UA80644C2 - Tetrahydronaphtalene derivatives, method for their production and their use as antiphlogistics agents - Google Patents

Abstract

The invention relates to polysubstituted tetrahydronaphtalene derivatives of formula (I), to methods for the production thereof, and to their use as antiphlogistics. The substituents are defined in Claim 1. (I)

Description

Description of the invention

The invention relates to tetrahydronaphthalene derivatives, the method of their preparation, and their use as anti-inflammatory agents.

Nonsteroidal acyclic anti-inflammatory agents are known from the prior art (OE 100 38 639 and MO 02/10143). These compounds, when used in experimental studies, show different activity in terms of anti-inflammatory and undesirable metabolic effects and thus they are superior to the non-steroidal glucocorticoids described so far or have at least the same good effect. 70 However, the selectivity of the prior art compounds as well as their pharmacokinetic parameters still need to be improved.

Therefore, the basis of this invention was the task of offering compounds in which selectivity with respect to other steroid receptors, as well as pharmacokinetic properties, would be the same or more perfect in comparison with compounds from the prior art. 19 This problem is solved with the help of the compounds described in the formula of the invention.

Accordingly, this invention relates to stereoisomers of the general formula (I), 1 c

Kk Kk

IS! 2 5

Kk sch t o

KE" El

NM. with "

E () h in which ee,

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, (a) an optionally substituted C 41 -C 10 -alkyl group, an optionally substituted C 4 -C -o-alkoxy group , C.4-C:o-alkylthio group, C4--C5-perfluoroalkyl group, cyano group, nitro group, CO or VK" and B? together represent a group selected from the groups -O-(CH 2 )y-O-, -O-(СНо)-СНо-, -О-СН-СН.-, "СНао)ва" "МНА(СНо) ln" "M(C-C3-alkyl)"CHa) di 1 -"MNAMASNU, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to directly "20 adjacent to by ring carbon atoms, -v c or MAZUR, and where BZ and KU, independently of each other, represent hydrogen, C.4-Cv-alkyl or (СО)-C.-Cv-alkyl, "» B" represents is a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted cyano group

a C.-C.ru-alkyl group, a C.4-C.sub.10-alkyl group, a C.-C.sub.-alkylthio group or a C.-C.sub.5-perfluoroalkyl group,

B" is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted C.-C.ru-alkyl group, or a C.4-C.sub.-alkyl group, (ав) BZ is a C 1- C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, b" by 1-3 C.-Cb-alkoxy groups, optionally substituted C.3-C.-cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group,

Its 50 which is optionally substituted, independently of each other, by one or more groups selected from

T» C.-Cv-alkyl groups (which may optionally be substituted with 1-3 hydroxy or 1-3 SOOMK "Z groups),

C.-C.-Alkoxy groups, halogen atoms, hydroxy groups, Me groups, exomethylene groups or an oxygen atom, and which optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, and this group can be connected by means of any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas, and B" represents a hydroxy group, group OK 79 or O(CO)CO'O group, where CO is any co-hydroxy-protecting group or C.-C.o-alkyl group,

BZ is a C 1-Cio-alkyl group or optionally partially or fully fluorinated C41-Cio-alkyl 60 group, C3-C,-cycloalkyl group, C4-C-alkyl-C3-C,-cycloalkyl group, Co- C-alkenyl-C3-C.-cycloalkyl group, heterocyclic group, C.--Cd-alkylheterocyclic group, C4-Cd-alkenylheterocyclic group, aryl group, C--Cv-alkylaryl group, Co-Cv-alkenylaryl group, Co -S-alkynylaryl groups, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1-2 keto groups, 1-2

C4-C5-alkyl groups, 1-2 C-C-Alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups and 65 which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1 -2 sulfur atoms, a C 1-Cv-alkylheteroaryl group or a C-Cv-alkenylheteroaryl group, or a C-Cv-alkynylheteroaryl group, and these groups can be connected by any position with the tetrahydronaphthalene system and optionally can be hydrogenated in one or more sections, 25 and K", independently of each other, represent a hydrogen atom, a methyl or ethyl group or, together with a carbon atom of the tetrahydronaphthalene system, a C3-Ce-cycloalkyl ring.

Stereoisomers of the general formula (I) according to item 2, in which

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted C 41-Cio-alkyl group, an optionally substituted C 4-Cio-alkoxy group, C4-C4o-alkylthio group, C4i-Cv-perfluoroalkyl group, cyano group or nitro group, or KB" and VK? together represent a group selected from the groups -O-(СН 5),-О-, -О-(СНо)д-СНо-, -О-СНе:СНУ.-, -(СНа)по-, "МНА( СНао)дни, -М(С4-C3-alkyl)-(СНа)дни, and -МН-МеСН-, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected with ring carbon atoms directly adjacent to them, or MAZRU, where KZ and KZ, independently of each other, can be hydrogen, C.4-Cv-alkyl or (CO)-C.-Cv-alkyl,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

a C.-C.d.-alkyl group, a C.41-C.sub.6-alkyl group, a C.-C.sub.6-alkylthio group or a C.-C.sub.5-perfluoroalkyl group,

В" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted 20.C.C.rualkyl group, or a C.4-Cio-alkyl group,

BZ is a C 1-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 C.-C.-alkyl groups, optionally substituted by C 3-C,.-cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted, independently of each other, by one or more groups selected from c

C.-Cv-alkyl groups (which may optionally be substituted with 1-3 hydroxy or 1-3 COOV "Z groups), where v'o represents hydrogen or C 4-Cv-alkyl), Si-Cv- aluoxy groups, halogen atoms, hydroxy groups, MEZVU groups, exomethylene groups or an oxygen atom, and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1 -2 keto groups, and this group can be connected through any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more sections, "

IN? represents a hydroxy group, an OK 79 group or an O(CO)K"O group, where BK"O is any hydroxy-protecting group or C.-C.o-alkyl group, o

BZ is a C 1-C.o-alkyl group or an optionally partially or fully fluorinated C 4-C.io-alkyl group and "c)

GROUP still, co

KK" and K", 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 C3-Ce-cycloalkyl ring, represent another variant of the implementation of this invention.

Stereoisomers of the general formula (I), in which "

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, in c a C.-C.p.-alkyl group, a C.4-C.sub.1-alkyl group, a C.sub.1-C.sub.-alkylthio group, C-- The s-perfluoroalkyl group, the cyano group or the nprogroup, "» or KB" and VK? together represent a group selected from the groups -O-(CH 2)4-O-, -«O-(СНо)-СНо-, - О-СНеСНУ.-, -(СНа)ано-, «МНА(СНао)ани, «М(С1-С3-alkyl)-(СНо)дниа or -МН-МеСН-, where n-1 or 2, and the final oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to ring carbon atoms directly (ee) adjacent to them, or MEZE?, where VZ and VU, independently of each other, can be hydrogen, P.4 -C1-alkyl or (CO)-C1-C1-alkyl,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted C.-C.ru-alkyl group, a C.4-C.sub.10-alkyl group, a C.-C.sub.4-alkylthio group or a C.-C.sub.5-perfluoroalkyl group, - 20 V"? represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

T» a C.-C.ru-alkyl group, or a C.4-C.O.-alkyl group,

BZ is a C 1-C 40 -alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 C.-Cb-alkoxy groups, an optionally substituted C 3-C,.-cycloalkyl group, not necessarily substituted

A heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted, independently of each other, by one or more groups selected from C 1 -C 6 -alkyl groups (which may optionally be substituted 1-3 hydroxy or 1-3 SOOMK "With groups), i.e.) C.-C-Alkoxy groups, halogen atoms or exomethylene groups, and which optionally contains 1-3 nitrogen atoms and/"or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, and this group can be connected through any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more sites,

IN? is a hydroxy group, an OK 79 group or an O(CO)K"O group, where BK"O is any hydroxy-protecting group or a C.4-C:o-alkyl group,

VE? represents a C 4-Cv-alkyl group or an optionally partially or fully fluorinated C 4-Cv-alkyl group, a C-C,-cycloalkyl group, a C.4-Cvd-alkyl-C3-C-cycloalkyl group, Co - C 1 -C 3 -C 3 -cycloalkyl group, heterocyclic group, C 3 -C 4 -alkyl heterocyclic group, Co -C 4 -alkenyl heterocyclic group,

Co-Cv-alkynylaryl groups, aryl group, C4-Cv-alkylaryl group, Co-Cv-alkenylaryl group, monocyclic or bicyclic heteroaryl group, which is optionally substituted with 1-2 keto groups, 1-2 C-Cb5-alkyl groups, 1-2 C.-Cv-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, C.- C-alkylheteroaryl group or

Co-Cv-alkenylheteroaryl group, and these groups can be connected by any position to the tetrahydronaphthalene system and can optionally be hydrogenated in one or more sites, 25 and K", independently of each other, represent an atom hydrogen, methyl or ethyl group or 70 together with the carbon atom of the tetrahydronaphthalene system represent a C3-C8-cycloalkyl ring, represent another variant of the invention.

Stereoisomers of the general formula (I), in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

C.-C.p-alkyl group, C.sub.4-C.sub.6-alkyl group, C.sub.1-C.sub.6-alkylthio group, C.sub.1-C.sub.4-perfluoroalkyl group, cyano group or nitro group or BK" and B" together represent a group selected from the groups - О-(СН 2)y-О-, -О-(СНо)-СНо-, -О-СН-СН.-, "СНао)ва" "МНА(СНо)ln" "М(С-Сз- alkyl)"СНа) action | - MNAMASNU, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to ring carbon atoms directly adjacent to them, or MURU, where KZ and KZ, independently of each other, can be hydrogen, C.4-Cv-alkyl or (CO)-C.-Cv-alkyl,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

a C.-C.ru-alkyl group, a C.4-C.sub.10-alkyl group, a C.-C.sub.-alkylthio group or a C.-C.sub.5-perfluoroalkyl group,

B" is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted with

C.-C.alkyl group, or C.4-Co-alkoxy group, o

BZ is a C 1-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 C.-C.-alkyl groups, optionally substituted by C 3-C,.-cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted, independently of each other, by one or more groups selected from "C1-C6-alkyl groups ( which may optionally be substituted by 1-3 hydroxy or 1-3 SOOMK "With groups), "g

C.-Cr.-Alkoxy groups, halogen atoms, exomethylene groups or oxygen atoms and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups , and this group can be linked by means of any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas,

IN? is a hydroxy group, an OK 79 group or an O(CO)K"O group, where BK"O is any hydroxy-protecting group or C.-C.o-alkyl group, 25 is C 1-C .o-alkyl group or optionally partially or fully fluorinated C .-Cv-alkyl group, "

B3 and 7", independently of each other, represent a hydrogen atom, a methyl or ethyl group, or, 73 with a carbon atom of the tetrahydronaphthalene system, represent a C3-Co-cycloalkyl ring, represent another variant of the implementation of this invention. ;" Stereoisomers of the general formula (I), in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted Co 4 -C 10 -alkyl group, a C 1 -C 10 -alkyl group, a C 4 -C 10 -alkylthio group, (ee) C.-Cv-perfluoroalkyl group, cyano group or nitro group, or BK" and VK? together represent a group selected from the groups -О- (СНао)д-О-, -ОО-(СНо)й-СНо-, -ОО-СН-СН-, «СНао)во-, «МНА(СНао ) dya, "M(C4-C3-alkyl)-(СНао) di and -МН-М-сСнН-, (o) where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms connected to ring carbon atoms immediately adjacent to them, or ME:ZE, where KZ and KZ, independently of each other, can be hydrogen, C.4-Cv-alkyl or (CO)-C. -Ct-alkyl,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted C.-C.ru-alkyl group, a C4-C10-alkyl group, a C4-C0-alkylthio group or a C.-C5-perfluoroalkyl group,

B" is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (F) C.-C.d.-alkyl group, or a C.-C.-6-alkyl group, where BZ is C 1-SiO - an alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms or 1-3 C.-C-alkyloxy groups, optionally substituted by C 53-C, -cycloalkyl group, optionally substituted by a heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by one or more groups selected from C 4 -C 5 -alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 SOOV "With groups where KZ is hydrogen or

C.-Cr-alkyl), C--Sulfoxy groups, halogen atoms or exomethylene groups, or which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, and this group 65 can be connected through any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas,

B" represents a hydroxy group, an OB 79 group or an O(CO)K'O group, where BK" represents any hydroxy-protecting group or C.-C.o-alkyl group,

BZ is a C1-C8-alkyl group or an optionally partially or fully fluorinated C41-C8-alkyl group, C1-C1-cycloalkyl group, C4-C8-alkyl-C3-C-cycloalkyl group, Co- C1-alkenyl-C3-C1-cycloalkyl group, heterocyclic group, C1-C2-alkylheterocyclic group, Co-C8-alkenylheterocyclic group,

Co-Cv-alkynylaryl groups, aryl group, C4-Cv-alkylaryl group, Co-Cv-alkenylaryl group, monocyclic or bicyclic heteroaryl group, which is optionally substituted with 1-2 keto groups, 1-2 C-Cb5-alkyl groups, 1-2 C.-C5-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups and which contains 1-3 nitrogen atoms 70 and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, C- -C 1 -alkylheteroaryl group or Co-C 2 -alkenylheteroaryl group, and these groups can be connected at any position to the tetrahydronaphthalene system, and may optionally be hydrogenated in one or more sites, 25 and K7, independently one from one, represent a hydrogen atom, a methyl or ethyl group, or, together with a carbon atom of the tetrahydronaphthalene system, a C3-C8-cycloalkyl ring, provided that at least three of the radicals ВЕ", В, В! and В" do not represent hydrogen, represent another variant of the implementation of this invention.

Stereoisomers of the general formula (I), in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted Co 4-Cio-alkyl group, C.--Cio-alkyl group, C.4-C:o -alkylthio group,

C.-Cv-perfluoroalkyl group, cyano group or nitro group, or BK" and VK" together represent a group selected from the groups -O-(СНа)-О-, -О-(СНо)-СНе-, -ОО-СН -СН-, "СНао)дяо-, "МНА(СНао)вни, "М(С4-С3-alkyl)-(СНо)пни- or -МН-МАСН-, where n-1 or 2, and end atoms oxygen and/or carbon atoms and/or nitrogen atoms are connected to the ring carbon atoms immediately adjacent to them, сч з or МЕЗКЗ, о) where KZ and BEU, independently of each other, can be hydrogen, C41-Cv-alkyl or (CO)-C.4-Cv-alkyl,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

C.-C.ru-alkyl group, C4-C10-alkyl group, C4-C0-alkylthio group or C.-C5-perfluoroalkyl group, "I

B" is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted by "

a C.-C.ru-alkyl group, or a C.4-C.-alkyl group,

BZ is a C 1-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 C.-Cb-alkoxy groups, optionally substituted by C 3-C,.- a cycloalkyl group, an optionally substituted α heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by one or more groups selected from C 4 -C 4 -alkyl groups (which may optionally be be substituted by 1-3 hydroxy or 1-3 SOOK Z groups), Ci-Cv-alkoxy groups, halogen atoms or exomethylene groups and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1 -2 sulfur atoms and/or 1-2 keto groups, and this group can be connected through any position to the amine of the tetrahydronaphthalene system, and can optionally be hydrogenated in one or more areas, with B? is a hydroxy group, an OK 79 group or an O(CO)K"O group, where BK"O is any hydroxy-protecting group or C.-C.o-alkyl group, ;" BZ is a C1-C8-alkyl group or an optionally partially or fully fluorinated C41-C8-alkyl group, C3-C-cycloalkyl group, C1-C8-alkyl-C3-C1-cycloalkyl group, Co-C8 -alkenyl-C3-C-cycloalkyl

Group, heterocyclic group, C.-Cv-alkylheterocyclic group, Co-Cv-alkenylheterocyclic group,

Go! Co-Cv-alkynylaryl groups, aryl group, C4-Cv-alkylaryl group, Co-Cv-alkenylaryl group, monocyclic or bicyclic heteroaryl group, which is optionally substituted with 1-2 keto groups, 1-2 C-Cb5-alkyl groups, with 1-2 C.-Cv-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or which contains 1-3 atoms

He» of nitrogen and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, C.-Cv-alkylheteroaryl group or

Co-Cv-alkenylheteroaryl group, and these groups can be connected by means of any position to the tetrahydronaphthalene system and can optionally be hydrogenated in one or more sites,

HT" 25 and K7, 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 C3-Ce-cycloalkyl ring, provided that at least three of the radicals B" B, B"! and B" do not represent hydrogen, represent another embodiment of this invention. o Stereoisomers of the general formula (I), in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, where an optionally substituted Co 4-Co-alkyl group, C.i-C-o-alkoxy group, C.-Cio -alkylthio group, C4-Cv- perfluoroalkyl group, cyano group or nitro group, or B! and 2? together represent a group selected from 60 groups - OSNO)-O-, -«O-(СНо)І-СНо-, - O-CH-CH-, "(CHNao)po-, ""MNA(CHNao)pni, -"M(C4-C3-alkyl)-(CHa)dni- and -"MH-M-CH-, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to ring carbon atoms immediately adjacent to them, or ME:ZE, where KZ and BEU, independently of each other, can be hydrogen, C.4-Cv-alkyl or (CO)-C.-Cv-alkyl, 55 V" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

a C.-C.ru-alkyl group, a C.4-C.sub.10-alkyl group, a C.-C.sub.-alkylthio group or a C.-C.sub.5-perfluoroalkyl group,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

a C.-C.ru-alkyl group, or a C.4-C.-alkyl group,

BZ is a C 1-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 C.-C.-alkyl groups, optionally substituted by C 3-C,.-cycloalkyl a group, an optionally substituted heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by one or more groups selected from C 4 -C 4 -alkyl groups (which may optionally be substituted 1 -3 hydroxy or 1-3 SOOK Z groups), Ci-Cv-alkoxy groups, halogen atoms 70 or exomethylene groups, and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1- 2 sulfur atoms and/or 1-2 keto groups, and this group can be connected through any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas,

B is a hydroxy group, an OB 79 group or an O(CO)B'O group, where B'O is any hydroxy-protecting group or a C.-C.o-alkyl group, and BZ is C 1- C-alkyl group or optionally partially or fully fluorinated C 41-C-alkyl group, 25 and K", independently of each other, represent a hydrogen atom, methyl or ethyl group, or together with a carbon atom of the tetrahydronaphthalene system represent C3 -Ce-cycloalkyl ring, provided that at least three of the radicals K", B, B"! and B" do not represent hydrogen, represent another variant of the implementation of this invention.

Stereoisomers of the general formula (I), in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

a C1-C16-alkyl group, a C1-C10-alkyl group, a C1-C0-alkylthio group, a C--C6-perfluoroalkyl group, a cyano group or an M29 nitro group, or BK" and BK? together represent a group selected from the groups -O-(СН2)y-О-, -О-(СНо)-СНе-, о -0-снН-СнН-, «СНао)daо-, where n-1 or 2, and terminal oxygen atoms and/or carbon atoms are connected to ring carbon atoms directly adjacent to them, or MAN, where BZ and VU, independently of each other, can be hydrogen, C.4-Cv-alkyl or (CO)-C. -Sv-alkyl, "I

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted with

a C.-C.ru-alkyl group, a C.4-C.sub.10-alkyl group, a C.-C.sub.-alkylthio group or a C.-C.sub.5-perfluoroalkyl group,

B" is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted by

C.-C.alkyl group, or C.-C.io-alkoxy group, p

BZ is a C 1-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 C.-Cb-alkoxy groups, optionally substituted phenyl group or naphthyl group, monocyclic or a bicyclic heteroaryl group, which is optionally substituted by 1-2 keto groups, 1-2 C 4-C alkyl groups, 1-2-2.-C 5-alkyl groups, 1-3 halogen atoms or 1-2 exomethylene groups and which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, and these groups can be connected with the help of ts in any position to the amine of the tetrahydronaphthalene system, and can optionally be hydrogenated in one or more sites, "B" represents a hydroxy group,

BZ is a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl group, an aryl group, a C--Cv-alkylaryl group, a C-Cv-alkenylaryl group, C3-C,. -cycloalkyl group, C.4-Cv-alkyl-C3-C-cycloalkyl group, or Co-Cv-alkenyl-C3-C-cycloalkyl group? (ав) БЕ and Б", independently of each other, represent a hydrogen atom, a methyl or ethyl group, or, together with a carbon atom of the tetrahydronaphthalene system, a C3-Cbo-cycloalkyl ring, provided that at least THREE of the B radicals ", B2, B! and B" do not represent hydrogen, - represent another variant of the invention.

T» Stereoisomers of the general formula (I), in which

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

a C.-C.p-alkyl group, a C4-C10-alkyl group, a C1-C0-alkylthio group, a C1-C8-perfluoroalkyl group, a cyano group or a nitro group, or BK! and CC? together represent a group selected from groups. -O-(CH 2)p-O-, -O-(CHo)y-CHnoeo-, o -0-CH:CH- or -(CHo)do-, where p-1 or 2, and the terminal oxygen atoms and/or carbon atoms are connected to ring carbon atoms directly adjacent to them, or MAZUR, 60 where KZ and KZ, independently of each other, can be hydrogen, C.4-Cv-alkyl or (СО)- C.-Sv-alkyl,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

a C.-C.ru-alkyl group, a C.4-C.sub.10-alkyl group, a C.-C.sub.-alkylthio group or a C.-C.sub.5-perfluoroalkyl group,

В" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted 65 C.-C.o-alkyl group, a C1-C10-alkyl group,

BZ is a C 1 -C 40 -alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms or 1-3 C.-Cv-alkoxy groups, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group, which optionally substituted by 1-2 keto groups, 1-2 C by 4-C-alkyl groups, 1-2

C.i-Cv-alkoxy groups, 1-3 halogen atoms or 1-2 exomethylene groups and which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, and these groups can be linked by means of any position to the amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more areas,

B" is a hydroxy group,

BZ represents a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl 70 group, an aryl group, a C--Cv-alkylaryl group, a C-Cv-alkenylaryl group, C3-C, .-cycloalkyl group,

C.4-Cv-alkyl-C3-C,-cycloalkyl group, or Co-Cv-alkenyl-C3-C,-cycloalkyl group, 29 and VE", independently of each other, represent a hydrogen atom, methyl or ethyl group , or, together with the carbon atom of the tetrahydronaphthalene system, a C3-Ce-cycloalkyl ring, provided that at least three of the radicals B", B2, B! and B" do not represent hydrogen, 19 represent another embodiment of the invention.

Stereoisomers of the general formula (I), in which

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

C-C5-alkyl group, C-C-Alkoxy group, C--C-perfluoroalkyl group, or cyano group, or B and B? together, or represent a group selected from the groups -O-(СНо)в-О-, -О-(СНо)-СНе»-, -ОО-СНЕСН- and «СНао)дго-, where n-1 or 2, and terminal oxygen atoms and/or carbon atoms are connected to ring carbon atoms directly adjacent to them,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

C.-C.ru-alkyl group, C4-C10-alkyl group, C4-C10-alkylthio group or C.-C5-perfluoroalkyl group, m.p. 25 V" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally replaced by

a C.-C.ru-alkyl group, or a C.4-C.-alkyl group,

BZ is a C 4-Sio-alkyl group, which is optionally substituted by 1-3 hydroxy groups or halogen atoms, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, "30 quinolone , isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, "g cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, which is optionally substituted by C 4-C 5 -alkyl, halogen , hydroxy or ise)

Ci-Cv-alkoxy, and these groups can be connected with the help of any position to the amine of the tetrahydronaphthalene system and can optionally be substituted in one or more positions 1-2

With keto groups, 1-2 C.-C3-alkyl groups, 1-2 C.-C3-alkyl groups, 1-3 halogen atoms or 1-2 with exomethylene groups, and may optionally be hydrogenated in one or more sites ,

B" is a hydroxy group,

VE? represents a C 4-Cv-alkyl group or an optionally partially or fully fluorinated C 1-Cv-alkyl " group, w-v and K7, independently of each other, represent a hydrogen atom, a methyl or ethyl group, or, c together with the carbon atom of the tetrahydronaphthalene system, represent a C3-Co-cycloalkyl ring, with the condition that at least three of the radicals B", B, B" and B" do not represent hydrogen, represent another variant of the invention.

Stereoisomers of the general formula (I), in which B" and K", independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, a C-Cr-alkyl group, a C-Cv-perfluoroalkyl group, a cyano group, C-C-Alkoxy group, or together represent a C-C-Alkylenedioxy group, in this case BK and B? must be directly adjacent,

Me. B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted 20 C.-C.d.-alkyl group, a C41-Cio-alkyl group, a C41-C0-alkylthio group or a C--Cv- perfluoroalkyl group,

T" B"" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

a C.-C.ru-alkyl group, or a C.4-C.-alkyl group,

BZ is phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolyl, isoquinolinyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, 1nyl, or 1-phenylcinnyl, (F) ,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, or benzimidazolyl or indolyl group, which is optionally substituted with C 4-C 5 -alkyl, halogen, hydroxy or

C.-C.-Alkoxy, and these groups can be connected by means of any position to the amine of the tetrahydronaphthalene system and can optionally be substituted in one or more places by 1-2 keto groups, 1-2 C-C3- alkyl groups or 1-2 exomethylene groups and may optionally be hydrogenated in one or more areas,

B" is a hydroxy group,

BZ represents a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl group, 25 and K", independently of each other, represent a hydrogen atom, a methyl or ethyl group or,

together with the carbon atom of the tetrahydronaphthalene system, the C3-Ce-cycloalkyl ring, provided that at least three of the radicals B", 2, B"! and B", do not represent hydrogen, represent another variant of the invention.

Stereoisomers of the general formula (I), in which

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

a C1-C1-alkyl group, a C4-C10-alkyl group, a C1-C0-alkylthio group, a C1-C6-perfluoroalkyl group, a cyano group or a nitro group, or BK" and K" together represent a group selected from the groups -O-(СН 2)4-О-, -О-(СНо)-СНо-, -О-сСнН-СН- and «СНао)рдао-, where n-1 or 2, and the terminal oxygen atoms and/ or carbon atoms are connected to ring carbon atoms directly adjacent to them, or MAZUR, where ВЗ and ВУ, independently of each other, can be hydrogen, C.4-Св-alkyl or (СО)-С.-Св- alkyl,

BZ is a C 41 -C 10 -alkyl group, which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms or 1-3 C.-Cv-alkoxy groups, an optionally substituted phenyl group or a naphthyl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1-2 keto groups, 1-2 C-C-alkyl groups, 1-2 C-C-alkyl groups, 1-3 halogen atoms, 1-2 exomethylene groups and which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, and these groups can be connected through any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas,

B" is a hydroxy group,

VE? is a C 4-Cv-alkyl group or an optionally partially or fully fluorinated C 4-Cv-alkyl Ha group, aryl group, C--Cv-alkylaryl group, Co-Cv-alkenylaryl group, C3-C,-cycloalkyl group,

C.4-Cv-alkyl-C3-C,-cycloalkyl group, or Co-Cv-alkenyl-C3-C,-cycloalkyl group, and 9) 25 and K7, independently of each other, represent a hydrogen, methyl or ethyl atom group, or, together with the carbon atom of the tetrahydronaphthalene system, a C3-Ce-cycloalkyl ring, provided that at least three of the radicals ВЕ", В, В! and В" do not represent hydrogen, "And represent another variant of the implementation of the invention. "

Stereoisomers of the general formula (I), in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, etc.)

A C1-C2-alkyl group, a C1-C10-alkylthio group, a C1-C10-alkylthio group, a C--C1-perfluoroalkyl group, a cyano group or a nitro group, or BK" and K" together represent a group selected from group -O-(CH 2)4-O-, -O-(СНо)-СНо-, 35.О-СНЕСН- or "(СНа)вю-, so where n-1 or 2, and terminal oxygen atoms and/or carbon atoms are connected to ring carbon atoms directly adjacent to them, or MAN, "where BZ and KU, independently of each other, represent hydrogen, C.4-Cv-alkyl or (CO)-C.- C1-alkyl, with c BZ is a C1-C10-alkyl group, which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms or 1-3 C-C5-alkoxy groups, an necessarily substituted phenyl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1-2 keto groups, 1-2

C-Cv-alkyl groups, 1-2 C.i-Cv-alkoxy groups, 1-3 halogen atoms or 1-2 exomethylene groups (ee) and which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and /or 1-2 sulfur atoms, and these groups can be connected by means of any position to the amine of the tetrahydronaphthalene o system and can optionally be hydrogenated in one or more areas, (o) B" is a hydroxy group, is a C 4-Cv-alkyl group or an optionally partially or fully fluorinated C 4-Cv-alkyl group, an aryl group, a C--Cv-alkylaryl group, a C-Cv-alkenylaryl group, C3- The C,.-cycloalkyl group, i» C,4-Ci-alkyl-C3-C,-cycloalkyl group, or Co-Ci-alkenyl-C3-C,-cycloalkyl group, 25 and K7, independently of each other, represent is a hydrogen atom, a methyl or ethyl group, or, together with a carbon atom of the tetrahydronaphthalene system, a C3-Ce-cycloalkyl ring, provided that at least three of the radicals B", B, B"! and B" are not hydrogen,

GF) represent another embodiment of the invention. kyu Stereoisomers of the general formula (I), in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, a C.-C.sub.5-alkyl group, a C.-C.sub.-alkyl group, a C.--C.sub.-perfluoroalkyl group, or a cyano group, or В and В? together represent a group selected from the groups -О-(СНа)в-О-, -ОО-(СНо)д-СН»о-, -О-СНеСН- and «СНао)дао-, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms are connected to ring carbon atoms directly adjacent to them,

BZ is a C 1-C.o-alkyl group, which may optionally be substituted by 1-3 hydroxy groups, 65 halogen atoms, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl,

quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, which is optionally substituted by C 4-C 5 -alkyl, halogen, hydroxy or

C.i-Cv-alkoxy, and these groups can be connected by means of any position to the amine of the tetrahydronaphthalene system and may optionally be substituted in one or more places by 1-2 keto groups, 1-2 C.i- C3-alkyl groups, 1-2 C.i-C3-alkoxy groups, 1-3 halogen atoms or 1-2 exomethylene groups, and may optionally be hydrogenated in one or more areas,

B" represents a hydroxy group, 70 BZ represents a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl group, 29 and ВЕ", independently of each other, represent a hydrogen atom, methyl or an ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a C3-Ce-cycloalkyl ring, provided that at least three of the radicals B", B2, B! and B" do not represent hydrogen, 19 represent another embodiment of the invention.

Stereoisomers of the general formula (I), in which

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

a C.-Cb-alkyl group, a C.-Cv-perfluoroalkyl group, a cyano group or a C.-Cv-alkyl group, or together

S.-Co-alkylenedioxy group, in this case KE! and B? must be directly adjacent,

BZ is phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolinyl, isoquinolinyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, 1-7-8, or cinnolazinyl. a naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, or benzimidazolyl or indolyl group, which is optionally substituted with C 4 -C 5 -alkyl, halogen, hydroxy or

C.-C.-Alkoxy, and these groups can be connected by means of any position to the amine i) of the tetrahydronaphthalene system and may optionally be substituted in one or more places by 1-2 keto groups, 1-2 C.- C3-alkyl groups, 1-2 exomethylene groups and may optionally be hydrogenated in one or more areas, "E

B" is a hydroxy group,

BZ represents a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl C group, (Ce) 29 and ВЕ", independently of each other, represent a hydrogen atom, methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a C3-Ce-cycloalkyl ring, provided that at least three of the radicals БЕ", 2, Б"! and Б" do not represent hydrogen, so represent another embodiment of the invention.

According to another embodiment of the invention, it offers stereoisomers of the general formula (1), "in Hey 3 with E! with

And 5 so Kk i-o 4

F Kk tou V o ry2

NM. WITH

Y and (9 5B in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

F, an optionally substituted C 41-Cio-alkyl group, an optionally substituted C 4-C-o-alkyl group, a C.4-C:o-alkylthio group, a C-Cv-perfluoroalkyl group, a cyano group or nitro group, or B" and 2 together represent a group selected from the group -O-(СНа)н-О-, -ОО-(СНо)й-СНо-, -ОО-СНАСН-, -СНао)во- , "MH-A(CHNao)dni, M(C4-C3-alkyl)-(CHNao)dni, and 6bo -MH-M-CH-, where n-1 or 2, and terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to ring carbon atoms directly adjacent to them, or MAZUR, where ВЗ and ВУ, independently of each other, can be hydrogen, С.4-Св-alkyl or (СО)-С.- C-alkyl, because B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

a C.-C.ru-alkyl group, a C.4-C.sub.10-alkyl group, a C.-C.sub.-alkylthio group or a C.-C.sub.5-perfluoroalkyl group,

B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted

C.-C.alkyl group, or C.4-C.io-alkyl group, BZ is a C.4-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms or 1-3 C.- St-Alkoxy groups, optionally substituted

a C3-C1-cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group which is optionally substituted, independently of each other, by one or more groups selected from C.4- C-alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 SOOC "Z groups), C-C-Alkoxy groups, halogen atoms, exomethylene groups or oxygen atoms, 70 of which optionally contains 1 -3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, and this group can be connected by any position to the amine of the tetrahydronaphthalene system and optionally can be hydrated in one or more areas,

B" is a hydroxy group, or an OB group, /5 where KO is a C.1-C.o-alkyl group,

BZ represents a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl group, 25 and K", independently of each other, represents a hydrogen atom, a methyl or ethyl group, or, together with by a carbon atom of the tetrahydronaphthalene system, a C3-Ce-cycloalkyl ring. 20 Stereoisomers of the formula ІІ also fall under the general formula |.

According to another embodiment of the invention, it offers stereoisomers of the general formula (1), 7 6

Кк к сч 25 КК! about "I

Kk « e F 2 o

NM. ez so in which "

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

C.-C.p-alkyl group, C.sub.4-C.sub.6-alkyl group, C.sub.1-C.sub.6-alkylthio group, C.sub.1-C.sub.4-perfluoroalkyl group, cyano group or C.sub.c nitro group, or K" and K" together represent a group selected from the groups -O-(CH2)4-O-, -O-(СНо)-СНо-, :з» -0-снН-сСн-, «СНао)вао-, «МН-А(СНао)вняі, M(C4-C3-alkyl)-(CHo) give and -"MH-MeCH-, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to those directly adjacent to them ring carbon atoms, because either ME:ZE, where KZ and KZ, independently of each other, can be hydrogen, C.4-Cv-alkyl or (CO)-C.-Cv-alkyl, and BZ is C 1-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms

He») or 1-3 C.i.-C.-alkyl groups, an optionally substituted C 3-C-cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which optionally substituted by one or more groups selected from C 4-Cv-alkyl groups (which can optionally be substituted by 1-3 hydroxy or 1-3 SOOC C groups), C-Cv- alkoxy groups, halogen atoms or exomethylene groups, and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, and this group can be connected with any - of any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more areas, o B" represents a hydroxy group, or a group OB 79, where KO represents a C.1-C.o-alkyl group, o BZ represents a C 1-Cv-alkyl group or optionally a partially or fully fluorinated C 41-Cv-alkyl group, because 29 and VE", independently of each other, represent is a hydrogen atom, a methyl or ethyl group, or, together with a carbon atom of the tetrahydronaphthalene system, represents a C3-C-cycloalkyl ring.

Stereoisomers of the general formula (I), in which

B" and K?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, a 65 C.-C.di-alkyl group, a C1-Cio-alkyl group, a C1-C0-alkylthio group, C-- C-perfluoroalkyl group, cyano group or nitro group, or B" and B? together represent a group selected from groups. -О-(СН 2)4-О-, -О-(СНо)п-СНо-,

-0-сСнН-СН- and "СНао)рдао-, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms are connected to the ring carbon atoms immediately adjacent to them, or ME:ZE, where ВЗ and VU, independently of each other, can be hydrogen, C4-Cv-alkyl or (CO)-C4-Cv-alkyl,

BZ is a C.1-C.o-alkyl group, which can optionally be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1- 2 keto groups, 1-2 C.-C5-alkyl groups, 1-2 C.-C5-alkoxy groups, 1-3 halogen atoms or 1-2 exomethylene groups and which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, and these groups can be connected through any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas,

B" is a hydroxy group,

BZ is a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl 19 group, an aryl group, a C--Cv-alkylaryl group, a C-Cv-alkenylaryl group, C3-C, .-cycloalkyl group,

C.1-Cv-alkyl-C3-C-cycloalkyl group, or Co-Cv-alkenyl-C3-C-cycloalkyl group, 29 and ВЕ", independently of each other, represent a hydrogen atom, methyl or ethyl group, or , together with the carbon atom of the tetrahydronaphthalene system, the C3-C-cycloalkyl ring, represent another embodiment of the invention.

Stereoisomers of the general formula (I), in which

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

C1-C1 alkyl group, C4-C10-alkylthio group, C4-C10-alkylthio group, C1-C6-perfluoroalkyl group, cyano group or nitro group, or B" and B" together represent a group selected from the groups -O- (СН 2)4-О-, -О-(СНо)д-СНое-, with doubles -О-СНЕСН- and (СНа)ву-, where n-1 or 2, and terminal oxygen atoms and/or atoms carbons are connected to ring carbon atoms immediately adjacent to them and 9) or MAZUR, where VZ and VU, independently of each other, can be hydrogen, C.4-Cv-alkyl or (СО)-C.-Cv- alkyl, "I 30 BZ represents a C 4-Cio-alkyl group, which is optionally substituted by 1-3 hydroxy groups or halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted 1-2 keto groups, 1-2 C.-C5-alkyl groups, 1-2 C.-C5-alkoxy groups, 1-3 ise) halogen atoms or 1-2 exomethylene groups, and which contains 1-3 nitrogen atoms and/ or 1-2 oxygen atoms and/or 1-2 sulfur atoms, and these groups can be linked by any lying down with amine

From the tetrahydronaphthalene system, and may optionally be hydrogenated in one or more areas, so

B" is a hydroxy group,

BZ represents a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl group, " 20 29 and B", independently of each other, represent a hydrogen atom, a methyl or a stylish group, or, -o together with the carbon atom of the ring, C3-C-cycloalkyl ring, c represent another variant of the implementation of this invention.

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, a 45 C.-Ci-alkyl group or a C.-Ci-alkyl group, or B! and B? together represent a group selected from groups (ee) -0-(СнНо)д-о-, -0-(СНо)д-СН»е-, -0-СНе:СН- or -(СНао)дао-, о | where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms are connected to ring carbon atoms directly adjacent to them, b" BZ is a C 4-Sio-alkyl group, which is optionally substituted by 1-3 hydroxy groups or atoms 20 галогену, фенільну, фталідильну, ізоіндолільну, дигідроіндолільну, дигідроізоіндолільну, дигідроізохінолінільну, тіофталідильну, бензоксазинонільну, фталазинонільну, хінолінільну, ізохінолінільну, ї» хінолонільну, ізохінолонільну, індазолільну, бензотіазолільну, хіназолінільну, хіноксалінільну, циннолінільну, фталазинільну, 1,7- або 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group, which is optionally substituted by C 4-Cv-alkyl, halo nom, hydroxy or 55 Ci-Cv-alkoxy, and these groups can be connected by means of any position with an amine

Gee! of the tetrahydronaphthalene system and may optionally be substituted in one or more places by 1-2 keto groups, 1-2 C.i-C3-alkyl groups, 1-2 C.i-C3-alkyl groups, 1-3 halogen atoms or 1 -2 with exomethylene groups, and may optionally be hydrogenated in one or more areas,

B" represents a hydroxy group, 60 ВЕ? represents a C 4-Cv-alkyl group or an optionally partially or fully fluorinated C 4-Cv-alkyl group, and K7, independently of each other, represent a hydrogen atom, methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a C3-C-cycloalkyl ring, represent another variant of the implementation of this invention. because Stereoisomers of the general formula (I), in which

B" and B, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom,

a C.-Cr-alkyl group or a C.-Cv-alkyl group, or together a C.i-C-alkylenedioxy group, in this case V'y v? must be directly adjacent,

BZ is phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolinyl, isoquinolinyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, 1-7-8, or cinnolazinyl. a naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group, which is optionally substituted by C -C5 -alkyl, halogen, hydroxy or 70 cCi -Cv -alkoxy, and these groups can be connected by means of any position to the amine of the tetrahydronaphthalene system and may optionally be substituted in one or more places by 1-2 keto groups, 1-2 C-C3-alkyl groups or 1-2 exomethylene groups and may optionally be hydrogenated in one or more places,

B" represents a hydroxy group, ТBZ represents a C 1-Cv-alkyl group or an optionally partially or fully fluorinated C 41-Cv-alkyl group, 29 and ВЕ", independently of each other, represent a hydrogen atom, methyl or an ethyl group, or, together with a carbon atom of the tetrahydronaphthalene system, a C3-Co-cycloalkyl ring represent another embodiment of this invention.

Stereoisomers according to point 1, which bear substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group that includes C 4-Cv-alkyl, C-Cv-alkyl, SOOK"Z, MAU, C-Cv-perfluoroalkyl, halogen, o hydroxy, cyano, nitro, -O-(СНо)й-О-, -0-(СНо)2-СНо-, -ОО-СНЕСН-, -(«СНо)до-, / «"МНА»СНа)dai -, -M(C4-C3-alkyl)-(СНо)н-и or -МН-М-СН-, where n-1 or 2, and terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms connected to ring carbon atoms immediately adjacent to them, and divalent radicals can be considered as two substituents according to the definitions of this invention, represent i) a special variant of the invention.

B "Z represents hydrogen or C-C10-alkyl or C4-Cv-alkyl. If K"/VK2 represents SOOV "Z, then the preferred value for B "Z is tert-butyl. "AND

A special embodiment of the invention are compounds in which VK Z is formed by a radical, which as a substituent "contains SOOK "Z and B Z is C4-Cio-alkyl or C.4-Cv-alkyl.

Stereoisomers according to point 2, which bear three substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group that includes C1-C6-alkyl, C-C6-alkyl, C4-C6-perfluoroalkyl, halogen, hydroxy, cyano .

Zo -M(C.-C3-alkyl)-(CHO)pi-, or -MH-M-CH-, where n-1 or 2, and terminal oxygen atoms and/or carbon atoms and/or co nitrogen atoms with "connected with ring carbon atoms immediately adjacent to them, and divalent radicals can be considered as two substituents according to the definitions of this invention, represent another variant of the invention. "

Stereoisomers of formula I or II according to item 2, in which KE! and B? together represent the radicals - t0 -0-(Сно)й-О-, -0-(СНо)-СНо-, -О-СН-СН-, -СНао)во-, «МНА(СНао)вни-; "-M(C1-C3-alkyl)-(СНо)дниай or -МН-М-СН-, c represent subgroups of these stereoisomers. In each case, the terminal atoms of the divalent groups,

From" presented above, connected to the ring carbon atoms of the tetrahydronaphthalene system directly adjacent to them.

Stereoisomers in accordance with point 2, in which B", B, KE" or EK" are selected from the group that includes C.-Cv-alkyl, because 15 C.-Cv-alkyl, C.-Cv-perfluoroalkyl, halogen, hydroxy , cyano, or nitro, are a subgroup.

Stereoisomers according to item 1 or 2, in which B", K2, B"! or KVK" selected from the group that includes optionally substituted C 1 -C 1 -alkyl, optionally substituted C 4 -C 4 -alkyl, C -C 1 -perfluoroalkyl, halogen,

Ge" hydroxy or cyano, represent another subgroup.

Stereoisomers of formula I or II according to point 2 form another subgroup in which alkyl radicals B! and B? represent -(СНо)о- and, therefore, together with the carbon atom of the ring form a 5- and b-membered ring.

Chl» Stereoisomers of the general formula | or II, which bear one or two substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group that includes C.-Cv-alkyl, C--Cv-alkyl, C4-Cv-perfluoroalkyl, halogen, hydroxy, nitro, -0- (СнНао)н-О-, -0-СНо)д-СнНе-, -0-сСнАсн»-, -(СНао)до-, -МН-(СНо) days,

M(C1-C3-alkyl)-(CHO)n-i or -MH-Me:CH-, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected directly to ring carbon atoms adjacent to them, represent iF) a special variant of the invention. ko Stereoisomers of the general formula I, which bear two substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group that includes C 4-Cv-alkyl, C-Cv-alkoxy, C-Cv-perfluoroalkyl, halogen, hydroxy, bo Cyano, nitro, -0О-(СНо)в-О-, -0О-(СНо)-СНо-, -0О-СНеСН-, "(СНао)вно-, """МНА(СНо)вня, "М(С4-Сз- alkyl)-(СНо)дя-4- or -МН-МАСН-, where n-1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to ring carbon atoms directly adjacent to them, and divalent radicals can be considered as two substituents according to the definitions of this invention, represent a subgroup.

Stereoisomers of the general formula I or II according to item 1 or 2, in which B C is a b5 C.-C.alkyl group, which can optionally be replaced by 1-3 hydroxy groups, halogen atoms, 1-3

C.i.-C.sub.-alkyl groups, an optionally substituted C.sub.3-C.cycloalkyl group, an optionally substituted heterocyclic group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by one or more groups selected from C.i. -Cv-alkyl groups, C.i.-Cv-alkoxy groups, halogen atoms or exomethylene groups, and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/ or 1-2 keto groups, and these groups can be connected by means of any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas, represent another variant of the invention.

Stereoisomers of the formula I or II, in which KZ is a C1-Cio-alkyl group, which can optionally be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl group, a monocyclic or 70 bicyclic heteroaryl group, which is optionally necessarily substituted by 1-2 keto groups, 1-2 C by 1-Cv-alkyl groups, 1-2

C.-Cv-alkoxy groups, 1-3 halogen atoms or 1-2 exomethylene groups, and which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, and these groups can be connected by means of any position to a nitrogen atom and may optionally be hydrogenated in one or more sections, represent another variant of the invention.

Stereoisomers of the general formula I or II, in which B C is a phenyl or naphthyl group, which is optionally substituted by one or more radicals from the group that includes C 4-Cv-alkyl, C4-Cv-alkoxy, hydroxy, halogen, cyano , CE", nitro, SOOV3, or MEZEU, represent an embodiment of the invention.

Compounds of the general formula I or II in accordance with points 1-6, in which KZ is a monocyclic or bicyclic heteroaryl group, which is optionally substituted by one or more groups, independently of each other selected from C-Cv-alkyl groups, which themselves are not 1-3 hydroxy or 1-3 sovB"Z groups, where BZ is hydrogen or C 1-Cv-alkyl, C4--Cv-alkoxy groups, halogen atoms, hydroxy groups, MAZE? groups, exomethylene groups or an oxygen atom, and which optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, and this group can be connected with of any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more sections, represent a preferred variant of the implementation of this invention.

Compounds of the general formula I! or II according to clauses 1-6, in which BZ is a monocyclic or bicyclic heteroaryl group, which is optionally substituted by one or more groups, independently of each other, selected from C1-C6-alkyl groups, which themselves are optionally can be replaced by 1-3 hydroxy or 1-3 "zo soov"Z groups, where "Z represents hydrogen or C 1-Cv-alkyl, C4--Cv-alkoxy groups, halogen atoms, hydroxy groups, MAZEZ groups, exomethylene groups or oxygen atoms, and which optionally contains 1-4 nitrogen atoms and/or M 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, and this group can be connected with by means of (Те) any position with the amine of the tetrahydronaphthalene system, and may optionally be hydrogenated in one or more areas, and KU represents an optionally partially or fully fluorinated C .4-Cv-alkyl group, o represent another preferred embodiment of this invention. (se)

Stereoisomers of the general formula I, in which KZ is a C 1-Sio-alkyl group, which may optionally be substituted by 1-3 hydroxy groups, halogen atoms, phenyl, naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydroquinolinyl, thiophthalidyl, " benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or - with 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoimidolinyl, or any benzylinyl group, h» is optionally substituted by C 4-C 4-alkyl, halogen, hydroxy or C 1-C 4-alkyloxy, represent a preferred embodiment of the invention.

Stereoisomers of the general formula I or II, in which KZ is a C.-C.o-alkyl group, which may optionally be substituted by 1-3 hydroxy groups, halogen atoms, or phenyl, phthalidyl, isoindolyl, co-dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, o phthalazinonyl, quinolinyl, isoquinolinyl, quinolyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or me) 1,8-naphthyridinyl, dihydroindolinolide, benzoindolinoinyl, or , which 20 of them are optionally substituted by C-C-alkyl, halogen, hydroxy or C-C-Alkoxy, represent a special embodiment of the invention.

T» Stereoisomers of formula (I), in which BK C is a phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, thiophthalidyl, indazolyl, benzothiazolyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, represent another embodiment of the invention.

HF) Stereoisomers of formula (I), in which BZ is dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, 7-phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, represent another embodiment of the invention. Stereoisomers of the general formula 1, in which KZ is an isoquinolonyl, quinolonyl, quinazolinyl or phthalazinyl group, represent another variant of the invention.

Stereoisomers of the general formula I or II, in which BZ is an optionally substituted isoquinolonyl, quinolonyl, quinazolinyl, phthalazinyl, indazolyl, quinolinyl, isoquinolinyl, isoquinolonyl, dihydroindolonyl, dihydroindolyl, dihydroindolonyl, naphthyl, pyridyl or phthalidyl group, 65 represent another embodiment .

Stereoisomers of the general formula I, in which B C is isoquinolin-1(2H)one-5yl, quinoline-2(1H)-one-bByl,

8- or 7-fluoro-2-methyl-quinazoline, 7,8-difluoro-4-methyl-quinazoline, 7,8-difluoro-2-methyl-quinazoline or 2-methyl-phthalazin-1-one are another option implementation of the invention.

The KZ radical is connected with the help of an amine to the tetrahydronaphthalene system. If K Z has several positions in which it is chemically possible to form a bond with the ring system, then this invention covers all such possibilities.

The EZ radical also falls within the scope of this invention if it is hydrogenated in one or more areas.

As substituents of monocyclic or bicyclic heteroaryl groups (heterocyclic groups) of KZ, as they were previously defined, suitable in all chemically suitable positions are, for example, hydroxy, halogen atoms, 70 especially fluorine and chlorine, C-C5-alkyl groups (which themselves may optionally be substituted by hydroxy groups,

C.-C5-Alkoxy groups or soov"Z groups, where "C is hydrogen or C1-C8-alkyl), especially methyl, (C.-C8)-alkenyl groups, fully or partially fluorinated C.-C8- alkyl groups, especially SEz, SEN", or

Sovv, C4-Cv-alkoxy groups, especially methoxy and ethoxy, MAU? groups, especially МН2, п(СНа)» or МН(СН»), /5 cyano groups, as well as keto groups, which are formed by Kk! the carbon atom of the ring of the heteroaryl group and oxygen, which forms an M-oxide with a nitrogen atom optionally present in the ring. Of the above, as a preferred group of substituents for the KZ radical, as defined in clause 1 and in all other clauses of the formula, there is such a group as fluorine, chlorine, OH,

CH», SEz, SEN», or SoEv, OSNz, OSON5», MNo, M(CHnaz)» and MH(CH”), cyano, keto, or oxygen.

As the substituents of the heterocyclic group VU, as defined earlier for the above-described variants of the implementation of the invention, suitable in all suitable positions are, for example, halogen atoms, C 4-C 5 -alkyl groups (which are themselves substituted by hydroxy groups or SOOMK"Z groups), where KZ is hydrogen or C o/4-Cv-alkyl), (C.-C,)-alkenyl groups, fluorinated C.4-Cv-alkyl groups, C.-Cv-alkyl groups or cyano groups.

Stereoisomers of the general formula I! or II, in which BE is phenyl or naphthyl, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,,)ide SM isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, o phthalazinyl, 1,7-or A 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, which is optionally substituted by C 1 -C 2 -alkyl, halogen, hydroxy or C 1 -C 2 -alkyl, also represents a preferred embodiment of the invention.

Stereoisomers of the general formula I, in which B C is phenyl, phthalidyl, thiophthalidyl, " benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolyl, isoquinolonyl, " indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1, An 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, which (Ce) is optionally substituted with C 1 -C 6 -alkyl, halogen, hydroxy or C 1 -C 5 -alkoxy, is a more preferred embodiment of the invention. 3о Heterocyclic group KZ is not aromatic and can be, for example, pyrrolidine, imidazolidine, co-pyrazolidine or piperidine.

The hydroxy group in E7 can be protected with one of the commonly used hydroxy protecting groups known to those skilled in the art, such as, for example, a simple silyl ether or ester.

C.4-Cio-organic acids or as C.4-Cv-simple ether or benzyl ether, preferably as such or usually - 70 used hydroxy-protecting groups or as C 1-Cv-simple ether. How radical is KE? the c hydroxy group is particularly preferred. :z» Commonly used hydroxy-protecting groups are described in more detail in |G. MU. Sgeepe, R. b. M. MUtsiv "Rgogesiime Sgoshrz ip Ogdapis Zupipeziv," 2nd edition, Chdopp UMieu "5 Bopv, 19911.

Preferred groups are preferably alkyl, aryl or mixed alkylaryl-substituted silyl groups, such as, for example, trimethylsilyl (TM5), triethylsilyl (TEZ), tert-butyldimethylsilyl (TVOM5), tert-butyldiphenylsilyl (TVORB5) or triisopropylsilyl group (TIR5) or other standard (α) hydroxy-protecting group (methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl, or tetrahydrofuranyl groups).

Radical KE? directly related to the tetrahydronaphthalene system. If the radical K? has several positions in which it is chemically possible to form a bond with the ring system, then the present invention covers all such

T" possibilities.

Stereoisomers of the general formula I, in which BE? represents a C-C-alkyl group or an optionally partially or fully fluorinated C-C-C-alkyl group, C3-C,U-cycloalkyl group, C4-Cv-alkyl-C3-C,-cycloalkyl two TrUpU, Co-Cv-alkenyl-C3-C7-cycloalkyl group, heterocyclic group, C.-Cv-alkylheterocyclic group,

A Co-Cv-alkenylheterocyclic group, an aryl group, a C4--Cv-alkylaryl group, or a Co-Cv-alkenylaryl group, (F, represent another variant of the invention. ko Stereoisomers of the general formula I according to item 1, in which BC? represents is a C 3-C,-cycloalkyl group, a C4-Cv-alkyl-C3-C,-cycloalkyl group, a C-Cv-alkenyl-C3-C-cycloalkyl group, a heterocyclic group, because a C-Cv-alkylheterocyclic group, C» o-Cvd-alkenylheterocyclic group, aryl group, Ci-Cv-alkylaryl group, Co-Cv-alkenylaryl group, monocyclic or bicyclic heteroaryl group, which is optionally substituted with 1-2 keto groups, 1-2 Ci-C5-alkyl groups, 1-2 C-Cv-alkoxy groups, 1-3 halogen atoms or 1-2 exomethylene groups and which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms,

C.-Cv-alkylteteroaryl group or Co-Cv-alkenylheteroaryl group, or Co-Cv-alkynylheteroaryl group, 65 and these groups can be connected by any position with the tetrahydronaphthalene system and can optionally be hydrogenated in one or more sections, represent another subgroup according to the invention.

Stereoisomers of the general formula I, in which KE? represents a C.-Cv-alkyl group or an optionally partially or fully fluorinated C.-Cv-alkyl group, an aryl group, a C.-Cv-alkylaryl group, a C.-Cv-alkenylaryl

Group, C3-C1-cycloalkyl group, C4-C6-alkyl-C3-C1-cycloalkyl group, or

Co-Cv-alkenyl-C3-C3-cycloalkyl group represent a variant of the invention.

Stereoisomers of the general formula I or II according to points 1-6, in which KV? is a C4-C3o-alkyl group or an optionally partially or fully fluorinated C.1-C4o-alkyl group, preferably a C.-C5-alkyl group or an optionally partially or fully fluorinated C.4-Cb5-alkyl group, more preferably 70 C 1 -C 3 -alkyl group or optionally partially or fully fluorinated C 4 -C 3 -alkyl group, especially optionally partially or fully fluorinated C 41 -C 3 -alkyl group, most preferably CE 3 or CoEB, represent another variant of the invention.

Stereoisomers of the general formula I or II according to points 5 and 6, in which KE? represents a C.-Cv-alkyl group or an optionally partially or fully fluorinated C.4-Cv-alkyl group, represent another variant 75 of the implementation of the invention. KE? is preferably a trifluoromethyl group or a pentafluoroethyl group.

Preferred are stereoisomers according to items 1-6, in which the radical B? represents an optionally partially or fully fluorinated C.i.-C.v.-alkyl group, especially an optionally partially or fully fluorinated C.-C.sub.3-alkyl group.

Radicals and all subcombinations thereof, which are exemplified, represent a more preferred subgroup as disclosed herein.

The term "halogen atom" or "halogen" means an atom of fluorine, chlorine, bromine or iodine. A fluorine, chlorine or bromine atom is preferred.

C.-Sio- or C.4-Cv-alkyl groups B", 2, KU, B? 5, 7,7, "2 and KZ can have a straight or branched chain and represent, for example, methyl, ethyl, n - a propyl, isopropyl, n-butyl, tert-butyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, as well as a hexyl, heptyl, nonyl or decyl group and their arbitrarily branched derivatives.

A methyl or ethyl group is preferred.

The above-described alkyl groups can optionally be replaced by 1-5 groups, independently of each other, selected from hydroxy, piano, nitro, C.-C.sub.5-alkoxy groups, halogen, MAZE?, partially or fully fluorinated C.4 -C3-alkyl group; substituents 1-3 halogen atoms and/or 1-3 hydroxy- and/or 1-3 cyano- and/or Ж 1-3 сОвВС'С groups represent a subgroup. Fluorine atoms, or hydroxy, methoxy, and/or cyano groups of He represent a predominant subgroup.

Alkyl groups can optionally be replaced only by 1-3 hydroxy groups and/or 1-3 SOOVK "Z" groups. o

Hydroxy groups are more preferred. with

For a partially or fully fluorinated C 4-C3-alkyl group, consider, for example, the following partially or fully fluorinated groups: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1- trifluoroethyl, tetrafluoroethyl and pentafluoroethyl. Among them, a trifluoromethyl group or a pentafluoroethyl group is preferred, and for a fully fluorinated group, a 70 perfluoroalkyl group is also preferred. Reagents that are optionally used in the synthesis are commercially available or are described in published syntheses of relevant reagents that fall within the scope of the known state of the art, or can be used in published syntheses in a similar manner. "» C4-C10- or C1-C8-alkoxy groups can have a straight or branched chain and represent, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group Preferred are C--C5-Alkoxy group Most preferred is methoxy or ethoxy group.

The above-described alkoxy groups may optionally be substituted with 1-3 groups selected from halogen, especially fluorine, chlorine, hydroxy and piano. b C.i-Cv-alkylthio groups can have a straight or branched chain and represent, for example, Mmethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio, e 2.2 -dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group. A methylthio or an ethylthio group is preferred.

I» The MEZO substitute is, for example, МН 5», МН(СНаз), М(СНа)», МН(СоНв), М(СоНв)», МН(СзН7), М(СзН),

МН(САН), М(САНе)», МН(СнНИий), М(СнН.и4)», МН(СО)СН5У, МН(СО)СОН, МН(СО)СЗН;, МН(СО)С,; Not either

МН(СО)С НУ.

A cycloalkyl group is a saturated cyclic group containing 3-7 ring carbon atoms, which is optionally substituted by one or more groups selected from hydroxy groups, halogen atoms,

C.-Cv-alkyl groups, C-Cv-alkoxy groups, MAE? groups, SOOBK"Z groups, CHO or piano, such as, for example, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl or methylcycloheptyl. 6o C.-Cv-alkyl-C3-C,- cycloalkyl group KE? is defined as a cycloalkyl group that is connected to the ring system by means of a chain of a straight or branched C.-C.-alkyl structural unit.

Co-Cv-alkenyl-Ca-C.-cycloalkyl group KE? is defined as a cycloalkyl group that is connected to the ring system by means of a straight-chain or branched Co-Cv-alkenyl structural unit.

The heterocyclic group is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine or piperidine. Heterocyclic groups are also perhydroquinoline and perhydroisoquinoline.

As substituents of heterocyclic and heteroaryl groups, take into account, for example, substituents from the group, which includes an optionally substituted C 4-Cv-alkyl group, hydroxy-, C.

SOOK 13. | SNO-. Also, substituents may not necessarily be bound to a nitrogen atom, so M-oxides also fall under this definition.

Aryl groups in the context of this invention are aromatic or partially aromatic carbocyclic groups, which consist of 6-14 carbon atoms and have a ring, such as, for example, phenyl or phenylene or some fused rings, such as, for example, naphthyl or anthranill. Examples include phenyl, naphthyl, tetralinyl, anthranyl, indanyl, and indenyl.

Aryl groups may be substituted at any suitable site resulting in the formation of a stable stereoisomer by one or more radicals from the group consisting of hydroxy, halogen, or C 1 -C 1 -alkyl,

C-C-Alkoxy, cyano, C3, or nitro, which are optionally substituted with 1-3 hydroxy groups or SOOK "Z groups.

Optionally substituted phenyl group and naphthyl group are preferred.

C.-C-alkylaryl group is an aryl group, as already described above, which is connected to the ring system 75 by means of a straight-chain or branched C.-C-alkyl structural unit.

Co-Cv-alkenylaryl group is an aryl group, as already described above, which is connected to the ring system by means of a straight-chain or branched Co-Cv-alkenyl structural unit.

The Co-Cv-alkynylaryl group is an aryl group, as already described above, which is connected to the ring system by means of a straight-chain or branched Co-Cv-alkynyl structural unit.

The monocyclic or bicyclic heteroaryl group may be optionally substituted with one or more substituents selected from the group consisting of a C--Cv-alkyl group, a C--Cv-alkyl group, a halogen or exomethylene, which are optionally substituted by 1-3 hydroxy in groups or 1-3 NIPPLE WITH groups. Substituents can optionally also be bound to a heteroatom. M-oxides are also part of this invention.

A monocyclic or bicyclic heteroaryl group may contain 0-9 groups, optionally from the group of 29 nitrogen atoms, oxygen atoms, sulfur atoms or keto groups, of which it may contain no more than 3 (47?) nitrogen atoms, not more than 2 oxygen atoms, no more than 2 sulfur atoms, and no more than 2 keto groups. Any subcombination of these groups is possible. A heteroaryl group can be hydrogenated in one or more sites.

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

Біциклічні гетероарильні групи можуть являти собою, наприклад, фталідильну, тіофталідильну, індолільну, ізоіндолільну, дигідроіндолільну, дигідроізоіндолільну, індазолільну, бензотіазолільну, індолонільну, ісе) дигідроіндолонільну, ізоіндолонільну, дигідроізоіндолонільну, бензофуранільну, бензимідазолільну, о дигідроізохінолінільну, дигідрохінолінільну, бензоксазинонільну, фталазинонільну, хінолінільну, ізохінолінільну, хінолонільну, ізохінолонільну, хіназолінільну, хіноксалінільну, циннолінільну, со фталазинільну, 1,7- або 1,8-нафтиридинільну, кумаринільну, ізокумаринільну, індолізинільну, ізобензофуранільну, азаіндолільну, азаізоіндолільну, фуранопіридильну, фуранопіримідинильну, фуранопіразинильну, фуранопіридазинильну, дигідробензофуранільну, дигідрофуранопіридильну, « dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl or dihydrobenzofuranyl groups. If the heteroaryl groups are partially or fully hydrogenated, then stereoisomers of the formula 1 or 1, in which BC Z is tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridine, are part of this invention -2-onyl, 1H-pyridin-4-onyl, 4-aminopyridyl, 1H-pyridin-4-ylidenaminyl, chromanil, isochromanil, thiochromanil, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinoline -4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, so dihydroisoquinolinyl, 3,4-dihydro-2H-benzi|1,oxazinyl, 1,2-dihydro|1,3|benzoxazin-4-onyl,

And av | 3,4-dihydrobenz(|1,oxazin-4-onyl, 3,4-dihydro-2H-benzo|1,4|thiazinyl, 4H-benzo|1,4)thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl . 4-tetrahydro|1,5)naphthyridinyl, dihydro-1H-(1,5)naphthyridyl, t» 250 1H-P,5Inaphthyridin-4-onyl, 5,6,7,8-tetrahydro-AN-naphthyridin-4- onyl, 1,2-dihydrotridoyiZ,2-41)/1,3)oxazin-4-onyl,

I» octahydro-1H-indolyl, 2,3-dihydro-1H-indolyl, octahydro-2H-isoindolyl, 1,3-dihydro-2H-isoindolyl, 1,2-dihydroindazolyl, 1H-pyrrolo|2,3-B| Ipyridyl, 2,3-dihydro-1H-pyrrolo|2,3-v|pyridyl, 2,2-dihydro-1H-pyrrolo|2,3-v|Ipyridine-Z-onyl.

C-C-alkylheteroaryl group is a heteroaryl group, as already described above, which is connected to the 99 ring system by means of a straight-chain or branched C-C-alkyl structural unit.

HF) Co-Cv-alkenylheteroaryl group is a heteroaryl group, as already described above, which is connected to the ring system by means of a straight-chain or branched Co-Cv-alkenyl structural unit.

The Co-Cv-alkynyleetheraryl group is a heteroaryl group, as already described above, which is connected to the ring system by means of a straight-chain or branched Co-Cv-alkynyl structural unit. 60 C.-Cv-alkyl heterocyclic group is a heterocyclic group, as already described above, which is connected to the ring system by means of a straight-chain or branched C.1-Cv-alkyl structural unit with a ring system.

Co-Cv-alkenyl heterocyclic group is a heterocyclic group, as already described above, which is connected to the ring system by means of a straight-chain or branched C 5-Cv-alkenyl structural unit.

Stereoisomers of the general formula | or II according to the invention due to the presence of asymmetric centers in them can exist in the form of stereoisomers. The objects of this invention are all possible diastereomers (for example, КК, К5, ЗК, 55), as well as racemates and in enantiomerically pure form. The term "stereoisomers" also includes all possible diastereomers and regioisomers and tautomers (eg, keto-enol tautomers) in which the stereoisomers according to the invention can be found and which are also objects of the invention.

The compounds according to the invention can also be in the form of salts with physiologically compatible anions, for example in the form of hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate. 70 Stereoisomers according to the invention are obtained with the help of acyclic precursors of the general formula HER,

IS

ЕЕ в в ' ХА is not necessarily related to acids or Lewis acids р в в

Kp ok: vir nm "v s 29 (IN) a) o which are obtained according to methods well known from the state of the art, and which are then cyclized to obtain stereoisomers of the general formula I! or II or without an additional reagent in a solvent, preferably chlorinated hydrocarbons , such as, for example, methylene chloride or dichloroethane or concentrated organic acids, preferably glacial acetic acid, or by adding inorganic or organic acids or acids C

Lewis at a temperature in the range from -702С to -802С (mainly in the range from -302С; to 8020). "AND

If compound Sha is used, which differs from compound PP only in the presence of only two substituents on the tetrahydronaphthalene ring, then a compound of the general formula II is obtained. what

Therefore, the object of this invention is also a method of obtaining stereoisomers of the general formula I! or II, which av) is characterized by the fact that imines of the general formula II are cyclized to stereoisomers of the general formula I or II, 39 either without an additional reagent in a solvent or concentrated organic acids or by adding 09 inorganic or organic acids or Lewis acids at a temperature in in the range from -702C to -802C (mainly in the range -302C to 802), as well as their immediate predecessors of the PP formula.

New imines for cyclization are also objects of this invention, especially those described in the examples. "20 The binding of the compounds proposed in the invention to the glucocorticoid receptor (OC) and other receptors of steroid hormones (mineralocorticoid receptors (MC), progesterone receptors (RC) and androgen receptors (AK)) is checked using recombinantly obtained receptors. :z» At the same time, preparations of cytosol from 519 cells infected with recombinant baculoviruses encoding (zK-receptor) are used in binding studies. The degree of affinity that manifests

The compounds proposed in the invention to the OK-receptor, in comparison with the comparative substance, which serves as I"NI-dexamethasone, can be evaluated as high and very high. Thus, for the compound from example 285, the value of ICvo(3K)-86bnM and ICvoi was determined (RK)-"1000, and for the compound from example 49, the value of ISvo(OK)-95BNnM and ISvo(RK)-460 was determined. b The important molecular mechanism underlying the anti-inflammatory action of glucocorticoids is considered to be mediated by C- the receptor inhibits the transcription of cytokines, adhesion molecules, enzymes, and other proinflammatory factors. Such transcription inhibition is due to the interaction of the SC receptor with other transcription factors, for example, AR-1 and ME-kappa-B (reviewed information on this can be found in Sai

A.S.V. and M/ade E., BioAvzauz, 18, 1996, p. 371-378I.

The compounds of the general formula I! inhibit lipopolysaccharide (LPS) 5B-induced cytokine I/-8 secretion in human monocytes of the TNR-1 line. The concentration of cytokines was determined in the supernatant using commercially available kits for EI IZA analysis. The compound from example 285 exhibits inhibition (F. ISvo(1-8)-40OnM (7995 ef.); and the compound from example 49 exhibits inhibition of IS5o(II 8)-19Nm. ka The anti-inflammatory effect of stereoisomers of the general formula I was studied in an experiment on animals conducting an experiment with croton oil-induced inflammation in rats and mice |). Ex. Mead., 182, 1995, pp. 99-108). For this, croton oil in an ethanol solution was applied locally to the ears of animals. Simultaneously with treatment with croton oil or two hours before it, the tested substances were also applied locally or systemically. After 16-24 hours, the weight of the ears was measured, which served as a measure of inflammatory edema, and peroxidase activity, which served as a measure of granulocyte influx, and elastase activity, which served as a measure of neutrophil granulocyte influx, were determined. In this study, stereoisomers of the general formula I inhibit after their b5 local application, as well as after their systemic introduction into the body, the three above parameters of inflammation.

One of the undesirable effects that occurs most often with glucocorticoid therapy is the so-called "steroid diabetes". Nai" N.), "zIisosopisoide: Bptypoiodizsye Sgypaiadep, RIaptakKkoiodie pa

TNegariegispcipiep, (Glucocorticoids: immunological basis, pharmacology and therapeutic indications), in-vo

MUizzepzspapyispe Megiadzdezeizstpay tН, Stuttgart, 1998). The cause of steroid diabetes is the stimulation of gluconeogenesis in the liver, due to the induction of enzymes responsible for this and the action of free amino acids, which are formed as a result of the breakdown of proteins (catabolic action of glucocorticoids). The key enzyme of catabolic metabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme, which can be determined photometrically in liver homogenates, serves as an effective indicator of the undesirable effect of 7/0 glucocorticoids on metabolism. To determine the induction of TAT, animals are killed 8 hours after the introduction of the tested substances, livers are obtained from them, and TAT activity in the homogenate is measured. In this study, the stereoisomers of the general formula I, in the doses in which they have anti-inflammatory efficacy, do not induce tyrosine aminotransferase at all or induce it only to a small degree.

Proposed in the invention stereoisomers of the general formula | due to their anti-inflammatory action, as well as additional anti-allergic, immunosuppressive and anti-proliferative action, can be used as medicinal products for the treatment or prevention of the following pathological conditions in mammals and humans, which are referred to in the following description collectively as "diseases" and which include the following indications: (i ) lung diseases caused by inflammatory, allergic and/or proliferative processes: - chronic obstructive lung diseases of any origin, 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 granulomatosis, primarily Beck's disease; (i) rheumatic diseases/autoimmune diseases/joint diseases caused by inflammatory, skin allergic and/or proliferative processes: - all forms of rheumatic diseases, primarily rheumatic arthritis, acute rheumatic fever, and) polymyalgia rheumatica, - reactive arthritis, - inflammatory diseases soft tissues of other origin, "E zo - symptoms of arthritis in degenerative joint diseases (arthrosis), - traumatic arthritis, - - collagenoses of any origin, for example, systemic lupus erythematosus, scleroderma, polymyositis, "o dermatomyositis, Gougeret's syndrome Sjogren's disease, Steele's disease, Felty's syndrome; (ii) allergies caused by inflammatory and/or proliferative processes: o - all forms of allergic reactions, for example, Quincke's edema, hay fever, allergy to insect bites, o allergic reactions to medicines, blood preparations, contrast agents and other similar allergens, anaphylactic shock, urticaria, contact dermatitis; (MI) inflammation of vessel walls (vasculitis): - panarteritis nodosa, temporal arteritis, erythema nodosum; "(M) skin diseases caused by inflammatory, allergic and/or proliferative processes: with c - atopic dermatitis (primarily in children), . - psoriasis, and? - lichen planus, - erythematous diseases caused by various pathogenic factors, for example, radiation, chemicals, burns, etc., o - bullous dermatoses, - lichenoid diseases, o - skin itching (for example, of allergic origin), b - seborrheic eczema, - rosacea, o - common pemphigus, i" - multiform exudative erythema, - balanitis, - vulvitis, 5B - hair loss, for example, alopecia areata, - cutaneous T-cell lymphoma;

F) (mi) kidney diseases caused by inflammatory, allergic and/or proliferative processes: ka - nephrotic syndrome, - all forms of nephritis; in (my) liver diseases caused by inflammatory, allergic and/or proliferative processes: - acute breakdown of liver cells, - acute hepatitis of various origins, for example, viral, toxic, medicinal, - chronic aggressive and/or chronic persistent hepatitis; (my) gastrointestinal diseases caused by inflammatory, allergic and/or proliferative 65 processes: - regional enteritis (Crohn's disease),

- ulcerative colitis, - gastritis, - reflux esophagitis, - non-specific ulcerative colitis of other origin, for example, celiac disease; (their) proctological diseases caused by inflammatory, allergic and/or proliferative processes: - eczema of the anus, - fissures, - hemorrhoidal nodes, 70 - idiopathic proctitis; (9) eye diseases caused by inflammatory, allergic and/or proliferative processes: - allergic keratitis, uveitis, iritis, - conjunctivitis, - blepharitis, - optic neuritis, - choroiditis, - sympathetic ophthalmia; (xi) otorhinolaryngological diseases caused by inflammatory, allergic and/or proliferative processes: - allergic rhinitis, hay fever, - otitis externa caused, for example, by contact dermatitis, infection, etc., - otitis media; (hiii) neurological diseases caused by inflammatory, allergic and/or proliferative processes: - cerebral edema, primarily tumor-induced cerebral edema, c - multiple sclerosis, - acute encephalomyelitis, i) - meningitis, - various forms of seizures, for example, lightning convulsions; (hiii) hematological diseases caused by inflammatory, allergic and/or proliferative processes: "Ezo - acquired hemolytic anemia, - idiopathic thrombocytopenia; "(chemical) oncological diseases caused by inflammatory, allergic and/or proliferative processes: Ge - acute lymphocytic leukemia, - malignant lymphoma, o - lymphogranulomatosis, so - lymphosarcoma, - large metastasis, primarily in breast, bronchus and prostate cancer; (hu) endocrine diseases caused by inflammatory, allergic and/or proliferative processes: - endocrine orbitopathy, « - thyrotoxic crisis, c - De Quervain's thyroiditis, - Hashimoto's thyroiditis, c - Basedov's disease; (dicks) organ and tissue transplantation, "transplant versus host" reaction; (chemical) conditions of severe shock, for example, anaphylactic shock, systemic inflammatory response syndrome (SIR);

Go! (chemicals) replacement therapy for: - congenital primary insufficiency of the adrenal cortex, for example, congenital adrenogenital o syndrome,

Ge" - acquired primary insufficiency of the adrenal cortex, for example, Addison's disease, autoimmune inflammation of the adrenal glands, post-infectious insufficiency of the adrenal cortex, tumors, metastases, etc., ve - congenital secondary insufficiency of the adrenal cortex, for example, congenital hypopituitarism, i » - acquired secondary insufficiency of the adrenal cortex, for example, post-infectious insufficiency of the adrenal cortex, tumors, etc.; (hi) vomiting caused by inflammatory, allergic and/or proliferative processes, for example, vomiting caused by the use of cytostatics in combination with a 5-HT3 antagonist; (xx) pain of inflammatory origin, for example, lumbago.

Ф) In addition, stereoisomers of the general formula | are proposed in the invention can also be used for the treatment and prevention of other pathological conditions not listed above, in which artificial glucocorticoids are currently used (for information on this issue, see Nai» N.). Uuizzepzspayisne Megpiadzdezeiissnai tHN, Stuttgart, 19981).

All of the indications (i)-(xx) considered above are described in detail in | Nai» N.), Сийсосописоиде: рптипоиодизспе

Sgypayadep, Rpaptakoiodie ipa TnegariegispTsipivep, v-vo M/izzepzspayispe Megiadzdezeiizspaytn, Stuttgart, 1998).

The dosage in which the compounds proposed in the invention must be used to achieve a therapeutic effect in the pathological conditions indicated above is a variable value and depends, for example, on the effectiveness of a particular compound of the general formula I, the host, the method of introducing the medicinal product into the body, the type and severity of the conditions , which are subject to treatment, as well as whether the compound proposed in the invention is used as a prophylactic or therapeutic agent.

The invention also relates to the use of the claimed compounds/stereoisomers for the preparation of a medicinal product.

The objects of this invention are also the following: () the use of one of the compounds/isomers proposed in the invention of the general formula | or mixtures thereof for the preparation of a medicinal product for the treatment of a "disease"; (i) a method of treating a "disease", which consists in the fact that a patient in need of such a drug is administered the compound proposed in the invention in an amount effective to suppress the disease; (its) pharmaceutical composition for the treatment of "disease", which contains one of the compounds proposed in / about the invention or their mixture and at least one pharmaceutical excipient and/or carrier.

