UA108746C2 - Substituted isoquinolinones and quinazolinones - Google Patents

Abstract

The present invention relates to substituted nitrogen-containing bicyclic heterocycles of formula (I) in which Z is C or N-R and X, R, R, R, R, R and n are as defined in the description. Such compounds are suitable for the treatment of disorders or diseases, which is mediated by the activity of MDM2 and / or MDM4 or variants thereof.

Description

The present invention relates to substituted nitrogen-containing bicyclic heterocycles of the formula (I), in which 7 denotes SNeo or M-B: and X, B", B-, B", Bhe, B" and n are as defined in the description.

Such compounds are useful for the treatment of a disorder or disease mediated by the activity of MOM2 and/or MOMA or variants thereof. c) B c"

M Shchi v' v! in! p x () z v ve" Shchi v'

F y

H

Introduction

The present invention relates to substituted nitrogen-containing bicyclic heterocycles capable of inhibiting the interaction between p53 or its variants and MOM2 and/or MOMA or their variants, respectively, preferably binding to MOM2 and/or MOMA4 or their variants, to the method of obtaining such compounds, to pharmaceutical preparations containing such compounds, to the uses and methods of using such compounds for treatment (including therapy and/or prevention) and/or to the related entities listed below. P5Z means all genes and/or proteins encoded by them, which have the names TRBZ, ro3, TR7Z, p73, TRBZ, TR7ZI, rb3.MOM2 means all genes and/or proteins encoded by them, which have the names MOM2, Matg2, NOM2, Nata.

MOMA means all genes and/or proteins encoded by them, which have the names MOM4, Mat, NOMA,

Nata, MOMH, Math, NOMU, Nath.

The p53 protein is known to be a tumor suppressor protein that helps regulate cell integrity and prevents the proliferation of persistently damaged cells by initiating, among other responses, growth arrest or apoptosis (controlled cell death). ROS works by being a transcription factor capable of regulating a number of genes that regulate, for example, the cell cycle and apoptosis. Therefore, p5Z3 is an important inhibitor of the cell cycle. This activity is effectively controlled by MOM2, an important negative regulator of the tumor suppressor p53. "MOM2" (an abbreviation formed from the oncogene "tighipe doibie tipshe 2") means the name of the gene, as well as the protein encoded by this gene. The MOM2 protein acts both as an ubiquitin ligase ESR, which recognizes the M-terminal transactivating domain (TAD) of the p5Z3 tumor suppressor and thus mediates ubiquitin-dependent degradation of p53, and as an inhibitor of p53 transcriptional activation.

The original mouse oncogene, which encodes the MOM2 protein, was first cloned from a modified mouse cell line. The human homologue of this protein was identified later and is sometimes also called НОМ2 (abbreviation for "nytap doibiye tipshe 2"). As additional confirmation of the role

MOM2 as an oncogene has been shown to be upregulated in some types of human tumors and proliferative diseases, including but not limited to soft tissue sarcomas, bone cancers such as osteosarcomas, breast tumors, bladder cancer, Li-Fraumeni syndrome , brain tumor, rhabdomyosarcoma and adrenocortical carcinoma, etc. Another protein belonging to the MOM2 family is MOMA, also known as

IOM

Thus, dysregulation of the MOM2/p53 ratio, for example, due to mutations, polymorphisms or molecular defects in the affected cells, can be detected in many proliferative diseases. As a result of the mentioned effects of MOM2, it is able to inhibit the activity of the tumor suppressor protein p53, which leads to the loss of p53's activity as a tumor suppressor and the inhibition of regulatory mechanisms that prevent uncontrolled cell proliferation. As a result, uncontrolled proliferation can occur, leading to the formation of tumors, leukemias or other proliferative diseases.

Thus, new drugs are needed that can interfere with the interaction between ro53 and

MOM2 or, preferably, their oncogenic variants and thus allow p53 to have a beneficial effect on uncontrolled tumor growth, allowing it to, for example, accumulate, arrest the cell cycle and/or induce apoptosis of damaged cells.

