Substituted heterocycle fused gamma-carbolines

γ-condensed carbolines with substituted heterocycles.

Field of the Invention

The present invention relates to certain novel compounds represented by the structural formula (Ia).

<figref>1</figref>

or pharmaceutically salt forms acceptable thereof, wherein R 1, R 5, R 6a, R 6b, R 7, R 8, R 9, x, b, k, m, yn, and the line of Scripts are as described herein. The invention relates also to pharmaceutical formulations comprising these novel compounds as active ingredients and the use of novel compounds and their formulations in the treatment of certain disorders The compounds of this invention are agonists and serotonin antagonists and are useful in the control or prevention of disorders of the central nervous system including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with pain cephalic, social phobias, and gastrointestinal disorders such as dysfunction of the motility of the tract gastrointestinal.

Background of the invention

There is a substantial correlation for relationship between 5-HT2 receptor modulation and A variety of diseases and therapies. To date, they have identified three subtypes of the receptor class 5-HT2: 5-HT2A, 5-HT2B, and 5-HT2C. Before At the beginning of the '90s, reference was made to the recipients of 5-HT2C and 5-HT2A as 5-HT1C and 5-HT2, respectively.

Agonism or receptor antagonism of 5-HT2, either selectively or nonselectively, has been associated with the treatment of various disorders of the central nervous system (CNS). It has been shown that ligands that have affinity for 5-TH2 receptors have numerous physiological and behavioral effects (Trends in Pharmacological Sciences, 11, 181, 1990). In the recent past it has the contribution of serotonergic activity has been well documented to the mode of action of antidepressant drugs. Have been developed successfully compounds that increase the overall basal tone of the serotonin in the CNS as antidepressants. Inhibitors of selective serotonin reabsorption (SSRI) work by increasing the amount of serotonin present in the nervous synapse. These Significant treatments, however, are not exempt from side effects and suffer from delay in the onset of action (Leonard, J. Clin. Psychiatry, 54 (supl.), 3, 1993). Due to the mechanism of action of the SSRIs, they affect the activity of an amount of serotonin receptor subtypes. This modulation non-specific serotonin receptor family plays the most likely a significant role in the effects profile secondary. In addition, these compounds often have a high affinity for a number of serotonin receptors as well as also a multitude of other monoamine neurotransmitters and recipients of discomfort. The elimination of some reactivity receiver crusade would allow the examination and possible development of powerful therapeutic ligands with a profile of side effects improved.

There is ample evidence supporting the role of selective 5-HT2 receptor ligands in a amount of disease therapies. Receptor modulation of 5-HT2 has been associated with the treatment of schizophrenia and psychosis (Ugedo, L, and other (s), Psychopharmacology, 98, 45, 1989). Humor, behavior and halucinogenesis can be affected by recipients of 5-HT2 in the limbic system and the cerebral cortex. 5-HT2 receptor modulation in the hypothalamus It can influence appetite, thermoregulation, sleep, sexual behavior, motor activity, and endocrine function (Hartig, P. and other (s), Annals New York Academy of Science, 149, 159). There is also evidence indicating that the recipients of 5-HT2 mediate hypoactivity, have effects on feeding in rats, and mediated penile erections (Psychopharmacology, 101, 57, 1990).

Compounds that exhibit selectivity for 5-HT2B receptor are useful in the treatment of conditions such as tachyigastria, hypermotility associated with irritable bowel disorder, constipation, dyspepsia, and others peripherally mediated conditions.

It has been shown that antagonists of 5-HT2A are effective in the treatment of schizophrenia, anxiety, depression, and migraines (Koek, W., Neuroscience and Behavioral reviews, 16, 95, 1996). Apart from the beneficial antipsychotic effects, the classic neuroleptics are frequently responsible for the provocation of effects Acute extrapyramidal secondary and endocrine disturbances. These compounds generally possess significant affinity for the D2 dopamine receptor (as well as another affinity for the nuisance receptor) that is often associated with symptoms extrapyramidal and tardive dyskinesia, detracting from its effectiveness as first line treatments in schizophrenia and disorders related. Compounds that have a more selectivity profile favorable would represent a possible improvement for the treatment of CNS disorders

U.S. Patent Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936; and 4,238,607 disclose pyridopyrrolobenzoheterocycles of the formula:

<figref>2</figref>

in which X is O, S, S (= O), or SO2; n is 0 or 1; R1 represents various substituents carbonates; and Z is a monosubstituent of H, methyl or chlorine.

U.S. Patent No. 4,219,550 gives Know pyridopyrrolobenzoheterocycles of the formula:

<figref>3</figref>

in which X is O or S; R1 is C 1-4 alkyl or cyclopropyl; R2 is H, CH 3, OCH 3, Cl, Br, F, or CF 3; and (A) is -CH 2 -, -CH (CH 3) -, or -CH 2 CH 2 -.

US 3,299,078 describes pyridopyrrindoindoles and quinolines that have analgesic, antipyretic activity, anti-inflammatory, antiserotonin and system stimulant central nervous

Synthesis of the invention

An objective of the present invention is provide novel compounds that are useful as agonists or 5-HT2 receptor antagonists, more specifically 5-HT2A receptors and 5-HT2C, or pharmaceutically acceptable salts or prodrogas of the same.

It is another objective of the present invention provide pharmaceutical compositions comprising a vehicle pharmaceutically acceptable and a therapeutically amount effective of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.

It is another objective of the present invention provide compounds for use in therapy. More specifically, the The present invention provides compounds for use in the treatment of central nervous system disorders including Obesity, schizophrenia, and depression.

These and other objectives, which will be done manifests in the course of the following detailed description, have been made through the discovery of the inventors of which compounds of the formula (Ia):

<figref>4</figref>

or forms of salts or prodrug pharmaceutically acceptable thereof, wherein R1, R 5, R 7, R 8, R 9, x, b, k, m, and n are as defined below, are effective agonists or antagonists of receivers of 5-HT2.

Detailed description of the achievements

Thus, in a first embodiment, the present invention provides a novel compound of the formula (Ia):

<figref>5</figref>

or pharmaceutically salt forms acceptable of them, in where

b is a link simple;

x is -S- u -OR-;

R1 is selected from

- (CH 2) 3 C (= O) (4-fluorophenyl),

- (CH 2) 3 C (= O) (4-bromo-phenyl),

- (CH 2) 3 C (= O) (4-methyl-phenyl),

- (CH 2) 3 C (= O) (4-methoxy-phenyl),

- (CH 2) 3 C (= O) (4- (3,4-dichloro-phenyl) phenyl),

- (CH 2) 3 C (= O) (3-methyl-4-fluorophenyl),

- (CH 2) 3 C (= O) (2,3-dimethoxy-phenyl),

- (CH 2) 3 C (= O) (phenyl),

- (CH 2) 3 C (= O) (4-chlorophenyl),

- (CH 2) 3 C (= O) (3-methylphenyl),

- (CH 2) 3 C (= O) (4-t-butyl-phenyl),

- (CH 2) 3 C (= O) (3,4-difluor-phenyl),

- (CH 2) 3 C (= O) (2-methoxy-5-fluorophenyl),

- (CH 2) 3 C (= O) (4-fluor-1-naphthyl),

- (CH 2) 3 C (= O) (benzyl),

- (CH 2) 3 C (= O) (4-pyridyl),

- (CH 2) 3 C (= O) (3-pyridyl),

- (CH 2) 3 CH (OH) (4-fluorophenyl),

- (CH 2) 3 CH (OH) (4-pyridyl),

- (CH 2) 3 CH (OH) (2,3-dimethoxy-phenyl),

- (CH 2) 3 S (3-fluorophenyl),

- (CH 2) 3 S (4-fluorophenyl),

- (CH 2) 3 S (= O) (4-fluorophenyl),

- (CH 2) 3 SO 2 (3-fluorophenyl),

- (CH 2) 3 SO 2 (4-fluorophenyl),

- (CH 2) 3 O (4-fluorophenyl),

- (CH 2) 3 O (phenyl),

- (CH 2) 3 O (3-pyridyl),

- (CH 2) 3 O (4-pyridyl),

- (CH 2) 3 O (2-NH2 -phenyl),

- (CH 2) 3 O (2-NH 2 -5-F-phenyl),

- (CH 2) 3 O (2-NH2-4-F-phenyl),

- (CH 2) 3 O (2-NH2 -3-F-phenyl),

- (CH 2) 3 O (2-NH2-4-Cl-phenyl),

- (CH 2) 3 O (2-NH2-4-OH-phenyl),

- (CH 2) 3 O (2-NH2-4-Br-phenyl),

- (CH 2) 3 O (2-NHC (= O) Me-4-F-phenyl),

- (CH 2) 3 O (2-NHC (= O) Me-phenyl),

- (CH 2) 3 NH (4-fluorophenyl),

- (CH 2) 3 N (methyl) (4-fluorophenyl),

- (CH 2) 3 CO 2 (ethyl),

- (CH 2) 3 C (= O) N (methyl) (methoxy),

- (CH 2) 3 C (= O) NH (4-fluorophenyl),

- (CH 2) 2 NHC (= O) (phenyl),

- (CH 2) 2 NMeC (= O) (phenyl),

- (CH 2) 2 NHC (= O) (2-fluorophenyl),

- (CH 2) 2 NMeC (= O) (2-fluorophenyl),

- (CH 2) 2 NHC (= O) (4-fluorophenyl),

- (CH 2) 2 NMeC (= O) (4-fluorophenyl),

- (CH 2) 2 NHC (= O) (2,4-difluor-phenyl),

- (CH 2) 2 NMeC (= O) (2,4-difluor-phenyl),

- (CH 2) 3 (3-indolyl),

- (CH 2) 3 (1-methyl-3-indolyl),

- (CH 2) 3 (1-indolyl),

- (CH 2) 3 (1-indolinyl),

- (CH 2) 3 (1-benzimidazolyl),

- (CH 2) 3 (1H-1,2,3-benzotriazol-1-yl),

- (CH 2) 3 (1H-1,2,3-benzotriazol-2-yl),

- (CH 2) 2 (1H-1,2,3-benzotriazol-1-yl),

- (CH 2) 2 (1H-1,2,3-benzotriazol-2-yl),

- (CH 2) 3 (3,4-dihydro-1 (2H) -quinolinyl),

- (CH 2) 2 C (= O) (4-fluorophenyl),

- (CH 2) 2 C (= O) NH (4-fluorophenyl),

-CH2CH2 (3-indolyl),

-CH2CH2 (1-phthalimidyl),

- (CH 2) 4 C (= O) N (methyl) (methoxy),

- (CH 2) 4 CO 2 (ethyl),

- (CH 2) 4 C (= O) (phenyl),

- (CH 2) 3 CH (phenyl) 2,

-CH 2 CH 2 CH = C (phenyl) 2,

-CH 2 CH 2 CH = CMe (4-F-phenyl),

- (CH 2) 3 CH (4-fluorophenyl) 2,

-CH 2 CH 2 CH = C (4-fluorophenyl) 2,

- (CH 2) 2 (2,3-dihydro-1H-inden-2-yl),

- (CH 2) 3 C (= O) (2-NH2 -phenyl),

- (CH 2) 3 C (= O) (2-NH 2 -5-F-phenyl),

- (CH 2) 3 C (= O) (2-NH2-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NH2 -3-F-phenyl),

- (CH 2) 3 C (= O) (2-NH2-4-Cl-phenyl),

- (CH 2) 3 C (= O) (2-NH2-4-OH-phenyl),

- (CH 2) 3 C (= O) (2-NH2-4-Br-phenyl),

- (CH 2) 3 (1H-indazol-3-yl),

- (CH 2) 3 (5-F-1H-indazol-3-yl),

- (CH 2) 3 (7-F-1H-indazol-3-yl),

- (CH 2) 3 (6-Cl-1H-indazol-3-yl),

- (CH 2) 3 (6-Br-1H-indazol-3-yl),

- (CH 2) 3 C (= O) (2-NHMe-phenyl),

- (CH 2) 3 (1-benzothien-3-yl),

- (CH 2) 3 (6-F-1H-indole-1-yl),

- (CH 2) 3 (5-F-1H-indole-1-yl),

- (CH 2) 3 (6-F-2,3-dihydro-1H-indole-1-yl),

- (CH 2) 3 (5-F-2,3-dihydro-1H-indole-1-yl),

- (CH 2) 3 (6-F-1H-indole-3-yl),

- (CH 2) 3 (5-F-1H-indole-3-yl),

- (CH 2) 3 (5-F-1H-indole-3-yl),

- (CH 2) 3 (9H-purin-9-yl),

- (CH 2) 3 (7H-purin-7-yl),

- (CH 2) 3 (6-F-1H-indazol-3-yl),

- (CH 2) 3 C (= O) (2-NHSO2 Me-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHC (= O) Me-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHC (= O) Me-phenyl),

- (CH 2) 3 C (= O) (2-NHCO2 Et-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHC (= O) NHEt-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHCHO-4-F-phenyl),

- (CH 2) 3 C (= O) (2-OH-4-F-phenyl),

- (CH 2) 3 C (= O) (2-MeS-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHSO2 Me-4-F-phenyl),

- (CH 2) 2 C (Me) CO 2 Me,

- (CH 2) 2 C (Me) CH (OH) (4-F-phenyl) 2,

- (CH 2) 2 C (Me) CH (OH) (4-Cl-phenyl) 2,

- (CH 2) 2 C (Me) C (= O) (4-F-phenyl),

- (CH 2) 2 C (Me) C (= O) (2-MeO-4-F-phenyl),

- (CH 2) 2 C (Me) C (= O) (3-Me-4-F-phenyl),

- (CH 2) 2 C (Me) C (= O) (2-Me-phenyl),

- (CH 2) 2 C (Me) C (= O) phenyl,

<figref>6</figref>

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

<figref>60</figref>

<figref>600</figref>

R 7, R 8, and R 9, in each case, are independently selected from

<dl><dt>quad</dt><dd>hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, benzyl, HC (= O) -, methylC (= O) -, ethylC (= O) -, propylC (= O) -, isopropylC (= O) -, n-butylC (= O) -, iso-butylC (= O) -, sec-butylC (= O) -, tert-butylC (= O) -, phenylC (= O) -, methylC (= O) NH-, ethylC (= O) NH-, propylC (= O) NH-, isopropylC (= O) NH-, n-butylC (= O) NH-, iso-butylC (= O) NH-, sec-butylC (= O) NH-, tert-butylC (= O) NH-, phenylC (= O) NH-, methylamino-, ethylamino-, propylamino-, isopropylamino-, n-butylamino-, isobutyl-amino-, sec-butylamino-, tert-butylamino-, phenylamino-,</dd></dl>

with the proviso that two of the substituents R 7, R 8, and R 9 are independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy;

k is 1 or two,

m is 1 or 2, and

n is 1 or two.

In a preferred embodiment of the present invention, the compound of the formula (Ia) is select from the formula (II-a) or the formula (III-a):

<figref>7</figref>

in the which:

b is a simple link, in which bridge hydrogens are in a position cis;

R1 is selected from

- (CH 2) 3 C (= O) (4-fluorophenyl),

- (CH 2) 3 C (= O) (4-bromo-phenyl),

- (CH 2) 3 C (= O) (4-methyl-phenyl),

- (CH 2) 3 C (= O) (4-methoxy-phenyl),

- (CH 2) 3 C (= O) (4- (3,4-dichloro-phenyl) phenyl),

- (CH 2) 3 C (= O) (3-methyl-4-fluorophenyl),

- (CH 2) 3 C (= O) (2,3-dimethoxy-phenyl),

- (CH 2) 3 C (= O) (phenyl),

- (CH 2) 3 C (= O) (4-chloro-phenyl),

- (CH 2) 3 C (= O) (3-methyl-phenyl),

- (CH 2) 3 C (= O) (4-t-butyl-phenyl),

- (CH 2) 3 C (= O) (3,4-difluor-phenyl),

- (CH 2) 3 C (= O) (2-methoxy-5-fluorophenyl),

- (CH 2) 3 C (= O) (4-fluor-1-naphthyl),

- (CH 2) 3 C (= O) (benzyl),

- (CH 2) 3 C (= O) (4-pyridyl),

- (CH 2) 3 C (= O) (3-pyridyl),

- (CH 2) 3 CH (OH) (4-fluorophenyl),

- (CH 2) 3 CH (OH) (4-pyridyl),

- (CH 2) 3 CH (OH) (2,3-dimethoxy-phenyl),

- (CH 2) 3 S (3-fluorophenyl),

- (CH 2) 3 S (4-fluorophenyl),

- (CH 2) 3 S (= O) (4-fluorophenyl),

- (CH 2) 3 SO 2 (3-fluorophenyl),

- (CH 2) 3 SO 2 (4-fluorophenyl),

- (CH 2) 3 O (4-fluorophenyl),

- (CH 2) 3 O (phenyl),

- (CH 2) 3 NH (4-fluorophenyl),

- (CH 2) 3 N (methyl) (4-fluorophenyl),

- (CH 2) 3 CO 2 (ethyl),

- (CH 2) 3 C (= O) N (methyl) (methoxy),

- (CH 2) 3 C (= O) NH (4-fluorophenyl),

- (CH 2) 2 NHC (= O) (phenyl),

- (CH 2) 2 NMeC (= O) (phenyl),

- (CH 2) 2 NHC (= O) (2-fluorophenyl),

- (CH 2) 2 NMeC (= O) (2-fluorophenyl),

- (CH 2) 2 NHC (= O) (4-fluorophenyl),

- (CH 2) 2 NMeC (= O) (4-fluorophenyl),

- (CH 2) 2 NHC (= O) (2,4-difluor-phenyl),

- (CH 2) 2 NMeC (= O) (2,4-difluor-phenyl),

- (CH 2) 3 (3-indolyl),

- (CH 2) 3 (1-methyl-3-indolyl),

- (CH 2) 3 (1-indolyl),

- (CH 2) 3 (1-indolinyl),

- (CH 2) 3 (1-benzimidazolyl),

- (CH 2) 3 (1H-1,2,3-benzotriazol-1-yl),

- (CH 2) 3 (1H-1,2,3-benzotriazol-2-yl),

- (CH 2) 2 (1H-1,2,3-benzotriazol-1-yl),

- (CH 2) 2 (1H-1,2,3-benzotriazol-2-yl),

- (CH 2) 3 (3,4-dihydro-1 (2H) -quinolinyl),

- (CH 2) 2 C (= O) (4-fluorophenyl),

- (CH 2) 2 C (= O) NH (4-fluorophenyl),

-CH2CH2 (3-indolyl),

-CH2CH2 (1-phthalimidyl),

- (CH 2) 4 C (= O) N (methyl) (methoxy),

- (CH 2) 4 CO 2 (ethyl),

- (CH 2) 4 C (= O) (phenyl),

- (CH 2) 4 (cyclohexyl ),

- (CH 2) 3 CH (phenyl) 2,

-CH 2 CH 2 CH = C (phenyl) 2,

-CH 2 CH 2 CH = CMe (4-F-phenyl),

- (CH 2) 3 CH (4-fluorophenyl) 2,

-CH 2 CH 2 CH = C (4-fluorophenyl) 2,

- (CH 2) 2 (2,3-dihydro-1H-inden-2-yl),

- (CH 2) 3 C (= O) (2-NH2 -phenyl),

- (CH 2) 3 C (= O) (2-NH 2 -5-F-phenyl),

- (CH 2) 3 C (= O) (2-NH2-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NH2 -3-F-phenyl),

- (CH 2) 3 C (= O) (2-NH2-4-Cl-phenyl),

- (CH 2) 3 C (= O) (2-NH2-4-OH-phenyl),

- (CH 2) 3 C (= O) (2-NH2-4-Br-phenyl),

- (CH 2) 3 (1H-indazol-3-yl),

- (CH 2) 3 (5-F-1H-indazol-3-yl),

- (CH 2) 3 (7-F-1H-indazol-3-yl),

- (CH 2) 3 (6-Cl-1H-indazol-3-yl),

- (CH 2) 3 (6-Br-1H-indazol-3-yl),

- (CH 2) 3 C (= O) (2-NHMe-phenyl),

- (CH 2) 3 (1-benzothien-3-yl),

- (CH 2) 3 (6-F-1H-indole-1-yl),

- (CH 2) 3 (5-F-1H-indole-1-yl),

- (CH 2) 3 (6-F-2,3-dihydro-1H-indole-1-yl),

- (CH 2) 3 (5-F-2,3-dihydro-1H-indole-1-yl),

- (CH 2) 3 (6-F-1H-indole-3-yl),

- (CH 2) 3 (5-F-1H-indole-3-yl),

- (CH 2) 3 (5-F-1H-indole-3-yl),

- (CH 2) 3 (9H-purin-9-yl),

- (CH 2) 3 (7H-purin-7-yl),

- (CH 2) 3 (6-F-1H-indazol-3-yl),

- (CH 2) 3 C (= O) (2-NHSO2 Me-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHC (= O) Me-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHC (= O) Me-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHCO2 Et-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHC (= O) NHEt-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHCHO-4-F-phenyl),

- (CH 2) 3 C (= O) (2-OH-4-F-phenyl),

- (CH 2) 3 C (= O) (2-MeS-4-F-phenyl),

- (CH 2) 3 C (= O) (2-NHSO2 Me-4-F-phenyl),

- (CH 2) 2 C (Me) CO 2 Me,

- (CH 2) 2 C (Me) CH (OH) (4-F-phenyl) 2,

- (CH 2) 2 C (Me) CH (OH) (4-Cl-phenyl) 2,

- (CH 2) 2 C (Me) C (= O) (4-F-phenyl),

- (CH 2) 2 C (Me) C (= O) (2-MeO-4-F-phenyl),

- (CH 2) 2 C (Me) C (= O) (3-Me-4-F-phenyl),

- (CH 2) 2 C (Me) C (= O) (2-Me-phenyl),

- (CH 2) 2 C (Me) C (= O) phenyl,

<figref>8</figref>

<figref>9</figref>

<dl><dt>quad</dt><dd>R 7, R 8, and R 9, in each case, are independently select hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylC (= O) -, ethylC (= O) -, propylC (= O) -, isopropylC (= O) -, methylC (= O) NH-, ethylC (= O) NH-, propylC (= O) NH-, isopropylC (= O) NH-, methylamino-, ethylamino-, propylamino- and isopropylamino,</dd></dl>

with the proviso that two of the substituents R 7, R 8, and R 9 are independently selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy and trifluoromethoxy.

In a more preferred embodiment of the present invention, the compounds of the formula (Ia) are select from Table 1.

In a more preferred embodiment of the present invention, the compounds of the formula (Ia) are select from Table 2.

In an even more preferred embodiment of the present invention, the compounds of the formula (Ia) are selected from Table 3.

In an even more preferred embodiment of the present invention, the compounds of the formula (Ia) are selected from Table 4.

In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of the formula (Ia) or a salt form pharmaceutically acceptable thereof and a vehicle pharmaceutically acceptable.

In a third embodiment, the present invention provides a compound of the formula (Ia) or a pharmaceutically acceptable salt form thereof for use in therapy.

In a preferred embodiment the compound is a 5HT2a antagonist.

In another preferred embodiment the compound is a 5HT2c agonist.

In a more preferred embodiment, the present invention provides a compound of the formula (Ia) or a pharmaceutically acceptable salt form thereof for use in the treatment of system disorders central nervous that include obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with headache, social phobias, and gastrointestinal disorders such as dysfunction of the motility of the gastrointestinal tract.

In another preferred embodiment the disorder of Central nervous system comprises obesity.

In another preferred embodiment the disorder of Central nervous system comprises schizophrenia.

In another preferred embodiment the disorder of Central nervous system includes depression.

In another preferred embodiment the disorder of Central nervous system comprises anxiety.

In a fifth embodiment the present invention provides the use of novel compounds of the formula (Ia) or pharmaceutically acceptable salt forms of the same in the manufacture of a medication for treatment of disorders of the central nervous system that include obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with pain cephalic, social phobias, and gastrointestinal disorders, in particular for the treatment of obesity, schizophrenia or depression.

Definitions

The compounds described herein They may have asymmetry centers. The compounds of the present invention that contain an asymmetrically substituted atom can be isolated in optically active or racemic forms. Is good known in the art the preparation of forms optically active, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, double bonds C = N, and similar, may also be present in the compounds described herein, and all these stable isomers are contemplated in the present invention. Isomers are described geometric cis and trans compounds of the present invention and they can be isolated as a mixture of isomers or as forms Isomerics separated. It is intended to include all forms chiral, diasteromeric and racemic and all isomeric forms geometric patterns of a structure, unless indicated specifically stereochemistry or isomeric form concrete.

The numbering of the tetracyclic ring system present in the compounds of the formula (Ia), such as defined by the nomenclature known to all those with experience in the specialty, is shown in the case of two examples in formula (I '), when k is 1, m is 1, and n is 1; and in The formula (I '') when k is 1, m is 1, and n is 2:

<figref>10</figref>

The tetracyclic ring system present in the compounds of the formula (I) appear as "cis" isomers or "trans" when the carbon-carbon b bond in Formula (I) is a simple link. As such, the terms "cis" and "trans", in conjunction with the annular structure tetracyclic, refers to the configuration of atoms of hydrogen in carbon atoms 7a and 11a in formula (I ') or, for example, in carbon atoms 8a and 12a in formula (I '') previous. When both hydrogens are on the same side with respect to the average plane determined by the portion octahydro-tetracyclic then the configuration is designated "cis", if not, the configuration is designated "trans". It is understood that the above example is only for demonstrative purposes and is not intended to limit the scope of the tetracyclic ring system present in the compounds of the formula (I). Similarly, it is understood that someone with experience in the specialty of organic chemistry can apply the numbering system prior to other values ​​of k, m, and n in the framework of the compounds of the formula (I) to determine the appropriate numbering. Additional examples of the numbering of the tetracyclic ring system later in the Synthesis Examples Finally, it is understood that the use of "cis" or "trans" in the identification of the ring system tetracyclic is not intended to explain the configuration of any another cis or trans geometric isomer in the molecule, for example, cis or trans butene.

The term "substituted", as used here, it means that any one or more hydrogens in the atom designated is replaced by a selection from the indicated group, with the condition that the normal valence of the atom is not exceeded designated, and that the substitution of how a compound resulted stable. When a substituent is keto (that is, = O), then two hydrogens in the atom are replaced.

When any variable (for example, R2) appears more than once in any constituent or formula in the case of a compound, its definition in each occurrence is independent of its definition in any other occurrence. A) Yes, for example, if a group is shown to be substituted with 0-2 R2, then said group may be optionally substituted with up to two groups R2 and R2 in each occurrence is selected regardless of the definition of R2. Also, combinations of substituents are permissible. and / or variables only if such combinations result in stable compounds

When it shows that a union to a substituent crosses a bond that connects two atoms in a ring, then said substituent can be attached to any atom in the ring. When a substituent is listed without indicating the atom through which such substituent is attached to the rest of the compound of a given formula, then such substituent can be bound through any atom in such substituent. The combinations of substituents and / or variables are permissible only if such combinations result in compounds stable.

The phrase "pharmaceutically acceptable" is used here to refer to those compounds, materials, compositions, and / or dosage forms that are, within scopes of a correct medical criterion, suitable for employment in contact with the tissues of humans and animals without toxicity, excessive irritation, allergic response, or other problems or complications, in conjunction with a benefit / risk ratio reasonable.

As used herein, "salts pharmaceutically acceptable "refers to derivatives of described compounds in which the compound of origin is modified by preparing acidic or basic salts of the same. Examples of pharmaceutically acceptable salts include, but not limited to mineral or organic salts of basic waste such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and the like Salts Pharmaceutically acceptable include conventional salts not toxic or quaternary ammonium salts of the compound of origin formed, for example, from non-inorganic or organic acids Toxic For example, such non-toxic conventional salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the The present invention can be synthesized from the compound of origin that contains a basic or acidic portion by methods conventional chemicals Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the base or the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally preferred non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. He find lists of suitable salts in <i>Remington's Pharmaceutical Sciencies</i>, 17th edition, Mack Publishing Company, Easton, PA, 1985, page 1418, whose description is incorporated into the present for reference.

"Stable compound" and "structure stable "are intended to mean a compound that is sufficiently robust to survive isolation with a useful degree of purity from a reaction mixture, and the formulation in a effective therapeutic agent.

Synthesis

In all the details of the invention, they are used The following abbreviations with the following meanings:

<tables><table><tgroup cols="2"><tbody><row><entry>Reagents</entry><entry /></row><row><entry>MCPBA</entry><entry>acid m-chloroperoxybenzoic</entry></row><row><entry>DIBAL</entry><entry>hydride from diisobutyl aluminum</entry></row><row><entry>Et 3 N</entry><entry>triethylamine</entry></row><row><entry>TFA</entry><entry>acid trifluoroacetic</entry></row><row><entry>THE H</entry><entry>lithium hydride aluminum</entry></row><row><entry>NBS</entry><entry>N-Bromosuccinimide</entry></row><row><entry>Red-Al</entry><entry>hydride of sodium bis (2-methoxyethoxy) aluminum</entry></row><row><entry>PD_ {d} dba_ {3}</entry><entry>tris (dibenzylidene ketone) dipaladium (0)</entry></row><row><entry>ACE-Cl</entry><entry>chloroformate 2-chloroethyl</entry></row></tbody></tgroup></table></tables>

<tables><table><tgroup cols="2"><tbody><row><entry>Solvents</entry><entry /></row><row><entry>THF</entry><entry>tetrahydrofuran</entry></row><row><entry>MeOH</entry><entry>methanol</entry></row><row><entry>EtOH</entry><entry>ethanol</entry></row><row><entry>EtOAc</entry><entry>acetate of ethyl</entry></row><row><entry>HOAC</entry><entry>acid acetic</entry></row><row><entry>DMF</entry><entry>dimethyl formamide</entry></row><row><entry>DMSO</entry><entry>dimethyl sulfoxide</entry></row><row><entry>DME</entry><entry>dimethoxyethane</entry></row><row><entry>Et 2 O</entry><entry>ether diethyl</entry></row><row><entry>iPrOH</entry><entry>isopropanol</entry></row><row><entry>MEK</entry><entry>methyl ethyl ketone</entry></row></tbody></tgroup></table></tables>

<tables><table><tgroup cols="2"><tbody><row><entry>Others</entry><entry /></row><row><entry>Ar</entry><entry>aryl</entry></row><row><entry>Ph</entry><entry>phenyl</entry></row><row><entry>Me</entry><entry>methyl</entry></row><row><entry>Et</entry><entry>ethyl</entry></row><row><entry>NMR</entry><entry>resonance magnetic nuclear</entry></row><row><entry>MHz</entry><entry>megahertz</entry></row><row><entry>BOC</entry><entry>tert-butoxycarbonyl</entry></row><row><entry>CBZ</entry><entry>benzyloxycarbonyl</entry></row><row><entry>Bn</entry><entry>benzyl</entry></row><row><entry>Bu</entry><entry>butyl</entry></row><row><entry>Pr</entry><entry>propyl</entry></row><row><entry>cat.</entry><entry>catalytic</entry></row><row><entry>mL</entry><entry>milliliter</entry></row><row><entry>nM</entry><entry>nanometer</entry></row><row><entry>ppm</entry><entry>part by million</entry></row><row><entry>mmol</entry><entry>millimol</entry></row><row><entry>mg</entry><entry>milligram</entry></row><row><entry>g</entry><entry>gram</entry></row><row><entry>kg</entry><entry>kilogram</entry></row><row><entry>FTA</entry><entry>chromatography thin layer</entry></row><row><entry>HPLC</entry><entry>phase chromatography high pressure liquid</entry></row><row><entry>rpm</entry><entry>revolutions per minute</entry></row><row><entry>ta</entry><entry>temperature ambient</entry></row><row><entry>ac.</entry><entry>watery</entry></row><row><entry>sat.</entry><entry>saturated</entry></row></tbody></tgroup></table></tables>

The compounds of the present invention can be prepared in a variety of ways well known for those with experience in the technique of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, in conjunction with synthetic methods known in the specialty of chemistry organic synthesis, or variations in these as appreciated by those with knowledge in the field. Preferred Methods include, but not limited to, those described more ahead.

All references cited here are incorporated hereby in its entirety by reference.

The novel compounds of this invention can be prepared using the reactions and techniques described in this section The reactions are carried out in solvents appropriate for the reagents and materials used and are suitable for the transformations to be made. Also in the description of the synthesis methods described below, It is understood that all proposed reaction conditions, including the choice of solvent, the reaction atmosphere, the reaction temperature, the duration of the experiment and the processes of elaboration, they are chosen so that they are the standard conditions for such a reaction, which will be easily recognized by someone With experience in the specialty. It is understood that someone with experience in the technique of organic synthesis that the functionality present in several portions of the molecule must be compatible with the reagents and the proposed reactions. Such restrictions on the substituents being compatible with the reaction conditions they will be easily understood by someone with knowledge in the field and should be used Then alternative methods.

The preparation of compounds of the formula (I) of the present invention can be carried out in a form of convergent or sequential synthesis. Synthesis preparations Details of the compounds of the formula (I) are shown in the following reaction schemes. The expertise required in the preparation and purification of the compounds of the formula (I) and the intermediates that lead to these compounds is known for those with technical experience. The procedures of purification include, but is not limited to, phase chromatography normal or inverse, crystallization, and distillation.

In the schemes and examples shown below various methods for the preparation of the compounds are illustrated of the present invention. Substitutions are as it is described and defined above.

The compounds of the formula (I) of this invention can be prepared as shown in scheme 1. From this way, the preparation of an aryl hydrazine (III) is achieved, for example, by treating an aniline correspondingly substituted (II) with NaNO2 followed by reduction of the N-nitroso intermediate with an agent reducer such as LAH or zinc and an organic acid, such as acid acetic or trifluoroacetic acid at low temperature. Assembly of the nuclear tetracyclic intermediate indole (V) is achieved by Fischer's indole cyclisation of aryl hydrazine and a ketone properly substituted (i.e. (IV)) by methods described by, but not limited to, RJ Sundberg, "Indoles, Best Synthetic Methods "[" Indoles, best methods of synthesis"], <b>1996</b>, Academic Press, San Diego, CA. By example, the treatment of aryl hydrazine (III) as the base free or the corresponding mineral acid salt with ketone (IV) (R 1 = H, Bn, CBZ, CO 2 Et, etc.) in an alcoholic solvent in the presence of mineral acid provides the indoles (V) as the free bases (after treatment with NaOH aq.) Reduction of the indoles to those corresponding to the corresponding cis or trans substituted dihydroindoles is achieved, for example, through hydrogen treatment in the presence of a catalyst such as platinum or palladium oxide on carbon, or with a metal such as zinc and a mineral acid such as hydrochloric acid, or with sodium and liquid ammonia, or with borane-amine complex such as borane-triethylamine in tetrahydrofuran, or preferably by treatment with NaCNBH 3 in an acid such as acetic or trifluoroacetic acid.

The corresponding enantiomers can be isolated by separating the racemic mixture of (I) in a chiral stationary phase column using HPLC techniques of normal or reverse phase, the details of which are described in the examples. Alternatively, a mixture can be prepared diasteromérica of (I) by treatment of (I, R1 = H) with an appropriate chiral acid (or properly substituted derivative), for example, dibenzoyl tartrate or the like (see, for example, Kinbara, K. and other (s) <i>J. Chem. Soc</i>., <i>Perkin Trans</i>. <i>2</i>, <b>1996</b>, 2615; and Tomori, H. and others), <i>Bull. Chem. Soc. Jpn</i>., <b>1996</b>, 3581). The diastereomers could then be separated by techniques traditional (i.e. silica chromatography, crystallization, HPLC, etc.) followed by the removal of the chiral auxiliary to supply (I) enatiomerically pure. In cases where the carboline nitrogen has been protected (VI) (i.e. R 1 = Boc, Bn, CBZ, CO 2 R), can be removed under a variety of conditions as described in Greene, TW; Wuts, PG W .; "Protective Groups in Organic Synthesis, 2nd Edition "[" Protective Groups in Organic Synthesis, 2nd. Edition "], John Wiley and Sons, Inc., New York, pages 309-405, <b>1991</b>. The free secondary amine it could then be rented, for example, by treatment with a suitably substituted alkyl halide (R 1 Cl, or R 1 l) and a base to provide additional compounds of the type (I), as described, for example, by Glennon, RA and others), <i>Med. Chem. Res</i>., <b>1996</b>, 197.

