HK1175470B

HK1175470B - Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline

Info

Publication number: HK1175470B
Application number: HK13102808.3A
Authority: HK
Inventors: M．埃克哈特; S.彼得斯; H．纳尔; F．希默尔斯巴赫; 庄淩航
Original assignee: 生命医药公司; 贝林格尔‧英格海姆国际有限公司
Priority date: 2009-11-06
Filing date: 2010-11-05
Publication date: 2016-05-20

Abstract

The present invention relates to compounds defined by formula I, wherein the variables R1, R2, R3, R4, and m are defined as in claim 1, possessing valuable pharmacological activity. Particularly, the compounds are inhibitors of 11 β-hydroxysteroid dehydrogenase (HSD) 1 and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this enzyme, such as metabolic diseases, in particular diabetes type 2, obesity, and dyslipidemia.

Description

Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline

RELATED APPLICATIONS

This application claims priority from european patent application No.09175233.7 filed on 6.11.2009, the entire teachings of which are incorporated by reference into this application.

Technical Field

The present invention relates to hexahydroindenopyridines and octahydrobenzoquinolines and their use as inhibitors of 11 beta-hydroxysteroid dehydrogenase 1(HSD 1), to pharmaceutical compositions comprising said compounds and to their use for the treatment of metabolic diseases such as metabolic syndrome, diabetes, obesity and dyslipidemia. Furthermore, the present invention relates to processes for preparing the pharmaceutical compositions and compounds of the invention.

Background

In the literature, compounds having an inhibitory effect on the enzyme 11 β -hydroxysteroid dehydrogenase (HSD)1 are proposed for the treatment of metabolic syndrome, in particular type 2 diabetes, obesity and dyslipidemia.

In Bulletin of the Chemical Society of Japan 1959, 32, p.1005-7 and Journal of Organic Chemistry 1964, 29, p.1419-24, compounds having the following structures have been disclosed:

a chromatographic process for separating enantiomers of heterocyclic amines is disclosed in Journal of Organic Chemistry 1984, 49, p.2504-6, and in particular the enantiomers of the following racemic compounds:

the following compounds are disclosed as intermediates for the separation of cis and trans isomers in Journal of Medicinal Chemistry 1981, 24, p.1432-7:

object of the Invention

It was surprisingly found that the compounds of the invention not only have an inhibitory effect on HSD 1 in vitro and/or in vivo, but also have a significant metabolic stability, which makes them suitable for use as medicaments. It is therefore an object of the present invention to find hexahydroindenopyridines and octahydrobenzoquinolines which have an inhibitory effect on HSD 1 in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties for their use as medicaments.

Other aspects of the present invention are to provide novel pharmaceutical compositions suitable for use in the prevention and/or treatment of metabolic diseases.

Other aspects of the invention relate to physiologically acceptable salts of the compounds of the general formula I according to the invention with inorganic or organic acids or bases.

Further aspects of the present invention relate to pharmaceutical compositions comprising at least one compound of the general formula I according to the invention or a physiologically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents.

Other aspects of the invention relate to compounds of the general formula I or physiologically acceptable salts thereof for the treatment or prophylaxis of diseases or disorders which can be influenced by the inhibition of the enzyme 11 β -hydroxysteroid dehydrogenase (HSD)1, for example metabolic diseases.

A further aspect of the invention relates to the use of at least one compound of the general formula I or a physiologically acceptable salt thereof for the preparation of a pharmaceutical composition suitable for the treatment or prevention of diseases or disorders which can be influenced by the inhibition of the enzyme 11 β -hydroxysteroid dehydrogenase (HSD)1, for example metabolic diseases.

Other objects of the present invention will become apparent to those skilled in the art directly from the foregoing and following description.

Disclosure of Invention

In a first aspect, the present invention relates to compounds of general formula I, tautomers thereof, stereoisomers thereof, mixtures thereof and salts thereof:

wherein

R¹R selected from the group consisting of^1a：

Phenyl, naphthyl, pyrrolyl, furyl, thienyl, pyridyl, indolyl, benzofuryl, benzothienyl, quinolyl, isoquinolyl,

Wherein optionally 1 or 2 CH groups may be replaced by N in pyrrolyl, furyl, thienyl and pyridyl groups, and optionally 1 to 3 CH groups may be replaced by N in indolyl, benzofuryl, benzothienyl, quinolinyl and isoquinolinyl groups,

2-oxo-1, 2-dihydro-pyridinyl, 4-oxo-1, 4-dihydro-pyridinyl, 3-oxo-2, 3-dihydro-pyridazinyl, 3, 6-dioxo-1, 2, 3, 6-tetrahydro-pyridazinyl, 2-oxo-1, 2-dihydro-pyrimidinyl, 4-oxo-3, 4-dihydro-pyrimidinyl, 1, 2, 3, 4-tetrahydro-2, 4-dioxo-pyrimidinyl, 2-oxo-1, 2-dihydro-pyrazinyl, 2, 3-dioxo-1, 2, 3, 4-tetrahydro-pyrazinyl, indanyl, 1-oxo-indanyl, 2, 3-dihydro-indolyl, 2-oxo-1, 3-dihydro-pyridazinyl, 4-dihydro-pyrimidinyl, 4-oxo-pyridazinyl, 4-oxo-pyrimidinyl, 2, 3-tetrahydro-pyrazinyl, indanyl, 1-oxo-indanyl, 2, 3, 2, 3-dihydro-isoindolyl, 2-oxo-2, 3-dihydro-indolyl, 1-oxo-2, 3-dihydro-isoindolyl, 2, 3-dihydrobenzofuranyl, 2-oxo-2, 3-dihydro-benzimidazolyl, 2-oxo-2, 3-dihydro-benzoxazolyl, benzo [1, 3] dioxolyl (benzol 1, 3) dioxolyl), 2-oxo-benzo [1, 3] dioxolyl, 1, 2, 3, 4-tetrahydro-naphthyl, 1, 2, 3, 4-tetrahydro-quinolinyl, 2-oxo-1, 2-dihydro-quinolinyl, 4-oxo-1, 4-dihydro-quinolinyl, 1, 2, 3, 4-tetrahydro-isoquinolinyl, 1-oxo-1, 2-dihydro-isoquinolinyl, 4-oxo-1, 4-dihydro-cinnolinyl, 2-oxo-1, 2-dihydro-quinazolinyl, 4-oxo-1, 4-dihydro-quinazolinyl, 2, 4-dioxo-1, 2, 3, 4-tetrahydro-quinazolinyl, 2-oxo-1, 2-dihydro-quinoxalinyl, 3-oxo-1, 2, 3, 4-tetrahydro-quinoxalinyl, 2-oxo-1, 2, 3, 4-tetrahydro-quinoxalinyl, 2, 3-dioxo-1, 2, 3, 4-tetrahydro-quinoxalinyl, 1-oxo-1, 2-dihydro-phthalazinyl, 1, 4-dioxo-1, 2, 3, 4-tetrahydro-phthalazinyl, chromanyl, coumarinyl, 2, 3-dihydro-benzo [1, 4] dioxin-yl (dioxinyl), 3-oxo-3, 4-dihydro-benzo [1, 4] oxazinyl, tetrazolyl, 2-oxo-2, 3-dihydro-benzothiazolyl and imidazo [1, 2-a ] pyridyl,

Wherein the group R^1aIs linked to the carbonyl group of formula I via an aromatic carbon atom, and

wherein the group R^1aMay be optionally substituted by one R⁵One to three identical and/or different R⁶And/or one R⁷Substituted with the proviso that if R is¹Is phenyl, then the substituent R⁵、R⁶And/or R⁷(ii) is not attached to a carbon atom adjacent to the carbon atom attached to the carbonyl group in formula I;

R²r selected from the group consisting of^2a：

Hydrogen, halogen, (hetero) aryl, cyano, nitro, amino, hydroxy, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Alkenyl and C_2-6Alkynyl, wherein at each C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Alkenyl and C_2-6In alkynyl, one CH₂The radicals being optionally substituted by CO or SO₂Instead of, one CH₂The radicals being optionally substituted by O or NR^NAnd one CH group is optionally replaced by N, and wherein each of these groups may optionally be mono-or polyfluorinated and optionally mono-or, independently of one another, disubstituted by:

chlorine, C_1-3Alkyl, cyano, (hetero) aryl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, hydroxy, C_1-3Alkoxy, (hetero) aryloxy, C_1-3Alkylsulfanyl (alkylsulfanyl), C_1-3Alkylsulfinyl orC_3-6Cycloalkyl radicals, in which C_3-6One or two CH's of cycloalkyl₂The radicals being optionally substituted independently of one another by carbonyl, O or NR ^NAnd one CH group is optionally replaced by N, and which may optionally be substituted by fluorine or C_1-3Alkyl is mono-or independently di-substituted;

R³、R⁴are selected independently of one another from the group R consisting of^3/4a：

Hydrogen, halogen, C_1-3Alkyl, trifluoromethyl, hydroxy, C_1-3Alkoxy and cyano, or

R^3/4aRepresents R³And R⁴Bonded to adjacent carbon atoms and linked to form methylenedioxy, ethylenedioxy or C_3-5Alkylene each of which may be optionally substituted with one or two groups independently selected from fluoro and methyl, or, together with the carbon atom to which it is attached, form a benzo, pyrido, pyrimido, pyrazino, pyridazino, pyrazolo, imidazo, triazolo, oxazolo, thiazolo, isoxazolo or isothiazolo ring, each of which may be optionally substituted with one or two groups independently selected from halogen, C_1-3Alkyl, trifluoromethyl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, hydroxy and C_1-3Substituted by a substituent of alkoxy;

R⁵r selected from the group consisting of^5a：

Halogen, (hetero) aryl, cyano, nitro, amino, hydroxy, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Alkenyl and C_2-6Alkynyl, wherein in each radical one CH ₂The radicals being optionally substituted by CO or SO₂Instead of, one CH₂The radicals being optionally substituted by O or NR^NAnd one CH group is optionally replaced by N, and wherein each group may optionally be mono-or polyfluorinated, and optionally mono-or disubstituted independently of each other by:

chlorine, C_1-3Alkyl, cyano, (hetero) aryl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, hydroxy, C_1-3Alkoxy, (hetero) aryloxy, C_1-3Alkylsulfanyl group, C_1-3Alkylsulfinyl or C_3-6Cycloalkyl radicals, in which C_3-6One or two CH's in cycloalkyl₂The radicals being optionally independently carbonyl, O or NR^NAnd one CH group is optionally replaced by N, and which may optionally be fluorine or C_1-3Alkyl is mono-or independently di-substituted;

R⁶、R⁷are selected independently of one another from the group R consisting of^6/7a: halogen, C_1-3Alkyl radical, C_2-3Alkynyl, trifluoromethyl, hydroxy, C_1-3Alkoxy and cyano, and/or

R^6/7aRepresents and R⁷Bound R⁶Which are bonded to adjacent carbon atoms and form methylenedioxy, difluoromethylenedioxy, ethylenedioxy, C_3-5Alkylene, or together with the carbon atom to which it is attached, forms a pyrazolo, imidazo, oxazolo, isoxazolo, thiazolo or isothiazolo ring, each of which may optionally be substituted by C _1-3Alkyl, trifluoromethyl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, hydroxy, C_1-3Alkoxy is monosubstituted or, independently of one another, disubstituted;

R^Nare selected independently of one another from the group R consisting of^Na：

Hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, (hetero) aryl, C_1-4Alkylcarbonyl, (hetero) arylcarbonyl, C_1-4Alkylaminocarbonyl, di (C)_1-3Alkyl) aminocarbonyl, (hetero) arylaminocarbonyl, C_1-4Alkoxycarbonyl group, C_1-4Alkylsulfonyl and (hetero) arylsulfonyl,

wherein each one ofAlkyl, alkenyl and alkynyl groups optionally mono-or polysubstituted with fluorine and optionally (hetero) aryl, cyano, aminocarbonyl, C_1-3Alkylaminocarbonyl, di (C)_1-3Alkyl) aminocarbonyl, carboxyl, C_1-4Alkoxycarbonyl, amino, C_1-4Alkylamino radical, di (C)_1-3Alkyl) amino, C_1-4Alkylcarbonylamino, hydroxy, C_1-4Alkoxy radical, C_1-4Alkylsulfanyl group, C_1-4Alkylsulfinyl or C_1-4-monosubstitution of the alkylsulfonyl group;

(hetero) aryl groups independently of each other are selected from the group HA consisting of^a：

wherein in pyrrolyl, furanyl, thienyl and pyridyl 1 or 2 CH groups may optionally be replaced by N, and in indolyl, benzofuranyl, benzothienyl, quinolinyl and isoquinolinyl 1 to 3 CH groups may optionally be replaced by N,

2-oxo-1, 2-dihydro-pyridinyl, 4-oxo-1, 4-dihydro-pyridinyl, 3-oxo-2, 3-dihydro-pyridazinyl, 3, 6-dioxo-1, 2, 3, 6-tetrahydro-pyridazinyl, 2-oxo-1, 2-dihydro-pyrimidinyl, 4-oxo-3, 4-dihydro-pyrimidinyl, 2, 4-dioxo-1, 2, 3, 4-tetrahydro-pyrimidinyl, 2-oxo-1, 2-dihydro-pyrazinyl, 2, 3-dioxo-1, 2, 3, 4-tetrahydro-pyrazinyl, 2-oxo-2, 3-dihydro-indolyl, 4-oxo-1, 2, 3-tetrahydro-pyrazinyl, 2-oxo-2, 3-dihydro-indolyl, 2, 3-dihydro-benzofuranyl, 2-oxo-2, 3-dihydro-benzimidazolyl, 2-oxo-2, 3-dihydro-benzoxazolyl, 2-oxo-1, 2-dihydro-quinolinyl, 4-oxo-1, 4-dihydro-quinolinyl, 1-oxo-1, 2-dihydro-isoquinolinyl, 4-oxo-1, 4-dihydro-cinnolinyl, 2-oxo-1, 2-dihydro-quinazolinyl, 4-oxo-1, 4-dihydro-quinazolinyl, 2, 4-dioxo-1, 2, 3, 4-tetrahydro-quinazolinyl, 2-oxo-1, 2-dihydro-quinoxalinyl, 3-oxo-1, 2, 3, 4-tetrahydro-quinoxalinyl, 2, 3-dioxo-1, 2, 3, 4-tetrahydro-quinoxalinyl, 1-oxo-1, 2-dihydro-phthalazinyl, 1, 4-dioxo-1, 2, 3, 4-tetrahydro-phthalazinyl, chromanyl, coumarinyl, 2, 3-dihydro-benzo [1, 4] dioxinyl, 3-oxo-3, 4-dihydro-benzo [1, 4] oxazinyl and tetrazolyl,

And wherein the above (hetero) aryl group may be optionally substituted with 1 to 3R which may be the same or different¹⁰Substitution;

R¹⁰are selected independently of one another from the group R consisting of^10a：

Halogen, C_1-3Alkyl, difluoromethyl, trifluoromethyl, cyano, aminocarbonyl, C_1-3Alkylaminocarbonyl, di (C)_1-3Alkyl) -aminocarbonyl, carboxyl, C_1-4Alkoxycarbonyl, nitro, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, acetylamino, methylsulfonylamino, hydroxy, C_1-3Alkoxy, difluoromethoxy, trifluoromethoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, aminosulfonyl and phenyl,

wherein the phenyl-group may be optionally substituted with 1 or 2 substituents independently from each other selected from fluoro, methyl, methoxy, cyano and hydroxy;

m represents 0 or 1;

and wherein the aliphatic part of the tricyclic core structure of the formula I is substituted by 1 or 2 different or identical radicals R⁸The substitution is carried out by the following steps,

R⁸are selected independently of one another from the group R consisting of hydrogen, methyl and ethyl^8a；

However the following compounds were excluded:

in a further aspect, the present invention relates to a process for the preparation of a compound of formula I, characterized in that a compound of formula II:

wherein the variable R²、R³、R⁴And m is as defined above and below, with the general formula R ¹-CO-Y, optionally prepared in situ from the corresponding carboxylic acid (Y ═ OH), wherein R is¹As defined above and below, and

y is a leaving group and particularly represents

Fluorine, chlorine, bromine, cyano, C_1-4Alkoxy radical, C_2-4Alkenyloxy radical, C_2-4Alkynyloxy, C_1-4Alkylsulfanyl, aryltriazolyloxy, heteroaryltriazolyloxy, heteroar-N-yl, succinyl-N-oxy, C_1-4Alkylcarbonyloxy, di (C)_1-4Alkyl) aminocarbonyloxy, pyrrolylcarbonyloxy, piperidinylcarbonyloxy, morpholinylcarbonyloxy, [ tri (C)_1-4Alkyl) carbamimidoyl (carbamimidoyl)]Oxy, [ di (C)_1-4Alkyl) amino][ di (C1-4 alkyl) imino group]Methoxy { ═ C { [ (C)_1-4Alkyl radical)₂N]₂C⁺-O- }, (N, N' -dicyclohexyl-carbamoyl) oxy, di (C)_1-4Alkoxy) -phosphoryloxy, bis [ di (C)_1-4Alkyl) amino]Phosphoryloxy, [ bis (pyrrolidin-1-yl) -phosphoryl]Oxy, aryloxy, arylsulfanyl, heteralkyloxy or heteraryloxy,

and the alkyl, alkenyl and alkynyl groups mentioned above in the definition of the leaving group may optionally be substituted by fluorine, chlorine, C_1-3Alkyl or C_1-3Alkoxy is mono-or polysubstituted.

And aryl mentioned in the definition of the leaving group above, alone or as part of another group, represents phenyl or naphthyl, and heteroaryl mentioned in the definition of the above groups, Alone or as part of another group, represents pyridyl, pyrimidyl, triazinyl, imidazolyl, pyrazolyl, triazolyl or tetrazolyl, and both aryl and heteroaryl are optionally substituted by fluorine, chlorine, bromine, C_1-3Alkyl radical, C_1-3Alkoxy, nitro, cyano and/or di (C)_1-3Alkyl) amino groups are monosubstituted or, independently of one another, polysubstituted,

aqueous and alcoholic solutions may also be used for some of the above listed combinations, preferably at-10 to 120 ℃, optionally in the presence of a base such as a tertiary or aromatic amine (e.g. ethyldiisopropylamine, triethylamine, imidazole or pyridine) or an inorganic salt (e.g. potassium carbonate or calcium oxide), and/or another additive such as 4-dimethylaminopyridine or 1-hydroxybenzotriazole, in a solvent preferably selected from tetrahydrofuran, 1, 2-dimethoxyethane, ether, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, ethyl acetate, dichloromethane, 1, 2-dichloroethane, toluene, benzene and hexane;

and, if necessary, any protecting groups used in the above-described reactions may be simultaneously or subsequently cleaved;

if desired, resolving the compound of general formula I thus obtained into its stereoisomers;

If desired, the compounds of the general formula I thus obtained are converted into their salts, in particular into their physiologically acceptable salts for pharmaceutical use.

Detailed Description

Unless otherwise indicated, groups, residues and substituents, in particular R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R¹⁰、R^NAnd m is as defined above and below. If a residue, substituent or group occurs several times in a compound, it may have the same or different meaning. Some preferred meanings of the radicals and substituents of the compounds according to the invention are given below.

A preferred embodiment of the invention is characterized by the following definitions:

in other embodiments of the invention, R¹R selected from the group consisting of^1b：

wherein optionally 1 CH group can be replaced by N in pyrrolyl, furanyl, thienyl and pyridyl and optionally 1 or 2 CH groups can be replaced by N in indolyl, benzofuranyl, benzothienyl, quinolinyl and isoquinolinyl,

indanyl, 2, 3-dihydro-indolyl, 2-oxo-2, 3-dihydro-indolyl, 2, 3-dihydro-benzofuranyl, 2-oxo-2, 3-dihydro-benzimidazolyl, 2-oxo-2, 3-dihydro-benzothiazolyl, benzo [1, 3] dioxolyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2, 3, 4-tetrahydroquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 2-oxo-1, 2-dihydro-quinoxalinyl, 3-oxo-1, 2, 3, 4-tetrahydro-quinoxalinyl, chromanyl and imidazo [1, 2-a ] pyridyl,

Wherein the group R^1bIs linked to the carbonyl group in formula I through an aromatic carbon atom, and

wherein the group R^1bMay be optionally substituted by one R⁵A R⁶And/or one R⁷Substituted with the proviso that if R is¹Is phenyl, a substituent R⁵、R⁶And/or R⁷Is not attached to a carbon atom adjacent to the carbon atom attached to the carbonyl group in formula I.

In other embodiments of the invention, R¹R selected from the group consisting of^1c：

Phenyl, naphthyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, indolyl, benzofuryl, benzothienyl, wherein in indolyl, benzofuryl and benzothienyl 1 or 2 CH groups may optionally be replaced by N,

indanyl, 2, 3-dihydro-indolyl, 2-oxo-2, 3-dihydro-indolyl, 2, 3-dihydrobenzofuranyl, 2-oxo-2, 3-dihydro-benzimidazolyl, 2-oxo-2, 3-dihydro-benzothiazolyl, benzo [1, 3] dioxolyl, 1, 2, 3, 4-tetrahydroquinolinyl, 2-oxo-1, 2-dihydro-quinoxalinyl, chromanyl and imidazo [1, 2-a ] pyridyl,

wherein the group R^1cIs linked to the carbonyl group in formula I through an aromatic carbon atom, and

Wherein the group R^1cMay be optionally substituted by one R⁵A R⁶And/or one R⁷Substituted with the proviso that if R is¹Is phenyl, then the substituent R⁵、R⁶And/or R⁷Is not attached to a carbon atom adjacent to the carbon atom attached to the carbonyl group in formula I.

In other embodiments of the invention, R¹R selected from the group consisting of^1d：

Phenyl, indolyl, 2-oxo-2, 3-dihydro-indolyl, benzimidazolyl, indazolyl, imidazo [1, 2-a ] pyridyl, 2-oxo-2, 3-dihydro-benzimidazolyl, 2-oxo-2, 3-dihydro-benzothiazolyl, imidazopyridyl, benzotriazolyl, benzothiazolyl and 2-oxo-1, 2-dihydro-quinoxalinyl,

wherein the group R^1dIs linked to the carbonyl group of formula I through an aromatic carbon atom, and

wherein the group R^1dMay be optionally substituted by one R⁵A R⁶And/or one R⁷Substituted with the proviso that if R is¹Is phenyl, then the substituent R⁵、R⁶And/or R⁷Is not attached to a carbon atom adjacent to the carbon atom attached to the carbonyl group in formula I.

In other embodiments of the invention, R¹R selected from the group consisting of^1d2: 4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4-amino-3-chloro-phenyl, 3-chloro-4-hydroxy-phenyl, indol-3-yl, indol-5-yl, indol-6-yl, 1-methyl-indol-3-yl, benzimidazol-5-yl, 6-methyl-benzimidazol-5-yl, 7-methyl-benzimidazol-5-yl, indazol-5-yl, and benzothiazol-6-yl.

In other embodiments of the invention, R¹R selected from the group consisting of^1e: 4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4-amino-3-chloro-phenyl, 3-chloro-4-hydroxy-phenyl, indol-3-yl, indol-5-yl, indol-6-yl, 1-methyl-indol-3-yl, benzimidazol-5-yl, indazol-5-yl, and benzothiazol-6-yl.

In other embodiments of the invention, R¹R selected from the group consisting of^1f: benzimidazol-5-yl, 6-methyl-benzimidazol-5-yl and 7-methyl-benzimidazol-5-yl.

In other embodiments of the invention, R²R selected from the group consisting of^2b：

Hydrogen, halogen, (hetero) aryl, cyano, nitro, amino, hydroxy, C_2-6Alkynyl, C_1-6Alkyl and C_3-6A cycloalkyl group,

wherein at C_1-6Alkyl and C_3-6In cycloalkyl, one CH₂The radicals being optionally substituted by CO or SO₂Instead of, one CH₂The radicals being optionally substituted by O or NR^NAnd one CH group may optionally be replaced by N, and wherein these groups may each optionally be mono-or polyfluorinated and may optionally be mono-or disubstituted independently of each other by:

chlorine, C_1-3Alkyl, cyano, (hetero) aryl, amino, C_1-3Alkylamino radical, di (C) _1-3Alkyl) amino, hydroxy, C_1-3Alkoxy, (hetero) aryloxy, C_1-3Alkylsulfanyl group, C_1-3Alkylsulfinyl and/or C_3-6Cycloalkyl, wherein at C_3-6In cycloalkyl, one or two CH₂The radicals being optionally substituted independently of one another by carbonyl, O or NR^NAnd one CH group may optionally be replaced by N, and which may optionally be substituted by fluorine or C_1-3Alkyl is mono-substituted or independently di-substituted.

In other embodiments of the invention, R²R selected from the group consisting of^2c：

Hydrogen, fluorine, chlorine, bromine, C_1-3Alkyl radical, C_3-6Cycloalkylmethyl, cyclopropyl, (hetero) arylmethyl, C_2-4Alkynyl, (hetero) aryl, cyano-C_1-3Alkyl, aminocarbonyl-C_1-3Alkyl radical, C_1-3alkyl-aminocarbonyl-C_1-3Alkyl, di (C)_1-3Alkyl) aminocarbonyl-C_1-3Alkyl, pyrrolidin-1-yl-carbonyl-C_1-3Alkyl, piperidin-1-yl-carbonyl-C_1-3Alkyl, morpholin-4-yl-carbonyl-C_1-3Alkyl, carboxy-C_1-3Alkyl radical, C_1-3alkoxy-carbonyl-C_1-3Alkyl radical, C_1-3alkylcarbonyl-amino-C_1-3Alkyl, N- (C)_1-3Alkyl) -C_1-3alkylcarbonyl-amino-C_1-3Alkyl, 2-oxo-pyrrolidin-1-yl-C_1-3Alkyl, 2-oxo-piperidin-1-yl-C_1-3Alkyl, 3-oxo-morpholin-4-yl-C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, trifluoromethyl, difluoromethyl, cyano, aminocarbonyl, C _1-3Alkyl-aminocarbonyl, di (C)_1-3Alkyl) -aminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, carboxy, C_1-3Alkoxy-carbonyl, amino, C_1-3Alkylamino radical, C_1-3Alkyl-carbonylamino, (hetero) aryl-carbonylamino, N- (C)_1-3Alkyl) -C_1-3Alkyl-carbonylamino, N- (C)_1-3Alkyl) - (hetero) aryl-carbonylaminesYl, 2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl, C_1-3Alkyl-sulfonylamino, N- (C)_1-3Alkyl) -C_1-3Alkyl-sulfonylamino, N- (C)_1-3Alkyl) - (hetero) aryl-sulfonylamino, hydroxy, C_1-4Alkoxy radical, C_3-6Cycloalkoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, difluoromethoxy, trifluoromethoxy, (hetero) aryloxy, cyano-C_1-3Alkoxy, aminocarbonyl-C_1-3Alkoxy radical, C_1-3alkyl-aminocarbonyl-C_1-3Alkoxy, di (C)_1-3Alkyl) -aminocarbonyl-C_1-3Alkoxy, pyrrolidin-1-yl-carbonyl-C_1-3Alkoxy, piperidin-1-yl-carbonyl-C_1-3Alkoxy, morpholin-4-yl-carbonyl-C_1-3Alkyl-oxy, carboxy-C_1-3Alkoxy radical, C_1-3alkoxy-carbonyl-C_1-3Alkoxy, hydroxy-C_1-3Alkoxy radical, C_1-3alkoxy-C_1-3Alkoxy, tetrahydrofuryl-C _1-3Alkoxy, tetrahydropyranyl-C_1-3Alkoxy radical, C_1-4Alkylsulfonyl radical, C_3-6Cycloalkylsulfonyl, aminosulfonyl, C_1-3Alkyl-aminosulfonyl and di (C)_1-3Alkyl) -aminosulfonyl-amino-sulfonyl,

wherein the term (hetero) aryl represents phenyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, all of which may optionally be substituted by R¹⁰Mono-or di-substituted.

In other embodiments of the invention, R²Selected from the group consisting of^2d：

Hydrogen, fluorine, chlorine, bromine, methyl, ethynyl, cyclopropyl, C_3-6Cycloalkyl-methyl, phenylmethyl, hydroxy-C_1-3Alkyl, phenyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,Carboxy, methoxycarbonyl, amino, acetylamino, methylsulfonylamino, hydroxy, C_1-3Alkoxy, phenoxy and pyridazinyloxy groups,

and the phenyl and pyridazinyl groups mentioned above may optionally be mono-substituted by fluorine, methyl, cyano or methoxy.

In other embodiments of the invention, R²R selected from the group consisting of ^2e：

Hydrogen, fluoro, bromo, cyclohexylmethyl, phenylmethyl, 4-methoxy-phenylmethyl, hydroxymethyl, 2-hydroxypropan-2-yl, phenyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, carboxy, methoxycarbonyl, amino, hydroxy, methoxy, 4-methoxyphenoxy and 6-methyl-pyridazin-3-yloxy.

In other embodiments of the invention, R²R selected from the group consisting of^2f：

Hydrogen and cyano.

In other embodiments of the invention, R³、R⁴Are selected independently of one another from the group R consisting of^3/4b：

Hydrogen, fluorine, chlorine, C_1-3Alkyl, trifluoromethyl, cyano, hydroxy and C_1-3Alkoxy radical, or

R^3/4bRepresents R³And R⁴Which is attached to adjacent carbon atoms and combines to form a methylenedioxy or ethylenedioxy group, or, together with the carbon atom to which it is attached, forms an imidazo, oxazolo or thiazolo ring, each of which may be optionally substituted with one or two substituents independently selected from methyl, dimethylamino, hydroxy and methoxy.

In other embodiments of the invention, R³、R⁴Are selected independently of one another from the group R consisting of^3/4c：

Hydrogen, fluoro, chloro, methyl, trifluoromethyl, cyano, hydroxy and methoxy.

In other embodiments of the invention, R³、R⁴Independently of one another, from the group R consisting of^3/4c2：

Hydrogen, fluorine and methyl.

In other embodiments of the invention, R³、R⁴Are selected independently of one another from the group R consisting of hydrogen and fluorine^3/4d。

In other embodiments of the invention, R⁵R selected from the group consisting of^5b：

Fluorine, chlorine, bromine, C_1-4Alkyl radical, C_3-6cycloalkyl-C_1-3Alkyl radical, C_3-6Cycloalkyl, (hetero) aryl-C_1-3Alkyl, (hetero) aryl, cyano-C_1-3Alkyl, aminocarbonyl-C_1-3Alkyl radical, C_1-3alkyl-aminocarbonyl-C_1-3Alkyl, di (C)_1-3Alkyl) -aminocarbonyl-C_1-3Alkyl, pyrrolidin-1-yl-carbonyl-C_1-3Alkyl, piperidin-1-yl-carbonyl-C_1-3Alkyl, piperazin-1-yl-carbonyl-C_1-3Alkyl, 4- (C)_1-3Alkyl) -piperazin-1-yl-carbonyl-C_1-3Alkyl, morpholin-4-yl-carbonyl-C_1-3Alkyl, carboxy-C_1-3Alkyl radical, C_1-3alkoxy-carbonyl-C_1-3Alkyl, amino-C_1-3Alkyl radical, C_1-3alkylamino-C_1-3Alkyl, di (C)_1-3Alkyl) -amino-C_1-3Alkyl, pyrrolidin-1-yl-C_1-3Alkyl, piperidin-1-yl-C_1-3Alkyl, piperazin-1-yl-C_1-3Alkyl, 4- (C)_1-3Alkyl) -piperazin-1-yl-C_1-3Alkyl, morpholin-4-yl-C_1-3Alkyl radical, C_1-3Alkylcarbonylamino-C_1-3Alkyl, (hetero) arylcarbonylamino-C_1-3Alkyl, 2-oxo-pyrrolidin-1-yl-C_1-3Alkyl, 2-oxo-piperidin-1-yl-C _1-3Alkyl radical2-oxo-piperazin-1-yl-C_1-3Alkyl, 3-oxo-piperazin-1-yl-C_1-3Alkyl, 2-oxo-4- (C)_1-3Alkyl) -piperazin-1-yl-C_1-3Alkyl, 3-oxo-4- (C)_1-3Alkyl) -piperazin-1-yl-C_1-3Alkyl, 3-oxo-morpholin-4-yl-C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, (hetero) aryloxy-C_1-3Alkyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoro-1-hydroxyethyl, 2, 2, 2-trifluoro-1-hydroxy-1-methylethyl, 2, 2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl, cyano, aminocarbonyl, C_1-3Alkyl-aminocarbonyl, di (C)_1-3Alkyl) -aminocarbonyl, (hetero) aryl-C_1-3Alkylaminocarbonyl, N- (C)_1-3Alkyl) - (hetero) aryl-C_1-3Alkylaminocarbonyl, (hetero) arylaminocarbonyl, N- (C)_1-3Alkyl) - (hetero) aryl-aminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, piperazin-1-yl-carbonyl, 4- (C)_1-3Alkyl) -piperazin-1-yl-carbonyl, morpholin-4-yl-carbonyl, carboxyl, C_1-3Alkoxy-carbonyl, nitro, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4- (C)_1-3Alkyl) -piperazin-1-yl, 4- (C)_1-3Alkylcarbonyl) -piperazin-1-yl, 4- (C)_1-3Alkoxycarbonyl) -piperazin-1-yl, 4- (C)_1-3Alkylsulfonyl) -piperazin-1-yl, morpholin-4-yl, C _1-3Alkyl-carbonylamino, N- (C)_1-3Alkyl) -C_1-3Alkyl-carbonylamino, (hetero) arylcarbonylamino, N- (C)_1-3Alkyl) - (hetero) arylcarbonylamino, (hetero) aryl-C_1-3Alkyl-carbonylamino, N- (C)_1-3Alkyl) - (hetero) aryl-C_1-3Alkyl-carbonylamino, 2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-piperazin-1-yl, 2-oxo-4- (C)_1-3Alkyl) -piperazin-1-yl, 3-oxo-4- (C)_1-3Alkyl) -piperazin-1-yl, 3-oxo-morpholin-4-yl, aminocarbonylamino, N- (aminocarbonyl) -C_1-3Alkylamino radical, C_1-3Alkyl-aminocarbonylamino, N- (C)_1-3Alkyl-aminesAlkylcarbonyl) -C_1-3Alkylamino, N- [ di (C)_1-3Alkyl) aminocarbonyl]-C_1-3Alkylamino radical, di (C)_1-3Alkyl) -aminocarbonyl-amino, pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino, piperazin-1-yl-carbonylamino, 4- (C)_1-3Alkyl) -piperazin-1-yl-carbonylamino, morpholin-4-yl-carbonylamino, C_1-3Alkoxy-carbonylamino, N- (C)_1-3Alkyl) -C_1-3Alkoxy-carbonylamino, C_1-3Alkyl-sulfonylamino, N- (C)_1-3Alkyl) -C_1-3Alkyl-sulfonylamino, (hetero) arylsulfonylamino, N- (C)_1-3Alkyl) - (hetero) arylsulfonylamino, oxo-imidazolidin-1-yl, hydroxy, C_1-4Alkoxy radical, C _3-6cycloalkyl-C_1-3Alkoxy, (hetero) aryl-C_1-3Alkoxy radical, C_3-6Cycloalkoxy, (hetero) aryloxy, cyano-C_1-3Alkoxy, aminocarbonyl-C_1-3Alkoxy radical, C_1-3alkyl-aminocarbonyl-C_1-3Alkoxy, di (C)_1-3Alkyl) -aminocarbonyl-C_1-3Alkoxy, pyrrolidin-1-yl-carbonyl-C_1-3Alkoxy, piperidin-1-yl-carbonyl-C_1-3Alkoxy, piperazin-1-yl-carbonyl-C_1-3Alkoxy, 4- (C)_1-3Alkyl) -piperazin-1-yl-carbonyl-C_1-3Alkoxy, morpholin-4-yl-carbonyl-C_1-3Alkoxy, carboxy-C_1-3Alkoxy radical, C_1-3alkoxy-carbonyl-C_1-3Alkoxy, amino-C_1-3Alkoxy radical, C_1-3alkylamino-C_1-3Alkoxy, di (C)_1-3Alkyl) -amino-C_1-3Alkoxy, pyrrolidin-1-yl-C_1-3Alkoxy, piperidin-1-yl-C_1-3Alkoxy, piperazin-1-yl-C_1-3Alkoxy, 4- (C)_1-3Alkyl) -piperazin-1-yl-C_1-3Alkoxy, morpholin-4-yl-C_1-3Alkoxy, 2-oxo-pyrrolidin-1-yl-C_1-3Alkoxy, 2-oxo-piperidin-1-yl-C_1-3Alkoxy, 2-oxo-piperazin-1-yl-C_1-3Alkoxy, 3-oxo-piperazin-1-yl-C_1-3Alkoxy, 2-oxo-4- (C)_1-3Alkyl) -piperazin-1-yl-C_1-3Alkoxy, 3-oxoGeneration-4- (C)_1-3Alkyl) -piperazin-1-yl-C_1-3Alkoxy, 3-oxo-morpholin-4-yl-C_1-3Alkoxy, hydroxy-C_1-3Alkoxy radical, C_1-3alkoxy-C_1-3Alkoxy, tetrahydrofuran-3-yl-oxy, tetrahydropyran-4-yl-oxy, tetrahydrofuryl-C _1-3Alkoxy, tetrahydropyranyl-C_1-3Alkoxy, difluoromethoxy, trifluoromethoxy, C_1-3alkylsulfanyl-C_1-3Alkoxy radical, C_1-3alkylsulfinyl-C_1-3Alkoxy radical, C_1-3alkylsulfonyl-C_1-3Alkoxy radical, C_1-3Alkylsulfonyl, (hetero) arylsulfonyl, aminosulfonyl, C_1-3Alkyl-aminosulfonyl, di (C)_1-3Alkyl) -aminosulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl and 4- (C)_1-3Alkyl) -piperazin-1-yl-sulfonyl,

wherein the term (hetero) aryl is as defined above or below.

