OA16399A

OA16399A - Crystalline forms of hydrochloride salt of (4AR, 9A-S)-1-(1H-benzoimidazole-5-car-bonyl)-2, 3, 4, 4A 9, 9A-hexahydro-1H-indeno[2, 1-B] pyridine6-carbonitrile and their use as HSD 1 inhibitors.

Info

Publication number: OA16399A
Application number: OA1201300181
Authority: OA
Inventors: Matthias Eckhardt; HansJuergen MARTIN; Martin Schuehle; Sandra Sick; Bing-Shiou Yang
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2010-11-05
Filing date: 2011-11-04
Publication date: 2015-10-07

Abstract

The present invention relates to compounds defined by formula I

Description

Aryi- and heteroarylcarbonyl dérivatives of hexahydroindenopyridine and octahydrobenzoquinoline

Related Applications

This applications claims the benefit of U.S. Provisional Application Serial No. 61/484,995, filed May 11,2011. This applications also claims priority to International Application Serial No. PCT/US2010/055586, filed November 5, 2010. The entire teachings of these two applications are incorporated herein by reference.

Field of the invention

The présent invention relates to hexahydroindenopyridines and octahydrobenzoquinolines and their use as inhibitors of 11ft-hydroxysteroid dehydrogenase 1 (HSD 1 ), to pharmaceutical compositions containing said compounds as well as their use for the treatment of metabolic disorders like metabolic syndrome, diabètes, obesity, and dyslipidemia. In addition, the invention relates to processes for preparing a pharmaceutical composition as well as a compound according to the invention.

Background of the invention

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

In Bulletin ofthe Chemical Society ofJapan 1959, 32, p. 1005-7 and Journal ofOrganic

Chemistry 1964, 29, p. 1419-24, the compounds of the following structures hâve been disclosed:

In Journal of Organic Chemistry 1984, 49, p. 2504-6 a chromatographie method to separate enantiomers of heterocyclic amines, inter alia the enantiomers of the following racemic compound are disclosed:

In Journal of Médicinal Chemistry 1981, 24, p. 1432-7 the following compound is described as an intermediate in order to separate cis- and trans-isomer:

Aim of the invention

It has been surprisingly found that compounds of the présent invention hâve not only an inhibitory effect on HSD 1 in vitro and/or in vivo but also possess significant metabolic stability which makes them suitable to be used as médicaments. Accordingly, aim of the présent invention is to discover hexahydroîndenopyridines and octahydrobenzoquinolines having an inhibitory effect on HSD 1 in vitro and/or in vivo and possessing suitable pharmacological and pharmacokinetic properties to use them as médicaments.

A further aspect of the présent invention is to provide new pharmaceutical compositions which are suitable for the prévention and/or treatment of metabolic disorders.

A further aspect of the invention relates to the physiologically acceptable salts of the compounds of general formula I according to this invention with inorganic or organic acids or bases.

In a further aspect this invention relates to pharmaceutical compositions, containing at least one compound of general formula I or a physiologically acceptable sait according to the invention, optionally together with one or more inert carriers and/or diluents.

In a further aspect this invention relates to the compounds according to general formula I or the physiologically acceptable salts thereof for treatment or prévention of diseases or conditions which can be influenced by inhibiting the enzyme 11 β-hydroxysteroid dehydrogenase (HSD) 1, such as metabolic disorders.

In a further aspect this invention relates to the use of at least one compound according to general formula I or a physiologically acceptable sait thereof for preparing a pharmaceutical composition which is suitable for the treatment or prévention of diseases or conditions which can be influenced by inhibiting the enzyme 11B-hydroxysteroid dehydrogenase (HSD) 1, such 5 as metabolic disorders.

Other aims of the présent invention will become apparent to the skilled man directly from the foregoing and following remarks.

Brief Description of the Drawinqs

FIG. 1 is an XRPD pattern obtained from a sample of Form I of the compound of formula (II).

FIG. 2 is a ¹³C SSNMR spectrum obtained from a sample of Form I of the compound of formula 15 (II).

FIG. 3 is a thermal analysis profile obtained from a sample of Form I of the compound of formula (II) determined by DSC measurements.

FIG. 4 is a thermal analysis profile obtained from a sample of Form I of the compound of formula (11) determined by TGA measurements.

FIG. 5 is an XRPD pattern obtained from a sample of Form II of the compound of formula (II).

FIG. 6 is a ¹³C SSNMR spectrum obtained from a sample of Form II of the compound of formula (II).

FIG. 7 is a thermal analysis profile obtained from a sample of Form II of the compound of formula (II) determined by DSC measurements.

FIG. 8 is a thermal analysis profile obtained from a sample of Form II of the compound of formula (11) determined by TGA measurements.

Detailed description

In a first aspect the présent invention relates to compounds of general formula I

wherein

R¹ is selected from the group R^1a consisting of phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, wherein in the pyrrolyl, furanyl, thienyl, and pyridyl group optionally 1 or 2 CH groups may be replaced by N, and wherein in the indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl group 1 to 3 CH groups may optionally be replaced by N,

2-oxo-l ,2-dihydro-pyridinyl, 4-oxo-1,4-dihydro-pyridinyl, 3-oxo-2,3-dihydropyridazinyl, 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-1,2dihydro-pyrazinyl, 2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl, indanyl, 1-oxo-indanyl, 2,3-dihydro-indolyl, 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, 2oxo-2,3-dihydro-benzoxazolyl, benzofl ,3]dioxolyl, 2-oxo-benzo[1,3]dioxolyl,

1.2.3.4- tetrahydro-naphthyl, 1,2,3,4-tetrahydro-quinolinyl, 2-oxo-1,2,3,4tetrahydro-quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, 4-oxo-1,4-dihydro-quinolinyl,

1.2.3.4- tetrahydro-isoquinolinyl, 1-oxo-1,2,3,4-tetrahydro-isoquinolinyl, 1-oxo-1,2dihydro-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-1,2,3,4tetrahydro-quinoxalinyl, 1-oxo-1,2-dihydro-phthalazinyl, 1,4-dioxo-1,2,3,4tetrahydro-phthalazinyl, chromanyl, coumarinyl, 2,3-dihydro-benzo[1,4]dioxin-yl, 3oxo-3,4-dihydro-benzo[1,4]oxazinyl, tetrazolyî, 2-oxo-2,3-dihydro-benzothiazolyl, and imidazo[1,2-a]pyridinyl, wherein the members of the group R^1a are attached to the carbonyl group in formula I via an aromatic carbon atom and wherein the members of the group R^1a may optionally be substituted with one R⁵, one to three identical and/or different R⁶, and/or one R⁷, provided that in case R¹ is a phenyl group, the substituents R⁵, R⁶, and/or R⁷ are not attached to the carbon atoms next to the carbon atom which is attached to the carbonyl group in formula I;

R²	is selected from the group R^2a consisting of hydrogen, halogen, (het)aryl, cyano, nitro, amino, hydroxy, Ci^-alkyl, C₃.₆cycloalkyl, C₂.₆-alkenyl, and C₂._e-alkynyl, wherein in each C^-alkyl-, C₃.6-cycloalkyl-, C₂-6-alkenyl- or C₂.6-alkynyl-group one CH₂ group may optionally be replaced by CO or SO₂₁ one CH₂ group optionally by 0 or NRⁿ and one CH group optionally by N, and wherein each of those groups may optionally be mono- or polyfluorinated and optionally mono- or independently of each other disubstituted with chlorine, C^a-alkyl, cyano, (het)aryl, amino, Ci_₃-alkylamino, di-(C₁.₃-alkyl)amino, hydroxy, Ci.₃-alkyloxy, (het)aryloxy, Ci.₃-alkylsulfanyi, 0,.3alkylsulfinyl, or C₃^-cycloalkyl, wherein one or two CH₂ groups of the C₃.₆cycloalkyI group may optionally be replaced independently of each other by carbonyl, 0 or NRⁿ and one CH group optionally by N, and which may optionally be mono- or independently disubstituted with fluorine or Cj.s-alkyl;
R³, R⁴	are selected independently of each other from the group R³'^4a consisting of hydrogen, halogen, Ci.₃-alkyl, trifluoromethyl, hydroxy, Ci.₃-alkyloxy, and cyano, or R³'^4a dénotés R³ and R⁴ that are bound to adjacent carbon atoms and joined to form a methylenedioxy, ethylenedioxy, or C₃.₅-alkylene group, each of which may optionally be substituted with one or two groups independently selected from fluorine and methyl, or, together with the carbon atoms they are attached, form a benzo, pyrido, pyrimido, pyrazino, pyridazino, pyrazolo, imidazo, triazolo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring, each of which may optionally be substituted with one or two substituents selected independently from halogen, C,. 3-alkyl, trifluoromethyl, amino, Ci.₃-alkylamino, di-fC^-alkylJamino, hydroxy, and Ci.₃-alkyloxy;
R⁵	is selected from the group R^5a consisting of halogen, (het)aryl, cyano, nitro, amino, hydroxy, C^-alkyl, C₃^-cycloalkyl, C₂._c-alkenyl, and C₂._G-alkynyl, wherein in each group one CH₂ group may optionally be replaced by CO or SO₂, one CH₂ group optionally by 0 or NR^N, and one CH group optionally by N, and wherein each group may optionally be mono- or polyfluorinated and optionally mono- or independently of each other disubstituted with chlorine, C^a-alkyl, cyano, (het)aryl, amino, Cvralkylamino, di-(C_V3-alkyl)amino, hydroxy, Ci.₃-alkyloxy, (het)aryloxy, Ci.₃-alkylsulfanyl, Ci_₃-

	alkylsulfinyl, or C₃.₆-cycloalkyl, wherein one or two CH₂ groups of the C₃.₆cycloalkyl group may optionally be replaced independently of each other by carbonyl, 0 or NRⁿ and one CH group optionally by N, and which may optionally be mono- or independently disubstituted with fluorine or Cu-alkyl;
R⁶, R^T	are selected independently of each other from the group R^6l7a consisting of halogen, C_f.₃-alkyl, C₂.₃-alkynyl, trifluoromethyl, hydroxy, C^-alkyloxy, and cyano, and/or R^6i7a dénotés one R⁶ combined with R⁷, which are bound to adjacent carbon atoms, that form a methylenedioxy, difluoromethylenedioxy, ethylenedioxy, C₃.₅alkylene group, or form, together with the carbon atoms they are attached, a pyrazolo, imidazo, oxazolo, isoxazolo, thiazolo, or isothiazolo ring, each of which may optionally be mono- or disubstituted independently of each other with Ci_₃alkyl, trifluoromethyl, amino, Ci.₃-alkylamino, di-(Ci.₃-alky!)amino, hydroxy, C_v3alkyloxy;
Rⁿ	is selected independently of each other from the group R^Na consisting of hydrogen, C^-alkyl, C_M-cycloalkyl, C₃^-alkenyl, C₃.₆-alkynyl, (het)aryl, C-malkylcarbonyl, (het)arylcarbonyl, Cvi-alkylaminocarbonyl, di-(C₁.₃-alkyl)aminocarbonyl, (het)arylaminocarbonyl, C_M-alkyloxycarbonyl, C^-alkylsulfonyl and (het)arylsulfonyl, wherein each alkyl, alkenyl and alkynyl group may optionally be mono- or polysubstituted with fluorine and optionally monosubstituted with (het)aryl, cyano, aminocarbonyl, Cva-alkylaminocarbonyl, di-ÎCvs-alkyljaminocarbonyl, carboxy, C_M-alkyloxycarbonyl, amino, C;.₄-alkylamino, di-(Ci.₃-alkyl)amino, Cm-alkylcarbonylamino, hydroxy, C^-alkyloxy, C,^-alkylsulfanyl, Ci_₄alkylsulfinyl, or C^-alkylsulfonyl;
(het)aryl	is selected independently of each other from the group HA^a consisting of phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, wherein in the pyrrolyl, furanyl, thienyl, and pyridyl group optionally 1 or 2 CH groups may be replaced by N, and wherein in the indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl group 1 to 3 CH groups optionally may be replaced by N, 2-oxo-l ,2-dihydro-pyridinyl, 4-oxo-1,4-dihydro-pyridinyI, 3-oxo-2,3-dihydropyridazinyl, 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-1,2dihydro-pyrazinyl, 2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl, 2-oxo-2,3-dihydroindolyl, 2,3-dihydrobenzo-furanyl, 2-oxo-2,3-dihydro-benzimidazolyl₁ 2-oxo-2,3dihydro-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-dihydroquinazolinyl, 4-oxo-1,4-dihydro-quinazolinyl, 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl, 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-d i hyd ro-p ht halaziny 1, 1,4dioxo-1,2,3,4-tetrahydro-phthalazinyl, chromanyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxinyl, 3-oxo-3,4-dihydro-benzo[1,4]oxazinyl, and tetrazolyl, and wherein the above-mentioned (het)aryl groups may optionally be substituted with one to three R¹⁰ which may be identical or different;

R¹⁰ is selected independently of each other from the group R^10a consisting of halogen, C^a-alkyl, difluoromethyl, trifluoromethyl, cyano, aminocarbonyl, Ci-3-alkylaminocarbonyl, di-(Ci-3-alkyl)-aminocarbonyl, carboxy,

CM-alkyloxycarbonyï, nitro, amino, Ci.₃-alkylamino, dÎ-(Ci.₃-alkyl)amino, acetylamino, methylsulfonylamino, hydroxy, C^-alkyloxy, difluoromethoxy, trifluoromethoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, aminosulfonyl and phenyl, wherein the phenyl-group may optionally be substituted with 1 or 2 substituents independently of each other selected from fluorine, methyl, methoxy, cyano, and hydroxy;

dénotés 0 or 1 ;

and wherein the aliphatic part of the tricyclic core structure of general formula I is substituted with one or two different or identical groups selected independently of each other from the group R^8a consisting of hydrogen, methyl, and ethyl;

the tautomers thereof, the stereoisomers thereof, the mixtures thereof, and the salts thereof, while the following compounds are excluded:

In a further aspect the présent invention relates to a process for preparing the compounds of general formula I, characterized in that a compound of general formula II

wherein the variables R², R³, R⁴, and m are defined as hereinbefore and hereinafter, is reacted with a compound of general formula R¹-CO-Y, optionally prepared in situ from the corresponding carboxylic acid (Y = OH), wherein R¹ is defined as hereinbefore and hereinafter and

Y is a leavïng group and in particular dénotés fluorine, chlorine, bromine, cyano, Ci.₄-alkoxy, C₂-4-alkenyloxy, C₂_4-alkynyloxy, C^alkyIsulfanyl, arylotriazoloxy, heteroarylotriazoloxy, heteroar-N-yl, succinyl-N-oxy, C^alkylcarbonyloxy, di-fC^-alkylJ-aminocarbonyloxy, pyrrolylcarbonyloxy, piperidinylcarbonyloxy, morpholinylcarbonyloxy, [tri-(C_V4-alkyl)-carbamimidoyl]oxy, [di-(C-i_4-alkyl)20 amino][di-(Ci.₄-alkyl)-iminiumyl]methoxy {= [(C_M-alkyl)₂N]₂C⁺-O-}, (N,N’-dicyclohexylcarbamidoyl)oxy, di-fC^-alkyloxyJ-phosphoryloxy, bis[di-(C_M-alkyl)-amino]phosphoryloxy, [bis(pyrrolidin-1-yl)-phosphoryl]oxy, aryloxy, arylsulfanyl, heterosulfanyl, or heteroaryloxy, while the alkyl, alkenyl, and alkynyl groups mentioned in the définition of the above leaving groups optionally may be mono- or polysubstituted with fluorine, chlorine, C1.3alkyl, or C^-alkoxy, while the aryl groups mentioned in the définition of the above leaving groups, either alone or as part of another group, dénoté phenyl or naphthyl and the heteroaryl groups

A mentioned in the définition of the above groups, either alone or as part of another group, dénoté pyridinyl, pyrimidinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, whilst both, the aryl and heteroaryl groups, may optionally be mono- or polysubstituted independently of each other with fluorine, chlorine, bromine, C^-alkyl, C^-alkyloxy, nitro, cyano, and/or di-(Ci.₃-alkyl)amino, optionally in the presence of a base such as a tertiary or an aromatic amine, e.g. ethyldiisopropyl-amine, triethylamine, imidazole, or pyridine, or an inorganic sait, e.g. potassium carbonate or calcium oxide, and/or another additive such as 4-dimethylaminopyridine or 110 hydroxybenzotriazol, in solvents preferably selected from tetrahydrofuran, 1,2-dimethoxyethane, ether, 1,4-dioxane, Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidinone, acetonîtrile, ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, benzene, and hexanes, also aqueous and alcoholic solutions may be usable for some of the combinations listed above, preferably at -10 to 120 °C;

and, if necessary, any protective group used in the reactions described above is cleaved concurrently or subsequently;

if desired, a compound of general formula I thus obtained is resolved into its stereoisomers;

if desired, a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof.

Detailed Description of the invention

Uniess otherwise stated, the groups, residues, and substituents, particularly R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R®, R¹⁰, Rⁿ, and m are defined as above and hereinafter. If residues, substituents, or groups occur several fîmes in a compound they may hâve the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention will be given hereinafter.

Preferred embodiments of the invention are characterized by the following définitions:

In a further embodiment of the présent invention is selected from the group R^1b consisting of phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl,

wherein in the pyrrolyl, furanyl, thienyl, and pyridyl group optionally 1 CH group may be replaced by N, and wherein in the indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl groups optionally 1 or 2 CH groups may be replaced by N, indanyl, 2,3-dihydro-indolyl, 2-oxo-2,3-dihydro-indolyl, 2,3-dihydro-benzofuranyl, 2oxo-2,3-dihydro-benzoimidazolyl, 2-oxo-2,3-dihydro-benzothiazolyl, benzo[1,3]d ioxolyl, 1,2,3,4-tetrahydronaphthy 1, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2-oxo-1₁2-dihydro-quinoxalinyl, 3-oxo-1,2,3,4tetrahydro-quinoxalinyl, chromanyl, and imidazo[1,2-a]pyridinyl, wherein the members of the group R^1b are attached to the carbonyl group in formula I via an aromatic carbon atom and wherein the members of the group R^1b may optionally be substituted with one R⁵, one R⁶, and/or one R⁷, provided that in case R¹ is a phenyl group, the substituents R⁵, R⁶, and/or R⁷ are not attached to the carbon atoms next to the carbon atom which is attached to the carbonyl group in formula I.

In a further embodiment of the présent invention

R¹ is selected from the group R^1c consisting of phenyl, naphthyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, wherein in the indolyl, benzofuranyl, and benzothiophenyl group optionally 1 or 2 CH groups may be replaced by N, indanyl, 2,3-dihydro-indolyl, 2-oxo-2,3-dihydro-indolyI, 2,3-dihydrobenzofuranyl, 2oxo-2,3-dihydro-benzoimidazolyl, 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-aJpyridinyl, wherein the members of the group R^1c are attached to the carbonyl group in formula I via an aromatic carbon atom and wherein the members of the group R^lc may optionally be substituted with one R⁵, one R⁶, and/or one R⁷, provided that in case R¹ is a phenyl group, the substituents R⁵, R⁶, and/or R⁷ are not attached to the carbon atoms next to the carbon atom which is attached to the carbonyl group in formula

In a further embodiment of the présent invention

R¹ is selected from the group R^ld consisting of phenyl, indolyl, 2-oxo-2,3-dihydro-indolyl, benzimidazolyl, indazolyl, imidazo[1,2ajpyridinyl, 2-oxo-2,3-dihydro-benzoimidazolyl, 2-oxo-2,3-dihydro-benzothiazolyl, imidazopyridinyl, benzotriazolyl. benzothiazolyl and 2-oxo-1,2-dihydroquinoxalinyl, wherein the members of the group R^1d are attached to the carbonyl group in formula I via an aromatic carbon atom and wherein the members of the group R^1d may optionally be substituted with one R^s, one R⁶, and/or one R⁷, provided that in case R¹ is a phenyl group, the substituents R⁵, R⁶, and/or R⁷ are not attached to the carbon atoms next to the carbon atom which is attached to the carbonyl group in formula I.

In a further embodiment of the présent invention

R¹ is selected from the group R^1dZ consisting of

4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4amino-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, e-methyl-benzimidazol-S-yl, 7-methylbenzimidazol-S-yl, indazol-5-yl and benzothiazol-6-yl.

In a further embodiment of the présent invention

R¹ is selected from the group R'^e consisting of

4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fiuoro-4-hydroxy-phenyl, 4amino-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 a further embodiment of the présent invention

R¹ is selected from the group R¹’ consisting of benzimidazol-S-yl, 6-methyl-benzimidazol-5-yl and ï-methyl-benzimidazol-S-yl.

In a further embodiment of the présent invention

R² is selected from the group R^2b consisting of

hydrogen, halogen, (het)aryl, cyano, nitro, amino, hydroxy, C₂.₆-alkynyl,

C^-alkyl and C_M-cycloalkyl, wherein in the Ci.₆-aikyI and C₃._G-cycloalkyl group one CH₂ group may optionally be replaced by CO or SO₂, one CH₂ group optionally by O or NRⁿ, and one CH groupoptionally by N, and wherein both of these groups may optionally be mono- or polyfluorinated and optionally mono- or independently of each other disubstituted with chlorine, Cj^-alkyl, cyano, (het)aryl, amino, Cj^-alkylamino, di-(Ct.₃-alkyl)amino, hydroxy, Ci_₃-alkyloxy, (het)aryloxy, Cj-3-alkylsuifanyl, C^alkylsulfinyl, and/or C_3Î-cycloalkyl, wherein in the C₃.₆-cycloalkyl group one or two CH₂ groups may optionally be replaced independently of each other by carbonyl, O or NRⁿ, and one CH group optionally by N, and which may optionally be mono- or independently disubstituted with fluorine or Ci.₃alkyl.

In a further embodiment of the présent invention

R² is selected from the group R^2c consisting of hydrogen, fluorine, chlorine, bromine, Cv₃-alkyl, C₃^-cycloalkylmethyl, cyclopropyl, (het)aryl-methyl, C₂-»-alkynyl, (het)aryl, cyano-Ci.₃-alkyl, aminocarbonyl-Ci_₃-alkyl, Cvs-alkyl-aminocarbonyl-Ci-3-alkyl, di-fC-i.a-alkyQ-aminocarbonyl-Cvs-alkyl, pyrrolidin-l-yl-carbonyl-Cva-alkyl, piperidin-l-yl-carbonyl-Cvs-alkyl, morpholin-4-ylcarbonyl-Cvralkyl, carboxy-Cv₃-alkyl, C^-alkyloxy-carbonyl-Ci-s-alkyl, Cvs-alkylcarbonyl-amino-C^-alkyl, N-ÎCva-alkylJ-Cva-alkylcarbonyl-amino-Cioalkyl, 2-oxo-pyrrolidin-1-yl-C₁.₃-alkyl, 2-oxo-piperidin-1-yl-C₁.₃-alkyl, 3-oxomorpholin-4-yl-Cu-alkyl, hydroxy-Cvij-alkyl, Cra-alkyloxy-Ci^-alkyl, trifluoromethyl, difluoromethyl, cyano, aminocarbonyl, C^-alkyl-aminocarbonyl, di-(C₁.₃-alkyl)aminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, morpholin-4-ylcarbonyl, carboxy, C_V3-alkyloxy-carbonyl, amino, C^-alkylamino, C,.₃-alkylcarbonylamino, (het)aryl-carbonylamino, N-(Ci.₃-alkyl)-Ci_₃-alkyl-carbonylamino, N-(C₁.₃-alkyl)-(het)aryl-carbonylamino, 2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl, Ci.₃-alkyl-sulfonylamino, N-fCvs-alkyO-C,^alkyl-sulfonylamino, N-fCvs-alkylHhetJaryl-sulfonylamino, hydroxy, C_M-alkyloxy, C₃.₆-cycloalkyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, difluoromethoxy, trifluoromethoxy, (het)aryloxy, cyano-Ci.₃-alkyloxy, aminocarbonyl-C^-alkyloxy, Ci.3-alkyl-aminocarbonyl-C1.3

alkyloxy, di-tCi.rj-alkyQ-aminocarbonyl-Cvralkyloxy, pyrrolidin-1 -yl-carbonyl-C^alkyloxy, piperidin-1 -yl-carbonyl-Cva-alkyloxy, morpholin-4-yl-carbonyl-Ci_3-alkyloxy, carboxy-Cvj-alkyloxy, Cvralkyloxy-carbonyl-Cvralkyloxy, hydroxy-Ct.3alkyloxy, Cbralkyloxy-Cï.g-alkyloxy, tetrahydrofuranyl-Cva-alkyloxy, tetrahydropyranyl-Ci-3-alkyloxy, C^-alkylsulfonyl, C₃.₆-cyc!oalkylsulfonyl, aminosulfonyl, Ci.₃-alkyl-aminosulfonyl and di-(Ci.₃-alkyl)-aminosulfonyl, wherein the above-mentioned term (het)aryl dénotés phenyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, ail of whîch may optionally be mono- or disubstituted with R¹⁰.

In a further embodiment of the présent invention

R² is selected from the group R^2d consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethynyl, cyclopropyl, C₃.₆-cycloalkylmethyl, phenylmethyl, hydroxy-C^-alkyl, phenyl, cyano, aminocarbonyl, methyiaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, morpholin4-ylcarbonyl, carboxy, methoxycarbonyl, amino, acetylamino, methlysulfonylamino, hydroxy, Ci.₃-alkyloxy, phenyloxy, and pyridazinyloxy, while the mentioned phenyl and pyridazinyl groups may optionally be monosubstituted with fluorine, methyl, cyano, or methoxy.

In a further embodiment of the présent invention

R² is selected from the group R^2e consisting of hydrogen, fluorine, bromine, cyclohexylmethyl, phenylmethyl, 4-methoxyphenylmethyl, hydroxymethyl, 2-hydroxyprop-2-yl, phenyl, cyano, aminocarbonyl, methyiaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, morpholin4-ylcarbonyl, carboxy, methoxycarbonyl, amino, hydroxy, methoxy, 4methoxyphenoxy, and 6-methyl-pyridazin-3-yloxy.

In a further embodiment of the présent invention

R²

is selected from the group R^Zf consisting of hydrogen and cyano.

In a further embodiment of the présent invention

R³, R⁴ are selected independently of each other from the group R^3/4b consisting of hydrogen, fluorine, chlorine, Ci.₃-alkyl, trifluoromethyI, cyano, hydroxy, and Ο_ν3alkyloxy, or

R^3/4b dénotés R³ and R⁴ that are attached to adjacent carbon atoms and joined to form a methylenedioxy or ethylenedioxy group, or, together with the carbon atoms they are attached, an imidazo, oxazolo, or a thiazolo ring, each of which may optionally be substituted with one or two substituents independently selected from methyl, dimethylamino, hydroxy, and methoxy.

In a further embodiment of the présent invention

R³, R⁴ are selected independently of each other from the group R^3,4c consisting of hydrogen, fluorine, chlorine, methyl, trifluoromethyl, cyano, hydroxy, and methoxy.

In a further embodiment of the présent invention

R³, R⁴ are selected independently of each other from the group R^3/4cZ consisting of hydrogen, fluorine and methyl.

In a further embodiment of the présent invention

R³, R⁴ are selected independently of each other from the group R^3/4d consisting of hydrogen and fluorine.

In a further embodiment of the présent invention

R⁵ is selected from the group R^5b consisting of fluorine, chlorine, bromine, C_lJ(-alkyI, C3.₆-cycloalkyl-C_V3-alkyl, C₃.₆-cycloalkyl, (het)aryl-Cv3-alkyl, (het)aryl, cyano-Cv₃-alkyl, aminocarbonyl-Cvs-alkyl, Cvg-alkylaminocarbonyl-C^-alkyl, di-fCvs-alkylj-aminocarbonyl-Cva-alkyl, pyrrolidin-1 -ylcarbonyl-Cva-alkyl, piperidin-1 -yl-carbonyl-Ci*₃-aIkyt, piperazin-1 -yl-carbonyl-C-|.₃alkyl, 4-(C₁.₃-alkyl)-piperazin-1 -yl-carbonyl-Cvs-alkyl, morpholin-4-yl-carbonyl-Ci.₃alkyl, carboxy-C^-alkyl, C^-alkyloxy-carbonyl-C^-alkyl, amino-Ci.₃-alkyl, Ο-|.₃alkylamino-Cva-alkyl, di-ÎC^j-alkylj-amino-Ci.s-alkyl, pyrrolidin-1 -yl-Cu-alkyl, piperidin-1 -yl-Ct-3-alkyl, piperazin-1 -yl-Cvj-alkyl, 4-(Ci.₃-alkyl)-piperazin-1-yl-C₎.₃16399

alkyl, morpholin-4-yl-C,.₃-alkyl, Ci-3-alkylcarbonylamino-C,.₃-alkyl, (het)arylcarbonylamino-C,.3-alkyl, 2-oxo-pyrrolidin-1-yl-C₁.₃-alkyl, 2-oxo-piperidin1-yl-C,.₃-alkyl, 2-oxo-piperazin-1-yl-Ci.₃-alkyl, S-oxo-piperazin-l-yl-Cvs-alkyl, 2oxo-4-(C,.₃-alkyl)-piperazin-1 -yl-C,.₃-alkyl, 3-oxo-4-(Ci.₃-alkyl)-piperazin-1 -yl-C,.₃alkyl, 3-oxo-morpholin-4-yl-C,.₃-alkyl, hydroxy-C,.₃-alkyl, C,.₃-alkyloxy-Ci.₃-alkyl, (het)aryloxy-C,.₃-alkyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoro-1hydroxyethyl, 2,2,2-trifluoro-1-hydroxy-1-methylethyl, 2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl, cyano, aminocarbonyl, C,.₃-alkyl-aminocarbonyl, ΰί-(Ο,.₃alkyl)-aminocarbonyl, (het)aryl-C,.3-alkylaminocarbonyl, N-(Ci.₃-alkyl)-(het)aryl-Ci. 3-alkylaminocarbonyl, (het)arylaminocarbonyl, N-(C,.₃-alkyl)-(het)arylaminocarbonyl, pyrrolidin-1-yl-carbonyl_T piperidin-1-yl-carbonyl, piperazin-1-ylcarbonyl, 4-(C₁.₃-alkyl)-piperazin-1-yl-carbonyl, morpholin-4-yl-carbonyl, carboxy, Ci.₃-alkyloxy-carbonyl, nitro, amino, C,.₃-alkylamino, di-(C,.₃-alkyl)amino, pyrrolidin-1-yl, piperidîn-1 -yl, piperazin-1 -yl, 4-(C₁.₃-alkyl)-piperazin-1-yl, 4-(0,.3alkylcarbonyl)-piperazin-1 -yl, 4-(Ci_₃-alkyloxycarbonyl)-piperazin-1 -yl, 4-(C,.₃alkylsulfonyl)-piperazîn-1-yl, morpholin-4-yl, C,.₃-alkyl-carbonylamino, N-(Ci.₃alkyl)-C,.₃-alkyl-carbonylamino, (het)arylcarbonylamino, N-(C,.₃-alkyl)(het)arylcarbonylamino, (het)aryi-C₁.₃-alkyi-carbonylamino, N-(C,.₃-alkyl)-(het)arylCi.₃-alkyl-carbonylamino, 2-oxo-pyrrolidin-1 -yl, 2-oxo-piperidin-1-yl, 2-oxopiperazin-1 -yl, 2-oxo-4-(C₁.₃-alkyl)-piperazin-1-yl, 3-oxo-piperazin-1-yl, 3-oxo-4(Cvs-alkylJ-piperazin-l-yl, 3-oxo-morpholin-4-yl, aminocarbonylamino, N(aminocarbonyl)-Ci.₃-alkylamino, C,.₃-alkyl-aminocarbonylamino, N-(Ci.₃-alkylaminocarbonyl)-Ci.₃-alkylamino, N-(di-(Ci.₃-alkyl)aminocarbonyl]-Ci.₃-alkylamino, di-(C,.3-alkyl)-aminocarbonyl-amino, pyrrolidin-1 -yl-carbonylamîno, pîperidin-1 -ylcarbonylamino, piperazin-1-yl-carbonylamtno, 4-(C₁.₃-alkyl)-piperazin-1-ylcarbonylamino, morpholin-4-yl-carbonylamino, C,.₃-alkyloxy-carbonylamino, N-(Ci. ₃-alkyl)-C,.₃-alkyloxy-carbonylamino, C,.₃-alkyl-sulfonylamino, N-(C,.₃-alkyl)-Ci_₃alkyl-sulfonylamino, (het)arylsulfonylamino. N-(C,.₃-alkyl)-(het)arylsulfonylamino, oxo-imidazolidin-1-yl, hydroxy, C^-alkyloxy, C₃.₆-cycloalkyl-Ci.₃-alkyloxy, (het)aryl0,.3-alkyloxy, C₃.₆-cycloalkyloxy, (het)aryloxy, cyano-C,.₃-alkyloxy, aminocarbonylC,.₃-alkyloxy, Ci.3-alkyl-aminocarbonyl-Ci.₃-alkyloxy, di-(C,.₃-alkyl)-aminocarbonylCi.3-alkyloxy, pyrrolidin-1 -yl-carbonyl-C,.₃-alkyloxy, piperidin-1-yl-carbonyl-C,.₃alkyloxy, piperazin-1-yl-carbonyl-C,.₃-alkyloxy. 4-(C,.₃-alkyl)-piperazin-1-ylcarbonyl-C,.₃-alkyloxy, morpholin-4-yl-carbonyl-Ci.₃-alkyloxy, carboxy-Ci.₃alkyloxy, Ci.₃-alkyloxy-carbonyl-Ci.₃-alkyloxy, amino-Ci.₃-alkyloxy, C,.₃-alkylaminoCi.₃-alkyloxy, di-(C₁.₃-alkyl)-amino-C,.₃-alkyloxy, pyrrolidin-1 -yl-C,,₃-alkyloxy, piperidin-1 -yl-C,.₃-alkyloxy, piperazin-1-yl-C,.₃-alkyloxy, 4-(Ci.₃-alkyl)-piperazin-1-

yl-Cva-alkyloxy, morpholin-4-yl-Ci.₃-alkyloxy, 2-oxo-pyrrolidin-1-yl-C₁.₃-alkyloxy, 2oxo-piperidin-1 -yl-C_v3-alkyloxy, 2-oxo-piperazin-1 -yl-Ci.₃-alkyloxy, 3-oxopiperazin-1 -yl-Cvj-alkyloxy, 2-oxo-4-(C₁.₃-alkyl)-piperazin-1 -yl-C^-alkyloxy, 3-oxo4-(Ci.₃-alkyl)-piperazin-1-yl-Ci.₃-alkyloxy_t 3-oxo-morpholin-4-yl-C₁.₃-alkyloxy, hydroxy-Ci-3-alkyloxy, Ci.₃-alkyloxy-Ci.₃-alkyloxy, tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy, tetrahydropyran-4-yl-oxy, tetrahydrofuranyl-Cvs-alkyloxy, tetrahydropyranyl-C^-alkyloxy, difluoromethoxy, trifluoromethoxy, C-|.₃alkylsulfanyl-Ci.₃-alkyloxy, C_v3-alkylsulfinyl-Ci.₃-alkyloxy, C₁.₃-alkylsulfonyl-C₁.₃alkyloxy, Ci_₃-alkylsulfonyl, (het)arylsulfonyl, aminosulfonyl, Ci_₃-alkylaminosulfonyl, di-(Ci.₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-1 -ylsulfonyl, morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl, and 4-(Ci.₃-alkyl)pïperazin-1 -yl-sulfonyl, wherein the above-mentioned term (het)aryl is defined as hereinbefore or hereinafter.

In a further embodiment of the présent invention

R⁵ is selected from the group R^Sc consisting of fluorine, chlorine, C-j^-aikyJ, (het)aryl-Ci.₃-alkyl, (het)aryl, aminosulfonyl, amino-Ci.₃-alkyl, Cvralkylamino-Cvs-alkyl, di-fCvralkylJ-amino-Ci^-alkyl, pyrrolrdin-1 -yl-C,.—alkyl, morpholin-4-yl-Ci.₃-alkyl, C^-alkylcarbonylaminoC^-alkyl, (hefiarylcarbonylamino-Cv-j-alkyl, 2-oxo-pyrrolidin-1 -yl-Ci.₃-alkyl, 3-oxo-morpholin-4-y!-Ci.₃-alkyl, hydroxy-Ci.₃-alkyl, C^-alkyloxy-Csa-alkyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-hydroxy-1-methylethyl, 2,2,2trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl, trifluoromethyl, cyano, aminocarbonyl, Ci.₃-alkyl-aminocarbonyl, di-(Ci.₃-alkyl)-aminocarbonyl, (het)arylaminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, piperazîn-1 -yl-carbonyl, morpholin-4-yl-carbonyl, 4-(C₁.₃-alkyl)-piperazin-1 -ylcarbonyl, carboxy, C₁.₃-alkyloxy-carbonyl, amino, Ci.₃-alkylamino, di-ÎC,^alkyl)amino, pyrrolidin-1 -yl, piperidin-1-yl, piperazin-1 -yl, morpholin-4-yl, 2oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-piperazin-1-yl, 3-oxopiperazin-1 -yl, 3-oxo-morpholin-4-yl, C^-alkyl-carbonylamino, (het)arylcarbonylamino, aminocarbonylamîno, C^j-alkyl-aminocarbonylamino, di-(Ci.₃-alkyl)aminocarbonylamino, pyrrolidin-1 -yl-carbonylamino, piperidin-1 -yl-carbonylamino, piperazin-1 -yl-carbonylamino, morpholin-4-ylcarbonylamino, Ci.₃-alkyloxy-carbonylamino, hydroxy, C^-alkyloxy,

0/ hydroxy-C_V3-aîkyloxy_t Cvralkyloxy-Cvralkyloxy, difluoromethoxy, trifluoromethoxy, and (het)aryloxy, wherein the above-mentioned term (het)aryl dénotés phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, triazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which may optionally be substituted with one or two R¹⁰.

In a further embodiment of the présent invention is selected from the group R^Sd consisting of fluorine, chlorine, Ci_₃-alkyl, hydroxy-C;.₃-alkyl, aminocarbonyl, Cu-alkylaminocarbonyl, amino, Ci.₃-alkylamino, Ci-₃-alkyl-carbonylamino, hydroxy, Ci.₃-alkyloxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, and aminosulfonyl.

In a further embodiment of the présent invention is selected from the group R⁵® consisting of fluorine, chlorine, methyl, amino, hydroxy, and methoxy.

In a further embodiment of the présent invention

R⁶, R⁷ are selected independently of each other from the group R^B/7b consisting of fluorine, chlorine, bromine, C-|.₃-alkyl, C₂.₃-alkynyl, trifluoromethyl, hydroxy, 0^3alkyloxy, and cyano, and/or

R^B/7b dénotés one R⁶ and R⁷ that are attached to adjacent carbon atoms and joined to form a methylenedioxy, difluoromethylenedioxy, ethylenedioxy, or C₃.₅alkylene group.

In a further embodiment of the présent invention

R⁶, R⁷ are selected independently of each other from the group R^G/7c consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, and ethoxy.

In a further embodiment of the présent invention

R⁶, R⁷ are selected independently of each other from the group R^6/7d consisting of fluorine, chlorine, methyl, hydroxy, and methoxy.

In a further embodiment of the présent invention

R¹⁰ îs selected independently of each other from the group R^10b consisting of fluorine, chlorine, bromine, Ci.₃-alkyJ, phenyl, difluoromethyl, trifluoromethyl, cyano, aminocarbonyl, C^-alkylaminocarbonyl, di-(C₁.₃-alkyl)-aminocarbonyl, carboxy, C^-alkyloxycarbonyl, nitro, amino, acetylamino, methylsulfonylamino, hydroxy, C^-alkyloxy, difluoromethoxy, trifluoromethoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, and aminosulfonyl.

In a further embodiment of the présent invention

R¹⁰ is selected independently of each other from the group R^10c consisting of fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy, and trifluoromethoxy.

In a further embodiment of the présent invention

R¹⁰ is selected Independently of each other from the group R^10d consisting of fluorine, methyl, cyano, and methoxy.

In a further embodiment of the présent invention

Rⁿ is selected independently of each other from the group R^Nb consisting of hydrogen, C^-alkyl, C_3Î-cycloalkyl, C₃.₆-alkenyl, phenyl, C^-alkylcarbonyl, phenylcarbonyl, C^-alkylanninocarbonyl, phenylaminocarbonyl, Ομ₄alkyloxycarbonyl, ÛM-alkylsulfonyl, and phenylsulfonyl, wherein the C^-alkyl group optionally may be mono- or polysubstituted with fluorine and optionally monosubstituted with phenyl, cyano, aminocarbonyl, C_V3-alkylaminocarbonyl, di-(Ci.₃-alkyl)aminocarbonyl, carboxy, Cv^-alkoxycarbonyl, Ci.4-alkylcarbonylamino, hydroxy, or C_M-alkoxy.

In a further embodiment of the présent invention

R^N is selected independently of each other from the group R^Nc consisting of hydrogen, phenyl, Ci.₄-alkylcarbonyl, phenylcarbonyl, C^-alkylaminocarbonyl, phenylaminocarbonyl, CM-alkyloxycarbonyl, C^-alkylsulfonyl, phenylsulfonyl, and a C_M-alkyl group, which optionally may be mono- or polyfluorinated and optionally monosubstituted with hydroxy, Cn-alkoxy, cyano, or phenyl.

In a further embodiment of the présent invention

R^N is selected independently of each other from the group R^Nd consisting of hydrogen, methyl, benzyl, phenyl, acetyl, tert-butoxycarbonyl, and methylsulfonyl.

In a further embodiment of the présent invention

R⁸ is selected independently of each other from the group R^8b consisting of hydrogen and methyl.

In a further embodiment of the présent invention

R® is selected independently of each other from the group R^Bc consisting of hydrogen.

In a further embodiment of the présent invention m is 0.

Each R¹*, R^2x, R³'⁴’, R^Sx, R®™. R^Nx, R^8x, R¹⁰*, m represents a characterized, individual embodiment for the corresponding substituent as described above. Thus given the above définitions, preferred individual embodiments of the first aspect of the invention are fully characterized by the term (R^1x, R²*, R³'⁴*, R^5x, R^6/7x, R^Nx, R^8x, R^10x, m), wherein for each index x an individual figure is given that ranges from a to the highest letter given above. Indices x and m vary independently from each other. Ail individual embodiments described by the term in parantheses with full permutation of the indices x and m, referring to the définitions above, shall be comprîsed by the présent invention.

The following Table 1 shows, exemplarily and in the order of increasing preference from the first line to the last line, such embodiments E-1 to E-36 of the invention that are considered preferred. This means that embodiment E-36, represented by the entries in the last row of Table 1, is the most preferred embodiment.

