1.0 molar equivalent)₂Cl₂Solution and Et₃To N (2.0 molar equivalent), N₂Methanesulfonyl chloride (1.5 molar equivalents) was added at 0 ° C. in the atmosphere. The reaction mixture was stirred at 0 ° C. for 1-4 hours and quenched by the addition of 1N HCl. Separate the layers and Et the water layer₂Extracted with O. Combined organic solution H₂Washed with O and saline. Then the organic layer is PEG₄Chromatography on a silica gel column by drying in, filtering, concentrating in vacuo and eluting with EtOAc / Hexane gave the title compound. [0661] (General procedure for bromination) Alcohol (1.0 molar equivalent) and Ph₃In a DMF solution of P (1.05 molar equivalent), N₂Br at 0 ° C in the atmosphere until the solution remains orange₂Was added dropwise. The reaction mixture is stirred at 20 ° C for 30 minutes and H₂Quenched by adding O. The layers were separated and the aqueous layer was extracted with hexane. Combined organic solution H₂Washed with O and saline. Then the organic layer is PEG₄Chromatography on a silica gel column by drying in, filtering, concentrating in vacuo and eluting with EtOAc / Hexane gave the title compound. [0662] cis- (8a, 12a) -11-ethyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0663] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (25 mg, 0.10 mmol) and bromoethane (25 mg, 0.23 mmol) were prepared as pale yellow oil (20 mg, 73%).¹1 H NMR (CDCl₃, 300MHz) δ1.11 (t, 3H, J = 6.9Hz), 1.87 (t, 1H, J = 10.6Hz), 1.94-2.20 (m, 4H), 2.22-2.35 (m, 1H), 2.43 (dq) , 2HJ = 2.2,7.0Hz), 2.72-2.80 (m, 1H), 2.83 (ddd, 1HJ = 1.8,5.9,11.7Hz), 2.93 (ddd, 1H, J = 3.3,5.9,14.3Hz), 3.04 ( ddd, 1H, J = 2.6,5.5,13.6Hz), 3.20-3.30 (m, 2H), 3.55 (ddd, 1H, J = 5.5,10.5, 16.1Hz), 3.83 (ddd, 1H, J = 4.4,10.7) , 15.3Hz), 6.62 (t, 1H, J = 7.7Hz), 6.87 (dd, 1H, J = 0.8,7.4Hz), 6.95 (dd, 1H, J = 1.5,8.1Hz) ppm. [0664] (Example 44) cis- (8a, 12a) -11-propyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0665] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (23 mg, 0.093 mmol) and 1-bromopropane (23 mg, 0.19 mmol) were prepared as pale yellow oil (20 mg, 74%).¹1 H NMR (CDCl₃, 300MHz) δ0.89 (t, 3H, J = 7.4Hz), 1.55 (se, 1H, J = 8.4Hz), 1.85-2.20 (m, 5H), 2.22-2.40 (m, 3H), 2.72- 2.77 (m, 1H), 2.83 (ddd, 1H, J = 1.8,6.0,11.6Hz), 2.93 (ddd, 1H, J = 3.7,5.5,14.3Hz), 3.05 (ddd, 1H, J = 2.6,5.1) , 13.5Hz), 3.17-3.30 (m, 2H), 3.55 (ddd, 1H, J = 5.6, 10.6, 16.1Hz), 3.82 (ddd, 1H, J = 4.0, 11.0, 15.0Hz), 6.62 (t, 1H, J = 7.7Hz), 6.86 (d, 1H, J = 7.0Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0666] (Example 45) cis- (8a, 12a) -11-Butyl-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3] , 4-hi] Indole [0667] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (11 mg, 0.047 mmol) and 1-Bromobutane (9.6 mg, 0.071 mmol) prepared as pale yellow oil (5.0 mg, 32%). ..¹1 H NMR (CDCl₃, 300MHz) δ0.92 (t, 3H, J = 7.3Hz), 1.32 (se, 1H, J = 7.7Hz), 1.57 (qu, 2H, J = 7.7Hz), 1.90-2.22 (m, 5H), 2.35-2.50 (m, 3H), 2.80-3.00 (m, 3H), 3.02-3.10 (m, 1H), 3.30-3.40 (m, 2H), 3.55 (ddd, 1H, J = 5.5,10.7, 16.2Hz ), 3.83 (ddd, 1H, J = 4.0,11.0,15.0Hz), 6.63 (t, 1H, J = 7.3Hz), 6.87 (dd, 1H, J = 0.8,7.0Hz), 6.96 (dd, 1H, J = 1.1,7.7Hz) ppm. [0668] (Example 46) cis- (8a, 12a) -11- Pentyl-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3] , 4-hi] Indole [0669] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (26 mg, 0.11 mmol) and 1-bromopentane (32 mg, 0.21 mmol) were prepared as pale yellow oil (30 mg, 90%).¹1 H NMR (CDCl₃, 300MHz) δ0.88 (t, 3H, J = 6.9Hz), 1.20-1.37 (m, 4H), 1.54 (qu, 2H, J = 7.7Hz), 1.85-2.20 (m, 5H), 2.22-2.40 (m, 3H), 2.70-2.85 (m, 2H), 2.93 (ddd, 1H, J = 3.3,5.5,14.2Hz), 3.04 (ddd, 1H, J = 2.2,5.1,13.6Hz), 3.18-3.30 (m, 2H), 3.55 (ddd, 1H, J = 5.2,10.7,15.8Hz), 3.82 (ddd,1H, J = 4.4,11.4,15.4Hz), 6.62 (t, 1H, J = 7.4Hz), 6.86 (d, 1H, J = 6.2Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0670] (Example 47) cis- (8a, 12a) -11-hexyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0671] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (29 mg, 0.12 mmol) and 1-Bromohexane (40 mg, 0.24 mmol) were prepared as pale yellow oil (32 mg, 82%).¹1 H NMR (CDCl₃, 300MHz) δ0.87 (t, 3H, J = 6.9Hz), 1.22-1.37 (m, 6H), 1.54-0.64 (m, 2H), 1.90-2.20 (m, 5H), 2.33-2.50 (m, 3H), 2.80-2.97 (m, 3H), 3.04 (ddd, 1H, J = 2.6,5.1,13.5Hz), 3.16-3.40 (m, 2H), 3.54 (ddd, 1H, J = 5.5,10.6,15.8) Hz), 3.83 (ddd, 1H, J = 4.4,11.3,15.4Hz), 6.64 (t, 1H, J = 7.7Hz), 6.87 (dd, 1H, J = 1.1,7.3Hz), 6.96 (dd, 1H) , J = 1.1,7.7Hz) ppm. [0672] (Example 48) cis- (8a, 12a) -11- (2-propyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0673] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (15.7 mg, 0.064 mmol) and 2-bromopropane (12 mg, 0.10 mmol) prepared as pale yellow oil (13 mg, 71%). ..¹1 H NMR (CDCl₃, 300MHz) δ0.98 (d, 3H, J = 2.6Hz), 1.00 (d, 3H, J = 2.6Hz), 1.87-2.15 (m, 5H), 2.35-2.45 (m, 1H), 2.60-2.80 (m, 3H), 2.86 (ddd, 1H, J = 3.3,5.4,14.2Hz), 2.97 (ddd, 1H, J = 2.6,5.5,13.2Hz), 3.13-3.25 (m, 2H), 3.50 (ddd) , 1H, J = 5.5,11.0,16.1Hz), 3.76 (ddd, 1H, J = 4.0,10.9,15.3Hz), 6.56 (t, 1H, J = 7.3Hz), 6.81 (dd, 1H, J = 1.1) , 7.3Hz), 6.89 (dd, 1H, J = 1.1,7.6Hz) ppm. [0674] (Example 49) cis- (8a, 12a) -11-sec-butyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2 , 3,4-hi] Indole [0675] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (23 mg, 0.93 mmol) and 2-Bromobutane (21 mg, 0.19 mmol) were prepared as pale yellow oil (9.0 mg, 32%).¹1 H NMR (CDCl₃, 300MHz) δ0.86-0.98 (m, 6H), 1.21-1.37 (m, 1H), 1.55-1.70 (m, 1H), 1.85-2.22 (m, 6H), 2.42-2.77 (m, 3H), 2.87-2.97 (m, 1H), 3.00-3.13 (m, 1H), 3.15-3.31 (m, 2H), 3.50-3.63 (m, 1H), 3.78-3.87 (m, 1H), 6.62 (t, 1H) , J = 7.4Hz), 6.86 (d, 1H, J = 7.4Hz), 6.95 (dd, 1H, J = 1.1,8.1Hz) ppm. [0676] (Example 50) cis- (8a, 12a) -11- (1-methylbutyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0677] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (30 mg, 0.12 mmol) and 2-bromopentane (37 mg, 0.24 mmol) were prepared as pale yellow oil (23 mg, 61%).¹1 H NMR (CDCl₃, 300MHz) δ0.91 (t, 3H, J = 6.8Hz), 1.01 (t, 3H, J = 5.9Hz), 1.21-1.40 (m, 3H), 1.55-1.70 (m, 1H), 1.85-2.22 (m, 6H), 2.52-2.80 (m, 3H), 2.85-2.96 (m, 1H), 3.02-3.13 (m, 1H), 3.29 (m, 2H), 3.52-3.65 (m, 1H), 3.78 -3.87 (m, 1H), 6.64 (t, 1H, J = 7.7Hz), 6.86 (d, 1H, J = 6.9Hz), 6.96 (d, 1H, J = 7.7Hz) ppm. [0678] (Example 51) cis- (8a, 12a) -11- (1-methylpentyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0679] (Step A) 2-Hexyl methane sulfonate. The title compound was prepared as a colorless oil (408 mg, 68%) from 2-hexanol (312 mg, 2.90 mmol) and methanesulfonyl chloride (500 mg, 4.40 mmol) by following the general procedure for mesylation of Example 43.¹1 H NMR (CDCl₃, 300MHz) δ0.89-0.94 (m, 3H), 1.31-1.43 (m, 5H), 1.57-1.71 (m, 4H), 2.99 (s, 3H), 4.76-4.82 (m, 1H) ppm. [0680] (Step B) The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] thiazepino [2,3,4-hi] from indole (30 mg, 0.12 mmol) and 2- (methylsulfonyl) hexane (66 mg, 0.37 mmol) as pale yellow oil (25 mg, 62%) Prepared.¹1 H NMR (CDCl₃, 300MHz) δ0.80-0.90 (m, 6H), 1.13-1.25 (m, 5H), 1.45-1.60 (m, 2H), 1.85-2.20 (m, 6H), 2.50-2.70 (m, 2H), 2.84-2.89 (m, 1H), 2.96-3.05 (m, 1H), 3.14-3.24 (m, 2H), 3.44-3.54 (m, 1H), 3.69-3.79 (m, 1H), 6.56 (t, 1H) , J = 7.7Hz), 6.80 (d, 1H, J = 6.9Hz), 6.88 (d, 1H, J = 7.6Hz) ppm. [0681] (Example 52) cis- (8a, 12a) -11-isobutyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0682] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (25 mg, 0.10 mmol) and 1-bromo-2-methylpropane (28 mg, 0.20 mmol) to pale yellow oil (23 mg, 75%) Prepared as.¹1 H NMR (CDCl₃, 300MHz) δ0.88-0.92 (m, 6H), 1.75-1.93 (m, 3H), 1.95-2.23 (m, 6H), 2.55-2.62 (m, 1H), 2.68 (dd, 1H, J = 6.2 , 11.3Hz), 2.95 (ddd, 1H, J = 3.6,5.8,14.6Hz), 3.02-3.19 (m, 2H), 3.26 (qu, 1H, J = 3.3Hz), 3.54 (ddd, 1H, J = 5.1,10.2,14.3Hz), 3.81 (ddd, 1H, J = 4.4,11.0,14.0Hz), 6.61 (t, 1H, J = 7.3Hz), 6.85 (d, 1H, J = 6.9Hz), 6.93 ( dd, 1H, J = 1.1, 7.7Hz) ppm. [0683] (Example 53) cis- (8a, 12a) -11-[(1S) -1-methylpropyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0684] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and (S)-(+)-1-bromo-2-methylbutane (36 mg, 0.24 mmol) to pale yellow Prepared as oil (26 mg, 68%).¹1 H NMR (CDCl₃, 300MHz) δ0.84-0.92 (m, 6H), 1.01-1.17 (m, 1H), 1.38-50 (m, 1H), 1.52-1.67 (m, 1H), 1.79-1.93 (m, 3H), 1.95-2.22 (m, 5H), 2.55-2.63 (m, 1H), 2.62-2.73 (m, 1H), 2.88-2.99 (m, 1H), 3.02-3.19 (m, 2H), 3.21-3.29 (m) , 1H), 3.50-3.61 (m, 1H), 3.78-3.85 (m, 1H), 6.61 (t, 1H, J = 7.4Hz), 6.85 (d, 1H, J = 6.9Hz), 6.94 (dd, dd, 1H, J = 1.1,8.1Hz) ppm. [0685] (Example 54) cis- (8a, 12a) -11- (2-methylpentyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0686] (Step A) 2-Methyl-1-pentylmethane sulfonate. The title compound is a colorless oil (856 mg, 89%) from 2-methyl-1-pentanol (497 mg, 4.90 mmol) and methanesulfonyl chloride (821 mg, 7.30 mmol) by following the general procedure for mesylation of Example 43. ).¹1 H NMR (CDCl₃, 300MHz) δ0.89-0.93 (m, 3H), 0.98 (d, 3H, J = 6.6Hz), 1.15-1.43 (m, 4H), 1.88-1.90 (m, 1H), 3.00 (s, 3H) , 3.98-4.11 (m, 2H) ppm. [0687] (Step B) The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (52 mg, 0.20 mmol) and 2-methyl-1- (methylsulfonyl) pentane (73 mg, 0.40 mmol) to pale yellow oil (60 mg, 89%).¹1 H NMR (CDCl₃, 300MHz) δ0.87-0.92 (m, 6H), 1.00-1.06 (m, 2H), 1.21-1.38 (m, 3H), 1.55-1.65 (m, 2H), 1.77-1.88 (m, 2H), 1.95-2.19 (m, 4H), 2.51-2.59 (m, 1H), 2.62-2.68 (m, 1H), 2.91-2.98 (m, 1H), 3.05-3.16 (m, 2H), 3.24-3.27 (m) , 1H), 3.49-3.59 (m, 1H), 3.76-3.85 (m, 1H), 6.61 (t, 1H, J = 7.7), 6.85 (d, 1H, J = 7.4), 6.93 (dd, 1H, J = 1.1,7.7) ppm. [0688] (Example 55) cis- (8a, 12a) -11- (2-ethylbutyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0689] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] thiazepino [2,3,4-hi] from indole (30 mg, 0.12 mmol) and 1-bromo-2-ethylbutane (40 mg, 0.24 mmol) as pale yellow oil (24 mg, 61%) Prepared.¹1 H NMR (CDCl₃, 300MHz) δ0.78-0.92 (m, 6H), 1.25-1.43 (m, 5H), 1.77-1.93 (m, 3H), 1.95-2.23 (m, 5H), 2.55-2.61 (m, 1H), 2.68 (dd, 1H, J = 6.6, 11.3Hz), 2.95 (ddd, 1H, J = 3.6, 5.8, 14.6Hz), 3.02-3.19 (m, 2H), 3.26 (qu, 1H, J = 3.3Hz) , 3.55 (ddd, 1H, J = 5.2,10.3,15.8Hz), 3.81 (ddd,1H, J = 4.1,10.7,14.0Hz), 6.61 (t, 1H, J = 7.7Hz), 6.85 (d, 1H) , J = 7.0Hz), 6.94 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0690] (Example 56) cis- (8a, 12a) -11- (2-methylpentyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0691] (Step A) 3-Methyl-1-pentylmethane sulfonate. The title compound is a colorless oil (384 mg, 67%) from 3-methyl-1-pentanol (300 mg, 2.90 mmol) and methanesulfonyl chloride (500 mg, 4.40 mmol) by following the general procedure for mesylation of Example 43. ).¹1 H NMR (CDCl₃, 300MHz) δ0.86-0.95 (m, 6H), 1.15-1.25 (m, 1H), 1.33-1.42 (m, 1H), 1.51-1.60 (m, 2H), 1.76-1.84 (m, 1H), 3.00 (s, 3H), 4.23-4.31 (m, 2H) ppm. [0692] (Step B) The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and 3-methyl-1- (methylsulfonyl) pentane (68 mg, 0.36 mmol) to pale yellow oil (29 mg, 72%).¹1 H NMR (CDCl₃, 300MHz) δ0.84-0.88 (m, 6H), 1.12-1.18 (m, 1H), 1.28-1.38 (m, 2H), 1.50-1.60 (m, 3H), 1.84-1.99 (m, 3H), 2.01-2.14 (m, 2H), 2.25-2.34 (m, 2H), 2.66-2.70 (m, 1H), 2.76-2.80 (m, 1H), 2.90-2.97 (m, 1H), 3.02-3.08 (m) , 1H), 3.13-3.18 (m, 1H), 3.25-3.29 (m, 1H), 3.51-3.61 (m, 1H), 3.78-3.88 (m, 1H), 6.62 (t, 1H, J = 7.6Hz) ), 6.86 (d, 1H, J = 6.9Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz). [0693] (Example 57) cis- (8a, 12a) -11- (3-methylbutyl)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0694] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] thiazepino [2,3,4-hi] from indole (29 mg, 0.12 mmol) and 1-bromo-3-ethylbutane (36 mg, 0.24 mmol) as pale yellow oil (27 mg, 73%) Prepared.¹1 H NMR (CDCl₃, 300MHz) δ0.88 (d, 3H, J = 6.6Hz), 0.89 (d, 3H, J = 6.6Hz), 1.38-1.47 (m, 2H), 1.43 (he, 1H, J = 4.4), 1.84 -2.17 (m, 5H), 2.23-2.40 (m, 3H), 2.70-2.78 (m, 1H), 2.81 (dd, 1H, J = 5.8, 11.0Hz), 2.93 (ddd, 1H, J = 3.6, 5.8,14.6Hz), 3.04 (ddd, 1H, J = 2.5,5.1,13.5), 3.19-3.29 (m, 2H), 3.55 (ddd, 1H, J = 5.5,11.0,16.1Hz), 3.83 (ddd, 1H, J = 4.4,11.0,15.4Hz), 6.62 (t, 1H, J = 7.7Hz), 6.86 (d, 1H, J = 6.6Hz), 6.95 (dd, 1H, J = 1.1,7.7Hz) ppm .. [0695] (Example 58) cis- (8a, 12a) -11- (4-methylpentyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0696] (Step A) 4-Methyl-1-pentylmethane sulfonate. The title compound is a colorless oil (620 mg, 63%) from 4-methyl-1-pentanol (511 mg, 5.00 mmol) and methanesulfonyl chloride (844 mg, 7.50 mmol) by following the general procedure for mesylation of Example 43. ).¹1 H NMR (CDCl₃, 300MHz) δ0.88 (d, 6H, J = 4.7Hz), 1.23-1.31 (m, 2H), 1.53-1.62 (m, 1H), 1.70-1.80 (m, 2H), 3.00 (s, 3H) , 4.21 (t, 2H, J = 6.6Hz) ppm [0697] (Step B) The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] thiazepino [2,3,4-hi] indole (53 mg, 0.20 mmol) and 4-methyl-1- (methylsulfonyl) pentane (77 mg, 0.40 mmol) to pale yellow oil (46 mg, 69%).¹1 H NMR (CDCl₃, 300MHz) δ0.87 (d, 6H, J = 6.6Hz), 1.15 (m, 3H), 1.44-1.56 (m, 3H), 1.81-1.94 (m, 3H), 2.00-2.13 (m, 2H) , 2.23-2.30 (m, 2H), 2.66-2.69 (m, 1H), 2.74-2.80 (m, 1H), 2.93 (m, 1H), 3.05 (m, 1H), 3.14-3.18 (m, 1H) , 3.25-3.28 (m, 1H), 3.56 (ddd, 1H, J = 5.5, 10.6, 15.7Hz), 3.82 (ddd, 1H, J = 4.0, 11.0, 15.0Hz), 6.62 (t, 1H, J = 7.7Hz), 6.86 (d, 1H, J = 7.0Hz), 6.94 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0698] (Example 59) cis- (8a, 12a) -11- (cyclopropylmethyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0699] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (30 mg, 0.12 mmol) and (bromomethyl) cyclopropane (25 mg, 0.19 mmol) prepared as pale yellow oil (26 mg, 72%) ..¹1 H NMR (CDCl₃, 300MHz) δ0.18 (d, 2H, J = 5.8Hz), 0.60 (dd, 2H, J = 1.5,8.5), 0.97-1.06 (m, 1H), 1.98-2.27 (m, 5H), 2.41 ( d, 2H, J = 6.6Hz), 2.48 (t, 1H, J = 11.7Hz), 2.92 (ddd, 1H, J = 3.3,5.5,14.2Hz), 3.01-3.15 (m, 3H), 3.31-3.37 (m, 1H), 3.38-3.47 (m, 1H), 3.54 (ddd, 1H, J = 5.1,10.6,15.8Hz), 3.83 (ddd, 1H, J = 4.0,11.0,15.3Hz), 6.65 (t , 1H, J = 7.7Hz), 6.89 (dd, 1H, J = 0.7,7.3Hz), 6.97 (dd, 1H, J = 1.5,8.0Hz) ppm. [0700] (Example 60) cis- (8a, 12a) -11- (cyclobutylmethyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0701] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (14 mg, 0.054 mmol) and (bromomethyl) cyclopropane (13 mg, 0.084 mmol) prepared as pale yellow oil (14 mg, 82%) ..¹1 H NMR (CDCl₃, 300MHz) δ1.62-1.95 (m, 7H), 1.97-2.27 (m, 5H), 2.37 (d, 2H, J = 6.7Hz), 2.48-2.75 (m, 3H), 2.95 (ddd, 1H, J = 3.2,5.7,14.3Hz), 3.06 (ddd, 1H, J = 2.3,5.6,14.5), 3.11-3.20 (m, 1H), 3.23 (qu, 1H, J = 3.3Hz), 3.55 (ddd, 1H, J = 5.4,10.6,15.7Hz), 3.81 (ddd, 1H, J = 4.4,11.0,15.0Hz), 6.61 (t, 1H, J = 7.4Hz), 6.84 (d, 1H, J = 7.3Hz) ), 6.94 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0702] (Example 61) cis- (8a, 12a) -11- (cyclohexylmethyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole [0703] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (22 mg, 0.089 mmol) and (bromomethyl) cyclohexane (18 mg, 0.10 mmol) were prepared as pale yellow oil (24 mg, 78%).¹1 H NMR (CDCl₃, 300MHz) δ0.86 (q, 2H, J = 11.0Hz), 1.13-1.30 (m, 3H), 1.42-1.57 (m, 1H), 1.60-1.93 (m, 9H), 1.95-2.20 (m, 4H), 2.55-2.60 (m, 1H), 2.63-2.73 (m, 1H), 2.94 (ddd, 1H, J = 3.6, 5.8, 14.2Hz), 3.02-3.20 (m, 2H), 3.24 (qu, 1H, J = 3.3Hz), 3.55 (ddd, 1H, J = 5.5,10.6,15.8Hz), 3.81 (ddd, 1H, J = 4.1,11.0,13.6Hz), 6.61 (t, 1H, J = 7.3Hz) ), 6.86 (d, 1H, J = 6.6Hz), 6.93 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0704] (Example 62) cis- (8a, 12a) -11-allyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0705] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (19 mg, 0.077 mmol) and allyl bromide (14 mg, 0.12 mmol) were prepared as pale yellow oil (10 mg, 45%).¹1 H NMR (CDCl₃, 300MHz) δ1.84 (t, 1H, J = 11Hz), 1.89-2.17 (m, 4H), 2.24 (dt, 1H, J = 4.4,8.4Hz), 2.63-2.74 (m, 1H), 2.78 ( ddd, 1H, J = 1.8,6.2,12.1Hz), 2.90-3.00 (m, 3H), 3.02-3.10 (m, 1H), 3.12-3.20 (m, 1H), 3.27 (qu, 1H, J = 2.8) Hz), 3.56 (ddd, 1H, J = 5.1,10.6,15.7Hz), 3.83 (ddd, 1H, J = 4.4,11.3,15.0Hz), 5.12 (d, 1H, J = 1.1Hz), 5.17 (dd , 1H, J = 1.1,4.8Hz), 5.80-5.95 (m, 1H), 6.62 (t, 1H, J = 7.7Hz), 6.86 (d, 1H, J = 7.4Hz), 6.95 (dd, 1H, J = 1.1,7.7Hz) ppm. [0706] (Example 63) cis- (8a, 12a) -11- (2-methyl-2-propenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [0707] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (25 mg, 0.10 mmol) and 3-bromo-2-methylpropene (21 mg, 0.16 mmol) to pale yellow oil (23 mg, 77%) Prepared as.¹1 H NMR (CDCl₃, 300MHz) δ1.76 (s, 3H), 1.79-1.95 (m, 3H), 2.00-2.21 (m, 3H), 2.50-2.61 (m, 1H), 2.68 (dd, 1H, J = 6.2,12.3) Hz), 2.82 (s, 2H), 2.95 (ddd, 1H, J = 3.3,5.5,14.3Hz), 3.02-3.20 (m, 3H), 3.27 (qu, 1H, J = 3.3Hz), 3.55 (ddd) , 1H, J = 5.5,10.6,15.7Hz),3.82 (ddd,1H, J = 4.0,10.6,15.0Hz), 4.84 (s, 2H), 6.61 (t, 1H, J = 7.4Hz), 6.85 ( d, 1H, J = 7.3Hz), 6.94 (dd, 1H, J = 1.5,8.1Hz) ppm [0708] (Example 64) cis- (8a, 12a) -11-[(2E) -2-butenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [0709] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (19 mg, 0.077 mmol) and trans-1-chloro-2-pentene (7.1 mg, 0.078 mmol) to pale yellow oil (14 mg, 61 mmol) %) Was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.69 (d, 3H, J = 5.1Hz), 1.80-2.25 (m, 6H), 2.68-2.75 (m, 1H), 2.76-2.85 (m, 1H), 2.86-3.05 (m, 4H), 3.10-3.21 (m, 1H), 3.27 (qu, 1H, J = 3.6Hz), 3.55-3.63 (m, 1H), 3.78-3.88 (m, 1H), 5.43-5.72 (m, 2H) , 6.62 (t, 1H, J = 7.4Hz), 6.86 (d, 1H, J = 7.0Hz), 6.95 (dd, 1H, J = 1.7, 7.7Hz) ppm. [0710] (Example 65) cis- (8a, 12a) -11- (3-methyl-2-butenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [0711] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (61 mg, 0.25 mmol) and 4-bromo-2-methyl-2-butene (55 mg, 0.37 mmol) to pale yellow oil (66 mg, 85%).¹1 H NMR (CDCl₃, 300MHz) δ1.61 (s, 3H), 1.74 (s, 3H), 1.81 (t, 1H, J = 11.0Hz), 1.90-1.97 (m, 2H), 2.00-2.23 (m, 3H), 2.65 -2.73 (m, 1H), 2.78 (ddd, 1H, J = 1.8, 6.2, 11.4Hz), 2.86-2.97 (m, 3H), 3.02-3.10 (m, 1H), 3.15 (dt, 1H, J = 6.9,10.6Hz), 3.26 (qu, 1H, J = 3.6Hz), 3.57 (ddd, 1H, J = 5.2,9.6,16.1Hz), 3.83 (ddd, 1H, J = 4.1,11.0,13.6Hz), 5.24--5.28 (m, 1H), 6.62 (t, 1H, J = 7.7Hz), 6.86 (dd, 1H, J = 0.7, 7.3Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz) ppm .. [0712] (Example 66) cis- (8a, 12a) -11- (3-butenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0713] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] indole (22 mg, 0.089 mmol) and 4-bromo-1-butene (19 mg, 0.14 mmol) as pale yellow oil (18 mg, 67%) Prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.84-1.95 (m, 3H), 2.01-2.20 (m, 2H), 2.24-2.33 (m, 3H), 2.37-2.44 (m, 2H), 2.63-2.74 (m, 1H), 2.70-2.82 (m, 1H), 2.90-2.99 (m, 1H), 3.02-3.20 (m, 2H), 3.27 (qu, 1H, J = 2.9Hz), 3.56 (ddd, 1H, J = 5.5,10.7) , 16.1Hz), 3.83 (ddd, 1H, J = 4.0,11.0,15.0Hz), 5.01 (dd, 1H, J = 1.1,10.2Hz), 5.08 (dd, 1H, J = 1.1,15.4Hz), 5.75 -5.85 (m, 1H), 6.62 (t, 1H, J = 7.3Hz), 6.86 (d, 1H, J = 6.6Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0714] (Example 67) cis- (8a, 12a) -11-[(2E) -2-pentenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [0715] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (27 mg, 0.11 mmol) and trans-1-bromo-2-pentene (25 mg, 0.17 mmol) to pale yellow oil (20 mg, 58%) ).¹1 H NMR (CDCl₃, 300MHz) δ0.99 (t, 3H, J = 7.7Hz), 1.81 (t, 1H, J = 9.0Hz), 1.87-2.22 (m, 7H), 2.67-2.75 (m, 1H), 2.76-2.83 (m, 1H), 2.85-3.00 (m, 3H), 3.02-3.10 (m, 1H), 3.10-3.21 (m, 1H), 3.27 (qu, 1H, J = 3.0Hz), 3.56 (ddd, 1H) , J = 5.1, 10.1, 15.8Hz), 3.83 (ddd, 1H, J = 4.0, 11.0, 13.5Hz), 5.43-5.72 (m, 2H), 6.62 (t, 1H, J = 7.3Hz), 6.86 ( d, 1H, J = 6.6Hz), 6.94 (dd, 1H, J = 1.1,6.7Hz) ppm. [0716] (Example 68) cis- (8a, 12a) -11-[(2Z) -2-pentenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [0717] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (25 mg, 0.10 mmol) and cis-1-bromo-2-pentene (30 mg, 0.20 mmol) to pale yellow oil (20 mg, 63%) ).¹1 H NMR (CDCl₃, 300MHz) δ0.94 (t, 3H, J = 7.4Hz), 1.83 (t, 1H, J = 11.0Hz), 1.89-2.28 (m, 7H), 2.67-2.75 (m, 1H), 2.76-2.82 (m, 1H), 2.85-3.10 (m, 4H), 3.12-3.23 (m, 1H), 3.27 (qu, 1H, J = 3.0Hz), 3.56 (ddd, 1H, J = 5.2,10.7,15.8Hz ), 3.82 (ddd, 1H, J = 4.0,11.0,13.5Hz), 5.40-5.65 (m, 2H), 6.62 (t, 1H, J = 7.7Hz), 6.86 (d, 1H, J = 6.7Hz) , 6.94 (dd, 1H, J = 0.7, 7.7Hz) ppm. [0718] (Example 69) cis- (8a, 12a) -11- (4-pentenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0719] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] from indole (63 mg, 0.26 mmol) and 5-bromo-1-pentene (57 mg, 0.39 mmol) as pale yellow oil (68 mg, 85%) Prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.62 (qu, 2H, J = 8.0Hz), 1.85-2.20 (m, 7H), 2.22-2.38 (m, 3H), 2.66-2.74 (m, 1H), 2.73-2.82 (m, 1H), 2.85-2.95 (m, 1H), 3.02-3.13 (m, 1H), 3.15-3.23 (m, 1H), 3.27 (qu, 1H, J = 3.3Hz), 3.55 (ddd, 1H, J = 5.5,10.6,15.7Hz),3.82 (ddd, 1H, J = 4.3,11.0,13.9Hz), 4.93-5.07 (m, 2H), 5.75-5.85 (m, 1H), 6.62 (t, 1H, J = 7.3Hz), 6.86 (d, 1H, J = 6.6Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0720] (Example 70) cis- (8a, 12a) -11- (4-methyl-3-pentenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [0721] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (24 mg, 0.097 mmol) and 5-bromo-2-methyl-2-pentene (18 mg, 0.11 mmol) to pale yellow oil (23 mg, 74%).¹1 H NMR (CDCl₃, 300MHz) δ1.61 (s, 3H), 1.68 (s, 3H), 1.83-2.38 (m, 10H), 2.67-2.76 (m, 1H), 2.79 (ddd, 1H, J = 1.4,6.2,11.3) Hz), 2.85-2.97 (m, 1H), 3.02-3.12 (m, 1H), 3.18 (dt, 1H, J = 6.2, 10.6Hz), 3.27 (qu, 1H, J = 3.3Hz), 3.57 (ddd , 1H, J = 5.5,9.0,14.6Hz), 3.83 (ddd, 1H, J = 4.0,10.8,13.6Hz), 5.04--5.15 (m, 1H), 6.62 (t, 1H, J = 7.3Hz) , 6.86 (d, 1H, J = 7.3Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0722] (Example 71) cis- (8a, 12a) -11- (3,3-dichloro-2-propenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0723] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (29 mg, 0.12 mmol) and 1,1,3-trichloropropene (34 mg, 0.23 mmol) to pale yellow oil (7.0 mg, 17%) ).¹1 H NMR (CDCl₃, 300MHz) δ1.81-2.20 (m, 5H), 2.34 (dt, 1H, J = 3.6,11.0Hz), 2.60-2.68 (m, 1H), 2.73 (ddd, 1H, J = 1.8,6.2,11.4) Hz), 2.86-2.97 (m, 1H), 3.02-3.18 (m, 4H), 3.26 (qu, 1H, J = 4.0Hz), 3.56 (ddd, 1H, J = 5.1,10.6,15.7Hz), 3.82 (ddd, 1H, J = 4.0,11.0,13.7Hz), 6.00 (t, 1H, J = 6.6Hz), 6.63 (t, 1H, J = 7.3Hz), 6.87 (d, 1H, J = 7.6Hz) , 6.95 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0724] (Example 72) cis- (8a, 12a) -11-benzyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0725] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (26 mg, 0.11 mmol) and benzyl bromide (36 mg, 0.21 mmol) were prepared as pale yellow oil (22 mg, 63%).¹1 H NMR (CDCl₃, 300MHz) δ1.87-1.98 (m, 3H), 1.99-2.20 (m, 2H), 2.25-2.35 (m, 1H), 2.60-2.68 (m, 1H), 2.70-2.79 (m, 1H), 2.93-3.01 (m, 1H), 3.04-3.19 (m, 2H), 3.28 (qu, 1H, J = 3.3Hz), 3.45 (s, 2H), 3.55 (ddd, 1H, J = 5.5,10.6,14.4) Hz), 3.81 (ddd, 1H, J = 4.0,10.6,13.6Hz), 6.60 (t, 1H, J = 7.3Hz), 6.79 (d, 1H, J = 6.9Hz), 6.94 (dd, 1H, J = 1.1,7.7Hz), 7.24-7.35 (m, 5H) ppm. [0726] (Example 73) cis- (8a, 12a) -11- (2-methylbenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0727] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Prepared as pale yellow oil (28 mg, 67%) from indole (30 mg, 0.12 mmol) and 2-methylbenzyl bromide (44 mg, 0.24 mmol) did.¹1 H NMR (CDCl₃, 300MHz) δ1.84-2.20 (m, 5H), 2.25-2.35 (m, 1H), 2.35 (s, 3H), 2.55-2.63 (m, 1H), 2.67-2.77 (m, 1H), 2.93- 3.01 (m, 1H), 3.04-3.17 (m, 2H), 3.27 (qu, 1H, J = 3.3Hz), 3.40 (d, 2H, J = 7.4Hz), 3.56 (ddd, 1H, J = 5.5, 10.6,13.6Hz), 3.75 (ddd, 1H, J = 4.0,11.0,13.6Hz), 6.60 (t, 1H, J = 7.3Hz), 6.79 (d, 1H, J = 6.7Hz), 6.94 (dd, 1H, J = 1.1,7.7Hz), 7.11-7.20 (m, 3H), 7.25-7.30 (m, 1H) ppm. [0728] (Example 74) cis- (8a, 12a) -11- (3-methylbenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0729] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Prepared as pale yellow oil (40 mg, 95%) from indole (30 mg, 0.12 mmol) and 3-methylbenzyl bromide (44 mg, 0.24 mmol) did.¹1 H NMR (CDCl₃, 300MHz) δ1.84-1.95 (m, 3H), 2.00-2.20 (m, 2H), 2.25-2.34 (m, 1H), 2.35 (s, 3H), 2.58-2.67 (m, 1H), 2.69- 2.77 (m, 1H), 2.93-3.01 (m, 1H), 3.04-3.19 (m, 2H), 3.28 (qu, 1H, J = 3.3Hz), 3.41 (s, 2H), 3.56 (ddd, 1H, J = 5.5,10.6,14.6Hz), 3.80 (ddd, 1H, J = 4.0,10.6,13.5Hz), 6.60 (t, 1H, J = 7.7Hz), 6.80 (d, 1H, J = 7.0Hz), 6.94 (dd, 1H, J = 1.1,8.1Hz), 7.05-7.24 (m, 4H) ppm. [0730] (Example 75) cis- (8a, 12a) -11- (4-methylbenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0731] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Prepared from indole (33 mg, 0.12 mmol) and 4-methylbenzyl bromide (44 mg, 0.24 mmol) as pale yellow oil (35 mg, 85%) did.¹1 H NMR (CDCl₃, 300MHz) δ1.84-1.95 (m, 3H), 1.98-2.15 (m, 2H), 2.22-2.34 (m, 1H), 2.35 (s, 3H), 2.58-2.67 (m, 1H), 2.69- 2.77 (m, 1H), 2.90-3.01 (m, 1H), 3.04-3.19 (m, 2H), 3.26 (qu, 1H, J = 3.3Hz), 3.41 (s, 2H), 3.55 (ddd, 1H, J = 5.1, 10.3, 14.3Hz), 3.80 (ddd, 1H, J = 4.4, 11.0, 13.9Hz), 6.59 (t, 1H, J = 7.3Hz), 6.80 (d, 1H, J = 6.5Hz), 6.94 (dd, 1H, J = 1.1, 7.7Hz), 7.12 (d, 2H, J = 8.1Hz), 7.20 (d, 2H, J = 8.1Hz) ppm. [0732] (Example 76) cis- (8a, 12a) -11- (2,5-dimethylbenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0733] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (29 mg, 0.12 mmol) and bromide 2,5-dimethylbenzyl (36 mg, 0.24 mmol) to pale yellow oil (22 mg, 51%) Prepared as.¹1 H NMR (CDCl₃, 300MHz) δ1.82-2.20 (m, 5H), 2.22-2.34 (m, 7H), 2.55-2.63 (m, 1H), 2.67-2.74 (m, 1H), 2.93-3.02 (m, 1H), 3.06-3.17 (m, 2H), 3.27 (qu, 1H, J = 3.3Hz), 3.36 (d, 2H, J = 6.2Hz), 3.56 (ddd, 1H, J = 5.5, 10.2, 15.3Hz), 3.80 (ddd, 1H, J = 4.4,10.6,14.7Hz), 6.60 (t, 1H, J = 7.7Hz), 6.80 (d, 1H, J = 7.0Hz), 6.94 (dd, 1H, J = 1.1,8.1) Hz), 6.96-7.08 (m, 3H) ppm. [0734] (Example 77) cis- (8a, 12a) -11- (2,4-dimethylbenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0735] (Step A) 2,4-Dimethylbenzyl bromide. The title compound was prepared from 2,4-dimethylbenzyl alcohol (300 mg, 2.20 mmol) as a colorless oil (180 mg, 41%) by following the general procedure for bromination in Example 43.¹1 H NMR (CDCl₃, 300MHz) δ2.31-2.38 (m, 6H), 4.52 (s, 2H), 6.98-7.02 (m, 2H), 7.20 (d, 1H, J = 7.3Hz) ppm. [0736] (Step B) The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (30 mg, 0.12 mmol) and bromide 2,4-dimethylbenzyl (73 mg, 0.36 mmol) to pale yellow oil (34 mg, 79%) Prepared as.¹1 H NMR (CDCl₃, 300MHz) δ1.86-1.96 (m, 3H), 2.03-2.13 (m, 2H), 2.28-2.38 (m, 7H), 2.57-2.68 (m, 1H), 2.70-2.74 (m, 1H), 2.93-3.00 (m, 1H), 3.06-3.12 (m, 2H), 3.25-3.42 (m, 3H), 3.51-3.61 (m, 1H), 3.75-3.83 (m, 1H), 6.59 (t, 1H) , J = 7.4Hz), 6.79 (d, 1H, J = 7.3Hz), 6.92-6.98 (m, 3H), 7.13 (d, 1H, J = 7.3Hz) ppm. [0737] (Example 78) cis- (8a, 12a) -11- (3,5-dimethylbenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0738] (Step A) 3,5-Dimethylbenzyl bromide. The title compound was prepared from 3,5-dimethylbenzyl alcohol (300 mg, 2.20 mmol) as a colorless oil (122 mg, 28%) by following the general procedure for bromination in Example 43.¹1 H NMR (CDCl₃, 300MHz) δ2.31 (s, 6H), 4.44 (s, 2H), 6.93 (s, 1H), 7.01 (s, 2H) ppm. [0739] (Step B) The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (30 mg, 0.11 mmol) and bromide 3,5-dimethylbenzyl (122 mg, 0.61 mmol) to pale yellow oil (39 mg, 88%) Prepared as.¹1 H NMR (CDCl₃, 300MHz) δ1.87-1.94 (m, 3H), 2.00-2.14 (m, 2H), 2.22-2.35 (s, 7H), 2.62-2.70 (m, 1H), 2.72-2.76 (m, 1H), 2.92-3.00 (m, 1H), 3.06-3.19 (m, 2H), 3.26-3.33 (m, 1H), 3.38 (s, 2H), 3.51-3.61 (m, 1H), 3.76-3.85 (m, 1H) ), 6.60 (t, 1H, J = 7.4Hz), 6.81 (d, 1H, J = 6.5Hz), 6.90-6.99 (m, 4H) ppm. [0740] (Example 79) cis- (8a, 12a) -11- (2,4,6-trimethylbenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0741] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (30 mg, 0.12 mmol) and 2,4,6-trimethylbenzyl chloride (41 mg, 0.24 mmol) to pale yellow oil (27 mg, 60%) ).¹1 H NMR (CDCl₃, 300MHz) δ1.75-1.90 (m, 2H), 1.97-2.20 (m, 3H), 2.27 (s, 3H), 2.33-2.39 (m, 7H), 2.47-2.55 (m, 1H), 2.63- 2.72 (m, 1H), 2.93-3.17 (m, 3H), 3.20-3.30 (m, 1H), 3.38 (s, 2H), 3.56 (ddd, 1H, J = 5.5, 10.3, 15.4Hz), 3.71- 3.80 (m, 1H), 6.60 (t, 1H, J = 7.4Hz), 6.78 (d, 1H, J = 7.0Hz), 6.83 (s, 2H) .6.94 (dd, 1H, J = 1.1,8.1Hz) ) ppm. [0742] (Example 80) cis- (8a, 12a) -11- (3-methoxybenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0743] (Step A) 3-Methoxybenzyl methanesulfonate. The title compound was prepared as a colorless oil (292 mg, 93%) from 3-methoxybenzyl alcohol (200 mg, 1.45 mmol) and methanesulfonyl chloride (249 mg, 2.17 mmol) by following the general procedure for mesylation of Example 43. did.¹1 H NMR (CDCl₃, 300MHz) δ2.92 (s, 3H), 3.83 (s, 3H), 5.22 (s, 2H), 6.90-7.03 (m, 3H), 7.32 (t, 1H, J = 7.7Hz) ppm. [0744] (Step B) The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (30 mg, 0.12 mmol) and 3-methoxybenzyl methanesulfonate (52 mg, 0.24 mmol) prepared as pale yellow oil (13 mg, 30%) did.¹1 H NMR (CDCl₃, 300MHz) δ1.85-2.20 (m, 5H), 2.25-2.34 (m, 1H), 2.58-2.67 (m, 1H), 2.68-2.77 (m, 1H), 2.90-3.00 (m, 1H), 3.04-3.19 (m, 2H), 3.27-3.32 (m, 1H), 3.43 (s, 2H), 3.50-3.61 (m, 1H), 3.76-3.83 (m, 4H), 6.59 (t, 1H, J = 7.4Hz), 6.79-6.83 (m, 2H), 6.85-6.94 (m, 3H), 7.22 (t, 1H, J = 8.0Hz) ppm. [0745] (Example 81) cis- (8a, 12a) -11- (3,5-dimethoxybenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0746] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (30 mg, 0.12 mmol) and bromide 3,5-dimethoxybenzyl (56 mg, 0.24 mmol) to pale yellow oil (42 mg, 88%) Prepared as.¹1 H NMR (CDCl₃, 300MHz) δ1.85-2.20 (m, 5H), 2.25-2.34 (m, 1H), 2.58-2.67 (m, 1H), 2.70-2.77 (m, 1H), 2.92-3.01 (m, 1H), 3.06-3.19 (m, 2H), 3.24-3.32 (m, 1H), 3.39 (s, 2H), 3.50-3.61 (m, 1H), 3.78-3.88 (m, 7H), 6.37 (t, 1H, J = 2.2Hz), 6.51 (d, 2H, J = 2.2Hz), 6.60 (t, 1H, J = 7.7Hz), 6.81 (d, 1H, J = 7.3Hz), 6.94 (d, 1H, J = 7.5) Hz) ppm. [0747] (Example 82) cis- (8a, 12a) -11- (2,3,4,5,6-pentafluorobenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4, 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0748] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (29 mg, 0.12 mmol) and bromide 2,3,4,5,6-pentafluorobenzyl (62 mg, 0.24 mmol) to pale yellow Prepared as oil (21 mg, 42%).¹1 H NMR (CDCl₃, 300MHz) δ1.80-2.20 (m, 5H), 2.28-2.40 (m, 1H), 2.61-2.69 (m, 1H), 2.71-2.81 (m, 1H), 2.89-2.99 (m, 1H), 3.01-3.11 (m, 1H), 3.12-3.20 (m, 1H), 3.20-3.27 (m, 1H), 3.53 (ddd, 1H, J = 5.1,10.6,14.7Hz), 3.67 (s, 2H), 3.79 (ddd, 1H, J = 4.4, 10.4, 13.7Hz), 6.63 (t, 1H, J = 7.3Hz), 6.85 (d, 1H, J = 7.3Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz) ppm. [0749] (Example 83) cis- (8a, 12a) -11- (2-phenylethyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0750] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Prepared from indole (33 mg, 0.13 mmol) and (2-bromoethyl) benzene (50 mg, 0.27 mmol) as pale yellow oil (28 mg, 60%) did.¹1 H NMR (CDCl₃, 300MHz) δ1.90-2.20 (m, 5H), 2.34 (dt, 1H, J = 4.4,7.3Hz), 2.55-2.65 (m, 2H), 2.71-2.98 (m, 5H), 3.02-3.15 ( m, 1H), 3.18-3.23 (m, 1H), 3.28 (qu, 1H, J = 3.8Hz), 3.56 (ddd, 1H, J = 5.1,10.6, 14.3Hz), 3.84 (ddd, 1H, J = 4.0,11.0,13.5Hz), 6.63 (t, 1H, J = 7.6Hz), 6.88 (d, 1H, J = 6.7Hz), 6.96 (dd, 1H, J = 1.1,7.7Hz), 7.17-7.31 ( m, 5H) ppm. [0751] (Example 84) cis- (8a, 12a) -11- (1-methyl-2-phenylethyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0752] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (25 mg, 0.10 mmol) and 2-bromo-1-phenylpropane (40 mg, 0.20 mmol) to pale yellow oil (11 mg, 30%) Prepared as.¹1 H NMR (CDCl₃, 300Mhz) δ0.92 (d, 3H, J = 5.1Hz), 1.90-2.26 (m, 5H), 2.30-2.45 (m, 1H), 2.55-2.72 (m, 3H), 2.75-3.03 (m, 5H), 3.07-3.23 (m, 1H), 3.27-3.35 (m, 1H), 3.56-3.65 (m, 1H), 3.79-3.90 (m, 1H), 6.60-6.70 (m, 1H), 6.89 ( t, 1H, J = 7.3Hz), 6.93-6.98 (m, 1H), 7.14-7.29 (m, 5H) ppm. [0753] (Example 85) cis- (8a, 12a) -11-[(2E) -3-Phenyl-2-propenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3- b] [1,4] Chiazepino [2,3,4-hi] Indole [0754] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (25 mg, 0.10 mmol) and trans-3-bromo-1-phenyl-1-propen (40 mg, 0.20 mmol) to pale yellow oil (40 mg, 0.20 mmol) It was prepared as 17 mg (47%).¹1 H NMR (CDCl₃, 300MHz) δ1.90-2.20 (m, 5H), 2.29 (dt, 1H, J = 4.3,7.3Hz), 2.70-2.80 (m, 1H), 2.81-2.90 (m, 1H), 2.91-2.99 ( m, 1H), 3.03-3.21 (m, 4H), 3.28 (qu, 1H, J = 3.7Hz), 3.56-3.63 (m, 1H), 3.79-3.89 (m, 1H), 6.29 (dt, 1H, J = 6.6, 16.1Hz), 6.49 (d, 1H, J = 15.8Hz), 6.61 (t, 1H, J = 7.7Hz), 6.85 (d, 1H, J = 6.6Hz), 6.95 (dd, 1H, J = 1.1,7.7Hz), 7.21-7.40 (m, 5H) ppm. [0755] (Example 86) cis- (8a, 12a) -11- (4-phenylbutyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0756] (Step A) 1-Bromo-4-phenylbutane. The title compound was prepared from 4-phenyl-1-butanol (200 mg, 1.33 mmol) as a colorless oil (202 mg, 71%) by following the general procedure for bromination in Example 43.¹1 H NMR (CDCl₃, 300MHz) δ1.72-1.95 (m, 4H), 2.65 (t, 2H, J = 7.4Hz), 3.42 (t, 2H, J = 7.0Hz), 7.16-7.32 (m, 5H) ppm. [0757] (Step B) The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (30 mg, 0.12 mmol) and 1-bromo-4-phenylbutane (39 mg, 0.18 mmol) to pale yellow oil (32 mg, 70%) Prepared as.¹1 H NMR (CDCl₃, 300MHz)) δ1.55-1.70 (m, 4H) 1.90-2.20 (m, 5H), 2.27-2.47 (m, 3H), 2.58-2.65 (m, 2H), 2.71-2.90 (m, 2H) , 2.92-2.99 (m, 1H), 3.02-3.10 (m, 1H), 3.20-3.30 (m, 2H), 3.54 (ddd, 1H, J = 5.0, 10.8, 14.1Hz), 3.82 (ddd, 1H, J = 3.9,10.7,13.6Hz), 6.63 (t, 1H, J = 7.7Hz), 6.86 (dd, 1H, J = 1.1,7.3Hz), 6.96 (dd, 1H, J = 1.1,8.1Hz), 7.15-7.30 (m, 5H) ppm. [0758] (Example 87) cis- (8a, 12a) -11-([1,1'-biphenyl] -4-ylmethyl)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [0759] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Indole (23 mg, 0.093 mmol) and 4-phenylbenzyl chloride (38 mg, 0.19 mmol) prepared as pale yellow oil (19 mg, 50%). ..¹1 H NMR (CDCl₃, 300MHz) δ1.87-1.98 (m, 3H), 1.99-2.20 (m, 2H), 2.25-2.35 (m, 1H), 2.62-2.71 (m, 1H), 2.73-2.81 (m, 1H), 2.92-3.01 (m, 1H), 3.04-3.20 (m, 2H), 3.29 (qu, 1H, J = 3.3Hz), 3.49 (s, 2H), 3.56 (ddd, 1H, J = 5.4,10.7,13.6 Hz), 3.78-3.88 (m, 1H), 6.60 (t, 1H, J = 7.3Hz), 6.82 (d, 1H, J = 6.9Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz), 7.31-7.47 (m, 5H), 7.54-7.62 (m, 4H) ppm. [0760] (Example 88) cis- (8a, 12a) -11-([1,1'-biphenyl] -2-ylmethyl)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [0761] The title compound is cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-] by following the general coupling procedure of Example 43. b] [1,4] Thiazepino [2,3,4-hi] Prepared as pale yellow oil (35 mg, 71%) from indole (30 mg, 0.12 mmol) and 2-phenylbenzyl bromide (59 mg, 0.24 mmol) did.¹1 H NMR (CDCl₃, 300MHz) δ1.80-1.90 (m, 3H), 1.95-2.15 (m, 2H), 2.19-2.28 (m, 1H), 2.50-2.58 (m, 1H), 2.62-2.75 (m, 1H), 2.89-2.98 (m, 1H), 3.05-3.15 (m, 2H), 3.24-3.30 (m, 1H), 3.36 (d, 2H, J = 8.4Hz), 3.42-3.56 (m, 1H), 3.75- 3.82 (m, 1H), 6.59 (t, 1H, J = 7.4Hz), 6.78 (d, 1H, J = 6.6Hz), 6.92 (dd, 1H, J = 1.5,8.1Hz), 7.20-7.41 (m , 8H), 7.58 (d, 1H, J = 7.0Hz) ppm. [0762] (Example 115) Bromo-6,7,9,12-Tetrahydro-5H-Pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (10H) -tert-Butyl Carbonate [0763] The title compound was 1-bromo-6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,] by the method of Example 107. 4-hi] Indole (339 mg, 1.10 mmol) and Boc₂It was prepared from O (263 mg, 1.20 mmol) as a white amorphous solid (404 mg, 90%) after purification by chromatography.¹1 H NMR (CDCl₃, 300MHz) δ7.00 (d, 1H, J = 7.9Hz), 6.83 (d, 1H, J = 7.9Hz), 4.94 (s, 2H), 4.54 (t, 2H, J = 5.9Hz), 3.80 ( bt, 2H), 3.33 (t, 2H, J = 7.0Hz), 2.71 (bt, 2H), 2.25-2.31 (m, 2H), 1.50 (s, 9H) ppm. MS (CI, NH₃): 425 (base, M + H). [0764] (Example 116) 1- (2,3-dichlorophenyl) -6,7,9,12-tetrahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (10H) )-Tert-Butyl carbonate [0765] 1-Bromo-6,7,9,12-Tetrahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (10H) -tert-butyl carbonate (55 mg, 0.13 mmol) was dissolved in DME (3 mL) and 2M sodium carbonate (0.55 mL) was added. 2,3-Dichlorophenylboronic acid (51.3 mg, 0.27 mmol), followed by Pd₂dba₃(7.0 mg, 0.0007 mmol) was added. P (Ph)₃(6.8 mg, 0.026 mmol) was added. The reaction flask was degassed and kept in a nitrogen atmosphere. The suspension was refluxed for 18 hours and cooled to room temperature. After concentrating the reaction in vacuo, water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saline (2 x 10 mL), dried and concentrated to give a crude brown amorphous solid (214 mg). Purification of this residue by column chromatography (20-40% EtOAc / Hexanes) gave the title compound (63.1 mg, 99%) as a white amorphous solid. δ₇.3-7.5 (m, 1H), 7.2-7.3 (m, 2H), 7.01 (d, 1H, J = 7.2Hz), 6.65 (d, 1H, J = 7.2Hz), 4.4-4.6 (m, 2H) ), 3.5-3.9 (m, 4H), 3.2-3.4 (m, 2H), 2.5-2.7 (m, 2H), 2.1-2.4 (m, 2H), 1.30 (s, 9H) ppm. [0766] (Example 117) 1- (3,4-dichlorophenyl) -6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0767] The title compound was 1-bromo-6,7,9,12-tetrahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] by the method of Example 116. From indole-11 (10H) -tert-butyl carbonate (72 mg, 0.18 mmol) and 3,4-dichlorophenylboronic acid (67.1 mg, 0.35 mmol) after chromatographic purification (65.7 mg, 74.6%) white amorphous solid Prepared as.¹1 H NMR (CDCl₃, 300MHz) δ7.39 (s, 1H), 7.1-7.3 (m, 2H), 6.99 (d, 1H, J = 7.8Hz), 6.68 (d, 1H, J = 7.5Hz), 4.52 (t, 2H) , J = 6.0Hz), 3.68 (t, 2H, 6.0Hz), 3.34 (t, 2H, J = 6.9Hz), 2.66 (t, 2H, J = 6.00Hz), 2.2-2.3 (m, 2H), 1.49 (s, 9H) ppm. [0768] (Example 118) 1- [2-Chloro-4- (trifluoromethyl) phenyl] -6,7,9,12-tetrahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indole-11 (10H) -tert-butyl carbonate [0769] The title compound was 1-bromo-6,7,9,12-tetrahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] by the method of Example 116. After purification by chromatography from amorphous-11 (10H) -tert-butyl carbonate (60 mg, 0.15 mmol) and 2-chloro-4-trifluoromethylphenylboronic acid (62.3 mg, 0.29 mmol) (60.0 mg, 95%) Prepared as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.73 (s, 1H), 7.49 (d, 1H, J = 8.1Hz), 7.43 (d, 1H, J = 8.1Hz), 7.07 (d, 1H, J = 7.2Hz), 6.7 ( d, 1H, 7.2Hz), 4.4-4.7 (m, 2H), 3.5-4.0 (m, 4H), 3.41 (dt, 2H, J = 2.4,6.6Hz), 2.6-2.8 (m, 2H), 2.2 -2.4 (m, 2H), 1.54 (s, 9H) ppm. [0770] (Example 119) 1- (2,3-dichlorophenyl) -6,7,9,10,11,12-hexahydro-5<u style="single">H</u>-Pirido [3', 4': 4,5] Pyrrolo [1,2,3-ef] [1,5] Benzodiazepines [0771] 1- (2,3-dichlorophenyl) -6,7,9,10,11,12-hexahydro-5H-pyrido [3', 4': 4,5] pyrolo [1,2,3-ef] [1 , 5] Benz-thiazepinyl-11-tert-butyl carbonate (63.1 mg, 0.13 mmol) was dissolved in 20% TFA dissolved in methylene chloride (4 mL) and stirred at room temperature for 2 hours. The reaction solution was cooled to 0 ° C. and basified with 1 M aqueous NaOH solution until pH 14 was higher. The layers were separated. The aqueous phase was extracted with methylene chloride (2 x 10 mL). The organic layer was washed with saline and dried. Concentration gave the title compound (50 mg, 99%) as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.40 (m, 1H), 7.14 (d, 1H, J = 3.3Hz), 7.12 (s, 1H), 6.98 (d, 1H, J = 7.5Hz), 6.63 (d, 1H, J = 7.8Hz), 4.51 (m, 2H), 3.2-3.4 (m, 3H), 3.0-3.2 (m, 3H), 2.59 (t, 2H, J = 5.7Hz), 2.26 (m, 2H) ppm. MS (CI, NH₃): 389 (base, M + H). [0772] (Example 120) 1- (3,4-dichlorophenyl) -6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0773] The title compound (44.5 mg, 100%) was prepared by the method of Example 119 with 1- (3,4-dichlorophenyl) -6,7,9,12-tetrahydro-5H-pyrido [4,3-b] [1. , 4] Thiazepino [2,3,4-hi] Indole-11 (10H) -tert-butyl carbonate (67.5 mg, 0.14 mmol) was prepared as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.46 (s, 1H), 7.43 (d, 1H, J = 8.1Hz), 7.20 (dd, 1H, J = 1.8, 8.1Hz), 7.04 (d, 1H, J = 7.8Hz), 6.73 (d, 1H, J = 7.2Hz), 4.60 (t, 2H, J = 6.00Hz), 3.44 (s, 2H), 3.40 (s, 2H, J = 6.60Hz), 3.19 (t, 2H, J = 6.00Hz), 2.69 (t, 2H, J = 6.00Hz), 2.33 (m, 2H) ppm. MS (CI, NH₃): 389 (base, M + H). [0774] (Example 121) 1- [2-Chloro-4- (trifluoromethyl) phenyl] -6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole [0775] The title compound (46.9 mg, 92%) was 1- [2-chloro-4- (trifluoromethyl) phenyl] -6,7,9,12-tetrahydro-5H-pyrido [4] by the method of Example 119. , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (10H) -tert-butyl carbonate (64.4 mg, 0.12 mmol) was prepared as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.72 (s, 1H), 7.51 (d, 1H, J = 7.5Hz), 7.06 (d, 1H, 7.5Hz), 6.70 (d, 1H, J = 7.2Hz), 4.4-4.7 ( m, 2H), 3.3-3.5 (m, 3H), 3.1-3.3 (m, 3H), 2.67 (t, 2H, J = 5.1Hz), 2.2-2.4 (m, 2H) ppm. MS (CI, NH₃): 423 (base, M + H). [0776] (Example 122) (8aS, 12aR) -1- (2,3-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0777] 1- (2,3-dichlorophenyl) -6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (47.0 mg, 0.12 mmol) was dissolved in TFA (2 mL). The reaction was cooled to 0 ° C. NaCNBH₃(22.7 mg, 0.36 mmol) was added. The reaction was stirred at 0 ° C for 2 hours. Ice (2 pieces) was added. The reaction was basicized with 50% NaOH up to pH 14 while keeping the temperature below 7 ° C. CH reaction mixture₂Cl₂Extracted with (3 x 10 mL). The combined organic layers were washed with saline, dried and concentrated to give the title compound (40.5 mg, 86%) as a pure white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.43 (d, 1H, 7.3Hz), 7.23-7.30 (m, 2H), 7.00 (d, 1H, 8.1Hz), 6.48 (d, 1H, 8.1Hz), 3.94-4.03 (m, 1H), 3.62-3.70 (m, 1H), 3.21-3.40 (m, 1H), 2.80-3.07, m, 5H), 2.50-2.55 (m, 1H), 1.94-2.48 (m, 4H), 1.68- 1.76 (m, 1H) ppm. MS (CI, NH₃): 391 (base, M + H). [0778] (Example 123) (8aS, 12aR) -1- (3,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole The title compound (28.8 mg, 73%) was 1- (3,4-dichlorophenyl) -6,7,9,10,11,12-hexahydro-5H-pyridole [4,3-" by the method of Example 122. b] [1,4] Thiazepino [2,3,4-hi] Indole (39.2 mg, 0.10 mmol) and NaCNBH₃Prepared as a white amorphous solid from (28.8 mg, 0.30 mmol).¹1 H NMR (CDCl₃, 300MHz) δ7.25-7.45 (m, 2H), 7.21 (dd, 1H, 2.4Hz, 8.1Hz), 7.00 (d, 1H, 7.8Hz), 6.55 (d, 1H, 8.1Hz), 4.0 (ddd , 1H, 4.0Hz, 12.1Hz, 13.6Hz), 3.65 (ddd, 1H, 5.1Hz, 11.3Hz, 14.3Hz), 3.37-3.41 (m, 1H), 3.20 (dt, 1H, 6.6Hz, 17.7Hz) , 3.04 (bdd, 1H, 4.5Hz, 13.5Hz), 2.93 (ddd, 1H, 2.1Hz, 5.7Hz, 14.4Hz), 2.84 (dd, 2H, 2.4Hz, 9.9Hz), 2.6 (dd, 1H, 6.3) Hz, 12.2Hz), 1.8-2.3 (m, 4H), 1.7-1.8 (m, 1H) ppm. MS (CI, NH₃): 391 (base, M + H). [0779] (Example 124) (8aS, 12aR) -1- [2-Chloro-4- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [0780] The title compound (44.3 mg, 95%) was 1- [2-chloro-4- (trifluoromethyl) phenyl] -6,7,9,10,11,12-hexahydro-5H by the method of Example 122. -Pirido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (46.8 mg, 0.11 mmol) and NaCNBH₃Prepared as a white amorphous solid from (21.0 mg, 0.33 mmol). The enantiomers of the title compound were separated by preparative HPLC on a Chriacel OD column using non-gradient 6% IPA / hexane as the eluate.¹1 H NMR (CDCl₃, 300MHz) δ7.70 (s, 1H), 7.52 (d, 1H, 7.7Hz), 7.34 (bd, 1H), 7.01 (d, 1H, 8.1Hz), 6.46 (bd, 1H), 3.95-4.05 ( m, 1H), 3.58-3.78 (m, 1H), 3.30-3.41 (m, 1H), 2.81-3.07, m, 5H), 1.9-2.4 (m, 5H), 1.68-1.76 (m, 1H) ppm .. MS (CI, NH₃): 425 (base, M + H). [0781] (Example 125) cis- (8a, 12a) -1-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole-11 (8aH) -tert-butyl carbonate [0782] The title compound was cis- (8a, 12a) -1-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] by the method of Example 107. ] [1,4] Thiazepino [2,3,4-hi] Indole (157 mg, 0.48 mmol) and BOC₂It was prepared from O (116 mg, 0.53 mmol) as a white amorphous solid (152 mg, 75%) after purification by chromatography.¹1 H NMR (CDCl₃, 300MHz) δ7.73 (d, 1H, J = 8.3Hz), 6.66 (d, 1H, J = 8.3Hz), 3.35-4.1 (m, 5H), 2.70-3.35 (m, 5H), 1.75-2.20 (m, 4H), 1.33 (s, 9H) ppm. [0783] (Example 126) cis- (8a, 12a) -1- (2,6-difluorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate [0784] cis- (8a, 12a) -1-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole-11 (8aH) -tert-butyl carbonate (70 mg, 0.16 mmol) was dissolved in DME (3 mL). TEA (0.3 mL) was added. Boronic acid 2 (52 mg, 0.33 mmol) followed by Pd (dppf) Cl₂(6.7 mg, 0.0082 mmol) was added. The reaction flask was degassed and kept in a nitrogen atmosphere. The suspension was refluxed for 18 hours and cooled to room temperature. After concentrating the reaction in vacuo, water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saline (2 x 10 mL), dried and concentrated to give a crude brown amorphous solid (214 mg). Purification of this residue by column chromatography (20-40% EtOAc / Hexanes) gave the title compound (29.5 mg, 40%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300Mhz) δ7.20-7.25 (m, 1H) .6.97 (d, 1H, 7.7Hz), 6.51 (d, 1H, 7.7Hz), 3.90-3.99 (m, 1H), 3.60-3.75 (m, 1H) ), 3.43-3.59 (m, 1H), 3.35-3.42 (m, 2H), 2.81-3.04 (m, 4H), 2.40-2.60 (m, 1H), 1.60-2.20 (m, 4H), 1.21 (bs) , 9H) ppm. [0785] (Example 127) cis- (8a, 12a) -1- (2,6-difluorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0786] cis- (8a, 12a) -1- (2,6-difluorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (18.2 mg, 0.04 mmol) was dissolved in 20% TFA dissolved in methylene chloride (4 mL) and stirred at room temperature for 2 hours. The reaction solution was cooled to 0 ° C. and basified with 1 M NaOH until above pH 14. The layers were separated. The aqueous phase was extracted with methylene chloride (2 x 10 mL). The organic layer was washed with saline and dried. Concentration gave the title compound (14 mg, 100%) as a pale yellow amorphous solid. The enantiomers of the title compound were separated by preparative HPLC on a chiracel OD column using non-gradient 5% IPA / hexane as the eluate.¹1 H NMR (CDCl₃, 300MHz) δ7.15-7.26 (m, 2H), 6.95 (d, 1H, 8.1Hz), 6.81-6.81 (m, 1H), 6.48 (d, 1H, 7.7Hz), 3.94 (ddd, 1H, 4.1) Hz, 11.8Hz, 13.5Hz), 3.62 (ddd, 1H, 5.1Hz, 11.3Hz, 14.6Hz), 3.29-3.33 (m, 1H), 2.95 (bdd, 1H, 4.8Hz, 13.6Hz), 2.75-2.90 (m, 3H), 2.50 (dd, 1H, 6.6Hz, 12.5Hz), 2.28 (t, 1H, 11.7Hz), 1.80-2.20 (m, 3H), 1.45-1.80 (m, 2H) ppm. MS (CI, NH₃): 359 (base, M + H). [0787] (Example 128) cis- (8a, 12a) -2- (2,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4 ] Chiazepino [2,3,4-hi] Indole [0788] (Step A) A solution of 5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (32.21 g, 0.166 mol) in THF (650 mL) was applied so that the temperature did not rise above 27-29 ° C.₂It was added dropwise to LAH (1.0 MTHF solution, 166 mL). When the addition was complete, the mixture was stirred at room temperature for 1 hour. Cool in an ice bath, H₂O (7.3 mL) was added dropwise, followed by treatment with 1N NaOH (32.4 mL). The mixture was filtered at room temperature and the filtrate was evaporated under reduced pressure. CH the residue₂Cl₂Dissolve in (200 mL) and H₂Wash with O and DDL₄Drying in and evaporating the solvent under reduced pressure gave 29.42 g (98%) of crude product. Purification by column chromatography (EtOAc) gave a liquid of 3,4-dihydro-1,5-benzothiazepine-5 (2H) -amine 17.69 g (yield 59%), which had a melting point of 202 ° C. (Decomposition) was converted to an HCl salt. (M + H)⁺180. [0789] (Step B) 4-Piperidinone hydrate HCl (4.55 g, 29.62 mmol) was vigorously stirred with 2H, 3H, 4H-benzo [b] 1,4-thiazepine-5-ylamine (6.42 g, 29.62 mmol) i-PrOH. It was added to the (250 mL) solution. The mixture was refluxed for 2 hours. The white precipitate is collected and converted to free base with 1N NaOH, followed by CH.₂Cl₂Extracted with (3 x 25 mL). Combined extract EDTA₄Dry in and evaporate the solvent using reduced pressure to as oil 6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole 4.66g (64%) was obtained. (M + H)⁺244. [0790] (Step C) N₂6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (4.66 g, 19.07 mmol) stirred in In TFA (42 mL) solution (0-5 ° C), N₂Sodium cyanoborohydride (3.78 g, 60.07 mmol) was added in small portions. After stirring at room temperature for 4 hours, the mixture was carefully treated with 6N HCl (44 mL) and refluxed for 1 hour. Base the mixture with 25% NaOH and CHCl₃Extracted with (3 x 50 mL). Combined extract EDTA₄Dry in and evaporate the solvent under reduced pressure to cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole 4.08g (87%) was obtained.¹1 H NMR (CDCl₃ 300MHz) δ6.93 (dd, 1H), 6.84 (dd, 1H), 6.60 (t, 1H), 3.78 (qd, 1H), 3.64 (dq, 1H), 3.32-3.40 (m, 1H), 3.19 ( dt, 1H), 2.86 (tt, 2H), 2.59 (td, 1H), 2.27 (s, 1H), 2.00-2.20 (m, 2H), 1.80 (qq, 2H) ppm. (M + H)⁺246. [0791] (Step D) Di-tert-butyl bicarbonate (9.04 g, 41.40 mmol), cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3- b] [1,4] Chiazepino [2,3,4-hi] CH of indole (4.08 g, 16.56 mmol)₂Cl₂It was added to the (50 mL) solution and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Dissolve the residue in 1% NaOH (50 mL) and CH₂Cl₂Extracted with (3 x 30 mL). Combined extract EDTA₄The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (66% hexane in EtOAc) with cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro. -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate 3.59 g (68%) was obtained.¹1 H NMR (CDCl₃ 300MHz) δ6.98 (d, 1H), 6.90 (d, 1H), 6.61 (t, 1H), 3.80 (qd, 1H), 3.61 (dq, 1H), 3.40-3.58 (m, 2H), 3.14- 3.40 (m, 4H), 2.98 (dt, 2H), 2.00-2.19 (m, 1H), 1.82-1.91 (m, 2H), 1.22 (s, 9H) ppm. (M + H)⁺347,247. [0792] (Step E) CHCl₃Bromine (0.462 g, 2.89 mmol) in (5 mL) was added to cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b). ] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (1.0 g, 2.89 mmol) cold (0-5 ° C) CHCl₃Dropped into (60 mL) solution. After stirring the mixture at room temperature for 20 hours, LVDS₃Wash with aqueous solution and deli₄Dry in and evaporate the solvent under reduced pressure to give cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4] as a reddish brown liquid. , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 1.12 g (91%) was obtained.¹1 H NMR (CDCl₃ 300MHz) δ7.08 (d, 1H), 6.98 (d, 1H), 3.78 (qd, 1H), 3.39-3.53 (m, 4H), 3.17-3.24 (m, 3H), 2.92-3.01 (m, 2H) ), 2.02-2.17 (m, 2H), 1.80-1.88 (m, 2H), 1.42 (s, 9H) ppm. (M + H)⁺425,369,325. [0793] (Step F) cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole-11 (8aH) -tert-butyl carbonate (0.800 g, 1.88 mmol) in a benzene (40 mL) solution with 2,4-dichlorobenzeneboronic acid (0.717 g, 3.76 mmol), bis (triphenylphosphine) palladium (II) Chloride (0.072g), and 2M Na₂CO₃(3.04 mL) was added. The combined mixture was refluxed for 24 hours and then evaporated to dryness under reduced pressure. Residue H₂It was dissolved in O (80 mL) and extracted with EtOAc (3 x 10 mL). Combined extract EDTA₄Drying in and evaporating the solvent under reduced pressure gave a mixture of 85% product and 15% unreacted starting material. Purification of the resin product by normal phase HPLC (75% hexane in EtOAc) results in (8a, 12a) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro as bubbles. -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate 0.612g (66%) was obtained.¹1 H NMR (CDCl₃ 300MHz) δ7.44 (s, 1H), 7.18-7.24 (m, 2H), 7.04 (s, 1H), 7.00 (s, 1H), 3.79-3.88 (m, 2H), 3.60-3.80 (m, 2H) ), 3.40-3.59 (m, 2H), 3.20-3.40 (m, 2H), 3.00-3.18 (m, 1H), 2.10-2.21 (m, 2H), 1.82-1.96 (m, 2H), 1.38 (s) , 9H), 1.61 (t, 1H) ppm. (M + H)⁺492,436,392. [0794] (Step G) (8a,12a) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.612g, 1.25 mmol)₂Cl₂The (10 mL) solution was treated with TFA (3 mL) and stirred in a closed vial at room temperature for 18 hours. Base the solution with 1N NaOH (20 mL) and CH₂Cl₂Extracted with (3 x 10 mL). Combined extract EDTA₄Dry in and evaporate the solvent under reduced pressure to form bubbles cis- (8a, 12a) -2- (2,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole 0.380g (78%) was obtained.¹1 H NMR (CDCl₃ 300MHz) δ7.42 (d, 1H), 7.21-7.27 (m, 2H), 7.01 (dd, 1H), 6.97 (s, 1H), 3.90 (qd, 1H), 3.58 (dq, 1H), 3.42- 3.50 (m, 1H), 3.22-3.41 (m, 1H), 2.98-3.21 (m, 5H), 2.91-2.93 (m, 1H), 2.62-2.74 (m, 1H), 2.00-2.20 (m, 4H) ) ppm. (M + H)⁺392. [0795] (Example 129) cis- (8a, 12a) -2-phenyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0796] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G.¹1 H NMR (CDCl₃ 300MHz) δ7.42 (dd, 2H), 7.36-7.40 (m, 2H), 7.26-7.31 (m, 1H), 7.24 (d, 1H), 7.16 (d, 1H), 3.96 (qd, 1H), 3.59 (dq, 1H), 3.31-3.44 (m, 4H), 3.19 (td, 1H), 2.96-3.09 (m, 2H), 2.72 (dd, 1H), 2.20-2.39 (m, 1H), 2.16- 2.20 (m, 2H) ppm. (M + H)⁺323. [0797] (Example 130) cis- (8a, 12a) -2- (4-fluorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0798] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺341. [0799] (Example 131) cis- (8a, 12a) -2- (4-chlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0800] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺357. [0801] (Example 132) cis- (8a, 12a) -2- (2-chlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0802] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G.¹1 H NMR (CDCl₃ 300MHz) δ7.38 (dd, 2H), 7.10-7.18 (m, 2H), 7.00 (dd, 1H), 6.91 (d, 1H), 3.84 (qd, 1H), 3.57 (dq, 1H), 3.38 ( m, 2H), 2.80-3.25 (m, 8H), 2.62 (dd, 1H), 2.01-2.18 (m, 2H) ppm. (M + H)⁺357. [0803] (Example 133) cis- (8a, 12a) -2- (2-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0804] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺353. [0805] (Example 134) cis- (8a, 12a) -2- [2-chloro-4- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [0806] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺425. [0807] (Example 135) cis- (8a, 12a) -2- (2,4-dimethylphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0808] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G.¹1 H NMR (CDCl₃ 300MHz) δ6.99-7.10 (m, 3H), 6.94 (d, 1H), 6.80 (d, 1H), 3.80 (qd, 1H), 3.58 (dq, 1H), 3.40-3.43 (m, 1H), 2.80-3.21 (m, 6H), 2.66 (dd, 1H), 2.37-2.42 (m, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 2.01-2.21 (m, 2H), 1.83- 1.91 (m, 2H), 1.26-1.28 (m, 1H) ppm. (M + H)⁺351. [0809] (Example 136) cis- (8a, 12a) -2- (2-chloro-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0810] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G.¹1 H NMR (CDCl₃ 300MHz) δ7.28 (dd, 2H), 7.18 (dd, 1H), 7.04 (d, 1H), 6.94 (d, 1H), 3.92 (qd, 1H), 3.59 (dq, 1H), 3.41-3.51 ( m, 1H), 2.97-3.30 (m, 5H), 2.72 (dd, 1H), 2.01-2.19 (m, 4H) ppm. (M + H)⁺387. [0811] (Example 137) cis- (8a, 12a) -2- (4-isopropylphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0812] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G.¹1 H NMR (CDCl₃ 300MHz) δ7.42 (d, 1H), 7.39 (d, 1H), 7.22 (d, 1H), 7.19 (d, 1H), 7.08 (s, 1H), 3.78 (qd, 1H), 3.51-3.60 ( m, 1H), 3.39-3.45 (m, 1H), 2.80-3.22 (m, 8H), 2.68 (dd, 1H), 2.38 (s, 1H), 2.01-2.23 (m, 2H), 1.80-1.96 ( m, 2H), 1.28 (d, 6H) ppm. (M + H)⁺365. [0813] (Example 138) cis- (8a, 12a) -2- (4-Butylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0814] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺379. [0815] (Example 139) cis- (8a, 12a) -2- (2-fluoro-4-methoxy-6-methylphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [0816] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G.¹1 H NMR (CDCl₃ 300MHz) δ6.92 (dd, 2H), 6.80 (dd, 2H), 3.92 (s, 3H), 3.90 (qd, 1H), 3.79 (dq, 1H), 3.43 (m, 1H), 2.98-3.36 ( m, 8H), 2.69 (dd, 1H), 2.21 (s, 3H), 2.00-2.20 (m, 4H) ppm. (M + H)⁺385. [0817] (Example 140) cis- (8a, 12a) -2- (4-Methoxy-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0818] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G.¹1 H NMR (CDCl₃ 300MHz) δ7.10 (d, 1H), 6.92 (d, 1H), 6.75-6.80 (m, 3H), 3.84 (qd, 1H), 3.81 (s, 3H), 3.59 (dq, 1H), 3.41 ( m, 1H), 2.97-3.31 (m, 7H), 2.68 (dd, 1H), 2.22 (s, 3H), 2.00-2.20 (m, 4H) ppm. (M + H)⁺367. [0819] (Example 141) cis- (8a, 12a) -2- [2-chloro-4- (trifluoromethoxy) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [0820] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺441. [0821] (Example 142) cis- (8a, 12a) -2-mesityl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0822] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺365. [0823] (Example 143) cis- (8a, 12a) -2- (3-chlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0824] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺357. [0825] (Example 144) cis- (8a, 12a) -2- (4-methylphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺337. [0826] (Example 145) cis- (8a, 12a) -2- (4-Chloro-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0827] The title compound was prepared by hydrolysis of the BOC-protected amine adduct obtained by the procedure of Example 128, Step F and the corresponding arylboronic acid, followed by the procedure of Example 128, Step G. (M + H)⁺371. [0828] (Example 146) cis- (8a, 12a) -2- (2,5-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4 ] Chiazepino [2,3,4-hi] Indole [0829] The title compound was prepared by hydrolysis according to the procedure of Example 128, Step F and the corresponding arylboronic acid followed by Example 128 of the resulting BOC protected amine adduct, Step G. (M + H)⁺391. [0830] (Example 147) cis- (8a, 12a) -2- (4-isopropyl-2-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0831] The title compound was prepared by hydrolysis according to the procedure of Example 128, Step F and the corresponding arylboronic acid followed by Example 128 of the resulting BOC protected amine adduct, Step G. (M + H)⁺395. [0832] (Example 148) cis- (8a, 12a) -2- (2,6-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4 ] Chiazepino [2,3,4-hi] Indole [0833] (Step A) Step E of Example 128 cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (0.100 g, 0.24 mmol) in a solution of 1,2-dimethoxyethane (5 mL) with 2,6-dichlorophenylboronic acid (0.092 g, 0.48 mmol), a complex of 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride with dichloromethane (0.005 g), and triethylamine (0.34 mL) were added. When the mixture was refluxed for 24 hours, 55% of the starting material was converted to the product. 0.48 mmol of 2,6-dichlorobenzeneboronic acid, 0.005 g of Pd (dppf), and 0.34 mL of TEA were newly added to the mixture, and the mixture was refluxed for 24 hours and evaporated to dryness under reduced pressure. Residue H₂It was dissolved in O (20 mL) and extracted with EtOAc (3 x 5 mL). Combined extract EDTA₄Drying in and evaporating the solvent under reduced pressure gives a mixture of 95% product and 5% unreacted starting material, which is purified by normal phase HPLC (75% hexane in EtOAc) as foam (75% hexane in EtOAc). 8aS, 12aR) -2- (2,6-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -tert-butyl carbonate 0.088 g (76%) was obtained. (M + H)⁺491, 435, 391. [0834] (Step B) cis- (8a, 12a) -2- (2,6-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4 ] Thiazepino [2,3,4-hi] indole is cis- (8a, 12a) -2- (2,6-dichlorophenyl) -6,7,9,10 as illustrated in step G of Example 128. , 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -prepared from tert-butyl carbonate, 0.034 as foam g (49%) was obtained. (M + H)⁺391. [0835] (Example 149) cis- (8a, 12a) -2- (2,6-difluorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0836] The title compound is Example 128, step E cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate and the corresponding arylboronic acid were utilized in Example 148, by the method of step A, followed by the obtained BOC. Prepared by hydrolysis according to Example 148 of the protective amine adduct, step B. (M + H)⁺358. [0837] (Example 150) cis- (8a, 12a) -2- [4-methoxy-2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [0838] The title compound is Example 128, step E cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate and the corresponding arylboronic acid were utilized in Example 148, by the method of step A, followed by the obtained BOC. Prepared by hydrolysis according to Example 148 of the protective amine adduct, step B.¹1 H NMR (CDCl₃ 300MHz) δ7.20 (dd, 2H), 7.04 (dd, 1H), 6.90 (d, 1H), 6.79 (d, 1H), 3.84 (s, 3H), 3.82 (qd, 1H), 3.58 (dq, 1H), 3.42 (m, 1H), 2.94-3.21 (m, 5H), 2.63 (dd, 2H), 2.38 (s, 1H), 2.01-2.21 (m, 2H), 1.80-1.97 (m, 2H) ppm. (M + H)⁺421. [0839] (Example 151) cis- (8a, 12a) -2- [2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0840] The title compound is Example 128, step E cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate and the corresponding arylboronic acid were utilized in Example 148, by the method of step A, followed by the obtained BOC. Prepared by hydrolysis according to Example 148 of the protective amine adduct, step B. (M + H)⁺391. [0841] (Example 152) cis- (8a, 12a) -2- (4-pyridinyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0842] (Step A) Step E of Example 128 cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyridole [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.100 g, 0.24 mmol) in a toluene (3 mL) solution with pyridine-4-trimethylstannan (0.058 g, 0.24 mmol), ( Ph₃P)₂PdCl₂(0.005 g) and a few crystals of 2,6-di-tert-butyl-4-methylphenol were added. The combined mixture was refluxed for 13 hours and then evaporated to dryness under reduced pressure. Residue H₂It was dissolved in O (20 mL) and extracted with EtOAc (3 x 5 mL). Combined extract EDTA₄Drying in and evaporating the solvent under reduced pressure gave a mixture of product and unreacted starting material. (8aS, 12aR) -2- (4-pyridinyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indole-11 (8aH) -tert-butyl carbonate was purified on a preparative TLC silica plate (50% EtOAc / Hexanes) and isolated as a viscous liquid. Yield 0.017g (17%). (M + H)⁺423, 367, 323. [0843] (Step B) cis- (8a, 12a) -2- (4-pyridinyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole is (8aS, 12aR) -2- (4-pyridinyl) -6,7,9,10,12,12a-hexahydro as illustrated in step G of Example 128. -5H-Pirido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -Prepared from tert-butyl carbonate, 5.0 mg (38%) as foam Obtained. (M + H)⁺323. [0844] (Example 153) cis- (8a, 12a) -2- (4-frill) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0845] The title compound is Example 128, step E cis- (8a, 12a) -2- (2,3-dihydro-2-furanyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido. [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -using tert-butyl carbonate and the corresponding arylboronic acid in Example 152, of step A By method, the resulting BOC-protected amine adduct was prepared by hydrolysis in Example 128, step G procedure.¹1 H NMR (CDCl₃ 300MHz) δ7.38 (d, 1H), 7.31 (d, 1H), 7.18 (d, 1H), 6.41-6.44 (m, 2H), 3.80 (qd, 2H), 3.54 (dq, 2H), 3.40- 3.48 (m, 1H), 2.98-3.24 (m, 5H), 2.68 (dd, 2H), 2.00-2.21 (m, 2H), 1.89-1.99 (m, 1H) ppm. (M + H)⁺312. [0846] (Example 154) cis- (8a, 12a) -2- (4-thienyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0847] The title compound is Example 128, step E cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate and the corresponding arylboronic acid were utilized in Example 152, by the method of step A, followed by the resulting BOC. Prepared by hydrolysis of the protected amine adduct in Example 128, step G procedure.¹1 H NMR (CDCl₃ 300MHz) δ7.26 (d, 1H), 7.10-7.18 (m, 3H), 7.00 (m, 1H), 3.82 (qd, 1H), 3.57 (dq, 1H), 3.41 (m, 1H), 3.10- 3.30 (m, 2H), 2.96-3.06 (m, 2H), 2.70-2.92 (m, 1H), 2.68 (dd, 1H), 2.02-2.10 (m, 2H), 1.99 (m, 2H) ppm. (M + H)⁺329. [0848] (Example 155) cis- (8a, 12a) -2- (4-fluorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0849] (Step A) Example 128, step E cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (1.50 g, 3.53 mmol)₂Cl₂TFA (3 mL) was added to the (30 mL) solution and the resulting mixture was stirred at room temperature for 18 hours. Then, make it basic with 1N NaOH aqueous solution (50 mL), and CH₂Cl₂Extracted with (3 x 30 mL). Combined extract H₂Wash with O and DDL₄The solvent was evaporated under reduced pressure. The residue (0.900 mg, 2.8 mmol) was dissolved in NMP (15 mL) and p-nitrophenyl-carbonate Wang resin (1.50 g, 1.40 mmol) was added thereto. The mixture was shaken at 180 RPM for 20 hours. Filter the resin, 2 x DMF, 2 x DMF / H₂O, 2 × H₂O, 2 × DMF, 2 × CH₂Cl₂, Washed with 1 × diethyl ether and dried in vacuum for 18 hours to obtain 1.50 g of Wang resin to which benzothiazepinylamine was bound as a yellow resin. [0850] (Step B) In a 13 mm glass tube, amine-bonded resin (0.050 g), o-tolylbenzeneboronic acid (0.054 g, 0.4 mmol), 2 M Na₂CO₃Aqueous solution (200 μL), (PPh₃)₄It was charged with Pd (0) (0.005 g) and THF (1 mL) and shaken at 70 ° C. and 180 RPM for 20 hours. Resin 3 x DMF, 2 x H₂O, 1 × DMF, 2 × CH₂Cl₂, And washed with 1 × diethyl ether. The dried resin was shaken with TFA (1 mL) at room temperature for 2 hours. Filter the resin and CH₂Cl₂Washed with (3 x 3 mL). The solvent of the filtrate was evaporated and dried in vacuo. Reversed phase HPLC (20% CH₃CN / H₂When the residue is purified by O), cis- (8a, 12a) -2- (4-fluorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4] , 3-b] [1,4] Chiazepino [2,3,4-hi] indole (0.008 g, 44% yield) was obtained and solidified. (M + H)⁺341. [0851] (Example 156) cis- (8a, 12a) -2- (2,3-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4 ] Chiazepino [2,3,4-hi] Indole [0852] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺391. [0853] (Example 157) cis- (8a, 12a) -2- (4-ethylphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0854] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺351. [0855] (Example 158) cis- (8a, 12a) -2- (2,4-dimethoxyphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [0856] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺383. [0857] (Example 159) cis- (8a, 12a) -2- (3-Chloro-2-fluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0858] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺375. [0859] (Example 160) cis- (8a, 12a) -2- (4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0860] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺353. [0861] (Example 161) cis- (8a, 12a) -2- [4- (methylsulfanyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [0862] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺369. [0863] (Example 162) 4- [cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-2-yl] Benzonitrile [0864] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺348. [0865] (Example 163) cis- (8a, 12a) -2- [3- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0866] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺391. [0867] (Example 164) cis- (8a, 12a) -2- (2-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0868] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺353. [0869] (Example 165) cis- (8a, 12a) -2- (1-naphthyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0870] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺373. [0871] (Example 166) 1- {4- [cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indoru-2-yl] Phenyl} Etanone [0872] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺265. [0873] (Example 167) N- {4- [cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indoru-2-yl] Phenyl} acetamide [0874] The title compound was prepared by the method of Example 155 and the corresponding arylboronic acid. (M + H)⁺380. [0875] (Example 168) cis- (8a, 12a) -2- (2,4-dichlorophenyl) -11-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0876] cis- (8a, 12a) -2- (2,4-dichlorophenyl) -11-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole follows Example 128 steps A-G with 1-methyl-4-piperidone hydrochloride in step B instead of 4-piperidin monohydrate. Prepared by use, 0.204 g (68%) of oil was obtained.¹1 H NMR (CDCl₃ 300MHz) δ7.42 (d, 1H), 7.23 (m, 2H), 7.01 (d, 1H), 6.98 (d, 1H), 3.90 (qd, 1H), 3.58 (dq, 1H), 3.38-3.50 ( m, 1H), 2.82-3.17 (m, 5H), 2.04 (s, 3H), 2.0-2.10 (m, 6H) ppm. (M + H)⁺405. [0877] (Example 169) cis- (8a, 12a) -2-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0878] Cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] obtained from step E of Example 128 ] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.100g, 0.24 mmol) and (PPh)₃)₂PdCl₂In (0.005 g) anhydrous THF (2 mL) solution, add 2 M trimethylaluminum hexane solution (0.17 mL, 0.34 mmol) to N.₂Added below. Reflux the mixture for 3 hours, cool to room temperature and a small amount of H₂Carefully treated with O, unreacted Al (CH₃)₃Was disassembled. Then H the mixture₂It was dissolved in O (50 mL) and extracted with EtOAc (3 x 10 mL). Combined extract EDTA₄The solvent was removed under reduced pressure to give a mixture of the desired product and the hydrolyzed product. The mixture was hydrolyzed as illustrated in Step G of Example 128 to give 0.027 g (44%) of the title compound as an oil to solidify. (M + H)⁺261. [0879] (Example 170) cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole-2-Carbonitrile [0880] Copper cyanide (0.161 g, 1.8 mmol) was added to cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- obtained from step E of Example 128. Pyrid [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.425 g, 1.0 mmol) in anhydrous DMF (5 mL) solution N₂It was added under gas and refluxed for 5 hours. The mixture was stirred for 14 hours at room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ammonium hydroxide and extracted with EtOAc (3 x 5 mL). Combined extract EDTA₄The solvent was removed under reduced pressure to give a mixture of the desired product and the hydrolyzed product in an amount of 0.260 g (81%). The mixture was hydrolyzed to the title compound with TFA and dichloromethane. The product was purified by flash chromatography using a solution of 9% methanol and 1% TEA in THF to give 0.070 g (54%) of the title compound as an oil. (M + H)⁺271. [0881] (Example 171) cis- (8a, 12a) -2-ethyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [0882] (Step A) Cis- (8a, 12a) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] obtained from step E of Example 128 ] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.680 g, 1.6 mmol) in a toluene (7 mL) solution with bis- (triphenylphosphine) palladium dichloride (0.032 g, 0.045 mmol) and some crystals of 2,6-di-tert-butyl-4-methylphenol were added. The mixture was refluxed for 3 hours and then evaporated to dryness under reduced pressure. Residue H₂It was dissolved in O (50 mL) and extracted with EtOAc (3 x 15 mL). Combined extract EDTA₄The solvent was removed under reduced pressure to give a mixture of product and unreacted starting material. The product was purified by flash chromatography (66% hexane in EtOAc) and as oil (8aS, 12aR) -2-vinyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-". b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate was isolated. Yield 0.080g (14%).¹1 H NMR (CDCl₃ 300MHz) δ6.94 (d, 2H), 6.48 (dd, 1H), 5.49 (d, 1H), 5.01 (d, 1H), 3.61-3.75 (m, 2H), 3.30-3.46 (m, 4H), 3.06-3.31 (m, 3H), 2.98-3.01 (m, 1H), 2.05 (s, 2H), 1.77-1.82 (m, 2H), 1.36 (s, 9H) ppm. (M + H)⁺273. [0883] (Step B) cis- (8a, 12a) -2-vinyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole-11 (8aH) -tert-butyl carbonate (0.080 g, 0.21 mmol) was added to a solution of EtOH (50 mL) with 10% Pd carbon (0.020 g). The mixture was hydrogenated at 50 psi (about 0.34 MPa) for 24 hours. At this point, an additional equivalent of 10% Pd carbon (0.020 g) was added and hydrogenated at 48 psi (about 0.33 MPa) for 48 hours. The mixture was filtered through Celite and evaporated to dryness under reduced pressure to give 0.038 g of foam. CH the obtained foam₂Cl₂It was dissolved in (3 mL) and TFA (0.5 mL) was added thereto. The mixture was stirred for 24 hours and then dissolved in 1N NaOH (5 mL). CH the product₂Cl₂Extract with (3 x 3 mL) and deli₄The mixture was dried under reduced pressure, evaporated to dryness under reduced pressure, collected with ether, and the title compound was obtained as a white powder. Yield 0.012g (43%).¹1 H NMR (CDCl₃ 300MHz) δ6.78 (d, 1H), 6.62 (d, 1H), 3.68 (qd, 1H), 3.44 (dq, 1H), 3.21-3.28 (m, 1H), 2.80-3.20 (m, 7H), 2.56 (m, 1H), 2.40 (q, 2H), 1.80-2.10 (m, 4H), 1.18 (t, 3H), 0.78-0.84 (m, 2H) ppm. (M + H)⁺275. [0884] (Example 172) cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi] Indole [4,3-b ] Indole [0885] (Step A) 2-Benzooxazoline (94.0 g, 0.70 mol) was added to an EtOH (800 mL) slurry of sodium methoxide (37.8 g, 0.70 mol). After refluxing the mixture for 1 hour, 1-bromo-3-chloropropane (220.42 g, 1.40 mol) was added. The mixture was refluxed for 18 hours, cooled to room temperature, filtered, then concentrated under reduced pressure and dried. The residue was dissolved in 10% KOH (500 mL) and extracted with ether (3 x 200 mL). Rinse the combined extracts with water and deli₄The solvent was removed under reduced pressure to give 3- (3-chloropropyl) -1,3-benzoxazole-2 (3H) -one 35.75 g (32%). Melting point 62-64 ° C. (M + H)⁺212. [0886] (Step B) Powdered KOH (37.60g, 0.67mol), N₂It was added under gas to a 3- (3-chloropropyl) -1,3-benzoxazole-2 (3H) -one (35.75 g, 0.169 mol) n-butanol (450 mL) slurry and refluxed for 52 hours. The mixture was filtered, concentrated under reduced pressure and dried. Residue H₂It was dissolved in O (500 mL) and extracted with ether (3 x 200 mL). Wash organic matter with 10% HCl (2 x 200 mL) and deli₄The solvent was removed under reduced pressure. Purification by flash chromatography (50% EtOAc in hexanes) gave 13.72 g (54%) of 2,3,4,5-tetrahydro-1,5-benzoxazepine as a powder. Melting point 50-51 ° C. (M + H)⁺149. [0887] (Step C) NaNO in a cold slurry of 2,3,4,5-tetrahydro-1,5-benzoxazepine (13.72 g, 91.96 mmol) and 2N aqueous HCl solution (105 mL) with stirring.₂(7.30 g, 105.75 mmol) H₂O (16 mL) solution was added dropwise, and the mixture was stirred at room temperature for 2 hours. Mixture H₂Dissolve in O (800 mL), extract with ether (3 x 200 mL), DDL₄The solvent was removed under reduced pressure to obtain 15.59 g (95%) of 5-nitroso-2,3,4,5-tetrahydro-1,5-benzoxazepine as a yellowish brown powder. (M + H)⁺178. [0888] (Step D) Using 5-nitroso-2,3,4,5-tetrahydro-1,5-benzoxazepine as a starting material, the title compound was prepared by steps A-C of Example 128 to give 36% as a powder. It was. Melting point 94-98 ° C.¹1 H NMR (CDCl₃ 300MHz) δ6.78 (m, 2H), 6.72 (d, 1H), 4.40 (dt, 1H), 3.78-3.82 (m, 1H), 3.30-3.41 (m, 3H), 3.18 (dt, 1H), 3.04 (dd, 1H), 2.82-2.94 (m, 2H), 2.42-2.61 (m, 2H), 2.08-2.14 (m, 2H), 1.90-2.01 (m, 1H), 1.74-1.82 (m, 1H) ) ppm. (M + H)⁺230. [0889] (Example 173) cis- (6b, 10a) -5- (2,4-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] Pirido [4,3-b] Indole [0890] As an amine cis- (8a, 12a) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridod Using [4,3-b] indole and the corresponding boronic acid, the title compound was prepared by the method shown in steps D-G of Example 128.₁1 H NMR (CDCl₃ 300MHz) δ7.39 (dd, 1H), 7.15-7.17 (m, 2H), 6.68 (dd, 1H), 6.64 (dd, 1H), 4.38-4.42 (m, 2H), 3.20-3.40 (m, 4H) ), 3.09-3.21 (m, 1H), 2.82-3.06 (m, 2H), 2.70-2.81 (m, 2H), 1.84-2.38 (m, 2H) ppm. (M + H)⁺361. [0891] (Example 174) cis- (6b, 10a) -5- (2-chloro-4-methoxyphenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4 -hi] Pirido [4,3-b] Indole [0892] cis- (8a, 12a) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4 , 3-b] Using indole and the corresponding boronic acid, the title compound was prepared by the method shown in steps D-G of Example 128. (M + H)⁺357. [0893] (Example 175) 11-Methyl-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole [0894] The title compound was prepared by step B of Example 128 as modified in Example 168.¹1 H NMR (CDCl₃ 300MHz) δ7.18 (dd, 1H), 7.01 (dd, 1H), 6.88 (m, 1H), 4.52 (t, 2H), 3.61 (s, 2H), 3.38 (t, 2H), 2.79-2.84 ( m, 4H), 2.58 (s, 3H), 2.25-2.34 (m, 2H) ppm. (M + H)⁺258. [0895] (Example 176) trans (8a, 12a) -11-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indole [0896] 11-Methyl-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole (2.41g, 9.33 mmol) ) In THF (30 mL) solution, BH₃-THF (1.0M, 20mL) N₂Dropped under gas. The mixture was then refluxed for 90 minutes. Once at room temperature, 6N HCl was added dropwise to decompose the excess borane and then saturated with 6N HCl (35 mL) and glacial acetic acid (12 mL). The acidic mixture was refluxed for 1 hour and then stirred overnight at room temperature. Remove the solvent under reduced pressure and leave the residue in H₂It was dissolved in O (10 mL) and NaOH (80 mL) and extracted with EtOAc (3 x 50 mL). Combined extract EDTA₄The solvent was removed under reduced pressure, and the mixture was purified by flash chromatography (9% MeOH in THF, 1% TEA) to obtain 1.42 g (58%) of the title compound as a colorless crystalline solid. Melting point 75-78 ° C.¹1 H NMR (CDCl₃ 300MHz) δ6.98 (dd, 1H), 6.80 (dd, 1H), 6.64 (t, 1H), 3.76-3.78 (m, 1H), 3.58-3.62 (m, 1H), 3.40 (dd, 1H), 3.00-3.08 (m, 2H), 2.78-2.91 (m, 2H), 2.40 (m, s, 4H), 2.20-2.26 (m, 1H), 2.10-2.19 (m, 2H), 1.99-2.06 (m) , 2H) ppm. [0897] (Example 177) trans (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [0898] A solution of methyl chloroformate (0.374 g, 3.96 mmol) in benzene (9 mL) with trans (8a, 12a) -11-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole (1.03 g, 3.96 mmol) was added to a solution of benzene (20 mL) and refluxed for 3 hours. The mixture was hot filtered and the solvent was removed from the filtrate under reduced pressure. The residue was dissolved in n-butanol (20 mL), powdered KOH (3.0 g) was added thereto, and the mixture was refluxed for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in ice water (80 mL) and extracted with CHCl (3 x 20 mL). Combined extract EDTA₄The solvent was removed under reduced pressure. The title compound was recovered with ether to give 0.032 g (4%) as a pure powder. Melting point 234 ° C (decomposition).