Brief description of the essence of the invention

According to the invention, it was established that the compounds of a new class of substituted nitrogen-containing bicyclic heterocycles are active inhibitors of the MOM2/p53 interaction (this term, when used in this invention, includes the MOM2/p53 interaction and/or the MOMA4/rzz3 interaction, preferably the Natg/p53 interaction and/or Nata/p53) and thus related compounds represent a new group of compounds that are useful for the treatment of a number of disorders such as proliferative diseases. Therefore, the present invention relates to these compounds as drugs, as well as to the other embodiments mentioned above and below .

Detailed description of the invention

The first object of this invention is a compound of formula (I) and/or its tautomer and/or M-oxide and/or a pharmaceutically acceptable salt and/or solvate,

about with B in Shchi in'

Fo x () in which 27 denotes SNeo or M-Ve;

X denotes halogen;

B" is selected from the group that includes: H-, C-C7-alkyl-;

Bhe is independently selected from the group which includes: H-, B'O-, (B")2IM-;

B" is independently selected from the group that includes: E'O-, (B")2M-; each EB" is independently selected from the group which includes: H-, C-C7-alkyl-, C--C7-alkenyl-, halogen-

C1-C;-alkyl-, halogen-C1-C7-alkenyl-, C3-C12-cycloalkyl-, heterocyclyl-, aryl-, hydroxy-C1-C7- alkyl-, C1-C- alkoxy-C1-C7-alkyl -, amino-Ci-C7-alkyl-, M-Ci-C7-alkylamino-Ci-C7-alkyl-, M,M-di-

C1-C7-alkylamino-C1-C7-alkyl-, C3-C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-C1-C7-alkyl-, aryl-

C1-C;-alkyl-, C-C7-alkylcarbonyl-, halogen-Ci-C7-alkylcarbonyl-, hydroxy-Ci-C7-alkylcarbonyl-,

C1-C;-Alkoxy-Ci-C7-alkylcarbonyl-, amino-Ci-C7-alkylcarbonyl-, M-Ci-C7-alkylamino-C1-C7-alkylcarbonyl-, M,M-di-C1-C7-alkylamino- C-C7-alkylcarbonyl-, C3-C12-cycloalkylcarbonyl-, heterocyclyl-C1-C7-alkylcarbonyl-, aryl-Ci-C7-alkylcarbonyl-, C3-C12-cycloalkyl-C1-C7-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl- , C1-C7-alkylcarbonyl-C1-C7-alkyl-, halogen-

C1-C7-alkylcarbonyl-C1-C7-alkyl-, hydroxy-C1-C7-alkylcarbonyl-C1-C7-alkyl-, C1-C7-alkoxy-C1-C7- alkylcarbonyl-C1-C7-alkyl-, amino-C1 -C7-alkylcarbonyl-C1-C7-alkyl-, M-C1-C7-alkylamino-C1-C7- alkylcarbonyl-C1-C7-alkyl-, M,M-di-C1-C7-alkylamino-C1-C7-alkylcarbonyl -Ci-C7-alkyl-, C3-C12-cycloalkylcarbonyl-C1-C7-alkyl-, heterocyclylcarbonyl-Ci-C7-alkyl-, arylcarbonyl-Ci-C7-alkyl-, carbonyl-Ci-C7-alkyl-, hydroxycarbonyl- C1-C7-alkyl-, C1-C7-alkoxycarbonyl-Ci-C7-alkyl-, aminocarbonyl-Ci-C7-alkyl-, M-C1-C7-alkylaminocarbonyl-Ci-C7-alkyl-, M,M-di- C1-C7- alkylaminocarbonyl-C1-C7-alkyl-, C3-C12- cycloalkylcarbonyl-C1-C7-alkyl-, heterocyclylcarbonyl-