In the treatment of animals, generally satisfactory results can be expected when using the compound proposed in the invention in a daily dose of 10 mg to 10 mg per kg of body weight. In the body of larger mammals, for example, humans, the compound proposed in the invention is recommended to be administered in a daily dose of mcg to 10 Ωg per kg of body weight. In a preferred version, the dose of the compound proposed in the invention should be from 1 Ωkg to 30 Ωg per kg/5 of body weight, more preferably from 1 Ωkg to 1 Ωg per kg of body weight. It is advisable to introduce such a dose into the body in several smaller doses during the day. For the treatment of acute shock (for example, anaphylactic shock), the compound proposed in the invention can be used in single doses that significantly exceed the above dosage range.

Pharmaceutical preparations based on the new compounds proposed in the invention are prepared according to known technology

By processing the active substance together with carriers, fillers, substances that affect the disintegration of the dosage form, binders, moisture-retaining agents, lubricants, absorbents, thinners, substances that improve taste, dyes, etc., which are widely used in pharmaceuticals. and transfer to the necessary medicinal form. Regarding this, you can refer to the book of Ketipdiopye Rpagtaseciis! Zsiepse, 15th ed., in Musc Rybriizpipd Sotrapu, Eastern Pennsylvania, 1980). high school

For oral use, tablets, coated tablets, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions are primarily suitable. and)

Formulations for injections and infusions can be used for parenteral use.

Appropriately prepared crystalline suspensions can be used for intra-articular injection. For intramuscular injection, you can use aqueous and oily solutions for injections or suspensions or appropriate depot preparations. "

For rectal use, the new compounds proposed in the invention can be used for therapeutic purposes both systemically and locally as part of suppositories, capsules, solutions (which are administered, for example, by means of enemas) and ointments. at

Aerosols and inhalation agents can be used to introduce the new compounds proposed in the invention into the lungs.

For local use on the eyes, external auditory canal, middle ear, nasal cavities and paranasal sinuses, the new compounds proposed in the invention can be used as part of appropriate pharmaceutical preparations in the form of drops, ointments and tinctures. "

For external use, you can use preparations in the form of gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures. To achieve a sufficient pharmacological effect, the content of compounds. of the general formula I in such dosage forms should be from 0.01 to 20905. The scope of the invention also includes the proposed compounds of the general formula I! as therapeutic active substances. In addition, the scope of the invention includes the proposed compounds of the general formula | as

Therapeutic active substances in combination with pharmaceutically compatible and acceptable excipients and carriers.

The object of the invention is also a pharmaceutical composition containing one of the pharmaceutically active compounds proposed in the invention or their mixture or its pharmaceutically acceptable salt or pharmaceutically

Acceptable excipients and carriers.

Experimental part of Example 1 4-C8-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-dihydroisoindol-1-one 5B Methyl ester of 2-methyl-3-nitrobenzoic acid

100 g (165.6 mmol) of 2-methyl-3-nitrobenzoic acid was added to 150 ml of methanol, and the mixture was heated in a flask (F) under reflux for 2 days, then 2.9 ml of concentrated sulfuric acid was added. After cooling, the crystallisate (25.55 g-7990) was sucked off and in this way included in the next stage. "H-NMR (300 MHz, DMSO-α): 5 - 2.50 (ZH), 3.85 (ZH), 7.56 (1H), 8.00 (1H), 8.05 (1H). 60 2-(Bromomethyl)-3-nitrobenzoic acid methyl ester 25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester was added to 3 mL of carbon tetrachloride and mixed with 25.6 g (141.7 mmol) of M-bromosuccinimide and 62.8 mg of benzoyl peroxide.

The mixture was heated in a reflux flask for seven days, then, after cooling, the succinimide was sucked off, and the filtrate was centrifuged until the anhydrous state was reached. This required compound 65 in crude form was used in the next step in this form. "H-NMR (300 MHz, SOSI»v): 5 - 4.00 (ZH), 5.66 (2H), 7.55 (1H), 7.95 (1H), 8.10 (1H).

Methyl ether of 2-(azidomethyl)-3-nitrobenzoic acid 10 g (36.5 mmol) of methyl ether of 2-(bromomethyl)-3-nitrobenzoic acid was mixed with Zbml

of M,M-dimethylformamide and 24 ml of water. Then 3.54 g of sodium azide was added and the batch was stirred overnight.

The reaction mixture was diluted with methyl tert-butyl ether and washed twice with water and once with saline. After drying over sodium sulfate, the resulting product was filtered, and the solvent was removed by centrifugation. The necessary azide was obtained with a yield of 89.65 (7.72 g) and was further used in its crude form. "H-NMR (300 MHz, SOSI»v): 5 - 4.00 (ZH), 4.93 (2H), 7.58 (1H), 7.96 (1H), 8.12 (1H). 4 -amino-2,3-dihydroisoindol-1-one 1 g (4 2 mmol) of methyl ester of 2-(azidomethyl)-3-nitrobenzoic acid was added to 1 ml of ethanol and 2 ml of glacial acetic acid and mixed with 148.5 mg of Ra/C. After mixing overnight at room temperature under a hydrogen atmosphere, the catalyst was sucked off using a glass fiber filter, and the filtrate was evaporated to an anhydrous state. The residue was chromatographed on a RIazptavieg support (mobile solvent). 75,391.5 mg (62,495) of the required compound was isolated. "H-NMR (300 MHz , DMSO-aiva): 5 - 4.10 (2H), 5.36 (2H), 6.75 (1H), 6.85 (1H), 7.15 (1H), 8.35 (1H). 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal 6.55 g (21.11 mmol) rac-4-(5-fluoro-2-methoxyphenyl)-4- methyl-2-trifluoromethyl)-pentane-1,2-diol (MO 00/325841 was dissolved in 224 ml of dichloromethane and mixed at room temperature with 74 ml of anhydrous dimethyl sulfoxide and 10.68 g (105.55 mmol) of triethylamine. At a temperature from 15 to 1823 portions 10.08g (63.33mmol) of ZO3/pyridine complex was added over 40 minutes. After stirring overnight at room temperature, 84ml of saturated ammonium chloride solution was added. Slight heating occurred.

After stirring for 15 minutes at room temperature, the mixture was extracted twice each time

ZbOml of diethyl ether. The organic phases were washed with water and brine and dried (sodium sulfate). E.M

After filtering off the solvent and removing the solvent by centrifugation, the residue that remained (he) was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.85 g (9095) of the required compound was isolated. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.40 (ZH), 1.46 (ZH), 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). t 4-C4-(5-fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene|amino)2,3-dihydroisoindole-1-o chE n 400 mg (1.297 mmol) rac-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy- 4-methyl-2-trifluoromethyl)-pentanal was stirred with 192.1 mg (1.297 mmol) of 4-amino-2,3-dihydroisoindol-1-one in 1.89 ml of glacial acetic acid and stirred for four days at room temperature The mixture was mixed with toluene three times and evaporated to

From the anhydrous state on a rotary evaporator. The residue was chromatographed on silica gel (mobile solvent: co ethyl acetate/hexane). 429.7 mg (75.596) of the required compound was isolated. 7"H-NMR (300 MHz, SOSI): 5 - 1.37 (ZN), 1.52 (ZN), 2.22 (1H), 3.42 (1H), 3.84 (ZN), 4, 37 (2H), 4.68 (1H), 6.53-6.68 (ZH), 6.72-6.95 (2H), 7.37 (1H), 7.49 (1H), 7, 75 (1H). " 20 4-C8-fluoro-2-hydroxy-5-methoxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino) -2,3-dihydroisoindol-1-one (diastereomer A); c 4-C8-fluoro-2,5-dihydroxy-4, :3" 4-dimethyl-2-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalene-1-Camino)-2,3-dihydroisoindol-1-one (diastereomer A); 4-C8-fluoro-2,5-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3 ,4-tetrahydronaphthalene-1-ylamino)-2,3-dihydroisoindol-1-one (diastereomer B) about 420 mg (0.958 mmol) of the compound 4-C4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4- methyl-2-(trifluoromethyl)pentylideneamino)2,3-dihydroisoindol-1-one, which is described in the previous paragraph, was mixed with 9U.bml of a 1M solution of boron tribromide in dichloromethane, and the mixture was stirred for 45 minutes at room temperature. the mixture was mixed dropwise with 5 g of saturated sodium bicarbonate at a temperature of -30 9С, especially at pH up to 8. After diluting with ethyl acetate, the cooling bath was removed and intensively stirred for 15 minutes. After that two

They were extracted several times with ethyl acetate, the organic phases were washed with water and saturated sodium chloride solution. Then the solvent was dried (sodium sulfate) and removed by centrifugation, the residue was chromatographed on a carrier

Niazptazvieg (silica gel, MNO phase) (mobile solvent: dichloromethane/methanol). 67.7 mg (16,690) of 4-"8-fluoro-2-hydroxy-5-methoxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2 ,3-dihydroisoindol-1-one (diastereomer A, (F. ET); 12.9 mg (3.290) 4-(C8-fluoro-2,5 dihydroxy-4, co 4-dimethyl-2-(trifluoromethyl)-1 ,2,3,4-tetrahydronaphthalene-1-ylamino)-2,3-dihydroisoindol-1-one (diastereomer A,

E2), and 32.2 mg (7.990) 4-(8-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino) -2,3-dihydroisoindol-1-one (diastereomer B,

EZ).

E1: "NA-NMR (300 MHz, MeOb): 5 - 1.47 (ZH), 1.60 (ZH), 2.07 (1H), 2.25 (1H), 3.49 (ZH), 4 ,19-4.40 (2H), 5.20 (1H), 6.31 (1H), 7.00 (1H), 7.15-7.30 (2H), 7.38 (1H).

E2: "H-NMR (300 MHz, MeOb): 5 - 1.50 (ZH), 1.59 (ZH), 2.05 (1H), 2.28 (1H), 4.20-4.42 ( 2H), 5.18 (1H), 65 6.61 (1H), 6.80-6.90 (1H), 7.15 (1H), 7.20-7.40 (2H).

EZ: "H-NMR (300 MHz, MeOb): 5 - 1.52 (ZH), 1.69 (ZH), 2.03 (1H), 2.23 (1), 4.20-4.39 ( 2H), 5.18 (1H), 6.65-6.80 (2H), 7.10-7.23 (2H), 7.35 (1H).

Example 2 5-((7-chloro-2,5-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-isoquinoline-1(2H )-one 5-amino-isoquinolin-1(2H)-one 5-nitroisocoumarin 16.4 g (84.03 mmol) of methyl ester of 2-methyl-3-nitrobenzoic acid, which is described in example 1, 70 was mixed with 26 b.8 g ( 225.1 mmol) of M,M-dimethylacetal of dimethylformamide in 85 ml of dimethylformamide for 12 hours at 1302C. The solvent was removed on a rotary evaporator, the residue was resuspended in methyl tert-butyl ether and washed three times with water. After washing with saturated Massey solution, the organic phase was dried. Then the desiccant was filtered off and the solvent was removed by centrifugation, the residue which remained was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane) to give 8.73g (544965) of the desired compound 75.

TN-NMR (300 MHz, SOSIv): 5 - 7.39 (1H), 7.45 (1H), 7.68 (1H), 8.49 (1H), 8.65 (1H). 5-nitroisoquinolin-1(2H)-one 2.51 g (13.13 mmol) of 5-nitroisocoumarin was added to 100 ml of ethanol. Ammonia was compressed under pressure in an autoclave. The product settled and was suctioned off. 1.98 g (79.795) of the required compound was isolated. "H-NMR (300 MHz, DMSO-iv): 5 - 6.97 (1H), 7.45 (1H), 7.65 (1H), 8.43 (1H), 8.57 (1H), 11 5 (1H). 5-Aminoisoquinolin-1(2H)-one 268.0 mg (1.51 mmol) of 5-nitroisoquinolin-1(2H)-one was added to 376.5 mg of ammonium chloride and 2.bml of water in 14 ml of ethanol and 5.4 ml of tetrahydrofuran. Then 1.23 g of zinc powder was added in portions (heating to 30-35 2), the mixture was stirred for two hours. The reaction mixture was suctioned using a glass fiber filter and washed again with ethyl acetate. Then the filtrate was washed with water and saturated chloride solution (3 sodium, the organic phase was dried as usual. The desiccant was filtered off and the solvent was removed by centrifugation to give 196.5 mg (88.195) of the required amine. "H-NMR (300 MHz, DMSO-α): 5 - 5.6 (2H), 6.68 (1H), 6.87.45 (1H), 7.00 (1H), 7.17 (1H), 7.39 (1H), 11.7 (1H). 2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol

A solution of 3g ethyl ether of 2-hydroxy-4-methylene-2-(trifluoromethyl)valeric acid in 22 ml of 3-chloroanisole was mixed with aluminum trichloride in portions at room temperature. After stirring for 48 hours at room temperature, the batch was mixed with 2N. hydrochloric acid and hexane and was stirred for an additional hour. After washing 2n. hydrochloric acid and water, the excess of Z-chloroanisole was distilled off under vacuum. The residue that remained was purified by silica gel chromatography (mobile solvent: co hexane/ethyl acetate). 2.85 g of a mixture of ethyl ether 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeric acid and the regioisomeric compound of ethyl ether 4-(2-chloro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-"(trifluoromethyl)valeric acid in the form of a yellow oil. This mixture of substances was mixed with 445 mg of lithium aluminum hydride in 3 ml of ether at 02C and stirred for 12 hours. The batch was added to a saturated solution of sodium bicarbonate and filtered through diatomaceous earth. The phases were separated and the aqueous phase was extracted with ethyl acetate. it was washed with water and brine, dried over sodium sulfate and concentrated by evaporation in vacuo. a After chromatography on silica gel (mobile solvent: hexane/ethyl acetate), 1.87 g of the required compound 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol were obtained in the form of the first fraction and 16bOmg of the regioisomeric compound 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol in the form

Go) of the second fraction in the form of colorless oils. 1st fraction: "H-NMR (SOS), 5 - 1.41 (ZH), 1.51 (ZH), 2.24 (1), 2.51 (1H), 2.84 (1H), 3.36 (1H), 3.48 o (1H), 3.85 (ZH), 6.88 (1H), 6.92 (1H), 7.24 (1H). (o) 2nd fraction : "H-NMR (SOS), 5 - 1.52 (ZH), 1.62 (ZH), 2.18 (1H), 2.76 (1H), 2.93 (1H), 3.33 ( 1H), 3.55 iz 20 (1H), 3.80 (ZH), 6.78 (1H), 6.90 (1H), 7.38 (1H). 4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal 854.bmg (6.7333 mmol) of oxalyl chloride in 14.5 ml of dichloromethane was introduced into a heated flask. At -702С, 1.05 bml of DMSO dissolved in 3 ml of dichloromethane was added dropwise, and the batch was stirred additionally for five minutes. After that, 2 g (6.12 mmol) of 5 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol, dissolved in bml of dichloromethane, was added dropwise.

HF) After stirring for 20 minutes, the batch was carefully mixed with 4.24 ml (30.61 mmol) of triethylamine, in particular at a temperature in the range from -700 to -602C. After stirring for 5 minutes at -70 °C, the reaction mixture can be slowly warmed to room temperature. 25 ml of water was added, and the batch was stirred for another hour at room temperature. After phase separation, the aqueous phase was shaken once with 100 ml of dichloromethane. The combined organic extracts were washed with 195% sulfuric acid, 590% sodium bicarbonate solution, and saline. According to the usual method, 1.92 g (96.9905) of the necessary aldehyde was obtained, which was used in the next stage in crude form. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.37 (ZH), 1.45 (ZH), 2.22 (1H), 3.35 (1H), 3.59 (1H), 3.90 (ZH), 6.80-6.92 (2H), 7.04 (1H), 9.02 (1H). 65 5-14-(4-chloro-2-methoxyphenyl)-2-hydroxy-4- methyl-2-trifluoromethyl)-pentylideneamino)isoquinolin-1(2H)-one

100 mg (0.924 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal was 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. The mixture was mixed with toluene three times and evaporated to an anhydrous state on a retro-evaporator. The residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane).

382.4 mg (88.695) of the required compound was isolated. 7TH-NMR (300 MHz, SOSI): 5 - 1.37 (ZN), 1.58 (ZN), 2.26 (1H), 3.43 (1H), 3.85 (ZN), 4.80 ( 1H), 6.43 (1H), 6.59 (1H), 6.70-6.77 (2H), 7.00 (1H), 7.15-7.25 (1H), 7.30- 7.45 (2H), 8.32 (1H), 11.00 (1H). 5-C7-chloro-2, 5-dihydroxy-4, 70 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-isoquinolin-1(2H)-one 5 mg (0.107 mmol) of the compound 5-(C4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene|amino)2,3-isoquinolin-1-one, which is described in the previous paragraph, was mixed at -202C with 2.1 ml of a 1M solution of boron tribromide in dichloromethane, and the mixture was stirred for two and a half hours at a temperature in the range from -202C to 02C. The reaction mixture 75 was mixed dropwise at -20 °C with a saturated solution of sodium bicarbonate. After dilution with ethyl acetate, the batch was allowed to warm to room temperature, stirred for 15 minutes and extracted twice with ethyl acetate. The combined organic extracts were washed with water and saturated Massey solution. After drying over sodium sulfate, the solvent was removed by centrifugation, and the remaining residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 12.5 mg (25905) of the required compound was isolated. "H-NMR (30 MHz, MeOb): 5 - 1.55 (ZH), 1.65 (ZH), 2.03-2.20 (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 C (3-6-fluoro-1-(1H-indazol-4-yl)amino1-4,4-dimethyl-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol. and c 29 (-)-6-fluoro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-Griftomethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol Ge ) 2,6-difluoroanisole 20 g (153.74 mmol) of 2,6-difluorophenol was dissolved in 200 ml of acetone and mixed in a nitrogen atmosphere with 42.5 g (307.4 mmol) of potassium carbonate. Then 19.1 ml of methyl iodide (2 equivalents) was added, and the mixture was heated in a reflux flask for three and a half hours. After cooling, the reaction mixture was filtered, the residue after filtration was washed with acetone, and the filtrate was centrifuged until the anhydrous state was reached. "AND

The residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 17.27 g (77.9905) of the required product were obtained. It should be taken into account that the product is slightly volatile. Therefore, the temperature of the bath should not exceed 302C, and the vacuum of the rotary evaporator should be adapted. Ha") "H-NMR (300MHC, SOCI"): 5 - 4.00 (ZH), 6.80-7.00 (ZH). so 2-(3Z-fluoro-2-methoxyphenyl)-2-methylpropanenitrile 10 g (69.39 mol) of 2,6-difluoroanisole was dissolved in 200 ml of toluene and mixed at room temperature with 5.75 g (83.27 mmol) of isobutyric acid nitrile. 16.5 ml of a 0.5 molar solution of potassium hexamethyldisilazide in toluene was added dropwise during C5 minutes. In this case, the temperature was slightly raised to 27.52 C. It was stirred for 16 hours at room temperature, and then the reaction mixture from c was mixed with 200 ml of water and 400 ml of ethyl acetate and acidified with a 1095 solution of sulfuric acid to pH 4. The organic phase was separated, and the aqueous phase was shaken once with ethyl acetate (200ml). The combined organic extracts were shaken with water and brine. The solvent was then dried, filtered and removed by centrifugation, and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/ hexane).

7.66 g (57.195) of the required compound were isolated. o 7H-NMR (300 MHz, SOCIa): 5 - 1.76 (6H), 4.08 (ZN), 6.95-7.13 (ZN). 2-(33-fluoro-2-methoxyphenyl)-2-methylpropanal about 7.66 mg (39.64 mmol) of the above-described nitrile was dissolved in 158 ml of toluene. At a temperature from -65 to -602C, 49.5 ml of a 1.2 molar solution of OIV AN in toluene was added dropwise for 40 minutes. At this temperature, 1" 50 was stirred for 1 hour, then 493 ml of a 1095% solution of 1-(g)-tartaric acid was added dropwise. After adding 100 ml, the temperature was raised to -102C. A solution of tartaric acid was quickly added,

I" that remained, and the batch was vigorously stirred for two hours at room temperature. The reaction mixture was shaken twice each time with 400 ml of diethyl ether. The combined organic extracts were shaken with water and brine, dried, and the solvent removed by centrifugation. The resulting residue (7.8g-10290) was used at the next stage in crude form.

He) 7H-NMR (300 MHz, SOSI»z): 5 - 1.40 (6H), 3.88 (ZH), 6.95-7.10 (ZH), 9.60 (1H). (E/2)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enoic thioether and 21.3 ml of a 2 molar solution of IFA in THF was added dropwise at 0 C to a solution of 9.87 g (39.75 mmol ) of triethyl ether of 2-ethoxy-phosphonoacetic acid in 40 ml of absolute THF. It was stirred for 30 60 minutes at 02, then 7.g (39.75 mmol) of 2-(3-fluoro-2-methoxyphenyl)-2-methylpropanal, dissolved in 2 bml of THF, was quickly added dropwise at 09Сb. The cooling bath was removed and the batch was stirred for 16 hours at room temperature. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried, and the solvent was removed by centrifugation after filtering off the desiccant. The residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 8.39 g (68.2905) of the required compound was isolated.

MO (SI): 328 (2996), 265 (100965), 181 (56905), 167 (4290). (E/2)-4-(3-fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid 8.39 g (27.03 mmol) ethyl ether (E/2)-4-(3-fluoro-2 -methoxyphenyl)-4-methylpent-2-enoic acid was mixed with 270 ml of alcohol. Mahon in ethanol/water (2:1) and stirred for two days at room temperature.

Ethanol was removed on a rotary evaporator, and the residue was extracted twice with 150 ml of diethyl ether each time.

The combined organic extracts were washed with water and discarded after TLC observation. The aqueous phases were acidified to pH 3 with the help of concentrated hydrochloric acid and extracted twice each time with 30 ml of 7/0 diethyl ether. The ether extracts were washed with water and saline, dried, the solvent was removed by centrifugation, and the residue (5.89g-77.295) was used in the next step in crude form.

MO (SI): 300 (10095), 282 (1095), 237 (27905), 167 (26960). 4-(33-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid 5.89 g (20.6 mmol) (E/2)-4-(3-fluoro-2-methoxyphenyl)-4- methylpent-2-enoic acid was mixed at room /5 temperature with 12 bml of 1 molar sulfuric acid, and then 21 ml of glacial acetic acid was added, the mixture was stirred for 15 hours at a bath temperature of 9020. When cooling in an ice bath, the reaction mixture was carefully mixed (intense pin formation ) with solid potassium carbonate until the pH value is 9.

The mixture was extracted twice with diethyl ether. The combined organic extracts were washed with water and discarded

TSH The combined aqueous phases were acidified with concentrated hydrochloric acid until the value was reached

BH 4, and extracted twice each time with 30 ml of diethyl ether. The ether extracts were washed with water and brine, dried, and the solvent was removed by centrifugation. Since the residue still contained acetic acid, it was removed by centrifugation twice with 100 ml of toluene each time. The remaining residue (4.14g-78.190) was used in the next stage in crude form. "H-NMR (300 MHz, SOSI»v): 5 - 1.50 (6H), 3.53 (2H), 3.93 (ZH), 6.90-7.10 (ZH). s

4-(33-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ether (5) 4.14 g (16.28 mmol) 4-(3-fluoro-2-methoxyphenyl)-4-methyl -2-oxo-pentanoic acid was dissolved in 97 ml of ethanol, mixed with 1.79 ml of sulfuric acid and heated in a reflux flask for four hours.

Ethanol was removed on a rotary evaporator, and the residue was carefully mixed with saturated sodium bicarbonate solution until pH 9 was reached. The mixture was extracted twice with 100 ml of ethyl acetate each time, and the combined organic extracts were washed with water and then with brine. Then the desiccant was dried and filtered, and after that the solvent was centrifuged, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 4.16 g (90.695) of the required compound was isolated. (Ce) "H-NMR (300 MHz, SOSIv): SOSIZ - 1.29 (ZH), 1.48 (6H), 3.40 (2H), 3.98 (ZH), 6.89-7.09 (ZN). Fr

4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ether with 4.16 g (14.74 mmol) of 4-(3-fluoro-2- methoxyphenyl)-4-methyl-2-oxo-pentanoic acid was dissolved in 24 ml of THF and mixed at 09C with 2.51 g (17.6 mmol) of (trifluoromethyl)-trimethylsilane and 36 mg of tetrabutylammonium fluoride. Then it was stirred for 2.5 hours at a temperature from 0 to 52C, the batch was poured into 500 ml of a mixture of water and ice. The mixture was extracted twice with 150 ml of diethyl ether each time, and the combined organic extracts were processed as usual. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 5.24 g (83.895 g) of the required compound were obtained. "from MS(SI): 442 (10095), 425 (41905). " 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentan-1-ol 5 .24 g (12.34 mmol) of d-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentanoic acid ethyl ether was dissolved in 45 ml

of diethyl ether and mixed at a temperature from 0 to 59C in portions with 936.9 mg (24.69 mmol) of HIA!IN y. Then aw! was stirred for 4.5 hours at room temperature, the reaction mixture was carefully mixed with saturated

Manso" while cooling in an ice bath, stirred for 1 hour under cold conditions and overnight at room temperature. After carrying out the usual processing, 4.11 g (87.190) of the mixture was obtained, which includes "" 20 the required compound and the compound into which the silyl ether migrated. The mixture was used in the next stage in crude form.

T» 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-1-ol was dissolved in biml of THF, mixed with 3.39 g (10.74 mmol) of ViAME trihydrate, and stirred for 1 hour at room temperature. poured into water and extracted twice with diethyl ether.

GF) The organic phases were washed, as usual, with water and saline solution. Then the desiccant was dried and filtered, and after that the solvent was centrifuged, the residue that remained was chromatographed on o silica gel (mobile solvent: ethyl acetate/hexane). 2.71 g (81.495) of the required compound was isolated. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.45 (ZH), 1.54 (ZH), 2.20 (1H), 2.54 (1H), 2.90 (1H), 3.30 -3.50 (2H), 3.98 60 (ZH), 6.90-7.13 (ZH). 4-(3Z-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl -pentpanal 765mg (6.033mmol) of oxalyl chloride in 13ml of dichloromethane was placed in a heated flask. At a temperature of -189C0, 0.855ml of DMSO dissolved in 2.5ml of dichloromethane was added dropwise, and the batch was stirred for an additional 65 minutes for five minutes. 1.7 g (5.48 mmol) of 4-(33-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanol dissolved in bml of dichloromethane was added dropwise.

After stirring for 15 minutes, the batch was carefully mixed with 3.79 mL (27.40 mmol) of triethylamine, stirred for five minutes at -782C, and then allowed to slowly warm to room temperature.

20 ml of water was added, and the batch was stirred for another hour at room temperature. After separating the phases, the aqueous phase was shaken once with 100 ml of dichloromethane. The combined organic extracts were washed with 195% sulfuric acid, 596% sodium bicarbonate solution, and saline. After carrying out the usual method, 1.617g (96.290) of aldehyde was obtained, which was used at the next stage in an unpurified form. 7TH-NMR (300 MHz, SOSIvZ): 5 - 1.40 (ZN), 1.49 (ZN), 2.29 (1H), 3.29 (1H), 3.59 (1H), 4.00 ( ZN), 6.85-7.08 (ZN), 9.13 (1H). 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-2-K1H-indazol-4-yl)iminomethyl|-4-methylpentan-2-ol 1.46g (4.746bmmol) 4-( 3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal was stirred with 632 mg (4.74 mmol) of 4-aminoindazole in 6 b.78 ml of glacial acetic acid for 2 days at room temperature. The reaction mixture was evaporated three times with toluene on a rotary evaporator, and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 1.47 g (73.5905) of the required compound 75 was isolated.

MS (Eq): 424 (10096). (-3-6-fluoro-5-methoxy-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2- oil (-)-6-fluoro-5-methoxy-1-(1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2- ol 1.32 g (3.117 mmol) of the above-described imine, 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-2-(1H-indazol-4-yl)iminomethyl|-4-methylpentan-2 -ol, was dissolved in 22.8 ml of dichloromethane. To this solution was added 9.35 ml of a 1M solution of TiSi in dichloromethane (3 equivalents) at -302С, especially in a nitrogen atmosphere for 15 minutes. The reaction mixture was stirred for 3.5 hours at a temperature of -30 to -159C. The batch was mixed dropwise with a saturated solution of sodium bicarbonate at a temperature of -309C. After dilution with ethyl acetate, the mixture was stirred for 15 minutes at room temperature. Then it was extracted twice with 150 ml of ethyl acetate each time, the organic phases were washed (with water, saline solution), dried (Ma»3O)), and the solvent was removed by centrifugation. After chromatography on silica gel (mobile solvent: dichloromethane/methanol), 1.07 g (81.195) of the required product was obtained in the form of a racemate. The product was separated into its enantiomers (Spigagrak AO 5 w mobile solvent: hexane/ethanol). "r (4)-Enantiomer showed a rotation angle | aIr--1.62 (s-1, MeOH), and the (-)-enantiomer exhibited a rotation angle (o1o--1.32 (s-1, MeOH). i-th (-3-6-fluoro-1 -(1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol (in 200 mg (0.472 mmol) of the above-described ( -3-6-fluoro-5-methoxy-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol was mixed at room temperature with 4.7 ml of a 1M solution of BVgz in dichloromethane and stirred for 3.5 hours at room temperature. The reaction mixture was mixed dropwise with a saturated solution of sodium bicarbonate at a temperature of -302C, in particular until the pH was equal to 8. After dilution with ethyl acetate , " 20 the cooling bath was removed, and the batch was vigorously stirred for 15 minutes. It was then shaken twice with ethyl acetate, the combined organic extracts were washed with water and brine. It was then dried over sodium sulfate, and then the solvent was filtered and removed by centrifugation, The residue was chromatographed on silica gel (mobile solvent: dichloromethane/methanol). 171.3 mg (88.695) of the required compound were obtained. The angle of rotation measured at room temperature was | o|p-/,3 (c-1, 415 meon). o (-)-6-fluoro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol 200mg (0.472 mmol) of the above-described o (-)-6-fluoro-5-methoxy-1-(1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3, 4-tetrahydronaphthalene-2-ol was mixed at room temperature with 4.7 ml of a 1M solution of BVgz in dichloromethane and stirred for 3 hours and 45 minutes at room temperature. The reaction mixture was mixed dropwise at -3092C with a saturated solution of sodium bicarbonate, in particular, until the pH was equal to 8. After diluting with ethyl acetate, the cooling

The T" bath was removed, and the batch was vigorously stirred for 15 minutes. Then it was shaken twice with ethyl acetate, the combined organic extracts were washed with water and saturated saline. It was then dried over sodium sulfate, after which the solvent was filtered and removed by centrifugation, and the residue was chromatographed on silica gel (mobile solvent: dichloromethane/methanol). 179.4 mg (92.8965) of the required compound was obtained. The angle of rotation measured at room temperature was (odr--7.8 (s-1, meon). (F, Example 4 ka 4-C8-fluoro-2,5-dihydroxy-4,4-dimethyl-2- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-6-fluoro-2,3-dihydroisoindol-1-one 60 4-amino-b-fluoro-2,3-dihydroisoindol-1- he 2-methyl-5-fluoro-3-nitrobenzoic acid 11 bml of sulfuric acid was introduced and mixed in portions at -15 9С with 14.70 g (95.37 mmol) of 5-fluoro-2-methylbenzoic acid. A nitrating mixture was added dropwise to this mixture (4.79ml of fuming nitric acid, and 21.8ml of concentrated sulfuric acid), especially at a temperature of -15 to -109C for 90 65 minutes. After stirring for more than three hours, the reaction mixture was poured into a mixture of ice water and vigorously stirred for approx. for 30 min. The precipitated crystals were filtered off with suction, washed with neutral water and dried. 8.56 bg (45.195) of a mixture of various regioisomers and by-products were obtained.

Then this mixture in this form was used in the next stage (esterification) and purified at this stage.

2-Methyl-5-fluoro-3-nitrobenzoic acid methyl ester 8.56 g (42.99 mmol) of 2-methyl-5-fluoro-3-nitrobenzoic acid was added to 7 bml of M,M-dimethylformamide and mixed with 9.15 g (64 .48 mmol) of methyl iodide and 8.91 g (64.48 mmol) of potassium carbonate. After stirring for 65 hours at room temperature, the reaction mixture was added to a mixture of water and ice and extracted several times with ethyl acetate. The combined organic extracts were washed with water and saline. After drying (sodium sulfate), the desiccant was suctioned off, and the solvent was removed by centrifugation. After 70 repeated chromatography on silica gel (mobile solvent: ethyl acetate/hexane), the desired compound was obtained, namely with a yield of 25.990 (2.37). "H-NMR (300 MHz, SOSI»v): 5 - 2.60 (ZH), 3.96 (ZH), 7.61 (1), 7.77 (1H).

2-(bromomethyl)-5-fluoro-3-nitrobenzoic acid methyl ether 2.37 g (11.12 mmol) of 5-fluoro-2-methyl-3-nitrobenzoic acid methyl ether was added to 35 ml of 75% carbon tetrachloride and mixed with 2.24 g (12.24 mmol) of M-bromosuccinimide and 5.4 mg of benzoyl peroxide. After four days of heating in a reflux flask, the succinimide was suctioned off (glass fiber filter) after cooling, and then the filtrate was centrifuged until anhydrous. After chromatography on a RIazptavieg support, 2.47 g (75.995) of the required compound were obtained. "H-NMR (300 MHz, SOSI»v): 5 - 4.01 (ZH), 5.13 (2H), 7.72 (1H), 7.87 (1H).

Methyl ether of 2-(azidomethyl)-5-fluoro-3-nitrobenzoic acid 2.A47 g (846 mmol) of methyl ether of 2-(bromomethyl)-5-fluoro-3-nitrobenzoic acid was mixed with 8.3 ml

of M,M-dimethylformamide and 5.5 ml of water. Then 0.82 g (12.6 mmol) of sodium azide was added and the batch was stirred overnight. The reaction mixture was added to water and extracted three times with methyl tert-butyl ether. The combined organic extracts were washed with water and saline. After drying over sodium sulfate, the product was filtered, and the solvent was removed by centrifugation. After chromatography on the Riazptavzieg carrier, 2.06 g (95.895) of the required azide was obtained. "H-NMR (300 MHz, SOSI»v): 5 - 4.00 (3H), 4.90 (2H), 7.73 (1H), 7.87 (1H). 4-amino-b-fluoro- 2,3-Dihydroisoindol-1-one 1.86 g (7.32 mmol) of 2-(azidomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester was added to 4 bml of 3 ethanol and 3.4 ml of glacial acetic acid and mixed with 256, bmg Ra/C. After stirring overnight at room temperature under a hydrogen atmosphere, the catalyst was filtered off with suction through a glass fiber filter, and the filtrate was evaporated to dryness. The residue, 1.18 mg (97.595) of the desired compound, was further used in crude form. o "H-NMR (300 MHz, DMSO-iv): 5 - 4.10 (2H), 5.75 (2H), 6.46-6.57 (2H), 8.50 (1H). 4-C4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene|amino)b-fluoro-2,3-dihydroisoin sodol-1-one 400mg (1.297 mmol) of rac-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal was mixed with 215.5 mg (1.297 mmol) of 4-amino-b-fluoro-2,3 -dihydroisoindol-1-one in 1.89 ml of glacial acetic acid « 20 for four days at room temperature. Since the starting material was still present, according to TLC, the reaction mixture was mixed with toluene and boiled in a water separator for 20 hours. The mixture was mixed with toluene three times and evaporated to an anhydrous state on a rotary evaporator. The residue "c" was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 383.4 mg (64.7905) of the required compound was isolated. "H-NMR (ZO0MHC, SOSIv): 5 - 1.37 (ZN), 1.53 (ZN), 2.20 (1H), 3.47 (1H), 3.88 (ZN), 4.32 (2H), 4.57 (1H), 6.22 (1H), 6.63-6.88 (4H), 7.42 (1H), 7.48 (1H). 4-C8-fluoro- 2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-6-fluoro-2,3-d ohydroisoindol-1-one

He» Zvomg (0.832 mmol) 50 0 4-Ch4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene)amino)b-fluoro-2,3-dihydroisoindole- and 1-one was mixed at room temperature with 8.3 ml of a 1M solution of BVgz in dichloromethane and stirred for one hour at the temperature of an ice bath. Processing of the batch was carried out as described in example 4. After chromatography of the crude product on a BRIIazptavzieg support (amine phase; mobile solvent: methanol/dichloromethane), 9.2 mg (2.790) of the required compound were obtained. "H-NMR (З00МГЦц, СО8О0): 5 - 1.53 (ЗН), 1.69 (ЗН), 2.02 (1Н), 2.22 (1Н), 4.28 (2Н), 5.09 (1H), 6.60-7.00 (4H).

Example 5

IF) 4-((5-fluoro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-2,3-dihydro cozoindol-1-one 2-fluoro-3-methoxybenzaldehyde 60 27ml (240.62mmol) of 2-fluoroanisole was dissolved in 70Oml of tetrahydrofuran.At a temperature of -709C, 20Oml of tvor-Vi!i (1.3M solution in cyclohexane) was added dropwise. The mixture was stirred for 1 hour at a temperature of -709C, and then 152 ml of M,M-dimethylformamide, dissolved in 50 ml of tetrahydrofuran, was added dropwise at this temperature. After another hour of stirring at a temperature of -702C, 380 ml of hydrochloric acid (m. -1095). In this case, the batch was slowly warmed to room temperature. After stirring overnight at room temperature, methyl tert-butyl ether was added, and the organic phase was separated after vigorous stirring. The aqueous phase was extracted twice more with methyl tert-butyl ether . The combined organic extracts were washed with brine and dried. The desiccant was then filtered was washed, the solvent was removed by centrifugation, and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 25.66 bg (69.2905) of the required compound was isolated. "H-NMR (Z00MHZ, SOSI"): 5 - 3.95 (ZH), 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 was dissolved in 140 ml of ethanol and mixed in portions at 02 with 3.15 g (83.35 mmol) of sodium borohydride. It was stirred at room temperature for 1 hour , and then the reaction mixture was mixed with water and extracted three times with methyl tert-butyl ether. The combined organic 70 extracts were shaken with water and brine, dried, the desiccant was suctioned off, and the solvent was removed by centrifugation. The residue that remained was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 24.79 g (95.395) of the required compound were obtained. "H-NMR (300 MHC, SOCI"): 5 - 3.90 (ZH), 4.78 (2H), 6.87-7, 10 (ZN). 2-Fluoro-3-methoxybenzyl chloride 24.79 g (158.75 mmol) of 2-fluoro-3-methoxybenzyl alcohol was dissolved in Zb5 ml of dichloromethane. With slight cooling, 58.4 mL of thionyl chloride was added dropwise, and the batch was then stirred overnight at room temperature. The reaction mixture was centrifuged until it reached an anhydrous state, the residue was dissolved in methyl tert-butyl ether, and the mixture was shaken twice with a half-saturated solution of potassium carbonate. The aqueous phase was extracted once with methyl tert-butyl ether. The combined organic extracts were processed as usual.

The resulting residue was used at the next stage in crude form. 7H-NMR (300 MHz, SOCI3): 5 - 3.90 (ZH), 4.65 (2H), 6.90-7.10 (ZH). 2-fluoro-3-methoxybenzyl cyanide 24.89 g (142.5 mmol) of 2-fluoro-3-methoxybenzyl chloride was stirred in 200 ml of DMSO with 8.38 g (171.07 mmol) of sodium cyanide for three hours at 902C. The reaction mixture was poured into water and extracted four times with methyl tert-butyl ether. The combined organic phases were washed with saline solution, dried, the desiccants (U) were suctioned off, and the solvent was removed by centrifugation. Initially, only a portion of the residue (21.43 g) was used in the next step in crude form. - 3.77 (2H), 3.90 (ZH), 6.89-7.07 (2H), 7.08-7.15 (1H). « zo 2-(2-fluoro-3-methoxyphenyl) -2-methylpropanenitrile 4 g (24.22 mmol) of 2-fluoro-3-methoxybenzyl cyanide was dissolved in 1 ml of M,M-dimethylformamide and mixed with 6.87 g (48.35 mmol) of methyl iodide. At a temperature of 09, 2.11 g (48, 35 mmol) of sodium hydride (55965) for 45 minutes. It was stirred for 20 hours at room temperature, then the batch was poured into a mixture of water and ice and extracted three times with 200 ml of diethyl ether each time. The organic phases were washed with

With water and salt solution and dried. The desiccant was filtered off, then the solvent was removed by centrifugation, and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 4.66 g (99.595) of the required compound was isolated. "H-NMR (Z00MHZ, SOSI"): 5 - 1.80 (6H), 3.90 (ZH), 92-7.02 (1H), 7.02-7.11 (2H). "2- (2-fluoro-3-methoxyphenyl)-2-methylpropanal 4.66 g (24.12 mmol) of 2-(2-fluoro-3-methoxyphenyl)-2-methylpropanenitrile was dissolved in 10 ml of toluene. At a temperature from -652C to - 602С; 36.18 mmol) of a 1.2 molar solution of OIVAN in toluene was added dropwise. It was stirred for 3.5 hours at a temperature of -6592С, then 27bml of a 1096% solution of »M(n)-tartaric acid was added dropwise at at this temperature. In this case, the temperature was raised to 02C. The cooling bath was removed, and the batch was vigorously stirred at room temperature for 1 hour. The reaction mixture was extracted three times with 30 mL of diethyl ether each time. The combined organic extracts were treated as usual (water, brine solution, drying). After removal of the solvent by centrifugation, 4.78 g (a little more than 10095) of the required compound remained. .85-6.7.00 (2H), 7.08-7.15 (1H) , 9.65 (1H). b E/27-4-(2-fluoro-3-methoxyphenyl)-4-methylpent-2-enoic acid methyl ester 20.26 g (111.2 mmol) of trimethyl ester of phosphonoacetic acid was introduced into b8 ml of tetrahydrofuran. At

At a temperature of 02C, biml of a 2M solution of IA in THF/heptane/ethylbenzene was added dropwise. It was stirred for 45 minutes, then 21.83 g (111.2 mmol) of 2-(2-fluoro-3-methoxyphenyl)-2-methylpropanal, dissolved in 8 ml of tetrahydrofuran at 02С, was added dropwise. After stirring overnight, the reaction mixture was mixed with water while cooling in an ice bath, and extracted three times with methyl tert-butyl ether. The combined organic extracts were processed as usual, and the residue obtained was chromatographed on

HF) silica gels (mobile solvent: ethyl acetate/hexane). 23.30 g (75.895) of the required compound were isolated.

GI "H-NMR (Z00MHZ, SOSI"): 5 - 1.50 (6H), 3.73 (ZH), 3.88 (ZH), 5.74 (1H), 5.80 (1H), 6 ,80-7,10 (ZN).

Methyl ether of 4-(2-fluoro-3-methoxyphenyl)-4-methylpentanoic acid in 23.30 g (84.33 mmol) of methyl ether E/27-4-(2-fluoro-3-methoxyphenyl)-4-methylpent-2 -enoic acid was mixed with 1.2 g of palladium on charcoal in 10 ml of ethanol, and the mixture was stirred under a hydrogen atmosphere overnight at room temperature. The catalyst was removed by filtration with a glass fiber filter, and the residue remaining after concentration by evaporation was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 19.58 g (83.495) of the required compound was isolated. 65 "H-NMR (300 MHz, SOSI»v): 5 - 1.48 (6H), 2.00-2.18 (4H), 3.60 (ZN), 3.90 (ZN), 6.78 -7.03 (ZN).

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

19.58 g (//mmol) of 4-(2-fluoro-3-methoxyphenyl)-4-methylpentanoic acid methyl ether was added to 245 mL of tetrahydrofuran, and the reaction mixture was cooled to -702C. During 1 hour, 220.7 mL of a 0.5 molar solution of potassium bis-(trimethylsilylamide) in toluene was added dropwise, and then the reaction mixture was stirred for more than 45 minutes at a temperature of -702C. At this time, 28.3 g (107.79 mmol) of Davis reagent dissolved in 245 bml of tetrahydrofuran was added dropwise over 40 minutes. It was stirred for two hours at a temperature of -702C, then 250 ml of saturated ammonium chloride solution was slowly added dropwise, and in this case, the batch was brought to room temperature. After extraction with methyl tert-butyl ether, the combined organic extracts were treated as usual with water and brine. After removal of the solvent by 70 C centrifugation, the residue was chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane). At the end, 12.14 g (58.395) of the required compound were isolated. 7TH-NMR (ZO0MHZ, SOSI): 5 - 1.45 (ZN), 1.49 (ZN), 1.90-2.01 (1H), 2.38-2.50 (2H), 3.70 (ZN), 3.90 (ZN), 3.92-4.03 (1H), 6.80-7.08 (ZN).

Methyl 4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentananoate 11.14 g (41.22 mmol) methyl 4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl- pentanoate was added to 200 ml of dichloromethane and 71.3 ml of dimethyl sulfoxide. Then 20.8 g (205.78 mmol) of triethylamine was added and the batch was mixed with 13 g (81.71) of the 5Oz/pyridine complex and then stirred overnight at room temperature.

The reaction mixture was mixed with 100 ml of saturated ammonium chloride solution with slight cooling, and it was intensively stirred. The mixture was then extracted three times with methyl tert-butyl ether and the combined organic phases were processed as usual. The residue that remained after removing the solvent by centrifugation was chromatographed together with the residue obtained from the sample batch (1 g) on silica gel (mobile solvent: ethyl acetate/hexane). 10.03 g (83.295, from both batches) of the required compound were isolated. 7H-NMR (300 MHz, SOSI»z): 5 - 1.49 (6H), 3.39 (2H), 3.73 (ZH), 3.89 (ZH), 6.80-6.91 (2H ), 6.95-7.07 (1H).

Methyl 4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-«-trimethylsilyloxy)-pentanoate with 10.03 g (37.39 mmol) methyl-4-(2-fluoro- 3-Methoxyphenyl)-4-methyl-2-oxopentanoate was dissolved in b3 ml of He) tetrahydrofuran, mixed with 5.68 g (39.98 mmol) of (trifluoromethyl)-trimethylsilane and then with 82.3 mg of tetrabutylammonium fluoride. After stirring overnight at room temperature, the batch was added to a mixture of ice water, extracted with methyl thyret-butyl ether, and the combined organic extracts were processed as usual. After removing the solvent by centrifugation, the residue was chromatographed on silica gel (mobile C solvent: ethyl acetate/hexane). In addition to 6.94 g (45.295) of the required product, 2.75 g of the original "I substance (contaminated) was isolated, which was again subjected to the same method. As a result, another 1.91 g of methyl 4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate was isolated. at

MS (SI): 428 (10096), 395 (6796). av 4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)pentan-i-ol. and

So 4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-1--(trimethylsilyloxy)pentan-2-ol so 8.85g (21.5bmmol) methyl-4-(2- fluoro-3-methoxyphenyl)-4-methyl-2-trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate was dissolved in 77 ml of diethyl ether. 1.64 g (43.12 mmol) of lithium aluminum hydride was added in portions to this solution at a temperature of 02С. It was stirred for four hours at room temperature, then the mixture was again -70 cooled to 02C and about ZOml of saturated sodium bicarbonate solution was carefully added dropwise. After that, it was intensively stirred at room temperature for 1 hour. The batch was extracted several times with methyl tert-butyl ether. The combined organic extracts were washed with water and then with saline. After drying over sodium sulfate, the desiccant was sucked off, the solvent was centrifuged, and the residue (7.36 g; a mixture of two regioisomeric silyl ethers) was used in the next stage in an unpurified CO 35 form. 4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol (c) 7.36 g (19.24 mmol) of a mixture of two silyl ethers were dissolved in 108 ml of tetrahydrofuran, mixed from 6.07 g

FU (19.24 mmol) of tetrabutylammonium fluoride trihydrate and stirred overnight at room temperature.

The reaction mixture was diluted with methyl tert-butyl ether, washed with water and brine, and then 50% organic solvent was removed by centrifugation after drying. After chromatography on silica gel

GT" (mobile solvent: ethyl acetate/hexane), 5.3 g (88.890) of the required compound were obtained. "NA-NMR (ZO0MHZ, SOS): 5 - 1.45 (ZN), 1.58 (ZN), 2.20 (1), 2.38 (2), 2.93 (1H), 3.30 -3.40 (1H), 3.50-3.60 (1H), 3.89 (ZH), 6.85-6.98 (2H), 6.98-7.09 (1H). 5B 4 -(2-fluoro-3-methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal 2.5 g (8.0 mmol) rac-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2- -trifluoromethyl)pentane-1,2-diol was added to a mixture (F) containing 52 ml of dichloromethane, 14 ml of dimethyl sulfoxide and 4.08 g (40.29 mmol) of triethylamine. At room temperature, 2.57 g (16.11 mmol) of complex 5 Oz was added /pyridine, and the batch was stirred overnight at this temperature. The reaction mixture was mixed with saturated ammonium chloride solution and stirred vigorously. 60 After additional conventional workup, 2.11 g (8595) of the required aldehyde was obtained. - 1.45 (ZH), 1.50 (ZH), 2.30 (1H), 3.12 (1H), 3.62 (1), 3.89 (ZH), 6.75 (1H), 6.90 (1H), 7.00 (1H), 9.15 (1H). 4-C5-fluoro-2-hydroxy-6-methoxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2,3-dihydroisoindol-1-one 65 150 mg (0.487 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2--rifluoromethyl-pentanal was mixed in 0.9 ml of glacial acetic acid with 72.7 mg (0.487 mmol) of 4-amino-2, of 3-dihydroisoindol-1-one, and the mixture was stirred for two days at room temperature. The batch was centrifuged until anhydrous, and the residue was chromatographed (Riazptazgieg). 119.8 mg (56.2965) of the required cyclic compound was isolated. "H-NMR (ZO0MHC, SOSIv): 5 - 1.50 (ZN), 1.65 (ZN), 2.05 (1H), 2.20 (1H), 3.83 (ZN), 4.29 (2H), 4.40 (1H), 5.00 (1H), 6.79 (1H), 6.93 (1H), 7.00-7.12 (2H), 7.21 (1H), 7.35 (1H). 4-C5-fluoro-2, b-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2,3- dihydroisoindol-1-one 109.8 mg (0.250 mmol) (rec.) 4-C5-fluoro-2-hydroxy-6-methoxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalene-1-ylamino)-2,3-dihydroisoindol-1-one was mixed with 3.4 ml of a 70.1 M solution of BVgz in dichloromethane and stirred for four hours at room temperature. The batch was mixed at 02C with saturated sodium bicarbonate solution and extracted twice ethyl acetate. The combined organic extracts were dried over sodium sulfate. The desiccant was then filtered, and after removal of the solvent by centrifugation, the residue was chromatographed on Riazptavieg support. 15.bmg (14.790) of the final product was isolated. 7"H-NMR (Z00MgCz, CO3O0): 5 - 1.53 (ZH), 1.67 (ZH), 2.03-2.20 (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-tetrahydronaphthalene-1-ylamino)-1,3-dihydroindole-2- one 4-amino-1,3-dihydroindol-2-one

Dimethyl-2-(2,6-dinitrophenyl)-malonate 42.95 g (311.03 mmol) of dimethyl malonate was dissolved in ZOO ml of M,M-dimethylformamide and mixed in portions with 35.15 g (296.22 mmol) of potassium tert-butylate. Then the obtained tert-butanol was distilled off, the reaction mixture was cooled to 209С. 300 g (148.11 mmol) of 2,6b-dichlorobenzene was quickly added to the mixture in portions. c 29 It was stirred for 3 hours at a temperature of 90 2C, then the mixture was stirred overnight at room temperature. The reaction mixture was added to 800 ml of Masson's 196th solution (cooled on ice) and extracted three times with methyl tert-butyl ether. The combined organic phases were discarded according to TLC control. The aqueous phase was carefully acidified with concentrated nitric acid (m.-6595) while cooling in an ice bath. After carrying out six cycles of extraction with methyl tert-butyl ether and with the usual treatment of the combined organic extracts (water, brine, drying, filtration and removal of the solvent by centrifugation), a residue was obtained, which was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane ). 12.09g (27.0995) of the required compound was isolated. and "H-NMR (300 MHz, SOSI"): 5 - 3.82 (6BN), 5.39 (1H), 7.75 (1H), 8.27 (2H). (av) from Methyl- (2,6-dinitrophenyl)-acetate with 10.08 g (33.mmol) of dimethyl-2-(2,6-dinitrophenyl)-malonate was mixed in 54 ml of glacial acetic acid with 2.7 ml of perchloric acid and heated in a reflux flask at a temperature of 12520. In this case, the ethyl acetate thus obtained was distilled off. After 90 minutes, the reaction was stopped, since no more starting material was detected according to TLC. The reaction mixture was poured into a mixture of ice water and extracted three times with ethyl acetate. The combined organic extracts was shaken with a 5956 solution of sodium bicarbonate, - with water and a saline solution. Then the organic phase was dried, the desiccant was filtered and the solvent was removed by centrifugation, a residue was obtained, which was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 4 was isolated, 69 g of (2,6-dinitrophenyl)-acetic acid, which was then esterified with methanol (1 bml) and concentrated sulfuric acid (0.4 ml). For this, the acid and reagents were heated in a flask with

Refrigerate for seven hours. The methanol was removed by centrifugation, and the residue was treated in the usual way. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 4.43 g (8995) of the required ester was obtained. and 7H-NMR (300 MHz, SOSI»a): 5 - 3.75 (3H), 4.20 (2H), 7.69 (1H), 8.19 (2H).

Gee! 4-amino-1,3-dihydroindol-2-one 4.43 g (18.45 mmol) of methyl-(2,6-dinitrophenyl)-acetate was added to 38.8 ml of glacial acetic acid and 11 ml of water and mixed with 3.75 g of iron powder and stirred for more than four hours. In this case

HT" was heated to 40-60 oC. The reaction mixture was added to a mixture of water and ice, mixed with ethyl acetate and stirred intensively for ten minutes. The mixture was filtered using a glass fiber filter, the organic phase was separated, and the aqueous phase was extracted two more times with ethyl acetate. The combined organic extracts were washed with brine, dried, and the solvent was removed by centrifugation after filtering off the desiccant. The residue was chromatographed on silica gel (eluent: methanol/dichloromethane). 2.38 g of 4-nitro-indol-2-one was isolated. The nitro compound was again mixed in glacial acetic acid/water with 2.7 g of iron powder, and the above cycle was repeated. 1.63 g of the necessary amine was isolated. 60 "H-NMR (300 MHz, DMSO-IV): 5 - 3.19 (2H), 5.03 (2H), 6.08 (1H), 6.22 (1H), 6.85 (1H), 10.10 (1H). 4-(4-bromo-2-methoxyphen!)-4-methyl-2-trifluoromethyl)-pentane-1,2-diol 2.55 g (6.17 mmol) of ethyl ether 4-( 4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanoic acid (synthesized in two stages, using 4-(4-bromo-2-methoxyphenyl)-2-oxopentanoic acid as a starting material acid, MUO 98/54159)) b5 was dissolved in 102 ml of diethyl ether, mixed in portions at a temperature from 0 to -592C, with 351.3 mg (9.25 mmol) of lithium aluminum hydride and stirred for 3.5 hours at room temperature. The reaction mixture was added dropwise was mixed with saturated sodium bicarbonate solution while cooling in an ice bath and stirred for 15 minutes at 52C and then for 1 hour at room temperature. The precipitate was suctioned off, washed again with diethyl ether, and the filtrate was concentrated by rotary evaporation. The residue was chromatographed on silica ale (mobile solvent: ethyl acetate/hexane).

In addition to 38mg of aldehyde (see the next stage), 2.025g (88.490) of diol was obtained. 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal 2.03g (5442 mmol) 4-(4-bromo-2-methoxyphenyl)-4-methyl-2 -(trifluoromethyl)-pentane-1,2-diol was oxidized to the aldehyde according to Swern, as described in example 3. 1.839 g (91.495) of the required compound was isolated. 70 "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.39 (ZH), 1.45 (ZH), 2.23 (1H), 3.35 (1H), 3.58 (1H), 3, 90 (ZH), 6.93-7.09 (ZH), 9.03 (1H). 4-C4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl) -pentylidene|amino)-1,3-dihydroindol-2-one

Zb0Omg (0.812 mmol) of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal was stirred in 1.5 ml of glacial acetic acid with 120.4 mg (0.812 mmol) of 4-amino- of 1,3-dihydroindol-2-one for two days at 75 room temperature. The reaction mixture was evaporated to dryness, and the residue was placed on a Riazptazvieg support column. 235.9 mg (58.195) of the required imine was isolated. "H-NMR (ZO0MHC, SOSIv): 5 - 1.35 (ZH), 1.53 (ZH), 2.20 (1H), 3.30 (1H), 3.42 (2H), 3.85 (ЗН), 4.71 (1Н), 6.05 (1Н), 6.78 (1Н), 6.80-6.90 (2Н), 6.98 (1Н), 7.19 (1Н), 7.45 (1H), 8.25 (1H). 4-(7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)amino)-1,3-dihydrondol-2-one 235.9 mg 4-(4-(4bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene|amino)- 1,3-Dihydroindol-2-one was mixed at 092C with 6b.42ml of a 1M solution of BVgz in dichloromethane and stirred for four hours at room temperature. At a temperature of 09C, a saturated solution of sodium bicarbonate was carefully added dropwise. Then, the organic phases were extracted three times with ethyl acetate dried over sodium sulfate. The desiccant (U was suctioned off and the solvent was removed by centrifugation. The residue was chromatographed on Riazptavieg support.

125.4 mg (5495) of the required compound was isolated. "H-NMR (SO0MHCc, CO500): 5 - 1.52 (ZH), 1.65 (ZH), 1.98-2.18 (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 "I (3-4-(17-hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphthoyl|1,2-41|-1,3-dioxol-b -ilyamino)-2,3s-dihydroisoindol-1-one and (-)-4-(17-hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphthoyl) 2-a41-1,3-dioxol-b-yl)iamino)-2,3 (ab) z -dihydroisoindol-1-one so

Methyl ether of 1,3-benzdioxol-4-carboxylic acid

A solution of 2,3-dihydroxybenzoic acid in 450 ml of methanol was mixed dropwise with 5 ml of thionyl chloride at room temperature. After that, the solution was heated for five hours to 602C and continued to be stirred overnight at room temperature. The solvent was completely removed in vacuo and the remaining oil was resuspended in diethyl ether and extracted with saturated sodium bicarbonate solution. After washing with saline solution, drying with sodium sulfate and removing the solvent in a vacuum, 46 g of 2,3-dihydroxybenzoic acid methyl ether were obtained. It was mixed in 575 ml of DMF and 20.2 ml of dibromomethane with 56.7 g of potassium carbonate, and the mixture was heated to 100,260 for five hours in an argon atmosphere.

After that, the mixture was stirred overnight at room temperature. After mixing with water, the mixture was extracted three times with ethyl acetate. The organic phase was washed several times with water and dried over sodium sulfate. The solvent was removed in vacuo to give 50.2 g of 1,3-benzdioxole-4-carboxylic acid methyl ester as a brown solid. o Melting point: 55-5720

Ge») 4-(1,3-benzdioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ether 4.76 g of 1,3-benzdioxol-4-carboxylic acid methyl ether in bbml of anhydrous THF was added dropwise - at room temperature to a solution of 2 ml of methylmagnesium chloride in THF in an argon atmosphere. Reaction mixture

It was stirred for three hours and then slowly mixed with yin. hydrochloric acid. It was then extracted with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate, and the solvent was removed in vacuo. 5 g of 1-(1,3-benzdioxol-4-yl)-1-methylethanol was obtained in the form of a brown oil. inv Tertiary alcohol (27.17 mmol) was mixed together with 7.8 g (41. mmol) of ethyl ether of 2-(trimethylsilyloxy)-acrylic acid in 100 ml of dichloromethane at a temperature of -7092C with 5.4 g (20.8 mmol)

F, tin tetrachloride. After stirring for 15 minutes at a temperature of -70 oC, the solution was poured into a half-saturated solution of sodium carbonate, mixed with ethyl acetate and intensively stirred. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and the solvent was removed in vacuo. 7.15 g of yellow oil was obtained, which was distilled together with products from some batches treated similarly.

4-(1,3-benzdioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanoic acid ethyl ether b, 1 g (21.9 mmol) 4-(1,3-benzdioxol-4) ethyl ether -yl)-4-methyl-2-oxopentanoic acid, dissolved in 130 ml of tetrahydrofuran, was reacted with 9.5 ml (65.7 mmol) of (trifluoromethyl)trimethylsilane and 4.42 ml of a 1M 65 solution of tetrabutylammonium fluoride in tetrahydrofuran. The interaction was carried out as described in example 3.

The crude product obtained was purified together with one of the similarly treated batches.

19.19 g (33.02 mmol) of 4-(1,3-benzdioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ether as a starting substance | by chromatography on silica gel (mobile solvent: ethyl acetate/hexane). 16.45 g (86905) of the required product was isolated from two batches. 4-(1,3-benzdioxol-4-yl)-4-methyl-2-trifluoromethyl)pentane-1,2-diol 12.5 g (36.03 mmol) 4-(1,3-benzdioxol-4) ethyl ether -yl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanoic acid was introduced into 43 Oml of diethyl ether and mixed in portions with 2.05 g (54, Tmmol) of lithium aluminum hydride at a temperature of 02С. After stirring overnight at room temperature, the batch was carefully added to the sodium bicarbonate solution. The 7/0 mixture was filtered through diatomaceous earth and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried, and the solvent was removed by centrifugation after filtering off the desiccant. After chromatography of the residue on silica gel (mobile solvent: ethyl acetate/hexane), 6.7 g (6195) of the required alcohol was obtained. 4-(1,3-benzdioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal 2.26 g (7.38 mmol) 4-(1,3-benzdioxol-4-yl)- 4-Methyl-2-(trifluoromethyl)pentane-1,2-diol was oxidized to the aldehyde as described in Example C according to Swern. After carrying out the usual processing, the residue was chromatographed on a RIazptavieg medium. 1.85 g (82.3905) of the required aldehyde was obtained. "NA-NMR (ZO0MHz, SOSISCH): 5 - 1.39 (ZN), 1.48 (ZN), 2.27 (1), 3.10 (IN), 3.67 (1H), 5.92 -6.02 (2H), 6.60-6.70 (1H), 6.70-6.88 (2H), 9.06 (1H). (1)-4-(17-hydroxy-9, 9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphthoyl|1,2-α41-1,3-dioxol-b-yl)amino)-2,3-dihydroisoindol-1-one and ( -)-4-(17-hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphthoyl|1,2-a41-1,3-dioxol-b-yl)iamino) -2,3-dihydroisoindol-1-one 800 mg (2.63 mmol) of 4-(1,3-benzdioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl)ipentanal was mixed in

B2ml of glacial acetic acid with 38O9mg (2.63mmol) 4-amino-2,3-dihydroisoindol-1-one overnight at room (5) temperature. The reaction mixture was centrifuged until it reached an anhydrous state, and the residue was chromatographed on Riazptazieg medium. 725 mg (62.895) of the required compound was isolated in the form of a racemate. When the racemate was split (Spigairak AO 20u; mobile solvent: hexane/ethanol/diethylamine) 279.2 mg of the (k)-enantiomer Chodr-20.7 (c-1.03, methanol)) and 297.5 mg of the (-)-enantiomer were obtained Cho1r--23.4 (c-1.02, methanol)) "

Example 8 "5-(8-chloro-2, 5-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-isoquinoline-1(2H )-one ise) 4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)pentanal o 2 g (6.12 mmol) 4-(5-chloro-2-methoxyphenyl)- hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol was oxidized with 854.bmg (6.73 mmol) of oxalyl chloride and 1.05 ml (14.812 mmol) of DMSO as described in example 2 according to Swern. After carrying out the usual processing, 1.95 g (98.495) of the necessary aldehyde was obtained, which was used in the next stage in crude form. "H-NMR (ZO0MHZ, SOSIV): 5 - 1.39 (ZH), 1.49 (ZH), 2.27 (1H), 3.32 (1H), 3.59 (1H), 3.88 (ZH), 6.78 (1H), « 7.10 (1H), 7.20 (1H), 9.09 (1H). C 70 5-C4-(5-chloro-2-methoxyphenyl)-2 -hydroxy-4-methyl-2-trifluoromethyl)-pentylidene|amino)isoquinolin-1(2H)-one with ZOOmg (0.924 mmol) 4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl- 2-("trifluoromethyl)-pentanal z" was stirred 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. The mixture was poured into toluene three times and evaporated on a rotary evaporator until the anhydrous state was reached. The residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 345.8 mg (80.1965) of the required compound was isolated. , 1.57 (ZH), 2.29 (1H), 3.49 (1H), 3.83 (ZH), 4.82 (1H), 6.57-6.65 (in) (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).

Fu 5-(8-chloro-2, 5-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-isoquinoline-1(2H)- on t. 5Omg (0.107mmol) of the compound

T» 5-(C4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene|amino)2,3-isoquinolin-1-one, which is described in the previous paragraph, was mixed at -202C with 2.1 ml of a 1M solution of boron tribromide in dichloromethane, and the mixture was stirred for two and a half hours at a temperature in the range from -209C to 02C. The reaction mixture 5B was mixed dropwise at -20 C with a saturated sodium bicarbonate solution. After diluting with ethyl acetate, the cooling bath was removed and the batch was stirred for 15 minutes at room temperature.

F) temperature. The mixture was extracted twice each time with 30 ml of ethyl acetate. The combined organic extracts were washed with water and a saturated solution of MacCl. After drying over sodium sulfate, the solvent was removed by centrifugation, and the remaining residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 16.5 mg (3390) of the required compound was isolated.

MO(EB Kk): 453455

Example 9 8-bromo-1-K1H-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 ether 65 34.45 g (258.91 mmol) of aluminum trichloride was added to 354.35 g (237.02 mmol) 4-bromoanisole. 38.95 g (172.19 mmol) of 2-hydroxy-4-methylene-2-trifluoromethyl)pentanoic acid ethyl ether was added dropwise to this mixture over the course of one hour. After stirring overnight at room temperature, the batch was added to a mixture of ice water and acidified with 10905 hydrochloric acid. It was then extracted three times with ethyl acetate and the combined organic extracts were washed with water. hydrochloric acid and salt solution. After drying on magnesium sulfate, the solvent was removed by centrifugation. Most of the excess 4-bromoanisole was distilled off (1Ombar; bath temperature 110 22). After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 36.87 g (51.895) of the required compound were obtained. 7TH-NMR (300 MHz, SOSIv): 5 - 1.39 (ZH), 1.46 (ZH), 2.49 (1H), 2.85 (1H), 3.48 (1H), 3.62- 3.75 (1H), 3.85 (ZH), 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

3 g (7.25 mmol) of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid ethyl ether was dissolved in 120 ml of diethyl ether, and the reaction mixture was cooled to 02C. 426.5 mg (10.869 mmol) of lithium aluminum hydride was added in portions. After stirring for two hours at room temperature, the starting material was no longer detected. The batch was mixed with a saturated solution of sodium bicarbonate at 75°C cooling in an ice bath, the precipitate was suctioned off, and it was washed with diethyl ether. After centrifugation, the residue was chromatographed on Niazpitazieg medium. In addition to 540.5 mg of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal, 1.14 g of the required alcohol (which, however, also contains a debromo compound) was isolated. 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal 1.13 g. (3.0 mmol) of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol was added to 20 ml of dichloromethane and 5.4 ml of DMSO. After mixing with 1.55 g (15.32 mmol) of triethylamine and 975.28 mg (6.13 mmol) of the ZO3/pyridine complex, the batch was stirred overnight at room temperature. After TLC, the ZO z/pyridine complex was added at the tip of the spatula, and the mixture was further stirred for several hours. The reaction mixture was mixed with a saturated solution of ammonium chloride and shaken three times with methyl tert-butyl ether. SM

The combined organic extracts were washed with water and saline. Then the solvent was dried and removed by centrifugation, the residue was chromatographed on Riazptavieg medium. 902.7 mg (79.8195) of the required aldehyde was isolated (together with the debrominated compound). "H-NMR (ZO0MHZ, SOSIV): 5 - 1.40 (ZN), 1.50 (ZN), 2.28 (1H), 3.30 (1H), 3.87 (ZN), 6.73 (1), 7.22 (1H), 7.35 (1H), 9.09 (1H). in 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-2-( 1H-indazol-4-yl)iminomethyl|-4-methylpentan-2-ol «

Zb0Omg (0.8133 mmol) of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)pentanal was mixed in 1.19 ml of glacial acetic acid with 108.2 mg (0.8133 mmol) of 4 -aminoindazole, and the mixture was stirred for about four days at room temperature. The batch was centrifuged until the anhydrous state was reached, and the residue was diluted three times with toluene. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane) was obtained

From 352.5 mg (89.596) of the required imine (together with the imine of the desbrominated compound). so 7TN-NMR (Z00MHz, SOSI"): 5 - 1.48 (ZN), 1.55 (ZN), 2.28 (1H), 3.44 (1H), 3.80 (ZN), 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-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalgn-2-ol 100 mg ( 0.20 mmol) of 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-2-K1H-indazol-4-yl)iminomethyl|-4-methylpentan-2-ol was dissolved in 1 ml of dichloromethane , and the reaction mixture was cooled to -302C. 4 ml of a 1 M solution of BVgz in dichloromethane was added dropwise over 15 minutes, and then the batch was stirred for more than 45 minutes at a temperature of -3020. At a temperature of -30C, approximately 1 Oml of a saturated solution of sodium bicarbonate was carefully added dropwise. After diluting with ethyl acetate, the mixture was stirred for ten minutes and then extracted twice with 5 Oml of ethyl acetate each time. The combined organic extracts were washed with water and saline. The resulting residue, after drying the solvent and removing it by centrifugation, was chromatographed several times on silica gel (mobile solvent: ethyl acetate/dichloromethane). 21 mg of the required compound was isolated (together with the corresponding debrominated compound). 7TH-NMR (ZO0MHCz, СО3О0): 5 - 1.55 (ЗН), 1.67 (ЗН), 2.10 (1Н), 2.43 (1Н), 3.89 (ЗН), 5.25 ( 1H), 6.72 t (1H), 6.83 (1H), 6.90 (1H), 7.22 (1H), 7.49 (1H), 8.25 (1H).

ChT» 8-bromo-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol 21 mg (0, 0433mmol) 8-bromo-5-methoxy-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

It was mixed at room temperature with 04 ml of a 1M solution of VViz and stirred for 19 hours at room temperature. Then the reaction mixture was mixed with ice, a saturated sodium bicarbonate solution was added dropwise, and the mixture was diluted with ethyl acetate. The organic phases were washed neutrally as usual and the residue which remained after centrifugation of the solvent was chromatographed on silica gel (mobile solvent: methanol/dichloromethane). 17.1 mg (83.890) of the required compound was isolated (together with the debrominated compound). 60 "H-NMR (ZO0MHCc, CO500): 5 - 1.59 (ZH), 1.71 (ZH), 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-(H-indazol-4-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol 2-hydroxy-4-methyl- 4-phenyl-2-trifluoromethyl)pentanal 65 10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (MU098/54159)| in 250 ml of dimethylformamide was mixed at

-BeS with 4.1 ml of thionyl chloride, and after 15 minutes, it was mixed with 4 ml of methanol. After 15 hours at room temperature, the batch was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, dried (NaCl3O)) and concentrated by evaporation to give 9.3 g of 4-methyl-2-oxo-4-phenylpentanoic acid methyl ester. It was mixed in 558 ml of DMF at -59C with 15.5 ml (104.63 mmol) of (trifluoromethyl)trimethylsilane and 20.5 g (63.28 mmol) of cesium carbonate, and the mixture was stirred for 16 hours at room temperature. Water was added, the mixture was extracted with ethyl acetate, the organic phase was washed with water and dried (Ma»5O)). The intermediate product, which was concentrated by evaporation, was resuspended in 200 ml of THF, and 50 ml of a 1 M solution of tetrabutylammonium fluoride in THF was added. The mixture 70 was stirred for 2 hours, water was added, the mixture was extracted with ethyl acetate, the organic phase was washed with water and dried (Ma»5O)). After chromatography on silica gel with hexane-ethyl acetate (0-30905), 8.35 g of methyl ester of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl)pentanoic acid was obtained. The ester (8.3 g, 28.59 mmol) was dissolved in 1800 ml of THF, and 1.52 g (36.20 mmol) of lithium aluminum hydride was added in small portions over 2.5 hours. After complete conversion, 5 ml of ethyl acetate was added dropwise, and after another 10 minutes, 1 ml of water was carefully added. The precipitate formed was filtered off and carefully washed with ethyl acetate.

After chromatography on silica gel (Kk) with hexane-ethyl acetate (0-3596), 5.40 g of 4-methyl-4-phenyl-2-trifluoromethyl)pentane-1,2-diol was obtained. 5./ml (40.3 mmol) of triethylamine was added to 2.5 g (9.5 mmol) of diol in 75 ml of dichloromethane and 28 ml of DMSO, and 5 g of the pyridine/5O3 complex was added in portions over the course of minutes. The mixture was stirred for 2 hours, and 40 ml of saturated ammonium chloride solution was added. The mixture was stirred for another 15 minutes, the phases were separated, and they were extracted with dichloromethane. The mixture was washed with water and dried over sodium sulfate. The solvent was removed in vacuo to give the product 3g. "NA-NMR (Z00MHZ, SOS): 5 - 1.34 (in, ZN), 1.44 (in, ZN), 2.34 (9, 2H), 2.66 (4, 1), 3, 64 (in, 1H), 7.03-7.41 (t, 4H), 8.90 (in, 1H). 1,1,1-trifluoro-4-phenyl-2-((1H-indazole-4 -yl)iminomethyl)|-4-methylpentan-2-ol with 1300 mg (0.500 mmol) of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl)-pentanal was dissolved in 15 ml of toluene and mixed with 7 mg ( 0.55 mmol) of 4-amino-indazole and 0.22 mL of titanium triethylate and stirred at 1002 C for 2.5 hours under an argon atmosphere.For routine workup, the reaction solution was mixed with 1 mL of saturated sodium chloride solution and the mixture was stirred for 30 minutes. Then the suspension was suctioned through Celite and washed with 200 ml of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in a vacuum: 246 mg. After column chromatography on silica gel with pentane-ethyl acetate, 19 mg of the product was obtained. 7TH-NMR (Z00MHz, DMSO-yv): 5 - 1.35 (in, ZN), 1.47 (z, ZN), 2.26 (d, 1), 2.73 (9, 1), 6.13 ( in 1H), about 6.24 (y, 1H), 6.94 (y, 1H), 7.06 (y, 2H), 7.23 (M, 1H), 7.34-7.40 (t, ЗН), 7.56 (in, 1Н), 8.00 (in, 1Н), 13.17 (in, 1Н). Ha") 1-(H-indazol-4-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

190 mg (0.51 mmol) of 1,1,1-trifluoro-4-phenyl-2-K1H-indazol-4-yl)iminomethyl|4-methylpentan-2-ol was dissolved in 100 ml of dichloromethane and cooled to -702С. The solution was mixed for 10 minutes with 0ml of a solution of titanium tetrachloride (Imol in dichloromethane), and the mixture was stirred for 1 hour at a temperature of -7096.

After that, the cold solution was poured into 200 ml of saturated sodium bicarbonate solution and stirred for 15 minutes. For routine processing, the mixture was extracted with dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum: 208 mg. After column chromatography with dichloromethane-methanol, 5 mg:z" (2895) of the required product was obtained. 7TH-NMR (300 MHz, DMSO-iv): 5 - 1.36 (5, ЗН), 1.51 (з, ЗН), 2.08 (0, 2Н), 5.35 (d, 1Н), 5 .93 (z, 1H), 58.24 (y, 1H), 6.32 (0, 1H), 6.74 (0, 1H), 7.05-7.12 (t, 2H), 7, 21-7.28 (t, 2H), 7.43 (d, 1H), 8.15 (c, 1H), 12.81 (c, 1H). o Example 11 1-K2-methylbenzothiazol-7-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol o 1,1,1-trifluoro- 4-phenyl-2-((2-methylbenzothiazolyl-7-yl)iminomethyl)-4-methylpentan-2-ol b "H-NMR (SO0MHC, DMSO-dv): 5 - 1.33 (in, ЗН), 1.47 (c, ЗН), 2.24 (y, 1), 2.71 (a, 1), 2.82 (z, ЗН), 6.19, (c, 1Н), 6.54 ( a, 1H), 6.91 (Ii, 1H), 7.02 (i, 2H), 7.31-7.40 (t, ZH), 7.51 (8, 1H), 7.78 (a , 1H). e 1-K2-methylbenzothiazol-7-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

I» TN-NMR (300 MHz, DMSO-iv): 5 - 1.34 (in, ZN), 1.47 (in, ZN), 1.99-2.12 (t, 2H), 2.78 ( в, ЗН), 5.38 (a, 1Н), 5.68 (4, 1Н), 6.10 (в, 1Н), 6.78 (da, 1Н), 7.07-7.16 (t , 2H), 7.20-7.28 (t,ZH), 7.41 (a, 1Hn).