¹1 H NMR (CDCl₃ 300MHz) δ7.00 (d, 1H), 6.78 (d, 1H), 6.74 (t, 1H), 3.80-3.98 (m, 2H), 3.57-3.64 (m, 2H), 2.94-3.09 (m, 4H) ), 2.62-2.76 (m, 1H), 2.20-2.36 (m, 2H), 1.98-2.14 (m, 1H), 1.30-1.42 (m, 2H) ppm. (M + H)⁺246. [0899] (Example 178) 4- (cis- (8a, 12a) -3-chloro-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone [0900] cis- (8a, 12a) -3-chloro-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole (90 mg, 0.32 mmol), 4-chloro-4'-fluorobutyrobenzophenone (161 mg, 0.8 mmol), KI (10 mg), and K₂CO₃(132, 0.96 mmol) was suspended in dioxane (0.6 mL). The resulting mixture was heated to reflux for 24 hours. After cooling to 23 ° C, H the reaction mixture₂O-CHCl₃Divided between (1: 1, 40 mL). Separate the layers and CHCl the aqueous layer₃Back extraction was performed with (2 x 30 mL). Combine the extracts and dry (EDTA)₄) And concentrated under vacuum. CHCl₃(100%), then 50: 1 CHCl₃-The residue was purified by column silica gel chromatography eluting with MeOH to give the title compound as a semi-solid (90 mg, 25%).¹H NMR (CD)₃OD, 300MHz) δ8.99 (dd, 2H, J = 8.8, 5.5Hz), 7.12 (t, 2H, J = 8.4Hz), 6.72 (s, 2H), 4.03-3.91 (m, 1H), 3.77- 3.62 (m, 1H), 3.27-3.00 (m, 1H), 3.09-2.81 (m, 7H), 2.78-2.69 (m, 3H), 2.42-2.32 (m, 2H), 2.30-2.19 (m, 1H) ), 2.16-1.75 (m, 4H) ppm. [0901] (Example 179) 4- (cis- (8a, 12a) -3-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone [0902] cis- (8a, 12a) -3-methyl-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole (0.033g, 0.09mmol), KI (0.0179g, 0.108mmol), K₂CO₃Combined with 4-chloro-4'-fluorobutyrophenone (0.0176 g, 0.09 mmol) in (0.062 g, 0.45 mmol) and 1,2-dioxane (0.7 mL). The mixture was refluxed for 4 days. Water was added and the layers were separated. CHCl the water layer₃Extract with (3 x 15 mL), wash the combined organic matter with saline and water, and dry (Na).₂SO₄) And evaporated. The yellow oil was purified by preparative silica gel TLC (70% EtOAc / Hexanes) to give the title compound (0.017 g, 45%) as a clear, colorless oil.¹H NMR (CD)₃OD, 300MHz) δ8.02 (q, 2H, J = 5.5, 3.7Hz), 7.16 (t, 2H, J = 2.9Hz), 6.73 (d, 1H, J = 7.7Hz), 6.53 (d, 1H, J = 8Hz), 3.94-4.05 (m, 1H), 4.6-4.78 (m, 1H), 3.18-3.24 (m, 1H), 3.05-3.16 (m, 3H), 2.97 (t, 2H, J = 7.3) Hz), 2.65-2.81 (m, 2H), 2.28-2.48 (m, 2H), 2.15 (s, 3H), 2.0-2.18 (m, 1H), 1.82-2.0 (m, 5H) ppm. [0903] (Example 180) cis- (8a, 12a) -11-{3-[(4-fluorophenyl) sulfanyl] propyl} -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [0904] cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indol (100 mg, 0.32 mmol) in a 1,4-dioxane (2 mL) solution, 3-chloro-1- (3-fluorophenylthio) propane (65.4 mg, 0.32 mmol), potassium iodide (64 mg, 0.38 mmol) ) And potassium carbonate (133 mg, 0.96 mmol) were added. The mixture was heated to reflux with stirring for 60 hours. At this point 1 equivalent (32.4 mg, 0.32 mmol) of TEA was added, followed by heating under reflux for an additional 3 days, followed by thin layer chromatography (9: 1 CH).₂Cl₂: MeOH) was performed. After 132 hours, water was added and the organic layer was extracted with EtOAc (3 x 50 mL), the extracts were combined and concentrated to give 170 mg crude oil. Column chromatography (concentration gradient: CH₂Cl₂Cis- (8a, 12a) -11-{3-[(4-fluorophenyl) sulfanyl] propyl} -6,7,8a, 9,10,12,12a with 1% and 10% MeOH) -Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (20 mg, 16%) was purified.¹1 H NMR (CDCl₃, 300MHz): δ7.26-7.21 (m, 2H), 7.08-7.00 (m, 1H), 6.94 (dd, 1H, J = 7.7Hz, J = 7.7Hz), 6.87-6.81 (m, 2H), 6.5 (t, 1H, J = 7.3Hz), 3.86-3.76 (m, 1H), 3.59-3.49 (m, 1H), 3.27-3.25 (m, 1H), 3.17-2.91 (m, 4H), 2.75- 2.72 (m, 1H), 2.61-2.58 (m, 1H), 2.45-2.39 (m, 2H), 2.31-2.2.2 (m, 1H), 2.18-2.02 (m, 3H), 1.99-1.82 (m) , 3H), 1.50 (s-broad, 1H), 1.25 (s, 2H) ppm. Mass spectrometry (ESI): 415 (base, M + H). [0905] (Example 181) 4- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanol [0906] 4- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Methanol (1 mL) was added to indol-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone (25 mg, 0.06 mmol). The flask was cooled to 0 ° C in an ice bath. Sodium cyanoborohydride (38 mg, 0.35 mmol) was added slowly and slowly. The reaction mixture was warmed to room temperature over 1 hour. Acetic acid (5 drops) was added and then concentrated under reduced pressure to give a residue. The residue is extracted with dichloromethane (1 x 50 mL), washed with sodium hydrogen carbonate (1 x 25 mL) and brine (1 x 25 mL), then dried (sodium sulfate) and concentrated under reduced pressure to give an oil. It was. A hydrochloride was formed by dissolving the oil in a minimum amount of chloroform and then adding an ether solution of hydrogen chloride (1M) until a precipitate formed. The solid was filtered off to give the title compound (21.1 mg, 81%).¹H NMR (CD)₃OD, 300MHz): δ7.40-7.37 (m, 2H), 7.06 (t, 2H, J = 8.7Hz), 6.95 (d, 2H, J = 8.1Hz), 6.66 (t, 1H, J = 7.4Hz) ), 4.8-4.7 (m, 1H), 3.83 (m, 1H), 3.1-3.53 (m, 3H), 3.45-3.30 (m, 2H), 3.22-3.18 (m, 3H), 3.18 (m, 1H) ), 2.91 (m, 1H), 2.59 (m, 1H), 2.37 (m, 1H), 2.0-2.2 (m, 5H) ppm. Mass spectrometry (ESI): 399 (base, M + H). [0907] (Example 182) cis-4-((6b,10a) -1,2,6b,9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyridoru [4,3-b] indol-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [0908] According to General Method A of Example 197, 3-chloro-4'-fluorobutyrophenone was added to cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1, 4] The title compound was prepared by addition to oxazepino [2,3,4-hi] pyrido [4,3-b] indole.¹1 H NMR (300MHz, CDCl₃) δ7.94-8.00 (m, 2H), 7.08-7.11 (m, 2H), 6.58-6.70 (m, 3H), 4.39-4.43 (m, 2H), 3.17-3.23 (m, 4H), 2.97- 3.09 (m, 4H), 2.66-2.80 (m, 2H), 2.37-2.52 (m, 2H), 1.90-2.10 (m, 4H) .MS-ESI: 381 [MH]⁺[0909] (Example 183) 1- (4-fluorophenyl) -4- (6- (trifluoromethyl) -1,2,9,10-tetrahydropyrido [4,3-b] [1,4] thiadino [2,3,4] -hi] Indoru-8 (7H) -Il) -1-Butanol [0910] 1- (4-fluorophenyl) -4- (6- (trifluoromethyl) -1,2,9,10-tetrahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3- b] Indol-8 (7H) -yl) -1-butanone (20 mg, 0.04 mmol) was dissolved in MeOH (0.8 mL) and cooled to 0 ° C in an ice bath. Sodium borohydride (9.8 mg, 0.25 mmol) was added slowly and the reaction was warmed to room temperature, which was stirred for 2 hours. Acetic acid (4 drops) was added and the reaction mixture was concentrated to give the title compound.¹H NMR (CD)₃OD, 300MHz): δ7.39-7.32 (m, 3H), 7.07-7.01 (m, 3H), 4.72 (s, 1H), 4.63-4.57 (m, 1H), 4.42-4.31 (m, 2H), 3.99-3.85 (m, 1H), 3.53 (t, 2H, J = 6.4Hz), 3.40-3.30 (m, 2H), 3.29-3.20 (m, 2H), 2.11-1.92 (m, 1H), 1.84- 1.40 (m, 4H) ppm. [0911] (Example 184) 8- {3- [2- (4-fluorophenyl) -1,3-dioxolane-2-yl] propyl} -6- (trifluoromethyl) -1,2,7,8,9,10-hexahydro Pirido [4,3-b] [1,4] Chiazino [2,3,4-hi] Indole [0912] 1- (4-fluorophenyl) -4- (6- (trifluoromethyl) -1,2,9,10-tetrahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3- b] Indol-8 (7H) -yl) -1-butanone (70 mg, 0.15 mmol) and ethylene glycol (10.4 mg, 0.17 mmol) anhydrous in a round bottom flask equipped with a Dean-Stark apparatus and a 3 Å molecular sieve. They were mixed together in toluene (5 mL). Some crystals of p-TsOH were added and the reaction was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, then extracted with dichloromethane (2 x 25 mL), washed with saturated sodium carbonate (1 x 15 mL) and brine (1 x 15 mL), dried (sodium sulfate) and concentrated. The product was purified by preparative thin layer chromatography on silica gel with 10% MeOH in dichloromethane as an eluent to give the title compound.¹1 H NMR (CDCl₃, 300MHz): δ8.00-7.95 (m, 2H), 7.10-6.92 (m, 4H), 4.30-4.26 (m, 2H), 4.03-4.00 (m, 1H), 3.79-3.71 (m, 3H) , 3.28-3.23 (m, 2H), 2.92-2.82 (m, 5H), 2.73 (t, 2H, J = 7.1Hz), 2.60 (t, 1H, J = 7.5Hz), 2.10-2.05 (m, 2H) ) ppm. [0913] (Example 185) cis- (6b, 10a) -8- [4- (4-fluorophenyl) butyl] -6- (trifluoromethyl) -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] Chiazino [2,3,4-hi] Indole [0914] 1- (4-fluorophenyl) -4- (6- (trifluoromethyl) -1,2,9,10-tetrahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3- b] Indol-8 (7H) -yl) -1-butanone (34.5 mg, 0.07 mmol) was dissolved in trifluoroacetic acid (0.5 mL) and cooled to 0 ° C. in an ice bath. Sodium cyanoborohydride (14 mg, 0.22 mmol) was added slowly and then stirred for 1 hour at 0 ° C. A 1N aqueous HCl solution (0.5 mL) was added and the reaction was heated to reflux for 0.5 hours. 50% sodium hydroxide was added until pH 11 was higher, extracted with dichloromethane (2 x 20 mL), dried (sodium sulfate) and concentrated to give the title compound.¹H NMR (CD)₃OD, 300MHz): δ7.18-7.15 (m, 2H), 7.12-6.91 (m, 3H), 6.81 (d, 1H, J = 6.8Hz), 3.69-3.65 (m, 1H), 3.56-3.28 ( m, 4H), 3.12-3.10 (m, 1H), 2.93-2.87 (m, 1H), 2.71-2.56 (m, 2H), 2.35-2.22 (m, 1H), 2.21-2.01 (m, 1H), 1.95-1.78 (m, 1H), 1.75-1.47 (m, 4H), 1.37-1.13 (m, 2H), 0.87-0.71 (m, 1H) ppm. [0915] (Example 186) 4- (trans (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru -11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone [0916] 4- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone (70 mg, 0.282 mmol), potassium iodide (28.2 mg, 0.17 mmol), potassium carbonate (84.5 mg, 0.61 mmol), And 4-Chloro-4'-fluorobutyrophenone (57 mg, 0.28 mmol) were combined in 1,4-dioxane (4 mL) and heated to reflux for 48 hours. The reaction was diluted with water (15 mL), extracted with diethyl ether (3 x 25 mL) and concentrated to give a residue. The residue was purified on a chiral cell OD column (8% 2-propanol in hexane) to give the respective enantiomers of the title compound (1 mg, 0.5%).¹H NMR (CD)₃OD, 300MHz): δ8.07 (t, 2H, J = 7.4Hz), 7.19 (t, 2H, J = 7.5Hz), 6.84 (dd, 2H, J = 8Hz, J = 7.7Hz), 6.64 (t , 1H, J = 7.7Hz), 3.70-3.61 (m, 1H), 3.52-3.45 (m, 2H), 3.18-3.01 (m, 3H), 2.90-2.82 (m, 1H), 2.63-2.58 (m) , 3H), 2.21-1.96 (m, 7H), 1.73-1.63 (m, 1H), 0.91-0.80 (m, 1H) ppm. [0917] (Example 187) 4- (cis- (8a, 12a) -2-methoxy-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone [0918] cis- (8a, 12a) -2-methoxy-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole (43 mg, 0.16 mmol) was dissolved in 1.2 mL MEK. KI (27 mg, 0.16 mmol) and K₂CO₃(66 mg, 0.48 mmol), and 2a (112 mg, 0.56 mmol) were added. The suspension was refluxed for 48 hours and then cooled to room temperature. Filter the suspension and CH the residue₂Cl₂Washed with (5 ml). The solution was concentrated under vacuum. Column chromatography of residue (10% MeOH-CH₂Cl₂) To give the title compound (67 mg, 95%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.95-8.02 (m, 2H), 7.08-7.12 (m, 2H), 6.42 (dd, 2H, 2.2Hz, 8.8Hz), 3.60-3.80 (m, 5H), 3.40-3.58 (m) , 2H), 3.15-3.25 (m, 1H), 2.90-3.10 (m, 4H), 2.70-2.88 (m, 2H), 2.50-2.68 (m, 1H), 2.39 (dt, 2H, 3.7Hz, 7.4 Hz), 2.24 (dt, 1H, 4.1Hz, 11.0Hz), 1.70-2.10 (m, 5H) ppm. MS (ESI): 441.1 (M + H). [0919] (Example 188) cis-4-((6b,10a) -1,2,6b,9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] indoru -8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [0920] cis- (6b, 10a) -1,2,6b,7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] Indole (99 mg, 0.43 mmol), 4-chloro-4'-fluorobutyrophenone (112 mg, 0.56 mmol), KI (71 mg, 0.43 mmol), and K₂CO₃After chromatographic purification from (177 mg, 1.28 mmol) by the method of Example 187, the title compound (55.9 mg, 50%) was prepared as a white amorphous solid. The enantiomers of the title compound were separated on a chiral cell OD column using non-gradient 6% IPA / hexane as eluent.¹1 H NMR (CDCl₃, 300MHz) δ7.26-8.01 (m, 2H), 7.12 (t, 2H, 8.4Hz), 6.81 (t, 2H, 7.7Hz), 6.19 (t, 1H, 7.6Hz), 3.38-3.62 (m, 2H), 3.25-3.37 (m, 1H), 2.85-3.20 (m, 5H), 2.70-2.85 (m, 1H), 2.50-2.70 (m, 1H), 2.45-2.68 (m, 2H), 2.20 ( dt, 1H, 3.0Hz, 11.4Hz), 1.70-2.10 (m, 5H) ppm. MS (ESI): 397.2 (base, M + H). [0921] (Example 192) 4- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (4-bromophenyl) -1-butanone [0922] cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole (594.00 mg, 2.44 mmol), 4-chloro-4'-fluorobutyrophenone (831.00 mg, 3.18 mmol), KI (406.00 mg, 2.44 mmol), and K₂CO₃After chromatographic purification from (638.00 mg, 7.33 mmol) by the method of Example 187, the title compound (932 mg, 81%) was prepared as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.87-7.92 (m, 2H), 7.64-7.68 (m, 2H), 6.94-6.99 (m, 2H), 6.67 (t, 1H, 7.4Hz), 3.70-3.90 (m, 2H) , 3.41-3.68 (m, 4H), 2.30-3.40 (m, 1H), 3.00-3.29 (m, 5H), 2.80-2.98 (m, 1H), 2.61-2.68 (t, 1H, 11.7Hz), 1.90 -2.50 (m, 6H) ppm. MS (CI, NH₃): 473 (base, M + H). [0923] (Example 193) (8aS, 12aR) -11-{3-[(4-fluorophenyl) sulfonyl] propyl} -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (139.00 mg, 0.49 mmol), 3- (3-fluorophenylsulfonyl) propyl chloride (116.00 mg, 0.49 mmol), KI (48.00 mg, 0.29 mmol), and K₂CO₃After chromatographic purification from (135.00 mg, 0.98 mmol) by the method of Example 187, the title compound (188.00 mg, 86%) was prepared as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.71 (bd, 1H, 6.6Hz), 7.54-7.65 (m, 2H), 7.36-7.40 (m, 1H), 6.93 (dd, 1H, 1.1Hz, 7.7Hz), 6.62 (m, 1H), 3.73-3.76 (m, 1H), 3.45-3.52 (m, 1H), 3.18-3.30 (m, 3H), 2.90-3.18 (m, 3H), 2.57-2.62 (m, 1H), 2.41- 2.55 (m, 1H), 2.17-2.41 (m, 3H), 1.95-2.17 (m, 2H), 1.65-1.94 (m, 5H) ppm. MS (ESI): 447.2 (base, M + H). [0924] (Example 194) 4- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (3', 4'-dichloro [1,1'biphenyl] -4-yl) -1-butanone [0925] 4- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (4-bromophenyl) -1-butanone (123.9 mg, 0.26 mmol) was dissolved in DME (4 mL). A 2 M aqueous sodium carbonate solution (0.75 mL) was added. After adding 3,4-dichlorophenylboric acid (100.4 mg, 0.53 mmol), Pd₂(dba)₃(13.5 mg, 0.013 mmol) was added. PPh₃(13.8 mg, 0.053 mmol) was added. The reaction flask was degassed and maintained in a nitrogen atmosphere. The suspension was refluxed for 18 hours and cooled to room temperature. After concentrating the reaction under vacuum, water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried and concentrated to give a crude brown amorphous solid (187 mg). The residue was purified by column chromatography (20-40% EtOAc / Hexanes) to give the title compound (140.0 mg, 100%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ8.03-8.06 (m, 1H), 7.43-7.71 (m, 6H), 6.93 (dd, 1H, 1.1Hz), 6.84 (bd, 1H, 6.6Hz), 6.58-6.63 (m, 1H) ), 3.70-3.90 (m, 1H), 3.50-3.60 (m, 1H), 3.15-3.30 (m, 1H), 2.90-3.18 (m, 4H), 2.50-2.80 (m, 2H), 2.20-2.50 (m, 3H), 1.50-2.20 (m, 8H) ppm. MS (ESI): 537.2 (base, M + H). [0926] (Example 195) 1- (4-fluorophenyl) -4- (6- (trifluoromethyl) -1,2,9,10-tetrahydropyrido [4,3-b] [1,4] thiadino [2,3,4] -hi] Indoru-8 (7H) -Il) -1-Butanone [0927] 6- (Trifluoromethyl) -1,2,7,8,9,10-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole (60mg, 0.20 mmol) was dissolved in 1.2 mL of MEK. KI (33 mg, 0.20 mmol) and K₂CO₃(52 mg, 0.60 mmol), and 4-chloro-4'-fluorobutyrophenone (52.5 mg, 0.26 mmol) were added. The suspension was refluxed for 48 hours and then cooled to room temperature. Filter the suspension and CH the residue₂Cl₂Washed with (5 ml). The solution was concentrated under vacuum. Column chromatography of residue (10% MeOH-CH₂Cl₂) To obtain the title compound (33 mg, 37%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.94-8.02 (m, 2H), 7.29 (d, 1H, 8.4Hz), 7.05-7.10 (m, 2H), 6.95 (d, 1H, 7.7Hz), 4.27-4.30 (m, 2H) ), 3.81 (s, 2H), 3.25-3.29 (m, 2H), 3.07 (t, 2H, 7.0Hz), 2.95 (m, 2H), 2.86 (m, 2H), 2.78 (t, 2H, 6.9Hz) ), 2.06-2.19 (m, 2H) ppm. MS (ESI): 463.2 (base, M + H). [0928] (Example 197) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (4-methylphenyl) -1-butanone [0929] (General method A) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole The corresponding chlorobutyrophenone (0.5-1.0 mmol), potassium iodide (100 mg) and potassium carbonate (300 mg) were added to a (0.5 mmol) 1,4-dioxane (3 mL) suspension. The reaction mixture was heated to reflux for 2 days. The solvent was removed under reduced pressure. The residue was treated with water (50 mL) and extracted with diethyl ether (3 x 50 mL). The ether extract is washed with saline solution (150 mL) and deli₄It was dried in, filtered and concentrated to give a residue. Flash column chromatography (silica gel, CH) of the residue₂Cl₂: CH₃Purified by OH9: 1). The product was dissolved in ether (2 mL), stirred at 0 ° C for 10 minutes and a 1N HCl ether solution (0.5 mL) was added at 0 ° C. The white crystalline solid was collected by filtration to give the title compound in 50-90% yield. [0930] (General method B) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole To a suspension of (0.5 mmol) 1,4-dioxane (3 mL) was added the corresponding alkyl halides (0.5-1.0 mmol), potassium iodide (100 mg) and triethylamine (1.5 mmol). The reaction mixture was heated to reflux for 2 days. The solvent was removed under reduced pressure. The residue was treated with water (50 mL) and extracted with diethyl ether (3 x 50 mL). The ether extract is washed with saline solution (150 mL) and deli₄It was dried in, filtered and concentrated to give a residue. Flash column chromatography (silica gel, CH) of the residue₂Cl₂: CH₃Purified by OH9: 1). The product was dissolved in ether (2 mL), stirred at 0 ° C for 10 minutes and a 1N HCl ether solution (0.5 mL) was added at 0 ° C. The white crystalline solid was collected by filtration to give the title compound in 50-90% yield. [0931] 4-Chloro-4'-methylbutyrophenone (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] according to general method A above. The title compound was prepared by adding to [1,4] butyrophenone [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ7.86 (d, J = 8.0Hz, 2H), 7.25 (d, J = 8.0Hz, 2H), 6.94 (d, J = 7.7Hz, 1H), 6.84 (d, J = 7.3Hz, 1H) , 6.61 (dd, J = 7.7Hz, 7.3Hz, 1H), 3.72-3.86 (m, 2H), 3.44-3.59 (m, 2H), 3.22-3.27 (m, 1H), 2.98-3.14 (m, 7H) ), 2.41 (s, 3H), 2.68-2.84 (m, 2H), 1.89-2.16 (m, 6H) ppm. MS-ESI: 407 [MH]⁺[0932] (Example 198) 4-((8aS, 12aR) 1-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru -11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone [0933] 4-Chloro-4'-fluorobutyrophenone (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3] according to General Method A of Example 197. -b] [1,4] Thiazepino [2,3,4-hi] Indole was added to prepare the title compound.¹1 H NMR (300MHz, CDCl₃) δ7.97-8.02 (m, 2H), 7.10-7.16 (m, 2H), 6.95 (d, J = 8.0Hz, 1H), 6.85 (d, J = 7.3Hz, 1H), 6.62 (dd, J = 7.2Hz, 7.3Hz, 1H), 3.76-3.86 (m, 1H), 3.44-3.59 (m, 2H), 3.24-3.30 (m, 1H), 2.90-3.14 (m, 4H), 2.68-2.84 ( m, 4H), 2.24-2.58 (m, 4H), 1.99-2.11 (m, 4H) ppm. MS-ESI: 411 [MH]⁺[0934] (Example 199) 4-((8aS, 12aR) l-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru -11 (8aH) -yl) -1- (4-methoxyphenyl) -1-butanone [0935] 4-Chloro-4'-methoxybutyrophenone (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3] according to General Method A of Example 197. -b] [1,4] Thiazepino [2,3,4-hi] Indole was added to prepare the title compound.¹1 H NMR (300MHz, CDCl₃) δ7.93-7.99 (m, 2H), 6.88-6.98 (m, 3H), 6.84 (d, J = 7.0Hz, 1H), 6.61 (dd, J = 8.0Hz, 7.3Hz, 1H), 3.87 ( s, 3H), 3.70-3.90 (m, 2H), 3.48-3.58 (m, 1H), 3.22-3.27 (m, 1H), 2.90-2.99 (m, 4H), 2.62-2.80 (m, 4H), 2.27-2.42 (m, 4H), 1.90-2.13 (m, 4H) ppm. MS-ESI: 423 [MH]⁺[0936] (Example 200) 3-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (4-fluorophenyl) -1-propanone [0937] 3-Chloro-4'-fluoropropiophenone (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4] according to General Method A of Example 197. , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole was added to prepare the title compound.¹1 H NMR (300MHz, CDCl₃) δ7.98-8.03 (m, 2H), 7.12-7.18 (m, 2H), 6.88 (d, J = 7.6Hz, 1H), 6.87 (d, J = 6.2Hz, 1H), 6.65 (dd, J = 7.7Hz, 7.3Hz, 1H), 3.79-3.88 (m, 1H), 3.7 (s, 2H), 3.50-3.60 (m, 1H), 3.25-3.38 (m, 3H), 2.89-3.01 (m, 7H), 1.90-2.15 (m, 4H) .MS-ESI: 397 [MH]⁺[0938] (Example 201) (8aS, 12aR) -11-{3-[(4-fluorophenyl) sulfonyl] propyl} -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [0939] According to General Method A of Example 197, 3-chloro-1-[(4-fluorophenyl) sulfonyl) propane was added to (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-. The title compound was prepared by adding to 5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ7.90-7.96 (m, 2H), 7.22-7.28 (m, 2H), 9.38 (d, J = 7.7Hz, 1H), 6.82 (d, J = 6.6Hz, 1H), 6.61 (dd, J = 7.7Hz, 7.3Hz, 1H), 3.72-3.81 (m, 1H), 3.45-3.55 (m, 1H), 3.15-3.29 (m, 4H), 3.02-3.12 (m, 2H), 2.92-2.99 ( m, 1H), 2.57-2.62 (m, 1H), 2.46-2.55 (m, 1H), 2.30-2.37 (m, 2H), 2.18-2.27 (m, 1H), 1.94-2.09 (m, 2H), 1.78-1.92 (m, 4H) ppm. MS (CI, NH₃) m / e446 (base, M + H⁺). [0940] (Example 202) (8aS, 12aR) -11-{3-[(4-fluorophenyl) sulfinyl] propyl} -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [0941] According to General Method A of Example 197, 3-chloro-1-[(4-fluorophenyl) sulfinyl] propane was added to (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro- The title compound was prepared by adding to 5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CD₃OD) δ7.65-7.80 (m, 2H), 7.27-7.31 (m, 2H), 6.95 (d, J = 8.1Hz, 2H), 6.63 (dd, J = 8.1Hz, 7.7Hz, 1H), 3.63 -3.93 (m, 1H), 3.38-3.62 (m, 4H), 3.10-3.25 (m, 4H), 3.26-3.36 (m, 2H), 2.92-3.09 (m, 3H), 2..50-2.62 (m, 1H), 2.30-2.42 (m, 1H), 1.94-2.28 (m, 4H) ppm. MS (CI, NH₃) m / e430 (base, 287). [0942] (Example 203) (8aS, 12aR) -11- [3- (4-fluorophenoxy) propyl] -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1,4 ] Chiazepino [2,3,4-hi] Indole [0943] According to General Method A of Example 197, 3-chloro-1- (4-fluorophenoxy) propane was added to (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido. The title compound was prepared by adding to [4,3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ6.91-7.00 (m, 3H), 6.79-6.87 (m, 3H), 6.62 (dd, J = 7.7Hz, 7.3Hz, 1H), 3.97 (t, J = 6.2,2H), 3.70-3.87 (m, 1H), 3.50-3.60 (m, 1H), 3.18-3.31 (m, 2H), 2.90-3.12 (m, 2H), 2.70-2.80 (m, 2H), 2.40-2.62 (m, 2H) , 2.22-2.38 (m, 1H), 1.90-2.11 (m, 7H) ppm. MS-ESI: 399 [MH]⁺[0944] (Example 204) (8aS, 12aR) -11- (3-phenoxypropyl) -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole [0945] According to General Method B of Example 197, 3-chloro-1-phenoxypropane (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] Indole was added to prepare the title compound.¹1 H NMR (300MHz, CDCl₃) δ7.25-7.30 (m, 2H), 6.85-6.97 (m, 5H), 6.62 (dd, J = 7.7Hz, 7.3Hz, 1H), 4.02 (t, J = 6.2Hz, 2H), 3.78- 3.88 (m, 1H), 3.50-3.60 (m, 1H), 3.17-3.31 (m, 2H), 2.90-3.10 (m, 2H), 2.72-2.86 (m, 2H), 2.51-2.58 (m, 2H) ), 2.30-2.37 (m, 1H), 1.92-2.15 (m, 7H) ppm. MS (CI, NH₃) m / e380 (base, M + H⁺). [0946] (Example 205) (8aS, 12aR) -11-[3-[(4-fluorophenyl) sulfanyl] propyl] -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [0947] According to General Method B of Example 197, 3-chloro-1- (4-fluorophenylthio) propane was added to (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- The title compound was prepared by adding to pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ7.31-7.36 (m, 2H), 6.93-7.02 (m, 4H), 6.84 (d, J = 7.3Hz, 1H), 6.2 (dd, J = 7.3Hz, 7.3Hz, 1H), 3.76- 3.84 (m, 1H), 3.48-3.59 (m, 1H), 3.24-3.28 (m, 2H), 2.88-3.17 (m, 6H), 2.60-2.74 (m, 2H), 2.25-2.45 (m, 2H) ), 2.00-2.11 (m, 2H), 1.77-1.93 (m, 4H) ppm. MS (CI, NH₃) m / e414 (base, M + H⁺). [0948] (Example 206) N- [3-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-11 (8aH) -yl) propyl] -4-fluoroaniline [0949] According to General Method B of Example 197, 3-chloropropyl-4-fluorophenylamine (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,, The title compound was prepared by adding to 3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ6.97 (d, J = 8.1Hz, 1H), 6.93-7.02 (m, 3H), 6.64 (dd, J = 7.7Hz, 7.3Hz, 1H), 6.47-6.52 (m, 2H), 3.75- 3.85 (m, 1H), 3.46-3.56 (m, 1H), 3.25-3.35 (m, 2H), 2.91-3.20 (m, 6H), 2.60-2.74 (m, 2H), 1.91-2.17 (m, 8H) ) ppm. MS (CI, NH₃) m / e397 (base, M + H⁺). [0950] (Example 207) N- [3-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-11 (8aH) -yl) propyl] -4-fluoro-N-methylaniline [0951] According to General Method B of Example 97, 3-chloropropyl-4-fluorophenylmethylamine (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4] , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole was added to prepare the title compound.¹1 H NMR (300MHz, CDCl₃) δ6.84-6.99 (m, 4H), 6.59-6.67 (m, 3H), 3.77-3.90 (m, 1H), 3.47-3.59 (m, 1H), 3.19-3.33 (m, 4H), 2.67- 3.09 (m, 4H), 2.87 (s, 3H), 2.33-2.37 (m, 3H), 1.76-2.17 (m, 7H) ppm. MS (CI, NH₃) m / e411 (base, M + H⁺). [0952] (Example 208) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (4-pyridinyl) -1-butanone [0953] 4-Chloro-1- (4-pyridyl) butane-1-one (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-according to General Method A of Example 197. The title compound was prepared by adding to 5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ8.79 (dd, J = 5.9Hz, 1.5Hz, 2H), 7.73 (dd, J = 6.2Hz, 1.8Hz, 2H), 6.93 (d, J = 7.7Hz, 1H), 6.82 (d, J) = 7.4Hz, 1H), 6.59 (dd, J = 7.7Hz, 7.4Hz, 1H), 3.64-3.82 (m, 4H), 3.46-3.56 (m, 2H), 3.19-3.24 (m, 2H), 2.88 -3.06 (m, 4H), 2.60-2.75 (m, 2H), 2.28-2.42 (m, 2H), 1.87-2.09 (m, 4H) ppm. MS (CI, NH₃) m / e393 (base, M + H⁺). [0954] (Example 209) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (3-pyridinyl) -1-butanone [0955] 4-Chloro-1- (3-pyridyl) butane-1-one (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-according to General Method A of Example 197. The title compound was prepared by adding to 5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ9.18 (d, J = 2.2Hz, 1H), 8.76 (dd, J = 4.7Hz, 1.8Hz, 1H), 8.23 (dt, J = 8.1Hz, 1.8Hz, 1H), 7.40 (dd, J = 8.1Hz, 4.8Hz, 1H), 6.91-6.95 (m, 1H), 6.82-6.87 (m, 1H), 6.57-6.63 (m, 1H), 3.49-3.83 (m, 4H), 3.06-3.25 ( m, 2H), 3.01 (t, J = 7.0Hz, 2H), 2.52-2.94 (m, 4H), 2.26-2.39 (m, 2H), 1.83-2.10 (m, 6H) ppm. MS (CI, NH₃) m / e393 (base, M + H⁺). [0956] (Example 210) cis-4-((6b,10a) -3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2,3 -de] Quinoxaline-8 (7H) -yl) -1- (4-pyridinyl) -1-butanone [0957] 4-Chloro-1- (4-pyridyl) butane-1-one was added to cis- (6b, 10a) -3-methyl-2,3,6b, 7,8,9, according to General Method A of Example 197. The title compound was prepared by adding to 10,10a-octahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] quinoxaline.¹1 H NMR (300MHz, CDCl₃) δ8.79 (dd, J = 4.4Hz, 1.8Hz, 2H), 7.74 (dd, J = 4.4Hz, 1.4Hz, 2H), 6.64 (dd, J = 7.4Hz, 7.6Hz, 1H), 6.49 ( d, J = 6.9Hz, 1H), 6.39 (d, J = 7.7Hz, 1H), 3.54-3.62 (m, 1H), 3.23-3.31 (m, 2H), 3.13-3.17 (m, 1H), 2.95 -3.03 (m, 2H), 2.85 (s, 3H), 2.76-2.84 (m, 2H), 2.57-2.60 (m, 1H), 2.31-2.41 (m, 1H), 2.22 (td, J = 11.7Hz , 2.9Hz, 1H), 1.92-2.02 (m, 3H), 1.83-1.88 (m, 1H), 1.66-1.76 (m, 2H) ppm. MS (CI, NH₃) m / e376 (base, M + H⁺). [0958] The title compound was separated into the corresponding enantiomers by chiral chromatography separation (chiral pack AD column, methanol / ethanol: 50/50).¹1 H NMR (300MHz, CDCl₃) δ8.79 (dd, J = 4.4Hz, 1.8Hz, 2H), 7.74 (dd, J = 4.4Hz, 1.4Hz, 2H), 6.64 (dd, J = 7.4Hz, 7.6Hz, 1H), 6.49 ( d, J = 6.9Hz, 1H), 6.39 (d, J = 7.7Hz, 1H), 3.54-3.62 (m, 1H), 3.23-3.31 (m, 2H), 3.13-3.17 (m, 1H), 2.95 -3.03 (m, 2H), 2.85 (s, 3H), 2.76-2.84 (m, 2H), 2.57-2.60 (m, 1H), 2.31-2.41 (m, 1H), 2.22 (td, J = 11.7Hz , 2.9Hz, 1H), 1.92-2.02 (m, 3H), 1.83-1.88 (m, 1H), 1.66-1.76 (m, 2H) ppm. MS (CI, NH₃) m / e376 (base, M + H⁺). [0959] (Example 211) cis- (6b, 10a) -2,3,6b, 7,8,9,10,10a-Octahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2,3-de] Quinoxaline [0960] (Step A) Using the methods described in steps E through G of Example 4, the corresponding amines 1,3,4-trihydroquinoxaline-2-one and 4-oxopiperidine ethyl carbonate to 2-oxo-2,3 , 9,10-Tetrahydro-1H-Pyrid [3', 4': 4,5] Pyrrolo [1,2,3-de] Quinoxaline-8 (7H) -Ethyl carbonate was prepared. This indole (5.74 g, 19.2 mmol) was dissolved in TFA (100 mL). The reaction was cooled to 0 ° C. NaCNBH₃(3.96 g, 63.0 mmol) was added in small portions over 30 minutes while maintaining a temperature below 5 ° C. The reaction was stirred at room temperature for 4 hours. Ice was added to the reaction flask and the reaction was basicized with 50% NaOH to pH = 12. Water (80 mL) was added to dissolve the precipitate. Reactant CHCl₃Extracted with (3 x 200 mL). The combined organic layers were washed with saline, dried, concentrated and cis- (6b, 10a) -2-oxo-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3'. , 4': 4,5] Pyrrolo [1,2,3-de] quinoxaline-8 (7H) -ethyl carbonate (4.41 g, 77%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ8.45 (bs, 1H), 6.86 (d, J = 7.4Hz, 1H), 6.74 (dd, J = 7.7Hz, 7.7Hz, 1H), 6.63 (d, J = 7.3Hz, 1H) , 4.15 (q, J = 7.0Hz, 2H), 3.89-3.993 (m, 2H), 3.41-3.47 (m, 2H), 3.33-3.41 (m, 2H), 3.12-3.31 (m, 1H), 2.69 -2.75 (m, 2H), 1.90-1.92 (m, 2H), 1.28 (t, J = 7.3Hz, 3H) ppm. MS-APcI: 302 [MH]⁺[0961] (Step B) cis- (6b, 10a) -2-oxo-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] Quinoxaline-8 (7H) -ethyl carbonate (4.41g, 14.6 mmol) with 1M BH₃A THF complex solution (36.6 mL) was added. The reaction was heated to reflux for 5 hours. After cooling the reaction to room temperature, 6N HCl (40 mL) was added dropwise while cooling. The reaction was heated to reflux for 30 minutes. After cooling to room temperature, 1N NaOH was added to adjust the pH to 8. CH reactant₂Cl₂Extracted with (2 x 200 mL). The combined organic layer was washed with saline solution and deli was used.₄Dry and concentrate with cis- (6b, 10a) -2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2, 3-de] Quinoxaline-8 (7H) -ethyl carbonate (4.10 g, 98%) was obtained. The product was used in the next step without further purification. MS-APcI: 288 [MH]⁺.. [0962] (Step C) cis- (6b, 10a) -2,3,6b, 9,10,10a-Hexahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2,3-de] Quinoxaline-8 ( To 7H) -ethyl carbonate (4.10 g, 14.3 mmol) was added n-butanol (18.0 mL) and KOH powder (3.0 g). The reaction was heated to 119 ° C for 18 hours in a closed tube. The solvent was removed under reduced pressure. Add water (30 mL) to the residue and CH₂Cl₂Extracted with (3 x 50 mL). The combined organic layer was washed with saline solution and deli was used.₄It was dried in and concentrated to give the title compound as a pale yellow oil (2.70 g, 78%). MS-ESI: 216 [MH]⁺.. [0963] (Example 212) cis-4-((6b, 10a) -2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] quinoxaline -8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [0964] (Step A) cis- (6b, 10a) -2,3,6b, 7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2,3-de] To quinoxaline (2.70 g, 10.8 mmol) was added 1N NaOH (40.0 mL) and dioxane (40.0 mL). Boc₂O was added in small portions at 0 ° C for 30 minutes. The reaction was stirred at room temperature for 18 hours. CH reactant₂Cl₂Extracted with (3 x 150 mL). The combined organic layer was washed with saline solution and deli was used.₄Dry and concentrate to obtain a residue, which is purified by flash column chromatography (hexane / ethyl acetate: 50/50) to cis-2,3,6b,7,8,9,10,10a. -Octahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] -quinoxaline-8-yl-tert-butyl carbonate was obtained. The racemic compound was separated by a chiral cell OD column (5 cm × 50 cm, 20u; IPA / hexane: 8%) to give the corresponding enantiomers. [0965] (Step B) cis-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] -quinoxaline-8-yl -20% TFA / CH in any of the enantiomers of tert-butyl carbonate (790 mg, 2.25 mmol)₂Cl₂(5 mL) was added and stirred at room temperature overnight. The solution was concentrated to a residue to give the TFA salt in 99% yield. To this indoline TFA salt (493.5 mg, 1.5 mmol), triethylamine (0.4 mL), K₂CO₃(300 mg), KI (100 mg) and 1,4-dioxane (6 mL) were added. The reaction was heated to 103 ° C for 24 hours in a closed tube. The solvent was removed under reduced pressure. Add water (30 mL) to the residue and CH₂Cl₂Extracted with (3 x 50 mL). The combined organic layer was washed with saline solution and deli was used.₄It was dried in and concentrated to obtain a residue. The residue was purified by flash column chromatography to give the title compound (280 mg, 53% yield).¹1 H NMR (CDCl₃, 300MHz) δ7.97-8.02 (m, 2H), 7.09-7.15 (m, 2H), 6.51-6.61 (m, 2H), 6.38 (dd, J = 7.3Hz, J = 1.4Hz, 1H), 3.64 -3.72 (m, 2H), 3.26-3.49 (m, 2H), 3.13-3.24 (m, 2H), 2.99-3.04 (m, 2H), 2.91-2.97 (m, 1H), 2.61-2.79 (m, 2H), 2.43-2.53 (m, 2H), 2.34-2.43 (m, 1H), 1.95-2.13 (m, 4H) ppm. MS-ESI: 380 [MH]⁺[0966] (Example 213) cis-4-((6b, 10a) -5-methyl-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3,4] -hi] Indol-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [0967] 4-Chloro-4'-fluorobutyrophenone was added to cis- (6b, 10a) -5-methyl-1,2,6b, 7,8,9,10,10a-octahydropyri according to General Method A of Example 197. The title compound was prepared by adding to do [4,3-b] [1,4] thiazino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ7.90-8.03 (m, 2H), 6.81-7.16 (m, 4H), 3.75-3.80 (m, 1H), 3.39-3.52 (m, 2H), 3.18-3.24 (m, 2H), 3.06- 3.13 (m, 2H), 2.84-2.94 (m, 1H), 1.92-2.52 (m, 10H), 2.24 (s, 3H) ppm. MS-ESI: 411 [MH]⁺[0968] (Example 214) (8aS, 12aR) -11-[3- (6-fluoro-1,2-benzoisooxasol-3-yl) propyl] -6,7,8a, 9,10,12,12a-octahydro-5H- Pirido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0969] According to General Method A of Example 197, 3- (3-chloropropyl) -6-fluorobenzo [d] isooxazole was added to (8aS, 12aR) -6,7,8a, 9,10,11,12,12a- The title compound was prepared by adding to octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ7.66 (dd, J = 8.4Hz, 5.1Hz, 1H), 7.23 (dd, J = 8.5Hz, 1.8Hz, 1H), 7.06 (ddd, J = 8.7Hz, 8.8Hz, 2.2Hz, 1H) , 6.93 (dd, J = 7.7Hz, 0.9Hz, 1H), 6.84 (d, J = 6.6Hz, 1H), 6.61 (dd, J = 7.7Hz, 7.3Hz, 1H), 3.70-3.83 (m, 1H) ), 3.48-3.56 (m, 1H), 3.23-3.27 (m, 1H), 2.91-3.12 (m, 5H), 2.71-2.77 (m, 1H), 2.61-2.65 (m, 1H), 2.39-2.46 (m, 2H), 2.24-2.28 (m, 1H), 1.90-2.11 (m, 4H), 1.84-1.88 (m, 3H) ppm. MS-ESI: 424 [MH]⁺[0970] (Example 215) (8aS, 12aR) -11- [3- (1,2-benzoisooxasol-3-yl) propyl] -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4, 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [0971] According to General Method A of Example 197, 3- (3-chloropropyl) benzo [d] isoxazole was added to (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- The title compound was prepared by adding to pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ7.67 (dd, J = 7.7Hz, 1.1Hz, 1H), 7.53-7.55 (m, 2H), 7.27-7.33 (m, 1H), 6.94 (dd, J = 7.7Hz, 1.1Hz, 1H) , 6.84 (d, J = 6.6Hz, 1H), 6.61 (dd, J = 7.6Hz, 7.4Hz, 1H), 3.76-3.84 (m, 1H), 3.48-3.58 (m, 1H), 3.23-3.27 ( m, 1H), 2.91-3.17 (m, 5H), 2.67-2.82 (m, 2H), 2.45-2.51 (m, 2H), 2.24-2.38 (m, 1H), 1.89-2.14 (m, 7H) ppm .. MS (CI, NH₃) m / e405 (base, M + H⁺). [0972] (Example 217) cis- (6b, 10a) -8- [3- (6-fluoro-1,2-benzoisooxasol-3-yl) propyl] -3-methyl-2,3,6b, 7,8,9, 10,10a-Octahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] quinoxaline [0973] (Step A) To a cold boron trifluoride (280 mmol) ether solution was added 3-fluorophenol or phenol (89 mmol) and 4-chlorobutyryl chloride (178 mmol). The resulting solution was stirred for 18 hours at 130 ° C. The reaction mixture was cooled and poured into ice water (100 mL). After stirring for 10 minutes, the water mixture was extracted with ether (3 x 100 mL). The ether layer is washed with saline solution (100 mL) and deli₄Dry, filter, concentrate to residue, 4-chloro-1- (4-fluoro-2-hydroxyphenyl) butane-1-one and 4-chloro-1- (2-hydroxyphenyl) butane-1 -On was obtained in yields of 52% to 67%. This was used in the next step without further purification. [0974] (Step B) To pyridine (25 mL) was added the corresponding ketone (46.5 mmol) and hydroxylamine hydrochloride (53.5 mmol) obtained from step A. The resulting mixture was stirred at ambient temperature overnight and then poured into diluted HCl (100 mL). The mixture was stirred for 5 minutes and extracted with ether (3 x 50 mL). CTL ether layer₄It was dried in, filtered and concentrated to a residue to give the corresponding oxime in 99% yield. This was used in the next step without further purification. [0975] (Step C) The corresponding oxime (40.0 mmol) obtained from step B was added to acetic anhydride (10 mL). The reaction mixture was heated to 60 ° C. for 2 hours and then poured into ether (10 mL). Saturate the mixture LVDS₃Washed with solution (4 x 10 mL) and saline (10 mL). Separate the organic layer and EDTA₄The bisacylated derivative was obtained in 61% to 75% yield. [0976] (Step D) KOH (14.4 mmol) was added to a solution of the corresponding bisacylated derivative (5.2 mmol) obtained in step C in ethanol (4 mL). The reaction mixture was refluxed for 2 hours, cooled to room temperature, ethyl acetate (10 mL) was added, washed with brine (10 mL), and deli was added.₄It was dried in, filtered, and concentrated to give a residue. The residue was purified by silica gel flash column chromatography (ethyl acetate / hexane: 3: 7) to 3- (3-chloropropyl) -6-fluorobenzo [d] isoxazole and 3- (3-chloropropyl) benzo [ d] Isoxazole was obtained in 32% yield. [0977] (Step E) According to General Method A of Example 197, 3- (3-chloropropyl) -6-fluorobenzo [d] isoxazole obtained from Step D was cis- (6b, 10a) -3-methyl-2,3, The title compound was prepared by adding to 6b,7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] quinoxaline.¹1 H NMR (300MHz, CDCl₃) δ7.63 (dd, J = 8.8Hz, 4.7Hz, 1H), 7.20-7.24 (m, 1H), 7.03-7.10 (m, 1H), 6.65 (dd, J = 7.7Hz, 7.7Hz, 1H) , 6.50 (d, J = 7.3Hz, 1H), 6.41 (d, J = 7.3Hz), 3.73-3.77 (m, 1H), 3.55-3.62 (m, 1H), 3.21-3.32 (m, 3H), 2.91-3.10 (m, 3H), 2.86 (s, 3H), 2.75-2.82 (m, 2H), 2.54-2.63 (m, 1H), 2.41-2.48 (m, 1H), 1.95-2.11 (m, 6H) ) ppm. MS (CI, NH₃) m / e407 (base, M + H⁺). [0978] (Example 218) cis- (6b, 10a) -8- [3- (1,2-benzoisooxasol-3-yl) propyl] -3-methyl-2,3,6b,7,8,9,10,10a- Octahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] quinoxaline [0979] According to General Method A of Example 197, 3- (3-chloropropyl) benzo [d] isoxazole obtained from Step D of Example 22 was cis- (6b, 10a) -3-methyl-2,3, The title compound was prepared by adding to 6b,7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] quinoxaline.¹1 H NMR (300MHz, CDCl₃) δ7.59-7.62 (m, 1H), 7.46-7.50 (m, 2H), 7.20-7.25 (m, 1H), 6.57 (dd, J = 7.7Hz, 7.3Hz, 1H), 6.43 (d, J) = 6.9Hz, 1H), 6.33 (d, J = 7.3Hz), 3.48-3.52 (m, 1H), 3.06-3.25 (m, 4H), 2.94-2.99 (m, 2H), 2.70-2.89 (m, 4H), 2.79 (s, 3H), 2.20-2.65 (m, 3H), 1.92-2.07 (m, 4H) ppm. MS (CI, NH₃) m / e389 (base, M + H⁺). [0980] (Example 219) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) ethyl butane [0981] (General method) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole To a suspension of (3 mmol) 1,4-dioxane (18 mL), the corresponding alkyl halides (3.3 mmol), potassium iodide (100 mg) and potassium carbonate (900 mg) were added and the reaction mixture was heated to reflux for 2 days. I let you. The solvent was removed under reduced pressure. The residue was treated with water (50 mL) and extracted with diethyl ether (3 x 50 mL). The ether extract is washed with saline solution (150 mL) and deli₄It was dried in, filtered, and concentrated to give a residue. Flash column chromatography (silica gel, CH) of the residue₂Cl₂: CH₃Purification by OH 9: 1) gave the title compound in yields of 47% to 64%. [0982] Ethyl 4-chlorobutate (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4 ] The title compound was prepared by adding to thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ6.94 (bd, J = 7.7Hz, 1H), 6.86 (bd, J = 6.9Hz, 1H), 6.62 (dd, J = 7.4Hz, 7.3Hz, 1H), 4.08-4.15 (m, 2H) , 3.77-3.86 (m, 1H), 3.47-3.59 (m, 2H), 3.10-3.29 (m, 2H), 2.89-3.08 (m, 2H), 2.64-2.82 (m, 2H), 2.31-2.44 ( m, 4H), 1.83-2.12 (m, 7H), 1.23-1.27 (m, 3H) ppm. MS-ESI: 361 [MH]⁺[0983] (Example 220) 5-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) ethyl pentanate [0984] Ethyl 5-chloropentate (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ The title compound was prepared by adding to 1,4] thiazepino [2,3,4-hi] indole.¹1 H NMR (300MHz, CDCl₃) δ6.95 (bd, J = 7.7Hz, 1H), 6.86 (bd, J = 7.4Hz, 1H), 6.62 (dd, J = 7.7Hz, 7.3Hz, 1H), 4.08-4.15 (m, 2H) , 3.77-3.87 (m, 1H), 3.47-3.59 (m, 1H), 3.21-3.28 (m, 2H), 2.89-3.08 (m, 2H), 2.64-2.84 (m, 2H), 2.29-2.34 ( m, 5H), 1.90-2.16 (m, 5H), 1.55-1.64 (m, 4H), 1.22-1.27 (m, 3H) ppm. MS-ESI: 375 [MH]⁺[0985] (Example 221) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -N-methoxy-N-methylbutane amide [0986] (General method) A solution of 2M of trimethylaluminum in toluene (6.0 mmol) was added to a mixture of N, O-dimethylhydroxyamine hydrochloride (2.0 mmol) in dry toluene (20 mL) with stirring at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour and 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido] obtained from Examples 219 and 220 [ 4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) ethyl butane or 5-((8aS, 12aR) -6,7,9,10 , 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl) ethyl pentanate in toluene (1 mL) Was added at 0 ° C. The mixture was stirred at 0 ° C for 2 hours and then at room temperature for 3 hours. 1 M tartaric acid (27 mL) was slowly added to the reaction at 0 ° C and stirred at 0 ° C for 30 minutes. CHCl the reaction mixture₃Extracted with (3 x 50 mL). Wash the organic layer with saline solution and Na₂SO₄It was dried in, filtered, and concentrated to give a residue. Flash column chromatography (silica gel, CH) of the residue₂Cl₂: CH₃Purification by OH9: 1) gave the title compound in 70% to 90% yield. [0987] According to the general method described above, the corresponding ester 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound was prepared from ethyl [2,3,4-hi] indol-11 (8aH) -yl) butanate.¹1 H NMR (300MHz, CDCl₃) δ6.94 (bd, J = 7.7Hz, 1H), 6.85 (bd, J = 6.6Hz, 1H), 6.61 (dd, J = 7.6Hz, 7.4Hz, 1H), 3.77-3.86 (m, 1H) , 3.67 (s, 3H), 3.48-3.59 (m, 1H), 3.21-3.28 (m, 2H), 3.17 (s, 3H), 2.89-3.08 (m, 2H), 2.71-2.84 (m, 2H) , 2.29-2.52 (m, 5H), 1.84-2.16 (m, 7H) ppm. MS-ESI: 376 [MH]⁺[0988] (Example 222) 5-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -N-methoxy-N-methylpentane amide [0989] According to the general method of Example 221 the corresponding ester 5-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] The title compound was prepared from ethyl thiazepino [2,3,4-hi] indol-11 (8aH) -yl) pentanate.¹1 H NMR (300MHz, CDCl₃) δ6.95 (bd, J = 7.7Hz, 1H), 6.86 (bd, J = 7.4Hz, 1H), 6.62 (dd, J = 7.7Hz, 7.4Hz, 1H), 3.77-3.87 (m, 1H) , 3.67 (s, 3H), 3.47-3.59 (m, 1H), 3.23-3.29 (m, 2H), 3.16 (s, 3H), 2.77-3.06 (m, 4H), 2.33-2.44 (m, 5H) , 1.91-2.13 (m, 5H), 1.61-1.65 (m, 4H) ppm. MS (CI, NH₃) m / e389 (base, M + H⁺). [0990] (Example 223) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (4-fluoro-3-methylphenyl) -1-butanone [0991] (General method) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino obtained from Example 221 and Example 222 [2,3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutaneamide or 5-((8aS, 12aR) -6,7,9,10,12,12a- Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl) -N-methoxy-N-methylpentaneamide (0.1 mmol) A solution of arylmagnesium bromide (0.5 mmol) in THF (or diethyl ether) was added dropwise to the solution of THF (2 mL) or diethyl ether (2 mL) at ambient temperature. The resulting mixture was stirred at room temperature for 2-5 hours. Add a few drops of concentrated HCl and CH₂Cl₂Extracted with (15 mL). Saturated organic layer LVDS₃Wash with (15 mL), saline (15 mL) and Na₂SO₄It was dried in, filtered and concentrated to give a residue. Preparative TLC (silica gel, CH) obtained₂Cl₂: CH₃Purification by OH9: 1) gave the title compound in 70% to 90% yield. [0992] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, The title compound was prepared by adding 4-hi] indol-11 (8aH) -yl) -N-methoxy-N-methylbutaneamide.¹1 H NMR (300MHz, CD₃OD) δ7.84-7.94 (m, 2H), 7.08-7.16 (m, 1H), 6.92-6.99 (m, 2H), 6.64-6.72 (m, 1H), 3.79-3.93 (m, 1H), 3.48 -3.70 (m, 3H), 3.36-3.47 (m, 1H), 2.98-3.14 (m, 7H), 2.84-2.94 (m, 1H), 2.58-2.68 (m, 1H), 2.31 (bs, 3H) , 1.89-2.21 (m, 6H) ppm. MS (CI, NH₃) m / e424 (base, M + H⁺). [0993] (Example 224) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1-phenyl-1-butanone [0994] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,,] according to the general method of Example 223. 3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutane amide was added with phenylmagnesium bromide to prepare the title compound.¹1 H NMR (300MHz, CDCl₃) δ7.96 (d, J = 7.3Hz, 2H), 7.55-7.97 (m, 1H), 7.44-7.49 (m, 2H), 7.18-7.33 (m, 3H), 4.72-4.82 (m, 1H) , 4.25-4.50 (m, 2H), 3.90-4.06 (m, 3H), 3.60-3.76 (m, 3H), 2.99-3.24 (m, 7H), 2.54-2.60 (m, 1H), 2.28-2.40 ( m, 2H), 2.11-2.26 (m, 1H) ppm. MS (CI, NH₃) m / e392 (base, M + H⁺). [0995] (Example 225) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (4-chlorophenyl) -1-butanone [0996] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,,] according to the general method of Example 223. 3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutane amide was added with 4-chlorophenylmagnesium bromide to prepare the title compound.¹1 H NMR (300MHz, CD₃OD) δ7.97-8.02 (m, 2H), 7.50-7.56 (m, 2H), 6.95-7.02 (m, 2H), 6.62-6.72 (m, 1H), 3.80-3.90 (m, 1H), 3.40 -3.59 (m, 8H), 2.99-3.24 (m, 6H), 2.85-2.95 (m, 1H), 1.96-2.21 (m, 4H) ppm. MS (CI, NH₃) m / e426 (base, M + H⁺). [0997] (Example 226) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (3-methylphenyl) -1-butanone [0998] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,,] according to the general method of Example 223. 3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutane amide was added with m-toluyl magnesium chloride to prepare the title compound.¹1 H NMR (300MHz, CD₃OD) δ7.79-7.84 (m, 2H), 7.38-7.44 (m, 2H), 6.95-7.05 (m, 2H), 6.62-6.72 (m, 1H), 3.80-3.90 (m, 1H), 3.40 -3.59 (m, 8H), 2.99-3.24 (m, 6H), 2.85-2.95 (m, 1H), 2.38 (s, 3H), 1.96-2.21 (m, 4H) ppm. MS (CI, NH₃) m / e406 (base, M + H⁺). [0999] (Example 227) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (4-tert-butylphenyl) -1-butanone [1000] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,,] according to the general method of Example 223. 3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutane amide was added with tert-butylphenylmagnesium bromide to prepare the title compound.¹1 H NMR (300MHz, CD₃OD) δ7.97-8.02 (m, 2H), 7.50-7.56 (m, 2H), 6.92-7.00 (m, 2H), 6.65-6.75 (m, 1H), 3.80-3.90 (m, 1H), 3.40 -3.59 (m, 4H), 3.26-3.38 (m, 4H), 2.99-3.24 (m, 6H), 2.85-2.95 (m, 1H), 1.96-2.21 (m, 4H), 1.32 (s, 9H) ppm. MS (CI, NH₃) m / e448 (base, M + H⁺). [1001] (Example 228) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (3,4-difluorophenyl) -1-butanone [1002] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,,] according to the general method of Example 223. 3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutane amide was added with 3,4-difluorophenylmagnesium bromide to prepare the title compound.¹1 H NMR (300MHz, CD₃OD) δ7.88-7.94 (m, 2H), 7.38-7.44 (m, 1H), 6.92-7.00 (m, 2H), 6.65-6.75 (m, 1H), 3.80-3.90 (m, 1H), 3.40 -3.59 (m, 4H), 3.26-3.38 (m, 4H), 2.99-3.24 (m, 6H), 2.85-2.95 (m, 1H), 1.96-2.21 (m, 4H) ppm. MS (CI, NH₃) m / e428 (base, M + H⁺). [1003] (Example 229) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (5-fluoro-2-methoxyphenyl) -1-butanone [1004] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,,] according to the general method of Example 223. 3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutane amide was added with 3-fluoro-6-methoxyphenylmagnesium bromide to prepare the title compound.¹1 H NMR (300MHz, CD₃OD) δ7.40-7.48 (m, 1H), 7.24-7.34 (m, 1H), 7.10-7.18 (m, 1H), 6.92-7.00 (m, 2H), 6.65-6.75 (m, 1H), 3.74 -3.92 (m, 2H), 3.90 (s, 3H), 3.36-3.59 (m, 4H), 3.26-3.34 (m, 4H), 3.05-3.20 (m, 6H), 2.85-2.95 (m, 1H) , 1.96-2.21 (m, 4H) ppm. MS (CI, NH₃) m / e440 (base, M + H⁺). [1005] (Example 230) 5- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1-phenyl-1-pentanone [1006] 5-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylpentane amide was added with phenylmagnesium bromide to prepare the title compound.¹1 H NMR (300MHz, CDCl₃) δ7.84-7.94 (m, 2H), 7.50-7.58 (m, 1H), 7.44-7.50 (m, 2H), 6.92-7.00 (m, 2H), 6.70-6.79 (m, 1H), 3.76- 3.82 (m, 1H), 3.58-3.68 (m, 2H), 3.45-3.56 (m, 1H), 3.18-3.21 (m, 2H), 2.64-2.98 (m, 7H), 2.30-2.35 (m, 1H) ), 1.80-1.92 (m, 4H), 1.60-1.72 (m, 4H) ppm. MS (CI, NH₃) m / e406 (base, M + H⁺). [1007] (Example 231) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (4-fluoro-1-naphthyl) -1-butanone [1008] (General method) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] obtained from Example 26 , 4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutaneamide (0.1 mmol) in THF (1 mL) with the corresponding arylmagnesium bromide (0.5 mmol) in THF. It was added dropwise at room temperature. The reaction mixture was stirred at ambient temperature for 18-20 hours and then heated at 72 ° C. for 1 hour. The reaction was concentrated to give a residue. Preparative residue TLC (silica gel, CH)₂Cl₂: CH₃Purification by OH9: 1) gave the title compound in yields of 36% -40%. [1009] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, The title compound was prepared by adding 4-fluoro-1-naphthylmagnesium bromide to 4-hi] indol-11 (8aH) -yl) -N-methoxy-N-methylbutaneamide.¹1 H NMR (300MHz, CD₃OD) δ8.72-8.80 (m, 1H), 8.10-8.18 (m, 2H), 7.62-7.68 (m, 2H), 7.24-7.30 (m, 1H), 6.92-7.00 (m, 2H), 6.64 -6.70 (m, 1H), 3.82-3.92 (m, 1H), 3.52-3.64 (m, 2H), 3.24-3.44 (m, 7H), 2.90-3.14 (m, 2H), 2.68-2.84 (m, 2H), 2.30-2.44 (m, 2H), 1.99-2.11 (m, 4H) ppm. MS-ESI: 461 [MH]⁺[1010] (Example 232) 5-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1-phenyl-2-pentanone [1011] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,,] according to the general method of Example 231. 3,4-hi] Benzylmagnesium bromide was added to indol-11 (8aH) -yl) -N-methoxy-N-methylbutaneamide to prepare the title compound.¹1 H NMR (300MHz, CD₃OD) δ7.22-7.28 (m, 5H), 6.92-6.98 (m, 2H), 6.62-6.68 (m, 1H), 4.88 (s, 2H), 3.82-3.92 (m, 1H), 3.52-3.64 (m, 2H), 3.24-3.44 (m, 7H), 2.82-3.18 (m, 4H), 2.32-2.44 (m, 2H), 1.92-2.30 (m, 4H) ppm. MS (CI, NH₃) m / e406 (base, M + H⁺). [1012] (Example 233) 3-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -N- (4-fluorophenyl) propanamide [1013] (General method) 3-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -N-methoxy-N-methylpropanamide or 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] ] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -N-methoxy-N-methylbutaneamide (0.06 to 0.1 mmol) in a methanesulfonate (0.5 mL) solution , NaN₃(1.5 eq) was added. The resulting mixture was stirred at ambient temperature for 1 hour, then water (5 mL) was added. Add ammonium hydroxide solution to adjust pH to 11 and CH₂Cl₂Extracted with (20 mL). EDTA the organic layer₄It was dried in, filtered and concentrated to give a residue. Preparative residue TLC (silica gel; CH)₂Cl₂: CH₃Purified with OH9 / 1). The product was dissolved in ether (1 mL), stirred at 0 ° C for 10 minutes and a 1N HCl ether solution (0.5 mL) was added at 0 ° C. The white crystalline solid was collected by filtration to give the title compound in yields of 50% to 52%. [1014] According to the above general method, 3-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, The title compound was prepared from 4-hi] indol-11 (8aH) -yl) -N-methoxy-N-methylpropanamide.¹1 H NMR (300MHz, CDCl₃) δ7.30-7.35 (m, 2H), 6.90-7.15 (m, 3H), 6.87 (d, J = 7.0Hz, 1H), 6.59 (dd, J = 7.7Hz, 7.3Hz, 1H), 3.62- 3.72 (m, 1H), 3.22-3.48 (m, 5H), 3.04-3.12 (m, 1H), 2.55-2.86 (m, 7H), 2.07-2.15 (m, 2H), 1.97-2.00 (m, 2H) ) ppm. MS (CI, NH₃) m / e411 (base, M + H⁺). [1015] (Example 234) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -N- (4-fluorophenyl) butaneamide [1016] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,,] according to the general method of Example 233. The title compound was prepared from 3,4-hi] indol-11 (8aH) -yl) -N-methoxy-N-methylbutane amide.¹1 H NMR (300MHz, CDCl₃) δ7.33-7.37 (m, 2H), 6.88-6.97 (m, 3H), 6.78 (d, J = 7.0Hz, 1H), 6.54 (dd, J = 7.7Hz, 7.3Hz, 1H), 3.64- 3.74 (m, 1H), 3.37-3.48 (m, 1H), 3.21-3.26 (m, 1H), 3.00-3.17 (m, 2H), 2.86-2.94 (m, 1H), 2.70-2.76 (m, 1H) ), 2.58-2.62 (m, 1H), 2.33-2.45 (m, 4H), 1.94-2.09 (m, 4H), 1.83-1.90 (m, 4H) ppm. MS (CI, NH₃) m / e425 (base, M + H⁺). [1017] (Example 235) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanol [1018] 4-((8aS, 12aR) 1-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru -11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone or 1- (4-pyridyl) -4- (2,3,6b, 7,8,9,10,10a-octahydro -3-Methyl-1H-pyrido [3'4': 4,5] -pyrrolo [1,2,3-de] quinoxaline-8-yl) -1-butanone (0.06 mmol) in methanol (1 mL) solution , Sodium borohydride (0.36 mmol) was added in 3 portions at 0 ° C. After stirring the reaction mixture at ambient temperature for 2 hours, add 2 drops of concentrated HCl to add excess NaBH.₄Was disassembled. NH₄Add OH (1 mL) and CH₂Cl₂Extracted with (10 mL). EDTA the organic layer₄It was dried in, filtered, and concentrated to give a residue. The residue was dissolved in ether (1 mL) and a 1N HCl ether solution was added. Concentration gave the residue to give the title compound in yields of 60% to 65%. [1019] 4-((8aS, 12aR) 1-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] according to the above general method , 4-hi] Indol-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone was used to prepare the title compound.¹1 H NMR (300MHz, CD₃OD) δ7.34-7.40 (m, 2H), 6.98-7.10 (m, 2H), 6.90-6.95 (m, 2H), 6.62-6.70 (m, 1H), 4.70 (m, 1H), 3.76-3.86 (m, 1H), 3.44-3.59 (m, 4H), 3.24-3.30 (m, 1H), 2.90-3.14 (m, 4H), 2.05-2.45 (m, 4H), 1.80-2.02 (m, 4H) ppm. MS-ESI: 413 [MH]⁺[1020] (Example 236) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (4-pyridinyl) -1-butanol [1021] 1- (4-pyridyl) -4- (2,3,6b, 7,8,9,10,10a-octahydro-3-methyl-1H-pyrido [3'4': The title compound was prepared from 4,5] -pyrrolo [1,2,3-de] quinoxaline-8-yl) -1-butanone.¹1 H NMR (300MHz, CDCl₃) δ8.53-8.57 (m, 2H), 7.32-7.36 (m, 2H), 6.90-6.98 (m, 1H), 6.84-6.87 (m, 1H), 6.60-6.66 (m, 1H), 4.66- 4.72 (m, 1H), 3.80-3.92 (m, 1H), 3.55-3.71 (m, 3H), 3.22-3.30 (m, 2H), 2.64-3.02 (m, 4H), 2.31-2.54 (m, 3H) ), 1.69-2.03 (m, 8H) ppm. MS (CI, NH₃) m / e395 (base, M + H⁺). [1022] (Example 237) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (2,3-dimethoxyphenyl) -1-butanol [1023] (Step A) CH Oxalyl Chloride (55 mmol)₂Cl₂Dissolve in (25 mL), cool to -60 ° C, CH in DMSO (120 mmol)₂Cl₂The (10 mL) solution was added dropwise. The reaction mixture was stirred at -60 ° C for 10 minutes. CH of 1-chlorobutane-4-ol (50 mmol)₂Cl₂The (10 mL) solution was added slowly over 10 minutes. The reaction mixture was stirred at the same temperature for 15 minutes. Et₃N was added at -60 ° C for about 5 minutes. The cooling tub was removed, water was added at room temperature and stirring was continued for 10 minutes. The organic layer was separated. CH the water layer₂Cl₂Extracted with (3 x 50 mL). Combine the organic layers and EDTA₄It was dried in, filtered and concentrated to give a residue to give 1-chlorobutane-4-ar in 64% yield. The product was distilled under reduced pressure to give the aldehyde in 60% yield (5 mmHg, 88-90 ° C). [1024] (Step B) To a solution of TMEDA (6.6 mmol) in dry THF (15 mL) was slowly added sec-BuLi (6.6 mmol) at -78 ° C. The reaction mixture was stirred at 78 ° C. for 10 minutes and a solution of veratrol (6.0 mmol) in THF (3 mL) was added slowly. The reaction was stirred at -78 ° C for 30 minutes, 1-chlorobutane-4-ar (6.6 mmol) was added and the mixture was stirred at -78 ° C for 2 hours. The reaction mixture was warmed to room temperature, saline (1 mL) was added and filtered. Deduct the filtrate₄It was dried in, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography (silica gel; ethyl acetate / hexane: 3/7) to give 1- (2,3-dimethoxyphenyl) -4-chlorobutane-1-ol in 20% yield.¹1 H NMR (300MHz, CDCl₃) δ7.05 (dd, J = 8.0Hz, 7.7Hz, 1H), 6.94 (bd, J = 7.7Hz, 1H), 6.85 (bd, J = 8.1Hz, 1H), 4.91-4.97 (m, 1H) , 3.88 (s, 3H), 3.84 (s, 3H), 3.56-3.60 (m, 2H), 2.44-2.45 (m, 1H), 1.81-2.00 (m, 4H) ppm. MS (CI, NH₃) m / e244 (base, M + H⁺). [1025] (Step C) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole In a suspension of (1.17 mmol) 1,4-dioxane (4 mL), the alcohol obtained from step B, 1- (2,3-dimethoxyphenyl) -4-chlorobutane-1-ol (0.78 mmol), Potassium iodide (100 mg) and potassium carbonate (300 mg) were added. The reaction mixture was heated to reflux for 2 days. The solvent was removed under reduced pressure. The residue was treated with water (50 mL) and extracted with methylene chloride (3 x 50 mL). CH₂Cl₂The extract is washed with saline solution (150 mL) and deli₄It was dried in, filtered, and concentrated to give a residue. Flash column chromatography (silica gel, CH) of the residue₂Cl₂: CH₃Purified by OH9: 1). The product was dissolved in ether (2 mL), stirred at 0 ° C for 10 minutes and a 1N HCl ether solution (0.5 mL) was added at 0 ° C. The white crystalline solid was collected by filtration to give the title compound in 62% yield.¹1 H NMR (300MHz, CDCl₃) δ7.07 (d, J = 7.6Hz, 1H), 6.99 (dd, J = 7.7Hz, 8.1Hz, 1H), 6.89 (dd, J = 1.5Hz, 8.0Hz, 1H), 6.83 (dd, J = 1.1Hz, 7.4Hz, 1H), 6.75 (dd, J = 1.5Hz, 7.7Hz, 1H), 6.57 (dd, J = 7.3Hz, 7.7Hz, 1H), 4.92 (m, 1H), 3.79 (s , 6H), 3.46-3.56 (m, 1H), 3.16-3.20 (m, 2H), 2.67-2.95 (m, 4H), 2.31-2.34 (m, 3H), 1.80-2.05 (m, 5H), 1.64 -1.76 (m, 6H) ppm. MS (CI, NH₃) m / e455 (base, M + H⁺). [1026] (Example 238) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (2,3-dimethoxyphenyl) -1-butanone [1027] Of powder₄A Alcohol containing molecular sieves 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indoru-11 (8aH) -yl) -1- (2,3-dimethoxyphenyl) -1-butanol (0.11 mmol) and N-methylmorpholin N-oxide (0.17 mmol) CH₂Cl₂Solid tetrapropylammonium perluthenate (0.006 mmol) was added to the (2 mL) solution at one time at room temperature. The reaction mixture was stirred at room temperature for 4 hours, filtered and concentrated to give a residue. Flash column chromatography (silica gel, CH) of the residue₂Cl₂/ CH₃Purification by OH9: 1) gave the title compound in a yield of 94%.¹1 H NMR (300MHz, CDCl₃) δ7.05 (d, J = 7.3Hz, 1H), 7.02 (d, J = 7.4Hz, 1H), 6.97 (dd, J = 6.9Hz, 7.7Hz, 1H), 6.87 (d, J = 7.7Hz) , 1H), 6.77 (d, J = 6.6Hz, 1H), 6.53 (dd, J = 7.7Hz, 7.3Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.70-3.80 (m) , 1H), 3.43-3.56 (m, 1H), 3.17-3.22 (m, 1H), 2.82-3.05 (m, 5H), 2.56-2.76 (m, 2H), 2.10-2.30 (m, 3H), 1.80 -2.05 (m, 7H) ppm. [1028] (Example 239) cis- (8a, 12a) -11- (4-cyclohexylbutyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1029] (Step A) From 4 -chlorohexyl-1-butanol (515 mg, 3.20 mmol) and methanesulfonyl chloride (540 mg, 4.80 mmol), 4-cyclohexyl-1-butylmethanesulfonate, according to the general method of Example 43 for mesylation. Prepared as a colorless oil (734 mg, 95%).¹1 H NMR (CDCl₃, 300MHz) δ0.83-0.90 (m, 2H), 1.13-1.25 (m, 5H), 1.34-1.44 (m, 2H), 1.60-1.76 (m, 8H), 2.99 (s, 3H), 4.21 ( t, 2H, J = 6.5Hz) ppm. [1030] (Step B) According to the general coupling procedure of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] The title compound was prepared as a pale yellow oil from thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and 4-cyclohexylbutyl methylsulfonate (86 mg, 0.37 mmol).¹1 H NMR (CDCl₃, 300Mhz) δ0.81-0.85 (m, 2H), 1.09-1.18 (m, 9H), 1.52-1.69 (m, 8H), 1.98-2.13 (m, 4H), 2.37-2.43 (m, 2H), 2.81-3.07 (m, 3H), 3.28-3.32 (m, 2H), 3.54-3.64 (m, 2H), 3.78-3.87 (m, 1H), 6.63 (t, 1H, J = 7.7Hz), 6.87 ( dd, 1H, J = 1.1,7.3Hz), 6.96 (dd, 1H, J = 1.1,7.7Hz) ppm. [1031] (Example 240) cis- (8a, 12a) -11- (4,4-diphenylbutyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1032] (Step A) Pd / C (10%, 50 mg) was added to a solution of 4-chloro-1,1-diphenyl-1-butene (200 mg, 0.82 mmol) in EtOAc (8.0 mL). H the reaction mixture₂The mixture was stirred at 20 ° C for 15 hours under an atmosphere. The reaction mixture was filtered through Celite and the filtrate was concentrated to give analytically pure 4-chloro-1,1-diphenylbutane (201 mg, 99%) as a colorless oil.¹1 H NMR (CDCl₃, 300MHz) δ1.70-1.81 (m, 2H), 2.16-2.25 (m, 2H), 3.54 (t, 2H, J = 6.5Hz), 3.91 (t, 1H, J = 7.8Hz), 7.15-7.31 (m, 10H) ppm. [1033] (Step B) According to the general coupling procedure of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] The title compound was prepared as a pale yellow oil from [1,4] thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and 4-chloro-1,1-diphenylbutane (44 mg, 0.18 mmol). (48 mg, 88%).¹1 H NMR (CDCl₃, 300Mhz) δ1.42-1.53 (m, 2H), 1.78 (t, 1H, J = 12.0Hz), 1.82-1.92 (m, 2H), 1.95-2.20 (m, 5H), 2.25-2.37 (m, 2H), 2.56-2.63 (m, 1H), 2.65-2.73 (m, 1H), 2.88-2.97 (m, 1H), 3.00-3.17 (m, 2H), 3.22-3.28 (m, 1H), 3.50- 3.63 (m, 1H), 3.76-3.85 (m, 1H), 3.89 (t, 1H, J = 7.9Hz), 6.60 (t, 1H, J = 7.7Hz), 6.82 (d, 1H, J = 7.3Hz) ), 6.93 (d, 1H, J = 7.7Hz), 7.13-7.35 (m, 10H) ppm. [1034] (Example 241) cis- (8a, 12a) -11- (4,4-diphenyl-3-butenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1035] (Step A) Chloropropyl diphenylmethanol (500 mg, 2.23 mmol) was dissolved in a solution of 1 MHCl in i-PrOH (4.0 mL). The reaction mixture was then heated at 60 ° C. for 1 hour. Cool the reactants to 20 ° C and Et₂Diluted with O (100 mL). H organic layer₂O, LVDS₃It was washed continuously with saturated aqueous solution and saline solution. Then DDL₄Dried in, filtered, concentrated under vacuum and chromatographed on a silica gel column eluting with hexanes to give 4-chloro-1,1-diphenyl-1-butene (506 mg, 93%) as a colorless oil. ..¹1 H NMR (CDCl₃, 300MHz) δ2.59 (q, 2H, J = 6.9Hz), 3.58 (t, 2H, J = 6.9Hz), 6.12 (t, 1H, J = 7.3Hz), 7.16-7.42 (m, 10H) ppm .. [1036] (Step B) According to the general coupling procedure of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] The title compound as a pale yellow oil from [1,4] thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and 4-chloro-1,1-diphenyl-1-butene (44 mg, 0.18 mmol). Was prepared (33 mg, 61%).¹1 H NMR (CDCl₃, 300MHz) δ1.79-1.92 (m, 3H), 1.94-2.17 (m, 2H), 2.20-2.37 (m, 3H), 2.40-2.49 (m, 2H), 2.55-2.63 (m, 1H), 2.65-2.73 (m, 1H), 2.88-2.97 (m, 1H), 3.00-3.17 (m, 2H), 3.23-3.29 (m, 1H), 3.50-3.62 (m, 1H), 3.76-3.87 (m) , 1H), 6.06 (t, 1H, J = 7.3Hz), 6.61 (t, 1H, J = 7.3Hz), 6.82 (d, 1H, J = 6.6Hz), 6.94 (dd, 1H, J = 1.1, 7.7Hz), 7.17-7.41 (m, 10H) ppm. [1037] (Example 242) cis- (8a, 12a) -11- [4,4-bis (4-fluorophenyl) butyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [1038] According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ From 1,4] thiazepino [2,3,4-hi] indole (68 mg, 0.27 mmol) and 1,1-bis- (4'-fluorophenyl) -4-chlorobutane (90 mg, 0.32 mmol), pale yellow The title compound was prepared as an oil (89 mg, 51%).¹1 H NMR (CDCl₃, 300MHz) δ1.38-1.48 (m, 2H), 1.79 (t, 1H, J = 11.2Hz), 1.83-1.91 (m, 2H), 1.95-2.21 (m, 5H), 2.23-2.35 (m, 2H), 2.53-2.62 (m, 1H), 2.63-2.75 (m, 1H), 2.89-2.99 (m, 1H), 3.01-3.16 (m, 2H), 3.22-3.27 (m, 1H), 3.52- 3.62 (m, 1H), 3.76-3.85 (m, 1H), 3.86 (m, 1H, J = 8.1Hz), 6.61 (t, 1H, J = 7.3Hz), 6.82 (d, 1H, J = 6.6Hz) ), 6.90-6.99 (m, 5H), 7.13-7.22 (m, 4H) ppm. [1039] (Example 243) cis- (8a, 12a) -11- [4,4-bis (4-fluorophenyl) -3-butenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [ 4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1040] (Step A) N 4-fluorophenylmagnesium bromide in a solution of cyclopropyl- (4-fluorophenyl) ketone (520 mg, 3.17 mmol) in THF (10 mL).₂In an atmosphere, the droplet was added at 0 ° C. The reaction mixture is stirred at 0 ° C. for 1 hour, saline is added to quench the reaction, and Et.₂Extracted with O. Then saturate the organic layer LVDS₃Washed with aqueous solution and saline. Then DDL₄It was dried in, filtered and concentrated under vacuum to give crude bis (4-fluorophenyl) -cyclopropylmethanol. Without further purification, it was used in the ring-opening reaction according to the method for the formation of 4-chloro-1,1-diphenyl-1-butene. 1,1-bis (4-fluorophenyl) -4-chloro-1-butene (780 mg, 88%) was obtained as a colorless oil.¹1 H NMR (CDCl₃, 300MHz) δ2.57 (q, 2H, J = 6.9Hz), 3.58 (t, 2H, J = 6.9Hz), 6.04 (t, 1H, J = 7.3Hz), 6.92-7.21 (m, 8H) ppm .. [1041] (Step B) According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] From thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1,1-bis- (4'-fluorophenyl) -4-chloro-1-butene (51 mg, 0.18 mmol) The title compound (40 mg, 68%) was prepared as a pale yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ1.79-1.93 (m, 3H), 1.98-2.18 (m, 2H), 2.19-2.37 (m, 3H), 2.38-2.48 (m, 2H), 2.55-2.63 (m, 1H), 2.63-2.73 (m, 1H), 2.90-2.99 (m, 1H), 3.01-3.18 (m, 2H), 3.22-3.28 (m, 1H), 3.48-3.60 (m, 1H), 3.75-3.86 (m) , 1H), 5.98 (t, 1H, J = 7.3Hz), 6.61 (t, 1H, J = 7.3Hz), 6.83 (d, 1H, J = 7.3Hz), 6.88-7.01 (m, 3H), 7.01 -7.20 (m, 6H) ppm. [1042] (Example 244) N- [2- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indol-11 (8aH) -Il) Ethyl] Benzamide [1043] (Step A) Benzoyl chloride (520 mg, 3.60 mmol) in THF solution of ethanolamine (1.09 g, 17.8 mmol) N₂In an atmosphere, the droplet was added at 0 ° C. The reaction mixture was stirred for 10 minutes and quenched with 1 M HCl. The mixture is then diluted with EtOAc and saturated with acrylamide.₃Washed with aqueous solution and saline. EDTA the organic layer₄It was dried in, filtered and concentrated under vacuum. The residue was crystallized to give N- (2-hydroxyethyl) benzamide (593 mg, 97%) as a white crystalline solid.¹1 H NMR (CDCl₃, 300MHz) δ3.41 (s, 1H), 3.49-3.59 (m, 2H), 3.75 (t, 2H, J = 5.2Hz), 7.10 (s, 1H), 7.32-7.38 (m, 2H), 7.42 -7.48 (m, 1H), 7.72-7.76 (m, 2H) ppm. [1044] 2-Benzamide ethylmethane as a colorless oil from N- (2-hydroxyethyl) benzamide (245 mg, 1.30 mmol) and methanesulfonyl chloride (223 mg, 1.94 mmol) according to the general method of Example 43 for mesylation. Sulfonates (291 mg, 84%) were prepared.¹1 H NMR (CDCl₃, 300MHz) δ2.85 (s, 3H), 4.48 (t, 2H, J = 9.5Hz), 5.10 (t, 2H, J = 10.2Hz), 7.58-7.63 (m, 2H), 7.74-7.80 (m) , 1H), 8.20-8.23 (m, 2H) ppm. [1045] (Step B) According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 Prepare the title compound (38 mg, 79%) as a pale yellow oil from thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and 2-benzamide ethylmethanesulfonate (119 mg, 0.49 mmol). did.¹1 H NMR (CDCl₃, 300MHz) δ1.87-1.92 (m, 2H), 2.05-2.12 (m, 2H), 2.16-2.23 (m, 1H), 2.40-2.50 (m, 1H), 2.55-2.60 (m, 2H), 2.77-2.84 (m, 2H), 2.92-3.05 (m, 1H), 3.15-3.24 (m, 1H), 3.31-3.34 (m, 1H), 3.44-3.57 (m, 2H), 3.69-3.78 (m) , 2H), 4.45-4.51 (m, 1H), 6.59 (t, 1H, J = 7.7Hz), 6.83-6.86 (m, 1H), 6.91-6.97 (m, 1H), 7.15-7.23 (m, 1H) ), 7.35-7.5 (m, 2H), 7.61 (dd, 1H, J = 1.1,8.4Hz) ppm. [1046] (Example 245) N- [2- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indol-11 (8aH) -yl) ethyl] -2-fluorobenzamide [1047] (Step A) Ethanolamine (1.00 mg, 15.8 mmol) and 2-fluorobenzoyl chloride (504 mg, 3.15 mmol) are coupled according to the method for preparing N- (2-hydroxyethyl) benzamide to N- (2-hydroxyethyl). -2'-Fluorobenzamide (460 mg, 79%) was obtained.¹H NMR (CD)₃OD, 300MHz) δ3.49 (t, 2H, J = 5.9Hz), 3.68 (t, 2H, J = 2.9Hz), 7.15-7.28 (m, 2H), 7.47-7.55 (m, 1H), 7.72- 7.78 (m, 1H) ppm. [1048] From N- (2-hydroxyethyl) -2'-fluorobenzamide (130 mg, 0.71 mmol) and methanesulfonyl chloride (122 mg, 1.06 mmol) to N, according to the chlorination method in 2- (2-chloroethyl) isoindolinone synthesis. -(2-Chloroethyl) -2'-fluorobenzamide (130 mg, 70%) was prepared as a colorless oil.¹1 H NMR (CDCl₃, 300MHz)₁1 H NMR (CDCl₃) δ3.72-3.76 (m, 2H), 3.82-3.87 (m, 2H), 7.11-7.18 (m, 2H), 7.25-7.28 (m, 1H), 7.46-7.53 (m, 1H), 8.08- 8.13 (m, 1H) ppm. [1049] (Step B) According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] From thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and N- (2-chloroethyl) -2'-fluorobenzamide (74 mg, 0.37 mmol), the title compound as a pale yellow oil ( 56 mg, 90%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.92-2.15 (m, 6H), 2.37-2.39 (m, 1H), 2.55-2.58 (m, 1H), 2.61-2.65 (m, 1H), 2.75-2.80 (m, 1H), 2.91-2.99 (m, 1H), 3.11-3.18 (m, 2H), 3.27-3.31 (m, 1H), 3.49-3.60 (m, 4H), 3.78-3.82 (m, 1H), 6.59 (t, 1H) , J = 7.3Hz), 6.85 (d, 1H, J = 7.0Hz), 6.94 (dd, 1H, J = 1.5,8.1Hz), 7.08,7.15 (m, 1H), 7.24-7.29 (m, 1H) , 7.43-7.51 (m, 1H), 8.08-8.14 (dt, 1H, J = 1.8,8.1Hz) ppm. [1050] (Example 246) N- [2- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indol-11 (8aH) -yl) ethyl] -4-fluorobenzamide [1051] (Step A) According to the method for preparing N- (2-hydroxyethyl) benzamide, ethanolamine (0.96 mg, 15.8 mmol) and 4-fluorobenzoyl chloride are coupled to N- (2-hydroxyethyl) -4'-fluorobenzamide (. 482 mg, 81%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ3.47 (t, 2H, J = 5.9Hz), 3.68 (t, 2H, J = 5.7), 7.13-7.20 (m, 2H), 7.82-7.92 (m, 2H) ppm. [1052] 2 as white crystals from N- (2-hydroxyethyl) -4'-fluorobenzamide (130 mg, 0.71 mmol) and methanesulfonyl chloride (122 mg, 1.06 mmol) according to the general method of Example 43 for mesylation. -(4'-Fluorobenzamide) ethyl methanesulfonate (130 mg, 70%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ2.85 (s, 3H), 4.48 (t, 2H, J = 9.5Hz), 5.10 (t, 2H, J = 10.2Hz), 7.08-7.18 (m, 2H), 7.70-7.82 (m) , 3H) ppm. [1053] (Step B) According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] From thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and N- [2- (methylsulfonyl) ethyl] -4-fluorobenzamide (63 mg, 0.24 mmol) as a pale yellow oil The title compound (45 mg, 91%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.85-1.93 (m, 2H), 2.05-2.15 (m, 2H), 2.24 (dd, 1H, J = 8.7, 11.3Hz), 2.39-2.47 (m, 1H), 2.52-2.61 ( m, 3H), 2.71-2.80 (m, 1H), 2.98-3.07 (m, 1H), 3.10-3.20 (m, 1H), 3.20-3.30 (m, 1H), 3.31-3.39 (m, 1H), 3.40-3.50 (m, 1H), 3.54 (q, 2H, J = 6.2Hz), 3.65-3.76 (m, 1H), 6.58 (t, 1H, J = 7.7Hz), 6.82-6.92 (m, 2H) , 6.95 (dd, 1H, J = 1.1,8.1Hz), 7.05-7.17 (m, 2H), 7.70-7.80 (m, 2H) ppm. [1054] (Example 247) cis- (8a, 12a) -11- [3- (1H-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [1055] (Step A) From 3- (3-indrill) -1-propanol (145 mg, 0.83 mmol) and methanesulfonyl chloride (142 mg, 1.24 mmol), 3-(as a colorless oil) according to the general method of Example 43 for mesylation. 3-Indrill) -1-propylmethanesulfonate (170 mg, 81%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ2.17 (qu, 2H, J = 7.3Hz), 2.92 (t, 2H, J = 7.0Hz), 2.99 (s, 3H), 4.27 (t, 2H, J = 6.4Hz), 7.04 ( d, 1H, J = 2.2Hz), 7.12 (dt, 1H, J = 1.1,7.0Hz), 7.21 (dt, 1H, J = 1.1,7.0Hz), 7.38 (d, 1H, J = 8.1Hz), 7.59 (d, 1H, J = 7.3Hz), 8.00 (br, 1H) ppm. [1056] (Step B) According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] From thiazepino [2,3,4-hi] indole (21 mg, 0.084 mmol) and 3- (3-indrill) propyl methylsulphonate (32 mg, 0.13 mmol), the title compound (20 mg, 20 mg, as a pale yellow oil. 59%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.93-2.22 (m, 7H), 2.40-2.53 (m, 1H), 2.55-2.65 (m, 2H), 2.77-2.95 (m, 5H), 2.97-3.07 (m, 1H), 3.26-3.40 (m, 2H), 3.48-3.60 (m, 1H), 3.77-3.88 (m, 1H), 6.63 (t, 1H, J = 7.7Hz), 6.85 (d, 1H, J = 7.3Hz) , 6.96 (dd, 1H, J = 1.1,8.1Hz), 7.01 (d, 1H, 1.8Hz), 7.10 (t, 1H, J = 7.3Hz), 7.19 (t, 1H, J = 7.4Hz), 7.36 (d, 1H, J = 8.1Hz), 7.58 (d, 1H, J = 7.7Hz), 8.00 (s, 1H) ppm. [1057] (Example 248) cis- (8a, 12a) -11-[3- (1-methyl-1H-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1058] (Step A) 3-Indolpropionic acid (946 mg, 5.0 mmol) was added to a dry DMSO (10 mL) solution of KOH (2.24 g, 40.0 mmol) followed by MeI (3.0 g, 4.0 mmol) immediately. The reaction mixture is stirred at 20 ° C. for 1.5 hours, quenched by pouring into water, and CHCl.₃Extracted with (3 x 20 mL). The organic layer is then washed with saline and DDL₄Dry with, filter, concentrate under vacuum and chromatograph on a silica gel column eluting with EtOAc / Hexanes to make methyl 3- (1-methyl-3-indrill) propionate (1.00 g, 92%) colorless. Obtained as oil.¹1 H NMR (CDCl₃, 300MHz) δ2.71 (t, 2H, J = 8.1Hz), 3.09 (t, 2H, J = 7.0Hz), 3.68 (s, 3H), 3.74 (s, 3H), 6.87 (s, 1H), 7.11 (dt, 1H, J = 1.1,6.8Hz), 7.22 (dt, 1H, J = 1.1,8.0Hz), 7.29 (d, 1H, J = 8.1Hz), 7.59 (d, 1H, J = 7.7Hz) ) ppm. [1059] Et of 3- (1-methyl-3-indrill) methyl propionate (300 mg, 1.38 mmol)₂In O (3.0 mL) solution, N₂LiAlH at 0 ° C under atmosphere₄Was added. The reaction mixture is stirred at 0 ° C for 30 minutes and H₂O was carefully added and quenched. EtOAc was added to the quenched reaction mixture. The organic layer is separated, washed with saline solution and deli₄It was dried in. It was then concentrated under vacuum and chromatographed on a silica gel column eluting with EtOAc / Hexanes to give 3- (1-methyl-3-indrill) -1-propanol (250 mg, 96%) as a colorless oil. ..¹1 H NMR (CDCl₃, 300MHz) δ1.28 (t, 1H, J = 6.2Hz), 1.98 (qu, 2H, J = 7.7Hz), 2.85 (t, 2H, J = 7.3Hz), 3.70-3.78 (m, 4H), 6.86 (s, 1H), 7.10 (dt, 1H, J = 1.1, 7.0Hz), 7.22 (dt, 1H, J = 1.1, 7.5Hz), 7.29 (d, 1H, J = 8.1Hz), 7.60 (d , 1H, J = 7.7Hz) ppm Colorless oil from 3- (1-methyl-3-indrill) -1-propanol (245 mg, 1.30 mmol) and methanesulfonyl chloride (223 mg, 1.94 mmol) according to the general method of Example 43 for mesylation. 3- (1-Methyl-3-indrill) -1-propylmethanesulfonate (291 mg, 84%) was prepared as a preparation.¹1 H NMR (CDCl₃, 300MHz) δ2.15 (qu, 2H, J = 7.0Hz), 2.90 (t, 2H, J = 7.0Hz), 2.99 (s, 3H), 3.76 (s, 3H), 4.27 (t, 2H, J = 6.2Hz), 6.88 (s, 1H), 7.11 (dt, 1H, J = 1.1, 6.9Hz), 7.23 (dt, 1H, J = 1.1, 7.0Hz), 7.29 (d, 1H, J = 8.5Hz) ), 7.57 (d, 1H, J = 8.1Hz) ppm. [1060] (Step B) According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Thiazepino [2,3,4-hi] indole (25 mg, 0.10 mmol) and methyl sulfonic acid 3- (1-methyl-3-indrill) propyl (32 mg, 0.12 mmol), entitled as pale yellow oil Compounds (36 mg, 86%) were prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.92-2.18 (m, 7H), 2.35-2.46 (m, 1H), 2.48-2.60 (m, 2H), 2.74-2.95 (m, 5H), 2.96-3.07 (m, 1H), 3.25-3.35 (m, 2H), 3.46-3.58 (m, 1H), 3.74 (s, 3H), 3.77-3.87 (m, 1H), 6.63 (t, 1H, J = 7.3Hz), 6.82-6.88 ( m, 2H), 6.96 (d, 1H, J = 7.7Hz), 7.09 (t, 1H, J = 7.0Hz), 7.20-7.32 (m, 2H), 7.57 (d, 1H, J = 7.7Hz) ppm .. [1061] (Example 249) cis- (8a, 12a) -11- [2- (1H-indole-3-yl) ethyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [1062] According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] From thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and 3- (2-bromoethyl) indole (54 mg, 0.24 mmol), the title compound (33 mg, 71%) as a pale yellow oil. Was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.93-2.20 (m, 5H), 2.35-2.43 (m, 1H), 2.64-2.77 (m, 2H), 2.78-2.87 (m, 1H), 2.89-3.15 (m, 5H), 3.20-3.35 (m, 2H), 3.49-3.61 (m, 1H), 3.77-3.87 (m, 1H), 6.64 (t, 1H, J = 7.7Hz), 6.90 (d, 1H, J = 7.3Hz) , 6.97 (dd, 1H, J = 1.1,8.1Hz), 7.02 (d, 1H, 2.2Hz), 7.08-7.21 (m, 2H), 7.35 (d, 1H, J = 8.0Hz), 7.61 (d, 1H, J = 8.1Hz), 7.98 (s, 1H) ppm. [1063] (Example 250) cis- (8a, 12a) -11- [3- (1H-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [1064] (Step A) Indole (500 mg, 4.24 mmol) is added to a solution of 1-bromo-3-chloropropane (2.00 g, 12.7 mmol) in DMF (7.0 mL), and then powdered KOH (262 mg, 4.66 mmol) is added at 20 ° C. did. The reaction mixture was then stirred at 20 ° C. for 15 hours. Reaction H₂Quench with the addition of O and Et₂Extracted with O. Organic solution H₂Rinse with O and saline and CTL₄It was dried in, filtered and concentrated under vacuum. 1- (3-Chloro-1-propyl) indole (580 mg, 71%) was isolated as a pale yellow oil by flash chromatography on a silica gel column eluting with EtOAc / Hexanes.¹1 H NMR (CDCl₃, 300MHz) δ2.28 (qu, 2H, J = 6.3Hz), 3.46 (t, 2H, J = 6.2Hz), 4.36 (t, 2H, J = 6.6Hz), 6.51 (d, 1H, J = 3.3) Hz), 7.09-7.18 (m, 2H), 7.20-7.25 (m, 1H), 7.38 (d, 1H, J = 8.5Hz), 7.64 (d, 1H, J = 7.7Hz) ppm. [1065] (Step B) According to the general coupling method of Example 43, cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] From thiazepino [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (3-chloropropyl) indole (46 mg, 0.24 mmol), the title compound (46 mg, 95%) as a pale yellow oil. ) Was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.90-2.15 (m, 7H), 2.18-2,33 (m, 3H), 2.52-2.60 (m, 1H), 2.66-2.75 (m, 1H), 2.89-2.98 (m, 1H) ), 3.02-3.18 (m, 2H), 3.26-3.33 (m, 1H), 3.48-3.59 (m, 1H), 3.77-3.87 (m, 1H), 4.21 (t, 2H, J = 7.0Hz), 6.62 (t, 1H, J = 7.3Hz), 6.85 (d, 1H, J = 6.6Hz), 6.95 (dd, 1H, J = 1.1,7.7Hz), 7.05-7.16 (m, 2H), 7.20 (dt) , 1H, J = 1.1,7.0Hz), 7.38 (d, 1H, J = 8.4Hz), 7.63 (d, 1H, J = 8.1Hz) ppm. [1066] (Example 251) cis- (8a, 12a) -11-[3- (2,3-dihydro-1H-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H -Pirido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1067] (Step A) Et in a solution of 1-bromo-3-chloropropane (1.98 g, 12.6 mmol) and indoline (500 mg, 4.20 mmol) in 1,4-dioxane (6.0 mL) at 20 ° C.