1-amino-2-oxy-substituted tetrahydronaphtalene derivatives, methods for the production thereof, and their use as antiphlogistics

The present invention therefore relates to stereoisomers of general formula (I),

<img file="PL1670458T3_D0001.tif" />

(I) in which

R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted (C1-C10) -alkyl group, an optionally substituted (C1-C10) -alkoxy group, a (C1-C10) alkylthio group, a (C1-C5) group - perfluoroalkyl, cyano, nitro, or R¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, -NH (CH2) n + 1, -N (C1-C3-alkyl) - (CH2) n + 1, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bound with directly adjacent ring carbon atoms, or NR⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, optionally substituted

C1-C10) alkoxy, (C1-C5) hydroxyl group, optionally substituted C1-C10) alkoxy atom, (C1-C10) alkyl group, (C1-C10) alkylthio group, perfluoroalkyl group,

R¹² represents a hydrogen atom, a halogen group, a cyanide group, a (C1-C10) -alkyl group, a group optionally substituted by 1-3 groups, a halogen atom, 1-3 groups (C1-C5) group a group, a group

C1-C10 alkyl group,

C3-C7) -cycloalkyl, heterocyclyl, optionally optionally optionally substituted with more aryl groups, optionally from each other by one or

R³ is hydroxy, substituted alkoxy substituted substituted independently selected from: (C 1 -C 5) alkyl (which may be optionally substituted with 1-3 hydroxyl groups or 1-3 COOR groups¹³), (C1-C5) alkoxy groups, halogen atoms, hydroxyl groups, NR groups⁸R⁹, exomethylene groups, oxygen atom, optionally containing 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, mono- or bicyclic heteroaryl group, this group can be bonded through any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group, OR group¹⁰ or group

O (CO) R¹⁰, with R¹⁰ is any hydroxy or C1-C10alkyl protecting group,

R⁵ means a (C1-C10) alkyl group or optionally partially or fully fluorinated (C1-C10) alkyl group, (C3-C7) cycloalkyl group, (C1C8) alkyl (C3-C7) cycloalkyl group, (C2-C8) alkenyl group (C3C7) cycloalkyl, heterocyclyl group, (C1 group aryl group, (C2-C8) (C1C8) alkylheterocyclyl, alkenylheterocyclyl group,

C8) alkylaryl, (C2-C8) alkynylaryl, optionally substituted with 1-2 ketone groups, 1-2 (C1-C5) -alkyl groups, 1-2 (C1-C5) -alkoxy groups,

1-3 halogen, 1-2 exomethylene, containing 1-3 nitrogen and / or 1-2 oxygen and / or

1-2 sulfur atoms, mono or bicyclic heteroaryl group, (C1-C8) alkylheteroaryl group or (C2-C8) alkenylheteroaryl group, (C2C8) alkynylheteroaryl group, these groups can be connected to the tetrahydronaphthalene system through any position can be hydrogenated in one or more positions,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring.

A further object of the present invention are stereoisomers of general formula (I) according to claim 2 in which

R¹ and R² independently of each other represent a hydrogen atom, a hydroxyl group, a halogen atom, optionally

C2-C8) alkenyl aryl, substituted (C1-C10) -alkyl group, optionally substituted (C1-C10) alkoxy group, (C1-C10) alkylthio group, (C1-C5) -perfluoroalkyl group, cyano group, nitro group , or R¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, -NH (CH2) n + 1, -N (C1-C3-alkyl) - (CH2) n + 1, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bound with directly adjacent ring carbon atoms, or NR⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group, a (C1-C10) -alkylthio group, a (C1-C5) perfluoroalkyl group,

R¹² represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group,

R³ is optionally substituted with 1-3 hydroxyl, alkoxy groups, substituted substituted halogen, 1-3 groups

C1-C5 C1-C10-alkyl group, (C3-C7) -cycloalkyl group, heterocyclyl group, substituted aryl group, substituted with each other from: optionally optionally optionally optionally independently of one or more (C1-C5) -alkyl groups (which groups may optionally be substituted with 1-3 hydroxyl or 1-3 COOR groups¹³, with R¹³ is hydrogen or (C1-C5) -alkyl), (C1-C5) -alkoxy groups, halogen atoms, hydroxyl groups, NR groups⁸R⁹, exomethylene groups, oxygen, optionally containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, a mono- or bicyclic heteroaryl group, which group any position may be associated with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group, OR group¹⁰ or group

O (CO) R¹⁰, with R¹⁰ is any hydroxy or C1-C10alkyl protecting group,

R⁵ is a (C1-C10) alkyl or optionally partially or fully fluorinated (C1-C10) alkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring.

A further subject of the present invention are stereoisomers of general formula (I) in which R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C1-C10) alkyl group, a (C1-C10) alkoxy group, a (C1-C10) alkylthio group, a (C1-C5) -perfluoralkyl group, a cyanide group, nitro group, or R¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2 -, 'NH (CH2) n + 1, -N (C1-C3-alkyl) - (CH2) n + 1, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bound with directly adjacent ring carbon atoms, or NR⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group, a (C1-C10) -alkylthio group, a (C1-C5) perfluoroalkyl group,

R¹² represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group,

R³ is optionally substituted with 1-3 hydroxyl, alkoxy groups, substituted substituted halogen, 1-3 groups

C1-C5 optionally optionally optionally optionally independently of one or more (C1-C5) -alkyl groups C1-C10-alkyl group, (C3-C7) -cycloalkyl group, heterocyclyl group, substituted aryl group, substituted with each other selected from: (which may optionally be substituted with 1-3 hydroxyl groups or 1-3 COOR groups¹³), (C1-C5) alkoxy groups, halogen atoms, exomethylene groups, optionally containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, mono- or a bicyclic heteroaryl group, which group can by any position be bonded to the amine of the tetrahydronaphthalene system and optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group, OR group¹⁰ or a (C1-C5) -alkyl group, 1-3 halogen,

O (CO) R¹⁰, with R¹⁰ is any hydroxy or C1-C10alkyl protecting group,

R⁵ means (C1-C5) -alkyl or optionally partially or fully fluorinated (C1-C5) alkyl, (C3-C7) cycloalkyl, (C1C8) alkyl (C3-C7) cycloalkyl, (C2-C8) alkenyl ( C3C7) cycloalkyl, heterocyclyl group, (C1C8) alkylheterocyclyl group, (C2-C8) alkenylheterocyclyl group, (C2-C8) alkynyl aryl group, aryl group, (C1-C8) alkylaryl group, (C2C8) alkenylaryl group, optionally substituted with 1- 2 ketone groups, 1-2

1-2 (C1-C5) alkoxy groups,

1-2 exomethylene groups containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or

1-2 sulfur atoms, a mono or bicyclic heteroaryl group, a (C1-C8) alkylheteroaryl group or a (C2-C8) alkenylheteroaryl group, which groups can be attached to the tetrahydronaphthalene system through any position and optionally can be hydrogenated at one or more positions,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring.

A further subject of the present invention are stereoisomers of general formula (I) in which R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C1-C10) alkyl group, a (C1-C10) alkoxy group, a (C1-C10) alkylthio group, a (C1-C5) -perfluoralkyl group, a cyano group, nitro or R group¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, -NH (CH2) n + 1, -N (C1-C3-alkyl) - (CH2) n + 1-, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bonded to directly adjacent ring carbon atoms, or NR^BR⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, optionally substituted

C1-C10) alkoxy, (C1-C5) hydroxyl, (C1-C10) -alkyl, (C1-C10) -alkylthio, perfluoroalkyl,

R¹² represents a hydrogen atom, a halogen group, a cyanide group, an optionally substituted (C1-C10) alkyl group, a (C1-C10) alkoxy group,

R³ means optionally substituted with 1-3 hydroxyl groups, halogen atoms, 1-3 group (C1-C5) C1-C10-alkyl group, optionally (C3-C7) cycloalkyl group, optionally heterocyclyl group, aryl group, optionally from each other by one or alkoxy, substituted substituted substituted independently selected optionally substituted more groups among: (C1-C5) -alkyl groups which may be optionally substituted with 1-3 hydroxyl groups or 1-3 COOR groups¹³), (C1-C5) alkoxy groups, halogen atoms, exomethylene groups, oxygen, optionally containing 1-3 nitrogen atoms and / or 12 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, mono- or a bicyclic heteroaryl group, which group can by any position be bonded to the amine of the tetrahydronaphthalene system and

<td>possibly maybe</td><td>be</td><td>hydrogenated in</td><td>one or</td><td>many</td>

<td>positions</td><td></td><td></td><td></td><td></td>

<td colspan="4">R⁴ is a hydroxyl group, OR group¹⁰ or</td><td>a</td>

<td>O (CO) R¹⁰at</td><td>and</td><td>R¹⁰ means</td><td>any</td><td>a</td>

<td>protecting</td><td>a</td><td>hydroxy</td><td>or group</td><td>C1-C10</td>

<td>alkyl group,</td><td></td><td></td><td></td><td></td>

<td colspan="2">R⁵ means group (</td><td>C1-C5) alkyl</td><td colspan="2">or possibly</td>

<td>partly or</td><td colspan="3">fully fluorinated group (</td><td>C1-C5) -</td>

alkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring.

A further subject of the present invention are stereoisomers of general formula (I) in which R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) alkoxy group, a (C1-C10) -alkylthio group, a (C1-C5) perfluoroalkyl group, cyanide, nitro or R¹ and R² together they represent a group selected from the groups: -O {CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, -NH (CH2) n + 1, -N (C1-C3-alkyl) - (CH2) n + 1-, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bonded to directly adjacent ring carbon atoms, or NR⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkylthio group, a perfluoroalkyl group,

C1-C10) alkoxy, (C1-C5) R group¹² is hydrogen, halogen, cyano, (C1-C10) alkyl, hydroxyl, optionally substituted (C1-C10) alkoxy,

R³ is optionally substituted with 1-3 hydroxyl, alkoxy groups, substituted substituted substituted halogen, 1-3 groups

C1-C5 C1-C10-alkyl, (C3-C7) -cycloalkyl, heterocyclyl, aryl, optionally optionally optionally substituted with one or more groups selected from:

C1-C5 alkyl which may optionally be substituted with 1-3 hydroxyl groups or 1-3 groups

COOR¹³, with R¹³ is hydrogen or (C1-C5) -alkyl), (C1-C5) -alkoxy groups, halogen atoms, exomethylene groups, optionally containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, a mono- or bicyclic heteroaryl group, which group may by any position be attached to the amine of the tetrahydronaphthalene system and optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group, OR group¹⁰ or group

O (CO) R¹⁰, with R¹⁰ is any hydroxy or C1-C10alkyl protecting group,

R⁵ means (C1-C5) -alkyl or optionally partially or fully fluorinated (C1-C5) alkyl, (C3-C7) cycloalkyl, (C1C8) alkyl (C3-C7) cycloalkyl, (C2-C8) alkenyl (C3C7) cycloalkyl, heterocyclyl group, (C1C8) alkylheterocyclyl group, (C2-C8) alkenylheterocyclyl group, (C2-C8) alkynyl aryl group, aryl group, (C1-C8) alkylaryl group, (C2C8) alkenylaryl group, optionally substituted with 1-2 ketone groups, 1-2 (C1-C5) -alkyl groups, 1-3 halogen atoms,

1-2 (C1-C5) alkoxy groups,

1-2 exomethylene groups containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or

1-2 sulfur atoms, a mono or bicyclic heteroaryl group, a (C1-C5) alkylheteroaryl group or a (C2-Cs) alkenylheteroaryl group, which groups can be attached to the terahydronaphthalene system through any position and optionally can be hydrogenated at one or many positions,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹, R², R¹¹ and are not hydrogen.

A further subject of the present invention are stereoisomers of general formula (I) in which R¹ and R² independently of each other are hydrogen, hydroxyl, halogen, optionally substituted alkoxy, perfluoroalkyl, (C1-C10) -alkyl, (C1-C10) -alkylthio, cyano, group or R¹ and R² together they represent a group selected from

C1-C10) (C1-C5) nitro groups: -OCH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, -NHCH2) n +1, -N (C1-C3-alkyl) - (CH2) n + 1-, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bonded to directly adjacent ring carbon atoms, or NR⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group, a (C1-C10) -alkylthio group, a (C1-C5) perfluoroalkyl group,

R¹² represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group,

R³ means optionally substituted with 1-3 hydroxyl groups, halogen atoms, 1-3 (C1-C5) alkoxy groups, substituted substituted optionally optionally optionally substituted groups be a C1-C10-alkyl group, (C3-C7) -cycloalkyl group, heterocyclyl, aryl, optionally by one or more groups selected from: (C1-C5) -alkyl (which may be optionally substituted with 1-3 hydroxyl groups or 1-3 COOR groups¹³), (C1-C5) -alkoxy groups, halogen atoms, exomethylene groups, optionally containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, mono - or a bicyclic heteroaryl group, which group may by any position be bonded to the amine of the tetrahydronaphthalene system and optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group, OR group¹⁰ or group

O (CO) R¹⁰, with R¹⁰ any hydroxyl protecting group or a C1-C10 alkyl group,

R⁵ means a (C1-C5) -alkyl group or optionally partially or fully fluorinated (C1-C5) alkyl group, (C3-C7) cycloalkyl group, (C1-C8) alkyl (C3-C7) cycloalkyl group, (C2-C8) alkenyl (C3-C7) cycloalkyl, heterocyclyl group, (C1C8) alkylheterocyclyl group, (C2-C8) alkenylheterocyclyl group, (C2-C8) alkynyl aryl group, aryl group, (C1-C8) alkylaryl group, (C2C8) alkenylaryl group, optionally substituted with 1-2 ketone groups, 1-2 (C1-C5) -alkyl groups, 1-2 (C1-C5) -alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms, mono- or bicyclic heteroaryl group, (C1-C8) alkylheteroaryl group or (C2-C8) alkenylheteroaryl group, these groups can be attached to the tetrahydronaphthalene system through any position and optionally can be hydrogenated in one or many positions,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹, R², R¹¹ and R¹² do not mean hydrogen.

A further subject of the present invention are stereoisomers of general formula (I) in which R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted (C1-C1O) -alkyl group, a (C1-C10) alkoxy group, a (C1-C10) -alkylthio group, a (C1-C5) cyano group, perfluoroalkyl, cyano, nitro or R¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2 -, 'NH (CH2) n + 1, -N (C1-C3-alkyl) - (CH2) n + 1-, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bonded to directly adjacent ring carbon atoms, or NR⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, optionally substituted

C1-C10) alkoxy, (C1-C5) hydroxyl, an optionally substituted atom

C1-C10) -alkoxy, (C1-C10) -alkyl group, (C1-C10) -alkylthio, perfluoroalkyl group,

R¹² represents a hydrogen atom, a halogen group, a cyanide group, a (C1-C10) alkyl group, a group

R³ is optionally substituted with 1-3 hydroxyl, alkoxy groups, substituted substituted halogen, 1-3 groups

C1-C5 C1-C10-alkyl, (C3-C7) -cycloalkyl, heterocyclyl, optionally optionally substituted aryl, optionally substituted with one or more groups selected from (C1-C5) -alkyl (which optionally it can be substituted by 1-3 hydroxyl groups or 1-3 COOR groups¹³), (C1-C5) -alkoxy groups, halogen atoms, exomethylene groups, optionally containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, mono - or a bicyclic heteroaryl group, which group may by any position be bonded to the amine of the tetrahydronaphthalene system and optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group, OR group¹⁰ or group

O (CO) R¹⁰, with R¹⁰ is any hydroxy or C1-C10alkyl protecting group,

R⁵ is a (C 1 -C 5) alkyl or optionally partially or fully fluorinated (C 1 -C 5) alkyl group

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹, R², R¹¹ and R¹² do not mean hydrogen.

The invention further relates to stereoisomers of general formula (I) in which R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C1-C10) alkyl group, a (C1-C10) alkoxy group, a (C1-C10) alkylthio group, a (C1-C5) perffluoroalkyl group, a cyanide group, nitro or R group¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, where n is 1 or 2 and terminal oxygen and / or carbon atoms are attached to directly adjacent ring or NR carbon atoms⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, optionally substituted

C1-C10) alkoxy, (C1-C5) hydroxyl group, alkyl atom, (C1-C10) -alkyl group, (C1-C10) -alkylthio group, perfluoroalkyl group,

R¹² represents a hydrogen atom, a halogen group, a cyanide group, an optionally substituted (C1-C10) alkyl group, a (C1-C10) alkoxy group,

R³ means optionally substituted with 1-3 hydroxyl groups, halogen atoms, 1-3 (C1-C5) alkoxy groups, C1-C10-alkyl group, optionally substituted phenyl or naphthyl group, optionally substituted with 1-2 ketone groups, 1-2 (C1-C5) alkyl groups, 1-2 (C1-C5) alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1 -2 sulfur atoms, mono- or bicyclic heteroaryl group, these groups may be bonded via any position to the amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ means (C1-C5) -alkyl or optionally partially or fully fluorinated (C1-C5) aryl, (C1-C8) alkylaryl, C2-C8) alkenylaryl, (C3-C7) cycloalkyl, (C1- C8) alkyl (C3-C7) cycloalkyl, (C2-C8) alkenyl (C3-C7) cycloalkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹, R², R¹¹ and are not hydrogen.

A further subject of the invention are stereoisomers of general formula (I) in which

R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C1-C10) alkyl group, a (C1-C10) alkoxy group, a (C1-C10) alkylthio group, a (C1-C5) perffluoroalkyl group, a cyanide group, nitro or R group¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, where n is 1 or 2 and terminal oxygen and / or carbon atoms are attached to directly adjacent ring or NR carbon atoms⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, optionally substituted

C1-C10) alkoxy, (C1-C5) hydroxyl, optionally substituted C1-C10) alkoxy, {C1-C10) -alkyl, (C1-C10) -alkylthio, perfluoroalkyl,

R¹² represents a hydrogen atom, a halogen group, a cyanide group, a (C1-C10) alkyl group, a group

R³ is hydroxy, alkoxy, optionally substituted with 1-3 halogens, 1-3 groups (C1-C5) C1-C10 alkyl, optionally substituted phenyl, optionally substituted with 1-2 ketone, 1-2 ( C1-C5) -alkyl, 12 (C1-C5) -alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups containing 1-3 nitrogen atoms and / or

1-2 oxygen atoms and / or 1-2 sulfur atoms, mono- or bicyclic heteroaryl group, these groups can be bonded to the amine of the tetrahydronaphthalene system through any position and optionally can be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ means a (C1-C5) -alkyl group or optionally partially or fully fluorinated (C1-C5) alkyl group, aryl group, (C1-C8) alkylaryl group, (C2-C8) alkenylaryl group, (C3-C7) cycloalkyl group , (C 1 -C 8) alkyl (C 3 -C 7) cycloalkyl, (C 2 -C 8) alkenyl (C 3 -C 7) cycloalkyl,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹, R², R¹¹ and R¹² do not mean hydrogen.

A further object of the invention are stereoisomers of general formula (I) in which R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C1-C5) alkyl group, a (C1-C5) alkoxy group, a (C1-C5) perfluoroalkyl group, a cyano group or R¹ and R²together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms are attached to directly adjacent ring carbon atoms,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group, a (C1-C10) -alkylthio group, a (C1-C5) perfluoroalkyl group,

R¹² represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group,

R³ is optionally substituted with 1-3 hydroxyl groups or halogen atoms, C1-C10-alkyl group, optionally substituted with C1-C5-alkyl, halogen, hydroxyl group, C1-C5-alkoxy group, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl group , dihydroisoquinolinyl, thiophthalidyl, benzoxazinyl, phthalazinonyl, isoquinolinyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolyl, quinazolinyl, phthalazinyl, quinolone benzothiazolyl, cinolinyl,

1,7lub

1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl, these groups can be connected to the amine of the tetrahydronaphthalene system by any position and optionally one or more times they can be substituted with 1-2 ketone groups, 1-2 groups (C1- C3) -alkyl, 1-2 (C1-C3) alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups, and optionally can be hydrogenated in one or more positions

R⁴ is a hydroxyl group

R⁵ is a (C1-C5) alkyl or optionally partially or fully fluorinated (C1-C5) alkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹ R², R¹¹ and R¹²do not mean hydrogen.

A further object of the invention are stereoisomers of general formula (I) in which R¹ and R² independently of each other are hydrogen, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) -perfluoroalkyl, cyano, (C1-C5) -alkoxy, or together (C1-C2) ) -alkylene dioxy, wherein then R¹ and R² must be in the immediate vicinity,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group, a (C1-C10) -alkylthio group, a (C1-C5) perfluoroalkyl group,

R¹² represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group,

R³ is optionally substituted C1-C5-alkyl, halogen, hydroxy, C1-C5-alkoxy, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidinyl, benzoxazinylinyl, chalinolininyl, isylquinolinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinolinyl, phthalazinyl-, 1,7- or

1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl, these groups can be connected to the amine of the tetrahydronaphthalene system by any position and optionally one or more times they can be substituted with 1-2 ketone groups, 1-2 groups (C1- C3) -alkyl, 1-2 exomethylene groups and may optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ is (C 1 -C 5) -alkyl or optionally partially or completely. fluorinated (C1-C5) alkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹, R², R¹¹ and R¹² do not mean hydrogen.

The invention further relates to stereoisomers of general formula (I) in which R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C1-C10) alkyl group, a (C1-C10) alkoxy group, a (C1-C10) alkylthio group, a (C1-C5) perffluoroalkyl group, a cyanide group, nitro or R group¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms are directly attached to adjacent ring or NR carbon atoms⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R³ is a C ^ C group₁₀-alkyl which may optionally be substituted with a group selected from 1-3 hydroxyl groups, halogen atoms, or i-3 (C1-C5) alkoxy groups, optionally substituted phenyl or naphthyl groups, optionally substituted with i-2 ketone groups, and-2 (C 1 -C 5) -alkyl groups, and-2 (C 1 -C 5) alkoxy groups, i-3 halogen atoms, and-2 exomethylene groups, containing i-3 nitrogen atoms and / or i-2 oxygen atoms and / or -2 sulfur atoms, mono- or bicyclic heteroaryl group, these groups may by any position be attached to the amine of the tetrahydronaphthalene system and optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ is (C 1 -C 5) alkyl or optionally partially or fully fluorinated (C 1 -C 5) alkyl, aryl, (C 1 -C 8) alkylaryl, (C 2 -C 8) alkenyl aryl, (C 3 -C 7) cycloalkyl, (C 1 -C 8) alkyl (C 3 -C 7) cycloalkyl; a (C2-C8) alkenyl (C3-C7) cycloalkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups^and, R², Rⁱⁱ and Rⁱ² they are not hydrogen.

A further subject of the invention are stereoisomers of general formula (I) in which

R^and and R² independently of each other are hydrogen, hydroxyl, halogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, (C 1 -C 10) alkylthio, (C 1 -C 5) -perfluoroalkyl, cyano, nitro or R group^and and R² together they represent a group selected from the groups: -O20 (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, where n is 1 or 2 and terminal oxygen and / or carbon atoms are bonded directly to adjacent ring or NR carbon atoms⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R³ is a C1-C10-alkyl group which may optionally be substituted with a group selected from 1-3 hydroxyl groups, halogen atoms, or 1-3 (C1-C5) alkoxy groups, optionally substituted phenyl group, optionally substituted with 1-2 ketone groups , 1-2 (C1-C5) -alkyl groups, 1-2 (C1-C5) alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms, mono- or bicyclic heteroaryl group, these groups may by any position be attached to the amine of the tetrahydronaphthalene system and optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ means a (C1-C5) -alkyl group or optionally partially or fully fluorinated (C1-C5) alkyl group, aryl group, (C1-C8) alkylaryl group, (C2-C8) alkenylaryl group, (C3-C7) cycloalkyl group, (C 1 -C 8) alkyl (C 3 -C 7) cycloalkyl group, (C 2 -C 8) alkenyl (C 3 -C 7) cycloalkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹, R², R¹¹ and R¹² do not mean hydrogen.

A further object of the invention are stereoisomers of general formula (I) in which R¹ and R² are independently of each other hydrogen, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) -alkoxy, (C1-C5) perfluoroalkyl, cyano or R¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-. - (CH2) n + 2-, where n is 1 or 2 and terminal oxygen and / or carbon atoms are bonded directly to adjacent ring carbon atoms.

R³ is a C1-C10-alkyl group which may optionally be substituted with 1-3 hydroxyl groups, halogen atoms, optionally substituted with C1-C5-alkyl, halogen, hydroxyl group, C1-C5-alkoxy group, phenyl group. phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl. benzoxazinyl, phthalazinonyl, isoquinolinyl, quinolonyl, indazolyl, benzothiazolyl, quinoxalinyl, cinolinyl,

1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl groups, these groups can be connected to the amine of the tetrahydronaphthalene system by any position and optionally they can be substituted with 1-2 ketone groups one or more times, 1- 2 (C1-C3) -alkyl, 1-2 (C1-C3) -alkoxy groups,

1-3 halogen atoms, 1-2 exomethylene groups, and optionally can be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ is a (C1-C5) alkyl or optionally partially or fully fluorinated (C1-C5) alkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups¹, _R², R¹¹_and

Rⁱ² do not mean hydrogen.

A further subject of the invention are stereoisomers of general formula (I) in which

R^and and R² independently of each other are hydrogen, hydroxyl, halogen, (C 1 -C 5) alkyl, (C 1 -C 5) -perfluoroalkyl, cyano, (C 1 -C 5) alkoxy, or together (C 1 -C 2) -alkylene dioxy, wherein then R^and and R² must be in the immediate vicinity, R³ is optionally substituted C 1 -C 5 -alkyl, halogen, hydroxy, C 1 -C 5 -alkoxy, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophalidyl, benzoxazinolyl, chalinolininyl, isylquinolinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinolinyl, phthalazinyl, and, 7- or i, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, indolyl, these groups may be tetrahydronaphthalene via an amine-linked benzimidazolyl system or any position and may be substituted one or more times with k-2 ketone, and-2 (C 1 -C 3) -alkyl groups, and-2 exomethylene groups and can optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ is (C 1 -C 5) alkyl or optionally partially or fully fluorinated (C 1 -C 5) alkyl

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring, provided that at least three of the R groups^and, R², Rⁱⁱ and Rⁱ² do not mean hydrogen.

A further object of the present invention relates to stereoisomers of general formula (I),

<img file="PL1670458T3_D0002.tif" />

a hydroxyl group, a substituted group, a substituted alkylthio group, optionally optionally wherein

R¹ and R² independently of each other are hydrogen, halogen, (C1-C10) -alkyl,

C1-C10) -alkoxy, (C1-C10) group (C1-C5) -perfluoroalkyl, cyano, nitro or R¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, -NH (CH2) n + 1, N (C1-C3-alkyl) - (CH2) n + 1, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are directly bonded z are contiguous carbon atoms in the shadow ring, or NR⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R¹¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group, an optionally substituted (C1-C10) -alkyl group, a (C1-C10) -alkoxy group, a (C1-C10) -alkylthio group, a (C1-C5) perfluoroalkyl group.

R¹² represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyanide group. optionally substituted (C1-C10) -alkyl group, (C1-C10) -alkoxy group.

R³ is optionally substituted with 1-3 hydroxyl groups, halogen atoms, 1-3 (C1-C5) alkoxy groups, C1-C10-alkyl group.

optionally substituted (C3-C7) cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted independently with one or more groups selected from: (C1-C5) -alkyl (which may optionally be substituted with 1 -3 hydroxyl groups or 1-3 COOR groups¹³), (C1-C5) alkoxy groups, halogen atoms, exomethylene groups, oxygen, optionally containing 1-3 nitrogen atoms and / or 12 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, mono- or a bicyclic heteroaryl group, which group can by any position be bonded to the amine of the tetrahydronaphthalene system and optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group, OR group¹⁰, with R¹⁰ is a C1-C10-alkyl group,

R⁵ is a (C1-C5) alkyl or optionally partially or fully fluorinated (C1-C5) alkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring.

Stereoisomers of formula II are included in general formula I. A further object of the present invention relates to stereoisomers of general formula (II),

<img file="PL1670458T3_D0003.tif" />

(II) (II) in which

R¹ and R² are independently of each other a hydrogen atom, optionally an hydroxyl group, a halogen atom, a (C1-C10) alkyl group, a (C1-C10) alkoxy group, a (C1-C10) alkylthio group, a (C1-C5) -perfluoroalkyl group, cyanide, nitro or R¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2, -NH (CH2) n + 1 , N (C1-C3-alkyl) - (CH2) n + 1, -NH-N = CH, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are directly related to are they sit down carbon atoms in the ring, or NR⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R³ is optionally substituted with 1-3 hydroxyl groups, halogen atoms, 1-3 (C1-C5) alkoxy groups, C1-C10-alkyl group, optionally substituted (C3-C7) cycloalkyl group, substituted heterocyclyl group, substituted aryl group, optionally substituted with one or more groups selected from: (C1-C5) -alkyl groups (which may be optionally substituted with 1-3 hydroxyl groups or 1-3 groups

COOR¹³), (C1-C5) -alkoxy, halogen, exomethylene atoms, optionally containing 1-3 nitrogen and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto, mono- or bicyclic groups heteroaryl group, which group can be bonded to the amine of the tetrahydronaphthalene system through any position and can optionally be hydrogenated in one or more positions, the group of atoms represents a hydroxyl group, the OR group¹ wherein it represents a C1-C10-alkyl group,

R⁵ is a (C1-C5) alkyl or optionally partially or fully fluorinated (C1-C5) alkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a ring (C326

Cs) -cycloalkyl.

A further subject of the invention are stereoisomers of general formula (II) in which

R^and and R² independently of each other are hydrogen, hydroxyl, halogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, (C 1 -C 10) alkylthio, (C 1 -C 5) -perfluoroalkyl, cyano, nitro or R group^and and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, where n is i or 2 and terminal oxygen and / or carbon atoms are bonded directly to adjacent ring or NR carbon atoms⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C 1 -C 5 -alkyl or (CO) -C 1 -C 5 -alkyl,

R³ is a C 1 -C 10 -alkyl group which may be optionally substituted by i-3 hydroxyl groups, halogen atoms, an optionally substituted phenyl group, optionally substituted with i-2 ketone groups, and-2 (C 1 -C 5) -alkyl groups, and 2 (C 1 -C 5) alkoxy groups, i-3 halogen atoms, i-2 exomethylene groups, containing i-3 nitrogen atoms and / or i-2 oxygen atoms and / or i-2 sulfur atoms, mono- or bicyclic group heteroaryl, these groups may by any position be attached to the amine of the tetrahydronaphthalene system and optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ (C 1 -C 5) -alkyl or optionally partially or fully fluorinated (C 1 -C 5) -alkyl, aryl, (C 1 -C 8) alkylaryl, (C 2 -C 8) alkenyl aryl, (C 3 -C 7) cycloalkyl, (C 1 -C 8) alkyl (C 3 -C 7) cycloalkyl group, (C 2 -C 8) alkenyl (C 3 -C 7) cycloalkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a ring (C327

C6) -cycloalkyl.

A further subject of the present invention are stereoisomers of general formula (II) in which

R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C1-C10) alkyl group, a (C1-C10) alkoxy group, a (C1-C10) alkylthio group, a (C1-C5) perffluoroalkyl group, a cyanide group, nitro or R group¹ and R² together they represent a group selected from the groups: -O (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, - (CH2) n + 2-, where n is 1 or 2 and terminal oxygen and / or carbon atoms are bonded directly to adjacent ring or NR carbon atoms⁸R⁹, with R⁸ and R⁹ independently of each other may be hydrogen, C1-C5-alkyl or (CO) -C1-C5-alkyl,

R³ is optionally substituted with hydroxyl or halogen atoms,

1-3 groups with a C1-C10alkyl group, optionally substituted phenyl group, optionally substituted with 1-2 (C1-C5) -alkyl, alkoxy groups, 1-3 atoms with ketone groups, 1-2 1-2 (C1-C5) halogen groups , 1-2 exomethylene groups, containing 1-3 nitrogen and / or 1-2 sulfur, mono- or wherein these groups are oxygen and / or 1-2 bicyclic heteroaryl, can be linked via any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ is a (C1-C5) alkyl or optionally partially or fully fluorinated (C1-C5) alkyl group,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a chain carbon atom represent a (C3-C6) cycloalkyl ring.

A further subject of the present invention are stereoisomers of general formula (II) in which R¹ and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C1-C5) alkyl group, a (C1-C5) alkoxy group, or R¹ and R² together they represent a group selected from the groups: -quinquinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, (CH2) nO-. -O- (CH2) n-CH2-, -O-CH = CH-. - (CH2) n + 2-, where n is 1 or 2 and terminal oxygen and / or carbon atoms are bonded directly to adjacent ring carbon atoms,

R³ is optionally substituted with 1-3 hydroxyl groups or halogen atoms, group C₁-C₁₀^,alkyl, optionally substituted C 1 -C 5 -alkyl, halogen, hydroxy, C 1 -C 5 -alkoxy, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, isoquinolinyl , cinolinyl, i, 7- or i, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl, wherein these groups can by any position be bonded to the amine of the tetrahydronaphthalene system and optionally one or more times be substituted with i-2 ketone groups, i-2 (C 1 -C 3) -alkyl groups, and-2 (C 1 -C 3) groups -alkoxy, and -3 halogen atoms, and -2 exomethylene groups, and optionally can be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ is (C 1 -C 5) alkyl or optionally partially or fully fluorinated (C 1 -C 5) alkyl,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring.

A further subject of the present invention are stereoisomers of general formula (II) in which R^and and R² are independently of each other a hydrogen atom, a hydroxyl group, a halogen atom, a (C 1 -C 5) alkyl group, a (C 1 -C 5) alkoxy group, or a (C 1 -C 2) alkylene dioxy group together, then R^and and

R² must be in the immediate vicinity,

R³ is optionally substituted C 1 -C 5 -alkyl, halogen, hydroxy, C 1 -C 5 -alkoxy, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophalidyl, benzoxazinolyl, chalinolininyl, isylquinolinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinolinyl, phthalazinyl-, i, 7- or i, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl, these groups being via any position may be bonded to the amine of the tetrahydronaphthalene system and optionally one or more times may be substituted with i-2 ketone groups, and-2 (C 1 -C 3) -alkyl groups, and-2 exomethylene groups and can optionally be hydrogenated in one or more positions,

R⁴ is a hydroxyl group

R⁵ is (C 1 -C 5) alkyl or optionally partially or fully fluorinated (C 1 -C 5) alkyl,

R⁶ and R⁷ independently of each other represent a hydrogen atom, a methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent a (C3C6) -cycloalkyl ring.

A particular subject of the invention are stereoisomers according to claim and which have aromatic substituents on the aromatic ring of the tetrahydronaphthalene system selected from the group: C 1 -C 5 alkyl group, C 1 -C 5 alkoxy group, COORⁱ³, NO⁸R⁹, group C_and-C₅perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O- (CH2) nO-, -O- (CH2) nCH2-, -O-CH = CH-, - (CH2) n + 2-, -NH - (CH2) n + i-, - N (C 1 -C 3 alkyl) - (CH2) n + i-, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bonded directly to are contiguous carbon atoms in the ring. Then, divalent residues in the sense of the invention should be counted as two substituents.

R¹³ is hydrogen or C1-C10- or C1-C5-alkyl. When R¹/ R² means COOR¹³, then tert-butyl is preferred as R¹³.

A special subject is when R³ is formed by the remainder that contains COOR¹³ as a substituent, wherein R¹³ is C1-C10- or C1C5-alkyl.

The further subject of the invention are stereoisomers according to claim 2, which have three substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group: C1-C5-alkyl group, C1-C5-alkoxy group, C1-C5-perfluoroalkyl group, halogen, hydroxyl group, cyano group, nitro group, -O (CH2) nO-, -O- (CH2) n-CH2-, - O-CH = CH-, - (CH2) n + 2-, -NH (CH2) n + i-, -N (C1-C3-alkyl) - (CH2) n + 1-, -NH-N = CH - wherein n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are directly attached to adjacent ring carbon atoms. Then, divalent residues in the sense of the invention should be counted as two substituents.

A subgroup of these stereoisomers are stereoisomers of formula I or II according to claim 2, in which R¹ and R²together they are residues -O- (CH2) nO-, -O- (CH2) n-CH2-, O-CH = CH-, - (CH2) n + 2-, -NH- (CH2) n + 1-, -N (C1-C3-alkyl) (CH2) n + 1, -NH-N = CH-. Each terminal atoms of the above divalent groups are directly related to the adjacent atoms of the tetrahydronaphthalene system.

2, in the C1-C5 group C1-C5-perfluoroalkyl group, halogen,

The subgroup is stereoisomers according to claim which R¹, R², R¹¹ or R^1Z are selected from: C1-C5-alkyl, alkoxy, hydroxyl, cyano, nitro. A further subgroup is stereoisomers according to claim 1 or 2 in which R¹, R² R¹¹ or R¹² are selected from the group consisting of: optionally substituted C1-C5alkyl, optionally substituted C1-C5alkoxy, C1-C5-perfluoroalkyl, halogen, hydroxy, cyano.

A further subgroup is stereoisomers of formula I or II according to claim 2, wherein the alkyl residues R¹ and R² have the meaning - (CH2) n + 2- and thus together with the carbon atom of the chain form a 5 to 6-membered ring.

A special subject of the invention are stereoisomers of general formula I or II, which in the aromatic ring of the tetrahydronaphthalene system have one or two substituents selected from the group: C1-C5alkyl group, C1-C5-alkoxy group, C1-C5perfluoroalkyl group, halogen, hydroxyl group , nitro group, -O- (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-, (CH2) n + 2-, -NH- (CH2) n + 1. N (C1-C3-alkyl) - (CH2) n + 1, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are directly related to they sit down carbon atoms in the chest shadow.

The subgroup is stereoisomers of general formula I which have two substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group: C1-C5-alkyl group, C1-C5-alkoxy group, C1-C5-perfluoroalkyl group, halogen, hydroxyl group, cyano group, nitro group, -O- (CH2) nO-, -O- (CH2) n-CH2 -, -O-CH = CH-, - (CH2) n + 2-, -NH- (CH2) n + 1-, N (C1-C3-alkyl) - (CH2) n + 1, -NH-N = CH-, where n is 1 or 2 and terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are bonded directly to adjacent ring carbon atoms. Then, divalent residues in the sense of the invention should be counted as two substituents.

A further subject of the invention are stereoisomers of general formula I or II according to claim 1 or 2, in which R³ is a C1-C10-alkyl group which may optionally be substituted with 1-3 hydroxyl groups, halogen atoms, 1-3 (C1-C5) 32 alkoxy groups, optionally substituted (C3-C7) cycloalkyl group, optionally substituted heterocyclyl group, optionally substituted with one or more groups selected from: (C1-C5) alkyl groups, (C1-C5) alkoxy groups, halogen atoms, exomethylene groups, optionally containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or

1-2 sulfur atoms and / or 1-2 ketone groups, a mono- or bicyclic heteroaryl group, these groups may at any position be bonded to the amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more positions.

A further subject of the invention are stereoisomers of formula I or II in which R³ is a C1-C10alkyl group which may optionally be substituted with 1-3 hydroxyl groups, halogen atoms, optionally substituted with a phenyl group, optionally substituted with 1-2 ketone groups, 1-2 (C1-C5) -alkyl groups, 1-2 groups ( C1-C5) -alkoxy, 1-3 halogen atoms, 12 exomethylene groups, containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms, mono- or bicyclic heteroaryl group, wherein these groups can be bonded to the nitrogen atom at any position and optionally can be hydrogenated at one or more positions.

The present invention relates to stereoisomers of general formula I or II in which R³ is optionally substituted with one or more residues from the group: C1-C5-alkyl, C1-C5-alkoxy, hydroxyl, halogen, cyano, CF3, nitro, COOR¹³, NO⁸R⁹ , substituted phenyl or naphthyl.

A preferred subject of the present invention are compounds of general formula I or II according to claim 1-6, in which R³ is optionally substituted with one or more groups independently selected from: (C1-C5) -alkyl groups which themselves may optionally be substituted with 1-3 hydroxyl groups or 1-3 tetrahydronaphthalene groups hydrogenated in one

COOR¹³, with R¹³ is hydrogen or (C1-C5) -alkyl, (C1-C5) -alkoxy groups, halogen atoms, hydroxyl groups, NR groups⁸R⁹, exomethylene groups, oxygen, optionally containing 1-4 nitrogen atoms and / or 12 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, mono- or bicyclic heteroaryl group, this group by any position it may be bonded to the amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more positions.

A further preferred object of the present invention are compounds of general formula I or II according to claim 1-6, in which R³ is optionally substituted with one or more groups independently selected from: (C1-C5) -alkyl groups which themselves may optionally be substituted with 1-3 hydroxyl groups or 1-3 COOR groups¹³, with R¹³ is hydrogen or (C1-C5) -alkyl, (C1-C5) -alkoxy groups, halogen atoms, hydroxyl groups, NR groups⁸R⁹, exomethylene groups, oxygen, optionally containing 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 ketone groups, mono- or bicyclic heteroaryl group, this group being any position may be associated with the amine of the system and optionally there may be or multiple positions, and R⁵is optionally partially or fully fluorinated (C1-C5) alkyl.

A preferred subject of the invention are stereoisomers of general formula I in which R³ is a C1-C10alkyl group which may be optionally substituted with 1-3 hydroxyl groups, halogen atoms, optionally substituted with C1-C5-alkyl, halogen, hydroxyl group, C1-C5-alkoxy group, phenyl, naphthyl, phthalidyl, isoindolyl, dihydroindolyl group , dihydroisoindolyl, dihydroisoquinolinyl, dihydroquinolinyl, thiophalidyl, benzoxazinyl, phthalazinonyl, quinolinyl, isoquinolyl, quinazolinyl, phthalazinyl, isoquinolinyl, indazolyl, quinoxalinyl, and, 7-quinolonyl, benzothiazolyl, cinolinyl, or i, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl.

A particular subject of the invention are stereoisomers of general formula I or II in which R³ is a C 1 -C 10 -alkyl group which may be optionally substituted with i-3 hydroxyl groups, halogen atoms, optionally substituted with C 1 -C 5 -alkyl, halogen, hydroxy group, C 1 -C 5 -alkoxy group, phenyl, phthalidyl, isoindolyl, dihydroindolyl group, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinyl, phthalazinonyl, isoquinolinyl, indazolyl, quinoxalinyl, and, 7- or i, 8-quinolonyl, benzothiazolyl, cinolinyl, naphthyridinyl, dihydroisoindolonyl, isoquinolinyl, quinazolinyl, quinolinyl, isoquinolonyl, quinazolinyl, phthalazinyl, dihydroindolonyl, benzimidazole or indolyl.

A further subject of the invention are stereoisomers of formula (I) in which R³ means a phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, thiophalidyl, indazolyl, benzothiazolyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group.

A further subject of the invention are stereoisomers of formula (I) in which R³ is a dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinyl, phthalazinonyl, quinolinyl, quinolinyl, isoquinolonyl, quinoxalinyl, cinolinyl, phthalazinyl, and, 7- or i, 8-naphthyridinyl group.

A further subject of the invention are stereoisomers of general formula I in which R³ is an isoquinolonyl, quinolone, quinazolinyl or phthalazinyl group.

The invention further relates to stereoisomers of general formula I or II, wherein R³ is optionally quinolonyl, indazolyl, isoquinolonyl, dihydroindolyl, substituted quinazolinyl, quinolinyl, isoquinolonyl, phthalazinyl, isoquinolinyl, dihydroindolonyl, dihydroindolonyl, naphthyl, pyridyl or pyridylyl.

A further subject of the invention are stereoisomers of general formula I, which R³ means isoquinolin1 (2H) on-5-yl, quinolin-2 (1H) -on-5-yl-, 8- or 7-fluoro-2-methyl-quinazoline, 7,8-difluoro-4-methyl-quinazoline, 7,8-difluoro- 2-methyl-quinazoline or 2-methylphthalazine-1-one. Rest of R³ is bound to the tetrahydronaphthalene system by an amine. When the rest of R³ has a number of positions that are chemically possible to bind to the ring system, then the present invention covers all these possibilities. Rest of R³ is also encompassed by the present invention when it is hydrogenated in one or more positions.

As substituents of mono- or bicyclic heteroaryl groups (heterocyclic groups) _R3 as defined above, chemically appropriate positions, for example, a hydroxyl group, halogen atoms, especially fluorine and chlorine, (C 1 -C 5) alkyl groups (which themselves may optionally be substituted by hydroxyl groups, (C 1 -C 5) alkoxy groups are also suitable). is hydrogen or (C1-C5) or COOR¹³, with R¹³ alkyl), especially methyl, fully or partially (C2-C5) -alkenyl groups, fluorinated (C1-C5) alkyl groups, especially CF3, CFH2, or C2F5, (C1-C5) alkoxy groups, especially methoxy and ethoxy, NR groups⁸R⁹, especially NH2, N (CH3) 2 or NH (CH3), cyanide groups as well as ketone groups which are formed from the heteroaryl ring of the optionally available nitrogen of the ring forms N-oxide. Hence, as a preferred group of substituents for the carbon atom oxygen, with one R residue³as defined in claim 1 for or naphthyl, benzoxazinyl, isoquinolinyl, any further claims, a group consisting of: fluorine, chlorine, OH, CH3, CF3, CFH2, or C2F5,

OCH3, OC2H5, NH2, N (CH3) 2 and NH (CH3), cyanide, ketone, oxygen.

As substituents of heterocyclic groups R³as defined above in the aforementioned objects of the invention, halogen atoms, (C 1 -C 5) -alkyl groups (which themselves are substituted by hydroxyl groups or COORs) can be considered in the correct positions.ⁱ³, with Rⁱ³ is hydrogen or (C 1 -C 5) -alkyl), (C 2 -C 5) alkenyl groups, fluorinated (C 1 -C 5) alkyl groups, (C 1 -C 5) alkoxy groups or cyano groups.

Also preferred are stereoisomers of general formula I or II in which R³ is optionally substituted C 1 -C 5 -alkyl, halogen, hydroxy, C 1 -C 5 -alkoxy, phenyl phthalidyl, thiophalidyl, phthalazinonyl, quinolinyl, quinolonyl, isoquinolyl, indazolyl, benzothiazolyl, quinazolinyl, chinazolinyl, chinazolinyl, - or i, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl.

A particularly preferred subject are stereoisomers of general formula I in which R³ is optionally substituted C 1 -C 5 -alkyl, halogen, hydroxy, C 1 -C 5 -alkoxy, phenyl, phthalidyl, thiophalidyl, benzoxazinyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolone, isoquinolyl, indazolinyl, chinotolinyl, benzothiazinyl phthalazinyl, i, 7- or i, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl.

R heterocyclyl group³ it is not aromatic and may for example be pyrrolidine, imidazolidine, pyrazolidine, piperidine.

The hydroxyl group in R⁴ may be protected by one of the hydroxyl protecting groups commonly known to the skilled person, such as, for example, a silyl ether or ester of organic C 1 -C 10 acids or as a C 1 -C 5 ether or benzyl ether, preferably as one of the typical hydroxyl protecting groups or as C 1-10 C5-ether. As the rest of R⁴ a hydroxyl group is particularly preferred.

Typical hydroxyl protecting groups are described extensively in TW Greene, PGM Wuts "Protective Groups in Organic Synthesis", 2^nd Edition, John Wiley &amp; Sons, i99i).

The protecting groups are preferably alkyl, aryl or mixed alkylaryl substituted silyl groups, e.g. trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl type (TIPS) hydroxyl protecting group (methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl, tetrahydropyranyl).

Rest of R⁵ is directly related to the tetrahydronaphthalene system. When the rest of R⁵ has a number of positions that are chemically possible to bind to the ring system, then the present invention covers all these possibilities.

A further subject of the invention are stereoisomers of general formula I in which R⁵ means (C 1 -C 5) alkyl or optionally partially or fully fluorinated (C 1 -C 5) alkyl, (C 3 -C 7) cycloalkyl, (C 1 -C 8) alkyl (C 3 -C 7) cycloalkyl, (C 2 -C 8) ) alkenyl (C3-C7) cycloalkyl, heterocyclyl group, (C1-C8) alkylheterocyclyl group, (C2-C8) alkenylheterocyclyl group, aryl group, (C1-C8) alkylaryl group, (C2-C8) alkenylaryl group.

A further subgroup of the invention are stereoisomers of general formula I according to claim i. in which R⁵ means a (C3-C7) cycloalkyl group, (C1-C8) alkyl (C3-C7) cycloalkyl group, (C2-C8) alkenyl (C3-C7) cycloalkyl group, heterocyclyl group, (C1-C5) alkylheterocyclyl group, (C2 -C8) alkenylheterocyclyl, aryl, (C1-C8) alkylaryl, (C2-C8) alkenylaryl, optionally substituted with -2 ketone groups, and -2 (C1-C5) -alkyl groups, and -2 (C1-8) C5) -alkoxy, i-3 halogen atoms, i-2 exomethylene groups, containing i-3 nitrogen atoms and / or i-2 oxygen atoms and / or i-2 sulfur atoms, mono- or bicyclic heteroaryl group, (C1-C8) alkylheteroaryl group or (C2-C8) alkenylheteroaryl group, (C2- C8) alkynyl heteroaryl, these groups being via any position may be attached to the tetrahydronaphthalene system and may optionally be hydrogenated in one or more positions.

The present invention relates to stereoisomers of general formula I in which R⁵ is (C 1 -C 5) -alkyl or optionally · partially or fully fluorinated (C 1 -C 5) -alkyl, aryl, (C 1 -C 8) alkylaryl, (C 2 -C 8) alkenylaryl, (C 3 -C 7) cycloalkyl , (C 1 -C 8) alkyl (C 3 -C 7) cycloalkyl, (C 2 -C 8) alkenyl (C 3 -C 7) cycloalkyl.

A further subject of the invention are stereoisomers of general formula I or II according to claim and up to 6 in which R⁵ is a (C 1 -C 10) -alkyl group or optionally a partially or fully fluorinated (C 1 -C 10) -alkyl group, preferably a (C 1 -C 5) -alkyl group or optionally a partially or fully fluorinated (C 1 -C 5) alkyl group, particularly preferably (C 1 -C 3) alkyl or optionally partially or fully fluorinated (C 1 -C 3) alkyl, especially optionally partially or fully fluorinated (C 1 -C 3) alkyl, especially especially CF3 or C2F5.

A further subject of the invention are stereoisomers of general formula I or II according to claim 5 and 6, in which butyl, pentyl,

R⁵ is a (C 1 -C 5) alkyl or optionally partially or fully fluorinated (C 1 -C 5) alkyl group. Preferably R⁵ means trifluoromethyl or pentafluoroethyl.

Stereoisomers according to claims 1 to 6, the residue R of which are preferred⁵ is optionally partially or fully fluorinated (C 1 -C 5) alkyl, especially optionally partially or fully fluorinated (C 1 -C 3) alkyl.

Particularly preferred subgroups as disclosed for the present invention are residues and any combinations thereof among themselves which are supported by examples.

The name halogen or halogen means fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine is preferred.

C1-C10- or C1-C5-alkyl groups R¹, R², R⁴, R⁵, R⁶, R⁷, R¹¹, R¹² and R¹³ they may be straight chain or branched and for example refer to methyl, ethyl, n-propyl, iso-propyl, low-butyl, tert-butyl or n2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl as well as heptyl , nonyl, decyl cyano, hexyl, and any branched derivatives thereof. A methyl or ethyl group is preferred.

The above-mentioned alkyl groups may optionally be substituted with 1-5 groups independently selected from: hydroxyl group, nitro group, COOR¹³, C1-C5-alkoxy groups, halogen, NR⁸R⁹, partially or fully fluorinated C1-C3-alkyl;

the subgroup consists of: 1-3 halogen atoms and / or 1-3 hydroxyl and / or 1-3 cyanide groups and / or

1-3 COOR groups¹³. A preferred fluorine, hydroxyl group, cyanide group.

Alkyl groups can subgroup are: methoxy atom and / or optionally substituted

1-3 hydroxyl groups only be and / or 1-3 COOR groups¹³. Hydroxyl groups are then preferred.

For the partially or fully fluorinated C1-C5-alkyl group, for example, the following partially or fully fluorinated groups may be considered: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,

1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1 trifluoroethyl, tetrafluoroethyl, pentafluoroethyl. Of these groups, trifluoromethyl or pentafluoroethyl is preferable. The fully fluorinated group is also called perfluoroalkyl. Reagents, optionally used during the synthesis, are commercially available or published syntheses of the relevant reagents belong to the state of the art or analogous published syntheses can be used.

C1-C10- or C1-C5-alkoxy groups can be straight chain or branched and for example they are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, tert-butoxy or n-pentoxy, 2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy. C1-C5-alkoxy groups are preferred. A methoxy or ethoxy group is particularly preferred.

The above-mentioned alkoxy groups may optionally be substituted with 1-3 groups selected from: halogen, especially fluorine, chlorine, hydroxyl and cyanide.

The C1-C5-alkylthio groups can be straight chain or branched and, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2 -methylbutylthio or 3-methylbutylthio. The methylthio or ethylthio group is preferred.

Substituent NO⁸R⁹ is, for example, NH2, NH (CH3),

N (CH3) 2, NH (C5H11), N (C5H11) 2, NH (CO) CH3, NH (CO) C2H5, NH (CO) C3H7, NH (CO) C4H9, NH (CO) C5H11.

Cycloalkyl means optionally substituted with one or more groups selected from: hydroxyl groups, halogen atoms, (C1-C5) alkyl groups, (C1-C5) alkoxy groups, NR groups⁸R⁹, COOR groups¹³, CHO, cyanide group, saturated cyclic group with 3 to 7 ring carbon atoms, such as, for example, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.

Through a (C1-C8) alkyl (C3-C7) cycloalkyl group⁵should be understood as a cycloalkyl group which is bonded to the ring system through a straight or branched (C1-C8) alkyl moiety.

Through a (C2-C8) alkenyl (C3-C7) cycloalkyl group⁵should be understood as a cycloalkyl group which is bonded to the ring system through a straight chain or branched (C2-C8) alkenyl moiety.

The heterocyclyl group is not aromatic and may for example be pyrrolidine, imidazolidine, pyrazolidine, piperidine. Perhydroquinoline and perhydroisoquinoline also belong to the heterocyclyl groups included in the invention. As substituents of heterocyclyl and heteroaryl groups, for example, substituents from the group of: optionally substituted C1-C5-alkyl group, hydroxyl group, C1-C5-alkoxy group, NR are considered⁸R⁹-, halogen, cyanide, COOR¹³-, CHO-. The substituents can optionally also be bonded to a nitrogen atom; then they are also included in the definition of N-oxides.

Aryl groups within the meaning of the invention are aromatic partially aromatic carbocyclic groups with 6 to 14 carbon atoms that have a ring. such as phenyl or phenylene or a series of fused rings such as naphthyl or anthranil. Examples include phenyl, naphthyl, tetralinyl, anthranil, indanyl and indenyl.

Aryl groups can be substituted at any suitable position that leads to a stable stereoisomer, with one or more residues from the group consisting of: hydroxyl, halogen, optionally substituted with 1-3 hydroxyl groups or COOR groups¹³, a C 1 -C 5 -alkyl group, a C 1 -C 5 alkoxy group, a cyanide group, a CF 3 group, a nitro group. The optionally substituted phenyl and naphthyl groups are preferred.

The (C 1 -C 8) alkylaryl group is an aryl group, as already described above, which is bonded to the ring system via a straight chain or branched (C 1 -C 8) alkyl group.

The (C2-C8) alkenyl aryl group is an aryl group, as already described above, which is bonded to the ring system via a straight chain or branched (C2-C8) alkenyl moiety.

The (C2-C8) alkynyl aryl group is an aryl group, as already described above, which is bonded to the ring system via a straight chain or branched (C2-C8) alkynyl moiety.

The mono- or bicyclic heteroaryl group may optionally be substituted with one or more substituents selected from: optionally substituted with 1-3 hydroxyl groups or 1-3 COOR groups¹³, C1C5-alkyl group, C1-C5-alkoxy group, halogen, exomethylene group. Substituents can optionally also be directly bonded to the heteroatom. N-oxides also belong to the present invention.

The mono- or bicyclic heteroaryl group may optionally contain 0-9 groups from the group: nitrogen atoms, oxygen atoms, sulfur atoms or ketone groups, of which a maximum of 3 (4?) Nitrogen atoms, a maximum of 2 oxygen atoms, a maximum of 2 sulfur atoms and a maximum of 2 ketone groups. Any sub-combination of these groups is possible.

The heteroaryl group may be hydrogenated in one or more positions.

Monocyclic heteroaryl groups may, for example, be: pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran, furan, thiophene, 1H- and 4H-pyrazole, 1H43 and 2H-pyrrole, oxazole, thiazole, furazan, 1H- and 4Himidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole.