Example 12 22 6-(1H-indazol-4-yl)amino|-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphthoic|1,2-41|-1, 3-dioxol-7-ol

Gee! 4-(1,3-benzdioxol-4-yl)-1,1,1-trifluoro-2-I(1H-indazol-4-yl)iminomethyl|-4-methylpentan-2-ol "H-NMR (ZO0MHC , DMSO-dv): 5 - 1.34 (in, ZN), 1.48 (in, ZN), 2.28 (4, 1), 2.93 (y, 1), 5.90 (z, 2H), o 6.15 (c, 71H), 6.29 (a, 1), 6.45 (i, 1), 6.56 (aa, 1n), 6.62 (4, 1), 7 .23 (5 1), 7.40 (y, 1), 7.74 (v, 1H), 8.00 (v, 1H), 13.17 (8, 1H). because 6-(1H-indazole -4-yl)amino|-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphthoic|1,2-41|-1,3-dioxol-7-ol

TN-NMR (300 MHz, DMSO-yv): 5 - 1.43 (in, ZN), 1.55 (in, ZN), 2.04-2.12 (t, 2H), 5.26 (d, 1H), 5.95 (c, 1H), 6.00 (c, 2H), 6.19 (a, 1H), 6.29 (d, 1H), 6.70-6.78 (t, ЗН ), 7.07 (i, 1H), 8.12 (8, 1H), 12.81 (c, 1H).

Example 13 1-(2-methylquinolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol 65 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, 7 mg of 5-amino-2-methylquinoline and 16 µl of titanium triethylate were mixed in 3 ml of toluene for 2 hours at 1002. After cooling, the batch was mixed with 2 ml of water , stirred for 15 minutes at room temperature, and concentrated by evaporation in vacuo. After column chromatography on silica gel with cyclohexane-ethyl acetate, 111 mg of the product was obtained. "H-NMR (Z0OMHC, SOSIi): 5 - 1.35 (zv, ZN), 1.55 (v, ZN), 2.45 (a, 1H), 2.75 (z, ZN), 2, 80 (а, 1Н), 5.00 (85, 1Н), 6.15 (а, 1Н), 6.9-7.1 (t, ЗН), 7.30 (t, ЗН), 7.35 (y, 1H), 7.45 (y, 1H), 7.90 (d, 1H), 8.35 (a, 1Hn). 1-(2-methylquinolin-5-yl)amino|-4,4 -dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol 5.ml of a 1M solution of titanium tetrachloride-"SNHSI" was added dropwise to a solution of 111ml of 1,1,1-trifluoro-4-phenyl -2-((2-methylquinolin-5-yl)iminomethyl|-4-methylpentan-2-ol in 4 ml of СНоСиИ» at a temperature of -1820. After 1 hour at a temperature of -782С, the batch was mixed with saturated Manso» and heated to room temperature temperature. The phases were separated, the aqueous phase was extracted with CHCl", the combined organic phases were dried (Ma»zoO)) and concentrated by evaporation in a vacuum. After column chromatography on silica gel with 75 cyclohexane-ethyl acetate, 94 mg of product was obtained. "H-NMR (Z0OMHC, SOSI): 5 - 1.45 (zv, ЗН), 1.60 (в, ЗН), 2.15 (а, 1Н), 2.20 (9, 1Н), 2.75 (з, ZN), 3.05 (bg., 71), 4.85 (rgM. a, tn), 5.20 (a , tn), 685 (a, 1), 7.10 (5 1), 7.20 (a, 1), 7.30 (Her, 1H), 7.40 (sa, 1H), 7.50 ( 4, 1H), 7.55 (Her, 1H), 8.05 (a, 1Hn).

Example 14 1-Kquinolin-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

Similarly to example 13, 120 mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanal and 1 mg of 5-aminoquinoline were converted into 95 mg of product. 7TH-NMR (ZO0MHZ, SOSI): 5 - 1.35 (in, ЗН), 1.60 (з, ЗН), 2.45 (y, 1Н), 2.80 (0, 1Н), 5.00 (in, 1H), 6.20 s (d, 1H), 6.95-7.1 (t, ЗН), 7.30 (t, 2H), 7.50 (t, 2H), 8.00 (d, 1H), 8.45 (j, 1H), 8.95 (t, 1H). H0) 1-Quinolin-5-yl)amino)-4,4-dimethylpyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol

Similarly to example 13, 95 mg of 1,1,1-trifluoro-4-phenyl-2-(quinolin-5-yl)iminomethyl)|-4-methylpentan-2-ol was converted into 390 mg of product. ""H-NMR (ZO0MHZ, SOSIZ): 5 - 1.45 (in, ЗН), 1.60 (in, ЗН), 2.15 (а, 1), 2.20 (9, 1Н), 3 .25 (bg., 1H), 4.95 (bg. a, 1), 5.20 (a, tn), 6.90 (aa, yin), 7.10 (5 71), 7.25- 7.35 (t, 4H), 7.40 (a, tn), 7.60 (t, 2H), 8.15 " (d, 1H), 8.90 (t, 1H). "o

Example 15 5-PC2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-quinolin-2(1H)-one o 5-CH2-hydroxy- 4-methyl-4-phenyl-2-(trifluoromethyl)pentylidene|amino)quinolin-2(1H)-one so

Similarly to example 13, 100 mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl)pentanal and 337 mg of 5-aminoquinolin-2(1H)-one (52313) were converted into 57 mg of product.

TNA-NMR (ZO0MHZ, SOSI): 5 - 1.35 (in, ЗН), 1.55 (5, ЗН), 2.40 (а, 1), 2.80 (а, 1Н), 4.70 (Bk. c, 1H), 5.80 (4, 1), 6.75 (y, 1H), 7.05 (i, 1H), 7.15 (her, 2H), 7.30 (t, 4H), 8.00 (a, 1H), 9.05 (g. c, 1H). « 5-C2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2(1H)-one - c Similarly to example 13, 23 mg 5-C2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl)pentylideneamino)quinolin-2(IIH)-one was converted into 11 mg of "" product. 7TH-NMR (300 MHz, DMSO-iv): 5 - 1.35 (in, ZN), 1.50 (in, ZN), 2.00 (4, 1), 2.10 (a, 1), 5.35 (a, tn), 6.05 (in , 1H), 6.20 (y, 1H), 6.40 (a, 1H), 6.55 (Yii, 1H), 7.25 (t, 2H), 7.45 (a, 1H), 8 .20 (y, 1H), 11.60 (Bg.8, 1H). (og) Example 16 about 1-(2-methoxyquinolin-5-yl)amino|-4,4-dimethyl-2-trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol 1,1,1-trifluoro-4-phenyl-2-((2-methoxyaminolin-5-yl)iminomethyl|-4-methylpentan-2-ol (o ) Similarly to example 13, 20mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl)pentanal and 122mg of 50 5-amino-2-methoxyquinoline were converted into 19mg of the product.

TN-NMR (ZO0MHZ, SOSIz): 5 - 1.35 (in, ЗН), 1.55 (з, ЗН), 2.45 (y, 1Н), 2.80 (0, 1Н), 4.10 (c, ЗН), 5.00 t" (5, 1Н), 6.10 (а, 1Н), 6.90 (а, 1Н), 6.95 (и, 1Н), 7.05 (и, 2H), 7.30 (4, 2H), 7.35 (i, 1H), 7.70 (a, 1h), 8.30 (a, 1Hn). 1-(2-methoxyquinolin-5-yl)amino|-4,4-dimethyl-2-trifluoromethyl)-1,2,3.4-tetrahydronaphthalen-2-ol

Similarly to example 13, 185 mg of 29 1,1,1-trifluoro-4-phenyl-2-(2-methoxyquinolin-5-yl)iminomethyl|-4-methylpentan-2-ol was converted into 127 mg

GF) of the product. yyu "H-NMR (Z0OMHC, SOSI): 5 - 1.45 (zv, ЗН), 1.60 (в, ЗН), 2.15 (а, 1Н), 2.20 (9, 1Н), 310 (z, 1H), 410 (5, ЗН), 4.75 (Bg. а, 1Н), 5.20 (а, 1Н), 6.75 (а, 1Н), 6.85 (y, 1Н) , 7.1 (6, 1), 7.25-7.45 (t, 4H), 7.50 (i, 1H), 8.00 (a, 1Hn).

Example 17 60 1-Cphenylamino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol 1,1,1-trifluoro-4-phenyl-2-Cphenyl) iminomethyl|-4-methylpentan-2-ol

Analogously to example 1, 200 mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl)pentanal and 4 μl of aniline were converted into 18 mg of the product. be TN-NMR (ZO0MHZ, SOSIz): 5 - 1.35 (v, ЗН), 1.50 (z, ЗН), 2.35 (y, 1Н), 2.70 (d, 1Н), 5, 05 (in, 1H), 6.65 (9, 2H), 7.05 (, 1H), 7.15-7.30 (t, 7H).

1-Kphenylamino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol 9.bml of a 1M solution of titanium tetrachloride-"SNOSI" was added dropwise to a solution of 175 mg 1 ,1,1-trifluoro-4-phenyl-2-Cphenyl)iminomethyl|-4-methylpentan-2-ol in 1 bO0ml СНоСи» at a temperature of -7890.

First, the mixture was stirred for 1 hour at a temperature of -782C, and then 1 ml of titanium tetrachloride-CHClCl solution was additionally added, the mixture was stirred for 60 hours at room temperature.

The batch was mixed with saturated ManHcSO»z, the phases were separated, the aqueous phase was extracted with CHCl», the combined organic phases were dried (Ma»5O)) and concentrated by evaporation in a vacuum. After column chromatography on silica gel with cyclohexane-ethyl acetate, 45 mg of the product was obtained. 7TH-NMR (SOSIV): 5 - 1.40 (in, ЗН), 1.50 (in, ЗН), 2.00 (4, 1), 2.20 (4, 1Н), 3.40 (in , 1H), 3.80 (4, 1H), 4.95 (a, 1H), 6.80 (a, 2H), 6.85 (i, 1H), 7.15 (t, 1H), 7 ,20-7,30 (t, 4H), 7,40 (a, 1H).

Example 18 4-(2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-(trifluoromethyl)benzonitrile 1,1,1-trifluoro -4-phenyl-2-((4-cyano-3--trifluoromethyl)phenyl)iminomethyl|-4-methylpentan-2-ol

Similarly to example 13, 120 mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl)ipentanal and 78 mg of 4-cyano-3-trifluoromethyl)anil were converted into 71 mg of product. "H-NMR (Z0OMHC, SOSIi): 5 - 1.35 (zv, ЗН), 1.55 (в, ЗН), 2.40 (а, 1Н), 2.75 (9, 1Н), 4, 55 (z, 1H), 6.75 (da, 1n), 6.95 (a, 1), 7.10 (i, 1H), 7.20 (t, ЗН), 7.30 (t, 2H ), 7.70 (a, 1H). 4-C2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-(trifluoromethyl)benzoni trill

Similarly to example 13, 71 mg of 1,1,1-trifluoro-4-phenyl-2-((4-cyano-3--trifluoromethyl)phenyl)iminomethyl|-4-methylpentan-2-ol was converted into 58 mg of product. c 7TN-NMR (ZO0MHZ, SOSIv): 5 - 1.40 (in, ЗН), 1.50 (in, НН), 2.15 (in, 2Н), 2.60 (in, 1Н), 5, 05 (a, 1), 510. (U (d, 1n), 6.85 (da, 1n), 7.00 (9, 1H), 7.20 (c, 2H), 7.35 (t, 1H), 7.40 (a, 1H), 7.60 (a, 1H).

Example 19 5-C5-bromo-2-hydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-isoquinolin-1(2H)-one h (2 -bromophenyl)-acetonitrile and 25 g (10 b0 mmol) of 2-bromobenzyl bromide were mixed in 100 ml of M,M-dimethylformamide and b4 ml of water with 9.75 g (1500 mmol) of potassium cyanide and stirred overnight at room temperature. The reaction mixture was poured into a mixture of water and ice. It was then extracted three times with methyl tert-butyl ether, and the combined organic extracts were washed with brine, dried, and the solvent was removed by centrifugation. Remainder! ! and , o we se) were chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 18.9 g (96.4905) of the required compound were obtained. "H-NMR (300 MHz, SOSI"): 5 - 3.85 (2H), 7.23 (1H), 7.48 (1H), 7.55 (1H), 7.62 (1H). 2- (2-bromophenyl)-2-methyl-propionitrile " 18.9 g (96.41 mmol) of (2-bromophenyl)-acetonitrile and 31.41 g (221.74 mmol) of methyl iodide were dissolved in 150 ml of 2 M, M-dimethylformamide. At temperature 8.87 g (221.74 mmol) of sodium hydride (as a boFO suspension in oil) was added portionwise to 02 C, and the batch was stirred overnight at room temperature. The reaction mixture was poured into ice water and worked up as usual. Since the compound isolated after chromatography (20.9Hg) still contained 2-(2-bromophenyl)-propionitrile in addition to the required product, the entire amount was reacted again with the same amount of reagent. This reaction also yielded only the substance which all

Ho) also contains a mono-methyl compound. After additional alkylation using 15 g of methyl iodide and 4.45 g of sodium hydride in 150 ml of M,M-dimethylformamide, 18.57 g of the required compound was isolated. o 7H-NMR (300 MHz, SOCI3): δ - 1.91 (6H), 7.20 (1H), 7.35 (1H), 7.49 (1H), 7.68 (1H). (o) 2-(2-bromophenyl)-2-methyl-propanal from 50 18.57 g (82.21 mmol) of 2-(2-bromophenyl)-2-methyl-propionitrile was reduced in 325 ml of toluene with 102.72 ml of 1.2 M solution of PIVAN in toluene, in particular, as described in example 3. After processing, 18.17 g (97.34905) of the necessary

ChT" of aldehyde, which was used in the next stage in its crude form. "H-NMR (300 MHz, SOSI»v): 5 - 1.51 (6H), 7.20 (1H), 7.33-7.45 (2H), 7.61 (1H), 9.8 ( 1H).

Ethyl ether of (E/2)-4-2-bromophenyl)-4-methylpent-2-enoic acid 18.17 g (80.02 mmol) of 2-(2-bromophenyl)-2-methyl-propanal was treated similarly to the Horner reaction Wittiga, what

GF! described in example 3. After processing and subsequent chromatography on silica gel (mobile solvent: ethyl acetate/hexane), as described in the invention, 22.3 g (81.6795) of the required product were isolated. o (E/2)-4-(2-bromophenyl)-4-methylpent-2-enoic acid 22.3 g (65.349 mmol) of ethyl ether (E/2)-4-(-2-bromophenyl)-4-methylpent -2-enoic acid was saponified with b50 ml of 60 sodium hydroxide solution (In. in ethanol/water 2:1), as described in example 3. After carrying out the usual treatment, 14.32 g (69.995) of the required acid was isolated. 4-(2-bromophenyl)-4-methyl-2-oxo-pentanoic acid 14.32 g (45.72 mmol) of (E/2)-4-2-bromophenyl)-4-methylpent-2-enoic acid was subjected to the reaction with sulfuric acid in glacial acetic acid, as described in Example 3, to obtain the required ketocarboxylic acid. 13Zg (99.695) were allocated.

"H-NMR (300 MHz, SOSI»z): 5 - 1.60 (6H), 3.91 (2H), 7.09 (1H), 7.30 (1H), 7.49 (1H), 7 .57 (1H).

Ethyl ether of 4-(2-bromophenyl)-4-methyl-2-oxo-pentanoic acid 13 g (45.59 mmol) of 4-(2-bromophenyl)-4-methyl-2-oxo-pentanoic acid were reacted with ethanol and concentrated sulfuric acid to obtain a complex ester. After implementation and processing (see example 3), 13.01 g (91.195) of the required compound were obtained after chromatography on silica gel. "H-NMR (300 MHz, SOSI»v): 5 - 1.30 (ZH), 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 13g (41, 5 mmol) of 4-(2-bromophenyl)-4-methyl-2-oxo-pentanoic acid ethyl ether was reacted with Ruppert's reagent 70 as described in Example 3. After treatment and after chromatography on silica gel (mobile solvent: ethyl acetate/hexane) , isolated 16.15 g (85.695) of the required compound. 73.bml (88.39mmol) of OSIVAN solution (1.2M in toluene) was added dropwise (35 minutes) to a solution of 6.1g (35.45mmol) of the above-described trifluoromethyl alcohol in 148ml of toluene at a temperature of -109С. It was stirred for 30 minutes at a temperature from -102С to -59С, 24.2 ml of isopropanol and then water at a temperature of -109С were carefully added dropwise. After two hours of vigorous stirring at room temperature, the obtained precipitate was suctioned on a frit 54, washed with ethyl acetate, and the filtrate was centrifuged until the anhydrous state was reached. The residue (a regioisomeric mixture of two silyl ethers; 14.5g-95.495-35.08mmol) was reacted with tetrabutylammonium fluoride trihydrate in tetrahydrofuran at room temperature, as described in example 3. After carrying out the usual work-up and chromatography, 5.26g of the required compound was isolated. "H-NMR (Z00MHZ, SOSI): 5 - 1.62 (ZH), 1.70 (ZH), 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 2g (5.86 mmol) 4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-yl-ol was oxidized with a complex of 3-3-pyridine , as described in example 1. 1.72 g (86.8 mmol) of the necessary aldehyde was isolated. "H-NMR (SO0MHC, SOCIv): δ - 1.60 (6Н), 2.29 (1Н), 3.65 (1Н ), 3.78 (1H), 7.09 (1), 7.25 (1), 7.34 (1H), o) 7.58 (1H), 9.20 (1H). 4-C4-(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-trifluoromethyl-pentanal was stirred for five days at room temperature with 94.3 mg (0.589 mmol) of 5-aminoisoquinolin-1(2H)-one (example 2) in 0.vbml glacial acetic acid. After carrying out the usual processing and after chromatography on silica gel (mobile - solvent: ethyl acetate/hexane), 170.8 mg (60.2905) of the required compound were isolated. He) "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.59 (ZH), 1.70 (ZH), 2.29 (1H), 3.86 (1H), 4.89 (1H), 6 .58 (1H), 6.70-6.90 (ZH), 7.15-7.37 (ZH), 7.48 (1H), 7.59 (1H), 8.30 (1H), 11 .00 (1H). o 5-H5-bromo-2-hydroxy-4, (ee) 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-isoquinoline -1(2H)-one 5mg (0.104 mmol) 4-(4-(2-bromophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylideneamino))isoquinolin-1(2H)-one was mixed with ml " 1 M solution of BVgz in dichloromethane and stirred for 45 minutes at room temperature. After 470 Carrying out the usual treatment (see example 2) and after chromatography on silica gel (mobile solvent: - with methanol/dichloromethane), 49.2 mg (98.495) of the required compounds. h» "H-NMR (30 MHz, DMSO-dv): 5 - 1.67 (ZH), 1.79 (ZH), 2.09 (1H), 2.21 (1H), 5.48 ( 1H), 6.02 (18), 6.26 " (1H), 6.81 (1H), 7.00-7.30 (5H), 7.49-7.62 (2H), 11.25 (1H).

When using the corresponding aldehydes and amines described in the above examples as starting materials, the following cyclic compounds were obtained with the help of imines. (ee) Example 20 about 5-bromo-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The product was obtained after cyclization, as described in example 19. ia 7"H-NMR (ZO0MHCz, СО30О0): δ - 1.73 (ЗН), 1.88 (ЗН), 2.10-2.30 (2Н), 5.30 (1H), 6.39 (1H), 6.85 (1H), 7.01 "iz" 20 (1H), 7.24 (1H), 7.48 (1H), 7.58 ( 1H), 8.13 (1H).

Example 21

T" 5-bromo-4,4-dimethyl-1-propylamino-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The product was obtained after cyclization, as described in example 19. "H-NMR (ZO0MHCz, СО53О0): δ - 0.90-1.02 (ZH), 1.48-1.60 (2H), 1.63 (ZH ), 1.70 (ZH), 1.91 (1H), 2.15 (1H), 2.65-2.78 (1H), 2.91-3.05 (1H), 7.12 (1H ), 7.45 (1H), 7.56 (1H).

GF) Example 22

Ge 5-bromo-1-((3-hydroxypropyl)amino1-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The product was obtained after cyclization, as described in example 19. in "H-NMR (ZO0MHCz, СО50О0): δ - 1.63 (ЗН), 1.71 (ЗН), 1.94 (1Н), 1.99-2 .11 (2H), 2.17 (1H), 2.84-2.98 (1H), 3.09-3.20 (1H), 3.55 (2H), 7.13 (1H), 7 .49 (1H), 7.59 (1H).

Example 23 5-(8-fluoro-2, 5-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-isoquinoline-1(2H) -on 65 The product was obtained after cyclization as described in example 19.

Ministry of Education (EB'i, ASM/NhOO, 0195 TFC): 437 (10096)

Example 24 4-(7-chloro-2, 5-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-b-fluoro-2,3- dihydroisoindol-1-one

The product was obtained after cyclization as described in example 19. 7H-NMR (300 MHz, CO3O0): 5 - 1.58 (ZH), 1.65 (ZH), 2.01-2.10 (2H), 4.20 -4.45 (2H), 5.10 (1H), 6.70-6.89 (4H).

Example 25 5-Cb-fluoro-2-hydroxy-5-methoxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-isoquinoline-1(2H)- on 70 The product was obtained after cyclization, as described in example 3. "NA-NMR (300MgC, CO53O0): 5 - 1.53 (ZH), 1.58 (ZH), 2.14 (2H), 3.99 ( ЗН), 5.15 (1Н), 6.84 (1Н), 6.95 (1Н), 7.00-7.10 (2Н), 7.18 (1Н), 7.39 (1Н), 7 .69 (1H).

The product thus obtained was separated into its enantiomers (SpigaIrak AO 20; mobile solvent: hexane/ethanol/pEA), and they were then used in the cleavage of a simple ether (analogous to example 3): 5-Cb-fluoro-2,5 -dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyaminoNzoquinolin-1(2H)-one (cis, enantiomer A) 7"H-NMR (ZO0MHCc, CO300 ): 5 - 1.62 (ZH), 1.72 (ZH), 2.04-2.21 (2H), 5.13 (1H), 6.75-6.92 (ZH), 7.05 (1H), 7.18 (1H), 7.39 (1H), 7.69 (1H). 5-C6-fluoro-2, 5-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1 ,2,3,4-tetrahydronaphthalene-1-ylamino)-isoquinolin-1(2H)-one (cis, enantiomer B) "H-NMR (ZO0MHCc, CO500): 5 - 1.62 (ZH), 1.72 (ЗН), 2.04-2.21 (2Н), 5.13 (1Н), 6.75-6.92 (ЗН), 7.05 (1Н), 7.18 (1Н), 7.39 (1H), 7.69 (1H).

Example 26 ch 4-(C6b-fluoro-2,5-dihydroxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2,3-dihydroisoindole-1 -he (o)

The product was obtained after cyclization and cleavage of the simple ether as described in Example 3.

TN-NMR (ZO0MHz, CO3O0): 5 - 1.60 (ZH), 1.69 (ZH), 1.99-2.20 (2H), 4.23-4.45 (2H), 5.13 (1H), 6.80-7.03 (ZH), 7.18 (1H), 7.39 (1H). "AND

Example 27 b-chloro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol in

3-Chloro-2-methoxybenzylcyanide (He) 39.4 g (221.3 mmol) of МВ5 and 100 mg of benzoyl peroxide were added to 31.6 g (201.7 mmol) of 3-chloro-2-methoxytoluene in 50 Oml of SSI)/. The mixture was heated in a reflux flask for 16 hours, allowed to cool and filtered. The solvent was removed from the filtrate, and the filtrate was dissolved in 214 mL of M,M-dimethylformamide and 142 mL of water. 20.9 g (322.1 mmol) of potassium cyanide were added at a temperature of 090 and stirred for 16 hours.

The reaction mixture was diluted with water and extracted several times with tert-butyl methyl ether. The organic phase was washed several times with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed in vacuo and after purification by chromatography on silica gel (hexane/ethyl acetate 20905), 470 yielded 29.7 g of product. - c 7"H-NMR (SOSI"v): 5 - 3.76 (b, 2H), 3.95 (b, 3H), 7.08 (i, 1H), 7.31 (a, 1H) , 7.37 (4.1H). m 4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-trifluoromethyl)-pentane-1,2-diol and 29.7 g (163 7mmol) of 4-chloro-2-methoxybenzylcyanide and 46.5g (327.4mmol) of methyl iodide in 26b0ml of DMF were mixed at a temperature of 09C in portions with 13.2g (327.4mmol) of sodium hydride (b09o in oil). The mixture was stirred overnight and then mixed with water and ethyl acetate. The phases were separated, and the aqueous phase was extracted several times with ethyl acetate. It was washed with water and saturated sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation in vacuo. After chromatography on silica gel (hexane/ethyl acetate 95:5), 32.4 g of 2-(4-chloro-2-methoxy-phenyl)-2-methylpropionitrile was obtained in the form

Me, colorless oil. 7g (33.4mmol) of nitrile was slowly mixed in toluene at a temperature of -7892C with 41.bml of iz 20 (BO 1mmol) diisobutylaluminum hydride solution (2095 in toluene), and after 3 hours at -782C, 5.55ml of isopropanol was added dropwise. The mixture was allowed to warm up to -52C, and 38Oml of a 10 9% aqueous solution of wine was added

T" acid. After dilution with ether, the mixture was intensively stirred, the organic phase was separated, and the aqueous phase was extracted several times with ether. It was washed with saline, dried over sodium sulfate, and concentrated by evaporation in vacuo. After chromatography on silica gel 25 (hexane/ethyl acetate 95:5), 7.1 g of 2-(4-chloro-methoxy-phenyl)-2-methylpropanal was obtained in the form of a colorless

GF) oil. A solution of 8.95 g (33.4 mmol) of ethyl ester of 2-diethylphosphono-2-ethoxyacetic acid in 30 mL of tetrahydrofuran was mixed, while it was cooled on ice for 20 minutes with 19 mL (33.4 mmol) of a 2 M solution of lithium isopropylamide in tetrahydrofuran-heptane-toluene. , and the mixture was stirred for 15 minutes at a temperature of 09C. During 30 minutes, a solution of 7.1 g (334 mmol) of 2-(3-chloro-2-methoxyphenyl)-2-methylpropanal in 27 ml of tetrahydrofuran was added dropwise at 02C. After 20 hours at room temperature, water was added, and the mixture was extracted several times with ether and ethyl acetate. The mixture was washed with a saturated solution of ammonium chloride, dried (Ma»3O)) and concentrated by evaporation.

The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate 1090), and 8.5 g of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-3-ethoxy-2-ene-valerianic ethyl ether was obtained acid

The intermediate product was saponified with 80 ml of ZM sodium hydroxide solution/1 bO0 ml of ethanol. 5.3 g of acid was obtained, which was mixed with 8 Oml of 2N. of sulfuric acid at a temperature of 909 for 16 hours. After cooling, it was alkalized with potassium carbonate, washed with ether, and acidified with hydrochloric acid. After extraction with ethyl acetate, washing with a saturated solution of sodium chloride and removal of the solvent, 4.0 g of 4-(3-chloro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid was obtained. b,bg /(24.3 mmol) 4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-oxo-valeric acid and 2.74 ml (51.4 mmol) sulfuric acid (9695) were heated in a flask under reflux in 150 ml of ethanol for 5 hours. The batch was concentrated by evaporation in vacuo, and the residue was resuspended in saturated sodium bicarbonate solution. The mixture was extracted several times with ethyl acetate, washed with saturated sodium bicarbonate solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. After purification by chromatography on silica gel (hexane/ethyl acetate 10905), 5.9 g of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-oxo-valeric acid ethyl ester were obtained. This complex ester and 3.4 g (23.8 mmol) of (trifluoromethyl)-trimethylsilane in 34 ml of THF were mixed with 49 mg of tetrabutylammonium fluoride at a temperature of 020.

The mixture was stirred for 16 hours at room temperature, and then the reaction mixture was added to water. it 75 was extracted several times with ethyl acetate, washed with a saturated solution of sodium chloride, dried with the help of sodium sulfate, and concentrated by evaporation in a vacuum. 2.96 g of 4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ether was obtained in the form of a yellow oil.

This oil was mixed in 24 ml of diethyl ether at a temperature of 09C with 510 mg of lithium aluminum hydride and stirred for more than 4 hours at room temperature. 20 ml of a saturated solution of sodium bicarbonate was carefully added to the batch at a temperature of 02C, and the mixture was intensively stirred for more than 1 hour. it was extracted several times with tert-butyl methyl ether, washed with water and saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. The crude product was mixed in 33ml THF with 1.83 (5.7U9mmol) tetrabutylammonium fluoride trihydrate, and the mixture was stirred for 16 hours. It was poured into a mixture of water and ice, extracted several times with tertiary methyl ether, the CM was washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated (5) by evaporation in a vacuum. After purification by chromatography on silica gel (hexane/ethyl acetate 2590), 1.81 g of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol was obtained. "H-NMR (Z0OMHC, SOSIV), 5 - 1.47 (v, ЗН), 1.56 (v, ЗН), 2.21 (а, 1Н), 2.54 (9, 1Н), 2, 91 (in, 1H), 3.31 (da, 1n), 3.42 (9, 1H), 4.01 (in, ЗН), 7.00 (i, 1H), 7.20-7.35 (t, 2H) - 4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal g 1.87 g (18.5 mmol) of triethylamine and, in portions during 10 minutes, 1.17 g (7.4 mmol) of pyridine complex 5O»z was added to 1.2 g (3.7 mmol) of diol in 24 ml of dichloromethane and 4 ml of DMSO. The mixture was stirred for 5 hours, and 30 ml of saturated ammonium chloride solution was added. The mixture was stirred for another 15 minutes, the solid phases were separated and extracted with tert-butyl methyl ether, the mixture was washed with water and dried over

With sodium sulfate. The solvent was removed in vacuo, and after purification by silica gel chromatography (hexane/ethyl acetate, 0-5095), 0.98 g of product was obtained. "H-NMR (SOSIV): 5 - 1.44 (in, ЗН), 1.50 (з, ЗН), 2.29 (9, 2Н), 3.28 (а, 1Н), 3.55 ( c, 1H), 4.01 (z, ЗН), 6.95 (i, 1H), 7.07 (aa, 1Hn), 7.30 (ad, 1n), 8.90 (c, 1H). « 1,1,1-trifluoro-4-(3Z-chloro-2-methoxyphenyl)-2-(1H-indazol-4-yl)iminomethyl|-4-methylpentan-2-ol 7 70 125 mg (0.385 mmol) 4 -(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal was mixed with 0.7 ml of glacial acetic acid from 51.3 mg (0.385 mmol) of 4-aminoindazole, and the mixture was stirred overnight at room temperature. After concentration by evaporation to dryness, it was chromatographed on Riazptazwieg support. 11.9 mg (74.195) of the desired compound was isolated. b-chloro-1-K1H-indazol-4-yl)amino| -5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol so 75 116.9 mg (0.285 mmol) of imine was dissolved in 2.bml of dichloromethane and mixed at - 2592С with 1.13 ml of a 1M solution of titanium tetrachloride in dichloromethane. After stirring for more than six hours at a temperature from (ав) -202С; to -102С, the mixture of was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. After drying with sodium sulfate, the organic phases were centrifuged until the anhydrous state was reached.

After chromatography of the residue on a Hyazptazieg support, 91.9 mg (78.6905) of the required cyclic compound t" (together with the deschlorine compound) was obtained.

T» b-chloro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol 69.9 mg ( 0.159 mmol) b-chloro-1-1H-indazol-4-yl)amino|-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol was mixed with 1.45 ml of a 1M solution of BVgz in dichloromethane, and the mixture was stirred for five hours at room temperature. After carrying out the usual work-up, the residue was chromatographed on Riazptazieg support. Isolated (F) 28.1 mg (41.595) of the required compound. Melting point: 112-1202С Example 28 cis-7-chloro-1-(2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene -2-ol in 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal 2-(4-chlorophenyl)-2-methylpropanal 10 g of 4-chlorobenzyl cyanide and 14.3 ml of methyl iodide in 140 ml of DMF were mixed at a temperature of 09 portions with sodium hydride (6095th in oil). The mixture was stirred overnight and then mixed with water and ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. 65 It was carefully extracted with water, washed with brine, dried over sodium sulfate, and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/Oethyl acetate 95:5),

obtained 11.73 g of 2-(4-chlorophenyl)-2-methylpropionitrile in the form of a colorless oil. It was slowly mixed in toluene at a temperature of -782C with 554 ml of isobutylaluminum hydride solution (2095 in toluene), and after 4 hours at -78C, 50 ml of ethyl acetate was added dropwise. The mixture was stirred overnight, during which time it was heated to room temperature, and water was added. After filtration through diatomaceous earth, the phases were separated and the aqueous phase was extracted with ethyl acetate. It was washed with water and brine, dried over sodium sulfate, and concentrated by evaporation in vacuo. After chromatography on silica gel (hexane/ethyl acetate 95:5), 10.2 g of 2-(4-chlorophenyl)-2-methylpropanal was obtained as a colorless oil. "H-NMR (Z00MHZ, SOSI"), 5 - 1.46 (in, 6H), 7.20 (4, 1H), 7.29-7.43 (t, ЗН), 9.48 (z, 1H) 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid

A solution of ethyl ether of 15.04 g of 2-diethylphosphono-2-ethoxyacetic acid in bBOml of tetrahydrofuran was mixed with 30 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene, at this time it was cooled on ice for 20 minutes, and the mixture was stirred for 15 minutes at temperature 0 20.

During 30 minutes, a solution of 10.2 g of 2-(4-chlorophenyl)-2-methylpropanal in 5 Oml of tetrahydrofuran 12 at a temperature of 09С was added there. After 20 hours at room temperature, 2N was added. sulfuric acid, the mixture was extracted with ethyl acetate, dried (Ma»3O)) and concentrated by evaporation. The crude product was saponified with 200 ml of 2M sodium hydroxide solution/4000 ml of ethanol. 13.8 g of acid was obtained, which was heated in a reflux flask for 3 hours with 30 ml of 2N. of sulfuric acid and 100 ml of glacial acetic acid, while intensively stirring it. After extraction with ethyl acetate and washing with water, 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid was obtained as a red oil. 7H-NMR (300 MHz, SOSI"), 5 - 1.47 (in, 6H), 3.28 (in, 2H), 7.28 (t, 4H), 7.73 (rv, 1H) 4-( 4-chlorophenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol

Similarly to the synthesis of 4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal (example 27), 4.22 g of 4-(4-chlorophenyl)-4-methyl -2-trifluoromethyl)pentane-1,2-diol in the form of a colorless oil with 29 by esterification of 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid in ethanol/sulfuric acid, Ge) interaction of the product with (trifluoromethyl)trimethylsilane and tetrabutylammonium fluoride and reduction of the formed complex hydroxy ether with lithium aluminum hydride.

TN-NMR (SOSIv), 5 (parts, per million) - 1.39 (in, ZN), 1.49 (in, ZN), 2.07 (4, 1), 2.19 (a, 1Н ), 2.83 (vv, « zo 1H), 3.27 (d, 1H), 3.41 (a, 1H), 7.26-7.38 (t, 4H). 4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal - b.vml (33.3 mmol) of triethylamine and, in portions over 20 minutes, 1.5 g of the pyridine Oz complex was added to 2 g of (6b, 7 mmol) of diol in 10 ml of dichloromethane and 22 ml of DMSO. The mixture was stirred for 5 hours, and 40 ml of saturated ammonium chloride solution was added. The mixture was stirred for another 15 minutes, the phases were separated, and their (a) with 5 was extracted with dichloromethane. The mixture was washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and after chromatography on silica gel (hexane/ethyl acetate 0-3095), 1.27 g of product was obtained. "NA-NMR (Z00MHZ, SOS): 5 - 1.34 (in, ZN), 1.44 (in, ZN), 2.34 (9, 2H), 2.66 (4, 1), 3, 64 (in, 1H), 7.23-7.31 (t, 4H), 8.90 (in, 1H). 7-chloro-1-(2-methylquinazolin-5-yl)amino|-4,4 -dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol "

Using the above-described aldehyde as a starting material, the required compound was synthesized with the help of /Ш-) with imine, as described in example 83. c 7TH-NMR (ZO0MHC, SOCIv); 5 - 1.45 (v, ЗН), 1.63 (z, ЗН), 2.19 (y, 1Н), 2.31 (0, 1Н), 2.87 (в, ЗН), 5.05 ,» (a, tn), 5.98 (a, 1H), 6.78 (a, 1H), 7.28 -7.37 (t, 4H), 7.76 (i, 1H), 9, 36 (in, 1H).

Example 29 5,8-difluoro-1-((2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol ( ee) 4-(2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol 54 g (15.5 mmol) of 4-(2,5-difluorophenyl)-2-hydroxy-4-ethyl ether -methyl-2-trifluoromethyl-valeric (ав) and им, acids (MUO 02/10143) were dissolved at a temperature of 02С in diethyl ether and mixed for 20 minutes with 1.76 g (46.5 mmol) of lithium aluminum hydride. The mixture was left to stir at room temperature for 4 to 50 hours, and then a sufficient amount of a saturated solution of ManNSO 2 was cautiously added until no gas evolution ceased. The mixture was diluted with ethyl acetate, stirred for an additional 15 minutes, and the precipitate formed was filtered off. It was concentrated by evaporation and chromatographed on silica gel Kk) hexane/ethyl acetate (5096). 2.45 g of 2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol was obtained in the form of a slightly yellowish oil, which crystallizes.

Gee! 4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal 800 mg (2.8 mmol) 4-(2,5-difluorophenyl)-4-methyl-2--rifluoromethyl-pentane- 1,2-diol was added to 20 ml of dichloromethane, and at a temperature of 03, 9.5 ml of DMSO and 1.95 ml of triethylamine were added. The solution was slowly mixed with 1.34 g (8 4 mmol) of ZO3-pyridine complexes, and the mixture was stirred for 2 hours at 02С. The mixture was partitioned between saturated ammonium chloride solution and MTBE, the phases were separated, and the aqueous phase was extracted with MTBE. The combined organic phases were washed with water and saturated Masi solution and dried using Mabzo. The mixture was concentrated by evaporation and chromatographed on silica gel with hexane/ethyl acetate (3096).

Received 710 mg of the required product. "NA-NMR (Z00MHZ, SOS): 5 - 1.41 (in, ZN), 1.48 (in, ZN), 2.39 (9, 2H), 3.02 (4, 1), 3, 61 (in, 1H), 65 in, 84-7,18 (t, ZN), 9.23 (in, 1H).

5,8-difluoro-1-((2-methylquinazolin-5-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The required compound was synthesized using an imine (diastereomer A). 7"H-NMR (Z0OMHC, SOSIv): 5 - 1.51 (in, ЗН), 1.68 (in, ЗН), 2.11 (9, 9-15Hz, 1Н), 2.23 (9, 9-15Hz, 1H), 2.84 (8, ЗН), 4.23 (in, B, 1H), 4.84 (a, 2-8Hz, 1), 5.32 (a, 9-8Hz, 1H), 6.80-6.90 (t, 1H), 6.95-7.02 (t, 1H), 7.05 (a, 2-8Hz, 1), 7.39 (a, u9- 8Hz, 1), 7.77 (aa, -8Hz/8Hz, 1H), 9.19 (in, 1H).

Example 30 5-(4,4-dimethyl-b-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinolin-2(1H)-one 70 5-aminoquinolin-2(1H)-one: 4.5 g. 5-nitroquinolin-2(1H)-one | Spec. RNAgpt. You. 29, 1981, pp. 651-56 hydrogenated with hydrogen in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 450 mg of palladium on activated carbon as a catalyst at atmospheric pressure until the completion of the reaction. The catalyst was removed by filtration through diatomaceous earth, and the reaction solution was concentrated by evaporation in vacuo. 3.8 g of the title compound 75 was obtained as a yellow solid. "H-NMR (DMSO): 5 - 5.85 (rev, 2H), 6.27 (4, 1H), 6.33 (4, 1H), 6.43 (49, 1H), 7.10 ( and, 1H), 8.07 (4, 1H), 11.39 (bv, 1H) 5-14,4-dimethyl-b-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2, 3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2(1H)-one:

Similarly to example C, the corresponding name was obtained, leaving Kk! BOOmg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2--rifluoromethyl-pentanal and 26bOmg of 5B-aminoquinolin-2(1H)-one.

20 mg of the title compound was obtained by reacting 8 mg of imine with 0.5 ml of titanium tetrachloride (1 M in dichloromethane).

Examples 31 and 32 5-(4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinoline-2(1H)-o c

H, diastereomer B of 5-C2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-quinolin-2(1H)-one. diastereomer A 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)pentanal 19.3 g of 4-(2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ether |ММО 00 /32584| in bZOml Ж of diethyl ether was mixed in portions at 02С with 3.3 g of lithium aluminum hydride. After stirring for 10 hours, the mixture was added to a saturated bicarbonate solution and filtered through diatomaceous earth. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (Ma»5O)) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0-21090), 16.3 g of diol was obtained as a yellow oil.

2.0 g of diol, 5.2 ml of triethylamine and 5.12 g of sulfur trioxide-pyridine complexes in 24 ml of DMSO were stirred at room temperature for 48 hours. The mixture was added to 0.5 n. hydrochloric acid and extracted with ethyl acetate.

The organic phase was washed with water and brine, dried (Ma 250) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0-3905), 1.44 g of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal was obtained as a yellow oil. 70 "H-NMR (Z00MHZ, SOSIV), 5 - 1.40 (v, ZN), 1.47 (v, ZN), 2.2 (9, 1), 3.46 (4, 1H), 3 ... 8.94 (in, 1H) 5-(4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinoline-2 (1H)-one, diastereomer B and 5-C2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinoline-2(1H)- one, diastereomer A: Analogously to example 2, the corresponding imine was obtained starting from 1.0 g of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 553 mg of 5-aminoquinoline-2 (1H)-one.

And av | 21 mg of 5-(4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2(1H)-one was obtained

F as the first fraction 1 mg t» 50 5-C2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinolin-2(1H)-one as

I" the second fraction by the interaction of 5 Omg of imine with 0.22 ml of VVg" (In. in dichloromethane).

Fraction 1: "H-NMR (ZO0MHC, СО3О0): 5 - 1.50 (in, ЗН), 1.63 (in, ЗН), 2.04 (9, 1Н), 2.12 (9, 1Н) , 3.83 (with,

ZN), 5.17 (in, 1H), 6.48 (a, tn), 6.6O (a, yin), 6.67 (a, tn), 6.90 (a, 1), 6, 92 (0, 1), 7.10 (B tn), 7.35 (B 1n), 8.20 (a, 1n)

Flash point - 269-27096 iF) Fraction 2: "H-NMR (SO0MHC, СО3О0): 5 - 1.39 (v, ЗН), 1.52 (v, ЗН), 2.05 (9, 1Н), 2.23 (9, 1H), 5.28 (z, ime) 1nH), 6.38 (a, 1H), 6.58 (a, 1H), 6.68 (a, 1H), 6.92 (a, 1), 7.00 (a, 1), 7.11 (i, 1H), 7.38 (i, 1H), 8.14 (a, tn)

Examples 33 and 34 60 (-)-5-44,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinoline-2(1

H)-one (-3-5-44,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-quinoline-2(1

N)-on

Separation of βEO00CH-)-5-44,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinolin-2(1H)-one:

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKA RAK AO F, company

RA!SEI)) with hexane/ethanol (90:10, vol.). In this way, the (-)-enantiomer was obtained: MS (EBI): M'-1-433, Todo - 70.12 "(c-1.0, CHO") and (-enantiomer: MS (E5I): M" -1-433, (odr 78.52 "(с-1.0, SNO").

Example 35 (-)-5-H2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2(1H)-one, diastereomer B

Analogously to example 3, Omg of the title compound was obtained by reacting 5O0mg of 10. (43-5-C4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1 -ilyamino)-quinoline-2(1H)-one and 0.22 ml of VVg" (1M in dichloromethane). "H-NMR (ZO0MHCz, СО50О0): 5 - 1.56 (z, ЗН), 1.68 (з, ЗН), 2.06 (9, 1Н), 2.15 (4, 1Н), 5, 15 (c, 1H), 6.51 (d, 1n), 6.62 (y, 1Hn), 6.68 (a, 1H), 6.70 (a, 1H), 6.81 (a, 1H ), 6.95 (i, 1H), 7.37 (i, 1H), 8.23 (a, 1H)

Example 36 12 (-)-5-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl)iamino)-quinolin-2(1H)-one . diastereomer B

Similarly to example 3, 32mg of the title compound was obtained by reacting 7mg of (-)-5-44,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1- ilyIamino)-quinoline-2(1H)-one and 0.32 ml of VVgz (1M in dichloromethane). "H-NMR (ZO0MHz, СО50О0): 5 - 1.57 (z, ЗН), 1.68 (з, ЗН), 2.05 (9, 1Н), 2.14 (4, 1Н), 5, 15 (c, 1H), 6.51 (d, 1n), 6.62 (j, 1Hn), 6.67 (a, 1H), 6.68 (a, 1H), 6.81 (a, 1H ), 6.95 (Her, 1H), 7.37 (i, 1H), 8.22 (a, 1H)

Example 37 5-C7-chloro-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-quinolin-2(1H)-one Similarly to example 2, the corresponding name was obtained, leaving Кк! 1.0 g of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)ipentanal and 492 mg of 5-aminoquinolin-2(1H)-one. (o) 200 mg of the title compound was obtained by reacting 300 mg of imine with 3.2 ml of BVgz (In. in dichloromethane). "H-NMR (Z00MHC, DMSO): 5 - 1.46 (z, ZN), 1.58 (b, ZN), 1.95 (9, 1), 2.05 (a, yin), 5, 28 (a, tn), 6.08 (5, 7H), 6.20 (y, 1H), 6.40 (a, yin), 6.50-6.66 (t, ЗН), 6.77 (in, 1H), 7.24 (B 7H), 7.35 (5 1), 819 (9, «p zo 1H), 10.04 (Be, 1H), 11.57 (p, 1H)

Example 38 "5-(42,5-dihydroxy-4,4-dimethyl-b-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-quinoline-2)1H)- Hey he

Similarly to example 2, the corresponding name was obtained, leaving Кк! 1.0 g of 35 4-(33-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal (example C) and 520 mg of 5-aminoquinolin-2(1H)-one. 255 mg of the title compound was obtained by reacting Zb0Omg imine with Z,Zml

VVgz (In. in dichloromethane). "H-NMR (ZO0MHz, СО50О0): 5 - 1.58 (z, ЗН), 1.70 (з, ЗН), 2.07 (9, 1), 2.15 (9, 1Н), 5, 13 (c, 1H), 6.51 " (d, 1n), 6.60 (a, 1Hn), 6.68 (a, 1H), 6.74-6.95 (t, 2H), 7, 36 (i, 1H), 8.22 (a, 1H) 40 Examples 39 and 40 - c (-)-5-(2,5-dihydroxy-4,4-dimethyl-b-fluoro-2-trifluoromethyl-1 ,2,3,4-tetrahydronaphthalen-1-yl)iamino)-quinolin-2( c 1H)-one and ," (-)-5-(42,5-dihydroxy-4,4-dimethyl-b-fluoro -2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinolin-2(1H)-one 45 Separation of (ee) (9-)-5-ShC2,5-dihydroxy-4,4- dimethyl-b-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinolin-21H o)-one:

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKAI RAK JSC, RAISEI company) with hexane/ethanol (90:10, vol.). In this way, the (-)-enantiomer was obtained:; MS (EI): M -436, their 20 Io 723.62 "(c-1.0, CHO) and (t)-enantiomer: MS (EI): M -436, (oo 25.02 "(c- 1.0, SNO").

Their Example 41 5-(4,4-dimethyl-5-methoxy-7-methyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl|amino)-quinolin-2(1H)-one, diastereomer A

4-(2-Methoxy-4-methylphenyl)-4-methyl-2-oxopentanoic acid ethyl ester:

Similarly to example 7, methyl ester of 2-methoxy-4-methylbenzoic acid was obtained from Zob0g

HF) of 2,4-cresotic acid and 58.bml of methyl iodide from 124.3g of potassium carbonate in b643ml of DMF. The ester was reacted with 14 ml of methylmagnesium chloride (ZM in THF) in 475 ml of THF to give 1-(2-methoxy-4-methylphenyl)-1-methylethanol. 5 g of the obtained product was reacted with 2.4 g of ethyl ether of 2-(trimethylsilyloxy)-acrylic acid in 102 ml of dichloromethane at a temperature of -709C with 2.3 ml of tin tetrachloride to obtain 4.84 g of the title compound.

TN-NMR (ZO0MHZ, SOSI): 5 - 1.44 (in, 6H), 2.31 (5, ЗН), 3.38 (z, 2Н), 3.81 (z, ЗН), 6.66 (z, 1H), 6.72 (a, 1n), 7.12 (a, 1n) 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal: c5 Similarly to example 7, 4.84 g of 4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoic acid ethyl ether was reacted with 7 ml of trifluoromethyltrimethylsilane and 3 ml of tetrabutylammonium fluoride solution (1 M in

THF) in 5 bml of TgF to obtain 4.14 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanoic acid ethyl ether. The product was reduced from 856 bmg of lithium aluminum hydride in 170 ml of diethyl ether to 3.58 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanol. Oxidation of the diol was carried out similarly to example 7 under Swern conditions with 1.1 ml of oxalyl chloride, 2.1 ml of DMSO and 8.0 ml of triethylamine, obtaining 33.01 g of the title compound. "H-NMR (Z0OMHC, SOSIi): 5 - 1.38 (5, ЗН), 1.43 (в, ЗН), 2.18 (а, 1), 3.45 (4, 1Н), 3, 87 (z, 3H), 6.67 (5, 1H), 6.70 (a, 1Hn), 6.98 (a, 1H), 8.92 (c, 1H) 70 5-(4,4- dimethyl-5-methoxy-7-methyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-quinolin-2(1H)-one:

Similarly to example 2, the corresponding name was obtained, leaving Кк! 280 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-"(trifluoromethyl)pentanal and 156 mg of 5-aminoquinolin-2(1H)-one.

This substance was stirred at room temperature with 10 mg of aluminum chloride for 2.5 hours. The batch was added to a saturated bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with water and 75% saline solution, dried (MgSO)) and concentrated by evaporation in a vacuum. After chromatography on silica gel (dichloromethane/2-propanol 0-25965), 24 mg of the title compound was obtained.

TN-NMR (SO0MHC, СО3О0): 5 - 1.50 (in, ZN), 1.62 (5, ZN), 2.04 (4, 1), 2.13 (4, IN), 2.20 (z, ЗН), 3.85 (5, ЗН), 5.13 (в, 1Н), 6.51 (y, 1Н), 6.62 (y, 1Н), 6.70 (d, 1Н) , 6.75 (c, 1H), 6.78 (c, 1H), 7.39 (i, 1H), 8.23 (a, 1H)

Example 42 20 5-(4,4-dimethyl-7-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-quinoline- 2(1H )-one 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal: 16.8 g of 4-(4-fluoro-2-methoxyphenyl)-4-methyl ethyl ether -2-oxo-pentanoic acid (MIMO 00/32584) in bOOml of diethyl ether was mixed in portions at 02C with 2.7 g of lithium aluminum hydride. After stirring for 10 s 25 h, the mixture was added to a saturated bicarbonate solution and filtered through diatomaceous earth. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (Ma»5O)) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0-»21090), 6.7 g of diol and 2.65 g of the title compound were obtained.

The preparation of the title compound from the obtained diol was carried out by reacting 3,8 diol, 30 mL of triethylamine and 6.5 g of sulfur trioxide-pyridine complex in 34 mL of DMSO at room temperature for 48 hours of reaction time. The mixture was added to 0.5 N. hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (Ma 250) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0-21595), 2 g of the title compound was obtained as a yellow oil.

Zo 7TN-NMR (ZO0MHZ, SOSIv), 5 - 1.38 (in, ЗН), 1.46 (з, ЗН), 2.19 (y, 1Н), 3.37 (d, 1Н), 3, 58 (in, 1H), 3.87 so (5, ЗН), 6.55-6.64 (t, 2H), 7.06 (da, 1H), 8.97 (in, 1H) 5-14 ,4-dimethyl-7-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl|amino)-quinolin-2(1H)-one: "

Similarly to example A1, the corresponding name was obtained, leaving Kk! BOOmg of 37Z 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)ipentanal and 26bOmg of 5-aminoquinolin-2(1H)-one. c 1mg of the title compound was obtained by reacting 22mg of imine with 197mg of aluminum chloride. :z» TNA-NMR (СО5О0): 5 - 1.51 (in, НН), 1.63 (in, НН), 2.07 (9, 1Н), 2.14 (0, 1Н), 5, 15 (c, 1H), 6.53 (4, 1H), 6.58-6.77 (t, 4H), 7.40 (i, 1Hn), 8.23 (a, 1H)

Example 43 about (-3-5-(42,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2(1H-one

Analogously to example C, Omg of the title compound was obtained by reacting 5O0mg o (-3-5-44,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1 -yl|Iamino)-quinoline-2(1H)-o b well and 0.22 ml of VVg" (1M in dichloromethane). "H-NMR (ZO0MHz, СО50О0): 5 - 1.57 (z, ЗН), 1.69 (з, ЗН), 2.06 (9, 1Н), 2.15 (4, 1Н), 5, 16 (c, 1H), 6.51 shk (d, 1h), 6.62 (j, 1Hn), 6.69 (a, 1H), 6.71 (a, 1H), 6.82 (a, 1H), 6.95 (Her, 1H), 7.37 (i, 1H), 8.23 (a, 1H)

Example 44 4-C2-hydroxy-4,4-dimethyl-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-yl)iamino)-phthalide

Similarly to example 10, the corresponding name was obtained, leaving Кк! bOOmg 5 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2--'trifluoromethyl)pentanal and ZOZmg 4-amino-phthalide |Vsh. Zos. goiter

Vge (adpe 26, 1951, special edition 5, p. 7, 96). As in example 2, 65 mg of imine was reacted with 7.7 ml of BVgz iF) (1M in dichloromethane), and 16b5mg of the title compound was obtained. ime) "H-NMR (SO0MHC, DMSO-ydv): 5 - 1.30 (in, ZN), 1.46 (in, ZN), 1.93 (4, 1), 2.18 (a, 1 ), 3.57 (z, ZN), 5.10 (a, 1), 5.20 (a, tn), 5.32 (a, 1), 5.55 (y, 71Н), 5.81 (c, 1H), 6.80 (a, tn), 7.03 (a, tn), 7.04 (a, 6o 1H), 7.20 (a, 1n), 7.27 (6 1H) , 7.37 (UK 1H)

Example 45 7-chloro-1-(1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

Similarly to example 2, the corresponding name was obtained, leaving Кк! 10 mg of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)ipentanal and 168 mg of 4-aminoindazole. 98mg 65 of the compound indicated in the title was obtained by reacting 20mg of imine with 6b, 7ml of VVg" (In. in dichloromethane). 7TH-NMR (Z00MHC, DMSO-iv): 5 - 1.48 (c, ЗН), 1.59 (c, ЗН), 1.97 (ad, 1), 2.07 (а, 1), 5 ,27 (a, tn),

5.95 (85, 1H), 6.21 (a, 1), 6.31 (a, 1), 6.72 (c, 1H), 6.74 (j, 1), 6.76 (c , 71H), 7.08 (i, 1H), 8.13 (in, 1H), 9.94 (in, 1H), 12.83 (in, 1H)

Examples 46 and 47 (-)-7-chloro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5 -diol ()-7-chloro-1-I(1H-indazol-4-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5 -diol

Separation of (7-)-7-chloro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

The mixture of enantiomers was separated by chromatography on a chiral carrier (SNIKARAK AO 9, RAIISEI. 7/0 Sotrapu) with hexane/2-propanol (98:2, vol.). The (-)-enantiomer was obtained in this way: MS (EI): M'-425/427,

Isdo 3.02 "(c-1.0, CHO") and (4)-enantiomer: MS (EI): M" - 425/427, (oo 5.09 "(c-1.0, SNCI8).

Examples 48 and 49 7-fluoro-1-((1H-indazol-4-yl)amino)|-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene- 2-ol 7-fluoro-1-((1H-indazol-4-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

Similarly to example 2, the corresponding name was obtained, leaving Кк! 1.8 g of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 78 mg of 4-aminoindazole. 13 mg of 7-fluoro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-5-methoxy-2-trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2-ol as the first fraction and ZOmg 7-fluoro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-trifluoromethyl)-1, 2,3,4-tetrahydronaphthalene-2,5-diol as the second fraction.

Fraction 1: "H-NMR (ZOOMHC, SOSIZ): 5 - 1.48 (v, ЗН), 1.62 (v, ЗН), 2.05 (9, 1Н), 2.16 (9, 1Н) , 3.85 (with,

ZH), 4.62 (9, 1H), 5.07 (a, 1H), 6.43 (a, 1Hn), 6.55 (da, 1H), 6.71 (ad, 1h), 6, 92 (a, 1H), 7.27 (I, 1H), 8.01 (c, 1H)

Fraction 2: "H-NMR (ZOOMHC, SOSIv): 5 - 1.54 (in, ЗН), 1.65 (in, ЗН), 2.07 (9, 1Н), 2.17 (9, 1Н) , 4.62 (a, ch 1H), 5.07 (a, 1H), 6.37-6.47 (t, 2H), 6.72 (ad, 1H), 6.94 (a, 1) , 7.28 (Her, 1H), 8.02 (8, 1H) o

Examples 50 and 51 (-)-7-fluoro-1-K1H-indazol-4-yl)amino1-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5- diol (-)-7-fluoro-1-((1H-indazol-4-yl)amino1-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol "

Separation of (4--)-7-fluoro-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5- diol: "

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKARAK JSC 9, RAIISEI.

Sotrapu) with hexane/2-propanol (98:2, vol.). In this way, the (-)-enantiomer was obtained: MS (EII!): M"-409, Fo -40.59 "(c-0.2, СНСИв8) and (k)-enantiomer: MS (EII!): M "-409. at

Examples 52 and 53 with 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 - with 4.12 g of 4-(2-fluoro-4-methoxyphenyl)-4-methyl ethyl ether -2-oxo-pentanoic acid in 140 ml of diethyl ether was mixed in portions at 02С with 6 bbmg of lithium aluminum hydride. After stirring for 10 hours, the mixture was added to a saturated bicarbonate solution and filtered through diatomaceous earth. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and saline solution, dried (Ma»3O),) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0-»1096), (ee) 2.74 g of diol and 416 mg of the title compound were obtained.

The title compound was obtained from the obtained diol by reacting C,O diol, b,b ml o triethylamine, and 6.5 g of the sulfur trioxide-pyridine complex in 34 ml DMSO at room temperature for 48 hours (e) of reaction time. The mixture was added to 0.5 N. hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (Ma 250) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0-21595), 1.73 g of the title compound was obtained as a yellow oil. "H-NMR (Z0OMHC, SOSIV), 5 - 1.39 (z, ЗН), 1.46 (в, ЗН), 2.26 (а, 1), 3.09 (4, 1Н), 3, 63 (z, 1H), 3.78 (5, ЗН), 6.52 - 6.65 (t, 2H), 7.03 (i, 1H), 9.04 (v, 1H) oo 5-fluorine -1-(1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol,

Gee! diastereomer A Y 5-fluoro-1-(1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol, diastereomer B:

Similarly to example 2, the corresponding name was obtained, leaving Кк! 1.7 g of 60 0 4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)ipentanal and 7 mg of 4-aminoindazole. 12 mg of 5-fluoro-1-((1H-indazol-4-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1 . (trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol, 65 of diastereomer A as the second fraction.

Fraction 1: "H-NMR (ZO0MHC, SOCIz): 5 - 1.48 (in, ЗН), 1.58 (in, НН), 2.06 (d, 1Н), 2.23 (d, 1Н) , 4.95 (a, 1H)U, 5.11 (a, 1n), 6.37 (y, 1H), 6.48 (ad, 1H), 6.64 (y, 1H), 6.75 (8, 1H), 7.25 (i, 1H), 7.48 (in, 1H)

Fraction 2: "H-NMR (ZO0MHZc, SOSIv): 5 - 1.48 (in, ЗН), 1.58 (з, ЗН), 2.05 (а, 1Н), 2.24 (а, 1Н) , 5.04 (a, 1H), 5.12 (j, 1H), 6.37 (da, 1H), 6.48 (ad, 1H), 6.58 (ad, 1H), 6.78 ( a, 1H), 7.24 (I, 1H), 7.29 (c, 1H)

Example 54 1-(H-indazol-4-yl)amino|-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, diastereomer A

Similarly to example A1, the corresponding name was obtained, leaving Kk! 850 mg of 70. 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 39 mg of 4-aminoindazole. 138 mg of the title compound was obtained by reacting 50 mg of imine with 495 mg of aluminum chloride. "H-NMR (Z0OMHC, SOSIV), 5 - 1.52 (zv, ЗН), 1.66 (в, ЗН), 2.05 (а, 1Н), 2.16 (4, 1Н), 3, 85 (z, ZN), 4.57 (d, 1n), 5.23 (j, 1Hn), 6.48 (a, 1), 6.82 (a, 1H), 6.92 (y, 1H ), 6.95 (a, 1H), 7.12 (i, 1H), 7.29 (i, 1H), 7.97 (c, 1H)

Example 55 12 1-(H-indazol-4-yl)amino|-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, diastereomer B

Similarly to example 2, ZbOmg of imine, which was obtained in example 54, was subjected to a reaction with 11 ml of BVgz (1 N. in dichloromethane) to obtain 24 mg of the compound indicated in the title. "H-NMR (SO0MHCc, СО500), 5 - 1.42 (in, ЗН), 1.55 (з, ЗН), 2.08 (9, 1Н), 2.23 (4, 1Н), 3, 33 (c, ЗН), 5.33 720 (5, 1Н), 6.63 (49, 1Н), 6.72 (a, 1Нн), 6.88 (а, 1Нн), 7.06 (а, 1H), 7.20-7.31 (t, 2H), 8.17 (v, 1H)

Example 56 1-(H-indazol-4-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol 10 mg of the compound from example 54 was subjected to the reaction is similar to example 1 with 33.7/ml VVgz (In. in dichloromethane) with obtaining 47 mg of the compound specified in the title. c 7TH-NMR (SO0MHC, СО53О0), 5 - 1.40 (in, НН), 1.54 (in, НН), 2.10 (4, 1), 2.25 (4, 1Н), 5, 36 (z, 1H), 6.60 o) (d, 1n), 6.94 (a, 1H), 7.12 (6, 1H), 7.18-7.33 (t, ЗН), 8 ,20 (in, 1H)

Example 57 7-chloro-1-(1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol similar to example 2, the corresponding name was obtained, leaving Kk! ZBOmMg of 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-«-trifluoromethyl)ipentanal and 158 mg of 4-aminoindazole. 29 mg of the title compound was obtained by the reaction of 5 mg of imine with 1.vml of BVg" (Tn. in dichloromethane). He "H-NMR (Z0OMHC, SOSIV), 5 - 1.41 (z, ZN), 1.54 (z, ZN), 2.10 (9, yin), 2.19 (a, 1H), 4 .63 (a, 1H), 5.14 (d, 1Hn), 6.43 (a, 1Hn), 6.95 (a, 1H), 7.23-7.37 (t, AN), 8, 03 (in, 1H) o

Example 58 Ge 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 of 4-nitroindazole | Spet. Veg., 37, 1904, 25831, 1.9 ml of methyl iodide and 14.4 g of cesium carbonate in 110 ml of DMF were stirred for 2 hours at 02С and then for 12 hours at room temperature. The mixture was added to water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried ((Ma»SO)) and concentrated by evaporation. The residue was recrystallized from ethyl acetate/hexane. 2.49 g of 1-methyl-4-nitroindazole were obtained. It was hydrogenated with hydrogen in 7 Oml THF with 420 mg of palladium on activated carbon at atmospheric pressure. The batch was filtered through diatomaceous earth and completely concentrated by evaporation. 2.1 g of the title compound was obtained. 7"H-NMR (300 MHz, CO), 5 - 3.96 (v, 3H), 6.35 (a, 1H), 6.75 (4, 1H), 7.16 (a, 1H), 8 .06 (v, 1H) so 1-((1-methyl-indazol-4-yl)amino|-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene -2-ol o Analogously to example C, the corresponding imine was obtained, starting with 296 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)ipentanal and 150 mg of 4-amino-1-methylindazole By the way

By reacting 10 mg of imine with 0.5 ml of titanium tetrachloride, 10 mg of the title compound was obtained. iz 70 Melting point: 172-1742С

Examples 59 and 60 7-ethyl-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-5-methoxy-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2 -ol 7-ethyl-1-1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Methyl ether of 2-hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethylvaleric acid: 52 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid MUO 98/54159)| 1.3 ml was added to the solution

F! of thionyl chloride in 12 ml of methanol at a temperature of 09C and stirred for 10 hours at room temperature. The mixture was added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with a bicarbonate solution and a saline solution, dried (Ma 250.4) and concentrated by evaporation. 3.2 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid methyl ester 60 was obtained as a crude product. This ester was mixed with 4.5 ml of trifluoromethyltrimethylsilane in 7 bml of DMF and 1.63 g of cesium carbonate at a temperature of 09 and stirred for 10 hours at room temperature.

20 mg of tetrabutylammonium fluoride was added, and the mixture was stirred for another 30 minutes at room temperature. The batch was added to water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (Ma 250;) and concentrated by evaporation. After chromatography on 65 silica gel (hexane/ethyl acetate 0-21595), 1.47 g of the title compound was obtained as a yellow oil.

7TH-NMR (ZO0MHZ, SOSIv), 5 - 1.34 (in, ЗН), 1.42 (in, ЗН), 2.30 (0, 1Н), 2.97 (d, 1Н), 3.36 (z, ZN), 3.84 (z, ZN), 6.88 (aa, 1H), 7.13 (aa, 1H), 7.23 (aa, 1n) 4-(4-ethyl-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal: 1 g of methyl ester of 2-hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid, 8 mg of tributyltin, 10 mg of the palladium-dibenzylideneacetone complex and ZOmg of triphenylphosphine in 17 ml of THF was heated in a reflux flask in an argon atmosphere for 57 hours. The mixture was filtered through diatomaceous earth and completely concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0O-»2906), 339mg of methyl ester 70. 2-tihydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoromethylvaleric acid was obtained. It was stirred with 5 mg of lithium aluminum hydride in 11 ml of diethyl ether at room temperature for 10 hours. The mixture was added to saturated bicarbonate solution, filtered through diatomaceous earth and extracted with ethyl acetate. The organic phase was washed with a bicarbonate solution and a saline solution, dried (Ma»5O)) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0-21095), 148 mg of 75 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoromethylpentanol were obtained. It was hydrogenated with hydrogen in 4 mg of ethyl acetate with 14 mg of palladium on activated carbon at atmospheric pressure. The batch was filtered through diatomaceous earth and completely concentrated by evaporation. 127 mg of 4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanol was obtained. The obtained diol was reacted with 0.29 ml of triethylamine and 2800 mg of sulfur trioxide-pyridine complex in 1.x) ml of DMSO at room temperature of 20 for 10 hours of reaction time. The mixture was added to a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (Ma»5O)) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0-2390), 94 mg of the title compound was obtained as a colorless oil. "H-NMR (ZO00MHz, SOSIV), 5 - 1.24 (B ZN), 1.38 (5, ZN), 1.44 (v, ZN), 2.17 (y, 1), 2.62 (4, 2H), 346. CM 25 (d, 1H), 3.88 (5, ЗН), 6.68 (5, 1H), 6.72 (d, 1H), 7.02 (y, 1H ), 8.91 (in, 1H) o 7-ethyl-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-5-methoxy-2-trifluoromethyl)-1,2,3, 4-tetrahydronaphthalene-2-ol and 7-ethyl-1-1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol :

Similarly to example 2, the corresponding name was obtained, leaving Кк! 9 mg of 4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)ipentanal and 38 mg of 4-aminoindazole. 1 mg of 7-ethyl-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-5-methoxy-2 -"trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol as the first fraction and 7 mg of 7-ethyl-1-K1H-indazol-4-yl)amino|-4,4-dimethyl-2-(trifluoromethyl )-1,2,3,4-tetrahydronaphthalen-2-ol as the second o fraction.

Zo Fraction 1: "H-NMR (ZOOMHCc, SOSIv), 5 - 1.24 (B ЗН), 1.42 (в, ЗН), 1.51 (з, ЗН), 2.03 (9, 1Н) . (c, 1H), 6.70 (a, 1H), 6.85 (c, 1H), 6.98 (9, 1), 7.32 (i, 2H), 7.89 (c, 1H)

Fraction 2: "H-NMR (ZO0OMHC, SOSIv), 5 - 1.00 (B, ЗН), 1.55 (в, ЗН), 1.65 (з, ЗН), 2.04 (9, 1Н) . 47 (ad, 1H), 6.48 (5, 1H), 6.76 (in, 1H), 6.92 - s (ad, 1), 7.29 (Her, 2H), 8.00 (in , 1H)

Example 61; c» 1-((1-methyl-indazol-4-yl)amino1-4,4-dimethyl-2-(trifluoromethide)/-1,2,3,4-tetrahydronaphthalene-2,5-diol

Analogously to the example, 2.16 mg of imine, which is described according to example 58, was reacted with 0.97 ml

VVgz (In. in dichloromethane) to obtain 44 mg of the compound indicated in the title. oo "H-NMR (SO0MHC, СО500), 5 - 1.56 (z, ЗН), 1.68 (з, ЗН), 2.05 (9, 1Н), 2.14 (4, 1Н), 4 .02 (in, ЗН), 5.15 (5, 1Н), 6.34 (а, 1Н), 6.67 (а, 1Н), 6.78 (ad, 1Н), 6.82-6 98 (t, 2H), 7.25 (I, 2H), 8.07 (5, 1H) o Examples 62 and 63

He" 5-T7-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-isoquinoline-1( 2H)-one and 5-H7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-isoquinoline-1" ( 2H)-on

Similarly to example 2, the corresponding name was obtained, leaving Кк! 35 mg of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 200 mg of 5-aminoisoquinolin-1(2H)-one. ov By reacting Zb0Omg of imine with 70.0 ml of VVg 3 (in. in dichloromethane) /1Omg of 5-ShT7-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2 was obtained. 3,4-tetrahydronaphthalene-1-yl|amino)-isoquinoline

F) -4(2H)-one as the first fraction and 100 mg of 5-Ш7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1 -ilamino)-isoquinolin-1(2H)-one as the second fraction. in Fraction 1: "H-NMR (300 MHz, DMSO-ydv), 5 - 1.32 (z, ZN), 1.47 (z, ZN), 1.95 (9, 1H), 2.24 (a , 1Н), 3.44 (5, ЗН), 5.01-5.14 (t, 2Н), 5.85 (z, 1Н), 6.70 (aa, 1н), 6.78 (а, 1n), 6.86 (aa, 1), 6.98 (aa, 1n), 7.22 (a, 1H9U, 7.31 (6 1H), 7.52 (a, 1H), 11.10 ( ra, 1n)

Fraction 2: "H-NMR (ZOOMM Hz, DMSO-ydv), 5 - 1.47 (in, ZN), 1.58 (in, ZN), 1.97 (a, 1H), 2.08 (a , 1H), 5.30 (4, 71), 5.94 (y, 1H), 6.13 (5, 1H), 6.35 (aa, 1n), 6.54 (aa, yin), 6 ... , 1Н), 11.25 (ra, 1Н)

Examples 64 and 65

(-)-5-4T7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-isoquinol yn-1(2H) -one (-3-5-T7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-isoquinol in- 1(2H)-on

Separation of (/-)-5-4T7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-isoquinoline -1(2H )-onu:

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKA RAK AO 9, company 7/0 BAISEI) with hexane/ethanol (90:10, vol.) In this way, the (-)-enantiomer was obtained: MS (EI): M -436 ,

Isdo 762.52 "(c-0.5, CHO) and (t)-enantiomer: MS (EI): M'-436, (to 75.69 "(c-0.8, CHO 5).

Example 66 5-C6-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2-methyl phthalazine-1- one, diastereomer A 5-amino-2-methyl-phthalazin-1-one:

Z-bromo-4-nitro-phthalide 5.37 g of 4-nitrophthalide (TeTGrapyedgoop ey. 42, 2001, p. 1647-50), 8.04 g of M-bromosuccinimide and 196 mg of benzoyl peroxide were heated in a reflux flask in VOml of benzotrifluoride and heated by exposure to light until the reaction is complete. The mixture was added to water, extracted with dichloromethane, washed several times with water, dried, and the solvent was removed in vacuo. 7.24 g of 3-bromo-4-nitro-phthalide was obtained as a solid. 7H-NMR (300 MHz, SOSI33), 5 - 7.26 (in, 1H), 7.88 (i, 1H), 8.3 (4, 1H), 8.56 (a, 1H) 5-Nitro- phthalazin-1-one: 18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate were mixed in 10 ml of DMF at a temperature of 1002 °C for 1 hour. After that, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF was added, and the mixture was stirred for 4 hours at 1002C. It was added to water, extracted several times with ethyl acetate, and the organic phase was washed with water and brine. The mixture was dried and the solvent was removed in vacuo. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-1-one was obtained as a solid. (i, 1H), 8.57-8.66 (t, 2H), 8.73 (c, 1H), 13.13 (bv, 1H) 2-methy-5-nitro-phthalazin-1-one - 1.6 g of 5-nitro-phthalazin-1-one and 2.31 g of potassium carbonate were stirred for 10 minutes at room temperature in 0.5 mL of DMF. 1.1 mL of methyl iodide was added and the mixture was stirred overnight. It was added to water and extracted several times. ethyl acetate, and the organic phase was washed with water and brine. The mixture was dried, and the solvent was removed in vacuo. 1.57 g of 2-methy-5-nitro-phthalazin-1-one was obtained as a yellow solid. NMR (300 MHz, DMSO-av), 5 - 3.73 ( 5, 3H), 8.05 (i, 1H), 8.62 (a, 2H), 8.75 (c, 1H) 5-amino-2-methyl-phthalazin-1-one « 1.57g. 2-methyl-5-nitro-phthalazin-1-one and 1330 mg of palladium on activated carbon were suspended in 45 bml of ethyl acetate and hydrogenated with hydrogen at atmospheric pressure. The mixture was filtered through diatomaceous earth, and the remaining solvent was removed in vacuo. 1.26 g of 5-amino-2-methyl-phthalazin-1-one was obtained as a yellow solid. i 7H-NMR (300MHz, SOSI»z), - 3.81 (c, 3H), 7.0 (a, 1H), 7.5 (i, 1H), 7.8 (4, 1H), 8 ,16 (5, 1H) 5-C6-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2- methyl phthalazin-1-one (ee) Analogously to example 10, the corresponding imine was obtained starting from 200 mg of 4-(33-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 114 mg 5-amino-2-methyl-phthalazin-1-one. As in example 3, 5 mg of imine was reacted with 0.2 ml of titanium (o) tetrachloride, and 12 mg of the title compound was obtained. 50 of them Melting point: 262-2632C

Example 67 5-C6-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-phthalase-1 (2H)-one 5-amino-phthalazin-1-one: oo 980 mg of 5-nitro-phthalazin-1-one (Example 66) and 100 mg of palladium on activated carbon were suspended in 5 ml of ethyl acetate and 1 ml of triethylamine, and the mixture was hydrogenated with hydrogen at atmospheric pressure. The mixture was filtered through diatomaceous earth and the solvent was removed in vacuo. 830 g of 5-amino-phthalazin-1-one were obtained as a solid substance as a crude product. 7H-NMR (300 MHz, DMSO-av), 5 - 6.26 (rv, 2H), 7.00 (4, 1H), 7.32 (a, 1H), 7.44 (i, 1H), 8 ,48 (in, 1H), 12.35 (rv, 1H) 60 5-C6-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-"(trifluoromethyl)-1,2,3, 4-tetrahydronaphthalene-1-ylamino)-phthalase in-1(2H)-one:

Similarly to example 10, the corresponding name was obtained, leaving Кк! 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 105 mg of 5-amino-phthalazin-1-one. As in example 3, 5mg of imine was reacted with 0.22ml of titanium tetrachloride, and Zbmg of the title compound was obtained. -BO0-

7TH-NMR (SO0MHC, СО53О0), 5 - 1.53 (in, ZN), 1.64 (z, ZN), 2.12 (in, 2H), 3.94 (4, ZN), 5.24 (c, 1H), 6.96 (aa, 1n), 7.03 (aa, 1n), 7.24 (aa, 1Hn), 7.58-7.65 (t, 2H), 8.55 ( in, 1H)

Example 68 5-(H7-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-2-methylphthalazine-1 - he

Similarly to example 10, the corresponding name was obtained, leaving Кк! 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 108 mg of 5-amino-2-methyl-phthalazin-1-one. As in example 2, 225 mg of imine was reacted with 2.3 ml of BVgz (IM in 70 dichloromethane), and 12 mg of the title compound was obtained. "H-NMR (SO0MHCc, СО500), 5 - 1.55 (z, ЗН), 1.66 (з, ЗН), 2.08 (9, 1Н), 2.14 (4, 1Н), 5, 22 (in, 1H), 6.74 (85, 1H), 6.78 (in, 1H), 7.18-7.27 (t, 1H), 7.62-7.72 (t, 2H) , 8.57 (8.1H)

Example 69 5-C6b-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)|amino)-2-methyl lphthalazin-1-one. diastereomer B

Similarly to example 10, the corresponding name was obtained, leaving Кк! 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in example 2, 112 mg of imine was reacted with O.Zbml of VVgz (1M in dichloromethane), and Zvmg of the title compound was obtained. 7TH-NMR (Z00MHZ, SOSIv), 5 - 1.53 (in, ZN), 1.64 (z, ZN), 2.11 (0, 1H), 3.85 (z, ZN), 3.97 (4, ZN), 5.02 (d, 1n), 5.13 (a, 1n), 6.97 (ad, 1H), 7.00 (aa, tn), 7.08 (a, 1H) , 7.61 (i, 1H), 7.83 (d, 1H), 8.15 (c, 1H)

Example 70 5-C6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazin-1-one c 29 mg of the compound from example 69 was subjected to a reaction similar to the example with O0.1 ml of VVgz (In. in dichloromethane) with (9 by obtaining 18 mg of the compound indicated in the title. 7TH-NMR (ZO0MHC, СО53О0), 5 - 1.60 (in, ZN), 1.71 (in, ZN), 2.09 (4, IN), 2.16 (4, IN), 3.83 (z, ZN), 5.23 (5, 1H), 6.79 (ad, 1Hn), 6.90 (ad, 1H), 7.22 (ad, 1n) , 7.59-7.68 (t, 2H), 8.56 (v, 1H) "

Example 71 5-C6-fluoro-2,5-dihydroxy-4M4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)iamino)-phthalazin-1("2H)-one 800 mg of the compound from example 67 was reacted similarly to example 1 with 0.5 ml of BVgz (In. in dichloromethane) to obtain 15 mg of the compound indicated in the title. (ав) "H-NMR (ZO0MHC, СО5О0), 5 - 1.60 (z, ЗН), 1.71 (з, ЗН), 2.14 (9, 2Н), 5.23 (в, 1Н) , 6.80 (aa, 1H), 6.90 so (aa, 1h), 7.25 (da, 1h), 7.58-7.68 (t, 2H), 8.56 (c, 1H)

Examples 72 and 73 5-C2-hydroxy-4,4-dimethyl-5-methoxy-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-phthalazine-1(2H")- one 5-(2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|amino)-phthalazin-1(2H)-one with c Similarly to example 10, the corresponding name was obtained, leaving Kk! BOOmg. 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)ipentanal and 277 mg of 5-amino-phthalazin-1-one. As in and? example 2, 32 mg of 5-C2-hydroxy-4,4-dimethyl-5-methoxy-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino-phthalazin-1(2H)-one were obtained

In the first fraction, І З5ммг

Go! 5-(2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-phthalazin-1(2H)-one as the third fraction by the interaction of 47Omg of imine with 5.4 ml of VVg»z (1M in dichloromethane). o Fraction 1: "H-NMR (300 MHz, DMSO-in), 5 - 1.32 (in, ZN), 1.50 (z, ZN), 1.96 (j, 1), 2.23 (j , 1H), 347

He") (5, ZN), 5.17 (y, 1), 5.93 (z, 1H), 6.06 (a, tn), 6.78 (a, 1), 7.04 (a . , 12.39 (in, 1H)

Fraction 3: "H-NMR (ZOOMHz, СО5О0), 5 - 1.57 (in, ЗН), 1.69 (з, ЗН), 2.07 (а, 1Н), 2.15 (d, IN) . 57-7.70 (t, 2H), 8.57 (8, 1H)

Examples 74, 75 and 76 5-PC2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2-methylphthalase yn-1- 5-(42,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazine-1-one, diastereomer A 5-(42,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazine-1-one, diastereomer B 60 Similar to example 10, the corresponding name was obtained, leaving Kk! BOOmg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-"-trifluoromethyl)ipentanal and 302mg of 5-amino-2-methylphthalazin-1-one. As

And in example 2, 158 mg of 5-C2-hydroxy-4,4-dimethyl-5-methoxy-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2-methylphthalazine-1- one as the first fraction, bbmg b5 5-42,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazin-1-one, of diastereomer A, as the fourth fraction, and 77 mg

5-C2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|amino)-2-methylphthalazin-1-one, diastereomer A, as p fraction by the interaction of 57 Ωg of imine with b, 4 ml of BVg»z (1M in dichloromethane).