Scheme 1

<figref>11</figref>

Alternatively, the compounds of the formula (I) can be prepared as described in Scheme 2. The treatment of an ortho halonitrobenzene compound (VII) with a nucleophilic alkyl halide (X = OH, SH, NHR, (VIII)) (as is described by Kharasch, N .; Langford, RB;<i>J. Org. Chem</i>., <b>1963</b>, 1903) and an adequate basis followed by reduction Subsequent of the corresponding nitroaryl derivative produces the aniline (IX). The reduction can be carried out with a variety of reducing agents, for example, LAH, SnCl2, NaBH4, N_ {2} H_ {4}, etc. or with hydrogen in the presence of a catalyst suitable, such as palladium on carbon, or platinum oxide, etc., (see Hudlicky, M., "Reductions in Organic Chemistry" ["Reductions in Organic Chemistry"], Ellis Horwood, Ltd., Chichester, United Kingdom, <b>1984</b>). The formation of the aril Hydrazine (X) can be achieved as previously described in the Scheme 1 or more directly by aniline treatment (IX) with aq. hydrochloric acid, stannous chloride and NaNO2 a room temperature (see, Buck, JS; Ide, WS; <i>Org. Syn. Coll</i>. <i>Vol</i>. <i>2</i>, <b>1943</b>, 130). This aril Primary hydrazine (X) can be cycled under conditions of Fischer indole cyclization as detailed above for the compound (V), to supply the indole (XI) as the salt correspondent. After treatment of indole (XI) with a base such as potassium hydroxide or t-butoxide Potassium in a solvent such as DME or THF provides the tetracyclic indole intermediates (V). These indoles can also be reduced to the corresponding cis or trans indolines (I) as previously described in Scheme 1.

Scheme two

<figref>12</figref>

Another related pathway that leads to compounds of Formula (I) is shown in Scheme 3. Starting synthesis with a nitrobenzene derivative such as (XII), this approach gives rise to A variety of derivative formation. Can be obtained nitrobenzenes with greater substitution by manipulation of traditional synthesis (i.e. aromatic substitution) and is known to those skilled in the art (see Larock, RC;<i>Comprehensive Organic Transformations</i> ["Full Review of Organic Transformations "], VCH Publishers, New York,<b>1989</b>). Treatment of nitrobenzene derivative with a reducing agent such as LAH, etc., as described above (see Hudlicky and other (s)), supply the corresponding aniline intermediary. The subsequent training of hydrazine followed by Fischer's indole cyclization with a properly functionalized ketone as previously described (i.e. Scheme 3, (III) to (V)) provides the g-carbolin indole (XIII). At this point the ring condensate can be attached by condensation of an acid haloalkyl carboxylic acid or a related activated carboxylic acid (i.e. acid chloride, mixed anhydride, etc.), such as (XIV). The reduction of the resulting heterocyclic carbonyl can be made with various reducing agents, for example, borohydride sodium, diisobutyl aluminum hydride, and the like (see, Larock, RC; <i>Comprehensive Organic Transformations</i>["Full Review of Organic Transformations"], VCH Publishers, New York, <b>1989</b> and / or Hudlicky, M .; "Reductions in Organic Chemistry" ["Reductions in Chemistry Organic "], Ellis Horwood, Ltd., Chichester, United Kingdom,<b>1984</b>) .to provide the tetracyclic indoles (V). Other reduction of indole (V) to give indole (I) is what previously described in Scheme 1.

<pre listing-type="other">\ newpage</pre>

Scheme 3

<figref>13</figref>

The preparation of aniline precursors (II) for Fischer's indole cyclisations is shown in the Scheme Four.

The treatment of an aniline properly ortho-functionalized (XVI) with an acid or ester chloroalkyl carboxylic (or equivalent substrate, that is, Acrylic acid, acryloyl chloride, etc.) and condensation concomitant, followed by reduction of heterocyclic carbonyl resulting with a reducing agent such as LAH, DIBAL, or Red-Al supplies benzene derivatives condensed heterocyclics (II). A higher can be obtained diversity of intermediaries of (II) by forming the ortho aniline substituted from ortho nitrobenzenes corresponding substitutes and concomitant reduction of the nitro portion as described above. Besides, the aromatic replacement of fluoride functionality (or other halo nitrobenzene derivative) of (XV) per one portion of oxygen, or of Sulfur is achieved, for example, by treating (XV) with a nucleophile, such as sodium sulfide or an alcohol, followed by the formation of the necessary thiophenol or phenol, respectively, using standard techniques known to those experts in the technique (see, Larock, RC; <i>Comprehensive Organic Transformations</i> ["Complete Transformation Review Organic "], VCH Publishers, New York, <b>1989</b>, page 481). Nitro reduction as indicated above provides the substituted anilines (XVI).

Scheme 4

<figref>14</figref>

An alternative approach to anilines condensed (II) is shown in Scheme 5. The treatment of phenol (X = OH), thiophenol (X = SH), or other aromatic derivative nucleophilically substituted (XVII) with, for example, an acid haloalkyl carboxylic (or activated haloalkylcarboxylic acid equivalent, (i.e. acid halide, mixed anhydride, acid Acrylic, acryloyl chloride, etc.)), supplies the derivative (XVIII), which when treated under acylation conditions of Friedel-Crafts (see Olah, G. TO.; (Ed.); "Friedel-Crafts and Related Reactions" ["Friedel-Crafts and Related Reactions"], J. Wiley and Sons, New York, <b>1964</b>, vol. 3, points 1 and 2 or<i>Chem. Rev</i>., <b>1955</b>, 229, or Olah, GA, "Friedel-Crafts Chemistry" ["The Chemistry of Friedel-Crafts "], Wiley Interscience, New York, <b>1973</b>, to find out about different conditions and protocols), that is, strong Lewis acids (AlCl 3, FeCl 3, etc.), provides the cyclic alkylphenols (XIX). The Incorporation of nitrogen functionality can be achieved from various ways For example, the rearrangement of Schmidt (as described in Smith, PAS; <i>J. Am. Chem. Soc</i>., <b>1948</b>, 320) by treatment of the derivative of carbonyl (XIX) with NaN3 and methanesulfonic acid for provide bicyclic lactam (XX). Alternatively, this transformation can be performed using the protocol of Hoffmann rearrangement (see, for example, Dike, SY and others); <i>Bioorg Med. Chem. Lett</i>., <b>1991</b>, 383), by the initial formation of the oxime derivative of (XXI) by hydroxylamine hydrochloride treatment. Rearrangement subsequent to breastfeeding is efficiently achieved by heating in polyphosphoric acid providing lactam (XX). Lactam reduction (XX) can be performed with a variety of reducing agents, for example, DIBAL, Red-Al and similar to supply the aniline (II).

Scheme 5

<figref>15</figref>

The preparation of compounds of the formula (I) with a variety of additional functionalization of the aromatic ring A of the tetracycle is shown in Scheme 6 and Scheme 7 and is describe here. Due to the nature of the synthesis pathway of Scheme 1 to give derivatives of the formula (I), compounds with halogen substituents in ring A are difficult preparation. However, bromination of the indolines (I, R 8 = H) when the amine is protected, for example, with the groups Boc or CBZ protectors, with, for example, NBS in DMF supplies the brominated R 8 derivatives (XXII). These aryl derivatives activated (XXII) act as excellent counterparts for a amount of important synthesis transformations.

For example, biaryl coupling is achieved. using the Suzuki coupling protocol. For a review and cross-coupling reaction guide references catalyzed with palladium, see Miyaura, N .; Suzuki, A .; <i>Chem Rev</i>., <b>1995</b>, 2457. One such procedure involves the treatment of aryl bromide (XXII) with an aryl boronic acid functionalized (XXIII) in the presence of a species of Pd (0) catalytic, such as Pd (PPh3) 4, Pd (PPh 3) 2 Cl 2, Pd (OAc) 2, Pd 2 (dba) 3 and a suitable ligand such as PPh_ {3}, AsPh_ {3}, etc., or other of such catalysts of Pd (0), and a base such as Na 2 CO 3 or Et 3 N in a suitable solvent such as DMF, toluene, THF, DME or the like, to provide the indolines (XXIV). Alternatively, the formation of indole boronic acid a from the bromine derivative (XXII) (ie, (I, R 8 = B (OH) 3)) would lead to greater diversity in the subsequent coupling of this indole boronic acid with derivatives commercially available haloaromatics in a strategy of similar Suzuki coupling as described above to obtain the indolines (XXIV).

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Scheme 6

<figref>16</figref>

In a similar way the coupling of bromine derivatives (XXV), easily obtainable by synthesis sequence exemplified in Scheme 2, (starting with bromine nitrobenzenes (II) properly functionalized), shown in Scheme 7. This approach leads to the preparation of biaryl indoles as well as indoline derivatives corresponding. The protection of amine functionality should be carried out if R1 = H (see Greene and other (s) for amines protections). This is easily achieved, by example, by treating bromine derivatives (XXV) with (Boc) 2 O in aqueous sodium hydroxide and dioxane. He Subsequent Suzuki coupling with a variety of aryl acids Boronic is carried out as described above in the Scheme 6, to provide biaryl adducts (XXVI). East protocol is applicable to derivatives of bromide, iodide, triflates, and / or diazo of R 7, R 8, and R 9 (see Miyaura, N .; Suzuki, A .; <i>Chem. Rev</i>., <b>1995</b>, 2457, for a review of aryl couplings).

Scheme 7

<figref>17</figref>

In addition and as an extension of this approach to a quick preparation of a long series of biaryl derivatives indole and indoline, these bromide derivatives (XXV) may be attached to a solid support and Suzuki couplings can be carried out on a solid support (see XXVIII) as illustrated in Scheme 8. Towards the end the treatment of indoline (XXV) with TFA in CH2Cl2 to remove the Boc protecting group, followed by extraction from aqueous base, allows to obtain the Free amine (XXXVII). The free amine can be charged in a suitable solid support such as (XXVIII) using conditions well known to those with experience in the specialty. A) Yes, Wang's resin of p-nitrophenyl chloroformate (XXVIII) that can be obtained commercially from such suppliers as Novabiochem, Inc. is swollen in an appropriate solvent such as N-methyl pyrrolidinone and treated with 1.5 equiv. from amine to supply the functionalized resin (XXIX). The Suzuki links are then carried out in a format in series by resin treatment (XXIX) with a source of suitable palladium such as Pd (PPh3) 4 or Pd (dppf) Cl_ {2} and a suitable base such as K 2 CO 3 or 2 M aqueous Na 2 CO 3 or triethylamine with an excess (typically 5 equivalents) of an aryl boronic acid (They are well known to those with experience in the specialty procedures for solid phase Suzuki couplings and others couplings of palladium, see, for example, LA Thompson and JA Ellman, <i>Chem. Rev</i>., <b>1996</b>, <i>96</i>, (1), 555-600). The coupling can be repeated for ensure complete conversion into the desired coupled product. The excision of the solid support by treatment with TFA provides the corresponding indoles and indolines (XXX) as their salts of TFA

Scheme 8

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<figref>18</figref>

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In addition, there is a wide variety of procedures and protocols to functionalize compounds haloaromatic, aryldiazonium and aryl triflate. These procedures are well known to those experts in the technique and are described, for example, by Stanforth, SP;<i>Tetrahedron</i>, <b>1998</b>, 253; Buchwald, SL and others); <i>J. Am. Chem. Soc</i>., <b>1998</b>, 9722; Stille, JK and other (s); <i>J. Am. Chem. Soc</i>., <b>1984</b>, 7500. Among these procedures are links, alkylations, acylations, aminations, and biaryl amidations. The power of catalyzed functionalization with palladium nuclei Aromatic has been explored in depth in the last decade. A Excellent work in this field can be found in J. Tsuji, "Palladium Reagents and Catalysts, Innovations in Organic Synthesis "[" Palladium Reagents and Catalysis, Innovations in Organic Synthesis "], J. Wiley and Sons, New York, <b>1995</b>.

One such method for preparing compounds of formula (I) with R1 side chains substituted by a more directly shown in Scheme 9. The alkylation of indole or indoline derivatives (I, R1 = H) with an ester haloalkyl, such as ClCH 2 (CH 2) p CO 2 Me, in the presence of NaI or KI and a base such as K2CO3, Na2CO3 or similar, in dioxane or THF or other similar solvent while heats (see Glennon, RA and other (s); <i>Med. Chem. Beef</i>., <b>1996</b>, 197) supplies the esters of R1 rented. Subsequent formation of activated amides (XXXI) is achieved by treatment of the ester with hydrochloride of N, O-dimethylhydroxylamine and a Lewis acid such as trimethylaluminum or triethylaluminum in toluene (see, for example, Golec, JMC and other (s); <i>Tetrahedron</i>, <b>1994</b>, 809) at 0 ° C. The treatment of amide (XXXI) with a variety of organometallic agents, such as reagents of Grignard R1a MgBr, alkyl or aryl lithium reagents, etc. (see Sibi, MP and other (s); <i>Tetrahedron Lett</i>., <b>1992</b>, 1941; and more generally House, HO;<i>Modern Synthetic Reactions</i> [<i>Modern Synthesis Reactions</i>], W. A. Benjamin, Inc., Menlo Park, CA, <b>1972</b>), in a solvent suitable such as THF, ether, etc. at low temperatures provides the substituted ketones (XXXII).

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Scheme 9

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<figref>19</figref>

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The preparation of compounds of the formula (I) in the one that m = 0, k = 1 is summarized in scheme 10 and described here. Fischer's indole cyclisation of hydrazine previously described (III) with a 2,3-dioxopyrrolidine Protected name (Carlson, EH and other (s<i>)</i>;<i> J. Org. Chem</i>., <b>1956</b>, 1087) under a variety of conditions Typical cyclisation supplies tetracyclic indole (XXXIII). The reduction can be carried out with a variety of agents reducers, for example, LAH. DIBAL, etc., to supply the indole condensed with pyrrole (XXXIV). This derivative can then be unprotected and subsequently rented as has been uncreated previously (see Greene, TW; Wuts, PG W .; "Protective Groups in Organic Synthesis, 2nd Edition "[" Protective Groups in Organic Synthesis, 2nd. Edition "], John Wiley and Sons, Inc., New York, <b>1991</b>, and Scheme 1), to give the analogues of indole rented in R1 (XXXV). Alternatively, the reduction from indole to indoline, as previously described (see Scheme 1), followed by deprotection of the benzyl group to give (XXXVI) and alkylation allows access to indole derivatives rented in corresponding R1 (XXXVII). All methods described above to functionalize the aromatic ring, and to provide derivatives of different side chains of R1 are applicable to these cores.

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(Scheme turns to page following)

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Scheme 10

<figref>20</figref>

Examples

The chemical abbreviations used in Examples have been defined above. The detailed processes for the preparation of the compounds of the formula (I) are illustrated by middle of the following Examples. It is understood, however, that this invention is not limited to the specific details of these examples. The Examples as set forth are intended to demonstrate the scope of the invention, but are not intended to limit The scope of the invention. MRI spectra Proton nuclear (1 H NMR) were measured in chloroform-d (CDCl3) unless indicated opposite and the peaks are presented in parts per million (ppm) tetramethylsilane downstream (TMS). Coupling patterns They are presented as follows: s, singlet; d, double up; dd, double of doublets; t, triplet; q, quartet; m. multiplet; bs, wide singlet; bm, wide multiplet.

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] indole-11 (8aH) -yl) -1- (4-fluorphenyl) -1-butanone

They were suspended in dioxane (0.6 mL) cis- (8a, 12a) -3-chloro-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (90 mg; 0.32 mmol), 4-chloro-4'-fluor-butyrobenzophenone (161 mg; 0.8 mmol), KI (10 mg) and K 2 CO 3 (132 mg; 0.96 mmol). The resulting mixture was heated under reflux for 24 hours. After it was cooled to 23 ° C the reaction mixture was partitioned between H 2 O-CHCl 3 (1: 1; 40 mL). Layers they were separated and the aqueous layer was extracted again with CHCl3 (2 x 30 mL). The extracts were combined, dried (MgSO4) and They were concentrated in vacuo. Purification of this residue by silica gel column chromatography eluting with CHCl3 (100%), then with CHCl 3 -MeOH 50: 1 provided the title compound as a semi-solid (90 mg; 25%)

1 H NMR (CD 3 OD, 300 MHz) δ 8.99 (dd, 2 H, J = 8.8; 5.5 Hz); 7.12 (t, 2 H, J = 8.4 Hz); 6.72 (s, 2 H); 4.03-3.91 (m, 1 H); 3.77-3.62 (m, 1 H); 3.27-3.00 (m, 1 H); 3.09-2.81 (m, 7 H); 2.78-2.69 (m, 3 H); 2.42-2.32 (m, 2 H); 2.30-2.19 (m, 1 H); 2.16-1.75 (m, 4 H) ppm.

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] indole-11 (8aH) -yl) -1- (4-fluorphenyl) -1-butanone

It combined cis- (8a, 12a) -3-methyl-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (0.033 g; 0.09 mmol) with 4-chloro-4'-fluorbutyrophenone (0.0176 g; 0.09 mmol), KI (0.0179 g; 0.108 mmol), K 2 CO 3 (0.062 g; 0.45 mmol) and 1,2-dioxane (0.7 mL). This mixture was heated under reflux for 4 days. Water was added and the layers separated. The aqueous layer was extracted with CHCl3 (3 x 15 mL) and the combined organic layers were washed with brine, water and dried (Na2SO4) and evaporated. Oil yellow was purified by preparatory silica gel TLC (70% EtOAc / hexanes) providing the title compound (0.017 g; 45%) as a clear colorless oil.

1 H NMR (CD 3 OD, 300 MHz) δ 8.02 (q, 2 H, J = 5.5; 3.7 Hz); 7.16 (t, 2 H, J = 2.9 Hz); 6.73 (d, 1 H, J = 7.7 Hz); 6.53 (d, 1 H, J = 8 Hz); 3.94-4.05 (m, 1 H); 4.6-4.78 (m, 1 H); 3.18-3.24 (m, 1 H); 3.05-3.16 (m, 3 H); 2.97 (t, 2 H, J = 7.3 Hz); 2.65-2.81 (m, 2 H); 2.28-2.48 (m, 2 H); 2.15 (s, 3 H); 2.0-2.18 (m, 1 H); 1.82-2.0 (m, 5 H) ppm.

Example 180

cis- (8a, 12a) -11- {3 - [(4-fluorphenyl) sulfanyl] propyl} -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole

To a solution of cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole (100 mg; 0.32 mmol) in 1,4-dioxane (2 mL) was added 3-Chloro-1- (3-fluorphenylthio) propane (65.4 mg; 0.32 mmol), potassium iodide (64 mg; 0.38 mmol), and potassium carbonate (133 mg; 0.96 mmol). This mixture was heated in reflux with stirring for 60 hours. At this point 1 was added equivalent (32.4 mg; 0.32 mmol) of TEA and then heated in reflux for another 3 days, which was followed by chromatography of thin layer (CH 2 Cl 2: MeOH 9: 1). After 132 hours it water was added and the organic layer was extracted with EtOAc (3 x 50 mL), and the extracts were combined and concentrated to produce 170 mg of crude oil Column chromatography was used (gradient: 1% and 10% MeOH in CH 2 Cl 2) to purify the cis- (8a, 12a) -11- {3 - [(4-fluorphenyl) sulfanyl] -propyl} -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] thiazepino [2,3,4-hi] indole (20 mg; 16%).

1 H NMR (CDCl 3, 300 MHz) δ 7.26-7.21 (m, 2 H); 7.08-7.00 (m, 1 H); 6.94 (dd 1 H, J = 7.7 Hz, J = 7.7 Hz); 6.87-6.81 (m, 2 H); 6.5 (t, 1 H, J = 7.3 Hz); 3.86-3.76 (m, 1 H); 3.59-3.49 (m, 1 H); 3.27-3.25 (m, 1 H); 3.17-2.91 (m, 4 H); 2.75-2.72 (m, 1 H); 2.61-2.58 (m, 1 H); 2.45-2.39 (m, 2 H); 2.31-2.22 (m, 1 H); 2.18-2.02 (m, 3 H); 1.99-1.82 (m, 3 H); 1.50 (broad s, 1 H); 1.25 (s, 2 H) ppm.

Mass spectroscopy (ESI, electrospray ionization, electrospray ionization): 415 (base M + H).

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] indole-11 (8aH) -yl) -1- (4-fluorphenyl) -1-butanol

TO 4- (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) -il) -1- (4-fluorphenyl) -1-butanone (25 mg; 0.06 mmol) methanol (1 mL) was added. The flask cooled at 0 ° C in an ice bath. Sodium cyanoborohydride (38 mg; 0.35 mmol) slowly in portions. The mixture was allowed to reaction will warm to room temperature over the course of 1 hour. Acetic acid (5 drops) was added, then concentrated to reduced pressure to give a residue. The residue was extracted with dichloromethane (1 x 50 mL), washed with sodium bicarbonate (1 x 25 mL) and brine (1 x 25 mL), then dried (sodium sulfate), and concentrated until an oil remained under reduced pressure. Salt hydrochloride was formed by collecting the oil in a minimal amount of chloroform, then adding hydrogen chloride in ether (1 M) until precipitation. The solid was filtered off to give the title compound (21.1 mg; 81%).

1 H NMR (CD 3 OD, 300 MHz) δ 7.40-7.37 (m, 2 H); 7.06 (t, 2 H, J = 8.7 Hz); 6.95 (d, 2 H, J = 8.1 Hz); 6.66 (t, 1 H, J = 7.4 Hz); 4.8-4.7 (m, 1 H); 3.83 (m, 1 H); 3.1-3.53 (m, 3 H); 3.45-3.30 (m, 2 H); 3.22-3.18 (m, 3 H); 3.18 (m, 1 H); 2.91 (m, 1 H); 2.59 (m, 1 H); 2.37 (m, 1 H); 2.00-2.2 (m, 5 H) ppm.

Mass spectroscopy (ESI): 389 (base M + H).

Example 182

cis-4 - ((6b, 10a) -1,2,6b, 9,10,10a-hexahydro [1,4] oxazino [2,3,4-hi] pyrido [4,3-b] indole-8 (7H) -il) -1- (4-fluorphenyl) -1-butanone

The title compound was prepared from the addition of 3-Chloro-4'-fluorbutyronophenone to cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>- [1,4] oxazepino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole following the general procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.94-8.00 (m, 2 H); 7.08-7.11 (m, 2 H); 6.58-6.70 (m, 3 H); 4.39-4.43 (m, 2 H); 3.17-3.23 (m, 4 H); 2.97-3.09 (m, 4 H); 2.66-2.80 (m, 2 H); 2.37-2.52 (m, 2 H); 1.90-2.10 (m, 4 H).

MS (ESI): 381 (M + H).

Example 185

cis- (6b, 10a) -8- [4- (4-fluorphenyl) butyl] -6-trifluoromethyl} -1,2,6b, 7,8,9,10,10a-octahydropyrid [4,3-b] [1,4] thiazino [2,3,4-hi] indole

It dissolved 1- (4-fluorphenyl) -4- (6- (trifluoromethyl) -1,2,9,10-tetrahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole-8 (7<i>H</i>) -il) -1-butanone (34.5 mg; 0.07 mmol) in trifluoroacetic acid (0.5 mL) and cooled at 0 ° C in an ice bath. Sodium cyanoborohydride (14 mg; 0.22 mmol) slowly, and then stirred at 0 ° C for 1 hour. 1N aqueous HCl (0.5 mL) was added and the reaction was heated in reflux for 0.5 hours, 50% sodium hydroxide was added until pH&gt; 11 and extracted with dichloromethane (2 x 20 mL), dried (sodium sulfate) and concentrated to give the compound of Title.

1 H NMR (CD 3 OD, 300 MHz) δ 7.18-7.15 (m, 2 H); 7.12-6.91 (m, 3 H); 6.81 (d, 1H, J = 6.8 Hz); 3.69-3.65 (m, 1 H); 3.56-3.28 (m, 4 H); 3.12-3.10 (m, 1 H); 2.93-2.87 (m, 1 H); 2.71-2.56 (m, 2 H); 2.35-2.22 (m, 1 H); 2.21-2.01 (m, 1 H); 1.95-1.78 (m, 1 H); 1.75-1.47 (m, 4 H); 1.37-1.13 (m, 2 H); 0.87-0.71 (m, 1 H) ppm.

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] indole-11 (8aH) -il) -1- (4-fluorphenyl) -1-butanone

They were combined in 1,4-dioxane (4 mL) 4-cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11- (8aH) -yl) -1- (4-fluorphenyl) -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'-fluorbutyrophenone (57 mg; 0.28 mmol) and heated under reflux for 48 hours. The reaction was diluted with water (15 mL) and extracted with diethyl ether (3 x 25 mL), and concentrated until a residue remained. The residue was purified on a Chiralcel OD column (8% of 2-propanol in hexanes) to give (1 mg; 0.5%) of each enantiomer of the title compound.

1 H NMR (CD 3 OD, 300 MHz) δ 8.07 (t, 2 H, J = 7.4 Hz); 7.19 (t, 2 H, J = 7.5 Hz); 6.84 (dd, 2 H, J = 8 Hz, J = 7.7 Hz); 6.64 (t, 1 H, J = 7.7 Hz); 3.70-3.61 (m, 1 H); 3.52-3.45 (m, 2 H); 3.18-3.01 (m, 3 H); 2.90-2.82 (m, 1 H); 2.63-2.58 (m, 3 H); 2.21-1.96 (m, 7H); 1.73-1.63 (m, 1 HOUR); 0.91-0.80 (m, 1 H) ppm.

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] indole-11 (8aH) -yl) -1- (4-fluorphenyl) -1-butanone

It was dissolved in 1.2 mL of MEK cis- (8a, 12a) -2-methoxy-6,7,8a, 9,10,11,12,12a-octa-hydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (43 mg; 0.16 mmol). KI (27 mg; 0.16 mmol) were added, K 2 CO 3 (66 mg; 0.48 mmol), and 2a (112 mg; 0.56 mmol). The suspension was refluxed for 48 hours and then cooled to ta. The suspension was filtered and the residue was washed with CH 2 Cl 2 (5 ml). The solution was concentrated in vacuo. He residue was purified by column chromatography (10% of MeOH-CH 2 Cl 2) to provide the title compound (67 mg; 95%) as a white amorphous solid.

1 H NMR (CDCl 3, 300 MHz) δ 7.95-8.02 (m, 2 H); 7.08-7.12 (m, 2 H); 6.42 (dd, 2 H, 2.2 Hz; 8.8 Hz); 3.60-3.80 (m, 5 H); 3.40-3.58 (m, 2 H); 3.15-3.25 (m, 1 H); 2.90-3.10 (m, 4 H); 2.70-2.88 (m, 2 H); 2.50-2.68 (m, 1 H); 2.39 (dt, 2 H, 3.7 Hz; 7.4 Hz); 2.24 (dt, 1 H, 4.1 Hz; 11.0 Hz); 1.70-2.10 (m, 5H) ppm.

MS (ESI): 441.1 (M + H).

Example 188

cis-4- (6b, 10a) -1,2,6b, 9,10,10a-hexahydropyrid [4,3-b] [1,4] thiazino [2,3,4-hi] indole-8 (7H ) -il) -1- (4-fluorphenyl) -1-butanone

The title compound was prepared by method of Example 187 from cis- (6b, 10a) -1,2,6b, 7,8,9,10,10a-octahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole (99 mg; 0.43 mmol), 4-chloro-4'-fluorbutyrophenone (112 mg; 0.56 mmol), KI (71 mg; 0.43 mmol), and K 2 CO 3 (177 mg; 1.28 mmol) after chromatographic purification as a solid white amorphous. The enantiomers of the title compound are Chiralcel OD column separated using 6% IPA / hexane Isocratic as eluent.

1 H NMR (CDCl 3, 300 MHz) δ 7.26-8.01 (m, 2 H); 7.12 (t, 2 H, 8.4 Hz); 6.81 (t, 2 H, 7.7 Hz); 6.19 (t, 1 H, 7.6 Hz); 3.38-3.62 (m, 2 H); 3.25-3.37 (m, 1 H); 2.85-3.20 (m, 5 H); 2.70-2.85 (m, 1 H); 2.50-2.70 (m, 1 H); 2.45-2.68 (m, 2 H); 2.20 (dt, 1 H, 3.0 Hz; 11.4 Hz); 1.70-2.10 (m, 5H) ppm.

MS (ESI): 397.2 (base, M + H).

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] indole-11 (8aH) -il) -1- (4-bromophenyl) -1-butanone

The title compound (932 mg; 81%) was prepared by the method of Example 187 starting from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole (594.00 mg; 2.44 mmol), 4-chloro-4'-fluorbutyrophenone (831.00 mg; 3.18 mmol), KI (406.00 mg; 2.44 mmol, and K 2 CO 3 (638.00 mg; 7.33 mmol) after purification Chromatographic as a white amorphous solid.

1 H NMR (CDCl 3, 300 MHz) δ 7.87-7.92 (m, 2 H); 7.64-7.68 (m, 2 H); 6.94-6.99 (m, 2 H); 6.67 (t, 1 H, 7.4 Hz); 3.70-3.90 (m, 2 H); 3.41-3.68 (m, 4 H); 2.30-3.40 (m, 1 H); 3.00-3.29 (m, 5 H); 2.80-2.98 (m, 1 H); 2.61-2.68 (t, 1 H, 11.7 Hz); 1.90-2.50 (m, 6 H) ppm.

MS (CI, chemical ionization, chemical ionization, NH3): 473 (base, M + H).

Example 193

(8aS, 12aR) -11- {3 - [(4-fluorphenyl) sulfonyl] propyl} -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] thiazepino [2,3,4-hi] indole

The title compound (188.00 mg; 86%) is prepared by the method of Example 187 from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (139.00 mg; 0.49 mmol), chloride 3- (3-fluorphenylsulfonyl) propyl (116.0 mg; 0.49 mmol), KI (48.00 mg; 0.29 mmol), and K 2 CO 3 (135.00 mg; 0.98 mmol) after chromatographic purification as a solid white amorphous

1 H NMR (CDCl 3, 300 MHz) δ 7.71 (bd, 1 H, 6.6 Hz); 7.54-7.65 (m, 2 H); 7.36-7.40 (m, 1 H); 6.93 (dd 1 H, 1.1 Hz, 7.7 Hz); 6.62 (m, 1 H); 3.73-3.76 (m, 1 H); 3.45-3.52 (m, 1 H); 3.18-3.30 (m, 3 H); 2.90-3.18 (m, 3 H); 2.57-2.62 (m, 1 H); 2.41-2.55 (m, 1 H); 2.17-2.41 (m, 3 H); 1.95-2.17 (m, 2 H); 1.65-1.94 (m, 5 H) ppm.

MS (ESI): 447.2 (base M + H).

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] indole-11 (8aH) -il) -1- (3 ', 4'-dichloro [1,1'biphenyl] -4-yl) -1-butanone

It dissolved 4- (cis- (8a, 12a) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepine [2,3,4-hi] indole-11 (8aH) -yl) -1- (4-bromophenyl) -1-butanone (123.9 mg; 0.26 mmol) in DME (4 mL). Sodium carbonate was added 2M aqueous (0.75 mL). Acid was added 3,4-dichloro-phenylboronic (100.4 mg; 0.53 mmol), followed by Pd 2 (dba) 3 (13.5 mg; 0.013 mmol). PPh3 (13.8 mg; 0.053 mmol) was added. Flask reaction was degassed and kept under an atmosphere of nitrogen. The suspension was refluxed for 18 hours and was cooled to ta. The reaction was concentrated in vacuo, after which Water (10 mL) and EtOAc (10 mL) were added. The layers separated and The aqueous phase was extracted with EtOAc (2 x 10 mL). Layers The combined organics were washed with brine (2 x 10 mL), dried and concentrated to provide a brown amorphous solid crude (187 mg). The residue was purified by chromatography of column (20-40% EtOAc / hesano) supplying the title compound (140.0 mg, 100%) as an amorphous solid White.

1 H NMR (CDCl 3, 300 MHz) δ 8.03-8.06 (m, 1 H); 7.43-7.71 (m, 6 H); 6.93 (dd, 1 H, 1.1 Hz); 6.84 (bd, 1 H, 6.6 Hz); 6.58-6.63 (m, 1 H); 3.70-3.90 (m, 1 H); 3.50-3.60 (m, 1 H); 3.15-3.30 (m, 1 H); 2.90-3.18 (m, 4 H); 2.50-2.80 (m, 2 H); 2.20-2.50 (m, 3 H); 1.50-2.20 (m, 8 H) ppm.

MS (ESI): 537.2 (base M + H).

Example 197

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (4-methylphenyl) -1-butanone

General procedure TO

To a suspension of (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (0.5 mmol) in 1,4-dioxane (3 mL) was added the corresponding chlorobutyrophenone (0.5-1.0 mmol), potassium iodide (100 mg) and potassium carbonate (300 mg). The reaction mixture was heated under reflux for 2 days. Solvent It 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 brine (150 mL), dried over MgSO4, filtered and It was concentrated until a residue remained. The residue was purified by flash column chromatography (silica gel, CH 2 Cl 2: CH 3 OH, 9: 1). The product dissolved in ether (2 mL) and stirred at 0 ° C for 10 minutes, HCl 1 was added N in ether (0.5 mL) at 0 ° C. The white crystalline solid was collected by filtration to give the title compound with a 50-90% yield.

General procedure B

To a suspension of (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (0.5 mmol) in 1,4-dioxane (3 mL) was added the corresponding alkyl halide (0.5-1.0 mmol), potassium iodide (100 mg) and triethylamine (1.5 mmol). Mix The reaction was heated under reflux for 2 days. The solvent is removed under reduced pressure. The residue was treated with water (50 mL) and It was extracted with diethyl ether (3 x 50 mL). The ether extract is washed with brine (150 mL), dried over MgSO4, filtered and It was concentrated until a residue remained. The residue was purified by flash column chromatography (silica gel, CH 2 Cl 2: CH 3 OH, 9: 1). The product dissolved in ether (2 mL) and stirred at 0 ° C for 10 minutes, HCl 1 was added N in ether (0.5 mL) at 0 ° C. The white crystalline solid was collected by filtration to give the title compound with a 50-90% yield.

The title compound was prepared from the addition of 4-chloro-4'-methyl-butyrophenone to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following the General Procedure A above.

1 H NMR (300 MHz, CDCl 3) δ 7.86 (d, J = 8.0 Hz, 2 H); 7.25 (d, J = 8.0 Hz, 2 H); 6.94 (d, J = 7.7 Hz, 1 H); 6.84 (d, J = 7.3 Hz, 1 H); 6.61 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 3.72-3.86 (m, 2 H); 3.44-3.59 (m, 2 H); 3.22-3.27 (m, 1 H); 2.98-3.14 (m, 7 H); 2.41 (s, 3 H); 2.68-2.84 (m, 2 H); 1.89-2.16 (m, 6 H) ppm.

MS (ESI): 407 [MH] +.

Example 198

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (4-fluorphenyl) -1-butanone

The title compound was prepared from the addition of 4-chloro-4'-fluorbutyro-pheone to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.97-8.02 (m, 2 H); 7.10-7.16 (m, 2 H); 6.95 (d, J = 8.0 Hz, 1 H); 6.85 (d, J = 7.3 Hz, 1 H); 6.62 (dd, J = 7.2 Hz, 7.3 Hz, 1 H); 3.76-3.86 (m, 1 H); 3.44-3.59 (m, 2 H); 3.24-3.30 (m, 1 H); 2.90-3.14 (m, 4 H); 2.68-2.84 (m, 4 H); 2.24-2.58 (m, 4 H); 1.99-2.11 (m, 4 H) ppm.

MS (ESI): 411 [MH] +.