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

		R²	R^s/R⁴	R⁵	R^e/R⁷	R¹⁰	R^B	rⁿ	m
E-1	R'b	_R2b	p3/4b	_R5b	_R6/7b	Rl°b	_r63	R^Nb	0,1
E-2	R'C	_R2e	_R3/4c	_R5c	_r6/7c	_Rl°c	R^0a		0,1
E-3	R^w	R2b	_R3Md	_r5c	_R6/7d	R^10d	_R0a	R^Nd	0,1
E-4	R^,b	_R2b	^3/4d	_R5d	_R6/7d	RWd	_R8b	RNd	0,1
E-5	Rlb	_R2b	_R3Md	R^5e	_R6/7d	RWd	Rflb	RNd	0.1
E-6	R^1c	_R2b	j^3/4b	_RSC	_R6/7c	_R1°d	_R8b	RNd	0,1
E-7	_R1C	_R2b	_RWb	_R5d	_R6/7d	RWd	R8b	RNd	0,1
E-8	_R1b	_R2e	_R3/4c	RSC	_rB/7c	_R ¹°d	_R8b	•Λ	0,1
E-9	R^1c	_R2b	f^3/4c	_R5C	j^6/7c	_R1°d	_R8b	RNd	0.1
E-10	R^1c	r^2c	_r3/4c	_R5C	_R6f7c	R^10d	_R8b	★	0,1
E-11	R^1c	_R2c	_r3/4c	_R5d	_R6/7d	RWd	R8b	★	0,1
E-12	_Rw	_R2C	_r3/4c2	_R5C	_R6/7c	RW_d	_R8b	*	0.1
E-13	R^1c	_R2b	_r3/4c2	_R5C	p6/7c	_R10d	_R8b	RNd	0,1
E-14	Rie	r^2c	_r3/4c2	r5c	_R6/7c	RWd	_R8b		0,1
E-15	_R1c	r^2c	_r3/4c2	_R5d	_R6/7d	RWO	R^8b		0,1
E-16	R^1c	r^2c	_R3/4d	RSd	_R6/7d	R^10d	_R8b		0.1
E-17	R^1d	R2C	_R3/4d	RSd	p6/7d	_RWd	_R8b		0,1
E-18	Rld	r2c	_R3Md	_R5e	_R6/7d	RWd	_R8b		0,1
E-19	R’d	_R2d	_R3/4d	R^5e	p6/7d	*	_R8b	♦	0,1
E-20	R’d	R^2e	_R3»d	_R5e	_R6/7d		_R8b		0,1
E-21	_R1d2	_R2e	_R3/4d	*		★	_R8b		0,1
E-22	_Rie	_R2e	_R3/4d	*		*	_R8b	A	0,1
E-23	_R1e	_R2e	R™	*	«	*	rBc	«	0,1

Table 1 continued

	R¹	R²	R³/R⁴	R⁵	R⁶/R⁷	R¹⁰	R®	rⁿ	m
E-24	R^1e	_R2e			A	A	RBC	_A	0
E-25	R’d	R²'	R3Md	rSC	R6/7d	_A	R^eb	A	0,1
E-26	R^1e	R^2f	R3Md	*	*	*	R®^b	A	0,1
E-27	R^1e	R^2f	p3/4d	-*	_*	*	rBC	-*	0,1
E-28	Rie	R²'	\|^3/4d	*	A	A	r8c	A	0
E-29	_R1d2	r2c	R3Md			RWd	R^eb	A	0,1
E-30	R’dZ	R2d	R3Md	_A	_A		_R8b	A	0,1
E-31	_R1d2	R^2e	f^3/4d	Λ	A	Λ	_R8b	A	0,1
E-32	R^1d2	R²'	R3Md	_A	*	A	_R8b	A	0,1
E-33	_R1d2	R²'	R3/4d	_A	_A	A	_R8b	A	0
E-34	R^1f	R²’	_R3Md	_*	_A	_*	_R8b	^A	0,1
E-35	R^1f	R²'	p3/4d	_A	_A	_A	_R8C	_A	0,1
E-36	R^1f	R²'	R3/4d	*	_A	_A	r8c	A	0

-*means that the respective variable does not exist in the corresponding embodiment the tautomers thereof, the stereoisomers thereof, the mixtures thereof, and the salts thereof, while the following compounds are excluded:

Accordingly, E-24 covers compounds of formula I, wherein

R¹ is selected from the group R¹⁶ consisting of

4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4amino-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,

R² is selected from the group R^2e consisting of hydrogen, fluorine, bromine, cyclohexylmethyl, phenylmethyl, 4-methoxyphenylmethyl, hydroxymethyl, 2-hydroxyprop-2-yl, phenyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, morpholin4-ylcarbonyl, carboxy, methoxycarbonyl, amino, hydroxy, methoxy, 4methoxyphenoxy, and e-methyl-pyridazin-S-yloxy.

R³, R⁴ are selected independently of each other from the group R^3Md consisting of hydrogen and fluorine,

R⁸ is selected independently of each other from the group R^8c consisting of hydrogen, and m = 0, the tautomers thereof, the stereoisomers thereof, the mixtures thereof, and the salts thereof.

Accordingly, E-28 covers compounds of formula I, wherein

R¹ is selected from the group R^1e consisting of

4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4amino-3-chloro-phenyl, 3-chloro-4-hydroxy-phenyl, indol-3-yl, indol-5-yl, îndol-6-yl, 1-methyl-indol-3-yl, benzimidazol-5-yl, indazol-5-yl and benzothiazol-6-yl,

R² is selected from the group R²' consisting of hydrogen and cyano,

R³, R⁴ are selected independently of each other from the group R^3/4d consisting of hydrogen and fluorine,

R³ is selected independently of each other from the group R^0C consisting of hydrogen, and m = 0, the tautomers thereof, the stereoisomers thereof, the mixtures thereof, and the salts thereof.

Accordingly, E-33 covers compounds of formula I, wherein

R¹ is selected from the group R^1d2 consisting of

4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4amino-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-methyl16399

benzimidazol-5-yl, indazol-5-yl and benzothiazol-6-yl,

R^z is selected from the group R²' consisting of hydrogen and cyano,

R⁸ is selected independently of each other from the group R^Sb consisting of hydrogen and methyl and m = 0, the tautomers thereof, the stereoîsomers thereof, the mixtures thereof, and the salts thereof.

Accordingly, E-36 covers compounds of formula I, wherein

R¹ is selected from the group R^1f consisting of benzimidazol-5-yl, 6-methyl-benzimidazol-5-yl and 7-methyl-benzimidazol-5-yl,

R² is selected from the group R^2f consisting of hydrogen and cyano,

R⁸ is selected independently of each other from the group R^8c consisting of hydrogen, and m = 0, the tautomers thereof, the stereoîsomers thereof, the mixtures thereof, and the salts thereof.

Another preferred embodiment of this invention is described by formula l.a

wherein the piperidine substructure and the tetraline (m=1 ) or indane (m=0) substructure form a c/s configured tricyclic core structure, while the variables R¹, R², R³, R⁴, and m are defined as

Λ'

hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.

A further preferred embodiment of this invention is described by formula l.b

R¹

l.b wherein the trïcyclic core structure is R configured at C-10b (for m=1 )/C-4a (for m=0) and S configured at C-4a (for m=1)/C-9a (for m=0), while the variables R¹, R², R³, R⁴, and m are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.

Accordingly, one embodiment of preferred compounds according to the invention comprises compounds of formula l.b,

R¹

l.b wherein

R¹ is selected from the group R^1e consisting of

4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl. 3-fiuoro-4-hydroxy-phenyl, 4amino-3-chloro-phenyl, 3-chloro-4-hydroxy-phenyl, indol-3-yl, îndol-5-yl, indol-6-yl, 1 -methyl-indol-3-yl, benzimidazol-5-yl, indazol-5-yl and benzothiazol-6-yl,

R² is selected from the group R^Ze consisting of hydrogen, fluorine, bromine, cyclohexylmethyl, phenylmethyl, 4-methoxyphenylmethyl, hydroxymethyl, 2-hydroxyprop-2-yl, phenyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, morpholin4-ylcarbonyl, carboxy, methoxycarbonyl, amino, hydroxy, methoxy, 4methoxyphenoxy, and 6-methyl-pyridazin-3-yloxy.

Another embodiment of preferred compounds according to the invention are compounds of formula l.b, wherein

R¹ is selected from the group R^1e consisting of

4-hydroxy-phenyl, 4-amino-3-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4amino-3-chloro-phenyl, 3-chloro-4-hydroxy-phenyl, indol-3-yl, indol-5-yl, indot-6-yl, 1-methyl-indol-3-yl, benzimidazol-5-yl, indazol-5-yl and benzothiazol-6-yl,

R² is selected from the group R^2f consisting of hydrogen and cyano,

R⁸ is selected independently of each other from the group R^Bc consisting of hydrogen, and m = 0, the tautomers thereof, the stereoisomers thereof, the mixtures thereof, and the salts thereof.

R² is selected from the group R²' consisting of hydrogen and cyano,

R® is selected independently of each other from the group R®^c consisting of hydrogen, and m = 0,

Λ the tautomers thereof, the stereoisomers thereof, the mixtures thereof, and the salts thereof.

Regarding the définitions of N-containing heteroaromatic groups, such as (het)aryl possessing one or more nitrogens within its framework, that bear a hydroxy group at the carbon atom adjacent to the nitrogen or another position of the ring which allows a mesomeric interaction with the nitrogen, these groups can form a tautomeric amide substructure which is part of the invention; the tautomeric amide obtained from combining a hydroxy group and an N-containing heteroaromatic may bear substituents other than hydrogen on the amide nitrogen. Examples of such substructures of heteroaromatic groups wherein a tautomeric amide may be formed are depicted in the following compilation:

wherein R^N is defined as described above. These tautomeric structures may be annelated to hereroaromatic and aromatic groups like such that are comprised by (het)aryl.

In some embodiments, the présent teachings provide crystalline compounds of the following structural formula (II):

As used herein, crystalline refers to a solid in which molécules are arranged in an orderly repeating pattern in three dimensions. Crystalline compounds of formula (II) can be a single crystalline form or a mixture of different crystalline forms, A single crystalline form means a compound of formula (II) as a single crystal or a plurality of crystals in which each crystal has the same crystal form.

In a particular embodiment, at least a particular percentage by weight of the compound of formula (II) is a single crystalline form. Particular weight percentages include 50%, 52%, 55%, 57%, 60%, 62%, 65%. 67%, 70%. 72%, 75%, 77%, 80%, 82%, 85%, 86%, 87%, 88%, 89%,

90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or a percentage between 50% and 100%.

When a particular percentage by weight of the compound of formula (II) is defined as a crystalline form, the-remainder of the compound of formula (II) is some combination of amorphous forms of the compound of formula (II). When a particular percentage by weight of the compound of formula (II) is defined as a single crystalline form, the-remainder of the compound of formula (II) is some combination of amorphous forms of the compound of formula (II) and/or one or more crystalline forms of the compound of formula (II) other than the single crystalline form. Examples of single crystalline forms include Forms I and II of the compound of formula (II), as well as single crystalline forms characterized by one or more properties as discussed herein.

In the following description of particular crystalline forms of the compound of formula (II), embodiments of the invention may be described with reference to a particular crystalline “Form” of the compound of formula (II), However, the particular crystalline forms may also be characterized by one or more of the characteristics of the crystalline forms as described herein, with or without regard to referencing a particular Form.

Form I

In one embodiment, a single crystalline form of the compound of formula (II) is characterized as crystalline Form I. In another embodiment, at least a particular percentage by weight of the compound of formula (II) is crystalline Form I. Particular weight percentages include 50%, 52%, 55%, 57%, 60%, 62%, 65%, 67%. 70%, 72%, 75%, 77%, 80%, 82%, 85%, 86%, 87%, 88%,

89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or a percentage between 50% and 100%.

In some embodiments, the crystalline form is characterized by the X-ray powder diffraction (herein referred to as XRPD) pattern shown in FIG. 1, e.g., with values of 2T angles, d30 spacings and relative intensities as listed in Table 1, obtained using CuKa radiation. In some embodiments, the crystalline form is characterized by one, two, three, four, five or six XRPD peaks at 2T angles selected from 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.1°. In some embodiments, the crystalline form is characterized by at least three XRPD peaks at 2T angles selected from 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.1°. In some embodiments, the crystalline form is characterized by at least four XRPD peaks at 2T angles selected from 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.Γ. In some embodiments, the crystalline form is characterized by at least five XRPD peaks at 2T angles selected from 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.1°.

In some embodiments, the crystalline form is characterized by XRPD peaks at 2T angles of 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.Γ. In some embodiments, the crystalline form is characterized by one, two, three or four major XRPD peaks at 2T angles selected from 12.5°, 14.8°, 22.2° and 26.1°. In some embodiments, the crystalline form is characterized by at least three XRPD peaks at 2T angles selected from 12.5°, 14.8°, 22.2° and 26. Γ. In some embodiments, the crystalline form is characterized by XRPD peaks at 2T angles of 12.5°, 14.8°, 22.2° and 26.1°. In some embodiments, the crystalline form is characterized by one, two, three or four major XRPD peaks at 2T angles selected from 12.5°, 14.8°, 22.2° and 26.1°. In some embodiments, the crystalline form is characterized by major XRPD peaks at 2T angles of 12.5°,

14.8°, 22.2° and 26.1°. It is to be understood that a specified 2T angle means the specified value ±0.1°.

As used herein, major XRPD peak refers to an XRPD peak with a relative intensity greater than 25%. Relative intensity is calculated as a ratio of the peak intensity of the peak of interest 15 versus the peak intensity of the largest peak.

Table 1:XRPD Peaks from FIG. 1

2T H	d-value [A]	Intensity l/l_o[%]
5.77	15.30	5
5.93	14.88	4
6.47	13.65	17
9.81	9.01	3
11.55	7.66	2
11.94	7.40	5
12.54	7.05	100
12.88	6.87	23
14.83	5.97	31
16.04	5.52	12
16.54	5.35	4
17.35	5.11	5
18.67	4.75	2
19.52	4.54	5
19.59	4.53	5
19.98	4.44	21
20.20	4.39	7
20.46	4.34	5

2T n	d-value [A]	Intensity l/l₀[%]
20.66	4.30	4
20.90	4.25	3
21.14	4.20	5
21.55	4.12	4
22.18	4.01	49
23.14	3.84	8
23.26	3.82	11
23.49	3.78	10
23.99	3.71	3
24.32	3.66	4
24.91	3.57	9
25.02	3.56	14
25.39	3.51	4
26.09	3.41	60
26.52	3.36	12
26.84	3.32	2
27.10	3.29	1
27.33	3.26	2
28.30	3.15	14
29.12	3.06	3
29.91	2.98	4

In sonne embodiments, the crystalline form is characterized by the ¹³C solid-state nuclear magnetic résonance (herein referred to as SSNMR) pattern shown in FIG. 2, e.g., with chemical shifts as listed in Table 2, obtained using magic angle spinning. In a particular embodiment, the crystalline form is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17 or 18 ¹³C SSNMR peaks at chemical shifts selected from 170.3 ppm, 146.5 ppm,

142.8 ppm, 135.0 ppm, 130.6 ppm, 128.1 ppm, 122.1 ppm, 116.7 ppm, 115.6 ppm, 112.8 ppm,

109.8 ppm, 107.6 ppm, 44.6 ppm, 43.3 ppm, 41.4 ppm, 30.3 ppm, 26.3 ppm and 23.9 ppm. In one embodiment, the crystalline form is characterized by at least ten ¹³C SSNMR peaks at chemical shifts selected from 170.3 ppm, 146.5 ppm, 142.8 ppm, 135.0 ppm, 130.6 ppm, 128.1 ppm, 122.1 ppm, 116.7 ppm, 115.6 ppm, 112.8 ppm, 109.8 ppm, 107.6 ppm, 44.6 ppm, 43.3 ppm, 41.4 ppm, 30.3 ppm, 26.3 ppm and 23.9 ppm. In one embodiment, the crystalline form is characterized by at least fifteen ¹³C SSNMR peaks at chemical shifts selected from 170.3 ppm,

146.5 ppm, 142.8 ppm, 135.0 ppm, 130.6 ppm, 128.1 ppm, 122.1 ppm, 116.7 ppm, 115.6 ppm,

112.8 ppm, 109.8 ppm, 107.6 ppm, 44.6 ppm, 43.3 ppm, 41.4 ppm, 30.3 ppm, 26.3 ppm and 23.9 ppm. In one embodiment, the crystalline form is characterized by ¹³C SSNMR peaks at chemical shifts of 170.3 ppm, 146.5 ppm, 142.8 ppm, 135.0 ppm, 130.6 ppm, 128.1 ppm, 122.1 ppm, 116.7 ppm, 115.6 ppm, 112.8 ppm, 109.8 ppm, 107.6 ppm, 44.6 ppm, 43.3 ppm, 41.4 ppm, 30.3 ppm, 26.3 ppm and 23.9 ppm.

Table 2. ¹³C NMR Chemical Shifts from FIG 2

Peak	Chemical Shift (ppm)
1	170.3
2	148.7
3	146.5
4	142.8
5	135.0
6	130.6
7	128.1
8	122.1
9	116.7
10	115.6
11	112.8
12	109.8
13	107.6
14	54.9
15	44.6
16	43.3
17	41.4
18	30.3
19	26.3
20	23.9

In some embodiments, the crystalline form is characterized by an endothermie transition having 10 an onset of about 231.7 ± 0.5°C in the differential scanning (herein referred to as DSC) profile.

In some embodiments, the crystalline form is characterized by a DSC profile as shown in FIG. 3. The profile plots the heat flow as a function of température from a sample containing Form I.

The DSC is performed on the sample using a scanning rate of 10°C/minute.

Form I is also characterized by the thermal gravimétrie analysis (herein referred to as TGA) profile shown in FIG. 4. The profile graphs the percent loss of weight of the sample as a function of température with the température rate change being 10°C/minute. The profile shows

a weight loss of approximately 2.1% as the température of the sample is changea from room température to 150°C, which indicates that Form I is anhydrous.

Form //

In one embodiment, a single crystalline form of the compound of formula (II) is characterized as crystalline Form II. In another embodiment, at least a particular percentage by weight of the compound of formula (II) is crystalline Form II. Particular weight percentages include 50%, 52%, 55%, 57%, 60%, 62%, 65%, 67%, 70%, 72%, 75%, 77%, 80%, 82%, 85%, 86%. 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or a percentage between 50% and 100%,

In some embodiments, the crystalline form is characterized by the XRPD pattern shown in FIG. 5, e.g., with values of 2T angles, d-spacings and relative intensities as listed in Table 3, obtained using CuKa radiation. In a particular embodiment, the crystalline form is characterized by one, two, three, four, five, six or seven, eight, nîne, ten, eleven or twelve XRPD peaks at 2T angles selected from 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°. In a particular embodiment, the crystalline form is characterized by at least seven, eight, nïne, ten or eleven XRPD peaks at 2T angles selected from 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°. 21.9°, 23.3°, 25.6^e and 26.5°. In some embodiments, the crystalline form is characterized by XRPD peaks at 2T angles of 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°. In some embodiments, the crystalline form is characterized by XRPD peaks at2T angles of 13.7°, 17.6°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°. In some embodiments, the crystalline form is characterized by XRPD peaks at 2T angles of 13.7°, 17.6°, 19.7, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°. In some embodiments, the crystalline form is characterized by XRPD peaks at2T angles of 13.7°, 17.6°, 19.7, 20.9, 21.3^e, 21.9°, 23.3°, 25.6’ and 26.5°. In some embodiments, the crystalline form is characterized by XRPD peaks at2T angles of 13.7°, 17.6^e, 19.3, 19.7,20.9,21.3°, 21.9°, 23.3°, 25.6° and 26.5°. In some embodiments, the crystalline form is characterized by XRPD peaks at 2T angles of 13.3°, 13.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°. In some embodiments, the crystalline form is characterized by XRPD peaks at 2T angles of 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°. In some embodiments, the crystalline form is characterized by one, two, three, four, five, six or seven major XRPD peaks at 2T angles selected from 13.7^e, 17.6°, 21.3^e, 21.9^e, 23.3^e, 25.6^e and 26.5^e. In some embodiments, the crystalline form is characterized by major XRPD peaks at 2T angles of 13.7^e, 17.6^e, 21.3^e, 21.9^e, 23.3^e, 25.6^e and 26.5^e.

Table 3: XRPD Peaks from FIG. 5

21 H	d-value [A]	Intensity l/l₀[%]
9.79	9.03	19
10.73	8.24	18
12.54	7.05	3
13.31	6.65	26
13.70	6.46	100
14.83	5.97	2
15.71	5.63	20
16.68	5.31	19
17.58	5.04	40
18.41	4.82	7
19.07	4.65	10
19.27	4.60	33
19.66	4.51	39
20.88	4.25	38
21.32	4.16	48
21.56	4.12	8
21.91	4.05	50
22.99	3.87	10
23.29	3.82	56
23.61	3.77	8
24.27	3.66	19
24.89	3.57	9
25.37	3.51	15
25.55	3.48	40
26.05	3.42	5
26.50	3.36	41
26.79	3.32	10
27.68	3.22	19

In some embodiments, the crystalline form is characterized by the ¹³C SSNMR pattern shown in FIG. 6, e.g., with chemical shifts as listed in Table 4, obtained using magic angle spinning. In a particular embodiment, the crystalline form is characterized by 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 5 13, 14, 15,16, 17 or 18 ¹³C SSNMR peaks at chemical shifts selected from 172.6 ppm, 147.1 ppm 144.1 ppm, 132.9 ppm 129.6 ppm, 125.9 ppm 121.2 ppm, 119.5 ppm, 117.7 ppm, 114.6

ppm, 110.2 ppm, 45.1 ppm, 42.4 ppm, 32.6 ppm, 28.3 ppm and 24.4 ppm. In one embodiment, the crystalline form is characterized by at least ten ¹³C SSNMR peaks at chemical shifts selected from 172.6 ppm, 147.1 ppm 144.1 ppm, 132.9 ppm 129.6 ppm, 125.9 ppm 121.2 ppm,

119.5 ppm, 117.7 ppm, 114.6 ppm, 110.2 ppm, 45.1 ppm, 42.4 ppm, 32.6 ppm, 28.3 ppm and

24.4 ppm. In one embodiment, the crystalline form is characterized by at least thirteen ¹³C SSNMR peaks at chemical shifts selected from 172.6 ppm, 147.1 ppm 144.1 ppm, 132.9 ppm

129.6 ppm, 125.9 ppm 121.2 ppm, 119.5 ppm, 117.7 ppm, 114.6 ppm, 110.2 ppm, 45.1 ppm,

42.4 ppm, 32.6 ppm, 28.3 ppm and 24.4 ppm. In one embodiment, the crystalline form is characterized by ¹³C SSNMR peaks at chemical shifts of 172.6 ppm, 147.1 ppm 144.1 ppm,

132.9 ppm 129.6 ppm, 125.9 ppm 121.2 ppm, 119.5 ppm, 117.7 ppm, 114.6 ppm, 110.2 ppm, 45.1 ppm, 42.4 ppm, 32.6 ppm, 28.3 ppm and 24.4 ppm.

Table 4. ¹³C NMR Chemical Shifts from FIG 6

Peak	Chemical Shift (ppm)
1	172.6
2	148.7
3	147.1
4	144.1
5	132.9
6	129.6
7	125.9
8	121.2
9	119.5
10	117.7
11	114.6
12	110.2
13	55.0
14	45.1
15	42.4
16	32.6
17	28.3
18	24.4

In some embodiments, the crystalline form is characterized by an endothermie transition having an onset of about 235.5 ± 0.5°C in the DSC profile. In some embodiments, the crystalline form is characterized by a DSC profile as shown in FIG. 7. The profile plots the heat flow as a function of température from a sample containing Form II. The DSC is performed on the sample using a scanning rate of 10’C/minute.

In some embodiments, the crystalline form is characterized by the thermal gravimétrie analysis (herein referred to as TGA) profile shown in FIG. 8. The profile graphe the percent loss of weight of the sample as a function of température with the température rate change being 10°C/minute, The profile shows a weight loss of approximately 0.1% as the température of the sample is changed from room température to 150°C, which indicates that Form II is anhydrous.

Other embodiments of the invention are directed to a single crystalline form of the compound of formula (II) is characterized by a combination of the aforementioned characteristics of any of the single crystalline forms discussed herein. The characterization can be any combination of one or more of the XRPD, TGA, DSC and SSNMR described for a particular crystalline form. For example, the single crystalline form of the compound of formula (II) can be characterized by any combination of the 2T peaks in an XRPD scan and/or any combination of the chemical shift peaks of an SSNMR spectrum and/or any combination of Information obtained from the DSC déterminations and/or the weight change in a sample obtained by TGA. It is to be understood that the présent teachings include any combination of analytical techniques to characterize a crystalline form.

The présent teachings also include compositions which include any of the compounds described herein, In some embodiments, the présent teachings provide a pharmaceutical composition including any of the compounds described herein and a pharmaceutically acceptable carrier or diluent. In some embodiments, the présent teachings provide a pharmaceutical composition comprising the crystalline compound of Formula (II) and a pharmaceutically acceptable carrier or diluent.

Some terms used above and hereinafter to describe the compounds according to the invention will now be defined more closely.

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the spécification, however, unless specified to the contrary, the following terms hâve the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for exampie C-|.₆-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent aryl-Cva-alkyl- means an aryl group which is bound to a C^-alkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.

In general, the attachment site of a given residue to another group shall be variable, i.e. any capable atom, bearing hydrogens to be replaced, within this residue may be the linking spot to the group being attached, unless otherwise indicated.

Unless specifically indicated, throughout the spécification and the appended daims, a given chemical formula or name shall encompass ail conceivable constitutional isomers and stereoisomers, including enantiomers, diastereomers, cis/trans isomers, E/Z isomers, etc., and mixtures thereof, for example, 1:1 mixtures of enantiomers (termed racemates), mixtures of different proportions of separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvatés thereof such as, for instance, hydrates, including solvatés of the free compounds or solvatés of a sait of the compound.

The phrase pharmaceutically acceptable is employed herein to refer 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 animais without excessive toxicity, irritation, allergie response, or other problem or complication, and 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 sélection from the indicated group, provided that the designated atom’s viable valence number is not exceeded, and that the substitution results in a stable compound.

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

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

The term Ci._n-alkyl, wherein n may hâve a value of 1 to 18, dénotés a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyI, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc..

The term Ci._n-alkylene wherein n is an integer of 1 to n, either alone or in combination with another radical, dénotés an acyclic, straight or branched chain divalent alkyl radical containing 1 to n carbon atoms. For example, the term Cm-alkylene includes ~(CH₂)~. -(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(CH₃)(CH₂CH₃)-.

The term C^-alkenyl, wherein n has a value of 3 to 10, dénotés a branched or unbranched hydrocarbon group with 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, etc..

The term C₂._n-alkynyl, wherein n has a value of 3 to 10, dénotés a branched or unbranched hydrocarbon group with 2 to n C atoms and a C=C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. Unless otherwise stated alkynyl groups are connected to the remainder of the molécule via the C atom in position 1. Therefore terms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. are équivalent to the terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc.. This also applies analogously to C₂._nalkenyl groups.

The term Ci._n-alkoxy dénotés a Cm-alkyl-0 group, wherein C^n-alkyl is as hereinbefore defined. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy, etc..

The term C^-alkylcarbonyl dénotés a C₁._n-alkyl-C(=O) group, wherein Ci.n-alkyl is as hereinbefore defined. Examples of such groups include methylcarbonyl, ethylcarbonyl, npropylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tertbutylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentyl-carbonyl, nhexylcarbonyl, iso-hexylcarbonyl, etc..

The term C₃._n-cycloalkyl dénotés a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1 Joctyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.. Preferably the term C₃.₇-cycloalkyl dénotés saturated monocyclic groups.

The term C₅._n-cycloalkenyl dénotés a Cg.n-cycloalkyl group which is as hereinbefore defined and additionally has at least one C=C double bond.

The term C₃._n-cycloalkylcarbonyl dénotés a C₃._n-cycloalkyl-C(=0) group wherein C₃._n-cyclo-alkyl is as hereinbefore defined.

The term C₃._n-heterocycloalkyl dénotés a saturated mono-, bi-, tri- or spirocarbocyclic group, which is as hereinbefore defined, with 3-m to n-m C atoms, wherein m carbon atoms are replaced with m heteroatoms independently selected from N, NRⁿ, O, S, SO, and SO₂. Examples of such groups include aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, thiomorpholinyl, azepanyl, oxepanyl, thiepanyl, 1-aza-bicyclo[2.2.2]octane, 1,4-diaza-bicyclo[2.2.2]octane, etc.. Preferably, the term heterocycloalkyl dénotés saturated monocyclic C₅^-cycloalkyl groups wherein one or two carbon atoms are replaced with N and/or O.

The term tri-(C_M-alkyl)silyl comprises silyl groups which hâve identical or two or three different alkyl groups.

The term di-fCvralkylJamino comprises amino groups which hâve two identical or different alkyl groups.

If groups or residues are optionally substituted, this applies to any form of the group or residue. For instance, if an alkyl group is optionally mono- or polyfluorinated this comprises also alkyl residues which are part of larger groups, e.g. alkyloxy, alkylcarbonyl, alkoxyalkyl, etc., or if a (het)aryl group is optionally mono- or polysubstituted with a certain substituent or a set of substituents this also includes (het)aryl groups which are part of larger groups, e.g. (het)aryl-Ci. n-alkyl, (het)aryloxy, (het)aryloxy-Ci._n-alkyl, (het)aryl-Ci._n-alkyloxy, etc.. Accordingly, in cases where e.g. R^z or R⁵ has, for example, the meaning (het)aryloxy, while (het)aryl residues are optionally mono- or polyfluorinated and (het)aryl dénotés inter alia phenyl, the meanings mono-, di-, tri-, tetra-, and pentafluorophenoxy are also comprised. The same applies to groups or residues in which a part of the group or residue is replaced by another group, e.g. a CH2 group is optionally replaced by O, S, NRⁿ, CO, or SO2. For instance, a residue having inter alia the meaning hydroxy-Ci.₃-alkyl in which a CH₂ group is optionally replaced by CO (= carbonyl), this also comprises carboxy, carboxymethyl, hydroxymethylcarbonyl, 1-hydroxy-2-oxo-ethyl, carboxyethyl, 2-carboxyethyl, 1-carboxyethyl, hydroxymethylcarbonylmethyl, 1-hydroxy-2-oxopropyl, hydroxyethylcarbonyl, (2-hydroxyethyl)carbonyl, hydroxy-3-oxo-propyl, 1-hydroxy-3-oxo-

propyl, 2-hydroxy-3-oxo-propyl, (l-hydroxyethyl)-carbonyl, 2-hydroxy-1-oxo-prop-2-yl, hydroxy2-oxo-prop-2-yl and 3-hydroxy-1-oxo-prop-2-yl. Analogously, a définition such as Ci._n-alkyl wherein one or more CH_Z groups are optionally replaced by, for example, carbonyl and which is optionally substituted with e.g. hydroxy or amino also comprises explicit residues having no CH and/or CH₂ group, e.g. carboxy and aminocarbonyl.

Ail atoms/elements described herein, including atoms that are part of a group, comprise ail stable isotopic forms of the respective element. For instance, whenever hydrogen is mentioned, either explicitly or as part of a group such as methyl, this includes hydrogen and deuterium as stable isotopic forms of the element hydrogen.

The compounds according to the invention may be obtained using methods of synthesis known in princtple. Preferably, the compounds are obtained by the foliowing methods according to the invention which are described in more detail hereinafter.

A general route to access the core structures of the compounds of the invention is given in Scheme 1 employing a tricyclic pyridine as precursor for the tricyclic piperidine framework; R², R³, R\ and m hâve the meanings as defined hereinbefore and hereinafter. The tricyclic pyridine may be obtained from 2-indanones (m=0) or 2-tetralones (m=1) and propargylamine or a dérivative thereof by combining the two starting compounds in the presence of a catalyst, such as salis or complexes of gold and copper, preferably NaAuCL and CuCI₂ (see J. Org. Chem. 2003, 68, 6959-6966). The reaction is usually run in alcohols, such as éthanol, at températures of 20 to 120 °C through conventional heating or microwave irradiation. The pyridine structure obtained is transformed to the piperidine dérivative by réduction with hydrogen in the presence of a transition métal catalyst, such as PtO₂, Pt/C, Pd/C, Rh/C, Raney-Ni, or mixtures thereof. Alcohols, e.g. methanol and éthanol, ethyl acetate, acetic acid, water, ether, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidinone, hexanes, methylcyclohexane, or mixtures thereof are among the preferred solvents, optionally used in combination with additives, such as acid, e.g. trifluoroacetic acid, hydrochloric acid, and sulfuric acid, at températures of 10 to 150 ’C, preferably 20 to 80 °C, and hydrogen pressures of 1 to 150 bar, preferably 1 to 20 bar. Alternatively, the réduction may be accomplished, after transforming the pyridine into a pyridinium ion by N-alkylation, N-acylation, or N-sulfonylation, by treatment with a hydride source such as NaBH₄ or LiAIH₄. The latter reagent is preferably employed in hydrocarbons, ether, tetrahydrofuran, 1,4-dioxane, benzene, ortoluene, while the former is preferably used in alcohols, e.g. methanol or éthanol, and water, optionally combined with a co-solvent such as tetrahydrofuran, 1,4-dioxane, or N-methylpyrrolidinone and an additive such as acid, e.g. acetic acid, or base, e.g. sodium hydroxide.

Scheme 1. Strategy 1 to build the tricyclic skeleton

Another viable synthetic route to the tricyclic pyridine precursor described in Scheme 1 is delineated in Scheme 2; R², R³, R⁴, and m hâve the meanings as defined hereinbefore and hereinafter. Transition métal catalyzed coupling of a phenylmethyl (for m=0) or phenethyl (for m=1) métal dérivative with a 2,3-dihalo or pseudohalo pyridine furnishes a requisite intermediate. Suited métal residues in the phenylalkyl métal dérivative may be e.g. MgCI, MgBr, B(OH)₂, B(0CMe₂CMe₂O), BF₃K, ZnCI, ZnBr, or Znl, and suited halo or pseudohalo at the pyridine is preferably Cl, Br, I, F3CSO3, p-TolSO₃, and MeSO₃. Depending on the coupling partners, different catalysts may be suitable which are predominantly derived from Pd, Ni, Cu, or Fe. Pd(PPh₃)₄, Pd[1,1’-bis(diphenylphosphino)ferrocene)]CI₂, Pd(PPh₃)₂Cl2, Ni(PPh₃)₂CI₂, or Pd on C, nanoparticles of Pd or Fe, Pd(ll), Ni(ll), Fe(ll), or Fe(lll) salts, such as Pd(O₂CCH₃)₂, PdCI₂, NiCI₂, or FeCI₃₎ optionally combined with a 2-(optionally substituted phenyljphenyldicyclohexyl or di-ferf-butylphosphine, triphenylphosphîne, tritolylphosphine, trifurylphosphine, tri-tert-butyl-phosphine, tricyclohexylphosphine, a 1,3-diaryl imidazolidinium sait, or a 1,3-diaryl dihydroimidazolidinium sait, are a few more often employed catalysts. The couplings are preferably conducted in toluene, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,Ndimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidinone, or mixtures thereof, which, depending on the coupling partners, are optionally combined with alcohol, e.g. methanol, water, alkali métal salts, such as LiCI, NaOH, Na₂CO₃, K₂CO₃, Cs₂CO₃, NaO₂CCH₃₁ or K₃PO₄, ammonium salts, e.g. Bu₄NCI, or silver salts, e.g. AgO₃SCF₃, at températures of -10 to 150 °C. The subséquent cyclization of the benzyl- or phenethylpyridine to the tricyclic pyridine structure may be accomplished by anothertransition métal catalyzed reaction, preferably Pd, e.g derived from Pd(O₂CC₃)₂ or Pd(O₂CCMe₃)₂, and a phosphine ligand, such as e.g. di-tert-butyl-methylphosphine, tricyclohexylphosphine, triphenyl-phosphine, tri(4-fluorophenyl)phosphine, or 2-(2dimethylaminophenyl)phenyl-diphenyl-phosphine. The cyclization is most preferably carried out in the presence of a potassium sait, e.g. K₂CO₃ or KO₂CCH₃, optionally combined with a silver sait, e.g. Ag₂CO₃ or AgO₃SCF₃, and/or pivalic acid in Ν,Ν-dimethylacetamide at 40 to 160 °C (see e.g. Tetrahedron 2008, 64,6015-20 and référencés quoted therein).

Scheme 2. Strategy 2 to build the tricyclic skeleton

X, Y = e.g. Cl, Br, I, O₃SCF₃

M = e.g. MgCI/Br/l, B(OH)₂, BF₃K, ZnCI/Br/l,

An alternative strategy to access the tricyclic pyridine precursor described in Scheme 1 is described in Scheme 3; R², R³, R⁴, and m hâve the meanings as defined hereinbefore and hereinafter. A transition métal catalyzed coupling of a phenyl métal dérivative, métal is e.g. MgCI, MgBr, B(OH)₂, B(OCMe₂CMe₂O), BF₃K, ZnCI, ZnBr, or Znl, with a pyridine-2-carboxylic acid dérivative or a 3-halogen or pseudohalogen substituted pyridine-2-carboxylic acid dérivative (m=0) or pyrid-2-ylacetic acid dérivative (m=1 ), carboxylic acid dérivative preferably is carboxylic acid, carboxylic ester, or carbonitrile, provides the first intermediate. Depending on the coupling partners, different catalysts may be suitable, which are preferably derived from Pd, e.g. Pd(PPh₃)₄, Pd[1,r-bis(diphenylphosphino)ferrocene]CI₂, Pd(PPh₃)₂CI₂, Pd on C, nanoparticles of Pd, Pd(11) salts such as Pd(O₂CCH₃)₂ or PdCI₂, optionally combined with a 2(optionally substituted phenyl)phenyl-dicyclohexyl or di-tert-butyl-phosphine, triphenylphosphine, tritolylphosphine, trifurylphosphine, tri-tert-butyl-phosphine, tricyclohexylphosphine, a 1,3-diaryl imidazolidinium sait, or a 1,3-diaryl dîhydroimidazolidinium sait, optionally in the presence of alkali métal salts, such as LÎCI, NaOH, NaO'Bu, KO'Bu, Na₂CO₃, K₂CO₃, Cs₂CO₃, NaO₂CCH₃, or K₃PO₄, ammonium salts, e.g. Bu₄NCI, and/or silver salts, e.g. AgO₃SCF₃, preferably employed in toluene, tetrahydrofuran, 1,4-dioxane, N,Ndimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidinone, or mixtures thereof, which are optionally combined with water, at -10 to 150 °C. Subséquent intramolecular Friedel-Crafts acylation establishes the tricyclic pyridine scaffold by activating the carboxy functionality, e.g. carboxylic acid, anhydride, mixed anhydride, or ester, carbonyl chloride, or nitrile, with a Lewis acid, depending on the kind of carboxy group and the electronic nature of the benzene substructure, e.g. hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluormethanesulfonic acid, SnCI₄, FeCI₃, AIBr_3l AICI₃, SbCI₅, BCI₃₁ BF₃, ZnCI₂, montmorillonites, POCI₃, and PCI₅, preferably in an inert solvent, e.g. acetonitrile, dichloromethane, 1,2-dichloromethane, 1,4-dioxane, 1,216399

dimethoxyethane, hydrocarbons, nitrobenzene, or chlorobenzene, at 0 to 180 °C. Réduction of the keto group formed thereafter is preferably conducted with hydrogen in the présence of a transition métal catalyst, e.g. Pd/C, Pd(OH)_Zl PtO₂, Pt/C, or Rh/C, in alcohol, e.g. methanol, glycol, or éthanol, water, acetic acid, ethyl acetate, N-methylpyrrolidinone, tetrahydrofuran, 1,45 dioxane, ether, or mixtures thereof, optionally in the presence of acid, e.g. hydrochloric acid, at to 180 °C, preferably 20 to 120 °C, and hydrogen pressures of 1 to 100 bar, preferably 1 to 10 bar. Alternative^, réduction of the keto group may be accomplished with a hydride, e.g. triethylsilane, borane, sodium borohydride, or lithium aluminum hydride, optionally in the presence of a Lewis acid, e.g. BF₃, AICI₃, lnCI₃, SnCI₄, FeCI₃, ZnCI₂, acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, or trifluoromethanesulfonic acid, at 0 to 140 °C.

Scheme 3. Strategy 3 to build the tricyclic skeleton

Y = e.g. Cl, Br, I, OSO₂CF₃

X = e.g. OH, OC_M-alkyl, or CN for COX

X preferably introduced after coupling: Cl, anhydride residue, mixed anhydride residue

M = e.g. MgCI/Br/l, B(OH)_Z, BF₃K, ZnCI/Br/l,

Scheme 4 describes a strategy suited for accessing the scaffold of compounds of the invention wherein m equals 0; R^z, R³, and R⁴ hâve the meanings as defined hereinbefore and hereinafter. The phenyl-pyridyl structure is assembled by a transition métal catalyzed coupling as described in Scheme 3. A nucleophilic phenyl group, bearing M, and an electrophilic pyridine group, bearing Y, are used for this purpose, though, the aromatic building blocks may be employed with opposite reactivity, i.e. phenyl bears Y and pyridine M, providing the same coupling product. The compound obtained bears two potential leaving groups, preferably fluorine, chlorine, bromine, arylsulfonate, nitro, or arylsulfonyl, one on each (hetero)aromatic ring adjacent to the phenyl-pyridyl bond. A dianionic methylene synthon, e.g. malonic acid, malonic diester, malodinitrile, cyanoacetic acid, or cyanoacetic ester, combined with a base, e.g.

Cs₂CO₃, K₂CO₃, Na₂CO₃, KO'Bu, NaOEt, NaOMe, NEt₃₁ ’Pr₂NEt, 1,8-diazabicyclo[5.4.0]-undec16399

7-ene, consecutively replaces both leaving groups by aromatîc nucleophîlic substitutions to establish the indenopyridine framework. N-Methylpyrrolidinone, Ν,Ν-dimethylacetamide, N,Ndimethylfomnamide, alcohol, e.g. éthanol, isopropanol, or tert-butanol, water, dimethyl sulfoxide, 1,4-dioxane, tetra hydrofuran, or mixtures thereof are among the preferred solvents for this transformation, which is preferably conducted at 0 to 180 °C. The carboxylic electronwithdrawing groups are removed by hydrolysis with base, e.g. NaOH or KOH, or acid, e.g. HCl or H₂SO₄₁ in aqueous or alcoholic solution to form the carboxy group which decarboxylates spontaneously or by heating in the acidic or basic medium. This proceeding is particularly suited for compounds bearing one or more electron-withdrawing groups on the phenyl ring.