Bicyclic heteroaryl groups may, for example, be: group phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroizoindolilowa, indazolyl, benzothiazolyl, indolonylowa, dihydroindolonylowa, dihydroizoindolonylowa, benzimidazolyl, dihydrochinolinylowa, izoindolonylowa, benzofuranyl, dihydroizochinolinylowa, benzoksazynonylowa, ftalazynonylowa, chinolonylowa, quinolyl, isoquinolyl, izochinolonylowa, quinazolinyl, quinoxalinyl, cinolinylowa , phthalazinyl, 1,7- or

1,8-naphthyridinyl, kumarynylowa, izokumarynylowa, indolizinyl, isobenzofuranyl, azaindolyl, azaizoindolilowa, furanopirydylowa, furanopirymidynylowa, furanopirazynylowa, furanopirydazynylowa, dihydrobenzofuranyl, dihydrofuranopirydylowa, dihydrofuranopirymidynylowa, dihydrofuranopirazynylowa, dihydrofuranopirydazynylowa, dihydrobenzofuranyl.

If the heteroaryl groups are partially or fully hydrogenated, stereoisomers of formula I or II in which R³ is tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-oneyl, 1H-pyridin-4-oneyl,

4-aminopyridyl, 1H-pyridin-4-ylidonaminyl, chromanyl, isochromanyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decohydroisoquinolinyl, dihydroquinolyl, dihydroquinolin 2H-benz [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazin-4-oneyl, 3,4-dihydrobenz [1,4] oxazin-4-oneyl, 3,4-dihydro-2Hbenzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnolin-4-oneyl, 3H-quinazolin-4-oneyl, 1H-quinazolin-4-oneyl, 3,4-dihydro44

1H-quinoxalin-2-oneyl, 2,3-1,2,3,4-tetrahydro [1.5] naphthyridinyl, dihydro-1H [1.5] naphthyridyl, 1H- [1.5] naphthyridin-4-oneyl, 5 , 6,7,8tetrahydro-1H-naphthyridin-4-oneyl, 1,2-dihydropyrido [3,2d] [1,3] oxazin-4-oneyl, octahydro-1H-indolyl, 2,3dihydro-1H-indolyl, octahydro-2H-isoindolyl, 1,3-dihydro-2H-isoindolyl, 1,2-dihydroindazolyl, 1H-pyrrolo [2,3-b] pyridyl, 2,3-dihydro-1H-pyrrolo [2,3b] pyridyl, 2,2- dihydro-1H-pyrrolo [2,3-b] pyridin-3-oneyl belong to the present invention.

The (C1-C8) alkylheteroaryl group is a heteroaryl group, as already described above, which is bonded to the ring system via a straight chain or branched (C1C8) alkyl group.

The (C2-C8) alkenyl heteroaryl group is a heteroaryl group, as already described above, which is bonded to the ring system via a straight chain or branched (C2C8) alkenyl moiety.

The (C2-C8) alkynyl heteroaryl group is a heteroaryl group, as already described above, which is bonded to the ring system via a straight chain or branched (C2C8) alkynyl moiety.

The (C1-C8) alkylheterocyclyl group is a heterocyclyl group, as already described above, which is bonded to the ring system via a straight chain or branched (C1C8) alkyl group.

The (C2-C8) alkenyl heterocyclyl group is a heterocyclyl group, as already described above, which is bonded to the ring system via a straight chain or branched (C2C8) lenyl moiety .

The stereoisomers of the general formula I or II according to the invention can exist as stereoisomers by the existence of asymmetric centers. The present invention relates to all possible diastereomers. (e.g. RR, RS, SR, SS), both as racemates and in the form of pure enantiomers. The term stereoisomers also includes all possible diastereomers and regioisomers and tautomers (e.g. keto-enol tautomers) in which stereoisomers according to the invention may be present, which therefore also form the subject of the invention.

The stereoisomers of the invention may also be in the form of salts with physiologically tolerable anions, for example in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.

The stereoisomers according to the invention are prepared by forming open-chain precursors of the general formula III according to the state of the art,

<img file="PL1670458T3_D0004.tif" />

which are then cyclized either without further reagent in a solvent, preferably in chlorinated hydrocarbons, e.g. methylene chloride or dichloroethane, or in concentrated organic acids, preferably in glacial acetic acid, or by the addition of inorganic or organic acids or Lewis acids at temperatures in the range of -7 ° C to + 8 ° C (preferably in the range of -3 ° C to + 8 ° C), for stereoisomers of general formula I or II.

When compound IIIa is used, which differs from compound III only in that it has only two substituents on the tetrahydronaphthalene ring, a compound of general formula II is obtained.

The present invention therefore also relates to a process for the preparation of stereoisomers of general formula I or II, characterized in that the imine of general formula III either with no further reagent in a solvent or in concentrated organic acids or by the addition of inorganic or organic acids or Lewis acids at temperatures in the range -70 ° C to + 80 ° C (preferably in the range -30 ° C to + 80 ° C), cyclized to stereoisomers of general formula I or II, as well as their immediate precursors of formula III.

New names for cyclization are also the subject of the present invention, especially those disclosed by the examples.

Binding of the substance to the glucocorticoid receptor (GR) and further steroid hormone receptors (mineralocorticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) are checked using recombinantly produced receptors. Cytosolic preparations of Sf9 cells infected with recombinant GR coding baculoviruses are used for binding studies.

Compared with reference substance - [³H] dexamethasone, substances show high affinity for GR. For example, for the compound of Example 285 IC50 (GR) = 86 nM and IC50 (PR) =&gt; 1000, and for the compound of Example 49 IC50 (GR) = 95 nM and IC50 (PR) = 460.

GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes and other proinflammatory agents is considered to be a significant molecular mechanism of the anti-inflammatory effect of gluocorticoids. This inhibition works by interacting with GR with other transcription factors, e.g. AP-1 and NFkappa-B (for review see Gato ACB, Wade E, BioEssays 18, 371-378 1996).

The stereoisomers of the general formula I according to the invention inhibit the secretion of IL-8 cytokine triggered by lipopolysaccharide (LPS) in the human THP-1 monocyte cell line. Cytokine concentration was determined in the protrusion using a commercially available ELISA kit. The compound of Example 285 showed inhibition of IC50 (11L8) = 40 nM (79% efficacy), and the compound of Example 49 showed inhibition of IC50 (IL8) = 19 nM.

The anti-inflammatory effect of stereoisomers of general formula I was tested in animal experiments in ear weight as a measure of peroxidase as a measure of adverse effects. "diabetes HJ, Glucocorticoide: Pharmakologie and Wissenschafliche from liver homogenates and the adverse effects of croton oil inflammation in rat and mouse (J. Exp. Med. (1995), 182, 99-108). Croton oil was applied to the ears of the animals ethanol solution. Test substances were applied simultaneously or two hours before croton oil also locally or systemically. After 16-24 hours, inflammatory edema, granulocyte invasion activity and elastase activity were measured as a measure of neutrophil invasion. Stereoisomers of general formula I inhibit in this study the three parameters of inflammation mentioned above both after topical and systemic administration.

One of the most common steroid glucocorticoid therapy "[see Hatz,

Immunologische Grundlagen,

Therapierichtlinien,

Verlagsgesellschaft mbH, Stuttgart, 1998]. The reason is the stimulation of gluconeogenesis in the liver by the induction of the enzymes responsible for it and by the free amino acids arising from the breakdown of proteins (catabolic effect of glucocorticoids). Tyrosineaminotranferase (TAT) is a key enzyme for catabolic metabolism in the liver. The activity of this enzyme can be determined photometrically a good measure of metabolic glucocorticoids. To measure TAT induction - animals are killed 8 hours after administration of the test substances, the liver is removed and the TAT homogenate is measured well. Stereoisomers of general formula I in this study at doses in which they are anti-inflammatory, do not induce or induce only a small amount of tyrosineaminotransferase.

Due to their anti-inflammatory and additional antiallergic, immunosuppressive and antiproliferative effects, the stereoisomers of the general formula I according to the invention may find use as therapeutic agents for the treatment or prevention of the following disease states in mammals and humans: the term "disease" refers to the following indications :

(i) lung diseases that occur with inflammatory, allergic and / or proliferative processes:

- chronic obstructive pulmonary diseases of all origins, primarily bronchial asthma

- bronchitis of various origins - all forms of restrictive lung diseases, primarily allergic alveolitis

- all forms of pulmonary edema, primarily toxic pulmonary edema - sarcoidosis and Hodgkin's disease, especially Beck's disease (ii) rheumatic / autoimmune diseases / joint diseases that are associated with inflammatory, allergic and / or proliferative processes:

- all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polyarthritis rheumatic pain

- reactive arthritis

- inflammatory soft tissue diseases of another origin

- rheumatic symptoms with degenerative joint diseases (arthrosis)

- post-traumatic arthritis

- collagen diseases of all origin, e.g.

systemic lupus erythematosus, scleroderma, polyarthritis, dermatomyositis, Sjogren's syndrome, Still's disease, Felti syndrome (iii) allergies that occur with inflammatory and / or proliferative processes:

- all forms of allergic reactions, e.g. Quincke's edema, hay fever, insect bites, allergic drug reactions, blood derivatives, contrast agents etc., anaphylactic shock, urticaria, contact dermatitis, (iv) vascular disease (vasculitis)

- nodular arteritis, temporal arteritis, erythema nodosum (v) dermatological diseases that occur with inflammatory, allergic and / or proliferative processes:

- atopic dermatitis (primarily in children)

- psoriasis

- red bellows dandruff

- erythematous diseases caused by various harmful factors, e.g. radiation, chemicals, burns etc.

- bullous dermatoses

- lichen-like diseases

itching (e.g. of allergic origin)

- seborrheic dermatitis

- rosacea

- pemphigus vulgaris

- erythema multiforme exudative

- penile glans inflammation

- vulvitis

- Hair loss, such as alopecia areata

- cutaneous T (vi) lymphoma of the kidney disease, which proceeds with inflammatory, allergic and / or proliferative processes:

- nephrotic syndrome

- all types of nephritis that occur with allergic and / or (vii) liver disease, inflammatory, proliferative processes:

- acute hepatic cell disorders of various toxic, chronic content of other origin,

- acute hepatitis of origin, e.g. viral, drug induced

- chronic aggressive and / or intermittent hepatitis (viii) gastrointestinal diseases that occur with inflammatory, allergic and / or proliferative processes:

- local enteritis (disease

Crohn's disease)

- ulcerative colitis

- gastritis

- gastroesophageal inflammation

- gastritis e.g. local psylosis, (ix) proctological diseases that are associated with inflammatory, allergic and / or proliferative processes

- anal eczema

- fistulas

- hemorrhoids

- idiopathic proctitis (x) eye diseases that occur with inflammatory, allergic and / or proliferative processes:

- allergic keratitis, uveitis, iritis

- conjunctivitis

- eyelid dermatitis

- optic neuritis

- uveitis

- sympathetic choroid (xi) throat-nose-ear diseases that occur with inflammatory, allergic and / or proliferative processes:

- allergic rhinitis, hay fever

- otitis externa, e.g. due to contact eczema, infection etc.

- otitis media (xii) neurological diseases that proceed with inflammatory, allergic and / or proliferative processes:

- brain edema, primarily tumor edema

- multiple sclerosis

- acute encephalomyelitis

- meningitis

- various forms of seizures, e.g. propulsive epilepsy petit mal (xiii) blood diseases that occur with inflammatory, inflammatory, allergic and / or proliferative processes:

- acquired haemolytic anemia

- idiopathic thrombocytopenia (xiv) neoplastic diseases that occur with inflammatory, allergic and / or proliferative processes:

- acute lymphocytic leukemia

- malignant lymphomas

- Hodgkin's disease

- lymphosarcoma

- extensive metastases, primarily breast, bronchial and prostate (xv) endocrine diseases that occur with inflammatory, allergic and / or proliferative processes:

- endocrine orbitopathy

- thyrotoxic switch

- de Quervain thyroiditis

- Hashimoto's thyroiditis

- Basedow disease (xvi) organ and tissue transplants, graft versus host reaction (xvii) severe shock conditions, e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS) (xviii) replacement therapy for: congenital primary adrenal insufficiency, e.g. congenital syndrome adrenocortical primary insufficiency, Addison's disease, adrenalitis, tumors, metastatic insufficiency insufficiency

- acquired adrenal gland, e.g. autoimmune, non-infectious, related, etc.

- congenital secondary adrenal glands, e.g. congenital pituitary gland

- acquired secondary metastatic insufficiency, e.g. non-infectious, associated with tumors, etc.

(xix) Vomiting that occurs with inflammatory, allergic and / or proliferative processes:

- e.g. in combination with 5-HT3 antagonists with vomiting due to cytostatics (xx) pain of inflammatory origin, e.g. lumbar pain.

In addition, stereoisomers according to the invention of the formula can be used in therapy or other disease states not above in which glucocorticoids are currently used (see Hatz, HJ, Immunologische Grundlagen, und Therapierichtlinien, general and prophylaxis of the listed synthetic Glucocorticoide: Pharmacologies

Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, i998).

All the indications (i) to (xx) mentioned above are exhaustively described by Hatz, HJ, in Glucocorticoide: Immunologische Grundlagen,

Pharmakologie und Therapierichtlinien, Wissenschafliche Velagsgesellschaft mbH, Stuttgart, 1998.

Different doses are required for therapeutic effect in the aforementioned disease states; for example, they depend on the potency of the compound of general formula I, the patient, the route of administration and the type and severity of the condition being treated, as well as the use as a prophylactic or therapeutic agent.

The invention relates to the use of compounds / stereoisomers for the preparation of drugs.

The invention further provides:

(i) the use of compounds / stereoisomers of the invention of general formula I or a mixture thereof for the preparation of medicaments for the treatment of a disease;

(ii) a method of treating a disease, which comprises administering an amount of a compound (s) of the invention, said amount arresting the disease, and that amount of the compound (s) receiving a patient in need of such a drug;

(iii) a pharmaceutical composition for treating a disease, the composition comprising one of the compounds of the invention or a mixture thereof and at least one pharmaceutical excipient and / or carrier.

In general, satisfactory results are expected in animals when the daily doses range from 1 μg to 100,000 μg of the compound of the invention per kg body weight. In large mammals, for example humans, the recommended daily dose is in the range of 1 μg to 100,000 μg per kg body weight. Preferably the dose is from 10 to 30,000 μg per kg body weight, more preferably the dose is from 10 to 10,000 μg per kg body weight. For example, this dose may be appropriately administered repeatedly throughout the day. For the treatment of acute shock (e.g. anaphylactic shock) single doses may be administered which are clearly higher than the above-mentioned doses.

The preparation of pharmaceutical preparations based on new compounds is carried out in a known manner, in which the active substance is combined with carriers, fillers, compounds decomposing, binding compounds, drying compounds, slipping compounds, compounds affecting absorption, diluting compounds, compounds used in art taste correctors, dyes etc. and converted into the desired dosage form. See Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, East Pennsylvania (1980).

In particular, tablets, dragees, capsules, pills, powder, granules, pastilles, suspensions, emulsions or solutions are used for oral administration.

For parenteral administration, injection and infusion preparations may be used.

Properly prepared crystalline suspensions may be used for administration of intra-articular injections.

For intramuscular injections, aqueous and oily injection solutions or suspensions and appropriate prolonged formulations may be used.

For rectal administration, new compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments, which are used not only for general therapy, but also for topical therapy.

New compounds in the form of aerosols and inhalations can be used for pulmonary administration.

For topical administration to the eyes, external auditory canal, middle ear, nostrils, new compounds can be used as drops, ointments and tinctures in the form of suitable pharmaceutical preparations.

For topical use, preparations in the form of gels, ointments, fatty ointments, creams, pastes, powder, lotions and tinctures are possible. Doses of compounds of general formula I should be 0.01% -20% in these preparations to achieve sufficient pharmacological effect.

The invention also includes the compounds of the invention of general formula I as a therapeutic active substance. Furthermore, the invention includes the compounds of the invention of general formula I as a therapeutic active substance together with pharmaceutically tolerated and acceptable excipients and carriers.

The invention also encompasses a pharmaceutical composition which comprises the pharmaceutically active compounds of the invention or a mixture thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically tolerated salt or pharmaceutically tolerated excipients and carriers.

Experimental part

Example 1

4 - {[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl} -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2,3-dihydroisoindol-1-one

4-Amino-2,3-dihydro-isoindol-1-one

2-Methyl-3-nitrobenzoic acid methyl ester g (165.6 mmol) 2-methyl-3-nitrobenzoic acid is added to 150 ml of methanol, after adding 2.9 ml of concentrated sulfuric acid, the mixture is heated under reflux for two days. After cooling, the crystallized solid is filtered off (25.55 g = 79%) and used in the next step.

¹H-NMR (300 MHz, DMSO-d6): δ = 2.50 (3H), 3.85 (3H), 7.56 (1H), 8.00 (1H), 8.05 (1H).

2- (Bromomethyl) -3-nitrobenzoic acid methyl ester

25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester are added to 300 ml of carbon tetrachloride, followed by 25.6 g (141.7 mmol) of N-brososuccinimide and 62.8 mg of benzoyl peroxide. After seven days of heating under reflux, the succinimide is sucked off after cooling and the filtrate is rotary evaporated to dryness. The desired compound remains, which is used in the next step without purification.

¹H-NMR (300 MHz, CDCl3): δ = 4.00 (3H), 5.66 (2H), 7.55 (1H), 7.95 (1H), 8.10 (1H).

2- (Azidomethyl) -3-nitrobenzoic acid methyl ester

To 10 g (36.5 mmol) of 2 (bromomethyl) -3-nitrobenzoic acid methyl ester are added 36 ml of N, N-dimethylformamide and 24 ml of water. After adding 3.54 g of sodium azide, the mixture is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, washed twice with water and once with brine. After drying over sodium sulfate, it is filtered and the solvent is rotary evaporated. The desired azide is obtained in a yield of 89.6% (7.72 g) and is used without further purification.

¹H-NMR (300 MHz, CDCl3): δ = 4.00 (3H), 4.93 (2H), 7.58 (1H), 7.96 (1H), 8.12 (1H).

4-Amino-2,3-dihydroisoindol-1-one g (4.2 mmol) of 2- (azidomethyl) 3-nitrobenzoic acid methyl ester is added to 10 ml of ethanol and 2 ml of glacial acetic acid, followed by 148, 5 mg Pd / C. After stirring overnight at room temperature under a hydrogen atmosphere, the catalyst is suction filtered through a glass fiber filter and the filtrate is concentrated to dryness. The residue is chromatographed using Flashmaster (Mobile phase). 391.5 mg (62.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, DMSO-d6): 6.75 (1H), 6.85 (1H), 7.15 (1H) δ = 4.10 (2H), 8.35 (1H).

5.36 (2H),

4- (5-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl) -pentanal

6.55g (21.11 mmol) of rac-4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-trifluoromethyl) pentane-1,2-diol (WO 00/32584) is dissolved in 224 ml of dichloromethane and in 74 ml dry dimethyl sulfoxide and 10.68 g (105.55 mmol) triethylamine are added at room temperature. At 15 to 18 ° C, 10.08 g (63.33 mmol) of the pyridine SO3 complex are added portionwise over 40 minutes. After stirring overnight at room temperature, 84 ml of saturated ammonium chloride solution are added. There is slight heating. After stirring for 15 minutes at room temperature, it is extracted twice with 300 ml diethyl ether. The organic phases are washed with water and brine and dried (sodium sulfate). After filtering off the solvent and rotary evaporation of the solvent, the residue obtained is chromatographed on silica gel (mobile phase:

ethyl acetate / hexane). 5.85 g (90%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.40 (3H), 1.46 (3H),

2.22 (1H), 3.38 (1H), 3.59 (1H), 3.86 (1H), 6.70-6.80 (1H), 6.82 ~ 6.97 (2H), 9.05 (1H).

4 - {[4- (5-Fluoro-2-methoxyphenyl-2-hydroxy-4-methyl-2- (trifluoromethyl) pentylidene] amino} 2,3-dihydroizoindol1-one

400 mg (1.297 mmol) rac-4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluormethyl) pentanal and 192.1 mg (1.297 mmol) 4-amino-2,3-dihydroisoindole 1st in

1.89 ml glacial acetic acid is stirred for four days at room temperature. The mixture is mixed with toluene three times and concentrated to dryness on a rotational basis. Chromatography residue on silica gel (mobile phase: ethyl acetate / hexane). 429.7 mg (75.5%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.37 (3H),

2.22 (1H), 3.42 (1H), 3.84 (3H), 4.37 (2H),

6.53-6.68 (3H), 6.72-6.95 (2H), 7.37 (1H),

7.75 (1H).

on the evaporator it is given up

1.52 (3H),

4.68 (1H)

7.49 (1H),

4 - {[8-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2,3-dihydro-1- he (diastereomer A);

4 - {[8-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl} amino} -2,3-dihydroisoindol-1-one ( diastereomer A);

4 - {[8-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2,3-dihydroisoindol-1-one ( diastereomer B)

To 420 mg (0.958 mmol) of the compound described in the previous paragraph - 4 - {[4- (5-fluoro-2-methoxyphenyl) -2-hydroxy4-methyl-2- (trifluormethyl) pentylidene] amino} 2,3-dihydroisoindol-1- onu - 9.6 ml of a 1 M solution of boron tribromide in dichloromethane are added and stirred at room temperature for three quarters of an hour. Saturated sodium bicarbonate solution is added dropwise to pH 8 at -30 ° C to the reaction mixture. After dilution with ethyl acetate, the cooling bath is removed and stirred vigorously for 15 minutes. After extraction with ethyl acetate twice, the organic phases are washed with water and saturated sodium chloride solution. After drying (sodium sulfate) and rotary evaporation of the solvent, the residue is chromatographed (mobile phase: dichloromethane / methanol) using Flashmaster (silica gel, NH2 phase). 67.7 mg (16.6%) of 4 - {[8-fluoro-2-hydroxy-5-methoxy4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) is isolated. amino} -2,3-dihydroisoindol-1-one (diastereomer A, F1);

12.9 mg (3.2%)) 4 - {[8-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} - 2,3-dihydroisoindol-1one (diastereomer A, F2) and 32.2 mg (7.9%) 4 - {[8-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2 , 3,4-tetrahydronaphthalen-1-yl] amino} -2,3-dihydroisoindol-1-one (B, F3 diastereomer).

F1: ¹H-NMR (300 MHz, MeOD): δ = 1.47 (3H),

2.07 (1H), 2.25 (1H), 3.49 (3H), 4.19-4.40 (2H),

6.31 (1H), 7.00 (1H), 7.15-7.30 (2H), 7.38 (1H).

F2: ¹H-NMR (300 MHz, MeOD): δ = 1.50 (3H),

2.05 (1H), 2.28 (1H), 4.20-4.42 (2H), 5.18 (1H), 6.80-6.90 (1H), 7.15 (1H), 7.20-7.40 (2H).

F3: ¹H-NMR (300 MHz, MeOD): δ = 1.52 (3H),

2.03 (1H), 2.23 (1H), 4.20-4.39 (2H), 5.18 (1H) 6.80 (2H), 7.10-7.23 (2H), 7 , 35 (1H).

1.60 (3H),

5.20 (1H),

1.59 (3H),

6.61 (1H),

1.69 (3H), 6.65 Example 2

5 - {{7-Chloro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isoquinolin-1 (2H) -one

5-Amino-isoquinolin-1 (2H) -one

5-Nitroizokumaryna

16.4 g (84.03 mmol), described in Example 1, of 2-methyl-3-nitrobenzoic acid methyl ester are mixed with 26.8 g (225.1 mmol) of N, N-dimethylformamidodimethylacetal in 85 ml of dimethylformamide for 12 hours at 130 ° C. The solvent is removed on a rotary evaporator, the residue is taken up in methyl tert-butyl ether and washed three times with water. After washing with saturated NaCl solution, the organic phase is dried. After filtering off the drying agent and rotary evaporation of the solvent, the residue obtained is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 8.73 g (54.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 7.39 (1H), 7.45 (1H), 7.68 (1H), 8.49 (1H), 8.65 (1H).

5-Nitroizochinolin-1 (2H) -one

2.51 g (13.13 mmol) of 5-nitroisocoumarin is added to 100 ml of ethanol. Ammonia is introduced under pressure in the autoclave. The product precipitates and is subjected to filtration under reduced pressure. Is isolated

1.98 g (79.7%) of the desired compound.

¹H-NMR (300 MHz, DMSO-d6): δ = 6.97 (1H), 7.45 (1H), 7.65 (1H), 8.43 (1H), 8.57 (1H), 11 5 (1H).

5-Aminoisoquinolin-1 (2H) -one

268.3 mg (1.51 mmol) of 5-nitroisoquinolin-1 (2H} -one is added to 376.5 mg of ammonium chloride and 2.6 ml of water in 14 ml of ethanol and 5.4 ml of tetrahydrofuran. , 23 g zinc dust (heating to 30 to 35 ° C) is stirred for two hours. The reaction mixture is suction filtered through a glass fiber filter and washed with ethyl acetate. After washing the filtrate with water and saturated sodium chloride solution, the organic phase is dried as usual. . Filtration of the drying agent and rotary evaporation of the solvent gives 196.5 mg (88.1%) of the desired amine.

¹H-NMR (300 MHz, DMSO-d6): δ = 5.6 (2H), 6.68 (1H),

6.87.45 (1H), 7.00 (1H), 7.17 (1H), 7.39 (1H), 11.7 (1H).

4- (4-Chloro-2-methoxyphenyl] -2-hydroxy-4-methyl-2- (trifluoromethyl) pentan-1-ol

To a solution of 3 g of 2-hydroxy-4-methylene-2- (trifluoromethyl) valerate ethyl ester in 22 ml of 3-chloroanisole at room temperature is added aluminum trichloride in portions. After stirring for 48 hours at room temperature, 2 N hydrochloric acid and hexane are added to the mixture and stirred for a further hour. After washing with 2 N hydrochloric acid and water, the excess 3-chloroanisole is distilled off under reduced pressure. The obtained residue is purified by silica gel chromatography (mobile phase: hexane / ethyl acetate). 2.85 g of a mixture of 4- (4-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) valeric acid ethyl ester and 4- (2-chloro-4-methoxyphenyl) ethyl ester compound are obtained. ) -2-hydroxy-4-methyl-2- (trifluoromethyl) valerate as a yellow oil. To this mixture of substances in 90 ml of ether at 0 ° C, 445 mg of lithium aluminum hydride is added and stirred for 12 h. The mixture is added to saturated sodium bicarbonate solution and filtered through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. It is washed with water and brine, dried with sodium sulfate and concentrated under reduced pressure. After silica gel chromatography (mobile phase: hexane / ethyl acetate) is obtained as 1. 1.87 g fraction of the desired compound 4- (4-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-262 (trifluoromethyl) pentan-1-ol and as the second fraction - 160 mg of a regioisomeric compound - 4- (2- chloro-4-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentan-1-ol in the form of colorless oils.

1. fraction: ¹H-NMR (CDCl3), δ = 1.41 (3H), 2.24 (1H), 2.51 (1H), 2.84 (1H), 3.36 (1H), 3.85 (3H) , 6.88 (1H), 6.92 (1H), 7.24 (1H).

2. fraction: ¹H-NMR (CDCl3), δ = 1.52 (3H),

2.18 (1H), 2.76 (1H), 2.93 (1H), 3.33 (1H), 3.80 (3H), 6.78 (1H), 6.90 (1H), 7 , 38 (1H).

1.51 (3H),

3.48 (1H),

1.62 (3H),

3.55 (1H), dichloromethane.

dissolved

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4- (4-Chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal

854.6 mg (6.733 mmol oxalyl chloride in 14.5 mL) are added dropwise to a heated flask, 1.05 mL DMSO, dichloromethane, and then five minutes. Then 2 g (6.12 mmol chloro-2-methoxyphenyl) is added dropwise. ) -2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol, dissolved milliliters of dichloromethane. After stirring for 20 minutes, 4.24 ml (30.61 mmol) of triethylamine are carefully added to the mixture at a temperature between 70 and 60 ° C. After stirring for five minutes at -70 ° C, the reaction mixture is allowed to slowly reach room temperature. 25 ml of water are added and the mixture is stirred for a further hour at room temperature. After phase separation, the aqueous phase is shaken once with 100 ml of dichloromethane. The combined organic extracts are washed with 1% sulfuric acid, 5% sodium bicarbonate solution and brine. A typical procedure yields 1.92 g (96.9%) of the desired aldehyde, which is used in the next step without purification.

¹H-NMR (300 MHz, CDCl3): δ = 1.37 (3H), 1.45 (3H),

2.22 (1H), 3.35 (1H), 3.59 (1H), 3.90 (3H), 6.80-6.92 (2H), 7.04 (1H), 9.02 ( 1H).

5 - {[4- (4-Chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl) pentylidene] amino} isoquinolin-1 (2H) -one 300 mg (0.924 mmol) 4- (4-chloro -2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal is mixed with 148 mg (0.924 mmol) of 5-amino-isoquinolin-1-one in 1.33 ml of glacial acetic acid for four days at room temperature. Toluene is added to the mixture three times and concentrated on a rotary evaporator to dryness. The residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 382.4 mg (88.6%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.37 (3H), 1.58 (3H), 2.26 (1H), 3.43 (1H), 3.85 (3H), 4.80 (1H), 6.43 (1H), 6.59 (1H), 6.70-6.77 (2H), 7.00 (1H), 7.15-7.25 (1H), 7.307.45 (2H), 8.32 (1H), 11.00 (1H).

5 - {[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) amino} isoquinolin-1 (2H) -one

To 50 mg (0.107 mmol) of the compound described in the previous paragraph -5 - {[4- (4-chloro-2-methoxyphenyl) -2-hydroxy4-methyl-2- (trifluoromethyl) pentylidene] amino} 2,3isoquinolin-1- of onium, at -20 ° C, 2.1 ml of a 1 M solution of boron tribromide in dichloromethane are added and the mixture is stirred at a temperature range between 20 ° C and 0 ° C for two and a half hours. Saturated sodium bicarbonate solution is added dropwise to the reaction mixture at -20 ° C. After dilution with ethyl acetate, the mixture is allowed to reach room temperature, stirred for 15 minutes and extracted twice with ethyl acetate. The combined organic extracts are washed with water and saturated NaCl solution. After drying over sodium sulfate, the solvent is rotary evaporated and the residue obtained is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 12.5 mg (25%) of the desired compound is isolated.

¹H-NMR (300 MHz, MeOD): δ = 1.55 (3H), 1.65 (3H), 2.003.20 (2H), 5.13 (1H), 6.73 (1H), 6.80 (1H), 6.87 (1H),

7.09 (1H), 7.19 (1H), 7.40 (1H), 7.70 (1H).

Example 3 (+) - 6-fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol and

(-) - 6-fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimetylo2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2,5-diol

2,6-Difluoroanisole g (153.74 mmol) 2,6-difluorophenol is dissolved in 200 ml of acetone and 42.5 g (307.48 mmol) of potassium carbonate are added in a nitrogen atmosphere. After adding 19.1 ml of methyl iodide (2 equivalents), the mixture is heated under reflux for three and a half hours. After cooling, the reaction mixture is filtered, the filter residue is washed with acetone and the filtrate is evaporated to dryness by rotary evaporation. The residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 17.27 g (77.9%) of the desired product are obtained. Be careful that the product is easily volatile. The bath temperature should not exceed 30 ° C and the vacuum of the rotary evaporator should be adjusted.

¹H-NMR (300 MHz, CDCl3): δ = 4.00 (3H), 6.80-7.00 (3H).

2- (3-Fluoro-2-methoxyphenyl) -2-methylpropanenitrile 10 g (69.39 mol) of 2,6-difluoroanisole is dissolved in 200 ml of toluene and added at room temperature

5.75 g (83.27 mmol) of isobutyric acid nitrile. 166.5 ml of a 0.5 molar solution of potassium hexamethyldisilazide in toluene are added dropwise over 35 minutes. There is a slight increase in temperature to 27.5 ° C stirring at room temperature to

After 16 hours, the reaction mixture is added 200 ml water and 400 ml ethyl acetate and acidified with 10% sulfuric acid to pH 4. The organic phase is separated and the aqueous phase is shaken once with ethyl acetate (200 ml). The combined organic extracts are shaken with water and brine. After drying, filtration and rotary evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 7.66 g (57.1%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.76 (6H), 4.08 (3H), 6.957.13 (3H).

2- (3-Fluoro-2-methoxyphenyl) -2-methylpropanal

7.66 g (39.64 mmol) of the nitrile described above is dissolved in 158 mL of toluene. At -65 to -60 ° C, 49.5 ml of a 1.2 molar solution of DIBAH in toluene are added dropwise over 40 minutes. After stirring for one hour at this temperature, 493 ml of a 10% solution of L - (+) - tartaric acid are added dropwise. After 100 milliliters, the temperature rises to -10 ° C. The rest of the tartaric acid solution is quickly added and the mixture is vigorously stirred for two hours at room temperature. The reaction mixture is shaken twice with diethyl ether (400 ml each). The combined organic extracts are shaken with water and brine, dried and the solvent is rotary evaporated. The obtained residue (7.8 g = 102%) is used crude in the next step.

¹H-NMR (300 MHz, CDCl3): δ: 1.40 (6H), 3.88 (3H), 6.957.10 (3H), 9.60 (1H).

(E / Z) -4- (3-fluoro-2-methoxyphenyl) 4-methylpent-2-enoic acid ethyl ester

To a solution of 9.87 g (39.75 mmol) of 2-ethoxyphosphonoacetic acid triethyl ester in 40 ml of absolute THF is added dropwise at 0 ° C 21.3 ml of a 2 molar solution of LDA in THF. After stirring for 30 minutes at 0 ° C, 7.8 g (39.75 mmol) of 2- (3-fluoro-2-methoxyphenyl) -2-methylpropanal, dissolved in 26 ml of THF, are added dropwise at 0 ° C. The cooling bath is removed and the mixture is stirred for 16 hours at room temperature. The reaction mixture is poured onto water and extracted twice with ethyl acetate. The combined organic extracts are washed with water and brine, dried and the solvent is evaporated by rotary filtration after drying. The residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 8.39 g (68.2%) of the desired compound is isolated.

MS (CI): 328 (29%), 265 (100%), 181 (56%), 167 (42%).

(E / Z) -4- (3-fluoro-2-methoxyphenyl) -4-methylpent-2enoic acid

To 8.39 g (27.03 mmol) of (E / Z) -4 (3-fluoro-2-methoxyphenyl) -4-methylpent-2-enoic acid ethyl ester is added 270 ml of 1 N NaOH in ethanol / water ( 2: 1) and two days are stirred at room temperature. Ethanol is removed by rotary evaporation and the residue is extracted twice with diethyl ether (150 ml each). The combined organic extracts are washed with water and discarded after control by TLC. The aqueous phases are acidified with conc. hydrochloric acid to pH 3 and extracted twice with diethyl ether (300 ml each). The ether extracts are washed with water and brine, dried, the solvent is rotary evaporated and the residue (5.89 g = 77.2%) is used crude in the next step.

MS (CI): 300 (100%), 282 (10%), 237 (27%), 167 (26%).

4- (3-fluoro-2-methoxyphenyl} -4-methyl-2-oxopentanoic acid

To 5.89 g (20.86 mmol) of (E / Z) -4- (3-fluoro-2-methoxyphenyl) -4-methylpent-2-enoic acid is added 126 ml of 1 molar sulfuric acid at room temperature and after addition of 21 ml glacial acetic acid is stirred for 15 hours at 90 ° C bath temperature. To the reaction mixture, while cooling in an ice bath, solid potassium carbonate is added carefully (strong foaming) to pH 9. It is extracted twice with diethyl ether. The combined organic extracts are washed with water and discarded after TLC. The combined aqueous phases are acidified with conc. hydrochloric acid to pH 4 and extracted twice with diethyl ether (300 ml each). The ether extracts are washed with water and brine, dried and the solvent is evaporated on a rotary basis. Since the residue still contains acetic acid, it is rotary evaporated twice with toluene (100 ml each). The obtained residue (4.14 g = 78.1%) is used crude in the next step.

¹H-NMR (300 MHz, CDCl3): δ = 1.50 (6H), 3.53 (2H), 3.93 (3H), 6.90-7.10 (3H).

4- (3-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-pentanoic acid ethyl ester

4.14 g (16.28 mmol) of 4- (3-fluoro-2-methoxyphenyl) 4-methyl-2-oxo-pentanoic acid is dissolved in 97 ml of ethanol, 1.79 ml of sulfuric acid are added and heated under reflux condenser. on a rotary evaporator and a saturated sodium bicarbonate solution is carefully added to the residue to pH 9. It is extracted twice with ethyl acetate (100 ml each) and the combined organic extracts are washed with water and then with brine. After filtration of the drying agent and evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 4.16 g (90.6%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.29 (3H), 1.48 (6H), 3.40 (2H), 3.98 (3H), 6.89-7.09 (3H) .

at reflux four are removed by drying in a rotary ethanol

4- (3-fluoro-2-methoxyphenyl} -4-methyl-2- (trifluoromethyl} -2-trimethylsilyloxypentanoic acid ethyl ester

4.16 g (14.74 mmol) of 4- (3-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-pentanoic acid ethyl ester are dissolved in 24 ml of THF and 2.51 g (17) are added at 0 ° C. , 68 mmol) (trifluoromethyl) trimethylsilane and 36.1 mg tetrabutylammonium fluoride. After stirring for two and a half hours at a temperature between 0 and 5 ° C, the mixture is poured onto 50 ml of ice water. It is extracted twice with diethyl ether (150 ml each) and the combined organic extracts are treated as usual. After chromatography on silica gel (mobile phase: ethyl acetate / hexane), 5.24 g (83.8%) of the desired compound are obtained.

MS (CI): 442 (100%), 425 (41%).

4- (3-fluoro-2-methoxyphenyl] -4-methyl-2- (trifluoromethyl] -2-trimethylsilyloxy-pentan-1-ol

5.24 g (12.34 mmol) of 4- (3-fluoro-2-methoxyphenyl) -4-methyl-2-trifluoromethyl-2-trimethylsilylpentanoic acid ethyl ester are dissolved in 45 ml of diethyl ether and in portions are added in portions at 0 to 5 ° C

936.9 mg (24.69 mmol) LiAlH4. After stirring at room temperature for four and a half hours, saturated NaHCO3 solution is carefully added to the reaction mixture under cooling in an ice bath, stirred for one hour in the cold and overnight at room temperature. After a typical treatment, 4.11 g (87.1%) of a mixture of the desired compound and the compound in which the silyl ether has been removed is obtained. The mixture is used crude in the next step.

4- (3-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentan-1-ol

4.11 g (10.75 mmol) 4- (3-fluoro-2-methoxyphenyl) -4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentan-1ol is dissolved in 61 ml THF, 3.39 g (10.746 are added) mmol) Bu4NF trihydrate and stir for one hour at room temperature. The reaction mixture is poured onto water and extracted twice with diethyl ether. The organic phases are washed as usual with water and brine. After drying, filtration of the drying agent and rotary evaporation of the solvent, the residue obtained is chromatographed on silica gel (mobile phase: ethyl acetate / hexane).

2.71 g (81.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.45 (3H), 1.54 (3H),

2.20 (1H), 2.54 (1H), 2.90 (1H), 3.30-3.50 (2H), 3.98 (3H),

6,90-7,13 (3H).

4- (3-Fluoro-2-methoxy-phenyl} -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal

765 mg (6.03 mmol) of oxalyl chloride in 13 ml of dichloromethane are placed in a heated flask. At -78 ° C 0.855 ml DMSO, dissolved in 2.5 ml dichloromethane, are added dropwise, and then the mixture is stirred for five minutes. 1.7 g (5.48 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanol, dissolved in five milliliters of dichloromethane, are then added dropwise. After stirring for 15 minutes, 3.79 ml (27.40 mmol) of triethylamine are carefully added to the mixture, stirred for five minutes at -78 ° C and then slowly left at room temperature. Ml water is added and the mixture is stirred for a further hour at room temperature. After phase separation, the aqueous phase is shaken once

100 ml of dichloromethane.

The combined organic extracts are washed with 1% sulfuric acid, 5% sodium bicarbonate solution and brine. A typical procedure yields 1.617 g (96.2%) of aldehyde, which is used in the next step without purification.

¹H-NMR (300 MHz, CDCl3): δ = 1.40 (3H), 1.49 (3H),

2.29 (1H), 3.29 (1H), 3.59 (1H), 4.00 (3H), 6.85-7.08 (3H), 9.13 (1H).

1,1,1-Trifluoro-4- (3-fluoro-2-methoxyphenyl) -2 - [(1Hindazol-4-yl) iminomethyl] -4-methylpentan-2-ol

1.46 g (4.746 mmol) 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentanal for two days at room temperature mixed with 632 mg (4.746 mmol) 4- aminoindazole in 6.78 ml glacial acetic acid. The reaction mixture is concentrated three times with toluene on a rotary evaporator and the residue is chromatographed on silica gel (mobile phase:

ethyl acetate / hexane). 1.47 g (73.5%) of the desired compound is isolated.

MS (ES +): 424 (100%).

(+) - 6-fluoro-5-methoxy-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol and ( -) - 6-fluoro-5-methoxy-1 - {(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

1.32 g (3.117 mmol) of the above-mentioned imine, 1,1,1-trifluoro-4- (3-fluoro-2-methoxyphenyl) -2 - [(1H-indazol4-yl) iminomethyl] -4-methylpentan-2-ol , dissolved in 22.8 ml of dichloromethane. To this solution, 9.35 ml of a 1 M solution of TiCl4 in dichloromethane (3 equivalents) is added at -30 ° C under a nitrogen atmosphere over 15 min. The reaction mixture is stirred for three and a half hours at -30 to -15 ° C. Saturated sodium bicarbonate solution is added dropwise to the mixture at -30 ° C. After dilution with ethyl acetate, it is stirred for 15 minutes at room temperature. After extraction with ethyl acetate twice, the organic phases are washed with brine), dried (Na2SO4) and the solvent is rotary evaporated. After silica gel chromatography (mobile phase, 1.07g (81.1%) racemate is obtained. The product is separated into its enantiomers (Chiralpak AD 5μ; Mobile phase: hexane / ethanol). (+) The enantiomer shows a rotation of 150 ml (water, dichloromethane / methanol) of the desired product as c = 1, [α] π = +1.6 enantiomer [a]_D = -1.3 ° (c = 1, MeOH)

MeOH) (+) - 6-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol Up to 200 mg (0.472 mmol) of the above (+) - 6-fluoro-5-methoxy-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-271 (trifluoromethyl) -1,2,3 , 4-tetrahydronaphthalen-2-ol at room temperature is added 4.7 ml of a 1 M solution of BBr3 in dichloromethane and stirred for three and a half hours at room temperature. Saturated sodium bicarbonate solution is added dropwise to the reaction mixture at -30 ° C to pH 8. After dilution with ethyl acetate, the cooling bath is removed and the mixture is stirred vigorously for 15 minutes. After shaking twice with ethyl acetate, the combined organic extracts are washed with water and saturated brine. After drying over sodium sulfate, filtration and rotary evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol).

171.3 mg (88.6%) of the desired compound are obtained.

The rotation, measured at room temperature, is [αΐπ = +7.3 (c = 1, MeOH).

(-) - 6-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol Up to 200 mg (0.472 mmol) of the above described (-) - 6-fluoro-5-methoxy-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2 (trifluoromethyl) -1,2,3,4 -tetrahydronaphthalen-2-ol at room temperature 4.7 ml of a 1 M solution of BBr3 in dichloromethane are added and the mixture is stirred at room temperature for three and three quarters of an hour. Saturated sodium bicarbonate solution is added dropwise to the -30 ° C reaction mixture to pH 8. After dilution with ethyl acetate, the cooling bath is removed and the mixture is stirred vigorously for 15 minutes. After shaking twice with ethyl acetate, the combined organic extracts are washed with water and saturated brine. After drying over sodium sulfate, filtration and rotary evaporation of the solvent, the residue on silica gel (mobile phase: dichloromethane / methanol) is chromatographed. 179.4 mg (92.8%) of the desired compound are obtained. Rotation, measured at room temperature, is [a]_D = -7.8 (c = 1, MeOH).

Example 4

4 - {[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -6-fluoro-2,3-dihydroizoindol- 1-one

4-Amino-6-fluoro-2,3-dihydro-isoindol-1-one

2-Methyl-5-fluoro-3-nitrobenzoic acid

116 ml sulfuric acid are introduced and 14.70 g (95.37 mmol) of 5-fluoro-2-methylbenzoic acid are added in portions at -15 ° C. To this mixture, the nitrating mixture (4.79 ml of fuming nitric acid and 21.8 ml of concentrated sulfuric acid) is added dropwise at -15 to 10 ° C during 90 min. After stirring for three hours, the reaction mixture is poured onto ice water and stirred vigorously for about half an hour. The precipitated crystals are suction filtered, washed with inert water and dried. The yield is 8.56 g (45.1%) of a mixture of various regioisomers and by-products. The mixture is used in the next step (esterification) and purified at this stage.

2-methyl-5-fluoro-3mmol) acid is added and added

2-methyl-5-fluoro-3do 76 ml N, N9.15 g (64.48 mmol)

Nitrobenzoic acid methyl ester

8.56 g (42.99 nitrobenzoic dimethylformamide methyl iodide and 8.91 g (64.48 mmol) potassium carbonate. After 65 hours of stirring at room temperature, the reaction mixture is added to ice water and repeatedly extracted with ethyl acetate. Combined organic extracts washed with water and brine. After drying (sodium sulfate), the solvent is sucked off from the center, and the solvent is rotary evaporated, silica gel chromatography (mobile phase: ethyl acetate / hexane) gives the desired compound in 25.9% yield (2.37 g).

drying and multiple ¹H-NMR (300 MHz, CDCl3): δ = 2.60 (3H), 3.96 (3H),

7.61 (1H), 7.77 (1H).

2- (Bromomethyl} -5-fluoro-3-nitrobenzoic acid methyl ester

2.37 g (11.12 mmol) of 5-fluoro-2-methyl-3-nitrobenzoic acid methyl ester is added to 35 ml of carbon tetrachloride and 2.24 g (12.24 mmol) of N-brososuccinimide and 5.4 mg of benzoyl peroxide are added . After refluxing for four days, after cooling, the succinimide is suction filtered (fiberglass filter) and then the filtrate is evaporated to dryness by rotary evaporation. Chromatography using Flashmaster gives 2.47 g (75.9%) of the desired compound.

¹H-NMR (300 MHz, CDCl3): δ = 4.01 (3H), 5.13 (2H), 7.72 (1H), 7.87 (1H).

Nitrobenzoic acid methyl ester

Up to 2.47 g (8.46 mmol)

2- (azidomethyl) -5-fluoro-3-methyl ester 2 (bromomethyl) -5-fluoro-3-nitrobenzoic acid is added

8.3 ml N, N-dimethylformamide and 5.5 ml water. After adding 0.82 g (12.66 mmol) of sodium azide, the mixture is stirred overnight. The reaction mixture is poured onto water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with water and brine. After drying over sodium sulfate, it is filtered and the solvent is evaporated on a rotary basis.

Chromatography using Flashmaster gives 2.06 g (95.8%) of the desired azide.

¹H-NMR (300 MHz, CDCl3): δ = 4.00 (3H), 4.90 (2H), 7.73 (1H), 7.87 (1H).

4-Amino-6-fluoro-2,3-dihydro-isoindol-1-one

1.86 g (7.32 mmol) of 2 (azidomethyl) -5-fluoro-3-nitrobenzoic acid methyl ester are added to 46 ml of ethanol and 3.4 ml of glacial acetic acid and 256.6 mg of Pd / C are added. After stirring overnight at room temperature under a hydrogen atmosphere, the catalyst is suction filtered through a glass fiber filter and the filtrate is concentrated to dryness. The residue, 1.18 mg (97.5%) of the desired compound is used without further purification.

¹H-NMR (300 MHz, DMSO-d6): δ = 4.10 (2H), 5.75 (2H), 6.466.57 (2H), 8.50 (1H),

4 - {[4- (5-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentylidene] amino} -6-fluoro-2,3-dihydroisoindol-1-one

400 mg (1.297 mmol) rac-4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl) pentanal for four days at room temperature is mixed with 215.5 mg (1.297 mmol) 4- amino-6-fluoro-2,3-dihydroisoindol-1one in 1.89 ml glacial acetic acid. Since the starting material is still contained according to TLC, toluene is added to the reaction mixture and heated to reflux for 20 hours on a water separator. Toluene is added to the mixture three times and concentrated to dryness on a rotary evaporator. The residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 383.4 mg (64.7%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.37 (3H), 1.53 (3H), 2.20 (1H), 3.47 (1H), 3.88 (3H), 4.32 (2H), 4.57 (1H), 6.22 (1H), 6.63-6.88 (4H), 7.42 (1H), 7.48 (1H).

4 - {[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -6-fluoro-2,3-dihydroizoindol- 1-one

To 380 mg (0.832 mmol) of 4 - {[4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentylidene] amino} 6-fluoro-2,3-dihydroisoindol-1-one is added at room temperature 8.3 ml of a 1 M solution of BBr3 in dichloromethane and stirred for one hour at ice bath temperature. The working up of the mixture takes place as described in the Example

4. Chromatography of the crude product using Flashmaster (Amine phase; Mobile phase: methanol / dichloromethane) affords 9.2 mg (2.7%) of the desired compound.

¹H-NMR (300 MHz, CD3OD): δ = 1.53 (3H), 1.69 (3H),

2.02 (1H), 2.22 (1H), 4.28 (2H), 5.09 (1H), 6.60-7.00 (4H).

Example 5

4 - {[5-Fluoro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2,3-dihydroisoindol-1-one

2-Fluoro-3-methoxybenzaldehyde (240.62 mmol) 2-fluoroanisole is dissolved in 700 ml of tetrahydrofuran. At -70 ° C, 200 ml sec. Are added dropwise. BuLi (1.3 m solution is stirred at -70 ° C cyclohexane for an hour) and then

152 ml of N, N-dimethylformamide, dissolved in butyl and organic ml, are added dropwise at this temperature. extracts tetrahydrofuran. After a further stirring hour at -70 ° C, 380 ml of hydrochloric acid (w = 10%) are added dropwise. The mixture slowly reaches room temperature. After stirring overnight at room temperature, tert-methyl ether is added. After vigorous stirring, the aqueous phase is separated off twice more with tert-butyl methyl ether.

The combined organic extracts are washed with brine and dried. After filtering off the drying agent, the solvent is evaporated by rotary evaporation and the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane).

25.66 g (69.2%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 3.95 (3H), 7.13-7.26 (2H), 7.38-7.45 (1H), 10.4 (1H).

2-fluoro-3-methoxybenzyl alcohol

25.66 g (166.47 mmol) of 2-fluoro-3-methoxybenzaldehyde are dissolved in 140 ml of ethanol and 3.15 g (83.35 mmol) of sodium borohydride are added in portions at 0 ° C. After stirring for one hour at room temperature, water is added to the reaction mixture and extracted three times with methyl tert-butyl ether. The combined organic extracts are shaken with water and brine, dried, the drying medium is suction filtered and the solvent is rotary evaporated. The residue obtained is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 24.79 g (95.3%) of the desired compound are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 3.90 (3H), 4.78 (2H), 6.887.10 (3H).

butyl solution is extracted and carbonate twice

2-fluoro-3-methoxybenzyl chloride

24.79 g (158.75 mmol) of 2-fluoro-3-methoxybenzyl alcohol are dissolved in 35 ml of dichloromethane. 58.4 ml of thionyl chloride are added dropwise with slight cooling and the mixture is then stirred at room temperature overnight. The reaction mixture is rotary evaporated to dryness, the residue is dissolved in tert-methyl ether and shaken with semi-saturated potassium. The aqueous phase once with methyl tert-butyl ether. The combined organic extracts are treated as usual. The residue obtained is used crude in the next step.

¹H-NMR (300 MHz, CDCl3): δ = 3.90 (3H)

7.10 (3H).

4.65 (2H), 6.90 2-fluoro-3-methoxybenzyl cyanide

24.89 g (142.56 mmol) of 2-fluoro-3-methoxybenzyl chloride are mixed in 200 ml of DMSO with 8.38 g (171.07 mmol) of sodium cyanide for three hours at 90 ° C. The reaction mixture is poured onto water and extracted four times with methyl tert-butyl ether.

The combined organic phases are washed with brine, dried, the drying medium is suction filtered and the solvent is rotary evaporated. First, only a portion of the residue (21.43 g) is used crude in the next step.

¹H-NMR (300 MHz, CDCl3): δ = 3.77 (2H), 3.90 (3H), 6.897.07 (2H), 7.08-7.15 (1H).

2- (2-Fluoro-3-methoxyphenyl) -2-methylpropanenitrile 4 g (24.22 mmol) of 2-fluoro-3-methoxybenzyl cyanide is dissolved in 38 ml of N, N-dimethylformamide and 6.87 g (48 g) is added , 35 mmol) methyl iodide. At 0 ° C, 2.11 g (48.35 mmol) of sodium hydride (55%) are added portionwise over 45 minutes. After stirring for 20 hours at room temperature, the mixture is poured onto ice water and extracted three times with 200 ml diethyl ether each time. The organic phases are washed with water and brine and dried. After filtering off the drying agent and rotary evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 4.66 g (99.5%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.80 (6H), 3.90 (3H), 927.02 (1H), 7.02-7.11 (2H).

2- (2-Fluoro-3-methoxyphenyl) -2-methylpropanal

4.66 g (24.12 mmol) 2- (2-fluoro-3-methoxyphenyl) -2-methylpropanenitrile is dissolved in 96 ml of toluene. At -65 ° C to -60 ° C, 30 ml (36.18 mmol) of a 1.2 molar solution of DIBAH in toluene are added dropwise. After stirring for three and a half hours at -65 ° C at this temperature, 276 ml of 10% L (+) - tartaric acid solution are added dropwise. The temperature rises to 0 ° C. The cooling bath is removed and the mixture is stirred vigorously for one hour at room temperature. The reaction mixture is extracted three times with 300 ml diethyl ether each time. The combined organic extracts are treated as usual (water, brine, drying). 4.78 g (slightly more than 100%) of the desired compound remains after rotary evaporation of the solvent.

¹H-NMR (300 MHz, CDCl3): δ = 1.46 (6H), 3.89 (3H), 6.856.7.00 (2H), 7.08-7.15 (1H), 9.65 ( 1H).

E / Z-4- (2-fluoro-3-methoxyphenyl) 4-methylpent-2-enoic acid methyl ester

20.26 g (111, 26 mmol) of phosphonoacetic acid trimethyl ester are placed in 68 ml of tetrahydrofuran. 61 ml of a 2M solution of LDA in THF / heptane / ethylbenzene are added dropwise at 0 ° C. After stirring for 45 minutes, 21.83 g (111.26 mmol) of 2- (2-fluoro-3-methoxyphenyl) -2-methylpropanal, dissolved in 68 ml of tetrahydrofuran, are added dropwise at 0 ° C. After stirring overnight while cooling in an ice bath, water is added to the reaction mixture and extracted three times with methyl tert-butyl ether. The combined organic extracts are treated as usual and the residue obtained is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 23.30 g (75.8%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.50 (6H), 3.73 (3H), 3.88 (3H), 5.74 (1H), 5.80 (1H), 6.80 -7.10 (3H).

4- (2-fluoro-3-methoxyphenyl} -4-methylpentanoic acid methyl ester

To 23.30 g (84.33 mmol) of E / Z-4- (2-fluoro-3-methoxyphenyl) -4-methylpent-2-enoic acid methyl ester in 310 ml of ethanol is added 1.2 g of palladium on carbon and hydrogen atmosphere is stirred at room temperature overnight. The catalyst is removed by filtration through a glass fiber filter and the residue remaining after concentration is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 19.58 g (83.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ 1.48 (6H), 2.00-2.18 (4H), 3.60 (3H), 3.90 (3H), 6.78-7.03 (3H).

4- (2-fluoro-3-methoxyphenyl} -2-hydroxy-4-methylpentanoic acid methyl ester

19.58 g (77 mmol) of 4- (2-fluoro-3-methoxyphenyl) -4-methylpentanoic acid methyl ester are placed in 245 ml of tetrahydrofuran and the reaction mixture is cooled to -70 ° C. 220.7 ml of a 0.5 molar solution of potassium bis- (trimethylsilylamide) in toluene are added dropwise within one hour, and the reaction mixture is then stirred 45 minutes at -70 ° C. 28.3 g (107.79 mmol) of Davis reagent dissolved in 245 ml of tetrahydrofuran are added dropwise within 40 minutes. After stirring for 2 hours at -70 ° C, 250 ml of saturated ammonium chloride solution are slowly added dropwise and the mixture is brought to room temperature. After extraction with tert-butyl methyl ether, the combined organic extracts are treated as usual with water and brine. After rotary evaporation of the solvent, the residue is repeatedly chromatographed on silica gel (mobile phase: ethyl acetate / hexane). Finally, 12.14 g (58.3%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.45 (3H), 1.49 (3H), 1.902.01 (1H), 2.38-2.50 (2H), 3.70 (3H) , 3.90 (3H), 3.924,03 (1H), 6.80-7.08 (3H).