Example 199

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (4-methoxyphenyl) -1-butanone

The title compound was prepared from the addition of 4-chloro-4'-methoxy-butyrophenone to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.93-7.99 (m, 2 H); 6.88-6.98 (m, 3 H); 6.84 (d, J = 7.0 Hz, 1 H); 6.61 (dd, J = 8.0 Hz, 7.3 Hz, 1 H); 3.87 (s, 3 H); 3.70-3.90 (m, 2 H); 3.48-3.58 (m, 1 H); 3.22-3.27 (m, 1 H); 2.90-2.99 (m, 4 H); 2.62-2.80 (m, 4 H); 2.27-2.42 (m, 4 H); 1.90-2.13 (m, 4 H) ppm.

MS (ESI): 423 [MH] +.

Example 200

3 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -1- (4-fluorphenyl) -1-propanone

The title compound was prepared from the addition of 3-Chloro-4'-fluorpropio-phenyl to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.98-8.03 (m, 2 H); 7.12-7.18 (m, 2 H); 6.88 (d, J = 7.6 Hz, 1 H); 6.87 (d, J = 6.2 Hz, 1 H); 6.65 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 3.79-3.88 (m, 1 H); 3.7 (s, 2 H); 3.50-3.60 (m, 1 H); 3.25-3.38 (m, 3 H); 2.89-3.01 (m, 7 H); 1.90-2.15 (m, 4 H) ppm.

MS (ESI): 397 [MH] +.

Example 201

(8aS, 12aR) -11- {3 - [(4-fluorphenyl) sulfonyl] propyl} -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1 , 4] thiazepino [2,3,4-hi] indole

The title compound was prepared from the addition of 3-Chloro-1 - [(4-fluorphenyl) -sulfonyl] propane to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.90-7.96 (m, 2 H); 7.22-7.28 (m, 2 H); 9.38 (d, J = 7.7 Hz, 1 H); 6.82 (d, J = 6.6 Hz, 1 H); 6.61 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 3.72-3.81 (m, 1 H); 3.45-3.55 (m, 1 H); 3.15-3.29 (m, 4 H); 3.02-3.12 (m, 2 H); 2.92-2.99 (m, 1 H); 2.57-2.62 (m, 1 H); 2.46-2.55 (m, 1 H); 2.30-2.37 (m, 2 H); 2.18-2.27 (m, 1 H); 1.94-2.09 (m, 2 H); 1.78-1.92 (m, 4 H) ppm.

MS (CI, NH3): 446 (base M + H +).

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] thiazepino [2,3,4-hi] indole

The title compound was prepared from the addition of 3-Chloro-1 - [(4-fluorphenyl) -sulfinyl] propane to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CD 3 OD) δ 7.65-7.80 (m, 2 H); 7.27-7.31 (m, 2 H); 6.95 (d, J = 8.1 Hz, 2 H); 6.63 (dd, J = 8.1 Hz, 7.7 Hz, 1 H); 3.63-3.93 (m, 1 H); 3.38-3.62 (m, 4 H); 3.10-3.25 (m, 4 H); 3.26-3.36 (m, 2 H); 2.92-3.09 (m, 3 H); 2.50-2.62 (m, 1 H); 2.30-2.42 (m, 1 H); 1.94-2.28 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 430 (base, 287).

Example 203

(8aS, 12aR) -11- {3 - [(4-fluorophenoxy) propyl} -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1,4 ] thiazepino [2,3,4-hi] indole

The title compound was prepared from the addition of 3-chloro-1- (4-fluorophenoxy) propane to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 6.91-7.00 (m, 3 H); 6.79-6.87 (m, 3 H); 6.62 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 3.97 (t, J = 6.2 Hz, 2 H); 3.70-3.87 (m, 1 H); 3.50-3.60 (m, 1 HOUR); 3.18-3.31 (m, 2 H); 2.90-3.12 (m, 2 H); 2.70-2.80 (m, 2 H); 2.40-2.62 (m, 2 H); 2.22-2.38 (m, 1 H); 1.90-2.11 (m, 7 H) ppm.

MS (ESI): 399 [MH] +.

Example 204

(8aS, 12aR) -11- (3-phenoxypropyl} -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b] [1,4] thiazepine [2,3] , 4-hi] indole

The title compound was prepared from the addition of 3-chloro-1-phenoxy-propane to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following General Procedure B of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.25-7.30 (m, 2 H); 6.85-6.97 (m, 5 H); 6.62 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 4.02 (t, J = 6.2 Hz, 2 H); 3.78-3.88 (m, 1 H); 3.50-3.60 (m, 1 HOUR); 3.17-3.31 (m, 2 H); 2.90-3.10 (m, 2 H); 2.72-2.86 (m, 2 H); 2.51-2.58 (m, 2 H); 2.30-2.37 (m, 1 H); 1.92-2.15 (m, 7 H) ppm.

MS (CI, NH3) <i>m</i> / <i>and</i> 380 (base, M + H +).

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] thiazepino [2,3,4-hi] indole

The title compound was prepared from the addition of 3-Chloro-1- (4-fluorphenylthio) -propane to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following General Procedure B of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.31-7.36 (m, 2 H); 6.93-7.02 (m, 4 H); 6.84 (d, J = 7.3 Hz, 1 H); 6.2 (dd, J = 7.3 Hz, 7.3 Hz, 1 H); 3.76-3.84 (m, 1 H); 3.48-3.59 (m, 1 H); 3.24-3.28 (m, 2 H); 2.88-3.17 (m, 6 H); 2.60-2.74 (m, 2 H); 2.25-2.45 (m, 2 H); 2.00-2.11 (m, 2 H); 1.77-1.93 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 414 (base, M + H +).

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 ] indole-11 (8aH) -yl) propyl] -4-fluoraniline

The title compound was prepared from the addition of 3-chloropropyl-4-fluorphenyl-amine to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following General Procedure B of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 6.97 (d, J = 8.1 Hz, 1 H); 6.93-7.02 (m, 3 H); 6.64 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 6.47-6.52 (m, 2 H); 3.75-3.85 (m, 1 H); 3.46-3.56 (m, 1 H); 3.25-3.35 (m, 2 H); 2.91-3.20 (m, 6 H); 2.60-2.74 (m, 2 H); 1.91-2.17 (m, 8 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 397 (base, M + H +).

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 ] indole-11 (8aH) -yl) propyl] -4-fluor-N-methylaniline

The title compound was prepared from the addition of 3-chloropropyl-4-fluorphenylmethylamine to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following General Procedure B of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 6.84-6.99 (m, 4 H); 6.59-6.67 (m, 3 H); 3.77-3.90 (m, 1 H); 3.47-3.59 (m, 1 H); 3.19-3.33 (m, 4 H); 2.67-3.09 (m, 4 H); 2.87 (s, 3 H); 2.33-2.37 (m, 3 H); 1.76-2.17 (m, 7 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 411 (base, M + H +).

Example 208

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (4-pyridinyl) -1-butanone

The title compound was prepared from the addition of 4-Chloro-1- (4-pyridyl) -butan-1-one to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 8.79 (dd, J = 5.9 Hz, 1.5 Hz, 2 H); 7.73 (dd, J = 6.2 Hz, 1.8 Hz, 2 H); 6.93 (d, J = 7.7 Hz, 1 H); 6.82 (d, J = 7.4 Hz, 1 H); 6.59 (dd, J = 7.7 Hz, 7.4 Hz, 1 H); 3.64-3.82 (m, 4 H); 3.46-3.56 (m, 2 H); 3.19-3.24 (m, 2 H); 2.88-3.06 (m, 4 H); 2.60-2.75 (m, 2 H); 2.28-2.42 (m, 2 H); 1.87-2.09 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 393 (base, M + H +).

Example 209

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (3-pyridinyl) -1-butanone

The title compound was prepared from the addition of 4-chloro-1- (3-pyridyl) -butan-1-one to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 9.18 (d, J = 2.2 Hz, 1 H); 8.76 (dd, J = 4.7 Hz, 1.8 Hz, 1 H); 8.23 (dt, J = 8.1 Hz, 1.8 Hz, 1 H); 7.40 (dd, J = 8.1 Hz, 4.8 Hz, 1 H); 6.91-6.95 (m, 1 H); 6.82-6.87 (m, 1 H); 6.57-6.63 (m, 1 H); 3.49-3.83 (m, 4 H); 3.06-3.25 (m, 2 H); 3.01 (t, J = 7.0 Hz, 2 H); 2.52-2.94 (m, 4 H); 2.26-2.39 (m, 2 H); 1.83-2.10 (m, 6 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 393 (base, M + H +).

Example 213

cis-4 - ((6b, 10a) -5-methyl-1,2,6b, 9,10,10a-hexahydropyrid [4,3-b] [1,4] thiazino [2,3,4-hi] indole-8 (7H) -yl) -1- (4-fluorphenyl) -1-butanone

The title compound was prepared from the addition of 4-chloro-4'-fluorbutyro-pheone to cis-4 - ((6b, 10a) -5-methyl-1,2,6b, 7,8,9,10,10a-octahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.90-8.03 (m, 2 H); 6.81-7.16 (m, 4 H); 3.75-3.80 (m, 1 H); 3.39-3.52 (m, 2 H); 3.18-3.24 (m, 2 H); 3.06-3.13 (m, 2 H); 2.84-2.94 (m, 1 H); 1.92-2.52 (m, 10 H); 2.24 (s, 3 H) ppm

MS (ESI): 411 [MH] +.

Example 214

(8aS, 12aR) -11- [3- (6-fluor-1,2-bencisoxazol-3-yl) propyl] -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] thiazepino [2,3,4-hi] indole

The title compound was prepared from the addition of 3- (3-chloropropyl) -6-fluorbenzo [d] isoxazole to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole benzothiazepine following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.66 (dd, J = 8.4 Hz, 5.1 Hz, 1 H); 7.23 (dd, J = 8.5 Hz, 1.8 Hz, 1 HOUR); 7.06 (ddd, J = 8.7 Hz, 8.8 Hz, 2.2 Hz, 1 H); 6.93 (dd, J = 7.7 Hz, 0.9 Hz, 1 H); 6.84 (d, J = 6.6 Hz, 1 H); 6.61 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 3.70-3.83 (m, 1 H); 3.48-3.56 (m, 1 H); 3.23-3.27 (m, 1 H); 2.91-3.12 (m, 5 H); 2.71-2.77 (m, 1 H); 2.61-2.65 (m, 1 H); 2.39-2.46 (m, 2 H); 2.24-2.28 (m, 1 H); 1.90-2.11 (m, 4 H); 1.84-1.88 (m, 3 H) ppm.

MS (ESI): 424 [MH] +.

Example 215

(8aS, 12aR) -11- [3- (1,2-bencisoxazol-3-yl) propyl] -6,7,8a, 9,10,12,12a-octahydro-5H-pyrido [4,3-b ] [1,4] thiazepino [2,3,4-hi] indole

The title compound was prepared from the addition of 3- (3-Chloropropyl) -benzo [d] isoxazole to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole following the General Procedure A of Example 197.

1 H NMR (300 MHz, CDCl 3) δ 7.67 (dd, J = 7.7 Hz, 1.1 Hz, 1 H); 7.53-7.55 (m, 2 H); 7.27-7.33 (m, 1 H); 6.94 (dd, J = 7.7 Hz, 1.1 Hz, 1 H); 6.84 (d, J = 6.6 Hz, 1 H); 6.61 (dd, J = 7.6 Hz, 7.4 Hz, 1 HOUR); 3.76-3.84 (m, 1 H); 3.48-3.58 (m, 1 H); 3.23-3.27 (m, 1 H); 2.91-3.17 (m, 5 H); 2.67-2.82 (m, 2 H); 2.45-2.51 (m, 2 H); 2.24-2.38 (m, 1 H); 1.89-2.14 (m, 7 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 405 (base, M + H +).

<pre listing-type="other">\ newpage</pre>

Example 219

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) butanoate of ethyl

Process general

To a suspension of (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole (3 mmol) in 1,4-dioxane (18 mL) was added halide corresponding alkyl (3.3 mmol), potassium iodide (100 mg) and potassium carbonate (900 mg), and the reaction mixture was heated in reflux for 2 days. The solvent was removed under reduced pressure. The residue was treated with water (50 mL) and extracted with ether diethyl (3 x 50 mL). The ether extract was washed with brine (150 mL), dried over MgSO4, filtered and concentrated to That a residue remained. The residue was purified by chromatography. column flash (silica gel, CH 2 Cl 2: CH 3 OH, 9: 1) to give the title compound with returns of 47-64%.

The title compound was prepared from the addition of ethyl 4-chlorobutanoate to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following the previous General Procedure.

1 H NMR (300 MHz, CDCl 3) δ 6.94 (bd, J = 7.7 Hz, 1 H); 6.86 (bd, J = 6.9 Hz, 1 H); 6.62 (dd, J = 7.4 Hz, 7.3 Hz, 1 H); 4.08-4.15 (m, 2 H); 3.77-3.86 (m, 1 H); 3.47-3.59 (m, 2 H); 3.10-3.29 (m, 2 H); 2.89-3.08 (m, 2 H); 2.64-2.82 (m, 2 H); 2.31-2.44 (m, 4 H); 1.83-2.12 (m, 7 H); 1.23-1.27 (m, 3 H) ppm.

MS (ESI): 361 [MH] +.

Example 220

5 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) pentanoate of ethyl

The title compound was prepared from the addition of ethyl 5-chloropentanoate to (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole following the General Procedure of Example 219.

1 H NMR (300 MHz, CDCl 3) δ 6.95 (bd, J = 7.7 Hz, 1 H); 6.86 (bd, J = 7.4 Hz, 1 H); 6.62 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 4.08-4.15 (m, 2 H); 3.77-3.87 (m, 1 H); 3.47-3.59 (m, 1 H); 3.21-3.28 (m, 2 H); 2.89-3.08 (m, 2 H); 2.64-2.84 (m, 2 H); 2.29-2.34 (m, 5 H); 1.90-2.16 (m, 5 H); 1.55-1.64 (m, 4 H); 1.22-1.27 (m, 3 H) ppm.

MS (ESI): 375 [MH] +.

Example 221

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide

Process general

A solution of trimethylaluminium 2 M in toluene (6.0 mmol) was added to a stirred mixture of hydrochloride of N, O-dimethyl hydroxyamine (2.0 mmol) in toluene dry (20 mL) at 0 ° C. The resulting mixture was stirred at temperature room for 1 hour and added to a solution of 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -yl) butanoate from ethlio o 5 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) pentanoate of ethyl of Example 219 and of Example 220 in toluene (1 mL) at 0 ° C. The mixture was stirred at 0 ° C for 2 hours, then at temperature atmosphere for 3 hours. 1M tartaric acid was added slowly (27 mL) to the reaction at 0 ° C and stirred at 0 ° C for 30 minutes. The Reaction mixture was extracted with CHCl3 (3 x 50 mL). The layer organic was washed with brine, dried over Na2SO4, dried filtered and concentrated until a residue remained. The residue is purified by flash column chromatography (silica gel, CH 2 Cl 2: CH 3 OH, 9: 1) to obtain the compound of title with yields of 70-90%.

The title compound was prepared from ester 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -butanoate of corresponding ethyl following the General Procedure previous.

1 H NMR (300 MHz, CDCl 3) δ 6.94 (bd, J = 7.7 Hz, 1 H); 6.85 (bd, J = 6.6 Hz, 1 H); 6.61 (dd, J = 7.6 Hz, 7.4 Hz, 1 H); 3.77-3.86 (m, 1 H); 3.67 (m, 3 H); 3.48-3.59 (m, 1 H); 3.21-3.28 (m, 2 H); 3.17 (s, 3 H); 2.89-3.08 (m, 2 H); 2.71-2.84 (m, 2 H); 2.29-2.52 (m, 5 H); 1.84-2.16 (m, 7 H) ppm.

MS (ESI): 376 [MH] +.

Example 222

5 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylpentanamide

The title compound was prepared from ester 5 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -pentanoate of corresponding ethyl following the General Procedure of Example 221.

1 H NMR (300 MHz, CDCl 3) δ 6.95 (bd, J = 7.7 Hz, 1 H); 6.86 (bd, J = 7.4 Hz, 1 H); 6.62 (dd, J = 7.7 Hz, 7.4 Hz, 1 H); 3.77-3.87 (m, 1 H); 3.67 (s, 3 H); 3.47-3.59 (m, 1 H); 3.23-3.29 (m, 2 H); 3.16 (s, 3 H); 2.77-3.06 (m, 4 H); 2.33-2.44 (m, 5 H); 1.91-2.13 (m, 5 H); 1.61-1.65 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 389 (base, M + H +).

Example 223

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -1- (4-fluor-3-methylphenyl) -1-butanone

Process general

To a solution of 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -yl) -N-methoxy-N-methylbutanamide or 5 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methyl-pentanamide of Example 221 and Example 222 (0.1 mmol) in THF (2 mL) or ether diethyl (2 mL) at room temperature, was added dropwise the corresponding aryl magnesium bromide (0.5 mmol) in THF (or diethyl ether). The resulting mixture was stirred at temperature ambient for 2 to 5 hours. Several drops of HCl were added conc., was extracted with CH2Cl2 (15 mL). The organic layer is washed with NaHCO 3 sat. (15 mL), brine (15 mL), dried over Na 2 SO 4, was filtered and concentrated until there was a residue. The resulting residue was purified by preparative TLC (silica gel, CH 2 Cl 2: CH 3 OH 9: 1) to supply the title compound with yields of 70-90%

The title compound was prepared from the addition of 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the previous General Procedure.

1 H NMR (300 MHz, CD 3 OD) δ 7.84-7.94 (m, 2 H); 7.08-7.16 (m, 1 H); 6.92-6.99 (m, 2 H); 6.64-6.72 (m, 1 H); 3.79-3.93 (m, 1 H); 3.48-3.70 (m, 3 H); 3.36-3.47 (m, 1 H); 2.98-3.14 (m, 7 H); 2.84-2.94 (m, 1 H); 2.58-2.68 (m, 1 H); 2.31 (bs, 3 H); 1.89-2.21 (m, 6 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 424 (base, M + H +).

Example 224

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1-phenyl-1-butanone

The title compound was prepared from the addition of phenyl magnesium bromide to 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the General Procedure of Example 223.

1 H NMR (300 MHz, CDCl 3) δ 7.96 (d, J = 7.3 Hz, 2 H); 7.55-7.97 (m, 1 H); 7.44-7.49 (m, 2 H); 7.18-7.33 (m, 3 H); 4.72-4.82 (m, 1 H); 4.25-4.50 (m, 2 H); 3.90-4.06 (m, 3 H); 3.60-3.76 (m, 3 H); 2.99-3.24 (m, 7 H); 2.54-2.60 (m, 1 H); 2.28-2.40 (m, 2 H); 2.11-2.26 (m, 1 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 392 (base, M + H +).

Example 225

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (4-chlorophenyl) -1-butanone

The title compound was prepared from the addition of 4-chlorophenyl magnesium bromide to 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the General Procedure of Example 223.

1 H NMR (300 MHz, CD 3 OD) δ 7.97-8.02 (m, 2 H); 7.50-7.56 (m, 2 H); 6.95-7.02 (m, 2 H); 6.62-6.72 (m, 1 H); 3.80-3.90 (m, 1 H); 3.40-3.59 (m, 8 H); 2.99-3.24 (m, 6 H); 2.85-2.95 (m, 1 H); 1.96-2.21 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 426 (base, M + H +).

Example 226

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (3-methylphenyl) -1-butanone

The title compound was prepared from the bromide addition of <i>m</i>-tolil magnesium a 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the General Procedure of Example 223.

1 H NMR (300 MHz, CD 3 OD) δ 7.79-7.84 (m, 2 H); 7.38-7.44 (m, 2 H); 6.95-7.05 (m, 2 H); 6.62-6.72 (m, 1 H); 3.80-3.90 (m, 1 H); 3.40-3.59 (m, 8 H); 2.99-3.24 (m, 6 H); 2.85-2.95 (m, 1 H); 2.38 (s, 3 H); 1.96-2.21 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 406 (base, M + H +).

Example 227

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (4-<i>ter</i>-butylphenyl) -1-butanone

The title compound was prepared from the bromide addition of 4-<i>ter</i>-butyl-phenyl magnesium a 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the General Procedure of Example 223.

1 H NMR (300 MHz, CD 3 OD) δ 7.79-8.02 (m, 2 H); 7.50-7.56 (m, 2 H); 6.92-7.00 (m, 2 H); 6.65-6.75 (m, 1 H); 3.80-3.90 (m, 1 H); 3.40-3.59 (m, 4 H); 3.26-3.38 (m, 4 H); 2.99-3.24 (m, 6 H); 2.85-2.95 (m, 1 H); 1.96-2.21 (m, 4 H); 1.32 (s, 9 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 448 (base, M + H +).

Example 228

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (3,4-difluorphenyl) -1-butanone

The title compound was prepared from the bromide addition of 3,4-difluor-phenyl magnesium a 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the General Procedure of Example 223.

1 H NMR (300 MHz, CD 3 OD) δ 7.88-7.94 (m, 2 H); 7.38-7.44 (m, 1 H); 6.92-7.00 (m, 2 H); 6.65-6.75 (m, 1 H); 3.80-3.90 (m, 1 H); 3.40-3.59 (m, 4 H); 3.26-3.38 (m, 4 H); 2.99-3.24 (m, 6 H); 2.85-2.95 (m, 1 H); 1.96-2.21 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 428 (base, M + H +).

Example 229

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (5-fluor-2-methoxyphenyl) -1-butanone

The title compound was prepared from the bromide addition of 3-fluor-6-methoxyphenyl magnesium a 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the General Procedure of Example 223.

1 H NMR (300 MHz, CD 3 OD) δ 7.40-7.48 (m, 1 H); 7.24-7.34 (m, 1 H); 7.10-7.18 (m, 1 H); 6.92-7.00 (m, 2 H); 6.65-6.75 (m, 1 H); 3.74-3.92 (m, 2 H); 3.90 (s, 3 H); 3.36-3.59 (m, 4 H); 3.26-3.34 (m, 4 H); 3.05-3.20 (m, 6 H); 2.85-2.95 (m, 1 H); 1.96-2.21 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 440 (base, M + H +).

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] indole-11 (8aH) -yl) -1-phenyl-1-pentanone

The title compound was prepared from the addition of phenyl magnesium bromide to 5 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylpentanamide following the General Procedure of Example 223.

1 H NMR (300 MHz, CDCl 3) δ 7.84-7.94 (m, 2 H); 7.50-7.58 (m, 1 H); 7.44-7.50 (m, 2 H); 6.92-7.00 (m, 2 H); 6.70-6.79 (m, 1 H); 3.76-3.82 (m, 1 H); 3.58-3.68 (m, 2 H); 3.45-3.56 (m, 1 H); 3.18-3.21 (m, 2 H); 2.64-2.98 (m, 7 H); 2.30-2.35 (m, 1 H); 1.80-1.92 (m, 4 H); 1.60-1.72 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 406 (base, M + H +).

Example 231

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -il) -1- (4-fluor-1-naphthyl) -1-butanone

Process general

To a solution of 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide of Example 26 (0.1 mmol) in THF (1 mL) at room temperature is the corresponding aryl magnesium bromide was added dropwise (0.5 mmol) in THF. The reaction mixture was stirred at temperature. ambient for 18-20 hours, then heated to 72 ° C for 1 hour. The reaction was concentrated until there was a residue. The residue was purified by preparative TLC (gel silica, CH 2 Cl 2: CH 3 OH 9: 1) to supply the title compounds with yields of 36-40%

The title compound was prepared from the bromide addition of 4-fluor-1-naphthyl magnesium a 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole-11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the previous General Procedure.

1 H NMR (300 MHz, CD 3 OD) δ 8.72-8.80 (m, 1 H); 8.10-8.18 (m, 2 H); 7.62-7.68 (m, 2 H); 7.24-7.30 (m, 1 H); 6.92-7.00 (m, 2 H); 6.64-6.70 (m, 1 H); 3.82-3.92 (m, 1 H); 3.52-3.64 (m, 2 H); 3.24-3.44 (m, 7 H); 2.90-3.14 (m, 2 H); 2.68-2.84 (m, 2 H); 2.30-2.44 (m, 2 H); 1.99-2.11 (m, 4 H) ppm.

MS (ESI): 461 (MH] +.

Example 232

5 - ((8aS, 12Ra) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -1-phenyl-2-pentanone

The title compound was prepared from the addition of benzyl magnesium bromide to 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the General Procedure of Example 231.

1 H NMR (300 MHz, CD 3 OD) δ 7.22-7.28 (m, 5 H); 6.92-6.98 (m, 2 H); 6.62-6.68 (m, 1 H); 4.88 (s, 2 H); 3.82-3.92 (m, 1 H); 3.52-3.64 (m, 2 H); 3.24-3.44 (m, 7 H); 2.82-3.18 (m, 4 H); 2.32-2.44 (m, 2 H); 1.92-2.30 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 406 (base, M + H +).

Example 233

3 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N- (4-fluorphenyl) propanamide

Process general

TO 3 - ((8a<i>S</i>, 12th<i>R</i>) -6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -<i>N</i>-methoxy-<i>N</i>-methylpropanamide or 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N-methoxy-N-methylbutanamide (0.06-0.1 mmol) in methanesulfonic acid (0.5 mL) NaN3 (1.5 equiv.) was added. The resulting mixture was stirred at room temperature for 1 hour, then water (5 mL) was added. Ammonium hydroxide solution was added to adjust the pH to 11. It was extracted with CH 2 Cl 2 (20 mL). The organic layer was dried over MgSO4, filtered and concentrated until a residue. The residue was purified by preparative TLC (gel silica, CH 2 Cl 2: CH 3 OH 9: 1). The product is dissolved in ether (1 mL) and stirred at 0 ° C for 10 minutes, it was added 1 N HCl in ether (0.5 mL) at 0 ° C. White solid crystalline was collected by filtration to deliver the compound of the title with yields of 50-52%.

The title compound was prepared from 3 - ((8a<i>S</i>, 12th<i>R</i>) -6,7,9,10,12,12a-hexa-hydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -<i>N</i>-methoxy-<i>N</i>-methylpropanamide following the previous General Procedure.

1 H NMR (300 MHz, CDCl 3) δ 7.30-7.35 (m, 2 H); 6.90-7.15 (m, 3 H); 6.87 (d, J = 7.0 Hz, 1 H); 6.59 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 3.62-3.72 (m, 1 H); 3.22-3.48 (m, 5 H); 3.04-3.12 (m, 1 H); 2.55-2.86 (m, 7 H); 2.07-2.15 (m, 2 H); 1.97-2.00 (m, 2 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 411 (base, M + H +).

Example 234

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -N- (4-fluorphenyl) butanamide

The title compound was prepared from 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepine [2,3,4-hi] indole-11 (8aH) -yl) -N-methoxy-N-methylbutanamide following the General Procedure of Example 233.

1 H NMR (300 MHz, CDCl 3) δ 7.33-7.37 (m, 2 H); 6.88-6.97 (m, 3 H); 6.78 (d, J = 7.0 Hz, 1 H); 6.54 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 3.64-3.74 (m, 1 H); 3.37-3.48 (m, 1 H); 3.21-3.26 (m, 1 H); 3.00-3.17 (m, 2 H); 2.86-2.94 (m, 1 H); 2.70-2.76 (m, 1 H); 2.58-2.62 (m, 1 H); 2.33-2.45 (m, 4 H); 1.94-2.09 (m, 4 H); 1.83-1.90 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 425 (base, M + H +).

Example 235

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -1- (4-fluorphenyl) -1-butanol

TO 4 - ((8aS, 12aR) 1-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -il) -1- (4-fluorphenyl) -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] quinoxalin-8-yl) -1-butanone (0.06 mmol) in methanol (1 mL) was added sodium borohydride (0.36 mmol) in three portions at 0 ° C. The reaction mixture was stirred. at room temperature for 2 hours, which was followed by adding two drops of concentrated HCl to destroy excess NaBH_ {4}. NH4OH (1 mL) was added and extracted with CH 2 Cl 2 (10 mL). The organic layer was dried over MgSO4, It was filtered and concentrated until a residue remained. The residue is dissolved in ether (1 mL), HCl in ether was added. He concentrated until a residue remained to supply the title compound with yields of 60-65%.

The title compound was prepared from 4 - ((8aS, 12aR) 1-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole -11 (8aH) -il) -1- (4-fluorphenyl) -1-butanone following the previous General Procedure:

1 H NMR (300 MHz, CD 3 OD) δ 7.34-7.40 (m, 2 H); 6.98-7.10 (m, 2 H); 6.90-6.95 (m, 2 H); 6.62-6.70 (m, 1 H); 4.70 (m, 1 H); 3.76-3.86 (m, 1 H); 3.44-3.59 (m, 4 H); 33.24-3.3 (m, 1 H); 2.90-3.14 (m, 4 H); 2.05-2.45 (m, 4 H); 1.80-2.02 (m, 4 H) ppm.

MS (ESI): 413<i />(MH) +.

Example 236

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -1- (4-pyridinyl) -1-butanol

The title compound was prepared from 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] quinoxalin-8-yl) -1-butanone following the General Procedure of Example 235.

1 H NMR (300 MHz, CDCl 3) δ 8.53-8.57 (m, 2 H); 7.32-7.36 (m, 2 H); 6.90-6.98 (m, 1 H); 6.84-6.87 (m, 1 H); 6.60-6.66 (m, 1 H); 4.66-4.72 (m, 1 H); 3.80-3.92 (m, 1 H); 3.55-3.71 (m, 3 H); 3.22-3.30 (m, 2 H); 2.64-3.02 (m, 4 H); 2.31-2.54 (m, 3 H); 1.69-2.03 (m, 8 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 395 (base, M + H +).

Example 237

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -1- (2,3-dimethoxyphenyl) -1-butanol

Stage TO

Oxalyl chloride (55 mmol) was dissolved in CH 2 Cl 2 (25 mL), cooled to -60 ° C, and added dropwise DMSO solution (120 mmol) in CH 2 Cl 2 (10 mL). The reaction mixture was stirred at -60 ° C for 10 minutes. Slowly added 1-chlorobutan-4-ol (50 mmol) in CH2Cl2 (10 mL) in 10 minutes. The mixture of The reaction was stirred at the same temperature for 15 minutes. He added Et3N in about 5 minutes at -60 ° C. The cooling bath was removed and water was added at rt, continuing stirring for 10 minutes. The layer was separated organic The aqueous phase was extracted with CH2Cl2 (3 x 50 mL) The organic layer was combined, dried over MgSO4, filtered, and concentrated until a residue was left to supply 1-chlorobutan-4-al with a yield of 64%. The product was distilled under pressure reduced to supply the aldehyde with a yield of 60% (5 mm Hg, 88-90 ° C).

Stage B

To a solution of TMEDA (6.6 mmol) in dry THF (15 mL), it was added <i>sec</i>-BuLi (6.6 mmol) slowly at -78 ° C. The reaction mixture is stirred at -78 ° C for 10 minutes, and added slowly veratrole (6.0 mmol) in THF (3 mL). The reaction is stirred at -78 ° C for 30 minutes, was added 1-chlorobutan-4-al (6.6 mmol) and stirred at -78 ° C for 2 hours. The reaction mixture was heated to room temperature, added brine (1 mL), and filtered. The filtrate was dried over MgSO4, It was filtered and concentrated until a residue remained. The residue is purified by flash column chromatography (silica gel; ethyl acetate / hexane: 3/7) to provide 1- (2,3-dimethoxyphenyl-4-chlorobutan-1-ol with a yield of 20%.

1 H NMR (300 MHz, CDCl 3) δ 7.05 (dd, J = 8.0 Hz, 7.7 Hz, 1 H); 6.94 (bd, J = 7.7 Hz, 1 H); 6.85 (bd, J = 8.1 Hz, 1 H); 4.91-4.97 (m, 1 H); 3.88 (s, 3 H); 3.84 (s, 3 H); 3.56-3.60 (m, 2 H); 2.44-2.45 (m, 1 H); 1.81-2.00 (m, 4 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 244 (base, M + H +).

Stage C

To a suspension of (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (1.17 mmol) in 1,4-dioxane (4 mL) will be added the alcohol of Stage B 1- (2,3-dimethoxyphenyl-4-chlorobutan-1-ol (0.78 mmol), potassium iodide (100 mg) and potassium carbonate (300 mg). The reaction mixture was heated under reflux for 2 days. The solvent was removed under reduced pressure. The residue is treated with water (50 mL) and extracted with methylene chloride (3 x 50 mL) The CH 2 Cl 2 extract was washed with brine (150 mL), dried over MgSO4, filtered and concentrated until left a residue The residue was purified by flash chromatography of column (silica gel, CH 2 Cl 2: CH 3 OH, 9: 1). He product was dissolved in ether (2 mL) and stirred at 0 ° C for 10 minutes, 1 N HCl in ether (0.5 mL) was added at 0 ° C. Solid White crystalline lens was collected by filtration to give the title compound with a yield of 62%.

1 H NMR (300 MHz, CDCl 3) δ 7.07 (d, J = 7.6 Hz, 1 H); 6.99 (dd, J = 7.7 Hz, 8.1 Hz, 1 H); 6.89 (dd, J = 1.5 Hz, 8.0 Hz, 1 H); 6.83 (dd, J = 1.1 Hz, 7.4 Hz, 1 H); 6.75 (dd, J = 1.5 Hz, 7.7 Hz, 1 H); 6.57 (dd, J = 7.3 Hz, 7.7 Hz, 1 H); 4.92 (m, 1 H); 3.79 (s, 6 H); 3.46-3.56 (m, 1 H); 3.16-3.20 (m, 2 H); 2.67-2.95 (m, 4 H); 2.31-2.34 (m, 3 H); 1.80-2.05 (m, 5 H); 1.64-1.76 (m, 6 H) ppm.

MS (CI, NH3): <i>m</i> / <i>and</i> 455 (base, M + H +).

Example 238

4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -1- (2,3-dimethoxyphenyl) -1-butanone

To a solution of alcohol 4 - ((8aS, 12aR) -6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3,4-hi] indole- 11 (8aH) -yl) -1- (2,3-dimethoxyphenyl) -1-butanol (0.11 mmol) and N-methylmorpholine N-oxide (0.17 mmol) in CH2Cl2 (2 mL) with powdered molecular sieves from 4 Å to ta tetrapropyl perrutenate was added ammonium (0.006 mmol) in one serving. The reaction mixture was stirred. at rt for 4 hours, it was filtered and concentrated until a residue. The residue was purified by flash chromatography of column (silica gel, CH 2 Cl 2: CH 3 OH, 9: 1) to supply the title compound with a yield of 94%.

1 H NMR (300 MHz, CDCl 3) δ 7.05 (d, J = 7.3 Hz, 1 H); 7.02 (d, J = 7.4 Hz, 1 H); 6.97 (dd, J = 6.9 Hz, 7.7 Hz, 1 H); 6.87 (d, J = 7.7 Hz, 1 H); 6.77 (d, J = 6.6 Hz, 1 H); 6.53 (dd, J = 7.7 Hz, 7.3 Hz, 1 H); 3.82 (s, 3 H); 3.80 (s, 3 H); 3.70-3.80 (m, 1 H); 3.43-3.56 (m, 1 H); 3.17-3.22 (m, 1 H); 2.82-3.05 (m, 5 H); 2.56--2.76 (m, 2 H); 2.10-2.30 (m, 3 H); 1.80-2.05 (m, 7 H) ppm.

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 ] thiazepine [2,3,4-hi] indole

Stage TO

To a solution of 4-chloro-1,1-diphenyl-1-butene (200 mg; 0.82 mmol) in EtOAc (8.0 mL) was added Pd / C (10%, 50 mg) The reaction mixture was stirred under H2 atmosphere. for 15 hours at 20 ° C. The reaction mixture was filtered through celite and the filtrate was concentrated to give the 4-chloro-1,1-diphenyl-1-butane (201 mg; 99%) as a colorless oil.