₃N (2.12 g, 21.0 mmol) was added. The reaction mixture was then stirred at 70 ° C. for 15 hours. Cool the reaction mixture to 20 ° C and H₂O was added to quench the reactants. Et the product₂Extracted with O. Then H the organic solution₂Rinse with O and saline and CTL₄It was dried in, filtered and concentrated under vacuum. 1- (3-Chloro-1-propyl) indoline (373 mg, 45%) was isolated as a pale yellow oil by flash chromatography on a silica gel column eluting with EtOAc / Hexanes.¹1 H NMR (CDCl₃, 300MHz) δ2.07 (qu, 2H, J = 6.2Hz), 2.97 (t, 2H, J = 8.2Hz), 3.24 (t, 2H, J = 6.6Hz), 3.35 (t, 2H, J = 8.3) Hz), 3.68 (t, 2H, J = 6.2Hz), 6.50-6.56 (m, 1H), 6.66 (t, 1H, J = 6.6Hz), 7.04-7.10 (m, 2H) ppm. [1068] (Step B) According to the general coupling method of Example 43, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [3', 4': 4,5] From Pyrrolo [1,2,3-ef] [1,5] benzothiazepine (30 mg, 0.12 mmol) and 1- (3-chloropropyl) indoline (47 mg, 0.24 mmol), the title compound as a pale yellow oil ( 36 mg, 74%) was prepared.¹1 H NMR (CDCl₃, 300Mhz) δ1.80-2.18 (m, 7H), 2.23-2.35 (m, 2H), 2.43-2.55 (m, 1H), 2.70-2.85 (m, 2H), 2.89-2.98 (m, 3H), 3.02-3.19 (m, 4H), 3.28-3.38 (m, 3H), 3.48-3.61 (m, 1H), 3.78-3.90 (m, 1H), 6.45-6.52 (m, 1H), 6.59-6.70 (m) , 2H), 6.82-6.90 (m, 1H), 6.92-6.98 (m, 1H), 7.02-7.13 (m, 2H) ppm. [1069] (Example 252) cis- (8a, 12a) -11- [3- (1H-benzoimidazol-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1070] (Step A) In a dry DMF (10 mL) solution of benzimidazole (355 mg, 3.00 mmol), N₂Under the atmosphere, NaH (83 mg, 3.3 mmol) was added at 20 ° C. The reaction mixture was stirred for 30 minutes, 1,3-dibromopropane (1.82 g, 9.00 mmol) was added and further stirred at 20 ° C. for 15 hours. H₂O was added to quench the reaction and the product was extracted with EtOAc. Then H the organic solution₂Rinse with O and saline and CTL₄It was dried in, filtered and concentrated under vacuum. 1- (3-Bromo-1-propyl) benzimidazole (530 mg, 74%) was isolated as a pale yellow oil by flash chromatography on a silica gel column eluting with EtOAc / Hexanes.¹1 H NMR (CDCl₃, 300MHz) δ2.40 (qu, 2H, J = 6.6Hz), 3.33 (t, 2H, J = 6.2Hz), 4.42 (t, 2H, J = 6.6Hz), 7.12-7.20 (m, 1H), 7.27-7.48 (m, 2H), 7.43-7.49 (m, 1H), 7.78-7.86 (m, 1H) ppm. [1071] (Step B) According to the general coupling method of Example 43, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [3', 4': 4,5] From Pyrrolo [1,2,3-ef] [1,5] benzothiazepine (30 mg, 0.12 mmol) and 1- (3-chloropropyl) benzimidazole (58 mg, 0.24 mmol), the title compound as a pale yellow oil (21 mg, 43%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.83-1.95 (m, 3H), 2.00-2.17 (m, 4H), 2.20-2.33 (m, 3H), 2.50-2.60 (m, 1H), 2.64-2.72 (m, 1H), 2.90-2.99 (m, 1H), 3.05-3.18 (m, 2H), 3.29-3.35 (m, 1H), 3.50-3.59 (m, 1H), 3.77-3.87 (m, 1H), 4.28 (dt, 2H) , J = 2.2, 6.2Hz), 6.63 (t, 1H, J = 7.7Hz), 6.85 (d, 1H, J = 6.6Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz), 7.27-7.35 (m, 2H), 7.40-7.47 (m, 1H), 7.78-7.86 (m, 1H), 7.92 (s, 1H) ppm. [1072] (Example 253) 2- [2- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indole-11 (8aH) -Il) Ethyl] -1H-isoindole-1,3 (2H) -Zeon [1073] According to the general coupling method of Example 43, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [3', 4': 4,5] From Pyrrolo [1,2,3-ef] [1,5] benzothiazepine (30 mg, 0.12 mmol) and N- (2-bromoethyl) phthalimide (61 mg, 0.24 mmol), the title compound (40 mg) as a pale yellow oil. , 79%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.80-2.20 (m, 5H), 2.25-2.39 (m, 1H), 2.58 (t, 2H, J = 6.6Hz), 2.69-2.77 (m, 1H), 2.79-2.89 (m, 1H), 2.90-2.98 (m, 1H), 3.02-3.13 (m, 2H), 3.17-3.27 (m, 1H), 3.50-3.61 (m, 1H), 3.77-3.87 (m, 3H), 6.57 ( t, 1H, J = 7.7Hz), 6.84 (d, 1H, J = 7.0Hz), 6.92 (dd, 1H, J = 1.1, 7.7Hz), 7.68-7.78 (m, 2H), 7.82-7.89 (m) , 2H) ppm. [1074] (Example 254) 2- [2- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indol-11 (8aH) -yl) Ethyl] -1-isoindolinone [1075] (Step A) Ethanolamine (4.78 g, 78.3 mmol) and phthalide (10.0 g, 74.6 mmol) were placed in a round bottom flask equipped with a Dean-stark trap. The reaction mixture was heated at 150 ° C for 4 hours and then at 205 ° C for 18 hours. The product was cooled and solidified. CHCl₃Recrystallized in / hexane to isolate pure 2- (2-hydroxyethyl) isoindolinone (10.8 g, 82%) as white crystals.¹1 H NMR (CDCl₃, 300MHz) δ3.02-3.15 (br, 1H), 3.78 (t, 2H, J = 5.0Hz), 3.93 (t, 2H, J = 4.4Hz), 4.52 (s, 2H), 7.42-7.58 (m) , 3H), 7.84 (d, 1H, J = 7.4Hz) ppm. [1076] Thionyl chloride (1.34 g, 11.3 mmol) was added to a solution of 2- (2-hydroxyethyl) isoindolinone (1.0 g, 5.64 mmol) in toluene (3.5 mL). The reaction mixture was stirred at 20 ° C for 3 hours and then at 60 ° C for 4 hours. The reaction mixture was concentrated under vacuum to remove excess thionyl chloride and toluene. Flash chromatography on a silica gel column eluting with EtOAc / Hexane gave 2- (2-chloroethyl) isoindolinone (1.01 g, 92%) as a white solid.¹1 H NMR (CDCl₃, 300MHz) δ3.81 (t, 2H, J = 5.5Hz), 3.97 (t, 2H, J = 5.9Hz), 4.59 (s, 2H), 7.44-7.58 (m, 3H), 7.86 (d, 1H) , J = 6.9Hz) ppm. [1077] (Step B) According to the general coupling method of Example 43, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [3', 4': 4,5] From Pyrrolo [1,2,3-ef] [1,5] benzothiazepine (30 mg, 0.12 mmol) and 2- (2-chloroethyl) isoindolinone (47 mg, 0.24 mmol), the title compound as a pale yellow oil (42 mg, 86%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.80-1.95 (m, 3H), 2.00-2.18 (m, 3H), 2.37 (dt, 1H, J = 3.6, 11Hz), 2.60 (t, 2H, J = 6.6Hz), 2.63- 2.72 (m, 1H), 2.75-2.82 (m, 1H), 2.89-2.98 (m, 1H), 3.05-3.18 (m, 2H), 3.26-3.33 (m, 1H), 3.48-3.59 (m, 1H) ), 3.73-3.84 (m, 3H), 4.49 (s, 2H), 6.58 (t, 1H, J = 7.3Hz), 6.83 (d, 1H, J = 6.6Hz), 6.94 (dd, 1H, J = 1.1,7.7Hz), 7.42-7.55 (m, 3H), 7.85 (d, 1H, J = 7.3Hz) ppm. [1078] (Example 255) cis- (6b, 10a) -3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2, 3-de] Quinoxaline [1079] 2-oxo-2,3,9,10-tetrahydro-1H-pyridine [3', 4': 4,5] pyrolo [1,2, 3-de] Ethyl quinoxaline-8 (7H) -ethyl carbonate was prepared from the corresponding amines 1,3,4-trihydroquinoxaline-2-one and 4-oxopiperidine ethyl carbonate. [1080] (Step A) Sodium cyanoborohydride (4.0 g, 65 mmol) cooled in an ice water bath 2-oxo-2,3,9,10-tetrahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1 , 2,3-de] Quinoxaline-8 (7H) -ethyl carbonate (11.97 g, 40 mmol) was added little by little under nitrogen to a solution of trifluoroacetic acid (125 mL) with vigorous stirring. After completion of the addition, the mixture was stirred for 30 minutes and then slowly poured into ammonium hydroxide (300 mL) containing ice, after which a sufficient amount of 1N sodium hydroxide was added to make the mixture basic. The mixture was extracted with dichloromethane (2x), the extract was washed with water, dried over magnesium sulphate, evaporated to dryness and cis- (6b, 10a) -2-oxo-2,3,6b, 9, 10,10a-Hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] quinoxalin-8 (7H) -ethyl carbonate 10.89g (90%) grayish white Obtained as a powder. Melting point 167 ~ 168 ° C (decomposition, sintered at 70 ° C).¹1 H NMR (CDCl₃, 300MHz) δ1.28 (t, J = 7Hz, 3H), 1.81-1.95 (m, 2H), 3.13-3.22 (m, 1H), 3.23-3.39 (m, 1H), 3.44 (d, J = 14.7) Hz, 1H), 3.41-3.51 (m, 1H), 3.80-3.95 (m, 1H), 3.98 (d, J = 14.7Hz, 2H), 4.16 (q, 2H), 6.59 (d, J = 7.7Hz) , 1H), 6.74 (t, J = 7.7Hz, 1H), 6.83 (d, J = 7.7Hz, 1H), 8.17 (s, 1H) ppm. MS (CI): 302 (M + H)⁺). [1081] (Step B) Sodium hydride (60% dispersion in oil, 900 mg, 22.5 mmol) was washed with hexane and suspended in anhydrous dimethylformamide (5 mL). cis- (6b, 10a) -2-oxo-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2,3-de] This suspension was added to a solution of quinoxaline-8 (7H) -ethyl carbonate (6.02 g, 20 mmol) in anhydrous dimethylformamide (50 mL) with stirring under nitrogen. After the gas generation subsided, the mixture was cooled in an ice water bath and treated with iodomethane (3.55 g, 25 mmol). The mixture was stirred at room temperature for 1 hour and concentrated. The residue was treated with water, extracted with dichloromethane (2x), the extract was washed with brine, dried over magnesium sulfate, evaporated to dryness and cis- (6b, 10a) -3-methyl-2- Oxo-2,3,6b, 9,10,10a-Hexahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2,3-de] Kinoxalin-8 (7H) -Ethyl carbonate 5.48 g (87%) was obtained as a yellowish brown solid. Melting point 149 ~ 151 ° C (decomposition). [M + H] Calculated value 316, measured value 316.¹1 H NMR (CDCl₃, 300MHz) δ1.28 (t, J = 7.3Hz, 3H), 1.85to1.93 (m, 1H), 2.65to2.82 (m, 1H), 3.08to3.25 (m, 1H), 3.25to3. 40 (m, 1H), 3.30-3.50 (m, 1H), 3.34 (s, 3H), 3.42 (d, J = 14.3Hz, 1H), 3.85to4.0 (m, 1H), 4.02 (d, J) = 14.3Hz, 1H, 4.15 (q, J = 7.2Hz, 4H), 6.76 (d, J = 8.1Hz, 1H), 6.83 (t, J = 7.3Hz, 1H), 6.90 (d, J = 7.3Hz) , 1H) .MS (CI): 316 (M + H)⁺). [1082] (Step C) cis- (6b, 10a) -3-methyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2, 3-de] A solution of borane in tetrahydrofuran (1M, 33 mL, 33 mmol) was added dropwise to a solution of quinoxaline-8 (7H) -ethyl carbonate (5.24 g, 16.6 mmol) in anhydrous tetrahydrofuran (25 mL) with stirring under nitrogen. After completion of the addition, the mixture was stirred, heated to reflux for 1 hour, cooled and treated with 6N hydrochloric acid (15 mL). Then, it was heated to reflux for 30 minutes, cooled, and evaporated to dryness under reduced pressure. The residue was dissolved in a minimum amount of water, the solution was basified with 1N sodium hydroxide and extracted with dichloromethane (2x). The extract is washed with water, dried over magnesium sulphate, concentrated and concentrated as cis- (6b, 10a) -3-methyl-2,3,6b, 9,10,10a-hexahydro-1H- Pyrido [3', 4': 4,5] pyrolo [1,2,3-de] quinoxaline-8 (7H) -ethyl carbonate 4.65 g (93%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ1.28 (t, J = 7Hz, 3H), 1.68-1.78 (m, 1H), 1.78-1.93 (m, 2H), 2.81-2.90 (m, 2H), 2.86 (s, 3H), 3.05-3.26 (m, 2H), 3.26-3.38 (m, 2H), 3.56-3.75 (m, 2H), 3.79-3.87 (m, 1H), 4.16 (q, J = 7Hz, 2H), 6.41 (d , J = 8.1Hz, 1H), 6.61 (d, J = 8.1Hz, 1H), 6.67 (t, J = 8.1Hz, 1H) ppm. MS (CI): 302 (M + H)⁺). [1083] (Step D) cis- (6b, 10a) -3-methyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] Add powdered potassium hydroxide (10.0 g) to a warm 1-butanol (50 mL) solution of quinoxaline-8 (7H) -ethyl carbonate (4.52 g, 15.0 mmol) with stirring and heat the resulting mixture for 5 hours. It circulated. It was then evaporated under reduced pressure and the residue was treated with water and extracted with dichloromethane (2x). The extract was washed with water, dried over magnesium sulphate and concentrated to give 3.27 g (95%) of the title compound as a viscous solution.¹1 H NMR (CDCl₃, 300MHz) δ1.74-1.93 (m, 4H), 2.57-2.71 (m, 1H), 2.80-2.95 (m, 3H), 2.87 (s, 3H), 2.95-3.12 (m, 2H), 3.26- 3.38 (m, 3H), 3.55-3.64 (m, 1H), 6.41 (d, J = 7.3Hz, 1H), 6.51 (d, J = 7.3Hz, 1H), 6.65 (t, J = 7.3Hz, 1H) ) ppm. MS (CI): 230 (M + H)⁺). [1084] (Example 256) cis- (6b, 10a) -3-ethyl-2,3,6b, 7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2, 3-de] Quinoxaline [1085] Using the substance obtained from Step A of Example 255, the title compound was prepared as a light brown amorphous solid according to the methods of Steps B to D of Example 255 except that ethyl iodide was used as the alkyl halide. ..¹1 H NMR (CDCl₃, 300MHz) δ1.15 (t, 3H), 1.70-2.01 (m, 3H), 2.65-2.70 (t, J = 9.6Hz, 3H), 2.70-2.95 (m, 2H), 2,95-3.13 ( m, 2H), 3.13-3.72 (m, 5H), 3.60-3.95 (m, 1H), 6.39 (d, J = 8.0Hz, 1H), 6.47 (d, J = 7,4Hz, 1H), 6, 64 (t, J = 7.3Hz), 1H) ppm. MS (CI): 244 (M + H)⁺). [1086] (Step B) cis- (6b, 10a) -3-ethyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2, 3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 70%. MS (CI) 330 (M + H)⁺). [1087] (Step C) cis- (6b, 10a) -3-ethyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 70%. MS (CI): 316 (M + H)⁺). [1088] (Example 257) cis- (6b, 10a) -3-propyl-2,3,6b, 7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2, 3-de] Quinoxaline [1089] Using the substance obtained from Step A of Example 255, the title compound was prepared as an amorphous brown solid according to the methods of Steps B to D of Example 255 except that propyl iodide was used as the alkyl halide.¹1 H NMR (CDCl₃, 300MHz) δ0.94 (t, 2H), 1.40-2.01 (m, 6H), 2.65-2.70 (t, J = 9.6Hz, 2H), 2.70-2.95 (m, 2H), 2.95-3.45 (m, 7H)), 3.3.60-3.95 (m, 1H), 6.37 (d, J = 7.7Hz, 1H), 6.46 (d, J = 7.0Hz, 1H), 6.64 (t, J = 7.6Hz) ppm. MS (CI): 258 (M + H)⁺). [1090] (Step B) cis- (6b, 10a) -3-propyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2, 3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 72%. MS (CI) 344 (M + H)⁺). [1091] (Step C) cis- (6b, 10a) -3-propyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] Quinoxaline-8 (7H) -ethyl carbonate. Light brown viscous liquid. Yield 69%. MS (CI): 330 (M + H)⁺). [1092] (Example 258) cis- (6b, 10a) -3-Isopropyl-2,3,6b,7,8,9,10,10a-Octahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2, 3-de] Quinoxaline [1093] Using the substance obtained from Step A of Example 255, the title compound was prepared as a brown viscous solution according to the methods of Steps B to D of Example 255 except that propyl iodide was used as the alkyl halide.¹1 H NMR (CDCl₃, 300MHz) δ1.18 (d, 6H), 1.60-1.67 (m, 1H), 1.71-1.94 (m, 2H), 2.63-2.75 (m, 2H), 2.81-2.95 (m, 2H), 2.99- 3.20 (m, 2H), 3.30-3.55 (m, 3H), 3.99-4.12 (m, 1H), 6.45 (d, J = 7.4Hz, 2H), 6.65 (t, J = 7.3Hz, 1H) ppm. MS (CI): 258 (M + H)⁺). [1094] (Step B) cis- (6b, 10a) -3-Isopropyl-2-oxo-2,3,6b, 9,10,10a-Hexahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2, 3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 69%. MS (CI) 344 (M + H)⁺). [1095] (Step C) cis- (6b, 10a) -3-Isopropyl-2,3,6b, 9,10,10a-Hexahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2,3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 97%. MS (CI): 330 (M + H)⁺). [1096] (Example 259) cis- (6b, 10a) -3-Butyl-2,3,6b,7,8,9,10,10a-Octahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2, 3-de] Quinoxaline [1097] Using the substance obtained from Step A of Example 255, the title compound was prepared as a brown viscous solution according to the methods of Steps B to D of Example 255 except that butyl iodide was used as the alkyl halide.¹1 H NMR (CDCl₃, 300Mhz) δ0.95 (t, 3H), 1.30-1.45 (m, 2H), 1.50-1.65 (m, 2H), 1.95-2.15 (m, 2H), 2.65-2.80 (m, 2H), 2.65- 2.80 (m, 2H), 2.85-3.08 (m, 1H), 3.08-3.22 (m, 3H), 3.22-3.40 (m, 6H), 3.68-3.78 (m, 1H), 6.38 (d, J = 7.1) Hz), 6.46 (d, J = 7.1Hz, 1H), 6.66 (t, J = 7.7Hz, 1H) ppm. MS (CI): 436 (M + H)⁺). [1098] (Step B) cis- (6b, 10a) -3-Butyl-2-oxo-2,3,6b, 9,10,10a-Hexahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2, 3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 82%. MS (CI): 358 (M + H)⁺). [1099] (Step C) cis- (6b, 10a) -3-Butyl-2,3,6b, 9,10,10a-Hexahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2,3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 92%. MS (CI): 344 (M + H)⁺). [1100] (Example 260) cis- (6b, 10a) -3-Benzyl-2,3,6b,7,8,9,10,10a-Octahydro-1H-pyrido [3', 4': 4,5] Pyrrolo [1,2, 3-de] Quinoxaline [1101] Using the substance obtained from Step A of Example 255, the title compound was prepared as a viscous solution according to the methods of Steps B to D of Example 255 except that benzyl iodide was used as the alkyl halide.¹1 H NMR (CDCl₃, 300MHz) δ1.60-2.0 (m, 2H), 2.55-2.95 (m, 4H), 2.95-3.15 (m, 2H), 3.20-3.45 (m, 3H), 4,40 (q, J = 16.1 Hz, 2H), 6.41 (d, J = 7.1Hz, 1H), 6.51 (d, J = 7.1Hz, 1H), 6.62 (t, J = 7.1Hz, 1H), 7.20-7.40 (m, 5H) ppm .. MS (CI): 306 (M + H)⁺). [1102] (Step B) cis- (6b, 10a) -3-benzyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2, 3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 80%. MS (CI): 392 (M + H)⁺). [1103] (Step C) cis- (6b, 10a) -3-benzyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrolo [1,2,3-de] Quinoxaline-8 (7H) -ethyl carbonate. Brown viscous liquid. Yield 85%. MS (CI) 378 (M + H)⁺). [1104] (Example 261) cis-4-((6b, 10a) -3-methyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2,3 -de] Quinoxaline-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [1105] cis- (6b, 10a) -3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2, 3-de] Kinoxalin (3.20 g, 14 mmol), 4-chloro-4'-fluoro-butyrophenone (4.21 g, 21 mmol), triethylamine (3 mL), potassium iodide (3.48 g, 21 mmol), dioxane (25 mL) and toluene The mixture (25 mL) was stirred and refluxed in a nitrogen atmosphere for 15 hours and then evaporated under reduced pressure to remove volatiles. The residue was ground with a small amount of dichloromethane and decanted from the insoluble material. This method was repeated twice more and the combined dichloromethane solution was added to a 0.5N hydrogen chloride ether solution (200 mL). The separated salts were filtered off, washed with ether, immediately dissolved in a minimum amount of water and the solution was extracted with ether. The ether extract was discarded and the aqueous layer was basified with 10% aqueous sodium hydroxide solution. The resulting mixture was extracted with dichloromethane (2x), the extract was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 4.15 g (75%) of a brown highly viscous solution.¹1 H NMR (CDCl₃, 300MHz) δ1.79-2.13 (m, 6H), 2.21-2.32 (m, 1H), 2.32-2.44 (m, 2H), 2.60-2.71 (m, 1H), 2.75-2.92 (m, 2H), 2.86 (s, 3H), 2.98 (t, J = 7.3Hz, 2H), 3.04-3.16 (m, 1H), 3.16-3.35 (m, 2H), 3.55-3.64 (m, 1H), 6.39 (d, J = 8.1Hz, 1H), 6.50 (d, J = 8.1Hz, 1H), 6.64 (t, J = 7.7Hz, 1H), 7.12 (t, 2H), 8.01 (m, 2H) ppm. MS (CI): 394 (M + H)⁺). [1106] The above compounds were separated into their isomers on a chiral HPLC column. 4-((6bR, 10aS) -3-methyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2,3-de ] Quinoxaline-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone. Brown viscous liquid. [a]^D= -36.8 ° (c = 0.886, CHCl₃). MS (CI): 394 (M + H)⁺). [1107] 4-((6bS, 10aR) -3-methyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2,3-de ] Quinoxaline-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone. Brown viscous liquid. [a]^D= + 33.6 ° (c = 0.646, CHCl₃). MS (CI): 394 (M + H)⁺). [1108] (Example 262) cis-4-((6b, 10a) -3-ethyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2,3 -de] Quinoxaline-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [1109] According to the method of Example 261, cis- (6b, 10a) -3-ethyl-2,3,6b, 7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5 ] Pyrrolo [1,2,3-de] quinoxaline was treated to give the title compound as a brown viscous solution in good yield.¹1 H NMR (300MHz, CDCl₃) δ1.15 (t, J = 7.0Hz, 3H), 1.75-2.03 (m, 5H), 2.20to2.30 (m, 1H), 2.30-2.42 (m, 2H), 2.63to2.77 (m, 3H), 2.77to2.87 (m, 1H), 2.98 (t, J = 7.0HZ, 2H), 3.04-3.43 (m, 5H), 3.64-3.72 (m, 1H0,6.30 (d, J = 7.7Hz) , 1H), (6.47d, J = 7.7Hz, 1H), 6.64 (d, J = 7.7Hz, 1H), 7.12 (t, J = 8.5Hz, 2H), 7.98to8.03 (m, 2H) ppm . MS (CI): 408 (M + H)⁺). [1110] (Example 263) cis-4-((6b,10a) -3-isopropyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2,3 -de] Quinoxaline-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [1111] According to the method of Example 261, cis- (6b, 10a) -3-isopropyl-2,3,6b, 7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5 ] Pyrrolo [1,2,3-de] quinoxaline was treated to give the title compound as a brown viscous solution in good yield.¹1 H NMR (CDCl₃, 300MHz) δ1.18 (d, J = 6.6Hz, 6H), 1.82-1.84 (m, 5H), 2.21-2.29 (m, 1H), 2.29-2.41 (m, 2H), 2.64-2.68 (m, 2H), 2.79-2.87 (m, 1H), 2.98 (t, J = 7.3Hz, 2H), 3.03-3.17 (m, 2H), 3.21-3.45 (m, 3H), 4.03 (dt, J = 6.6, 2.3Hz, 1H), 6.45 (d, J = 6.2Hz, 2H), 6.64 (t, J = 7.7Hz, 1H), 7.12 (t, J = 8.3Hz, 2H), 8.0-8.03 (m, 2H) ppm. MS (CI): 422 (M + H)⁺). [1112] (Example 264) cis-4-((6b, 10a) -3-benzyl-2,3,6b, 9,10,10a-hexahydro-1H-pyrido [3', 4': 4,5] pyrrolo [1,2,3 -de] Quinoxaline-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [1113] According to the method of Example 261, cis- (6b, 10a) -3-benzyl-2,3,6b, 7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5 ] Pyrrolo [1,2,3-de] quinoxaline was treated to give the title compound as a brown viscous solution in good yield. Yield 23%.¹1 H NMR (CDCl₃, 300MHz,) δ1.84-2.05 (m, 5H), 2.20-2.31 (m, 1H), 2.31-2.43 (m, 2H), 2.64-2.72 (m, 1H), 2.72-2.80 (m, 1H) , 2.80-2.89 (m, 1H), 2.99 (t, J = 7.3Hz, 2H), 3.06-3.14 (m, 1H), 3.14-3.26 (m, 1H), 3.26-3.34 (m, 2H), 3.65 -3.74 (m, 1H), 4,43 (q, J = 16.5Hz, 2H), 6.40 (d, J = 8.0Hz, 1H), 6.50 (d, J = 7.0Hz, 1H),) 6.61 (t , J = 8.1Hz, 1H), 7.13 (t, J = 8.5Hz, 2H) 7.20-7.35 (m, 5H), 8.00-8.03 (m, 2H) ppm. MS (CI): 470 (M + H)⁺). [1114] (Example 266) cis-4-((6b,10a) -6-methyl-1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] ] Indol-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone [1115] According to the method of Example 261, cis- (6b, 10a) -6-methyl-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi ] Pyrido [4,3-b] indole was treated to give the title compound as a viscous light brown liquid in good yield. Yield 53%.¹1 H NMR (CDCl₃, 300MHz) δ1.82-2.10 (m, 5H), 2.18 (s, 3H), 2.20-2.35 (m, 1H), 2.43 (t, J = 6.9Hz, 2H), 2.60-2.80 (m, 2H) , 2.88-3.05 (m, 1H), 2.99 (t, J = 7.3Hz, 2H), 3.07-3.20 (m, 2H), 3.25 (d, J = 11Hz, 1H), 4.35-4.45 (m, 2H) , 6.44 (d, J = 8.1Hz, 1H), 6.53 (d, J = 8.1Hz, 1H), 7.13 (t, 8.4Hz, 2H), 7.99-8.04 (m, 2H) ppm. MS (CI): 395 (M + H)⁺). [1116] (Example 268) 4- (cis- (8a, 12a) -2-fluoro-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone [1117] According to the method of Example 261, cis- (8a, 12a) -2-fluoro-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] indole was treated to give the title compound as a viscous oil in good yield. Melting point 226 ~ 227 ° C. Yield 27%.¹1 H NMR (CDCl₃, 300MHz) δ1.50-2.20 (m, 8H), 2.20-2.32 (m, 1H), 2.32-2.50 (m1H), 2.50-2.63 (m, 1H), 2.63-2.78 (m, 1H), 2.78 = 3.30 (m, 6H), 3.45-3.60 (m, 1H), 3.60-3.77 (m, 1H), 6.57 (d, J = 7.7Hz, 1H), 6.67 (t, J = 6.2Hz, 1H), 7.13 (t, J = 7.8Hz, 2H), 7.97-8.02 (m, 2H) ppm. MS (CI): 429 (M + H)⁺). [1118] (Example 269) cis- (6b, 10a) -8- [3- (4-fluorophenoxy) propyl] -3-methyl-2,3,6b, 7,8,9,10,10a-octahydro-1H-pyrido [3' , 4': 4,5] Pyrrolo [1,2,3-de] Quinoxaline [1119] According to the method of Example 203, cis- (6b, 10a) -3-methyl-2,3,6b, 7,8,9,10,10a-octahydro-1H-pyrido [3', 4': 4,5 ] Pyrrolo [1,2,3-de] quinoxaline was treated to give the title compound as a viscous solution in good yield. Yield 30%.¹1 H NMR (CDCl₃, 300MHz): δ1.85-2.10 (m, 5H), 2.20-2.40 (m, 1H) 2.40-2.60 (m, 2H), 2.66-2.78 (m, 1H), 2.78-2.95 (m, 2H), 2.87 (t, 3H), 3.10-3.35 (m, 4H), 3.55-3.70 (m, 1H), 3.97 (t, J = 6.2Hz, 2H), 6.40 (d, J = 7.7Hz, 1H), 6.52 (d, J = 7.3Hz, 1H), 6.65 (t, J = 7.7Hz, 1H), 6.79-6.90 (m, 2H), 6.96 (t, J = 8.5Hz, 2H) ppm. MS (CI): 382 (M + H)⁺). [1120] (Example 270) cis- (6b, 10a) -8- [3- (4-fluorophenoxy) propyl] -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3, 4-hi] Pirido [4,3-b] Indole [1121] According to the method of Example 203, cis- (6b, 10a) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridodole [4 , 3-b] Indole was treated to give the title compound as a viscous solution in good yield. Yield 32%.¹1 H NMR (CDCl₃, 300MHz) δ1.91-2.02 (m, 3H), 2.06 (t, J = 11.4Hz, 1H), 2.26-2.40 (m, 2H), 2.40-2.60 (m, 2H), 2.65-2.80 (m, 2H), 2.80-2.95 (m, 1H), 3.05-3.22 (m, 1H), 3.22-3.32 (m, 2H), 3.98 (t, J = 6.3, Hz, 2H), 4.40-4.50 (m, 2H) ), 6.60-6.65 (m, 2H), 6.65-6.75 (m, 1H), 6.75-6.85 (m, 2H), 6.85-7.0 (m, 2H) ppm. MS (CI): 369 (M + H)⁺). [1122] (Example 271) cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole [1123] Freshly powdered synthetic sodium cyanoborohydride (49.92 g, 0.8 mol) with 6,7,9,10,11,12-hexahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] indole (48.8 g, 0.2 mol) was added little by little under nitrogen to a cold solution of trifluoroacetic acid (300 mL) with vigorous stirring. After completion of the addition, the mixture was stirred at room temperature for 4 hours and then carefully treated with 6N aqueous HCl (350 mL) with vigorous stirring. The mixture was then heated to reflux for 30 minutes, cooled, basified with 20% aqueous sodium hydroxide solution and extracted with chloroform (3x). The extract was washed with water, dried over magnesium sulfate, evaporated to dryness under reduced pressure, and recrystallized from hexane to give a colorless solid, yielding 42.8 g (87%) of the product as colorless crystals. Melting point 72-73 ° C.¹1 H NMR (CDCl₃, 300MHz) δ1.30 (s, 1H), 1.68-1.85 (m, 2H), 1.95-2.20 (m, 2H), 2.53-2.65 (m, 1H), 2.73-2.93 (m, 2H), 2.93- 3.10 (m, 3H), 3.10-3.28 (m, 1H), 3.33-3.45 (m, 1H), 3.45-3.58 (m, 1H), 3.68-3.83 (m, 1H), 6.63 (t, 1H, J = 7.3Hz), 6.85 (d, 1H, J = 7.3Hz), 6.95 (d, 1H, J = 7.3Hz) ppm. MS (CI): 247 (M + H)⁺). [1124] This is thus obtained by separating Example 271 into its enantiomers by high performance liquid chromatography using a chiral column, then dissolving each individually in a small amount of tetrahydrofuran and adding the resulting solution to excess hydrogen chloride ether solution. The enantiomers obtained were converted to these hydrochlorides. The salt was collected by filtration, washed with ether and dried under vacuum at 45 ° C. for 4 hours. [1125] (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole Hydrochloride. Colorless solid. Melting point 268-269 ° C (decomposition). [a]^D=-127.48 ° (c = 0.644, MeOH).¹H NMR (Me₂SO-d₆, 300MHz) δ1.85-2.15 (m, 4H), 2.91-3.08 (m, 2H), 3.08-3.20 (m, 2H), 3.20-3.31 (m, 1H), 3.31-3.41 (m, 3H), 3.41-3.55 (m, 1H), 3.55-3.65 (m, 1H), 6.65 (t, 1H, J = 7.3Hz), 6.90d, 1H, J = 7.3Hz), 6.98 (d, 1H, J = 7.3) Hz), 9.08 (bs, 1H), 9.15 (bs, 1H) ppm. [1126] cis- (8aR, 12aS) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indole hydrochloride. Colorless solid. Melting point 269 ~ 270 ° C (decomposition). [a]^D= + 127.91 ° (c = 0.634, MeOH). [1127] (Example 272) cis- (6b, 10a) -1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole [1128] The benzo [b] morpholine was treated according to the method of Step E of Example 4 followed by the methods of Steps A to C of Example 128 to obtain the title compound as colorless crystals. Melting point 100-101 ° C.¹1 H NMR (CDCl₃, 300MHz) δ1.77-1.95 (m, 2H), 2.15 (s, 1H), 2.61-2.85 (m, 2H), 2.85-3.00 (m, 2H), 3.03-3.21 (m, 2H), 3.28- 3.41 (m, 2H), 4.40-4.51 (m, 2H), 6.60-6.68 (m, 2H), 6.68-6.73 (m, 1H) ppm. MS (CI): 217 (M + H)⁺). [1129] (Example 273) cis- (8a, 12a) -2-fluoro-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole [1130] Treatment with p-fluoroaniline according to the methods of Steps A to D of Example 10 followed by the method of Example 11 gave the title compound as colorless crystals. Melting point 67-68 ° C.¹1 H NMR (CDCl₃, 300MHz) δ1.65 (s, 1H), 1.65-1.93 (m, 2H), 1.95-2.20 (m, 2H), 2.53-2.63 (m, 1H), 2.78-2.93 (m, 2H), 2.93- 3.05m, 3H), 3.08-3.21 (m, 1H), 3.30-3.40 (m, 1H), 3.48-3.60 (m, 1H), 3.60-3.73 (m, 1H) ppm. MS (CI): 265 (M + H)⁺). [1131] (Example 274) (8aS, 12aR) -3-Bromo-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] indole hydrochloride [1132] (Step A) A mixture of 2-chloro-3-nitrobenzoic acid (15 g, 74.4 mmol), red mercury oxide (24.2 g, 112 mmol), and carbon tetrachloride (350 mL) was irradiated with a 100 watt bulb and heated to reflux. Bromine (5.75 mL, 112 mmol) was added dropwise over 30 minutes. This was stirred under reflux for 3.5 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution (250 mL) was added, and the mixture was vigorously stirred for 20 minutes. The mixture was filtered and the solid was washed with excess chloroform. The two-phase solution was separated and the aqueous layer was back-extracted with chloroform (2 x 200 mL). The organic layer was collected, washed with brine (150 mL) and water (150 mL), dried (magnesium sulfate) and concentrated to give 3-bromo-2-chloronitrobenzene (10.6 g, 60.4%).¹1 H NMR (CDCl₃, 300MHz): δ7.86 (dd, 1H, J = 8.1,1.5), 7.73 (dd, 1H, J = 8.1,1.5Hz), 7.31 (t, 1H, J = 8.1Hz) ppm. [1133] (Step B) 3-Bromo-2-chloronitrobenzene (9 g, 38.1 mmol) and 3-chloro-1-propanethiol were dissolved in anhydrous tetrahydrofuran (75 mL) and cooled to 0 ° C. in an ice bath. Potassium hydroxide (3.2 g, 57.2 mmol) was added slowly. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction was filtered and the filtrate was concentrated to give 1-bromo-2-[(3-chloropropyl) thio] -3-nitrobenzene (11.18 g, 94.6%).¹1 H NMR (CDCl₃, 300MHz): δ7.84 (dd, 1H, J = 8.1,1.1Hz), 7.51 (dd, 1H, J = 8,1.4Hz), 7.3-7.267 (m, 1H), 3.63 (t, 2H, J = 6.2Hz), 3.09 (t, 2H, J = 6.95Hz), 2.04-1.95 (m, 2H) ppm. [1134] (Step C) 1-Bromo-2-[(3-chloropropyl) thio] -3-nitrobenzene (6.78 g, 21.9 mmol) was dissolved in ethyl alcohol (125 mL) and cooled to 0 ° C. in an ice bath. Tin (II) chloride dihydrate (7.4 g, 32.8 mmol) was dissolved in concentrated hydrochloric acid (25 mL) and then added to the first solution over 20 minutes. The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0 ° C. in an ice bath, and a solution of tin (II) chloride dihydrate (1.5 eq, 7.4 g) in concentrated hydrochloric acid (25 mL) was added. This was stirred at 0 ° C. for 30 minutes, warmed to room temperature and stirred until there was no starting material. The reaction was then basified to pH 12 with ammonium hydroxide and then filtered. The filtrate was concentrated in aqueous slurry solution, then the slurry was diluted with water (100 mL) and extracted with ethyl acetate (3 x 300 mL). The organic extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to give 1-bromo-2-[(3-chloropropyl) thio] -benzeneamine (5.7 g, 93.2%).¹1 H NMR (CDCl₃, 300MHz): δ7.02-6.87 (m, 2H), 6.65 (dd, 1H, J = 7.7,1.9Hz), 4.63 (s-broad, 2H), 3.68 (t, 2H, J = 6.4Hz), 2.92 (t, 2H, J = 6.95Hz), 2.04-1.95 (m, 2H) ppm. [1135] (Step D) 1-Bromo-2-[(3-chloropropyl) thio] -benzeneamine (5.7 g, 20.4 mmol) is dissolved in trifluoroacetic acid (52 mL), concentrated hydrochloric acid (48 mL) is added, and 0 in an ice bath. Cooled to ° C. A solution of sodium nitrite (1.69 g, 24.48 mmol) in water (6 mL) was slowly added to the reaction mixture over 20 minutes so that the reaction temperature was maintained below 8 ° C. This was stirred at 0 ° C for 1 hour. Tin (II) chloride dihydrate (10.1 g, 44.79 mmol) was dissolved in concentrated hydrochloric acid (12 mL), cooled to 0 ° C. in an ice bath and then slowly added to the reaction mixture over 20 minutes. After addition, the reaction was warmed to room temperature and stirred for 14 hours. The reaction was filtered, the filtered cake was dissolved in water, basified with saturated potassium carbonate to pH = 10, and then extracted with chloroform (3 x 200 mL). The organic extract was washed with water (100 mL) and dried over magnesium sulfate. The organic matter was concentrated to give 1- [3-bromo-2-[(3-chloropropyl) thio] phenyl] -hydrazine (4.5 g, 75.3%).¹1 H NMR (CDCl₃, 300MHz): δ7.16-7.01 (m, 3H), 6.70 (s-broad, 1H), 3.68 (t, 2H, J = 6.25Hz), 3.61 (s-broad, 2H), 2.89 (t, 2H) , J = 7Hz), 2.01-1.92 (m, 2H) ppm. [1136] (Step E) 1- [3-Bromo-2-[(3-chloropropyl) thio] phenyl] -hydrazine (2.4 g, 7.25 mmol) is suspended in isopropyl alcohol (14 mL), followed by hydrogen chloride gas in suspension. Upon blowing, the suspension became a solution after 15 minutes. The reaction was sealed in a pressure flask and heated at 80 ° C. for 14 hours. It is cooled to room temperature and filtered to give 7-bromo-6-[(3-chloropropyl) sulfanyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3b] indole hydrochloride, Obtained as a tan solid (1.9 g, 66%).¹H NMR (CD)₃OD, 300MHz): δ7.34-7.29 (m, 2H), 4.40 (s, 2H), 3.67-3.58 (m, 4H), 3.18-3.16 (m, 2H), 3.01 (t, 2H, J = 6.95) ), 1.87-1.82 (m, 2H) ppm. [1137] (Step F) 7-Bromo-6-[(3-chloropropyl) sulfanyl] -2,3,4, tetrahydro-1H-pyrido [4,3b] indole hydrochloride (2.06 g, 5.75 mmol), potassium hydroxide (3.2 g, 57.5 mmol) and potassium iodide (1.14 g, 6.9 mmol) were dissolved in diethylene glycol dimethyl ether (192 mL) and heated under reflux for 13 hours. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. The oil was mostly dissolved in chloroform, refiltered and the filtrate was concentrated again under reduced pressure to give a brown oil. The oil is purified by silica gel column chromatography eluting with a chloroform solution of methanol (0%, 10%, and 25%) and 3-bromo-6,7,9,10,11,12-hexahydro-5H-pyrido as oil. [4,3-b] [1,4] thiazepino [2,3,4-hi] indol (210 mg, 12%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.12 (d, 1H, J = 8.1Hz), 6.94 (d, 1H, J = 8.1Hz), 4.42 (t, 2H, J = 5.85Hz), 4.01 (s, 2H), 3.37 -3.28 (m, 4H), 2.71 (t, 2H, J = 5.5), 2.28-2.20 (m, 2H) ppm. [1138] (Step G) 3-Bromo-6,7,9,10,11,12-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (480 mg, 1.5 mmol) Was dissolved in trifluoroacetic acid (8 mL) at room temperature and then cooled to 0 ° C. in an ice bath. Sodium cyanoborohydride (408 mg, 6.0 mmol) was added in small portions over 30 minutes. The mixture was stirred at 0 ° C. for an additional 6 hours. This solution was transferred to a solution of saturated aqueous potassium carbonate solution and ice pieces (total volume 200 mL) by cannula over 10 minutes. The mixture was stirred at ambient temperature for 3 minutes, tetrahydrofuran (200 mL) was added, followed by 4- (dimethylamino) pyridine (20 mg, 0.163 mmol) and di-tert-butyl bicarbonate (330 mg, 1.5 mmol). .. The two-phase mixture was vigorously stirred at room temperature for 1.5 hours. This stirring was started at room temperature and warmed to room temperature. The reaction is extracted with ethyl acetate (3 x 100 mL), the combined extracts are washed with brine (200 mL), water (200 mL), dried over magnesium sulfate and then concentrated under reduced pressure to give the oil. It was. Purify the oil by silica gel column chromatography (5 g) eluting with a hexane solution of ethyl acetate (20%) to (8aS, 12aR) -3-bromo-6,7,9,10,12,12a-hexahydro-5H. -Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (235 mg, 35%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ6.93 (d, 1H, J = 7.7Hz), 6.84 (d, 1H, J = 7.7Hz), 3.87-3.83 (m, 1H), 3.59-3.40 (m, 3H), 3.39- 2.93 (m, 4H), 2.10-1.98 (m, 2H), 1.81-1.76 (m, 2H), 1.52 (s-broad, 2H), 1.34 (s-broad, 9H) ppm. Mass spectrometry (CI): 426 (base, M + H). [1139] (Step H) (8aS, 12aR) -3-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole -11 (8aH) -tert-butyl carbonate (23 mg, 0.054 mmol) was dissolved in chloroform (2 mL) and methyl alcohol (0.5 mL) at room temperature. Hydrogen chloride gas was blown in for 10 minutes. The reaction was then concentrated under reduced pressure to give the title compound (15 mg, 77%).¹H NMR (CD)₃OD, 300MHz): δ6.96 (d, 1H, J = 8Hz); 6.83 (d, 1H, J = 8.1Hz); 4.92-3.98 (m, 1H); 3.17-3.60 (m, 1H); 3.39- 3.11 (m, 6H); 3.09-2.99 (m, 1H); 2.78-2.70 (m, 1H); 2.23-1.87 (m, 4H) ppm. Mass spectrometry (ApCI): 326 (base, M + H). [1140] (Example 275) (8aS, 12aR) -3- (2,6-difluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] indole, trifluoroacetic acid salt [1141] (Step A) (8aS, 12aR) -3-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -tert-butyl carbonate (40 mg, 0.094 mmol), triphenylphosphine (5 mg, 0.019 mmol), copper (II) bromide (3 mg, 0.019 mmol) and dichlorobis (triphenylphosphine) palladium (II) (7 mg, 0.0094 mmol) was dissolved in N, N-dimethylformamide (1.0 mL). This solution was degassed for 10 minutes, then a degassed solution of tin (2,6-difluoro-phenyl) trimethylhydride (40 mg, 0.141 mmol) in degassed N, N-dimethylformamide (0.5 mL) was added, then 60 ° C. The mixture was heated and stirred with C for 45 minutes. Then, a degassed solution of tin (2,6-difluoro-phenyl) trimethylhydrogenide (20 mg, 0.071 mmol) was added, and the reaction was heated at 140 ° C for 10 minutes. did. Finally, a degassed solution of tin (2,6-difluoro-phenyl) trimethylhydrogen (20 mg, 0.071 mmol) in N, N-dimethylformamide (0.4 mL) was added and the reaction was heated at 140 ° C for 1.25 hours. It was heated. The reaction temperature was then raised to 154 ° C and heated for 2 hours, cooled to room temperature and then diluted with ethyl acetate (10 mL) and water (10 mL). The organic matter was separated, washed with water (3 x 20 mL), dried over magnesium sulfate and concentrated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography eluting with a hexane solution of ethyl acetate (10%). The oil isolated by high pressure liquid chromatography on a chiral cell OD column, eluting a hexane solution of 2% ethyl alcohol (0.05% diethylamine modifier) at 7 mL / min, was purified and used as oil (8aS, 12aR) -3- ( 2,6-difluorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,¹1 H NMR (CDCl₃, 300MHz): δ7.35-7.7.27 (m, 1H), 6.98-6.90 (m, 3H), 6.64 (d, 1H, J = 7.3Hz), 4.10-4.01 (m, 1H), 3.68-3.51 (m, 4H), 3.38-3.22 (m, 2H), 3.20-3.09 (m, 1H), 2.98-2.81 (m, 1H), 2.18-2.00 (m, 2H), 1.91-1.86 (m, 2H) , 1.60-1.55 (m, 1H), 1.43 (s-broad, 9H) ppm. MS (ApCI): 459 (base, M + H). [1142] (Step B) (8aS, 12aR) -3- (2,6-difluorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (9.3 mg, 0.0203 mmol) was dissolved in chloroform (5 mL), cooled to 0 ° C in an ice bath, and trifluoroacetic acid (1 mL). Was added, and the mixture was stirred for 3 hours, during which the reaction was warmed to room temperature. The reaction was concentrated under reduced pressure to give a residue and then held under reduced pressure for 13 hours to give the title compound (10 mg, 83%) as an amorphous solid.¹H NMR (CD)₃OD, 300MHz): δ7.41-7.31 (m, 1H), 7.08-6.91 (m, 3H), 6.60 (d, 1H, J = 7.7Hz), 4.07-3.91 (m, 1H), 3.63-3.34 ( m, 4H), 3.22-3.13 (m, 2H), 2.92-2.78 (m, 2H), 2.31-1.85 (m, 5H) ppm. MS (ApCI): 359 (base, M + H) [1143] (Example 276) (8aS, 12aR) -3- (4-Methoxy-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1144] (8aS, 12aR) -3-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol -11 (8aH) -tert-butyl carbonate (100 mg, 0.235 mmol), 2-methyl-4-methoxyphenylboronic acid (125 mg, 0.282 mmol) and barium hydroxide (112 mg, 0.353 mmol) in ethylene glycol dimethyl ether (3.2 mL) ) And water (1.1 mL). The solution was degassed for 3 minutes, then tetrakis (triphenylphosphine) palladium (0) (6 mg, 0.0047 mmol) was added and the reaction was heated at 90 ° C. for 14 hours. The reaction is cooled to room temperature, then 2-methyl-4-methoxyphenylboronic acid (125 mg, 0.282 mmol) and tetrakis (triphenylphosphine) palladium (0) (6 mg, 0.0047 mmol) are added, followed by 90 ° C. Was heated for 14 hours. The reaction was cooled and diluted with ethyl acetate (25 mL) and water (5 mL). The organic matter was separated, washed with brine (25 mL) and dried over magnesium sulfate. The oil was concentrated under reduced pressure to obtain an oil, which was purified by silica gel column chromatography eluting with a hexane solution of ethyl acetate (14%). The oil was dissolved in chloroform (10 mL), cooled to 0 ° C. in an ice bath, trifluoroacetic acid (2 mL) was added and stirred for 3 hours, during which the reaction was warmed to room temperature. This was basified to pH = 12 with concentrated ammonium hydroxide and then extracted with chloroform (3 × 20 mL). The organics were filtered and then concentrated under reduced pressure to give a brown oil. The oil was further purified by high pressure liquid chromatography on a chiral cell OD column eluting a hexane solution of 6% ethyl alcohol (0.05% diethylamine modifier) at 7 mL / min to give the title compound as the oil.¹1 H NMR (CDCl₃, 300MHz): δ7.07-7.03 (m, 1H), 6.86-6.72 (m, 3H), 6.50-6.46 (m, 1H), 4.08-3.83 (m, 1H), 3.81 (s, 3H), 3.60 -3.51 (m, 1H), 3.44-3.37 (m, 1H), 3.29-2.80 (m, 5H), 2.77-2.51 (m, 1H), 2.14 (d, 3H, J = 10.6), 2.10-1.70 ( m, 5H) ppm. MS (ApCI): 367 (base, M + H). [1145] (Example 277) (8aS, 12aR) -3- [4- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1146] (8aS, 12aR) -3-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol -11 (8aH) -tert-butyl carbonate (86 mg, 0.202 mmol), 4-trifluoromethylphenylboronic acid (46 mg, 0.243 mmol) and barium hydroxide (96 mg, 0.304 mmol) with ethylene glycol dimethyl ether (3.2 mL) and Dissolved in water (1.1 mL). The solution was degassed for 3 minutes, then tetrakis (triphenylphosphine) palladium (0) (5 mg, 0.00405 mmol) was added and the reaction was heated at 90 ° C. for 14 hours. The reaction is cooled to room temperature, then 4-trifluoromethylphenylboronic acid (46 mg, 0.243 mmol) and tetrakis (triphenylphosphine) palladium (0) (5 mg, 0.00405 mmol) are added, followed by 14 at 90 ° C. Heated for hours. The reaction was cooled and diluted with ethyl acetate (10 mL) and water (10 mL).The organic matter was separated, washed with saline and then dried over magnesium sulphate. The filtrate was then filtered and concentrated under reduced pressure to give an oil, which was purified by silica gel column chromatography eluting with a hexane solution of ethyl acetate (14%) to give the oil. The oil was dissolved in chloroform (10 mL), cooled to 0 ° C. in an ice bath, trifluoroacetic acid (2 mL) was added and stirred for 3 hours, during which the reaction was warmed to room temperature. This was basified to pH = 12 with concentrated ammonium hydroxide and then extracted with chloroform (3 x 25 mL). The organic matter was separated, washed with saline and then dried over magnesium sulphate. The organics were filtered and then concentrated under reduced pressure to give a brown oil. The oil was further purified by high pressure liquid chromatography on a chiral cell OD column eluting a hexane solution of 6% ethyl alcohol (0.05% diethylamine adjuster) at 7 mL / min to give the title compound (5.6 mg, 7%) as the oil. Obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.63 (d, 2H, J = 8.1Hz), 7.48 (d, 2H, J = 8Hz), 6.89 (d, 1H, J = 7.3Hz), 6.60 (d, 1H, J = 7.3) Hz), 4.07-3.98 (m, 1H), 3.59-3.49 (m, 1H), 3.47-3.42 (m, 1H), 3.27-3.20 (m, 1H), 3.09-3.01 (m, 2H), 2.97- 2.81 (m, 3H), 2.72-2.63 (m, 1H), 2.15-1.58 (m, 4H) ppm. MS (ApCI): 391 (base, M + H). [1147] (Example 278) (8aS, 12aR) -3- (2,3-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [1148] The title compound (8aS, 12aR) -3- (2,3-dichlorophenyl) -6,7,8a, 9,10,11,12, using the appropriate boronic acid according to the method shown in Example 277. , 12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (32 mg, 35%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.44 (d, 1H, J = 6.9Hz); 7.24-7.12 (m, 2H); 6.90-6.86 (m, 1H); 6.49 (dd, 1H, J = 2.2,7.4Hz); 4.03-3.80 (m, 1H); 3.62-2.61 (m, 9H); 2.18-1.82 (m, 4H) ppm. MS (ApCI): 391 (base, M + H). [1149] (Example 279) (8aS, 12aR) -3- (2,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [1150] The title compound (8aS, 12aR) -3- (2,4-dichlorophenyl) -6,7,8a, 9,10,11,12, using the appropriate boronic acid according to the method shown in Example 277. , 12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (13.5 mg, 15%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.45 (d, 1H, J = 5.5Hz); 7.40-7.04 (m, 2H); 6.90 (d, 1H, J = 7.3Hz); 6.51 (d, 1H, J = 6.2Hz) 4.16-3.84 (m, 1H); 3.65-2.84 (m, 8H); 2.70 (t, 1H, J = 10.5Hz); 2.17-1.83 (m, 4H) ppm. MS (ApCI): 391 (base, M + H). [1151] (Example 280) (8aS, 12aR) -3- [2-Chloro-4- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1152] The title compound (8aS, 12aR) -3- [2-chloro-4- (trifluoromethyl) phenyl] -6,7,8a, using the appropriate boronic acid according to the method shown in Example 277. 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (13.5 mg, 15%) was obtained.¹1 H NMR (CDCl₃, 300MHz): δ7.72 (d, 1H, J = 5.2Hz); 7.55 (t, 1H, J = 8.25Hz); 7.39-7.35 (m, 1H); 6.94 (dd, 1H, J = 7.3,2.6) Hz); 6.53 (q, 1H, J = 3.8Hz); 4.11-3.80 (m, 2H); 3.63-3.40 (m, 2H); 3.29-2.85 (m, 5H); 2.73 (t, 1H, J = 10.8Hz); 2.20-1.82 (m, 4H) ppm. MS (ApCI): 425 (base, M + H). [1153] (Example 281) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-Pirido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole -3-Carbonitrile dihydrochloride [1154] (8aS, 12aR) -3-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole -11 (8aH) -tert-butyl carbonate (425 mg, 0.995 mmol) and copper (I) cyanide (107 mg, 1.19 mmol) were dissolved in N, N-dimethylformamide (8 mL). The solution was degassed 5 times under vacuum and nitrogen and heated at 120 ° C. for 14 hours. The reaction was cooled to room temperature and quenched with aqueous sodium cyanide solution (20 mg in 20 mL). Extracted with benzene (3 x 50 mL). The organic matter was washed with saline (50 mL) and water (50 mL) and then dried over magnesium sulphate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a brown oil, which was purified by silica gel column chromatography eluting with a hexane solution of ethyl acetate (20%) to give the oil. The oil was dissolved in chloroform (5 mL) and ethanol (5 mL), then hydrogen chloride gas was blown in for 2 hours. The reaction was concentrated under reduced pressure to give the title compound as a salt.¹H NMR (CD)₃OD, 300MHz): δ7.08 (s, 2H), 4.01-3.88 (m, 1H), 3.78-3.65 (m, 1H), 3.52-3.33 (m, 3H), 3.24-3.02 (m, 4H), 2.80-2.71 (m, 1H), 2.30-2.00 (m, 4H) ppm. MS (ApCI): 272 (base, M + H). [1155] (Example 282) (8aS, 12aR) -2-Bromo-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indole-3-carbonitrile dihydrochloride [1156] (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -3-Carbonitrile dihydrochloride (95 mg, 0.256 mmol) was dissolved in N, N-dimethylformamide (1 mL) and cooled to 0 ° C. in an ice bath. In another flask, the imide N-bromosuccinate was dissolved in N, N-dimethylformamide (1 mL) and slowly added to the first solution over 10 minutes. The reaction was stirred for 10 minutes and then observed by thin layer chromatography until no starting material was present in the reaction. The reaction was then quenched with water (10 mL) and extracted with benzene (3 x 15 mL). The organic layer was collected, washed with brine (1 x 20 mL) and water (1 x 20 mL), dried over magnesium sulphate, then filtered and the filtrate concentrated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography eluting with a hexane solution of ethyl acetate (23, 30, 40%). Fractions were collected and concentrated under reduced pressure to give a colorless oil. The oil was dissolved in chloroform (10 mL), cooled to 0 ° C. in an ice bath, trifluoroacetic acid (2 mL) was added and stirred for 3 hours, during which the reaction was warmed to room temperature. This was basified to pH 12 with concentrated ammonium hydroxide and then extracted with chloroform (3 x 50 mL). The organic layer was collected and concentrated under reduced pressure to give an oil. The oil was dissolved in chloroform (2 mL), then 1 M solution of diethyl ether hydrogen chloride was added until no precipitation occurred and this was concentrated under reduced pressure to give the title compound (24 mg, 41%).¹H NMR (CD)₃OD, 300MHz): δ7.36 (s, 1H); 4.01-3.89 (m, 1H); 3.82-3.70 (m, 1H); 3.58-3.37 (m, 3H); 3.27-3.09 (m, 5H); 2.23-2.00 (m, 4H) ppm. MS (ApCI): 391 (base, M + H). [1157] (Example 283) (8aS, 12aR) -3-Benzyl-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] indole dihydrochloride [1158] (8aS, 12aR) -3-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol -11 (8aH) -tert-butyl carbonate (150 mg, 0.353 mol), zinc bromide (250 mg, 1.06 mmol), copper (I) iodide (29 mg, 0.353 mmol), and bis (triphenylphosphine) palladium ( II) Chloride (29 mg, 0.0353 mmol) was dissolved in tetrahydrofuran (5 mL) under a nitrogen atmosphere and then heated to reflux for 13 hours. The reaction was concentrated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography eluting with a hexane solution of ethyl acetate (16%). Fractions were collected and concentrated under reduced pressure to give a colorless oil. The oil was dissolved in chloroform (10 mL), cooled to 0 ° C. in an ice bath, trifluoroacetic acid (2 mL) was added and stirred for 3 hours, during which the reaction was warmed to room temperature. This was basified to pH 12 with concentrated ammonium hydroxide and then extracted with chloroform (3 x 50 mL). The organic layer was collected, dried over magnesium sulphate and then concentrated under reduced pressure to give an oil. The oil was dissolved in chloroform (2 mL), then 1 M solution of diethyl ether hydrogen chloride was added until no precipitation occurred and this was concentrated under reduced pressure to give the title compound (25 mg, 21%).¹H NMR (CD)₃OD, 300MHz): δ7.21-7.09 (m, 5H); 6.94 (d, 1H, J = 7.7Hz); 6.67 (d, 1H, J = 7.7Hz); 3.99 (s, 2H); 3.97-3.89 (m, 1H); 3.62-3.17 (m, 7H); 3.00-2.80 (m, 2H); 2.21-1.86 (m, 4H) ppm. MS (ApCI): 337 (base, M + H). [1159] (Example 284) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -3-Calvaldehydrodihydrochloride [1160] (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-Pirido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole -3-Carbonitrile dihydrochloride (62 mg, 0.167 mol) was dissolved in dichloromethane (1 mL), cooled to 0 ° C. in an ice bath, and stirred for 10 minutes under a nitrogen atmosphere. Aluminum diisobutyl hydride (71 mg, 0.501 mmol) was then added dropwise and then stirred for 2 hours. The reaction was quenched with methanol (5 mL), Rochelle salt (5 mL) and chloroform (5 mL) and stirred vigorously at room temperature for 12 hours. The reaction mixture was separated and the aqueous layer was back-extracted with chloroform (3 × 10 mL). The organic layer was collected, dried over magnesium sulphate and then filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography eluting with a hexane solution of ethyl acetate (20%). Fractions were collected and concentrated under reduced pressure to give a colorless oil. The oil was dissolved in chloroform (2 mL), then 1 M solution of diethyl ether hydrogen chloride was added until no precipitation occurred and this was concentrated under reduced pressure to give the title compound (7 mg, 18%).¹H NMR (CD)₃OD, 300MHz): δ6.98 (d, 2H, J = 1.8Hz); 5.44 (s, 1H); 4.03-3.98 (m, 1H); 3.58-3.30 (m, 2H); 3.25-3.13 (m, 5H); 2.98-2.87 (m, 1H); 2.79-2.67 (m, 1H); 2.22-1.86 (m, 4H) ppm. MS (ApCI): 275 (base, M + H). [1161] (Example 285) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -3-Dicarbonate [1162] (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-Pirido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indore -3-Carbonitrile dihydrochloride (65 mg, 0.175 mol) was dissolved in methanol (0.6 mL), water (0.8 mL) and tetrahydrofuran (0.4 mL), then potassium hydroxide (190 mg, 3.33 mmol) was added. Then, it was heated and refluxed for 23 hours. The reaction was acidified to pH = 7 with 1N hydrochloric acid. The reaction mixture was extracted with chloroform (3 x 10 mL). The organic layer was collected, dried over magnesium sulphate and then filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography eluting with a hexane solution of ethyl acetate (16%) followed by methanol (100%). Fractions were collected and concentrated under reduced pressure to give a colorless oil. The oil was dissolved in chloroform / methanol (3/2 mL) and then hydrogen chloride gas was blown in for 20 minutes. The reaction solution was concentrated under reduced pressure to give the title compound (20 mg, 53%).¹H NMR (CD)₃OD, 300MHz): δ7.26 (d, 1H, J = 7.3Hz); 6.98 (d, 1H, J = 7.7Hz); 4.10-4.01 (m, 1H); 3.62-3.54 (m, 2H); 3.42 -3.30 (m, 3H); 3.25-3.09 (m, 2H); 2.92-2.83 (m, 1H); 2.81-2.73 (m, 1H); 2.24-1.83 (m, 4H) ppm. [1163] (Example 286) N- [2-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-11 (8aH) -yl) ethyl] -2,4-difluorobenzamide [1164] (Step A) N 2,4-difluorobenzoyl chloride (500 mg, 2.83 mmol) in a THF solution of ethanolamine (1.10 g, 15.8 mmol)₂Added at 0 ° C below. The reaction mixture was stirred at 0 ° C for 4 hours, then diluted with ethyl acetate (100 mL), 1N HCl (50 mL), saturated LVDS.₃Washed with (50 mL) and saturated NaCl (50 mL). EDTA organic solution₄And concentrated under vacuum to give 2,4-difluoro-N- (2-hydroxyethyl) benzamide (495 mg, 87%) as a white solid. [1165] (Step B) CH of 2,4-difluoro-N- (2-hydroxyethyl) benzamide (299 mg, 1.49 mmol) and triethylamine (302 mg, 2.98 mmol)₂Cl₂Methanesulfonyl chloride (335 mg, 2.98 mmol) was added to the solution at 0 ° C under nitrogen. The reaction mixture was stirred at 0 ° C. for 1 hour. Quench the reactants by adding 1N HCl (5 mL), dilute the solution with ethyl acetate (100 mL) and saturate LVDS.₃Wash with (100 mL) and saturated NaCl (100 mL) and deli₄It was dried in, filtered and concentrated under vacuum. Purification by column chromatography (hexane: EtOAc 4: 1) gave 2-[(2,4-difluorobenzoyl) amino] ethylmethanesulfonate (300 mg, 72%) as a clear liquid. [1166] (Step C) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole In a solution of (30 mg, 0.12 mmol) and 2-[(2,4-difluorobenzoyl) amino] ethylmethanesulfonate (102 mg, 0.36 mmol) in 1,4-dioxane (0.6 mL), K₂CO₃(24 mg, 0.17 mmol) and KI (catalytic amount) were added and the reaction mixture was stirred at 100 ° C. for 48 hours. CHCl the reaction mixture₃Diluted with (50 mL) and filtered. Column purification (CHCl)₃: MeOH99: 1) was performed to isolate the title compound (43 g, 77%) as a pale yellow oil.¹1 H NMR (CDCl₃) δ1.65 (br-s, 1H), 1.86-2.13 (m, 5H), 2.39 (td, 1H, J = 3.3,11.0Hz), 2.52-2.66 (m, 3H), 2.72-2.78 (m, 1H), 2.93-3.00 (m, 1H), 3.08-3.18 (m, 2H), 3.28-3.33 (m, 1H), 3.49-3.59 (m, 3H), 3.77-3.85 (m, 1H), 6.59 ( t, 1H, J = 7.4Hz), 6.82-7.03 (m, 4H), 8.10-8.18 (m, 1H) ppm. [1167] (Example 287) N- [2-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-11 (8aH) -yl) ethyl] -N-methylbenzamide [1168] According to the methods of steps A and B of Example 286, from benzoyl chloride (545 mg, 3.6 mmol) and 2 (methylamino) ethanol (1.35 g, 18 mmol) to 2- (benzoyl (methyl) amino) ethylmethanesulfonate (987 mg, 49%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 2- (benzoyl (methyl) amino) ethylmethanesulfonate (48 mg, 0.24 mmol), the title compound (35 mg, 33%) as a yellow oil Isolated.¹1 H NMR (CDCl₃) δ1.69-1.95 (m, 3H), 2.01-2.19 (m, 2H), 2.34-2.51 (m, 2H), 2.57-2.81 (m, 2H), 2.93-3.10 (m, 6H), 3.25- 3.58 (m, 2H), 2.61-2.85 (m, 3H), 6.61 (t, 1H, J = 7.5Hz), 6.94 (d, 1H, J = 7.7Hz), 7.26-7.50 (m, 4H) ppm. MS (ESI): 408 (base, M + H). [1169] (Example 288) N- [2-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-11 (8aH) -yl) ethyl] -2-fluoro-N-methylbenzamide [1170] From 2-fluorobenzoyl chloride (1.12 g, 6.4 mmol) and 2 (methylamino) ethanol (2.70 g, 32 mmol), 2-[(2-fluorobenzoyl (methyl)) according to the methods of steps A and B of Example 286. Amino) ethylmethanesulfonate (531 mg, 85%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 2-[(2-fluorobenzoyl) (methyl) amino) ethylmethanesulfonate (48 mg, 0.24 mmol), the title compound (35 mg) as a yellow oil , 66%) were isolated.¹1 H NMR (CDCl₃) δ1.65-1.93 (m, 1H), 2.01-2.17 (m, 3H), 2.25-2.44 (m, 3H), 2.54-2.91 (m, 3H), 2.95-3.05 (m, 3H), 3.10- 3.22 (m, 3H), 3.27-3.40 (m, 1H), 3.45-3.90 (m, 4H), 6.58-6.64 (m, 1H), 6.81 (dd, 1H, J = 6.6,38.9Hz), 6.92- 6.96 (m, 1H), 7.06-7.19 (m, 1H), 7.19 (t, 1H, J = 6.9Hz), 7.32-7.40 (m, 2H) ppm. MS (ESI): 426 (base, M + H). [1171] (Example 289) N- [2-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-11 (8aH) -yl) ethyl] -2,4-difluoro-N-methylbenzamide [1172] From 2,4-difluorobenzoyl chloride (1.04 g, 5.9 mmol) and 2 (methylamino) ethanol (2.13 g, 28 mmol), 2-[(2,4-difluoro) according to the methods of steps A and B of Example 286. Benzoyl (methyl) amino) ethylmethanesulfonate (482 mg, 86%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 2-[(2,4-difluorobenzoyl) (methyl) amino) ethylmethanesulfonate (57 mg, 0.24 mmol), the title compound as a yellow oil (17 mg, 31%) was isolated.¹1 H NMR (CDCl₃) δ1.89-2.01 (m, 2H), 2.05-2.14 (m, 2H), 2.38-2.52 (m, 3H), 3.55-3.78 (m, 2H), 2.81-2.91 (m, 1H), 2.94- 3.07 (m, 3H), 3.10-3.19 (m, 2H), 3.24-3.36 (m, 2H), 3.45-3.60 (m, 1H), 3.61-3.85 (m, 3H), 6.61 (t, 1H, J = 7.5Hz), 6.74-6.96 (m, 4H), 7.33-7.38 (m, 1H) ppm. [1173] (Example 290) N- [2-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-11 (8aH) -yl) ethyl] -4-fluoro-N-methylbenzamide [1174] From 4-fluorobenzoyl chloride (1.12 g, 3.2 mmol) and 2 (methylamino) ethanol (2.70 g, 16 mmol), 2-[(4-fluorobenzoyl (methyl)) according to the methods of steps A and B of Example 286. Amino) ethylmethanesulfonate (482 mg, 86%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 2-[(4-fluorobenzoyl) (methyl) amino) ethylmethanesulfonate (53 mg, 0.24 mmol), the title compound (37 mg) as a yellow oil , 69%) were isolated.¹1 H NMR (CDCl₃) δ1.73-1.95 (m, 3H), 1.98-2.21 (m, 3H), 2.35-2.55 (m, 3H), 3.60-3.78 (m, 1H), 2.86-2.97 (m, 1H), 2.98- 3.21 (m, 5H), 3.27-3.45 (m, 1H), 3.52-3.59 (m, 2H), 3.72-3.86 (m, 2H), 6.62 (t, 1H, J = 7.5Hz), 6.71-6.83 ( m, 1H), 6.95 (dd, 1H, J = 1.17.8Hz), 7.08 (t, 2H, J = 8.6Hz), 7.30-7.50 (m, 2H) ppm. [1175] (Example 291) (8aS, 12aR) -11-[3- (1H-1,2, benzotriazol-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1176] (Step A) 1-Bromo-3-chloropropane (437 mg, 2.77 mmol) was added to a DMSO solution of benzotriazole (303 mg, 2.54 mmol) and powdered NaOH (101 mg, 2.52 mmol). The reaction mixture was stirred at 20 ° C. for 16 hours. The reaction mixture is then diluted with EtOAc (100 mL) and H₂Wash with O (100 mL) and saturated NaCl (100 mL) and deli₄It was dried in and concentrated under vacuum. Column purification (hexane: EtOAc 4: 1) was performed to obtain 1- (3-chloropropyl) -1H-1,2,3-benzotriazole (167 mg, 34%). According to step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indole (30 mg, 0.12 mmol) and 1- (3-chloropropyl) -1H-1,2,3-benzotriazole (48 mg, 0.24 mmol) from the title compound (21 mg) as a yellow oil. , 42%) was prepared.¹1 H NMR (CDCl₃) δ1.88-1.98 (m, 3H), 1.99-2.18 (m, 2H), 2.20-2.41 (m, 5H), 2.51-2.60 (m, 1H), 2.64-2.71 (m, 1H), 2.89- 3.00 (m, 1H), 3.03-3.13 (m, 2H), 3.21-3.27 (m, 1H), 3.47-3.60 (m, 1H), 3.76-3.88 (m, 1H), 4.73 (t, 2H, J = 6.6Hz), 6.61 (t, 1H, J = 7.4Hz), 6.84 (d, 1H, J = 6.6Hz), 6.94 (dd, 1H, J = 1.1,8.1Hz), 7.37 (td, 1H, J = 1.1,7.4Hz), 7.49 (td, 1H, J = 1.1,7.8Hz), 7.57 (d, 1H, J = 8.0Hz), 8.07 (d, 1H, J = 8.4Hz) ppm. [1177] (Example 292) (8aS, 12aR) -11-[3- (2H-1,2,3-triazol-2-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1178] 2- (3-Chloropropyl) -1H-1,2 with benzotriazole (303 mg, 2.54 mmol) and 1-bromo-3-chloropropane (437 mg, 2.77 mmol) according to the method of Step A of Example 291. , 3-Benzotriazole (182 mg, 37%) was obtained. According to step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] From indole (30 mg, 0.12 mmol) and 2- (3-chloropropyl) -1H-1,2,3-benzotriazole (48 mg, 0.24 mmol), the title compound (20 mg) as a yellow oil , 40%) was prepared.¹1 H NMR (CDCl₃) δ1.84-1.94 (m, 3H), 1.99-2.20 (m, 2H), 2.25-2.52 (m, 5H), 2.64-2.72 (m, 1H), 2.74-2.82 (m, 1H), 2.88- 3.00 (m, 1H), 3.02-3.18 (m, 2H), 3.22-3.28 (m, 1H), 3.51-3.61 (m, 1H), 3.74-3.85 (m, 1H), 4.80 (t, 2H, J = 6.7Hz), 6.61 (t, 1H, J = 7.5Hz), 6.92 (dd, 2H, J = 6.6,24.9Hz), 7.35-7.41 (m, 2H), 7.83-7.85 (m, 2H) ppm. [1179] (Example 293) (8aS, 12aR) -11-{[(2S) -1-benzoylpyrrolidinyl] methyl} -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3- b] [1,4] Chiazepino [2,3,4-hi] Indole [1180] From (S) -2-pyrrolidin-methanol (150 mg, 1.48 mmol) and benzoyl chloride (208 mg, 1.48 mmol), as in steps A-B of Example 286, [(2S) -1-benzoylpyrrolidinyl]. Methylmethane sulfonate (94 mg, 50%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and [(2S) -1-benzoylpyrrolidinyl] methylmethane sulfonate (55 mg, 0.24 mmol), the title compound (52 mg, 100) as a yellow oil. %) Was isolated.¹1 H NMR (CDCl₃) δ1.26 (s, 1H), 1.58-2.30 (m, 8H), 2.35-2.86 (m, 3H), 2.90-3.30 (m, 4H), 3.37-3.61 (m, 4H), 3.75-3.86 ( m, 2H), 4.38-4.50 (m, 1H), 6.55-6.96 (m, 2H), 7.31-7.96 (m, 6H) ppm. MS (ESI): 434 (base, M + H). [1181] (Example 294) (8aS, 12aR) -11-{[(2R) -1-benzoylpyrrolidinyl] methyl} -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3- b] [1,4] Chiazepino [2,3,4-hi] Indole [1182] From (R) -2-pyrrolidin-methanol (150 mg, 1.48 mmol) and benzoyl chloride (208 mg, 1.48 mmol), as in steps A-B of Example 286, [(2R) -1-benzoylpyrrolidinyl]. Methylmethane sulfonate (98 mg, 52%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and [(2R) -1-benzoylpyrrolidinyl] methylmethane sulfonate (55 mg, 0.24 mmol), the title compound (36 mg, 68 mmol) as a yellow oil. %) Was isolated.¹1 H NMR (CDCl₃) δ1.58-2.27 (m, 12H), 2.64-3.30 (m, 4H), 3.49-3.61 (m, 3H), 3.72-3.84 (m, 2H), 6.60 (td, 1H, J = 1.9,7.5) Hz), 6.93 (d, 1H, J = 7.5Hz), 7.31-7.55 (m, 6H) ppm. MS (ESI): 434 (base, M + H). [1183] (Example 295) (8aS, 12aR) -11-{[(2S) -1- (4-fluorobenzoyl) pyrrolidinyl] methyl} -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1184] From (S) -2-pyrrolidine-methanol (155 mg, 1.53 mmol) and 4-fluorobenzoyl chloride (235 mg, 1.48 mmol), as in steps A-B of Example 286, [(2S) -1- (4). -Fluorobenzoyl) pyrrolidinyl] methylmethane sulfonate (152 mg, 68%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and [(2S) -1- (4-fluorobenzoyl) pyrrolidinyl] methylmethane sulfonate (59 mg, 0.24 mmol), the title compound as a yellow oil ( 24 mg, 44%) was isolated.¹1 H NMR (CDCl₃) δ1.63 (s, 2H), 1.70-2.20 (m, 10H), 2.67-3.31 (m, 5H), 3.37-3.55 (m, 4H), 3.71-3.82 (m, 2H), 6.61 (td, 1H, J = 2.0,7.5Hz), 6.93 (d, 1H, J = 7.7Hz), 7.03-7.18 (m, 3H), 7.45-7.56 (m, 2H) ppm. MS (ESI): 452 (base, M + H). [1185] (Example 296) (8aS, 12aR) -11-{[(2R) -1- (4-fluorobenzoyl) pyrrolidinyl] methyl} -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1186] From (R) -2-pyrrolidine-methanol (155 mg, 1.53 mmol) and 4-fluorobenzoyl chloride (235 mg, 1.48 mmol), as in steps A-B of Example 286, [(2R) -1- (4). -Fluorobenzoyl) pyrrolidinyl] methylmethane sulfonate (147 mg, 80%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and [(2R) -1- (4-fluorobenzoyl) pyrrolidinyl] methylmethane sulfonate (59 mg, 0.24 mmol), the title compound as a yellow oil ( 27 mg, 49%) was isolated.¹1 H NMR (CDCl₃) δ1.59-2.21 (m, 11H), 2.94-3.35 (m, 4H), 3.47-3.60 (m, 4H), 3.73-3.84 (m, 2H), 4.39-4.47 (1H, m), 4.77- 4.02 (m, 1H), 6.61 (td, 1H, J = 1.8, 7.4Hz), 6.83 (d, 1H, J = 9.5Hz), 7.01-7.14 (m, 3H), 7.47-7.64 (m, 2H) ppm. [1187] (Example 297) (8aS, 12aR) -11-[2- (1H-1,2,3-triazol-1-yl) ethyl]-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1188] From benzotriazole (300 mg, 2.52 mmol) and 1-bromo-2-chloroethane (397 mg, 2.77 mmol), 1- (2-chloroethyl) -1H-1,2,3-benzotriazole ( Prepare 164 mg, 36%). According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (2-chloroethyl) -1H-1,2,3-benzotriazole (44 mg, 0.24 mmol), the title compound as a yellow oil ( 48 mg, 98%) was isolated.¹1 H NMR (CDCl₃) δ1.69-2.20 (m, 4H), 2.39-2.45 (m, 1H), 2.61-2.68 (m, 1H), 2.72-2.81 (m, 1H), 2.84-3.01 (m, 2H), 3.03- 3.12 (m, 2H), 3.20-3.27 (m, 1H), 3.49-3.60 (m, 1H), 3.74-3.84 (m, 1H), 4.06 (t, 1H, J = 6.7Hz), 4.76 (t, 1H, J = 6.6Hz), 4.96 (t, 1H, J = 6.2Hz), 6.61 (t, 1H, J = 7.5Hz), 6.82 (d, 1H, J = 7Hz), 6.95 (dd, 1H, J = 1.1,7.7Hz), 7.34-7.62 (m, 3H), 8.08 (t, 1H, J = 7.6Hz) ppm. [1189] (Example 298) (8aS, 12aR) -11-[2- (2H-1,2,3-triazol-2-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1190] From benzotriazole (300 mg, 2.52 mmol) and 1-bromo-3-chloropropane (397 mg, 2.77 mmol) to 2- (3-chloropropyl) -1H-1,2,3-benzotriazole according to the method of Example 291. (200 mg, 44%) was prepared. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 2- (3-chloropropyl) -1H-1,2,3-benzotriazole (44 mg, 0.24 mmol), the title compound as a yellow oil (26 mg, 54%) was isolated.¹1 H NMR (CDCl₃) δ1.81-1.93 (m, 2H), 1.96-2.14 (m, 3H), 2.41 (td, 1H, J = 3.7,11.7Hz), 2.64-2.72 (m, 1H), 2.80-2.90 (m, 1H), 2.92-3.00 (m, 1H), 3.02-3.16 (m, 4H), 3.21-3.26 (m, 1H), 3.51-3.62 (m, 1H), 3.78-3.86 (m, 1H), 4.85 ( t, 2H, J = 7.0Hz), 6.61 (t, 1H, J = 7.5Hz), 6.83 (d, 1H, J = 6.6Hz), 6.94 (dd, 1H, J = 1.2,8.1Hz), 7.36- 7.41 (m, 2H), 7.84-7.88 (m, 2H) ppm. [1191] (Example 299) (8aS, 12aR) -11-[3- (3,4-dihydro-1 (2H) -quinolinyl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [ 4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1192] Et. in a solution of 1,2,3,4-tetrahydroquinoline (505 mg, 3.79 mmol) and 1-bromo-3-chloropropane (1.77 g, 11 mmol) in 1,4-dioxane (6 mL).₃N (1.90 g, 19 mmol) was added. The reaction mixture is stirred at 70 ° C for 17 hours and H₂O (2 mL) was added and quenched. Et₂Dilute with O (100 mL), wash with saline (100 mL), EDTA₄It was dried in and concentrated under vacuum. Purification by column chromatography (hexane: EtOAc 49: 1) gave 1- (3-chloropropyl) -1,2,3,4-tetrahydroquinoline (187 mg, 24%) as a colorless oil. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (3-chloropropyl) -1,2,3,4-tetrahydroquinoline (51 mg, 0.24 mmol), the title compound as a yellow oil (22 mg, 43%) was isolated.¹1 H NMR (CDCl₃) δ1.77-2.19 (m, 10H), 2.24-2.41 (m, 2H), 2.61-2.69 (m, 1H), 2.75-2.84 (m, 3H), 2.91-3.02 (m, 1H), 3.10- 3.21 (m, 2H), 3.26-3.34 (m, 5H), 3.52-3.61 (m, 1H), 3.77-3.96 (m, 1H), 6.49-6.65 (m, 3H), 6.85 (d, 1H, J = 7.3Hz), 6.92-6.96 (m, 2H), 6.99-7.05 (m, 1H) ppm. [1193] (Example 300) (8aS, 12aR) -11-[(3E) -4- (4-fluorophenyl) 3-pentenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4, 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1194] (Step A) Cyclopropyl-4-fluorophenylketone (523 mg, 3.19 mmol) in THF (10 mL) solution, N₂A 3M ether solution of methylmagnesium bromide (1.7 mL, 5.1 mmol) was added at 0 ° C. below. After 90 minutes at 0 ° C, saline (10 mL) was added to quench the reaction and Et.₂Diluted with O (100 mL). Saturated organic solution LVDS₃Washed with (100 mL) and saline (100 mL). Column purification (hexane: EtOAc 9: 1) was performed to obtain 1-cyclopropyl-1- (4-fluorophenyl) ethanol (512 mg, 89%) as a colorless oil. [1195] (Step B) 1-Cyclopropyl-1- (4-fluorophenyl) ethanol (307 mg, 1.70 mmol) was heated at 60 ° C. for 1 hour in 1 N HCl isopropyl alcohol solution (3.6 mL). The reaction mixture was then concentrated under vacuum and purified by column chromatography to give 1-[(1E) -4-chloro-1-methyl-1-butenyl] -4-fluorobenzene (282 mg, 84) as a colorless oil. %) Was obtained. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1-[(1E) -4-chloro-1-methyl-1-butenyl] δ-4-fluorobenzene (48 mg, 0.24 mmol), The title compound (36 mg, 70%) was isolated as the yellow oil.¹1 H NMR (CDCl₃) δ1.62 (br-s, 1H), 1.90-2.20 (m, 9H), 2.31-2.44 (m, 5H), 2.71-2.80 (m, 1H), 2.81-2.89 (m, 1H), 2.92- 3.00 (m, 1H), 3.04-3.13 (m, 1H), 3.17-3.24 (m, 2H), 3.27-3.31 (m, 1H), 3.51-3.63 (m, 1H), 3.80-3.91 (m, 1H) ), 5.64-5.73 (m, 1H), 6.62 (t, 1H, J = 7.5Hz), 6.87 (d, 1H, J = 6.6Hz), 6.91-7.00 (m, 3H), 7.29-7.34 (m, 2H) ppm) [1196] (Example 301) (8aS, 12aR) -11- [2- (2,3-dihydro-1H-indene-2-yl) ethyl]-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1197] (Step A) In a NaH (400 mg, 17 mmol) DME (25 mL) slurry, N₂Triethylphosphonoacetate (3.39 g, 15 mmol) was added at 20 ° C. below. The reaction mixture was stirred for 45 minutes. To this white solution was added a DME (5 mL) solution of 2-indanone (2.00 g, 15 mmol) and the temperature was maintained below 25 ° C. The reaction mixture is stirred for 30 minutes, then H₂Quenched with O (5 mL). Et the reaction mixture₂Extraction was performed using O (3 × 100 mL). Then H the organic solution₂O (200 mL), saturated LVDS₃Wash with (200 mL) and saline (200 mL) and deli₄It was dried in and concentrated under vacuum. Ethyl 1,3-dihydro-2H-indene-2-iriden acetate (2.04 g, 67%) was isolated as a yellow oil. [1198] (Step B) Add 5% Pd / C (76 mg) to a solution of 1,3-dihydro-2H-indene-2-idene ethyl acetate (302 mg, 1.49 mmol) in EtOAc (10 mL) and add H in this slurry.₂Was blown in for 20 hours. The slurry was then filtered through Celite and the organic solution was concentrated under vacuum. Ethyl 2,3-dihydro-1H-indene-2-yl acetate (285 mg, 94%) was isolated as a colorless oil without purification. [1199] (Step C) Et of 2,3-dihydro-1H-indene-2-yl ethyl acetate (285 mg, 1.39 mmol)₂In O (5 mL) solution, N₂LAH (53 mg, 1.39 mmol) was added at 0 ° C below. After stirring at 0 ° C for 40 minutes, 0.4 mL of H₂O was added to quench the reaction. The reaction mixture is diluted with EtOAc (100 mL) and EDTA₄Was added and stirred. The reaction mixture was then filtered and concentrated under vacuum to give a clear oil. Further, 2- (2,3-dihydro-1H-inden-2-yl) ethanol was isolated without purification. [1200] From 2- (2,3-dihydro-1H-inden-2-yl) ethanol (88 mg, 0.54 mmol) as clear oil 2- (2,3-dihydro-1H-) by the method of step B of Example 286. Inden-2-yl) ethylmethane sulfonate (128 mg, 98%) was isolated. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino Titled as yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 2- (2,3-dihydro-1H-indene-2-yl) ethylmethane sulfonate (59 mg, 0.24 mmol) Compound (28 mg, 61%) was isolated.¹1 H NMR (CDCl₃) δ1.65-1.79 (m, 3H), 1.82-1.94 (m, 3H), 2.00-2.21 (m, 2H), 2.24-2.35 (m, 1H), 2.36-2.51 (m, 2H), 2.57- 2.78 (m, 3H), 2.77-2.85 (m, 1H), 2.89-2.99 (m, 1H), 3.02-3.14 (m, 3H), 3.17-3.22 (m, 1H), 3.28-3.32 (m, 1H) ), 3.57-3.63 (m, 1H), 3.80-3.92 (m, 1H), 6.62 (t, 1H, J = 7.5Hz), 6.86 (d, 1H, J = 6.6Hz), 6.95 (dd, 1H, J = 1.1,7.7Hz), 7.10-7.19 (m, 4H) ppm. [1201] (Example 302) 4-((8aS, 12aR) -6,7 ,, 9,10 ,, 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (2-aminophenyl) -1-butanone [1202] (Step A) BCl₃-Me₂In a solution of S (2.12 g, 12 mmol) in benzene (10 mL), N₂A solution of aniline (1.00 g, 11 mmol) in benzene (10 mL) was added while cooling with ice. This was stirred for 30 minutes, 4-chlorobutyronitrile (1.33 g, 12.8 mmol) was added, and then AlCl was immediately added.₃(1.57 g, 12 mmol) was added at once. The reaction mixture was then refluxed for 16 hours. The reaction mixture was cooled to 0 ° C, 2N HCl (16 ml) was added dropwise, then heated to 80 ° C and stirred for 1 hour. CHCL the reaction mixture₃Extract with (3 x 100 mL) and H₂Wash with O (100 mL) and saline (100 mL) and DEV₄It was dried in and concentrated under vacuum. Purification by column chromatography gave 1- (2-aminophenyl) -4-chloro-1-butanone as a yellow oil (394 mg, 19%). [1203] (Step B) According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (48 mg, 0.24 mmol), the title compound (19 mg, 19 mg, as yellow oil) 37%) was isolated.¹1 H NMR (CDCl₃) δ1.85-2.21 (m, 7H), 2.23-2.37 (n, 1H), 2.37-2.44 (m, 2H), 2.63-2.70 (m, 1H), 2.71-2.82 (m, 1H), 2.94- 3.16 (m, 5H), 3.24-3.29 (m, 1H), 3.53-3.62 (m, 1H), 3.78-3.86 (m, 1H), 6.26 (br-s, 2H), 6.59-6.67 (m, 3H) ), 6.85 (d, 1H, J = 7.4Hz), 6.94 (dd, 1H, J = 1.1,8.1Hz), 7.23-7.29 (m, 1H), 7.77 (dd, 1H, J = 1.5,8.4Hz) ppm. [1204] (Example 303) 4-((8aR, 12aS) -6,7 ,, 9,10 ,, 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (2-aminophenyl) -1-butanone [1205] According to the method of step C of Example 286, (8aR, 12aS) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (150 mg, 0.61 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (241 mg, 1.2 mmol), the title compound (45 mg, 45 mg, as yellow oil) 18%) was isolated.¹1 H NMR (CDCl₃) δ1.85-2.21 (m, 7H), 2.23-2.37 (n, 1H), 2.37-2.44 (m, 2H), 2.63-2.70 (m, 1H), 2.71-2.82 (m, 1H), 2.94- 3.16 (m, 5H), 3.24-3.29 (m, 1H), 3.53-3.62 (m, 1H), 3.78-3.86 (m, 1H), 6.26 (br-s, 2H), 6.59-6.67 (m, 3H) ), 6.85 (d, 1H, J = 7.4Hz), 6.94 (dd, 1H, J = 1.1,8.1Hz), 7.23-7.29 (m, 1H), 7.77 (dd, 1H, J = 1.5,8.4Hz) ppm. [1206] (Example 304) 4-((8aS, 12aR) -6,7 ,, 9,10 ,, 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (2-amino-5-fluorophenyl) -1-butanone [1207] 1- (2-Amino-5-fluorophenyl) -4-chloro-1-butanone (462 mg, 24%) as a yellow solid from 4-fluoroaniline (1.00 g, 9.0 mmol) according to the method of step A of Example 302. ) Was obtained. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino Titled as yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (2-amino-5-fluorophenyl) -4-chloro-1-butanone (53 mg, 0.24 mmol) Compound (13 mg, 25%) was isolated.¹1 H NMR (CDCl₃) δ1.83-2.20 (m, 7H), 2.24-2.42 (m, 3H), 2.62-2.72 (m, 1H), 2.74-2.83 (m, 1H), 2.87-3.00 (m, 3H), 3.02- 3.18 (m, 2H), 3.24-3.30 (m, 1H), 3.51-3.63 (m, 1H), 3.78-3.87 (m, 1H), 6.12 (br-s, 2H), 6.57-6.63 (m, 2H) ), 6.85 (d, 1H, J = 6.6Hz), 6.94 (dd, 1H, J = 1.1, 7.7Hz), 7.01-7.08 (m, 1H), 7.47 (dd, 1H, J = 2.7, 10.1Hz) ppm. [1208] (Example 305) 4-((8aS, 12aR) -6,7 ,, 9,10 ,, 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (2-amino-3-fluorophenyl) -1-butanone [1209] 1- (2-Amino-3-fluorophenyl) -4-chloro-1-butanone (238 mg, 12%) as a yellow solid from 2-fluoroaniline (1.00 g, 9.0 mmol) according to the method of step A of Example 302. ) Was obtained. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino Titled as yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (2-amino-3-fluorophenyl) -4-chloro-1-butanone (53 mg, 0.24 mmol) Compound (12 mg, 23%) was isolated.¹1 H NMR (CDCl₃) δ1.87-2.19 (m, 7H), 2.24-2.45 (m, 3H), 2.63-2.69 (m, 1H), 2.72-2.81 (m, 1H), 2.93-3.15 (m, 5H), 3.24- 3.30 (m, 1H), 3.50-3.61 (m, 1H), 3.78-3.86 (m, 1H), 6.32 (br-s, 2H), 655-6.64 (m, 2H), 6.84 (d, 1H, J = 7.4Hz), 6.94 (dd, 1H, J = 1.1, 7.7Hz), 7.07-7.14 (m, 1H), 7.56 (d, 1H, J = 8.4Hz) ppm. [1210] (Example 306) 4-((8aS, 12aR) -6,7 ,, 9,10 ,, 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (2-amino-4-chlorophenyl) -1-butanone [1211] 1- (2-Amino-4-chlorophenyl) -4-chloro-1-butanone (586 mg, 32%) as a yellow solid from 3-chloroaniline (1.00 g, 7.9 mmol) according to the method of step A of Example 302. Got According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (2-amino-4-chlorophenyl) -4-chloro-1-butanone (53 mg, 0.24 mmol), the title compound as a yellow oil (10 mg, 19%) was isolated.¹1 H NMR (CDCl₃) δ1.83-2.17 (m, 7H), 2.19-2.41 (m, 3H), 2.57-2.61 (m, 1H), 2.68-2.77 (m, 1H), 2.83-2.92 (m, 3H), 2.96- 3.13 (m, 2H), 3.20-3.26 (m, 1H), 3.45-3.58 (m, 1H), 3.71-3.82 (m, 1H), 6.28 (br-s, 2H), 6.51-6.58 (m, 3H) ), 6.78 (d, 1H, J = 6.6Hz), 6.87 (dd, 1H, J = 1.2, 7.9Hz), 7.62 (d, 1H, J = 8.8Hz) ppm. [1212] (Example 307) 4-((8aS, 12aR) -6,7 ,, 9,10 ,, 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (2-amino-4-hydroxyphenyl) -1-butanone [1213] 1- (2-Amino-4-hydroxyphenyl) -4-chloro-1-butanone (100 mg, 5%) as a yellow solid from meta-anisidine (1.00 g, 8.2 mmol) according to the method of step A of Example 302. Got According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino Titled as yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (2-amino-4-hydroxyphenyl) -4-chloro-1-butanone (56 mg, 0.24 mmol) Compound (5 mg, 9%) was isolated.¹1 H NMR (CDCl₃) δ1.90-2.19 (m, 6H), 2.31-2.48 (m, 3H), 2.68-2.77 (m, 1H), 2.78-2.84 (m, 1H), 2.89-3.00 (m, 5H), 3.02- 3.18 (m, 1H), 3.24-3.31 (m, 1H), 3.54-3.61 (m, 1H), 3.78-3.87 (m, 1H), 4.21 (br-s, 2H), 6.11-6.16 (m, 2H) ), 6.61 (t, 1H, J = 7.5Hz), 6.85 (d, 1H, J = 6.6), 6.94 (dd, 1H, J = 1.1, 7.7Hz), 7.56 (d, 1H, J = 8.4Hz) , 12.93 (br-s, 1H) ppm. [1214] (Example 308) 4-((8aS, 12aR) -6,7 ,, 9,10 ,, 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (2-amino-4-bromophenyl) -1-butanone [1215] 1- (2-Amino-4-Bromophenyl) -4-chloro-1-butanone (558 mg, 17%) as a yellow solid from 3-bromoaniline (2.00 g, 11.7 mmol) according to the method of step A of Example 302. ) Was obtained. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino Titled as yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (2-amino-4-bromophenyl) -4-chloro-1-butanone (68 mg, 0.24 mmol) Compound (21 mg, 35%) was isolated.¹1 H NMR (CDCl₃) δ1.89-2.22 (m, 8H), 2.24-2.45 (m, 3H), 2.61-2.70 (m, 1H), 2.73-2.81 (m, 1H), 2.91-3.01 (m, 2H), 3.04- 3.17 (m, 2H), 3.24-3.29 (m, 1H), 3.51-3.62 (m, 1H), 3.78-3.87 (m, 1H), 6.33 (br-s, 2H), 6.61 (t, 1H, J = 7.5Hz), 6.75 (dd, 1H, J = 2.0,8.6Hz), 6.81-6.87 (m, 2H), 6.94 (dd, 1H, J = 1.1,7.7Hz), 7.60 (d, 1H, J = 8.4Hz) ppm. [1216] (Example 309) (8aS, 12aR) -11- [3- (1H-indazole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1217] NaNO in concentrated HCl (3.5 mL) suspension of 1- (2-aminophenyl) -4-chloro-1-butanone (508 mg, 2.6 mmol) at -5 ° C₂(193 mg, 2.8 mmol) H₂O (0.75 mL) solution was added and the reaction mixture was stirred for 1 hour. SnCl₂-2H₂A solution of concentrated O (1.37 g, 6.07 mmol) in HCl (1.9 mL) was added to the solution at -5 ° C, which was then stirred under ice cooling for 1 hour. Reaction H₂Quench with O, Et₂Extracted with O (100 mL). Organic solution H₂Wash with O (50 mL) and saline (50 mL) and DEV₄It was dried in and concentrated under vacuum. Purification by column chromatography gave 3- (3-chloropropyl) -1H-indazole (126 mg, 25%) as a yellow solid. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 3- (3-chloropropyl) -1H-indazole (44 mg, 0.24 mmol), the title compound (38 mg, 77%) as a yellow oil Isolated.¹1 H NMR (CDCl₃) δ1.83-2.19 (m, 7H), 2.23-2.35 (m, 1H), 2.43-2.54 (m, 2H), 2.72-2.79 (m, 1H), 2.81-2.88 (m, 1H), 2.92- 3.11 (m, 4H), 3.12-3.21 (m, 1H), 3.24-3.29 (m, 1H), 3.51-3.62 (m, 1H), 3.80-3.92 (m, 1H), 6.61 (t, 1H, J = 7.5Hz), 6.84 (d, 1H, J = 6.6Hz), 6.94 (dd, 1H, J = 1.1,7.7Hz), 7.11-7.16 (m, 1H), 7.34-7.48 (m, 2H), 7.70 (d, 1H, J = 8.0Hz) ppm. [1218] (Example 310) (8aS, 12aR) -11- [3- (5-fluoro-1H-indazole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1219] 1- (2-Amino-5-fluorophenyl) -4-chloro-1-butanone (200 mg, 0.93 mmol) to 3- (3-chloropropyl) -6-fluoro-1H-indazole according to the method of Example 309 (91 mg, 46%) was obtained. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 3- (3-chloropropyl) -6-fluoro-1H-indazole (52 mg, 0.24 mmol), the title compound as yellow oil (35 mg, 35 mg, 66%) was isolated.¹1 H NMR (CDCl₃) δ1.92-2.15 (m, 7H), 2.34-2.42 (m, 1H), 2.42-2.55 (m, 2H), 2.72-3.10 (m, 6H), 3.20-3.34 (m, 2H), 3.50- 3.61 (m, 1H), 3.77-3.86 (m, 1H), 6.61 (t, 1H, J = 7.5Hz), 6.84 (d, 1H, J = 7.4Hz), 6.95 (dd, 1H, J = 1.1, 7.7Hz), 7.13 (td, 1H, J = 2.3,8.8Hz), 7.29-7.39 (m, 2H) ppm. [1220] (Example 311) (8aS, 12aR) -11- [3- (7-fluoro-1H-indazole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1221] 1- (2-Amino-3-fluorophenyl) -4-chloro-1-butanone (136 mg, 0.63 mmol) to 3- (3-chloropropyl) -7-fluoro-1H-indazole according to the method of Example 309 (14 mg, 10%) was obtained. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (17 mg, 0.07 mmol) and 3- (3-chloropropyl) -7-fluoro-1H-indazole (14 mg, 0.07 mmol), the title compound (10 mg, 0.07 mmol) as a yellow oil. 66%) was isolated.¹1 H NMR (CDCl₃) δ1.81-2.11 (m, 7H), 2.24-3.33 (m, 1H), 2.42-2.54 (m, 2H), 2.67-3.04 (m, 6H), 3.18-3.26 (m, 2H), 3.42- 3.57 (m, 1H), 3.71-3.85 (m, 1H), 6.54 (d, 1H, J = 7.5Hz), 6.77 (dd, 1H, J = 1.1, 7.0Hz), 6.88 (dd, 1H, J = 1.3,7.9Hz), 6.94-7.01 (m, 2H), 7.37-7.41 (m, 1H) ppm. [1222] (Example 312) (8aS, 12aR) -11- [3- (6-Chloro-1H-Indole-3-yl) Propyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-Pirido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1223] According to the method of Example 309, 1- (2-amino-4-chlorophenyl) -4-chloro-1-butanone (202 mg, 0.87 mmol) to 3- (3-chloropropyl) -6-chloro-1H-indazole ( 107 mg, 54%) was obtained. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 3- (3-chloropropyl) -6-chloro-1H-indazole (56 mg, 0.24 mmol), the title compound as yellow oil (37 mg, 37 mg, 69%) was isolated.¹1 H NMR (CDCl₃) δ1.93-2.20 (m, 8H), 2.37-3.38 (m, 1H), 2.41-2.48 (m, 2H), 2.69-2.77 (m, 1H), 2.79-2.86 (m, 1H), 2.91- 3.10 (m, 4H), 3.16-3.23 (m, 1H), 3.26-3.31 (m, 1H), 3.50-3.61 (m, 1H), 3.77-3.85 (m, 1H), 6.61 (t, 1H, J = 7.5Hz), 6.89 (d, 1H, J = 6.6Hz), 6.94 (dd, 1H, J = 1.1,7.7Hz), 7.09 (dd, 1H, J = 1.7,7.8Hz), 7.42 (d, 1H) , J = 1.1Hz), 7.61 (d, 1H, J = 8.4Hz) [1224] (Example 313) (8aS, 12aR) -11- [3- (6-Bromo-1H-Indole-3-yl) Propyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1225] 1- (2-Amino-4-bromophenyl) -4-chloro-1-butanone (311 mg, 1.1 mmol) to 3- (3-chloropropyl) -6-bromo-1H-indazole according to the method of Example 309 (228 mg, 74%) was obtained. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.07 mmol) and 3- (3-chloropropyl) -6-bromo-1H-indazole (67 mg, 0.24 mmol), the title compound as yellow oil (40 mg, 40 mg, 69%) was isolated.¹1 H NMR (CDCl₃) δ1.94-2.17 (m, 7H), 2.34-2.41 (m, 1H), 2.45-2.56 (m, 2H), 2.73-2.81 (m, 1H), 2.83-2.90 (m, 1H), 2.90- 3.11 (m, 4H), 3.24-3.35 (m, 2H), 3.49-3.61 (m, 1H), 3.77-3.89 (m, 1H), 6.61 (t, 1H, J = 7.5Hz), 6.84 (d, 1H, J = 7.4Hz), 6.95 (d, 1H, J = 7.7Hz), 7.20-7.26 (m, 1H), 7.53-7.60 (m, 1H) ppm. [1226] (Example 314) 4-((8aS, 12aR) -6,7 ,, 9,10 ,, 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -yl) -1- (2- (methylamino) phenyl) -1-butanone [1227] According to the method of Step A of Example 302, 1- (2-methylaminophenyl) -4-chloro-1-butanone (886 mg, 22%) was obtained as a yellow solid from N-methylaniline (2.00 g, 18 mmol). .. According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (2-methylaminophenyl) -4-chloro-1-butanone (52 mg, 0.24 mmol), the title compound (23 mg) as a yellow oil , 45%) were isolated.¹1 H NMR (CDCl₃) δ1.91-2.23 (m, 6H), 2.24-3.36 (m, 1H), 2.37-2.44 (m, 2H), 2.63-2.71 (m, 1H), 2.75-2.82 (m, 1H), 2.89- 3.17 (m, 9H), 3.24-3.30 (m, 1H), 3.47-3.62 (m, 1H), 3.79-3.87 (m, 1H), 6.56-6.63 (m, 2H), 6.69 (d, 1H, J = 8.4Hz), 6.84 (d, 1H, J = 7.0Hz), 6.94 (dd, 1H, J = 1.1,7.7Hz), 7.35-7.41 (m, 1H), 7.80 (dd, 1H, J = 8.6Hz) ), 8.81 (br-s, 1H) ppm. [1228] (Example 315) (8aS, 12aR) -11- [3- (1-benzothien-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1229] According to the method of step C of Example 286, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino From [2,3,4-hi] indole (55 mg, 0.23 mmol) and 3- (1-benzothien-3-yl) propylmethanesulfonate (122 mg, 0.45 mmol), the title compound (49 mg, 52%) as a yellow oil. ) Was isolated.¹1 H NMR (CDCl₃) δ1.97-2.20 (m, 7H), 2.31-2.41 (m, 1H), 2.44-2.56 (m, 2H), 2.71-2.79 (m, 1H), 2.81-2.99 (m, 4H), 3.04- 3.11 (m, 1H), 3.19-3.35 (m, 2H), 3.50-3.62 (m, 1H), 3.79-3.88 (m, 1H), 6.62 (t, 1H, J = 7.5Hz), 6.85 (d, 1H, J = 7.3Hz), 6.95 (dd, 1H, J = 1.3,7.9Hz), 7.11 (s, 1H), 7.34-7.41 (m, 2H), 7.74-7.78 (m, 1H), 7.85 (dd) , 1H, J = 1.5,6.2Hz) ppm. [1230] (Example 316) (8aS, 12aR) -2- (2,3-Dimethylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1231] (Step A) In a solution of 3-bromo-o-xylene (500 mg, 2.7 mmol) in THF (15 mL), N₂A 1.7 M pentane solution of tert-butyllithium (1.77 mL, 3.0 mmol) was added slowly at -78 ° C below. This was stirred at 78 ° C. for 30 minutes. B (OiPr) in the reaction mixture₃(2.05 g, 11 mmol) was added, and the reaction mixture was heated to 20 ° C. and stirred for 2 hours. 3N HCl (10 mL) was added to the reaction mixture and the acidic solution was stirred for 90 minutes. The reaction mixture was extracted with EtOAc (4 x 50 mL) and the organic solution was extracted with 1N NaOH solution (100 mL). Aqueous solution Et₂It was washed with O (2 x 50 mL), acidified to pH 1 with concentrated HCl and then extracted with EtOAc (4 x 50 mL). The organic solution is then washed with saline solution (100 mL) and deli₄And concentrated under vacuum to give 2,3-dimethylphenylboronic acid compound (750 mg, 45%) as a white solid. [1232] (Step B) According to the method of steps A and B of Example 436, (8aS, 12aR) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (100 mg, 0.24 mmol) and 2,3-dimethylphenylboronic acid (71 mg, 0.48 mmol), yellow The title compound (65 mg, 77%) was obtained as the oil of.¹1 H NMR (CDCl₃) δ1.84-1.97 (m, 2H), 2.04-2.18 (m, 2H), 2.17 (s, 3H), 2.31 (s, 3H), 2.61-2.68 (m, 1H), 2.76 (br-s, 1H), 2.90-3.22 (m, 6H), 3.45-3.51 (m, 1H), 3.54-3.64 (m, 1H), 3.77-3.84 (m, 1H), 6.78 (d, 1H, J = 1.5Hz) , 6.91 (d, 1H, J = 1.5Hz), 7.01-7.12 (m, 3H). [1233] (Example 317) (8aS, 12aR) -2- (5-Fluoro-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1234] According to the method of Step A of Example 316, 5-fluoro-2-methylphenylboronic acid (237 mg, 57%) was obtained as a white solid from 2-bromo-4-fluorotoluene (507 mg, 2.7 mmol). According to the method of steps A and B of Example 436, (8aS, 12aR) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] From [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (100 mg, 0.24 mmol) and 5-fluoro-2-methylphenylboronic acid (71 mg, 0.48 mmol) , The title compound (63 mg, 71%) was obtained as yellow oil.¹1 H NMR (CDCl₃) δ1.93 (br-s, 1H), 2.01-2.22 (m, 2H), 2.33 (s, 3H), 2.62-2.68 (m, 1H), 2.92-3.04 (m, 3H), 3.06-3.45 ( m, 6H), 3.47-3.58 (m, 1H), 3.77-3.85 (m, 1H), 6.96-7.10 (m, 3H), 7.13-7.19 (m, 2H) ppm. [1235] (Example 318) (8aS, 12aR) -2- (2-Fluoro-5-Methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1236] 2-Fluoro-5-methylphenylboronic acid (280 mg, 68%) was obtained as a white solid from 3-bromo-4-fluorotoluene (507 mg, 2.7 mmol) according to the method of Step A of Example 316. According to the method of steps A and B of Example 436, (8aS, 12aR) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] From [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (100 mg, 0.24 mmol) and 2-fluoro-5-methylphenylboronic acid (71 mg, 0.48 mmol) , The title compound (70 mg, 76%) was obtained as a yellow oil. MS (ESI): 355 (base, M + H). [1237] (Example 319) (8aS, 12aR) -2- (5-Fluoro-2-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1238] According to the method of Step A of Example 316, 5-fluoro-2-methoxyphenylboronic acid (350 mg, 42%) was obtained as a white solid from 2-bromo-4-fluoroanisole (1.00 g, 4.9 mmol). According to the method of steps A and B of Example 436, (8aS, 12aR) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] From [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (100 mg, 0.24 mmol) and 5-fluoro-2-methoxyphenylboronic acid (80 mg, 0.48 mmol) , The title compound (50 mg, 58%) was obtained as yellow oil. MS (ESI): 371 (base, M + H). [1239] (Example 320) (8aS, 12aR) -2- (3-Chloro-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1240] According to the method of Step A of Example 316, 3-chloro-2-methylphenylboronic acid (750 mg, 45%) was obtained as a white solid from 2-bromo-6-chlorotoluene (2.00 g, 9.7 mmol). According to the method of steps A and B of Example 436, (8aS, 12aR) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] From [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (100 mg, 0.24 mmol) and 3-chloro-2-methylphenylboronic acid (84 mg, 0.48 mmol) , The title compound (83 mg, 88%) was obtained as a yellow oil.¹1 H NMR (CDCl₃) δ1.92-2.13 (m, 4H), 2.21 (s, 3H), 2.54-2.62 (m, 1H), 2.90-3.24 (m, 6H), 3.34-3.40 (m, 1H), 3.44-3.59 ( m, 1H), 3.76-3.84 (m, 1H), 5.08 (br-s, 1H), 6.69 (d, 1H, J = 1.6Hz), 6.83 (d, 1H, J = 1.6Hz), 9.98-7.08 (m, 2H), 7.23 (dd, 1H, J = 1.6Hz) ppm. MS (ESI): 371 (base, M + H). [1241] (Example 321) (8aS, 12aR) -2- (3-Nitrophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1242] According to the method of Example 436, (8aS, 12aR) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] From thiazepino [2,3,4-hi] indoru-11 (8aH) -tert-butyl carbonate (100 mg, 0.24 mmol) and 3-nitrophenylboronic acid (80 mg, 0.48 mmol), the title compound as an orange oil ( 69 mg, 91%) was obtained. MS (ESI): 368 (base, M + H). [1243] (Example 322) (8aS, 12aR) -2- (2-Nitrophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1244] According to the method of steps A and B of Example 436, (8aS, 12aR) -2-bromo-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (100 mg, 0.24 mmol) and 2-nitrophenylboronic acid (80 mg, 0.48 mmol), orange The title compound (14 mg, 17%) was obtained as an oil. MS (ESI): 368 (base, M + H). [1245] (Example 323) (8aS, 12aR) -2- (2-Chloro-4-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1246] By step F of Example 128 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 2-chloro-4-methylbenzeneboronic acid by the method of step G of Example 128. Hydrolyzed to prepare the title compound. (M + H)⁺371. [1247] (Example 324) (8aS, 12aR) -2- (2-Methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1248] By step F of Example 128 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 2-methoxybenzeneboronic acid was hydrolyzed by the method of step G of Example 128. , The title compound was prepared.¹1 H NMR (CDCl₃, 300MHz) δ7.28-7.22 (m, 2H), 7.15 (d, 1H), 7.05 (d, 1H), 7.00-6.92 (m, 2H), 3.81 (s, 3H), 3.55 (dq, 1H) , 3.44-3.43 (m, 1H), 3.22 (dt, 1H), 3.09-2.99 (m, 3H), 2.92-2.86 (m, 2H), 2.70-2.66 (m, 1H), 2.09-1.84 (m, 2H), 1.90-1.70 (m, 2H). (M + H)⁺353. [1249] (Example 325) (8aS, 12aR) -2- (2,3-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole [1250] By step F of Example 128 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indol-11 (8aH) -tert-butyl carbonate and the corresponding 2,3-dichlorobenzeneboronic acid is hydrolyzed by the method of step G of Example 128. The title compound was prepared.¹1 H NMR (CDCl₃, 300MHz) δ7.39 (dd, 1H), 7.21-7.17 (m, 2H), 7.00 (d, 1H), 6.92 (d, 1H), 3.83 (dq, 1H), 3.57 (qd, 1H), 3.47 -3.45 (m, 1H), 3.22 (dt, 1H), 3.10-2.99 (m, 3H), 2.89-2.86 (m, 2H), 2.65 (td, 1H), 2.20-2.01 (m, 2H), 1.86 -1.62 (m, 2H). (M + H)⁺392 [1251] (Example 326) (8aS, 12aR) -2- [2-Chloro-4- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1252] By step F of Example 128 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, Step 128 of Example 128 with BOC-protected amine adduct obtained from 3,4-hi] indole-11 (8aH) -tert-butyl carbonate and the corresponding 2-chloro-4- (trifluoromethyl) benzeneboronic acid. The title compound was prepared by hydrolysis by the method of G.¹1 H NMR (CDCl₃, 300MHz) δ7.68 (s, 1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.04 (d, 1H), 6.96 (d, 1H), 3.85 (qd, 1H), 3.59 (dq) , 1H), 3.57-3.45 (m, 1H), 3.25 (dt, 1H), 3.13-3.00 (m, 3H), 2.98-2.04 (m, 2H), 1.87-1.78 (m, 2H). (M + H)⁺425. [1253] (Example 327) (8aS, 12aR) -2- (4-ethoxy-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1254] By step F of Example 128 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4-ethoxy-2-methylbenzeneboronic acid by the method of step G of Example 128. Hydrolyzed to prepare the title compound.¹1 H NMR (CDCl₃, 300MHz) δ7.09 (d, 1H), 6.89 (s, 1H), 6.80-6.71 (m, 3H), 4.02 (q2H), 3.78 (qd, 1H), 3.59 (dq, 1H), 3.50-3.40 (m, 1H), 3.20 (dt, 1H), 3.12-2.82 (m, 5H), 2.64 (td, 1H), 2.25 (s, 3H), 2.20-2.00 (m, 2H), 1.99-1.76 (m) , 2H), 1.41 (t, 3H). (M + H)⁺381. [1255] (Example 328) (8aS, 12aR) -2- (4-Fluoro-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1256] By step F of Example 128 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4-fluoro-2-methylbenzeneboronic acid by the method of step G of Example 128. Hydrolyzed to prepare the title compound.¹1 H NMR (CDCl₃, 300MHz) δ7.08 (dd, 2H), 6.94 (d, 1H), 6.93-6.83 (m, 1H), 6.78 (d, 1H), 3.97 (qd, 1H), 3.62 (dq, 1H), 3.48 -3.42 (m, 1H), 3.36 (dt, 1H), 3.35-2.95 (m, 6H), 2.25-2.08 (m, 4H), 2.22 (s, 3H). (M + H)⁺355. [1257] (Example 329) (8aS, 12aR) -2- (4-Butylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1258] By step F of Example 128 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4-butylbenzeneboronic acid was hydrolyzed by the method of step G of Example 128. , The title compound was prepared.¹1 H NMR (CDCl₃, 300MHz) δ7.39 (d, 2H), 7.19 (d, 2H), 7.16 (d, 1H), 7.06 (d, 1H), 3.78 (qd, 1H), 3.56 (dq, 1H), 3.43-3.39 (m, 1H), 3.22 (dt, 1H), 3.17-3.00 (m, 3H), 2.98-2.80 (m, 2H), 2.71-2.60 (m, 3H, 2.21-2.60 (m, 3H), 2.21- 2.01 (m, 2H), 1.96-1.76 (m, 2H), 1.76-1.59 (m, 2H), 1.4201.35 (m, 2H), 0.95 (t, 3H). (M + H)⁺379. [1259] (Example 330) (8aS, 12aR) -2- [2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1260] (Step A) (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -tert-butyl carbonate (0.500 g, 1.18 mmol) in DME (25 mL) solution with 2- (trifluoromethyl) benzeneboronic acid (0.448 g, 2.36 mmol), 1,1'-bis ( Diphenylphosphino) ferrocene palladium (II) (0.025 g) and triethylamine (1.70 mL) were added. The combined mixture was refluxed for 24 hours and then evaporated to dryness under reduced pressure. Residue H₂It was dissolved in O (150 mL) and extracted with EtOAc (3 x 50 mL). Combined extract EDTA₄The solvent was removed under reduced pressure to give a mixture of 85% product. The resin product is purified by normal phase HPLC (75% hexane in EtOAc) as foam (8aS, 12aR) -2- [2- (trifluoromethyl) phenyl] -6,7,9,10,12, 12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate 0.152 g (30%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ7.69 (d, 1H), 7.49 (t, 1H), 7.39 (t, 1H), 7.28-7.26 (m, 1H), 6.93 (d, 1H), 6.85 (d, 1H), 3.92 -3.80 (m, 2H), 3.69-3.60 (t, 1H), 3.60-3.51 (m, 2H), 3.38-3.17 (m, 3H), 3.03-2.95 (dt, 1H), 2.20-2.04 (m, 2H), 1.57 (s, 9H) ppm. (M + H)⁺491,435,391. [1261] (Step B) (8aS, 12aR) -2- [2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.066 g, 0.13 mmol)₂Cl₂The (5 mL) solution was treated with TFA (1 mL) and stirred in a closed vial at room temperature for 18 hours. Base the solution with 1N NaOH (10 mL) and CH₂Cl₂Extracted with (3 x 5 mL). Combined extract with Na₂SO₄Dry in and remove the solvent under reduced pressure to form bubbles (8aS, 12aR) -2- [2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a- Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole 0.032 g (63%) was obtained. The product was purified by reverse phase HPLC (water containing 0.1% TFA, 0-100% gradient of acetonitrile) to give 0.021 g (63%) of pure water product.¹1 H NMR (CDCl₃, 300MHz) δ7.70 (d, 1H), 7.49 (dt, 1H), 7.40 (dd, 1H), 7.31 (d, 1H), 6.91 (d, 1H), 6.81 (d, 1H), 3.82 (qd) , 1H), 3.58 (dq, 1H), 3.50-3.43 (m, 1H), 3.22 (dt, 1H), 3.18-2.98 (m, 3H), 2.97-2.85 (m, 2H), 2.66 (td, 1H) ), 2.20-2.10 (m, 2H), 1.89-1.80 (m, 2H). (M + H)⁺391. [1262] (Example 331) (8aS, 12aR) -2- (2-Chloro-6-fluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [ 1, 4] Chiazepino [2,3,4-hi] Indole [1263] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 2-chloro-6-fluorobenzeneboronic acid by the method of step B of Example 330. Hydrolyzed to prepare the title compound. (M + H)⁺375. [1264] (Example 332) (8aS, 12aR) -2- [2-chloro-4- (difluoromethoxy) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1265] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from tert-butyl carbonate and the corresponding 2-chloro-4- (difluoromethoxy) benzeneboronic acid indole-11 (8aH) -step B of Example 330. The title compound was prepared by hydrolysis according to the above method.¹1 H NMR (CDCl₃, 300MHz) δ7.22 (d, 1H), 7.05 (dd, 1H), 7.00 (d, 1H), 6.92 (d, 1H), 6.52 (t, 1H, J = 10), 3.82 (qd, 1H) , 3.57 (dq, 1H), 3.51-3.43 (m, 1H), 3.25 (dt, 1H) 3.25 (dt, 1H), 3.11-2.98 (m, 3H), 2.96-2.80 (m, 2H), 2.64 ( td, 1H), 2.20-2.01 (m, 2H), 1.92-1.70 (m, 3H). (M + H)⁺423. [1266] (Example 333) (8aS, 12aR) -2- [4- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1267] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4- (trifluoromethyl) benzeneboronic acid by the method of step B of Example 330. Hydrolyzed to prepare the title compound.¹1 H NMR (CDCl₃, 300MHz) δ6.96 (d, 1H), 6.93 (d, 1H), 6.86 (d, 1H), 6.83 (d, 1H), 6.62 (t, 2H), 3.75 (qd, 1H), 3.75 (dq) , 1H), 3.40-3.38 (m, 1H), 3.21 (dt, 1H), 3.04-2.96 (m, 3H), 2.95-2.82 (m, 2H), 2.61 (td, 1H), 2.20-2.00 (m) , 2H), 1.82-1.73 (m, 2H). (M + H)⁺391. [1268] (Example 334) (8aS, 12aR) -2- (4-Methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1269] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4-methylbenzeneboronic acid was hydrolyzed by the method of step B of Example 330. , The title compound was prepared.¹1 H NMR (CDCl₃, 300MHz) δ7.40 (s, 1H), 7.37 (s, 1H), 7.19 (s, 2H), 7.16 (s, 1H), 7.06 (d, 1H), 3.78 (qd, 1H), 3.58 (dq) , 1H), 3.50-3.40 (m, 1H), 3.23 (dt, 1H), 3.18-3.00 (m, 3H), 2.92-2.80 (m, 2H), 2.70 (td, 1H), 2.36 (s, 3H) ), 2.21-2.07 (m, 2H), 1.85-1.72 (m, 2H). (M + H)⁺337. [1270] (Example 335) (8aS, 12aR) -2- [4- (trifluoromethoxy) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1271] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4- (trifluoromethoxy) benzeneboronic acid by the method of step B of Example 330. Hydrolyzed to prepare the title compound.¹1 H NMR (CDCl₃, 300MHz) δ7.49 (d, 2H), 7.21 (dd, 2H), 7.19 (d, 1H), 7.03 (d, 1H), 3.80 (qd, 1H), 3.57 (dq, 1H), 3.44-3.41 (m, 1H), 3.24 (dt, 1H), 3.18-3.00 (m, 3H), 2.98-2.83 (m, 2H), 2.73-2.63 (m, 1H), 2.20-2.04 (m, 2H), 1.96 -1.80 (m, 2H). (M + H)⁺407. [1272] (Example 336) (8aS, 12aR) -2- (2-fluoro-4,6-dimethoxyphenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [1273] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 2,4-dimethoxy-6-fluorobenzeneboronic acid in step B of Example 330. The title compound was prepared by hydrolysis by the method.¹1 H NMR (CDCl₃, 300MHz) δ7.00 (d, 1H), 6.88 (d, 1H), 6.32-6.29 (m, 2H), 3.82-3.78 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H) , 3.56 (dq, 1H), 3.48-3.40 (m, 1H), 3.19 (dt, 1H), 3.10-2.98 (m, 3H), 2.98-2.82 (m, 2H), 2.73 (td, 1H), 2.20 -2.00 (m, 2H), 1.96-1.83 (m, 2H). (M + H)⁺401 [1274] (Example 337) (8aS, 12aR) -2- (2-Methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1275] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 2-methylbenzeneboronic acid was hydrolyzed by the method of step B of Example 330. , The title compound was prepared.¹1 H NMR (CDCl₃, 300MHz) δ7.22-7.18 (m, 4H), 6.91 (d, 1H), 6.80 (d, 1H), 3.80 (qd, 1H), 3.58 (dq, 1H), 3.43-3.40 (m, 1H) , 3.23 (dt, 1H), 3.09-2.98 (m, 3H), 2.96-2.80 (m, 2H), 2.65 (td, 1H), 2.28 (s, 3H), 2.21-2.02 (m, 2H), 1.96 -1.78 (m, 2H). (M + H)⁺337. [1276] (Example 338) (8aS, 12aR) -2- [2-fluoro-6- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1277] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 2-fluoro-6- (trifluoromethyl) benzeneboronic acid in step 330 of Example 330. The title compound was prepared by hydrolysis by the method of B.¹1 H NMR (CDCl₃, 300MHz) δ7.49-7.35 (m, 3H), 7.19 (t, 1H), 7.06 (t, 1H), 3.85 (qd, 1H), 3.58 (dq, 1H), 3.56-3.47 (m, 1H) , 3.28-3.00 (m, 4H), 3.00-2.92 (m, 2H), 2.68 (td, 1H), 2.21-2.00 (m, 2H), 1.98-1.84 (m, 2H). (M + H)⁺409. [1278] (Example 339) (8aS, 12aR) -2- [2- (thiomethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1279] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 2- (thiomethyl) benzeneboronic acid is hydrolyzed by the method of step B of Example 330. The title compound was prepared.¹1 H NMR (CDCl₃, 300MHz) δ7.27-7.13 (m, 4H), 7.01 (d, 1H), 6.93 (d, 1H), 3.82 (qd, 1H), 3.58 (dq, 1H), 3.49-3.42 (m, 1H) , 3.21 (dt, 1H), 3.12-2.96 (m, 3H), 2.95-2.80 (m, 2H), 2.65 (td, 1H), 2.37 (s, 3H), 2.20-2.01 (m, 2H), 1.96 -1.76 (m, 2H). (M + H)⁺369. [1280] (Example 340) (8aS, 12aR) -2- (2,3,4-trifluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [1281] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from tert-butyl carbonate and the corresponding 2,4,6-trifluorobenzeneboronic acid indole-11 (8aH) -method of step B of Example 330. Hydrolyzed to prepare the title compound.¹1 H NMR (CDCl₃, 300MHz) δ7.02 (d, 1H), 6.89 (d, 1H), 6.70 (d, 1H), 3.82 (qd, 1H), 3.59 (dq, 1H), 3.57-3.42 (m, 1H), 3.25 (dt, 1H), 3.09-3.01 (m, 3H), 2.88-2.85 (m, 2H), 2.66 (td, 1H), 2.20-2.00 (m, 2H), 1.85-1.79 (m, 2H). (M + H)⁺377. [1282] (Example 341) (8aS, 12aR) -2- (2,4,6-trichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1283] By step A of Example 330 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indol-11 (8aH) -tert-butyl carbonate and the corresponding 2,4,6-trichlorobenzeneboronic acid by the method of step B of Example 330. Hydrolyzed to prepare the title compound.¹1 H NMR (CDCl₃, 300MHz) δ7.37 (s, 2H), 6.81 (d, 1H), 6.69 (d, 1H), 3.85 (qd, 1H), 3.59 (dq, 1H), 3.49-3.44 (m, 1H), 3.23 (dt, 1H), 3.17-2.94 (m, 3H), 2.92-2.83 (m, 2H), 2.65 (td, 1H), 2.21-2.04 (m, 2H), 1.89-1.73 (m, 2H). (M + H)⁺426. [1284] (Example 342) (8aS, 12aR) -2- (2,6-dichloro-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [1285] (Step A) (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol Copper (I) bromide (0.13 g, 0.094 mmol), triphenylphosphine (0.025 g, 0.094) in a degassed DMF (15 mL) solution of -11 (8aH) -tert-butyl carbonate (0.200 g, 0.47 mmol). mmol), and bis (triphenylphosphine) palladium (II) chloride (0.033 g, 0.047 mmol) were added under nitrogen gas. After stirring at room temperature for 5 minutes, a solution of (2,6-dichloro-4-methoxyphenyl) (trimethyl) tin hydride (0.479 g, 1.41 mmol) in DMF (3 mL) was added. The mixture was then heated at 140 ° C. for 2 hours. Once at room temperature, dilute the solution with EtOAc (200 mL) and H₂Wash with O (4 x 100 mL) and deli₄And then concentrated under reduced pressure and dried to give an oil. The crude product is purified by column chromatography with 30% EtOAc / Hexanes and normal phase HPLC (25% EtOAc in Hexanes) as foam (8aS, 12aR) -2- (2,6-dichloro-4-methoxyphenyl). )-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -tert carbonate -I got butyl. [1286] (Step B) (8aS, 12aR) -2- (2,6-dichloro-4-methoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] CH of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.204 g, 0.13 mmol)₂Cl₂The (50 mL) solution was treated with TFA (5 mL) and stirred in a closed vial at room temperature for 18 hours. Base the solution with 1N NaOH (100 mL) and CH₂Cl₂Extracted with (3 x 50 mL). Combined extract with Na₂SO₄Dry in and remove the solvent under reduced pressure to form bubbles (8aS, 12aR) -2- (2,6-dichloro-4-methoxyphenyl) -6,7,8a, 9,10,11,12, We obtained 0.160 g (63%) of 12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole. The product was purified by reverse phase HPLC (water containing 0.1% TFA, 0-100% gradient of acetonitrile) to give 0.145 g (63%) of pure water product. (M + H)⁺422. [1287] (Example 343) (8aS, 12aR) -2- (2,3,4-trifluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [1288] By step A of Example 342, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, Examples include BOC-protected amine adducts obtained from 3,4-hi] indole-11 (8aH) -tert-butyl carbonate and the corresponding (2,3,4-trifluorophenyl) (trimethyl) tin hydride. The title compound was prepared by hydrolysis by the method of step B of 342.¹1 H NMR (CDCl₃, 300MHz) δ7.10 (t, 1H), 7.08-6.93 (m, 2H), 7.00 (t, 1H), 3.84 (qd, 1H), 3.58 (dq, 1H), 3.48-3.42 (m, 1H) , 3.28-2.97 (m, 6H), 2.70 (td, 1H), 2.21-2.02 (m, 2H), 1.99-1.87 (m, 2H). (M + H)⁺377. [1289] (Example 344) (8aS, 12aR) -2- (4-Chloro-2,6-difluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [1290] By step A of Example 342, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, Performed BOC-protected amine adducts obtained from 3,4-hi] indole-11 (8aH) -tert-butyl carbonate and the corresponding (4-chloro-2,6-difluorophenyl) (trimethyl) tin hydride The title compound was prepared by hydrolysis by the method of step B of Example 342.¹1 H NMR (CDCl₃, 300MHz) δ7.33 (dd, 1H), 7.18 (dd, 1H), 6.85 (d, 1H), 6.73 (d, 1H), 3.82 (qd, 1H), 3.59 (dq, 1H), 3.59 (qd) , 1H), 3.52-3.45 (m, 1H), 3.24 (dt, 1H), 3.14-2.98 (m, 3H), 2.96-2.82 (m, 2H), 2.64 (td, 1H), 2.21-2.03 (m) , 2H), 1.98-1.99 (m, 2H). (M + H)⁺403. [1291] (Example 345) (8aS, 12aR) -2- (2,3,4,6-tetrafluorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1292] By step A of Example 342, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adducts obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding (2,3,4,6-tetrafluorophenyl) (trimethyl) tin hydride. The title compound was prepared by hydrolysis by the method of step B of Example 342.¹1 H NMR (CDCl₃, 300MHz) δ7.02 (d, 1H), 6.83 (d, 1H), 6.85-6.78 (m, 1H), 3.83 (tt, 1H), 3.61-3.39 (m, 2H), 3.24 (dt, 1H) , 3.12-2.98 (m, 2H), 2.97-2.80 (m, 2H, 2.68 (dd, 1H), 2.22-2.01 (m, 2H), 1.97-1.72 (m, 2H). (M + H)⁺395. [1293] (Example 346) (8aS, 12aR) -2- (2,3,4,5,6, -pentafluorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] Chiazepino [2,3,4-hi] Indole [1294] By step A of Example 342, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding (2,3,4,5,6-pentafluorophenyl) (trimethyl) tin hydride The product was hydrolyzed by the method of step B of Example 342 to prepare the title compound.¹1 H NMR (CDCl₃, 300MHz) δ7.03 (d, 1H), 6.90 (d, 1H), 3.83 (qd, 1H), 3.58 (dq, 1H), 3.27 (dt, 1H), 3.18-2.98 (m, 3H), 2.98 -2.90 (m, 2H), 2.65 (dd, 1H), 2.21-2.01 (m, 2H), 1.98-1.78 (m, 2H). (M + H)⁺413. [1295] (Example 347) (8aS, 12aR) -2- [2,6-di (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1296] By step A of Example 342 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, BOC-protected amine adduct obtained from 3,4-hi] indole-11 (8aH) -tert-butyl carbonate and the corresponding [2,6-bis (trifluoromethyl) phenyl] (trimethyl) hydride. The title compound was prepared by hydrolysis by the method of step B of Example 342.¹1 H NMR (CDCl₃, 300MHz) δ7.83 (s, 1H), 7.81 (s, 1H), 7.50 (t, 1H), 6.73 (s, 1H), 6.60 (s, 1H), 3.80-3.63 (m, 1H), 3.58 -3.40 (m, 2H), 3.19 (dt, 1H), 3.03-2.78 (m, 5H), 2.56 (dd, 1H), 2.19-1.98 (2H), 1.98-1.75 (m, 2H). (M + H)⁺459. [1297] (Example 348) (8aS, 12aR) -2- [2- (trifluoromethoxy) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1298] (Step A) (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -tert-butyl carbonate (0.200 g, 0.47 mmol) in DMF (5 mL) solution with 2- (trifluoromethoxy) benzeneboronic acid (0.116 g, 0.56 mmol), bis (triphenylphosphine) palladium (II) Chloride (0.030 g), barium hydroxide octahydrate (0.224 g, 0.71 mmol), and H₂O (2 mL) was added. The combined mixture was refluxed for 4 hours. Once at room temperature, H the mixture₂It was dissolved in O (100 mL) and extracted with EtOAc (3 x 50 mL). Combined extract EDTA₄The solvent was removed under reduced pressure. Purified by normal phase HPLC using a hexane solution of 25% EtOAc (8aS, 12aR) -2- [2- (trifluoromethoxy) phenyl] -6,7,9,10,12,12a-hexahydro-5H -Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate 0.194 g (82%) was obtained. [1299] (Step B) (8aS, 12aR) -2- [2- (trifluoromethoxy) phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.194 g, 0.38 mmol)₂Cl₂The (30 mL) solution was treated with TFA (6 mL) and stirred in a closed vial at room temperature for 18 hours. Base the solution with 1N NaOH (100 mL) and CH₂Cl₂Extracted with (3 x 50 mL). Combined extract with Na₂SO₄Dry in and remove the solvent under reduced pressure to form bubbles (8aS, 12aR) -2- [2- (trifluoromethoxy) phenyl] -6,7,8a, 9,10,11,12,12a- Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole 0.103 g (67%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ7.41-7.37 (m, 1H), 7.36-7.27 (m, 3H), 7.05 (d, 1H), 6.99 (d, 1H), 3.80 (qd, 1H), 3.57 (dq, 1H) , 3.52-3.42 (m, 1H), 3.25 (dt, 1H), 3.14-2.98 (m, 3H), 2.98-2.80 (m, 2H), 2.70-2.60 (m, 1H), 2.21-2.01 (m, 2H), 1.96-1.76 (m, 2H). (M + H)⁺407. [1300] (Example 349) (8aS, 12aR) -2- [4-ethoxy-2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1301] By step A of Example 348 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4-ethoxy-2- (trifluoromethyl) benzeneboronic acid in step 348 of Example 348. The title compound was prepared by hydrolysis by the method of B.¹1 H NMR (CDCl₃, 300MHz) δ7.27-7.18 (m, 2H), 7.06-6.98 (m, 1H), 6.89 (s, 1H), 6.79 (s, 1H), 4.06 (q, 2H), 3.79 (qd, 1H) , 3.57 (dq, 1H), 3.44-3.40 (m, 1H), 3.24 (dt, 1H), 3.13-2.97 (m, 3H), 2.96-2.80 (m, 2H), 2.63 (td, 1H), 2.21 -2.01 (m, 2H), 1.98-1.78 (m, 2H), 1.44 (t, 3H). (M + H)⁺435. [1302] (Example 350) (8aS, 12aR) -2- [4-isopropoxy-2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3- b] [1,4] Chiazepino [2,3,4-hi] Indole [1303] By step A of Example 348 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4-isopropoxy-2- (trifluoromethyl) benzeneboronic acid of Example 348. The title compound was prepared by hydrolysis by the method of step B.¹1 H NMR (CDCl₃, 300MHz) δ7.21-7.17 (m, 2H), 6.98 (dd, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 4.61-4.56 (m, 1H), 3.78 (qd, 1H) , 3.55 (dq, 1H), 3.43-3.40 (m, 1H), 3.21 (dt, 1H), 3.10-2.98 (m, 3H), 1.97-2.80 (m, 2H), 2.62 (td, 1H), 2.20 -2.01 (m, 2H), 1.97-1.75 (m, 2H), 1.38 (d, 6H). (M + H)⁺449. [1304] (Example 351) (8aS, 12aR) -2- (2-naphthyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2 , 3,4-hi] Indole [1305] By step A of Example 348 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 2-naphthalenboronic acid was hydrolyzed by the method of step B of Example 348. The title compound was prepared.¹1 H NMR (CDCl₃, 300MHz) δ7.93 (s, 1H), 7.83 (t, 3H), 7.65 (dd, 1H), 7.52-7.40 (m, 2H), 7.35 (d, 1H), 7.22 (d, 1H), 3.81 (qd, 1H), 3.58 (dq, 1H), 3.50-3.43 (m, 1H), 3.28 (dt, 1H), 3.20-3.01 (m, 3H), 3.00-2.80 (m, 2H), 2.80-2.74 (m, 1H), 2.23-2.04 (m, 2H), 1.98-1.78 ((m, 2H). (M + H)⁺373. [1306] (Example 352) (8aS, 12aR) -2- [4-Chloro-2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1307] By step A of Example 348 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4-chloro-2- (trifluoromethyl) benzeneboronic acid in step 348 of Example 348. The title compound was prepared by hydrolysis by the method of B.¹1 H NMR (CDCl₃, 300MHz) δ7.67 (d, 1H), 7.46 (dd, 1H), 7.23 (s, 1H), 6.86 (d, 1H), 6.77 (s, 1H), 3.80 (qd, 1H), 3.56 (dq) , 1H), 3.48-3.42 (m, 1H), 3.22 (dt, 1H), 3.12-2.97 (m, 3H), 2.97-2.80 (m, 2H), 2.64-2.59 (m, 1H), 2.21-2.00 (m, 2H), 1.97-1.75 (m, 2H). (M + H)⁺425. [1308] (Example 353) (8aS, 12aR) -2- [4-fluoro-2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1309] By step A of Example 348 (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] BOC-protected amine adduct obtained from indole-11 (8aH) -tert-butyl carbonate and the corresponding 4-fluoro-2- (trifluoromethyl) benzeneboronic acid in step 348 of Example 348. The title compound was prepared by hydrolysis by the method of B.¹1 H NMR (CDCl₃, 300MHz) δ7.68 (dd, 1H), 7.67-7.60 (m, 1H), 7.18 (t, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 3.79 (qd, 1H), 3.55 (dq, 1H), 3.50-3.46 (m, 1H), 3.22 (dt, 1H), 3.17-3.00 (m, 3H), 2.98-2.80 (m, 2H), 2.77-2.60 (m, 1H), 2.21 -2.02 (m, 2H), 1.98-1.75 (m, 2H). (M + H)⁺409. [1310] (Example 354) (8aS, 12aR) -2- (2,6-difluorophenyl) -11-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [1311] By the method of Example 437, (8aS, 12aR) -2- (2,6-difluorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] Indole (0.14, 0.39 mmol), HCHO (0.40 mL, 5.3 mmol) and formic acid (0.24 mL, 6.4 mmol) as white foam title compound (0.12) g, 83%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.92-2.25 (m, 5H), 2.25-2.50 (m, 4H), 2.68-2.80 (m, 1H), 2.80-2.92 (m, 1H), 2.92-3.05 (m, 1H), 3.05-3.12 (m, 1H), 3.28-3.44 (m, 2H), 3.52-3.68 (m, 1H), 3.88-4.00 (m, 1H), 6.88-7.02 (m, 3H), 7.08-7.20 (m) , 1H), 7.15-7.26 (m, 1H) ppm. MS (ESI): 373 (base, M + H). [1312] (Example 355) 2- [2-((±) -cis-6,7,9,10,12a-hexahydro-5H-pyridine [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru -11 (8aH) -yl) ethyl] [1,2,4] trizolo [4,3-a] pyridine-3 (2H) -on [1313] (Step A) In a solution of [1,2,4] trizolo [4,3-a] pyridine-3 (2H) -one (200 mg, 1.47 mmol) in DMF (7.0 mL), N₂NaH (43 mg, 1.76 mmol) was added at 0 ° C. below. The reaction mixture was stirred at 0 ° C. for 30 minutes, then 1-bromo-2-chloroethane (424 mg, 2.96 mmol) was added dropwise. The reaction mixture is stirred at 20 ° C for 15 hours, then H₂Add O and quench, CHCl₃Extracted with. Saturate the combined organic solution LVDS₃Wash with aqueous solution and saline solution in order, then deli₄It was dried in, filtered and concentrated under vacuum. Chromatograph the residue (silica gel, CHCl)₃: MeOH99: 1) to give 2- (2-chloroethyl) [1,2,4] trizolo [4,3-a] pyridine-3 (2H) -one (260 mg, 90%) as a white solid. [1314] (Step B) (±)-cis-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole In a solution of (30 mg, 0.12 mmol) in 1,4-dioxane (0.72 mL), 2- (2-chloroethyl) [1,2,4] trizolo [4,3-a] pyridine-3 (2H) -one ( 36 mg, 0.18 mmol), KI (catalytic amount) and K₂CO₃(25 mg, 0.18 mmol) was added. The reaction mixture was heated at 100 ° C. for 48 hours. Cool the reaction mixture to 20 ° C, then CHCl₃Diluted with. Filter the solution for excess K₂CO₃The filtrate is concentrated under vacuum and then chromatograph (silica gel, CHCl).₃: MeOH 98: 2) to give the title compound (32 mg, 65%) as a pale yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ1.65-1.77 (br-s, 1H), 1.82-1.95 (m, 2H), 1.97-2.20 (m, 3H), 2.39 (dt, J = 11.0, 4.1Hz, 1H), 2.70- 2.90 (m, 3H), 2.92-2.99 (m, 1H), 3.02-3.18 (m, 2H), 3.20-3.24 (m, 1H), 3.49-3.60 (m, 1H), 3.77-3.85 (m, 1H) ), 4.13 (t, J = 16.5Hz, 2H), 6.48 (qu, J = 3.5Hz, 1H), 6.60 (t, J = 7.7Hz, 1H), 6.85 (d, J = 7.0Hz, 1H), 6.93 (d, J = 7.7Hz, 1H), 7.05-7.09 (m, 2H), 7.75 (d, J = 7.0Hz, 1H) ppm. [1315] (Example 356) (±) -cis-11- [3- (6-fluoro-1H-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1316] (Step A) To a solution of 1-bromo-3-chloropropane (700 mg, 4.44 mmol) in DMF (2.4 mL) was added 6-fluoroindole (200 mg, 1.48 mmol) and powdered KOH (92 mg, 1.63 mmol) at 20 ° C. The reaction mixture is stirred at 20 ° C for 15 hours, then H₂Add O, quench and Et₂Extracted with O. The combined organic solutions are washed sequentially with saline solution and deli₄It was dried in, filtered and concentrated under vacuum. The residue was chromatographed to give 1- (3-chloropropyl) -6-fluoroindole (190 mg, 66%) as a colorless oil. [1317] (Step B) By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound (50 mg, 99%) as a yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (3-chloropropyl) -6-fluoroindole (36 mg, 0.18 mmol). Prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.85-2.30 (m, 10H), 2.57-2.60 (m, 1H), 2.62-2.70 (m, 1H), 2.92-2.98 (m, 1H), 3.03-3.20 (m, 2H), 3.27-3.32 (m, 1H), 3.49-3.60 (m, 1H), 3.78-3.85 (m, 1H), 4.16 (t, J = 16.6Hz, 2H), 6.46 (d, J = 2.9Hz, 1H) , 6.62 (t, J = 7.3Hz, 1H), 6.82-6.90 (m, 2H), 6.95 (dd, J = 8.1, 0.8Hz, 1H), 7.07-7.13 (m, 2H), 7.51 (dd, J = 8.8,5.5Hz, 1H) ppm. [1318] (Example 357) (±) -cis-11- [3- (5-fluoro-1H-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1319] (Step A) By the method of Step A of Example 355, 1- (3-chloropropyl) -5-fluoroindole (190 mg, 66%) was prepared as a colorless oil from 5-fluoroindole (200 mg, 1.48 mmol). [1320] (Step B) By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound (48 mg, 95%) as a yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 1- (3-chloropropyl) -5-fluoroindole (36 mg, 0.18 mmol). Prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.86-2.30 (m, 10H), 2.55-2.59 (m, 1H), 2.65-2.72 (m, 1H), 2.92-3.00 (m, 1H), 3.05-3.21 (m, 2H), 3.27-3.33 (m, 1H), 3.47-3.59 (m, 1H), 3.75-3.86 (m, 1H), 4.20 (t, J = 16.6Hz, 2H), 6.44 (d, J = 3.3Hz, 1H) , 6.62 (t, J = 7.3Hz, 1H), 6.85 (d, J = 6.9Hz, 1H), 6.90-6.98 (m, 2H), 7.14 (d, J = 2.9Hz, 1H), 7.23-7.31 ( m, 2H) ppm. [1321] (Example 358) (±) -cis-11- [3- (6-fluoro-2,3-dihydro-1H-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro -5H-Pirido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1322] (±) -cis-11- [3- (6-fluoro-1H-indru-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] thiazepino [2,3,4-hi] indol (25 mg, 0.054 mmol) in acetic acid (0.8 mL) solution at 10 ° C. NaCNBH₃(10.2 mg, 0.16 mmol) was added slowly. The reaction mixture was slowly warmed to 20 ° C and stirred for 2 hours. The reaction was quenched by the addition of ice followed by 1N NaOH. CHCl the product₃Extract with, and combine the organic solutions with DDL.₄It was dried in. Flash column chromatography gave the title compound (19 mg, 83%) as a colorless oil.¹1 H NMR (CDCl₃, 300MHz) δ1.77 (qu, J = 7.0Hz, 2H), 1.80-2.20 (m, 5H), 2.22-2.45 (m, 3H), 2.62-2.72 (m, 1H), 2.73-2.82 (m, 1H), 2.87-2.98 (m, 3H), 3.03-3.22 (m, 4H), 3.25-3.32 (m, 1H), 3.40 (t, J = 8.5Hz, 2H), 3.50-3.61 (m, 1H) , 3.78-3.88 (m, 1H), 6.16 (dd, J = 10.6, 2.2Hz, 1H), 6.26 (dt, J = 8.0, 2.5Hz, 1H), 6.62 (t, J = 7.3Hz, 1H), 6.84-6.97 (m, 3H) ppm. MS (CI, NH₃): 424.3 (base, M + H). [1323] (Example 359) (±) -cis-11- [3- (5-fluoro-2,3-dihydro-1H-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro -5H-Pirido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1324] By the method of Example 358, (8aS, 12aR) -11- [3- (6-fluoro-1H-indru-1-yl) propyl] -6,7,8a, 9,10,11,12,12a- The title compound (19 mg, 69%) was prepared as a colorless oil from octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru (30 mg, 0.065 mmol). ..¹1 H NMR (CDCl₃, 300MHz) δ1.74-1.84 (m, 2H), 1.86-2.20 (m, 5H), 2.22-2.45 (m, 3H), 2.64-2.82 (m, 2H), 2.87-3.22 (m, 7H), 3.25-3.38 (m, 3H), 3.50-3.62 (m, 1H), 3.78-3.85 (m, 1H), 6.35 (dd, J = 8.8, 4.4Hz, 1H), 6.62 (t, J = 7.3Hz, 1H), 6.70-6.90 (m, 3H), 6.95 (dd, J = 8.0,1.0Hz, 1H) ppm. [1325] (Example 360) (±) -cis-11- [3- (6-fluoro-1H-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1326] (Step A) A solution of 6-fluoroindre (300 mg, 2.22 mmol), acrylic acid (352 mg, 4.88 mmol) and acetic anhydride (453 mg, 4.44 mmol) in acetic acid (1.1 mL) was heated at 90 ° C. for 15 hours. The reaction mixture was cooled to 20 ° C. and concentrated under vacuum. The residue was dissolved in 3N NaOH. The solution is filtered to remove insoluble material, the filtrate is acidified with concentrated HCl, then CHCl.₃Extracted with. EDTA organic solution₄It was dried in, filtered and concentrated under vacuum to give 3- (6-fluoroindrill) propionic acid (240 mg, 52%) as a yellow oil. [1327] (Step B) In a solution of 3- (6-fluoroindrill) propionic acid (235 mg, 1.13 mmol) in THF (5.3 mL), N₂LiAlH at 0 ° C below₄(86 mg, 2.26 mmol) was added slowly. The reaction mixture was heated to 20 ° C and stirred for 15 hours. Reaction H₂O (0.5 mL) was added, quenched and diluted with EtOAc. Divide the obtained solution₄It was dried in, filtered through Celite and concentrated under vacuum. The residue was chromatographed to give 6-fluoro-3- (3-hydroxypropyl) indole (142 mg, 65%) as a colorless oil. [1328] (Step C) CH of 6-fluoro-3- (3-hydroxypropyl) indole (140 mg, 0.72 mmol)₂Cl₂(4.5 mL) and Et₃In N (147 mg, 1.45 mmol) solution, N₂Methanesulfonyl chloride (125 mg, 1.09 mmol) was added at 0 ° C. below. The reaction mixture was stirred at 0 ° C. for 2 hours. The reaction was quenched by adding 1N HCl and Et.₂Diluted with O. Separate the layers and make the organic layer CTL₄It was dried in, filtered and concentrated under vacuum. The residue was chromatographed to give 3- (6-fluoroindolyl) -propylmethanesulfonate (140 mg, 71%) as a colorless oil. [1329] (Step D) By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound (35 mg, 69%) as a yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 3- (6-fluoroindolyl) -propylmethanesulfonate (49 mg, 0.18 mmol). Prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.86-2.20 (m, 7H), 2.25-2.36 (m, 1H), 2.39-2.46 (m, 2H), 2.67-2.85 (m, 4H), 2.85-2.96 (m, 1H), 3.02-3.15 (m, 1H), 3.17-3.25 (m, 1H), 3.28 (qu, J = 3.3Hz, 1H) 3.50-3.62 (m, 1H), 3.77-3.87 (m, 1H), 6.62 (t) , J = 7.4Hz, 1H), 6.83-6.91 (m, 2H), 6.93-6.97 (m, 2H), 7.01 (dd, J = 9.9, 2.2Hz, 1H), 7.48 (dd, J = 8.5,5.2) Hz, 1H), 7.93-7.99 (br-s, 1H) ppm. [1330] (Example 361) (8aS, 12aR) -11- [3- (6-fluoro-1H-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1331] (8aS, 12aR)-6,7,8a,9,10,11,12,12a-Octahydro-5H-Pirido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol A solution of HCl salt (20 mg, 0.063 mmol) in 1,4-dioxane (0.4 mL) and N, N-diisopropylethylamine (82 mg, 0.63 mmol) in 3- (6-fluoroindolyl) -propylmethanesulfonate (26 mg, 0.89 mmol) and KI (catalytic amount) were added. The reaction mixture was heated at 100 ° C. for 15 hours. The reaction mixture is cooled to 20 ° C, concentrated under vacuum and chromatograph (silica gel CHCl).₃: MeOH 98: 2) to give the title compound (24 mg, 91%) as a yellow oil. The title compound was spectroscopically identical to Example 360. [1332] (Example 362) (±) -cis-11- [3- (5-fluoro-1H-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1333] (Step A) 3- (5-Fluoroindrill) propionic acid (272 mg, 60%) was prepared as a yellow solid from 5-fluoroindole (300 mg, 2.22 mmol) by the method of Step A of Example 360. [1334] (Step B) 5-Fluoro-3- (3-hydroxypropyl) indole (185 mg, 74%) as a colorless solid from 3- (5-fluoroindolyl) propionic acid (270 mg, 1.30 mmol) by the method of step B of Example 360. Was prepared. [1335] (Step C) From 5-fluoro-3- (3-hydroxypropyl) indole (167 mg, 0.86 mmol) to 3- (5-fluoroindolyl) -propylmethanesulfonate (185 mg, 74) as a colorless solid by the method of step C of Example 360. %) Was prepared. [1336] (Step D) By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound (35 mg, 69%) as a yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 3- (5-fluoroindolyl) -propylmethanesulfonate (49 mg, 0.18 mmol). Prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.88-2.19 (m, 7H), 2.24-2.35 (m, 1H), 2.37-2.47 (m, 2H), 2.68-2.85 (m, 4H), 2.88-2.97 (m, 1H), 3.02-3.12 (m, 1H), 3.15-3.30 (m, 2H), 3.48-3.60 (m, 1H), 3.77-3.87 (m, 1H), 6.62 (t, J = 7.3Hz, 1H), 6.85 ( d, J = 6.6Hz, 1H), 6.89-6.97 (m, 2H), 7.03 (s, 1H), 7.21-7.30 (m, 2H), 7.93-8.01 (br-s, 1H) ppm. [1337] (Example 363) (8aS, 12aR) -11- [3- (5-fluoro-1H-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1338] By the method of Example 361, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, Prepare the title compound (19 mg, 72%) as a yellow oil from 3,4-hi] indole HCl salt (20 mg, 0.063 mmol) and 3- (5-fluoroindolyl) -propylmethanesulfonate (26 mg, 0.094 mmol). did. The title compound was spectroscopically identical to Example 362. [1339] (Example 364) (±) -cis-11- [3- (9H-purine-9-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1340] (Step A) In a solution of purine (360 mg, 3.00 mmol) and 1-bromo-3-chloropropane (1.42 g, 9.0 mmol) in DMF (10 mL), K₂CO₃(622 mg, 4.5 mmol) was added at 20 ° C. The reaction mixture was stirred at 20 ° C. for 24 hours and filtered. The filtrate is concentrated under vacuum and the residue is chromatographed as a colorless oil 9- (3-chloropropyl) purine (400 mg, 68%) and 7- (3-chloropropyl) purine (136 mg, 23%). Got [1341] (Step B) By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound (40 mg, 82%) was prepared as a yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 9- (3-chloropropyl) purine (36 mg, 0.18 mmol).¹1 H NMR (CDCl₃, 300MHz) δ1.78-2.20 (m, 7H), 2.22-2.33 (m, 3H), 2.47-2.55 (m, 1H), 2.60-2.68 (m, 1H), 2.94 (dt, J = 14.3,4.5) Hz, 1H), 3.03-3.15 (m, 2H), 3.28 (qu, J = 3.0Hz, 1H), 3.47-3.55 (m, 1H), 3.72-3.82 (m, 1H), 4.38 (dt, J = 6.6,1.1Hz, 2H), 6.62 (t, J = 7.3Hz, 1H), 6.85 (d, J = 6.6Hz, 1H), 6.94 (dd, J = 7.7, 0.9Hz, 1H), 8.12 (s, 1H), 8.98 (s, 1H), 9.14 (s, 1H) ppm. [1342] (Example 365) (±) -cis-11- [3- (7H-purine-7-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1343] By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound (34 mg, 70%) was prepared as a yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 7- (3-chloropropyl) purine (36 mg, 0.18 mmol).¹1 H NMR (CDCl₃, 300MHz) δ1.80-2.30 (m, 10H), 2.45-2.53 (m, 1H), 2.58-2.65 (m, 1H), 2.94 (dt, J = 13.9, 4.6Hz, 1H), 3.05-3.17 ( m, 2H), 3.30 (qu, J = 3.6Hz, 1H), 3.45-3.55 (m, 1H), 3.75-3.83 (m, 1H), 4.36-4.45 (m, 2H), 6.63 (t, J = 7.6Hz, 1H), 6.85 (d, J = 6.9Hz, 1H), 6.95 (d, J = 7.7Hz, 1H), 8.25 (s, 1H), 9.00 (s, 1H), 9.16 (s, 1H) ppm. [1344] (Example 366) 4- [5-((±) -cis6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru -11 (8aH) -ylmethyl) 4,5-dihydro-3-isooxazolyl] Benzonitrile [1345] (Step A) By the method of step C of Example 360, from 4- [5- (hydroxymethyl) -4,5-dihydro-3-isooxazolyl] benzonitrile (51 mg, 0.25 mmol) as a yellow solid [3- (4-cyanophenyl) ) -4,5-Dihydro-5-isooxazolyl] Methylmethane sulfonate (69 mg, 99%) was prepared. [1346] (Step B) By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino Yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and {3- (4-cyanophenyl) -4,5-dihydro-5-isooxazolyl} methylmethane sulfonate (50 mg, 0.18 mmol) The title compound (50 mg, 96%) was prepared as.¹1 H NMR (CDCl₃, 300MHz) δ1.89 (qu, J = 4.4Hz, 2H), 2.02-2.20 (m, 3H), 2.40-2.80 (m, 4H), 2.88-2.99 (m, 1H), 3.05-3.35 (m, 5H), 3.43-3.55 (m, 2H), 3.75-3.83 (m, 1H), 4.92-5.01 (m, 1H), 6.58 (td, J = 13.9, 7.2Hz, 1H), 6.84 (dd, J = 7.0,3.0Hz, 1H), 6.92-6.97 (m, 1H), 7.67-7.60 (m, 4H) ppm. [1347] (Example 367) (±) -cis-11- [3- (6-fluoro-1H-indazole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1348] (Step A) BCl₃ Me₂A solution of 3-fluoroaniline (1.00 g, 9.0 mmol) in benzene (9 mL) is added to a solution of S (1.78 g, 9.9 mmol) in anhydrous benzene (9 mL).₂Drops were added while cooling the ice. 4-Chlorobutyronitrile (1.12 g, 10.8 mmol) and AlCl in this reaction mixture₃Was added in order. The reaction mixture was refluxed for 20 hours and cooled to 20 ° C. Ice-cooled 2N HCl was added to the reaction mixture to form a yellow solid. The resulting mixture was reheated at 80 ° C for 1 hour. Cool the solution to 20 ° C and CHCl₃Extracted with. Organic solution H₂Rinse with O and saline and CTL₄It was dried in, filtered and concentrated under vacuum. The residue was chromatographed to give 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (1.07 g, 55%) as a white solid. [1349] (Step B) NaNO in a concentrated HCl (3.2 mL) suspension of 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (500 mg, 2.3 mmol)₂H₂O solution (0.7 mL) was added, and the mixture was stirred at -6 to 0 ° C for 1 hour. SnCl₂ 2H₂A solution of concentrated O (1.25 g, 5.51 mmol) in HCl (1.7 mL) was added to the reaction mixture and stirred at 0 ° C. for an additional hour. The reaction is quenched by the addition of ice water and Et.₂Extracted with O. Combined organic layer H₂Rinse with O and saline and CTL₄It was dried in, filtered and concentrated under vacuum to give a white solid. It was recrystallized to give pure 3- (3-chloropropyl) -6-fluoroindazole (420 mg, 86%). [1350] (Step C) By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound (34 mg, 67%) as a yellow oil from [2,3,4-hi] indole (30 mg, 0.12 mmol) and 3- (3-chloropropyl) -6-fluoroindazole (39 mg, 0.18 mmol). Prepared¹1 H NMR (CDCl₃, 300MHz) δ1.86-2.20 (m, 7H), 2.22-2.33 (m, 1H), 2.39-2.47 (m, 2H), 2.65-2.73 (m, 1H), 2.75-2.83 (m, 1H), 2.88-3.08 (m, 4H), 3.12-3.20 (m, 1H), 3.27 (qu, J = 3.3Hz, 1H) 3.50-3.60 (m, 1H), 3.77-3.87 (m, 1H), 6.61 (t) , J = 7.5Hz, 1H), 6.83 (d, J = 7.9Hz, 1H), 6.86-6.95 (m, 2H), 7.06 (dd, J = 9.1, 2.2Hz, 1H), 7.62 (dd, J = 8.8,5.1Hz, 1H), 9.85-10.15 (br-s, 1H) ppm. [1351] (Example 368) (8aS, 12aR) -11- [3- (6-fluoro-1H-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1352] By the method of Example 361, (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, Prepare the title compound (21 mg, 50%) as a yellow oil from 3,4-hi] indole HCl salt (32 mg, 0.10 mmol) and 3- (3-chloropropyl) -6-fluoroindazole (32 mg, 0.15 mmol). did. The title compound was spectroscopically identical to Example 367. [1353] (Example 369) (8aR, 12aS) -11- [3- (6-fluoro-1H-indazole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1354] By the method of Example 361, (8aR, 12aS) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, Prepare the title compound (31 mg, 73%) as a yellow oil from 3,4-hi] indole HCl salt (32 mg, 0.10 mmol) and 3- (3-chloropropyl) -6-fluoroindazole (32 mg, 0.15 mmol). did. The title compound was spectroscopically identical to Example 367. [1355] (Example 370) 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone [1356] By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino The title compound as a red oil from [2,3,4-hi] indole (300 mg, 0.121 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (400 mg, 1.85 mmol). (330 mg, 64%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.83-2.18 (m, 7H), 2.22-2.40 (m, 3H), 2.60-2.69 (m, 1H), 2.72-2.80 (m, 1H), 2.89-2.99 (m, 3H), 3.03-3.17 (m, 2H), 3.25 (qu, J = 2.9Hz, 1H), 3.49-3.59 (m, 1H), 3.78-3.87 (m, 1H), 6.28-6.38 (m, 2H), 6.40- 6.48 (br-s, 2H), 6.61 (t, J = 7.4Hz, 1H), 6.85 (d, J = 7.0Hz, 1H), 6.94 (dd, J = 8.1, 1.1Hz, 1H), 7.77 (dd) , J = 8.8,6.4Hz, 1H) ppm. [1357] (Example 371) 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru- 11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone [1358] By the method of step B of Example 355 (8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ The title compound from 2,3,4-hi] indole (320 mg, 1.3 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (564 mg, 2.6 mmol) as a yellow oil ( 130 mg, 24%) was prepared. The title compound was spectroscopically identical to Example 370. [1359] (Example 372) N- {2- [4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) butanoyl] -5-fluorophenyl} methanesulfonamide [1360] 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- CH of 11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone (30 mg, 0.070 mmol)₂Cl₂In (0.5 mL) solution, N₂Et at 0 ° C below₃After adding N (15 mg, 0.14 mmol), methanesulfonyl chloride (12 mg, 0.11 mmol) was added. The reaction mixture was stirred at 0 ° C. for 4 hours, then HCl (1.0 N, 1.0 mL) was added and quenched. CHCl the resulting solution₃Extracted with. Combined organic solutions to CTL₄It was dried in. Flash column chromatography (silica gel; CHCl)₃: MeOH99: 1) gave the title compound (35 mg, 99%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ1.85-2.18 (m, 7H), 2.24-2.42 (m, 3H), 2.58-2.66 (m, 1H), 2.69-2.77 (m, 1H), 2.89-3.17 (m, 5H), 3.23-3.30 (m, 1H), 3.49-3.59 (m, 4H), 3.74-3.85 (m, 1H), 6.60 (t, J = 7.7Hz, 1H), 6.80-88 (m, 2H), 6.94 ( d, J = 8.1Hz, 1H), 7.13 (dd, J = 8.5, 2.2Hz, 1H), 7.20-7.25 (m, 1H), 7.77 (dd, J = 8.8, 5.9Hz, 1H) ppm. [1361] (Example 373) N- {2- [4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) butanoyl] -5-fluorophenyl} acetamide [1362] 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- CH of 11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone (28 mg, 0.066 mmol)₂Cl₂(0.5 mL) N in solution₂Pyridine (16 mg, 0.20 mmol) was added at 20 ° C. below, followed by acetic anhydride (13 mg, 0.13 mmol). The reaction mixture is stirred at 20 ° C for 15 hours and H₂O was added and quenched. CHCl the resulting solution₃Extracted with. Combined organic solutions to CTL₄It was dried in. Flash column chromatography (silica gel; CHCl)₃: MeOH99: 1) gave the title compound (28 mg, 91%) as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ1.90-2.18 (m, 10H), 2.49-2.69 (m, 3H), 2.88-3.07 (m, 6H), 3.27-3.38 (m, 2H), 3.49-3.59 (m, 1H), 3.79-3.90 (m, 1H), 6.25-6.38 (m, 2H), 6.41-6.50 (br-s, 1H), 6.64 (t, J = 7.3Hz, 1H), 6.87 (d, J = 7.0Hz, 1H), 6.97 (dd, J = 7.7,1.1Hz, 1H), 7.73 (dd, J = 9.2,6.6Hz, 1H) ppm. [1363] (Example 374) N- {2- [4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) butanoyl] -5-fluorophenyl} acetamide [1364] By the method of Example 373, 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indoru-11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone (43 mg, 0.10 mmol) as a white amorphous solid (28 mg, 91%) The title compound (37 mg, 80%) was prepared. The title compound was spectroscopically identical to Example 373. [1365] (Example 375) 2- [4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-11 (8aH) -yl) butanoyl] -ethyl-5-fluorophenylcarbamate [1366] 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyridine [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- Ethyl chloroformate (16 mg, 0.10 mmol) N in a pyridine (0.2 mL) solution of 11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone (35 mg, 0.082 mmol)₂Added at 0 ° C below. The reaction mixture was stirred at 0 ° C. for 40 minutes and concentrated under vacuum. Chromatograph the residue (silica gel; CHCl₃: MeOH99: 1) to give the title compound (6.0 mg, 51%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ1.32 (t, J = 7.3Hz, 3H), 1.83-2.18 (m, 7H), 2.25-2.50 (m, 3H), 2.70-2.87 (br-s, 2H), 2.89-3.17 ( m, 5H), 3.25-3.32 (m, 1H), 3.50-3.61 (m, 1H), 3.77-3.87 (m, 1H), 4.23 (q, J = 7.3Hz, 2H), 6.61 (t, J = 7.4Hz, 1H), 6.72-6.80 (m, 1H), 6.85 (d, J = 7.4Hz, 1H), 6.94 (dd, J = 7.7,1.1Hz, 1H), 7.94 (dd, J = 9.1,6.3) Hz, 1H), 8.28 (dd, J = 12.1, 2.5Hz, 1H), 11.39-11.43 (br-s, 1H) ppm. [1367] (Example 376) N- {2- [4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) butanoyl] -5-fluorophenyl-N'-ethylurea [1368] 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone (32 mg, 0.075 mmol) was dissolved in ethyl isocyanate (50 μL) and the solution was N.₂The mixture was stirred at 20 ° C for 20 hours. The reaction mixture is concentrated under vacuum and then chromatograph (silica gel; CHCl).₃: MeOH99: 1) to give the title compound (30 mg, 81%) as a pale yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ1.21 (t, J = 7.0Hz, 3H), 1.90-2.18 (m, 7H), 2.25-2.50 (m, 3H), 2.65-2.87 (br-s, 2H), 2.90-3.17 ( m, 4H), 3.19-3.35 (m, 4H), 3.50-3.59 (m, 1H), 3.78-3.87 (m, 1H), 4.73-4.79 (br-s, 1H), 6.57-6.77 (m, 2H) ), 6.84 (d, J = 6.2Hz, 1H), 6.95 (dd, J = 7.7, 1.1Hz, 1H), 7.91 (dd, J = 8.7, 6.2Hz, 1H), 8.41 (dd, J = 12.4, 2.6Hz, 1H), 11.39-11.43 (br-s, 1H) ppm. MS (CI, NH₃): 497.2 (base, M + H). [1369] (Example 377) 2- [4-((±) -cis-6,7,9,10,12,12a-hexahydroδ-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indol-11 (8aH) -yl) butanoyl] -5-fluorophenylformamide [1370] 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone (38 mg, 0.090 mmol) was dissolved in formic anhydride (0.2 mL). N the reaction mixture₂The mixture was stirred at 60 ° C for 2 hours. The reaction mixture is concentrated under vacuum and the residue is chromatographed (silica gel; CHCl).₃: MeOH99: 1) to give the title compound (31 mg, 76%) as a pale yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ1.89-2.18 (m, 7H), 2.37-2.57 (m, 3H), 2.75-2.97 (m, 3H), 2.99-3.12 (m, 3H), 3.15-3.30 (m, 2H), 3.48-3.58 (m, 1H), 3.77-3.87 (m, 1H), 6.62 (t, J = 7.5Hz, 1H), 6.82-6.90 (m, 2H), 6.95 (dd, J = 7.7,1.1Hz, 1H), 7.99 (dd, J = 9.1, 6.2Hz, 1H), 8.50 (d, J = 1.1Hz, 1H), 8.55 (dd, J = 11.8, 2.5Hz, 1H), 11.83-11.87 (br-s) , 1H) ppm. [1371] (Example 378) 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) butanoyl] -1- (4-fluoro-2-hydroxyphenyl) -1-butanone [1372] By the method of step B of Example 355 (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ The title compound (1,3,4-hi] indole (100 mg, 0.41 mmol) and 4-chloro-1- (4-fluoro-2-hydroxyphenyl) -1-butanone (176 mg, 0.81 mmol) as a yellow oil. 36 mg, 21%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.80-2.18 (m, 7H), 2.22-2.45 (m, 3H), 2.57-2.77 (m, 2H), 2.85-3.15 (m, 5H), 3.22-3.27 (m, 1H), 3.47-3.59 (m, 1H), 3.77-3.85 (m, 1H), 6.57-6.70 (m, 3H), 6.83 (d, J = 6.7Hz, 1H), 6.94 (dd, J = 7.7,1.1Hz, 1H), 7.80 (dd, J = 8.7, 6.4Hz, 1H) ppm. [1373] (Example 379) 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -1- [4-fluoro-2- (methylsulfanyl) phenyl] -1-butanone [1374] (Step A) In a solution of 3-fluorothiophenol (4.73 g, 37.0 mmol) in diethyl carbonate (11 mL, 129 mmol), K₂CO₃(7.67 g, 55.5 mmol) and 18-crown-6 ether (100 mg, 0.37 mmol) were added. The reaction mixture was refluxed at 100 ° C. for 12 hours. Cool the reaction mixture to 20 ° C, then H₂Add O to quench and Et₂Extracted with O. Combined organic solution H₂Rinse with O and saline and CTL₄Drying with, 1-fluoro-3- (methylsulfanyl) benzene (5.10 g, 97%) was obtained as a colorless oil. [1375] (Step B) CH of 1-fluoro-3- (methylsulfanyl) benzene (1.98 g, 14.0 mmol) and 4-chlorobutyryl chloride₂Cl₂In a (15 mL) solution, AlCl₃(2.06 g, 15.4 mmol) N₂Added at 20 ° C below. The reaction mixture is stirred for 15 hours at 20 ° C for 12 hours and H₂Add O, quench and Et₂Extracted with O. Combined organic solution H₂Rinse with O and saline and CTL₄It was dried in, filtered and concentrated under vacuum. The obtained white solid was recrystallized to obtain 4-chloro-1- [4-fluoro-2- (methylsulfanyl) phenyl] -1-butanone (2.80 g, 81%) as white needle-like crystals. [1376] (Step C) By the method of step B of Example 355, (±) -cis-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino Yellow oil from [2,3,4-hi] indole (100 mg, 0.41 mmol) and 4-chloro-1- [4-fluoro-2- (methylsulfanyl) phenyl] -1-butanone (50 mg, 0.20 mmol) The title compound (45 mg, 45%) was prepared as.¹1 H NMR (CDCl₃, 300MHz) δ1.82-2.18 (m, 7H), 2.24-2.49 (m, 3H), 2.51 (s, 3H), 2.60-2.82 (m, 2H), 2.85-3.15 (m, 5H), 3.21- 3.27 (m, 1H), 3.48-3.60 (m, 1H), 3.76-3.87 (m, 1H), 6.61 (t, J = 7.3,1H), 6.83-6.97 (m, 3H), 7.03 (dd, J) = 8.5,1.9Hz, 1H), 7.79 (t, J = 8.0Hz, 1H) ppm. [1377] (Example 380) (8aS, 12aR) -2- (2-Chloro-4-ethoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1378] (Step A) Anhydrous THF (50 mL) solution of 4-bromo-3-chloro-phenol (24 mmol, 5 g), N₂It was added to a solution of NaH (60% in mineral oil, 120 mmol, 4.8 g) in THF (100 mL) and DMF (42 mL) with stirring at room temperature below. The solution was stirred for 30 minutes. Iodoethane (240 mmol, 19.2 mL) was then added. The solution was stirred and refluxed overnight. Cool the reactants, quench with 1N HCl (150 mL), CH₂Cl₂Extract with (2 x 150 mL) and deli₄It was dried in, concentrated under vacuum and then distilled under vacuum to give 1-bromo-2-chloro-4-ethoxybenzene (4.59 g, 81%) as a brown oil.¹1 H NMR (CDCl₃, 300MHz): 7.42 (1H, d, J8.7Hz), 6.96 (1H, d, J2.9Hz), 6.64 (1H, dd, J8.8 and 2.5Hz), 3.95 (2H, q, J7.0Hz) , 1.39 (3H, t, J7.0Hz.) [1379] (Step B) n-Butyllithium (1.6M hexane solution, 23.5 mmol, 14.7 mL) in THF (120 mL) solution of 1-bromo-2-chloro-4-ethoxybenzene (19.5 mmol, 4.59 g) under nitrogen atmosphere, -78 Added at ° C. After stirring for 30 minutes, trimethylboric acid (76.6 mmol, 8.7 mL) was added over 20 minutes. The reaction was heated to room temperature overnight with stirring. The solution was then acidified with HCl (3M, 200 mL) and extracted with EtOAc. EtOAc was then extracted with NaOH (1N, 4 x 100 mL) and subsequently acidified with concentrated HCl to form a white precipitate. The white precipitate (2.25 g, 58%) was filtered and dried to give (2-chloro-4-ethoxyphenyl) boronic acid.¹1 H NMR (CDCl₃, 300MHz): 7.87 (1H, d, J8.4Hz), 6.88 (1H, d, J2.5Hz), 6.84 (1H, dd, J8.4 and 2.5Hz), 5.53 (2H, br.s), 4.06 (2H, q, J7.07Hz), 1.42 (3H, t, J7.0Hz.) [1380] (Step C) (2-Chloro-4-ethoxyphenyl) boric acid (0.94 mmol, 188 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3 -b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.47 mmol, 200 mg), barium hydroxide (0.71 mmol, 222 mg), DME (15 mL) And H₂O (5 mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02 mmol, 27 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography eluting with EtOAc / Hexanes (1: 5) to give the desired adduct (183 mg, 78%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.19 (1H, d, J8.8Hz), 7.02 (1H, d, J1.8Hz), 6.98-6.96 (2H, m), 6.80 (1H, dd, J8.4 and 2.5Hz), 4.04 (2H, q, J6.9Hz), 3.85 (2H, ddd, J13.9, 10.2, and 4.7Hz), 3.66-3.48 (3H, m), 3.27-3.13 (3H, m), 2.97 (2H, dt) , J14.7 and 4.8Hz), 2.14-2.04 (2H, m), 1.90-1.87 (2H, m), 1.42 (12H, tJ7.0Hz.) [1381] (Step D) (8aS, 12aR) -2- (2-Chloro-4-ethoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.37 mmol, 183 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution at room temperature under a nitrogen atmosphere with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (144 mg, 98%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.20 (1H, d, J8.8Hz), 7.00 (1H, d, J1.9Hz), 6.96 (1H, d, J2.5Hz), 6.93 (1H, d, J1.9Hz), 6.80 ( 1H, dd, J8.4 and 2.6Hz), 4.03 (2H, q, J7.0Hz), 3.80 (1H, ddd, J13.9, 9.9 and 4.4Hz), 3.56 (1H, ddd, J15.0, 9.9) And 5.5Hz), 3.46-3.41 (1H, m), 3.21 (1H, dt, J13.6 and 4.1Hz), 3.11-2.81 (5H, m), 2.68-2.61 (1H, m), 2.15-2.04 ( 2H, m), 1.90-1.70 (2H, m), 1.43 (3H, t, J7.0Hz.) [1382] (Example 381) (8aS, 12aR) -2- (2-Chloro-4-iso-propoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [ 1,4] Chiazepino [2,3,4-hi] Indole [1383] (Step A) K₂CO₃A sample (52.8 mmol, 7.4 g) was added to a solution of 4-bromo-3-chloro-phenol (24 mmol, 5 g) in anhydrous DMF (100 mL), followed by 2-iodopropane (100 mmol, 10 mL). This was heated and stirred overnight at 60 ° C. The reaction is cooled, extracted with EtOAc (150 mL) and H₂Wash with O (2L) and DEV₄And concentrated under vacuum to give 1-bromo-2-chloro-4-isopropoxybenzene (4.85 g, 81%) as a brown oil.¹1 H NMR (CDCl₃, 300MHz): 7.35 (1H, d, J8.7Hz), 6.89 (1H, d, J2.9Hz), 6.57 (1H, dd, J8.8 and 2.9Hz), 4.38 (1H, m), 1.22 (6H) , d, J6.2Hz.) [1384] (Step B) n-Butyllithium (1.6 M hexane solution, 23.5 mmol, 14.7 mL) in THF (120 mL) solution of 1-bromo-2-chloro-4-iso-propoxybenzene (19.4 mmol, 4.85 g) under nitrogen atmosphere , Added at -78 ° C. After stirring for 30 minutes, trimethylboric acid (76.6 mmol, 8.7 mL) was added over 20 minutes. The reaction was warmed to room temperature overnight with stirring. The solution was then acidified with HCl (3M, 200 mL) and extracted with EtOAc. EtOAc was then extracted with NaOH (1N, 4 x 100 mL) and subsequently acidified with concentrated HCl to give a white precipitate of (2-chloro-4-iso-propoxyphenyl) boric acid (1.82 g, 44%). Was formed, which was filtered and dried.¹H NMR (CD)₃OD, 300MHz): 7.19 (1H, d, J8.4Hz), 6.87 (1H, d, J2.2Hz), 6.82 (1H, dd, J8.4 and 2.2Hz), 4.58 (1H, m), 1.28 ( 6H, d, J5.9Hz.) [1385] (Step C) (2-Chloro-4-iso-propoxyphenyl) boronic acid (0.94 mmol, 201 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4 , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.47,200 mg), barium hydroxide (0.71 mmol, 222 mg), DME (15 mL) ) And H₂O (5 mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02, 27 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. This oil was purified by column chromatography eluting with EtOAc / Hexane (1: 9) and as a yellow oil (8aS, 12aR) -2- (2-chloro-4-iso-propoxyphenyl) -6,7,9. , 10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (171 mg, 71%) ) Was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.18 (1H, d, J8.8Hz), 7.02 (1H, d, J1.5Hz), 6.98-6.95 (2H, m), 6.78 (1H, dd, J8.4 and 2.5Hz), 4.58 -4.50 (1H, m), 3.85 (2H, ddd, J14.3, 10.3, and 4.8Hz), 3.65-3.48 (3H, m), 3.27-3.13 (3H, m), 2.97 (2H, dt, J14) .3 and 4.8Hz), 2.14-2.05 (2H, m), 1.90-1.87 (2H, m), 1.42 (9H, s), 1.35 (6H, d, J5.8Hz.) [1386] (Step D) (8aS, 12aR) -2- (2-Chloro-4-iso-propoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] CH of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.33 mmol, 171 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution at room temperature under a nitrogen atmosphere with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (107 mg, 78%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.19 (1H, d, J8.5Hz), 7.00 (1H, d, J1.4Hz), 6.96 (1H, d, J2.6Hz), 6.94 (1H, d, J1.5Hz), 6.80 ( 1H, dd, J8.4 and 2.6Hz), 4.58-4.50 (1H, m), 3.80 (1H, ddd, J13.9, 9.9 and 4.4Hz), 3.56 (1H, ddd, J15.0, 9.9 and 5.5) Hz), 3.45-3.43 (1H, m), 3.21 (1H, dt, J13.6 and 4.0Hz), 3.08-2.82 (5H, m), 2.68-2.61 (1H, m), 2.18-2.05 (2H, m), 1.89-1.71 (2H, m), 1.35 (6H, t, J6.2Hz.) [1387] (Example 382) (8aS, 12aR) -2- (2-Ethyl-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1388] (Step A) (2-formyl-4-methoxyphenyl) boric acid (0.94, 169 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.47, 200 mg), Na₂CO₃(2M, 2.5mL), and DME (5mL) were combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02, 27 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. This oil was purified by column chromatography eluting with EtOAc / Hexane (1: 5) and as a yellow oil (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10. , 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (189 mg, 84%) Obtained.¹1 H NMR (CDCl₃, 300MHz): 9.97 (1H, s), 7.47 (1H, d, J2.5Hz), 7.32 (1H, d, J8.5Hz), 7.16 (1H, dd, J8.4 and 2.9Hz)), 6.95 ( 1H, m), 6.86 (1H, m), 3.92-3.82 (5H, m), 3.65-3.49 (3H, m), 3.40-3.18 (3H, m), 3.00 (2H, dt, J14.3 and 4.8) Hz), 2.17-2.05 (2H, m), 1.92-1.86 (2H, m), 1.41 (9H, s.) [1389] (Step B) N-BuLi sample (1.6 M hexane solution, 2.1 mmol, 1.4 mL) in THF (3 mL) solution of methyltriphenylphosphonium bromide (2.3 mmol, 824 mg)₂Below, added with stirring. When this was stirred for 30 minutes, it became a red solution. To this, (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] A solution of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.51 mmol, 254 mg) in THF (3 mL) was added. The orange solution was stirred overnight. The solid was filtered off and washed with EtOAc (20 mL). EtOAc to H₂Wash with O (20 mL) and DEV₄It was dried in and concentrated under vacuum. The oil was purified by column chromatography eluting with EtOAc / Hexane (1: 9) and as a yellow oil (8aS, 12aR) -2- (4-methoxy-2-vinylphenyl) -6,7,9,10, 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8a H) -tert -butyl carbonate (100 mg, 41%) Obtained.¹1 H NMR (CDCl₃, 300MHz): 7.16 (1H, d, J8.4Hz), 7.12 (1H, d, J3.0Hz), 6.93 (1H, d, J1.8Hz), 6.86-6.83 (2H, m), 6.80-6.50 ( 1H, m), 5.67 (1H, dd, J17.3 and 1.1Hz), 5.20 (1H, dd, J11.0 and 1.5Hz), 3.87-3.85 (5H, m), 3.84-3.50 (3H, m) , 3.40-2.90 (5H, m), 2.17-2.05 (2H, m), 1.92-1.86 (2H, m), 1.41 (9H, s.) [1390] (Step C) (8aS, 12aR) -2- (4-Methoxy-2-vinylphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.21 mmol, 100 mg) was dissolved in a suspension of palladium (-10% carbon, 10 mg) in ethanol (10 mL). This is H on the Parr device₂Shake overnight under (50 psi) (about 0.35 MPa). The palladium residue was removed by filtration through silica eluting with EtOAc / Hexane (1: 5) and as a yellow oil (8aS, 12aR) -2- (2-ethyl-4-methoxyphenyl) -6,7,9, 10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (44mg, 44%) Got¹1 H NMR (CDCl₃, 300MHz): 7.08 (1H, d, J8.4Hz), 6.89 (1H, d, J1.5Hz), 6.82 (1H, d, J2.6Hz), 6.80 (1H, s), 6.740 (1H, ddJ8. 4 and 2.9Hz), 3.87-3.77 (5H, m), 3.66 (1H, dt, J12.8 and 4.0Hz), 3.59-3.49 (2H, m), 3.34-3.13 (3H, m), 2.96 (2H) , dt, J14.3 and 4.4Hz), 2.58 (2H, q, J7.7Hz), 2.18-2.05 (2H, m), 1.90-1.88 (2H, m), 1.42 (9H, s), 1.12 (3H) , t, J7.3Hz.) ppm. [1391] (Step D) (8aS, 12aR) -2- (2-ethyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.09 mmol, 44 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (34 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.09 (1H, d, J8.5Hz), 6.87 (1H, d, J1.5Hz), 6.81 (1H, d, J2.6Hz), 6.75-6.71 (2H, m), 3.82 (3H, s), 3.77 (1H, ddd, J14.2, 10.2 and 5.5Hz), 3.56 (1H, ddd, J14.6, 9.9 and 5.5Hz), 3.43-3.41 (1H, m), 3.20 (1H, dt, J13.5 and 3.7Hz), 3.08-2.81 (5H, m), 2.67-2.54 (3H, m), 2.20-2.02 (2H, m), 1.91-1.71 (2H, m), and 1.12 (3H, t) , J7.7Hz) ppm; m / z (ES) 381.2 (M + H)⁺.. [1392] (Example 383) 2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2,3,4- hi] indole-2-yl] -5-methoxybenzaldehyde [1393] (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.06 mmol, 30 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄It was dried in and concentrated under vacuum to give the desired product (24 mg, 100%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 9.97 (1H, s), 7.46 (1H, d, J2.6Hz), 7.33 (1H, d, J8.4Hz), 7.15 (1H, dd, J8.4 and 2.5Hz), 6.94 (1H) , dJ1.5Hz), 6.80 (1H, d, J1.4Hz), 3.88 (3H, s), 3.82 (1H, ddd, J14.2, 10.2 and 5.5Hz), 3.57 (1H, ddd, J14.6, 9.9 and 5.5Hz), 3.46-3.43 (1H, m), 3.24 (1H, dt, J13.5 and 3.7Hz), 3.11-2.81 (5H, m), 2.69-2.60 (1H, m), 2.20-2.05 (2H, m), 1.91-1.73 (2H, m.) [1394] (Example 384) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole-2-yl] -5-methoxyphenyl} ethanol [1395] (Step A) (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.42 mmol, 200 mg) in THF (10 mL) with methylmagnesium bromide (3.0 M ether solution, 1.26 mmol, 0.42 mL) N₂Add below with stirring at 0 ° C. The solution is stirred at room temperature for 2 hours, followed by saturated NH₄Quenched with Cl (10 mL). The reaction was extracted with EtOAc (40 mL) and Na₂SO₄Dry in and concentrate under vacuum as a yellow oil (8aS, 12aR) -2-2- [2- (1-hydroxyethyl) -4-methoxyphenyl) -6,7,9,10,12 , 12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (192.0 mg, 92%) It was.¹1 H NMR (CDCl₃, 300MHz): 7.17 (1H, d, J1.8Hz), 7.09 (1H, d, J8.5Hz), 6.87-6.79 (3H, m), 5.02-4.98 (1H, m), 3.88-3.64 (5H, m), 3.59-3.40 (3H, m), 3.36-3.13 (3H, m), 3.02-2.93 (2H, m), 2.12-2.08 (2H, m), 1.88-1.80 (2H, m), 1.73- 1.50 (3H, m), 1.43 (9H, s); m / z (ES) 497.1 (M + H)⁺.. [1396] (Step B) (8aS, 12aR) -2-2- [2- (1-Hydroxyethyl) -4-methoxyphenyl] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.39 mmol, 192 mg)₂Cl₂TFA (8 mL) was added to the (40 mL) solution under a nitrogen atmosphere at room temperature with stirring. Stir the solution at room temperature for 1 hour, CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (76 mg, 50%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.17 (1H, d, J2.2Hz), 7.10 (1H, d, J8.5Hz), 6.85 (1H, s), 6.81 (1H, dd, J8.4 and 2.6Hz), 6.74 (1H) , S), 5.00-4.95 (1H, m), 3.85-3.74 (5H, m), 3.57-3.52 (1H, m), 3.42-3.38 (1H, m), 3.20-2.90 (6H, m), 2.66 -2.56 (1H, m), 2.24-2.01 (4H, m), 1.93-1.81 (2H, m); m / z (ES) 397.1 (M + H)⁺.. [1397] (Example 385) (8aS, 12aR) -2- [4-Methoxy-2- (1-methoxyethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3- b] [1,4] Chiazepino [2,3,4-hi] Indole [1398] (Step A) NaH (60% in mineral oil, 0.76 mmol, 30 mg) was dissolved in THF (3 mL) at room temperature under nitrogen. In this suspension, (8aS, 12aR) -2-2- [2- (1-hydroxyethyl) -4-methoxyphenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [ A solution of tert-butyl carbonate (0.19 mmol, 93 mg) in THF (4 mL) of 4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -butyl carbonate was added through a cannula. .. This was stirred at room temperature for 30 minutes. Finally, MeI (0.95 mmol, 60 μl) was added to the solution and stirred overnight. Then saturate the reactant NH₄Quench with Cl (10 mL), extract with EtOAc (50 mL), Na₂SO₄It was dried in and concentrated under vacuum. The oil was subjected to column chromatography eluting with EtOAc / Hexane (1: 3) as a yellow oil (8aS, 12aR) -2- [4-methoxy-2- (1-methoxyethyl) phenyl] -6,7,9. , 10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (80mg, 83%) ) Was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.10-7.08 (2H, m), 6.85-6.81 (2H, m), 6.75 (1H, s), 4.46-4.40 (1H, m), 3.88-3.80 (5H, m), 3.70-3.62 (1H, m), 3.60-3.54 (2H, m), 3.36-3.14 (6H, m), 3.01-2.96 (2H, m), 2.17-2.06 (2H, m), 1.921.91 (2H, m) , 1.45 (9H, s), and 1.35 (3H, d, J6.3Hz.) [1399] (Step B) (8aS, 12aR) -2- [4-Methoxy-2- (1-methoxyethyl) phenyl] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.16 mmol, 80 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (17 mg, 26%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.03-6.97 (2H, m), 6.76-6.72 (2H, m), 6.63-6.62 (1H, m), 4.36-4.33 (1H, m), 3.79-3.68 (4H, m), 3.51 (1H, ddd, J15.0, 9.9 and 5.1Hz), 3.37-3.35 (1H, m), 3.12 (1H, dt, J13.6 and 4.0Hz), 3.06 (3H, d, J4.4), 2.99 -2.80 (4H, m), 2.58-2.51 (1H, m), 2.10-1.97 (2H, m), 1.86-1.80 (3H, m), 1.8 (3H, dd, J6.6 and 4.8); m / z (ES) 411.1 (M + H)⁺.. [1400] (Example 386) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole-2-yl] -5-Methoxyphenyl} Etanone [1401] (Step A) CH of oxalyl chloride (4.2 mmol, 366.0 μl)₂Cl₂CH of DMSO (8.4 mmol, 596 μl) in solution (10 mL) at -78 ° C under nitrogen₂Cl₂The (5 mL) solution was added through the cannula. Then (8aS, 12aR) -2-2- [2- (1-hydroxyethyl) -4-methoxyphenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (2.10 mmol, 1.04 g)₂Cl₂A (10 mL) solution was added to this solution through a cannula and stirred for 30 minutes. Finally, NEt₃(16.8 mmol, 2.25 mL) was added, and the solution was allowed to warm to room temperature with stirring for 2 hours. CH reactant₂Cl₂Dilute with 30 mL and saturate NH₄Quench with Cl (15 mL), H₂Washed with O (2 x 40 mL). Organic layer, DDL₄It was dried in and concentrated under vacuum. The oil was purified by column chromatography eluting with EtOAc / Hexane (1: 4) and as a yellow oil (8aS, 12aR) -2- (2-acetyl-4-methoxyphenyl) -6,7,9,10, Obtained 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (685 mg, 66%) It was.¹1 H NMR (CDCl₃, 300MHz): 7.23 (1H, s), 7.02-6.93 (3H, m), 6.78 (1H, s), 3.89-3.79 (5H, m), 3.66-3.49 (3H, m), 3.34-3.29 (3H) , M), 3.20-2.99 (2H, m), 2.13-2.04 (5H, m), 1.89-1.85 (2H, m), 1.42 (9H, s.) [1402] (Step B) (8aS, 12aR) -2- (2-Acetyl-4-methoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (1.39 mmol, 685 mg)₂Cl₂TFA (8 mL) was added to the (40 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (40 mL), wash with NaOH (1N, 2 x 35 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (54 mg, 100%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.18-7.15 (1H, m), 6.92-6.89 (2H, m), 6.85 (1H, d, J1.9Hz), 6.62 (1H, dJ1.8Hz), 6.76-3.66 (4H, m) , 3.46 (1H, ddd, J15.0, 9.9 and 5.5Hz), 3.35-3.30 (1H, m), 3.10 (1H, dt, J13.6 and 3.7Hz), 2.99-2.77 (5H, m), 2.52 -2.43 (1H, m), 2.09-1.94 (5H, m), 1.82-1.64 (2H, m); m / z (ES) 395.1 (M + H)⁺.. [1403] (Example 387) (8aS, 12aR) -2- (2-Hydroxymethyl-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [1404] (Step A) (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.42 mmol, 200 mg) N₂Lower CH₂Cl₂It was dissolved in (4 mL) and then cooled to 0 ° C. DIBAL the solution (1.0 M CH₂Cl₂The solution was treated with 0.63 mmol, 0.63 mL) and then stirred for 1 hour. Quench the reaction with MeOH (1 mL) and CH₂Cl₂It was diluted with (20 mL) and then vigorously stirred with Rochelle salt (15 mL) for 1 hour. CH the water layer₂Cl₂Extract twice with (20 mL), then pool the organic layer and Na₂SO₄It was dried in. The liquid is concentrated under vacuum as a yellow oil (8aS, 12aR) -2- [2- (hydroxymethyl) -4-methoxyphenyl] -6,7,9,10,12,12a-hexahydro-5H- Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (204 mg, 100%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.17 (1H, d, J8.5Hz), 7.07 (1H, s), 6.93-6.91 (2H, m), 6.84 (1H, dd, J8.5 and 2.5Hz), 4.60-4.40 (2H) , m), 3.84 (3H, s), 3.79-3.04 (9H, m), 2.11-2.05 (2H, m), 1.91-1.48 (3H, m), 1.43 (9H, s.) [1405] (Step B) (8aS, 12aR) -2- [2- (Hydroxymethyl) -4-methoxyphenyl] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4 ] Chiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.42 mmol, 204 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (108 mg, 67%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.16 (1H, d, J8.4Hz), 7.11 (1H, d, J2.5Hz), 6.91 (1H, d, J1.1Hz), 6.86-6.81 (2H, m), 4.60 (2H, s), 3.85-3.74 (4H, m), 3.55 (1H, ddd, J14.6, 9.9 and 5.5Hz), 3.40-3.38 (1H, m), 3.19 (1H, dt, J13.2 and 4.4Hz) , 3.09-2.82 (6H, m), 2.20-2.02 (2H, m), 1.93-1.80 (2H, m); m / z (ES) 383.1 (M + H)⁺.. [1406] (Example 388) (8aS, 12aR) -2- [4-Methoxy-2- (methoxymethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1407] (Step A) NaH (60% in mineral oil, 0.76 mmol, 30 mg) was dissolved in THF (3 mL) under nitrogen at room temperature. In this suspension, (8aS, 12aR) -2- [2- (hydroxymethyl) -4-methoxyphenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.20 mmol, 98 mg) in THF (4 mL) was added through a cannula. This was stirred at room temperature for 30 minutes. Finally, MeI (1.0 mmol, 60 μl) was added to the solution and stirred overnight. Then NH₄Quench with Cl (10 mL), extract with EtOAc (50 mL), Na₂SO₄It was dried in and concentrated under vacuum. The oil was subjected to column chromatography eluting with EtOAc / Hexane (1: 4) as a yellow oil (8aS, 12aR) -2- [4-methoxy-2- (methoxymethyl) phenyl] -6,7,9,10. , 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (70 mg, 71%) Obtained.