HK1131784A

HK1131784A - 8-sulfonyl-l, 3, 4, 8-tetrahydr0-2h- [1, 4] oxazepino [6, 7-e] indole derivatives and their use as 5-ht6 receptor ligands

Info

Publication number: HK1131784A
Application number: HK09111469.0A
Authority: HK
Inventors: 韦‧贝尔茨; 彼得‧勃兰特; 克里斯廷‧汉默; 索菲亚‧亨里克松; 本斯顿‧林奎斯特; 埃里克‧林贝里; 鲁内‧林格姆
Original assignee: 比奥维特罗姆上市公司
Priority date: 2006-10-30
Filing date: 2007-10-30
Publication date: 2010-02-05

Description

8-sulfonyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] oxazepine  o [6, 7-E ] indole derivatives and their use as 5-HT6 receptor ligands

Technical Field

The invention relates to novel chemical compoundsTo pharmaceutical compositions comprising said compounds, to processes for their preparation, and to the use of said compounds for the preparation of a medicament against 5-HT₆Use of a medicament for a receptor-associated disease.

Background

Obesity is a disease characterized by an increase in body fat content that results in body weight exceeding acceptable standards. Obesity is the most important nutritional disorder in the western world and represents a major health problem in all industrialized countries. The disease results in increased mortality due to increased morbidity of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and type 2 diabetes. The search for compounds that reduce body weight has been going on for decades. One route of research is to activate the 5-hydroxytryptamine energy system by direct activation of the 5-hydroxytryptamine receptor subtype or by inhibition of 5-hydroxytryptamine reuptake. The precise receptor subtype pattern required is not known.

5-hydroxytryptamine (5-hydroxytryptamine or 5-HT) is a key transmitter of the peripheral and central nervous systems and it regulates a wide variety of physiological and pathological functions, including anxiety, sleep regulation, aggression, feeding and depression. Various 5-hydroxytryptamine receptor subtypes have been identified and cloned. Several groups have cloned one of these, 5-HT in 1993₆A receptor. (Ruat, M.et al (1993) biochem. Biophys. Res. Commun. (Biochemical Biophysical research communication) 193: 268-. This receptor is positively coupled to adenylate cyclase and shows affinity for antidepressants such as clozapine. Recently, 5-HT has been reported₆Antagonists and 5-HT₆The effect of antisense oligonucleotides on reducing food intake in rats (Bentley, J.C. et al (1999) Br J Pharmacol., journal of British Pharmacol, 126, page 66; Bentley, J.C. et al (1997) J.Psychopharmacol., journal of psychopharmacology A64, 255; Woolley M.L. et al (2001) Neuropharmacology 41: 210-.

Have been identified for 5-HT₆Compounds with increased affinity and selectivity for receptors are described, for example, in WO 00/34242 and Isaac, M. et al (2000) 6-Bicyclopropenizyl-1-aryl-sulfoindels and 6-Bicyclopropenizyl-1-arylsulfoindels as novel, potential and selective 5-HT₆RECEPTOR ANTAGONISTS (6-BICYCLOPYRIDAZOLYL-1-ARYLSULFONYLINDOLE AND 6-BICYCLOPYRIDYL-1-ARYLSULFONYLINDOLE DERIVATIVES AS NOVEL EFFECTIVE AND SELECTIVE 5-HT₆Receptor antagonists). Bioorganic&Medicinal chemistry letters (bio-organic and Medicinal chemistry communications) 10: 1719-&Medicinal Chemistry Letters (bio-organic and Medicinal Chemistry communications) 13: 3355-.

Disclosure of Invention

It has surprisingly been found that the compounds according to the invention exhibit a nanomolar range for 5-HT₆Affinity of the receptor. The compounds of the present invention and their pharmaceutically acceptable salts have 5-HT₆Receptor antagonist, agonist and partial agonist activity, preferably antagonist activity, and are believed to be useful for: treatment or prevention of obesity and type 2 diabetes, achieving a reduction in body weight and weight gain, and treatment or prevention of diseases of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive-compulsive disorders, psychosis, alzheimer's disease, parkinson's disease, huntington's chorea and/or schizophrenia, panic attacks, Attention Deficit Hyperactivity Disorder (ADHD), withdrawal from drug abuse (e.g. amphetamine abuse, cocaine abuse and/or nicotine), neurodegenerative diseases characterized by impaired neuronal growth, and pain. Weight loss and reduction of weight gain (e.g. treatment of weight disorders) can be achieved in particular by reducing food intake. As used herein, the term "weight disorders"refers to a disease caused by an imbalance between energy intake and energy expenditure resulting in abnormal (e.g., excessive) body weight. Such weight disorders include, but are not limited to, obesity, overweight, anorexia, cachexia, insulin resistance, and diabetes.

An object of the present invention are compounds of formula (I), and pharmaceutically acceptable salts, hydrates, solvates, geometric isomers, tautomers, optical isomers, and prodrug forms thereof,

wherein:

represents a single bond or a double bond;

a is N or NR⁵；

X is O, S, N-H or N-C_1-6-an alkyl group;

R¹is a group selected from:

(a)C_1-6-an alkyl group,

(b)C_3-7-a cycloalkyl group,

(c)C_3-6-an alkenyl group,

(d) an aryl group, a heteroaryl group,

(e) aryl-C_2-6-an alkenyl group,

(f) aryl-C_1-6-an alkyl group,

(g) (ii) a heteroaryl group, wherein,

(h) heteroaryl-C_2-6-alkenyl, and

(i) heteroaryl-C_1-6-an alkyl group,

wherein any heteroaryl or aryl residue, alone or as part of another group, is optionally independently substituted at one or more positions with a substituent selected from:

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) methyl-C_3-7-a cycloalkyl group,

(f) fluorine-C_3-7-a cycloalkyl group,

(g)C_2-6-an alkenyl group,

(h) fluorine-C_2-6-an alkenyl group,

(i) an ethynyl group;

(j) hydroxy-C_1-4-an alkyl group,

(k) a hydroxyl group(s),

(l)C_1-6-alkoxy radical

(m) fluorine-C_1-6-alkoxy radical

(n)C_3-7-cycloalkoxy radical

(o) methyl-C_3-7-cycloalkoxy radical

(p) fluoro-C_3-7-cycloalkoxy radical

(q)-SCF₃，

(r)-SCF₂H，

(s)-SO₂NR¹⁰R¹⁰，

(t)-S(O)_eR¹¹Wherein e is 0, 1, 2 or 3,

(u)-CN，

(v)-NR¹⁰R¹⁰，

(w)-NHSO₂R¹¹，

(x)-NR¹²COR¹¹，

(y)-NO₂，

(z)-CONR¹⁰R¹⁰，

(aa)-CO-R¹¹，

(bb)-COOH，

(cc)C_1-6-an alkoxycarbonyl group, a carbonyl group,

(dd) an aryl group, in which,

(ee) a heteroaryl group, and (ee),

(ff) aryloxy, and

(gg) a heteroaryloxy group,

wherein any (dd) aryl or (ee) heteroaryl, alone or as part of another group, is optionally substituted at one or more positions with a substituent selected from:

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R²is a group selected from:

(a) hydrogen

(b) The halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d) fluorine-C_1-6-an alkyl group,

(e)C_3-7-a cycloalkyl group,

(f) methyl-C_3-7-a cycloalkyl group,

(g) fluorine-C_3-7-a cycloalkyl group,

(h)C_2-6-an alkenyl group,

(i) fluorine-C_2-6-an alkenyl group,

(j) an acetylene group,

(k) hydroxy-C_1-4-an alkyl group,

(l) A hydroxyl group(s),

(m)C_1-6-an alkoxy group,

(n) fluoro-C_1-6-an alkoxy group,

(o)C_3-7-a cycloalkoxy group,

(p) methyl-C_3-7-a cycloalkoxy group,

(q) fluoro-C_3-7-a cycloalkoxy group,

(r)-SCF₃，

(s)-SCF₂H，

(t)-SO₂NR¹⁰R¹⁰，

(u)-S(O)_eR¹¹wherein e is 0, 1, 2 or 3,

(v)-CN，

(w)-NR¹⁰R¹⁰，

(x)-NR¹²SO₂R¹¹，

(y)-NR¹²COR¹¹，

(z)-NO₂，

(aa)-CONR¹⁰R¹⁰，

(bb)-OCONR¹⁰R¹⁰，

(cc)-CO-R¹¹，

(dd) -COOH, and

(ee)C_1-6-an alkoxycarbonyl group;

R³is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b) the halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) hydroxy-C_1-4-an alkyl group,

(f)C_3-7-cycloalkyl-hydroxy-C_1-4-alkyl radical

(g)C_1-2-alkoxy-C_1-4-alkyl radical

(h)-COOR¹²，

(i)-CONR¹⁰R¹⁰，

(j)-CO-R¹¹，

(k)-CN，

(l) Aryl, and

(m) a heteroaryl group, in which,

wherein any heteroaryl or aryl residue is optionally independently substituted at one or more positions with a substituent selected from the group consisting of:

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R⁴is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d)C_3-5-a cycloalkyl group,

(e) fluorine-C_3-5-a cycloalkyl group,

(f) hydroxy-C_1-4-alkyl, and

(g) a cyano group;

R⁵is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d) 2-cyanoethyl group, a 2-cyanoethyl group,

(e) hydroxy-C_2-4-an alkyl group,

(f)C_3-4-an alkenyl group,

(g)C_3-4-an alkynyl group,

(h)C_3-7-a cycloalkyl group,

(i) methyl-C_3-7-cycloalkyl radical

(j) fluorine-C_3-7-a cycloalkyl group,

(k)C_3-4-cycloalkyl-C_1-4-alkyl, and

(l)C_1-4-alkoxy-C_2-4-alkyl, or

R⁶，R⁷，R⁸Or R is⁹One of the radicals and R⁵Together with the atoms to which they are attached form a heterocyclic ring, and R⁶，R⁷，R⁸Or R⁹The other three of (a) are hydrogen;

R⁶，R⁷，R⁸and R⁹Each independently selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group,

provided that R is⁶，R⁷，R⁸And R⁹Three of (a) are hydrogen, unless R is⁶，R⁷，R⁸And R⁹At least two of which are methyl groups and the remainder of which are hydrogen,

R⁶，R⁷，R⁸or R is⁹Two of the radicals together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, and R⁶，R⁷，R⁸Or R⁹The other two of (A) are hydrogen, or

R⁶，R⁷，R⁸Or R is⁹One of the radicals and R⁵Together with the atoms to which they are attached form a heterocyclic ring and R⁶，R⁷，R⁸Or R⁹The other three of (a) are hydrogen;

R¹⁰each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_2-6-alkyl, and

(d)C_3-7-cycloalkyl, or

Two R¹⁰The groups together with the nitrogen to which they are attached form a heterocyclic ring optionally substituted with methyl;

R¹¹each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) methyl-C_3-7-a cycloalkyl group,

(f) aryl, and

(g) (ii) a heteroaryl group, wherein,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxyl group and a hydroxyl group, wherein the hydroxyl group is a hydroxyl group,

R¹²each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group,

or when in the group NR¹²COR¹¹When present, R¹¹And R¹²Together with the atoms to which they are attached form a lactam ring, or when present as a group NR¹²SO₂R¹¹When present, R¹¹And R¹²Together with the atoms to which they are attached form a sultam ring.

A preferred group are compounds of the formula (II)

Wherein:

represents a single bond or a double bond;

A，X，R¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸，R⁹，R¹⁰，R¹¹and R¹²As defined for formula (I).

Another preferred group are compounds of the formula (III),

wherein:

to representA single bond or a double bond;

x is O, S, N-H, or N-C_1-6-an alkyl group;

R¹is a group selected from:

(a)C_1-6-an alkyl group,

(b)C_3-7-a cycloalkyl group,

(c)C_3-6-an alkenyl group,

(d) an aryl group, a heteroaryl group,

(e) aryl-C_2-6-an alkenyl group,

(f) aryl-C_1-6-an alkyl group,

(g) (ii) a heteroaryl group, wherein,

(h) heteroaryl-C_2-6-alkenyl, and

(i) heteroaryl-C_1-6-an alkyl group,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) methyl-C_3-7-a cycloalkyl group,

(f) fluorine-C_3-7-a cycloalkyl group,

(g)C_2-6-an alkenyl group,

(h) fluorine-C_2-6-an alkenyl group,

(i) an ethynyl group;

(j) hydroxy-C_1-4-an alkyl group,

(k) a hydroxyl group(s),

(l)C_1-6-alkoxy radical

(m) fluorine-C_1-6-alkoxy radical

(n)C_3-7-cycloalkoxy radical

(o) methyl-C_3-7-cycloalkoxy radical

(p) fluoro-C_3-7-cycloalkoxy radical

(q)-SCF₃，

(r)-SCF₂H，

(s)-SO₂NR¹⁰R¹⁰，

(t)-S(O)_eR¹¹Wherein e is 0, 1, 2 or 3,

(u)-CN，

(v)-NR¹⁰R¹⁰，

(w)-NHSO₂R¹¹，

(x)-NR¹²COR¹¹，

(y)-NO₂，

(z)-CONR¹⁰R¹⁰，

(aa)-CO-R¹¹，

(bb)-COOH，

(cc)C_1-6-an alkoxycarbonyl group, a carbonyl group,

(dd) an aryl group, in which,

(ee) a heteroaryl group, and (ee),

(ff) aryloxy, and

(gg) heteroaryloxy;

wherein any (dd) aryl or (ee) heteroaryl, alone or as part of another group, is optionally independently substituted at one or more positions with a substituent selected from:

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R²is a group selected from:

(a) hydrogen

(b) The halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d) fluorine-C_1-6-an alkyl group,

(e)C_3-7-a cycloalkyl group,

(f) methyl-C_3-7-a cycloalkyl group,

(g) fluorine-C_3-7-a cycloalkyl group,

(h)C_2-6-an alkenyl group,

(i) fluorine-C_2-6-an alkenyl group,

(j) an acetylene group,

(k) hydroxy-C_1-4-an alkyl group,

(l) A hydroxyl group(s),

(m)C_1-6-an alkoxy group,

(n) fluoro-C_1-6-an alkoxy group,

(o)C_3-7-a cycloalkoxy group,

(p) methyl-C_3-7-a cycloalkoxy group,

(q) fluoro-C_3-7-a cycloalkoxy group,

(r)-SCF₃，

(s)-SCF₂H，

(t)-SO₂NR¹⁰R¹⁰，

(u)-S(O)_eR¹¹wherein e is 0, 1, 2 or 3,

(v)-CN，

(w)-NR¹⁰R¹⁰，

(x)-NR¹²SO₂R¹¹，

(y)-NR¹²COR¹¹，

(z)-NO₂，

(aa)-CONR¹⁰R¹⁰，

(bb)-OCONR¹⁰R¹⁰，

(cc)-CO-R¹¹，

(dd) -COOH, and

(ee)C_1-6-an alkoxycarbonyl group;

R³is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c)C_3-7-a cycloalkyl group,

(d) hydroxy-C_1-4-an alkyl group,

(e)C_1-2-alkoxy-C_1-4-alkyl radical

(f)-COOR¹¹，

(g)-CONR¹⁰R¹⁰，

(h)-CO-R¹¹，

(i)-CN，

(j) Aryl, and

(k) (ii) a heteroaryl group, wherein,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R⁴is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d)C_3-5-a cycloalkyl group,

(e) fluorine-C_3-5-a cycloalkyl group,

(f) hydroxy-C_1-4-alkyl, and

(g) a cyano group;

R⁵is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d) 2-cyanoethyl group, a 2-cyanoethyl group,

(e) hydroxy-C_2-4-an alkyl group,

(f)C_3-4-an alkenyl group,

(g)C_3-4-an alkynyl group,

(h)C_3-7-a cycloalkyl group,

(i) methyl-C_3-7-cycloalkyl radical

(j) fluorine-C_3-7-a cycloalkyl group,

(k)C_3-4-cycloalkyl-C_1-4-alkyl, and

(1)C_1-4-alkoxy-C_2-4-alkyl, or

R⁵And R⁶，R⁷，R⁸Or R is⁹One of the radicals together with the atom to which they are attached forms a heterocycle and R⁶，R⁷，R⁸Or R⁹The other three of (a) are hydrogen;

R⁶，R⁷，R⁸and R⁹Each independently selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group,

provided that R is⁶，R⁷，R⁸And R⁹Three of (a) are hydrogen, unless R is⁶，R⁷，R⁸And R⁹At least two of which are methyl groups and the remaining groups of which are hydrogen,

R¹⁰each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_2-6-alkyl, and

(d)C_3-7-cycloalkyl, or

R¹¹each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) methyl-C_3-7-a cycloalkyl group,

(f) aryl, and

(g) (ii) a heteroaryl group, wherein,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

R¹²each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group,

Preferred in formula (II) are:

represents a single bond or a double bond;

X＝O；

R¹is a group selected from:

(a) an aryl group, a heteroaryl group,

(b) (ii) a heteroaryl group, wherein,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) fluorine-C_3-7-a cycloalkyl group,

(f)C_2-6-an alkenyl group,

(g) fluorine-C_2-6-an alkenyl group,

(h) an ethynyl group;

(i) hydroxy-C_1-4-an alkyl group,

(j) a hydroxyl group(s),

(k)C_1-6-alkoxy radical

(l) fluorine-C_1-6-alkoxy radical

(m)C_3-7-cycloalkoxy radical

(n) fluoro-C_3-7-cycloalkoxy radical

(o)-SCF₃，

(p)-SCF₂H，

(q)-SO₂NR¹⁰R¹⁰，

(r)-S(O)_eR¹¹Wherein e is 0, 1, 2 or 3,

(s)-CN，

(t)-NR¹⁰R¹⁰，

(u)-NHSO₂R¹¹，

(v)-NR¹²COR¹¹，

(w)-NO₂，

(x)-CONR¹⁰R¹⁰，

(y)-CO-R¹¹and are and

(z) an aryl group, wherein,

R²is a group selected from:

(a) hydrogen

(b) The halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d) fluorine-C_1-6-an alkyl group,

(e)C_3-7-a cycloalkyl group,

(f) fluorine-C_3-7-a cycloalkyl group,

(j) hydroxy-C_1-4-an alkyl group,

(k) a hydroxyl group(s),

(l)C_1-6-an alkoxy group,

(m) fluorine-C_1-6-an alkoxy group,

(n)C_3-7-a cycloalkoxy group,

(o) fluoro-C_3-7-a cycloalkoxy group,

(p)-SCF₃，

(q)-SCF₂H，

(r)-SO₂NR¹⁰R¹⁰，

(s)-S(O)_eR¹¹wherein e is 0, 1, 2 or 3,

(t)-CN，

(u)-NR¹⁰R¹⁰，

(v)-NR¹²SO₂R¹¹，

(w)-NR¹²COR¹¹，

(x)-CONR¹⁰R¹⁰，

(y)-OCONR¹⁰R¹⁰，

(z)-CO-R¹¹；

R³is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b) the halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) hydroxy-C_1-4-an alkyl group,

(f)C_3-7-cycloalkyl-hydroxy-C_1-4-an alkyl group,

(g)-CO-R¹¹，

(h)-CN，

(i) aryl, and

(j) a heteroaryl group;

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R⁴is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d)C_3-5-a cycloalkyl group,

(e) fluorine-C_3-5-a cycloalkyl group, and

(f) hydroxy-C_1-4-an alkyl group;

R⁵is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d) 2-cyanoethyl group, a 2-cyanoethyl group,

(e) hydroxy-C_2-4-an alkyl group,

(g)C_3-7-a cycloalkyl group,

(h) fluorine-C_3-7-a cycloalkyl group,

(i)C_3-4-cycloalkyl-C_1-4-alkyl, and

(j)C_1-4-alkoxy-C_2-4-alkyl, or

R⁵And R⁶，R⁷，R⁸Or R is⁹One of the radicals together with the atom to which they are attached forms a heterocycle, and R⁶，R⁷，R⁸Or R⁹The other three of (a) are hydrogen;

R⁶，R⁷，R⁸and R⁹Each independently selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d) hydroxy-C_1-4-an alkyl group,

R¹⁰each independently selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_2-6-alkyl, and

(d)C_3-7-cycloalkyl, or

R¹¹each independently selected from:

(a)C_1-6-an alkyl group,

(b) fluorine-C_1-6-an alkyl group,

(c)C_3-7-a cycloalkyl group,

(d) methyl-C_3-7-a cycloalkyl group,

(e) aryl, and

(f) (ii) a heteroaryl group, wherein,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R¹²each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group;

or when in the group NR¹²COR¹¹When present, R¹¹And R¹²Together with the atoms to which they are attached form a lactam ring, or when present as a group NR¹²SO₂R¹¹When present, R¹¹And R¹²Together with the atoms to which they are attached form a sultam ring,

and pharmaceutically acceptable salts, hydrates, solvates, geometric isomers, tautomers, optical isomers, and prodrug forms thereof.