Scheme 4. Strategy 4 to build the tricyclic skeleton

Y = e.g. Cl, Br, I, OSO₂CF₃

M = e.g. MgCI/Br/l, B(OH)₂, B(OCMe₂CMe₂O), BF₃K, ZnCI/Br/l

LG = leaving group, e.g. F, Cl, Br

EWG = electron-withdrawing group, e.g. CO₂H, CO^^^-alkyl, CN, NO_Z, SO₂Ph, SOjC^-alkyl

Scheme 5 outlines the assembly of the tricyclic scaffoid of the invention starting from the corresponding pyrrolidine enamine of 2-indanones or 2-tetralones and acryl amide; R², R³, R⁴, and m hâve the meanings as defined hereinbefore and hereinafter. The desired tricyclic structure as a dihydropyridinone is obtained by heating the two reaction partners at 60 to 150 °C. Réduction of the double bond with hydrogen in the presence of a transition métal, such as palladium on carbon, or with a hydride source, such as a trialkylsilane, e.g. triethylsilane, borohydride, e.g. NaBH₄, NaBH(O2CCH₃)3, or NaH₃BCN, or alanate, e.g. LiAIH₄, optionally in the presence of an additive, such as a Lewis acid, e.g. acetic acid, trifluoroacetic acid, AICI₃₁ or BF₃*OEt₂, provides then the tricyclic piperidinone. Eventual amide réduction is preferably achieved with a hydride source, e.g. NaBH₄ combîned with acetic acid in 1,4-dioxane, LiAIH₄ in tetrahydrofuran or ether, or sodium dihydrobis(2-methoxyethoxy)aluminate in ethylene glycol dimethyl ether, at 0 to 100 °C.

Scheme 5. Strategy 5 to buîld the tricyclic skeleton

Another generally applicable approach to access the core structures of the compounds of the invention is based on an electrophilic aromatic substitution reaction (Scheme 6); R^z, R³, R⁴, and m hâve the meanings as defined hereinbefore and hereinafter, Thereby the aromatic part of the molécule reacts with a positively charged carbon atom of the piperidine ring to form the tricyclic framework. The reactive intermediate bearing the positively charged carbon atom in the azacycle may be generated by the addition of a Lewis acid to an olefinic bond or a carbonyl group or by the activation of an appropriately positioned leaving group, such as Cl, Br, I, OH, O3SCF3, 0₃SMe, or O₃S-p-Tol. A huge number of Lewis acids hâve been described for this classical reaction that may also be employed here. The following énumération is supposed to give a few more widely used of them: hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, phosphoric acid, Ρ₄Ο₁₀, trifluoroacetic acid, methanesulfonicacid, toluenesulfonic acid, trifluormethanesulfonic acid, Sc(O₃SCF₃)₃, lnCI₃, lnBr₃, SnCI₄₁ FeCI₃, AIBr₃, AICI₃, SbCI₅, BCI₃, BF_3i ZnCI₂, montmorillonites, POCI₃, and PCI₅. Depending on the inclination of the leaving group to be substituted and the electronic nature of the aromatic ring, a more or less powerful acid catalyst has to be used. Besides the acid catalysts mentioned, silver salts, e.g. AgO₃SCF₃, may be useful in the reactions using halides as leaving group. Preferred solvents are hydrocarbons such as hexane or cyclohexane, chlorinated hydrocarbons, such as dichloromethane or 1,2-dichloroethane, perfluorinated hydrocarbons, nitrobenzene, acetonitrile, chlorinated benzenes, heteroaromatics, such as quinoline, 1,2-dimethoxyethane, 1,4-dioxane, ether, ionic liquids, water, aceticacid, or mixtures thereof, though, not ail of these solvents are usable with ail above listed Lewis acids. The reactions are carried out between -10 and 220 “C, preferably between 20 °C and 180 ’C. The reactions may also be conducted under microwave irradiation.

Scheme 6. Strategy 6 to build the tricyclic skeleton

LG = leaving group such as Cl, Br, I, OH, O₃SCF₃, O₃STol, O₃SCH₃, or =0

The synthetic routes presented may rely on the use of protecting groups. Suitable protecting groups for the respective functionalities and their removal are described hereinafter and may analogously be employed (see also: Protecting Groups, Philip J. Kocienski, 3^,d édition, Georg Thieme Verlag, Stuttgart, 2004 and référencés quoted therein).

In the following a few feasible derivatizations of compounds of general formula I or precursors thereof, obtained as described above, bearing certain functional groups to assemble other compounds of general formula I or precursors thereof are vicariously summarized. This compilation is by no means meant to be complété but is only supposed to give some possibilities by way of example.

If in the process of manufacture according to the invention a compound of general formula I or a precursor thereof is obtained which contains an amino, alkylamino, or imino group, this may be converted by acylation or sulfonylation into a corresponding acyl or sulfonyl compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains a hydroxy group, this may be converted by acylation or sulfonylation into a corresponding acyl or sulfonyl compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains a hydroxy group, this may be converted by alkylation into a corresponding ether of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains an amino, alkylamino, or imino group, this may be converted by alkylation or reductive alkylation into a corresponding alkyl compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains a nitro group, this may be converted by réduction into a corresponding amino compound.

If a compound of general formula I or a precursor thereof is obtained which contains an imino group, this may be converted by nitrosation and subséquent réduction into a corresponding Namino-imino compound.

If a compound of general formula I or a precursor thereof is obtained which contains a C^alkyloxycarbonyl group, this may be converted by cleavage of the ester into the corresponding carboxy compound.

If a compound of general formula I or a precursor thereof is obtained which contains a carboxy group, this may be converted into a corresponding ester of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains a carboxy or ester group, this may be converted by reaction with an amine into a corresponding amide of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains an aromatic substructure, this may be derivatized with a chlorine, bromine, or iodine atom or a nitro, sulfonic acid, chlorosulfonyl, or acyl group by an electrophilic substitution reaction to a corresponding compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains an amino group that is attached to an aromatic or a heteroaromatic group, this may be transformed into a corresponding cyano, fluoro, chloro, bromo, iodo, hydroxy, mercapto, or azido derivatized compound of general formula I or a precursor thereof by diazotization and subséquent replacement of the diazo group with cyanide, fluoride, chloride, bromide, iodide, hydroxide, alkyl or hydrogen sulfide, or azide, respectively.

If a compound of general formula I or a precursor thereof is obtained which contains an amino group that is attached to an aromatic or a heteroaromatic group, this may be converted into a corresponding aryl derivatized aromatic compound of general formula I or a precursor thereof by diazotization of the amino group and subséquent replacement of the resulting diazo group with an appropriate aryl nucleophile mediated by a suited transition métal species.

If a compound of general formula I or a precursor thereof is obtained which contains a chloro, bromo, or iodo atom, or a trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group which is attached to an aromatic or a heteroaromatic group, this may be converted into a corresponding aryl, alkenyl, alkynyl, or alkyl derivatized compound of general formula I or a precursor thereof by replacement of the respective group by aryl, alkenyl, alkynyl, or alkyl using a transition métal species mediated process.

If a compound of general formula I or a precursor thereof is obtained which contains a chloro, bromo, or iodo atom, or a trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group which is attached to an aromatic or a heteroaromatic group, this may be replaced with cyano to give a corresponding aromatic compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains a chloro, bromo, or iodo atom, or a trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group which is attached to an aromatic or a heteroaromatic group, this may be replaced with hydrogen to give a corresponding aromatic compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains two heteroatoms at adjacent carbon atoms that are amino and hydroxy, amino, or mercapto, these heteroatoms may be linked via a carboxy carbon atom to form a cyclic amidine, imino ester, or imino thioester substructure that may be part of an aromatic ring.

If a compound of general formula I or a precursor thereof is obtained which contains a cyano group, this may be converted by réduction into an aminoalkyl derivatized compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains a cyano group, this may be converted into an N-hydroxycarbamimidoyl group by the treatment with hydroxylamine.

If a compound of general formula I is obtained which contains an N-hydroxycarbamimidoyl group, this may be converted to an oxadiazole derivatized compound of general formula I or a precursor thereof by the treatment with a carboxylic or related group.

If a compound of general formula I or a precursor thereof is obtaîned which contains an aminocarbonyl group, this may be converted by déhydration into a corresponding cyano compound of general formula or a precursor thereof I.

If a compound of general formula I or a precursor thereof is obtaîned which contains a keto or aldehydic group, this may be converted by réduction into a corresponding hydroxy compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtaîned which contains a carboxylic acid or aminocarbonyl group, this may be converted by a rearrangement reaction into a corresponding amino derivatized compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtaîned which contains a keto or aldéhyde group, this may be converted into an alkenyl derivatized compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtaîned which contains an olefinic C=C double or a C=C triple bond, this may be reduced to give the corresponding saturated compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtaîned which contains a keto or aldehydic group, this may be converted into a corresponding tertiary or secondary hydroxy compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtaîned which contains a carboxylic ester group, this may be converted into a tertiary alcohol by the addition of two équivalents of an organo métal compound.

If a compound of general formula I or a precursor thereof is obtaîned which contains a primary or secondary hydroxy group, this may be converted by oxidation into a corresponding carbonyl compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtaîned which contains an olefinic bond, this may be converted into a corresponding hydroxy compound of general formula I or a precursor thereof by hydroboration followed by oxidation.

If a compound of general formula I or a precursor thereof is obtained which contains an olefinic bond, this may be converted by dihydroxylation into a corresponding 1,2-dihydroxy compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains an olefinic bond, this may be converted by ozonolysis into a corresponding carbonyl compound compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains an olefinic bond, this may be converted into a corresponding hydroxy compound of general formula I or a precursor thereof by epoxidation followed by oxirane opening with a hydride source.

If a compound of general formula I or a precursor thereof is obtained which contains an olefinic bond, this may be converted by Wacker oxidation into a corresponding carbonyl compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains an olefinic bond, this may be converted by hydrocyanation into a corresponding cyano compound of general formula I or a precursor thereof.

If a compound of general formula I or a precursor thereof is obtained which contains a cyano group, this may be converted by water addition into a corresponding aminocarbonyl compound of general formula I or a precursor thereof.

The subséquent estérification is optionally carried out in a solvent such as methylene chloride, Ν,Ν-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, phosphores trichloride, phosphores pentoxide, N,N'-carbonyldiimidazole, Ν,Ν'-dicyclohexylcarbodiimide, triphenylphosphine combined with carbon tetrachloride, or combinations thereof optionally in the presence of 4-dimethylaminopyridine and/or 1-hydroxybenzotriazole. The reactions are conducted between 0 and 150 °C, preferably between 0 and 80 °C.

The ester formation may also be carried out by reacting a compound which contains a carboxy group with a corresponding alkyl halide in the presence of a base.

The subséquent acylation or sulfonylation is optionally carried out in a solvent such as methylene chloride, N.N-dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, 1,4-dioxane, or mixtures thereof with a corresponding acyl or sulfonyl electrophile, optionally in the presence of a tertiary organic base, an inorganic base, or a dehydrating agent. Routinely used agents are e.g. isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, Ν,Ν’-dicyclohexylcarbodiimide, Ν,Ν'-carbonyldiimidazole, triphenylphosphine combined with carbon tetrachloride, or combinations thereof that may be employed in the presence of 4dimethylaminopyridine and/or 1-hydroxybenzotriazole at températures between 0 and 150 °C, preferably between 0 and 80 °C.

The subséquent alkylation is optionally carried out in methylene chloride, N,Ndimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, 1,4-dioxane, or mixtures thereof with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. methyl iodide, ethyl bromide, dimethyl sulfate, or benzyl chloride, optionally in the presence of a tertiary organic base or an inorganic base at températures between 0 and 150 ’C, preferably between 0 and 100 °C.

The subséquent reductive alkylation is carried out with a corresponding carbonyl compound such as formaldéhyde, acetaldehyde, propionaldéhyde, acetone, or butyraldéhyde in the presence of a complex métal hydride, such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride, conveniently at a pH of 6-7 and ambient température, or using hydrogen in the presence of a transition métal catalyst, e.g. palladium on charcoal, at hydrogen pressures of 1 to 5 bar. Méthylation may also be carried out in the presence of formic acid as reducing agent at elevated température, e.g. between 60 and 120 °C.

The subséquent réduction of a nitro group is carried out, for example, with hydrogen and a catalyst such as palladium on carbon, platinum dioxide, or Raney nickel, or using other reducing agents such as tin(ll) chloride, iron, or zinc optionally in the presence of an acid such as acetic acid.

The subséquent nitrosation of an imino group followed by réduction to obtain an N-amino-imino compound is carried out, for example, with an alkyl nitrite such as isoamyl nitrite to form the Nnitroso-imino compound that is then reduced to the N-amino-imino compound using, for example, zinc in the presence of an acid such as acetic acid.

The subséquent cleaving of a Cn-alkyloxycarbonyl group to obtain the carboxy group is carned out, for example, by hydrolysis with an acid such as hydrochloric acid or sulfuric acid or an alkali métal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide. The tertbutyl group is preferably removed by treatment with a strong acid, e.g. trifluoroacetic acid or hydrochloric acid, in an inert solvent such as dichloromethane, 1,4-dioxane, or ethyl acétate.

The subséquent amide formation is carried out by reacting a corresponding reactive carboxylic acid dérivative with a corresponding amine in a solvent such as methylene chloride, N,Ndimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, 1,4-dioxane, or mixtures thereof, or without an solvent in an excess of the amine, optionally in the presence of a tertiary organic base, an inorganic base, 4-dimethylaminopyridine, and/or 1-hydroxy-benzotriazole, at températures between 0 and 150 °C, preferably between 0 and 80 °C. Using the carboxylic acid may lead to the desired amide by in situ activation of the carboxy function with e.g. isobutyl chloroformate, thionyl chloride, oxalyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, Ν,Ν'-carbonyldiimidazole, triphenylphosphine combined with carbon tetrachloride, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluroborate, Ν,Ν'-dicyclohexylcarbodiimide, or combinations thereof.

The subséquent introduction of a chlorine, bromine, or iodine atom into an aromatic substructure may be carried out by reacting the aromatic compound with an appropriate electrophile of the respective halogen atom. Suited chlorine and bromine electrophiles may be e.g. N-halosuccinimide, HOCI, HOBr, tert-BuOCI, fert-BuOBr, chlorine, bromine, dibromoisocyanuric acid, pyridinium dichlorobromate, pyridinium tribromide, or sulfuryl chloride that may be used alone or in combination with an acid, e.g. hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, triflic acid, sulfuric acid, or acetic acid, or a Lewis acid, e.g. iron(lll) halide, boron trifluoride hydrate, boron trifluoride etherate, or aluminum halide. Further useful combinations may be LiBr and ceric ammonium nitrate, KCI or KBr with Oxone®, or KBr and sodium perborate. Suited iodine electrophiles may be generated from iodine and an oxidizing agent such as nitric acid, sulfur trioxide, manganèse dioxide, HIO₃, hydrogen peroxide, sodium periodate, peroxydisulfates, and Oxone®. Further suited iodine electrophiles may be e.g. iodine chloride, dichloroiodates, and N-iodosuccinimide. These iodine electrophiles are optionally used without an additive or in the presence of an acid such as acetic acid, trifluoroacetic acid, or sulfuric acid or a Lewis acid such as boron trifluoride hydrate or copper salts. If a nitro group is to be introduced appropriate nitro electrophile sources may be, for instance, nitric acid, acetyl nitrate, ceric ammonium nitrate, sodium nitrate, N₂O₅, alkyl nitrate, and nitronium tetrafluoroborate. Some of these reagents may be used without an additive, though, several of them are better used in combination with an acid, e.g. sulfuric acid or triflic acid, acetic

anhydride, trifluoroacetic anhydride, Lewis acid, e.g. ytterbium triflate or iron acetate, P_ZO₅, or a base. The SO₃H group may be inlroduced by reacting the aromatic compound with, for example, concentrated sulfuric acid, SO₃₁ CISO₃K, or CISO₂NMe₂ combined with indium triflate. Reacting the aromatic compound with CISO₃H gives the corresponding chlorosulfonylated dérivative that may be hydrolyzed to the sulfonic acid. Acylating the aromatic part is conducted using an acyl electrophile that may be generated from the respective acyl halide, e.g. chloride, or acyl anhydride and a Lewis acid such as aluminum halide, diethylaluminum halide, indium halide, iron(lll) halide, tin(IV) halide, boron trifluoride, titanium(IV) halide, or a Bronsted acid, e.g. sulfuric acid or triflic acid. The formyl group is preferably introduced using the so-called

Vilsmeier or Vilsmeier-Haack conditions: dialkylformamide combined with phosgene, thionyl chloride, POCI₃₁ or oxalyl chloride. Preferred solvents for the electrophilic substitutions described may differ dependîng on the electrophile employed; in the following some more generally applicable are mentioned: methylene chloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, ether, 1,4-dioxane, fluorinated hydrocarbons, hexanes, quinoline, and acetonitrile. Températures preferably applied range from 0 to 180 °C.

The subséquent replacement of an amino group that is attached to an aromatic or a heteroaromatic group is initiated by diazotization of the amino group using a nitrous acid or nitrosonium source or équivalent such as a nitrite sait combined with an acid, e.g. sodium nitrite and hydrochloric acid, nitrosonium tetrafluoroborate, or an alkylnitrite, e.g. ferf-butyl nitrite or /so-amyl nitrite. The diazotization is optionally carried out in methylene chloride, 1,2dichloroethane, Ν,Ν-dimethylformamide, N-methylpyrrolidinone, benzene, toluene, chlorobenzene, tetrahydrofuran, water, ethyl acetate, alcohol, ether, 1,2-dimethoxyethane, 1,4dioxane, or mixtures thereof at températures between -10 and 100 °C (diazotization of amino groups is detailed in, for example, Angew. Chem. Int. Ed. 1976, 15, 251). The subséquent displacement of the diazo group with a cyano group, chlorine, or bromine atom using copper cyanide, chloride, or bromide, respectively, is known as the Sandmeyer reaction (see e.g. March's Advanced Organic Chemistry, Michael B. Smith and Jerry March, John Wiley & Sons Inc., 6. Ed., New Jersey, 2007 and references quoted thereîn); the reaction is optionally conducted between -10 and 120 °C in one of the solvents or mixtures mentioned above. The replacement of the diazo group with a fluorine atom may be achieved with a tetrafluoroborate sait or tetrafluoroboric acid and heating to 20 to 160 °C; the reaction is known as the Schiemann reaction, lodine may be introduced by treatment of the diazo compound with an iodide sait, e.g. sodium iodide, preferably using water or an aqueous solvent mixture at températures between 0 and 120 °C. The diazo group is replaced with hydroxy using water or an aqueous solvent mixture at températures between 0 and 180 “C. The reaction usually works without further additives but the addition of copper oxide or strong acid may be advantageous. Mercapto or alkylmercapto may be introduced via their corresponding disulfide salts or dialkyldisulfides at températures between 0 and 120 °C; depending on the sulfur species used an inert solvent or aqueous solvent System may be preferred (see e.g. Synth. Commun. 2001, 31, 1857 and référencés quoted therein).

The subséquent replacement of an amino group that is attached to an aromatic or a heteroaromatic group by an aryl group may be accomplished via the corresponding diazo compound obtainable as described above. The reaction with an aryl nucleophile, preferably an aryl boronic acid, boronic ester, trifluoroborate, zinc halide, or stannane, is conducted in the presence of a transition métal species derived from palladium, nickel, rhodium, copper, or iron, preferably palladium. The active catalyst may be a complex of the transition métal with ligands such as e.g. phosphines, phosphites, imdiazole carbenes, imidazolidine carbenes, dibenzylideneacetone, allyl, or nitriles, an elemental form of the transition métal such as palladium on carbon or nanoparticles, or salts such as chloride, bromide, acetate, or trifluoroacetate. The diazo compound is preferably employed as its tetrafluoroborate sait optionally in water, N-methylpyrrolidinone, Ν,Ν-dimethylformamide, methylene chloride, benzene, toluene, tetrahydrofuran, ethyl acetate, alcohol, ether, 1,2-dimethoxyethane, 1,4dioxane, or mixtures thereof at températures between 10 and 180 °C, preferably between 20 and 140 °C.

The subséquent replacement of a chloro, bromo, or iodo atom or a trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group that is attached to an aromatic or a heteroaromatic group with an aryl, alkenyl, alkynyl, or alkyl residue is preferably mediated by a transition métal species derived from palladium, nickel, copper, or iron. The active catalyst may be a complex of the transition métal with ligands such as phosphines, e.g. tri-tert-butylphosphine, tricyclohexylphosphine, 2-(substituted phenyl)phenyl-dicyclohexylphosphines, 2-(substituted phenyl)phenyl-di-tert-butylphosphines, 1,1'-bis(diphenylphosphino)ferrocene, triphenylphosphine, tritolylphosphine, or trifuryl-phosphine, phosphites, 1,3-disubstituted imdiazole carbenes, 1,3-disubstituted imidazolidine carbenes, dibenzylideneacetone, allyl, or nitriles, an elemental form of the transition métal such as palladium on carbon or nanoparticles of iron or palladium, or a sait such as fluorîde, chloride, bromide, acetate, triflate, or trifluoroacetate. The replacement reaction is preferably conducted with a trifluoroborate, boronic acid, or boronic ester (Suzuki or Suzuki-type reaction), zinc halide (Negishi or Negishi-type reaction), stannane (Stille or Stille-type reaction), silane (Hiyama or Hiyama-type reaction), magnésium halide (Kumada or Kumada-type reaction) of the aryl, alkenyl, or alkyl residue to be introduced. The terminal alkyne is preferably used as such or as its zinc acetylide dérivative. Depending on the nature of the electrophilic and nucleophilic reaction partners additives such as halide salts, e.g. lithium chloride, potassium fluoride, tetrabutylammonium fluoride, hydroxide sources such as potassium hydroxide or potassium carbonate, silver salts such as silver oxide or triflate, and/or copper salts such as copper chloride or copper thiophene-2-carboxylate may be advantageous or even essential. Copper iodide is a preferred additive in the coupling with terminal alkynes (Sonogashira reaction). The coupling reactions are preferably conducted in benzene, toluene, ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,Ndimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidinone, alcohol, water, or mixtures thereof, though, depending on the nucleophile some of them are less or not suited at ail. Preferred températures are in the range from -10 to 180 °C.

The subséquent replacement of a chlorine, bromîne, or iodine atom or a mesyloxy, trifluoromethylsulfonyloxy, or tosyloxy group that Is attached to an aromatic or a heteroaromatic group with a cyano group is preferably achieved via a transition métal mediated process. Copper, nickel, and palladium are the most frequently employed metals for this transformation and used as éléments, salts, or complexes in combination with a cyanide source. Copper iodide, copper sulfate, copper cyanide, nickel chloride, nickel bromide, nickel cyanide, bis(triphenylphosphine)nickel dtchloride, palladium on carbon, tetrakisitriphenylphosphinejpalladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, palladium trifluoroacetate, palladium chloride, palladium cyanide, optionally combined with a ligand, such as tricyclohexylphosphine, tri-tert-butyl-phosphine, triphenylphosphine, 1,1’bis(diphenylphosphino)ferrocene, diadamantyl-n-buty!-phosphine, or Xantphos, are among the catalysts that are routinely employed. Common cyanide sources are sodium cyanide, potassium cyanide, zinc cyanide, copper cyanide, nickel cyanide, potassium hexacyanoferrate, and acetone cyanohydrin. The reactions are preferably carried out in Ν,Ν-dimethylformamide, N,Ndimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, pyridine, acetonitrile, quinoline, toluene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or mixtures thereof, at 20 to 280 °C, preferably at 60 to 200 °C. Additives, such as zinc, sodium carbonate, potassium iodide, water, and pyridine, and or the use of microwave irradiation may be advantageous to some of the reaction conditions.

The subséquent replacement of a chlorine, bromine. or iodine atom or a trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group that is attached to an aromatic or a heteroaromatic group with a hydrogen atom is preferably mediated by a transition métal species derived from palladium, nickel, platinum, or rhodium. The active catalyst may be a complex of the transition métal with ligands, an elemental form, or a sait of the transition métal as mentioned above. Raney nickel or palladium on carbon are among the preferred catalyst species. Suited hydrogen sources may be hydrogen, preferably at pressures of 1 to 10 bar,

silanes, e.g. trialkoxysilane or polymethylhydrosiloxane, boranes, hydrides, e.g. alkali métal borohydride, formic acid, or formates, e.g. ammonium formate. The reactions are preferably carried out in N.N-dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidinone, benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohol, ether, 1,2-dimethoxyethane, 1,4-dioxane, or mixtures thereof at -10 to 180 ’C, more preferably at 20 to 140 °C.

The subséquent cyclization slarting from a compound bearing two heteroatoms at adjacent carbon atoms is optionally conducted with a carboxy équivalent such as nîtrile, carboxylic chloride or fluoride, carboxylic acid, ketene, carboxylic ester, or carboxylic thioester. The overall transformation comprises two reaction steps: attachment of the carboxy équivalent to one of the two heteroatoms followed by cyclization with the other heteroatom. The first step is an amide formation with the amino functionality that may be carried out as described hereinbefore. The ensuing reaction step, cyclization 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. The use of dehydrating reagents such as anhydrides, e.g. acetic anhydride, orthoesters, e.g. trimethyl orthoformate, thionyl chloride, phosgene, diphosgene, triphosgene, phosphorous oxychloride, phosphorous pentachloride, dialkylcarbodiimides, combinations with phosphines, e.g. triphenylphosphine or trialkylphosphine with dialkyl azodicarboxylates, bromine, iodine, or 1,2dihaloethanes, e.g. 1,2-dibromotetrafluoroethane, may be advantageous. The reactions are preferably carried out in inert solvents or mixtures such as methylene chloride, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, ether, or combinations thereof, though, cyclization in the presence of an acid or a base may also be conducted in water or an alcohol, e.g. methanol, éthanol, fso-propanol, or tert-butanol, or combinations with these solvents. The reactions are carried out at températures between 0 and 200 °C, preferably between 20 and 140 °C.

The subséquent réduction of a cyano group to obtain an aminomethyl group is preferably conducted with hydrogen in the presence of a transition métal species or with a hydride. Suited transition metals may be derived from palladium, nickel, platinum, rhodium, or ruthénium such as palladium on charcoal, palladium hydroxide, platinum oxide, or Raney nickel that may be used in solvents such as ethyl acetate, alcohols, e.g. methanol or éthanol, dichloromethane, tetrahydrofuran, ether, benzene, toluene, Ν,Ν-dimethylformamide, or N-methylpyrrolidinone at hydrogen pressures between 1 and 10 bar and at températures between 0 and 160 °C. Additives such as acids, e.g. hydrochloric acid, methanesulfonic acid, sulfuric acid, or acetic acid, may be bénéficiai for the réduction with transition métal catalysts. Among the preferred hydride sources are e.g. borohydrides, e.g. sodium borohydride, potassium tri-sec-butylboro-

hydride, borane, or lithium triethylborohydride, and alanates, e.g. lithium aluminum hydride or diisobutylaluminum hydride. Some of these reagents are best used in combination with nickel chloride or cobalt chloride as sodium borohydride. These reagents may be used in e.g. tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, benzene, or toluene; some are also compatible with alcoholic or aqueous solutions. Preferred reaction températures range from -80 to 160 °C, more preferred from -40 to 80 °C.

The subséquent formation of a N-hydroxycarbamimidoyl group from a cyano group may be carrîed out by the treatment of the cyano compound with hydroxylamine. The reaction is preferably conducted in aqueous or alcoholic solvents at températures between 0 and 140 °C.

The subséquent formation of an oxadiazole from an N-hydroxycarbamimidoyl is conducted with a carboxy équivalent such as nitrile, carboxylic chloride or fluoride, carboxylic acid, ketene, carboxylic ester, or carboxylic thioester. The transformation is related to the formation of a ring starting from two heteroatoms at adjacent carbon atoms described above and may be carrîed out analogously.

The subséquent formation of a cyano group from an aminocarbonyl group is preferably conducted by using a dehydrating reagent such as anhydride, e.g. acetic anhydride, trifluoroacetic anhydride, or triflic anhydride, phosgene, thionyl chloride, oxalyl chloride, POCI₃, PCI₅, P₄O_1o, triphenylphosphite, or triphenyl- or trialkylphosphine combined with tetrachloromethane, 1,2-dibromotetrafluoroethane, or bromine. The reactions are preferably carrîed out in dichloromethane, 1,2-dichloroethane, hexanes, ether, 1,4-dioxane, benzene, toluene, acetonitrile, mixtures thereof, orwithout a solvent at températures between 0 and 140 °C. Additives such as amines, e.g. pyridine or triethylamine, or Ν,Ν-dimethylformamide may be bénéficiai.

The subséquent réduction of a keto or an aldehydic group to obtain a secondary or primary alcohol may be carrîed out with a complex métal hydride such as sodium borohydride, lithium borohydride, lithium triethylborohydride, diisobutylaluminum hydride, or lithium aluminum hydride. The réductions may be conducted in e.g. dichloromethane, 1,2-dichloroethane, hexanes, ether, 1,4-dioxane, tetrahydrofuran, Ν,Ν-dimethylformamide, N-methylpyrrolidone, benzene, toluene, alcohols, e.g. methanol, water, or mixtures thereof, though, not ail reducing agents are compatible with ail of these solvents. Preferred températures range from -80 to 140 °C depending on the reducing power of the reagent. Alternatively, hydrogen in the presence of a transition métal catalyst may be used for the réduction.

The subséquent conversion of a carboxy group into an amino group by rearrangement may be accomplished by heating an acyl azide resulting in the formation of an isocyanate (Curtius rearrangement). The isocyanate may be hydrolyzed to produce the free amine or converted into a urea or carbamate dérivative by treatment with an amine or an alcohol, respectively. The acyl azide may be obtained by treating an appropriate acyl electrophile, e.g. acyl chloride, carboxylic anhydride, or carboxylic ester, with an azide source, such as e.g. sodium azide or trimethylsilyl azide, in a solvent such as 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N-methylpyrrolidinone, Ν,Ν-dimethylformamide, toluene, benzene, hexanes, or mixtures thereof; water or alcohols may be usable in certain cases as well. The reactions are routinely carried oui between -10 and 120 °C. Alternative^, the acyl electrophile may be generated in situ from the acid and then converted into the acyl azide: diphenylphosphoryl azide in the presence of a base, e.g. triethylamine or ethyldiisopropylamine, in a solvent such as acetonitrile, benzene, toluene, or an alcohol at elevated température has proven to be an effective reagent for this direct conversion. The direct conversion may also be achieved with hydrazoic acid and an acid catalyst such as sulfuric acid in e.g. chloroform at elevated températures (Schmidt reaction). Another method to accomplish this overall transformation is the Lossen rearrangement: starting from an acyl electrophile such as acyl chloride the corresponding suited hydroxamic acid dérivative is formed that in turn rearranges to give the isocyanate and then the amine by heating and/or treatment with a base, e.g. sodium hydroxide (see e.g. J. Org. Chem. 1997, 62, 3858 and Synthesis 1990, 1143 and references quoted therein).

An unsubstituted carboxylic amîde may be converted into an amine by the so-called Hoffmann rearrangement. Among the suited reagents for this transformation are NaOBr, bromine combined with sodium methoxide, N-bromosuccinimide and sodium methoxide, Phl(O₂CCF₃)₂, 25 and Phl(OH)OTs (Ts is 4-tolylsulfonyl).

The subséquent conversion of an aldehydic or a keto functionality into an olefin may be accomplished by, for example, the so-called Wittig reaction and modifications thereof, Peterson olefination, and Julia reaction and modifications thereof. These reactions hâve large precedence in organic synthèses and are detailed in e.g. March's Advanced Organic Chemistry, Michael B. Smith and Jerry March, John Wiley & Sons Inc., 6. Ed., New Jersey, 2007 and references quoted therein.

The subséquent réduction of a C=C double or C=C triple bond is preferably conducted with hydrogen in the presence of a transition meta! species derived from palladium, nickel, platinum, ruthénium, or rhodium, preferably Raney nickel, palladium on charcoal, platinum oxide, and RhCI(PPh)₃. The reactions are preferably carried out in methylene chloride, N,N16399 dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidinone, benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohol, ether, 1,2-dimethoxyethane, 1,4-dioxane, or mixtures thereof, at 0 to 180 °C, more preferabiy at 20 to 140 °C, and hydrogen pressures of 1 to 10 bar, preferabiy 1 to 5 bar.

The subséquent transformation of an aldéhyde or a ketone to a secondary or tertiary alcohol is preferabiy accomplished by addition of a carbon nucleophile, e.g. alkyl, allyl, alkenyl, aryl, or alkynyl lithium, magnésium, or cérium compound, in tetrahydrofuran, ether, 1,4-dioxane, 1,2dimethoxyethane, toluene, hexanes, or mixtures thereof, at -80 to 80 °C.

The subséquent transformation of a carboxylic ester into a tertiary hydroxy group is preferabiy conducted with two or more équivalents of a carbon nucleophile, e.g. alkyl, allyl, alkenyl, aryl, or alkynyl lithium, magnésium, or cérium compound, in tetrahydrofuran, ether, 1,4-dioxane, 1,2dimethoxyethane, toluene, hexanes, or mixtures thereof, at températures of -80 to 80 °C.

The subséquent oxidation of a primary or secondary hydroxy compound may be achieved by using an oxidîzing agent, such as dimethyl sulfoxide combined with e.g. oxalyl chloride, acetic anhydride, SO₃*pyridine, or dicyclohexylcarbodiimide, pyridinium chlorochromate (PCC), pyrdidinium dichromate (PDC), Dess-Martin periodinane, manganèse dioxide, 2,2,6,6tetramethylpiperidine-N-oxide (TEMPO) optionally combined with a co-oxidant, or tetrapropylammonium perrhutenate (TPAP) combined with a co-oxidant such as N-methylmorpholine-N-oxide, which are optionally used in the presence of a base, e.g. triethylamine, preferabiy in toluene, dichloromethane, or 1,2-dichloroethane, at -70 to 60 °C. Alternative^, the transformation may be performed as an Oppenauer oxidation with e.g. AI(OtBu)₃ and acetone.

The subséquent hydroboration and oxidation of an olefinic bond is conducted with a borane, e.g. borane complexed with tetrahydrofuran, trimethylamine, or dimethyl sulfide, diethylborane, thexylborane, 9-borabicyclo[3.3.1]nonane, NaBH₄ combined with BF₃ or TiCI₄, or dtchloroborane, preferabiy used in tetrahydrofuran at -20 to 60 °C. The hydroboration product is subsequently treated with e.g. hydrogen peroxide and sodium hydroxide in an aqueous solution to replace the boron group in the intermediate with hydroxy.

The subséquent dihydroxylation of an olefinic bond is preferabiy conducted with osmium tetroxide or potassium osmate combined with a co-oxidant, e.g. N-methyl-morpholine-N-oxide or K₃Fe(CN)₆, preferabiy in water combined with tBuOH, tetrahydrofuran, and/or 1,4-dioxane, at -20 to 60 ’C.

The subséquent cleavage of an olefinic bond by ozonolysis is conducted with ozone, preferably in dichloromethane at -50 to -78 ‘0. The intermediate obtained thereafter may be transformed into a carbonyl compound by treatment with e.g. dimethyl sulfide, zinc combined with acetic acid, hydrogen in the presence of palladium, or triphenylphosphine. Treatment of the intermediate with sodium borohydride or lithium aluminum hydride affords the corresponding hydroxy compound.

The subséquent epoxidation of an olefinic bond is preferably conducted with mchloroperbenzoic acid (mCPBA), hydrogen peroxide combined with formic acid or acetic acid, or Oxone® combined with acetone or 1,1,1-trifluoroacetone, preferably in dichloromethane at -20 to 40 °C. The oxirane ring can be opened with a hydride source such as lithium aluminum hydride or lithium triethylborohydride in an inert solvent, e.g. tetrahydrofuran, to furnish the hydroxy compound.

The subséquent Wacker oxidation of an olefinic bond is preferably conducted with PdCI₂ and CuCI or CuCI₂, in the presence of oxygen, in an aqueous solvent to provide the corresponding carbonyl compound.

The subséquent hydrocyanation of an olefinic bond can be conducted with 4-tolylsulfonyl cyanide in the presence of phenylsilane and a cobalt catalyst (see e.g. Angew. Chem. 2007, 119, 4603-6).

The subséquent formai water addition to cyano groups can be done by treating 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, optionally at elevated température, preferably at 0 to 140 °C. Alternative^, this transformation can be achieved in an aqueous solution with a transition métal catalyst such as PdCI₂.

In the reactions described hereinbefore, any reactive group présent, such as hydroxy, carbonyl, carboxy, amino, alkylamino, or imino, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, a protecting group for a hydroxy group may be a trimethylsilyl, tertbutyldimethylsilyl, triisopropylsilyl, acetyl, pivaloyl, benzoyl, methyl, terf-butyl, allyl, trityl, benzyl, 4-methoxybenzyl, tetrahydropyranyl, methoxymethyl, ethoxymethyl, or 2trimethylsilylethoxymethyl group,protecting groups for a carboxy group may be trimethylsilyl, methyl, ethyl, tert-butyl, allyl, benzyl, or tetrahydropyranyl,

protecting groups for a ketone or aldéhyde may be a ketal or acetal, respectively, e.g. derived from methanol, ethylene glycol, propane-1,3-diol, or propane-1,3-dithiol, protecting groups for an amino, alkylamino, or imino group may be methyl, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4methoxybenzyl, or 2,4-dimethoxybenzyl and for the amino group additionally phthalyl and tetrachlorophthalyl, and protecting groups for a termina! alkyne may be trimethylsilyI, trisopropylsilyl, tertbutyldimethylsilyl, or 2-hydroxy-prop-2-yl.

Any acyl protecting group may be cleaved, for example, hydrolytically 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 such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid or in the presence of an alkali métal base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide at températures between 0 and 120 °C, preferably between 10 and 100 ’C. The transformation may be conducted aprotically with e.g. iodotrimethylsilane in dichloromethane or 1,2-dichlorethane at -70 to 60 °C. Trifluoroacetyl is also cleaved by treating with an acid such as hydrochloric acid optionally in a solvent such as acetic acid at températures between 50 and 120 ’C or by treating with aqueous sodium hydroxide solution optionally in an additional solvent such as tetrahydrofuran or methanol at températures between 0 and 80 ’C.

Any acetal or ketal protecting group used may be cleaved, for example, hydrolytically in an aqueous solvent, e.g. water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or 1,4dioxane/water, in the presence of an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid, or sulfuric acid at températures between 0 and 120 ’C, preferably between 10 and 100 ’C. Iodotrimethylsilane in dichloromethane is a variant to achieve this transformation aprotically.

A trimethyIsilyl group is cleaved, for example, in water, an aqueous solvent mixture or an alcohol, such as methanol or éthanol, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate, or sodium methoxide. Acids such as e.g. hydrochloric acid, trifluoroacetic acid, or acetic acid may also be suitable. The cleavage usually takes place at comparatively low températures, e.g. between -60 and 60 ’C. Silyl groups other than trimethylsilyl are preferentially cleaved in the presence of an acid, e.g. trifluoroacetic acid, hydrochloric acid, or sulfuric acid, at températures between 0 and 100 ’C. A particularly suited cleaving method for silyl groups is based on the use of fluoride salts, e.g. tetrabutylammonium

fluoride, hydrogen fluoride, or potassium fluoride, in organic solvents, such as for example diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, benzene, 1,2dichloroethane, or dichloromethane at températures between -20 and 100 °C.

A benzyl, methoxybenzyl, or benzyloxycarbonyl group is advantageously cleaved hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium on carbon or palladium hydroxide, in a solvent such as methanol, éthanol, ethyl acetate, acetic acid or mixtures thereof optionally in the presence of an acid such as hydrochloric acid at températures between 0 and 100 °C, preferably between 20 and 60 ’C, and at hydrogen pressures of 1 to 10 bar, preferably 3 to 5 bar. Trimethylsilyl iodide, boron trichloride, or boron trifluoride in the presence of a scavenger such as anisol, thioanisol, or pentamethylbenzene may also be used with benzylether dérivatives. An electron-rich benzyl residue such as methoxybenzyl may also be cleaved oxidatively with e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ceric ammonium nitrate (CAN) preferably in an alcoholic or aqueous solvent at températures between 10 and 120 °C. A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of a scavenger such as anisole.

A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid, sulfuric acid, or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, 1,4-dioxane, methanol, isopropanol, water, or diethylether.

A methyl group at an tertiary amine may be cleaved by the treatment with 1-chloroethyl chloroformate or vinyl chloroformate. Hydrobromic acid and boron tribromide are particularly suited for the cleavage of methylethers.

The compounds of general formula I may be resolved into their enantiomers and/or diastereomers as mentioned before. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers and racemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatography into the cis and trans isomers thereof. The compounds of general formula I which occur as racemates may be separated by methods known perse (cf. Allinger N. L. and Eliel E. L. in Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and diastereomeric mixtures of compounds of general formula I may be resolved into their diastereomers by taking advantage of their different physico-chemical properties using methods

known per se, e.g. chromatography and/or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned above.

The racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or dérivatives such as esters or amides with the racemic compound. Salts may be formed with enantiomerically pure acids for basîc compounds and with enantiomerically pure bases for acidic compounds. Diastereomeric dérivatives are formed with enantiomerically pure auxiliary compounds, e.g. acids, their activated dérivatives, or alcohols. Séparation of the diastereomeric mixture of salts or dérivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g. différences in solubility; the free antipodes may be released from the pure diastereomeric salts or dérivatives by the action of suitable agents, Optically active acids in common use for such a purpose are e.g. the D- and L-forms of tartaric acid, dibenzoyltartaric acid, ditoloyitartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, or quinic acid. Optically active alcohols applicable as auxiliary resîdues may be, for example, (+) or (-)-menthol and optically active acyl groups in amides may be, for example, (+)- or (-)-menthyloxycarbonyl.

As mentioned above, the compounds of formula I may be converted into salts, particularly for pharmaceutical use into the pharmaceutically acceptable salts. As used herein, pharmaceutically acceptable salts refer to dérivatives 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, minerai or organic acid salts of basic resîdues such as amines, alkali or organic salts of acidic resîdues such as carboxylic acids, and the like. For example, such salts include acétates, ascorbates, benzenesulfonates (besylates), benzoates, bicarbonates, bitartrates, bromides/hydrobromides, Caedetates/edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, ethane disulfonates (edisylates), estolates, esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsanilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates/diphosphates, polygalacturonates, propionates, salicylates, stéarates, subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates (tosylates), triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines, and procaines. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminum, calcium, lithium, magnésium, potassium, sodium, zinc, and the like (also see

Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19). Some of the salts mentioned above may also be useful for purifying or isolating the compounds of the invention.

The pharmaceutically acceptable salts of the présent invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, 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 in an organic diluent like ether, ethyl acetate, éthanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the présent invention (e.g. trifluoroacetate salts), also comprise a part of the invention.

The compounds according to the invention are advantageously also obtainable using the methods described in the examples that follow, which may also be combined for this purpose with methods known to the skilled man from the literature.