In other embodiments of the invention, R⁵R selected from the group consisting of^5c：

Fluorine, chlorine, C_1-4Alkyl, (hetero) aryl-C_1-3Alkyl, (hetero) aryl, aminosulfonyl, amino-C_1-3Alkyl radical, C_1-3alkylamino-C_1-3Alkyl, di (C)_1-3Alkyl) -amino-C_1-3Alkyl, pyrrolidin-1-yl-C_1-3Alkyl, morpholin-4-yl-C_1-3Alkyl radical, C_1-3Alkylcarbonylamino-C_1-3Alkyl, (hetero) arylcarbonylamino-C_1-3Alkyl, 2-oxo-pyrrolidin-1-yl-C_1-3Alkyl, 3-oxo-morpholin-4-yl-C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 2, 2, 2-trifluoro-1-hydroxyethyl, 2, 2, 2-trifluoro-1-hydroxy-1-methylethyl, 2, 2, 2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, trifluoromethyl, cyano, aminocarbonyl, C _1-3Alkyl-aminocarbonyl, di(C_1-3Alkyl) -aminocarbonyl, (hetero) arylaminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, piperazin-1-yl-carbonyl, morpholin-4-yl-carbonyl, 4- (C)_1-3Alkyl) -piperazin-1-yl-carbonyl, carboxy, C_1-3Alkoxy-carbonyl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-morpholin-4-yl, C_1-3Alkyl-carbonylamino, (hetero) arylcarbonylamino, aminocarbonylamino, C_1-3Alkyl-aminocarbonylamino, di (C)_1-3Alkyl) aminocarbonylamino, pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino, piperazin-1-yl-carbonylamino, morpholin-4-yl-carbonylamino, C_1-3Alkoxy-carbonylamino, hydroxy, C_1-4Alkoxy, hydroxy-C_1-3Alkoxy radical, C_1-3alkoxy-C_1-3Alkoxy, difluoromethoxy, trifluoromethoxy and (hetero) aryloxy,

wherein the term (hetero) aryl represents phenyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, triazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which may optionally be substituted by one or two R ¹⁰And (4) substitution.

In other embodiments of the invention, R⁵R selected from the group consisting of^5d：

Fluorine, chlorine, C_1-3Alkyl, hydroxy-C_1-3Alkyl, aminocarbonyl, C_1-3Alkyl-aminocarbonyl, amino, C_1-3Alkylamino radical, C_1-3Alkyl-carbonylamino, hydroxy, C_1-3Alkoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, and aminosulfonyl.

In other embodiments of the invention, R⁵R selected from the group consisting of^5e：

Fluorine, chlorine, methyl, amino, hydroxy and methoxy.

In other embodiments of the invention, R⁶、R⁷Are selected independently of one another from the group R consisting of^6/7b：

Fluorine, chlorine, bromine, C_1-3Alkyl radical, C_2-3Alkynyl, trifluoromethyl, hydroxy, C_1-3Alkoxy and cyano and/or

R^6/7bRepresents R⁶And R⁷Which are linked to and bound to adjacent carbon atoms to form methylenedioxy, difluoromethylenedioxy, ethylenedioxy or C_3-5An alkylene group.

In other embodiments of the invention, R⁶、R⁷Are selected independently of one another from the group R consisting of^6/7c：

Fluorine, chlorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy.

In other embodiments of the invention, R⁶、R⁷Are selected independently of one another from the group R consisting of ^6/7d：

Fluorine, chlorine, methyl, hydroxy and methoxy.

In other embodiments of the invention, R¹⁰Are independently selected from the group R^10b：

Fluorine, chlorine, bromine, C_1-3Alkyl, phenyl, difluoromethyl, trifluoromethyl, cyano, aminocarbonyl, C_1-3Alkylaminocarbonyl, di (C)_1-3Alkyl) -aminocarbonyl, carboxyl, C_1-4Alkoxycarbonyl, nitro, amino, acetylamino, methylsulfonylamino, hydroxy, C_1-3Alkoxy, difluoromethoxy, trifluoromethoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, and aminosulfonyl.

In other embodiments of the invention, R¹⁰Are independently selected from the group R^10c：

Fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy and trifluoromethoxy.

In other embodiments of the invention, R¹⁰Are independently selected from the group R^10d：

Fluoro, methyl, cyano and methoxy.

In other embodiments of the invention, R^NAre selected independently of one another from the group R consisting of^Nb：

Hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Alkenyl, phenyl, C_1-4Alkylcarbonyl, phenylcarbonyl, C_1-3Alkylaminocarbonyl, phenylaminocarbonyl, C _1-4Alkoxycarbonyl group, C_1-4An alkylsulfonyl group and a phenylsulfonyl group,

wherein C is_1-6Alkyl may be optionally mono-or polysubstituted with fluorine and may optionally be phenyl, cyano, aminocarbonyl, C_1-3Alkylaminocarbonyl, di (C)_1-3Alkyl) aminocarbonyl, carboxyl, C_1-4Alkoxycarbonyl group, C_1-4Alkylcarbonylamino, hydroxy or C_1-4Alkoxy is monosubstituted.

In other embodiments of the invention, R^NAre selected independently of one another from the group R consisting of^Nc：

Hydrogen, phenyl, C_1-4Alkylcarbonyl, phenylcarbonyl, C_1-3Alkylaminocarbonyl, phenylaminocarbonyl, C_1-4Alkoxycarbonyl group, C_1-4Alkylsulfonyl, phenylsulfonyl and C_1-4Alkyl which may optionally be mono-or polyfluorinated and may optionally be substituted by hydroxy, C_1-4Alkoxy, cyano or phenyl monosubstitution.

In other embodiments of the invention, R^NAre selected independently of one another from the group R consisting of^Nd：

Hydrogen, methyl, benzyl, phenyl, acetyl, tert-butoxycarbonyl and methylsulfonyl.

In other embodiments of the invention, R⁸Are selected independently of one another from the group R consisting of hydrogen and methyl^8b。

In other embodiments of the invention, R⁸Are selected independently of one another from the group R consisting of hydrogen^8c。

Each R^1x、R^2x、R^3/4x、R^5x、R^6/7x、R^Nx、R^8x、R^10xM represents a single embodiment of the characterization of the corresponding substituent as described above. Thus, given the above definitions, a preferred single embodiment of the first aspect of the present invention consists entirely of the term (R) ^1x、R^2x、R^3/4x、R^5x、R^6/7x、R^Nx、R^8x、R^10xM), wherein for each index x a single value ranging from "a" to the highest letter given above is given. The indices x and m vary independently of each other. All individual embodiments described by the parenthetical terms with all permutations of indices x and m as indicated by the above definitions are intended to be included in the present invention.

Table 1 below shows such embodiments E-1 to E-36 of the invention (which are considered to be preferred) in an exemplary and increasing order of preference from the first row to the last row. This means that the embodiment E-36 represented by the entries in the last row of table 1 is the most preferred embodiment.

Table 1: preferred embodiments of the invention E-1 to E-36

R¹

R²

R³/R⁴

R⁵

R⁶/R⁷

R¹⁰

R⁸

R^N

m

E-1

R^1b

R^2b

R^3/4b

R^5b

R^6/7b

R^10b

R^8a

R^Nb

0、1

E-2

R^1c

R^2c

R^3/4c

R^5c

R^6/7c

R^10c

R^8a

-*

0、1

E-3

R^1b

R^2b

R^3/4d

R^5c

R^6/7d

R^10d

R^8a

R^Nd

0、1

E-4

R^1b

R^2b

R^3/4d

R^5d

R^6/7d

R^10d

R^8b

R^Nd

0、1

E-5

R^1b

R^2b

R^3/4d

R^5e

R^6/7d

R^10d

R^8b

R^Nd

0、1

E-6

R^1c

R^2b

R^3/4b

R^5c

R^6/7c

R^10d

R^8b

R^Nd

0、1

E-7

R^1c

R^2b

R^3/4b

R^5d

R^6/7d

R^10d

R^8b

R^Nd

0、1

E-8

R^1b

R^2c

R^3/4c

R^5c

R^6/7c

R^10d

R^8b

-*

0、1

E-9

R^1c

R^2b

R^3/4c

R^5c

R^6/7c

R^10d

R^8b

R^Nd

0、1

E-10

R^1c

R^2c

R^3/4c

R^5c

R^6/7c

R^10d

R^8b

-*

0、1

E-11

R^1c

R^2c

R^3/4c

R^5d

R^6/7d

R^10d

R^8b

-*

0、1

E-12

R^1b

R^2c

R^3/4c2

R^5c

R^6/7c

R^10d

R^8b

-*

0、1

E-13

R^1c

R^2b

R^3/4c2

R^5c

R^6/7c

R^10d

R^8b

R^Nd

0、1

E-14

R^1c

R^2c

R^3/4c2

R^5c

R^6/7c

R^10d

R^8b

-*

0、1

E-15

R^1c

R^2c

R^3/4c2

R^5d

R^6/7d

R^10d

R^8b

-*

0、1

E-16

R^1c

R^2c

R^3/4d

R^5d

R^6/7d

R^10d

R^8b

-*

0、1

E-17

R^1d

R^2c

R^3/4d

R^5d

R^6/7d

R^10d

R^8b

-*

0、1

E-18

R^1d

R^2c

R^3/4d

R^5e

R^6/7d

R^10d

R^8b

-*

0、1

E-19

R^1d

R^2d

R^3/4d

R^5e

R^6/7d

-*

R^8b

-*

0、1

E-20

R^1d

R^2e

R^3/4d

R^5e

R^6/7d

-*

R^8b

-*

0、1

E-21

R^1d2

R^2e

R^3/4d

-*

R^8b

-*

0、1

E-22

R^1e

R^2e

R^3/4d

-*

R^8b

-*

0、1

E-23

R^1e

R^2e

R^3/4d

-*

R^8c

-*

0、1

E-24

R^1e

R^2e

R^3/4d

-*

R^8c

-*

0

E-25

R^1d

R^2f

R^3/4d

R^5e

R^6/7d

-*

R^8b

-*

0、1

E-26

R^1e

R^2f

R^3/4d

-*

R^8b

-*

0、1

E-27

R^1e

R^2f

R^3/4d

-*

R^8c

-*

0、1

E-28

R^1e

R^2f

R^3/4d

-*

R^8c

-*

0

E-29

R^1d2

R^2c

R^3/4d

-*

R^10d

R^8b

-*

0、1

E-30

R^1d2

R^2d

R^3/4d

-*

R^8b

-*

0、1

E-31

R^1d2

R^2e

R^3/4d

-*

R^8b

-*

0、1

E-32

R^1d2

R^2f

R^3/4d

-*

R^8b

-*

0、1

E-33

R^1d2

R^2f

R^3/4d

-*

R^8b

-*

0

E-34

R^1f

R^2f

R^3/4d

-*

R^8b

-*

0、1

E-35

R^1f

R^2f

R^3/4d

-*

R^8c

-*

0、1

E-36

R^1f

R^2f

R^3/4d

-*

R^8c

-*

0

Denotes that no corresponding variable is present in the corresponding embodiment

Their tautomers, their stereoisomers, their mixtures and their salts,

however the following compounds were excluded:

thus, E-24 relates to compounds of formula I, their tautomers, their stereoisomers, mixtures thereof and salts thereof, wherein

R¹R selected from the group consisting of^1e: 4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4-amino-3-chloro-phenyl, 3-chloro-4-hydroxy-phenyl, indol-3-yl, indol-5-yl, indol-6-yl, 1-methyl-indol-3-yl, benzimidazol-5-yl, indazol-5-yl and benzothiazol-6-yl,

R²R selected from the group consisting of^2e: hydrogen, fluoro, bromo, cyclohexylmethyl, phenylmethyl, 4-methoxy-phenylmethyl, hydroxymethyl, 2-hydroxypropan-2-yl, phenyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, carboxy, methoxycarbonyl, amino, hydroxy, methoxy, 4-methoxyphenoxy and 6-methyl-pyridazin-3-yloxy.

R³、R⁴Are selected independently of one another from the group R consisting of^3/4d: hydrogen and fluorine, and a process for the preparation of,

R⁸are selected independently of one another from the group R consisting of hydrogen^8c，

And m is 0.

Thus, E-28 relates to compounds of formula I, their tautomers, their stereoisomers, mixtures thereof and salts thereof, wherein

R²r selected from the group consisting of^2f: hydrogen and a cyano group, and a salt thereof,

R⁸Are selected independently of one another from the group R consisting of^8c: the presence of hydrogen in the presence of hydrogen,

and m is 0.

Thus, E-33 relates to compounds of formula I, their tautomers, their stereoisomers, mixtures thereof and salts thereof, wherein

R¹R selected from the group consisting of^1d2: 4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4-amino-3-chloro-phenyl, 3-chloro-4-hydroxy-phenyl, indol-3-yl, indol-5-yl, indol-6-yl, 1-methyl-indol-3-yl, benzimidazol-5-yl, 6-methyl-benzimidazol-5-yl, 7-methyl-benzimidazol-5-yl, indazol-5-yl and benzothiazol-6-yl,

R⁸independently of one another, from the group consisting ofGroup R^8b: hydrogen and a methyl group, and a salt thereof,

and m is 0.

Thus, E-36 relates to compounds of formula I, their tautomers, their stereoisomers, mixtures thereof and salts thereof, wherein

R¹R selected from the group consisting of^1f: benzimidazol-5-yl, 6-methyl-benzimidazol-5-yl and 7-methyl-benzimidazol-5-yl,

R³、R⁴are selected independently of one another from the group R consisting of ^3/4d: hydrogen and fluorine, and a process for the preparation of,

and m is 0.

Another preferred embodiment of the invention is described by formula i.a, tautomers thereof, stereoisomers thereof, mixtures thereof and salts thereof:

wherein the piperidine substructure and the tetralin (m ═ 1) or indane (m ═ 0) substructure form a tricyclic core structure in the cis configuration, and the variable R¹、R²、R³、R⁴And m is as defined above and below.

Further preferred embodiments of the present invention are described by formula I.b, its tautomers, its stereoisomers, mixtures thereof and its salts:

wherein the tricyclic core structure is in the R configuration at C-10b (for m ═ 1)/C-4a (for m ═ 0) and in the S configuration at C-4a (for m ═ 1)/C-9a (for m ═ 0), and the variable R is in the S configuration¹、R²、R³、R⁴And m is as defined above and below.

Accordingly, one embodiment of preferred compounds of the present invention includes compounds of formula I.b, tautomers thereof, stereoisomers thereof, mixtures thereof and salts thereof,

wherein

and m is 0.

Another embodiment of the preferred compounds of the present invention are compounds of formula I.b, its tautomers, its stereoisomers, mixtures thereof and salts thereof, wherein

and m is 0.

R¹R selected from the group consisting of^1f: benzimidazol-5-yl, 6-methylbenzimidazole-5-yl and 7-methyl-benzimidazol-5-yl,

and m is 0.

With respect to the definition of N-containing heteroaromatic groups bearing a hydroxyl group at a carbon atom adjacent to the nitrogen or at another position in the ring which allows for mesomeric interaction with the nitrogen (e.g. (hetero) aryl) groups having one or more nitrogens within their structure), these groups may form tautomeric amide substructures which are part of the present invention; the tautomeric amides resulting from combining the hydroxyl group and the N-containing heteroaromatic may bear substituents other than hydrogen on the amide nitrogen. Examples of such heteroaromatic radical substructures (where tautomeric amides may be formed) are described in the following:

Wherein R is^NAs defined above. These tautomeric structures can be cyclized to heteroaromatic and aromatic groups, such as those contained within (hetero) aryl groups.

Some of the terms used above and below to describe the compounds of the present invention are now more specifically defined.

Terms not specifically defined herein shall have the meanings that would be apparent to one skilled in the art in light of this disclosure and the context. However, as used in the specification, the following terms have the indicated meanings and are given the following conventions unless otherwise specified.

In the groups, radicals or moieties defined below, the number of carbon atoms is generally indicated before the group, e.g. C_1-6Alkyl represents an alkyl group or radical having 1 to 6 carbon atoms. Typically, for groups containing two or more subgroups, the last named subgroup is the point of radical attachment, e.g. the substituent "aryl-C_1-3Alkyl- "represents with C_1-3Alkyl-linked aryl radicals, C_1-3The alkyl group is attached to the core or to the group to which the substituent is attached.

In general, the attachment position of a given residue to another group should be variable, i.e., any capable atom bearing a hydrogen that can be replaced in the residue can serve as the point of attachment for the attached group, unless otherwise specified.

Throughout the specification and the appended claims, unless otherwise indicated, a given formula or name shall include all conceivable constituent isomers and stereoisomers, including enantiomers, diastereomers, cis/trans isomers, E/Z isomers, and the like, and mixtures thereof, such as 1: 1 mixtures of enantiomers (referred to as racemates), mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures of any of the foregoing forms in the presence of such isomers, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof, e.g., hydrates, including solvates of the free compound or solvates of a salt of the compound.

As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "substituted" as used herein means that any one or more hydrogens on the designated atom is replaced with a selection from the designated group, provided that the designated atom does not exceed its available valence, and that the substitution results in a stable compound.

The term "partially unsaturated" as used herein means that 1, 2 or more double bonds, preferably 1 or 2 double bonds, are present in the indicated group or moiety. Preferably, as used herein, the term "partially unsaturated" does not include fully unsaturated groups or moieties.

The term halogen represents an atom selected from the group consisting of F, Cl, Br and I.

Term C_1-nAlkyl (where n may have a value of 1 to 18) represents a saturated, branched or unbranched hydrocarbon group having 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-butylPentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like.

The term "C_1-nAlkylene "(where n is an integer from 1 to n, alone or in combination with another group) represents a non-cyclic, linear or branched divalent alkyl group containing from 1 to n carbon atoms. For example, the term C_1-4Alkylene includes- (CH)₂)-、-(CH₂-CH₂)-、-(CH(CH₃))-、-(CH₂-CH₂-CH₂)-、-(C(CH₃)₂)-、-(CH(CH₂CH₃))-、-(CH(CH₃)-CH₂)-、 -(CH₂-CH(CH₃))-、-(CH₂-CH₂-CH₂-CH₂)-、-(CH₂-CH₂-CH(CH₃))-、-(CH(CH₃)-CH₂-CH₂)-、-(CH₂-CH(CH₃)-CH₂)-、-(CH₂-C(CH₃)₂)-、-(C(CH₃)₂-CH₂)-、-(CH(CH₃)-CH(CH₃))-、-(CH₂-CH(CH₂CH₃))-、-(CH(CH₂CH₃)-CH₂)-、-(CH(CH₂CH₂CH₃))-、-(CHCH(CH₃)₂) -and-C (CH)₃)(CH₂CH₃)-。

Term C_2-nAlkenyl (where n has a value of 3 to 10) represents a branched or unbranched hydrocarbon radical having 2 to n C atoms and a C ═ C double bond. Examples of such groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like.

Term C_2-nAlkynyl (wherein n has a value of from 3 to 10) represents a branched or unbranched hydrocarbon radical having from 2 to n C atoms and a C.ident.C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-Hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Unless otherwise indicated, alkynyl groups are attached to the rest of the molecule via the C atom in position 1. Thus, for example, the terms 1-propynyl, 2-propynyl, 1-butynyl and the like correspond to the terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl and the like. This also applies analogously to C_2-nAn alkenyl group.

Term C_1-nAlkoxy represents C_1-nalkyl-O group, wherein C_1-nAlkyl is as defined above. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy and the like.

Term C_1-nAlkylcarbonyl represents C_1-nalkyl-C (═ O) groups, where C is_1-nAlkyl is as defined above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl, and the like.

Term C_3-nCycloalkyl represents a saturated mono-, di-, tri-or spiro-carbocyclic group having 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1 ] n]Octyl, spiro [4.5 ]]Decyl, norpinanyl (norpinyl), norbornyl, norcaranyl (norcaranyl), adamantyl, and the like. Preferably, the term C_3-7Cycloalkyl represents a saturated monocyclic group.

Term C_5-nCycloalkenyl represents C as defined above and additionally having at least one C ═ C double bond_5-nA cycloalkyl group.

Term C_3-nCycloalkylcarbonyl represents C_3-ncycloalkyl-C (═ O) groups, where C is_3-nCycloalkyl is as defined above.

Term C_3-nHeterocycloalkyl represents a saturated mono-, di-, tri-or spiro-carbocyclic group as defined above having 3-m to n-m C atoms, wherein m carbon atoms are independently selected from N, NR^NO, S, SO and SO₂Is substituted with a heteroatom of (a). Examples of such groups include aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1, 3-dioxanyl, 1, 4-dioxanyl, thiomorpholinyl, azepanyl, oxepanyl, thiepanyl, 1-aza-bicyclo [2.2.2 ] bicyclo ]Octane, 1, 4-diaza-bicyclo [2.2.2]Octane, and the like. Preferably, the term heterocycloalkyl represents a saturated monocyclic C_5-6Cycloalkyl groups in which one or two carbon atoms are replaced by N and/or O.

The term three (C)_1-4Alkyl) silyl groups include silyl groups having the same or two or three different alkyl groups.

The term two (C)_1-3Alkyl) amino comprises an amino group having two alkyl groups which may be the same or different.

This applies to any form of group or residue, provided that the group or residue is optionally substituted. For example, if the alkyl group is optionally mono-or polyfluorinated, this also includes alkyl residues as part of a larger group, e.g. alkoxy, alkylcarbonyl, alkoxyalkyl and the like, or if the (hetero) aryl group is optionally mono-or polysubstituted by a substituent or group of substituents, this also includes (hetero) aryl groups as part of a larger group, e.g. (hetero) aryl-C_1-nAlkyl, (hetero) aryloxy-C_1-nAlkyl, (hetero) aryl-C_1-nAlkoxy, and the like.

Thus, in, for example, R²Or R⁵In the case of radicals having the meaning, for example, (hetero) aryloxy, when the (hetero) aryl residue is optionally monofluoroWhen the (hetero) aryl radicals represent in particular phenyl radicals, the meaning of mono-, di-, tri-, tetra-and pentafluorophenoxy is also included. The above also applies to groups or residues in which part of a group or residue is replaced by another group, e.g. CH ₂The radicals being optionally O, S, NR^NCO or SO₂And (4) replacing. For example, having in particular a hydroxy group-C_1-3Residue in the meaning of alkyl (where CH₂Optionally the group is replaced by CO (═ carbonyl)), which also includes carboxy, carboxymethyl, hydroxymethylcarbonyl, 1-hydroxy-2-oxo-ethyl, carboxyethyl, 2-carboxyethyl, 1-carboxyethyl, hydroxymethylcarbonylmethyl, 1-hydroxy-2-oxo-propyl, hydroxyethylcarbonyl, (2-hydroxyethyl) carbonyl, hydroxy-3-oxo-propyl, 1-hydroxy-3-oxo-propyl, 2-hydroxy-3-oxo-propyl, (1-hydroxyethyl) -carbonyl, 2-hydroxy-1-oxo-propan-2-yl, hydroxy-2-oxo-propan-2-yl, and 3-hydroxy-1-oxo-propan-2-yl. Similarly, e.g. C_1-nAlkyl (in which one or more CH's are present₂The definition of a group optionally substituted by, for example, a carbonyl group and which is optionally substituted by, for example, a hydroxyl or amino group) also includes the absence of a CH group and/or CH₂Well-defined residues of groups such as carboxyl and aminocarbonyl.

All atoms/elements described herein (including atoms that are part of a group) include all stable isotopic forms of the respective elements. For example, when hydrogen is mentioned, it is either explicitly mentioned or as part of a group such as methyl, which includes hydrogen as well as deuterium in the form of a stable isotope of elemental hydrogen.

The compounds according to the invention can in principle be obtained by known synthetic methods. Preferably, the compounds are obtained by the following process of the invention, described in more detail below.

A general route to obtain the core structure of the compounds of the present invention is given in scheme 1, which uses tricyclic pyridines as precursors to the tricyclic piperidine skeleton; r²、R³、R⁴And m has the meaning defined hereinbefore and hereinafter. The tricyclic pyridine may be prepared from 2-indanone (m ═ 0) or 2-tetralone (m ═ 1) and propargylamine or its derivative through reactionCatalyst (e.g. gold and copper salts or complexes, preferably NaAuCl)₄And CuCl₂) Obtained by mixing the two starting compounds in the presence of (cf. J. org. chem.2003, 68, 6959-one 6966). The reaction is usually carried out in an alcohol (e.g. ethanol) by conventional heating or microwave irradiation at a temperature of 20 to 120 ℃. The resulting pyridine structure can be used in transition metal catalysts (e.g., PtO)₂Pt/C, Pd/C, Rh/C, raney Ni or mixtures thereof) to piperidine derivatives by reduction with hydrogen. Alcohols (e.g. methanol and ethanol), ethyl acetate, acetic acid, water, ethers, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, hexane, methylcyclohexane or mixtures thereof are preferred solvents, optionally in combination with additives (e.g. acids, such as trifluoroacetic acid, hydrochloric acid and sulfuric acid) at temperatures of from 10 to 150 ℃ (preferably from 20 to 80 ℃) and at hydrogen pressures of from 1 to 150 bar (preferably from 1 to 20 bar). Alternatively, the reduction may be carried out by converting the pyridine to pyridinium ions via N-alkylation, N-acylation or N-sulfonylation, followed by reaction with a hydride source (e.g., NaBH) ₄Or LiAlH₄) The process is completed. LiAlH₄Preferably in hydrocarbons, ethers, tetrahydrofuran, 1, 4-dioxane, benzene or toluene, with NaBH₄Preferably used in an alcohol (e.g. methanol or ethanol) and water, optionally in combination with a co-solvent such as tetrahydrofuran, 1, 4-dioxane or N-methylpyrrolidone, and an additive such as an acid (e.g. acetic acid) or a base (e.g. sodium hydroxide).

Scheme 1: strategy 1 for constructing a three-Ring framework

Another possible synthetic route to the tricyclic pyridine precursors described in scheme 1 is depicted in scheme 2; r²、R³、R⁴And m has the meaning defined hereinbefore and hereinafter. Transition metal catalyzed phenylmethyl (for m ═ 0) or phenylethyl (for m ═ 1)_{Reduction of}Derivatives with 2, 3-bisThe coupling of halogenated or pseudohalogenated pyridines provides the necessary intermediates. Suitable metal residues in phenylalkyl metal derivatives may be, for example, MgCl, MgBr, B (OH)₂、B(OCMe₂CMe₂O)、BF₃K. Suitable halogenation or pseudohalogenation of ZnCl, ZnBr or ZnI, and of pyridine is preferably Cl, Br, I, F₃CSO₃、p-TolSO₃And MeSO₃. Depending on the coupling partner, different catalysts derived predominantly from Pd, Ni, Cu or Fe may be suitable. Pd (PPh)₃)₄Pd [1, 1' -bis (diphenylphosphino) ferrocene)]Cl₂、Pd(PPh₃)₂Cl₂、Ni(PPh₃)₂Cl₂Or nanoparticles of Pd, Pd or Fe on C, Pd (II), Ni (II), Fe (II) or Fe (III) salts (e.g. Pd (O) ₂CCH₃)₂、PdCl₂、NiCl₂Or FeCl₃) Optionally in combination with 2- (optionally substituted phenyl) phenyl-dicyclohexyl or di-tert-butylphosphine, triphenylphosphine, tritolylphosphine, trifuranylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 1, 3-diarylimidazolium salts or 1, 3-diaryldihydroimidazolinium salts are some of the more frequently used catalysts. The coupling is preferably carried out in toluene, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or mixtures thereof, optionally at temperatures of from-10 to 150 ℃ with alcohols (e.g.methanol), water, alkali metal salts (e.g.LiCl, NaOH, Na) depending on the coupling partner₂CO₃、K₂CO₃、Cs₂CO₃、NaO₂CCH₃Or K₃PO₄) Ammonium salts (e.g. Bu)₄NCl) or silver salts (e.g. AgO)₃SCF₃) And (4) combining. Subsequent cyclization of the benzyl-or phenethylpyridines to tricyclic pyridine structures can be catalyzed by another transition metal, preferably Pd (e.g., derived from Pd (O)₂CC₃)₂Or Pd (O)₂CCMe₃)₂) And phosphine ligands (e.g. di-tert-butyl-methyl-phosphine, tricyclohexylphosphine, triphenylphosphine, tris (4-fluorophenyl) phosphine or 2- (2-dimethylaminophenyl) phenyl-diphenyl-phosphine) To complete. Cyclization is most preferably at 40 to 160 ℃ in the potassium salt (e.g. K) ₂CO₃Or KO₂CCH₃) Optionally with silver salts (e.g. Ag) in the presence of₂CO₃Or AgO₃SCF₃) And/or pivalic acid in N, N-dimethylacetamide (see, e.g., Tetrahedron 2008, 64, 6015-20 and references cited therein).

Scheme 2: strategy 2 for constructing a three-Ring framework

An alternative strategy to obtain the tricyclic pyridine precursors described in scheme 1 is described in scheme 3; r²、R³、R⁴And m has the meaning defined hereinbefore and hereinafter. Transition metal catalyzed phenyl metal derivatives (metals are e.g. MgCl, MgBr, B (OH)₂、B(OCMe₂CMe₂O)、BF₃K. Coupling of ZnCl, ZnBr or ZnI) with pyridine-2-carboxylic acid derivatives or 3-halogen or pseudohalogen substituted pyridine-2-carboxylic acid derivatives (m ═ 0) or pyridin-2-ylacetic acid derivatives (m ═ 1) (the carboxylic acid derivatives are preferably carboxylic acids, carboxylic esters or nitriles) provides a first intermediate. Depending on the coupling partner, at temperatures of-10 to 150 ℃ different catalysts may be suitable, which are preferably derived from Pd (e.g.Pd (PPh)₃)₄Pd [1, 1' -bis (diphenylphosphino) ferrocene]Cl₂、Pd(PPh₃)₂Cl₂Or Pd on C, nanoparticles of Pd, Pd (II) salts (e.g. Pd (O)₂CCH₃)₂Or PdCl₂) Optionally in admixture with 2- (optionally substituted phenyl) phenyl-dicyclohexyl-or di-tert-butylphosphine, triphenylphosphine, tritolylphosphine, trifuranylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 1, 3-diarylimidazolinium salts or 1, 3-diaryldihydroimidazolinium salts, optionally in alkali metal salts (e.g. LiCl, NaOH, NaO) ^tBu、KO^tBu、Na₂CO₃、K₂CO₃、Cs₂CO₃，NaO₂CCH₃Or K₃PO₄) Ammonium salts (e.g. Bu)₄NCl) and/or silver salts (e.g. AgO)₃SCF₃) In the presence of, preferably in toluene, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or mixtures thereof, optionally in admixture with water. The subsequent intramolecular Friedel-Crafts acylation is carried out by reacting a Lewis acid (depending on the type of carboxyl group and the electronic nature of the benzene substructure, for example hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, SnCl) with a Lewis acid in an inert solvent (for example acetonitrile, dichloromethane, 1, 2-dichloromethane, 1, 4-dioxane, 1, 2-dimethoxyethane, hydrocarbons, nitrobenzene or chlorobenzene) at from 0 to 180 ℃ and preferably in an inert solvent (for example acetonitrile, dichloromethane, 1, 2-dichloromethane, 1, 4-dioxane, 1, 2-dimethoxyethane, hydrocarbons, nitrobenzene or chlorobenzene)₄、FeCl₃、AlBr₃、AlCl₃、SbCl₅、BCl₃、BF₃、ZnCl₂Montmorillonite, POCl₃And PCl₅) Activation of a carboxyl functional group (e.g., carboxylic acid, anhydride, mixed anhydride or ester, carbonyl chloride, or nitrile) establishes a tricyclic pyridine framework. The ketone group formed thereafter is preferably in a transition metal catalyst (e.g., Pd/C, Pd (OH)₂、PtO₂Pt/C or Rh/C) in an alcohol (e.g. methanol, glycol or ethanol), water, acetic acid, ethyl acetate, N-methylpyrrolidone, tetrahydrofuran, 1, 4-dioxane, ether or a mixture thereof, optionally in the presence of an acid (e.g. hydrochloric acid), at a temperature of from 0 to 180 ℃, preferably from 20 to 120 ℃ and a hydrogen pressure of from 1 to 100 bar, preferably from 1 to 10 bar. Alternatively, the ketone group may optionally be in a Lewis acid (e.g., BF) ₃、AlCl₃、InCl₃、SnCl₄、FeCl₃、ZnCl₂Acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid or trifluoromethanesulfonic acid) at 0 to 140 c with a hydride (e.g., triethylsilane, borane, sodium borohydride or lithium aluminum hydride).