A more preferred group of compounds of formula (II) are those wherein:

represents a single bond or a double bond;

X＝O；

R¹selected from aryl and heteroaryl, wherein any heteroaryl or aryl residue is optionally independently substituted at one or more positions with a substituent selected from:

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-3-an alkyl group,

(c) a trifluoromethyl group,

(d) the free radical of the methoxy group,

(e) a trifluoro-methoxyl group,

(f) a methyl sulfonyl group, a carboxyl group,

(g) -CN, and

(h) a phenyl group;

R²is a group selected from:

(a) hydrogen

(b) The halogen(s) are selected from the group consisting of,

(c)C_1-6-alkyl, and

(d)C_1-6an alkoxy group;

R³is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b) the halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d) hydroxy-C_1-4-an alkyl group,

(e)C_3-7-cycloalkyl-hydroxy-C_1-4-alkyl, and

(f)-CO-C_1-6-an alkyl group;

R⁴is selected from hydrogen and C_1-4-a group of alkyl groups;

R⁵selected from hydrogen, C_1-3Alkyl and fluoro-C_1-3-an alkyl group; or

R⁵And R⁶And R⁸One of which together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine ring, with the proviso that R⁷And R⁹Are all hydrogen;

R⁶is hydrogen, or together with R⁵Together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine ring, with the proviso that R⁷And R⁹Are all hydrogen;

R⁷selected from hydrogen and methyl:

R⁸is hydrogen, or together with R⁵Together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine ring, with the proviso that R⁷And R⁹Are all hydrogen;

R⁹selected from hydrogen and methyl.

Yet a more preferred group of compounds of formula (II) are those wherein:

represents a single bond or a double bond;

X＝O；

R¹selected from phenyl, naphthyl, pyridyl, isoxazolyl, imidazolyl, 1, 4-benzodioxanyl, benzofuranyl, furanyl, 1, 3-benzothiazolyl, chromanyl, thienyl and benzothienyl, each of which is optionally substitutedIndependently at one or more positions with a substituent selected from the group consisting of:

(a) a halogen selected from the group consisting of fluorine and chlorine,

(b)C_1-3-an alkyl group,

(c) a trifluoromethyl group,

(d) the free radical of the methoxy group,

(e) a trifluoro-methoxyl group,

(f) a methyl sulfonyl group, a carboxyl group,

(g) -CN, and

(h) phenyl radical

R²Is hydrogen, fluoro, methyl or methoxy;

R³is hydrogen, chloro, methyl, 1-hydroxy-ethyl, 1-hydroxy-1-methyl-ethyl, acetyl, isobutyryl or cyclopropyl-hydroxymethyl;

R⁴selected from hydrogen, methyl and isopropyl;

R⁵selected from hydrogen, methyl, ethyl, isopropyl, and 2-fluoroethyl-1-yl; or

R⁶is hydrogen or R⁶Together with R⁵Together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine ring, with the proviso that R⁷And R⁹Are all hydrogen;

R⁷selected from hydrogen and methyl;

R⁸is hydrogen or together with R⁵Together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine ring, with the proviso that R⁷And R⁹Are all hydrogen;

R⁹selected from hydrogen and methyl.

Yet a more preferred group of compounds of formula (II) are those wherein:

represents a single bond or a double bond;

X＝O；

R¹selected from phenyl, 1-naphthyl, 2-naphthyl, 3-pyridyl, 4-isoxazolyl, 4-imidazolyl, 1, 4-benzodioxine-6-yl, 2-benzofuranyl, 3-furanyl, 1, 3-benzothiazol-6-yl, 6-benzopyranyl, 2-thienyl, 3-thienyl, 2-benzothienyl, and 3-benzothienyl, each of which is optionally independently substituted at one or more positions with a substituent selected from the group consisting of:

(a) the fluorine is introduced into the reaction mixture containing the fluorine,

(b) the chlorine is added to the reaction mixture in the presence of chlorine,

(c) the methyl group is a group selected from the group consisting of,

(d) the propyl group is a compound of formula (I),

(e) the isopropyl group is a group selected from the group consisting of isopropyl,

(f) a trifluoromethyl group,

(g) the free radical of the methoxy group,

(h) a trifluoro-methoxyl group,

(i) a methyl sulfonyl group, a carboxyl group,

(j) -CN, and

(k) a phenyl group;

R²is hydrogen, fluoro, methyl or methoxy;

R⁴selected from hydrogen, methyl and isopropyl

R⁷selected from hydrogen and methyl;

R⁸is hydrogen or R⁸Together with R⁵Together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine ring, with the proviso that R⁷And R⁹Are all hydrogen;

R⁹selected from hydrogen and methyl.

Preferred compounds of formula (I) include:

2, 5-methylene-9- (phenylsulfonyl) -1, 2, 3, 4, 5, 9-hexahydro [1, 5] oxazocino [3, 2-e ] indole;

2, 4-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-isopropyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-Ethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-methyl radical-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (2, 3-dihydro-1, 4-benzodioxine-6-ylsulfonyl) -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (3, 4-Dimethoxyphenyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (1-benzofuran-2-ylsulfonyl) -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 5-dimethyl-3-furanyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (1, 3-benzothiazol-6-ylsulfonyl) -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-methyl-8- { [4- (methylsulfonyl) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (4-isopropylphenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 2-dimethyl-3, 4-dihydro-2H-benzofuran-6-yl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-chloro-4-fluorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (3, 4-dichlorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (4-fluorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 6-difluorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-methyl-8- { [4- (trifluoromethoxy) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-methyl-8- (2-naphthylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (3-chloro-4-methylphenyl) sulfonyl- ]Base of]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (4, 5-dichloro-2-thienyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (5-chloro-3-methyl-1-benzothien-2-yl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 4-dichlorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- { [ 4-fluoro-3- (trifluoromethyl) phenyl]Sulfonyl } -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-methyl-8- (2-thienylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-methyl-8- [ (4-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-methoxy-5-methylphenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (3-fluoro-4-methylphenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (1-Benzothien-3-ylsulfonyl) -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (4-methoxyphenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-methyl-8- { [4- (trifluoromethyl) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2-methyl-8- [ (4-propylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

3-chloro-4- [ (2-methyl-1, 2, 3, 4-tetrahydro-8H- [1, 4]]OxazazemAnd [6, 7-e ]]Indol-8-yl) sulfonyl]A benzonitrile;

8- [ (2, 5-dimethyl-3-thienyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2- [ (2-methyl-1, 2, 3, 4-tetrahydro-8H- [1, 4]]OxazazemAnd [6, 7-e ]]Indol-8-yl) sulfonyl]A benzonitrile;

2-methyl-1- [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indol-9-yl]Propan-1-one;

1- [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indol-9-yl]An ethanone;

9-chloro-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2- [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indol-9-yl]Propan-2-ol;

cyclopropyl [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]]OxazazemAnd [6, 7-e ]]Indol-9-yl]Methanol;

1- [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indol-9-yl]Ethanol;

10-chloro-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

(7aR) -3- (phenylsulfonyl) -3, 7a, 8, 9, 10, 12-hexahydro-7H-pyrrolo [2 ', 1': 3,4][1，4]OxazazemAnd [6, 7-e ]]Indole;

(7aS) -3- (phenylsulfonyl) -3, 7a, 8, 9, 10, 12-hexahydro-7H-pyrrolo [2 ', 1': 3,4][1，4]OxazazemAnd [6, 7-e ]]Indole;

(3S) -3-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

(3S) -2, 3-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2, 7-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

6-methoxy-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

2- (2-fluoroethyl) -8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-methoxy-5-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 4-dichlorophenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- { [3- (trifluoromethyl) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (3, 4-Dimethoxyphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (2-Naphthylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-methoxy-4-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (4-Propylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (4-isopropylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (1-benzofuran-2-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 5-dimethyl-3-thienyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (3-fluoro-4-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (4-methoxyphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 5-dimethyl-3-furanyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (4-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (2-Thienylsulfonyl) -1, 3, 48-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- { [2- (trifluoromethoxy) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (Biphenyl-3-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- { [2- (trifluoromethyl) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (1-Benzothien-2-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (1-Naphthylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (5-fluoro-2-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

(3R) -3-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

(3R) -2, 3-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

6-methoxy-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

9-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-8- [ (4-fluorophenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

3- [ (10-chloro-1, 2, 3, 4-tetrahydro-8H- [1, 4]]OxazazemAnd [6, 7-e ]]Indol-8-yl) sulfonyl]A benzonitrile;

10-chloro-8- (pyridin-3-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-chlorophenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-methyl radical-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

(1S) -1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

(1R) -1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

6-fluoro-1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

6-methoxy-1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-chlorophenyl) sulfonyl group]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

6-methoxy-1-methyl-8- [ (2-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 6-difluorophenyl) sulfonyl group]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

6-methoxy-8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 4-dichlorophenyl) sulfonyl group]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-isopropyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-isopropyl-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1, 2 dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-1-methyl-8- (pyridin-3-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-1, 2-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1, 2-dimethyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-8- [ (2-fluorophenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-8- [ (2-fluorophenyl) sulfonyl group]-1, 2-dimethyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-8- [ (3-fluorophenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

10-chloro-8- [ (3-fluorophenyl) sulfonyl group]-1, 2-dimethyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-methyl-8- (pyridin-3-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-chlorophenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-methyl-8- [ (2-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 6-difluorophenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 4-dichlorophenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-methoxy-5-methylphenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2-methoxy-4-methylphenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 5-dimethyl-3-thienyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (2, 5-dimethyl-3-furanyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-methyl-8- (2-thienylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-methyl-8- [ (5-methylisoxazol-4-yl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (1, 2-dimethyl-1H-imidazol-4-yl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

and pharmaceutically acceptable salts thereof.

The compound of formula (I) may be 5-HT₆Agonists, partial agonists or antagonists of the receptor. Preferably, the compounds act as 5-HT₆Partial agonists or antagonists of the receptor. More preferably, the compounds act as 5-HT₆An antagonist of the receptor. The term "5-HT₆Partial agonist of receptor "refers to binding to human 5-HT in the intrinsic activity assay described herein₆Compounds that are receptors and do not fully antagonize 5-HT-induced cAMP formation (see "biological assays").

Another object of the present invention is the use for the treatment, in particular for the treatment or prevention of 5-HT₆A compound of formula (I) for receptor-related disorders.

5-HT₆Examples of receptor-related disorders include: obesity, type II diabetes, diseases of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge-eating disorders, obsessive-compulsive disorders, psychosis, alzheimer's disease, parkinson's disease, huntington's chorea, schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD), withdrawal from drug abuse (e.g. cocaine, amphetamine and/or nicotine abuse), neurodegenerative diseases characterized by impaired neuronal growth, and pain.

Another object of the present invention is a pharmaceutical formulation comprising as active ingredient a compound of formula (I), in combination with a pharmaceutically acceptable diluent or carrier, in particular for use in the treatment or prevention of 5-HT₆A receptor-associated disorder.

Another object of the invention is to treat patients suffering from 5-HT₆A method of treating a human or animal subject for a receptor-related disorder. The methods can include administering to a subject (e.g., human or animal, dog, cat, horse, cow) in need thereof an effective amount of one or more compounds of formula (I), their salts, or a composition containing the compounds or salts.

Another object of the invention is a method for reducing body weight or reducing body weight gain. The method comprises administering to a subject in need thereof an effective amount of a compound of formula (I).

The methods described herein may further comprise identifying a need for treatment of 5-HT₆A subject for a receptor-associated disorder. Identifying a subject in need of such treatment can be judged by the subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

Another object of the present invention is the use of the above compounds for the preparation of a medicament for the treatment or prevention of 5-HT₆Receptor-related disorders such as obesity, type II diabetes and central nervous system disorders; and/or to achieve a reduction in body weight loss and body weight gain.

Another object of the present invention is a cosmetic composition for oral administration comprising, as active ingredient, a compound as described above, in combination with a diluent, excipient or carrier suitable for oral administration, to achieve a reduction in body weight and/or a reduction in body weight gain.

The cosmetic composition is provided, according to the use according to the invention, in all the pharmaceutical forms normally used for oral administration, in particular in the form of tablets, granules, capsules, gelatin capsules, solutes, suspensions or solutions which may or may not be friable.

Description of chemical structures in the schemes herein equally defined variables (moieties, atoms, etc.) are defined herein with chemical groups at corresponding positions in the general formulae of the compounds herein, whether or not by the same variable name (i.e., R)¹、R²R, R', X, etc.).

The chemicals used in the synthetic routes described herein may include, for example, solvents, reagents, catalysts and protecting and deprotecting reagents. The above methods may further comprise additional steps to add or remove suitable protecting groups before or after the steps specifically described herein to ultimately allow synthesis of the compounds.

In addition, various synthetic steps may be performed in alternating order or sequence to obtain a desired compound. Synthetic chemical Transformations for synthesizing applicable compounds are known in the art and include, for example, those described in r.larock, Comprehensive Organic Transformations (Organic Transformations universe), VCH publishers (1989); l Fieser and m.fieser, Fieser and Fieser's Reagents for organic Synthesis, John Wiley and Sons (1994); and L Patquette, eds., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995) and reissues thereof.

Methods for carrying out the above reactions are well known to those skilled in the art. The starting materials necessary for the preparation of the compounds of the formula (I) are known or can be prepared in a similar manner to the preparation of known compounds.

The compounds of formula (I) may have one or more chiral carbon atoms and they may thus be obtained in the form of optical isomers, for example as pure enantiomers, or as mixtures of enantiomers (racemates) or as mixtures comprising diastereomers. Separation of mixtures of optical isomers to obtain pure enantiomers is known in the art and can be obtained, for example, by fractional crystallization using a salt of an optically active (chiral) acid or by chromatographic separation on a chiral column. For the compounds described herein, all possible isomeric forms (pure enantiomers, diastereomers, tautomers, racemic mixtures and unequal mixtures of the two enantiomers) are within the scope of the present invention. When the compounds described herein contain an olefinic double bond with geometric asymmetry, it is intended to include both trans and cis (E and Z) geometric isomers.

The compounds of formula (I) can be used as such or, if appropriate, as pharmaceutically acceptable salts (acid or base addition salts) thereof. The above-mentioned pharmaceutically acceptable addition salts are intended to include the therapeutically active non-toxic acid and base addition salt forms which the compounds are capable of forming. Compounds having basic properties may be converted into their pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. Exemplary acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are sodium salts, potassium salts, calcium salts and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine and amino acids such as, for example, arginine and lysine. The term addition salt as used herein also includes solvates which the compounds and salts thereof are able to form, such as for example hydrates, alcoholates and the like.

For clinical use, the compounds of the invention may be formulated as pharmaceutical preparations for oral, rectal, parenteral or other mode of administration. Pharmaceutical formulations are generally prepared by mixing the active substance or a pharmaceutically acceptable salt thereof with conventional pharmaceutical excipients. Examples of excipients are water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like. The formulations may also contain other pharmaceutically active agents and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers and the like. Generally, the amount of active compound is between 0.1 and 95% by weight of the formulation, preferably between 0.2 and 20% by weight of the formulation for parenteral application and more preferably between 1 and 50% by weight of the formulation for oral administration.

The formulations can also be prepared by known methods such as granulation, compression, microencapsulation, spray coating and the like. The preparation can be prepared in the dosage forms of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections by a conventional method. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable excipients. The tablets and granules may be coated in a conventional manner.

The dose level and frequency of dosage for a particular compound will vary with a variety of factors including the potency of the particular compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition being treated, and the ongoing treatment of the patient. The daily dose may, for example, be in the range of about 0.001mg to about 100mg per kg of body weight, administered in single or multiple doses, e.g. about 0.01mg to about 25mg each time. Typically, the dose is administered orally, but parenteral administration may also be selected.

Cosmetic compositions have the active ingredient in combination with diluents, excipients or carriers suitable for oral administration and may contain, for example, water, gelatin, lactose, starch, talc, petrolatum, gum arabic, polyalkylene glycols and magnesium stearate. The cosmetic composition may be in the form of a tablet, powder, granule, lozenge, gelatin capsule, suspension or solution. The tablets, powders, granules, lozenges or gelatin capsules may contain binders, fillers, powdered carriers; solutions or suspensions may contain diluents, solvents and thickening agents.

Definition of

The following definitions will be used throughout the specification and appended claims.

Unless otherwise indicated or specified, the term "C_1-6-alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms. Said C is_1-6Examples of-alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and straight and branched pentyl and hexyl groups. For the range "C_1-6-alkyl "moieties, intended to include all subgroups thereof such as C_1-5-alkyl radical, C_1-4-alkyl radical, C_1-3-alkyl radical, C_1-2-alkyl radical, C_2-6-alkyl radical, C_2-5-alkyl radical, C_2-4-alkyl radical, C_2-3-alkyl radical, C_3-6-alkyl radical, C_4-5-alkyl, etc. Likewise, "aryl-C_1-6-alkyl "means C substituted by aryl_1-6-an alkyl group. Examples include benzyl, 2-phenylethyl, 1-phenylethyl and 1-naphthylmethyl.

Unless otherwise indicated, "fluoro-C_1-6-alkyl "means C substituted by one or more fluorine atoms_1-6-an alkyl group. The fluorine-C_1-6Examples of the-alkyl group include 2-fluoroethyl, fluoromethyl, trifluoromethyl and 2, 2, 2-trifluoroethyl.

Unless otherwise indicated or specified, the term "hydroxy-C_1-4-alkyl "means a straight or branched chain alkyl group whose hydrogen atom is replaced by OH. The hydroxy group-C_1-4Examples of the-alkyl group include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 2-hydroxy-2-methylpropyl.

Unless otherwise indicated or specified, the term "C_1-6-alkoxy "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms. Said "C_1-6Examples of alkoxy "include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and straight and branched pentoxy and hexoxy. For the range "C_1-6-alkoxy "moieties, intended to include all subgroups thereof such as C_1-5-alkoxy radical, C_1-4-alkoxy radical, C_1-3-alkoxy radical, C_1-2-alkoxy radical, C_2-6-alkoxy radical, C_2-5-alkoxy radical, C_2-4-alkoxy radical, C_2-3-alkoxy radical, C_3-6-alkoxy radical, C_4-5-alkoxy, etc.

Unless otherwise indicated or specified, "fluoro-C_1-6-alkoxy "means C substituted by one or more fluorine atoms_1-6-alkoxy groups. The fluorine-C_1-6Examples of the-alkoxy group include trifluoromethoxy group, difluoromethoxy group, monofluoromethoxy group, 2-fluoroethoxy group, 2, 2, 2-trifluoroethoxy group, and 1, 1, 2, 2-tetrafluoroethoxy group.

Unless otherwise indicated or specified, the term "C_1-4-alkoxy-C_2-4-alkyl "means a straight or branched chain alkoxy group having 1 to 4 carbon atoms, linked to an alkyl group having 1 to 4 carbon atoms. Said C is_1-4-alkoxy-C_2-4Examples of the-alkyl group include methoxymethyl, ethoxymethyl, isopropoxymethyl, n-butoxymethyl, and tert-butoxymethyl groups. For the range "C_1-4-alkoxy-C_2-4-alkyl "moieties, intended to include the sameAll subgroups as C_1-3-alkoxy-C_2-4-alkyl radical, C_1-4-alkoxy-C_2-3-alkyl radical, C_1-2-alkoxy-C_2-3-alkyl radical, C_2-4-alkoxy-C_2-4-alkyl radical, C_2-3-alkoxy-C_2-4-alkyl radical, C_2-4-alkoxy-C_2-3-alkyl, etc.

Unless otherwise indicated or specified, the term "C_2-6-alkenyl "means a straight or branched chain alkenyl group having 2 to 6 carbon atoms. Said C is_2-6Examples of the-alkenyl group include vinyl, allyl, 2, 3-dimethylallyl, 1-butenyl, 1-pentenyl, and 1-hexenyl. For the range "C_2-6-alkenyl "moieties, intended to include all subgroups thereof such as C_2-5-alkenyl radical, C_2-4-alkenyl radical, C_2-3-alkenyl radical, C_3-6-alkenyl radical, C_4-5Alkenyl, etc. Likewise, "aryl-C_2-6-alkenyl "means C substituted by aryl_2-6-an alkenyl group. Said aryl group-C_2-6Examples of-alkenyl groups include styryl and cinnamyl.

Unless otherwise indicated or specified, the term "fluoro-C_2-6-alkenyl "means a straight or branched chain alkenyl group having 2 to 6 carbon atoms substituted with one or more fluorine atoms. The fluorine-C_2-6Examples of the alkenyl group include a 1-fluorovinyl group, a 1, 2-difluorovinyl group, a trifluorovinyl group, and a 2-fluoro-2-propen-1-yl group.