Fraction 1: "H-NMR (ZO0OMHC, СО53О0), δ - 1.42 (in, ЗН), 1.58 (in, ЗН), 2.08 (9, 1Н), 2.26 (9, 1Н) , 347 (zv,

ЗН), 3.77 (8, ЗН), 5.33 (z, 1Н), 6.76 (9, 1Н), 7.07 (a, 1Н), 7.29 (i, 1Н), 7, 52 (ad, 1H), 7.60-7.71 (t, 2H), 8.51 (c, 1H)

Fraction 4: "H-NMR (ZO0OMHC, СО53О0), 5 - 1.42 (in, ЗН), 1.56 (in, ЗН), 2.09 (9, 1Н), 2.27 (9, 1Н) , 3.78 (with,

ЗН), 5.33 (8, 1Н), 6.62 (y, 1Н), 6.95 (а, 1Н), 7.14 (и, 1НН), 7.56 (aa, 1Н), 7, 59-7.70 (t, 2H), 8.54 (in, 1H)

Fraction 5: "H-NMR (SO0MHC, СО53О0), 5 - 1.57 (in, ЗН), 1.68 (in, ЗН), 2.07 (9, 1Н), 2.14 (9, 1) , 3.77 (in,

ZH), 5.33 (8, 1H), 6.71 (y, 1H), 6.80 (a, 1H), 6.96 (y, 1H), 7.22 (aa, 1nH), 7, 58-7.69 (t, 2H), 8.56 (v, 1H) 70 Examples 77 and 78 (-)-5-C2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)- 1,2,3,4-tetrahydronaphthalen-1-yl)amino)-2-methylphthalazin-1-one (-3-5-C2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazin-1-one

Separation of (/-)-5-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)iamino)-2-methylphthalazine- 1st:

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKAI RAK JSC, company

OAISEI) with hexane/ethanol (90:10, vol.) In this way, the (-)-enantiomer was obtained:; MS (E): M" -447,

IsCh 748.02 "(c-0.7, SNI) and (t)-enantiomer: MS (EI): M"-447, (odr 45.62 "(c-0.8, CHO c).

Examples 79 and 80 (-)-5-42,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazine-1-one , diastereomer A c (--5-Х2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)iamino)-2-methylphthalazine -1- he, diastereomer A and)

Separation of (9-)-5-C2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazin-1-one, diastereomer A: "

The mixture of enantiomers was separated by chromatography on a chiral carrier (SNIKAI RAK AF, BAISEI company) with hexane/ethanol (85:15, vol.). In this way, the (-)-enantiomer was obtained: MS (EI): M"-433, Godot -25.32 (c-1.0, CHO") and the (k)-enantiomer: MS (EI): M" -433. (Se)

Examples 81 and 82 (-)-5-42,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazine o -1- he, diastereomer A (ee) (--5-S2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)iamino)-2-methylphthalazine -1-one, diastereomer A

Separation of "(9-)-5-C2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazin-1-one, of diastereomer B: - c The mixture of enantiomers was separated by chromatography on a chiral carrier (SNIKAI RAK JSC, RAISEI company) with hexane/ethanol (90:10, vol.). In this way, the (-)-enantiomer was obtained: MS (E): M'-433, "Ivo 710.12 "(c-0.8, CHO Iv) and (t)-enantiomer: MS (EI): M" -433, (dr 5.89 "(c-0.9, SNO").

Example 83 with 75 cis-1-(2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol.: (Magkiv

Vegodeg) "in 5-amino-2-methylquinazoline 12.7g (b2mmol) of 2-methyl-5-nitro-ZN-quinazolin-4-one IM. T. Vodepy, M. 9. Spatbregv U. Ogd Spet. 1905,

F 649-658) and 37.5 g of phosphorus pentachloride were heated in a reflux flask in 7 bml of phosphoryl chloride g" 50 for 20 hours. After cooling, the mixture was poured into a saturated solution of Manso 53 and extracted

T" ethyl acetate. The organic phase was dried and the solvent was removed. 14 g of 4-chloro-2-methyl-5-nitroquinazoline were obtained, of which 4.5 g (20.2 mmol) were dissolved in 225 ml of ethyl acetate and 22.5 ml of triethylamine. 2g of palladium on charcoal was added and the mixture was stirred while it was cooled on ice for 4 hours in a hydrogen atmosphere at atmospheric pressure. The catalyst was removed from the solution by filtration through celite, then the product was washed again with 200 ml of ethanol and concentrated by evaporation.

GF) After chromatography on silica gel with ethyl acetate-ethanol (0-1095), 53 mg of product was obtained. d) 7H-NMR (Z00MGu, SOSI»z); 5 - 2.87 (in, ЗН), 4.52 (bBg., 2Н), 6.77 (y, 1Н), 7.33 (4, 1Н), 7.65 (и, 1Н), 9, 40 (c, 1H). (rac)-1,1,1,-Trifluoro-4-phenyl-2-KE/2)-(2-methyl-quinazol-5-yl)iminomethyl/|-4-methyl-pentan-2-ol in O 3 ml of titanium triethylate was added to 140 mg (0.54 mmol) of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl)-pentanal and 100 mg (0.6 mmol) of 5-amino-2-methylquinazoline in 15 ml of toluene, and the mixture was heated for 2 hours to 1002C. After cooling, it was poured into water and continued to be intensively stirred. The suspension was filtered through celite and thoroughly washed again with ethyl acetate.

The filtrate phases were separated and the mixture was extracted again with ethyl acetate. it was dried over sodium sulfate, and the solvent was removed in vacuo. After purification by chromatography on silica gel (hexane/ethyl acetate 0-60905), 123 mg were obtained

(rac)-1,1,1,-trifluoro-4-phenyl-2-KE/2)-(2-methyl-quinazol-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 was resuspended in 7 ml of dichloromethane and cooled to -702C. 0.vml (0.vmmol) of a 1M solution of titanium tetrachloride in dichloromethane was added dropwise for 10 minutes, and the mixture was stirred for another 6 hours at -6592C. The solution was poured into a saturated sodium bicarbonate solution and intensively stirred for 5 minutes. The mixture was extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 0-6595), 4 mg of the required product was obtained. ), 2.19 (y, 1H), 2.29 (0, 1H), 2.87 (c, ЗН), 5.14 (d, 1х), 5.97 (a, 1H), 6.81 (ad, 1H), 7.15 (Her, 1H), 7.36-7.43 (t, 2H), 7.42 (d, 1H), 7.75 (Her, 1H), 9.42 ( in, 1H).

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 was obtained similarly to example 83. "H-NMR (Z0OMHC, SOSIV); δ - 1.43 (8, ЗН), 1.54 (в, ЗН), 2.07 (y, 1Н), 2.18 ( 9, 1Н), 2.84 (z, ЗН), 3.21 (5, ЗН), 4.31 (а, 1), 5.38 (а, тн), 6.63 (а, 1), 7.05 (a, tn), 7.18 (a, yin), 7.31 (5 tn), 7.43 (a, tn), 7.81 (y, 1H), 9.13 (c, 1H).

Example 85 cis-b-chloro-5-methoxy-1-((2-methylquinazolin-5-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene -2-ol

The compound was obtained similarly to example 83. 7TN-NMR (ZO0MHC, SOSIv); 5 - 1.58 (v, ЗН), 1.74 (v, ЗН), 2.14 (0, 1Н), 2.25 (d, 1Н), 2.88 (в, ЗН), 3.97 (5, ЗН), 5.05 (а, 1Н), 5.92 (а, 1Н), 6.79 (9, 1Н), 7.09 (а, 1НН), 7.19 (а, 1Н) , 7.30 (4, 1H), 7.75 (i, 1H), 9.39 (v, 1H). ch 29 Example 86 Ge) cis-b-fluoro-5-methoxy-1-((2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4 - tetrahydronaphtha lin-2-ol

The compound was obtained analogously to example 83. ""H-NMR (SOSIV); . .93 (da, 1), 7.07 (da, 1n), 7.29 (d, 1H), 7.74 (a, 1H), 9.33 (c, 1H).

Example 87 "with cis-6-(2-methylquinazolin-5-yl)amino|-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphthoic|1,2-α41- 1,3-dioc sol-7-ol o

The compound was synthesized as described in example 83. co "H-NMR (Z0OMHC, SOSIV); 5 - 1.52 (8, ЗН), 1.66 (в, ЗН), 2.10 (а, 1Н), 2 ... 1H), 6.80 (a, 1H), 6.86 (a, 1H), 7.76 (Her, 1H), 9.52 (c, 1H).

Example 88 "cis-b-chloro-1-(2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-di 4 ol - s The compound was obtained by splitting a simple ether, as described in example 3. a "H-NMR (Z0OMHC, SOSIV); 5 - 1.54 (z, ZN), 1.68 (v, ZN), 2, 06 (а, 1Н), 2.20 (9, 1Н), 2.81 (z, ЗН), 4.98 » (d, 1н), 5.81 (а, 1Н), 5.91 (Bg. , 1H), 6.73 (a, 1H), 6.86 (a, 1H), 7.08 (a, 1H), 7.23 (j, 1H), 9.35 (c, 1H).

Example 89 cis-b-fluoro-1-(2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-di (ee) ol o The compound was obtained by cleavage of a simple ether, as described in example 3. "H-NMR (Z0OMHC, SOSIV); 5 - 1.62 (8, ZN), 1.77 (b, ZN), 2.13 (a , 1H), 2.27 (9, yin), 2.88 (z, ЗН), 5.03

Fo (d, 1H), 5.67 (Bg, 1H), 5.78 (y, 1Hn), 6.79 (a, 1H), 6.91 (a, 2H), 7.29 (a, 1H ), 7.73 (Her, 1H), 9.35 (in, 1H). iz 70 Example 90 cis-6-((7-fluoro-2-methylquinazolin-5-yl)amino|-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho|1 ,2-a41-1

T»,3-dioxol-7-ol 5-amino-7-fluoro-2-methyquinazoline 17g (70.5 mmol) 3,6b-difluoro-2-M-pivaloylaminobenzaldehyde |. Riogmaiyi, I. Radegmaiyi, 1.-05- Iagevsop, 5. 29 V. Kozv, Eig. U. Med. Spent 34, 1999, 137-151, 9.2 g of acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g

F! molecular sieve (4A) was combined in 7 Oml of butyronitrile. The mixture was heated with vigorous stirring for 17 hours to 1452C, and the solvent was removed in vacuo. After chromatography of the residue on silica gel with I and hexane/ethyl acetate (0-7095), 4.5 g of 7-fluoro-5-M-pivaloylamino-2-methyquinazoline was obtained. 1 g (3.82 mmol) of 7-fluoro-5-M-pivaloylamino-2-methyquinazoline was dissolved in 74 ml of toluene and cooled to 60 tes. 9.5 ml (11.4 mmol) of a 1.2 M solution of isobutylaluminum hydride in toluene was added dropwise over 30 minutes. The reaction mixture was allowed to warm to -40C and stirred for 4 hours at -402C. Water was added slowly and stirred for 30 minutes at room temperature until a precipitate formed, which was removed by filtration through celite. The phases were separated, washed with saturated sodium chloride solution and dried over sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-100905), ba4mg of product was obtained.

7H-NMR (300 MHz, SOSI); 5 - 2.83 (in, ZN), 4.67 (Bg., 2H), 6.50 (ad, 1H), 6.93 (ad, 1H), 9.23 (in, 1H).

OTml of titanium triethylate was added to bomg (0.4bmmol) of rac. 4-(1,3-benzdioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal and 32 mM (0.18 mmol) of 5-amino-7-fluoro-2-methylquinazoline in 7 ml of toluene , and the mixture was heated for 2.5 hours to 100 20. After cooling, it was poured into water, and intensive stirring was continued. The suspension was filtered through celite and thoroughly washed again with ethyl acetate. The filtrate phases were separated and the mixture was extracted again with ethyl acetate. it was dried over sodium sulfate and the solvent was removed in vacuo. Crude 4-(1,3-benzdioxol-4-yl)-1,1,1-trifluoro-2-KE/2)-(7-fluoro-2-methylquinazolin-5-yl)iminomethyl|-4-methyl- pentan-2-ol, 70 obtained in this way, was resuspended in 3 ml of dichloromethane and cooled to -702С. 1.1 ml (1.immol) of a 1M solution of titanium tetrachloride in dichloromethane was added dropwise over 10 minutes, and the mixture was stirred for an additional hour at a temperature of -70 °C. The solution was poured into a saturated sodium bicarbonate solution and intensively stirred for 5 minutes. The mixture was extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration of 72 by evaporation and chromatography on silica gel (hexane-ethyl acetate 0-7595), 2 mg of the required product was obtained. 5 - 1.53 (z, ЗН), 1.66 (in, ЗН), 2.12 (y, 1Н), 2.27 (9, 1Н), 2.84 (з, ЗН), 4.94 (d, 1H), 5.99 (c, 1H), 6.00 (c, 1H), 6.02 (a, 1H), 6.50 (aa, 1Hn), 6.68 (49, 1H) , 6.83 (j, 1H), 6.89 (ad, 1H), 9.26 (c, 1H).

Example 91 trans-5-methoxy-1-((7-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene- 2-ol

The compound was obtained similarly to example 83. "H-NMR (Z0OMHC, SOSIV); 5 - 1.42 (b, ЗН), 1.55 (b, ЗН), 2.07 (а, 1Н), 2.17 ( 9, yin), 2.80 (z, ЗН), 3.33 ря (5, ЗН), 4.57 (d, 1Н), 5.31 (4, 1Н), 6.66 (y, 1Н) , 6.88 (ad, 1n), 7.00 (ach, 1H), 7.05 (a, 1H), 7.30 (I, 1H), 9.03 (c, 1H).

Example 92 about cis-b-chloro-1-K7-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2, 5-diol

The compound was obtained by cleavage of a simple ether, as described in example 3. - by "H-NMR (Z0OMHC, SOSIV); 5 - 1.60 (in, ZN), 1.73 (in, ZN), 2.12 (4 , 1H), 2.24 84, 1H), 2.84 (z, 3H), 4.96 (d, 1h), 5.98 (a, 1H), 6.01 (c, 1H), 6 51 (da, 1n), 6.88 (9, 1H), 6.91 (ad, 1n), 7.17 (a, 1H), 9.23 (c, 1H).

Example 93 "I cis-b-fluoro-1-(7-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene - 2,5-diol o 35 The compound was obtained by cleavage of a simple ether, as described in example 3. co

TNA-NMR (ZO00MHZ, СО5О0); 5 - 1.61 (v, ЗН), 1.72 (v, ЗН), 2.15 (t, 2Н), 2.78 (в, ЗН), 5.30 (з, 1Н), 6.72 -6.82 (t, ZN), 6.92 (ad, 1H), 9.55 (in, 1H).

Example 94 "trans-7-fluoro-1-((7-fluoro-2-methylquinazolin-5-yl)amino|-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3, 4-tetra 40 hydronaphthalen-2-ol - s "H-NMR (ZO0MHz, CO500); 5 - 1.40 (z, ЗН), 1.53 (з, ЗН), 2.07 (9, 1Н), 2.18 (4, 1Н), 2.81 (в, ЗН), 3.34 "» (8, ЗН), 4.52 (а, 1Н), 5.25 (а, 1н), 6.41 (ad, 1n), 6.74 (aa, 1n), 6.86 (aa, 1H), 7.01 (aa, 1), 9.03 (c, 1H). " Example 95 cis-6b-chloro -1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene 45 -9.5-diol and 5-amino- 8-fluoro-2-methylquinazoline o A solution of 2.4g (18.bmol) of 2,5-difluoroaniline in 1ml of water and 1.bml of concentrated hydrochloric acid (37905), the temperature of which was 502С, was added to a solution of 3.35g (20, 25 mmol) of chloral hydrate and 21.27 g (149.7 mmol)

Me, sodium sulfate in 72 ml of water, which was previously stirred at this temperature for 1 hour. The mixture of these 20 was stirred for another 30 minutes at room temperature, and then 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml of water was added, the mixture was heated for 45 minutes to 1252 and kept at this temperature

T" for 5 minutes. After cooling and after another hour, the precipitated light brown precipitate was filtered off, washed with water and dried. 3.0 g (15.00 mmol) of hydroxylimine was obtained as an intermediate product, which was dissolved in portions in 1 bml of concentrated sulfuric acid at a temperature of 20 °C. After completion of the addition, the mixture was heated for 2 hours to 80 2C and for 4 hours to 90260. It was given

GF) was allowed to cool, and the solution was poured into 100 g of ice. The mixture was extracted with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate, and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0-4595), 1.2 g (7, mmol) of 4,7-diphthorezine was obtained. 1.ml of a 3095% solution of hydrogen peroxide was added dropwise to isatin in 30ml of a 1-molar solution of sodium hydroxide for 10 minutes. After 2 hours of stirring at room temperature, the mixture was cooled to 02C, and 5 ml of 4-molar hydrochloric acid was added and diluted with 5O0 ml of water. The mixture was extracted with ethyl acetate, dried over sodium sulfate, concentrated by evaporation, and 1.27 g of 3,6-difluoroanthranilic acid was obtained in quantitative yield, which was subjected to the reaction without additional purification. 65 C,6b-difluoroanthranilic acid was heated in ml of acetic anhydride for 45 minutes to 100260.

After cooling, the obtained acetic acid and excess acetic anhydride were removed azeotropically from -B4-

toluene in a vacuum. The residue was mixed with 40 ml of 2595 ammonia solution, at which time the mixture was cooled on ice, and the mixture was stirred for 72 hours. it was diluted with water and acidified with acetic acid.

The mixture was extracted with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate and

Concentrated by evaporation. 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-ZN-quinazolin-4-one and bg of phosphorus pentachloride obtained in this way were heated in 2 Oml of phosphoryl chloride for 12 hours to 12520. After cooling, the mixture was poured into saturated Manso solution with and extracted with ethyl acetate. The organic phase was dried and the solvent was removed. It was obtained with a quantitative yield of 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline, which was dissolved in bOml of ethyl acetate and 5 ml of triethylamine. Added bOOmg/o palladium on charcoal and shaken for 2 hours (480 ml of hydrogen absorption) in a hydrogen atmosphere at atmospheric pressure. The catalyst was removed from the solution by filtration through celite, then the product was washed again with 1000 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40965), 5500 mg of 5,8-difluoro-2-methylquinazoline was obtained. 89 mg (13.7 mmol) of sodium azide was added to 24 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-b in 1 mL of 75 DMF, and the mixture was heated for 8 hours to 12520 The solvent was removed in vacuo and the mixture was chromatographed on silica gel with ethyl acetate to give 52 mg of product. "H-NMR (Z00MHZ, SOSI"); 5 - 2.92 (in, ЗН), 4.31 (rg., 2Н), 6.67 (da, 1Н), 7.38 (ad, 1Н), 9.37 (in, 1H). 0.23ml (1.Tmmol) of titanium triethylate was added to 140mg (0.4bmmol) of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-( trifluoromethyl)-pentanal and 100 mg (0.5 mmol) of 5-amino-8-fluoro-2-methylquinazoline in 14 ml of toluene, and the mixture was heated for 2 hours to 100 20. After cooling, it was poured into water, and intensive stirring was continued. filtered through celite and washed thoroughly again with ethyl acetate. The filtrate phases were separated and the mixture was back-extracted with ethyl acetate. It was dried over sodium sulfate and the solvent was removed in vacuo. Crude 4-(3-chloro-2-methoxyphenyl)-1,1,1 -trifluoro-2-KE/2)-(8-fluoro-2-methylquinazolin-5-yl)iminomethyl|-4-methyl-pentan-2-ol c , which was obtained in this way, was resuspended in 23 ml of dichloromethane and cooled to - 302 C. 7.8 ml (7.8 mmol) of a 1 M solution of boron tribromide in dichloromethane was added dropwise over 10 minutes, allowed to warm to room temperature rature for 1 hour, and stirred for another 16 hours. The solution was poured into a mixture of ice and saturated sodium bicarbonate solution and intensively stirred for 15 minutes. The mixture was extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate «g 0-5095), 4 mg of the required product was obtained. "H-NMR (Z0OMHC, SOSIV); 5 - 1.60 (z, ЗН), 1.74 (в, ЗН), 2.07 (а, 1Н), 2.26 (9, 1Н), 2, 93 (z, ZN), 4.99 o (d, 1n), 5.66 (a, 1H), 5.99 (Bg., 1H), 6.67 (da, 1H), 6.91 (d , 1H), 7.16 (a, 1H), 7.49 (ad, 1H), 9.41 (c, 1H). av

Example 96 cis-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol 09 7TH- NMR (ZO0MHC, SOSIv); 5 - 1.45 (in, ZN), 1.61 (z, ZN), 2.17 (0, 1Н), 2.26 (0, 1Н), 2.92 (in, ZN), 5.08 (d, 1n), 5.69 (y, 1Hn), 6.69 (ad, 1H), 7.16 (Yii, 1H), 7.35 (t, 2H), 7.42 (d, 1H) , 7.49 (i, 1H), 9.44 (in, 1H).

Example 97 "20 trans-8-fluoro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-5-methoxy-4,4-dimethyl-2-trifluoromethyl)-1,2,3, 4-tetrahydrogen with hydronaphthalene-2-ol. "H-NMR (Z0OMHC, SOSIV); 5 - 1.50 (v, ЗН), 1.63 (v, ЗН), 2.14 (z, 2Н), 2.89 (v, ЗН), 3, 21 (c, ZN), 4.25 "» (d, 1n), 5.21 (a, 1n), 6.59 (ad, 1n), 6.98 (ad, 1H), 7.04 (aa , 1H), 7.52 (yes, 1H), 9.21 (in, 1H).

Example 98 cis-7-chloro-1-((-8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene

Ge | n-2-ol o 7TH-NMR (ZO0MHC, SOSIv); 5 - 1.44 (v, ЗН), 1.60 (z, ЗН), 2.18 (y, 1Н), 2.27 (d, 1Н), 2.93 (в, ЗН), 5.00 (d, 1n), 5.71 (a, 1n), 6.66 (ad, 1n), 7.28-7.37 (t, ЗН), 7.50 (ad, 1Н), 9.39 ( in, 1H). (e)) Example 99 of 50 ,2,3,4-tetrahyd ronaphthalen-2-ol iz" H-NMR (30OMHC, SOSIV); 5 - 1.57 (8, ZN), 1.72 (in, ZN), 2.12 (i , 1Н), 2.22 (9, 1Н), 2.93 (z, ЗН), 3.97 (5, ЗН), 4.99 (d, 1Н), 5.65 (4, 1Н), 6 .67 (da, 1n), 7.07 (9, 1H), 7.21 (a, 1n), 7.49 (ad, 1Hn), 9.39 (c, 1H).

Example 100 59 cis-b-fluoro-1-((8-fluoro-2-methylquinazolin-5-yl)lamino|-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3, 4-tetrahyde

HF) ronaphthalene-2-ol by "H-NMR (30OMHC, SOSIV); 5 - 1.56 (8, ЗН), 1.71 (в, ЗН), 2.11 (а, 1Н), 2.22 (9, 1H), 2.93 (z, ЗН), 3.97 (5, ЗН), 4.97 (d, 1Н), 5.60 (4, 1Н), 6.67 (aa, 1нН) , 6.93 (ad, 1H), 7.06 (aa, 1h), 7.48 (aa, 1H), 9.37 (c, 1H).

Example 101 bo cis-6-(8-fluoro-2-methylquinazolin-5-yl)amino|-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho|1,2 -a41-1,3-dioxol-7-ol 7TH-NMR (ZO0MHC, SOSIv); 5 - 1.52 (v, ЗН), 1.67 (v, ЗН), 2.10 (0, 1Н), 2.27 (d, 1Н), 2.94 (в, ЗН), 4.96 (d, 1H), 5.67 (a, 1H), 5.99 (c, 1H), 6.01 (c, 1H), 6.67 (y, 1H), 6.68 (ad, 1H) , 6.86 (4, 1H), 7.49 (ad, 1H), 9.44 (c, 1H). 65 Example 102 cis-b-fluoro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene

-2,5-diol "H-NMR (30MHz, CO500); 5 - 1.60 (z, ЗН), 1.72 (в, ЗН), 2.09 (9, 1Н), 2.17 (4 , 1H), 2.86 (in, 3H), 523 (85, 1H), 6.80-6.93 (t, 3H), 7.57 (ad, 1H), 9.66 (in, 1H) .

Example 103 cis-6-(2-methylquinolin-5-yl)amino)|-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho|1,2-41-1 ,3-dioxo l-7-ol 7TH-NMR (ZO0MHC, SOCIv); 5 - 1.50 (in, ZN), 1.60 (z, ZN), 2.08 (y, 1H), 2.20 (y, 1H), 2.73 (in, ZN), 4.85 (d, 71), 5.09 (0, 71H), 5.98 (85, 71H), 5.99 (c, 1H), 6.62 (j, 1), 6.81 (t, 2H) , 7.22 (0, 1), 7.50 (a, NN), 70 7.56 (i, 1H), 8.09 (i, 1H).

Example 104 cis-6-(2-methyl-1,7-naphthyridin-5-yl)amino|-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphthoic|1, 2-941-1,

3-dioxol-7-ol "H-NMR (30 MHz, CO500); 9, 1), 2.76 (in, ЗН), 5.06 72 (in, 1Н), 5.96 (in, 2Н), 6.61 (4, 1Н), 6.82 (4, 1Н) , 7.50 (4, 1H), 7.90 (in, 1H), 8.33 (4, 1H), 8.69 (in, 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) Melting point: 209-21120

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: 11590

Example 107

Rac.-5-fluoro-1-(2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-dithiol (diastereomer B) Ho) 7TH-NMR (ZO00MHC, CO3O0); 5 - 1.51 (in, ЗН), 1.66 (in, ЗН), 2.08 (a, 9U-14Hz, 1), 2.18 (y, 9-14Hz, 1Н), 2.82 ( 8, ZN), 5.21 (v, 1H), 6.71-6.93 (t, ZN), 7.19 (a, U-8Hz, 1), 7.77 (aa, U-9Hz/ 8HzC, 1H), 9.57 (in, 1H).

Example 108 g zo Rac.-5-fluoro-1-(2-methylquinazolin-5-yl)amino|-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalene-2-diol (diastereomer A) MS (9EZT): 4590 (M'-1) "

Example 109 "so b-fluoro-1-((2-hydroxymethyl)-quinolin-5-yl)amino|)-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4 -tetrahydro onanaphthalen-2-ol o

5-I4-(3Z-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylideneamino|-quinoline-2-carboxylic acid methyl ester

A solution containing 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal (872 mg, 2.84 mmol) and 5-aminoquinoline-2-carboxylic acid methyl ester (57 mg, 2.84 mmol) in 5.Oml of concentrated acetic acid, left to stir for 2 days at room temperature. After repeated "

Co-evaporation with toluene, the residue was purified on silica gel with hexane/ethyl acetate (0-10096 -o with ethyl acetate). Received 82Omg (5995 from theory) of the product. and 7TH-NMR (ZO0MHZ, SOSIv): 5 - 1.41 (in, ЗН), 1.59 (з, ЗН), 2.35 (0, 1Н), 3.33 (4, 1Н), 4, 00 (4, ZN), 4.11 "» (5, ZN), 4.76 (in, 1H), 6.32-6.39 (t, 1H), 6.49-6.56 (t, 1H), 6.66 (a, 1), 6.81 (a, 1), 7.60-7.65 (t, 2H), 8.14-8.24 (t, 2H), 8.52 (a, 1Hn).

Methyl ether (oo) 5-(6-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalene-1-ylamino)-quinoline-2 -carbonic acid o Methyl ether

Ge) 5-I4-(33-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylideneamino|-quinoline-2-carboxylic acid (120 mg, 0.2433 mmol) was dissolved in 2.0 ml of dichloromethane . Titanium tetrachloride (1M solution in water dichloromethane, 0.7Zml, O0.7Zmmol) was added dropwise for 5 minutes at a temperature of -30 C. After that, the reaction mixture

ChT" was left to stir for 3 hours at a temperature from -30 "С to -159С. When adding a saturated solution of sodium bicarbonate at a temperature of -302C, the interaction stopped. The mixture was extracted with ethyl acetate, the combined organic phases were washed with water and saturated sodium chloride solution. After drying over sodium sulfate and after removal of the solvent in vacuo, as well as subsequent purification on silica gel with o dichloromethane/methanol (0-395 methanol), 7Omg (5895 from theory) of product was obtained. "H-NMR (ZO0MHz, CO50O0): 5 - 1.56 (z, ЗН), 1.68 (в, ЗН), 2.16 (в, 2Н), 3.96 (4, ЗН), 4, 08 (in, ZN), 5.28 o (85, 1H), 6.91-6.99 (t, 2H), 7.03-7.09 (t, 1H), 7.57 (y, 1H ), 7.68 (Yii, 1H), 8.12 (y, 1H), 8.72 (a, 1Hn). b-fluoro-1-((2-hydroxymethyl)-quinolin-5-yl)amino1) 5-Methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro bo onaphthalin-2-ol

5-(6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalene-1-ylamino)-quinoline-2-carbonate methyl ester acid (7mg, 0.14mmol) was dissolved in 5.0ml of methanol and mixed with sodium borohydride (22mg, 0.57mmol). After one hour and after 2 hours, in each case, the same amounts were added to the sodium borohydride (total amounts: bbmg, 0.171mmol). When water was added, the interaction stopped. The mixture was extracted -58v-

ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent in vacuo, purification of the residue on silica gel was carried out with hexane/ethyl acetate (0-10095 ethyl acetate). 21mg (3295 from theory) of the product was obtained. "NA-NMR (SO0MHC, DMSO-dv): 5 - 1.48 (in, ZN), 1.61 (in, ZN), 2.01 (a, 1), 2.14 (94, yin), 3.88 (4, ZN), 4.70 (a, 2H), 5.40 (a, 1), 5.51 (Her, 7H), 6.19 (c, 71H), 6.35 (a , 7H), 6.83 (y, 1H), 6.91-6.96 (t, 1H), 7.04-7.11 (t, 1H), 7.21 (da, 1H), 7, 48 (her, 1H), 7.58 (4, 1H), 8.64 (a, 1H).

Example 110: 1-(5-chloro-1H-indazol-4-yl)amino|-b-fluoro-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene 70. -2-ol 5-chloro-4-nitro-1H-indazole 2.24 g (12 mmol) of 4-chloro-2-methyl-3-nitrophenylamine obtained as described in the literature (Mogi et al., Spet.

RPpapt. You. 34, 1986, 4859 and following pages, as well as Vgapa and 7o0Peg, Spet. Veg 1907, 3324 and following pages), dissolved in 100 ml of acetic acid. At a temperature of 109, 2 ml of a 75 molar aqueous solution of sodium nitrite was added dropwise. The suspension was then added to boiling acetic acid (150 mL) over 15 minutes, and the reaction mixture was allowed to heat in a reflux flask for 4 hours. After removal of acetic acid in vacuo, the residue was resuspended in ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate.

After removal of the solvent in vacuo, the crude product was subjected to further reaction (1.81 g, 7690). 7H-NMR (300 MHz, DMSO-iv): 5 - 7.65 (y, 1H), 7.97 (d, 1H), 8.32 (v, 1H), 13.97 (v, 1H). 5-chloro-1H-indazol-4-ylamine

A solution containing 5-chloro-4-nitro-1H-indazole (872 mg, 4.41 mmol) was mixed with 150 mg of palladium on carbon (1095) and stirred under a hydrogen atmosphere at room temperature. After 45 minutes, the catalyst was sucked off on one frit and washed with methanol. The filtrate was concentrated by evaporation, and the residue was resuspended in EM in 200 ml of ethyl acetate and heated. After repeated suction and concentration by evaporation of the filtrate, purification on silica gel was carried out with hexane/ethyl acetate (100-3395 hexane). 296bmg (40905 from theory) of the product were obtained. "H-NMR (300 MHz, DMSO-aiv): 5 - 5.97 (in, 2H), 6.66 (a, 1H), 7.05 (a, 1H), 8.19 (in, 1H), 12.83 (in, 1H). 2-((5-chloro-1H-indazol-4-ilimino)-methyl|-1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4 -methyl-pentan-2-ol t

A solution containing 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoro-methylpentanal (278mg, hU

0.0 mmol) and 5-chloro-1H-indazol-4-ylamine (121 mg, 0.72 mmol) in 20 mL of xylene, mixed with titanium(IM) ethylate (0.42 mL, 2.0 mmol) and heated in a reflux flask within 10 hours. After cooling to room temperature, the xylene was distilled off and the residue was purified on silica gel with hexane/ethyl acetate (30-10090 av ethyl acetate). 12 Zmg (3795 from theory) of the product were obtained. "H-NMR (400 MHz, SOSIi): 5 - 1.43 (z, ZN), 1.57 (z, ZN), 2.38 (9, yin), 3.22 (8, 1H), 3, 94 (a, ZN), 4.91 so (85, 1H), 6.41-6.52 (t, 2H), 6.90 (a, 1H), 7.28 (d, 1H), 7, 38 (y, 1H), 7.56 (8, 1H), 7.72 (v, 1H), 10.26 (rg, 1H). 1-(5-chloro-1H-indazol-4-ylamino)- 6-fluoro-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetprahydro-naphthalen-2-ol « 20 Similarly to example 109, 27 mg (2495 from theory) of the product was obtained by interaction with c 2-((5-chloro-1H-indazol-4-ilimino)-methyl|-1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-pentane-2- beer (111mg,

0.24 mmol) with titanium tetrachloride (0.72 ml of a 1M solution in dichloromethane, 0.72 mmol) in 2.00 ml of dichloromethane after purification by preparative thin-layer chromatography. 7TH-NMR (400 MHz, SOSIv): 5 - 1.56 (in, ЗН), 1.65 (in, ЗН), 2.09-2.17 (24, 2Н), 3.97 (а, ЗН) , 5.34-5.36 (t, 2H), 6.87-6.95 (t, 2H), 7.15 (ad, 1H), 7.32 (d, 1H), 8.05 (in , 1H). o Example 111 1-(5-methyl-1H-indazol-4-ylamino)-b6-fluoro-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalene-2,5-diol - B-methyl-1H-indazol-4-ylamine b A solution containing 2,4-dimethylaniline (12.4 mg, 1000 mmol) in 8 Oml of concentrated sulfuric acid was mixed at 02C with 5 Oml of fuming nitric acid and stirred for 20 minutes at a temperature of 4920 °C, and then for 30 minutes at room temperature. The reaction mixture was poured into a bOOml mixture of water with

ЧТ» with ice, and the pH value was set equal to 10 with the help of 5bn. sodium hydroxide solution. The precipitate was suctioned off, washed with water and dried. 15.72 g (9595 from theory) of 2,4-dimethylnitrophenylamine were obtained in the form of a mixture of regioisomers.

Similarly to the preparation of 5-chloro-4-nitro-1H-indazole, 1.14 g (5795 from theory) of the product was obtained in the form of a mixture of two regioisomers by the interaction of 2,4-dimethylnitrophenylamine (2.0 g, 12 mmol) with bOml of 2 molar aqueous of a solution of sodium nitrite in acetic acid (250 ml). ime) MS (EB'k, acetonitrile/water 1:1 and - 0.0195 formic acid): pt/2 (90) 178 (M.-1, 100).

Similarly, to obtain 5-chloro-1H-indazol-4-ylamine, the regioisomeric mixture from the previous reaction (1.0Og, 60o 5.b4mmol)) was reacted with 100 mg of palladium on carbon in methanol in a hydrogen atmosphere for 16 hours at room temperature. After purification on silica gel with hexane/ethyl acetate (3395 hexane, then 10090 ethyl acetate), 53 mg (695 from theory) of 5-methyl-1H-indazol-4-ylamine were obtained. "H-NMR (300 MHz, DMSO-iv): 5 - 2.12 (b, 3H), 5.41 (z, 2H), 6.57 (a, 1H), 6.90 (a, 1H), 8.10 (5, 1H), 12.5 (in, 1H). 1-(5-methyl-1H-indazol-4-ylamino)-6-fluoro-4,4-dimethyl-2-(trifluoromethyl)- 1,2,3,4-tetrahydro-naphthalene-2,5-diol 65 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)-pentanal (ZO8mg, 1, 0 mmol) and 5-methyl-1H-indazol-4-ylamine (148 mg, 1.0 mmol) were added to 15.0 ml of xylene and mixed with titanium ethylate (IM)

(0.42 ml, 2.0 mmol). After 3 hours in the reflux flask, the reaction mixture was allowed to cool to room temperature. Then ethyl acetate and a saturated solution of sodium chloride were added, the mixture was intensively stirred for 30 minutes at room temperature. The deposited sediment was sucked off, the aqueous phase was separated, and the organic phase was dried over sodium sulfate. Purification was carried out by chromatography on silica gel with hexane/ethyl acetate (30-4095 ethyl acetate). 345 mg (7995 from theory) of 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(5-methyl-1H-indazole-4-ilimino)methyl|-pentane were obtained -2-olu. 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-((5-methyl-1H-indazol-4-ilimino)-methyl|-pentan-2-ol ( 1500 mg, 0.34 mmol) was mixed with boron tribromide (3.40 mL of a 1 M solution in dichloromethane, 3.4 mmol) at room temperature 7/0. After 4 hours at room temperature, the reaction mixture was allowed to stand overnight at -302C, then added saturated sodium bicarbonate solution and ethyl acetate. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent in vacuo and purification by preparative thin layer chromatography on silica gel with hexane/ethyl acetate (5095 ethyl acetate), 56 bmg (3995 from 75 theory) of the product were obtained. "H-NMR (300 MHC, SOCI): 5 - 1.61 (z, ZN), 1.68 (v, ZN), 2.09-2.14 (t, 4H), 2.24 (y, 1H), 4.24-4.33 (Brg, 1H), 5.22-5.23 (t, 1H), 6.84-6.91 (t , ZH), 7.14 (y, 1H), 8.04 (v, 1H).

MS (Eizh): t/2(90) - 423 (Mk, 45), 147 (100).

Example 112 7-bromo-1-K1H-indazol-4-yl)amino|-5-methoxy-4,4-dimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol (5I . 4753-4) "H-NMR (ZO0MHCc, CO500): 5 - 1.52 (ZH), 1.66 (ZH), 2.00-2.22 (2H), 3.88 (ZH), 5 .18 (1H), 6.35 (1H), 6.89 (1H), 7.05 (1H), 7.15-7.29 (2H), 8.13 (1H).

Example 113 with 5-K2-hydroxy-4,4-pentamethylene-2-(trifluoromethyl)-1,2,3,4-tetrahydro-1-naphthyl)amino|-2-quinolone o 5-(2-hydroxy-4 -phenyl-4,4-pentamethylene-2-trifluoromethylbutyl-1-imino|-2-quinolone

Similarly to example 15, 150 mg of 2-hydroxy-4-phenyl-4,4-pentamethylene-2-trifluoromethylbutyraldehyde was condensed with 88 mg of 5-aminoquinolone in the presence of 0.21 ml of titanium triethylate to form an imine (102 mgHg). "H-NMR (ZO0MHC, SOSIZ): 5 - 1.40-2.05 (t, 10 H), 2.40 (9, 1H), 2.65 (4, 1H), 4.80 (Bg. c, 1H), 6.15 (a, M 1H), 6.80 (4, 1H), 6.85 (Ii, 1H), 7.00 (t, 2H), 7.20 - 7.35 ( t, 4H), 8.20 (a, 1H), 12.00 (bBg. c, 1H). "And 5-K2-hydroxy-4,4-pentamethylene-2-(trifluoromethyl)-1,2,3 ,4-tetrahydro-1-naphthyl)amino|-2-quinolone

Similarly to example 15, 10 mg of imine was converted from 4 ml of a 1 M solution of titanium tetrachloride-CH2SiO into 59 mg of the product. | "c) "H-NMR (DMSO-iv): 5 - 1.35-1.80 (t, 11H), 2.15 (t, 1H), 5.35 (4, 1H), 5.95 ( c, 1H), 6.25 (a, 1Hn), 6.40 so (d, 1H), 6.55 (Ii, 2H), 7.15 (t, 2H), 7.25 (i, 1H) , 7.30 (t, 1H), 7.55 (d, 1H), 8.20 (y, 1H), 11.55 (rg.v, 1H).

Example 114 cis-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diol 200 mg (3.Tmmol) of potassium cyanide in 2 ml of water was added to 0.55 g (2.7 mmol) of 1,1,1-trifluoro-4-phenyl-butan-2-one « 20 IO. Mapo; M.-K. Whoopo; 7. Map 9. Oh. Spent 2000; 65; 4179-4184| in 4 ml of THF and 2 ml of water. The mixture was cooled down to 092C, and 2595 ml of sulfuric acid was added, allowed to warm to room temperature and stirred for 16 hours. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate. After washing with saturated sodium chloride solution and drying over sodium sulfate, crude cyanide was obtained with a quantitative yield, which was dissolved in 15 ml of diethyl ether and cooled to -702С. 4.bml (5.5 mmol) of 1.2M RIVAG solution was added dropwise. in toluene for 10 minutes. Mixtures were allowed

Go) to warm up for 2 hours to room temperature, hardened with the help of a 1095 solution of tartaric acid, and continued intensive stirring. After extraction with ethyl acetate, 5 g of silica gel and - 1 bOml of 1 M sulfuric acid were added. The mixture was vigorously stirred for 12 hours and filtered through celite. Phases

F was separated, and the mixture was again extracted with ethyl acetate. After chromatography on silica gel (hexane/ethyl acetate 3090), 30 mg of still contaminated 2-hydroxy-4-phenyl-2-(trifluoromethyl)-butanal were obtained. 0.bml (2.4 mmol) of titanium triethylate was added to the aldehyde and 200 mg (1.13 mmol)

T» of 5-amino-8-fluoro-2-methylquinazoline in 1 bml of toluene, and the mixture was heated for 2 hours to 100 20. After cooling, the mixture was poured into water, and intensive stirring was continued. The suspension was filtered through celite and thoroughly washed again with ethyl acetate. The filtrate phases were separated and the mixture was extracted again with ethyl acetate. it was dried over sodium sulfate and the solvent was removed in vacuo. After chromatography on silica gel (hexane/ethyl acetate 300), 100 mg of 1-(8-fluoro-2-methylquinazolin-5-ilimino)-4-phenyl-2-(trifluoromethyl)butan-2-ol was obtained. The imine was resuspended in Bbml of dichloromethane and cooled to -702C. 1ml (t1mmol) of 1M solution of titanium tetrachloride in dichloromethane was added dropwise for 10 minutes and stirred for 1 hour. The solution was poured into a saturated solution of 60 sodium bicarbonate and intensively stirred for 15 minutes. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 50905), 44 mg of the required product was obtained. "H-NMR (Z0OMHCc, SOSIV); 5 - 2.25-2.32 (t, 2H), 2.91 (da, tn), 2.92 (z, ЗН), 3.19 (dacha, tn ), 5.09 (a, b5 1H), 5.26 (a, 1n), 6.78 (aa, 1H), 7.15-7.29 (t, 4H), 7.49 (ad, 1H ), 9.34 (8.1H).

Example 115 cis-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol "H-NMR (Z0OMHC, SOSIV); 5 - 1.59 (b, ЗН), 1.72 (b, ЗН), 2.11 (а, 1Н), 2.21 (9, 1Н), 2, 93 (z, ZN), 5.05 (a, tn), 5.28 (rg, 1H), 5.40 (a, 1Hn), 6.66 (a, 1H), 6.71 (da, 1n ), 6.94 (y, 1H), 7.03 (Her, 1H), 7.47 (ad, 1Hn), 9.37 (8, 1H).

Example 116 cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol 5- amino-7,8-difluoro-2-methyquinazoline 70 15 bml (39 mmol) of a 2.5 M solution of butyllithium in hexane was added dropwise to 41.7 g (180 mmol) of 2,2-dimethyl-M-(3,4,5-trifluorophenyl) -propionamide in 38b5ml of THF at a temperature of -709С. The mixture was allowed to stir for 1 hour, and then 38.bml DMF in 390ml THF was added dropwise, and the solution could be heated to -602oC. It was stirred for an additional hour at a temperature of -702C, and then the cooled reaction solution was poured into a mixture of 2 kg of ice and 400 ml of concentrated hydrochloric acid. It was intensively stirred several times with diethyl ether after 1 hour. The organic phase was washed neutrally with water and dried over sodium sulfate. After concentration by evaporation, 49.3 g (18.8 mmol) of crude 4,5,6-trifluoro-2-M-pivaloylaminobenzaldehyde was obtained, which was added together with 26 g (275 mmol) of acetamidine hydrochloride, 38.3 g (277 mmol) of potassium carbonate and 30 g of molecular sieve (4A) in 20 bml of butyronitrile. The mixture was heated with vigorous stirring for 18 hours to 1452, and the solvent was removed in vacuo. After chromatography of the residue on silica gel with hexane/ethyl acetate (0-10090), 9.1 g of 7,8-difluoro-5-M-pivaloylamino-2-methylquinazoline was obtained. 2.0 g (7.2 mmol) of 7,8-difluoro-5-M-pivaloylamino-2-methyquinazoline was dissolved in 140 ml of toluene and cooled to -702C. 24 ml (28.8 mmol) of a 1.2 M solution of diisobutylaluminum hydride in toluene was added dropwise over 30 minutes. The reaction mixture was allowed to warm to -252C for 2 hours and stirred for 2 hours at 29 -2B9C. Isopropanol and water were then slowly added and stirred for 12 hours at room temperature (3) until a precipitate formed, which was removed by filtration through celite. It was again thoroughly washed with methylene chloride/methanol and concentrated by evaporation. The residue was vigorously stirred in 200 mL of ethyl acetate and 500 mL of methanol together with 100 g of silica gel and 20 g of manganese dioxide. The mixture was filtered through Celite, thoroughly washed again with a methylene chloride-methanol mixture and concentrated by evaporation.

After chromatography on silica gel with hexane-ethyl acetate (0-10095), 370 mg of the product was obtained. chE 7H-NMR (300 MHz, SOZO0); 5 - 2.81 (in, ZN), 6.64 (ad, 1H), 9.52 (in, 1H). c cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(triphipormethyl)-1,2,3,4-tetrahydronaphthalen-2-ol | "c) "H-NMR (Z0OMHC, SOSIV); δ - 1.46 (z, ЗН), 1.61 (c, ЗН), 2.20 (а, 1Н), 2.24 (9, 1Н) . (i, 1H), 7.29 (i, 1H), 7.32 (i, 1H), 7.43 (d, 1H), 9.28 (c, 1H).

Example 117 cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-b-fluoro-5-methoxy-2-"(trifluoromethyl)-1,2,3, 4-tetrahydronaphthalene-2-ol « 7TH-NMR (ZO0MHC, SOSIv); 5 - 1.59 (in, ЗН), 1.70 (in, ЗН), 2.12 (0, 1Н), 2.22 (0, 1), 2.91 (in, ЗН), 3.98 . .ShZ with (5, ZN), 4.90 (9, 1H), 5.80 (4, 1H), 6.56 (ad, 1H), 6.94 (da, 1Hn), 7.00 (aa , 1H), 9.24 (in, 1H). a Example 118 "» 5-P2-hydroxy-4,4-dimethyl-2,5-bis(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinolin-2(1H)-one

Preparation was carried out as described in example 15 (13). However, crystallization of the imine to the product in trifluoroacetic acid in a reflux flask occurred instead from TiCl/ in toluene. co TN-NMR (ZO0MHZ, SOSI): 5 - 1.55 (in, ЗН), 1.65 (in, ЗН), 2.05 (4, 1), 2.30 (4, 1), 5, 10 (a, 1H), 5.30 o (a, 71n), 6.35 (a, yin), 6.6Oo (a, yin), 6.70 (a, 1H), 7.25 (t, 1), 7.30 (5 MN), 7.55 (a, 1), 7.75 (a, tn), 7.95 (4, 1H), 10.85 (bBg. c, 1H).

Fo MS (EV): MH": 471. 1" 50 Example 119 5-(C6b-chloro-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1 The synthesis was carried out as described in example 15. ), 2.10 (a, 1H), 2.20 (a, 1H), 5.05 (Bg., 1H), 5.70 (Bg., 1H), 6.50 (j, 1H), 6 .60 (t, 2H), 7.05 (da, 1Hn), 7.20 (a, 1H), 7.35 (t, 2H), 8.30 (a, 1H), 10.40 (rg. , 1H).

MS (E5): МН": 437/ 439 (3:1). (F; Example 120

HI 5-C2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1-methylquinolin-2(1H)-one "H-NMR (30OMHC . , 5.15 6o (a, tn), 5.45 (a, 1Hn), 6.60 (a, 1H), 6.65 (a, 1H), 6.75 (a, 1H), 7.10 (i, 1H), 7.30 (t, 1H), 7.40 (t, 2H), 8.00 (ai, 1H).

MS (E5): МН": 417.

Example 121 5-C2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-5,6-trimethylene-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-quinoline-2(1H)- on 65 "H-NMR (Z0OMHC, SOSIi): 5 - 1.45 (v, ZN), 1.65 (v, ZN), 1.95-2.15 (t, ZN), 2.20 (9 , 1H), 2.80 (t, 2H), 3.15 (t, 2H), 5.10 (a, 1), 5.25 (a, 1), 6.55 (t, ЗН), 7 .00 (a, tn), 7.10 (a, 1nH), 7.30 (Yii, tn), 8.00 (a,

1H), 10.10 (rg., 1H).

MS (E5): МН": 443.

Separation of enantiomers was carried out using chiral HPLC (SNigairak AO 20 u-column with hexane-ethanol 95:5 as eluent); (-Y-enantiomer eluted at 11.4 minutes, (y)-enantiomer - at 14.1 minutes.

Example 122 5-Cb-chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|amino)-quinol n-2 (1H)-on

TN-NMR (ZO0MHZ, SOSI): 5 - 1.55 (in, ЗН), 1.70 (in, НН), 2.10 (0, 1Н), 2.20 (d, 1Н), 3.95 (c, ЗН), 5.05 70 (9, 1Н), 5.35 (4, 1Н), 6.55 (t, ЗН), 7.00 (a, 1Н), 7.15 (d, 1Н ), 7.35 (i, 1H), 8.05 (a, 1H), 9.95 (rg., 1H).

MS (E5): МН": 467/469 (3/1).

Example 123 5-(C6b-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2(1H)-one "H-NMR (Z00MHZ, SOSI): 5 - 1.60 (v, ZN), 1.70 (v, ZN), 2.05 (9, 1H), 2.20 (9, 1H), 4, 20 (Bg. 1H), 5.05 (d, 1H), 5.40 (a, 1H), 5.95 (rg.v, 1H), 6.55 (t, ЗН), 6.85 (y , 1H), 7.10 (a, 1H), 7.35 (Her, 1H), 8.10 (a, 1H), 9.75 (rg., 1H).

MS (E5): МН": 453/455 (3/1).

Separation of enantiomers was carried out using chiral HPLC (SNigasey OO 20 u-column with hexane-ethanol 85:15 as eluent); The (u)-enantiomer eluted at 10.4 minutes, the (-)-enantiomer at 14.8 minutes. (i-)-Enantiomer: 7TH-NMR (I0I16-DMSO): 5 - 1.50 (in, ZN), 1.65 (z, ZN), 1.95 (0, 1), 2.10 (4 , 1), 5.30 (4, 1H), 6.05 (z, 1), 6.20 (a, tn), 6.40 (a, 1n), 6.55 (t, 2H), 6 .70 (a, 1H), 7.20 (t, 2H), 8.20 (y, 1), 9.05 (c, 1H), 11.55 (5, 1H). (-)-Enantiomer: Ha 25 "H-NMR (01--DMSO): 5 - 1.50 (in, ZN), 1.65 (in, ZN), 1.95 (y, 1), 2, 10 (a, 1), 5.30 (4, 1H), 6.05 (c, o 1H), 6.20 (a, 1n), 6.40 (a, 1H), 6.55 (t, 2H), 6.70 (9, 1H), 7.20 (t, 2H), 8.20 (y, 1H), 9.05 (8, 1H), 11.55 (v, 1H).

Example 124 5-C5-bromo-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinolin-2(1H)-one

Crystallization of the imine precursor to the product was carried out in trifluoroacetic acid in a flask with a reflux Zh 30 refrigerator instead of TiSi); in toluene. "

TN-NMR (Z00MHZ, SOSIi): 5 - 1.70 (in, ZN), 1.85 (in, ZN), 2.10 (4, 1), 2.25 (9, 1), 5.10 (a, 1H), 5.40 (a, yin), 6.50 (a, 1H), 6.55 (a, tn), 6.60 (a, tn), 6.90 (5 1), 7.30 (a, 1), 7.35 (5 1), 7.55 (a, tn), ke, 8.05 (j, 1H), 10.40 (bBg. c, 1H). at

MS (E5): MH": 481/483 (1/1). 3o Example 125 so 5-(1b-chloro-2-hydroxy-5-methoxy-2-"(trifluoromethyl)-4,4-trimethylene-1 ,2,3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2(1H)-one 7TH-NMR (SOOHMCH, SOCIi): 5 - 2.05-2.40 (t, 5H), 2.60 (4, 1Н), 2.85 (t, 2Н), 4.10 (z, ЗН), 4.95 (а, 1Н), « 5.05 (а, 1Н), 6.55 (t, 2Н ), 6.65 (a, 1), 6.70 (a, tn), 6.95 (a, 1), 7.15 (a, tn), 7.35 (5 1), 7.90 ( a, -o 1H), 10.50 (rg., 1H). c MS (EB5): MNK: 478/480 (3/1). :z» Example 126 5-(6b-chloro-2,5- dihydroxy-2-(trifluoromethyl)-4,4-trimethylene-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2 415 (1H)-one o 7TH-NMR (I016-DMSO): 5 - 1.80 (t, 1H), 2.05 (t 2H), 2.20 (a, 1H), 2.30 (t, 1H), 2.60 (a, 1H), 2.90 (d, 1), 3.25 (a, 1), 5.30 (a, 1), 5.90 (c, 1H), 6.10 (a, tn), 6.35 (a, yin), 6, 55 (a, 2H), 6.70 (a, tn), 7.20 o (d, 1H), 7.25 (i, 1H), 8.15 (a, 1H), 9.30 (c, 1H), 11.55 (Bg. 5, 1H).

Ge") MS (E5): MN": 465/467 (3/1).

Separation of enantiomers was carried out using chiral HPLC (SNigairak AO 20 u-column with hexane-ethanol as an eluent); the (-)-enantiomer eluted first. iz" "H-NMR (016-DMSO): 5 - 1.80 (t, 1H), 2.05 (t 2H), 2.20 (9, 1H), 2.30 (t, 1H), 2 .60 (4, 1H), 2.90 (4, 1), 3.25 (a, 1), 5.30 (a, 1), 5.90 (c, 1H), 6.10 (a, tn), 6.35 (a, yin), 6.55 (a, 2H), 6.70 (a, tn), 7.20 (d, 1H), 7.25 (I, 1H), 8, 15 (y, 1H), 9.30 (v, 1H), 11.55 (rg. 5, 1H). (y)-Enantiomer: 29 "H-NMR (016-DMSO): 5 - 1.80 ( t, 1H), 2.05 (t 2H), 2.20 (9, 1H), 2.30 (t, 1H), 2.60 (4, 1H), 2.90 (4,

HF) 1), 3.25 (a, 1), 5.30 (a, 1), 5.90 (c, 1H), 6.10 (a, tn), 6.35 (a, yin), 6.55 (a, 2H), 6.70 (a, tn), 7.20 (d, 1H), 7.25 (i, 1H), 8.15 (a, 1H), 9.30 (c , 1H), 11.55 (Bg. 5, 1H). name)

Example 127 5-C5-difluoromethoxy-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinoline 60 2(1n)-one

Crystallization of the imine to the product was carried out in trifluoroacetic acid in a reflux flask instead of TiCl/; in toluene. 7TH-NMR (I016-DMSO): 5 - 1.45 (in, 1H), 1.60 (z, 1H), 2.00 (9, 1), 2.15 (d, 1H), 5.40 (d, 1H), 6.15 (z, v5 1H), 6.20 (a, 1n), 6.40 (a, 1n), 6.55 (4, 1Hn), 6.60 (y, 1H ), 7.05 (t, 2H), 7.20 (i, 1H), 7.30 (, SNR", TneE-75Hz), 8.20 (d, 1H), 11.55 (v, 1H) .

MS (E5): МН": 469.

Example 128 4-(6b-chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-indazole "H-NMR ( ZO0MHC, SOSIZ): 5 - 1.40 (in, ЗН), 1.55 (in, ЗН), 2.05 (а, 1), 2.20 (9, 1Н), 5.15 (Bg., 2H), 6.40 (d, 1n), 6.90 (a, 1n), 7.05 (da, 1n), 7.25-7.35 (t, 4H), 8.55 (Bg., 1H).

MS (EB): МН"-410/412 (3:1).

Example 129 5-(6-chloro-2-hydroxy-7-methoxy-4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinol 70 n-2-one 4-(3-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-"'trifluoromethyl)-pentanal 75 ml of methylmagnesium chloride (2295 in THF) was added to 200 ml of THF and at a temperature of 09C, solution 9 was added dropwise. 17g (45.7mmol) of methyl 3-chloro-4-methoxybenzoate in 200ml of THF for | hour. After the conversion was complete, the reaction was quenched by adding 30ml of saturated ammonium chloride solution, and the mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulfate, and concentrated by rotary evaporation. 4.5 g (22.4 mmol) of the crude product (yield 9895) was placed in 100 mL of dichloromethane and first added dropwise b.Og (42./mmol) of ethyl ether of 2-trimethylsilanyloxy-acrylic acid, and then 1.85 ml of tin tetrachloride at a temperature of -70 2C. After 10 minutes, the reaction mixture was added to a saturated solution of potassium carbonate. The aqueous phase was extracted with dichloromethane, the combined organic phases were washed with 1M hydrochloric acid solution, water and saturated sodium chloride solution, dried with sodium sulfate and evaporated on a rotary evaporator. After column chromatography (silica gel, hexane/ethyl acetate 9:1), 2.0 g (29905) of the required intermediate was obtained. with 1.5 g (5000 mmol) of this keto ether was mixed in THF at a temperature of -7090 with 2 l ml (U trimethyl-trifluoromethylsilane) and 6 b20 ml of tetrabutylammonium fluoride (1 M solution in THF). The mixture was left to thaw to room temperature and was stirred for 18 hours, then was mixed at 02C with bml of tetrabutylammonium fluoride (1M solution in THF). After another 10 minutes, the mixture was partitioned between ethyl acetate and 1M hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with 1M hydrochloric acid solution, water and sat. sodium chloride, dried with sodium sulfate and concentrated by evaporation on a rotary evaporator. 1.81 g of the necessary intermediate product was obtained, which, dissolved in 15 ml of diethyl ether, was added dropwise at 02 to a suspension of

Oh, 40 g of lithium aluminum hydride in diethyl ether. After 1 hour at 09 and 18 hours at room temperature, the reaction was stopped by adding 25 ml of saturated sodium bicarbonate solution. The resulting precipitate was filtered off, washed again with ethyl acetate, and the filtrate was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation on a rotary evaporator. After column chromatography (silica gel, hexane/oethyl acetate 8:2), 1.04 g (65965) of the required diol intermediate was obtained. In 20 V dichloromethane, 109 μl (1.12 mmol) of oxalyl chloride was introduced, and at a temperature of -7592C, first 1900 μl (2.6 v6 mmol) of DMSO was added dropwise from c and, after stirring for 15 minutes, a solution of Zbbmg (1.12 mmol) of the diol intermediate from the previous step in dichloromethane. Then, after 15 minutes, 830 μmol (5.62 mmol) of triethylamine (at -502) was added dropwise. The mixture was left to thaw slowly and stirred for another 18 hours. The interaction was terminated by adding a saturated ammonium chloride solution, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with 1M hydrochloric acid, water and

Ho) with a saturated solution of Masi and dried with the help of Mazo). The obtained substance was concentrated by evaporation and chromatographed on silica gel with hexane/ethyl acetate (4:11). 302 mg (84965) of the required 4-(3-chloro-4-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal were obtained.

He») "H-NMR (SOSIV): 5 - 1.34 (v, ZN), 1.40 (z, ZN), 2.30 (9, yin), 2.62 (y, 1H), 3 .66 (in, 1H), 3.90 (z, ЗН), their 50 6.84 (a, 1n), 7.13 (aa, 1), 7.91 (a, 1H), 8.90 ( c, 1H). 5-(6-chloro-2-hydroxy-7-methoxy-4,4 chz" dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H- quinolin-2-one 100mg (0.3mmol) 4-(3-chloro-4-methoxy-phenyl)-2-hydroxy-4-methyl-2--rifluoromethyl-pentanal and 5mg (0.3mmol) 5-amino- 1H-quinolin-2-one was added to 30 ml of toluene, and 0.1 bml of titanium triethylate was added dropwise.

The mixture was stirred for 1 hour at a bath temperature of 1002. After cooling, the solution was added to ice, a few ml of saturated sodium bicarbonate solution were added, the mixture was filtered through diatomaceous earth and washed again with ethyl acetate and water. The phases were separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation on a rotary evaporator. The imine (3095), which was obtained after purification by chromatography (silica gel, hexane/ethyl acetate 95:5 to 25:75), was resuspended in dichloromethane and mixed at -509C with 3.bml of titanium tetrachloride (1 g in toluene). It was allowed to thaw, and after 18 hours of stirring, the mixture was added to ice, separated, extracted with dichloromethane, washed with saturated sodium chloride solution, and dried over sodium sulfate.

After concentration by rotary evaporation, the crude product was chromatographed on silica gel (eluent: 2956 methanol in dichloromethane). The product thus obtained was recrystallized from hexane/diethyl ether (yield: 2895).

Melting point: 18220; "'H-NMR (СО500): 5 - 1.28 (in, ЗН), 1.42 (з, ЗН), 1.95 (а, 1Н), 2.07 (4, 1Н), 3.54 (z, ЗН), 4.88 (в, 1Н), 6.42-6.48 (t, 2Н), 6.58 (y, 1Н), 6.82 (8, 1Н), 7.25- 7.30 (t, 2H), 7.97 (a, 1Hn).

Example 130 5-(6-chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-isoquinoline-1 - he

This compound was prepared using the aldehyde described in previous example 129 and the corresponding amine.

Melting point: 8592, MS (E51): 467 (M'1).

Example 131 5-(6-chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-phthalazine-1 - he

Example 131 was prepared as described in example 129, using the appropriate starting materials. "'NA-NMR (СО5О0): 5 - 1.39 (in, ZN), 1.53 (in, ZN), 2.16 (44, 2Н), 3.12 (in, ZN), 5.30 (in, 1H), 6.94 (in, 1H), 7.31 (da, 1H), 7.42 (in, 1H), 7.64-7.71 (t, 2H), 8.59 ( in, 1H).

Example 132 b-chloro-7-methoxy-4,4-dimethyl-1-(2-methylquinolin-5-ylamino)-2-"'trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Example 132 was synthesized as described in example 129, using the appropriate starting materials.

TNA-NMR (SOS): 5 - 1.39 (in, ZN), 1.52 (z, ZN), 2.15 (ad, 2H), 2.73 (5, ZN), 3.49 (in , ZH), 4.97 (y, 1H), 5.10 (4, 1H), 6.80-6.84 (t, 2H), 7.24 (a, 1H), 7.36 (c, 1H), 7.49 (a, 1H), 7.55 (ad, 1H), 8.08 (a, 1H).

Example 133 b-chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2 -ol sch

The compound was obtained similarly to example 129. Go)

TN-NMR (SOSIV): 5 - 1.42 (in, ZN), 1.56 (zv, ZN), 2.19 (da, 2H), 3.62 (in, ZN), 4.31 (in , Bg, 1H), 5.01 (a, 1H), 5.56 (4, 1H), 6.70 (ad, 1H), 6.90 (c, 1H), 7.39 (c, 1H) , 7.46-7.52 (t, 1H), 9.39 (v, 1H).

Example 134 "g zo 5-(6-chloro-2,7-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinoline-2 -one: 20 mg of 5-I4-(3-chloro-4-methoxyphenyl)-2,2-dihydroxy-4-methylpentylamino|-1H-quinolin-2-one (43 μmol) was introduced into dichloromethane, mixed with 0.8 mmol of tribromide boron (1 M solution in dichloromethane), and stirred for three hundred hours at room temperature. The interaction was completed with a saturated solution of sodium bicarbonate. The mixture was extracted with dichloromethane, the organic phases were washed with saturated sodium chloride solution and dried.

3 with sodium sulfate and concentrated by evaporation. The crude product was recrystallized from hexane/diethyl ether. Received mg (4095) of the required product.

Melting point: 15822; MS (E51): 453 (M'-1).

Example 135 1-(8-fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol 2- tihydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal shshc Aldehyde was obtained from 4-methoxybenzylcyanide as described in example 5. c "H-NMR (SOSIV): 5 - 1.34 (z, ЗН), 1.43 (в, ЗН), 2.30 (а, 1Н), 2.69 (а, 1Н), 3.66 (в, 1Н), 3.80 (в, ЗН) , "» 6.85 (4, 2H), 7.21 (a, 2H), 8.76 (c, 1H). 1-(8-fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-

Ol. (ee) The above compound was prepared using the appropriate starting materials as described in Example 129.

Melting point 972; MS (E51): 450 (M-1). ("in)

Example 136 (22) 5-(2-hydroxy-7-methoxy-4,4-dimethyl-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinoline-2- he

The preparation was carried out as described in example 129, using it. ! with. y, 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.

I» Melting point 1282С; MS (E51): 433 (M-1).

Example 137 5-(2-hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-isoquinoline-1 29 -OH

Gee! The preparation was carried out as described in example 129, using 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine. where the melting point is 1122С; MS (E51): 433 (M-1).

Example 138 bo 5-(2-hydroxy-7-methoxy-4.4-dimethyl-2-"(trifluoromethyl)-1.2.3.4-tetrahydronaphthalene-1-ylamino)-2H-phthalazin-1-one

The preparation was carried out as described in example 129, using 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.

Melting point 1972С; MS (E51): 434 (M-1). because Example 139

7-Methoxy-4,4-dimethyl-1-(2-methylquinolin-5-ylamino)-2-"'trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol

The preparation was carried out as described in example 129, using 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.

Melting point 842; MS (E51): 431 (M--1).

The racemate was separated into enantiomers by chiral HPLC.

Analytical HPLC: SpigaIrak AO 10, 250x4, bmm, Tml min.7, hexane/ethanol 90/10 (4)-Enantiomer: K/-7, Ohv; melting point 8422; MS (EI): 431 (M'-1); (3-Enantiomer: K-17.8 min; melting point 8522; MS (E5I): 431 (Ma-1); in particular, optical rotation: -5.9 70. (s-0.14, CHO").

Example 140 4,4-dimethyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2, 7-diol.

The simple ether described in example 139 was cleaved from VVgz similarly to example 134.

Melting point 1272С; MS (E51): 417 (M--1).

Example 141 5-(2,7-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-phthalazin-1-one

The simple ether described in example 138 was cleaved from VVgz similarly to example 134.

Melting point 1162С; MS (E51): 420 (M--1).

Example 142 1-(8-Fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalene-2, 7-diol.

The simple ether described in example 135 was cleaved from VVgz similarly to example 134. "'H-NMR (СО500): 5 - 1.41 (in, ЗН), 1.54 (з, ЗН), 2.02 (а , 1H), 2.17 (9, 1H), 2.82 (c, 3H), 4.32 (c, 1H), 6.93 (da, 1H), 7.01 (a, 1Hn), 7 ,32-7.43 (t, 2H), 7.52-7.66 (t, ZN);

MS (EI): 436 (M-n1). p 29 Example 143 Ge) 5-(2,7-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinolin-2-one.

The simple ether described in example 136 was cleaved from VVgz similarly to example 134.

TNA-NMR (СО5О0): 5 - 1.38 (in, ZN), 1.52 (zv, ZN), 2.13 (da, 2H), 5.17 (in, 1H), 6.53 (a , 1H), 6.62 (a, « zo 1H), 6.68-6.78 (t, 2H), 7.26 (d, 1H), 7.39 (da, 1n), 8.26 ( a, 1);

MS (EI): 419 (M-n1). "

Example 144 with 5-(2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinolin-2-one

The above-described compound was prepared as described in example 129 using (c) 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine. co

Melting point 2282; MS (EI): 405 (M'-1)

Example 145 1-(8-Fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-2-(trifluoromethyl)-1,2,3.4-tetrahydro-naphthalen-2-ol.

The above-described compound was prepared as described in example 129, using "2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-"(trifluoromethyl)-pentanal and the corresponding amine. -о с Melting point 1322; MS (EI): 422 (M.-1) and Example 146 "" 7-chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1 ,2,3,4-tetrahydronaphthalene-2,6-diol 2-chloro-5-methylanisole

Go) God (350.65 mmol) of 2-chloro-5-methylphenol was dissolved in 450 ml of acetone and mixed in a nitrogen atmosphere with 96.5 g (701.3 mmol) of potassium carbonate. Then 43.bml of methyl iodide (2 equivalents) was added, and the mixture was heated in a reflux flask for three hours. After cooling, the reaction mixture was filtered, the residue

He"), after filtering, was washed with acetone, and the filtrate was centrifuged until it reached an anhydrous state of 5p (bath temperature 3022). Since the residue still contained potassium carbonate, it was resuspended in a small amount of diethyl ether and repeatedly filtered. After removing the solvent by centrifugation,

Chl" obtained 57 g (103.85) of the required compound, which was used as a crude product at the next stage. "H-NMR (300 MHz, SOSI»v): 5 - 2.35 (ZH), 3.90 (ZH), 6.68-6.79 (2H), 7.22 (1H). 4-chloro- 57 g (363.9 mmol) of 3-methoxybenzyl bromide of 2-chloro-5-methylanisole was dissolved in 800 ml of carbon tetrachloride and mixed at room temperature with 69.9 g (393.08 mmol) of M-bromosuccinimide. Then 174.0 mg of benzoyl peroxide was added, and the mixture was heated in a reflux flask for five hours (bath temperature 10522). The reaction mixture was suction filtered through a glass fiber filter, washed again, and the solution was centrifuged on a rotary evaporator. 83.6 bg (97.595) of the required product (which contains traces of the starting material) was obtained and 60 dibromide), which was used at the next stage in an unpurified form. "H-NMR (300MHZ, SOSI"): 5 - 3.91 (ZH), 4.48 (2H), 6.90-6.98 (2H ), 7.32 (1H). 4-chloro-3-methoxybenzyl cyanide 83.6bg (354.97mmol) of crude bromide was dissolved in 255ml of DMF and mixed with 26bml of water. After adding 34.7 g (532.45 mmol) of potassium cyanide (heating), the mixture was stirred for three hours at room temperature. The reaction mixture was poured into one liter of a mixture of water and ice and extracted three times with 500 ml of diethyl ether each time. The combined organic extracts were washed with water and saline. After drying over sodium sulfate, the product was filtered and the solvent was removed by centrifugation. The residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 44.7 g (69.4965) of the required compound were obtained. 7H-NMR (300 MHz, SOSI»a): δ - 3.75 (2H), 3.94 (3H), 6.80-6.91 (2H), 7.38 (1H). 2-(4-chloro-3-methoxyphenyl)-2-methylpropanenitrile 44.7g (246.1mmol) of the nitrile described above was dissolved in 380ml of DMF and mixed with 69.8g (492.2mmol) of methyl iodide. After cooling to 0 C, 21.5 g (492.2 mmol) of Ma 70 (5596-na suspension) was added to the reaction mixture in portions over 3.5 hours. After 18 hours at room temperature, the batch was poured into a bO0ml mixture of water and ice and extracted three times with 500ml of diethyl ether each time. The combined organic phases were washed with water and saline. After drying over sodium sulfate, the desiccant was filtered off and the solvent was removed by centrifugation on a rotary evaporator. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 42.37 g (81.195) of the required compound were obtained. 7H-NMR (300 MHz, SOSI»v): δ - 1.75 (6H), 3.96 (3H), 6.97 (1H), 7.07 (1H), 7.49 (1H). 2-(4-chloro-3-methoxyphenyl)-2-methylpropanal 25g (119.23mmol) of the nitrile described above was dissolved in 475ml of toluene. At a temperature from -65 to -609C, 149ml of a 1.2 molar solution of SIVAN in toluene was added dropwise over 60 minutes. After stirring for two hours at this temperature, b8ml of a 20% solution of 1-(g)-tartaric acid was added dropwise. After adding 200 ml, the temperature rose by -10 °C. The remaining tartaric acid solution was added rapidly and the batch was vigorously stirred for 16 hours at room temperature. The reaction mixture was shaken twice each time with 0.000 ml of diethyl ether. The combined organic extracts were shaken with water and brine, dried, and the solvent removed by centrifugation. The resulting residue (25g-98,890) was used at the next stage in crude form. s "H-NMR (Z00MHZ, SOSI»z): 5 - 1.48 (6H), 3.90 (ZH), 6.70-6.88 (2H), 7.37 (1H), 9.49 (1H). Go)

Ethyl E-4-(4-chloro-3-methoxyphenyl)-4-methylpent-2-enoate 25.6 g (114, Zmmol) of triethylphosphonoacetate was added to 148 ml of tetrahydrofuran. At a temperature of 09C, 600 ml of a 2M solution of IOA in THF/heptane/ethylbenzene was added dropwise (within 15 minutes). After stirring for one hour at a temperature of 0 C, 22.1 g (103.9 mmol) of 2-(4-chloro-3-methoxyphenyl)-2-methylpropanal, dissolved in 100 ml of tetrahydrofuran, was added dropwise. After stirring for five days at room temperature, the reaction mixture was poured into 200 ml of a diluted solution of ammonium chloride and extracted twice with 30 ml of diethyl ether each time. The combined organic extracts were processed as usual, and the resulting residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 24.1 g (8295) of the required compound was isolated. co "H-NMR (ZO0MHC, SOSIZ): 5 - 1.30 (ZH), 1.47 (6H), 3.90 (ZH), 4.20 (2H), 5.80 (1H), 6, 80-6.88 (2H), 7.09 (1H), 7.29 (1H).