Methyl 4- (2-Fluoro-3-methoxyphenyl) -4-methyl-2-oxopentanoate

11.14 g (41.22 mmol) of methyl 4- (2-fluoro-3-methoxyphenyl} -2-hydroxy-4-methyl-pentanoate are added to 260 ml of dichloromethane and 71.3 ml of dimethyl sulfoxide. After addition of 20.8 g ( 205.78 mmol) triethylamine, 13 g (81.71) of the SO3 / pyridine complex are added to the mixture and then stirred at room temperature overnight, 100 ml of saturated ammonium chloride solution is added to the reaction mixture under gentle cooling and vigorously stirred. After extraction three times with methyl tert-butyl ether, the combined organic phases are treated as usual. The residue obtained after rotary evaporation of the solvent together with the residue obtained from the sample taken (1 g), is subjected to silica gel chromatography (Mobile phase: ethyl acetate / hexane).

10.03 g (83.2%, from two mixtures) of the desired compound are isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.49 (6H), 3.39 (2H),

3.73 (3H), 3.89 (3H), 6.80-6.91 (2H), 6.95-7.07 (1H).

Methyl 4- (2-Fluoro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl] -2- (trimethylsilyloxy) -pentanoate

10.03 g (37.39 mmol) of methyl 4- (2-fluoro-3-methoxyphenyl) -4-methyl-2-oxopentanoate are dissolved in 63 ml of tetrahydrofuran, 5.68 g (39.98 mmol) (trifluoromethyl) are added -trimethylsilane and then 82.3 mg tetrabutylammonium fluoride. After stirring overnight at room temperature, the mixture is added to ice water, extracted with tert-butyl methyl ether and the combined organic extracts are processed as usual. After rotary evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). Next to

6.94 g (45.2%) of the desired product, 2.75 g of starting material (impure) is isolated, which is subjected to the same procedure again. As a result, a further 1.91 g of methyl 4- (2-fluoro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -2 (trimethylsilyloxy) pentanoate is provided.

MS (CI): 428 (100%), 395 (67%).

4- (2-Fluoro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl] -2- (trimethylsilyloxy) pentan-1-ol and

4- (2-fluoro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl} -1- (trimethylsilyloxy) pentan-2-ol

8.85 g (21.56 mmol) of methyl 4- (2-fluoro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -2- (trimethylsilyloxy) pentanoate are dissolved in 77 ml of diethyl ether. To this solution is added in portions at 0 ° C

1.64 g (43.12 mmol) of lithium aluminum hydride. After stirring for 4 hours at room temperature, it is again cooled to 0 ° C. and circa 80 ml of saturated sodium bicarbonate solution is carefully added dropwise. Then stir for an hour at room temperature. The mixture is repeatedly extracted with tert-butyl methyl ether. The combined organic extracts are washed with water and then with brine. After drying over sodium sulfate, the drying agent is suction filtered, the solvent is rotated and the residue (7.36 g; a mixture of both silyl ether regioisomers) is used crude in the next step.

6.07 g (19.24 tetrabutylammonium at room temperature

After completion (mobile phase: 5.3 g (88.8%)

4- (2-Fluoro-3-methoxyphenyl) -4-m -ethyl-2- (trifluoromethyl) pentane-1,2-diol

7.36 g (19.24 mmol) of the mixture of both silyl ethers is dissolved in 108 ml of tetrahydrofuran, mmol) of fluoride trihydrate is added and stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, washed with water and brine and then the organic solvent after drying is rotary evaporated. silica gel chromatography (ethyl acetate / hexane) to obtain the desired compound.

¹H-NMR (300 MHz, CDCl3): δ = 1.45 (3H), 1.58 (3H),

2.20 (1H), 2.38 (2H), 2.93 (1H), 3.30-3.40 (1H), 3.60 (1H), 3.89 (3H), 6.85- 6.98 (2H), 6.98-7.09 (1H)

3,504- (2-Fluoro-3-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) -pentanal

2.5 g (8.06 mmol) rac-4- (2-fluoro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentane-1,2-diol is placed in a mixture of 52 ml dichloromethane, 14 ml dimethyl sulfoxide and 4.08 g (40.29 mmol) of triethylamine. 2.57 g (16.11 mmol) of the SO3 / pyridine complex is added at room temperature and the mixture is stirred at this temperature overnight. Saturated ammonium chloride solution is added to the reaction mixture and stirred vigorously. After further typical work-up, 2.11 g (85%) of the desired aldehyde are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 1.45 (3H), 1.50 (3H), 2.30 (1H), 3.12 (1H), 3.62 (1H), 3.89 (3H), 6.75 (1H), 6.90 (1H), 7.00 (1H), 9.15 (1H).

4 - {[5-Fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2,3-dihydro-1- he

To 150 mg (0.487 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-2-trifluoromethylpentanal in 0.9 ml of glacial acetic acid is added 72.7 mmol) 4-amino-2,3-dihydroisoindole -1-one and stirred at room temperature. The mixture is dry evaporated by rotary evaporation and the residue is chromatographed (Flashmaster). 119.8 of the desired cyclic compound is isolated.

MHz, CDCl3): δ = 1.50 (3H)

2.20 (1H), 3.83 (3H), 4.29 (2H), mg (0.487 two days mg (56.2% ¹H-NMR (300 2.05 (1H),

5.00 (1H)

7.35 (1H),

6.79 (1H)

6.93 (1H)

7,00-7,12 (2H)

1.65 (3H),

4.40 (1H)

7.21 (1H),

4 - {[5-Fluoro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2, 3,4-tetrahydronaphthalen-1-yl] amino} -2,3-dihydroisoindol-1-one

Up to 109.8 mg (0.250 mmol) (rac.) 4 - {[5-fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalene-1- yl] amino} -2,3-dihydroisoindol-1-one, 3.4 ml of a 1 M solution of BBr3 in dichloromethane are added and the mixture is stirred at room temperature for four hours. Saturated sodium bicarbonate solution is added to the mixture at 0 ° C and extracted twice with ethyl acetate. The combined organic extracts are dried over sodium sulfate. After filtering off the drying agent and rotary evaporation of the solvent, the residue is chromatographed using Flashmaster. 15.6 mg (14.7%) of the final product are isolated.

¹H-NMR (300 MHz, CD3OD): δ = 1.53 (3H), 1.67 (3H), 2.003.20 (2H), 4.28-4.43 (2H), 5.13 (1H) , 6.78 (1H), 6.90 (2H), 7.18 (1H), 7.38 (1H).

Example 6

4 - {[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl} -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -1,3-dihydro-indol-2-one

4-Amino-1,3-dihydro-indol-2-one

Dimethyl 2- (2,6-dinitrophenyl) malonate 42.95 g (311.03 mmol) dimethyl malonate is dissolved in 300 ml of N, N-dimethylformamide and added in portions

35.15 g (296.22 mmol) by distilling the resulting reaction is cooled to tert-butanol tert-butylate, to 20 ° C. To potassium. After the mixture is stirred, 30 g (148.11 mmol) are continuously added in portions.

2,6-dichlorobenzene. After stirring for three hours at 90 ° C, it is stirred at room temperature overnight. The reaction mixture is added to 800 ml of 1% NaOH solution (ice-cooled) and extracted three times with methyl tert-butyl ether. The combined ether phases are discarded after control by TLC. The aqueous phase, while cooling on an ice bath, is carefully acidified with concentrated nitric acid (w = 65%). Extraction six times with methyl tert-butyl ether, typical treatment of combined organic extracts (water, brine, drying, filtration and rotary evaporation of the solvent) provides a residue which is subjected to silica gel chromatography (mobile phase: ethyl acetate / hexane). 12.09 g (27.09%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ =

7.75 (1H), 8.27 (2H).

3.82 (6H), 5.39 (1H), (2,6-Dinitrophenyl) methyl acetate

To 10.08 g (33.8 mmol) of dimethyl 2- (2,6-dinitrophenyl) malonate in 54 ml of glacial acetic acid is added

2.7 ml of perchloric acid and heated at reflux at 125 ° C. The ethyl acetate formed is distilled off. After 90 minutes, the reaction is terminated because according to TLC there is no more starting material. The reaction mixture is poured onto ice water and extracted three times with ethyl acetate. The combined organic extracts are shaken with a 5% sodium bicarbonate solution, water and brine. After drying the organic phase, filtering off the drying agent and rotary evaporation of the solvent, a residue is obtained which is subjected to silica gel chromatography (Mobile phase: ethyl acetate / hexane). 4.69 g (2,6-dinitrophenyl) acetic acid is isolated, which is then esterified with methanol (16 mL) and conc. sulfuric acid (0.4 ml). To this end, the acid and reagents are refluxed for seven hours. The methanol is rotary evaporated and the residue is typically treated. After silica gel chromatography (mobile phase: ethyl acetate / hexane), 4.43 g (89%) of the desired ester is obtained.

¹H-NMR (300 MHz, CDCl3): δ = 3.75 (3H), 4.20 (2H), 7.69 (1H), 8.19 (2H).

4-Amino-1,3-dihydro-indol-2-one

4.43 g (18.45 mmol) (methyl 2,6-dinitrophenyl) -acetate are added to 38.8 mL glacial acetic acid and 11 mL water, 3.75 g iron dust are added and then stirred for four hours. Heating to 40 to 60 ° C occurs. The reaction mixture is added to ice water, ethyl acetate is added and stirred vigorously for ten minutes. The mixture is filtered through a glass fiber filter, the organic phase is separated off and the aqueous phase is extracted twice more with ethyl acetate.

The combined organic extracts are washed with brine, dried and the solvent after filtration of the drying agent is evaporated by rotary evaporation. The residue is chromatographed on silica gel (mobile phase: methanol / dichloromethane). 2.38 g of 4-nitro-indol-2-one are isolated. 2.7 g of iron dust are added once more to the nitro compound in glacial acetic acid / water and the above described cycle is repeated. 1.63 g of the desired amine is isolated.

¹H-NMR (300 MHz, DMSO-d6): δ = 3.19 (2H), 5.03 (2H), 6.08 (1H), 6.22 (1H), 6.85 (1H), 10 10 (1H).

4- (4-Bromo-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentane-1,2-diol

2.55 g (6.17 mmol) of 4- (4-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanoic acid ethyl ester (synthesized in two steps starting from 4- (4- bromo-2-methoxyphenyl) -2-oxopentane, WO 98/54159) is dissolved in 102 ml diethyl ether, 351.3 mg (9.256 mmol) of lithium aluminum hydride are added portionwise at 0 to -5 ° C and for three half hour is stirred at room temperature. Saturated sodium bicarbonate solution is added dropwise to the reaction mixture under cooling in an ice bath, for 15 minutes at 5 ° C and then stirred for one hour at room temperature. The precipitate is suction filtered, washed with diethyl ether and the filtrate is concentrated on a rotary evaporator. The residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). In addition to 308 mg of aldehyde (see next step) 2.025 g (88.4%) of diol are obtained.

4- (4-Bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentanal

2.03 g (5.444 mmol) 4- (4-bromo-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentane-1,2-diol is oxidized to aldehyde according to the Swern method as described in

Example 3. 1.839 g (91.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.39 (3H), 1.45 (3H),

2.23 (1H), 3.35 (1H), 3.58 (1H), 3.90 (3H), 6.93-7.09 (3H)

9.03 (1H).

4 - {[4- {4-Bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentylidene] amino} -1,3-dihydro-indol-2-one

300 mg (0.812 mmol) 4- (4-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanal in 1.5 ml glacial acetic acid is mixed with 120.4 mg (0.812 mmol) 4- amino-1,3-dihydroindol-2-one over the weekend at room temperature. The reaction mixture is concentrated to dryness and the residue is applied to a column

<td>applying</td><td>Flashmaster. extracts</td><td>235.9</td><td>mg (58.1%)</td>

<td>desired</td><td>imine.</td><td></td><td></td>

<td>¹H-NMR</td><td>(300 MHz, CDCl3): δ =</td><td>1.35 (3H)</td><td>1.53 (3H),</td>

<td>2.20 (1H)</td><td>, 3.30 (1H), 3.42 (2H),</td><td>3.85 (3H),</td><td>4.71 (1H),</td>

<td>6.05 (1H)</td><td>, 6.78 (1H), 6.80-6.90 (2H)</td><td>, 6.98 (1H)</td><td>, 7.19 (1H),</td>

<td>7.45 (1H)</td><td>, 8.25 (IH).</td><td></td><td></td>

4 - {{l-Bromo-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1ylol) amino} -1,3-dihydro-indol-2-one

To 235.9 mg of 4 - {[4- (4-bromo-2-methoxyphenyl) -2-hydroxy4-methyl-2- (trifluoromethyl) pentylidene] amino} -1,3-dihydroindol-2-one is added at 0 ° C 6, 42 ml of a 1 M solution of BBr3 in dichloromethane and stirred for four hours at room temperature. At 0 ° C, saturated sodium bicarbonate solution is carefully added dropwise. After extraction three times with ethyl acetate, the organic phases are dried over sodium sulfate, the drying agent is suction filtered and the solvent is rotary evaporated. The residue is chromatographed using Flashmaster. 125.4 mg (54%) of the desired compound is isolated.

¹H-NMR (300 MHz, CD3OD): δ = 1.52 (3H), 1.65 (3H), 1.982.18 (2H), 3.25-3.49 (2H), 4.98 (1H) , 6.37 (1H), 6.47 (1H),

6.87 (1H), 7.02 (1H), 7.11 (1H).

Example 7 (+) - 4 - ({7-Hydroxy-9,9-dimethyl-7- (trifluoromethyl) 6,7,8,9-tetrahydronaphtho [1,2-d] -1,3-dioxol-6-yl} amino) -2,3-dihydroisoindol-1-one and (-) - 4 - {{7-Hydroxy-9,9-dimethyl-7- (trifluoromethyl) 6,7,8,9-tetrahydronaphto [1,2- d] -1,3-dioxol-6-yl} amino) -2,3-dihydroisoindol-1-one

1,3-Benzodioxole-4-carboxylic acid methyl ester To 50 g of 2,3-dihydroxybenzoic acid in 450 ml of methanol at room temperature, 50 ml of thionyl chloride are added dropwise. The solution is then heated to 60 ° C. for five hours and stirred at room temperature overnight. The solvent is completely removed under reduced pressure and the remaining oil is taken up in diethyl ether and extracted with saturated sodium bicarbonate solution. After washing with brine, drying with sodium sulfate and removing the solvent under reduced pressure, 46 g of 2,3-dihydroxybenzoic acid methyl ester are obtained, to which in 575 ml DMF and 20.2 ml dibromomethane 56.7 g potassium carbonate are added and for five hours in an argon atmosphere, it heats up to 100 ° C. Then stir overnight at room temperature. After treatment with water, extraction is carried out three times with ethyl acetate. The organic phase is washed several times with water and dried over sodium sulfate. The solvent is removed under reduced pressure to give 50.2 g of 1,3-benzodioxole-4-carboxylic acid methyl ester as a brown solid.

Melting point: 55-57 ° C

4- (1,3-benzodioxol-4-yl) -4-methyl-2-oxopentanoic acid ethyl ester

4.76 g of 1,3-benzodioxole-4-carboxylic acid methyl ester in 65 ml of dry THF are added dropwise at room temperature to a solution of 21 ml of 3 M methylmagnesium chloride in THF under argon. The reaction mixture is stirred for three hours and then 1N hydrochloric acid is slowly added. After extraction with ethyl acetate and washing the organic phase with water, it is dried over sodium sulfate and the solvent is removed under reduced pressure. 5 g of 1- (1,3-benzodioxol-4-yl) -1-methylethanol are obtained as a brown oil. To tertiary alcohol (27.17 mmol) together with 7.8 g (41.6 mmol) of 2 (trimethylsilyloxy) acrylic acid ethyl ester in 100 ml of dichloromethane at -70 ° C, 5.4 g (20.8 mmol) are added. ) tin tetrachloride. After 15 minutes of stirring at -70 ° C, the solution is poured onto a semi-saturated sodium carbonate solution, ethyl acetate is added and mixed vigorously. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure. 7.15 g of a yellow oil are obtained, which are distilled together with products from many mixtures of similar order of magnitude.

4- (1,3-benzodioxol-4-yl] -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester

6.1 g (21.91 mmol) of 4- (1,3-benzodioxol-4-yl) -4-methyl-2-oxopentanoic acid ethyl ester dissolved in 130 ml of tetrahydrofuran are reacted with 9.5 ml (65, 7 mmol) (trifluoromethyl) trimethylsilane and 4.42 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction and the treatment are carried out as described in Example 3. The obtained crude product together with a mixture of a similar order of size [9.19 g (33.02 mmol) of 4- (1,3-benzodioxol-4-yl} 4-methyl-2-oxopentanoic acid ethyl ester as starting material] is purified by silica gel chromatography (mobile phase: ethyl acetate / hexane) 16.45 g (86%) of the desired product are isolated from the two mixtures together.

4- (1,3-benzodioxol-4-yl) -4-methyl-2- (trifluoromethyl) pentane-1,2-diol

12.5 g (36.03 mmol) of 4- (1,3-benzodioxol-4-yl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentanoic acid ethyl ester are placed in 430 ml of diethyl ether and at 0 ° C 2.05 g (54.1 mmol) of lithium aluminum hydride are added in portions. After stirring overnight at room temperature, the mixture is carefully added to the sodium bicarbonate solution. It is filtered with diatomaceous earth and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried and the solvent is evaporated by rotation after filtering off the drying agent.

Chromatography of the residue on silica gel (mobile phase: ethyl acetate / hexane) gives 6.7 g (61%) of the desired alcohol.

4- (1,3-benzodioxol-4-yl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal

2.26 g (7.38 mmol) 4- (1,3-benzodioxol-4-yl) -4-methyl2- (trifluoromethyl) pentane-1,2-diol is oxidized according to the Swern method as described in Example 3, to aldehyde. After a typical treatment, the residue is chromatographed using Flashmaster. 1.85 g (82.3%) of the desired aldehyde are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 1.39 (3H), 1.48 (3H), 2.27 (1H), 3.10 (1H), 3.67 (1H), 5.92 -6.02 (2H), 6.606.70 (1H), 6.70-6.88 (2H), 9.06 (1H).

(+) - 4 - ({7-Hydroxy-9,9-dimethyl-7- (trifluoromethyl) -6,7,8,9-tetrahydronaphtho [1,2-d] -1,3-dioxol-6-yl} amino) -2,3-dihydroisoindol-1-one and (-) - 4 - ({7-Hydroxy-9,9-dimethyl-7- (trifluoromethyl) 6,7,8,9-tetrahydronaphto [1,2-d] -1,3-dioxol-6-yl} amino) -2,3-dihydroisoindol-1-one

800 mg (2.63 mmol) 4- (1,3-benzodioxol-4-yl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal in 5.2 ml glacial acetic acid is stirred overnight at room temperature with 389 mg (2.63 mmol) 4-amino2,3-dihydroisoindol-1-one. The reaction mixture is rotary evaporated to dryness and the residue is chromatographed using Flashmaster. 725 mg (62.8%) of the desired compound is isolated as a racemate.

Separation of the racemate (Chiralpak AD 20μ; mobile phase: hexane / ethanol / diethylamine) gives 279.2 mg (+) of the {[α] D = + 20.7 (c = 1.03, Methanol)} and 297.5 mg (-) - enantiomer {[a]_D = - 23.4 (c = 1.02, Methanol)}

Example 8

5 - {[8-Chloro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isoquinolin-1 (2H) -one

4- (5-Chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal g (6.12 mmol) 4- (5-chloro-2-methoxyphenyl) hydroxy-4-methyl-2- trifluoromethyl-pentan-1-ol is oxidized according to the Swern method using 854.6 mg (6.733 mmol) oxalyl chloride and 1.05 ml (14.812 mmol) DMSO as described in Example 2. After processing 1.95 g (98 , 4%) of the desired aldehyde, which is used in the next step without purification.

¹H-NMR (300 MHz, CDCl3): δ = 1.39 (3H), 1.49 (3H),

2.27 (1H), 3.32 (1H), 3.59 (1H), 3.88 (3H), 6.78 (1H),

7.10 (1H), 7.20 (1H), 9.09 (1H).

5- {[4- {5-Chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl) pentylidene] amino} isoquinolin-1 (2H) -one

300 mg (0.924 mmol) 4- (5-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentanal is stirred for four days at room temperature with 148 mg (0.924 mmol) of 5-amino-isoquinolines -1-one in 1.33 ml glacial acetic acid. The mixture is mixed with toluene three times and concentrated to dryness on a rotary evaporator. The residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 345.8 mg (80.1%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.39 (3H), 1.57 (3H), 2.29 (1H), 3.49 (1H), 3.83 (3H), 4.82 (1H), 6.57-6.65 (2H), 6.72 (1H), 6.89 (1H), 7.03 (1H), 7.18-7.29 (1H), 7.36 (1H), 7.40 (1H), 8.32 (1H), 10.98 (1H).

5 - {[8-Chloro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isoquinolin-1 (2H) -one

To 50 mg (0.107 mmol) of the compound described in the previous paragraph - 5 - {[4- (5-chloro-2-methoxyphenyl) -2-hydroxy4-methyl-2- (trifluoromethyl) pentylidene] amino} 2,3isoquinolin-1- 2.1 ml of a 1 M solution of boron tribromide in dichloromethane is added at -20 ° C and the mixture is stirred at a temperature range between -20 ° C and 0 ° C for two and a half hours. Saturated sodium bicarbonate solution is added dropwise to the reaction mixture at -20 ° C. After dilution with ethyl acetate, the cooling bath is removed and the mixture is stirred for 15 minutes at room temperature. Extracted twice with 30 ml of ethyl acetate. The combined organic extracts are washed with water and saturated NaCl solution. After drying over sodium sulfate, the solvent is rotary evaporated and the residue obtained is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 16.5 mg (33%) of the desired compound is isolated.

MS (ES +): 453.445

Example 9

8-Bromo-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol)

4- (5-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanoic acid ethyl ester

34.45 g (258.91 mmol) of aluminum trichloride are placed in 354.35 g (237.02 mmol) of 4-bromoanisole. 38.95 g (172.19 mmol) of 2-hydroxy-4-methylene-2- (trifluoromethyl) pentanoic acid ethyl ester are added dropwise to this mixture over one hour. After stirring overnight at room temperature, the mixture is added to ice water and acidified with 10% hydrochloric acid. After extraction three times with ethyl acetate, the combined organic extracts are washed with 1 N hydrochloric acid and brine. After drying over magnesium sulfate, the solvent is rotary evaporated. Most of the excess 4-bromoanisole is distilled off (10 mbar; bath temperature 110 ° C). Chromatography on silica gel (mobile phase: ethyl acetate / hexane) gives 36.87 g (51.8%) of the desired compound.

¹H-NMR (300 MHz, CDCl3): δ = 1.39 (3H), 1.46 (3H), 2.49 (1H), 2.85 (1H), 3.48 (1H), 3.62 -3.75 (1H), 3.85 (3H), 4.02-4.15 (1H), 6.73 (1H), 7.23-7.33 (2H).

4- (5-Bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentan-1-ol g (7.25 mmol) 4- (5-bromo-2-methoxyphenyl) -2-ethyl ethyl ester -hydroxy-4-methyl-2- (trifluoromethyl) pentane is dissolved in 120 ml of diethyl ether and the reaction mixture is cooled to 0 ° C. 426.5 mg (10.89 mmol) of lithium aluminum hydride are added in portions. After stirring for two hours at room temperature, there is no more starting material. Saturated sodium bicarbonate solution is added to the mixture while cooling with an ice bath, the precipitate is suction filtered and washed with diethyl ether. After rotary evaporation, the residue is chromatographed using Flashmaster. Next to 540.5 mg of 4- (5-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal, 1.14 g of the desired alcohol (which, however, also contains the desbrom compound) is isolated.

4- (5-Bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl} pentanal

1.13 g (3.06 mmol) 4- (5-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentan-1-ol is added to 20 ml of dichloromethane and 5.4 ml of DMSO . After treatment, 1.55 g (15.32 mmol) triethylamine and 975.28 mg (6.13 mmol) of the SO3 / pyridine complex are stirred overnight at room temperature. After TLC, the SO3 / pyridine complex is added (amount as at the end of the blade) and mixed for a further few hours. Saturated ammonium chloride solution is added to the reaction mixture and shaken three times with methyl tert-butyl ether. The combined organic extracts are washed with water and brine. After drying and rotary evaporation of the solvent, the residue is chromatographed using Flashmaster. 902.7 mg (79.81%) of the desired aldehyde is isolated (together with the desbrom compound).

¹H-NMR (300 MHz, CDCl3): δ = 1.40 (3H), 1.50 (3H), 2.28 (1H), 3.30 (1H), 3.87 (3H), 6.73 (1H), 7.22 (1H), 7.35 (1H), 9.09 (1H).

1,1,1-Trifluoro-4- (5-bromo-2-methoxy-phenyl} -2 - [(1Hindazol-4-yl) iminomethyl] -4-methylpentan-2-ol

To 300 mg (0.813 mmol) of 4- (5-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal in 1.19 ml of glacial acetic acid is added 108.2 mg (0.813 mmol) 4 -aminoindazole and stirred for four days at room temperature. The mixture is rotary evaporated to dryness and the residue is concentrated three times with toluene. Chromatography on silica gel (mobile phase: ethyl acetate / hexane) gives 352.5 mg (89.5%) of the desired imine (together with the imine of the desbrom compound).

¹H-NMR (300 MHz, CDCl3): δ = 1.48 (3H), 1.55 (3H),

2.28 (1H), 3.44 (1H), 3.80 (3H), 4.98 (1H), 6.35 (1H),

6.53 (1H), 6.99 (1H), 7.30 (1H), 7.29-7.40 (1H), 7.55 (1H), 7.99 (1H), 10.28 ( 1H).

8-Bromo-5-methoxy-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

100 mg (0.206 mmol) 1,1,1-trifluoro-4- (5-bromo-2-methoxyphenyl) -2 - [(1H-indazol-4-yl) iminomethyl] -4-methylpentan-2-ol is dissolved in one ml of dichloromethane and the reaction mixture is cooled to 30 ° C. Four ml of a 1 M solution of BBr3 in dichloromethane are added dropwise over 15 minutes and the mixture is then stirred for 45 minutes at -30 ° C. At -30 ° C, about 10 ml of saturated sodium bicarbonate solution are carefully added dropwise. After dilution with ethyl acetate, the mixture is stirred for ten minutes and then extracted twice with 50 ml of ethyl acetate. The combined organic extracts are washed with water and brine. The residue obtained after drying and rotary evaporation of the solvent is repeatedly chromatographed on silica gel (mobile phase: ethyl acetate / dichloromethane). 21 mg of the desired compound is isolated (together with the corresponding desbromous compound).¹H-NMR (300 MHz, CD3OD): δ = 1.55 (3H), 1.67 (3H),

2.10 (1H), 2.43 (1H), 3.89 (3H), 5.25 (1H), 6.72 (1H),

6.83 (1H), 6.90 (1H), 7.22 (1H), 7.49 (1H), 8.25 (1H).

8-Bromo-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol Up to 21 mg (0.043 mmol) 8-bromo-5-methoxy-1 - [(1H-indazol4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol at room temperature added 0.4 ml of 1 M BBr3 solution and stirring for 19 hours at room temperature. After adding ice to the reaction mixture, saturated sodium bicarbonate solution is added dropwise and diluted with ethyl acetate. The organic phases are, as usual, washed in an inert medium and the residue obtained after rotary evaporation of the solvent is chromatographed on silica gel (mobile phase: methanol / dichloromethane). 17.1 mg (83.8%) of the desired compound is isolated (together with a desbrom compound).

¹H-NMR (300 MHz, CD3OD): δ = 1.59 (3H), 1.71 (3H), 2.10 (1H), 2.42 (1H), 5.25 (1H), 6.64 -6.78 (2H), 6.83 (1H), 7.20-7.34 (2H), 8.25 (1H).

Example 10

1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

Extracts (Na2SO4) and

2-Hydroxy-4-methyl-4-phenyl-2- (trifluoromethyl) pentanal

To 10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (W098 / 54159) in 250 ml of dimethylformamide, 4.1 ml of thionyl chloride and 5 ml of methanol after 15 min are added at 5 ° C. After 15 h at room temperature, the mixture is diluted with water and extracted with ethyl acetate.

the organics are washed with water, dried and concentrated to give 9.3 g of 4-methyl-2-oxo-4-phenylpentanoic acid methyl ester, to which 15.5 ml (558 ml DMF at -5 ° C) are added 104.63 mmol) (trifluoromethyl) trimethylsilane and 20.5 g (63.28 mmol) of cesium carbonate and stirring at room temperature for 16 h. Water is added, extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). The concentrated intermediate is taken up in 200 ml THF, and 50 ml 1 M tetrabutylammonium fluoride solution in THF are added, stirred for 2 hours, water added, extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). Chromatography on silica gel with hexane-ethyl acetate (0-30%) yields 8.35 g of 2-hydroxy acid methyl ester96

4-methyl-4-phenyl-2- (trifluoromethyl) pentanoic acid. The ester (8.3 g, 28.59 mmol) is dissolved in 180 ml THF, and 1.52 g (36.20 mmol) of lithium aluminum hydride are added in small portions over a period of 2.5 hours. After complete conversion, 5 ml of ethyl acetate are added dropwise and after a further 10 min, carefully added

The solid formed is filtered off and after chromatography with hexane-ethyl acetate 5.40 g 4-methyl-4-phenyl-2- (trifluoromethyl) pentane-1,2-diol. To 2.5 g (9.53 mmol) of diol in 75 ml of dichloromethane and 28 ml of DMSO are added 5.7 ml (40.3 mmol) of triethylamine and 5 g of the pyridine / SO3 complex in portions for 20 min. Stir for 2 hours and add 40 ml sat. ammonium chloride solution. The mixture is stirred for an additional 15 min, the phases are separated, and extracted with dichloromethane. It is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure to give 3 g of product.

¹H-NMR (300 MHz, CDCl3): δ = 1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H), 2.66 (d, 1H), 3, 64 (s, 1H), 7.03-7.41 (m, ethyl acetate, silica

4H)

8.90 (s, 1H) in 10 ml water. thoroughly washed on a gel (0-35%)

1,1,1-trifluoro-4-phenyl-2 - [(1H-indazol-4-yl) iminomethyl] -4-methylpentan-2-ol

130 mg (0.50 mmol) 2-hydroxy-4-methyl-4-phenyl-2- (trifluoromethyl) pentanal is dissolved in 15 ml toluene and 73 mg (0.55 mmol) 4-amino-indazole and 0.22 ml are added titanium tetraethylate and at 100 ° C for 2.5 h are stirred under an argon atmosphere. For workup, 1 ml of saturated sodium chloride solution is added to the reaction solution and stirred for 30 min. The suspension is then suction filtered through celite and washed with 200 ml ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure: 246 mg. Column chromatography on silica gel with pentane-ethyl acetate provides 190 mg of product.

¹H-NMR (300 MHz, DMSO-d6): δ = 1.35 (s, 3H), 1.47 (s, 3H),

2.26 (d, 1H), 2.73 (d, 1H), 6.13 (s, 1H), 6.24 (d, 1H),

6.94 (t, 1H), 7.06 (t, 2H), 7.23 (t, 1H), 7.34-7.40 (m,

3H), 7.56 (s, 1H), 8.00 (s, 1H), 13.17 (s, 1H).

1 - [(1H-Indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol 190 mg (0.51 mmol) 1.1 , 1-trifluoro-4-phenyl-2 - [(1Hindazol-4-yl) iminomethyl] -4-methylpentan-2-ol is dissolved in 10.0 ml of dichloromethane and cooled to -70 ° C. 9 ml of titanium tetrachloride solution (1 molar solution in dichloromethane) are added to the solution for 10 min and stirred at -70 ° C for 1 h. The cold solution is then poured into 200 ml of saturated sodium bicarbonate solution and stirred for 15 min. For working up, the mixture is extracted with dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated under reduced pressure: 208 mg.

Dichloromethane-methanol column chromatography provides 53 mg (28%) of the desired product.

¹H-NMR (300 MHz, DMSO-d6): δ = 1.36 (s, 3H), 1.51 (s, 3H), 2.08 (d, 2H), 5.35 (d, 1H), 5.93 (s, 1H), 6.24 (d, 1H),

6.32 (d, 1H), 6.74 (d, 1H), 7.05-7.12 (m, 2H), 7.221.28 (m, 2H), 7.43 (d, 1H), 8 , 15 (s, 1H), 12.81 (s, 1H). Example 11

1 - [(2-methyl-7-yl) amino] -4,4-dimethyl-2 (trifluorometylolo-1,2,3,4-tetrahydronaphthalen-2-ol

1,1,1-trifluoro-4-phenyl-2 - [(2-methyl-7-yl) iminomethyl} -4-methylpentan-2-ol ¹H-NMR (300 MHz, DMSO-d6): δ = 1.33 (s, 3H), 1.47 (s, 3H),

2.24 (d, 1H), 2.71 (d, 1H 2.82 (s, 3H), 6.19, (s, 1H),

6.54 (d, 1H), 6.91 (t, 1H), 7.02 (t, 2H), 7.31-7.40 (m,

3H), 7.51 (s, 1H), 7.78 (d, 1H).

1 - [(2-methyl-7-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol ¹H-NMR (300 MHz, DMSO-d6): δ = 1.3 (s, 3H), 1.47 (s, 3H), 1.99-2.12 (m, 2H), 2.78 (s , 3H), 5.38 (d, 1H), 5.68 (d, 1H), 6.10 (s, 1H), 6.78 (dd, 1H), 7.07-7.16 (m, 2H), 7,207.28 (m, 3H), 7.41 (d, 1H).

Example 12

6 - [(1H-indazol-4-yl) amino] -9,9-dimethyl-7- (trifluoromethyl) -6,7,8,9-tetrahydronaphtho [1,2-d] -1,3diokso-7-ol

4- (1,3-benzodioxol-4-yl) -1,1,1-trifluoro-2- [1Hindazol-4-yl) iminomethyl] -4-methylpentan-2-ol ¹H-NMR (300 MHz, DMSO-d6): δ = 1.34 (s, 3H), 1.48 (s, 3H),

<td>2.28 (d,</td><td>1H),</td><td>2.93 (d,</td><td>1H),</td><td>5.90 (s,</td><td>2H);</td><td>6.15 (s,</td><td>1H)</td>

<td>6.29 (d,</td><td>1H),</td><td>6.45 (t,</td><td>1H),</td><td>6.56 (dd,</td><td>1H),</td><td>6.62 (d,</td><td>1H)</td>

<td>7.23 (t,</td><td>1H),</td><td>7.40 (d,</td><td>1H),</td><td>7.74 (s,</td><td>1H),</td><td>8.00 (s,</td><td>1H)</td>

13.17 (s, 1H).

6 - [(1H-indazol-4-yl) amino] -9,9-dimethyl-7- (trifluoromethyl) -6,7,8,9-tetrahydronaphtho {1,2-d} -1,3diokso-7-ol ¹H-NMR (300 MHz, DMSO-d6): δ = 1.43 (s, 3H), 1.55 (s, 3H), 2.04-2.12 (m, 2H), 5.26 (d , 1H), 5.95 (s, 1H), 6.00 (s, 2H), 6.19 (d, 1H), 6.29 (d, 1H), 6.70-6.78 (m, 3H), 7.07 (t, 1H), 8.12 (s, 1H), 12.81 (s, 1H).

Example 13

1 - [(2-methylquinolin-5-yl] amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

1,1,1-trifluoro-4-phenyl-2 - [(2-methylquinolin-5-yl) iminomethyl) -4-methylpentan-2-ol

120 mg of 2-hydroxy-4-methyl-4-phenyl-2- (trifluoromethyl) pentanal, 67 mg of 5-amino-2-methylquinoline and 163 μL of titanium tetraethylate are stirred in 8 ml of toluene for 2 h at 100 ° C. After cooling, 2 ml of water are added to the mixture, stirred for 15 min at room temperature and concentrated under reduced pressure. Silica gel cyclohexane-ethyl acetate column chromatography provides

111 mg of product.

<td>¹H-NMR (</td><td>300 MHz, CDCl3): δ</td><td>= 1.35 (s,</td><td>3H);</td><td> 1,55</td><td>(S,</td><td>3H);</td>

<td>2.45 (d,</td><td>1H), 2.7 (s, 3H),</td><td>2.80 (d,</td><td>1H),</td><td> 5,00(</td><td>s</td><td>1H),</td>

<td>6.15 (d,</td><td>1H), 6.9-7.1 (m, 3H)</td><td>, 7.30 (m,</td><td>3H);</td><td> 7,35</td><td>(D,</td><td>1H),</td>

7.45 (t, 1H), 7.90 (d, 1H), 8.35 (d, 1H).

1 - [(2-Methylquinolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl] -1,2,3,4-tetrahydronaphthalen-2-ol For a solution of 111 mg 1,1,1-trifluoro -4-phenyl-2 - [(2-methylquinolin-5-yl) iminomethyl] -4-methylpentan-2-ol in 84 ml of CH2Cl2 is added dropwise at -78 ° C to 5.1 ml of a 1 M solution of 1 M at -78 ° C to the mixture and heated to the temperature of titanium tetrachloride-CH2Cl2, sat. NaHCO3 room added. The phases are separated, the aqueous phase is extracted with CH 2 Cl 2, the combined organic phases are dried (Na 2 SO 4) and concentrated under reduced pressure. Silica gel cyclohexane-ethyl acetate column chromatography provides 94 mg of product.

<td>¹H-NMR</td><td> (300</td>

<td>2.15 (d,</td><td>1H),</td>

<td>4.85 (br</td><td>. d</td>

<td>7.20 (d,</td><td>1H),</td>

<td>7.55 (t,</td><td>1H),</td>

3) δ = 1.45 (s, 3H), 1.60 (s, 3H)

2.20 (d, 1H), 2.75 (s, 3H), 3.05 (br., 1H)

H), 5.20 (d, 1H), 6.85 (d, 1H), 7.10 (t, 1H)

7.30 (t, 1H), 05 (d, 1H).

7.40 (d, 1H)

7.50 (d, 1H)

Example 14

1 - [(quinolin-5-yl] amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

1,1,1-trifluoro-4-phenyl-2 - [(quinolin-5-yl) iminomethyl] -4-methylpentan-2-ol

In analogy to Example 13, 120 mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanal and 61 mg of 5-aminoquinoline are carried out in 95 mg of product.

100

<td>¹H-NMR (300 MHz, CDCl3):</td><td>δ = 1.35 (s, 3H),</td><td> 1,60(</td><td>s</td><td>3H);</td>

<td>2.45 (d, 1H), 2.80 (d, 1H</td><td>), 5.00 (s, 1H),</td><td> 6,20(</td><td>d</td><td>1H),</td>

<td>6.95-7.1 (m, 3H), 7.30 (m,</td><td>2H), 7.50 (m, 2H),</td><td> 8,00</td><td>(D,</td><td>1H),</td>

8.45 (d, 1H), 8.95 (m, 1H).

1 - [(quinolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

Analogous to Example 13, 95 mg are carried out

1,1,1-trifluoro-4-phenyl-2 - [(quinolin-5-yl) iminomethyl] -4-methylpentan-2-ol in 90 mg of the product. ¹H-NMR (300 MHz, CDCl3): δ = 1.45 (s, 3H), 1.60 (s, 3H),

2.15 (d, 1H), 2.20 (d, 1H), 3.25 (br, 1H), 4.95 (br d, 1H), 5.20 (d, 1H), 6, 90 (dd, 1H), 7.10 (t, 1H), 7.257.35 (m, 4H), 7.40 (d, 1H), 7.60 (m, 2H), 8.15 (d, 1H ), 8.90 (m, 1H).

Example 15

5 - {[2-Hydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

5 - {[2-Hydroxy-4-methyl-4-phenyl-2- (trifluoromethyl) pentylidene] amino} quinolin-2 (1H) -one 600 mg of 2-hydroxy-4-methyl-4-phenyl are carried out analogously to Example 13 2- (trifluoromethyl) pentanal and 337 mg of 5-aminoquinolin-2 (1H) -one (52313) in 570 mg of product.

¹H-NMR (300 MHz, CDCl3): δ = 1.35 (s, 3H), 1.55 (s, 3H),

2.40 (d, 1H), 2.80 (d, 1H), 4.70 (br. S, 1H), 5.80 (d, 1H), 6.75 (d, 1H), 7.05 (t, 1H), 7.15 (t, 2H), 7.30 (m, 4H), 8.00 (d, 1H), 9.05 (br. s, 1H).

5 - {[2-Hydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

Analogously to Example 13, 23 mg of {[2-hydroxy-4-methyl-4-phenyl-2101 (trifluoromethyl) pentylidene] amino} quinolin-2 (1H) -one is carried out per mg of product.

<td>¹H-NMR (300</td><td>MHz, DMSO-d6):</td><td>δ = 1.35 (s, 3H),</td><td>1.50 (s,</td><td>3H);</td>

<td>2.00 (d, 1H</td><td>), 2.10 (d, 1H)</td><td>, 5.35 (d, 1H),</td><td>6.05 (s,</td><td>1H),</td>

<td>6.20 (d, 1H</td><td>), 6.40 (d, 1H)</td><td>, 6.55 (t, 1H),</td><td>7.25 (m,</td><td>2H);</td>

<td>7.45 (d, 1H)</td><td>, 8.20 (d, 1H),</td><td>11.60 (br.s, 1H).</td><td></td><td></td>

Example 16

1 - [(2-methoxy-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

1,1,1-trifluoro-4-phenyl-2 - [(2-methoxy-5-yl) iminomethyl] -4-methylpentan-2-ol

Analogously to Example 13, 200 mg of 2-hydroxy-4-methyl-4-phenyl-2- (trifluoromethyl) pentanal and 122 mg of 5-amino-2-methoxyquinoline are carried out in 190 mg of product.

<td>¹H-NMR (</td><td>300 MHz, CDCl3)</td><td>: δ</td><td>= 1.35 (s,</td><td>3H);</td><td> 1,55</td><td>(S,</td><td>3H);</td>

<td>2.45 (d,</td><td>1H), 2.80 (d,</td><td>1H),</td><td>4.10 (s,</td><td>3H);</td><td> 5,00(</td><td>s</td><td>1H),</td>

<td>6.10 (d,</td><td>1H), 6.90 (d,</td><td>1H),</td><td>6.95 (t,</td><td>1H),</td><td> 7,05(</td><td>t</td><td>2H);</td>

7.30 (d, 2H), 7.35 (t, 1H), 7.70 (d, 1H), 8.30 (d, 1H).

1 - [(2-methoxy-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

Analogous to Example 13, 185 mg are carried out

1,1,1-trifluoro-4-phenyl-2 - [(2-methoxyquinolin-5-yl) iminomethyl] -4-methylpentan-2-ol in 127 mg of product.

¹H-NMR (300 MHz, CDCl3): δ = 1.45 (s, 3H), 1.60 (s, 3H), 2.15 (d, 1H), 2.20 (d, 1H), 3, 10 (s, 1H), 4.10 (s, 3H), 4.75 (br d, 1H), 5.20 (d, 1H), 6.75 (d, 1H), 6.85 (d , 1H), 7.1 (t, 1H), 7.25-7.45 (m, 4H), 7.50 (t, 1H), 8.00 (d, 1H).

Example 17

1 - [(Phenylamino] -4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2-ol

102

1,1,1-trifluoro-4-phenyl-2 - [(phenyl) iminomethyl} -4-methylpentan-2-ol

Analogously to Example 1, 200 mg 2-hydroxy-4-methyl-4-phenyl-2- (trifluoromethyl) pentanal and 64 μL aniline are carried out in 180 mg of product.

¹H-NMR (300 MHz, CDCl3): δ: 1.35 (s, 3H), 1.50 (s, 3H), 2.35 (d, 1H), 2.70 (d, 1H), 5, 05 (s, 1H), 6.65 (d, 2H), 7.05 (t, 1H), 7.15-7.30 (m, 7H).

1 - [(Phenylamino] -4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2-ol

To a solution of 175 mg 1,1,1-trifluoro-4-phenyl-2 [(phenyl) iminomethyl] -4-methylpentan-2-ol in 160 mL CH2Cl2 is added dropwise at -78 ° C with 9.6 mL of a 1 M tetrachloride solution titanium CH2Cl2. First, for 1 h at -78 ° C, and after adding a further 10 ml of titanium tetrachloride-CH2Cl2 solution for 60 h, stir in room. Us is added to the mixture. is separated, the aqueous product is extracted with temperature

NaHCO3, phases are CH2Cl2, the combined organic phases are dried (Na2SO4) and concentrated under reduced pressure. Silica gel cyclohexane-ethyl acetate column chromatography provides 45 mg of product.

¹H-NMR (CDCl3): δ = 1.40 (s, 3H), 1.50 (s, 3H), 2.00 (d, 1H), 2.20 (d, 1H), 3.40 (s , 1H), 3.80 (d, 1H), 4.95 (d,

1H)

6.80 (d, 2H)

6.85 (t, 1H)

7.15 m,

1H)

7,207.30 (m, 4H), 7.40 (d, 1H)

Example 18

4 - {[2-Hydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2- (trifluoromethyl) benzonitrile

1,1,1-trifluoro-4-phenyl-2 - [(4-cyano-3- (trifluoromethyl) phenyl) iminomethyl] -4-methylpentan-2-ol

120 mg of 2-hydroxy-4-methyl-4-phenyl-2- (trifluoromethyl) pentanal is carried out analogously to Example 13

103 and 78 mg of 4-cyano-3- (trifluoromethyl) aniline in 71 mg of product.

¹H-NMR (300 MHz, CDCl3): δ = 1.35 (s, 3H), 1.55 (s, 3H), 2.40 (d, 1H), 2.75 (d, 1H), 4, 55 (s, 1H), 6.75 (dd, 1H), 6.95 (d, 1H), 7.10 (t, 1H), 7.20 (m, 3H), 7.30 (m, 2H ), 7.70 (d, 1H).

4 - {[2-Hydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2- (trifluoromethyl) benzonitrile

71 mg are carried out analogously to Example 13

1,1,1-trifluoro-4-phenyl-2 - [(4-cyano-3- (trifluoromethyl) phenyl) iminomethyl] -4-methylpentan-2-ol in 58 mg of the product.

<td>¹H-NMR (300 MHz, CDCl3)</td><td>: δ = 1.40</td><td>(S,</td><td>3H);</td><td> 1,50</td><td>(S,</td><td>3H);</td>

<td>2.15 (s, 2H), 2.60 (s,</td><td>1H), 5.05</td><td>(D,</td><td>1H),</td><td> 5,10</td><td>(D,</td><td>1H),</td>

<td>6.85 (dd, 1H), 7.00 (</td><td>d, 1H), 7,</td><td> 20</td><td>(S,</td><td>2H);</td><td> 7,35</td><td>(M,</td>

1H), 7.40 (d, 1H), 7.60 (d, 1H).

Example 19

5 - {[5-Bromo-2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isoquinolin-1 (2H) -one (2-Bromophenyl) acetonitrile

To 25 g (100 mmol) of 2-bromobenzyl bromide in 100 ml of N, N-dimethylformamide and 64 ml of water are added 9.75 g (150 mmol) of potassium cyanide and stirring overnight at room temperature. The reaction mixture is poured onto ice water. After extraction three times with methyl tert-butyl ether, the combined organic extracts are washed with brine, dried and the solvent is rotary evaporated. The residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 18.9 g (96.4%) of the desired compound are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 3.85 (2H), (1H), 7.55 (1H), 7.62 (1H).

7.23 (IH), 7.48

104

2- (2-Bromophenyl) -2-methyl-propionitrile

18.9 g (96.41 mmol) (2-bromophenyl) -acetonitrile and 31.41 g (221.74 mmol) methyl iodide are dissolved in 150 ml of N, N-dimethylformamide. At 0 ° C, portions are added

8.87 g (221.74 mmol) of sodium hydride (as a 60% suspension in oil) and the mixture is stirred overnight at room temperature. The reaction mixture is poured into ice water and treated as usual. Because the compound (20.9 g) isolated after chromatography contains next to the desired product still contains

2- (2-bromophenyl) propionitrile, all is reacted again with the same amounts of reagents. Also this reaction only provides material that still contains the mono-methyl compound. After further alkylation with 15 g of methyl iodide and

4.45 g of sodium hydride in 150 ml of N, N-dimethylformamide, 18.57 g of the desired compound are isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.91 (6H), 7.20 (1H), 7.35 (1H), 7.49 (1H), 7.68 (1H).

2- (2-Bromophenyl) -2-methyl-propanal

18.57 g (82.21 mmol) of 2- (2-bromophenyl) -2-methylpropionitrile is reduced in 325 ml of toluene using

102.72 ml of a 1.2 M solution of DIBAH in toluene as described in Example 3. After working up, isolate

18.17 g (97.34%) of the desired aldehyde, which is used in the next step without purification.

¹H-NMR (300 MHz, CDCl3): δ = 1.51 (6H), 7.20 (1H), 7.333.45 (2H), 7.61 (1H), 9.8 (1H).

(E / Z) -4- (2-bromophenyl) -4-methylpent-2-enoic acid ethyl ester

18.17 g (80.02 mmol) of 2- (2-bromophenyl) -2-methylpropanal are analogously subjected to the Horner-Wittig reaction described in Example 3. After the treatment described therein followed by gel chromatography

105 silica (mobile phase: ethyl acetate / hexane) to obtain 22.3 g (81.67%) of the desired product.

(E / Z) -4- (2-bromophenyl) -4-methylpent-2-enoic acid

22.3 g (65.349 mmol) of (E / Z) -4- (2-bromophenyl) -4-methylpent-2-enoic acid ethyl ester as described in Example 3 is saponified using 650 ml of sodium hydroxide solution (1N in ethanol / water 2: 1). Is isolated after treatment

14.32 g (69.9%) of the desired acid.

4- (2-bromophenyl) -4-methyl-2-oxo-pentanoic acid

14.32 g (45.72 mmol) of (E / Z) -4- (2-bromophenyl) -4-methylpent-2-enoic acid with sulfuric acid in glacial acetic acid, as described in Example 3, is reacted to the desired ketocarboxylic acid. 13 g (99.6%) is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.60 (6H), 3.91 (2H), 7.09 (1H), 7.30 (1H), 7.49 (1H), 7.57 (1H).

4- (2-Bromophenyl) -4-methyl-2-oxopentanoic acid ethyl ester g (45.59 mmol) 4- (2-bromophenyl) 4-methyl-2-oxo-pentanoic acid is reacted with ethanol and conc. sulfuric acid to the ester. After preparation and working up (see Example 3) and after silica gel chromatography, 13.01 g (91.1%) of the desired compound are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 1.30 (3H), 1.60 (6H), 3.72 (2H), 4.17 (2H), 7.05 (1H), 7.27 (1H), 7.47 (1H), 7.57 (1H).

4- (2-Bromophenyl) -4-methyl-2- (trifluoromethyl) pentane-1,2-diol g (41.5 mmol) 4- (2-bromophenyl) -4-methyl-2-oxo-pentanoic acid ethyl ester reaction with Ruppert's Reagent as described in Example 3. After working up and gel chromatography

106 silica (mobile phase: ethyl acetate / hexane), 16.15 g (85.6%) of the desired compound is isolated.

To a solution of 6.1 g (35.45 mmol) of the just described trifluoromethyl alcohol in 148 ml of toluene is added dropwise (35 min) at -10 ° C 73.6 ml (88.39 mmol) of DIBAH solution (1.2 M in toluene ). After thirty minutes of stirring at a temperature between -10 ° C and -5 ° C, 24.2 ml of isopropanol are added dropwise at -10 ° C followed by water. After vigorous stirring for two hours at room temperature, the precipitate formed is suction filtered through a G4 frit, washed with ethyl acetate and the filtrate is rotary evaporated to dryness. The residue (regioisomeric mixture of both silyl ethers; 14.5 g = 95.4% = 35.08 mmol) is reacted with tetrabutylammonium fluoride trihydrate in tetrahydrofuran at room temperature as described in Example 3. After typical work-up and chromatography, 5 are isolated, 26 g of the desired compound.

¹H-NMR (300 MHz, CDCl3): δ = 1.62 (3H), 1.70 (3H), 2.19 (1H), 2.90-3.01 (2H), 3.27-3, 89 (1H), 3.59 (1H), 7.09. (1H), 7.30 (1H), 7.53 (1H), 7.60 (1H).

4- (2-Bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal g (5.86 mmol) 4- (2-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol oxidizes SO3-pyridine complex as described in Example 1. 1.72 g (86.8 mmol) of the desired aldehyde are isolated. ¹H-NMR (300 MHz, CDCl3): δ = 1.60 (6H), 2.29 (1H), 3.65 (1H), 3.78 (1H), 7.09 (1H), 7.25 (1H), 7.34 (1H), 7.58 (1H), 9.20 (1H).

4 - {[4- (2-Bromophenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentylidene] amino} isoquinolin-1 (2H) -one 200 mg (0.589 mmol) 4- (2-bromophenyl) - 2-hydroxy-4-methyl-2-trifluoromethylpentanal is mixed with 94.3 mg (0.589 mmol) 5-aminoisoquinolin-1 (2H) -one (Example 2) in 0.86 ml glacial acetic acid for five days at room temperature . After typical machining and execution

107 silica gel chromatography (mobile phase:

ethyl acetate / hexane), 170.8 mg (60.2%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.59 (3H), 1.70 (3H), 2.29 (1H), 3.86 (1H), 4.89 (1H), 6.58 (1H), 6.70-6.90 (3H), 7.15-7.37 (3H), 7.48 (1H), 7.59 (1H), 8.30 (1H), 11.00 (1H).

5 - {[5-Bromo-2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isoquinolin-1 (2H) -one

To 50 mg (0.104 mmol) of 4 - {[4- (2-bromophenyl) -2-hydroxy4-methyl-2 {trifluoromethyl) pentylidene] amino}} isoquinolin-1 (2H) on is added one ml of a 1 M solution of BBr3 in dichloromethane and stirred for three quarters of hours at room temperature. After typical work-up (see Example 2), silica gel chromatography (mobile phase: methanol / dichloromethane) gives 49.2 mg (98.4%) of the desired compound.

¹H-NMR (300 MHz, DMSO-d6): δ = 1.67 (3H), 1.79 (3H), 2.09 (1H), 2.21 (1H), 5.48 (1H), 6 , 02 (1H), 6.26 (1H),

6.81 (1H), 7.00-7.30 (5H), 7.49-7.62 (2H), 11.25 (1H).

Using the appropriate starting aldehydes and amines described in the above examples, the following cyclic compounds are prepared via imines.

Example 20

5-Bromo-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

The product is obtained after cyclization as described in Example 19.

¹H-NMR (300 MHz, CD3OD): δ = 1.73 {3H), 1.88 (3H),

2.10 · 2.30 (2H), 5.30 (1H), 6.39 (1H), 6.85 (1H), 7.01 (1H), 7.24 (1H), 7.48 ( 1H), 7.58 (1H), 8.13 (1H).

Example 21

108

5-Bromo-4,4-dimethyl-1-propylamino-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

The product is obtained after cyclization as described in

Example 19.

¹H-NMR (300 MHz, CD3OD): δ = 0.90-1.02 (3H), 1.48-1.60 (2H), 1.63 (3H), 1.70 (3H), 1, 91 (1H), 2.15 (1H), 2.652.78 (1H), 2.91-3.05 (1H), 7.12 (1H), 7.45 (1H), 7.56 (1H) .

Example 22

5-Bromo-1 - [(3-hydroxypropyl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

<td colspan="2">The product is obtained after Example 19.</td><td>cyclization, like</td><td colspan="2">described in</td>

<td>¹H-NMR (300 MHz,</td><td>CD3OD): δ =</td><td>1.63 (3H), 1.71</td><td>(3H)</td><td> , 1,94</td>

<td>(1H), 1.99-2.11</td><td>(2H), 2.17</td><td>(1H), 2.84-2.98 (</td><td>1H),</td><td> 3,09-</td>

<td>3.20 (1H), 3.55</td><td>(2H), 7.13 (</td><td>1H), 7.49 (1H), 7</td><td> ,59</td><td>(1H).</td>

Example 23

5 - {[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isoquinolin-1 (2H) -one

The product is obtained after cyclization as described in Example 19.