Scheme 3: strategy 3 for constructing a three-Ring framework

Scheme 4 describes a strategy suitable for obtaining a backbone of a compound of the present invention (where m equals 0); r²、R³And R⁴Have the meaning defined hereinbefore and hereinafter. The phenyl-pyridyl structure is assembled by transition metal catalyzed coupling as described in scheme 3. Nucleophilic phenyl (bearing M) and electrophilic pyridyl (bearing Y) are used for this purpose, although aromatic building blocks with opposite reactivity, i.e. phenyl bearing Y and pyridine bearing M, may also be used, providing the same coupling product. The resulting compound carries two potential leaving groups, preferably fluorine, chlorine, bromine, arylsulfonate, nitro or arylsulfonyl, one of which is located on each (hetero) aromatic ring adjacent to the phenyl-pyridyl bond. Dianionic methylene synthons (e.g. malonic acid, malonic diester, malononitrile, cyanoacetic acid or cyanoacetate) with bases (e.g. Cs)₂CO₃、K₂CO₃、Na₂CO₃、KO^tBu、NaOEt、NaOMe、NEt₃、ⁱPr₂NEt, 1, 8-diazabicyclo [5.4.0]-undec-7-ene) combinations that successively replace two leaving groups by aromatic nucleophilic substitution to create an indenopyridine backbone. N-methylpyrrolidone, N-dimethylacetamide, N-dimethylformamide, alcohols (such as ethanol, isopropanol, or tert-butanol), water, dimethylsulfoxide, 1, 4-dioxane, tetrahydrofuran, or mixtures thereof are preferred solvents for this conversion, which is preferably carried out at 0 to 180 ℃. The carboxylic acid electron withdrawing group is formed by reacting a base (e.g., NaOH or KOH) or an acid (e.g., HCl or H) in an aqueous or alcoholic solution ₂SO₄) To form a spontaneously decarboxylated carboxyl group or by heating in an acidic or basic medium. The process is particularly applicable to compounds having one or more electron withdrawing groups on the phenyl ring.

Scheme 4: strategy 4 for constructing a three-Ring framework

Scheme 5 depicts the assembly of the tricyclic skeletons of the present invention, starting from the corresponding pyrrolidinenamine of 2-indanone or 2-tetralone and acrylamide; r²、R³、R⁴And m has the meaning defined hereinbefore and hereinafter. The desired tricyclic structure as dihydropyridone is obtained by heating the two reaction partners at 60 to 150 ℃. Reduction of the double bond with hydrogen in the presence of a transition metal (e.g. palladium on carbon), or with a hydride source (e.g. trialkylsilanes such as triethylsilane, borohydrides such as NaBH₄、NaBH(O₂CCH₃)₃Or NaH₃BCN or alanates such as LiAlH₄) Reduction, optionally in additives (e.g. Lewis acids, such as acetic acid, trifluoroacetic acid, AlCl)₃Or BF₃*OEt₂) In the presence of a solvent, thereby providing a tricyclic piperidone. The final amide reduction is preferably performed at 0 to 100 deg.C with a hydride source (e.g., NaBH)₄) With acetic acid in 1, 4-dioxane, LiAlH in tetrahydrofuran or in ethers₄Or sodium dihydrobis (2-methoxyethoxy) aluminate in glycol dimethyl ether.

Scheme 5: strategy 5 for constructing a three-Ring framework

Another generally feasible route to obtain the core structure of the compounds of the present invention is based on electrophilic aromatic substitution (scheme 6); r²、R³、R⁴And m has the meaning defined hereinbefore and hereinafter. Thus, the aromatic portion of the molecule reacts with the positively charged carbon atom of the piperidine ring to form a tricyclic backbone. Reactive intermediates with positively charged carbon atoms in the azacycle can be generated by addition of Lewis acids to the olefinic bond or carbonyl group, or by activation of appropriately located leaving groups (e.g., Cl, Br, I, OH, O)₃SCF₃、O₃SMe or O₃S-p-Tol). A number of lewis acids are described for use in this classical reaction and may also be used herein. Some of the more widely used lewis acids are listed below: hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, phosphoric acid, P₄O₁₀Trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, Sc (O)₃SCF₃)₃、InCl₃、InBr₃、SnCl₄、FeCl₃、AlBr₃、AlCl₃、SbCl₅、BCl₃、BF₃、ZnCl₂Montmorillonite, POCl₃And PCl₅. Depending on the tendency of the leaving group to be substituted and the electrical nature of the aromatic ring, more or less strong acid catalysts are used. In addition to the acid catalysts mentioned, silver salts (e.g. AgO)₃SCF₃) Useful in reactions where halides are used as leaving groups. Preferred solvents are hydrocarbons (e.g. hexane or cyclohexane), chlorinated hydrocarbons (e.g. dichloromethane or 1, 2-dichloroethane), perfluorinated hydrocarbons, nitrobenzene, acetonitrile, chlorinated benzenes, heteroaromatic compounds (e.g. quinoline), 1, 2-dimethoxyethane, 1, 4-dioxane, ethers, ionic liquids, water, acetic acid or mixtures thereof, although not all of these solvents can be used with all of the above lewis acids. The reaction is carried out at-10 to 220 ℃, preferably at 20 ℃ to 180 ℃. The reaction can also be carried out under microwave irradiation.

Scheme 6: strategy 6 for constructing a three-Ring framework

The synthetic route presented may depend on the use of protecting groups. Protecting Groups suitable for the corresponding functional Groups and their removal are described below and can be used analogously (see also: Protecting Groups, Philip J. Kocienski, 3 rd edition, Georg Thieme Verlag, Stuttgart, 2004 and the references cited therein).

In the following, a representative summary is given of some possible derivatizations of the compounds of the general formula I or their precursors obtained as described above, which carry specific functional groups in combination with other compounds of the general formula I or their precursors. This compilation is by no means complete and is intended only to suggest some possibilities by way of example.

If, in the preparation process according to the invention, the resulting compound of the general formula I or a precursor thereof contains an amino, alkylamino or imino group, it can be converted into the corresponding acyl or sulfonyl compound of the general formula I or a precursor thereof by acylation or sulfonylation.

If the resulting compound of the general formula I or a precursor thereof contains a hydroxyl group, it can be converted into the corresponding acyl or sulfonyl compound of the general formula I or a precursor thereof by acylation or sulfonylation.

If the resulting compound of the formula I or a precursor thereof contains a hydroxyl group, it can be converted by alkylation into the corresponding ether of the formula I or a precursor thereof.

If the resulting compound of the general formula I or a precursor thereof contains an amino, alkylamino or imino group, it can be converted into the corresponding alkyl compound of the general formula I or a precursor thereof by alkylation or reductive alkylation.

If the resulting compound of the general formula I or a precursor thereof contains a nitro group, it can be converted into the corresponding amino compound by reduction.

If the resulting compound of the general formula I or a precursor thereof contains an imino group, it can be converted into the corresponding N-amino-imino compound by nitrosation and subsequent reduction.

If the resulting compound of the formula I or its precursor contains C_1-4Alkoxycarbonyl, which can be converted into the corresponding carboxyl compound by cleavage of the ester.

If the resulting compound of the formula I or a precursor thereof contains a carboxyl group, it can be converted into the corresponding ester of the formula I or a precursor thereof.

If the resulting compound of formula I or a precursor thereof contains a carboxyl or ester group, it may be converted to the corresponding amide of formula I or a precursor thereof by reaction with an amine.

If the resulting compound of the general formula I or a precursor thereof contains an aromatic substructure, it can be derivatized by electrophilic substitution with a chlorine, bromine or iodine atom or a nitro, sulfonic acid, chlorosulfonyl or acyl group reaction to the corresponding compound of the general formula I or a precursor thereof.

If the resulting compound of formula I or a precursor thereof contains an amino group attached to an aryl or heteroaryl group, it may be converted to the corresponding cyano, fluoro, chloro, bromo, iodo, hydroxy, mercapto or azido-derived compound of formula I or a precursor thereof by diazotization and subsequent substitution of the diazo group with cyanide, fluoride, chloride, bromide, iodide, hydroxide, alkyl sulfide or hydrogen sulfide or azide, respectively.

If the resulting compound of formula I or a precursor thereof contains an amino group attached to an aryl or heteroaryl group, it may be converted to the corresponding aryl-derived aromatic compound of formula I or a precursor thereof by diazotization of the amino group and subsequent substitution of the resulting diazo group with a suitable aryl nucleophile mediated through a suitable transition metal species.

If the resulting compound of formula I or a precursor thereof contains a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy, methylsulfonyloxy or tosyloxy group attached to an aryl or heteroaryl group, it can be converted to the corresponding aryl, alkenyl, alkynyl or alkyl derivative compound of formula I or a precursor thereof by substituting the corresponding group with an aryl, alkenyl, alkynyl or alkyl group using a process mediated by a transition metal species.

If the resulting compound of formula I or a precursor thereof contains a chlorine, bromine or iodine atom attached to an aryl or heteroaryl group or a trifluoromethylsulfonyloxy, methylsulfonyloxy or tosyloxy group, it may be substituted with a cyano group to give the corresponding aromatic compound of formula I or a precursor thereof.

If the resulting compound of formula I or a precursor thereof contains a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy, methylsulfonyloxy or tosyloxy group attached to an aryl or heteroaryl group, it may be substituted with hydrogen to give the corresponding aromatic compound of formula I or a precursor thereof.

If the resulting compound of formula I or its precursor contains two heteroatoms at adjacent carbon atoms (as amino and hydroxyl, amino or sulfhydryl groups), these heteroatoms may be joined via the carboxyl carbon atom to form a cyclic amidine, imidoester or iminothioester structure which may be part of an aromatic ring.

If the resulting compound of formula I or precursor thereof contains a cyano group, it may be converted by reduction to an aminoalkyl-derived compound of formula I or precursor thereof.

If the resulting compound of formula I or a precursor thereof contains a cyano group, it may be converted to N-hydroxycarbamimidoyl by treatment with hydroxylamine.

If the resulting compound of formula I or a precursor thereof contains an N-hydroxycarbamimidoyl group, it can be converted into an oxadiazole derivative compound of formula I or a precursor thereof by treatment with a carboxylic acid or a related group.

If the resulting compound of the general formula I or a precursor thereof contains an aminocarbonyl group, it can be converted by dehydration into the corresponding cyano compound of the general formula I or a precursor thereof.

If the resulting compound of the formula I or a precursor thereof contains a keto group or an aldehyde group, it can be converted by reduction into the corresponding hydroxy compound of the formula I or a precursor thereof.

If the resulting compound of formula I or precursor thereof contains a carboxylic acid or aminocarbonyl group, it may be converted by a rearrangement reaction to the corresponding amino derivative compound of formula I or precursor thereof.

If the resulting compound of formula I or a precursor thereof contains a keto or aldehyde group, it may be converted into the corresponding alkenyl derivative compound of formula I or a precursor thereof.

If the resulting compound of formula I or a precursor thereof contains an olefinic C ≡ C double bond or a C ≡ C triple bond, it may be reduced to form the corresponding saturated compound of formula I or a precursor thereof.

If the resulting compound of the formula I or a precursor thereof contains a keto or aldehyde group, it can be converted into the corresponding tertiary or secondary hydroxyl compound of the formula I or a precursor thereof.

If the resulting compound of the general formula I or a precursor thereof contains a carboxylate group, it can be converted into a tertiary alcohol by adding two equivalents of the organometallic compound.

If the resulting compound of formula I or a precursor thereof contains a primary or secondary hydroxyl group, it can be converted by oxidation into the corresponding carbonyl compound of formula I or a precursor thereof.

If the resulting compound of formula I or precursor thereof contains an olefinic bond, it may be converted to the corresponding hydroxy compound of formula I or precursor thereof by hydroboration followed by oxidation.

If the resulting compound of the formula I or a precursor thereof contains an olefinic bond, it can be converted by dihydroxylation into the corresponding 1, 2-dihydroxy compound of the formula I or a precursor thereof.

If the resulting compound of the general formula I or a precursor thereof contains an olefinic bond, it can be converted by ozonolysis into the corresponding carbonyl compound of the general formula I or a precursor thereof.

If the resulting compound of formula I or precursor thereof contains an olefinic bond, it may be converted to the corresponding hydroxy compound of formula I or precursor thereof by epoxidation followed by ring opening of the oxirane with a hydride source.

If the resulting compound of the general formula I or a precursor thereof contains an olefinic bond, it can be converted by Wacker oxidation into the corresponding carbonyl compound of the general formula I or a precursor thereof.

If the resulting compound of the formula I or a precursor thereof contains an olefinic bond, it can be converted by hydrocyanation into the corresponding cyano compound of the formula I or a precursor thereof.

If the resulting compound of the general formula I or a precursor thereof contains a cyano group, it can be converted into the corresponding aminocarbonyl compound of the general formula I or a precursor thereof by adding water.

The subsequent esterification is optionally carried out in a solvent (e.g. dichloromethane, N-dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, 1, 4-dioxane or mixtures thereof) or particularly advantageously in the corresponding alcohol, optionally in the presence of an acid (e.g. hydrochloric acid) or a dehydrating agent (e.g. isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N '-carbonyldiimidazole, N' -dicyclohexylcarbodiimide, triphenylphosphine (in combination with carbon tetrachloride) or combinations thereof, optionally in the presence of 4-dimethylaminopyridine and/or 1-hydroxybenzotriazole. the reaction is carried out at from 0 to 150 ℃, preferably from 0 to 80 ℃.

The formation of esters can also be carried out by reacting a compound containing a carboxyl group with the corresponding alkyl halide in the presence of a base.

The subsequent acylation or sulphonylation is optionally carried out in a solvent (e.g. dichloromethane, N-dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, 1, 4-dioxane or mixtures thereof) with the corresponding acyl or sulphonyl electrophile, optionally in the presence of a tertiary organic base, an inorganic base or a dehydrating agent. Reagents conventionally used are, for example, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N '-dicyclohexylcarbodiimide, N' -carbonyldiimidazole, triphenylphosphine (in combination with carbon tetrachloride) or combinations thereof, which can be used in the presence of 4-dimethylaminopyridine and/or 1-hydroxybenzotriazole at temperatures of from 0 to 150 ℃, preferably from 0 to 80 ℃.

The subsequent alkylation is optionally carried out with an alkylating agent (e.g. the corresponding halide or sulfonate, such as methyl iodide, ethyl bromide, dimethyl sulfate or benzyl chloride) in dichloromethane, N-dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, 1, 4-dioxane or mixtures thereof, optionally in the presence of a tertiary organic or inorganic base, at a temperature of from 0 to 150 ℃ (preferably at from 0 to 100 ℃).

The subsequent reductive alkylation is conveniently carried out with the corresponding carbonyl compound (e.g. formaldehyde, acetaldehyde, propionaldehyde, acetone or butyraldehyde) in the presence of a complex metal hydride (e.g. sodium borohydride, lithium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride), conveniently at pH 6-7 and ambient temperature, or with hydrogen in the presence of a transition metal catalyst (e.g. palladium on charcoal) at hydrogen pressures of 1 to 5 bar. Methylation may also be carried out in the presence of formic acid as a reducing agent at elevated temperatures (e.g., 60 to 120 ℃).

The subsequent reduction of the nitro group is carried out, for example, with hydrogen and a catalyst, for example palladium on charcoal, platinum dioxide or raney nickel, or with other reducing agents, for example tin (II) chloride, iron or zinc, optionally in the presence of an acid, for example acetic acid.

Subsequent nitrosation of the imino group followed by reduction gives the N-amino-imino compound, for example with an alkyl nitrite (e.g. isoamyl nitrite) to form the N-nitroso-imino compound, which is then reduced to the N-amino-imino compound, for example using zinc, in the presence of an acid (e.g. acetic acid).

Subsequent C_1-4Cleavage of the alkoxycarbonyl group to give the carboxyl group is carried out, for example, by hydrolysis with an acid (e.g., hydrochloric acid or sulfuric acid) or an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide or potassium hydroxide). Preferably, the t-butyl group is removed by treatment with a strong acid (e.g., trifluoroacetic acid or hydrochloric acid) in an inert solvent (e.g., dichloromethane, 1, 4-dioxane, or ethyl acetate).

The subsequent amide formation is carried out by reacting the corresponding reactive carboxylic acid derivative with the corresponding amine in a solvent (e.g. dichloromethane, N-dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, 1, 4-dioxane or mixtures thereof) or without solvent, in an excess of amine, optionally in the presence of a tertiary organic base, an inorganic base, 4-dimethylaminopyridine and/or 1-hydroxy-benzotriazole, at a temperature of from 0 to 150 ℃ (preferably from 0 to 80 ℃). The use of carboxylic acids allows the formation of the desired amides by in situ activation of the carboxyl function with: such as isobutyl chloroformate, thionyl chloride, oxalyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N '-carbonyldiimidazole, triphenylphosphine (in combination with carbon tetrachloride), 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, N' -dicyclohexylcarbodiimide, or combinations thereof.

The subsequent introduction of a chlorine, bromine or iodine atom into the aromatic substructure can be carried out by reacting the aromatic compound with a suitable electrophile corresponding to the halogen atom. Suitable chlorine and bromine electrophiles can be, for example, N-halosuccinimide, HOCl, HOBr, t-BuOCl, t-BuOBr, chlorine, bromine, dibromoisocyanuric acid, pyridinium dichloroborate, pyridinium tribromide or sulfonyl chloride, which can be used alone or in combination with an acid, such as hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, trifluoromethanesulfonic acid, sulfuric acid, or acetic acid, or a lewis acid, such as an iron (III) halide, boron trifluoride hydrate, boron trifluoride etherate or aluminum halide. Other useful combinations may be LiBr with cerium ammonium nitrate, KCl or KBr with OxoneOr KBr and sodium perborate. Suitable electrophilic iodine reagents may be prepared from iodine and oxidizing agents (e.g. nitric acid, sulphur trioxide, manganese dioxide, HIO)₃Hydrogen peroxide, sodium periodate, peroxodisulfate and OxoneAnd (4) generating. Other suitable iodophors may be, for example, iodine chloride, dichloroiodate, and N-iodosuccinimide. These iodoelectrophiles are optionally used without additives or in the presence of acids (e.g. acetic acid, trifluoroacetic acid or sulfuric acid) or lewis acids (e.g. boron trifluoride hydrate or copper salts). If nitro groups are introduced, it is appropriate The source of nitro electrophile may be, for example, nitric acid, acetyl nitrate, ceric ammonium nitrate, sodium nitrate, N₂O₅Alkyl nitrates and nitronium tetrafluoroborates. Although some of these reagents may be used without additives, some are preferably reacted with an acid (e.g., sulfuric acid or trifluoromethanesulfonic acid), acetic anhydride, trifluoroacetic anhydride, a Lewis acid (e.g., ytterbium trifluoromethanesulfonate or ferric acetate), P₂O₅Or a base may be used together. SO (SO)₃The H groups can be formed by reacting aromatic compounds with, for example, concentrated sulfuric acid, SO₃、ClSO₃H or ClSO₂NMe₂In combination with indium triflate. Reacting an aromatic compound with ClSO₃The reaction of H gives the corresponding chlorosulfonylated derivative, which can be hydrolyzed to sulfonic acid. Acylation of aromatic moieties is carried out by using acyl electrophiles, which can be prepared from the corresponding acyl halides (e.g., chlorides or acyl anhydrides) and Lewis acids (e.g., aluminum halides, diethylaluminum halides, indium halides, iron (III) halides, tin (IV) halides, boron trifluoride, titanium (IV) halides) orAcids such as sulfuric acid or trifluoromethanesulfonic acid). The formyl groups are preferably introduced using the so-called Vilsmeier or Vilsmeier-Haack conditions: dialkyl formamide with phosgene, thionyl chloride, POCl₃Or a combination of oxalyl chlorides. The preferred solvent for the electrophilic substitution may vary depending on the electrophile used; some of the more common solvents are described below: dichloromethane, 1, 2-dichloroethane, chlorobenzene, dichlorobenzene, ethers, 1, 4-dioxane, fluorinated hydrocarbons, hexane, quinoline, and acetonitrile. The preferred temperature range of use is from 0 to 180 ℃.

Subsequent substitution of the aryl or heteroaryl attached amino group begins with diazotization of the amino group using a nitrous or nitrosonium source or equivalent (e.g., nitrite) in combination with an acid (e.g., sodium nitrite and hydrochloric acid, nitrosonium tetrafluoroborate) or an alkyl nitrite (e.g., tert-butyl nitrite or isoamyl nitrite). The diazotisation is optionally carried out in dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-methylpyrrolidone, benzene, toluene, chlorobenzene, tetrahydrofuran, water, ethyl acetate, alcohols, ethers, 1, 2-dimethoxyethane, 1, 4-dioxane or mixtures thereof, at temperatures of-10 to 100 ℃ (diazotisation of the amino group is for example detailed in angelw.chem.int.ed.1976, 15, 251). Subsequent reactions utilizing copper cyanide, chloride or bromide to replace the diazonium group with a cyano, chlorine or bromine atom, respectively, are known as Sandmeyer reactions (see, e.g., March's Advanced Organic Chemistry, Michael b. smith and Jerry March, John Wiley & Sons inc., sixth edition, New Jersey, 2007 and references cited therein); the reaction is optionally carried out in one of the above solvents or mixtures at-10 to 120 ℃. The substitution of the diazo group with a fluorine atom can be accomplished using tetrafluoroborate or tetrafluoroboric acid and heating to 20 to 160 ℃; this reaction is known as the Schiemann reaction. The iodine can be introduced by treating the diazo compound with an iodide salt (e.g. sodium iodide), preferably using water or an aqueous solvent mixture at a temperature of 0 to 120 ℃. The diazo group is substituted with a hydroxyl group using water or an aqueous solvent mixture at a temperature of 0 to 180 ℃. The reaction is usually carried out without further additives, but the addition of copper oxide or strong acids may be advantageous. The mercapto or alkylmercapto group may be introduced via the corresponding disulfide salt or dialkyl disulfide at a temperature of from 0 to 120 ℃; depending on the sulfur-containing species used, inert solvents or aqueous solvent systems may be preferred (see, e.g., synth. commun.2001, 31, 1857 and references cited therein).

Subsequent substitution of the amino group attached to the aryl or heteroaryl group with an aryl group can be accomplished via the corresponding diazo compound available as described above. The reaction with the aryl nucleophile, preferably an arylboronic acid, boronic ester, trifluoroboronic ester, zinc halide or stannane, is carried out in the presence of a transition metal species derived from palladium, nickel, rhodium, copper or iron, preferably palladium. The active catalyst may be a complex of a transition metal with a ligand (e.g. a phosphine, phosphite, imidazole carbene, imidazoline carbene, dibenzylidene acetone, allyl, or nitrile), an elemental form of a transition metal (e.g. palladium on carbon or nanoparticles), or a salt (e.g. chloride, bromide, acetate, or trifluoroacetate). The diazo compound is preferably used as its tetrafluoroborate salt (optionally in water, N-methylpyrrolidone, N-dimethylformamide, dichloromethane, benzene, toluene, tetrahydrofuran, ethyl acetate, alcohols, ethers, 1, 2-dimethoxyethane, 1, 4-dioxane or mixtures thereof) at a temperature of from 10 to 180 ℃ (preferably from 20 to 140 ℃).

Subsequent substitution of the chlorine, bromine or iodine atom or the trifluoromethylsulfonyloxy, methylsulfonyloxy or tosyloxy group attached to the aryl or heteroaryl group with an aryl, alkenyl, alkynyl or alkyl residue is preferably mediated by transition metal species derived from palladium, nickel, copper or iron. The active catalyst may be a complex of a transition metal with a ligand such as a phosphine (e.g. tri-tert-butylphosphine, tricyclohexylphosphine, 2- (substituted phenyl) phenyl-dicyclohexylphosphine, 2- (substituted phenyl) phenyl-di-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, triphenylphosphine, tritolylphosphine or trifuranyl-phosphine, a phosphite, 1, 3-disubstituted imidazolecene, 1, 3-disubstituted imidazolinecene, dibenzylideneacetone, allyl or nitrile), an elemental form (e.g. palladium on carbon or nanoparticles of iron or platinum) or a salt (e.g. fluoride, chloride, bromide, acetate, triflate or trifluoroacetate) of a transition metal. The substitution reaction is preferably carried out with a trifluoroborate, a boronic acid or a boronic ester to be introduced into the aryl, alkenyl or alkyl residue (Suzuki or Suzuki-type reaction), a zinc halide (Negishi or Negishi-type reaction), a stannane (Stille or Stille-type reaction), a silane (Hiyama or Hiyama-type reaction), a magnesium halide (Kumada or Kumada-type reaction). Preferably, the terminal alkynyl group can be used as such or as a zinc acetylenic derivative thereof. Depending on the nature of the electrophilic and nucleophilic reactions, the partner additives, for example halide salts (such as lithium chloride, potassium fluoride, tetrabutylammonium fluoride), hydroxide sources (such as potassium hydroxide) or potassium carbonate, silver salts (such as silver oxide or silver triflate) and/or copper salts (such as copper chloride or copper thiophene-2-carboxylate) may be advantageous or even critical. Copper iodide is a preferred additive in the coupling with terminal alkynes (Sonogashira reaction). The coupling reaction is preferably carried out in benzene, toluene, ether, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, alcohol, water or mixtures thereof, although some of these are less suitable or not at all depending on the nucleophile. The preferred temperature is from-10 to 180 ℃.

Subsequent substitution of the chlorine, bromine or iodine atom or the methanesulfonyloxy, trifluoromethylsulfonyloxy or toluenesulfonyloxy group attached to the aryl or heteroaryl group with a cyano group is preferably accomplished via a transition metal mediated process. Copper, nickel and palladium are the most commonly used metals for this conversion and are used as elements, salts or complexes in combination with cyanide sources. Copper iodide, copper sulfate, copper cyanide, nickel chloride, nickel bromide, nickel cyanide, bis (triphenylphosphine) nickel dichloride, palladium on carbon, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium trifluoroacetate, palladium chloride, palladium cyanide, optionally in combination with a ligand such as tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 1' -bis (diphenylphosphino) ferrocene, adamantyl-n-butylphosphine, or xanthphos, are among the catalysts conventionally used. Common cyanide sources are sodium cyanide, potassium cyanide, zinc cyanide, copper cyanide, nickel cyanide, potassium hexacyanoferrate and acetone cyanohydrin. The reaction is preferably carried out in N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, pyridine, acetonitrile, quinoline, toluene, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 4-dioxane or a mixture thereof at 20 to 280 ℃ (preferably 60 to 200 ℃). Additives (e.g., zinc, sodium carbonate, potassium iodide, water, and pyridine) and/or the use of microwave radiation may be beneficial for some reaction conditions.

Subsequent substitution of the chlorine, bromine or iodine atom or the trifluoromethylsulfonyloxy, methylsulfonyloxy or tosyloxy group attached to the aryl or heteroaryl group with a hydrogen atom is preferably mediated by transition metal species derived from palladium, nickel, platinum or rhodium. The active catalyst may be a complex of a transition metal with a ligand, as described above, in elemental form, or a transition metal salt. Raney nickel or palladium on carbon are among the preferred catalyst species. Suitable hydrogen sources may be hydrogen (preferably at pressures of 1 to 10 bar), silanes (e.g. trialkoxysilanes or polymethylhydrosiloxanes), boranes, hydrides (e.g. alkali metal borohydrides), formic acid or formates (e.g. ammonium formate). The reaction is preferably carried out in N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohols, ethers, 1, 2-dimethoxyethane, 1, 4-dioxane or mixtures thereof at-10 to 180 ℃ (preferably at 20 to 140 ℃).

The subsequent cyclization reaction starting from compounds bearing two heteroatoms at adjacent carbon atoms is optionally carried out by carboxyl equivalents such as nitriles, carboxyl chlorides or fluorides, carboxylic acids, ketenes, carboxylic esters or carboxylic thioesters. The overall conversion reaction comprises two reaction steps: the carboxy equivalent is attached to one of the two heteroatoms followed by cyclization with the other heteroatom. The first step is the formation of an amide with the amino functionality, which may be performed as previously described. The subsequent reaction step (i.e., the cyclization reaction with the second heteroatom) may be accomplished by heating in the presence of an acid (e.g., acetic acid, trifluoroacetic acid, sulfuric acid, or hydrochloric acid) or a base (e.g., sodium hydroxide, sodium ethoxide, or sodium tert-butoxide). It may be advantageous to use a dehydration reagent (e.g. an anhydride such as acetic anhydride, an orthoester such as trimethyl orthoformate, thionyl chloride, phosgene, diphosgene, triphosgene, phosphorus oxychloride, phosphorus pentachloride, dialkylcarbodiimide) in combination with a phosphine (e.g. triphenylphosphine or trialkylphosphine) and a dialkyl azodicarboxylate, bromine, iodine or 1, 2-dihaloethane (e.g. 1, 2-dibromotetrafluoroethane). The reaction is preferably carried out in an inert solvent or mixture (e.g., dichloromethane, 1, 2-dichloroethane, benzene, toluene, tetrahydrofuran, ether, or combinations thereof), although the cyclization reaction in the presence of an acid or base can also be carried out in water or an alcohol (e.g., methanol, ethanol, isopropanol, or tert-butanol) or in combination with such solvents. The reaction is carried out at a temperature of from 0 to 200 deg.C (preferably from 20 to 140 deg.C).

The subsequent reduction of the cyano group to give the aminomethyl group is preferably carried out in the presence of a transition metal species together with hydrogen or with a hydride. Suitable transition metals may be derived from palladium, nickel, platinum, rhodium or ruthenium (e.g. palladium on carbon, palladium hydroxide, platinum oxide or raney nickel), which may be used in solvents (e.g. ethyl acetate, alcohols such as methanol or ethanol, dichloromethane, tetrahydrofuran, ethers, benzene, toluene, N-dimethylformamide or N-methylpyrrolidinone) at hydrogen pressures of 1 to 10 bar and temperatures of 0 to 160 ℃. Additives such as acids (e.g., hydrochloric acid, methane sulfonic acid, sulfuric acid, or acetic acid) may be advantageous for reduction using the transition metal catalyst. Among the preferred hydride sources are, for example, borohydrides (such as sodium borohydride, potassium tri-sec-butylborohydride, borane or lithium triethylborohydride) and aluminum oxides (such as lithium aluminum hydride or diisobutylaluminum hydride). Some of these agents, such as sodium borohydride, are preferably used in combination with nickel chloride or cobalt chloride. These reagents may be used, for example, in tetrahydrofuran, ethers, 1, 4-dioxane, 1, 2-dimethoxyethane, dichloromethane, 1, 2-dichloroethane, benzene or toluene; some of which are also compatible with alcoholic or aqueous solutions. The preferred reaction temperature range is from-80 to 160 deg.C, more preferably from-40 to 80 deg.C.

The subsequent formation of the N-hydroxyamidino group from the cyano group can be carried out by treating the cyano compound with hydroxylamine. The reaction is preferably carried out in an aqueous solvent or an alcoholic solvent at a temperature of 0 to 140 ℃.

Subsequent formation of oxadiazoles from N-hydroxyamidines is carried out using carboxyl equivalents (e.g. nitriles, carboxychlorides or fluorides, carboxylic acids, ketenes, carboxylic esters or carboxylic thioesters). The conversion reaction involves the formation of a ring starting from a heteroatom on two adjacent carbon atoms as described above and can proceed in a similar manner.

Subsequent formation of a cyano group from an aminocarbonyl group is preferably carried out using a dehydrating agent (e.g., an acid anhydride such as acetic anhydride, trifluoroacetic anhydride or trifluoromethanesulfonic anhydride), phosgene, sulfuryl chloride, oxalyl chloride, POCl₃、PCl₅、P₄O₁₀Triphenyl phosphite or triphenyl-or trialkylphosphines in combination with tetrachloromethane, 1, 2-dibromotetrafluoroethane or bromine). The reaction is preferably carried out in dichloromethane, 1, 2-dichloroethane, hexane, ether, 1, 4-dioxane, benzene, toluene, acetonitrile and mixtures thereof or without solvent at temperatures of from 0 to 140 ℃. Examples of additivesSuch as amines (e.g. pyridine or triethylamine) or N, N-dimethylformamide may be advantageous.

Subsequent reduction of the keto or aldehyde group to obtain a secondary or primary alcohol can be carried out with a complex metal hydride such as sodium borohydride, lithium triethylborohydride, diisobutylaluminum hydride or lithium aluminum hydride. The reduction reaction may be carried out in, for example, dichloromethane, 1, 2-dichloroethane, hexane, ether, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone, benzene, toluene, alcohol (e.g., methanol), water, or mixtures thereof, although not all reducing agents are compatible with all such solvents. The preferred temperature range is from-80 to 140 ℃ depending on the reducing power of the reagent. Alternatively, hydrogen may be used for reduction in the presence of a transition metal catalyst.

Subsequent conversion of the carboxyl group to an amino group by rearrangement can be accomplished by heating the acyl azide. Thereby forming isocyanates (Curtius rearrangement). Isocyanates can be hydrolyzed to yield free amines or converted to urea or carbamate derivatives by treatment with amines or alcohols, respectively. Acyl azides can be obtained from an azide source (e.g., sodium azide or trimethylsilyl azide) by treating a suitable acyl electrophile (e.g., an acid chloride, carboxylic anhydride, or carboxylic ester) in a solvent (e.g., 1, 4-dioxane, 1, 2-dimethoxyethane, acetonitrile, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, N-methylpyrrolidone, N-dimethylformamide, toluene, benzene, hexane, or mixtures thereof); in some cases water or alcohol may also be used. The reaction is usually carried out at-10 to 120 ℃. Alternatively, the acyl electrophile may be generated in situ from the acid and then converted to an acyl azide: diphenylphosphorylazide in the presence of a base (e.g. triethylamine or ethyldiisopropylamine) in a solvent (e.g. acetonitrile, benzene, toluene or alcohol) and at elevated temperature has proven to be an effective reagent for such direct conversion. The direct conversion can also be achieved with an azido acid and an acid catalyst (e.g., sulfuric acid) in, for example, chloroform at elevated temperatures (Schmidt reaction).

Another way to achieve this overall conversion reaction is the Lossen rearrangement: starting from an acyl electrophile (e.g., an acyl chloride), the corresponding appropriate hydroxamic acid derivative is formed, which rearranges to form an isocyanate, which is then treated by heating and/or treatment with a base (e.g., sodium hydroxide) to form an amine (see, e.g., j. org. chem.1997, 62, 3858 and Synthesis 1990, 1143 and references cited therein).

The unsubstituted carboxylic acid amides can be converted into amines by the so-called hofmann rearrangement. Suitable reagents for this conversion are NaOBr, bromine in combination with sodium methoxide, N-bromosuccinimide, and sodium methoxide, PhI (O)₂CCF₃)₂And PhI (OH) OTs (Ts is 4-tolylsulfonyl).