Unless otherwise indicated or specified, the term "C_3-4-alkynyl "means a straight or branched chain alkynyl group having 3 to 4 carbon atoms. Said C is_3-4Examples of the alkynyl group include a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, and a 1-methylpropan-2-yn-1-yl group.

Unless otherwise indicated or specified, the term "C_3-7-cycloalkyl "refers to cycloalkyl groups having a ring size of 3 to 7 carbon atoms. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. For the range "C_3-7-part of a cycloalkyl group ", intended toIncluding all subgroups thereof such as C_3-6-cycloalkyl radical, C_3-5-cycloalkyl radical, C_3-4-cycloalkyl radical, C_4-7-cycloalkyl radical, C_4-6-cycloalkyl radical, C_4-5-cycloalkyl radical, C_5-7-cycloalkyl radical, C_6-7-cycloalkyl, and the like.

Unless otherwise indicated or specified, the term "methyl-C_3-7-cycloalkyl "refers to C substituted by one or two methyl groups_3-7-a cycloalkyl group. Said "methyl-C_3-7Examples of the "cycloalkyl group" include 4-methylcyclohexyl, 3, 3-dimethylcyclopentyl and 1-methylcyclopropyl.

Unless otherwise indicated or specified, the term "methyl-C_3-7-Cycloalkoxy "means C substituted by one or two methyl groups_3-7-a cycloalkoxy group. Said "methyl-C_3-7Examples of the "cycloalkoxy group" include 4-methylcyclohexyloxy group, 3, 3-dimethylcyclopentyloxy group and 1-methylcyclopropoxy group.

Unless otherwise indicated or specified, the term "fluoro-C_3-7-cycloalkyl "refers to C substituted by one or two fluorine atoms_3-7-a cycloalkyl group. Said "fluoro-C_3-7Examples of the "cycloalkyl group" include 2, 2-difluorocyclopropyl and 4-fluorocyclohexyl.

Unless otherwise indicated or specified, the term "fluoro-C_3-7-Cycloalkoxy "means C substituted by one or two fluorine atoms_3-7-a cycloalkoxy group. Said "fluoro-C_3-7Examples of the "cycloalkoxy group" include a 2, 2-difluorocyclopropoxy group and a 4-fluorocyclohexyloxy group.

Unless otherwise indicated or specified, the term "aryl" refers to a hydrocarbon ring system having at least one aromatic ring and having one, two, or three rings (preferably one or two rings) of 6 to 14 (preferably 6 to 10) carbon atoms. Examples of aryl groups are phenyl, pentalenyl, indenyl, indanyl, 1, 2, 3, 4-tetrahydronaphthyl, 1-naphthyl, 2-naphthyl, fluorenyl and anthracenyl. The aromatic ring may be optionally substituted. Similarly, aryloxy refers to an aryl group attached to an oxygen atom.

The aryl group can be attached to the remainder of the molecule through any available ring carbon, whether in an aromatic ring or a partially saturated ring.

The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring system in which only one ring needs to be aromatic, and the heteroaryl moiety can be attached to the rest of the molecule through any ring carbon or nitrogen atom, and has 5 to 10 ring atoms (monocyclic or bicyclic), one or more of which are other than carbon, such as nitrogen, sulfur, oxygen, and selenium. Examples of such heteroaryl rings include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, chromanyl, quinazolinyl, indolyl, isoindolyl, indolinyl, isoindolyl, indazolyl, pyrazolyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl. If a bicyclic heteroaryl ring is substituted, it may be substituted in any ring.

Unless otherwise indicated or specified, the term "heterocycle" refers to a non-aromatic (i.e., partially or fully saturated) mono-or bicyclic ring system having from 4 to 10 ring atoms having at least one heteroatom such as O, N, or S therein, and the remaining ring atoms being carbon. Preferably, "heterocycle" refers to a fully saturated, non-aromatic, monocyclic ring system having 4-7 ring atoms, and wherein one or two atoms are heteroatoms selected from O, N and S and the remaining ring atoms are carbon. Examples of heterocyclic groups include piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, azaAnd (b) a group selected from azetidinyl, pyrrolidinyl, morpholinyl, imidazolinyl, thiomorpholinyl, pyranyl, dioxanyl, and piperazinyl. When present in a heterocyclyl group, the sulfur atom may optionally be present in oxidized form (i.e., S ═ O or O ═ S ═ O).

Unless otherwise specified or indicated, the term "carbocycle" refers to a non-aromatic (i.e., partially or fully saturated) monocyclic ring system having 3 to 6 carbon ring atoms. Examples of carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclohexene.

The term "halogen" means fluorine, chlorine, bromine or iodine unless otherwise indicated or specified.

term-S (O)_eR¹¹Wherein e is 0, 1, 2 or 3, having the meaning exemplified by formulae (VI) - (IX):

the term "lactam" refers to a lactam group selected from the group consisting of 2-azetidinone-1-yl, 2-pyrrolidone-1-yl, and 2-piperidone-1-yl.

The term "sultam" refers to a sultam group selected from tetrahydro-1, 1-dioxo (dioxido) -2H-1, 2-thiazin-2-yl and 1, 1-dioxo-2-isothiazolidinyl.

"optional" or "optionally" means that the subsequently described event or fact may, but need not, occur, and that the description includes instances where the event or fact occurs and instances where it does not.

"pharmaceutically acceptable" means for preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, including for veterinary use as well as human pharmaceutical use.

"treating" as used herein includes preventing a so-called disease or condition, or ameliorating or eliminating a disease once it has developed.

An "effective amount" refers to an amount of a compound that confers a therapeutic effect on the subject being treated. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of the effect or feels the effect).

References to "compounds of formula I" in the embodiments herein also include compounds of any of the general formulae recited herein.

The term "prodrug form" means a pharmaceutically acceptable derivative, such as an ester or amide, that is biotransformed in vivo to form the active drug. Reference is made to Goodman and Gilman's, The pharmacological lbs of Therapeutics (pharmacological basis of therapeutic agents), 8 th edition, Mc-Graw-Hill, int.Ed.1992, "Biotransformation of Drugs", pages 13-15; and Richard B.Silverman, "The Organic Chemistry of Drug Design and Drug action", Richard B.Silverman. Chapter 8, page 352 (Academic Press, Inc. (Academic Press Co., Ltd.) 1992.ISBN 0-12-643730-0).

Combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds. The term "stable" as used herein refers to a compound that possesses sufficient stability to permit manufacture, and which maintains the integrity of the compound for a sufficient period of time for purposes detailed herein (e.g., therapeutic administration to a subject for treatment of a 5-HT 6-mediated disease or condition (including those recited herein), obesity, type 2 diabetes).

The recitation of a list of chemical groups in any definition of a variable herein includes definitions of the variable as any single group or combination of listed groups. Recitation of embodiments of variables herein includes those embodiments taken as any single embodiment or in combination with any other embodiments or portions thereof.

The following abbreviations are used:

CV refers to the coefficient of variation,

DCM refers to the amount of dichloromethane that is present,

DMSO refers to a solvent selected from the group consisting of dimethyl sulfoxide,

the EDTA refers to the ethylene diamine tetraacetic acid,

EGTA refers to ethylene bis (oxyethylene-nitrilo) tetraacetic acid,

ESI refers to the ionization of an electrospray,

HEPES means 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid,

HPLC refers to the high performance liquid chromatography of,

LSD refers to the concentration of lysergic acid, diethylamine,

MeCN refers to the group of acetonitrile,

SPA refers to scintillation proximity assay

TFA refers to the group of trifluoroacetic acid,

THF is taken to mean tetrahydrofuran which is present,

UV means ultraviolet ray

MeOH means methanol

The designation BnBr refers to the benzyl bromide,

DCE refers to the molar ratio of 1, 2-dichloroethane,

TMAD refers to (E) -N, N, N ', N' -tetramethyldiazene-1, 2-dicarboxamide.

Examples

The invention will now be further illustrated by the following non-limiting examples. The following specific examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All references and publications cited herein are hereby incorporated by reference in their entirety.

Method

¹H Nuclear Magnetic Resonance (NMR) and¹³c NMR was recorded at 400.1 and 100.6MHz respectively on a Bruker Advance DPX 400 spectrophotometer, or at 400 and 100, 5MHz respectively on a Varian Inova 400 spectrophotometer, or at 500.1MHz and 125.1MHz respectively on a Bruker NMR 500 spectrophotometer, or at 270.0MHz and 67.5MHz respectively on a JEOL eclipse 270 spectrophotometer. All spectra were recorded using residual solvent as an internal standard.

Preparative HPLC/MS were performed using an Agilent 1100/1200 series chromatography/Mass Spectroscopy Selective Detector (MSD) (Singel Quadrupole) (1946A/1946C/1956C/6110) equipped with an electrospray interface.

Preparative HPLC/MS was performed on a Waters/Micromass platform ZQ system and preparative HPLC/UV was performed on a Gilson system.

Preparative flash chromatography was performed on Merck silica gel 60(230- & 400 mesh). ACD Name6.0 was used to name the compounds, except that for the compound in example 1, the compound of example 1 was 2, 5-methylene-9- (phenylsulfonyl) -1, 2, 3, 4, 5, 9-hexahydro [1, 5] oxazocino (oxazocino) [3, 2-e ] indole. Microwave reactions were carried out with a Personal chemical Smith creator (Personal Chemistry Smith reactor) using 0.5-2mL or 2-5mL Smith treatment vials equipped with aluminum caps and septa.

TABLE I

Intermediate 1

2-bromo-3-methyl-4-nitro-phenol

A2: 1 mixture of 2-bromo-3-methyl-4-nitro-phenol and 2-bromo-5-methyl-4-nitro-phenol was prepared by bromination of 3-methyl-4-nitrophenol as described in the literature (Muntwyler, R., Widmer, J., Keller-Schierlein, W.Synthese des 5-chlorine-6-methyl-，eines Abbauproduktes des Chlorothricins.Helv Chim Acta 1970，53，1544-1547)。

Intermediate 2

5- (benzyloxy) -4-bromo-1H-indole

K triturated in anhydrous acetone (150mL)₂CO₃(11.4g, 83.0mmol) of a regiomixture of bromophenols (regiotexture), (intermediate 1, 12.4g, 53.5mmol) and BnBr (9.42g, 55.1mmol) were added and the mixture was heated at reflux for 2 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressureTo provide an oil, which was used in the next step without further purification. The crude anisole was dissolved in anhydrous DMF (100mL) and dimethylformamide dimethyl acetal (13.0g, 109mmol) was added and the reaction was heated at 90 ℃ for 2 days. On each of the next three days, a portion of dimethylformamide dimethyl acetal (1.0g, 8.0mmol) was added at 90 ℃. The solvent was removed under reduced pressure, and the black/red oily residue was dissolved in acetic acid (20 mL). The viscous solution was carefully added to a well-stirred suspension of iron powder (9.15g, 164mmol) in warm acetic acid (60mL) over a period of 10 minutes. The thick reaction mixture was heated at reflux for 1 hour, the solid was filtered, and the filtrate was evaporated under reduced pressure. Dissolve the black residue in warm CHCl₃To (350mL) was added 50g of silica gel followed by heptane (350 mL). The mixture was filtered through a pad of silica gel and the solvent was evaporated. The black residue was purified by flash chromatography on silica gel using petroleum ether/EtOAc 90:10 as eluent to give the title compound as a dark green oil (4.0 g). MS M/z 302/304[ M + H ]]⁺。

Intermediate 3

4-bromo-5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole

To a solution of 4-bromo-5-benzyloxy-1H-indole (intermediate 2, 3.85g, 12.7mmol) in DCM (30mL) was added benzenesulfonyl chloride (2.47g, 14.0mmol), tetrabutylammonium hydrogen sulfate (0.41g, 1.3mmol) and 3M NaOH (13mL, 39mmol) and the mixture was stirred vigorously at room temperature for 30 min. The organic phase was washed with water and brine and dried (MgSO)₄) And concentrated to dryness to give the title compound (5.7g) as a solid. MS M/z 442/444[ M + H ]]⁺。

Intermediate 4

5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole-4-carbaldehyde

To a warm solution of 4-bromo-5-benzyloxy-1- (phenylsulfonyl) -1H-indole (intermediate 3, 4.74g, 10.7mmol) in toluene (100mL) was added tributylvinyltin (6.80g, 21.4 g)mmol) and Pd (PPh)₃)₂Cl₂(0.37g, 0.50 mmol). The solution was heated at reflux for 2 hours and more Pd (PPh) was added₃)₂Cl₂(0.20g, 0.30mmol) and the reaction mixture was refluxed overnight. Add 1 teaspoon of silica gel and filter the mixture through a pad of silica gel. The solvent was removed under reduced pressure and the resulting oil was triturated with petroleum ether to give a semi-crystalline material (3.6g), which was dissolved in dioxane (110mL) and 2, 6-lutidine (2.00g, 18.7mmol) and OsO was added₄(0.24g, 0.94 mmol). The reaction was stirred at room temperature for 5 minutes. To the dark solution was added a solution of sodium periodate (8.02g, 37.5mmol) in water (35mL) and the resulting suspension was stirred for 30 minutes. More dioxane (40mL) was added and the mixture was filtered. The filtrate was evaporated to give a dark red oil. The crude product was purified by flash chromatography on silica gel using petroleum ether/EtOAc 90:10 followed by 80:20 as eluent to give the title compound (2.44g) as a yellow solid. MS M/z 392[ M + H ]]⁺。

Example 1

2, 5-methylene-9- (phenylsulfonyl) -1, 2, 3, 4, 5, 9-hexahydro [1, 5] oxazocino [3, 2-e ] indole

To a solution of 5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole-4-carbaldehyde (intermediate 4,100mg, 0.250mmol) in DCE (3mL) was added 3-hydroxypyrrolidine, (33mg, 0.38mmol) and sodium triacetoxyborohydride (0.16g, 0.77mmol), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in MeOH (2mL) and Pd/C10 wt% (0.020g, 0.019mmol) was added and the mixture was taken up with N₂And (5) air flushing. Ammonium formate (0.050g, 0.80mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in CHCl₃/H₂O and the mixture was washed with water and brine and dried (MgSO)₄) And the solvent was removed under reduced pressure to give 4- [ (3-hydroxypyrrolidin-1-yl) methyl group as an oil]-1- (phenylsulfonyl) -1H-indol-5-ol (85 mg). MS (Mass Spectrometry) m/z 373[M+H]⁺。

The oil (85mg, 0.23mmol) was dissolved in anhydrous DCM (3mL) and triphenylphosphine (179mg, 0.680mmol) was added followed by 1, 1' -azobis (N, N-dimethylformamide) (118mg, 0.680mmol) and the mixture was stirred at rt overnight. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) was added to the residue to give the title compound (8.0mg) as a brown oil. MS M/z 355[ M + H ]]⁺。

Example 2

2, 4-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

To a solution of 5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole-4-carbaldehyde (intermediate 4, 0.050g, 0.12mmol) in DCE (3mL) was added 1-amino-2-propanol, (0.020g, 0.27mmol) and sodium triacetoxyborohydride (0.080g, 0.38mmol) and the mixture was stirred at room temperature overnight. Adding formaldehyde to the reaction mixture (in H)₂37% by weight in O, 0.10mL, 1.2mmol) and sodium triacetoxyborohydride, (0.10g, 0.48mmol) and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in MeOH (2 mL). Pd/C10 wt% (0.020g, 0.019mmol) was added and the mixture was treated with N₂And (5) air flushing. Ammonium formate (0.050g, 0.80mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the semi-solid was charged to CHCl₃/H₂O and the mixture was washed with water and brine and dried (MgSO)₄) And the solvent was removed under reduced pressure. The crude product was dissolved in anhydrous DCM (1mL) and triphenylphosphine (8.0mg, 0.030mmol) was added followed by 1, 1' -azobis (N, N-dimethylformamide) (5.2mg, 0.030mmol) and the mixture was stirred at rt overnight. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (ACE C8, 0.1%TFA-CH₃CN) to give the title compound as the trifluoroacetate salt (7.4 mg). MS M/z357[ M + H]⁺。

Example 3

2-isopropyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

To a solution of 5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole-4-carbaldehyde (intermediate 4, 0.033g, 0.084mmol) in DCE (2.5mL) were added N-isopropylethanolamine (0.017g, 0.17mmol) and sodium triacetoxyborohydride (0.036g, 0.17mmol), and the mixture was stirred in a sealed pyrex glass tube at 40 ℃ overnight. The solvent was removed under reduced pressure, and the residue was dissolved in MeOH (2 mL). Pd/C10 wt% (0.020g, 0.019mmol) was added and the mixture was treated with N₂And (5) air flushing. Ammonium formate (0.021g, 0.34mmol) was added and the reaction mixture was stirred at 40 ℃ overnight. The reaction mixture was filtered through a plug of water matrix with DCM as eluent and the filtrate was evaporated. The crude was dissolved in anhydrous DCM (1mL) and triphenylphosphine (0.044g, 0.017mmol) was added followed by 1, 1' -azobis (N, N-dimethylformamide) (0.029g, 0.017mmol) and the mixture was stirred at rt overnight. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (5.2mg) as a colorless oil as trifluoroacetate salt. MS M/z371[ M + H]⁺。

Example 4

2-Ethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

To a solution of 5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole-4-carbaldehyde (intermediate 4, 0.033g, 0.084mmol) in DCE (2.5mL) was added N-ethyl acetateMonoethanolamine (0.015g, 0.17mmol) and sodium triacetoxyborohydride (0.036g, 0.17mmol), and the mixture was stirred in a sealed pyrex tube at 40 ℃ overnight. The solvent was removed under reduced pressure, and the residue was dissolved in MeOH (2 mL). Pd/C10 wt% (0.010g, 0.0095mmol) was added and the mixture was stirred with N₂And (5) air flushing. Ammonium formate (0.021g, 0.34mmol) was added and the reaction mixture was stirred at 40 ℃ overnight. The reaction mixture was filtered through a plug of water matrix with DCM as eluent and the filtrate was evaporated. The crude was dissolved in anhydrous DCM (1mL) and triphenylphosphine (0.044g, 0.017mmol) was added followed by 1, 1' -azobis (N, N-dimethylformamide) (0.029g, 0.017mmol) and the mixture was stirred at rt overnight. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (0.8mg) as a colorless oil as trifluoroacetate salt. MS M/z357[ M + H]⁺。

Intermediate 5

4- { [ (2-hydroxy-ethyl) -methyl-amino ] -methyl } -1H-indol-5-ol

Paraformaldehyde (0.060g, 2mmol) and 2-methylaminoethanol (0.15g, 2.0mmol) were suspended in ethanol (10mL) and heated at 50 ℃ for 20 minutes. The solution was cooled to room temperature and 5-hydroxyindole (0.27mg, 2.0mmol) was added. The solution was incubated at room temperature under N₂Stir under atmosphere overnight. The solution was evaporated to give the title compound (441mg), which was used in the next step without further purification. MS M/z 221[ M + H ]]⁺。

Intermediate 6

2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Coupling 4- { [ (2-hydroxy-ethyl) -methyl-amino]-methyl } -1H-indol-5-ol (intermediate 5, 0.44g, 2.0mmol), 1, 1' -azobis (N, N-dimethylformamide) (0.52mg, 3.0mmol) and triphenylphosphine (0.79mg, 3.0mmol) were dissolved in THF (10mL) and stirred at room temperature overnight. The mixture was evaporated and the crude material was purified by flash chromatography on silica gel with a MeOH-ethyl acetate gradient, 4-32% MeOH, to give 136mg of the title compound. MS M/z 203[ M + H ]]⁺。

Example 5

2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

DMF (15mL) was added to the solution containing 2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]]OxazazemAnd [6, 7-e ]]Indole (intermediate 6, 0.250g, 1.24mmol) and sodium hydride (60% in mineral oil, 0.100g, 2.50 mmol). The mixture was stirred at room temperature for 20 minutes, after which benzenesulfonyl chloride (0.327g, 1.85mmol) was added. The reaction was allowed to stir for 30 minutes, after which 2M HCl (0.5mL) was added and the mixture was taken up with 1M Na₂CO₃And diethyl ether. The organic phase was washed with water and dried (MgSO)₄) And evaporated. The crude product was dissolved in DCM (2mL) and added (20 mL). The mixture was allowed to stand overnight, and the pale yellow crystals were filtered and washed with hexane to give the title compound (202mg) as a pale yellow solid. MS M/z343[ M + H ]]⁺。

General procedure for preparation of examples 6-34

2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole (intermediate 6, 0.010g, 0.050mmol) was dissolved in anhydrous DMF (0.2mL) and sodium hydride (60% in mineral oil, 0.6mg, 0.1mmol) was added. The reaction mixture was shaken at room temperature for 10 min and the necessary sulfonyl chloride (0.1mmol in 0.15mL anhydrous DMF) was added. The reaction was shaken at room temperature for 10-20 minutes, andthen quenched by the addition of 1mL of methanol and acetic acid (1: 1). The crude product was purified as follows.