1 H NMR (CDCl 3, 300 MHz) δ 1.70-1.81 (m, 2 H); 2.16-2.25 (m, 2 H); 3.54 (t, 2 H, J = 6.5 Hz); 3.91 (t, 1 H, J = 7.8 Hz); 7.15-7.31 (m, 10 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (48 mg; 88%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 4-chloro-1,1-diphenyl-1-butane (44 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.42-1.53 ​​(m, 2 H); 1.78 (t, 1 H, J = 12.0 Hz); 1.82-1.92 (m, 2 H); 1.95-2.20 (m, 5 H); 2.25-2.37 (m, 2 H); 2.56-2.63 (m, 1 H); 2.65-2.73 (m, 1 H); 2.88-2.97 (m, 1 H); 3.00-3.17 (m, 2 H); 3.22-3.28 (m, 1 H); 3.50-3.63 (m, 1 H); 3.76-3.85 (m, 1 H); 3.89 (t, 1 H, J = 7.9 Hz); 6.60 (t, 1 H, J = 7.7 Hz,); 6.82 (d, 1 H, J = 7.3 Hz); 6.93 (d, 1 H, J = 7.7 Hz); 7.13-7.35 (m, 10 H) ppm.

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] thiazepine [2,3,4-hi] indole

Stage TO

Cyclopropyldiphenylmethanol (500 mg; 2.23 mmol) in 1 M HCl in <i>i</i>-PrOH (4.0 mL). The reaction mixture was then heated at 60 ° C for 1 hour. The The reaction was cooled to 20 ° C and diluted with Et2O (100 mL). The organic solution was washed successively with H2O, solution saturated aqueous NaHCO3 and brine. Then dried over MgSO4, filtered, concentrated in vacuo and chromatographed on a silica gel column by elusion with hexanes to give 4-chloro-1,1-diphenyl-1-butene (506 mg; 93%) as a colorless oil.

1 H NMR (CDCl 3, 300 MHz) δ 2.59 (q, 2 H, J = 6.9 Hz); 3.58 (t, 2 H, J = 6.9 Hz), 6.12 (t, 1 H, J = 7.3 Hz); 7.16-7.42 (m, 10 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (33 mg; 61%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 4-chloro-1,1-diphenyl-1-butene (44 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.79-1.92 (m, 3 H); 1.94-2.17 (m, 2 H); 2.20-2.37 (m, 3 H); 2.40-2.49 (m, 2 H); 2.55-2.63 (m, 1 H); 2.65-2.73 (m, 1 H); 2.88-2.97 (m, 1 H); 3.00-3.17 (m, 2 H); 3.23-3.29 (m, 1 H); 3.50-3.62 (m, 1 H); 3.76-3.87 (m, 1 H); 6.06 (t, 1 H, J = 7.3 Hz); 6.61 (t, 1 H, J = 7.3 Hz); 6.82 (d, 1 H, J = 6.6 Hz); 6.94 (dd, 1 H, J = 1.1, 7.7 Hz); 7.17-7.41 (m, 10 H) ppm.

Example 242

cis- (8a, 12a) -11- [4,4-bis (4-fluorphenyl) butyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepine [2,3,4-

hi

] indole

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (89 mg; 51%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (68 mg; 0.27 mmol) and 1,1-bis (4'-fluorphenyl) -4-chlorobutane (90 mg; 0.32 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.38-1.48 (m, 2 H); 1.79 (t, 1 H, J = 11.2 Hz); 1.83-1.91 (m, 2 H); 1.95-2.21 (m, 5 H); 2.23-2.35 (m, 2 H); 2.53-2.62 (m, 1 H); 2.63-2.75 (m, 1 H); 2.89-2.99 (m, 1 H); 3.01-3.16 (m, 2 H); 3.22-3.27 (m, 1 H); 3.52-3.62 (m, 1 H); 3.76-3.85 (m, 1 H); 3.86 (m, 1 H, J = 8.1 Hz); 6.61 (t, 1 H, J = 7.3 Hz,); 6.82 (d, 1 H, J = 6.6 Hz); 6.90-6.99 (m, 5 H); 7.13-7.22 (m, 4 H) ppm.

Example 243

cis- (8a, 12a) -11- [4,4-bis (4-fluorphenyl) -3-butenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4 , 3-b] [1,4] thiazepino [2,3,4-hi] indole

Stage TO

To a solution of cyclopropyl- (4-fluorphenyl) ketone (520 mg, 3.17 mmol) in THF (10 mL) was added dropwise 4-fluorphenyl magnesium at 0 ° C under the atmosphere of N_ {2}. The reaction mixture was stirred for one hour at 0 ° C, it was quenched by the addition of brine and extracted with Et2O. The organic layer was then washed with saturated aqueous solution of NaHCO 3 and brine. It was then dried over MgSO4, filtered, concentrated in vacuo to give bis (4-fluorphenyl) -cyclopropylmethanol raw. It was used for the ring opening reaction following the procedure for training 4-chloro-1,1-diphenyl-1-butene without further purification. It was obtained 1,1-bis (4-fluorphenyl) -4-chloro-1-butene (780 mg; 88%) as a colorless oil.

1 H NMR (CDCl 3, 300 MHz) δ 2.57 (q, 2 H, J = 6.9 Hz); 3.58 (t, 2 H, J = 6.9 Hz); 6.04 (t, 1 H, J = 7.3 Hz); 6.92-7.91 (m, 8 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (40 mg; 68%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1,1-bis (4'-fluorphenyl) -4-chloro-1-butene (51 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.79-1.93 (m, 3 H); 1.98-2.18 (m, 2 H); 2.19-2.37 (m, 3 H); 2.38-2.48 (m, 2 H); 2.55-2.63 (m, 1 H); 2.63-2.73 (m, 1 H); 2.90-2.99 (m, 1 H); 3.01-3.18 (m, 2 H); 3.22-3.28 (m, 1 H); 3.48-3.60 (m, 1 H); 3.75-3.86 (m, 1 H); 5.98 (t, 1 H, J = 7.3 Hz); 6.61 (t, 1 H, J = 7.3 Hz,); 6.83 (d, 1 H, J = 7.3 Hz); 6.88-7.01 (m, 3 H); 7.01-7.20 (m, 6 H) ppm.

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] indole-11 (8aH) -yl) ethyl] benzamide

Stage TO

To a solution of ethanolamine (1.09 g; 17.8 mmoles) in THF was added dropwise benzoyl chloride (520 mg; 3.60 mmol) at 0 ° C under N2 atmosphere. The mixture of The reaction was stirred for 10 minutes and then quenched with 1M HCl. The mixture was then diluted with EtOAc and washed with satd NaHCO3. ac. and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallized to give N- (2-hydroxyethyl) benzamide (593 mg; 97%) As a crystalline solid.

1 H NMR (CDCl 3, 300 MHz) δ 3.41 (s, 1 H); 3.49-3.59 (m, 2 H); 3.75 (t, 2 H,<i>J</i> = 5.2 Hz); 7.10 (s, 1 H); 7.32-7.38 (m, 2 H); 7.42-7.48 (m, 1 H); 7.72-7.76 (m, 2 H) ppm.

Methanesulfonate was prepared from 2-benzamidoethyl following the General Procedure of Example 43 by mesylation as a colorless oil (291 mg; 84%) from N- (2-hydroxyethyl) benzamide (245 mg; 1.30 mmol) and methanesulfonyl chloride (223 mg; 1.94 mmoles).

1 H NMR (CDCl 3, 300 MHz) δ 2.85 (s, 3 H); 4.48 (t, 2 H, <i>J</i> = 9.5 Hz); 5.10 (t, 2 H,<i>J</i> = 10.2 Hz); 7.58-7.63 (m, 2 H); 7.74-7.80 (m, 1 H); 8.20-8.23 (m, 2 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (38 mg; 79%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate 2-benzamidoethyl (119 mg; 0.49 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.87-1.92 (m, 2 H); 2.05-2.12 (m, 2 H); 2.16-2.23 (m, 1 H); 2.40-2.50 (m, 1 H); 2.55-2.60 (m, 2 H); 2.77-2.84 (m, 2 H); 2.92-3.05 (m, 1 H); 3.15-3.24 (m, 1 H); 3.31-3.34 (m, 1 H); 3.44-3.57 (m, 2 H); 3.69-3.78 (m, 2 H); 4.45-4.51 (m, 1 H); 6.59 (t, 1 H, J = 7.7 Hz); 6.83-6.86 (m, 1 H); 6.91-6.97 (m, 1 H); 7.15-7.23 (m, 1 H); 7.35-7.5 (m, 2 H); 7.61 (dd, 1 H, J = 1.1; 8.4 Hz) ppm.

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] indole-11 (8aH) -yl) ethyl] -2-fluorbenzamide

Stage TO

Ethanolamine (1.00 mg; 15.8 mmol) was coupled and 2-fluorbenzoyl chloride (504 mg; 3.15 mmol) to give N- (2-hydroxyethyl) -2'-fluorbenzamide (460 mg; 79%) following the procedure for the preparation of N- (2-hydroxyethyl) benzamide.

1 H NMR (CD 3 OD, 300 MHz) δ 3.49 (t, 2 H, <i>J</i> = 5.9 Hz); 3.68 (t, 2 H,<i>J</i> = 2.9 Hz); 7.15-7.28 (m, 2 H); 7.47-7.55 (m, 1 H); 7.72-7.78 (m, 1 H) ppm.

Was prepared N- (2-Chloroethyl) -2'-fluorbenzamide following the chlorination procedure in the synthesis of 2- (2-Chloroethyl) isoindolinone as an oil colorless (130 mg; 70%) from N- (2-hydroxyethyl) -2'-fluorbenzamide (130 mg; 0.71 mmol) and methanesulfonyl chloride (122 mg; 1.06 mmoles).

1 H NMR (CDCl 3, 300 MHz) δ 3.72-3.76 (m, 2 H); 3.82-3.87 (m, 2 H); 7.11-7.18 (m, 2 H); 7.25-7.28 (m, 1 H); 7.46-7.53 (m, 1 H); 8.08-8.13 (m, 1 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (56 mg; 90%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and N- (2-Chloroethyl) -2'-fluorbenzamide (74 mg; 0.37 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.92-2.15 (m, 6 H); 2.37-2.39 (m, 1 H); 2.55-2.58 (m, 1 H); 2.61-2.65 (m, 1 H); 2.75-2.80 (m, 1 H); 2.91-2.99 (m, 1 H); 3.11-3.18 (m, 1 H); 3.27-3.31 (m, 1 H); 3.49-3.60 (m, 4 H); 3.78-3.82 (m, 1 H); 6.59 (t, 1 H,<i>J</i> = 7.3 Hz); 6.85 (d, 1 H,<i>J</i> = 7.0 Hz); 6.94 (dd, 1 H,<i>J</i> = 1.5; 8.1 Hz); 7.08; 7.15 (m, 1 H); 7.24-7.29 (m, 1 H); 7.43-7.51 (m, 1 H); 8.08-8.14 (dt, 1 H, <i>J</i> = 1.8; 8.1 Hz) ppm.

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] indole-11 (8aH) -yl) ethyl] -4-fluorbenzamide

Stage TO

Ethanolamine (0.96 mg; 15.8 mmol) was coupled and 4-fluorbenzoyl chloride to give N- (2-hydroxyethyl) -4'-fluorbenzamide (482 mg; 81%) following the procedure for the preparation of N- (2-hydroxyethyl) benzamide.

1 H NMR (CD 3 OD, 300 MHz) δ 3.47 (t, 2 H, <i>J</i> = 5.9 Hz); 3.68 (t, 2 H,<i>J</i> = 5.7 Hz); 7.13-7.20 (m, 2 H); 7.82-7.92 (m, 2 H) ppm.

Methanesulfonate was prepared from 2- (4'-fluorbenzamido) ethyl following the general procedure of Example 43 for mesylation as a crystal white (130 mg; 70%) from N- (2-hydroxyethyl) -4'-fluorbenzamide (130 mg; 0.71 mmol) and methanesulfonyl chloride (122 mg; 1.06 mmoles).

1 H NMR (CDCl 3, 300 MHz) δ 2.85 (s, 3 H); 4.48 (t, 2 H, <i>J</i> = 9.5 Hz); 5.10 (t, 2 H,<i>J</i> = 10.2 Hz); 7.08-7.18 (m, 2 H); 7.70-7.82 (m, 3 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (45 mg; 91%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate N- [2- (methylsulfonyl) ethyl] -4-fluorbenzamide (63 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.85-1.93 (m, 2 H); 2.05-2.15 (m, 2 H); 2.24 (dd, 1 H, J = 8.7; 11.3 Hz); 2.39-2.47 (m, 1 HOUR); 2.52-2.61 (m, 3 H); 2.71-2.80 (m, 1 H); 2.98-3.07 (m, 1 H); 3.10-3.20 (m, 1 H); 3.20-3.30 (m, 1 H); 3.31-3.39 (m, 1 H); 3.40-3.50 (m, 1 H); 3.54 (q, 2 H, J = 6.2 Hz); 3.65-3.76 (m, 1 H); 6.58 (t, 1 H, J = 7.7 Hz); 6.82-6.92 (m, 2 H); 6.95 (dd, 1 H, J = 1.1; 8.1 Hz); 7.05-7.17 (m, 2 H); 7.70-7.80 (m, 2 H) ppm.

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] thiazepino [2,3,4-hi] indole

Stage TO

Methanesulfonate was prepared from 3- (3-indolyl) -1-propyl following the general procedure of Example 43 for mesylation as a colorless oil (170 mg; 81%) from 3- (3-indolil) -1-propanol (145 mg; 0.83 mmol) and methanesulfonyl chloride (142 mg; 1.24 mmoles).

1 H NMR (CDCl 3, 300 MHz) δ 2.17 (qu, 2 H, J = 7.3 Hz); 2.92 (t, 2 H, J = 7.0 Hz); 2.99 (s, 3 H); 4.27 (t, 2 H, J = 6.4 Hz); 7.04 (d, 1 H, J = 2.2 Hz); 7.12 (dt, 1 H, J = 1.1; 7.0 Hz); 7.21 (dt, 1 H, J = 1.1; 7.0 Hz); 7.38 (d, 1 H, J = 8.1 Hz); 7.59 (d, 1 H, J = 7.3 Hz); 8.00 (br, 1 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (20 mg; 59%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (21 mg; 0.084 mmol) and methylsulfonate of 3- (3-indolyl] propyl (32 mg; 0.13 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.93-2.22 (m, 7 H); 2.40-2.53 (m, 1 H); 2.55-2.65 (m, 2 H); 2.77-2.95 (m, 5 H); 2.97-3.07 (m, 1 H); 3.26-3.40 (m, 2 H); 3.48-3.60 (m, 1 H); 3.77-3.88 (m, 1 H); 6.63 (t, 1 H, J = 7.7 Hz); 6.85 (d, 1 H, J = 7.3 Hz); 6.96 (dd, 1 H, J = 1.1; 8.1 Hz); 7.01 (d, 1 H, J = 1.8 Hz); 7.10 (t, 1 H, J = 7.3 Hz); 7.19 (t, 1 H, J = 7.4 Hz); 7.36 (d, 1 H, J = 8.1 Hz); 7.58 (d, 1 H, J = 7.7 Hz); 8.00 (s, 1 H) ppm.

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] thiazepino [2,3,4-hi] indole

Stage TO

To a solution of KOH (2.24 mg; 40.0 mmol) in Dry DMSO (10 mL) acid added 3-indolpropionic (946 mg; 5.0 mmol) followed immediately from MeI (3.0 g; 4.0 mmol). The reaction mixture is stirred for 1.5 hours at 20 ° C, turned off by pouring it into water and extracted with CHCl3 (3 x 20 mL). The organic layer was washed then with brine, dried over MgS4, filtered, concentrated in vacuo and chromatographed on a gel column of silica by elution with EtOAc / hexanes to give 3- (1-methyl-3-indolyl) propionate of methyl (1.00 g; 92%) as a colorless oil.

1 H NMR (CDCl 3, 300 MHz) δ 2.71 (t, 2 H, J = 8.1 Hz); 3.09 (t, 2 H, J = 7.0 Hz); 3.68 (s, 3 H); 3.74 (s, 3 H);); 6.87 (s, 1 H); 7.11 (dt, 1 H, J = 1.1; 6.8 Hz); 7.22 (dt, 1 H, J = 1.1; 8.0 Hz); 7.29 (d, 1 H, J = 8.1 Hz); 7.59 (d, 1 H, J = 7.7 Hz) ppm.

To a solution of 3- (1-methyl-3-indolyl) propionate of methyl (300 mg; 1.38 mmol) in Et2O (3.0 mL) was added LiAlH 4 at 0 ° C under an atmosphere of N 2. Reaction mixture stirred for 30 minutes at 0 ° C and turned off by addition careful of H2O. EtOAc was added to the reaction mixture off The organic layer was separated, washed with brine and dried over MgSO4. It was then concentrated in vacuo and chromatographed on a silica gel column by elution with EtOAc / hexanes to give 3- (1-methyl-3-indolyl) -1-propanol (250 mg; 96%) as a colorless oil.

1 H NMR (CDCl 3, 300 MHz) δ 1.28 (t, 1 H, J = 6.2 Hz); 1.98 (qu, 2 H, J = 7.7 Hz); 2.85 (t, 2 H, J = 7.3 Hz); 3.70-3.78 (m, 4 H); 6.86 (s, 1 H); 7.10 (dt, 1 H, J = 1.1; 7.0 Hz); 7.22 (dt, 1 H, J = 1.1; 7.5 Hz); 7.29 (d, 1 H, J = 8.1 Hz); 7.60 (d, 1 H, J = 7.7 Hz) ppm.

Methanesulfonate was prepared from 3- (1-methyl-3-indolyl) -1-propyl following the general procedure of Example 43 for mesylation as a colorless oil (291 mg; 84%) from 3- (1-methyl-3-indolyl) -1-propanol (245 mg; 1.30 mmol) and methanesulfonyl chloride (223 mg; 1.94 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 2.15 (qu, 2 H, J = 7.0 Hz); 2.90 (t, 2 H, J = 7.0 Hz); 2.99 (s, 3 H); 3.76 (s, 3 H); 4.27 (t, 2 H, J = 6.2 Hz); 6.88 (s, 1 H); 7.11 (dt, 1 H, J = 1.1; 6.9 Hz); 7.23 (dt, 1 H, J = 1.1; 7.0 Hz); 7.29 (d, 1 H, J = 8.5 Hz); 7.57 (d, 1 H, J = 8.1 Hz) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (36 mg; 86%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (25 mg; 0.10 mmol) and methylsulfonate of 3- (1-methyl-3-indolyl] propyl (32 mg; 0.12 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.92-2.18 (m, 7 H); 2.35-2.46 (m, 1 H); 2.48-2.60 (m, 2 H); 2.74-2.95 (m, 5 H); 2.96-3.07 (m, 1 H); 3.25-3.35 (m, 2 H); 3.46-3.58 (m, 1 H); 3.74 (s, 3 H); 3.77-3.87 (m, 1 H); 6.63 (t, 1 H, J = 7.3 Hz); 6.82-6.88 (m, 2 H); 6.96 (d, 1 H, J = 7.7 Hz); 7.09 (t, 1 H, J = 7.0 Hz); 7.20-7.32 (m, 2 H); 7.57 (d, 1 H, J = 7.7 Hz) ppm.

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] thiazepino [2,3,4-hi] indole

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (33 mg; 71%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 3- (2-bromoethyl) indole (54 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.93-2.20 (m, 5 H); 2.35-2.43 (m, 1 H); 2.64-2.77 (m, 2 H); 2.78-2.87 (m, 1 H); 2.89-3.15 (m, 5 H); 3.20-3.35 (m, 2 H); 3.49-3.61 (m, 1 H); 3.77-3.87 (m, 1 H); 6.64 (t, 1 H, J = 7.7 Hz); 6.90 (d, 1 H, J = 7.3 Hz); 6.97 (dd, 1 H, J = 1.1; 8.1 Hz); 7.02 (d, 1 H, J = 2.2 Hz); 7.08-7.21 (m, 2 H); 7.35 (d, 1 H, J = 8.0 Hz); 7.61 (d, 1 H, J = 8.1 Hz); 7.98 (s, 1 H) ppm.

<pre listing-type="other">\ newpage</pre>

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] thiazepino [2,3,4-hi] indole

Stage TO

To a solution of 1-bromo-3-chloropropane (2.00 g; 12.7 mmol) in DMF (7.0 mL) indole (500 mg; 4.24 mmol) followed by powdered KOH (262 mg; 4.66 mmol) at 20 ° C. The reaction mixture was then stirred for 15 hours at 20 ° C. The reaction was quenched by the addition of H2O and the product. it was extracted with Et2O. The organic solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated to empty. It was isolated 1- (3-Chloro-1-propyl) indole (580 mg; 71%) by flash chromatography on a gel column silica eluting with EtOAc / hexanes as a yellow oil pale.

1 H NMR (CDCl 3, 300 MHz) δ 2.28 (qu, 2 H, J = 6.3 Hz); 3.46 (t, 2 H, J = 6.2 Hz); 4.36 (t, 2 H, J = 6.6 Hz); 6.51 (d, 1 H, J = 3.3 Hz); 7.09-7.18 (m, 2 H); 7.20-7.25 (m, 1 H); 7.38 (d, 1 H, J = 8.5 Hz); 7.64 (d, 1 H, J = 7.7 Hz) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (46 mg; 95%) from cis- (8a, 12a) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (3-chloropropyl) indole (46 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.90-2.15 (m, 7 H); 2.18-2.33 (m, 3 H); 2.52-2.60 (m, 1 H); 2.66-2.75 (m, 1 H); 2.89-2.98 (m, 1 H); 3.02-3.18 (m, 2 H); 3.26-3.33 (m, 1 H); 3.48-3.59 (m, 1 H); 3.77-3.87 (m, 1 H); 4.21 (t, 2 H, J = 7.0 Hz); 6.62 (t, 1 H, J = 7.3 Hz); 6.85 (d, 1 H, J = 6.6 Hz); 6.95 (dd, 1 H, J = 1.1; 7.7 Hz); 7.05-7.16 (m, 2 H); 7.20 (dt, 1 H, J = 1.1; 7.0 Hz); 7.38 (d, 1 H, J = 8.4 Hz); 7.63 (d, 1 H, J = 8.1 Hz) ppm.

Example 251

cis- (8a, 12a) -11- [3- (2,3-dihydro-1H-indol-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H - beep [4,3-b] [1,4] thiazepino [2,3,4-hi] indole

Stage TO

To 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) was added Et3N (2.12 g; 21.0 mmol) at 20 ° C. The reaction mixture was then stirred. for 15 hours at 70 ° C. The reaction mixture was cooled to 20 ° C and it was turned off by adding H2O. The product was extracted with Et 2 O. The organic solution was then washed with H2O and brine, dried over MgSO4, filtered and concentrated to empty. It was isolated 1- (3-Chloro-1-propyl) indoline (373 mg; 45%) by flash chromatography on a gel column silica by elution with EtOAc / hexanes as a yellow oil pale.

1 H NMR (CDCl 3, 300 MHz) δ 2.07 (qu, 2 H, J = 6.2 Hz); 2.97 (t, 2 H, J = 8.2 Hz); 3.24 (t, 2 H, J = 6.6 Hz); 3.35 (t, 2 H, J = 8.3 Hz); 3.68 (t, 2 H, J = 6.2 Hz); 6.50-6.56 (m, 1 H); 6.66 (t, 1 H, J = 6.6 Hz); 7.04-7.10 (m, 2 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (36 mg; 74%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [3 ', 4': 4,5] pyrrolo [1,2,3-<i>ef</i>] [1,5] benzothiazepine (30 mg; 0.12 mmol) and 1- (3-chloropropyl) indoline (47 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.80-2.18 (m, 7 H); 2.23-2.35 (m, 2 H); 2.43-2.55 (m, 1 H); 2.70-2.85 (m, 2 H); 2.89-2.98 (m, 3 H); 3.02-3.19 (m, 4 H); 3.28-3.38 (m, 3 H); 3.48-3.61 (m, 1 H); 3.78-3.90 (m, 1 H); 6.45-6.52 (m, 1 H); 6.59-6.70 (m, 2 H); 6.82-6.90 (m, 1 HOUR; 6.92-6.98 (m, 1 H); 7.02-7.13 (m, 2 H) ppm.

Example 252

cis- (8a, 12a) -11- [3- (1H-benzimidazol-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [4,3 -b] [1,4] thiazepino [2,3,4-hi] indole

Stage TO

To a solution of benzimidazole (355 mg; 3.00 mmol) in dry DMF (10 mL) NaH (83 mg; 3.3 mmol) was added at 20 ° C under N2 atmosphere. The reaction mixture was stirred for 30 minutes, and then it was added 1,3-dibromopropane (1.82 g; 9.00 mmol) and stirred for an additional 15 hours at 20 ° C. The reaction was quenched by addition. of H2O, and the product was extracted with EtOAc. The solution organic was then washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. It was isolated 1- (3-Bromo-1-propyl) benzimidazole (530 mg; 74%) by flash chromatography on a gel column silica by elution with EtOAc / hexanes as a yellow oil pale.

1 H NMR (CDCl 3, 300 MHz) δ 2.40 (qu, 2 H, J = 6.6 Hz); 3.33 (t, 2 H, J = 6.2 Hz); 4, 42 (t, 2 H, J = 6.6 Hz); 7.12-7.20 (m, 1 H); 7.27-7.48 (m, 2 H); 7.43-7.49 (m, 1 H); 7.78-7.76 (m, 1 H) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (21 mg; 43%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [3 ', 4': 4,5] pyrrolo [1,2,3-<i>ef</i>] [1,5] benzothiazepine (30 mg; 0.12 mmol) and 1- (3-chloropropyl) benzimidazole (58 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.83-1.95 (m, 3 H); 2.00-2.17 (m, 4 H); 2.20-2.33 (m, 3 H); 2.50-2.60 (m, 1 H); 2.64-2.72 (m, 1 H); 2.90-2.99 (m, 1 H); 3.05-3.18 (m, 2 H); 3.29-3.35 (m, 1 H); 3.50-3.59 (m, 1 H); 3.77-3.87 (m, 1 H); 4.28 (dt, 2 H, J = 2.2; 6.2 Hz); 6.63 (t, 1 H, J = 7.7 Hz); 6.85 (d, 1 H, J = 6.6 Hz); 6.95 (dd, 1 H, J = 1.1; 7.7 Hz); 7.27-7.35 (m, 2 H); 7.40-7.47 (m, 1 H); 7.78-7.86 (m, 1 H); 7.92 (s, 1 H) ppm.

Example 253

2- [2- (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) -yl) ethyl] -1H-isoindole-1,3 (2H) -dione

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (40 mg; 79%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [3 ', 4': 4,5] pirrolo [1,2,3-<i>ef</i>] [1,5] benzothiazepine (30 mg; 0.12 mmol) and N- (2-bromoethyl) phthalimide (61 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.80-2.20 (m, 5 H); 2.25-2.39 (m, 1 H); 2.58 (t, 2 H, J = 6.6 Hz); 2.69-2.77 (m, 1 H); 2.79-2.89 (m, 1 H); 2.90-2.98 (m, 1 H); 3.02-3.13 (m, 2 H); 3.17-3.27 (m, 1 H); 3.50-3.61 (m, 1 H); 3.77-3.87 (m, 3 H); 6.57 (t, 1 H, J = 7.7 Hz); 6.84 (d, 1 H, J = 7.0 Hz); 6.92 (dd, 1 H, J = 1.1; 7.7 Hz); 7.68-7.78 (m, 2 H); 7.82-7.89 (m, 2 H) ppm.

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] indole-11- (8aH) -yl) ethyl] -1-isoindoline

Stage TO

Ethanolamine (4.78 g; 78.3 mmol) and phthalate (10.0 g; 74.6 mmol) in an equipped round bottom flask with Dean-Stark trap. The reaction mixture is heated at 150 ° C for 4 hours, then 18 hours at 205 ° C. He product solidified after cooling. It was isolated Pure 2- (2-hydroxyethyl) isoindolinone (10.8 g; 82%) by recrystallization from CHCl3 / hexanes as a white crystal

1 H NMR (CDCl 3, 300 MHz) δ 3.02-3.15 (br, 1 H); 3.78 (t, 2 H, J = 5.0 Hz); 3, 93 (t, 2 H, J = 4.4 Hz); 4.52 (s, 2 H); 7.42-7.58 (m, 3 H); 7.84 (d, 1 H, J = 7.4 Hz) ppm.

To a solution of 2- (2-hydroxyethyl) isoindolinone (1.0 g; 5.64 mmol) in toluene (3.5 mL) thionyl chloride (1.34 was added g; 11.3 mmol). The reaction mixture was stirred at 20 ° C for 3 hours, then 4 hours at 60 ° C. The reaction mixture was concentrated at vacuum to remove excess thionyl chloride and toluene. He obtained 2- (2-chloroethyl) isoindolinone (1.01 g; 92%) by flash chromatography on a silica gel column by elution with EtOAc / hexanes as a pale yellow oil.

1 H NMR (CDCl 3, 300 MHz) δ 3.81 (t, 2 H, J = 5.5 Hz); 3.97 (t, 2 H, J = 5.9 Hz); 4.59 (s, 2 H); 7.44-7.58 (m, 3 H); 7.86 (d, 1 H, J = 6.9 Hz) ppm.

Stage B

The title compound was prepared following the general coupling procedure of Example 43 as an oil pale yellow (42 mg; 86%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5H-pyrido [3 ', 4': 4,5] pyrrolo [1,2,3-<i>ef</i>] [1,5] benzothiazepine (30 mg; 0.12 mmol) and 2- (2-Chloroethyl) isoindolinone (47 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.80-1.95 (m, 3 H); 2.00-2.18 (m, 3 H); 2.37 (dt, 1 H, J = 3.6; 11 Hz); 2.60 (t, 2 H, J = 6.6 Hz); 2.63-2.72 (m, 1 H); 2.75-2.82 (m, 1 H); 2.89-2.98 (m, 1 H); 3.05-3.18 (m, 2 H); 3.26-3.33 (m, 1 H); 3.48-3.59 (m, 1 H); 3.73-3.84 (m, 3 H); 4.49 (s, 2 H); 6.58 (t, 1 H, J = 7.3 Hz); 6.83 (d, 1 H, J = 6.6 Hz); 6.94 (dd, 1 H, J = 1.1; 7.7 Hz); 7.42-7.55 (m, 3 H); 7.85 (d, 1 H, J = 7.3 Hz) ppm.

Example 266

cis-4 - ((6b, 10a) -6-methyl-1,2,6b, 9,10,10a-hexahydro [1,4] -oxazino [2,3,4-hi] pyrido [4,3- b] indole-8- (7H) -yl) -1- (4-fluorphenyl) -1-butanone

The tratment of cis- (6b, 10a) -6-methyl-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole according to the procedure of Example 261 supplied the title compound with good performance as a brown liquid clear viscous. Yield 53%.

1 H NMR (CDCl 3, 300 MHz) δ 1.82-2.10 (m, 5 H); 2.18 (s, 3 H); 2.20-2.35 (m, 1 H); 2.43 (t, J = 6.9 Hz, 2 H); 2.60-2.80 (m, 2H); 2.88-3.05 (m, 1 H); 2.99 (t, J = 7.3 Hz, 2 H); 3.07-3.20 (m, 2 H); 3.25 (d, J = 11 Hz, 1 H); 4.35-4.45 (m, 2 H); 6.44 (d, J = 8.1 Hz, 1 H); 6.53 (d, J = 8.1 Hz, 1 H); 7.13 (t, J = 8.4 Hz, 2 H); 7.99-8.04 (m, 2 H) ppm.

MS (CI): 395 (M + H) +.

Example 268

4- (cis- (8a, 12a) -2-fluor-6,7,9,10,12,12a-hexahydro-5H-pyrido [4,3-b] [1,4] thiazepino [2,3, 4-hi] indole-11- (8aH) -yl) -1- (4-fluorphenyl) -1-butanone

The tratment of cis- (8a, 12a) -2-fluor-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole according to the procedure of Example 261 supplied the title compound with good performance as an oil viscous. Melting point: 226-227 ° C. performance 27%

1 H NMR (CDCl 3, 300 MHz) δ 1.50-2.20 (m, 8 H); 2.20-2.32 (m, 1 H); 2.32-2.50 (m, 1 H); 2.50-2.63 (m, 1 H); 2.63-2.78 (m, 1 H); 2.78-3.30 (m, 6 H); 3.45-3.60 (m, 1 H); 3.60-3.77 (m, 1 H); 6.57 (d, J = 7.7 Hz, 1 H); 6.67 (t, J = 6.2 Hz, 1 H); 7.13 (t, J = 7.8 Hz, 2 H); 7.97-8.02 (m, 2 H) ppm.

MS (CI): 429 (M + H +).

Example 270

cis- (6b, 10a) -8- [3- (4-fluorophenoxy) pro pil] -1,2,6b, 7,8,9,10,10a-octahydro [1,4] -oxazino [2,3 , 4-hi] pyrido [4,3-b] indole

The tratment of cis- (6b, 10a) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-b] indole according to the procedure of Example 203 provided the title compound with good performance as a liquid viscous. Yield 32%.

1 H NMR (CDCl 3, 300 MHz) δ 1.91-2.02 (m, 3 H); 2.06 (t, J = 11.4 Hz, 1 H); 2.26-2.40 (m, 2 H); 2.40-2.60 (m, 2 H); 2.65-2.80 (m, 2H); 2.80-2.95 (m, 1 H); 3.05-3.22 (m, 1 H); 3.22-3.32 (m, 2 H); 3.98 (t, J = 6.3 Hz, 2 H); 4.40-4.50 (m, 2 H); 6.60-6.65 (m, 2 H); 6.65-6.75 (m, 1 H); 6.75-6.85 (m, 2 H); 6.85-7.0 (m, 2 H) ppm.

MS (CI): 369 (M + H +).

Example 272

cis-4- (6b, 10a) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-

hi

] pyrido [4,3-

b

] indole

The treatment of benzo [b] morpholine according to the procedure of Example 4, Stage E, followed by procedure of Example 128, Stages AC, supplied the title compound as colorless crystals. Point of fusion; 100-101 ° C.

1 H NMR (CDCl 3, 300 MHz) δ 1.77-1.95 (m, 2 H); 2.15 (s, 1 H); 2.61-2.85 (m, 2H); 2.85-3.00 (m, 2 H); 3.03-3.21 (m, 2 H); 3.28-3.41 (m, 2 H); 4.40-4.51 (m, 2 H); 6.60-6.68 (m, 2 H); 6.68-6.73 (m, 1 H) ppm.

MS (CI): 217 (M + H) +.

Example 286

N

- [2- (8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -yl) ethyl] -2,4-difluorbenzamide

Stage TO

To a solution of ethanolamine (1.10 g; 15.8 mmoles) in THF at 0 ° C under N 2 was added chloride of 2,4-difluorbenzoyl (500 mg; 2.83 mmol). Mix The reaction was stirred at 0 ° C for 4 hours, then diluted with ethyl acetate (100 mL) and washed with 1 N HCl (50 mL), Saturated NaHCO3 (50 mL), and saturated NaCl (50 mL). The solution The organic was dried over MgSO4 and concentrated in vacuo to give 2,4-difluor-<i>N</i>- (2-hydroxy-ethyl) benzamide as a white solid (495 mg; 87%).

Stage B

To a solution of 2,4-difluor-<i>N</i>- (2-hydroxyethyl) benzamide (299 mg; 1.49 mmol) and triethylamine (302 mg; 2.98 mmol) in CH 2 Cl 2 under nitrogen at 0 ° C was added methanesulfonyl (335 mg; 2.98 mmol). The reaction mixture is stirred for 1 hour at 0 ° C. 1N HCl (5 mL) was added to turn off the reaction and the solution was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (100 mL), and saturated NaCl (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The purification by column chromatography (hexanes: EtOAc, 4: 1) produced methanesulfonate of 2 - [(2,4-difluorbenzoyl) amino] ethyl (300 mg; 72%) as a clear liquid.

Stage C

To a solution of (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate 2 - [(2,4-difluor-benzoyl) amino] ethyl (102 mg; 0.36 mmol) in 1.4 dioxane (0.6 mL) was added K 2 CO 3 (24 mg; 0.17 mmol) and KI (catalytic amount) and the reaction mixture was stirred at 100 ° C for 48 hours. The mixture of The reaction was diluted with CHCl3 (50 mL) and filtered. The compound of the title was isolated as a light yellow oil (43 g; 77%). after purification by means of column (CHCl3: MeOH, 99 : 1).