Ethyl 4-(4-chloro-3-methoxyphenyl)-4-methylpentanoate 24.1 g (85.23 mmol) of ethyl E-4-(4-chloro-3-methoxyphenyl)-4-methylpent-2-enoate was mixed in 228ml of ethyl acetate with 2.A41g of palladium on charcoal (1096) and stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration with a glass fiber filter, and the residue that remained after concentration by evaporation (24.1g-99.195) was used in the next step in its crude form. ): 5 - 1.21 (ЗН), 1.34 (6Н), 1.90-2.10 (4Н), 3.92 (ЗН), 4.10 (2Н), 6.82-6.90 (2H), 7.29 (1H).

Ethyl 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate (ee) 241 g (84.63 mmol) of ethyl 4-(4-chloro-3-methoxyphenyl)-4-methylpentanoate were dissolved in 296 bml of tetrahydrofuran, and the reaction mixture was cooled to a temperature in the range from -702C to -6592C. During 45 minutes, 236.9 ml of a 0.5 molar solution of potassium bis--trimethylsilylamide) in toluene was added dropwise, and then the reaction mixture was stirred for another 75 minutes at a temperature of -702C. Then 30.9 g (118.48 mmol) of 20 Davis reagent dissolved in 296 ml of tetrahydrofuran was added dropwise over 60 minutes. After stirring for two hours at a temperature of -702C, 152 ml of saturated ammonium chloride solution was slowly added dropwise,

The cooling bath was removed, and the mixture was vigorously stirred for thirty minutes. After extraction with diethyl ether, the combined organic extracts were treated as usual with water and brine. After removing the solvent by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 21.4 g (84.295) of the required compound (slightly contaminated) was isolated.

HF) Ethyl 4-(4-chloro-3-methoxyphenyl)-4-methyl-2-oxopentanoate 6b, 15g (20.45 mmol) ethyl 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4- methyl pentanoate was dissolved in 21 mL of dichloromethane and mixed with 7 mL of dimethyl sulfoxide. Then 10.3g (102.23mmol) of triethylamine was added, and the batch was mixed in portions with 8.1g (51.12mmol) of the 5O3/pyridine complex and then stirred overnight at 60°C. The reaction mixture was mixed with 8 ml of a saturated solution of ammonium chloride with slight cooling, and it was intensively stirred. Then it was extracted twice with diethyl ether, the combined organic phases were processed as usual. The residue that remained after removal of the solvent by centrifugation was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane) together with the residue obtained from another batch (15.27 g). 15.46 g (72.995, from two batches) of the required compound were isolated. for 7H-NMR (300 MHz, SOSIv): 5 - 1.25 (ZH), 1.48 (6H), 3.16 (2H), 3.90 (ZH), 4.12 (2H), 6.83 -6.94 (2H), 7.28 (1H).

(research) EEthyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate 15.46bg (51./75mmol) ethyl-4-(4 -chloro-3-methoxyphenyl)-4-methyl-2-oxopentanoate was dissolved in 85 Bml of tetrahydrofuran and mixed at 02С with 8.83 g (62.09 mmol) of (trifluoromethyl)-trimethylsilane. After adding 126.mg of tetrabutylammonium fluoride, the mixture was stirred for two hours at a temperature from 0 to 590.

The batch was added to 150 ml of ice water, extracted twice with diethyl ether, and the combined organic extracts were processed as usual. After removing the solvent by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 14.11 g (61.895) of the necessary product (contaminated) was isolated, which was used in this form at the next stage. 70 MS (SI): 458 (10096).

Ethyl 4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxypentanoate 8.9 g (20.18 mmol) of contaminated ethyl 4-(4-chloro-3-methoxyphenyl) )-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate was dissolved in 11 bml of tetrahydrofuran and mixed at room temperature with 6.37 g (20.18 mmol) of tetrabutylammonium fluoride trihydrate 75 and stirred for 1 hour at room temperature . The reaction mixture was mixed with water and extracted twice with 250 ml of diethyl ether each time. The combined organic extracts were washed with water and saline. After drying over sodium sulfate, the desiccant was filtered off, the solvent was removed by centrifugation, and the remaining residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 4.03g (54.2965) of the required compound was isolated. Other batches were treated similarly. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.19 (ZH), 1.39 (ZH), 1.49 (ZH), 2.28 (1H), 2.49 (1H), 3.60 -3.71 (2H), 3.93 (ZH), 3.98-4.10 (1H), 6.82-6.93 (2H), 7.28 (1H). 4-(4-chloro -3-methoxyphenyl)-2-hydroxy-2--trifluoromethyl)-pentanal 5.257 (14.24 mmol) (rec.) ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2--trifluoromethyl) -2-hydroxypentanoate was dissolved in 53 ml of diethyl ether and mixed at 02 C with 405.2 mg (10.68 mmol) of lithium aluminum hydride for 6 minutes. The reaction mixture was stirred for more than 15 minutes at 02 C. For hydrolysis, the mixture was mixed dropwise with 12 .5 ml of saturated sodium bicarbonate solution while cooling in an ice bath. It was stirred vigorously for 30 minutes while cooling in an ice bath and for 60 minutes at room temperature. The precipitate was suctioned off and washed with diethyl ether. The filtrate was concentrated by evaporation on a rotary evaporator, and the residue was chromatographed on silica gel (mobile solvent: - 30 ethyl acetate/hexane). 3.29g (71.295) of the required alde guide, which still contained some amount of the original ester, and 54.7 mg of the corresponding diol was isolated. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.39 (ZH), 1.48 (ZH), 2.34 (1H), 2.69 (1H), 3.69 (1H), 3.92 (ZH), 6.80-6.93 i-th (2H), 7.30 (1H), 8.90 (1H). av) 4-(4-chloro-3-methoxy-phenyl)-1, 1,1-trifluoro-2-((E)-8-fluoro-2-methyl-quinazolin-5-ilimino|1-methyl)-4-methyl-pentane so -2-ol

350 mg (1.08 mmol) of (rec.)-4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal was mixed in 5.8 ml of ortho-xylene with 190.9 mg (1.08 mmol ) of 5-amino-8-fluoro-2-methylquinazoline. After adding 0.b4ml (2.16) of titanium isopropylate (IM), the mixture was heated in a reflux flask for three hours (bath temperature 12022). After cooling, the batch was added to a saturated solution of sodium chloride and intensively stirred for 20 minutes. After that, it was extracted twice with ethyl acetate, and the combined organic extracts were washed with saline solution. After drying over sodium sulfate, suction of the desiccant, and removal of the solvent by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 327.5 mg (62.8905) of the required imine was isolated. "H-NMR (ZO0MHZ, SOSIV): 5 - 1.38 (ZN), 1.58 (ZN), 2.45 (1H), 2.71 (1H), 2.99 (ZN), 3.69 (ZH), 4.75 (1H), about 6.28 (1H), 6.79-6.90 (2H), 7.08 (1H), 7.37-7.49 (2H), 9, 63 (1H). 7-chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-b6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaf o talin-2-ol b 8Omg (0.165 mmol) of imine was dissolved in 1.2 ml of dichloromethane, mixed dropwise at a temperature of 0 2 with 0.5 ml of titanium tetrachloride and stirred for 45 minutes at this temperature. The reaction mixture was mixed dropwise at 02С with a saturated solution of sodium bicarbonate, and it was mixed with ethyl acetate.

The body of the bath was removed, and the batch was intensively stirred for 20 minutes. After extraction with ethyl acetate, the combined organic extracts were processed as usual. After chromatography on silica gel (mobile solvent: methanol/dichloromethane), 60.7 mg (75.895) of the required compound was obtained. "H-NMR (300 MHz, DMSO-iv): 5 - 1.40 (ZH), 1.56 (ZH), 1.99-2.15 (2H), 2.78 (ZH), 3.90 ( ЗН), 5.40 (1Н), about 6.18 (1Н), 6.72-6.90 (2Н), 7.10-7.20 (2Н), 7.60 (1Н), 9.79 (1H). 7-chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6- name) diol

ZBmg (0.072 mmol) of the compound described in the previous paragraph was mixed with 0.7 ml of a 1M solution of boron tribromide 60 in dichloromethane under cooling in an ice bath, and the mixture was stirred for two hours under cooling in an ice bath. The reaction mixture was mixed dropwise at -30°C with saturated sodium bicarbonate solution, initially to pH 8. The cooling bath was removed, and the batch was intensively stirred for 15 minutes at room temperature. After that, it was extracted twice with ethyl acetate, and the organic extracts were processed as usual. After chromatography on silica gel (mobile solvent: 65 methanol/dichloromethane), 17.7 mg (52.2 mg) of the desired compound was isolated in the end.

7TH-NMR (ZO00MHZc, СО30О0): 5 - 1.40 (ZN), 1.56 (ZN), 2.07-2.20 (2H), 2.89 (ZN), 5.23 (1), 6.83 (1H), 6.99 (1), 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-tetrahydronaphthalene-1-ylamino-2H-isoquinolin-1-one 5 -I4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-repy-ylideneamino)-2H-isoquinolin-1-one 400 mg (1.232 mmol) 4-(4-chloro -3-methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal, which is described in the previous example, was subjected to a reaction to form an imine with 197.3 mg (1.232 mmol) of 70. 5-amino-2H-isoquinolin-1-one . After the interaction, the usual processing and chromatography, 332.9 mg (57.9905) of the required imine was obtained. "H-NMR (ZO0MHC, SOSIv): 5 - 1.38 (ZN), 1.56 (ZN), 2.43 (1H), 2.72 (1H), 3.70 (ZN), 4.95 (1H), 6.41 (1H), 6.75-6.98 (ZH), 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-tetrahydronaphthalene-1-ylamino-2H-isoquinolin-1-one 100 mg (0.214 mmol) of imine was reacted with titanium tetrachloride as described in example 146. 36.0 mg (36.9905) of the required cyclic compound was isolated, in particular in the form of a diastereomeric mixture at a ratio of 65:35.

MS (EB): 467 (10095) 5-(7-chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino-2 H -isoquinolin-1-one 27 mg (0.058 mmol) of the simple ether described in the previous paragraph was reacted with boron tribromide as described in Example 146. After carrying out the reaction and after carrying out the usual work-up, 19.0 mg (75.995) of the required compound was obtained , in particular in the form of a homogeneous diastereomer. 7TH-NMR (ZO00MHZc, СО30О0): 5 - 1.29 (ЗН), 1.43 (ЗН), 1.98-2.09 (2Н), 5.00 (1Н), 6.75 (1), 6.86 (1H), 6.93 s 29 (1H), 7.00-7.10 (2H), 7.29 (1H), 7.59 (1H). Go)

Example 148 5-(7-chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino-2-methyl-2H-phthalazine- 1-one 5-I4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentylideneamino)-2-methyl-2H-phthalazine-1-Zone

35 mg (1.078 mmol) of the above-described 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal was reacted to form an imine with 251.8 mg (1.078 mmol) of 5-amino-2-methyl- 2H-phthalazin-1-one. 328.4 mg (63.295) of the required imine was obtained after e.g., interaction, conventional treatment and chromatography. Ha") "H-NMR (ZO0MHZ, SOSIV): 5 - 1.38 (ZN), 1.58 (ZN), 2.43 (1H), 2.72 (1H), 3.70 (ZN), 3.89 (ZH), 4.70 (1H), 6.51 (1H), 6.80-6.89 (2H), 7.10 (1H), 7.40 (1H), 7.63 ( 1H), 8.33 (1H), 8.42 (1H). so 5-(7-chloro-2-hydroxy-b6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3 ,4-tetrahydronaphthalene-1-ylamino-2-methyl-2

N-phthalazin-1-one 100mg (0.207mmol) of imine was cyclized to dichloromethane with titanium tetrachloride as described in example 146. 30.5mg (30.595) of the required compound was isolated, in particular in the form of a diastereomeric mixture. with

MS (EC): 482 (10095) s 5-(7-chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino-2 24 mg (0.049 mmol) of the ether described in the previous paragraph was reacted with boron tribromide 15 as described in Example 146. After carrying out the reaction and after carrying out the usual work-up, 18.7 mg (75.9965) of the required compound were obtained, in particular in the form of a mixture of diastereomers.

MS (EC): 468 (10095) (ав) Example 149 5-(7-chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1 -ylamino-1H-quinolin-2-one 5-I4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-"-trifluoromethyl)-pentylideneamino)-1H-quinolin-2-one t » 50 ZBOmg (1.078 mmol) of 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(-trifluoromethyl)-pentanal, which is described in

I" in the previous example, was subjected to a reaction to form an imine from 172.bmg (1.078 mmol) of 5-amino-1H-quinolin-2-one.

After the interaction, the usual treatment and chromatography, 319.4 mg (63.4995) of the required imine was obtained. "H-NMR (ZO0MHC, SOSIv): 5 - 1.34 (ZN), 1.55 (ZN), 2.43 (1H), 2.70 (1H), 3.70 (ZN), 4.85 (1H), 6.00 (1H),

B 8.70-6.90 (ЗН), 7.13 (1Н), 7.29-7.45 (ЗН), 8.17 (1Н), 12.30 (1Н). 5-(7-chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino-1H-quinolin-2-one

F) 10 mg (0.227 mmol) of imine was mixed at -202C with 2.33 ml of a 1M solution of boron tribromide in dichloromethane, and the mixture was stirred for two hours at a temperature in the range from -20 to 02C. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate solution and processed as usual. After chromatography on silica gel (mobile solvent: methanol/dichloromethane), 55.1 mg (53.5905) of the required cyclic compound was isolated in the form of free phenol. 7"H-NMR (Z00MHCz, CO300): 5 - 1.41 (ZH), 1.55 (ZH), 2.05-2.20 (2H), 5.12 (1H), 6.49-6 .64 (2H), 6.73 (1H), 6.98 (1H), 7.16 (1H), 7.40 (1H), 8.25 (1H).

Example 150 65 7-chloro-1-(2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6b-diol 4-(4 -chloro-3-methoxyphenyl)-1,1,1-triftpor-2-(2-methylquinazolin-5-ilimino)-methyl|-4-methyl-pentan-2-ol

200 mg (0.61 mmol) of (rec.)-4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal was reacted to form an imine as described in Example 146, with 98.1 mg (0.61 bmmol) of 5-amino-2-methylquinazoline.

After the usual processing and purification, 184.Zmg (64.295) of the required imine was isolated. "H-NMR (ZO0MHC, SOSIv): 5 - 1.36 (ZN), 1.59 (ZN), 2.45 (1H), 2.73 (1H), 2.93 (ZN), 3.68 (ЗН), 4.82 (1Н), 6.30 (1Н), 6.78-6.90 (2Н), 7.08 (1Н), 7.48 (1Н), 7.71 (1Н), 7.84 (1H), 9.60 (1H). 7-chloro-1-(2-methylquinazolin-5-ylamino)-b6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2, 3,4-Tetrahydronaphthalene-2-ol 180mg (0.38bmmol) of the imine was cyclized as described with titanium tetrachloride. 165.bmg 70. (92906) of the desired cyclic compound was isolated. "H-NMR (Z00MgCl, CO500): 5 - 1.49 (ZN), 1.61 (ZN), 2.10-2.25 (2H), 2.84 (ZN), 3.93 (ZN), 5.31 (1H), 6, 95 (1), 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-2,6b-diol

BOmg (0.107 mmol) of the derivative described in the previous paragraph was reacted with boron tribromide to give the corresponding phenol 712. 30.2 mg (66.1905) of the required compound was isolated.

TN-NMR (300 MHz, DMSO-ydv): 5 - 1.33 (ZH), 1.48 (ZH), 1.95-2.13 (2H), 2.72 (ZH), 5.39 (1 ), 6.15 (1Н), 6.80-6.95 (2Н), 6.95-7.13 (ЗН), 7.69 (1Н), 9.72 (1Н), 10.03 (1Н ).

Example 151 7-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6- diol 4-(4-chloro-3-methoxyphenyl)-1,1,1-trifluoro-2-K7-fluoro-2-methylquinazolin-5-ilimino)-methyl|-4-methyl-pentan-2-ol 200 mg (0.61 bmmol) of aldehyde was reacted with 109.1 mg (0.616) of 5-amino-7-fluoro-2-methylquinazoline, as already described several times. 17 Zmg (58,195) of the required imine were isolated. "H-NMR (ZO0MHZ, SOSIV): 5 - 1.39 (ZN), 1.58 (ZN), 2.47 (1H), 2.73 (1H), 2.90 (ZN), 3.72 (ZH), 4.64 (1H), sch 6.17 (1H), 6.80-6.90 (2H), 7.09 (1H), 7.40-7.50 (2H), 9, 49 (1H). o 7-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-b6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalene-2-ol 170 mg (0.35 mmol) of the above-described imine was cyclized from 1.05 ml (1.053 mol) of titanium tetrachloride in 1.5 ml of Med in dichloromethane. After the usual treatment and subsequent chromatography, 168.4 mg were isolated (9995) of the necessary cyclic compound in the form of a simple ether. "I" H-NMR (Z00MHCz, CO500): 5 - 1.49 (ZH), 1.61 (ZH), 2.20 (2H), 2.80 ( ЗН), 3.93 (ЗН), 5.33 (1Н), 6.70-6.85 so (2Н), 7.10 (1Н), 7.20 (1Н), 9.57 (1Н). 7-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-d o

Zv l so

BOmg (0.1033 mmol) of the simple ether described in the previous paragraph was subjected, as usual, to the cleavage reaction of the simple ether with boron tribromide. After processing and conventional chromatography on silica gel (mobile solvent: methanol/dichloromethane), 32.2 mg (66.4965) of the required compound was isolated. "H-NMR (30 MHz, DMSO-iv): 5 - 1.32 (ZH), 1.49 (ZH), 1.95-2.13 (2H), 2.70 (ZH), 548 (1H) , 6.15 (1H), « 40... 6.79 (1H), 6.88 (1H), 6.95-7.16 (2H), 9.68 (1H), 10.03 (1H ). - c Example 152 with" 7-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4- Tetrahydronaphthalene-2 and 6-diol 4-(4-chloro-3-methoxyphenyl)-1,1,1-trifluoro-2-(7,8-difluoro-2-methylquinazolin-5-ilimino)-methyl)|- 4-methyl-pentane-2

Dol (ee) 200 mg (0.61 bmmol) of aldehyde was reacted with 120 mg (0.616) of 5-amino-7,8-difluoro-2-methylquinazoline, as already described several times. 201.Zmg (65.195) of the required imine was isolated. 7TH-NMR (300 MHz, SOSI): 5 - 1.38 (ZN), 1.58 (ZN), 2.46 (1), 2.72 (1H), 2.96 (ZN), 3.72 ( ЗН), 4.59 (1Н),

Me, 6.28 (1H), 6.80-6.90 (2H), 7.10 (1H), 7.46 (1H), 9.53 (1H). iz 20 7-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-b6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro naphthalene 200 mg (0.398 mmol) of the previously described imine was cyclized from 1.19 ml (1.194 mmol) of titanium tetrachloride in dichloromethane. After carrying out the usual treatment and subsequent chromatography, 163.bmg (81.8905) of the required cyclic compound was isolated. 52 "NA-NMR (300 MHz, CO53O0): 5 - 1.48 (ZN), 1.61 (ZN), 2.19 (2H), 2.86 (ZN), 3.93 (ZN), 5, 30 (1H), 6.88

HF) (1H), 7.09 (1H), 7.21 (1H), 9.62 (1H). 7-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2»6-diol

B5Omg (0.099 mmol) of the simple ether, which is described in the previous paragraph, was subjected, as usual, to reaction 60 cleavage of the simple ether with boron tribromide. After treatment and purification by flash chromatography (mobile solvent: methanol/dichloromethane), 29.5 mg (60.7905) of the desired compound was isolated. "H-NMR (30 MHz, DMSO-iv): 5 - 1.32 (ZH), 1.47 (ZH), 1.95-2.12 (2H), 2.78 (ZH), 545 (1) , 6.13 (1H), 6.92-7.18 (4H), 9.73 (1H), 10.02 (1H). b Example 153 4-(7-chloro-2,6-dihydroxy-4 ,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1,3-dihydroindol-2-one 4-(4-(4-chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino|-1,3-dihydroindol-2-one 150 mg (0.462 mmol) of aldehyde was boiled in a water separator Kk! 102.7 mg (0.693 mmol) of 4- of amino-1,3-dihydroindol-2-one in xylene, then titanium tetraisopropylate was added as already described in the previous examples. After carrying out the usual work-up and chromatography, 119.1 mg (56.790) of the required imine was isolated. , SOSIZ): 5 - 1.35 (ZN), 1.50 (ZN), 2.49 (1H), 2.66 (1H), 3.35-3.59 (2H), 3.75 (ZN ), 4.89 (1H), 5.98 (1H), 6.70-6.90 (ZH), 7.09-7.22 (2H), 7.33 (1H), 8.22 (1H ). 70 4-(7-chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1,3-di droindol-2-one 119 mg (0.261 mmol j) the above-described imine was cyclized, as usual, in dichloromethane with 0.78 ml of titanium tetrachloride. After processing and chromatography, 78.1 mg (65.695) of the required compound was obtained. "H-NMR (SO0MHCc, CO500): 5 - 1.42 (ZH), 1.59 (ZH), 2.00-2.20 (2H), 3.23-3.49 (2H), 3, 91 (ZH), 5.03 (1H), 6.37 (1H), 6.48 (1H), 7.03 (1H), 7.10 (1H), 7.29 (1H). 4-( 7-chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1,3-dihydroindol-2-one b5mg (0 .14 mmol) of the simple ether described in the previous paragraph was mixed with 1.4 boron tribromide in dichloromethane. After treatment and chromatography, 45.4 mg (72.195) of the required phenol was obtained. 1.39 (ZN), 1.51 (ZN), 1.98-2.20 (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-(naphthalene-1-ylamino)-6-"-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol 1,1,1-trifluoro-4-( 2-methoxyphenyl)-4-methyl-2-(naphthalene-1-iliminomethyl)-pentan-2-ol with 1500 mg (0.517 mmol) 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl )-pentanal was converted into (3 imine) from 74 mg (0.517 mmol) of 1-naphthylamine in toluene with the help of titanium tetraisopropylate. After treatment and chromatography, 166.7 mg (77.790) of the required imine was isolated. - 1.42 (ZN), 1.59 (ZN), 2.29 (IR), 3.57 (1H), 3.88 (ZN), 5.09 (1), 6.10 (1H), from 6.48 (1H), 6.79 (1H), 7.00 (1H), 7.10 (1H), 7.22 (1H), 7.40 (1H), 7.47-7, 58 (2H), 7.69 (1H), 7.80 (1H), 8.05 (1H). 8,8-dimethyl-5-(naphthalene-1-ylamino)-6-«-(trafluoromethyl)- 5,6,7,8-tetrahydronaphthalene-1,6b-diol "And 160.9 mg (0.387 mmol) of the previously described imine was treated, as usual, with boron tribromide at a temperature of 02C, and after the usual treatment and chromatography on a Riazptavieg support, received 100.9 mg (62.795) of the necessary cyclic about phenol. o "H-NMR (ZO0MHC, SOSIZ): 5 - 1.60 (ZH), 1.73 (ZH), 2.00-2.28 (2H), 3.09 (1H), 4.79 (1H ), 5.02 (1H), 5.20 so (1H), 6.62 (1H), 6.85-7.02 (ZH), 7.30-7.58 (4H), 7.73- 7.90 (ZN).

Example 155 8,8-dimethyl-5-(naphthalene-2-ylamino)-6-"-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol « 1,1,1-trifluoro-4- (2-Methoxyphenyl)-4-methyl-2-(naphthalene-2-iminomethyl)-pentan-2-ol 150 mg (0.517 mmol) 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-«( trifluoromethyl)-pentanal was converted into the s imine from 74 mg (0.517 mmol) of 2-naphthylamine in toluene with the help of titanium tetraisopropylate. After work-up and chromatography, 192.8 mg (89.895) of the required amine was isolated. SOLUTIONS): 5 - 1.40 (ZN), 1.58 (ZN), 2.20 (1H), 3.58 (1H), 3.89 (ZN), 5.09 (1H), 6.69 (1H), 6.80-6.90 (2H), 6.95 (1H), 7.05-7.18 (2H), 7.38-7.53 (ZH), 7.63-7, 85 (ZN). 8,8-Dimethyl-5-(naphthalene-2-ylamino)-6-"-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol with 173.0mg (0.416bmmol) of the previously described imine was treated, as usual, with boron tribromide at a temperature of 02C, and after carrying out the usual treatment and chromatography on a Riazptavieg carrier, 132.bmg (76.695) of the necessary cyclic phenol were obtained. ЗН), 1.66 (ЗН), 2.00-2.24 (2Н), 3.04 (1Н), 5.00 (1Н), 5.09 (1Н), 6.62 sh» 50 (1Н ), 6.92-7.10 (4Н), 7.28 (1Н), 7.40 (1Н), 7.60-7.78 (ЗН).

T» Example 156 2-chloro-5-(6-hydroxynaphthalene-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol 5 -(4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino|-naphthalen-2-ol 200 mg (0.61 bmmol) 2-hydroxy-4-(3 -chloro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl)-pentanal was subjected to 59 reactions to form an imine as usual with 98.1 mg (0.61 mmol) of 5-amino-2-naphthol. 185.1 mg (64.595) were allocated

HF) of the required compound. d) 7TN-NMR (Z00MHz, SOSI): 5 - 1.47 (ZN), 1.62 (ZN), 2.40 (1H), 3.23 (1), 4.00 (ZN), 4, 99 (1H), 5.15 (1H), 6.39 (1H), 6.49 (1H), 6.83 (1H), 7.00 (1H), 7.05-7.20 (2H) , 7.23-7.32 (2H), 7.52-7.63 (2H), 7.95 (1H). in 2-chloro-5-(6-hydroxynaphthalene-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol 185.1 mg ( 0.397 mmol) of the imine was cyclized with boron tribromide as described several times. 146.9 mg (81.895) of the required phenol was isolated. "H-NMR (Z00MHZ, SOSI): 5 - 1.59 (ZH), 1.70 (ZH), 2.02-2.28 (2H), 3.00 (1H), 4.75 (1H) , 5.10-5.19 (2H), 5.95 (1H), 6.73 (1H), 6.88 (1H), 7.00-7.12 (2H), 7.12-7, 22 (2H), 7.34 (1H), 7.70 (1H). 65 Example 157 2-chloro-5-(5-hydroxynaphthalene-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)- 5,6,7,8-tetrahydro-naphthalene-1,6-diol

5-(4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino|-naphthalen-1-ol 200 mg (0.61 bmmol) 2-hydroxy-4-( 3-chloro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl)-pentanal was reacted to form an imine as usual with 98.1 mg (0.61 mmol) of 5-amino-1-naphthol. 145.Omg (50.595) of the required compound was isolated. 7TH-NMR (300 MHz, SOSI): 5 - 1.45 (ZN), 1.62 (ZN), 2.40 (1H), 3.25 (1H), 4.01 (ZN), 5.01 ( 1H), 5.39 (1H), 6.46 (1H), 6.53 (1H), 6.80-6.91 (2H), 7.02 (1H), 7.30-7.40 ( 2H), 7.59 (1H), 7.64 (1H), 8.10 (1H). 2-chloro-5-(5-hydroxynaphthalene-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol 145.Omg (0.311 mmol) of the imine was cyclized with boron tribromide as previously described several times. 70 87.bmg (62.3965) of the required phenol was isolated. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.58 (ZH), 1.70 (ZH), 2.05-2.28 (2H), 3.00 (1H), 4.78 (1H) , 5.15 (1H), 5.49 (1H), 5.95 (1H), 6.80-6.93 (ZH), 7.10 (1H), 7.29 (1H), 7.32 -7.45 (2H), 7.68 (1H).

Example 158

3-chloro-5-(6-hydroxynaphthalene-1-ylamino)-8,8-dimethyl-6b-"(trifluoromethyl)-5,6,7 8-tetrahydro-naphthalene-1,6-diol 5-(4-(4 -chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino|-naphthalen-2-ol 200mg (0.616bmmol) 2-hydroxy-4-(4-chloro-2-methoxyphenyl) -4-methyl-2-trifluoromethyl)-pentanal was reacted to form an imine as usual with 98.1 mg (0.61 mmol) of 5-amino-2-naphthol. 113.Omg (39.4905) of the required compound was isolated. 7TN-NMR (Z00MHz, SOSI"): 5 - 1.38 (ZN), 1.58 (ZN), 2.30 (1H), 3.40 (1H), 3.85 (ZN), 5.00 (1Н), 5.15 (1Н), в.06 (1Н), 6.50 (1Н), 6.75 (1Н), 6.99 (1Н), 7.05-7.20 (2Н), 7.28 (1H), 7.45 (1H), 7.58 (1H), 7.93 (1H).

C-chloro-5-(6-hydroxynaphthalene-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7 8-tetrahydro-naphthalene-1,6-diol 113.Omg (0, 243mmol) of the imine was cyclized with boron tribromide, as has already been described several times. 85.7 mg (78.295) of the required compound was isolated. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.55 (ZH), 1.65 (ZH), 2.01-2.23 (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, 10-7.23 (2H), 7.35 (1H), 7.74 (1H). o

Example 159 2-chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-"-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6b-diol 4-(3-chloro -2-methoxyphenyl)-1,1,1-"-trifluoromethyl)-4-methyl-(pyridin-3-iliminomethyl)-pentan-2-ol « 200mg (0.61bmmol) 2-hydroxy-4-(3- chloro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl)-pentanal was reacted to form an imine as usual with 57.9 mg (0.61 mmol) of 3-aminopyridine. 197.2 mg (79.995) of the required compound was isolated. co "H-NMR (SO0MHC, SOSIv): 5 - 1.43 (ZN), 1.60 (ZN), 2.28 (1H), 3.25 (1H), 3.98 (ZN), 4, 70 (1), 6.75 (1H), 6.95 (1H), 7.00-7.15 (2H), 7.23 (1H), 7.58 (1H), 8.12 (1H) , 8.49 (1H). o b-chloro-5-methoxy-4,4-dimethyl-1-(pyridin-3-ylamino)-2-"-trifluoromethyl)-1,2,3,4-tetrahydro- naphthalene-2-ol so 190.0 mg (0.474 mmol) of the imine was cyclized with titanium tetrachloride, as already described several times.

184.Omg (96.895) of the required cyclic compound was isolated in the form of a simple ether. "H-NMR (SO0MHCc, CO500): 5 - 1.54 (ZH), 1.62 (ZH), 2.11 (2H), 3.95 (ZH), 5.05 (1H), 7.11 (1), 7.15-7.28 " (ZH), 7.83 (1H), 8.09 (1H). 2-chloro-8,8-dimethyl-5-(pyridin-3-ylamino)- 6-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,b-diol - with 100 mg (0.249 mmol) of the previously described simple ether was treated as usual with boron tribromide. After carrying out the usual treatment and chromatography, isolated 85.8 mg (88.995) of the required compound. i 7TH-NMR (ZO0MHCz, CO3O0): 5 - 1.58 (ZH), 1.69 (ZH), 2.00-2.20 (2H), 5.00 ( 1H), 6.89 (1H), 7.10-7.30 (ZH), 7.81 (1H), 8.06 (1H).

Example 160 with 166-dihydroxy-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7 8-tetrahydro-naphthalene-2-carbonitrile l o BOmg 2-chloro- 8,8-dimethyl-5-(pyridin-3-ylamino)-6-"'trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, which (22) is described in example 159, was dissolved in 0.12 ml of 1-methyl-2-pyrrolidinone and mixed with 12.2 mg (0.258 mmol) of sodium cyanide 20 and 28.2 mg (0.129 mmol) of nickel (II) bromide. The reaction mixture was exposed to the influence of microwaves (2002С, 20 bar) as described in the literature by M. Ogdu. Spect. 68, 9122 (2003)). After cooling, the reaction mixture was diluted with ethyl acetate, and then a small amount of water was added. The mixture was filtered on EhigeIsche (mobile solvent: ethyl acetate). The solvent was removed by centrifugation, and the residue was chromatographed on silica gel (mobile solvent: methanol/dichloromethane). 9.4 mg (19.2905) of the required nitrile was isolated. 29 MS (CI): 378 (10096); IR (KWh): 2228,

F! Example 161 2-chloro-8,8-dimethyl-5-(pyridin-4-ylamino)-6-"'trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6b-diol o 4-(3- chloro-2-methoxyphenyl)-1,1,1-"-trifluoromethyl)-4-methyl-(pyridin-4-iliminomethyl)-pentan-2-ol 200mg (0.61bmmol) 2-hydroxy-4-(3- chloro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl)-pentanal was subjected to 60 reactions to form an imine as usual with 57.9 mg (0.616 mmol) of 4-aminopyridine. 167.Omg (68.095) of the required compound was isolated. 7TH-NMR (300 MHz, SOSIv): 5 - 1.43 (ZN), 1.60 (ZN), 2.29 (1H), 3.26 (1H), 4.00 (ZN), 4.55 ( 1H), 6.59-6.65 (2H), 6.80 (1H), 7.01 (1H), 7.11 (1H), 7.55 (1H), 8.46-8.55 ( 2H). b-chloro-5-methoxy-4,4-dimethyl-1-(pyridin-4-ylamino)-2-"-trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol bo 160.00mg (0.399 mmol) of the imine was cyclized with titanium tetrachloride as previously described several times.

45.2 mg (28.295) of the required cyclic compound was isolated in the form of a simple ether. "H-NMR (Z00MHCz, СО50О0): 5 - 1.55 (ZH), 1.69 (ZH), 2.12 (2H), 3.98 (ZH), 5.28 (1H), 6.80 -6.93 (2H), 6.99 (1H), 7.28 (1H), 7.98-8.20 (2H). 2-chloro-8,8-dimethyl-5-(pyridine-4- ylamino)-6-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6b-diol

37 mg (0.092 mmol) of the previously described simple ether was treated as usual with boron tribromide. After the usual work-up and chromatography, 13.8 mg (38.695) of the required compound was isolated. 7"H-NMR (ZO0MHCz, СО3О0): 5 - 1.58 (ЗН), 1.70 (ЗН), 2.00-2.20 (2Н), 5.19 (1Н), 6.70-6 .89 (ZH), 7.19 (1H), 7.90-8.20 (2H).

Example 162 5-(2,5-dihydroxy-b-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-isoquinolin-1-one

Methyl-3-isopropyl-2-methoxybenzoate 28g (156.25mmol) of 2-hydroxy-3-isopropylbenzoic acid was dissolved in 280ml of DMF and added dropwise to the mixture of 47.5g of potassium carbonate in 274ml of DMF. After stirring for more than one hour at room temperature, 21.4 mL (343.7 mmol) of iodomethane was added dropwise, and the mixture was stirred for one day at room temperature. After acidification with 10905 sulfuric acid to pH 3-4 (cooling in an ice bath), the reaction mixture was extracted four times with 500 ml of methyl tert-butyl ether each time. The combined organic extracts were washed with water and brine and dried over sodium sulfate. After filtering off the desiccant, the solvent was removed by centrifugation, and the residue was chromatographed several times on silica gel (mobile solvent: methyl tert-butyl ether/hexane).

25.59 g (79.0295) of the required compound was isolated. "H-NMR (300 MHz, SOSI»v): 5 - 1.26 (6H), 3.42 (1H), 3.85 (ZH), 3.96 (ZH), 7.15 (1H), 7 .43 (1H), 7.65 (1H). 2-(3-isopropyl-2-methoxyphenyl)-propan-2-ol with 25.59 g (142.81 mmol) of methyl 3-isopropyl-2-methoxybenzoate was dissolved in 2500 ml of tetrahydrofuran and (He) was added dropwise to 114.25 ml (342.74 mmol) of methylmagnesium bromide (ZM in diethyl ether). In this case, the temperature was raised to 462 C. It was stirred for 3 hours at room temperature and then added dropwise to the reaction mixture 6b25ml of saturated ammonium chloride solution. After three cycles of extraction with methyl tert-butyl ether, the combined organic extracts were washed with water and brine and dried (sodium sulfate). The desiccant was filtered off, the solvent was removed by centrifugation, and the residue (28.16g-95 ,15965) was used at the next stage in an unpurified form. 7H-NMR (300 MHz, SOCI3): δ - 1.25 (6H), 1.63 (6H), 3.31 (1H), 3.90 (ZH), 4.78 (1H), 7.00-7.23 (ZH).

Ethyl 4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-oxo-pentanoate | "c) 15.3 ml (129.71 mmol) of tin tetrachloride was added dropwise to a mixture cooled to -72 C, which contained 28.16 g (135.19 mmol) of 2-(3-isopropyl-2-methoxyphenyl)-propane- 2-ol and 50.9 g (270.38 mmol) of 2-trimethylsilanyloxy-acrylic acid ethyl ether in 420 ml of dichloromethane. In this case, the temperature rose to -6529C. After stirring for 30 minutes at this temperature range, the reaction mixture was poured into a mixture containing a saturated solution of sodium carbonate and dichloromethane (in each case, 250 ml). After stirring for 30 minutes at room temperature, the batch was transferred to a 50s spherical separatory funnel and a 1:1 mixture of water and dichloromethane was added until phase separation. Then the organic phase was shaken with sodium carbonate, In. NOI and water, and it was dried with the help of sodium sulfate. a After carrying out the usual procedure, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 20.44 g (48.35965) of the required compound were obtained.

TN-NMR (ZO0MHZ, SOSI): 5 - 1.15-1.34 (9H), 3.28 (1H), 3.38 (2H), 3.78 (ZH), 4.09-4.21 (2H), 7.05 (1H), (ee) 7.10-7.19 (2H). o Ethyl-2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanoate 11.82g (38.58mmol) ethyl-4-(3-isopropyl-2-methoxyphenyl) )-4-methyl-2-oxopentanoate and 6.58 g (46.29 mmol) of (o) (trifluoromethyl)-trimethylsilane were dissolved in 7 Oml of tetrahydrofuran and mixed with 5 Omg of tetrabutylammonium fluoride trihydrate (a slight increase in temperature). Since, after three hours, the reaction was still not complete, the same amount of tetrabutylammonium fluoride trihydrate was added again. After mixing

ChT" during the night, 12.17 g of tetrabutylammonium fluoride trihydrate was added to the cleaved silyl simple ether, which was obtained at the same time, and in this way the free hydroxyl compound was directly obtained.

The reaction mixture was diluted with methyl tert-butyl ether and the organic extract was washed with water and brine. After drying (sodium sulfate), filtering off the desiccant, and after filtering off the solvent, the residue was chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane).

11.04 g (7695) of the required compound was isolated. where "H-NMR (Z0OMHC, SOSIV): 5 - 1.13-1.32 (9H), 1.40-1.48 (6H), 2.48 (1H), 2.72 (1H), 3 .32 (1H), 3.57 (1H), 3.65-3.78 (1H), 3.85 (ZH), 4.08-4.20 (1H), 6.96-7.09 ( 2H), 7.18 (1H). bo 4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol 11.04g (29.333mmol) ester , which is described in the previous paragraph, was dissolved in 90 ml of diethyl ether and mixed with 2.23 g (58.6 mmol) of lithium aluminum hydride in portions at 22 C. After stirring overnight at room temperature, 50 ml of a saturated sodium bicarbonate solution was carefully added dropwise while cooling in an ice bath . After 1 hour of vigorous stirring at room temperature, the mixture was extracted three times with methyl tert-butyl ether. The combined organic extracts were worked up as usual, and the residue which remained after removal of the solvent by centrifugation was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane ). 7.15 g (72.9905) of the necessary diol were isolated. "H-NMR (ZO0MHC, SOSIV): 5 - 1.25 (ЗН), 1.29 (ЗН), 1.50 (ЗН), 1.58 (ЗН), 1.80 (1), 2.23 (1), 2.61 (1Н), 2.83 ( 1Н), 3.23-3.49 (ЗН), 3.89 (ЗН), 7.09 (1Н), 7.17-7.26 (2Н). 2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-trifluoromethyl)-pentanal 3.17 g (25.04 mmol) of oxalyl chloride was added to 8 ml of dichloromethane and cooled to -782C. At this temperature, 3.9 g (50.08 mmol) of dimethyl sulfoxide dissolved in 100 ml of dichloromethane was added dropwise.

After stirring for 5 minutes, 715 g (21.3 in 8 mmol) of 70. 4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol, dissolved in 21.4 ml, were added. dichloromethane.

After that, the reaction mixture was stirred for two hours at this low temperature. 10.8 g (106 b, o0 mmol) of triethylamine was carefully added dropwise, and then the batch was intensively stirred at room temperature for 1 hour. After adding water and stirring for an additional ten minutes, the mixture was extracted twice with dichloromethane. The combined organic extracts were washed with 195% sulfuric acid, saturated sodium bicarbonate solution, and saline. Then the solvent was dried and removed by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane).

As a result, 5.93 g (83.4495) of the required aldehyde was obtained. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.20 (ZH), 1.32 (ZH), 1.40-1.54 (6H), 2.22 (1H), 3.30 (1H) , 3.40 (1H), 3.59 (1H), 3.83 (ZH), 6.95-7.07 (2H), 7.20 (1H), 8.91 (1H). 5-( 2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentylideneamino|-2H-isoquinolin-1-one 147 Zmg (0.44 Zmmol) of aldehyde, which is described in the previous paragraph , was stirred with 71 mg (0.44 mmol) of 5-amino-2H-isoquinolin-1-one in 1.3 ml of glacial acetic acid overnight at room temperature. The reaction mixture was poured three times with toluene, and the residue was chromatographed on Riazptavieg support. 157 mg was isolated (7590) of the required imine. c 29 "H-NMR (ZO0MHz, DMSO-4v): 5 - 0.93 (ZN), 1.19 (ZN), 1.43 (ZN), 1.55 (ZN), 2.18 (1H), 3.18 (IN), 3.29 Go) (IN, half submerged in DMSO), 3.75 (ZN), 6.19 (1H), 6.33 (1H), 6 .63 (1H), 6.77 (1H), 6.89-6.99 (2H), 7.16-7.32 (ZH), 8.03 (1H), 11.33 (1H). 5-(2-hydroxy-b-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-isoquinolin-1-one 157 mg of imine (0.331 mmol) was dissolved in 2.5 ml of dichloromethane and mixed dropwise at 0 °C with 0 mL of titanium (IM) chloride (0.993 mmol). After stirring for one hour at a temperature of 0 C, the reaction mixture was mixed dropwise with saturated sodium bicarbonate solution and diluted with ethyl acetate.

The cooling bath was removed and the batch was vigorously stirred at room temperature for 30 (av) minutes. After that, it was extracted twice with ethyl acetate, and the organic extracts were processed as usual. After her, Fr. and d) chromatography of the residue on Riazptavieg support, 108 mg (68.9895) of the required cyclic compound was obtained in the form of a racemate. 7TH-NMR (ZO00MHZc, СО3О0): 5 - 1.10-1.30 (6Н), 1.55 (ЗН), 1.70 (ЗН), 2.13 (2Н), 3.39 (1Н, shipadeg From here!

SNAON), 3.80 (ZH), 5.19 (1H), 6.86 (1H), 6.99-7.20 (4H), 7.39 (1H), 7.70 (1H). « 5-(2,5-dihydroxy-b-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-isoquin - c olin-1- 7Omg (0.147 mmol) of the previously described cyclic ether was mixed at room temperature with 1.5 ml of a 1M solution of boron tribromide in dichloromethane and stirred for five hours at room temperature.

The reaction mixture was mixed with pieces of ice. it was carefully added dropwise to a saturated solution of sodium bicarbonate, in particular to pH 8. After diluting the mixture with ethyl acetate, it was intensively stirred. After (ee) this was extracted twice with ethyl acetate, the combined organic extracts were washed with water and brine and dried (sodium sulfate). The solvent was then filtered and removed by centrifugation, and the residue was chromatographed on silica gel (mobile solvent: methanol/dichloromethane). 43.2mMg (He) (63.695) of the required compound was isolated. of them 50 7"H-NMR (300 MHz, DMSO-dv): 5 - 0.96-1.20 (6H), 1.52 (ZH), 1.68 (ZH), 1.90-2.11 ( 2H), 3.30 (1H, half of the signal under water), 5.29 (1H), 5.91 (1H), 6.00 (1H), 6.70 (1H), 6.81 (1H), 6.97 (1H), 7.05 (1H), 7.17 (1H),

I" 7.25 (1H), 7.49 (1H), 8.09 (1H), 11.20 (1H).

Example 163 5-(2,5-dihydroxy-b-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinoli n-2-one o 5-(2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-(trifluoromethyl)-pentylideneamino|-1H-quinolin-2-one

300 mg (0.903 mmol) of 2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-trifluoromethyl)-pentanal, which is described in Example 162, was reacted and treated with 5- amino-1H-quinolin-2-one, as described in the previous example. After chromatography on Riazptazvieg support, 372 mg (86.9195) of the required imine was isolated. 6o 7TN-NMR (300 MHz, DMSO-ydv): 5 - 0.90 (ZN), 1.18 (ZN), 1.40 (ZN), 1.54 (ZN), 2.15 (1H), 3 ,15 (1H), 3.29 (IN, half submerged in DMSO), 3.75 (ZH), 5.90 (1H), 6.20 (1H), 6.53 (1H), 6.64 ( 1H), 6.85-6.98 (2H), 7.13 (1), 7.22-7.36 (2H), 8.09 (1H), 11.77 (1H). 5-(2-hydroxy-b-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalene-1-ylamino)-13-quinoline-2- 120 mg (0.253 mmol) of the described imine was cyclized with titanium(M) chloride in dichloromethane as described in Example 162. After treatment and chromatography, 64.0 mg (53.695) of the required cyclic compound was obtained. "H-NMR (Z0OMHC, SOSIV): 5 - 1.10-1.30 (6H), 1.58 (ZH), 1.71 (ZH), 2.00-2.20 (2H), 3, 31 (1H), 3.80 (ZH), 4.01 (1H), 5.09 (1H), 5.25 (1H), 6.50-6.70 (ZH), 7.00-7, 12 (2H), 7.35 (1H), 8.01 (1H), 10.78 (1H). 5-(2,5-dihydroxy-b-isopropyl-4,4-dimethyl-2-(trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinol n-2-one 114 mg (0.240 mmol) of the described imine was cooled to -202C and mixed with 2.4 ml of a 1 M solution of boron tribromide in dichloromethane. was stirred for two hours at a temperature in the range of -209C to 09 and then for 30 minutes at room temperature. The reaction mixture was mixed dropwise at -20C with 70 saturated sodium bicarbonate solution to pH 8. The cooling bath was removed and the batch was vigorously stirred for 10 minutes at room temperature. After extraction with ethyl acetate, the combined organic extracts were shaken as usual. After removal of the solvent by centrifugation, 48 mg of a mixture containing a cyclic simple ether and a cyclic phenol was obtained . To obtain a homogeneous compound with a cleaved simple ether, the mixture was once again treated with 1.2 ml of boron tribromide solution, but in this case at room temperature of 72 (stirring for 3.5 hours). After the usual, already described treatment, 52.bmg (92.9965) of the required compound was obtained after chromatography on silica gel. "H-NMR (ZO0MHCz, СО50О0): 5 - 1.10-1.30 (6Н), 1.60 (ЗН), 1.72 (ЗН), 2.00-2.20 (2Н), 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-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol 1 ,1,1-trifluoro-2-KK7-fluoro-2-methylquinazolin-5-ilimino)-methyl-1-4-(3-isopropyl-2-methoxy-phenyl)-4-methyl-penta n-2-ol 1500 mg (0.451 mmol) of the aldehyde described in Example 162 was reacted to form an imine with 79.9 mg (0.451 mmol) of 7-fluoro-2-methylquinazolin-5-ylamine in xylene using titanium(IM) isopropylate. After carrying out the usual processing, 207.8 mg (93.695) of the required compound were obtained. "H-NMR (ZO0MHC, SOSIv): 5 - 0.83 (ZN), 1.20 (ZN), 1.41 (ZN), 1.62 (ZN), 2.25 (1H), 2.90 (ЗН), 3.20 (1Н), 3.68 (1Н), 3.83 (ЗН), 4.61 (1Н), 5.95 (1Н), 6.54 (1Н), 6.80 ( 1H), 6.99 (1H), 7.30-7.42 (2H), 9.30 (1H). " 20 1-(7-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl- 5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol "And 207 mg (0.422 mmol) of the imine, which is described in the previous paragraph, was cyclized from 1, 2 bml of titanium chloride (IM) in dichloromethane. According to the method described in example 162, 194.4 mg (93.595) of the required compound was isolated. 1.30 (6Н), 1.60 (ЗН), 1.75 (ЗН), 2.10-2.28 (2Н), 2.87 (ЗН), 3.33 (1Н), с 3.80 (ЗН), 4.99 (1Н), 6.09 (1Н), 6.20 (1Н), 6.54 (1Н), 6.90 (1Н), 7.06-7.19 (2Н), 9.20 (1H). (-1-(7-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2 -ol (-)-1-(7-fluoro-2-methylinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4- tetra "hydronaphthalen-2-ol" with 94 mg of the racemic compound was separated on a chiral column at the stage of a simple ether to obtain enantiomers. Zbmg of the (-)-enantiomer and C2mg of the (k)-enantiomer were isolated. 34.42 (c-1, CHZON); (g)-enantiomer: (or 31.772 (c-1, CHZON) 5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8 -dimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

Ge | 100 mg (0.20 mmol) 1-(7-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4- tetrahydron o phthalin-2-diol was subjected to a reaction with BVgz in dichloromethane, as has already been described several times. After processing and

Ge") chromatography, 18.5 mg (19.195) of the required phenol was obtained. iz 50 7TN-NMR (ZO0MHCc, СО3О0): 5 - 1.05-1.30 (6Н), 1.65 (ЗН), 1.74 (ЗН), 2.28 (2Н), 2.79 (ЗН ), 3.27 (1H), 5.30 (1H), 6.65-6.90 (2H), 6.93-7.17 (2H), 9.55 (1H).

I" (-)-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1 ,6-diol (-)-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene- 1,6-diol o The enantiomerically pure ethers described above were converted to enantiomerically pure phenols as described for the racemate. 10.4 mg (43.5) of phenol was obtained from 24.7 mg of the simple ether ((-)-enantiomer). 5.1 mg (19.695 g) of phenol was isolated from 26.7 mg of a simple ether (the (i)-enantiomer).

Example 165 60 5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1, 6-diol 1,1,1-trifluoro-2-K((7,8-difluoro-2-methylquinazoline-5-ilimino)-methyl-1-4-(3-isopropyl-2-methoxy-phenyl)-4 -methyl-pentan-2-ol 15mg (0.451mmol) of the aldehyde described in example 162 was reacted to form an imine with 88mg 65 (0.451mmol) of 7,8-difluoro-2-methylquinazolin-5-ylamine in xylene according to with titanium isopropylate (IM).After carrying out the usual work-up, 208.bmg (90.795) of the required compound was obtained.

7TH-NMR (ZO00MHz, SOSIa): 5 - 0.90 (ZN), 1.23 (ZN), 1.43 (ZN), 1.63 (ZN), 2.23 (1), 2.98 ( ЗН), 3.22 (1Н), 3.69 (1Н), 3.83 (ЗН), 4.58 (1Н), 5.99 (1Н), 6.58 (1Н), 6.88 (1Н ), 6.99 (1H), 7.39 (1H), 9.39 (1H). 1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5o-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2 -ol 208.bmg (0.409 mmol) of the imine, which is described in the previous paragraph, was cyclized from 1.23 ml of titanium chloride (IM) in dichloromethane. According to the method described in example 162, 198 mg (95.9965) of the required compound was isolated.

TN-NMR (ZO0MHC, SOSIv): 5 - 1.10-1.30 (6H), 1.63 (ZH), 1.76 (ZH), 2.09-2.25 (2H), 2.91 (ЗН), 3.32 (1Н), 3.80 (ЗН), 4.94 (1Н), 5.40 (1Н), 5.82 (1Н), 6.58 (1Н), 7.03- 7.19 (2H), 9.27 (1H). (1-(7,8-difluoro-2-methythinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-the trahydronaphthalene- 2-ol (-)-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5o-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3 ,4-t tetrahydronaphthalen-2-ol 8mg of the racemic compound was separated on a chiral column at the stage of a simple ether to obtain enantiomers. 38.1mg of (-)-enantiomer and 35.5mg of (k)-enantiomer were obtained. (--Enantiomer: (c1p --38.52 (c-1, SNZON); (t)-enantiomer: (sr 372 (s-1, SNZON) 5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl -8,8-dimethyl-6-trifluoromethyl)-5,6,7-8-tetrahydronaphthalene-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-tetrahydro onanaphthalen-2-ol was reacted with BVgz in dichloromethane, as already described several times. processing and chromatography, 33 mg (33.995) of the required phenol were obtained. "H-NMR (ZO0MHCc, СО5О0): 5 - 1.05-1.30 (6Н), 1.63 (ЗН), 1.74 (ЗН), 2 ,12 (2H), 2.83 (ZH), 3.26 (1H), 5.38 (1H), 6.73-6.90 (2H), 7.03 (1H), 9.59 (1H). c 29 (-)-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydron Ge ) naphthalene-1,6-diol (3-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-"(trifluoromethyl)-5,6, 7,8-tetrahydron aphthalene-1,6-diol

The enantiomerically pure ethers described above were converted to enantiomerically pure phenols as described for the t racemate. b, b mg (22.995) of phenol was obtained from 29.7 mg of simple ether ((-)-enantiomer. 10.7 mg (40.695) of phenol "Ж was isolated from 27.1 mg of simple ether ((-)-enantiomer).

Example 166 and 5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-av! 1,6-diol

Zo 1,1,1-trifluoro-2-(8-fluoro-2-methylquinazolin-5-ilimino)-methyl-1-4-(3-isopropyl-2-methoxy-phenyl)-4-methyl-penta so n -2-ol 15O0 mg (0.451 mmol) of the aldehyde described in Example 162 was reacted to form an imine with 79.9 mg (0.451 mmol) of 8-fluoro-2-methylquinazolin-5-ylamine in xylene using titanium(IM) isopropylate . After carrying out the usual treatment, 17 mg (79.3905) of the required compound were obtained. 37Z is "H-NMR (ZO0MHZ, SOSIv): 5 - 0.82 (ZN), 1.20 (ZN), 1.45 (ZN), 1.62 (ZN), 2.25 (1H), 3 ... .70 (1H), 6.98 (1H), 7.28-7.40 (2H), 9.48 (1H). 11-(8-fluoro-2-methylquinazolin-5-ylamino)- 6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol 176 mg (0.358 mmol) of the imine, which is described in the previous paragraph, was cyclized from 1 .1 ml of titanium chloride (IM) in dichloromethane. After carrying out the usual treatment and chromatography, as described in example 162, 147 mg (83.695) of the required compound were isolated. 1.35 (6H), 1.60 (ZH), 1.75 (ZH), 2.05-2.25 (2H), 2.93 (ZH), 3.33 (1H),

He») 3.80 (ЗН), 4.88 (1Н), 5.02 (1Н), 5.52 (1Н), 6.70 (1Н), 7.00-7.18 (2Н), 7 .49 (1H), 9.35 (1H). 5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

Ta» 5Omg (0.102 mmol) 1-(8-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4 -tetrahydron phthalin-2-ol was reacted with VViz in dichloromethane, as has already been described several times. After processing and

Chromatography gave 13.7 mg (28.295) of the required phenol. o 7TH-NMR (ZO0MHCz, СО3О0): 5 - 1.05-1.30 (6Н), 1.65 (ЗН), 1.76 (ЗН), 2.00-2.20 (2Н), 2, 88 (ZH), 3.27 (1H), 5.25 (1H), 6.77-6.94 (2H), 7.00 (1H), 7.59 (1H), 9.68 (1H) . eat) Example 167 4-(2,5-dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalene-1-ylamino)-1,3- digi 60 dro-indol-2-one 4-(2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentylideneamino|-1,3-dihydro-indole-2 250 mg (0.90 mmol) of 2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal, which is described in example 162, was reacted with 4-amino-1 . ), 1.25 (ZN), 1.46 (ZN), 1.54 (ZN), 2.20 (1H), 3.27 (1H), 3.42 (2H),

3.49 (1H), 3.84 (ZH), 4.79 (1H), 5.90 (1H), 6.68-6.82 (2H), 6.90-7.09 (ZH), 8.28 (1H). 4-(2-hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalene-1-ylamino)-1,

Z-dihydro-indol-2-one 23O0 mg (0.497 mmol) of the described imine was cyclized with titanium chloride (M) in dichloromethane, as described in example 162. After processing and chromatography, 208.Zmg (90.595) of the required cyclized compound were obtained.

TNA-NMR (Z00MHC, CO5O0): 58 - 1.10-1.30 (6H), 1.51 (ZN), 1.66 (ZN), 1.96-2.16 (2), 3.38 (ZN, located under the methanol signal), 3.79 (ZN), 5.03 (1H), 6.33 (1H), 6.49 (1H), 7.00-7.20 (ZN). 4-(2,5-dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1,3-dihydro-indole-2 5mg (0.108mmol) of the described simple ether was reacted with a solution of BVgz in dichloromethane. After the previously described treatment and chromatography, 35.bmg (73.495) of the required compound was obtained. "H-NMR (ZO0MHz, СО50О0): 5 - 1.10-1.30 (6Н), 1.61 (НН), 1.70 (НН), 1.95-2.18 (2Н), 3, 27 (1H), 3.38 (2H, located under the methanol signal), 5.01 (1H), 6.33 (1H), 6.49 (1H), 6.89 (1H), 6.95-7 ,15 (2H).

The following compounds were synthesized similarly from the corresponding aldehydes and amines.

Example 168 cis-b-chloro-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4 -tetrahydronaphthalene-2-ol 7TH-NMR (ZO0MHC, SOCIv); 5 - 1.58 (in, ЗН), 1.72 (8, ЗН), 2.14 (0, 1Н), 2.22 (d, 1Н), 2.92 (in, ЗН), 3.97 (5, ЗН), 4.91 (а, 1НН), 5.83 (а, 1Н), 6.55 (da, 1НН), 7.03 (9, 1Н), 7.23 (y, 1Н) , 9.24 (in, 1H).

Example 169 cis-1-K8-fluoro-2-methylquinazolin-5-yl)amino|-7-methoxy-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol "H-NMR (300MHC , SOSIV); 85 - 2.24-2.34 (t, 2H), 2.86 (ada, tn), 2.91 (v, ЗН), 3.12 (4da, tn), 3.63 ( in, p

ЗН), 5.00 (9, 1Н), 5.47 (а, 1НН), 6.75 (ad, 1Н), 6.79 (а, 1Н), 6.84 (в, 1Н), 7, 11 (a, 1H), 7.49 (aa, 1H), 9.35 (c, 1H). (at)

Example 170 cis-b-chloro-1-K(7,8-difluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahy ;pronaphthalene-2,5-diol " by 7TH-NMR (ZO0MHCc, СО53О0); 5 - 1.60 (v, ЗН), 1.72 (v, ЗН), 2.16 (5, 2Н), 2.84 (в, ЗН), 5.30 (з, 1Н), 6.84 (d, 1n), 6.86 (aa, 1H), 7.17 (9, 1H), 9.60 (c, 1H). "

Example 171 He cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-6-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene -2,5-diol o

TN-NMR (300 MHz, CO800); 5 - 1.61 (in, ЗН), 1.72 (in, ЗН), 2.14 (8, 2Н), 2.84 (з, ЗН), 3.98 (in, ЗН), 527 o ( 85, 1H), 6.76-6.94 (t, ЗН), 9.59 (in, 1H).

Example 172 cis-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2, 7-diol "

TN-NMR (30MHz, CO8O0); 5 - 2.16-2.35 (t, 2H), 2.81 (ada, 1H), 2.85 (z, ЗН), 3.08 (acha, 1H), 5.24 (v, 1nH) , 6.67 (da, 1n), 6.78 (a, 1n), 6.89 (aa, 1Hn), 7.02 (d, 1Hn), 7.59 (da, 1n), 9.67 ( in, 1H). o, c Example 173 "» 2-hydroxy-3-(1-phenylcyclohexyl)-2--trifluoromethyl)propanal " 12.6 g (45, Umol) ethyl 2-oxo-3-(1-phenylcyclohexyl)-propionate ( |M/09854159| and 19.0ml (133vmmol) (trifluoromethyl)-trimethylsilane in 215ml of THF were cooled to -702C and mixed with 8.bml of a 1 molar solution of tetrabutylammonium fluoride in THF. The reaction mixture was allowed to warm for 18 hours to room temperature and then poured into saturated sodium chloride solution. The mixture was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation in vacuo. After purification by silica gel chromatography

Me, (hexane/ethyl acetate 2095), obtained 13.1 g of ethyl 2-hydroxy-3-(1-phenylcyclohexyl)-2-trifluoromethyl)-propionate 20 in the form of a yellow oil. At a temperature of 02С, a solution of 3.33 g (87.7 mmol) of lithium aluminum hydride in 1733 ml of THF was added dropwise to 13.1 g (38.1 mmol) of the complex ether in 174 ml of THF, and the mixture was stirred for 16 hours at room temperature. 20 ml of a saturated solution of ammonium chloride was carefully added to the batch at a temperature of 09C, and it was intensively stirred for an additional 15 minutes. The mixture was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in vacuo. After purification by chromatography

HF) on silica gel (hexane/ethyl acetate Oo-3390), b1g received 3-(1-phenyl)-cyclohexyl)-2-"-trifluoromethyl)-propane-1,2-diol. 15.7 ml (1133 mmol) of triethylamine and, 13.8 g (V/mmol) of the pyridine - ZO complex was added to 6.1 g (20.2 mmol) of the diol in 245 ml of dichloromethane and 70 ml of DMSO in portions over 10 minutes. The mixture was stirred for 3 hours, and a saturated solution of 60 ammonium chloride was added . The mixture was stirred for another 15 minutes, the phases were separated and extracted with dichloromethane. The mixture was washed with water and dried over sodium sulfate. The solvent was removed in vacuo and after purification by silica gel chromatography (hexane/ethyl acetate, 0-3395) gave required product with quantitative yield.

TN-NMR (SOSIV): 85 - 1.17 -1.78 (t, 9H), 1.98-2.05 (t, 1H), 2.41 (a, 1), 3.46 (4, 1H), 3.66 (c, 1H), 7.18 b5 (9, 2H), 7.24 (i, 2H), 7.91 (y, 1H), 8.55 (5, 1H).

cis-2-((8-fluoro-2-methylquinazolin-5-yl)amino|-3,4-dihydro-3(trifluoromethyl)-spiroYcyclohexane-1,1(2'H)-na phthalin|-3'- ol "H-NMR (Z0OMHC, SOSIV); 5 - 1.25-1.85 (t, 9H), 1.97 (a, 1), 2.11 (9, yin), 2.68 (a, 1H), 2.91 (z, ZN), 5.084, 1H), 5.38 (a, 1H), 6.69 (aa, 1Hn), 7.18 (5, 1), 7.34 (a, 1H), 7.35 (Her, 1H), 7.47 (ad, 1H), 7.56 (y, 1H), 9.36 (c, 1H).

Example 174 cis-2-((7,8-difluoro-2-methylquinazolin-5-yl)amino|-3,4-dihydro-3trifluoromethyl)-spiro|cyclohexane-1,1(2'H )-naphthalene|- 3'-ol 7TH-NMR (ZO0MHC, SOCIv); 5 - 1.25-1.90 (t, 9H), 1.93 (y, 1H), 2.02 (y, 1H), 2.64 (4, IN), 2.89 (z, ЗН) , 70 4.99 (y, 1H), 5.66 (y, 1H), 6.54 (aa, 1), 7.18 (y, 1), 7.29 (a, 1H), 7.36 (h, 1H), 7.54 (h, 1H), 9.25 (c, 1H).

Example 175 cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2, 5-diol "NA-NMR (SO0MHC, СО53О0); 5 - 1.58 (in, ZN), 1.70 (in, ZN), 2.13 (in, 2H), 2.84 (in, ZN), 5, 28 (in, 1H), 72. 8.71-68.87 (t, ЗН), 6.99 (i, 1H), 9.59 (in, 1H).

Example 176 trans-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-b-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydrophthalene- 2,5-diol "H-NMR (30OMHC, SOSIV); 5 - 1.40 (zv, ЗН), 1.54 (в, ЗН), 2.05 (а, 1Н), 2.19 (9, 1H), 2.76 (z, ЗН), 3.57 720 (g, 1H), 4.62 (y, 1H), 5.27 (da, 1H), 6.54 (Bg, 1H), 6 .90-6.97 (t, 2H), 7.07 (ad, 1H), 9.10 (c, 1H).

Example 177 cis-5-134-Dihydro-3'hydroxy-3(trifluoromethyl)-spiro|cyclohexane-1,1(2'H)-naphthalene-4"-ylIamino)-quinol n-2(1H)-one sc 7"H-NMR (ЗООМГСц, СО3О0); 5 - 0.91 (t, 1H), 1.12 (t, ЗН), 1.89 (a, 1H), 2.44 (a, 1H), 5.29 (c, 1H), 6.51 (d, 1n), 6.67 (a, 1Hn), 6.71 (a, 1n), 6.79 (a, 1H), 7.09 (i, 1H), 7.21 (6 1H), 7.24 (a, 1H), 7.39 (I, 1H), 8.24 (a, 1n). and)

Example 178 cis-4-(8-fluoro-2-methylquinazolin-5-yl)amino|-3,4"-dihydro-3-(trifluoromethyl)-spiro|cyclopropane-1,1(2'H)-na phthalein |-3'-ol "h" H-NMR (30 MHz, CO500); 5 - 0.92-0.98 (t, 1H), 1.13-1.19 (t, ЗН), 1.98 (9, 1H), 2.40 (a, 1H), 2.85 ( in,

ЗН), 5.36 (c, 1Н), 6.81 (а, 1НН), 6.91 (ad, 1Н), 7.10 (и, 1Н), 7.23 (и, 1Н), 7, 28 (9, 1H), 7.59 (aa, 1), 9.68 (c, 1H). WITH

Example 179 (se) cis-b-chloro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene . | "c) n-2,5-diol 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-"'trifluoroethyl)-pentanal (ee) 1.0 g (3.35 mmol) ethyl -4-(3-chloro-2-methoxyphenyl)-4-methyl-2-oxovalerate and 0.96 (5.0 mmol) (pentafluoroethyl)-trimethylsilane in 7 ml of THF was mixed with 2 mg (0.67 mmol) of tetramethylammonium fluoride at a temperature of - 40 C. The mixture was stirred for 2 hours at -252 C, then ml of 1T hydrochloric acid was added to the reaction mixture and poured into water after 10 minutes. The mixture was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated - by evaporation in a vacuum. 1.44 g of ethyl 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-valerate was obtained, which was mixed in 14.5 ml. of diethyl ether at 09C with 0.22 g (5.9 mmol) of lithium aluminum hydride and stirred for 2 hours at room temperature. The batch was poured into a mixture of ice water and vigorously stirred for an additional 15 minutes. The mixture was filtered through celite, extracted several times with diethyl ether, washed (ee) with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After purification by chromatography on silica gel (hexane/ethyl acetate 0960-2095), 0.77 g of 4-(3-chloro-2-methoxyphenyl)-2-(pentafluoroethyl)-4-methyl-propane-1,2-diol was obtained. 0.84 ml (6 b, Tmmol) (22) of triethylamine and 388 mg (2.44 mmol) of the pyridine-5O3 complex were added to 0.46 bg (1.22 mmol) of diol in 9.5 ml of dichloromethane and 2.5 ml of DMSO. The mixture was stirred for 2 hours and then 388 ml (2.44 mmol) of the pyridine-5O3 complex was additionally dosed into it. After 1 hour of stirring, a saturated solution of ammonium chloride was added. The mixture was stirred for another 15 minutes, the phases were separated, and they were extracted with diethyl ether.

The mixture was washed with saturated ammonium chloride solution and dried over sodium sulfate. The solvent was removed in vacuo, and after purification by chromatography on silica gel (hexane/ethyl acetate, 30905), 357 g of product was obtained.

GF! TN-NMR (SOSIi): 5 - 1.43 (in, ZN), 1.48 (in, ZN), 2.34 (4, 1), 3.29 (a, 1H), 3.58 (in . o cis-b-chloro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2, 5-diol 60 "H-NMR (ZO0MHz, CO500); 5 - 1.61 (5, ЗН), 1.74 (in, ЗН), 2.14 (9, 1Н), 2.20 (8, 1Н ), 2.86 (c, 3H), 5.34 (85, 1H), 6.84 (y, 1H), 6.86 (aa, 1h), 7.12 (a, 1H), 7.57 (ad, 1H), 9.65 (c, 1H).

Example 180 cis-6b-chloro-1-(K7-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2 ,5-diol 55 7TH-NMR (ZO0MHC, SOSIv); 5 - 1.58 (in, ЗН), 1.72 (8, ЗН), 2.17 (0, 1Н), 2.26 (0, 1Н), 2.84 (in, ЗН), 3.95

(5, ZN), 5.05 (9, 1H), 6.07 (4, 1H), 6.51 (yes, 1n), 6.91 (yes, 1n), 7.04 (a, 1n) , 7.18 (a, 1H), 9.17 (c, 1H).

Example 181 trans-6b-chloro-1-(7-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2 ,5-diol 7TH-NMR (ZO0MHCc, СО5300); 5 - 1.45 (in, ЗН), 1.61 (in, ЗН), 2.29 (4, 1Н), 2.37 (4, 1Н), 2.74 (з, ЗН), 3.65 (5, ZN), 5.58 (c, 1H), 6.83 (ad, 1H), 6.98 (ad, 1H), 7.30 (aa, 1H), 7.42 (d, 1H) , 9.52 (in, 1H).

Example 182 cis-5-6-chloro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-x 70. inolin- 2(1H)-one "H-NMR (Z0OMHC, SOSIV); 5 - 1.55 (8, ЗН), 1.72 (в, ЗН), 2.07 (y, 1Н), 2.20 (9 , yin), 3.96 (z, ZN), 5.12 (d, 1H), 5.46 (Bg, 1H), 5.81 (a, 1H), 6.44-6.53 (t, ЗН), 6.95 (а, 1Н), 7.06 (j, 1Н), 7.32 (и, 1Н), 8.28 (d, 1Н), 9.92 (c, 1Н).

Example 183 cis-5-X2,5-dihydroxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinolin-2(1H)-one 7TH-NMR (ZO0MHC, SOSIv); 5 - 1.58 (in, 3H), 1.76 (in, 3H), 2.08 (a, 1H), 2.24 (a, 1H), 2.63 (in, 1H), 5.11 (d, 71), 5.54 (c, 1H), 5.85 (j, 1H), 5.97 (c, 1H), 642 (a, tn), 6.49 (a, yin), 6 .49 (a, tn), 6.52 (a, tn), 7.60 (aa, 1H), 7.31 (her, 1H), 8.31 (a, 1H), 9.77 (c, 1H).

Example 184 cis-7-Fluoro-4-((8-fluoro-2-methylquinazolin-5-yl)amino|-3,4-dihydro-8'-methoxy-3-(trifluoromethyl)-spiroYcyclohexan-1,1 (2'H)-naphthalene-3'-ol 3-(1-(33-fluoro-2-methoxyphenyl)-cyclohexyl|-2-hydroxy-2--trifluoromethyl)propanal

385 mg of a 0.5 molar (182 mmol) solution of potassium bis-(trimethylsilyl)-amide in toluene was added dropwise to 26.5 g (1 in 84 mmol) of 2,6-difluoroanisole and 24 mL (198 mmol) of cyclohexylcyanide in 5 mL of toluene at a temperature of 02 for 40 minutes. The mixture was stirred for 18 hours at room temperature and mixed with water, at which time it was cooled on ice, and the pH of the solution was adjusted to 4 with 4N. of hydrochloric acid.

The organic phase was separated, and the aqueous phase was extracted several times with diethyl ether. it was washed with saline, dried over sodium sulfate, and concentrated by evaporation in vacuo.

After purification by chromatography on silica gel (hexane/ethyl acetate 5950-1095), 28.5 g of 3o 1-(3-fluoro-2-methoxyphenyl)-cyclohexylnitrile were obtained. 27.5 g (118 mmol) of nitrile was slowly mixed in 430 ml of toluene at a temperature of -7892C with 147 ml (17 mmol) of diisobutylaluminum hydride solution (2095 in toluene), and after 3 s hours at -782C, 35 ml of isopropanol was added dropwise. The mixture was allowed to warm up to -5 C, and bOOml of a 10 9% aqueous solution of tartaric acid was added. After diluting with ether, the mixture was stirred intensively ("in"), the organic phase was separated, and the aqueous phase was extracted several times with ethyl acetate. It was washed with saline, dried over sodium sulfate, and concentrated by evaporation in vacuo. 27.5 g of aldehyde was obtained in the form of a yellow oil. A solution of 5.7 g (21.2 mmol) of 2-diethylphosphono-2-ethoxyacetic acid ethyl ether in 25 ml of tetrahydrofuran was mixed, at this time it was cooled on ice, for 15 minutes with 13.b ml (27.2 mmol) of a 2 M solution of lithium isopropylamide. in « 20 tetrahydrofuran-heptane-toluene, and the mixture was stirred for 20 minutes at a temperature of 02С. A solution of 5 g (21.2 mmol) of 1-(33-fluoro-2-methoxyphenyl)-cyclohexylformanal in bml of tetrahydrofuran at 02С was added dropwise over 30 seconds. After 16 hours at room temperature, ice was added to the water, and the mixture several;" times extracted with simple ether. it was washed with saturated ammonium chloride solution, dried over sodium sulfate, and concentrated by evaporation. The crude product was saponified with sodium hydroxide solution

OOml of ethanol and 5Oml of water for 4 days at room temperature. 1.7 g of acid was obtained, which

Go) was stirred for 30 hours at 9029 with Zbml 2n. of sulfuric acid and 7 ml of acetic acid. After cooling, it was alkalized with potassium carbonate, washed with ether and acidified with hydrochloric acid. After extraction with ethyl acetate, washing with saturated sodium chloride solution and removal

Ge") of the solvent, 1.09 g of crude keto acid was obtained. 1.09 g (3.7 mmol) of 50. 33-(1-(3-fluoro-2-methoxyphenyl)-cyclopropyl|-2-oxopropionic acid and 0.45 ml of sulfuric acid (96905) were heated in a reflux flask in 4 Oml of ethanol for 2 hours.The batch was concentrated by

GT" evaporation in a vacuum, the residue was added to a mixture of water and ice and alkalized using a saturated solution of sodium bicarbonate. The mixture was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in a vacuum. After cleaning for

1.05 g of ethyl 3-(1-(3-fluoro-2-methoxyphenyl)-cyclopropyl)|-2-oxopropionate was obtained by chromatography on silica gel (hexane/ethyl acetate 20905).

F, 1.05 g (3.3 mmol) of ethyl 3-(1-(3-fluoro-2-methoxyphenyl)-cyclohexyl|-2-oxopropionate and 0.74 ml (Bbmmol) of (trifluoromethyl)-trimethylsilane were mixed in 7 ml of THF with b2mg of tetramethylammonium fluoride at a temperature of -402C. The mixture was stirred for 2 hours at -259C, and then 0.35ml (2.4mmol) of bo(trifluoromethyl)-trimethylsilane and b2mg of tetramethylammonium fluoride were additionally added. After another 2 hours, 2n ml was added. hydrochloric acid, and the reaction mixture was added to water. It was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation in vacuo. After purification by silica gel chromatography (hexane/Oethyl acetate 1095-4096), 800 mg of ethyl 3-(1-(3-fluoro-2-methoxyphenyl)-cyclopropyl|-2-hydroxy-2--trifluoromethyl)-propionate was obtained. In the form of a yellow oil. This oil was mixed in 40 ml of diethyl ether at a temperature of 09C with 150 g (4 mmol) of lithium aluminum hydride and stirred for more than 2.5 hours at room temperature. 20 ml of a saturated solution of ammonium chloride was carefully added to the batch at a temperature of 02C, and it was intensively stirred for 15 minutes. The mixture was extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum.

After purification by chromatography on silica gel (hexane/ethyl acetate 1095-1595), 630 g of 3-11-(3-fluoro-2-methoxyphenyl)-cyclopropyl|-2-(trifluoromethyl)-propane-1,2-diol was obtained. "H-NMR (SOSIV): 5 - 1.44-1.87 (t, TON), 2.19-2.38 (t, 4H), 3.15-3.42 (g, 2H), 3 .96 (z, 3H), 6.9 (aa, 1H), 7.01 (a, 1), 7.16 (dach, 1n). 1.b6ml (11mmol) of triethylamine and, in portions over 10 minutes, was added 1.4 g (/Omol) of the pyridine complex - 70.5 oz to 700 mg (2 mmol) of diol in 20 ml of dichloromethane and 7.adml of DMSO. The mixture was stirred for 3 hours, and a saturated solution of ammonium chloride was added. The mixture was stirred for another 15 minutes, the phases were separated , and extracted with dichloromethane. The mixture was washed with water and dried over sodium sulfate. The solvent was removed in vacuo to give the desired aldehyde in quantitative yield. cis-7-Fluoro-4-((8-fluoro-2-methylquinazolin-5-yl) amino|-3,4"-dihydro-8'-methoxy-3-"-trifluoromethyl)-spiroYcyclo 75 hexane-1,1(2'H)-naphthalene|-3'-ol "H-NMR (30OMHC, SOSIV ); 5 - 1.25-1.85 (t, 8H), 2.00 (4, 1), 2.44 (dach, yin), 2.64 (acha, yin), 2.91 (zv,

ZN), 2.92 (a, 1), 4.00 (c, ZN), 4.96 (a, 1H), 5.41 (a, yin), 6.66 (aa, yin), 6, 93 (da, yin), 7.04 (aa, tn), 7.47 (aa, 1), 9.34 (c, 1H).