Example 6

8- (2, 3-dihydro-1, 4-benzodioxine-6-ylsulfonyl) -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2, 3-dihydro-1, 4-benzodioxine-6-sulfonyl chloride (0.023g, 0.10mmol)

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (11 mg). MS M/z 401[ M + H ]]⁺。

Example 7

8- [ (3, 4-Dimethoxyphenyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 3, 4-Dimethoxybenzenesulfonyl chloride (0.024g, 0.10mmol)

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (10.9 mg). MS M/z 403[ M + H ]]⁺。

Example 8

8- (1-benzofuran-2-ylsulfonyl) -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 1-benzofuran-2-sulfonyl chloride (0.022g, 0.10mmol)

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (5.5 mg). MS M/z 383[ M + H ]]⁺。

Example 9

8- [ (2, 5-dimethyl-3-furyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2, 5-dimethyl-3-furansulfonyl chloride (0.019g, 0.10mmol)

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (11.4 mg). MS M/z361[ M + H ]]⁺。

Example 10

8- (1, 3-benzothiazol-6-ylsulfonyl) -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 1, 3-benzothiazole-6-sulfonyl chloride (0.023g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (7.1 mg). MS M/z 400[ M + H ]]⁺。

Example 11

2-methyl-8- { [4- (methylsulfonyl) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4-Methylsulfonylbenzenesulfonyl chloride (0.025g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18,50mM NH₄HCO₃ pH 10-CH₃CN) to give the title compound (9.5 mg). MS M/z 421[ M + H ]]⁺。

Example 12

8- [ (4-isopropylphenyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4-isopropylbenzene-1-sulfonyl chloride (0.022g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (10.7 mg). MS M/z 385M + H]⁺。

Example 13

8- [ (2, 2-dimethyl-3, 4-dihydro-2H-benzofuran-6-yl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2, 2-dimethyl-6-chromansulfonyl chloride (0.026g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (9.6 mg). MS M/z 427[ M + H ]]⁺。

Example 14

8- [ (2-chloro-4-fluorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2-chloro-4-fluorobenzenesulfonyl chloride (0.023g, 0.10 mmol).

The crude product is preparedHPLC(XTerra C18，50mM NH₄HCO₃ pH 10-CH₃CN) to give the title compound (10.3 mg). MS M/z395[ M + H]⁺。

Example 15

8- [ (3, 4-dichlorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 3, 4-Dichlorobenzenesulfonyl chloride (0.025g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (12.2 mg). MS M/z 412[ M + H ]]⁺。

Example 16

8- [ (4-fluorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4-fluorobenzenesulfonyl chloride (0.019g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (12.8 mg). MS M/z361[ M + H ]]⁺。

Example 17

8- [ (2, 6-difluorophenyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2, 6-difluorobenzenesulfonyl chloride (0.021g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (11.2 mg). MS M/z379[ M + H ]]⁺。

Example 18

2-methyl-8- { [4- (trifluoromethoxy) phenyl group]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4- (trifluoromethoxy) benzene-1-sulfonyl chloride (0.026g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (16.8 mg). MS M/z 427[ M + H ]]⁺。

Example 19

2-methyl-8- (2-naphthylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2-Naphthalenesulfonyl chloride (0.023g, 0.10 mmol). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (19.8 mg). MS M/z 393[ M + H ]]⁺。

Example 20

8- [ (3-chloro-4-methylphenyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 3-chloro-4-methylbenzenesulfonyl chloride (0.023g, 0.10 mmol). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (2.2 mg). MS M/z 391[ M + H]⁺。

Example 21

8- [ (4, 5-dichloro-2-thienyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2, 3-dichlorothiophene-5-sulfonyl chloride (0.025g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (11.5 mg). MS M/z 418[ M + H ]]⁺。

Example 22

8- [ (5-chloro-3-methyl-1-benzothien-2-yl) sulfonyl ] sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 5-chloro-3-methylbenzo (b) thiophene-2-sulfonyl chloride (0.028g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (9 mg). MS M/z 447[ M + H ]]⁺。

Example 23

8- [ (2, 4-dichlorophenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2, 4-Dichlorobenzenesulfonyl chloride (0.025g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (9 mg). MS m/z 412[M+H]⁺。

Example 24

8- { [ 4-fluoro-3- (trifluoromethyl) phenyl]Sulfonyl } -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (0.026g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (4 mg). MS M/z 429[ M + H [)]⁺。

Example 25

2-methyl-8- (2-thienylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2-Thienylsulfonyl chloride (0.018g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (2 mg). MS M/z 349[ M + H]⁺。

Example 26

2-methyl-8- [ (4-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4-tosyl chloride (0.019g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (12 mg). MS M/z357[ M + H]⁺。

Example 27

8- [ (2-methoxy-5-methylphenyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2-methoxy-5-methylbenzenesulfonyl chloride (0.022g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (12 mg). MS M/z387[ M + H ]]⁺。

Example 28

8- [ (3-fluoro-4-methylphenyl) sulfonyl]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 3-fluoro-4-methylbenzenesulfonyl chloride (0.021g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (12 mg). MS M/z 375[ M + H ]]⁺。

Example 29

8- (1-benzothien-3-ylsulfonyl) -2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 1-benzothiophene-3-sulfonyl chloride (0.023g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (12 mg). MS M/z 399[ M + H ]]⁺。

Example 30

8- [ (4-methoxyphenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4-Methoxybenzenesulfonyl chloride (0.021g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (6.2 mg). MS M/z 373[ M + H ]]⁺。

Example 31

2-methyl-8- { [4- (trifluoromethyl) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4- (trifluoromethyl) -benzenesulfonyl chloride (0.024g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (11.6 mg). MS M/z 411[ M + H ]]⁺。

Example 32

2-methyl-8- [ (4-propylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 4-Propylbenzenesulfonyl chloride (0.022g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (13 mg). MS M/z 385M + H]⁺。

Example 33

3-chloro-4- [ (2-methyl-1, 2, 3, 4-tetrahydro-8H- [1, 4]]OxazazemAnd [6, 7-e ]]Indol-8-yl) sulfonyl]Benzonitrile

Sulfonyl chloride: 2-chloro-4-cyanobenzenesulfonyl chloride (0.024g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (2 mg). MS M/z 402[ M + H ]]⁺。

Example 34

8- [ (2, 5-dimethyl-3-thienyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sulfonyl chloride: 2, 5-dimethyl-3-thiophenesulfonyl chloride (0.021g, 0.10 mmol).

The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (11.3 mg). MS M/z 377[ M + H ]]⁺。

Example 35

2- [ (2-methyl-1, 2, 3, 4-tetrahydro-8H- [1, 4]]OxazazemAnd [6, 7-e ]]Indol-8-yl) sulfonyl]Benzonitrile

NaH (60% in mineral oil, 0.040g, 1.0mmol) was charged to a pyrex glass tube under nitrogen and 2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] in anhydrous DMF (1mL) was added]OxazazemAnd [6, 7-e ]]Indole (intermediate)6,100mg, 0.492 mmol). The reaction mixture was stirred at room temperature for 20 minutes, after which 2-cyanobenzenesulfonyl chloride (0.11g, 0.50mmol) was added and the reaction mixture was stirred for 1 hour. Water (2mL) was added and the solution was extracted with DCM. The combined organics were evaporated and the solid residue was washed with diethyl ether to give 64mg of the title compound. MS M/z 368[ M + H]⁺。

Example 36

2-methyl-1- [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indol-9-yl]Propan-1-one trifluoroacetate salt

2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in THF (1mL)]OxazazemAnd [6, 7-e ]]The indole (example 5, 0.020g, 0.058mmol) was cooled to-78 ℃ under a nitrogen atmosphere. BuLi (1.6M in hexane, 0.11mL, 0.18mmol) was added, and the solution was stirred for 10 minutes before methyl isobutyrate (0.20mL, 0.18mmol) was added. Stirring was continued overnight and the temperature of the reaction mixture was allowed to reach room temperature. The reaction mixture was evaporated and subjected to preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (6mg) as the trifluoroacetate salt. MS M/z 413[ M + H ]]⁺。

Example 37

1- [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indol-9-yl]Ethanone trifluoroacetate salt

2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in THF (1mL)]OxazazemAnd [6, 7-e ]]The indole (example 5, 0.020g,0.058mmol) was cooled to-78 ℃ under a nitrogen atmosphere. BuLi (1.6M in hexanes, 0.11mL, 0.18mmol) was added, and the solution was stirred for 10 minutes before acetic anhydride (0.18mL, 0.18mmol) was added. Stirring was continued overnight and the temperature of the reaction mixture was allowed to reach room temperature. The reaction mixture was evaporated and subjected to preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (18mg) as the trifluoroacetate salt. MS M/z 385M + H]⁺。

Example 38

9-chloro-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in THF (1mL)]OxazazemAnd [6, 7-e ]]The indole (example 5, 0.030g, 0.088mmol) was cooled to-78 ℃ under a nitrogen atmosphere. BuLi (2.5M in hexane, 0.053mL, 0.13mmol) was added. The solution was stirred for 15 min and thiophene-2-sulfonyl chloride (24mg, 0.13mmol) was added. The temperature of the reaction mixture was allowed to rise to room temperature overnight and evaporated. This material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was added to the reaction solution to give the title compound (5.2mg) as a trifluoroacetate salt. MS M/z 377[ M + H ]]⁺。

Example 39

2- [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indol-9-yl]Propan-2-ol trifluoroacetate salt

2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] at-78 ℃ under a nitrogen atmosphere]OxazazemAnd [6, 7-e ]]The indole (example 5, 0.030g, 0.088mmol) was dissolved in anhydrous THF (1 mL). BuLi (2.5M in hexanes, 0.053mL, 0.13mmol) was added and the solution was stirred for 15 minutes before acetone (0.010mL, 0.13mmol) was added. The temperature of the reaction mixture was allowed to rise to room temperature overnight. This material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was added to the reaction solution to give the title compound (10.5mg) as a trifluoroacetate salt. MS M/z 401[ M + H ]]⁺。

Example 40

Cyclopropyl [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indol-9-yl]Methanol

2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]The indole (example 5, 0.030g, 0.088mmol) was dissolved in anhydrous THF (1mL) at-78 deg.C under a nitrogen atmosphere. BuLi (2.5M in hexane, 0.053mL, 0.13mmol) was added. The solution was stirred for 15 minutes, after which methyl cyclopropanecarboxylate (0.013mL, 0.13mmol) was added. The temperature of the reaction mixture was allowed to rise to room temperature overnight. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (1.5 mg). MS M/z 413[ M + H ]]⁺。

EXAMPLE 41

1- [ 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indol-9-yl]Trifluoroacetic acid salt of ethanol

2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]The indole (example 5, 0.030g, 0.88mmol) was dissolved in anhydrous THF (1mL) at-78 deg.C under a nitrogen atmosphere. BuLi (2.5M in hexane, 0.053mL, 0.13mmol) was added. The solution was stirred for 15 minutes, after which acetic anhydride (0.012mL, 0.13mmol) was added. The temperature of the reaction mixture was allowed to rise to room temperature overnight. This material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (4.1mg) as a white solid as a trifluoroacetate salt. MS M/z387[ M + H ]]⁺。

Example 42

10-chloro-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

N-chlorosuccinimide (NCS) (29mg, 0.21mmol) was added to 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in THF (2mL)]OxazazemAnd [6, 7-e ]]Indole example 5, 0.050g, 0.15mmol) and the reaction mixture was heated at 50 ℃ overnight. Additional NCS (0.030g, 0.22mmol) was added and the mixture was heated at 50 ℃ for 4 days. The mixture was evaporated and the crude material was flash chromatographed on silica gel with MeOH: DCM: NEt₃(2:97:1) to give 7.3mg of a white solid. MS M/z 377[ M + H ]]⁺。

Intermediate 7

5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole

4M NaOH (100mL, 0.4mol) was added to a solution of 5-benzyloxyindole (20g, 0.09mol), tetrabutylammonium bisulfate (6.1g, 0.018mol), and benzenesulfonyl chloride (27g, 0.15mol) in DCM (500 mL). The mixture was stirred at room temperature for 6 hours and additional benzenesulfonyl chloride (4.1g, 0.023mol) was added. The mixture was stirred overnight and diluted with water and DCM. The mixture was transferred to a separatory funnel and extracted with DCM (2 ×), dried (MgSO)₄) And evaporated. The crude product was suspended in diethyl ether (1000mL) and filtered. The solid filter cake was washed with diethyl ether (2 ×) and discarded. The filtrate was evaporated to about 100mL (precipitation of white solid) and filtered. The white crystals were washed with cold diethyl ether (2 ×) and dried in vacuo to give 15g of a white solid. MS M/z 364[ M + H]⁺

Intermediate 8

1- (phenylsulfonyl) -1H-indol-5-ols

Pd/C10 wt% (0.10g, 0.094mmol) was added to a solution of 5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole (intermediate 7, 6.00g, 16.5mmol) and ammonium formate (15.6g, 248mmol) in THF/MeOH 1:1(300 mL). The reaction mixture was stirred at room temperature overnight and filtered through a short plug of silica gel. The filtrate was evaporated and dissolved in DCM and filtered through a plug of silica gel eluting with 2.5% MeOH in DCM. The purest fraction (monitored by TLC) was evaporated to give the title compound as a white powder (4.2 g). MS M/z 273[ M + H ]]⁺。

Intermediate 9

4- (hydroxymethyl) -1- (phenylsulfonyl) -1H-indol-5-ol

1- (phenylsulfonyl) -1H-indol-5-ol (intermediate 8, 0.80g, 2.9mmol) was dissolved in MeOH (20mL) and formaldehyde (37 wt% in H) was added₂O, 4.0mL, 49mmol) followed by addition of a solution of KOH (1.64g, 29.3mmol) in water (20 mL). The reaction mixture was heated at 40 ℃ overnight. The mixture was acidified with 1M HCl and diluted with DCM, transferred to a separatory funnel and extracted with DCM (2 ×). The combined organics were washed with brine (1 ×), dried (MgSO)₄) And evaporated. The crude product was dissolved in diethyl ether (100mL) and evaporated to about 20mL (precipitation of white crystals). The white crystals were filtered and washed with diethyl ether (2 ×) to give 0.43g of the title compound as a white solid. MS M/z 286[ M + H-H₂O]⁺。

Intermediate 10

5-hydroxy-1- (phenylsulfonyl) -1H-indole-4-carbaldehyde

4- (hydroxymethyl) -1- (phenylsulfonyl) -1H-indol-5-ol (intermediate 9,439mg, 1.45mmol) was dissolved in anhydrous DCM (25mL) and magnesium dioxide (0.75g, 8.7mmol) was added all in one portion. The reaction mixture was stirred at room temperature for 2 hours, and the mixture was filtered through a pad of silica gel. The filtrate was washed with water (1 ×), dried (MgSO)₄) And evaporated to give 0.2g of an orange oil. MSm/z 302[ M + H ]]⁺。

Example 43

(7aR) -3- (phenylsulfonyl) -3, 7a, 8, 9, 10, 12-hexahydro-7H-pyrrolo [2 ', 1': 3,4][1，4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

1, 1' -azobis (N, N-dimethylformamide) (23mg, 0.13mmol) was added to a solution of 5-hydroxy-1- (phenylsulfonyl) -1H-indole-4-carbaldehyde (intermediate 10, 0.020g, 0.067mmol), (R) -1-Boc-2-pyrrolidinemethanol (26.7mg, 0.133mmol) and triphenylphosphine (34.8mg, 0.133mmol) in DCM (2 mL). The reaction mixture was stirred at rt overnight, evaporated and the crude was purified by flash chromatography on silica gel with 2.5% MeOH in DCM as eluent. The purest fractions were evaporated and dissolved in DCM (3mL) and TFA (1mL) was added. The mixture was stirred for 2 hours, evaporated and dissolved in THF (1 mL). Sodium triacetoxyborohydride (56mg, 0.27mmol) was added, and the mixture was stirred at room temperature for 15 minutes and evaporated. This material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (8mg) as a light brown liquid as a trifluoroacetate salt. MS M/z 369[ M + H ]]+。

Example 44

(7aS) -3- (phenylsulfonyl) -3, 7a, 8, 9, 10, 12-hexahydro-7H-pyrrolo [2 ', 1': 3, 4][1，4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

1, 1' -azobis (N, N-dimethylformamide) (34mg, 0.20mmol) was added to a solution of 5-hydroxy-1- (phenylsulfonyl) -1H-indole-4-carbaldehyde (intermediate 10, 0.030g, 0.10mmol), (S) -1-Boc-2-pyrrolidinemethanol (40.0mg, 0.20mmol) and triphenylphosphine (52mg, 0.20mmol) in DCM (2 mL). The reaction mixture was stirred at 45 ℃ for 3 hours, evaporated and the crude was purified by flash chromatography on silica gel with 1% to 2.5% MeOH in DCM as eluent. The boc-protected intermediate was dissolved in DCM (2mL) and TFA (1mL) was added. The mixture was stirred at room temperature for 1 hour and evaporated. The residue was dissolved in THF (2mL) and sodium triacetoxyborohydride (84.0mg, 0.40mmol) was added. The mixture was stirred for 20 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (9mg) as a yellow oil as trifluoroacetate salt. MS M/z 369[ M + H ]]⁺。

Example 45

(3S) -3-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 1' -azobis (N, N-dimethylformamide) (57mg, 0.33mmol) was added to a solution of 5-hydroxy-1- (phenylsulfonyl) -1H-indole-4-carbaldehyde (intermediate 10, 0.050g, 0.16mmol), S- (-) -2- (tert-butoxycarbonylamino) -1-propanol (58mg, 0.33mmol) and triphenylphosphine (87mg, 0.33mmol) in DCM (5 mL). The mixture was stirred at 45 ℃ for 2 days and the mixture was evaporated. The crude was purified by flash chromatography with 1% to 2.5% MeOH in DCM. The boc-protected intermediate was dissolved in DCM (3mL) and TFA (1mL) was added. The mixture was stirred for 1 hour and evaporated. The residue was dissolved in THF (3mL), and sodium triacetoxyborohydride (30.0mg, 0.141mmol) was added in one portion. The reaction mixture was stirred for 20 minutes and evaporated. Flash chromatography of the crude product on silica gel with MeOH, DCM, NEt₃(5:94:1) as eluent to obtain the productTitle compound as a yellow solid (15 mg). MS M/z343[ M + H ]]⁺。

Example 46

(3S) -2, 3-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Mixing (3S) -3-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]The indole (example 45, 0.010g, 0.029mmol) was dissolved in THF (1mL) and formaldehyde (37 wt% in H) was added₂0.020mL, 0.25mmol in O). The mixture was stirred for 5 minutes, after which sodium triacetoxyborohydride (7.5mg, 0.044mmol) was added all in one portion. The mixture was stirred at room temperature for 1 hour and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) to give the title compound as a pale yellow gum (11.5mg) as the trifluoroacetate salt. MS M/z357[ M + H]⁺。

Intermediate 11

7-methyl-1H-indol-5-ol

Prepared according to PCT International application WO 9523141, 1995.