In some embodiments, the présent teachings also provide methods for producing crystalline forms of a compound represented by the following structural formula (II):

Ni

In some embodiments, the présent teachings provide methods for producing crystalline form I of a compound represented by structural formula (II). In some embodiments, the présent teachings provide methods for producing crystalline form II of a compound represented by structural formula (II).

In some embodiments, the method for producing crystalline form I of a compound represented by structural formula (II) includes dissolving a free base represented by the following structural formula (III):

n:

(III)

in éthanol at a température below about 30°C; protonating the dissolved free base with hydrochloric acid (e.g., in an aqueous solution, such as a 30-40 wt % aqueous solution, e.g., a 36.5 wt % aqueous solution); and allowing crystalline form I to form by cooling the protonated dissolved free base (e.g., at a température below about 30°C).

For example, in some embodiments, the method includes dissolving the free base in éthanol at 20-30°C, protonating the dissolved free base with hydrochloric acid (e.g., in an aqueous solution, such as a 30-40 wt % aqueous solution, e.g., a 36.5 wt % aqueous solution), and allowing crystalline form l to form at a température at -5° to 5°C (or dissolving at about room température and crystallizing at about 0°C). In some embodiments, the method includes dissolving the free base in éthanol at about room température, protonating the dissolved free base with hydrochloric acid (e.g., in an aqueous solution, such as a 30-40 wt % aqueous solution, e.g., a 36.5 wt % aqueous solution), and allowing crystalline form I to form at room température over a period of at least six hours, e.g., at least eight hours, e.g., at least ten hours. In still other embodiments, the method includes dissolving the free base in éthanol at a température above about 30°C, protonating the dissolved free base with hydrochloric acid (e.g., in an aqueous solution, such as a 30-40 wt % aqueous solution, e.g., a 36.5 wt % aqueous solution) at a température below about 30°C, and allowing crystalline form I to form at a température below about 30°C.

In some embodiments, the method for producing crystalline form II of a compound represented by structural formula (II) includes contacting a compound represented by structural formula (II) (e.g., crystalline form I of a compound represented by structural formula (II)) with éthanol (e.g., 200 proof absolute éthanol) to form a suspension, and stirring the suspension for a period of time sufficient to form crystalline form II. In some embodiments, a period of time suffîcient to form crystalline form II is at least about three days, at least about four days, at least about five days, at least about six days, or at least about one week.

In some embodiments, the method for producing crystalline form II of a compound represented by structural formula (II) includes dissolving a compound represented by structural formula (II) in ethyl acetate at a température above about 40^eC (e.g., at least about 50°C or from 40°-60°C); and allowing crystalline form II to form by cooling the dissolved compound (e.g., at a température below about 30°C or at or below about room température).

In some embodiments, the method for producing crystalline form II of a compound represented by structural formula (II) includes dissolving a free base represented by structural formula (III) in isopropanol at a température above about 40°C (e.g., above about 50°C, above about 60°C, or even at or above about 75°C); protonating the dissolved free base with hydrochloric acid (e.g., in isopropanol); and allowing crystalline form II to form by cooling the dissolved protonated free base (e.g., at a température below about 15°C, below about 10°C or below about 5°C). Alternatively, the free base is dissolved at a température between 50°-70°C and form II is formed atO°-15°C.

In some embodiments, the method for producing crystalline form II of a compound represented by structural formula (II) includes dissolving a free base represented by structural formula (III) in éthanol (e.g., 200 proof absolute éthanol) at a température of above about 40°C (e.g., at or above about 50°C); protonating the dissolved free base with hydrochloric acid (e.g., in éthanol, such as 200 proof absolute éthanol); maintaining the dissolved protonated free base at the elevated température for at least two hours and allowing crystalline form II to form by cooling the dissolved protonated free base (e.g., at a température below about 15°C, below about 10°C, below about 5°C, or even at or below about 0°C). Alternatively, the free base is dissolved at 45°-70^<>C, the dissolved protonated free base is maintained at 45°-70°C for 2-3 hours and form Il is formed at between 0°-25°C orfrom 0°-15°C.

In some embodiments, the methods for producing crystalline forms of a compound represented by structural formula (II) further include the use of one or more seed crystals (e.g., seed crystals of crystalline form I or crystalline form II.

As already mentioned, the compounds of general formula I and the compounds of formula (II) according to the invention and the physiologîcally acceptable salts thereof hâve valuable pharmacological properties, particularly an inhibitory effect on the enzyme 11ft-hydroxysteroid dehydrogenase (HSD) 1.

Biological Examples

a) The biological properties (inhibitory activity on 11B-hydroxysteroid dehydrogenase 1 ) of the new compounds may be investigated as follows:

In vitro inhibition of 11 β-HSDI by test compounds is determined with HTRF (Homogeneous Time-Resolved Fluorescence) technology (cisbio international, France) detecting cortisol generated from cortisterone by human lîver microsomes. Briefly, compounds are incubated for 1 hour at 37°C in Tris buffer (20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH (200μΜ) and cortisone (80nM). Cortisol generated in the reaction is then detected with a compétitive immunoassay, involving two HTRF conjugales: cortisol linked to XL665 and anti-cortisol

) 65 antibody labeled with Europium cryptate. The incubation period for détection reaction is typically 2 hours. The amount of cortisol is 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 émission signais is then calculated (Em665*10000/Em615). Each assay contains incubations with vehicle controls instead of compound as controls for non-inhibited cortisol génération (100% CTL; ’high values') and incubations with carbenoxolone as controls for fully inhibited enzyme and cortisol background (0% CTL; ’low values'). Each assay also contains a calibration curve with cortisol to transform the fluorescent data into cortisol concentrations. Percent inhibition (%CTL) of each compound is determined relative to the carbenoxolone signal and IC₅₀ curves are generated.

The compounds of general formula I according to the invention tested as described above for example hâve IC₅₀ values below 10000 nM, particularly below 1000 nM, most preferably below 500 nM.

Table 2. Inhibitory activity on Ιΐβ-HSD 1 of Examples compiled in the experimental part

Example	IC₅₀ [nM]	Example	IC₅₀ [nM]	Example	IC₅₀ [nM]	Example	IC₅₀ [nM]
1	106	32	954	63	1337	94	90
2	65	33	676	64	2871	95	1033
3	1380	34	651	65	212	96	1107
4	573	35	3137	66	631	97	526
5	861	36	310	67	722	98	1252
6	296	37	150	68	435	99	3523
7	410	38	1474	69	371	100	850
8	342	39	1515	70	350	101	712
9	481	40	2148	71	915	102	3119
10	321	41	1121	72	656	103	670
11	94	42	418	73	447	104	847
12	367	43	1629	74	1960	105	263
13	257	44	2151	75	324	106	31
14	405	45	1066	76	933	107	26
15	1617	46	3618	77	685	108	150
16	1412	47	2157	78	257	109	1458
17	2107	48	514	79	650	110	1561
18	1027	49	1469	80	1971	111	1376
19	1902	50	4266	81	1730	112	724
20	227	51	2867	82	1338	113	2658

Example	IC50 [nM]	Example	IC₅₀ [nM]	Example	IC₅₀ [nM]	Example	IC₅₀ [nM]
21	1132	52	1595	83	2058	114	185
22	123	53	979	84	2067	115	2077
23	551	54	471	85	1625	116	1795
24	1794	55	4680	86	2110	117	1654
25	475	56	356	87	8854	118	1067
26	1512	57	969	88	705	119	365
27	297	58	1112	89	1319	120	383
28	2504	59	2095	90	2255	121	4439
29	831	60	1051	91	244	122	230
30	2210	61	821	92	884	123	644
31	469	62	940	93	121	124	1322
125	484	137	1119	149	141	161	212
126	1758	138	1054	150	674	162	354
127	1129	139	484	151	188	163	67
128	1917	140	1622	152	24	164	1315
129	1490	141	326	153	48	165	449
130	1137	142	996	154	449	166	182
131	6428	143	1409	155	83	167	573
132	320	144	609	156	432	168	313
133	854	145	777	157	1155	169	429
134	389	146	55	158	998	170	248
135	585	147	1738	159	1786	171	218
136	527	148	214	160	367	174	67

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

The inhibition of a microsomal préparation of 1Ιβ-HSDI by compounds of the invention is measured essentially as previously described (K. Solly, S.S. Mundt, H.J. Zokian, G.J. Ding, A. Hermanowski-Vosatka, B. Strulovici, and W. Zheng, High-Throughput Screening of 11-BetaHydroxyseroid Dehydrogenase Type 1 in Scintillation Proximity Assay Format. Assay Drug Dev Technol 3 (2005) 377-384). Ail reactions are carried out at room température in 96 well clear flexible PET Microbeta plates (PerkinElmer). The assay begins by dispensing 49 pl of substrate solution (50 mM HEPES, pH 7.4,100 mM KCi, 5 mM NaCI, 2 mM MgCI₂, 2 mM NADPH and

160 nIVI [³H]cortîsone (1 Ci/mmol)) and mixing in 1 pL of the test compounds in DMSO zX

previously diluted in half-log incréments (8 points) starting at 0.1 mM. After a 10 minute preincubation, 50 pL of enzyme solution containing microsomes isolated from CHO cells overexpressing human 11B-HSD1 (10-20 pg/ml of total protein) is added, and the plates are incubated for 90 minutes at room température. The reaction is stopped by adding 50 pl of the

SPA beads suspension containing 10 μΜ 18B-glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GE Healthcare) and 3.3 pg/ml of anti-cortisol antibody (East Coast Biologics) in Superblock buffer (Bio-Rad), The plates are shaken for 120 minutes at room température, and the SPA signal corresponding to [³H]cortisol is measured on a Microbeta plate reader.

Table 3. Inhibitory activity on 11B-HSD 1 of Examples compiled in the experimental part

Example	IC₅₀ [nM]	Example	IC₅₀ [nM]	Example	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 new compounds may be investigated as follows:

The metabolic dégradation of the test compound is assayed at 37 °C with pooled liver microsomes from various species. The final incubation volume of 100 pl per time point contains TRIS buffer pH 7.6 at room température (0.1 M), magnésium chloride (5 mM), microsomal protein (0.5 mg/mL) and the test compound at a final concentration of 1 μΜ. Following a short preîncubation period at 37°C, the reactions are initiated by addition of betanicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM), and terminated by transferring an aliquot into solvent after different time points. After centrifugation (10000 g, 5 min), an aliquot of the supernatant is assayed by LC-MS/MS for the amount of parent compound. The half-life is determined by the slope of the semi-logarithmic plot of the concentration-time profile.

Table 4. Stability in human liver microsomes of Examples compiled in the experimental part

Example	tu [min]	Example	t» [min]	Example	t» [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 theirability to inhibit the enzyme 11 β-hydroxysteroid dehydrogenase (HSD) 1, the compounds of general formula I according to the invention and the corresponding pharmaceutically acceptable salts thereof, as well as the compounds of formula (II) are theoretically suitable for the treatment and/or preventative treatment of ail those conditions or diseases which may be affected by the inhibition of the 11 β-hydroxysteroid dehydrogenase (HSD) 1 activity. Therefore, compounds according to the invention are particularly suitable for the prévention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabètes mellitus, complications of diabètes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies, slow or poor wound healing), metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin résistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema and hyperuricaemia. These substances may also be suitable for preventing beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta-cells. The substances may also be suitable for improving or restoring the functionality of pancreatic cells, and also of increasing the number and size of pancreatic beta-cells. The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prévention and treatment of acute rénal failure.

Additionally, inhibition of 11 β-hydroxysteroid dehydrogenase (HSD) 1 has been shown to lower intraocular pressure in subjects with ocular hypertension, therefore the compounds could be used to treat glaucoma.

In view of the rôle of 11 β-hydroxysteroid dehydrogenase (HSD) 1 in modulating cortisol levels for interaction with the glucocorticoid receptor and the known rôle of excess glucocorticoids in bone loss, the compounds may hâve bénéficiai effects agaînst osteoporosis.

Stress and/or glucocorticoids hâve been shown to influence cognitive function, and excess cortisol has been associated with brain neuronal loss or dysfunction. Treatment with an 11 βhydroxysteroid dehydrogenase (HSD) 1 inhibitor may resuit in amelioration or prévention of cognitive impairment. Such compounds may also be useful in treating anxiety or dépréssion.

The dynamic interaction between the immune System and the HPA (hypothalamopituitaryadrenal) axis is known, and glucocorticoids help balance between cell-mediated responses and humoral responses. The immune reaction is typîcally biased towards a humoral response in certain disease states, such as tuberculosis, leprosy, and psoriasis. More appropriate would be a cell-based response. An 11 β-hydroxysteroid dehydrogenase (HSD) 1 inhibitor would bolster a

temporal immune response in association with immunization to ensure that a cell based response would be obtaîned, and as such could be useful in immunomodulation.

In particular, the compounds according to the invention, including the physiologically acceptable salts thereof, are suitable for the prévention or treatment of diabètes, particularly type 1 and type 2 diabètes mellitus, and/or diabetic complications.

In a further aspect of the présent invention the présent invention relates to methods for the treatment or prévention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula I to a human being. In a further embodiment, the présent teachings relate to methods for the treatment or prévention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of formula (II) to a human being.

The dosage required to achieve the corresponding activity for treatment or prévention usually dépends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to décidé. Expediently, the dosage may be from 1 to 100 mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day.

The actual pharmaceutically effective amount or therapeutic dosage will of course dépend on factors known by those skilled in the art such as âge and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.

Suitable préparations for administering the compounds of formula I will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, élixirs, sachets, injectables, inhalatives, powders, etc.. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 95 wt.%, preferably 5.0 to 90 wt.-% of the composition as a whole.

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

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

The compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prévention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include, for example, those which potentiate the therapeutic effect of an 11 β-hydroxysteroid dehydrogenase (HSD) 1 antagonist according to the invention with respect to one of the indications mentioned and/or which allow the dosage of an 11 β-hydroxysteroid dehydrogenase (HSD) 1 antagonist according to the invention to be reduced. Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedîones (e.g. rosiglitazone, pioglitazone), SGLT 2 inhibitors (e.g. dapagliflozin, remogliflozin etabonate, sergliflozin, canagliflozin, 1-chloro-4-^-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]-benzene), PPAR-gamma-agonists (e.g. Gl 262570) and antagonists, PPARgamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors (e.g. Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendrn-

4) or amylin. The list also includes inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase and glucokinase activators, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the dérivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholestérol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, SDRIs, axokine, leptin, leptin mimetics, antagonists of the cannabinoidl receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or B3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-ll antagonists or ACE inhibitors, ECE inhibitors, diuretics, Bblockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-25 adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable, Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, taso-sartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc.. Angiotensin II receptor antagonists are preferably used for the treatment or prévention of high blood pressure and complications of diabètes, often combined with a diuretic such as hydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prévention of goût.

A combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein-kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prévention of complications of diabètes.

The dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.

Therefore, in another aspect, this invention relates to the use of a compound according to the invention or a physiologically acceptable sait of such a compound combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prévention of diseases or conditions which can be affected by inhibiting the enzyme 11 B-hydroxysteroid dehydrogenase (HSD) 1. These are preferably metabolic diseases, particularly one of the diseases or conditions listed above, most particularly diabètes or diabetic complications.

The use of the compound according to the invention, or a physiologically acceptable sait thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; while if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physiologically acceptable sait of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.

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

The compound according to the invention, or a physiologically acceptable sait thereof, and the additional active substance to be combined therewith may both be présent together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.

The Examples that follow are intended to illustrate the présent invention without restricting it:

Analytical HPLC and TLC parameters employed for characterization of products:

method 1	Merck Cromolith Speed ROD,	method 2	Waters Xbridge C18,
column	RP18e, 50x4.6 mm		column	30*4.6 mm,	2.5 pm
mobile	A: water + 0.1% HCO₂H	mobile	A: water + 0.1% NH₃
phase	B: acetonitrile + 0.1% HCO₂H	phase	B: methanol
	TIME (min)	A%	B%		TIME (min)	A%	B%
	0.00	90	10		0	90	10
	4.50	10	90		0.15	90	10
	5.00	10	90		4.00	0	100
	5.50	90	10		4.40	0	100
					4.55	90	10
					5.00	90	10
flow rate	1.5 mL/min	flow rate	1.6 mL/min
wavelength	UV 220, 230, or 254 nm	wavelength	UV 220, 230, or 254 nm

method 3 column

Sunfrre C18, 50*4.6 mm, 3.5 pm, 40°C

method 4 column

Sunfire C18, 50*4.6 mm, 3.5 pm, 40°C

mobile phase	A: water + 0.1% F₃CCO₂H B: methanol	mobile phase	A: water + 0.1% F₃CCO₂H B: methanol
TIME (min)	A%	B%	TIME (min)	A%	B%
0.00	95	5	0.00	95	5
1.30	0	100	1.30	0	100
3.00	0	100	2.50	0	100
4.00	95	5	2.60	95	5
flow rate	1.5 mL/min	flow rate	1.5 mL/min
wavelength	UV 210-500 nm	wavelength	UV 210-500 nm

method 5 column	Waters Xbridge C18, 50*2.1 mm, 1.7 pm, 60 °C	TLC were conducted on Polygram® S IL G/UV₂₅₄plates coated with 0.2 mm silica gel
mobile phase	A: water + 0.032% NH₄OH; B: acetonitrile
TIME (min)	A%	B%
0	95	5
2.00	0	100
2.50	0	100
2.60	95	5
flow rate	1.3 mL/min
wavelength	UV 210-500 nm

method 6 column	StableBond SB-C18 30*4.6 mm, 1.8 pm	method 7 column	YMC-PACK ODS-AQ 50*2.0 mm, 5pm, 50 °C
mobile phase	A: water + 0.1% F₃CCO₂H B: methanol	mobile phase	A: water + 0.0375% F₃CCO₂H B: acetonitrile + 0.0187% F3CCO2H
TIME (min)	A%	B%
0,00	90	10
1.80	0	100	TIME (min)	A%	B%
2.00	0	100	0	90	10
2.15	90	10	2.2	20	80
2.35	90	10	2.5	20	80
flow rate	1.75 mL/min	flow rate	1.0 mL/min
wavelength	UV 220, 230, or 254 nm wavelength	UV 220 nm

In the following, whenever a benzoimidazole bearing a hydrogen on one of its two nitrogens is part of a molécule both tauomeric structures, 1H-benzoimidazole and 3H-benzoimidazole, are meant, though, only one is explicitly named or drawn.

Intermediates 1 and 2:

c/s-1.2.3,4,4a,5,6,10b-Octahydro-benzofflquinoline and trans-1,2,3,4,4a,5,6,10b-Octahydrobenzofflquinoline

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

Propargylamîne (5 mL) is added to a flask charged with a stir bar, 2-tetralone (10.00 g), NaAuCI₄*2H₂O (0.65 g), and éthanol (50 mL) (caution: a very exothermic reaction may evolve afterwards -> keep an ice bath at hand). The resulting mixture is stirred at room température for 15 min and then at reflux température for 1 h. Aftercooling the mixture to room température, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 60:40) to afford the title compound as an oil. Yield: 6.78 g (56% of theory); LC (method 1): = 1.81 min; Mass spectrum (ESI*): m/z = 182 [M+Hf.

Alternative^, the reaction may be conducted in a microwave oven heating with microwave irradiation to 100 °C for 10 min.

Step 2: cis- and trans-1.2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline

A mixture of 5,6-dihydro-benzo[f]quinoline (8.78 g), PtO₂ (1.00 g), and acetic acid is shaken under hydrogen atmosphère (10 bar) at room température for 24 h (in case the transformation is not complété after this time, another portion of PtO₂ (0.20 g) is added and shaking under hydrogen is continued until completion). The catalyst is separated by filtration and the solvent is evaporated. The residue is taken up in 2 M aqueous NaOH solution and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (MgSOJ and concentrated. The residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH₃95:5->80:20) to afford the two title compounds separated. c/s-1,2,3,4,4a,5,6,10b-Octahydro-benzo[f]quinoline: Yield: 6.30 g (69% of theory); LC (method 1): t_R = 1.85 min; Mass spectrum (ESf): m/z = 188 [M+Hf; Ή NMR (400 MHz. DMSO-d_c) d

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 (broad s, 1H and water), 7.007.11 (m, 3H), 7.15-7.19 (m, 1H).

Alternatively, c/s-1,2,3,4,43,5,6,10b-octahydro-benzo[f]quinoline may be obtained in a departure of the synthesis described in J. Heterocyclic Chem. 1996, 33, 983-5 by conducting the enamide réduction with H₂ (3 bar) and 10% palladium on carbon in methanol containing 5% acetic acid. trans-1,2,3,4,48,5,6,1 Ob-Octahydro-benzo[f]quinoline: Yield: 0.41 g (5% of theory); Mass spectrum (ESC): m/z = 188 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) d 1.20-1.33 (m, 1H), 1.671.89 (m, 3H), 1.98-2.07 (m, 1H), ca. 2.47-2.55 (2H, m) superimposed on DMSO-d₅ signal, 2.592.68 (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), 7.257.31 (m, 1H).

Alternatively, trans-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline may be obtained as described in J. Heterocyclic Chem. 1996, 33, 983-5.

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

Step 3: 3-bromo-2-phenethyl-pyridine

Tetrakis(triphenylphosphine)palladium(0) (2.0 g) is added to a flask charged with a stir bar, phenethylzinc bromide (0.5 mol/L in tetrahydrofuran, 100 mL), 2,3-dibromopyridine (10.50 g), and tetrahydrofuran (100 ml) and kept under argon atmosphère at room température. The resulting mixture is stirred at room température for 3 h and at 40 °C for another 16 h. After cooling the mixture to room température, the solvent is evaporated and the residue is chromatographed on siiica gel (cyclohexane/ethyl acetate 90:10—>75:25) to afford the tïtle compound as an oil that solidified upon treatment with ether. Yield: 9.32 g (81% of theory); LC (method 1): t_R = 4.28 min; Mass spectrum (EST): m/z = 262/264 (Br) [M+Hf.

Step 4: 5,6-dïhydro-benzo[f]quinoline

N,N-Dimethylacetamide (15 mL) is added to a flask charged with a stir bar, 3-bromo-2phenethyl-pyridine (3.34 g), freshly dried K₂CO₃ (3.52 g), palladium(ll) acetate (0.14 g), and tricyclohexylphosphonium tetrafluoroborate (0.47 g) and kept under argon atmosphère at room température. The flask is put into a 150 °C hot oil bath and the mixture is stirred therein for 2 h. After cooling the mixture to room température, the solvent is evaporated and the residue is chromatographed twice on siiica gel (1. dichloromethane/methanol 98:2; 2. cyclohexane/ethyl acetate 90:10—>50:50) to afford the title compound as an oil. Yield: 1.51 g (65% of theory); LC (method 1): t_R ~ 1.83 min; Mass spectrum (ESl·): m/z = 182 [Μ+ΗΓ.

Intermediates 3 and 4 c/s-7-Methoxv-1,2,3,4,48.5,6,1 Ob-octahydro-benzofflquinoline and frans-7-Methoxy1,2,3,4,4a,5,6,10b-octahydro-benzoff]quinoline

The title compounds are obtained following a route analogous to that described in Step 1 and Step 2 for Intermediates 1 and 2 employing 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 spectrum (EST): m/z = 212 [M+Hf.

Step 2: c/s-7-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline; Yield: 54% of theory; LC (method 1 ): t_R = 2.02 min; Mass spectrum (EST): m/z = 218 [M+H]⁺.

trans-7-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline; Yield: 20% of theory; Mass spectrum (EST): m/z = 218 [M+Hf.

Intermediates 5 and 6 c/s-IO-Methoxy-I^.S^^a.S.e.lOb-octahvdro-benzofflquinoline and trans-10-Methoxv1,2,3,4,4a,5.6,10b-octahydro-benzoiflquinoline

The title compounds are obtained following a route analogous to that described in Step 1 and Step 2 for Intermediates 1 and 2 employing 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_R = 2.02 min; Mass spectrum (ESI⁺): m/z = 212 [M+Hf.

Step 2: c/s-IO-methoxy-I^.SAâa.S.e.lOb-octahydro-benzofflquinoline; Yield: 50% of theory; Mass spectrum (EST): m/z = 218 [M+Hf.

frans-10-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline; Yield: 11% of theory; Mass spectrum (ESf): m/z = 218 [Μ+ΗΓ.

Intermediates 7 and 8 c/s-10b-Methvl-1.2,3.4,48.5,6,10b-octahydro-benzoffîquinoline and trans-1 Ob-Methyl1,2,3,4,4a,5,6,1Ob-octahvdro-benzofflquinoline

NH

The title compounds are obtained following a route analogous to that described in Step 1 and Step 2 for Intermediates 1 and 2.

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

Propargylamine (0.21 mL) is added to a microwave oven suited vessel charged with a stir bar, 1-methyl-2-tetralone (0.50 mL), NaAuCI₄*2H₂O (27 mg), and éthanol (3 mL) (caution: a very exothermic reaction may evolve afterwards -> keep an ice bath at hand). The resulting mixture is stirred under microwave irradiation at 100 ’C for 10 min. After cooling the mixture to room température, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 25:75->0:100) to afford the title compound as an oil. Yield: 0.29 g (50% of theory); LC (method 1): t_R = 1.78 min; Mass spectrum (EST): m/z = 198 [M+H]⁺.

Step 2: c/s-10b-methyl-1,2,3,4,48,5,6,10b-octahydro-benzo[f]quinoline and frans-10b-methyl1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline

A mixture of 10b-methyl-3,5,6,10b-tetrahydro-benzo[f]quinoline (8.78 g), 10% Pd on carbon (1.00 g), acetic acid (0.3 mL), and methanol (10 mL) is shaken under hydrogen atmosphère (3 bar) at room température for 14 h. The catalyst is separated by filtration and the solvent is evaporated. The residue is taken up in half-concentrated aqueous Na₂CO₃ solution and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (MgSO₄) and then concentrated to afford the two title compounds in a ca. 3:1 mixture (cis/trans). Yield: 0.24 g (86% of theory); LC (method 1): t_R = 1.92 min (trans-IOb-methyl-I^.S^^a.S.ô.lOb-octahydrobenzo[f]quinoline) and t_R = 2.02 min (c/s-10b-methyl-1,2,3,4,4a,5,6,1 Ob-octahydrobenzo[f]quinoline); Mass spectrum (EST): m/z = 202 [M+Hf.

Intermediates 9 and 10 c/s-9-Methoxy-1,2,3,4,4a,5.6,10b-octahydro-benzo[f|quinoline and trans-9-Methoxy1,2,3,4,4a,5,6,10b-octahvdro-benzofflquinoline

O.

NH

The title compounds are obtained following a route analogous to that described in Step 1 and Step 2 for Intermediates 1 and 2 employing 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_R = 1.99 min; Mass spectrum (ESl*): m/z = 212 [M+Hf.

Step 2: c/s-G-methoxy-V.a.Ma.S.ejOb-octahydro-benzolfjqiiinoline; Yield: 19% of theory; Mass spectrum (EST): m/z = 218 [M+Hf.

irans-9-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline; Yield: 22% of theory; Mass spectrum (ESl*): m/z = 218 [M+Hf.

Intermediates 11 and 12 c/s-7,9-Difluoro-1,2.3.4,4a,5,6,10b-octahvdro-benzo[f1quinoline and /rans-7,9-Difluoro1,2,3,4,4a,5,6.10b-octahydro-benzofflquinoline

The title compounds are obtained foliowing a route analogous to that described in Step 1 and Step 2 for Intermediates 1 and 2 employing 5,7-difluoro-2-tetralone and propargylamine in Step 1 and /.G-difluoro-S.G-dihydro-benzotfIquinoline in Step 2.

Step 1: 7,9-difluoro-5,6-dihydro-benzo[f]quinoline; Yield: 53% of theory; LC (method 1): t_R = 2.54 min; Mass spectrum (ESl*): m/z = 224 [M+Hf.

Step 2: c/s-7,9-difluoro-1,2,3,4,4a,5_l6_l10b-octahydro-benzo[f]quinoline; Yield: 38% of theory; TLC: r₍ = 0.37 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESl*): m/z = 218 [M+Hf.

/rans-7,9-difluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f|qutnoline; Yield: 26% of theory; TLC: r₍ = 0.37 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESl*): m/z - 224 [M+Hf.

Intermediates 13 and 14 c/s-8-Methoxy-1,2,3,4,4a,5,6,10b-octahvdro-benzo[flquinoline and frans-8-Methoxy1,2,3,4,4a, 5,6,10b-octahydro-benzo[flquinoline

The title compounds are obtained foliowing a route analogous to that described in Step 1 and Step 2 for Intermediates 1 and 2 employing 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_R = 1,95 min; Mass spectrum (ESl*): m/z = 212 [M+Hf.

Step2: c/s-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline; Yield: 52% of theory; TLC: r_f = 0.22 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (EST): m/z = 218 [M+Hf.

trans-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quÎnoline; Yield: 21% of theory; TLC: rf = 0.28 (silica gel, CH₂Cl2/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESI*): m/z = 218 [M+Hf.

Intermediates 15 and 16 cfs-10-Fluoro-1,2.3.4.4a,5,6.10b-octahvdro-benzoff1quinoline and trans-10-Fluoro1,2,3,4,4a, 5,6,10b-octahydro-benzo[f|quinoline

NH

The title compounds are obtained foilowing a route analogous to that described in Step 1 and Step 2 for Intermediates 1 and 2 employing 8-fluoro-2-tetralone and propargylamine in Step 1 and 10-fluoro-5,6-dihydro-benzo[f]quinolîne în Step 2.

Step 1: 10-fluoro-5,6'dihydro-benzo[f]quinoline; Yield: 55% of theory; Mass spectrum (ESI*): m/z = 200 [M+H]⁺.

Step 2: c/s-10-fluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline; Yield: 63% of theory; TLC: r_f = 0.38 (silica gel, CH₂Cl_z/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESI*): m/z= 206 [M+HJ*.

irans-10-fluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline; Yield: 13% of theory; TLC: r_t = 0.46 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESI*): m/z = 206 [M+Hf.

Intermediates 17 and 18 cfs-8-Phenvl-1,2,3,4,4a,5.6,10b-octahvdro-benzo[f|quinoline and frans-8-Phenyl1,2.3.4,4a,5,6,10b-octahydro-benzo[flquinoline

Br ° Step 1

Br

NH

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

The title compound is prepared from 6-bromo-2-tetralone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 69% of theory; Mass spectrum (ESI*): m/z = 260/262 (Br) [M+Hf.

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

A flask charged with a stir bar, 8-bromo-5,6-dihydro-benzo[f]quinoline (0.28 g), phenylboronic acid (0.24 g), 2 M aqueous Na₂CO₃ solution (1.1 mL), and N,N-dimethylformamide (3 ml) is sparged with argon at room température for 10 min. [1,r-Bis(diphenylphosphino)ferrocenejdichloropalladium dichloromethane complex (30 mg) is then added and the resulting mixture is heated to 90 °C and stirred at this température for 4 h. After cooling the mixture to room température, ethyl acetate and water are added and the mixture is filtered over Celite. The organic phase of the filtrate is separated and washed with brine and dried (Na₂SO₄). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1) to afford the title compound as a solid. Yield: 0.24 g (ca. 80% pure); LC (method 1): t_R = 3.16 min; Mass spectrum (EST): m/z = 258 [M+Hf.

Step3: c/s-8-phenyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline and trans-8-phenyl1,2,3,4,4a,5,6,10b'Octahydro-benzo[f]quinoline

The title compounds are prepared from 8-phenyl-5,6-dihydro-benzo[f]quinoline following a procedure analogous to that described in Step 2 of Intermediates 1 and 2. c/S“8Phenyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline: Yield: 56% of theory; Mass spectrum (ESI⁺): m/z = 206 [M+Hf.

trans-B-Phenyl-I^.S^^a.S.e.lOb-octahydro-benzotfJquinoline: Yield: 11% of theory; Mass spectrum (ESl⁺): m/z = 206 [M+Hf.

Intermediates 19 and 20 c/s-1,2,3,4,4a,5,6,10b-Octahydro-benzo[flquinoline-8-carboxylic acid methyl ester and trans-

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

A flask charged with 8-bromo-5,6-dihydro-benzo[f]quinoline (4.00 g), triethylamine (3.0 mL), [1,r-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.63 g), N,N-dimethylformamide (5 mL), and methanol (20 ml) is flushed with argon for 5 min and with carbon monoxide for another 5 min. The mixture is then heated to 80 °C under carbon monoxide atmosphère (4 bar) and shaken at this température ovemight. After cooling to room température, the mixture is filtered and concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and brine and dried (NaïSCTi). The solvent is

evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyi acetate

1:1 —*0:1 ) to afford the title compound as a solid. Yield: 3.16 g (86% of theory): LC (method 1): t_R= 2.18 min; Mass spectrum (EST): m/z = 240 [M+H]⁺.

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

The title compounds are prepared from 5,6-dihydro-benzo[f]quinoline-8-carboxylic acid methyl ester following a procedure analogous to that described in Step 2 of Intermediates 1 and 2. c/s-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester: Yield: 79% of theory; LC (method 1 ): t_R = 1.93 min; Mass spectrum (ESI⁺): m/z = 246 [M+Hf.

trans-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester: Yield: 10% of theory; Mass spectrum (EST): m/z = 246 [M+H]⁺.

Intermediates 21 and 22 c/s-8-BenzyM ,2,3.4.4a.5,6,10b-octahydro-benzo[f]quinoline and c/s-8-Cvclohexvlmethyl1,2,3,4,4a,5,6.1 Ob-octahvdro-benzofflquÎnoline

Step 1: 8-Benzyl-5,6-dihydro-benzo[f]quinoline

Benzylzinc bromide (0.5 mol/L in tetrahydrofuran, 7.7 mL) is added to a flask charged with a stir bar, tetrakis(triphenylphosphine)palladium(0) (53 mg), and 8-bromo-5,6-dihydrobenzo[f|quinoline (0.20 g) and kept under argon atmosphère at room température. The resulting solution is heated to reflux température and stirred at this température for 6 h. After cooling the solution to room température, aqueous NH₄CI solution is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine and dried (Na₂SO₄). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyi acetate 4.Ί—>1:1) to afford the title compound as an oil. Yield: 0.17 g (81% of theory); LC (method 1): t_R = 3.08 min; Mass spectrum (EST): m/z = 272 [M+H]T

Step 2: c/s-e-benzyl-I^.S^Aa.SAIOb-octahydro-benzoffJquinoline and c/s-8-cyclohexylmethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline

The title compounds are prepared from 8-benzyl-5,6-dihydro-benzo[f]quinoline following a procedure analogous to that described in Step 2 of Intermediates 1 and 2 and obtained in a ca. 30:70 mixture that is used as such in the next reaction step. Yield: 81% of theory (ca. 30:70 mixture).

G/s-8-Benzyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline: LC-MS (method 1): t_R = 2.91 min; Mass spectrum (EST): m/z = 278 [M+Hf.

c/s-e-Cyclohexyl-methyl-I^.S^^a.S.e.lOb-octahydro-benzotflquinoline: LC-MS (method 1): t_R = 3.41 min; Mass spectrum (ESf): m/z = 284 [M+Hf.

Intermediate 23 c/s-4-( 1 H-Benzoimidazole-5-carbonyl)-1.2,3.4,4a,5.6.10b-octahvdro-benzo[f|quino1ine-10carboxylic acid methyl ester

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

The title compound is prepared from 8-bromo-2-tetralone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 49% of theory ; LC (method 1): t_R = 2.68 min; Mass spectrum (ESf): m/z = 260/262 (Br) [M+Hf.

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

The title compound is prepared from 10-bromo-5,6-dihydro-benzo[f]quinoline following a procedure analogous to that described in Step 1 of Intermediates 19 and 20. Yield: 84% of theory ; LC (method 1): t_R = 1.95 min; Mass spectrum (EST): m/z = 240 [M+Hf.

Step 3: 0/5-1,2,3,4,48,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid methyl ester The title compound is prepared from 5,6-dihydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Step 2 of Intermediates 1 and 2. Yield: 52% of theory ; LC (method 1 ): t_R = 2.07 min; Mass spectrum (ESI⁺): m/z = 246 [M+Hf. Step 4: c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline10-carboxylic acid methyl ester

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cisI^.SA^a.S.e.lOb-octahydro-benzoIfJquinoline-IO-carboxylic acid methyl ester following a procedure analogous to that described in Example 1. Yield: 43% of theory; TLC: r_f = 0.30 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESl·): m/z = 390 [M+Hf.

Intermediate 24 cis-10-(4-Methoxv-benzvl)-1_l2,3,4,4a,5,6,10b-octahydro-benzo[f|quinoline

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

The title compound is prepared from 4-methoxybenzylzinc chloride and 10-bromo-5,6-dihydrobenzo[f]quînoline following a procedure analogous to that described in Step 1 of Intermediates 21 and 22. Yield: 85% of theory; LC (method 1): t_R = 3.09 min; Mass spectrum (ESI⁺): m/z = 302 [M+Hf.

Step 2: c/s-10-(4-methoxy-benzyl)-1,2,3,4,43,5,6,1Ob-octahydro-benzo[f]quinoline

The title compound is prepared from 10-(4-methoxy-benzyl)-5,6-dihydro-benzo[f]quinoline following a procedure analogous to that described in Step 2 of Intermediates 1 and 2. Yield: 12% of theory; LC-MS (method 1 ): t_R = 2.82 min; Mass spectrum (ESl⁺): m/z = 308 [M+Hf.

Intermediate 25 c/s-6.6-Dimethvl-1.2.3.4,4a,5.6,10b-octahvdro-benzo[f]quinoline

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

The title compound is prepared from 4,4-dimethyl-3,4-dihydro-1H-naphthalen-2-one and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 49% of theory; LC (method 1): t_R = 2.40 min; Mass spectrum (ESI*): m/z = 210 [M+Hf.

Step 2: c/s-6,6-Dimethyl-1 ,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline

The title compounds is prepared from 6,6-dimethyl-5,6-dihydro-benzo[f]quinoline following a procedure analogous to that described in Step 2 of Intermediates 1 and 2. Yield: 72% of theory; LC-MS (method 1): t_R = 2.38 min; Mass spectrum (EST): m/z = 216 [M+Hf.

intermediate 26 c/s-4-( 1 H-Benzoimidazole-5-carbonyl)-1.2,3,4,48,5,6,10b-octahydro-benzo[f|quinoline-10carboxylic acid

The title compound is prepared from c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5, 6,10boctahydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Example 35 except for stirring the solution at 50 °C. Yield: 69% of theory; Mass spectrum (ESl·): m/z = 376 [M+Hf.

Intermediate 27 c/s-S-Î^Methoxv-phenoxvl-I^.S^^a.S.e.lOb-octahydro-benzoiflquinoline

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

Trifluoroacetic anhydride (0.75 mL) is added to a solution of c/$-8-methoxy-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline (0.79 g) and triethylamine (0.90 mL) in dichloromethane (10 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room température overnight. Water and dichloromethane are then added and stirring is continued for another 30 min. The organic phase is separated and washed with aqueous NaHCOa solution and dried (Na₂SO.;). The solvent is evaporated to afford the title compound as a solid. Yield: 100% of theory; LC (method 1): t_R = 4.38 min; Mass spectrum (EST): m/z = 3.14 [M+H]⁺. Step 2: c/s-2,2,2-trifluoro-1 -(8-hydroxy-2,3,4a,5,6,10b-hexahydro-1 H-benzo[f]quiπolin-4-yI)ethanone

The title compound is prepared from c/s-2,2,2-trifluoro-1-(8-methoxy-2,3,4a,5,6,10b-hexahydro1H-benzo[f]quinolîn-4-yl)-ethanone following a procedure analogous to that described in Example 7. Yield: 93% of theory; LC (method 1): t_R = 3.58 min; Mass spectrum (EST): m/z 300 [M+Hf.

Step 3: c/s-2,2,2-trifluoro-1-[8-(4-methoxy-phenoxy)-2,3,4a,5,6,10b-hexahydro-1Hbenzo[f]quinolin-4-yl]-ethanone

A mixture of c/s-2,2₁2-trifluoro-1-(8-hydroxy-2,3_l4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)ethanone (0.98 g), 4-methoxyphenylboronic acid (1.00 g), pyridine (1.30 mL), copper(ll) acetate (0.60 g), molecular sieves 3A (3.60 g), and dichloromethane (15 mL) is stirred in air at room température overnight. The mixture is diluted with dichloromethane and filtered over Celite. The filtrate is concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH₃ 99:1->95:5) to give the title compound as a coloriess resin-like solid. Yield: 1.05 g (79% of theory); LC (method 1): t_R = 5.00 min; Mass speclrum (ESP): m/z = 406 [M+H]⁺.

Step 4: c/s-8-(4-methoxy-phenoxy)-1,2,3,4,4a,5,6,1Ob-octahydro-benzo[f]quinoline

M aqueous NaOH solution (10 mL) is added to a solution of c/s-2,2,2-trifluoro-1-[8-(4methoxy-phenoxy)-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl]-ethanone (0.95 g) in tetrahydrofuran (10 mL)at room température. The resulting solution is stirred at 35 °C overnight and then cooled to room température. The solution is extracted with ethyl acetate, the combined extracts are washed with brine and dried (Na₂SO₄). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH₃ 95:5—>70:30) to give the title compound as a coloriess resin-like solid. Yield: 0.64 g (88% of theory); LC (method 1): t_R = 2.75 min; Mass spectrum (EST): m/z = 310 [M+H]⁺.

Intermediates 28 and 29 c/S“1.2,3.4,4a,5,6.10b-Octahydro-benzofflquinolin-9-vlamine and trans-1,2,3,4,4a,5,6,10bOctahvdro-benzoiflauinolin-9-ylamine

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

The title compound is prepared from 7-nitro-2-tetralone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 41% of theory; LC (method 1): t_R - 2.20 min; Mass spectrum (ESP): m/z = 227 [M+Hp.

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

A mixture of 9-nitro-5,6-dihydro-benzo[f]quinoline (1.90 g), 10% palladium on carbon (0.20 g), and methanol (10 mL) is shaken under hydrogen atmosphère (3 bar) at room température for 3 h. The catalyst is then separated by filtration and the filtrate is concentrated to give an oil that is submitted to the next reaction without further purification. Yield: 1.67 g (crude); Mass spectrum (ESI⁴): m/z = 197 [M+H]⁴.

Step 3: c/s-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-9-ylamine and transV.S.A^a.S.e.lOb-octahydro-benzofflquinolin-g-ylamine

The tille compounds are prepared from 9-amino-5,6-dihydro-benzo[f]quinoline following a procedure analogous to that described in Step 2 of Intermediates 1 and 2. c/s-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-9-ylannine: Yield: 40% of theory; LC (method

2): t_R = 2.50 min; Mass spectrum (ESC): m/z = 203 [M+H]⁴.

trans-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-9-ylamine: Yield: 24% of theory; LC (method 2): t_R = 2.70 min; Mass spectrum (ESI⁴): m/z = 203 [M+H]⁴.