MS (ES +, ACN / H2O + 0.01% TFA): 437 (100%)

Example 24

4 - {[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -6-fluoro-2,3-dihydroizoindol- 1-one

The product is obtained after cyclization as described in Example 19.

¹H-NMR (300 MHz, CD3OD): δ = 1.58 (3H), 1.65 (3H), 2.002.10 (2H), 4.20-4.45 (2H), 5.10 (1H) , 6.70-6.89 (4H).

Example 25

109

5 - {[6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isoquinolin-1 (2H) -one

The product is obtained after cyclization as described in

Example 3.

¹H-NMR (300 MHz, CD3OD): δ = 1.53 (3H), 1.58 (3H), 2.14 (2H), 3.99 (3H), 5.15 (1H), 6.84 (1H), 6.95 (1H), 7.00 · 7.10 (2H), 7.18 (1H), 7.39 (1H), 7.69 (1H).

The resulting product is separated into its enantiomers (Chiralpak AD 20μ; mobile phase: hexane / ethanol / DEA) and then used when ether breaks up (analogously to Example 3):

5 - {[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -isoquinolin-1 (2H) -one (cis , Enantiomer A) ¹H-NMR (300 MHz, CD3OD): δ = 1.62 (3H), 1.72 (3H), 2.042.21 (2H), 5.13 (1H), 6.75-6.92 (3H) , 7.05 (1H), 7.18 (1H), 7.39 (1H), 7.69 (1H).

5 - {[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -isoquinolin-1 (2H) -one (cis , Enantiomer B) ¹H-NMR (300 MHz, CD3OD): δ = 1.62 (3H), 1.72 (3H), 2.042.21 (2H), 5.13 (1H), 6.75-6.92 (3H) , 7.05 (1H), 7.18 (1H), 7.39 (1H), 7.69 (1H).

Example 26

4 - {[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2,3-dihydroisoindol-1-one

The product is obtained after cyclization and cleavage of ether as described in Example 3.

¹H-NMR (300 MHz, CD3OD): δ = 1.60 (3H), 1.69 (3H), 1.992.20 (2H), 4.23-4.45 (2H), 5.13 (1H) , 6.80-7.03 (3H),

7.18 (1H), 7.39 (1H).

Example 27

110

6-Chloro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol

3-chloro-2-methoxybenzyl cyanide

To 31.6 g (201.7 mmol) 3-chloro-2-methoxytoluene in 500 ml CCl4 are added 39.4 g (221.3 mmol) NBS and 100 mg benzoyl peroxide. Heated to reflux for 16 hours, allowed to cool and filtered. The solvent is removed from the filtrate and dissolved in 214 ml of N, N-dimethylformamide and 142 ml of water. 20.9 g (322.1 mmol) of potassium cyanide are added at 0 ° C and stirred for 16 hours. The reaction mixture is diluted with water and repeatedly extracted with tert-butyl methyl ether. The organic phase is washed several times with saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure and after chromatographic purification on silica gel (hexane / ethyl acetate 20%) is obtained

29.7 g product.

¹H-NMR (CDCl3): δ = 3.76 (s, 2H), 3.95 (s, 3H), 7.08 (t, 1H), 7.31 (d, 1H), 7.37 (d 1H).

4- (3-Chloro-2-methoxy-phenyl) -4-methyl-2- (trifluoromethyl) -pentane-1,2-diol

29.7 g (163.7 mmol) of 4-chloro-2-methoxybenzyl cyanide and 46.5 g (327.4 mmol) of methyl iodide in 260 ml of DMF at 0 ° C are added portionwise to 13.2 g (327.4 g mmol) sodium hydride (60% in oil). Stir overnight and then add water and ethyl acetate. The phases are separated and the aqueous phase is repeatedly extracted with ethyl acetate. It is washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (hexane / ethyl acetate 95: 5) gives 32.4 g of 2- (4-chloro-2-methoxy-phenyl) -2-methyl-propionitrile as a colorless oil. To 7 g (33.4 mmol) of nitrile in toluene at -78 ° C is slowly added 41.6 ml (50.1 mmol) of diisobutylaluminum hydride solution

111 (20% in toluene) and after 3 h at -78 ° C, 5.55 ml of isopropanol are added dropwise. It is allowed to warm to -5 ° C and 380 ml of a 10% aqueous tartaric acid solution are added. After dilution with ether, the mixture is stirred vigorously, the organic phase is separated off and the aqueous phase is extracted several times with ether. It is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (hexane / ethyl acetate 95: 5) gives 7.1 g of 2- (4-chloro-methoxy-phenyl) -2-methyl-propanal as a colorless oil. To a solution of 8.95 g (33.4mmol) of 2-diethylphosphono-2-ethoxyacetic acid ethyl ester in 30 ml of tetrahydrofuran under ice-cooling, 19 ml (38 mmol) of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptanetoluene is added over 20 minutes. mix for 15 minutes at 0 ° C. A solution of 7.1 g (33.4 mmol) of tetrahydrofuran 2- (3-chloro-2-methoxyphenyl) -2-methylpropanal at 0 ° C. is added dropwise over 30 minutes. After 20 hours at 27 ml room temperature, water is added and repeatedly extracted with ether and ethyl acetate. ammonium chloride solution, The crude product column chromatography (hexane / ethyl acetate 10%) and saturated and concentrated. using

Wash, dry (Na2SO4) and purify on silica gel to obtain 8.5 g of 4- (3-chloro-2-methoxy-phenyl) -4-methyl-3-ethoxy-2-ene-valeric acid ethyl ester. The intermediate is saponified with 80 ml 3 M sodium hydroxide solution / 160 ml ethanol. 5.3 g of acid are obtained, which is stirred for 16 hours with 80 ml of 2 N sulfuric acid at 90 ° C. After cooling, it is basified with potassium carbonate, washed with ether and acidified with hydrochloric acid. After extraction with ethyl acetate, washing with saturated sodium chloride solution and removal of the solvent, 4.0 g of 4- (3-chloro-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid are obtained. 6.6 g (24.3 mmol) of 4- (3-chloro-2-methoxy-phenyl) -4-methyl-2-oxo-valeric acid and 2.74 ml (51.4 mmol) of sulfuric acid (96%) is heated in 150 ml of ethanol for 5

112 saturated extract and then repeatedly under reflux. The mixture is concentrated under reduced pressure and the residue is taken up in sodium bicarbonate solution. Repeatedly washed with ethyl acetate, washed with saturated sodium bicarbonate solution, dried (sodium sulfate) and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 10%) gives 5.9 g of 4- (3-chloro-2-methoxy-phenyl) -4-methyl-2-oxo-valeric acid ethyl ester. To this ester and 3.4 g (23.8 mmol) {trifluoromethyl) trimethylsilane in 34 mL THF are added 49 mg tetrabutylammonium fluoride at 0 ° C. The reaction mixture is added to water for 16 h at room temperature.

extracted with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated under reduced pressure. 2.96 g of 4- (3-chloro-2-methoxy-phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester in the form of a yellow oil are obtained. To this oil in 24 ml diethyl ether at 0 ° C 510 mg lithium aluminum hydride is added and stirring is continued for 4 hours at room temperature. To the mixture at 0 ° C, 20 ml of saturated sodium bicarbonate solution are carefully added and then stirred vigorously for 1 hour. It is extracted several times with methyl tert-butyl ether, washed with water and saturated sodium chloride solution, dried with sodium sulfate and concentrated under reduced pressure. 1.83 (5.79 mmol) tetrabutylammonium fluoride trihydrate is added to the crude product in 33 ml THF and stirred for 16 hours; It is poured onto ice water, extracted several times with methyl tert-butyl ether, washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 25%) gives 1.81 g of 4- (3-chloro-2113 methoxy-phenyl} -4-methyl-2-trifluoromethyl-pentane-1,2-diol.

¹H-NMR (300 MHz, CDCl3), δ = 1.47 (s, 3H), 1.56 (s, 3H),

2.21 (d, 1H), 2.54 (d, 1H), 2.91 (s, 1H), 3.31 (dd,

1H), 3.42 (d, 1H), 4.01 (s, 3H), 7.00 (t, 1H), 7.20-7.35 (m, 2H)

4- (3-Chloro-2-methoxy-phenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentanal

To 1.2 g (3.7 mmol) diol in 24 ml dichloromethane and 6.4 ml DMSO is added 1.87g (18.5 mmol) triethylamine and 1.17 g (7.4 mmol) of the complex in portions for 10 min pyridine / SO3. Stir for 5 hours and add 30 ml sat. ammonium chloride solution. The mixture is stirred for a further 15 min, the phases are separated and extracted with tert-butyl methyl ether. It is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure, and after chromatographic purification on silica gel (hexane / ethyl acetate, 0-50%), 0.98 g of product is obtained.

¹H-NMR (CDCl3): δ = 1.44 (s, 3H), 1.50 (s, 3H), 2.29 (d, 2H), 3.28 (d, 1H), 3.55 (s , 1H), 4.01 (s, 3H) 6.95 (t,

1H), 7.07 (dd, 1H), 7.30 (dd, 1H), 8.90 (s, 1H).

1,1,1-Trifluoro-4- (3-chloro-2-methoxyphenyl) -2 - [(1Hindazol-4-yl) iminomethyl] -4-methylpentan-2-ol

To 125 mg (0.385 mmol) of 4- (3-chloro-2-methoxy-phenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentanal in 0.7 ml of glacial acetic acid is added 51.3 mg ( 0.385 mmol) 4-aminoindazole and stir overnight at room temperature. After concentration to dryness, it is chromatographed using Flashmaster. Is isolated

II, 9 mg (74.1%) of the desired compound.

6-Chloro-1 - [(1H-indazol-4-yl) amino] -5-methoxy-4,4dimetylo-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

114

116.9 mg (0.285 mmol) of imine are dissolved in 2.6 ml of dichloromethane and 1.13 ml of a 1 M solution of titanium tetrachloride in dichloromethane are added at -25 ° C. After stirring for six hours between -20 ° C and + 10 ° C, saturated sodium bicarbonate solution is added and extracted with ethyl acetate. The organic phases after drying with sodium sulfate are evaporated in a rotary evaporation to dryness. Chromatography of the residue using Flashmaster gives 91.9 mg (78.6%) of the desired cyclic compound (together with the deschlor compound).

6-Chloro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl] -1,2,3,4-tetrahydronaphthalene-2,5-diol Up to 69.9 mg (0.159 mmol) 6-chloro-1 - [(1H-indazol-4-yl) amino] -5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2-ol is added 1.45 ml of a monomolar solution of BBr3 in dichloromethane and stirred for five hours at room temperature After typical work-up, the residue is chromatographed using Flashmaster, 28.1 mg (41.5%) of the desired compound is isolated.

Melting point: 112-120 ° C

Example 28 cis-7-Chloro-1 - [(2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

4- (4-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal

2- (4-Chloro-phenyl} -2-methylpropanal

Sodium hydride (60% in oil) is added in portions to 10 g of 4-chlorobenzyl cyanide and 14.3 ml of methyl iodide in 140 ml of DMF at 0 ° C. Stir overnight and then add water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. It is extracted thoroughly with water, washed with brine, dried with sulfate

115 sodium and concentrated under reduced pressure. Chromatography on silica gel (hexane / ethyl acetate 95: 5) gives 11.73 g of 2- (4-chlorophenyl) -2-methylpropionitrile as a colorless oil. To this oil in toluene at -78 ° C, 55.4 ml of diisobutyl aluminum hydride solution (20% in toluene) is slowly added and after 4 h at -78 ° C 50 ml of ethyl acetate are added dropwise.

When warming to room temperature, the oil is stirred overnight and water is added. After filtration through diatomaceous earth, the phases are separated and the aqueous phase is extracted with ethyl acetate. It is washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (hexane / ethyl acetate 95: 5) gives 10.2 g of 2- (4-chlorophenyl) -2-methylpropanal as a colorless oil.

¹H-NMR (300 MHz, CDCl3), δ = 1.46 (s, 6H), 7.20 (d, 1H), 7.29-7.43 (m, 3H), 9.48 (s, 1H )

4- (4-Chloro-phenyl] -4-methyl-2-oxo-valeric acid To a solution of 15.04 g of 2-diethylphosphono-2-ethoxyacetic acid ethyl ester in 50 ml of tetrahydrofuran under ice-cooling, 30 ml of a 2 M solution are added over 20 minutes tetrahydrofuran-heptane-toluene diisopropylamide and stirred at 0 ° C. A solution of 10.2 g of 2- (4-chlorophenyl) -2-methylpropanal in 50 ml of lithium is added dropwise over 30 minutes, room tetrahydrofuran is added for 15 minutes with ethyl acetate, hour at sulfur temperature, extracted (Na2SO4) and concentrated.

at 0 ° C. After 20 N 2 acid is dried

The crude product is saponified with 200 ml 2 M sodium hydroxide solution / 400 ml ethanol. 13.8 g of acid are obtained, which with 300 ml of 2 N sulfuric acid and 100 ml of glacial acetic acid is heated under reflux for 3 hours. Extraction with ethyl acetate and washing with water gives 10.9 g of 4- (4-chlorophenyl) -4-methyl-2-oxo-valeric acid as a red oil.

116 ¹H-NMR (300 MHz, CDCl3), δ = 1.47 (s, 6H), 3.28 (s, 2H),

7.28 (m, 4H), 7.73 (bs, 1H)

4- (4-chlorophenyl) -4-methyl-2- (trifluoromethyl) pentane-1,2-diol

Analogously to the synthesis of 4- (3-chloro-2-methoxy-phenyl) 2-hydroxy-4-methyl-2-trifluoromethyl-pentanal (Example 27) by esterifying 10.9 g of 4- (4-chlorophenyl) -4-methyl 2-oxo-valerate in ethanol / sulfuric acid, reaction of the product with (trifluoromethyl) trimethylsilane and tetrabutylammonium and reduction of the hydroxyester with lithium aluminum hydride

4.22 g 4- (4-chlorophenyl) -4-methyl-2- (trifluoromethyl) pentane-1,2-diol as a colorless oil.

formed fluoride ¹H-NMR (CDCl3 δ (ppm) = 1.39 (s, 3H), 1.49 (s, 3H)

2.07 (d, 1H), 2.19 (d, 1H)

1H)

3.41 (d, 1H), 7.26-7.38

2.83 (bs, m, 4H).

1H)

3.27 (d,

4- (4-chlorophenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentanal

To 2 g (6.7 mmol) diol in 50 ml dichloromethane and 22 ml DMSO is added 6.8 ml (33.3 mmol) triethylamine and 1.5 g pyridine-SO3 complex is added portionwise over 20 min. Stir for 5 hours and add 40 ml sat. solutionammonium chloride . The mixture is stirred for a further 15 min, the phases are separated and extracted with dichloromethane. It is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure and after chromatography on silica gel (hexane / ethyl acetate 0-30%) is obtained

1.27 g product.

¹H-NMR (300 MHz, CDCl3): δ = 1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H), 2.66 (d, 1H), 3, 64 (s, 1H), 7.23-7.31 (m, 4H), 8.90 (s, 1H).

117

7-Chloro-1 - [(2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

Starting from the above described aldehyde, the desired compound is synthesized via imine as described in Example 83.

¹H-NMR (300 MHz, CDCl 3); δ = 1.45 (s, 3H), 1.63 (s, 3H),

2.19 (d, 1H), 2.31 (d, 1H), 2.87 (s, 3H), 5.05 (d, 1H),

5.98 (d, 1H), 6.78 (d, 1H), 7.28 -7.37 (m, 4H), 7.76 (t, 1H), 9.36 (s, 1H).

Example 29

5,8-Difluoro-1 - [(2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

4- (2,5-Difluorophenyl) -4-methyl-2-trifluorometylopentano-1,2-diol

5.4 g (15.5 mmol) 4- {2,5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeric acid ethyl ester (WO 02/10143) at 0 ° C is dissolved in diethyl ether and over min 1.76 g (46.5 mmol) of lithium aluminum hydride is added. The mixture is stirred at room temperature for 4 h, carefully added so much saturated NaHCO3 solution until no gas evolution is observed. The mixture is diluted with ethyl acetate, stirred for a further 15 min and then the precipitate formed is filtered off. It is concentrated and chromatographed on silica gel with hexane / ethyl acetate (50%); 2.45 g 2,5-difluorophenyl) -4-methyl-2-trifluoromethylpentane-1,2-diol is obtained as a slightly yellowish crystallizing oil.

4- (2,5-Difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal

800 mg (2.8 mmol) 4- (2,5-difluorophenyl) -4-methyl-2-trifluoromethyl-pentane-1,2-diol is placed in 20 ml of dichloromethane and 9.5 ml of DMSO and 1 are added at 0 ° C, 95 ml

118 triethylamine. 1.34 g (8.4 mmol) of the SO3-pyridine complex is slowly added to the solution and stirred at 0 ° C for 2 h. The mixture is partitioned between us. ammonium chloride solution and MTBE, the phases are separated and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water and sat. NaCl solution and dried over NaSO4. It is concentrated and chromatographed on silica gel with hexane / ethyl acetate (30%). 710 mg of the desired product are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 1.41 (s, 3H), 1.48 (s, 3H), 2.39 (d, 2H), 3.02 (d, 1H), 3, 61 (s, 1H), 6.84-7.18 (m,

3H), 9.23 (s, 1H).

5,8-Difluoro-1 - [(2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

The desired compound (diastereomer A) is synthesized via imine.

<td>¹H-NMR (300</td><td>MHz, CDCl3</td><td>): δ = 1.51 (s, 3H),</td><td> 1,</td><td>68 (s,</td><td>3H);</td>

<td>2.11 (d, J =</td><td>15Hz, 1H),</td><td>2.23 (d, J = 15 Hz,</td><td>1H)</td><td> , 2,84</td><td>(S,</td>

<td>3H), 4.23 (</td><td>s, br, 1H</td><td>), 4.84 (d, J = 8 Hz,</td><td>1H)</td><td> , 5,32</td><td>(D,</td>

<td>J = 8 Hz, 1H),</td><td> 6,80-6,90</td><td>(m, 1H), 6.95-7.02</td><td>(m</td><td>, 1H),</td><td> 7,05</td>

<td>(d, J = 8 Hz,</td><td>1H), 7,</td><td>39 (d, J = 8 Hz, 1H)</td><td>^,</td><td> 7,77</td><td>(Dd,</td>

J = 8 Hz / 8 Hz, 1H), 9.19 (s, 1H).

Example 30

5 - {[4,4-dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

5 aminoquinoline-2 (1H) -one:

4.5 g 5-nitroquinolin-2 (1H) -one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) in 200 ml ethyl acetate and 500 ml methanol in the presence of 450 mg palladium on activated carbon as a catalyst under normal pressure hydrogen is hydrogenated to complete the reaction. The catalyst is removed by filtration through diatomaceous earth and the reaction solution is concentrated under reduced pressure

119 pressure. 3.8 g of the title compound are obtained as a yellow solid.

¹H-NMR (DMSO): δ = 5.85 (bs, 2H), 6.27 (d, 1H), 6.33 (d,

1H), 6.43 (d, 1H), 7.10 (t, 1H), 8.07 (d, 1H), 11.39 (bs, 1H)

5 - {[4,4-dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one:

Analogously to Example 3, starting from 500 mg of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanal and 260 mg of 5-aminoquinolin2 (1H) -one, the corresponding imine is prepared. By reacting 80 mg of imine with 0.5 ml of titanium tetrachloride (1M in dichloromethane), 20 mg of the title compound are obtained.

Examples 31 and 32

5 - {[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) -one, diastereomer B

5 - {[2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) on, diastereomer A

4- (2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal

To 19.3 g of 4- (2-methoxyphenyl) -4-methyl-2-oxo-pentanoic acid ethyl ester (WO 00/32584) in 630 ml of diethyl ether, 3.3 g of lithium aluminum hydride are added portionwise at 0 ° C. After stirring for 10 h, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated. After chromatography on silica gel (hexane / acetate

120 ethyl (0&gt; 10%), 16.3 g of diol are obtained in the form of a yellow oil.

2.0 g diol, 5.2 ml triethylamine and 5.12 g sulfur trioxide-pyridine complex in 24 ml DMSO are stirred at room temperature for 48 h; added to 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. After chromatography on silica gel (hexane / ethyl acetate 0 -&gt; 3%), 1.44 g of 4- (2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal are obtained in the form of a yellow oil.¹H-NMR (300 MHz, CDCl3), δ = 1.40 (s, 3H), 1.47 (s, 3H),

2.2 (d, 1H), 3.46 (d, 1H), 3.60 (s, 1H), 3.88 (s, 3H), 6.83 - 6.94 (m, 2H), 7 , 13 (dd, 1H), 7.24 (dt, 1H),

8.94 (s, 1H)

5 - {{4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) -one, diastereomer B and 5 {[ 2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) he, diastereomer A

Analogously to Example 2, starting from 1.0 g of 4- (2-methoxyphenyl} -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 553 mg of 5-aminoquinolin2 (1H) -one, the corresponding imine is prepared. By reacting 50 mg of imine with 0.22 ml of BBr3 (1N in dichloromethane), 21 mg of 5 - {[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene- 1-yl] amino} -quinolin-2 (1H) -one as a fraction of 1 and 5 mg {[2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) onu as fraction 2.

<td>Fraction 1: ¹H-NMR</td><td> (300</td><td>MHz,</td><td>CD3OD):</td><td>δ =</td><td> 1,50</td><td>(S,</td><td>3H);</td>

<td>1.63 (s, 3H), 2.04</td><td>(D,</td><td>1H),</td><td>2.12 (d,</td><td>1H),</td><td> 3,83</td><td>(S,</td><td>3H);</td>

<td>5.17 (s, 1H), 6.48</td><td>(D,</td><td>1H),</td><td>6.60 (d,</td><td>1H),</td><td> 6,67</td><td>(D,</td><td>1H),</td>

121

6.90 (d, 1H), 6.92 (d, 1H), 7.10 (t, 1H), 7.35 (t, 1H),

8.20 (d, 1H)

Melting point = 269-270 ° C

<td>Frakc</td><td>I</td><td> 2:</td><td>¹H-NMR</td><td> (300</td><td>MHz,</td><td>CD 3 OD</td><td>): δ =</td><td> 1,39</td><td>(S,</td><td>3H);</td>

<td> 1,52</td><td>(S,</td><td>3H</td><td> ), 2,05</td><td>(D,</td><td>1H),</td><td> 2,23 (</td><td>d, 1H),</td><td> 5,28</td><td>(S,</td><td>1H),</td>

<td> 6,38</td><td>(D,</td><td>1H</td><td> ), 6,58</td><td>(D,</td><td>1H),</td><td> 6,68 (</td><td>d, 1H),</td><td> 6,92</td><td>(D,</td><td>1H),</td>

<td> 7,00</td><td>(D,</td><td>1H)</td><td> , 7,11</td><td>(T,</td><td>1H),</td><td> 7,38 (</td><td>t, 1H),</td><td> 8,14</td><td>(D,</td><td>1H)</td>

Examples 33 and 34 (-) - 5 - {[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) - he (+} - 5 - ([4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) -one

Separation (+/-) - 5 - {[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one :

The enantiomer mixture is separated by chiral support chromatography (CHIRALPAK AO®,

Company DAICEL) Obtained: (-) - Enantiomer: 1.0, CHCl3) and (+) - Enantiomer: 1.0, CHCl3) with hexane / ethanol (90:10, vvv).

MS (ESI): M ++ 1 = 433. [a] D -70.10 (c =

MS (ESI): M ++ 1 = 433. [a] D + 78.5 ° (c =

Example 35 (+) - 5 - {[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) he, diastereomer B

Analogously to Example 3, by reaction of 50 mg (+) - 5 {[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin- 2 (1H) onone and 0.22 ml BBr3 (1 M in dichloromethane) gives 5 mg of the title compound.

¹H-NMR (300 MHz, CD3OD): δ = 1.56 (s, 3H), 1.68 (s, 3H), 2.06 (d, 1H), 2.15 (d, 1H), 5, 15 (s, 1H), 6.51 (d, 1H),

122

6.62 (d, 1H), 6.68 (d, 1H), 6.70 (d, 1H), 6.81 (d, 1H),

6.95 (t, 1H), 7.37 (t, 1H), 8.23 ​​(d, 1H)

Example 36 (-) - 5 - {[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl 1.2.3.4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) he, diastereomer B

Analogously to Example 3, by reaction 70 mg (-) - 5 {[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl 1.2.3.4-tetrahydronaphthalen-1-yl) amino} quinolin-2 ( 1H) onone and 0.32 ml BBr3 (1M in dichloromethane) 32 mg of the title compound are obtained.

¹H-NMR (300 MHz, CD3OD): δ = 1.57 (s, 3H), 1.68 (s, 3H), 2.05 (d, 1H), 2.14 (d, 1H), 5, 15 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.67 (d, 1H), 6.68 (d, 1H), 6.81 (d, 1H )

6.95 (t, 1H), 7.37 (t, 1H), 8.22 (d, 1H)

Example 37

5 - {[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

Analogously to Example 2, starting from 1.0 g of 4- (4-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 492 mg of 5-aminoquinolin2 (1H) -one, the corresponding imine is prepared. By reaction

<td>300 mg of name with</td><td> 3,2</td><td>ml BBr3 (1 N in</td><td>dichloromethane)</td>

<td>20 is obtained</td><td colspan="2">mg of the title compound.</td><td></td>

<td>¹H-NMR (300 MHz,</td><td>DMSO)</td><td>: δ = 1.46 (s, 3H</td><td>), 1.58 (s, 3H),</td>

<td>1.95 (d, 1H), 2,</td><td>05 (d,</td><td>1H), 5.28 (d, 1H</td><td>), 6.08 (s, 1H),</td>

<td>6.20 (d, 1H), 6,</td><td>40 (d,</td><td>1H), 6.50-6.66 (</td><td>m, 3H), 6.77 (s,</td>

1H), 7.24 (t, 1H), 7.35 (t, 1H), 8.19 (d, 1H), 10.04 (bs, 1H), 11.57 (bs, 1H)

Example 38

5 - {[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

123

Analogously to Example 2 starting with 1.0 g of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal (Example 3) and 520 mg 5-

<td>aminoquinolines-2 (1H)</td><td>-one</td><td>produced</td><td>appropriate</td><td>name.</td>

<td>By reaction of 300</td><td>mg</td><td>names with 3.3</td><td>ml BBr3 (</td><td>1 N in</td>

<td>dichloromethane)</td><td colspan="2">is obtained</td><td>255 mg</td><td>Relationship</td>

<td>the title compound.</td><td></td><td></td><td></td><td></td>

<td>¹H-NMR (300 MHz, CD</td><td>3 OD):</td><td>δ = 1.58 (s,</td><td>3H), 1.70 (</td><td>s, 3H),</td>

<td>2.07 (d, 1H), 2.15</td><td>(D,</td><td>1H), 5.13 (s,</td><td>1H), 6.51 (</td><td>d, 1H),</td>

<td>6.60 (d, 1H), 6.68</td><td>(D,</td><td>1H), 6.74-6.95</td><td>(m, 2H), 7</td><td>, 36 (t,</td>

<td>1H), 8.22 (d, 1H)</td><td></td><td></td><td></td><td></td>

Examples 39 and 40 (-) - 5 - {[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H } -one and (+) - 5 - {[2,5-dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -he

Separation (+/-) -5 - {[2,5-dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl) amino} quinolin-2 (1H) -one:

The enantiomer mixture is separated by chiral support chromatography (CHIRALPAK AD®, with hexane / ethanol (90: 10, vvv).

The DAICEL company) The following are obtained: (-) - Enantiomer: 1.0, CHCl3) and

MS (EI): M + = 436, +) - Enantiomer: MS (EI) [a] D -23.6 ° (c =: M + = 436, [a]_D + 25.0 ° (c = 1.0, CHCl3

Example 41

5 - {[4,4-Dimethyl-5-methoxy-7-methyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) on, diastereomer A

4- (2-methoxy-4-methylphenyl) -4-methyl-2-oxopentanoic acid ethyl ester:

124

Analogously to Example 7, 2-methoxy-4-methylbenzoic acid methyl ester is prepared from 30 g of acid

2,4-cresotine and 58.6 ml of methyl iodide using

124.3 g potassium carbonate in 643 ml DMF. The ester is converted by reaction with 141 ml of methylmagnesium chloride (3M in THF) in 475 ml of methylphenyl) -1-methylethanol.

at -70 ° C is reacted with 6.4 g of 2 (trimethylsilyloxy) acrylic acid ethyl ester in 102 ml of dichloromethane with 2.3 ml of tin tetrachloride to the title.

THF, in 1- (2-methoxy-45 g of the product obtained

4.84 g of compound ¹H-NMR (300 MHz, CDCl3 δ = 1.44 (s, 6H), 2.31 (s, 3H)

3.38 (s, 2H) 7.12 (d, 1H)

3.81 (s, 3H)

6.66 (s, 1H), 6.72 (d, 1H)

4- (2-methoxy-4-methylphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal:

Analogously to Example 7, 4.84 g of 4- (2-methoxy-4-methylphenyl) -4-methyl-2-oxopentanoic acid ethyl ester is reacted with 7 ml of trifluoromethyltrimethylsilane and 3 ml of a solution of tetrabutylammonium fluoride (1 M in THF) in 56 ml THF to 4.14 g of 4- (2-methoxy-4-methylphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanoic acid ethyl ester.

The product is reduced by 856 mg lithium aluminum hydride in 170 ml diethyl ether to 3.58 g 4- (2-methoxy-4-methylphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanol. Oxidation of the diol is analogous to Example 7 according to the Swern method with 1.1 ml oxalyl chloride, 2.1 ml DMSO and 8.0 ml triethylamine to 3.01 g of the title compound.

¹H-NMR (300 MHz, CDCl3): δ = 1.38 (s, 3H), 1.43 (s, 3H),

2.18 (d, 1H), 3.45 (d, 1H), 3.87 (s, 3H), 6.67 (s, 1H),

6.70 (d, 1H), 6.98 (d, 1H), 8.92 (s, 1H)

5 - {[4,4-Dimethyl-5-methoxy-7-methyl-2-trifluorometylo1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one:

125

Analogously to Example 2, starting from 280 mg of 4- (2-methoxy-4-methylphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 156 mg of 5-aminoquinolin2 (1H) -one, the corresponding imine is prepared. At room temperature, it is mixed with 93 mg of aluminum chloride for 2.5 hours. The mixture is added to a saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. After chromatography on silica gel (dichloromethane / 2-propanol 0 -&gt; 5%), 24 mg of the title compound are obtained.

<td>¹H-NMR</td><td> (</td><td> 300</td><td>MHz, CD3</td><td>FROM)</td><td>: δ = 1.50</td><td>(S,</td><td>3H);</td><td> 1,62</td><td>(S,</td><td>3H);</td>

<td> 2,04 (</td><td>d</td><td>1H</td><td> ), 2,13</td><td>(D,</td><td>1H), 2.20</td><td>(S,</td><td>3H);</td><td> 3,85</td><td>(S,</td><td>3H);</td>

<td> 5,13 (</td><td>s</td><td>1H</td><td> ), 6,51</td><td>(D,</td><td>1H), 6.62</td><td>(D,</td><td>1H),</td><td> 6,70</td><td>(D,</td><td>1H),</td>

<td> 6,75 (</td><td>s</td><td>1H)</td><td> , 6,78 (</td><td>s</td><td>1H), 7.39</td><td>(T,</td><td>1H),</td><td> 8,23</td><td>(D,</td><td>1H)</td>

Example 42

5 - {[4,4-Dimethyl-7-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

4- (4-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal

To 16.8 g of 4- (4-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-pentanoic acid ethyl ester (WO 00/32584) in 600 ml of diethyl ether at 0 ° C, 2.7 g of hydride are added in portions lithium aluminum hydride. After stirring for 10 h, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated. After chromatography on silica gel (hexane / ethyl acetate 0 -&gt; 10%), 6.7 g of diol and 2.65 g of the title compound are obtained.

The title compound is prepared from the resulting diol by reacting 3.0 g of diol, 6.6 ml of triethylamine and 6.5 g of sulfur trioxide 126 pyridine in 34 ml of DMSO at room temperature with a reaction time of 48 h. 0.5 N acid hydrochloric and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. After chromatography on

<td>silica gel</td><td colspan="2">(hexane / ethyl acetate 0</td><td> -&gt;</td><td> 15%)</td>

<td>2.7 are obtained</td><td>g relationship</td><td>title in</td><td colspan="2">form</td>

<td>yellow oil.</td><td></td><td></td><td></td><td></td>

<td colspan="2">¹H-NMR (300 MHz, CDCl3), δ = 1.38</td><td>(s, 3H), 1.46</td><td>(S,</td><td>3H);</td>

<td>2.19 (d, 1H), 3.37 (</td><td>d, 1H), 3.58</td><td>(s, 1H), 3.87</td><td>(S,</td><td>3H);</td>

<td>6.55 - 6.64 (m, 2H),</td><td>7.06 (dd, 1H</td><td>), 8.97 (s, 1H)</td><td></td><td></td>

5 - ({4,4-dimethyl-7-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-y] amino} quinolin-2 (1H) -one:

Analogously to Example 41, starting from 500 mg of 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 260 mg of 5-aminoquinolin2 (1H) -one, the corresponding imine is prepared. By reacting 220 mg of imine with 197 mg of aluminum chloride, 10 mg of the title compound are obtained.

¹H-NMR (CD3OD): δ = 1.51 (s, 3H), 1.63 (s, 3H), 2.07 (d, 1H), 2.14 (d, 1H), 5.15 (s , 1H), 6.53 (d, 1H), 6.586,77 (m, 4H), 7.40 (t, 1H), 8.23 ​​(d, 1H)

Example 43 (+) - 5 - {[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 (1H) on

Analogously to Example 3, by reaction of 50 mg (+) - 5 {[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin- 2 (1H) onone and 0.22 ml BBr3 (1M in dichloromethane) gives 5 mg of the title compound.

<td>¹H-NMR</td><td colspan="2"> (300</td><td colspan="2">MHz, CD3OD)</td><td>: δ = 1.57</td><td>(S,</td><td>3H);</td><td> 1,</td><td> 69</td><td>(S,</td><td>3H);</td>

<td> 2,06 (</td><td>d</td><td>1H</td><td> ), 2,15</td><td>(D,</td><td>1H), 5.16</td><td>(S,</td><td>1H),</td><td> 6,</td><td> 51</td><td>(D,</td><td>1H),</td>

<td> 6,62 (</td><td>d</td><td>1H</td><td> ), 6,69</td><td>(D,</td><td>1H), 6.71</td><td>(D,</td><td>1H),</td><td> 6,</td><td> 82</td><td>(D,</td><td>1H),</td>

<td> 6,95 (</td><td>t</td><td>1H)</td><td> , 7,37 (</td><td>t</td><td>1H), 8.23</td><td>(D,</td><td>1H)</td><td></td><td></td><td></td><td></td>

127

Example 44

4 - {[2-Hydroxy-4,4-dimethyl-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -ftalid

Analogous to Example 10, starting with 600 mg 4- (2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 308 mg 4-amino-phthalide (Bull. Soc. Sci. Bretagne 26, 1951, Special Issue 5 , s, 7, 96) the corresponding imine is prepared. As in

Example 2, 650 mg of imine by reaction with 7.7 ml BBr3 (1 M in dichloromethane) is converted to give 165 mg of the title compound.

<td>¹H</td><td>NMR (300</td><td>M</td><td>Hz,</td><td>DMSO-d6</td><td>): δ =</td><td> 1,3</td><td> 0 (</td><td>s</td><td>3H);</td><td> 1,46</td><td>(S,</td>

<td>3H)</td><td> , 1,93 (</td><td>d</td><td>1H)</td><td> , 2,18 (</td><td>d, 1H)</td><td> , 3,</td><td> 57</td><td>(S,</td><td>3H);</td><td> 5,10</td><td>(D,</td>

<td>1H)</td><td> , 5,20 (</td><td>d</td><td>1H)</td><td> , 5,32 (</td><td>d, 1H)</td><td> , 5,</td><td> 55</td><td>(D,</td><td>1H),</td><td> 5,81</td><td>(S,</td>

<td>1H)</td><td> , 6,80 (</td><td>d</td><td>1H)</td><td> , 7,03 (</td><td>d, 1H)</td><td> , 7,</td><td> 04</td><td>(D,</td><td>1H),</td><td> 7,20</td><td>(D,</td>

<td>1H)</td><td> , 7,27 (</td><td>t</td><td>1H)</td><td> , 7,37 (</td><td>t, 1H)</td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 45

7-Chloro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol. Analogous to Example 2 starting from 410 mg of 4- (4-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 168 mg of 4-aminoindazole, the corresponding imine is prepared. By reacting 200 mg imine with 6.7 ml BBr3 (1N in dichloromethane) 98 mg of the title compound are obtained.

<td colspan="2">¹H-NMR</td><td> (300</td><td>MHz, DMSO-d6)</td><td colspan="2">: δ =</td><td> 1,48 (</td><td>s</td><td>3H);</td><td> 1,59</td><td>(S,</td>

<td>3H)</td><td> , 1,</td><td> 97 (</td><td>d, 1H), 2.07 (</td><td>d</td><td>1H)</td><td> , 5,27</td><td>(D,</td><td>1H),</td><td> 5,95</td><td>(S,</td>

<td>1H)</td><td> , 6,</td><td> 21 (</td><td>d, 1H), 6.31 (</td><td>d</td><td>1H)</td><td> , 6,72</td><td>(S,</td><td>1H),</td><td> 6,74</td><td>(D,</td>

<td>1H)</td><td> , 6,</td><td> 76 (</td><td>s, 1H), 7.08 (</td><td>t</td><td>1H)</td><td> , 8,13</td><td>(S,</td><td>1H),</td><td> 9,94</td><td>(S,</td>

<td>1H)</td><td> , 12</td><td> ,83</td><td>(s, 1H)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Examples 46 and 47 (-) - 7-Chloro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diiol

128 (+) - 7-Chloro-1 - [(1H-indazol-4-yl) amino] -4,4-dimetylo2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5diol

Separation (+/-) - 7-chloro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-

<td colspan="5">tetrahydronaphthalene-2,5-diol</td>

<td>A mixture of</td><td>enantiomers</td><td>partitioned</td><td>up</td><td>by</td>

<td>chromatography</td><td>on the carrier</td><td>chiral</td><td>(CHIRALPAK</td><td>AD®,</td>

<td>DAICEL company)</td><td>with hexane / 2</td><td>propanol</td><td> (98: 2,</td><td>vvv).</td>

<td>You get:</td><td></td><td></td><td></td><td></td>

<td>(-) - enantiomer</td><td>: MS (EI): M +</td><td> = 425/427,</td><td>[αΐπ -3.0 °</td><td>(c =</td>

<td>1.0, CHCl3) and</td><td></td><td></td><td></td><td></td>

<td>(+) - enantiomer</td><td>: MS (EI): M +</td><td> = 425/427,</td><td>[αΐπ + 5,0 °</td><td>(c =</td>

1.0, CHCl3)

Examples 48 and 49

7-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

7-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol. Analogous to Example 2 starting the corresponding imine is prepared from 1.8 g of 4- (4-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 780 mg of 4-aminoindazole. By reacting 300 mg of imine with 10.6 ml of BBr3 (1 N in dichloromethane), 13 mg of 7-fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-5-methoxy-2- is obtained. (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol as fraction 1 and 30 mg of 7fluoro-1- [(1H-indazol-4-yl) amino] -4,4-dimethyl-2 (trifluoromethyl) -1 , 2,3,4-tetrahydronaphthalene-2; 5-diol as fraction 2.

<td>Fraction 1: ¹H-NMR (</td><td>300 MHz</td><td>CDCl3):</td><td>δ = 1.48 (s,</td><td>3H);</td>

<td>1.62 (s, 3H), 2.05 (</td><td>d, 1H),</td><td>2.16 (d,</td><td>1H), 3.85 (s,</td><td>3H);</td>

<td>4.62 (d, 1H), 5.07</td><td>(d, 1H)</td><td> , 6,43</td><td>(d, 1H), 6.55</td><td>(Dd,</td>

<td>1H), 6.71 (dd, 1H),</td><td> 6,92 (</td><td>d, 1H),</td><td>7.27 (t, 1H),</td><td> 8,01</td>

(S, 1H)

129

<td colspan="2">Fraction</td><td> 2: ¹H-NMR (300 MHz,</td><td>CDCl3):</td><td>δ =</td><td>1.54 (s,</td><td>3H);</td>

<td> 1,65</td><td>(S,</td><td>3H), 2.07 (d, 1H),</td><td>2.17 (d,</td><td>1H),</td><td>4.62 (d,</td><td>1H),</td>

<td> 5,07</td><td>(D,</td><td>1H) ,, 6.37-6.47 (m,</td><td>2H), 6,</td><td> 72 (</td><td>dd, 1H),</td><td> 6,94</td>

<td>(D,</td><td>1H),</td><td>7.28 (t, 1H), 8.02</td><td>(s, 1H)</td><td></td><td></td><td></td>

Examples 50 and 51 (-) - 7-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diiol (+) - 7-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimetylo2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5diol

Separation of (+/-) - 7-fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol:

The mixture of enantiomers is separated by chiral support chromatography (CHIRALPAK AO®, Company DAICEL) with hexane / 2-propanol (98: 2, vvv). You get:

(-) -Enantiomer: MS (EI): M + = 409, [a] D -40.5 ° (c =

0.2, CHCl3) and (+) - Enantiomer: MS (EI): M + = 409

Examples 52 and 53

5-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol, diastereomer A

5-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl} -1,2,3,4-tetrahydronaphthalene-2,5-diol, diastereomer B

4- (2-Fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal

To 4.12 g of 4- (2-fluoro-4-methoxyphenyl) -4-methyl-2-oxo-pentanoic acid ethyl ester in 140 ml of diethyl ether are added portionwise at 0 ° C 666 mg of lithium aluminum hydride. After stirring for 10 h, it is added to saturated bicarbonate solution and filtered

130 through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase is washed and concentrated; after silica water and brine, dried by chromatography (hexane / ethyl acetate 0-&gt; 10% (Na2SO4) and 2.74 g diol and 416 mg of the title compound are obtained on the gel.

from the obtained diol g diol, 6.6 ml

The title compound is prepared by reacting 3.0 triethylamine and 6.5 g of sulfur pyridine trioxide complex in 34 ml DMSO at room temperature with a reaction time of 48 hours. It is poured onto 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. After chromatography on silica gel (hexane / ethyl acetate 0 -&gt; 15%), 1.73 g of the title compound is obtained in a yellow oil.

¹H-NMR (300 MHz, CDCl3), δ = 1.39

2.26 (d, 1H), 3.09 (d, 1H), 3.63 s, 3H), 1.46 s, 1H), 3.78 forms s, 3H), s, 3H),

6.52 - 6.65, 2H),

7.03 (t, 1H), 9.04 (s, 1H)

5-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol, diastereomer A and

5-Fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol, diastereomer B:

Analogously to Example 2, starting from 1.7 g of 4- (2-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 736 mg of 4-aminoindazole, the corresponding imine is prepared. By reacting 300 mg of imine with 10.6 ml of BBr3 (1N in dichloromethane), 12 mg of 5-fluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1 is obtained. , 2,3,4-tetrahydronaphthalene-2,5-diol, diastereomer B, as fraction 1 and 90 mg of 5-fluoro-1 - [(1H-indazol-4-yl) amino] 4,4-dimethyl-2- (trifluoromethyl ) -1,2,3,4131 tetrahydronaphthalene-2,5-diol, diastereomer A as fraction 2.

<td>Fraction 1</td><td> : ¹H-NMR</td><td>(300 MHz,</td><td>CDCl3): δ =</td><td> 1,48</td><td>(S,</td><td>3H);</td>

<td>1.58 (s,</td><td>3H), 2.06</td><td>(d, 1H),</td><td>2.23 (d, 1H)</td><td> , 4,95</td><td>(D,</td><td>1H),</td>

<td>5.11 (d,</td><td colspan="2">1H), 6.37 {d. 1 H}</td><td>, 6.48 (dd,</td><td>1H),</td><td> 6,64</td><td>(D,</td>

<td>1H), 6.75</td><td>(s, 1H),</td><td>7.25 (t,</td><td>1H), 7.48 (p</td><td>, 1H)</td><td></td><td></td>

<td>Fraction 2</td><td> : ¹H-NMR</td><td>(300 MHz,</td><td>CDCl3): δ =</td><td> 1,48</td><td>(S,</td><td>3H);</td>

<td>1.58 (s,</td><td>3H), 2.05</td><td>(d, 1H),</td><td>2.24 (d, 1H)</td><td> , 5,04</td><td>(D,</td><td>1H),</td>

<td>5.12 (d,</td><td>1H), 6.37</td><td>(d, 1H)</td><td>, 6.48 (dd,</td><td>1H), 6</td><td> ,58</td><td>(Dd,</td>

<td>1H), 6.78</td><td>(d, 1H),</td><td>7.24 (t,</td><td>1H), 7.29 (p</td><td>, 1H)</td><td></td><td></td>

Example 54

1 - [(1H-Indazol-4-yl) amino] -4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer A

Analogously to Example 41, starting from 850 mg of 4- (2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 390 mg of 4-aminoindazole, the corresponding imine is prepared. By reacting 500 mg of imine with 495 mg of aluminum chloride, 138 mg of the title compound are obtained.

<td colspan="4">¹H-NMR (300 MHz, CDCl3), δ = 1.52</td><td>(S,</td><td>3H);</td><td> 1,66</td><td>(S,</td><td>3H);</td>

<td> 2,05</td><td>(D,</td><td>1H), 2.16</td><td>(d, 1H), 3.85</td><td>(S,</td><td>3H);</td><td> 4,57</td><td>(D,</td><td>1H),</td>

<td> 5,23</td><td>(D,</td><td>1H), 6.48</td><td>(d, 1H), 6.82</td><td>(D,</td><td>1H),</td><td> 6,92</td><td>(D,</td><td>1H),</td>

<td> 6,95</td><td>(D,</td><td>1H), 7.12</td><td>(t, 1H), 7.29</td><td>(T,</td><td>1H),</td><td> 7,97</td><td>(S,</td><td>1H)</td>

Example 55

1 - [(1H-Indazol-4-yl) amino] -4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol, diastereomer B

Analogously to Example 2, 300 mg of the imine obtained in Example 54 is reacted with 11 ml of BBr3 (1 N in dichloromethane) to 24 mg of the title compound.

<td>¹H-NMR (300 MHz, CD3OD)</td><td>, δ =</td><td> 1,42</td><td>(S,</td><td>3H);</td><td> 1,</td><td> 55</td><td>(S,</td><td>3H);</td>

<td>2.08 (d, 1H), 2.23 (d,</td><td>1H),</td><td> 3,33</td><td>(S,</td><td>3H);</td><td> 5,</td><td> 33</td><td>(S,</td><td>1H),</td>

<td>6.63 (d, 1H), 6.72 (d,</td><td>1H),</td><td> 6,88</td><td>(D,</td><td>1H),</td><td> 7,</td><td> 06</td><td>(D,</td><td>1H),</td>

7.20-7.31 (m, 2H), 8.17 (s, 1H)

132

Example 56

1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol

100 mg of the compound of Example 54 is reacted analogously to Example with 3.7 ml of BBr3 (1 N w

<td>dichloromethane) to</td><td> 47</td><td>mg</td><td>Relationship</td><td colspan="2">title of that.</td><td></td>

<td>¹H-NMR (300 MHz, CD3</td><td>FROM)</td><td>, δ</td><td> = 1,40</td><td>(s, 3H),</td><td> 1,54</td><td>(s, 3H),</td>

<td>2.10 (d, 1H), 2.25</td><td>(D,</td><td>1H)</td><td> , 5,36</td><td>(s, 1H),</td><td> 6,60</td><td>(d, 1H),</td>

<td>6.94 (d, 1H), 7.12</td><td>(T,</td><td>1H)</td><td> , 7,18-</td><td>7.33 (m,</td><td>3H);</td><td>8.20 (s,</td>

1H)

Example 57

7-Chloro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

Analogously to Example 2, starting from 350 mg of 4- (4-chlorophenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 158 mg of 4-aminoindazole, the corresponding imine is prepared. By reacting 50 mg of imine with 1.8 ml of BBr3 (1 N in dichloromethane) 29 mg of the title compound are obtained.

<td>¹H-NMR</td><td> (300</td><td>MHz, CDCl3)</td><td>, δ =</td><td> 1,41</td><td>(S,</td><td>3H);</td><td> 1,54</td><td>(s, 3H),</td>

<td> 2,10 (</td><td>d, 1H</td><td>), 2.19 (d,</td><td>1H),</td><td> 4,63</td><td>(D,</td><td>1H),</td><td> 5,14</td><td>(d, 1H),</td>

<td> 6,43 (</td><td>d, 1H</td><td>), 6.95 (d,</td><td>1H),</td><td> 7,23-</td><td> 7,37</td><td>(M,</td><td>4H),</td><td>8.03 (s,</td>

1H)

Example 58

1 - [(1-methyl-indazol-4-yl) amino] -4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

4-Amino-1-methylindazole:

6.5 g 4-nitroindazole (Chem. Ber. (1904), 37.2583), 1.9 ml methyl iodide and 14.4 g cesium carbonate in 110 ml DMF are stirred for 2 h at 0 ° C and then for 12 h h at room temperature. The mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated. The residue is recrystallized from ethyl acetate / hexane.

133

2.49 g of 1-methyl-4-nitroindazole are obtained. It is hydrogenated in 70 ml THF with hydrogen with 420 mg palladium on activated carbon under normal pressure. The mixture is filtered and concentrated completely. Is obtained

2.1 g of the title compound. ¹H-NMR (300 MHz, CD3OD), δ =

3.96 (s, 3H), 6.35 (d, 1H), 6.75 (d, 1H), 7.16 (d, 1H), 8.06 (s, 1H)

1- {(1-Methyl-indazol-4-yl) amino] -4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

Analogously to Example 3, starting from 296 mg of 4- (2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 150 mg of 4-amino-1-methylindazole, the corresponding imine is prepared. By reacting 100 mg of imine with 0.5 ml of titanium tetrachloride, 100 mg of the title compound is obtained.

Melting point: 172-174 ° C

Examples 59 and 60

7-Ethyl-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

7-Ethyl-1 - [(1H-indazol-4-yl] amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

2-hydroxy-4- (4-iodo-2-methoxyphenyl) -4-methyl-2-trifluoromethyl valeric acid methyl ester: 3 g of 4- (4-iodo-2-methoxyphenyl) -4-methyl-2-oxovaleric acid (WO 98/54159 ) is added to the solution

1.3 ml thionyl chloride in 12 ml methanol at 0 ° C and stirred at room temperature for h. It is poured onto a saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated. 3.2 g of 4- (4-iodo-2-methoxyphenyl) -4-methyl-2-oxovaleric acid methyl ester are obtained as the crude product. 4.5 ml are added to this ester

134 trifluoromethyltrimethylsilane in 70 ml DMF and 1.63 g cesium carbonate at 0 ° C and stirred for 10 h at room temperature. 20 mg tetrabutylammonium fluoride are added and stirring is continued for a further 30 min at room temperature. The mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated. After chromatography on silica gel (hexane / ethyl acetate 0 -&gt; 15%), 1.47 g of the title compound is obtained in the form of a yellow oil.

¹H-NMR (300 MHz, CDCl3), δ = 1.34 (s, 3H), 1.42 (s, 3H),

2.30 (d, 1H), 2.97 (d, 1H), 3.36 (s, 3H), 3.84 (s, 3H),

6.88 (dd, 1H), 7.13 (dd, 1H), 7.23 (dd, 1H) with a reflux condenser. completely concentrates.

ml of room diethyl ether. Gives up to

4- (4-Ethyl-2-methoxyphenyl) -2-hydroxy-4-methyl-2trifluorometylopentanal:

g of 2-hydroxy-4- (4-iodo-2-methoxyphenyl) -4-methyl-2-trifluoromethylvaleric acid methyl ester, 860 mg of tributylvinyltin, 103 mg of palladdibenzylideneacetone complex and 30 mg of triphenylphosphine in 17 ml of THF under argon Filtered through diatomaceous earth and After chromatography on silica gel (hexane / ethyl acetate 0 -&gt; 2%), 339 mg of 2-hydroxy-4- (2-methoxy-4-vinylphenyl) -4-methyl-2-trifluoromethyl valeric acid methyl ester is obtained. . It is mixed with 56 mg of lithium aluminum hydride for 10 h at a saturated bicarbonate solution temperature, filtered through diatomaceous earth and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated. Chromatography on silica gel (hexane / ethyl acetate 0 -&gt; 10%) gives 148 mg of 2-hydroxy-4- (2-methoxy-4-vinylphenyl) -4-methyl-2-trifluoromethylpentanol. They are hydrogenated in 4.3 ml of ethyl acetate under normal hydrogen pressure with 14 mg of palladium

135 activated carbon. The mixture is filtered through diatomaceous earth and concentrated completely. 127 mg of 4- (4-ethyl-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanol are obtained. The diol obtained is transformed with 0.29 ml of triethylamine and 280 mg of sulfur trioxide-pyridine complex in 1.3 ml of DMSO at room temperature during a reaction time of 10 h. It is added to a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. Chromatography on silica gel (hexane / ethyl acetate 0 -&gt; 3%) gives 94 mg of the title compound as a colorless oil.

<td>¹H-NMR</td><td> (300</td><td>MHz, CDCl3), δ =</td><td> 1,24 (</td><td>t</td><td>3H);</td><td> 1,38 (</td><td>s</td><td>3H</td>

<td> 1,44 (</td><td>s, 3H</td><td>), 2.17 (d, 1H)</td><td> , 2,62</td><td>(Q,</td><td>2H)</td><td> , 3,46</td><td>(D,</td><td>1H</td>

<td> 3,88 (</td><td>s, 3H</td><td>), 6.68 (s, 1H),</td><td> 6,72 (</td><td>d</td><td>1H),</td><td> 7,02 (</td><td>d</td><td>1H</td>

<td> 8,91 (</td><td>s, 1H)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

7-Ethyl-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol and

7-ethyl-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol: Analogously to Example 2 starting from 90 mg of 4- (4-ethyl-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 38 mg of 4-aminoindazole make the corresponding imine. By reacting 68 mg of imine with 0.39 ml BBr3 (1N in dichloromethane) 16 mg of 7-ethyl-1 - [(1H-indazol-4-yl) amino) -4,4-dimethyl-5-methoxy-2- ( trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol as a fraction of 1 and 7 mg 7-ethyl1 - [(1H-indazol-4-yl) amino) -4,4-dimethyl-2 (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalen-2-ol as fraction 2.

Fraction 1: ¹H-NMR (300 MHz, CDCl3), δ = 1.24 (t, 3H), 1.42 (s, 3H), 1.51 (s, 3H), 2.03 (d, 1H), 2, 14 (d, 1H),

2.63 (q, 2H), 3.18 (s, 3H), 3.74 (bd, 1H), 5.33 (bd,

136

<td>1H),</td><td> 6,48</td><td>(s, 1H),</td><td> 6,70</td><td>(D,</td><td>1H), 6.85 (s, 1H),</td><td> 6,98</td><td>(D,</td>

<td>1H),</td><td> 7,32</td><td>(t, 2H),</td><td> 7,89</td><td>(S,</td><td>1H)</td><td></td><td></td>

<td colspan="2">Fraction 2</td><td> : ¹H-NMR</td><td> (300</td><td>MHz</td><td>, CDCl3), δ = 1.00</td><td>(T,</td><td>3H);</td>

<td> 1,55</td><td>(S,</td><td>3H), 1.65</td><td>(S,</td><td>3H);</td><td>2.04 (d, 1H), 2.18</td><td>(D,</td><td>1H),</td>

<td> 2,36</td><td>(Q,</td><td>2H), 3.18</td><td>(S,</td><td>3H</td><td>), 4.65 (bd, 1H), 5</td><td> ,09</td><td>(Bd,</td>

<td>1H),</td><td> 6,47</td><td>(d, 1H),</td><td> 6,48</td><td>(S,</td><td>1H), 6.76 (s, 1H),</td><td> 6,92</td><td>(D,</td>

<td>1H),</td><td> 7,29</td><td>(t, 2H),</td><td> 8,00</td><td>(S,</td><td>1H)</td><td></td><td></td>

Example 61

1 - [(1-methyl-indazol-4-yl) amino] -4,4-dimethyl-2-trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol

In analogy to Example 2, 163 mg are reacted

<td>name described according to</td><td>Example 58 with</td><td> 0,97</td><td>ml</td><td>BBr3 (</td><td>1N century</td>

<td>dichloromethane) up to 44</td><td colspan="3">mg of the title compound.</td><td></td><td></td>

<td>¹H-NMR (300 MHz, CD3OD)</td><td>, δ = 1.56 (s,</td><td>3H);</td><td> 1,</td><td>68 (s,</td><td>3H);</td>

<td>2.05 (d, 1H), 2.14 (d,</td><td>1H), 4.02 (s,</td><td>3H);</td><td> 5,</td><td>15 (s,</td><td>1H),</td>

<td>6.34 (d, 1H), 6.67 (d,</td><td>1H), 6.78 (d,</td><td>1H),</td><td> 6,</td><td> 82-6,98</td><td>(M,</td>

<td colspan="2">2H), 7.25 (t, 2H), 8.07 (s, 1H)</td><td></td><td></td><td></td><td></td>

Examples 62 and 63

5 - {[7-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} min} isoquinolin-1 (2H) -he

5 - {[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isoquinolin-1 (2H) -one

Analogously to Example 2, starting from 385 mg of 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 200 mg of 5-aminoisoquinoline (2H) -one, the corresponding imine is prepared. By reacting 300 mg of imine with 10.0 ml of BBr3 (1 N in dichloromethane), 10 mg of 5 - {[7-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1.2 is obtained. , 3,4-tetrahydronaphthalen-1-yl] amino} -isoquinolin-1 (2H) -one as a fraction of 1 and 100 mg of 5 - {[7-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) - 1,2,3,4137 tetrahydronaphthalen-1-yl] amino} -isoquinolin-1 (2H) -one as fraction 2.