Subsequent conversion of the aldehyde or ketone functional group to an alkene can be achieved, for example, by the so-called Wittig reaction and modifications thereof, Peterson olefination and Julia reaction and modifications thereof. These reactions have numerous precedent in Organic synthesis and are detailed in, for example, March's Advanced Organic Chemistry, Michael b. smith and Jerry March, John Wiley & Sons inc., 6.ed., New Jersey, 2007 and references cited therein.

The subsequent reduction of the C ═ C double bond or C ≡ C triple bond is preferably carried out with hydrogen on a catalyst derived from palladium, nickel, platinum, ruthenium or rhodium (preferably Raney nickel, palladium on carbon, platinum oxide and RhCl (PPh) ₃) In the presence of a transition metal species of (a). The reaction is preferably carried out in dichloromethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohols, ethers, 1, 2-dimethoxyethane, 1, 4-dioxane or mixtures thereof, at 0 to 180 ℃ (preferably 20 to 140 ℃) and at a hydrogen pressure of 1 to 10 bar (preferably 1 to 5 bar).

The subsequent reaction of the aldehyde or ketone to convert to a secondary or tertiary alcohol is preferably carried out by addition of a carbon nucleophile (e.g., an alkyl, allyl, alkenyl, aryl or alkynyl lithium, magnesium or cerium compound) in tetrahydrofuran, ether, 1, 4-dioxane, 1, 2-dimethoxyethane, toluene, hexane or mixtures thereof at-80 to 80 ℃.

The subsequent reaction of the carboxylic ester to convert to a tertiary hydroxyl group is preferably carried out with the equivalent of two or more carbon nucleophiles (e.g., alkyl, allyl, alkenyl, aryl or alkynyl lithium, magnesium or cerium compounds) in tetrahydrofuran, ether, 1, 4-dioxane, 1, 2-dimethoxyethane, toluene, hexane, or mixtures thereof at temperatures of-80 to 80 ℃.

Subsequent oxidation of the primary or secondary hydroxyl compound can be accomplished by using an oxidizing agent (e.g., dimethyl sulfoxide in combination with, for example, oxalyl chloride, acetic anhydride, SO) ₃Pyridine or dicyclohexylcarbodiimide, pyridinium chlorochromate (PCC), Pyridinium Dichlorochromate (PDC), Dess-Martin oxidizer (Dess-Martin periodinane), manganese dioxide, 2, 6, 6-tetramethylpiperidine-N-oxide (TEMPO) optionally in combination with a co-oxidant or tetrapropylammonium perruthenate (TPAP) in combination with a co-oxidant, e.g. N-methyl-morpholine-N-oxide, optionally in the presence of a base, e.g. triethylamine, preferably in toluene, dichloromethane or 1, 2-dichloroethane at-70 to 60 ℃. Alternatively, the conversion reaction may be carried out using Al (OtBu)₃And acetone as an Oppenauer oxidation reaction.

Subsequent hydroboration and oxidation of olefinic bonds with boranes (e.g. boranes complexed with tetrahydrofuran, trimethylamine or dimethylsulfide), diethylboranes, 1, 2-trimethylpropylboranes (thexylboranes), 9-borabicyclo [3.3.1 ]]Nonane, bound BF₃Or TiCl₄NaBH of₄Or dichloroborane, which is preferably used in tetrahydrofuran at-20 to 60 ℃. The hydroboration product is then treated with an aqueous solution of, for example, hydrogen peroxide and sodium hydroxide to replace the boron group in the intermediate with a hydroxyl group.

The subsequent dihydroxylation of the olefinic bond is preferably carried out using osmium tetroxide or potassium osmate in combination with a co-oxidant (e.g.N-methyl-morpholine-N-oxide or K) ₃Fe(CN)₆) Preferably, the incorporation of tBuOH, tetrahydrofuran and/or 1, 4-dioxane in water is carried out at-20 to 60 ℃.

Subsequent cleavage of the olefinic bond by ozonolysis is carried out using ozone, preferably in dichloromethane, at temperatures of-50 to-78 ℃. The resulting intermediate can then be converted to a carbonyl compound by treatment with, for example, dimethyl sulfide, zinc in combination with acetic acid, hydrogen in the presence of palladium, or triphenylphosphine. The intermediate is treated with sodium borohydride or lithium aluminum hydride to provide the corresponding hydroxy compound.

The subsequent epoxidation of the olefinic bond is preferably carried out with m-chloroperbenzoic acid (mCPBA), hydrogen oxide with excess binding of formic acid or acetic acid or Oxone with binding of acetone or 1, 1, 1-trifluoroacetonePreferably in dichloromethane at-20 to 40 ℃. The oxirane ring can be opened with a hydride source (e.g., lithium aluminum hydride or lithium triethylborohydride) in an inert solvent (e.g., tetrahydrofuran) to give the hydroxy compound.

The subsequent Wacker oxidation of the olefinic bond is preferably carried out with PdCl₂And CuCl or CuCl₂In the presence of oxygen in an aqueous solvent to provide the corresponding carbonyl compound.

Subsequent hydrocyanation of olefinic bonds can be carried out using 4-tolylsulfonyl cyanide in the presence of phenylsilane and a cobalt catalyst (see, e.g., Angew. chem.2007, 119, 4603-6).

The subsequent addition of water to the cyano group can be carried out by treating (optionally at elevated temperature, preferably 0 to 140 ℃) an aqueous solution of the nitrile with a strong acid (e.g. sulfuric acid or hydrochloric acid) or a base (e.g. NaOH or KOH). Alternatively, the conversion reaction may be carried out using a transition metal catalyst (e.g., PdCl)₂) In aqueous solution.

In the above-described reactions, any reactive group present (e.g., hydroxyl, carbonyl, carboxyl, amino, alkylamino, or imino) may be protected during the reaction by a conventional protecting group, which is cleaved again after the reaction.

For example, the protecting group for the hydroxyl group may be trimethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, acetyl, pivaloyl, benzoyl, methyl, t-butyl, allyl, trityl, benzyl, 4-methoxybenzyl, tetrahydropyranyl, methoxymethyl, ethoxymethyl or 2-trimethylsilylethoxymethyl, the protecting group for the carboxyl group may be trimethylsilyl, methyl, ethyl, t-butyl, allyl, benzyl or tetrahydropyranyl, the protecting groups for the ketone or aldehyde may be ketals or acetals, respectively, for example derived from methanol, ethylene glycol, propane-1, 3-diol or propane-1, 3-dithiol,

The protecting group for amino, alkylamino or imino can be methyl, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl or 2, 4-dimethoxybenzyl, and the protecting group for amino can additionally be that of phthaloyl and tetrachlorophthaloyl and the protecting group for the terminal alkynyl can be trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or 2-hydroxy-prop-2-yl.

Any acyl protecting group may be cleaved hydrolytically, for example at a temperature of 0 to 120 ℃ (preferably at 10 to 100 ℃), in an aqueous solvent (e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or 1, 4-dioxane/water), in the presence of an acid (e.g. trifluoroacetic acid, hydrochloric acid or sulfuric acid) or in the presence of an alkali metal base (e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide). The conversion reaction can be carried out aprotic in dichloromethane or 1, 2-dichloroethane at-70 to 60 ℃ using, for example, iodotrimethylsilane. Trifluoroacetyl groups can also be cleaved by treatment with an acid (e.g. hydrochloric acid), optionally in a solvent (e.g. acetic acid) at a temperature of 50 to 120 ℃ or with aqueous sodium hydroxide solution, optionally in other solvents (e.g. tetrahydrofuran or methanol) at 0 and 80 ℃.

Any acetal or ketal protecting group used may also be cleaved, for example, hydrolytically in an aqueous solvent (e.g., water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or 1, 4-dioxane/water) in the presence of an acid (e.g., acetic acid, trifluoroacetic acid, hydrochloric acid, or sulfuric acid) at temperatures of 0 to 120 ℃ (preferably at 10 to 100 ℃). Iodotrimethylsilane in dichloromethane is a variation to achieve this conversion in an aprotic manner.

The trimethylsilyl group is cleaved, for example, in water, an aqueous solvent mixture or an alcohol (e.g., methanol or ethanol) in the presence of a base (e.g., lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide). Acids such as hydrochloric acid, trifluoroacetic acid or acetic acid are also suitable. The cutting is usually carried out at a relatively low temperature (e.g., at-60 to 60 ℃). Silyl groups other than trimethylsilyl are preferentially cleaved in the presence of an acid (e.g., trifluoroacetic acid, hydrochloric acid, or sulfuric acid) at temperatures of 0 to 100 ℃. Particularly suitable methods for the cleavage of silyl groups are based on the use of fluoride salts, such as tetrabutylammonium fluoride, hydrogen fluoride or potassium fluoride, in organic solvents, such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, toluene, benzene, 1, 2-dichloroethane or dichloromethane, at temperatures of from-20 to 100 ℃.

The benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved hydrogenolytically, for example using hydrogen in the presence of a catalyst, for example palladium on carbon or palladium hydroxide, in a solvent, for example methanol, ethanol, ethyl acetate, acetic acid or mixtures thereof, optionally in the presence of an acid, for example hydrochloric acid, at a temperature of from 0 to 100 c, preferably from 20 to 60 c, and at a hydrogen pressure of from 1 to 10 bar, preferably from 3 to 5 bar. Trimethylsilyl iodide, boron trichloride or boron trifluoride may also be used with benzyl ether derivatives in the presence of scavengers such as anisole, benzyl sulfide or pentamethylbenzene. The electron-rich benzyl residue (e.g. methoxybenzyl) CAN also be cleaved oxidatively with, for example, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) or Cerium Ammonium Nitrate (CAN), preferably in an alcohol or aqueous solvent at temperatures of 10 to 120 ℃. The 2, 4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of a scavenger, such as anisole.

The tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treatment with an acid (e.g. trifluoroacetic acid, sulfuric acid or hydrochloric acid) or by treatment with iodotrimethylsilane, optionally with a solvent (e.g. dichloromethane, 1, 4-dioxane, methanol, isopropanol, water or diethyl ether).

The methyl group on the tertiary amine can be cleaved by treatment with 1-chloroethyl chloroformate or vinyl chloroformate. Hydrobromic acid as well as boron tribromide are particularly suitable for the cleavage of methyl ethers.

The compounds of general formula I can also be resolved into their enantiomers and/or diastereomers as described previously. Thus, for example, cis/trans mixtures can be resolved into their cis and trans isomers, and racemic compounds can be resolved into their enantiomers.

The cis/trans mixture can be resolved into its cis and trans isomers, for example, by chromatography. The compounds of the formula I which are present as racemates can be resolved into their optical enantiomers by methods known per se (cf. Allinger N.L. and Eliel E.L.in "Topics in stereoschemistry", Vol.6, Wiley Interscience, 1971) and diastereomeric mixtures of the compounds of the formula I can be resolved into their diastereomers by methods known per se, for example chromatography and/or fractional crystallization, taking advantage of their different physicochemical properties; if the compound is then obtained as a racemate, it can be resolved into the enantiomers as described previously.

The racemate is preferably resolved by column chromatography on a chiral phase, or by crystallization from an optically active solvent, or by reaction with an optically active substance which forms a salt or derivative such as an ester or amide with the racemic compound. For basic compounds, salts can be formed with enantiomerically pure acids, and for acidic compounds, salts can be formed with enantiomerically pure bases. Diastereomeric derivatives are formed with an enantiomerically pure auxiliary compound (e.g., an acid, an activated derivative thereof, or an alcohol). The resolution of the diastereomeric mixture of salts or derivatives thus obtained can be achieved by virtue of their different physicochemical properties (e.g. differences in solubility); the free enantiomer may be released from the pure diastereomeric salt or derivative by the action of a suitable reagent. Optically active acids which are frequently used for this purpose are, for example, the D-and L-forms of tartaric acid, dibenzoyltartaric acid, ditolyltetratartaric acid, maleic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. The optically active alcohol which may be an auxiliary residue may be for example (+) or (-) -menthol and the optically active acyl group in the amide may be for example (+) -or (-) -menthyloxycarbonyl.

As mentioned above, the compounds of formula I may be converted into salts, in particular into pharmaceutically acceptable salts for pharmaceutical use. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), basic or organic salts of acidic residues (e.g., carboxylic acids), and the like. Such salts include, for example, acetate, ascorbate, benzenesulfonate (besylates), benzoate, bicarbonate, bitartrate, bromide/hydrobromide, calcium/edetate, camsylate (Camsylates), carbonate, chloride/hydrochloride, citrate, ethane disulfonate (edisylates), etonate (estolate), ethylsulfonate (esylate), fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycollate (glycollylarsanilate), hexylresorcinate, hydrabamine (hydrabamine), hydroxymaleate, hydroxynaphthoate, iodide, isothioglycolate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, mucate (mucates), naphthalenesulfonate (napsylates), nitrate, oxalate, pamoate (pamoates), and pamoate (pamoates), Pantothenate (panthenates), phenylacetate, phosphate/diphosphate, polygalacturonate (polygalacturonates), propionate, salicylate, stearate, subacetate, succinate, sulfonamide, sulfate, tannate, tartrate, chlorotheophylline (teoclates), tosylate (tosilates), triiodonium (triethiodode), ammonium, benzathine (benzathine), chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine. Other pharmaceutically acceptable salts can form with cations from metals (e.g., aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc.) (see also Pharmaceutical salts, Berge, s.m. et al, j.pharm.sci, (1977), 66, 1-19). Some of the salts described above may also be used to purify or isolate the compounds of the invention.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or mixtures thereof.

Salts of other acids than those mentioned above, e.g. trifluoroacetic acid salts, which may be used, for example, for the purification or isolation of the compounds of the invention, also form part of the invention.

The compounds according to the invention can also be obtained advantageously using the methods described in the examples below, which can also be combined for this purpose with methods known to the person skilled in the art from the literature.

As mentioned above, the compounds of general formula I according to the invention and their pharmaceutically acceptable salts have advantageous pharmacological properties, in particular an inhibitory effect on the enzyme 11 beta-hydroxysteroid dehydrogenase (HSD) 1.

Biological examples

a) The biological properties (inhibitory activity on 11 β -hydroxysteroid dehydrogenase 1) of the novel compounds can be investigated as follows:

the in vitro inhibitory effect of test compounds on 11 β -HSD1 was determined by detecting cortisol produced by corticosterone by human liver microsomes using HTRF (homogeneous time-resolved fluorescence) technology (France). Briefly, compounds were incubated in Tris buffer (20mM tromethamine, 5mM EDTA, pH 6.0) containing NADPH (200. mu.M) and cortisone (80nM) for 1 hour at 37 ℃. Cortisol produced in the reaction was subsequently detected using a competitive immunoassay, involving two HTRF conjugates: cortisol linked to XL665 and anti-cortisol antibodies labelled with europium cryptate. For inspecting The incubation time for the assay reaction is typically 2 hours. The amount of cortisol was determined by reading the time-resolved fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and 665/7.5 nm). The ratio of the two transmitted signals (Em665 10000/Em615) is then calculated. Each assay included incubation with vehicle control instead of compound as control for non-inhibited cortisol production (100% CTL; "high value") and with carbenoxolone as enzyme for complete inhibition and cortisol background control (0% CTL; "low value"). Each assay also included converting fluorescence data to cortisol concentration using a cortisol calibration curve. The percent inhibition (% CTL) of each compound relative to the carbenoxolone signal was determined and IC was generated₅₀Curve line.

The compounds of the formula I according to the invention tested as described above have, for example, an IC of less than 10000nM, in particular less than 1000nM, most preferably less than 500nM₅₀The value is obtained.

Table 2: the 11 β -HSD1 inhibitory Activity of the examples pooled in the Experimental section

b) The inhibitory activity of the novel compounds on 11 β -hydroxysteroid dehydrogenase 1 can also be investigated as follows:

the inhibition of the microparticulate formulation of 11 β -HSD1 by the compounds of the invention was determined essentially as previously described (K.Solly, S.S.Mundt, H.J.Zokian, G.J.Ding, A.Hermanowski-Vosatka, B.Strulovici and W.Zong, High-Throughput Screening of 11-Beta-Hydroxysteroid Dehydrogene Type 1 in scientific promotion analysis Format.Assay Drug Technol 3(2005) 377-384). All reactions were performed at room temperature in 96-well transparent flexible PET Microbeta plates (Perkinelmer). The assay was performed by dispensing 49. mu.l of substrate solution (50mM HEPES, pH 7.4, 100mM KCl, 5mM NaCl, 2mM MgCl)₂2mM NADPH and 160nM 2³H]Cortisone (1Ci/mmol)) and mixed in 1 μ l of test compound in DMSO diluted (8 points) in semilog increments starting at 0.1mM beforehand. After 10 minutes of pre-incubation, 50 μ L of enzyme solution containing microsomes isolated from CHO cells overexpressing human 11 β -HSD1 (10-20 μ g/ml total protein) was added and the plates were incubated for 90 minutes at room temperature. The reaction was stopped by adding 50. mu.l of SPA bead suspension containing 10. mu.M 18. beta. -glycyrrhetinic acid, 5mg/ml protein A coated YSi SPA beads (GE Healthcare), and 3.3. mu.g/ml anti-cortisol antibody (East Coast Biologics) in Superlock buffer (Bio-Rad). The plate was shaken at room temperature for 120 minutes and measured on a Microbeta plate reader to correspond to [ 2 ]³H]SPA signal of cortisol.

Table 3: the 11 β -HSD1 inhibitory Activity of the examples pooled in the Experimental section

Examples	IC₅₀[nM]	Examples	IC₅₀[nM]	Examples	IC₅₀[nM]
						172	5.6	173	18.6	174	3.6
175	58.4	176	46.5	177	＞100

c) The metabolic stability of the novel compounds can be investigated as follows:

metabolic degradation of test compounds was determined using mixed liver microsomes from various species at 37 ℃. The final 100 μ l incubation volume at each time point contained TRIS buffer at pH 7.6 (0.1M), magnesium chloride (5mM), microsomal protein (0.5 mg/ml) and test compound at a final concentration of 1 μ M at room temperature. After a short pre-incubation period at 37 ℃, the reaction was started by adding β -nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH, 1mM) and stopped by transferring aliquots to the solvent after different time points. After centrifugation (10000g, 5min), an aliquot of the supernatant was assayed for the amount of parent compound by LC-MS/MS. The half-life is determined by the slope of the semilogarithmic curve of the concentration-time diagram.

Table 4: stability of the examples pooled in the experimental section in human liver microsomes

Examples	t_1/2[min]	Examples	t_1/2[min]	Examples	t_1/2[min]
						1	＞90	42	＞90	108	＞90
2	29	91	＞90	146	＞45

10	＞45	93	＞90	148	＞90
						11	38	105	22	152	＞90
20	＞90	106	＞90	153	＞90
						37	＞90	107	＞90	155	28

In view of their ability to inhibit the enzyme 11 β -hydroxysteroid dehydrogenase (HSD)1, the compounds of the general formula I according to the invention and their corresponding pharmaceutically acceptable salts are theoretically suitable for the therapeutic and/or prophylactic treatment of all these disorders or diseases which can be influenced by the inhibition of the activity of 11 β -hydroxysteroid dehydrogenase (HSD) 1. The compounds of the invention are therefore particularly suitable for the prophylaxis or treatment of diseases, in particular metabolic diseases or disorders, such as type 1 and type 2 diabetes, diabetic complications (such as retinopathy, nephropathy or neuropathy, diabetic foot, ulcers, macroangiopathy, slow or poor wound healing), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of different origin, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema, hyperuricemia. These substances may also be suitable for preventing degeneration of beta cells, such as apoptosis or necrosis of pancreatic beta cells. These agents may also be useful for improving or restoring pancreatic cell function, as well as increasing pancreatic β -cell number and size. The compounds of the invention are also useful as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.

Furthermore, it has been shown that inhibition of 11 β -hydroxysteroid dehydrogenase (HSD)1 lowers intraocular pressure in subjects with ocular hypertension, and thus the compounds are useful for the treatment of glaucoma.

In view of the effects of 11 β -hydroxysteroid dehydrogenase (HSD)1 in modulating cortisol levels for interaction with the glucocorticoid receptor and the known effects of excess glucocorticoid in bone loss, this compound may have beneficial effects against osteoporosis.

Stress and/or glucocorticoids have been shown to affect cognitive function, and excess cortisol has been associated with loss or dysfunction of brain neurons. Treatment with 11 β -hydroxysteroid dehydrogenase (HSD)1 inhibitors may lead to improvement or prevention of cognitive impairment. Such compounds are also useful in the treatment of anxiety or depression.

The dynamic interaction between the immune system and the HPA (hypothalamic-pituitary-adrenal) axis is known, and glucocorticoids contribute to the balance between cell-mediated and humoral responses. In certain disease states (e.g. tuberculosis, leprosy, psoriasis etc.) the immune response is often biased towards a humoral response. More suitably will be a cell-based response. Inhibitors of 11 β -hydroxysteroid dehydrogenase (HSD)1 will potentiate the temporary immune response associated with immune action to ensure that a cell-based response is obtained and as such can be used for immunomodulation.

In particular, the compounds of the invention, including their physiologically acceptable salts, are suitable for the prevention or treatment of diabetes, especially type 1 and type 2 diabetes, and/or diabetic complications.

In other aspects of the invention, the invention relates to methods for the treatment or prevention of the diseases and conditions described above, which methods comprise administering an effective amount of a compound of formula I to a human.

The dosage required to achieve the corresponding activity for treatment or prevention will generally depend on the compound to be administered, the patient, the nature and severity of the disease or condition, and the method and frequency of administration, and is determined by the patient's physician. Conveniently, the dose may be from 1 to 100mg, preferably from 1 to 30mg (intravenous route), and from 1 to 1000mg, preferably from 1 to 100mg (oral route), in each case administered from 1 to 4 times daily.

The actual pharmaceutically effective amount or therapeutic dose will, of course, depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any event, the combination is administered in a dosage and manner that delivers a pharmaceutically effective amount, depending on the unique condition of the patient.

Formulations suitable for administration of the compounds of formula I will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, troches, lozenges, solutions, syrups, elixirs, sachets, injections, inhalants, powders and the like. The content of the pharmaceutically active compound should be 0.1 to 95 wt%, preferably 5.0 to 90 wt% of the total composition.

Suitable tablets may be obtained, for example, by mixing one or more compounds of formula I with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablet may also consist of several layers.

For this purpose, the compounds of the formula I prepared according to the invention can optionally be formulated together with other active substances, together with one or more customary inert carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, citric acid, tartaric acid, water, polyvinylpyrrolidone, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof.

The compounds of the invention can also be used in combination with other active substances, in particular for the treatment and/or prophylaxis of the diseases and disorders mentioned above. Other active substances suitable for such a combination include, for example, those which potentiate the therapeutic effect of the 11 β -hydroxysteroid dehydrogenase (HSD)1 antagonist of the invention for one of the mentioned indications and/or which reduce the dose of the 11 β -hydroxysteroid dehydrogenase (HSD)1 antagonist of the invention. Therapeutic agents suitable for such a combination include, for example, antidiabetic drugs such as metformin, sulfonylureas (e.g., glyburide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g., rosiglitazone, pioglitazone), SGLT 2 inhibitors (e.g., doparwell (dapagliflozin), remogliflozin etazin, sjogrezin, canagliflozin, 1-chloro-4- (β -D-glucopyranos-1-yl) -2- [4- (S) -tetrahydrofuran-3-yloxy ] -benzyl) -benzene), PPAR- γ -agonists (e.g., GI262570) and antagonists, PPAR- γ/α modulators (e.g., KRP 297), α -glucosidase inhibitors (e.g., acarbose, Voglibose), DPPIV inhibitors (e.g. sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin), α 2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin 4) or amylin. The list also includes inhibitors of protein tyrosine phosphatase (tyrosinephosphatase)1, substances affecting the production of intrahepatic deregulated glucose (e.g. inhibitors of glucose-6-phosphatase or fructose-1, 6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrogenase kinase and glucokinase activators, lipid lowering drugs such as e.g. HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-agonists, ACTA inhibitors (e.g. rubia) or cholesterol absorption inhibitors (e.g. such as ezetimibe), bile acid-binding substances (e.g., such as cholestyramine), ileal bile acid transport inhibitors, HDL raising compounds (such as CETP inhibitors or ABC 1 modulators), or obesity treating active substances such as sibutramine (sibutramine) or tetrahydrolipstatin (SDRIs), axokine, leptin (leptin), leptin mimetics (leptin mimetics), cannabinoid 1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or beta 3-agonists (such as SB-418790 or AD-9677) and 5HT2c receptor agonists.

Furthermore, combinations with drugs for influencing hypertension, chronic heart failure or atherosclerosis, such as a-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β -blockers, Ca-antagonists, centrally acting antihypertensive agents, α -2-adrenoceptor antagonists, neutral endopeptidase inhibitors, platelet aggregation inhibitors and other drugs or combinations thereof are suitable. Examples of angiotensin II receptor antagonists are candesartan cilexetil, losartan potassium, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, and the like. Vasopressin II receptor antagonists are preferably used for the treatment or prevention of hypertension and diabetic complications, and are usually combined with diuretics (e.g. hydrochlorothiazide).

Combinations with uric acid synthesis inhibitors or uricosuric agents are suitable for the treatment or prevention of gout.

In combination with a GABA receptor antagonist, a Na channel blocker, topiramate, a protein kinase C inhibitor, an advanced glycation end product (advanced glycation end product) inhibitor or an aldose reductase inhibitor, may be used for treating or preventing diabetic complications.

The dosage of the above mentioned combination partner is effectively 1/5 of the lowest generally recommended dose up to 1/1 of the generally recommended dose.

Thus, in a further aspect, the present invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound in combination with at least one of the above-mentioned active substances as combination partner for the preparation of a pharmaceutical composition suitable for the treatment or prevention of a disease or condition which can be affected by the inhibition of 11 β -hydroxysteroid dehydrogenase (HSD) 1. These diseases are preferably metabolic diseases, in particular one of the diseases or disorders listed above, most particularly diabetes or diabetic complications.

The combined use of a compound of the invention or a physiologically acceptable salt thereof and another active substance can be carried out simultaneously or at intervals, but in particular within short time intervals. If they are administered simultaneously, the two active substances are administered to the patient together; whereas if they are used in time staggered, the two active substances are administered to the patient in a time less than or equal to 12 hours, in particular less than or equal to 6 hours.

Thus, in a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of the invention or a physiologically acceptable salt of such a compound and, as combination partner, at least one of the active substances mentioned above, optionally together with one or more inert carriers and/or diluents.

Thus, for example, the pharmaceutical compositions of the present invention comprise a combination of a compound of formula I according to the present invention or a physiologically acceptable salt of such a compound and at least one angiotensin II receptor antagonist, optionally together with one or more inert carriers and/or diluents.

The compounds according to the invention or their physiologically acceptable salts, and the other active substances to be combined therewith, can be present together in one formulation, for example a tablet or capsule, or in two identical or different formulations, respectively, for example as a so-called kit-of-parts (kit-of-parts).

The following examples are intended to illustrate the invention but not to limit it:

analytical HPLC and TLC parameters for product identification

In the following, whenever benzimidazole with a hydrogen on one of the two nitrogens is part of the molecule, two tautomeric structures, 1H-benzimidazole and 3H-benzimidazole, are meant, although only one of them is explicitly named or drawn.

Intermediates 1 and 2:

cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Step 1: 5, 6-dihydro-benzo [ f ] quinolines

Propargylamine (5mL) was added to a solution containing a stir bar, 2-tetralone (10.00g), NaAuCl ₄*2H₂O (0.65g) and ethanol (50mL) (note: a vigorous exothermic reaction may occur later → an ice bath was maintained at hand). The resulting mixture was stirred at room temperature for 15 minutes and then at reflux temperature for 1 hour. After cooling the mixture to room temperature, the solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 60: 40) to give the title compound as an oil. Yield: 6.78g (56% of theory); LC (method 1): t is t_R1.81 min; mass spectrometry (ESI)⁺)：m/z＝182[M+H]⁺. Alternatively, the reaction may be carried out in a microwave oven heated to 100 ℃ by microwave irradiation for 10 minutes.

Step 2: cis-and trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinolines

5, 6-dihydro-benzo [ f)]Quinoline (8.78g), PtO₂(1.00g) and acetic acid were shaken under a hydrogen atmosphere (10 bar) at room temperature for 24 hours (if the conversion was not complete after this time, another portion of PtO was added₂(0.20g) and shaking under hydrogen was continued until conversion was complete). The catalyst was isolated by filtration and the solvent was evaporated. The residue was dissolved in 2M aqueous NaOH and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO)₄) And concentrating. The residue was chromatographed on silica gel (dichloromethane/methanol containing 1% NH) ₃95: 5 → 80: 20) to give two separate title compounds. Cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline: yield: 6.30g (69% of theory); LC (method 1): t is t_R1.85 minutes; mass spectrometry (ESI)⁺)：m/z＝188[M+H]⁺； ¹H NMR(400MHz，DMSO-d₆)1.30-1.45(m, 2H), 1.57-1.66(m, 1H), 1.66-1.76(m, 1H), 1.84-1.97(m, 1H), 1.99-2.10(m, 1H), 2.59-2.79(m, 4H), 2.83-2.92(m, 1H), 3.03-3.10(m, 1H), 3.27 (width s, 1H and water), 7.00-7.11(m, 3H), 7.15-7.19(m, 1H).

Or, cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinolines can be initiated in the synthesis described in J.Heterocyclic chem.1996, 33, 983-5 by using H₂(3 bar) and 10% palladium on carbon5% acetic acid in methanol.

Trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline: yield: 0.41g (5% of theory); mass spectrometry (ESI)⁺)：m/z＝188[M+H]⁺；¹H NMR(400MHz，DMSO-d₆)1.20-1.33(m, 1H), 1.67-1.89(m, 3H), 1.98-2.07(m, 1H), about 2.47-2.55(2H, m) superimposed in DMSO-d₅Signals, 2.59-2.68(m, 1H), 2.70-2.80(m, 2H), 2.82-2.90(m, 2H), 3.12-3.20(m, 1H), 7.05-7.18(m, 3H), 7.25-7.31(m, 1H).

Alternatively, trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline is available as described in j.heterocyclic Chem.

Alternatively, the 5, 6-dihydro-benzo [ f ] quinoline may be obtained as follows:

and step 3: 3-bromo-2-phenylethyl-pyridine

Tetrakis (triphenylphosphine) palladium (0) (2.0g) was added to a flask equipped with a stir bar, phenethyl zinc bromide (0.5mol/L in tetrahydrofuran, 100mL), 2, 3-dibromopyridine (10.50g), and tetrahydrofuran (100mL) and kept under an argon atmosphere at room temperature. The resulting mixture was stirred at room temperature for 3 hours and at 40 ℃ for a further 16 hours. After cooling to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90: 10 → 75: 25) to give the title compound as an oil which solidifies on treatment with ether. Yield: 9.32g (81% of theory); LC (method 1): t is t_R4.28 min; mass spectrometry (ESI)⁺)：m/z＝262/264(Br)[M+H]⁺。

And 4, step 4: 5, 6-dihydro-benzo [ f ] quinolines

N, N-Dimethylacetamide (15mL) was added to freshly dried K, 3-bromo-2-phenylethyl-pyridine (3.34g), equipped with a stir bar₂CO₃(3.52g), palladium (II) acetate (0.14g) and tricyclohexyltetrafluoroboric acid phosphine (0.47g) were placed in a flask and kept under an argon atmosphere at room temperature. The flask was placed in a 150 ℃ hot oil bath and the mixture was mixedThe contents were stirred therein for 2 hours. After cooling the mixture to room temperature, the solvent was evaporated and the residue was chromatographed twice on silica gel (1, dichloromethane/methanol 98: 2; 2, cyclohexane/ethyl acetate 90: 10 → 50: 50) to give the title compound as an oil. Yield: 1.51g (65% of theory); LC (method 1): t is t _R1.83 minutes; mass spectrometry (ESI)⁺)：m/z＝182[M+H]⁺。

Intermediates 3 and 4

Cis-7-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-7-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was obtained following a route analogous to that described for intermediates 1 and 2, step 1 and step 2, using 5-methoxy-2-tetralone and propargylamine in step 1 and 7-methoxy-5, 6-dihydro-benzo [ f ] quinoline in step 2.

Step 1: 7-methoxy-5, 6-dihydro-benzo [ f)]Quinoline; yield: 55% of theory; mass spectrometry (ESI)⁺)：(ESI⁺)：m/z＝212[M+H]⁺。

Step 2: cis-7-methoxy-1, 2, 3, 4, 4a, 5, 610 b-octahydro-benzo [ f]Quinoline; yield: 54% of theory; LC (method 1): t is t_R2.02 minutes; mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Trans-7-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 20% of theory; mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Intermediates 5 and 6

Cis-10-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-10-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was obtained following a route analogous to that described for intermediates 1 and 2, step 1 and step 2, using 8-methoxy-2-tetralone and propargylamine in step 1 and 10-methoxy-5, 6-dihydro-benzo [ f ] quinoline in step 2.

Step 1: 10-methoxy-5, 6-dihydro-benzo [ f)]Quinoline; yield: 54% of theory; LC (method 1): t is t_R2.02 minutes; mass spectrometry (ESI)⁺)：m/z＝212[M+H]⁺。

Step 2: cis-10-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 50% of theory; mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Trans-10-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 11% of theory; mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Intermediates 7 and 8

Cis-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was obtained following a similar route as described for intermediates 1 and 2 in step 1 and step 2.

Step 1: 10 b-methyl-3, 5, 6, 10 b-tetrahydro-benzo [ f ] quinoline

Propargylamine (0.21mL) was added to a stirred rod, 1-methyl-2-tetralone (0.50mL), NaAuCl₄*2H₂A microwavable container of O (27mg) and ethanol (3mL) was used (note: a vigorous exothermic reaction could then occur → keeping an ice bath at hand). The resulting mixture was subjected to microwave irradiation at 100 ℃ for 10 minutes. After cooling the mixture to room temperature, the solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 25: 75 → 0: 100) to give the title compound as an oil. Yield: 0.29g (50% of theory); LC (method 1): t is t _R1.78 minutes; mass spectrometry (ESI)⁺)：m/z＝198[M+H]⁺。

Step 2: cis-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

10 b-methyl-3, 5, 6, 10 b-tetrahydro-benzo [ f]A mixture of quinoline (8.78g), 10% Pd on carbon (1.00g), acetic acid (0.3mL) and methanol (10mL) was shaken under a hydrogen atmosphere (3 bar) at room temperature for 14 h. The catalyst was isolated by filtration and the solvent was evaporated. The residue was semi-concentrated in Na₂CO₃The aqueous solution was taken up and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO)₄) Concentration then gave the two title compounds as an approximately 3: 1 mixture (cis/trans). Yield: 0.24g (86% of theory); LC (method 1): t is t_R1.92 min (trans-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f)]Quinoline) and t_R2.02 min (cis-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f)]Quinoline); mass spectrometry (ESI)⁺)：m/z＝202[M+H]⁺。

Intermediates 9 and 10

Cis-9-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-9-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was obtained following a route analogous to that described in step 1 and step 2 of intermediates 1 and 2, using 7-methoxy-2-tetralone and propargylamine in step 1 and 9-methoxy-5, 6-dihydro-benzo [ f ] quinoline in step 2.