¹1 H NMR (CDCl₃, 300MHz): 7.16 (1H, d, J8.4Hz), 7.05 (1H, d, J3.0Hz), 6.95 (1H, d, J1.5Hz), 6.88-6.83 (2H, m), 4.32 (2H, s), 3.89-3.79 (5H, m), 3.71-3.12 (10H, m), 2.96 (1H, dt, J14.7 and 5.5), 2.14-2.05 (2H, m), 1.90-1.89 (2H, m) ), And 1.43 (9H, s); m / z (ES) 497.1 (M + H)⁺.. [1408] (Step B) (8aS, 12aR) -2- [4-Methoxy-2- (methoxymethyl) phenyl] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4 ] Chiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.14 mmol, 70 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (52 mg, 94%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.17 (1H, d, J8.8Hz), 7.04 (1H, d, J2.6Hz), 6.93 (1H, d, J1.8Hz), 6.86-6.83 (2H, m), 4.32 (2H, s), 3.84-3.74 (4H, m), 3.57 (1H, ddd, J14.7, 9.9 and 5.5Hz), 3.45-3.41 (1H, m), 3.37 (3H, s), 3.21 (1H, dt, J13.2 and 3.7Hz), 3.09-2.82 (5H, m), 2.68-2.60 (1H, m), 2.17-2.05 (2H, m), 1.91-1.73 (2H, m); m / z (ES) 397.1 (M + H)⁺.. [1409] (Example 389) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indoru-2-yl] -5-methoxyphenyl} -1-propanol [1410] 2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indol-2-yl] -5-Methoxybenzaldehyde (0.42 mmol, 162 mg) in THF (10 mL) with ethyl magnesium bromide (1.0 M in THF, 4.2 mmol, 4.2 mL) N₂Add below with stirring at 0 ° C. The solution is stirred at room temperature for 2 hours, followed by saturated NH₄Quenched with Cl (10 mL). The reaction was extracted with EtOAc (40 mL) and Na₂SO₄It was dried in and concentrated under vacuum. The product was further purified by reverse phase HPLC to give the title compound (43 mg, 25%) as a yellow oil. m / z (ES) 411.1 (M + H)⁺.. [1411] (Example 390) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole-2-yl] -5-methoxyphenyl} -1-propanone [1412] (Step A) (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.42 mmol, 200 mg) in THF (10 mL) with ethylmagnesium bromide (1.0 M in THF, 1.26 mmol, 1.26 mL). N₂Add below with stirring at 0 ° C. The solution is stirred at room temperature for 2 hours, followed by saturated NH₄Quenched with Cl (10 mL). The reaction was extracted with EtOAc (40 mL) and Na₂SO₄Dry in, concentrated under vacuum, and subjected to column chromatography eluting with EtOAc / Hexanes (1: 4) as yellow oil (8aS, 12aR) -2-2- [2- (1-hydroxypropyl) -4. -Methoxyphenyl] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -Tert-Butyl carbonate (137.0 mg, 64%) was obtained. m / z (ES) 511.2 (M + H)⁺.. [1413] (Step B) CH of oxalyl chloride (0.43 mmol, 38.0 μl)₂Cl₂CH in DMSO (0.88 mmol, 63 μl) in solution (2 mL) at -78 ° C under nitrogen₂Cl₂The (2 mL) solution was added through the cannula. Then (8aS, 12aR) -2-2- [2- (1-hydroxypropyl) -4-methoxyphenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.22 mmol, 110 mg)₂Cl₂A (2 mL) solution was added to this solution through a cannula and stirred for 30 minutes. Finally, NEt₃(1.76 mmol, 0.251 mL) was added, and the solution was allowed to warm to room temperature with stirring for 2 hours. CH reactant₂Cl₂Dilute with 30 mL and saturate NH₄Quench with Cl (15 mL), H₂Washed with O (2 x 40 mL). EDTA the organic layer₄It was dried in and concentrated under vacuum. The oil was purified by column chromatography eluting with EtOAc / Hexanes (1: 4) and as a yellow oil (8aS, 12aR) -2- (4-methoxy-2-propionylphenyl) -6,7,9,10, Obtained 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (52 mg, 47%) It was.¹1 H NMR (CDCl₃, 300MHz): 7.2-7.24 (1H, m), 6.99 (1H, dd, J8.4 and 2.6Hz), 6.91-6.76 (3H, m), 3.88-3.80 (4H, m), 3.79-2.94 (9H) , M), 2.31 (2H, q, J7.3Hz), 2.17-2.08 (2H, m), 1.89-1.87 (2H, m), 1.42 (9H, s), and 0.96 (3H, t, J7.4Hz) .) [1414] (Step C) (8aS, 12aR) -2- (4-Methoxy-2-propionylphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.1 mmol, 52 mg)₂Cl₂TFA (8 mL) was added to the (40 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (40 mL), wash with NaOH (1N, 2 x 35 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (40 mg, 100%) as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.28-7.25 (1H, m), 6.98 (1H, d, J8.4 and 1.4Hz), 6.94-6.91 (2H, m), 6.70 (1H, dJ1.8Hz), 3.84-3.75 (4H) , M), 3.56 (1H, ddd, J14.7, 9.9 and 5.2Hz), 3.43-3.39 (1H, m), 3.19 (1H, dt, J13.5 and 3.6Hz), 3.07-2.51 (6H, m) ), 2.34-2.27 (2H, m), 2.19-2.03 (2H, m), 1.91-1.69 (2H, m), and 0.95 (3H, t, J7.0Hz.) [1415] (Example 391) (2Z) -3- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-2-yl] -5-Methoxyphenyl} -2-Methyl propeneate [1416] (Step A) 18-Crown-6 (2.1 mmol, 555 mg) and bis (2,2,2-trifluoroethyl) methoxycarbonylmethyl) -phosphonate (0.42 mmol, 134 mg) were dissolved in THF (5 mL) under a nitrogen atmosphere and- Cooled to 78 ° C. This is KN (TMS)₂Treated with (0.5 M toluene solution, 0.42 mmol, 0.84 mL). Finally, (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] A solution of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.42 mmol, 200 mg) in THF (5 mL) was added through a cannula. This was stirred at 78 ° C. for 30 minutes. Warm the reactants to room temperature and saturate NH₄It was quenched with Cl (10 mL) and then extracted with EtOAc (50 mL). Na₂SO₄It was dried in and concentrated under vacuum. The product was subjected to column chromatography eluting with EtOAc / Hexane (1: 4) and as a yellow oil (8aS, 12aR) -2- [4-methoxy-2-[(1Z) -3-methoxy-3-oxo- 1-propenyl] phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 ( 8aH) -tert-butyl carbonate (152 mg, 99%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.22 (1H, d, J8.4Hz), 7.14 (1H, s), 6.94-6.81 (4H, m), 5.92 (1H, d, J12.1Hz), 3.90-2.93 (15H, m) , 2.14-2.05 (2H, m), 1.89-1.88 (2H, m), and 1.42 (9H, s.) [1417] (Step B) (8aS, 12aR) -2- [4-Methoxy-2-[(1Z) -3-methoxy-3-oxo-1-propenyl] phenyl] -6,7,9,10,12,12a-Hexahydro-5H -CH of pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.21 mmol, 75 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (70 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.23 (1H, d, J8.8Hz), 7.14 (1H, d, J2.2Hz), 6.92-6.80 (4H, m), 5.91 (1H, d, J12.4Hz), 3.88-3.70 ( 7H, m), 3.56 (1H, ddd, J14.7, 9.9 and 5.5Hz), 3.25-3.19 (2H, m), 3.08-2.57 (6H, m), 2.18-2.08 (2H, m), 1.90- 1.72 (2H, m.) [1418] (Example 392) Methyl 3- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indoru-2-yl] -5-methoxyphenyl} [1419] (Step A) (8aS, 12aR) -2- [4-Methoxy-2-[(1Z) -3-methoxy-3-oxo-1-propenyl] phenyl] -6,7,9,10,12,12a-Hexahydro-5H -Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.1 mmol, 55 mg) and Wilkinson's catalyst (0.011 mmol, 10 mg) To a solution of benzene (3 mL) was added triethylsilane (0.64 mmol, 0.1 mL) under a nitrogen atmosphere at room temperature with stirring. This was stirred at room temperature for 15 hours and concentrated under vacuum. The product was subjected to column chromatography eluting with EtOAc / Hexane (1: 4) and as a yellow oil (8aS, 12aR) -2- [4-methoxy-2- (3-methoxy-3-oxopropyl) phenyl]-. 6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (25 mg, 46%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.09 (1H, d, J8.1Hz), 6.86 (1H, d, J1.9Hz), 6.78-6.74 (3H, m), 3.88-2.88 (18H, m), 2.47 (2H, t, J7.7Hz), 2.15-2.05 (2H, m), 1.90-1.88 (2H, m), and 1.43 (9H, s); m / z (ES) 539.1 (M + H)⁺.. [1420] (Step B) (8aS, 12aR) -2- [4-Methoxy-2- (3-Methoxy-3-oxopropyl) phenyl] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.05 mmol, 25 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (23 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.10 (1H, d, J8.1Hz), 6.85 (1H, s), 6.76 (1H, d, J8.8Hz), 3.81-3.74 (4H, m), 3.64-3.51 (4H, m) , 3.44-3.42 (1H, m), 3.24-3.20 (1H, m), 3.07-2.63 (8H, m), 2.46 (2H, t, J8.0Hz), 2.16-2.07 (2H, m), and 1.85 -1.78 (2H, m); m / z (ES) 439.4 (M + H)⁺.. [1421] (Example 393) (2Z) -3- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-2-yl] -5-methoxyphenyl} -2-propen-1-ol [1422] (Step A) (8aS, 12aR) -2- [4-Methoxy-2-[(1Z) -3-methoxy-3-oxo-1-propenyl] phenyl] -6,7,9,10,12,12a-Hexahydro-5H -CH of pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.19 mmol, 100 mg)₂Cl₂DIBAL (1.0 M CH) in (4 mL) solution₂Cl₂The solution (0.48 mmol, 0.48 mL) was added under a nitrogen atmosphere at 0 ° C. with stirring. This was stirred overnight at room temperature. The reaction is quenched with MeOH (0.5 mL) and CH₂Cl₂It was diluted with (10 mL) and then stirred with Rochelle salt (10 mL) for 1 hour. Na organic layer₂SO₄Dry in, concentrated under vacuum, and then subjected to column chromatography eluting with EtOAc / Hexanes (1: 1) as yellow oil (8aS, 12aR) -2- {2-[(1Z) -3-hydroxy- 1-Propenyl] -4-Methoxyphenyl} -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (50 mg, 52%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.21 (1H, d, J8.4Hz), 6.94 (1H, d, J1.9Hz), 6.86 (1H, d, J2.9Hz), 6.84 (1H, d, J2.5Hz), 6.76 ( 1H, d, J2.6Hz), 6.46 (1H, d, J1.7Hz), 5.82-5.78 (1H, m), 4.31-4.30 (2H, m), 3.85-2.96 (9H, m), 2.12-2.05 (2H, m), 1.87 (2H, br.s), and 1.42 (9H, s.) [1423] (Step B) (8aS, 12aR) -2- {2-[(1Z) -3-Hydroxy-1-propenyl] -4-methoxyphenyl} -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4 , 3-b] [1,4] Thiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.10 mmol, 50 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (26 mg, 65%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.22 (1H, d, J8.4Hz), 6.93-6.75 (3H, m), 6.47 (1H, d, J11.4Hz), 5.80-5.76 (1H, m), 4.30-4.27 (2H, m), 3.85-3.44 (6H, m), 3.25-2.64 (7H, m), 2.11-2.05 (2H, m), and 1.85-1.76 (2H, m); m / z (ES) 409.4 (M +) H)⁺.. [1424] (Example 394) (2E) -3- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-2-yl] -5-Methoxyphenyl} -2-Methyl propeneate [1425] (Step A) (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.42 mmol, 200 mg)₂Cl₂Methyl (triphenylphosphoranylidene) acetate (1.26 mmol, 421 mg) was added to the (5 mL) solution with stirring. This was stirred overnight at room temperature. The product is concentrated under vacuum and then subjected to column chromatography eluting with EtOAc / Hexanes (1: 3) as a yellow oil (8aS, 12aR) -2- [4-methoxy-2-[(1E) -3). -Methoxy-3-oxo-1-propenyl] phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indol-11 (8aH) -tert-butyl carbonate (187 mg, 83%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.74 (1H, d, J16.1Hz), 7.23 (1H, s), 7.14 (1H, d, J2.2Hz), 6.96 (1H, dd, J8.8Hz), 6.90 (1H, d, J1.4Hz), 6.77 (1H, s), 6.37 (1H, d, J15.7Hz), 3.91-3.77 (7H, m), 3.71-2.95 (9H, m), 2.17-2.05 (2H, m), 1.90-1.89 (2H, m), and 1.42 (9H, s.) [1426] (Step B) (8aS, 12aR) -2- [4-Methoxy-2-[(1E) -3-methoxy-3-oxo-1-propenyl] phenyl] -6,7,9,10,12,12a-Hexahydro-5H -CH of pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.04 mmol, 23 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (16 mg, 86%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.77 (1H, d, J15.8Hz), 7.27-7.25 (1H, m), 7.14 (1H, d, J2.6Hz), 6.96 (1H, dd, J8.5 and 2.6Hz), 6.90 (1H, d, J1.5Hz), 6.72 (1H, d, J1.5Hz), 6.36 (1H, d, J15.7), 3.86-3.71 (7H, m), 3.61-3.45 (2H, m), 3.28-3.23 (1H, m), 3.07-2.65 (6H, m), 2.18-2.00 (2H, m), and 1.90-1.74 (2H, m); m / z (ES) 437.1 (M + H)⁺.. [1427] (Example 395) (2E) -3- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-2-yl] -5-methoxyphenyl} -2-propen-1-ol [1428] (Step A) (8aS, 12aR) -2- [4-Methoxy-2-[(1Z) -3-methoxy-3-oxo-1-propenyl] phenyl] -6,7,9,10,12,12a-Hexahydro-5H -CH of pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.19 mmol, 100 mg)₂Cl₂DIBAL (1.0 M CH) in (4 mL) solution₂Cl₂The solution (0.48 mmol, 0.48 mL) was added at 0 ° C. under a nitrogen atmosphere with stirring. This was stirred overnight at room temperature. The reaction is quenched with MeOH (0.5 mL) and CH₂Cl₂It was diluted with (10 mL) and then stirred with Rochelle salt (10 mL) for 1 hour. Na organic layer₂SO₄Dried in, concentrated under vacuum, and then subjected to column chromatography eluting with EtOAc / Hexanes (1: 1) as yellow oil (8aS, 12aR) -2- {2-[(1e) -3-hydroxy- 1-Propenyl] -4-Methoxyphenyl} -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (74 mg, 77%) was obtained. m / z (APc) 509.1 (M + H)⁺.. [1429] (Step B) (8aS, 12aR) -2- {2-[(1e) -3-Hydroxy-1-propenyl] -4-methoxyphenyl} -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4 , 3-b] [1,4] Thiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.15 mmol, 74 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄It was dried in and concentrated under vacuum. The product was further purified by reverse phase HPLC to give the title compound (19 mg, 31%) as a yellow solid. m / z (ES) 409.1 (M + H)⁺.. [1430] (Example 396) (8aS, 12aR) -2- [4-Methoxy-2- (methoxyethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1431] (Step A) To a solution of methoxymethyltriphenylphosphonium chloride (2.1 mmol, 720 mg) in THF (3 mL) was added t-butoxypotassium (1 M solution in THF, 1.89 mmol, 1.89 mL) under a nitrogen atmosphere with stirring at 0 ° C. .. The solution was stirred at room temperature for 30 minutes. Then (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] A solution of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.42 mmol, 200 mg) in THF (3 mL) was added through a cannula and the solution was stirred overnight at room temperature. The reaction is diluted with EtOAc (30 mL) and then saturated NH₄Washed with Cl (2 x 15 mL). The product is Na₂SO₄Dry in, concentrated under vacuum, and then subjected to column chromatography eluting with EtOAc / Hexanes (1: 6) as a mixture of isomers (8aS, 12aR) -2- [4-methoxy-2-[(1E)). -2-Methoxyethenyl] phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol -11 (8aH) -tert-butyl carbonate (140 mg, 66%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.69 (0.3H, d, J2.5Hz), 7.13 (1H, t, J8.4Hz), 6.99-6.73 (3.3H, m), 6.11 (0.3H, d, J7.3Hz), 5.83 (0.7H, d, J12.8Hz), 5.23 (0.3H, d, J7.4Hz), 3.87-3.52 (16H, m), 2.15-2.06 (2H, m), 1.90-1.89 (2H, m), And 1.44 (9H, s.) [1432] (Step B) (8aS, 12aR) -2- [4-Methoxy-2- [(1E) -2-methoxyethenyl] phenyl] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3 -b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.23 mmol, 115 mg), ethanol (10 mL) of platinum (IV) oxide (10 mg) Dissolved in suspension. This is H on the Parr device₂Shake overnight under (50 psi) (about 0.35 MPa). The residue was removed by filtration through silica eluting with EtOAc. The product is further purified by HPLC as a yellow oil (8aS, 12aR) -2- [4-methoxy-2- (2-methoxyethyl) phenyl] -6,7,9,10,12,12a- Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (34 mg, 30%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.09 (1H, d, J8.5Hz), 6.88 (1H, d, J1.8Hz), 6.85 (1H, d, J2.5Hz), 6.79-6.74 (2H, m), 3.87-3.77 ( 4H, m), 3.67 (1H, dt, J13.2 and 5.2Hz), 3.58-3.45 (5H, m), 3.35-3.12 (6H, m), 2.95 (2H, dt, J14.3 and 4.8Hz) , 2.84 (2H, t, J7.7Hz), 2.17-2.05 (2H, m), 1.89-1.88 (2H, m), and 1.43 (9H, s.) [1433] (Step C) (8aS, 12aR) -2- [4-Methoxy-2- (2-methoxyethyl) phenyl] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.06 mmol, 34 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (27 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.11 (1H, d, J8.4Hz), 6.86 (1H, d, J1.8Hz), 6.94 (1H, d, J3.0Hz), 6.78-6.74 (2H, m), 3.82-3.71 ( 4H, m), 3.60-3.41 (4H, m), 3.28 (3H, s), 3.20 (1H, dt, J13.5 and 4.0Hz), 3.09-2.59 (8H, m), 2.18-2.03 (2H, m), 1.91-1.74 (2H, m.) M / z (ES) 411.1 (M + H)⁺.. [1434] (Example 397) (8aS, 12aR) -2- (2-Fluoro-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1435] (Step A) n-Butyllithium (1.6M hexane solution, 29.1 mmol, 18.2 mL) in THF (150 mL) solution of 1-bromo-2-fluoro-4-methoxybenzene (24.4 mmol, 5.0 g) under a nitrogen atmosphere, -78 Added at ° C. After stirring for 30 minutes, trimethylboric acid (95.1 mmol, 10.8 mL) was added over 20 minutes. The reaction was allowed to warm to room temperature overnight with stirring. The solution was then acidified with HCl (3M, 200 mL) and extracted with EtOAc. EtOAc was then extracted with NaOH (1N, 4 × 100 mL) and subsequently acidified with concentrated HCl to form (2-fluoro-4-methoxyphenyl) boronic acid as a white precipitate. The white precipitate (2.04 g, 49%) was filtered and dried.¹H NMR (CD)₃OD, 300MHz): 7.29 (1H, t, J8.0Hz), 6.73 (1H, dd, J8.5 and 2.2Hz), 6.62 (1H, dd, J11.4 and 2.2Hz), 3.78 (3H, s. ) [1436] (Step B) (2-Fluoro-4-methoxyphenyl) boronic acid (0.94 mmol, 160 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3 -b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.47, 200 mg), DME (15 mL) and Na₂CO₃(2M, 2.5mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02, 27 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. This oil was purified by HPLC eluting with EtOAc / Hexane (1: 4) and as a yellow oil (8aS, 12aR) -2- (2-fluoro-4-methoxyphenyl) -6,7,9,10, Obtained 12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (105 mg, 48%) It was.¹1 H NMR (CDCl₃, 300MHz): 7.29-7.26 (1H, m), 7.12 (1H, d, J1.5Hz), 7.05 (1H, d, J1.9Hz), 6.74-6.64 (2H, m), 3.88-3.77 (4H, m), 3.63-3.47 (4H, m), 3.35-3.13 (5H, m), 2.97 (2H, dt, J14.3 and 4.8Hz), 2.17-2.01 (2H, m), 1.90-1.83 (2H, m), 1.42 (9H, s.) [1437] (Step C) (8aS, 12aR) -2- (2-Fluoro-4-methoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.22 mmol, 105 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (84 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.30-7.25 (1H, m), 7.11-7.10 (1H, m), 7.02-7.01 (1H, m), 6.73-6.64 (2H, m), 3.81-3.78 (4H, m), 3.54 -3.52 (1H, m), 3.44-3.39 (1H, m), 3.24-3.10 (1H, m), 3.07-2.85 (5H, m), 2.69-2.65 (1H, m), 2.12-2.10 (2H, m), and 1.85-1.82 (2H, m); m / z (ES) 371.2 (M + H)⁺.. [1438] (Example 398) (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole 4,4-dioxide [1439] (Step A) (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -tert-butyl carbonate (2.43 mmol, 1.0 g) was dissolved in MeOH (40 mL), buffered to pH 10 and then cooled at 0 ° C. Oxone® (3.65 mmol, 2.24 g) was added thereto, and the solution was stirred at room temperature for 2 hours. The pH was observed and maintained at 10 with 1N NaOH. The product was concentrated under vacuum and dissolved in EtOAc (150 mL), H₂Wash with O (70 mL) and Na₂SO₄It was dried in and concentrated under vacuum. Oil MeOH / CH₂Cl₂Column chromatography eluting at (1:49) as a white solid (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [ 1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (181 mg, 16%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.77 (1H, s), 7.29 (1H, s), 3.84 (2H, br.s), 3.55-3.34 (8H, m), 2.29-2.21 (2H, m), 1.98-1.82 (2H) , M), and 1.40 (9H, s.) [1440] (Step B) (2,4-dichlorophenyl) Boronic acid (0.88 mmol, 168 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.44, 200 mg), barium hydroxide (0.66 mmol, 208 mg), DME (15 mL) ) And H₂O (5 mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02, 25 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. This oil was subjected to column chromatography eluting with EtOAc / Hexane (1: 3) and as a yellow oil (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a- Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate 4,4-dioxide (90 mg, 40%) Obtained.¹1 H NMR (CDCl₃, 300MHz): 7.72 (1H, d, J1.9Hz), 7.47 (1H, d, J1.9), 7.33 (1H, d, J1.1Hz), 7.31-7.22 (2H, m), 3.86-3.80 ( 1H, m), 3.67-3.34 (9H, m), 2.35-2.26 (2H, m), 2.05-1.91 (2H, m), and 1.39 (9H, s.) [1441] (Step C) (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] CH of indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.17 mmol, 90 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (12 mg, 17%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.71 (1H, d, J1.9Hz), 7.47 (1H, d, J1.5Hz), 7.30-7.27 (3H, m), 3.74-3.69 (1H, m), 3.57-3.43 (4H, m), 3.26 (1H, q, J6.6Hz), 3.08 (1H, dd, 12.8 and 6.2Hz), 2.92-2.87 (2H, m), 2.69 (1H, dd, J12.8 and 10.0Hz), 2.38 -2.17 (2H, m), 1.96-1.86 (1H, m), and 1.71 (1H, s); m / z (ES) 423.0 (M + H)⁺.. [1442] (Example 399) (8aS, 12aR) -2- (2,6-difluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] indole 4,4-dioxide [1443] (2,6-difluorophenyl) baronic acid (0.88 mmol, 139 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b ] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.44, 200 mg), barium hydroxide (0.66 mmol, 208 mg), DME ( 15 mL) and H₂O (5 mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02, 25 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography eluting with EtOAc / Hexanes (1: 3) to give the desired adduct as a yellow oil. CH₂Cl₂The oil was immediately deprotected by dissolving the product in (10 mL) and treating with TFA (2 mL). Stir this for 2 hours, followed by CH₂Cl₂Dilute with (40 mL), wash with NaOH (1N, 2 x 20 mL) and Na₂SO₄To dry and concentrate under vacuum to give the desired product (4 mg, 2%).¹H NMR (CD)₃OD, 300MHz): 7.63 (1H, s), 7.37-7.32 (2H, m), 7.04 (2H, t, J8.0Hz), 3.70-3.67 (1H, m), 3.58-3.25 (5H, m), 3.02 (1H, dd, J12.8 and 6.6Hz), 2.88-2.83 (2H, m), 2.52 (1H, dd, J13.2 and 9.9Hz), 2.28-2.18 (2H, m), and 2.09-1.89 (2H, m); m / z (ES) 391.2 (M + H)⁺.. [1444] (Example 400) (8aS, 12aR) -2- (2-chlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indole 4,4-dioxide [1445] (Step A) (2-Chlorophenyl) Boronic Acid (0.88 mmol, 138 mg), (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1 , 4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.44, 200 mg), barium hydroxide (0.66 mmol, 208 mg), DME (15 mL) and H₂O (5 mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02, 25 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. This oil was purified by column chromatography eluting with EtOAc / Hexane (1: 3) and as a yellow oil (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,9,10,12, 12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate 4,4-dioxide (80 mg, 37%) ) Was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.75 (1H, d, J1.5Hz), 7.46-7.43 (1H, m), 7.38 (1H, d, J1.1Hz), 7.33-7.24 (3H, m), 3.86-3.85 (1H, m), 3.59-3.39 (9H, m), 2.33-2.29 (2H, m), 2.01-1.93 (2H, m), and 1.39 (9H, s.) [1446] (Step B) (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] CH of indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.16 mmol, 80 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (35 mg, 56%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.75 (1H, d, J1.5Hz), 7.44 (1H, dd, J6.9 and 1.4Hz), 7.41-7.22 (4H, m), 3.73-3.68 (1H, m), 3.59-3.40 (4H, m), 3.25 (1H, q, J2.9Hz), 3.08 (1H, dd, 12.8 and 6.2Hz), 2.96-2.82 (2H, m), 2.69 (1H, dd, J12.5 and 9.8Hz) ), 2.37-2.26 (2H, m), and 1.91-1.86 (2H, m.) [1447] (Example 401) (8aS, 12aR) -2- (2-Fluoro-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indole 4,4-dioxide [1448] (Step A) (2-Fluoro-4-methoxyphenyl) boric acid (0.88 mmol, 150 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3 -b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.44, 200 mg), barium hydroxide (0.66 mmol, 208 mg), DME (15 mL) and H₂O (5 mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02, 25 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. This oil was purified by column chromatography eluting with EtOAc / Hexane (1: 3) and as a yellow oil (8aS, 12aR) -2- (2-fluoro-4-methoxyphenyl) -6,7,9,10. , 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate 4,4-dioxide (70mg) , 33%).¹1 H NMR (CDCl₃, 300MHz): 7.80 (1H, d, J1.1Hz), 7.41 (1H, s), 7.33-7.25 (1H, m), 6.76-6.67 (2H, m), 3.83 (3H, s), 3.59-3.37 (9H, m), 2.34-2.28 (2H, m), 1.94-1.93 (2H, m), 1.67 (1H, s), and 1.39 (9H, br.s.) [1449] (Step B) (8aS, 12aR) -2- (2-Fluoro-4-methoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.14 mmol, 70 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (5 mg, 8%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.80 (1H, d, J1.4Hz), 7.40-7.25 (1H, m), 6.80-6.66 (3H, m), 3.83 (3H, s), 3.70-3.65 (1H, m), 3.56 -3.41 (4H, m), 3.29-3.21 (1H, m), 3.08 (1H, dd, 12.8 and 6.2Hz), 2.92-2.86 (2H, m), 2.76-2.65 (1H, m), 2.33-2.27 (2H, m), and 1.90-1.85 (2H, m.) [1450] (Example 402) (8aS, 12aR) -2- (2-Methyl-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indole 4,4-dioxide [1451] (Step A) (2-Methyl-4-methoxyphenyl) Boronic Acid (0.80 mmol, 128 mg), (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3 -b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.40, 181 mg), barium hydroxide (0.60 mmol, 189 mg), DME (10 mL) and H₂O (3.5 mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02, 23 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. This oil was purified by column chromatography eluting with EtOAc / Hexane (1: 3) and as a yellow oil (8aS, 12aR) -2- (2-methyl-4-methoxyphenyl) -6,7,9,10. , 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate 4,4-dioxide (159mg) , 80%).¹1 H NMR (CDCl₃, 300MHz): 7.62 (1H, d, J1.5Hz), 7.18 (1H, s), 7.11 (1H, d, J8.0Hz), 6.85-6.74 (2H, m), 3.82 (3H, s), 3.76 -3.37 (10H, m), 2.32-2.17 (5H, m), 2.05-1.95 (2H, m), and 1.40 (9H, br.s.) [1452] (Step B) (8aS, 12aR) -2- (2-Methyl-4-methoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate 4,4-dioxide (0.32 mmol, 159 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (139 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.62 (1H, d, J1.8Hz), 7.13-7.10 (2H, m), 6.79-6.74 (2H, m), 3.82 (3H, s), 3.69-3.38 (5H, m), 3.25 -3.18 (1H, m), 3.06 (1H, dd, 12.8 and 6.2Hz), 2.91-2.84 (2H, m), 2.64 (1H, dd, J12.8 and 9.5Hz), 2.34-2.26 (5H, m) ), And 1.91-1.85 (2H, m); m / z (ES) 399.1 (M + H)⁺.. [1453] (Example 403) (8aS, 12aR) -2- (2-Chloro-4-fluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1454] (Step A) n-Butyllithium (1.6 M hexane solution, 23.5 mmol, 14.7 mL) in THF (120 mL) solution of 2-chloro-4-fluoro-1-iodobenzene (19.6 mmol, 5.0 g) under a nitrogen atmosphere, -78 Added at ° C. After stirring for 30 minutes, trimethylboric acid (76.6 mmol, 8.7 mL) was added over 20 minutes. The reaction was allowed to warm to room temperature overnight with stirring. The solution was then acidified with HCl (3M, 200 mL) and extracted with EtOAc. EtOAc was then extracted with NaOH (1N, 4 × 100 mL) and subsequently acidified with concentrated HCl to form (2-chloro-4-fluorophenyl) boronic acid as a white precipitate. The white precipitate (1.10 g, 33%) was filtered and dried.¹1 H NMR (CDCl₃, 300MHz): 7.96 (1H, t, J8.1Hz), 7.11 (1H, dd, J8.8 and 2.5Hz), 7.04 (1H, td, J8.4 and 2.5Hz), 5.28 (2H, s.) [1455] (Step B) (2-Chloro-4-fluorophenyl) boric acid (0.94 mmol, 163 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3 -b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.47 mmol, 200 mg), barium hydroxide (0.71 mmol, 222 mg), DME (15 mL) And H₂O (5 mL) was combined and degassed with nitrogen for 20 minutes. Then Pd (PPh)₃)₄(0.02 mmol, 27 mg) was added to the stirred solution. The solution was refluxed and stirred overnight. Remove DME under vacuum, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried in and concentrated under vacuum to give a yellow oil. This oil was purified by column chromatography eluting with EtOAc / Hexane (1: 9) and as a yellow oil (8aS, 12aR) -2- (2-chloro-4-fluorophenyl) -6,7,9,10. , 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (150mg, 67%) Obtained.¹1 H NMR (CDCl₃, 300MHz): 7.33-7.23 (2H, m), 7.17 (1H, dd, J8.8 and 1.8Hz), 7.01-6.91 (2H, m), 3.91-2.97 (10H, m), 2.17-2.05 (2H) , M), 1.89-1.87 (2H, m), 1.42 (9H, m.) [1456] (Step C) (8aS, 12aR) -2- (2-Chloro-4-fluorophenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.32 mmol, 150 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (121 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.29-7.24 (1H, m), 7.17 (1H, dd, J8.8 and 3.0Hz), 7.01-6.95 (2H, m), 6.91 (1H, d, J1.4Hz), 3.81 (1H) , ddd, J13.9, 9.9 and 4.4Hz), 3.56 (1H, ddd, J15.0, 9.9 and 5.5Hz), 3.47-3.43 (1H, m), 3.22 (1H, dt, J13.6 and 4.1Hz) ), 3.11-2.82 (5H, m), 2.70-2.61 (1H, m), 2.18-2.05 (2H, m), 1.90-1.73 (2H, m.) [1457] (Example 404) (8aS, 12aR) -2- (2-Chloro-4-fluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole 4-oxide [1458] (Step A) (8aS, 12aR) -2- (2-Chloro-4-fluorophenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.21 mmol, 105 mg) in acetone (5 mL) and H₂NaIO in O (1 mL) solution₄(2.1 mmol, 449 mg) was added with stirring. This was stirred at room temperature overnight. The product was concentrated under vacuum and dissolved in EtOAc (30 mL), LVDS.₃Wash with (20 mL) and Na₂SO₄It was dried in and concentrated under vacuum. The product was subjected to column chromatography eluting with EtOAc and as a yellow oil (8aS, 12aR) -2- (2-chloro-4-fluorophenyl) -6,7,9,10,12,12a-hexahydro-5H- Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate 4-oxide (50 mg, 49%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.46 (1H, d, J1.4Hz), 7.29-7.24 (2H, m), 7.20 (1H, dd, J8.4 and 2.5Hz), 7.02 (1H, td, J11.3 and 2.9Hz) ), 3.88-3.18 (9H, m), 3.05-2.85 (1H, m), 2.60-2.32 (2H, m), 2.03-2.01 (1H, m), 1.73 (1H, s), and 1.37 (9H, br.s); m / z (ES) 491.2 (M + H)⁺.. [1459] (Step B) (8aS, 12aR) -2- (2-Chloro-4-fluorophenyl) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate 4-oxide (0.10 mmol, 50 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (39 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.47 (1H, d, J1.9Hz), 7.30-7.18 (3H, m), 7.01 (1H, td, J8.4 and 1.4Hz), 3.61-2.05 (10H, m), 2.01-1.88 (4H, m); m / z (ES) 391.1 (M + H)⁺.. [1460] (Example 405) (8aS, 12aR) -2-[(E) -2- (2-chlorophenyl) ethenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1461] (Step A) Pd (OAc)₂MeCN (2 mL) solution of (0.056 mmol, 10 mg) and tri-o-tolylphosphine (0.056 mmol, 30 mg), (8aS, 12aR) -2-vinyl-6,7,9,10,12,12a-hexahydro -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (0.49 mmol, 183 mg), 1-bromo-2- It was added to a solution of chloro-benzene (2.5 mmol, 0.3 mL) and triethylamine (4.9 mmol, 0.56 mL) in MeCN (10 mL) under a nitrogen atmosphere at room temperature with stirring. The mixture was stirred and heated to reflux overnight. The solution is concentrated under vacuum and purified by column chromatography and normal phase HPLC eluting with EtOAc / Hexanes (1: 9) to (8aS, 12aR) -2-[(E) -2- (2-chlorophenyl) ethenyl. ] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert carbonate -Butyl (64 mg, 27%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.62 (1H, dd, J7.7 and 1.5Hz), 7.36 (1H, dd, J7.7 and 1.1Hz), 7.31-7.12 (5H, m), 6.91 (1H, d, J16.1Hz) ), 3.90-3.70 (2H, m), 3.54-3.15 (6H, m), 2.99 (2H, dt, J14.3 and 4.8Hz), 2.15-2.03 (2H, m), 1.88-1.86 (2H, m) ), 1.44 (9H, s) [1462] (Step B) (8aS, 12aR) -2-[(E) -2- (2-chlorophenyl) ethenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1, 4] CH of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.09 mmol, 42 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (33 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.62 (1H, dd, J7.6 and 1.4Hz), 7.36 (1H, dd, J7.7 and 1.1Hz), 7.31-7.09 (5H, m), 6.91 (1H, d, J16.1Hz) ), 3.77 (1H, ddd, J13.9, 9.9 and 4.4Hz), 3.56-3.41 (2H, m), 3.24 (1H, dt, J13.2 and 4.0Hz), 3.11-2.61 (5H, m), 2.17-2.03 (2H, m), 1.88-1.76 (3H, m); m / z (ES) 383.1 (M + H)⁺.. [1463] (Example 406) (8aS, 12aR) -2-[(E) -2- (3-chlorophenyl) ethenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] Chiazepino [2,3,4-hi] Indole [1464] (Step A) Pd (OAc)₂MeCN (2 mL) solution of (0.056 mmol, 10 mg) and tri-o-tolylphosphine (0.056 mmol, 30 mg), (8aS, 12aR) -2-vinyl-6,7,9,10,12,12a-hexahydro -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (0.56 mmol, 209 mg), 1-bromo-3- It was added to a solution of chloro-benzene (2.8 mmol, 0.34 mL) and triethylamine (5.6 mmol, 0.64 mL) in MeCN (10 mL) under a nitrogen atmosphere at room temperature with stirring. The mixture was stirred and heated to reflux overnight. The solution is concentrated under vacuum and purified by column chromatography eluting with EtOAc / Hexanes (1: 4) and normal phase HPLC as a yellow oil (8aS, 12aR) -2-[(E) -2- (3). -Chlorophenyl) ethenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) )-Tert-Butyl carbonate (169 mg, 63%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.42 (1H, d, J1.4Hz), 7.32-7.15 (3H, m), 7.10 (1H, d, J1.5Hz), 7.07 (1H, d, J1.5Hz), 6.93-6.78 ( 2H, m), 3.88-3.78 (2H, m), 3.62-3.13 (6H, m), 2.98 (2H, dt, J14.2 and 5.1Hz), 2.14-2.03 (2H, m), 1.87-1.86 ( 2H, m), 1.44 (9H, s.) [1465] (Step B) (8aS, 12aR) -2-[(E) -2- (3-chlorophenyl) ethenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1, 4] CH of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.23 mmol, 111 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (80 mg, 93%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.43 (1H, s), 7.31-7.14 (3H, m), 7.10 (1H, d, J1.4Hz), 7.04 (1H, d, J1.4Hz), 6.94 (1H, dJ16.5Hz) , 6.81 (1H, d, J16.1Hz), 3.76 (1H, ddd, J14.0, 9.6 and 4.8Hz), 3.55-3.40 (2H, m), 3.24 (1H, dt, J13.5 and 4.4Hz) , 3.09-2.61 (5H, m), 2.18-2.00 (2H, m), 1.87-1.70 (3H, m); m / z (ES) 383.1 (M + H)⁺.. [1466] (Example 407) (8aS, 12aR) -2-[(E) -2- (2,6-difluorophenyl) ethenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4, 3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1467] (Step A) Pd (OAc)₂A solution of (0.046 mmol, 8.5 mg) and tri-o-tolylphosphine (0.046 mmol, 24 mg) in MeCN (2 mL) to (8aS, 12aR) -2-vinyl-6,7,9,10,12,12a- Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.46 mmol, 170 mg), 2-bromo-1 , 3-Difluorobenzene (2.3 mmol, 0.29 mL) and triethylamine (4.6 mmol, 0.56 mL) were added to a solution of MeCN (10 mL) under a nitrogen atmosphere at room temperature with stirring. The mixture was stirred and heated to reflux overnight. The solution is concentrated under vacuum and purified by column chromatography and normal phase HPLC eluting with EtOAc / Hexanes (1: 4) to (8aS, 12aR) -2-[(E) -2- (2,6-difluoro). Phenyl) ethenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -Tert-Butyl carbonate (100 mg, 45%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.72-6.61 (7H, m), 3.86-3.84 (1H, m), 3.54-2.10 (9H, m), 2.09-1.88 (2H, m), 1.86-1.80 (2H, m), 1.44 (9H, s.) [1468] (Step B) (8aS, 12aR) -2-[(E) -2- (2,6-difluorophenyl) ethenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] CH of indole-11 (8aH) -tert-butyl carbonate (0.21 mmol, 100 mg)₂Cl₂TFA (2 mL) was added to the (10 mL) solution under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature overnight and CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄And concentrated under vacuum to give the title compound (3.6 mg, 3%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.30-7.20 (2H, m), 7.136.85 (5H, m), 3.86-3.78 (1H, m), 3.51-3.42 (2H, m), 3.26-2.65 (6H, m), 2.12 -1.79 (4H, m), and 1.62 (1H, s); m / z (ES) 385.2 (M + H)⁺.. [1469] (Example 410) (8aS, 12aR) -2-cyclohexyl-6,7,8a,9,10,11,12,12a-octahydro-5H-pyridole [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indole [1470] (Step A) (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole -11 (8aH) -tert-butyl carbonate (200 mg, 0.47 mmol), PdCl₂Cyclohexyl zinc bromide (0.5 M THF solution, 0.71 mmol, 1.4 mL) in an anhydrous THF (5 mL) mixture of (dppf) (19 mg, 0.024 mmol) and CuI (10 mg, 0.052 mmol) at room temperature in a nitrogen atmosphere. Added with stirring. The mixture was stirred, heated at 45 ° C. for 5 minutes, cooled to room temperature, stirred at room temperature for 2 hours, then stirred and heated to reflux overnight. The mixture is cooled to room temperature, quenched with 1N HCl (10 mL), extracted with EtOAc (20 mL) and benzyl.₄It was dried in and concentrated under vacuum. The residue was purified by column chromatography eluting with EtOAc / Hexane (1: 4) and as a colorless oil (8aS, 12aR) -2-cyclohexyl-6,7,9,10,12,12a-hexahydro-5H-pyrido. [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (45 mg, 22%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 6.81 (1H, d, J1.5Hz), 6.74 (1H, s), 3.80-3.60 (2H, m), 3.55-3.05 (6H, m), 2.96-2.90 (2H, m), 2.38 -2.28 (1H, m), 2.16-2.00 (2H, m), 1.86-1.64 (7H, m), 1.45 (9H, s), 1.37-1.24 (5H, m); 13CNMR (CDCl)₃, 75.4MHz) 154.8,150.2,140.0,132.2,127.2,120.3,119.1,79.4,64.5,48.0,43.8,41.0,34.7,34.6,32.0,30.9,28.4,26.9 and 26.2; m / z (ES) 429.1 ( M + H)⁺.. [1471] (Step B) (8aS, 12aR) -2-cyclohexyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole TFA (2 mL) was added to a solution of tert-butyl carbonate (45 mg, 0.105 mmol) in DCM (10 mL) under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature for 3 hours, washed with NaOH (1N, 2 x 25 mL) and Na.₂SO₄It was dried in and concentrated under vacuum to give the desired product (34 mg, 99%) as a colorless oil.¹1 H NMR (CDCl₃, 300MHz): 6.80 (1H, d, J1.8Hz), 6.70 (1H, d, J1.5Hz), 3.70 (1H, ddd, J14.1, 10.2 and 4.1Hz), 3.51 (1H, ddd, J15. 0,10.3 and 5.1Hz), 3.56-3.31 (1H, m), 3.12 (1H, dt, J13.6 and 4.3Hz), 3.05-2.80 (4H, m), 2.63-2.53 (1H, m), 2.40 -2.25 (2H, m), 2.14-1.96 (2H, m), 1.89-1.69 (7H, m), 1.41-1.17 (5H, m); 13CNMR (CDCl)₃, 75.4MHz) 150.1,139.9,132.5,126.8,119.8,119.4,64.4,48.9,47.3,43.8,41.7,41.0,34.7,34.6,32.0,27.0,26.2 and 26.1; m / z (ES) 329.2 (M +) H)⁺.. [1472] (Example 411) (8aS, 12aR) -2-Cyclopentyl-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indole [1473] (Step A) (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole -11 (8aH) -tert-butyl carbonate (170 mg, 0.40 mmol), PdCl₂Cyclopentyl zinc bromide (0.5 M THF solution, 2.0 mmol, 4.0 mL) in an anhydrous THF (5 mL) mixture of (dppf) (33 mg, 0.040 mmol) and CuI (17 mg, 0.088 mmol) at room temperature in a nitrogen atmosphere. Added with stirring. The mixture was stirred and heated to reflux overnight. The mixture is cooled to room temperature, quenched with 1N HCl (5 mL), extracted with EtOAc (50 mL) and benzyl.₄It was dried in and concentrated under vacuum. The residue was purified by column chromatography eluting with EtOAc / Hexanes (1: 3) and (8aS, 12aR) -2-cyclopentyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3). -b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (68 mg, 41%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 6.85 (1H, d, J1.8Hz), 6.78 (1H, d, J1.1Hz), 3.78-3.58 (2H, m), 3.53-3.06 (6H, m), 2.92 (1H, dt, J14.3 and 4.8Hz), 2.85-2.79 (1H, m), 2.15-1.90 (4H, m), 1.87-1.49 (9H, m), 1.45 (9H, s); m / z (ES) 415.1 ( M + H)⁺.. [1474] (Step B) (8aS, 12aR) -2-cyclopentyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole TFA (2 mL) was added to a solution of tert-butyl carbonate (68 mg, 0.16 mmol) in DCM (10 mL) under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature for 2 hours, washed with NaOH (1N, 2 x 20 mL) and Na.₂SO₄Dryed in, concentrated under vacuum to give the desired product (54 mg, 100%).¹1 H NMR (CDCl₃, 300MHz): 6.83 (1H, d, J1.5Hz), 6.74 (1H, d, J1.4Hz), 3.70 (1H, ddd, J14.1, 10.3 and 4.1Hz), 3.52 (1H, ddd, J14. 8,10.1 and 5.0Hz), 3.36-3.32 (1H, m), 3.13 (1H, dt, J13.6 and 4.2Hz), 3.05-2.79 (5H, m), 2.58 (1H, dd, J14.5 and 11.9Hz), 2.13-1.45 (13H, m.) [1475] (Example 412) (8aS, 12aR) -2-Cyclohexylmethyl-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3, 4-hi] Indole [1476] (Step A) (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole -11 (8aH) -tert-butyl carbonate (130 mg, 0.31 mmol), PdCl₂Cyclohexylmethylzinc bromide (0.5 M THF solution, 1.84 mmol, 3.7 mL) in an anhydrous THF (5 mL) mixture of (dppf) (26 mg, 0.031 mmol) and CuI (13 mg, 0.067 mmol) at room temperature in a nitrogen atmosphere. Was added with stirring. The mixture was stirred and heated to reflux for 2 hours. The mixture is cooled to room temperature, diluted with EtOAc (20 mL), washed with 1N HCl (10 mL) and deli₄It was dried in and concentrated under vacuum. The residue was purified by column chromatography eluting with EtOAc / Hexane (1: 4) and as a colorless oil (8aS, 12aR) -2-cyclohexylmethyl-6,7,9,10,12,12a-hexahydro-5H- Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (24 mg, 18%) was obtained. m / z (ES) 443.2 (M + H)⁺.. [1477] (Step B) (8aS, 12aR) -2-Cyclohexylmethyl-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] TFA (1 mL) was added to a solution of indole-11 (8aH) -tert-butyl carbonate (24 mg, 0.054 mmol) in DCM (10 mL) under a nitrogen atmosphere at room temperature with stirring. The solution is stirred at room temperature for 2 hours, diluted with DCM (30 mL), washed with NaOH (1N, 2 x 20 mL) and Na.₂SO₄It was dried in and concentrated under vacuum to give the desired product (18 mg, 97%) as a colorless oil.¹1 H NMR (CDCl₃, 300MHz): 6.72 (1H, d, J1.5Hz), 6.62 (1H, d, J1.5Hz), 3.72-3.63 (1H, m), 3.55-3.46 (1H, m), 3.34-3.32 (1H, m), 3.17-3.12 (1H, m), 3.03-2.80 (4H, m), 2.61-2.53 (1H, m), 2.30 (2H, d, J6.9Hz), 2.18-2.01 (2H, m), 1.86-1.62 (11H, m), 1.43-1.38 (1H, m), 1.20-1.10 (2H, m); m / z (ES) 343.2 (M + H)⁺.. [1478] (Example 413) 3-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-yl] Ethyl propanoate [1479] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (170 mg, 0.40 mmol), PdCl₂4-ethoxy-4-oxopropyl zinc bromide (0.5 M in THF) with stirring a mixture of (dppf) (32 mg, 0.040 mmol) and CuI (16 mg, 0.088 mmol) in anhydrous THF (5 mL). , 2.4 mmol, 4.8 mL) was added. The mixture was stirred and heated to reflux overnight. The mixture is cooled to room temperature, quenched with aqueous HCl (1N, 10 mL), extracted to EtOAc (2 x 30 mL) and EDTA.₄It was dried on top and concentrated under reduced pressure. Purification of the residue by normal phase HPLC eluting with EtOAc / Hexanes (1: 3), (8aS, 12aR) -2- (3-ethoxy-3-oxopropyl) -6,7,9,10,12,12a -Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (60 mg, 34%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 6.80 (1H, s), 6.73 (1H, s), 4.13 (2H, q, J7.1Hz), 3.78-3.60 (3H, m), 3.52-3.42 (2H, m), 3.33-3.08 (4H, m), 2.92 (1H, dt, J14.2 and 9.5Hz), 2.78 (2H, t, J7.9), 2.53 (2H, t, J7.7Hz), 2.11-2.04 (2H, m) , 1.86-1.84 (2H, m), 1.45 (9H, s), 1.26 (3H, t, J7.2Hz.) [1480] (Step B) (8aS, 12aR) -2- (3-ethoxy-3-oxopropyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] in a nitrogen atmosphere at room temperature [1,4] Thiazepino [2,3,4-hi] TFA (1 mL) was added with stirring a solution of indole-11 (8aH) -tert-butyl carbonate (40 mg, 0.090 mmol) in DCM (10 mL). The solution is stirred at room temperature for 2 hours, diluted with DCM (30 mL), washed with NaOH (1N, 2 x 20 mL) and Na.₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (25 mg, 81%).¹1 H NMR (CDCl₃, 300MHz) 6.78 (1H, d, J1.5Hz), 6.69 (1H, d, J1.5Hz), 4.12 (2H, q, J7.2Hz), 3.68 (1H, ddd, J14.1, 9.7and4.5Hz) ), 3.50 (1H, ddd, J14.8,9.7and5.3Hz), 3.36-3.31 (1H, m), 3.18-3.12 (1H, m), 3.03-2.75 (7H, m), 2.61-2.52 (3H) , m), 2.12-2.01 (2H, m), 1.85-1.74 (2H, m), 1.24 (3H, t, J7.2Hz.) [1481] (Example 414) 4-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-yl] Ethyl butane [1482] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (140 mg, 0.33 mmol), PdCl₂4-ethoxy-4-oxobutylzinc bromide (0.5 M in THF) with stirring a mixture of (dppf) (27 mg, 0.033 mmol) and CuI (14 mg, 0.072 mmol) in anhydrous THF (5 mL). The solution, 1.64 mmol, 3.3 mL) was added. The mixture was stirred and heated to reflux overnight. Cool the mixture to room temperature and NH₄Quench with Cl aqueous solution (5 mL), extract to EtOAc (2 x 50 mL) and deli₄It was dried on top and concentrated under reduced pressure. Purification of the residue by column chromatography eluting with EtOAc / Hexanes (1: 4) shows that (8aS, 12aR) -2- (4-ethoxy-4-oxobutyl) -6,7,9,10,12,12a-hexahydro -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (125 mg, 82%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 6.78 (1H, d, J1.5Hz), 6.71 (1H, d, J1.5Hz), 4.13 (2H, q, J7.2Hz), 3.78-3.58 (2H, m), 3.54-3.40 ( 2H, m), 3.35-3.05 (5H, m), 2.97-2.87 (1H, m), 2.48 (2H, t, J7.7Hz), 2.30 (2H, t, J7.5Hz), 2.17-1.99 (2H) , m), 1.95-1.80 (4H, m), 1.45 (9H, s), 1.26 (3H, t, J7.2Hz.) [1483] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2- (4-ethoxy-4-oxobutyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [ TFA (1 mL) was added with stirring a solution of 1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (25 mg, 0.054 mmol) in DCM (10 mL). The solution is stirred at room temperature for 2 hours, diluted with DCM (20 mL), washed with NaOH (1N, 2 x 20 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the desired product (17 mg, 87%).¹1 H NMR (CDCl₃, 300MHz) 6.78 (1H, d, J1.5Hz), 6.67 (1H, d, J1.4Hz), 4.12 (2H, q, J7.1Hz), 3.71 (1H, ddd, J14.1, 10.5 and 4.0Hz ), 3.51 (1H, ddd, J14.8, 10.0 and 5.1Hz), 3.35-3.32 (1H, m), 3.16-2.66 (6H, m), 2.63-2.54 (1H, m), 2.48 (2H, t) , J7.5Hz), 2.29 (2H, t, J7.5Hz), 2.17-2.00 (2H, m), 1.92-1.79 (2H, m), 1.26 (3H, t, J7.2Hz); m / z ( ES) 361.1 (M + H)⁺.. [1484] (Example 415) 4-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-yl] Ethyl pentanate [1485] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (230 mg, 0.54 mmol), PdCl₂4-ethoxy-4-oxopentyl zinc bromide (0.5 M in THF) with stirring a mixture of (dppf) (44 mg, 0.054 mmol) and CuI (14 mg, 0.12 mmol) in anhydrous THF (5 mL). The solution, 3.2 mmol, 6.5 mL) was added. The mixture was stirred and heated to reflux overnight. Cool the mixture to room temperature and NH₄Quench with Cl aqueous solution (5 mL), extract in EtOAc (2 x 50 mL), EDTA₄It was dried on top and concentrated under reduced pressure. Purification of the residue by column chromatography eluting with EtOAc / Hexanes (1: 4) shows that (8aS, 12aR) -2- (5-ethoxy-5-oxopentyl) -6,7,9,10,12,12a- Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (150 mg, 58%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 6.78 (1H, d, J1.4Hz), 6.70 (1H, d, J1.1Hz), 4.12 (2H, q, J7.2Hz), 3.66-3.58 (2H, m), 3.52-3.38 ( 2H, m), 3.36-3.05 (5H, m), 2.97-2.85 (1H, m), 2.46 (2H, t, J7.3Hz), 2.31 (2H, t, J7.2Hz), 2.16-2.00 (2H) , m), 1.90-1.80 (2H, m), 1.70-1.60 (4H, m), 1.45 (9H, s), 1.25 (3H, t, J7.2Hz); m / z (ES) 475.3 (M +) H)⁺.. [1486] (Step B) (8aS, 12aR) -2- (5-ethoxy-5-oxopentyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] in a nitrogen atmosphere at room temperature [1,4] Thiazepino [2,3,4-hi] TFA (1 mL) was added with stirring a solution of indole-11 (8aH) -tert-butyl carbonate (45 mg, 0.095 mmol) in DCM (6 mL). The solution is stirred at room temperature for 2 hours, diluted with DCM (20 mL), washed with NaOH (1N, 2 x 20 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the desired product (35 mg, 100%).¹1 H NMR (CDCl₃, 300MHz): 6.76 (1H, d, J1.9Hz), 6.66 (1H, d, J1.4Hz), 4.12 (2H, q, J7.2Hz), 3.67 (1H, ddd, J14.1, 10.1 and 4.3 Hz), 3.49 (1H, ddd, J14.8, 9.9 and 5.2Hz), 3.38-3.31 (1H, m), 3.15 (1H, dt, J12.8 and 4.1Hz), 3.03-2.78 (5H, m) , 2.57 (1H, dd, J14.1 and 11.6Hz), 2.45 (2H, t, J7.3Hz), 2.31 (2H, t, J7.2Hz), 2.15-2.00 (2H, m), 1.87-1.54 ( 6H, m), 1.25 (3H, t, J7.2Hz.) [1487] (Example 416) (8aS, 12aR) -2-allyl-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indole [1488] (Step A) 2-Bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] in a nitrogen atmosphere at room temperature Pd (PPh) through a cannula with stirring a solution of tert-butyl carbonate (58 mg, 0.14 mmol) and allyltributyltin (0.085 mL, 0.27 mmol) in anhydrous THF (3 mL).₃)₄A solution of THF (1 mL + 1 mL for cleaning) was introduced. The solution was stirred and heated to reflux for 5 days. The mixture is cooled to room temperature, concentrated under reduced pressure and Et.₂It was diluted with O (10 mL) and stirred with aqueous KF solution (10 mL) for 1 hour. The mixture was extracted into EtOAc (20 mL) and EDTA₄Dry above, concentrated under reduced pressure and purified by column chromatography eluting with EtOAc / Hexanes (1: 9), (8aS, 12aR) -2-allyl-6,7,9,10,12,12a- Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (25 mg, 48%) obtained as a colorless oil Was done.¹1 H NMR (CDCl₃, 300MHz): 6.80 (1H, d, J1.1Hz), 6.72 (1H, d, J1.5Hz), 5.94-5.85 (1H, m), 5.09-5.01 (2H, m), 3.76-3.57 (3H, m), 3.52-3.09 (8H, m), 2.95-2.89 (1H, m), 2.11-2.03 (2H, m), 1.87-1.83 (2H, m), 1.44 (9H, s); m / z ( ES) 387.2 (M + H)⁺.. [1489] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-allyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (25 mg, 0.065 mmol) and 2,6-lutidine (0.019 mmol, 0.163 mmol) in DCM (2 mL) with stirring while stirring dimethylsilyltrifluoro tert-Butylmethane sulfonate (0.030 mL, 0.13 mmol) was added. The solution is stirred at room temperature for 2 hours, washed with 1N HCl and deli₄It was dried on top and concentrated under reduced pressure. The residue is dissolved in THF (5 mL), treated with tetrabutylammonium fluoride (1.0 M solution in THF, 3.0 mL, 3.0 mmol) for 5 minutes, washed with saturated sodium hydrogen carbonate solution and Na.₂SO₄Drying on top and concentrating under reduced pressure gave a colorless oil (15 mg, 81%).¹1 H NMR (CDCl₃, 300MHz) 6.78 (1H, d, J1.5Hz), 6.68 (1H, J1.1Hz), 5.95-5.86 (1H, m), 5.10-5.01 (2H, m), 3.69 (1H, ddd, J14.1) , 9.8 and 4.3Hz), 3.51 (1H, ddd, J14.9, 9.9 and 5.3Hz), 3.36-3.32 (1H, m), 3.22 (2H, d, J6.9Hz), 3.19-3.11 (1H, m) ), 3.03-2.84 (5H, m), 2.58 (1H, dd, J14.1 and 11.5Hz), 2.13-2.97 (2H, m), 1.88-1.74 (2H, m.) [1490] (Example 417) (8aS, 12aR) -2-propyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indole [1491] (Step A) In a hydrogen atmosphere, (8aS, 12aR) -2-allyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] A suspension of -hi] indole-11 (8aH) -tert-butyl carbonate (35 mg, 0.091 mmol) and 10% palladium-carbon (5 mg) in EtOAc (2 mL) was stirred for 2 days. The suspension was filtered through Celite and concentrated under reduced pressure to give (8aS, 12aR) -2-propyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b]. [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (33 mg, 94%) was obtained.¹1 H NMR (300MHz, CDCl₃): 6.78 (1H, d, J1.5Hz), 6.71 (1H, d, J1.1Hz), 3.75-3.58 (3H, m), 3.51-3.07 (5H, m), 2.92 (2H, dt, J14. 3 and 9.9Hz), 2.41 (2H, t, J7.7Hz), 2.11-2.03 (2H, m), 1.87-1.84 (2H, m), 1.45 (9H, s), 1.42-1.30 (2H, m) , 0.95-0.89 (3H, m); m / z (ES) 389.2 (M + H)⁺.. [1492] (Step B) At room temperature (8aS, 12aR) -2-propyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indole-11 (8aH) -tert-butyl carbonate (33 mg, 0.085 mmol) Et₂Ethereal HCl (1M, 5 mL) was added to the O (2 mL) solution with stirring, and the mixture was stirred overnight at room temperature. Et this mixture₂Dilute with O (20 mL), wash with NaOH (1N, 10 mL), Na₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (22 mg, 90%). m / z (ES): 289.2 (M + H)⁺.. [1493] (Example 418) (8aS, 12aR) -2-Benzyl-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indole [1494] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (150 mg, 0.35 mmol), PdCl₂benzyl zinc bromide (0.5 M solution in THF, 1.06 mmol, 2.1 mL) with stirring a mixture of (dppf) (29 mg, 0.035 mmol) and CuI (15 mg, 0.078 mmol) in anhydrous THF (15 mL). ) Was added. The mixture is stirred, heated to reflux overnight, quenched with 1N HCl (5 mL), extracted to EtOAc (2 x 20 mL) and EDTA.₄Drying on top and concentrating under reduced pressure gave a brown oil. Purification of this oil by column chromatography eluting with EtOAc / Hexanes (1: 3) shows that (8aS, 12aR) -2-benzyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,, 3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (90 mg, 58%) was obtained as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.29-7.25 (2H, m), 7.18 (3H, t, J6.6Hz), 6.80 (1H, d, J1.5Hz), 6.70 (1H, s), 3.80 (2H, s), 3.72 (1H, ddd, J14.3, 10.5 and 4.2Hz), 3.61 (1H, dt, J12.8 and 4.6Hz), 3.52-3.07 (6H, m), 2.94-2.89 (2H, m), 2.17-2.00 (2H, m), 1.86-1.83 (2H, m), 1.43 (9H, s.) [1495] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-benzyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] TFA (2 mL) was added with stirring a solution of indole-11 (8aH) -tert-butyl carbonate (90 mg, 0.206 mmol) in DCM (10 mL). The solution is stirred at room temperature for 2 hours, diluted with DCM (20 mL), washed with NaOH (1N, 2 x 10 mL) and Na.₂SO₄It was dried on top and concentrated under reduced pressure to give the desired product (70 mg, 100%) as a yellow solid.¹1 H NMR (CDCl₃, 300MHz): 7.30-7.20 (2H, m), 7.19-7.16 (3H, m), 6.79 (1H, d, J1.5Hz), 6.66 (1H, d, J1.4Hz), 3.80 (2H, s) , 3.68 (1H, ddd, J14.1, 10.1 and 4.3Hz), 3.50 (1H, ddd, J14.8, 9.7 and 5.3Hz), 3.35-3.30 (1H, m), 3.14 (1H, dt, J13. 6 and 8.4Hz), 3.00-2.92 (3H, m), 2.89-2.78 (2H, m), 2.56 (1H, dd, J14.2 and 11.6Hz), 2.16-1.97 (2H, m) and 1.89-1.67 (2H, m) ppm; m / z (ES) 337.2 (M + H)⁺.. [1496] (Example 419) (8aS, 12aR) -2- (2-Fluorobenzyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1497] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (200 mg, 0.47 mmol), PdCl₂2-Fluorobenzyl zinc chloride (0.5 M solution in THF, 2.82 mmol) with stirring a mixture of (dppf) (39 mg, 0.047 mmol) and CuI (19 mg, 0.10 mmol) in anhydrous THF (5 mL). , 5.6 mL) was added. The mixture is stirred, heated to reflux overnight, quenched with 1N HCl (5 mL), extracted to EtOAc (2 x 20 mL) and EDTA.₄Oil was obtained by drying on top and concentrating under reduced pressure. Purification of this oil by column chromatography eluting with EtOAc / Hexanes (1: 3) reveals (8aS, 12aR) -2- (2-fluorobenzyl) -6,7,9,10,12,12a-hexahydro-5H. -Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (250 mg, 117%) was obtained as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.21-7.11 (2H, m), 7.06-6.98 (2H, m), 6.82 (1H, s), 6.73 (1H, s), 3.82 (2H, s), 3.729 (1H, ddd, J14) .3,10.6 and 4.0Hz),3.64-3.57 (1H, m), 3.52-3.06 (7H, m), 2.93-2.87 (1H, m), 2.13-2.0 (2H, m), 1.86-1.83 (2H) , m), 1.43 (9H, s) [1498] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-benzyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] TFA (4 mL) was added with stirring a solution of indole-11 (8aH) -tert-butyl carbonate (250 mg, 0.55 mmol) in DCM (20 mL). The solution is stirred at room temperature for 2 hours, diluted with DCM (30 mL), washed with NaOH (1N, 2 x 30 mL) and Na.₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (150 mg, 77%) as a white solid.¹1 H NMR (CDCl₃, 300MHz): 7.20-7.12 (2H, m), 7.07-6.98 (2H, m), 6.80 (1H, d, J1.4Hz), 6.69 (1H, s), 3.82 (2H, s), 3.68 (1H) , ddd, J14.1, 10.1 and 4.3Hz), 3.50 (1H, ddd, J14.8, 9.9 and 5.2Hz), 3.35-3.31 (1H, m), 3.14 (1H, dt, J13.6 and 4.2Hz) ), 3.00-2.91 (3H, m), 2.88-2.77 (2H, m), 2.56 (1H, dd, J14.2 and 11.6Hz), 2.14-1.99 (2H, m) and 1.86-1.68 (2H, m) ) ppm. [1499] (Example 420) (8aS, 12aR) -2- (3-Fluorobenzyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1500] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (150 mg, 0.35 mmol), PdCl₂A mixture of (dppf) (30 mg, 0.035 mmol) and CuI (15 mg, 0.078 mmol) in anhydrous THF (5 mL) with stirring, 3-fluorobenzylzinc chloride (0.5 M solution in THF, 2.12 mmol). , 4.2 mL) was added. The mixture is stirred, heated to reflux overnight, quenched with 1N HCl (10 mL), extracted to EtOAc (2 x 20 mL) and EDTA.₄Oil was obtained by drying on top and concentrating under reduced pressure. Purification of this oil by column chromatography eluting with EtOAc / Hexane (1: 3) reveals (8aS, 12aR) -2- (3-fluorobenzyl) -6,7,9,10,12,12a-hexahydro-5H. -Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (150 mg, 94%) was obtained as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.24-7.19 (1H, m), 6.95 (1H, d, J7.7Hz), 6.87 (1H, J8.8Hz), 6.78 (1H, d, J1.8Hz), 6.68 (1H, d, J1.4Hz), 3.78 (2H, s), 3.78-3.69 (1H, m), 3.64-3.57 (1H, m), 3.52-3.08 (7H, m), 2.96-2.88 (1H, m), 2.14- 2.01 (2H, m), 1.86-1.83 (2H, m), 1.43 (9H, s) [1501] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2- (3-fluorobenzyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] TFA (4 mL) was added with stirring a solution of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (150 mg, 0.33 mmol) in DCM (20 mL). The solution is stirred at room temperature for 2 hours, diluted with DCM (50 mL), washed with NaOH (1N, 2 x 30 mL) and Na.₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (110 mg, 94%) as a white solid.¹1 H NMR (CDCl₃, 300MHz): 7.24-7.19 (1H, m), 6.96 (1H, d, J7.7Hz), 6.90-6.84 (2H, m), 6.77 (1H, d, J1.9Hz), 6.64 (1H, d, J1.9Hz) J1.5Hz), 3.79 (2H, s), 3.69 (1H, ddd, J14.1, 10.3 and 4.2Hz), 3.50 (1H, ddd, J14.9, 9.9 and 5.2Hz), 3.36-3.32 (1H, m), 3.15 (1H, dt, J13.6 and 4.4Hz), 3.01-2.89 (3H, m), 2.88-2.77 (2H, m), 2.56 (1H, dd, J14.3 and 11.4Hz), 2.16 -2.00 (2H, m) and 1.86-1.69 (2H, m) ppm. [1502] (Example 421) (8aS, 12aR) -2- (4-Fluorobenzyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1503] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (150 mg, 0.35 mmol), PdCl₂4-Fluorobenzyl zinc chloride (0.5 M solution in THF, 2.12 mmol) with stirring a mixture of (dppf) (30 mg, 0.035 mmol) and CuI (15 mg, 0.078 mmol) in anhydrous THF (5 mL). , 4.2 mL) was added. The mixture is stirred, heated to reflux overnight, quenched with 1N HCl (10 mL), extracted to EtOAc (2 x 20 mL) and EDTA₄Oil was obtained by drying on top and concentrating under reduced pressure. Purification of this oil by column chromatography eluting with EtOAc / Hexanes (3: 7) reveals (8aS, 12aR) -2- (4-fluorobenzyl) -6,7,9,10,12,12a-hexahydro-5H. -Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (150 mg, 94%) was obtained as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.24-7.19 (1H, m), 6.95 (1H, d, J7.7Hz), 6.87 (1H, J8.8Hz), 6.78 (1H, d, J1.8Hz), 6.68 (1H, d, J1.4Hz), 3.78 (2H, s), 3.78-3.69 (1H, m), 3.64-3.57 (1H, m), 3.52-3.08 (7H, m), 2.96-2.88 (1H, m), 2.14- 2.01 (2H, m), 1.86-1.83 (2H, m), 1.43 (9H, s) [1504] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2- (4-fluorobenzyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] TFA (4 mL) was added with stirring a solution of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (150 mg, 0.33 mmol) in DCM (20 mL). The solution is stirred at room temperature for 2 hours, diluted with DCM (50 mL), washed with NaOH (1N, 2 x 30 mL) and Na.₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (110 mg, 94%) as a white solid.¹1 H NMR (CDCl₃, 300MHz): 7.24-7.19 (1H, m), 6.96 (1H, d, J7.7Hz), 6.90-6.84 (2H, m), 6.77 (1H, d, J1.9Hz), 6.64 (1H, d, J1.9Hz) J1.5Hz), 3.79 (2H, s), 3.69 (1H, ddd, J14.1, 10.3 and 4.2Hz), 3.50 (1H, ddd, J14.9, 9.9 and 5.2Hz), 3.36-3.32 (1H, m), 3.15 (1H, dt, J13.6 and 4.4Hz), 3.01-2.89 (3H, m), 2.88-2.77 (2H, m), 2.56 (1H, dd, J14.3 and 11.4Hz), 2.16 -2.00 (2H, m) and 1.86-1.69 (2H, m) ppm. [1505] (Example 422) (8aS, 12aR) -2- (3-Methoxybenzyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1506] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (210 mg, 0.49 mmol), PdCl₂A mixture of (dppf) (42 mg, 0.049 mmol) and CuI (21 mg, 0.11 mmol) in anhydrous THF (5 mL) with stirring, 3-methoxybenzyl zinc chloride (0.5 M solution in THF, 2.97 mmol). , 5.9 mL) was added. The mixture was stirred and heated to reflux overnight. The mixture is cooled to room temperature, quenched with 1N HCl (30 mL), extracted to EtOAc (50 mL) and benzyl.₄It was dried on top and concentrated under reduced pressure. Purification by column chromatography eluting the residue with EtOAc / Hexanes (1: 4) shows that (8aS, 12aR) -2- (3-methoxybenzyl) -6,7,9,10,12,12a-hexahydro-5H- Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (215 mg, 94%) was obtained as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.19 (1H, t, J7.7Hz), 6.81-6.70 (5H, m), 3.78 (3H, s), 3.77 (2H, s), 3.77-3.58 (3H, m), 3.52-3.07 (8H, m), 2.93-2.89 (2H, m), 2.10-2.01 (2H, m), 1.85-1.83 (2H, m), 1.43 (9H, s.) [1507] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2- (3-methoxybenzyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] TFA (2 mL) was added with stirring a solution of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (215 mg, 0.46 mmol) in DCM (10 mL). The solution is stirred at room temperature for 1 hour, diluted with DCM (50 mL), washed with NaOH (1N, 2 x 20 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the desired product (168 mg, 100%).¹1 H NMR (CDCl₃, 300MHz) 7.19 (1H, t, J8.3Hz), 6.79 (1H, s), 6.75 (1D, d, J7.0Hz), 6.72 (1H, s), 6.66 (1H, d, J1.4Hz), 3.78 (5H, s), 3.68 (1H, ddd, J14.1, 10.3 and 4.1Hz), 3.50 (1H, ddd, J14.9, 9.7 and 5.3Hz), 3.47-3.30 (1H, m), 3.14 ( 1H, dt, J13.5 and 4.4Hz), 3.00-2.78 (5H, m), 2.56 (1H, dd, J14.2 and 11.5Hz), 2.14-2.00 (2H, m), 1.86-1.68 (2H, m); m / z (ES) 367.1 (M + H)⁺.. [1508] (Example 423) 3-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-ylmethyl] Phenol [1509] (8aS, 12aR) -2- (3-methoxybenzyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] in a nitrogen atmosphere at room temperature [1,4] Boron tribromide (0.4 M solution in DCM, 0.68 mmol, 1.7 mL) while stirring a DCM solution of thiazepino [2,3,4-hi] indole (50 mg, 0.14 mmol). added. The resulting suspension was stirred at room temperature for 1 hour, diluted with EtOAc (30 mL) and LVDS.₃Wash with (2 x 10 mL) and Na₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (30 mg, 63%) as an orange foam. m / z (ES) 353.2 (M + H)⁺.. [1510] (Example 424) (8aS, 12aR) -2- (2-Methoxybenzyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [ 2,3,4-hi] Indole [1511] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (190 mg, 0.45 mmol), PdCl₂A mixture of (dppf) (38 mg, 0.045 mmol) and CuI (19 mg, 0.098 mmol) in anhydrous THF (5 mL) with stirring, 2-methoxybenzylzinc chloride (0.5 M solution in THF, 2.68 mmol). , 5.4 mL) was added. The mixture was stirred and heated to reflux overnight. The mixture is cooled to room temperature, quenched with 1N HCl (30 mL), extracted to EtOAc (50 mL) and benzyl.₄It was dried on top and concentrated under reduced pressure. Purification by column chromatography eluting the residue with EtOAc / Hexanes (1: 4) shows that (8aS, 12aR) -2- (2-methoxybenzyl) -6,7,9,10,12,12a-hexahydro-5H- Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (215 mg, 94%) was obtained as a yellow oil.¹1 H NMR (CDCl₃, 300MHz): 7.18 (1H, td, J7.9 and 1.6Hz), 7.05 (1H, d, J6.2Hz), 6.89-6.84 (2H, m), 6.74 (1H, s), 3.82 (3H, s) ), 3.80 (2H, s), 3.77-3.61 (3H, m), 3.52-3.05 (6H, m), 2.92-2.87 (1H, m), 2.18-2.03 (2H, m), 1.85-1.83 (2H) , m), 1.44 (9H, s.) [1512] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2- (2-methoxybenzyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] TFA (2 mL) was added with stirring a solution of thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (65 mg, 0.14 mmol) in DCM (15 mL). The solution is stirred at room temperature for 2 hours, diluted with DCM (20 mL), washed with NaOH (1N, 2 x 10 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the desired product (50 mg, 98%). m / z (ES) 367.0 (M + H)⁺.. [1513] (Example 425) 2-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-ylmethyl] Phenol [1514] In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2- (2-methoxybenzyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (60 mg, 0.13 mmol) in DCM (5 mL) with stirring, boron tribromide (0.4 M in DCM) The solution, 1.3 mmol, 3.2 mL) was added. The resulting suspension is stirred at room temperature for 30 minutes and LVDS.₃Quench with (10 mL), extract to EtOAc (100 mL), Na₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (40 mg, 87%) as a white solid.¹H NMR (CD)₃OD, 300MHz) 7.02-6.91 (2H, m), 6.81 (1H, d, J3.6Hz), 6.77-6.68 (3H, m), 3.75 (2H, s), 3.73-3.32 (3H, m), 3.25 -3.06 (4H, m), 2.95-2.87 (2H, m), 2.60 (1H, dd, J14.5 and 12.7Hz), 2.19-1.90 (4H, m); m / z (ES) 353.2 (M +) H)⁺.. [1515] (Example 426) 2-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-yl] -5-Methyl benzoate [1516] (Step A) In a nitrogen atmosphere, at -78 ° C (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (420 mg, 0.99 mmol) in anhydrous THF (15 mL) with stirring, tert-butyllithium (1.7 M solution in hexanes, 2.2 mmol, 1.3 mL) was added. The solution was stirred at -78 ° C for 1 hour, then tri-n-butyltin chloride (1.2 mmol, 0.32 mL) was added in one portion. The solution was returned to room temperature, stirred at room temperature for 3 hours and then quenched with water (10 mL). The mixture was extracted into EtOAc (2 x 20 mL) and Na₂SO₄It was dried on top and concentrated under reduced pressure to give a colorless oil. Column chromatography (NEt) in which this oil is eluted with EtOAc / Hexanes (1: 9)₃Purified with (washing silica), (8aS, 12aR) -2- (tributylstannyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (120 mg, 19%) was obtained as a colorless oil.¹1 H NMR (300MHz, CDCl₃): 7.01 (1H, s), 6.94 (1H, s), 3.87-3.77 (1H, m), 3.66-3.60 (1H, m), 3.54-3.46 (2H, m), 3.35-3.18 (2H, m) ), 3.10-3.06 (2H, m), 2.93 (2H, dt, J14.3 and 9.5Hz), 2.15-2.00 (2H, m), 1.921.82 (2H, m), 1.56-1.45 (15H, m) ), 1.38-1.26 (6H, sextet, J7.3Hz), 1.01-0.96 (6H, m), 0.89 (9H, t, J7.4Hz.) [1517] (Step B) (8aS, 12aR) -2- (tributylstannyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] in a nitrogen atmosphere at room temperature Anhydrous THF (3 mL) of thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (120 mg, 0.19 mmol) and methyl-2-bromo-5-methoxybenzoate (70 mg, 0.29 mmol) Pd through the cannula while stirring the solution₂dba₃An anhydrous THF (1 mL) solution of (17 mg, 0.019 mmol) and triphenylarsine (25 mg, 0.076 mmol) was introduced. The resulting solution was stirred and heated to reflux overnight. The resulting mixture was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography eluting with EtOAc / Hexanes (1: 4), where (8aS, 12aR) -2- [4-methoxy-2- (Methoxycarbonyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 ( 8aH) -tert-butyl carbonate (32 mg, 33%) was obtained as a yellow oil.¹1 H NMR (300MHz, CDCl₃) 7.31-7.23 (2H, m), 7.02 (1H, dd, J8.6 and 2.7Hz), 6.93 (1H, d, J1.5Hz), 6.79 (1H, d, J1.3Hz), 3.88-3.78 ( 4H, m), 3.71-3.63 (4H, m), 3.57-3.47 (2H, m), 3.31-3.11 (4H, m), 2.97-2.93 (2H, m), 2.20-2.05 (2H, m), 1.93-1.83 (2H, m), 1.43 (9H, s.) [1518] (Step C) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2- [4-methoxy-2- (methoxycarbonyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3 -b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (32 mg, 0.063 mmol) in dichloromethane (10 mL) with stirring TFA (2 mL) added. The solution is stirred at room temperature for 2 hours, diluted with DCM (20 mL), washed with 1N NaOH (2 x 10 mL) and Na.₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (25 mg, 100%) as a colorless oil.¹1 H NMR (300MHz, CDCl₃): 7.27-7.23 (2H, m), 7.01 (1H, dd, J8.6 and 2.7Hz), 6.92 (1H, d, J1.8Hz), 6.75 (1H, d, J1.8Hz), 3.85 (3H) , S), 3.83-3.73 (1H, m), 3.69 (3H, s), 3.55 (1H, ddd, J14.9, 9.9 and 5.3Hz), 3.44-3.40 (1H, m), 3.21-3.15 (1H) , m), 3.09-2.87 (4H, m), 2.66-2.58 (2H, m), 2.15-2.05 (2H, m), 1.91-1.74 (2H, m); m / z (ES) 411.1 (M +) H)⁺[1519] (Example 427) (8aS, 12aR) -2- (2,6-difluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1520] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (650 mg, 1.53 mmol), PPh₃(80 mg, 0.31 mmol), CuBr (44 mg, 0.31 mmol), and PdCl₂(PPh₃)₂DMF (25 cm) degassed through a cannula into a mixture of (110 mg, 0.15 mmol)³) Was added. After stirring at room temperature for 5 minutes, degassed DMF (5 cm)³) In (2,6-difluoro) (trimethyl) stannane (640 mg, 2.3 mmol) was added through the cannula. The mixture is stirred and heated at 60 ° C for 30 minutes before degassing DMF (2.5 cm).³) In (2,6-difluoro) (trimethyl) stannane (320 mg, 1.1 mmol) was added through a cannula and the reaction was stirred and heated to 140 ° C. After 10 minutes, the solution began to turn black and degassed DMF (2.5 cm)³) Medium (2,6-difluoro) (trimethyl) stannane (320 mg, 1.1 mmol) final addition was added. The mixture is stirred, heated at 140 ° C for 1 hour, cooled to room temperature, diluted with EtOAc (100 mL), washed with water (4 x 100 mL) and deli₄Drying on top and concentrating under reduced pressure gave a yellow oil. Purified by column chromatography (10% EtOAc / Hexanes), (8aS, 12aR) -2- (2,6-difluorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4, 3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (510 mg, 71%) was obtained as a white foam.¹1 H NMR (300MHz, CDCl₃): 7.25-7.15 (1H, m), 7.10-7.08 (1H, m), 6.99 (1H, d, J1.5Hz), 6.93 (2H, t, J8.1Hz), 3.91 (1H, ddd, J14. 3,10.5 and 4.1Hz), 3.63-3.13 (8H, m), 2.99 (1H, dt, J14.2 and 4.9Hz), 2.15-2.05 (2H, m), 1.90-1.88 (2H, m), 1.42 (9H, s.) [1521] (Step B) (8aS, 12aR) -2- (2,6-difluorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] TFA (15 mL) was added to a solution of indole-11 (8aH) -tert-butyl carbonate (680 mg, 1.48 mmol) in DCM (100 mL), and the mixture was stirred overnight at room temperature. The solution was washed with 1N NaOH (3 x 50 mL), extracted to EtOAc (100 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the indicated compound (550 mg, 103%) as foam. m / z (ES) 359.3 [M + H]⁺.. [1522] (Example 428) (8aS, 12aR) -2-[(E) -2-Phenyletenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] Indole [1523] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-cyclopentyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Palladium acetate through a cannula with stirring a solution of indol-11 (8aH) -tert-butyl carbonate (650 mg, 1.53 mmol) and vinyl tributylstannan (0.67 mL, 2.3 mmol) in toluene (10 mL). (II) A solution of (34 mg, 0.15 mmol) and triphenylphosphine (80 mg, 0.31 mmol) in THF (5 mL) was added. The solution was stirred, heated to reflux overnight, cooled to room temperature and concentrated under reduced pressure to give a black oil. Purification of this oil by column chromatography eluting with EtOAc / Hexanes (1: 4) reveals that (8aS, 12aR) -2-vinyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,, 3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (500 mg, 88%) was obtained as a colorless oil.¹1 H NMR (CDCl₃, 300MHz): 7.00 (2H, dd, J6.6 and 1.5Hz), 6.53 (1H, dd, J17.4 and 10.9Hz), 5.55 (1H, d, J17.5Hz), 5.04 (1H, d, J10) .9 and 1.0Hz), 3.79 (1H, ddd, J14.1, 10.1 and 4.3Hz), 3.61-3.12 (8H, m), 2.96 (1H, dt, J14.3 and 9.5Hz), 2.16-2.02 ( 2H, m), 2.02-1.83 (2H, m), 1.43 (9H, s.) [1524] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-cyclopentyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (200 mg, 0.47 mmol), trans-phenylethenylboronic acid (135 mg, 0.94 mmol), and tetrakis (triphenylphosphine) palladium (0) ( Sodium carbonate (2M, 2.5mL, 5.0 mmol) was added with stirring a 27 mg, 0.024 mmol) degassed DME (5 mL) solution. The mixture was stirred, heated to reflux overnight, cooled to room temperature, extracted into EtOAc (2 x 20 mL) and Na.₂SO₄It was dried on top and concentrated under reduced pressure. Purification of the resulting oil by column chromatography eluting with EtOAc / Hexanes (1: 4) revealed that (8aS, 12aR) -2-[(E) -2-phenylethenyl] -6,7,9,10, 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (150 mg, 71%) obtained Was done.¹1 H NMR (CDCl₃, 300MHz): 7.46 (1H, d, J8.4Hz), 7.36-7.19 (4H, m), 7.11 (1H, d, J7.7Hz), 6.92 (1H, d, J3.3Hz), 3.87-3.77 ( 2H, m), 3.61-3.15 (7H, m), 3.01-2.95 (1H, m), 2.18-2.07 (2H, m), 1.88-1.86 (2H, m), 1.44 (9H, s.) [1525] (Step C) (8aS, 12aR) -2-[(E) -2-phenylethenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] TFA (1 mL) was added while stirring a solution of indole-11 (8aH) -tert-butyl carbonate (30 mg, 0.067 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 1 hour. .. This solution was quenched with 1N NaOH (10 mL), extracted into DCM (10 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the desired product (17 mg, 73%).¹1 H NMR (CDCl₃, 300MHz): 7.47 (1H, d, J1.1Hz), 7.44-7.21 (4H, m), 7.09 (1H, dd, J16.9 and 1.5Hz), 3.82-3.70 (1H, m), 3.57-2.84 (8H, m), 2.70-2.60 (1H, m), 2.20-2.05 (2H, m), 1.90-1.87 (2H, m.) [1526] (Example 429) (8aS, 12aR) -2-[(E) -2- (4-Methoxy-2-methylphenyl) ethenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [ 4,3-b] [1,4] Chiazepino [2,3,4-hi] Indole [1527] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-vinyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (140 mg, 0.38 mmol), 4-bromo-3-methylanisole (0.23 mL, 1.9 mmol), and triethylamine (0.46 mmol, 3.8 mmol) Pd (OAc) with stirring MeCN (5 mL) solution₂A solution of (7 mg, 0.038 mmol) and tri-o-tolylphosphine (20 mg, 0.076 mmol) in MeCN (2 mL) was added. The mixture was stirred and heated to reflux overnight. The solution was concentrated under reduced pressure and purified by column chromatography eluting with EtOAc / Hexanes (1: 4) and normal phase HPLC at (8aS, 12aR) -2-[(E) -2- (4-methoxy-). 2-Methylphenyl) ethenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (14 mg, 8%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 7.47 (1H, d, J8.4Hz), 7.11-7.02 (3H, m), 6.75-6.70 (3H, m), 3.87-3.76 (4H, m), 3.65-3.10 (8H, m) , 3.02-2.90 (1H, m), 2.39 (3H, s), 2.12-2.02 (2H, m), 1.921.82 (2H, m), 1.44 (9H, s.) [1528] (Step B) (8aS, 12aR) -2-[(E) -2- (4-Methoxy-2-methylphenyl) ethenyl] -6,7,9,10,12,12a-hexahydro-5H in a nitrogen atmosphere at room temperature -Stir a solution of pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (14 mg, 0.028 mmol) in dichloromethane (5 mL). While adding TFA (1 mL). The solution is stirred at room temperature overnight, diluted with DCM (20 mL), washed with 1N NaOH (2 x 10 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the desired product (10 mg, 90%). m / z (ES) 393.2 (M + H)⁺.. [1529] (Example 430) N, N-Dimethyl-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru -2-Amine. [1530] (Step A) 2-Bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] in a nitrogen atmosphere at room temperature Toluene-11 (8aH) -tert-butyl carbonate (120 mg, 0.28 mmol), BINAP (13 mg, 0.014 mmol), benzophenone imine (61 mg, 0.057 mL, 0.34 mmol), and sodium tert-butoxide (38 mg, 0.40 mmol) Pd while stirring an anhydrous degassed toluene (5 mL) solution₂dba₃(13 mg, 0.014 mmol) was added. The mixture was stirred, heated under reflux for 3 days, cooled to room temperature, concentrated under reduced pressure and purified by column chromatography eluting with EtOAc / Hexanes (3:17) to give 2-[(diphenylmethylene) amino]-. 6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (136 mg, 92%) was obtained as a yellow oil. m / z (ES) 526.1 (M + H)⁺.. [1531] (Step B) At room temperature, 2-[(diphenylmethylene) amino] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indole-11 (8aH) -tert-butyl carbonate (10 mg, 0.019 mmol) and sodium acetate (3.7 mg, 0.046 mmol) in methanol (1 mL) while stirring with hydroxylamine hydrochloride (2.4 mg, 0.034 mmol). added. The mixture was stirred at room temperature for 15 minutes, NaOH (0.2 M, 3 mL) was added, quenched and extracted into DCM (2 x 15 mL). Organic extract Na₂SO₄Dry above, concentrated under reduced pressure and purified by column chromatography eluting with EtOAc / Hexanes (3: 7), 2-amino-6,7,9,10,12,12a-hexahydro-5H-pyrido [ 4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (5 mg, 73%) was obtained.¹1 H NMR (CDCl₃, 300MHz): 6.42 (1H, d, J1.8Hz), 6.37 (1H, s), 4.00-2.82 (10H, m), 2.10-2.05 (2H, m), 1.90-1.88 (2H, m), 1.45 (9H, s); m / z (ES) 362.2 (M + H)⁺.. [1532] (Step C) 2-Amino-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1, while stirring a solution of sulfuric acid (3M, 0.019 mL, 0.058 mmol) and formaldehyde 4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (84 mg, 0.23 mmol) and sodium borohydride (63 mg, 1.6 mmol) in THF (2 mL) for 5 minutes. Dropped at 0 ° C. The mixture was quenched with NaOH (100 mg), extracted to EtOAc (20 mL) and Na.₂SO₄Dry above, concentrated under reduced pressure and purified by column chromatography eluting with EtOAc / Hexanes (1: 4), 2- (dimethylamino) -6,7,9,10,12,12a-hexahydro-5H -Pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (40 mg, 44%) was obtained.¹1 H NMR (300MHz, CDCl₃): 6.47 (1H, d, J1.8Hz), 6.43 (1H, d, J1.8Hz), 3.71-3.02 (9H, m), 2.942.82 (7H, mands), 2.12-2.00 (2H, m) , 1.87-1.79 (2H, m), 1.46 (9H, s.) [1533] (Step D) 2- (Dimethylamino) -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 ( TFA (1 mL) was added with stirring a solution of 8aH) -tert-butyl carbonate (40 mg, 0.10 mmol) in DCM (10 mL), and the mixture was stirred overnight at room temperature. This solution is diluted with EtOAc (20 mL), washed with NaOH (1N, 10 mL) and Na₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (30 mg, 100%).¹1 H NMR (300MHz, CD₃OD): 7.32 (1H, d, J2.6Hz), 7.25 (1H, d, J2.5Hz), 3.93-3.83 (1H, m), 3.61 (1H, ddd, J15.2, 10.7 and 4.9Hz), 3.50-3.38 (4H, m), 3.32-3.13 (8H, m and s), 3.07-2.99 (1H, m), 2.76 (1H, dd, J9.0 and 12.3Hz), 2.28-2.03 (4H, m) .) [1534] (Example 431) 2- (1-pyrrolidinyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi ] Indoru-2-amine. [1535] (Step A) 2-Amino-6,7,9,10,12,12a-Hexahydro-5H-Pyrid [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH)- A mixture of tert-butyl carbonate (114 mg, 0.32 mmol) and 1,4-dibromobutane was heated at 100 ° C. for 2 hours, cooled to room temperature, washed with 1N HCl (10 mL) and Na.₂SO₄It was dried on top and concentrated under reduced pressure. The reaction mixture was purified by column chromatography eluting with EtOAc / Hexanes (1: 4) and purified by 2- (1-pyrrolidinyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4, 3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (39 mg, 30%) was obtained. m / z (ES) 415.4 (M + H)⁺.. [1536] (Step B) At room temperature, 2- (1-pyrrolidinyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (15 mg, 0.036 mmol) Et₂Ethereal HCl (1.0 M, 2.0 mL, 2.0 mmol) was added with stirring the O (2 mL) solution. The mixture was stirred at room temperature for 1 hour, filtered and the residue was basified with 1N NaOH, extracted to EtOAc and Na.