1 H NMR (CDCl 3) δ 1.65 (br s, 1 HOUR); 1.86-2.13 (m, 5 H); 2.39 (td, 1 H,<i>J</i> = 3.3; 11.0 Hz); 2.52-2.66 (m, 3 H); 2.72-2.78 (m, 1 H); 2.93-3.00 (m, 1 H); 3.08-3.18 (m, 2 H); 3.28-3.33 (m, 1 H); 3.49-3.59 (m, 3 H); 3.77-3.85 (m, 1 H); 6.59 (t, 1 H,<i>J</i> = 7.4 Hz); 6.82-7.03 (m, 4 H); 8.10-8.18 (m, 1 H) ppm.

Example 287

N

- [2 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) ethyl] -

N

-methylbenzamide

2- [Benzoyl (methyl) methanesulfonate was prepared amino] ethyl (987 mg; 49%) from benzoyl chloride (545 mg; 3.6 mmol) and 2- (methylamino) ethanol (1.35 g; 18 mmol) of according to the procedure of Example 286, Stages A and B. The title compound was isolated as a yellow oil according to the method of Example 286, Stage C (35 mg; 33%) from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 2- [benzoyl (methyl) methanesulfonate amino] ethyl (48 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.69-1.95 (m, 3 H); 2.01-2.19 (m, 2 H); 2.34-2.51 (m, 2 H); 2.57-2.81 (m, 2 H); 2.93-3.10 (m, 6 H); 3.25-3.58 (m, 2 H); 2.61-2.85 (m, 3 H); 6.61 (t, 1 H,<i>J</i> = 7.5 Hz); 6.94 (d, 1 H,<i>J</i> = 7.7 Hz); 7, 26-7.50 (m, 4 H) ppm.

MS (ESI): 408 (base, M + H).

Example 288

N

- [2 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) ethyl] -2-fluor-

N

-methylbenzamide

Methanesulfonate was prepared from 2 - [(2-fluorbenzoyl) (methyl) amino] ethyl (531 mg; 85%) from 2-fluorbenzoyl chloride (1.12 g; 6.4 mmol) and 2- (methylamino) ethanol (2.70 g; 32 mmoles) according to the procedure of Example 286, Stages A and B. The title compound was isolated as a yellow oil of according to the method of Example 286, Step C (35 mg; 66%) a start from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate 2 - [(2-fluorbenzoyl) (methyl) amino] ethyl (48 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.65-1.93 (m, 1 H); 2.01-2.17 (m, 3 H); 2.25-2.44 (m, 3 H); 2.54-2.91 (m, 3 H); 2.95-3.05 (m, 3 H); 3.10-3.22 (m, 3 H); 3.27-3.40 (m, 1 H); 3.45-3.90 (m, 4 H); 6.58-6.64 (m, 1 H); 6.81 (dd, 1 H, <i>J</i> = 6.6; 38.9 Hz); 6.92-6.96 (m, 1 H); 7.06-7.19 (m, 1 H); 7.19 (t, 1 H, <i>J</i> = 6.9 Hz); 7, 32-7.40 (m, 2 H) ppm.

MS (ESI): 426 (base, M + H).

Example 289

N

- [2 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) ethyl] -2,4-difluor-

N

-methylbenzamide

Methanesulfonate was prepared from 2 - [(2,4-difluorbenzoyl) (methyl) amino] ethyl (482 mg; 86%) from chloride 2,4-difluorbenzoyl (1.04 g; 5.9 mmol) and 2- (methylamino) ethanol (2.13 g; 28 mmol) according to the procedure of Example 286, Stages A and B. The compound of title was isolated as a yellow oil according to the method of Example 286, Step C (17 mg; 31%) from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate 2 - [(2,4-difluorbenzoyl) (methyl) amino] ethyl (57 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.89-2.01 (m, 2 H); 2.05-2.14 (m, 2 H); 2.38-2.52 (m, 3 H); 3.55-3.78 (m, 2 H); 2.81-2.91 (m, 1 H); 2.94-3.07 (m, 3 H); 3.10-3.19 (m, 2 H); 3.24-3.36 (m, 2 H); 3.45-3.60 (m, 1 H); 3.61-3.85 (m, 3 H); 6.61 (t, 1 H,<i>J</i> = 7.5 Hz); 66.74-6.96 (m, 4 H); 7, 33-7.38 (m, 1 H) ppm.

Example 290

N

- [2 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) ethyl] -4-fluor-

N

-methylbenzamide

Methanesulfonate was prepared from 2 - [(4-fluorbenzoyl) (methyl) amino] ethyl (482 mg; 86%) from 4-fluorbenzoyl chloride (1.12 g; 3.2 mmol) and 2- (methylamino) ethanol (2.70 g; 16 mmoles) according to the procedure of Example 286, Stages A and B. The title compound was isolated as a yellow oil of according to the method of Example 286, Step C (37 mg; 69%) a start from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate 2 - [(4-fluorbenzoyl) (methyl) amino] ethyl (53 mg; 0.24 mmol).

1 H NMR (CDCl 3,) δ 1.73-1.95 (m, 3 H); 1.98-2.21 (m, 3 H); 2.35-2.55 (m, 3 H); 3.60-3.78 (m, 1 H); 2.86-2.97 (m, 1 H); 2.98-3.21 (m, 5 H); 3.27-3.45 (m, 1 H); 3.52-3.59 (m, 2 H); 3.72-3.86 (m, 2 H); 6.62 (t, 1 H, <i>J</i> = 7.5 Hz); 6.71-6.83 (m, 1 H); 6.95 (dd, 1 H,<i>J</i> = 1.1; 7.8 Hz); 7.08 (t, 2 H,<i>J</i> = 8.6 Hz); 7, 30-7.50 (m, 2 H) ppm.

Example 291

(8a

S

, 12th

R

)-11-[3-(1

H

-1,2,3-benzotriazol-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Stage TO

To a solution of benzotriazole (303 mg; 2.54 mmol) and NaOH powder (101 mg; 2.52 mmol) in DMSO was added 1-Bromo-3-Chlorine Propane (437 mg; 2.77 mmol). The reaction mixture was stirred. for 16 hours at 20 ° C. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H2O (100 mL) and saturated NaCl (100 mL), dried over MgSO4 and concentrated in vacuo. The column purification (hexanes: EtOAc, 4: 1) produced 1- (3-Chloropropyl) -1<i>H</i>-1,2,3-benzotriazole (167 mg; 34%). The title compound was prepared according to the Example 286, Step C as a yellow oil (21 mg; 42%) from from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>- beep [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (3-Chloropropyl) -1<i>H</i>-1,2,3-benzotriazole (48 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.88-1.98 (m, 3 H); 1.99-2.18 (m, 2 H); 2.20-2.41 (m, 5 H); 2.51-2.60 (m, 1 H); 2.64-2.71 (m, 1 H); 2.89-3.00 (m, 1 H); 3.03-3.13 (m, 2 H); 3.21-3.27 (m, 1 H); 3.47-3.60 (m, 1 H); 3.76-3.88 (m, 1 H); 4.73 (t, 2 H,<i>J</i> = 6.6 Hz); 6.61 (t, 1 H,<i>J</i> = 7.4 Hz); 6.84 (d, 1 H,<i>J</i> = 6.6 Hz); 6.94 (dd, 1 H,<i>J</i> = 1.1; 8.1 Hz); 7.37 (td, 1 H, <i>J</i> = 1.1; 7.4 Hz); 7.49 (td, 1 H,<i>J</i> = 1.1; 7.8 Hz); 7.57 (d, 1 H, <i>J</i> = 8.0 Hz); 8.07 (d, 1 H,<i>J</i>= 8.4 Hz) ppm.

Example 292

(8a

S

, 12th

R

)-11-[3-(2

H

-1,2,3-benzotriazol-2-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Benzotriazole (303 mg; 2.54 mmol) were used and 1-bromo-3-chloro propane (437 mg; 2.77 mmol) according to the method of Example 291, Stage A, to obtain 2- (3-chloropropyl) -1<i>H</i>-1,2,3-benzotriazole (182 mg; 37%). The title compound was prepared according to the Example 286, Step C as a yellow oil (20 mg; 40%) from from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 2- (3-chloropropyl) -1<i>H</i>-1,2,3-benzotriazole (48 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.84-1.94 (m, 3 H); 1.99-2.20 (m, 2 H); 2.25-2.52 (m, 5 H); 2.64-2.72 (m, 1 H); 2.74-2.82 (m, 1 H); 2.88-3.00 (m, 1 H); 3.02-3.18 (m, 2 H); 3.22-3.28 (m, 1 H); 3.51-3.61 (m, 1 H); 3.74-3.85 (m, 1 H); 4.80 (t, 2 H,<i>J</i> = 6.7 Hz); 6.61 (t, 1 H,<i>J</i> = 7.5 Hz); 6.92 (dd, 2 H, <i>J</i> = 6.6; 24.9 Hz); 7.35-7.41 (m, 2 H); 7.83-7.85 (m, 2 H) ppm.

Example 293

(8a

S

, 12th

R

)-11-{[(2

S

) -1-benzoylpyrrolidinyl] methyl} -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Methanesulfonate was prepared from [(two<i>S</i>) -1-benzoylpyrrolidinyl] methyl (94 mg; 50%) from (<i>S</i>) -2-pyrrolidin-methanol (150 mg; 1.48 mmol) and benzoyl chloride (208 mg; 1.48 mmol) as in Example 286, Stages AB. The compound of the title was isolated as a yellow oil (52 mg; 100%) of according to the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate [(two<i>S</i>) -1-benzoylpyrrolidinyl] methyl (55 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.26 (s, 1 H); 1.58-2.30 (m, 8 H); 2.35-2.86 (m, 3 H); 2.90-3.30 (m, 4 H); 3.37-3.61 (m, 4 H); 3.75-3.86 (m, 2 H); 4.38-4.50 (m, 1 H); 6.55-6.96 (m, 2 H); 7.31-7.96 (m, 6 H) ppm.

MS (ESI): 434 (base, M + H).

Example 294

(8a

S

, 12th

R

)-11-{[(2

R

) -1-benzoylpyrrolidinyl] methyl} -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Methanesulfonate was prepared from [(two<i>R</i>) -1-benzoylpyrrolidinyl] methyl (98 mg; 52%) from (<i>R</i>) -2-pyrrolidino-methanol (150 mg; 1.48 mmol) and benzoyl chloride (208 mg; 1.48 mmol) as in Example 286, Stages AB. The compound of the title was isolated as a yellow oil (36 mg; 68%) according with the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate [(two<i>R</i>) -1-benzoylpyrrolidinyl] methyl (55 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.58-2.27 (m, 12 H); 2.64-3.30 (m, 4 H); 3.49-3.61 (m, 3 H); 3.72-3.84 (m, 2 H); 6.60 (td, 1 H,<i>J</i> = 1.9; 7.5 Hz); 6.93 (d, 1 H,<i>J</i> = 7.5 Hz); 7.31-7.55 (m, 6 H) ppm.

MS (ESI): 434 (base, M + H).

Example 295

(8a

S

, 12th

R

)-11-{[(2

S

) -1- (4-fluorbenzoyl) pyrrolidinyl] methyl} -6,7,8a, 9,10,11,12,12a-octahydro-5

H

- beep [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Methanesulfonate was prepared from [(two<i>S</i>) -1- (4-fluorbenzoyl) pyrrolidinyl] methyl (152 mg; 68%) from (<i>S</i>) -2-pyrrolidino-methanol (155 mg; 1.53 mmol) and chloride 4-fluor-benzoyl (235 mg; 1.48 mmoles) as in Example 286, Stages AB. He title compound was isolated as a yellow oil (24 mg; 44%) according to the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate [(two<i>S</i>) -1- (4-fluorbenzoyl) pyrrolidinyl] methyl (59 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.63 (s, 2 H); 1.70-2.20 (m, 10 H); 2.67-3.31 (m, 5 H); 3.37-3.55 (m, 4 H); 3.71-3.82 (m, 2 H); 6.61 (td, 1 H, <i>J</i> = 2.0; 7.5 Hz); 6.93 (d, 1 H,<i>J</i> = 7.7 Hz); 7.03-7.18 (m, 3 H); 7.45-7.56 (m, 2 H) ppm.

MS (ESI): 452 (base, M + H).

Example 296

(8a

S

, 12th

R

)-11-{[(2

R

) -1- (4-fluorbenzoyl) pyrrolidinyl] methyl} -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Methanesulfonate was prepared from [(two<i>R</i>) -1- (4-fluorbenzoyl) pyrrolidinyl] methyl (147 mg; 80%) from (<i>R</i>) -2-pyrrolidino-methanol (155 mg; 1.53 mmol) and chloride 4-fluor-benzoyl (235 mg; 1.48 mmoles) as in Example 286, Stages AB. He title compound was isolated as a yellow oil (27 mg; 49%) according to the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate [(two<i>R</i>) -1- (4-fluorbenzoyl) pyrrolidinyl] methyl (59 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.59-2.21 (m, 11 H); 2.94-3.35 (m, 4 H); 3.47-3.60 (m, 4 H); 3.73-3.84 (m, 2 H); 4.39-4.47 (m, 1 H); 4.77-4.02 (m, 1 H); 6.61 (td, 1 H,<i>J</i> = 1.8; 7.4 Hz); 6.83 (d, 1 H,<i>J</i> = 9.5 Hz); 7.01-7.14 (m, 3 H); 7.47-7.64 (m, 2 H) ppm.

Example 297

(8a

S

, 12th

R

)-11-[2-(1

H

-1,2,3-benzotriazol-1-yl) ethyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Was prepared 1- (2-Chloroethyl) -1<i>H</i>-1,2,3-benzotriazole (164 mg; 36%) from benzotriazole (300 mg; 2.52 mmol) and 1-Bromo-2-Chlorine ethane (397 mg; 2.77 mmol) according to the procedure of Example 291. The title compound was isolated as an oil. yellow (48 mg; 98%) according to the method of Example 286, Stage C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (2-Chloroethyl) -1<i>H</i>-1,2,3-benzotriazole (44 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.69-2.20 (m, 4 H); 2.39-2.45 (m, 1 H); 2.61-2.68 (m, 1 H); 2.72-2.81 (m, 1 H); 2.84-3.01 (m, 2 H); 3.03-3.12 (m, 2 H); 3.20-3.27 (m, 1 H); 3.49-3.60 (m, 1 H); 3.74-3.84 (m, 1 H); 4.06 (t, 1 H, <i>J</i> = 6.7 Hz); 4.76 (t, 1 H,<i>J</i>= 6.6 Hz); 4.96 (t, 1 H,<i>J</i> = 6.2 Hz); 6.61 (t, 1 H,<i>J</i>= 7.5 Hz); 6.82 (d, 1 H,<i>J</i> = 7 Hz); 6.95 (dd, 1 H, <i>J</i>= 1.1; 7.7 Hz); 7.34-7.62 (m, 3 H); 8.08 (t, 1 H,<i>J</i> = 7.6 Hz) ppm.

Example 298

(8a

S

, 12th

R

)-11-[2-(2

H

-1,2,3-benzotriazol-2-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Was prepared 2- (3-chloropropyl) -1<i>H</i>-1,2,3-benzotriazole (200 mg; 44%) from benzotriazole (300 mg; 2.52 mmol) and 1-Bromo-3-Chlorine Propane (397 mg; 2.77 mmol) according to the procedure of Example 291. The title compound was isolated as an oil. yellow (26 mg; 54%) according to the method of Example 286, Stage C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 2- (3-chloropropyl) -1<i>H</i>-1,2,3-benzotriazole (44 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.81-1.93 (m, 2 H); 1.96-2.14 (m, 3 H); 2.41 (td, 1 H,<i>J</i> = 3.7; 11.7 Hz); 2.64-2.72 (m, 1 H); 2.80-2.90 (m, 1 H); 2.92-3.00 (m, 1 H); 3.02-3.16 (m, 4 H); 3.21-3.26 (m, 1 H); 3.51-3.62 (m, 1 H); 3.78-3.86 (m, 1 H); 4.85 (t, 2 H,<i>J</i> = 7.0 Hz); 6.61 (t, 1 H, <i>J</i> = 7.5 Hz); 6.83 (d, 1 H,<i>J</i> = 6.6 Hz); 6.94 (dd, 2 H, <i>J</i> = 1.2; 8.1 Hz); 7.36-7.41 (m, 2 H); 7.84-7.88 (m, 2 H) ppm.

Example 299

(8a

S

, 12th

R

) -11- [3- (3,4-dihydro-1 (2

H

) -quinolinyl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

To a solution of 1,2,3,4-tetrahydroquinoline (505 mg; 3.79 mmol) and 1-Bromo-3-Chlorine Propane (1.77 g; 11 mmol) in 1,4-dioxane (6 mL) is Et3N (1.90 g; 19 mmol) was added. The reaction mixture is stirred at 70 ° C for 17 hours, and turned off by adding H2O (2 mL). The reaction was diluted with Et2O (100 mL) and was washed with brine (100 mL), dried over MgSO4 and concentrated under vacuum Purification by column chromatography (hexanes: EtOAc, 49: 1) allowed to obtain 1- (3-Chloropropyl) -1,2,3,4-tetrahydroquinoline (187 mg; 24%) as a colorless oil. The title compound is isolated as a yellow oil (22 mg; 43%) according to the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (3-chloropropyl) -1,2,3,4-tetrahydroquinoline (51 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.77-2.19 (m, 10 H); 2.24-2.41 (m, 2 H); 2.61-2.69 (m, 1 H); 2.75-2.84 (m, 3 H); 2.91-3.02 (m, 1 H); 3.10-3.21 (m, 2 H); 3.26-3.34 (m, 5 H); 3.52-3.61 (m, 1 H); 3.77-3.96 (m, 1 H); 6.49-6.65 (m, 3 H); 6.85 (d, 1 H,<i>J</i> = 7.3 Hz); 6.92-6.96 (m, 2 H); 6.99-7.05 (m, 1 H) ppm.

Example 300

(8a

S

, 12th

R

)-11-[(3

AND

) -4- (4-fluorphenyl) -3-pentenyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Stage TO

To a solution of cyclopropyl-4-fluorphenyl ketone (523 mg; 3.19 mmol) in THF (10 mL) at 0 ° C under N2 was added 3M methyl magnesium bromide (1.7 mL; 5.1 mmol) in Et2O. After 90 minutes at 0 ° C, the reaction was quenched by addition. brine (10 mL) and diluted with Et2O (100 mL). The solution Organic was washed with saturated NaHCO3 (100 mL) and brine (100 mL) Purification by column (hexanes: EtOAc, 9: 1) allowed to obtain 1-cyclopropyl-1- (4-fluorphenyl) ethanol (512 mg; 89%) as a colorless oil.

Stage B

It got hot 1-cyclopropyl-1- (4-fluorphenyl) ethanol (307 mg; 1.70 mmol) in a solution of 1 N HCl in alcohol Isopropyl (3.6 mL) at 60 ° C for 1 hour. Reaction mixture it was then concentrated in vacuo, and purification by means of column chromatography allowed to obtain 1 - [(1<i>AND</i>) -4-Chloro-1-methyl-1-butenyl] -4-fluorbenzene (282 mg; 84%) as a colorless oil. The title compound is isolated as a yellow oil (36 mg; 70%) according to the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1 - [(1<i>AND</i>) -4-Chloro-1-methyl-1-butenyl] -4-fluorbenzene (48 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.62 (br s, 1 HOUR); 1.90-2.20 (m, 9 H); 2.31-2.44 (m, 5 H); 2.71-2.80 (m, 1 H); 2.81-2.89 (m, 1 H); 2.92-3.00 (m, 1 H); 3.04-3.13 (m, 1 H); 3.17-3.24 (m, 2 H); 3.27-3.31 (m, 1 H); 3.51-3.63 (m, 1 H); 3.80-3.91 (m, 1 H); 5.64-5.73 (m, 1 H); 6.62 (t, 1 H,<i>J</i> = 7.5 Hz); 6.87 (d, 1 H,<i>J</i> = 6.6 Hz); 6.91-7.00 (m, 3 H); 7.29-7.34 (m, 2 H) ppm.

Example 301

(8a

S

, 12th

R

) -11- [2- (2,3-dihydro-1

H

-inden-2-yl) ethyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Stage TO

To a suspension of NaH (400 mg; 17 mmol) in DME (25 mL) at 20 ° C under N 2 was added phosphonoacetate of triethyl (3.39 g; 15 mmol). The reaction mixture was stirred. for 45 minutes To that white solution was added a solution of 2-indanone (2.00 g; 15 mmol) in DME (5 mL), keeping the temperature below 25ºC. Reaction mixture It was stirred for 30 minutes and then quenched with H2O (5 mL). The reaction mixture was extracted using Et2O (3 x 100 mL). The organic solution was then washed with H2O (200 mL), Saturated NaHCO3 and concentrated in vacuo. It was isolated 1,3-dihydro-2<i>H</i>-inden-2-ylidenacetate ethyl (2.04 g; 67%) as a yellow oil.

Stage B

To a solution of 1,3-dihydro-2<i>H</i>-inden-2-ylidenacetate of ethyl (302 mg; 1.49 mmol) in EtOAc (10 mL) Pd / C was added 5% (76 mg) and H2 was bubbled through the suspension for 20 hours The suspension was then filtered through Celite and the organic solution was concentrated in vacuo. It was isolated 2,3-dihydro-1<i>H</i>-inden-2-ilacetate ethyl (285 mg; 94%) as a colorless oil without purification.

Stage C

To a solution of 2,3-dihydro-1<i>H</i>-inden-2-ilacetate of ethyl (285 mg; 1.39 mmol) in Et2O (5 mL) at 0 ° C under N 2 LAH (53 mg; 1.39 mmol) was added. After stirring for 40 minutes at 0 ° C, 0.4 mL of H2O was added to turn off the reaction. The reaction mixture was diluted with EtOAc (100 mL) and was MgSO4 added with stirring. The reaction mixture was filtered. then and concentrated in vacuo until an oil remained transparent. It was isolated 2- (2,3-dihydro-1<i>H</i>-inden-2-yl) ethanol Without other purification.

Methanesulfonate was isolated from 2- (2,3-dihydro-1<i>H</i>-inden-2-yl) ethyl (128 mg; 98%) as a clear oil by the method of Example 286, Stage B from 2- (2,3-dihydro-1<i>H</i>-inden-2-yl) ethanol (88 mg; 0.54 mmol). The title compound was isolated as an oil. yellow (28 mg; 61%) according to the method of Example 286, Stage C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate 2- (2,3-dihydro-1<i>H</i>-inden-2-yl) ethyl (59 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.65-1.79 (m, 3 H); 1.82-1.94 (m, 3 H); 2.00-2.21 (m, 2 H); 2.24-2.35 (m, 1 H); 2.36-2.51 (m, 2 H); 2.57-2.78 (m, 3 H); 2.77-2.85 (m, 1 H); 2.89-2.99 (m, 1 H); 3.02-3.14 (m, 3 H); 3.17-3.22 (m, 1 H); 3.28-3.32 (m, 1 H); 3.57-3.63 (m, 1 H); 3.80-3.92 (m, 1 H); 6.62 (t, 1 H, <i>J</i> = 7.5 Hz); 6.86 (d, 1 H,<i>J</i> = 6.6 Hz); 6.95 (dd, 1 H,<i>J</i> = 1.1; 7.7 Hz); 7.10-7.19 (m, 4 H) ppm.

Example 302

4 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-aminophenyl) -1-butanone

Stage TO

To a solution of BCl 3 -Me 2 S (2.12 g; 12 mmol) in benzene (10 mL) under N2 and cooling with ice was added a solution of anlina (1.00 g; 11 mmol) in benzene (10 mL). The same stirred for 30 minutes and added 4-chlorobutyronitrile (1.33 g; 12.8 mmol), followed immediately from the addition of AlCl 3 (1.57 g; 12 mmol) in a portion. The reaction mixture was then refluxed. for 16 hours The reaction mixture was cooled to 0 ° C and added dropwise 2N HCl (16 mL), and then heated to 80 ° C and stirred for 1 hour. The reaction mixture was extracted with CHCl3 (3 x 100 mL), washed with H2O (100 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo. Purification by means column chromatography supplied 1- (2-aminophenyl) -4-chloro-1-butanone as a yellow solid (394 mg; 19%).

Stage B

The title compound was isolated as an oil. yellow (19 mg; 37%) according to the method of Example 286, Stage C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (48 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.85-2.21 (m, 7 H); 2.23-2.37 (n, 1 H); 2.37-2.44 (m, 2 H); 2.63-2.70 (m, 1 H); 2.71-2.82 (m, 1 H); 2.94-3.16 (m, 5 H); 3.24-3.29 (m, 1 H); 3.53-3.62 (m, 1 H); 3.78-3.86 (m, 1 H); 6.26 (br s, 2 H); 6.59-6.67 (m, 3 H); 6.85 (d, 1 H, <i>J</i> = 7.4 Hz); 6.94 (dd, 1 H,<i>J</i> = 1.1; 8.1 Hz); 7.23-7.29 (m, 1 H); 7.77 (dd, 1 H,<i>J</i>= 1.5; 8.4 Hz) ppm.

Example 303

4 - ((8a

R

, 12th

S

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-aminophenyl) -1-butanone

The title compound was isolated as an oil. yellow (45 mg; 18%) according to the method of Example 286, Stage C from (8a<i>R</i>, 12th<i>S</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (150 mg; 0.61 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (241 mg; 1.2 mmol).

1 H NMR (CDCl 3) δ 1.85-2.21 (m, 7 H); 2.23-2.37 (n, 1 H); 2.37-2.44 (m, 2 H); 2.63-2.70 (m, 1 H); 2.71-2.82 (m, 1 H); 2.94-3.16 (m, 5 H); 3.24-3.29 (m, 1 H); 3.53-3.62 (m, 1 H); 3.78-3.86 (m, 1 H); 6.26 (br s, 2 H); 6.59-6.67 (m, 3 H); 6.85 (d, 1 H, <i>J</i> = 7.4 Hz); 6.94 (dd, 1 H,<i>J</i> = 1.1; 8.1 Hz); 7.23-7.29 (m, 1 H); 7.77 (dd, 1 H,<i>J</i> = 1.5; 8.4 Hz) ppm.

Example 304

4 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-amino-5-fluorphenyl) -1-butanone

It was obtained 1- (2-amino-5-fluorphenyl) -4-chloro-1-butanone (462 mg; 24%) as a yellow solid according to the procedure of Example 302, Stage A, from 4-fluoraniline (1.00 g; 9.0 mmol). The compound of the title was isolated as a yellow oil (13 mg; 25%) according with the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (2-amino-5-fluorphenyl) -4-chloro-1-butanone (53 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.83-2.20 (m, 7 H); 2.24-2.42 (m, 3 H); 2.62-2.72 (m, 1 H); 2.74-2.83 (m, 1 H); 2.87-3.00 (m, 3 H); 3.02-3.18 (m, 2 H); 3.24-3.30 (m, 1 H); 3.51-3.63 (m, 1 H); 3.78-3.87 (m, 1 H); 6.12 (br s, 2 H); 6.57-6.63 (m, 2 H); 6.85 (d, 1 H, <i>J</i> = 6.6 Hz); 6.94 (dd, 1 H,<i>J</i> = 1.1; 7.7 Hz); 7.01-7.08 (m, 1 H); 7.47 (dd, 1 H,<i>J</i> = 2.7; 10.1 Hz) ppm.

Example 305

4 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-amino-3-fluorphenyl) -1-butanone

It was obtained 1- (2-amino-3-fluorphenyl) -4-chloro-1-butanone (238 mg; 12%) as a yellow solid according to the procedure of Example 302, Stage A, from 2-fluoraniline (1.00 g; 9.0 mmol). The compound of the title was isolated as a yellow oil (12 mg; 23%) according with the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (2-amino-3-fluorphenyl) -4-chloro-1-butanone (53 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.87-2.19 (m, 7 H); 2.24-2.45 (m, 3 H); 2.63-2.69 (m, 1 H); 2.72-2.81 (m, 1 H); 2.93-3.15 (m, 5 H); 3.24-3.30 (m, 1 H); 3.50-3.61 (m, 1 H); 3.78-3.86 (m, 1 H); 6.32 (br s, 2 H); 6.55-6.64 (m, 2 H); 6.84 (d, 1 H,<i>J</i> = 7.4 Hz); 6.94 (dd, 1 H,<i>J</i> = 1.1; 7.7 Hz); 7.07-7.14 (m, 1 H); 7.56 (d, 1 H,<i>J</i> = 8.4 Hz) ppm.

Example 306

4 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-amino-4-chlorophenyl) -1-butanone

It was obtained 1- (2-amino-4-chlorophenyl) -4-chloro-1-butanone (586 mg; 32%) as a yellow solid according to the procedure of Example 302, Stage A, from 3-Chloroaniline (1.00 g; 7.9 mmol). The compound of the title was isolated as a yellow oil (10 mg; 19%) according with the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (2-amino-4-chlorophenyl) -4-chloro-1-butanone (53 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.83-2.17 (m, 7 H); 2.19-2.41 (m, 3 H); 2.57-2.61 (m, 1 H); 2.68-2.77 (m, 1 H); 2.83-2.92 (m, 3 H); 2.96-3.13 (m, 2 H); 3.20-3.26 (m, 1 H); 3.45-3.58 (m, 1 H); 3.71-3.82 (m, 1 H); 6.28 (br s, 2 H); 6.51-6.58 (m, 3 H); 6.78 (d, 1 H, <i>J</i> = 6.6 Hz); 6.87 (dd, 1 H,<i>J</i> = 1.2; 7.9 Hz); 7.62 (d, 1 H,<i>J</i> = 8.8 Hz) ppm.

Example 307

4 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-amino-4-hydroxyphenyl) -1-butanone

It was obtained 1- (2-amino-4-hydroxyphenyl) -4-chloro-1-butanone (100 mg; 5%) as a yellow solid according to the procedure of Example 302, Stage A, from meta-anisidine (1.00 g; 8.2 mmol). The compound of the title was isolated as a yellow oil (5 mg; 9%) according with the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (2-amino-4-hydroxyphenyl) -4-chloro-1-butanone (56 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.90-2.19 (m, 6 H); 2.31-2.48 (m, 3 H); 2.68-2.77 (m, 1 H); 2.78-2.84 (m, 1 H); 2.89-3.00 (m, 5 H); 3.02-3.18 (m, 1 H); 3.24-3.31 (m, 1 H); 3.54-3.61 (m, 1 H); 3.78-3.87 (m, 1 H); 4.21 (br s, 2 H); 6.11-6.16 (m, 2 H); 6.61 (t, 1 H, <i>J</i> = 7.5 Hz); 6.85 (d, 1 H,<i>J</i> = 6.6 Hz); 6.94 (dd, 1 H, <i>J</i> = 1.1; 7.7 Hz); 7.56 (d, 1 H,<i>J</i> = 8.4 Hz); 12.93 (br s; 1 H) ppm.

Example 308

4 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-amino-4-bromophenyl) -1-butanone

It was obtained 1- (2-amino-4-bromophenyl) -4-chloro-1-butanone (558 mg; 17%) as a yellow solid according to the procedure of Example 302, Stage A, from 3-Bromoaniline (2.00 g; 11.7 mmol). The compound of the title was isolated as a yellow oil (21 mg; 35%) according with the method of Example 286, Step C from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (2-amino-4-bromophenyl) -4-chloro-1-butanone (68 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.89-2.22 (m, 8 H); 2.24-2.45 (m, 3 H); 2.61-2.70 (m, 1 H); 2.73-2.81 (m, 1 H); 2.91-3.01 (m, 2 H); 3.04-3.17 (m, 2 H); 3.24-3.29 (m, 1 H); 3.51-3.62 (m, 1 H); 3.78-3.87 (m, 1 H); 6.33 (br s, 2 H); 6.61 (t, 1 H,<i>J</i> = 7.5 Hz); 6.75 (dd, 1 H, <i>J</i> = 2.0; 8.6 Hz); 6.81-6.87 (m, 2 H); 6.94 (dd, 1 H,<i>J</i> = 1.1; 7.7 Hz); 7.60 (d, 1 H, <i>J</i>= 8.4 Hz) ppm.

Example 309

(8a

S

, 12th

R

)-11-[3-(1

H

-indazol-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

To a suspension of 1- (2-aminophenyl) -4-chloro-1-butanone (508 mg; 2.6 mmol) in concentrated HCl (3.5 mL) at -5 ° C a solution of NaNO2 (193 mg; 2.8 mmol) was added in H2O (0.75 mL), and the reaction mixture was stirred for 1 hour. A solution of SnCl2 -2H2O was added (1.37 g; 6.07 mmol) in concentrated HCl (1.9 mL) at -5 ° C to the solution, and it was stirred for 1 hour refrigerating with ice. The reaction was quenched with H2O and extracted with Et 2 O (100 mL). The organic solution was washed with H2O (50 mL) and brine (50 mL), dried over MgSO4 and concentrated to empty. Purification by column chromatography supply 3- (3-chloropropyl) -1<i>H</i>-indazol (126 mg; 25%) as a yellow solid. The title compound is isolated as a yellow oil (38 mg; 77%) according to the method of Example 286, Step C, from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 3- (3-chloropropyl) -1<i>H</i>-indazol (44 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.83-2.19 (m, 7 H); 2.23-2.35 (m, 1 H); 2.43-2.54 (m, 2 H); 2.72-2.79 (m, 1 H); 2.81-2.88 (m, 1 H); 2.92-3.11 (m, 4 H); 3.12-3.21 (m, 1 H); 3.24-3.29 (m, 1 H); 3.51-3.62 (m, 1 H); 3.80-3.92 (m, 1 H); 6.61 (t, 1 H,<i>J</i> = 7.5 Hz); 6.84 (d, 1 H,<i>J</i> = 6.6 Hz); 6.94 (dd, 1 H, <i>J</i> = 1.1; 7.7 Hz); 7.11-7.16 (m, 2 H); 7.34-7.48 (m, 2 H); 7.70 (d, 1 H, <i>J</i> = 8.0 Hz) ppm.

Example 310

(8a

S

, 12th

R

) -11- [3- (5-fluor-1

H

-indazol-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

It was obtained 3- (3-chloropropyl) -6-fluor-1<i>H</i>-indazol (91 mg; 46%) according to the procedure of Example 309 a start from 1- (2-amino-5-fluorphenyl) -4-chloro-1-butanone (200 mg; 0.93 mmol). The title compound was isolated as a yellow oil (35 mg; 66%) according to the method of Example 286, Stage C, from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 3- (3-chloropropyl) -6-fluor-1<i>H</i>-indazol (52 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.92-2.15 (m, 7 H); 2.34-2.42 (m, 1 H); 2.42-2.55 (m, 2 H); 2.72-3.10 (m, 6 H); 3.20-3.34 (m, 2 H); 3.50-3.61 (m, 1 H); 3.77-3.86 (m, 1 H); 6.61 (t, 1 H,<i>J</i> = 7.5 Hz); 6.84 (d, 1 H, <i>J</i> = 7.4 Hz); 6.95 (dd, 1 H,<i>J</i> = 1.1; 7.7 Hz); 7.13 (td, 1 H,<i>J</i> = 2.3; 8.8 Hz); 7.29-7.39 (m, 2 H) ppm.

Example 311

(8a

S

, 12th

R

) -11- [3- (7-fluor-1

H

-indazol-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

It was obtained 3- (3-chloropropyl) -7-fluor-1<i>H</i>-indazol (14 mg; 10%) according to the procedure of Example 309 a start from 1- (2-amino-3-fluorphenyl) -4-chloro-1-butanone (136 mg; 0.63 mmol). The title compound was isolated as a yellow oil (10 mg; 66%) according to the method of Example 286, Stage C, from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (17 mg; 0.07 mmol) and 3- (3-chloropropyl) -7-fluor-1<i>H</i>-indazol (14 mg; 0.07 mmol).