Step 1: 9-methoxy-5, 6-dihydro-benzo [ f)]Quinoline; yield: 58% of theory; LC (method 1): t is t_R1.99 min; mass spectrometry (ESI)⁺)：m/z＝212[M+H]⁺。

Step 2: cis-9-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 19% of theory; mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Trans-9-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 22% of theory; mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Intermediates 11 and 12

Cis-7, 9-difluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-7, 9-difluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was obtained following a route analogous to that described for intermediates 1 and 2 in step 1 and step 2, using 5, 7-difluoro-2-tetralone and propargylamine in step 1 and 7, 9-difluoro-5, 6-dihydro-benzo [ f ] quinoline in step 2.

Step 1: 7, 9-difluoro-5, 6-dihydro-benzo [ f)]Quinoline; yield: 53% of theory; LC (method 1): t is t_R2.54 minutes; mass spectrometry (ESI)⁺)：m/z＝224[M+H]⁺。

Step 2: cis-7, 9-difluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ ]]Quinoline; yield: 38% of theory; TLC: r is_f0.37 (silica gel, CH) ₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Trans-7, 9-difluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 26% of theory; TLC: r is_f0.37 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝224[M+H]⁺。

Intermediates 13 and 14

Cis-8-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-8-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was obtained following a route analogous to that described for intermediates 1 and 2 in step 1 and step 2, using 6-methoxy-2-tetralone and propargylamine in step 1 and 8-methoxy-5, 6-dihydro-benzo [ f ] quinoline in step 2.

Step 1: 8-methoxy-5, 6-dihydro-benzo [ f)]Quinoline; yield: 14% of theory; LC (method 1): t is t_R1.95 minutes; mass spectrometry (ESI)⁺)：m/z＝212[M+H]⁺。

Step 2: cis-8-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 52% of theory; TLC: r is_f0.22 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Trans-8-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 21% of theory; TLC: r is _f0.28 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Intermediates 15 and 16

Cis-10-fluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-10-fluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was obtained following a route analogous to that described for intermediates 1 and 2, step 1 and step 2, using 8-fluoro-2-tetralone and propargylamine in step 1 and 10-fluoro-5, 6-dihydro-benzo [ f ] quinoline in step 2.

Step 1: 10-fluoro-5, 6-dihydro-benzo [ f)]Quinoline; yield: 55% of theory; mass spectrometry (ESI)⁺)：m/z＝200[M+H]⁺。

Step 2: cis-10-fluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 63% of theory; TLC: r is_f0.38 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝206[M+H]⁺。

Trans-10-fluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline; yield: 13% of theory; TLC: r is_f0.46 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝206[M+H]⁺。

Intermediates 17 and 18

Cis-8-phenyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-8-phenyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Step 1: 8-bromo-5, 6-dihydro-benzo [ f ] quinolines

The title compound was prepared from 6-bromo-2-tetralone and propargylamine following a procedure analogous to that described in step 1 for intermediates 1 and 2. Yield: 69% of theory; mass spectrometry (ESI)⁺)：m/z＝260/262(Br)[M+H]⁺。

Step 2: 8-phenyl-5, 6-dihydro-benzo [ f ] quinolines

Equipped with a stirring rod, 8-bromo-5, 6-dihydro-benzo [ f]Quinoline (0.28g), phenylboronic acid (0.24g), 2M Na₂CO₃A flask of aqueous solution (1.1mL) and N, N-dimethylformamide (3mL) was purged with argon at room temperature for 10 minutes. Then [1, 1' -bis (diphenylphosphino) -ferrocene ] is added]Palladium dichloride dichloromethane complex (30mg) and the resulting mixture was heated to 90 ℃ and stirred at this temperature for 4 hours. After the mixture was cooled to room temperature, ethyl acetate and water were added and the mixture was filtered through celite. The organic phase of the filtrate was separated and washed with brine and dried (Na)₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 1: 1) to give the title compound as a solid. Yield: 0.24g (purity about 80%); LC (method 1): t is t_R3.16 minutes; mass spectrometry (ESI)⁺)：m/z＝258[M+H]⁺。

And step 3: cis-8-phenyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and trans-8-phenyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was prepared from 8-phenyl-5, 6-dihydro-benzo [ f ] quinoline according to the procedure described in analogy to step 2 of intermediates 1 and 2.

Cis-8-phenyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline: yield: 56% of theory; mass spectrometry (ESI)⁺)：m/z＝206[M+H]⁺。

Trans-8-phenyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline: yield: 11% of theory; mass spectrometry (ESI)⁺)：m/z＝206[M+H]⁺。

Intermediates 19 and 20

Cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxylic acid methyl ester and trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxylic acid methyl ester

Step 1: 5, 6-dihydro-benzo [ f ] quinoline-8-carboxylic acid methyl ester

To the mixture of 8-bromo-5, 6-dihydro-benzo [ f]Quinoline (4.00g), triethylamine (3.0mL), [1, 1' -bis (diphenylphosphino) ferrocene]A flask of dichloropalladium dichloromethane complex (0.63g), N-dimethylformamide (5mL) and methanol (20mL) was purged with argon for 5 minutes and then with carbon monoxide for 5 minutes. The mixture was then heated to 80 ℃ in a carbon monoxide atmosphere (4 bar) and shaken at this temperature overnight. After cooling to room temperature, the mixture was filtered under reduced pressure and concentrated. The residue was dissolved in ethyl acetate and washed with water and brine and dried (Na) ₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 1: 1 → 0: 1) to give the title compound as a solid. Yield: 3.16 g (86% of theory); LC (method 1): t is t_R2.18 minutes; mass spectrometry (ESI)⁺)：m/z＝240[M+H]⁺。

Step 2: cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxylic acid methyl ester and trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxylic acid methyl ester

The title compound was prepared from methyl 5, 6-dihydro-benzo [ f ] quinoline-8-carboxylate following a procedure analogous to that described for intermediates 1 and 2, step 2.

Cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline-8-carboxylic acid methyl ester: yield: 79% of theory; LC (method 1): t is t_R1.93 minutes; mass spectrometry (ESI)⁺)：m/z＝246[M+H]⁺。

Trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline-8-carboxylic acid methyl ester: yield: 10% of theory; mass spectrometry (ESI)⁺)：m/z＝246[M+H]⁺。

Intermediates 21 and 22

Cis-8-benzyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and cis-8-cyclohexylmethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Step 1: 8-benzyl-5, 6-dihydro-benzo [ f ] quinolines

Benzylzinc bromide (0.5mol/L in tetrahydrofuran, 7.7mL) was added to a flask equipped with a stir bar, tetrakis (triphenylphosphine) palladium (0) (53mg), and 8-bromo-5, 6-dihydro-benzo [ f/] ]Quinoline (0.20g) in a flask and kept under argon atmosphere at room temperature. The resulting solution was heated to reflux temperature and stirred at that temperature for 6 hours. After cooling the solution to room temperature, NH was added₄Aqueous Cl and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (Na)₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 4: 1 → 1: 1) to give the title compound as an oil. Yield: 0.17g (81% of theory); LC (method 1): t is t_R3.08 min; mass spectrometry (ESI)⁺)：m/z＝272[M+H]⁺。

Step 2: cis-8-benzyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline and cis-8-cyclohexylmethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was prepared from 8-benzyl-5, 6-dihydro-benzo [ f ] quinoline following a procedure similar to that described in step 2 for intermediates 1 and 2 and yielded an approximately 30: 70 mixture which was used in the next reaction step. Yield: 81% of theory (about 30: 70 mixture).

Cis-8-benzyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline: LC-MS (method 1): t is t_R2.91 min; mass spectrometry (ESI)⁺)：m/z＝278[M+H]⁺。

Cis-8-cyclohexyl-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]Quinoline: LC-MS (method 1): t is t_R3.41 minutes; mass spectrometry (ESI)⁺)：m/z＝284[M+H]^+。。

Intermediate 23

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-10-carboxylic acid methyl ester

Step 1: 10-bromo-5, 6-dihydro-benzo [ f ] quinolines

The title compound was prepared from 8-bromo-2-tetralone and propargylamine following a procedure analogous to that described in step 1 for intermediates 1 and 2. Yield: 49% of theory; LC (method 1): t is t_R2.68 minutes; mass spectrometry (ESI)⁺)：m/z＝260/262(Br)[M+H]⁺。

Step 2: 5, 6-dihydro-benzo [ f ] quinoline-10-carboxylic acid methyl ester

The title compound according toStep 1 of intermediates 19 and 20-like the procedure described for the preparation of 10-bromo-5, 6-dihydro-benzo [ f]Quinoline. Yield: 84% of theoretical; LC (method 1): t is t_R1.95 minutes; mass spectrometry (ESI)⁺)：m/z＝240[M+H]⁺。

And step 3: cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-10-carboxylic acid methyl ester

The title compound was synthesized from 5, 6-dihydro-benzo [ f ] according to the procedure described in step 2 analogous to intermediates 1 and 2]Quinoline-10-carboxylic acid methyl ester. Yield: 52% of theory; LC (method 1): t is t_R2.07 min; mass spectrometry (ESI)⁺)：m/z＝246[M+H]⁺。

And 4, step 4: cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-10-carboxylic acid methyl ester

The title compound is prepared in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline-10-carboxylic acid methyl ester. Yield: 43% of theory; TLC: r is_f0.30 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrum (ESI +): 390[ M + H ] M/z]⁺。

Intermediate 24

Cis-10- (4-methoxy-benzyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Step 1: 10- (4-methoxy-benzyl) -5, 6-dihydro-benzo [ f ] quinoline

The title compound was synthesized from 4-methoxybenzylzinc chloride and 10-bromo-5, 6-dihydro-benzo [ f ] according to the procedure described in analogy to intermediate 21 and 22, step 1]Quinoline. Yield: 85% of theory; LC (method 1): LC (method)1)：t_R3.09 minutes; mass spectrometry (ESI)⁺)：m/z＝302[M+H]⁺。

Step 2: cis-10- (4-methoxy-benzyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was synthesized from 10- (4-methoxy-benzyl) -5, 6-dihydro-benzo [ f ] according to a procedure analogous to that described for intermediates 1 and 2, step 2]Quinoline. Yield: 12% of theory; LC-MS (method 1): t is t_R2.82 minutes; mass spectrometry (ESI)⁺)：m/z＝308[M+H]⁺。

Intermediate 25

Cis-6, 6-dimethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Step 1: 6, 6-dimethyl-5, 6-dihydro-benzo [ f ] quinolines

The title compound was prepared from 4, 4-dimethyl-3, 4-dihydro-1H-naphthalen-2-one and propargylamine following a procedure analogous to that described in step 1 for intermediates 1 and 2. Yield: 49% of theory; LC (method 1): t is t_R2.40 minutes; mass spectrometry (ESI)⁺)：m/z＝210[M+H]⁺。

Step 2: cis-6, 6-dimethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was synthesized from 6, 6-dimethyl-5, 6-dihydro-benzo [ f ] according to a procedure analogous to that described for intermediates 1 and 2, step 2]Quinoline. Yield: 72% of theory; LC-MS (method 1): t is t_R2.38 minutes; mass spectrometry (ESI)⁺)：m/z＝216[M+H]⁺。

Intermediate 26

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-10-carboxylic acid

The title compound was synthesized in analogy to the procedure described in example 35 (except the solution was stirred at 50 ℃) from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline-10-carboxylic acid methyl ester. Yield: 69% of theory; mass spectrometry (ESI)⁺)：m/z＝376[M+H]⁺。

Intermediate 27

Cis-8- (4-methoxy-phenoxy) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Step 1: cis-2, 2, 2-trifluoro-1- (8-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -ethanone

Trifluoroacetic anhydride (0.75mL) was added to cis-8-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ -f ]]Quinoline (0.79g) and triethylamine (0.90mL) in dichloromethane (10mL) (cooled in an ice bath). The cooling bath was removed and the solution was stirred at room temperature overnight. Then water and dichloromethane were added and stirring was continued for another 30 minutes. The organic phase is separated and washed with NaHCO₃The aqueous solution was washed and dried (Na)₂SO₄). The solvent was evaporated to obtain the title compound as a solid. Yield: 100% of theory; LC (method 1): t is t_R4.38 minutes; mass spectrometry (ESI)⁺)：m/z＝3.14[M+H]⁺。

Step 2: cis-2, 2, 2-trifluoro-1- (8-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -ethanone

The title compound was synthesized from cis-2, 2, 2-trifluoro-1- (8-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] according to an analogous procedure as described in example 7]Quinolin-4-yl) -ethanone. Yield: 93% of theory; LC (method 1): t is t_R3.58 minutes; mass spectrometry (ESI)⁺)：m/z＝300[M+H]⁺。

And step 3: cis-2, 2, 2-trifluoro-1- [8- (4-methoxy-phenoxy) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -ethanone

Reacting cis-2, 2, 2-trifluoro-1- (8-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f [ ] ]Quinolin-4-yl) -ethanone (0.98g), 4-methoxyphenylboronic acid (1.00g), pyridine (1.30mL), copper (II) acetate (0.60g), molecular sievesA mixture of (3.60g) and dichloromethane (15mL) was stirred at room temperature in air overnight. The mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and the residue was chromatographed on silica gel (dichloromethane/methanol with 1% NH)₃99: 1 → 95: 5) to give the title compound as a colorless resin-like solid. Yield: 1.05g (79% of theory); LC (method 1): t is t_R5.00 min; mass spectrometry (ESI)⁺)：m/z＝406[M+H]⁺。

And 4, step 4: cis-8- (4-methoxy-phenoxy) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

1M aqueous NaOH solution (10mL) was added to cis-2, 2, 2-trifluoro-1- [8- (4-methoxy-phenoxy) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] at room temperature]Quinolin-4-yl]-ethanone (0.95g) in tetrahydrofuran (10 mL). The resulting solution was stirred at 35 ℃ overnight and then cooled to room temperature. The solution was extracted with ethyl acetate and the combined extracts were washed with brine and dried (Na)₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel (dichloromethane/methanol with 1% NH)₃95: 5 → 70: 30) to give the title compound as a colorless resin-like solid. Yield of the product : 0.64g (88% of theory); LC (method 1): t is t_R2.75 minutes; mass spectrometry (ESI)⁺)：m/z＝310[M+H]⁺。

Intermediates 28 and 29

Cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinolin-9-ylamine and trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinolin-9-ylamine

Step 1: 9-nitro-5, 6-dihydro-benzo [ f ] quinolines

The title compound was prepared from 7-nitro-2-tetralone and propargylamine following a procedure analogous to that described in step 1 for intermediates 1 and 2. Yield: 41% of theory; LC (method 1): t is t_R2.20 minutes; mass spectrometry (ESI)⁺)：m/z＝227[M+H]⁺。

Step 2: 9-amino-5, 6-dihydro-benzo [ f ] quinolines

Reacting 9-nitro-5, 6-dihydro-benzo [ f)]A mixture of quinoline (1.90g), 10% palladium on carbon (0.20g) and methanol (10mL) was shaken under a hydrogen atmosphere at room temperature for 3 hours. The catalyst was then isolated by filtration and the filtrate was concentrated to give an oil which was subjected to the next reaction without further purification. Yield: 1.67g (crude); mass spectrometry (ESI)⁺)：m/z＝197[M+H]⁺。

And step 3: cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinolin-9-ylamine and trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinolin-9-ylamine

The title compound was prepared from 9-amino-5, 6-dihydro-benzo [ f ] quinoline following a procedure analogous to that described for intermediate 1 and 2, step 2.

Cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinolin-9-ylamine: yield: theory of things40% of theoretical value; LC (method 2): t is t_R2.50 minutes; mass spectrometry (ESI)⁺)：m/z＝203[M+H]⁺。

Trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinolin-9-ylamine: yield: 24% of theory; LC (method 2): t is t_R2.70 minutes; mass spectrometry (ESI)⁺)：m/z＝203[M+H]⁺。

Intermediate 30

Cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-9-carbonitrile

Sodium nitrite (0.12g) dissolved in water (0.7mL) was added dropwise to cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] cooled to about-5 deg.C]Solution of quinolin-9-ylamine (0.36g) in semi-concentrated sulfuric acid (0.6 ml). The solution was stirred in the cooling bath for 15 minutes before urea (30mg) was added. The resulting solution was added to a vigorously stirred solution of sodium cyanide (0.32g) and copper (I) cyanide (0.19g) in water (1.4 ml) cooled to about-5 ℃. The mixture was stirred in the cooling bath for another 10 minutes and then removed from the cooling bath. After stirring at room temperature for 10 minutes, the mixture was heated to 70 ℃ and stirred at this temperature for 1 hour. The mixture was cooled to room temperature, basified with 4M NaOH solution (1.5mL) and extracted with dichloromethane. The combined extracts were dried (Na) ₂SO₄) And the solvent was evaporated. The residue was chromatographed on silica gel [ dichloromethane/(dichloromethane/methanol/NH)₄OH 50∶48∶2)80∶20→40∶60]The title compound was obtained as a resin-like solid. Yield: 0.12g (31% of theory); mass spectrometry (ESI)⁺)：m/z＝213[M+H]⁺。

Intermediate 31

Trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-9-carbonitrile

The title compound is synthesized in analogy to the procedure described for intermediate 30 from trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinolin-9-ylamine. Yield: 22% of theory; LC (method 1): t is t_R1.64 minutes; mass spectrometry (ESI)⁺)：m/z＝213[M+H]⁺。

Intermediate 32

Cis-10- (6-methyl-pyridazin-3-yloxy) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Step 1: 5, 6-dihydro-benzo [ f ] quinolin-10-ols

The title compound was synthesized from 10-methoxy-5, 6-dihydro-benzo [ f ] according to an analogous procedure as described in example 7]Quinoline. Yield: 94% of theory; LC (method 1): t is t_R1.48 minutes; mass spectrometry (ESI)⁺)：m/z＝198[M+H]⁺。

Step 2: cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinolin-10-ol

The title compound was synthesized from 5, 6-dihydro-benzo [ f ] according to a procedure analogous to that described for intermediate 1 and 2, step 2]Quinoline-10-ol. Yield: 60% of theory; LC (method 2): t is t _R2.71 minutes; mass spectrometry (ESI)⁺)：m/z＝204[M+H]⁺。

And step 3: cis-10-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (0.69g) is added at room temperature to the mixture of cis-1, 2, 3, 4,4a, 5, 6, 10 b-octahydro-benzo [ f]Solution of quinolin-10-ol (0.64g) and triethylamine (0.5mL) in dichloromethane (25 mL). The solution was stirred at room temperature overnight and then diluted with dichloromethane. The resulting solution was washed with 2M aqueous citric acid and brine, dried (Na)₂SO₄) And concentrated. The residue was treated with a small amount of methanol and the precipitate formed thereafter was isolated by filtration and dried to give the title compound as a colorless solid. Yield: 0.35g (37% of theory); LC (method 1): t is t_R4.20 minutes; mass spectrometry (ESI)⁺)：m/z＝304[M+H]⁺。

And 4, step 4: cis-10- (6-methyl-pyridazin-3-yloxy) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carboxylic acid tert-butyl ester

Cis-10-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f]A mixture of tert-butyl quinoline-4-carboxylate (0.40g), 3-chloro-6-methyl-pyridazine (0.13g), cesium carbonate (0.35g) and N-methylpyrrolidone (5mL) was stirred at 150 ℃ for 1.5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine and dried (Na) ₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 3: 1 → 1: 2) to give the title compound. Yield: 0.14 g (impure); LC (method 1): t is t_R4.19 minutes; mass spectrometry (ESI)⁺)：m/z＝396[M+H]⁺。

And 5: cis-10- (6-methyl-pyridazin-3-yloxy) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Hydrochloric acid (4mol/L in 1, 4-dioxane, 0.7mL) was added to cis-10- (6-methyl-pyridazin-3-yloxy) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] n at room temperature]Quinoline-4-carboxylic acid tert-butyl ester (0.13g) in dichloromethane (5 mL). The solution was stirred at room temperature for 2 hours and then concentrated to give the crude title compound as its hydrochloride salt, which was used without further purification. Yield: 0.12g (crude); LC (method 1): t is t_R1.90 minutes; mass spectrometry (ESI)⁺)：m/z＝296[M+H]⁺。

Intermediate 33

Cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Step 1: 1, 3, 4, 9-tetrahydro-indeno [2, 1-b ] pyridin-2-one

A mixture of 1- (1H-inden-2-yl) -pyrrolidine (5.34g) and acrylamide (6.15g) was stirred at 100 ℃ for 30 minutes under argon. The temperature was then raised to 130 ℃ and stirring continued for 15 minutes. After cooling to room temperature, water (50mL) and acetic acid (5 drops) were added and the mixture was stirred for 30 minutes. The mixture was filtered and the organic phase of the filtrate was separated and washed with brine. By drying (MgSO) ₄) And after evaporation of the solvent, the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 1: 1 → 0: 1) to give a brown solid, which was triturated with ethyl acetate and dried to give the title compound. Yield: 1.12g (21% of theory); mass spectrometry (ESI)⁺)：m/z＝186[M+H]⁺。

Step 2: cis-1, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-2-one

Reacting 1, 3, 4, 9-tetrahydro-indeno [2, 1-b ]]A mixture of pyridin-2-one (1.10g), 10% palladium on carbon (0.15g), acetic acid (0.75mL) and methanol (20mL) was shaken under a hydrogen atmosphere (3 bar) at room temperature for 6 hours. The catalyst was then separated by filtration and the filtrate was concentrated. The residue was triturated with tert-butyl methyl ether and dried to give the title compound as a colorless solid. Yield: 0.99g (89% of theory); LC (method 1): t is t_R2.53 min; mass spectrometry (ESI)⁺)：m/z＝188[M+H]⁺。

And step 3: cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Lithium aluminum hydride (1mol/L in tetrahydrofuran, 12mL) was added to cis-1, 3, 4, 4a at room temperature9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-2-one (0.95g) in tetrahydrofuran (15 mL). The resulting solution was heated to reflux temperature and stirred at that temperature for 2 hours. After cooling to room temperature, the solution was poured into ice-cold water, 1M aqueous NaOH and ethyl acetate were added, and the resulting mixture was filtered over celite. The aqueous phase of the filtrate was separated and extracted with ethyl acetate, and the extract was combined with the organic phase of the filtrate. The organic phase was washed with brine and dried (MgSO ₄). Evaporation of the solvent gave the title compound as a colorless solid. Yield: 0.83g (94% of theory); LC (method 1): t is t_R1.29 minutes; mass spectrometry (ESI)⁺)：m/z＝174[M+H]⁺。

Alternatively, intermediate 33 is obtained as follows:

and 4, step 4: 9H-indeno [2, 1-b ] pyridines

The title compound was prepared from 2-indanone and propargylamine following a procedure analogous to that described in step 1 for intermediates 1 and 2. Yield: 56% of theory; mass spectrometry (ESI)⁺)：m/z＝168[M+H]⁺。

And 5: cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

9H-indeno [2, 1-b ]]Pyridine (0.20g), PtO₂A mixture of (70mg), concentrated aqueous hydrochloric acid (0.1mL) and ethanol (10mL) was shaken under a hydrogen atmosphere at room temperature for 16 h (if the conversion was not complete after this time, another portion of PtO was added₂(30mg) and continued shaking under hydrogen until conversion was complete). The catalyst was isolated by filtration and the solvent was evaporated to give the crude title compound as its hydrochloride salt, which was used without further purification. Yield: 0.25 g (crude); mass spectrometry (ESI)⁺)：m/z＝174[M+H]⁺。

Intermediates 34 and 35

Cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carboxylic acid methyl ester and cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-7-carboxylic acid methyl ester

Step 1: 2, 2, 2-trifluoro-1- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-inden [2, 1-b ] pyridin-1-yl) -ethanone

The title compound is synthesized from cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] by a procedure analogous to that described in step 1 of intermediate 27]Pyridine. Yield: 76% of theoretical; mass spectrometry (ESI)⁺)：m/z＝270[M+H]⁺。

Step 2: cis-1- (6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -2, 2, 2-trifluoro-ethanone and cis-1- (7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -2, 2, 2-trifluoro-ethanone

Bromine (0.80mL) was added to 2, 2, 2-trifluoro-1- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] at room temperature]Pyridin-1-yl) -ethanone (4.00g) in a suspension of water (32 ml). The mixture was heated to 70 ℃ and stirred at this temperature for 4 hours. After cooling to room temperature, Na was added₂S₂O₃The aqueous solution was extracted with dichloromethane. The combined extracts were dried (Na)₂SO₄) And the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 1: 1) to give a mixture of the two title compounds and a small amount of the other monobrominated isomer. Yield: 3.40g (66% of theory); LC (method 1): t is t _R4.70 minutes; mass spectrometry (ESI)⁺)：m/z＝348/350(Br)[M+H]⁺。

And step 3: cis-6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine and cis-7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound was prepared from the compound mixture of step 2 above following a procedure analogous to that described for intermediate 27, step 4, and was used as the isomeric mixture for the next step. Yield: 69% of theory.

And 4, step 4: cis- (1H-benzimidazol-5-yl) - (6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone and cis- (1H-benzimidazol-5-yl) - (7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was prepared from the isomeric mixture of step 3 above by a procedure analogous to that described in example 1 and used in the next step as the isomeric mixture. Yield: 85% of theory (purity about 85%); mass spectrometry (ESI)⁺)：m/z＝396/398(Br)[M+H]⁺。

And 5: cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carboxylic acid methyl ester and cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-7-carboxylic acid methyl ester

The title compound was prepared from the isomeric mixture of step 4 above following a procedure analogous to that described for step 1 for intermediates 19 and 20 and was used in the next step as the isomeric mixture. Yield: 80% of theory (purity about 90%); mass spectrometry (ESI) ⁺)：m/z＝376[M+H]⁺。

Intermediates 36 and 37

(4a-R, 9a-S) -6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine and (4a-R, 9a-S) -7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound was prepared as described for intermediates 34 and 35, and the resulting isomeric mixture (2.2g) was subjected to SFC (column: DAICEL IC) on chiral phase250x20mm, 5 μm; mobile phase: methanol/sc carbon dioxide with 0.2% diethylamine 20: 80; flow rate: 70mL/min) to give pure (4a-R, 9a-S) -7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indene [2, 1-b ]]Pyridine [0.23 g; LC (chiral SFC as described): t is t_R16.27 min-]And (4a-R, 9a-S) -6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Mixture of pyridine with its enantiomer and another isomer, which was subjected to a second SFC on chiral phase (column: DAICEL ADH 250X20mm, 5 μm; mobile phase: isopropanol/sc carbon dioxide with 0.2% diethylamine 15: 85; flow rate: 70mL/min) to give pure (4a-R, 9a-S) -6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine [0.21 g; LC (second chiral SFC as described): t is t_R20.30 min]。

Intermediate body 38

(1H-benzimidazol-5-yl) - [ (4a-R, 9a-S) -6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and (4a-R, 9a-S) -6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 95% of theory; LC (method 1): t is t_R2.83 minutes; mass spectrometry (ESI)⁺)：m/z＝396/398(Br)[M+H]⁺。

Intermediate 39

(1H-benzimidazol-5-yl) - [ (4a-R, 9a-S) -7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

HeadlineingCompound was prepared from 1H-benzimidazole-5-carboxylic acid and (4a-R, 9a-S) -7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] according to an analogous procedure to that described in example 1]Pyridine. Yield: 94% of theory; LC (method 1): t is t_R2.88 minutes; mass spectrometry (ESI)⁺)：m/z＝396/398(Br)[M+H]⁺。

Intermediate 40

Trans-10 b-ethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

Step 1: 1-ethyl-2-tetralone

Iodothane (0.81mL) was added to a solution of 1- (3, 4-dihydro-naphthalen-2-yl) -pyrrolidine (2.05g) in acetonitrile (20 mL). The solution was heated to reflux temperature and stirred at this temperature for 4 hours. Another portion of iodoethane (0.3mL) was then added and stirring continued overnight. After cooling to room temperature, the solution was concentrated and treated with water and 2M aqueous citric acid. The resulting mixture was heated to 50 ℃ and stirred at this temperature for 15 minutes. After cooling to room temperature, the mixture was extracted with ethyl acetate and the combined extracts were extracted with NaHCO ₃The aqueous solution and brine were washed and dried (Na)₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 98: 2 → 80: 20) to give the title compound as an oil. Yield: 0.20g (11% of theory); mass spectrometry (ESI)⁺)：m/z＝175[M+H]⁺。

Step 2: 10 b-ethyl-3, 5, 6, 10 b-tetrahydro-benzo [ f ] quinoline

The title compound was prepared from propargylamine and 1-ethyl-2-tetralone following the following procedure analogous to step 1 of intermediates 7 and 8. Yield: 19% of theory; LC (method 1): t is t_R2.06 minutes; mass spectrometry (ESI)⁺)：m/z＝212[M+H]⁺。

And step 3: trans-10 b-ethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline

The title compound was synthesized from 10 b-ethyl-3, 5, 6, 10 b-tetrahydro-benzo [ f ] according to a procedure analogous to that described for intermediate 7 and 8, step 2]Quinoline. Yield: 67% of theory; TLC: r is_f0.45 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝216[M+H]⁺。

Intermediate 41

Cis-6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Step 1: 3- (3-methoxy-phenyl) -pyridine-2-carbonitrile

With stirring bar, 3-chloro-2-cyanopyridine (8.16g), 3-methoxyphenylboronic acid (13.42g), K₃PO₄A flask of (25.00g) and toluene (100mL) was purged with argon for 10 minutes. Palladium (II) acetate (0.13g) and n-butyl-bis- (1-adamantyl) -phosphine (0.42g) were added and the resulting mixture was placed in a 100 ℃ hot oil bath and stirred therein for 3.5 hours. After cooling to room temperature, ethyl acetate (250mL) was added and the mixture was washed with 2M aqueous NaOH and brine. The organic phase was dried (Na) ₂SO₄) And the solvent was evaporated. The residue was triturated with methanol and dried to give the title compound as a colorless solid. Yield: 12.05g (97% of theory); LC (method 1): t is t_R3.32 minutes; mass spectrometry (ESI)⁺)：m/z＝211[M+H]⁺。

Step 2: 3- (3-methoxy-phenyl) -pyridine-2-carboxylic acid

A mixture of 3- (3-methoxyphenyl) -pyridine-2-carbonitrile (12.00g), 15M aqueous NaOH (40mL), and methanol (60mL) was stirred at reflux temperature for 7 h. Cooling downAfter reaching room temperature, most of the methanol was evaporated and the residue was cooled in an ice bath and the pH was adjusted to about 4-5 by careful addition of concentrated hydrochloric acid. The resulting mixture was concentrated to about 50mL by evaporation and extracted several times with dichloromethane/methanol (9: 1). The aqueous phase is then adjusted to pH 2-3 using concentrated hydrochloric acid and extracted again with dichloromethane/methanol (9: 1). The combined extracts were dried (Na)₂SO₄) And the solvent was evaporated to give the title compound as a foamy solid. Yield: 11.88g (91% of theory); LC (method 1): t is t_R1.70 minutes; mass spectrometry (ESI)⁺)：m/z＝230[M+H]⁺。

And step 3: 3- (3-methoxy-phenyl) -pyridine-2-carbonyl chloride

Thionyl chloride (8mL) and N, N-dimethylformamide (several drops) were added to a solution of 3- (3-methoxy-phenyl) -pyridine-2-carboxylic acid (11.86g) in dichloromethane (80 mL). The mixture was heated to 40 ℃ and stirred at this temperature overnight. The solution was then concentrated and the residue taken up in toluene and concentrated again to give the crude title compound which was used in the next step without further purification. Yield: 12.80g (crude).