₂SO₄Drying on top and concentrating under reduced pressure gave the product (10 mg, 88%) as a colorless oil.¹1 H NMR (CDCl₃, 300MHz): 6.23 (2H, s), 3.49-3.41 (2H, m), 3.27-2.80 (11H, m), 2.65-2.56 (1H, m), 2.09-2.05 (2H, m), 1.971.92 (4H, m), 1.83-1.78 (4H, m); m / z (ES) 316.2 (M + H)⁺.. [1537] (Example 432) N- [6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-2- Il] -4-methyl-N-[(4-methylphenyl) sulfonyl] benzenesulfonamide [1538] (Step A) At room temperature, 2-amino-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 ( N, N-dimethylamino with stirring a DCM (3 mL) solution of 8aH) -tert-butyl carbonate (65 mg, 0.18 mmol), paratoluenesulfonyl chloride (114 mg, 0.60 mmol), and triethylamine (0.075 mL, 0.54 mmol). Ppyridine (2 mg, 0.018 mmol) was added. The mixture is stirred at room temperature for 6 hours, diluted with EtOAc (20 mL), washed with 1N HCl (5 mL), extracted to EtOAc (30 mL) and Na.₂SO₄It was dried on top and concentrated under reduced pressure. The unpurified reaction mixture was purified by column chromatography eluting with EtOAc / Hexanes (1: 4) to give 2- {bis [(4-methylphenyl) sulfonyl] amino} -6,7,9,10,12, 12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (30 mg, 25%) was obtained. .. m / z (AP) 669.2 (M)⁺.. [1539] (Step B) At room temperature, 2- {bis [(4-methylphenyl) sulfonyl] amino} -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Add ethereal HCl (1.0 M, 3 mL, 3 mmol) with stirring a solution of indole-11 (8aH) -tert-butyl carbonate (30 mg, 0.049 mmol) in diethyl ether (2 mL). It was. The solution is stirred at room temperature overnight and Et.₂Dilute with O (10 mL), wash with NaOH (1 M, 2 x 5 mL) and Na₂SO₄Drying on top and concentrating under reduced pressure gave the desired product (20 mg, 72%). m / z (ES) 570.1 (M + H)⁺.. [1540] (Example 433) (8aS, 12aR) -2-Methoxy-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indole [1541] (Step A) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (300 mg, 0.71 mmol) and CuI (70 mg, 0.37 mmol) in sodium anhydrous MeOH (2 mL) and anhydrous DMF (2 mL). Methanol (700 mg, 13.5 mmol) was added. The mixture was stirred, heated to reflux for 24 hours, cooled to room temperature and quenched by the addition of water (30 mL). The mixture was extracted in EtOAc (2 x 20 mL) and EDTA₄Dry above, concentrated under reduced pressure, purified by HPLC eluting with EtOAc / Hexanes (3: 7), (8aS, 12aR) -2-methoxy-6,7,9,10,12,12a-hexahydro -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (37 mg, 14%) obtained as a colorless oil It was.¹1 H NMR (CDCl₃, 300MHz): 6.54-6.52 (2H, m), 3.71 (3H, s), 3.68-3.07 (9H, m), 2.94-2.87 (1H, m), 2.13-2.02 (2H, m), 1.85-1.82 (2H, m), 1.45 (9H, s); m / z (ES) 377.2 (M + H)⁺.. [1542] (Step B) At room temperature (8aS, 12aR) -2-methoxy-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] TFA (1 mL) was added with stirring a solution of indole-11 (8aH) -tert-butyl carbonate (37 mg, 0.098 mmol) in DCM (5 mL). The solution is stirred at room temperature for 18 hours, quenched with NaOH (1N, 10 mL), extracted into DCM (2 x 10 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the desired product (20 mg, 74%).¹1 H NMR (CDCl₃, 300MHz): 6.52 (1H, d, J2.6Hz), 6.48 (1H, d, J2.6Hz), 3.71 (3H, s), 3.62-3.46 (2H, m), 3.32-3.30 (1H, m) , 3.18-3.12 (1H, m), 3.01-3.82 (5H, m), 2.63-2.55 (1H, m), 2.12-2.03 (2H, m), 1.81-1.71 (2H, m); m / z ( ES) 277.2 (M + H)⁺.. [1543] (Example 434) (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indole oxide. [1544] (Step A) At room temperature (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (100 mg, 0.21 mmol) THF / H₂NaIO with stirring O (5 mL: 5 mL) solution₄(88 mg, 0.41 mmol) was added and the mixture was stirred for 3 hours. This mixture is LVDS₃Quench with (20 mL), extract to EtOAc (100 mL), Na₂SO₄When dried above and filtered through a silica filler, (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 4-oxide (50 mg, 48%) was obtained as a diastereomeric mixture.¹1 H NMR (300MHz, CDCl₃): 7.48-7.46 (2H, m), 7.30-7.21 (3H, m), 3.86-3.35 (7H, m), 3.27-3.18 (2H, m), 3.05-2.84 (1H, m), 2.60-2.44 (1H, m), 2.40-2.24 (1H, m), 2.05-1.96 (1H, m), 1.95-1.67 (1H, m), 1.37 (9H, s.) [1545] (Step B) At room temperature (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] TFA (5 mL) was added with stirring a solution of indole-11 (8aH) -tert-butyl carbonate 4-oxide (50 mg, 0.099 mmol) in DCM (20 mL). The solution is stirred at room temperature overnight, quenched with NaOH (1N, 50 mL), extracted into DCM (2 x 50 mL) and Na.₂SO₄Drying on top and concentration under reduced pressure gave the desired product (38 mg, 94%). m / z (ES) 407.1 (M + H)⁺.. [1546] (Example 435) (8aS, 12aR) -2- (4-Methoxy-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indole 4-oxide. [1547] (Step A) At 0 ° C in a nitrogen atmosphere (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (1.3 g, 3.1 mmol) MeOH / H₂NaIO with stirring O (50 mL: 15 mL) solution₄(660 mg, 3.1 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. This mixture is LVDS₃Quench with (200 mL), extract to EtOAc (2 x 200 mL) and Na₂SO₄It was dried on top and concentrated under reduced pressure. Purification of the solid by column chromatography eluting with EtOAc shows that (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate 4-oxide (1.1 g, 82%) was obtained as a diastereomeric mixture.¹1 H NMR (300MHz, CDCl₃): 7.55 (1H, d, J1.8Hz), 7.23 (1H, d, J1.8Hz), 3.9-3.31 (8H, m), 3.20-3.14 (1H, m), 2.99-2.78 (1H, m) , 2.56-2.17 (2H, m), 1.97-1.85 (2H, m), 1.44 (9H, s); m / z (ES) 441.1 and 443.1 (M + H)⁺.. [1548] (Step B) In a nitrogen atmosphere, at room temperature (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indol-11 (8aH) -tert-butyl carbonate 4-oxide (180 mg, 0.41 mmol), 4-methoxy-2-methylphenylboronic acid (130 mg, 0.82 mmol), and barium hydroxide octahydrate Japanese (105 mg, 0.61 mmol) DME / H₂Pd (PPh) with stirring O (13 mL: 2 mL) solution₃)₄(25 mg, 0.020 mmol) was added. The mixture is then stirred, heated to reflux overnight, cooled to room temperature, concentrated under reduced pressure and extracted to EtOAc (2 x 20 mL) and Na.₂SO₄It was dried on top and concentrated under reduced pressure. Purification of this mixture by column chromatography eluting with MeOH / DCM (1:49) shows (8aS, 12aR) -2- (4-methoxy-2-methylphenyl) -6,7,9,10,12, 12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate 4-oxide (160 mg, 81%) Obtained as a diastereomeric mixture.¹1 H NMR (300MHz, CDCl₃): 7.36 (1H, d, J1.8Hz), 7.15-7.09 (2H, m), 6.80-6.73 (2H, m), 3.82 (3H, s), 3.80-3.17 (9H, m), 2.99-2.84 (1H, m), 2.62-2.20 (5H, m and s), 2.20-1.80 (2H, m), 1.39 (9H, s); m / z (AP) 438.1 (M + H)⁺.. [1549] (Step C) (8aS, 12aR) -2- (4-Methoxy-2-methylphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] in a nitrogen atmosphere at room temperature [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate 4-oxide (160 mg, 0.33 mmol) in DCM (10 mL) while stirring TFA (2 mL) In addition, it was stirred overnight at room temperature. This solution is quenched with NaOH (1N, 10 mL), extracted into DCM (2 x 20 mL) and Na.₂SO₄Drying on top and concentrating under reduced pressure gave the product (110 mg, 86%) as a yellow solid.¹1 H NMR (CDCl₃ 300MHz): 7.37 (1H, d, J1.8Hz), 7.14-7.08 (2H, m), 6.79-6.74 (2H, m), 3.82 (3H, s), 3.75-3.50 (3H, m), 3.42- 3.37 (1H, m), 3.26-2.86 (5H, m), 2.27-2.25 (3H, m), 2.17-2.14 (1H, m), 2.04-1.82 (2H, m); m / z (ES) 383.2 (M + H)⁺.. [1550] (Example 436) (6bR, 10aS) -5- (2-chlorophenyl) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] Indole [1551] (Step A) (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] Indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2-chlorophenylboronic acid (156 mg, 2.0 mmol) in a DME (30 mL) solution with 2 M Na₂CO₃(10 mL) was added. The solution was degassed at 40 ° C for 10 minutes. Pd (PPh) in this solution₃)₄(22 mg, 0.02 mmol) was added all at once and the reaction mixture was degassed again at the same temperature for 10 minutes. This reaction mixture is N₂After stirring in for 20 hours, Et₂Dilute with O (100 mL), wash with saline (100 mL), EDTA₄It was dried on top and concentrated under reduced pressure. By column chromatography, (6bR, 10aS) -5- (2-chlorophenyl) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyridodole [4, 3-b] Indole-8 (7H) -tert-butyl carbonate (179 mg, 84%) was obtained as a colorless oil. [1552] (Step B) (6bR, 10aS) -5- (2-chlorophenyl) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] CH of indole-8 (7H) -tert-butyl carbonate₂Cl₂TFA (0.6 mL) was added to the (2.4 mL) solution and the reaction mixture was stirred for 3 hours. The reaction mixture is concentrated under reduced pressure and CH₂Cl₂Dilute with (100 mL) and LVDS₃Wash with (100 mL) and saline (100 mL) and deli₄Drying on top and concentration under reduced pressure gave the title compound (130 mg, 95%) as a pale yellow oil.¹1 H NMR (CDCl₃) δ1.78-1.99 (m, 2H), 2.11 (br-s, 1H), 2.76-2.95 (m, 4H), 3.09-3.20 (m, 2H), 2.32-2.39 (m, 1H), 2.41- 2.46 (m, 1H), 4.44-4.52 (m, 2H), 6.76 (dd, 1H, J = 1.5, 13.2Hz), 7.19-7.36 (m, 4H), 7.42 (dd, 1H, J = 1.4,7.7) Hz) ppm. [1553] (Example 437) (7aS, 11aR) -2- (2,6-difluorophenyl) -10-methyl-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido [3', 4': 4 , 5] Pyrrolo [3,2,1-ij] Quinoline [1554] (7aS, 11aR) -2- (2,6-difluorophenyl) -5,6,7a, 8,9,10,11,11a-Octahydro-4H-pyrido [3', 4': 4,5] Pyrrolo A mixture of [3,2,1, -ij] quinoline (0.050, 0.15 mmol), HCHO (0.20 mL, 2.9 mmol), and formic acid (1.0 mL, 2.9 mmol) was heated at 80 ° C for 4 hours to room temperature. Cooled. Add water (5.0 mL) and saturate Na until this solution is above pH 8.₂CO₃Made it basic. CH this mixture₂Cl₂Extract with (3 x 10 mL) and dry (Na₂SO₄) And flash column chromatography (CHCl)₃When applied to 1-5% of MeOH), the title compound (0.032 g, 62%) was obtained as a white foam.¹1 H NMR (CDCl₃, 300MHz) δ2.00-2.20 (m, 5H), 2.20-2.50 (m, 4H), 2.55-2.68 (m, 1H), 2.68-2.82 (m, 3H), 2.86-2.98 (m, 1H), 3.28-3.42 (m, 3H), 6.90-7.08 (m, 4H), 7.14-7.25 (m, 1H) ppm. MS (ESI): 341 (base, M + H). [1555] (Example 438) 1- (2-Aminophenyl) -4-((6bR, 10aS) -1,2,6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2, 3,4-hi] Indoru-8 (7H) -Il) -1-Butanone [1556] According to the method of step C of Example 286, (6bR, 10aS) -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiazino [ Yellow title compound (95 mg, 37%) from 2,3,4-hi] indole (150 mg, 0.65 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (255 mg, 1.29 mmol) Isolated as oil.¹1 H NMR (CDCl₃) δ1.94-2.03 (M, 5H), 2.21-2.33 (m, 1H), 2.37-2.44 (m, 2H), 2.63-2.71 (m, 1H), 2.82-2.89 (m, 1H), 2.90- 3.21 (m, 5H), 3.33-3.40 (m, 1H), 3.45-3.64 (m, 2H), 6.60-6.67 (m, 3H), 6.80-6.85 (m, 2H), 7.22-7.28 (m, 1H) ), 7.76 (dd, 1H, J = 1.5,8.5Hz) ppm. [1557] (Example 439) 1- (2-Aminophenyl) -4-((6bS, 10aR) -1,2,6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2, 3,4-hi] Indoru-8 (7H) -Il) -1-Butanone [1558] According to the method of step C of Example 286, (6bS, 10aR) -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiazino [ Yellow title compound (98 mg, 38%) from 2,3,4-hi] indole (150 mg, 0.65 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (255 mg, 1.29 mmol) Isolated as oil.¹1 H NMR (CDCl₃) δ1.94-2.03 (M, 5H), 2.21-2.33 (m, 1H), 2.37-2.44 (m, 2H), 2.63-2.71 (m, 1H), 2.82-2.89 (m, 1H), 2.90- 3.21 (m, 5H), 3.33-3.40 (m, 1H), 3.45-3.64 (m, 2H), 6.60-6.67 (m, 3H), 6.80-6.85 (m, 2H), 7.22-7.28 (m, 1H) ), 7.76 (dd, 1H, J = 1.5,8.5Hz) ppm. [1559] (Example 440) 1- (2-Amino-4-fluorophenyl) -4-((6bR, 10aS) -1,2,6b, 9,10,10a-Hexahydro [4,3-b] [1,4] Thiadino- [ 2,3,4-hi] Indoru-8 (7H) -Il) -1-Butanone [1560] By the method of step B of Example 355, (6bR, 10aS) -1,2,6b, 7,8,9,10,10a-octahydro [4,3-b] [1,4] thiazino- [2, From 3,4-hi] indole (100 mg, 0.43 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (186 mg, 0.85 mmol) the title compound (103 mg, 59%) Prepared as yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ1.90-2.05 (m, 5H), 2.23-2.33 (m, 1H), 2.39-2.47 (m, 2H), 2.63-2.75 (m, 1H), 2.82-2.98 (m, 4H), 3.02-3.10 (m, 1H), 3.12-3.20 (m, 1H), 3.35-3.40 (m, 1H), 3.43-3.60 (m, 2H), 6.27-6.39 (m, 2H), 6.40-6.50 (br -s, 2H), 6.64 (t, J = 7.3Hz, 1H), 6.80-6.89 (m, 2H), 7.76 (dd, J = 9.1,6.6Hz, 1H) ppm. [1561] (Example 441) 1- (2-Amino-4-fluorophenyl) -4-((6bS, 10aR) -1,2,6b, 9,10,10a-Hexahydro [4,3-b] [1,4] Thiadino- [ 2,3,4-hi] Indoru-8 (7H) -Il) -1-Butanone [1562] By the method of step B of Example 355, (6bS, 10aR) -1,2,6b, 7,8,9,10,10a-octahydro [4,3-b] [1,4] thiazino- [2, From 3,4-hi] indole (100 mg, 0.43 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (186 mg, 0.85 mmol) the title compound (101 mg, 58%) Prepared as yellow oil. According to the spectroscope, the title compound and Example 440 were the same. [1563] (Example 442) N- {2- [4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) butanoyl] -5-fluorophenyl} methanesulfonamide [1564] N₂Medium, at 0 ° C 4-((±) -cis-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone (30 mg, 0.070 mmol) CH₂Cl₂In a (0.5 mL) solution, Et₃N (15 mg, 0.14 mmol) was added, followed by methanesulfonyl chloride (12 mg, 0.11 mmol). The reaction mixture was stirred at 0 ° C. for 4 hours, then HCl (1.0 N, 1.0 mL) was added and quenched. CHCl the resulting solution₃Extracted with. Combined organic solutions to CTL₄Dry on top. Flash column chromatography (silica gel; CHCl)₃When attached to: MeOH99: 1), the title compound (35 mg, 99%) was obtained as a white amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ1.85-2.18 (m, 7H), 2.24-2.42 (m, 3H), 2.58-2.66 (m, 1H), 2.69-2.77 (m, 1H), 2.89-3.17 (m, 5H), 3.23-3.30 (m, 1H), 3.49-3.59 (m, 4H), 3.74-3.85 (m, 1H), 6.60 (t, J = 7.7Hz, 1H), 6.80-88 (m, 2H), 6.94 ( d, J = 8.1Hz, 1H), 7.13 (dd, J = 8.5, 2.2Hz, 1H), 7.20-7.25 (m, 1H), 7.77 (dd, J = 8.8, 5.9Hz, 1H) ppm. [1565] (Example 443) (6bR, 10aS) -5- (2,3-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiadino [ 2,3,4-hi] Indole [1566] (Step A) (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] indole- 8 (7H) -tert-butyl carbonate (150 mg, 0.37 mmol) and 2,3-dichlorophenylboronic acid (143 mg, 0.75 mmol) in benzene (10 mL) and 2 M Na₂CO₃The solution in aqueous solution (0.74 mL, 1.48 mmol) was degassed at 20 ° C. Pd (PPh)₃)₂Cl₂(7.8 mg, 0.01 mmol) was added and the reaction mixture was degassed again. The reaction mixture was refluxed for 15 hours and then cooled to 20 ° C. The reaction mixture is diluted with EtOAc and saturated with LVDS.₃And washed with saline solution. Combine the organic layers and EDTA₄It was dried on top, filtered and concentrated under reduced pressure. Chromatography (silica gel; hexane: EtOAc 3: 1) shows that (6bR, 10aS) -5- (2,3-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4 , 3-b] [1,4] Thiadino [2,3,4-hi] indole tert-butyl carbonate (140 mg, 81%) was obtained as a pale yellow solid. [1567] (Step B) (6bR, 10aS) -5- (2,3-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] Thiadino [2,3, 4-hi] CH of tert-butyl carbonate (10 mg, 0.21 mmol) of indole₂Cl₂TFA (1.0 mL) was added to the (4.0 mL) solution. The reaction mixture was stirred at 20 ° C. for 1 hour and then concentrated under reduced pressure. Residue H₂It was dissolved in O, and 1N HCl was added to this solution to adjust the pH to 2. Et the water layer₂After washing with O, 50% NaOH was added to make it basic to pH 12. CHCl this solution₃Extract with, wash the organic layer with saline solution,₄Drying on top, filtering and concentrating under reduced pressure gave the title compound (79 mg, 99%) as a pale yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ1.93-2.05 (br-s, 2H), 2.65-2.99 (m, 4H), 3.01-3.25 (m, 4H), 3.44-3.68 (m, 3H), 6.88 (s, 1H), 6.90 (s, 1H), 7.18 (d, J = 4.6Hz, 2H), 7.40 (t, J = 4.6Hz, 1H) ppm. [1568] (Example 444) (6bR, 10aS) -5- (2,3-difluorophenyl) -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiadino [2,3,4-hi] Indole [1569] By the method of step A of Example 443, (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [ 2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate (100 mg, 0.25 mmol) and 2,3-difluorophenylboronic acid (80 mg, 0.50 mmol) to (6bR, 10aS) -5-( 2,3-Difluorophenyl) -1,2,6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole tert-carbonate Butyl (50 mg, 45%) was prepared as a yellow oil. Example 443 By the method of step B (6bR, 10aS) -5- (2,3-difluorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1 , 4] Thiadino [2,3,4-hi] indole The title compound (22 mg, 96%) was prepared as a yellow oil from tert-butyl carbonate (30 mg, 0.067 mmol).¹1 H NMR (CDCl₃, 300MHz) δ1.91-2.05 (m, 2H), 2.60-2.80 (m, 1H), 2.81-3.02 (m, 2H), 3.03-3.18 (m, 2H), 3.20-3.38 (m, 2H), 3.39-3.63 (m, 4H), 6.97 (dd, J = 22.4, 2.2Hz, 1H), 7.02-7.14 (m, 4H) ppm. [1570] (Example 445) 2- (4-Methoxy-2-methylphenyl) -1-methyl-6,7,8a,9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole [1571] (Step A) 2-Bromo-1-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] by the method of step C of Example 89. , 3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (220 mg, 0.5 mmol) and the corresponding 4-methoxy-2-methylphenylboronic acid (166 mg, 1.0 mmol) to 2- (4-methoxy) -2-Methylphenyl) -1-Methyl-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate was prepared. Purification by chromatography gave the desired compound (186 mg, 78%). MS-ApCI: 481 [M + H⁺]. [1572] (Step B) 2- (4-Methoxy-2-methylphenyl) -1-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1] by the method of Example 98 , 4] The title compound was prepared from thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate. The title compound (18 mg, 87%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ6.93-7.04 (m, 1H), 6.69-6.77 (m, 3H), 3.85-3.94 (m, 1H), 3.81 (s, 3H), 3.57-3.73 (m, 1H), 3.31- 3.33 (m, 1H), 2.86-3.15 (m, 6H), 2.40-2.49 (m, 1H), 1.76-2.14 (m, 11H) ppm. MS-ApCI: 381 [M + H⁺]. [1573] (Example 446) 2- [4-Methoxy-2- (trifluoromethyl) phenyl] -1-methyl-6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1, 4] Chiazepino [2,3,4-hi] Indole [1574] (Step A) 2-Bromo-1-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] by the method of step C of Example 89. , 3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (220 mg, 0.5 mmol) and the corresponding 4-methoxy-2- (trifluoromethyl) phenylboronic acid (220 mg, 1.0 mmol) to 2- [4-Methoxy-2- (trifluoromethyl) phenyl] -1-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate was prepared. Purification by chromatography gave the desired compound (196 mg, 73%). MS-ApCI: 535 [M + H⁺]. [1575] (Step B) 2- [4-Methoxy-2- (trifluoromethyl) phenyl] -1-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] by the method of Example 98 ] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -The title compound was prepared from tert-butyl carbonate. The title compound (21 mg, 89%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ6.99-7.21 (m, 3H), 6.72 (d, 1H, 7.6Hz), 3.81-3.99 (m, 1H), 3.87 (s, 3H), 3.56-3.68 (m, 1H), 3.31 -3.35 (m, 1H), 2.86-3.16 (m, 6H), 2.38-2.49 (m, 1H), 1.74-2.15 (m, 5H), 1.81 (s, 3H) ppm. MS-ESI: 435 [MH]⁺.. [1576] (Example 447) (6bR, 10aS) -5- (2,6-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-Octahydropyrido [4,3-b] [1,4] Thiadino [ 2,3,4-hi] indole hydrochloride [1577] (Step A) Commercially available 2H-1,4-benzothiazine-3 (4H) -on (190 g, 1.15 mol) in a 5 L three-necked round-bottom flask equipped with a mechanical stirrer, dropping funnel and condenser at room temperature in a nitrogen atmosphere. ), Then anhydrous benzene (950 mL) was charged. The mixture was cooled in an ice / acetone bath and Vitride (640 mL, 2.30 mol) was added dropwise over 2.5 hours. After completion of the addition, the reaction mixture was refluxed for 1.5 hours. After the starting material has completely disappeared (TLC, 70:30 hexane, ethyl acetate), cool the mixture to 0 ° C and carefully pour 1N NaOH solution (1.7L) while keeping the internal temperature below 20 ° C. Dropped in. After the addition, the mixture was extracted with benzene (3 x 1.0 L). The organic extracts are combined, washed with water and saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to dryness to give the desired product 3,4-dihydro-2H-1,4- Benzothiazine (171.2 g, 98%) was obtained as a brown oil. It was used in the next step without further purification.¹1 H NMR (300MHz, CDCl₃) δ2.92-3.03 (m, 2H), 3.49-3.57 (m, 2H), 3.79-4.09 (br-s, 1H), 6.40 (d, 2H, J = 9.90Hz), 6.59 (t, 1H, J1 = 7.70Hz, J2 = 9.90Hz), 6.88 (t, 2H, J1 = 7.70Hz, J2 = 9.90Hz), 6.96 (d, 1H, J = 9.90Hz) ppm. [1578] (Step B) A solution of 3,4-dihydro-2H-1,4-benzothiazine (50.0 g, 330.8 mmol) in acetic acid (170 mL) was cooled to -10 ° C in an ice / acetone bath and sodium nitrite (27.4 mL) in 75 mL of water. g, 397.1 mmol) was added over 35 minutes. After the addition, the mixture was warmed to room temperature and stirred for an additional 1.5 hours. Cold water (150 mL) was added and the resulting mixture was extracted with dichloromethane (4 x 250 mL). The organic extracts were combined, washed with water and saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to dryness, 4-nitroso-3,4-dihydro-2H-1,4-benzothiazine ( 60.26 g, 101%) was obtained as a semi-solid. It was used in the next step without further purification.¹1 H NMR (300MHz, DMSO-d₆) δ2.99-3.05 (m, 2H), 4.16-4.24 (m, 2H), 7.15-7.31 (m, 3H), 7.88-7.97 (m, 1H) ppm. [1579] (Step C) A solution of 4-nitroso-3,4-dihydro-2H-1,4-benzothiazine (59.6 g, 330.8 mmol) in THF 150 mL in a THF solution (1 M) (331 mL, 331 mmol) of lithium aluminum hydride in a nitrogen atmosphere. Was added at -15 ° C for 2 hours. After the addition, the mixture was slowly warmed to room temperature. After 4 hours, the reaction was completed (TLC, 70:30 hexane, ethyl acetate). Sodium sulphate hydrate (about 150 g) was carefully added until foaming stopped. The resulting slurry mixture was filtered and washed with THF (5 x 50 mL). The organic filtrate was concentrated under reduced pressure to give a red oil. The residue was dissolved in EtOAc (300 mL), cooled to 0 ° C. and treated with 1 M etheric hydrochloric acid solution (230 mL). The resulting precipitate was collected by filtration, washed with EtOAc (50 mL) and dried under reduced pressure to 2,3-dihydro-4H-1,4-benzothiazine-4-amine hydrochloride (48.8 g, 73%). ) Was obtained as a white solid.¹1 H NMR (300MHz, CDCl₃) δ3.21-3.32 (m, 2H), 3.69-3.78 (m, 2H), 4.70-5.11 (br-s, 2H), 6.98-7.36 (m, 4H) ppm. [1580] (Step D) 2,3-Dihydro-4H-1,4-benzothiazine-4-amine hydrochloride (30.6 g, 0.15 mol) and 4-piperidinone hydrochloride hydrate (23.3 g, 0.15 mol) were mixed with isopropanol (300 mL). The mixture was heated under reflux for 30 minutes. The mixture was then cooled to room temperature, concentrated hydrochloric acid (37.7 mL, 0.45 mol) was added all at once and refluxed overnight. This is cooled, the resulting solid is filtered, washed with cold isopropanol (10 mL), dried in air and a grayish white solid 1,2,7,8,9,10-hexahydropyrido [ 4,3-b] [1,4] Thiadino [2,3,4-hi] Indole hydrochloride (39.58 g, 98%) was used.¹1 H NMR (DMSO, 500MHz) δ3.01-3.11 (m, 2H), 3.29 (s, 2H), 3.40-3.50 (m, 2H), 4.21-4.32 (m, 4H), 6.91-6.98 (m, 2H) ), 7.24-7.31 (m, 1H), 9.62-9.71 (brs, 1H) ppm. MS (CI, methane) m / z = 231 [C₁₃H₁₄N₂S + H]⁺.. [1581] (Step E) 1,2,7,8,9,10-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole Hydrochloride (35.8g, unpurified, 134.2 mmol) ) Was added to a solution in 450 mL of trifluoroacetic acid in small portions over 2 hours at -15 ° C with sodium cyanoborohydride (32.0 g, 507.9 mmol). After the addition, the slurry was vigorously stirred at room temperature for 2 hours and then carefully quenched with 6N HCl (900 mL). The resulting mixture was then heated to reflux for 1 hour. The solvent was removed under reduced pressure and the residue was neutralized with 50% wt / wt NaOH. The aqueous layer was repeatedly extracted with dichloromethane (3 x 500 mL). Organic extract with 1N NaOH (250 mL) and Boc₂It was mixed with O (32.0 g, 146.6 mmol). The two-phase mixture was stirred overnight, the organic layer was separated, washed with brine (250 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave the desired indoline product as a semi-solid. When this residue is ground with hexane, 1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] indole-8 ( 7H) -tert-butyl carbonate (31.4 g, 70%) was obtained as a white solid.¹1 H NMR (CDCl₃, 300MHz) δ1.47 (s, 9H), 1.86-1.94 (m, 2H), 2.78-3.29 (m, 5H), 3.34-4.10 (m, 5H), 6.64 (t, 1H, J = 7.92), 6.82-6.88 (m, 2H) ppm. MS (CI, methane) m / z = 333 [C₁₈H₂₄N₂O₂S + H]⁺.. [1582] (Step F) 1,2,6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate ( 2.00 g, 6.02 mmol) was dissolved in anhydrous DMF (50 mL) and then cooled in an ice / acetone bath at -10 ° C for 20 minutes. Then N-bromosuccinimide (1.18 g, 6.62 mmol) was added all at once. The reaction mixture was stirred at -10 ° C for 40 minutes and then poured onto an ice / water mixture (300 mL). The resulting suspension was stirred at room temperature for 30 minutes and extracted with diethyl ether (4 x 100 mL). Organic extracts were collected, washed with brine and dried over anhydrous sodium sulfate. When the solvent is removed under reduced pressure, 5-bromo-1,2,6b,9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate (2.24 g, 91%) was obtained as a yellow foam.¹1 H NMR (300MHz, CDCl₃) δ1.47 (s, 9H), 1.77 (m, 2H), 3.46-3.48 (m, 4H), 2.87-3.48 (m, 6H), 6.93 (s, 1H), 6.97 (s, 1H) ppm. [1583] (Step G) General procedure for coupling stannane with aryl bromide: N₂In the atmosphere, at room temperature (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3, 4-hi] Indole-8 (7H) -tert-butyl carbonate (316 mg, 0.768 mmol), PPh₃(40.4 mg, 0.154 mmol), CuBr (22 mg, 0.20 mmol), and Pd (PPh)₃)₂Cl₂Degassed DMF (25 mL) was added through a cannula to the mixture (55 mg, 0.0768 mmol). After stirring the reaction mixture at room temperature for 5 minutes, 2,6-dichlorophenyltrimethylstannan (357 mg, 1.15 mmol) was added as a solution of degassed DMF (2.5 mL) and the reaction mixture was heated to 140 ° C. After 10 minutes, the solution began to turn black. After 1 hour, the second addition (178 mg, 0.575 mmol) was added, and after 1 hour, the final dose (178 mg, 0.575 mmol) was added. After heating for an additional 30 minutes, the reaction mixture was cooled to room temperature and diluted with ethyl acetate / water (20 mL / 20 mL). The organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure and dried to give a dark oil. Purification of this residue by flash chromatography eluting with 10% EtOAc / Hexanes revealed that (6bR, 10aS) -5- (2,4-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [ 4,3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate (185 mg, 50%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ1.46 (s, 9H), 1.82-2.00 (m, 2H), 2.93-3.33 (m, 5H), 3.40-3.51 (m, 4H), 3.52-3.75 (m, 1H), 6.71 ( s, 1H), 6.75 (s, 1H), 7.12 (t, 1H, J = 7.9Hz), 7.33 (d, 2H, J = 7.9Hz) ppm. [1584] (Step H) Using the procedure described in Step B of Example 448, (6bR, 10aS) -5- (2,4-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3 The title compound (71 mg, 43%) was prepared from -b] [1,4] thiadino [2,3,4-hi] indole-8 (7H) -tert-butyl carbonate (197 mg).¹H NMR (CD)₃OD, 300MHz) δ2.09-2.21 (m, 1H), 2.32-2.45 (dm, 1H, J = 13.0Hz), 2.78 (t, 1H, J = 13.0Hz), 2.99 (dt, 1H, J = 1.8) , 11.2Hz), 3.12-3.65 (m, 8H), 3.70-3.80 (m, 1H), 6.72 (s, 1H), 6.81 (s, 1H), 7.25-7.30 (m, 1H), 7.43 (s, 1H), 7.47 (s, 1H) ppm. CIMS (methane) m / z = 378 [C₁₉H₁₈Cl₂N₂S + H]⁺.. [1585] (Example 448) (6bR, 10aS) -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] indole 3 , 3-Dioxide hydrochloride [1586] (Step A) Typical procedure for oxidizing sulfur to sulfone: Solid (6bR, 10aS) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] indole at room temperature -8 (7H) -tert-butyl carbonate (150 mg, 0.451 mmol) was dissolved in MeOH (6 mL). LVDS₃Prepared by diluting the saturated solution of No. 1 with the same amount of water and adjusting the pH to pH 11 to 12 with 6N NaOH.₃/ NaOH buffer aqueous solution (4 mL) was added to form a single homogeneous layer. The suspension was cooled to about 0 ° C. in an ice / water bath and solid Oxone® (416 mg, 0.677 mmol) was added in one portion. The suspension was stirred at about 0 ° C. for 15 minutes and then warmed to room temperature. After this reaction, TLC chromatography (SiO)₂, 60% EtOAc: 40% Hexane), the starting material disappeared (2-14 hours). The suspension was evaporated under reduced pressure to form a paste. The paste was dissolved in ethyl acetate (50 mL) and water (25 mL) and the aqueous layer was extracted with ethyl acetate (10 mL). Combine organic layers, wash with saturated NaCl (30 mL) and dry (Na)₂SO₄), And when evaporated under reduced pressure, 130 mg of crude sulfone was obtained as a colorless and transparent foam. Flash column chromatography (SiO) with a portion of 80 mg of crude sulfone₂Purified by (: 14 mm × 38 cm), purified (6bR, 10aS) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2, 3,4-hi] Indole-8 (7H) -tert-butyl carbonate 3,3-dioxide 63 mg (79%) was obtained as a colorless solid. [1587] (Step B) (6bR, 10aS) -1,2,6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -Tert-Butyl carbonate 3,3-dioxide (130 mg) was mixed with cold ethanol (4M) (5 mL) and the solution was stirred at 0 ° C for 10 minutes. The solvent was removed under reduced pressure and the residue was dissolved in hot acetonitrile with a small amount of methanol. When this was cooled to room temperature, the title compound (78 mg, 73%) was obtained as a white crystalline material.¹H NMR (CD)₃OD, 500MHz) δ2.13-2.22 (m, 1H), 2.23-2.32 (m, 1H), 2.88 (t, 1H, J = 11.3Hz), 3.19-3.35 (m, 4H), 3.45-3.66 (m) , 4H), 3.78-3.88 (m, 2H), 6.92 (t, 1H, J = 7.8Hz), 7.39 (d, 1H, J = 7.8Hz), 7.49 (d, 1H, J = 8.5Hz) ppm. CIMS (methane) m / z = 265 [C₁₃H₁₆N₂O₂S + H]⁺.. [1588] (Example 449) (6bS, 10aR) -1,2,6b,7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] indole 3 --Indole [1589] (Step A) Typical procedure for oxidizing sulfides to sulfoxides: (6bS, 10aR) -1,2,6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -Tert-Butyl carbonate (110 mg, 0.331 mmol) 2.5: 1 methanol, H₂It was dissolved in O (7 mL) and cooled to 0 ° C. Sodium periodate (71.0 mg, 0.331 mmol) was then added and the reaction mixture was stirred at 0 ° C. Stirring was continued until the reaction was completed (3-6 hours) by monitoring with TLC (silica gel; 60:40 hexane, ethyl acetate). The suspension was then filtered through a sintered glass funnel and the precipitate was washed with methanol (50 mL). The filtrates were combined and concentrated under reduced pressure to give an aqueous slurry solution, and the obtained residue was diluted with brine. Then, CH this aqueous solution₂Cl₂Extracted with (4 x 75 mL). Combine the organic layers with Na₂SO₄When dried above and concentrated under reduced pressure, (6bS, 10aR) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3] , 4-hi] A diastereomeric mixture of indole-8 (7H) -tert-butyl carbonate 3-oxide (110 mg, 96%) was obtained as a colorless oil.¹1 H NMR (300MHz, CDCl₃) δ1.37, (s, 9H), 1.82-2.18 (m, 2H), 2.63-3.62 (m, 7H), 3.63-4.25 (m, 3H), 6.58-6.88 (m, 1H), 7.11-7.29 (m, 1H), 7.29-7.49 (m, 1H) ppm. [1590] (Step B) (6bS, 10aR) -1,2,6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -CH with tert-butyl carbonate 3-oxide (110 mg)₂Cl₂The title compound (28 mg, 17%) was prepared by treatment with medium and excess TFA at 0 ° C. and then with 1N aqueous NaOH solution.¹1 H NMR (300MHz, CDCl₃) 1.79-1.99 (m, 1H), 2.10 (d, 1H, J = 12.2Hz), 2.39-2.57 (m, 1H), 2.72-3.01 (m, 3H), 3.01-3.22 (m, 2H), 3.22 -3.51 (m, 3H), 3.61-3.72 (m, 1H), 6.69-6.89 (m, 1H), 7.17 (d, 1H, J = 7.0Hz), 7.42 (d, 1H, J = 9.6Hz) ppm CIMSm / z = 249 [C₁₃H₁₆N₂OS + H]⁺.. [1591] (Example 450) (6bR, 10aS) -5- [4-Methoxy-2- (trifluoromethyl) phenyl] -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole 3,3-dioxide hydrochloride [1592] (Step A) Following the procedure in Part A of Example 398, (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [ 2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate to (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3] -b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate 3,3-dioxide was prepared. [1593] (Step B) Typical procedure for Suzuki coupling: Bromo-indoline (0.6 mmol), boronic acid (0.8 mmol), and barium hydroxide (1 mmol) were stirred and added to a solution of water (4 mL) and DME (8 mL), followed by bubbling an argon gas stream 60. Heated at ° C for 20 minutes. The reaction mixture is then cooled to room temperature and Pd (PPh).₃)₂Cl₂(0.03 mmol) and PPh₃(0.09 mmol) was added quickly and refluxed for 4 hours. When TLC showed that the reaction was complete, ethyl acetate (10 mL) was added and the mixture was filtered through a bed of Celite. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 10% EtOAc / Hexanes to give the desired product in 60-95% yield. Using the general procedure described above, (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiadino [ 2,3,4-hi] Indol-8 (7H) -tert-butyl carbonate 3,3-dioxide (150 mg, 0.338 mmol) and 2-trifluoromethyl-4-methoxyphenylboronic acid (112 mg, 0.507 mmol) By coupling with (6bR, 10aS) -5- [4-methoxy-2- (trifluoromethyl) phenyl] -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b ] [1,4] Thiadino [2,3,4-hi] Indol-8 (7H) -tert-butyl carbonate 3,3-dioxide (135 mg, 74%) was prepared. [1594] (Step C) Using the procedure described in step B of Example 448, (6bR, 10aS) -5- [4-methoxy-2- (trifluoromethyl) phenyl] -1,2,6b, 9,10,10a-hexa Hydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate 3,3-dioxide (135 mg) to the title compound (75 mg, 63%) was prepared.¹H NMR (CD)₃OD, 500MHz) δ2.15-2.24 (m, 1H), 2.31-2.39 (m, 1H), 2.91 (t, 1H, J = 12.1Hz), 3.22-3.32 (m, 2H), 3.48-3.70 (m) , 6H), 3.90 (s, 5H), 7.21 (d, 1H, J = 3.0Hz), 7.27 (m, 2H), 7.36 (s, 1H), 7.38 (s, 1H) ppm. CI-MS (methane) m / z = 439 [C₂₁H₂₁F₃N₂O₃S + H]⁺.. [1595] (Example 451) (6bR, 10aS) -5- (2,4-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-Octahydropyrido [4,3-b] [1,4] Thiadino [ 2,3,4-hi] Indole 3,3-dioxide hydrochloride [1596] (Step A) Using the procedure described in Step A of Example 450, (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4 ] Thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate 3,3-dioxide (93 mg, 0.210 mmol) and 2,4-dichlorophenylboronic acid (60 mg, 0.315 mmol) cup By ring, (6bR, 10aS) -5- (2,4-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiadino [2 , 3,4-hi] Indole-8 (7H) -tert-butyl carbonate 3,3-dioxide (94 mg, 88%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.42 (s, 9H), 1.82-2.05 (m, 2H), 3.30-3.60 (m, 6H), 3.60-4.00 (m, 4H), 7.20-7.32 (m, 3H), 7.45 ( s, 1H), 7.51 (s, 1H) ppm. [1597] (Step B) Using the procedure described in step B of Example 448, (6bR, 10aS) -5- (2,4-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3- b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate 3,3-dioxide (52 mg) was used to prepare the title compound (37 mg, 80%).¹H NMR (CD)₃OD, 500MHz) δ2.20-2.25 (m, 1H), 2.25-2.35 (m, 1H), 3.00 (t, 1H, 12.5Hz), 3.18-3.38 (m, 3H), 3.45-3.75 (m, 5H) ), 3.83-3.95 (m, 2H), 7.35 (d, 1H, J = 6.8Hz), 7.40 (m, 1H), 7.49 (m, 1H), 7.51 (m, 1H), 7.59 (m, 1H) ppm. CIMS (methane) m / z = 410 [C₁₉H₁₈Cl₂N₂O₂S + H]⁺.. [1598] (Example 452) (6bR, 10aS) -5- (4-Methoxy-2-methylphenyl) -1,2,6b, 7,8,9,10,10a-Octahydropyrido [4,3-b] [1,4 ] Thiadino [2,3,4-hi] Indole Hydrochloride [1599] (Step A) Using the procedure described in Step A of Example 450, (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1, 4] Coupling of thiazino [2,3,4-hi] indol-8 (7H) -tert-butyl carbonate (700 mg, 1.70 mmol) and 2-methyl-4-methoxyphenylboronic acid (424 mg, 2.55 mmol) By (6bR, 10aS) -5- (4-Methoxy-2-methylphenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiadino [ 2,3,4-hi] Indol-8 (7H) -tert-butyl carbonate (420 mg, 55%) was prepared. [1600] (Step B) Using the procedure described in step B of Example 448, (6bR, 10aS) -5- (4-methoxy-2-methylphenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4 , 3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate was used to prepare the title compound (338 mg, 94%).¹H NMR (CD)₃OD, 500MHz) δ2.12-2.23 (m, 1H), 2.21 (s, 3H), 2.36 (d, 1H, 13.0Hz), 2.80 (t, 1H, J = 12.4Hz), 2.96 (t, 1H, J = 11.4Hz), 3.20-3.35 (m, 2H), 3.37-3.60 (m, 6H), 3.72 (td, 1H, J = 2.0, 8.5Hz), 3.79 (s, 3H), 6.75 (m, 2H) ), 6.78 (s, 1H), 6.83 (s, 1H), 7.03 (d, 1H, J = 9.0Hz) ppm. CI-MS (methane) m / z = 353 [C₂₁H₂₄N₂OS + H]⁺.. [1601] (Example 453) (6bR, 10aS) -5- (2-Chloro-6-fluorophenyl) -1,2,6b, 7,8,9,10,10a-Octahydropyrido [4,3-b] [1,4 ] Thiadino [2,3,4-hi] Indole Hydrochloride [1602] (Step A) (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4] as illustrated in the general procedure described in step G of Example 447. , 3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate (1.0 g, 1.043 mmol) and 2-chloro-6-fluorophenyltrimethylstannan By coupling with (3.0 g, 3.129 mmol), (6bR, 10aS) -5- (2-chloro-6-fluorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [ 4,3-b] [1,4] thiazino [2,3,4-hi] indole-8 (7H) -tert-butyl carbonate (276 mg, 57%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.44 (s, 9H), 1.83-1.99 (m, 2H), 2.80-3.32 (m, 5H), 3.33-3.50 (m, 2H), 3.55-3.71 (m, 3H), 6.82 ( d, 1H, J = 8.1Hz), 7.01 (t, 1H, J = 8.1Hz), 7.12-7.35 (m, 3H) ppm. [1603] (Step B) Using the procedure described in Step B of Example 448, (6bR, 10aS) -5- (2-chloro-6-fluorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [ The title compound (101 mg, 43%) was formed from 4,3-b] [1,4] thiadino [2,3,4-hi] indole-8 (7H) -tert-butyl carbonate (270 mg).¹H NMR (CD)₃OD, 300MHz) δ2.16 (m, 1H), 2.31 (d, 1H, J = 12.8Hz), 2.85 (t, 1H, J = 13.0Hz), 3.00 (t, 1H, J = 12.4Hz), 3.15 -3.20 (m, 3H), 3.20-3.30 (m, 1H), 3.33-3.39 (m, 2H), 3.40-3.51 (m, 2H), 3.79 (m, 1H), 6.83 (s, 1H), 6.90 (s, 1H), 7.15 (m, 1H), 7.31 (m, 2H) ppm. CIMS (methane) m / z = 362 [C₁₉H₁₈ClFN₂S + H +]. [1604] (Example 454) (6bR, 10aS) -5- (2,6-difluorophenyl) -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] Indole hydrochloride [1605] (Step A) Using the procedure described in Step G of Example 447, (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1, 4] Cup of thiazino [2,3,4-hi] indole-8 (7H) -tert-butyl carbonate (0.350 g, 0.851 mmol) and 2,6-difluorophenyltrimethylstannan (0.707 g, 2.553 mmol) By ringing (6bR, 10aS) -5- (2,6-difluorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate (288 mg, 76%) was prepared. [1606] (Step B) Using the procedure described in Step B of Example 448, (6bR, 10aS) -5- (2,6-difluorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4, The title compound (200 mg, 80%) was prepared from 3-b] [1,4] thiadino [2,3,4-hi] indole-8 (7H) -tert-butyl carbonate (288 mg).¹H NMR (CD)₃OD, 300MHz) δ2.09-2.25 (m, 1H), 2.30-2.42 (m, 1H), 2.80 (t, 1H, J = 14Hz), 3.00 (t, 1H, J = 9.4Hz), 3.12-3.29 (m, 3H), 3.38-3.65 (m, 5H), 3.75 (td, 1H, J = 1.1, 10.2Hz), 6.92 (s, 1H), 6.98-7.10 (m, 3H), 7.25-7.49 (m) , 1H) ppm. CI-MS (methane) m / z = 345 [C₁₉H₁₈F₂N₂S + H]⁺.. [1607] (Example 455) (6bR, 10aS) -5- (2,4-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-Octahydropyrido [4,3-b] [1,4] Thiadino [ 2,3,4-hi] Indole hydrochloride [1608] (Step A) Appropriate (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [ 1,4] Chiadino [2,3,4-hi] Indole-8 (7H) -tert-butyl carbonate (250 mg, 0.608 mmol) and 2,4-dichlorophenylboronic acid (116 mg, 0.608 mmol) are coupled. By (6bR, 10aS) -5- (2,4-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2, 3,4-hi] Indole-8 (7H) -tert-butyl carbonate (136 mg, 47%) was prepared. [1609] (Step B) Using the procedure described in Step B of Example 448, (6bR, 10aS) -5- (2,4-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydropyrido [4,3 The title compound (80 mg, 68%) was prepared from -b] [1,4] thiadino [2,3,4-hi] indole-8 (7H) -tert-butyl carbonate (116 mg).¹H NMR (CD)₃OD, 300MHz) δ2.05-2.12 (m, 1H), 2.30-2.41 (m, 1H), 2.74-2.88 (m, 1H), 2.95 (t, 1H, J = 11.2Hz), 3.12-3.25 (m) , 3H), 3.35-3.60 (m, 5H), 3.69-3.79 (m, 1H), 6.92 (s, 1H), 6.99 (s, 1H), 7.25-7.40 (m, 2H), 7.51 (d, 1H) , J = 0.8Hz) ppm. ESIMSm / z = 378 [C₁₉H₁₈Cl₂N₂S + H]⁺.. [1610] (Example 456) 4-((6bS, 10aR) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] indoru-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone hydrochloride [1611] (Step A) Typical procedure for alkylation of amines: A mixture of indoline hydrochloride (about 200 mg) in dioxane (4 mL) was treated with Hunig's base (10 eq) and heated to reflux for 15 minutes. The reaction mixture was cooled, 4-chloro-1- (4-fluorophenyl) -1-butanone (5 eq), KI (0.9 eq) was added, and then the entire mixture was refluxed for 48 hours. The reaction was then diluted with chloroform (20 mL) and extracted once with a saturated solution of ammonium chloride (10 mL) and twice with ice-cold water (100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and dried. Purification of the residue by flash chromatography with gradient elution with hexane / ethyl acetate (eg 96: 4 to 50:50) and then methanol / dichloromethane (eg 1:99 to 3:97) gives the desired product. Was done. [1612] Using the procedure described above, (6bS, 10aR) -1,2,6b, 7,8,9,10,10a-octahydropyrido [4,3-b] [1,4] thiazino [2,3, 4-hi] Indole hydrochloride (750 mg, 2.79 mmol) and 4-chloro-1- (4-fluorophenyl) -1-butanone (3.0 mL, 15.24 mmol) to 4-((6bS, 10aR) -1,2 , 6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H) -Il) -1- (4- Fluorophenyl) -1-butanone (478 mg, 52%) was obtained. [1613] (Step B) 4-((6bS, 10aR) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] using the procedure described in step B of Example 448. ] The title compound (483 mg, 81%) was prepared from thiazino [2,3,4-hi] indol-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone (578 mg).¹1 H NMR (DMSO, 300MHz) δ1.92-2.13 (m, 2H), 2.28 (br-s, 2H), 2.80 (t, 1H, J = 9.9Hz), 2.92-3.63 (m, 12H), 3.63- 3.75 (m, 1H), 6.67 (t, 1H, J = 7.9), 6.87 (d, 1H, J = 8.9), 6.96 (d, 1H, J = 6.9), 7.30-7.48 (m, 2H), 7.48 -8.12 (m, 2H), 10.43 (br-s, 1H) ppm. m / z = 397 [C₂₃H₂₅FN₂OS + H]⁺.. [1614] (Example 457) 4-((6bR, 10aS) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] thiazino [2,3,4-hi] indoru-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone hydrochloride [1615] (Step A) Using the procedure described in step A of Example 456, (6bR, 10aS) -1,2,6b,7,8,9,10,10a-octahydropyrido [4,3-b] [1, 4] Thiadino [2,3,4-hi] indole hydrochloride (750 mg, 2.79 mmol) and 4-chloro-1- (4-fluorophenyl) -1-butanone (3.0 mL, 15.24 mmol) to 4-(( 6bR, 10aS) -1,2,6b, 9,10,10a-Hexahydropyrido [4,3-b] [1,4] Thiadino [2,3,4-hi] Indole-8 (7H)- Indole -1- (4-fluorophenyl) -1-butanone (349 mg, 25%) was prepared. [1616] (Step B) 4-((6bR, 10aS) -1,2,6b, 9,10,10a-hexahydropyrido [4,3-b] [1,4] using the procedure described in step B of Example 448. ] The title compound (72 mg, 25%) was prepared from thiazino [2,3,4-hi] indol-8 (7H) -yl) -1- (4-fluorophenyl) -1-butanone (340 mg).¹1 H NMR (DMSO, 300MHz) δ1.92-2.13 (m, 2H), 2.28 (br-s, 2H), 2.80 (t, 1H, J = 9.9Hz), 2.92-3.63 (m, 12H), 3.63- 3.75 (m, 1H), 6.67 (t, 1H, J = 7.9), 6.87 (d, 1H, J = 8.9), 6.96 (d, 1H, J = 6.9), 7.30-7.48 (m, 2H), 7.48 -8.12 (m, 2H), 10.43 (br-s, 1H) ppm. m / z = 397 [C₂₃H₂₅FN₂OS + H]⁺.. [1617] (Example 458) (8aS, 12aR) -2- [4-Methoxy-2- (trifluoromethyl) phenyl] -3-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole hydrochloride [1618] (Step A) Using the procedure described in Step A of Example 450, (8aS, 12aR) -2-bromo-3-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (145 mg, 0.33 mmol) and 2-trifluoromethyl-4-methoxyphenylboronic acid (109 mg,) By coupling with 0.49 mmol), (8aS, 12aR) -2- [4-methoxy-2- (trifluoromethyl) phenyl] -3-methyl-6,7,9,10,12,12a-hexahydro -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (49 mg, 28%) was prepared. This material was used in the next step without further purification. [1619] (Step B) Using the procedure described in step B of Example 448, (8aS, 12aR) -2- [4-methoxy-2- (trifluoromethyl) phenyl] -3-methyl-6,7,9,10,12 , 12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (49 mg) to title compound (25 mg, 58%) was prepared.¹H NMR (CD)₃OD, 300MHz) δ1.89 (d, 3H, J = 3.2Hz), 1.93-2.12 (m, 3H), 2.19-2.35 (m, 3H), 2.66-2.79 (m ,, 1H), 2.95-3.39 ( m, 3H), 3.21-3.49 (m, 1H), 3.62-3.90 (m ,, 5H), 4.05-4.14 (m, 1H), 6.70 (s, 1H), 7.03-7.11 (m, 1H), 7.12 -7.18 (m, 1H), 7.22-7.25 (s, 1H) .m / z = 435 [C₂₃H₂₅F₃N₂OS + H]⁺.. [1620] (Example 459) (8aS, 12aR) -2- (2,4-dichlorophenyl) -3-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] Chiazepino [2,3,4-hi] indole hydrochloride [1621] (Step A) Using the procedure described in Step A of Example 450, (8aS, 12aR) -2-bromo-3-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3- b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (105 mg, 0.239 mmol) and 2,4-dichlorophenylboronic acid (69 mg, 0.350 mmol) By coupling, (8aS, 12aR) -2- (2,4-dichlorophenyl) -3-methyl-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (45 mg, 37%) was prepared.¹1 H NMR (CDCl₃, 300NMR) δ1.45 (s, 9H), 1.81-1.89 (m, 2H), 1.98-2.19 (m, 5H), 2.98-3.42 (m, 5H), 3.43-3.95 (m, 3H), 4.03- 4.18 (m, 2H), 6.58-6.63 (m, 1H), 7.07-7.14 (m, 1H), 7.19-7.28 (m, 1H), 7.45 (s, 1H). [1622] (Step B) Using the procedure described in Step B of Example 448, (8aS, 12aR) -2- (2,4-dichlorophenyl) -3-methyl-6,7,9,10,12,12a-hexahydro-5H- The title compound (11 mg, 27%) was prepared from pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (45 mg).¹1 H NMR (500MHz, CD₃OD) δ1.97-2.11 (m, 6H), 2.18-2.32 (m, 3H), 2.72-2.82 (m, 1H), 3.00-3.09 (m, 1H), 3.12-3.19 (m, 1H), 3.20 -3.45 (m, 3H), 3.69-3.71 (m, 1H), 4.03-4.14 (m, 1H), 6.71 (s, 1H), 7.01-7.09 (m, 1H), 7.31-7.38 (m, 1H) , 7.51 (s, 1H) .m / z = 406 [C₂₁H₂₂C_l2N₂+ H]⁺.. [1623] (Example 460) 3-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-yl] Benzonitrile, trifluoroacetate [1624] (Step A) (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol -11 (8aH) -tert-butyl carbonate (0.32 g, 0.74 mmol) in solution in 75 mL of 1,2-dimethoxyethane and 25 mL of water 3-cyanophenylboronic acid (0.22 g, 1.48 mmol) and barium hydroxide Hydrate (0.70 g, 2.22 mmol) was added. The mixture was degassed with a stream of nitrogen for 20 minutes, then tetrakis (triphenylphosphine) palladium (26 mg, 0.02 mmol) was added and the mixture was stirred at 100 ° C. for 3 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and brine, and dried (DDL).₄), Filtered with Celite, and concentrated under reduced pressure. Purification of the residue by flash chromatography (eluted with hexane / ethyl acetate) reveals (8aS, 12aR) -2- (3-cyanophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4]. , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 0.22 g (52%) was obtained.¹1 H NMR (CDCl₃): δ7.76 (s, 1H), 7.70 (appd, 1H, J = 7.6Hz), 7.52 (appdt, 1H, J = 7.7,1.5Hz), 7.47 (t, 1H, J = 7.7Hz), 7.18 (d, 1H, J = 1.9Hz), 7.09 (d, 1H, J = 1.9Hz), 3.90-3.80 (m, 2H), 3.63-3.52 (m, 2H), 3.51-3.45 (m, 1H), 3.42-3.28 (m, 3H), 3.21 (dt, 1H, J = 13.1, 4.2Hz), 3.02, (dt, 1H, J = 13.6, 4.9Hz), 2.15-2.10 (m, 2H), 1.91-1.87 (m, 2H), 1.41 (s, 9H). [1625] (Step B) Part A (8aS, 12aR) -2- (3-cyanophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.20 g, 0.45 mmol) was added to a solution in 80 mL of methylene chloride with 20 mL of trifluoroacetic acid and the mixture was stirred at ambient temperature for 3 hours. .. Volatile components are removed under reduced pressure and the residue is preparative HPLC (C18 reverse phase column, H with 0.5% TFA).₂O / CH₃Purification by gradient elution with CN) and lyophilization gave 45 g (22%) of the title compound.¹1 H NMR (CDCl₃): δ9.62 (broads, 1H), 9.39 (broads, 1H), 7.74 (s, 1H), 7.69 (appd, 1H, J = 7.7Hz), 7.57 (appd, 1H, J = 7.7Hz), 7.49 (t, 1H, J = 7.7Hz), 7.24 (d, 1H, J = 1.5Hz), 7.09 (d, 1H, J = 1.9Hz), 4.02-3.92 (m, 1H), 3.65-3.55 (m, 1H), 3.50-3.45 (m, 2H), 3.41-3.30 (m, 2H), 3.26-3.19 (m, 1H), 3.10-2.96 (m, 2H), 2.78-2.70 (m, 1H), 2.26- 2.10 (m, 4H) .LRMS (ES)⁺): 348.2 (M + H)⁺.. [1626] (Example 461) 4-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indol-2-yl] -3-methylbenzonitrile, trifluoroacetate [1627] The title compound was prepared with 2-methyl-4-cyanophenylboronic acid according to the procedure described in Example 460.¹1 H NMR (CDCl₃): δ9.61 (broads, 1H), 9.26 (broads, 1H), 7.45 (s, 1H), 7.41 (d, 1H, J = 8.0Hz), 7.17 (d, 1H, J = 8.0Hz), 6.89 (s, 1H), 6.74 (s, 1H), 3.97-3.85 (m, 1H), 3.60-3.50 (m, 1H), 3.42-3.35 (m, 2H), 3.30-3.20 (m, 2H), 3.18 -3.10 (m, 1H), 3.00-2.87 (m, 2H), 2.70-2.60 (m, 1H), 2.22 (s, 3H), 2.15-2.02 (m, 4H) .LRMS (ES)⁺): 362.2 (M + H)⁺.. [1628] (Example 462) 3-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indol-2-yl] -2-methylbenzonitrile, trifluoroacetate [1629] The title compound was prepared with 2-methyl-3-cyanophenylboronic acid according to the procedure described in Example 460.¹1 H NMR (CDCl₃): δ9.21 (broads, 1H), 8.95 (broads, 1H), 7.57 (dd, 1H, J = 7.5, 1.3Hz), 7.36 (dd, 1H, J = 7.4, 1.4Hz), 7.27 (t, 1H, J = 7.7Hz), 6.93 (d, 1H, J = 1.1Hz), 6.78 (d, 1H, J = 1.1Hz), 4.02-3.95 (m, 1H), 3.65-56 (m, 1H), 3.50-3.42 (m, 2H), 3.41-3.32 (m, 2H), 3.22-3.15 (m, 1H), 3.10-2.96 (m, 2H), 2.78-2.72 (m, 1H), 2.44 (s, 3H) ), 2.25-2.10 (m, 4H) .LRMS (ES)⁺): 362.4 (M + H)⁺.. [1630] (Example 463) 2-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-yl] Benzonitrile, trifluoroacetate [1631] (Step A) (8aS, 12aR)-6,7,9,10,12,12a-Hexahydro-5H-Pirido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) )-Tert-Butyl carbonate (5.0 g, 14.4 mmol) was added to the solution in 50 mL of DMF with N-iodosuccinimide (3.6 g, 15.9 mmol) at 0 ° C. The reaction was stirred for 4 hours while slowly warming to ambient temperature. The mixture is diluted with ethyl acetate, washed with water and saline and dried (DDL).₄), Filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography (eluted with hexane / ethyl acetate) reveals (8aS, 12aR) -2-iodo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b]. [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 1.6 g (23%) was obtained.¹1 H NMR (CDCl₃): δ7.23 (d, 1H, J = 1.9Hz), 7.12 (d, 1H, J = 1.4Hz), 3.80-3.65 (m, 2H), 3.52-3.38 (m, 5H), 3.18 (appq, 2H, J = 6.2Hz), 3.00-2.90 (m, 1H), 2.08-2.00 (m, 2H), 1.85-1.78 (m, 2H), 1.43 (s, 9H). [1632] (Step B) (8aS, 12aR) -2-iodo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole To a solution of -11 (8aH) -tert-butyl carbonate (1.60 g, 3.39 mmol) in 100 mL DMSO was added diboron pinacol ester (1.29 g, 5.09 mmol) and potassium acetate (1.0 g, 10.2 mmol). The mixture was degassed with a stream of nitrogen for 20 minutes, then tetrakis (triphenylphosphine) palladium (200, 0.17 mmol) was added and the mixture was stirred at 80 ° C. for 16 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate, washed with saline and dried (DDL).₄), Filtered with Celite, and concentrated under reduced pressure. Purification of the residue by flash chromatography (eluted with hexane / ethyl acetate) reveals (8aS, 12aR) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -6. , 7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate 0.76 g (48%) was obtained.¹1 H NMR (CDCl₃): δ7.45 (d, 1H, J = 0.8Hz), 7.32 (apps, 1H), 3.89-3.80 (m, 2H), 3.65-3.60 (m, 1H), 3.59-3.39 (m, 4H), 3.26-3.18 (m, 2H), 3.05-2.95 (m, 1H), 2.12-2.02 (m, 2H), 1.88-1.80 (m, 2H), 1.43 (s, 9H), 1.30 (s, 12H). [1633] (Step C) (8aS, 12aR) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate (0.10 g, 0.21 mmol) in 1,2-dimethoxyethane 15 mL and water To the solution in 5 mL was added 2-bromobenzonitrile (0.08 g, 0.42 mmol) and barium hydroxide octahydrate (0.20 g, 0.63 mmol). The mixture was degassed with a stream of nitrogen for 20 minutes, then tetrakis (triphenylphosphine) palladium (10 mg, 0.009 mmol) was added and the mixture was stirred at 80 ° C. for 3 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and brine, and dried (DDL).₄), Filtered with Celite, and concentrated under reduced pressure. Purification of the residue by flash chromatography (eluted with hexane / ethyl acetate) reveals (8aS, 12aR) -2- (2-cyanophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4]. , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 55 mg (61%) was obtained.¹1 H NMR (CDCl₃): δ7.69 (dd, 1H, J = 7.3, 0.8Hz), 7.56 (td, 1H, J = 7.7, 1.5Hz), 7.42 (appd, 1H, J = 7.7Hz), 7.33 (td, 1H, J = 7.7,1.1Hz), 7.14 (s, 1H), 7.11 (s, 1H), 3.94-3.82 (m, 2H), 3.3.63-3.43 (m, 4H), 3.41-3.28 (m, 2H) , 3.21-3.10 (m, 1H), 3.04-2.96, (m, 1H), 2.18-2.02 (m, 2H), 1.94-1.85 (m, 2H), 1.39 (s, 9H) .LRMS (ES)⁺): 448.1 (M + H)⁺.. [1634] (Step D) Part A (8aS, 12aR) -2- (2-cyanophenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.10 g, 0.22 mmol) was added to a solution in 20 mL of methylene chloride, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at ambient temperature for 4 hours. did. Volatile components are removed under reduced pressure and the residue is preparative HPLC (C18 reverse phase column, H with 0.5% TFA).₂O / CH₃Purification by gradient elution with CN) and lyophilization gave 65 mg (64%) of the title compound.¹1 H NMR (CDCl₃): δ9.40 (broads, 1H), 9.23 (broads, 1H), 7.69 (d, 1H, J = 7.7Hz), 7.59 (appt, 1H, J = 7.7Hz), 7.43 (d, 1H, J = 7.7Hz), 7.38 (t, 1H, J = 7.7Hz), 7.18 (d, 1H, J = 1.8Hz), 7.16 (s, 1H), 4.06-3.96 (m, 1H), 3.67-3.58 (m, 1H), 3.52-3.48 (m, 2H), 3.43-3.33 (m, 2H), 3.26-3.19 (m, 1H), 3.10-2.96 (m, 2H), 2.80-2.70 (m, 1H), 2.25- 2.05 (m, 4H) .LRMS (ES)⁺): 348.3 (M + H)⁺.. [1635] (Example 464) 4-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indol-2-yl] -3- (trifluoromethyl) benzonitrile, trifluoroacetate [1636] The title compound was prepared with 4-bromo-3- (trifluoromethyl) benzonitrile according to the procedures described in Part C and D of Example 463.¹1 H NMR (CDCl₃): δ9.38 (broads, 1H), 9.02 (broads, 1H), 7.99 (s, 1H), 7.81 (d, 1H, J = 7.6Hz), 7.43 (d, 1H, J = 7.7Hz), 6.97 (s, 1H), 6.83 (s, 1H), 4.06-3.96 (m, 1H), 3.68-3.58 (m, 1H), 3.52-3.45 (m, 2H), 3.44-3.30 (m, 2H), 3.27 -3.18 (m, 1H), 3.10-2.95 (m, 2H), 2.78-2.64 (m, 1H), 2.25-2.05 (m, 4H) .LRMS (ES)⁺): 416.3 (M + H)⁺.. [1637] (Example 465) 3-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-yl] benzaldehyde, trifluoroacetate [1638] (Step A) (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole -11 (8aH) -tert-butyl carbonate (0.50 g, 1.17 mmol) in a solution in 75 mL of 1,2-dimethoxyethane and 25 mL of water, 3-formylphenylboronic acid (0.52 g, 3.52 mmol) and barium hydroxide. Octahydrate (1.11 g, 3.52 mmol) was added. The mixture was degassed with a stream of nitrogen for 20 minutes, then tetrakis (triphenylphosphine) palladium (0.04 g, 0.035 mmol) was added and the mixture was stirred at 100 ° C. for 3 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and brine, and dried (DDL).₄), Filtered with Celite, and concentrated under reduced pressure. Purification of the residue by flash chromatography (eluted with hexane / ethyl acetate) reveals (8aS, 12aR) -2- (3-formylphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4 , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate 0.51 g (96%) was obtained.¹1 H NMR (CDCl₃) δ10.05 (s, 1H), 8.00 (s, 1H), 7.78-7.74 (m, 2H), 7.54 (t, J = 7.7Hz, 1H), 7.16 (d, J = 1.9Hz, 2H) 7.16 &amp; 7.07 (twodduetorotomers, J = 1.8Hz, 1H), 4.85-2.97 (broadm, 8H), 2.18-2.04 (m, 2H), 1.89-1.81 (m, 2H), 1.63-1.49 (m, 2H), 1.42, (s, 9H) .LRMS (ApcI): 451.0 (M + H)⁺.. [1639] (Step B) (8aS, 12aR) -2- (3-formylphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, To a solution of 4-hi] indole-11 (8aH) -tert-butyl carbonate (0.051 g, 0.113 mmol) in 20 mL of methylene chloride was added 5 mL of trifluoroacetic acid and the mixture was stirred at ambient temperature for 3 hours. Volatile components are removed under reduced pressure and the residue is separated by preparative HPLC (C18 reverse phase column, 0.5% TFA, H).₂O / CH₃Purification by gradient elution with CN) and lyophilization gave 25 mg (45%) of the title compound.¹H NMR (DMSO-d₆) δ10.04 (s, 1H), 8.68 (broads, 4H), 8.08 (s, 1H), 7.91 (d, J = 8Hz, 1H), 7.80 (d, J = 7.6Hz, 1H), 7.62 (t) , J = 7.6Hz 1H), 7.42 (d, 1.8Hz), 7.37 (d, 1.9Hz, 1H), 7.17 &amp; 7.05 (twodduetorotomers, J = 1.8Hz, 1H), 4.50 &amp; 4.38 (twom, duetorotomers, 1H) ), 3.70-2.95 (broadm, 7H), 2.17-1.90 (broadm, 6H) .LRMS (ES)⁺): 351.2 (M + H)⁺.. [1640] (Example 466) {3-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indol-2-yl] phenyl} methanol, trifluoroacetate [1641] (Step A) (8aS, 12aR) -2- (3-formylphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.28 g, 0.62 mmol) in a solution in 50 mL of methanol, NaBH₄(0.045 g, 1.24 mmol) was added and the mixture was stirred at room temperature for 2 hours. Volatile components were removed under reduced pressure and the residue was purified by column chromatography (eluted with 1: 1 EtOAc / Hexanes) to (8aS, 12aR) -2- [3- (hydroxymethyl) phenyl] -6,7,9, 10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate 120 mg (43%) Obtained.¹1 H NMR (300MHz, CDCl₃) δ7.79-7.14 (m, 6H), 4.74 (s, 2H), 3.90-2.95 (broadm, 10H), 2.20-1.85 (broadm, 4H), 1.43 (s, 9H) .LRMS (ApcI): 453.1 (M + H)⁺.. [1642] (Part B) According to the procedure described in Part B of Example 465, (8aS, 12aR) -2- [3- (hydroxymethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4 , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate was converted to the title compound.¹H NMR (DMSO-d₆) δ8.72-8.68 (m, 4H), 7.58-7.18 (broadm, 6H), 4.52 (s, 2H), 3.70-2.95 (broadm, 7H), 2.78-2.65 (m, 1H), 2.19-1.89 ( broadm, 4H) .LRMS (ES)⁺): 353.2 (M + H)⁺.. [1643] (Example 467) 3-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indol-2-yl] benzyl methyl ether, trifluoroacetate [1644] (Step A) (8aS, 12aR) -2- [3- (hydroxymethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2] , 3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.12 g, 0.27 mmol) was added to a solution in 100 mL of THF with NaH (0.03 g, 1.27 mmol) and iodomethane (0.165 mL, 2.65 mmol). , The solution was stirred at room temperature overnight. The solution was quenched with methanol, the solution was diluted with ethyl acetate and washed with brine. Organics are dried over magnesium sulphate, filtered through a silica gel pad and volatiles removed under reduced pressure and used without purification (8aS, 12aR) -2- [3- (methoxymethyl) phenyl]- 6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate 100 mg (81%) was obtained.¹1 H NMR (CDCl₃) δ7.48-7.06 (broadm, 6H), 4.51 (s, 2H), 3.85-1.85 (broadm, 11H), 1.65-1.25 (13H) .LRMS (ApcI): 467.1 (M + H)⁺.. [1645] (Step B) According to the procedure described in Part B of Example 465, (8aS, 12aR) -2- [3- (methoxymethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4 , 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate was converted to the title compound.¹H NMR (DMSO-d₆) δ8.71 (m, 4H), 7.45-7.17 (m, 6H), 4.40 (s, 2H), 3.63-2.97 (broadm, 10H), 2.68 (m1H), 2.08-1.93 (broadm, 4H) .LRMS (ES⁺): 367.2 (M + H)⁺.. [1646] (Example 468) N- {3-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indol-2-yl] benzyl} -N, N-dimethylamine, bistrifluoroacetate [1647] (Step A) (8aS, 12aR) -2- (3-formylphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.15 g, 0.33 mmol) in 150 mL of THF, dimethylamine (0.66 mL, 1.33 mmol of 2M solution in methanol), NaBH (OAc)₃(0.14 g, 0.60 mmol), and excess HOAc (1 mL) were added. The reaction was stirred at room temperature overnight. The solution was filtered through a silica gel pad to remove volatile components. When the reaction is passed through a short column of silica gel (eluted with 4: 1 EtOH: EtOAc), (8aS, 12aR) -2- [3- (dimethylaminomethyl) phenyl] -6,7,9,10,12,12a -Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate was obtained.¹1 H NMR (CDCl₃) δ7.52-7.13 (broadm, 6H), 3.95 (s, 2H), 3.88-2.96 (broadm, 10H), 2.57 (s, 6H), 2.20-2.07 (broadm, 2H), 1.90 (broads, 2H) , 1.42 (broads, 9H) .LRMS (ApcI): 480.1 (M + H)⁺.. [1648] (Step B) According to the procedure described in Part B of Example 465, (8aS, 12aR) -2- [3- (dimethylaminomethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H-pyrido [ 4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate was converted to the title compound.¹H NMR (DMSO-d₆) δ8.85-8.79 (m, 3H), 7.68 (s, 1H), 7.62 (d, J = 6.6Hz, 1H), 7.45 (t, J = 7.3Hz, 1H), 7.35-7.32 (m, 2H) ), 7.24 (s, 1H), 4.28 (s, 2H), 3.66-2.97 (broadm, 9H), 2.74 (s, 6H), 2.70 (s, 1H), 2.20-1.94 (m, 4H) .LRMS ( ES⁺): 380.1 (M + H)⁺.. [1649] (Example 469 and Example 470) 5-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-yl] -2-fluorobenzonitrile trifluoroacetate (Example 469) and 5-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-2-yl] -2-fluorobenzamide trifluoroacetate (Example 470) [1650] Following the procedure described in Example 460, using 3-cyano-4-fluorophenylboronic acid, 5-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a- Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-2-yl] -2-fluorobenzonitrile trifluoroacetate was prepared and also 5 -[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] ] Indol-2-yl] -2-fluorobenzamide Trifluoroacetate was isolated as a by-product. Example 469:¹1 H NMR (CDCl₃): δ9.55 (broads, 1H), 9.26 (broads, 1H), 7.68-7.63 (m, 2H), 7.26-7.22 (m, 1H), 7.17 (d, 1H, J = 1.5Hz), 7.03 ( s, 1H), 4.00-3.90 (m, 1H), 3.63-3.52 (m, 1H), 3.50-3.43 (m, 2H), 3.41-3.30 (m, 2H), 3.24-3.18 (m, 1H), 3.10-2.95 (m, 2H), 2.55-2.45 (m, 1H), 2.25-2.10 (m, 4H) .LRMS (ES)⁺): 366.6 (M + H)⁺.. Example 470: LRMS (ES)⁺): 384.1 (M + H)⁺.. [1651] (Example 471) 6,7,9,10,11,12,13,13a-Octahydro-5H, 8aH-Azepino [4,5-b] [1,4] Chiazepino [2,3,4-hi] Indole [1652] (Step A) EtOH (40 mL) of 3,4-dihydro-1,5-benzothiazepine-5 (2H) -amine hydrochloride (3.96 g, 22 mmol) and hexahydro-4H-azepine-4-one hydrochloride (3.3 g, 22 mmol) ) Suspended in. 12 M HCl (3.7 mL, 44 mmol) was added. The reaction was degassed and refluxed in a nitrogen atmosphere for 48 hours. The reaction was cooled to room temperature and stirred for 18 hours. The precipitate was filtered, washed with cold EtOH and dried in air for 18 hours. 6,7,10,11,12,13-Hexahydro-5H, 9H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole hydrochloride (4.42g, 15 mmol, 68%) were isolated as white powder.¹1 H NMR (CDCl₃, 300MHz) δ7.22 (1H, dd, 1.1Hz, 7.7Hz), 6.99 (1H, dd, 1.1Hz, 7.4Hz), 6.89 (1H, t, 7.6Hz), 4.60 (2H, t, 5.9Hz) , 3.38 (2H, t, 6.6Hz), 3.07-3.14 (4H, m), 2.82-2.96 (4H, m), 2.03-2.31 (2H, m). [1653] (Step B) 6,7,10,11,12,13-Hexahydro-5H, 9H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole hydrochloride (4.42g, 15 mmol) Was dissolved in TFA (40 mL). After cooling this solution to 0 ° C, NaCNBH₃(2.8 g, 45 mmol) was added in small portions while maintaining the temperature below 15 ° C. After completion of the addition, the reaction was stirred at 0 ° C. for 1 hour. Ice pieces (about 3 g) were added to the reaction flask, and 50% NaOH was added up to pH = 14. CHCl an aqueous solution of this mixture₃Extracted with (3 x 30 mL). The organic layers were combined, washed with saline, dried and concentrated. The organic residue was dissolved in dioxane and 1M NaOH. Cool this solution to 0 ° C and BOC₂O was added. The reaction was stirred at room temperature for 3 hours and then concentrated. EtOAc and saline were added to the residue and the mixture was stirred for 10 minutes. The layers were separated and the aqueous mixture solution was extracted again with EtOAc. The organic layers were combined, washed with saline, dried and concentrated to give 4 g of a brown viscous oil. Purification of this crude material by column chromatography (10-50% EtOAc / Hexanes) revealed 6,7,8a, 9,10,12,13,13a-octahydro-5H, 11H-azepino [4,5-b]. [1,4] Thiazepino [2,3,4-hi] Indole-11-tert-butyl carbonate (3.47 g, 9.6 mmol, 64%) was obtained as a clear light brown amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ6.95 (1H, d, 7.7Hz), 6.82 (1H, d, 7.4Hz), 6.16 (1H, t, 7.7Hz), 3.7-3.9 (1H, m), 3.2-3.9 (8H, m), 2.9-3.05 (1H, m), 2.75-2.9 (1H, m), 1.8-2.2 (5H, m), 1.45 (9H, s). [1654] (Step C) 6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole-11-Carbonate tert-Butyl (1.7 g, 4.7 mmol) was dissolved in TFA (20 mL). The solution was stirred for 2 hours. Ice was added to the reaction vessel and 50% NaOH was added to pH = 14. CHCl this aqueous solution₃Extracted with (2 x 15 mL). The organic layers were combined, washed with saline, dried and concentrated to give the title compound (1.2 g, 4.6 mmol, 98%) as a light brown amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ6.95 (1H, d, 7.7Hz), 6.82 (1H, d, 7.3Hz), 6.16 (1H, t, 7.6Hz), 3.75-3.9 (1H, m), 3.3-3.7 (3H, m), 2.6-3.2 (6H, m), 1.7-2.2 (6H, m) [1655] (Example 472) 4- [6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Chiazepino [2,3,4-hi] Indoru- 11-yl] -1- (4-fluorophenyl) -1-butanone [1656] 6,7,9,10,11,12,13,13a-Octahydro-5H, 8aH-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole (200mg, 0.78) mmol), 4-chloro-4'-fluorobutyrophenone (213 mg, 1.6 mmol), KI (129 mg, 0.78 mmol), K₂CO₃(322 mg, 2.3 mmol), and 2 drops of TEA were suspended in MEK (4 mL). The mixture was heated for 60 hours. The reaction was cooled to room temperature and concentrated. Column chromatography of residue (5, 7, 10% MeOH / CH₂Cl₂), The title compound (234 mg, 0.55 mmol, 71%) was obtained as a light brown viscous oil.¹1 H NMR (CDCl₃, 300MHz) δ6.95 (2H, ddd, 2.9Hz, 5.1Hz, 12.1Hz), 7.06 (2H, m), 6.91 (1H, 7.7Hz), 6.74 (1H, d, 7.3Hz), 6.55 (1H, 1H, t, 7.7Hz), 3.65-3.75 (1H, m), 3.45-3.61 (2H, m), 3.29-3.38 (1H, m), 2.85-3.0 (4H, m), 2.2-2.8 (6H, m) , 1.7-2.2 (8H, m) .MS (ESI): 425.3 (base, M + H) [1657] (Example 473) (8aS, 13aS) -11- [3- (4-fluorophenoxy) propyl] -6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [4,5-b] [1,4] Chiazepino [2,3,4-hi] Indole [1658] 6,7,9,10,11,12,13,13a-Octahydro-5H, 8aH-Azepino [4,5-b] [1,4] Chiazepino [2,3,4-hi] Indole (43.3mg, 0.17 mmol), 1- (3-chloropropoxy) -4-fluorobenzene (40.8 mg, 0.22 mmol), KI (27.6 mg, 0.17 mmol), and K₂CO₃(69 mg, 0.50 mmol) was suspended in 4 mL of MEK. The suspension was heated at 80 ° C. for 18 hours. The reaction was cooled to room temperature and concentrated. Column chromatography of residue (5, 7, 10% MeOH / CH₂Cl₂), The racemic form of the title compound (24.5 mg, 0.06 mmol, 35%) was obtained as a light brown viscous oil. Separation of enantiomers on the Chiracelle OD column using hexane / IPA / TFA (75/25 / 0.1) as the eluate gave the title compound.¹1 H NMR (CDCl₃, 300MHz) δ6.85-6.95 (2H, m), 7.06 (2H, m), 6.68-6.80 (2H, m), 6.53 (1H, t, 7.6Hz), 3.90 (2H, t, 6.2Hz), 3.70-3.80 (1H, m), 3.32-3.59 (3H, m), 2.71-2.94 (3H, m), 2.46-2.58 (5H, m), 1.7-2.1 (8H, m) .MS (ESI): 413.3 (base, M + H) [1659] (Example 474) 11-[2- (6-fluoro-1,2-benzoisooxasol-3-yl) propyl] -6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [ 4,5-b] [1,4] Chiazepino [2,3,4-hi] Indole [1660] 6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [4,5-b] [1,4] thiazepino [2] by the same general method as in Example 473. , 3,4-hi] The title compound was prepared from indole (45 mg, 0.17 mmol) and 3- (3-chloropropyl) -1,2-benzisooxazole (61.3 mmol, 0.35 mmol). After purification by chromatography, the desired product (46.1 mg, 11 mmol, 62%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ7.71 (1H, dd, 5.1Hz, 8.8Hz), 7.23 (1H, dd, 1.8Hz, 8.4Hz), 7.06 (1H, dt, 2.2Hz, 8.4Hz), 6.94 (1H, br- d, 7.6Hz), 6.80 (1h, 7.4Hz), 6.59 (1H, t, 7.3Hz), 3.81 (1H, ddd, 5.1Hz, 9.9Hz, 13.6Hz), 3.38-3.65 (3H, m), 2.92 -3.00 (3H, m), 2.68-2.88 (2H, m), 2.44-2.61 (5H, m), 1.87-2.12 (8H, m) .MS (ESI): 438.2 (base, M + H) [1661] (Example 475) 4- [6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Chiazepino [2,3,4-hi] Indoru- 11-il] -1- (4-pyridinyl) -1-butanone [1662] 6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [4,5-b] [1,4] thiazepino [2] by the same general method as in Example 473. , 3,4-hi] The title compound was prepared from indole (275 mg, 1.1 mmol) and 4-chloro-1- (4-pyridinyl) -1-butanone (387 mmol, 2.1 mmol). After purification by chromatography, the desired product (60.2 mg, 0.15 mmol, 14%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ8.81 (2H, dd, 1.4Hz, 4.4Hz), 7.73 (2H, dd, 1.4Hz, 4.4Hz), 6.99 (1H, d, 7.7Hz), 6.81 (1H, d, 7.3Hz) , 6.61-6.60 (1H, m), 3.5-3.8 (3H, m), 3.3-3.5 (1H, m), 2.5-3.1 (9H, m), 1.8-2.4 (10H, m) .MS (ESI) : 408.4 (base, M + H) [1663] (Example 476) 6,7,9,10,11,12,13,13a-Octahydro-5H, 8aH-Azepino [3,4-b] [1,4] Chiazepino [2,3,4-hi] Indole [1664] (Step A) 6,7,8a,11,12,12a-Hexahydro-5H- [1,4] thiazepino [2,3,4-jk] carbazol-10 (9H) -one (455 mg, 1.75 mmol) MeSO₃Dissolved in H4 mL. The solution was cooled to 0 ° C. NaN³(171 mg, 2.63 mmol) was added at one time. Ice pieces (about 2 g) were added and the reaction was basicized to pH = 14 with 50% NaOH. CH reactant₂Cl₂Extracted with (3 x 10 mL). The organic layers were combined, washed with saline, dried and concentrated to give 551 mg of brown powder. Purification of this crude product by column chromatography revealed that 6,7,8a, 9,11,12,13,13a-octahydro-5H, 10H-azepino [4,5-b] [1,4] thiazepino [2, 3,4-hi] Indoru-10-on and 6,7,8a, 9,11,12,13,13a-Octahydro-5H, 11H-Azepino [3,4-b] [1,4] Chiazepino [2] An inseparable 1: 1 mixture (504 mg, 105%) of indol-11-one was obtained as a white powder.¹1 H NMR (CDCl₃, 300MHz) δ6.94-6.99 (1H, m), 6.82-6.86 (1H, m), 6.61-6.69 (1H, m), 3.65-3.85 (1H, m), 3.1-3.8 (6H, m), 2.8-3.05 (2H, m), 2.5-2.7 (1H), 1.7-2.3 (4H, m). [1665] (Step B) 6,7,8a, 9,11,12,13,13a-Octahydro-5H, 10H-Azepino [4,5-b] [1,4] Chiazepino [2,3,4-hi] Indoru-10-on And 6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-Azepino [3,4-b] [1,4] Chiazepino [2,3,4-hi] Indoru-11- The mixture of on (483 mg, 1.76 mmol) was dissolved in toluene (10 mL). The solution was cooled to 0 ° C. and a 65% RED-Al toluene solution (1.59 mL, 5.29 mmol) was added dropwise. The reaction was warmed to room temperature, stirred for 1 hour, and then heated to reflux for 2 hours. The reaction was cooled to room temperature and quenched with 1 M NaOH (2 mL). The layers were separated and the aqueous layer was extracted again with toluene (2 x 15 mL). When the organic layers are combined, washed with saline, dried and concentrated, 6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [4,5-b] [1, 4] Chiazepino [2,3,4-hi] indole and (8aR, 13aS) -6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [3,4-b] A mixture of [1,4] thiazepino [2,3,4-hi] indole (343 mg, 1.32 mmol, 75%) was obtained as a brown oil. The positional isomer was separated on a chiracel OD column using 10% IPA / hexane as the eluate to give the title compound.¹1 H NMR (CDCl₃, 300MHz) δ6.94-6.99 (1H, m), 6.81-6.86 (1H, m), 6.57-6.66 (1H, m), 3.3-3.8 (4H, m) , 2.6-3.3 (6H, m), 1.6-2.2 (6H, m) .MS (ESI): 261.2 (base, M + H) [1666] (Example 477) 4- [6,7,8a, 9,11,12,13,13a-Octahydro-5H, 10H-Azepino [3,4-b] [1,4] Chiazepino [2,3,4-hi] Indoru- 10-yl] -1- (4-fluorophenyl) -1-butanone [1667] 6,7,9,10,11,12,13,13a-Octahydro-5H, 8aH-Azepino [3,4-b] [1,4] Thiazepino [2,3,4-hi] Indole (14.7mg, 0.056 mmol), 4-chloro-4'-fluorobutyrophenone (14.7 mg, 0.073 mmol), KI (9.4 mg, 0.056 mmol), K₂CO₃(23.4 mg, 0.17 mmol) was suspended in MEK (4 mL). The mixture was heated for 18 hours. The reaction was cooled to room temperature and concentrated. Column chromatography of residue (5, 7, 10% MeOH / CH₂Cl₂), The title compound (9.9 mg, 0.024 mmol, 42%) was obtained as a light brown viscous oil.¹1 H NMR (CDCl₃, 300MHz) δ7.93 (2H, ddd, 2.6Hz, 4.8Hz, 12.2Hz), 7.04 (2H, t, 8.6Hz), 6.90 (1H, 7.7Hz), 6.75 (1H, 7.3Hz), 6.54 (1H) , dd, 7.3Hz, 7.7Hz), 3.5-3.7 (2H, m), 3.2-3.7 (2H, m), 2.75-3.0 (5H, m), 2.3-2.74 (4H, m) 2.3-2.4 (1H) , m), 1.5-2.1 (10H, m) .MS (ESI): 425.3 (base, M + H) [1668] (Example 478) 10- [2- (6-fluoro-1,2-benzoisooxasol-3-yl) ethyl]-6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [ 3,4-b] [1,4] Chiazepino [2,3,4-hi] Indole [1669] 6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [3,4-b] [1,4] thiazepino [2] by the same general method as in Example 477. , 3,4-hi] Indole (56.5 mg, 0.22 mmol) and 3- (3-chloropropyl) -1,2-benzisooxazole (77 mg, 0.43 mmol) to 10- [2- (6-fluoro-1) , 2-Benzisoxazole-3-yl) ethyl] -6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [3,4-b] [1,4] Thiazepino [2,3,4-hi] indole was prepared. After purification by chromatography, the title compound (59.6 mg, 14 mmol, 62%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ7.60 (1H, dd, 5.1Hz, 8,4Hz), 7.23 (1H, m), 7.06 (1H, dt, 2.1Hz, 8.8Hz), 6.95 (1H, d, 7.7Hz), 6.83 (1H, 6.9Hz), 6.58-6.63 (1H, m), 3.3-3.8 (4H, m), 2.8-3.1 (5H, m), 2.6-2.8 (4H, m), 2.3-2.4 (1H, m) ), 1.9-2.21 (3H, m), 1.6-1.8 (4H, m) .MS (ESI): 424.2 (base, M + H) [1670] (Example 479) 2- (2,4-dichlorophenyl) -6,7,9,10,11,12,13,13a-octahydro-5H,8aH-azepino [4,5-b] [1,4] thiazepino [2,3] , 4-hi] Indole [1671] (Step A) 6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Chiazepino [2,3,4-hi] Indole-11-Carbonate To a solution of tert-butyl (3.17 g, 8.8 mmol) in 15 mL of DMF was added a solution of NBS (in 1.72 g, 1.1 mmol, 10 mL DMF) at 0 ° C. The reaction was warmed to room temperature and stirred for 2 hours. Saline (20 mL) and EtOAc (20 mL) were added to the reaction flask and the two-phase mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was extracted again with EtOAc (2 x 20 mL). The organic layers were combined, washed with saline, dried and concentrated to give 3.8 g of brown oil. When this crude material is purified by column chromatography, 2-bromo-6,7,8a, 9,10,12,13,13a-octahydro-5H, 11H-azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] indole-11-tert-butyl carbonate (2.57 g, 80%) was obtained as an amorphous solid.¹1 H NMR (CDCl₃, 300MHz) 7.07 (1H, d, 1.8Hz), 6.89 (1H, br-s), 3.39-3.78 (8H, m), 2.940-2.99 (1H, m), 2.80-2.85 (1H, m), 1.8 -2.2 (6H, m), 1.46 (9H, m). [1672] (Step B) 2-Bromo-6,7,8a,9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole Tert-Butyl carbonate (231 mg, 0.53 mmol) was dissolved in 3: 1 DME: H2O (4 mL). Then 2,4-dichlorophenylboronic acid (110 mg, 0.59 mmol), Pd (PPh)₃)₄(12 mg, 0.01 mmol), and Ba (OH)₂(149 mg, 0.79 mmol) was added. The reaction vessel was degassed four times and maintained in a nitrogen atmosphere. The reaction was refluxed for 18 hours and then cooled to room temperature. The reaction was concentrated under reduced pressure. Saline (10 mL) and EtOAc (10 mL) were added to the reaction flask and the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was extracted again with EtOAc (2 x 20 mL). The organic layers were combined, washed with saline, dried and concentrated to give a crude brown oil. Purification of this crude product by column chromatography (20-40% EtOAc / Hexanes) shows 2- (2,4-dichlorophenyl) -6,7,8a, 9,10,12,13,13a-octahydro-5H, 11H-azepino [4,5-b] [1,4] thiazepino [2,3,4-hi] indole-11-tert-butyl carbonate (195 mg, 0.39 mmol, 73%) was obtained as an amorphous solid. It was. [1673] (Step C) (8aS, 13aS) -2- (2,4-dichlorophenyl) -6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4 ] Thiazepino [2,3,4-hi] indol-11-tert-butyl carbonate was dissolved in 20% TFA in methylene chloride (3.5 mL) and stirred at room temperature for 1 hour. The reaction was cooled to 0 ° C and two pieces of ice were added to the reaction. The mixture was basified to pH 14 with 50% NaOH. 5 mL of saline solution and 5 mL of chloroform were added. Separate the layers and CHCl the aqueous layer₃Extracted again with (2 x 15 mL). The organic layers were combined, washed with saline (2 x 30 mL), dried and concentrated to give the title compound (148.6 mg, 95%) as an amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.43-7.44 (1H, m), 7.23 (2H, d, 1.1Hz), 6.91-7.0 (1H, m), 6.90-6.91 (1H, m), 3.92 (1H, ddd, 4.8, 10.6,13.5Hz),3.69-3.76 (1H, m), 3.45-3.64 (2H, m), 3.15 (1H, dd, 8.4,13.2Hz), 2.70-3.05 (5H, m), 1.80-2.20 (6H) , m) .MS (ESI): 405 (base, M + H) [1674] (Example 480) 2- (2-Chloro-4-methoxyphenyl) -6,7,9,10,11,12,13,13a-octahydro-5H,8aH-azepino [4,5-b] [1,4] thiazepino [ 2,3,4-hi] Indole [1675] (Step A) 2-Bromo-6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-azepino [4,5-b] [1,4] by the same method as in step B of Example 479. ] Thiazepino [2,3,4-hi] Indol-11-tert-butyl carbonate (250.7 mg, 0.57 mmol), 2-chloro-4-methoxyphenylboronic acid (107 mg, 0.63 mmol) to 2- (2-chloro -4-Methoxyphenyl) -6,7,8a,9,10,12,13,13a-octahydro-5H, 11H-azepino [4,5-b] [1,4] thiazepino [2,3,4- hi] Indol-11-tert-butyl carbonate was prepared. Purified by chromatography, 2- (2-chloro-4-methoxyphenyl) -6,7,8a, 9,10,12,13,13a-octahydro-5H, 11H-azepino [4,5-b] [1 , 4] Thiazepino [2,3,4-hi] indole-11-tert-butyl carbonate (250 mg, 0.49 mmol, 88%) was obtained as a white amorphous solid.