<td>Fraction 1: ¹H-NMR (</td><td>300 MHz</td><td>DMSO-d6). δ</td><td> = 1,32 (</td><td>s, 3H),</td>

<td>1.47 (s, 3H), 1.95</td><td>(d, 1H),</td><td>2.24 (d, 1H)</td><td> , 3,44 (</td><td>s, 3H),</td>

<td>5.01-5.14 (m, 2H),</td><td>5.85 (p</td><td>, 1H), 6.70 (</td><td>dd, 1H)</td><td> , 6,78-</td>

<td>(d, 1H), 6.86 (dd,</td><td>1H), 6,</td><td>98 (dd, 1H),</td><td> 7,22 (</td><td>d, 1H),</td>

<td>7.31 (t, 1H), 7.52</td><td>(D, 1H),</td><td>11.10 (na</td><td colspan="2">1H) Fraction 2:</td>

<td colspan="2">¹H-NMR (300 MHz, DMSO-d6),</td><td>δ = 1.47 (s,</td><td>3H), 1</td><td>, 58 (s,</td>

<td>3H);</td><td> 1,97</td><td>(D,</td><td>1H),</td><td> 2,08</td><td>(d, 1H), 5.30 (d, 1H), 5.94 (d,</td>

<td>1H),</td><td> 6,13</td><td>(S,</td><td>1H),</td><td> 6,35</td><td>(dd, 1H), 6.54 (dd, 1H), 6.81</td>

<td>(D,</td><td>1H),</td><td> 7,03</td><td>(D,</td><td>1H),</td><td>7.17 (dd, 1H), 7.25 (t, 1H),</td>

<td> 7,51</td><td>(D,</td><td>1H),</td><td> 9,98</td><td>(Bs,</td><td>1H), 11.25 (bd, 1H)</td>

Examples 64 and 65 (-) - 5 - {[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -isoquinolin- 1 (2H) -one (+) - 5 - {[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} - isoquinolin-1 (2H) -one

Separation (+/-) - 5 - {[7-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -isoquinolin-1 ( 2H) -one: The enantiomer mixture is separated by chiral support chromatography (CHIRALPAK AD®.

with hexane / ethanol (90: 10, vvv).

DAICEL company) You receive:

(-) - Enantiomer: 0.5, CHCl3) and

MS (EI): M + = 436, +) - Enantiomer: MS (EI) [a] D -62.5 ° (c =: M + = 436, [a]_D + 75.6 ° (c = 0.8, CHCl3

Example 66

5 - {[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-metyloftalazyn-1-one, diastereomer A

5-Amino-2-methyl-phthalazin-1-one:

138

3-Bromo-4-nitro-phthalide

5.37 g 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g N-bromosuccinimide and 196 mg benzoyl peroxide in 80 ml benzotrifluoride under reflux and under heating of light overall reaction. It is added to water, extracted with dichloromethane, washed several times with water, dried and the solvent removed under reduced pressure. 7.24 g of 3-bromo-4-nitro-phthalide are obtained as a solid.

¹H-NMR (300 MHz, CDCl3), δ = 7.26 (s, 1H), 7.88 (t, 1H),

8.3 (d, 1H), 8.56 (d, 1H)

5-Nitro-phthalazin-1-one:

18.25 g hydrazine sulfate and 14.88 g sodium carbonate in 300 ml DMF are stirred at 100 ° C for 1 h. Then 7.24 g 3-bromo-4-nitro-phthalide in 100 ml DMF are added and mixed for a further 4 h at 100 ° C. It is added to water, extracted several times with ethyl acetate and the organic phase is washed with water and brine. Dried and the solvent removed under reduced pressure. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazine-1-one are obtained as a solid.

¹H-NMR (300 MHz, DMSO-d6), δ = 8.05 (t, 1H), 8.57-8.66 (m, 2H), 8.73 (s, 1H), 13.13 (bs , 1H)

2-Methyl-5-nitro-phthalazin-1-one

1.6 g 5-nitro-phthalazine-1-one and 2.31 g potassium carbonate for 10 min. is stirred at room temperature in 60 ml DMF. 1.1 ml of methyl iodide are added and stirred overnight; added to water, extracted several times with ethyl acetate and the organic phase washed with water and brine. Dried and the solvent removed under reduced pressure. 1.57 g of 2-methyl-5-nitro-phthalazine-1-one are obtained as a yellow solid.

¹H-NMR (300 MHz, DMSO-d6), δ = 3.73 (s, 3H), 8.05 (t, 1H), 8.62 (d, 2H), 8.75 (s, 1H)

139

5-Amino-2-methyl-phthalazin-1-one

1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 130 mg of palladium on activated carbon are suspended in 45 ml of ethyl acetate and hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth and the solvent is removed under reduced pressure. 1.26 g of 5-amino-2-methyl-phthalazine-1-one are obtained as a yellow solid.

¹H-NMR (300 MHz, CDCl3), δ = 3.81 (s, 3H), 7.0 (d, 1H),

7.5 (t, 1H), 7.8 (d, 1H), 8.16 (s, 1H)

5 - {[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-metyloftalazyn-1-one

Analogously to Example 10, starting from 200 mg of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 114 mg of 5-amino-2-methylphthalazin-1-one, the corresponding imine is prepared. As in Example 3, 50 mg of imine is converted by reaction with 0.23 ml of titanium tetrachloride to give 12 mg of the title compound.

Melting point: 262-263 ° C

Example 67

5 - {[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} phthalazin-1 (2H) -one

5-Amino-phthalazin-1-one:

980 mg of 5-nitro-phthalazin-1-one (Example 66) and 100 mg of palladium on activated carbon are suspended in 50 ml of ethyl acetate and 1 ml of triethylamine and hydrogenation with hydrogen under normal pressure. It is filtered through diatomaceous earth and the solvent is removed under reduced pressure. 830 g of 5-amino-phthalazine-1 -one as a solid are obtained as crude product.

¹H-NMR (300 MHz, DMSO-d6), δ = 6.26 (bs, 2H), 7.00 (d, 1H), 7.32 (d, 1H), 7.44 (t, 1H), 8.48 (s, 1H), 12.35 (bs, 1H)

140

5 - {[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} phthalazin-1 (2H) -one :

Analogously to Example 10, starting from 200 mg of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 105 mg of 5-amino-phthalazin-1one, the corresponding imine is prepared. As in Example 3, 50 mg of imine is converted by reaction with 0.22 ml of titanium tetrachloride to give 36 mg of the title compound.

¹H-NMR (300 MHz, CD3OD), δ = 1.53 (s, 3H), 1.64 (s, 3H),

2.12 (s, 2H), 3.94 (d, 3H), 5.24 (s, 1H), 6.96 (dd, 1H),

7.03 (dd, 1H}, 7.24 (dd, 1H), 7.58-7.65 (m, 2H),

8.55 (s, 1H)

Example 68

5 - {[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2 (trifluorometylolo-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-metyloftalazyn-1-one

Analogously to Example 10, starting from 200 mg of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 108 mg of 5-amino-2-methylphthalazin-1-one, the corresponding imine is prepared. As in Example 2, 225 mg of imine is converted by reaction with 2.3 ml of BBr3 (1M in dichloromethane) to give 12 mg of the title compound.

<td>¹H-NMR</td><td>(300 MHz, CD3OD), δ = 1.55</td><td>(s, 3H), 1.66</td><td>(S,</td><td>3H);</td>

<td> 2,08 (</td><td>d, 1H), 2.14 (d, 1H), 5.22</td><td>(s, 1H), 6.74</td><td>(S,</td><td>1H),</td>

<td> 6,78</td><td>(s, 1H), 7.18-7.27 (m, 1H)</td><td> , 7,62-7,72</td><td>(M,</td><td>2H);</td>

<td> 8,57 (</td><td>s, 1H)</td><td></td><td></td><td></td>

Example 69

5 - {[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-metyloftalazyn-1-one, Diastereomer B Analogously to Example 10, starting from 200 mg of 4- (3-fluoro-2-methoxyphenyl} -2-hydroxy-4-methyl-2141 {trifluoromethyl) pentanal and 114 mg of 5-amino-2-methylphthalazin-1-one, the corresponding imine. As in

Example 2 is converted to 112 mg of imine by reaction with 0.36 ml BBr3 (1 M in dichloromethane) to give 38 mg of the title compound.

<td>¹H-NMR</td><td>(300 MHz, CDCl3)</td><td>, δ = 1.53</td><td>(S,</td><td>3H);</td><td> 1,64</td><td>(S,</td><td>3H);</td>

<td> 2,11 (</td><td>d, 1H), 3.85 (s,</td><td>3H), 3.97</td><td>cd,</td><td>3H);</td><td> 5,02</td><td>(D,</td><td>1H),</td>

<td> 5,13 (</td><td>d, 1H), 6.97 (d,</td><td>1H), 7.00 (</td><td>dd,</td><td>1H),</td><td> 7,08</td><td>(D,</td><td>1H),</td>

<td> 7,61 (</td><td>t, 1H), 7.83 (d,</td><td>1H), 8.15</td><td>(S,</td><td>1H)</td><td></td><td></td><td></td>

Example 70

5 - {[6-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazin-1-one mg compound with Example 69 is reacted in analogy to Example 1 with 0.13 ml BBr3 (1 N in dichloromethane) to 18 mg of the title compound.

¹H-NMR (300 MHz, CD3OD), δ = 1.60 (s, 3H), 1.71 (s, 3H), 2.09 (d, 1H), 2.16 (d, 1H), 3, 83 (s, 3H), 5.23 (s, 1H),

6.79 (dd, 1H), 6.90 (dd, 1H), 7.22 (dd, 1H), 7.59-7.68 (m, 2H), 8.56 (s, 1H)

Example 71

5 - {[6-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} phthalazine-1 (2H) -one mg compound from Example 67, analogous to Example 1, was reacted with 0.35 ml BBr3 (1 N in dichloromethane) to 15 mg of the title compound.

¹H-NMR (300 MHz, CD3OD), δ = 1.60 (s, 3H), 1.71 (s, 3H),

<td>2.14 (d,</td><td>2H);</td><td> 5,23</td><td>(s, 1H),</td><td>6.80 (dd, 1H)</td><td>, 6.90 (dd,</td>

<td>1H), 7.25</td><td>(Dd,</td><td>1H),</td><td> 7,58-7,68</td><td>(m, 2H), 8.56</td><td>(s, 1H)</td>

<td>Examples</td><td>72 and</td><td> 73</td><td></td><td></td><td></td>

5 - {[2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} phthalazin-1 (2H) -one

142

5 - {[2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} phthalazin-1 (2H) -one

Analogously to Example 10, starting from 500 mg of 4- (2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 277 mg of 5-amino-phthalazine-1one, the corresponding imine is prepared. As in Example 2, by reacting 470 mg of imine with 5.4 ml of BBr3 (1 M in dichloromethane) 32 mg of 5 - {[2-hydroxy4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1.2 is obtained. , 3,4-tetrahydronaphthalen-1-yl] amino} -phthalazine-1 (2H) -one as a fraction of 1 and 35 mg of 5 - {[2,5-dihydroxy-4,4-dimethyl-2 (trifluoromethyl) -1,2 , 3,4-tetrahydronaphthalen-1-yl] amino} -phthalazine-1 (2H) -one as fraction 3. δ = 1.32

<td colspan="2">Fraction</td><td>_1:¹</td><td>H-NMR (</td><td> 300</td><td>MHz,</td><td>DMSO</td><td>d6)</td>

<td> 1,50</td><td>(S,</td><td>3H)</td><td> , 1,96</td><td>(D,</td><td>1H),</td><td> 2,23</td><td>(D,</td>

<td> 5,17</td><td>(D,</td><td>1H)</td><td> , 5,93</td><td>(S,</td><td>1H),</td><td> 6,06</td><td>(D,</td>

<td> 7,04</td><td>(D,</td><td>1H)</td><td> , 7,27</td><td>(T,</td><td>1H),</td><td> 7,37</td><td>(D,</td>

<td> 7,62</td><td>(T,</td><td>1H)</td><td> , 8,67</td><td>(S,</td><td>1H),</td><td> 12,39</td><td>(S,</td>

<td colspan="2">Fraction</td><td> 3:</td><td>¹H-NMR</td><td> (300</td><td>MHz,</td><td colspan="2">CD 3 OD),</td>

<td> 1,69</td><td>(S,</td><td>3H)</td><td> , 2,07</td><td>(D,</td><td>1H),</td><td> 2,15</td><td>(D,</td>

<td> 6,72</td><td>(D,</td><td>1H</td><td colspan="3">), 6.81 (d, 1H)</td><td> , 6,</td><td> 96 (</td>

<td>1H),</td><td colspan="2"> 7,57-7,</td><td>70 (m,</td><td>2H);</td><td> 8,57</td><td>(S,</td><td>1H)</td>

s, 3H), s, 3H), d, 1H), d, 1H), s, 3H), s, 1H), 7.24 (dd,

1H), 3.47 1H), 6.78 1H), 7.44 1H) δ = 1.57 1H), 5.24 t, 1H)

Examples 74, 75 and 76

5 - {[2-Hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-metyloftalazyn-1-one

5 - {[2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazin-1-one, diastereomer A.

5 - {[2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazin-1-one, diastereomer B.

Analogous to Example 10, starting from 500 mg of 4- (2-methoxyphenyl} -2-hydroxy-4-methyl-2 (trifluoromethyl} pentanal and 302 mg of 5-amino-2-methylphthalazin-1-one, the corresponding imine is prepared.

143

As in Example 2, by reacting 570 mg of imine with 6.4 ml

BBr3 (1 M in dichloromethane) gives 158 mg of 5 {[2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl} -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazin-1-one as a fraction of 1.66 mg 5 - {[2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine -1-one, diastereomer A as fraction 4 and 77 mg of 5 - {[2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2- methylphthalazine-1-one, diastereomer A as fraction 5.

<td>Fraction 1: ¹H-NMR (</td><td> 300</td><td>MHz, CD3OD), δ =</td><td>1.42 (s,</td><td>3H);</td>

<td>1.58 (s, 3H), 2.08 (</td><td>d</td><td>1H),} 5 2.26 (</td><td>d, 1H),</td><td> 3,47</td>

<td>(s, 3H), 3.n (s, 3H</td><td> ),</td><td>5.33 (s, 1 H), 6.76</td><td>(d, 1H),</td><td> 7,07</td>

<td>(d, 1H), 7.29 (t,</td><td>1H)</td><td>, 7.52 (dd, 1H),</td><td> 7,60-7,71</td><td>(M,</td>

<td>2H), 8.51 (s, 1H)</td><td></td><td></td><td></td><td></td>

<td>Fraction 4: ¹H-NMR (</td><td> 300</td><td>MHz, CD3OD), δ =</td><td>1.42 (s,</td><td>3H);</td>

<td>1.56 (s, 3H), 2.09</td><td>(D,</td><td>1H), 2.27 (d, 1H),</td><td>3.78 (s,</td><td>3H);</td>

<td>5.33 (s, 1H), 6.62 (</td><td>d</td><td>1H), 6.95 (d, 1H),</td><td>7.14 (t,</td><td>1H),</td>

7.56 (dd, 1H), 7.59-7.70 (m, 2H), 8.54 (s, 1H)

<td>Frakc</td><td>I</td><td> 5: ¹H-NMR</td><td>(300 MHz,</td><td>CD 3 OD</td><td>), δ =</td><td> 1,57</td><td>(S,</td><td>3H);</td>

<td> 1,68</td><td>(S,</td><td>3H), 2.07</td><td>(d, 1H),</td><td> 2,14 (</td><td>d, 1H)</td><td> , 3,77</td><td>(S,</td><td>3H);</td>

<td> 5,33</td><td>(S,</td><td>1H), 6.71</td><td>(d, 1H),</td><td> 6,80 (</td><td>d, 1H)</td><td> , 6,96</td><td>(T,</td><td>1H),</td>

<td> 7,22</td><td>(dd</td><td>, 1H), 7.58</td><td>-7.69 (m,</td><td>2H);</td><td> 8,56 (</td><td>s, 1H)</td><td></td><td></td>

Examples 77 and 78 (-) - 5 - {[2-Hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine- 1-one (+} - 5 - {[2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine-1 -he

Separation (+/-) - 5 - {[2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine-1- onu: The enantiomeric mixture is separated by chiral support chromatography (CHIRALPAK AD®,

144

DAICEL) with hexane / ethanol (90: 10, vvv).

You get:

(-) - Enantiomer: MS (EI): M + = 447, [α] D -48.0 ° (c =

0.7, CHCl₃) and (+) - Enantiomer: MS (EI): M + = 447, [a]_D + 45.6 ° (c = 0.8, CHCl3)

Examples 79 and 80 (-) - 5 - {[2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine-1- he, the diastereomer A (+) - 5 - {[2,5-dihydroxy-4,4-dimethyl-2 (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine-1- he. diastereomer A Resolution {+/-) -5 - {[2,5-dihydroxy-4,4-dimethyl-2 {trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine-1 -one, diastereoisomer A:

<td>A mixture of</td><td>enantiomers</td><td>partitioned</td><td>up</td><td>by</td>

<td>chromatography</td><td>on the carrier</td><td colspan="2">chiral (CHIRALPAK</td><td>AD®,</td>

<td>DAICEL company)</td><td>with hexane /</td><td>ethanol (85</td><td> : 15,</td><td>vvv).</td>

<td>You get:</td><td></td><td></td><td></td><td></td>

<td>(-) - enantiomer</td><td>: MS (EI): M +</td><td>= 433, [a] D</td><td> -25,3°</td><td>(c =</td>

<td>1.0, CHCl3) and (</td><td>+) - enantiomer:</td><td>MS (EI): M + =</td><td> 433</td><td></td>

Examples 81 and 82 (-) - 5 - {[2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine-1- he. diastereomer A (+) - 5 - {[2,5-dihydroxy-4,4-dimethyl-2 (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazin-1-one. diastereomer A Resolution {+/-) -5 - {[2,5-dihydroxy-4,4-dimethyl-2 {trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazine-1 -one, diastereomer B: A mixture of enantiomers is separated by chiral support chromatography (CHIRALPAK AD®, Company DAICEL) with hexane / ethanol (90: 10, vvv).

You get:

145 (-) - Enantiomer: MS (EI): M + = 433, [a] D -10.1 ° (c =

0.8, CHCl₃) and (+) -Enantiomer: MS (EI): M + = 433, [a] D + 5.8 ° (c = 0.9, CHCl3)

Example 83 cis-1 - [(2-Methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol (Markus Berger)

5-amino-2-methylquinazoline

12.7 g (62 mmol) 2-methyl-5-nitro-3H-quinazolin-4-one (MT Bogert, V, J. Chambers J. Org Chem. 1905,649-658) and 37.5 g phosphorus pentachloride in 75 ml of phosphoryl chloride is heated under reflux for 20 hours. After cooling it is poured into us. NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried and the solvent removed. 14 g of 4-chloro-2-methyl-5-nitroquinazoline are obtained, of which 4.5 g (20.2 mmol) are dissolved in 225 ml of ethyl acetate and 22.5 ml of triethylamine. 2 g of palladium on carbon are added and the mixture is cooled with ice for 4 hours under hydrogen atmosphere at normal pressure. The solution is removed from the catalyst by means of celite filtration, it is then washed with 200 ml of ethanol and concentrated. Chromatography on silica gel with ethyl acetate-ethanol (0-10%) yields 530 mg of product.

¹H-NMR (300 MHz, CDCl 3); δ = 2.87 (s, 3H), 4.52 (br.,

2H), 6.77 (d, 1H), 7.33 (d, 1H), 7.65 (t, 1H), 9.40 (s, 1H).

(Rac) -1,1,1-trifluoro-4-phenyl-2 - [(E / Z) - (2-metylochinazol-5-yl) iminomethyl} -4-methyl-pentan-2-ol.

To 140 mg (0.54 mmol) 2-hydroxy-4-methyl-4-phenyl-2- (trifluoromethyl) pentanal and 100 mg (0.63 mmol) 5 amino-2-methylquinazoline in 15 ml toluene are added 0.3 ml titanium tetraethylate and the mixture is heated to 100 ° C for 2 hours. After cooling, it is poured onto water

146 and mixed intensively. The suspension is made through celite and is then thoroughly washed with ethyl acetate. The filtrate phases are separated and extracted once more with ethyl acetate. Dry over sodium sulfate and remove the solvent under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 0-60%) gives 123 mg (rac) -1,1,1, -trifluoro-4-phenyl-2 - [(E / Z) - (2-methyl-quinazole -5-yl) iminomethyl] -4-methyl-pentan-2-ol.

cis-1 - [(2-Methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol 82 mg (0.20 mmol) of imine introduced into 7 ml of dichloromethane and cooled to -70 ° C. 0.8 ml (0.8 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane is added dropwise over 10 minutes and stirred for a further 6 hours at 65 ° C. The solution is poured onto a saturated sodium bicarbonate solution and stirred vigorously for 5 minutes. Extract with dichloromethane, wash with saturated sodium chloride solution and dry over sodium sulfate. After concentration and chromatography on silica gel (hexane / ethyl acetate 0-65%), 46 mg of the desired product is obtained.

<td>¹H-NMR</td><td>(300 MHz,</td><td>CDCl3);</td><td>δ =</td><td> 1,</td><td> 46</td><td>(S,</td><td>3H);</td><td> 1,</td><td> 63</td><td>(s, 3H),</td>

<td> 2,19 (</td><td>d, 1H), 2,</td><td>29 (d,</td><td>1H),</td><td> 2,</td><td> 87</td><td>(S,</td><td>3H);</td><td> 5,</td><td> 14</td><td>(d, 1H),</td>

<td> 5,97 (</td><td>d, 1H), 6,</td><td>81 (d,</td><td>1H),</td><td> 7,</td><td> 15</td><td>(T,</td><td>1H),</td><td> 7,</td><td> 36-</td><td>7.43 (m,</td>

<td>2H), 7</td><td>, 42 (d, 1H</td><td> ), 7,75</td><td>(T,</td><td>1H</td><td> ),</td><td> 9,42</td><td>(S,</td><td>1H</td><td> ).</td><td></td>

Example 84 trans-5-Methoxy-1 - [(2-methylquinazolin-5-yl) amino] 4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

The compound is prepared in analogy to Example 83.

<td>¹H-NMR</td><td> (300</td><td>MHz, CDCl3)</td><td>; δ =</td><td> 1,43</td><td>(S,</td><td>3H);</td><td> 1,</td><td> 54</td><td>(S,</td><td>3H);</td>

<td> 2,07 (</td><td>d, 1H</td><td>), 2.18 (d,</td><td>1H),</td><td> 2,84</td><td>(S,</td><td>3H);</td><td> 3,</td><td> 21</td><td>(S,</td><td>3H);</td>

<td> 4,31 (</td><td>d, 1H</td><td>), 5.38 (d,</td><td>1H),</td><td> 6,63</td><td>(D,</td><td>1H),</td><td> 7,</td><td> 05</td><td>(D,</td><td>1H),</td>

147

7.18 (d, 1H), 7.31 (t, 1H), 7.43 (d, 1H), 7.81 (t, 1H),

9.13 (s, 1 H).

Example 85 cis-6-Chloro-5-methoxy-1 - [(2-methylquinazolin-5-yl] amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

The compound is prepared in analogy to Example 83.

¹H-NMR (300 MHz, CDCl 3); δ = 1.58 (s, 3H), 1.74 (s, 3H),

<td> 2,</td><td> 14</td><td>(d, 1H),</td><td> 2,25</td><td>(d, 1H), 2.88</td><td>(s, 3H), 3.97</td><td>(S,</td><td>3H);</td>

<td> 5,</td><td> 05</td><td>(d, 1H),</td><td> 5,92</td><td>(d, 1H), 6.79</td><td>(d, 1H), 7.09</td><td>(D,</td><td>1H),</td>

<td> 7,</td><td> 19</td><td>(d, 1H),</td><td> 7,30</td><td>(d, 1H), 7.75</td><td>(t, 1H), 9.39</td><td>(S,</td><td>1H).</td>

Example 86 cis-6-fluoro-5-methoxy-1 - [(2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalen-2-ol

The compound is prepared in analogy to Example 83.

¹H-NMR (CDCl3); δ = 1.57 (s, 3H), 1.74 (s, 3H), 2.13 (d, 1H), 2.26 (d, 1H), 2.88 (s, 3H), 3.97 (s, 3H), 5.02 (d, 1H), 5.85 (d, 1H), 6.79 (d, 1H), 6.93 (dd, 1H), 7.07 (dd, 1H) , 7.29 (d, 1H), 7.74 (d, 1H), 9.33 (s, 1H).

Example 87 cis-6 - [(2-Methylquinazolin-5-yl) amino] -9,9-dimethyl-7- (trifluoromethyl} -6,7,8,9-tetrahydronaphtho [1,2d] -1,3-dioxol-7 ol

The compound was synthesized as described in Example 83.

<td>¹H-NMR (300 MHz, CDCl3)</td><td>; δ =</td><td> 1,52</td><td>(S,</td><td>3H);</td><td> 1,66</td><td>(S,</td><td>3H);</td>

<td>2.10 (d, 1H), 2.26 (d,</td><td>1H),</td><td> 2,88</td><td>(S,</td><td>3H);</td><td> 5,04</td><td>(D,</td><td>1H),</td>

<td>5.94 {d, 1H}, 5.99 (d,</td><td>2H);</td><td> 6,65</td><td>(D,</td><td>1H),</td><td> 6,80</td><td>(D,</td><td>1H),</td>

6.86 (d, 1H), 7.76 (t, 1H), 9.52 (s, 1H).

Example 88 cis-6-chloro-1 - [(2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol

148

The compound is prepared as described in Example 3 by ether cleavage.

<td>¹H-NMR (</td><td> 300</td><td colspan="2">MHz, CDCl3); δ = 1.54</td><td>(s, 3H),</td><td> 1,68</td><td>(S,</td><td>3H);</td>

<td>2.06 (d</td><td>, 1H)</td><td> , 2,20</td><td>(d, 1H), 5</td><td> 2,81 (</td><td>s, 3H</td><td> ),</td><td> 4,98</td>

<td>(d, 1H)</td><td> , 5,</td><td>81 (d,</td><td>1H), 5.91 (br</td><td>., 1H),</td><td> 6,73 (</td><td>d</td><td>1H),</td>

<td>6.86 (d</td><td>, 1H)</td><td> , 7,08</td><td>(d, 1H), 7.23 (</td><td>d, 1H),</td><td> 9,35 (</td><td>s</td><td>1H).</td>

Example 89 cis-6-fluoro-1 - [(2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol

The compound is prepared as described in Example 3 by ether cleavage.

<td>¹H-NMR (300 MHz,</td><td>CDCl3); δ = 1,</td><td>62 (s,</td><td>3H), 1,</td><td> 77</td><td>(S,</td><td>3H);</td>

<td>2.13 (d, 1H), 2,</td><td>27 (d, 1H) , 2,</td><td>88 (s,</td><td>3H), 5,</td><td> 03</td><td>(D,</td><td>1H),</td>

<td>5.67 (br, 1H),</td><td>5.78 (d, 1H),</td><td> 6,79</td><td>(d, 1H)</td><td>^,</td><td> 6,91</td><td>(D,</td>

<td>2H), 7.29 (d, 1H</td><td>), 7.73 (t, 1H</td><td> ), 9,35</td><td>(s, 1H</td><td> ).</td><td></td><td></td>

Example 90 cis-6 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -9,9-dimethyl-7- (trifluoromethyl) -6,7,8,9-tetrahydronaphtho [1,2-d] - 1,3-dioxo-7-ol

5-amino-7-fluoro-2-methylquinazoline g (70.5 mmol) 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall, I Fagervall, L.-G-Larsson, SB Ross, Eur.J. Med Chem. 34 (1999) 137-151), 9.2 g acetamidine hydrochloride, 13.4 g potassium carbonate and 10.4 g molecular sieve (4A) are mixed together in 70 ml butyronitrile. It is heated for 17 hours to 145 ° C with vigorous stirring and the solvent is removed under reduced pressure. Chromatography of the residue on silica gel with hexane / ethyl acetate (0-70%) gives 4.5 g of 7-fluoro-5-N-pivaloylamino-2-methyquinazoline.

g (3.82 mmol) 7-fluoro-5-N-pivaloylamino-2-methyquinazoline is dissolved in 74 ml of toluene and cooled to -70 ° C. 9.5 ml are added dropwise over 30 min

149 (11.4 mmol) 1.2 M solution of diisobutylaluminum hydride in toluene. The reaction mixture is allowed to warm to -40 ° C and stirred for 4 hours at -40 ° C. Water is added slowly and stirred for 30 minutes at room temperature until a precipitate forms which is removed by filtration through celite. The phases are separated, washed with saturated sodium chloride solution and dried over sodium sulfate. Chromatography on silica gel with hexane-ethyl acetate (0-100%) gives 64 mg of product.

¹H-NMR (300 MHz, CDCl 3); δ = 2.83 (s, 3H), 4.67 (br.,

2H), 6.50 (dd, 1H), 6.93 (dd, 1H), 9.23 (s, 1H).

Up to 60 mg (0.46 mmol) flares 4- (1,3-benzodioxol-4-yl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 32 mg (0.18 mmol) 5-amino-7-fluoro-2-methylquinazoline in 7 ml of toluene, 0.1 ml of titanium tetraethylate are added and the mixture is heated to 100 ° C for 2.5 hours. After cooling, it is poured onto water and then mixed vigorously. The suspension is filtered through celite, which is thoroughly washed with ethyl acetate. The filtrate phases are separated and extracted once more with ethyl acetate. Dried over sodium sulfate and the solvent removed under reduced pressure. The crude 4- (1,3-benzodioxol-4-yl) -1,1,1-trifluoro-2 - [(E / Z) - (7-fluoro-2-methylquinazolin-5-yl) iminomethyl] -4-methyl pentan-2-ol is added to 8 ml of dichloromethane and cooled to -70 ° C. 1.1 ml (1.1 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane are added dropwise over 10 minutes and stirred for an additional hour at -70 ° C. The solution is poured onto a saturated sodium bicarbonate solution and stirred vigorously for 5 minutes. Extract with dichloromethane, wash with saturated sodium chloride solution and dry over sodium sulfate. After concentration and chromatography on silica gel (hexane / ethyl acetate 0 - 75%), 26 mg of the desired product are obtained.¹H-NMR (300 MHz, CDCl 3); δ = 1.53 (s, 3H), 1.66 (s, 3H),

2.12 (d, 1H), 2.27 (d, 1H), 2.84 (s, 3H), 4.94 (d, 1H),

150

5.99 (s, 1H), 6.00 (s, 1H), 6.02 (d, 1H), 6.50 (dd,

1H), 6.68 (d, 1H), 6.83 (d, 1H), 6.89 (dd, 1H), 9.26 (s, 1H).

Example 91 trans-5-Methoxy-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

The compound is prepared in analogy to Example 83.

¹H-NMR (300 MHz, CDCl 3); δ = 1.42 (s, 3H), 1.55 (s, 3H), 2.07 (d, 1H), 2.17 (d, 1H), 2.80 (s, 3H), 3.33 (s, 3H),

4.57 (d, 1H), 5.31 (d, 1H), 6.66 (d, 1H), 6.88 (dd, 1H), 7.00 (dd, 1H), 7.05 (d , 1H), 7.30 (t, 1H), 9.03 (s, 1H).

Example 92 cis-6-Chloro-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalene-2,5-diol

The compound is prepared as described in Example 3 by ether cleavage.

¹H-NMR (300 MHz, CDCl 3); δ = 1.60 (s, 3H), 1.73 (s, 3H),

2.12 (d, 1H), 2.24 8d, 1H), 2.84 (s, 3H), 4.96 (d, 1H),

5.98 (d, 1H), 6.01 (s, 1H), 6.51 (dd, 1H), 6.88 (d,

1H), 6.91 (dd, 1H), 7.17 (d, 1H), 9.23 (s, 1H).

Example 93 cis-6-Fluoro-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalene-2,5-diol

The compound is prepared as described in Example 3 by ether cleavage ¹H-NMR (300 MHz, CD3OD); δ = 1.61 (s, 3H), 1.72 (s, 3H), 2.15 (m, 2H), 2.78 (s, 3H), 5.30 (s, 1H), 6.72 -6.82 (m, 3H), 6.92 (dd, 1H), 9.55 (s, 1H).

Example 94

151 trans-7-Fluoro-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2- ol

<td colspan="2">¹H-NMR (300 MHz, CD3OD); δ = 1.40 (</td><td>s, 3H), 1.53 (</td><td>s</td><td>3H);</td>

<td>2.07 (d, 1H), 2.18</td><td>(d, 1H), 2.81 (</td><td>s, 3H), 3.34 (</td><td>s</td><td>3H);</td>

<td>4.52 (d, 1H), 5.25</td><td>(d, 1H), 6.41</td><td>(dd, 1H), 6,</td><td> 74</td><td>(Dd,</td>

<td>1H), 6.86 (dd, 1H),</td><td>7.01 (dd, 1H),</td><td>9.03 (s, 1H).</td><td></td><td></td>

Example 95 cis-6-Chloro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalene-2,5-diol

5-Amino-8-fluoro-2-methylquinazoline

To a solution of 3.35 g (20.25 mmol) of chloral hydrate and

21.27 g (149.7 mmol) of sodium sulfate in 72 ml of water are added a warm (50 ° C) solution of 2.4 g (18.6 mmol) of 2.5-difluoroaniline in 11 ml of water and 1.6 ml of conc. hydrochloric acid (37%) which was previously stirred at this temperature for 1 h. It is stirred for a further 30 min at room temperature and heated after adding 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml of water for 45 min to 125 ° C and maintains this temperature for 5 min. After cooling and a further hour, the light brown precipitate is filtered off, washed with water and dried. 3.0 g (15.0 mmol) of hydroxylimine are obtained as an intermediate which is dissolved in portions in 15 ml of conc. sulfuric acid at 60 ° C. After complete addition, it is heated for 2 hours to 80 ° C and for 4 hours to 90 ° C. It is allowed to cool and the solution is poured onto 100 g of ice, extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and concentrated. Chromatography on silica gel with hexane-ethyl acetate (0-45%) gives 1.2 g (7.1 mmol) of 4,7-difluoroisatin. 1.8 ml of 30% hydrogen peroxide solution are added dropwise to isatin in 30 ml of 1 molar sodium hydroxide solution. After 2 hours of stirring at room temperature, it is cooled to

152 g

ml chloride

0 ° C, 5 ml of 4 molar hydrochloric acid are added and diluted with 50 ml of water. It is extracted with ethyl acetate, dried over sodium sulfate, concentrated and obtained quantitatively

1.27 g 3,6-difluoroanthranilic acid, which is reacted without further purification.

3,6-difluoroantranilic acid is heated in 8 ml of acetic anhydride for 45 min to 100 ° C. After cooling, the acetic acid formed and excess acetic anhydride are azeotropically removed with toluene under reduced pressure. 40 ml of a 25% ammonia solution are added to the residue under ice-cooling, and stirred for 72 hours. It is diluted with water and acidified with acetic acid. Extract with ethyl acetate, wash the organic phase with water, dry over sodium sulfate and concentrate. The thus obtained 1.03 g (5.25 mmol) of 5.8-difluoro-2-methyl-3H-quinazolin-4-one and phosphorus pentachloride are heated in phosphoryl for 12 h to 125 ° C. After cooling it is poured into us. NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried and the solvent removed. 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline are obtained quantitatively, which is dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine. 600 mg palladium on carbon are added and shaken for 2 h (480 ml of absorbed hydrogen) under hydrogen atmosphere at normal pressure. The solution is removed from the catalyst by filtration through celite, then washed with 100 ml of ethanol and concentrated. Chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%) gives 550 mg of 5,8-difluoro-2-methylquinazoline. To 240 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) 18-crown-6 in 10 890 mg (13.7 mmol) of sodium azide and ml of DMF are added warmed

The solvent is removed and the mixture is removed for 8 h to 125 ° C. under reduced pressure, silica gel chromatography with ethyl acetate gives 52 mg of product.

153 ¹H-NMR (300 MHz, CDCl3) 2H), 6.67 (dd, 1H), 7.38 To 140 mg (0.46 mmol) δ = 2.92 (s, 3H), 4.31 (br. (dd, 1H), 9.37 (s, 1H).

4- (3-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 100 mg (0.56 mmol) 5-amino-8-fluoro-2-methylquinazoline in 14 ml toluene 0.23 ml (1.1 mmol) of titanium tetraethylate h are added to 100 ° C. After vigorously stirring and the mixture is heated for 2 hours, it is poured onto water and washed. The suspension is filtered through celite and then thoroughly washed with ethyl acetate.

The filtrate phases are separated and extracted once more with ethyl acetate. Dried over sodium sulfate and the solvent removed under reduced pressure. The crude 4- (3-chloro-2-methoxyphenyl) 1,1,1-trifluoro-2 - [(E / Z) - (8-fluoro-2-methylquinazolin-5-yl) iminomethyl] -4-methyl-pentane thus obtained -2-ol is added to 23 ml of dichloromethane and cooled to -30 ° C. 7.8 ml (7.8 mmol) of a 1 M solution of boron tribromide in dichloromethane are added dropwise over 10 minutes, allowed to stand for 1 hour at room temperature and stirred for a further 16 hours.

The solution is poured onto a bicarbonate solution for 15 minutes. washed with saturated sodium ice mixture and stirred, extracted and saturated intensively with dichloromethane, sodium chloride solution and dried over sodium sulfate. After concentration and silica gel chromatography (# hexane / ethyl acetate 0-50%), 64 mg of the desired product are obtained.

¹H-NMR (300 MHz, CDCl 3); δ = 1.60 (s, 3H), 1.74 (s, 3H), 2.07 (d, 1H), 2.26 (d, 1H), 2.93 (s, 3H), 4.99 (d, 1H),

5.66 (d, 1H), 5.99 (br., 1H), 6.67 (dd, 1H), 6.91 (d,

1H)

7.16 (d, 1H), 7.49 (dd, 1H), 9.41 (s, 1H)

Example 96 cis-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol

154

<td colspan="2">¹H-NMR (300 MHz, CDCl 3); δ = 1.45 (s,</td><td>3H);</td><td> 1,61</td><td>(s, 3H),</td>

<td> 2,17</td><td>(d, 1H), 2.26 (d, 1H), 2.92 (s,</td><td>3H);</td><td> 5,08</td><td>(d, 1H),</td>

<td> 5,69</td><td>(d, 1H), 6.69 (dd, 1H), 7.16</td><td>(T,</td><td>1H),</td><td>7.35 (m,</td>

<td>2H);</td><td>7.42 (d, 1H), 7.49 (t, 1H), 9.44</td><td>(S,</td><td>1H).</td><td></td>

Example 97 trans-8-fluoro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalene- 2-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.50 (s, 3H), 1.63 (s, 3H),

2.14 (s, 2H), 2.89 (s, 3H), 3.21 (s, 3H), 4.25 (d, 1H),

5.21 (d, 1H), 6.59 (dd, 1H), 6.98 (dd, 1H), 7.04 (dd, 1H), 7.52 (dd, 1H), 9.21 (s , 1H).

Example 98 cis-7-chloro-1 - [(- 8-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.44 (s, 3H), 1.60 (s, 3H),

2.18 (d, 1H), 2.27 (d, 1H), 2.93 (s, 3H), 5.00 (d, 1H),

5.71 (d, 1H), 6.66 (dd, 1H), 7.28 ~ 7.37 (m, 3H), 7.50 (dd, 1H), 9.39 (s, 1H).

Example 99 cis-6-chloro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalene- 2-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.57 (s, 3H), 1.72 (s, 3H),

2.12 (d, 1H), 2.22 (d, 1H), 2.93 (s, 3H), 3.97 (s, 3H),

4.99 (d, 1H), 5.65 (d, 1H), 6.67 (dd, 1H), 7.07 (d, 1H), 7.21 (d, 1H), 7.49 (dd , 1H), 9.39 (s, 1H).

Example 100 cis-6-fluoro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalene- 2-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.56 (s, 3H), 1.71 (s, 3H),

2.11 (d, 1H), 2.22 (d, 1H), 2.93 (s, 3H), 3.97 (s, 3H),

155

4.97 (d, 1H), 5.60 (d, 1H), 6.67 (dd, 1H), 6.93 (dd,

1H), 7.06 (dd, 1H), 7.48 (dd, 1H), 9.37 (s, 1H).

Example 101 cis-6 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -9,9-dimethyl-7- (trifluoromethyl) -6,7,8,9-tetrahydronaphtho [1,2-d] - 1,3-dioxo-7-ol

<td>¹H-NMR (300 MHz, CDCl 3); δ = 1.52 (s,</td><td>3H), 1.67</td><td>(S,</td><td>3H);</td>

<td>2.10 (d, 1H), 2.27 (d, 1H), 2.94 (s,</td><td>3H), 4.96</td><td>(D,</td><td>1H),</td>

<td>5.67 (d, 1H), 5.99 (s, 1H), 6.01 (s,</td><td>1H), 6.67</td><td>(D,</td><td>1H),</td>

<td>6.68 (dd, 1H), 6.86 (d, 1H), 7.49</td><td>(dd, 1H),</td><td> 9,44</td><td>(S,</td>

1H).

Example 102 cis-6-fluoro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalene-2,5-diol ¹H-NMR (300 MHz, CD3OD); δ = 1.60 (s, 3H), 1.72 (s, 3H), 2.09 (d, 1H), 2.17 (d, 1H), 2.86 (s, 3H), 5.23 (s, 1H), 6.80-8.93 (m, 3H), 7.57 (dd, 1H), 9.66 (s, 1H).

Example 103 cis-6 - [(2-Methylquinolin-5-yl) amino] -9,9-dimethyl-7- (trifluoromethyl) -6,7,8,9-tetrahydro-naphtho [1,2-d] -1 , 3-dioxol-7-ol

<td>¹H-NMR (300 MHz, CDCl 3);</td><td>δ =</td><td> 1,50</td><td>(S,</td><td>3H);</td><td> 1,60</td><td>(s, 3H),</td>

<td>2.08 (d, 1H), 2.20 (d,</td><td>1H),</td><td> 2,73</td><td>(S,</td><td>3H);</td><td> 4,85</td><td>(d, 1H),</td>

<td>5.09 (d, 1H), 5.98 (s,</td><td>1H),</td><td> 5,99</td><td>(S,</td><td>1H),</td><td> 6,62</td><td>(d, 1H),</td>

<td>6.81 (m, 2H), 7.22 (d,</td><td>1H),</td><td> 7,50</td><td>(D,</td><td>1H),</td><td> 7,56</td><td>(t, 1H),</td>

8.09 (d, 1H).

Example 104 cis-6 - [(2-methyl-1,7-naphthyridin-5-yl) amino] -9,9-dimethyl-7- (trifluoromethyl) -6,7,8,9-tetrahydronaphtho [1,2-d ] -1,3-dioxo-7-ol ¹H-NMR (300 MHz, CD3OD); δ = 1.48 (s, 3H), 1.57 (s, 3H), 2.02 (d, 1H), 2.17 (d, 1H), 2.76 (s, 3H), 5.06 (s, 1H),

156

5.96 (s, 2H), 6.61 (d, 1H), 6.82 (d, 1H), 7.50 (d, 1H),

7.90 (s, 1H), 8.33 (d, 1H), 8.69 (s, 1H)

Example 105

Rac.-5,8-difluoro-1 - [(1H-indazol-4-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol (diastereomer B) temperature Melting point: 209-211 ° C Example 106

Rac.-5-fluoro-1 - [(2-methylquinazolin-5-yl) amino] -6-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2-diol (diastereomer B ) melting point: 115 ° C

Example 107

Rac.-5-fluoro-1 - [(2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol (diastereomer B) ¹H-NMR (300 MHz, CD3OD); δ = 1.51 (s, 3H), 1.66 (s, 3H), 2.08 (d, J = 14Hz, 1H), 2.18 (d, J = 14Hz, 1H), 2.82 ( s, 3H), 5.21 (s, 1H), 6.71-6.93 (m, 3H), 7.19 (d, J = 8Hz, 1H), 7.77 (dd, J = 9Hz / 8Hz, 1H), 9.57 (s, 1H)

Example 108

Rac.-5-fluoro-1 - [(2-methylquinazolin-5-yl] amino] -6-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2-diol (Al diastereomer MS (ESI): 4590 (M + 1)

Example 109

6-fluoro-1 - {[(2-hydroxymethyl) -quinolin-5-yl) amino] -5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

5- [4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylideneamino] quinoline-2-carboxylic acid methyl ester

157

Stir for two days at room temperature a solution of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoro-methylpentanal (872 mg, 2.84 mmol) and 5-aminoquinoline-2-carboxylic acid methyl ester (570 mg, 2.84 mmol) in 5.0 mL concentrated acetic acid. After repeatedly pairing with

<td colspan="2">toluene residue</td><td>purified</td><td>si</td><td colspan="2">ę na</td><td>gel</td>

<td>silica</td><td>with use</td><td colspan="2">hexane / ethyl</td><td>ethyl</td><td> (0</td><td> -100%</td>

<td>ethyl acetate)</td><td>. receives</td><td>up 820</td><td>mg</td><td> (59%</td><td colspan="2">theor.)</td>

<td>product.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>¹H-NMR (300 MHz</td><td>, CDCl3): δ</td><td>= 1.41 (s,</td><td>3H);</td><td> 1,59</td><td>(S,</td><td>3H);</td>

<td>2.35 (d, 1H),</td><td>3.33 (d, 1H)</td><td>, 4.00 (d,</td><td>3H);</td><td> 4,11</td><td>(S,</td><td>3H);</td>

<td>4.76 (s, 1H),</td><td> 6,32-6,39</td><td>(m, 1H),</td><td> 6,49-</td><td> 6,56 (</td><td>m</td><td>1H),</td>

<td>6.66 (d, 1H),</td><td colspan="2">6.81 (d, 1H), 7.60-7</td><td> ,65 (</td><td>m, 2H</td><td> ),</td><td> 8,14-</td>

8.24 (m, 2H), 8.52 (d, 1H).

5- (6-Fluoro-2-hydroxy-5-methoxy4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino) -quinoline-2-carboxylic acid methyl ester 5- methyl ester [4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylideneamino] quinoline-2-carboxylic acid (120 mg, 0.243 mmol) is dissolved in 2.0 mL of dichloromethane. Titanium tetrachloride (1M solution in dichloromethane, 0.73 mL, 0.73 mmol) is added dropwise over 15 minutes at -30 ° C. The reaction mixture is then stirred at -30 ° C to -15 ° C for 3 hours. The reaction is quenched by the addition of a saturated sodium bicarbonate solution at -30 ° C. Extract with ethyl acetate, wash the combined organic phases with water and saturated sodium chloride solution. After drying over sodium sulfate, removal of the solvent under reduced pressure and purification on silica gel with dichloromethane / methanol (0-3% methanol), 70 mg (58% of theory) of product are obtained.¹H-NMR (300 MHz, CD3OD): δ = 1.56 (s, 3H), 1.68 (s, 3H),

<td> 2,16</td><td>(s, 2H),</td><td> 3,96</td><td>(D,</td><td>3H)</td><td>, 4.08 (s, 3.H),</td><td> 5,28</td><td>(S,</td>

<td>1H),</td><td> 6,91-6,99</td><td>(M,</td><td>2H);</td><td> 7,</td><td>03-7,09 (m, 1H),</td><td> 7,57</td><td>(D,</td>

<td>1H),</td><td>7. ~ 8 (t ,,</td><td>1H),</td><td> 8,12</td><td>(D,</td><td>1H), 8.72 (d, 1H)</td><td>_.</td><td></td>

158

6-fluoro-1 - {[(2-hydroxymethyl) -quinolin-5-yl) amino]} 5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

5- (6-Fluoro-2-hydroxy-5-methoxy4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino) -quinoline-2-carboxylic acid methyl ester (70 mg, 0.14 mmol) is dissolved in 5.0 mL of methanol and mixed with sodium borohydride (22 mg, 0.57 mmol). After one hour and 2 hours, equal amounts of sodium borohydride (Total amounts: 66 mg, 0.171 mmol) are added each time. The reaction is stopped by adding water. It is extracted with ethyl acetate, the combined organic phases are washed with a saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent under reduced pressure, the residue is purified on silica gel with hexane / ethyl acetate (0-100% ethyl acetate). 21 mg (32% of theory) of product are obtained.

¹H-NMR (300 MHz, DMSO-d6): δ = 1.48 (s, 3H), 1.61 (s,

3H), 2.01 (d, 1H), 2.14 (d, 1H), 3.88 (d, 3H), 4.70 (d, 2H), 5.40 (d, 1H), 5, 51 (t, 1H), 6.19 (s, 1H), 6.35 (d, 1H), 6.83 (d, 1H), 6.91-6.96 (m, 1H), 7.04 -7.11 (m, 1H), 7.21 (d, 1H), 7.48 {t, 1H}, 7.58 (d, 1H), 8.64 (d, 1H).

Example 110:

1 - [(5-chloro-1H-indazol-4-yl) amino] -6-fluoro-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

5-chloro-4-nitro-1H-indazole

2.24 g (12 mmol) of 4-chloro-2-methyl-3-nitrophenylamine, prepared according to the literature (Mori et al., Chem. Pharm. Bull, are dissolved in 100 ml of acetic acid).

1986, 34, 4859 and further, as well as Brand and Zoller,

Chem. Ber. 1907, 3324 et seq.). 6.0 ml of a 2 molar aqueous sodium nitrite solution are added dropwise at 10 ° C. Next

159 the suspension is added to boiling acetic acid (150 mL) over 15 minutes and the reaction mixture is left under reflux for 4 hours. After removing the acetic acid under reduced pressure, the residue is taken up in ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent under reduced pressure, the crude product (1.81 g, 76%) is further reacted.

¹H-NMR (300 MHz, DMSO-d6): δ = 7.65 (d, 1H), 7.97 (d, 1H), 8.32 (s, 1H), 13.97 (s, 1H). 5-chloro-1H-indazol-4-ylamine

To a solution of 5-chloro-4-nitro-1H-indazole (872 mg, 4.41 mmol) is added 150 mg of palladium on carbon (10%) and stirred at room temperature under a hydrogen atmosphere. After 45 minutes, the catalyst is suction filtered and washed with methanol. The filtrate is concentrated, the residue is taken up in 200 ml of ethyl acetate and heated. After again suction and concentration of the filtrate, purification is carried out on silica gel with hexane / ethyl acetate (100-33% hexane). 296 mg (40% of theory) of product are obtained.

¹H-NMR (300 MHz, DMSO-d6): δ = 5.97 (s, 2H), 6.66 (d, 1H), 7.05 (d, 1H), 8.19 (s, 1H), 12.83 (s, 1 H).

2 - [(5-chloro-1H-indazol-4-iloimino) methyl] -1,1,1-trifluoro-4- (3-fluoro-2-methoxyphenyl) -4-methyl-pentan-2-ol

To a solution of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoro-methylpentanal (278 mg, 0.9 mmol) and 5-chloro-1H-indazol-4-ylamine (121 mg, 0.72 mmol) in 20 ml of xylene titanium (IV) ethoxide (0.42 ml, 2.0 mmol) is added and refluxed for 10 hours. After cooling to room temperature, the xylene is distilled off and the residue is gel purified

160 silica with hexane / ethyl acetate (30-100% ethyl acetate). 123 mg (37% of theory) of product are obtained.

<td>¹H-NMR (400 MHz, CDCl3): δ =</td><td> 1,43</td><td>(s, 3H), 1.57</td><td>(s, 3H),</td>

<td>2.38 (d, 1H), 3.22 (d, 1H),</td><td> 3,94</td><td>(d, 3H), 4.91</td><td>(s, 1H),</td>

<td>6.41-6.52 (m, 2H), 6.90 (d,</td><td>1H),</td><td>7.28 (d, 1H),</td><td>7.38 (d,</td>

<td>1H), 7.56 (s, 1H), 7.72 (s,</td><td>1H),</td><td>10.26 (br, 1H)</td><td>_.</td>

1- (5-chloro-1H-indazol-4-ylamino) -6-fluoro-5-metoksy4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-2-ol

In analogy to Example 109, the reaction 2 - [(5-chloro-1H-indazol-4-ylimino) methyl) -1,1,1-trifluoro4- (3-fluoro-2-methoxyphenyl) -4-methyl-pentan-2- olu (111 mg, 0.24 mmol) with titanium tetrachloride (0.72 mL of a 1M solution in dichloromethane, 0.72 mmol) in 2.0 mL · dichloromethane after purification by preparative thin layer chromatography gave 27 mg (24% of theory). ) product.

¹H-NMR (400 MHz, CDCl3): δ = 1.56 (s, 3H), 1.65 (s, 3H),

2.09-2.17 (2d, 2H), 3.97 (d, 3H), 5.34-5.36 (m, 2H), 6.87-6.95 (m, 2H), 7, 15 (dd, 1H), 7.32 (d, 1H), 8.05 (s, 1H).

Example 111

1- (5-methyl-1H-indazol-4-ylamino) -6-fluoro-4,4dimetylo-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-2,5-diol

5-methyl-1H-indazol-4-ylamine

To a solution of 2,4-dimethylaniline (12.4 mL, 100 mmol) in 80 mL concentrated sulfuric acid is added at 0 ° C 5.0 mL of fuming nitric acid and stirred at 4 ° C for 20 minutes, followed by stirring for 30 minutes at room temperature. The reaction mixture is poured onto 600 ml of ice water, the pH is adjusted to 10 with 5N sodium hydroxide solution. The precipitate is suction filtered, washed with water and dried. 15.72 g (95% of theory) of 2,4-dimethylnitrophenylamine are obtained as a mixture of regioisomers.

161

Analogously to the preparation of 5-chloro-4-nitro-1Hindazole by the reaction of 2,4-dimethylnitrophenylamine (2.0 g, 12 mmol) with 6.0 ml of a 2 molar aqueous solution of sodium nitrite in acetic acid (250 ml), 1.14 was obtained g (57% of theory) of the product as a mixture of both regioisomers.

MS (ES +, Acetonitrile / Water 1: 1 + 0.01% formic acid): m / z (%) 178 (M + 1, 100).

Analogously to the preparation of 5-chloro-1H-indazol-4-amine, the mixture of regioisomers from the previous reaction (1.0 g, 5.64 mmol) was reacted with 100 mg palladium on carbon in methanol under hydrogen atmosphere for 16 hours at room temperature. Purification on silica gel using hexane / ethyl acetate (33% hexane, then 100% ethyl acetate) gives 53 mg (6% of theory) of 5-methyl-1H-indazol-4-ylamine.¹H-NMR (300 MHz, DMSO-d6): δ = 2.12 (s, 3H), 5.41 (s,

2H), 6.57 (d, 1H), 6.90 (d, 1H), 8.10 (s, 1H), 12.5 (s, 1H).

1- (5-methyl-1H-indazol-4-ylamino) -6-fluoro-4,4dimetylo-2- (trifluoromethyl] -1,2,3,4-tetrahydronaphthalene-2,5-diol

4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentanal (308 mg, 1.0 mmol) and 5-methyl-1H-indazol-4-ylamine (148 mg, 1 , 0 mmol) is placed in 15.0 ml of xylene and titanium (IV) ethoxide (0.42 ml, 2.0 mmol) is added. After 3 hours, the reaction mixture is allowed to cool to room temperature. After addition of ethyl acetate and saturated sodium chloride solution, the mixture is vigorously stirred for 30 minutes at room temperature. The precipitate formed is suction filtered, the aqueous phase is separated off and the organic phase is dried over sodium sulfate. Purification is carried out by silica gel chromatography using hexane / ethyl acetate (30-40% ethyl acetate). 345 mg (79% of theory) are obtained.