And 4, step 4: 6-methoxy-indeno [2, 1-b ] pyridin-9-one

Aluminum chloride (7.33g) was added to a solution of 3- (3-methoxy-phenyl) -pyridine-2-carbonyl chloride (crude, 5.40 g) in dichloromethane (100mL) cooled in an ice bath. The cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was then poured onto crushed ice and the resulting mixture was extracted with dichloromethane. With NaHCO₃The combined extracts were washed with aqueous solution and dried (Na)₂SO₄). The solvent was evaporated and the residue triturated with a mixture of cyclohexane and ethyl acetate (1: 1) and allowed to dry to give the title compound as a yellow solid. Yield: 3.00g (65% of theory); LC (method 1): t is t_R2.84 minutes; mass spectrometry (ESI)⁺)：m/z＝212[M+H]⁺。

And 5: cis-6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Reacting 6-methoxy-indeno [2, 1-b ]]A mixture of pyridin-9-one (2.00g), 10% palladium on carbon (0.30g), 4M aqueous hydrochloric acid (6mL), and methanol (100mL) was shaken under a hydrogen atmosphere (3 bar) at room temperature for 4 hours. Then adding PtO₂(0.20g) and shaken under a hydrogen atmosphere (1 bar) at room temperature for 36 hours. The catalyst was separated by filtration and the filtrate was concentrated. The residue was basified by addition of 2M aqueous NaOH and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (Na) ₂SO₄) And the solvent is allowed to evaporate. The residue was chromatographed on silica gel (dichloromethane/methanol with 1% NH)₃90: 10 → 75: 25) to give the title compound as a colorless oil. Yield: 1.00g (52% of theory); LC (method 1): t is t_R1.50 minutes; mass spectrometry (ESI)⁺)：m/z＝204[M+H]⁺。

Intermediate body 42

Trifluoromethanesulfonic acid cis-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl ester and trifluoromethanesulfonic acid cis-1- (3-trifluoromethanesulfonyl-3H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl ester

Trifluoromethanesulfonic anhydride (0.60mL) dissolved in dichloromethane (3mL) was added dropwise to (1H-benzimidazol-5-yl) - (cis-6-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] cooled to-10 deg.C]Pyridin-1-yl) -methanone (0.45g) and pyridine (0.40 mL) in dichloromethane (10 mL). The solution was stirred in a cooling bath for 1 hour and then diluted with dichloromethane. The solution is prepared from citric acid aqueous solution and NaHCO₃The aqueous solution was washed and dried (Na)₂SO₄). The solvent was evaporated to give the two title compounds as a mixture, which was used directly in the next step. Yield: 0.72g (of theory) 89%); LC (method 1): t is t_R4.75 minutes; mass spectrometry (ESI)⁺)：m/z＝598[M+H]⁺。

Intermediate 43

Cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-ylamine

Step 1: 7-Nitro-9H-indeno [2, 1-b ] pyridines

A cold mixture of nitric acid (65%, 1.1mL) and sulfuric acid (96%, 1.6mL) at about 10 ℃ was added dropwise to 9H-indeno [2, 1-b ]]Pyridine (2.44 g) in sulfuric acid (96%, 3mL) and in a solution cooled in an ice bath. The solution was stirred in the cooling bath for 1 hour and poured onto crushed ice. The precipitate formed was isolated by filtration and the filtrate was neutralized with 4M aqueous NaOH. The precipitate formed was separated by filtration and combined with the previously separated precipitate. The precipitate was triturated with acetone and dried to give the title compound as a solid. Yield: 2.64g (theoretical 85%); LC (method 1): t is t_R2.93 minutes; mass spectrometry (ESI)⁺)：m/z＝213[M+H]⁺。

Step 2: cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-ylamine

Reacting 7-nitro-9H-indeno [2, 1-b ]]A mixture of pyridine (3.25g), 10% palladium on carbon (0.35g) and methanol (50mL) was shaken under a hydrogen atmosphere (3 bar) at room temperature for 22 h. Then adding PtO₂(0.50g) and 4M aqueous hydrochloric acid (3.2mL) and shaking continued at room temperature under a hydrogen atmosphere (1 bar) for 22 h. The catalyst was isolated by filtration and the filtrate was concentrated to give the crude title compound as its hydrochloride salt, which was used without further purification or was converted to the free base via treatment with aqueous NaOH and extracted with ethyl acetate. Yield: 4.20 g (purity about 80%); LC (method 1): t is t _R0.52 min; mass spectrometry (ESI)⁺)：m/z＝189[M+H]⁺。

Intermediate 44

Cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-ol

Sodium nitrite (92mg) dissolved in water (0.5mL) was added dropwise to cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-7-ylamine dihydrochloride (0.30g) in semi-concentrated sulfuric acid (0.6mL) in a cooled solution in an ice bath. The solution was stirred in the cooling bath for 15 minutes before adding semi-concentrated sulfuric acid (5 mL). The resulting solution was heated to 120 ℃ and stirred at this temperature for 3 hours. The mixture was cooled to room temperature, diluted with water and basified with 4M NaOH. The resulting mixture was extracted with ethyl acetate and the combined extracts were dried (Na)₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel [ dichloromethane/(dichloromethane/methanol/NH)₄OH 50∶48∶2)80∶20→40∶60]To give the title compound. Yield: 0.07g (32% of theory); LC (method 1): t is t_R0.83 min; mass spectrometry (ESI)⁺)：m/z＝190[M+H]⁺。

Intermediate 45

Cis-4-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Step 1: 4-methyl-9H-indeno [2, 1-b ] pyridine

The title compound was prepared from inden-2-one and but-2-enamine following a procedure analogous to that described for step 1 of intermediates 1 and 2; the reaction was carried out in a microwave oven at 100 ℃ for 12 minutes. Yield: 22% of theory; LC (method 1): t is t_R1.98 minutes; mass spectrometry (ESI)⁺)：m/z＝182[M+H]⁺。

Step 2: 1-benzyl-4-methyl-9H-indeno [2, 1-b ] pyridinium bromide

4-methyl-9H-indeno [2, 1-b ]]A mixture of pyridine (0.64g) and benzyl bromide (0.42mL) in acetone (5mL) was stirred at reflux temperature for 4 hours. After cooling to room temperature, the precipitate was isolated by filtration, washed with a small amount of diethyl ether and dried to give the title compound as a pale brown solid. Yield: 0.93g (75% of theory); LC (method 1): t is t_R2.49 minutes; mass spectrometry (ESI)⁺)：m/z＝272[M-Br]⁺。

And step 3: 1-benzyl-4-methyl-2, 3, 9, 9 a-tetrahydro-1H-indeno [2, 1-b ] pyridine

Sodium borohydride (0.15g) was added to 1-benzyl-4-methyl-9H-indeno [2, 1-b ]]A suspension of pyridinium bromide (0.92g) in ethanol (10mL) and cooled in an ice bath. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour and at 60 ℃ for 2 hours. Sodium borohydride (0.18 g) was added and stirring was continued at reflux temperature for 4 hours. After addition of another portion of sodium borohydride (0.10g), the mixture was stirred at reflux temperature overnight. After cooling to room temperature, ice-cold water was added and the precipitate was isolated by filtration. The precipitate was dissolved in ether and the resulting solution was dried (Na) ₂SO₄) And the solvent was evaporated to give a crude product, which was used without further purification. Yield: 0.66 g (crude); mass spectrometry (ESI)⁺)：m/z＝276[M+H]⁺。

And 4, step 4: cis-4-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Reacting 1-benzyl-4-methyl-2, 3, 9, 9 a-tetrahydro-1H-indeno [2, 1-b ]]Pyridine (0.65g), Pd (OH)₂A mixture of (100mg) and ethanol (10mL) was shaken under a hydrogen atmosphere (5 bar) at room temperature for 16 h. Then another portion of Pd (OH) is added₂(100mg) and shaking was continued overnight under a hydrogen atmosphere (5 bar). Separating the catalyst by filtration and dissolvingThe solvent was evaporated to give the crude title compound, which was used without further purification. Yield: 0.43g (crude).

Intermediate 46

Cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

Step 1: 2, 2, 2-trifluoro-1- (cis-6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone

Trifluoroacetic anhydride (4.5mL) was added dropwise to cis-6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine (5.0g), triethylamine (5.6mL) and 4-dimethylaminopyridine (about 5 mol%) in dichloromethane (60 mL) and maintained below 10 ℃. The solution was stirred for 1 hour with cooling and for 2 hours at room temperature. With dichloromethane (100mL) and NaHCO ₃The aqueous diluted solution was then stirred vigorously for 15 minutes. The organic phase was separated, washed with 1M hydrochloric acid (25mL) and water (50mL), and dried (MgSO₄). The solvent was evaporated to give the title compound as an oil. Yield: 8.1g (quantitative); LC (method 1): t is t_R4.24 minutes; (ii) a Mass spectrometry (ESI)⁺)：m/z＝300 [M+H]⁺。

Step 2: 2, 2, 2-trifluoro-1- (cis-6-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone

Boron tribromide (1mol/L in heptane, 27 mL) was added to 2, 2, 2-trifluoro-1- (cis-6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] cooled in an ice bath]Pyridin-1-yl) -ethanone (8.1g) in dichloromethane (120 mL). The resulting mixture was warmed to room temperature overnight in a cooling bath. The solution was cooled again in an ice bath, diluted with dichloromethane (50mL) and 25% K was added carefully₂CO₃(20mL) aqueous solution (20 mL). Stirring and mixingThis was acidified for 30 min by addition of 4M aqueous hydrochloric acid (60 mL). The organic phase was separated, washed with 1M aqueous hydrochloric acid (40mL) and dried (MgSO)₄). The solvent was evaporated to give the title compound as a solid. Yield: 7.3g (95% of theory); LC (method 1): t is t_R3.43 minutes; mass spectrometry (ESI) ⁺)：m/z＝286[M+H]⁺。

And step 3: trifluoromethanesulfonic acid cis-1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl ester

Trifluoromethanesulfonic anhydride (5.6mL) was added dropwise to 2, 2, 2-trifluoro-1- (cis-6-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] cooled in an ice bath]Pyridin-1-yl) -ethanone (7.3g), triethylamine (7.2mL) and 4-dimethylaminopyridine (50mg) in dichloromethane (60 mL). The solution was stirred for 1 hour with cooling and for 2 hours at room temperature. Water (100mL) and dichloromethane (100mL) were then added and the organic phase was separated. The organic phase was washed with water (50mL) and dried (MgSO)₄) And concentrated to give the title compound as a black oil. Yield: 10.7g (quantitative); TLC: r is_f0.50 (silica gel, cyclohexane/ethyl acetate 3: 1); mass spectrometry (ESI)⁺)：m/z＝418[M+H]⁺。

And 4, step 4: cis-1- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

With stirring bar, zinc cyanide (5.0g), trifluoromethanesulfonic acid cis-1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]A flask of pyridin-6-yl ester (10.7g) and N, N-dimethylformamide (60mL) was purged with argon for 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (4.0g) was then added and the resulting mixture was stirred at 100 ℃ for 2 h. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO) ₄) And concentrated. Chromatography of the residue on silica gel (ethyl acetate/cyclohexane 1: 9 → 4: 1) gave the title compound as a solid. Yield: 5.5g (73% of theory)；TLC：r_f0.25 (silica gel, cyclohexane/ethyl acetate 3: 1); mass spectrometry (ESI)⁺)：m/z＝295[M+H]⁺。

And 5: cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

Stirring cis-1- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] at room temperature]Pyridine-6-carbonitrile (5.50g) and a 4M NaOH solution (5.6mL) in methanol (30mL) for 2 hours. Brine (150mL) was then added and the resulting mixture was extracted with ethyl acetate (3 × 75 mL). The combined extracts were dried (MgSO)₄) And concentrated to give the title compound as an oil which solidified upon standing. Yield: 3.70g (quantitative); mass spectrometry (ESI)⁺)：m/z＝295[M+H]⁺。

The racemic mixture can be separated by SFC on the chiral phase (column: Daicel ADH 250X20mm, 5 μm; mobile phase: isopropanol/sc carbon dioxide containing 0.2% diethylamine 20: 80; flow rate: 70mL/min) to give

1. (4a-R, 9a-S) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile, yield: 1.60g (43% of theory), LC (analytical SFC for chiral phase: column: Daicel ADH 250X 4.6 mm; mobile phase: isopropanol/sc carbon dioxide comprising 0.2% diethylamine 20: 80; flow rate: 4 mL/min): t is t _R4.05 min.

2. (4a-S, 9a-R) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile, yield: 1.70g (46% of theory), LC (analytical SFC for chiral phase: column: Daicel ADH250x 4.6.6 mm; mobile phase: isopropanol/sc carbon dioxide 20: 80 containing 0.2% diethylamine; flow rate: 4 mL/min): t is t_R2.81 minutes.

Enantiomerically pure (ee > 99%) intermediate 46 was also obtained using the following scheme:

step 1: 3-chloro-pyridine-2-carboxylic acid methyl ester

To the autoclave were added 2, 3-dichloropyridine (2.5kg), degassed methanol (12.5L) and triethylamine (3.42 kg). Catalyst solution was added [ prepared as follows: palladium acetate (19g), 1, 3-bis (diphenylphosphino) propane (38.5g), and methanol (1L) were added to the flask. The mixture was stirred at 20-25 ℃ until the palladium acetate was completely dissolved (about 30 minutes) ]. After purging the apparatus twice with nitrogen and twice with carbon monoxide, the mixture was stirred for 20 hours at 60-65 ℃ under an atmosphere of carbon monoxide (100 psi). After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated.

Step 2/3: 3- (3-methoxy-phenyl) -pyridine-2-carboxylic acid

2-methyl-tetrahydrofuran (500mL) was added to the crude 3-chloro-pyridine-2-carboxylic acid methyl ester (58.0g) and the resulting solution was washed with water (200mL) and 5% aqueous sodium chloride (200mL) and concentrated (to a total volume of about 450 mL). 3-Methoxyphenylboronic acid (61.6g) and potassium phosphate (143.3g) were added, and nitrogen gas was purged to the resulting mixture for 20 minutes. Palladium acetate (0.76g) and diamantanyl n-butylphosphine (2.42g) were added and the resulting mixture was heated to 80 ℃ and stirred at that temperature for 12 hours. After cooling to room temperature, the mixture was washed with water (300mL) and 1mol/L aqueous NaOH (200 mL). The organic phase was diluted with methanol (100mL) and 30% aqueous NaOH (27.04g) was added at a rate to maintain the solution temperature below 40 ℃. The resulting mixture was stirred at room temperature for 2 hours, then diluted with water (100mL) and methyl tert-butyl ether (100 mL). The ether layer was separated and concentrated hydrochloric acid (60mL) was added to the aqueous phase (pH about 2-3). The aqueous phase was extracted with dichloromethane (2 × 250mL) and the combined extracts were diluted with toluene (6L). The organic solution was concentrated below 40 ℃ and the crude title compound was used in the next step.

Step 4/5: 6-methoxy-indeno [2, 1-b ] pyridin-9-one

Thionyl chloride (0.95L) was added to a solution of 3- (3-methoxy-phenyl) -pyridine-2-carboxylic acid (crude; 2.0kg) and N, N-dimethylformamide (34mL) in dichloromethane (9L) at 40 ℃ over 30 minutes. The addition vessel was rinsed with dichloromethane (1L) and the solution was stirred at 40 ℃ for 2 hours. The solution was diluted with toluene (10L) and most of the solvent was evaporated (about 2L of remaining toluene). Dichloromethane (10L) was added to obtain a homogeneous solution. The solution was heated to 35 ℃ and added over 30 minutes to a vessel containing aluminium chloride (1.75kg) and dichloromethane (10L) and maintained at gentle reflux. The mixture was stirred at 40 ℃ for 30 minutes and then cooled to 0 ℃. Water (4L) was added at a rate to maintain the solution temperature below 40 ℃. The aqueous layer was adjusted to a pH of 2.5-3.5 using 2M aqueous NaOH and the resulting mixture was stirred for 15 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 ×). The combined organic phases were concentrated (to about 10L) and toluene (10L) was added to the residue. The residual amount of dichloromethane was evaporated and the precipitate was separated, washed with toluene (2L) and heptane (4L) and dried under vacuum to give the title compound.

Step 6: cis-6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

A mixture of sulfuric acid (98%, 6kg), water (6L) and methanol (6L) was charged to an autoclave charged with 6-methoxy-indeno [2, 1-b ] pyridin-9-one (1.2kg) and wet 10% palladium on carbon (50%, 0.48 kg). The autoclave was purged with nitrogen and then purged with hydrogen (100 psi). The mixture was heated to 60 ℃ and maintained at this temperature and hydrogen pressure until complete consumption of the starting material (2-12 hours). The mixture was cooled to 50-55 ℃ and filtered through celite. The diatomaceous earth is washed several times with a 1: 1 mixture of warm water and methanol (20L total). The combined filtrates were charged to an autoclave containing wet 10% palladium on carbon (50%, 0.96 kg). The autoclave was purged with nitrogen and then purged with hydrogen (100 psi). The mixture was heated to 60 ℃ and the temperature and hydrogen pressure were maintained until the intermediate was completely consumed (12-24 hours). The mixture was cooled to ambient temperature and filtered through celite. The celite was washed with a mixture of methanol and water (5L/5L). The combined filtrates were cooled to 0-10 ℃ and the pH adjusted to 10-11 with 30% aqueous NaOH while maintaining the solution temperature below 40 ℃. Water (10L) was added and the resulting mixture was extracted with dichloromethane (2 × 5L). The combined extracts were washed with 10% aqueous NaCl and concentrated. The residue was taken up twice in methyl ethyl ketone and concentrated again to give the crude title compound.

And 7: (4a-R, 9a-S) -6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Di-p-toluoyl-D-tartaric acid (403g) was added to crude cis-6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine (ca. 0.53kg of pure compound) dissolved in methyl ethyl ketone (5.3 liters). The solution was heated to 50 ℃ and some seed crystals were added. The mixture was stirred at 50 ℃ for 1 hour and at 15 ℃ overnight. The resulting slurry was filtered to give a white solid (386g, 95% de). The solid was dissolved in dichloromethane (6L) and 10% aqueous NaOH was added. The resulting mixture was stirred at room temperature for 1 hour. The organic phase was separated and concentrated to give the title compound. Yield: 170g (95% ee).

And 8: (4a-R, 9a-S) -2, 2, 2-trifluoro-1- (6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone

4-dimethylaminopyridine (6.9g), triethylamine (0.24L), (4a-R, 9a-S) -6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] were charged]A vessel of pyridine (231g) and dichloromethane (2.3L) was cooled to 10-15 ℃. Trifluoroacetic anhydride (0.21L) was added at a rate to maintain the solution temperature below 25 ℃. The mixture was heated to 20-25 ℃ and stirred at this temperature for 1 hour. Saturated NaHCO was added ₃Aqueous solution (1.5L) and the resulting mixture was stirred for 15 minutes. The organic layer was separated, washed with 1M aqueous HCl (1.2L) and water (0.9L), concentrated and azeotropically dried with dichloromethane to give the title compound.

And step 9: (4a-R, 9a-S) -2, 2, 2-trifluoro-1- (6-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone

Boron tribromide (0.14kg) was added to a solution of (4a-R, 9a-S) -2, 2, 2-trifluoro-1- (6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone (0.34kg) in dichloromethane (5.7L) cooled to 10-15 ℃ at a rate such that the temperature of the solution was maintained below 25 ℃. The solution was stirred at 20-25 ℃ for 5 hours. The solution was poured into water (1.7L) at a rate such that the solution temperature was maintained below 35 ℃ and the resulting mixture was stirred for 30 minutes. The organic phase was separated, washed with water (1.3L) and concentrated. The residue was dried azeotropically with dichloromethane to give the title compound.

Step 10: (4a-R, 9a-S) -1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (0.23L) was added to a solution of 4-dimethylamino-pyridine (6.9g), triethylamine (0.24L) and (4a-R, 9a-S) -2, 2, 2-trifluoro-1- (6-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone (0.32kg) in dichloromethane (3.4 liters) cooled to 0-5 deg.C at a rate such that the temperature of the solution was maintained at 0 to 5 deg.C. After stirring the solution at 0-5 ℃ for 30 minutes, water (1.2L) was added at such a rate that the solution temperature was maintained at 0-5 ℃. After stirring for 15 min, the organic phase was separated, washed with water (1.2L) and concentrated. The residue was passed through a plug of silica gel (ethyl acetate/hexane 1: 2) to give the title compound as an oil. Yield: 0.42kg (98% of theory).

Step 11: (4a-R, 9a-S) -1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

A mixture of (4a-R, 9a-S) -1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl trifluoromethanesulfonate (189g), zinc cyanide (79.8g) and N, N-dimethylformamide (1.9L) was purged with nitrogen for 15 minutes. Tris (dibenzylidene-acetone) dipalladium (0) (16.6g) and 1, 1' -bis (diphenylphosphino) ferrocene (25.1g) were added and the resulting mixture was purged with nitrogen at room temperature. The mixture was heated to 80 ℃ and stirred at this temperature for 12 hours. After cooling to room temperature, water (2L) and ethyl acetate (2L) were added and the resulting mixture was stirred for 10 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water (4 × 1L) and concentrated. The residue was passed through a plug of silica gel (hexane/ethyl acetate 2: 1.5) to give the title compound as a solid. Yield: 133g (quantitative).

Step 12/13: (4a-R, 9a-S) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

2M aqueous NaOH (300mL) was added to a slurry of (4a-R, 9a-S) -1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile (135g) in methanol (600mL) at a rate such that the slurry temperature was maintained below 40 ℃. The mixture was stirred at room temperature for 2 hours and diluted with water (300mL) and dichloromethane (600 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2 × 500 mL). The combined organic phases were washed with 10% aqueous NaCl and concentrated to give the crude title compound as an oil (90g, 93-95% ee). The crude title compound (90g) in isopropanol (540mL) was heated to 50 ℃ and dibenzoyl-D-tartaric acid (109g) was added. The resulting mixture was stirred at 90 ℃ for 1 hour and at room temperature for 2 hours. The precipitate was separated and washed with isopropanol (3 × 50 mL). The precipitate was dissolved in dichloromethane (1L) and the resulting mixture was treated with 2M aqueous NaOH (500 mL). The mixture was stirred at room temperature for 1 hour. The organic phase was separated, washed with 10% aqueous NaCl (500mL) and concentrated to give the title compound as an oil. Yield: 80g (> 99% ee).

Intermediate 47

Cis-6-phenyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Step 1: cis-2, 2, 2-trifluoro-1- (6-phenyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone

The title compound was synthesized from cis-1- (2, 2, 2-trifluoro-acetyl) following a procedure analogous to that described for intermediate 17 and 18, step 2) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-6-yl trifluoromethanesulfonate and phenylboronic acid. Yield: 70% of theory; LC (method 1): t is t_R5.02 minutes; mass spectrometry (ESI)⁺)：m/z＝346[M+H]⁺。

Step 2: cis-6-phenyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound was synthesized by a procedure analogous to that described for intermediate 46, step 5, starting from cis-2, 2, 2-trifluoro-1- (6-phenyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl) -ethanone. Yield: 60% of theory; LC (method 1): t is t_R2.70 minutes; mass spectrometry (ESI)⁺)：m/z＝250[M+H]⁺。

Intermediate 48

Cis-6-furan-3-yl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Step 1: cis-2, 2, 2-trifluoro-1- (6-furan-3-yl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone

The title compound was synthesized by a procedure analogous to that described for intermediate 17 and 18, step 2, starting from cis-1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-6-yl trifluoro-methanesulfonate and furan-3-yl-boronic acid. Yield: 61% of theory; LC (method 1): t is t_R4.60 minutes; mass spectrometry (ESI)⁺)：m/z＝336[M+H]⁺。

Step 2: cis-6-furan-3-yl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound was synthesized from cis-2, 2, 2-trifluoro-1- (6-furan) following a procedure analogous to that described for intermediate 46, step 5-3-yl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl) -ethanone. Yield: 93% of theory; LC (method 1): t is t_R2.27 min; mass spectrometry (ESI)⁺)：m/z＝240[M+H]⁺。

Intermediate 49

Cis-6- (1-methyl-1H-pyrazolyl-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Step 1: cis-2, 2, 2-trifluoro-1- [6- (1-methyl-1H-pyrazolyl-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -ethanone

The title compound was synthesized by a procedure analogous to that described for intermediate 17 and 18, step 2, starting from cis-1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Pyridin-6-yl trifluoromethanesulfonate and 1-methyl-pyrazol-4-yl-boronic acid. Yield: 32% of theory; LC (method 1): t is t_R3.88 minutes; mass spectrometry (ESI)⁺)：m/z＝350[M+H]⁺。

Step 2: cis-6- (1-methyl-1H-pyrazol-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound is synthesized by a procedure analogous to that described for intermediate 46, step 5, starting from cis-2, 2, 2-trifluoro-1- [6- (1-methyl-1H-pyrazol-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl]-ethanone. Yield: quantifying; LC (method 1): t is t_R1.70 minutes; mass spectrometry (ESI)⁺)：m/z＝254[M+H]⁺。

Intermediate 50

Cis-6-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

Step 1: cis-2, 2, 2-trifluoro-1- (6-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -ethanone

Tetrakis (triphenylphosphine) palladium (0) (17mg) was added to cis-1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] equipped with a stir bar at room temperature under argon]Pyridin-6-yl trifluoromethanesulfonate (200mg), Trimethylboroxine (81. mu.L), K₃PO₄(0.15g) and 1, 4-dioxane (4 mL). The reaction mixture was heated to 100 ℃ and stirred at this temperature overnight. Then another portion of trimethylboroxine (40. mu.L) and tetrakis (triphenylphosphine) palladium (0) (17mg) were added and stirring was continued at 100 ℃. After stirring every 6 hours, the addition of further amounts of trimethylboroxine and tetrakis (triphenylphosphine) palladium (0) was repeated until complete consumption of the starting material. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (Na) ₂SO₄) And concentrated and the residue chromatographed on silica gel (dichloromethane/methanol 1: 0 → 9: 1) to give the title compound. Yield: 50mg (37% of theory); LC (method 1): t is t_R4.62 minutes; mass spectrometry (ESI)⁺)：m/z＝284[M+H]⁺。

Step 2: cis-6-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound was synthesized by a procedure analogous to that described for intermediate 46, step 5, starting from cis-2, 2, 2-trifluoro-1- (6-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl) -ethanone. Yield: 94% of theory; LC (method 1): t is t_R1.91 min; mass spectrometry (ESI)⁺)：m/z＝188[M+H]⁺。

Intermediate 51

Cis- (3H-benzimidazol-5-yl) - [6- (3, 6-dihydro-2H-pyran-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

Step 1: 1- [ cis-6- (3, 6-dihydro-2H-pyran-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -2, 2, 2-trifluoro-ethanone

Argon-purged 1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] with stir bar]Flask for 5 min of pyridin-6-yl trifluoromethanesulfonate (0.20g), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.23g), cesium carbonate (2mol/L in water, 0.7mL), tetrahydrofuran (4mL) and toluene (1 mL). Bis (1, 1' -diphenylphosphino) ferrocene-dichloropalladium (44mg) was added and the mixture was heated to 100 ℃. After stirring overnight at 100 deg.C, another portion of 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.05g) and bis (1, 1' -diphenylphosphino) ferrocene-dichloropalladium (20mg) was added and stirring continued at 100 deg.C for 5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and NH ₄Washed with aqueous Cl solution and dried (Na)₂SO₄) And concentrated. Chromatography of the residue on silica gel (dichloromethane/methanol 1: 0 → 9: 1) gave the title compound. Yield: 0.16g (impure); LC (method 1): t is t_R4.36 minutes; mass spectrometry (ESI)⁺)：m/z＝352[M+H]⁺。

Step 2: cis-6- (3, 6-dihydro-2H-pyran-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound is synthesized by a procedure analogous to that described for intermediate 46, step 5, starting from 1- [ cis-6- (3, 6-dihydro-2H-pyran-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl]-2, 2, 2-trifluoro-ethanone. Yield: 37% of theory; LC (method 1): t is t_R1.97 min; mass spectrometry (ESI)⁺)：m/z＝256[M+H]⁺。

And step 3: cis- (3H-benzimidazol-5-yl) - [6- (3, 6-dihydro-2H-pyran-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-6- (3, 6-dihydro-2H-pyran-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 69% of theory; LC (method 1): t is t_R2.65 minutes; mass spectrometry (ESI)⁺)：m/z＝400[M+H]⁺。

Intermediate body 52

Cis- (3H-benzimidazol-5-yl) - (6-cyclopent-1-enyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

Step 1: 1- (cis-6-cyclopent-1-enyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -2, 2, 2-trifluoro-ethanone

The title compound was synthesized by a procedure analogous to that described for intermediate 51, step 1, starting from 1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-6-yl trifluoro-methanesulfonate and cyclopentenyl-1-boronic acid pinacol ester. Yield: 31% of theory; LC (method 1): t is t_R5.34 minutes; mass spectrometry (ESI)⁺)：m/z＝336[M+H]⁺。

Step 2: cis-6-cyclopent-1-enyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridines

The title compound was synthesized by a procedure analogous to that described for intermediate 46, step 5, starting from 1- (cis-6-cyclopent-1-enyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl) -2, 2, 2-trifluoro-ethanone. Yield: quantifying; LC (method 1): t is t_R2.73 minutes; mass spectrometry (ESI)⁺)：m/z＝240[M+H]⁺。

And step 3: cis- (3H-benzimidazol-5-yl) - (6-cyclopent-1-enyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-6-cyclopent-1-enyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Pyridine. Yield: 49% of theory; LC (method 1): t is t_R2.64 min; mass spectrometry (ESI)⁺)：m/z＝384[M+H]⁺。

Intermediate 53

N- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-yl) -acetamide

Step 1: cis-7-amino-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carboxylic acid tert-butyl ester

The title compound is synthesized by a procedure analogous to that described for step 3 of intermediate 32 from cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-7-ylamine and di-tert-butyl dicarbonate. Yield: 25% of theory; LC (method 1): t is t_R2.69 minutes; mass spectrometry (ESI)⁺)：m/z＝289[M+H]⁺。

Step 2: cis-7-acetylamino-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carboxylic acid tert-butyl ester

Acetic anhydride (50. mu.L) was added to cis-7-amino-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] at room temperature]Pyridine-1-carboxylic acid tert-butyl ester (140mg) and triethylamine (70. mu.L) in dichloromethane (3 mL). The solution was stirred at room temperature for 1 hour, then NaHCO was added₃An aqueous solution. Vigorously stirring and mixingThe mixture was taken up for 20 minutes and then extracted with dichloromethane. The combined extracts were concentrated and the residue was chromatographed (cyclohexane/ethyl acetate 7: 3 → 1: 9) to give the title compound. Yield: 100mg (62% of theory); LC (method 1): t is t _R3.60 minutes.

And step 3: n- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-yl) -acetamide

The title compound is synthesized by a procedure analogous to that described for intermediate 32, step 5, starting from cis-7-acetylamino-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridine-1-carboxylic acid tert-butyl ester. Yield: quantifying; LC (method 1): t is t_R0.92 min; mass spectrometry (ESI)⁺)：m/z＝231[M+H]⁺。

Intermediate body 54

N- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-yl) -methanesulfonamide

Step 1: cis-7-Methanesulfonylamino-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carboxylic acid tert-butyl ester

Methylsulfonyl chloride (42 μ L) was added to cis-7-amino-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] at room temperature]Pyridine-1-carboxylic acid tert-butyl ester (160mg) and triethylamine (76. mu.L) in dichloromethane (3 mL). The solution was stirred at room temperature for 1 hour and then NaHCO was added₃An aqueous solution. The mixture was stirred vigorously for 20 minutes and then extracted with dichloromethane. The combined extracts were concentrated and the residue was chromatographed (cyclohexane/ethyl acetate 7: 3 → 1: 9) to give the title compound. Yield: 120mg (59% of theory); LC (method 1): t is t_R3.80 minutes; mass spectrometry (ESI) ^-)：m/z＝365[M-H]^-。

Step 2: n- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-yl) -methanesulfonamide

The title compound is synthesized by following a procedure analogous to that described for intermediate 32, step 5, from cis-7-methanesulfonylamino-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridine-1-carboxylic acid tert-butyl ester. Yield: quantifying; LC (method 1): t is t_R0.97 min; mass spectrometry (ESI)⁺)：m/z＝267[M+H]⁺。

Intermediate 55

Cis-7-nitro-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-ol

A cold mixture of nitric acid (65%, 0.36mL) and sulfuric acid (96%, 0.55mL) at about 10 ℃ was added dropwise to cis-1- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] cooled in an ice bath]Pyridin-6-yl triflate (2.00g) in sulfuric acid (96%, 12 ml). The solution was stirred in a cooling bath for 1 hour and then poured onto crushed ice. The precipitate formed was isolated by filtration and taken up in methanol (10 mL). With saturated K₂CO₃The resulting solution was treated with aqueous solution (or with NaOH) until the trifluoromethylsulfonyl and trifluoroacetyl groups were cleaved (TLC or HPLC). Water was then added and the resulting mixture was extracted with ethyl acetate. The combined extracts were concentrated to give the crude title compound, which was used without further purification. Yield: 1.10 g (crude); LC (method 1): t is t _R1.44 minutes; mass spectrometry (ESI)⁺)：m/z＝235[M+H]⁺。

Intermediate 56

Cis-6-methoxy-7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound was prepared from 3-bromo-pyridine-2-carboxylic acid and 4-methyl-3-methoxyboronic acid following the synthetic sequence and scheme described for intermediate 41; since 3-bromo-pyridine-2-carboxylic acid was used for the Suzuki-Miyaura coupling (step 1 of intermediate 41) instead of 3-bromo-pyridine-2-carbonitrile, nitrile hydrolysis (step 2 of intermediate 41) was omitted. LC (method 7): t is t_R0.74 min; mass spectrometry (ESI)⁺)：m/z＝218[M+H]⁺。

Intermediate 57

Cis-6-methoxy-5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine

The title compound was prepared according to the synthetic sequence and scheme described for intermediate 41 from 3-bromo-pyridine-2-carboxylic acid and 2- (3-methoxy-2-methyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan (dioxaborolan) (which may be prepared as described in WO 2001053268); since 3-bromo-pyridine-2-carboxylic acid was used for the Suzuki-Miyaura coupling (step 1 of intermediate 41) instead of 3-bromo-pyridine-2-carbonitrile, nitrile hydrolysis (step 2 of intermediate 41) was omitted.

Intermediate 58

Cis-7-methyl-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl trifluoromethanesulfonate and cis-7-methyl-1- (3-trifluoromethanesulfonyl-3H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl trifluoromethanesulfonate

The title compound was prepared according to an analogous procedure as described for intermediate 42 from (1H-benzimidazol-5-yl) - (cis-6-hydroxy-7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone and used in the next step as a mixture.

Intermediate 59

(1H-benzimidazol-5-yl) - (cis-6-methoxy-5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was prepared in analogy to the procedure described for example 1 from 1H-benzimidazole-5-carboxylic acid and cis-6-methoxy-5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine.

Intermediate body 60

(1H-benzimidazol-5-yl) - (cis-6-hydroxy-5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was prepared in analogy to the procedure described for example 7 from (1H-benzimidazol-5-yl) - (cis-6-methoxy-5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone.

Intermediate 61

Cis-5-methyl-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl trifluoromethanesulfonate and cis-5-methyl-1- (3-trifluoromethanesulfonyl-3H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl trifluoromethanesulfonate

The title compound was prepared according to an analogous procedure as described for intermediate 42 from (1H-benzimidazol-5-yl) - (cis-6-hydroxy-5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone and used in the next step as a mixture.

Example 1

(1H-benzimidazol-5-yl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (0.50 g; alternatively, 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate) can be used was added to a solution of 1H-benzimidazole-5-carboxylic acid (0.23g) and ethyl-diisopropylamine (0.50mL) in N, N-dimethylformamide (2mL) at room temperature. After addition of cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in N, N-dimethylformamide (2mL)]The solution was stirred for 20 minutes before quinoline (0.30 g). The resulting solution was stirred at room temperature for 3 hours. 32% aqueous ammonia (1mL) in methanol (2mL) was then added, and the mixture was stirred for an additional 30 minutes. The mixture was diluted with ethyl acetate and washed with water and brine, and dried (Na)₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel (dichloromethane/1% NH) ₃95: 5 → 80: 20) to give the title compound as a foamy solid, which is triturated with ether and dried to give a colorless solid [ alternatively, the product can be purified by reverse phase HPLC (MeOH/H)₂O)]. Yield: 0.38g (80% of theory); LC (method 1): t is t_R2.53 min; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺；¹H NMR(400MHz，DMSO-d₆Mixture of 2 rotamers) 1.52-1.82(m, 4H), 1.82-1.94(m, 1H), 2.24-about 2.48(m, 1.5H), 2.71-3.02(m, 3H), 3.03-3.18(m, 0.5H), 3.50-3.65(m, 0.5H), 3.88-4.05(m, 0.5H), 4.39-4.56(m, 0.5H), 4.83-4.99(m, 0.5H), 6.89-7.20(m, 4H), 7.21-7.27(m, 1H), 7.56-7.70(m, 2H), 8.23-8.35(m, 1H), 12.58 (width s, 1H).

Example 2

(1H-benzimidazol-5-yl) - [ (4a-S, 10b-R) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -methanone

The title compound is prepared by reacting (1H-benzimidazol-5-yl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f]Chromatography of the racemic mixture of quinolin-4-yl-methanone (100mg) on a chiral phase (SFC; column: 1 × ASH 250 × 10mm, 5 μm; mobile phase: methanol/sc carbon dioxide with 0.2% diethylamine 25: 75; flow rate: 10 mL/min). Yield: 48 mg; LC (SFC; column: Daicel ASH 250X 4.6mm, 5 μm; mobile phase: methanol/sc carbon dioxide with 0.2% diethylamine 25: 75; flow rate: 4 mL/min): t is t _R2.73 minutes; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺(ii) a Reference example 1¹H NMR。

Example 3

(1H-benzimidazol-1-5-yl) - [ (4a-R, 10b-S) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -methanone

The title compound is prepared by reacting (1H-benzimidazol-5-yl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f]The racemic mixture of quinolin-4-yl-methanone (100 mg) was chromatographed on the chiral phase (SFC; column: 1 × ASH 250 × 10mm, 5 μm; mobile phase: methanol/sc carbon dioxide with 0.2% diethylamine 25: 75; flow rate: 10 mL/min). Yield: 45 mg; LC (SFC; column: Daicel ASH 250X 4.6mm, 5 μm; mobile phase: methanol/sc carbon dioxide with 0.2% diethylamine 25: 75; flow rate: 4 mL/min): t is t_R2.13 minutes; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺(ii) a Reference example 1¹H NMR。

Example 4

(1H-benzimidazol-5-yl) - (trans-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] according to an analogous procedure to that described in example 1]Quinoline. Yield: 31% of theory; TLC: r is_f0.40 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI) ⁺)：m/z＝332[M+H]⁺；¹H NMR(400MHz，DMSO-d₆)1.32-1.46(m, 1H), 1.53-1.76(m, 2H), 2.14-2.24(m, 1H), 2.30-2.43(m, 1H), about 2.49-2.56 are substituted with D₃CSOCHD₂Signal overlap (m, 1H), 2.77-2.93(m, 2H), 3.03-3.13(m, 1H), about 3.25-3.34 by H₂O signal superposition (m, 1H), 3.34-3.43(m, 1H), 3.67-3.76(m, 1H),7.07-7.19(m, 3H), 7.26-7.32(m, 2H), 7.59-7.70(m, 2H), 8.30(s, 1H), 12.60 (width s, 1H).