¹1 H NMR (CDCl₃, 500MHz) δ7.24 (1H, d, 8.8Hz), 7.01 (1H, br-d, 1.5Hz), 6.97 (1H, d, 2.6Hz), 6.92 (1H, br-s), 6.81 (1H, dd, 2.9,8.8Hz), 3.3-4.0 (11H, m), 2.97-3.04 (1H, m), 2.82-2.90 (1H, m), 1.8-2.2 (6H, m), 1.46 (9H, s) .. [1676] (Step B) 2- (2-Chloro-4-methoxyphenyl) -6,7,8a, 9,10,12,13,13a-octahydro-5H, 11H- by the same general method as in Step C of Example 479. The title compound was prepared from azepino [4,5-b] [1,4] thiazepino [2,3,4-hi] indole-11-tert-butyl carbonate (238.9 mg, 0.48 mmol). The desired product (173.8 mg, 0.44 mmol, 91%) was obtained as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.21 (1H, d, 8.4Hz), 7.01 (1H, d, 1.5Hz), 6.97 (1H, d, 2.6Hz), 6.91 (1H, m), 6.81 (1H, dd, 2.5, 8.8Hz), 3.4-4.0 (7H, m), 2.6-3.2 (6H, m), 1.80-2.20 (6H, m) .MS (ESI): 401 (base, M + H) [1677] (Example 481) 2- (4-Methoxy-2-methylphenyl) -6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [4,5-b] [1,4] thiazepino [ 2,3,4-hi] Indole [1678] (Step A) 2-Bromo-6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-azepino [4,5-b] [1,4] by the same method as in step B of Example 479. ] Thiazepino [2,3,4-hi] Indol-11-tert-butyl carbonate (261.9 mg, 0.60 mmol), 2-methyl-4-methoxyphenylboronic acid (109 mg, 0.66 mmol) to 2- (4-methoxy) -2-Methylphenyl) -6,7,8a, 9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4- hi] Indol-11-tert-butyl carbonate was prepared. Purified by chromatography, 2- (4-methoxy-2-methylphenyl) -6,7,8a, 9,10,12,13,13a-octahydro-5H, 11H-azepino [4,5-b] [1 , 4] Thiazepino [2,3,4-hi] indole-11-tert-butyl carbonate (274 mg, 0.57 mmol, 100%) was obtained as a white amorphous solid.¹1 H NMR (CDCl₃, 500MHz) δ7.43-7.44 (1H, m), 7.23 (2H, d, 1.5Hz), 7.0 (1H, d, 1.5Hz), 6.91 (1H, br-s), 3.8-4.0 (1H, m) ), 3.3-3.8 (7H, m), 2.91-3.04 (1H, m), 2.84-2.90 (1H, m),), 1.8-2.2 (6H, m), 1.46 (9H, s). [1679] (Step B) 2- (4-Methoxy-2-methylphenyl) -6,7,8a, 9,10,12,13,13a-octahydro-5H, 11H- by the same general method as in Step C of Example 479. The title compound was prepared from azepino [4,5-b] [1,4] thiazepino [2,3,4-hi] indole-11-tert-butyl carbonate (269.4 mg, 0.56 mmol). The desired product (216.5 mg, 0.56 mmol, 100%) was obtained as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.11 (1H, d, 8.5Hz), 6.90 (1H, m), 6.72-6.77 (3H, m), 3.3-4.0 (7H, m), 2.6-3.25 (6H, m), 1.80 -2.30 (9H, m) .MS (ESI): 381 (base, M + H) [1680] (Example 482) 2-Bromo-6,7,9,10,11,12,13,13a-Octahydro-5H, 8aH-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole [1681] 2-Bromo-6,7,8a,9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole CH -11-tert-butyl carbonate (157 mg, 0.36 mmol), TFA (3 mL)₂Cl₂Dissolved in a 20% solution dissolved in. The reaction was stirred at room temperature for 2 hours. After adding ice pieces, the reaction was basicized with 50% NaOH to pH = 14. Saline (5 mL) was added to the reaction mixture. CHCl the resulting solution₃Extracted with (3 x 15 mL). The organic layers were combined, washed with saline, dried and concentrated to give the title compound (130 mg, 106%) as a light brown oil.¹1 H NMR (CDCl₃, 300MHz) δ7.06-7.08 (1H, m), 6.87-6.88 (1H, m), 3.78 (1H, ddd, 4.8Hz, 10.6Hz, 13.5Hz), 3.65 (1H, ddd, 3.7Hz, 8.8Hz) , 10.6Hz) 3.39-3.56 (2H, m), 3.11 (1H, dd, 8.8Hz, 13.5Hz), 2.68-2.99 (5H, m), 1.75-2.2 (6H, m). [1682] (Example 483) 4- [2-Bromo-6,7,8a,9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4- hi] Indol-11-yl] -1- (4-fluorophenyl) -1-butanone [1683] 2-Bromo-6,7,9,10,11,12,13,13a-Octahydro-5H, 8aH-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole (121 mg, 0.36 mg), 4-chloro-4'-fluorobutyrophenone (107 mg, 0.53 mmol), KI (59.2 mg, 0.36 mmol), and K2CO3 (148 mg, 1.1 mmol) were added to 4 mL of MEK. The reaction was refluxed for 18 hours. The reaction was then cooled to room temperature and concentrated. The resulting residue was rapidly column chromatographed (2, 5, 7% MeOH / CH).₂Purification with Cl) gave the title compound (115.6 mg, 64%) as a light brown oil.¹1 H NMR (CDCl₃, 300MHz) δ7.96-8.02 (2H, m), 7.10-7.16 (2H, m), 7.05-7.06 (1h, m), 6.86-6.87 (1H, m), 3.73-3.83 (1H, m), 3.59 (1H, dt, 4Hz, 10.3Hz), 3.36-3.51 (2H, m), 2.91-3.00 (3H, m), 2.76-2.84 (2H, m), 2.59-2.65 (1H, m), 2.42- 2.53 (4H, m), 1.81-2.10 (9H, m) .MS (ESI): 505.3 (base, M + H) [1684] (Example 484) 3- [2-Bromo-6,7,8a,9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4- hi] Indoru-11-yl] Propyl 4-fluorophenyl ether [1685] 2-Bromo-6,7,9,10,11,12,13,13a-octahydro-5H, 8aH-azepino [4,5-b] [1,4] by the same general method as in Example 483. ] Thiazepino [2,3,4-hi] indole (141 mg, 0.42 mmol) and 1- (3-chloropropoxy) -4-fluorobenzene (118 mg, 0.62 mmol) to 3- [2-bromo-6,7, 8a,9,10,12,13,13a-Octahydro-5H, 11H-Azepino [4,5-b] [1,4] Thiazepino [2,3,4-hi] Indole-11-yl] Propyl-4 -Fluorophenyl ether was prepared. Purification by chromatography gave the title compound (158 mg, 77%).¹1 H NMR (CDCl₃, 300MHz) δ7.08 (1H, 1.8Hz), 6.93-6.99 (2H, m), 6.88-.689 (1H, m), 6.78-6.85 (2H, m), 3.97 (2H, t, 6.2Hz) , 3.72-3.82 (1H, m), 3,64 (1H, dt, 3.6Hz, 10.2Hz), 3.36-3.56 (2H, m), 2.78-2.99 (3H, m), 2.59-2.76 (5H, m) ), 1.89-2.11 (8H, m) .MS (ESI): 491.2 + (base, M + H) [1686] (Example 485) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl )-2-Methylbutanoic acid [1687] (Step A) CH 3-methyldihydro-2 (3H) -furanone (2.13 g, 21.3 mmol)₂Cl₂Dissolved in (15 mL). BBr₃, 1M CH₂Cl₂Dropped as a solution. The reaction was stirred at room temperature for 18 hours. MeOH (2 mL) was added at room temperature. Saturated Na₂CO₃Aqueous solution (20 mL) and CH₂Cl₂(10 mL) was added. Separate the layers and CH the aqueous layer₂Cl₂Extracted again with (2 x 20 mL). The organic layers were combined, washed with saline, dried and concentrated to give a brown liquid (3.77 g). Purification of this crude product by column chromatography gave methyl 4-bromo-2-methylbutanoate 3.39 g, 82%) as a clear liquid.¹1 H NMR (CDCl₃, 300MHz) δ3.69 (3H, s), 3.42 (2H, t, 6.6Hz), 2.68-2.75 (1H, m), 2.20-2.32 (1H, m), 1.86-1.97 (1H, m), 1.19 (3H, d, 7.0Hz). [1688] (Step B) 6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (302 mg, 1.24 mmol) , 4-Bromo-2-methylbutanomethyl (315 mg, 1.62 mmol), KI (206 mg, 1.24 mmol), and K₂CO₃(514 mg, 3.72 mmol) was suspended in MEK. The reaction was refluxed for 18 hours. The reaction was cooled and concentrated. Column chromatography of residue (3, 5, 7% MeOH / CH₂Cl₂), The title compound (477 mg, 99%) was obtained as a transparent amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ6.93 (1H, d, 7.7Hz), 6.84 (1H, d, 7.3Hz), 6.61 (1H, m), 3.71-3.86 (1H, m), 3.67 (3H, d, 5.1Hz) , 2.5-3.3 (10H, m), 1.4-2.4 (10H, m), 1.12 (3H, d, 6.9Hz). CIMS (NH)₃): 390 (base, M + H) [1689] (Example 486) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl ) -1,1-bis (4-fluorophenyl) -2-methyl-1-butanol [1690] 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl )-2-Methylbutanoic acid (110.5 mg, 0.28 mmol) was dissolved in THF (0.5 mL). 4-Fluorophenylmagnesium bromide (1.4 mL, 1.4 mmol) was added as a 1 M solution of THF. The reaction was stirred at room temperature for 20 hours. The reaction was quenched with 1 M HCl (5 mL). CH reactant₂Cl₂Extracted with (3 x 15 mL). The organic layers were combined, washed with saline, dried and concentrated to give 125 mg of viscous oil. Purification of this crude material by column chromatography gave the title compound (72.9 mg, 50%) as a pale yellow oil.¹1 H NMR (CDCl₃, 300MHz) δ7.61-7.68 (2H, m), 7.46-7.51 (2H, m), 6.8-7.1 (6H, m), 6.5-6.7 (2H, m), 3.7-4.0 (1H, m), 3.4-3.7 (1H, m), 3.1-3.4 (2H, m), 2.5-3.1 (5H, m), 2.3-2.45 (1H, m), 1.7-2.2 (8H, m), 1.2-1.4 (1H) , m), 0.88 (3H, d, 7.0Hz) .CIMS (NH)₃): 521 (base, M + H) [1691] (Example 487) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl ) -1,1-bis (4-chlorophenyl) -2-methyl-1-butanol [1692] 4-((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] by the same general method as in Example 486] Thiazepino [2,3,4-hi] indol-11 (8aH) -yl) -2-methylbutanomethyl (108 mg, 0.36 mmol) and 4-chlorophenylmagnesium bromide (1.8 mL, 1.8 mmol) to 4- (6,6, 7,9,10,12,12a-Hexahydro-5H-Pyrid [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -Il) -1,1 -Bis (4-chlorophenyl) -2-methyl-1-butanol was prepared. The title compound (106.9 mg, 54%) was obtained as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.5-7.7 (2H, m), 7.2-7.5 (4H, m), 7.15-7.25 (2H, m), 6.8-7.0 (2H, m), 6.5-6.7 (2H, m), 3.7-3.9 (1H, m), 3.4-3.65 (1H, m), 3.2-3.4 (2H, m), 2.5-3.1 (5H, m), 2.3-2.5 (1H, m), 1.7-2.2 (7H) , m), 1.2-1.5 (2H, m), 0.88 (3H, d, 7.0Hz) .ESIMS: 553.2 (base, M + H) [1693] (Example 488) 1,2,6b, 7,8,10,11,11a-Octahydro-9H-Azepino [4,5-b] [1,4] Thiadino [2,3,4-hi] Indole-9-tert-Carbonate Butyl [1694] (Step A) 1,2,8,9,10, from 2,3-dihydro-4H-1,4-benzothiazine-4-amine and hexahydro-4H-azepine-4-one hydrochloride, according to the procedure of step A of Example 471, 11-Hexahydro-7H-Azepino [4,5-b] [1,4] Thiadino [2,3,4-hi] Indole hydrochloride was prepared and 1,2,8,9,10,11-Hexahydro- 7H-azepino [4,5-b] [1,4] thiazino [2,3,4-hi] indole hydrochloride was obtained. [1695] Step B-NaBH₃Typical procedure for CN reduction: A solution of indole (40 mmol) in trifluoroacetic acid (135 mL) was stirred at room temperature for 1.5 hours, cooled in an ice bath and treated in small portions every 15 minutes with sodium cyanoborohydride (200 mmol) over 3 hours. .. After continuing stirring for 4 hours at room temperature, 6N hydrochloric acid (350 mL) was added and the resulting mixture was refluxed for 30 minutes, evaporated under reduced pressure and dried. The residue was strongly alkaline to pH = 10 with 1N NaOH and the mixture was extracted with dichloromethane (3 x 400 mL). The extracts were combined, dried over sodium sulfate and concentrated to a solid. The solid proceeded without further purification and was re-dissolved in dichloromethane (1.2 L). 1N NaOH solution (200 mL), then Boc₂O (1 eq) was added. The reaction mixture was stirred overnight. Separate the organic layer and Na₂SO₄It was dried above and concentrated to a residue, which was ground with ether / hexane (1: 1) to give the desired product. [1696] 1,2,8,9,10,11-hexahydro-7H-azepino [4,5-b] [1,4] thiazino [2,3,4-hi] indole hydrochloride using the general procedure described above The title compound (1.15 g, 62%) was prepared from salt (1.85 g, 5.37 mmol).¹1 H NMR (CDCl₃, 300MHz) δ1.49 (br-s, 9H), 1.83-2.15 (m, 4H), 2.98-3.13 (m, 2H), 3.34-3.61 (m, 7H), 3.70-3.81 (m, 1H), 6.59-6.65 (m, 1H), 6.76-6.85 (m, 2H) ppm. [1697] (Example 489) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl )-1- (4-Fluorophenyl) -2-methyl-1-butanone [1698] (Step A) NO-Dimethylhydroxylamine hydrochloride (1.11 g, 11.4 mmol) was dissolved in toluene (30 mL). Cool this solution to 0 ° C and add 2M AlMe₃Toluene solution (8.5 mL, 17 mmol) was added. The reaction was heated to room temperature and stirred for 1 hour. The reaction is then cooled to 0 ° C again and 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] Indol-11 (8aH) -yl) -2-methyl Methylbutanoate (2.05 g, 5.71 mmol) was added as a toluene solution (20 mL). The reaction was stirred at room temperature for 1 hour and then at 4 ° C. for 18 hours. The reaction was heated to room temperature and stirred for 2 hours. Additional NO-dimethylhydroxylamine hydrochloride (277 mg, 2.83 mmol) and AlMe₃(1.4 mL, 2.8 mmol) was added. The reaction was stirred at room temperature for at least 2 hours. It was cooled to 0 ° C and quenched with 1 M aqueous tartaric acid solution (25 mL). Separate the layers and CHCl the aqueous layer₃Extracted with (3 x 15 mL). The combined organic layers were washed with brine, dried and concentrated to give 3.0 g of an amorphous solid. Column chromatography of crude product (5.7% MeOH / CH₂Cl₂), And 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol- 11 (8aH) -yl) -N-methoxy-N, 2-dimethylbutaneamide (1.81 g, 81%) was obtained as a pale yellow amorphous solid. [1699] (Step B) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl )-N-Methoxy N,2-dimethylbutaneamide (109.9 mg, 0.28 mmol) was dissolved in THF (0.5 mL). 4-Fluorophenylmagnesium bromide (1.41 mL, 1.41 mmol) was added as a 1M solution in THF. The reaction was stirred at room temperature for 18 hours. Further THF (1 mL) and 4-fluorophenylmagnesium bromide (1.41. mg, 1.41 mmol) were added. The reaction was stirred for an additional 2 hours and then quenched with 1 M HCl (3 mL). The layers were separated and then the aqueous phase was made basic with 1 M NaOH (aqueous solution) to pH = 14. CH the water layer₂Cl₂Extracted with (3 x 10 mL). The combined organic layers were washed with brine, dried and concentrated to give 167.7 mg of brown oil. Column chromatography on this material (5, 7, 10% MeOH / CH₂Cl₂) To give the title compound (36.4 mg, 31%) as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.9-8.1 (2H, m), 7.0-7.2 (2H, m), 6.93 (1H, d, 7.7Hz), 6.7-6.9 (1H, m), 6.5-6.6 (1H, m) , 3.6-3.9 (1H, m), 3.4-3.6 (2H, m), 2.7-3.2 (4H, m), 2.3-2.7 (2H, m), 1.7-2.3 (7H, m), 1.18 (3H, d, 7.0Hz) .ESIMS: 425.3 (base, M + H). [1700] (Example 490) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl ) -1- (4-Fluoro-2-methoxyphenyl) -2-methyl-1-butanone [1701] 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl ) -N-Methoxy N,2-dimethylbutaneamide (48 mg, 0.12 mmol) was dissolved in THF (0.5 mL). 4-Fluoro-2-methoxyphenylmagnesium bromide (0.62 mL, 0.62 mmol) was added as a 1M solution in THF. The reaction was stirred at room temperature for 8 hours, then 4-fluoro-2-methoxyphenylmagnesium bromide (0.62 mL, 0.62 mmol) was added. The reaction was stirred for 18 hours and quenched with 1 M HCl (3 mL). The layers were separated and the aqueous layer was made basic with 1 M NaOH to pH = 14. CH the water layer₂Cl₂Extracted with (3 x 10 mL). The combined organic layers were washed with brine, dried and concentrated to give 65 mg of brown material. This crude product is column chromatographed (5, 7, 10% MeOH / CH).₂Cl₂) To give the title compound (45 mg, 82%) as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.27-7.32 (1H, m), 7.09-7.15 (1H, m), 6.80-6.95 (3H, m), 6.57-6.62 (1H, m), 3.7-2.9 (4H, m), 3.3-3.6 (3H, m), 3.1-3.3 (1H, m), 2.8-3.1 (3H, m), 2.5-2.7 (2H, m), 1.7-2.4 (10H, m), 1.4-1.7 (1H) , m), 1.13 (3H, d, 6.9Hz). CIMS (NH)₃): 455 (base, M + H). [1702] (Example 491) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl ) -1- (4-Fluoro-3-methylphenyl) -2-methyl-1-butanone [1703] 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl )-N-Methoxy-N, 2-dimethylbutaneamide (108.2 mg, 0.28 mmol) and 4-fluoro-3-methylphenylmagnesium bromide (1.39 mL, 1.39 mmol) from Example 489, the same general as in step B. 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 Purification using chromatography to prepare (8aH) -yl) -1- (4-fluoro-3-methylphenyl) -2-methyl-1-butanone gave the title compound (45.6 mg, 37%).¹1 H NMR (CDCl₃, 300MHz) δ7.82-7.84 (2H, m), 7.05-7.080 (1H, m), 6.91-6.94 (1H, m), 6.82-6.85 (1H, m), 6.59-6.60 (1H, m), 3.4-3.9 (4H, m), 2.8-3.2 (4H, m), 2.4-2.7 (2H, m), 1.7-2.4 (13H, m), 1.17 (3H, d, 7.0Hz) .ESIMS: 439.3 ( M + H). [1704] (Example 492) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl ) -2-Methyl-1- (2-methylphenyl) -1-butanone [1705] 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl ) -N-Methoxy-N, 2-dimethylbutaneamide (92.2 mg, 0.31 mmol) was dissolved in THF (0.5 mL). 2-Methylphenylmagnesium bromide (0.77 mL, 0.77 mmol) was added as a 1 M solution in THF. The reaction was stirred for 18 hours, then additional 2-methylphenylmagnesium bromide (0.39 mL, 0.39 mmol) was added. The reaction was stirred for an additional 24 hours and then quenched with 1M HCl (3 mL). The layers were separated and the aqueous layer was made basic with 1 M NaOH to pH = 14. CH the water layer₂Cl₂Extracted with (3 x 10 mL). The combined organic layers were washed with brine, dried and concentrated to give 105 mg of brown material. This crude product is column chromatographed (5, 7, 10% MeOH / CH).₂Cl₂) To give the title compound (73.2 mg, 56%) as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.59-7.64 (1H, m), 7.32-7.38 (1H, m), 7.20-7.26 (1H, m), 7.20-7.22 (1H, m), 6.9-7.0 (1H, m), 6.8-6.9 (1H, m), 6.5-6.7 (1H, m), 3.3-3.9 (3H, m), 3.1-3.3 (1H, m), 2.8-3.1 (3H, m), 1.4-2.8 (15H) , m), 1.14 (3H, d, 7.0Hz) .ESIMS: 421.3 (base, M + H). [1706] (Example 493) 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl )-2-Methyl-1-phenyl-1-butanone [1707] 4- (6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -yl ) -N-Methoxy-N, 2-dimethylbutaneamide (52.5 mg, 0.13 mmol) was dissolved in THF (0.5 mL). Phenylmagnesium bromide (0.22 mL, 0.66 mmol) was added as a 1 M solution in THF. The reaction was stirred at room temperature for 18 hours and then quenched with 1 M HCl (3 mL). The layers were separated and the aqueous layer was made basic with 1 M NaOH to pH = 14. CH the water layer₂Cl₂Extracted with (3 x 10 mL). The combined organic layers were washed with brine, dried and concentrated to give 75 mg of brown material. This crude product is column chromatographed (5, 7, 10% MeOH / CH).₂Cl₂) To give the title compound (14.1 mg, 27%) as a pale yellow amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.95-7.99 (2H, m), 7.42-7.55 (3H, m), 6.92 (1H, d, 8.1Hz), 6.84 (1H, d, 6.6Hz), 6.77 (1H, d, 6.6) Hz), 6.56-6-63 (1H, m), 3.4-3.7 (3H, m), 2.4-3.2 (5H, m), 1.5-2.4 (11H, m), 1.19 (3H, d, 7.0Hz) .ESIMS: 421.3 (base, M + H). CIMS (NH₃): 407 (base, M + H). [1708] (Example 494) 1- (2-aminophenyl) -4-((6bR, 10aS) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyridoru [4, 3-b] Indol-8 (7H) -Il) -1-Butanone [1709] (6bR, 10aS) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole (150mg, From 0.68 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (274 mg, 1.38 mmol), the title compound is yellow oil (105 mg, 41%) by the method of Example 286, Step C. Isolated as.¹1 H NMR (CDCl₃) δ1.90-2.00 (m, 3H), 2.03-2.11 (m, 1H), 2.29-2.38 (m, 1H), 2.39-2.47 (m, 2H), 2.67-2.80 (m, 2H), 2.91- 3.04 (m, 4H), 3.12-3.21 (m, 1H), 3.24-3.35 (m, 2H), 4.40-4.46 (m, 2H), 6.26 (br-s, 2H), 6.61-6.73 (m, 4H) ), 7.23-7.29 (m, 2H), 7.77 (dd, 1H, J = 1.3, 8.3Hz) ppm. [1710] (Example 495) 1- (2-aminophenyl) -4-((6bS, 10aR) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyridoru [4, 3-b] Indol-8 (7H) -Il) -1-Butanone [1711] (6bS, 10aR) -1,2,6b, 7,8,9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi] Pyrid [4,3-b] Indole (150mg, From 0.68 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (274 mg, 1.38 mmol), the title compound is yellow oil (115 mg, 44%) by the method of Example 286, Step C. Isolated as.¹1 H NMR (CDCl₃) δ1.90-2.00 (m, 3H), 2.03-2.11m, 1H), 2.29-2.38 (m, 1H), 2.39-2.47 (m, 2H), 2.67-2.80 (m, 2H), 2.91-3.04 (m, 4H), 3.12-3.21 (m, 1H), 3.24-3.35 (m, 2H), 4.40-4.46 (m, 2H), 6.26 (br-s, 2H), 6.61-6.73 (m, 4H) , 7.23-7.29 (m, 2H), 7.77 (dd, 1H, J = 1.3, 8.3Hz) ppm. [1712] (Example 496) (6bR, 10aS) -8- [3- (1H-indazole-3-yl) propyl] -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3 , 4-hi] Pirido [4,3-b] Indole [1713] (6bR, 10aS) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole (31mg, From 0.14 mmol) and 3- (3-chloropropyl) -1H-indazole (56 mg, 0.28), the title compound was isolated as yellow oil (54 mg, 100%) by the method of Example 286, Step C.¹1 H NMR (CDCl₃) δ1.92-2.17 (m, 5H), 2.29-2.40 (m, 1H), 2.47-2.59 (m, 2H), 2.73-2.81 (m, 2H), 2.91-3.07 (m, 3H), 3.21- 3.34 (m, 3H), 4.42-4.47 (m, 2H), 6.59-6.69 (m, 3H), 7.13 (t, 1H, J = 7.0Hz), 7.33-7.45 (m, 2H), 7.70 (d, 1H, J = 8.1Hz) ppm. [1714] (Example 497) (6bR, 10aS) -5- (2-chlorophenyl) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] Indole [1715] (Step A) (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridod in DME (30 mL) [ 4,3-b] Indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2-chlorophenylboronic acid (156 mg, 2.0 mmol) to 2 M Na₂CO₃(10 mL) was added. The solution was degassed at 40 ° C for 10 minutes. Pd (PPh)₃)₄(22 mg, 0.02 mmol) was added to the solution all at once and the reaction mixture was degassed again at the same temperature for 10 minutes. The reaction mixture, N₂Stir down at 75 ° C for 20 hours, then Et₂Dilute with O (100 mL), wash with saline (100 mL), EDTA₄It was dried on top and concentrated under vacuum. By column chromatography, (6bR, 10aS) -5- (2-chlorophenyl) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyridodole [4, 3-b] Indole-8 (7H) -tert-butyl carbonate (179 mg, 84%) was obtained as a colorless oil. [1716] (Step B) CH₂Cl₂(6bR, 10aS) -5- (2-chlorophenyl) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyridod in (2.4 mL) 4,3-b] TFA (0.6 mL) was added to a solution of indol-8 (7H) -tert-butyl carbonate, and the reaction mixture was stirred for 3 hours. The reaction mixture is concentrated under vacuum and CH₂Cl₂Dilute with (100 mL) and LVDS₃Wash with (100 mL) and saline (100 mL) and deli₄It was dried on top and concentrated under vacuum to give the title compound (130 mg, 95%) as a pale yellow oil.¹1 H NMR (CDCl₃) δ1.78-1.99 (m, 2H), 2.11 (br-s, 1H), 2.76-2.95 (m, 4H), 3.09-3.20 (m, 2H), 2.32-2.39 (m, 1H), 2.41- 2.46 (m, 1H), 4.44-4.52 (m, 2H), 6.76 (dd, 1H, J = 1.5, 13.2Hz), 7.19-7.36 (m, 4H), 7.42 (dd, 1H, J = 1.4,7.7) Hz) ppm [1717] (Example 498) (6bR, 10aS) -5- (3-chlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] indole [4, 3-b] Indole [1718] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 3-chlorophenylboronic acid (156 mg, 1.0 mmol) by the method of Example 497, Steps A, B, the title compound is a yellow oil ( Obtained as 102 mg, 71%).¹1 H NMR (CDCl₃) δ1.84-1.99 (m, 2H), 2.73-2.86 (m, 2H), 2.91-3.00 (m, 2H), 3.10-3.31 (m, 3H), 3.32-3.42 (m, 2H), 4.43- 4.49 (m, 2H), 6.88 (dd, 2H, J = 1.3,8.1Hz), 7.20-7.48 (m, 4H) ppm. [1719] (Example 499) (6bR, 10aS) -5- (3-Fluorophenyl) -1,2,6b, 7,8,9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi] Indole [4 , 3-b] Indole [1720] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 3-fluorophenylboronic acid (140 mg, 1.0 mmol), the title compound is a yellow oil by the method of Example 497, Steps A, B. Obtained as (110 mg, 69%).¹1 H NMR (CDCl₃) δ1.89-2.00 (m, 2H), 2.74-2.87 (m, 3H), 2.92-2.99 (m, 2H), 3.16-3.27 (m, 2H), 3.31-3.42 (m, 2H), 4.48 ( dd, 2H, J = 2.2, 6.2Hz), 6.87 (d, 1H, J = 1.4Hz), 6.91-6.99 (m, 2H), 7.16-7.37 (m, 3H) ppm. [1721] (Example 500) (6bR, 10aS) -5- (4-chlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] indole [4, 3-b] Indole [1722] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 4-chlorophenylboronic acid (156 mg, 1.0 mmol), the title compound is a yellow oil (from Example 497, steps A, B). Obtained as 126 mg, 77%).¹1 H NMR (CDCl₃) δ1.87-2.07 (m, 3H), 2.73-2.83 (m, 2H), 2.86-2.90 (m, 2H), 3.07-3.19 (m, 2H), 3.31-3.40 (m, 2H), 4.45- 4.52 (m, 2H), 6.83 (s, 1H), 6.90 (s, 1H), 7.33 (d, 2H, J = 8.5Hz), 7.42 (d, 2H, J = 8.4Hz) ppm. [1723] (Example 501) (6bR, 10aS) -5- (4-fluorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridore [4 , 3-b] Indole [1724] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 4-fluorophenylboronic acid (140 mg, 1.0 mmol), the title compound is a yellow oil by the method of Example 497, Steps A, B. Obtained as (109 mg, 70%).¹1 H NMR (CDCl₃) δ1.78-2.14 (m, 3H), 2.70-2.82 (m, 2H), 2.87-2.95 (m, 2H), 3.06-3.20 (m, 2H), 3.32-3.43 (m, 2H), 4.44- 4.50 (m, 2H), 6.82 (d, 1H, J = 1.5Hz), 6.88 (d, 1H, J = 1.5Hz), 7.01-7.10 (m, 2H), 7.40-7.47 (m, 2H) ppm. [1725] (Example 502) (6bR, 10aS) -5- (2,3-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridore [ 4,3-b] Indole [1726] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2,3-dichlorophenylboronic acid (191 mg, 1.0 mmol), yellow the title compound by the method of Example 497, steps A, B. Obtained as oil (148 mg, 52%).¹1 H NMR (CDCl₃) δ1.77-1.92 (m, 2H), 2.69-2.84 (m, 3), 2.86-2.91 (m, 2H), 3.04-3.13 (m, 2H), 3.24-3.30 (m, 1H), 3.32- 3.40 (m, 1H), 4.38-4.44 (m, 2H), 6.65 (dd, 2H, J = 1.4,12.4Hz), 7.06-7.19 (m, 2H), 7.29-7.34 (m, 1H), ppm. [1727] (Example 503) (6bR, 10aS) -5- (2,3-difluorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridode [4,3-b] Indole [1728] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2,3-difluorophenylboronic acid (158 mg, 1.0 mmol), yellow the title compound by the method of Example 497, steps A, B. Obtained as oil (58 mg, 36%).¹1 H NMR (CDCl₃) δ1.82-2.07 (m, 3H), 2.75-2.96 (m, 4H), 3.09-3.21 (m, 2H), 3.35-3.46 (m, 2H), 4.43-4.49 (m, 2H), 6.83 ( t, 1H, J = 1.5Hz), 6.89 (t, 1H, J = 1.5Hz), 7.03-7.16 (m, 3H) ppm. [1729] (Example 504) (6bR, 10aS) -5- (3,5-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridore [ 4,3-b] Indole [1730] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 3,5-dichlorophenylboronic acid (190 mg, 1.0 mmol), yellow the title compound by the method of Example 497, steps A, B. Obtained as oil (152 mg, 84%).¹1 H NMR (CDCl₃) δ1.85-1.98 (m, 2H), 2.04 (br-s, 1H), 2.69-2.91 (m, 4H), 3.04-3.17 (m, 2H), 3.30-3.41 (m, 2H), 4.43- 4.48 (m, 2H), 6.85 (dd, 2H, J = 1.5,10.9Hz), 7.22 (t, 1H, J = 1.8Hz), 7.36 (d, 2H, J = 1.7Hz) ppm. [1731] (Example 505) (6bR, 10aS) -5- (3,5-difluorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridode [4,3-b] Indole [1732] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 3,5-difluorophenylboronic acid (158 mg, 1.0 mmol), yellow the title compound by the method of Example 497, steps A, B. Obtained as oil (129 mg, 78%). MS (ESI): 329 (base, M + H). [1733] (Example 506) (6bR, 10aS) -5- (3,4-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridore [ 4,3-b] Indole [1734] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 3,4-dichlorophenylboronic acid (191 mg, 1.0 mmol), yellow the title compound by the method of Example 497, steps A, B. Obtained as oil (126 mg, 70%).¹1 H NMR (CDCl₃) δ1.81-2.09 (m, 3H), 2.69-2.88 (m, 4H), 3.04-3.18 (m, 2H), 3.29-3.41 (m, 2H), 4.43-4.49 (m, 2H), 6.85 ( dd, 2H, J = 1.4,10.5Hz), 7.31 (dd, 1H, J = 2.2,8.5Hz), 7.41 (d, 1H, J = 8.5Hz), 7.57 (d, 1H, J = 1.8Hz) ppm .. [1735] (Example 507) (6bR, 10aS) -5- (3,4-difluorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridode [4,3-b] Indole [1736] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 3,4-difluorophenylboronic acid (156 mg, 1.0 mmol), yellow the title compound by the method of Example 497, steps A, B. Obtained as oil (115 mg, 70%).¹1 H NMR (CDCl₃) δ1.80-1.99 (m, 2H), 2.28 (br-s, 1H), 2.70-2.83 (m, 2H), 2.842.91 (m, 2H), 3.04-3.19 (m, 2H), 3.31- 3.43 (m, 2H), 4.45-4.50 (m, 2H), 6.79 (d, 1H, J = 1.3Hz), 6.86 (d, 1H, J = 1.3Hz), 7.09-7.31 (m, 3H) ppm. [1737] (Example 508) (6bR, 10aS) -5- (3-chloro-4-fluorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi ] Pirido [4,3-b] Indole [1738] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 3-chloro-4-fluorophenylboronic acid (174 mg, 1.0 mmol), the title compound by the method of Example 497, steps A, B. Was obtained as yellow oil (160 mg, 93%).¹1 H NMR (CDCl₃) δ1.87-1.96 (m, 2H), 2.70-2.84 (m, 2H), 2.91-3.01 (m, 2H), 3.09-3.24 (m, 3H), 3.29-3.42 (m, 2H), 4.46- 4.51 (m, 2H), 6.78 (s, 1H), 6.85 (d, 1H, J = 1.1Hz), 7.11 (t, 1H, J = 8.6Hz), 7.29-7.33 (m, 1H), 7.49 (dd) , 1H, J = 2.2,7.0Hz) ppm. [1739] (Example 509) (6bR, 10aS) -5- (4-Chloro-2-fluorophenyl) -1,2,6b, 7,8,9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi ] Pirido [4,3-b] Indole [1740] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 4-chloro-2-fluorophenylboronic acid (174 mg, 1.0 mmol), the title compound by the method of Example 497, steps A, B. Was obtained as yellow oil (149 mg, 85%).¹1 H NMR (CDCl₃) δ1.82-1.99 (m, 2H), 2.69-2.86 (m, 3H), 2.92-2.99 (m, 2H), 3.13-3.23 (m, 2H), 3.35-3.46 (m, 2H), 4.44- 4.49 (m, 2H), 6.80 (t, 1H, J = 1.5Hz), 6.85 (d, 1H, J = 1.4Hz), 7.10-7.19 (m, 2H), 7.26-7.33 (m, 1H) ppm. [1741] (Example 510) (6bR, 10aS) -5- (2-Chloro-4-fluorophenyl) -1,2,6b, 7,8,9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi ] Pirido [4,3-b] Indole [1742] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2-chloro-4-fluorophenylboronic acid (174 mg, 1.0 mmol), the title compound by the method of Example 497, steps A, B. Was obtained as yellow oil (57 mg, 33%).¹1 H NMR (CDCl₃) δ1.77-1.91 (m, 2H), 2.59-2.79 (m, 3H), 2.91-2.96 (m, 2H), 3.03-3.13 (m, 2H), 3.24-3.39 (m, 2H), 4.38- 4.45 (m, 2H), 6.63 (d, 2H, J = 14.3Hz), 6.89-6.97 (m, 1H), 7.08-7.12 (m, 1H), 7.16-7.22 (m, 1H) ppm. MS (ESI): 345 (base, M + H) [1743] (Example 511) (6bR, 10aS) -5- (2,5-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridore [ 4,3-b] Indole [1744] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2,5-dichlorophenylboronic acid (156 mg, 1.0 mmol), yellow the title compound by the method of Example 497, steps A, B. Obtained as oil (58 mg, 32%).¹1 H NMR (CDCl₃) δ1.81-1.99 (m, 2H), 2.39 (br-s, 1H), 2.70-2.92 (m, 4H), 3.08-3.19 (m, 2H), 3.35-3.39 (m, 1H), 3.43- 3.48 (m, 1H), 4.43-4.48 (m, 2H), 6.71 (d, 1H, J = 1.3Hz), 6.75 (d, 1H, J = 1.3Hz), 7.15-7.20 (m, 1H), 7.29 -7.39 (m, 2H) ppm. [1745] (Example 512) (6bR, 10aS) -5- (2,6-dichlorophenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridore [ 4,3-b] Indole [1746] tert-Butyl (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3 -b] To a solution of indole (200 mg, 0.50 mmol) in DMF (10 mL), N₂In the presence of₂(PPh₃)₂(35 mg, 0.50 mmol), CuBr (14 mg, 0.1 mmol) and PPh₃(26 mg, 0.1 mmol) was added. This was degassed at 60 ° C. for 10 minutes, to which a solution of (2,6-chlorophenyl) (trimethyl) stannane (230 mg, 0.75 mmol) in DMF (2 mL) was added. This was stirred for 30 minutes. A solution of (2,6-dichlorophenyl) (trimethyl) stannane (116 mg, 0.37 mmol) in DMF (1 mL) was added to the reaction mixture and heated at 140 ° C. for 10 minutes. A solution of (2,6-dichlorophenyl) (trimethyl) stannane (116 mg, 0.37 mmol) in DMF (1 mL) was then added thereto, and the reaction mixture was stirred at 140 ° C. for 1 hour. Cool the reaction mixture to 20 ° C and Et₂Dilute with O (100 mL) and H₂Washed with O. Water phase Et₂Extract with O (3 x 50 mL), wash the combined organic solution with saline (50 mL), and EDTA₄It was dried on top and concentrated under vacuum. Purification by column (hexane: EtOAc 4: 1), (6bR, 10aS) -5- (2,6-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,, 3,4-hi] pyrido [4,3-b] indole-8 (7H) -tert-butyl carbonate (155 mg, 67%) was obtained as a colorless oil. (6bR, 10aS) -5- (2,6-dichlorophenyl) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3- b] From indole-8 (7H) -tert-butyl carbonate (155 mg, 0.43 mmol), the title compound was obtained as a yellow oil (125 mg, 100%) by the method of Example 497, Step B. MS (ESI): 361 (base, M + H). [1747] (Example 513) (6bR, 10aS) -5- [2- (trifluoromethyl) phenyl] -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi ] Pirido [4,3-b] Indole [1748] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2- (trifluoromethyl) phenylboronic acid (190 mg, 1.0 mmol) by the method of Example 497, steps A, B, the title compound. Was obtained as yellow oil (127 mg, 71%).¹1 H NMR (CDCl₃) δ1.86-2.02 (m, 2H), 2.72-2.87 (m, 2H), 2.92-2.98 (m, 2H), 3.10-3.21 (m, 2H), 3.27-3.46 (m, 3H), 4.41- 4.47 (m, 2H), 6.63 (d, 2H, J = 11.1Hz), 7.31 (d, 1H, J = 7.7Hz), 7.39 (t, 1H, J = 7.5Hz), 7.49 (t, 1H, J = 7.2Hz), 7.69 (d, 1H, J = 8.0Hz) ppm. [1749] (Example 514) (6bR, 10aS) -5- (4- (trifluoromethyl) phenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi ] Pirido [4,3-b] Indole [1750] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 4- (trifluoromethyl) phenylboronic acid (190 mg, 1.0 mmol) by the method of Example 497, Steps A, B, the title compound. Was obtained as yellow oil (130 mg, 73%).¹1 H NMR (CDCl₃) δ1.91-2.02 (m, 2H), 2.66 (br-s, 1H), 2.71-2.89 (m, 2H), 2.94-3.01 (m, 2H), 3.18-3.28 (m, 2H), 3.35- 3.44 (m, 2H), 4.51 (dd, 2H, J = 2.6, 6.3Hz), 6.91 (d, 1H, J = 1.3Hz), 6.98 (d, 1H, J = 1.3Hz), 7.58-7.65 (m) , 4H) ppm. [1751] (Example 515) (6bR, 10aS) -5- (2,4-bis (trifluoromethyl) phenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3, 4-hi] Pirido [4,3-b] Indole [1752] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2,4-bis (trifluoromethyl) phenylboronic acid (258 mg, 1.0 mmol) by the method of Example 497, steps A and B. , The title compound was obtained as yellow oil (86 mg, 40%). MS (ESI): 429 (base, M + H). [1753] (Example 516) (6bR, 10aS) -5- (2-chloro-4- (trifluoromethyl) phenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3 , 4-hi] Pirido [4,3-b] Indole [1754] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From Indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2-chloro-4- (trifluoromethyl) phenylboronic acid (224 mg, 1.0 mmol), methods of Example 497, steps A, B. Obtained the title compound as yellow oil (130 mg, 63%).¹1 H NMR (CDCl₃) δ1.89-2.05 (m, 2H), 2.74-2.90 (m, 3H), 2.95-3.01 (m, 2H), 3.16-3.25 (m, 2H), 3.36-3.42 (m, 1H), 3.49- 3.54 (m, 1H), 4.50-4.57 (m, 2H), 6.75 (d, 1H, J = 1.4Hz), 6.80 (d, 1H, J = 1.4Hz), 7.44 (d, 1H, J = 8.0Hz) ), 7.52 (dd, 1H, J = 1.1,8.0Hz), 7.71 (s, 1H) ppm. MS (ESI): 395 (base, M + H). [1755] (Example 517) (6bR, 10aS) -5- (2-Methoxyphenyl) -1,2,6b, 7,8,9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi] Indole [4 , 3-b] Indole [1756] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (100 mg, 0.25 mmol) and 2-methoxyphenylboronic acid (76 mg, 0.5 mmol), the title compound is yellow oil by the method of Example 497, Steps A, B. Obtained as (58 mg, 71%). MS (ESI): 323 (base, M + H). [1757] (Example 518) (6bR, 10aS) -5- (2,4-dimethoxyphenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyridodole [4,3-b] Indole [1758] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2,4-dimethoxyphenylboronic acid (182 mg, 1.0 mmol), yellow the title compound by the method of Example 497, steps A, B. Obtained as oil (163 mg, 91%). MS (ESI): 353 (base, M + H). [1759] (Example 519) (6bR, 10aS) -5- (5-isopropyl-2-methoxyphenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi ] Pirido [4,3-b] Indole [1760] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 2-methoxy-5-isopropylphenylboronic acid (194 mg, 1.0 mmol) by the method of Example 497, steps A, B, the title compound. Was obtained as yellow oil (140 mg, 77%).¹1 H NMR (CDCl₃) δ1.23-1.29 (m, 7H), 1.94-1.99 (m, 2H), 2.79-2.97 (m, 3H), 2.97-3.02 (m, 2H), 3.17-3.25 (m, 2H), 3.30- 3.35 (m, 1H), 3.39-3.44 (m, 1H), 3.79 (s, 3H), 4.45-4.50 (m, 2H), 6.86-6.91 (m, 3H), 7.10-7.17 (m, 2H) ppm .. [1761] (Example 520) (6bR, 10aS) -5- (3-Nitrophenyl) -1,2,6b, 7,8,9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi] Indole [4 , 3-b] Indole [1762] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 3-nitrophenylboronic acid (167 mg, 1.0 mmol), the title compound is an orange oil by the method of Example 497, Steps A, B. Obtained as (162 mg, 96%).¹H NMR (DMSO-d₆) δ1.70-1.84 (m, 1H), 1.86-1.93 (m, 1H), 2.68-2.58 (m, 3H), 3.06-3.19 (m, 2H), 3.24-3.45 (m, 4H), 4.29- 4.40 (m, 1H), 4.43-4.50 (m, 1H), 6.95 (d, 1H, J = 1.4Hz), 7.12 (d, 1H, 1.1Hz), 7.63 (t, 1H, J = 8.0Hz), 7.98 (d, 1H, J = 8.4Hz), 8.06 (dd, 1H, J = 1.8, 7.5Hz), 8.26 (t, 1H, J = 2.0Hz) ppm. [1763] (Example 521) 2-[(6bR, 10aS) -1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole -5- Indole] Benzaldehyde [1764] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From indole-8 (7H) -tert-butyl carbonate (500 mg, 0.50 mmol) and 2-formylphenylboronic acid (380 mg, 1.0 mmol), the title compound is yellow oil by the method of Example 497, Steps A, B. Obtained as (19 mg, 48%). MS (ESI): 321 (base, M + H). [1765] (Example 522) 1- {2-[(6bR, 10aS) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-] b] Indole-5-yl] Phenyl} Ethanol [1766] (6bR, 10aS) -5- (2-formylphenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4 , 3-b] Indole-8 (7H) -tert-butyl carbonate was prepared as in Example 521. To this solution (30 mg, 0.07 mmol) in THF (1.5 mL) at -10 ° C, N₂In the presence of Et₂3 MCH in O (0.21 mL)₃MgBr was added. Stir this for 1 hour and saturate NH₄Quench with Cl solution (0.5 mL) and Et₂It was diluted with O (50 mL) and washed with saline (30 mL). EDTA organic solution₄It was dried on top and concentrated under vacuum to give a colorless oil. To this, CH₂Cl₂(2.9 mL) and TFA (0.1 mL) were added sequentially and the solution was stirred for 30 minutes. Post-treatment as in Example 497 gave the title compound as a yellow oil (28 mg, 91%). MS (ESI): 337 (base, M + H). [1767] (Example 523) {2-[(6bR, 10aS) -1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] Indole-5-yl] phenyl} methanol [1768] (6bR, 10aS) -5- (2-formylphenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4 , 3-b] CH of indole-8 (7H) -tert-butyl carbonate (30 mg, 0.07 mmol)₂Cl₂To (1.5 mL) solution, at -78 ° C, N₂In the presence of₂Cl₂1M DIBAL (0.11 mL, 0.11 mmol) in the mixture was added dropwise. The reaction mixture was raised to 20 ° C. and 0.05 mL of MeOH was added to stop the reaction. The reaction mixture was filtered and concentrated in vacuo to give a colorless oil. This is done by the method of Example 522, CH₂Cl₂And treated with TFA to give the title compound as a yellow oil (24 mg, 93%).¹1 H NMR (CDCl₃) δ1.84-1.97 (m, 2H), 2.57-2.82 (m, 4H), 2.89-2.99 (m, 2H), 3.05-3.21 (m, 2H), 3.23-3.36 (m, 2H), 3.38- 3.45 (m, 2H), 4.56 (s, 1H), 6.57 (d, 1H, J = 1.5Hz), 6.62 (d, 1H, J = 1.1Hz), 7.20-7.31 (m, 3H), 7.41-7.45 (m, 1H) ppm. MS (ESI): 323 (base, M + H). [1769] (Example 524) 2-[(6bR, 10aS) -1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole -5-Indole] -5-Methoxybenzaldehyde [1770] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] Except for performing the deprotection method from indole-8 (7H) -tert-butyl carbonate (300 mg, 0.75 mmol) and 2-formyl-4-methoxyphenylboronic acid (270 mg, 1.5 mmol) as in Example 522. Obtained the title compound as yellow oil (124 mg, 45%) by the method of Example 497, Steps A, B.¹1 H NMR (CDCl₃) δ2.07-2.24 (m, 2H), 2.84-2.91 (m, 2H), 3.04-3.17 (m, 2H), 3.18-3.47 (m, 5H), 3.88 (s, 3H), 3.47-3.53 ( m, 2H), 6.66 (dd, 2H, J = 1.4, 6.2Hz), 7.15 (dd, 1H, J = 2.9, 8.4Hz), 7.29-7.33 (m, 1H), 7.45 (d, 1H, J = 2.6Hz) ppm. MS (ESI): 351 (base, M + H). [1771] (Example 525) 2-[(6bR, 10aS) -1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole -5- Indole] Phenol [1772] (6bR, 10aS) -5- (2-Methoxyphenyl) -1,2,6b, 7,8,9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi] Indole [4 , 3-b] CH of indole (20 mg, 0.06 mmol)₂Cl₂To (4 mL) solution, N₂In the presence of₂Cl₂0.91M BBr inside₃A (0.41 mL, 0.37 mmol) solution was added. The reaction mixture was stirred at 20 ° C. for 16 hours and then quenched with water (1 mL). The aqueous layer was made basic to pH 7 with 1N NaOH and the reaction mixture was CH.₂Cl₂Extracted with (3 x 30 mL). Organic solution then EDTA₄It was dried on top and concentrated in vacuo to give the title compound as a yellow oil (10 mg, 50%).¹1 H NMR (CDCl₃) δ1.88-2.01 (m, 2H), 2.10-2.22 (m, 1H), 2.60-2.79 (m, 2H), 2.90-2.99 (m, 1H), 3.18-3.37 (m, 3H), 3.36- 3.43 (m, 2H), 3.61-3.66 (m, 1H), 4.39-4.44 (m, 2H), 6.70-6.79 (m, 1H), 6.80-6.99 (m, 2H), 7.08-7.18 (m, 2H) ) ppm. [1773] (Example 526) (6bR, 10aS) -5- (4-ethoxy-2- (trifluoromethyl) phenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3 , 4-hi] Pirido [4,3-b] Indole [1774] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] Methods of Example 497, Steps A, B from Indole-8 (7H) -tert-butyl carbonate (200 mg, 0.50 mmol) and 4-ethoxy-2- (trifluoromethyl) phenylboronic acid (117 mg, 1.0 mmol). Obtained the title compound as yellow oil (67 mg, 62%).¹1 H NMR (CDCl₃) δ1.35 (t, 3H, J = 7.0Hz), 1.80-1.91 (m, 2H), 2.46 (br-s, 1H), 2.61-2.78 (m, 2H), 2.83-2.90 (m, 2H) , 3.01-3.13 (m, 2H), 3.22-3.30 (m, 1H), 3.31-3.36 (m, 1H), 3.99 (q, 2H, J = 7.0Hz), 3.35-4.41 (m, 2H), 6.48 (s, 1H), 6.52 (s, 1H), 6.91 (dd, 1H, J = 2.7, 8.3Hz), 7.10-7.14 (m, 2H) ppm. MS (ESI): 405 (base, M + H). [1775] (Example 527) (6bR, 10aS) -5- (4-isopropoxy-2- (trifluoromethyl) phenyl) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2, 3,4-hi] Pirido [4,3-b] Indole [1776] (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] From Indole-8 (7H) -tert-butyl carbonate (100 mg, 0.25 mmol) and 4-isopropoxy-2- (trifluoromethyl) phenylboronic acid (124 mg, 0.5 mmol), from Example 497, Steps A, B. The title compound was obtained as yellow oil (110 mg, 96%) by the method.¹1 H NMR (CDCl₃) δ1.37 (d, 6H, J = 6.3Hz), 1.88-1.98 (m, 2H), 2.77-91 (m, 3H), 2.96-3.01 (m, 2H), 3.09-3.23 (m, 2H) , 3.31-3.38 (m, 1H), 3.39-3.43 (m, 1H), 4.43-4.48 (m, 2H), 4.52-4.65 (m, 1H), 6.58 (s, 1H), 6.62 (s, 1H) , 6.99 (dd, 1H, J = 2.6,8.4Hz), 7.17-7.21 (m, 2H) ppm. MS (ESI): 419 (base, M + H). [1777] (Example 528) (6bR, 10aS) -8- [3- (6-fluoro-1H-indazole-3-yl) propyl] -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino -[2,3,4-hi] Pirido [4,3-b] Indole [1778] (6bR, 10aS) -1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole (63mg, From 0.29 mmol) and 3- (3-chloropropyl) -6-fluoroindazole (93 mg, 0.43 mmol), the title compound was obtained as a yellow oil (60 mg, 63%) by the method of Example 355, Step B.¹1 H NMR (CDCl₃, 300MHz) δ1.89-2.15 (m, 5H), 2.27-2.38 (m, 1H), 2.43-2.55 (m, 2H), 2.71-2.80 (m, 2H), 2.88-3.02 (m, 3H), 3.18-3.32 (m, 3H), 4.43 (dd, J = 6.2,1.8Hz, 2H) 6.60-6.72 (m, 3H), 6.90 (dt, J = 9.1,2.2Hz, 1H), 7.07 (dd, J = 9.2,1.9Hz, 1H), 7.63 (dd, J = 8.8, 5.1Hz, 1H), 9.85-10.15 (br-s, 1H) ppm. [1779] (Example 529) 1- (2-Amino-4-fluorophenyl) -4-((±) -cis-1,2,6b, 9,10,10a-hexahydro [1,4] oxadino- [2,3,4-hi ] Pirido [4,3-b] Indol-8 (7H) -Il) -1-Butanone [1780] (±) -cis-1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole (30 mg, From 0.12 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (51 mg, 0.24 mmol), the title compound was red oil (11 mg, 24%) by the method of Example 361. Got as.¹1 H NMR (CDCl₃, 300MHz) δ1.87-2.15 (m, 5H), 2.25-2.45 (m, 3H), 2.65-2.79 (m, 2H), 2.86-2.95 (m, 3H), 3.15-3.30 (m, 3H), 4.44 (dd, J = 6.9, 2.2Hz, 2H), 6.26-6.38 (m, 2H), 6.41-6.50 (br-s, 2H), 6.60-6.72 (m, 3H), 7.78 (dd, J = 9.1) , 6.6Hz, 1H) ppm. [1781] (Example 530) 1- (2-Amino-4-fluorophenyl) -4-((6bR, 10aS) -1,2,6b, 9,10,10a-hexahydro [1,4] oxadino- [2,3,4-hi ] Pirido [4,3-b] Indoru-8 (7H) -Il) -1-Butanone [1782] (6bR, 10aS) -1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole (165mg, From 0.76 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (329 mg, 1.5 mmol) to Example 355, step B, the title compound is yellow oil (172 mg). , 57%) obtained as. The title compound is identical to Example 529, according to the spectrometer. [1783] (Example 531) 4-((±) -cis-1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyridoru [4,3-b] indol-8 (7H) ) -Il) -1- (4-fluoro-2-hydroxyphenyl) -1-butanone [1784] (±) -cis-1,2,6b,7,8,9,10,10a-octahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole (30 mg, From 0.12 mmol) and 4-chloro-1- (4-fluoro-2-hydroxyphenyl) -1-butanone (52 mg, 0.24 mmol) to the title compound in yellow oil (8 mg, 17%) by the method of Example 361. ).¹1 H NMR (CDCl₃, 300MHz) δ1.85-2.13 (m, 5H), 2.25-2.47 (m, 3H), 2.63-2.95 (m, 3H), 2.99 (t, J = 7.0Hz, 2H), 3.17-3.35 (m, 3H), 4.43 (dd, J = 6.9, 2.2Hz, 2H), 6.59-6.75 (m, 5H), 7.81 (dd, J = 8.7, 6.6Hz, 1H) ppm. [1785] (Example 532) (6bR, 10aS) -5- (4-Methoxy-2-methylphenyl) -1,2,6b, 7,8,9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi ] Pirido [4,3-b] Indole [1786] (Step A) (6bR, 10aS) -5-bromo-1,2,6b, 9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole-8 ( 7H) -tert-butyl carbonate (0.20 g, 0.50 mmol), 4-methoxy-2-methylphenylboronic acid (0.17 g, 1.0 mmol), Pd (PPh)₃)₂Cl₂(17 mg, 0.025 mmol), Na₂CO₃From (2.0M, 1.0mL, 2.0mmol), according to the general method of Example 89, Step C, (6bR, 10aS) -5- (4-methoxy-2-methylphenyl) -1,2,6b, 9 , 10,10a-Hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole-8 (7H) -tert-butyl carbonate (0.16g, 73%) in white Obtained as foam. MS (ESI): 437 (base, M + H). [1787] (Step B) (6bR, 10aS) -5- (4-Methoxy-2-methylphenyl) -1,2,6b, 9,10,10a-Hexahydro [1,4] Oxadino [2,3,4-hi] Pyrid [4 , 3-b] From indole-8 (7H) -tert-butyl carbonate (0.16 g, 0.37 mmol), the title compound (0.12 g, 97%) was obtained as white foam by the general method of Example 98. ..¹1 H NMR (CDCl₃, 300MHz) δ1.80-2.00 (m, 2H), 2.07 (s, 1H), 2.29 (s, 3H), 2.70-2.88 (m, 2H), 2.88-2.96 (m, 2H), 3.15-3.20 ( m, 2H), 3.30-3.44 (m, 2H), 3.83 (s, 3H), 4.45-4.58 (m, 2H), 6.59 (d, J = 1.3Hz, 1H), 6.64 (d, J = 1.3Hz) , 1H), 6.72-6.82 (m, 2H), 7.12 (d, J = 8.4Hz, 1H) ppm. MS (ESI): 337 (base, M + H). [1788] (Example 533) (6bR, 10aS) -5- [4-Methoxy-2- (trifluoromethyl) phenyl] -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxadino [2,3 , 4-hi] Pirido [4,3-b] Indole [1789] (Step A) (6bR, 10aS) -5-bromo-1,2,6b, 7,8,9,10,10a-hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] Indole-8 (7H) -tert-butyl carbonate (0.20 g, 0.50 mmol), 4-methoxy-2- (trifluoromethyl) phenylboronic acid (0.22 g, 1.0 mmol), Pd (PPh)₃)₂Cl₂(17 mg, 0.025 mmol), Na₂CO₃From (2.0M, 1.0mL, 2.0mmol), according to Example 89, the general method of step C, (6bR, 10aS) -5- [4-methoxy-2- (trifluoromethyl) phenyl] -1,2 , 6b, 9,10,10a-Octahydro [1,4] Oxadino [2,3,4-hi] Pyrido [4,3-b] Indole-10 (7aH) -tert-Butyl Carbonate (0.21g, 87%) ) Was obtained as a white foam. MS (ESI): 491 (base, M + H). [1790] (Step B) (6bR, 10aS) -5- [4-Methoxy-2- (trifluoromethyl) phenyl] -1,2,6b, 9,10,10a-Hexahydro [1,4] Oxadino [2,3,4-hi ] From pyrido [4,3-b] indole-8 (7H) -tert-butyl carbonate (0.21 g, 0.43 mmol), whiten the title compound (0.16 g, 96%) by the general method of Example 98. Obtained as foam.¹1 H NMR (CDCl₃, 300MHz) δ1.80-2.00 (m, 2H), 2.32 (br-s, 1H), 2.68-2.78 (m, 2H), 2.78-2.98 (m, 2H), 3.15-3.20 (m, 2H), 3.35 (td, J = 2.4,10.6Hz, 1H), 3.40-3.48 (m, 1H), 3.87 (s, 3H), 4.45-4.58 (m, 2H), 6.59 (s, 1H), 6.63 (s, 1H), 7.04 (dd, J = 2.6,8.4Hz, 1H), 7.20-7.26 (m, 2H) ppm. MS (ESI): 391 (base, M + H). [1791] (Example 534) 5- (3,4,5-trimethoxyphenyl) -1,2,7,8,9,10,11,11a-octahydro-6bH-azepino [4,5-b] [1,4] oxadino [2 , 3,4-hi] Indole [1792] (Step A) NaBH₃Typical method for CN reduction: Trifluoroacetic acid (135 mL) of 1,2,7,8,9,10-hexahydro [1,4] oxadino [2,3,4-hi] pyrido [4,3-b] indole (10.0 g, 39.88 mmol) The solution was stirred at room temperature for 1.5 hours, cooled in an ice bath and treated with subdivided sodium cyanoborohydride (12.5 g, 199.4 mmol) for 15 minutes each over 3 hours. Stirring was continued for 4 hours at room temperature, then 6N hydrochloric acid (338 mL) was added and the resulting mixture was refluxed for 30 minutes, evaporated and dried under reduced pressure. The residue was made strong alkali with pH = 10 with 1N NaOH and the mixture was extracted with dichloromethane (3 x 400 mL). The combined extracts were dried over sodium sulfate and concentrated into solid foam. The solid (8.63 g) was redissolved in dichloromethane (1.2 mL) without further purification. 1N NaOH (200 mL) solution, then BoC₂O (9.57 g, 1 eq) was added. The reaction mixture was stirred overnight, the organic layer was separated and Na₂SO₄It was dried above, concentrated and the residual oil was ground with ether / hexane (1: 1) to give the desired product (8.87 g, 80%) as a white solid.¹1 H NMR (CDCl₃, 300MHz) δ1.49 (s, 9H), 1.80-1.95 (m, 2H), 2.72-2.85 (m, 1H), 2.75-3.00 (bs, 1H), 3.05-3.20 (m, 2H), 3.30- 3.45 (m, 2H), 3.70-3.80 (m, 1H), 3.90-4.20 (bs, 1H), 4.48-4.51 (m, 2H), 6.60-6.80 (m, 3H) ppm. CIMS (methane) m / z = 317 [MH]⁺.. [1793] (Step B) 1,2,6b, 7,8,10,11,11a-Octahydro-9H-Azepino [4,5-b] [1,4] Oxadino [2,3,4-hi] Indole-9-tert-Carbonate From butyl (0.993 g, 3.01 mmol) by the method of Example 89, step B, 5-bromo-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino [4,5- b] [1,4] Oxadino [2,3,4-hi] Indole-9-tert-butyl carbonate (0.90 g, 73%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ1.48 (s, 9H), 1.88 (br.s., 1H), 1.91-2.16 (m, 3H), 2.70-2.85 (m, 1H), 3.21 (d, 1H, J = 12.6Hz) ), 3.29-3.64 (m, 6H), 4.38 (s, 1H), 4.41 (s, 1H), 6.74 (s, 1H), 6.78 (s, 1H) ppm. MS (CI, methane) m / z = 408 [MH]⁺.. [1794] (Step C) Typical method for Suzuki coupling: 5-Bromo-1,2,6b,7,8,10,11,11a-Octahydro-9H-Azepino [4,5-b] [1,4] Oxadino [2,3,4-hi] Indole-9 -Tert-Butyl carbonate (1.0 eq), corresponding boronic acid (1.5-2 eq) and barium hydroxide (1.5 eq), agitated into a solution of water and DME, then whipping through a stream of argon gas at 60 ° C. Heated in 20 minutes. The reaction mixture was then cooled to room temperature and Pd (PPh).₃)₂Cl₂(2.5 ~ 5mol%) and PPh₃(3eq relative to Pd source) was added immediately and refluxed again for 4 hours. When the reaction was completed, judging from TLC, ethyl acetate was added and the mixture was filtered through a bed of Celite. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give an oil. The residue was eluted on a flash column with 10% EtOAc / Hexanes and purified to give the desired product . 5-Bromo-1,2,6b, 7,8,10,11,11a-Octahydro-9H-azepino [4,5-b] [1] as described above using the typical method of Suzuki coupling. , 4] Coupling of oxadino [2,3,4-hi] indole-9-tert-butyl carbonate (671 mg, 1.64 mmol) with 3,4,5-trimethoxyphenylboronic acid (522 mg, 2.46 mmol). By 5- (3,4,5-trimethoxyphenyl) -1,2,6b,7,8,10,11,11a-octahydro-9H-azepino [4,5-b] [1,4] oxadino [2,3,4-hi] Indole-9-tert-butyl carbonate (609 mg, 75%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ1.49 (s, 9H), 1.80-2.20 (m, 4H), 2.80-2.91 (m, 1H), 3.25 (d, 1H, J = 10.8Hz), 3.42-3.70 (m, 1H) , 3.83 (s, 3H), 3.88 (s, 6H), 4.40-4.51 (m, 2H), 6.69 (s, 2H), 6.82 (s, 1H), 6.86 (s, 1H) ppm. CIMS (methane) m / z = 497 [MH]⁺.. [1795] (Step D) Typical method for removing Boc protecting groups: The corresponding indoline (100-150 mg) from step A is mixed with cold ethanolic hydrochloric acid (4M) (5 mL) and the solution is stirred at 0 ° C for 10 minutes. The solvent is removed under reduced pressure and the residue is dissolved in hot acetonitrile containing a small amount of methanol. Cool to room temperature to obtain the desired salt as a crystalline material. [1796] The corresponding hydrochloride of the title compound was subjected to 5- (3,4,5-trimethoxyphenyl) -1,2,6b, 7,8,10,11,11a-octahydro-using the general method described above. It was prepared from 9H-azepino [4,5-b] [1,4] oxadino [2,3,4-hi] indole-9-tert-butyl carbonate (608 mg). The salt was then free-based with 6N NaOH to give the title compound (479 mg, 63%).¹1 H NMR (CDCl₃, 300MHz) δ1.81-2.08 (m, 3H), 2.09-2.26 (m, 2H), 2.70-2.96 (m, 3H), 3.01-3.30 (m, 3H), 3.45-3.60 (m, 1H), 3.65-3.80 (m, 1H), 3.89 (s, 3H), 3.90 (s, 6H), 4.45 (s, 2H), 6.69 (s, 2H), 6.82 (s, 1H), 6.86 (s, 1H) ppm. CIMS (methane) m / z = 397 [MH]⁺.. [1797] (Example 535) 5- (1-naphthyl) -1,2,7,8,9,10,11,11a-octahydro-6bH-azepino [4,5-b] [1,4] oxadino [2,3,4-hi ] Indole [1798] Example 534, 5-bromo-1,2,6b, 7,8,10,11,11a-octahydro-9H-azepino [4,5-, as described by the general method described in step C. b] [1,4] Oxadino [2,3,4-hi] Indole-9-tert-butyl carbonate (671 mg, 1.64 mmol) by coupling with 1-naphthylboronic acid (423 mg, 2.46 mmol) 5- (1-naphthyl) -1,2,6b, 7,8,10,11,11a-octahydro-9H-azepino [4,5-b] [1,4] oxadino [2,3,4-hi ] Indole-9-tert-butyl carbonate (671 mg, 90%) was prepared. CIMS (methane) m / z = 457 [MH]⁺.. Corresponding hydrochloride of the title compound, 5- (1-naphthyl) -1,2,6b, 7,8,10,11,11a-octahydro-9H-azepino [4,5-b] [1,4] Oxadino [2,3,4-hi] indole-9-tert-butyl carbonate (670 mg) was formed using the method described in Example 534, Step C. This salt was then made into a free base using 6N NaOH to give the title compound (527 mg, 99%).¹1 H NMR (CDCl₃, 300MHz) δ1.80-2.40 (m, 5H), 2.80-3.00 (m, 3H), 3.00-3.15 (m, 1H), 3.40-3.60 (m, 1H), 3.62-3.86 (m, 1H), 4.28-4.62 (m, 4H), 6.77 (s, 2H), 7.30-7.60 (m, 4H), 7.75 (d, 1H, J = 8.1Hz), 7.85 (d, 1H, J = 8.0Hz), 8.04 (d, 1H, J = 8.1Hz) ppm. CIMS (methane) m / z = 357 [MH]⁺.. [1799] (Example 536) 5- (3-Methoxyphenyl) -1,2,7,8,9,10,11,11a-Octahydro-6bH-Azepino [4,5-b] [1,4] Oxadino [2,3,4- hi] indole [1800] Example 534, 5-bromo-1,2,6b, 7,8,10,11,11a-octahydro-9H-azepino [4,5, as described by the general method described in step C. -b] [1,4] Oxadino [2,3,4-hi] Indol-9-tert-butyl carbonate (671 mg, 1.64 mol) was coupled with 3-methoxyphenylboronic acid (374 mg, 2.46 mmol). 5- (3-Methoxyphenyl) -1,2,6b, 7,8,10,11,11a-Octahydro-9H-azepino [4,5-b] [1,4] Oxadino [2,3,4- hi] Indol-9-tert-butyl carbonate (502 mg, 70%) was prepared. CIMS (methane) m / z = 437 [MH]⁺.. Corresponding hydrochloride of the title compound, 5- (3-methoxyphenyl) -1,2,6b, 7,8,10,11,11a-octahydro-9H-azepino [4,5-b] [1,4 ] Oxadino [2,3,4-hi] Indole-9-tert-butyl carbonate (500 mg) was formed from Example 534 by the method described in Step D. This salt was then used as a free base with 6N NaOH to give the title compound (395 mg, 99%).¹1 H NMR (CDCl₃, 500MHz) δ1.80-2.30 (m, 4H), 2.75-2.98 (m, 3H), 3.00-3.12 (m, 1H), 3.13-3.29 (m, 2H), 3.43-3.53 (m, 1H), 3.63-3.78 (m, 1H), 3.85 (s, 3H), 4.11 (brs, 1H), 4.41 (brs, 2H), 6.82 (dd, 1H, J = 0.8, 8.3Hz), 6.88 (s, 1H) , 6.90 (s, 1H), 7.02 (s, 1H), 7.10 (d, 1H, J = 8.3Hz), 7.30 (t, 1H, J = 8.3Hz) ppm. CIMS (methane) m / z = 337 [MH]⁺.. [1801] (Example 537) 5- (2,4-dichlorophenyl) -1,2,7,8,9,10,11,11aδ-octahydro-6bH-azepino [4,5-b] [1,4] oxadino [2,3,4 -hi] Indole [1802] Example 534, 5-bromo-1,2,6b, 7,8,10,11,11a-octahydro-9H-azepino [4,5-, as described in the general method described in step C. b] [1,4] Oxadino [2,3,4-hi] Indole-9-tert-butyl carbonate (671 mg, 1.64 mmol) is coupled with 2,4-dichlorophenylboronic acid (470 mg, 2.46 mmol). , 5- (2,4-dichlorophenyl) -1,2,6b,7,8,10,11,11a-octahydro-9H-azepino [4,5-b] [1,4] oxadino [2,3, 4-hi] Indole-9-tert-butyl carbonate (510 mg, 65%) was prepared.¹1 H NMR (CDCl₃, 300MHz) δ1.48 (s, 9H), 1.81-2.22 (m, 4H), 2.80-3.00 (m, 1H), 3.25 (d, 1H, J = 11.5Hz), 3.31-3.75 (m, 6H) , 4.49-4.50 (m, 2H), 6.66 (s, 1H), 6.72 (s, 1H), 7.23 (s, 2H), 7.43 (s, 1H) ppm. CIMS (methane) m / z = 476 [MH]⁺.. [1803] The corresponding hydrochloride of the title compound is 5- (2,4-dichlorophenyl) -1,2,6b, 7,8,10,11,11a-octahydro-9H-azepino [4,5-b] [1, 4] Oxadino [2,3,4-hi] Indole-9-tert-butyl carbonate (505 mg) was formed from Example 534, step D by the method described. The salt was then free-based with 6N NaOH to give the title compound (398 mg, 99%).¹1 H NMR (CDCl₃, 300MHz) δ1.60-2.30 (m, 5H), 2.70-3.30 (m, 6H), 3.40-3.60 (m, 1H), 3.70-3.80 (m, 1H), 4.30-4.60 (m, 2H), 6.70 (s, 1H), 6.73 (s, 1H), 7.28 (s, 1H), 7.29 (s, 1H), 7.43 (s, 1H) ppm. CIMS (methane) m / z = 376 [MH]⁺.. [1804] (Example 538) 1,2,7,8,9,10,11,11a-Octahydro-6bH-Azepino [4,3-b] [1,4] Oxadino [2,3,4-hi] Indole [1805] Example 545, 1,2,8,9,10,11-hexahydro-7H-azepino [4,3-b] [1,4] oxadino [2,3,4-hi] indole (250 mg) from step A , 0.76 mmol), NaBH₃Hydrochloride (130 mg, 51%) of the title compound was prepared by reduction with CN (267 mg, 4.26 mmol) according to the method described in Example 534.¹1 H NMR (300MHz, CDCl₃) δ1.77-1.94 (m, 1H), 2.08-2.45 (m, 2H), 2.86-3.00 (m, 1H), 3.34-3.59 (m, 6H), 3.68-3.91 (m, 2H), 4.36- 4.58 (m, 2H), 6.65 (m, 1H), 6.83 (m, 2H) ppm. CIMSm / z = 231 [MH]⁺[1806] (Example 539) 3- (1,2,6b, 7,8,10,11,11a-Octahydro-9H-Azepino [4,5-b] [1,4] Oxadino [2,3,4-hi] Indoru-9- Il) Propyl 4-fluorophenyl ether hydrochloride [1807] Typical method for alkylation of amines: A mixture of indoline hydrochloride (about 200 mg) in dioxane (4 mL) was treated with Hunig's base (10 eq), refluxed for 15 minutes and heated. Appropriate side chains (5eq), KI (0.9eq) were added to the cold reaction mixture, then the whole mixture was refluxed for 48 hours. The reaction was then diluted with chloroform (20 mL), extracted once with saturated ammonium chloride solution (10 mL) and extracted twice with ice-cold water (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure until dry. The residue is purified by flash chromatography by eluting with gradient hexane / ethyl acetate (eg 96: 4 to 50:50) followed by gradient methanol / dichloromethane (eg 1:99 to 3:97). Obtained the desired product. [1808] 1,2,7,8,9,10,11,11a-Octahydro-6bH-Azepino [4,5-b] [1,4] Oxadino [2,3,4-hi] Indole (560mg, 1.69 mmol) 3- (1,2,6b, 7,8,10,11,11a) by alkylating with 1- (3-chloropropoxy) -4-fluorobenzene (1.32 mL, 8.47 mmol) according to the method above. -Octahydro-9H-azepino [4,5-b] [1,4] oxadino [2,3,4-hi] indole-9-yl) propyl 4-fluorophenyl ether (400 mg, 62%) was obtained.¹1 H NMR (300MHz, CDCl₃) δ1.79-1.99 (m, 1H), 2.10 (d, 1H, J = 12.2Hz), 2.39-2.57 (m, 1H), 2.72-3.01 (m, 3H), 3.01-3.22 (m, 2H) , 3.22-3.51 (m, 3H), 3.61-3.72 (m, 1H), 6.69-6.89 (m, 1H), 7.17 (d, 1H, J = 7.0Hz), 7.42 (d, 1H, J = 9.6Hz) ) ppm. CIMSm / z = 249 [MH]⁺.. The title compound (380 mg, 89%) was obtained by the method described in Example 535, Step B.¹1 H NMR (300MHz, CD₃OD) δ2.19-2.60 (m, 5H), 2.59-2.96 (m, 1H), 3.01-3.19 (m, 1H), 3.25-3.91 (m, 9H), 3.92-4.21 (m, 2H), 4.32 -4.61 (m, 2H), 6.53-6.89 (m, 2H), 6.88-7.22 (m, 5H); CIMSm / z = 383 [MH]⁺.. [1809] (Example 540) 9- [3- (6-fluoro-1,2-benzoisooxasol-3-yl) propyl] -1,2,7,8,9,10,11,11a-octahydro-6bH-azepino [4, 5-b] [1,4] oxadino [2,3,4-hi] indole hydrochloride [1810] 1,2,7,8,9,10,11,11a-octahydro-6bH-azepino [4,5-b] [1,4] -oxadino [2] using the method described in Example 539. , 3,4-hi] By alkylating indole (595 mg, 1.80 mmol) with 3- (3-chloropropyl) -6-fluoro-1,2-benzisoxazole (1.54 g, 7.20 mmol) 9- [3- (6-fluoro-1,2-benzisoxazole-3-yl) propyl] -1,2,7,8,9,10,11,11a-octahydro-6bH-azepino [4, 5-b] [1,4] oxadino [2,3,4-hi] indole (351 mg, 48%) is obtained.¹H NMR (CD)₃OD, 300MHz) δ2.10-2.51 (m, 4H), 2.53-2.80 (m, 2H), 2.80-3.00 (m, 1H), 3.10-3.25 (m, 3H), 3.23-3.65 (m, 4H) , 3.70-3.90 (m, 3H), 4.12 (q, 1H, J = 9.0Hz), 4.40-4.60 (m, 2H), 6.58-6.80 (m, 1H), 6.92 (d, 1H, J = 8.1Hz) ), 7.06 (t, 1H, J = 8.1Hz), 7.12-7.25 (m, 1H), 7.35-7.45 (m, 1H), 7.80-7.90 (m, 1H) ppm. CIMS (methane) m / z = 408 [MH]⁺.. [1811] (Example 541) 6,7,9,10,11,12-Hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] indole hydrochloride [1812] Refluxing 3,4-dihydro-1,5-benzoxiazepine-5 (2H) -ylamine (2.85 g, 14.23 mol) and 4-piperidinone hydrochloride (2.21 g, 14.37 mol) in ethanol (50 mL) Heated overnight. The resulting suspension was then cooled, filtered, washed successively with ethanol (10 mL) and diethyl ether and air dried to give the title compound (2.28 g, 61%).¹H NMR (CD)₃OD, 300NMR) δ2.33-2.40 (m, 2H), 3.15 (t, 2H.J = 6.2), 3.65 (t, 2H, J = 6.2), 4.06 (t, 2H, J = 5.7), 4.26- 4.29 (m, 2H), 4.41 (s, 2H), 6.74 (d, 2H, J = 7.1), 6.96 (t, 1H, J = 8.0), 7.06 (d, 1H, J = 7.1) ppm. CIMS (methane) m / z = 435 [MH]⁺.. [1813] (Example 542) 6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole [1814] 6,7,9,10,11,12-hexahydro-5H- [1,4] -oxazepino [2,3,4-hi] pyrido [4,3] as described in Step A of Example 534. -b] NaBH indole₃Reduced with CN, 6,7,9,10,12,12a-hexahydro-5H- [1,4] -oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 ( 8aH) -tert-butyl carbonate was prepared.¹1 H NMR (CDCl₃, 500MHz) δ1.41 (s, 9H), 1.85-1.91 (m, 2H), 2.01-2.12 (m, 2H) .2.6-3.00 (m, 2H), 3.48-3.42 (m, 4H), 3.60- 3.69 (m, 4H), 3.70-4.2 (m, 2H), 4.35-4.40 (m, 1H), 6.62-6.70 (m, 1H), 6.76-6.82 (m, 2H) ppm. CIMS (methane) m / z = 331 [MH]⁺.. [1815] Example 534 Using the method described in step D, 6,7,9,10,12,12a-hexahydro-5H- [1,4] -oxazepino [2,3,4-hi] pyrido [4, 3-b] The title compound (82 mg, 86%) was prepared from indole-11 (8aH) -tert-butyl carbonate (117 mg).¹H NMR (DMSO-d₆, 300NMR) δ1.85-2.26 (m, 4H), 2.26-2.53 (m, 2H), 2.85-3.01 (m, 1H), 3.12-3.51 (m, 5H), 3.62-3.74 (m, 1H), 4.31-4.41 (m, 1H), 6.65-6.80 (m, 2H), 6.86-6.91 (m, 1H) ppm. CIMS (methane) m / z = 231 [MH]⁺.. [1816] (Example 543) 2- (2,6-difluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4, 3-b] indole hydrochloride [1817] Typical method of Stannan coupling: Allyl bromide (316 mg, 0.768 mmol), PPh₃(40.4 mg, 0.154 mmol), CuBr (22 mg, 0.20 mmol) and Pd (PPh)₃)₂Cl₂To a mixture consisting of (55 mg, 0.0768 mmol) via a cannula, N₂Degassed DMF (25 mL) was added under gas at room temperature. The reaction mixture was stirred at room temperature for 5 minutes, then aryltrimethylstannan (1.5 eq with respect to aryl bromide) was added as a solution in degassed DMF (2.5 mL) and the reaction mixture was heated at 140 ° C. After 10 minutes, the solution began to turn black, with the second additive (0.75 eq for aryl bromide) added after 1 hour and the final additive (0.75 eq for aryl bromide) after an additional 1 hour. Added. It was heated for an additional 30 minutes, then the reaction mixture was cooled to room temperature and diluted with ethyl acetate / water (20 mL / 20 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure until dry to give a dark oil. The residue was purified by flash chromatography eluting with 10% EtOAc / Hexanes to give the desired product. [1818] 2-Bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] -oxazepino [2,3,4-hi] pyridode [4] as described in the general method above. , 3-b] By coupling indole-11 (8aH) -tert-butyl carbonate (217 mg, 0.53 mmol) to 2,6-difluorophenyltrimethylstannan (440 mg, 1.6 mmol), 2- (2,2, 6-Difluorophenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] -Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole-11 ( 8aH) -tert-butyl carbonate (179 mg, 77%) was prepared. Example 534 The deprotection method described in Step C gave the title compound (50 mg, 58%).¹H NMR (CD)₃OD, 300MHz) δ2.03-2.20 (m, 4H), 2.31-2.42 (m, 1H), 2.04-2.21 (m, 2H), 3.15-3.58 (m, 5H), 3.64-3.84 (m, 1H) , 4.39-4.50 (m, 1H), 6.81-7.05 (m, 4H), 7.27-7.39 (m, 1H) ppm. CIMS (methane) m / z = 343 [MH]⁺.. [1819] (Example 544) 4- (6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indol-11 (8aH) -Il )-1- (4-Fluorophenyl) -1-butanone hydrochloride [1820] 6,7,8a,9,10,11,12,12a-octahydro-5H- [1,4] -oxazepino [2,3,4-hi] pyrido [4,, by the method described in Example 539. 3-b] Indole (188 mg, 0.7 mmol) alkylated with 4-chloro-4'-fluoro-butyrophenone (608 mg, 3.5 mmol) and 4- (6,7,9,10,12,12a-hexahydro- 5H- [1,4] -oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -yl) -1- (4-fluorophenyl) -1-butanone (100 mg) , 55%). Example 534 The method described in Step C was used to obtain the title compound.¹H NMR (CD)₃OD, 300MHz) δ2.01-2.29 (m, 4H), 2.43-2.61 (m, 2H), 3.11-3.80 (m, 13H), 4.39-4.59 (m, 1H), 6.71-6.83 (m, 2H) , 6.82-6.91 (m ,, 1H), 7.18-7.20 (m, 2H), 8.03-8.13 (m, 2H) ppm. CIMS (methane) m / z = 395 [MH]⁺.. [1821] (Example 545) 1,2,7,8,9,10,11,11a-Octahydro-6bH-Azepino [4,5-b] [1,4] Oxadino [2,3,4-hi] Indole [1822] (Step A) 2,3-Dihydro-4H-1,4-benzoxazine-4-amine (494 mg, 2.64 mmol) and hexahydro-4H-azepine-4-one (396 mg, 2.64 mmol) were dissolved in EtOH (5 mL). The solution was refluxed for 10 minutes and then cooled to room temperature again. The solvent was foamed with HCl gas for 10 seconds. The reaction was then refluxed for an additional 2 hours and cooled to room temperature. 1M NaOH (15 mL) and dioxane (10 mL) were added to the reaction flask. Cool the flask to 0 ° C and BOC₂O (578 mg, 2.90 mmol) was added. The reaction was heated to room temperature and heated for 18 hours. The reaction was concentrated. Saline (20 mL) and CHCl₃(20 mL) was added to the residue; the mixture was stirred for 10 minutes. Separate the layers and CHCl the aqueous layer₃Re-extracted with (2 x 20 mL). The combined organic layers were washed with brine, dried and concentrated to give 805 mg of red-orange oil. Column chromatography (0, 1, 2% MeOH / CH₂Cl₂), And about 10% yield of stereoisomer 1.2.8.9.10.11-hexahydro-7H-azepino [4,3-b] [1,4] oxadino [2,3,4-hi] indole compound In addition, the title compound (666 mg, 77%) was obtained as an amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ7.03-7.06 (1H, m), 6.60 (1H, m), 6.60 (1H, d, J = 7.7Hz), 4.52 (2H, t, J = 4.8Hz), 4.11 (2H, t , J = 5.2Hz), 3.64-3.75 (4H, m), 2.92-2.99 (4H, m), 1.49 (9H, s). [1823] (Step B) 1,7,8,10,11,11b-Hexahydropyrano [4', 3', 2': 3,4] Indeno [1,2-d] Azepine-9 (2H) -tert-butyl carbonate ( 407 mg, 1.24 mmol) was dissolved in TFA (10 mL). Cool this solution to 0 ° C and NaCNBH₃(234 mg, 3.72 mmol) was added in small portions. The reaction was stirred at 0 ° C for 1 hour. Concentrated HCl (5 mL) was added to the reaction flask, then the mixture was refluxed at 50 ° C. for 30 minutes. The reaction was cooled to 0 ° C again and ice chips were added. The solution was made basic with 50% NaOH to pH = 14. Reactant CHCl₃Extracted with (3 x 20 mL). The combined organic layers were washed with brine, dried and concentrated to give the title compound (321 mg, 100%) as an amorphous solid.¹1 H NMR (CDCl₃, 300MHz) δ6.57-6.67 (3H, m), 4.39-4.43 (2H, m), 3.61-3.69 (1H, m), 3.45 (1H, dt, J = 3.3Hz, 9.2Hz), 3.00-3.24 (3H, m), 2.69-2.89 (3H, m), 2.02-2.16 (2H, m), 1.83-1.97 (2H, m). [1824] (Example 546) 4- (1,2,6b, 7,8,10,11,11a-Octahydro-9H-Azepino [4,5-b] [1,4] Oxadino [2,3,4-hi] Indoru-9- Il) -1- (4-fluorophenyl) -1-butanone [1825] 1,2,7,8,9,10,11,11a-Octahydro-6bH-Azepino [4,5-b] [1,4] Oxadino [2,3,4-hi] Indole (97.8mg, 0.42 mmol) ), 4-Chloro-1- (4-fluorophenyl) -1-butanone (172 mg, 0.86 mmol), KI (71.2 mg, 0.43 mmol) and DIEA (550 mg, 4.3 mmol) were suspended in dioxane (2 mL). .. The reaction mixture was refluxed for 18 hours. The solution was concentrated after cooling to room temperature. The residue was immediately purified by column chromatography to give the title compound. MS-ESI: 395 [MH]⁺.. [1826] (Example 547) (8aS, 12aR) -2- [4-Methoxy-2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [ 2,3,4-hi] Pirido [4,3-b] Indole [1827] (Step A) Using a chiral cell OJ preparative high performance liquid chromatography column, 6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3- b] By chiral separation of indole-11 (8aH) -tert-butyl carbonate, (8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2] , 3,4-hi] Pyrido [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was obtained. [1828] (Step B) Example 89 By the method of step B, (8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4, 3-b] Indole-11 (8aH) -tert-butyl carbonate (4.4 g, 13.3 mmol) to (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-[ 1,4] Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate was prepared to obtain the desired product (4.9 g, 12.1 mmol). It was. MS-ApCI: 409 [M + H⁺]. [1829] (Step C) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (409 mg, 1.0 mmol) and the corresponding 4-methoxy-2- (trifluoromethyl) phenylboronic acid (440 mg, 2.0 mmol) ( 8aS, 12aR) -2- [4-Methoxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4] -Hi] Pyrid [4,3-b] Indol-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (360 mg, 71%).¹1 H NMR (CDCl₃, 300MHz) δ7.20-7.23 (m, 2H), 7.02 (dd, 1H, J = 8.4Hz, 2.6Hz), 6.75 (s, 1H), 6.74 (s, 1H), 4.41-4.45 (m, 1H) ), 3.85 (s, 3H), 3.24-3.80 (, 7H), 2.56-3.00 (m, 2H), 1.94-2.08 (m, 4H), 1.44 (s, 9H) ppm. MS-ApCI: 505 [M + H⁺]. [1830] (Step D) By the method of Example 98, (8aS, 12aR) -2- [4-methoxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4 ] The title compound was prepared from oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (260 mg, 90%).¹1 H NMR (CDCl₃, 300MHz) δ7.20-7.24 (m, 2H), 7.02 (dd, 1H, J = 8.5Hz, 2.6Hz), 6.75 (s, 1H), 6.70 (s, 1H), 4.39-4.46 (m, 1H) ), 3.86 (s, 3H), 3.75-3.83 (m, 1H), 3.39-3.44 (m, 2H), 3.16-3.24 (m, 1H), 3.01-3.08 (m, 1H), 2.89-2.93 (m) , 2H), 2.52-2.62 (m, 2H), 2.48 (bs, 1H), 1.83-2.13 (m, 4H) ppm. MS-ApCI: 405 [M + H⁺]. [1831] (Example 548) (8aS, 12aR) -2- (4-Methoxy-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3, 4-hi] Pirido [4,3-b] Indole [1832] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (409 mg, 1.0 mmol) and the corresponding 4-methoxy-2-methylphenylboronic acid (332 mg, 2.0 mmol) (8aS, 12aR) -2- (4-Methoxy-2-methylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3 -b] Indol-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (265 mg, 59%).¹1 H NMR (CDCl₃, 300MHz) δ7.12-7.14 (m, 1H), 6.74-6.79 (m, 4H), 4.41-4.47 (m, 1H), 4.11-4.13 (m, 1H), 3.81 (s, 3H), 3.66- 3.78 (m, 2H), 3.24-3.48 (m, 4H), 2.58-3.04 (m, 2H), 2.28 (s, 3H), 1.96-2.12 (m, 4H), 1.45 (s, 9H) ppm. MS-ApCI: 451 [M + H⁺]. [1833] (Step B) By the method of Example 98, (8aS, 12aR) -2- (4-methoxy-2-methylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2] , 3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was used to prepare the title compound to give the title compound (150 mg, 73%).¹1 H NMR (CDCl₃, 300MHz) δ7.11-7.14 (m, 1H), 6.70-6.78 (m, 4H), 4.40-4.46 (m, 1H), 3.81 (s, 3H), 3.37-3.44 (m, 2H), 3.19- 3.26 (m, 1H), 3.03-3.10 (m, 1H), 2.92-2.95 (m, 2H), 2.51-2.61 (m, 2H), 2.27 (s, 3H), 1.85-2.17 (m, 6H) ppm .. MS-ESI: 351 [MH]⁺.. [1834] (Example 549) (8aS, 12aR) -2- [2-Chloro-4- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [ 2,3,4-hi] Pirido [4,3-b] Indole [1835] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2-chloro-4- (trifluoromethyl) phenylboronic acid (212 mg, 1.0 mmol) (8aS, 12aR) -2- [2-Chloro-4- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3, 4-hi] pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired compound (130 mg, 51%).¹1 H NMR (CDCl₃, 300MHz) δ7.63 (s, 1H), 7.44 (d, 1H, J = 8.1Hz), 7.34 (d, 1H, J = 8.1H), 6.85 (s, 2H), 4.34-4.39 (m, 1H) ), 3.64-4.02 (m, 2H), 3.44-3.64 (m, 2H), 3.20-3.42 (m, 3H), 2.58-3.02 (m, 2H), 1.86-2.10 (m, 4H), 1.36 (s) , 9H) ppm. MS-ApCI: 509 [M + H⁺]. [1836] (Step B) By the method of Example 98 (8aS, 12aR) -2- [2-chloro-4- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate was prepared to give the title compound (79 mg, 76%).¹1 H NMR (CDCl₃, 300MHz) δ7.62 (s, 1H), 7.44 (d, 1H, J = 8.0Hz), 7.35 (d, 1H, J = 8.0Hz), 6.80-6.85 (m, 2H), 4.33-4.39 (m) , 1H), 3.72-3.80 (m, 1H), 3.31-3.39 (m, 1H), 3.14-3.22 (m, 2H), 2.98-3.02 (m, 1H), 2.80-2.87 (m, 2H), 2.45 -2.59 (m, 2H), 1.75-2.07 (m, 5H) ppm. MS-ESI: 409 [MH]⁺.. [1837] (Example 550) (8aS, 12aR) -2- (2,3-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi ] Pirido [4,3-b] Indole [1838] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2,3-dichlorophenylboronic acid (191 mg, 1.0 mmol) to (8aS, 12aR) -2- (2,3-Dichlorophenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (124 mg, 52%).¹1 H NMR (CDCl₃, 300MHz) δ7.28-7.32 (m, 2H), 7.07-7.18 (m, 2H), 6.81 (s, 2H), 4.33-4.39 (m, 1H), 3.17-4.01 (m, 7H), 2.55- 3.02 (m, 2H), 1.87-2.05 (m, 4H), 1.36 (s, 9H) ppm. MS-ApCI: 475 [M + H⁺]. [1839] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2,3-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3, The title compound was prepared from 4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (79 mg, 79%).¹1 H NMR (CDCl₃, 300MHz) δ7.32-7.42 (m, 1H), 7.15-7.23 (m, 2H), 6.84-6.92 (m, 2H), 4.39-4.46 (m, 1H), 3.78-3.86 (m, 1H), 3.38-3.45 (m, 2H), 3.16-3.27 (m, 1H), 3.00-3.07 (m, 1H), 2.87-2.95 (m, 2H), 2.51-2.65 (m, 2H), 1.77-2.17 (m) , 5H) ppm. MS-ApCI: 375 [M + H⁺]. [1840] (Example 551) (8aS, 12aR) -2- (2,4-dimethoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4- hi] Pirido [4,3-b] Indole [1841] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2,4-dichlorophenylboronic acid (182 mg, 1.0 mmol), (8aS, 12aR) -2 -(2,4-Dimethoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole -11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (180 mg, 77%). MS-ApCI: 467 [M + H⁺]. [1842] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2,4-dimethoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3] The title compound was prepared from, 4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (130 mg, 92%). MS-ApCI: 367 [M + H⁺]. [1843] (Example 552) (8aS, 12aR) -2- (3,4-dimethoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4- hi] Pirido [4,3-b] Indole [1844] (Step A) Example 8 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 3,4-dimethoxyphenylboronic acid (182 mg, 1.0 mmol), (8aS, 12aR)- 2- (3,4-dimethoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (124 mg, 52%).¹1 H NMR (CDCl₃, 300MHz) δ6.95-7.01 (m, 4H), 6.82 (d, 1H, J = 8.4Hz), 4.35-4.39 (m, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.22 -3.80 (m, 7H), 2.54-3.02 (m, 2H), 1.88-2.02 (m, 4H), 1.38 (s, 9H) ppm. MS-ApCI: 467 [M + H⁺]. [1845] (Step B) By the method of Example 98, (8aS, 12aR) -2- (3,4-dimethoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3] The title compound was prepared from, 4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (70 mg, 71%). δMS-ApCI: 367 [M + H⁺]. [1846] (Example 553) (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi ] Pirido [4,3-b] Indole [1847] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2,4-dichlorophenylboronic acid (191 mg, 1.0 mmol), (8aS, 12aR) -2 -(2,4-Dichlorophenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole- 11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (98 mg, 41%).¹1 H NMR (CDCl₃, 300MHz) δ7.37 (s, 1H), 7.16 (s, 2H), 6.81 (s, 2H), 4.32-4.38 (m, 1H), 3.18-4.05 (m, 7H), 2.55-2.97 (m, 2H), 1.81-2.05 (m, 2H), 1.37 (s, 9H) ppm. MS-ApCI: 475 [M + H⁺]. [1848] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3, The title compound was prepared from 4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (63 mg, 81%).¹1 H NMR (CDCl₃, 300MHz) δ7.43-7.44 (m, 1H), 7.24 (s, 2H), 6.84-6.88 (m, 2H), 4.40-4.45 (m, 1H), 3.78-3.85 (m, 1H), 3.40- 3.44 (m, 2H), 2.83-3.23 (m, 4H), 2.44-2.64 (m, 2H), 1.76-2.13 (m, 5H) ppm. MS-ApCI: 375 [M + H⁺]. [1849] (Example 554) (8aS, 12aR) -2- (3,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi ] Pirido [4,3-b] Indole [1850] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 3,4-dichlorophenylboronic acid (191 mg, 1.0 mmol) to (8aS, 12aR) -2- (3,4-Dichlorophenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (90 mg, 38%). MS-ApCI: 475 [M + H⁺]. [1851] (Step B) By the method of Example 98, (8aS, 12aR) -2- (3,4-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3, The title compound was prepared from 4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (41 mg, 58%). MS-ApCI: 375 [M + H⁺]. [1852] (Example 555) (8aS, 12aR) -2- (2,5-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi ] Pirido [4,3-b] Indole [1853] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2,5-dichlorophenylboronic acid (191 mg, 1.0 mmol), (8aS, 12aR) -2 -(2,5-Dichlorophenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole- 11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (119 mg, 50%).¹1 H NMR (CDCl₃, 300MHz) δ7.18-7.24 (m, 2H), 7.08 (dd, 1H, J = 8.8Hz, 2.6Hz), 6.82 (s, 2H), 4.31-4.36 (m, 1H), 3.08-4.02 (m) , 7H), 2.54-3.02 (m, 2H), 1.84-2.02 (m, 4H), 1.36 (s, 9H) ppm. MS-ApCI: 475 [M + H⁺]. [1854] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2,5-dichlorophenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3, The title compound was prepared from 4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (61 mg, 65%).¹1 H NMR (CDCl₃, 300MHz) δ7.29-7.37 (m, 2H), 7.15-7.19 (m, 1H), 6.85-6.97 (m, 2H), 4.39-4.59 (m, 1H), 3.78-3.86 (m, 1H), 3.34-3.44 (m, 2H), 3.17-3.25 (m, 1H), 3.02-3.09 (m, 1H), 2.83-2.96 (m, 2H), 2.51-2.64 (m, 2H), 1.78-2.20 (m) , 5H) ppm. MS-ApCI: 375 [M + H⁺]. [1855] (Example 556) (8aS, 12aR) -2- [2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3, 4-hi] Pirido [4,3-b] Indole [1856] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2- (trifluoromethyl) phenylboronic acid (190 mg, 1.0 mmol), (8aS, 12aR) ) -2- [2- (Trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4, 3-b] Indol-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (124 mg, 52%).¹1 H NMR (CDCl₃, 300MHz) δ7.69 (d, 1H, J = 7.6Hz), 7.48-7.53 (m, 1H), 7.37-7.42 (m, 1H), 7.31 (d, 1H, J = 7.7Hz), 6.79 (s) , 1H), 6.77 (s, 1H), 4.41-4.46 (m, 1H), 3.23-4.02 (m, 7H), 2.60-2.91 (m, 2H), 1.95-2.12 (m, 4H), 1.44 (s) , 9H) ppm. MS-ApCI: 475 [M + H⁺]. [1857] (Step B) By the method of Example 98, (8aS, 12aR) -2- [2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2] A title compound was prepared from, 3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (85 mg, 87%).¹1 H NMR (CDCl₃, 300MHz) δ7.69 (d, 1H, J = 7.7Hz), 7.52-7.61 (m, 1H), 7.41-7.50 (m, 1H), 7.31 (d, 1H, J = 7.3Hz), 6.78 (s , 1H), 6.73 (s, 1H), 4.39-4.46 (m, 1H), 3.76-3.84 (m, 1H), 3.39-3.45 (m, 2H), 3.13-3.21 (m, 1H), 2.94-3.05 (m, 1H), 2.86-2.91 (m, 2H), 2.48-2.62 (m, 2H), 1.76-2.18 (m, 5H) ppm. MS-ApCI: 375 [M + H⁺]. [1858] (Example 557) (8aS, 12aR) -2- (2-Methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pirido [4,3-b] indole [1859] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2-methylphenylboronic acid (136 mg, 1.0 mmol), (8aS, 12aR) -2- (2-Methylphenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indol-11 ( 8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (134 mg, 64%).¹1 H NMR (CDCl₃, 300MHz) δ7.10-7.18 (m, 4H), 6.72 (s, 1H), 6.70 (s, 1H), 4.35-4.40 (m, 1H), 3.59-4.05 (m, 3H), 3.16-3.42 ( m, 4H), 2.52-3.02 (m, 2H), 2.22 (s, 3H), 1.88-2.05 (m, 4H), 1.37 (s, 9H) ppm. MS-ApCI: 421 [M + H⁺]. [1860] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2-methylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4] The title compound was prepared from -hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (81 mg, 79%).¹1 H NMR (CDCl₃, 300MHz) δ7.07-7.17 (m, 4H), 6.70 (s, 1H), 6.68 (s, 1H), 4.31-4.36 (m, 1H), 3.67-3.75 (m, 1H), 3.24-3.40 ( m, 2H), 2.91-3.11 (m, 2H), 2.78-2.85 (m, 2H), 2.40-2.49 (m, 2H), 2.20 (s, 3H), 1.77-2.02 (m, 5H) ppm. MS-ApCI: 321 [M + H⁺]. [1861] (Example 558) (8aS, 12aR) -2- (2-chlorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi] Indole [4,3-b] Indole [1862] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2-chlorophenylboronic acid (156 mg, 1.0 mmol), (8aS, 12aR) -2-( 2-Chlorophenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -Tert-Butyl carbonate was prepared and purified by chromatography to give the desired product (145 mg, 66%).