Intermediate 12

4- { [ (2-hydroxyethyl) (methyl) amino ] methyl } -7-methyl-1H-indol-5-ol

Paraformaldehyde (82.0mg, 2.71mmol) in EtOH (2mL) and 2-methylaminoethanol (0.218mL, 2.71mmol) were heated at 50 ℃ for 20 minutes. 7-methyl-1H-indol-5-ol (intermediate 11,500mg, 3.4mmol) in EtOH (10mL) was added and the mixture was stirred at room temperature for 1.5H. The mixture was diluted with DCM (15mL) and divided into two portions for purification on two SCX-columns (5g), pretreated with DCM/MeOH 1:1(20mL) and with DCM/MeOH 1:1(50mL) containing sm only and 1M MeOH (40mL) (containing product) eluted to give 490mg of a brown oil which became a solid. MS M/z 235[ M + H ]]⁺。

Intermediate 13

2, 7-dimethyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

4- { [ (2-hydroxyethyl) (methyl) amino in THF (10mL)]Methyl } -7-methyl-1H-indol-5-ol (intermediate 12,490mg, 2.1mmol), triphenylphosphine (883mg, 3.14mmol) and 1, 1' -azobis (N, N-dimethylformamide) (540mg, 3.1mmol) were stirred at room temperature overnight. The mixture was diluted with MeOH and the material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (60.8mg) as a brown oil as trifluoroacetate salt. MS M/z 217[ M + H ]]⁺。

Example 47

2, 7-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Sodium hydride (60% in mineral oil, 14mg, 0.54mmol, 95%) was added to 2, 7-dimethyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] in DMF (2mL)]OxazazemAnd [6, 7-e ]]A solution of indole trifluoroacetate (intermediate 13, 0.060g, 0.18mmol) and stirred at room temperature for 5 minutes before addition of benzenesulfonyl chloride (0.035mL, 0.27 mmol). The mixture was stirred at room temperature for 10 min and quenched with ice/water and extracted with DCM. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (14mg) as a brown oil in the form of trifluoroacetate salt. MS M/z357[ M + H]⁺。

Intermediate 14

5- (benzyloxy) -6-methoxy-1- (phenylsulfonyl) -1H-indole

3M NaOH (5mL, 15mmol) was added to a solution of 5- (benzyloxy) -6-methoxy-indole (1.0g, 3.9mmol), tetrabutylammonium hydrogen sulfate (0.400g, 1.18mmol) and benzenesulfonyl chloride (1.04g, 5.92mmol) in DCM (25 mL). The mixture was stirred at room temperature overnight and diluted with DCM and water. The organic phase was washed with water (1 ×), dried (MgSO)₄) And evaporated. The crude product was purified by silica gel using DCM as eluent to give the title compound (1.1g) as a white solid. MS M/z 394[ M + H ]]⁺。

Intermediate 15

6-methoxy-1- (phenylsulfonyl) -1H-indol-5-ol

To a suspension of 5- (benzyloxy) -6-methoxy-1- (phenylsulfonyl) -1H-indole (intermediate 14, 6.6g, 17mmol) and Pd/C10 wt% (2.0g, 1.9mmol) in EtOH (30mL) was added cyclohexene (9mL) and concentrated HCl (9 mL). The reaction mixture was heated in a microwave heater at 150 ℃ for 5 minutes. Pd/C was filtered off and the solvent was removed under reduced pressure to give the title compound (5.0g) as a black gum. MS M/z 304[ M + H ]]⁺。

Intermediate 16

4- { [ (2-hydroxyethyl) (methyl) amino ] methyl } -6-methoxy-1- (phenylsulfonyl) -1H-indol-5-ol

To 2- (methylamino) ethanol (0.37g, 4.9mmol) and paraformaldehyde (0.15g, 4.9mmol) was added ethanol (5 mL). The reaction mixture was heated at 65 ℃ for 5 minutes and a clear solution formed. 6-methoxy-1- (phenylsulfonyl) -1H-indol-5-ol (intermediate 15, 0.75g, 2.5mmol) in EtOH (10mL) was added in one portion. The mixture was stirred at 70 ℃ for 2 hours. The solvent was removed under reduced pressure and the crude was dissolved in DCM and washed with brine. The organic layer was collected and dried (MgSO₄) To provide the title compound (400 mg). MS M/z 391[ M + H]⁺。

Example 48

6-methoxy-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

THF (15mL) was added to the reaction solution with 4- { [ (2-hydroxyethyl) (methyl) amino]Methyl } -6-methoxy-1- (phenylsulfonyl) -1H-indol-5-ol (intermediate 16, 1.02mmol, 400mg), triphenylphosphine (2.05mmol, 537mg) and 1, 1' -azobis (N, N-dimethylformamide) (2.05mmol, 353mg) were filled with pyrex glass tubes. The reaction mixture was heated at 150 ℃ for 90 minutes in a microwave heater. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (137 mg). MS M/z 373[ M + H ]]⁺。

Example 49

8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Adding 1-chloroethyl chloroformate (1.0mL, 7.0mmol) to 2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in DCM (10mL)]OxazazemAnd [6, 7-e ]]A solution of indole (example 5, 0.15g, 0.44mmol), and 1, 8-bis- (dimethylamino) -naphthalene (proton sponge) (0.056g, 0.26mmol), and the mixture was stirred at 43 ℃ for 1 hour. 1.0M HCl in diethyl ether (2.5mL, 2.5mmol) was added and the mixture was evaporated. The residue was dissolved in anhydrous MeOH (10mL) and heated at 78 ℃ for 30 min and evaporated. The residue was dissolved in DCM and washed with water, brine and the organic phase was dried (MgSO)₄) And evaporated. The crude product was flash chromatographed on silica gel using MeOH, DCM and NEt₃(5:94:1) as eluent to obtain a light pink solidThe title compound (11mg) in form. MS M/z 329[ M + H ]]⁺。

Intermediate 17

8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester

Reacting 8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]The indole (example 49, 0.60g, 1.8mmol) was dissolved in DCM (20mL) and di-tert-butyl dicarbonate (0.48g, 2.2mmol) was added all in one portion. The mixture was stirred at room temperature for 1 hour, washed with water and the organic phase was dried (MgSO₄) And evaporated. The crude product was purified by silica gel plug using DCM as eluent to provide the title compound (0.75g) as a colourless liquid. MS M/z 373[ M + H-tert-butyl group])⁺。

Example 50

2- (2-fluoroethyl) -8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Reacting 8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 17, 16mg, 0.040mmol) was dissolved in DCM (1mL) and TFA (0.5mL) was added. The reaction mixture was heated to reflux and immediately cooled to room temperature. The solution was evaporated and the residue was dissolved in DMF (0.5 mL). Triethylamine (0.011mL, 0.080mmol) was added and the reaction mixture was stirred for 5 minutes before 1-fluoro-2-iodoethane (0.063mL, 0.080mmol) was added. The solution was stirred at 60 ℃ overnight. The solution was evaporated and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (6.9 mg). MS M/z 375[ M + H ]]⁺。

Intermediate 18

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (69mg, 0.32mmol) and 4-dimethylaminopyridine (3.0mg, 0.020mmol) are added to 8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4-in DCM (3mL)]OxazazemAnd [6, 7-e ]]A solution of the indole (example 49, 80.0mg, 0.244 mmol). The reaction was stirred at room temperature for 1 hour, diluted with DCM and washed with 0.5N HCl. The organic phase was dried (MgSO)₄) And evaporated. The residue was dissolved in EtOH (3mL) and a solution of 4N NaOH (0.3mL, 1.2mmol) was added, and the mixture was heated at 75 ℃ for 3 h and evaporated. The residue was dissolved in DCM and taken up with saturated NaHCO₃Washed with aqueous solution and dried (MgSO)₄) And evaporated. The crude product was purified by silica gel plug using 2.5% MeOH in DCM as eluent to provide the title compound (49mg) as a white solid. MS M/z 233[ M + H-tert-butyl ]]⁺。

Example 51

8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sodium hydride (60% in mineral oil, 16.6mg, 0.312mmol) was added to 1, 3, 4, 8-tetrahydro-2H- [1, 4] in DMF (3mL)]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 0.060g, 0.21mmol) solution. Mixing the raw materialsThe mixture was stirred at room temperature for 20 minutes, after which (2-methoxy-5-methylphenyl) sulfonyl chloride (69mg, 0.31mmol) was added. The mixture was stirred for 20 minutes and diluted with water and DCM. The aqueous phase was adjusted to pH3 with 1M HCl and extracted with DCM (2 ×). The combined organics were evaporated to approximately 5 mL. TFA (2mL) was added and the mixture was stirred at room temperature for 3 hours, and the reaction mixture was evaporated. The residue was dissolved in DCM and triethylamine (1mL) was added and the mixture was evaporated. Flash chromatography of the crude product on silica gel with MeOH, DCM, NEt₃(3:96:1) as eluent to give a white solid, which was suspended in diethyl ether and filtered. The white powder was washed with cold diethyl ether (2 ×) and dried in vacuo to give the title compound (65 mg). MS M/z 373[ M + H ]]⁺。

Example 52

8- [ (2, 4-dichlorophenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 2, 4-Dichlorobenzenesulfonyl chloride (25mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (1.9mg) as an off-white solid. MSm/z 398[ M + H ]]⁺。

Example 53

8- { [3- (trifluoromethyl) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 3- (trifluoromethyl) benzenesulfonyl chloride (24mg, 0.10mmol in 0.15mL anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (2.7mg) as an off-white solid. MS M/z 397[ M + H ]]⁺。

Example 54

8- [ (3, 4-Dimethoxyphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 3, 4-Dimethoxybenzenesulfonyl chloride (24mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in MeOH (1)mL, 1mmol) and 1M NH in MeOH (1mL)₃In (1). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (6.2mg) as an off-white solid. MS M/z 389[ M + H ]]⁺。

Example 55

8- (2-Naphthylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. Naphthalene-2-sulfonyl chloride (23mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (5.2mg) as an off-white solid. MS M/z379[ M + H ]]⁺。

Example 56

8- [ (2-methoxy-4-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60%,in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 2-methoxy-4-methylbenzenesulfonyl chloride (22mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1M NH in MeOH (1mL, 1mmol) and MeOH (1mL)₃In (1). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (7.8mg) as an off-white solid. MS M/z 373[ M + H ]]⁺。

Example 57

8- [ (4-Propylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 4-Propylbenzenesulfonyl chloride (22mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (12.8 mg). MS M/z371[ M + H]⁺。

Example 58

8- [ (4-isopropylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 4-isopropylbenzenesulfonyl chloride (22mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (2.9mg) as an off-white solid. MS M/z371[ M + H]⁺。

Example 59

8- (1-benzofuran-2-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 1-benzofuran-2-sulfonyl chloride (22mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) purification to give an off-white solid formThe title compound (0.4 mg). MS M/z 369[ M + H ]]⁺。

Example 60

8- [ (2, 5-dimethyl-3-thienyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 2, 5-Dimethylthiophene-3-sulfonyl chloride (21mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (3.2mg) as an off-white solid. MS M/z 363[ M + H ]]⁺。

Example 61

8- [ (3-fluoro-4-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 3-fluoro-4-methylbenzenesulfonyl chloride (21mg, 0.10mmol in 0.15mL of anhydrous DMF) was added toThe solution is described. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (1.4mg) as an off-white solid. MS M/z361[ M + H ]]⁺。

Example 62

8- [ (4-methoxyphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 4-Methoxybenzenesulfonyl chloride (21mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (5.5mg) as an off-white solid. MS M/z359[ M + H]⁺。

Example 63

8- [ (2, 5-dimethyl-3-furyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 2, 5-dimethylfuran-3-sulfonyl chloride (19mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (5.2mg) as an off-white solid. MS M/z 347[ M + H ]]⁺。

Example 64

8- [ (2-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 2-Methylbenzenesulfonyl chloride (19mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of Me0H/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1M NH of Me0H₃(1mL, 1mmol) and Me0H (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (5.0mg) as an off-white solid. MS M/z343[ M + H ]]⁺。

Example 65

8- [ (4-Methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 4-Methylbenzenesulfonyl chloride (19mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (4.9mg) as an off-white solid. MS M/z343[ M + H ]]⁺。

Example 66

8- (2-Thienylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. Thiophene-2-sulfonyl chloride (18mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. Dissolving the residue in1M NH in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (10.2mg) as an off-white solid. MS M/z335[ M + H ]]⁺。

Example 67

8- { [2- (trifluoromethoxy) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 2- (trifluoromethoxy) benzenesulfonyl chloride (26mg, 0.10mmol in 0.15mL anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (1.0mg) as an off-white solid. MS M/z 413[ M + H ]]⁺。

Example 68

8- (Biphenyl-3-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18,14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. Biphenyl-3-sulfonyl chloride (25mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (2.0mg) as an off-white solid. MS M/z405[ M + H ]]⁺。

Example 69

8- { [2- (trifluoromethyl) phenyl]Sulfonyl } -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 2- (trifluoromethyl) benzenesulfonyl chloride (24mg, 0.10mmol in 0.15mL anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (3.3mg) as an off-white solid. MS M/z 397[ M + H ]]⁺。

Example 70

8- (1-benzothien-2-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 1-benzothiophene-2-sulfonyl chloride (23mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (1.9mg) as an off-white solid. MS M/z 385M + H]⁺。

Example 71

8- (1-Naphthylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. Naphthalene-1-sulfonyl chloride (23mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (1.5mg) as an off-white solid. MS M/z379[ M + H ]]⁺。

Example 72

8- [ (5-fluoro-2-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 18, 14mg, 0.05mmol), NaH (60% in mineral oil, 6.4mg, 0.10mmol) and anhydrous DMF (0.2mL) were shaken at room temperature for 10 min. 5-fluoro-2-methylbenzenesulfonyl chloride (21mg, 0.10mmol in 0.15mL of anhydrous DMF) was added to the solution. The reaction mixture was shaken at room temperature for an additional 20 minutes and a mixture of MeOH/1M HCl (3:1, 1mL) was added. The reaction mixture was stirred overnight and evaporated. 1M NH dissolving the residue in MeOH₃(1mL, 1mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (2.7mg) as an off-white solid. MS M/z361[ M + H ]]⁺。

Intermediate 19

((1R) -tert-butyl 2- { [ 4-formyl-1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } -1-methylethyl) carbamate

1, 1' -azobis (N, N-dimethylformamide) (201mg, 1.16mmol) was added to a solution of 5-hydroxy-1- (phenylsulfonyl) -1H-indole-4-carbaldehyde (intermediate 10, 0.070g, 0.23mmol), R- (+) -2- (tert-butoxycarbonylamino) -1-propanol (81.6mg, 0.465mmol), and triphenylphosphine (302mg, 1.16mmol) in DCM (14 mL). The mixture was stirred at 45 ℃ for 2 days, then at room temperature for 2 days. The mixture was diluted with 0.5N NaOH and DCM. The organic layer was separated and dried (MgSO)₄) And evaporated. Subjecting the crude product to flash chromatographyMethod was purified with 1% to 2.5% MeOH in DCM to give the title compound as a white solid (70 mg). MS M/z359[ M + H-Boc]⁺。

Example 73

(3R) -3-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Coupling ((1R) -2- { [ 4-formyl-1- (phenylsulfonyl) -1H-indol-5-yl)]Oxy } -1-methylethyl) carbamic acid tert-butyl ester (intermediate 19, 0.040g, 0.087mmol) was dissolved in DCM (2mL) and TFA (0.5mL) was added. The mixture was stirred at room temperature for 1 hour and evaporated. The residue was dissolved in THF (2mL) and sodium triacetoxyborohydride (37.0mg, 0.176mmol) was added. The mixture was stirred for 1 hour, evaporated and purified by flash chromatography using 2.5% to 5% MeOH in DCM as eluent to afford the title compound (25mg) as a white solid. MS M/z343[ M + H ]]⁺。

Example 74

(3R) -2, 3-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sodium triacetoxyborohydride (7.5mg, 0.040mmol) was added to (3R) -3-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in THF (1mL)]OxazazemAnd [6, 7-e ]]Indole (example 73, 0.010g, 0.029mmol) and Formaldehyde (37 wt.% in H₂0.020mL, 0.25mmol) in O. The mixture was stirred for 20 min, evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (4mg) as a white solid as trifluoroacetate salt. MS M/z357[ M + H]⁺。

Example 75

6-methoxy-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

To 6-methoxy-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole (example 48, 0.030g, 0.081mmol), 1, 8-bis (dimethylamino) -naphthalene (0.010g, 0.048mmol) and 1-chloroethyl chloroformate (25mg, 0.18mmol) were added, followed by anhydrous DCM (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the crude was dissolved in anhydrous MeOH (3 mL). The reaction mixture was heated at reflux for 2h, cooled and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (3 mg). MS M/z359[ M + H]⁺。

Example 76

9-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt (ester)

Reacting 8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 17, 0.020g, 0.050mmol) was dissolved in THF (1mL) and washed with ethanol/CO₂Cooling on the bath. BuLi (2.5M in hexanes, 0.054mL, 0.15mmol) was added and the solution was stirred at-78 ℃ for 27 minutes. MeI (0.012mL, 0.20mmol) was added. The temperature was allowed to rise to room temperature overnight. Water was added and the solution was extracted with EtOAc. The organic phase was evaporated and the residue was dissolved in DCM (1 mL). TFA (0.5mL) was added and the solution heated at reflux, and immediatelyIt was cooled to room temperature. The reaction mixture was evaporated to give the title compound (21 mg). MS M/z343[ M + H ]]⁺。

Example 77

10-chloro-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Reacting 8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 17, 15mg, 0.035mmol) was dissolved in CHCl₃(2mL) and N-chlorosuccinimide (7.0mg, 0.053mmol) was added. The mixture was heated at 70 ℃ overnight. The mixture was cooled to room temperature, TFA (1mL) was added and the mixture was stirred for 10 min and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (4.1mg) as a pale yellow solid in the form of trifluoroacetate salt. MS M/z 363[ M + H ]]⁺。

Intermediate 20

10-chloro-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester

8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] with N-chlorosuccinimide (0.23g, 0.54mmol) added to chloroform (4mL)]OxazazemAnd [6, 7-e ]]A solution of indole-2-carboxylic acid tert-butyl ester (intermediate 17, 0.23g, 0.54mmol) and heated in a microwave heater at 130 ℃ for 40 minutes. The mixture was evaporated and purified by flash chromatography on silica gel with MeOH and DCM (1:99) as eluents to give 167mg of 10-chloro-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4-]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester. This intermediate (167mg, 0.360mmol) was dissolved in EtOH (20mL) and a solution of 10M KOH (0.2mL, 2mmol) was added. The mixture was heated at 65 ℃ for 20 min and the reaction mixture was evaporated and purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give an off-white solid (40mg) as the trifluoroacetate salt. MS M/z 223[ M + H-Boc]⁺。

Example 78

10-chloro-8- [ (4-fluorophenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Mixing 10-chloro-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 20, 10mg, 0.031mmol) was dissolved in anhydrous DMF (1mL) and sodium hydride (60% in mineral oil, 2.5mg, 0.062mmol) was added all in one portion. The mixture was stirred at room temperature for 10 minutes, after which 4-fluorobenzenesulfonyl chloride (12mg, 0.062mmol) was added. The reaction mixture was stirred for 10 minutes, and TFA (1mL) was added dropwise. The reaction mixture was heated at 50 ℃ overnight and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (9.8mg) as the trifluoroacetate salt. MS M/z 381[ M + H ]]⁺。

Example 79

3- [ (10-chloro-1, 2, 3, 4-tetrahydro-8H- [1, 4]]OxazazemAnd [6, 7-e ]]Indol-8-yl) sulfonyl]Benzonitrile trifluoroacetic acid salt

Mixing 10-chloro-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 20, 10mg, 0.031mmol) was dissolved in anhydrous DMF (1mL) and sodium hydride (60%, in mineral oil, 2.5mg, 0.062mmol) was added. The mixture was stirred at room temperature for 10 minutes, after which 3-cyanobenzene-1-sulfonyl chloride (13mg, 0.062mmol) was added. The reaction mixture was stirred for 20 minutes, after which TFA (2mL) was added and the mixture was heated at 50 ℃ overnight. The reaction mixture was evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as the trifluoroacetate salt as an off-white solid (1.3 mg). MS M/z 388[ M + H ]]⁺。

Example 80

10-chloro-8- (pyridin-3-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole bis (trifluoroacetate)

Preparation of free base: pyridine-3-sulfonyl chloride hydrochloride (20mg, 0.093mmol) was dissolved in dichloromethane and saturated NaHCO₃In a mixture of aqueous solutions, and the organic layer was dried (MgSO)₄) And evaporated to afford pyridine-3-sulfonyl chloride. Mixing 10-chloro-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 20, 10mg, 0.031mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 2.5mg, 0.062mmol) was added. The mixture was stirred for 10 min, after which pyridine-3-sulfonyl chloride (0.093mmol) in DMF (1mL) was added. The reaction mixture was stirred at room temperature for 10 minutes, after which TFA (2mL) was added and the mixture was heated at 50 ℃ overnight. The reaction mixture was evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to provide the title compound as the trifluoroacetate salt as a white solid (2.6 mg). MS M/z 364[ M + H]⁺。

Example 81

8- [ (2-chlorophenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

DMF (1mL) was added to 1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]A mixture of tert-butyl indole-2-carboxylate (intermediate 18, 10.0mg, 0.035mmol) and 60% NaH (5.56mg, 0.139 mmol). The reaction mixture was stirred at room temperature for 10 minutes, after which 2-chlorophenylsulfonyl chloride (11mg, 0.052mmol) was added all in one portion. After 30 min, TFA (1mL) was added and the mixture was stirred for 10 min and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (9.6mg) as a white solid as a trifluoroacetate salt. MS M/z 363[ M + H ]]⁺。

Intermediate 21

4-bromo-1- (phenylsulfonyl) -1H-indol-5-ol

NBS (32.6mg, 0.180mmol) in DMF (1mL) was added to a solution of 1- (phenylsulfonyl) -1H-indolin-5-ol (intermediate 8, 50.0mg, 0.183mmol) in DMF (1mL) at room temperature. The mixture was stirred for 30 minutes and diluted with water and diethyl ether and transferred to a separatory funnel. The organic phase was washed with water (3 ×), dried (MgSO)₄) And evaporated. The crude product was purified by flash chromatography using 10% pentane in DCM as eluent to provide the title compound (50mg) as a white solid. MS M/z 352/354[ M + H ]]⁺。