Example 5

4- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carbonyl) -benzamide

The title compound was prepared from terephthalic acid monoamide (terephthalic acid) and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] according to an analogous procedure to that described in example 1]Quinoline. Yield: 58% of theory; LC (method 1): t is t_R3.16 minutes; mass spectrometry (ESI)⁺)：m/z＝335[M+H]⁺。

Example 6

(1H-benzimidazol-5-yl) - (cis-7-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and cis-7-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline. Yield: 85% of theory; LC (method 1): t is t_R2.62 minutes; mass spectrometry (ESI) ⁺)：m/z＝362[M+H]⁺。

Example 7

(1H-benzimidazol-5-yl) - (cis-7-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

Boron tribromide (1mol/L in dichloromethane, 0.5mL) was added to (1H-benzimidazol-5-yl) - (cis-7-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] at room temperature]Quinolin-4-yl) -methanone (60mg) in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 2 hours. Addition of half-saturated NaHCO₃The aqueous solution was combined and the resulting neutral mixture was extracted with dichloromethane and dichloromethane/methanol (95: 5). The combined extracts were washed with brine and dried (Na)₂SO₄). The solvent was evaporated, the residue triturated with diethyl ether and dried to give the title compound as a colourless solid. Yield: 30mg (52% of theory); TLC: r is_f0.45 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：(ESI⁺)：m/z＝348[M+H]⁺。

Example 8

(1H-benzimidazol-5-yl) - (cis-10-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-10-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline. Yield: 55% of theory; LC (method 1): t is t _R2.67 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 9

(1H-benzimidazol-5-yl) - (trans-10-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and trans-10-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline. Yield: 51% of theory; LC (method 2): t is t_R3.63 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 10

(1H-benzimidazol-5-yl) - (cis-10 b-methyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline and trans-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ ]]Quinoline isomer mixture to give example 10 and example 11 mixtures, which were separated by reverse phase HPLC (MeOH/H)₂O/NH₄OH). Yield: 20% of theory; LC (method 2): t is t_R3.40 minutes; mass spectrometry (ESI)⁺)：m/z＝346[M+H]⁺；¹H NMR(400MHz，DMSO-d₆Mixture of two rotamers) 1.33(s, 3H), 1.42-1.53(m, 2H), 1.62-1.78(m, 1H), 2.15-2.23(m, 1H), 2.27-2.35(m, 1H), 2.75-2.90(m, 3H), 3.07-3.18(m, 1H), 3.43-3.49(m, 1H), 3.69-3.77(m, 1H), 7.04-7.18(m, 3H), 7.20-7.34(m, 2H), 7.56 (width s, 0.75H), 7.58 (width s, 0.25H), 7.67 (width s, 0.75H), 7.69 (width s, 0.25H), 8.29(s, 1H), 12.53-12.62(m, 1H).

Example 11

(1H-benzimidazol-5-yl) - (trans-10 b-methyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline and trans-10 b-methyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ ]]Quinoline isomer mixture to give example 10 and example 11 mixtures, which were separated by reverse phase HPLC (MeOH/H)₂O/NH₄OH). Yield: 15% of theory; LC (method 2): t is t_R3.26 minutes; mass spectrometry (ESI)⁺)：m/z＝346[M+H]⁺。

Example 12

(1H-benzimidazol-5-yl) - (trans-7-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid andtrans-7-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline. Yield: 49% of theory; LC (method 1): t is t_R2.68 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 13

(1H-benzimidazol-5-yl) - (cis-10-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 7 from (1H-benzimidazol-5-yl) - (cis-10-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f)]Quinolin-4-yl) -methanone. Yield: 68% of theory; LC (method 1): t is t_R2.25 minutes; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 14

(1H-benzimidazol-5-yl) - (cis-9-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-9-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline. Yield: 69% of theory; LC (method 1): t is t_R2.55 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 15

(1H-benzimidazol-5-yl) - (trans-9-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and trans-9-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline. Yield: 77% of theory; LC (method 1): t is t_R2.61 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 16

(1H-benzimidazol-5-yl) - (cis-9-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 7 from (1H-benzimidazol-5-yl) - (cis-9-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f)]Quinolin-4-yl) -methanone. Yield: 58% of theory; LC (method 1): t is t_R2.08 min; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 17

(1H-benzimidazol-5-yl) - (trans-9-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 7 from (1H-benzimidazol-5-yl) - (trans-9-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f)]Quinolin-4-yl) -methanone. Yield: 61% of theory; LC (method 1): t is t_R2.10 minutes; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 18

(1H-benzimidazol-5-yl) - (trans-10-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 7 from (1H-benzimidazol-5-yl) - (trans-10-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ]]Quinolin-4-yl) -methanone. Yield: 14% of theory; LC (method 1): t is t_R2.33 minutes; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 19

(1H-benzimidazol-5-yl) - (trans-7-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared by a procedure analogous to that described in example 7(1H-benzimidazol-5-yl) - (trans-7-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f)]Quinolin-4-yl) -methanone. Yield: 36% of theory; LC (method 1): t is t_R2.19 minutes; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 20

(1H-benzimidazol-5-yl) - (cis-7, 9-difluoro-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-7, 9-difluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline. Yield: 72% of theory; TLC: r is_f0.37 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝368[M+H]⁺。

Example 21

(1H-benzimidazol-5-yl) - (trans-7, 9-difluoro-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and trans-7, 9-difluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline. Yield: 70% of theory; TLC: r is_f0.43 (silica gel, CH)₂Cl₂90 portions of MeOH/32 percent ammonia water10: 1); mass spectrometry (ESI) ⁺)：m/z＝368[M+H]⁺。

Example 22

(1H-benzimidazol-5-yl) - (cis-8-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-8-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline. Yield: 78% of theory; LC (method 1): t is t_R2.54 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 23

(1H-benzimidazol-5-yl) - (trans-8-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and trans-8-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline. Yield: 71% of theory; LC (method 1): t is t_R2.61 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 24

(1H-benzimidazol-5-yl) - (trans-8-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 7 from (1H-benzimidazol-5-yl) - (trans-8-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f)]Quinolin-4-yl) -methanone. Yield: 48% of theory; LC (method 1): t is t _R2.07 min; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 25

(1H-benzimidazol-5-yl) - (cis-8-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 7 from (1H-benzimidazol-5-yl) - (cis-8-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f)]Quinolin-4-yl) -methanone. Yield: 39% of theory; LC (method 1): t is t_R2.03 minutes; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 26

(1H-benzimidazol-5-yl) - (trans-10-fluoro-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and trans-10-fluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline. Yield: 41% of theory; LC (method 1): t is t_R2.76 min; mass spectrometry (ESI)⁺)：m/z＝350 [M+H]⁺。

Example 27

(1H-benzimidazol-5-yl) - (cis-10-fluoro-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-10-fluoro-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline. Yield: 75% of theory; LC (method 1): t is t _R2.66 minutes; mass spectrometry (ESI)⁺)：m/z＝350[M+H]⁺。

Example 28

(1H-benzimidazol-5-yl) - (trans-8-phenyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and trans-8-phenyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline. Yield: 19% of theory; TLC: r is_f0.43 (silica gel,CH₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝408[M+H]⁺。

Example 29

(1H-benzimidazol-5-yl) - (cis-8-phenyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-8-phenyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline. Yield: 29% of theory; TLC: r is_f0.49 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝408[M+H]⁺。

Example 30

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1H-imidazo [4, 5-b ] pyridin-5-yl) -methanone

The title compound was synthesized from 1H-imidazo [4, 5-b ] following an analogous procedure to that described in example 1]Pyridine-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ [ f ] ]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 57% of theory; LC (method 3): t is t_R2.10 minutes; mass spectrometry (ESI)⁺)：m/z＝333[M+H]⁺。

Example 31

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -imidazo [1, 2-a ] pyridin-6-yl-methanone

The title compound was synthesized from imidazo [1, 2-a ] following an analogous procedure to that described in example 1]Pyridine-6-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 72% of theoretical value; LC (method 3): t is t_R1.82 minutes; mass spectrometry (ESI)⁺)：m/z＝335[M+H]⁺。

Example 32

6- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carbonyl) -3H-benzothiazol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 2-oxo-2, 3-dihydro-benzothiazole-6-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 56% of theory; LC (method 3): t is t _R2.32 minutes; mass spectrometry (ESI)⁺)：m/z＝365[M+H]⁺。

Example 33

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxylic acid methyl ester

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline-8-carboxylic acid methyl ester. Yield: 92% of theory; LC (method 1): t is t_R2.57 min; mass spectrometry (ESI)⁺)：m/z＝390[M+H]⁺。

Example 34

(1H-benzimidazol-5-yl) - (cis-8-hydroxymethyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

Lithium aluminum hydride (1mol/L in tetrahydrofuran, 0.5mL) was added to cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] cooled to-10 deg.C]Quinoline-8-carboxylic acid methyl ester (150mg) in tetrahydrofuran (6 mL). The resulting solution was stirred for 2 hours while warming to about-3 ℃ in a cooling bath. A small amount of water was carefully added and the resulting mixture was filtered over celite. The filtrate was diluted with ethyl acetate and dried (MgSO₄). The solvent was evaporated, the residue triturated with ethyl acetate and dried to give the title compound as a solid. Yield: 56 mg (40% of theory); LC (method 1): t is t _R2.03 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 35

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxylic acid

1M aqueous NaOH solution (15mL) was added to cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] at room temperature]Quinoline-8-carboxylic acid methyl ester (1.60g) in tetrahydrofuran (15 mL). The resulting solution was stirred at room temperature for 5 hours. The solution was concentrated under reduced pressure and water (100mL) was added to the residue. Then 1M aqueous hydrochloric acid (15mL) was added and the precipitate formed was isolated by filtration. The precipitate was washed with water and diethyl ether and dried to give the title compound as a solid. Yield: 1.24 g (80% of theory); LC (method 1): t is t_R2.09 minutes; mass spectrometry (ESI)⁺)：m/z＝376[M+H]⁺。

Example 36

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxylic acid carboxamide

The title compound was synthesized from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline-8-carboxylic acid and methylamine (2mol/L in tetrahydrofuran). Yield: 75% of theory; LC (method 1): t is t _R1.91 min; mass spectrometry (ESI)⁺)：m/z＝389[M+H]⁺。

Example 37

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxamide

The title compound was synthesized from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline-8-carboxylic acid and ammonia (28% in water). Yield: 58% of theory; LC (method 1): t is t_R1.78 minutes; mass spectrometry (ESI)⁺)：m/z＝375[M+H]⁺。

Example 38

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carboxylic acid dimethylamide

The title compound was synthesized from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline-8-carboxylic acid and dimethylamine (2mol/L in tetrahydrofuran). Yield: 20% of theory; LC (method 1): t is t_R2.08 min; mass spectrometry (ESI)⁺)：m/z＝403[M+H]⁺。

Example 39

(1H-benzimidazol-5-yl) - [ cis-8- (pyrrolidine-1-carbonyl) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -methanone

The title compound was synthesized from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1 ]Quinoline-8-carboxylic acid and pyrrolidine. Yield: 57% of theory; LC (method 1): t is t_R2.27 min; mass spectrometry (ESI)⁺)：m/z＝429[M+H]⁺。

Example 40

(1H-benzimidazol-5-yl) - [ cis-8- (morpholine-4-carbonyl) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -methanone

The title compound was synthesized from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline-8-carboxylic acid and morpholine. Yield: 63% of theory; LC (method 1): t is t_R2.05 minutes; mass spectrometry (ESI)⁺)：m/z＝445[M+H]⁺。

EXAMPLE 41

(1H-benzimidazol-5-yl) - [ cis-8- (1-hydroxy-1-methyl-ethyl) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -methanone

MeMgBr [1.4mol/L in toluene/tetrahydrofuran (3: 1), 1.1mL]Adding cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] cooled to-10 DEG C]Quinoline-8-carboxylic acid methyl ester (200mg) in tetrahydrofuran (4 mL). The resulting solution was stirred for 3 hours with cooling and then another portion of MeMgBr [1.4mol/L in toluene/tetrahydrofuran (3: 1), 0.8mL, was added]. The solution was allowed to warm to room temperature overnight in a cooling bath. The solution was poured into ice-cold water and the resulting mixture was filtered over celite. The filtrate was diluted with ethyl acetate and the organic phase was separated, washed with brine and dried (MgSO) ₄). The solvent was evaporated and the residue was chromatographed on silica gel [ dichloromethane/(dichloromethane/methanol/7M NH ]₃50: 48: 2) in methanol 88: 12 → 50: 50]The title compound was obtained as a colorless solid. Yield: 59mg (29% of theory); LC (method 1): t is t_R2.27 min; mass spectrometry (ESI)⁺)：m/z＝390[M+H]⁺。

Example 42

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-8-carbonitrile

Trifluoroacetic anhydride (0.4mL) was added to cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] cooled in an ice bath]Quinoline-8-carboxamide (140mg) and triethylamine (0.6mL) in dichloromethane (4 mL). The cooling bath was removed and the solution was stirred at room temperature for 3 hours. Then another portion of trifluoroacetic anhydride (0.4mL) and triethylamine (0.6mL) was added and stirring was continued overnight at 35 ℃. The solution was diluted with dichloromethane and washed with water and brine. Drying (MgSO)₄) Thereafter, the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 20: 1 → 1: 1) to give a yellow solidTitle compound of body. Yield: 50mg (38% of theory); mass spectrometry (ESI)⁺)：(ESI⁺)：m/z＝357[M+H]⁺。

Example 43

(2-amino-benzothiazol-6-yl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 2-amino-benzothiazole-6-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 24% of theory; LC (method 4): t is t_R1.80 minutes; mass spectrometry (ESI)⁺)：m/z＝364[M+H]⁺。

Example 44

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (3-hydroxy-4-methyl-phenyl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-hydroxy-4-methyl-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 77% of theory; LC (method 4): t is t_R2.00 min; mass spectrometry (ESI)⁺)：m/z＝322[M+H]⁺。

Example 45

(3-amino-4-methoxy-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-amino-4-methoxy-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline ]. Yield: 63% of theory; LC (method 4): t is t_R1.79 minutes; mass spectrometry (ESI)⁺)：m/z＝337[M+H]⁺。

Example 46

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (2-methyl-1H-indol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 2-methyl-1H-indole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 46% of theory; LC (method 4): t is t_R2.03 minutes; mass spectrometry (ESI)⁺)：m/z＝345[M+H]⁺。

Example 47

5- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carbonyl) -1-methyl-1, 3-dihydro-benzimidazol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 1-methyl-2-oxo-2, 3-dihydro-1H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 15% of theory; LC (method 4): t is t_R1.92 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 48

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1H-indol-6-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-indole-6-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 27% of theory; LC (method 4): t is t_R2.01 minutes; mass spectrometry (ESI)⁺)：m/z＝331[M+H]⁺。

Example 49

5- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carbonyl) -1, 3-dihydro-indol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 2-oxo-2, 3-dihydro-1H-indole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 25% of theory; LC (method 4): t is t_R1.90 minutes; mass spectrometry (ESI)⁺)：m/z＝347[M+H]⁺。

Example 50

6- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carbonyl) -1, 3-dihydro-indol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 2-oxo-2, 3-dihydro-1H-indole-6-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline ]. Yield: 12% of theory; LC (method 4): t is t_R1.90 minutes; mass spectrometry (ESI)⁺)：m/z＝347[M+H]⁺。

Example 51

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1-methyl-1H-benzimidazol-5-yl) -methanone

The title compound was prepared from 1-methyl-1H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 83% of theory; LC (method 5): t is t_R1.05 minutes; mass spectrometry (ESI)⁺)：m/z＝346[M+H]⁺。

Example 52

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1-methyl-1H-benzotriazol-5-yl) -methanone

The title compound was prepared from 1-methyl-1H-benzotriazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] according to an analogous procedure to that described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 53% of theory; LC (method 4): t is t_R1.90 minutes; mass spectrometry (ESI)⁺)：m/z＝347[M+H]⁺。

Example 53

(cis-7-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1-methyl-1H-indol-3-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1-methyl-1H-indole-3-carboxylic acid and cis-7-methoxy-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline. Yield: 82% of theory; LC (method 1): t is t_R4.39 minutes; mass spectrometry (ESI)⁺)：m/z＝375[M+H]⁺。

Example 54

(3-fluoro-4-hydroxy-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 3-fluoro-4-hydroxy-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] according to an analogous procedure to that described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 40% of theory; LC (method 4): t is t_R1.94 minutes; mass spectrometry (ESI)⁺)：m/z＝326[M+H]⁺。

Example 55

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (2-methyl-3H-benzimidazol-5-yl) -methanone

The title compound was prepared in analogy to the procedure described in example 1 from 2-methyl-3H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of quinoline [ causeWith 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ]And separated as its trifluoroacetic acid salt. Yield: 59% of theory; LC (method 4): t is t_R1.64 minutes; mass spectrometry (ESI)⁺)：m/z＝346[M+H]⁺。

Example 56

(4-amino-3-chloro-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 4-amino-3-chloro-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 52% of theory; LC (method 4): t is t_R1.99 min; mass spectrometry (ESI)⁺)：m/z＝341/343(Cl)[M+H]⁺。

Example 57

(2-amino-3H-benzimidazol-5-yl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 2-amino-3H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]And with its trifluoroacetic acid saltAnd (5) separating. Yield: 58% of theory; LC (method 4): t is t_R1.66 minutes; mass spectrometry (ESI)⁺)：m/z＝347[M+H]⁺。

Example 58

Benzothiazol-6-yl- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from benzothiazole-6-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 24% of theory; LC (method 4): t is t_R1.97 min; mass spectrometry (ESI)⁺)：m/z＝349[M+H]⁺。

Example 59

(4-chloro-3-hydroxy-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared in analogy to the procedure described in example 1 from 4-chloro-3-hydroxy-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 46% of theory; LC (method 4): t is t_R1.99 min; mass spectrometry (ESI)⁺)：m/z＝342/344(Cl)[M+H]⁺。

Example 60

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (3H-imidazo [4, 5-b ] pyridin-5-yl) -methanone

The title compound was synthesized from 3H-imidazo [4, 5-b ] following an analogous procedure to that described in example 1]Pyridine-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline ]And separated as its trifluoroacetic acid salt. Yield: 40% of theory; LC (method 4): t is t_R1.83 minutes; mass spectrometry (ESI)⁺)：m/z＝333[M+H]⁺。

Example 61

5- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carbonyl) -1, 3-dihydro-benzimidazol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 2-oxo-2, 3-dihydro-1H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 14% of theory; LC (method 4): t is t_R1.89 minutes; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 62

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (3-methyl-3H-benzimidazol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-methyl-3H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 91% of theory; LC (method 4): t is t_R1.65 minutes; mass spectrometry (ESI)⁺)：m/z＝346[M+H]⁺。

Example 63

(3-amino-4-fluoro-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-amino-4-fluoro-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 47% of theory; LC (method 4): t is t_R1.94 minutes; mass spectrometry (ESI)⁺)：m/z＝325[M+H]⁺。

Example 64

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -imidazo [1, 2-a ] pyridin-7-yl-methanone

The title compound was synthesized from imidazo [1, 2-a ] following an analogous procedure to that described in example 1]Pyridine-7-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 95% of theory; LC (method 4): t is t_R1.59 minutes; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺。

Example 65

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1H-indazol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 1 from 1H-indazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline ]. Yield: 39% of theory; LC (method 4): t is t_R1.94 minutes; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺。

Example 66

5- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carbonyl) -3, 3-dimethyl-1, 3-dihydro-indol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 19% of theory; LC (method 4): t is t_R1.95 minutes; mass spectrometry (ESI)⁺)：m/z＝375[M+H]⁺。

Example 67

(4-amino-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 4-amino-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 66% of theory; LC (method 4): t is t_R1.81 minutes; mass spectrometry (ESI)⁺)：m/z＝307[M+H]⁺。

Example 68

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (4-hydroxy-phenyl) -methanone

The title compound was prepared from 4-hydroxy-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 28% of theory; LC (method 4): t is t_R1.93 minutes; mass spectrometry (ESI)⁺)：m/z＝308[M+H]⁺。

Example 69

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1H-indol-5-yl) -methanone

The title compound was prepared from 1H-indole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] f in analogy to the procedure described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 51% of theory; LC (method 4): t is t_R1.99 min; mass spectrometry (ESI)⁺)：m/z＝331[M+H]⁺。

Example 70

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1H-indol-3-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-indole-3-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of quinoline [ causeWith 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ]. Yield: 43% of theory; LC (method 4): t is t_R2.01 minutes; mass spectrometry (ESI)⁺)：m/z＝331[M+H]⁺。

Example 71

(3, 5-dichloro-4-hydroxy-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 1 from 3, 5-dichloro-4-hydroxy-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 26% of theory; LC (method 4): t is t_R2.03 minutes; mass spectrometry (ESI)⁺)：m/z＝376/378/380(2Cl)[M+H]⁺。

Example 72

(1H-benzotriazol-5-yl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzotriazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 58% of theory; LC (method 4): t is t_R1.90 minutes; mass spectrometry (ESI)⁺)：m/z＝333[M+H]⁺。

Example 73

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1-methyl-1H-indol-3-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1-methyl-1H-indole-3-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 28% of theory; LC (method 4): t is t_R2.05 minutes; mass spectrometry (ESI)⁺)：m/z＝345[M+H]⁺。

Example 74

(cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (3-hydroxy-4-methoxy-phenyl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-hydroxy-4-methoxy-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 42% of theory; LC (method 4): t is t_R1.93 minutes; mass spectrometry (ESI)⁺)：m/z＝338[M+H]⁺。

Example 75

(3-chloro-4-hydroxy-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-chloro-4-hydroxy-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline ]. Yield: 42% of theory; LC (method 4): t is t_R1.98 minutes; mass spectrometry (ESI)⁺)：m/z＝342/344(Cl)[M+H]⁺。

Example 76

(3-amino-4-chloro-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-amino-4-chloro-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 46% of theory; LC (method 4): t is t_R1.28 minutes; mass spectrometry (ESI)⁺)：m/z＝341/343(Cl)[M+H]⁺。

Example 77

(3-amino-4-methyl-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-amino-4-methyl-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 95% of theory; LC (method 4): t is t_R1.85 minutes; mass spectrometry (ESI)⁺)：m/z＝321[M+H]⁺。

Example 78

(4-amino-3-methoxy-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 4-amino-3-methoxy-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 64% of theory; LC (method 4): t is t_R1.84 minutes; mass spectrometry (ESI)⁺)：m/z＝337[M+H]⁺。

Example 79

(4-amino-3-fluoro-phenyl) - (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 4-amino-3-fluoro-benzoic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline]. Yield: 64% of theory; LC (method 4): t is t_R1.94 minutes; mass spectrometry (ESI)⁺)：m/z＝325[M+H]⁺。

Example 80

6- (cis-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinoline-4-carbonyl) -1H-quinoxalin-2-one

The title compound is prepared from 2-oxo-1, 2-dihydro-quinoxaline-6-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] f in analogy to the procedure described in example 1]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] with quinoline ]. Yield: 19% of theory; LC (method 4): t is t_R1.92 minutes; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 81

(cis-7-hydroxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) - (1-methyl-1H-indol-3-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from (cis-7-methoxy-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f)]Quinolin-4-yl) - (1-methyl-1H-indol-3-yl) -methanone. Yield: 10% of theory; LC (method 1): t is t_R3.58 minutes; mass spectrometry (ESI)⁺)：m/z＝361[M+H]⁺。

Example 82

(1H-benzimidazol-5-yl) - (cis-8-benzyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-8-benzyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline and cis-8-cyclohexylmethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f [ [ f ]]Quinoline (about 30: 70) and was also separated from the compound formed in example 83 by reverse phase HPLC (MeOH/H)₂O/NH₄OH). Yield: 12% of theory; LC (method 1): t is t_R3.35 min; mass spectrometry (ESI)⁺)：m/z＝422[M+H]⁺。

Example 83

(1H-benzimidazol-5-yl) - (cis-8-cyclohexylmethyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-8-benzyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ]]Quinoline and cis-8-cyclohexylmethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline mixture (about 30: 70) and also separated from the compound formed in example 82 by HPLC on reverse phase (MeOH/H)₂O/NH₄OH). Yield: 50% of theory; LC (method 1): t is t_R4.06 minutes; mass spectrometry (ESI)⁺)：m/z＝428[M+H]⁺。

Example 84

(1H-benzimidazol-5-yl) - (cis-10-hydroxymethyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] according to an analogous procedure as described in example 34]Quinoline-10-carboxylic acid methyl ester. Yield: 46% of theory; TLC: r is_f0.27 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrum M/z 362[ M + H [ ]]⁺。

Example 85

(1H-benzimidazol-5-yl) - [ cis-10- (4-methoxy-benzyl) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -methanone

The title compound is as followsPrepared from 1H-benzimidazole-5-carboxylic acid and cis-10- (4-methoxy-benzyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in the procedure described in example 1 ]Quinoline. Yield: 17% of theory; LC (method 1): t is t_R3.21 minutes; mass spectrometry (ESI)⁺)：m/z＝452[M+H]⁺。

Example 86

(1H-benzimidazol-5-yl) - (cis-6, 6-dimethyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-6, 6-dimethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline. Yield: 58% of theory; LC (method 1): t is t_R2.84 minutes; mass spectrometry (ESI)⁺)：m/z＝360[M+H]⁺。

Example 87

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-10-carboxamide

The title compound was synthesized from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline-10-carboxylic acid and ammonia (7mol/L in methanol). Yield: 58% of theory; TLC: r is_f0.24 (silica gel, CH)₂Cl₂MeOH/32% ammoniaWater 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝375[M+H]⁺。

Example 88

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-10-carbonitrile

The title compound was synthesized from cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] according to an analogous procedure as described in example 42 ]Quinoline-10-carboxamide. Yield: 66% of theory; TLC: r is_f0.45 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺。

Example 89

(1H-benzimidazol-5-yl) - [ cis-8- (4-methoxy-phenoxy) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-8- (4-methoxy-phenoxy) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline. Yield: 72% of theory; LC (method 1): t is t_R3.16 minutes; mass spectrometry (ESI)⁺)：m/z＝454[M+H]⁺。

Example 90

Trans-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-9-carbonitrile

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and trans-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] according to an analogous procedure to that described in example 1]Quinoline-9-carbonitrile. Yield: 18% of theory; LC (method 1): t is t_R2.49 minutes; mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺。

Example 91

Cis-4- (1H-benzimidazole-5-carbonyl) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] quinoline-9-carbonitrile

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and cis-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1 ]Quinoline-9-carbonitrile. Yield: 64% of theory; LC (method 1): t is t_R2.40 minutes; mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺。

Example 92

(1H-benzimidazol-5-yl) - [ cis-10- (6-methyl-pyridazin-3-yloxy) -2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl ] -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-10- (6-methyl-pyridazin-3-yloxy) -1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f]Quinoline. Yield: 17% of theory; LC (method 1): t is t_R2.39 minutes; mass spectrometry (ESI)⁺)：m/z＝440[M+H]⁺。

Example 93

(1H-benzimidazol-5-yl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 60% of theory; LC (method 1): t is t_R2.44 minutes; mass spectrometry (ESI)⁺)：m/z＝318[M+H]⁺； ¹H NMR(400MHz，DMSO-d₆Mixtures of rotamers) 1.20-1.34(m, 1H), 1.41-1.56(m, 1H), 1.56-1.71(m, 1H), 1.92-2.02(m, 1H), 2.68-3.11(m, 3H), 3.11-3.27(m, 1H), 3.47-5.43 (very broad signal, 2H), 7.07-7.30(m, 5H), 7.54-7.62(m, 1H), 7.64-7.72(m, 1H), 8.29(s, 1H), 12.51-12.65(m, 1H).

Example 94

(1H-benzimidazol-5-yl) - [ (4a-R, 9a-S) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

The title compound is prepared by reacting (1H-benzimidazol-5-yl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]A racemic mixture of pyridin-1-yl-methanone (100mg) was subjected to chromatography in the chiral phase (column: 1 × ASH 250 × 10mm, 250 μm; mobile phase: methanol/sc carbon dioxide 25: 75 containing 0.2% diethylamine; flow rate: 10 mL/min). Yield: 47 mg; LC (as above method on chiral phase): t is t_R2.35 min; mass spectrometry (ESI)⁺)：m/z＝318[M+H]⁺(ii) a Reference example 94¹H NMR。

Example 95

(1H-benzimidazol-5-yl) - [ (4a-S, 9a-R) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

The title compound is prepared by reacting (1H-benzimidazol-5-yl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]A racemic mixture of pyridin-1-yl-methanone (100mg) was subjected to chromatography in the chiral phase (column: 1 × ASH 250 × 10mm, 250 μm; mobile phase: methanol/sc carbon dioxide 25: 75 containing 0.2% diethylamine; flow rate: 10 mL/min). Yield: 44 mg; LC (as above method on chiral phase): t is t_R1.98 minutes; mass spectrometry (ESI) ⁺)：m/z＝318 [M+H]⁺(ii) a Reference example 94¹H NMR。

Example 96

4- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carbonyl) -benzamide

The title compound was synthesized in analogy to the procedure described in example 1 from terephthalic acid mono-and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 50% of theory; LC (method 1): t is t_R3.07 min; mass spectrometry (ESI)⁺)：m/z＝321[M+H]⁺。

Example 97

About a 1: 1 mixture of cis- (1H-benzimidazol-5-yl) - (6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone and cis- (1H-benzimidazol-5-yl) - (7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

A portion of the impure mixture obtained from step 4 of intermediates 34 and 35 was purified by reverse phase HPLC (acetonitrile/water) to give an approximately 1: 1 mixture of the title compound. Mass spectrometry (ESI)⁺)：m/z＝396/398(Br)[M+H]⁺。

Example 98

Cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carboxylic acid

Title compoundThe procedure was analogous to that described in example 35 from cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carboxylic acid methyl ester and cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]An approximately 1: 1 mixture of pyridine-7-carboxylic acid methyl ester was prepared and separated from example 99 by HPLC on reverse phase (MeCN/H)₂O). Yield: 4% of theory; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 99

Cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-7-carboxylic acid

The title compound was synthesized in analogy to the procedure described for example 35 from cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carboxylic acid methyl ester and cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]An approximately 1: 1 mixture of pyridine-7-carboxylic acid methyl ester was prepared and separated from example 98 by HPLC on reverse phase (MeCN/H)₂O). Yield: 5% of theory; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 100

Cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carboxamide

The title compound was synthesized in analogy to the procedure described in example 1 from cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carboxylic acid and ammonia (0.5mol/L in 1, 4-dioxane). Yield: 64% of theory; LC (method 1): t is t _R1.64 minutes; mass spectrometry (ESI)⁺)：m/z＝361[M+H]⁺。

Example 101

Cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-7-carboxylic acid methylamide

The title compound was synthesized in analogy to the procedure described in example 1 from cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-7-carboxylic acid and methylamine (2mol/L in tetrahydrofuran). Yield: 19% of theory; LC (method 1): t is t_R1.86 minutes; mass spectrometry (ESI)⁺)：m/z＝375[M+H]⁺。

Example 102

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-imidazo [4, 5-b ] pyridin-5-yl) -methanone

The title compound was synthesized from 1H-imidazo [4, 5-b ] following an analogous procedure to that described in example 1]Pyridine-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of pyridine [ using 2- (7-aza-1H-benzotriazol-1-yl)1, 1, 3, 3-tetramethyluronium hexafluorophosphate]. Yield: 74% of theory; LC (method 3): t is t_R2.10 minutes; mass spectrometry (ESI)⁺)：m/z＝319[M+H]⁺。

Example 103

6- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carbonyl) -3H-benzoxepin-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 2-oxo-2, 3-dihydro-benzothiazole-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 74% of theory; LC (method 3): t is t_R2.28 min; mass spectrometry (ESI)⁺)：m/z＝351[M+H]⁺。

Example 104

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -imidazo [1, 2-a ] pyridin-6-yl-methanone

The title compound was synthesized from imidazo [1, 2-a ] following an analogous procedure to that described in example 1]Pyridine-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 85% of theory; LC (method 3): t is t_R1.81 minutes; mass spectrometry(ESI⁺)：m/z＝318[M+H]⁺。

Example 105

(1H-benzimidazol-5-yl) - (trans-10 b-ethyl-2, 3, 4a, 5, 6, 10 b-hexahydro-1H-benzo [ f ] quinolin-4-yl) -methanone

The title compound was prepared from 1H-benzimidazole-5-carboxylic acid and trans-10 b-ethyl-1, 2, 3, 4, 4a, 5, 6, 10 b-octahydro-benzo [ f ] in analogy to the procedure described in example 1]Quinoline. Yield: 44% of theory; TLC: r is_f0.42 (silica gel, CH)₂Cl₂MeOH/32% ammonia 90: 10: 1); mass spectrometry (ESI)⁺)：m/z＝360[M+H]⁺。

Example 106

Cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

The title compound was synthesized in analogy to the procedure described for example 42 from cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carboxylic acid amide. Yield: 64% of theory; LC (method 1): t is t_R2.33 minutes; mass spectrometry (ESI)⁺)：m/z＝343[M+H]⁺(ii) a Reference example 108¹H NMR。

The title compound can also be obtained as follows:

to a flask equipped with a stir bar, zinc cyanide (0.32g), cis-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] -c]A flask of pyridin-6-yl triflate (1.08 g for the isomer mixture of sulfonyl linkage at N-1 or N-3 of benzimidazole) and N, N-dimethylformamide (5mL) was purged with argon for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (0.31g) was then added and the resulting mixture heated to 100 ℃ and stirred at that temperature for 2 hours. After cooling to room temperature, 1-hydroxybenzotriazole hydrate (0.45g) and water (1.5mL) were added and stirring was continued at room temperature for 3 hours. Adding ethyl acetate, a small amount of methanol and saturated Na₂CO₃The aqueous solution was filtered over celite. The aqueous phase of the filtrate was separated, neutralized with 2M aqueous citric acid and extracted with ethyl acetate. The organic phases were mixed and washed with brine and dried (Na) ₂SO₄). The solvent was evaporated and the residue was chromatographed on silica gel (dichloromethane/methanol 96: 4 → 90: 10) to give the title compound as a solid. Yield: 0.42g (68% of theory).