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 7TH-NMR (ZO00MHCz, CO3O0); 5 - 1.22-1.85 (t, 8H), 2.03 (0, 1), 2.82 (ada ) , 7.56 (yes, 1H), 9.65 (in, 1H).

Example 186 p 29 cis-7-Fluoro-4-((7-fluoro-2-methylquinazolin-5-yl)amino|-3,4-dihydro-8'-methoxy-3-(trifluoromethyl)-spiroYcyl He)oxane -1,1(2'H)-naphthalene|-3'-ol "H-NMR (ZO0MHC, SOCIv); 5 - 1.25-1.90 (t, TON), 2.17 (9, 1H) , 2.34 (4, 1Н), 2.80 (в, ЗН), 3.56 (в, ЗН), 4.59 (а, 1Н), 5.33 (а, 1Н), 6.91 ( aa, 1H), 7.00 (aa, 1H), 7.10 (ad, 1H), 7.17 (da, 1H), 9.03 (c, 1H).

Example 187 cis-5-(7-Fluoro-34"-dihydro-3-hydroxy-8'-methoxy-3-(trifluoromethyl)-spiro|cyclohexane-1,1(2'"H)-naphthalene « -4- yl|amino)-quinoline-2(1H)-one "so" H-NMR (30OMHC, SOSIV); 5 - 1.25-1.90 (t, 8H), 2.09 (4, 1), 2 .41 (ada, yin), 2.60 (aad, yin), 2.90 (49, 1H), 3.99 (v, ЗН), 4.85 (v, 1H), 5.00 (a, 1H), 5.67 (a, yin), 6.48-6.55 (t, ЗН), 6.83 (aa, tn), 6.96 (aa, tn), o 7.31 (y, 1H), 8.22 (y, 1H), 9.79 (v, 1H). so

Example 188 cis-6b-chloro-1-(7-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-I(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene 2,5-diol «

TN-NMR (Z00MHZ, СО50О0); 5 - 1.61 (v, ЗН), 1.74 (z, ЗН), 2.18 (v, 2Н), 2.79 (v, ЗН), 5.42 (в, 1Н), 6.76 -6.82 (t, ЗН), 7.15 (a, 1Н), 9.54 (c, 1Н). - c Example 189 "with cis-b-chloro-1-(2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2, 5-d "iol" H-NMR (30 MHz, CO500); ЗН), 5.40 (c, 1Н), 6.84 (а, 1Н), 6.95 (А, 1Н), 7.10 (а, 1Н), 7.20 (а, 1Н), 7, 79 (i, 1H), 9.62 (c, 1H). so Example 190 o cis-5-(7-Chloro-3,4-dihydro-3',8'-dihydroxy-3(trifluoromethyl)-spiro-cyclohexane- 1,1(2'H)-naphthalene-4"-yl-aminoI-quinolin-2(1H)-one b"H-NMR (30 MHz, CO500); 5 - 1.25-1.90 (t, 8H ), 2.02 (a, yin), 2.80 (aad, tn), 2.91 (4, yin), 3.05 (avda, t» 50 1H)U, 5.12 (a, 1H) , 5.51 (a, 1Hn), 6.59 (a, 1H), 6.69 (y, 1H), 6.81 (ad, 1H), 6.986 (ad, 1H), 7.37 (Her, 1H), 8.23 (y, 1Hn).

I» Example 191 cis-b-fluoro-1-((8-fluoro-2-methylquinazolin-5-yl)amino|-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3 ... -fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate 0.98 g (5.1 mmol)

HF) (pentafluoroethyl)-trimethylsilane in /ml of THF was mixed with 5 mg (0./mmol) of tetramethylammonium fluoride at a temperature of -402C. The reaction mixture was heated to -259C and stirred at this temperature. After 4.5 hours, iml 2n was added. of hydrochloric acid, and the reaction mixture was added to water. The mixture was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation in vacuo. 1.65 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate was obtained as a crude product.

The complex ether was mixed in 8Oml of diethyl ether at a temperature of 02C with 30Oml (mmol) of lithium aluminum hydride and stirred for more than 3.5 hours at room temperature. A small amount of water at a temperature of 09C was carefully added to the batch, and the mixture was intensively stirred for an additional 15 minutes. It was filtered through celite, and the precipitate was again thoroughly washed with ethyl acetate. The filtrate was dried over sodium sulfate and concentrated by evaporation in vacuo. After purification by silica gel chromatography (hexane/ethyl acetate 1095-1590), 80mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol was obtained. 1.8 ml (13 mmol) of triethylamine and, in portions over 10 minutes, 1.6 mg (10 mmol) of the pyridine - ZO complex were added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 U ml of DMSO. The mixture was stirred for 2.5 hours, and a saturated solution of ammonium chloride was added. The mixture was stirred for another 15 minutes, the phases were separated, and they were extracted with dichloromethane.

The mixture was washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and the required aldehyde was obtained in quantitative yield.

TN-NMR (SOSIV): 5 - 1.40 (z, ZN), 1.46 (v, ZN), 2.35 (d, 1H), 3.28 (a, 1H), 3.60 (z . cis-b-fluoro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene -2-ol "H-NMR (30OMHC, SOSIV); 5 - 1.55 (z, ЗН), 1.69 (в, ЗН), 2.13 (а, 1Н), 2.20 (9, 1Н ), 2.92 (z, ЗН), 3.97 75 (в, ЗН), 5.08 (y, 1Н), 5.41 (а, 1Н), 6.70 (aa, 1н), 6, 90 (aa, 1H), 7.00 (aa, tn), 7.48 (aa, 1H), 9.33 (c, 1H).

Example 192 cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino-b-fluoro-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4- tet raghydronaphthalene-2-ol 7TH-NMR (ZO0MHCc, СО3О0); 5 - 1.55 (in, ZN), 1.68 (5, ZN), 2.14 (4, 1), 2.21 (4, 1H), 2.84 (z, ZN), 3.97 (v, 3H), 5.39 (v, 1H), 6.88 (44, 1H), 6.98 (44, 1H), 7.03 (aa, 1H), 9.59 (v, 1H) .

Example 193 cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-6b-fluoro-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene- 2,5-diol "H-NMR (30OMHC, SOSIV); 5 - 1.61 (8, ЗН), 1.72 (в, ЗН), 2.15 (а, 1Н), 2.22 (9, 1H), 2.91 (z, ЗН), 5.00 s (d, 1H), 5.61 (rg, 1H), 5.71 (a, 1Hn), 6.56 (ad, 1nH), 6 .83 (ad, 1H), 6.92 (ad, 1H), 9.24 (c, 1H). o

Example 194 cis-5-6b-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-xinolin- 2(1H)-one " by TN-NMR (ZO00MHC, SOSIv); 5 - 1.54 (in, NL), 1.69 (in, NL), 2.07 (a, IN), 2.17 (а, IN), 3.97 (in, NL), 4.58 (p, 1H), 5.10 (a, 1n), 545 (a, tn), 6.52-6.56 (t, ЗН), 6.83 (ad, 1H), 6.94 (aa, 1), 7.34 (B 1), 8.12 (a, - 1H), 10.11 (c, 1H). "at

Example 195 cis-b-fluoro-1-((8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene o n -2,5-diol co 7TH-NMR (ZO0MHC, SOCIv); 5 - 1.61 (in, ЗН), 1.72 (8, ЗН), 2.15 (0, 1Н), 2.23 (d . .85 (aa, 1nH), 6.90 (aa, 1H), 7.48 (ad, 1H), 9.33 (c, 1H).

Example 196 "cis-2-(7,8-difluoro-2-methylquinazolin-5-yl)amino|-7-fluoro-34-dihydro-8'-methoxy-3-(trifluoromethyl)-spiro cyclopropane-1,1 (2'H)-naphthalene|-3'-ol - s Ethyl-3-(1-(3-fluoro-2-methoxyphenyl)-cyclopropyl|-2-oxopropionate c ZO9bml 0.5 molar (198 mmol) solution of bis- "Potassium (trimethylsilyl)-amide in toluene was added dropwise under 02 over 40 minutes to 26 g (180 mmol) of 2,6-difluoroanisole and 14.bml (198 mmol) of cyclopropyl cyanide in 500 ml of toluene. The mixture was stirred for 18 hours at room temperature and was mixed with water and 1M sulfuric acid while cooling on ice. The organic phase was separated and the aqueous phase was extracted several times (ee) with ethyl acetate. It was washed with brine, dried over sodium sulfate, and concentrated by evaporation in vacuo. After purification by chromatography on silica gel (hexane/ethyl acetate 1095-2090), 12.7 g of 1-(3-fluoro-2-methoxyphenyl)-cyclopropylnitrile were obtained. 12.7 g (o) (66.1 mmol) of nitrile were slowly mixed in t of toluene at a temperature of -782 with 82.7 ml (99.2 mmol) of a solution of isobutylaluminum hydride (2095 in toluene), and after 3 hours at -782C, 11.1 ml of isopropanol was added dropwise. The mixture was allowed to warm up to -59C, and 150 ml of a 1095% aqueous solution of tartaric acid was added. After breeding

T" simple ether, the mixture was intensively stirred, the organic phase was separated, and the aqueous phase was extracted several times with ethyl acetate. it was washed with saline, dried over sodium sulfate, and concentrated by evaporation in vacuo. 11.8 g of aldehyde was obtained in the form of a yellow oil. Solution 22 16.3 g (60.7 mmol) of 2-diethylphosphono-2-ethoxyacetic acid ethyl ether in bOml of tetrahydrofuran

HF) was mixed, during this time it was cooled on ice, for 20 minutes with 333.4 ml (66.8 mmol) of a 2M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene and stirred for 30 minutes at a temperature of 02С. During 30 minutes, a solution of 11.8 g (60.7 mmol) in 2 ml of tetrahydrofuran at 0 260 was added dropwise.

After 20 hours at room temperature, ice was added to the water, and the mixture was extracted several times with ether and ethyl acetate. It was washed with saturated ammonium chloride solution, dried over sodium sulfate and concentrated by evaporation. The crude product was saponified with 170ml of a 2M solution of sodium hydroxide in 17Oml of ethanol for 15 hours at room temperature. 13.9 g of acid was obtained, which was mixed with 87 ml of 2N. of sulfuric acid at a temperature of 9027 for 16 hours. After cooling, it was alkalized with potassium carbonate, washed with ether and acidified with hydrochloric acid. After extraction with ethyl acetate, washing with a saturated solution of sodium chloride and removal of the solvent, 10.2 g of crude keto acid was obtained. 10.2 g (40.bmmol) of 3-(1-(3-fluoro-2-methoxyphenyl)-cyclopropyl|-2-oxopropionic acid and 4.5 ml (85.3 mmol) of sulfuric acid (9695) were heated in a reflux flask in 200 ml of ethanol for 1 hour.The batch was concentrated by evaporation in vacuo, the residue was added to the mixture

WATER With ice and basted with saturated sodium bicarbonate solution. The mixture was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in a vacuum. After purification by chromatography on silica gel (hexane/ethyl acetate 20965), 9.bg of ethyl 3-(1-(3-fluoro-2-methoxyphenyl)-cyclopropyl|-2-oxopropionate was obtained. "H-NMR (SOSIV): 85 - 0.90 (t, 4H), 1.29 (Ii, ЗН), 3.09 (в, 2Н), 3.99 (4, ЗН), 4.20 (4, 2), 6.87 (acha, tn), 70 6.95 (davd, 1nH), 7.07 (9, 1H), 9.26, 3-(1-(3Z-fluoro-2-methoxyphenyl)-cyclopropyl|-2-hydroxy -2-trifluoromethyl)propanal 9.bg (34.3mmol) ethyl 3-(1-(3-fluoro-2-methoxyphenyl)-cyclopropyl|-2-oxopropionate and 34.bg 5mMl (2333mmol) (trifluoromethyl)-trimethylsilane in 343 ml of DMF was mixed with 46.9 g of cesium carbonate at a temperature of 0 2. The mixture was stirred for 2 hours at 0 2 and then the reaction solution was added to water. The mixture was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in vacuo After purification by chromatography on silica gel (hexane/ethyl acetate 1095-4090), 10.4 g of ethyl-3-(1-(3-fluoro-2-methoxyphenyl)- cyclopropyl ()-2-hydroxy-2-(trifluoromethyl)-propionate as a yellow oil. This oil was mixed with 2.25 g (59.4 mmol) of lithium aluminum hydride in 297 ml of diethyl ether at a temperature of 09С and stirred for another hour at room temperature. 20 ml of a saturated solution of ammonium chloride was carefully added to the batch at a temperature of 09C, and the mixture was intensively stirred for an additional 15 minutes. it was extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After purification by chromatography on silica gel (hexane/ethyl acetate 1095-5095), 5 g of 3-(1-(3-fluoro-2-methoxyphenyl)-cyclopropyl|-2-(trifluoromethyl)-propane-1,2-diol was obtained 12 4 ml (VOUmmol) g) of triethylamine and, in portions over 10 minutes, 11 g (/Ommol) of the pyridine/ZO complex were added to 5.6 bg (18.1 mmol) of diol in 100 ml of dichloromethane and 2 ml of DMSO. The mixture was stirred for 3 hours, and a saturated solution of ammonium chloride was added. The mixture was stirred for another 15 minutes, the phases were separated, and they were extracted with dichloromethane. The mixture was washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and after purification by chromatography on silica gel (hexane/ethyl acetate, 0-5096), 5.9 g of product was obtained. 7"H-NMR (SOSIV): 5 - 0.68-0.76 (t, 2H), 0.90-1.02 (t, 2), 2.03 (4, 1H), 2.91 ( a, 1H), 3.85 (c, 1H), 4.03 i-th (5, ЗН), 6.80 (y, 1H), 6.87 (davd, 1H), 6.98 (ad, 1H), 9.26 (in, 1H). -3-(trifluoromethyl)-spiro cyclopropan-1,1(2'H)-naphthalene|-3'-ol 09

TN-NMR (30MHz, CO5O0); 5 - 0.83 (dai, 1), 0.99 (ada, 1H), 1.42 (ada, yin), 1.89 (ada, 1), 2.01 (a, 1H), 2.15 (y, 1Н), 2.84 (5, ЗН), 3.85 (в, ЗН), 5.19 (в, 1Н), 6.65 (ad, 1Н), 6.96 (ad, 1Н) , 7.04 (ad, 1H), 9.63 (in, 1H).

Example 197 "20 cis-7-Fluoro-34'-dihydro-8'-methoxy-2-(2-methylquinazolin-5-yl)amino|-3'(trifluoromethyl)-spirocyclopropane with c -1, (2'H )-naphthalene|-3'-ol . "H-NMR (Z00MHC, SOSIv); 5 - 0.82 (adcha, tn), 1.00 (aad, yin), 1.54 (ada, yin), 1.86 (aaa, yin), 1, 91 (а, "» 1Н), 2.32 (0, 71), 2.84 (85, ЗН), 3.87 (в, ЗН), 5.08 (а, тн), 5.78 (а , tn), 6.67 (a, 1n), 6.88 (ad, tn), 7.05 (aa, 1n), 7.28 (a, 1), 7.70 (i, 1H), 9 ,36 (in, 1H).

Example 198

Ge | cis-7-Fluoro-34-dihydro-4-|((2-methylquinazolin-5-yl)amino|-3i(trifluoromethyl)-spiro|cyclopropane-1,1(2'H)-naphthalene-3,8' -diol o "H-NMR (30 MHz, CO500); 5 - 0.67 (aa, tn), 0.90 (adcha, tn), 1.77 (adcha, yin), 1.93 (a, yin) , 2.12 (avda, (o) 1H), 2.21 (9, 1H), 2.81 (v, 3H), 5.28 (8, 1H), 6.75-6.88 ( 3H), 7.18 (a, 1H), 7.78 (Hii, 1H), 9.65 (c, 1H). their 50 Example 199 cis-2-((7,8-difluoro-2-methylquinazoline- 5-yl)amino|-7-fluoro-3-4-dihydro-3(trifluoromethyl)-spiroYcyclopropane

I»-1,1(2'H)-naphthalene|-3,8'-diol 7TH-NMR (ZO0MHC, SOCIv); 5 - 0.71 (dad, yin), 0.91 (ada, yin), 1.81 (4, 1H), 1.83-2.00 (t, 2H), 2.39 (4, 1H) . 9.28 (c, 1H). 99 Example 200

HF) cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-5-fluoro-b-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4 -tetrahydronaphthalen-2-ol by "H-NMR (SO0MHCc, CO500); 5 - 1.53 (in, 3H), 1.65 (in, 3H), 2.17 (in, 2H), 2.84 (z, ЗН), 3.85 (в, ЗН), 5.32 (5, 1Н), 6.87 (ad, 1Нн), 6.95 (ad, 1Н), 7.07 (а, 1Н) , 9.61 (in, 1H). bo Example 201 cis-1-K7,8-difluoro-2-methylquinazolin-5-yl)amino|-5-fluoro-4,4-dimethyl-2-(trifluoromethyl)- 1,2,3,4-tetrahydronaphthalene-2,6-diol "H-NMR (Z00MGCs, CO500); 5 - 1.54 (in, ZN), 1.66 (in, ZN), 2.16 (in, 2H), 2.84 (z, ZN), 3.98 (in, ZN), 5.29 65 (5, 1H), 6.78 (ad, 1H), 6.86 (ad, 1H), 6.94 (ad, 1H), 9.60 (c, 1H).

Example 202 cis-7-Fluoro-4-|((8-fluoro-2-methylquinazolin-5-yl)amino|-3'4-dihydro-3(trifluoromethyl)-spiroYcyclopropane-1,1 (2'H)- naphthalene)-3",8'-diol "H-NMR (Z0OMHC, SOSIV); 5 - 0.71 (aaYa, yin), 0.93 (ada, tn), 1.79 (4, 1H), 1.90-2.06 (t, 2H), 2.39 (49, 1H) , 2.91 (v, ZN), 3.80 (rg, 1H), 5.05 (4, 1), 5.39 (a, 1), 5.48 (Bbg, 71H), 6.65 aa, tn), 6.80-6.90 (t, 2H), 7.46 (aa, 1H), 9.35 (c, 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" H-NMR (ZO0MHC, SOCIv); 5 - 1.20-2.10 (t, TON), 2.10 (9, 1), 2.47 ( a, 1H), 2.68 (z, ЗН), 4.66 (a, 1H), 5.33 (4, 1H), 6.91 (a, 2H), 7.03 (da, 1n), 7.10 (ad, 1n), 9.01 (c, 1H).

Example 204 cis-b-chloro-5-methoxy-1-((2-methylquinolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene 2-ol 7TH-NMR (ZO0MHCz, СО3О0); 5 - 1.56 (in, ЗН), 1.69 (in, ЗН), 2.16 (5, 2Н), 2.72 (in, ЗН), 3.97 (z, ЗН), 5.25 (5, 1Н), 6.82 (а, 1Н), 7.11 (а, 1н), 7.20 (а, 1), 7.32 (а , 1Hn), 7.36 (9, 1H), 7.55 (i, 1H), 8.45 (a, 1H).

Example 205 cis-b-chloro-1-(2-methylquinolin-5-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol "H - NMR (30 MHz, CO500); c, ЗН), 523,720 (5, 1Н), 6.82 (а, 1Н), 6.87 (а, 1), 7.11 (а, 1н), 7.31 (а, 1н), 7 .35 (d, 1H), 7.55 (i, 1H), 8.45 (a, 1H).

Example 206 cis-1-(2-methyl-1-quinolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol-M- oxide "H-NMR (ZO0MHCc, СО500); 5 - 1.44 (in, ЗН), 1.58 (in, НН), 2.19 (in, 2Н), 2.76 (з, НН), 5 ... 2H), 7.71 (B, 1H), 7.96 (y, 1H), 8.29 (a, 1H).

Example 207 (8) cis-b-chloro-1-(2-methylquinolin-5-yl)amino)|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2, 5-diol

M-oxide 75 mg of 7tO96-nium meta-chloroperbenzoic acid was added to 84 mg (0.19 mmol) of cis-6b-chloro-1-(2-methylquinolin-5-yl)amino)-4,4-dimethyl-2- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol.- in ml of dichloromethane, and the solution was stirred for two hours. 5mg of solid sodium bicarbonate was added, and the mixture was poured into water after 30 minutes. it was extracted with dichloromethane, washed with saturated sodium chloride solution, and dried over sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 0-10095), 58 mg of the title compound was obtained.

TN-NMR (300 MHz, CO800); 5 - 1.61 (in, ЗН), 1.73 (in, ЗН), 2.13 (0, 1Н), 2.18 (а, 1), 2.75 (in, ЗН), 5.30 so (5, 1H), 6.85 (a, 1H), 7.01 (a, 1), 7.13 (a, 1H), 7.48 (a, 1n), 7.70 (i, 1H ), 7.96 (a, 1H), 8.27 (a, 1Hn).

Example 208 cis-6-(2-methyl-quinolin-5-yl)amino|-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphthoic|1,2-a41- 1,3-diox "ol-7-ol M-oxoxide" H-NMR (30OMHC, SOSIV); 5 - 1.49 (zv, ZN), 1.58 (v, ZN), 2.06 (a, 1H), 2.20 (9, 1H), 2.61 (z, ЗН), 5.08 - s (0, 1), 5.62 (y, tn), 5.99 (v, 2H), 6.64 (a, yin), 6.83 (a, 71n), 685 (a, 1), 7.13 (a, 1), 7.55 (i, tn), "» 7.96 (a , 1n), 8.03 (a, 1Нn). Example 209 cis-7-Fluoro-4-|((7-fluoro-2-methylquinazolin-5-yl)amino|-3'4-dihydro-3(trifluoromethyl)-spiroYcyclopropane-1, 1 (2'H) -naphthalene|-3,8-diol

Co TN-NMR (30MHz, CO5O0); 5 - 0.66 (give, 1H), 0.89 (ada, yin), 1.86 (ada, yin), 1.93 (a, 1H), 2.10 (ada, av! 1H), 2 ,22 (9, 2H), 2.78 (v, ЗН), 5.26 (v, 1H), 6.67 (ad, 1H), 6.75-6.82 (t, 2H), 6, 87 (ad, 1H), 9.58 (8, 1H).

Example 210 b cis-5-17-Fluoro-3,4-dihydro-3,8'-dihydroxy-3(trifluoromethyl)-spiro(cyclopropane-1,1(2'H)-naphthalen-4-yl "iz" 20 1-amino)-quinolin-2(1H)-one

T» "H-NMR (ZO0MHz, CO5O0); 5 - 0.66 (ada, tn), 0.90 (adcha, tn), 1.71 (adcha, yin), 1.88 (a, tn), 2.09 (avda, 1H), 2.20 (9, 2H), 5.15 (c, 1H), 6.51-6.54 (t, 2H), 6.70 (a, 1Hn), 6 .79 (ad, 1H), 6.85 (ad, 1H), 7.36 (Her, 1H), 8.25 (4, 1Hn).

Example 211 cis-7-Chloro-4-Y(7-fluoro-2-methylquinazolin-5-yl)lamino|-3'4-dihydro-3(trifluoromethyl)-spiro|cyclopropane-1,1 (2'H) -naphthalene|-3',8'-diol (F. "H-NMR (ZO00MHC, SOCIv); 85 - 0.70 (adcha, yin), 0.91 (aad, yin), 1.70 (ada, tn), 1.77 (94, 1Hn), 2.08 (avda, ka 1H), 2.44 (y, yin), 2.82 (v, ЗН), 5.06 (y, 1H) 5, 77 (c, 1H), 5.88 (y, 1H), 6.44 (aa, yn), 6.88 (a, tn), 6.91 (aa, 1H), 7.13 (9, 1H ), 9.23 (in, 1H). in Example 212 cis-7-Chloro-34"-dihydro---((2-methylquinolin-5-yl)amino|-3i(trifluoromethyl)-spiro|cyclopropane-1 ,1(2'"H)-na phthalin)|-3,8'-diol

TN-NMR (30MHz, CO5O0); 5 - 0.68 (dai, 1), 0.91 (ada, yin), 1.69 (ada, yin), 1.91 (a, 1H), 2.11 (avda, 13, 2.22 ( a, 1), 2.72 (8, ZN), 5.20 (c, 1H), 6.70 (a, yin), 6.78-6.85 (t, 2H), 7.30 (a , 1), 7.36 (a, MH), 65 7.53 (I, 1H), 8.47 (y, 1H).

Example 213 cis-7-Chloro-34"-dihydro--2-((2-methyl-quinolin-5-yl)amino|-3'"trifluoromethyl)-spiroYcyclopropane-1,1'(2'H)-n naphthalene (|-3,8'-diol. M-oxide "H-NMR (ZO0MHz, CO500); 5 - 0.67 (aa, tn), 0.91 (adcha, tn), 1.74 (adcha, yin), 1.91 (a, tn), 2.10 (avda, 1H), 2.23 (0, 1H), 2.75 (v, ЗН), 5.25 (v, 1H), 6, 78 (ad, tn), 6.84 (aa, yin), 6.90 (a, tn), 7.49 (a, 1n), 7.69 (B tn), 7.95 (a, 1n) , 8.30 (a, 1n).

Example 214 cis-7-Chloro-2-(7-fluoro-2-methylquinazolin-5-yl)amino!|-3,4-dihydro-8'-methoxy-3(trifluoromethyl)-spiro|dicyclohexane-1, 1(2'H)-naphthalene|-3'-ol "H-NMR (30OMHC, SOSIV); 5 - 1.20-1.85 (t, 8H), 2.05 (9, 1), 2, 44 (dach, yin), 2.63 (aCha, yin), 2.82 (in,

ZN), 2.97 (a, 1H), 4.00 (c, ZN), 4.95 (a, 1), 5.92 (a, tn), 6.49 (aa, tn), 6, 91 (aa, yin), 7.04 (a, tn), 7.22 (d, 1H), 9.16 (c, 1H).

Example 215 cis-7-Chloro-2-(7-fluoro-2-methylquinazolin-5-yl)amino!|-3,4"-dihydro-3(trifluoromethyl)-spiroYcyclohexane-1,1" 15. (2' H)-naphthalene)|-3,8'-diol

TN-NMR (ZO0MHC, SOSIv); 5 - 1.25-1.85 (t, 8H), 1.86 (4, 1H), 2.79 (dacha, tn), 2.82 (z, ЗН), 2.93 (ada, 1H) , 2.97 (y, 1Hn), 4.95 (y, 1H), 5.85 (y, 1H), 6.14 (v, 1H), 6.48 (ad, 1H), 6.89- 6.93 (t, 2H), 7.19 (j, 1H), 9.19 (c, 1H).

Example 216 cis-7-Chloro-34-dihydro-4-|((2-methylquinazolin-5-yl)amino|-3'trifluoromethyl)-spiroYcyclopropane-1,1(2'H)-naphthalene-3,8' -diol "H-NMR (ZO0MHz, CO5O0); 5 - 0.69 (ada, tn), 0.92 (adcha, tn), 1.71 (adcha, yin), 1.95 (a, tn), 2.13 (avda, 1H), 2.20 (9, 1H), 2.81 (c, ЗН), 5.29 (c, 1H), 6.85 (a, 2H), 7.10 (a , 1), 7.19 (d, 1H), 7.78 (i, 1H), 9.65 (a, 1H).

Example 217 (-)-2-chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1, b-diol and cm (-)-2-chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-"(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1, 6-diol (o) (-)-6-chloro-1-(1H-indazol-4-ylamino)-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalene-2-ol

AND

(-3-6-chloro-1-(1H-indazol-4-ylamino)-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol "

The racemic compound (324.2 mg), obtained according to the methods described in the above examples, was separated at the stage of a simple ether on a chiral column (Spigazirak AO 20 u, eluent hexane/ethanol) into its Ж enantiomers. 122.8 mg of (-)-enantiomer and 147 mg of (k)-enantiomer were obtained. "so (--Enantiomer: |(zhIr--0.8 (s-1, MeOH) (4)-Enantiomer: (91p--1.0 (s-1, MeOH) o (-)-2-chloro -5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1,b-diol and co (-)- 2-chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-"(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1,6-diol 24 mg (21 .4965) of phenol was obtained from 115.8 mg of (-)-enantiomer simple ether by splitting the simple ether from VVgz. 91.5 mg (66.996) of phenol was obtained from 141.2 mg of (y)-enantiomeric simple ether by splitting the " simple ether from VVgz. Example 218. 5-(4,4-Dimethyl-2-hydroxy-5-methoxy-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinoline-2(1H )-one 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal:

Similarly to example 7, 687 mg of ethyl 4-(2-methoxyphenyl)-4-methyl-2-oxopentanoate (MO 00/325841 | with 1 g

(H0) (pentafluoroethyl)trimethylsilane and 00.5 ml (a solution of tetrabutylammonium fluoride (1M in THF)) in 1 ml of THF were reacted to obtain ethyl-4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl) -pentanoate 450 mg of the obtained ester in 12 ml of diethyl ether was mixed in portions at 0 9 with bbmg

Gee! lithium aluminum hydride. After stirring for 11 hours, the mixture was added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases were separated and the aqueous phase was extracted with ethyl acetate. shk The organic phase was washed with water and saline solution, dried (Ma 250) and concentrated by

GT" evaporation. 42Omg of diol was obtained in the form of a yellow oil. 400 mg of diol was oxidized to the corresponding aldehyde with 0.11 ml of oxalyl chloride, 0.21 ml of DMSO and 1 ml of triethylamine. The mixture was washed with water and brine, dried over sodium sulfate, and concentrated by evaporation in vacuo. After chromatography on silica gel (hexane/ethyl acetate 0-2595), 268 mg of the title compound was obtained as a yellow oil. o "H-NMR (SOSIv), 5 (parts per million) - 1.39 (in, ZN), 1.46 (z, ZN), 2.26 (a, 1H), 3.46 (a . .95 (in, 1H) 5-(4,4-dimethyl-2-hydroxy-5-methoxy-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinoline-2(1H 60)-on

Similarly to example 10, the corresponding name was obtained, leaving Кк! 180 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 83 mg of 5-aminoquinolin-2(1H)-one.

7mg of the title compound was obtained by reacting 7mg of imine with 5mg of aluminum trichloride in 1.5ml of dichloromethane. for "'H-NMR (СО500): 5 - 1.52 (in, ЗН), 1.66 (з, ЗН), 2.09 (а, 1Н), 2.15 (4, 71Н), 3, 85 (in, ZN), 5.27 (in, 1H),

6.51 (a, 1Hn), 6.62 (a, 1n), 6.70 (9, 1H), 6.92 (a, 2H), 7.11 (ad, 1n), 7.38 (i , 1Н), 8.23 (а, 1Н)

Example 219: 5-C6b-chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-6-methylquinoline- 2(1H)-one 5-amino-6-methylquinolin-2(1H)-one: 4.12 g of 2-chloro-6-methylquinoline (U. May. Spec. 1992, p. 2761-2768 | added at a temperature of 09C to a solution containing 15 ml of 100 95 nitric acid and 2 ml of 96 95 sulfuric acid. After 4 hours at 02 C, the mixture was added to water, and the product was filtered. 4.66 bg of 2-chloro-b6-methyl-5- nitroquinoline in the form of 7/0 beige solid. It was reacted for 80 hours at 1002C in 4 bml of glacial acetic acid and 26 bml of water. The thus obtained b-methyl-5-nitroquinolin-2(1H)-one was filtered from the reaction solution.

3.45 g of the obtained product was subjected to a reaction on activated carbon to obtain aniline with hydrogen at atmospheric pressure in methanol on palladium. 2.89 g of the title compound were obtained as a beige solid. "H-NMR (DMSO): 5 - 2.08 (in, 3H), 5.56 (in, 2H), 6.25 (d, 1H), 6.42 (4, 1H), 7.06 ( a, 1H-, 8.18 (4, 1H), 11.32 (c, 1H) 5-C6b-chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-"(trifluoromethyl)-1 ,2,3,4-tetrahydronaphthalene-1-ilyamino)-6-methylquinolin-2(1H)-one

Similarly to example 10, the corresponding name was obtained, leaving Кк! BOOmg of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal AND ZOOmg of 5-amino-6-methylquinolin-2(1H)-one. 1mg of the title compound was obtained by reacting 8mg of imine with 2.5ml of a solution of titanium tetrachloride (1M in dichloromethane) in 4.3ml of dichloromethane. "NA-NMR (DMSO): 5 - 1.57 (in, ZN), 1.68 (in, ZN), 1.87 (9, 1), 2.12 (9, yin), 2.38 ( z, ZN), 3.88 (z, ZN), 4.87 (a, 1Hn), 5.85 (a, 1H), 5.96 (y, 1H), 6.62 (a, 1H), 6.81 (9, 1H), 7.11 (a, 1H), 7.44 (a, 1H), 8.42 (8, 1H), 11.57 (c, 1H)

Example 220 s 5-(2,5-dihydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalene-1-ylamino)-quinolin-2(1H)-one Ge )

Similarly to example 3, 19U9mg of the title compound was obtained, starting from 74mg of the compound from example 41 with 0.48ml of a solution of BVgz (1M in dichloromethane) at a temperature of 4026.

TNA-NMR (СО53О0): 5 - 1.53 (in, ЗН), 1.65 (in, ЗН), 2.01 (y, 1Н), 2.10 (з, ЗН), 2.12 (a . 7.39 (i, 1H), 8.22 (a, 1H)

Example 221 "5-C2-hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-quinoline-2 so (1H)- he 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal ("c")

Similarly to the synthesis of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-pentanal, 1.05 g of the compound indicated in the title was obtained, starting from 1.7 g of ethyl-4-(2-methoxy -4-methylphenyl)-4-methyl-2-oxopentanoate (example 41) with 1.4 g of (pentafluoroethyl)trimethylsilane, subsequent reduction with 344 mg of lithium aluminum hydride and final oxidation under Swern conditions.

TN-NMR (SOSIV): 5 - 1.36 (z, ZN), 1.42 (in, ZN), 2.23 (d, 1H), 2.32 (in, ZN), 3.48 (i . ), 8.93 (in, 1H) - c 5-C2-hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino) -quinolin-2 and (1H)-one"? Similarly to example 10, the corresponding imine was obtained, starting from 200 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl) ipentanal and UZmg of 5-aminoquinolin-2(1H)-one. 2mg of the title compound was obtained by reacting 8mg of imine with 1.6ml of titanium tetrachloride solution

Ge | (1M in dichloromethane) in 5 ml of dichloromethane. o TNA-NMR (СО53О0): δ - 1.48 (in, ЗН), 1.62 (in, ЗН), 2.05 (0, 1Н), 2.12 и, 1Н), 2.16 (with ) .75 (in, 2H), 7.40 (i, 1n), 8.23 (a, 1n) (22) Example 222 and 50 5-PC2-hydroxy-5-methoxy-2-(trifluoromethyl)-4, 4,6-trimethyl-1,2,3,4-tetrahydronaphthalene-1-yl)iamino)-quinolin-2(1H)-one

Ethyl 4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate

Similarly to example 7, methyl-2-methoxy-3-methylbenzoate was obtained from 30g of 3-methylsalicylic acid and 100ml of methyl iodide from 125g of potassium carbonate in 40ml of DMF. The ester was reacted to obtain 1--2-methoxy-4-methylphenyl)-1-methylethanol by reaction with 129 ml of methylmagnesium chloride (ZM in THF) in 435 ml of THF. 20.8 g of the obtained product was reacted with 27.1 g of ethyl ether of 2-(trimethylsilyloxy)-acrylic acid in 410 ml of dichloromethane at a temperature of 02C with 10.4 ml of tin tetrachloride to obtain 12.63 g of the indicated compound in the title.

TNA-NMR (Z00MHZ, SOS): 5 - 1.28 (B ZN), 1.48 (in, 6H), 2.29 (in, ZN), 3.37 (in, 2H), 3.76 ( c, 3H), 4.14 60 (da, 2H), 6.95 (i, 1H), 7.05 (4, 1H), 7.13 (a, 1H) 4-(2-methoxy-4- methylphenyl)-2-hydroxy-4-methyl-2-(hprefluoromethyl)pengpanal

Similarly to example 7, 14.68 g of ethyl 4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoate was reacted with 21.6 ml of (trifluoromethyl)trimethylsilane and 9.7 ml of a solution of tetrabutylammonium fluoride (1 M in THF ) in 195 ml

THF to obtain 13.73 g of ethyl 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanoate. The product was reduced from 2.84 g of lithium aluminum hydride in B5 ml of diethyl ether to /11.62 g

4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanol. Oxidation of the diol was carried out similarly to example 7 under Swern conditions with 3.1 ml of oxalyl chloride, 7.1 ml of DMSO and 26.5 ml of triethylamine to 5.91 g of the title compound. "H-NMR (SOSIV): 5 - 1.44 (in, ZN), 1.48 (z, ZN), 2.22 (y, 1H), 3.36 (a, 1H), 3.83 ( with, ZN), 6.90-7.12 (t,

ЗН), 8.93 (in, 1Н) 5-C2-hydroxy-5-methoxy-2-"(trifluoromethyl)-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl| iamino)-quinolin-2(1H)-one

Similarly to example 10, the corresponding name was obtained, leaving Кк! bOOmg 70. 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)ipentanal and 315 mg of 5-aminoquinolin-2(1H)-one. 12mg of the title compound was obtained by reacting 37Omg of imine with 8.3ml of titanium tetrachloride (1M in dichloromethane) in 20ml of dichloromethane.

TNA-NMR (СО5О0): 5 - 1.52 (in, ZN), 1.67 (8, ZN), 2.10 (z, 2H), 2.30 (z, ZN), 3.79 (z , ZH), 5.16 (z, 1H), 6.51 (a, 1H), 6.61 (a, 1H), 6.70 (d, 1H), 7.00 (c, 2H), 7 .38 (I, 1H), 8.21 (a, 1n)

Examples 223 and 224 4-(14,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-phthalide. and 4-C2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)|amino)-phthalide

Similarly to example 10, the corresponding name was obtained, leaving Кк! b00 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 308 mg of 4-aminophthalide. 165 mg of 4-C4,4-dimethyl-2-hydroxy-5-methoxy-2-"(trifluoromethyl)-1,2,3,4- tetrahydronaphthalen-1-yl|Iamino)-phthalide as the first fraction and 115 mg of 4-C2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)iamino )-phthalide as the second fraction. p 29 Fraction 1: "H-NMR (SOSIv): 5 - 1.40 (z, ЗН), 1.49 (в, ЗН), 2.03 (9, 1Н), 2.13 (9, 1Н) . ), 6.66 (a, 1H), 7.03 (y, 1), 7.21-7.32 (t, 2H), 7.39-7.50 (t, 2H)

Fraction 2: "H-NMR (СО3О0): 5 - 1.55 (in, НН), 1.67 (in, НН), 2.04 (0, 1), 2.12 (9, 1Н), 5 ,15 (c, 1H), 5.21 (a, 1n), 5.32 (a, 1n), 6.70 (a, 1n), 6.84 (j, 1H), 6.96 (I, 1H), 7.07 (a, 1), 7.18 (a, In), 7.42 (its, 1H) « from Examples 225 and 226 (-)-4-44,4-dimethyl-2-hydroxy -5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-phthalide and "(13-4-44 4-dimethyl-2-hydroxy-5-methoxy-2- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|Iamino)-phthalide

Separation of (1-)-4--44,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-phthalide (α)

The mixture of enantiomers was separated by chromatography on a chiral carrier (SNIKAI RAK AO F, Co. RAI!SEI)) with hexane/ethanol (95:5, vol.). In this way, the (-)-enantiomer was obtained: MS (EI): M'-421, (41p-79.39 (c-0.9, CHO") and (n-enantiomer: MO (E): M" - 421 "

Examples 227 and 228 (-)-4-(2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylidamino)-phthalide. (3-4-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-phthalide c Separation "» (47-)-4- 42,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-phthalide

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKAI RAK AO F, 5 OAISE company) with hexane/ethanol (90:10, vol.). In this way, (ee) (-enantiomer: MS (EI): M"-407, (odro -66.02 "(c-1.0, SNCIv) and o (-enantiomer: MO (EI): M" were obtained -407

Example 229 me) 5-C5-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl and 20 -1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazine-1 - he

Similarly to example 10, the corresponding name was obtained, leaving Кк! BOOmg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 288 mg of 5-amino-2-methylphthalazin-1-one. As in example 3, 90 mg of imine was reacted with 04 ml of titanium tetrachloride (1 M in dichloromethane) in 5 ml of dichloromethane, and 25 mg of the title compound was obtained. 29 "NA-NMR (DMSO): 5 - 1.42 (in, ZN), 1.57 (in, ZN), 1.95 (9, 1), 2.05 (9, 1H), 2.14 (in, ZN), 3.70 (from, ZN),

HF) 3.80 (5, ЗН), 5.38 (y, 71Н), 5.98 (в, 1Н), 6.57 (а, 1), 6.66 (з, 1Н), 6.80 (c, 1), 7.25 (a, 1), 7.47 (a, q 1H), 7.58 (i, 1H), 8.63 (8, 1H)

Examples 230 and 231 (-)-5-(5-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethide-1,2,3,4-tetrahydronaphthalen-1-yl|amino)- 2-methy 60 lphthalazin-1-one and (-3-5-C5-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalene-1- ilyamino)-2-methyl phthalazin-1-one

Separation of (49-)-5-15-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)iamino)-2-methylph because of thalazin-1-one

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKARAK JSC 9, RAIISEI.

Sotrapu) with ethanol as an eluent. In this way, the (-)-enantiomer was obtained: MS (EI): M'-461 and (k)-enantiomer: MS (EI): M"-461, (oLo 4.92 "(c-0.7, SNSI »)

Example 232 5-(6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-fluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methyl phthalazin-1-one

Similarly to example 10, the corresponding name was obtained, leaving Кк! 1.0 g of 70 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 542 mg of 5-amino-2-methyl-phthalazin-1-one. As in example 3, 840 mg of imine was reacted with 43.bml of titanium tetrachloride (1M in dichloromethane) in 40 ml of dichloromethane, and 114 mg of the title compound was obtained.

TN-NMR (DMSO): 5 - 1.47 (in, ZN), 1.61 (in, ZN), 2.00 (4, 1), 2.14 (y, 1H), 3.71 (in ) .27 (9, 1H), 7.33 (4, 1H), 7.49 (a, 1H), 7.60 (i, 1H), 8.64 (c, 1H)

Examples 233 and 234 (-)-5-1b-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-"'trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|amino )-2-methylphthalazin-1-one and (-3-5-C6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene- 1-ylamino!-2-methylphthalazin-1-one

Separation of (9-)-5-16-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)- 2-me tylphthalazin-1-one

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKAI RAK JSC, RAI!ISEI)) with hexane/ethanol (90:10, vol.). In this way, c 29 (--enantiomer: MS (EI): M"-481/483 and o (k)-enantiomer: MS (EI): M"-481/483 were obtained, (930 10.62 "(s -0.8, SNI")

Example 235 5-(C6b-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-amino)-2-meth "ylphthalazine -1-on

Similarly to example 3, 109 mg of the title compound was obtained, starting from 20 mg of "I 5-(6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3, 4-tetrahydronaphthalene-1-yl)amino)-2-methylphtsalazin-1-one with 0.1 ml of a solution of BVgz (1M in dichloromethane) at a temperature of 4026.

TN-NMR (DMSO): 5 - 1.52 (z, ZN), 1.65 (in, ZN), 2.00 (4, 1), 2.11 (4, 1), 3.70 (in ) 7.26 (ad, 1n), 7.47 (a, 1H), 7.58 (i, 1H), 8.63 (5, 1H), 9.09 (c, 1H) s

Example 236 (-)-5-16b-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-amino)-2 - methylphthalazin-1-one "

Similarly to example C, 2 mg of the title compound was obtained starting from 2 mg of 40. (-)-5-1H-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-trifluoromethyl)-1,2 . DMSO): 5 - 1.52 (in, ЗН), 1.65 (in, ЗН), 2.00 (4, 1Н), 2.11 (а, 1Н), 3.70 (з, НН), 5.42 (a, 1H), nya 6.07 (c, 1H), 6.58 (a, 1H), 6.74 (a, 1H), 7.20 (a, 1Hn), 7.26 ( y, 1H), 7.47 (a, 1H), 7.58 (y, 1H), 8.63 (c, 1H), 9.09 (c, 1H)

Example 237 (I)-5-C6-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-amino)-2 co -methylphthalazin-1-one o Similarly to example C, 12 mg of the title compound was obtained starting from 20 mg of (-3-5-16-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl )-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methyl (22) phthalazin-1-one from 0.4 ml of a solution of BVgz (1M in dichloromethane) in 0.25 ml of dichloromethane at a temperature of 4026. 20 "NA-NMR (DMSO): 5 - 1.52 (in, ЗН), 1.65 (in, ЗН), 2.00 (4, 1Н), 2.11 (а, 1Н), 3.70 (z, ZN), 5.42 (a, 1H),

They are 6.07 (c, 1H), 6.58 (a, 1H), 6.74 (a, 1H), 7.20 (a, 1Hn), 7.26 (y, 1H), 7.47 ( a, 1H), 7.58 (i, 1H), 8.63 (c, 1H), 9.09 (c, 1H)

Example 238 (-3-5-S2,5-dihydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-amino)-2-methylphthalazine -1-on

Analogously to example C, 109 mg of the title compound was obtained starting from 20 mg

HF) 5-C5-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazin-1-one with 0.1 ml of a solution of BB" (1 M in dichloromethane) at a temperature of 4020. "NA-NMR (DMSO): 5 - 1.46 (in, ZN), 1.60 (z, ZN), 1.94 (a, 1H), 2.01 (9, 1), 2.06 (in, ЗН), 3.70 (z, ЗН), in 5.35 (а, 1), 5.92 (in, 1Н), 6 .51 (in, 71H), 6.53-6.63 (t, 2H), 7.26 (a, 1), 7.46 (a, 1), 7.57 (i tn), 8.63 (85, 1H), 9.31 (in, 1H)

Example 239 5-C5-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene-1-ylidamino)-2-methylphthalazin-1-one 65 Similarly to example 10, the corresponding name was obtained, leaving Кк! bOOmg of 4-(3-methyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 316bmg

5-amino-2-methylphthalazin-1-one. As in example 3, 46bOmg of imine was reacted with 5.2ml of titanium tetrachloride (1M in dichloromethane) in 23ml of dichloromethane, and Zbmg of the title compound was obtained. "NA-NMR (DMSO): 5 - 1.45 (in, ZN), 1.60 (in, ZN), 1.96 (9, 1), 2.10 (9, 1), 2.24 ( в, ЗН), 3.70 (з, ЗН), 3.72 (в, ЗН), 540 (а, ин), 6.03 (в, 71Н), 6.57 (а, 1), 6, 87 (a, tn), 7.03 (a, 1), 7.25 (a, tn), 7.46 (a, 1H), 7.58 (i, 1H), 8.63 (8, 1H )

Example 240 5-(6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-phthalase yn-1-one 70 Similarly to example 10, the corresponding imine was obtained starting from 1.0 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 494 mg of 5-amino-phthalazine-1 -onu As in Example 3, 775 mg of imine was reacted with 24.9 ml of titanium tetrachloride (1M in dichloromethane) in 4 bml of dichloromethane, and 483 mg of the title compound was obtained. "NA-NMR (DMSO): 5 - 1.47 (in, ZN), 1.61 (in, ZN), 1.99 (4, 1H), 2.13 (a, yin), 3.88 ( z, ЗН), 5.45 (a, 1Н), 12 6.17 (c, 1Н), 6.57 (9, 1Н), 7.00 (а, 1Нн), 7.28 (а, 1Н) , 7.33 (a, 1H), 7.46 (a, 1H), 7.57 (Y, 1H), 8.61 (8, 1H), 12.56 (c, 1H)

Examples 241 and 242 (-)-5-16b-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-ft Alazin-1-one and (-3-5-D6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl) amino)-ft alazine-1-one

Separation of (1-/-)-5-C6b-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino) -phthalazin-1-one

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKAI RAK JSC, RAI!ISEI)) with hexane/ethanol (90:10, vol.). In this way, c (-U-enantiomer: flash point - 267-2709С and o ()-enantiomer: flash point - 263-2652С, (oo 6.592 "(с-1,2, CHO")

Example 243 5-(C6b-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-amino)-phthalazine- 1-he in

Similarly to example C, 109 mg of the title compound was obtained, starting from 20 mg of "5-(6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4 -tetrahydronaphthalene-1-ilyamino)-phthalazin-1-one from 0.1 ml of a solution of VVg" (1M in dichloromethane) at a temperature of 4026. ke, "'HA-NMR (DMSO): 5 - 1.43 (in, 1H) . (a, 1n), 6.65 (a, 1Hn), 7.12 (9, 1H), 7.18 (a, 1H), 7.36 (d, 1H), 7.49 (i, 1H) , 8.52 (in, 1H), 9.02 (in, 1H), 12.46 (in, 1H) so

Example 244 (-)-5-(6b-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-amino)-2 -methylphthalazin-1-one

Analogously to example C, 94 mg of the title compound was obtained, starting from 100 mg of "20 (-)-5-1b-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-"-trifluoromethyl)-1, 2,3,4-tetrahydronaphthalene-1-yl)iamino)-phthalase-in-1-one with 2.1 ml of a solution of VViz (1 M in dichloromethane) in 1 ml of dichloromethane at a temperature of 4026. "NA-NMR (DMSO) : 5 - 1.43 (v, 1H), 1.56 (v, ZH), 1.91 (4, 71H), 2.01 (a, yin), 5.33 (4, 1H), 6, 00 (z, 1H), "» 6.44 (a, 1n), 6.65 (a, 1Hn), 7.12 (9, 1H), 7.18 (a, 1H), 7.36 (d , 1H), 7.49 (i, 1H), 8.52 (in, 1H), 9.02 (in, 1H), 12.46 (in, 1H)

Example 245 (t)-5-C6-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-amino)-f

Ge | thalazin-1-one

Similarly to example C, 82 mg of the title compound was obtained, starting from 100 mg of o (-3-5-Ch6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2, 3,4-tetrahydronaphthalene-1-ilyamino)-phthalase

Gee! yn-1-one from 2.1 ml of a solution of BB" (1M in dichloromethane) in 1 ml of dichloromethane at a temperature of 4020. their 50 "NA-NMR (DMSO): 5 - 1.43 (in, 1H), 1.56 ( c, ZN), 1.91 (4, 71H), 2.01 (a, yin), 5.33 (4, 1H), 6.00 (z, 1H), 6.44 (a, 1n), 6.65 (a, 1Hn), 7.12 (9, 1H), 7.18 (a, 1H), 7.36 (d, 1H), 7.49 (i, 1H), 8.52 (in . ,2,3,4-tetrahydronaphthalene-1-ylidamino)-phthalazin-1-one 25 Analogously to example 10, the corresponding imine was obtained, starting from Kk!BOOmg

Gee! 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 287 mg of 5-amino-phthalazin-1-one. As in example 3, 320 mg of imine was reacted with 7.2 ml of titanium tetrachloride (1 M in dichloromethane) in 20 ml of dichloromethane, and 8 mg of the title compound was obtained.

TN-NMR (DMSO): 5 - 1.43 (in, 1H), 1.57 (in, 3H), 1.95 (y, 1H), 2.06 (y, 1H), 2.15 (in ) 79 (c, 1), 7.25 (a, yin), 7.44 (a, 1), 7.57 (y, 1H), 8.61 (c, 1H), 12.54 (c, 1H )

Examples 247 and 248 (-)-5-C2-hydroxy-5-methoxy-2-("trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)iamino)- Phthalase in-1-one and bo (-3-5-F2-hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalene-1-ilyamino) -2-methylphthalazin-1-one

Separation of (9-)-5-16-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)- 2-me tylphthalazin-1-one

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKARAK JSC 9, RAIISEI.

Sotrapu) with ethanol as an eluent. In this way, the (-)-enantiomer was obtained: MO (E!): M"-447, (oo -3.4e "(c-0.7, SNCIv) and (-enantiomer: MC (EI): M" - 447, (oo 3.72 "(c-1.1, SNSIz)

Example 249 5-C2-hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl|amino)-phthalazin-1-one

Similarly to example 10, the corresponding name was obtained, leaving Кк! 250 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)ipentanal and 118 mg of 5-amino-phthalazin-1-one.

As in example C, 5 mg of imine was reacted with 0.3 ml of titanium tetrachloride (1M in dichloromethane) in 1 ml of dichloromethane, and 8 mg of the title compound was obtained. "'H-NMR (CO500): 5 - 1.40 (in, 1H), 1.55 (z, 3H), 2.19 (y, 1H), 2.29 (8, 1H), 2.33 (in, ЗН), 3.47 (in, ЗН), 5.46 (5, 1Н), 6.61 (in, 1Н), 6.90 (in, 1Н), 7.54-7.63 ( t, 2H), 7.63-7.73 (t, 2H), 8.43 (in, 1H)

Example 250 5-(6-chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-8-fluoro -quinolin-2(1H)-one 5-amino-8-fluoroquinolin-2(1H)-one 10 g of 2,5-difluoroaniline and bg pyridine in 3500 ml of dichloromethane were mixed dropwise at a temperature of 09C with 12.9 g of cinnamic acid chloride and stirred until the end of the transformation at a temperature of 0 C. Batch c 29 was added to 2n. of hydrochloric acid, and it was extracted with dichloromethane. The mixture was washed with water, dried over sodium sulfate, and concentrated by evaporation in vacuo. The resulting solid was mixed with 11.1 g of aluminum chloride and heated to 1502C for 8 hours. After chromatography on silica gel, 2.9 g of 5,8-difluoroquinolin-2(1H)-one was obtained. It was subjected to interaction with 100 ml of ethylene glycol in the presence of - 20,780 mg of copper oxide (II) for 20 hours at 2002 in an ammonia atmosphere at a beaver pressure. After chromatography on silica gel, in this case, 5-amino-8-fluoroquinolin-20I1H)-one was obtained as fraction A. and - 2,5-diamino-8-fluoroquinoline was obtained as fraction B.

Fraction A: "H-NMR (DMSO): 5 - 5.73 (in, 2H), 6.28 (da, yin), 6.35 (a, 1H), 7.07 (44, yin), 8 .08 (yes, tn), 11.31 (in, 1H). o

Fraction B: "H-NMR (DMSO): 5 - 5.36 (c, 2H), 6.23 (449, 1H), 6.47 (z, 2H), 6.63 (a, 1H), 6 .96 (ad, 1H), 8.07 (44, 1H). (ee) 5-(6-chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-"(trifluoromethyl)-1, 2,3,4-tetrahydronaphthalene-1-ilyamino)-8-fluoro-quinolin-2(1H)-one

Similarly to example 10, the corresponding name was obtained, leaving Кк! 250 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 137 mg of 5-amino-8-fluoroquinolin-2(1H)-one. The compound specified in the title was obtained similarly to example C by reacting the formed imine with 1.4 ml of titanium tetrachloride (1M in dichloromethane). "» "'H-NMR (СО500): 5 - 1.53 (in, ЗН), 1.67 (in, НН), 2.22 (in, 2Н), 3.96 (in, НН), 5 ,14 (v, 1H), 6.51-6.61 (t, " 2H), 7.09 (a, 1Hn), 7.20 (9, 1H), 7.24 (aa, 1n), 8 ,21 (aa, 1n).

Example 251 2-amino-5-(6b-chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|amino so 1-8-fluoro-quinoline o Similarly to example 10, the corresponding imine was obtained, starting with 250 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)ipentanal and 137 mg of 2 ,5-diamino-8-fluoroquinoline.

Me, The compound indicated in the title was obtained similarly to example C by reacting the formed imine with 1.0 ml of a 20% solution of titanium tetrachloride (1 M in dichloromethane).

TNA-NMR (СО5О0): 5 - 1.54 (z, ZN), 1.67 (in, ZN), 2.20 (in, 2H), 3.94 (z, ZN), 5.11 (in , 1H), 6.43 (ad, t» 1H), 6.81 (a, 1Hn), 7.11 (a, 1n), 7.15 (a, 1n), 7.20 (a, 1n) , 8,18 (ad, 1n).

Examples 252 and 253 5-(4,4-dimethyl-b-fluoro-2-hydroxy-5-methoxy-2-"(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-8-fluoro 59 -quinolin-2(1H)-one and

HF) 2-amino-5-C4,4-dimethyl-b-fluoro-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)- 8- t fluoro-quinoline

Similarly to example 10, a mixture of the corresponding imines was obtained, starting from 237 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)ipentanal and 137 mg of a mixture containing 60 5-amino -8-fluoroquinolin-2(1H)-one and 2,5-diamino-8-fluoroquinoline. Similarly to example 3, a mixture of imines was reacted with 2.5 ml of a solution of titanium tetrachloride (1M in dichloromethane), and the two compounds indicated in the title were obtained after chromatography on silica gel.

Fraction A: С H-NMR (СО5О0): 5 - 1.53 (в, ЗН), 1.65 (з, ЗН), 2.08 (а, 1Н), 2.23 (а, 1Н), 3 .95 (4, ZN), 65 5.11 (8, 1H), 6.50-6.61 (t, 2H), 6.98 (aa, 1Hn), 7.06 (aa, 1n), 7 .23 (da, 1n), 8.22 (aa, tn).

Fraction B: H-NMR (СО3О0): 5 - 1.52 (в, ЗН), 1.66 (з, ЗН), 2.08 (а, 1), 2.15 (9, 1Н), 3, 95 (a, tn),

5.09 (in, 1H), 6.40-6.57 (t, 2H), 6.82 (y, 1H), 6.94 (da, 1n), 7.02-7.20 (t, 2H), 8.18 (i, 1H).

Example 254 5-C7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1"-naphthalene-4-ilyamino) and thinoline-2( 1H)-one 3-(3-fluoro-2-methoxyphenyl)-cyclobutyl)-2-hydroxy-2--trifluoromethyl)-pentanal

Similarly to the synthesis of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal in example 3, 3-(3-fluoro-2-methoxyphenyl)-cyclobutyl)-2 -hydroxy-2-(trifluoromethyl)-pentanal was obtained starting from 2,6-difluoroanisole and cyclobutanecarbonitrile.

TN-NMR (SOSIv): 85 - 1.75-1.90 (t, 1H), 2.10-2.40 (t, ЗН), 2.46-2.57 (t, 2H), 2, 83 (y, 1H), 3.00 (a, tn), 3.94 (4, ЗН), 6.75 (ai, 1H), 6.83-7.02 (t, 2H), 8.94 (in, 1H). 5-17-fluoro-3-hydroxy-8-methoxy-3-trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1"-naphthalene-4-ilyamino)-quinoline-2(1H) - he

Similarly to example 10, the corresponding name was obtained, leaving Кк! ZBOg 15. 3-(3-fluoro-2-methoxyphenyl)cyclobutyl)-2-hydroxy-2-(trifluoromethyl)pentanal and 200 mg of 5-amino-quinolin-2(1H)-one. Similarly to example C, the imine was reacted with 1.bml of a solution of titanium tetrachloride (1 M in dichloromethane), and 35 mg of the title compound was obtained.

TNA-NMR (СО53О0): 5 - 2.10-2.29 (t, 4H), 2.40-2.56 (t, 1H), 2.65-2.80 (t, 2H), 2, 93-3.06 (t, 1H), 4.09 (d, ЗН), 5.14 (c, 1H), 6.49 (a, 1H), 6.63 (9, 1H), 6.70 (a, 1H), 6.97 (9, 2H), 8.20 (a, 1Hn).

Example 255 5-1N3,8-dihydroxy-7-fluoro-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1"-naphthalene-4-ylamino|-quinol in-2(1H )-he

Similarly to example C, 12 mg of the title compound was obtained starting from 20 mg of 5-C7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1 "-naphthalene-4-yl)amino)-quinolin-2(1H)-one with 0.22 ml of a solution of VVg" (1 M in dichloromethane) at room temperature. o "HA-NMR (СО50О0): 5 - 1 .81-1.94 (t, 1H), 2.08-2.27 (t, ЗН), 2.28-2.41 (t, 1H), 2.75 (4, 1H), 3.08 (ad, 1H), 3.44 (4, 71), 5.13 (c, 1H), 6.48 (a, yin), 6.63 (a, 1H), 6.68 (a, tn) , 6.73 (aa, yin), 6.90 (ad, tn), 7.37 (B 1Hn), 8.20 (a, 1n).

Example 256 in 5-S7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(piclopentane-1,1-naphthalen-4-yl|amino) Its -quinoline -2(1H)-one 3-(3-fluoro-2-methoxyphenyl)-cyclopentyl)-2-hydroxy-2--trifluoromethyl)-pentanal ee,

Similarly to the synthesis of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal in the example "with

C, 3-(3-fluoro-2-methoxyphenyl)-cyclopentyl)-2-hydroxy-2-trifluoromethyl-pentanal was obtained starting from 30 2,6-difluoroanisole and cyclopentanecarbonitrile. co

T'NMR (CO500): 5 - 1.15-2.26 (t, 8H), 2.33 (4, 1), 311 (a, MH), 3.57 (c, 71H), 3.98 (а, ЗН), 6.82-6.93 (t, 2Н), 6.94-7.05 (t, 1Н), 8.98 (c, 1Н). 5-T7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1"-naphthalen-4-yl|amino « 20 |-quinolin- 2(1H)-one with

Similarly to example 10, the corresponding name was obtained, leaving Кк! ZBOg with 3-(3-fluoro-2-methoxyphenyl)cyclobutyl)-2-hydroxy-2-trifluoromethyl)pentanal and 190 mg of 5-amino-quinolin-2(1H)-one. Similarly to example C, the imine was reacted with 5.25 ml of a solution of titanium tetrachloride (1 M in dichloromethane), and 19 mg of the title compound was obtained. "H-NMR (SOSIV): 85 - 1.53-1.67 (t, 1H), 1.73-2.15 (t, 6H), 2.28-2.48 (t, ZN), 3 ... .82 (da, 1n), 6.93 (da, 1H), 7.32 (i, 1H), 8.18 (a, 1Hn).

Example 257 about 5-(13,8-dihydroxy-7-fluoro-3-"(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1"-naphthalene-4-yl|amino)-quino

He" lin-2(1H)-one

Similarly to example C, 17/mg of the title compound was obtained starting from bomg and 5-ShT7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane- 1,1"-naphthalene-4-yl|amino)-hyi"nolin-2(1H)-one with 0.25 ml of a solution of BVgz (1M in dichloromethane) at room temperature.

TNA-NMR (СО3О0): 5 - 1.45-1.57 (t, МН), 1.72-1.88 (t, 2Н), 1.90-2.12 (t, ЗН), 2, 18-2.43 (t, ZN), 2.70-2.85 (t, 1H), 5.18 (c, 1H), 6.51 (a, yin), 6.63 (a, tn) , 6.70 (a, tn), 6.78 (aa, yin), 6.87 (ad, tn), 7.38 (,1H), 8.22 (y, 1H).

Example 258

IF) 5-(2,5-dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalim)azine-1 - he

Similarly to example 10, the corresponding name was obtained, leaving Кк! 1.0 g of 60 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 5 mg of 5-amino-2-methylphthalazin-1-one. As in example 3, the formed imine was reacted with 10 ml of boron tribromide solution (1 M in dichloromethane), and 45 mg of the title compound was obtained. "NA-NMR (DMSO): 5 - 1.47 (in, ZN), 1.59 (in, ZN), 1.97 (9, 1), 2.07 (9, 1), 3.70 ( c, ЗН), 5.41 (c, 1H), 6.11 (c, 1H), 6.41 (da, 1n), 6.56 (ad, 1n), 7.27 (a, 1Hn), 7.48 (9, 1H), 7.59 (i, 1H), 8.63 (c, 1H), 10.00 (c, 1H). 65 Examples 259 and 260 (-)-5-(2, 5-dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-2-methylphthalazin-1-one and (-3- 5-(42,5-dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)iamino)-2-methylphthalazin-1-one

Separation of (-)-5-ShC2,5-dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-2-methylphthalazine -1-one:

The mixture of enantiomers was separated by chromatography on a chiral support (SNIKAI RAK JSC, RAI!ISEI)) with hexane/ethanol (90:10, vol.). In this way, the (-)-enantiomer 70 was obtained: MS (EI): M'-451, (oo -34.6e "(c-1,3, SNCIv) and (k)-enantiomer: MS (EI): M "-451, OR 35.49 "(c-1.3, SNO").

Examples 261 and 262 5-X17-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylidamino)-2-methylphthalazine-1- one, diastereomer B and 5-X17-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylidamino)-2-methylphthalazine-1-one , diastereomer A

Similarly to example 10, the corresponding name was obtained, leaving Кк! 800 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 20 mg of 5-amino-2-methylphthalazin-1-one. As in example 3, the formed imine was reacted with 94 ml of a solution of boron tribromide M in dichloromethane), and 37 mg of diastereomer B 5-Х17-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1 was obtained ,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazin-1-one as fraction A and 11 mg of diastereomer A )-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-2-methylphthalazine-1-one as fraction B. p. 29 Fraction A: С H-NMR (СО5О0): 5 - 1.40 (in, ЗН ), 1.55 (in, ZN), 1.92 (y, 1), 2.25 (9, IN), 3.84 (z, ZN), d) 5.27 (in, 1H), 6 .70 (d, 1H), 7.19-7.29 (t, 2H), 7.51 (i, 1H), 7.60 (d, 1H), 8.52 (c, 1H).

Fraction Bi "H-NMR (СО5О0): 5 - 1.55 (in, ЗН), 1.66 (з, ЗН), 2.07 (9, 1), 2.15 (0, 1Н), 3, 83 (z, ZN), 5.24 (c, 1H), 6.88 (d, 1H), 6.94 (a, 1H), 7.18-7.28 (t, 1H), 7.62 -7.70 (t, 2H), 8.56 (v, 1H).

Example 263 5-(S7-chloro-3,8-dihydroxy-3-trifluoromethyl)-3,4-dihydro-2H-spiro(diclohexane-1,1-naphthalene-4-ylamino)-quinoline -2(1H)-one so 3-(1-(3-chloro-2-methoxyphenyl)-cyclohexyl|-2-hydroxy-2--trifluoromethyl)propanal 9.57g (30.79mmol) 3-(1-( 3-chloro-2-methoxyphenyl)-cyclohexyl|-2-oxopropionic acid (using "(2 appropriate starting substances, this compound was obtained analogously to the instructions given in (MO 98/54159))) was mixed with 191 ml of ethanol and 34 ml of concentrated sulfuric acid After five hours of heating in a reflux flask, the batch was centrifuged until anhydrous and the residue was mixed with

BOOml of saturated sodium bicarbonate solution. The aqueous phase was extracted three times with ethyl acetate, and the combined organic extracts were washed with brine. The solvent was then dried and removed by centrifugation, and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 7.07 g (67.8905) of the necessary complex ether were obtained. c 7.07 g (20.87 mmol) of ethyl 3-(1-(3-chloro-2-methoxyphenyl)-cyclohexyl|-2-oxopropionate was dissolved in 33 ml of tetrahydrofuran and mixed with 3.56 g (25.04 mmol) (trifluoromethyl)-trimethylsilane. After addition of 51.1 mg of tetrabutylammonium fluoride, the batch was stirred overnight. The reaction mixture was diluted with methyl tert-butyl ether, washed once with water and then with brine. After the usual work-up, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane).The isolated 5.71 g (60.495) of the product was mixed in 7 Oml of tetrahydrofuran with 3.98 g (12.61 mmol) of tetrabutylammonium fluoride and stirred for 1 hour at room temperature. Then the reaction mixture was mixed with water, its extracted with methyl tert-butyl ether.After the usual work-up, the residue was chromatographed on

Риязптавзвгиег. 2.63 g (51.196) of the required compound were isolated: 50 g of ethyl 2-(1-(3-chloro-2-methoxyphenyl)-cyclohexylmethyl)-3,3,3-trifluoro-2-hydroxypropionate.

I» 1.59 g (3.89 mmol) of the above-described complex ether was dissolved in 14 ml of diethyl ether and mixed at 02С in portions with 110.7 mg (2.92 mmol) of lithium aluminum hydride. After stirring for two hours at a temperature ranging from 0 to 52C, 3.4 ml of saturated sodium bicarbonate solution was carefully added dropwise. The mixture was vigorously stirred at room temperature for ten minutes. After repeated extraction of the aqueous phase with methyl tert-butyl ether, the combined organic extracts were processed as usual. After (F. chromatography on a Riazpitazieg medium, 7500 mg (52.8905) of a mixture was obtained, which contains two-thirds of the required aldehyde and one-third of the complex ether. Additionally, 201.4 mg of the corresponding alcohols (contaminated) were obtained. 5-2-(I1-( 3-chloro-2-methoxyphenyl)-cyclohexylmethyl/|-3,3,3-trifluoro-2-hydroxy-propylidenamino)-1H-quinolin-2-one in 375 mg (0.683 mmol) of aldehyde, which is described in the previous paragraph, ( together with the ester) was heated in a reflux flask in 3.bml xylene with 109.4mg (0.683mmol) 5-amino-1H-quinolin-2-one and 388.3mMg (1.36bmmol) titanium isopropylate (M) for three hours. After cooling, the reaction mixture was mixed with a saturated solution of sodium chloride and ethyl acetate. After ten minutes of vigorous stirring, the mixture was added to Ehigeish and eluted with 100 ml of dichloromethane. After removing the solvent by centrifugation, 65 The residue that remained was chromatographed on Riazptavzieg support. Additionally to 145 mg of complex ether, 231.bmg (66.995, with respect to the content of aldehyde) of the required imine.

TNA-NMR (ZO00MHz, SOSI): 5 - 1.15-2.18 (9H), 2.38-2.65 (2H), 2.96 (1H), 3.93 (ZH), 4.61 (1H), 6.40-6.60 (2H), 6.62-6.81 (2H), 7.08 (1H), 7.29-7.59 (ZH), 8.07 (1H) , 12.28 (1H). 5-(ShC7-chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1"-naphthalen-4-ylLamine o-quinopine-2(1H )-one 151.6 mg (0.299 mmol) of the above-described imine was dissolved in 2.8 ml of dichloromethane. After adding 1.96 ml (1.79 mmol) of titanium tetrachloride dropwise at a temperature of -159C, the mixture was stirred for four hours at this temperature. At a temperature of 09C saturated sodium bicarbonate solution was carefully added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried, and the solvent was removed by centrifugation. After chromatography on Riazptazvieg support, 67.9 mg (44.8905) of the desired compound was obtained. 7TH - NMR (ZO00MHZc, СО3О0): 5 - 1.30-1.90 (8Н), 2.18 (1Н), 2.30 -2.50 (1Н), 2.53-2.70 (1Н), 2.90 (1H), 4.00 (ZH), 5.19 (1H), 6.52 (1H), 6.62 (1H), 6.70 (1H), 7.09 (1H), 7 .23 (1H), 7.38 (1H), 8.23 (1H). 5-ShC7-chloro-3,8-dihydroxy-3-trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane- 1,1-naphthalene-4-yl)amino)-quinolin-2 (1H)-one 65.9mg (0.13mmol) of the cyclic ether described in the previous paragraph was mixed with 2.bml of boron tribromide (1M in dichloromethane) and stirred for three hours at room temperature. At a temperature of -59C, a saturated solution of sodium bicarbonate was carefully added dropwise, and then the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and the residue which remained after removal of the solvent by centrifugation was chromatographed on

Riazpitazieg. 51.Zmg (80.195) of the required phenol was isolated.

TH-nMR (300 MHz, DMSO-α): 5 - 1.15-1.87 (8H), 2.01 (1H), 2.40-2.90 (ZH, DMSO signal is in this range), 5 .29 (1H), 6.02 (1H), 6.20 (1H), 6.43 (1H), 6.48-6.65 (2H), 6.75 (1H), 7.15-7 .30 (2H), 8.20 (1H), average 9.10 (1H), 11.58 (1H).

Example 264 o 5-(ShC7-chloro-3,8-dihydroxy-3-trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1-naphthalen-4-yl)|amino)-2H- isoquinolin-1-one 5-(ShC7-chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1"-naphthalen-4-ylamine) - 20 o)-2H-isoquinolin-1-one 149.7 mg (0.295 mmol) of the imine (obtained according to the instructions described in Example 263, using FZ appropriate starting materials) was cyclized from 1.9 ml (1.772 mmol) of titanium tetrachloride. After carrying out c by conventional treatment and chromatography, 34.9 g (23.390) of the required compound were obtained. ), 2.69 (1), 3.93 (ZN), 5.34 (13), 5.98. F

Sv (NU, 6.13 (1H), 6.80 (1H), 6.97 (1H), 7.05 (1H), 7.18 (1H), 7.20-7.38 (2H), 7.50 (1N), 11.25 (1N). naphthalene-4-yl)|amino)-2H-isoquinolin-1-one 26.8 mg (0.053 mmol) of the above-described simple ether was subjected to cleavage of the simple ether as described in example 263. After carrying out the reaction in the usual way and after chromatography, 13 was obtained, 5 g « 40. (51.8905) of the necessary phenol. ssh s "H-NMR (SO0MHC, DMSO-dv): 5 - 1.15-1.85 (8H), 2.00 (1H), 2.40-2.90 (ZH), 5.30 (1H ), 5.95 (1H), 6.09 c (1H), 6.73 (1H), 6.81 (1H), 7.04 (1H), 7.10-7.30 (ZH), 7 .50 (1H), 9.12 (1H), 11.23 (1H). "» Example 265 7T-Chloro-4-|(8-fluoro-2-methylquinazolin-5-yl)amino)|-3' ,4-dihydro-8'-methoxy-3-(trifluoromethyl)-spiro|cyclohexan-1,1(2'H)-naphthalene|-3'-ol (ee) 1.61 mg (1.48 in 8 mmol) of titanium chloride (M) was added dropwise to 129.8 mg (0.248 mmol) of the corresponding imine dissolved in 2.4 ml of dichloromethane at a temperature of -202C. After 1.5 hours of stirring at a temperature between -20°C and 59°C, the batch was processed as usual. After chromatography on Riazptazvieg, (o) 11.4 mg (8.895) of the required compound was isolated. their 50 MS (SI): 524 (10096)

Example 266 5-(C7-chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropyl-1,1-naphthalen-4-yl))amine o)-quinolin-2(1H)one 3-(1-(3-chloro-2-methoxyphenyl)-cyclopropyl|-2-hydroxy-2--trifluoromethyl)propanal 22 15.12g. (56.27 mmol) of 3-(1-(3-chloro-2-methoxyphenyl)-cyclopropyl|-2-oxopropionic acid (using

Gee! corresponding starting substances, this compound was obtained similarly to the instructions given in (MO 98/54159)) was mixed with 300 ml of ethanol and 600 ml of concentrated sulfuric acid. After five hours of heating in a reflux flask, the batch was centrifuged until anhydrous, and the residue was mixed with 7OOml of saturated sodium bicarbonate solution. The aqueous phase was extracted three times with ethyl acetate, and the combined 60 organic extracts were washed with sodium bicarbonate solution and brine. Then the solvent was dried and removed by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 12.36 g (7490) of the necessary ester were obtained. b.18 g (20.83 mmol) of ethyl 3-(1-(3-chloro-2-methoxyphenyl)-cyclopropyl|-2-oxopropionate was dissolved in 33 ml of tetrahydrofuran and mixed with 3.55 g (24.99 mmol) of (trifluoromethyl)- trimethylsilane. After addition of 51 mg 65 of tetrabutylammonium fluoride, the batch was stirred overnight. The reaction mixture was diluted with methyl tert-butyl ether, washed once with water and then with brine. After the usual work-up, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). The isolated 5.65 g (66.495) of the product was mixed in 7 bml of tetrahydrofuran with 4.34 g (13.75 mmol) of tetrabutylammonium fluoride and stirred for 1 hour at room temperature. The reaction mixture was then mixed with water and extracted with methyl tert-butyl ether. After carrying out the usual processing, the residue was chromatographed on a RIazptavieg medium.

2.39 g (47496) of the required compound were isolated: ethyl 2-(1-(3-chloro-2-methoxyphenyl)-cyclopropylmethyl!i-3,3,3-trifluoro-2-hydroxypropionate. 0.85 mg (2.32 mmol ) of the above-described complex ether was dissolved in ml of diethyl ether and mixed in portions at 029 with bbmg (1.74 mmol) of lithium aluminum hydride. After stirring for two hours in the 7/0 interval between 0 and 59 C, 2.7 ml of saturated sodium bicarbonate solution was carefully added dropwise. The mixture was stirred vigorously at room temperature for ten minutes. After re-extraction of the aqueous phase with methyl tert-butyl ether, the combined organic extracts were worked up as usual. After chromatography on a Riazptazieg support, 49mg (65,590) of a mixture containing almost two-thirds of the required aldehyde and a third of the ester. 5-2-(I1-(3-chloro-2-methoxyphenyl)-cyclopropylmethyl/|-3,3,3-trifluoro-2-hydroxy-propylidenamino)-1H-quinolin-2-one 490mg (0.972 mmol) of the aldehyde described in the previous paragraph (in the form of a mixture with a complex rum) was heated in a reflux flask for three hours in 5.1 ml of xylene with 155.7 mg (0.972 mmol) of 5-amino-1H-quinolin-2-one and 552.bmg (1.944 mmol) of titanium(M) isopropylate. After cooling, the reaction mixture was mixed with a saturated solution of sodium chloride and ethyl acetate. After ten minutes of vigorous stirring, the mixture was added to Ehigeishi and eluted with 200 ml of dichloromethane. After removing the solvent by centrifugation, the residue that remained was chromatographed on Riazptavzieg media. In addition to 93.9 mg of the ester, 312.8 mg (69.296, relative to the aldehyde content) of the necessary imine was isolated.