1 H NMR (CDCl 3) δ 1.81-2.11 (m, 7 H); 2.24-3.33 (m, 1 H); 2.42-2.54 (m, 2 H); 2.67-3.04 (m, 6 H); 3.18-3.26 (m, 2 H); 3.42-3.57 (m, 1 H); 3.71-3.85 (m, 1 H); 6.54 (d, 1 H,<i>J</i> = 7.5 Hz); 6.77 (dd, 1 H,<i>J</i> = 1.1; 7.0 Hz); 6.88 (dd, 1 H,<i>J</i> = 1.3; 7.9 Hz); 6.94-7.01 (m, 2 H); 7.37-7.41 (m, 1 H) ppm.

Example 312

(8a

S

, 12th

R

) -11- [3- (6-chloro-1

H

-indazol-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

- beep [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

It was obtained 3- (3-chloropropyl) -6-chloro-1<i>H</i>-indazol (107 mg; 54%) according to the procedure of Example 309 a start from 1- (2-amino-4-chlorophenyl) -4-chloro-1-butanone (202 mg; 0.87 mmol). The title compound was isolated as a yellow oil (37 mg; 69%) according to the method of Example 286, Stage C, from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 3- (3-chloropropyl) -6-chloro-1<i>H</i>-indazol (56 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.93-2.20 (m, 8 H); 2.37-3.38 (m, 1 H); 2.41-2.48 (m, 2 H); 2.69-2.77 (m, 1 H); 2.79-2.86 (m, 1 H); 2.91-3.10 (m, 4 H); 3.16-3.23 (m, 1 H); 3.26-3.31 (m, 1 H); 3.50-3.61 (m, 1 H); 3.77-3.85 (m, 1 H); 6.61 (t, 1 H,<i>J</i> = 7.5 Hz); 6.89 (d, 1 H,<i>J</i> = 6.6 Hz); 6.94 (dd, 1 H, <i>J</i> = 1.1; 7.7 Hz); 7.09 (dd, 1 H,<i>J</i> = 1.7; 7.8 Hz); 7.42 (d, 1 H, <i>J</i> = 1.1 Hz); 7.61 (d, 1 H,<i>J</i> = 8.4 Hz) ppm.

Example 313

(8a

S

, 12th

R

) -11- [3- (6-bromo-1

H

-indazol-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

- beep [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

It was obtained 3- (3-Chloropropyl) -6-Bromo-1<i>H</i>-indazol (228 mg; 74%) according to the procedure of Example 309 a start from 1- (2-amino-4-bromophenyl) -4-chloro-1-butanone (311 mg; 1.1 mmol). The title compound was isolated as a yellow oil (40 mg; 69%) according to the method of Example 286, Stage C, from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.07 mmol) and 3- (3-Chloropropyl) -6-Bromo-1<i>H</i>-indazol (67 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.94-2.17 (m, 7 H); 2.34-2.41 (m, 1 H); 2.45-2.56 (m, 2 H); 2.73-2.81 (m, 1 H); 2.83-2.90 (m, 1 H); 2.90-3.11 (m, 4 H); 3.24-3.35 (m, 2 H); 3.49-3.61 (m, 1 H); 3.77-3.89 (m, 1 H); 6.61 (t, 1 H,<i>J</i> = 7.5 Hz); 6.84 (d, 1 H,<i>J</i>= 7.4 Hz); 6.95 (d, 1 H,<i>J</i> = 7.7 Hz); 7.20-7.26 (m, 1 H); 7.53-7.60 (m, 1 H) ppm.

Example 314

4 - ((8a

S

, 12th

R

) -6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2- (methylamino) phenyl) -1-butanone

It was obtained 1- (2-methylaminophenyl) -4-chloro-1-butanone (886 mg; 22%) as a yellow solid according to the procedure of Example 302, Stage A, from<i>N</i>-methylaniline (2.00 g; 18 mmol). He title compound was isolated as a yellow oil (21 mg; 45%) according to the method of Example 286, Step C, from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (2-methylaminophenyl) -4-chloro-1-butanone (52 mg; 0.24 mmol).

1 H NMR (CDCl 3) δ 1.91-2.23 (m, 6 H); 2.24-3.36 (m, 1 H); 2.37-2.44 (m, 2 H); 2.63-2.71 (m, 1 H); 2.75-2.82 (m, 1 H); 2.89-3.17 (m, 9 H); 3.24-3.30 (m, 1 H); 3.47-3.62 (m, 1 H); 3.79-3.87 (m, 1 H); 6.56-6.63 (m, 2 H); 6.69 (d, 1 H,<i>J</i> = 8.4 Hz); 6.84 (d, 1 H,<i>J</i> = 7.0 Hz); 6.94 (dd, 1 H,<i>J</i> = 1.1; 7.7 Hz); 7.35-7.41 (m, 1 H); 7.80 (dd, 1 H, <i>J</i> = 8.6 Hz); 8.81 (br s, 1 H) ppm.

Example 315

(8a

S

, 12th

R

) -11- [3- (1-benzothien-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

The title compound was isolated as an oil. yellow (49 mg; 52%) according to the method of Example 286, Stage C, from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (55 mg; 0.23 mmol) and methanesulfonate 3- (1-benzothien-3-yl) propyl (122 mg; 0.45 mmol).

1 H NMR (CDCl 3) δ 1.97-2.20 (m, 7 H); 2.31-2.41 (m, 1 H); 2.44-2.56 (m, 2 H); 2.71-2.79 (m, 1 H); 2.81-2.99 (m, 4 H); 3.04-3.11 (m, 1 H); 3.19-3.35 (m, 2 H); 3.50-3.62 (m, 1 H); 3.79-3.88 (m, 1 H); 6.62 (t, 1 H, <i>J</i> = 7.5 Hz); 6.85 (d, 1 H,<i>J</i>= 7.3 Hz); 6.95 (dd, 1 H,<i>J</i> = 1.3; 7.9 Hz); 7.11 (s, 1 H); 7.34-7.41 (m, 2 H); 7.74-7.78 (m, 1 H); 7.85 (dd, 1 H,<i>J</i> = 1.5; 6.2 Hz) ppm.

Example 355

2- [2 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) ethyl] [1,2,4] triazolo [4,3, -

to

] pyridin-3 (2

H

) -one

Stage TO

To a solution of [1,2,4] triazolo [4,3, -<i>to</i>] pyridin-3 (2<i>H</i>) -one (200 mg; 1.47 mmol) in DMF (7.0 mL) NaH (43 mg; 1.76 mmol) at 0 ° C under N2. The reaction mixture was stirred. for 30 minutes at 0 ° C, and then added dropwise 1-Bromo-2-Chloroethane (424 mg; 2.96 mmol). The reaction mixture was stirred for 15 hours at 20 ° C and then turned off by adding H2O and then extracted with CHCl3. The combined organic solution was washed successively with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to empty. The residue was chromatographed (silica gel, CHCl3: MeOH, 99: 1) to give 2- (2-chloroethyl) [1,2,4] triazolo [4,3, -<i>to</i>] pyridin-3 (2<i>H</i>) -one as a white solid (260 mg; 90%).

Stage B

To a solution of (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) in 1,4-dioxane (0.72 mL) is given added 2- (2-chloroethyl) [1,2,4] triazolo [4,3, -<i>to</i>] pyridin-3 (2<i>H</i>) -one (36 mg; 0.18 mmol), KI (catalytic amount) and K 2 CO 3 (25 mg; 0.18 mmol). The reaction mixture was heated at 100 ° C for 48 hours. The reaction mixture was cooled to 20 ° C to be then diluted with CHCl3. The solution was filtered to remove the excess of K 2 CO 3 and the filtrate was concentrated in vacuo and Chromatograph (silica gel, CHCl3: MeOH, 98: 2) to give the title compound (32 mg; 65%) as a yellow oil pale.

1 H NMR (CDCl 3, 300 MHz) δ 1.65-1.77 (br s, 1 H); 1.82-1.95 (m, 2 H); 1.97-2.20 (m, 3 H); 2.39 (dt,<i>J</i> = 11.0; 4.1 Hz, 1 H); 2.70-2.90 (m, 3 H); 2.92-2.99 (m, 1 H); 3.02-3.18 (m, 2 H); 3.20-3.24 (m, 1 H); 3.49-3.60 (m, 1 H); 3.77-3.85 (m, 1 H); 4.13 (t,<i>J</i> = 16.5 Hz, 2 H); 6.48 (qu, <i>J</i> = 3.5 Hz, 1 H); 6.60 (t,<i>J</i>= 7.7 Hz, 1 H); 6.85 (d,<i>J</i> = 7.0 Hz, 1 H); 6.93 (d,<i>J</i>= 7.7 Hz, 1 H); 7.05-7.09 (m, 2 H); 7.75 (d,<i>J</i> = 7.0 Hz, 1 H) ppm.

Example 356

(\p.m)-

cis

-11- [3- (6-fluor-1

H

-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Stage TO

To a solution of 1-bromo-3-chloropropane (700 mg; 4.44 mmol) in DMF (2.4 mL) was added 6-fluorindole (200 mg; 1.48 mmol) and KOH powder (92 mg; 1.63 mmol) at 20 ° C. The reaction mixture was stirred for 15 hours at 20 ° C and then turned off by adding H 2 O and it was extracted with Et2O. The combined organic solution was washed successively with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed to give 1- (3-chloropropyl) -6-fluorindole (190 mg; 66%) as a colorless oil.

Stage B

The title compound was prepared by method of Example 355, Step B, as a yellow oil (50 mg; 99%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (3-chloropropyl) -6-fluorindole (36 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.85-2.30 (m, 10 H); 2.57-2.60 (m, 1 HOUR); 2.62-2.70 (m, 1 H); 2.92-2.98 (m, 1 H); 3.03-3.20 (m, 2 H); 3.27-3.32 (m, 1 H); 3.49-3.60 (m, 1 H); 3.78-3.85 (m, 1 H); 4.16 (t,<i>J</i> = 16.6 Hz, 2 H); 6.46 (d,<i>J</i> = 2.9 Hz, 1 H); 6.62 (t,<i>J</i> = 7.3 Hz, 1 HOUR); 6.82-6.90 (m, 2 H); 6.95 (dd,<i>J</i> = 8.1; 0.8 Hz, 1 H); 7.07-7.13 (m, 2 H); 7.51 (dd,<i>J</i> = 8.8; 5.5 Hz, 1 H) ppm.

Example 357

(\p.m)-

cis

-11- [3- (5-fluor-1

H

-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Stage TO

Was prepared 1- (3-chloropropyl) -5-fluorindole (190 mg; 66%) by the method of Example 355, Step A, as a colorless oil from 5-fluorindole (200 mg; 1.48 mmol).

Stage B

The title compound was prepared by method of Example 355, Step B, as a yellow oil (48 mg; 95%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 1- (3-chloropropyl) -5-fluorindole (36 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.86-2.30 (m, 10 H); 2.55-2.59 (m, 1 HOUR); 2.65-2.72 (m, 1 H); 2.92-3.00 (m, 1 H); 3.05-3.21 (m, 2 H); 3.27-3.33 (m, 1 H); 3.47-3.59 (m, 1 H); 3.75-3.86 (m, 1 H); 4.20 (t,<i>J</i> = 16.6 Hz, 2 H); 6.44 (d,<i>J</i> = 3.3 Hz, 1 H); 6.62 (t,<i>J</i> = 7.3 Hz, 1 HOUR); 6.85 (d,<i>J</i> = 6.9 Hz, 1 H); 6.90-6.98 (m, 2 H); 7.14 (d,<i>J</i> = 2.9 Hz, 1 H); 7.23-7.31 (m, 2 H) ppm.

Example 358

(\p.m)-

cis

-11- [3- (6-fluor-2,3-dihydro-1

H

-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

To a solution of (\p.m)-<i>cis</i>-11- [3- (6-fluor-1<i>H</i>-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (25 mg; 0.054 mmol) in acetic acid (0.8 mL) was added slowly at 10 ° C NaCNBH 3 (10.2 mg; 0.16 mmol). The mixture of The reaction was slowly heated to 20 ° C and stirred for 2 hours. The reaction was quenched by the addition of ice followed by 1 N NaOH. The product was extracted with CHCl3 and the organic solution The combined was dried over MgSO4. The title compound is obtained by means of column flash chromatography as an oil colorless (19 mg; 83%).

1 H NMR (CDCl 3, 300 MHz) δ 1.77 (qu, J = 7.0 Hz, 2 H); 1.80-2.20 (m, 5 H); 2.22-2.45 (m, 3 H); 2.62-2.72 (m, 1 H); 2.73-2.82 (m, 1 H); 2.87-2.98 (m, 3 H); 3.03-3.22 (m, 4 H); 3.25-3.32 (m, 1 H); 3.40 (t, <i>J</i> = 8.5 Hz, 2 H); 3.50-3.61 (m, 1 H); 3.78-3.88 (m, 1 H); 6.16 (dd, J = 10.6; 2.2 Hz, 1 H); 6.26 (dt,<i>J</i>= 8.0; 2.5 Hz, 1 H); 6.62 (t, <i>J</i>= 7.3 Hz, 1 H); 6.84-6.97 (m, 3 H) ppm.

MS (CI, NH3): 424.3 (base, M + H).

Example 359

(\p.m)-

cis

-11- [3- (5-fluor-2,3-dihydro-1

H

-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

The title compound was prepared by Method of Example 358 as a colorless oil (19 mg; 69%) at start from (8a<i>S</i>, 12th<i>R</i>) -11- [3- (6-fluor-1<i>H</i>-indole-1-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.065 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.74-1.84 (m, 2 H); 1.86-2.20 (m, 5 H); 2.22-2.45 (m, 3 H); 2.64-2.82 (m, 2 H); 2.87-3.22 (m, 7 H); 3.25-3.38 (m, 3 H); 3.50-3.62 (m, 1 H); 3.78-3.85 (m, 1 H); 6.35 (dd, J = 8.8; 4.4 Hz, 1 HOUR); 6.62 (t, J = 7.3 Hz, 1 H); 6.70-6.90 (m, 3 H); 6.95 (dd, J = 8.0; 1.0 Hz, 1 H) ppm.

Example 360

(\p.m)-

cis

-11- [3- (6-fluor-1

H

-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Stage TO

The solution was heated at 90 ° C for 15 hours. 6-fluorindole (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). The reaction mixture was cooled to 20 ° C and then concentrated in vacuo. The residue was dissolved in 3N NaOH. solution was filtered to remove insoluble material and the filtrate it was acidified with concentrated HCl and extracted with CHCl3. The Organic solution was dried over MgSO4, filtered and concentrated under vacuum to give acid 3- (6-fluorindolyl) propionic (240 mg; 52%) As a yellow solid.

Stage B

To an acid solution 3- (6-fluorindolyl) propionic (235 mg; 1.13 mmol) in THF (5.3 mL) was added slowly at 0 ° C under N2 LiAlH 4 (86 mg; 2.26 mmol). The reaction mixture was warm. at 20 ° C and stirred for 15 hotras. The reaction was quenched by addition of H2O (0.5 mL) and diluted with EtOAc. The solution resulting was dried over MgSO4, filtered through celite and concentrated in vacuo. The residue was chromatographed to give 6-fluor-3- (3-hydroxypropyl) indole (142 mg; 65%) as a colorless oil.

Stage C

To a solution of 6-fluor-3- (3-hydroxypropyl) indole (140 mg; 0.72 mmol) in CH 2 Cl 2 (4.5 mL) and Et 3 N (147 mg; 1.45 mmol) methane sulfonyl chloride (125) was added mg; 1.09 mmol) at 0 ° C under N 2. The reaction mixture was stirred. for 2 hours at 0 ° C. The reaction was quenched by the addition of HCl. 1 N and diluted with Et 2 O. The layer was separated and the organic layer dried over MgSO4, filtered and concentrated in vacuo. He residue was chromatographed to give methane sulfonate of (3- (6-fluorindolyl) -propyl (140 mg; 71%) as a colorless oil.

<pre listing-type="other">\ newpage</pre>

Stage D

The title compound was prepared by method of Example 355, Step B, as a yellow oil (35 mg; 69%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octa-hydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methane sulphonate (3- (6-fluorindolyl) -propyl (49 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.86-2.20 (m, 7 H); 2.25-2.36 (m, 1 H); 2.39-2.46 (m, 2 H); 2.67-2.85 (m, 4 H); 2.85-2.96 (m, 1 H); 3.02-3.15 (m, 1 H); 3.17-3.25 (m, 1 H); 3.28 (qu, J = 3.3 Hz, 1 H); 3.50-3.62 (m, 1 H); 3.77-3.87 (m, 1 H); 6.62 (t, J = 7.4 Hz, 1 H); 6.83-6.91 (m, 2 H); 6.93-6.97 (m, 2 H); 7.01 (dd,<i>J</i> = 9.9; 2.2 Hz, 1 H); 7.48 (dd,<i>J</i> = 8.5; 5.2 Hz, 1 H); 7.93-7.99 (br s, 1 H) ppm.

Example 361

(8a

S

, 12th

R

) -11- [3- (6-fluor-1

H

-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

To a solution of (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole, salt HCl, (20 mg; 0.063 mmol) in 1,4-dioxane (0.4 mL) and <i>N</i>,<i>N</i>-diisopropylethylamine (82 mg; 0.63 mmol) methane sulfonate was added (3- (6-fluor-indolyl) -propyl (26 mg; 0.89 mmol) and KI (catalytic amount). The mixture of reaction was heated at 100 ° C for 15 minutes. The mixture of reaction was cooled to 20 ° C and then concentrated in vacuo and chromatography (silica gel , CHCl3: MeOH, 98: 2) to give the desired title compound (24 mg; 91%) as an oil yellow. The title compound is spectroscopically identical. to that of Example 360.

Example 362

(\p.m)-

cis

-11- [3- (5-fluor-1

H

-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Stage TO

Acid was prepared 3- (5-fluorindolyl) propionic (272 mg; 60%) by the method of Example 360, Step A, as a solid yellow from 5-fluorindole (300 mg; 2.22 mmoles).

Stage B

Was prepared 5-fluor-3- (3-hydroxypropyl) indole (185 mg; 74%) by the method of Example 360, Step B, as a colorless solid from acid 3- (5-fluorindolyl) propionic (270 mg; 1.30 mmoles).

Stage C

Methane sulfonate was prepared from (3- (5-fluorindolyl) -propyl (185 mg; 74%) by the method of Example 360, Step C, as a solid colorless from 5-fluor-3- (3-hydroxypropyl) indole (167 mg; 0.86 mmol).

Stage D

The title compound was prepared by method of Example 355, Step B, as a yellow oil (35 mg; 69%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octa-hydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methane sulphonate (3- (5-fluorindolyl) -propyl (49 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.88-2.19 (m, 7 H); 2.24-2.35 (m, 1 H); 2.37-2.47 (m, 2 H); 2.68-2.85 (m, 4 H); 2.88-2.97 (m, 1 H); 3.02-3.12 (m, 1 H); 3.15-3.30 (m, 2 H); 3.48-3.60 (m, 1 H); 3.77-3.87 (m, 1 H); 6.62 (t, J = 7.3 Hz, 1 H); 6.85 (t, J = 6.6 Hz, 1 H); 6.89-6.97 (m, 2 H); 7.03 (s, 1 H); 7.21-7.30 (m, 2 H); 7.93-8.01 (br s, 1 H) ppm.

Example 363

(8a

S

, 12th

R

) -11- [3- (5-fluor-1

H

-indole-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

The title compound was prepared by Method of Example 361 as a yellow oil (19 mg; 72%) at start from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole, HCl salt, (20 mg; 0.063 mmol) and methane sulphonate (3- (5-fluorindolyl) -propyl (26 mg; 0.094 mmol). The title compound is spectroscopically identical to that of Example 362.

<pre listing-type="other">\ newpage</pre>

Example 364

(\p.m)-

cis

-11-[3-(9

H

-purin-9-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

Stage TO

To a purine solution (360 mg; 3.00 mmol) and 1-bromo-3-chloropropane (1.42 g; 9.0 mmol) in DMF (10 mL) was added K2CO3 (622 mg; 4.5 mmol) at 20 ° C. The reaction mixture was stirred for 24 hours at 20 ° C and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed to give 9- (3-chloropropyl) purine (400 mg; 68%) and 7- (3-chloropropyl) purine (136 mg; 23%) as colorless oils

Stage B

The title compound was prepared by method of Example 355, Step B, as a yellow oil (40 mg; 82%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 9- (3-chloropropyl) purine (36 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.78-2.20 (m, 7 H); 2.22-2.33 (m, 3 H); 2.47-2.55 (m, 1 H); 2.60-2.68 (m, 1 H); 2.94 (dt, J = 14.3; 4.5 Hz, 1 H); 3.03-3.15 (m, 2 H); 3.28 (qu, J = 3.0 Hz, 1 H); 3.47-3.55 (m, 1 H); 3.72-3.82 (m, 1 H); 4.38 (dt, J = 6.6; 1.1 Hz, 2 H); 6.62 (t, J = 7.3 Hz, 1 H); 6.85 (d, J = 6.6 Hz, 1 H); 6.94 (dd, J = 7.7; 0.9 Hz, 1 H); 8.12 (s, 1 HOUR); 8.98 (s, 1 H); 9.14 (s, 1 H) ppm.

Example 365

(\p.m)-

cis

-11-[3-(7

H

-purin-9-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepine [2,3,4-

hi

] indole

The title compound was prepared by method of Example 355, Step B, as a yellow oil (34 mg; 70%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 7- (3-chloropropyl) purine (36 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.80-2.30 (m, 10 H); 2.45-2.53 (m, 1 HOUR); 2.58-2.65 (m, 1 H); 2.94 (dt, J = 13.9; 4.6 Hz, 1 H); 3.05-3.17 (m, 2 H); 3.30 (qu, J = 3.6 Hz, 1 HOUR); 3.45-3.55 (m, 1 H); 3.75-3.83 (m, 1 H); 4.36-4.45 (m, 2 H); 6.63 (t, J = 7.6 Hz, 1 HOUR); 6.85 (d, J = 6.9 Hz, 1 H); 6.95 (d, J = 7.7 Hz, 1 H); 8.25 (s, 1 H); 9.00 (s, 1 H); 9.16 (s, 1 H) ppm.

Example 366

4- [5 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -ylmethyl) -4,5-dihydro-3-isoxazolyl] benzonitrile

Stage TO

Methanesulfonate was prepared from [3- (4-Cyanophenyl) -4,5-dihydro-5-isoxazolyl] methyl (69 mg; 99%) by the method of Example 360, Step C, as a yellow solid from 4- [5-hydroxymethyl] -4,5-dihydro-3-isoxazolyl] benzonitrile (51 mg; 0.25 mmol).

Stage B

The title compound was prepared by method of Example 355, Step B, as a yellow oil (50 mg; 96%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and methanesulfonate [3- (4-Cyanophenyl) -4,5-dihydro-5-isoxazolyl] methyl (50 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.89 (qu, J = 4.4 Hz, 2 H); 2.02-2.20 (m, 3 H); 2.40-2.80 (m, 4 H); 2.88-2.99 (m, 1 H); 3.05-3.35 (m, 5 H); 3.43-3.55 (m, 2 H); 3.75-3.83 (m, 1 H); 4.92-5.01 (m, 1 H); 6.58 (td, J = 13.9; 7.2 Hz, 1 H); 6.84 (dd, J = 7.0; 3.0 Hz, 1 H); 6.92-6.97 (m, 1 H); 7.67-7.60 (m, 4 H) ppm.

Example 367

(\p.m)-

cis

-11- [3- (6-fluor-1H-indazol-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepine [2,3,4-

hi

] indole

Stage TO

To a solution of BCl_ {3} \ cdotMe_ {2} S (1.78 g; 9.9 mmol) in anhydrous benzene (9 mL) was added dropwise a solution of 3-fluoraniline (1.00 g; 9.0 mmol) in benzene (9 mL) under N2 cooling with ice. To this mix reaction was added 4-Chlorobutyro-nitrile (1.12 g; 10.8 mmoles) and AlCl_3, successively. The reaction mixture is refluxed for 20 hours, and then cooled to 20 ° C. He added ice cold 2N HCl to the reaction mixture, thereby forming a yellow liquid The resulting mixture was reheated at 80 ° C. for 1 hour. The solution was cooled to 20 ° C and extracted with CHCl 3. The organic solution was washed with H2O and brine, washed dried over MgSO4, filtered and concentrated in vacuo. He residue was chromatographed to give 1- (2-amino-4-fluorphenyl) -4-chloro-1-butanone (1.07 g; 55%) as a white solid.

Stage B

To a suspension of 1- (2-amino-4-fluorphenyl) -4-chloro-1-butanone (500 mg; 2.3 mmol) in concentrated HCl (3.2 mL) was added a NaNO2 solution in H2O (0.7 mL) and stirred for 1 hour at -6-0ºC. A solution was added of SnCl 2 • 2 O 2 (1.25 g; 5.51 mmol) in HCl concentrate (1.7 mL) to the reaction mixture and stirred for 1 hour more at 0 ° C. The reaction was quenched by adding water. frozen and extracted with Et2O. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give a white solid. Recrystallized to give 3- (3-chloropropyl) -6-fluorindazole pure (420 mg; 86%).

Stage C

The title compound was prepared by method of Example 355, Step B as a yellow oil (34 mg; 67%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (30 mg; 0.12 mmol) and 3- (3-chloropropyl) -6-fluor-indazole (39 mg; 0.18 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.86-2.20 (m, 7 H); 2.22-2.33 (m, 1 H); 2.39-2.47 (m, 2 H); 2.65-2.73 (m, 1 H); 2.75-3.83 (m, 1 H); 2.88-3.08 (m, 4 H); 3.12-3.20 (m, 1 H); 3.27 (qu, J = 3.3 Hz, 1 H); 3.50-3.60 (m, 1 H); 3.77-3.87 (m, 1 H); 6.61 (t, J = 7.5 Hz, 1 H); 6.83 (d, J = 7.9 Hz, 1 H); 6.86-6.95 (m, 2 H); 7.06 (dd, J = 9.1; 2.2 Hz, 1 H); 7.62 (dd, J = 8.8; 5.1 Hz, 1 H); 9.85-10.15 (br s, 1 H) ppm.

Example 368

(8a

S

, 12th

R

) -11- [3- (6-fluor-1H-indazol-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepine [2,3,4-

hi

] indole

The title compound was prepared by Method of Example 361 as a yellow oil (21 mg; 50%) at start from (8a<i>S</i>, 12th<i>R</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole, HCl salt, (32 mg; 0.10 mmol) and 3- (3-chloropropyl) -6-fluorindazole (32 mg; 0.15 mmol). The title compound is spectroscopically identical to that of Example 367.

Example 369

(8a

R

, 12th

S

) -11- [3- (6-fluor-1H-indazol-3-yl) propyl] -6,7,8a, 9,10,11,12,12a-octahydro-5

H

- beep [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

The title compound was prepared by Method of Example 361 as a yellow oil (31 mg; 73%) at start from (8a<i>R</i>, 12th<i>S</i>) -6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole, HCl salt, (32 mg; 0.10 mmol) and 3- (3-Chloro-propyl) -6-fluorindazole (32 mg; 0.15 mmol). The title compound is spectroscopically identical to that of Example 367.

Example 370

4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-amino-4-fluorphenyl) -1-butanone

The title compound was prepared by method of Example 355, Step B, as a red oil (330 mg; 64%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (300 mg; 0.121 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (400 mg; 1.85 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.83-2.18 (m, 7 H); 2.22-2.40 (m, 3 H); 2.60-2.69 (m, 1 H); 2.75-2.80 (m, 1 H); 2.89-2.99 (m, 3 H); 3.03-3.17 (m, 2 H); 3.25 (qu, J = 2.9 Hz, 1 H); 3.49-3.59 (m, 1 H); 3.78-3.87 (m, 1 H); 6.28-6.38 (m, 2 H); 6.40-6.48 (br s, 2 H); 6.61 (t, J = 7.4 Hz, 1 H); 6.85 (d, J = 7.0 Hz, 1 H); 6.94 (dd, J = 8.1; 1.1 Hz, 1 H); 7.77 (dd, J = 8.8; 6.4 Hz, 1 H) ppm.

Example 371

4 - ((8a

S

, 12th

R

-) - 6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-amino-4-fluorphenyl) -1-butanone

The title compound was prepared by Method of Example 355, Stage B, as a red oil (130 mg; 24%) from (8a<i>S</i>, 12th<i>R</i>-) - 6,7,8a, 9,10,11,12,12a-octa-hydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (320 mg; 1.3 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (564 mg; 2.6 mmol). The title compound is spectroscopically identical to that of Example 370.

Example 372

N

- (2- [4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -yl) butanoyl] -5-fluorphenyl) methanesulfonamide

To a solution of 4 - ((\ pm) -<i>cis</i>-6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole-11- (8a<i>H</i>) -il) -1- (2-amino-4-fluorphenyl) -1-butanone (30 mg; 0.070 mmol) in CH 2 Cl 2 (0.5 mL) was added Et 3 N (15 mg; 0.14 mmol) followed by methanesulfonyl chloride (12 mg; 0.11 mmol) at 0 ° C under N 2. The reaction mixture is stirred for 4 hours at 0 ° C and then turned off by adding HCl (1.0 N; 1.0 mL). The resulting solution was extracted with CHCl 3. The combined organic solution was dried over MgSO4. The title compound was obtained by means of flash column chromatography (silica gel, CHCl3: MeOH, 99 : 1) as a white amorphous solid (35 mg; 99%).

1 H NMR (CDCl 3, 300 MHz) δ 1.85-2.18 (m, 7 H); 2.24-2.42 (m, 3 H); 2.58-2.66 (m, 1 H); 2.69-2.77 (m, 1 H); 2.89-3.17 (m, 5 H); 3.23-3.30 (m, 1 H); 3.49-3.59 (m, 4 H); 3.74-3.85 (m, 1 H); 6.60 (t, J = 7.7 Hz, 1 H); 6.80-6.88 (m, 2 H); 6.94 (d, J = 8.1 Hz, 1 H); 7.13 (dd, J = 8.5; 2.2 Hz, 1 H); 7.20-7.25 (m, 1 H); 7.77 (dd, J = 8.8; 5.9 Hz, 1 H) ppm.

Example 373

N

- (2- [4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) butanoyl] -5-fluorphenyl) acetamide

To a solution of 4 - ((\ pm) -<i>cis</i>-6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11- (8a<i>H</i>) -il) -1- (2-amino-4-fluorphenyl) -1-butanone (28 mg; 0.066 mmol) in CH2Cl2 (0.5 mL) was added pyridine (16 mg; 0.20 mmol) followed by acetic anhydride (13 mg; 0.13 mmol) at 20 ° C under N 2. The reaction mixture was stirred. for 15 hours at 20 ° C and then turned off by adding H2O. The resulting solution was extracted with CHCl3. The Combined organic solution was dried over MgSO4. The compound of the title was obtained by means of column flash chromatography (silica gel, CHCl3: MeOH, 99: 1) as an amorphous solid white (28 mg; 91%).

1 H NMR (CDCl 3, 300 MHz) δ 1.90-2.18 (m, 10 H); 2.49-2.69 (m, 3 H); 2.88-3.07 (m, 6 H); 3.27-3.38 (m, 2 H); 3.49-3.59 (m, 1 H); 3.79-3.90 (m, 1 H); 6.25-6.38 (m, 2 H); 6.41-6.50 (br s, 1 H); 6.64 (t, J = 7.3 Hz, 1 H); 6.87 (d, J = 8.0 Hz, 1 H); 6.97 (dd, J = 7.7; 1.1 Hz, 1 H); 7.73 (dd, J = 9.2; 6.6 Hz, 1 H) ppm.

Example 374

N

- (2- [4 - ((8a

S

, 12th

R

-) - 6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) butanoyl] -5-fluorphenyl) acetamide

The title compound (37 mg; 80%) was prepared by the method of Example 373 from 4 - ((8a<i>S</i>, 12th<i>R</i>-) - 6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11- (8a<i>H</i>) -il) -1- (2-amino-4-fluorphenyl) -1-butanone (43 mg; 0.10 mmol) as an amorphous white solid (28 mg; 91%). He title compound is spectroscopically identical to that of the Example 373.

Example 375

2- [4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -yl) butanoyl] -5-fluorphenylcarbamate of ethyl

To a solution of 4 - ((\ pm) -<i>cis</i>-6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11- (8a<i>H</i>) -il) -1- (2-amino-4-fluorphenyl) -1-butanone (35 mg; 0.082 mmol) in pyridine (0.2 mL) chloroformate was added ethyl (16 mg; 0.10 mmol) at 0 ° C under N 2. The mixture of The reaction was stirred for 40 minutes at 0 ° C and then concentrated to empty. The residue was chromatographed (silica gel, CHCl3: MeOH, 99: 1) to give the title compound as an oil yellow (6.0 mg; 51%).

1 H NMR (CDCl 3, 300 MHz) δ 1.32 (t, J = 7.3 Hz, 3 H); 1.83-2.18 (m, 7 H); 2.25-2.50 (m, 3 H); 2.70-2.87 (br s, 2 H); 2.89-3.17 (m, 5 H); 3.25-3.32 (m, 1 H); 3.50-3.61 (m, 1 H); 3.77-3.87 (m, 1 H); 4.23 (q, J = 7.3 Hz, 2 H); 6.61 (t, J = 7.4 Hz, 1 H); 6.72-6.80 (m, 1 H); 6.85 (d, J = 7.4 Hz, 1 H); 6.94 (dd, J = 7.7; 1.1 Hz, 1 H); 7.94 (dd, J = 9.1; 6.3 Hz, 1 H); 8.28 (dd, J = 12.1; 2.5 Hz, 1 H); 11.39-11.43 (br s, 1 H) ppm.

Example 376

N

-2- [4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) butanoyl] -5-fluorphenyl-

N '

-ethylurea

It dissolved 4 - ((\ pm) -<i>cis</i>-6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11- (8a<i>H</i>) -il) -1- (2-amino-4-fluorphenyl) -1-butanone (32 mg; 0.075 mmol) in ethyl isocyanate (50 µl), and the solution was stirred for 20 hours at 20 ° C under N2. Mix The reaction was concentrated in vacuo and then chromatographed (gel silica, CHCl3: MeOH, 99: 1) to give the title compound as a pale yellow oil (30 mg; 81%).

1 H NMR (CDCl 3, 300 MHz) δ 1.21 (t, J = 7.0 Hz, 3 H); 1.90-2.18 (m, 7 H); 2.25-2.50 (m, 3 H); 2.65-2.87 (br s, 2 H); 2.90-3.17 (m, 4 H); 3.19-3.35 (m, 4 H); 3.50-3.59 (m, 1 H); 3.78-3.87 (m, 1 H); 4.73-4.79 (br s, 1 H); 6.65-6.77 (m, 2 H); 6.84 (d, J = 6.2 Hz, 1 H); 6.95 (dd, J = 7.7; 1.1 Hz, 1 H); 7.91 (dd, J = 8.7; 6.2 Hz, 1 H); 8.41 (dd, J = 12.4; 2.6 Hz, 1 H); 11.39-11.43 (br s, 1 H) ppm.

MS (CI, NH3): 497.2 (base, M + H).

Example 377

2- [4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) butanoyl] -5-fluorphenylformamide

It dissolved 4 - ((\ pm) -<i>cis</i>-6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11- (8a<i>H</i>) -il) -1- (2-amino-4-fluorphenyl) -1-butanone (38 mg; 0.090 mmol) in formic acetic anhydride (0.2 mL). The reaction mixture was stirred for 2 hours at 60 ° C under N2. The reaction mixture was concentrated in vacuo, and the residue and chromatography (silica gel, CHCl3: MeOH, 99: 1) to give the title compound as a pale yellow oil (31 mg; 76%)

1 H NMR (CDCl 3, 300 MHz) δ 1.89-2.18 (m, 7 H); 2.37-2.57 (m, 3 H); 2.75-2.97 (m, 3 H); 2.99-3.12 (m, 3 H); 3.15-3.30 (m, 2 H); 3.48-3.58 (m, 1 H); 3.77-3.87 (m, 1 H); 6.62 (t, J = 7.5 Hz, 1 H); 6.82-6.90 (m, 2 H); 6.95 (dd, J = 7.7; 1.1 Hz, 1 H); 7.99 (dd, J = 9.1; 6.2 Hz, 1 H); 8.50 (d, J = 1.1 Hz, 1 H); 8.55 (dd, J = 11.8; 2.5 Hz, 1 H); 11.83-11.87 (br s, 1 H) ppm.