Example 107

(4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

The title compound is prepared by reacting cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile (600mg) was obtained by chromatography on the chiral phase (SFC; column: Daicel ASH 250X 20mm, 5 μm; mobile phase: isopropanol/sc carbon dioxide with 0.2% diethylamine 25: 75; flow rate: 90 mL/min; 40 ℃ C.). Yield: 112 mg; LC (preparative SFC on chiral phase as described above): t is t_R8.45 minutes; mass spectrometry (ESI)⁺)：m/z＝318[M+H]⁺(ii) a Reference example 108¹H NMR。

Alternatively, a compound can be prepared from (1H-benzimidazol-5-yl) - [ (4a-R, 9a-S) -6-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone by an analogous procedure as described in example 148. Yield: 26% of theory.

Alternatively, the title compound was prepared from 1H-benzimidazole-5-carboxylic acid and (4a-R, 9a-S) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile according to an analogous procedure as described in example 1. Yield: 81% of theory.

The title compound may also be prepared as follows:

1-hydroxybenzotriazole monohydrate (138.0g), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (172.7g) and triethylamine (262mL) were added in the order given to a solution of 1H-benzimidazole-5-carboxylic acid (146.1g) and (4a-R, 9a-S) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile (149.0g) in N, N-dimethylformamide (600mL) at room temperature. The mixture was stirred at room temperature overnight. Water (1.5L) and dichloromethane (1.5mL) were added, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (750 mL). The combined organic phases were washed with 2mol/L aqueous NaOH (750mL), 2mol/L aqueous hydrochloric acid (630mL) and water (3X1.5L) and concentrated below 50 ℃. Ethyl acetate (700mL) was added to the residue and the resulting mixture was heated to give a homogeneous solution. The solution was cooled to room temperature overnight and the precipitate was isolated by filtration and washed with ethyl acetate (2 × 100 mL). The precipitate was dried under vacuum at 50 ℃ for 5 hours to give the title compound as a white solid. Yield: 208.0g (84% purity, > 99% ee).

Two different crystal modifications to give the hydrochloride salt of (4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile:

Form I:

(4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile hydrochloride

Hydrochloric acid (5-6mol/L in isopropanol, 1.46mL) was added dropwise to stirred (4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] at room temperature]Pyridine-6-carbonitrile (2.10g) in ethanol (10 mL). Seed crystals were added and stirring continued at room temperature for 2 hours and at 0 ℃ for a further 2 hours. The precipitate was isolated by filtration (using the filtrate to prepare form II, see below), washed with a small amount of ethanol and dried (60 ℃) to give an orange solid (1.60 g). The solid was redissolved in ethanol (250mL) and charcoal (1g) was added to the solution. The mixture was stirred for 5 minutes and then filtered. The filtrate was concentrated to about 100mL and seed crystals were added. The solution was stirred at room temperature for 2 hours and at about-10 ℃ for 30 minutes. The precipitate was isolated by filtration (using the filtrate to prepare form II, see below) and dried (60 ℃) to give the title compound as a colourless crystalline solid (0.90 g); m is_p(initial) 252 ℃.

Seed crystals were prepared as follows: hydrochloric acid (5-6mol/L in isopropanol, 40. mu.L) was added to a stirred solution of (4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile (63mg) in ethanol (0.5 mL). The resulting solution was stirred at room temperature overnight. The precipitate was isolated by filtration, washed with a small amount of cold ethanol, and dried to give a colorless solid (30 mg).

Form II:

The filtrate prepared as form I above was concentrated, combined, and dissolved in ethyl acetate (75 mL). The resulting mixture was stirred at 50 ℃ for 4 hours. The suspension was cooled to room temperature, and the precipitate was isolated by filtration, washed with ethyl acetate (20mL) and dried (60 ℃ C.) to give a colorless solid (0.58 g). This solid (0.58g) was stirred in ethanol at room temperature overnight with the residue (ca 1g) obtained by concentrating the filtrate from the repeated preparation of form I. Tong (Chinese character of 'tong')The precipitate was isolated by filtration and dried (60 ℃) to give the title compound as colorless crystalline form II (0.65 g); m is_p(start) about 240 ℃.

Form II can also be prepared by the following process:

a reaction vessel containing (4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile (331.5g) and isopropanol (331.5g) was heated at 75 deg.C until a homogeneous solution was formed. 5.12mol/LHCl in isopropanol (29.7g) was added, and the addition vessel was then rinsed with isopropanol (5 g). (4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile hydrochloride (form II; 19.88 g; seed crystals milled and slurried in 30g of isopropanol for about 1 hour) was added, followed by rinsing the addition vessel with isopropanol (20 g). The solution was aged for 1 hour and then 5.12mol/L HCl in isopropanol (171.3g) was added over 4 hours. The mixture was cooled to 0-5 ℃ over 1 hour and aged at this temperature for 30 min. The precipitate was isolated by filtration, washed with heptane (0-5 ℃) and dried under vacuum at 65 ℃ for 8 hours. Yield: 368.9g (yield: 95%; corrected for seed addition).

Example 108

(4a-S, 9a-R) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

The title compound is prepared by reacting cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]A racemic mixture of pyridine-6-carbonitrile (600mg) was subjected to chromatography on the chiral phase (SFC; column: Daicel ASH 250X 20mm, 5 μm; mobile phase: isopropanol/sc carbon dioxide 25: 75 containing 0.2% diethylamine; flow rate: 90 mL/min; 40 ℃ C.) to yield a mixture of pyridine-6-carbonitrilePurity of about 90% ee was prepared (example 108/example 107 about 95: 5). Yield: 115 mg; LC (preparation SFC on chiral phase as described above): t is t_R6.00 min; mass spectrometry (ESI)⁺)：m/z＝318[M+H]⁺；¹H NMR(400MHz，DMSO-d₆Mixtures of rotamers) 1.22-1.35(m, 1H), 1.42-1.56(m, 1H), 1.57-1.69(m, 1H), 1.96-2.06(m, 1H), 2.86-3.18(m, 3H), 3.20-ca.3.29(m, 1H), ca.3.62-5.58 (very broad signal, 2H), 7.19-7.31(m, 1H), 7.41-7.49(m, 1H), 7.54-7.74(m, 4H), 8.29 (signal, 1H), 12.60 (broad s, 1H).

Example 109

(2-amino-benzothiazol-6-yl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 2-amino-benzothiazole-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 63% of theory; LC (method 4): t is t_R1.76 min; mass spectrometry (ESI)⁺)：m/z＝350[M+H]⁺。

Example 110

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (3-hydroxy-4-methyl-phenyl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-hydroxy-4-methyl-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 45% of theory; LC (method 4): t is t_R1.98 minutes; mass spectrometry (ESI)⁺)：m/z＝308[M+H]⁺。

Example 111

(3-amino-4-methoxy-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-amino-4-methoxy-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 77% of theory; LC (method 4): t is t_R1.75 minutes; mass spectrometry (ESI) ⁺)：m/z＝323[M+H]⁺。

Example 112

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (2-methyl-1H-indol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 2-methyl-1H-indole-5-carboxylic acid and cis-2, 3, 4,4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 39% of theory; LC (method 4): t is t_R2.01 minutes; mass spectrometry (ESI)⁺)：m/z＝331[M+H]⁺。

Example 113

5- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carbonyl) -1-methyl-1, 3-dihydro-benzimidazol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 1-methyl-2-oxo-2, 3-dihydro-1H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 27% of theory; LC (method 4): t is t_R1.89 minutes; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 114

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-indol-6-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-indole-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium ] using pyridineHexafluorophosphates]. Yield: 41% of theory; LC (method 4): t is t_R2.00 min; mass spectrometry (ESI)⁺)：m/z＝317[M+H]⁺。

Example 115

5- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carbonyl) -1, 3-dihydro-indol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 2-oxo-2, 3-dihydro-1H-indole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 29% of theory; LC (method 5): t is t_R0.98 min; mass spectrometry (ESI)⁺)：m/z＝333[M+H]⁺。

Example 116

6- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carbonyl) -1, 3-dihydro-indole-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 2-oxo-2, 3-dihydro-1H-indole-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 34% of theory; LC (method 4): t is t _R1.88 minutes; mass spectrometry (ESI)⁺)：m/z＝333[M+H]⁺。

Example 117

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1-methyl-1H-benzimidazol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1-methyl-1H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 90% of theory; LC (method 4): t is t_R1.62 minutes; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺。

Example 118

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1-methyl-1H-benzotriazol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1-methyl-1H-benzotriazol-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 65% of theory; LC (method 4): t is t_R1.88 minutes; mass spectrometry (ESI)⁺)：m/z＝333[M+H]⁺。

Example 119

(1H-benzimidazol-5-yl) - (cis-7-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-7-ol. Yield: 18% of theory; LC (method 1): t is t_R1.97 min; mass spectrometry (ESI)⁺)：m/z＝334[M+H]⁺。

Example 120

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (4-hydroxy-3-methyl-phenyl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 4-hydroxy-3-methyl-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 35% of theory; LC (method 4): t is t_R1.92 minutes; mass spectrometry (ESI)⁺)：m/z＝313[M+H]⁺。

Example 121

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (2-methyl-1H-benzimidazol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 2-methyl-1H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine ]. Yield: 89% of theory; LC (method 5): t is t_R0.95 min; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺。

Example 122

(4-amino-3-chloro-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 4-amino-3-chloro-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 38% of theory; LC (method 4): t is t_R1.96 minutes; mass spectrometry (ESI)⁺)：m/z＝327/329(Cl)[M+H]⁺。

Example 123

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-indazol-6-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-indazole-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 5% of theory; LC (method 4): t is t_R1.92 minutes; mass spectrometry (ESI)⁺)：m/z＝318[M+H]⁺。

Example 124

(2-amino-1H-benzimidazol-5-yl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 2-amino-1H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 71% of theory; LC (method 4): t is t_R1.64 minutes; mass spectrometry (ESI)⁺)：m/z＝333[M+H]⁺。

Example 125

Benzothiazol-6-yl- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound is as followsThe procedure described in example 1 was followed from benzothiazole-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 36% of theory; LC (method 4): t is t_R1.94 minutes; mass spectrometry (ESI)⁺)：m/z＝335[M+H]⁺。

Example 126

(4-chloro-3-hydroxy-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 4-chloro-3-hydroxy-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine ]. Yield: 44% of theory; LC (method 4): t is t_R1.97 min; mass spectrometry (ESI)⁺)：m/z＝328[M+H]⁺。

Example 127

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-imidazo [4, 5-b ] pyridin-6-yl) -methanone

The title compound was synthesized from 1H-imidazo [4, 5-b ] following an analogous procedure to that described in example 1]Pyridine-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of pyridine [ using 2- (7-)aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate]. Yield: 71% of theory; LC (method 4): t is t_R1.79 minutes; mass spectrometry (ESI)⁺)：m/z＝319[M+H]⁺。

Example 128

5- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carbonyl) -1, 3-dihydro-benzimidazol-2-one

The title compound was synthesized in analogy to the procedure described in example 1 from 2-oxo-2, 3-dihydro-1H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 11% of theory; LC (method 4): t is t_R1.86 minutes; mass spectrometry (ESI)⁺)：m/z＝334[M+H]⁺。

Example 129

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (3-methyl-3H-benzimidazol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-methyl-3H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 94% of theory; LC (Method 4): t is t_R1.62 minutes; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺。

Example 130

(3-amino-4-fluoro-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-amino-4-fluoro-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 68% of theory; LC (method 4): t is t_R1.91 min; mass spectrometry (ESI)⁺)：m/z＝311[M+H]⁺。

Example 131

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -imidazo [1, 2-a ] pyridin-7-yl-methanone

The title compound was synthesized from imidazo [1, 2-a ] following an analogous procedure to that described in example 1]Pyridine-7-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine ]. Yield: 18% of theory; LC (method 4): t is t_R1.56 minutes; mass spectrometry (ESI)⁺)：m/z＝318[M+H]⁺。

Example 132

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-indazol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-indazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 31% of theory; LC (method 4): t is t_R1.91 min; mass spectrometry (ESI)⁺)：m/z＝318[M+H]⁺。

Example 133

(4-amino-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 4-amino-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 70% of theory; LC (method 4): t is t_R1.77 minutes; mass spectrometry (ESI)⁺)：m/z＝293[M+H]⁺。

Example 134

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (4-hydroxy-phenyl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 4-hydroxy-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 25% of theory; LC (method 4): t is t_R1.91 min; mass spectrometry (ESI)⁺)：m/z＝294[M+H]⁺。

Example 135

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-indol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-indole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 43% of theory; LC (method 4): t is t_R1.97 min; mass spectrometry (ESI)⁺)：m/z＝317[M+H]⁺。

Example 136

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-indol-3-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-indole-3-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 35% of theory; LC (method 4): t is t_R1.99 min; mass spectrometry (ESI)⁺)：m/z＝317[M+H]⁺。

Example 137

(3, 5-dichloro-4-hydroxy-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3, 5-dichloro-4-hydroxy-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 32% of theory; LC (method 4): t is t_R2.01 minutes; mass spectrometry (ESI)⁺)：m/z＝362/364/366(Cl)[M+H]⁺。

Example 138

(1H-Benzotriazol-5-yl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzotriazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 19% of theory; LC (method 4): t is t_R1.87 min; mass spectrometry (ESI)⁺)：m/z＝319[M+H]⁺。

Example 139

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1-methyl-1H-indol-3-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1-methyl-1H-indole-3-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine ]. Yield: 26% of theory; LC (method 4): t is t_R2.02 minutes; mass spectrometry (ESI)⁺)：m/z＝331[M+H]⁺。

Example 140

(cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (3-hydroxy-4-methoxy-phenyl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-hydroxy-4-methoxy-benzoic acid and cis-2, 3, 4, 4a9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 45% of theory; LC (method 4): t is t_R1.91 min; mass spectrometry (ESI)⁺)：m/z＝324[M+H]⁺。

Example 141

(3-chloro-4-hydroxy-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-chloro-4-hydroxy-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 32% of theory; LC (method 4): t is t_R1.96 minutes; mass spectrometry (ESI)⁺)：m/z＝328/330(Cl)[M+H]⁺。

Example 142

(3-amino-4-chloro-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 3-amino-4-chloro-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: theory of things43% of theoretical value; LC (method 4): t is t_R1.97 min; mass spectrometry (ESI)⁺)：m/z＝327/329(Cl)[M+H]⁺。

Example 143

(3-amino-4-methyl-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example l from 3-amino-4-methyl-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 63% of theory; LC (method 4): t is t_R1.81 minutes; mass spectrometry (ESI)⁺)：m/z＝307[M+H]⁺。

Example 144

(4-amino-3-methoxy-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 4-amino-3-methoxy-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexa-fluorophosphate as pyridine ]. Yield: 59% of theory; LC (method 4): t is t_R1.80 minutes; mass spectrometry (ESI)⁺)：m/z＝323[M+H]⁺。

Example 145

(4-amino-3-fluoro-phenyl) - (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 4-amino-3-fluoro-benzoic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 62% of theory; LC (method 4): t is t_R1.91 min; mass spectrometry (ESI)⁺)：m/z＝311[M+H]⁺。

Example 146

(1H-benzimidazol-5-yl) - (cis-4-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-4-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 16% of theory; LC (method 1): t is t_R2.68 minutes; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺。

Example 147

6- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridine-1-carbonyl) -1H-quinoxalin-2-one

The title compound is prepared analogously to example 1 from 2-oxo-1, 2-dihydro-quinoxaline-6-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Preparation of [ using 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ] using pyridine]. Yield: 45% of theory; LC (method 4): t is t_R1.89 minutes; mass spectrometry (ESI)⁺)：m/z＝346[M+H]⁺。

Example 148

(4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-7-carbonitrile

To a flask equipped with a stir bar, zinc cyanide (94mg), (1H-benzimidazol-5-yl) - [ (4a-R, 9a-S) -7-bromo-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl]A flask of methanone (0.30g) and N, N-dimethylformamide (2mL) was purged with argon for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (0.10g) was then added and the resulting mixture heated to 100 ℃ and stirred at that temperature overnight. After cooling to room temperature, methanol was added and the resulting mixture was filtered. The filtrate was concentrated and water was added to the residue. The aqueous mixture was extracted with ethyl acetate and the combined extracts were dried (Na)₂SO₄) And the solvent was evaporated. The residue was purified by reverse phase HPLC (acetonitrile/water/trifluoroacetic acid) to give the title compound as its trifluoroacetate salt. Yield: 0.09g (25% of theory); LC (method 1): t is t_R2.31 minutes; mass spectrometry (ESI)⁺)：m/z＝343[M+H]⁺。

Example 149

(4a-R, 9a-S) - (1H-benzimidazol-5-yl) - (6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and (4a-R, 9a-S) -6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 89% of theory; LC (method 1): t is t_R2.43 minutes; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 150

(4a-R, 9a-S) - (1H-benzimidazol-5-yl) - (6-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 7 from (4a-R, 9a-S) - (1H-benzimidazol-5-yl) - (6-methoxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl) -methanone. Yield: 78% of theory; LC (method 1): t is t_R1.89 minutes; mass spectrometry (ESI)⁺)：m/z＝334[M+H]⁺。

Example 151

(cis-7-amino-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-benzimidazol-5-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-7-ylamine. Yield: 30% of theory; LC (method 1): t is t _R0.79 min; mass spectrometry (ESI)⁺)：m/z＝333[M+H]⁺。

Example 152

(4a-R, 9a-S) -1- (7-methyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

The title compound was synthesized in analogy to the procedure described in example 1 from 7-methyl-1H-benzimidazole-5-carboxylic acid and (4a-R, 9a-S) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile. Yield: 53% of theory; LC (method 6): t is t_R1.05 minutes; mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺。

Example 153

(4a-R, 9a-S) -1- (6-methyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile

The title compound was synthesized in analogy to the procedure described in example 1 from 6-methyl-1H-benzimidazole-5-carboxylic acid and (4a-R, 9a-S) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile. Yield: 69% of theory; LC (method 6): t is t_R0.99 min; mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺。

Example 154

Cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carboxylic acid methyl ester

To a reactor equipped with a stir bar, cis-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]A flask of pyridin-6-yl triflate (for the isomer mixture with sulfonyl linkage at N-1 or N-3 of benzimidazole, 0.50g), triethylamine (0.18mL), N-dimethylformamide (2mL) and methanol (1mL) was purged with argon for 5 minutes. Adding [1, 1' -bis (diphenylphosphino) ferrocene]Dichloropalladium dichloromethane complex (53mg) and carbon monoxide was bubbled through the mixture for an additional 5 minutes. The mixture was then heated to 70 ℃ under a carbon monoxide atmosphere (4 bar) and shaken at this temperature overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. Chromatography of the residue on silica gel (dichloromethane/methanol 1: 0 → 9: 1) gave the title compound. Yield: 0.27g (87% of theory); LC (method 1): t is t_R2.43 minutes; mass spectrometry (ESI)⁺)：m/z＝376[M+H]⁺。

Example 155

(1H-benzimidazol-5-yl) - (cis-6-ethynyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

To a reactor equipped with a stir bar, cis-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]A flask of pyridin-6-yl triflate (0.20 g for the isomer mixture linked to the sulfonyl group at N-1 or N-3 of benzimidazole) and N, N-dimethylformamide (2mL) was purged with argon for 5 minutes. Copper (I) iodide (13mg), Pd (PPh) were added in the given order ₃)₂Cl₂(25mg), triethylamine (0.31mL) and trimethylsilylacetylene (0.14mL), the vessel was sealed and the resulting mixture was heated to 60 ℃. After stirring the mixture at 60 ℃ overnight, it was cooled to room temperature and K was added₂CO₃An aqueous solution. The resulting mixture was extracted with ethyl acetate and the combined extracts were dried (Na)₂SO₄) And the solvent was evaporated. Chromatography of the residue on silica gel (dichloromethane/methanol 1: 0 → 9: 1) gave the title compound as trimethylsilylated, which was dissolved in methanol (3mL) and saturated K at room temperature₂CO₃The aqueous solution was treated for 2 hours. The mixture was then concentrated, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (Na)₂SO₄) And concentrated. Chromatography of the residue on silica gel (dichloromethane/methanol 1: 0 → 9: 1) gave the title compound. Yield: 0.03g (26% of theory); LC (method 1): t is t_R2.65 minutes; mass spectrometry (ESI)⁺)：m/z＝342[M+H]⁺。

Example 156

(1H-benzimidazol-5-yl) - (cis-6-hydroxymethyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 34 from cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Pyridine-6-carboxylic acid methyl ester. Yield: 30% of theory; LC (method 1): t is t_R1.87 min; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Example 157

(1H-Benzimidazol-5-yl) - [ cis-6- (1-hydroxy-1-methyl-ethyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

The title compound was synthesized from cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] by an analogous procedure as described in example 41, except that MeLi was used instead of MeMgBr]Pyridine-6-carboxylic acid methyl ester. Yield: 21% of theory; LC (method 1): t is t_R2.13 minutes; mass spectrometry (ESI)⁺)：m/z＝376[M+H]⁺。

Example 158

(1H-Benzimidazol-5-yl) - (cis-6-phenyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-6-phenyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 63% of theory; LC (method 1): t is t_R3.28 min; mass spectrometry (ESI)⁺)：m/z＝394[M+H]⁺。

Example 159

(1H-benzimidazol-5-yl) - (cis-6-phenylethynyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 155 from cis-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] ]Pyridin-6-yl ester (isomer mixture linked with sulfonyl group at N-1 or N-3 for benzimidazole) and phenylacetylene; in case the sulfonyl group on one of the benzimidazole nitrogens is not completely removed after the reaction, the mixture is treated with 1-hydroxy-benzotriazole and water. Yield: 24% of theory; LC (method 1): t is t_R3.58 minutes; mass spectrometry (ESI)⁺)：m/z＝418[M+H]⁺。

Example 160

(1H-Benzimidazol-5-yl) - (cis-6-furan-3-yl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-6-furan-3-yl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 14% of theory; LC (method 1): t is t_R2.89 minutes; mass spectrometry (ESI)⁺)：m/z＝384[M+H]⁺。

Example 161

(1H-Benzimidazol-5-yl) - (cis-6-prop-1-ynyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 155 from cis-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-6-yl ester (isomer mixture linked with sulfonyl group at N-1 or N-3 for benzimidazole) and propyne; in case the sulfonyl group on one of the benzimidazole nitrogens is not completely removed after the reaction, the mixture is treated with 1-hydroxy-benzotriazole and water. Yield: 30% of theory; LC (method 1): t is t _R2.92 minutes; mass spectrometry (ESI)⁺)：m/z＝356[M+H]⁺。

Example 162

(1H-benzimidazol-5-yl) - [ cis-6- (1-methyl-1H-pyrazolyl-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

The title compound is as followsThe procedure is analogous to that described in example 1 starting from 1H-benzimidazole-5-carboxylic acid and cis-6- (1-methyl-1H-pyrazolyl-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] o]Pyridine. Yield: 78% of theory; LC (method 1): t is t_R2.35 min; mass spectrometry (ESI)⁺)：m/z＝398[M+H]⁺。

Example 163

(1H-benzimidazol-5-yl) - (cis-6-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-6-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. Yield: 60% of theory; LC (method 1): t is t_R2.75 minutes; mass spectrometry (ESI)⁺)：m/z＝332[M+H]⁺。

Example 164

(1H-Benzimidazol-5-yl) - [ cis-6- (tetrahydro-pyran-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl ] -methanone

(1H-Benzimidazol-5-yl) - [6- (3, 6-dihydro-2H-pyran-4-yl) -2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] is shaken under hydrogen atmosphere (5 bar) at room temperature ]Pyridin-1-yl]A mixture of methanone (48mg), 10% palladium on carbon (10mg) and methanol (3mL) overnight. The catalyst was then separated by filtration and the filtrate was concentrated. Residue ofThe material was purified by chromatography on silica gel (dichloromethane/methanol 1: 0 → 9: 1) to give the title compound. Yield: 15mg (31% of theory); LC (method 1): t is t_R2.63 minutes; mass spectrometry (ESI)⁺)：m/z＝402[M+H]⁺。

Example 165

(1H-benzimidazol-5-yl) - (cis-6-cyclopentyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described for example 164 from (1H-benzimidazol-5-yl) - (6-cyclopent-1-enyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ]]Pyridin-1-yl) -methanone. Yield: 50% of theory; LC (method 1): t is t_R3.53 minutes; mass spectrometry (ESI)⁺)：m/z＝386[M+H]⁺。

Example 166

N- [ cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-yl ] -acetamide

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and N- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-7-yl) -acetamide. Yield: 34% of theory; LC (method 1): t is t _R1.97 min; mass spectrometry (ESI)⁺)：m/z＝375[M+H]⁺。

Example 167

N- [ cis-1- (1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-7-yl ] -methanesulfonamide

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and N- (cis-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-7-yl) -methanesulfonamide. Yield: 7% of theory; LC (method 1): t is t_R2.07 min; mass spectrometry (ESI)⁺)：m/z＝411[M+H]⁺。

Example 168

(1H-benzimidazol-5-yl) - (cis-6-hydroxy-7-nitro-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-7-nitro-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridin-6-ol. Yield: 32% of theory; LC (method 1): t is t_R2.43 minutes; mass spectrometry (ESI)⁺)：m/z＝379[M+H]⁺。

Example 169

(cis-7-amino-6-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) - (1H-benzimidazol-5-yl) -methanone

(1H-Benzimidazol-5-yl) - (cis-6-hydroxy-7-nitro-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] shaken under hydrogen atmosphere (1 bar) at room temperature ]A mixture of pyridin-1-yl) -methanone (0.56g), 10% palladium on carbon (50mg) and methanol (10mL) for 3 hours. The catalyst was separated by filtration and the filtrate was concentrated. The residue was chromatographed (dichloromethane/methanol 1: 1 → 7: 3) to give the title compound. Yield: 0.32g (63% of theory); LC (method 1): t is t_R0.65 min; mass spectrometry (ESI)⁺)：m/z＝349[M+H]⁺。

Example 170

(1H-benzimidazol-5-yl) - (cis-2-methyl-4 b, 5, 6, 7, 8a, 9-hexahydro-3-oxa-1, 8-diaza-cyclopenta [ b ] fluoren-8-yl) -methanone

(cis-7-amino-8-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] in triethyl orthoformate (0.5mL) was stirred at 60 deg.C]Pyridin-1-yl) - (1H-benzimidazol-5-yl) -methanone (0.10g) was used for 2 hours. After cooling to room temperature, the mixture was concentrated and the residue was chromatographed on silica gel (dichloromethane/methanol 1: 0 → 7: 3) to give the title compound. Yield: 64% of theory; LC (method 1): t is t_R2.28 min; mass spectrometry (ESI)⁺)：m/z＝373[M+H]⁺。

Example 171

(1H-benzimidazol-5-yl) - (cis-4 b, 5, 6, 7, 8a, 9-hexahydro-3-oxa-1, 8-diaza-cyclopenta [ b ] fluoren-8-yl) -methanone

(cis-7-amino-8-hydroxy-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b) ]A mixture of pyridin-1-yl) - (1H-benzimidazol-5-yl) -methanone (100mg), 4-toluenesulfonic acid hydrate (5mg), triethyl orthoformate (40. mu.L) and methanol (1mL) was stirred at 60 ℃ for 2 hours. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in ethyl acetate. The resulting solution was washed with 1M NaOH solution and dried (Na)₂SO₄) And concentrated to give the title compound. Yield: 50 mg (49% of theory); LC (method 1): t is t_R2.24 minutes; mass spectrometry (ESI)⁺)：m/z＝359[M+H]⁺。

Example 172

(1H-benzimidazol-5-yl) - (cis-6-methoxy-7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 1 from 1H-benzimidazole-5-carboxylic acid and cis-6-methoxy-7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine. LC (method 7): t is t_R1.04 min; mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺。

Example 173

(1H-benzimidazol-5-yl) - (cis-6-hydroxy-7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] pyridin-1-yl) -methanone

The title compound was synthesized in analogy to the procedure described in example 7 from (1H-benzimidazol-5-yl) - (cis-6-methoxy-7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-indeno [2, 1-b ] ]Pyridin-1-yl) -methanone. LC (method 7): t is t_R0.82 min; mass spectrometry (ESI)⁺)：m/z＝348[M+H]⁺。

Examples 174 and 175

(4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile (174) and (4a-S, 9a-R) -1- (1H-benzimidazole-5-carbonyl) -7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile (175)

(Absolute configuration of both Compounds is arbitrarily designated)

The title compound was prepared in analogy to the procedure described for example 106 from cis-7-methyl-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl-trifluoromethanesulfonate (isomer mixture linked to the sulfonyl group at N-1 or N-3 for benzimidazole) and zinc cyanide; the title compound was isolated by SFC on the chiral phase.

(4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile (174): LC (method 7): t is t_R0.88 min;mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺，379[M+Na]⁺。

(4a-S, 9a-R) -1- (1H-benzimidazole-5-carbonyl) -7-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile (175): LC (method 7): t is t _R0.88 min; mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺，379[M+Na]⁺。

Examples 176 and 177

(4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile (176) and (4a-S, 9a-R) -1- (1H-benzimidazole-5-carbonyl) -5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridine-6-carbonitrile (177)

(Absolute configuration of both Compounds is arbitrarily designated)

The title compound was prepared in analogy to the procedure described for example 106 from cis-5-methyl-1- (1-trifluoromethanesulfonyl-1H-benzimidazole-5-carbonyl) -2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ] pyridin-6-yl-trifluoromethanesulfonate (isomer mixture linked to the sulfonyl group at N-1 or N-3 for benzimidazole) and zinc cyanide; the title compound was isolated by SFC on the chiral phase.

(4a-R, 9a-S) -1- (1H-benzimidazole-5-carbonyl) -5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile (176): LC (method 7): t is t_R0.89 min; mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺，379[M+Na]⁺。

(4a-S, 9a-R) -1- (1H-benzimidazole-5-carbonyl) -5-methyl-2, 3, 4, 4a, 9, 9 a-hexahydro-1H-indeno [2, 1-b ]]Pyridine-6-carbonitrile (177): LC (liquid Crystal)(method 7): t is t_R0.89 min; mass spectrometry (ESI)⁺)：m/z＝357[M+H]⁺，379[M+Na]⁺。

Some formulation examples are described below in which the term "active agent" represents one or more compounds of the present invention, including salts thereof. The term "active substance" also includes other active substances in the case of one of the combinations with one or other active substances as described before.

Example A

Tablet comprising 100mg of active substance

Consists of the following components:

a sheet comprising:

the preparation method comprises the following steps:

the active substance, lactose and starch are mixed together and homogeneously moistened with an aqueous solution of polyvinylpyrrolidone. The wet composition was screened (2.0mm mesh size) and dried in a track dryer at 50 ℃ before being screened (1.5mm mesh size) again and the lubricant was added. The final mixture is compressed to form tablets.

Tablet weight: 220mg of

Diameter: 10mm, biplane, both facets and one notch.

Example B

Tablet comprising 150mg of active substance

Consists of the following components:

a sheet comprising:

preparation:

the active substance mixed with lactose, corn starch and silicon dioxide is moistened with a 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve with a mesh size of 1.5 mm. The granules dried at 45 ℃ are passed through the same sieve again and mixed with the specified amount of magnesium stearate. The mixture was compressed into tablets.

Tablet weight: 300mg

A mould: 10mm, flat

Example C

Hard gelatin capsules containing 150mg of active substance

Consists of the following components:

a capsule comprising:

preparation:

the active substance is mixed with the excipients, passed through a sieve with a mesh size of 0.75mm and mixed homogeneously with a suitable apparatus. The final mixture was filled into hard gelatin capsules No. 1.

The filling amount of the capsules is as follows: about 320mg

Capsule shell: hard gelatin capsule No. 1.

Example D

Suppository containing 150mg of active substance

Consists of the following components:

a suppository comprising:

preparation:

after melting the suppository base, the active substance is distributed homogeneously therein and the melt is poured into a cooled mold.

Example E

Ampoule containing 10mg of active substance

Consists of the following components:

active substance 10.0mg

Proper amount of 0.01N hydrochloric acid

Double distilled water to 2.0mL

Preparation:

the active substance is dissolved in the necessary amount of 0.01N HCl (made isotonic with the usual salts), sterile filtered and transferred into 2mL ampoules.

Example F

Ampoule containing 50mg of active substance

Consists of the following components:

active substance 50.0mg

Proper amount of 0.01N hydrochloric acid

Double distilled water to 10.0mL

Preparation:

the active substance is dissolved in the necessary amount of 0.01N HCl (made isotonic with the usual salts), sterile filtered and transferred into 10mL ampoules.

Claims

1. A compound of formula I:

wherein

R¹Selected from: benzimidazol-5-yl, 6-methyl-benzimidazol-5-yl and 7-methyl-benzimidazol-5-yl;

R²selected from: hydrogen and cyano;

R³、R⁴independently of one another, selected from: hydrogen and fluorine;

m represents 0 or 1;

and wherein the aliphatic moiety of the tricyclic core structure of formula I is optionally substituted with 1 or 2 methyl groups.

2. The compound of claim 1, wherein the compound is a compound having the structure of formula i.a or a pharmaceutically acceptable salt thereof

Wherein the piperidine substructure and the tetralin of m ═ 1 or the indane substructure of m ═ 0 form a tricyclic core structure in the cis configuration.

3. The compound of claim 1, wherein compound is a compound having the structure of formula I.b or a pharmaceutically acceptable salt thereof

Wherein the tricyclic core structure is of the R configuration at C-10b for m ═ 1/C-4 a for m ═ 0 and of the S configuration at C-4a for m ═ 1/C-9 a for m ═ 0.

4. A compound according to any one of claims 1 to 3, wherein m is 0.

5. The compound of claim 1, wherein the compound is of the formula:

6. the compound of any one of claims 1 to 3, wherein the compound is a compound of the following structural formula:

7. The compound of any one of claims 1 to 3, wherein the compound is a compound of the following structural formula:

8. a pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition which can be affected by inhibition of the enzyme 11 β -hydroxysteroid dehydrogenase 1.

10. The use of claim 9, wherein the disease or condition is selected from: type 1 and type 2 diabetes, metabolic disorders, retinopathy, nephropathy, neuropathy, reactive hypoglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, atherosclerosis, obesity, hypertension, chronic heart failure, edema, hyperuricemia, glaucoma, osteoporosis, cognitive impairment, anxiety, depression, tuberculosis, leprosy, and psoriasis.

11. The use of claim 10, wherein the renal disease is acute renal failure.

12. The use of claim 10, wherein the metabolic disease is metabolic syndrome.

13. The use of claim 10, wherein the disease or condition is selected from: type 2 diabetes, obesity, glucose intolerance, reactive hypoglycemia, insulin resistance, and dyslipidemia.

14. The use of claim 13, wherein the dyslipidemia is hyperlipidemia.

15. The use of claim 13, wherein the disease or disorder is type 2 diabetes.