TN-NMR (ZO00MHZ, SOSIi): 5 - 0.63-0.75 (1H), 0.79-0.90 (1H), 1.04-1.19 (2H), 2.10 (1H) , 3.10 (1H), 4.00 (ZN), 4.73 (1H), 6.74 (1H), 6.64 (1H), 6.75 (1H), 6.88-7.02 (2H), 7.29-7.43 (2H), 7.70 (1H), 8.10 (1H), 12.32 (1H). c 5-(S7-chloro-3-hydroxy-8-methoxy-3-"(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1"-naphthalen-4-ylamine o o)-quinoline -2(1H)-one 232.8 mg (0.501 mmol) of the above-described imine was dissolved in 4.7 ml of dichloromethane.

With 3 ml (3.009 mmol) of titanium tetrachloride at -202C, the mixture was stirred for four hours at this temperature. At a temperature of 090, a saturated solution of sodium bicarbonate was carefully added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with saline, dried, and the solvent was removed by centrifugation. After chromatography on the Riazptavzieg carrier, 111.8 mg (4895) of the required compound were obtained. ise)

TN-NMR (Z00Mhz, DMSO-jav): 5 - 0.78-1.15 (ZH), 1.78-2.09 (ZH), 3.75 (ZH), 5.06 (1H), 6 ,10-6.30 (ZH), "is 6.45 (1H), 6.60 (1H), 6.98 (1H), 7.20 (1H), 7.30 (1H), 8.23 (1H), 11.60 (1H).

Example 267 with 5-ShC7-chloro-3,8-dihydroxy-3-trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1"-naphthalen-4-yl)|amino)-2H- isoquinolin-1-one 5-(S7-chloro-3-hydroxy-8-methoxy-3-"(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1"-naphthalen-4-ylamine) o)-2H-isoquinopin-1-one 7 70 113.mg (0.245 mmol) of imine (obtained according to the instructions described in example 263, using the corresponding starting substances) dissolved in 2.3 ml of dichloromethane, cyclized with 1.bml (1.472 mmol) of titanium tetrachloride. After carrying out the usual treatment and chromatography, 36.8 g (32.390) of the required compound were obtained. , 1.82-2.09 (ZH), 3.76 (ZH), 5.09 (1H), 5.95 (1H), 6.37 (1H), 6.68 (1H), 6.81 (1H), 6.96 (1H), 7.16-7.28 (2H), 7.30 (1H), 7.52 (1H), 11.30 (1H). 3,8-dihydroxy-3-trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropan-1,1-naphthalen-4-yl))amino)-2H-isoquinolin-1-one about 22.7 mg (0.049 mmol) of the previously described simple ether was subjected to cleavage by p growth ether as described in

FD example 263. After carrying out the interaction in the usual way and after chromatography, 10.9 mg (45.5965) of the required phenol was obtained. "H-NMR (400 MHz, CO500): 5 - 0.55-0.63 (1H), 0.73-0.84 (1H), 1.40-1.51 (1H), 1.80 ( 1H), 1.95-2.10 (2H),

Ta» 5.02 (1H), 6.69 (1H), 6.75 (1H), 6.80 (1H), 6.98 (1H), 7.08 (1H), 7.25 (1H) , 7.59 (1H).

Example 268 7T-Chloro-2-(8-fluoro-2-methylquinazolin-5-yl)amino|-3,4-dihydro-3-(trifluoromethyl)spiro|diclopropane-1,1(2'H)-naphthalene| -3,8'-diol 7T-Chloro-2-(8-fluoro-2-methylquinazolin-5-yl)amino|-3'4-dihydro-8'-methoxy-3-trifluoromethyl)-spiroYcyclopropa iF) n -1,1(2'H)-naphthalene|-3'-ol co 1.64 ml (1.512 mmol) of titanium(M) chloride was added dropwise to 121.3 mg (0.252 mmol) of the corresponding imine dissolved in 2.4 ml of dichloromethane , at a temperature of -202C. After 1.5 hours of stirring at a temperature in the range of -202C to 59C, the batch was processed as usual. After chromatography on ERIazptavieg support, 7.4 mg (6.195) of the required compound (slightly contaminated) was isolated. "H-NMR (400 MHz, SOSIV): 5 - 0.84-1.10 (ZN), 1.92-2.13 (ZN), 2.82 (ZN), 3.79 (ZN), 4, 90 (1H), 5.65 (1H), 6.34 (1H), 7.00 (1H), 7.16 (1H), 7.37 (1H), 9.35 (1H). 7T-Chlorine -2-(8-fluoro-2-methylquinazolin-5-yl)amino|-3,4-dihydro-3--trifluoromethyl)spiro|cyclopropane-1,1(2'H)bo-naphthalene|-3,8 '-diol

4mg (0.08Zmmol) of the corresponding imine was mixed at 02C with 1.1ml of a 1M solution of boron tribromide in dichloromethane.

After 45 minutes of stirring at this temperature, saturated sodium bicarbonate solution was carefully added dropwise, and then the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with saline, dried, and the solvent was removed by centrifugation. After chromatography on Riazptavieg support, 15 mg (38.695) of the required phenol was obtained.

MS (SI): 468 (10096)

Example 269

1b-hydroxy--methoxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-"'trifluoromethyl)-5,6,7,8-tetrahydro 70 ronaphthalene- 2-yl|-acetonitrile

Methyl-2-methoxy-3-methylbenzoate (K5 2690 E2) 199.9g (1.45mol) of potassium carbonate was added to 1.5 liters of dimethylformamide. At room temperature, 100 g (657.29 mmol) of 2-hydroxy-3-methylbenzoic acid dissolved in 250 ml of dimethylformamide was added dropwise. After stirring for 30 minutes, 90 mL of methyl iodide was added dropwise, and batch 7/5 was stirred overnight. The reaction mixture was added to a mixture of water and ice and extracted three times with methyl tert-butyl ether. The organic phases were washed with water and saline. After drying, the solvent was removed by centrifugation and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 70.21 g (59.3905) of the required compound was isolated. "H-NMR (300 MHz, SOSI»v): 5 - 2.32 (ZH), 3.85 (ZH), 3.93 (ZH), 7.07 (1H), 7.35 (1H), 7 .65 (1H). 20 2-(2-methoxy-3-methylphenyl)-propan-2-ol 70.21 g (389.64 mmol) of methyl 2-methoxy-3-methylbenzoate, dissolved in 640 ml of tetrahydrofuran, was added dropwise to 311.7 mL of methylmagnesium bromide in diethyl ether (DM). In this case, the reaction mixture was heated to about 482. The batch was stirred for three hours at room temperature. While cooling in an ice bath, about 1.5 liters of saturated ammonium chloride solution was added dropwise and se 25 Vigorously stirred for 1 hour, then extracted three times with methyl tert-butyl ether, the combined organic extracts washed with brine, dried, and the solvent removed by centrifugation.

71.37 g (2100905) of the required compound was isolated, which was further used in its crude form. "H-NMR (Z00MHZ, SOSI"): 5 - 1.65 (6H), 2.33 (ZH), 3.89 (ZH), 4.55 (1H), 6.99 (1H), 7, 10 (1H), 7.18 (1H).

Ethyl 4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate in 30 71.37g (395.9bmmol) 2-(2-methoxy-3-methylphenyl)-propan-2-ol and 149g (791.92 mmol) of ethyl ether of 2-trimethylsilanyloxyacrylic acid was added to 1.1 liters of dichloromethane. At a temperature of -782C, 44.vml (379.91 mmol) of tin tetrachloride was added dropwise, and then the batch was stirred for three hours at this low temperature. 1.4 liters of semi-concentrated potassium carbonate solution was added dropwise, and in this way the reaction mixture was brought to room temperature. The batch was filtered and the filtrate was extracted three times with ethyl acetate. The combined organic extracts were washed with saline, dried over sodium sulfate, and the solvent was removed by centrifugation. The residue was chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane). The residue was chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane). 45.81 g (41.695) of the required compound were isolated. « 7TN-NMR (ZO00MHz, SOSIA): 5 - 1.30 (ZN), 1.50 (6H), 2.30 (ZN), 3.39 (2H), 3.78 (ZN), 4.17 (2H), 6.97 (1H), -o 40 7.07 (1H), 7.15 (1H). c Ethyl-2-hydroxy-4-(2-methoxy-3-methylphenyl)-4-methyl-2-(trifluoromethyl)pentanoate; 20 g (71.90) of ethyl 4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate and 12.3 g (86.28 mmol) of (trifluoromethyl)trimethylsilane were added to 117 ml of tetrahydrofuran. At room temperature, 180 mg of tetrabutylammonium fluoride was added (heated to approximately 3522). After stirring overnight, 22.7 g oo (71.9 b0mmol) of tetrabutylammonium fluoride was added, and the batch was stirred for three hours at room temperature. After dilution with methyl tert-butyl ether, the organic phase was washed three times with water and once with saline solution. Then the solvent was dried and removed by centrifugation, the residue was chromatographed

FO on silica gel (mobile solvent: ethyl acetate/hexane). 16.33g (65.290) of the required compound was isolated. "H-NMR (Z00MHZ, SOSI): 5 - 1.19 (ZH), 1.43 (ZH), 1.49 (ZH), 2.30-2.44 (4H), 2.82 (1H) , 3.50-3.68 (2H), e 3.84 (ZH), 4.00-4.13 (2H), 6.92 (1H), 7.00-7.10 (2H).

HT» 4-(2-methoxy-3-methylphenyl)-4-megyl-(trifluoromethyl)-pentane-1,2-diol 16.33 g (46.8 mmol) of the above-described complex ether was dissolved in 1 b0 ml of diethyl ether and mixed at 092 portions with 3.56 g (93.7 mmol) of lithium aluminum hydride. After stirring during the weekend at

At room temperature, a saturated solution of sodium bicarbonate was carefully added dropwise and then intensively stirred for 1 hour. Then extracted three times with methyl tert-butyl ether, combined organics

IF) extracts were washed with saline, dried and the residue was chromatographed on silica gel (mobile co-solvent: ethyl acetate/hexane) after removal of the solvent by centrifugation. 10.76 bg (74.9905) of the required diol was isolated. 60 "H-NMR (ZO0MHZ, SOSIV): 5 - 1.49 (ZN), 1.58 (ZN), 1.84 (1H), 2.24 (1H), 2.36 (ZN), 2, 59 (1H), 2.88 (1H), 3.28-3.40 (2H), 3.88 (ZH), 6.99 (1H), 7.10 (1H), 7.20 (2H) 4-(3-bromomethyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol

3 g (9.79 mmol) of 4-(2-methoxy-3-methylphenyl)-4-methyl-(trifluoromethyl)-pentane-1,2-diol was dissolved in 22 ml of carbon tetrachloride, mixed with 1.91 g (10.60 mmol) of MW5 and 5 mg of benzoyl peroxide, and heated in a reflux flask for 24 hours. After filtering the succinimide using a glass fiber filter, the mixture was washed again with dichloromethane, and the solvent was removed by centrifugation.

The residue (5.42g210095) was used in the next stage in crude form. (2-methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)phenyl)|-acetonitrile 5.42 g (14.07 mmol) of the above-described bromo compound was mixed in a mixture, containing dimethylformamide and water (14 and 10.5 mL), with 1.37 g (14.07 mmol) of potassium cyanide, and the mixture was stirred overnight at room temperature.

The reaction mixture was mixed with water and extracted three times with methyl tert-butyl ether. The combined organic phases were washed with brine, and the solvent was removed by centrifugation after drying. 2.6 bg (55.895) of the required compound were obtained after chromatography on a carrier of RIazptavzvgieg. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.49 (ZH), 1.60 (ZH), 1.72 (1), 2.22 (1H), 2.50 (1H), 2.92 (1H), 3.20-3.45 70 (2H), 3.80 (2H), 3.88 (ZH), 7.13 (1H), 7.30-7.42 (2H). (2 -methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-formyl-1,1-dimethylbutyl)phenyl|acetonitrile

0.2 bml (2.99 mmol) of oxalyl chloride was cooled in b.bml of dichloromethane to -782C. After the dropwise addition of 0.42 ml (5.98 mmol) of dimethylsulfoxide dissolved in 1.2 ml of dichloromethane, the mixture was stirred for more than 10 minutes, and then 900 mg (2.72 mmol) of 75 was added dropwise. |2-methoxy-3-(4 ,4,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)phenyl|acetonitrile in 2.bml of dichloromethane. After stirring for two hours at -78°C, 1.88 mL (13.58 mmol) of triethylamine was added dropwise, the batch was allowed to warm to room temperature, and then the mixture was stirred for 1.5 hours at room temperature. After mixing with water, the mixture was extracted three times with dichloromethane. The combined organic extracts were washed with 190% sulfuric acid, saturated sodium bicarbonate solution, and saline. Then the solvent was dried and removed by centrifugation, and the residue was chromatographed on a Riazptavieg medium. There remained 599 4 mg (67.195) of the required aldehyde. 7TH-NMR (300 MHz, SOSI): 5 - 1.45 (ZN), 1.51 (ZN), 2.32 (1H), 3.20 (1), 3.51 (1H), 3.78 ( 2H), 3.89 (ZH), 7.09 (1H), 7.19 (1H), 7.35 (1H), 9.06 (1H). 12-methoxy-3-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-|(2-oxo-1,2-dihydroquinoline-5-ilimino)-methyl|-butyl)- with 29 phengl)acetonitrile o 200 mg (0.607 mmol) of the above-described aldehyde in 34 ml of xylene was heated in a reflux flask for three hours with 97.2 mg (0.607 mmol) of 5-amino-1H-quinolin-2-one and 345.1 mg (1.214 mmol) of titanium isopropylate (IM). After completion of the reaction, saline solution and ethyl acetate were added. After 30 minutes of vigorous stirring at room temperature, the batch was added to EchigeIshsche and eluted with 200 ml of dichloromethane. After removing the solvent by centrifugation, the residue was chromatographed on Biazptavieg media. 228.7 MmMg « (79.8965) of the necessary imine was isolated. 7TH-NMR (300 MHz, SOSIvZ): 5 - 1.45 (ZH), 1.59 (ZH), 2.38 (1H), 3.26 (1H), 3.34-3.55 (2H), 3.85 (ZN), 4.66 sho (1H), 6.29 (1H), 6.69-6.80 (2H), 6.90 (1H), 7.16 (1H), 7.30 -7.47 (2H), 7.51 (1H), 7.97 (1H), 12.18 (1H). (av)

1b-hydroxy-1-methoxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2 -yl|-acetonitrile with 141.2 mg (0.299 mmol) of the imine was mixed at 02C with 4.5 ml of a 1 M solution of boron tribromide in dichloromethane, and the mixture was stirred for four hours. After adding a saturated solution of sodium bicarbonate dropwise, the mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with saline. Then, the solvent was dried and removed by centrifugation, and the residue was chromatographed on a Riazptavieg medium. 8 mg (5.895) of the required compound was isolated.

TN-NMR (300 MHz, SOSIv): 5 - 1.52 (ZH), 1.70 (ZH), 2.05 (1H), 2.19 (1H), 3.69 (2H), 3.79 ( ZN), 5.00-5.16 ;" (2H), 5.64 (1H), 6.38 (1H), 6.50 (1H), 6.62 (1H), 7.05-7.19 (2H), 7.30 (1H), 8.15 (1H), 10.76 (1H).

Example 270

15-(8-fluoro-2-methylquinazolin-5-ylamino)-6-hydroxy-1-methoxy-8,8-dimethyl-6b-(trifluoromethyl)-5,6,7,8-tetrahydro

12-Methoxy-3-(4,4,4-trifluoro-3-(8-fluoro-2-methylquinazolin-5-yl-iminomethyl)-3-hydroxy-1,1-dimethylbutyl) |phenyl)a - acetonitrile

F 200 mg (0.61 mmol) of the aldehyde described in Example 269 was heated in a reflux flask with 107.5 mg (0.6 mmol) of 5-amino-8-fluoro-2-methyquinazoline and 345.1 mg (1.214 mmol) of tetrachloride of titanium in 3.4 ml of xylene for 3 hours. After carrying out the usual treatment and chromatography, 129.5 mg (43.7905) were isolated

T" of the required name. 7TH-NMR (300 MHz, SOSIvZ): 5 - 1.41 (ZN), 1.67 (ZN), 2.35 (1H), 2.99 (ZN), 3.35 (1H), 3.38- 3.56 (2Н), 3.85 (ЗН), 4.61 (1Н), 6.50-6.60 (2Н), 6.75 (1Н), 7.17 (1Н), 7.45 ( 1H), 7.55 (1H), 9.47 (1H).

15-(8-fluoro-2-methylquinazolin-5-ylamino)-6-hydroxy-1-methoxy-8,8-dimethyl-6b-(trifluoromethyl)-5,6,7,8-tetrahydro onanaphthalen-2-yl |-acetonitrile with 100.9 mg (0.21 mmol) of the above-described imine was cyclized and treated, as usual, with 3.0 ml of a 1M solution of boron tribromide in dichloromethane at a temperature of 02C. After chromatography on Riazptazvgieg media and subsequent separation on a plate, 7.5 mg (7.790) of the required compound was isolated. for "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.58 (ZH), 1.74 (ZH), 2.09-2.28 (2H), 2.95 (ZH), 3.78 (2H ), 3.83 (ZH), 5.02 (1H), 5.30 (1H), 5.61 (1H), 6.69 (1H), 7.18-7.32 (2H), 7, 50 (1H), 9.38 (1H).

Example 271 1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol bo 2-hydroxy-4-(2-methoxy-3-methylphenyl)-4-methyl-2-trifluoromethyl)pentanal

2 g (6.53 mmol) of 4-(2-methoxy-3-methylphenyl)-4-methyl-(trifluoromethyl)-pentane-1,2-diol, which is described in example 269, was oxidized to an aldehyde according to Swern similarly to that described in this example . After carrying out the usual treatment and purification on the carrier Riazptazgieg, 1.20 g (60.395) of the necessary aldehyde was isolated. "H-NMR (ZO0MHC, SOSIv): 5 - 1.46 (ZN), 1.50 (ZN), 2.23 (1H), 2.32 (ZN), 3.38 (1H), 3.60 (1H), 3.85 (ZH), 6.93 (1H), 7.00 (1H), 7.10 (1H), 8.95 (1H). 1,1,1-trifluoro-2-K7 -fluoro-2-methylquinazolin-5-ilimino)-methyl/|-4-(2-methoxy-3-methylphenyl)-4-methylpentan-2-ol 15mg (0.493mmol) of the described aldehyde was reacted to form an imine as usual and, as already described several times, from 87.3 mg (049 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 280. mg (0.98 mmol) of titanium tetraisopropylate 70 in 2.5 ml of xylene. After chromatography, 174, Omg (76.695) of the required compound. "H-NMR (ZO0MHC, SOSIV): 5 - 1.41 (ZH), 1.65 (ZH), 2.01 (ZH), 2.29 (1H), 2.90 (ЗН), 3.49 (1Н), 3.80 (ЗН), 4.55 (1Н), 6.19 (1Н), 6.50-6.60 (2Н), 7.03 (1Н), 7.40 (1H), 7.62 (1H), 9.30 (1H). 1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,b-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol 174.9 mg (0.377 mmol) of the previously described imine was cyclized with titanium tetrachloride in dichloromethane at a temperature of 02C. Processing and chromatography were carried out as already described several times. 159.7 mg (91.3965) of the required compound was isolated in the form of a mixture of diastereomers at a ratio of 9:11 (NMR data refer to the main diastereomer). "H-NMR (ZO0MHC, SOSIZ): 5 - 1.59 (ZN), 1.73 (ZN), 2.10-2.28 (2H), 2.32 (ZN), 2.86 (ZN) , 3.81 (ZH), 4.99 (1H), 6.05 (1H), 6.10 (Bgoad, 1H), 6.52 (1H), 6.89 (1H), 6.95-7 .16 (2H), 9.20 (1H).

Example 272 1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2 -ol in 1,1,1-trifluoro-2-KK7,8-difluoro-2-methylquinazolin-5-ilimino)-methyl/|-4-(2-methoxy-3-methylphenip)-4-methylpentane-2 s -ol Ge) 15mg (0.493mmol) of the described aldehyde was reacted to form an imine, as usual and as already described several times, with 96.2mg (0.4933mmol) of 5-amino-7,8-difluoro-2-methylquinazoline and 280.3 mg (0.98 mmol) of titanium tetraisopropylate in 2.5 ml of xylene. After chromatography, 155.5 mg (65.5905) of the required compound was isolated. zo 7TN-NMR (ZO00MHz, SOSIA): 5 - 1.40 (ZN), 1.63 (ZN), 2.07 (ZN), 2.28 (1H), 2.98 (ZN), 3.50 (1H), 3.83 (ZH), t 4.49 (1H), 6.28 (1H), 6.52-6.62 (2H), 7.03 (1H), 7.62 (1H) , 9.36 (1H). 1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphtha 2-ol 155.5 mg (0.3233 mmol) of the previously described imine was cyclized with titanium tetrachloride in dichloromethane at a temperature of 02С. Processing and chromatography were carried out as already described several times. 101.bmg so (65.395) of the required compound was isolated. "H-NMR (ZO0MHC, SOSIZ): 5 - 1.60 (ZN), 1.73 (ZN), 2.08-2.28 (2H), 2.32 (ZN), 2.93 (ZN) , 3.81 (ZH), 4.93 (1H), 5.42 (1H), 5.81 (1H), 6.58 (1H), 6.95-7.09 (2H), 9.24 (1H). "

Example 273 5-(2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-2-methyl-2H-phthalazine- - c 1- 2-(3-methoxyphenyl)-2-methylpropanenitrile (339.72 mmol) of 3-methoxybenzyl cyanide was dissolved in 530 ml of DMF and mixed with 96.4 g (6792.4 mmol) of methyl iodide. After cooling to 02C, portions were added to the reaction mixture 21.5g (492.2mmol) of Ma (5595-n suspension) over four hours. After 18 hours at room temperature, the batch was poured into 7/0ml of a mixture (ee) of ice water and extracted three times with 500ml of diethyl ether each time. the combined organic phases were washed with water and brine. After drying over sodium sulfate, the desiccant was filtered off, and the solvent was removed by centrifugation on a rotary evaporator. After chromatography on silica gel (mobile solvent:

Ge) ethyl acetate/hexane), 48.9 g (82.290) of the required compound were obtained. their 50 "H-NMR MR (Z00MHZ, SOSIZ8): 5 - 1.73 (6H), 3.85 (ZH), 6.85 (1H), 7.02 (1H), 7.07 (1H), 7.31(1H). 2-(3-Methoxyphenyl)-2-methylpropanal iz" 25g (142.67mmol) of the nitrile described above was dissolved in 570ml of toluene. 178ml of a 1.2 molar solution of IVAN in toluene was added dropwise at a temperature of -65 to -602C for 75 minutes. After stirring for two hours at this temperature, 815 ml of a 2095% solution of B-(w)-tartaric acid 22 was added dropwise. After adding 150 ml, the temperature rose to -10 "C. The tartaric acid solution was quickly added , (PI remaining, and the batch was vigorously stirred at room temperature for 16 hours. The reaction mixture was shaken twice with b00ml of diethyl ether each time. The combined organic extracts were shaken with water and brine, dried, and the solvent was removed by centrifugation. The residue, which was obtained at the same time (25.1g-98.8905), was used at the next stage in an unpurified form. for "H-NMR (Z00MHC, SOSI"): 5 - 1.47 (6Н) , 3.83 (ZN), 6.78-6.90 (ZN), 7.30 (1H), 9.50 (1H).

Ethyl E-4-(3-methoxyphenyl)-4-methylpent-2-enoate 33.6 mg (114.3 mmol) of triethyl ester of phosphonoacetic acid was added to 148 ml of tetrahydrofuran. At a temperature of 09C, 79.7 ml of a 2M solution of HO0A in THF/heptane/ethylbenzene was added dropwise (1.5 hours). After stirring for one hour, 24.3 g (136.34 mmol) of b5, y and: 2-(3-methoxyphenyl)-2-methylpropanal, dissolved in 1300 ml of tetrahydrofuran, were added dropwise at 02С. After stirring for five days at room temperature, the reaction mixture was poured into 250 ml of dilute ammonium chloride solution and extracted twice with 4000 ml of diethyl ether each time. The combined organic extracts were processed as usual, and the resulting residue was chromatographed on silica gel (mobile

Vehicle: ethyl acetate/hexane). 27.2 g (80.495) of the required compound was isolated. 7TN-NMR (300 MHz, SOSIa): 5 - 1.30 (ZN), 1.49 (6N), 3.81 (ZN), 4.20 (2N), 5.80 (1N), 6.78 ( 1H), 6.85 (1H), 6.90 (1H), 7.12 (1H), 7.25 (1H).

Ethyl 4-(3-methoxyphenip)-4-methylpentanoate 27.2 g (109.5 mmol) of ethyl E-4-(3-methoxyphenyl)-4-methylpent-2-enoate was mixed in 293 ml of ethyl acetate with 2.72 g of palladium 70 on charcoal (1095) and stirred for 18 hours at room temperature under a hydrogen atmosphere.

The catalyst was removed by filtration with a glass fiber filter, and the residue left after concentration by evaporation (27.2g-99.290) was used in the next step in crude form. 7TH-NMR (300 MHz, SOSIvy): 5 - 1.21 (ZH), 1.32 (6H), 1.90-2.10 (4H), 3.82 (ZH), 4.05 (2H), 6.74 (1H), 6.89 (1H), 6.93 (1H), 7.25 (1H).

Ethyl 4-(3-methoxyphenyl)-2-hydroxy-4-methylpentanoate 27.2 g (108.65 mmol) of ethyl 4-(3-methoxyphenyl)-4-methylpentanoate was dissolved in 380 ml of tetrahydrofuran, and the reaction mixture was cooled to a temperature of in the range from -702С to -6520. During two hours, Zb4ml of a 0.5 molar solution of potassium bis--'trimethylsilylamide) in toluene was added dropwise, and then the reaction mixture was stirred for another 75 minutes at a temperature of -7020. Then, 39.7 g (152.11 mmol) of Davis reagent, dissolved in 38 Oml of tetrahydrofuran, was added dropwise over 90 minutes. After stirring for two hours at a temperature of -702C, 195 ml of saturated ammonium chloride solution was slowly added dropwise, the cooling bath was removed, and the mixture was intensively stirred for thirty minutes. After extraction with diethyl ether (twice, 800 ml each time), the combined organic extracts were treated, as usual, with water and saline solution. After removing the solvent by centrifugation, the residue from 29 was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 20.9 g (72.490) of the required He) compound was isolated. "H-NMR (ZO0MHC, SOSIv): 5 - 1.29 (ZN), 1.40 (ZN), 1.48 (ZN), 1.85 (1H), 2.20 (1H), 2.50 (1H), 3.81 (ZH), 3.99 (1H), 4.18 (2H), 6.76 (1H), 6.95 (1H), 7.00 (1H), 7.28 ( 1H). « 20 Ethyl 4-(3-methoxyphenyl)-4-methyl-2-oxopentanoate 2019g (78.47 mmol) ethyl 4-(3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate was dissolved in 820 ml of dichloromethane G was mixed with 2733 mL of dimethylsulfoxide. After adding 39.7 g (392.3 mmol) of triethylamine, batch c was mixed in portions with 31.2 g (196.18 mmol) of the 5Oz/pyridine complex and then stirred for 16 hours at room temperature. About 400 mL of dichloromethane was removed on a rotary evaporator. After that, the reaction (a) mixture was mixed with 312 ml of a saturated ammonium chloride solution with slight cooling, and the mixture was intensively stirred for 20 minutes. After two extractions with diethyl ether (800 ml each time), the combined organic phases were washed with water and salt solution. The residue that remained after removing the solvent by centrifugation, chromatog affluent on silica gel (mobile solvent: ethyl acetate/hexane).

15.59 g (75.395) of the required compound were isolated. " 20 "H-NMR (ZO0MHZ, SOSIv): 5 - 1.28 (ZH), 1.48 (6H), 3.18 (2H), 3.80 (ZH), 4.12 (2H), 6 .74 (1H), 6.90 (1H), - c 6.95 (1H), 7.25 (1H). Ethyl-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethyl-2- (trimethylsilyloxy)-pentanoate and 15.59 g (58.98 mmol) of ethyl 4-(3-methoxyphenyl)-4-methyl-2-oxopentanoate were dissolved in 9 bml of tetrahydrofuran and mixed at 02C with 10.1 g (70.78 mmol) of (trifluoromethyl )-trimethylsilane. After the addition of 144.5 mg of tetrabutylammonium fluoride was added, the mixture was stirred for 2 hours and 45 minutes at a temperature from 0 to 520. (ee) The batch was added to 1500 ml of a mixture of water and ice, extracted twice with diethyl ether (each time

ZOOml), and the combined organic extracts were processed as usual. After removing the solvent by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 17.10 g (71.390) (He) of the required product (contaminated) was isolated, which was used in this form at the next stage. 4-(3-Methoxyphenyl)-2-(trifluoromethyl)-pentane-1,2-diol e 6b,77g (16.65mmol) (rec.)

ЧТ» of ethyl 4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy)-pentanoate was dissolved in two ml of diethyl ether and mixed at 02С in portions with 1.26 g (33.31 mmol) of lithium aluminum hydride. The reaction mixture was stirred for 1 hour at a temperature of 52C and for 1.5 hours at room temperature. For hydrolysis, the mixture was mixed dropwise with 30 ml of a saturated solution of MansSO with cooling in an ice bath. o The mixture was vigorously stirred for 1 hour while cooling in an ice bath and vigorously stirred overnight at room temperature. The precipitate was suctioned off and washed with diethyl ether. The filtrate was concentrated by evaporation on a rotary evaporator, and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.64 g (71.2905) of the mixture was isolated, in which the trimethylsilyl group was partially attached to the 60 primary hydroxyl group and partially to the secondary hydroxyl group. Then the mixture (5.64 g) was diluted without additional purification in 72 ml of tetrahydrofuran and mixed with 4 g (12.7 μmol) of tetrabutylammonium fluoride trihydrate and stirred for 90 minutes at room temperature. The reaction mixture was diluted with water and extracted twice with 150 ml of diethyl ether each time. The combined organic phases were then washed with water and brine, and the solvent was dried and removed by centrifugation. Crude product (5.8g) 65 was chromatographed together with another obtained batch (7.97g of raw material, 10.4g yield of crude product) on silica gel (mobile solvent: ethyl acetate/hexane). From both batches, 10.07 g of the necessary diol was isolated.

7TH-NMR (ZO0MHZ, SOSI): 5 - 1.40 (ZN), 1.53 (ZN), 2.10-2.25 (1H), 2.80 (1H), 3.29-3.48 (2H), 3.83 (ZH), 6.78 (1H), 6.97 (1H), 7.00 (1H), 7.28 (1H). 4-(3-Methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal 10.07 g (34.45 mmol) of the above-described diol was oxidized to the corresponding aldehyde as already described several times according to Swern. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 7.16 g (71.695) of the required compound were obtained. 7TN-NMR (Z00MHz, SOSI"): 5 - 1.38 (ZN), 1.48 (ZN), 2.32 (1H), 2.69 (1H), 3.69 (1), 3.82 (ZH), 6.78 (1H), 6.88 (1H), 6.93 (1H), 7.25 (1H), 8.88 (1H). 5-I4-(3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentylideneamino)-2-methyl-2H-phthalazin-1-one

300 mg (1.033 mmol) of the above-described 4-(3-methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal was reacted to form an imine with 180.9 mg (1.03 mmol) of 5-amino-2-methyl-2H- phthalazin-1-one. After carrying out the interaction, the usual processing and chromatography, 318.2 mg (68.895) of the required imine were obtained. "H-NMR (ZO0MHC, SOSIv): 5 - 1.36 (ZN), 1.55 (ZN), 2.49 (1H), 2.78 (1H), 3.50 (ZN), 3.90 (ZH), 4.72 (1H), 72 vo (1H), 6.59 (1H), 6.78 (1H), 6.90 (1H), 7.05 (1H), 7.28 (1H , practically under chloroform), 7.53 (1H), 8.30 (1H), 8.43 (1H). 5-(2-hydroxy-b-methoxy-4,4-dimethyl-2-"(trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-ylamino-2-methyl-2H-phthalazin-1-one 100 mg (0.223 mmol) of the imine was cyclized with titanium tetrachloride in dichloromethane as described in Example 146.

43.4 mg (43.495) of the required compound was isolated, that is, in the form of a mixture of diastereomers.

MS (Eq): 448 (10095) 5-(2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-2-methyl-2H -phthalazine- 1-on

37 mg (0.082 mmol) of the simple ether, which is described in the previous paragraph, was reacted with 29 boron tribromide, as described in Example 146. After carrying out the reaction and the usual work-up, 20.9 mg (58.4965 He) of the required compound were obtained, i.e. in the form of a mixture of diastereomers.

MS (Eq): 434 (10095)

Example 274 1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthadiene-2,6-diol C 4-(3 -methoxyphenim)-1,1,1-trifluoro-2-(8-fluoro-2-methyginazolin-5-ilimino|-methyl)-4-methyl-pentan-2-ol "Her 400 mg (1.722 mmol) 4-( 33-Methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal was reacted to form an imine as described in Example 146 with 305.1 mg (1.722 mmol) of 5-amino-8-fluoro-2-methylquinazoline. After EE, chromatography isolated 494.4 mg (79.8905) of the required imine. Av

T'NA-NMR (SOSIV): 5 - 1.34 (ZN), 1.58 (ZN), 2.40 (1H), 2.79 (1), 3.00 (ZN), 348 (ZN) , 4.78 (1H), 6.29-6.42 (2H), 6.74 (1H), 6.90 (1H), 7.00 (1H), 7.28-7.40 (2H) , 9.64 (1H). so 1-(8-fluoro-2-methylquinazolin-5-ylsamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol (AM 2016) 15 mg (0.347 mmol) of the imine was cyclized in 2.5 ml of dichloromethane at a temperature of 02C with Timl of titanium tetrachloride, « 70 KA described in example 146. After chromatography on silica gel (mobile solvent: methanol/dichloromethane), 87.1 mg ( 58,190) of the required compound.

І "H-NMR (SO0MHCc, CO500): 5 - 1.42 (ZN), 1.58 (ZN), 2.08-2.23 (2H), 2.87 (ZN), 3.79 (ZN ), 5.28 (1H), 6.73 "» (1H), 6.82 (1H), 6.99 (1H), 7.23 (1H), 7.68 (1H), 9.68 ( 1H). 1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol bOomg (0.133 mmol) o 4 -(3-methoxyphenyl)-1,1,1-trifluoro-2-8-fluoro-2-methylquinazoline-5-ilimino|-methyl)-4-methylpentan-2-ol was mixed with 1.3 ml of a 1M solution of boron tribromide in dichloromethane while cooling in an ice bath. After 45 minutes of stirring at room temperature, the reaction mixture was mixed with ice, and a saturated solution of sodium bicarbonate was added dropwise until the pH was equal to 8. The cooling bath was removed, and the mixture was vigorously stirred for 15 minutes. After extraction with ethyl acetate, the combined organic extracts were washed with distilled water and then with brine. After drying, the solvent was removed by centrifugation, and the residue

Ta" was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). As a result, 19.5 mg (33.595) of the required compound was obtained.

TNA-NMR (ZO0MHC, CO5O0): 5 - 1.41 (ZN), 1.56 (ZN), 2.07-2.21 (2H), 2.89 (ZN), 5.24 (1H), 6.60 (1H), 6.78-6.91 (2H), 7.13 (1H), 7.59 (1H), 9.68 (1H). o Example 275 5-(2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-isoquinolin-1-one ime) 5- (2-hydroxy-4-(3-methoxyphenyl)-4-methyl-2--trifluoromethyl)pentylideneamino|-2H-isoquinolin-1-one 271mg (0.93bmmol) 4-(33-methoxyphenyl)-2-hydroxy -2-trifluoromethyl)-pentanal was reacted for imine formation with 150 mg (0.93 mmol) of 5-amino-2H-isoquinolin-1-one, as already described several times. After chromatography, 341.1 mg (84.595) of the required compound was isolated. 7TH-NMR (300 MHz, SOSIvZ): 5 - 1.33 (ZN), 1.55 (ZN), 2.39 (1), 2.79 (1H), 3.56 (ZN), 4.95 ( 1H), 6.38-6.55 (2H), 6.78 (1H), 6.79-6.95 (2H), 7.09 (1H), 7.12-7.35 (ZH), 8.31 (1H), 11.09 (1H). 5-(2-hydroxy-b-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-isoquinoline-1 b5 oon 150 mg (0.347 mmol) the above-described imine was cyclized to the required compound with titanium tetrachloride in dichloromethane as described in example 274. After chromatography, 18.8 mg (12.595) were isolated. "H-NMR (SO0MHCc, CO500): 5 - 1.42 (ZH), 1.58 (ZH), 2.05-2.24 (2H), 3.79 (ZH), 5.15 (1H) , 6.73 (1H), 6.89 (1H), 6.96 (1H), 7.05 (1H), 7.10-7.25 (2H), 7.49 (1H), 7.70 (1H). 5-(2,6-Dihydroxy-4,4-dimethylyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2H-isoquinolin-1-one

390 mg (0.208 mmol) of the previously described imine was cyclized to free phenol directly with boron tribromide as described in Example 274. After the usual work-up and chromatography, 53.8 mg (61.795) of the desired compound was obtained as a 3:2 diastereomer mixture.

MC (Eq): 419 (10095)

Example 276 5-(2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinolin-2-one 5-(2- hydroxy-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentyylideneamino|-1H-quinolin-2-one

ZbOOmg (1.0333mmol) of 4-(3-methoxyphenyl)-2-hydroxy-2-trifluoromethyl)-pentanal was reacted to form an imine, as already described several times, with 165.4mg (1.033mmol) of 5-amino -1H-quinolin-2-one. After 75 chromatography, 414.Zmg (92.790) of the required compound was isolated. "H-NMR (ZO0MHC, SOSIv): 5 - 1.33 (ZN), 1.53 (ZN), 2.40 (1H), 2.78 (1H), 3.58 (ZN), 4.85 (1H), 6.08 (1H), 6.49 (1H), 6.72-6.83 (2H), 6.90 (1H), 7.08 (1H), 7.28-7.38 (ZH), 8.18 (1H), 12.53 (1H). 5-(2-hydroxy-b-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene -1-ylamino)-1H-quinolin-2-one 15O0 mg (0.347 mmol) of the previously described imine was cyclized to the required compound with titanium tetrachloride in

Ddichloromethane as described in example 274. After chromatography, 35.8mg (23.8905) of diastereomer A was isolated, and an additional 14.Zmg (9.595) as a mixture of diastereomers. Spectral data refer to the pure diastereomer. "H-NMR (SO0MHCc, CO500): 5 - 1.42 (ZH), 1.59 (ZH), 2.05-2.24 (2H), 3.80 (ZH), 5.18 (1H) , 6.52 (1H), 6.61 (1H), 6.65-6.79 (2H), 6.95 (1H), 7.20 (1H), 7.39 (1H), 8.23 (1H). 5-(2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-1H-quinolin-2-one with 9Omg ( 0.208mmol) of the previously described imine was cyclized to free phenol directly with boron tribromide (3 boron as described in Example 274. After carrying out the usual work-up and chromatography, 37.bmg (43.1965) of the required compound was obtained as a mixture of diastereomers at a ratio of 4:1 .

MC (Eq): 419 (10095)

Example 277 in 7-fluoro-1-(8-fluoro-2-methylquinazolin-5-ylamino)4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-di" Its ol 4-bromomethyl-1-fluoro-2-methoxybenzop ee, 41.7g (297.54mmol) of 2-fluoro-5-methylanisole was heated in a reflux flask overnight with 59.9g of ХС(хСЗ3 (327.4в8mmol) of M-bromosuccinimide and 145 mg of benzoyl peroxide in 945 ml of carbon tetrachloride. The reaction mixture 3o was filtered using a glass fiber filter, and after removing the solvent by centrifugation, the residue (72.85 g 210095) was used in the next step in crude form. (4-fluoro-3-methoxyphenyl) -acetonitrile

72.85 g of the previously described bromine compound was added to a mixture containing 330 ml of dimethylformamide and 209 ml of water. After adding 32.5 g (498.8 mmol) of potassium cyanide at room temperature (slight heating), batch C was stirred overnight at room temperature. The reaction mixture was poured into a mixture of water and ice and extracted three times with methyl tert-butyl ether. The combined organic extracts were washed with saline, and

The solvent was removed by centrifugation after drying. The residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 33.34 g (61.4905) of the required nitrile was isolated. 7"H-NMR (SOSI"): 3.72 (2H), 3.93 (3H), 6.83 (1H), 6.93 (1H), 7.09 (1H). so 395 2- (4-fluoro-3-methoxyphenyl)-2-methylpropionitrile 16.67 g (100.93 mmol) of (4-fluoro-3-methoxyphenyl)-acetonitrile was added to 158 ml of dimethylformamide with 30.1 g (a) (211.9 mmol) of methyl iodide. 8.50 g (211.96 mmol) of a 55-6095-bu suspension of sodium hydride was added in portions at 09 C. After stirring overnight at room temperature, the reaction mixture was poured into a mixture of ice water and then extracted three times with methyl m2/n-butyl ether The combined organic vol. 50 extracts were washed with water and brine, then the solvent was dried and removed by centrifugation,

I" residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.11 g (26.2905) of the required compound and isolated 6.18 g of the monomethyl compound, which was re-alkylated. "H-NMR (SOSIV): 1.72 (6H), 3.92 (3H), 6.95 (1H), 7.00-7.12 (2H). 2-(4-fluoro-3-methoxyphenyl )-2-methylpropionaldehyde 9.37 g (48.50 mmol) of 2-(4-fluoro-3-methoxyphenyl)-2-methylpropionitrile was reduced from 39.98 ml (72.48 mmol) (F) of a 1.2 M solution of OIVAG in toluene at temperature -782С, in particular, as described in some previous examples. Isopropanol and tartaric acid were used for hydrolysis. 9.31 g of a mixture containing one-third of the starting material and two-thirds of the required aldehyde was isolated. This mixture was again reacted with OIVAI at a temperature of - 782С and after treatment a mixture (9.18g) containing nitrile, aldehyde and the corresponding alcohol was obtained.

This mixture was reconstituted again with SIVAY, but this time at a temperature from -10 to 09C. After hydrolysis with isopropanol, 1.45 g of the required aldehyde and 5.68 g of the corresponding alcohol were isolated. This alcohol was oxidized to the aldehyde under Swern's conditions, as has been described several times. After the usual treatment and purification, 5.09 g of the required aldehyde was isolated. 65 "H-NMR (SOSIV): 1.48 (6H), 3.90 (ZH), 6.75-6.87 (2H), 7.09 (1H), 9.49 (1H).

Ethyl-(E)-(4-fluoro-3-methoxyphenip)-4-methylpent-2-enoate

6.10 g (27.23 mmol) of triethylphosphonoacetate was dissolved in 16.5 ml of tetrahydrofuran. At a temperature of 09C, 14.9 ml (29.12 mmol) of IA was added dropwise, and the batch was stirred for 30 minutes at a temperature of 0 20.

After adding dropwise 5.34 g (27.22 mmol) of the above-described aldehyde dissolved in 16.5 mL of tetrahydrofuran, the reaction mixture was stirred overnight at room temperature. Water was carefully added dropwise at 09, stirred vigorously for ten minutes, and then shaken three times with tert-butyl ether. The combined organic extracts were washed with saline and dried. After removing the solvent by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.75 g (79.395) of the required compound was isolated. "H-NMR (SOSIV): 1.29 (ZN), 1.48 (6H), 3.90 (ZN), 4.20 (2H), 5.80 (1H), 6.79-6.90 (2H), 7.02 (1H), 7.10 (1H).

Ethyl-(4-fluoro-3-methoxyphenyl)-4-methylpentanoate 5.75 g (21.59 mmol) of ethyl-(E)-(4-fluoro-3-methoxyphenyl)-4-methylpent-2-enoate was hydrogenated overnight in hydrogen atmosphere in 8 Oml of ethanol with the help of 307, Zmg Pa/С (1095). The reaction mixture was suctioned using a glass fiber filter, and the solvent was removed by centrifugation. 5.69g (98.390) of the required compound was isolated, 75 which was further used in crude form. "H-NMR (SOSIV): 1.22 (ZN), 1.31 (6H), 1.90-2.10 (4H), 3.90 (ZN), 4.08 (2H), 6.83 (1H), 6.91 (1H), 7.00 (1H).

Ethyl 4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate 5.69 g (21.21 mmol) of ethyl-(4-fluoro-3-methoxyphenyl)-4-methylpentanoate was reacted with 7.76 g (26.7O0mmol) of Davis reagent as described in Example 273. After carrying out the usual work-up and after chromatography on silica gel (mobile solvent: ethyl acetate/hexane) as described in this application, 2.98 g (49.595) of the required compound were obtained. 7TH-NMR (300 MHz, SOSIvZ): 5 - 1.29 (ZN), 1.40 (ZN), 1.48 (ZN), 1.83 (1), 2.20 (1H), 2.56 ( 1H), 3.85-3.99 (4H), 4.13 (2H), 6.90 (1H), 6.95-7.08 (2H).

Ethyl 4-(4-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentanoate c 29 2.18 g (9.78 mmol) ethyl 4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4 -methylpentanoate was oxidized to Ge) corresponding o-ketoether with ZO3/Ru in dichloromethane, as described in example 273. After chromatography on a carrier

Niazptavieg obtained 2.48 g (89.9905) of the required compound. 7H-NMR (300 MHz, SOSI»v): 5 - 1.28 (ZH), 1.48 (6H), 3.15 (2H), 3.90 (ZH), 4.12 (2H), 6, 88 (1H), 6.90-7.03 (2H). 4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylphenyl-2-trifluoromethyl)-pentanal 2.48g (8.7U9mmol) ethyl-4-(4-fluoro-3-methoxyphenyl) -4-methyl-2-oxopentanoate was converted into an aldehyde - according to Swern using the sequence described in example 273, with trifluoromethylation using Ruppert's reagent, reduction of the complex ether with lithium aluminum hydride to the alcohol, and subsequent oxidation of the alcohol. As a result of the implementation of three stages, 382.Zmg of necessary aldehydes were isolated. o 7TH-NMR (300 MHz, SOSIv): 5 - 1.38 (ZH), 1.48 (ZH), 2.32 (1H), 2.66 (1H), 3.68 (1H), 3.90 (ZH), 6.80-6.92.. 0 (2H), 7.02 (1H), 8.88 (1H). 1,1,1-trifluoro-4-(4-fluoro-3-methoxyphenyl)-2-((8-fluoro-2-methylquinazolin-5-ilimino)-methyl)|-4-methylpentan-2-ol 127 4mMg (0.413 mmol) of 4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylphenyl-2--trifluoromethyl)-pentanal was reacted to obtain the corresponding imine with 73.2 mg (0.41 mmol) of 8-fluoro -2-methylquinazoline and 235.1 mg 70 (0.827 mmol) of titanium isopropylate (!M) in 2.2 ml of xylene, as has already been described several times. After - s chromatography on the RIazptavieg carrier, 138.5 mg (71.790) of the required compound was isolated. h» TN-NMR R (SOSIv): 5 - 1.35 (ZN), 1.56 (ZN), 2.44 (1H), 2.72 (1H), 2.99 (ZN), 3.68 (ЗН), 4.77 (1Н), 6.38 " (1Н), 6.70-6.90 (ЗН), 7.38-7.48 (2Н), 9.65 (1Н). 7- fluoro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol bo 20mg (0.043 mmol) of the above-described imine was subjected to a reaction with 0.5 ml of boron tribromide (1M solution in dichloromethane) at a temperature of 09C and thus converted into cyclized phenol. After chromatography on a Riazptazvieg support, 7.1 mg (36.6905) was isolated. b T' NA-NMR (СО50О0): 5 - 1.41 (НН), 1.56 (НН), 2.06-2.22 (2Н), 2.89 (НН), 5.24 (1Н), 6, 84 (1H), 6.89-7.04 iz 70 (Dn), 7.59 (1H), 9.69 (1H).

T» Example 278 5-(/-fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1H-quinol yn-2 -one 5-I4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino|-1H-quinolin-2-one 59 127 mg (0.4133 mmol) of aldehyde, which described in example 277, was subjected to a reaction to form an imine with

GF) 66.32mg (0.413mmol) of 5-amino-1H-quinolin-2-one as described in this application. After chromatography on a carrier of 7 Riazpitazieg, 89.2 mg (47.995) of the required compound were isolated.

TNA-NMR (SOS): 85 - 1.37 (ZN), 1.53 (ZN), 2.43 (1), 2.71 (1H), 3.71 (ZN), 4.85 (1) , 610 (1H), at 6.70-6.92 (4H), 7.30-7.42 (ZH), 8.15 (1H), 12.42 (1H). 5-(7/-fluoro-2-hydroxy-b-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1H-quinol yn-2- 89.2 mg (0.198 mmol) of the above-described imine was reacted to obtain a cyclic simple ether in 1.00 ml of dichloromethane with 1.3 ml (1.188 mmol) of titanium tetrachloride. After chromatography on Riazptazwieg, 65, 5.7 mg of the required compound was obtained. 7TNA-NMR (SOS): 5 - 1.40 (ZN), 1.60 (ZN), 2.00-2.29 (2H), 3.88 (ZN), 5.00 (1H), 5.07 (1H ), 5.68 (1H),

6.45-6.60 (ZH), 6.85-7.02 (2H), 7.32 (1H), 8.20 (1H), 10.05 (1H).

Example 279 b-fluoro-1-(2-methylquinolin-5-yl)amino|-4-ethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol "H-NMR (ZO0MHCc, СО500); 5 - 0.97 (z, ZN), 1.79 (da, 1H), 1.96 (daY, yin), 2.19 (449, 1H), 2.36 (aa, tn), 2.713 (v, ЗН), 3.40 (t, 1Н), 4.98 (a, yin), 5.12 (a, yin), 6.60 (a, 1n), 6.89 ( a, 2), 7.23 (a, tn), 7.43 (a, 1H), 7.51 (i, 1H), 8.11 (a, 1n).

Examples 280 and 281 5-X17-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|iamino)-quinoline-2(1H 70. )-one, diastereomer А І 5-Х17-bromo-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinoline-2( 1H)-one; diastereomer B

Similarly to example 10, the corresponding name was obtained, leaving Кк! 800 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal and 348 mg of 5B-amino-quinolin-2(1H)-one. 75 16 mg of diastereomer A was obtained 5-Sh17-bromo-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinoline-2(1H) -one in (fraction A) and 79 mg of diastereomer B 5-Sh17-bromo-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)- quinolin-2(1H)-one by the reaction of 80mg of imine with 7.9ml of boron tribromide solution (1H in dichloromethane).

Fraction A: С H-NMR (СО5О0): 5 - 1.40 (v, ЗН), 1.55 (v, ЗН), 1.90 (4, 1), 2.25 (9, 1Н), 5 ,22 (c, 1H), 6.11 (a, 1Hn), 6.58 (a, 1Hn), 6.67 (9, 1H), 7.12-7.30 (t, ЗН), 8, 20 (a, 1n).

Fraction B. "H-NMR (СО5О0): 5 - 1.54 (in, ЗН), 1.65 (з, ЗН), 2.05 (y, 1Н), 2.14 (9, 1), 5 ,13 (z, 1H), 6.53 (y, 1H), 6.62 (a, 1), 6.72 (d, 1H), 6.87 (c, 1H), 6.94 (8, 1H), 7.40 (i, 1H), 8.22 (a, 1Hn).

Example 282 p 29 1,6-dihydroxy-8,8-dimethyl-5-(1-oxo-1,2-dihydroisoquinolin-5-ylamino)-6-trifluoromethyl)-5,6,7,8-tetrahydron Ge ) naphthalene-2-carbonitrile 75mg (0.16bmmol) 5-(6-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino )-2H-isoquinolin-1-one was dissolved in 1.3 ml of 1-methyl-2-pyrrolidinone and reacted under the influence of microwaves with 16.27 ml (0.332 mmol) of sodium cyanide and 36.27 ml (0.16 mmol) of nickel bromide (II) as described in Example 160. The black reaction mixture was added using a glass fiber filter. After washing with ethyl acetate, the filtrate was also mixed additionally with bOml of ethyl acetate. The mixture was shaken with water and saline solution. After drying, the solvent was removed by centrifugation, and the residue was chromatographed on silica gel (amine plate; mobile solvent: (su methanol/dichloromethane). 16.2 mg (22.195) of the required nitrile was isolated.

From MS (Ek): 444 (10095); IR (microscope, matrix: diamond): 2230. so

Example 283 (research) 5-C6-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-isoquinoline-1 ( " 2H)-one Z 5-amino-isoquinolin-1(2H)-one s Methyl ether of 2-methyl-3-nitrobenzoic acid

100 g (165.mmol) of 2-methyl-3-nitrobenzoic acid was added to 150 mL of methanol, then 2.9 mL of concentrated sulfuric acid was added, and the mixture was heated in a reflux flask for 2 days. After cooling, the crystallisate (22.55g-7990) was sucked off and thus included in the next stage. so 15 "H-NMR (300 MHz, DMSO-IV): 5 - 2.50 (ZH), 3.85 (ZH), 7.56 (1H), 8.00 (1H), 8.05 (1H) .

Methyl ether of 2-(bromomethyl)-3-nitrobenzoic acid (c) 25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl ether was added to ZbOml of carbon tetrachloride and mixed with 25.6 g (141./ 7 mmol) of M-bromosuccinimide and 62.8 mg of benzoyl peroxide.

The mixture was heated in a reflux flask for seven days, then the succinimide was sucked off after 50 minutes of cooling, and then the filtrate was centrifuged until the anhydrous state was reached. It remained necessary

And" compound, which was used in the next stage in crude form. "H-NMR (300 MHz, SOSI»v): 5 - 4.00 (ZH), 5.66 (2H), 7.55 (1H), 7.95 (1H), 8.10 (1H). 5 -nitroisocoumarin 16.4 g (84.033 mmol) of 2-methyl-3-nitrobenzoic acid methyl ether was stirred with 26.8 g (225.1 mmol) of dimethyl acetal of M,M-dimethylformamide in 8 bml of dimethylformamide for 12 hours at 130920. The solvent (iF) was removed at rotary evaporator, the residue was resuspended in methyl tert-butyl ether and washed three times with water. After washing with saturated Massey solution, the organic phase was dried. The desiccant was then filtered and the solvent was removed by centrifugation, and the remaining residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 8.73 g (54.495) of the required compound were isolated. "H-NMR (300 MHC, SOCIv): 5 - 7.39 (1H), 7.45 (1H), 7.68 (1H), 8, 49 (1H), 8.65 (1H). 5-nitroisoquinolin-1(2H)-one 2.51 g (13.13 mmol) of 5-nitroisocoumarin was added to 100 ml of ethanol. Ammonia was compressed under pressure in an autoclave. The product settled and was suctioned off. 1.98 g (79.795) of the required compound was isolated. 65 "H-NMR (300 MHz, DMSO-iv): 5 - 6.97 (1H), 7.45 (1H), 7.65 (1H), 8.43 (1H), 8.57 (1H), 11.5 (1H) 5-aminoisoquinoline-1(2H)-one

268.Zmg (1.51 mmol) of 5-nitroisoquinolin-1(2H)-one was added to 376.5 mg of ammonium chloride and 2.bml of water in 14 ml of ethanol and 5.4 ml of tetrahydrofuran. After adding portions of 1.23 g of zinc powder (heating in the interval from 30 to 35922), the mixture was stirred for two hours. The reaction mixture was suctioned off using a glass fiber filter and washed repeatedly with ethyl acetate. Then the filtrate was washed with water and saturated sodium chloride solution, the organic phase was dried as usual. After filtering off the desiccant and removing the solvent by centrifugation, 196.5 mg (88.190) of the required amine was obtained. 7H-NMR (300 MHz, DMSO-iv): 5 - 5.6 (2H), 6.68 (1H), 6.87.45 (1H), 7.00 (1H), 7.17 (1H), 7.39 (1H), 11.7 (1H). 2-(33-fluoro-2-methoxy-4-methylphenyl)-2-methylpropanenitrile 14.48 g (91.5 mmol) of 2,6-difluoro-3-methylanisole was dissolved in 8000 ml of toluene. After adding 272.2 mL (137.35 mmol) of a 0.5 molar solution of potassium hexamethyldisilazide in toluene, 25.31 g (366.2 mmol) of isobutyronitrile was added dropwise. The batch was stirred for 10 days at room temperature and then added to a 1M solution of NS. After that, it was extracted three times with methyl tert-butyl ether, the combined organic extracts were washed with saturated Masi solution and dried. After centrifugation and chromatography on 75 silica gel (mobile solvent: ethyl acetate/hexane), 10.32 g (49.595) of the required compound were obtained. "H-NMR (300 MHz, SOSI»v): 5 - 1.77 (6H), 2.29 (ZH), 4.09 (ZH), 6.86 (1H), 6.95 (1H). 2 -(3-fluoro-2-methoxy-4-methylphenyl)-2-methylpropanal 10.32 g (45.33 mmol) of the nitrile described above was dissolved in 138 ml of toluene. Under gas protection, 37.4 ml of a 1.2 molar solution of OIVAN in toluene was added dropwise at -702 C. After stirring for three hours, 7.92 ml of isopropanol was added dropwise, and after a short period of stirring, 51 bml of the 1096 solution

of 1-(4-tartaric acid). The temperature was raised and the batch was stirred vigorously overnight at room temperature. The reaction mixture was shaken twice with methyl teretebutyl ether. The combined organic extracts were shaken with brine, dried, and the solvent was removed by centrifugation. Since the residue , which was obtained (11.61 g210095), still contained about 3095 of the starting substance, then it was subjected to reduction again, with the difference that isopropanol was removed during the treatment. 9.94 g of product was isolated, which, in addition to the required aldehyde , still contains the starting substance and the corresponding alcohol.

This mixture was again mixed with a 1.2 M solution of OIVAN in toluene, but this time at a temperature of -2092C and with additional stirring at a temperature in the range from -10 to 02C to obtain a homogeneous compound. After carrying out the usual treatment and after chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 5.82 g of the corresponding alcohol and 1.50 g of aldehyde were obtained as a result. Alcohol (5.82g-27.42mmol) was oxidized to ch;E aldehyde according to Swern at a temperature of -782C. After carrying out the usual treatment and after chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 5.22 g (90.695) of the required aldehyde was isolated. h-o "H-NMR (300 MHz, SOSI"): 5 - 1.38 (6H), 2.29 (ZH), 3.85 (ZH), 6.83-6.98 (2H), 9 .59 (1H). | "c)

Ethyl ether (E/7)-4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid with 17.L ml of a 2 molar solution of SHA in THF was added dropwise to a solution of triethyl ether 8 ,62g (32.9b6mmol) of 2-ethoxy-phosphonoacetic acid in 2Oml of absolute THF at a temperature of 090. After stirring for 40 minutes at a temperature of 09C, 6.72g (31.9bmmol) of 2-(3Z-fluoro-2- methoxy-4-methylphenyl)-2-methylpropanal, dissolved in 20 ml of THF, at 02С. After stirring overnight at room temperature, the reaction mixture was carefully mixed with 8 mL of water and extracted three times with methyl tert-butyl ether. The combined organic extracts were washed with saline, dried, and the solvent was removed by centrifugation after filtering off the desiccant. The residue was chromatographed on "" silica gel (mobile solvent: ethyl acetate/hexane). 8.74 g (84.390) of the mixture was isolated, which, in addition to the required compound, also contains the starting substance (aldehyde), which was separated at the next stage. (E/2) -4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid (ee) 8.74 g (26.95 mmol) ethyl ether (E/2)-4-(3-fluoro -2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid was mixed with 245 mL of in. Mahon in ethanol/water (2:11) and stirred overnight at room temperature. The ethanol was removed on a rotary evaporator, and the residue diluted with water and extracted twice with methyl tert-butyl (ter) ether. The combined organic extracts contained the unreacted aldehyde from the above reaction. The aqueous phases were carefully acidified with concentrated hydrochloric acid to pH 3 while cooling in an ice bath and extracted three times each time Extracted with methyl tert-butyl ether. These ether extracts were washed with brine, dried, and the solvent was removed cent by refugation, and the residue (6.41g-80.395) was used in the next stage in crude form. The reduced aldehyde was again subjected to the sequence of reactions according to

Horner-Wittig and subsequent saponification. As a result, an additional 2.29 g of the required compound (EB/2)-4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid was obtained. Since the compound is an E/7 mixture o (not in a 1:1 ratio), only the positions of the signals are indicated on the NMR spectrum. "H-NMR (Z00MHz, SOSI"): 5 - 0.98, 1.40, 1.53, 2.21, 3.38, 3.75-3.88, 6.72-6.85, 7 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid 8.7 g (29.3 mmol) -2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid, which was obtained from 60 of the previous batch, was mixed with 139 ml of 1 molar sulfuric acid and 13.9 ml of glacial acetic acid and stirred for two days at a bath temperature of 902C. After cooling, the batch was basified with solid potassium carbonate (caution, foam). The mixture was extracted three times with methyl tert-butyl ether, and the combined organic extracts were discarded after observation by TLC. The aqueous phase was acidified with concentrated hydrochloric acid and shaken three times with tert-butyl ether. The ether extracts were washed with brine, dried, and the solvent was removed by centrifugation. The residue that remained (6.04g-76.690) was used in the next step in crude form.

"H-NMR (30 MGu, SOSIv): 5 - 1.48 (6H), 2.25 (ZH), 3.50 (2H), 3.93 (ZH), 6.82 (1H), 6, 95 (1H).

4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ether b.04g (22.52 mmol) 4-(3-fluoro-2-methoxy-4-methylphenyl) )-4-methyl-2-oxo-pentanoic acid was dissolved in 140 ml of ethanol, mixed with 2.5 ml of sulfuric acid, and heated in a reflux flask for six hours. Ethanol was removed on a rotary evaporator, and the residue was carefully mixed with ZOOml of saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The combined organic extracts were washed once with saturated sodium bicarbonate solution and once with saline solution. After drying and after filtering off the desiccant and removing the solvent by centrifugation, the residue was chromatographed on 70 silica gel (mobile solvent: ethyl acetate/hexane). 5.58g (83.790) of the required compound was isolated. "H-NMR (300 MHz, SOSI»v): 5 - 1.29 (ZH), 1.47 (6H), 2.23 (ZH), 3.40 (2H), 3.95 (ZH), 4 .17 (2H), 6.79 (1H), 6.90 (1H).

Ethyl ether of 4-(33-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentanoic acid 5.58 g (18.83 mmol) of ethyl ether of 4-(3-fluoro-2- methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid was dissolved in 30 ml of THF and mixed at 09 with 3.21 g (22.6 mmol) of (trifluoromethyl)-trimethylsilane and 46.1 mg of tetrabutylammonium fluoride. After stirring for six hours at a temperature in the range from 0 to 5oC, the batch was added to a mixture of water and ice. It was extracted three times with methyl tert-butyl ether, and the combined organic extracts were washed with brine. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 7.5 g (90.895) of the required compound were obtained. 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol 7.5 g (17.1 mmol) of ethyl ether 4-(3-fluoro- 2-Methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid was dissolved in bOml of diethyl ether and mixed in portions with 1.3 g (34.2 mmol) of PIAEII at a temperature in the range from 0 to 592S. After stirring for five hours at room temperature, bOml of saturated MannHSO" was added dropwise to the reaction mixture while cooling in an ice bath. The mixture was intensively stirred for 1 hour at room temperature. After extraction with methyl tert-butyl ether, the organic phases were shaken with brine, dried, and the solvent was removed by centrifugation. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 3.6b5g (65.890) of the required "diol" were obtained. 3o MS (SI): 342 (10096), 181 (1896). 4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal 1.57 g (12.31 mmol) of oxalyl chloride was added to 27 ml of dichloromethane and cooled to -782С . After adding dropwise 1.p93g of DMSO dissolved in 5.2ml of dichloromethane, the batch was additionally stirred for five (a) minutes. After that, 3.65 g (11.2 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol, dissolved in 11.5 ml of dichloromethane. After stirring for two hours, the batch was carefully mixed with 6.6 mL (56.28 mmol) of triethylamine. After 1.5 hours of vigorous stirring at room temperature, water was added and the batch was shaken twice with dichloromethane. The combined organic extracts were washed with 195% sulfuric acid, saturated sodium bicarbonate solution, and brine. Then the organic phase was dried, the solvent was removed by centrifugation. 2.79 g (76.995) of the obtained aldehyde remained, which was further used in its crude form. :z» TN-NMR (300 MHz, SOSIi): 5 - 1.41 (ZN), 1.45 (ZN), 2.15-2.30 (5H), 3.29 (1H), 3.60 ( 1H), 4.02 (ZH), 6.70-6.82 (2H), 9.10 (1H). (research)-5-14-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene|amino)isoquinoline o -4(2H)-one 150 mg ( 046b5mmol) /4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)pentanal, about 74.5mg (0.465mmol) 5-amino-isoquinoline-1( 2H)-one and 264.4 mg (0.930 mmol) of titanium tetraisopropylate were stirred in 2.5 ml of xylene for five hours at 1202. The mixture was diluted with ethyl acetate and washed once with saline solution. The solvent was removed by centrifugation, and the residue was chromatographed on Riazptazieg support. 98.bmg (45.695) of the required compound was isolated. c» 7TN-NMR (300 MHz, SOSIa): 5 - 1.40 (ZN), 1.58 (ZN), 1.89 (ZN), 2.29 (1H), 3.30 (1), 4, 00 (ZH), 4.79 (1H), 6.38 (1H), 6.67-6.78 (2H), 6.80 (1H), 7.20 (1H), 7.38 (1H) , 7.55 (1H), 8.32 (1H), 11.0 (1H). (rec.) 5-Cb-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-isoquino lin-1(2H)-one) and 1.39 ml (1.27 mmol) of titanium tetrachloride were carefully added dropwise at a temperature of 02C to 98.bmg co (0.212 mmol) of the compound rac-5-44-(3-fluoro-2- methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene|amino)isoquinolin-1(2H) 60 -one, which is described in the previous paragraph, and then the mixture was stirred for three hours at room temperature. The reaction mixture was carefully mixed at 09C with a saturated sodium bicarbonate solution. It was then extracted three times with ethyl acetate and the combined organic extracts were washed with saturated Massey solution. After drying over sodium sulfate, the solvent was removed by centrifugation, and the remaining residue was chromatographed on Riazptazvieg media. 63.Zmg (64.295) of the required compound was isolated. for "H-NMR (ZO0MHCc, CO500): 5 - 1.52 (ZH), 1.67 (ZH), 2.05-2.20 (5H), 3.98 (ZH), 5.10 (1H ), 6.80-6.95 (2H),

7.08 (1H), 7.19 (1H), 7.40 (1H), 7.70 (1H). (researcher) 5-Tb-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-isoquinoline-1 (2H)-one 59.7 mg (0.128 mmol) (rec.) 5-C6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3, 4-tetrahydronaphthalene-1-yl|amino)-isoquino lin-1(2H)-one was mixed at 092C with 1.hml of a 1 molar solution of boron tribromide in dichloromethane, and the mixture was stirred for 1 hour at a temperature in the range from 0 to 59C. Then, at a temperature of -109C 70, a saturated solution of sodium bicarbonate was carefully added dropwise. After 10 minutes of vigorous stirring at room temperature, the batch was extracted three times with methyl tert-butyl ether. The organic phases were dried, and after removal of the solvent by centrifugation, the residue was chromatographed on the carrier

Niazptazvieg. 46.5 mg (80.395) of the required compound was isolated. 7TH-NMR (ZO0MHCz, СО3О0): 5 - 1.56 (ЗН), 1.70 (ЗН), 2.00-2.20 (5Н), 5.09 (1Н), 6.65 (1Н), 6.85 (1H), 7.05 15. (1H), 7.18 (1H), 7.39 (1H), 7.68 (1H).

Example 284 (research) 5-C6-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinoline-2 (1H)-one 5-aminoquinolin-2(1H)-one 4.5 g of 5-nitroquinolin-2(1H)-one | RIagt. You 29, 651, 19811) was hydrogenated with hydrogen in 200 ml of ethyl acetate and 50 ml of methanol in the presence of 450 mg of palladium on activated carbon as a catalyst at atmospheric pressure until the completion of the reaction. The catalyst was removed by filtration through diatomaceous earth, and the reaction solution was concentrated by evaporation in vacuo. 3.8 g of the title compound was obtained as a yellow solid. o 7"H-NMR (DMSO): 5 - 5.85 (rv, 2H), 6.27 (a, 1H), 6.33 (4, 1H), 6.43 (a, 1H), 7, 10 (i, 1H), 8.07 (a, 1H), 11.39 (rv, 1H) rac-5-44-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4- methyl-2-trifluoromethyl)pentylidene|amino)isoquinolin-2(1H)-one 150 mg (0.465 mmol) 4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-" trifluoromethyl)pentanal (described in example 1), 74.5 mg (046 bBmmol) of 5-amino-isoquinolin-201H)-one and 264.4 mg (0.930 mmol) of titanium tetraisopropylate were stirred in 2.5 ml of xylene for five hours at 120 "C. The mixture was diluted with ethyl acetate and washed once with saline solution. The solvent was removed by centrifugation, and the residue was chromatographed on Riazptavieg support. 132.2 mg (61.2905) of the required compound was isolated. ): 5 - 1.40 (ZN), 1.56 (ZN), 1.82 (ZN), 2.29 (1H), 3.28 (1), 3.98 (ZN), 4.70 ( 1H), so 6.30-6.45 (2H), 6.70-6.80 (2H), 7.30 (1H), 7.40 (1H), 7.63 (1H), 8.07 (1H), 12.27 (1H). (rec.) 5-C6b-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-"(trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)-isoquinolin-2(1H)-one « 20 1.66 ml (1.708 mmol) of titanium tetrachloride was carefully added dropwise to 132.2 mg (0.285 mmol) compounds - in rac-5-14-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-"(trifluoromethyl)pentylideneamino)isoquinolin-2(tH )-one, which described in the previous paragraph, at a temperature of 02C, and then the mixture was stirred for three hours at room temperature. The reaction mixture was carefully mixed at 09C with a saturated sodium bicarbonate solution. Then it was extracted three times with ethyl acetate and the combined organic extracts were washed with a saturated mass solution. After drying over sodium sulfate, the solvent was removed by centrifugation, and the remaining residue was chromatographed on a Riazptavieg medium. 106.7 mg (80.795) of the required compound was isolated. "H-NMR (ZO0MHZ, SOSIZ): 5 - 1.52 (ZH), 1.68 (ZH), 1.98-2.25 (5H), 3.95 (ZH), 4.60 (1H) , 4.99 (1H), 5.49 o (1H), 6.49-6.62 (ZH), 6.80 (1H), 7.35 (1H), 8.16 (1H), 10, 40 (1H). (2) (research) 0 5-Cb-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1 -yl|amino)-isoquinolin-2(t 1H)-one)

ChT" 101.4 mg (0.218 mmol) (rat.) 5-C6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene -1-yl|amino)-isoquino lin-2(1H)-one was mixed at 02 with 2.2 ml of a 1 molar solution of boron tribromide in dichloromethane and stirred for 1 hour at a temperature in the range from 0 to 52C. Then, at a temperature of -109C, a saturated solution of sodium bicarbonate was carefully added drop by drop. After 10 minutes of vigorous stirring at room temperature, the batch was extracted three times with methyl tert-butyl ether. The organic phases were dried, and after removing the solvent by centrifugation, the residue was chromatographed on Riazptavieg support. 93.7 mg (95.395) of the required compound was isolated. 60 "H-NMR (ZO0MHCz, СО50О0): 5 - 1.58 (ЗН), 1.69 (ЗН), 2.00-2.20 (Б5Н), 5.10 (1), 6.51 (1Н ), 6.55-6.74 (ZH), 7.39 (1H), 8.22 (1H).

Example 285 (race) b-fluoro-1-((8-fluoro-2-methylquinazolin-5-yl)amino)-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4 -tetrahydronaphthalene-2,5-diol b5 5-amino-8-fluoro-2-methylquinazoline

A solution of 2.4 g (18 mmol) of 2,5-difluoroaniline in 1 ml of water and 1 ml of concentrated hydrochloric acid (37905), the temperature of which was 50 C, was added to the 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, which was previously stirred at this temperature for 1 hour. The mixture was stirred for another 30 minutes at room temperature, and after adding 4.09g (58.9mmol) of hydroxylammonium chloride in 9Uml of water, the mixture was heated for 45 minutes to 12590 and this temperature was maintained for 5 minutes. After cooling and after another hour, the precipitated light brown precipitate was filtered off, washed with water and dried. As an intermediate product was obtained

C,Og (15.00 mmol) of hydroxylimine, which was dissolved in portions in 15 ml of concentrated sulfuric acid at 70°C. After the addition was complete, the mixture was heated for 2 hours to 80°C and for 4 hours to 902°C. it was left to cool, and the solution was poured into 100 g of ice. The mixture was extracted with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0-4595), 1.2 g (7.1 mmol) of 4,7-diphthorezine was obtained. 1.5 ml of a 30% solution of hydrogen peroxide in 30 ml of a 1-molar solution of sodium hydroxide 75 was added dropwise to isatin for 10 minutes. After 2 hours of stirring at room temperature, the mixture was cooled to 0°C, and 5 ml of 4-molar hydrochloric acid was added and diluted with 500 ml of water. The mixture was extracted with ethyl acetate, dried over sodium sulfate, concentrated by evaporation, and obtained with a quantitative yield of 1.27 g of 3,6-difluoroanthranilic acid, which was subjected to the reaction without additional purification. 3,b-difluoroanthranilic acid was heated in ml of acetic anhydride for 45 minutes to 10020. After cooling, the resulting acetic acid and excess acetic anhydride were removed azeotropically with toluene under vacuum. The residue was mixed with 40 ml of 25965 ammonia solution, while it was cooled on ice, and stirred for 72 hours. The mixture was diluted with water and acidified with acetic acid. it was extracted with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate, and concentrated by evaporation. 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-ZN-quinazolin-4-one and bg of phosphorus pentachloride obtained in this way were heated in 20 ml of phosphoryl chloride for 12 hours to 12520. After cooling, the mixture was poured in He) saturated MansSoO»z solution and extracted with ethyl acetate. The organic phase was dried and the solvent was removed.

A quantitative yield of 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline was obtained, which was dissolved in bOml of ethyl acetate and 5 ml of triethylamine. BOOmg of palladium on charcoal was added, and the mixture was shaken for 2 hours (480ml hydrogen absorption) in a hydrogen atmosphere at atmospheric pressure. The catalyst was removed from the solution by filtration through Celite, then the product was re-washed with 100 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-4096), 550 mg of 5,8-difluoro-2-methylquinazoline was obtained. 89mg (13.7mmol) of sodium azide was added to 240mg (1.33mmol) of ee, 5,8-difluoro-2-methylquinazoline, 300mg (1.133mmol) of 18-crown-b in 10ml of DMF, and the mixture was heated for 8 hours. ») to 12522. The solvent was removed in vacuo, the product obtained was chromatographed on silica gel with ethyl acetate, and

52 mg of the product was obtained. co "H-NMR (Z00MHC, SOSI"); 5 - 2.92 (z, ZN), 4.31 (Bg., 2H), 6.67 (ad, 1H), 7.38 (ad, 1H) ,9,37(z,1H). 1,1,1-trifluoro-4-(3-fluoro-2-methoxy-3-methylphenyl)-2-((8-fluoro-2-methyl-quinazolyl-5- yl)iminomethyl)|-4-methylpenta n-2-ol « 20 150 mg (0.465 mmol) 4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl )pentanal (described in example 1), 83.7 mg (0.465 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 264.4 mg (0.930 mmol) of titanium tetraisopropylate were mixed in 2.5 ml of xylene for for 4 hours at 120 °C. The mixture was diluted with ethyl acetate and washed once with brine. The solvent was removed by centrifugation, and the residue was chromatographed on Riazptavieg support. 152.8 mg (68.2905) of the desired compound was isolated. : 5 - 1.40 (ZN), 1.55-1.66 (6H), 2.29 (1H), 3.00 (ZN), 3.30 (1H), 3.98 (ZN), 4 .60 (ee) (1H), 6.29 (1H), 6.67 (1H), 6.78 (1H), 7.43 (1H), 7.71 (1H), 9.49 (1H) . (rec.)b-fluoro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-5-methoxy-4,4,7-trimethyl-2-"(trifluoromethyl)-1,2,3 ,4-tet o raghydronaphthalene-2-ol

Ge) 2.1 ml (1.902 mmol) of titanium tetrachloride was carefully added dropwise to 152.8 mg (0.317 mmol) of compound 50.1,1,1-trifluoro-4-(3-fluoro-2-methoxy-3-methylphenyl)-2- (8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl|-4-methylpentan-2-ve -ol, described in the previous paragraph, at a temperature of 02С, and then the mixture was stirred for three hours

Thursday" at room temperature. The reaction mixture was carefully mixed at 092 with saturated sodium bicarbonate solution. Then it was extracted three times with ethyl acetate and the combined organic extracts were washed with a saturated mass solution. After drying over sodium sulfate, the solvent was removed by centrifugation, and the remaining residue was chromatographed on Riazptazieg support. 121.8 mg (79.7905) of the required compound was isolated. o "H-NMR (ZO0MHC, SOSIZ): 5 - 1.57 (ZN), 1.72 (ZN), 2.05-2.29 (BN), 2.95 (ZN), 3.97 (ZN ), 4.93 (1H), 5.63 (1H), 5.90 (1H), 6.68 (1H), 6.90 (1H), 7.50 (1H), 9.35 (1H) . tetrahydronaphthalene-2,5-diol 60 111.2 mg (0.231 mmol) (rec.)b-fluoro-1-((8-fluoro-2-methylquinazolin-5-yl)amino|-5-methoxy-4,4 ,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol was mixed at 09C with 3.2 ml of a 1 molar solution of boron tribromide in dichloromethane, and the mixture was stirred for 1.5 hours at a temperature from 0 to 592 C. Then, at a temperature of 09 C, a saturated solution of sodium bicarbonate was carefully added dropwise. After 10 minutes of intensive stirring at room temperature, the batch was extracted three times with ethyl acetate. The organic phases were dried, and after removal of the solvent by centrifugation, the residue was chromatographed on Riazptavieg media. 66b.4mg (61.595) of the required compound." Н), 1.70 (ЗН), 2.00-2.20 (BN), 2.88 (ЗН), 5.20 (1Н), 6.68 (1Н), 6.85 (1Н), 7 .58 (1H), 9.65 (1H).