1,1,1-trifluoro-4- (3-fluoro-2-methoxyphenyl) -4-metylo162

2 - [(5-methyl-1H-indazole-4-iloimino) methyl] pentan-2-ol.

To 1,1,1-trifluoro-4- (3-fluoro-2-methoxyphenyl) -4-methyl-2 - [(5-methyl-1H-indazol-4-ylimino) methyl] pentan-2-ol (150 mg , 0.34 mmol) boron tribromide (3.40 mL of a 1 M solution in dichloromethane, 3.4 mmol) is added at room temperature. After 4 hours at room temperature, the reaction mixture is left overnight at -30 ° C, then saturated sodium bicarbonate solution and ethyl acetate are added. It is extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent under reduced pressure as well as purification by

<td>prep</td><td colspan="2">thin layer chromatography</td><td>on</td><td>gel</td>

<td>silica</td><td>with use</td><td colspan="2">hexane / ethyl acetate</td><td> (50%</td>

<td>ethyl acetate)</td><td>receives</td><td>56 mg (39%</td><td colspan="2">theor.)</td>

<td>product.</td><td></td><td></td><td></td><td></td>

<td>¹H-NMR (300 MHz</td><td>, CDCl3): δ</td><td>= 1.61 (s, 3H), 1.68</td><td>(S,</td><td>3H);</td>

<td>2.09-2.14 (m,</td><td>4H), 2.24</td><td>(d, 1H), 4.24-4.33</td><td>(Br,</td><td>1H),</td>

<td>5.22-5.23 (m,</td><td>1H), 6.84-</td><td>6.91 (m, 3H), 7.14</td><td>(D,</td><td>1H),</td>

<td>8.04 (s, 1H),</td><td></td><td></td><td></td><td></td>

MS (EI +): m / z (%) = 423 (M +, 45), 147 (100).

Example 112

7-bromo-1 - [(1H-indazol-4-yl) amino] -5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol (SL 4753-4) ¹H-NMR (300 MHz, CD3OD): δ = 1.52 (3H), 1.66 (3H), 2.002.22 (2H), 3.88 (3H), 5.18 (1H), 6.35 (1H), 6.89 (1H), 7.05 (1H), 7.15-7.29 (2H), 8.13 (1H).

Example 113

5 - [(2-hydroxy-4,4-pentamethylene-2- (trifluoromethyl) 1,2,3,4-tetrahydro-1-naphthyl) amino] -2-quinolone

5- [2-hydroxy-4-phenyl-4,4-pentamethylene-2trifluorometylobutylo-1-imino] -2-quinolone

163

Analogously to Example 15, 150 mg of 2-hydroxy-4-phenyl-4,4-pentamethylene-2-trifluoromethylbutyraldehyde is condensed with 88 mg of 5-aminoquinolone in the presence of 0.21 ml of titanium tetraethylate to imine (102 mg)

<td>¹H-NMR</td><td>(300 MHz, CDCl3): δ =</td><td> 1,40</td><td> - 2,05 (</td><td>m, 10H),</td><td> 2,</td><td> 40</td>

<td>(d, 1H</td><td>), 2.65 (d, 1H), 4.80</td><td>(Br.</td><td>S, 1H),</td><td>6.15 (d,</td><td>1H</td><td> ).</td>

<td> 6,80 (</td><td>d, 1H), 6.85 (t, 1H),</td><td> 7,00</td><td>(m, 2H</td><td> ), 7,20 -</td><td> 7,</td><td> 35</td>

<td>(m, 4H</td><td>), 8.20 (d, 1H), 12.00</td><td>(Br.</td><td>5, 1H).</td><td></td><td></td><td></td>

5 - [(2-hydroxy-4,4-pentamethylene-2- (trifluoromethyl) 1,2,3,4-tetrahydro-1-naphthyl) amino] -2-quinolone

Analogously to Example 15, 100 mg of imine is carried out with 4 ml of a 1 M solution of titanium tetrachloride-CH2Cl2 in 59 mg of the product.

<td>¹H</td><td>NMR</td><td> (</td><td>DMSO-d6): δ</td><td> = 1</td><td>, 35-1.80 (m</td><td>, 11H), 2.15</td><td>(M,</td><td>1H),</td>

<td> 5,</td><td> 35 (</td><td>d</td><td>1H), 5.95</td><td>(S,</td><td>1H), 6.25 (</td><td>d, 1H), 6.40</td><td>(D,</td><td>1H),</td>

<td> 6,</td><td> 55 (</td><td>t</td><td>2H), 7.15</td><td>(M,</td><td>2H), 7.25 (</td><td>t, 1H), 7.30</td><td>(M,</td><td>1H),</td>

<td> 7,</td><td> 55 (</td><td>d</td><td>1H), 8.20</td><td>(D,</td><td>1H), 11.55</td><td>(br.s, 1H).</td><td></td><td></td>

Example 114 cis-1 - [(8-Fluoro-2-methylquinazolin-5-yl) amino] -2 (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2-diol

To 0.55 g (2.7 mmol) 1,1,1-trifluoro-4-phenyl-butan-2one (D. Yang; MK. Wong; Z. Yan J. Org. Chem. (2000); 65; 4179-4184) in 4 ml THF and 2 ml water, 200 mg (3.1 mmol) potassium cyanide in 2 ml water are added. It is cooled to 0 ° C and 1 ml of 25% sulfuric acid added, allowed to warm to room temperature and stirred for 16 hours.

Saturated sodium bicarbonate solution is added and extracted with ethyl acetate. After washing with saturated sodium chloride solution and drying over sodium sulfate, a quantitative crude cyanide is obtained, which is dissolved in 15 ml of diethyl ether and cooled to -70 ° C. 4.6 ml (5.5 mmol) are added dropwise over 10 minutes.

1.2 M solution of DIBAL in toluene. It is allowed to warm to room temperature for 2 hours, quenched with 10% tartaric acid solution and then intensively

164 mixed up. After extraction with ethyl acetate, 5 g silica gel and 10 ml 1 M sulfuric acid are added.

Mixes celite.

acetate.

silica

300 mg is intensively held for 12 hours and filtered through the phases, separated and then extracted with acetate. After gel chromatography (hexane / ethyl acetate 30%), impure 2-hydroxy-4-phenyl-2 (trifluoromethyl) -butanal is obtained. To the aldehyde thus obtained and 200 mg (1.13 mmol) of 5-amino-8-fluoro-2-methylquinazoline in 15 ml of toluene, 0.5 ml (2.4 mmol) of titanium tetraethylate are added and the mixture is heated for 2 to 100 ° C . After cooling, it is poured on and intensively mixed. The suspension is filtered for one hour and the water is extracted once more with sodium sulfate and under reduced pressure. After silica gel (celite being thoroughly washed with ethyl acetate. The filtrate phases are separated with ### ethyl acetate. The dried solvent is removed by hexane / ethyl acetate chromatography 30%), 100 mg of 1- (8-fluoro-2-methylquinazolin-5) is obtained. -yloimino) -4-phenyl-2- (trifluoromethyl) butan-2-ol. Imine is introduced into 5 ml of dichloromethane and cooled to -70 ° C. 1 ml (1 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane are added dropwise over 10 minutes and stirred for one hour. The solution is poured onto a saturated sodium bicarbonate solution and stirred vigorously for 15 minutes. Extract with ethyl acetate, wash with saturated sodium chloride solution and dry over sodium sulfate. After concentration and chromatography on silica gel (hexane / ethyl acetate 50%), 44 mg of the desired product are obtained.

δ = 2.25-2.32 ¹H-NMR (300 MHz, CDCl3) (ddd, 1H), 2.92 (s, 3H), 3.19 5.26 (d, 1H), 6.78 (dd, 1H), (dd, 1H) , 9.34 (s, 1H).

m

2H)

2.91 ddd, 1H), 5.09 (d, 1H)

7.15-7.29 m,

4H)

7,49

Example 115

165 cis-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftaleno-2,5-diol

<td>¹H-NMR (300 MHz, CDCl3)</td><td>; δ</td><td>= 1.59 (s, 3H), 1.72 (</td><td>s</td><td>3H);</td>

<td>2.11 (d, 1H), 2.21 (d,</td><td>1H)</td><td>, 2.93 (s, 3H), 5.05 (</td><td>d</td><td>1H),</td>

<td>5.28 (br, 1H), 5.40 (</td><td>d</td><td>1H), 6.66 (d, 1H), 6,</td><td> 71</td><td>(Dd,</td>

<td>1H), 6.94 (d, 1H), 7,</td><td> 03</td><td>(t, 1H), 7.47 (dd, 1H</td><td> ),</td><td> 9,37</td>

(s, 1H).

Example 116 cis-1 - [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] 4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalen-2-ol

5-Amino-7,8-difluoro-2-methylquinazoline

To 41.7 g (180 mmol) 2,2-dimethyl-N- (3,4,5-trifluorophenyl) -propionamide in 385 ml THF are added dropwise at -70 ° C to 156 ml (391 mmol) 2.5 M butyllithium solution in hexane. It is stirred for one hour and then 38.6 ml DMF in 90 ml THF are added dropwise, the solution being able to warm to -60 ° C. Stir for an additional hour at 70 ° C and then pour the cold reaction solution onto a mixture of 2 kg of ice and 400 ml of concentrated hydrochloric acid. Stir intensively and after one hour extract repeatedly with diethyl ether. The organic phase is washed with inert water and dried over sodium sulfate. After concentration, 49.3 g (188 mmol) of crude 4,5,6-trifluoro-2-N-pivaloylaminobenzaldehyde are obtained, which together with 26 g (275 mmol) of acetamidine hydrochloride, 38.3 g (277 mmol) of potassium carbonate and 30 g molecular sieve (4A) is added to 206 ml butyronitrile. Heated to 18O &amp; lt; 0 &amp; gt; C for 18 hours with vigorous stirring and the solvent removed under reduced pressure. Chromatography of the residue on silica gel using hexane / ethyl acetate (0-100%) gives 9.1 g of 7,8-difluoro-5-N-pivaloylamino-2-methylquinazoline.

166

2.0 g (7.2 mmol) 7,8-difluoro-5-N-pivaloylamino-2-methoxyquinazoline is dissolved in 140 ml of toluene and cooled to -70 ° C. 24 ml (28.8 mmol) of a 1.2 M solution of diisobutylaluminum hydride in toluene are added dropwise over 30 min. The reaction mixture is allowed to warm to -25 ° C for 2 hours and stirred at -25 ° C for 2 hours. Isopropanol is added slowly followed by water and stirred for 12 hours at room temperature until a precipitate forms which is removed by filtration through celite. Then it is well washed with methylene chloride-methanol and concentrated. The residue is vigorously mixed in 200 ml ethyl acetate and 50 ml methanol with 100 g silica gel and 20 g manganese dioxide. It is filtered through celite, then washed well with a methylene chloride-methanol mixture and concentrated. Chromatography on silica gel with hexane-ethyl acetate (0-100%) gives 370 mg of product.

¹H-NMR (300 MHz, CD3OD; δ = 2.81 (s, 3H), 6.64 (dd, 1H), 9.52 (s, 1H).

cis-1 - [(7,8-difluoro-2-methylquinazolin-5-yl) amino] 4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

<td>¹H-NMR</td><td colspan="2">(300 MHz, CDCl3); δ =</td><td> 1,46</td><td>(S,</td><td>3H)</td><td> , 1,</td><td> 61</td><td colspan="2">(s, 3H),</td>

<td> 2,20 (</td><td>d, 1H), 2.24 (d, 1H</td><td> ),</td><td> 2,91</td><td>(S,</td><td>3H)</td><td> , 5,</td><td> 00</td><td>(D,</td><td>1H),</td>

<td> 5,86 (</td><td>d, 1H), 6.56 (dd,</td><td>1H</td><td> ), 6,</td><td> 71</td><td>(Dd,</td><td>1H)</td><td>^,</td><td> 7,18</td><td>(T,</td>

<td>1H), 7</td><td>, 29 (d, 1H), 7.32 (</td><td> 1,</td><td>1H),</td><td> 7,</td><td> 43 (</td><td>d, 1H</td><td> ),</td><td> 9,28</td><td>(S,</td>

1H).

Example 117 cis-1 - [(7,8-difluoro-2-methylquinazolin-5-yl) amino] 4.4-dimethyl-6-fluoro-5-methoxy-2- (trifluoromethyl) 1.2.3.4-tetrahydronaphthalen-2-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.59 (s, 3H), 1.70 (s, 3H),

2.12 (d, 1H), 2.22 (d, 1H), 2.91 (s, 3H), 3.98 (s, 3H),

4.90 (d, 1H), 5.80 (d, 1H), 6.56 (dd, 1H), 6.94 (dd,

1H), 7.00 (dd, 1H), 9.24 (s, 1H).

167

Example 118

5 - {[2-hydroxy-4,4-dimethyl-2,5-bis (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

Production is carried out as described in Example 15 (13). However, cyclization of the imine to the product occurs in trifluoroacetic acid under reflux instead of TiCl4 in toluene.

<td>¹H-NMR (300 MHz, CDCl3)</td><td>: δ =</td><td> 1,55</td><td>(S,</td><td>3H);</td><td> 1,65</td><td>(s, 3H),</td>

<td>2.05 (d, 1H), 2.30 (d,</td><td>1H),</td><td> 5,10</td><td>(D,</td><td>1H),</td><td> 5,30</td><td>(d, 1H),</td>

<td>6.35 (d, 1H), 6.60 (d,</td><td>1H),</td><td> 6,70</td><td>(D,</td><td>1H),</td><td> 7,25</td><td>(m, 1H),</td>

<td>7.30 (t, 1H), 7.55 (d,</td><td>1H),</td><td> 7,75</td><td>(D,</td><td>1H),</td><td> 7,95</td><td>(d, 1H),</td>

<td>10.85 (br. S, 1H). MS</td><td>(ES):</td><td colspan="2">MW: 471.</td><td></td><td></td><td></td>

Example 119

5 - {[6-chloro-2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

The synthesis proceeds as described in Example 15.

¹H-NMR (300 MHz, CDCl3): δ = 1.40 (s, 3H), 1.60 (s, 3H),

<td>2.10 (d,</td><td>1H),</td><td>2.20 (d,</td><td>1H),</td><td>5.05 (br., 1H), 5.70 (br.,</td>

<td>1H), 6.5</td><td>0 (d,</td><td>1H), 6,</td><td>60 (m</td><td>, 2H), 7.05 (dd, 1H), 7.20</td>

<td>(d, 1H),</td><td> 7,35</td><td>(m, 2H),</td><td> 8,30</td><td>(d, 1H), 10.40 (br., 1H),</td>

<td>MS (ES):</td><td>MH:</td><td> 437/439</td><td> (3:1).</td><td></td>

<td>Example</td><td> 120</td><td></td><td></td><td></td>

5 - {[2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-yl] amino} -1metylochinolin-2 (1H) -one

<td colspan="2">¹H-NMR (300 MHz, CDCl3):</td><td>δ =</td><td> 1,40</td><td colspan="2">(s, 3H), 1.60</td><td colspan="2">(s, 3H),</td>

<td> 2,10</td><td>(d, 1H), 2.20 (d,</td><td>1H),</td><td> 35</td><td> 3,60</td><td>(s, 3H),</td><td> 5,15</td><td>(D,</td>

<td>1H),</td><td>5.45 (d, 1H), 6.60</td><td>(D,</td><td>1H),</td><td> 6,65</td><td>(d, 1H),</td><td> 6,75</td><td>(D,</td>

<td>1H),</td><td>7.10 (t, 1H), 7.30</td><td>(M,</td><td>1H),</td><td> 7,40</td><td>(m, 2H),</td><td> 8,00</td><td>(D,</td>

1H).

MS (ES): MH +: 417.

Example 121

168

5 - {[2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -5,6trimetyleno-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

<td>¹H-NMR</td><td>(300 MHz, CDCl3):</td><td>δ = 1.45 (s, 3H),</td><td> 1,65</td><td>(S,</td><td>3H</td><td> ),</td>

<td> 1,95 -</td><td>2.15 (m, 3H), 2</td><td>, 20 (d, 1H), 2.80</td><td>(M,</td><td>2H);</td><td> 3,</td><td> 15</td>

<td>(m, 2H)</td><td>, 5.10 (d, 1H),</td><td>5.25 (d, 1H), 6.55</td><td>(to me</td><td>3H);</td><td> 7,</td><td> 00</td>

<td>(d, 1H)</td><td>, 7.10 (d, 1H)</td><td>, 7.30 (1, 1H), 8</td><td> ,00</td><td>(D,</td><td>1H</td><td> ),</td>

10.10 (br., 1H).

MS (ES): MH +: 443.

Separation of enantiomers is by chiral HPLC (Chiralpak AD. 20 μ column with hexane-ethanol 95: 5 as eluent); (-) - Enantiomer elutes at 11.4 min, (+) - enantiomer - at 14.1 min.

Example 122

5 - {[6-chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

<td>¹H-NMR (300 MHz, CDCl3)</td><td>: δ = 1.55 (s,</td><td>3H);</td><td> 1,70</td><td>(S,</td><td>3H);</td>

<td>2.10 (d, 1H), 2.20 (d,</td><td>1H), 3.95 (s,</td><td>3H);</td><td> 5,05</td><td>(D,</td><td>1H),</td>

<td>5.35 (d, 1H), 6.55 (m,</td><td>3H), 7.00 (d,</td><td>1H),</td><td> 7,15</td><td>(D,</td><td>1H),</td>

<td>7.35 (t, 1H), 8.05 (d,</td><td>1H), 9.95 (br.</td><td>, 1H)</td><td>^.</td><td></td><td></td>

<td>MS (ES): MH +: 467/469</td><td> (3/1).</td><td></td><td></td><td></td><td></td>

<td>Example 123</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="3">5 - {[6-chloro-2,5-dihydroxy-4,4-dimethyl-2</td><td> -</td><td></td><td></td>

<td>(Trifluoromethyl) -1,2,</td><td colspan="3">3,4-tetrahydro-1</td><td></td><td></td>

<td>yl] amino} quinolin-2 (</td><td>1H) -one</td><td></td><td></td><td></td><td></td>

<td>¹H-NMR (300 MHz, CDCl3)</td><td>: δ = 1.60 (s,</td><td>3H);</td><td> 1,70</td><td>(S,</td><td>3H);</td>

<td colspan="3">2.05 (d, 1H), 2.20 (d, 1H), 4.20 (br.,</td><td>1H),</td><td> 5,05</td><td>(D,</td>

<td>1H), 5.40 (d, 1H), 5,</td><td>95 (br.s, 1H),</td><td> 6,55</td><td>(M,</td><td>3H);</td><td> 6,85</td>

<td>(d, 1H), 7.10 (d, 1H),</td><td>7.35 (t, 1H),</td><td> 8,10</td><td>(D,</td><td>1H),</td><td> 9,75</td>

(br., 1H).

MS (ES): MH +: 453/455 (3/1).

Separation of enantiomers occurs by chiral HPLC (Chiracel, OD 20 μ column with 85:15 hexane-ethanol as the eluent); (+) - enantiomer elutes at 10.4 min, (-) - enantiomer - at 14.8 min.

169 (+) - enantiomer:

<td>¹H-NMR</td><td>([D] 6-DMSO)</td><td>: δ = 1.50</td><td>(S,</td><td>3H), 1.65</td><td>(S,</td><td>3H);</td><td> 1,95</td>

<td>(d, 1H)</td><td>, 2.10 (d,</td><td>1H), 5.30</td><td>(D,</td><td>1H), 6.05</td><td>(S,</td><td>1H),</td><td> 6,20</td>

<td>(d, 1H)</td><td>, 6.40 (d,</td><td>1H), 6.55</td><td>(M,</td><td>2H), 6.70</td><td>(D,</td><td>1H),</td><td> 7,20</td>

<td>(m, 2H)</td><td>, 8.20 (d,</td><td>1H), 9.05</td><td>(S,</td><td>1H), 11.55</td><td>(S,</td><td>1H).</td><td></td>

(-) - enantiomer:

<td>¹H-NMR</td><td>([D] 6-DMSO)</td><td>: δ = 1.50</td><td>(s, 3H), 1.65</td><td>(S,</td><td>3H);</td><td> 1,95</td>

<td>(d, 1H)</td><td>, 2.10 (d,</td><td>1H), 5.30</td><td>(d, 1H), 6.05</td><td>(S,</td><td>1H),</td><td> 6,20</td>

<td>(d, 1H)</td><td>, 6.40 (d,</td><td>1H), 6.55</td><td>(m. 2H), 6.70</td><td>(D,</td><td>1H),</td><td> 7,20</td>

<td>(m, 2H)</td><td>, 8.20 (d,</td><td>1H), 9.05</td><td>(s, 1H), 11.55</td><td>(S,</td><td>1H).</td><td></td>

Example 124

5 - {[5-bromo-2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

The cyclization of the imine precursor to the product occurs in trifluoroacetic acid under reflux instead of TiCl4 in toluene.

<td>¹H-NMR (300 MHz, CDCl3)</td><td>: δ =</td><td> 1,70</td><td>(S,</td><td>3H);</td><td> 1,85</td><td>(S,</td><td>3H);</td>

<td>2.10 (d, 1H), 2.25 (d,</td><td>1H),</td><td> 5,10</td><td>(D,</td><td>1H),</td><td> 5,40</td><td>(D,</td><td>1H),</td>

<td>6.50 (d, 1H), 6.55 (d,</td><td>1H),</td><td> 6,60</td><td>(D,</td><td>1H),</td><td> 6,90</td><td>(T,</td><td>1H),</td>

<td>7.30 (d, 1H), 7.35 (t,</td><td>1H),</td><td> 7,55</td><td>(D,</td><td>1H),</td><td> 8,05</td><td>(D,</td><td>1H),</td>

10.40 (br. S, 1H).

MS (ES): MH +: 481/483 (1/1).

Example 125

5 - {[6-chloro-2-hydroxy-5-methoxy-2- (trifluoromethyl) 4,4-trimethylene-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

<td>¹H</td><td>NMR (300</td><td>MH</td><td>z, CDCl3)</td><td>: δ =</td><td> 2,</td><td> 05 - 2,40</td><td>(M,</td><td>5H),</td><td> 2,60</td>

<td>(D,</td><td>1H), 2,</td><td> 85</td><td>(m, 2H),</td><td> 4,10</td><td>(S,</td><td>3H), 4.95</td><td>(D,</td><td>1H),</td><td> 5,05</td>

<td>(D,</td><td>1H), 6,</td><td> 55</td><td>(m, 2H),</td><td> 6,65</td><td>(D,</td><td>1H), 6.70</td><td>(D,</td><td>1H),</td><td> 6,95</td>

<td>(D,</td><td>1H), 7</td><td> ,15</td><td>(d, 1H)</td><td> , 7,</td><td> 35</td><td>(t, 1H), 7</td><td> ,90</td><td>(D,</td><td>1H),</td>

10.50 (br., 1H).

MS (ES): MH +: 478/480 (3/1).

Example 126

170

5 - {[6-chloro-2,5-dihydroxy-2- (trifluoromethyl) -4,4trimetyleno-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

<td>¹H</td><td>NMR</td><td colspan="2">([D] 6-DMSO)</td><td>: δ =</td><td> 1,80</td><td>(M,</td><td>1H), 2.05</td><td>(m</td><td>2H)</td><td> , 2,20</td>

<td>(D,</td><td>1H)</td><td> , 2,30</td><td>(M,</td><td>1H),</td><td> 2,60</td><td>(D,</td><td>1H), 2.90</td><td>(Q,</td><td>1H)</td><td> , 3,25</td>

<td>(Q,</td><td>1H)</td><td> , 5,30</td><td>(D,</td><td>1H),</td><td> 5,90</td><td>(S,</td><td>1H), 6.10</td><td>(D,</td><td>1H)</td><td> , 6,35</td>

<td>(D,</td><td>1H)</td><td> , 6,55</td><td>(D,</td><td>2H);</td><td> 6,70</td><td>(D,</td><td>1H), 7.20</td><td>(D,</td><td>1H)</td><td> , 7,25</td>

<td>(T,</td><td>1H)</td><td> , 8,15</td><td>(D,</td><td>1H),</td><td> 9,30</td><td>(S,</td><td>1H), 11.55</td><td>(br</td><td>.s,</td><td>1H).</td>

MS (ES): MH +: 465/467 (3/1).

Separation of enantiomers is by chiral HPLC (Chiralpak AD, 20 μ column with hexane-ethanol as eluent); (-) - The enantiomer is eluted first.

<td>¹H-NMR ([D] 6-DMSO)</td><td>: δ =</td><td> 1,80</td><td>(M,</td><td>1H), 2.05</td><td>(m 2H), 2.20</td>

<td>(d, 1H), 2.30 (m,</td><td>1H),</td><td> 2,60</td><td>(D,</td><td>1H), 2.90</td><td>(q, 1H), 3.25</td>

<td>(q, 1H), 5.30 (d,</td><td>1H),</td><td> 5,90</td><td>(S,</td><td>1H), 6.10</td><td>(d, 1H), 6.35</td>

<td>(d, 1H), 6.55 (d,</td><td>2H);</td><td> 6,70</td><td>(D,</td><td>1H), 7.20</td><td>(d, 1H), 7.25</td>

<td>(t, 1H), 8.15 (d,</td><td>1H),</td><td> 9,30</td><td>(S,</td><td>1H), 11.55</td><td>(br. S, 1H).</td>

<td>(+) - enantiomer:</td><td></td><td></td><td></td><td></td><td></td>

<td>¹H-NMR ([D] 6-DMSO)</td><td>: δ =</td><td> 1,80</td><td>(M,</td><td>1H), 2.05</td><td>(m 2H), 2.20</td>

<td>(d, 1H), 2.30 (m,</td><td>1H),</td><td> 2,60</td><td>(D,</td><td>1H), 2.90</td><td>(q, 1H), 3.25</td>

<td>(q, 1H), 5.30 (d,</td><td>1H),</td><td> 5,90</td><td>(S,</td><td>1H), 6.10</td><td>(d, 1H), 6.35</td>

<td>(d, 1H), 6.55 (d,</td><td>2H);</td><td> 6,70</td><td>(D,</td><td>1H), 7.20</td><td>(d, 1H), 7.25</td>

<td>(t, 1H), 8.15 (d,</td><td>1H),</td><td> 9,30</td><td>(S,</td><td>1H), 11.55</td><td>(br.s, 1H).</td>

<td>Example 127</td><td></td><td></td><td></td><td></td><td></td>

5 - {[5-difluoromethoxy-2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

Cyclization of the imine to the product occurs in trifluoroacetic acid under reflux instead of TiCl4 in toluene.

<td>¹H</td><td>NMR</td><td colspan="2">([D] 6-DMSO):</td><td>δ = 1.45 (</td><td>s</td><td>1H),</td><td> 1,60 (</td><td>s</td><td>1H),</td><td> 2,</td><td> 00</td>

<td>(D,</td><td>1H)</td><td> , 2,15</td><td>(D,</td><td>1H), 5.40</td><td>(D,</td><td>1H),</td><td> 6,15</td><td>(S,</td><td>1H),</td><td> 6,</td><td> 20</td>

<td>(D,</td><td>1H)</td><td> , 6,40</td><td>(D,</td><td>1H), 6.55</td><td>(d</td><td>, 1H)</td><td> ,6,60</td><td>(D,</td><td>1H),</td><td> 7,</td><td> 05</td>

<td>(M,</td><td>2H)</td><td> , 7,20</td><td>(T,</td><td>1H), 7.30</td><td>(T,</td><td>CHF2</td><td>, JHF =</td><td> 75</td><td>Hz),</td><td> 8,</td><td> 20</td>

<td>(D,</td><td>1H)</td><td> , 11,55</td><td>(S,</td><td>1H).</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>MS</td><td>(ES)</td><td>: MH +:</td><td> 469.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

171

Example 128

4 - {[6-chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -indazol ¹H-NMR (300 MHz, CDCl3): δ = 1.40 (s, 3H), 1.55 (s, 3H),

<td>2.05 (d,</td><td>1H),</td><td>2.20 (d, 1H),</td><td> 5,15</td><td>(br., 2H), 6.40 (d,</td>

<td colspan="2">1H), 6.90 (d,</td><td>1H), 7.05 (dd,</td><td>1H),</td><td>7.25-7.35 (m, 4H),</td>

<td>8.55 (br.</td><td>, 1H):</td><td></td><td></td><td></td>

<td>MS (ES):</td><td>MH + =</td><td> 410/412 (3:1).</td><td></td><td></td>

<td>Example</td><td> 129</td><td></td><td></td><td></td>

5- (6-chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1H-quinolin-2-one

4- (3-chloro-4-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal ml methylmagnesium chloride (22% in THF) is placed in 200 ml THF and dropwise added at 0 ° C over 1 h a solution of 9.17 g (45.7 mmol) of methyl 3-chloro-4-methoxybenzoate in 200 ml of THF. After complete conversion, the reaction is terminated by the addition of 30 ml sat. ammonium chloride solution and the mixture is partitioned between acetic acid ethyl ester and water. The aqueous phase is extracted with acetic acid ethyl ester, the combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. 4.5 g (22.4 mmol) of the crude product (98% yield) are placed in 100 ml of dichloromethane and at -70 ° C 6.0 g (42.7 mmol) of 2-trimethylsilanyloxy acrylic acid ethyl ester are first added dropwise, and then

1.85 ml tin tetrachloride. After 10 min, the reaction mixture is fed over us. potassium carbonate solution. The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with 1 m hydrochloric acid solution, water and sat. sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. After column chromatography (silica gel,

172 2.0 g are obtained

29% hexane / ethyl acetate 9: 1 of the desired intermediate.

To 1.5 g (5.0 mmol) of this ketoester in THF, 2.1 ml of trimethyl trifluoromethylsilane and 620 μΐ tetrabutylammonium fluoride (1 m solution in THF) are added at -70 ° C. It is allowed to thaw to room temperature and stirred for 18 h, then 6 ml tetrabutylammonium fluoride (1 m solution in THF) is added to the mixture at 0 ° C. After a further 10 min, the mixture is partitioned between ethyl acetate and 1 m hydrochloric acid solution. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with 1m hydrochloric acid solution, water and sat. sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. 1.81 g of the desired intermediate are obtained, which, dissolved in 15 ml of diethyl ether, are added dropwise to the suspension with diethyl ether at 0 ° C.

After silica, 1.04 g (65%)

0.40 g lithium aluminum hydride at 1 h at 0 ° C and 18 h at room temperature the reaction is terminated by adding 25 ml sat. sodium bicarbonate solution. The precipitate formed is filtered off, washed with ethyl acetate and the filtrate is washed with sat. sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator.

column chromatography (8: 2 hexane / ethyl acetate gel) gives the desired diol intermediate.

109 μl (1.12 mmol) of oxalyl chloride are placed in dichloromethane and 190 μl (2.68 mmol) of DMSO are added dropwise at -75 ° C and after stirring for 15 min a solution of 366 mg (1.12 mmol) from the intermediate diol stage dichloromethane. After a further 15 min, 830 μl (5.62 mmol) of triethylamine (-50 °) are added dropwise. It is allowed to thaw slowly and is stirred for a further 18 h. The reaction is terminated by adding us. ammonium chloride solution, the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with 1 m hydrochloric acid solution, water and sat. NaCl solution and dried over NaSO4. It is concentrated and chromatographed

173 on silica gel using hexane / ethyl acetate (4: 1). 302 mg (84%) of the desired 4- (3-chloro-4-methoxy-phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is obtained.

<td>¹H</td><td>NMR (CDCl3):</td><td>δ =</td><td> 1,34</td><td>(S,</td><td>3H);</td><td> 1,40</td><td>(s, 3H),</td><td> 2,30</td><td>(D,</td>

<td>1H)</td><td>, 2.62 (d,</td><td>1H),</td><td> 3,66</td><td>(S,</td><td>1H),</td><td> 3,90</td><td>(s, 3H)</td><td> 6,84</td><td>(D,</td>

<td>1H)</td><td>, 7.13 (dd,</td><td>1H),</td><td> 7,31</td><td>(D,</td><td>1H),</td><td> 8,90</td><td>(s, 1H).</td><td></td><td></td>

5- (6-chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1H-quinolin-2-one

100 mg (0.31 mmol) 4- (3-chloro-4-methoxy-phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 50 mg (0.31 mmol) 5-amino-1H-quinolin-2 -one is placed in 30 ml toluene and 0.16 ml titanium tetraethylate is added dropwise. The mixture is stirred for 1 h at a bath temperature of 100 ° C. After cooling, the solution is poured onto ice, a few ml of sat. Are added. sodium bicarbonate solution, filtered through diatomaceous earth and washed with ethyl acetate and water. The phases are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The imine obtained (30%) after chromatographic purification (silica gel, hexane / ethyl acetate 95: 5 to 25:75) is again added to dichloromethane and 3.6 ml of titanium tetrachloride (1 m in toluene) are added at -50 ° C. It is allowed to thaw and the mixture is poured onto ice after 18 h stirring, the phases are separated, extracted with dichloromethane, washed with sat. sodium chloride solution and dried over sodium sulfate. After concentration on a rotary evaporator, the crude product is chromatographed on silica gel (eluent: 2% methanol in dichloromethane). The product obtained is recrystallized from hexane / diethyl ether (yield: 28%).

melting point: 182 ° C;

¹H-NMR (CD3OD): δ = 1.28 (s, 3H), 1.42 (s, 3H), 1.95 (d, 1H), 2.07 (d, 1H), 3.54 es, 3H), 4.88 (s, 1H), 6.42174

6.48 (m, 2H), 6.58 (d, 1H), 6.82 (s, 1H), 7.25-7.30 (m,

2H), 7.97 (d, 1H).

Example 130

5- (6-chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -2H-isoquinolin-1-one

This compound is prepared using the aldehyde described in the previous Example 129 and the corresponding amine.

melting point: 85 ° C, MS (ESI): 467 (M + 1).

Example 131

5- (6-chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino} -2H-phthalazin-1-one

Example 131 compound is prepared as described in Example 129 using appropriate starting materials.

<td>¹H-NMR (CD3OD):</td><td>δ =</td><td> 1,39</td><td>(S,</td><td>3H);</td><td> 1,53</td><td>(S,</td><td>3H);</td><td> 2,16</td>

<td>(dd, 2H), 3.12</td><td>(S,</td><td>3H);</td><td> 5,30</td><td>(S,</td><td>1H),</td><td> 6,94</td><td>(S,</td><td>1H),</td>

<td>7.31 (dd, 1H),</td><td> 7,42</td><td>(S,</td><td>1H),</td><td colspan="2"> 7,64-7,71</td><td>(M,</td><td>2H);</td><td> 8,59</td>

(s, 1H).

Example 132

6-chloro-7-methoxy-4,4-dimethyl-1- (2-methylquinolin-5yloamino) -2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

Example 132 was synthesized using the appropriate starting materials as described in Example 129.

¹H-NMR (CDCl3): δ = 1.39 (s, 3H), 1.52 (s, 3H), 2.15 (dd, 2H), 2.73 (s, 3H), 3.49 (s , 3H), 4.97 (d, 1H),

5.10 (d, 1H), 6.80-6.84 (m, 2H), 7.24 (d, 1H), 7.36 (s,

1H), 7.49 (d, 1H), 7.55 (dd, 1H), 8.08 (d, 1H).

Example 133

175

6-chloro-1- (8-fluoro-2-methylquinazolin-5-ylamino) -7-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

The compound is prepared in analogy to Example 129.

<td colspan="2">¹H-NMR (CDCl3):</td><td>δ = 1.42 (s,</td><td>3H), 1.56</td><td>(s, 3H), 2.19</td>

<td>(Dd,</td><td>2H), 3.62</td><td>(s, 3H), 4.31</td><td>(s, br, 1H),</td><td>5.01 (d, 1H),</td>

<td> 5,56</td><td>(d, 1H),</td><td>6.70 (dd, 1H)</td><td>, 6.90 (s,</td><td>1H), 7.39 (s,</td>

<td>1H),</td><td> 7,46-7,52</td><td>(m, 1H), 9.39</td><td>(s, 1H).</td><td></td>

Example 134

5- (6-chloro-2,7-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1H-quinolin-2-one:

mg 5- [4- (3-chloro-4-methoxyphenyl) -2,2-dihydroxy-4-methylpentylamino) -1H-quinolin-2-one (43 pmol) is placed in dichloromethane, 0.86 mmol of boron tribromide ( 1 m solution in dichloromethane) and stirred at room temperature for 3 h. The reaction ends with us. sodium bicarbonate solution. Extract with dichloromethane, wash the organic phases with sat. sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is recrystallized from hexane / diethyl ether. 9 mg (40%) of the desired product are obtained.

melting point: 158 ° C; MS (ESI): 453 (M + 1).

Example 135

1- (8-Fluoro-2-methylquinazolin-5-ylamino) -7-metoksy4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

2-Hydroxy-4- (4-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentanal

The aldehyde is prepared as described in Example 5 from 4-methoxybenzyl cyanide.

<td>¹H-NMR (CDCl3)</td><td>: δ = 1.34</td><td>(S,</td><td>3H);</td><td> 1,</td><td> 43</td><td>(s, 3H),</td><td> 2,</td><td> 30</td><td>(D,</td>

<td>1H), 2.69 (d,</td><td>1H), 3.66</td><td>(S,</td><td>1H),</td><td> 3,</td><td> 80</td><td>(s, 3H),</td><td> 6,</td><td> 85</td><td>(D,</td>

<td>2H), 7.21 (d,</td><td>2H), 8.76</td><td>(S,</td><td>1H).</td><td></td><td></td><td></td><td></td><td></td><td></td>

176

1- (8-Fluoro-2-methylquinazolin-5-ylamino) -7-metoksy4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol.

The above compound is prepared using the appropriate starting materials as described in Example 129.

Melting point 97 ° C; MS (ESI): 450 (M + 1).

Example 136

5- (2-Hydroxy-7-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1H-quinolin-2-one.

Preparation took place as described in Example 129 using 2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanal and the corresponding amine.

Melting point 128 ° C; MS (ESI): 433 (M + 1).

Example 137

5- (2-Hydroxy-7-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -2H-isoquinolin-1-one

Preparation took place as described in Example 129 using 2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanal and the corresponding amine.

Melting point 112 ° C; MS (ESI): 433 (M + 1).

Example 138

5- (2-Hydroxy-7-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -2H-phthalazin-1-one

Preparation took place as described in Example 129 using 2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanal and the corresponding amine.

197 ° C: MS (ESI): 434 (M + 1).

177

Example 139

7-Methoxy-4,4-dimethyl-1- (2-methylquinolin-5-ylamino) 2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol. Preparation is as described in Example 129 using 2 -hydroxy-4- (4-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanal and the corresponding amine.

Melting point 84 ° C; MS (ESI): 431 (M + 1).

The racemate was separated by chiral HPLC into enantiomers. Analytical HPLC: Chiralpak AD 10ll, 250 x

4.6 mm, 1 ml min-1, hexane / ethanol 90/10 (+) - Enantiomer: Rt = 7.0 min; mp 84 ° C; MS (ESI): 431 (M + 1);

(-) - Enantiomer: Rt = 17.8 min; melting point 85 ° C; MS (ESI): 431 (M + 1); specific rotation: -5.9 (c = 0.14, CHCl3).

Example 140

4.4- Dimethyl-1- (2-methylquinolin-5-ylamino) -2 (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,7-diol.

The ether described in Example 139 in analogy to Example 134 was ether cleaved by BBr3.

Melting point 127 ° C: MS (ESI): 417 (M + 1),

Example 141

5- (2,7-Dihydroxy-4,4-dimethyl-2- (trifluoromethyl) 1.2.3.4-tetrahydronaphthalen-1-ylamino) -2H-phthalazin-1-one

Ether - described in Example 138 - in analogy to

Example 134 was subjected to ether cleavage by BBr3. Melting point 116 ° C; MS (ESI): 420 (M + 1). Example 142

1- (8-Fluoro-2-methylquinazolin-5-ylamino) -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,7-diol.

Ether - described in Example 135 - in analogy to

Example 134 was subjected to ether cleavage by BBr3.

178 ¹H-NMR (CD3OD): δ = 1.41 (s, 3H), 1.54 (s, 3H), 2.02 (d,

1H), 2.17 (d, 1H), 2.82 (s, 3H), 4.32 (s, 1H), 6.93 (dd, 1H), 7.01 (d, 1H), 7, 32-7.43 (m, 2H), 7.52-7.66 (m, 3H);

MS (ESI): 436 (M + 1).

Example 143

5- (2,7-Dihydroxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-1-ylamino) -1H-quinolin-2-one.

Ether - described in Example 136 - in analogy to

Example 134 was subjected to ether cleavage by BBr3.

<td>¹H-NMR (CD3OD): δ =</td><td> 1,38</td><td>(S,</td><td>3H);</td><td> 1,52</td><td>(S,</td><td>3H);</td><td> 2,13</td>

<td>(dd, 2H), 5.17 (s,</td><td>1H),</td><td> 6,53</td><td>(D,</td><td>1H),</td><td> 6,62</td><td>(D,</td><td>1H),</td>

<td>6.68-6.78 (m, 2H),</td><td> 7,26</td><td>(D,</td><td>1H),</td><td> 7,39</td><td>(Dd,</td><td>1H),</td><td> 8,26</td>

(d, 1H);

MS (ESI): 419 (M + 1).

Example 144

5- (2-Hydroxy-5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-ylamino) -1H-quinolin-2-one When using 2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentanal and the corresponding amine, the above compound is prepared as described in Example 129.

Melting point 228 ° C; MS (ESI): 405 (M + 1)

Example 145

1- (8-Fluoro-2-methylquinazolin-5-ylamino) -5-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydro-naphthalen-2-ol.

Using the 2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanal and the corresponding amine, the above compound is prepared as described in Example 129.

Melting point 132 ° C; MS (ESI): 422 (M + 1)

Example 146

179

7-Chloro-1- (8-fluoro-2-methylquinazolin-5-ylamino) 4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftaleno-2,6-diol

2-Chloro-5-methylanisole g (350.65 mmol) 2-chloro-5-methylphenol is dissolved in 450 ml of acetone and added under nitrogen

96.5 g (701.3 mmol) of potassium carbonate. After adding 43.6 ml of methyl iodide (2 equivalents) for three hours, refluxing is carried out. After cooling, the reaction mixture is filtered, the filter residue is washed with acetone and the filtrate is rotary evaporated to dryness (bath temperature 30 ° C). Since the residue still contains potassium carbonate, it is added to a small amount of diethyl ether and filtered again. Rotary evaporation of the solvent gives 57 g (103.8%) of the desired compound, which is used as the crude product in the next step.

¹H-NMR (300 MHz, CDCl3): δ = 2.35 (3H), 3.90 (3H), 6.686.79 (2H), 7.22 (1H).

4-chloro-3-methoxybenzyl bromide g (363.96 mmol) 2-chloro-5-methylanisole is dissolved in 800 ml of carbon tetrachloride and 69.9 g (393.08 mmol) of Nbromosuccinimide are added at room temperature. After adding 174.6 mg of benzoyl peroxide for five hours, reflux (bath temperature 105 ° C). The reaction mixture is suction filtered through a glass fiber filter, washed and the solution is evaporated on a rotary evaporator. 83.6 g (97.5%) of the desired product are obtained (contains traces of starting material and dibromide), which is used in the next step without purification.

¹H-NMR (300 MHz, CDCl3): δ = 3.91 (3H), 4.48 (2H), 6.906.98 (2H), 7.32 (1H).

180

4-chloro-3-methoxybenzyl cyanide

83.6 g (354.97 mmol) of crude bromide are dissolved in 255 ml of DMF and mixed with 266 ml of water. After adding

34.7 g (532.45 mmol) of potassium cyanide (heating) the mixture is stirred for three hours at room temperature. The reaction mixture is poured onto a liter of ice water and extracted three times with diethyl ether (500 ml each). The combined organic extracts are washed with water and brine. After drying over sodium sulfate, it is filtered and the solvent is evaporated on a rotary basis. The residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane).

44.7 g (69.4%) of the desired compound are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 3.75 (2H), 3.94 (3H), 6.806.91 (2H), 7.38 (1H).

2- (4-Chloro-3-methoxyphenyl) -2-methylpropanenitrile

44.7 g (246.1 mmol) of the nitrile described above are dissolved in 380 ml of DMF and mixed with 69.8 g (492.2 mmol) of methyl iodide. After cooling to 0 ° C, 21.5 g (492.2 mmol) NaH (55% suspension) is added portionwise to the reaction mixture over three and a half hours. After 18 hours at room temperature, the mixture is poured onto 600 ml of ice water and extracted three times with diethyl ether (500 ml each). The combined organic phases are washed with water and brine. After drying over sodium sulfate, the drying agent is filtered off and the solvent is evaporated on a rotary evaporator. After chromatography on silica gel (mobile phase: ethyl acetate / hexane), 42.37 g (81.1%) of the desired compound are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 1.75 (6H), 3.96 (3H), 6.97 (1H), 7.07 (1H), 7.49 (1H).

2- (4-Chloro-3-methoxyphenyl) -2-methylpropanal g (119.23 mmol) of the nitrile described above is dissolved in 475 ml of toluene. At -65 to -60 ° C, 149 ml of a 1.2 molar solution of DIBAH in dropwise is added dropwise over 60 minutes

181 toluene. After stirring for two hours at this temperature, 681 ml of a 20% solution of L - (+) - tartaric acid begins to dropwise. After 200 milliliters, the temperature rises to 10 ° C. The rest of the tartaric acid solution is quickly added and the mixture is stirred vigorously at room temperature for 16 hours. The reaction mixture is shaken twice with diethyl ether (600 ml each). The combined organic extracts are shaken with water and brine, dried and the solvent is rotary evaporated. The obtained residue (25 g = 98.8%) is used crude in the next step.

¹H-NMR (300 MHz, CDCl3): δ = 1.48 (6H), 3.90 (3H), 6.706.88 (2H), 7.37 (1H), 9.49 (1H).

Ethyl E-4- (4-Chloro-3-methoxyphenyl) -4-methylpent-2-enoate

25.6 g (114.3 mmol) of triethylphosphonoacetate are placed in 148 ml of tetrahydrofuran. 60.8 ml of a 2M solution of LDA in THF / heptane / ethylbenzene (1 hour and 15 minutes) are added dropwise at 0 ° C. After stirring for one hour at 0 ° C, 22.1 g (103.91 mmol) of 2- (4-chloro-3-methoxyphenyl) dissolved in 100 ml are added dropwise. After five days of stirring at room temperature, the reaction mixture is poured onto 200 ml of dilute chloride solution ammonium and extracted twice with diethyl ether (ml each). The combined organic extracts are subjected

2-methylpropanal, tetrahydrofuran.

usually treated with ethyl acetate / hexane). desired relationship.¹H-NMR (300 MHz, CDCl3 (3H), 4.20 (2H), 5.80 7.29 (1H).

the obtained residue is subjected to silica gel. Is isolated δ = 1.30

1H)

3H) (phase

24,1

1,47 (

300 how moving: g (82%)

6H)

6.80-6.88 (2H), 7.09

3,90

1H),

Ethyl 4- (4-chloro-3-methoxyphenyl) -4-methylpentanoate

To 24.1 g (85.23 mmol) of ethyl E-4- (4-chloro-3-methoxyphenyl) 4-methylpent-2-enoate in 228 ml of ethyl acetate

182 2.41 g palladium on carbon (10%) are added and the atmosphere is stirred overnight at room temperature. The catalyst is removed by filtration through a glass fiber filter and the residue obtained after concentration (24.1 g = 99.1%) is used crude in the next step.

¹H-NMR (300 MHz, CDCl3): δ = 1.21 (3H), 1.34 (6H), 1.902.10 (4H), 3.92 (3H), 4.10 (2H), 6.82 -6.90 (2H), 7.29 (1H).

Ethyl 4- (4-chloro-3-methoxyphenyl) -2-hydroxy-4-methylpentanoate

24.1 g (84.63 mmol) of ethyl 4- (4-chloro-3-methoxyphenyl) -4-methylpentanoate are dissolved in 296 ml of tetrahydrofuran and the reaction mixture is cooled to -70 ° C to -65 ° C. Over three quarters of an hour, 236.9 mL of a 0.5 molar solution of potassium bis (trimethylsilylamide) in toluene are added dropwise, and then the reaction mixture is stirred at -70 ° C for 75 minutes. 30.9 g (118.48 mmol) of Davis reagent dissolved in 296 ml of tetrahydrofuran are added dropwise over 60 minutes. After stirring for 2 hours at -70 ° C, 152 ml of saturated ammonium chloride solution are slowly added dropwise, the cooling bath is removed and the mixture is stirred vigorously for thirty minutes. After extraction with diethyl ether, the combined organic extracts are treated as usual with water and brine. After rotary evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 21.4 g (84.2%) of the desired compound is isolated (slightly impure).

Ethyl 4- (4-Chloro-3-methoxyphenyl) -4-methyl-2-oxopentanoate

6.15 g (20.45 mmol) of ethyl 4- (4-chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-pentanoate are dissolved in 213 ml of dichloromethane and 71 ml of dimethyl sulfoxide are added. After addition of 10.3 g (102.23 mmol)

183 triethylamine is added in portions 8.1 g (51.12 mmol) of the SO3 / pyridine complex and then stirred overnight at room temperature. Lightly cooling to the reaction mixture - 81 ml saturated ammonium chloride solution is added and stirred vigorously. After extracting twice with diethyl ether, the combined organic phases are treated as usual. The residue obtained after rotary evaporation of the solvent together with the residue, obtained from a further mixture (15.27 g), is subjected to silica gel chromatography (mobile phase: ethyl acetate / hexane). 15.46 g (72.9%, from two mixtures) of the desired compound are isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.25 (3H), 1.48 (6H), 3.16 (2H), 3.90 (3H), 4.12 (2H), 6.83 -6.94 (2H), 7.28 (1H).

(rac.) ethyl 4- (4-Chloro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -2- (trimethylsilyloxy) -pentanoate

15.46 g (51.75 mmol) of ethyl 4- (4-chloro-3-methoxyphenyl) -4-methyl-2-oxopentanoate are dissolved in 85 ml of tetrahydrofuran and 8.83 g (62.09 mmol) are added at 0 ° C (trifluoromethyl) trimethylsilane. After addition of 126.8 mg tetrabutylammonium fluoride for two hours is stirred at 0 to 5 ° C. The mixture is applied to 150 ml of ice water, extracted twice with diethyl ether and the combined organic extracts are treated as usual. After rotary evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 14.11 g (61.8%) of the desired product (impure) is isolated, which is used as it is in the next step.

MS (CI): 458 (100%).

Ethyl 4- (4-Chloro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -2-hydroxy-pentanoate

184

8.9 g (20.18 mmol) of impure ethyl 4- (4-chloro-3-methoxyphenyl) -4-methyl-2- (trifluormethyl) -2 (trimethylsilyloxy) pentanoate are dissolved in 116 ml of tetrahydrofuran and 6 are added at room temperature , 37 g (20.18 mmol) of tetrabutylammonium fluoride trihydrate and stirring for 1 hour at room temperature. Water is added to the reaction mixture and extracted twice with diethyl ether (250 ml each). The combined organic extracts are washed with water and brine. After drying over sodium sulfate, the drying agent is filtered off, the solvent is rotated and the residue obtained is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 4.03 g (54.2%) of the desired compound is isolated. Further mixtures are made in an analogous manner.

¹H-NMR (300 MHz, CDCl3): δ = 1.19 (3H), 1.39 (3H), 1.49 (3H), 2.28 (1H), 2.49 (1H), 3.60 -3.71 (2H), 3.93 (3H), 3.98-4.10 (1H), 6.82-6.93 (2H), 7.28 (1H).

4- (4-chloro-3-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) -pentanal

5.25 g (14.24 mmol) (rac.) Of 4- (4-chloro-3-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -2-hydroxypentanoate is dissolved in 53 ml of diethyl ether and at 0 ° C in 405.2 mg (10.68 mmol) of lithium aluminum hydride are added over 30 minutes. The reaction mixture is stirred for one hour and a quarter at 0 ° C. For hydrolysis, 12.5 ml of saturated sodium bicarbonate solution is added dropwise to the cooled mixture in an ice bath. For 30 minutes cooling in an ice bath and 60 minutes at room temperature intensively

The precipitate is suction filtered, washed with ether and stirred.

ether. The filtrate is concentrated on a rotary evaporator, the residue is subjected to silica (phase 3.29 g mobile gel chromatography: ethyl acetate / hexane).

71.2%) of the desired aldehyde, which

185 it still contains some starting ester and 54.7 mg of the corresponding diol.

¹H-NMR (300 MHz, CDCl3): δ = 1.39 (3H), 1.48 (3H), 2.34 (1H), 2.69 (1H), 3.69 (1H), 3.92 (3H), 6.80-6.93 (2H),

7.30 (1H), 8.90 (1H).

4- (4-chloro-3-methoxy-phenyl) -1,1,1-trifluoro-2 - {[(E) of 8-fluoro-2-methyl-quinazolin-5-yloimino] -methyl} -4-methyl-pentane -2-ol

To 350 mg (1.08 mmol) (rac.) -4- (4-chloro-3-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) -pentanal in 5.8 ml o-xylene is added 190.9 mg ( 1.08 mmol) 5-amino-8-fluoro-2-methylquinazoline. After adding 0.64 ml (2.16) of titanium (IV) isopropylate for three hours, reflux (bath temperature

120 ° C). After cooling, the mixture is added to a saturated sodium chloride solution and stirred vigorously for 20 minutes. After extraction with ethyl acetate twice, the combined organic extracts are washed with brine. After drying over sodium sulfate, suction drying and rotary evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: acetate

<td colspan="2">acetate / hexane).</td><td colspan="3">Is isolated 327,</td><td colspan="2">5 mg (62.8%) as desired</td>

<td>imine.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>¹H-NMR</td><td>(300 MHz</td><td>, CDCl3)</td><td>: δ =</td><td> 1,38 (</td><td>3H), 1.58</td><td>(3H), 2.45</td>

<td>(1H),</td><td>2.71 (1H)</td><td> , 2,99</td><td>(3H);</td><td> 3,69 (</td><td>3H), 4.75</td><td>(1H), 6.28</td>

<td>(1H),</td><td> 6,79-6,90</td><td>(2H),</td><td> 7,08</td><td>(1H),</td><td> 7,37-7,49</td><td>(2H), 9.63</td>

<td>(1H).</td><td></td><td></td><td></td><td></td><td></td><td></td>

7-Chloro-1- (8-fluoro-2-methylquinazolin-5-ylamino) -6-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol mg (0.165 mmol) the imines are dissolved in 1.2 ml of dichloromethane, 0.5 ml of titanium tetrachloride are added dropwise at 0 ° C. and stirred at this temperature for three quarters of an hour. Saturated sodium bicarbonate solution is added dropwise to the reaction mixture at 0 ° C

186 and ethyl acetate is added. The cooling bath is removed and the mixture is stirred vigorously for 20 minutes. After extraction with ethyl acetate, the combined organic extracts are treated as usual. After chromatography on silica gel (mobile phase: methanol / dichloromethane), 60.7 mg (75.8%) of the desired compound are obtained.

¹H-NMR (300 MHz, DMSO-d6): δ = 1.40 (3H), 1.56 (3H), 1.99-2.15 (2H), 2.78 (3H), 3.90 ( 3H), 5.40 (1H), 6.18 (1H), 6.72-6.90 (2H), 7.10-7.20 (2H), 7.60 (1H), 9.79 ( 1H).

7-Chloro-1- (8-fluoro-2-methylquinazolin-5-ylamino) 4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftaleno-2,6-diol

To 35 mg (0.072 mmol) of the compound described in the previous paragraph, cooled in an ice bath, is added 0.7 ml of a one-molar solution of boron tribromide in dichloromethane and stirred for two hours under cooling in an ice bath. Saturated sodium bicarbonate solution is added dropwise to the reaction mixture at -30 ° C to pH 8. The cooling bath is removed and the mixture is vigorously stirred for 15 minutes at room temperature. After extraction with ethyl acetate twice, the organic extracts are treated as usual. After silica gel chromatography (mobile phase: methanol / dichloromethane), 17.7 mg (52.2 mg) of the desired compound is finally isolated.

¹H-NMR (300 MHz, CD3OD): δ = 1.40 (3H), 1.56 (3H), 2.072.20 (2H), 2.89 (3H), 5.23 (1H), 6.83 (1H), 6.99 (1H),

7.20 (1H), 7.59 (1H), 9.69 (1H).