Intermediate 30 ¢/5-1,2.3,4,43,5.6.10b-Qctahvdro-benzo[f]quinoline-9-carbonitri le

Sodium nitrite (0.12 g) dissolved in water (0.7 mL) is added dropwise to a solution of cis1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-9-ylamine (0.36 g) in half-concentrated sulfuric acid (0.6 ml) cooled to ca. -5 °C. The solution is stirred for 15 min in the cooling bath prior to the addition of urea (30 mg). The resulting solution is added to a vigorously stirred solution of sodium cyanide (0.32 g) and copper(l) cyanide (0.19 g) in water (1.4 mL) cooled to ca. -5 °C. The mixture is stirred in the cooling bath for another 10 min and then the cooling bath is removed. After stirring at room température for 10 min, the mixture is heated to 70 °C and stirred at this température for 1 h. The mixture is cooled to room température, basified with 4 M NaOH solution (1.5 mL), and extracted with dichloromethane, The combined extracts are dried (Na₂SO₄) and the solvent is evaporated. The residue is chromatographed on silica gel [dichloromethane/(dichloromethane/methanol/NH₄OH 50:48:2) 80:20-»40:60] to give the title compound as a resin-like solid. Yield: 0.12 g (31% of theory); Mass spectrum (ESI⁴): m/z = 213 [M+H]⁴.

Intermediate 31 trans-1,2,3,4,4a,5,6,10b-Octahvdro-benzo[f1quinoline-9-carbonitrile

The title compound is prepared from trans-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-9ylamine following a procedure analogous to that described for Intermediate 30. Yield: 22% of theory; LC (method 1): t_R = 1.64 min; Mass spectrum (ESI⁴): m/z = 213 [M+H]⁴.

Intermediate 32 c/s-10-(6-Methvl-pyridazin-3-vloxv)-1,2.3,4,4a,5,6,10b-octahvdro-benzofflquinoIine

Step 1: 5,6-dihydro-benzo[f]quînolin-10-oI

The title compound is prepared from 10-methoxy-5,6-dihydro-benzo[f]quinoline following a procedure analogous to that described for Example 7. Yield: 94% of theory; LC (method 1 ): t_R = 1.48 min; Mass spectrum (ESI*): m/z = 198 [M+H]⁺.

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

The title compound is prepared from 5,6-dihydro-benzo[f]quinolin-10-ol following a procedure analogous to that described in Step 2 of Intermediates 1 and 2. Yield: 60% of theory; LC (method 2): t_R = 2.71 min; Mass spectrum (ESf): m/z = 204 [M+Hf.

Step 3: c/s-10-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinoline-4-carboxylic acid tertbutyl ester

Di-terf-butyl dicarbonate (0.69 g) is added to a solution of c/s-1,2,3,4,4a,5,6,1 Ob-octahydrobenzo[f]quinolin-10-ol (0.64 g) and triethylamine (0.5 mL) in dichloromethane (25 mL) at room température. The solution is stirred at room température overnight and then diluted with dichloromethane. The resulting solution is washed with 2 M aqueous citric acid and brine, dried (Na₂SO₄), and concentrated. The residue is treated with lîttle methanol and the precipitate formed thereafter is separated by filtration and dried to give the title compound as a colorless solid. Yield: 0.35 g (37% of theory); LC (method 1 ): t_R = 4.20 min; Mass spectrum (ESI⁺): m/z = 304 [M+H]⁺.

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

A mixture of c/s-10-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinoline-4-carboxylic acid tert-butyl ester (0.40 g), 3-chloro-6-methyl-pyridazine (0.13 g), césium carbonate (0.35 g), and N-methylpyrrolidinone (5 mL) is stirred at 150 °C for 1.5 h. After cooling to room température, the mixture is diluted with ethyl acetate and washed with water and brine and dried (Na₂SO₄). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl

acetate 3:1—>1:2) togive the title compound. Yield: 0.14 g (impure); LC (method 1): t_R = 4.19 min; Mass spectrum (ESΓ): m/z = 396 [M+Hf.

Step 5: c/s-10-(6-methyl-pyridazin-3-yloxy)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline Hydrochloric acid (4 mol/L in 1,4-dioxane, 0.7 mL) is added to a solution of c/s-10-(6-methylpyridazin-3-yloxy)-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinoline-4-carboxylic acid tert-butyl ester (0.13 g) in dichloromethane (5 mL) at room température. The solution is stirred at room température for 2 h and then concentrated to give the crude title compound as its hydrochloric acid sait that is used without further purification. Yield: 0.12 g (crude); LC (method 1 ): t_R = 1.90 min; Mass spectrum (EST): m/z = 296 [M+Hf.

Intermediate 33 cis-2,3,4,4a_l9,9a-Hexahvdro-1H-indeno[2,1-b1pyridine

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

A mixture of 1 -( 1 H-inden-2-yl)-pyrrolidine (5.34 g) and acrylamide (6.15 g) is stirred in argon atmosphère at 100 °C for 30 min. The température is then rised to 130 °C and stirring continued for another 15 min. After cooling to room température, water (50 mL) and acetic acid (5 drops) are added and the mixture is stirred for 30 min. The mixture is filtered and the organic phase of the filtrate is separated and washed with brine. After drying (MgSO₄) and evaporating the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1-> 0:1) to give a brown solid that is triturated with ethyl acetate and dried to afford the title compound. Yield: 1.12 g (21% of theory); Mass spectrum (EST): m/z = 186 [M+Hf.

Step 2: c/'s-1,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-2-one

A mixture of 1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (1.10 g), 10% palladium on carbon (0.15 g), acetic acid (0.75 mL), and methanol (20 mL) is shaken under hydrogen atmosphère (3 bar) at room température for 6 h. The catalyst is then separated by filtration and the filtrate is concentrated. The residue is triturated with terf-butyl methyl ether and dried to give the title compound as a colorless solid. Yield: 0.99 g (89% of theory); LC (method 1): t_R - 2.53 min; Mass spectrum (ESI⁺): m/z = 188 [M+Hf.

Step 3: c/s-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1-b]pyridine

Lithium aluminum hydride (1 mol/L in tetrahydrofuran, 12 mL) is added to a solution of cis1,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-2-one (0.95 g) in tetrahydrofuran (15 mL) at room température. The resulting solution is heated to reflux température and stirred at this température for 2 h. After cooling to room température, the solution is poured into ice-cold water, 1 M aqueous NaOH solution and ethyl acetate are added, and the resulting mixture is filtered over Celite. The aqueous phase of the filtrate is separated and extracted with ethyl acetate and the extracts are combined with the organic phase of the filtrate. The organic phase is washed with brine and dried (MgSO₄). The solvent is evaporated to give the title compound as a colorless solid. Yield: 0.83 g (94% of theory); LC (method 1): t_R = 1.29 min; Mass spectrum (Ε3Γ): m/z = 174 [M+Hf.

Alternatively, Intermediate 33 is obtained as follows:

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

The title compound is prepared from 2-indanone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 56% of theory; Mass spectrum (ESf): m/z = 168 [M+Hf.

Step 5: c/$-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1-b]pyridine

A mixture of 9H-indeno[2,1-b]pyridine (0.20 g), PtO₂ (70 mg), concentrated aqueous hydrochloric acid (0.1 mL), and éthanol (10 mL) is shaken under hydrogen atmosphère (2 bar) at room température for 16 h (in case the transformation is not complété after this time another portion of PtO₂ (30 mg) is added and shaking under hydrogen is continued until complété). The catalyst is separated by filtration and the solvent is evaporated to give the crude title compound as its hydrochloric acid sait that is used without further purification. Yield: 0.25 g (crude); Mass spectrum (ESI⁺): m/z = 174 [M+Hf.

Intermediates 34 and 35 c/s-1-(1H-Benzoimidazole-5-carbonvl)-2.3.4.4a,9,9a-hexahvdro-1H-indeno[2.1-blpyridine-6carboxylic acid methyl ester and c/s-1-(lH-Benzoimidazole-5-carbonvl)-2,3,4.4a,9.9ahexahydro-1H-indeno[2.1-blpyridine-7-carboxylic acid methyl ester

Step 1: 2,2,2-trifluoro-1-(c/s-2,3,4,4a,9_l9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-ethanone

The title compound is prepared from c/s-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1“b]pyridine following a procedure analogous to that described in Step 1 of Intermediate 27. Yield: 76% of theory; Mass spectrum (EST): m/z = 270 [M+Hf.

Step 2: Cfs-1-(6-bromo-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-2,2,2“trifluoroethanone and c/s-1-(7-bromo-2,3,4,4a,9₁9a-hexahydro-indeno[2₁1-b]pyridin-1-yl)-2,2,2-trifluoroethanone

Bromine (0.80 mL) is added to a suspension of 2,2,2-trifluoro-1-(c/s-2,3,4,4a,9,9a-hexahydrO' indeno[2,1-b]pyridin-1-yl)-ethanone (4.00 g) in water (32 mL) at room température. The mixture is heated to 70 °C and stirred at this température for 4 h. After cooling to room température, aqueous Na₂S₂O₃ solution is added and the resulting mixture is extracted with dichloromethane. The combined extracts are dried (Na₂SO«) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1 ) to give a mixture of the two title compounds and small amounts of further monobrominated isomers. Yield: 3,40 g (66% of theory); LC (method 1): t_R = 4.70 min; Mass spectrum (Ε5Γ): m/z = 348/350 (Br) [M+Hf.

Step 3: c/s-6-bromo-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine and c/s-7-bromo2,3,4,4a,9,9a-hexahydro-1H-indeno[2_r1-b]pyridine

The title compounds are prepared from the compound mixture in Step 2 above following a procedure analogous to that described in Step 4 of Intermediate 27 and submitted as an isomeric mixture to the next step. Yield: 69% of theory.

Step 4: c/s-(1H-benzoimidazol-5-yl)-(6-bromo-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1ylfmethanone and cZs-( 1 H'benzoimidazol-5-yl)-(7-bromo-2,3,4,4a,9,9a-hexahydro-indeno[2,1b]py ridin-1 -ylfmethanone

The title compounds are prepared from the isomeric mixture in Step 3 above following a procedure analogous to that described for Example 1 and submitted as an isomeric mixture to the next step. Yield: 85% of theory (ca. 85% pure); Mass spectrum (ESI⁺): m/z = 396/398 (Br) [M+Hf.

Step 5: c/s-1 -( 1 H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1 b]pyridine-6-carboxylic acid methyl ester and c/s-1-(1H-benzoimidazole-5-carbonyl)2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-7-carboxylic acid methyl ester

The title compounds are prepared from the isomeric mixture obtaîned in Step 4 above following a procedure analogous to that described in Step 1 of Intermediates 19 and 20 and submitted as an isomeric mixture to the next step. Yield: 80% of theory (ca. 90% pure); Mass spectrum (EST): m/z = 376 [M+Hf.

Intermediates 36 and 37 (4a-R.9a-S)-6-Bromo-2.3.4,4a.9,9a-hexahydro-1H-indeno[2,1-blpyridine and (4a-ff,9a-S)-7Bromo-2.3,4,4a,9,9a-hexahvdro-lH-indeno[2.1-b1pyridine

The title compounds are prepared as described in Step 3 of Intermediates 34 and 35 and the obtained isomeric mixture (2.2 g) is submitted to SFC on chiral phase (column: DAICEL IC 250x20 mm, 5 pm; mobile phase: methanol containing 0.2% diethylamine/sc carbon dioxide 20:80; flow rate: 70 mL/min) to give pure (4a-R,9a-S)-7-bromo-2,3,4,4a,9,9a-hexahydro-1Hindeno[2,1-b]pyridine [0.23 g; LC (chiral SFC as described): t_R = 16.27 min] and a mixture of (4a-R,9a-S)-6-bromo-2,3_l4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine with its enantiomer and another isomer which is submitted to a second SFC on chiral phase (column: DAICEL ADH 250x20 mm, 5 pm; mobile phase: isopropanol containing 0.2% diethylamine/sc carbon dioxide 15:85; flow rate: 70 mL/min) to afford pure (4a-/?,9a-S)-6-bromo-2_l3,4,4a,9_l9a-hexahydro-1Hindeno[2,1-b]pyridine [0.21 g; LC (second chiral SFC as described): t_R = 20.30 min].

Intermediate 38 (1H-Benzoimidazol-5-vlHf4a-/?,9a-S)-6-bromo-2,3,4.4a,9,9a-hexahvdro-indenof2.1-b1pyridin-1yll-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and (4a-R,9a-S)-6bromo-2,3,4,4a,9,9a-hexahydro-lH-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 95% of theory; LC (method 1): t_R = 2.83 min; Mass spectrum (ESI*): m/z = 396/398 (Br) [M+H]⁺.

Intermediate 39 (1H-Benzoimidazol-5-vlH(4a-R9a-S)-7-bromo-2.3.4,4a,9.9a-hexahydro-indeno[2,1-blpyridin-1yll-methanone

The tille compound is prepared from 1H-benzoimidazole-5-carboxylic acid and (4a-R,9a-S)-7bromo^.S^^a.g^a-hexahydro-lH-indeno^.l-bjpyridine following a procedure analogous to

that described in Example 1. Yield: 94% of theory; LC (method 1): t_R = 2.88 min; Mass spectrum (EST): m/z = 396/398 (Br) [M+Hf.

Intermediate 40 trans-1 Ob-Ethyl-1,2,3,4.4a.5,6.10b-octahydro-benzoffîquinoline

NH

Step 1: 1-ethyl'2-tetralone

Ethyl iodide (0.81 mL) is added to a solution of 1-(3,4-dihydro-naphthalen-2-yl)-pyrrolidine (2.05 g) in acetonitrile (20 mL). The solution is heated to reflux température and stirred at this température for 4 h. Another portion of ethyl iodide (0.3 mL) is then added and stirring continued overnight. After cooling to room température, the solution is concentrated and treated with water and 2 M aqueous citric acid. The resulting mixture is heated to 50 °C and stirred at this température for 15 min. After cooling to room température, the mixture is extracted with ethyl acetate and the combined extracts are washed with aqueous NaHCOg solution and brine and dried (Na₂SO₄). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 98:2—*80:20) to afford the title compound as an oil. Yield: 0.20 g (11% of theory); Mass spectrum (ESl·): m/z = 175 [M+H]⁺.

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

The title compound is obtained from propargylamine and 1-ethyl-2-tetralone following a procedure analogous to that described in Step 1 for Intermediates 7 and 8. Yield: 19% of theory; LC (method 1): t_R = 2.06 min; Mass spectrum (ESI⁺): m/z = 212 [M+H]⁺.

Step 3: trans-10b-ethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f|quinoline

The title compound is obtained from 10b“ethyl-3,5,6,10b-tetrahydro-benzo[f]quinoline following a procedure analogous to that described in Step 2 for Intermediates 7 and 8. Yield: 67% of theory; TLC: r_f = 0.45 (silica gel, CH2CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (EST): m/z = 216 [M+Hf.

Intermediate 41 c/s-6-Methoxv-2,3,4,4a,9,9a-hexahvdro-1H-indeno{2,1-b1pyridine

ο

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

A flask charged with a stir bar, 3-chloro-2-cyanopyridine (8.16 g), 3-methoxyphenylboronic acid (13.42 g), K3PO4 (25.00 g), and toluene (100 mL) is sparged with argon for 10 min. Palladium(ll) acetate (0.13 g) and n-butyl-di-(1-adamantyl)-phosphine (0.42 g) are added and the resulting mixture is put in a 100 °C hot oil bath and stirred in there for 3.5 h. After cooling to room température, ethyl acetate (250 mL) is added and the mixture is washed with 2 M aqueous

NaOH solution and brine. The organic phase is dried (Na₂SO₄) and the solvent is evaporated. The residue is triturated with methanol and dried to give the title compound as a colorless solid. Yield: 12.05 g (97% of theory); LC (method 1 ): t_R = 3.32 min; Mass spectrum (ESl·): m/z = 211 [M+H]⁺.

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

A mixture of 3-(3-methoxyphenyl)-pyridine-2-carbonitrile (12.00 g), 15 M aqueous NaOH solution (40 mL), and methanol (60 mL) is stirred at reflux température for 7 h. After cooling to room température, most of the methanol is evaporated and the residue is cooled in an ice bath and adjusted to pH value ca. 4-5 by the careful addition of concentrated hydrochloric acid. The resulting mixture is concentrated to ca. 50 ml by évaporation and extracted with dichloromethane/methanol (9:1) several times. The aqueous phase is then adjusted to pH value 2-3 using concentrated hydrochloric acid and extracted again with dichloromethane/methanol (9:1). The combined extracts are dried (Na₂SO₄) and the solvent is evaporated to give the title compound as a foam-like solid. Yield: 11.88 g (91 % of theory); LC (method 1 ): t_R = 1.70 min; Mass spectrum (EST): m/z = 230 [M+H]⁺.

Step 3: 3-(3-methoxy-phenyl)-pyridine-2-carbonyl chloride

Thionyl chloride (8 mL) and Ν,Ν-dimethylformamide (few drops) are added to a solution of 3-(3methoxy-phenyl)-pyridine-2-carboxylic acid (11.86 g) in dichloromethane (80 mL). The mixture is heated to 40 °C and stirred at this température overnight. The solution is then concentrated

and the residue is taken up in toluene and concentrated again to give the crude title compound that is used without further purification in the next step. Yield: 12.80 g (crude).

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

Aluminum chloride (7.33 g) is added to a solution of 3-(3-methoxy-phenyl)-pyridine-2-carbonyl chloride (crude, 5.40 g) in dichloromethane (100 mL) chilled in an ice bath. The cooling bath is removed and the mixture is stirred at room température overnight. The mixture is then poured on crushed ice and the resulting mixture is extracted with dichloromethane. The combined extracts are washed with aqueous NaHCO₃ solution and dried (Na₂SO₄). The solvent is evaporated and the residue is triturated with a mixture of cyclohexane and ethyl acetate (1:1 ) and dried to give the title compound as a yellowish solid. Yield: 3.00 g (65% of theory); LC (method 1): t_R = 2.84 min; Mass spectrum (ESl·): m/z = 212 [M+H]*.

Step 5: c/s-6-methoxy-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine

A mixture of 6-methoxy-indeno[2,1-b]pyridin-9-one (2.00 g), 10% palladium on carbon (0.30 g), 4 M aqueous hydrochloric acid (6 mL), and methanol (100 mL) is shaken under hydrogen atmosphère (3 bar) at room température for 4 h. PtO₂ (0,20 g) is then added and shaking is continued under hydrogen atmosphère (1 bar) at room température for another 36 h. The catalysts are separated by filtration and the filtrate is concentrated. The residue is basified by the addition of 2 M aqueous NaOH solution and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na₂SO₄), and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH₃ 90:10—>75:25) to give the title compound as a colorless oil. Yield: 1.00 g (52% of theory); LC (method 1 ): t_R = 1.50 min; Mass spectrum (ESf): m/z = 204 [M+H]⁺.

Intermediate 42

Trifluoromethanesulfonic acid c/s-1-(1-trifluoromethanesulfonyl-1H-benzoimidazole-5-carbonvl)2.3,4,4a,9.9a-hexahydro-1H-indenof2.1-b1pyridin-6-yl ester and Trifluoro-methanesulfonic acid c/s-1-(3-trifluoromethanesulfonvl-3H-benzoimidazole-5-carbonvl)-2.3.4,4a,9,9a-hexahydro-1Hindeno[2.1-blpyridin-6-yl ester

Trifluoromethanesulfonic anhydride (0.60 mL) dissolved in dichloromethane (3 mL) is added dropwise to a solution of (1H-benzoimÎdazol-5-yl)-(c/s-6-hydroxy-2,3,4,4a,9,9a-hexahydroindeno[2,1-b]pyridin-1-yl)-methanone (0.45 g) and pyridine (0.40 mL) in dichloromethane (10 mL) cooled to -10 °C. The solution is stirred in the cooling bath for 1 h and then diluted with

dichloromethane. The solution is washed with aqueous citric acid and aqueous NaHCO₃solution and dried (Na₂SO₄). The solvent is evaporated to give the two title compounds as a mixture that is used as such in the next step. Yield: 0.72 g (89% of theory); LC (method 1 ): t_R = 4.75 min; Mass spectrum (EST): m/z = 598 [M+Hf.

Intermediate 43 c/s-2.3,4,4a.9.9a-Hexahydro-1H-indeno[2,1-bÎPvridin-7-vlamine

Step 1: 7-nitro-9H-indeno[2,1-b]pyridine

A ca. 10 ’C-cold mixture of nitric acid (65%, 1.1 mL) and sulfuric acid (96%, 1.6 mL) is added dropwise to a solution of 9H-indeno[2,1-b]pyndine (2.44 g) in sulfuric acid (96%, 3 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 1 h and poured then onto crushed ice. The precipitate formed is separated by filtration and the filtrate is neutralized using 4 M aqueous NaOH solution. The precipitate formed is separated by filtration and combined with the precipitate separated before. The precipitate is triturated with acetone and dried to give the title compound as a solid. Yield: 2.64 g (85% of theory); LC (method 1): t_R = 2.93 min; Mass spectrum (ESI⁺): m/z = 213 [M+Hf.

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

A mixture of 7-nitro-9H-indeno[2,1-b]pyridine (3.25 g), 10% palladium on carbon (0.35 g), and methanol (50 mL) is shaken under hydrogen atmosphère (3 bar) at room température for 22 h. PtO₂ (0.50 g) and 4 M aqueous hydrochloric acid (3.2 mL) are then added and shaking is continued under hydrogen atmosphère (1 bar) at room température for another 22 h. The catalysts are separated by filtration and the filtrate is concentrated to give the crude title compound as its hydrochloric acid sait that is used without further purification or transformed to the free base by treatment with aqueous NaOH solution and extraction into ethyl acetate. Yield: 4.20 g (ca. 80% pure); LC (method 1): t_R =0.52 min; Mass spectrum (ESI⁺): m/z = 189 [M+Hf.

Intermediate 44 c/s-2,3,4,4a,9,9a-Hexahvdro-1H-indeno[2,1-blpvridin-7-ol

Sodium nitrite (92 mg) dissolved in water (0.5 mL) is added dropwise to a solution of cis2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ylamine dihydrochloride (0.30 g) in halfconcentrated sulfuric acid (0.6 ml) chilled in an ice bath. The solution is stirred for 15 min in the cooling bath prior to the addition of half-concentrated sulfuric acid (5 ml). The resulting solution

is heated to 120 ⁶C and stirred at this température for 3 h. The mixture is cooled to room température, diluted with water, and basified with 4 M NaOH, The resulting mixture is extracted with ethyl acetate and the combined extracts are dried (Na2SO₄). The solvent is evaporated and the residue is chromatographed on silica gel [dichloromethane/ (dichloromethane/methanol/NH₄OH 50:48:2) 80:20-+40:60] to give the title compound. Yield:

0.07 g (32% of theory); LC (method 1 ): t_R =0.83 min; Mass spectrum (ESf): m/z = 190 [M+H]⁺.

Intermediate 45 c/s-4-Methvl-2,3,4,4a,9,9a-hexahvdro-1 H-indenoi2,1-blpyridine

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

The title compound is prepared from indan-2-one and but-2-ynylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2; the reaction is carried out in a microwave oven at 100 °C for 12 min. Yield: 22% of theory; LC (method 1 ): t_R = 1.98 min; Mass spectrum (ESI⁺): m/z =182 [M+Hf.

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

A mixture of 4-methyl-9H-indeno[2,1-b]pyridine (0.64 g) and benzyl bromide (0.42 mL) in acetone (5 mL) is stirred at reflux température for 4 h. After cooling to room température, the precipitate is separated by filtration, washed with little diethyl ether, and dried to give the title compound as a beige solid. Yield: 0.93 g (75% of theory); LC (method 1 ): t_R = 2.49 min; Mass spectrum (ESI⁺): m/z = 272 [M-Br]\

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

Sodium borohydride (0.15 g) is added to a suspension of 1-benzyl-4-methyl-9H-indeno[2,1bjpyridinium bromide (0.92 g) in éthanol (10 mL) chilled in an ice bath. The cooling bath is removed and the mixture is stirred at room température for 1 h and at 60 °C for 2 h. More sodium borohydride (0.18 g) is added and stirring is continued at reflux température for 4 h. After the addition of another portion of sodium borohydride (0.10 g), the mixture is stirred at reflux température overnight. After cooling to room température, ice-cold water is added and the precipitate is separated by filtration. The precipitate is dissolved in ether, the resulting solution is dried (Na₂SO₄), and the solvent is evaporated to afford the crude product that is used without further purification. Yield: 0.66 g (crude); Mass spectrum (ESI⁺): m/z = 276 [M+H]‘.

Step 4: c/s-4-methyl-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1 -b]pyridine

A mixture of 1-benzyl-4-methyl-2,3,9,9a-tetrahydro-1 H-indeno[2,1-b]pyridine (0.65 g), Pd(OH)₂(200 mg), and éthanol (10 mL) is shaken under hydrogen atmosphère (5 bar) at room température for 16 h. Another portion of Pd(OH)₂ (100 mg) is then added and shaking under hydrogen atmosphère (5 bar) is continued overnight. The catalyst is separated by filtration and the solvent is evaporated to give the crude title compound that is used without further purification. Yield: 0.43 g (crude).

Intermediate 46 cÂs-2,3,4,4a,9,9a-Hexahvdro-1H-indeno[2,1-b1pyridine-6-carbonitrile

Step 1: 2,2,2-trifluoro-1-(c/s-6-methoxy-2,3,4₁4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)ethanone

Trifluoroacetîc anhydride (4.5 mL) is added dropwise to a solution of c/s-6-methoxy2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine (5.0 g), triethylamine (5.6 mL), and 4dimethylaminopyridine (ca. 5 mol%) in dichloromethane (60 mL) maintained below 10 °C. The solution is stirred with cooling for 1 h and at room température for 2 h. The solution is diluted with dichloromethane (100 mL) and aqueous NaHCO₃ solution and then stirred vigorously for 15 min. The organîc phase is separated, washed with 1 M hydrochloric acid (25 mL) and water (50 mL), and dried (MgSO₄). The solvent is evaporated to afford the title compound as an oil. Yield: 8.1 g (quantitative); LC (method 1): t_R = 4.24 min; Mass spectrum (ESl⁺): m/z = 300 [M+H]⁺. Step 2: 2,2,2-trifluoro-1-(c/s-6-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)ethanone

Boron tribromide (1 mol/L in heptane, 27 mL) is added to a solution of 2,2,2-trifluoro-1-(c/s-6methoxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-ethanone (8.1 g) in dichloromethane (120 mL) chilled in an ice bath. The resulting mixture is warmed in the cooling bath to room température overnight. The solution is cooled again in an ice bath, diluted with dichloromethane (50 mL), and then 25% aqueous K₂CO₃ (20 mL) is carefully added. The mixture is stirred for 30 min and then acidified by the addition of 4 M aqueous hydrochloric acid (60 mL). The organic phase is separated, washed with 1 M aqueous hydrochloric acid (40 mL),

and dried (MgSO₄). The solvent is evaporated to give the title compound as a solid. Yield: 7.3 g (95% of theory); LC (method 1): t_R = 3.43 min; Mass spectrum (ESl*): m/z = 286 [M+H]*.

Step 3: trifluoro-methanesulfonic acid c/s-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a.9,9a-hexahydro-1Hindeno[2,1-b]pyridin-6-yl ester

Trifluoromethanesulfonic anhydride (5.6 mL) is added dropwise to a solution of 2,2,2-trifluoro-1(c/s-6-hydroxy-2₁3,4,4a,9,9a-hexahydro-indeno[2,1 -bjpyridin-1 -yl)-ethanone (7.3 g), triethylamine (7.2 mL), and 4-dimethylaminopyridine (50 mg) in dichloromethane (60 mL) chilled in an ice bath. The solution is stirred with cooling for 1 h and at room température for 2 h. Water (100 mL) and dichloromethane (100 mL) are then added and the organic phase is separated. The organic phase is washed with water (50 mL), dried (MgSO₄), and concentrated to give the title compound as a dark oil. Yield: 10.7 g (quantitative); TLC: r_f = 0.50 (silica gel, cyclohexane/ethyl acetate 3:1); Mass spectrum (ESl*): m/z = 418 [M+H]*.

Step 4: c/s-1-(2,2,2-trifluoroacetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6carbonitrile

A flask charged with a stir bar, zinc cyanide (5.0 g), trifluoro-methanesulfonic acid c/s-1-(2,2,2trifluoro-acetyl^.S^^a.g^a-hexahydro-IH-indenop.l-bJpyridin-e-yl ester (10.7 g), and N,Ndimethylformamide (60 mL) is sparged with argon for 5 min. Tetrakis(triphenylphosphine)palladium(O) (4.0 g) is then added and the resulting mixture is stirred at 100 °C for 2 h. After cooling to room température, water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (MgSO₄), and concentrated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 1:9—>4:1) to give the title compound as a solid. Yield: 5.5 g (73% of theory); TLC: r, - 0.25 (silica gel, cyclohexane/ethyl acetate 3:1); Mass spectrum (ESC): m/z = 295 [M+H]*.

Step 5: c/s-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile

A solution of c/s-1-(2,2,2-trifluoroacetyl)-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1-b]pyridine-6carbonitrile (5.50 g) and 4 M NaOH solution (5.6 mL) in methanol (30 mL) is stirred at room température for 2 h. Brine (150 mL) is then added and the resulting mixture is extracted with ethyl acetate (3x75 mL). The combined extract is dried (MgSO₄) and concentrated to give the title compound as an oil that solidified upon standing. Yield: 3.70 g (quantitative); Mass spectrum (ESl*): m/z = 295 [M+H]*.

The racemîc mixture may be separated by SFC on chiral phase (column: Daicel ADH 250 x 20 mm, 5 pm; mobile phase: isopropanol containing 0.2% diethylamine/sc carbon dioxide 20:80; flow rate: 70 mL/min) to give

1. (4a-/?_>9a-S)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile, yield: 1.60 g (43% of theory), LC (analytical SFC on chiral phase: column: Daicel ADH 250 x 4.6 mm; mobile phase: isopropanol containing 0.2% diethylamine/sc carbon dioxide 20:80; flow rate: 4 mL/min): t_R = 4.05 min.

2. (4a-S,9a-R)-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1 -bJpyridine-6-carbonitrile, yield: 1.70 g (46% of theory), LC (analytical SFC on chiral phase: column: Daicel ADH 250 x 4.6 mm; mobile phase: isopropanol containing 0.2% diethylamine/sc carbon dioxide 20:80; flow rate: 4 mL/min): t_R = 2.81 min.

The enantiomerically pure (ee >99%) Intermediate 46 is also obtained employing the foilowing protocols:

O O

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

An autoclave is charged with 2,3-dichloropyridine (2.5 kg), degassed methanoi (12.5 L), and triethylamine (3.42 kg). A catalyst solution [prepared as follows: a flask is charged with palladium acetate (19 g), 1,3-bis(diphenylphosphino)propane (38.5 g), and methanoi (1 L). The mixture is stirred at 20-25 °C until palladium acetate is completely dissolved (ca. 30 min)] is added. After purging the apparatus with nitrogen twice and carbon monoxide twice, the mixture is stirred under carbon monoxide atmosphère (100 psi) at 60-65 °C for 20 h. After cooling to room température, the mixture is filtered over Celite and the filtrate is concentrated.

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

100

2-Methyl-tetrahydrofuran (500 mL) is added to crude 3-chloro-pyridine-2-carboxylic acid methyl ester (58.0 g) and the resulting solution is washed with water (200 mL) and 5% aqueous sodium chloride solution (200 mL) and concentrated (to ca, 450 mL total volume). 3Methoxybenzeneboronic acid (61.6 g) and potassium phosphate (143.3 g) are added and the resulting mixture is sparged with nitrogen for 20 min. Palladium acetate (0.76 g) and diadamantyl-n-butyl-phosphine (2.42 g) are added and the resulting mixture is heated to 80 °C and stirred at this température for 12 h. After cooling to room température, the mixture is washed with water (300 mL) and 1 mol/L aqueous NaOH solution (200 mL). The organic phase is diluted with methanol (100 mL) and 30% aqueous NaOH solution (27.04 g) is added at such a rate that the solution température maintained below 40 °C. The resulting mixture is stirred at room température for 2 h and then diluted with water (100 mL) and methyl tert-butyl ether (100 mL). The etheral layer is separated and concentrated hydrochloric acid (60 mL) is added to the aqueous phase (pH value ca. 2-3). The aqueous phase is extracted with dichloromethane (2x 250 mL) and the combined extract is diluted with toluene (6 L). The organic solution is concentrated at below 40 °C and the crude title compound is used as is for the next step. Steps 4/5:6-methoxy-indeno[2,1-b]pyridin-9-one

Thionyl chloride (0.95 L) is added over 30 min to a solution of 3-(3-methoxy-phenyl)-pyridine-2carboxylic acid (crude product; 2.0 kg) and N,N-dimethylformamide (34 mL) in dichloromethane (9 L) at 40 °C. The addition vessel is rinsed with dichloromethane (1 L) and the solution is stirred at 40 °C for 2 h. The solution is diluted with toluene (10 L) and most of the solvent is evaporated (residual toluene ca. 2 L). Dichloromethane (10 L) is added to obtain a homogeneous solution. The solution is heated to 35 °C and added over 30 min to a vessel charged with aluminum chloride (1.75 kg) and dichloromethane (10 L) while keeping mild reflux. The mixture is stirred at 40 °C for 30 min and then cooled to 0 °C. Water (4 L) is added at such a rate that the solution température maintained below 40 °C. The aqueous layer is adjusted to pH value 2.5-3.5 using 2 M aqueous NaOH solution and the resulting mixture is stirred for 15 min. The organic layer is separated and the aqueous layer is extracted with dichloromethane (2x). The combined organic phase is concentrated (to ca. 10 L) and toluene (10 L) is added to the residue. The residual amount of dichloromethane is evaporated and the precipitate is separated and washed with toluene (2 L) and heptane (4 L) and dried under vacuum to give the title compound.

Step 6: c/s-6-methoxy-2,3,4.4a,9,9a-hexahydro-1 H-indeno[2,1 -b]pyridine

A mixture of sulfuric acid (98%, 6 kg), water (6 L), and methanol (6 L) is added to an autoclave charged with 6-methoxy-indeno[2,1-b]pyridin-9-one (1.2 kg) and wet 10% palladium on carbon (50%, 0.48 kg). The autoclave is purged with nitrogen and filled then with hydrogen (100 psi). The mixture is heated to 60 °C and maintained at this température and hydrogen pressure until the starting material is completeiy consumed (2-12 h). The mixture is cooled to 50-55 °C and

101 filtered over Celite. TheCelite is washed with a warm 1:1 mixture of water and methanol sevaral times (total 20 L). The combined filtrate is added to an autoclave charged with wet 10% palladium on carbon (50%, 0.96 kg). The autoclave is purged with nitrogen and filled then with hydrogen (100 psi). The mixture is heated to 60 °C and maintained at this température and hydrogen pressure until the intermediate is completely consumed (12-24 h). The mixture is cooled to ambient température and filtered over Celite. The Celite is washed with a mixture of methanol and water (5 L/5 L). The combined filtrate is cooled to 0-10 °C and the pH value is adjusted to 10-11 using 30% aqueous NaOH solution while maintaîning the solution température below 40 °C. Water (10 L) is added and the resulting mixture is extracted with dichloromethane (2x 5 L). The combined extract is washed with 10% aqueous NaCI solution and concentrated. The residue is taken up twice in methyl ethyl ketone and concentrated again to give the crude title compound.

Step 7: (4a-R,9a-S)-6-methoxy-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1 -bjpyridine Di-p-toluoyl-D-tartaric acid (403 g) is added to crude CiS-6-methoxy-2,3,4,4a,9,9a-hexahydro1H-indeno[2,1-bjpyridine (ca. 0.53 kg of pure compound) dissolved in methyl ethyl ketone (5.3 L). The solution is heated to 50 °C and some seeds are added. The mixture is stirred at 50 °C for 1 h and at 15 °C overnight. The resulting slurry is filtered to give a white solid (386 g, 95% de). The solid is taken up in dichloromethane (6 L) and 10% aqueous NaOH solution is added. The resulting mixture is stirred at room température for 1 h. The organic phase is separated and concentrated to give the title compound. Yield: 170 g (95% ee).

Step 8: (4a-R,9a-S)-2,2,2-trifluoro-1 -(6-methoxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin1-yl)-ethanone

A vessel charged with 4-dimethylaminopyridine (6.9 g), triethylamine (0.24 L), (4a-/?,9a-S)-6methoxy-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1 -bjpyridine (231 g), and dichloromethane (2.3 L) is cooled to 10-15 °C. Trifluoroacetic anhydride (0.21 L) is added at such a rate that the solution température maintained below 25 °C. The mixture is heated to 20-25 °C and stirred at this température for 1 h. Salurated aqueous NaHCO₃ solution (1.5 L) is added and the resulting mixture is stirred for 15 min. The organic layer is separated, washed with 1 M aqueous HCl solution (1.2 L) and water (0.9 L), concentrated, and azeotropically dried using dichloromethane to give the title compound.

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

Boron tribromrde (0.14 kg) is added to a solution of (4a-R,9a-S)-2,2,2-trifluoro-1-(6-methoxy2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-ethanone (0.34 kg) in dichloromethane (5.7 L) cooled to 10-15 °C at such a rate that the solution tempeerature maintained below 25 °C. The solution is stirred at 20-25 °C for 5 h. The solution is poured into water (1.7 L) at such a rate that the solution température maintained below 35 °C and the resulting mixture is stirred for 30 min.

102

The organic phase is separated, washed with water (1,3 L), and concentrated. The residue is azetropically dried with dichloromethane to give the title compound.

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

Trifluoromethanesulfonic anhydride (0.23 L) is added to a solution of 4-dimethylamino-pyridine (6.9 g), triethylamine (0.24 L), and (4a-/?,9a-S)-2,2,2-trifluoro-1-(6-hydroxy-2,3,4,4a,9.9ahexahydro-indeno[2,1-b]pyridin-1-yl)-ethanone (0.32 kg) in dichloromethane (3.4 L) cooled to 05 °C at such a rate that the solution température maintained between 0 and 5 °C. After stirring the solution for 30 min at 0-5 ’C, water (1.2 L) is added at such a rate that the solution température maintained 0-5 ’C. After stirring for 15 min, the organic phase is separated, washed with water (1.2 L), and concentrated. The residue is passed through a plug of silica gel (ethyl acetate/hexane 1:2) to give the title compound as an oil. Yield: 0.42 kg (98% of theory). Step 11 : (4a-f?,9a-S)-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1b]pyridine-6-carbonitrile

A mixture of (4a-/?,9a-S)-trifluoro-methanesulfonic acid 1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (189 g), zinc cyanide (79.8 g), and N,Ndïmethylformamide (1.9 L) is purged with nitrogen for 15 min. Tris(dibenzylideneacetone)dipalladium(0)(16.6 g) and 1,T-bis(diphenylphosphino)ferrocene (25.1 g) are added and the resulting mixture is purged with nitrogen at room température. The mixture is heated to 80 ’C and stirred at this température for 12 h. After cooling to room température, water (2 L) and ethyl acetate (2 L) are added and the resulting mixture is stirred for 10 min. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phase is washed with water (4x 1 L) and concentrated. The residue is passed through a plug of silica gel (hexane/ethyl acetate 2:1.5) to give the title compound as a solid. Yield: 133 g (quantitative).

Steps 12/13: (4a-R,9a-S)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile 2 M aqueous NaOH solution (300 mL) is added to a slurry of (4a-/?,9a-S)-1-(2,2,2-trifluoroacetyl)-2,3,4,4a,9,9a-hexahydro-lH-indeno[2,1-b]pyridine-6-carbonitrile (135 g) in methanol (600 mL) at such a rate that the slurry température maintained below 40 ’C. The mixture is stirred at room température for 2 h and diluted then with water (300 mL) and dichloromethane (600 mL). The organic phase is separated and the aqueous phase is extracted with dichloromethane (2x 500 mL). The combined organic phase is washed with 10% aqueous NaCI solution and concentrated to give the crude title compound as an oil (90 g, 93-95% ee). The crude title compound (90 g) in isopropanol (540 mL) is heated to 50 ’C and di-benzoyi-D-tartaric acid (109 g) is added. The resulting mixture is stirred at 90 ’C for 1 h and at room température for 2 h. The precipitate is separated and washed with isopropanol (3x 50 mL). The precipitate is taken up in dichloromethane (1 L)and the resulting mixture is treated with 2 M aqueous NaOH

103 solution (500 mL). The mixture is stirred at room température for 1 h. The organic phase is separated, washed with 10% aqueous NaCI solution (500 mL), and concentrated to give the title compound as an oil. Yield: 80 g (>99% ee).

Intermediate 47 c/s-6-Phenyl-2,3,4,4a,9.9a-hexahydro-1 H-indeno[2,1 -blpyridine

Step 1: c/s-2,2,2-trifiuoro-1-(6-phenyl-2_l3,4,4a_l9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)ethanone

The title compound is prepared from trifluoro-methanesulfonic acid c/s-1 -(2,2,2-trifluoro-acetyl)2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and phenylboronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 70% of theory; LC (method 1): t_R =5.02 min; Mass spectrum (EST): m/z = 346 [M+Hf.

Step 2: c/s-6-phenyl-2,3,4,4a_l9_l9a-hexahydro-1H-indeno[2,1-b]pyridine

The title compound is prepared from c/s-2,2,2-trifluoro-1-(6-phenyl-2,3,4,4a,9,9a-hexahydroindeno^J-bjpyridin-l-ylJ-ethanone following a procedure analogous to that described in Step 5 of Intermediate 46. Yield: 60% of theory; LC (method 1 ): t_R = 2.70 min; Mass spectrum (EST): m/z = 250 [M+Hf.

Intermediate 48 cis-6-Furan-3-vl-2,3,4,4a,9.9a-hexahvdro-1 H-indeno[2,1 -blpyridine

Step 1: c/s-2,2,2-lrifluoro-1-(6-furan-3-yl-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)ethanone

The title compound is prepared from trifluoro-methanesulfonic acid c/s-1-(2,2,2-trifluoro-acetyl)2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and furan-3-yl-boronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 61% of theory; LC (method 1): l_R =4.60 min; Mass spectrum (ESl*): m/z = 336 [M+H]*.

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

104

The title compound is prepared from c/s^^^-trifluoro-l-ÎS-furan-S-yl^^.A^a^.Oa-hexahydroindeno[2,1-b]pyridin-1-yl)-ethanone following a procedure analogous to that described in Step 5 of Intermediate 46. Yield: 93% of theory; LC (method 1): t_R = 2.27 min; Mass spectrum (ESI⁺): m/z = 240 [M+H]⁺.