Intermediate 22

4-bromo-1- (phenylsulfonyl) -1H-indol-5-yl acetate

Triethylamine (0.29g, 2.8mmol) was added to a solution of 4-bromo-1- (phenylsulfonyl) -1H-indol-5-ol (intermediate 21, 0.67g, 1.9mmol) and acetyl chloride (0.22g, 2.8mmol) in THF (10 mL). The mixture was stirred at room temperature for 10 minutes andand (4) evaporating. The residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The reaction mixture was washed with saturated NaHCO₃The aqueous solution was washed and the organic phase was dried (MgSO₄) And evaporated to give the title compound (0.6g) as a red solid. MS M/z 394/396[ M + H ]]⁺。

Intermediate 23

1- [ 5-hydroxy-1- (phenylsulfonyl) -1H-indol-4-yl ] ethanone

In N₂4-bromo-1- (phenylsulfonyl) -1H-indol-5-yl acetate (intermediate 22, 0.57g, 1.5mmol) was dissolved in toluene (10mL) under a gas atmosphere and 1-ethoxyvinyl-tributylstannane (0.78g, 2.2mmol) and bis- (triphenylphosphine) -palladium (II) -chloride (50.8mg, 0.072mmol) were added and the mixture was heated at 110 ℃. After 30 min, additional catalyst (25mg, 0.036mmol) was added and the mixture was heated at 110 ℃ for an additional 3 h, cooled and filtered through a plug of silica gel using EtOAc as eluent. The filtrate was washed with 1M HCl and saturated aqueous brine solution, and passed through (MgSO)₄) Dried and evaporated. The crude product was dissolved in THF/1M HCl 2:1(40mL) and stirred at room temperature for 30 min. The mixture was evaporated and partitioned between water and DCM. The organic phase was dried (MgSO)₄) And evaporated. The crude material was purified by flash chromatography on silica gel using 10% petroleum ether in DCM as eluent to give the title compound (100mg) as a pale yellow solid. MS M/z 316[ M + H ]]⁺。

Example 82

1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1, 1' -azobis (N, N-dimethylformamide) (73mg, 0.43mmol) was added to 1- [ 5-hydroxy-1- (phenylsulfonyl) -1H-indol-4-yl in DCM (5mL)]Ethanone (intermediate 23, 67mg, 0.21mmol), tert-butyl N- (2-hydroxy-ethyl) carbamate (0.14g, 0.85 mm)ol) and triphenylphosphine (112mg, 0.430 mmol). The mixture was heated at 43 ℃ for 1 hour and additional 1, 1' -azobis (N, N-dimethylformamide) (0.030g, 0.17mmol) was added and the mixture was heated at 43 ℃ for an additional 2 hours. The mixture was cooled to room temperature and TFA (2.5mL) was added, and the mixture was stirred for 1 hour and evaporated. The residue was partitioned between DCM and 1M NaOH. The organic phase was dried (MgSO)₄) And evaporated. The crude product was purified by flash chromatography using 5% MeOH in DCM as eluent to give 75mg of 1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4]]OxazazemAnd [6, 7-e ]]Indole. Acetic acid (132mg, 2.20mmol) was added to 1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4] in DCM (10mL)]OxazazemAnd [6, 7-e ]]A solution of indole (75.0mg, 0.22mmol) and the mixture stirred at room temperature for 10 minutes after which sodium triethoxy hydride (0.070g, 0.33mmol) was added all in one portion. The mixture was stirred for 30 minutes and transferred to a separatory funnel and washed with 1M NaOH and brine. The organic phase was dried (MgSO)₄) And evaporated. Flash chromatography of the crude product on silica gel with MeOH, DCM, NEt₃(5:94:1) as an eluent to give the title compound (28mg) as a white solid. MSm/z 343[ M + H ]]⁺。

Example 83

(1S) -1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

A small sample of racemic 1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole example 82 preparative HPLC (Chiracel column OJ-H, 0.46cm 25cm, 30:70i-PrOHN-hexane) to give the title compound (0.7mg) as a white solid. MS M/z343[ M + H ]]⁺。

Example 84

(1R) -1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

A small sample of racemic 1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole example 82 was purified by preparative HPLC (Chiracel column OJ-H, 0.46 cm. times.25 cm, 30:70i-PrOH: n-hexane) to give the title compound (0.7mg) as a white solid. MS M/z343[ M + H ]]⁺。

Intermediate 24

2- { [1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } ethylamine

To 1- (phenylsulfonyl) -1H-indol-5-ol, (intermediate 8, 8.0g, 29mmol) was added 1, 1' -azobis (N, N-dimethylformamide) (7.6g, 44mmol), triphenylphosphine (15.4g, 580mmol), tert-butyl N- (2-hydroxy-ethyl) carbamate (9.4g, 58mmol) and DCM (200 mL). The reaction mixture was heated at 50 ℃ for 1.5 hours. The reaction mixture was cooled to room temperature and TFA (50mL) was added. The reaction mixture was stirred for 3 hours and evaporated. The crude material was purified by flash chromatography on silica gel (DCM: MeOH, 95:5) to give the title compound (9.6 g). MS M/z 317[ M + H ]]⁺。

Intermediate 25

N- (2- { [1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } ethyl) acetamide

2- { [1- (phenylsulfonyl) -1H-indol-5-yl in DCM (100mL)]Oxy } ethylamine (intermediate 24, 9.6g, 30mmol) was treated with triethylamine (12.8mL, 91.0mmol) and 4-dimethylaminopyridine (1.9g, 15 mmol).The solution was cooled to 0 ℃ and acetyl chloride (4.3mL, 61mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and saturated NaHCO was used₃(50mL) aqueous and 1M HCl (2X 50 mL). The organic phase was dried (MgSO)₄) And concentrated in vacuo to give the title compound (10.3 g). MS M/z359[ M + H]⁺。

Example 85

1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

To N- (2- { [1- (phenylsulfonyl) -1H-indol-5-yl) in acetonitrile (7.5L)]Oxy } ethyl) acetamide (intermediate 25, 5.0g, 14mmol) phosphorus oxychloride (100mL) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure to give a crude product (5.0g) of the title compound. A small amount of the crude was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (12 mg). MS M/z341[ M + H ]]⁺。

Intermediate 26

5-benzyloxy-6-fluoroindole

Prepared according to European patent application EP 0505322B 1, 1992.

Intermediate 27

N-benzenesulfonyl-5-benzyloxy-6-fluoroindole

To a stirred solution of 5-benzyloxy-6-fluoroindole (intermediate 26, 2.0g, 8.3mmol) in anhydrous DMF (30mL) at 0 deg.C was added sodium hydride (60% in mineral oil, 0.35g, 8.7 mmol). The solution was stirred at room temperature for 30 minutes, and the reaction mixture was cooled to 0 ℃ and benzenesulfonyl chloride (1.17mL, 9.12mmol) was added dropwise. The reaction mixture was kept at 4 ℃ overnight, and 1 drop of methanol was added and the solvent was evaporated. The crude was dissolved in DCM and saturated NaHCO₃Washing with an aqueous solution over MgSO₄Dried, filtered and evaporated. The crude was purified by flash chromatography on silica gel using DCM as eluent to give the title compound as a pale yellow oil (2.88 g). MS M/z 382[ M + H ]]⁺。

Intermediate 28

6-fluoro-1- (phenylsulfonyl) -1H-indol-5-ol

Pd/C10 wt% (250mg, 0.236mmol) was added to a solution of N-benzenesulfonyl-5-benzyloxy-6-fluoroindole (intermediate 27,250mg, 6.55mmol) in ethanol (100 mL). The reaction mixture was stirred under an atmosphere of hydrogen (1atm) at room temperature for 2 hours, filtered and evaporated. The crude was purified by flash chromatography on silica gel with 0.5% MeOH/DCM as eluent to give the title compound as a white solid (1.79 g). MS M/z 292[ M + H]⁺。

Intermediate 29

2- { [ 6-fluoro-1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } ethylamine

To 6-fluoro-1- (phenylsulfonyl) -1H-indol-5-ol (intermediate 28, 3.0g, 10mmol) was added 1, 1' -azobis (N, N-dimethylformamide) (3.5g, 21mmol), triphenylphosphine (5.4g, 21mmol), tert-butyl N- (2-hydroxy-ethyl) carbamate (3.3g, 21mmol) and DCM (20 mL). The mixture was heated in a microwave heater at 150 ℃ for 20 minutes. The reaction mixture was cooled to room temperature and TFA (20mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude was filtered through a plug of silica gel using DCM as eluent. The solvent was removed under reduced pressure, and the crude was dissolved in ethyl acetate (10mL) and the HCl salt of the title compound was precipitated upon addition of 1M HCl in diethyl ether (20 mL). The solid was filtered off, dissolved in DCM (100mL) and the organic phase was washed with saturated NaHCO₃Aqueous solution (40mL) was washed to give the title compound (2.0 g). MS M/z335[ M + H ]]⁺。

Intermediate 30

N- (2- { [ 6-fluoro-1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } ethyl) acetamide

2- { [ 6-fluoro-1- (phenylsulfonyl) -1H-indol-5-yl in DCM (100mL)]Oxy } ethylamine (intermediate 29, 2.0g, 6.0mmol) was treated with triethylamine (2.5mL, 18mmol) and 4-dimethylaminopyridine (0.37g, 3.0 mmol). The solution was cooled to 0 ℃ and treated with acetyl chloride (0.85mL, 12 mmol). The mixture was stirred at room temperature for 1.5 h and saturated NaHCO₃Aqueous (40mL) and 0.5M HCl (40 mL). The organic phase was dried (MgSO)₄) And concentrated in vacuo to give the title compound (2.0 g). MS M/z 377[ M + H ]]⁺。

Intermediate 31

6-fluoro-1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

To N- (2- { [ 6-fluoro-1- (phenylsulfonyl) -1H-indol-5-yl) in acetonitrile (20mL)]Oxy } ethyl) acetamide (intermediate 30, 0.020g, 0.053mmol) phosphorus oxychloride (0.5mL) was added and the reaction mixture was heated in a microwave heater at 200 ℃ for 30 minutes. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (1 mg). MS M/z359[ M + H]⁺。

Example 86

6-fluoro-1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Reacting 6-fluoro-1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole (intermediate 31, 0.010g, 0.028mmol) was dissolved in EtOH (2mL) and NaCNBH was added₃(3.5mg, 0.056 mmol). Will be provided withThe reaction mixture was heated at 50 ℃ for 1 hour. The reaction was quenched by addition of water and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (1.2 mg). MS M/z361[ M + H ]]⁺。

Intermediate 32

2- { [ 6-methoxy-1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } ethylamine

To 6-methoxy-1- (phenylsulfonyl) -1H-indol-5-ol (intermediate 15, 2.0g, 6.6mmol) was added 1, 1' -azobis (N, N-dimethylformamide) (2.3g, 13mmol), triphenylphosphine (3.5g, 13mmol), tert-butyl N- (2-hydroxy-ethyl) carbamate (2.1g, 13mmol) and DCM (40 mL). The mixture was heated in a microwave heater at 150 ℃ for 20 minutes. The reaction mixture was cooled to room temperature and TFA (30mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel with 5% MeOH in DCM as eluent to give the title compound (2.53g) MS M/z 347[ M + H ] 347]⁺。

Intermediate 33

N- (2- { [ 6-methoxy-1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } ethyl) acetamide

2- { [ 6-methoxy-1- (phenylsulfonyl) -1H-indol-5-yl in DCM (100mL)]Oxy } ethanolamine (intermediate, 2.0g, 5.8mmol) was treated with triethylamine (2.4mL, 17mmol) and 4-dimethylaminopyridine (0.35g, 2.9 mmol). The solution was cooled to 0 ℃ and acetyl chloride (0.82mL, 12mmol) was added. The mixture was stirred at room temperature for 1 hour with saturated NaHCO₃Aqueous (20mL) and 1M HCl (2X 20 mL). The organic phase was dried (MgSO)₄) And concentrated in vacuo to give the title compound (1.2 g). MS M/z 389[ M + H ]]⁺。

Intermediate 34

6-methoxy-1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1，4]OxazazemAnd [6, 7-e ]]Indoles

To a solution of N- (2- { [ 6-methoxy-1- (phenylsulfonyl) -1H-indol-5-yl) in acetonitrile (150mL)]Oxy } ethyl) acetamide (intermediate 33, 0.10g, 2.7mmol) phosphorus oxychloride (2mL) was added and the reaction mixture was heated at reflux for 5 days. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (0.010 g). MS M/z371[ M + H]⁺。

Example 87

6-methoxy-1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

To 6-methoxy-1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4] dissolved in EtOH (2mL)]OxazazemAnd [6, 7-e ]]Indole (intermediate 34, 0.010g, 0.027mmol) Add NaCNBH₃(3.5mg, 0.054mmol) and the reaction mixture was heated at 65 ℃ for 2 hours. The reaction mixture was quenched by addition of water and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (3.7 mg). MS M/z 373[ M + H ]]⁺。

Intermediate 35

6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

To 6-methoxy-1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-l dissolved in EtOH (2mL)-2H-[1，4]OxazazemAnd [6, 7-e ]]Indole (example 87, 0.12g, 0.32mmol) 2M NaOH (5mL, 10mmol) was added and the reaction mixture was heated at 80 ℃ for 2 h. The reaction mixture was cooled and extracted with DCM (50 mL). The organic layer was collected and dried (MgSO)₄) And evaporated to give the title compound (72 mg). MS M/z 233[ M + H ]]⁺。

Intermediate 36

6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (85mg, 0.39mmol) was added to 6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] in DCM (10mL)]OxazazemAnd [6, 7-e ]]Indole (intermediate 35, 72mg, 0.32mmol) solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 1M NaOH (5mL) and the organic layer was dried (MgSO)₄) And evaporated to give the title compound (100 mg). MS M/z 333[ M + H]⁺。

Example 88

8- [ (2-chlorophenyl) sulfonyl group]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Mixing 6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 36, 25mg, 0.059mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.15mmol) was added. The reaction mixture is placed in a chamberStir warm for 15 min before adding 2-chlorobenzenesulfonyl chloride (24mg, 0.11 mmol). The reaction mixture was stirred at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) purification to give 8- [ (2-chlorophenyl) sulfonyl]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (6mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (5.8 mg). MS M/z 407[ M + H ]]⁺。

Example 89

6-methoxy-1-methyl-8- [ (2-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Mixing 6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 36, 25mg, 0.059mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.15mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2-methylbenzenesulfonyl chloride (22mg, 0.113mmol) was added. The reaction mixture was stirred at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to obtain 6-methoxy-1-methyl-8- [ (2-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (3.3mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (3.4 mg). MS m/z387[M+H]⁺。

Example 90

8- [ (2, 6-difluorophenyl) sulfonyl]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Mixing 6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 36, 25mg, 0.059mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.15mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2, 6-difluorobenzenesulfonyl chloride (24.0mg, 0.113mmol) was added. The reaction mixture was stirred at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to obtain 8- [ (2, 6-difluorophenyl) sulfonyl]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (6.6mg, 0.013mmol), dissolved in DCM (1mL) and TFA (1mL) added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (6.8 mg). MS M/z 409[ M + H ]]⁺。

Example 91

6-methoxy-8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Mixing 6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 36, 25mg, 0.059mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.15mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2-methoxy-5-methylbenzenesulfonyl chloride (24.0mg, 0.113mmol) was added. The reaction mixture was stirred at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to obtain 6-methoxy-8- [ (2-methoxy-5-methylphenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (4.4mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (4.6 mg). MS M/z 417[ M + H ]]⁺。

Example 92

8- [ (2, 4-dichlorophenyl) sulfonyl group]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Mixing 6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 36, 25mg, 0.059mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.15mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2, 4-dichlorobenzenesulfonyl chloride (28mg, 0.113mmol) was added. The reaction mixture was stirred at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to obtain 8- [ (2, 4-dichlorophenyl) sulfonyl group]-6-methoxy-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (6mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (4.2 mg). MS M/z 442[ M + H ]]⁺。

Intermediate 37

2-methyl-N- (2- { [1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } ethyl) propanamide

2- { [1- (phenylsulfonyl) -1H-indol-5-yl in DCM (100mL)]Oxy } ethylamine (intermediate 24, 0.20g, 0.63mmol) was treated with triethylamine (0.27mL, 1.9mmol) and 4-dimethylaminopyridine (39mg, 0.32 mmol). The solution was cooled to 0 ℃ and treated with isobutyryl chloride (0.14g, 0.13 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated NaHCO₃Aqueous (50mL) and 1M HCl (2X 40 mL). The organic phase was dried (MgSO)₄) And concentrated in vacuo to give the title compound (133 mg). MS M/z387[ M + H ]]⁺。

Intermediate body 38

1-isopropyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

To acetonitrile (200mL) 2-methyl-N- (2- { [1- (phenylsulfonyl) -1H-indol-5-yl]Oxy } ethyl) propionamide (intermediate 37, 0.13g, 0.33mmol) phosphorus oxychloride (2.5mL) was added and the reaction mixture was heated at reflux for 20 hours. The reaction mixture was evaporated to give the title compound (120 mg). MS M/z 369[ M + H ]]⁺。

Example 93

1-isopropyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

To a solution of 1-isopropyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4] in EtOH (5mL)]OxazazemAnd [6, 7-e ]]Indole (intermediate 38,120mg, 0.330mmol) NaCNBH was added₃(41mg, 0.65mmol), and the reaction mixture was heated at 70 ℃ for 30 minutes. The reaction was quenched by addition of water and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (35 mg). MS M/z371[ M + H]⁺。

Example 94

1-isopropyl-2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-isopropyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole (example 93, 25mg, 0.068mmol) was dissolved in methanol (4mL) and formaldehyde (37 wt.% in H) was added₂0.090mL, 1.1mmol) followed by sodium triacetoxyborohydride (72mg, 0.34 mmol). The reaction mixture was stirred at room temperature overnight, evaporated and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (1.4 mg). MS M/z 385M + H]⁺。

Example 95

1, 2-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H-[1，4]OxazazemAnd [6, 7-e ]]The indole (example 82, 15mg, 0.044mmol) was dissolved in THF (2mL) and formaldehyde (37 wt.% in H) was added₂0.090mL, 1.1mmol) in O. The mixture was stirred for 10 min, after which sodium triacetoxyborohydride (0.010g, 0.048mmol) was added. The reaction was stirred at room temperature for 1 hour, evaporated and flash chromatographed on silica gel with MeOH: DCM: NEt₃(5:94:1) as an eluent to give the title compound (9.2mg) as a colorless liquid. MS M/z357[ M + H]⁺。

Intermediate 39

N- (2- { [ 3-chloro-1- (phenylsulfonyl) -1H-indol-5-yl ] oxy } ethyl) acetamide

NCS (0.42g, 3.2mmol) was added to N- (2- { [1- (phenylsulfonyl) -1H-indol-5-yl) in THF (20ml) at room temperature]Oxy } ethyl) acetamide (intermediate 25, 0.95g, 2.6 mmol). The reaction mixture was stirred at 40 ℃ for 6 hours. The reaction mixture was evaporated and the crude was purified by flash chromatography on silica gel with 3% MeOH in DCM as eluent to give the title compound as a white solid (1.11 g). MS M/z 393[ M + H ]]⁺。

Intermediate 40

10-chloro-1-methyl-3, 8-dihydro-4H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

N- (2- { [ 3-chloro-1- (phenylsulfonyl) -1H-indol-5-yl) in EtOH (25ml)]Oxy } ethyl) acetamide (intermediate 39, 1.07g, 2.73mmol, about 80% pure) and 2M NaOH (5ml) were mixed and heated at 75 ℃ for 1 hour. The reaction mixture was cooled, diluted with water and extracted with DCM. The organic phase was dried (MgSO)₄) And evaporated to give the crude (0.287g) as a colourless oil. The crude (0.250g, 0979mmol) was dissolved in MeCN (20ml) and POCl was added₃. Subjecting the reaction mixture to microwaveHeated in a heater at 120 ℃ for 15 minutes and evaporated. The crude material was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (99.7mg) as a white solid. MS M/z 235[ M + H ]]⁺。

Example 96

10-chloro-1-methyl-8- (phenylsulfonyl) -3, 8-dihydro-4H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sodium hydride (60% in mineral oil, 38mg, 0.95mmol) was added to 10-chloro-1-methyl-3, 8-dihydro-4H- [1, 4] in DMF (3ml)]OxazazemAnd [6, 7-e ]]Indole (intermediate 40, 45mg, 0.19mmol) and benzenesulfonyl chloride (74. mu.l, 0.58 mmol). The reaction mixture was stirred at room temperature for 10 minutes, after which water was added dropwise. The crude material was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (15mg) as a red solid. MS M/z 375[ M + H ]]⁺。