Example 147

5- (7-Chloro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino-2H-isoquinolin-1-one

187

5- [4- (4-Chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentylidenoamino) -2H-isoquinolin-1-one

400 mg (1.232 mmol) described in the previous example

4- (4-chloro-3-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) pentanal is reacted to an imine with 197.3 mg (1.232 mmol) of 5-amino-2H-isoquinolin-1one. After reaction, typical work-up and chromatography, 332.9 mg (57.9%) of the desired imine are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 1.38 (3H), 1.56 (3H), 2.43 (1H), 2.72 (1H), 3.70 (3H), 4.95 (1H), 6.41 (1H), 6.756.98 (3H), 7.08-7.31 (2H), 7.31-7.48 (2H), 11.2 (1H).

5- (7-chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-ylamino-2H-isoquinolin-1-one

100 mg (0.214 mmol) of imine is reacted as described in Example 146 with titanium tetrachloride.

36.9 mg (36.9%) of the desired cyclic compound is isolated as a 65:35 mixture of diastereomers.

MS (ES +): 467 (100%)

5- (7-Chloro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-ylamino-2H-isoquinolin-1-one mg (0.058 mmol) of ether described in the previous paragraph it is reacted as described in the Example

146 with boron tribromide. After carrying out the reaction and a typical work-up, 19.9 mg (75.9%) of the desired compound are obtained as a uniform diastereomer.

¹H-NMR (300 MHz, CD3OD): δ = 1.29 (3H), 1.43 (3H), 1.982.09 (2H), 5.00 (1H), 6.75 (1H), 6.86 (1H), 6.93 (1H), 7.00-7.10 (2H), 7.29 (1H), 7.59 (1H).

Example 148

5- (7-Chloro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino-2-methyl-2H-phthalazin-1-one

188

5- [4- (4-Chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentylidenoamino) -2-methyl-2Hftalazyn-1-one.

350 mg (1.078 mmol) of the above described 4- {4-chloro-3-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) -pentanal

<td>treated</td><td>reaction with</td><td> 251,8</td><td>mg (1,</td><td> 078</td><td>mmol)</td><td>5-amino-2-</td>

<td>methyl</td><td colspan="2">2H-phthalazine-1-on to</td><td>imine.</td><td>After</td><td>reaction</td><td>and, typical</td>

<td>treatment</td><td colspan="3">and chromatography is replaced</td><td>himself</td><td> 328,4</td><td>mg (63.2%)</td>

<td>desired</td><td>imine.</td><td></td><td></td><td></td><td></td><td></td>

<td>¹H-NMR (</td><td>300 MHz, CDCl3)</td><td>: δ =</td><td> 1,38 (</td><td>3H);</td><td> 1,58</td><td>(3H), 2.43</td>

<td>(1H), 2</td><td>, 72 (1H), 3.70</td><td>(3H);</td><td> 3,89 (</td><td>3H);</td><td> 4,70</td><td>(1H), 6.51</td>

<td>(1H), 6</td><td>, 80-6.89 (2H),</td><td> 7,10 (</td><td>1H), 7</td><td> ,40</td><td>(1H),</td><td>7.63 (1H),</td>

8.33 (1H), 8.42 (1H).

5- (7-Chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino-2-methyl-2H-phthalazin-1-one

100 mg (0.207 mmol) of imine is cyclized as described in Example 146 with titanium tetrachloride in dichloromethane. 30.5 mg (30.5%) of the desired compound is isolated as a mixture of diastereomers.

MS (ES +): 482 (100%)

5- (7-Chloro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-ylamino-2-methyl-2H-phthalazine-1-one mg (0.049 mmol) of the ether described in the previous paragraph is reacted with boron tribromide as described in Example 146. After carrying out the reaction and typical work-up, 18.7 mg (75.9%) of the desired compound are obtained as a mixture of diastereomers.

MS (ES +): 468 (100%)

Example 149

5- (7-Chloro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino-1 H-quinolin-2-one

189

5- [4- (4-Chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentylidenoamino) -1H-quinolin-2-one

350 mg (1.078 mmol) described in the previous example 4- (4-chloro-3-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) -pentanal is reacted with 172.6 mg (1.078 mmol) 5-amino-1H-quinoline -2-on to name. After the reaction, typical work-up and chromatography are obtained

319.4 mg (6349%) of the desired imine.

¹H-NMR (300 MHz, CDCl3): δ = 1.34 (3H), 1.55 (3H), 2.43 (1H), 2.70 (1H), 3.70 (3H), 4.85 (1H), 6.00 (1H), 6.706.90 (3H), 7.13 (1H), 7.29-7.45 (3H), 8.17 (1H), 12.30 (1H).

5- (1-Chloro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino-1 H-quinolin-2-one

To 106 mg (0.227 mmol) of imine at -20 ° C, 2.3 ml of a 1 M solution of boron tribromide in dichloromethane are added and the mixture is stirred at -20 to 0 ° C for two hours. The reaction mixture is treated with a saturated solution. After the silica gel is isolated as bicarbonate, sodium gel is usually subjected to pH 8 by chromatography on the mobile phase: methanol / dichloromethane) 55.1 mg (53.5%) of the desired cyclic compound as free phenol.

¹H-NMR (300 MHz, CD3OD): δ = 1.41

2.20 (2H), 5.12 (1H), 6.49-6.64 (1H), 7.16 (1H), 7.40 (1H), 8.25

3H), 1.55 (3H), 2.05 (2H)

1H).

6.73 (1H)

6,98

Example 150

7-Chloro-1- (2-methylquinazolin-5-ylamino) -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftaleno-2,6-diol

4- (4-Chloro-3-methoxyphenyl) -1,1,1-trifluoro-2 - [(5-2metylochinazolin yloimino) methyl} -4-methyl-pentan-2-ol

190

200 mg (0.616 mmol) (rac.) - 4- (4-chloro-3-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) -pentanal is reacted as described in Example 146 with

98.1 mg (0.616 mmol) of 5-amino-2-methylquinazoline to imine. After typical treatment and purification it is isolated

184.3 mg (64.2%) of the desired imine.

¹H-NMR (300 MHz, CDCl3): δ = 1.36 (3H), 1.59 (3H), 2.45 (1H), 2.73 (1H), 2.93 (3H), 3.68 (3H), 4.82 (1H), 6.30 (1H), 6.78-6.90 (2H), 7.08 (1H), 7.48 (1H), 7.71 (1H), 7.84 (1H), 9.60 (1H).

7-Chloro-1- (2-methylquinazolin-5-ylamino) -6-metoksy4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

180 mg (0.386 mmol) of imine is cyclized as described with titanium tetrachloride. 165.6 mg (92%) of the desired cyclic compound is isolated.

¹H-NMR (300 MHz, CD3OD): δ = 1.49 (3H), 1.61 (3H), 2.102.25 (2H), 2.84 (3H), 3.93 (3H), 5.31 (1H), 6.95 (1H),

7.10 (1H), 7.19-7.27 (2H), 7.81 (1H), 9.65 (1H).

7-Chloro-1- (2-methylquinazolin-5-ylamino) -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,6-diol mg (0.107 mmol) of the derivative described in the previous paragraph is subjected to react with the help of boron tribromide

<td>to the corresponding phenol.</td><td colspan="2">Is isolated</td><td> 30,2</td><td>mg (</td><td> 66,1%)</td>

<td>desired relationship.¹H-NMR (300 MHz, DMSO-d6</td><td>): δ =</td><td> 1,33 (</td><td>3H);</td><td> 1,48</td><td>(3H);</td>

<td>1.95-2.13 (2H), 2.72 (3H)</td><td> , 5,39</td><td>(1H),</td><td> 6,15 (</td><td>1H),</td><td> 6,80-</td>

<td>6.95 (2H), 6.95-7.13 (3H)</td><td> , 7,69</td><td>(1H),</td><td> 9,72 (</td><td>1H),</td><td> 10,03</td>

(1H).

Example 151

7-Chloro-1- (7-fluoro-2-methylquinazolin-5-ylamino) 4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftaleno-2,6-diol

191

4- (4-Chloro-3-methoxyphenyl) -1,1,1-trifluoro-2 - [(7-fluoro-2-methylquinazolin-5-yloimino) -methyl] -4-methylpentan-2-ol

200 mg (0.616 mmol) of aldehyde was reacted as described many times with 109.1 mg (0.61 6) of 5-amino-7-fluoro-2-methylquinazoline. 173 mg (58.1%) of the desired imine is isolated.

<td>¹H-NMR</td><td> (300</td><td>MHz,</td><td>CDCl3)</td><td>: δ =</td><td> 1,39</td><td>(3H), 1.58</td><td>(3H);</td><td> 2,</td><td> 47</td>

<td>(1H),</td><td> 2,73</td><td>(1H),</td><td> 2,90</td><td>(3H);</td><td> 3,72</td><td>(3H), 4.64</td><td>(1H)</td><td> ,6,</td><td> 17</td>

<td>(1H),</td><td> 6,80-</td><td> 6,90</td><td>(2H),</td><td> 7,09</td><td>(1H),</td><td> 7,40-7,50 (</td><td>2H);</td><td> 9,</td><td> 49</td>

(1H).

7-Chloro-1- (7-fluoro-2-methylquinazolin-5-ylamino) -6-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftalen-2-ol

170 mg (0.351 mmol) of the previously described imine is cyclized with 1.05 ml (1.053 mmol) of titanium tetrachloride in dichloromethane. After typical work-up and subsequent chromatography, 168.4 mg (99%) of the desired cyclic compound is isolated as ether.

¹H-NMR (300 MHz, CD3OD): δ = 1.49 (3H), 1.61 (3H), 2.20 (2H), 2.80 (3H), 3.93 (3H), 5.33 (1H), 6.70-6.85 (2H),

7.10 (1H), 7.20 (1H), 9.57 (1H).

7-Chloro-1- (7-fluoro-2-methylquinazolin-5-ylamino) 4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,6-diol mg (0.103 mmol) ether as described in the previous paragraph is subjected as usual to the cleavage of boron tribromide ether. After working up and typical chromatography on silica gel (mobile phase:

methanol / dichloromethane), 32.2 mg (66.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, DMSO-d6): δ = 1.32 (3H), 1.49 (3H),

1.95-2.13 (2H), 2.70 (3H), 5.48 (1H), 6.15 (1H), 6.79 (1H), 6.88 (1H), 6.95- 7.16 (2H), 9.68 (1H), 10.03 (1H).

Example 152

192

7-Chloro-1- (7,8-difluoro-2-methylquinazolin-5yloamino) -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4tetrahydronaftaleno-2,6-diol

4- (4-Chloro-3-methoxyphenyl) -1,1,1-trifluoro-2 - [(7,8difluoro-2-methylquinazolin-5-yloimino) -methyl] -4-methyl-pentan-2-ol

200 mg (0.616 mmol) of aldehyde is reacted as described many times with 120 mg (0.616) of 5-amino-

<td>7,8-difluoro-2-methylquinazoline.</td><td colspan="2">extracts</td><td>to 201.3</td>

<td>mg (65.1%) of the desired imine.¹H-NMR (300 MHz, CDCl3): δ = 1.38</td><td>(3H);</td><td> 1,58</td><td>(3H), 2.46</td>

<td>(1H), 2.72 (1H), 2.96 (3H), 3.72</td><td>(3H);</td><td> 4,59</td><td>(1H), 6.28</td>

(1H), 6.80-6.90 (2H), 7.10 (1H), 7.46 (1H), 9.53 (1H).

7-Chloro-1- (7,8-difluoro-2-methylquinazolin-5yloamino) -6-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2-ol

<td>200 mg</td><td colspan="3">(0.398 mmol) previously described</td><td>imine</td><td>cyclized</td>

<td>with</td><td>1.19 ml</td><td> (1,</td><td colspan="2">194 mmol) tetrachloride</td><td>titanium in</td>

<td colspan="2">dichloromethane.</td><td>After</td><td>typical processing</td><td>and</td><td>next</td>

<td colspan="4">the chromatography carried out is isolated</td><td>himself</td><td>163.6 mg</td>

<td> (81,8%)</td><td>desired</td><td colspan="2">cyclic relationship.</td><td></td><td></td>

<td>¹H-NMR (</td><td>300 MHz</td><td>CD 3 OD</td><td>): δ = 1.48 (3H),</td><td> 1,61 (</td><td>3H), 2.19</td>

<td>(2H), 2</td><td>, 86 (3H),</td><td> 3,93</td><td>(3H), 5.30 (1H),</td><td> 6,88 (</td><td>1H), 7.09</td>

<td>(1H), 7</td><td>, 21 (1H),</td><td> 9,62</td><td>(1H).</td><td></td><td></td>

7-Chloro-1- (7,8-difluoro-2-methylquinazolin-5-ylamino) -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,6-diol mg (0.099 mmol) of the ether described in the previous paragraph is as usual splitted with ether with boron tribromide. After working up and purification by flash chromatography (mobile phase:

methanol / dichloromethane) 29.5 mg (60.7%) of the desired compound is isolated.

193 ¹H-NMR (300 MHz, DMSO-d6): δ = 1.32 (3H), 1.47 (3H),

1.95-2.12 (2H), 2.78 (3H), 5.45 (1H), 6.13 (1H), 6.927,18 (4H), 9.73 (1H), 10.02 ( 1H).

Example 153

4- (7-Chloro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1,3-dihydro-indol-2-one

4- [4- (4-Chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentylidenoamino] -1,3-dihydro-indol-2-one

150 mg (0.462 mmol) of aldehyde is refluxed as already described in the previous examples with 102.7 mg (0.693 mmol) of 4-amino-1,3-dihydroindol-2-one in xylene after addition of titanium tetraisopropylate on a water separator. After typical work-up and chromatography, 119.3 mg (56.7%) of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 1.35 (3H), 1.50 (3H), 2.49 (1H), 2.66 (1H), 3.35-3.59 (2H) , 3.75 (3H), 4.89 (1H),

5.98 (1H), 6.70-6.90 (3H), 7.09-7.22 (2H), 7.33 (1H),

8.22 (IH).

4- (7-Chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1,3-dihydro-indol-2-one

<td>119 mg (0.261</td><td colspan="5">mmol) of the imine described above is cyclized</td>

<td>as usual</td><td colspan="2">in dichloromethane</td><td colspan="2">Applying</td><td>0.78 ml</td>

<td>tetrachloride</td><td>titanium.</td><td colspan="2">After processing</td><td>and</td><td>embodiment,</td>

<td>chromatography</td><td colspan="2">78 is obtained,</td><td>1 mg</td><td> (65,6</td><td>%) requested</td>

<td>relationship.</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2">¹H-NMR (300 MHz, CD3OD)</td><td>: δ = 1.42</td><td>(3H);</td><td> 1,59</td><td>(3H), 2.00-</td>

<td colspan="2">2.20 (2H), 3.23-3.49 (</td><td>2H), 3.91</td><td>(3H);</td><td> 5,03</td><td>(1H), 6.37</td>

<td>(1H), 6.48 (1H</td><td> ), 7,03 (</td><td>1H), 7.10</td><td>(1H),</td><td> 7,29</td><td>(1H).</td>

4- (7-Chloro-2,6-dihydroxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1,3-dihydro-indol-2-one

194

1.4 boron tribromide in dichloromethane is added to 65 mg (0.143 mmol) of the ether described in the previous paragraph. After working up and chromatography, 45.4 mg (72.1%) of the desired phenol are obtained.

¹H-NMR (300 MHz, CD3OD): δ = 1.39 (3H), 1.51 (3H), 1.982.20 (2H), 3.25-3.50 (2H), 5.00 (1H) , 6.37 (1H), 6.46 (1H), 6.93 (1H), 7.10 (1H), 7.21 (1H).

Example 154

8,8-Dimethyl-5- (naphthalen-1-ylamino) -6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

1,1,1-Trifluoro-4- (2-methoxyphenyl) -4-methyl-2- (naphthalen-1-yloiminometylo) pentan-2-ol

150 mg (0.517 mmol) 2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanal with 74 mg (0.517

<td>mmol)</td><td>1-naphthylamine</td><td>toluene</td><td colspan="2">is moving</td><td>from</td>

<td>help</td><td>tetraizopropylanu</td><td>titanium in</td><td>imine. After</td><td>treatment</td><td>and</td>

<td colspan="2">extracts chromatography</td><td>up 166,</td><td>7 mg (77.7</td><td colspan="2">%) requested</td>

<td>imine.¹H-NMR</td><td>(300 MHz, CDCl3): δ</td><td> = 1,42 (</td><td>3H), 1.59</td><td>(3H), 2,</td><td> 29</td>

<td>(1H),</td><td>3.57 (1H), 3.88 (3H</td><td> ), 5,09 (</td><td>1H), 6.10</td><td>(1H), 6,</td><td> 48</td>

<td>(1H),</td><td>6.79 (1H), 7.00 (1H</td><td> ), 7,10 (</td><td>1H), 7.22</td><td>(1H), 7,</td><td> 40</td>

<td>(1H),</td><td>7.47-7.58 (2H), 7.69</td><td>(1H), 7,</td><td>80 (1H), 8</td><td>, 05 (1H).</td><td></td>

8,8-Dimethyl-5- (naphthalen-1-ylamino) -6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

160.9 mg (0.387 mmol) of the previously described imine is treated as usual with boron tribromide at 0 ° C and after typical work-up and chromatography on

<td>Flashmasters provide 100.9</td><td>mg (</td><td> 62,7%)</td><td>desired</td>

<td>cyclic phenol.</td><td></td><td></td><td></td>

<td>¹H-NMR (300 MHz, CDCl3): δ = 1.60</td><td>(3H);</td><td> 1,73 (</td><td>3H), 2.00-</td>

<td>2.28 (2H), 3.09 (1H), 4.79 (1H),</td><td> 5,02</td><td>(1H),</td><td>5.20 (1H),</td>

<td>6.62 (1H), 6.85-7.02 (3H), 7.30</td><td> -7,58</td><td>(4H)</td><td> 7,73-7,90</td>

(3H).

Example 155

195

8,8-Dimethyl-5- (naphthalen-2-ylamino) -6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

1,1,1-Trifluoro-4- (2-methoxyphenyl) -4-methyl-2- (naphthalen-2-yloiminometylo) pentan-2-ol

150 mg (0.517 mmol) 2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2- (trifluoromethyl} -pentanal is carried out with 74 mg (0.517 mmol) of 2-naphthylamine in toluene with

<td>tetraisopropylate titanium</td><td>anu</td><td>by name.</td><td>After</td><td>machining and</td>

<td colspan="2">performing chromatography</td><td>extracts</td><td>himself</td><td>192.8 mg</td>

<td>(89.8%) of the desired name. ¹H-NMR (300 MHz, CDCl3)</td><td>: δ</td><td>1.40 (3H),</td><td> 1,58</td><td>(3H), 2.20</td>

<td>(1H), 3.58 (1H), 3.89 (</td><td>3H);</td><td>5.09 (1H),</td><td> 6,69</td><td>(1H), 6.80-</td>

<td>6.90 (2H), 6.95 (1H),</td><td> 7,05</td><td>-7.18 (2H),</td><td> 7,38</td><td>-7.53 (3H),</td>

7.63-7.85 (3H).

8,8-Dimethyl-5- (naphthalen-2-ylamino) -6 (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol 173.0 mg (0.416 mmol) of the previously described imine is treated as usually with boron tribromide at 0 ° C and after typical flash-chromatography and chromatography, it provides 132.6 mg (76.6%) of the desired cyclic phenol.

¹H-NMR (300 MHz, CDCl3): δ = 1.60 (3H), 1.66 (3H), 2.002.24 (2H), 3.04 (1H), 5.00 (1H), 5.09 (1H), 6.62 (1H), 6.92-7.10 (4H), 7.28 (1H), 7.40 (1H), 7.60-7.78 (3H). Example 156

2-Chloro-5- (6-hydroxy-naphthalen-1-ylamino) -8,8dimetylo-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

5- (4- (3-Chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentylideneamino] naphthalen-2-ol 200 mg (0.616 mmol) 2-hydroxy-4- (3 -chloro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanal with

98.1 mg (0.616 mmol) of 5-amino-2-naphthol is treated as

196

<td>usually (64.5%</td><td>reaction ) requested</td><td colspan="2">to name. relationship.</td><td colspan="2">extracts</td><td>himself</td><td> 185,</td><td>1 mg</td>

<td>¹H-NMR</td><td>(300 MHz,</td><td>CDCl3)</td><td>: δ =</td><td> 1,47</td><td>(3H);</td><td> 1,62</td><td>(3H);</td><td> 2,40</td>

<td>(1H),</td><td>3.23 (1H),</td><td> 4,00</td><td>(3H);</td><td> 4,99</td><td>(1H),</td><td> 5,15</td><td>(1H),</td><td> 6,39</td>

<td>(1H),</td><td>6.49 (1H),</td><td> 6,83</td><td>(1H),</td><td> 7,00</td><td>(1H),</td><td> 7,05-</td><td> 7,20</td><td>(2H),</td>

7.23-7.32 (2H), 7.52-7.63 (2H), 7.95 (1H).

2-Chloro-5- (6-hydroxy-naphthalen-1-ylamino) -8,8dimetylo-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

185.1 mg (0.397 mmol) of imine, as already described many times, is cyclized with boron tribromide. 146.9 mg (81.8%) of the desired phenol is isolated.

<td>¹H-NMR</td><td> (300</td><td>MHz,</td><td>CDCl3)</td><td>: δ = 1.59 (3H),</td><td> 1,70</td><td>(3H), 2.02-</td>

<td> 2,28 (</td><td>2H);</td><td> 3,00</td><td>(1H),</td><td>4.75 (1H), 5.10</td><td> -5,19</td><td>(2H), 5.95</td>

<td>(1H),</td><td> 6,73</td><td>(1H),</td><td> 6,88</td><td>(1H), 7.00-7.12</td><td>(2H)</td><td> , 7,12-7,22</td>

<td>(2H),</td><td> 7,34</td><td>(1H),</td><td> 7,70</td><td>(1H).</td><td></td><td></td>

Example 157

2-Chloro-5- (5-hydroxy-naphthalen-1-ylamino) -8,8dimetylo-6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

5- (4- (3-Chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentylideneamino] naphthalene-1-ol 200 mg (0.616 mmol) 2-hydroxy-4- (3 -chloro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanal with

98.1 mg (0.616 mmol) of 5-amino-1-naphthol as usual

<td colspan="2">is moving</td><td>by name.</td><td>extracts</td><td>himself</td><td>145.0 mg</td>

<td colspan="2">(50.5%) desired</td><td>relationship.</td><td></td><td></td><td></td>

<td>¹H-NMR (300</td><td>MHz,</td><td>CDCl3): δ =</td><td>1.45 (3H),</td><td> 1,62</td><td>(3H), 2.40</td>

<td>(1H), 3.25</td><td>(1H),</td><td>4.01 (3H),</td><td>5.01 (1H),</td><td> 5,39</td><td>(1H), 6.46</td>

<td>(1H), 6.53</td><td>(1H),</td><td> 6,80-6,91</td><td>(2H), 7.02</td><td>(1H),</td><td> 7,30-7,40</td>

<td>(2H), 7.59</td><td>(1 H), 7</td><td>, 64 (1H), 8</td><td>, 10 (1H).</td><td></td><td></td>

2-Chloro-5- (5-hydroxy-naphthalen-1-ylamino) -8,8dimetylo-6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

197

145.0 mg (0.311 mmol) of imine, as already described many times, is cyclized with boron tribromide. Is isolated

87.6 mg (62.3%) of the desired phenol.

<td>¹H-NMR (300 MHz,</td><td>CDCl.sub.3</td><td>): δ =</td><td> 1,58</td><td>(3H);</td><td> 1,70</td><td>(3H);</td><td> 2,05-</td>

<td>2.28 (2H), 3.00</td><td>(1H),</td><td> 4,78</td><td>(1H),</td><td> 5,15</td><td>(1H),</td><td> 5,49</td><td>(1H),</td>

<td>5.95 (1H), 6.80-</td><td> 6,93</td><td>(3H);</td><td> 7,10</td><td>(1H),</td><td> 7,29</td><td>(1H),</td><td> 7,32-</td>

<td>7.45 (2H), 7.68</td><td>(1H).</td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 158

3-Chloro-5- (6-hydroxy-naphthalen-1-ylamino) -8,8dimetylo-6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

5- (4- (4-Chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) -pentylidenoamino) -naphthalen-2-ol

200 mg (0.616 mmol) 2-Hydroxy-4- (4-chloro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl} -pentanal with

<td>98.1 mg (</td><td> 0,616</td><td>mmol) 5-amino-2-naphthol as</td><td>usually</td>

<td colspan="2">is moving</td><td>by name. 113 is isolated</td><td>, 0 mg</td>

<td colspan="2">(39.4%) desired</td><td>relationship.</td><td></td>

<td>¹H-NMR (300</td><td>MHz,</td><td>CDCl3): δ = 1.38 (3H), 1.58 (3H)</td><td> , 2,30</td>

<td>(1H), 3.40</td><td>(1H),</td><td>3.85 (3H), 5.00 (1H), 5.15 (1H)</td><td> , 6,06</td>

<td>(1H), 6.50</td><td>(1H),</td><td>6.75 (1H), 6.99 (1H), 7.05-7.20</td><td>(2H),</td>

<td> 7,28</td><td></td><td></td><td></td>

<td>(1H), 7.45</td><td>(1H),</td><td>7.58 (1H), 7.93 (1H).</td><td></td>

3-Chloro-5- (6-hydroxy-naphthalen-1-ylamino) -8,8dimetylo-6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

113.0 mg (0.243 mmol) of imine, as already described many times, is cyclized with boron tribromide. Is isolated

85.7 mg (78.2%) of the desired compound.

¹H-NMR (300 MHz, CDCl3): δ = 1.55 (3H), 1.65 (3H), 2.001.23 (2H), 2.95 (1H), 4.80 (1H), 5.10 (1H), 5.20 (1H),

5.48 (1H), 6.60-6.75 (2H), 6.93 (1H), 7.09 (1H), 7.107.23 (2H), 7.35 (1H), 7.74 ( 1H).

Example 159

198

2-Chloro-8,8-dimethyl-5- (pyridin-3-ylamino) -6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

4- (3-Chloro-2-methoxyphenyl) -1,1,1- (trifluoromethyl) -4metylo- (pyridin-3-yloiminometylo) pentan-2-ol

200 mg (0.616 mmol) of 2-hydroxy-4- (3-chloro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentanal with

<td> 57,9</td><td>mg (0.616</td><td>mmol) 3-aminopyridine as</td><td>usually</td>

<td colspan="2">is moving</td><td>by name. Isolated 197</td><td>, 2 mg</td>

<td> (79,9%</td><td>) requested</td><td>relationship.</td><td></td>

<td>¹H-NMR</td><td>(300 MHz,</td><td>CDCl3): δ = 1.43 (3H), 1.60 (3H)</td><td> , 2,28</td>

<td>(1H),</td><td>3.25 (1H),</td><td>3.98 (3H), 4.70 (1H), 6.75 (1H)</td><td> , 6,95</td>

<td>(1H),</td><td> 7,00-7,15 (</td><td>2H), 7.23 (1H), 7.58 (1H), 8.12</td><td>(1H),</td>

<td> 8,49 (</td><td>1H).</td><td></td><td></td>

6-Chloro-5-methoxy-4,4-dimethyl-1- (pyridin-3-ylamino) -2- (trifluoromethyl} -1,2,3,4-tetrahydro-naphthalen-2-ol.

<td>190.0 mg</td><td>(0.474 mmol)</td><td colspan="2">imine</td><td>how</td><td>many times</td>

<td>describes</td><td>cyclized</td><td>himself</td><td colspan="3">titanium tetrachloride.</td>

<td>extracts</td><td>to 184.0</td><td>mg</td><td> (96,</td><td> 8%)</td><td>desired relationship</td>

<td>cyclic</td><td>as an ether.</td><td></td><td></td><td></td><td></td>

<td>¹H-NMR (300</td><td>MHz, CD3OD):</td><td>δ =</td><td> 1,54</td><td>(3H)</td><td>, 1.62 (3H), 2.11</td>

<td>(2H), 3.95</td><td>(3H), 5.05 (</td><td>1H),</td><td> 7,11</td><td>(1H)</td><td>, 7.15-7.28 (3H),</td>

<td>7.83 (1H),</td><td>8.09 (1H),</td><td></td><td></td><td></td><td></td>

2-Chloro-8,8-dimethyl-5- (pyridin-3-ylamino) -6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

100 mg (0.249 mmol) of the ether previously described is treated as usual with boron tribromide. After typical work-up and chromatography, 85.8 mg (88.9%) of the desired compound is isolated.

¹H-NMR (300 MHz, CD3OD): δ = 1.58 (3H), 1.69 (3H), 2.002.20 (2H), 5.00 (1H), 6.89 (1H), 7.10 -7.30 (3H), 7.81 (1H), 8.06 (1H).

Example 160

199

1,6-Dihydroxy-8,8-dimethyl-5- (pyridin-3-ylamino) -6 (trifluoromethyl) -5,6,7,8-tetrahydro-naphthalene-2-carbonitrile mg 2-chloro-8,8-dimethyl -5- (pyridin-3-ylamino) -6 (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol described in Example 159 is dissolved in 0.12 ml of 1-methyl-2-pyrrolidinone and mixed with 12.6 mg (0.258 mmol) sodium cyanide and 28.2 mg (0.129 mmol) nickel II bromide. The reaction mixture is reacted as described in the literature (J. Org. Chem. 68, 9122 (2003) in a microwave machine (200 ° C, 20 bar). After cooling, the reaction mixture is diluted with ethyl acetate and then a small amount of water is added. The mixture is filtered through Extrelute (mobile phase: ethyl acetate). The solvent is rotary evaporated and the residue on silica gel (mobile phase: methanol / dichloromethane) is chromatographed. 9.4 mg (19.2%) of the desired nitrile is isolated.

MS (CI): 378 (100%); IR (KBr): 2228.

Example 161

2-Chloro-8,8-dimethyl-5- (pyridin-4-ylamino) -6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

4- (3-chloro-2-methoxyphenyl) -1,1,1- (trifluoromethyl) -4metylo- (pyridin-4-yloiminometylo) pentan-2-ol

200 mg (0.616 mmol) 2-hydroxy-4- (3-chloro-2-trifluoromethyl) -pentanal from aminopyridine as usual 167.9 mg methoxyphenyl) -4-methyl-2- (t 57.9 mg (0.616 mmol) 4 by name.

<td colspan="2">(68.0%) desired</td><td>relationship.</td>

<td>¹H-NMR (300</td><td>MHz,</td><td>CDCl3): δ =</td>

<td>(1H), 3.26</td><td>(1H),</td><td>4.00 (3H),</td>

<td>6.80 (1H),</td><td> 7,01</td><td>(1H), 7.11</td>

(2H).

<td> 1,43</td><td>(3H);</td><td>1.60 (3H),</td><td> 2,29</td>

<td> 4,55</td><td>(1H),</td><td> 6,59-6,65</td><td>(2H),</td>

<td>(1H),</td><td> 7,55</td><td>(1H), 8.46</td><td> -8,55</td>

6-Chloro-5-methoxy-4,4-dimethyl-1- (pyridin-4-ylamino) -2- (trifluoromethyl) -1,2,3,4-tetrahydro-naphthalen-2-ol

200

<td>160.0 mg</td><td>(0.399 mmol)</td><td colspan="2">name, like</td><td>many times</td>

<td>describes</td><td>cyclized</td><td>himself</td><td colspan="2">titanium tetrachloride.</td>

<td>extracts</td><td>45.2</td><td>mg</td><td> (28,2%)</td><td>desired relationship</td>

<td>cyclic</td><td>as an ether.</td><td></td><td></td><td></td>

<td>¹H-NMR (300</td><td>MHz, CD3OD):</td><td>δ =</td><td>1.55 (3H)</td><td>, 1.69 (3H), 2.12</td>

<td>(2H), 3.98</td><td>(3H), 5.28 (</td><td>1H),</td><td> 6,80-6,93</td><td>(2H), 6.99 (1H),</td>

<td>7.28 (1H),</td><td>7.98-8.20 (2H</td><td> ).</td><td></td><td></td>

2- Chloro-8,8-dimethyl-5- (pyridin-4-ylamino) -6 (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol 37 mg (0.092 mmol) of the previously described ether are treated as usual boron tribromide. After typical work-up and chromatography, 13.8 mg (38.6%) of the desired compound is isolated.

¹H-NMR (300 MHz, CD3OD): δ = 1.58 (3H), 1.70 (3H), 2.002.20 (2H), 5.19 (1H), 6.70-6.89 (3H) , 7.19 (1H), 7.908.20 (2H).

Example 162

5- (2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -2H-isoquinolin-1-one

Methyl 3-isopropyl-2-methoxybenzoate g (156.25 mmol) 2-hydroxy-3-isopropylbenzoic acid is dissolved in 280 ml DMF and added dropwise to a mixture of 47.5 g potassium carbonate in 274 ml DMF. After stirring for one hour at room temperature, 21.4 ml (343.76 mmol) of iodomethane are added dropwise and the mixture is stirred at room temperature for one day. After acidification with 10% sulfuric acid to pH 3-4 (cooling with an ice bath), the reaction mixture is extracted four times with methyl tert-butyl ether (500 ml each). The combined organic extracts are washed with water and brine and dried over sodium sulfate. After filtering off the drying agent, the solvent is rotary evaporated and the residue is chromatographed repeatedly

201 silica gel (mobile phase: methyl tert-butyl ether / hexane). 25.59 g (79.02%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl3): δ: = 1.26 (6H), 3.42 (1H), 3.85 (3H), 3.96 (3H), 7.15 (1H), 7, 43 (1H), 7.65 (1H).

2- (3-Isopropyl-2-methoxyphenyl) propan-2-ol

25.59 g (142.81 mmol) of methyl 3-isopropyl-2-methoxybenzoate are dissolved in 250 ml of tetrahydrofuran and added dropwise to 114.25 ml (342.74 mmol) of methyl magnesium bromide (3M in diethyl ether). The temperature rises to 46 ° C. After stirring for three hours at room temperature, 625 ml of saturated ammonium chloride solution are added dropwise to the reaction mixture. After extraction three times with methyl tert-butyl ether, the combined organic extracts are washed with water and brine and dried (sodium sulfate). The drying agent is filtered off, the solvent is rotary evaporated and the residue (28.16 g = 95.15%) is used as crude in the next step.

¹H-NMR (300 MHz, CDCl3): δ = 1.25 (6H), 1.63 (6H), 3.31 (1H), 3.90 (3H), 4.78 (1H), 7.00 -7.23 (3H).

Ethyl 4- (3-Isopropyl-2-methoxyphenyl) -4-methyl-2-oxopentanoate

15.3 ml (129.71 mmol) of tin tetrachloride are added dropwise to a mixture of 28.16 g (135.19 mmol) of 2- (3-isopropyl-2-methoxyphenyl) propan-2-ol cooled to -72 ° C. 50.9 g (270.38 mmol) of 2-trimethylsilanyloxy acrylic acid ethyl ester in 420 ml of dichloromethane. The temperature rises to -65 ° C. After stirring for 30 minutes in this temperature range, the reaction mixture is poured onto a mixture of saturated sodium carbonate solution and dichloromethane (250 ml each). After stirring for 30 minutes at room temperature, the mixture is transferred to a separatory funnel and a water-dichloromethane mixture (1: 1) is added until phase separation occurs. After shaking the phase

202 organic with sodium carbonate, 1N HCl and water, dried with sodium sulfate. According to a typical procedure, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 20.44 g (48.35%) of the desired compound are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 1.15-1.34 (9H), 3.28 (1H),

3.38 (2H), 3.78 (3H), 4.09-4.21 (2H), 7.05 (1H), 7.107.19 (2H).

Ethyl 2-hydroxy-4- (3-isopropyl-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentanoate 11.82 g (38.58 mmol) 4- (3-isopropyl-2-methoxyphenyl) 4- ethyl methyl-2-oxopentanoate and 6.58 g (46.29 mmol) (trifluoromethyl) trimethylsilane are dissolved in 70 ml tetrahydrofuran and 50 mg tetrabutylammonium fluoride trihydrate (slight increase in temperature) added. Because after three hours the reaction was still not complete, the same amount of tetrabutylammonium fluoride trihydrate was added once more. After stirring overnight, 12.17 g of tetrabutylammonium fluoride trihydrate were added to break down the silyl ether formed and thereby obtain the hydroxyl. The reaction mixture with tert-butyl methyl ether and the organic extract are washed with water and brine. After drying (sodium sulfate), filtration of the drying agent and filtration of the solvent, the residue is repeatedly chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 11.04 g (76%) of the desired compound is isolated.

the free compound is diluted ¹H-NMR (300 MHz, CDCl3 δ = 1.13-1.32

9H)

1.48 (6H), 2.48 3.65-3.78 (1H)

1H)

2.72 (1H), 3.32 (1H), 3.57

3.85 (3H)

4.08-4.20 (1H)

2H)

7.18 (1H)

4- (3-Isopropyl-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentane-1,2-diol

1.40 (1H),

6,96-7,09

203

11.04 g (29.33 mmol) of the ester described in the previous paragraph are dissolved in 90 ml of diethyl ether and 2.23 g (58.66 mmol) of lithium aluminum hydride are added in portions at 2 ° C. After stirring overnight at room temperature, 50 ml of saturated sodium bicarbonate solution is carefully added dropwise while cooling in an ice bath. After vigorous stirring at room temperature for one hour, it is extracted three times with methyl tert-butyl ether. The combined organic extracts are treated as usual and the residue obtained after rotary evaporation of the solvent is chromatographed on silica gel (mobile phase:

<td colspan="2">ethyl acetate / hexane).</td><td>extracts</td><td>himself</td><td> 7,15</td><td>^g</td><td> (72,9%)</td>

<td>desired diol. ¹H-NMR (300 MHz,</td><td>CDCl3)</td><td>: δ = 1.25</td><td>(3H);</td><td> 1,29</td><td>(3H</td><td> ), 1,50</td>

<td>(3H), 1.58 (3H),</td><td> 1,80</td><td>(1H), 2.23</td><td>(1H),</td><td> 2,61</td><td>(1 H</td><td> ), 2,83</td>

<td>(IH), 3.23-3.49</td><td>(3H);</td><td>3.89 (3H),</td><td> 7,09</td><td>(1H),</td><td> 7,</td><td> 17-7,26</td>

(2H).

2-Hydroxy-4- (3-isopropyl-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentanal

3.17 g (25.04 mmol) of oxalyl chloride are placed in 83 ml of dichloromethane and dimethyl sulfoxide is added dropwise, cooled to 3.9 g of dissolved

78 ° C. In this (50.08 mmol) in 10 ml of dichloromethane. After mixing for five minutes, add

7.15 g (21.38 mmol) 4- (3-isopropyl-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentane-1,2-diol, dissolved in 21.4 ml of dichloromethane. The reaction mixture is then stirred for two hours at this low temperature. 10.8 g (106.9 mmol) of triethylamine are carefully added dropwise and then the mixture is stirred vigorously for one hour. After adding water for 10 minutes, stir in with dichloromethane. The combined are washed with 1% sulfuric acid, saturated sodium bicarbonate solution and brine. After drying and extracts twice, the temperature is further extracted with organic

204 rotary evaporation of the solvent, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). Is finally obtained

5.93 g (83.44%) of the desired aldehyde.

¹H-NMR (300 MHz, CDCl3): δ = 1.20 (3H), 1.32 (3H), 1.401.54 (6H), 2.22 (1H), 3.30 (1H), 3.40 (1H), 3.59 (1H), 3.83 (3H), 6.95-7.07 (2H), 7.20 (1H), 8.91 (1H).

5- [2-hydroxy-4- (3-isopropyl-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentylidenoamino] -2H-1-one

147.3 mg (0.443 mmol) of the aldehyde described in the previous paragraph are stirred overnight at room temperature with 71 mg (0.443 mmol) of 5-amino-2H-isoquinolin-1-one in 1.3 ml of glacial acetic acid. The reaction mixture is concentrated three times with toluene and the residue is chromatographed on Flashmaster. 157 mg (75%) of the desired imine is isolated.

¹H-NMR (300 MHz, DMSO-d6): δ = 0.93 (3H), 1.19 (3H),

1.43 (3H), 1.55 (3H), 2.18 (1H), 3.18 (1H), 3.29 (1H, half underwater with DMSO), 3.75 (3H), 6, 19 (1H), 6.33 (1H), 6.63 (1H), 6.77 (1H), 6.89-6.99 (2H), 7.16-7.32 (3H), 8, 03 (1H), 11.33 (1H).

5- (2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -2H-isoquinolin-1-one

157 mg of imine (0.331 mmol) is dissolved in 2.5 ml of dichloromethane and 0.95 ml (0.993 mmol) of titanium (IV) chloride are added dropwise at 0 ° C. After stirring for one hour at 0 ° C, saturated sodium bicarbonate solution is added dropwise to the reaction mixture and diluted with ethyl acetate. The cooling bath is removed and the mixture is stirred vigorously for 30 minutes at room temperature. After extracting twice with ethyl acetate, the organic extracts are treated as usual. After chromatography of the residue

205 108 mg (68.98%) of the desired cyclic compound is obtained as a racemate on a Flashmaster.

<td>¹H-NMR</td><td> (300</td><td>MHz,</td><td>CD 3 OD)</td><td>: δ = 1.10-</td><td> 1,30</td><td>(6H),</td><td> 1,55 (</td><td>3H);</td>

<td> 1,70 (</td><td>3H);</td><td> 2,13</td><td>(2H),</td><td>3.39 (1H,</td><td>under</td><td>signal</td><td>em CH</td><td>3OH)</td>

<td> 3,80 (</td><td>3H);</td><td> 5,19</td><td>(1H),</td><td>6.86 (1H),</td><td> 6,99</td><td> -7,20</td><td>(4H)</td><td> 7,39</td>

<td>(1H),</td><td> 7,70</td><td>(1H).</td><td></td><td></td><td></td><td></td><td></td><td></td>

5- (2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -2H-isoquinolin-1-one

To 70 mg (0.147 mmol) of the cyclic ether described above is added at room temperature

1.5 ml of a 1 M solution of boron tribromide in dichloromethane and stirred for five hours at room temperature. Pieces of ice are added to the reaction mixture.

Saturated sodium bicarbonate solution is carefully added dropwise to pH 8. After dilution with ethyl acetate, the mixture is vigorously stirred. After extraction with ethyl acetate twice, the combined organic extracts are washed with water and brine and dried (sodium sulfate).

After filtration and rotary evaporation of the solvent, the residue obtained is chromatographed on silica gel (mobile phase: methanol / dichloromethane). 43.2 mg (63.6%) of the desired compound is isolated.

<td>¹H-NMR (300</td><td>MHz,</td><td>DMSO</td><td>d6):</td><td>δ =</td><td> 0,96-</td><td> 1,20</td><td>(6H),</td><td> 1,52</td>

<td>(3H), 1.68</td><td>(3H);</td><td> 1,90-</td><td> 2,11</td><td>(2H),</td><td> 3,30</td><td>(1H,</td><td>half</td><td>under</td>

<td colspan="2">water signal),</td><td> 5,29 (</td><td>1H),</td><td> 5,91</td><td>(1H),</td><td> 6,00</td><td>(1H),</td><td> 6,70</td>

<td>(1H), 6.81</td><td>(1H),</td><td> 6,97</td><td>(1H),</td><td> 7,05</td><td>(1H),</td><td> 7,17</td><td>(1H),</td><td> 7,25</td>

<td>(1H), 7.49 (</td><td>1H),</td><td> 8,09 (</td><td>1H),</td><td> 11,20</td><td>(1H).</td><td></td><td></td><td></td>

Example 163

5- (2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1H-quinolin-2-one

5- [2-Hydroxy-4- (3-isopropyl-2-methoxyphenyl) -4metylo- (trifluoromethyl) -pentylidenoamino] -1H-quinolin-2-one

206

300 mg (0.903 mmol) described in Example 162 2-hydroxy-4- (3-isopropyl-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentanal is reacted as described in the previous Example with 5-amino-1H-quinolin-

<td>2-he and surrenders</td><td>treatment.</td><td colspan="4">After chromatography</td>

<td>on Flashmaster</td><td>extracts</td><td>himself</td><td>372 mg</td><td> (86,</td><td>91%) desired</td>

<td>imine.</td><td></td><td></td><td></td><td></td><td></td>

<td>¹H-NMR (300 MHz,</td><td>DMSO-d6):</td><td>δ =</td><td> 0,90 (</td><td>3H);</td><td>1.18 (3H),</td>

<td>1.40 (3H), 1.54</td><td>(3H), 2.15</td><td>(1H)</td><td> , 3,15</td><td>(1H)</td><td>, 3.29 (1H,</td>

<td>half under water</td><td>from DMSO),</td><td> 3,75</td><td>(3H);</td><td> 5,90</td><td>(1H), 6.20</td>

<td>(1H), 6.53 (1H),</td><td>6.64 (1H),</td><td colspan="2"> 6,85-6,98</td><td>(2H)</td><td>, 7.13 (1H),</td>

<td>7.22-7.36 (2H), 8</td><td>, 09 (1H),</td><td> 11,77</td><td>(1H).</td><td></td><td></td>

5- (2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydro-naphthalen-1yloamino) -1H-quinolin-2-one

120 mg (0.253 mmol) of the described imine, as described in Example 162, is cyclized using titanium (IV) chloride in dichloromethane. After working up and chromatography, 64.3 mg (53.6%) of the desired cyclic compound are obtained.

¹H-NMR (300 MHz, CDCl3): δ = 1.10-1.30 (6H), 1.58 (3H),

1.71 (3H), 2.00-2.20 (2H), 3.31 (1H), 3.80 (3H), 4.01 (1H), 5.09 (1H), 5.25 ( 1H), 6.50-6.70 (3H), 7.00-7.12 (2H), 7.35 (1H), 8.01 (1H}, 10.78 (1H).

5- (2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1yloamino) -1H-quinolin-2-one

114 mg (0.240 mmol) of the described imine is cooled to 20 ° C and 2.4 ml of a 1 M solution of boron tribromide in dichloromethane are added. It is first stirred for two hours at -20 ° C to 0 ° C and then for 30 minutes at room temperature. Saturated sodium bicarbonate solution is added dropwise to the reaction mixture at -20 ° C to pH 8. The cooling bath is removed and the mixture is vigorously stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the combined extracts

207 organic shakes as usual. After rotary evaporation of the solvent, 48 mg of a mixture consisting of cyclic ether and cyclic phenol are obtained. To obtain a homogeneous compound with split ether, the mixture is treated once more with 1.2 ml of boron tribromide solution, but this time at room temperature (three and a half hours of stirring). According to the typical treatment already described, after chromatography on silica gel, 52.6 mg (92.9%) of the desired compound are obtained.

¹H-NMR (300 MHz, CD3OD): δ = 1.10-1.30 (6H), 1.60 (3H),

1.72 (3H), 2.00-2.20 (2H), 3.25 (1H), 5.15 (1H), 6.51 (1H), 6.63 (1H), 6.70 ( 1H), 6.88 (1H), 7.01 (1H), 7.39 (1H), 8.24 (1H).

Example 164

5- (7-Fluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

1,1,1-Trifluoro-2 - [(7-fluoro-2-methylquinazolin-5yloimino) -methyl] -4- (3-isopropyl-2-methoxy-phenyl) -4-methyl-pentan-2-ol

150 mg (0.451 mmol) of the aldehyde described in Example 162 of 79.9 mg (0.451 mmol) of 7-fluoro-2-methylquinazolin-5-ylamine in xylene with the help of titanium (IV) isopropylate is converted into imine. After typical work-up, 207.8 mg (93.6%) of the desired compound are obtained.

<td>¹H-NMR</td><td> (300</td><td>MHz,</td><td>CDCl3)</td><td>: δ =</td><td> 0,83</td><td>(3H), 1.20 (</td><td>3H);</td><td> 1,</td><td> 41</td>

<td>(3H);</td><td> 1,62</td><td>(3H);</td><td> 2,25</td><td>(1H)</td><td> , 2,90</td><td>(3H), 3.20</td><td>(1H)</td><td> ,3,</td><td> 68</td>

<td>(1H),</td><td> 3,83</td><td>(3H);</td><td> 4,61 (</td><td>1H),</td><td> 5,95</td><td>(1H), 6.54 (</td><td>1H),</td><td> 6,</td><td> 80</td>

<td>(1H),</td><td> 6,99</td><td>(1H),</td><td> 7,30-7</td><td> ,42</td><td>(2H), 9</td><td>, 30 (1H).</td><td></td><td></td><td></td>

1- (7-Fluoro-2-methylquinazolin-5-ylamino) -6izopropylo-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2-ol

207.8 mg (0.422 mmol) of the imine described in the previous paragraph is cyclized with 1.26 ml of titanium (IV) chloride in

208 dichloromethane. After completing the method described in

Example 162 isolates 194.4 mg (93.5%) of the desired compound.

¹H-NMR (300 MHz, CDCl3): δ = 1.10-1.30 (6H), 1.60 (3H),

1.75 (3H), 2.10-2.28 (2H), 2.87 (3H), 3.33 (1H), 3.80 (3H), 4.99 (1H), 6.09 ( 1H), 6.20 (1H), 6.54 (1H), 6.90 (1H), 7.06-7.19 (2H), 9.20 (1H).

(-) 1- (7-Fluoro-2-methylquinazolin-5-ylamino) -6isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2-ol ( +) - 1- (7-Fluoro-2-methylquinazolin-5-ylamino) -6isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2-ol mg the racemic compound at the ether stage is separated on a chiral column to obtain both enantiomers. 36 mg (-) - enantiomer and 32 mg (+) - enantiomer are isolated.

(-) -Enanc j omer: [a]_D = -34.4 ° (c = 1, CH₃OH); (+) enantiomer: [a]_D = +31.770 (c = 1, CH₃OH)

5- (7-Fluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

100 mg (0.203 mmol) 1- (7-fluoro-2-methylquinazolin-5-ylamino} -6-isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2- diol is treated, as has been repeatedly described, with BBr3 in dichloromethane, after working up and chromatography giving 18.5 mg (19.1%) of the desired phenol.

¹H-NMR (300 MHz, CD3OD): δ = 1.05-1.30 (6H), 1.65 (3H),

1.74 (3H), 2.28 (2H), 2.79 (3H), 3.27 (1H), 5.30 (1H), 6.66-6.90 (2H), 6.93- 7.17 (2H), 9.55 (1H).

(-) - 5- (7-Fluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

209 (+) - 5- (7-Fluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

The above-described are carried out enantiomerically pure enantiomerically as described for the phenol racemate.

24.7 mg enantiomer), 10.4 mg (43.5) of phenol ether are obtained.

mg phenol ether.

+) - enantiomer) 5.1 mg pure ((-) ethers 26.7 are isolated

19,6%)

Example 165

5- (7,8-difluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

1,1,1-Trifluoro-2 - [(7,8-difluoro-2-methylquinazolin-5yloimino) -methyl] -4- (3-isopropyl-2-methoxyphenyl) -4-methyl-pentan-2-ol

150 mg (0.451 mmol) of the aldehyde described in Example 162 of 88 mg (0.451 mmol) of 7,8-difluoro-2-methylquinazolin-5-ylamine in xylene with the help of titanium (IV) isopropylate is converted into imine. After typical work-up, 208.6 mg (90.7%) of the desired compound are obtained.

<td>¹H-NMR</td><td> (300</td><td>MHz,</td><td>CDCl.sub.3</td><td>): δ =</td><td> 0,90</td><td>(3H);</td><td> 1,23</td><td>(3H);</td><td> 1,</td><td> 43</td>

<td>(3H);</td><td> 1,63</td><td>(3H);</td><td> 2,23</td><td>(1H),</td><td> 2,98</td><td>(3H);</td><td> 3,22</td><td>(1H),</td><td> 3,</td><td> 69</td>

<td>(1H),</td><td> 3,83</td><td colspan="2">(3H) ,, 58 (</td><td>1H),</td><td> 5,99</td><td>(1H),</td><td> 6,58</td><td>(1H),</td><td> 6,</td><td> 88</td>

<td>(1H),</td><td> 6,99</td><td>(1H),</td><td> 7,39</td><td>(1H),</td><td> 9,39 (</td><td>1H).</td><td></td><td></td><td></td><td></td>

1- (7,8-difluoro-2-methylquinazolin-5-ylamino-6-isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl] 1,2,3,4-tetrahydronaphthalen-2-ol

208.6 mg (0.409 mmol) of the imine described in the previous paragraph is cyclized with 1.23 ml of titanium (IV) chloride in dichloromethane. After performing the method described in Example 162, 198 mg (95.9%) of the desired compound is isolated.

210 ¹H-NMR (300 MHz, CDCl3): δ

1.76 (3H), 2.09-2.25 (2H), (3H), 4.94 (1H), 5.40 (1H),

7.19 (2H), 9.27 (1H).

1,10-1,30

2.91 (3H), 5.82 (1H), (H), 1.63 (3H), 3.32 (1H), 3.80

6.58 (1H), 7.03 (-) - 1- (7,8-Difluoro-2-methylquinazolin-5-ylamino) -6isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1 , 2,3,4-tetrahydronaphthalen-2-ol (+) - 1- (7,8-Difluoro-2-methylquinazolin-5-ylamino) -6isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl ) 1,2,3,4-tetrahydronaphthalen-2-ol mg of the racemic compound at the ether stage is separated on a chiral column to obtain both enantiomers. 38.1 mg of the (-) enantiomer i are obtained

35.5 mg (+) - enantiomer.

(-) - Enantiomer: [a] D = -38.5 ° (c = 1, CH₃OH); (+) enantiomer: [a]_D = +370 (c = 1, CH₃OH)

5- (7,8-difluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

100 mg (0.196 mmol) 1- (7,8-difluoro-2-methylquinazolin-5-ylamino) -6-isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene- 2-ol, as already described many times, is treated with BBr3 in dichloromethane. After working up and chromatography, 33 mg (33.9%) of the desired phenol are obtained.

¹H-NMR (300 MHz, CD3OD): δ = 1.05-1.30 (6H), 1.63 (3H),

1.74 (3H), 2.12 (2H), 2.83 (3H), 3.26 (1H), 5.38 (1H), 6.73-6.90 (2H), 7.03 ( 1H), 9.59 (1H).

(-) - 5- (7,8-Difluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol ( +) - 5- (7,8-difluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

211

The above-described are carried out enantiomerically pure enantiomerically as described for the phenol racemate. From 29.7 mg of enantiomer), 6.6 mg (22.9%) of ether ((+) - enantiomer) is obtained, isolating (40.6%) of phenol.

Pure (-) phenol ether from 27.1 to 10.7 mg

Example 166

5- (8-Fluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8tetrahydronaftaleno-1,6-diol

1,1,1-Trifluoro-2 - [(8-fluoro-2-methylquinazolin-5yloimino) -methyl] -4- (3-isopropyl-2-methoxy-phenyl) -4-methyl-pentan-2-ol

150 mg (0.451 mmol) of the aldehyde described in Example 162 of 79.9 mg (0.451 mmol) of 8-fluoro-2-methylquinazolin-5-ylamine in xylene with the help of titanium (IV) isopropylate is converted into imine. After typical work-up, 176 mg (79.3%) of the desired compound are obtained.

<td>¹H-NMR</td><td> (300</td><td>MHz, CDCl3</td><td>): δ</td><td> = 0,</td><td> 82 (</td><td>3H), 1.20</td><td>(3H);</td><td> 1,</td><td> 45</td>

<td>(3H);</td><td> 1,62</td><td>(3H), 2.25</td><td>(1H)</td><td> , 3,</td><td> 00 (</td><td>3H), 3.20</td><td>(1H),</td><td> 3,</td><td> 63</td>

<td>(1H),</td><td> 3,83</td><td>(3H), 4.69</td><td>(1H)</td><td> , 6,</td><td> 20 (</td><td>1H), 6.47</td><td>(1H),</td><td> 6,</td><td> 70</td>

<td>(1H),</td><td> 6,98</td><td>(1H), 7.28-</td><td> 7,40</td><td>(2H)</td><td> , 9,</td><td>48 (1H).</td><td></td><td></td><td></td>

1- (8-Fluoro-2-methylquinazolin-5-ylamino) -6izopropylo-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) 1,2,3,4-tetrahydronaphthalen-2-ol

176 mg (0.358 mmol) of the imine described in the previous paragraph is cyclized with 1.1 ml of titanium (IV) chloride in dichloromethane. 147.3 mg (83.6%) of the desired compound are isolated after the work-up and chromatography carried out in Example 162.

¹H-NMR (300 MHz, CDCl3): δ = 1.10-1.35 (6H), 1.60 (3H),

1.75 (3H), 2.05-2.25 (2H), 2.93 (3H), 3.33 (1H), 3.80 (3H), 4.88 (1H), 5.02 ( 1H), 5.52 (1H); 6.70 (1H), 7.007.18 (2H), 7.49 (1H), 9.35 (1H).