Intermediate 49 c/s-6-(1-Methvl-1H-pvrazol-4-vl)-2,3,4,4a.9.9a-hexahvdro-1H-indeno[2,1-b]pyridine

Step 1: c/s^^^-trifluoro-l-te-fl-methyl-IH-pyrazol^-yO^^^^a^.ga-hexahydro-indeno^.lb]py rid i n-1 -yl]-ethanone

The title compound is prepared from trifluoro-methanesulfonic acid c/s-1-(2,2,2-trifluoro-acetyl)2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and l-methyl-pyrazol-4-yl-boronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 32% of theory; LC (method 1 ): t_R = 3.88 min; Mass spectrum (EST): m/z = 350 [M+H]⁺. Step 2: c/'s-6-(1-methyl-1H-pyrazol-4-yl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine The title compound is prepared from c/s-2,2,2-triiluoro-1-[6-(1-methyl-1H-pyrazol-4-yl)2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl]-ethanone following a procedure analogous to that described in Step 5 of Intermediate 46. Yield: quantitative; LC (method 1 ): t_R = 1.70 min; Mass spectrum (ESI⁺): m/z= 254 [M+H]*.

Intermediate 50 c/s-6-Methvl-2.3,4,4a,9_<9a-hexahydro-1H-indenoÎ2.1-blpyridine

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

Tetrakis(triphenylphosphine)pal!adium(0) (17 mg) is added to a flask charged with a stir bar, trifluoromethanesulfonic acid c/s-1-(2,2.2-trifluoro-acetyl)-2_l3,4,4a₁9.9a-hexahydro-1 Hindeno[2,1-b]pyridin-6-yl ester (200 mg), trimethylboroxine (81 pL), K₃PO₄ (0.15 g), and 1,4dioxane (4 mL) under argon atmosphère at room température. The reaction mixture is heated to 100 °C and stirred at this température overnight. Another portion of trimethylboroxine (40 pL)

and tetrakis(triphenylphosphine)palladium(0) (17 mg) is then added and stirring is continued at 100 “C. The addition of further amounts of trimethylboroxine and tetrakis(triphenylphosphine)palladium(O) is repeated after each 6 h of stirring until the starting material is completely consumed. After cooling to room température, water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na₂SO₄) and concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol 1:0—>9:1 ) to give the title compound. Yield: 50 mg (37% of theory); LC (method 1 ): t_R — 4.62 min; Mass spectrum (ESP): m/z = 284 [M+Hf.

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

The title compound is prepared from c/s-2,2,2'trifluoro-1-(6-methyl-2,3,4,4a,9,9a-hexahydroindeno[2,1-b]pyridin-1-yl)-ethanone following a procedure analogous to that described in Step 5 of Intermediate 46. Yield: 94% of theory; LC (method 1): t_R = 1.91 min; Mass spectrum (ESP): m/z = 188 [M+Hf.

Intermediate 51 c/s-(3H-Benzoimidazol-5-vl)-r6-(3,6-dihvdro-2H-pvran-4-vl)-2.3,4.4a.9.9a-hexahvdro-indeno[2,1blpyridin-1-vH-methanone

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

A flask charged with a stir bar, trifluoromethanesulfonic acid 1-(2,2,2-trifluoro-acetyl)2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (0.20 g), 3,6-dihydro-2H-pyran-4boronic acid pinacol ester (0.23 g), césium carbonate (2 mol/L in water, 0.7 mL), tetrahydrofuran (4 ml), and toluene (1 mL) is sparged with argon for 5 min. Bis(1 ,Tdiphenylphosphinojferrocene-dichloropalladium (44 mg) is added and the mixture is heated to

100 °C. After stirring at 100 °C overnight, another portion of 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.05 g) and bis(1 ,T-diphenylphosphino)ferrocene-dichloropalladium (20 mg) is added and stirring is continued at 100 °C for 5 h. After cooling to room température, the mixture is diluted with ethyl acetate, washed with aqueous NH₄CI solution, dried (Na₂SO₄), and

X

concentrated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0-+9:1) togive the title compound. Yield: 0.16 g (impure); LC (method 1): t_R = 4.36 min; Mass spectrum (EST): m/z =352 [M+H|*.

Step 2: cis-6-(3,6-dihydro-2H-pyran-4-yl)-2,3,4,4a,9₁9a-hexahydro-1H-indeno[2,1-b]pyridine

The title compound is prepared from 1-[c/s-6-(3,6-dihydro-2H-pyran-4-yl)-2,3,4,4a,9,9ahexahydro-indeno[2_t1-b]pyridin-1-yl]-2,2,2-trifluoro-ethanone foilowing a procedure analogous to that described in Step 5of Intermediate 46. Yield: 37% of theory; LC (method 1): t_R = 1.97 min; Mass spectrum (ESI*): m/z =256 [M+H]*.

Step 3: c/s-(3H-benzoimidazol-5-yl)-[6-(3₁6-dihydro-2H-pyran-4-yl)-2,3,4,4a,9₁9a-hexahydro10 indeno[2,1 -b] pyridin -1 -yl]-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-6-(3,6dihydro-2H-pyran-4-yl)-2,3_l4,4a_l9,9a-hexahydro-1H-indeno[2,1-b]pyridine foilowing a procedure analogous to that described in Example 1. Yield: 69% of theory; LC (method 1 ): t_R = 2.65 min; Mass spectrum (Ε5Γ): m/z = 400 [M+H]*.

Intermediate 52 c/s-(3H-Benzoimidazol-5-vl)-(6-cvclopent-1-envl-2.3.4,4a.9,9a-hexahydro-indeno[2,1-b]pvridin1-ylbmethanone

Step 1: 1-(c/s-6-cyclopent-1-enyl-2_l3_l4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-2,2,220 trifluoro-ethanone

The title compound is prepared from trifluoro-methanesulfonic acid 1-(2,2,2-trifluoro-acetyl)2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and cyclopentenyl-1-boronic acid pinacol ester foilowing a procedure analogous to that described in Step 1 of Intermediate 51.

Yield: 31% of theory; LC (method 1): t_R = 5.34 min; Mass spectrum (EST): m/z = 336 [M+H]*.

Step 2: c/s-6-cyclopent-1-enyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine

The title compound is prepared from 1-(c/s-6-cyclopent-1-enyl-2,3,4,4a,9,9a-hexahydroindeno[2,1 -bjpyridin-1 -yl)-2,2,2-trifluoro-ethanone foilowing a procedure analogous to that

107 described in Step 5 of Intermediate 46. Yield: quantitative; LC (method 1); t_R = 2.73 min; Mass spectrum (ESI⁺): m/z - 240 [M+Hf.

Step 3: c/s-(3H-benzoimidazol-5-yl)-(6-cyclopent-1-enyl-2,3,4,4a,9,9a-hexahydro-indeno[2,1b]pyridin-1-yl)-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-6-cyclopent1-enyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 49% of theory; LC (method 1 ): t_R = 2.64 min; Mass spectrum (ESI⁺): m/z = 384 [M+Hf.

Intermediate 53

N-(c/s-2.3,4.4a,9.9a-Hexahvdro-1H-indeno[2,1-bIpvridin-7-vl)-acetamide

Step 1: c/s-7-amino-2,3,4,4a_l9,9a-hexahydro-indeno[2,1-b]pyridine-1 -carboxylic acid tert-butyl ester

The title compound is prepared from c/s-2,3,4,4a_l9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7ylamine and di-tert-butyl dicarbonate following a procedure analogous to that described in Step 3 of Intermediate 32. Yield: 25% of theory; LC (method 1): t_R = 2.69 min; Mass spectrum (ESI⁺): m/z = 289 [M+Hf.

Step 2: c/s-7-acetylamino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tertbutyl ester

Acetic anhydride (50 pL) is added to a solution of c/s-7-amino-2,3,4,4a,9,9a-hexahydroindeno[2,1-b]pyridine-1-carboxylicacid tert-butyl ester (140 mg) and triethylamine (70 pL) in dichloromethane (3 mL) at room température. The solution is stirred for 1 h at room température and then aqueous NaHCO₃ solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3—>1:9) to give the title compound. Yield: 100 mg (62% of theory); LC (method 1): t_R =3.60 min.

Step 3: N-(c/s-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-acetamide

The title compound is prepared from c/s-7-acetylamîno-2,3,4,4a,9,9a-hexahydro-indeno[2,1blpyridine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described in

108

Step 5 of Intermediate 32. Yield: quantitative; LC (method 1 ): t_R = 0.92 min; Mass spectrum (ESI⁺): m/z = 231 [M+Hf.

Intermediate 54

N-(c/s-2.3,4,4a.9.9a-Hexahydro-1H-indenoi2_<1-blpvridin-7-v1)-methanesulfonannide

Step 1: c/s-7-methanesulfonylamino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tert-butyl ester

Methylsulfonyl chloride (42 pL) is added to a solution of c/s-7-amino-2,3,4₁4a,9,9a-hexahydroindeno[2,1-b]pyridine-1-carboxylicacid tert-butyl ester (160 mg) and triethylamine (76 pL) in dichloromethane (3 mL) at room température. The solution is stirred for 1 h at room température and then aqueous NaHCO₃ solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3—* 1:9) to give the title compound. Yield: 120 mg (59% of theory); LC (method 1): t_R =3.80 min; Mass spectrum (EST): m/z = 365 [M-H]‘. Step 2: N-(c/s-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1 -b]pyridin-7-yl)-methanesulfonamide The title compound is prepared from c/s-7-methanesulfonylamino-2,3,4,4a,9,9a-hexahydroindeno[2,1-b]pyridine-1-carboxylicacid tert-butyl ester following a procedure analogous to that described in Step 5 of Intermediate 32. Yield: quantitative; LC (method 1): t_R = 0.97 min; Mass spectrum (ESI⁺): m/z = 267 [M+Hf.

Intermediate 55 c/s-7-Nitro-2.3,4.4a,9,9a-hexahvdro-1H-indeno[2,1-blpyridin-6-ol

A ca. 10 °C-cold mixture of nitric acid (65%, 0.36 mL) and sulfuric acid (96%, 0.55 mL) is added dropwise to a solution of trifluoro-methanesulfonic acid c/s-1-(2,2,2-trifluoro-acetyl)2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (2.00 g) in sulfuric acid (96%, 12 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 1 h and poured then onto crushed ice. The precipitate formed is separated by filtration and taken up in methanol (10 mL). The resulting solution is treated with saturated aqueous K₂CO₃ solution (alternative^ NaOH is used) until the trifluoromethylsulfonyl and trifluoroacetyl group are cleaved off (TLC or HPLC).

109

Water is then added and the resulting mixture is extracted with ethyl acetate. The combined extract is concentrated to give the crude title compound that is used without further purification. Yield: 1.10 g (crude); LC (method 1): t_R = 1.44 min; Mass spectrum (EST): m/z = 235 [M+H]⁺.

Intermediate 56 c/s-6-Methoxy-7-methvl-2,3,4,4a,9,9a-hexahydro-1 H-indenof2,1 -b] p y ri d i n e

The title compound is prepared from 3-bromo-pyridine-2-carboxylic acid and 4-methyl-3methoxyboronic acid following the synthetic sequence and protocols described for Intermediate 41; since 3-bromo-pyridine-2-carboxylic acid instead of 3-bromo-pyridine-2-carbonitrile is used for the Suzuki-Miyaura coupling (Step 1 of Intermediate 41), hydrolysis of the nitrile (Step 2 of Intermediate 41 ) is omitted, LC (method 7): t_R = 0.74 min; Mass spectrum (ESI⁺): m/z = 218 [M+Hf.

Intermediate 57 c/s-6-Methoxy-5-methvl-2.3,4,4a.9.9a-hexahvdro-1H-indenof2.1-b|pyridine

The title compound is prepared from 3-bromo-pyridine-2-carboxylic acid and 2-(3-methoxy-2methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (may be prepared as in WO 2001053268 described) following the synthetic sequence and protocols described for Intermediate 41; since 3-bromo-pyridine-2-carboxylic acid instead of 3-bromo-pyridine-2carbonitrile is used for the Suzuki-Miyaura coupling (Step 1 of Intermediate 41), hydrolysis of the nitrile (Step 2 of Intermediate 41 ) is omitted.

Intermediate 58

Trifluoromethanesulfonic acid c/s-7-methvl-1-(1-trifluoromethanesulfonvl-1H-benzoimidazole-5carbonvl )-2,3,4,4a,9,9a-hexahvdro-1H-indeno[2,1-blpyridin-6-vl ester and Trifluoromethanesulfonic acid c/s-7-methvl-1-(3-trifluoromethanesulfonyl-3H-benzoimidazole-5carbonyl)-2.3.4,4a,9,9a-hexahvdro-1H-indeno[2.1-b1pvridin-6-yl ester

110

The tille compounds are prepared from (1H-benzoimidazol-5-yl)-(c/s-6-hydroxy-7-methyl2_l3_l4,4a,9,9a-hexahydro-indeno[2_l1-b]pyridin-1-yl)-methanone following a procedure analogous to that described in Intermediate 42 and used as a mixture in the following step.

Intermediate 59 (1H-Benzoimidazol-5-vl)-(c/s-6-methoxv-5-methvl-2,3,4,4a.9,9a-hexahvdro-indenof2,1-b]pyridinΙ-νΠ-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/‘s-6-methoxy-5methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno(2,1-b]pyridine following a procedure analogous to that described in Example 1.

Intermediate 60 (1H-BenzoimidazoÎ-5-yl)-(crs-6-hvdroxy-5-methvl-2.3,4.4a.9.9a-hexahydro-indenor2.1-blpyridin1-vl)-methanone

The title compound is prepared from (1 H-benzoimidazol-5-yl)-(cis-6-methoxy-5-methyl2,3,4,4a_l9_l9a-hexahyciro-indeno[2_l1-b]pyridin-1-yl)-methanone following a procedure analogous to that described in Example 7.

Intermediate 61

Trifluoromethanesulfonic acid c/'s-5-methvl-1-(1-trifluoromethanesulfonyl-1H-benzoimidazole-5carbonvl)-2,3,4,4a.9.9a-hexahvdro-1H-indenof2,1-blpyridin-6-vl ester and Trifluoromethanesulfonic acid c/s-5-methvl-1-(3-trifluoromethanesulfonyl-3H-benzoimidazole-5carbonvl)-2.3,4,4a.9,9a-hexahydro-1H-indenof2.1-blpyridin-6-vl ester

The title compounds are prepared from (1H-benzoimidazol-5-yl)-(c/s-6-hydroxy-5-methyl2,3,4,4a_l9,9a-hexahydro-indeno[2_>1-b]pyridin-1-yl)-methanonefollowing a procedure analogous to that described in Intermediate 42 and used as a mixture in the following step.

111

Example 1 (1H-Benzoimidazol-5-vl)-(c/s-2,3_t4a,5,6,10b-hexahvdro-1H-benzo[f1quinolin-4-yl)-methanone

2-(1H-Benzotriazol-1-yl)-1,1_l3,3-tetramethyluronium tetrafluoroborate (0.50 g; alternatively, 2-(7aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate may be used) is added toa solution of 1H-benzoimidazole-5-carboxylic acid (0.23 g) and ethyl-diisopropyl-amine (0.50 mL) in Ν,Ν-dimethylformarnide (2 mL) at room température. The solution is stirred for 20 min priorto the additionof c/s-I^^^Aa.S.e.lOb-octahydro-benzotfJquinoline (0.30 g) dissolved in Ν,Ν-dimethylformarnide (2 mL). The resulting solution is stirred at room température for 3 h. 32% aqueous ammonia (1 mL) in methanol (2 mL) is then added and the mixture is stirred for another 30 min. The mixture is diluled with ethyl acetate and washed with water and brine and dried (Na₂SO₄). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH₃ 95:5->80:20) to afford the title compound as a foam-like solid that is triturated with ether and dried to give a colorless solid [alternatively, the product may be purified by HPLC on reversed phase (MeOH/H₂O)]. Yield: 0.38 g (80% of theory); LC (method 1 ): t_R = 2.53 min; Mass spectrum (ESl*): m/z = 332 [M+H]⁺; ¹H NMR (400 MHz, DMSO-de, mixture of 2 rotamers) d 1.52-1.82 (m, 4H), 1.82-1.94 (m, 1H), 2.24-ca. 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 (broad s, 1H).

Example 2 (1H-Benzoimidazol-5-vl)-[(4a-S,10b-F?)-2,3, 4a.5.6,10b-hexahvdro-1H-benzorflquinolin-4-yl1methanone

The title compound is obtained by chromatographing a racemic mixture of (1H-benzoimidazol-5· yl)-(c/s-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)-methanone (100 mg) on chiral phase (SFC; column: 1x ASH 250 x 10 mm, 5 pm; mobile phase: methanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow rate: 10 mL/min). Yield: 48 mg; LC (SFC; column: Daicel ASH 250 x 4.6 mm, 5 pm; mobile phase: methanol containing 0.2% diethylamine/sc

112 carbon dioxide 25:75; flow rate: 4 mL/min): t_R = 2.73 min; Mass spectrum (ESI ): m/z = 332 [M+H]*; for ¹H NMR see Example 1.

Example 3 f 1 H-Benzoimidazol-5-yl)-[(4a-R,10b-S)-2,3, 4a,5,6,1Qb-hexahvdro-1 H-benzorflquinolin-4-νΠmethanone

The title compound is obtained by chromatographing a racemic mixture of (1 H-benzoimidazol-5yl)-(cis-2,3,4a,5,6,10b-hexahydro-1H-benzo[f|quinolin-4-yl)-methanone (100 mg) on chiral phase (SFC; column: 1x ASH 250 x 10 mm, 5 pm; mobile phase: methanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow rate: 10 mL/min). Yield: 45 mg; LC (SFC; column: Daicel ASH 250 x 4,6 mm, 5 pm; mobile phase: methanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow rate: 4 mL/min): t_R = 2.13 min; Mass spectrum (EST): m/z = 332 [M+Hf; for ¹H NMR see Example 1.

Example 4 (1H-Benzoimidazol-5-vl)-(trans-2,3,4a,5,6,10b-hexahydro-1H-benzoiflquinolin-4-vl)-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 31% of theory; TLC: r_f = 0.40 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESI⁺): m/z = 332 [M+Hf; ¹H NMR (400 MHz, DMSO-d₆) d 1.32-1.46 (m, 1H), 1.53-1.76 (m, 2H), 2.14-2.24 (m, 1H), 2.30-2.43 (m, 1H), ca. 2.49-2.56 superimposed by D₃CSOCHD₂ signal (m, 1H), 2.77-2.93 (m, 2H), 3.03-3.13 (m, 1H), ca. 3.253.34 superimposed by H₂O signal (m, 1 H), 3.34-3.43 (m, 1 H), 3.67-3.76 (m, 1 H), 7.07-7.19 (m, 3H), 7.26-7.32 (m, 2H), 7.59-7.70 (m, 2H), 8.30 (s, 1 H), 12.60 (broad s, 1H).

Example 5

4-(c/s-2,3.4a.5,6,10b-Hexahydro-1H-benzoff]quinoline-4-carbonyl)-benzamide

113

The title compound is prepared from terephthalamic acid and c/s-1,2,3,4,48,5,6,10b-octahydrobenzo[f]quinoline foliowing a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): t_R = 3.16 min; Mass spectrum (EST): m/z = 335 [M+Hf.

Example 6 ( 1 H-Benzoiinidazol-5-vl)-(c/s-7-methoxy-2,3,4a,5,6,1Ob-hexahvdro-1 H-benzoiflquinolin-4-νΠmethanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s-7-methoxy1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline foliowing a procedure analogous to that described in Example 1. Yield: 85% of theory; LC (method 1 ): t_R = 2.62 min; Mass spectrum (EST): m/z = 362 [M+Hf.

Example 7 (1H-Benzoimidazol-5-vl)-fc/s-7-hvdroxv-2,3.4a.5,6,10b-hexahvdro-1H-benzo[flquinolin-4-vlT methanone

Boron tribromide (1 mol/L in dichloromethane, 0.5 mL) is added to a solution of(1H-benzoimidazol-5-yl)-(c/s-7-methoxy-2_l3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)-methanone (60 mg) in dichloromethane (5 mL) at room température. The resulting solution is stirred at room température for 2 h. Aqueous half-saturated NaHCO₃ solution is added and the resulting neutral mixture is extracted with dichloromethane and dichloromethane/methanol (95:5). The combined extracts are washed with brine and dried (Na₂SO₄). The solvent is evaporated and the residue is triturated with diethyl ether and dried to give the title compound as a colorless solid. Yield: 30 mg (52% of theory); TLC: r_f = 0.45 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESI⁺): m/z= 348 [M+Hf.

114

Example 8 (IH-Benzoimidazol-S-ylHc/s-IO-methoxy-Z.S^a.S.e.lOb-hexahvdro-IH-benzoIflquinolirM-yl)methanone

The title compound is preparedfrom 1 H-benzoimidazole-5-carboxylic acid and c/s-10-methoxy1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 55% of theory; LC (method 1): t_R = 2.67 min; Mass spectrum (EST): m/z =362 [M+H]⁺.

Example 9 ( 1 H-Benzoimidazol-5-ylH transi 0-methoxy-2,3,4a,5,6,10b-hexahydro-1 H-benzofflquinolin-4-vl)methanone

The title compound is preparedfrom 1H-benzoimidazole-5-carboxylic acid and irans-10methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 51% of theory; LC (method 2): t_R = 3.63 min; Mass spectrum (ESI⁺): m/z = 362 [M+HJ*.

Example 10 (1H-Benzoimidazol-5-vlHcis-10b-methvl-2,3,4a,5,6,10b-hexahvdro-1H-benzoif|quinolin-4-yQmethanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and an isomeric mixture of c/s-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline and trans-10b-methyl1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 yielding a mixture of Example 10 and Example 11 which is separated by HPLCon reversed phase (MeOH/H₂O/NH₄0H). Yield: 20% of theory; LC (method 2): t_R = 3.40 min; Mass spectrum (EST): m/z = 346 [M+H]⁺; ’H NMR (400 MHz, DMSO-d₆, mixture of 2 rotamersjd 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,

115

3H), 7.20-7.34 (m, 2H), 7.56 (broad s, 0.75H), 7.58 (broad s, 0.25H), 7.67 (broad s, 0.75H), 7.69 (broad s, 0.25H), 8.29 (s, 1H), 12.53-12.62 (m, 1H).

Example 11 ( 1 H-Benzoimidazol-5-yl)-( transi 0b-methyl-2,3.4a.5,6.10b-hexahydro-1 H-benzoif|quinolin-4-vl)methanone

The title compound is preparedfrom 1H-benzoimidazole-5-carboxylic acid and an isomeric mixture of c/s-10b-methyl-1,2,3,4,4a,5,6,1 Ob-octahydro-benzo[f]quinoline and trans-10b-methyl-

1,2,3,4,48,5,6,1 Ob-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 yielding a mixture of Example 10 and Example 11 which is separated by HPLC on reversed phase (MeOH/H₂O/NH₄OH). Yield: 15% of theory; LC (method 2): t_R = 3.26 min; Mass spectrum (EST): m/z - 346 [M+H]⁺.

Example 12 ( 1 H-Benzoimidazol-5-vl)-f trans-7-methoxy-2.3.4a.5,6,10b-hexahydro-1 H-benzofflquinolin-4-vQmethanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-7-methoxy1,2,3,4,43,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 49% of theory; LC (method 1): t_R = 2.68 min; Mass spectrum (EST): m/z = 362 [M+Hf.

Example 13 (1 H-Benzoimidazol-5-yl)-( c/s-1 Q-hydroxy-2.3,4a,5,6,10b-hexahydro-1H-benzo[flquinolin-4-yi)methanone

The title compound is prepared from (1H-benzoimidazol-5-yl)-(c/s-10-methoxy-2,3₁4a,5,6,10bhexahydro-1H-benzo[f]quinolin-4-yl)-methanone following a procedure analogous to that

117

Example 17 (1H-Benzoimidazol-5-vl)-(frans-9-hvdroxv-2.3.4a,5,6,10b-hexahydro-1H-benzo[flquinolin-4-vl)methanone

The title compound is prepared from (IH-benzoimidazol-S-ylHtrans-g-methoxy^î.S^a.S.e.lObhexahydro-1H-benzo[f]quinolin-4-yl)-methanone following a procedure analogous to that described in Example 7. Yield: 61% of theory; LC (method 1): t_R = 2.10 min; Mass spectrum (ESC): m/z = 348 [M+Hf.

Example 18 ( 1 H-Benzoimidazol-5-vl)-( trans-10-hydroxv-2,3.4a,5,6,1Ob-hexahydro-1 H-benzoiflquinolin-4-γΙ)methanone

The title compound is prepared from (1H-benzoimidazol-5-yl)-(/rans-10-methoxy-2,3,4a,5,6_r10bhexahydro-1H-benzo[f]quinolin-4-yl)-methanone following a procedure analogous to that described in Example 7. Yield: 14% of theory; LC (method 1): t_R = 2.33 min; Mass spectrum (EST): m/z = 348 [M+Hf.

Example 19 (1H-Benzoimidazol-5-vl)-(frans-7-hvdroxy-2,3,4a,5.6.10b-hexahvdro-1H-benzo[flquinolin-4-Yl)methanone

The title compound is prepared from (1H-benzoimidazol-5-yl)-(trans-7-methoxy-2,3,4a,5,6,10bhexahydro-1H-benzo[f]quinolin-4-yl)-methanone following a procedure analogous to that described in Example 7. Yield: 36% of theory; LC (method 1): t_R = 2.19 min; Mass spectrum (ESC): m/z = 348 [M+Hf.

116 described in Example 7. Yield: 68% of theory; LC (method 1): t_R = 2.25 min; Mass spectrum (EST): m/z = 348 [M+Hf.

Example 14 (1H-Benzoimidazol-5-vl)-(c/s-9-methoxv-2,3,4a,5,6.10b-hexahvdro-1H-benzo[f|quinolin-4-yl)methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-9-methoxy1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 69% of theory; LC (method 1): t_R = 2.55 min; Mass spectrum (EST): m/z = 362[M+H]\

Example 15 (1H-Benzoimidazol-5-vlHfrans-9-methoxv-2,3,4a,5,6,10b-hexahvdro-1H-benzofflquinolin-4-vDmethanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and trans-9-methoxy-

1,2,3,4,43,5,6,1 Ob-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 77% of theory; LC (method 1): t_R = 2.61 min; Mass spectrum (ESI⁺): m/z = 362 [M+H]*.

Example 16 (1 H-Benzoimidazol-5-yl)-(c/s-9-hydroxy-2.3,4a,5,6,10b-hexahydro-lH-benzo[flquinolin-4-yl)methanone

The title compound is prepared from (1H-benzoimidazol-5-yl)-(c/s-9-methoxy-2,3,4a,5,6, 10bhexahydro-1H-benzo[f]quinolin-4-yl)-methanone following a procedure analogous to that described in Example 7. Yield: 58% of theory; LC (method 1 ): t_R = 2.08 min; Mass spectrum (ESI⁺): m/z = 348 [M+H]⁴.

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Example 20 (1H-Benzoimidazol-5-vl)-(c/s-7,9-difluoro-2,3.4a,5,6,10b-hexahvdro-1H-benzo[f1auinolin-4-yl)methanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s-7,9-difluoro1,2,3,4,43,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 72% of theory; TLC: r_r = 0.37 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESI⁺): m/z = 368 [M+H]⁺.

Example 21 (1H-Benzoimidazol-5-vl)-(frans-7.9-difluoro-2.3.4a.5,6,10b-hexahydro-1H-benzofnquinolin-4-yl)methanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and trans-7,9difluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 70% of theory; TLC: r_f= 0.43 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESI⁺): m/z = 368 [M+H]⁺.

Example 22 (1H-Benzoimidazol-5-yl)-(c/s-8-methoxy-2,3,4a,5.6,10b-hexahydro-1 H-benzofflquinolin-4-yl)methanone

The tille compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s-8-methoxy1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 78% of theory; LC (method 1): t_R = 2.54 min; Mass spectrum (ESI⁺): m/z = 362 [Μ+ΗΓ.

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Example 23 ( 1 H-Benzoimidazoi-5-vl)-(trans-8-methoxy-2,3,4a.5,6,10b-hexahydro-1 H-benzoiflquinolin-4-νΠmethanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and frans-8-methoxy1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 71% of theory; LC (method 1 ): t_R = 2.61 min; Mass spectrum (ESI⁺): m/z = 362 [M+Hf.

Example 24 (1H-Benzoimidazol-5-vl)-(trar7s-8-hvdroxv-2,3,4a,5.6,10b-hexahvdro-1H-benzo[flquinolin-4-yl)methanone

The title compound is prepared from (1H-benzoimidazol-5-yl)-(/rans-8-methoxy-2,3,4a,5,6,10bhexahydro-1H-benzo[f]quinolin-4-yl)-methanone following a procedure analogous to that described in Example 7. Yield: 48% of theory; LC (method 1): t_R = 2.07 min; Mass spectrum (EST): m/z = 348 [M+Hf.

Example 25 ( 1 H-Benzoimidazol-5-yl)--(c/s-8-hvdroxv-2,3,4a.5,6₁10b-hexahvdro-1 H-benzo[flquinolin-4-vl)methanone

The title compound is prepared from (1H-benzoimidazol-5-yl)-(c/s-8-methoxy-2,3,4a,5,6,10bhexahydro-1H-benzo[f]quinolin-4-yl)-methanone following a procedure analogous to that described in Example 7. Yield: 39% of theory; LC (method 1): t_R = 2.03 min; Mass spectrum (ESI⁺): m/z = 348 [M+Hf.

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Example 26 (IH-Benzoimidazol-S-vD-drans-IO-fluoro-S.SAa.S.G.IOb-hexahvdro-IH-benzofflquinolin-â-vl)methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10-fluoro-

1,2,3,4,48,5,6,1 Ob-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 41% of theory; LC (method 1 ): t_R = 2.76 min; Mass spectrum (ESC*): m/z = 350 [M+H]⁴.

Example 27 (1H-Benzoimidazol-5-yl)-(c/s-10-fluoro-2,3,4a,5,6.10b-hexahydro-1H-benzo[flquinolin-4-vl)methanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s-10-fluoro1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 75% of theory; LC (method 1): t_R = 2.66 min; Mass spectrum (ESI⁺): m/z = 350 [M+H]⁺.

Example 28 (1H-Benzoimidazol-5-vl)-(frans-8-phenvl-2,3,4a,5,6,10b-hexahvdro-1H-benzo[flquinolin-4-yl)methanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and trans-8-phenyl1,2,3,4,4a,5,6,1 Ob-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 19% of theory; TLC: r_f = 0.43 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (EST): m/z = 408 [M+H]⁴.

121

Example 29 (1H-Benzoimidazoi-5-vl)-(c/s-8-phenyl-2,3.4a.5.6.10b-hexahydro-1H-benzo[flquinolin-4-vQmethanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-8-phenyl1,2,3,4,4a,5,6,1 Ob-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 29% of theory; TLC: r_f = 0.49 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESI⁺): m/z = 408 [M+Hf.

Example 30 (c/s-2.3.4a,5,6,10b-Hexahydro-1H-benzo[nauinolin-4-vl)-(1H-imidazo[4,5-blpyridin-5-yl)methanone

The title compound is prepared from 1H-imidazo[4,5-b]pyridine-5-carboxylic acid and c/s1,2,3,4,4a,5,6,1 Ob-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 57% of theory; LC (method 3): t_R = 2.10 min; Mass spectrum (ESC): m/z = 333 [M+H]⁺.

Example 31 (c/s-2,3,4a.5,6.10b-Hexahvdro-1H-benzorflquinolin-4-vD-imidazo[1,2-a1pvridin-6-yl-methanone

The title compound is prepared from imidazo[1,2-a]pyridine-6-carboxylic acid and cis1,2,3,4,4a,5,6,1 Ob-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 72% of theory; LC (method 3): t_R = 1.82 min; Mass spectrum (ESC): m/z = 335 [M+Hf.

122

Example 32

6-(c/s-2.3,4a,5.6.10b-Hexahydro-1H-benzo[f1quinoline-4-carbonvl)-3H-benzothiazol-2-one

The title compound is prepared from 2-oxo-2,3-dihydro-benzothiazole-6-carboxylic acid and c/s-

1,2,3,4,48,5,6,1 Ob-octahydra-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 56% of theory; LC (method 3): t_R = 2.32 min; Mass spectrum (ESP): m/z = 365 [M+H]⁺.

Example 33 c/s-4-(1 H-Benzoimidazole-5-carbonyl)-1.2,3.4,4a.5,6,10b-octahvdro-benzo[f]quinoline-8-

The title compound is prepared from 1H-benzoimidazole-5-carboxylicacid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester following a procedure analogous to that described in Example 1. Yield: 92% of theory; LC (method 1): t_R = 2.57 min; Mass spectrum (ESP): m/z = 390 [M+Hf.

Example 34 (1H-Benzoimidazol-5-yl}-(c/s-8-hvdroxvmethyl-2,3,4a.5,6,10b-hexahydro-lH-benzorflquinolin-4vl)-methanone

Lithium aluminum hydride (1 mol/L in tetrahydrofuran, 0.5 mL) is added to a solution of c/s-4(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester(150 mg) in tetrahydrofuran (6 mL) cooled to -10 °C. The resulting solution is stirred for 2 h while warming to ca. -3 °C in the cooling bath. Little water is added carefully and the resulting mixture is filtered over Celite. The filtrate is diluted with ethyl acetate and dried (MgSOA The solvent is evaporated and the residue is triturated with ethyl acetate and dried to

give the title compound as a solid. Yield: 56 mg (40% of theory); LC (method 1 ); t_R = 2.03 min; Mass spectrum (ESΓ): m/z = 362 [M+H]⁺.

Example 35 c/s-4-( 1 H-Benzoinnidazole-5-carbonvl)-1,2,3,4,4a,5,6,10b-octahvdro-benzo[flquinoline-8carboxylic acid

M aqueous NaOH solution (15 mL) is added to a solution of c/s-4-(1H-benzoimidazole-5carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester (1.60 g) in tetrahydrofuran (15 mL) at room température. The resulting solution is stirred at room température for 5 h. The solution is concentrated under reduced pressure and water (100 mL) is added to the residue. 1 M Aqueous hydrochloric acid (15 mL) is then added and the precipitate formed is separated by filtration. The precipitate is washed with water and diethyl ether and dried to afford the title compound as a solid. Yield: 1.24 g (80% of theory); LC (method 1 ): t_R = 2.09 min; Mass spectrum (ESI⁺): m/z = 376 [M+H]⁺.

Example 36 cfs-4-(1H-Benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahvdro-benzorf|quinoline-8carboxylic acid methylamide

O

The title compound is prepared from c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b20 octahydro-benzo[f]quinoline-8-carboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 1. Yield: 75% of theory; LC (method 1): t_R = 1.91 min; Mass spectrum (ESl·): m/z= 389 [M+Hf.

Example 37 c/s-4-(1H-Benzoimidazole-5-carbonvl)-1.2,3,4,4a,5,6,10b-octahydro-benzo[f|quinoline-8

carboxylic acid amide

O

124

The title compound is prepared from c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline-8-carboxylic acid and ammonia (28% in water) following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1 ): t_R = 1.78 min; Mass spectrum (ESl*): m/z = 375 [M+H]⁺.

Example 38 α$-4-(1Η-Β6ηζοίηΓ^3ζοΐ6-5·θ3ώοηνΙΜ,2.3.4.43,5,6,10ΰ·οοί3ΐΊνΰΓθ-06ηζοίίΚιυΪηοΙΐηθ-8-

The title compound is prepared from c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline-8-carboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 1. Yield: 20% of theory; LC (method 1): t_R = 2.08 min; Mass spectrum (ESl*): m/z = 403 [M+H]⁺.

Example 39 (1Η-Β6ηζοίηηΐό3ζοΙ-5-νΠ-ίο/5-8·(ρνπΌ^Ιπ6-1-θ3ώοηνΙ)-2,3·43·5.6,10^ΐΊ6Χ3ΐΊνάΓθ-1Ηbenzofflquinolin-4-vll-methanone

The title compound is prepared from c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline-8-carboxylic acid and pyrrolidine following a procedure analogous to that described in Example 1. Yield: 57% of theory; LC (method 1 ): t_R = 2.27 min; Mass spectrum (ESl·): m/z= 429 [M+Hf.

Example 40 (1H-Benzoimidazol-5-vl)-[cis-8-(morpholine-4-carbonyl)-2,3,4a,5.6.10b-hexahydro-1Hbenzoiflauinolin-4-yl]-methanone

The title compound is prepared from c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline-8-carboxylic acid and morpholine following a procedure analogous

125 to that described in Example 1. Yield: 63% of theory; LC (method 1 ): t_R = 2.05 min; Mass spectrum (Ε3Γ): m/z = 445 [M+Hf.

Example 41 (1H-Benzoimidazol-5-viyrc/s-8-(1-hvdroxy-1-methvl-ethvn-2.3.4a,5,6,10b-hexahvdro-1Hbenzo[f]quinolin-4-yl1-methanone

MeMgBr [1.4 mol/L in toluene/tetrahydrofuran (3:1), 1.1 mL] is added to a solution of c/s-4-(1Hbenzoimidazole-5Carbonyl)-1,2,3,4,4a,5,6,10b-octahydrO'benzo[f]quinoline-8-carboxylic acid methyl ester (200 mg) in tetrahydrofuran (4 mL) cooled to -10 °C. The resulting solution is stirred with cooling for 3 h before another portion of MeMgBr [1.4 mol/L in toluene/tetrahydrofuran (3:1 ), 0.8 mL] is added. The solution is warmed in the cooling bath to room température overnight. The solution is poured into ice-cold water and the resulting mixture is filtered over Celite. The filtrate is diluted with ethyl acetate and the organic phase is separated, washed with brine, and dried (MgSO₄). The solvent is evaporated and the residue is chromatographed on silica gel [dichloromethane/ (dichloromethane/methanol/7 M NH₃ in methanol 50:48:2) 88:12->50:50] to furnish the title compound as a colorless solid. Yield: 59 mg (29% of theory); LC (method 1 ): t_n = 2.27 min; Mass spectrum (ESI*): m/z = 390 [M+H]⁺.

Example 42 c/s-4-(1H-Benzoimidazole-5-carbonvl)-1,2,3,4,4a.5,6,10b-octahvdro-benzo[f]quinoline-8carbonitrile

Trifluoroacetic anhydride (0.4 mL) is added to a solution of c/s-4-(1 H-benzoimidazole-5carbonylj-I^.S^^a.S.G.IOb-octahydro-benzoffiquinoline-B-carboxylic acid amide (140 mg) and triethylamine (0.6 mL) in dichloromethane (4 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room température for 3 h. Another portion of trifluoroacetic anhydride (0.4 mL) and triethylamine (0.6 mL)are then added and stirring is continued at 35 °C overnight. The solution is diluted with dichloromethane and washed with water and brine. After drying (MgSO₄), the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 20:1—* 1:1 ) to furnish the title compound as a yellowish solid. Yield: 50 mg (38% of theory); Mass spectrum (ESI‘): m/z = 357 [M+H]*.

126

Example 43 të-Amino-benzothiazol-G-vlHc/s-Z.S^a.SO.IOb-hexahydro-IH-benzorflquinolin^-vD-methanone

The title compound is prepared from 2-amino-benzothiazole-6-carboxylic acid and cîs1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 24% of theory; LC (method 4): t_R = 1.80 min; Mass spectrum (ESI⁺): m/z = 364 [M+H]\

Example 44 (c/s-2.3.4a.5.6.10b-Hexahvdro-1H-benzorf|quinolin-4-vlM3-hvdroxv-4-methvl-phenyl)methanone

The title compound is prepared from 3-hydroxy-4-methyl-benzoic acid and cis1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 77% of theory; LC (method 4): t_R = 2.00 min; Mass spectrum (EST): m/z = 322 [M+H]\

Example 45 (3-Amino-4-methoxy-phenvl)-(c/'5-2,3,4a,5,6,10b-hexahvdro-1H-benzofflquinolin-4-vl)methanone

The title compound is prepared from 3-amino-4-methoxy-benzoic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 63% of theory; LC (method 4): t_R = 1.79 min; Mass spectrum (EST): m/z = 337 [M+H]⁺.

127

Example 46 (c/'s-2,3.4a,5,6,10b-Hexahvdro-1H-benzoff]quinolin-4-vO-(2-methvl-1H-indol-5-yl)-methanone

The title compound is prepared from 2-methyl-1H-indole-5-carboxylic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline foilowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 46% of theory; LC (method 4): t_R = 2.03 min; Mass spectrum (EST): m/z = 345 [M+H]*.

Example 47

5-(c/'s-2,3,4a,5,6JOb-Hexahydro-1H-benzorflquinoline-4-carbonvl)-1-methvl-1,3-dihydrobenzoimidazol-2-one

The title compound is prepared from 1-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5carboxylie acid and c/s-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline foilowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate is used]. Yield: 15% of theory; LC (method 4): t_R = 1.92 min; Mass spectrum (ESI*): m/z = 362 [M+H]*.

Example 48 (c/s-2,3,4a,5.6,1 Ob-Hexahydro-1 H-benzo[f]quinolin-4-yl)-( 1 H-indol-6-yl)-methanone

The tille compound is prepared from 1 H-indole-6-carboxylic acid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline foilowing a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield:

27% of theory; LC (method 4): t_R = 2.01 min; Mass spectrum (ESI*): m/z = 331 [M+H]*.

128

Example 49

5-(c/s-2,3,4a,5,6,10b-Hexahydro-1H-benzo[f]quinoline-4-carbonyl)-1,3-dihydro-indol-2-one

The title compound is prepared from 2-oxo-2,3-dihydro-1 H-indole-5-carboxylic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolinefollowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotnazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 25% of theory; LC (method 4): t_R = 1.90 min; Mass spectrum (ESI⁺): m/z = 347 [M+Hf,

Example 50

6-(c/s-2,3,4a,5,6.10b-Hexahvdro-1H-benzofflquinoline-4-carbonyl)-1,3-dihydro-indol-2-one

The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid and cis1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 12% of theory; LC (method 4): t_R = 1.90 min; Mass spectrum (ESI⁺): m/z = 347 [M+H]⁺.

Example 51 (c/s-2,3,4a,5,6.10b-Hexahydro-1H-benzoff]quinolin-4-vl)-(1-methvl-1 H-benzoimidazol-5-yl)methanone

The title compound is prepared from 1 -methyl-1 H-benzoimidazole-5-carboxylic acid and cis1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 83% of theory; LC (method 5): t_R = 1.05 min; Mass spectrum (ESl·): m/z = 346 [M+Hf.

129

Example 52 (cis-2.3,4a,5,6,10b-Hexahydro-1H-benzo[f]quinolin-4-yl)-(1-methyl-1H-benzotriazol-5-vDmethanone

N N'

The title compound is prepared from 1-methyl-1H-benzotriazole-5-carboxylic acid and cis~ 1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 53% of theory; LC (method 4): t_R = 1.90 min; Mass spectrum (EST*): m/z = 347 [M+Hf.