Intermediate 41

1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (3.5g, 16mmol) is added to 1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in DCM (200mL)]OxazazemAnd [6, 7-e ]]Indole (example 82, 5.0g, 15mmol) solution. The reaction mixture was stirred at room temperature overnight and washed with 1M NaOH (100 mL). The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (2.88 g). MS M/z443[ M + H]⁺。

Intermediate body 42

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester

To a solution of 1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in EtOH (50mL)]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 41, 1.5g, 3.4mmol) 2M NaOH (10mL, 20mmol) was added and the reaction mixture was heated at 70 ℃ for 2 hours. EtOH was removed under reduced pressure and the aqueous phase was extracted with DCM (2 × 100 mL). The organic layer was collected and dried (MgSO)₄) And evaporated to give the title compound (0.98g) as a yellow solid. MS M/z 303[ M + H ]]⁺。

Intermediate 43

10-chloro-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester

N-chlorosuccinimide (13mg, 0.10mmol) was added to 1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] in THF (2mL)]OxazazemAnd [6, 7-e ]]A solution of tert-butyl indole-2-carboxylate (intermediate 42, 0.030g, 0.099mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude material was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to give the title compound (17.5mg) as a white solid. MS M/z 337[ M + H ]]⁺。

Example 97

10-chloro-1-methyl-8- (pyridin-3-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole bis (trifluoroacetate)

Mixing 10-chloro-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4%]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 43, 77mg, 0.23mmol) was dissolved in DCM (6mL) and 2M NaOH (0.25mL, 0.50mmol), tetrabutylammonium hydrogen sulfate (15.5mg, 0.046mmol) and pyridine-3-sulfonyl chloride (98.0mg, 0.458mmol) were added and the mixture was stirred at room temperature overnight. The organic layer was separated and concentrated to about 2 mL. TFA (3mL) was added and the mixture was stirred at rt for 30 min and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (16.8mg) as a brown oil as trifluoroacetate salt. MS M/z 378[ M + H]⁺。

Example 98

10-chloro-1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Sodium hydride (60% in mineral oil, 38mg, 0.95mmol) was added to 10-chloro-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] in DMF (2ml)]OxazazemAnd [6, 7-e ]]A solution of tert-butyl indole-2-carboxylate (intermediate 43, 18mg, 0.050mmol) and benzenesulfonyl chloride (0.030mL, 0.23 mmol). The reaction mixture was stirred at room temperature for 30 minutes. TFA (0.50mL) was added to the reaction mixture and the solvent was evaporated. The residue was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) purification to give trisThe title compound (16.8mg) as a white solid was obtained as the fluoroacetate salt. MS M/z 377[ M + H ]]⁺。

Example 99

10-chloro-1, 2-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

10-chloro-1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4] in MeOH (1mL)]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate (example 98, 59mg, 0.15mmol) with PL-HCO₃MP SPE (polymer laboratories) columns were converted to free amines. Formaldehyde (37% by weight in H)₂O, 0.20mL, 2.4mmol) was added to a solution of free amine (0.15mmol) in THF (1 mL). After stirring at room temperature for 10 min, sodium triacetoxy hydride (26mg, 0.12mmol) was added and the mixture was stirred for an additional 30 min and evaporated. The crude material was purified by preparative HPLC (Xterra C18, 10mM NH)₄HCO₃(pH10) -CH3CN) to give the title compound (28.9mg) as a white solid. MS M/z 391[ M + H]⁺。

Example 100

10-chloro-8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

Sodium hydride (60% in mineral oil, 18mg, 0.74mmol) was added to 6-methoxy-m-toluenesulfonyl chloride (98.3mg, 0.445mmol) and 10-chloro-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] in DMF (2ml) at room temperature]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 43, 50.0mg, 0.148mmol)The solution of (1). The reaction mixture was stirred at room temperature for 15 minutes, after which water (5mL) was added and the aqueous layer was extracted with DCM. Most of the organic solvent was evaporated and the residue was dissolved in DCM (1mL) and TFA (2mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the crude product was purified by preparative HPLC (Xterra C18, 10mM NH)₄HCO₃(pH10) -CH3CN) to give the title compound (16.8mg) as a white solid. MS M/z 421[ M + H ]]⁺。

Example 101

10-chloro-8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1, 2-dimethyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Formaldehyde (37% by weight in H)₂O, 0.20mL, 2.4mmol) 10-chloro-8- [ (2-methoxy-5-methylphenyl) sulfonyl group added to THF (1mL)]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole (example 100, 12mg, 0.029mmol) in solution. After stirring at room temperature for 10 min, sodium triacetoxyborohydride (9.2mg, 0.043mmol) was added and the mixture was stirred for a further 30 min and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was purified to give the title compound (12.7mg) as a white solid as a trifluoroacetate salt. MS M/z 435[ M + H [)]⁺。

Example 102

10-chloro-8- [ (2-fluorophenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Sodium hydride (60% in mineral oil, 18mg, 0.74mmol) was added to 2-fluorobenzene-1-sulfonyl chloride (86.7mg, 0.445mmol) in DMF (2ml) at room temperaturemmol) and 10-chloro-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]A solution of tert-butyl indole-2-carboxylate (intermediate 43, 50.0mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 15 minutes, after which water (5mL) was added and the aqueous layer was extracted with DCM. Most of the organic solvent was evaporated and the residue was dissolved in DCM (1mL) and TFA (2mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the crude product was purified by preparative HPLC (Xterra C18, 10mM NH)₄HCO₃(pH10) -CH3CN) to give the title compound (18mg) as a white solid in the form of trifluoroacetate salt. MS M/z395[ M + H]⁺.

Example 103

10-chloro-8- [ (2-fluorophenyl) sulfonyl]-1, 2-dimethyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Using PL-HCO₃MP SPE cartridge, 10-chloro-8- [ (2-fluorophenyl) sulfonyl group in MeOH (1mL)]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate (example 102, 12.5, 0.025mmol) was converted to the free amine. Formaldehyde (37% by weight in H)₂O, 0.20mL, 2.4mmol) was added to a solution of free amine (0.025mmol) in THF (1 mL). After stirring at room temperature for 10 min, sodium triacetoxyborohydride (10mg, 0.047mmol) was added and the mixture was stirred for an additional 30 min and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was added to the reaction solution to give the title compound as a colorless gum (11.2mg) as a trifluoroacetate salt. MS M/z 409[ M + H ]]⁺。

Example 104

10-chloro-8- [ (3-fluorophenyl) sulfonyl]1-methyl-1, 3, 4,8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Sodium hydride (60% in mineral oil, 18mg, 0.74mmol) was added to 3-fluorobenzene-1-sulfonyl chloride (86.7mg, 0.445mmol) and 10-chloro-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] in DMF (2ml) at room temperature]OxazazemAnd [6, 7-e ]]A solution of tert-butyl indole-2-carboxylate (intermediate 43, 50.0mg, 0.15 mmol). The mixture was stirred for 15 min, after which water (5mL) was added and the aqueous layer was extracted with DCM. Most of the organic solvent was evaporated and the residue was dissolved in DCM (1mL) and TFA (2mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the crude product was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) was added to the reaction solution to give the title compound (18.5mg) as a brown solid in the form of trifluoroacetate salt. MS M/z395[ M + H]⁺。

Example 105

10-chloro-8- [ (3-fluorophenyl) sulfonyl]-1, 2-dimethyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

Using a PL-HCO3MP SPE cartridge, 10-chloro-8- [ (3-fluorophenyl) sulfonyl was applied]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate (example 104, 11.8mg, 0.023mmol) was converted to the free amine. Formaldehyde (37% by weight in H)₂O, 0.20mL, 2.4mmol) was added to a solution of the free amine (0.023mmol) in THF (1 mL). After stirring at room temperature for 10 min, sodium triacetoxyborohydride (10mg, 0.047mmol) was added and the mixture was stirred for an additional 30 min and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) purification to give trisThe title compound (8.2mg) as a colorless gum in the form of fluoroacetate. MS M/z 409[ M + H ]]⁺。

Example 106

1-methyl-8- (pyridin-3-ylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole bis (trifluoroacetate)

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4] in DCM (2mL)]OxazazemAnd [6, 7-e ]]A solution of indole-2-carboxylic acid tert-butyl ester (intermediate 42, 0.030g (0,098 mmol)) was added tetrabutylammonium hydrogen sulfate (6.4mg, 0.020mmol), 2M NaOH (0.2mL, 0.4mmol) and pyridine-3-sulfonyl chloride hydrochloride (35mg, 0.20 mmol). the reaction mixture was stirred vigorously at room temperature for 1 hour more 2M NaOH (1mL, 2mmol) was added to the mixture followed by addition of sulfonyl chloride (17mg, 0.10mmol) (total 103mg) every four hours water (10mL) was added and CHCl was used₃(2 ×) the aqueous phase was washed and the combined organics were evaporated under reduced pressure. To the resulting oil was added TFA/DCM50/50(1mL) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) to give the title compound (7.4mg) as a bis (trifluoroacetate) salt. MS M/z 344[ M + H ]]⁺。

Example 107

8- [ (2-chlorophenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole trifluoroacetate salt

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate)Body 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2-chlorobenzenesulfonyl chloride (26.0mg, 0.125mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give boc-protected intermediate as a white solid (23mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) to give the title compound (0.010g) as a white solid in the form of trifluoroacetate salt. MS M/z 377[ M + H ]]⁺。

Example 108

1-methyl-8- [ (2-methylphenyl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2-methylbenzenesulfonyl chloride (22mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 1-methyl-8- [ (2-methylphenyl) sulfonyl group]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (21mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperatureStir for 1 hour, and remove the solvent under reduced pressure. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH)₃CN) to give the title compound (1.1mg) as a white solid. MS M/z357[ M + H]⁺。

Example 109

8- [ (2, 6-difluorophenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2, 6-difluorobenzenesulfonyl chloride (26mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 8- [ (2, 6-difluorophenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (17mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (6 mg). MS M/z379[ M + H ]]⁺。

Example 110

8- [ (2, 4-dichlorophenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2, 4-dichlorobenzenesulfonyl chloride (28mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 8- [ (2, 4-dichlorophenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (2mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (0.7 mg). MS M/z 412[ M + H ]]⁺。

Example 111

8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2-methoxy-5-methylbenzenesulfonyl chloride (25mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. By addingThe reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 8- [ (2-methoxy-5-methylphenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (7mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (2 mg). MS M/z387[ M + H ]]⁺。

Example 112

8- [ (2-methoxy-4-methylphenyl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2-methoxy-4-methylbenzenesulfonyl chloride (25mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 8- [ (2-methoxy-4-methylphenyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (21mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was reduced under reduced pressureAnd (4) removing. The crude material was purified by preparative HPLC (XTerrac18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (7 mg). MSm/z 387[ M + H ]]⁺。

Example 113

8- [ (2, 5-dimethyl-3-thienyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2, 5-dimethyl-3-thienylsulfonyl chloride (24mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerrac18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 8- [ (2, 5-dimethyl-3-thienyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (6mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerrac18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (4 mg). MSm/z 377[ M + H]⁺。

Example 114

8- [ (2, 5-dimethyl-3-furyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2, 5-dimethyl-3-furansulfonyl chloride (22mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 8- [ (2, 5-dimethyl-3-furyl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (19mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (2 mg). MS M/z361[ M + H ]]⁺。

Example 115

1-methyl-8- (2-thienylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 2-thiophenesulfonyl chloride (21mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. Tong (Chinese character of 'tong')The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 1-methyl-8- (2-thienylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (14mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (5 mg). MS M/z 349[ M + H]⁺。

Example 116

1-methyl-8- [ (5-methylisoxazol-4-yl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 5-methyl-4-isoxazolesulfonyl chloride (21mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃pH 10-CH₃CN) to obtain 1-methyl-8- [ (5-methylisoxazol-4-yl) sulfonyl]-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (0.010g), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. Will be provided withThe crude was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH10-CH₃CN) to give the title compound (1 mg). MS M/z348[ M + H ]]⁺。

Example 117

8- [ (1, 2-dimethyl-1H-imidazol-4-yl) sulfonyl]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indoles

1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (intermediate 42, 25mg, 0.083mmol) was dissolved in DMF (1mL) and sodium hydride (60% in mineral oil, 4.0mg, 0.17mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, after which 1, 2-dimethylimidazole-4-sulfonyl chloride (22mg, 0.11mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50mM NH)₄HCO₃ pH 10-CH₃CN) to obtain 8- [ (1, 2-dimethyl-1H-imidazol-4-yl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole-2-carboxylic acid tert-butyl ester (5mg), which was dissolved in DCM (1mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerrac18, 50mM NH)₄HCO₃pH 10-CH₃CN) to give the title compound (2 mg). MSm/z 361[ M + H ]]⁺。

Biological assay

The ability of the compounds according to the invention to bind to the 5-HT6 receptor, as well as for pharmaceutical use, can be determined using in vivo and in vitro tests known in the art.

(a)5-HT₆Receptor binding assays

The general method described in Boess F.G et al Neuropharmacology 36(4/5)713-³H]-LSD as labelled ligand in the presence of 5-HT₆Human 5-HT in receptor-transfected HEK293 cells₆Binding affinity assay for receptor.

Material

Cell culture

Will use human 5-HT₆Recipient-transfected HEK-293 cells were cultured in Dulbeccos' modified Eagles Medium containing 5% dialyzed fetal bovine serum (Gibco BRL10106-169), 0.5mM sodium pyruvate and 400. mu.g/ml geneticin (G-418) (Gibco BRL 10131-019). Cells were passaged 1:10 twice weekly.

Chemical product

Radioactive ligand [ alpha ], [³H]LSD 60-240Ci/mmol, obtained from Amersham pharmacia Biotech, (Amoxicillin Biotech), (Baijin Hanshire, England) was in ethanol and stored at-20 ℃. Compounds were dissolved in 100% DMSO and diluted with binding buffer.

Treatment of

Compounds were diluted in Costar96 pore V-bottom polypropylene plates (Corning inc. The samples were incubated in a Packard optical plate (Optiplate) (Packard Instruments b.v., groongen, the netherlands). In the presence of Microscint^TMThe total amount of radioligand added was measured in a Packard 24-well Barex plate (Packard Instruments B.V., Groningen, the Netherlands) in the case of 20 scintillation fluid (Packard Bioscience), Meriden, CT, USA).

Buffer solution

Binding buffer 20mM HEPES，150mM NaCl，10mM MgCl₂And 1mM, EDTA, pH 7.4.

Method

Membrane separation

Cells were cultured to about 90% confluence on 24.5 x 24.5mm petri dishes. After aspirating the medium and washing with ice-cold PBS, the cells were scraped off using 25mL Tris buffer (50mM Tris-HCl, 1mM EDTA, 1mM EGTA, pH 7.4) and a window scraper. The cells were then disrupted with a Polytron homogenizer and the remaining particulate material removed by low speed centrifugation at 1000Xg for 5 minutes. Finally, the membranes were collected by high speed centrifugation (20000xg), suspended in binding buffer and frozen in aliquots at-70 ℃.

Radioligand binding

Frozen cell membranes were thawed, immediately re-homogenized with a Polytron homogenizer, and coupled with SPA wheat germ agglutinin beads (Amersham Life Sciences, cardioff, england) for 30 minutes with continuous shaking of the tube. After coupling, the beads were centrifuged at 1000g for 10 min and then suspended in 20mL binding buffer/96 well plates. Next, the binding reaction is initiated by adding the radioligand and test compound to the bead-membrane suspension. After incubation at room temperature, the test plates were subjected to scintillation counting.

The original SPA method was performed except that The membrane was prepared from HEK293 cells expressing The human 5-HT6 receptor, but not from HeLa cells (Dinh DM, Zaworkki PG, GillGS, Schlactiter SK, Lawson CF, Smith MW. confirmed human 5-HT6 receptor expressed in HeLa cell membranes: saturation binding studies, pharmacological profiles of standard CNS agents and SPA color development (The Upjohn Company Technical Report) 7295-95-0641995; 12.27.d.)³H]Specific binding of LSD is saturable, while non-specific binding increases linearly with the concentration of added radioligand. [³H]Binding of LSD to 5-HT with high affinity₆A receptor. Based on four separate experiments, K was estimated_dThe value was 2.6. + -. 0.2 nM.

2 at 3nM³H]The total binding of-LSD is typically 6000dpm, which is the radioligand concentration used in the competition experiments, whereas the specific binding is over 70%. When tested against two different membrane preparations, 5-HT results in concentration-dependent inhibition³H]LSD binding with a global mean Ki value of 236 nM. The inter-test variability in three experiments showed a CV of 10%, the average K of which_iThe value was 173nM (SD30) and the Hill coefficient (Hill coefficient) was 0.94(SD 0.09). The inter-assay variation was 3% (n-4). All unlabeled ligands are substituted for [2 ] in a concentration-dependent manner³H]Specific binding of LSD, although substituted with different potency. Reference Compounds with 5-HT₆The order of the receptor affinities was methtepine (Ki 2nM)>Mianserin (190nM) approximately equal to 5-HT (236nM)>Ergot (482nM)>Mesulerger (1970 nM).

Protein assay

Protein concentrations were determined using the BioRad protein assay (Bradford MM.A. rapid and sensitive method for the quantification of proteins using the protein-dye binding principle), anal.biochem.1976; 72: 248-54). Bovine serum albumin was used as a standard.

Scintillation counting

In Packard TopCount^TMRadioactivity was determined in a scintillation counter (Packard Instruments, Meriden, CT, usa) with a counting efficiency of about 20%. The counting efficiency was determined in separate experimental groups.

Saturation experiment

The radioligand (0.1 to 20 nM)³H]-LSD)Duplicate were used in saturation experiments. Specific binding was calculated as the difference between total and non-specific binding, which was determined as the binding of the radioligand in the presence of 5 μ M lisuride. Determination of B by non-linear regression analysis using equation 1_maxAnd dissociation constant K_d。L_uIs the concentration of unbound radioligand and y is the amount bound.

(equation 1)

Competitive assay

The total and non-specific binding of radioligand was determined in 8 replicates each. Samples containing test compounds were run in duplicate at 11 concentrations. Incubate at room temperature for 3 hours. Will IC₅₀The value, i.e., the concentration of 50% of test compound that inhibits specific binding of the radioligand, was determined using non-linear regression analysis and using equation 2[ Cheng Y.C.biochem. Pharmacol (Biochemical drugs) 22, 3099-3108, 1973-]Carry out the calculation of K_iThe value is obtained.

(equation 2)

Binding of L ═ radioligand

K_dAffinity of radioligand

(b)5-HT₆Determination of intrinsic Activity

Expression of human 5-HT by measurement₆Inhibition of 5-HT-induced cAMP increase in HEK293 cells of the receptor characterise 5-HT in humans₆Antagonists of the receptor (see Boess et al (1997) Neuropharmacology 36: 713-720). Briefly, HEK293/5-HT₆Cells were seeded at 25,000 cells/well in polylysine coated 96-well plates at 37 ℃ in 5% CO₂The cultures were maintained in DMEM (Dulbecco's modified Eagle's medium) (without phenol red) containing 5% dialyzed fetal bovine serum for 48 hours. The medium was then aspirated and replaced with 0.1mL of test medium (Hanks Balanced salt solution containing 20mM HEPES, 1.5mM isobutylmethylxanthine and 1mg/mL bovine serum albumin). After addition of 50. mu.l of test substance dissolved in the test medium, the cells were incubated at 37 ℃ in 5% CO₂Incubate in the incubator for 10 minutes. The medium was aspirated again and the cAMP content was determined using a radioactive cAMP kit (Amersham Pharmacia Biotech (Amoxicillin Biotech), BIOTRAK RPA 559). By using type IC_50，corr＝IC₅₀/(1+[5HT]/EC₅₀) Determination of the cause of para-5-HT (in [ 5-HT)]＝EC₅₀8-fold) induced cAMP increase by a concentration of 50% inhibition to quantify the efficacy of the antagonist.

The compounds according to the invention have a 5-HT profile for humans₆Selective affinity of the receptor, K_iAnd IC_50，corrA value between 0.5nM and 5. mu.M, or at 50nM of p [ alpha ], [³H]-LSD% inhibition ≧ 20%, and it is for human 5-HT₆Antagonists, agonists or partial agonists of the receptor (see tables II and III). The compounds are shown to be relatively human 5-HT_1a，5-HT_1b，5-HT_2a，5-HT_2bAnd 5-HT_2cGood selectivity of the receptor.