Example 286 (Rats.). 5-ShCH6-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-2-methylphthalazin-1-one 5-amino-2-methyl-phthalazin-1-one: 70 C-bromo-4-nitro-phthalide 5.37 g of 4-nitrophthalide |TeTrapiedgoop ey. (2001). The mixture was added to water, extracted with dichloromethane, washed several times with water, dried, and the solvent was removed in vacuo. 7.24 g of 75 C-bromo-4-nitro-phthalide were obtained as a solid. 7H-NMR (300 MHz, SOSI»z), 5 - 7.26 (c, 1H), 7.88 (i, 1H), 8.30 (4, 1H), 8.56 (a, 1Hn) 5- nitro-phthalazin-1-one: 18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate were mixed in 30 ml of DMF at a temperature of 100 °C for 1 hour. After that, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF was added, and the mixture was stirred for another 4 hours at 1002C. The mixture was added to water, extracted several times with ethyl acetate, and the organic phase was washed with water and brine. It was dried and the solvent was removed in vacuo. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-1-one was obtained as a solid. 7H-NMR (300 MHz, DMSO-av), 5 - 8.05 (Y, 1H), 8.57-8.66 (t, 2H), 8.73 (v, 1H), 13.13 (bv, 1H) 2-methy-5-nitro-phthalazin-1-one mixture of 1.6 g of 5-nitro-phthalazin-1-one and 2.31 g of potassium carbonate was stirred for 10 minutes at room temperature in bbml of DMF. 1.1 ml of methyl iodide was added, and the mixture was stirred overnight. The mixture was added to water, extracted several times with ethyl acetate, and the organic phase was washed with water and brine. It was dried and the solvent was removed in vacuo. 1.57 g of 2-methyl-5-nitro-phthalazin-1-one was obtained as a yellow solid. WITH

2 H-NMR (300 MHz, DMSO-α), 5 - 3.73 (5, ЗН), 8.05 (i, 1Н), 8.62 (а, 2Н), 8.75 (в, 1Н) "5-amino-2-methyl-phtaphazin-1-one" with 1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 133 mg of palladium on activated carbon was suspended in 45 bml of ethyl acetate and hydrogenated with hydrogen at atmospheric pressure. The mixture was filtered through diatomaceous earth, and the solvent was removed in vacuo to give 1.26 g of 5-amino-2-methyl-phthalazin-1-one as a yellow solid. - 3.81 (c, 3H), 7.00 (a, 1H), 7.50 (i, 1H), 7.80 (a, 1H), 8.16 (c, 1H) (ratc.)- 5-14-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene|amino)2-methyl-" phthalazinon-1-one 400 mg (1.241 mmol) ( rad) -4 s 4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal, 271 4 mg (1.241 mmol) c 5-amino-2-methyl -phthalazin-1-one and 705.5 mg (2.482 mmol) of titanium tetraisopropylate were stirred in seven ml of xylene for five hours at 120 C. After cooling, the mixture was diluted with ethyl acetate and one washed once with saline solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried and the solvent was removed by centrifugation. The residue was chromatographed on Riazptazvieg medium. (ee) 40.9 mg (68.595) of the required compound was isolated. o 7"H-NMR (300 MHz, SOSIia), 5 - 1.39 (ZN), 1.60 (ZN), 1.78 (ZN), 2.28 (1H), 3.31 (1), 3 .90 (ZH), 3.99 (ZH), 4.58 (1H), 6.38 (1H), 6.78 (1H), 6.89 (1H), 7.58-7.68 (2H ), 8.27-8.35 (2H).

Pho (rec.) ich 50 5-Chb-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|Iamino)- 2-methylphthalazin-i-one Y (rat.) iz» 5-C6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4 -tetrahydronaphthalen-1-yl)|amino)-2-methyl phthalazin-1-one 100 mg (0.208 mmol) 255 (rat.)-5-14-(3-fluoro-2-methoxy-4-methylphenyl)-2- hydroxy-4-methyl-2-trifluoromethyl)pentylidene|amino)2-methyl-

GF! Phthalazinone-1-one was mixed at 02C with 2.1 ml of a 1M solution of boron tribromide in dichloromethane, and the mixture was stirred for two hours at a temperature of 0 to 52. After careful mixing with a saturated solution of sodium bicarbonate, the batch was extracted three times with ethyl acetate. The combined organic extracts were washed with saline solution, dried, and the residue that remained after centrifugation was chromatographed on a carrier of 60 RIavptavieg. 38.1 mg of a mixture containing the required compound and the corresponding simple ether was obtained. First, the simple ether was separated from phenol, in particular by means of HPLC (SpigaIse! OO 20, eluents: hexane/ethanol). The corresponding racemates were then separated into their respective enantiomers by chiral HPLC (Spigairac AO 20, eluents: hexane/2-propanol or hexane/ethanol), thus obtaining the following four compounds: bo (-3-5-C6-fluoro-2 ,5-dihydroxy-4,7-trimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2-methylphthalazin-1-one (-)-5-16 -fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-2-methylphthalazin-1-one "HA-NMR (З00МГЦц, СО53О0), ( 7- 1.59 (ZN), 1.70 (ZN), 2.03-2.20 (BN), 3.86 (ZN), 5.20 (1H), 6, 63 (1H), 7.23 (1H), 7.60-7.72 (2H), 8.58 (1H). (-3-5-C6-fluoro-2-hydroxy-5-methoxy-4, 4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|amino)-2-methylphthalazin-1-one "H-NMR (ZO0MHC, CO5O0), 5 - 1, 40 (ZN), 1.59 (ZN), 2.09 (1H), 2.20-2.35 (4H), 3.52 (ZN), 3.80 (ZN), 5.34 70. ( 1H), 7.08 (1H), 7.52 (1H), 7.62-7.78 (2H), 8.60 (1H). (-)-5-16-fluoro-2-hydroxy-5 -methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl|amino)-2-me tylphthalazin-1-one

Example 287 (research) 15. 5-Д46-chloro-2,5-diguroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-isoquinoline-1 (2

H)-one 2-(3-chloro-2-methoxy-4-methylphenyl)-2-methylpropanenitrile 17.6 g (100.8 mmol) of 2-chloro-6-fluoro-3-methylanisole was dissolved in 88 Oml of toluene. After adding 27.8 g (403.2 mmol) of isobutyric acid nitrile, 302.4 ml (151.2 mmol) of a 0.5 molar solution of potassium hexamethyldisilazide in toluene was added dropwise over 40 minutes (the temperature was raised to 27 2). After stirring for 19 days at room temperature, the batch was mixed with 30 mL of water and 400 mL of ethyl acetate and then acidified with 10965 sulfuric acid to pH 4. The aqueous phase was shaken with 200 mL of ethyl acetate. The combined organic extracts were washed with water and twice with saturated Massey solution and then dried. After centrifugation and chromatography on silica gel (mobile solvent: with ethyl acetate/hexane), 12.01 g (53.495) of the required compound were obtained. o "H-NMR (300 MHz, SOSI"): 5 - 1.75 (6BN), 2.40 (ZN), 4.09 (ZN), 6.99 (1H), 7.09 (1H). 2-(3-chloro-2-methoxy-4-methylphenyl)-2-methylpropanal 11 g (49.17 mmol) of the nitrile described above was dissolved in 19 bml of toluene. At a temperature in the range from -659C to -609C7, 61.5 ml of 1.2 molar of a solution of YIVAN in toluene dropwise in a nitrogen atmosphere. After t 3o stirring for two hours at a temperature of -65 °C, 280 ml of a 20905 solution of "I" was added dropwise

II-(4)-tartaric acid. The temperature rose up to 0 2C. The cooling bath was removed and batch c was vigorously stirred at room temperature for two hours. The reaction mixture was shaken twice with diethyl ether. The combined organic extracts were shaken with water and brine, dried, and ("c") the solvent was removed by centrifugation. After chromatography on silica gel (mobile solvent: SO ethyl acetate/hexane), 6.12 g of the required compound was obtained. "H-NMR (300 MHz, SOSI»v): 5 - 1.38 (6H), 2.39 (ZH), 3.79 (ZH), 7.03 (1H), 7.13 (1H), 9 .59 (1H).

Ethyl ether (E/2)-4-(3-chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic acid 14.9 ml of a 2 molar solution of IFA in THF was added dropwise for 20 minutes to a solution of 7.45 g of 40. (27.7 μmol) triethyl ether of 2-ethoxy-phosphonoacetic acid, dissolved in ZOml of absolute THF, at a temperature of 02C. After 45 minutes of stirring at a temperature of 09C, 6.3 g (27.79 μmol) of 2-(3-chloro-2-methoxy-4-methylphenyl)-2-methylpropanal, dissolved in 13 ml of THF, was quickly added dropwise at 020. After After stirring overnight at room temperature, the reaction mixture was poured into 100 ml of water and extracted twice with 250 ml of diethyl ether each time. The combined organic extracts were washed with water and brine, dried, and the solvent was removed by centrifugation after filtering off the desiccant. The residue (ee) was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 8.4 g was isolated, which, in addition to the required compound, also still contains the starting substance (aldehyde), which was separated at the next stage. ("c) and (E/2)-4 -(3-chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic acid (o) 8.4 g (24.65 mmol) ethyl ether (E/2)-4-(3 -chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic acid 1" 50 was mixed with 24 bml of 1M Mahon in ethanol/water (2:1) and stirred for 1 9 hours at room temperature. Ethanol was removed on a rotary evaporator and the residue was extracted twice with diethyl ether. The combined organic extracts were washed once with 5 ml of water. After drying, the solvent was removed by centrifugation. A residue (unreacted aldehyde from the above reaction) was obtained in the amount of 2 g and it was used again in the Horner-Wittig reaction followed by saponification. The combined aqueous phases were carefully acidified with concentrated hydrochloric acid until pH 3 was reached while cooling in an ice bath, and the mixture was extracted twice with 300 ml of diethyl ether each time. These ether extracts were washed with water and brine, dried, the solvent was removed by centrifugation, and the residue (5.62-72.990) was used in the next step in crude form. Since the compound is an E/7 mixture, the ratio of which is not equal to 1:1, only the positions of the signals are indicated in the NMR spectrum. for 7"H-NMR (300 MHz, SOSI"): 5 - 0.98, 1.40, 1.57, 2.31, 2.38, 3.39, 3.78, 3.80-3.90 , 5.79, 6.79, 6.88-6.98, 7.18. 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid 7.30g (23.34 mmol) of (E/2)-4-(3-chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic acid, which was obtained from the previous batch, was mixed at room temperature with 143 ml of 1 molar sulfuric acid and 20 ml of glacial acetic acid, and the mixture was stirred for 30 hours at a bath temperature of 90 C. After stirring for three days at room temperature, the mixture was intensively stirred for another two days at a temperature of 902 C. The batch was alkalized (pH 9) with solid potassium carbonate while cooling in an ice bath (caution, foam). The mixture was extracted twice with diethyl ether, and the combined organic extracts were discarded after observation by TLC. The aqueous phase was acidified with

of concentrated hydrochloric acid when cooled in an ice bath until pH 4 was reached, and the mixture was shaken twice with diethyl ether. The ether extracts were washed with water and brine, dried, and the solvent was removed by centrifugation. The remaining residue (5.37g-80.890) was used in the next stage in crude form. 7H-NMR (300 MHz, SOSI»v): 5 - 1.50 (6H), 2.34 (ZH), 3.50 (2H), 3.89 (ZH), 6.97 (1H),7, 15(1H).

4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ether 5.37g (18.8bmmol) 4-(3-chloro-2-methoxy-4-methylphenyl) )-4-methyl-2-oxo-pentanoic acid was dissolved in 112 ml of ethanol, mixed with 2 ml of concentrated sulfuric acid and heated in a reflux flask for five hours. Ethanol was removed on a rotary evaporator, and the residue was carefully mixed with saturated sodium bicarbonate solution, then 5 Oml of water was added. The mixture was extracted twice with ethyl acetate. The combined 75 organic extracts were washed with water and saline. After drying and after filtering off the desiccant and removing the solvent by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 4.81 g (81.6905) of the required compound was isolated. "H-NMR (300 MHz, SOSI»v): 5 - 1.30 (ZH), 1.48 (6H), 2.36 (ZH), 3.40 (2H), 3.90 (ZH), 4 .18 (2H), 6.92 (1H), 7.10 (1H). (rec.) 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-trifluoromethyl ethyl ether )-2-trimethylsilyloxy-pentanoic acid 4.8 g (15.35 mmol) of 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ether were dissolved in 25 ml of THF, mixed at a temperature of 02C with 2.62 g (18.41 mmol) of (trifluoromethyl)-trimethylsilane and 37.bmg of tetrabutylammonium fluoride and stirred for 1.5 hours at a temperature in the range from 0 to 520.

The batch was added to 5 Oml of a mixture of water and ice and extracted twice with diethyl ether. The combined organic extracts from 29 were washed with water and saline. After chromatography on silica gel (mobile solvent: Ge) ethyl acetate/hexane), 44 g (6390) of the required compound were obtained. "H-NMR (ZO0MHC, SOSIv): 5 - 0.03 (9H), 1.22 (ZN), 1.38 (ZN), 1.42 (ZN), 2.35 (ZN), 2.52 (1H), 2.69 (1H), 3.78 (1H), 3.99 (ZH), 4.03 (1H), 6.90 (1H), 7.00 (1H). " 20 (rats .) Ethyl ether of 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid « 4 Ag (9.67 mmol) of ethyl ether (rec.) c of 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid was dissolved in 5 bml of tetrahydrofuran and mixed with 3.05 g (9.67 mmol) of fluoride trihydrate tetrabutylammonium and (ab) were stirred for 1.5 hours at room temperature. The reaction mixture was diluted with water and extracted twice with diethyl ether. The organic phases were washed with water and brine. After drying, the solvent was removed by centrifugation, and the remaining residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 1.26 g of the required compound was isolated. "H-NMR (ZO0MHC, SOSIZ): δ - 1.20 (ZH), 1.40 (ZH), 1.49 (ZH) , 2.29-2.40 (4H), 2.82 (1H), 3.55 (1H) , 3.65 « 40. AN), 3.98 (ZN), 4.08 (1H), 6.90 (1H), 7.02 (1H). with c (rec.) 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)pentanal J (rec.) . 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-"-trifluoromethyl)-pentane-1,2-diol and 1.05 g (2.74 mmol) of ethyl ether (rec.) 4 -(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-"-trifluoromethyl)-2-hydroxy-pentanoic acid was dissolved in 1 ml of diethyl ether and mixed in portions at 02C with 7 ml (2.0 mmol) of CAIN . After stirring throughout

Ge | one hour at a temperature of 0 and additional stirring during an hour of stirring at a temperature between 0 and 102C, the reaction mixture was mixed dropwise with 2.4 ml of a saturated solution of ManSO» with cooling in an ice bath. The mixture was stirred for 30 minutes while cooling in an ice bath and (o) intensively stirred for 1.5 hours at room temperature. The precipitate was suctioned off, washed with 50% ethyl acetate, and the filtrate was concentrated by evaporation on a rotary evaporator. After chromatography of the residue on silica gel (mobile solvent: ethyl acetate/hexane), 425 mg (45.8905) of aldehyde and 420.4 mg (44.995) of diol were obtained.

Red aldehyde: "H-NMR (ZOOMHz, SOSIV): 5 - 1.46 (ZH), 1.49 (ZH), 2.28 (1H), 2.39 (ZH), 3.30 (1H), 3 ... ), 1.57 (ZH), 1.82 (1H), 2.20 (1H), 2.38 (ZH), 2.55 (1H),

HF) 2.91 (1H), 3.29-3.46 (2H), 4.00 (ZH), 6.96 (1H), 7Db (1H). (Rat.)-5-C4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentyldenylamino)isoquinol in-1(2H)- on 225 Mg (O0.6b4mmol) (rat.) 60 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)pentanal, 106, Zmg (O0.6b4mmol ) of 5-amino-isoquinolin-1(2H)-one and 0.39 ml (1.328 mmol) of titanium tetraisopropylate were stirred in 3.5 ml of ortho-xylene for two and a half hours at 12020. After cooling, the batch was poured into 15 ml of saturated saline and diluted with ethyl acetate. After intensive stirring for 20 minutes at room temperature, the mixture was filtered on a column filled with Ehigeishsche. The residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 224.7 mg (70.3905) of the required compound was isolated.

7TH-NMR (300 MHz, DMSO-dv): 5 - 1.49 (ZH), 1.52 (ZH), 1.89 (ZH), 2.25 (1H), 3.04 (1H), 3, 89 (ZH), 6.15 (1H), 6.65 (1H), 6.72 (1H), 6.79 (1H), 6.99 (1H), 7.20 (1H), 7.37 (1H), 7.57 (1H), 8.06 (1H), 11.35 (1H). (researcher) 5-Cb-chloro-2-hydroxy-5-methoxy-4,4,7-trimethgm-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-isoquinolin- 1(2H)-one 130 mg (0.27 mmol) compound (rec.)-5-14-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene| amino)isoquinoline-1(2

N)-one, which is described in the previous paragraph, was dissolved in 1.6 ml of dichloromethane and mixed at 02C dropwise with 70 O.vml (0.8 mmol) of titanium tetrachloride and then stirred for two and a half hours at room temperature. The reaction mixture was carefully mixed at 02С with a saturated solution of sodium bicarbonate (pH 8). It was diluted with ethyl acetate, the cooling bath was removed, and the mixture was vigorously stirred at room temperature for 15 minutes. After that, it was extracted twice with ethyl acetate, the combined organic extracts were washed with saline solution. After drying over sodium sulfate, the solvent was removed by centrifugation and the remaining residue was chromatographed on silica gel. 71.33 mg (54.890) of the required compound were isolated.

TN-NMR (ZO00MHC, СО3О0): 5 - 1.55 (ZN), 1.65 (ZN), 2.05-2.28 (BN), 3.95 (ZN), 5.14 (1H), 6.85 (1H), 7.00-7.12 (2H), 7.19 (1H), 7.40 (1H), 7.70 (1H). (researcher) 20 54|β-chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino)-isoquinoline-1( 2H)-one 4Omg (0.083mmol) (rec.) 5-(C6b-chloro-2-hydroxy-5-methoxy-4, 7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene -1-yl|amino)-isoquino lin-1(2H)-one was mixed at room temperature with 0.vml of 1 molar solution of boron tribromide in dichloromethane, p 29 | the mixture was stirred for four hours at room temperature. Since the starting substance was still present, 0.8 ml of boron tribromide solution was additionally added, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was mixed dropwise at -302C with a saturated solution of sodium bicarbonate (pH 8). The batch was mixed with ethyl acetate and the cooling bath was removed. After 10 minutes of vigorous stirring at room temperature, the batch was extracted twice with ethyl acetate. The organic phases were washed with water and brine, dried, and the residue was chromatographed on silica gel (mobile solvent: Her methanol/dichloromethane) after removal of the solvent by centrifugation. 19.9 mg (51.295) of the required compound was isolated. and "H-NMR (30 MHz, DMSO-4v): 5 - 1.50 (ZN), 1.65 (ZN), 1.92-2.20 (BN), 5.28 (1), 5 .90 (1H), 6.09 (IN), F 6.69 (1H), 6.80 (1H), 7.03 (1H), 7.18 (1H), 7.25 (1H), 7 .50 (1H), 8.90 (1H), 11.24 (1H). 35 g)

Example 288 (rec.) 5-C6b-chloro-2,5-dihydroxy-4,4L-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino!1-quinoline-2( 1H)-one (rec.)-5-C4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene|amino)isoquinoline « 20 -2(1H )-one -in 225 mg (O0.6b4mmol) (rec.) with 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentanal (described in the example 287) and 106.3 mg (0.6 b4 mmol) of 5-amino-isoquinolin-2(1H)-one (described in example 2) were mixed with 3.5 ml of xylene. After adding 0.00 ml (1.328 mmol) of titanium tetraisopropylate, the batch was stirred for two and a half hours at 1202C. The mixture was added to 15 ml of saturated salt solution and diluted with 20 ml of ethyl acetate. oo The reaction mixture was filtered on Ehigeishie and washed with 300 ml of a mixture containing ethyl acetate/dichloromethane.

The obtained solution was centrifuged and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 248.5 mg (77.8905) of the required compound was isolated.

He""H-NMR (ZO0MHz, DMSO-4v): 5 - 1.38 (ZH), 1.53 (ZH), 1.85 (ZH), 2.20 (1H), 3.05 (1H) , 3.85 (ZN), 6.18

МН), 6.32 (1Н), 6.52 (1Н), 6.65 (1Н), 7.00 (1Н), 7.18 (1Н), 7.39 (1Н), 7.58 (1Н ), 8.09 (1H), 11.78 (1H). t (Rats.)

HT" 5-(C6b-chloro-2-hydroxy-5-methoxy-4, 7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|amino)-isoquinolin- 2(1H)-on

0.vml (0.8mmol) of titanium tetrachloride was added dropwise to 133Omg (0.270mmol) of the compound (rec.)-5- 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4- methyl-2-trifluoromethyl)pentylidene|amino)isoquinolin-2(1H)-one, dissolved in 1.6 bml of dichloromethane, which is described in the previous paragraph at a temperature of 0 2С, and then batch i) was stirred for two hours at 02 and for two hours at room temperature. The reaction mixture was mixed dropwise with a saturated solution of sodium bicarbonate and ethyl acetate at a temperature of 02С. Then the cooling bath was removed, and the mixture was intensively stirred for another 15 minutes at 60 room temperature. After that, it was extracted twice with ethyl acetate, the combined organic extracts were washed with a saturated solution of Massey. After drying over sodium sulfate, the solvent was removed by centrifugation, and the remaining residue was chromatographed on silica gel (mobile solvent: ethyl acetate (hexane). 82 mg (63.1965) of the desired compound was isolated. 1.53 (ZN), 1.66 (ZN), 2.00-2.25 (5H), 3.96 (ZN), 4.80 (1H), 5.01 (1H), 5.58 bo (1H), 6.49-6.62 (ZH), 6.92 (1H), 7.35 (1H), 8.19 (1H), 10.25 (1H).

(researcher) 5-(1b-chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl|amino!-isoquinoline- 2(1H)-one 43mMg (0.089mmol) (rec.) 5-(C6b-chloro-2-hydroxy-5-methoxy-4, 7-trimethyl-2-(trifluoromethyl)-1,2,3,4 -tetrahydronaphthalene-1-yl|amino)-isoquinolin-2(1H)-one was mixed at room temperature with 00 ml of a 1 molar solution of boron tribromide in dichloromethane, and the mixture was stirred for two hours and 15 minutes at room temperature. Then at a temperature of -309C sat. silica gel (mobile solvent: ethanol/dichloromethane) after removal of the solvent by centrifugation. 37.8 mg (90.6 95) of the required compound was isolated. "H-NMR (SO0MHCc, CO500): 5 - 1.58 (ZH), 1 .70 (ZN), 2.00-2.24 (BN), 5.12 (1H), 6.51 (1H), 6.62 (1H), 6.70 75. (1H), 6.80 (1H), 7.39 (1H), 8.22 (1H).

Example 289 (rec.) b-chloro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalene-2,5-diol (rec.) 1,1,1-trifluoro-4-(3-chloro-2-methoxy-4-methylphenyl)-2-((8-fluoro-2-methyl-quinazolyl-5 -yl)iminomethyl)|-4-methylpentan-2-ol 225mg (0.6b4mmol) (rec.) 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2- -trifluoromethyl)pentanal (described in example 287) and. DC EM 117.bmg (0.6b4mmol) of 5-amino-8-fluoro-2-methylquinazoline was mixed with 3.bml of ortho-xylene. After adding (5)

0.30 ml (1.328 mmol) of titanium tetraisopropylate, the batch was stirred for two hours at 12090. The mixture was added to 15 ml of saturated saline solution and diluted with 20 ml of ethyl acetate. The reaction mixture was filtered on EhigeIshie and washed with 300 g of a mixture containing ethyl acetate/dichloromethane. The resulting solution was centrifuged, and the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 217.5 mg (65.790) of the required compound was isolated. ""H-NMR (ZO0MHC, SOSIv): 5 - 1.40 (ZN), 1.52 (ZN), 1.65 (ZN), 2.29 (1H), 3.00 (ZN), 3, 35 (1Н), 3.92 (ЗН), 4.59 (1Н), 6.48 (1Н), 6.77 (1Н), 7.00 (1Н), 7.44 (1Н), 7.78 (1H), 9.39 (1H). -2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol so 110 mg (0.221 mmol) compound (rec.) 1,1,1-trifluoro-4-(3-chloro-2-methoxy) -3-methylphenyl)-2-((8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl)|-4-methylpentan-2-ol, which is described in the previous paragraph, was dissolved in 1.3 ml of dichloromethane and mixed carefully at a temperature of 02C with 0.bbml (0.6633mmol) of titanium tetrachloride. After that, the mixture was stirred for two 70 hours at 02C and for an additional two hours at room temperature. The reaction mixture was mixed dropwise for 8 seconds with a saturated solution of sodium bicarbonate at a temperature 09 C. After diluting with ethyl acetate, the cooling bath was removed, and the batch was vigorously stirred at room temperature. After that, the extraction was carried out twice was washed with ethyl acetate, the combined organic extracts were washed with saturated Massey solution. After drying over sodium sulfate, the solvent was removed by centrifugation, and the remaining residue was chromatographed on silica gel (mobile solvent: methanol/dichloromethane). 76.5 mg (69.590) of the required compound was isolated in the form of a 9:1 mixture of diastereomers. The signals of the main diastereomers are indicated. o 7TH-NMR (ZO00MHZc, СО30О0): 5 - 1.57 (ZN), 1.69 (ZN), 2.08-2.29 (5H), 2.89 (ZN), 3.95 (ZN) , 5.28 (1H), 6.87 b (1H), 7.05 (1H), 7.59 (1H), 9.65 (1H). (rec.) ve b-chloro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene -2,5-diol 4Omg (0.08mmol) (rec.) b-chloro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-5-methoxy-4,4,7- trimethyl-2-«(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene 5B talin-2-ol was mixed at room temperature with 0.vml of a 1 molar solution of boron tribromide in dichloromethane, and the mixture was stirred for four hours at room temperature. Since the reaction did not occur, 0. ml of boron tribromide solution was additionally added to (F). It was stirred for 16 hours at room temperature, after which the reaction was complete. Then, at a temperature of -302C, a saturated solution of sodium bicarbonate was carefully added dropwise, and the batch was diluted with ethyl acetate. After that, the cooling bath was removed, and the mixture was intensively stirred at room temperature for 10 minutes. The batch was extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried, and the residue was chromatographed on silica gel (mobile solvent: methanol/dichloromethane) after removal of the solvent by centrifugation. 38.2 mg (98.495) of the required compound was isolated. "H-NMR (ZO0MHCz, СО50О0): 5 - 1.60 (ZH), 1.72 (ZH), 2.05-2.25 (5H), 2.88 (ZH), 5.22 (1H) , 6.80-6.90 (2H), 65 7.59 (1H), 9.68 (1H).

Example 290

(researcher) 5-ShC7-chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-isoquinol n- 1(2H)-one 2-(4-chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanitrile 16.78 g (93.97 mmol) of 3-chloro-2,6-difluoroanisole was dissolved in 800 ml of toluene. After adding 25.97g (375.88mmol) of isobutyronitrile, 283.97ml (140.95mmol) of a 0.5 molar solution of potassium hexamethyldisilazide in toluene was added dropwise. In this case, the temperature was raised to 2820. The batch was stirred for seven days at a temperature of 602C. After mixing with water and ethyl acetate, the pH value of 70 of the reaction mixture was adjusted to 4 with 1M sulfuric acid. After that, it was extracted twice with ethyl acetate, the combined organic extracts were washed with water and saturated Massey solution and dried. After centrifugation and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 7.46 g (21.495) of the required compound were obtained. 7H-NMR (300 MHz, SOCI3): 5 - 1.75 (6H), 4.10 (ZH), 6.95-7.14 (2H). 2-(4-chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanal 7 Abg (32.78 mmol) of the nitrile described above was dissolved in 131 ml of toluene. At a temperature in the range from -6590 to -6026C, 41.1 ml of a 1.2 molar solution of Yusivan in toluene was added dropwise under a nitrogen atmosphere. After stirring for two hours at a temperature of -65 °C, 374 ml of a 1095 solution was added dropwise

Y-(4)-tartaric acid. The batch was stirred overnight at room temperature. The reaction mixture was extracted three times with diethyl ether. The combined organic extracts were shaken with water and brine, dried, and the solvent removed by centrifugation. 7.35 g (97.290) of the required compound was obtained, which was used as a crude product in the next stage. (E/2)-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic acid ethyl ether 19.9 ml of 2 molar solution of OA in THF (1.25 equivalents) was added dropwise at 09C to a solution of 10.3 g of 29 (38.83 mmol) triethyl ether of 2-ethoxy-phosphonoacetic acid dissolved in 34 ml of absolute THF. (3

After 45 minutes of stirring at a temperature of 09C, 7.35 g (31.8 mmol) of 2-(4-chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanal, dissolved in 2 ml of THF, was quickly added dropwise at 02C. After stirring overnight at room temperature, the reaction mixture was added to water and extracted three times with diethyl ether. The combined organic extracts were washed with water and saline, dried, and after filtering off the desiccant, the solvent was removed by centrifugation. The residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 8.41 g was isolated, which, in addition to the required compound, also still contains the starting substance (aldehyde), which was separated at the next stage. (E/2)-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic acid (a) 8.41 g (24.3 U9 mmol) of ethyl ether (E/ 2)-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic acid was mixed with 222 ml of other Mahon in ethanol/water (2:11) and stirred overnight at room temperature.

Ethanol was removed on a rotary evaporator, and after mixing with water, the residue was extracted three times with methyl tert-butyl ether. Since the organic extracts still contain the required acid as well as the unreacted aldehyde, they were extracted with 1M NaOH. The organic extracts were then dried, and the solvent was removed by centrifugation. A residue (unreacted aldehyde from the above-described reaction) was obtained in the amount of 1.59 g and it was again used in the Horner-Wittig reaction with subsequent saponification. The combined aqueous phases were carefully acidified with concentrated hydrochloric acid while cooling in an ice bath and extracted three times with methyl tert-butyl ether. These ether extracts were washed with brine, dried, the solvent was removed by centrifugation, and the residue (5.99-77.595) was used in the next step in crude form. 15 Since the compound is an E/7 mixture, the ratio of which is not equal to 1:1, only the signal positions are indicated in the NMR spectrum. 7H-NMR (300 MHz, SOCIz): 5 - 0.98, 1.40, 1.49-1.59, 3.40, 3.78-3.90, 5.72, 6.70, 6.92 -7.09, o 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid

He»b,Obg (19.133mmol) (E/2)-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic acid, which 5r was obtained from the previous batch, was mixed at room temperature with 12 bml of 1 molar sulfuric acid and 12.b6 ml of glacial acetic acid, and the mixture was stirred for nine days at a bath temperature of 9020. The batch

Ta" was basified (pH 9) while cooling in an ice bath with solid potassium carbonate (caution, foam), and the mixture was extracted three times with methyl tert-butyl ether. The aqueous phase was acidified while cooling in an ice bath with concentrated hydrochloric acid to a pH of 4, and the mixture was shaken three times with 5v tert-butyl ether. The ether extracts were washed with water and brine, dried, and the solvent was removed by centrifugation. The remaining amount is 2.23g. Since the first ether phase still contained product, it was concentrated by evaporation, and the solid residue was resuspended in water and methyl tert-butyl ether. After acidification, the aqueous phase was extracted two more times with methyl tert-butyl ether.

After conventional processing, the combined organic extracts provided an additional 3.21 g of the required product. A total of 5.44 g (98.590) of acid was obtained, which was used in the next stage in crude form. "H-NMR (300 MHz, SOSI»v): 5 - 1.45 (6H), 3.55 (2H), 3.97 (ZH), 6.95-7.10 (2H).

4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ether 5.44g (18.84 mmol) 4-(4-chloro-3-fluoro-2-methoxyphenyl) )-4-methyl-2-oxo-pentanoic acid was dissolved in 117 ml of 65% ethanol, mixed with 2.1 ml of concentrated sulfuric acid, and heated in a reflux flask for six hours. The reaction mixture was added to 250 ml of saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution and saline. After drying and after filtering off the desiccant and removing the solvent by centrifugation, 5.19 g (8790) of the required compound were obtained. "H-NMR (300 MHz, SOSI"): 5 - 1.30 (ZH), 1.45 (6H), 3.40 (2H), 3.98 (ZH), 4.20 (2H), 6 .92-7.50 (2H). (rat.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester 5, 19 g (16.3 v8 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ether was dissolved in 2 bml of THF, mixed at room temperature with 2.79 g (19, 6bmmol) of 70% trifluoromethyl-trimethylsilane and 40.1 mg of tetrabutylammonium fluoride and stirred for two days.

The reaction mixture was mixed with methyl tert-butyl ether and washed with water and brine. The organic phase was dried, and after removal of the solvent by centrifugation, the residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 4.71 g (62.6905) of the required compound were obtained. (research) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxypentanoic acid 75 ACID 4.17g (10.2bmmol) ethyl ether ( rac.) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid was dissolved in 57 ml of tetrahydrofuran and mixed with 3.24 g (10.2 mmol) of tetrabutylammonium fluoride: after stirring overnight at room temperature, the reaction mixture was mixed with water and extracted three times with methyl tert-bouguial ether. The combined organic extracts were washed with saline. After drying, the solvent was removed by centrifugation, and the remaining residue was chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 3.07g (77.490) of the required compound was isolated. "H-NMR (ZO0MHZ, SOSIV): 5 - 1.25 (ZN), 1.38 (ZN), 1.47 (ZN), 2.45 (1H), 2.75 (1H), 3.50 (1H), 3.75 (1H), 4.03 (ZH), 4.13 (1H), 6.89 (1H), 7.00 (1H). s (rec.). 4-(4- chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 1.00 g (2.5 mol) of ethyl ether (rec.) 4-(4-chloro-3-fluoro -2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid was dissolved in 9.5 ml of diethyl ether and mixed in portions at 02C with 73.7 ml (1.94 mmol) of HIAIN; stirring was continued at room temperature 02C, and TLC was carried out every 15 minutes. After stirring for 40 minutes at 02C, the reaction mixture was mixed dropwise with 2.4 ml of saturated Manso solution while cooling in an ice bath.

The mixture was stirred for 30 minutes while cooling in an ice bath, and it was stirred vigorously overnight at room temperature. The precipitate was suctioned off, washed with ethyl acetate, and the filtrate was concentrated by evaporation on a rotary evaporator. After chromatography of the residue on Riazptavieg support, 560.2 mg was obtained. In this case, the obtained substance is a 3:2 mixture of aldehyde with the original ester. (research)-5-14-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylideneamino)isoquinoline so -4(2H)-one 5bOmg mixture, which contains (ration) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)ipentanal and (ration) ethyl ether "4-(4-chloro -3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid (since aldehyde is two-thirds of the mixture, 560.2 mg of the mixture corresponds to 336.1 mg (0.981 mmol) of aldehyde) was heated over 3 s two hours at 1209 with 157.1 mg (0.981 mmol) of 5-amino-isoquinolin-1(2H)-one and 0.557 mg (1.962 mmol) of titanium tetraisopropylate in bml of ortho-xylene. After cooling, the batch was diluted with ethyl acetate and mixed with brine. The organic phase was separated and processed as usual. After chromatography on RiIazptazieg support, 144.7 mg (30.495) of the required compound was obtained (relative to the proportion of aldehyde in the mixture). so 15 "H-NMR (ZO0MHZ, SOSIV): 5 - 1.40 (ZN), 1.58 (ZN), 2.38 (1H), 3.19 (1H), 4.03 (ZN), 4 .78 (1H), 6.65 (1H), 6.70-6.83 (ZH), 7.20 (1H), 7.44 (1H), 7.62 (1H), 8.35 (1H ), 10.95 (1H). o (rat.)

Fu 5-ShC7-chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-isoquinol n-1(2H )-one t. 80.3Mg (0O.166bmmol) (rat.)

T» 5-C4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene|amino)isoquinolin-1(2H)-one was mixed at room temperature with 1.7 ml of a 1 molar solution of boron tribromide in dichloromethane, and the mixture was stirred for two and a half hours at room temperature. The reaction mixture was mixed with ice, and then saturated sodium bicarbonate solution was added dropwise (pH 8). Ethyl acetate was then added, and after ten minutes of vigorous stirring at room temperature, the aqueous phase was extracted twice with (F) ethyl acetate. The combined organic phases were washed with water and saline, dried, and after removal

The solvent was removed by centrifugation, the residue was chromatographed on Riazptavieg medium. 24.bmg (31.6905) of the required compound was isolated. in "H-NMR (30 MHz, DMSO-4v): 5 - 1.50 (ZH), 1.60 (ZH), 1.90-2.14 (2H), 5.31 (1H), 5.92 (1H), 6.18 (1H), 6.70 (1H), 6.80 (1H), 7.05 (1H), 7.19 (1H), 7.27 (1H), 7.52 ( 1H), 10.05 (1H), 11.25 (1H).

Example 291 (research) 7-chloro-6b-fluoro-1-(8-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3, 4-tetrahydronaphthalene-65 2,5-diol (research)

1,1,1-trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-((8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl|-4-methylpentan-2 - 457 mg of a mixture containing (rat.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2--trifluoromethyl)ipentanal and (rat.) ethyl ether 4- (4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid (described in example 290) (since the aldehyde is two-thirds of the mixture, 457 mg of the mixture corresponds to 305, 3 (0.891 mmol) of aldehyde) and 158 ml (0.891 mmol) of 5-amino-8-fluoro-2-methylquinazoline were mixed with 5.5 ml of ortho-xylene. Then 506.bmg (1.782 mmol) of titanium tetraisopropylate was added and the batch was stirred for two hours at 70.12090. The mixture was diluted with ethyl acetate and mixed with brine. After ten minutes of vigorous stirring, the reaction mixture was filtered on Ehigeishche and eluted with dichloromethane. The resulting solution was centrifuged, and the residue was chromatographed on Riazptavieg medium. 295.8 mg (66.195) of the required compound was isolated. 7TH-NMR (ZO00MHz, SOSI): 5 - 1.40 (ZN), 1.52 (ZN), 2.34 (1), 3.00 (ZN), 3.21 (1), 4.00 ( ЗН), 4.59 (1Н), 75 6.58 (1Н), 6.70 (1Н), 6.85 (1Н), 7.49 (1Н), 7.78 (1Н), 9.49 ( 1H). (researcher) 7-chloro-6-fluoro-1-((8-fluoro-2-methylquinazolin-5-yl)amino!-4,4,7-trimethyl-2-(trifluoromethyl)-1,2, 3,4-tetrahydronaphthalene-2,5-diol 295.8 mg (0.589 mmol) (rec.) 20. 1,1,1-trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2 -((8-Fluoro-2-methyl-quinazolyl-5-yl)iminomethyl/|-4-methylpentan-2-ol was mixed at 02C with 1 ml of a 1 molar solution of boron tribromide in dichloromethane, and the mixture was stirred for two hours at temperature from 0 to 59 C. The reaction mixture was mixed with ice. After adding saturated sodium bicarbonate solution dropwise, the mixture was diluted with ethyl acetate and stirred intensively for ten minutes. The aqueous phase was extracted twice with ethyl acetate. The organic phases were washed with water and brine, dried, and after removal of the solvent by centrifugation, the residue was chromatographed several times on Riazptazvieg media. Zvmg (13.295) of the required compound was isolated. "H-NMR (ZO0MHCc, CO50O0): 5 - 1.60 (ZH), 1.70 (ZH), 2.05 -2.21 (2H), 2.83 (ZH), 5.23 (1H), 6.80-6.92 (2H), 7.59 (1H), 9.68 (1H) .

Example 292 C (research) "7-chloro-6-fluoro-1-K7-fluoro-2-methylquinazolin-5-yl)amino|-4,4-dimethyl-2-(trifluoromethyl)-1,2,3 ,4-tetrahydronaphthalene-2,5-diol and 5-amino-7-fluoro-2-methyquinazoline av) 17g (70.5 mmol) of 3,6b-difluoro-2-M-pivaloylaminobenzaldehyde |. Riogmaiyi, I. Radegmaiyi, 1.-05- Iagevsop, 5.

V. Kozv, Eig. U. May. Spent 34, 1999, 137-151), 9.2 g of acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g of molecular sieve (4A) were added together to 7 Oml of butyronitrile. The mixture was heated for 17 hours to 1452 with vigorous stirring, and the solvent was removed in vacuo. After chromatography of the residue on silica gel with hexane/ethyl acetate (0-7095), 4.5 g of 7-fluoro-5-M-pivaloylamino-2-methyquinazoline was obtained. 1 g (3.82 mmol) of 7-fluoro-5-M-pivaloylamino-2-methyquinazoline was dissolved in 74 ml of toluene and cooled to -1020°C. During 30 minutes, 9.5 ml (11.4 mmol) of a 1.2M solution of diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was allowed to warm to -40 °C and stirred for four hours at -4026. ;" Water was added slowly and the mixture was stirred for 30 minutes at room temperature until a precipitate formed, which was removed by filtration through celite. The phases were separated, washed with saturated chloride solution

Sodium, and dried over sodium sulfate. After chromatography on silica gel (mobile solvent:

Go! ethyl acetate/hexane), 4 mg of product was obtained. o "H-NMR (SOSI"); 5 - 2.83 (v, ZN), 4.67 (Bg., 2H), 6.50 (da, 1H), 6.93 (ad, 1H), 9 ,23 (z, 1H). (rat.)

Ge) 1,1,1-trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-(K7-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl|-4-methylpentan- 2-5 ol e 40Omg of the mixture containing (rec.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-t» 4-methyl-2--'trifluoromethyl)pentanal and (rec .) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ether (described in example 8) (since the aldehyde is two-thirds of the mixture, then 4000 mg of the mixture corresponds to 266.6 (0.778 mmol) of aldehyde) and 137.8 mg (0.778 mmol) of 5-amino-7-fluoro-2-methylquinazoline were mixed with bml of ortho-xylene. Then 442.Zmg (1.5 mmol) of titanium tetraisopropylate was added, and the batch was stirred for two hours at 12026. o The mixture was diluted with ethyl acetate and mixed with brine. After ten minutes of intensive stirring, the reaction mixture was filtered on Ehigeishche and eluted with dichloromethane. The resulting solution was centrifuged, and the residue was chromatographed on Riazptavieg medium. 312.4 mg (8095) of the required compound was isolated. 60 The yield corresponds to the aldehyde retained in the mixture. "H-NMR (ZO0MHC, SOSIv): 5 - 1.40 (ZN), 1.60 (ZN), 2.36 (1H), 2.92 (ZN), 3.23 (1H), 4.01 (ЗН), 4.49 (1Н), 6.49 (1Н), 6.65 (1Н), 6.89 (1Н), 7.45 (1Н), 7.79 (1Н), 9.32 ( 1H). 3,4-tetrahydronaphthalene-2,5-diol 312.4 mg (0.622 mmol) (rat.)

1,1,1-trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-((7-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl|-4-methylpentan-2 - ale was mixed at 092C with b4ml of a 1 molar solution of boron tribromide in dichloromethane, and the mixture was stirred for two hours at a temperature from 0 to 52. The reaction mixture was mixed with ice. Then a saturated sodium bicarbonate solution was carefully added dropwise, and the mixture was diluted with ethyl acetate and intensively was stirred for ten minutes. The aqueous phase was extracted twice with ethyl acetate. The organic phases were washed with water and brine, dried, and after removing the solvent by centrifugation, the residue was chromatographed several times on Riazptavieg support. 51 mg (16.7905) of the required compound was isolated. "H-NMR ( З00МГЦц, СО8О0): 5 - 1.60 (ЗН), 1.70 (ЗН), 2.15 (2Н), 2.79 (ЗН), 5.31 (1Н), 6.70-6.88 ( ЗН), 9.58 (1Н).

Similarly to the compounds described in detail earlier in examples 283-292, the following structures were synthesized using the appropriate starting materials.

Example 293 1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalene-2-ol

Example 294 5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene n-1 ,6-diol

Examples 295 and 296 1-(-2-Ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2 -ol, diastereomer A and 1-(2-ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene- 2-ol, diastereomer B

Example 297 5-(2-ethylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-b-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,b-diol, se diastereomer A at

Example 298 5-(2-ethylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-b-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,b-diol, diastereomer B

Examples 299 and 300 « 5-(2-Methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-b-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,b-diol, « diastereomer A and 5-(2-methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,b-diol, (Ce) diastereomer B o

Examples 301 and 302 (-3-5-Ch6-fluoro-2,5-dihydroxy-4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ilyamino)-quinol g ) in-2(1H)-one and (-)-5-16-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene- 1-ylamino)-quinol in-2(1H)-one « 8 mg of racemic 5-ShCh6-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4 -tetrahydronaphthalene-1-ylamino)-quinoline-2(1H) and c -one was separated on a chiral column (Spigazirak AO-H 5 y (eluents: hexane/ethanol) into its enantiomers. "» Zamg (t)-enantiomer was obtained and 33 mg of the (-)-enantiomer.

Examples 303 and 304 bo (-3-6-fluoro-1-(8-fluoro-2-methylquinazolin-5-yl)amino)|-4,4,7-trimethyl-2-Strifluoromethyl)-1,2,3 ,4-tetrahydronaphthoalin-2,5-diol and (-)-6-fluoro-1-((8-fluoro-2-methylquinazolin-5-yl)amino|-4,4,7-trimethyl-2- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol" 20 50.8 mg of racemic b-fluoro-1-((8-fluoro-2-methylquinazolin-5-yl)amino) -4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-

T" diol was separated on a chiral column (Spigadrak AO-H 5, (eluents: hexane/ethanol) into its enantiomers).

25.0 mg of the (w)-enantiomer and 23.8 mg of the (-)-enantiomer were isolated. (Io-97.8--1.1 (c-0.50, methanol) 25 (odo--53.3-0.3 (c-0.50, methanol)

HF) Example 305 7 5-(/-chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1H -hino lin-2-on

Example 306 bo 5-(/-chloro-6-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1 "With dihydroindol-2-one

Example 307 5-(/-chloro-6-fluoro-2,5-dihydroxy/-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1,3 dihydroindol-2-one bo Example 308

7-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4.4-dimethyl-2-(trifluoromethyl)-1.2.3.4-tetrahydronaphthalen-2-ol

Example 309

C-chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydrophthalene-1 ,6-diol

Examples 310 and 311 7-chloro-1-(2-ethylquinazolin-5-ylamino)-b6-fluoro-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2 -ol, diastereomer A Y 70. 7-chloro-1-(2-ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3, 4-tetrahydronaphthalene-2-ol, diastereomer B

Example 312

C-chloro-5-(2-ethylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol

Examples 313 and 314

C-chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6 -diol, enantiomer A and

C-chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6 -diol, enantiomer B 22.5 mg of the racemic compound

C-chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-b-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1"b-diol was separated on a chiral column (Spigazrak AO-H 5, (eluents: hexane/ethanol) into its enantiomers.

10.5mg of enantiomer A (retention time 5.28 minutes) and 9.ug enantiomer B (retention time 10.79 minutes) were isolated. high school

Examples 315 and 316 (-)-3-chloro-5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-"(trifluoromethyl)-5,6,7 8-tetrahydronaf i) talin-1,6-diol, enantiomer A and (-)-3-chloro-5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl- 6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, enantiomer B «g zo 4Omg of the racemic compound (-3-3-chloro-5-(8-fluoro-2-methylquinazoline- 5-ylamino)-2-fluoro-8,8-dimethyl-6-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol was separated on a chiral column (Spigairak AO 10), eluents: hexane /ethanol) into its enantiomers. In each case, 1 mg of two enantiomers was obtained. (c10o-953.1--0.6 (c-0.555, methanol) o

IsI0o--46.0--0.6 (c-0.58, methanol) ee

Example 317

C-fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-oxo-1,2-dihydroquinolin-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene -2-carbonitrile «

IR (microscope, matrix: diamond): 2232

Example 318 - c 3-fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-oxo-1,3-dihydroindol-4-ylamino)-7-"(trifluoromethyl)-5,6,7 ,8-tetrahydro onanaphthalene-2-carbonitrile "» IR (microscope, matrix: diamond): 2238

Example 319 b-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydron ( ee) aphthalin-2-ol o Example 320 2-chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-b-(trifluoromethyl)-5,6,7 8 -tetrahydronaphthalene-1,

He) b-diol 50 Example 321 b-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1 ,2,3,4-tetragy

ChT» dronaftalin-2-ol

Example 322 2-chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-6-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene 5B n -1,6-diol

Example 323 o 4-(b-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1,3 -d ko hydroindol-2-one

Example 324 60 4-(b-chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1,3-dihydro indol-2-one

Example 325 b-chloro-5-methoxy-4,4,7-trimethyl-1-(2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol 65 Example 326 2-chloro-3,8,8-trimethyl-5-(2-methylquinazolin-5-ylamino)-6-"-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol

Examples 327 and 328 (-3-6-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethide-2-"(trifluoromethyl)-1 ,2,3,4-tet raghydronaphthalen-2-ol and (-)-6-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7- trimethyl-2-trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-ol 88 mg of racemic b-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy- 4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydron aphthalin-2-ol was separated on a chiral column (Spigairak AOS-H 5, eluents: hexane/ethanol). 42.bmg of 70. (k)-enantiomer and 41.Zmg of (-)-enantiomer were obtained. (сИо--36.9--0.6 (с-0.50, methanol) (Сио--32.8-- 0.3 (с-0.51, methanol)

Example 329 (-)-2-chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-3,8,8,-trimethyl-b-(trifluoromethyl)-5,6,7,8 -tetrahydrona phthalene-1,6-diol 33.9 mg of simple ether (i)-enantiomer). described in example 45. was treated, as usual, with boron tribromide. 30.1 mg (91.495) of enantiomerically pure phenol was isolated. (c10--49.1--0.3 (c-0.55, methanol)

Example 330 (-)-2-chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-3,8,8,-trimethyl-6-"(trifluoromethyl)-5,6,7, 8-tetrahydrophthalene-1,6-diol 37.2 mg of the simple ether ((-)-enantiomer), described in example 45, was treated as usual with boron tribromide. C30.0mg (85.695) of enantiomerically pure phenol was isolated. (cM0--44.7--0.4 (c-0.55, methanol) sa

Examples 331 and 332 o (-3-6-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2 ,3,4-tetrahydronaphthalen-2-ol and (-)-6-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol "I 143 mg of racemic "b-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4 ,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalin-2-ol was separated on a chiral column (Spigaise! О0О-Н 5 u, eluents: hexane/ethanol). 58.4 mg ( Ce) of (i)-enantiomer and 51.2 mg of (-)-enantiomer.

IeIro--30.5-0.7 (s-0.50, methanol) (sd0--27.3-0.8 (s-0.51, methanol) so

Example 333 (-)-2-chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-3.8,8,-trimethyl-b-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalin-1 ,6-diol 5 mg of the simple ether ((i)-enantiomer) described in Example 49 was treated as usual with C 70 boron tribromide. 47.Zmg (95.595) of enantiomerically pure phenol was isolated. c (oLo-41.6-0.8 (c-0.55, methanol) "from Example 334 (-)-2-chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-3, 8,8,-trimethyl-6-"-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol 15 44.5 mg of the simple ether ((-)Y-enantiomer) described in example 49 was treated , as usual, with tribromide

So boron. 41.4 mg (95.895) of enantiomerically pure phenol was isolated.

And av | (10--40.2--0.6 (c-0.57, methanol) b» Examples 335 and 336 (-3-5-Ib-chloro-2-hydroxy-5-methoxy-4,4,7 -trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1 and 50 N.quinolin-2-one and

HT" (-)-5-(b-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino!| -1

N-quinolin-2-one 124 mg of racemic 5-Ib-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino |-1H-quinols of n-2-one were separated on a chiral column (SVigaise! 0O-H 5 y, eluents: hexane/ethanol). 54.7 mg of (F) (i)-enantiomer and 47 mg of (-)-enantiomer were obtained.

He (IsIro--37.0-0.6 (c-0.57, methanol) (10--46.6--0.4 (c-0.54, methanol) 60 Example 336 (-)-5 -Ib-chloro-2,5-dihydroxy-4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1H-quinolin-2-one 47, Zmg of the simple ether ((4)-enantiomer) described in example 334 was treated as usual with boron tribromide. 42.bmg (92.895) of enantiomerically pure phenol was isolated. 65 (e10-953.3-0.4 (c- 0.52, methanol)

Example 337

(-)-5-(b-chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-1-ylamino|-1H-quinolin-2 -one 42.4 mg of the simple ether ((-)-enantiomer) described in Example 334 was treated as usual with boron tribromide. 39.4 mg (95.895) of enantiomerically pure phenol was isolated. (10--96.3-- 0.4 (c-0.54, methanol)

Example 338 1,6-dihydroxy-3,8,8-trimethyl-5-(2-oxo-2,3-dihydroindol-4-ylamino)-6-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene -2-carbonitrile 70 IR (microscope, matrix: diamond): 2235

Example 338 5-(7-fluoro-2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-"-trifluoromethyl)-5,6,7 8-tetrahydrophthalene- 2-carbonitrile

IR (microscope, matrix: diamond): 2228

Similarly to the described compounds 283-292, the following structures can be synthesized using the appropriate starting substances:

3-fluoro-4,7-dihydroxy-5,5-dimethyl-8-(1-oxo-1,2-dihydroisoquinolin-5-ylamino)-7-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene -2-carbonitrile

C-fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-ylamino)-7-trifluoromethyl)-5,6, 7, 8-tetrahydronaphthalene-2-carbonitrile

3-fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-methyl-1-oxo-1,2-dihydrophthalazine-5-ylamino)-7-trifluoromethyl)-5,6,7, 8-tetrahydronaphthalene-2-carbonitrile

C-fluoro-4,7-dihydroxy-5,5-dimethyl-8-(1-oxo-1,2-dihydrophthalazine-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene -2-carbonitrile p

C-fluoro-8-(7-fluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydro onanaphthalene-2 -carbonitrile o

3-fluoro-8-(8-fluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydro onanaphthalene-2 -carbonitrile

3-fluoro-8-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetra And 3o hydronaphthalene-2-carbonitrile

3-Fluoro-8-(2-methmlquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7 8-tetrahydronaphtha in lin-2-carbonitrile He)

C-fluoro-8-(2-ethylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile -

3-fluoro-8-(2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene Ge)-2-carbonitrile

C-fluoro-8-(2,6-dimethylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-2-carbonitrile

3-fluoro-8-(6-chloro-2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7 8-tetrahydron "aphthalin-2 -carbonitrile shsh c 3-fluoro-8-(6-fluoro-2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7 8-tetrahydron and naphthalene-2-carbonitrile "" 3-fluoro-4,7-dihydroxy-8-(1H-indazol-4-ylamino)-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8- tetrahydronaphthalene-2-k arbonitrile

3-Fluoro-4,7-dihydroxy-5,5,-DIMethyl-8-(naphthalene-1-ylamino)-7-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

Z-fluoro-4,7-dihydroxy-5,5,-dimethyl-8-(naphthalene-2-ylamino)7-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-2-car o bonitrile b Z-fluoro -4,7-dihydroxy-5,5,-dimethyl-8-(b-hydroxynaphthalene-1-ylamino)-7-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile fluoro-4,7-dihydroxy-5,5,-dimethyl-8-(5-hydroxynaphthalene-1-ylamino)-7-trifluoromethyl)-5,6,7,8-tetrahydronaphth

Tain-2-carbonitrile

3-chloro-2-fluoro-5-(6-hydroxynaphthalene-1-ylamino)-8,8-dimethyl-6-trifluoromethyl)-5,6,7-8-tetrahydronaphthalene-1,6-diol

3-chloro-2-fluoro-5-(5-hydroxynaphthalene-1-ylamino)-8,8-dimethyl-6-trifluoromethyl)-5,6,7-8-tetrahydronaphthalene-1,6-diol iF) З- chloro-2-fluoro-5-(naphthalene-1-ylamino)-8,8-dimethyl-6-"-"trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol co C-chloro-2 -fluoro-5-(naphthalene-2-ylamino)-8,8-dimethyl-6-"-"trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol

C-chloro-2-fluoro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-b-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol in C-chloro -2-fluoro-5-(5-chloro-1H-indazol-4-ylamino)-8,8-dimethyl-b-(trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6-diol 5-( 7,8-difluoro-2-methylquinazolin-5-ylamino)-1"b-dihydroxy-3,8,8,-trimethyl-6b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile 5-(8-fluoro-2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-«-trifluoromethyl)-5,6,7 8-tetrahydro 65 phthalin-2 -carbonitrile 5-(2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-"-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-

2-carbonitrile 5-(2-ethylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile 1 ,6-dihydroxy-3,8,8-trimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-"trifluoromethyl)-5,6,7,8-tetrahydron aphthalin-2 -carbonitrile 1,6-dihydroxy-3,8,8-trimethyl-5-(1-oxo-1,2-dihydroisoquinoline-5-ylamino)-6-"-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene -2-carbonitrile 1,6-dihydroxy-33,8-trimethyl-5-(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-ylamino)-6-trifluoromethyl)-5,6,7, 8-t 70 tetrahydronaphthalene-2-carbonitrile 1,6-dihydroxy-3,8,8-trimethyl-5-(1-oxo-1,2-dihydrophthalazine-5-ylamino)-6-(trifluoromethyl)-5,6 ,7,8-tetrahydro naphthalene-2-carbonitrile 1,6-dihydroxy-3,8,8-trimethyl-5-(2-methyl-1-oxo-1,2-dihydrophthalazine-5-ylamino)-6-- trifluoromethyl)-5,6,7,8-the trahydronaphthalene-2-carbonitrile 1,6-dihydroxy-3,8,8,-trimethyl-5-(2-methylquinolin-5-ylamino)-6-"trifluoromethyl)- 5,6,7 8-tetrahydronaphthalene-2-carbonitrile 1,6-dihydroxy-3,8,8,-trimethyl-5-(2,6-dimethylquinolin-5-ylamino)-6-"-triph tormethyl)-5,6,7 8-tetrahydronaphthalene n-2-carbonitrile 1,6-dihydroxy-3,8,8,-trimethyl-5-(b-chloro-2-methylquinolin-5-ylamino)-6-" 'trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile 1,6-dihydroxy-3,8,8,-trimethyl-5-(b-fluoro-2-methylquinolin-5-ylamino)- 6--trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-2-carbonitrile 1,6-dihydroxy-5-(1H-indazolyl-4-ylamino)-3,8,8,-trimethyl-b-(trifluoromethyl )-5,6,7 8-tetrahydronaphthalene-2-carbonitrile with 1,6-dihydroxy-5-(5-chloro-1H-indazolyl-4-ylamino)-3,8,8,-trimethyl-b-( trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and) 1,6-dihydroxy-3,8,8,-trimethyl-5-(naphthalene-1-ylamino)-6-"-trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-2-carbon ytril 1,6-dihydroxy-3,8,8,-trimethyl-5-(naphthalene-2-ylamino)-6-"-trifluoromethyl)-5,6 ... ... - 5,6,7,8-tetrahydronaphthalene

Yin-2-carbonitrile o 2-chloro-5-(1H-indazol-4-ylamino)-3,8,8-trimethyl-6-trifluoromethyl)-5,6,7 8-tetrahydronaphthalene-1,6b-diol so 2-fluoro-5-(1H-ivdazol-4-ylamino)-3,8,8-trimethyl-6-"(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,b-diol 2-chloro -3,8,8-trimethyl-5-(naphthalene-1-ylamino b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6b-diol 2-fluoro-3,8,8-trimethyl- 5-(naphthalene-1-ylamino b-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6b-diol 2-chloro-3,8,8-trimethyl-5-(6-hydroxynaphthalene-1- ylamino)-6-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6b-diol « 2-fluoro-3,8,8-trimethyl-5-(6-hydroxynaphthalene-1-ylamino)-6 -(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,b-diol with 2-chloro-3,8,8-trimethyl-5-(5-hydroxynaphthalene-1-ylamino)-6--( trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6b-diol 2-fluoro-3,8,8-trimethyl-5-(5-hydroxynaphthalene-1-ylamino)-6-(trifluoromethyl)-5 ,6,7,8-tetrahydronaphthalene-1,b-diol 1,6-dihydroxy-8,8-dimethyl-5-(2-methylquinazolin-5-ylamino)-6--trifluoromethyl)-5, 6,7,8-tetrahydronaphthalene-2-carbonitrile 1,6-dihydro si-8,8-dimethyl-5-(2-ethylquinazolin-5-ylamino)-6-"-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carobonitrile 1,6-dihydroxy-8, 8-dimethyl-5-(7-fluoro-2-methylquinazolin-5-ylamino)-6-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

He» 1,6-dihydroxy-8,8-dimethyl-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-"'trifluoromethyl)-5,6,7,8-tetrahydrona phthalin- 2-carbonitrile and 1,6-dihydroxy-8,8-dimethyl-5-(8-fluoro-2-methylquinazolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene in-2-carbonitrile 1,6-dihydroxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-"-trifluoromethyl)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile

F!

Claims (1)

The formula of the invention is) 1. Compounds of the general formula (I) 60 b5 v (), v Shk KE ge v ry! ory2 NM dz 70 in which B" and vk, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted C.i.i.-Cio-alkyl group, an optionally substituted Co. 4-Cio-alkyl group, C .4-C.o-alkylthio group, C.-Cv-perfluoroalkyl group, cyano group, nitro group, or B! and K? together represent a group selected from the groups -0-(СНО)д-Оо-, -0-(СНО)д-СНе-, -0-СН:СН-, -СНо)вао-, "МНА(СНао) vniai, "M(C4-C3-alkyl)-(CHNao)dvniai and -MH-MeCH-, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are directly connected to ring carbon atoms adjacent to them, or MEZE?, where KZ and KU, independently of each other, represent hydrogen, C4-Cv-alkyl or (CO)-C.4-Cv-alkyl, VK"! represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted Co 4-Coo-alkyl group, a C.i-C.o.-alkyl group, a C.--Cio-alkylthio group or C.-Cv-perfluoroalkyl group, B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted C.-C.ru-alkyl group or C.4-C.o-alkyl group, BZ is a C 1-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 C.i. -C5-Alkoxy groups, an optionally substituted C5-C1-cycloalkyl group, an optionally substituted CH heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted, independently of by one, one or several groups selected from C.-Cv-alkyl groups, which themselves may optionally be substituted by 1-3 hydroxy or 1-3 COOMK"Z groups, where BK'Z is hydrogen or Co 4-Cv -alkil, with «C-s-'walkoxigroup, halogen atoms, hydroxygroup, megroup, exhometile groups or oxygen atoms, and which does not necessarily contain 1-4 nitrogen atoms and/or 1-2 oxygen atoms, and/or 1--- 2 sulfur atoms, and/or 1-2 keto groups, and this group can be connected by any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more in the sections, B" represents a hydroxy group, an OK "9 group or an O(SOV C group, where KO is any hydroxy-protecting o group or a C.-C.o-alkyl group, (ee) BZ is a C 1- C.o-alkyl group or optionally partially or fully fluorinated C.4-C.io-alkyl group, C.-C.-cycloalkyl group, C.4-C.sub.alkyl-C.sub.3-C-cycloalkyl group, C.-C.sub.-alkenyl- C3-C.-cycloalkyl group, heterocyclic group, C.--Cd-alkylheterocyclic group, Co-Cd-alkenylheterocyclic group, aryl group, C--Cv-alkylaryl group, Co-Cv-alkenylaryl group, Co-Cv- alkynylaryl groups, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1-2 keto groups, 1-2 C.-Cv-alkyl groups, 1-2 c. exomethylene groups, and which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a C-Cv-alkylheteroaryl group or a C-Cv-alkenylheteroaryl group, or a C-Cv -alkynylteteroaryl group, and these groups can be linked by means of any position with the tetrahydronaphthalene system and may optionally be hydrogenated in one or more sites, Ke and K7, independently of each other, represent a hydrogen atom, a methyl or ethyl group, or, (ee) together with a tetrahydronaphthalene carbon atom system, C3-C-cycloalkyl ring. o 2. Compounds according to claim 1 with the general formula (I) in the stereoisomeric form vve ;() (o) v! t 70, what are you? ory2 NM dz o in which B" and vk, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, optionally a substituted C4-Cio-alkyl group, C.4-Cio-alkyl group, C.4-C -o-alkylthio group, C.--C.-perfluoroalkyl group, cyano group or nitro group, 60 or KV! and B? together represent a group selected from the groups -O-(CH 2-0, -O-(CHNao)-CHO -, -"O-CH-CH-, ""CHNao)po-, -MH-A(CHNo)vya, -"M(C.-C3-alkyl)-(CHNo)vya or -MH-MeCH-, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to ring carbon atoms directly adjacent to them, or MURU, where VZ and BEU, independently of each other, can be hydrogen, C 1-Cv-alkyl or (CO)-C.4-Cv-alkyl, in" 62 represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted Co 4 -C 0 -alkyl group, C 1 -C 0 -alkyl group, C 1 -C 0 -alkylthio group or C.-Cv-perfluoroalkyl group, KK" is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted C.1-C.io-alkyl group or a C.4-C.o-alkyl group, ECZ is a C.- Cio-alkyl group, which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms or 1-3 C.-C.-Alkoxy group, optionally substituted C.sub.3-C.cycloalkyl group, optionally substituted heterocyclic group, optionally substituted aryl group, 70 monocyclic or bicyclic heteroaryl group which is optionally substituted by one or more groups, selected from C.-Cv-alkyl groups, which themselves can optionally be substituted by 1-3 hydroxy or 1-3 covB"Z groups, where BZ is hydrogen or C 1-Cv-alkyl, C-Cv- alkoxy groups, halogen atoms or exomethylene groups, and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, and this group can be linked by by means of any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more sites, B" is a hydroxy group, an OBO group or an O(SOB" group, where B is any hydroxy protecting group or C .4-Sio-alkyl group, VZ is a C 1-Cv-alkyl group or optionally partially or fully fluorinated C 41-C c-alkyl group, C-C,-cycloalkyl group, C.4-Cvd-alkyl-C3-C-cycloalkyl group, Co-Cv-alkenyl-C3-C.-cycloalkyl group, heterocyclic group, C.--Cd -alkylheterocyclic group, Co-Cv-alkenylheterocyclic group, aryl group, C--Cv-alkylaryl group, Co-Cv-alkenylaryl group, Co-Cv-alkynylaryl group, monocyclic or bicyclic heteroaryl group, which is optionally substituted 1-2 ketogroups, 1-2 C.-C5-alkyl groups, 1-2 C.i-Cv-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or which contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms, and/or 1-2 sulfur atoms, C--Cv-alkylteteroaryl group or c 29 Co-Cv-alkenylheteroaryl group, and these groups can be connected using any position of. (In the tetrahydronaphthalene system, and may optionally be hydrogenated in one or more areas, and K7, 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 C3-Ca-cycloalkyl ring, "zo provided that at least three of the radicals EK", B, B"! and 272 do not represent hydrogen. Z. Compounds of the general formula (I) according to claim 1 "in what) "I in sia | "c) " poh s v ry! ory2 NM. and "du in which -o B" and vk, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted C.i.i.Cio-alkyl group, an optionally substituted Co.4-Cio-alkyl group , C.4-C.o-alkylthio group, ;" C.-Cv-perfluoroalkyl group, cyano group or nitro group, or K" and VK? together represent a group selected from the groups -0О-(СНао)в-О-, -О-(СНо)д-СНо-, -ОО-СН - СН-, "СНао)пао-, "МНА(СНао)впн, -"M(C4-C3-alkyl)-(CHNao)vpni- and -MH-M-CH-, dep 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to directly (ee) ring carbon atoms adjacent to them, or MURU, where KZ and KZ, independently of each other, can be hydrogen, C.4-Cv-alkyl or (CO)-C.-Cv-alkyl, B" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted C.-C.p.-alkyl group, a C.-C.sub.-alkyl group, a C.-C.sub.-alkylthio group or a C.-C.sub.-perfluoroalkyl group, "250 V"? represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted HT» C.-C.d.-alkyl group or a C.4-C.io-alkyl group, BZ is a C.4-C.io-alkyl group, which optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 C.-C.sub.-alkyl groups, optionally substituted C.sub.3-C.cycloalkyl group, optionally substituted heterocyclic group, optionally substituted aryl group, (F ) a monocyclic or bicyclic heteroaryl group, which is optionally substituted, independently of each other, by one or more groups selected from C.-C.-alkyl groups, which may optionally be substituted by 1-3 hydroxy or 1-3 s "With groups where BZ is hydrogen or C 1 -C 1 -alkyl, with C 1 -C 5 -alkoxy groups, halogen atoms, hydroxy groups, MAZEZ groups, exomethylene groups or oxygen atoms, and which optionally contains 1-3 atoms nitrogen and/or 1-2 oxygen atoms, and/or 1-2 sulfur atoms, and/or 1-2 keto groups, and this group can be connected by any position to an amine of the tetrahydronaphthalene system and may optionally be hydrogenated in one or more sites, B" represents a hydroxy group, a group OK "9 or an O(SOV C group, where KO is any hydroxy-protecting 65 group or C.-Sio-alkyl group , BZ represents a C 1-C.o-alkyl group or an optionally partially or fully fluorinated C 4-C 10-alkyl group, 25 and KE", 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 C3-Co-cycloalkyl ring. 4. Compounds of the general formula (I) according to claim 1 in (), in "4 y, t, no ry! ory2 NM dz in which B" and 22, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted C.i.i.Cio-alkyl group, an optionally substituted Co. 4-Cio-alkyl group, C. 4-C.o-alkylthio group, C.-Cv-perfluoroalkyl group, cyano group or nitro group, or K" and VK? together represent a group selected from the groups -O-(СНао)в-О-, -О-(СНо)д-СНо-, -ОО- SNESN-, "СНао)до-, "МНА(СНао) pi, "М(С4-С3-alkyl)-(СНао)di- И -МН-МеСН-, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to ring carbon atoms directly adjacent to them, or ME:ZE, where ВЗ and КУ, independently of each other, can be hydrogen, C 1-Cv-alkyl or (СО)-С.4-Св-alkyl, в" represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted Со 4-С4о-alkyl group, С1-Сио-alkyl group, С4-Со-alkylthio group or C.-Cv-perfluoroalkyl group, c 29 V"? represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, optionally substituted by He) C.-C.sub.alkyl group or C.-C.o-alkyloxy group, KZ is a C.4-C.sub.0-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms or 1-3 C.-C.-aluoxy groups, an optionally substituted C3-C1 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group which is optionally substituted, independently of each other, by one or more groups which selected from C/-Cv-alkyl groups, which themselves may optionally be substituted by 1-3 hydroxy or 1-3 SOOMK'Z groups, where BC? represents hydrogen or Co .-Cv-alkyl, with C.-C-Alkoxy groups, halogen atoms, exomethylene groups or oxygen atoms, and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms, and/or 1-2 sulfur atoms, and/or 1- 2 - Keto groups, and this group can be connected by means of any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas, B" represents a hydroxy group or a group ОВ У, where ВК 9 represents is a C.-C.o-alkyl group, BE? is a C.4-C.alkyl group or an optionally partially or fully fluorinated C.4-C.alkyl "group, 25 and BE", independently of each other, represent a hydrogen atom, with a methyl or ethyl group, or, together with a carbon atom of the tetrahydronaphthalene system, a C3-Ce-cycloalkyl ring. And | and 5. Compounds according to claim 1 of the general formula (II) in the stereoisomeric form ВЕ (1), рі с Ше о | and Ф 4 Ky their 50 РЕ НМ with и" in which B" and вк?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, a C.-C.ru-alkyl group, a C41-Cio-alkyl group, a C4-Co-alkylthio group, a C-Cv-perfluoroalkyl group, a cyano group or a nitro group, or B and B? together represent a group selected from the groups -O-(СНа)-О-, -О-(СНо)-СНо-, -О-СНАСН- or ГФ) -(СНо)по-, where n is 1 or 2, and terminal oxygen atoms and/or carbon atoms are connected to ring carbon atoms immediately adjacent to them, or MAZV?, where KZ and KZ, independently of each other, can be hydrogen, C.4-Cv-alkyl or (CO )-C.-Cv-alkyl, in BZ is a C 1-C.o-alkyl group, which can optionally be substituted by 1-3 hydroxy groups, halogen atoms, optionally substituted phenyl group, monocyclic or bicyclic heteroaryl group , which is optionally substituted by 1-2 keto groups, 1-2 C.4-Cv-alkyl groups, 1-2 C.i-Cv-alkyl groups, 1-3 halogen atoms or 1-2 exomethylene groups, and which necessarily contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms, and/or 1-2 sulfur atoms, and these groups can be connected through any position to the 65 amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more sections, B" is a hyd roxygroup, VE? represents a C 4 -C 4 -alkyl group or an optionally partially or fully fluorinated C 4 -C 4 -alkyl group, an aryl group, a C 4 -C 4 -alkylaryl group, a C 4 -C 4 -alkenylaryl group, a C 3 -C,.- cycloalkyl group, C.4-Cv-alkyl-C3-C,-cycloalkyl group or Co-Cv-alkenyl-C3-C,-cycloalkyl group, 25 and KE", independently of each other, represent a hydrogen atom, methyl or ethyl group, or , together with the carbon atom of the tetrahydronaphthalene system, represent a C3-Cv cycloalkyl ring. 6. Claim 1 compounds of the general formula (II) ek (1), Hn | I'm still in Re NM. with What and in which B" and vk?, independently of each other, represent a hydrogen atom, a hydroxy group, a halogen atom, C.-C.ru-alkyl group, C.sub.41-C.sub.0-alkyl group, C.sub.4-C.sub.4-alkylthio group, C.sub.-C.sub.-perfluoroalkyl group, cyano group or nitro group, or K" and K? together represent a group selected from the groups -O-( СН 2)4-О-, -О-(СНо)-СНо-, -О-СНАН., 20. (СНа)дго-, «МНА(СНао)пиай M(С4-С3-alkyl)-(СНо)пяй, and -МН-М-СН-, where p o is 1 or 2, and the terminal oxygen atoms and /or carbon atoms are connected to ring carbon atoms directly adjacent to them, or MEZVU, where ВЗ and ВУ, independently of each other, can be hydrogen, C.4-Св-alkyl or (СО)-С.-Св -alkyl, BZ represents a C 1-C.o-alkyl group, which is optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 C.i-C.sub.5-alkyl groups, optionally substituted by C 5-C, -cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group, which is optionally substituted by one or more groups selected from C 4 -C 4 -alkyl groups (which may optionally to be substituted by 1-3 hydroxy or 1-3 "Z" groups), C-C-Alkoxy groups, halogen atoms or exomethylene groups, and which optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms, and/ or 1-2 g of sulfur atoms, and/or 1-2 keto groups, and this game pa can be connected by any position to the amine of the tetrahydronaphthalene system and can optionally be hydrogenated in one or more areas, "B" is a hydroxy group or a group of ОВ У, where ВК 9 is С.-С. o-alkyl group, "o VE? represents a C 4-Cv-alkyl group or an optionally partially or fully fluorinated C 4-Cv-alkyl o group, 25 and KE", independently of each other, represent a hydrogen atom, a methyl or ethyl group, or, together with an 00 atom carbon of tetrahydronaphthalene system, C3-Ce-cycloalkyl ring. 7. Compounds according to any of items 1-6, in which the radical Б У? represents a trifluoromethyl group or a pentafluoroethyl group. " 8. Compounds according to any of items 1-6, in the form of salts with physiologically compatible anions. 9. Use of compounds according to one of the previous points for obtaining a medicinal product. From p. 10. Application of compounds according to points 1-5 for obtaining a medicinal product for the treatment of inflammatory "» diseases. " 11. Pharmaceutical preparation, which contains at least one compound according to points 1-5 or their mixtures, as well as a pharmaceutically acceptable carrier. 12. The method of obtaining compounds of the general formula I in stereoisomeric form, in which the compounds of the general formula PI in the stereoisomeric form have the structure B, B, B, B, B, B 5, 9 and c have the values indicated above, are cyclized to compounds of the General formula I with the addition, optionally, of inorganic or organic or Lewis acids. F) Official Bulletin "Industrial Property". Book 1 "Inventions, Utility Models, Topographies of integrated microcircuits", 2007, M 16, 10.10.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 60 b5