Example 53 (c/'s-7-Methoxy-2,3,4a,5,6,10b-hexahvdro-1 H-benzorf]quinolin-4-vD-( 1 -methvl-1 H-indol-3-yl)methanone

The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and c/s-7-methoxy1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 82% of theory; LC (method 1): t_R = 4.39 min; Mass spectrum (ESI⁺): m/z = 375 [M+Hf.

Example 54 (3-Fluoro-4-hvdroxv-phenvD-(c/s-2.3.4a,5.6.10b-hexahydro-1 H-benzofflquinolin-4-vOmethanone

OH

The title compound is prepared from 3-fluoro-4-hydroxy-benzoic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used}. Yield: 40% of theory; LC (method 4): t_R = 1.94 min; Mass spectrum (ESI⁺): m/z = 326 [M+Hf.

130

Example 55 (c/s-2,3,4a,5.6,10b-Hexahvdro-1H-benzoffîquinolin-4-vl)-(2-methvl-3H-benzoimidazol-5-vl)methanone

The title compound is prepared from 2-methyl-3H-benzoimidazole-5-carboxylic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used] and isolated as its trifluoroacetic acid sait. Yield: 59% of theory; LC (method 4): t_R = 1.64 min; Mass spectrum (ESI⁺): m/z = 346 [M+Hf.

Example 56 (4-Amino-3-chloro-phenyl )-(c/s-2,3,4a,5.6,10b-hexahydro-1 H-benzofflquinolin-4-vlÎ-methanone

The title compound is prepared from 4-amino-3-chloro-benzoic acid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazo!-1-yl)-1_l1₁3,3-tetramethyluronium hexa-fiuorophosphate is used]. Yield: 52% of theory; LC (method 4): t_R = 1.99 min; Mass spectrum (ESI⁺): m/z = 341/343 (Cl) [M+H]⁺.

Example 57 (2-Amino-3H-benzoimidazoÎ-5-yl )-(cis-2,3,4a,5,6.10b-hexahvdro-1 H-benzofflquinolin-4-vl)methanone

The title compound is prepared from 2-amino-3H-benzoimidazole-5-carboxylic acid and cis1,2,3,4,4a,5,6,10b-octahydro-benzo[f|quÎnolrne following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used] and isolated as its trifluoroacetic acid sait. Yield: 58% of theory; LC (method 4): t_R = 1.66 min; Mass spectrum (ESI⁺): m/z = 347 [Μ+ΗΓ.

131

Example 58

Benzothiazol-6-vl-(c/s-2,3,4a,5.6,10b-hexahvdro-1H-benzo|flquinolin-4-v0-methanone

The title compound is prepared from benzothiazole-6-carboxylic acid and 0/5-1,2,3,4,48,5,6,10^ octahydro-benzo[f]quinoline following a procedure analogousto that described in Example 1 [2(Z-aza-IH-benzotriazol-l-yO-I.I.S.a-tetramethyluronium hexa-fluorophosphate is used]. Yield: 24% of theory; LC (method 4): t_R = 1.97 min; Mass spectrum (ESI⁺): m/z = 349 [M+H]*.

Example 59 (4-Chloro-3-hvdroxv-phenyl )-(c/s-2,3,4a. 5.6,1 Ob-hexahydro-1 H-benzoff|quinolin-4-yl)methanone

The title compound is prepared from 4-chloro-3-hydroxy-benzoic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolinefollowing a procedure analogousto that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 46% of theory; LC (method 4): t_R = 1.99 min; Mass spectrum (EST): m/z = 342/344 (Cl) [M+H]⁺.

Example 60 (c/s-2,3,4a,5.6,1Qb-Hexahvdro-1H-benzorf1quinolin-4-vl)-(3H-imidazo]4,5-blpvridin-5-yl)methanone

The tille compound is prepared from 3H-imidazo[4,5-b]pyridine-5-carboxylic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used] and isolated as ils trifluoroacetic acid sait. Yield: 40% of theory; LC (method 4): t_R = 1.83 min; Mass spectrum (EST): m/z = 333 [M+Hf.

132

5-(c/s-2,3.4a,5,6,10b-Hexahvdro-1H-benzo[f|quinoline-4-carbonyl)-1,3-dihydro-benzoimidazol-2Example 61 one

The title compound is prepared from 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and c/s-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 14% of theory; LC (method 4): t_R = 1.89 min; Mass spectrum (ESI*): m/z = 348 [M+H]⁴.

Example 62 (c/s-2,3,4a,5,6,10b-Hexahvdro-1 H-benzo[flquinolin-4-yl)-(3-methyl-3H-benzoimidazol-5-vl)methanone

The title compound is prepared from 3-methyl-3H-benzoimidazole-5-carboxylic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1_l3,3-tetramethyluronium hexafluorophosphate is used], Yield: 91% of theory; LC (method 4): t_R = 1.65 min; Mass spectrum (ESI⁴): m/z = 346 [M+H]⁴.

Example 63 (3-Amino-4-fluoro-phenyl)-(c/s-2,3,4a,5,6,10b-hexahvdro-1H-benzo[flquinoiin-4-vl)-methanone

NH.

The title compound is prepared from 3-amino-4-fluoro-benzoic acid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used). Yield: 47% of theory; LC (method 4): t_R = 1.94 min; Mass spectrum (ESI⁴): m/z = 325 [M+H]⁴.

133

Example 64 (c/s-2,3,4a,5,6_l10b-Hexahvdro-1H-benzo[f1quinolin-4-yl)-imidazo[1.2-a1pyridin-7-yl-methanone

The title compound is prepared from imidazo[1,2-a]pyridine-7-carboxylic acid and c/sI.Z.S^/a.S.ejOb-octahydro-benzo^quinoline foliowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-y!)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 95% of theory; LC (method 4): t_R = 1.59 min; Mass spectrum (ESl*): m/z = 332 [M+Hf.

Example 65 (c/$-2.3.4a.5,6.10b-Hexahvdro-1H-benzofflquinolin-4-vl)-(1H-indazol-5-yl)-methanone

The title compound is prepared from 1 H-indazole-5-carboxylic acid and 0/5-1,2,3,4,48,5,6,10boctahydro-benzo[f]quinoline foliowing a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazol-1“yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 39% of theory; LC (method 4): t_R = 1.94 min; Mass spectrum (ESl·): m/z = 332 [M+Hf.

Example 66

5-(c/s-2,3,4a,5.6,10b-Hexahvdro-1H-benzo[f]quinoline-4-carbonvl)-3,3-dimethyl-1,3-dihvdro-

The title compound is prepared from 3,3-dimethyt-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid and cÀs-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline foliowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 19% of theory; LC (method 4): t_R = 1.95 min; Mass spectrum (ESl*): m/z = 375 [M+Hf.

134

Example 67 (4-Amino-phenvl)-(c/s-2.3,4a,5,6,10b-hexahvdro-1H-benzo[flauinolin-4-yl)-methanone

The title compound is prepared from 4-amino-benzoic acid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 66% of theory; LC (method 4): t_R = 1.81 min; Mass spectrum (EST): m/z = 307 [M+Hf.

Example 68 (c/s-2,3,4a,5,6,10b-Hexahvdro-1H-benzoiflquinolin-4-yl)-(4-hvdroxv-phenyl)-methanone

The title compound is prepared from 4-hydroxy-benzoic acid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 28% of theory; LC (method 4): t_R = 1.93 min; Mass spectrum (ESI⁺): m/z = 308 [M+Hf.

Example 69 (ο/3-2.3.43,5,6,106-Η6Χ3ΐΊν0Γθ·1Η436ηζο[ί|ουίηοΙΐη-4-νΙΜ1Η-ίη8οΙ-5-νΟ-ΠΊ61ΐΊ3ηοη6

The title compound is prepared from 1H-indole-5-carboxylicacid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 51% of theory; LC (method 4): t_R = 1.99 min; Mass spectrum (EST): m/z = 331 [M+Hf.

Example 70 (c/s-2,3,4a.5,6,10b-Hexahydro-1H-benzo[f1quinolin-4-vl)-(1H-indol-3-vl)-methanone

The title compound is prepared from 1H-indole-3-carboxylic acid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-

135 (7-aza-1 H-benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 43% of theory; LC (method 4): t_R = 2.01 min; Mass spectrum (ESl*): m/z = 331 [M+H]*.

Example 71 (3,5-Dichloro-4-hvdroxv-phenvl)-fc/s-2,3,4a,5,6,10b-hexahvdrO“1H-benzo[flquinolin-4-yl)methanone

The title compound is prepared from 3,5-dichloro-4-hydroxy-benzoic acid and cis1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 26% of theory; LC (method 4): t_R = 2.03 min; Mass spectrum (ESl*): m/z = 376/378/380 (2 Cl) [M+H]*.

Example 72 (1H-Benzotriazol-5-vl)-(c/s-2,3,4a,5,6,10b-hexahvdro-1H-benzo[flquinolin-4-yl)-methanone

The title compound is prepared from 1 H-benzotriazole-5-carboxylic acid and cis1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1 H-benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 58% of theory; LC (method 4): t_R = 1.90 min; Mass spectrum (EST): m/z = 333 [M+H]*.

Example 73 (c/s-2,3,4a,5.6.10b-Hexahvdro-1H-benzo[f]quinolin-4-vl)-(1-methvl-1H-indol-3-vl)-methanone

The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1 H-benzotriazol-1-yl )-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 28% of theory; LC (method 4): t_R = 2.05 min; Mass spectrum (ESl*): m/z = 345 [M+H]*.

136

Example 74 (c/s-2,3,4a,5,6,10b-Hexahydro-1 H-benzofflquinolin-4-yl)-(3-hvdroxy-4-nnethoxy-phenyl)methanone

The title compound is prepared from 3-hydroxy-4-methoxy-benzoic acid and c/sI.Z.SAAa.S.ô.lOb-octahydro-benzoffiquinolinefollowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 42% of theory; LC (method 4): t_R = 1.93 min; Mass spectrum (EST): m/z = 338 [M+Hf.

Example 75 (3-Chloro-4-hydroxy-phenvl)-(c/s-2,3.4a.5.6,1 Ob-hexahvdro-1H-benzo|flquinolin-4-yl)methanone

The title compound is prepared from 3-chloro-4-hydroxy-benzoic acid and c/s1,2,3,4,48,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 42% of theory; LC (method 4): t_R = 1.98 min; Mass spectrum (ESI⁺): m/z =342/344 (CI) [M+H]⁺.

Example 76 (3-Amino-4-chloro-phenyl)-(c/s-2.3,4a,5,6,10b-hexahydro-1H-benzo]f]quinolin-4-vl)-methanone

The title compound is prepared from 3-amino-4-chloro-benzoic acid and c/s-1,2,3,4,48,5,6,10boctahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 46% of theory; LC (method 4): t_R = 1.28 min; Mass spectrum (ESI⁺): m/z = 341/343 (Cl) [M+H]⁺.

137

Example 77 (3-Amino-4-methyl-phenvl)-(c/s-2.3,4a,5,6.10b-hexahvdro-1H-benzofflquinolin-4-yl)-methanone

The title compound is prepared from 3-amino-4-methyl-benzoîc acid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f|quinoline following a procedure analogous to that described in Example 1 [2(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used], Yield: 95% of theory; LC (method 4): t_R = 1.85 min; Mass spectrum (ESΓ): m/z = 321 [M+H]⁺.

Example 78 t4-Amino-3-methoxY-phenvl)-(c/'s-2,3,4a,5_<6,10b-hexahvdro-1H-benzo[flquinolin-4-yl)methanone

The title compound is prepared from 4-amino-3-methoxy-benzoic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 64% of theory; LC (method 4): t_R = 1.84 min; Mass spectrum (ESI⁺): m/z = 337 [M+Hf

Example 79 (4-Amino-3-fiuoro-phenvl)-(c/s-2,3,4a,5,6,10b-hexahydro-1H-benzo[f|quinolin-4-vD-methanone

The title compound is prepared from 4-amino-3-fluoro-benzoic acid and c/s-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2(7-aza-1H-benzolriazol-1-yl)-1,1_l3,3-tetramethyluronium hexa-fluorophosphate is used], Yield: 64% of theory; LC (method 4): t_R = 1.94 min; Mass spectrum (EST): m/z = 325 [M+H]⁺.

Example 80

6-(c/s-2.3.4a,5,6,10b-Hexahvdro-1H-benzo[f|quinoline-4-carbonylMH-quinoxalin-2-one

138

The title compound is prepared from 2-oxo-1,2-dihydro-quinoxaline-6-carboxylic acid and c/s1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 19% of theory; LC (method 4): t_R = 1.92 min; Mass spectrum (EST): m/z = 362 [M+Hf.

Example 81 (c/s-7-Hvdroxy-2.3,4a,5.6.10b-hexahvdro-1H-benzoFflquinolin-4-yl)-(1-methvl-1H-indol-3-vll· methanone

The title compound is prepared from (c/s-7-methoxy-2,3,4a,5,6,10b-hexahydro-1Hbenzo[f]quinolin-4-yl)-(1-methyl-1H-indol-3-yl)-methanone following a procedure analogous to that described in Example 7. Yield: 10% of theory; LC (method 1 ): t_R = 3.58 min; Mass spectrum (ESf): m/z = 361 [M+Hf.

Example 82 (1 H-Benzoimidazol-5-yl)-f c/s-8-benzyl-2,3,4a,5,6,10b-hexahvdro-1H-benzo|f]quinolin-4-vlÎmethanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and a mixture of c/s-

8-benzyl-1,2,3,4,43,5,6,1 Ob-oclahydro-benzo[f]quinoline and c/s-8-cyclohexylmethyl1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (ca. 30:70) following a procedure analogous to that described in Example 1 and separated from the also formed Example 83 by HPLC on reversed phase (MeOH/H₂O/NH₄OH). Yield: 12% of theory; LC (method 1): t_R = 3.35 min; Mass spectrum (ESI⁺): m/z = 422 [M+H]⁺.

Example 83 (1H-Benzoimidazol-5-vl)-(c/s-8-cvclohexylmethyl-2,3.4a.5.6,10b-hexahydro-1H-benzoff|quinolin-

139

The title compound is prepared from IH-benzoimidazole-5-carboxylic acid and a mixture of c/s8-benzyl-1,2,3,4,4a,5,6,Wb-oclahydro-benzo[f|quinoline and c/s-8-cyclohexylmethyl1,2,3,4,4a,5,6_t10b-octahydro-benzo[f]quinoline (ca. 30:70) following a procedure analogous to that described in Example 1 and separated from the also formed Example 82 by HPLC on reversed phase (MeOH/H₂0/NH₄0H). Yield: 50% of theory; LC (method 1 ): t_R = 4.06 min; Mass spectrum (EST): m/z = 428 [M+Hf

Example 84 (1 H-Benzoimidazol-S-yD-fc/s-IO-hvdroxvmethyl^.SAa.S.e.lOb-hexahydro-IH-benzofflquinolin4-yl)-methanone

The title compound is prepared from c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10boctahydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Example 34. Yield: 46% of theory; TLC: r_r = 0.27 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (ESC): m/z = 362 [M+H]*.

Example 85 (1H-Benzoimidazol-5-ylÎ-[cis-10-(4-methoxv-benzvlÎ-2,3,4a,5.6.10b-hexahvdro-1HbenzoÎflquinolin-4-yll-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-10-(4methoxy-benzyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 17% of theory; LC (method 1): t_R = 3.21 min; Mass spectrum (Ε5Γ): m/z = 452 [M+Hf.

Example 86 (1 H-Benzoimidazol-5-yl)-(cjs-6,6-dimethvl-2,3,4a,5.6,10b-hexahydro-1 H-benzofflquinolin-4-yl)methanone

140

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s-6,6-dimethyl1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): t_R = 2.84 min; Mass spectrum (ESI⁺): m/z = 360 [M+Hf.

Example 87 c/s-4-(1H-Benzoimidazole-5-carbonvl)-1,2,3,4,4a,5,6,10b-octahvdro-benzo[flquinoline-10carboxylic acid amide

The title compound is prepared from c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10boctahydro-benzo[f]qurnoline-10-carboxylic acid and ammonia (7 mol/L in methanol) following a procedure analogous to that described in Example 1. Yield: 58% of theory; TLC: η = 0.24 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1 ); Mass spectrum (EST): m/z = 375 [M+H]⁺.

Example 88 c/s-4-(1H-Benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahvdro-benzoif1quinoline-10carbonitrile

Thetitlecompoundis preparedfrom c/s-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6, 10boctahydro-benzo[f]quinoline-10-carboxylic acid amide following a procedure analogous to that described in Example 42. Yield: 66% of theory; TLC: r_f = 0.45 (silica gel, CH₂CI₂/ MeOH/32% aqueous NH₃ 90:10:1); Mass spectrum (Ε3Γ): m/z = 357 [M+Hf.

Example 89 ( 1 H-Benzoimidazol-5-vl)4c/s-8-(4-methoxy-phenoxv)-2,3,4a,5,6₁10b-hexahydro-1 Hbenzorf|quinolin-4-yll-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-8-(4methoxy-phenoxy)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 72% of theory; LC (method 1): t_R = 3.16 min; Mass spectrum (EST): m/z = 454 [M+Hf.

141

Example 90 trans-4-( 1 H-Benzoimidazole-5-carbonyl)-1,2,3.4,4a,5,6.10b-octahydro-benzo[flquinoline-9carbonitrile

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline'9-carbonitrile following a procedure analogous to that described in Example 1. Yield: 18% of theory; LC (method 1): t_R = 2.49 min; Mass spectrum (ESP): m/z = 357 [M+H]*.

Example 91 c/s-4-(1H-Benzoimidazole-5-carbonvl)-1,2,3.4,4a,5,6.10b-octahvdro-benzoff|quinoline-9carbonitrile

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s1,2,3,4,48,5,6,10b-octahydro-benzo[f]quinoline-9-carbonitrile following a procedure analogous to that described in Example 1. Yield: 64% of theory; LC (method 1); t_R = 2.40 min; Mass spectrum (ESP): m/z = 357 [M+Hf.

Example 92 ( 1 H-Benzoïrnidazol-S-yD-ic/s-l 0-(6-methyl-pyridazin-3-vloxv)-2,3,4a,5.6.10b-hexahvdro-1 Hbenzoff|quinolin-4-vll-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylicacid and c/s-10-(6-methylpyridazin-3-yloxy)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 17% of theory; LC (method 1 ): t_R = 2.39 min; Mass spectrum (ESP): m/z = 440 [M+H]⁺.

142

Example 93 (1H-Benzoimidazol-5-vl)-(c/s-2,3,4,4a,9,9a-hexahvdro-indeno[2.1-blpyridin-1-vn-methanone

The tille compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis2,3,4,4a_l9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 60% of theory; LC (method 1): t_R = 2.44 min; Mass spectrum (ESl*): m/z = 318 [M+Hf; ¹H NMR (400 MHz, DMSO-d₆, mixture of rotamers) d 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 signais, 2H), 7.07-7.30 (m, 5H), 7.54-7.62 (m, 1 H), 7.64-7.72 (m, 1H), 8.29(s, 1H), 12.51-12.65 (m, 1H).

Example 94 (1H-Benzoimidazol-5-vl)-l(4a-/?.9a-S)-2.3.4,4a,9,9a-hexahvdro-indenof2.1-b1pyridin-1-vllmethanone

The title compound is obtained by chromatographing a racemic mixture of (1H-benzoimidazol-5yl)-(c/s-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-methanone (100 mg) on chiral phase (column: 1x ASH 250 x 10 mm, 250 pm; mobile phase: methanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow rate: 10 mL/min). Yield: 47 mg; LC (method as above on chiral phase): t_R = 2,35 min; Mass spectrum (EST): m/z = 318 [M+H]*; for ¹H NMR see Example 94.

Example 95 (1H-Benzoimidazol-5-vl)-[(4a-S,9a-R)-2.3,4,4a, 9,9a-hexahvdro-indenof2.1-b1pvridin-1-vl1methanone

The title compound is obtained by chromatographing a racemic mixture of (1H-benzoimidazol-5yl)-(c/s-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-methanone (100 mg) on chiral phase (column: 1x ASH 250 x 10 mm, 250 pm; mobile phase: methanol containing 0.2%

143 diethylamine/sc carbon dioxide 25:75; flow rate: 10 mL/min). Yield: 44 mg; LC (method as above on chiral phase): îr = 1.98 min; Mass spectrum (EST): m/z = 318 [M+Hf; for ¹H NMR see Example 94.

Example 96

4-(c/s-2,3,4.4a,9.9a-Hexahvdro-indeno[2,1-b]pvridine-1-carbonvD-benzamide

The title compound is prepared from terephthalamic acid and c/s-2,3,4,4a,9,9a-hexahydro-1Hindeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 50% of theory; LC (method 1): t_R = 3.07 min; Mass spectrum (ESf): m/z = 321 [M+Hf.

Example 97 ca. 1:1 mixture of cis-(1H-Benzoimidazol-5-vlM6-bromo-2.3.4.4a,9,9a-hexahvdro-indenor2,1blpyridin-1 -vl)-methanone and c/s-( 1 H-Benzoimidazol-5-vl)-(7-bromo-2.3.4,4a,9,9a-hexahydroindeno[2.1 -blpyridin-1 -vl)-methanone

N />

N

A part of the impure mixture obtained in Step 4 of Intermediates 34 and 35 is purified by HPLC on reversed phase (acetonitrile/water) to give a ca. 1:1 mixture of the title compounds. Mass spectrum (ESI⁺): m/z = 396/398 (Br) [M+Hf.

Example 98 c/s-1 -( 1 H-Benzoimidazole-5-carbonvl)-2.3.4,4a,9,9a-hexahvdro-1 H-indenof2,1 -blpyridine-6carboxylic acid

The title compound is prepared from a ca. 1:1 mixture of c/s-1-(1H-benzoimidazole-5-carbonyl)2,3,4,4a_l9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxylic acid methyl ester and c/s-1-(1Hbenzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1 - b] pyridine -7-carboxylic acid methyl ester following a procedure analogous to that described in Example 35 and

144 separated from Example 99 by HPLC on reversed phase (MeCN/H₂O). Yield: 4% of theory: Massspectrum (EST): m/z = 362 [M+Hf.

Example 99 c/s-1-(1H-Benzoimidazole-5-carbonvl)-2.3.4,4a.9.9a-hexahvdro-1H-indeno[2,1-blpyridine-7carboxylic acid

The title compound is prepared from a ca. 1:1 mixture of c/s-1-(1H-benzoimidazole-5-carbonyl)2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1-b]pyridine-6-carboxylic acid methyl ester and c/s-1-(1Hbenzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine -7-carboxylic acid methyl esterfollowing a procedure analogous to that described in Example 35 and separated from Example 98 by HPLC on reversed phase (MeCN/H₂O). Yield: 5% of theory; Mass spectrum (EST): m/z = 362 [M+Hf.

Example 100 c/s-1-(1H-Benzoimidazole-5-carbonvl)-2.3.4,4a.9.9a-hexahvdro-1H-indenof2,1-blpvridine-6carboxylic acid amide

The title compound is prepared from c/s-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine-6-carboxylic acid and ammonia (0.5 mol/L in 1,4-dioxane) following a procedure analogous to that described in Example 1. Yield: 64% of theory; LC (method 1): t_R = 1.64min; Massspectrum (EST): m/z = 361 [M+H]*.

Example 101 c/s-1-(1H-Benzoimidazole-5-carbonyl 1-2,3,4,4a,g.ga-hexahvdro-IH-indenofë.l-blpyridine-?-

145

The title compound is prepared from c/s-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine-7-carboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 1. Yield: 19% of theory; LC (method 1): t_fi = 1.86 min; Mass spectrum (ESC): m/z = 375 [M+H]⁺.

Example 102 (cÂs-2,3.4.4a,9.9a-Hexahvdro-indenoÎ2.1-blpvridin-1-vl)-(1H-imidazof4,5-b1pvridin-5-vlÎmethanone

N />

N

The title compound is prepared from 1H-imidazo[4,5-b]pyridine-5-carboxylic acid and c/s2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1“b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,34etramethyluronium hexafluorophosphate is used]. Yield: 74% of theory; LC (method 3): t_R = 2.10 min; Mass spectrum (ESI⁺): m/z = 319 [M+H]*.

Example 103

6-(c7s-2.3,4.4a_l9.9a-Hexahvdro-indenof2,1-blpyridine-1-carbonvl)-3H-benzothiazol-2-one

The title compound is prepared from 2-oxo-2,3-dihydro-benzothiazole-6-carboxylic acid and c/s2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 74% of theory; LC (method 3): t_R = 2.28 min; Mass spectrum (ESC): m/z= 351 [M+H]*.

Example 104 (c/s-2,3,4.4a.9.9a-Hexahvdro-indenor2.1-blpvridin-1-vll-imidazoÎ1.2-alpvridin-6-yl-methanone

The title compound is prepared from imidazo[1,2-a]pyridine-6-carboxylic acid and c/s2,3,4,4a,9.9a-hexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3’tetramethyluronium hexa-

146 fluorophosphate is used], Yield: 85% of theory; LC (method 3): t_R = 1.81 min; Mass spectrum (ESI*): m/z =318 [M+H]*.

Example 105 ( 1 H-Benzoimidazol-5-vl)-(trans-10b-ethyl-2,3,4a,5,6,1 Qb-hexahydro-1 H-benzoiflauinolin-4-yl)methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10b-ethyl1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline foilowing a procedure analogous to that described in Example 1. Yield: 44% of theory; TLC; r_f = 0.42 (silica gel, CH₂CI₂/MeOH/32% aqueous NH₃ 90:10:1 ); Mass spectrum (ESI*): m/z = 360 [M+H]*.

Example 106 c/s-1 -(1H-8enzoimidazole-5-carbonvl)-2.3.4.4a.9.9a-hexahydro-1H-indeno[2.1-blpvridine-6carbonitrile

The title compound is prepared from cis-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine-6-carboxylic acid amide foilowing a procedure analogous to that described in Example 42. Yield: 64% of theory; LC (method 1): t_R = 2.33 min; Mass spectrum (Ε3Γ): m/z = 343 [M+H]*; for ’H NMR see Example 108.

The title compound is also obtained as follows:

Aflask charged with a stir bar, zinc cyanide (0.32 g), trifluoromethanesulfonic acid c/s-1 -(1trifluoromethanesulfonyl-1H-benzoimidazole-5-carbonyl )-2,3,4,4a,9,9a-hexahydro-1Hindeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment at N-1 or N-3 of the benzimidazole, 1.08g), and N,N-dimethylformamide (5 mL) is sparged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0)(0.31 g) is then added and the resulting mixture is heated to 100 °C and stirred at this température for 2 h. After cooling to room température, 1 -hydroxybenzotriazole hydrate (0.45 g) and water (1.5 mL) are added and stirring is continued at room température for 3 h. Ethyl acetate, lîttle methanoi, and saturated aqueous Na_zCC>3 solution are added and the mixture ïs filtered over Celite. The aqueous phase of the filtrate is separated and neutralized with 2 M aqueous citric acid and extracted with ethyl acetate. The organic phases are combined and washed with brine and dried (Na₂SO₄). The solvent is evaporated and the residue is chromatographed on silica gel

147 (dichloromethane/methanol 96:4-»90:10) to give the title compound as a solid. Yield: 0.42 g (68% of theory).

Example 107 (4a-R9a-S)-1 -(1H-Benzoimidazole-5-carbonyl )-2,3,4,4a,9,9a-hexahydro-1H-indenof2,1blpvridine-6-carbonitnle

The title compound is obtaîned by chromatographing a racemic mixture of c/s-1-(1Hbenzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1 -b]pyridine-6-carbonitrile (600 mg)on chiral phase (SFC; column: Daicel ASH 250 x 20 mm, 5 pm; mobile phase: isopropanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow rate: 90 mL/min; 40 °C). Yield: 112 mg; LC (préparative SFC on chiral phase as above): t_R = 8.45 min; Mass spectrum (ESI⁺): m/z = 318 [M+H]*; for ’H NMR see Example 108.

Alternatively, the compound is obtaîned from (1H-benzoimidazol-5-ylH(4a-R,9a-S)-6-bromo2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl]-methanonefollowing a procedure analogous to that described in Example 148. Yield: 26% of theory.

Alternatively, the title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and (4aR,9a-S)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile following a procedure analogous tothat described in Example 1. Yield: 81% of theory.

The title compound is also prepared as follows:

1-Hydroxybenzotriazole monohydrate (138.0 g), 1-(dimethylaminopropyl)-3-ethylcarbodîimide hydrochloride (172.7 g), and triethylamine (262 mL) are added in the given order to a solution of

H-benzoimidazole-5-carboxylic acid (146.1 g) and (4a-/?,9a-S)-2,3,4,4a,9,9a-hexahydro-1Hindeno[2,1-b]pyridine-6-carbonitrile (149.0 g) in N,N-dimethylformamide (600 mL) at room température. The mixture is stirred at room température overnight. Water (1.5 L) and dichloromethane (1.5 mL) are added and the organic phase is separated and the aqueous phase is extracted with dichloromethane (750 mL). The combined organic phase is washed with mol/L aqueous NaOH solution (750 mL), 2 mol/L aqueous hydrochloric acid (630 mL), and water (3x 1.5 L) and concentrated at below 50 °C. Ethyl acetate (700 mL) is added to the residue and the resulting mixture is heated to obtain a homogeneous solution. The solution is cooled to room température overnight and the precipitate is separated by filtration and washed with ethyl acetate (2x 100 mL). The precipitate is dried under vacuum at 50 °C for 5 h to give the title compound as a white solid. Yield: 208.0 g (84% pure, >99% ee).

The title compound is also prepared as follows:

148 (4a-R,9a-S)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (19.8 g) and 40 ml 2-methyltetraherofuran are added to a 500 ml reactor with overhead agitator, followed by addition of water(200 ml) and Na₂CO3 (21.2 g, 200 mmol, 2 eq). A slurry of 1Hbenzoimidazole-5-carboxylic acid chloride in 2-methyltetrahedrofuran (19.8 g, 110 mmol, 1.1 eq, in 200 ml 2-methyltetrahedrofuran) is added slowly over a period of 3 h, and the resulting twophase reaction mixtureis stirred for another 3 h. The aqueous phase is removed, and the the organic organic phase is washed with 10% brine. The solution is concentrated at ~50 °C under reduced pressure, and solvent is switched to 250 mL ethyl acetate. A slurry forms at this stage and the reaction mixture is cooled to room température and stirred for 2 h. The precipitate is separated by filtration and washed with ethyl acetate (2x 15 mL). The precipitate is dried under vacuum at 50 ’C for 5 h to give the title compound as a white solid. Yield: 34.4 g (86% wt as ethyl acetate solvaté, 86% yield, >99% ee).

The hydrogen chloride sait of (4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile is obtained in two different crystalline modifications:

Crystal form I: f4a-/?,9a-S)-1-(1H-Benzoimidazole-5-carbonvlÎ-2.3,4.4a,9,9a-hexahvdro-1H-indenof2,1b1pvridine-6-carbonitrile*hydroqen chloride

Hydrochloric acid (5-6 mol/L in isopropanol, 1.46 mL) is added dropwise to a stirred solution of (4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1b]pyridine-6-carbonitrile (2.10 g) in éthanol (10 mL) at room température. A seed crystal is added, and stirring is continued at room température for 2 h and at 0 ’C for another 2 h. The precipitate is separated by filtration (the filtrate is used to préparé crystal form II, see below), washed with little éthanol, and dried (60 ’C) to give an orange-colored solid (1.60 g), The solid is redissolved in éthanol (250 mL) and charcoal (1 g) is added to the solution. The mixture is stirred for 5 min and then filtered. The filtrate is concentrated to ca. 100 mL and a seed crystal is added. The solution is stirred at room température for 2 h and at ca. -10 ’C for 30 min. The precipitate is separated by filtration (the filtrate is used to préparé crystal form II, see below) and dried (60 ’C) to give the title compound as a colorless, crystalline solid (0.90 g); m_p (onset) = 252 ’C.

The seed crystals are prepared as follows: hydrochloric acid (5-6 mol/L in isopropanol, 40 pL) is added to a stirred solution of (4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (63 mg) in éthanol (0.5 mL). The resulting solution is stirred at room température overnight. The precipitate is separated by filtration, washed with little cold éthanol, and dried to give a colorless solid (30 mg).

149

Crystal Form I can also be prepared by the following procedure:

A solution of (4a-R,9a-SJ-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1Hindeno[2,1-b]pyridine-6-carbonitrile (1.5 g) in éthanol (3.92g) is prepared by heating to 50 °C.

The solution is then cooled to ambient température within 30 mins. The solution is charged with aqueous HCl (36.5 wt%; 0.4 g) and aged until the slurry forms. The slurry is filtered and dried under vacuum at ~ 25 °C.

Crystal form II: (4a-R9a-S)-1-(1H-Benzoimidazole-5-carbonvn-2,3,4,4a,9,9a-hexahvdro-1H-indenof2.1blDvridine-6-carbonitrile*hvdroQen chloride

The filtrâtes of the above mentioned préparation of crystal form I are concentrated, combined, and taken up in ethyl acetate (75 mL). The resulting mixture is stirred at 50 °C for 4 h. The suspension is cooled to room température, the precipitate is separated by filtration, washed with ethyl acetate (20 mL), and dried (60°C) to give a colorless solid (0.58 g). This solid (0.58 g) together with a residue (ca. 1 g) obtained by concentration of a filtrate from a repeat préparation of crystal form I are stirred in éthanol at room température overnight. The precipitate is separated by filtration and dried (60 °C) to give the colorless, crystalline form II of the title compound (0.65 g); m_p (onset) = ca. 240 C. This procedure may be scaled up to the multigram, hundred gram oreven kilogram scale.

Crystal form II is also obtained by the following procedure:

A reaction vessel charged with (4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3_l4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (331.5 g) and isopropanol (331.5 g) is heated at 75 ’C until a homogeneous solution is formed. 5.12 mol/L HCl in isopropanol (29.7 g) is added followed by isopropanol (5 g) to rinse the addition vessel. (4a-R,9a-S)-1-(1HBenzoÎmidazole-5-carbonyl)-2,3_l4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile hydrochloride (crystal form II; 19.88 g; the seeds are milled and slurried in 30 g isopropanol for ca. 1 h) is added followed by isopropanol (20 g) to rinse the addition vessel. The solution is aged for 1 h and then 5.12 mol/L HCl in isopropanol (171.3 g) is added over 4 h. The mixture is cooled to 0-5 °C over 1 h and aged at this température for 30 min. The precipitate is separated by filtration, washed with heptane (0-5 °C), and dried under vacuum at 65 °C for 8 h. Yield: 368.9 g (yield: 95%; corrected forseed charge).

Crystal form II is also obtained by the following procedure:

Crystal form 1(150 mg) and absolute éthanol (0.6 mL) are stirred at room température for one week. The precipitate is separated by filtration, washed with little absolute éthanol and dried at 40^eC.

Crystal Form II can also be prepared by the following procedure:

150

A solution of (4a-R,9a-S)-1 -(1 H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1 Hindeno[2,1-b]pyridine-6-carbonitrile (26.07 g) in 200 proof absolute éthanol (104.30g) is prepared by heating to 50 °C. The solution is charged with 4.587 g HCl in 200 proof absolute éthanol (6.55 N) at 50 °C. 3.605 g Form II mîlled seed slurry is added (seed slurry is prepared by mixing 0.782 g mîlled Form II with 2.823 g EtOH) and âge at 50 °C for more than 2 hrs. The solution is charged with 5.045g HCl in EtOH (6.55 N) over 2 hrs, then cooled to 0 °C over 1 hr. The solution is aged at 0 ^qC for more than 1 hr. The crystals are separated by filtration and dried at 70 °C under vacuum for more than 12 hrs. This procedure may be scaled up to the multi-gram, hundred gram or even kilogram scale.

X-Ray Powder Diffraction - XRPD

X-ray powderdiffraction analyses for samples of Form I and Form II were conducted on a Bruker AXS X-Ray Powder Diffractometer Model D8 Advance, using CuKa radiation (1.54A) in parafocusing mode with a graphite monochromator and a scintillation detector. The pattern was obtained by scanning over a range of 2’ - 35° 2T, step size of 0.05° 2T, step time of 4 sec per step. ExemplaryXRPD spectraof Form I and Form II may be found in Figures 1 and 5, respectively.

Solîd-state NMR-SSNMR ¹³C Solid-state NMR (SSNMR) data for samples of Form I and Form II was acquired on a Bruker Avance III NMR speclrometer (Bruker Biospin, Inc., Billerica, MA) at 9.4T (1Η=400.46 MHz, 13C=100.70 MHz). Samples were packed in 4 mm O.D. zirconia rotors with Kel-F® drive tips.

A Bruker model 4BL CP BB WVT probe was used for data acquistion and sample spinning about the magic-angle (54.74°). Sample spectrum acquistion used a spinning rate of 12kHz. A standard cross-polarization puise sequence was used with a ramped Hartman-Hahn match puise on the proton channel at ambient température and pressure. The puise sequence used a 5 millisecond contact puise and a 30 second recycle delay. Two-pulse phase modulated (tppm) decoupling was also employed in the puise sequence. No exponential line broadening was used prior to Fourier transformation of the free incution decay. Chemical shifts were referenced using the secondary standard of adamantane, with the upfield résonance being set to 29.5 ppm. The magic-angle wasset using the 79Br signal from KBr powder at a spinning rate of 5 kHz. Exemplary ¹³C SSNMR spectra of Form I and Form II may be found in Figures 2 and 6, respectively.

TGA

TGA analysis was performed with a Perkin Elmer Pyris 1 TGA instrument, SN 537N9120103, using general procedure, 002-GP-00342. Samples were heated from RT (~25°C) to 300 °C and

151 the weight loss calculated from RT to 150 ’C. Exemplary TGA traces of Form l and Form II may be found in Figures 4 and 8, respectively. Results are reported below.

Sample ID	%Weight Loss	Ave. % IVt Loss
Form II	0.041	0.05
0.066
Form I	2.050	2.09
2.125

DSC

DSC analysis was performed with a Diamond DSC instrument, SN 536N6102101, using general procedure, 002-GP-00343. Samples were heated from 25°C to 300°C and the thermal events determined. Exemplary DSC traces of Form I and Form II may be found in Figures 3 and 7, respectively. Results are reported below. Form I also showed a thermal event at 67.4°C possibly due to loss of surface water as sample showed evidence of hygroscopicity.

Sample ID	Onset ofMelt w/Decomp. (°C)
Form II	235.5
Form I	231.7

Example 108 (4a-S.9a-R)-1-(1H-Benzoimi'dazole-5-carbonvl)-2.3,4,4a,9,9a-hexahvdro-1H-indenof2.1blpyridine-6-carbonitrile

The title compound is obtained by chromatographîng a racemic mixture of c/s-1-(1Hbenzoimidazole-5-cafbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (600 mg) on chiral phase (SFC; column: Daîcel ASH 250 x 20 mm, 5 pm; mobile phase: isopropanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow rate: 90 mL/min; 40 °C) in ca. 90% eepurity (Example 108/Example 107 ca. 95:5). Yield: 115 mg; LC (préparative SFC on chiral phase as above): t_R = 6.00 min; Mass spectrum (ESl*): m/z =318 [M+H]⁺; ‘H NMR (400 MHz, DMSO-d6, mixture of rotamers) d 1.22-1.35 (m, 1 H), 1.42-1.56 (m, 1 H), 1.57-1.69 (m, 1H), 1.96-2.06 (m, 1 H), 2.86-3.18 (m, 3H), 3.20-ca. 3.29 (m, 1H), ca. 3.62-5.58 (very broad signais, 2H), 7.19-7.31 (m, 1H), 7.41-7.49 (m, 1 H), 7.54-7.74 (m, 4H), 8.29 (s, 1 H), 12.60 (broad s, 1H).

152

Example 109 (2-Amino-benzothiazol-6-vl)-(c/s-2,3,4,4a,9.9a-hexahydro-indeno[2,1-b]pyridin-1-vl)-methanone

The title compound is prepared from 2-amino-benzothiazole-6-carboxylic acid and cis2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 63% of theory; LC (method 4): t_R = 1.76 min; Mass spectrum (ESI⁺): m/z = 350 [M+Hf.

Example 110 (c/s-2,3,4,4a,9,9a-Hexahydro-indeno[2,1-b]pyridin-1-vl)-(3-hydroxv-4-methvl-phenvl)methanone

The title compound is prepared from 3-hydroxy-4-methyl-benzoic acid and 0/5-2,3,4,43,9,98hexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 45% of theory; LC (method 4): t_R = 1.98 min; Mass spectrum (ESI⁺): m/z = 308 [M+Hf.

Example 111 (3-Amino-4-methoxv-phenvlKcis-2,3,4.4a,9,9a-hexahydro-indenof2.1-blpvridin-1-yl)-methanone

The title compound is prepared from 3-amino-4-methoxy-benzoic acid and 0/5-2,3,4,43,9,93hexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 77% of theory; LC (method 4): t_R = 1.75 min; Mass spectrum (ESI⁺): m/z = 323 [M+Hf.

153

Example 112 (c/s-2,3.4,4a,9,9a-Hexahvdro-indeno[2,1-blpvridin-1-vl)-(2-methvl-1H-indol-5-vl)-methanone

The title compound is prepared from 2-methyl-1H-indole-5-carboxylic acid and c/s2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 39% of theory; LC (method 4): t_R = 2.01 min; Mass spectrum (ESI⁺): m/z = 331 [M+H]⁺.

Example 113

5-(c/s-2,3,4.4a,9,9a-Hexahvdro-indeno[2,1-blovridine-1-carbonvl)-1-methvl-1,3-dihvdrobenzoimidazol-2-one

The tille compound is prepared from 1-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5carboxylic acid and c/s-2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate is used]. Yield: 27% of theory; LC (method 4): t_R = 1.89 min; Mass spectrum (EST): m/z = 348 [M+H]⁺.

Example 114 (c/s-2.3.4.4a,9,9a-Hexahvdro-indenor2.1-b1pvridin-1-vn-(1H-indol-6-vl)-methanone

The title compound is prepared from 1H-indole-6-carboxylic acid and c/s-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 41% of theory; LC (method 4): t_R = 2.00 min; Mass spectrum (EST): m/z = 317 [M+Hf.

154

Example 115

5-(0/5-2,3,4,48,9,9a-Hexahvdro-indeno[2.1-blpvridine-1-carbonvlM,3-dihydro-indol-2-one

The title compound îs prepared from 2-oxo-2,3-dihydro-1 H-indole-5-carboxylic acid and c/s2,3₁4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine foliowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 29% of theory; LC (method 5): t_R = 0.98 min; Mass spectrum (ESl·): m/z = 333 [M+Hf.

Example 116

6-(c/'s-2,3.4.4a,9,9a-Hexahydro-indeno[2,1-blpyridine-1-carbonvl)-1.3-dihvdro-indol-2-one

The title compound is prepared from 2-oxo-2,3-dihydro-1 H-indole-6-carboxylîc acid and c/s2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine foliowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 34% of theory; LC (method 4): t_R = 1.88 min; Mass spectrum (ESI⁺): m/z = 333 [M+Hf.