Example 378

4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) butanoyl] -1- (4-fluor-2-hydroxyphenyl) -1-butanone

The title compound was prepared by method of Example 355, Step B, as a yellow oil (36 mg; 21%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (100 mg; 0.41 mmol) and 4-Chloro-1- (4-fluor-2-hydroxyphenyl) -1-butanone (176 mg; 0.81 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.80-2.18 (m, 7 H); 2.22-2.45 (m, 3 H); 2.57-2.77 (m, 2 H); 2.55-3.15 (m, 5 H); 3.22-3.27 (m, 1 H); 3.47-3.59 (m, 1 H); 3.77-3.85 (m, 1 H); 6.57-6.70 (m, 3 H); 6.83 (d, J = 6.7 Hz, 1 H); 6.94 (dd, J = 7.7; 1.1 Hz, 1 H); 7.80 (dd, J = 8.7; 6.4 Hz, 1 H) ppm.

Example 379

4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- [4-fluor-2- (methylsulfanyl) phenyl) -1-butanone

Stage TO

To a solution of 3-fluortiophenol (4.73 g; 37.0 mmol) in diethyl carbonate (11 mL; 129 mmol) K 2 CO 3 (7.67 g; 55.5 mmol) and ether of 18-crown-6 (100 mg; 0.37 mmol). The Reaction mixture was refluxed at 100 ° C for 12 hours. The reaction mixture was cooled to 20 ° C and then quenched by addition of H2O and extracted with Et2O. The solution Combined organic was washed with H2O and brine, dried over MgSO4, to give 1-fluor-3- (methylsulfanyl) benzene (5.10 g; 97%) as a colorless oil.

Stage B

To a solution of 1-fluor-3- (methylsulfanyl) benzene (1.98 g; 14.0 mmol) and 4-chlorobutyryl chloride in CH 2 Cl 2 (15 mL) AlCl 3 (2.06 g; 15.4 was added mmol) at 20 ° C under N2. The reaction mixture was stirred for 15 hours at 20 ° C for 12 hours, and then turned off by addition of H2O and extracted with Et2O. Organic solution combined it was washed with H2O and brine, dried over MgSO4, It was filtered and concentrated in vacuo. The resulting white solid is recrystallized to give 4-chloro-1- [4-fluor-2- (methylsulfanyl) phenyl] -1-butanone (2.80 g; 81%) as a white needle-shaped crystal.

Stage C

The title compound was prepared by method of Example 355, Step B, as a yellow oil (45 mg; 45%) from (\p.m)-<i>cis</i>-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (100 mg; 0.41 mmol) and 4-chloro-1- [4-fluor-2- (methylsulfanyl) phenyl] -1-butanone (50 mg; 0.20 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.82-2.18 (m, 7 H); 2.24-2.49 (m, 3 H); 2.51 (s, 3 H); 2.60-2.82 (m, 2 H); 2.85-3.15 (m, 5 H); 3.21-3.27 (m, 1 H); 3.48-3.60 (m, 1 H); 3.76-3.87 (m, 1 H); 6.61 (t, J = 7.3 Hz, 1 H); 6.83-6.97 (m, 3 H); 7.03 (dd, J = 8.5; 1.9 Hz, 1 H); 7.79 (t, J = 8.0 Hz, 1 H) ppm.

Example 438

1- (2-aminophenyl) -4 - ((6b

R

, 10th

S

-) - 1,2,6b, 9,10,10a-hexahydropyrid [4,3-

b

] [1,4] thiazino [2,3,4-

hi

] indole-8 (7

H

) -il) -1-butanone

The title compound was isolated as an oil. yellow (95 mg; 37%) according to the method of Example 286, Stage C, from (6b<i>R</i>, 10th<i>S</i>-) - 1,2,6b, 7,8,9,10,10a-octahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole (150 mg; 0.65 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (255 mg; 1.29 mmol).

1 H NMR (CDCl 3) δ 1.94-2.03 (m, 5 H); 2.21-2.33 (m, 1 H); 2.37-2.44 (m, 2 H); 2.63-2.71 (m, 1 H); 2.82-2.89 (m, 1 H); 2.90-3.21 (m, 5 H); 3.33-3.40 (m, 1 H); 3.45-3.64 (m, 2 H); 6.60-6.67 (m, 3 H); 6.80-6.85 (m, 2 H); 7.22-7.28 (m, 1 H); 7.76 (dd, J = 1.5; 8.5 Hz, 1 H) ppm.

Example 439

1- (2-aminophenyl) -4 - ((6b

S

, 10th

R

-) - 1,2,6b, 9,10,10a-hexahydropyrid [4,3-

b

] [1,4] thiazino [2,3,4-

hi

] indole-8 (7

H

) -il) -1-butanone

The title compound was isolated as an oil. yellow (98 mg; 38%) according to the method of Example 286, Stage C, from (6b<i>S</i>, 10th<i>R</i>-) - 1,2,6b, 7,8,9,10,10a-octahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole (150 mg; 0.65 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (255 mg; 1.29 mmol).

1 H NMR (CDCl 3) δ 1.94-2.03 (m, 5 H); 2.21-2.33 (m, 1 H); 2.37-2.44 (m, 2 H); 2.63-2.71 (m, 1 H); 2.82-2.89 (m, 1 H); 2.90-3.21 (m, 5 H); 3.33-3.40 (m, 1 H); 3.45-3.64 (m, 2 H); 6.60-6.67 (m, 3 H); 6.80-6.85 (m, 2 H); 7.22-7.28 (m, 1 H); 7.76 (dd,<i>J</i> = 1.5; 8.5 Hz, 1 H) ppm.

Example 440

1- (2-amino-4-fluorphenyl) -4 - ((6b

R

, 10th

S

-) - 1,2,6b, 9,10,10a-hexahydro [4,3-

b

] [1,4] thiazino- [2,3,4-

hi

] indole-8 (7

H

) -il) -1-butanone

The title compound was prepared by the method of Example 355, Step B, as a yellow oil (103 mg; 59%) from (6b<i>R</i>, 10th<i>S</i>-) - 1,2,6b, 7,8,9,10,10a-octahydro [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole (100 mg; 0.43 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (186 mg; 0.85 mmol).

1 H NMR (CDCl 3) δ 1.90-2.05 (m, 5 H); 2.23-2.33 (m, 1 H); 2.39-2.47 (m, 2 H); 2.63-2.75 (m, 1 H); 2.82-2.98 (m, 4 H); 3.02-3.10 (m, 1 H); 3.12-3.20 (m, 1 H); 3.35-3.40 (m, 1 H); 3.43-3.60 (m, 2 H); 6.27-6.39 (m, 2 H); 6.40-6.50 (br s, 2 H); 6.64 (t, J = 7.3 Hz, 1 H); 6.80-6.89 (m, 2 H); 7.76 (dd, J = 9.1; 6.6 Hz, 1 H) ppm.

Example 441

1- (2-amino-4-fluorphenyl) -4 - ((6b

S

, 10th

R

-) - 1,2,6b, 9,10,10a-hexahydro [4,3-

b

] [1,4] thiazino- [2,3,4-

hi

] indole-8 (7

H

) -il) -1-butanone

The title compound was prepared by method of Example 355, Step B, as a yellow oil (101 mg; 58%) from (6b<i>S</i>, 10th<i>R</i>-) - 1,2,6b, 7,8,9,10,10a-octahydro [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole (100 mg; 0.43 mmol) and 1- (2-amino-4-fluorphenyl) -4-chloro-1-butanone (186 mg; 0.85 mmol). The title compound is spectroscopically identical to that of Example 440.

N

- {2- [4 - ((\ pm) -

cis

-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -yl) butanoyl] -5-fluorphenyl} methanesulfonamide

To a solution of 4 - ((\ pm) -<i>cis</i>-6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole-11- (8a<i>H</i>) -il) -1- (2-amino-4-fluorphenyl) -1-butanone (30 mg; 0.070 mmol) in CH 2 Cl 2 (0.5 mL) was added Et 3 N (15 mg; 0.14 mmol) followed by methanesulfonyl chloride (12 mg; 0.11 mmol) at 0 ° C under N 2. The reaction mixture is stirred for 4 hours at 0 ° C and then quenched by adding HCl (1.0 N; 1.0 mL). The resulting solution was extracted with CHCl3. The combined organic solution was dried over MgSO4. He title compound was obtained by means of flash chromatography on column (silica gel, CHCl3: MeOH, 99: 1) as a solid white amorphous (35 mg; 99%).

1 H NMR (CDCl 3, 300 MHz) δ 1.85-2.18 (m, 7 H); 2.24-2.42 (m, 3 H); 2.58-2.66 (m, 1 H); 2.58-2.66 (m, 1 H); 2.69-2.77 (m, 1 H); 2.89-3.17 (m, 5 H); 3.23-3.30 (m, 1 H); 3.49-3.59 (m, 4 H); 3.74-3.85 (m, 1 H); 6.60 (t, J = 7.7 Hz, 1 H); 6.80-6.88 (m, 2 H); 6.94 (d, J = 8.1 Hz, 1 H); 7.13 (dd, J = 8.5; 22.2 Hz, 1 H); 7.20-7.25 (m, 1 H); 7.77 (dd, J = 8.8; 5.9 Hz, 1 H) ppm.

Example 456

Hydrochloride 4 - ((6b

S

, 10th

R

) -1,2,6b, 9,10,10a-hexahydropyrid [4,3-

b

] [1,4] thiazino [2,3,4-

hi

] indole-8 (7

H

) -il) -1- (4-fluorphenyl) -1-butanone

Stage TO

Typical procedure for alkylation of amines

A mixture of indoline hydrochloride (approximately 200 mg) in dioxane (4 mL) was treated based on Hunig (10 equivalents) and heated under reflux for 15 minutes. The cooled reaction mixture was added 4-chloro-1- (4-fluorphenyl) -1-butanone (5 equivalents), KI (0.9 equivalents), then underwent reflux The whole mixture for 48 hours. The reaction was then diluted with chloroform (20 mL) and extracted once with saturated solution of ammonium chloride (10 mL) and twice with ice water (100 mL). The organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of hexane / acetate ethyl (for example 96: 4 to 50: 50), which was followed by a methanol / dichloromethane gradient (for example, 1: 99 to 3: 97) to give the desired product.

The 4 - ((6b<i>S</i>, 10th<i>R</i>-) - 1,2,6b, 9,10,10a-hexahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole-8 (7<i>H</i>) -il) -1- (4-fluorphenyl) -1-butanone (478 mg; 52%) was obtained from hydrochloride of (6b<i>S</i>, 10th<i>R</i>-) - 1,2,6b, 7,8,9,10,10a-octahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole (750 mg; 2.79 mmol) and 4-chloro-1- (4-fluorphenyl) -1-butanone (3.0 mL; 15.24 mmol) using the procedure described previously.

Stage B

The title compound (483 mg; 81%) was prepared from 4 - ((6b<i>S</i>, 10th<i>R</i>-) - 1,2,6b, 9,10,10a-hexahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole-8 (7<i>H</i>) -il) -1- (4-fluorphenyl) -1-butanone (578 mg) using the procedure described in Example 448, Stage B.

1 H NMR (DMSO, 300 MHz) δ 1.92-2.13 (m, 2 H); 2.28 (br s, 2 H); 2.80 (t, 1 H, J = 9.9 Hz); 2.93-3.63 (m, 12 H); 3.63-3.75 (m, 1 H); 6.67 (t, 1 H, J = 7.9 Hz); 6.87 (d, 1 H, J = 8.9 Hz); 6.96 (d, 1 H, J = 6.9 Hz); 7.30-7.48 (m, 2 H); 7.48-8.12 (m, 2 H); 10.43 (br s, 1 H) ppm.

m / z = 397 [C_ {23} H_ {25} FN_ {OS} H] +.

Example 457

Hydrochloride 4 - ((6b

R

, 10th

S

-) - 1,2,6b, 9,10,10a-hexahydropyrid [4,3-

b

] [1,4] thiazino [2,3,4-

hi

] indole-8 (7

H

) -il) -1- (4-fluorphenyl) -1-butanone

Stage TO

The 4 - ((6b<i>R</i>, 10th<i>S</i>-) - 1,2,6b, 9,10,10a-hexahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole-8 (7<i>H</i>) -il) -1- (4-fluorphenyl) -1-butanone (349 mg; 25%) was prepared from hydrochloride (6b<i>R</i>, 10th<i>S</i>-) - 1,2,6b, 7,8,9,10,10a-octahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole (750 mg; 2.79 mmol) with 4-chloro-1- (4-fluorphenyl) -1-butanone (3.0 mL; 15.24 mmol) using the procedure described in the Example 456, Stage A.

Stage B

The title compound (72 mg; 25%) was prepared at start from 4 - ((6b<i>R</i>, 10th<i>S</i>-) - 1,2,6b, 9,10,10a-hexahydropyrid [4,3-<i>b</i>] [1,4] thiazino [2,3,4-<i>hi</i>] indole-8 (7<i>H</i>) -il) -1- (4-fluorphenyl) -1-butanone (340 mg) using the procedure described in Example 448, Stage B.

1 H NMR (DMSO, 300 MHz) δ 1.92-2.13 (m, 2 H); 2.28 (br s, 2 H); 2.80 (t, 1 H, J = 9.9 Hz); 2.93-3.63 (m, 12 H); 3.63-3.75 (m, 1 H); 6.67 (t, 1 H, J = 7.9 Hz); 6.87 (d, 1 H, J = 8.9 Hz); 6.96 (t, 1 H, J = 6.9 Hz); 7.30-7.48 (m, 2 H); 7.48-8.12 (m, 2 H); 10.43 (br s, 1 H) ppm.

m / z = 397 [C_ {23} H_ {25} FN_ {OS} H] +.

Example 472

4- [6,7,8a, 9,10,12,13,13a-octahydro-5

H

,11

H

-azepino [4,5-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11-yl) -1- (4-fluorphenyl) -1-butanone

They were suspended 6,7,9,10,11,12,13,13a-octahydro-5<i>H</i>, 8th<i>H</i>-azepino [4,5-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (200 mg; 0.78 mmol), 4-chloro-4'-fluorbutyrophenone (213 mg; 1.6 mmol), KI (129 mg; 0.78 mmol), K2CO3 (322 mg; 2.3 mmol), and 2 drops of TEA in MEK (4 mL). The mixture is Heated for 60 hours. The reaction was cooled to temperature. Ambient and concentrated. The residue was purified by column chromatography (5, 7, 10% MeOH / CH 2 Cl 2) to deliver the title compound (234 mg; 0.55 mmol; 71%) as a pale brown viscous oil.

1 H NMR (CDCl 3, 300 MHz) δ 6.95 (2 H, ddd, 2.9 Hz, 5.1 Hz, 12.1 Hz); 7.06 (2 H, m); 6.91 (1 H, 7.7 Hz); 6.74 (1 H, d, 7.3 Hz); 6.55 (1 H, t, 7.7 Hz); 3.65-3.75 (1 H, m); 3.45-3.61 (2 H, m); 3.29-3.38 (1 H, m); 2.85-3.0 (4 H, m); 2.2-2.8 (6 H, m); 1.7-2.2 (8 H, m).

MS (ESI): 425.3 (base, M + H).

Example 473

(8a

S

, 13th

S

-) - 11- [3- (4-fluorphenoxy) propyl] -6,7,9,10,12,13,13a-octahydro-5

H

, 8th

H

-azepino [4,5-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

They were suspended 6,7,9,10,11,12,13,13a-octahydro-5<i>H</i>, 8th<i>H</i>-azepino [4,5-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (43.3 mg; 0.17 mmol), 1- (3-chloropropoxy) -4-fluorbenzene (40.8 mg; 0.22 mmol), KI (27.6 mg; 0.17 mmol), and K 2 CO 3 (69 mg; 0.50 mmol) in 4 mL of MEK. The suspension was heated to 80 ° C for 18 hours The reaction was cooled to room temperature and concentrated. The residue was purified by column chromatography. (5, 7, 10% MeOH / CH 2 Cl 2) to deliver the racemic title compound (24.5 mg; 0.06 mmol; 35%) as a pale brown viscous oil. The enantiomers separated into a Chiralcel OD column using hexane / IPA / TFA (75/25 / 0.1) as the eluent to give the title compound.

1 H NMR (CDCl 3, 300 MHz) δ 6.85-6.95 (2 H, m); 7.06 (2 H, m); 6.68-6.80 (2 H, m); 6.53 (1 H, t, 7.6 Hz); 3.90 (2 H, 7, 6.2 Hz); 3.70-3.80 (1 H, m); 3.32-3.59 (3 H, m); 2.71-2.94 (3 H, m); 2.46-2.58 (5 H, m); 1.7-2.1 (8 H, m).

MS (ESI): 413.3 (base, M + H).

Example 474

11- [2- (6-fluor-1,2-bencisoxazol-3-yl) propyl] -6,7,9,10,12,13,13a-octahydro-5

H

, 8th

H

-azepino [4,5-

b

] [1,4] thiazepino [2,3,4-

hi

] indole

The title compound was prepared by same general method of example 473 from 6,7,9,10,11,12,13,13a-octahydro-5<i>H</i>, 8th<i>H</i>-azepino [4,5-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (45 mg; 0.17 mmol), 3- (3-chloropropyl) -1,2-bencisoxazole (61.3 mg; 0.35 mmol) to deliver the desired product (46.1 mg; 11 mmol; 62%) after chromatographic purification.

1 H NMR (CDCl 3, 300 MHz) δ 7.71 (1 H, dd, 5.1 Hz, 8.8 Hz); 7.23 (1 H, dd, 1.8 Hz, 8.4 Hz); 7.06 (1 H, dt, 2.2 Hz, 8.4 Hz); 6.94 (1 H, br d, 7.6 Hz); 6.80 (1 H, 7.4 Hz); 6.59 (1 H, t, 7.3 Hz); 3.81 (1 H, ddd, 5.1 Hz, 9.9 Hz, 13.6 Hz); 3.38-3.65 (3 H, m); 2.92-3.00 (3 H, m); 2.68-2.88 (2 H, m); 2.44-2.61 (5 H, m); 1.87-2.12 (8 H, m).

MS (ESI): 438.2 (base, M + H).

Example 475

4- [6,7,8a, 9,10,12,13,13a-octahydro-5

H

,11

H

azepino [4,5-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11-yl] -1- (4-pyridinyl) -1-butanone

The title compound was prepared by same general method of example 473 from 6,7,9,10,11,12,13,13a-octahydro-5<i>H</i>, 8th<i>H</i>-azepino [4,5-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (275 mg; 1.1 mmol) and 4-chloro-1- (4-pyridinyl) -1-butanone (387 mg; 2.1 mmol) to deliver the desired product (60.2 mg; 0.15 mmol; 14%) after chromatographic purification.

1 H NMR (CDCl 3, 300 MHz) δ 8.81 (2 H, dd, 1.4 Hz, 4.4 Hz); 7.73 (2 H, dd, 1.4 Hz, 4.4 Hz); 6.99 (1 H, d, 7.7 Hz); 6.81 (1 H, d, 7.3 Hz); 6.61-6.60 (1 H, m); 3.5-3.8 (3 H, m); 3.3-3.5 (1 H, m); 2.5-3.1 (9 H, m); 1.8-2.4 (10 H, m).

MS (ESI): 408.4 (base, M + H).

Example 483

4- [2-Bromo-6,7,8a, 9,10,12,13,13a-octahydro-5

H

,11

H

-azepino [4,5-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11-yl) -1- (4-fluorphenyl) -1-butanone

They were added 2-Bromo-6,7,9,10,11,12,13,13a-octahydro-5<i>H</i>, 8th<i>H</i>-azepino [4,5-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (121 mg; 0.36 mmol), 4-chloro-4'-fluorbutyrophenone (107 mg; 0.53 mmol), KI (59.2 mg; 0.36 mmol), and K 2 CO 3 (148 mg; 1.1 mmol) to 4 mL of MEK. The reaction was subjected to reflux for 18 hours. The reaction was then cooled to room temperature and concentrated. The resulting residue is immediately purified by column chromatography (2, 5, 7% of MeOH / CH 2 Cl 2) to deliver the compound of Title (115.6 mg; 64%) as a light brown oil.

1 H NMR (CDCl 3, 300 MHz) δ 7.96-8.02 (2 H, m); 7.10-7.16 (2 H, m); 7.05-7.06 (1 H, m); 6.86-6.87 (1 H, m); 3.73-3.83 (1 H, m); 3.59 (1 H, dt, 4 Hz, 10.3 Hz); 3.36-3.51 (2 H, m); 2.91-3.00 (3 H, m); 2.76-2.84 (2 H, m); 2.59-2.65 (1 H, m); 2.42-2.53 (4 H, m); 1.18-2.10 (9 H, m).

MS (ESI): 505.3 (base, M + H).

Example 484

4-fluorenyl ether 3- [2-Bromo-6,7,8a, 9,10,12,13,13a-octahydro-5

H

,11

H-

azepino [4,5-

b

] [1,4] thiazepine [2,3,4-

hi

] indole-11-yl) -propyl

4-fluorenyl ether 3- [2-Bromo-6,7,8a, 9,10,12,13,13a-octahydro-5<i>H</i>,11<i>H-</i>azepino [4,5-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole-11-yl) -propyl it was prepared by the same general method as in Example 483 a start from 2-Bromo-6,7,9,10,12,13,13a-octahydro-5<i>H</i>, 8th<i>H-</i>azepino [4,5-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (141 mg; 0.42 mmol) and 1- (3-Chloropropoxy) -4-fluor-benzene (118 mg; 0.62 mmol) to deliver the title compound (158 mg; 77%) after chromatographic purification.

1 H NMR (CDCl 3, 300 MHz) δ 7.08 (1 H, 1.8 Hz); 6.93-6.99 (2 H, m); 6.88-6.89 (1 H, m); 6.78-6.85 (2 H, m); 3.97 (2 H, t, 6.2 Hz); 3.72-3.82 (1 H, m); 3.64 (1 H, dt, 3.6 Hz, 10.2 Hz); 3.36-3.56 (2 H, m); 2.78-2.99 (3 H, m); 2.59-2.76 (5 H, m); 1.89-2.11 (8 H, m).

MS (ESI): 491.2 (base, M + H).

Example 485

4- (6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11 (8a

H

) -il) -2-methyl-butanoate of methyl

Stage TO

It dissolved 3-Methyldihydro-2 (3<i>H</i>) -furanone (2.13 g; 21.3 mmol) in CH 2 Cl 2 (15 mL). Added BBr 3 dropwise as a 1 M solution in CH 2 Cl 2. The reaction was stirred at room temperature for 18 hours. He added MeOH (2 mL) at room temperature. They were added Aqueous saturated Na 2 CO 3 (20 mL) and CH 2 Cl 2 (10 mL) The layers were separated, and the aqueous was re-extracted with CH 2 Cl 2 (2 x 20 mL). The Combined organic layers were washed with brine, dried and dried. concentrated to provide 3.77 g of a brown liquid. East crude product was purified by column chromatography to provide 4-bromo-2-methylbutanoate of methyl (3.39 g; 82%) as a clear liquid.

1 H NMR (CDCl 3, 300 MHz) δ 3.69 (3 H, s); 3.42 (2 H, t, 6.6 Hz); 2.68-2.75 (1 H, m); 2.20-2.32 (1 H, m); 1.86-1.97 (1 H, m), 1.19 (3 ​​H, d, 7.0 Hz).

Stage B

They were suspended 6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepine [2,3,4-<i>hi</i>] indole (302 mg; 1.24 mmol), 4-bromo-2-methylbutanoate methyl (315 mg; 1.62 mmol), KI (206 mg; 1.24 mmol), and K 2 CO 3 (514 mg; 3.72 mmol) in MEK. The mixture was subjected at reflux for 18 hours. The reaction was cooled and concentrated. The residue was immediately purified by chromatography of column (3, 5, 7% MeOH / CH 2 Cl 2) to deliver the title compound (477 mg; 99%) as an amorphous solid transparent.

1 H NMR (CDCl 3, 300 MHz) δ 6.93 (1 H, d, 7.7 Hz); 6.84 (1 H, d, 7.3 Hz); 6.61 (1 H, m); 3.71-3.86 (1 H, m); 3.67 (3 H, d, 5.1 Hz); 2.5-3.3 (10 H, m); 1.4-2.4 (10 H, m); 1.12 (3 H, d, 6.9 Hz).

CI MS (NH3): 390 (base, M + H).

Example 486

4- (6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11 (8a

H

) -il) -1,1-bis (4-fluorphenyl) -2-methyl-1-butanol

It dissolved 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -2-methyl-butanoate of methyl (110.5 mg; 0.28 mmol) in THF (0.5 mL). Bromide was added of 4-fluorphenylmagnesium (1.4 mL; 1.4 mmol) as a 1 M solution in THF. The reaction was stirred at room temperature. for 20 hours The reaction was quenched with 1M HCl (5 mL). The reaction was extracted with CH2Cl2 (3 x 15 mL). Layers The combined organics were washed with brine, dried, and dried. concentrated to provide 125 mg of a viscous oil. East crude material was purified by column chromatogtraphy to supply the title compound (72.9 mg; 50%) as an oil light yellow.

1 H NMR (CDCl 3, 300 MHz) δ 7.61-7.68 (2 H, m); 7.46-7.51 (2 H, m); 6.8-7.1 (6 H, m); 6.5-6.7 (2 H, m); 3.7-4.0 (1 H, m); 3.4-3.7 (1 H, m); 3.1-3.4 (2 H, m); 2.5-3.1 (5 H, m); 2.3-2.45 (1 H, m); 1.7-2.2 (8 H, m); 1.2-1.4 (1 H, m); 0.88 (3 H, d, 7.0 Hz)

CI MS (NH3): 521 (base, M + H).

Example 487

4- (6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11 (8a

H

) -il) -1,1-bis (4-chlorophenyl) -2-methyl-1-butanol

Was prepared 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -1,1-bis (4-chlorophenyl) -2-methyl-1-butanol by the same general method as in Example 486 from 4 - ((8a<i>S</i>, 12th<i>R</i>) -6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -2-methyl-butanoate of methyl (108 mg; 0.36 mmol) and bromide of 4-chlorophenylmagnesium (1.8 mL; 1.8 mmol) for deliver the title compound (106.9 mg; 54%) as a solid pale yellow amorphous.

1 H NMR (CDCl 3, 300 MHz) δ 7.5-7.7 (2 H, m); 7.2-7.5 (4 H, m); 7.15-7.25 (2 H, m); 6.8-7.0 (2 H, m); 6.5-6.7 (2 H, m); 3.7-3.9 (1 H, m); 3.4-3.65 (1 H, m); 3.2-3.4 (2 H, m); 2.5-3.1 (5 H, m); 2.3-2.5 (1 H, m); 1.7-2.2 (7 H, m); 1.2-1.5 (2 H, m); 0.88 (3 H, d, 7.0 Hz).

ESI MS: 553.2 (base, M + H).

Example 489

4- (6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11 (8a

H

) -il) -1- (4-fluorphenyl) -2-methyl-1-butanone

Stage TO

Hydrochloride was dissolved from<i>N</i>-<i>OR</i>-dimethylhydroxylamine (1.11 g; 11.4 mmol) in toluene (30 mL). This solution was cooled to 0 ° C, and a 2M solution of AlMe 3 (8.5 mL; 17 mmol) was added in toluene The reaction was heated to room temperature and was stirred for 1 hour. The reaction was then cooled again to 0 ° C, and then added 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -2-methyl-butanoate of methyl (2.05 g; 5.71 mmol) as a solution in toluene (20 mL) The reaction was stirred at room temperature for 1 hour, and then for 18 hours at 4 ° C. The reaction was heated to temperature. ambient and stirred for 2 hours. More hydrochloride were added from<i>N</i>-<i>OR</i>-dimethylhydroxylamine (277 mg; 2.83 mmol) and AlMe3 (1.4 mL; 2.8 mmol). The The reaction was stirred an additional 2 hours at room temperature. He cooled again at 0 ° C and quenched with 1 M aqueous tartaric acid (25 mL). The layers were separated, and the aqueous one was extracted with CHCl3 (3 x 15 mL) The combined organic layers were washed with brine, dried and concentrated to provide 3.0 g of an amorphous solid. The crude product was purified by column chromatography (5, 7% MeOH / CH 2 Cl 2) to deliver the compound of Title 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -<i>N</i>-methoxy-<i>N</i>, 2-dimethylbutanamide (1.81 g; 81%) as a light yellow amorphous solid.

Stage B

It dissolved 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -<i>N</i>-methoxy-<i>N</i>, 2-dimethylbutanamide (109.9 mg; 0.28 mmol) in THF (0.5 mL). Bromide was added 4-fluorphenylmagnesium (1.41 mL; 1.41 mmol) as a 1 M solution in THF. The reaction was stirred at temperature. ambient for 18 hours. More THF (1 mL) and bromide were added. 4-fluorphenylmagnesium (1.41 mL; 1.41 mmol). The reaction was stirred for a further 2 hours and then quenched with 1M HCl (3 mL). The layers were separated and then the phase was made alkaline. aqueous with 1 M NaOH (aqueous) until pH = 14 is reached. The aqueous phase It was extracted with CH 2 Cl 2 (3 x 10 mL). The organic layers are washed with brine, dried, and concentrated to provide 167.7 mg of a brown oil. This material is purified by column chromatography (5, 7, 10% MeOH / CH 2 Cl 2) to deliver the title compound (36.4 mg; 31%) as a light yellow amorphous solid.

1 H NMR (CDCl 3, 300 MHz) δ 7.9-8.1 (2 H, m); 7.0-7.2 (2 H, m); 6.93 (1 H, d, 7.7 Hz); 6.7-6.9 (1 H, m); 6.5-6.6 (1 H, m); 3.6-3.9 (1 H, m); 3.4-3.6 (2 H, m); 2.7-3.2 (4 H, m); 2.3-2.7 (2 H, m); 1.7-2.3 (7 H, m); 1.18 (3 H, d, 7.0 Hz).

ESI MS: 425.3 (base, M + H).

Example 490

4- (6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11 (8a

H

) -il) -1- (4-fluor-2-methoxyphenyl) -2-methyl-1-butanone

It dissolved 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -<i>N</i>-methoxy-<i>N</i>, 2-dimethylbutanamide (48 mg; 0.12 mmol) in THF (0.5 mL). Bromide was added 4-fluor-2-methoxyphenylmagnesium (0.62 mL; 0.62 mmol) as a 1 M solution in THF. The reaction is stirred at room temperature for 8 hours and then added more bromide than 4-fluor-2-methoxyphenylmagnesium (0.62 mL; 0.62 mmol). The reaction was stirred for 18 hours and then it was quenched with 1M HCl (3 mL). The layers separated and were alkalinized the aqueous phase with 1 M NaOH until pH = 14. The Aqueous phase was extracted with CH2Cl2 (3 x 10 mL). Layers The combined organics were washed with brine, dried, and dried. concentrated to provide 65 mg of a brown material. East crude product was purified by column chromatography (5, 7, 10% MeOH / CH 2 Cl 2) to deliver the compound of titer (45 mg; 82%) as a light yellow amorphous solid.

1 H NMR (CDCl 3, 300 MHz) δ 7.27-7.32 (1 H, m); 7.09-7.15 (1 H, m); 6.80-6.95 (3 H, m); 6.57-6.62 (1 H, m); 3.7-2.9 (4 H, m); 3.3-3.6 (3 H, m); 3.1-3.3 (1 H, m); 2.8-3.1 (3 H, m); 2.5-2.7 (2 H, m); 1.7-2.4 (10 H, m); 1.4-1.7 (1 H, m); 1.13 (3 H, d, 6.9 Hz)

CI MS (NH3): 455 (base, M + H).

Example 491

4- (6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11 (8a

H

) -il) -1- (4-fluor-3-methylphenyl) -2-methyl-1-butanone

It was pepa 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -1- (4-fluor-3-methylphenyl) -2-methyl-1-butanone by the same general method as in Example 489, Step B, a start from 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -<i>N</i>-methoxy-<i>N</i>, 2-dimethylbutanamide (108.2 mg; 0.28 mmol) and bromide 4-fluor-3-methylphenylmagnesium (1.39 mL; 1.39 mmol) to provide the title compound (45.6 mg; 37%) after chromatographic purification.

1 H NMR (CDCl 3, 300 MHz) δ 7.82-7.84 (2 H, m); 7.05-7.080 (1 H, m); 6.91-6.94 (1 H, m); 6.82-6.85 (1 H, m); 6.59-6.60 (1 H, m); 3.4-3.9 (4 H, m); 2.8-3.2 (4 H, m); 2.4-2.7 (2 H, m); 1.7-2.4 (13 H, m); 1.17 (3 H, d, 7.0 Hz).

ESI MS: 439.3 (M + H).

Example 492

4- (6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11 (8a

H

) -il) -2-methyl-1- (2-methylphenyl) -1-butanone

It dissolved 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -<i>N</i>-methoxy-<i>N</i>, 2-dimethylbutanamide (92.2 mg; 0.31 mmol) in THF (0.5 mL). Bromide was added 2-methylphenylmagnesium (0.77 mL; 0.77 mmol) as a 1 M solution in THF. The reaction was stirred for 18 hours and then more bromide was added than 2-methylphenylmagnesium (0.39 mL; 0.39 mmol). The reaction was stirred for another 24 hours, and then quenched with HCl 1 M (3 mL). The layers were separated and the aqueous phase was made alkaline with 1 M NaOH until pH = 14. The aqueous phase was extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers are washed with brine, dried, and concentrated to provide 105 mg of a brown material. This raw product is purified by column chromatography (5, 7, 10% MeOH / CH 2 Cl 2) to deliver the title compound (73.2 mg; 56%) as a light yellow amorphous solid.

1 H NMR (CDCl 3, 300 MHz) δ 7.59-7.64 (1 H, m); 7.32-7.38 (1 H, m); 7.20-7.26 (1 H, m); 7.20-7.22 (1 H, m); 6.9-7.0 (1 H, m); 6.8-6.9 (1 H, m); 6.5-6.7 (1 H, m); 3.3-3.9 (3 H, m); 3.1-3.3 (1 H, m); 2.8-3.1 (3 H, m); 1.4-2.8 (15 H, m); 1.14 (3 H, d, 7.0 Hz)

CI MS (NH3): 421.3 (base, M + H).

Example 493

4- (6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11 (8a

H

) -il) -2-methyl-1-phenyl-1-butanone

It dissolved 4- (6,7,9,10,12,12a-hexahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole-11 (8a<i>H</i>) -il) -<i>N</i>-methoxy-<i>N</i>, 2-dimethylbutanamide (52.5 mg; 0.13 mmol) in THF (0.5 mL). Bromide was added phenylmagnesium (0.22 mL; 0.66 mmol) as a 1 M solution in THF. The reaction was stirred at room temperature for 18 hours and then it was quenched with 1M HCl (3 mL). The layers separated, and they alkalized the aqueous layer with 1 M NaOH until pH = 14 is reached. Aqueous phase was extracted with CH2Cl2 (3 x 10 mL). Layers The combined organics were washed with brine, dried, and dried. concentrated to provide 75 mg of a brown material. East crude product was purified by column chromatography (5, 7, 10% MeOH / CH 2 Cl 2) to deliver the compound of titer (14.1 mg; 27%) as a light yellow amorphous solid.

1 H NMR (CDCl 3, 300 MHz) δ 7.95-7.99 (2 H, m); 7.42-7.55 (3 H, m); 6.92 (1 H, d, 8.1 Mz); 6.84 (1 H, d, 6.6 Hz); 6.77 (1 H, d, 6.6 Hz); 6.56-6.63 (1 H, m); 3.4-3.7 (3 H, m); 2.4-3.2 (5 H, m); 1.5-2.4 (11 H, m); 1.19 (3 ​​H, d, 7.0 Hz).

ESI MS: 421.3 (base, M + H).

CI MS (NH3): 407 (base, M + H).