¹1 H NMR (CDCl₃, 300MHz) δ7.41-7.44 (m, 1H), 7.18-7.33 (m, 3H), 6.93 (s, 2H), 4.42-4.47 (m, 1H), 3.24-4.02 (m, 7H), 2.62- 3.02 (m, 2H), 1.95-2.12 (m, 4H), 1.44 (s, 9H) ppm. MS-ApCI: 441 [M + H⁺]. [1863] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2-chlorophenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4- The title compound was prepared from hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (81 mg, 72%).¹1 H NMR (CDCl₃, 300MHz) δ7.40-7.43 (m, 1H), 7.17-7.36 (m, 3H), 6.89-6.92 (m, 2H), 4.39-4.46 (m, 1H), 3.78-3.86 (m, 1H), 3.38-3.44 (m, 2H), 3.15-3.24 (m, 1H), 3.00-3.06 (m, 1H), 2.86-2.95 (m, 2H), 2.51-2.64 (m, 2H), 1.76-2.17 (m) , 5H) ppm. MS-ApCI: 341 [M + H⁺]. [1864] (Example 559) (8aS, 12aR) -2- (3-Fluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pirido [4,3-b] indole [1865] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 3-fluorophenylboronic acid (140 mg, 1.0 mmol), (8aS, 12aR) -2- (3-Fluorophenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole-11 ( 8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (108 mg, 51%). MS-ApCI: 425 [M + H⁺]. [1866] (Step B) By the method of Example 98, (8aS, 12aR) -2- (3-fluorophenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4] The title compound was prepared from -hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (38 mg, 46%).¹1 H NMR (CDCl₃, 300MHz) δ7.69 (d, 1H, J = 7.7Hz), 7.49-7.61 (m, 1H), 7.39-7.47 (m, 1H), 7.38 (d, 1H, J = 7.7Hz), 6.78 (s) , 1H), 6.73 (s, 1H), 4.39-4.46 (m, 1H), 3.76-3.84 (m, 1H), 3.39-3.45 (m, 2H), 3.13-3.21 (m, 1H), 2.98-3.05 (m, 1H), 2.86-2.91 (m, 2H), 2.48-2.62 (m, 2H), 1.76-2.18 (m, 5H) ppm. MS-ApCI: 325 [M + H⁺]. [1867] (Example 560) (8aS, 12aR) -2-Phenyl-6,7,8a,9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi] Indole [4,3 -b] Indole [1868] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding phenylboronic acid (122 mg, 1.0 mmol), (8aS, 12aR) -2-phenyl-6 , 7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-Butyl Carbonate It was prepared and purified by chromatography to give the desired product (80 mg, 40%). MS-ApCI: 407 [M + H⁺]. [1869] (Step B) By the method of Example 98, (8aS, 12aR) -2-phenyl-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridode [ 4,3-b] The title compound was prepared from indole-11 (8aH) -tert-butyl carbonate to give the title compound (54 mg, 90%).¹1 H NMR (CDCl₃, 300MHz) δ7.42-7.45 (m, 2H), 7.26-7.30 (m, 2H), 7.13-7.19 (m, 1H), 6.98 (d, 1H, J = 1.8Hz), 6.92 (d, 1H, J = 1.5Hz), 4.30-4.40 (m, 1H), 3.69-3.77 (m, 1H), 3.28-3.35 (m, 2H), 3.06-3.14 (m, 1H), 2.92-2.99 (m, 1H) , 2.77-2.82 (m, 2H), 2.42-2.53 (m, 2H), 1.66-2.05 (m, 4H), 1.51 (bs, 1H) ppm. MS-ApCI: 307 [M + H⁺]. [1870] (Example 561) (8aS, 12aR) -2- [4-ethoxy-2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [ 2,3,4-hi] Pirido [4,3-b] Indole [1871] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 4-ethoxy-2- (trifluoromethyl) phenylboronic acid (234 mg, 1.0 mmol) (8aS, 12aR) -2- [4-ethoxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3, 4-hi] pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (155 mg, 74%). MS-ApCI: 519 [M + H⁺]. [1872] (Step B) By the method of Example 98, (8aS, 12aR) -2- [4-ethoxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4 ] Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate was used to prepare the title compound to give the title compound (106 mg, 85%).¹1 H NMR (CDCl₃, 300MHz) δ7.10-7.16 (m, 2H), 6.93 (dd, 1H, J = 8.1Hz, 5.5Hz), 6.64 (s, 1H), 6.60 (s, 1H), 4.29-4.35 (m, 1H) ), 3.98 (q, 2H, J = 2.3Hz), 3.65-3.74 (m, 1H), 3.28-3.34 (m, 2H), 3.02-3.12 (m, 1H), 2.88-2.95 (m, 1H), 2.76-2.84 (m, 2H), 2.38-2.51 (m, 2H), 1.65-2.04 (m, 4H), 1.55 (bs, 1H), 1.34 (t, 3H, J = 2.3Hz) ppm. MS-ApCI: 419 [M + H⁺]. [1873] (Example 562) (8aS, 12aR) -2- [4-isopropoxy-2- (trifluoromethyl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] Pirido [4,3-b] Indole [1874] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 4-isopropoxy-2- (trifluoromethyl) phenylboronic acid (248 mg, 1.0 mmol) , (8aS, 12aR) -2- [4-isopropoxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2, 3,4-hi] pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (153 mg, 58%). MS-ApCI: 533 [M + H⁺]. [1875] (Step B) By the method of Example 98, (8aS, 12aR) -2- [4-isopropoxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1, 4] The title compound was prepared from oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (90 mg, 72%).¹1 H NMR (CDCl₃, 300MHz) δ7.18-7.22 (m, 2H), 7.00 (dd, 1H, J = 8.4Hz, 2.5Hz), 6.74 (s, 1H), 6.70 (s, 1H), 4.55-4.63 (m, 1H) ), 4.38-4.45 (m, 1H), 3.75-3.83 (m, 1H), 3.38-3.43 (m, 2H), 3.12-3.20 (m, 1H), 2.98-3.04 (m, 1H), 2.86-2.90 (m, 2H), 2.48-2.62 (m, 2H), 1.65-2.13 (m, 5H), 1.36 (d, 6H, J = 5.9Hz) ppm. MS-ESI: 433 [MH]⁺.. [1876] (Example 563) (8aS, 12aR) -2- (5-isopropyl-2-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3, 4-hi] Pirido [4,3-b] Indole [1877] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 5-isopropyl-2-methoxyphenylboronic acid (194 mg, 1.0 mmol), (8aS, 12aR) ) -2- (5-Isopropyl-2-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4, 3-b] Indol-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (180 mg, 75%). MS-ApCI: 479 [M + H⁺]. [1878] (Step B) By the method of Example 98, (8aS, 12aR) -2- (5-isopropyl-2-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2] , 3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was used to prepare the title compound to give the title compound (128 mg, 90%).¹1 H NMR (CDCl₃, 300MHz) δ7.08 (d, 1H, J = 2.2Hz), 7.02 (dd, 1H, J = 8.5Hz, 2.6Hz), 6.95 (d, 1H, J = 1.5Hz), 6.91 (m, 1H, J = 1.1Hz), 6.79 (d, 1H, J = 8.4Hz), 4.31-4.38 (m, 1H), 3.71-3.79 (m, 1H), 3.70 (s, 3H), 3.28-3.33 (m, 2H) ), 3.06-3.14 (m, 1H), 2.92-2.98 (m, 1H), 2.75-2.84 (m, 2H), 2.45-2.55 (m, 2H), 1.56-2.04 (m, 4H), 1.48 (bs) , 1H), 1.16 (d, 6H, J = 7.0Hz) ppm. MS-ESI: 379 [MH]⁺.. [1879] (Example 564) (8aS, 12aR) -2- (4-Chloro-2-fluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3, 4-hi] Pirido [4,3-b] Indole [1880] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 4-chloro-2-fluorophenylboronic acid (175 mg, 1.0 mmol), (8aS, 12aR) ) -2- (4-Chloro-2-fluorophenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4, 3-b] Indole-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (152 mg, 66%). MS-ApCI: 459 [M + H⁺]. [1881] (Step B) By the method of Example 98, (8aS, 12aR) -2- (4-chloro-2-fluorophenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2] , 3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was used to prepare the title compound to give the title compound (98 mg, 82%).¹1 H NMR (CDCl₃, 300MHz) δ7.30-7.48 (m, 1H), 7.08-7.15 (m, 2H), 6.98 (s, 1H), 6.95 (s, 1H), 4.38-4.46 (m, 1H), 3.79-3.87 ( m, 1H), 3.37-3.43 (m, 2H), 3.16-3.23 (m, 1H), 3.01-3.07 (m, 1H), 2.86-2.95 (m, 2H), 2.52-2.64 (m, 2H), 1.76-2.12 (m, 5H) ppm. MS-ApCI: 359 [M + H⁺]. [1882] (Example 565) (8aS, 12aR) -2- (2-Chloro-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxaazepino [2,3, 4-hi] Pirido [4,3-b] Indole [1883] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2-chloro-4-methoxyphenylboronic acid (170 mg, 1.0 mmol), (8aS, 12aR) ) -2- (2-Chloro-4-methoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4, 3-b] Indol-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (140 mg, 60%). MS-ApCI: 471 [M + H⁺]. [1884] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2-chloro-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2] , 3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was used to prepare the title compound to give the title compound (81 mg, 73%).¹1 H NMR (CDCl₃, 300MHz) δ7.23 (d, 1H, J = 8.5Hz), 6.98 (d, 1H, J = 2.6Hz), 6.80-6.88 (m, 3H), 4.39-4.46 (m, 1H), 3.78-3.86 (m, 1H), 3.81 (s, 3H), 3.37-3.42 (m, 2H), 3.14-3.22 (m, 1H), 3.00-3.06 (m, 1H), 2.86-2.90 (m, 2H), 2.51 -2.63 (m, 2H), 2.06-2.13 (m, 2H), 1.96-2.02 (m, 1H), 1.76-1.87 (m, 1H), 1.66 (bs, 1H) ppm. MS-ApCI: 371 [M + H⁺]. [1885] (Example 566) 2-[(8aS, 12aR) -6,7,8a,9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridoru [4,3- b] Indoru-2-yl] Benzaldehyde [1886] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2-formylphenylboronic acid (150 mg, 1.0 mmol), (8aS, 12aR) -2- (2-formylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 ( 8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (130 mg, 60%). MS-ApCI: 435 [M + H⁺]. [1887] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2-formylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4] The title compound was prepared from -hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (75 mg, 75%).¹1 H NMR (CDCl₃, 300MHz) δ10.01 (s, 1H), 7.97 (d, 1H, J = 8.1Hz), 7.55-7.61 (m, 1H), 7.39-7.44 (m, 2H), 6.84 (d, 1H, J = 1.8Hz), 6.76 (d, 1H, J = 1.5Hz), 4.40-4.47 (m, 1H), 3.79-3.87 (m, 1H), 3.40-3.46 (m, 2H), 3.16-3.24 (m, 1H) ), 3.01-3.07 (m, 1H), 2.87-2.95 (m, 2H), 2.51-2.66 (m, 2H), 1.78-2.17 (m, 5H) ppm. MS-ApCI: 335 [M + H⁺]. [1888] (Example 567) 2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridoru [4,3- b] Indol-2-yl] -5-methoxybenzaldehyde [1889] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] From pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2-formyl-4-methoxyphenylboronic acid (177 mg, 1.0 mmol), (8aS, 12aR) ) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4, 3-b] Indole-11 (8aH) -tert-butyl carbonate was prepared and purified by chromatography to give the desired product (120 mg, 52%). MS-ApCI: 465 [M + H⁺]. [1890] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2] , 3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was used to prepare the title compound to give the title compound (75 mg, 75%).¹1 H NMR (CDCl₃, 300MHz) δ9.97 (s, 1H), 7.45 (d, 1H, J = 2.9Hz), 7.34 (d, 1H, J = 8.4Hz), 7.15 (dd, 1H, J = 8.4Hz, 2.5Hz) , 6.80 (d, 1H, J = 1.4Hz), 6.72 (d, 1H, J = 1.8Hz), 4.39-4.46 (m, 1H), 3.88 (s, 3H), 3.78-3.86 (m, 1H), 3.40-3.45 (m, 2H), 3.16-3.24 (m, 1H), 3.01-3.07 (m, 1H), 2.88-2.91 (m, 2H), 2.50-2.65 (m, 2H), 2.41 (bs, 1H) ), 1.82-2.17 (m, 4H) ppm. MS-ApCI: 365 [M + H⁺]. [1891] (Example 568) {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridoru [4,3] -b] Indol-2-yl] -5-methoxyphenyl} methanol [1892] (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] CH pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (20 mg, 0.04 mmol)₂Cl₂Dissolved in. The mixture was cooled to -78 ° C in an inert atmosphere. CH₂Cl₂DIBAL (0.07 mL, 0.07 mmol) (1 mL) in the medium was added dropwise at -78 ° C. The reaction mixture was warmed to room temperature over 2 hours. The reaction mixture was concentrated in vacuo. CH₂Cl₂(2 mL) and saturated Rochelle salt solution (2 mL) were added and the layers were separated. EDTA the organic layer₄Dry on top and concentrate in vacuo, (8aS, 12aR) -2- [2- (hydroxymethyl) -4-methoxyphenyl] -6,7,9,10,12,12a-hexahydro-5H-[ 1,4] Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate was obtained. By the method of Example 98, (8aS, 12aR) -2- [2- (hydroxymethyl) -4-methoxyphenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] The title compound was prepared from oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (10 mg, 68%).¹1 H NMR (CDCl₃, 300MHz) δ7.17 (d, 1H, J = 8.4Hz), 7.09 (d, 1H, J = 2.5Hz), 6.84 (dd, 1H, J = 8.4Hz, 2.6Hz), 6.76 (d, 1H, J = 1.5Hz), 6.72 (d, 1H, J = 1.5Hz), 4.63 (s, 2H), 4.38-4.46 (m, 1H), 3.77-3.88 (m, 1H), 3.84 (s, 3H), 3.35-3.44 (m, 2H), 3.14-3.20 (m, 1H), 2.97-3.04 (m, 1H), 2.85-2.88 (m, 2H), 2.48-2.62 (m, 2H), 1.75-2.12 (m) , 5H), 1.25 (s, 1H) ppm. MS-ESI: 367 [MH]⁺.. [1893] (Example 569) {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridoru [4,3 -b] Indoru-2-yl] phenyl} methanol [1894] By the method of Example 568, (8aS, 12aR) -2- (2-formylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4] The title compound was prepared from -hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (20 mg, 0.05 mmol) to give the title compound (12 mg, 71%).¹1 H NMR (CDCl₃, 300MHz) δ7.49-7.53 (m, 1H), 7.24-7.36 (m, 3H), 6.82 (d, 1H, J = 1.8Hz), 6.77 (d, 1H, J = 1.5Hz), 4.65 (s , 2H), 4.39-4.46 (m, 1H), 3.77-3.85 (m, 1H), 3.39-3.45 (m, 2H), 3.14-3.21 (m, 1H), 2.98-3.05 (m, 1H), 2.86 -2.91 (m, 2H), 2.49-2.63 (m, 2H), 1.76-2.17 (m, 5H), 1.25 (s, 1H) ppm. MS-ESI: 337 [MH]⁺.. [1895] (Example 570) N- [4-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4] , 3-b] Indol-2-yl] -3- (trifluoromethyl) phenyl] -N-methylamine [1896] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] Pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 4-[(tert-butoxycarbonyl) (methyl) amino] -2- (trifluoromethyl) From phenylboronic acid (319 mg, 1.0 mmol), (8aS, 12aR) -2- [4-[(tert-butoxycarbonyl) (methyl) amino] -2- (trifluoromethyl) phenyl] -6,7,9 , 10,12,12a-Hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate was prepared and chromatographed. After purification with, the desired product (226 mg, 75%) was obtained. MS-ApCI: 604 [M + H⁺]. [1897] (Step B) By the method of Example 98, (8aS, 12aR) -2- [4-[(tert-butoxycarbonyl) (methyl) amino] -2- (trifluoromethyl) phenyl] -6,7,9,10,12 , 12a-Hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -Title compound prepared from tert-butyl carbonate, title compound (130 mg, 86%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ7.12 (d, 1H, J = 8.5Hz), 6.93 (d, 1H, J = 1.8Hz), 6.69-6.88 (m, 3H), 4.38-4.45 (m, 1H), 3.77-3.89 (m, 2H), 3.34-3.45 (m, 2H), 3.09-3.19 (m, 1H), 2.90-3.04 (m, 1H), 2.89 (s, 3H), 2.87 (s, 3H), 2.47-2.79 (m, 2H), 1.70-2.17 (m, 5H) ppm. MS-ApCI: 404 [M + H⁺]. [1898] (Example 571) 4-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3- b] Indol-2-yl] -3- (trifluoromethyl) phenylamine [1899] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] Pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 4-[(tert-butoxycarbonyl) amino] -2- (trifluoromethyl) phenylboronic acid From (305 mg, 1.0 mmol), (8aS, 12aR) -2- [4-[(tert-butoxycarbonyl) amino] -2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a -Hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate is prepared, purified by chromatography and desired. Product (145 mg, 50%) was obtained. [1900] (Step B) By the method of Example 98, (8aS, 12aR) -2- [4-[(tert-butoxycarbonyl) amino] -2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a- Hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -Title compound prepared from tert-butyl carbonate, title compound (8 mg, 8 mg, 84%) was obtained.¹1 H NMR (CDCl₃, 300MHz) δ7.10 (d, 1H, J = 8.1Hz), 6.98 (d, 1H, J = 2.2Hz), 6.78 (dd, 1H, J = 8.1Hz, 1.9Hz), 6.71 (d, 2H, J = 10.6Hz), 4.38-4.45 (m, 1H), 3.75-3.81 (m, 3H), 3.38-3.42 (m, 2H), 3.11-3.19 (m, 1H), 2.97-3.04 (m, 1H) , 2.85-2.89 (m, 2H), 2.47-2.60 (m, 2H), 1.76-2.12 (m, 4H), 1.62 (bs, 1H) ppm. MS-ESI: 390 [MH]⁺.. [1901] (Example 572) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridoru [4 , 3-b] Indoru-2-yl] Phenyl} Etanone [1902] (Step A) (8aS, 12aR) -2- (2-formylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino in freshly distilled THF (4 mL) [2, MeMgBr (0.44 mL, 1.3 mmol) was added dropwise to 3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (114 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. CH₃OH (0.5 mL) was added dropwise to the reaction mixture and concentrated in vacuo. Add EtOAc (5 mL), wash with saline (5 mL) and remove the organic layer with DDL.₄Dry on and concentrate (8aS, 12aR) -2- [2- (1-hydroxyethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate was obtained. The crude product was used in the next step. [1903] (Step B) CH oxalyl chloride (0.038 mL, 0.432 mol)₂Cl₂Dissolved in (3 mL) and cooled to -60 ° C. CH₂Cl₂DMSO in (1 mL) was added dropwise to the solution. After stirring the reaction mixture at -60 ° C for 10 minutes, CH₂Cl₂(8aS, 12aR) -2- [2- (1-Hydroxyethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino in (2 mL) 3,4-hi] Pyrid [4,3-b] indole-11 (8aH) -tert-butyl carbonate (97 mg, crude product of step 1) was added dropwise. The reaction mixture was stirred at -60 ° C for 15 minutes. Triethylamine (0.24 mL, 1.73 mmol) was added at -60 ° C. Except for cold bath, H₂O (6 mL) was added at room temperature and stirring was continued for about 10 minutes to separate the organic layer. CH the water layer₂Cl₂Extracted with (2 x 6 mL). Combined organic layer DDL₄After drying on and purifying by chromatography, through two steps, (8aS, 12aR) -2- (2-acetylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1 , 4] Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (48 mg, 41%) was obtained. MS-ApCI: 449 [M + H⁺]. [1904] (Step C) By the method of Example 98, (8aS, 12aR) -2- (2-acetylphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepina [2,3,4] The title compound was prepared from -hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate to give the title compound (32 mg, 86%).¹1 H NMR (CDCl₃, 300MHz) δ7.42-7.48 (m, 2H), 7.30-7.37 (m, 2H), 6.83 (d, 1H, J = 1.5Hz), 6.69 (d, 1H, J = 1.5Hz), 4.40-4.47 (m, 1H), 3.75-3.83 (m, 1H), 3.37-3.46 (m, 2H), 3.11-3.19 (m, 1H), 2.98-3.05 (m, 1H), 2.85-2.89 (m, 2H) , 2.44-2.61 (m, 2H), 1.96-2.12 (m, 3H), 2.00 (s, 3H), 1.75-1.86 (m, 1H), 1.64 (bs, 1H) ppm. MS-ESI: 349 [MH]⁺.. [1905] (Example 573) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridoru [4 , 3-b] Indoru-2-yl] -5-methoxyphenyl} etanone [1906] (Step A) By the method of Example 600, (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2] From, 3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (72 mg, 0.16 mmol) and MeMgBr (0.26 mL, 0.78 mmol), (8aS, 12aR) -2 -(2-Acetyl-4-methoxyphenyl) -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepina [2,3,4-hi] Pyrid [4,3-b ] Indole-11 (8aH) -tert-butyl carbonate was prepared and after two steps the desired product (24 mg, 33%) was obtained. MS-ApCI: 479 [M + H⁺]. [1907] (Step B) By the method of Example 98, (8aS, 12aR) -2- (2-acetyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepina [2] , 3,4-hi] Pyrid [4,3-b] Indole-11 (8aH) -tert-butyl carbonate was used to prepare the title compound to give the title compound (11 mg, 63%).¹1 H NMR (CDCl₃, 300MHz) δ7.27-7.29 (m, 1H), 6.99-7.01 (m, 2H), 6.79 (d, 1H, J = 1.8Hz), 6.65 (d, 1H, J = 1.5Hz), 4.39-4.46 (m, 1H), 3.74-3.88 (m, 1H), 3.84 (s, 3H), 3.38-3.44 (m, 2H), 3.11-3.19 (m, 1H), 2.98-3.05 (m, 1H), 2.73 -2.89 (m, 2H), 2.43-2.59 (m, 2H), 1.70-2.17 (m, 5H), 1.99 (s, 3H) ppm. MS-ESI: 379 [MH]⁺.. [1908] (Example 574) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridoru [4 , 3-b] Indoru-2-yl] Phenyl} Ethanol [1909] CH₃1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4] in OH (1 mL) -hi] Pyrid [4,3-b] Indol-2-yl] Phenyl} Etanone (10 mg, 0.03 mmol) to NaBH at room temperature₄(5.4 mg, 0.15 mmol) was added in 3 portions. The reaction mixture was stirred at room temperature for 2 hours. Two drops of 1N HCl were added to the reaction mixture and concentrated in vacuo. NH₄Add OH (1 mL) and water (2 mL), CH₂Cl₂Extracted with (3 x 3 mL). Combined organic layer DDL₄It was dried on top and concentrated to give the title compound (7 mg, 70%).¹1 H NMR (CDCl₃, 300MHz) δ7.62 (d, 1H, J = 3.7Hz), 7.17-7.38 (m, 3H), 6.69-6.77 (m, 2H), 5.01-5.08 (m, 1H), 4.40-4.45 (m, 1H), 3.78-3.84 (m, 1H), 3.38-3.44 (m, 2H), 3.11-3.17 (m, 1H), 2.97-3.06 (m, 1H), 2.86-2.89 (m, 2H), 2.48- 2.61 (m, 2H), 1.68-2.10 (m, 6H), 1.32-1.47 (m, 3H) ppm. MS-ESI: 351 [MH]⁺.. [1910] (Example 575) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyridoru [4 , 3-b] Indoru-2-yl] -5-methoxyphenyl} ethanol [1911] By the method of Example 574, 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3, The title compound was prepared from 4-hi] pyrido [4,3-b] indol-2-yl] -5-methoxyphenone} etanone (9 mg, 0.02 mmol) to give the title compound (8 mg, 80%).¹1 H NMR (CDCl₃, 300MHz) δ7.17 (d, 1H, J = 2.6Hz), 7.11 (d, 1H, J = 8.4Hz), 6.81 (dd, 1H, J = 8.4Hz, 2.6Hz), 6.70 (d, 1H, J = 2.6Hz), 6.65 (s, 1H), 4.99-5.05 (m, 1H), 4.40-4.44 (m, 1H), 3.85 (s, 3H), 3.75-3.81 (m, 1H), 3.38-3.43 (m, 2H), 3.10-3.17 (m, 1H), 2.95-3.01 (m, 1H), 2.84-2.88 (m, 2H), 2.46-2.60 (m, 2H), 1.67-2.11 (m, 6H) , 1.25-1.44 (m, 3H) ppm. MS-ESI: 381 [MH]⁺.. [1912] (Example 576) 4-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H- [1,4] oxazepino [2,3,4-hi] pyrido [4,3- b] Indol-2-yl] -3- (trifluoromethyl) phenol [1913] (Step A) Example 89 By the method of step C, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H- [1,4] oxazepino [2,3,4-hi] Pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (205 mg, 0.5 mmol) and the corresponding 2- (trifluoromethyl) -4-[(triisopropylsilyl) oxy] phenylboronic acid ( From 363 mg, 1.0 mmol), (8aS, 12aR) -2- [4-hydroxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4 ] Oxazepino [2,3,4-hi] pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate was prepared, purified by chromatography, and then (8aS, 12aR) -2- [4 -Hydroxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-Hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3- b] Indol-11 (8aH) -tert-butyl carbonate (47 mg, 19%) MS-ApCI: 491 [M + H⁺] And (8aS, 12aR) -2- {2- (trifluoromethyl) -4-[(triisopropylsilyl) oxy] phenyl} -6,7,9,10,12,12a-hexahydro-5H- [1 , 4] Oxazepino [2,3,4-hi] pyrido [4,3-b] Indole-11 (8aH) -tert-butyl carbonate (167mg, 52%) MS-ApCI: 647 [M + H⁺] Was obtained. [1914] (Step B) (8aS, 12aR) -2- {2- (trifluoromethyl) -4-[(triisopropylsilyl) oxy] phenyl} -6,7,9,10,12,12a-hexahydro-5H- [1,4 ] Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (167 mg, 0.26 mmol) CH₃Dissolved in CN (5 mL), KF2H₂O was added and the reaction mixture was stirred at room temperature for 20 hours under an inert atmosphere. Add EtOAc (20 mL) and saline (15 mL) and add pyridine to the organic layer.₄Dry on top and concentrate in vacuo, (8aS, 12aR) -2- [4-hydroxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (100 mg, 79%) was obtained. [1915] (Step C) By the method of Example 98, (8aS, 12aR) -2- [4-hydroxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4 ] Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (47 mg, 0.1 mmol) was used to prepare the title compound, and the title compound (20 mg, 51%) was prepared. ) Was obtained.¹1 H NMR (CDCl₃, 300MHz) δ7.02-7.06 (m, 2H), 6.81 (dd, 1H, J = 8.4Hz, 2.5Hz), 6.68 (s, 1H), 6.60 (s, 1H), 4.31-4.38 (m, 1H) ), 4.14 (bs, 1H), 3.68-3.76 (m, 1H), 3.31-3.36 (m, 2H), 3.10-3.17 (m, 1H), 2.88-3.02 (m, 3H), 2.46-2.56 (m) , 2H), 1.81-2.10 (m, 5H) ppm. MS-ESI: 391 [MH]⁺.. [1916] (Example 577) 4-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-Octahydro-5H- [1,4] Oxazepino [2,3,4-hi] Pyrid [4,3- b] Indol-2-yl] -3- (trifluoromethyl) phenyl acetate [1917] (Step A) (8aS, 12aR) -2- [4-Hydroxy-2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [1,4] in DMF (2 mL) Oxazepino [2,3,4-hi] pyrido [4,3-b] indole-11 (8aH) -tert-butyl carbonate (50 mg, 0.13 mmol), Et₃Acetyl chloride (0.45 mL, 3.2 mmol) was added to N (0.091 mL, 1.3 mmol) at room temperature and the reaction mixture was stirred at room temperature for 2 hours. EtOAc (4 mL) and water (2 mL) were added. EDTA the organic layer₄After drying on top, concentrating in vacuo and purifying by chromatography, the desired product (30 mg, 44%) was obtained. MS-ApCI: 553 [M + H⁺]. [1918] (Step B) By the method of Example 98, (8aS, 12aR) -2- [4- (acetyloxy) -2- (trifluoromethyl) phenyl] -6,7,9,10,12,12a-hexahydro-5H- [ The title compound was prepared from 1,4] oxazepino [2,3,4-hi] pyrido [4,3-b] indol-11 (8aH) -tert-butyl carbonate (30 mg, 0.06 mmol) and subjected to high pressure liquid chromatography. After purification, the title compound (5 mg, 21%) was obtained. MS-ESI: 433 [MH]⁺.. [1919] (Example 578) (8aS, 12aR) -N- (diphenylmethylene)-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2, 3,4-hi] Indoru-2-amine [1920] (Step A) (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indol -11 (8aH) -tert-butyl carbonate (0.25 g, 0.58 mmol), benzophenone imine (0.125 g, 0.69 mmol), sodium tert-butoxide (0.078 g, 0.82 mmol), and (R) BINAP (0.026 g, 0.042). N in toluene (10.4 mL) anhydrous₂Stir down for 15 minutes. Pd₂dba₃(0.026 g, 0.029 mmol) was added all at once and the reaction was brought to 80 ° C for 15 hours. The reaction was concentrated and purified by silica gel column chromatography (10% EtOAc / Hexanes). (8aS, 12aR) -2-[(diphenylmethylene) amino] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.261 g, 86%) was recovered as a bright red-orange semi-solid.¹1 H NMR (CDCl₃, 300MHz) 7.71 (d, 2H, J = 6.6Hz), 7.35-7.48 (m, 3H), 7.30-7.35 (m, 3H), 7.10-7.18 (m, 2H), 6.55 (brs, 1H), 6.19 (brs, 1H), 3.60-3.74 (m, 3H), 3.30-3.47 (m, 2H), 3.12-3.24 (m, 1H), 2.92-3.07 (m, 2H), 2.81-2.90 (m, 1H) , 1.98-2.10 (m, 3H), 1.80-1.88 (m, 2H), 1.47 (s, 9H) ppm. [1921] (Step B) (8aS, 12aR) -2-[(diphenylmethylene) amino] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.025 g, 0.047 mmol) CH with TFA (0.3 mL)₂Cl₂It was dissolved in (1 mL) and stirred at room temperature for 1 hour. Reactant (saturated) NH₄Base the pH 10 with OH and make the aqueous layer CHCl.₃Extracted with (3 x 10 mL). The combined extracts were washed with saline (5 mL) and dried (DDL).₄), The title compound was evaporated to give a pale yellow residue (0.016 g, 78% yield).¹1 H NMR (CDCl₃, 300MHz) 7.81 (dd, 4H, J = 1.1,6.9Hz), 7.57-7.64 (m, 2H), 7.48 (t, 4H, J = 7.7Hz), 6.36 (d, 1H, J = 2.6Hz), 6.30 (d, 1H, J = 2.2Hz), 3.41-3.59 (m, 3H), 3.25-3.36 (m, 2H), 3.08-3.18 (m, 1H), 2.79-2.98 (m, 3H), 2.57- 2.63 (m1H), 2.01-2.14 (m, 2H), 1.67-1.82 (m, 2H) ppm. [1922] (Example 579) (8aS, 12aR) -N- (diphenylmethylene)-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2, 3,4-hi] Indoru-3-amine [1923] (Step A) Example 578 According to the method of step A, (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (8aS, 12aR) -3-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4, 3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -Substituted for tert-butyl carbonate, (8aS, 12aR) -3-[(diphenylmethylene) amino]- 6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.304 g, 99%) was prepared.¹1 H NMR (CDCl₃, 300MHz) 7.89 (d, 2H, J = 6.9Hz), 7.39-7.48 (m, 3H), 7.19-7.25 (m, 5H), 6.57 (d, 1H, J = 7.7Hz), 5.81 (d, 1H) , J = 7.7Hz), 3.83-4.01 (m, 2H), 3.78-3.90 (m, 2H), 3.21-3.39 (m, 2H), 2.90-3.11 (m, 4H), 1.93-2.18 (m, 2H) ), 1.75-1.85 (m, 2H), 1.45 (s, 9H) ppm. [1924] (Step B) Example 578 The title compound (0.014 g, 68%) was prepared according to the method of Step B.¹1 H NMR (CDCl₃, 300MHz) 7.81 (dd, 4H, J = 1.5, 6.9Hz), 7.57-7.64 (m, 2H), 7.48 (t, 4H, J = 7.7Hz), 6.67 (t, 1H, J = 4.0Hz), 6.11 (d, 1H, J = 7.7Hz), 3.82-3.93 (m, 2H), 3.51-3.60 (m, 1H), 3.34-3.40 (m, 1H), 3.18-3.22 (m, 1H), 2.80- 3.07 (m, 4H), 2.58-2.62 (m, 1H), 2.01-2.18 (m, 2H), 1.70-1.81 (m, 2H) ppm. [1925] (Example 580) (8aS, 12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indoru -3-Amine [1926] (Step A) Example 430 According to the method of step B, (8aS, 12aR) -3-[(diphenylmethylene) amine] -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [ 1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -using tert-butyl carbonate as a starting material, (8aS, 12aR) -3-amino-6,7,9,10 , 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate yield 75% (0.051) Prepared in g).¹1 H NMR (CDCl₃, 300MHz) 6.71 (d, 1H, J = 7.6Hz), 6.12 (d, 1H, J = 7.7Hz), 3.97-4.01 (m, 1H), 3.42-3.65 (m, 4H), 3.21-3.39 (m) , 1H), 2.98-3.19 (m, 4H), 2.01-2.19 (m, 2H), 1.81-1.92 (m, 2H), 1.45 (s, 9H) ppm. [1927] (Step B) Example 578 According to the method of step B, (8aS, 12aR) -3-amino-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate was used as a starting material to prepare the title compound (0.012 g, 86%).¹1 H NMR (CDCl₃, 300MHz) 6.66 (t, 1H, J = 1.1Hz), 6.11 (d, 1H, J = 7.7Hz), 3.81-3.97 (m, 2H), 3.52-3.61 (m, 1H), 3.35-3.41 (m) , 1H), 3.10-3.22 (m, 1H), 2.81-3.05 (m, 5H), 2.58-2.62 (m, 1H), 2.01-2.21 (m, 2H), 1.78-1.83 (m, 2H) ppm. [1928] (Example 581) (8aS, 12aR) -N-Phenyl-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indoru-2-amine [1929] (Step A) CH₂Cl₂Triphenylbismuth (0.220 g, 0.50 mmol) and iodobenzene diacetate (0.177 g, 0.55 mmol) were stirred in (5 mL) at room temperature for 15 hours. Evaporate the solvent, Et₂O (2 mL) and heptane (2 mL) were added and heated. The obtained solid was hot filtered to give bis (acetate) triphenylbismuth (0.192 g, 70%) as a white flaky solid.¹1 H NMR (CDCl₃, 300MHz) 8.15 (dd, 6H, J = 1.1,8.4Hz), 7.62 (t, 6H, J = 7.3Hz), 7.50 (t, 3H, J = 8.4Hz), 1.81 (s, 6H) ppm. [1930] (Step B) (8aS, 12aR) -2-amino-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole CH -11 (8aH) -tert-butyl carbonate (0.260 g, 0.72 mmol)₂Cl₂It was combined with bis (acetate) triphenylbismuth (0.422 g, 0.756 mmol) and copper (II) acetate (0.013 g, 0.072 mmol) in (7.2 mL) and stirred for 30 minutes. The solvent was evaporated and the black residue was purified by silica gel column chromatography (10% EtOAc / Hexanes) to give blue foam. The compound was then dissolved in MeOH (2 mL) and foamed with HCl gas for 10 minutes. Evaporate the solvent and saturate the residue NH₄It was made basic with OH. CHCl the water layer₃Extract with (3 x 5 mL), wash with saline (10 mL) and dry (DDL)₄), The title compound was obtained in a yield of 70% (0.169 g).¹1 H NMR (CDCl₃, 300MHz) 7.20 (t, 2H, J = 8.4Hz), 6.87 (dd, 2H, J = 1.1,8.5Hz), 6.83 (t, 1H, J = 7.4Hz), 6.76 (d, 1H, J = 2.2) Hz), 6.71 (d, 1H, J = 2.2Hz), 5.37 (s, 1H), 3.60-3.72 (m, 1H), 3.47-3.59 (m, 1H), 3.36-3.42 (m, 1H), 3.12 -3.22 (m, 1H), 2.91-3.12 (m, 5H), 2.58-3.65 (m, 1H), 2.01-2.20 (m, 2H), 1.78-1.93 (m, 3H) ppm. [1931] (Example 582) (8aS, 12aR) -N-Phenyl-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indoru-3-amine [1932] Example 581 According to the method of step B, (8aS, 12aR) -3-amino-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate was used as a starting material to synthesize the title compound (0.029 g, 8%).¹1 H NMR (CDCl₃, 300MHz) 7.21-7.26 (m, 2H), 7.05 (dd, 2H, J = 1.1,8.8Hz), 6.91 (t, 1H, J = 7.3Hz), 6.74 (d, 1H, J = 7.7Hz), 6.70 (d, 1H, J = 8.1Hz), 5.91 (s, 1H), 3.94-4.01 (m, 1H), 3.57-3.62 (m, 1H), 3.36-3.42 (m, 1H), 3.12-3.22 ( m, 2H), 2.91-3.12 (m, 5H), 2.58-3.65 (m, 1H), 2.01-2.20 (m, 2H), 1.81-1.93 (m, 2H) ppm. [1933] (Example 583) (8aS, 12aR) -N- (4-fluorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indoru-2-amine [1934] (Step A) Bismuth oxychloride (III) (5.0 g, 15.8 mmol) was added to a solution of 4-fluorophenyl magnesium bromide (48.8 mL, 1.0 MTHF) in anhydrous diethyl ether (20 mL). The reaction was treated at room temperature for 2 hours. Ice was added and the aqueous layer was extracted with ether (3 x 25 mL). The combined extracts were washed with saline (25 mL) and dried (DDL).₄), Evaporated. CH₂Cl₂The residue was combined with iodobenzene diacetate (3.4 g, 10.5 mmol) in (20 mL) at room temperature for 15 hours. The solvent was evaporated to give bis (acetate) tris (4-fluorophenyl) bismuth in a total yield of 34%.¹1 H NMR (CDCl₃, 300MHz) 8.15-8.21 (m, 6H), 7.20-7.28 (m, 6H), 1.81 (s, 6H) ppm. [1935] (Step B) Example 581 According to Step B, the title compound (0.118 g, 39%) was prepared using bismuth (acetate) tris (4-fluorophenyl) bismuth.¹1 H NMR (CDCl₃, 300MHz) 6.81-6.99 (m, 4H), 6.71 (d, 1H, J = 2.2Hz), 6.63 (d, 1H, J = 2.2Hz), 5.27 (s, 1H), 3.60-3.72 (m, 1H) ), 3.47-3.59 (m, 1H), 3.36-3.42 (m, 1H), 3.12-3.22 (m, 1H), 2.91-3.12 (m, 5H), 2.58-3.65 (m, 1H), 2.01-2.20 (m, 2H), 1.78-1.93 (m, 3H) ppm. [1936] (Example 584) (8aS, 12aR) -N- (2,4-dichlorophenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indoru-2-amine [1937] (8aS, 12aR) -2-amino-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -tert-butyl carbonate (0.100 g, 0.27 mmol), 2,4-dichlorobenzeneboronic acid (0.104 g, 0.55 mmol), triethylamine (0.055 g, 0.55 mmol), cupric acetate (II) ( 0.049g, 0.27 mmol) and CH₂Cl₂Combined with (3 mL) and stirred for 24 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (15% EtOAc / Hexanes). The resulting oil was dissolved in MeOH (2 mL) and foamed in HCl (gas) for 10 minutes. Remove solvent and saturate residue NH₄OH and CHCl₃Distributed to. CHCl the water layer₃Extracted with (3 x 10 mL). The combined organic matter was washed with saline solution (5 mL) and dried (DDL).₄), The title compound was obtained in a yield of 14% (15 mg).¹1 H NMR (CDCl₃, 300MHz) 7.28 (d, 1H, J = 2.5Hz), 7.02 (dd, 1H, J = 2.6,8.8Hz), 6.84 (d, 1H, J = 9.2Hz), 6.79 (d, 1H, J = 2.2) Hz), 6.68 (d, 1H, J = 1.8Hz), 5.79 (s, 1H),), 3.62-3.72 (m, 1H), 3.47-3.59 (m, 1H), 3.36-3.42 (m, 1H) , 3.12-3.22 (m, 1H), 2.91-3.12 (m, 5H), 2.58-3.65 (m, 1H), 2.01-2.20 (m, 2H), 1.78-1.93 (m, 3H) ppm. [1938] (Example 585) N-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indoru-2-ilbenzamide [1939] (Step A) (8aS, 12aR) -2-amino-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -tert-butyl carbonate (0.070 g, 0.194 mmol), benzoyl chloride (0.033 g, 0.23 mmol), triethylamine (0.022 g, 0.213 mmol) and CH₂Cl₂(1.0 mL) was combined and stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by silica gel column chromatography (25% EtOAc / Hexanes). Recovered, (8aS, 12aR) -2- (benzoylamino) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole-11 (8aH) -tert-butyl carbonate was obtained as white foam (0.057 g, 63%).¹1 H NMR (CDCl₃, 300MHz) 7.83 (d, 2H, J = 6.6Hz), 7.62-7.71 (m, 1H), 7.25-7.39 (m, 2H), 3.61-3.83 (m, 2H), 3.41-3.58 (m, 2H) , 3.07-3.31 (m, 4H), 2.85-3.02 (m, 2H), 2.01-2.18 (m, 2H), 1.81-1.91 (m, 2H), 1.44 (s, 9H) ppm. [1940] (Step B) Example 578 The title compound was prepared as a pale yellow oil (89%) according to the method of step B.¹1 H NMR (CDCl₃, 300MHz) 7.83 (dd, 2H, J = 1.5, 6.9Hz), 7.70 (s, 1H), 7.42-7.58 (m, 3H), 7.35 (s, 1H), 7.05 (d, 1H, J = 1.9Hz) ), 3.60-3.72 (m, 1H), 3.47-3.59 (m, 1H), 3.36-3.42 (m, 1H), 3.17-3.22 (m, 1H), 2.82-3.12 (m, 5H), 2.58-2.65 (m, 1H), 2.01-2.20 (m, 2H), 1.78-1.93 (m, 3H) ppm. [1941] (Example 586) (8aS, 12aR) -N-Benzyl-6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indoru-2-amine [1942] N-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indol-2-ylbenzamide (0.055 g, 0.149 mmol) was dissolved in THF (0.57 mL) and LiAlH₄(0.299 mL, 1 MTHF) was added dropwise. The reaction was refluxed for 2 hours. The reaction was quenched and the mixture was filtered. The filtrate was evaporated and the product was purified by HPLC (Chiralcel OD / 20% EtOH / hexane w / 0.05% diethylamine 7 mL / min). The compound was recovered as a pale red-orange oil to give the title compound in a yield of 59% (0.031 g).¹1 H NMR (CDCl₃, 300MHz) 7.26-7.41 (m, 5H), 6.33 (d, 1H, J = 2.2Hz), 6.28 (d, 1H, J = 2.2Hz), 4.21 (s, 2H), 3.41-3.57 (m, 2H) ), 3.25-3.31 (m, 1H), 3.02-3.18 (m, 1H), 2.80-3.02 (m, 5H), 3.57-3.64 (m, 1H), 2.01-2.17 (m, 2H), 2.70-2.91 (m, 2H) ppm. [1943] (Example 587) (8aS, 12aR) -2- (Phenylsulfanyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2, 3,4-hi] Indole [1944] (Step A) (8aS, 12aR) -2-Bromo-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole -11 (8aH) -tert-butyl carbonate (0.100 g, 0.235 mmol) in diethyl ether (0.5 mL), along with N, N, N', N'-tetramethylethylenediamine (0.054 g, 0.47 mmol). N₂Stir down at -78 ° C for 10 minutes. tert-Butyllithium (0.276 mL, in 1.7 M hexane) was added dropwise and the reaction was stirred at -78 ° C for 20 minutes. S-Phenylbenzthiosulfonic acid (0.117 g, 0.47 mmol) was added and the reaction was allowed to room temperature for 1 hour. Reactant 1MH₃PO₄Pour on top and water layer CHCl₃Extracted with (3 x 10 mL). Saturate the combined extract LVDS₃Wash with (aqueous solution) (10 mL), saline solution (10 mL) and dry (DDL)₄), Evaporated. The obtained yellow oil was purified by silica gel column chromatography (10% EtOAc / Hexanes) and recovered (8aS, 12aR) -2- (phenylsulfanyl) -6,7,9,10,12,12a-hexahydro-. 5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate was obtained in 50% yield.¹1 H NMR (CDCl₃, 300MHz) 7.12-7.26 (m, 6H), 7.00 (s, 1H), 3.81-3.92 (m, 1H), 3.42-3.63 (m, 3H), 3.31-3.41 (m, 1H), 3.07-3.25 ( m, 3H), 2.87-3.04 (m, 2H), 2.01-2.19 (m, 2H), 1.82-1.91 (m, 2H), 1.43 (s, 9H) ppm. [1945] (Step B) (8aS, 12aR) -2- (phenylsulfanyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indole-11 (8aH) -tert-butyl carbonate was dissolved in ethanol (1 mL), 1N HCl / ether (2 mL) was added and the reaction was stirred for 1 hour. NH₄Add OH (saturation) and make the aqueous layer CHCl₃Distributed to. CHCl the water layer₃Extracted with (3 x 5 mL). The combined extracts were washed with saline (5 mL) and dried (DDL).₄), Evaporated. The yellow residue was purified by HPLC (Chiralcel OD column / 10% EtOH / hexane 0.05 diethylamine / flow velocity 7 mL / min) to give the title compound (0.033 g, 80%) as a clear, colorless oil.¹1 H NMR (CDCl₃, 300MHz) 7.12-7.26 (m, 6H), 6.96 (d, 1H, J = 1.8Hz), 3.81-3.89 (m, 1H), 3.51-3.62 (m, 1H), 3.40-3.49 (m, 1H) , 3.19-3.27 (m, 1H), 3.01-3.07 (m, 3H), 2.82-2.93 (m, 2H), 2.01-2.21 (m, 2H), 1.78-1.83 (m, 3H) ppm. [1946] (Example 588) (8aS, 12aR) -3-Methoxy-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indole [1947] (Step A) (8aS, 12aR) -3-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -tert-butyl carbonate (0.100 g, 0.235 mmol), copper (I) iodide (0.023 g, 0.121 mmol), sodium methoxide (0.233 g, 4.23 mmol), methanol (0.66 mL) and It was combined with dimethylformamide (0.66 mL) and stirred for 15 hours. Reactant with water and CHCl₃Distributed to. CHCl the water layer₃Extracted with (3 x 10 mL). Dry the combined organic matter (DDL₄), Evaporated. The resulting residue was purified by silica gel column chromatography (10% EtOAc / Hexanes) and (8aS, 12aR) -3-methoxy-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3]. -b] [1,4] Thiazepino [2,3,4-hi] Indol-11 (8aH) -tert-butyl carbonate was obtained in 29% yield.¹1 H NMR (CDCl₃, 300MHz) 6.81 (d, 1H, J = 8.0Hz), 6.24 (d, 1H, J = 8.1Hz), 3.98-4.11 (m, 1H), 3.82 (s, 3H), 3.61-3.74 (m, 3H) ), 3.42-3.51 (m, 1H), 3.22-3.37 (m, 1H), 2.95-3.19 (m, 4H), 1.95-2.21 (m, 2H), 1.81-1.87 (m, 2H), 1.45 (s) , 9H) ppm. [1948] (Step B) The title compound was prepared in 78% yield according to Example 578, step B method.¹1 H NMR (CDCl₃, 300MHz) 6.79 (d, 1H, J = 8.1Hz), 6.24 (d, 1H, J = 7.6Hz), 3.98-4.11 (m, 1H), 3.82 (s, 3H), 3.59-3.71 (m, 1H) ), 3.30-3.41 (m, 1H), 2.93-3.17 (m, 6H), 2.59-2.65 (1H), 1.95-2.21 (m, 2H), 1.87-1.99 (m, 2H) ppm. [1949] (Example 589) {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4] -hi] Indoru-2-yl] -5-methoxyphenyl} methaneamine [1950] (Step A) (8aS, 12aR) -2- (2-formyl-4-methoxyphenyl) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [ 2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.340 g, 0.70 mmol) with allylamine (0.040 g, 0.70 mmol), dichloroethane (3.5 mL) and acetic acid (1.5 mL). N₂Stir down for 0.5 hours. Slowly add saturated sodium carbonate and NH the mixture₄It was made basic at pH 10 with OH (saturation). Separate the layers and CHCl the aqueous layer₃Extracted with (3 x 25 mL). The combined organic matter was washed with saline solution (20 mL) and dried (DDL).₄), Evaporated. The obtained yellow foam was purified by silica gel column chromatography (30% EtOAC / hexane) and (8aS, 12aR) -2- {2-[(allylamino) methyl] -4-methoxyphenyl} -6,7,9. , 10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert-butyl carbonate (0.150g, 41) %) Was obtained as a pale yellow foam.¹1 H NMR (CDCl₃, 300MHz) 7.13 (d, 1H, J = 8.5Hz), 7.00 (d, 1H, J = 2.6Hz), 6.96 (d, 1H, J = 1.5Hz), 6.88 (s, 1H), 6.82 (dd, dd, 1H, J = 2.5,8.4Hz) 5.75-5.92 (m, 1H), 5.02-5.37 (m, 2H), 3.85 (s, 3H), 3.72-3.80 (m, 2H), 3.72 (s, 2H), 3.52-3.61 (m, 2H), 3.20-3.39 (m, 2H), 3.11-3.21 (m, 2H), 2.91-3.03 (m, 2H), 2.01-2.21 (m, 2H), 1.83-1.93 (m) , 2H), 1.44 (s, 9H) ppm. [1951] (Step B) (8aS, 12aR) -2- {2-[(allylamino) methyl] -4-methoxyphenyl} -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1 , 4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (0.080 g, 0.154 mmol), N, N-dimethylbarbituric acid (0.072 g, 0.462 mmol), Pd (PPh₃)₄(0.0017g, 1.54μmol) and CH₂Cl₂N with (0.5 mL)₂Stir down at 35 ° C for 3 hours. The solvent was evaporated and the residue was partitioned between EtOAc and sodium carbonate (saturated, aq). The organic layer is washed with sodium carbonate (saturated, aq, 2 x 10 mL) and dried (DDL)₄), Evaporated. The obtained residue is subjected to silica gel column chromatography (3% MeOH / CH).₂Cl₂). The recovered solid was dissolved in MeOH (2 mL) and foamed with HCl gas for 15 minutes. The solvent was evaporated and the solid was recrystallized in EtOH to give the title compound (0.020 g, 38%) as a light brown solid.¹H NMR (CD)₃OD, 300MHz) 7.17 (d, 1H, J = 8.4Hz), 7.07 (d, 1H, J = 2.6Hz), 6.91-7.97 (m, 1H), 6.91 (s, 2H), 4.04 (s, 2H) , 3.82 (s, 3H), 3.81-3.94 (m, 1H), 3.52-3.63 (m, 1H), 3.30-3.24 (m, 4H), 3.12-3.23 (m, 2H), 2.93-3.02 (m, 1H), 2.71-2.81 (m, 1H), 2.01-2.31 (m, 4H) ppm. [1952] (Example 590) 4-[(8aS, 12aR) -3-chloro-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2, 3,4-hi] Indol-2-yl] -3-Methylphenyl Methyl Ether [1953] (8aS, 12aR) -2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol -11 (8aH) -tert-butyl carbonate (0.050 g, 0.108 mmol), 2-methyl, 4-methoxyphenylboronic acid (0.021 g, 0.130 mmol) in ethylene glycol dimethyl ether (1.5 mL) and water (0.7 mL) ), Barium hydroxide octahydrate (0.030 g, 0.15 mmol) and degassed for 15 minutes. Pd (PPh)₃)₄(0.0047 g, 4 μmol) was added all at once and the reaction was refluxed for 15 hours. Evaporate the solvent and leave the residue with water and CHCl₃Distributed to. CHCl the water layer₃Extracted with (3 x 10 mL). The combined extracts were washed with saline (10 mL) and dried (DDL).₄), Evaporated. The residue was purified by silica gel column chromatography (10% EtOAc / Hexanes). The recovered residue was dissolved in MeOH (2 mL) and foamed with HCl gas for 15 minutes. Evaporate the solvent and NH the residue₄It was made basic with pH 12 by OH (saturation). CHCl the water layer₃Extracted with (3 x 5 mL). The combined organic matter was washed with saline solution (5 mL) and dried (DDL).₄), Evaporation to give the title compound (0.028 g, 65%) as a white solid.¹1 H NMR (CDCl₃, 300MHz) 6.91-7.01 (m, 1H), 6.62-6.75 (m, 3H), 6.58 (d, 1H, J = 2.9Hz), 3.86-4.01 (m, 1H), 3.70 (m, 3H), 3.68 -3.78 (m, 1H), 3.31-3.39 (m, 1H), 2.85-3.17 (m, 4H), 3.81-3.87 (m, 2H), 2.51-2.60 (m, 1H), 2.03 (d, 3H, J = 8.4Hz), 1.62-1.95 (m, 5H) ppm. [1954] The residue was chirally separated by HPLC (Chiralcel OD column / 8% EtOH / hexane 0.05% diethylamine / 7mL / min) to give both enantiomers of the title compound. [1955] (Example 591) 4-((8aS, 12aR) -3-chloro-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4- hi] Indol-11 (8aH) -yl) -1- (2-amino-4-fluorophenyl) -1-butanone [1956] (8aS, 12aR) -3-Chloro-6,7,8a,9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4] -hi] Indole (0.090 g, 0.38 mmol), 1- (2-amino-4-fluorophenyl) -5-1-pentanone (0.164 g, 0.76 mmol) in 1,4-dioxane (2 mL), carbonate The mixture was stirred with potassium (0.210 g, 1.52 mmol) and potassium iodide (0.020 g, 0.120 mmol) and refluxed for 72 hours. H₂Add O (5 mL) and make the aqueous layer CHCl₃Extracted with (3 x 10 mL). The combined extracts were washed with saline (10 mL) and dried (DDL).₄), Evaporated. The obtained residue is subjected to silica gel column chromatography (2.5% MeOH / CH).₂Cl₂), The title compound was obtained in a yield of 27% (0.046 g).¹1 H NMR (CDCl₃, 300MHz) 7.78-7.81 (m, 2H), 3.73 (s, 1H), 6.24-6.42 (m, 4H), 3.98-4.07 (m, 1H), 3.63-3.78 (m, 2H), 3.23-3.31 ( m, 2H), 2.81-3.07 (m, 4H), 2.61-2.80 (m, 3H), 2.11-2.31 (m, 2H), 1.82-2.01 (m, 6H) ppm. [1957] (Example 592) (8aS, 12aR) -N- (2-Methyl-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indol-2-amine [1958] (Step A) 3-Bromo-4-methylanisole (0.576 g, 3.0 mmol) was dissolved in anhydrous THF (15 mL). Then Mg scraps (1.46 g, 60 mmol) were added. Heat the reactants to 60 ° C, I₂Crystals were added and the magnesium debris was slowly crushed with a glass rod. Upon foaming, the remaining 3-bromo-4-methylanisole (5.18 g, 27 mmol) was added to 25 mL of THF. The reaction was continued at room temperature for 15 minutes. BiCl while cooling to 0 ° C₃The solution was slowly transferred to a flask containing (2.84 g, 9.0 mmol). A heterogeneous solution was obtained, which was stirred at room temperature for 4 hours. The mixture is then filtered through a bed of Celite and the filtrate is ice / H.₂Pour over O and EtOAc. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were evaporated to give an off-white solid. The solid was washed with cold EtOAc to give tris (2-methyl-4-methoxyphenyl) bismuth (2.29 g, 47%) as a white solid.¹1 H NMR (CDCl₃, 300MHz) 7.40 (d, 3H, J = 8.4Hz), 6.88 (d, 3H, J = 2.5Hz), 6.62 (dd, 3H, J = 2.5, 8.4Hz), 3.37 (s, 9H), 2.40 ( s, 3H) ppm. [1959] (Step B) Tris (2-methyl-4-methoxyphenyl) bismuth (0.933 g, 1.7 mmol), CH₂Cl₂It was combined with iodobenzene diacetate (0.544 g, 1.7 mmol) in 19 mL and stirred for 16 hours. The solvent was evaporated to give bis (acetate) tris (2-methyl-4-methoxyphenyl) bismuth (0.805 g, 74%) as an off-white solid.¹1 H NMR (CDCl₃, 300MHz) 8.22 (d, 3H, J = 8.5Hz), 6.95-7.00 (m, 6H), 3.85 (s, 9H), 2.57 (m, 9H), 1.73 (m, 6H) ppm. [1960] (Step C) Example 581 According to Step B, the title compound (0.032 g, 49%) was prepared using bismuth (acetate) tris (2-methyl-4-methoxyphenyl) bismuth.¹1 H NMR (CDCl₃, 300MHz) 7.01 (d, 1H, J = 8.8Hz), 6.63-6.77 (m, 2H), 6.45 (dd, 2H, J = 2.2,13.6Hz), 4.88 (s, 1h), 3.77 (s, 3H) ), 3.40-3.61 (m, 2H), 3.24-3.37 (m, 1H), 3.07-3.17 (m, 1H), 2.78-3.01 (m, 4H), 2.56-2.63 (m, 1H), 2.19 (s) , 3H), 2.00-2.20 (m, 2H), 1.65-1.83 (m, 3H) ppm. [1961] (Example 593) (8aS, 12aR) -N- (2-fluoro-4-methoxyphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indol-2-amine [1962] (Step A) In an oven-dried three-necked round-bottom flask, (8aS, 12aR) -2-amino-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (200 mg, 0.55 mmol), toluene anhydrous (4 mL), and NaOtBu (70.9 mg, 0.737 mmol), and 4-bromo. -3-Fluoroanisol (94.5 mg, 0.461 mmol) was charged under argon. The solvent was degassed with argon for 10 minutes at room temperature, then at 80 ° C. for 25 minutes, then cooled to room temperature. Pd to reaction flask₂(dba)₃(1.0 mg, 0.00115 mmol) and BINAP (2.1 mg, 0.00347 mmol) were added. The mixture was heated at 80 ° C. for 16 hours under an argon atmosphere until TLC analysis (1: 1, hexane: ethyl acetate) revealed the disappearance of the starting material. The mixture was cooled to room temperature, diluted with diethyl ether, filtered through a bed of Celite and the filtrate concentrated to give a dark oil. The latter residue was purified by chromatography on silica gel (CombiFlash) (gradient eluate 97: 3 to 75:25, hexane: ethyl acetate) and (8aS, 12aR) -2- (2-fluoro-4). -Methoxyanilino)-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) )-Tert-Butyl carbonate (118 mg, 53%) was obtained as a clear oil.¹1 H NMR (CDCl₃, 300MHz) δ1.43 (s, 9H), 1.83-1.86 (m, 3H), 2.04-2.10 (m, 3H), 2.88-3.69 (m, 8H), 3.78 (s, 3H), 5.18-5.19 ( m, 1H), 6.58-6.70 (m, 4H), 7.02-7.09 (m, 1H) .ESI-MSm / z = 486 [C₂₆H₃₂FN₃O₃S + H]⁺.. [1963] (Step B) Using trifluoroacetic acid (8aS, 12aR) -2- (2-fluoro-4-methoxyanilino) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b ] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate was deprotected to give the title compound. MS / ESIm / z = 386 [C₂₁H₂₄FN₃OS + H]⁺.. [1964] (Example 594) (8aS, 12aR) -N- (4-Methoxy-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indol-2-amine [1965] (Step A) Example 593 By the method described in Step A, 1-bromo-4-methoxy-2-methylbenzene (107.9 mg, 0.488 mmol) and (8aS, 12aR) -2-amino-6,7,9,10, 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (212 mg, 0.586 mmol) In reaction, (8aS, 12aR) -2- (4-methoxy-2-methylanilino) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (219 mg, 93%) was prepared.¹1 H NMR (CDCl₃, 500MHz) δ1.43 (s, 9H), 1.81-1.83 (m, 3H), 2.03-2.11 (m, 3H), 2.21 (s, 3H), 2.89-3.65 (m, 8H), 3.79 (s, 3H), 4.87-4.88 (m, 1H), 6.44-6.48 (m, 2H), 6.67-6.68 (m, 1H), 6.73 (s, 1H), 6.99-7.01 (m, 1H) .MS-ESIm / z = 382 [C₂₇H₃₅N₃O₃SC₅H₉O₂+ H]⁺.. [1966] (Step B) With ethanol / HCl (8aS, 12aR) -2- (4-methoxy- 2-Methylanilino)-6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -Tert-Butyl carbonate was deprotected to give the title compound.¹1 H NMR (CDCl₃, 500MHz) δ1.70-187 (m, 3H), 2.02-2.12 (m, 3H), 2.19 (s, 3H), 2.54-3.59 (m, 8H), 3.77 (s, 3H), 4.86 (s, 1H), 6.41 (s, 1H), 6.46 (s, 1H), 6.67 (dd, 1H, J = 8.6Hz, J = 2.7Hz), 6.74 (d, 1H, J = 2.7Hz), 6.99 (d, 1H, J = 8.6) .MS-ESIm / z382 [C₂₂H₂₇N₃OS + H]⁺.. [1967] (Example 595) (8aS, 12aR) -N- (4-Fluoro-2-methylphenyl) -6,7,8a, 9,10,11,12,12a-Octahydro-5H-pyrido [4,3-b] [1, 4] Thiazepino [2,3,4-hi] Indol-2-amine [1968] (Step A) Example 593 By the method described in Step A, 1-bromo-4-fluoro-2-methylbenzene (88.0 mg, 0.465 mmol) and (8aS, 12aR) -2-amino-6,7,9,10, 12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (202 mg, 0.56 mmol) In reaction, (8aS, 12aR) -2- (4-fluoro-2-methylanilino) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4 ] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate (176 mg, 85%) was prepared.¹1 H NMR (CDCl₃, 500MHz) δ1.43 (s, 9H), 1.82-1.83 (m, 3H), 2.04-2.11 (m, 3H), 2.22 (s, 3H), 2.89-3.88 (m, 8H), 4.92 (s, 1H), 6.52-6.58 (m, 2H), 6.75-6.82 (m, 1H), 6.83-6.89 (m, 1H), 6.92-6.97 (m, 1H) .MS-ESIm / z = 470 [C₂₆H₃₂FN₃O₂S + H]⁺.. [1969] (Step B) Using trifluoroacetic acid, (8aS, 12aR) -2- (4-fluoro-2-methylanilino) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [ 1,4] Thiazepino [2,3,4-hi] Indole-11 (8aH) -tert-butyl carbonate was deprotected to give the title compound.¹1 H NMR (CDCl₃, 500MHz) δ1.72-1.87 (m, 2H), 2.05-2.19 (m, 5H), 2.55-2.63 (m, 1H), 2.79-2.99 (m, 5H), 3.13-3.19 (m, 1H), 3.33-3.35 (m, 1H), 3.45-3.65 (m, 2H), 4.93 (s, 1H), 6.51 (d, 1H, J = 2.1Hz), 6.56 (d, 1H, J = 2.2Hz), 6.73 -6.98 (m, 3H) .MS-ESIm / z = 370 [C₂₁H₂₄FN₃S + H]⁺.. [1970] (Example 596) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indoru-2-yl] -5-fluorophenyl} ethanol [1971] (Step A) 2-Bromo-5-fluorobenzoic acid (4.60 g, 0.02 mmol), N, O-dimethylhydroxyamine hydrochloride (2.05 g, 0.02 mmol), carbon tetrachloride (6.9 g, 0.02 mmol), methylene chloride (100 mL) ) And trimethylamine (2.9 mL, 0.02 mol) were added to the mixture. Triphenylphosphine (5.53 g, 0.02 mol) was added to the solution over 1 hour and stirred for an additional hour. The solution was concentrated to give an oil. Hexane (100 mL) and ethyl acetate (100 mL) were added to the oil, stirred for 1 hour and filtered. The filtrate is concentrated and the residue is purified by chromatography on silica gel (hexane / ethyl acetate) to give 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide as a foamy white solid in a yield of 73%. Obtained.¹1 H NMR (CDCl_3,500MHz) δ3.00-3.98 (m, 6H), 6.97-7.08 (m, 2H), 7.51-7.54 (m, 1H). [1972] (Step B) 2-Bromo-5-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 0.015 mol) is dissolved in THF (30 mL) and the solution is N.₂Cooled to 0 ° C under the blanket. Methylmagnesium bromide (15.26 mL, 0.046 mol) was added dropwise over 30 minutes. The solution was heated to room temperature and stirred for 1 hour. The solution was cooled to 0 ° C and quenched with HCl / EtOH (9 mL, 4 M solution). Transfer the reaction mixture to a separatory funnel and H₂It was diluted with O (30 mL) and extracted with ethyl acetate (2 x 40 mL). Combined organic extracts H₂O, wash with saline solution, Na₂SO₄Dry on top. The solution was concentrated to give 1- (2-bromo-5-fluorophenyl) etanone as a yellow oil in 93% yield. This material was used in the next step without purification.¹1 H NMR (CDCl_3,500MHz) δ2.61 (s, 3H), 7.00-7.04 (m, 1H), 7.15-7.18 (m, 1H), 7.53-7.59 (m, 1H). [1973] (Step C) Ethylene glycol (25.6 mL, 458 mmol) and p-toluenesulfonic acid (4.36 g, 22.9 g) were stirred in benzene (250 mL) 1- (2-bromo-5-fluorophenyl) etanone (10.5 g, 45.8 mmol). ). The reaction mixture was loaded into a Dean-Stark trap containing a 4.0 angstrom molecular sieve and refluxed for 16 hours. Reactant 1: 1 H₂O and saturated LVDS₃It was transferred to a separatory funnel containing a mixture of (aqueous solution) and extracted with EtOAc (3 x 100 mL). Combined organic matter H₂O, wash with saline solution, Na₂SO₄Dried on top and concentrated. The obtained oil was purified by column chromatography to obtain 2- (2-bromo-5-fluorophenyl) -2-methyl-1,3-dioxolane (7.20 g) in a yield of 58%.¹1 H NMR (CDCl₃, 300MHz) δ2.60 (s, 3H) 4.02-4.20 (m, 4H), 6.85-6.90 (m, 1H), 7.29-7.33 (m, 1H), 7.48-7.56 (m, 1H). [1974] (Step D) A solution of t-butyllithium (19.0 mL) in anhydrous THF (40 mL) with 2- (2-bromo-5-fluorophenyl) -2-methyl-1,3-dioxolane (4.02 g, 15.40 mmol) and triisopropyl It was added dropwise to a solution consisting of borate (4.6 mL, 19.93 mmol) and stirred at -78 ° C under an inert atmosphere. The resulting yellow solution was stirred at -78 ° C for half an hour and then heated to -15 ° C. In-situ saturated NH of the obtained boronic acid ester₃Hydrolyzed at room temperature with Cl (aqueous solution). Transfer the reaction mixture to a separatory funnel and H₂It was diluted with O (50 mL) and extracted with EtOAc (3 x 50 mL). Combined organic matter H₂O, wash with saline solution, Na₂SO₄Dried on top and concentrated. The resulting residue was recrystallized from EtOAc and hexanes to give 4-fluoro-2- (2-methyl-1,3-dioxolan-2-yl) phenylboronic acid (2.62 g, 75%) as a red-orange solid. Obtained.¹1 H NMR (DMSO, 300MHz) δ1.60 (s, 3H), 3.61-3.67 (m, 2H), 3.87-3.93 (m, 2H), 7.02-7.08 (m, 2H), 7.24-7.30 (m, 1H) ), 7.59 (s, 1H) ppm;¹H NMR (DMSO + D₂O, 300MHz) δ1.61 (s, 3H), 3.61-3.67 (m, 2H), 3.78 (brs, 2H) 3.89-3.94 (m, 2H), 7.04-7.10 (m, 2H), 7.26-7.31 ( m, 1H) ppm. [1975] (Step E) 4-Fluoro-2- (2-methyl-1,3-dioxolane-2-yl) phenylboronic acid (0.94,212 mg), (8aS, 12aR) -2-bromo-6,7,9,10,12, 12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.47,200 mg), Na₂CO₃(2M, 8mL) and DME (15mL) were combined and degassed with nitrogen for 20 minutes. Pd (OAc)₂(0.047 mmol, 11 mg) and PPh₃(0.94 mmol, 26 mg) was combined in THF (5 mL) under nitrogen and added to the stirred solution via a cannula. The solution was refluxed and stirred overnight. Remove DME in vacuo, dissolve black oil in EtOAc (50 mL), H₂Wash with O (2 x 20 mL) and deli₄It was dried on top and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography eluting with EtOAc / Hexanes (1: 5) and (8aS, 12aR) -2- [4-fluoro-2- (2-methyl-1,3-dioxolane-2-yl) phenyl. ] -6,7,9,10,12,12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indol-11 (8aH) -tert carbonate -Butyl (190 mg, 77%) was obtained as a yellow oil; m / z (APcI) 527.1 (M + H)⁺.. [1976] (Step F) TFA (2mL), CH₂Cl₂Stirred in (10 mL) (8aS, 12aR) -2- [4-fluoro-2- (2-methyl-1,3-dioxolane-2-yl) phenyl] -6,7,9,10,12, 12a-Hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -tert-butyl carbonate (0.10 mmol, 50 mg), nitrogen atmosphere Below, added at room temperature. Stir the solution at room temperature for 1 hour, CH₂Cl₂Dilute with (20 mL), wash with NaOH (1N, 2 x 15 mL) and Na₂SO₄Dry on top and concentrate in vacuo (8aS, 12aR) -2- [4-fluoro-2- (2-methyl-1,3-dioxolane-2-yl) phenyl] -6,7,8a, Obtain 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole (41 mg, 100%) as yellow oil ; M / z (ES) 427.3 (M + H)⁺.. [1977] (Step G) (8aS, 12aR) -2- [4-fluoro-2- (2-methyl-1,3-dioxolane-2-yl) phenyl] -6,7,8a, 9,10,11,12,12a-octahydro -5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole with acetone (10 mL) and H₂Dissolve in O (10 mL), N₂It was treated with TsOH (10 mg) overnight at 40 ° C below. The reaction was cooled, diluted with EtOAc (50 mL) and washed with 1N NaOH (2 x 25 mL). EtOAc to Na₂SO₄Dry in, concentrate in vacuo, 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] Thiazepino [2,3,4-hi] Indole-2-yl] -5-fluorophenyl} Etanone (28, 73%) was obtained as a yellow oil; m / z (ES) 383.3 ( M + H)⁺.. [1978] (Step H) 1- {2-[(8aS, 12aR) -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3] , 4-hi] Indole-2-yl] -5-fluorophenyl} Etanone was dissolved in MeOH (2 mL) and NaBH₄Was treated at room temperature for 2 hours. The reaction was quenched with a drop of 1N HCl. Dilute the reaction with 30 mL of DCM and add 50% NH₄Washed with OH (2 x 10 mL). DCM to Na₂SO₄Dried and concentrated. The product was purified by reverse phase HPLC to give the title compound (18 mg, 67%) as a yellow oil; m / z (ES) 385.3 (M + H).⁺.. [1979] (Usefulness) The compounds of the invention are diseases or disorders associated with either the operability or antagonistism of the neurotransmitters serotonin (5-hydroxytryptamine or 5-HT) and 5-HT2 receptors, as shown by the assay below. Has usefulness in the treatment of. Its usefulness in treating these diseases or disorders may be involved in many biological processes affected by serotonin, including appetite, mood, sleep, sexual behavior, and arterial contraction, but is limited to the processes described above. There is no such thing. These biological processes are associated with many central nervous system (CNS) disorders, including emotional disorders of depression, anxiety, psychiatric disorders, and schizophrenia, as well as those associated with eating disorders such as anorexia, bulimia nervosa, and obesity. It's very important. The compounds of the present invention include other serotonin-related conditions such as migraine, attention deficit disorder or attention deficit hyperactivity disorder, behavioral addiction, and obsessive-compulsive disorder, as well as headache, social phobia, and gastrointestinal tract. It may have usefulness in the treatment of conditions associated with gastrointestinal disorders such as motor dysfunction. Finally, the compounds of the present invention may have utility in the treatment of neurodegenerative diseases and traumatic conditions such as Alzheimer's disease and brain / spinal cord injury. [1980] Pharmacological analysis of each compound for either antagonistic or operability at 5-HT2A and 5-HT2C receptors was tested in vitro and in vivo. K at 5-HT2A and 5-HT2C receptors for in vitro analysis_iMeasurements and evaluation of functional (ie, working or antagonistic) activity in each receptor class by IP3 hydrolysis assay were included. Other receptor assays were performed to assess the receptor specificity of 5-HT2A and 5-HT2C receptors for monoamine and interfering receptors (eg, histamine, dopamine, and muscarinic receptors). Compound IC₅₀Value or K_iIf the value is less than about 1 micromolar, preferably less than about 0.1 micromolar, more preferably less than about 0.01 micromolar, then the compound is considered active as a 5-HT2A antagonist or 5-HT2C agonist. The compounds of the invention are ICs of less than about 1 micromolar for 5-HT2A antagonistic or 5-HT2C operability.₅₀It has been shown to have a value. [1981] In vivo assays include a variety of kipazine-induced head spasms, acute and chronic feeding models, anxiety and depression models (learning despair, elevated plus maze, Geller-Siefter, taste aversion learning, taste response, satiety sequence). The activity of the compound in the behavioral paradigm was evaluated. In general, these models reflect activity as 5-HT2A antagonists (kipadin-induced head spasm, depression model) or 5-HT2C agonists (feeding model, anxiety model, depression model), bioavailability, metabolism and drugs. Provides dynamic indicators. [1982] Radioligand binding experiments were performed on recombinant human 5-HT2A and 5-T2C receptors expressed on HEK293E cells. The binding affinity of the compounds of the invention to these receptors is bound to 5-HT2A or 5-HT2C [¹²⁵I] -1- (2,5-dimethoxy-4-iodophenyl) -2-amino-Propane (DOI) by their competitive ability. General literature on binding assays includes 1) Lucaites VL, Nelson DL, Wainscott DB, Baez M (1996) Receptor subtype and density to determine the binding range of 5-HT2 receptor subfamilies. determine the coupling repertoire of the 5-HT2 receptor subfamily) Life Sci., 59 (13): 1081-95.J Med Chem 1988 Jan; 31 (1): 5-7; 2) Glennon RA, Seggel MR, Soine WH , Herrick-Davis K, Lyon RA, Titeler M (1988) [125I] -1- (2,5-dimethoxy-4-iodophenyl) -2-amino-propane: Radioligand iodide that specifically labels 5-HT2 serotonin receptors in the agonist high affinity state Lagent ([125I] -1- (2,5-dimethoxy-4-iodophenyl) -2-amino-propane: an iodinated radioligand that specifically labels the agonist high-affinity state of 5-HT2 serotonin receptors) J Med. Chem. 31 (1): 5-7; and 3) Leonhardt S, Gorospe E, Hoffman BJ, Teitler M (1992) Molecular pharmacology in the interaction of serotonin with 5-hydroxytryptamine 1C and 5-hydroxytryptamine 2 receptors Molecular pharmacological differences in the interaction of serotonin with 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors) Mol Pharmacol., 42 (2): 328-35. [1983] By assessing the functional properties (efficacy and strength) of a compound by assessing their ability to stimulate or inhibit receptor-mediated phosphoinositol hydrolysis in all cells expressing 5-HT2A or 5-HT2C receptors. Examined. The method used is described below. [1984] (In vitro binding assay) Stable expression of 5-HT2A and 5-HT2C receptors in HEK293E cells [1985] Stable cell lines were generated by transfecting 293EBNA cells with a plasmid containing human 5-HT2A, 5-HT2B, or 5-HT2C (VNV-edited isoform) cDNA using calcium phosphate. These plasmids are a cytomegalovirus (CMV) pre-early promoter to promote receptor expression, an EBV oriP to maintain them as an extrachromosomal factor, and an E. coli-derived hph gene to develop hygromycin B resistance. Also included (Horlick et al., 1997). Place the transfected cells in a moist environment (5% CO)₂), At 37 ° C, maintained for 10 days in Dulbecco's Modified Eagle's Medium (DMEM) containing dialyzed 10% fetal bovine serum. 5-HT2A cells were adapted to agitated culture for bulk processing, while other cell lines had to be maintained in adherent culture. On the day of recovery, cells were washed in phosphate buffered saline (PBS), counted and stored at -80 ° C. [1986] Membrane preparation Whole cell pellet expressing 5-HT2A or 5-HT2C receptor on the day of assay (approximately 1 x 10)⁸The cells (containing cells) were thawed on ice and homogenized with Brinkman Polytron (PT-10, setting 6 for 10 seconds) in 50 mM Tris HCl (pH 7.7) containing 1.0 mM EDTA. The homogenate was centrifuged at 48,000 xg for 10 minutes, and the resulting pellets were washed twice by repeating the homogenate and centrifugal sedimentation steps. The final pellet was resuspended in tissue buffer and protein quantified using bovine serum albumin as standard by bicinchoninic acid (BCA) assay (Pierce Co., Illinois). [1987] Radioligand binding assay for 5-HT2A and 5-HT2C receptors Radioligand binding assay to determine compound binding affinity (KI value) for human recombinant 5-HT2A, 5-HT2B, and 5-HT2C receptors (Fitzgerald et al., 1999). The assay was performed in a disposable polypropylene 96-well plate (Costar Corp., Cambridge, Mass.) For 5-HT2A and 5-HT2C receptors [¹²⁵I] For DOI (final concentration 0.3-0.5nM) or 5-HT2B receptor [³Assay buffers (50 mM Tris HCl, 0.5 mM EDTA, 10 mM pargyline, 10 mM DDL) containing or without H] LSD (final concentration 2 to 2.5 nM) and competing drugs (ie, newly synthesized chemicals)₄, 0.05% ascorbic acid, pH 7.5) by adding 5-HT2A, 5-HT2B, or 5-HT2C membrane homogenate (10-30 (g / well)) in tissue buffer. Typical competitive experiments. For 45 minutes, the reaction mixture was incubated at 37 ° C for 45 minutes to equilibrate and equilibrate with a fixed concentration of radioactive ligand with a duplicate concentration of ligand (12 levels ranging from 10 picomoles to 10 micromoles). The reaction was stopped by rapid filtration (cell collector; Inotech Biosystems Inc., Lansing, Michigan) through a GFF glass fiber filter pre-immersed in% polyethyleneimine. The filter was ice-cooled 50 mM Tris HCl buffer (pH 7.5). It was washed in and then counted by a gamma ray counter for 5-HT2A and 5-HT2C assays, or by liquid scintillation spectroscopy for 5-HT2B assays. [1988] Phosphoinocitide hydrolysis test A previously reported protocol (Berridge et.) Exhibits the ability of newly synthesized compounds to stimulate phosphoinositide (PI) hydrolysis. Whole cells were monitored using a modified method of al., 1982) (Egan et al., 1998). HEK293E cells expressing human 5-HT2A, 5-HT2B, or 5-HT2C receptors were taken with 0.5 mM EDTA, high glucose, 2 mM glutamine, 10% dialed fetal bovine serum, 250 (g / ml hygromycin B, and). Inoculated on a poly-D-lysine coated 24-well plate at a density of 100,000 / well in 250 (Dalveco-modified Eagle's serum (DMEM) containing g / ml G418). Growth medium after 24-48 hours. Was removed and replaced with fetal bovine serum and inositol-free DMEM (Gibco BRL), followed by cells at a final concentration of 0.5 uCi / well of myo-[³H] Incubated with DMEM containing inositol (without serum and inositol) for 16-18 hours. After this incubation, cells were washed with 10 mM LiCl and 10 (DMEM with M pargyline (without serum and inositol)) and then incubated in the same medium, this time with medium containing one of the test compounds, for 30 minutes. Was aspirated and the cells were thawed by freezing-thaw to stop the reaction.³H] Phosphoinocitide was extracted with chloroform / methanol (1: 2 v / v), separated by anion exchange chromatography (Bio-Rad AGI-X8 resin) and liquid as previously reported (Egan et al., 1998). Counted by scintillation spectroscopy. [1989] Data analysis The equilibrium apparent dissociation constant (Ki) from competing experiments was calculated using a successive nonlinear regression curve matching program (GraphPad Prism, San Diego, CA). For PI hydrolysis experiments, EC50 was calculated using a one-site "pseudo" Hill model: y = ((Rmax-Rmin) /(1+R/EC50)nH))+Rmax(but R = reaction) ( DeltaGraph, Monterey, CA). Emax (maximum response) was derived from the maximum fit curve (net IP stimulation) for each compound. The intrinsic activity (IA) was determined by expressing the Emax of the compound as a percentage of the Emax of 5-HT (IA = 1.0). [1990] (In vivo experiments on serotonergic ligands) Preclinical efficacy, strength, and side effect trends. [1991] a) Anti-serotonin effect Kipazine-induced head spasticity in rats. Kipadin, an agonist at the 5-HT receptor, causes a characteristic head spastic response in rats. 5-HT receptor antagonists effectively antagonize this 5-HT agonist-induced behavioral effect (Lucki et al., 1984). Therefore, the kipazine-induced head spasticity model in rats serves as an in vivo correlated behavior for 5-HT receptor binding. Compounds are administered 30 minutes prior to behavioral testing (25 minutes prior to kipazine) and examined for dose-related antagonistism of the kipazine response. [1992] b) Antipsychotic effect Inhibition of conditioned avoidance response (CAR) in rats. Rats are trained to consistently avoid foot electric shock (0.75 mA) applied to the grid floor of the test chamber (by climbing a hanging rod from the ceiling of the test chamber). All antipsychotics effectively block this condition avoidance response (Arnt, 1982). The ability of the compound to block this reaction is used to examine the antipsychotic effects of drug candidates. [1993] c) Extrapyramidal side effect trends Catalepsy induction in rats. Typical antipsychotics produce extrapyramidal side effects (EPS) at clinically effective doses. The most widely accepted clinical indicator of EPS propensity in humans is drug-induced catalepsy syndrome in rats (Costall and Naylor, 1975), which causes animals to remain stationary in externally forced postures (in humans). A condition (similar to tension stupor). After oral administration of the compound to rats, catalepsy induction is tested in a dose-response test. [1994] d) CNS penetration; in vivo brain receptor occupancy In vivo binding. The in vivo receptor binding protocol is used to determine the level of receptor occupancy in vivo. This method uses a suitable radioligand to label the receptor of interest. For example, to measure both dopamine D2 and 5-HT2A receptors in vivo,³HN-Methylspipperon (³H-NMSP) can be used (Frost, et. Al. 1987). This method uses overnight fasted rats (or mice). To measure the action of the compound on the receptor of interest, the compound is usually administered orally, eg, in a 0.25% metocell suspension, at 2 microliters per gram of body weight. Radiolabeled compound (in this example³H-NMSP) is administered by tail vein infusion (10 microcuries per 200 grams of rat). Time-lapse experiments are used to determine optimal binding times for both radiolabeled and unlabeled compounds. All subsequent dose-response experiments used these optimal time frames. After exposure to the compound / radioligand for an appropriate time frame, the animal is sacrificed, the relevant brain region is removed (frontal cortex for 5-HT2A, striatum for D2 receptor) and the radioactivity content is examined. .. Levels of non-specific binding are examined pharmacologically for regions of the brain that are known to be free of the receptor of interest (in this case, the cerebellum) or interact with the receptor. Investigate by overdosing the compound. [1995] (Citation) Arnt, J.Acta Pharmacol.et Toxicol.1982: 51,321-329. [1996] Berridge MJ, Downes PC, Hanley MR (1982) Lithium amplifies agonist-dependent phosphotidyinositol response in brain and salivary glands Biochem. J., 206, 587-595. [1997] Costall, B and Naylor, RJ. Psychopharmacology. 1975: 43,69-74. [1998] Egan CT, Herrick-Davis K., Miller K., Glennon RA, and Teitler M. (1998) Agonist activity of LSD and lisuride at cloned 5-HT2A and 5-HT2C receptors) Psychopharmacology, 136,409-414. [1999] Fitzgerald LW, Conklin DS, Krause CM, Marshall AP, Patterson JP, Tran DP, Iyer G, Kostich WA, Largent BL, Hartig PR (1999) High affinity agonist binding at human serotonin 5-HT2A and 5-HT2C receptors Correlate with efficacy (intrinsic activity): High-affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidence favoring the ternary complex and two-state models of agonist action) J. Neurochem., 72,2127-2134. [2000] In Vivo Binding of 3H-N-Methylspiperone to Frost, JJ, Smith, AC, Kuhar, MJ, Dannals, RF, Wagner, HN, 1987, dopamine and serotonin receptors to Dopamine and Serotonin Receptors. Life Sciences) Life Science, 40: 987-995. [2001] Hotlick, RA, Sperle, K., Breth, LA, Reid, CC, Shen, ES, Robbins, AK, Cooke, GM, Largent, BL (1997) Stable cells expressing corticotropin-releasing hormone receptors for drug discovery Rapid Generation of stable cell lines expressing corticotrophin-releasing hormone receptor for drug discovery Protein Expr. Purif. 9,301-308. [2002] Lucki, I, Nobler, MSFrazer, A., 1984, Differential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat J .Pharmacol.Exp.Ther.228 (1): 133-139. [2003] (Dose and formulation) The serotonin agonists and serotonin antagonist compounds of the present invention include obesity, anxiety, depression, psychiatric disorders, schizophrenia, sleep and sexual disorders, migraine and other conditions associated with headaches, social phobia, and gastrointestinal motor dysfunction. As a therapeutic agent for managing or preventing central nervous system disorders, including gastrointestinal disorders, the active substance can be administered by any means of contacting the site of action of the substance in the mammal, namely the 5-HT2 receptor. .. The compounds of the present invention can be administered by any conventional means that can be used in connection with a medicinal product, either alone or in combination with a plurality of therapeutic agents. The compounds of the invention can be administered alone, but are preferably administered with a pharmaceutical carrier selected based on the route of administration chosen and standard pharmaceutical practice. [2004] The compounds of the present invention are oral such as tablets, capsules (including sustained-release or long-acting formulations, respectively), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. It can be administered in dosage form. Similarly, it may be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly using a dosage form well known to technicians in the field of pharmacy. [2005] The dose to be administered is, of course, the pharmacodynamic characteristics of the particular substance, its mode and route of administration, the age, health and weight of the recipient, the nature and severity of the symptoms, the type of combination therapy, the frequency of treatment, and the desired effect. It will differ depending on known factors such as. As a general indicator, the daily dose of active ingredient can be expected to be from about 0.001 to about 1000 milligrams per kilogram of body weight, with preferred doses from about 0.01 to about 100 mg / kg and more preferred doses from about 0.1 to about 30 mg / kg. kg. Advantageously, the compounds of the present invention may be administered at a once-daily dose, or the entire daily dose may be administered in 2, 3, or 4 divided doses per day. [2006] Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient is usually contained in an amount of about 0.5-95% by weight of the total mass of the composition. The active ingredient can be orally administered in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions. It can also be administered parenterally in sterile liquid dosage form. [2007] Gelatin capsules contain active ingredients and powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Compressed tablets can also be made using similar diluents. Both tablets and capsules can be manufactured as sustained release formulations for sustained release of the drug over several hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablets from the atmosphere, or enteric coated to selectively disintegrate in the gastrointestinal tract. Liquid dosage forms for oral administration can include colorants or flavoring agents to increase the tolerance of the compound. [2008] In general, water, suitable oils, saline solutions, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. The solution for parenteral administration preferably contains a water-soluble salt of the active ingredient, a suitable stabilizer, and optionally a buffer. Antioxidants such as sodium hydrogen sulfite, sodium sulfite, or ascorbic acid are suitable stabilizers, either alone or in combination. Citric acid and its salts and EDTA sodium are also used. In addition, parenteral solutions can also contain preservatives such as benzalkonium chloride, methyl or propylparaben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Science, supra, which is the standard reference text in the art. [2009] Useful pharmaceutical dosage forms for administering the compounds of the present invention can be exemplified as follows. [2010] Capsules Many unit capsules can be prepared by filling standard two-part hard gelatin capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate, respectively. [2011] Soft gelatin capsule A mixture of active ingredients in a digestible oil such as soybean oil, cottonseed oil, or olive oil can be prepared and injected into gelatin by a positive displacement pump to form soft gelatin capsules containing 100 mg of active ingredient. The capsules must then be washed and dried. [2012] tablet Many tablets can be prepared by conventional methods so that the dose units are 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. it can. Appropriate coatings may be applied to enhance palatability or delay absorption. [2013] Suspension Prepare an aqueous suspension for oral administration so that each 5 mL contains 25 mg of finely separated active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of US Pharmacopeia sorbitol solution, and 0.025 mg of vanillin. Can be done. [2014] Injection A parenteral composition suitable for administration by injection can be prepared by stirring 10% by volume propylene glycol and 1.5% by weight of the active ingredient in water. Sterilize the solution by commonly used techniques. [2015] The table below shows typical examples of the compound of formula (I) of the present invention, and the synthesis thereof is as described above. [2016] [table 1]<img file="JP4916633B2_D0026.tif" />[2017] [Table 2]<img file="JP4916633B2_D0027.tif" />[2018] [Table 3]<img file="JP4916633B2_D0028.tif" />[2019] [Table 4]<img file="JP4916633B2_D0029.tif" />[2020] [Table 5]<img file="JP4916633B2_D0030.tif" />[2021] [Table 6]<img file="JP4916633B2_D0031.tif" />[2022] [Table 7]<img file="JP4916633B2_D0032.tif" />[2023] [Table 8]<img file="JP4916633B2_D0033.tif" />[2024] [Table 9]<img file="JP4916633B2_D0034.tif" />[2025] [Table 10]<img file="JP4916633B2_D0035.tif" />[2026] [Table 11]<img file="JP4916633B2_D0036.tif" />[2027] [Table 12]<img file="JP4916633B2_D0037.tif" />[2028] [Table 13]<img file="JP4916633B2_D0038.tif" />[2029] [Table 14]<img file="JP4916633B2_D0039.tif" />[2030] [Table 15]<img file="JP4916633B2_D0040.tif" />[2031] [Table 16]<img file="JP4916633B2_D0041.tif" />[2032] [Table 17]<img file="JP4916633B2_D0042.tif" />[2033] [Table 18]<img file="JP4916633B2_D0043.tif" />[2034] [Table 19]<img file="JP4916633B2_D0044.tif" />[2035] [Table 20]<img file="JP4916633B2_D0045.tif" />[2036] [Table 21]<img file="JP4916633B2_D0046.tif" />[2037] [Table 22]<img file="JP4916633B2_D0047.tif" />[2038] [Table 23]<img file="JP4916633B2_D0048.tif" />[2039] [Table 24]<img file="JP4916633B2_D0049.tif" />[2040] [Table 25]<img file="JP4916633B2_D0050.tif" />