Example 117 (c/s-2.3.4,4a.9,9a-Hexahvdro-indeno[2,1-blpvridin-1-vl)-(1-methyl-1H-benzoimidazol-5-vDmethanone

The title compound is prepared from 1-methyl-1H-benzoimidazole-5-carboxylic acid and c/s2,3,4,4a,9,9a-hexahydro-1H-indeno[2_l1-b]pyridine foliowing a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 90% of theory; LC (method 4): t_R = 1.62 min; Mass spectrum (ESl·): m/z = 332 [M+Hf.

155

Example 118 (cis-2,3,4,4a,9,9a-Hexahvdro-indeno[2,1-b1pyridin-1-vlH1-methYl-1H-benzotriazol-5-vOmethanone

N ,N

N

The title compound is prepared from 1-methyl’1H-benzotriazole-5-carboxylic acid and c/s2_l3₁4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 65% of theory; LC (method 4): t_R = 1.88 min; Mass spectrum (ESI⁺): m/z = 333 [M+H]⁺.

Example 119 (1H-Benzoimidazol-5-vD-(c/s-7-hvdroxy-2,3.4,4a,9,9a-hexahvdro-indenof2.1-blpvridin-1-yl)methanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ol following a procedure analogous to that described in Example 1. Yield: 18% of theory; LC (method 1): t_R = 1.97 min; Mass spectrum (ESI⁺): m/z = 334 [M+H]⁺.

Example 120 (c/s-2_l3.4,4a,9,9a-Hexahvdro-indenor2.1-b1pvridin-1-vl)-(4-hvdroxv-3-methvl-phenvl)-methanone

The title compound is prepared from 4-hydroxy-3-methyl-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 35% of theory; LC (method 4): t_R = 1.92 min; Mass spectrum (EST): m/z = 313 [M+H]*.

156

Example 121 (c/s-Z.S.^a.g.ga-Hexahvdro-indenoiZ.I-blpvridin-l-ylMZ-methvl-IH-benzoimidazol-S-yl)methanone

The title compound is prepared from 2-methyl-1H-benzoimidazole-5-carboxylic acid and c/'s2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 89% of theory; LC (method 5): t_R = 0.95 min; Mass spectrum (ESL): m/z= 332 (M+HJ*.

Example 122 (4-Amino-3-chloro-phenyl)-( c/s-2,3,4,4a,9,9a-hexahvdro-indenoi2.1-b1pvridln-1-yl)-methanone

The title compound is prepared from 4-amino-3-chloro-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridîne following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 38% of theory; LC (method 4): t_R = 1.96 min; Mass spectrum (ESI⁺): m/z = 327/329 (Cl) [M+Hf.

Example 123

The title compound is prepared from 1 H-indazole-6-carboxylic acid and c/'s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 5% of theory; LC (method 4): t_R = 1.92 min; Mass spectrum (EST): m/z = 318 [M+Hf.

157

Example 124 (2-Amino-1H-benzoimidazol-5-vn-(c/s-2,3.4,4a.9.9a-hexahvdro-indenof2,1-b1pvridin-1-vl)methanone

The title compound is prepared from 2-amino-1H-benzoimidazole-5-carboxylic acid and cis2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 71% of theory; LC (method 4): t_R = 1.64 min; Mass spectrum (ESl·): m/z = 333 [M+H]*.

Example 125

Benzothiazol-6-vl-(c/'s-2.3,4.4a,9,9a-hexahYdro-indenof2,1-blpyrÎdin-1-vn-methanone

The title compound is prepared from benzothiazole-6-carboxylic acid and c/s-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 36% of theory; LC (method 4): t_R = 1.94 min; Mass spectrum (ESl·): m/z = 335 [M+Hf.

Example 126 (4-Chloro-3-hvdroxv-phenvl)-(c/s-2.3.4,4a.9.9a-hexahydro-indeno[2.1-b1pvridin-1-vl)-methanone

The title compound is prepared from 4-chloro-3-hydroxy-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 44% of theory; LC (method 4): t_R = 1.97 min; Mass spectrum (EST): m/z = 328 [M+Hf.

158

Example 127 (c/s-2,3.4,4a,9,9a-Hexahydro-indenof2,1-blpvridin-1-vl)-(1H-imidazor4,5-blpvrÎdin-6-yl)methanone

The tille compound is prepared from 1H'imidazo[4,5-b]pyridine-6-carboxylic acid and cis2,3_<4,4a₍9,9a-hexahydro-1 H-indeno^J-blpyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 71% of theory; LC (method 4): t_R = 1.79 min; Mass spectrum (EST): m/z = 319 [M+Hf.

Example 128

5-(c/s-2,3,4,4a,9.9a-Hexahvdro-indeno[2,1-blpvridine-1-carbonyl)-1,3-dihvdro-benzoimidazol-2-

N >0

N

H

The title compound is prepared from 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and c/s-2,3,4_l4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 11% of theory; LC (method 4): t_R = 1.86 min; Mass spectrum (ESL): m/z= 334 [M+Hf.

Example 129 (c/s-2,3,4,4a,9,9a-Hexahvdro-indeno[2.1-blpvridin-1-vlH3-methyl-3H-benzoimidazol-5-vl)methanone

The title compound is prepared from 3-methyl-3H-benzoimidazole-5-carboxylic acid and c/s2,3_l4_l4a_l9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that describedin Example 1 [Z-fy-aza-IH-benzotriazol-l-ylfl.I.S.S-tetramethyluronium hexafluorophosphate is used]. Yield: 94% of theory; LC (method 4): t_R = 1.62 min; Mass spectrum (ESI⁺): m/z= 332 [M+Hf.

159

Example 130

O-Amino^-fluoro-phenvIKcis^.S^^a.g.ga-hexahydro-indeno^.l-blpvndin-l-vO-methanone

The title compound is prepared from 3-amino-4-fluoro-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 ^-(T-aza-IH-benzotriazol-l-yO-I.I.S.S-tetramethyluronium hexafluorophosphate is used]. Yield: 68% of theory; LC (method 4): t_R = 1.91 min; Mass spectrum (ESI⁴): m/z = 311 [M+H]⁺.

Example 131 (c/s-2,3,4,4a,9.9a-Hexahvdro-indeno[2,1-blpyridin-1-vl)-imidazof1,2-alpyridin-7-yl-methanone

The title compound is prepared from imidazo[1,2-a]pyridine-7-carboxylicacid and c/s2,3,4₁4a_l9,9a-hexahydro-1H-indeno[2_l1-b]pyridine following a procedure analogous to that described in Example 1 ^-(T-aza-IH-benzotriazol-l-yO-U.S.S-tetramethyluronium hexafluorophosphate is used], Yield: 18% of theory; LC (method 4): t_R = 1.56 min; Mass spectrum (EST): m/z = 318 [M+H]⁴.

Example 132 (c/s-2,3,4,4a.9,9a-Hexahvdro-indeno[2.1-blpvridin-1-vD-(1H-indazol-5-vl)-methanone

The title compound is prepared from 1H-indazole-5-carboxylic acid and c/s-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 31% of theory; LC (method 4): t_R = 1.91 min; Mass spectrum (ESI⁴): m/z = 318 [M+H]⁺.

160

Example 133 (4-Amino-phenyl)-(c/s-2₁3,4,4a,9,9a-hexahvdro-indeno[2,1-blpyridin-1-vl)-methanone

The title compound is prepared from 4-amino-benzoic acid and c/s-2,3,4,4a,9,9a-hexahydro-1Hindeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-azaIH-benzotriazol-l-yO-I.I.S.S-tetramethyluronium hexafluorophosphate is used]. Yield: 70% of theory; LC (method 4): t_R = 1.77 min; Mass spectrum (ESP): m/z = 293 [M+Hf.

Example 134 (c/s-2.3,4,4a,9,9a-Hexahydro-indenoi2,1-blpvridin-1-vl)-(4-hydroxv-phenyl)-methanone

The title compound is prepared from 4-hydroxy-benzoic acid and c/s-2,3,4,4a,9,9a-hexahydro1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 25% of theory; LC (method 4): t_R = 1.91 min; Mass spectrum (ESP): m/z = 294 [M+H]⁺.

Example 135 (c/s-2,3,4,4a,9,9a-Hexahydro-indeno[2.1-b1pvridin-1-vl)-(1H-indol-5-yl)-methanone

The titfe compound is prepared from 1 H-indole-5-carboxylic acid and 0/3-2,3,4,48,9,93hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 43% of theory; LC (method 4): t_R = 1.97 min; Mass spectrum (EST): m/z = 317 [M+H]⁺.

Example 136 (c/s-2.3,4.4a,9,9a-Hexahvdro-indenof2.1-b1pvridin-1-vl)-(lH-indol-3-vl)-methanone

161

The title compound is prepared from 1 H-indole-3-carboxylîc acid and c/'s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 35% of theory; LC (method 4): t_R = 1.99 min; Mass spectrum (ESI⁺): m/z= 317 [M+H]⁺.

Example 137 (3.5-Dichloro-4-hvdroxv-phenvl)-(c/s-2,3,4,4a,9,9a-hexahvdro-indenof2,1-b1pvridin-1-vl)methanone

OH

Cl

The title compound is prepared from 3,5-dichloro-4-hydroxy-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 32% of theory; LC (method 4): t_R = 2.01 min; Mass spectrum (ESI⁺): m/z = 362/364/366 (Cl) [M+H]⁺.

Example 138 (1H-Benzotriazol-5-vl)-(c/s-2.3.4.4a.9.9a-hexahvdro-indeno|2,1-blpvridin-1-vD-methanone

The title compound is prepared from 1H-benzotriazole-5-carboxylic acid and c/s-2,3,4,4a,9,9ahexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 19% of theory; LC (method 4): t_R = 1.87 min; Mass spectrum (ESI⁺): m/z = 319 [M+H]*.

Example 139 (c/s-2,3.4.4a,9.9a-Hexahvdro-indenor2.1-blpvridin-1-vl)-(1-methvl-1H-indol-3-vl)-methanone

The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and c/s2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-bjpyridine following a procedure analogous to that

162 described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 26% of theory; LC (method 4); t_R = 2.02 min; Mass spectrum (EST): m/z = 331 [M+Hf.

Example 140 (c/s-2,3,4,4a,9,9a-Hexahvdro-indenoi2,1-blPvridin-1-vl)-(3-hvdroxv-4-methoxy-phenvll· methanone

The title compound is prepared from 3-hydroxy-4-methoxy-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 45% of theory; LC (method 4): t_R = 1.91 min; Mass spectrum (ESC): m/z = 324 [M+Hf.

Example 141

The title compound is prepared from 3-chloro-4-hydroxy-benzoic acid and c/3-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used], Yield: 32% of theory; LC (method 4): t_R = 1.96 min; Mass spectrum (ESC): m/z = 328/330 (Cl) [M+Hf.

Example 142 (3-Amino-4-chloro-phenvl)-(c/s-2_l3,4,4a,9,9a-hexahvdro-indenor2.1-b1pvridin-1-vl)-methanone

The title compound is prepared from 3-amino-4-chloro-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used], Yield: 43% of theory; LC (method 4): t_R = 1.97 min; Mass spectrum (ΕΘΓ): m/z = 327/329 (Cl) [M+Hf.

163

Example 143 (3-Amino-4-methvl-phenvn-(c/s-2,3.4.4a.9.9a-hexahvdro-indeno[2,1-b]pvridin-1-vO-methanone

The title compound is prepared from 3-amino-4-methyl-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-{7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 63% of theory; LC (method 4): t_R = 1.81 min; Mass spectrum (EST): m/z = 307 [M+H]*.

Example 144 (4-Amino-3-methoxv-phenvl)-(c/‘s-2,3,4,4a.9,9a-hexahvdro-indenoi2,1-blpvridin-1-vl)-nnethanone

The title compound is prepared from 4-amino-3-methoxy-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 59% of theory; LC (method 4): t_R = 1.80 min; Mass spectrum (EST): m/z = 323 [M+H]*.

Example 145 (4-AminQ-3-fluoro-phenvlMc/s-2.3,4,4a.9.9a-hexahydro-indenor2,1-b1pvridin-1-yl)-methanone

The title compound is prepared from 4-amino-3-fluoro-benzoic acid and c/s-2,3,4,4a,9,9ahexahydro-1 H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 62% of theory; LC (method 4): t_R = 1.91 min; Mass spectrum (ESI⁺): m/z = 311 [M+H]*.

164

Example 146 (1H-Benzoimidazol-5-vl)-(c/s-4-methvl-2.3,4,4a.9.9a-hexahydro-indeno[2,1-b1pvridin-1-vl)methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-4-methyl2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 16% of theory; LC (method 1): t_R = 2.68 min; Mass spectrum (ESI⁴): m/z = 332 [M+H]⁴.

Example 147

6-(c/s-2,3,4,4a,9,9a-Hexahvdro-indeno[2.1-b]Dvridine-1-carbonvl)-1H-guinoxalin-2-one

The title compound is prepared from 2-oxo-1,2-dihydro-quinoxaline-6-carboxylic acid and c/s2_l3,4_l4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 45% of theory; LC (method 4): t_R = 1.89 min; Mass spectrum (ESI⁴): m/z = 346 [M+H]⁴.

Example 148 (4a-fî_l9a-S)-1-(1H-Benzoimidazole-5-carbonvl)-2_l3.4,4a.9,9a-hexahydro-1H-indeno[2,1blDvridine-7-carbonitrile

Aflask charged with a stir bar, zinc cyanide (94 mg), (1H-benzoimidazol-5-yl)-[(4a-R,9a-S)-7bromo-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl]-methanone (0.30 g), and N,Ndimethylformamide (2 mL) is sparged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(O) (0.10 g) is then added and the resulting mixture is heated to 100 °C and stirred at this température overnight. After cooling to room température, methanol is added and the resulting mixture is filtered. The filtrate is concentrated and water is added to the residue. The

165 aqueous mixture is extracted with ethyl acetate, the combined extracts are dried (Na₂SO4), and the solvent is evaporated. The residue is purified by HPLC on reversed phase (acetonitrile/water/trifluoroacetic acid) to give the title compound as its trifluoroacetic acid sait. Yield: 0.09 g (25% of theory); LC (method 1 ): t_R = 2.31 min; Mass spectrum (ESI⁺): m/z = 343 [M+Hf.

Example 149 (4a-f?,9a-S¾-(1H-Beπzoimidazol·5-vl)-(6-methoxv-2,3,4,4a,9,9a-hexahvdro-indenoF2.1-b1pyridin1-vl)-methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and (4a-R,9a-S)-6methoxy-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 89% of theory; LC (method 1): t_R = 2.43 min; Mass spectrum (ESf): m/z = 348 [M+Hf.

Example 150 (4a-/?,9a-S)-(1H-Benzoimidazol-5-vl)-(6-hvdroxv-2,3,4,4a,9,9a-hexahvdro-indeno[2,1blpyridin-1 -ylTmethanone

The title compound is prepared from (4a-R,9a-S)-(1H-benzoimidazol-5-yl)-(6-methoxy2,3,4_l4a_l9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-methanone following a procedure analogous to that described in Example 7. Yield: 78% of theory; LC (method 1): t_R = 1.89 min; Mass spectrum (EST): m/z = 334 [M+Hf.

Example 151 (c/s-7-Amino-2.3,4.4a,9,9a-hexahvdro-indeno[2.1-blpvridin-1-vl)-(1H-benzoimidazol-5-yl)methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ylamine following a procedure analogous to

166 that described in Example 1. Yield: 30% of theory; LC (method 1): t_R = 0.79 min; Mass spectrum (ESF): m/z = 333 [M+H]⁺.

Example 152 (4a-/?,9a-S)-1-(7-Methyl-1H-benzoimidazole-5-carbonyl)-2.3,4,4a,9,9a-hexahvdro-1Hindenof2,1-b|pvridine-6-carbonitrile

The title compound is prepared from 7-methyl-1 H-benzoimidazole-5-carboxylic acid and (4aR9a-S)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile following a procedure analogous to that described in Example 1. Yield: 53% of theory; LC (method 6): t_R = 1.05 min; Mass spectrum (EST): m/z = 357 [M+H]⁺.

Example 153 (4a-R.9a-S)-1-(6-Methvl-1 H-benzoimidazole-5-carbonyl)-2,3,4.4a. 9.9a-hexahvdro-1 Hindenof2,1-b1pyridine-6-carbonitrile

The title compound is prepared from 6-methyl-1H-benzoimidazole-5-carboxylic acid and (4a/?,98-5)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile following a procedure analogous to that described in Example 1. Yield: 69% of theory; LC (method 6): t_R = 0.99 min; Mass spectrum (ESI⁺): m/z = 357 [M+Hf.

Example 154 c/s-1-(1H-Benzoimidazole-5-carbonvD-2.3,4,4a,9.9a-hexahvdro-1H-indenof2.1-blpyridine-6carboxylic acid methvl ester

A flask charged with a stir bar, trifluoromethanesulfonic acid c/s-1-(1-trifluoromethane-sulfonyl1H-benzoimidazole-5-carbonyl)-2,3,4,4a.9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment to N-1 or N-3 of the benzimidazole, 0.50g), triethylamine (0.18 mL), N.N-dimethylforrnamide (2 mL), and methanol (1 ml) is sparged with argon for 5 min. [1,T-Bis(diphenylphosphino)ferrocene]-dichloropalladium dichloromethane

167 complex (53 mg) is added and the mixture is sparged with carbon monoxide for another 5 min. The mixture is then heated to 70 ^eC under carbon monoxide atmosphère (4 bar) and shaken at this température overnight. After cooling to room température, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0—>9:1 ) to afford the title compound. Yield: 0.27 g (87% of theory); LC (method 1): t_R = 2.43 min; Mass spectrum (ESI*): m/z = 376 [M+H]*.

Example 155 (1H-Benzoimidazol-5-vlÎ-(c/s-6-ethvnvl-2,3,4,4a,9,9a-hexahvdro-indeno[2,1-blpyridin-1-vl)methanone

A flask charged with a stir bar, trifluoromethanesulfonic acid c/s-1-(1-trifluoromethane-sulfonyl1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment to N-1 or N-3 of the benzimidazole, 0.20 g) and Ν,Ν-dimethylformarnide (2 mL) is sparged with argon for 5 min. Copper(l) iodide (13 mg), Pd(PPh₃)₂CI₂ (25 mg), triethylamine (0.31 mL), and trimethylsilylacetylene (0.14 mL) are added in the given order, the vessel is sealed, and the resulting mixture is heated to 60 ’C. After stirring the mixture at 60 °C overnight, it is cooled to room température and aqueous K₂CO₃solution is added. The resulting mixture is extracted with ethyl acetate, the combined extract is dried (Na₂SO₄), and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->9:1) to afford the trimethylsilylated title compound which is taken up in methanoi (3 mL) and treated with saturated aqueous K₂CO₃ solution at room température for 2 h. The mixture is then concentrated, water is added to the residue, and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na₂SO₄) and concentrated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->9:1 ) to afford the title compound. Yield: 0.03 g (26% of theory); LC (method 1 ): t_R = 2.65 min; Mass spectrum (ESl·): m/z = 342 [M+H]⁴.

Example 156 (1H-Benzoimidazol-5wl)-(c/s-6-hvdroxvmethvl-2,3,4,4a,9,9a-hexahvdro-indeno[2,1-blpvridin-1-

vl)-methanone

168

The title compound is prepared from c/s-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9ahexahydro-IH-indeno^.l-bJpyridine-e-carboxylic acid methyl ester following a procedure analogous to that described in Example 34. Yield: 30% of theory; LC (method 1 ): t_R = 1.87 min;

Mass spectrum (ESC): m/z = 348 [M+H]*.

Example 157 (1H-Benzoimiciazol-5-vl)-ic/s-6-(1-hvdroxv-1-methvl-ethvl )-2,3,4_l4a_l9,9a-hexahydro-indeno[2,1blpyridin-1 -yll-methanone

The title compound is prepared from c/s-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a.9,9ahexahydro-1H-indeno[2,1-b]pyridine-6-carboxylic acid methyl ester following a procedure analogous to that described in Example 41 except for using MeLi instead of MeMgBr. Yield: 21% of theory; LC (method 1): t_R= 2.13 min; Mass spectrum (ESC): m/z = 376 [M+H]*.

Example 158 (1H-Benzoimidazol-5-vl)-(c/s-6-phenyl-2,3,4.4a,9.9a-hexahvdro-indeno[2,1-blpvridin-1-yl)methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-6-phenyl2_l3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 63% of theory; LC (method 1): t_R = 3.28 min; Mass spectrum (ESC): m/z = 394 [M+H]*.

Example 159 (1H-Benzoimidazol-5-vl)-(c/s-6-phenvlethvnyl-2.3,4.4a.9.9a-hexahvdro-indeno[2.1-blpyridin-1vl)-methanone

The title compound is prepared from c/s-1-(1-trifluoromethane-sulfonyl-1H-benzoimidazole-5carbonylJ^.S^^a.g.Oa-hexahydro-IH-indeno^.l-bJpyridin-e-yl ester (mixture of isomers regarding sulfonyl group attachment to N-1 or N-3 of the benzimidazole) and phenylacetylene

169 following a procedure analogous to that described in Example 155; 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_R = 3.58 min; Mass spectrum (ESI⁺): m/z = 418 [M+H]⁺.

Example 160 (1H-Benzoimidazol-5-vl)-(c/s-6-furan-3-yl-2,3,4,4a,9,9a-hexahydro-indeno[2,1-blpyridin-1-vl)methanone

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-6-furan-3-yl2,3,4,4a,9,9a-hexahydro-1 H-indeno[2,1 -bjpyridine following a procedure analogous to that described in Example 1. Yield: 14% of theory; LC (method 1): t_R = 2.89 min; Mass spectrum (ESI⁺): m/z = 384 [M+H]⁺.

Example 161 dH-Benzoimidazol-5-vl)-(c/s-6-DroD-1-vnvl-2,3,4_l4a,9,9a-hexahvdro-indenoi2,1-blDvridin-1-yl)methanone

The title compound is prepared from c/s-1-(1-trifluoromethane-sulfonyl-1H-benzoimidazole-5carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment to N-1 or N-3 of the benzimidazole) and propyne following a procedure analogous to that described in Example 155; 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_R = 2.92 min; Mass spectrum (ESC): m/z = 356 [M+H]⁺.

Example 162 (1H-Benzoimidazol-5-vl)-fc/s-6-(Trnethvl-1 H-pvrazol-4-y0-2,3,4,4a,9,9a-hexahvdro-indenof2,1b]pvridin-1-yl1-methanone

170

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s-6-(1-mehyl1H-pyrazol-4-yl)-2,3,4,4a,9,9a-hexahydrO’1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 78% of theory; LC (method 1): t_R = 2.35 min;

Mass spectrum (ESI⁺): m/z = 398 [M+Hf.

Example 163 ( 1 H-Benzoimidazol-5-vlHc/s-6-methvl-2.3,4.4a,9,9a-hexahvdro-indenof2,1 -blpyridin-1 -vDmethanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s-6-methyl2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 60% of theory; LC (method 1): t_R = 2.75 min; Mass spectrum (ESf): m/z = 332 [M+Hf.

Example 164 (1H-Benzoimidazol-5-yll4cis-6-(tetrahydro-pvran-4-vl)-2,3,4,4a,9,9a-hexahvdro-indenol2.1 blpyridin-1-yll-methanone

A mixture of (1H-benzoimidazol-5-yl)-[6-(3,6-dihydro-2H-pyran-4-yl)-2,3,4,4a_l9,9a-hexahydroindeno[2,1-b]pyridin-1-yl]-methanone (48 mg), 10% palladium on carbon (10 mg), and methanol (3 mL) is shaken under hydrogen atmosphère (5 bar) at room température overnight. The catalyst is then separated by filtration and the filtrate is concentrated. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0-+9:1 ) to afford the title compound. Yield: 15 mg (31% of theory); LC (method 1): t_R = 2.63 min; Mass spectrum (EST): m/z = 402 [M+Hf.

Example 165 (1H-Benzoimidazol-5-vl)-(c/s-6-cyclopentvl-2.3,4.4a,9.9a-hexahvdro-indeno|2.1-b1pyridin-1-vDmethanone

171

The title compound is prepared from (1H-benzoimidazol-5-yi)-(6-cyclopent-1-enyl-2,3.4,4a₍9,9ahexahydro-indeno[2,1-b]pyridin-1-yl)-methanone following a procedure analogous to that described in Example 164. Yield: 50% of theory; LC (method 1): t_R = 3.53 min; Mass spectrum (ESl*): m/z = 386 [M+H]*.

Example 166

N-[ç/s-1-(1 H-Benzoimidazole-5-carbonvl 1-2,3,4,4a,9,9a-hexahydro-1H-indeno|2.1-blDvridin-7vll-acetamide

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and N-(c/s2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-acetamide following a procedure analogous to that described in Example 1. Yield: 34% of theory; LC (method 1 ): t_R = 1.97 min; Mass spectrum (ESl*): m/z = 375 [M+H]*.

Example 167

N-[c/s-1-(1H-Benzoimidazole-5-carbonvl)-2,3,4,4a,9,9a-hexahvdro-1H-indeno[2,1-b]pvridin-7-

H N

N />

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and N-(c/s2,3,4,4a,9,9a-Hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-methanesulfonamide following a procedure analogous to that described in Example 1. Yield: 7% of theory; LC (method 1 ): t_R = 2.07 min; Mass spectrum (ESl*): m/z = 411 [M+H]*,

Example 168 (1H-Benzoimidazol-5-vl)-(c/s-6-hydroxv-7-nitro-2,3,4,4a_<9,9a-hexah¥dro-indenor2,1-b]pvridin-1-

vl)-methanone

172

The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and c/s-7-nitro2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-ol following a procedure analogous to that described in Example 1. Yield: 32% of theory; LC (method 1): t_R = 2.43 min; Mass spectrum (ESI⁺): m/z = 379 [M+HJ*.

Example 169 (c/s-7-Amino-6-hvdroxy-2,3.4.4a_t9,9a-hexahvdro-indenor2.1-blpvridin-1-vD-(1H-benzoimidazol·

5-vD-methanone

A mixture of (1H-benzoimidazol-5-yl)-(c/s-6-hydroxy-7-nitro-2,3,4,4a,9,9a-hexahydro-indeno[2,1b]pyridin-1-yl)-methanone(O.56 g), 10% palladium on carbon (50 mg), and methanol (10 mL) is shaken under hydrogen atmosphère (1 bar) at room température for 3 h. The catalyst is separated by filtration and the filtrate is concentrated. The residue is chromatographed (dichloromethane/methanol 1:1 —>7:3) to give the title compound. Yield: 0.32 g (63% of theory); LC (method 1 ): t_R = 0.65 min; Mass spectrum (ESI⁺): m/z = 349 [M+Hf.

Example 170 (1H-Benzoimidazol-5-vl)-(c/s-2-methvl-4b,5.6.7,8a.9-hexahvdro-3-oxa-1,8-diazacvclopentafblfluoren-8-vÎ)-methanone

(c/s-7-Amino-8-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-(1H-benzoimidazol5-yl)-methanone (0.10 g) in triethyl orthoformate (0.5 mL) is stirred at 60 ^DC for 2 h. After cooling to room température, the mixture is concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol 1:0—>7:3) to afford the title compound. Yield: 64% of theory; LC (method 1): t_R = 2.28 min; Mass spectrum (ESI*): m/z = 373 [M+Hf.

173

Example 171

HH~Benzoimidazo[-5-vl)-(c/s-4b,5_l6,7,8a,9-hexahydro-3-oxa-1,8-diaza-cvclopenta[b1fluoren-8yl)-methanone

A mixture of (cîs-7-amÎno-8-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2_l1-b]pyridin-1-yl)-(1Hbenzoimidazol-5-yl)-methanone (100 mg), 4-toluenesulfonic acid hydrate (5 mg), triethyl orthoformate (40 pL), and methanol (1 mL) is stirred at 60 °C for 2 h. After cooling to room température, the mixture is concentrated and the residue is dissolved in ethyl acetate. The resulting solution is washed with 1 M NaOH solution, dried (NaaSO^), and concentrated to give the title compound. Yield: 50 mg (49% of theory); LC (method 1 ): t_R = 2.24 min; Mass spectrum (ESl*): m/z = 359 [M+Hf.

Example 172 (1H-Benzoimidazol-5-vl)-(c/.s-6-methoxv-7-methyl-2,3,4,4a.9,9a-hexahvdro-indeno[2,1-blpyridin1-vl)-methanone

The title compound is prepared from 1 H-benzoimidazole-5-carboxylic acid and c/s-6-methoxy-7methyl-2,3,4,4a,9,9a-hexahydro-lH-indeno[2,1-b]pyridinefollowing a procedure analogous to that described in Example 1. LC (method 7): t_R = 1.04 min; Mass spectrum (ESl*): m/z = 362 [M+H]*.

Example 173 (1H-Benzoimidazol-5-vl)-(c/s-6-hvdroxv-7-methvl-2.3.4.4a,9.9a-hexahvdro-indenor2.1-blpvridin1-vl)-methanone

The title compound is prepared from (IH-benzoïmidazol-S-ylXc/s-e-methoxy-T-methylZ.S^^a.g.Ga-hexahydro-indenop.l-bJpyridin-l-ylJ-methanone following a procedure analogous

174 to that described in Example 7. LC (method 7): t_R = 0.82 min; Mass spectrum (ESI ): m/z - 348 [M+HJ*.

Examples 174 and 175 (4a-f?,9a-S)-1 -(1H-Benzoimidazole-5-carbonvl)-7-methvl-2.3,4.4a.9.9a-hexahvdro-lHindeno[2,1-blpvridine-6-carbonitriie (174) and (4a-S,9a-f?)-1-(1H-Benzoimidazole-5-carbonyl)-7methvl-2,3,4,4a.9,9a-hexahvdro-1H-indeno[2.1-blDvridine-6-carbonitrile (175) (The absolute configuration of the two compounds is arbitrarily assiqned)

The title compounds are prepared from trifluoromethanesulfonic acid c/s-7-methyl-1-(1trifluoromethanesulfonyl-1 H-benzoimidazole-5-carbonyl)-2,3,4,4a_l9,9a-hexahydro-lHindeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment at N-1 or N-3 of the benzimidazole) and zinc cyanide following a procedure analogous to that described in Example 106; the title compounds are separated by SFC on chiral phase.

(4a-R_l9a-S)-1-(1H-Benzoimidazole-5-carbonyl)-7-methyl-2,3,4,4a,9,9a-hexahydro-1Hindeno[2,1-b]pyridine-6-carbonitrile (174): LC (method 7): t_R =0.88 min; Mass spectrum (ESI⁺): m/z = 357 [M+H]⁴, 379 [M+Na]⁴.

(4a-S,9a-/?)-1-( 1 H-Benzoimidazole-5-carbonyl)-7-methyl-2,3,4,4a,9,9a-hexahydro-1 Hindeno[2,1-b]pyridine-6-carbonitrile (175): LC (method 7): t_R =0.88 min; Mass spectrum (ESI*): m/z = 357 [M+H]⁴, 379 [M+Na]⁴.

Examples 176 and 177 (4a-R9a-S)-1 -(1H-Benzoimidazole-5-carbonyl)-5-methvl-2,3_l4.4a.9,9a-hexahvdro-1 Hindeno[2.1-b1pyridine-6-carbonitrile (176) and (4a-S.9a-R)-1-(1H-Benzoimidazole-5-carbonyl)-5methvl-2,3.4.4a.9,9a-hexahvdro-1H-indeno[2.1-blpyridine-6-carbonitrile (177) (The absolute configuration of the two compounds is arbitrarilv assiqned)

The title compounds are prepared from trifluoromethanesulfonic acid c/s-5-methyl-1-(1trifluoromethanesulfonyl-1 H-benzoimidazole-5-carbonyl )-2,3,4,4a,9,9a-hexahydro-1Hindeno[2,1 -b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment at N-1 or

N-3 of the benzimidazole) and zinc cyanide following a procedure analogous to that described in Example 106; the title compounds are separated by SFC on chiral phase. (4a-R_l9a-S)-1-(1H-Benzoimidazole-5-carbonyl)-5-methyl-2,3,4₍4a_l9,9a-hexahydro-1Hindeno[2,1-b]pyridine-6-carbonitrile (176): LC (method 7): t_R =0.89 min; Mass spectrum (EST): 5 m/z = 357 [M+Hf, 379 [M+Naf.

(4a-S₍9a-R)-1-(1H-Benzoimidazole-5-carbonyl)-5-methyî-2_l3,4,4a,9,9a-hexahydro-1Hindeno[2,1-b]pyridine-6-carbonitrile (177): LC (method 7): t_R =0.89 min; Mass spectrum (EST): m/z = 357 [M+Hf, 379 [M+Naf.

176

Some examples of formulations will now be described in which the term active substance dénotés one or more compounds according to the invention, including the salts thereof. In the case of one of the combinations with one or additional active substances as described previously, the term active substance” also includes the additional active substances.

Example A

Tablets containing 100 mg of active substance

Composition:

tablet contains:

active substance	100.0 mg
lactose	80.0 mg
corn starch	34.0 mg
polyvinylpyrrolidone	4.0 mg
magnésium stéarate	2.0 mg
	220.0 mg

Method of Préparation:

The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.

Weight of tablet: 220 mg

Diameter; 10 mm, biplanar, facetted on both sides and notched on one side.

Example B

Tablets containing 150 mg of active substance

Composition:

tablet contains:

active substance	150.0 mg
powdered lactose	89.0 mg
corn starch	40.0 mg
colloïdal silica	10.0 mg
polyvinylpyrrolidone	10.0 mg
magnésium stéarate	1.0 mg
	300.0 mg

177

Préparation:

The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. Thegranules, dried at45°C, are passed through the same screen again and mixed with the specified amount of magnésium stéarate. Tablets are pressed from the mixture.

Weight of tablet: 300 mg die: 10 mm, fiat

Example C

Hard gélatine capsules containing 150 mg of active substance

Composition:

capsule contains:

active substance	150.0 mg
corn starch (dried)	approx.	180.0 mg
lactose (powdered)	approx.	87.0 mg
magnésium stéarate		3.0 mg
	approx.	420.0 mg

Préparation:

The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gélatine capsules.

Capsule filling: approx. 320 mg

Capsule shell: size 1 hard gélatine capsule.

Example D

Suppositories containing 150 mg of active substance

Composition:

suppository contains: active substance polyethyleneglycol 1500 polyethyleneglycol 6000 polyoxyethylene sorbitan

150.0 mg

550.0 mg

460.0 mg monostearate 840.0 mg

2,000.0 mg

178

Préparation:

After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moutds.

Example E

Ampoules containing 10 mg active substance

Composition:

active substance 10.0 mg

0.01 N hydrochloric acid q.s.

double-distilled water ad 2.0 mL

Préparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonie with common sait, filtered stérile and transferred into 2 mL ampoules.

Example F

Ampoules containing 50 mg of active substance

Composition:

active substance 50.0 mg

0.01 N hydrochloric acid q.s.

double-distilled water ad 10.0 mL

Préparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonie with common sait, filtered stérile and transferred into 10 mL ampoules.

Claims

We claim:

1. A compound represented by the following structural formula:

wherein at least 50 % by weight of the compound is crystalline.
2. A compound represented by the following structural formula:

wherein at least 50 % by weight of the compound is a single crystalline form.
3. A compound represented by the following structural formula:

wherein at least 99% by weight of the compound is a single crystalline form.
4, The compound of any one of Claims 1-3, wherein at least 50 % by weight of the compound is crystalline Form I.
5. The compound of any one of Claims 2-4, wherein the single crystalline form is characterized by at least three x-ray powder diffraction peaks at 2T angles selected from 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.1°.
6. The compound of any one of Claims 2-4, wherein the single crystalline form is characterized by at least four x-ray powder diffraction peaks at 2T angles selected from 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.1°.

180
7. The compound of any one of Claims 2-4, wherein the single crystalline form is characterized by at least five x-ray powder diffraction peaks at 2T angles selected from 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.1°.
8. The compound of any one of Claims 2-4, wherein the single crystalline form is characterized by x-ray powder diffraction peaks at 2T angles 12.5°, 12.9°, 14.8°, 20.0°, 22.2° and 26.1°.
9. The compound of any one of Claims 2-4, wherein the single crystalline form is characterized by at least three x-ray powder diffraction peaks at 2T angles selected from 12.5°, 14.8°, 22.2° and 26.1°.
10. The compound of any one of Claims 2-4, wherein the single crystalline form is characterized by x-ray powder diffraction peaks at 2T angles 12.5°, 14.8°, 22.2° and 26.1°.
11. The compound of any one of Claims 2-4, wherein the single crystalline form is characterized by major x-ray powder diffraction peaks at 2T angles 12.5°, 14.8°, 22.2° and 26.1°.
12. The compound of any one of Claims 2-4, wherein the single crystalline form is characterized by the x-ray powder diffraction pattern of FIG. 1.
13. The compound of any one of Claims 2-12, wherein the single crystalline form is characterized by at least ten ¹³C solid-state nuclear magnetic résonance peaks at chemical shïfts selected from 170.3 ppm, 146.5 ppm, 142.8 ppm, 135.0 ppm, 130.6 ppm, 128.1 ppm, 122.1 ppm, 116.7 ppm, 115.6 ppm, 112.8 ppm, 109.8 ppm, 107.6 ppm, 44.6 ppm, 43.3 ppm, 41.4 ppm, 30.3 ppm, 26.3 ppm and 23.9 ppm.
14. The compound of any one of Claims 2-12, wherein the single crystalline form is characterized by ¹³C solid-state nuclear magnetic résonance peaks at chemical shifts of 170.3 ppm, 146.5 ppm, 142.8 ppm, 135.0 ppm, 130.6 ppm, 128.1 ppm, 122.1 ppm,

116.7 ppm, 115.6 ppm, 112.8 ppm, 109.8 ppm, 107.6 ppm, 44.6 ppm, 43.3 ppm, 41.4 ppm, 30.3 ppm, 26.3 ppm and 23.9 ppm.
15. The compound of any one of Claims 1-3, wherein the compound is crystalline Form II.

181
16. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized byx-ray powder diffraction peak at 2T angles 13.7°, 17.6°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
17. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized x-ray powder diffraction peaks at 2T angles 13.7°, 17.6°, 19.7,21.3°, 21.9*, 23.3°, 25.6° and 26.5°.
18. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized byx-ray powderdiffraction peaks at 2T angles 13.7°, 17.6°, 19.7, 20.9, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
19. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized byx-ray powderdiffraction peaks at 2T angles 13.7°, 17.6°, 19.3, 19.7, 20.9, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
20. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized byx-ray powderdiffraction peaks at 2T angles 13.3°, 13.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
21. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized by at least seven x-ray powder diffraction peaks at 2T angles selected from 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7^e, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
22. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized by at least eight x-ray powder diffraction peaks at 2T angles selected from 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
23. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized by at least nine x-ray powder diffraction peaks at 2T angles selected from 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
24. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized by at least ten x-ray powder diffraction peaks at 2T angles selected from 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7’, 20.9°, 21.3°, 21.9°, 23.3°, 25.6’ and 26.5°.

182
25. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized by at least eleven x-ray powder diffraction peaks at 2T angles selected from 13.3°, 13.7’, 15.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
26. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized by x-ray powder diffraction peaks at 2T angles selected from 13.3°, 13.7°, 15.7°, 17.6°, 19.3°, 19.7°, 20.9°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
27. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized by major x-ray powder diffraction peaks at 2T angles selected from 13.7°, 17.6°, 21.3°, 21.9°, 23.3°, 25.6° and 26.5°.
28. The compound of any one of Claims 2, 3 or 15, wherein the single crystalline form is characterized by x-ray powder diffraction pattern of FIG. 5.
29. The compound of any one of Claims 2, 3 or 15-28, wherein the single crystalline form is characterized by at least ten ¹³C solid-state nuclear magnetic résonance peaks at chemical shifts selected from 172.6 ppm, 147.1 ppm 144.1 ppm, 132.9 ppm 129.6 ppm, 125.9ppm 121.2 ppm, 119.5 ppm, 117.7 ppm, 114.6 ppm, 110.2 ppm, 45.1 ppm, 42.4 ppm, 32.6 ppm, 28.3 ppm and 24.4 ppm.
30. The compound of any one of Claims 2, 3 or 15-28, wherein the single crystalline form is characterized by ¹³C solid-state nuclear magnetic résonance peaks at chemical shifts of 172.6 ppm, 147.1 ppm 144.1 ppm, 132.9 ppm 129.6 ppm, 125.9 ppm 121.2 ppm, 119.5 ppm, 117.7 ppm, 114.6 ppm, 110.2 ppm, 45.1 ppm, 42.4 ppm, 32.6 ppm, 28.3 ppm and 24.4 ppm.
31. A pharmaceutical composition comprising the compound of any one of Claims 1-30 and a pharmaceutically acceptable carrier or diluent.
32. A compound or pharmaceutical composition according to any one of the preceding claims, for the treatment or prévention of diseases or conditions which can be influenced by inhibiting the enzyme 11B-hydroxysteroid dehydrogenase (HSD) 1.
33. The compound of claim 32, wherein the disease or condition which can be influenced by inhibiting the enzyme 11B-hydroxysteroid dehydrogenase (HSD) 1 is a metabolic disorder.

183
34. A method for producing crystalline form I of a compound represented by the following structural formula (II):

the method comprising:

dissolving a free base represented by the following structural formula (III):

protonating the dissolved free base with hydrochloric acid; and allowing crystalline form I to form by cooling the dissolved protonated free base (e.g., at a température below about 30°C.
35. A method for producing crystalline form II of a compound represented by the following structural formula (II):

the method comprising:

contacting a compound represented by structural formula (II) with éthanol to form a suspension, and stirring the suspension for a period of time sufficient to form crystalline form II.
36. A method for producing crystalline form II of a compound represented by the following structural formula (II):

the method comprising

184 dissolving a compound represented by structural formula (II) in ethyl acetate at a température above about 40°C; and allowing crystalline form II to form by cooling the dissolved compound (e.g., at a température below about 15°C).
37. A method for producing crystalline form II of a compound represented by the following structural formula (II):

the method comprising:

dissolving a free base represented by the following structural formula (lll):

in isopropanol at a température above about 40°C;

protonating the free base with hydrochloric acid; and allowing crystalline form II to form by cooling the dissolved protonated free base (e.g., at a température below about 15°C).
38. A method for producing crystalline form II of a compound represented by the following structural formula (II):

the method comprising dissolving a free base represented by the following structural formula (lll):

185 protonating the dissolved free base with hydrochloric acid and maintaining the dissolved protonated free base at a température above 40°C for at least two hours; and allowing crystallineform II to form by cooling the dissolved protonated free base (e.g., ata température belowabout 15’C).
39. A method according to claim 35 or claim 38, wherein the éthanol is 200 proof absolute éthanol.