TABLE II

To human 5-HT₆Binding affinity of the receptor (K)_i)

Examples	K_i(nM)
Examples	K_i(nM)	5	2
10	1	5	2
10	1	50	2

TABLE III

To human 5-HT₆Antagonist potency of the receptor (fKi ═ IC_50，corr)。

Examples	fK_i(nM)
Examples	fK_i(nM)	5	3
10	1	5	3
10	1	50	5

(c) In vivo testing for reduced food intake

For reviews of 5-hydroxytryptamine and food intake, see Blundell, J.E. and Halford, J.C.G. (1998) Serotonin and AN _ SNpetite Regulation. antibiotics for the pharmaceutical Treatment of Obesity (5-hydroxytryptamine and Appetite regulation. for the suggestion of drug therapy for Obesity). CNS Drugs (CNS Drugs) 9: 473-495.

Obese (ob/ob) mice were selected as the initial animal model for screening because such mutant mice consume large amounts of food, resulting in high signal-to-noise ratios. To further confirm and compare efficacy data, the effect of the compounds on food consumption was also studied in wild type (C57BL/6J) mice. The consumption of food during 15 hours of compound infusion was recorded.

Male mice of 8-9 weeks of age (obese C57BL/6 JBom-Lep) with an average body weight of 50g (obese) and 25g (lean)^obAnd leaner wild type C57BL/6 JBom; bomholtsgaard, denmark) was used in all studies. The animals were individually housed in cages at 23 ± 1 ℃, 40-60% humidity, with water and standard laboratory food ad libitum. An 12/12-hour light/dark cycle was set and the lights were turned off at 5 pm. Animals were acclimated for at least one week prior to the start of the experiment.

The test compound is dissolved in a solvent suitable for each specific compound such as cyclodextrin, cyclodextrin/methanesulfonic acid, polyethylene glycol/methanesulfonic acid, saline. Fresh solutions were prepared for each study. 30, 50 and 100mg kg were used^-1Sky^-1The dosage of (a). The purity of the test compound is analytical grade.

Animals were weighed at the beginning of the study and randomly grouped based on body weight. An Alzet osmotic minipump (model 2001D; infusion rate 8. mu.l/h) was used and loading was carried out essentially as recommended by the Alzet technical information handbook (Alza scientific Products, 1997; Theeuwes, F. and Yam, S.I.Ann.biomed.Eng.4 (4). 343- -353, 1976). Continuous subcutaneous infusion was used for 24 hours. The micropump is filled with different concentrations of the test compound dissolved in the excipient or with just the excipient solution and maintained in the excipient pre-warmed to 37 ℃ (about 1 hour). The micropump was implanted subcutaneously in the cervical/posterior region under short-acting anesthesia (metofane/enflurane). The surgical procedure lasts about 5 minutes.

The weight of the food pellets was measured at 5 pm and 8 pm, for 2 days, before (baseline) and one day after implantation of the osmotic minipump. Weighing was carried out with a computer-assisted Mettler Toledo PR 5002 balance. Occasional spillover (spill) is corrected. At the end of the study, animals were sacrificed by cervical dislocation and trunk blood samples were taken for subsequent plasma drug concentration analysis.

Plasma sample proteins were precipitated with methanol, centrifuged, and the supernatant transferred to HPLC vials and injected into a liquid phase/mass spectrometry system. The mass spectrometer was set to electrospray positive ion mode and multiple reaction monitoring. The concentration of the unknown sample was calculated using standard linear regression analysis forced through the origin.

Food consumption was measured for 15 hours, three consecutive days, and the percentage of baseline level values for the day before and the day after treatment was obtained for each animal. The values are expressed as mean ± SD and ± SEM of 8 animals per dose group. Statistical evaluation was performed by Kruskal-Wallis one-way ANOVA using the percentage baseline values. If statistical significance was achieved at a p <0.05 level, a Mann-Whitney U-test was performed to make statistical comparisons between control and treatment groups.

Claims

1. A compound of formula (I):

wherein:

represents a single bond or a double bond;

a is N or NR⁵；

X is O, S, N-H or N-C_1-6-an alkyl group;

R¹is a group selected from:

(a)C_1-6-an alkyl group,

(b)C_3-7-a cycloalkyl group,

(c)C_3-6-an alkenyl group,

(d) an aryl group, a heteroaryl group,

(e) aryl-C_2-6-an alkenyl group,

(f) aryl-C_1-6-an alkyl group,

(g) (ii) a heteroaryl group, wherein,

(h) heteroaryl-C_2-6-alkenyl, and

(i) heteroaryl-C_1-6-an alkyl group,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) methyl-C_3-7-a cycloalkyl group,

(f) fluorine-C_3-7-a cycloalkyl group,

(g)C_2-6-an alkenyl group,

(h) fluorine-C_2-6-an alkenyl group,

(i) an ethynyl group;

(j) hydroxy-C_1-4-an alkyl group,

(k) a hydroxyl group(s),

(l)C_1-6-alkoxy radical

(m) fluorine-C_1-6-alkoxy radical

(n)C_3-7-cycloalkoxy radical

(o) methyl-C_3-7-cycloalkoxy radical

(p) fluoro-C_3-7-cycloalkoxy radical

(q)-SCF₃，

(r)-SCF₂H，

(s)-SO₂NR¹⁰R¹⁰，

(t)-S(O)_eR¹¹Wherein e is 0, 1, 2 or 3,

(u)-CN，

(v)-NR¹⁰R¹⁰，

(w)-NHSO₂R¹¹，

(x)-NR¹²COR¹¹，

(y)-NO₂，

(z)-CONR¹⁰R¹⁰，

(aa)-CO-R¹¹，

(bb)-COOH，

(cc)C_1-6-an alkoxycarbonyl group, a carbonyl group,

(dd) an aryl group, in which,

(ee) a heteroaryl group, and (ee),

(ff) aryloxy, and

(gg) a heteroaryloxy group,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R²is a group selected from:

(a) hydrogen

(b) The halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d) fluorine-C_1-6-an alkyl group,

(e)C_3-7-a cycloalkyl group,

(f) methyl-C_3-7-a cycloalkyl group,

(g) fluorine-C_3-7-a cycloalkyl group,

(h)C_2-6-an alkenyl group,

(i) fluorine-C_2-6-an alkenyl group,

(j) an acetylene group,

(k) hydroxy-C_1-4-an alkyl group,

(l) A hydroxyl group(s),

(m)C_1-6-an alkoxy group,

(n) fluoro-C_1-6-an alkoxy group,

(o)C_3-7-a cycloalkoxy group,

(p) methyl-C_3-7-a cycloalkoxy group,

(q) fluoro-C_3-7-a cycloalkoxy group,

(r)-SCF₃，

(s)-SCF₂H，

(t)-SO₂NR¹⁰R¹⁰，

(u)-S(O)_eR¹¹wherein e is 0, 1, 2 or 3,

(v)-CN，

(w)-NR¹⁰R¹⁰，

(x)-NR¹²SO₂R¹¹，

(y)-NR¹²COR¹¹，

(z)-NO₂，

(aa)-CONR¹⁰R¹⁰，

(bb)-OCONR¹⁰R¹⁰，

(cc)-CO-R¹¹，

(dd) -COOH, and

(ee)C_1-6-an alkoxycarbonyl group;

R³is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b) the halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) hydroxy-C_1-4-an alkyl group,

(f)C_3-7-cycloalkyl-hydroxy-C_1-4-alkyl radical

(g)C_1-2-alkoxy-C_1-4-alkyl radical

(h)-COOR¹²，

(i)-CONR¹⁰R¹⁰，

(j)-CO-R¹¹，

(k)-CN，

(l) Aryl, and

(m) a heteroaryl group, in which,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R⁴is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d)C_3-5-a cycloalkyl group,

(e) fluorine-C_3-5-a cycloalkyl group,

(f) hydroxy-C_1-4-alkyl, and

(g) a cyano group;

R⁵is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d) 2-cyanoethyl group, a 2-cyanoethyl group,

(e) hydroxy-C_2-4-an alkyl group,

(f)C_3-4-an alkenyl group,

(g)C_3-4-an alkynyl group,

(h)C_3-7-a cycloalkyl group,

(i) methyl-C_3-7-cycloalkyl radical

(j) fluorine-C_3-7-a cycloalkyl group,

(k)C_3-4-cycloalkyl-C_1-4-alkyl, and

(l)C_1-4-alkoxy-C_2-4-alkyl, or

R⁶、R⁷、R⁸Or R⁹One of the radicals with R⁵Together with the atoms to which they are attached form a heterocyclic ring, and R⁶、R⁷、R⁸Or R⁹The other three of (a) are hydrogen;

R⁶，R⁷，R⁸and R⁹Each independently selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group,

R⁶，R⁷，R⁸or R is⁹Two of the radicals together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, and R⁶，R⁷，R⁸Or R⁹The remaining two of (A) are hydrogen, or

R¹⁰each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_2-6-alkyl, and

(d)C_3-7-cycloalkyl, or

R¹¹each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) methyl-C_3-7-a cycloalkyl group,

(f) aryl, and

(g) (ii) a heteroaryl group, wherein,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

R¹²each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group,

or when in the group NR¹²COR¹¹When present, R¹¹And R¹²Together with the atoms to which they are attached form a lactam ring, or when present as a group NR¹²SO₂R¹¹When present, R¹¹And R¹²Together with the atoms to which they are attached form a sultam ring;

2. A compound according to claim 1, which is a compound of formula (II):

wherein

Represents a single bond or a double bond;

a is N or NR⁵；

X is O, S, N-H or N-C_1-6-an alkyl group;

R¹is a group selected from:

(a)C_1-6-an alkyl group,

(b)C_3-7-a cycloalkyl group,

(c)C_3-6-an alkenyl group,

(d) an aryl group, a heteroaryl group,

(e) aryl-C_2-6-an alkenyl group,

(f) aryl-C_1-6-an alkyl group,

(g) (ii) a heteroaryl group, wherein,

(h) heteroaryl-C_2-6-alkenyl, and

(i) heteroaryl-C_1-6-an alkyl group,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) methyl-C_3-7-a cycloalkyl group,

(f) fluorine-C_3-7-a cycloalkyl group,

(g)C_2-6-an alkenyl group,

(h) fluorine-C_2-6-an alkenyl group,

(i) an ethynyl group;

(j) hydroxy-C_1-4-an alkyl group,

(k) a hydroxyl group(s),

(l)C_1-6-alkoxy radical

(m) fluorine-C_1-6-alkoxy radical

(n)C_3-7-cycloalkoxy radical

(o) methyl-C_3-7-cycloalkoxy radical

(p) fluoro-C_3-7-cycloalkoxy radical

(q)-SCF₃，

(r)-SCF₂H，

(s)-SO₂NR¹⁰R¹⁰，

(t)-S(O)_eR¹¹Wherein e is 0, 1, 2 or 3,

(u)-CN，

(v)-NR¹⁰R¹⁰，

(w)-NHSO₂R¹¹，

(x)-NR¹²COR¹¹，

(y)-NO₂，

(z)-CONR¹⁰R¹⁰，

(aa)-CO-R¹¹，

(bb)-COOH，

(cc)C_1-6-an alkoxycarbonyl group, a carbonyl group,

(dd) an aryl group, in which,

(ee) a heteroaryl group, and (ee),

(ff) aryloxy, and

(gg) a heteroaryloxy group,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R²is a group selected from:

(a) hydrogen

(b) The halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d) fluorine-C_1-6-an alkyl group,

(e)C_3-7-a cycloalkyl group,

(f) methyl-C_3-7-a cycloalkyl group,

(g) fluorine-C_3-7-a cycloalkyl group,

(h)C_2-6-an alkenyl group,

(i) fluorine-C_2-6-an alkenyl group,

(j) an acetylene group,

(k) hydroxy-C_1-4-an alkyl group,

(l) A hydroxyl group(s),

(m)C_1-6-an alkoxy group,

(n) fluoro-C_1-6-an alkoxy group,

(o)C_3-7-a cycloalkoxy group,

(p) methyl-C_3-7-a cycloalkoxy group,

(q) fluoro-C_3-7-a cycloalkoxy group,

(r)-SCF₃，

(s)-SCF₂H，

(t)-SO₂NR¹⁰R¹⁰，

(u)-S(O)_eR¹¹wherein e is 0, 1, 2 or 3,

(v)-CN，

(w)-NR¹⁰R¹⁰，

(x)-NR¹²SO₂R¹¹，

(y)-NR¹²COR¹¹，

(z)-NO₂，

(aa)-CONR¹⁰R¹⁰，

(bb)-OCONR¹⁰R¹⁰，

(cc)-CO-R¹¹，

(dd) -COOH, and

(ee)C_1-6-an alkoxycarbonyl group;

R³is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b) the halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) hydroxy-C_1-4-an alkyl group,

(f)C_3-7-cycloalkyl-hydroxy-C_1-4-alkyl radical

(g)C_1-2-alkoxy-C_1-4-alkyl radical

(h)-COOR¹²，

(i)-CONR¹⁰R¹⁰，

(j)-CO-R¹¹，

(k)-CN，

(l) Aryl, and

(m) a heteroaryl group, in which,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

(g) a hydroxymethyl group;

R⁴is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d)C_3-5-a cycloalkyl group,

(e) fluorine-C_3-5-a cycloalkyl group,

(f) hydroxy-C_1-4-alkyl, and

(g) a cyano group;

R⁵is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-4-an alkyl group,

(c) fluorine-C_1-4-an alkyl group,

(d) 2-cyanoethyl group, a 2-cyanoethyl group,

(e) hydroxy-C_2-4-an alkyl group,

(f)C_3-4-an alkenyl group,

(g)C_3-4-an alkynyl group,

(h)C_3-7-a cycloalkyl group,

(i) methyl radical-C_3-7-cycloalkyl radical

(j) fluorine-C_3-7-a cycloalkyl group,

(k)C_3-4-cycloalkyl-C_1-4-alkyl, and

(l)C_1-4-alkoxy-C_2-4-alkyl, or

R⁶，R⁷，R⁸and R⁹Each independently selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group,

R¹⁰each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_2-6-alkyl, and

(d)C_3-7-cycloalkyl, or

R¹¹each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group,

(e) methyl-C_3-7-a cycloalkyl group,

(f) aryl, and

(g) (ii) a heteroaryl group, wherein,

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-4-an alkyl group,

(c)C_1-4-an alkylthio group,

(d)C_1-4-an alkoxy group,

(e)-CF₃，

(f) -CN, and

R¹²each independently is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b)C_1-6-an alkyl group,

(c) fluorine-C_1-6-an alkyl group,

(d)C_3-7-a cycloalkyl group, and

(e) hydroxy-C_1-4-an alkyl group,

3. A compound according to claim 2, wherein:

X＝O；

(a) the halogen(s) are selected from the group consisting of,

(b)C_1-3-an alkyl group,

(c) a trifluoromethyl group,

(d) the free radical of the methoxy group,

(e) a trifluoro-methoxyl group,

(f) a methyl sulfonyl group, a carboxyl group,

(g) -CN, and

(h) a phenyl group;

R²is a group selected from:

(a) hydrogen

(b) The halogen(s) are selected from the group consisting of,

(c)C_1-6-alkyl, and

(d)C_1-6an alkoxy group;

R³is a group selected from:

(a) the presence of hydrogen in the presence of hydrogen,

(b) the halogen(s) are selected from the group consisting of,

(c)C_1-6-an alkyl group,

(d) hydroxy-C_1-4-an alkyl group,

(e)C_3-7-cycloalkyl-hydroxy-C_1-4-alkyl, and

(f)-CO-C_1-6-an alkyl group;

R⁴is selected from hydrogen and C_1-4-a group of alkyl groups;

R⁵selected from hydrogen, C_1-3Alkyl and fluoro-C_1-3-an alkyl group; or

R⁶And R⁸One of and R⁵Together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine ring, provided that R⁷And R⁹Are all hydrogen;

R⁷selected from hydrogen and methyl:

R⁹selected from hydrogen and methyl.

4. A compound according to claim 3, wherein:

R¹selected from phenyl, naphthyl, pyridyl, isoxazolyl, imidazolyl, 1, 4-benzodioxanyl, benzofuranyl, furanyl, 1, 3-benzothiazolyl, chromanyl, thienyl and benzothienyl, each of which is optionally independently substituted at one or more positions with a substituent selected from the group consisting of:

(a) fluorine

(b) The chlorine is added to the reaction mixture in the presence of chlorine,

(c)C_1-3-an alkyl group,

(d) a trifluoromethyl group,

(e) the free radical of the methoxy group,

(f) a trifluoro-methoxyl group,

(g) a methyl sulfonyl group, a carboxyl group,

(h) -CN, and

(i) phenyl radical

R²Is hydrogen, fluoro, methyl or methoxy;

R⁴selected from hydrogen, methyl and isopropyl;

R⁷selected from hydrogen and methyl;

R⁹selected from hydrogen and methyl.

5. A compound according to claim 4, wherein

R¹Selected from phenyl, 1-naphthyl, 2-naphthyl, 3-pyridyl, 4-isoxazolyl, 4-imidazolyl, 1, 4-benzodioxine-6-yl, 2-benzofuranyl, 3-furanyl, 1, 3-benzothiazol-6-yl, 6-benzopyranyl, 2-thienyl, 3-thienyl, 2-benzothienyl, and 3-benzothienyl, each of which is optionally independently substituted at one or two positions with a substituent selected from the group consisting of:

(b) the chlorine is added to the reaction mixture in the presence of chlorine,

(c) the methyl group is a group selected from the group consisting of,

(d) the propyl group is a compound of formula (I),

(f) a trifluoromethyl group,

(g) the free radical of the methoxy group,

(h) a trifluoro-methoxyl group,

(i) a methyl sulfonyl group, a carboxyl group,

(j) -CN, and

(k) a phenyl group.

6. A compound according to claim 5, selected from:

2-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (3-chloro-4-methylphenyl) sulfonyl group]-2-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

(7aR) -3- (phenylsulfonyl) -3, 7a, 8, 9, 10, 12-hexahydro-7H-pyrrolo [2 ', 1': 3, 4)][1，4]OxazazemAnd [6, 7-e ]]Indole;

(7aS) -3- (phenylsulfonyl) -3, 7a, 8, 9, 10, 12-hexahydro-7H-pyrrolo [2 ', 1': 3, 4)][1，4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (3, 4-Dimethoxyphenyl) sulfonyl]-1，3，4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- (2-Thienylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1-methyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

1, 2-dimethyl-8- (phenylsulfonyl) -1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole;

8- [ (1, 2-dimethyl-1H-imidazol-4-yl) sulfonyl group]-1-methyl-1, 3, 4, 8-tetrahydro-2H- [1, 4]OxazazemAnd [6, 7-e ]]Indole.

7. The compound according to any one of claims 1 to 6, which is 5-HT₆Receptor antagonists or partial agonists.

8. The compound according to claim 7, which is 5-HT₆A receptor antagonist.

9. A method for treating or preventing a disorder in a subject, the method comprising administering to the subject a composition comprising a compound according to any one of claims 1 to 8.

10. The method of claim 9, wherein the disorder is 5-HT₆A receptor-associated disorder.

11. The method of claim 10, wherein a reduction in body weight or a reduction in body weight gain is observed in the subject.

12. The method of claim 10, wherein the disorder is obesity.

13. A process for the manufacture of a composition comprising combining a compound according to any one of claims 1 to 8 with a pharmaceutically acceptable diluent or carrier.

14. A method for treating or preventing 5-HT₆A method of treating a receptor-related disorder, said method comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound according to any one of claims 1 to 8.

15. A method for the reduction of body weight or the reduction of body weight gain, which method comprises administering an effective amount of a compound according to any one of claims 1 to 8 to a mammal, including man, in need of such reduction.

16. For regulating 5-HT₆A method of receptor activity comprising administering an effective amount of a compound according to any one of claims 1 to 8 to a mammal, including a human.

17. Use of a compound according to any one of claims 1 to 8 for the preparation of a medicament for the treatment or prevention of 5-HT₆A receptor-associated disorder.

18. Use of a compound according to claim 17 for the preparation of a medicament for the reduction of body weight and the reduction of body weight gain.

19. The use of a compound according to any one of claims 1 to 8 for the preparation of medicaments for the treatment or prophylaxis of obesity.

20. A pharmaceutical formulation containing a compound according to any one of claims 1 to 8 as active ingredient in combination with a pharmaceutically acceptable diluent or carrier.

21. The pharmaceutical formulation according to claim 20, further comprising an additional therapeutic agent.

22. A pharmaceutical formulation according to claim 20, wherein a compound according to any one of claims 1 to 8 is useful in the reduction of body weight or in the reduction of body weight gain.

23. A non-therapeutic method for improving the physical appearance of a mammal, said method comprising administering to said mammal a compound according to any one of claims 1 to 8 in an amount effective to reduce appetite, and repeating said amount until a cosmetically beneficial weight loss has occurred.

24. A cosmetic composition comprising, as active ingredient, a compound according to any one of claims 1 to 8 in combination with a cosmetically acceptable diluent or carrier.

25. Cosmetic composition according to claim 21, further comprising an additional active ingredient.