212

5- (8-Fluoro-2-methylquinazolin-5-ylamino) -2-isopropyl-8,8-dimethyl-6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol mg (0.102 mmol) 1- (8-fluoro-2-methylquinazolin-5-ylamino) -6-isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol, as already described many times, BBr3 is treated in dichloromethane. After working up and chromatography, 13.7 mg (26.2%) of the desired phenol are obtained.

¹H-NMR (300 MHz, CD3OD): δ = 1.05-1.30 (6H), 1.65 (3H),

1.76 (3H), 2.00-2.20 (2H), 2.88 (3H), 3.27 (1H), 5.25 (1H), 6.77-6.94 (2H), 7.00 (1H), 7.59 (1H), 9.68 (1H).

Example 167

4- (2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydro-naphthalen-1yloamino) -1,3-dihydro-indol-2-one

4- [2-Hydroxy-4- (3-isopropyl-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentylidenoamino] -1,3dihydro-indol-2-one

250 mg (0.903 mmol) described in Example 162 2-hydroxy-4- (3-isopropyl-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentanal as described in the previous Example is reacted with 4-amino-1,3- dihydroindol-2-one and treats. After chromatography, 334.9 mg (92.2%) of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl3): δ = 0.99 (3H), 1.25 (3H), 1.46 (3H), 1.54 (3H), 2.20 (1H), 3.27 (1H), 3.42 (2H), 3.49 (1H), 3.84 (3H), 4.79 (1H), 5.90 (1H), 6.68-6.82 (2H),

6.90-7.09 (3H), 8.28 (1H).

4- (2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydro-naphthalen-1yloamino) -1,3-dihydro-indol-2 -he

230 mg (0.497 mmol) of the described imine is cyclized using titanium (IV) chloride in dichloromethane as described

213 in Example 162. After workup and chromatography, 208.3 mg (90.5%) of the desired cyclized compound are obtained.

¹H-NMR (300 MHz, CD3OD): δ = 1.10-1.30 (6H), 1.51 (3H),

1.66 (3H), 1.96-2.16 (2H), 3.38 (3H, under the methanol signal), 3.79 (3H), 5.03 (1H), 6.33 (1H), 6.49 (1H),

7.00-7.20 (3H).

4- (2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-ylamino) -1,3-dihydro-indol-2-one mg ( 0.108 mmol) of the ether described is treated with a solution of BBr3 in dichloromethane. 35.6 mg (73.4%) of the desired compound are obtained after the previously described work-up and chromatography.

¹H-NMR (300 MHz, CD3OD): δ = 1.10-1.30 (6H), 1.61 (3H),

1.70 (3H), 1.95-2.18 (2H), 3.27 (1H), 3.38 (2H, under the methanol signal), 5.01 (1H), 6.33 (1H), 6.49 (1H),

6.89 (1H), 6.95-7.15 (2H).

The following compounds are synthesized in an analogous manner from the corresponding aldehydes and amines.

Example 168 cis-6-Chloro-1 - [(7,8-difluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-5-methoxy-2- (trifluoromethyl) -

<td colspan="5">1,2,3,4-tetrahydronaphthalen-2-ol</td>

<td>¹H-NMR</td><td>(300 MHz, CDCl3); δ =</td><td> 1,</td><td>58 (s,</td><td>3H), 1.72 (s, 3H),</td>

<td> 2,14 (</td><td>d, 1H), 2.22 (d, 1H),</td><td> 2,</td><td>92 (s,</td><td>3H), 3.97 (s, 3H),</td>

<td> 4,91 (</td><td>d, 1H), 5.83 (d, 1H)</td><td>^,</td><td> 6,55 (</td><td>dd, 1H), 7.03 (d,</td>

<td>1H), 7</td><td>, 23 (d, 1H), 9.24 (s,</td><td>1H</td><td> ).</td><td></td>

Example 169 cis-1 - [(8-Fluoro-2-methylquinazolin-5-yl) amino] -7-methoxy-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol ¹H-NMR (300 MHz, CDCl3): δ = 2.24-2.34 (m, 2H), 2.86 (ddd, 1H), 2.91 (s, 3H), 3.12 (ddd, 1H ), 3.63 (s, 3H), 5.00 (d, 1H), 5.47 (d, 1H), 6.75 (dd, 1H), 6.79 (d,

214

1H), 6.84 (s, 1H), 7.11 (d, 1H), 7.49 (dd, 1H), 9.35 (s, 1H).

Example 170 cis-6-Chloro-1 - [(7,8-difluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5 propanediol ¹H-NMR (300 MHz, CD3OD); δ = 1.60 (s, 3H), 1.72 (s, 3H),

2.16 (s, 2H), 2.84 (s, 3H), 5.30 (s, 1H), 6.84 (d, 1H),

6.86 (dd, 1H), 7.17 (d, 1H), 9.60 (s, 1H).

Example 171 cis-1 - [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] -6fluoro-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5 propanediol ¹H-NMR (300 MHz, CD3OD); δ = 1.61 (s, 3H), 1.72 (s, 3H), 2.14 (s, 2H), 2.84 (s, 3H), 3.98 (s, 3H), 5.27 (s, 1H), 6.76-6.94 (m, 3H), 9.59 (S, 1H).

Example 172 cis-1 - [(8-Fluoro-2-methylquinazolin-5-yl) amino] -2 (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,7-diol ¹H-NMR (300 MHz, CD3OD); δ = 2.16-2.35 (m, 2H), 2.81 (ddd, 1H), 2.85 (s, 3H), 3.08 (ddd, 1H), 5.24 (s, 1H) .

6.67 (dd, 1H), 6.78 (d, 1H), 6.89 (dd, 1H), 7.02 (d,

1H), 7.59 (dd, 1H), 9.67 (s, 1H).

Example 173

2-Hydroxy-3- (1-phenylcyclohexyl) -2- (trifluoromethyl) propanal

12.6 g (45.9 mmol) of ethyl 2-oxo-3- (1-phenylcyclohexyl) propionate and WO9854159 and 19.9 ml (138 mmol) (trifluoromethyl) trimethylsilane in 215 ml THF is cooled to -70 ° C and 8.6 ml of a 1 molar solution of tetrabutylammonium fluoride in THF is added. The reaction mixture is allowed to warm to room temperature for 18 hours and then poured onto a saturated sodium chloride solution. Extracted many times

215 ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After chromatographic purification on silica gel (hexane / ethyl acetate 20%) is obtained

13.1 g of ethyl 2-hydroxy-3- (1-phenylcyclohexyl) -2 (trifluoromethyl) propionate as a yellow oil. To 13.1 g (38.1 mmol) of ester in 174 ml of THF at 0 ° C a solution of 3.33 g (87.7 mmol) of lithium aluminum hydride in 173 ml of THF is added dropwise and stirred for 16 hours at room temperature. To the mixture at 0 ° C, 20 ml of saturated ammonium chloride solution are carefully added and then stirred vigorously for 15 minutes. It is extracted several times with ethyl acetate, washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 0% -33%) gives 6.1 g of 3- (1-phenyl) cyclohexyl) -2- (trifluoromethyl) propane-1,2-diol.

To 6.1 g (20.2 mmol) diol in 245 ml dichloromethane and 79 ml DMSO are added 15.7 ml (113 mmol) triethylamine and 13.8 g (87 mmol) pyridine-SO3 complex in portions for 10 min. It is stirred for 3 hours and a saturated solution of ammonium chloride is added. The mixture is stirred for a further 15 min, the phases are separated and extracted with dichloromethane. It is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure and the chromatographic purification on silica gel (hexane / ethyl acetate, 0-33%) gives the desired product quantitatively.

¹H-NMR (CDCl3): δ = 1.17 -1.78 (m, 9H), 1.98-2.05 (m, 1H), 2.41 (d, 1H), 3.46 (d, 1H), 3.66 (s, 1H), 7.18 (d, 2H), 7.24 (t, 2H), 7.31 (d, 1H), 8.55 (s, 1H).

cis-4 '- [(8-Fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-3 '- (trifluoromethyl) spiro [cykloheksano1,1' (2 'H) -naphthalene) -3'-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.25-1.85 (m, 9H), 1.97 (d, 1H), 2.11 (d, 1H), 2.68 (d, 1H), 2.91 (s, 3H) ), 5.08

216

<td>(D,</td><td>1H),</td><td> 5,38</td><td>(D,</td><td>1H)</td>

<td> 7,34</td><td>(D,</td><td>1H),</td><td> 7,35</td><td>(t</td>

<td>1H),</td><td> 9,36</td><td>(S,</td><td>1H).</td><td></td>

6.69 (dd, 1H), 7.18 (t, 1H), 1H), 7.47 (dd, 1H), 7.56 (d,

Example 174 cis-4 '- [7,8-Difluoro-2-methylquinazolin-5-yl) amino] 3,4'-dihydro-3' - (trifluoromethyl) spiro [cyclohexane1,1 '(2'H) - naphthalen] -3'-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.25-1.90 (m, 9H), 1.93 (d, 1H), 2.02 (d, 1H), 2.64 (d, 1H), 2.89 (s, 3H) , 4.99 (d, 1H), 5.66 (d, 1H), 6.54 (dd, 1H), 7.18 (t, 1H), 7.29 (d, 1H), 7.36 ( t, 1H), 7.54 (d, 1H), 9.25 (s, 1H).

Example 175 cis-1 - [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] 4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalene-2,5-diol ¹H-NMR (300 MHz, CD3OD); δ = 1.58 (s, 3H), 1.70 (s, 3H),

2.13 (s, 2H), 2.84 (s, 3H), 5.28 (s, 1H), 6.71-6.87 (m, 3H), 6.99 (t, 1H), 9 , 59 (s, 1H).

Example 176 trans-1 - [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] 6-fluoro-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2, 5-diol ¹H-NMR (300 MHz, CDCl 3); δ = 1.40 (s, 3H), 1.54 (s, 3H), 2.05 (d, 1H), 2.19 (d, 1H), 2.76 (s, 3H), 3.57 (br, 1H), 4.62 (d, 1H), 5.27 (d, 1H), 6.54 (br, 1H), 6.906.97 (m, 2H), 7.07 (dd, 1H) , 9.10 (s, 1H).

Example 177 cis-5- {3 ', 4'-Dihydro-3'-hydroxy-3' - (trifluoromethyl) spiro [cyclohexane-1,1 '(2'H) -naphthalene-4'-yl] amino} quinoline -2 (1H) -one

<td>¹H-NMR (300 MHz, CD3OD); δ =</td><td> 0,91</td><td>(M,</td><td>1H), 1.12 (m, 3H),</td>

<td>1.89 (d, 1H), 2.44 (d, 1H),</td><td> 5,29</td><td>(S,</td><td>1H), 6.51 (d, 1H),</td>

<td>6.67 (d, 1H), 6.71 (d, 1H),</td><td> 6,79</td><td>(D,</td><td>1H), 7.09 (t, 1H),</td>

<td>7.21 (t, 1H), 7.24 (d, 1H),</td><td> 7,39</td><td>(T,</td><td>1H), 8.24 (d, 1H).</td>

217

Example 178 cis-4 '- [(8-Fluoro-2-methylquinazolin-5-yl) amino] -3,4'-dihydro-3' - (trifluoromethyl) -spiro [cyclopropane1,1 '(2'H) -naphthalene ] -3'-ol

<td>¹H</td><td>NMR</td><td> (300</td><td>MHz, CD</td><td>3 OD)</td><td>^;</td><td>δ</td><td> = 0,92-0,98 (</td><td>m, 1H), 1.13-</td>

<td> 1,</td><td> 19 (</td><td>m, 3H)</td><td> , 1,98 (</td><td>d</td><td>1H</td><td> ),</td><td>2.40 (d, 1H),</td><td>2.85 (s, 3H),</td>

<td> 5,</td><td> 36 (</td><td>s, 1H)</td><td> , 6,81 (</td><td>d</td><td>1H</td><td> ),</td><td>6.91 (dd, 1H)</td><td>, 7JO (t, 1H),</td>

<td> 7,</td><td> 23 (</td><td>t, 1H</td><td> ), 7,28</td><td>(d</td><td>^,</td><td>1H)</td><td>, 7.59 (dd,</td><td>1H), 9.68 (s,</td>

1H).

Example 179 cis-6-Chloro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol

4- (3-Chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2 (trifluoroethyl) -pentanal

To 1.0 g (3.35 mmol) of 4- (3-chloro-2-methoxyphenyl) -4-methyl-2-oxo-valerate and 0.96 (5.0 mmol) (pentafluoroethyl) trimethylsilane in 7 ml THF are added 62 mg (0.67 mmol) of tetramethylammonium fluoride at -40 ° C. The mixture is stirred at -25 ° C for 2 h, then 1 ml of 1 N hydrochloric acid is added to the reaction mixture and after 10 minutes poured onto water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. 1.44 g of ethyl 4- (3-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (pentafluoroethyl) valerate are obtained, in which

14.5 ml diethyl ether at 0 ° C is added 0.22 g (5.9 mmol) lithium aluminum hydride and stirred for 2 hours at room temperature. The mixture is poured onto ice water, and then stirred vigorously for 15 minutes, filtered through celite. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After cleaning

218 chromatography on silica gel (hexane / ethyl acetate 0% -20%), 0.77 g of 4- (3-chloro-2-methoxyphenyl) -2- (pentafluoroethyl) -4-methyl-propane-1,2-diol is obtained. To 0.46 g (1.22 mmol) diol in 9.5 ml dichloromethane and 2.5 ml DMSO 0.84 ml (6.1 mmol) triethylamine and 388 mg (2.44 mmol) pyridine-SO3 complex are added . A further 388 mg (2.44 mmol) of the pyridine SO3 complex is stirred and then dosed for 2 hours. After stirring for 1 hour, saturated ammonium chloride solution is added. The mixture is stirred for a further 15 min, the phases are separated and extracted with diethyl ether. It is washed with saturated ammonium chloride solution and dried

<td>over sodium sulfate. Solvent</td><td>removed</td><td>under</td>

<td>reduced pressure and after</td><td colspan="2">treatment</td>

<td colspan="2">chromatography on silica gel (hexane</td><td> /</td>

<td>ethyl acetate, 30%), 357 g are obtained</td><td>product.</td><td></td>

<td>¹H-NMR (CDCl3): δ = 1.43 (s, 3H), 1.48 (</td><td>s, 3H), 2.34</td><td>(D,</td>

<td>1H), 3.29 (d, 1H), 3.58 (s, 1H), 4.01</td><td>(s, 3H) 6.95</td><td>(T,</td>

<td>1H), 7.05 (dd, 1H), 7.30 (dd, 1H), 9.10</td><td>(s, 1H).</td><td></td>

cis-6-Chloro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (pentafluoretylo-1,2,3,4tetrahydronaftaleno-2,5-diol

<td>¹H-NMR</td><td>(300 MHz, CD3OD); δ = 1.61 (s,</td><td>3H);</td><td> 1,</td><td> 74</td><td>(s, 3H),</td>

<td> 2,14 (</td><td>d, 1H), 2.20 (d, 1H), 2.86 (s,</td><td>3H);</td><td> 5,</td><td> 34</td><td>(s, 1H),</td>

<td> 6,84 (</td><td>d, 1H), 6.86 (dd, 1H), 7.12</td><td>(D,</td><td>1H</td><td> ),</td><td>7.57 (dd,</td>

1H), 9.65 (s, 1H).

Example 180 cis-6-Chloro-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol ¹H-NMR (300 MHz, CDCl 3); δ = 1.58 (s, 3H), 1.72 (s, 3H),

2.17 (d, 1H), 2.26 (d, 1H), 2.84 (s, 3H), 3.95 (s, 3H), 5.05 (d, 1H), 6.07 ( d, 1H), 6.51 (dd, 1H), 6.91 (dd, 1H), 7.04 (d, 1H), 7.18 (d, 1H), 9.17 (s, 1H).

Example 181

219 trans-6-Chloro-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4tetrahydronaftaleno-2,5-diol

<td colspan="2">¹H-NMR (300 MHz, CD3OD); δ =</td><td> 1,45</td><td>(s, 3H)</td><td> , 1,61</td><td>(S,</td><td>3H);</td>

<td> 2,29</td><td>(d, 1H), 2.37 (d, 1H),</td><td> 2,74</td><td>(s, 3H)</td><td> , 3,65</td><td>(S,</td><td>3H);</td>

<td> 5,58</td><td>(s, 1H), 6.83 (dd, 1H)</td><td> , 6,</td><td>98 (dd,</td><td>1H),</td><td> 7,30</td><td>(Dd,</td>

1H), 7.42 (d, 1H), 9.52 (s, 1H).

Example 182 cis-5 - {[6-chloro-2-hydroxy-5-methoxy-4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 ( 1H) -one

<td>¹H-NMR (300 MHz, CDCl3)</td><td>; δ = 1,</td><td>55 (s,</td><td>3H);</td><td>1.72 (s,</td><td>3H);</td>

<td>2.07 (d, 1H), 2.20 (d,</td><td>1H), 3,</td><td>9B (s,</td><td>3H);</td><td>5.12 (d,</td><td>1H),</td>

<td>5.46 (br, 1H), 5.81</td><td>(d, 1H),</td><td>B, 44-</td><td> 6,53</td><td>(m, 3H),</td><td> 6,95</td>

<td>(d, 1H), 7.06 (d, 1H),</td><td>7.32 (vol</td><td>, 1H),</td><td> 8,28</td><td>(d, 1H),</td><td> 9,92</td>

(s, 1H).

Example 183 cis-5 - {[2,5-Dihydroxy-4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

<td>¹H-NMR (300 MHz, CDCl 3); δ =</td><td>1.58 (s,</td><td>3H), 1.76</td><td>(S,</td><td>3H);</td>

<td>2.08 (d, 1H), 2.24 (d, 1H),</td><td>2.63 (s,</td><td>1H), 5.11</td><td>(D,</td><td>1H),</td>

<td>5.54 (s, 1H), 5.85 (d, 1H),</td><td>5.97 (s,</td><td>1H), 6.42</td><td>(D,</td><td>1H),</td>

<td>6.49 (d, 1H), 6.49 (d, 1H)</td><td> , 6,52</td><td>(d, 1H), 7</td><td> ,00</td><td>(Dd,</td>

<td>1H), 7.31 (t, 1H), 8.31 (d,</td><td>1H) 9.77</td><td>(S, 1H).</td><td></td><td></td>

Example 184 cis-7'-Fluoro-4 '- [(8-fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-8'-methoxy-3 '(trifluoromethyl) -spiro [cyclohexane- 1,1 '(2'H) naphthalene] -3'-ol

3- [1- (3-Fluoro-2-methoxyphenyl) -cyclohexyl] -2-hydroxy-2- (trifluoromethyl) propanal

To 26.5 g (184 mmol) of 2,6-difluoroanisole and 24 ml (198 mmol) of cyclohexyl cyanide in 500 ml of toluene at 0 ° C

220 385 ml of a 0.5 molar (182 mmol) solution of bis- (trimethylsilyl)-potassium amide in toluene is added dropwise over 40 min. The mixture is stirred for 18 hours at room temperature under ice-cooling, water is added and the solution is adjusted to pH 4 using 4 N hydrochloric acid. The organic phase is separated and the aqueous phase is repeatedly extracted with diethyl ether. It is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 5% -10%) gives 28.5 g of 1- (3-fluoro-2-methoxyphenyl) cyclohexylnitrile. To 27.5 g (118 mmol) of nitrile in 430 ml of toluene at -78 ° C, 147 ml (176 mmol) of diisobutylaluminum solution (20% in toluene) is slowly added and after 3 h at -78 ° C ml isopropanol. It is allowed to warm to -5 ° C and 600 ml of a 10% aqueous tartaric acid solution are added. After dilution with ether, the mixture is stirred vigorously, the organic phase is separated off and the aqueous phase is repeatedly extracted with ethyl acetate. It is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. 27.5 g of aldehyde are obtained in the form of a yellow oil. To a solution of 5.7 g (21.2 mmol) of 2-diethylphosphono-2-ethoxyacetic acid ethyl ester in 25 ml of tetrahydrofuran under ice-cooling over 15 minutes is added 13.6 ml (27.2 mmol) of a 2 M solution of lithium diisopropylamide in tetrahydrofuran heptanietoluene and stirred at 0 ° C for 20 minutes. A solution of 5 g (21.2 mmol) of 1- (3-fluoro-2-methoxyphenyl) cyclohexylformanal in 5 ml of tetrahydrofuran is added dropwise at 0 ° C. over 30 minutes. After 16 hours at room temperature, ice water is added and extracted repeatedly with ether. It is washed with saturated ammonium chloride solution, dried over sodium sulfate and concentrated. The crude product is saponified with 6 g sodium hydroxide in 100 ml ethanol and 50 ml water for 4 days at room temperature. 1.7 g of acid are obtained, which is mixed with 35 ml of 2 N sulfuric acid and 7 ml for 30 hours

221 acetic acid at 90 ° C. After cooling, it is basified with potassium carbonate, washed with ether and acidified with hydrochloric acid. Extraction with ethyl acetate, washing with saturated sodium chloride solution and removal of the solvent gives 1.09 g of crude ketoacid. 1.09 g (3.7 mmol) of 3- [1- (3-fluoro-2-methoxyphenyl) cyclopropyl] -2-oxopropionic acid and 0.45 ml of sulfuric acid (96%) in 40 ml of ethanol for 2 hours, heated under reflux condenser. The mixture is concentrated under reduced pressure, the residue is added to ice water and basified with saturated sodium bicarbonate solution. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 20%) gives 1.05 g of ethyl 3- [1- (3-fluoro-2-methoxyphenyl) cyclopropyl] -2-oxopropionate. To 1.05 g (3.3 mmol) of ethyl 3- [1- (3-fluoro-2-methoxyphenyl) cyclohexyl] -2-oxopropionate and 0.74 ml (5 mmol) (trifluoromethyl) trimethylsilane in 7 ml THF are added at -40 ° C 62 mg tetramethylammonium fluoride. The mixture is stirred at -25 ° C for 2 hours and then 0.35 ml (2.4 mmol) (trifluoromethyl) trimethylsilane and 62 mg tetramethylammonium fluoride are added. After a further 2 hours, 1 ml of 2 N hydrochloric acid is added and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 10% -40%) gives 800 mg of ethyl 3- [1- (3-fluoro-2-methoxyphenyl) cyclopropyl] -2-hydroxy-2- (trifluoromethyl) propionate in yellow oil forms. To the oil in 40 ml of diethyl ether at 0 ° C is added 150 g (4 mmol) of lithium aluminum hydride and stirred for another 2.5 hours at room temperature. To the mixture at 0 ° C, 20 ml of saturated ammonium chloride solution are carefully added followed by 15 minutes

222 intensively mixed. It is extracted several times with diethyl ether, washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 10% -15%) gives 630 g of 3- [1- (3-fluoro-2-methoxyphenyl) cyclopropyl] -2- (trifluoromethyl) propane-1,2-diol.

¹H-NMR (CDCl3): δ = 1.44-1.87 (m, 10H), 2.19-2.38 (m, 4H), 3.15-3.42 (br, 2H), 3, 96 (s, 3H), 6.9 (ddd, 1H), 7.01 (d, 1H), 7.16 (ddd, 1H).

To 700 mg (2 mmol) diol in 20 ml dichloromethane and 7.8 ml DMSO is added 1.6 ml (11 mmol) triethylamine and 1.4 g (70 mmol) pyridine-SO3 complex in portions over 10 min. It is stirred for 3 hours and a saturated solution of ammonium chloride is added. The mixture is stirred for a further 15 min, the phases are separated and extracted with dichloromethane. It is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure to give the desired aldehyde quantitatively.

cis-7'-Fluoro-4 '- [(8-fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-8'-methoxy-3 '(trifluoromethyl) spiro [cyclohexane-1, 1 '(2'H) naphthalene] -3'-ol

<td>¹H-NMR (300 MHz</td><td>, CDCl</td><td> 3);</td><td>δ = 1.25-1,</td><td>85 (m,</td><td>8H)</td><td> , 2,00</td><td> (</td><td>d</td>

<td>1H), 2.44 (ddd,</td><td>1H),</td><td> 2,</td><td>64 (ddd, 1H)</td><td> , 2,91</td><td>(S,</td><td>3H);</td><td> 2,</td><td> 92</td>

<td>(d, 1H), 4.00 (</td><td>s, 3H)</td><td>^,</td><td>4.96 (d, 1H)</td><td> , 5,41</td><td>(D,</td><td>1H),</td><td> 6,</td><td> 66</td>

<td>(dd, 1H), 6.93</td><td>(Dd,</td><td>1H)</td><td>, 7.04 (dd,</td><td>1H), 7</td><td> ,47</td><td>(Dd,</td><td>1H</td><td> ),</td>

9.34 (s, 1 H).

Example 185 cis-7'-Fluoro-4 '- [(8-fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-3 '- (trifluoromethyl) spiro [cyclohexane-1,1' ( 2 'H) -naphthalene] -3', 8'-diol ¹H-NMR (300 MHz, CD3OD); δ = 1.22-1.85 (m. 8H), 2.03 (d, 1H), 2.82 (ddd, 1H), 2.85 (s, 3H), 2.91 (d, 1H) , 3,05

223 (ddd, 1H), 5.22 (s, 1H), 680-6.95 (m, 3H), 7.56 (dd,

1H), 9.65 (s, 1H).

Example 186 cis-7'-Fluoro-4 '- [(7-fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-8'-methoxy-3'trifluoromethyl) -spiro [cyclohexane-1 1 '(2'H) naphthalene] -3'-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.25-1.90 (m, 10H), 2.17 (d, 1H), 2.34 (d, 1H), 2.80 (s, 3H), 3.56 (s, 3H) , 4.59 (d, 1H), 5.33 (d, 1H), 6.91 (dd, 1H), 7.00 (dd, 1H),

7.10 (dd, 1H), 7.17 (dd, 1H), 9.03 (s, 1H).

Example 187 cis-5- {7'-Fluoro-3 ', 4'-dihydro-3'-hydroxy-8'-methoxy3' - (trifluoromethyl) -spiro [cyclohexane-1,1 '(2'H) naphthalene 4-yl] amino} quinolin-2 (1H) -one

<td>¹H-NMR (300 MHz, CDCl 3); δ</td><td> = 1,25-1,</td><td>90 (m,</td><td>8H)</td><td>, 2.09 (d,</td>

<td>1H), 2.41 (ddd, 1H), 2.60</td><td>(ddd, 1H)</td><td> , 2,90</td><td>(D,</td><td>1H), 3.99</td>

<td>(s, 3H), 4.85 (s, 1H),</td><td>5.00 (d,</td><td>1H),</td><td> 5,67</td><td>(d, 1H),</td>

<td>6.48-6.55 (m, 3H), 6.83</td><td>(dd, 1H),</td><td> 6,96</td><td>(Dd,</td><td>1H), 7.31</td>

(t, 1H), 8.22 (d, 1H), 9.79 (s, 1H).

Example 188 cis-6-Chloro-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol ¹H-NMR (300 MHz, CD3OD); δ = 1.61 (s, 3H), 1.74 (s, 3H),

2.18 (s, 2H), 2.79 (s, 3H), 5.42 (s, 1H), 6.76-6.82 (m,

3H), 7.15 (d, 1H), 9.54 (s, 1H).

Example 189 cis-6-Chloro-1- (2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol ¹H-NMR (300 MHz, CD3OD); δ = 1.61 (s, 3H), 1.74 (s, 3H),

2.18 (s, 2H), 2.82 (s, 3H), 5.40 (s, 1H), 6.84 (d, 1H),

224

6.95 (d, 1H), 7.10 (d, 1H), 7.20 (d, 1H), 7.79 (t, 1H),

9.62 (s, 1 H).

Example 190 cis-5- {7'-Chloro-3,4'-dihydro-3 ', 8'-dihydroxy-3' (trifluoromethyl) spiro [cyclohexane-1,1 '(2'H) naphthalene-4' yl] amino} quinolin-2 (1H) -one ¹H-NMR (300 MHz, CD3OD); δ = 1.25-1.90 (m, 8H), 2.02 (d, 1H), 2.80 (ddd, 1H), 2.91 (d, 1H), 3.05 (ddd, 1H) ; 5.12 (d, 1H), 5.51 (d, 1H), 6.59: (d, 1H), 6.69 (d, 1H), 6.81 (dd, 1H), 6.986 (dd, 1H), 7.37 (t, 1H), 8.23 ​​(d, 1H).

Example 191 cis-6-Fluoro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -5-methoxy-4,4-dimethyl-2- (pentafluoroethyl) 1,2,3,4-tetrahydronaphthalene- 2-ol

4- (3-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (pentafluoroethyl) pentanal

To 1.0 g (3.54 mmol) of ethyl 4- (3-fluoro-2-methoxyphenyl) -2-oxo-4-methyl valerate and 0.98 g (5.1 mmol) (pentafluoroethyl) trimethylsilane in 7 ml THF 65 mg (0.7 mmol) of tetramethylammonium fluoride are added at 40 ° C. The reaction mixture is warmed to -25 ° C and kept at this temperature. After 4.5 hours, 1 ml of 2 N hydrochloric acid is added and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. 1.65 g of ethyl 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (pentafluoroethyl) valerate are obtained as the crude product. To this ester in 80 ml of diethyl ether at 0 ° C is added 300 mg (8 mmol) of lithium aluminum hydride and stirring is continued for 3.5 hours at room temperature. Little water is carefully added to the mixture at 0 ° C and then stirred vigorously for 15 minutes, filtered through celite and

225

<td>next</td><td>exactly</td><td>washed</td><td>precipitate</td><td>ethyl acetate.</td>

<td>Filtrate</td><td>is drying</td><td>sulfate</td><td>sodium</td><td>and concentrates on</td>

<td>reduced</td><td colspan="2">pressure.</td><td>After</td><td>treatment</td>

chromatography on silica gel (hexane / ethyl acetate 10% -15%) gives 800 mg of 4- (3-fluoro-2-methoxyphenyl) -4-methyl-2- (pentafluoroethyl) pentane-1,2-diol. To 800 mg (2.2 mmol) diol in 25 ml dichloromethane and 8.9 ml DMSO is added 1.8 ml (13 mmol) triethylamine and 1.6 g (10 mmol) pyridine-SO3 complex in portions over 10 min. Mixed by through

2.5 hours and a saturated ammonium chloride solution is added. The mixture is stirred for a further 15 min, the phases are separated and extracted with dichloromethane. It is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure to give the desired aldehyde quantitatively.

¹H-NMR (CDCl3): δ = 1.40 (s, 3H), 1.46 (s, 3H), 2.35 (d, 1H), 3.28 (d, 1H), 3.60 (s , 1H), 4.02 (s, 3H), 6.86 (dd, 1H), 6.91 (ddd, 1H), 7.01 (ddd, 1H), 9.14 (s, 1H).

cis-6-Fluoro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -5-methoxy-4,4-dimethyl-2- (pentafluoroethyl) -

<td> 1,2,3,</td><td colspan="2">4-tetrahydronaphthalen-2-ol</td><td></td><td></td><td></td><td></td>

<td>¹H-NMR</td><td colspan="2">(300 MHz, CDCl3); δ = 1.55 (</td><td>s, 3H)</td><td> , 1,69 (</td><td>s</td><td>3H);</td>

<td> 2,13 (</td><td>d, 1H), 2.20</td><td>(d, 1H), 2.92 (</td><td>s, 3H)</td><td> , 3,97 (</td><td>s</td><td>3H);</td>

<td> 5,08 (</td><td>d, 1H), 5.41</td><td>(d, 1H), 6.70</td><td>(Dd,</td><td>1H), 6,</td><td> 90</td><td>(Dd,</td>

<td>1H), 7</td><td>, 00 (dd, 1H),</td><td>7.48 (dd, 1H),</td><td> 9,33</td><td>(s, 1H).</td><td></td><td></td>

Example 192 cis-1 - [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] -6-fluoro-5-methoxy-4,4-dimethyl-2- (pentafluoroethyl) 1,2,3,4- tetrahydronaphthalen-2-ol ¹H-NMR (300 MHz, CD3OD); δ = 1.55 (s, 3H), 1.68 (s, 3H),

2.14 (d, 1H), 2.21 (d, 1H), 2.84 (s, 3H), 3.97 (s, 3H), 5.39 (s, 1H), 6.88 (dd , 1H), 6.98 (dd, 1H), 7.03 (dd,

1H), 9.59 (s, 1H).

Example 193

226 cis-1 - [(7,8-difluoro-2-methylquinazolin-5-yl) amino] 4,4-dimethyl-6-fluoro-2- (pentafluoroethyl) -1,2,3,4tetrahydronaftaleno-2,5- diol

<td>¹H-NMR</td><td>(300 MHz, CDCl3); δ =</td><td> 1,</td><td> 61 (</td><td>s, 3H)</td><td> , 1,72</td><td>(S,</td><td>3H);</td>

<td> 2,15 (</td><td>d, 1H), 2.22 (d, 1H),</td><td> 2,</td><td> 91 (</td><td>s, 3H</td><td> ), 5,00</td><td>(D,</td><td>1H),</td>

<td> 5,61 (</td><td>br, 1H), 5.71 (d, 1H)</td><td>^,</td><td> 6,56</td><td>(Dd,</td><td>1H),</td><td> 6,83</td><td>(Dd,</td>

1H), 6.92 (dd, 1H), 9.24 (s, 1H).

Example 194 cis-5 - {[6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} -quinolin-2 ( 1H) -one

<td colspan="2">¹H-NMR (300</td><td>MHz</td><td>, CDCl3); δ = 1,</td><td>54 (s,</td><td>3H), 1.69 (s,</td><td>3H);</td>

<td> 2,07</td><td colspan="2">(d, 1H),</td><td>2.17 (d, 1H),</td><td> 3,97</td><td>(s, 3H), 4.58</td><td>(Br,</td>

<td>1H),</td><td> 5,10</td><td>(D,</td><td>1H), 5.45 (d,</td><td>1H),</td><td>6.52-6.56 (m,</td><td>3H);</td>

<td> 6,83</td><td>(Dd,</td><td>1H),</td><td>6.94 (dd, 1H),</td><td> 7,34</td><td>(t, 1H), 8.12</td><td>(D,</td>

<td>1H),</td><td> 10,11</td><td>(S,</td><td>1H).</td><td></td><td></td><td></td>

Example 195 cis-6-Fluoro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -4,4-dimethyl-2- (pentafluoroethyl) -1,2,3,4 tetrahydronaphthalene-2,5-diol

<td>¹H-NMR (300 MHz, CDCl 3); δ</td><td> = 1,61</td><td>(s, 3H)</td><td> , 1,72 (</td><td>s</td><td>3H);</td>

<td>2.15 (d, 1H), 2.23 (d, 1H</td><td> ), 2,92</td><td>(s, 3H)</td><td> , 5,08 (</td><td>d</td><td>1H),</td>

<td>5.38 (d, 1H), 5.64 (br,</td><td>1H), 6,</td><td>70 (dd,</td><td>1H), 6,</td><td> 85</td><td>(Dd,</td>

<td>1H), 6.90 (dd, 1H), 7.48 (</td><td>dd, 1H)</td><td> , 9,33</td><td>(s, 1H).</td><td></td><td></td>

Example 196 cis-4 '- [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] 7'-fluoro-3', 4'-dihydro-8'-methoxy-3 '(trifluoromethyl) spiro [cyclopropane-1,1 '(2'H) naphthalene] -3'-ol

Ethyl 3- {1- (3-Fluoro-2-methoxyphenyl) cyclopropyl] -2oxopropionate

To 26 g (180 mmol) 2,6-difluoroanisole and 14.6 ml (198 mmol) cyclopropyl cyanide in 500 ml toluene are added dropwise at 0 ° C for 40 min 396 ml 0.5 molar solution

227 (198 mmol) bis- (trimethylsilyl)-potassium amide in toluene. It is stirred for 18 h at room temperature and water and 1 M sulfuric acid are added under ice-cooling.

The organic phase is separated and the aqueous phase is repeatedly extracted with ethyl acetate. Wash with brine, dry over sodium sulfate and concentrate under reduced pressure. After chromatographic purification on hexane / ethyl acetate 10% -20% gel, g (1- (3-fluoro-2-methoxyphenyl) pressure) is obtained. 12.7 times silica brine, cyclopropylnitrile. To 12.7 g (66.1 mmol) of nitrile in toluene at -78 ° C, 82.7 ml (99.2 mmol) of diisobutyl-aluminum hydride solution (20% in toluene) are slowly added and after 3 h at -78 ° 11.1 ml isopropanol is added dropwise. It is allowed to warm to -5 ° C and 150 ml of a 10% aqueous tartaric acid solution are added. After dilution with ether, the mixture is stirred vigorously, the organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The wash is dried with sodium sulfate and concentrated under reduced pressure. 11.8 g of aldehyde are obtained in the form of a yellow oil. To a solution of 16.3 g (60.7 mmol) of 2-diethylphosphono-2-ethoxyacetic acid ethyl ester in 60 ml of tetrahydrofuran under ice-cooling over 20 minutes is added 33.4 ml (66.8 mmol) of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptanietoluene and stirred at 0 ° C for 30 minutes. A solution of 11.8 g tetrahydrofuran at 0 ° C. is added dropwise over 30 minutes. After 20

60.7 mmol) and at 61 ml hr temperature repeatedly. Washed in

ice water is added and the mixture is extracted with ether and ethyl acetate. saturated ammonium chloride solution, dried over sodium sulfate and concentrated. The crude product for 15 hours at room temperature is saponified with 170 ml 2 M sodium hydroxide solution in 170 ml ethanol. 13.9 g of acid are obtained, which is mixed with 87 ml of 2 N sulfuric acid at 90 ° C. for 16 hours. After cooling, it is basified with potassium carbonate, washed with ether and acidified with hydrochloric acid. After

228 extraction with ethyl acetate, washing with saturated sodium chloride solution and removal of the solvent is obtained

10.2 g of crude ketoacid. 10.2 g (40.6 mmol) of 3- [1- (3-fluoro-2-methoxyphenyl) cyclopropyl} -2-oxo-propionic acid and 4.5 ml (85.3 mmol) of sulfuric acid (96%) in 200 ml ethanol is heated under reflux for 1 hour. The mixture is concentrated under reduced pressure, the residue is added to ice water and basified with saturated sodium bicarbonate solution. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 20%) yields 9.6 g of ethyl 3- [1- (3-fluoro-2-methoxyphenyl) cyclopropyl] -2-oxo propionate.

¹H-NMR (CDCl3): δ = 0.90 (m, 4H), 1.29 (t, 3H), 3.09 (s, 2H), 3.99 (d, 3H), 4.20 (q , 2H), 6.87 (ddd, 1H),

6.95 (ddd, 1H), 7.07 (d, 1H), 9.26.

3- [1- (3-Fluoro-2-methoxyphenyl) -cyclopropyl] -2-hydroxy-2- (trifluoromethyl) propanal

To 9.6 g (34.3 mmol) of ethyl 3- [1- (3-fluoro-2-methoxyphenyl} cyclopropyl] -2-oxopropionate and 34.5 ml (233 mmol) (trifluoromethyl} trimethylsilane in 343 ml DMF 46.9 g of cesium carbonate are added at 0 ° C. It is stirred for 2 h at 0 ° C. and then the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated under reduced pressure pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 10% -40%) gives 10.4 g of 3- [1- (3-fluoro-2-methoxyphenyl} cyclopropyl] -2-hydroxy-2 (trifluoromethyl) propionate ethyl oil as a yellow oil To this oil in 297 ml diethyl ether at 0 ° C. is added 2.25 g (59.4 mmol) of lithium aluminum hydride and stirred for 1 hour at room temperature. To the mixture at 0 ° 20 ml saturated ammonium chloride solution is carefully added followed by through

229 minutes vigorously mixed. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification on silica gel (hexane / ethyl acetate 10% -50%) gives 5.6 g of 3- [1- (3-fluoro-2-methoxyphenyl) cyclopropyl] -2- (trifluoromethyl) propane-1,2- diol. To 5.6 g (18.1 mmol) of diol in 100 ml of dichloromethane and 61 ml of DMSO are added 12.4 ml (89 mmol) of triethylamine and 11 g (70 mmol) of the pyridine / SO3 complex in portions for 10 min. It is stirred for 3 hours and a saturated solution of ammonium chloride is added. The mixture is stirred for a further 15 min, the phases are separated and extracted with dichloromethane. It is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure and 5.9 g of product are obtained after silica gel chromatography (hexane / ethyl acetate, 0-50%).

¹H-NMR (CDCl3): δ = 0.68-0.76 (m, 2H), 0.90-1.02 (m,

2H), 2.03 (d, 1H), 2.91 (d, 1H), 3.85 (s, 1H), 4.03 (s,

3H), 6.80 (d, 1H), 6.87 (ddd, 1H), 6.98 (dd, 1H), 9.26 (s, 1H).

cis-4 '- [(7,8-difluoro-2-methylquinazolin-5-yl) amino] 7'-fluoro-3', 4'-dihydro-8'-methoxy-3 '(trifluoromethyl) spiro [cyclopropane -1,1 '(2H) naphthalene] -3'-ol ¹H-NMR (300 MHz, CD3OD); δ = 0.83 (ddd, 1H), 0.99 (ddd,

1H), 1.42 (ddd, 1H), 1.89 (ddd, 1H), 2.01 (d, 1H), 2.15 (d, 1H), 2.84 (s, 3H), 3, 85 (s, 3H), 5.19 (s, 1H), 6.65 (dd, 1H), 6.96 (dd, 1H), 7.04 (dd, 1H), 9.63 (s, 1H ). Example 197 cis-7'-Fluoro-3 ', 4'-dihydro-8'-methoxy-4' - [(2-methylquinazolin-5-yl) amino] -3 '- (trifluoromethyl) spiro [cyclopropane-1,1' (2 'H) -naphthalene] -3'-ol¹H-NMR (300 MHz, CDCl 3); δ = 0.82 (ddd, 1H), 1.00 (ddd,

1H), 1.54 (ddd, 1H), 1.86 (ddd, 1H), 1.91 (d, 1H), 2.32

230 (d, 1H), 2.84 (s, 3H), 3.87 (s, 3H), 5.08 (d, 1H), 5.78 (d, 1H), 6.67 (d, 1H) , 6.88 (dd, 1H), 7.05 (dd, 1H),

7.28 (d, 1H), 7.70 (t, 1H), 9.36 (s, 1H).

Example 198 cis-7'-Fluoro-3 ', 4'-dihydro-4' - [(2-methylquinazolin-5-yl) amino] -3 '- (trifluoromethyl) spiro [cyclopropane1,1' (2'H) - naphthalene-3 ', 8'-diol ¹H-NMR (300 MHz, CD3OD); δ = 0.67 (ddd, 1H), 0.90 (ddd, 1H), 1.77 (ddd, 1H), 1.93 (d, 1H), 2.12 (ddd, 1H), 2.21 (d, 1H), 2.81 (s, 3H), 5.28 (s, 1H), 6.75-6.88 (m, 3H),

7.18 (d, 1H), 7.78 (t, 1H), 9.65 (s, 1H).

Example 199 cis-4 '- [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] 7'-fluoro-3', 4'-dihydro-3 '- (trifluoromethyl) spiro [cyclopropane-1, 1 '(2' H) -naphthalene] -3 ', 8'-diol ¹H-NMR (300 MHz, CDCl 3); δ = 0.71 (ddd, 1H), 0.91 (ddd, 1H), 1.81 (d, 1H), 1.83-2.00 (m, 2H), 2.39 (d, 1H) , 2.87 (s, 3H), 4.98 (d, 1H), 5.75 (d, 1H), 6.49 (dd, 1H), 6.78-6.89 (m, 2H), 9.28 (s, 1 H).

Example 200 cis-1 - [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] -5-fluoro-6-methoxy-4,4-dimethyl-2- (trifluoromethyl} 1,2,3,4- tetrahydronaphthalen-2-ol ¹H-NMR (300 MHz, CD3OD); δ = 1.53 (s,

2.17 (s, 2H), 2.84 (s, 3H), 3.85 (s,

6.87 (dd, 1H), 6.95 (dd, 1H), 7.07 1H).

<td>3H);</td><td> 1,65</td><td>(s, 3H)</td>

<td>3H);</td><td> 5,32</td><td>(s, 1H)</td>

<td>(D,</td><td>1H),</td><td>9.61 (p</td>

Example 201 cis-1 - [(7,8-Difluoro-2-methylquinazolin-5-yl) amino] -5-fluoro-4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,6 propanediol ¹H-NMR (300 MHz, CD3OD); δ = 1.54 (s, 3H), 1.66 (s, 3H), 2.16 (s, 2H), 2.84 (s, 3H), 3.98 (s, 3H), 5.29 (s, 1H),

231

6.78 (dd, 1H), 6.86 (dd, 1H), 6.94 (dd, 1H), 9.60 (s,

1H).

Example 202 cis-7'-Fluoro-4 '- [(8-fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-3 '- (trifluoromethyl) spiro [cyclopropane-1,1' ( 2 'H) -naphthalene] -3', 8'-diol ¹H-NMR (300 MHz, CDCl 3); δ = 0.71 (ddd, 1H), 0.93 (ddd, 1H), 1.79 (d, 1H), 1.90-2.06 (m, 2H), 2.39 (d, 1H) .

2.91 (s, 3H), 3.80 (br, 1H), 5.05 (d, 1H), 5.39 (d, 1H), 5.48 (br, 1H), 6.65 (dd , 1H), 6.80-6.90 (m, 2H),

7.46 (dd, 1H), 9.35 (s, 1H).

Example 203 cis-7'-Fluoro-4 '- [(7-fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-3 '- (trifluoromethyl) spiro [cyclohexane-1,1' ( 2 'H) -naphthalene] -3', 8'-diol ¹H-NMR (300 MHz, CDCl 3); δ = 1.20-2.10 (m, 10H), 2.10 (d, 1H), 2.47 (d, 1H), 2.68 (s, 3H), 4.66 (d, 1H) , 5.33 (d, 1H), 6.91 (d, 2H), 7.03 (dd, 1H), 7.10 (dd, 1H), 9.01 (s, 1H).

Example 204 cis-6-Chloro-5-methoxy-1 - [(2-methylquinolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalen-2-ol ¹H-NMR (300 MHz, CD3OD); δ = 1.56 (s, 3H), 1.69 (s, 3H),

<td> 2,</td><td> 16</td><td>(S,</td><td>2H);</td><td> 2,72</td><td>(s, 3H), 3.97</td><td>(s, 3H)</td><td>, 5.25 (s, 1H),</td>

<td> 6,</td><td> 82</td><td>(D,</td><td>1H),</td><td> 7,11</td><td>(d, 1H), 7.20</td><td>(D, 1H),</td><td>7.32 (d, 1H),</td>

<td> 7,</td><td> 36</td><td>(D,</td><td>1H),</td><td> 7,55</td><td>(t, 1H), 8.45</td><td>(D, 1H).</td><td></td>

Example 205 cis-6-Chloro-1- (2-methylquinolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol ¹H-NMR (300 MHz, CD3OD); δ = 1.61 (s, 3H), 1.73 (s, 3H),

2.12 (d, 1H), 2.18 (d, 1H), 2.72 (s, 3H), 5.23 (s, 1H),

232

6.82 (d, 1H), 6.87 (d, 1H), 7.11 (d, 1H), 7.31 (d, 1H),

7.35 (d, 1H), 7.55 (t, 1H), 8.45 (d, 1H).

Example 206

Cis-1 - [- (2-methyl-1-quinolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol N-oxide ¹H-NMR (300 MHz, CD3OD); δ = 1.44 (s, 3H), 1.58 (s, 3H),

2.19 (s, 2H), 2.76 (s, 3H), 5.35 (s, 1H), 7.00 (dd, 1H), 7.12 {t, 1H}, 7.27-7 , 34 (m, 2H), 7.45-7.52 (m, 2H), 7.71 (t, 1H), 7.96 (d, 1H), 8.29 (d, 1H).

Example 207

Cis-6-chloro-1 - [(2-methylquinolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5-diol N-oxide

Up to 84mg (0.19 mmol) cis-6-chloro-1 - [(2-methylquinolin-5-yl) amino] -4,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2.5 -diol in 8 ml of dichloromethane is added 75 mg of 70% meta-chloroperbenzoic acid, and the solution is stirred through solid sodium bicarbonate water. Extract with saturated chlorine solution and sodium sulfate. After chromatography on ethyl gel 0-100%) is obtained

<td colspan="2">¹H-NMR (300 MHz, CD3</td><td>FROM)</td><td>; δ</td>

<td>2.13 (d,</td><td>1H), 2.18</td><td>(D,</td><td>1H</td>

<td>6.85 (d,</td><td>1H), 7.01</td><td>(D,</td><td>1H</td>

<td>7.70 (t,</td><td>1H), 7.96 (</td><td>d</td><td>1H)</td>

<td>Example</td><td> 208</td><td></td><td></td>

two hours 50 mg are added and after 30 minutes poured into dichloromethane, washed with sodium and dried over concentration and work up

<td colspan="2">silica</td><td>(Hexane / ethyl</td>

<td>58 mg</td><td>Relationship</td><td>the title compound.</td>

<td> 1,61</td><td>(s, 3H),</td><td>1.73 (s, 3H),</td>

<td> 2,75</td><td>(s, 3H),</td><td>5.30 (s, 1H),</td>

<td> 7,13 8,27 (</td><td>(d, 1H), d, 1H).</td><td>7.48 (d, 1H),</td>

Cis-6-N-oxide - [(2-methyl dimethyl-7- (trifluoromethyl) naphtho [1,2-d] -1,3-dioxol-7-o ¹H-NMR (300 MHz, CDCl 3); δ = 2.06 (d, 1H), 2.20 (d, 1H),

quinolin-5-yl) amino] -9,9-6,7,8,9-tetrahydrolu

1.49 (s, 3H), 1.58 (s, 3H), 2.61 (s, 3H), 5.08 (d, 1H),

233

<td>5.62 (d,</td><td>1H),</td><td> 5,99</td><td>(s, 2H),</td><td> 6,64</td><td>(d, 1H),</td><td> 6,83</td><td>(d, 1H),</td>

<td>6.85 (d,</td><td>1H),</td><td> 7,13</td><td>(d, 1H),</td><td> 7,55</td><td>(t, 1H),</td><td> 7,96</td><td>(d, 1H),</td>

<td>8.03 (d,</td><td>1H).</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Example</td><td> 209</td><td></td><td></td><td></td><td></td><td></td><td></td>

cis-7'-Fluoro-4 '- [(7-fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-3 '- (trifluoromethyl) spiro [cyclopropane-1,1' (2 ' H) -naphthalene] -3 ', 8'-diol

<td>¹H-NMR (300 MHz, CD3OD); δ</td><td> = 0,66</td><td>(Ddd,</td><td>1H), 0.89 (ddd,</td>

<td>1H), 1.86 (ddd, 1H), 1.93</td><td>(d, 1H),</td><td> 2,10</td><td>(ddd, 1H), 2.22</td>

<td>(d, 2H), 2.78 (s, 3H), 5,</td><td>26 (s,</td><td>1H),</td><td>6.67 (dd, 1H),</td>

6.75-6.82 (m,

2H), 6.87 (dd, 1H), 9.58 (s, 1H).

Example 210 cis-5- {7'-Fluoro-3 ', 4'-dihydro-3', 8'-dihydroxy-3 '(trifluoromethyl) spiro [cyclopropane-1,1' (2'H) naphthalene-4 yl] amino} quinolin-2 (1H) -one ¹H-NMR (300 MHz, CD3OD); δ = 0.66 (ddd, 1H), 0.90 (ddd, 1H), 1.71 (ddd, 1H), 1.88 (d, 1H), 2.09 (ddd, 1H), 2.20 (d, 2H), 5.15 (s, 1H), 6.51-6.54 (m, 2H), 6.70 (d, 1H),

6.79 (dd, 1H), 6.85 (dd, 1H), 7.36 (t, 1H), 8.25 (d, 1H).

Example 211 cis-7'-Chloro-4 '- [(7-fluoro-2-methylquinazolin-5-yl) amino] -3', 4'-dihydro-3 '- (trifluoromethyl) spiro [cyclopropane-1,1' ( 2 'H) -naphthalene] -3', 8'-diol ¹H-NMR (300 MHz, CDCl 3); δ = 0.70 (ddd, 1H), 0.91 (ddd, 1H), 1.70 (ddd, 1H), 1.77 (d, 1H), 2.08 (ddd, 1H), 2.44

<td>(D, 1H),</td><td> 2,82</td><td>(s, 3H),</td><td>5.06 (d, 1H) 5.77 (s,</td><td>1H), 5.88</td>

<td>(D, 1H),</td><td> 6,44</td><td>(dd, 1H)</td><td>, 6.88 (d, 1H), 6.91</td><td>(dd, 1H),</td>

<td>7.13 (d,</td><td>1H),</td><td>9.23 (s,</td><td>1H).</td><td></td>

<td>Example</td><td> 212</td><td></td><td></td><td></td>

cis-7'-Chloro-3 ', 4'-dihydro-4' - [(2-methylquinolin-5-yl) amino] -3 '- (trifluoromethyl) spiro [cyclopropane-1,1' (2 'H) -naphthalene] -3 ', 8'-diol

234 ¹H-NMR (300 MHz, CD3OD); δ = 0.68 (ddd, 1H), 0.91 (ddd,

1H), 1.69 (ddd, 1H), 1.91 (d, 1H), 2.11 (ddd, 1H), 2.22 (d, 1H), 2.72 (s, 3H), 5, 20 (s, 1H), 6.70 (d, 1H),

6.78-6.85 (m, 2H), 7.30 (d, 1H), 7.36 (d, 1H), 7.53 (t,

1H), 8.47 (d, 1H).

Example 213

Cis-7'-chloro-3 ', 4'-dihydro-4' - [(2-methylquinolin-5-yl) amino] -3 '- (trifluoromethyl) spiro [cyclopropane-1,1' (2'H) N-oxide ) -naphthalene] -3 ', 8'-diol

<td>¹H-NMR (300 MHz,</td><td>CD 3 OD); δ</td><td>= 0.67 (ddd,</td><td>1H), 0.91 (</td><td>ddd,</td>

<td>1H), 1.74 (ddd,</td><td>1H), 1.91</td><td>(d, 1H), 2.10</td><td>(ddd, 1H),</td><td> 2,23</td>

<td>(d, 1H), 2.75 (</td><td>s, 3H), 5</td><td>, 25 (s, 1H),</td><td>6.78 (dd,</td><td>1H),</td>

<td>6.84 (dd, 1H),</td><td>6.90 (d,</td><td>1H), 7.49 (d,</td><td>1H), 7.69</td><td>(T,</td>

1H), 7.95 (d, 1H), 8.30 (d, 1H).

Example 214 cis-7'-Chloro-4 '- [(7-fluoro-2-methylquinazolin-5-yl) amino] -3,4'-dihydro-8'-methoxy-3' (trifluoromethyl) -spiro [cyclohexane-1 1 '(2'H) naphthalene] -3'-ol ¹H-NMR (300 MHz, CDCl 3); δ = 1.20-1.85 (m, 8H), 2.05 (d,

<td>1H),</td><td>2.44 (ddd, 1H),</td><td> 2,63</td><td>(Ddd,</td><td>1H),</td><td> 2,</td><td> 82</td><td>(S,</td><td>3H), 2.97</td>

<td>(D,</td><td>1H), 4.00 (s, 3H)</td><td> , 4,</td><td>95 (d,</td><td>1H),</td><td> 5,</td><td> 92</td><td>(D,</td><td>1H), 6.49</td>

<td>(Dd,</td><td>1H), 6.91 (dd,</td><td>1H),</td><td> 7,04</td><td>(D,</td><td>1H)</td><td>^,</td><td> 7,22</td><td>(d, 1H),</td>

9.16 (s, 1H).

Example 215 cis-7'-Chloro-4 '- [(7-fluoro-2-methylquinazolin-5-yl) amino] -3,4'-dihydro-3' - (trifluoromethyl) spiro [cyclohexane-1,1 '(2 'H) -naphthalene] -3', 8'-diol ¹H-NMR (300 MHz, CDCl 3); δ = 1.25-1.85 (m, 8H), 1.86 (d,

<td>1H), 2.79 (ddd, 1H),</td><td>2.82 (s, 3H), 2,</td><td colspan="2">93 (ddd,</td><td>1H),</td><td> 2,97</td>

<td>(d, 1H), 4.95 (d, 1H)</td><td>, 5.85 (d, 1H),</td><td> 6,14</td><td>(S,</td><td>1H),</td><td> 6,48</td>

<td>(dd, 1H), 6.89-6.93</td><td>(m, 2H), 7.19</td><td>(D,</td><td>1H),</td><td> 9,19</td><td>(S,</td>