Example 494

1- (2-aminophenyl) -4 - ((6b

R

, 10th

S

) -1,2,6b, 9,10,10a-hexahydro [1,4] oxazino [2,3,4-

hi

] pyrido [4,3-

b

] indole-8 (7

H

) -il) -1-butanone

The title compound was isolated as an oil. yellow (105 mg; 41%) according to the method of Example 286, Stage C from (6b<i>R</i>, 10th<i>S</i>) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole (150 mg; 0.68 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (274 mg; 1.38 mmol).

1 H NMR (CDCl 3) δ 1.90-2.00 (m, 3 H); 2.03-2.11 (m, 1 H); 2.29-2.38 (m, 1 H); 2.39-2.47 (m, 2 H); 2.67-2.80 (m, 2 H); 2.91-3.04 (m, 4 H); 3.12-3.21 (m, 1 H); 3.24-3.35 (m, 2 H); 4.40-4.46 (m, 2 H); 6.26 (br s; 2 H); 6.61-6.73 (m, 4 H); 7.23-7.29 (m, 2 H); 7.77 (dd, 1 H,<i>J</i> = 1.3; 8.3 Hz) ppm.

Example 495

1- (2-aminophenyl) -4- (6b

S

, 10th

R

) -1,2,6b, 9,10,10a-hexahydro [1,4] oxazino [2,3,4-

hi

] pyrido [4,3-

b

] indole-8 (7

H

) -il) -1-butanone

The title compound was isolated as an oil. yellow (115 mg; 44%) according to the method of Example 286, Stage C, from (6b<i>S</i>, 10th<i>R</i>) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole (150 mg; 0.68 mmol) and 1- (2-aminophenyl) -4-chloro-1-butanone (274 mg; 1.38 mmol).

1 H NMR (CDCl 3) δ 1.90-2.00 (m, 3 H); 2.03-2.11 (m, 1 H); 2.29-2.38 (m, 1 H); 2.39-2.47 (m, 2 H); 2.67-2.80 (m, 2 H); 2.91-3.04 (m, 4 H); 3.12-3.21 (m, 1 H); 3.24-3.35 (m, 2 H); 4.40-4.46 (m, 2 H); 6.26 (br s; 2 H); 6.61-6.73 (m, 4 H); 7.23-7.29 (m, 2 H); 7.77 (dd, 1 H,<i>J</i> = 1.3; 8.3 Hz) ppm.

Example 496

(6b

R

, 10th

S

)-8-[3-(1

H

-indazol-3-yl) propyl] -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-

hi

] pyrido [4,3-

b

] indole

The title compound was isolated as an oil. yellow (54 mg; 100%) according to the method of Example 286, Stage C, from (6b<i>R</i>, 10th<i>S</i>) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole (31 mg; 0.14 mmol) and 3- (3-chloropropyl) -1<i>H</i>-indazol (56 mg; 0.28 mmol).

1 H NMR (CDCl 3) δ 1.92-2.17 (m, 5 H); 2.29-2.40 (m, 1 H); 2.47-2.59 (m, 2 H); 2.73-2.81 (m, 2 H); 2.91-3.07 (m, 3 H); 3.21-3.34 (m, 3 H); 4.42-4.47 (m, 2 H); 6.59-6.69 (m, 3H); 7.13 (t, 1 H,<i>J</i> = 7.0 Hz); 7.33-7.45 (m, 2 H); 7.70 (d, 1 H,<i>J</i> = 8.1 Hz) ppm.

Example 528

(6b

R

, 10th

S

) -8- [3- (6-fluor-1

H

-indazol-3-yl) propyl] - [1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-

hi

] pyrido [4,3-

b

] indole

The title compound was peparated by method of Example 355, Step B, as a yellow oil (60 mg; 63%) from (6b<i>R</i>, 10th<i>S</i>) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole (63 mg; 0.29 mmol) and 3- (3-chloropropyl) -6-fluorindazole (93 mg; 0.43 mmol).

1 H NMR (CDCl 3, 300 Mz) δ 1.89-2.15 (m, 5 H); 2.27-2.38 (m, 1 H); 2.43-2.55 (m, 2 H); 2.71-2.80 (m, 2 H); 2.88-3.02 (m, 3 H); 3.18-3.32 (m, 3 H); 4.43 (dd, J = 6.2; 1.8 Hz, 2 H); 6.60-6.72 (m, 3H); 6.90 (dt, J = 9.1; 2.2 Hz, 1 H); 7.07 (dd, J = 9.2; 1.9 Hz, 1 H); 7.63 (dd, J = 8.8; 5.1 Hz, 1 H); 9.85-10.15 (br s, 1 H) ppm.

Example 529

1- (2-amino-4-fluorphenyl) -4 - ((±) -

cis

-1,2,6b, 9,10,10a-hexahydro [1,4] oxazino [2,3,4-

hi

] pyrido [4,3-

b

] indole-8 (7

H

) -il) -1-butanone

The title compound was peparated by Method of Example 361 as a red oil (11 mg; 24%) from (\p.m)-<i>cis</i>-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole (30 mg; 0.12 mmol) and 1- (2-amino-4-fluorphenyl) -4-chloro-1-butanone (51 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.87-2.15 (m, 5 H); 2.25-2.45 (m, 3 H); 2.65-2.79 (m, 2 H); 2.86-2.95 (m, 3 H); 3.15-3.30 (m, 3 H); 4.44 (dd, J = 6.9; 2.2 Hz, 2 H); 6.26-6.38 (m, 2 H); 6.41-6.50 (br s; 2 H); 6.60-6.72 (m, 3 H); 7.78 (dd, J = 9.1; 6.6 Hz, 1 H) ppm.

Example 530

1- (2-amino-4-fluorphenyl) -4 - ((6b

R

, 10th

S

) -1,2,6b, 9,10,10a-hexahydro [1,4] oxazino [2,3,4-

hi

] pyrido [4,3-

b

] indole-8 (7

H

) -il) -1-butanone

The title compound was peparated by method of Example 355, Step B, as a yellow oil (172 mg; 57%) from (6b<i>R</i>, 10th<i>S</i>) -1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole (165 mg; 0.76 mmol) and 1- (2-amino-4-fluorophenyl) -4-chloro-1-butanone (329 mg; 1.5 mmol). The title compound was Spectroscopically identical to that of Example 529.

Example 531

4 - ((\ pm) -

cis

-1,2,6b, 9,10,10a-hexahydro [1,4] oxazino [2,3,4-

hi

] pyrido [4,3-

b

] indole-8 (7

H

) -il) -1- (4-fluor-2-hydroxyphenyl) -1-butanone

The title compound was prepared by Method of Example 361 as a yellow oil (8 mg; 17%) from from (\p.m)-<i>cis</i>-1,2,6b, 7,8,9,10,10a-octahydro [1,4] oxazino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole (30 mg; 0.12 mmol) and 4-Chloro-1- (4-fluor-2-hydroxyphenyl) -1-butanone (52 mg; 0.24 mmol).

1 H NMR (CDCl 3, 300 MHz) δ 1.85-2.13 (m, 5 H); 2.25-2.47 (m, 3 H); 2.63-2.95 (m, 3 H); 2.63-2.95 (m, 3 H); 2.99 (t, J = 7.0 Hz, 2 H); 3.17-3.35 (m, 3 H); 4.43 (dd, J = 6.9; 2.2 Hz, 2 H); 6.59-6.75 (m, 5 H); 7.81 (dd, J = 8.7; 6.6 Hz, 1 H) ppm.

Example 539

4-Fluorenyl Ether Hydrochloride 3- (1,2,6b, 7,8,10,11,11a-octahydro-9

H

-azepino [4,5-

b

] [1,4] oxazino [2,3,4-

hi

] indole-9-yl) -propyl

Typical procedure for alkylation of amines

A mixture of indoline hydrochloride (approximately 200 mg) in dioxane (4 mL) was treated based on Hunig (10 equivalents) and heated under reflux for 15 minutes. The side chain was added to the cooled reaction mixture appropriate (5 equivalents), KI (0.9 equivalents), then submitted at reflux the entire mixture for 48 hours. The reaction was diluted. then with chloroform (20 mL) and extracted once with solution saturated with ammonium chloride (10 mL) and twice with ice water (100 mL). The organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography eluting with a hexane gradient / ethyl acetate (for example 96: 4 to 50: 50), which was followed by a gradient of methanol / dichloromethane (for example, 1: 99 to 3: 97) to give the desired product.

4-fluorenyl ether 3- (1,2,6b, 7,8,10,11,11a-octahydro-9<i>H</i>-azepino [4,5-<i>b</i>] [1,4] oxazino [2,3,4-<i>hi</i>] indole-9-yl) -propyl (400 mg; 62%) was obtained from the alkylation of 1,2,7,8,9,10,11,11a-octahydro-6b<i>H</i>-azepino [4,5-<i>b</i>] [1,4] oxazino [2,3,4-<i>hi</i>] indole (560 mg; 1.69 mmol) with 1- (3-chloropropoxy) -4-fluorbenzene (1.32 mL; 8.47 mmol) using the procedures described previously.

1 H NMR (300 MHz, CDCl 3) δ 1.79-1.99 (m, 1 H); 2.10 (d, 1 H, J = 12.2 Hz); 2.39-2.57 (m, 1 H); 2.72-3.01 (m, 3 H); 3.01-3.22 (m, 2 H); 3.22-3.51 (m, 3 H); 3.61-3.72 (m, 1 H); 6.69-6.89 (m, 1 H); 7.17 (d, 1 H, J = 7.0 Hz); 7.42 (d, 1 H, J = 9.6 Hz) ppm.

MS CI m / z = 249 [MH] +.

The title compound (380 mg; 89%) was obtained by the procedure described in Example 535, Step B.

1 H NMR (300 MHz, CD 3 OD) δ 2.19-2.60 (m, 5 H); 2.59-2.96 (m, 1 H); 3.01-3.19 (m, 1 H); 3.25-3.91 (m, 9 H); 3.92-4.21 (m, 2 H); 4.32-4.61 (m, 2 H); 6.53-6.89 (m, 2 H); 6.88-7.22 (m, 5 H) ppm.

MS CI m / z = 383 [MH] +.

Example 540

Hydrochloride 9- [3- (6-fluor-1,2-bencisoxazol-3-yl) propyl] -1,2,7,8,9,10,11,11a-octahydro-6b

H

-azepino [4,5-

b

] [1,4] oxazino [2,3,4-

hi

] indole

It was obtained 9- [3- (6-fluor-1,2-bencisoxazol-3-yl) propyl] -1,2,7,8,9,10,11,11a-octahydro-6b<i>H</i>-azepino [4,5-<i>b</i>] [1,4] oxazino [2,3,4-<i>hi</i>] indole (351 mg; 48%) from the alkylation of 1,2,7,8,9,10,11,11a-octahydro-6b<i>H</i>-azepino [4,5-<i>b</i>] [1,4] oxazino [2,3,4-<i>hi</i>] indole (595 mg, 1.80 mmol) with 3- (3-chloropropyl) -6-fluorine-1,2-bencisoxazole (1.54 g; 7.20 mmol) using the procedure described in the Example 539.

1 H NMR (CD 3 OD, 300 MHz) δ 2.10-2.51 (m, 4 H); 2.53-2.80 (m, 2 H); 2.80-3.00 (m, 1 H); 3.10-3.25 (m, 3 H); 3.23-3.65 (m, 4 H); 3.70-3.90 (m, 3 H); 4.12 (q, 1 H, J = 9.0 Hz); 4.40-4.60 (m, 2 H); 6.58-6.80 (m, 1 H); 6.92 (d, 1 H, J = 8.1 Hz); 7.06 (t, 1 H, J = 8.1 Hz); 7.12-7.25 (m, 1 H); 7.35-7.45 (m, 1 H); 7.80-7.90 (m, 1 H) ppm.

CI MS (methane) m / z = 408 [MH] +.

Example 544

Hydrochloride 4- (6,7,9,10,12,12a-hexahydro-5

H

- [1,4] oxazepino [2,3,4-

hi

] pyrido [4,3-

b

] [1,4] indole-11 (8a

H

) -il) -1- (4-fluorphenyl) -1-butanone

It was obtained 4- (6,7,9,10,12,12a-hexahydroo-5<i>H</i>- [1,4] oxazepino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole-11 (8a<i>H</i>) -il) -1- (4-fluorphenyl) -1-butanone (100 mg; 55%) from the alkylation of 6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>- [1,4] oxazepino [2,3,4-<i>hi</i>] pyrido [4,3-<i>b</i>] indole (188 mg; 0.7 mmol) with 4-Chloro-4'-fluor-butyrophenone (608 mg; 3.5 mmol) using the procedure of Example 539. The title compound was obtained using the procedure described. in Example 534, Stage C.

1 H NMR (CD 3 OD, 300 MHz) δ 2.01-2.29 (m, 4 H); 2.43-2.61 (m, 2 H); 3.11-3.80 (m, 13 H); 4.39-4.59 (m, 1 H); 6.71-6.83 (m, 2 H); 6.82-6.91 (m, 1 H); 7.18-7.20 (m, 2 H); 8.03-8.13 (m, 2 H) ppm.

CI MS (methane) m / z = 395 [MH] +.

Example 546

4- (1,2,6b, 7,8,10,11,11a-octahydro-9

H

-azepino [4,5-

b

] [1,4] oxazino [2,3,4-

hi

] indole-9-yl) -1- (4-fluorphenyl) -1-butanone

They were suspended 1,2,7,8,9,10,11,11a-octahydro-6b<i>H</i>-azepino [4,5-<i>b</i>] [1,4] oxazino [2,3,4-<i>hi</i>] indole (97.8 mg; 0.42 mmol), 4-chloro-1- (4-fluorphenyl) -1-butanone (172 mg; 0.86 mmol), KI (71.2 mg; 0.43 mmol), and DIEA (550 mg; 4.3 mmol) in dioxane (2 mL). The reaction mixture was subjected to reflux for 18 hours. After cooling to temperature ambient, the solution was concentrated. The residue was purified immediately by column chromatography to deliver the title compound.

ESI MS: 395 [MH] +.

Example 591

4 - ((8a

S

, 12th

R

) -3-Chloro-6,7,9,10,12,12a-hexahydro-5

H

-pirido [4,3-

b

] [1,4] thiazepino [2,3,4-

hi

] indole-11- (8a

H

) -il) -1- (2-amino-4-fluorphenyl) -1-butanone

It stirred (8a<i>S</i>, 12th<i>R</i>) -3-Chloro-6,7,8a, 9,10,11,12,12a-octahydro-5<i>H</i>-pirido [4,3-<i>b</i>] [1,4] thiazepino [2,3,4-<i>hi</i>] indole (0.090 g; 0.38 mmol) with 1- (2-amino-4-fluorphenyl) -5,1-pentanone (0.164 g; 0.76 mmol), potassium carbonate (0.210 g; 1.52 mmol) and potassium iodide (0.020 g; 0.120 mmol) in 1,4-dioxane (2 mL) and refluxed for 72 hours. H2O (5 mL) was added and the aqueous layer was extracted with CHCl 3 (3 x 10 mL). The combined extracts were washed with brine (10 mL) and dried (MgSO4) and evaporated. He resulting residue was purified by column chromatography in silica gel (2.5% MeOH / CH2Cl2) providing the title compound with a yield of 27% (0.046 g).

1 H NMR (CDCl 3, 300 MHz) δ 7.78-7.81 (m, 2 H); 3.73 (s, 1 H); 6.24-6.42 (m, 4 H); 3.98-4.07 (m, 1 H); 3.63-3.78 (m, 2 H); 3.23-3.31 (m, 2 H); 2.81-3.07 (m, 4 H); 2.61-2.80 (m, 3 H); 2.11-2.31 (m, 2 H); 1.82-2.01 (m, 6 H) ppm.

Utility

The compounds of the present invention have therapeutic utility for diseases or disorders that involve neurotransmitter serotonin (5-hydroxy tryptamine or 5-HT) and both agonism and antagonism of 5-HT2 receptors, as demonstrated by the tests described below. The therapeutic utility in the case of these diseases or disorders could involve numerous biological processes affected by serotonin including, but not limited to, appetite, mood, sleep, sexual activity, and arterial constriction. These processes Biological can also be important for numerous disorders of the central nervous system (CNS) including those related with affective disorders of depression, anxiety, psychosis, and schizophrenia, as well as ingestion disorders of foods such as anorexia, bulimia and obesity. The compounds of the present invention potentially have therapeutic utility in other conditions in which serotonin has been implicated, such as migraine, attention deficit disorder or attention deficit hyperactivity, addictive behavior, and compulsive-obsessive disorder, as well as, conditions associated with headache, social phobias, and gastrointestinal disorders such as motility dysfunction of the gastrointestinal tract. Finally, the compounds of the present invention potentially have therapeutic effect on neurodegenerative diseases and traumatic conditions represented by examples of Alzheimer's disease and brain / spinal cord trauma.

Pharmacological analyzes of each compound both to determine antagonism and agonism at the level of 5-HT2A and 5-HT2C receptors consisted in studies <i>in vitro</i> and <i>in vivo</i>. The analysis<i>in vitro</i> included the determinations of K_ {i} at the level of 5-HT2A and 5-HT2C receptors and a evaluation of functional activity (i.e. agonism or antagonism) at the level of each kind of receptor by hydrolysis tests of IP3. Additional receptor assays were carried out to evaluate receptor receptor specificity 5-HT2A and 5-HT2C on receptors monoamine and discomfort (for example, histamine, dopamine, and muscarinics). A compound is considered active as a 5-HT2A antagonist or an agonist of 5-HT2C if it has a value of IC_ {50} or a value of Ki of less than about 0.1 micromolar; so more preferred of less than about 0.01 micromolar. Has been put it is clear that the compounds of the invention have a value of IC 50 of less than about 1 micromolar in the case of 5-HT2A antagonism or an agonism of 5-HT2C.

The essays <i>in vivo</i> determined the compound activity in a variety of paradigms of behavior including twitching head twitching Quipazine, acute and chronic feeding models, anxiety and depression (acquired impotence, confusion about Elevated, Geller-Siefter, dislike of taste conditioned, taste reactivity, satiety sequence). In together, these models reflect the activity as an antagonist of 5-HT2A (twitching head twitching quipazine, depression models) or agonist of 5-HT2C (power models, power models anxiety, depression models) and provide some indication on Regarding bioavailability, metabolism and Pharmacokinesia

The radioligand binding experiments are carried out on 5-HT2A receptors and Human recombinant 5-HT2C expressed in cells HEK293E. The affinities of the compounds of the present invention to join these receptors is determined by their ability to compete for [125 I] -1- (2,5-dimethoxy-4-iodophenyl) -2-amino-propane (DOI) that binds to 5-HT2A or 5-HT2C. General references for binding assays include 1) Lucaites, VL; Nelson, DL; Wainscott, D. B .; Baez, M .; (1996): Subtype and density determine the coupling receiver repertoire of the 5-HT2 subfamily receptor [The subtype and receptor density determine the repertoire of 5-HT2 receptor subfamily coupling], Life Sci., 59 (13): 1081-95, J. Med. Chem. 1988, January; 31 (1): 5-7; 2) Glennon, RA; Seggel, M. R .; Soine, WH; Herrick-Davis, K .; Lyon, R. TO.; Titeler, M .; (1988): [&lt;125&gt; I] -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 [[125 I] -1- (2,5-dimethoxy-4-iodophenyl) -2-amino-propane: An iodinated radioligand that specifically marks the discharge status affinity of serotonin receptor agonist 5-HT2], J. Med. Chem. 31 <pre listing-type="other">\ hbox {(1):}</pre>5-7; and 3) Leonhardt, S .; Gorospe, E .; Hoffman, B. J .; Teitler, M; (1992): Molecular pharmacological differences in the interaction of serotonin with 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors [Differences molecular pharmacological in the interaction of serotonin with 5-hydroxytryptamine1C receptors and 5-hydroxytryptamine2], Mol. Pharmacol., 42 (2): 328-35.

The functional properties of the compounds (efficacy and potency) were determined in whole cells that expressed 5-HT2A receptors or 5-HT2C by evaluating its ability to stimulate or inhibit the hydrolysis of phosphoinositol mediated by receiver. The procedures used are described more ahead.

Binding tests

in vitro

Stable expression of 5-HT2A receptors and 5-HT2C in HEK293E cells

Stable cell lines were generated by Transfection of 293EBNA cells with plasmids containing cDNAs of 5-HT2A, 5-HT2B or 5-HT2C (VNV edited isoform) using phosphate of calcium These plasmids also contained the early promoter. Immediate cytomegalovirus (CMV) to boost the expression of oriP receiver and EBV for maintenance as an element extrachromosomal, and the hph gene of <i>E. Coli</i> to produce resistance to hygromycin B (Horlick and other (s), 1997). Transfected cells were maintained in the middle of Eagle modified Dulbecco (DMEM) containing 10% bovine serum dialyzed fetal at 37 ° C in a humid environment (5% CO2) for 10 days. 5-HT2A cells adapted to "spinner" culture for bulk processing while it was necessary to keep the other lines as adherent crops. On the day of collection, the cells were washed in solution of phosphate buffered sodium chloride (PBS), were counted, and stored at -80 ° C.

Membrane preparation

On the day of the test, pellets were dissolved whole cells (containing approximately 1 x 10 8 cells) expressing the 5-HT2A receptor or 5-HT2C on ice and homogenized in Tris HCl 50 mM (pH 7.7) containing 1.0 mM EDTA using a Brinkman Polytron (PT-10, position 6 for 10 seconds). The homogenized product was centrifuged at 48,000 xg for 10 minutes and the resulting pellet was washed twice by the steps repeated homogenization and centrifugation. The final pellet is resuspended in tissue buffer and determinations of protein by means of the biquiconinic acid (BCA) assay (Pierce Co., IL) using bovine serum albumin as the standard.

Radioligand binding assays for the receptors of 5-HT2A and 5-HT2C

Radioligand binding studies were carried out. carried out to determine the binding affinities (value K_ {) of compounds in the case of 5-HT2A receptors, 5-HT2B, and 5-HT2C recombinants humans (Fitzgerald and other (s), 1999). Rehearsals are made in plates of 96 polypropylene receptacles disposable (Costar Corp., Cambridge, MA) and started by the addition of membrane homogenized material from 5-HT2A, 5-HT2B, and 5-HT2C in tissue buffer (10/30 (g / receptacle) a assay buffer (50 mM Tris HCl; 0.5 mM EDTA; 10 mM pargiline; 10 mM MgSO 4; 0.05% ascorbic acid, pH 7.5) containing [125 I] DOI for 5-HT2A receptors and 5-HT2C (0.3-0.5 nM, final) or [&lt;3&gt; H] LSD (2-2.5 nM, final) for the 5-HT2B receptor, with or without competing drug (it is say, recently synthesized chemical entity). For a typical competition experiment, one is competed fixed radioligand concentration with duplicate concentrations of ligand (12 concentrations ranging from 10 picomolar to 10 micromolar). The reaction mixtures were incubated to achieve equilibrium for 45 minutes at 37 ° C and were terminated by rapid filtration (cell collector, Inotech Biosystems Inc., Lansing, MI) through GFF fiberglass filters that had been pre-soaked with 0.3% polyethyleneimine. The Filters were washed with ice cold 50 mM Tris buffer (pH 7.5) and then they were counted in a gamma counter for the tests of 5-HT2A and 5-HT2C, or by liquid phase scintillation spectroscopy for the test of 5-HT2B.

Phosphoinositide hydrolysis studies

The ability of the compounds recently synthesized to stimulate the hydrolysis of phosphoinositide (PI) is monitored in whole cells using a variant (Egan and other (s), 1998) of a previously described protocol (Berridge and other (s), 1982). HEK293E cells were collected, expressing the 5-HT2A receptor, 5-HT2B, or 5-HT2C, with 0.5 mM EDTA and were applied with a density of 100,000 / receptacle on plates of 24 receptacles coated with poly-D-lysine (Biocoat, Becton Dickinson, Bedford, MA) in Dulbecco's modified Eagle serum (DMEM, Gibco BRL) containing high glucose, 2 mM glutamine, 10% of dialyzed fetal calf serum, 250 g / mL hygromycin B, and 250 g / mL of G418. After a period of 24-48 hours, it culture media were removed and replaced with DMEM without Fetal calf serum and inositol (Gibco BRL). The cells are then incubated with DMEM (without serum or inositol) containing a final concentration of 0.5 uCi / receptacle of myo - [3 H] inositol for 16-18 hours. After this incubation, the cells were washed with DMEM (without serum or inositol) containing 10 mM LiCl and 10 mM pargiline and then they were incubated for 30 minutes with the middle honeys but now containing one of the various test compounds. The reactions were terminated by aspiration of the media and the cell lysate by freeze-thaw. The [3 H] phosphoinositides with chloroform / methanol (1: 2 v / v), were separated by anion exchange chromatography (Bio-Rad AGI-X8 resin), and it counted by liquid phase scintillation spectroscopy as It has been previously described (Egan et al. (s), 1998).

Analysis of data

Dissociation constants were calculated apparent equilibrium (K_ {s}) from the experiments of competition using a regression curve adjustment program Non-linear iterative (GraphPad Prism, San Diego, CA). For the PI hydrolysis experiments, the EC50s were calculated using a "pseudo" Hill model of a site:

y = ((R_ {max} -R_ {min} / (1 + R / CE_ {50}) nH)) + R_ {max}

where R = answer (DeltaGraph, Monterrey, CA). E_ {max} (maximum response) is derived from the maximum of the adjusted curve (stimulation of net PI) for each compound. Intrinsic activity (AI) is determined by expressing the E_ {max} of a compound as a percentage of E_ {max} of 5-HT (AI = 1.0).

Experiments

in vivo

for serotonergic ligands

Preclinical efficacy, potency, and risk of effect secondary.

a) Anti-serotonin efficacy

Spasmodic twitching head antagonism induced by Quipazine in rat

Quipazine, an antagonist at the level of 5-HT receptors, produces a response from characteristic spasmodic twitching in rats. Antagonists 5-HT receptor effectively antagonize this agonist-induced behavior effect of 5-HT (Lucki and other (s), 1984). In consistency, the head jerking twitching model Quipazin-induced rat can function as a correlate of behavior <i>in vivo</i> regarding receptor binding 5-HT. The compounds are administered 30 minutes before the behavioral test (and 25 minutes before the quipazine), and a dose-related antagonism is determined of the response to quipazin.

b) Antipsychotic efficacy

Inhibition of the Conditional Abstinence Response (CAR.

C

onditioned

TO

voidance

R

sponse) in rat

Rats are trained to avoid consistently (by climbing to a suspended pole of the roof of the test chamber) an electric foot shock (0.75 mA) supplied to the grid floor of the test chamber. All antipsychotic drugs effectively inhibit this response from conditioned abstinence (Arnt, 1982). The capacity of a compound to inhibit this response to determine the effectiveness Antipsychotic of potential drug candidates.

c) Risk of extrapyramidal side effect

Induction of catalepsy in rat

Typical antipsychotic drugs produce extrapyramidal side effects (EPS,<u>and</u>xtra<u>p</u>yramidal <u>s</u>ide effects). The indicator most widely accepted preclinical risk of EPS in humans is a drug-induced catalepsy syndrome in rat (Costall and Naylor, 1975), a condition in which the animal will remain motionless in an externally imposed position (analogous to stupor catatonic in humans). The rats are tested for determine the induction of catalepsy in a trial of dose-response after oral administration of compounds.

d) Penetration into SNC: Receiver occupation in the brain

in vivo

Union

in vivo

To determine the level of receiver occupancy<i>in vivo</i>, a receptor binding protocol is used <i>in alive</i>. This procedure uses an appropriate radioligand to Mark the recipient of interest. For example, to measure both Dopamine D2 receptors such as 5-HT2A <i>in alive</i>, It can be used 3 HN-methyl espiperone (3 H-NMSP) (Prost et al. (S), 1987). East procedure employs rats (or mice) that were fasted all the night. To measure the effects of compounds on these receptors of interest, the compounds are dosed, usually orally, for example at a rate of 2 microliters / gram of weight 0.25% methocel suspension body. The compound Radiolabelled (in this example, 3 H-NMSP) is administered by intravenous injection into the tail vein (10 branded microcuries / 200 grams of rat). Experiments are used of time course to determine the optimal binding time both for the radiolabeled compound and for the unlabeled. These Optimum time frames are used for all experiments of response to subsequent doses. After the time frame Appropriate exposure to compound / radioligand, animals are sacrificed and dissected relevant brain regions (frontal cortex for 5-HT2A receptors and striatum for D2 receptors) and examined for determination of its radioactivity content. The level of non-specific binding is determined by examining a brain region that is known does not contain the recipient of interest (in this case the cerebellum) or by administering an excess of known compound interacts pharmacologically with the receptor.

References

<b>Arnt</b>, <i>J. Acta Pharmacol. et Toxicol</i>., <u>1982</u>: 51, 321-329

<b>Berridge</b>, MJ; <b>Downes</b>, PC;<b>Hanley</b>, MR; (<u>1982</u>), Lithium amplifies agonist-dependent phosphotidyinositol response in brain and salivary glands, [Lithium amplifies the response of phosphotidiinositol in brain and salivary glands], <i>Biochem J</i>., 206, 587-595.

<b>Costall</b>, B. and <b>Nailor</b>RJ<i>Pscichopharmacology</i>, <u>1975</u>: 43, 69-74.

<b>Egan</b>, T .;<b>Herrick-Davis</b>, K .; <b>Miller</b>, K .;<b>Glennon</b>, RA; and <b>Teitler</b>, M: (<u>1998</u>): Agonist activity of LSD and lisuride at cloned 5-HT2A and 5-HT2C receptors, [LSD agonist activity and lisuride at the level of 5-HT2A receptors and 5-HT2C cloned], <i>Psychopharmacology</i>, 135, 409-414.

<b>Fitzgerald</b>, LW; <b>Conklin</b>, D. S :;<b>Krause</b>, CM; <b>Marshall</b>, AP; <b>Patterson</b>J. P .; <b>Tran</b>, DP; <b>Yesterday</b>, G .; <b>Kostich</b>, WA; <b>Largent</b>, BL; <b>Hartig</b>, PR; (<u>1999</u>): High affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidende favoring the tenary complex and two-state models of agonist action, [High affinity agonist binds correlates effectively (activity intrinsic) at the level of serotonin receptors Human 5-HT2A and 5-HT2C: the evidence favors the ternary complex and the two-state models of agonist action], <i>J. Neurochem</i>., 72, 2127-2134.

<b>Frost</b>, JJ; <b>Smith</b>, AC;<b>Kuhar</b>, MJ; <b>Dannals</b>, RF; <b>Wagner</b>, HN;<u>1987</u>: <i>Live</i> Binding of 3 HN-Methyl spiperone to Dopamine and Serotonin Receptors, [Union <i>in vivo</i> from 3 HN-methyl espiperone a dopamine and serotonin receptors], <i>Life sciences</i>, 40 : 987-995.

<b>Horlick</b>, RA; <b>Blow up</b>, K .;<b>Breth</b>, THE; <b>Reid</b>, CC; <b>Shen</b>, IS;<b>Robbinds</b>, AK; <b>Cooke</b>, GM; <b>Largent</b>, BL; (<u>1997</u>): Rapid generation of stable cell lines expressing corticotro-phin-releasing hormone receptor for drug discovery, [Rapid generation of cell lines stable expressing hormone receptor releasing corticotrophin for drug discovery], <i>Protein Expr. Purif</i>., 9, 301-308.

<b>Lucki</b>, I .; <b>Nobler</b>, MS;<b>Frazer</b>, TO.; (<u>1984</u>): Differential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat, [Differential actions of antagonists of serotonin on two models of activation behavior of serotonin receptor in the rat], <i>J. Pharmacol. Exp. Ther</i>., 228 (1) : 133-139.

Dosage and formulation

The agonist compounds of serotonin and serotonin antagonists of this invention can be administered as a treatment for the control or prevention of central nervous system disorders that include obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders and sexual, migraine and other conditions associated with headache, social phobias, and gastrointestinal disorders such as dysfunction of the motility of the gastrointestinal tract by any means that produces contact of the active agent with the site of agent action, that is, 5-HT2 receptors, in the body of a mammal. It can be administered by any conventional medium available for use in conjunction with pharmaceuticals, either as a therapeutic agent individually or in a combination of therapeutic agents. It can administer alone, but is preferably administered with a selected pharmaceutical vehicle based on the route of chosen administration and current pharmaceutical practice.

The compounds of the present invention can be administered in oral dosage forms such as tablets, capsules (each of them including formulations of sustained or delayed release), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. In the same way they can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscularly, all using good dosage forms known to those with current knowledge in the pharmaceutical specialty

The dose administered will, of course, vary in function of known factors, such as characteristics pharmacodynamics of the particular agent and its mode and route of administration; the age, health and weight of the container; nature and extension of symptoms; the type of concurrent treatment; the frequency of treatment; and the desired effect. As a guide In general, you can expect a daily dose of ingredient active be about 0.001 to about 1000 milligrams per kilogram of body weight, being the preferred dose from about 0.01 to about 100 mg / kg, and the most preferred dose of about 0.1 to about 30 mg / kg Advantageously, the compounds of the present invention they can be administered in a single daily dose, or the dose Total daily can be administered in divided doses of two, Three or four times a day.

The 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 will be commonly present in an amount of approximately 0.5-99% by weight with respect to the total weight of the composition. The active ingredient can be administered orally 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 via parenteral, in sterile liquid dosage forms.

Hard gelatin capsules contain the active ingredient and powdered vegetables, such as lactose, starch, cellulose derivatives, magnesium stearate, acid stearic, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as release products sustained to provide continuous release of medication to over a period of hours. Compressed tablets can be coated with sugar or coated with a film to mask any unpleasant taste and protect the tablet from the atmosphere, or it can be enteric coated for the selective disintegration in the gastrointestinal tract. The forms Liquid dosing for oral administration contain agents dyes and flavorings to increase part acceptance of the patient.

In general, they are suitable vehicles for parenteral solutions water, an appropriate oil, solution of sodium chloride, aqueous dextrose (glucose), and sugar solutions related and glycols such as propylene glycol or polyethylene glycols Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, substances buffers Suitable oxidizing agents such as bisulfite of sodium, sodium sulphite, or ascorbic acid, both alone and in combination, they are appropriate stabilizing agents. I also know they use citric acid and its salts, and sodium EDTA. In addition, the parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl-o propyl paraben and chlorobutanol. Vehicles Suitable pharmacists are described in <i>Remington´s Pharmaceutical Sciences</i>, <i>supra</i>, a reference text standard in this field.

They can be illustrated as indicated below. Pharmaceutical dosage forms useful for administration of the compounds of this invention.

Capsules

A wide variety of capsules can be prepared unitary by filling two-piece hard gelatin capsules each with 100 mg of active ingredient powder, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

Soft gelatin capsules

An active ingredient mixture can be prepared in a digestible oil such as soybean oil, seed oil of cotton or olive oil and injected by means of a pump positive displacement in gelatin to form capsules of soft gelatin containing 100 mg of the active ingredient. The Capsules should then be washed and dried.

Tablets

A wide variety of tablets by conventional procedures so that the Dosing unit contains 100 mg of active ingredient, 0.2 mg colloidal silicon dioxide, 5 milligrams of stearate magnesium, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg lactose Appropriate coatings may be applied to increase acceptability or delayed absorption.

Suspension

An aqueous suspension can be prepared for oral administration so that every 5 mL contains 25 mg of finely divided active ingredient, 200 mg of carboxymethyl sodium cellulose, 5 mg of sodium benzoate, 1.0 mg of solution USP sorbitol, and 0.025 mg of vanillin.

Injectable

A parenteral composition can be prepared. suitable for administration by injection by stirring 1.5% in weight of active ingredient in 10% by volume of propylene glycol and Water. The solution is sterilized by use techniques common.

The following tables provide Examples representative, the synthesis of which has been described above, of the compounds of the formula (I) of the present invention.

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(Table goes to page following)

TABLE 1

<figref>21</figref>

TABLE 1 (continued)

<figref>22</figref>

TABLE 1 (continued)

<figref>23</figref>

TABLE 1 (continued)

<figref>24</figref>

TABLE 1 (continued)

<figref>25</figref>

TABLE 1 (continued)

<figref>26</figref>

TABLE 2

<figref>27</figref>

TABLE 3

<figref>28</figref>

TABLE 4

<figref>29</figref>