C-C;-alkyl-, arylcarbonyl-C--C7-alkyl-, C-C;-alkylcarbonylamino-C-C7-alkyl-, C-C;- alkylcarbonyl-M-C1-C7-alkylamino-C-C7 -alkyl-, halogen-C1-C7-alkylcarbonylamino-C1-C7-alkyl-, halogen-C1-C7-alkylcarbonyl-M-C1-C7-alkylamino-C1-C7-alkyl- de aryl, heterocyclyl and C3-C1i2- cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of: Ci-C7-alkyl, halogen-Ci-C7-alkyl, halogen, hydroxy group, C1-C7-

Z is an alkoxy group, an amino group, a nitro group or a cyano group; each E" is independently selected from the group consisting of: halogen-, cyano-, nitro-, C-C7-alkyl-, C1-

C;-alkenyl-, halogen-C1-C7-alkyl-, hydroxy-, C1-C7-alkyl-, amino-, M-Ci-C7-alkylamino-, M,M-di-

C-C;-alkylamino-, aminocarbonylamino-, /M-Ci-C7-alkylaminocarbonylamino-, /- M,M-di-C1-C7- alkylaminocarbonylamino-, C1-C;-alkylcarbonylamino-, aminocarbonyl-, M-C1 -C7- alkylaminocarbonyl-, M,M-di-C1-C7-alkylaminocarbonyl-, hydroxy-C1-C7-alkyl-, amino-C1-C7- alkyl-, M-Ci-C7-alkylamino-C1-C7-alkyl -, M, M-di-C1-C7-alkylamino-Ci-C7-alkyl-, C-C;- alkylcarbonylamino-C1-C7-alkyl-, C1-C7-alkylcarbonyl-M-C1-C7-alkylamino-C1 -C7-alkyl-; n equals 0, 1 or 2;

B2 is selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl, and said phenyl, 2-pyridyl or 3-pyridyl is substituted in the para-position (relative to isoquinolinone or quinazolinone) by the group (KZ)2M- U-, in which U is missing (connection), or (83)2M-U- selected from

K! In c |)

In | | I ' K) ' ' M ' VZ ! t ' sha v ' you v ki v? And the indicated phenyl, 2-pyridyl or 3-pyridyl optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C7-alkyl-, halogen-Ci-C7- alkyl-, hydroxy-, C-C7-alkyl-, hydroxy-C1-C7-alkyl-; or (B) phenyl, 2-pyridyl or 3-pyridyl, and said phenyl, 2-pyridyl or 3-pyridyl is substituted in the para-position (relative to isoquinolinone or quinazolinone) by a substituent selected from the group consisting of: cyano-, halogen -, nitro-, C1-C7-alkyl-, halogen-C1-C7-alkyl-, hydroxy-C1-C7- alkyl-, hydroxycarbonyl-, C-C7- alkoxycarbonyl-, C--C7-alkylcarbonyl-, C- C7-Alkoxy-, (attached through a C atom)-heterocyclyl-, where (attached through a C atom)-heterocyclyl is unsubstituted or contains 1-4 substituents selected from the group consisting of: C-C7-alkyl, halogen-Ci- C7-alkyl, halogen, hydroxy group, C1-C7- alkoxy group, amino group, nitro group or cyano group; and wherein said phenyl, 2-pyridyl and 3-pyridyl optionally contain 1-2 additional substituents independently selected from the group consisting of: halo-, cyano-, C-C7-alkyl-, halo-C1-C7-alkyl -, hydroxy-, C-C7-alkyl-, (attached through a C atom or an M atom) heterocyclyl- C1-C4-alkyl- and hydroxy-C1-C7-alkyl-; or (C) phenyl substituted in the ortho position (relative to isoquinolinone or quinazolinone) by a group

WZO- and which contains in the para- or meta-position a substituent selected from the group consisting of methyl, chlorine, C-C7-alkylcarbonyl- or C-C7-alkoxycarbonyl-; (C) (attached through a C atom)-heterocycle selected from where 4 denotes a 4-6-membered heterocyclic ring ringed with phenyl in the para- and meta-position, containing 1-3 heteroatoms selected from M, O or 5, which optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, C1-C7-alkyl-, halogen-C1-C7- alkyl-, hydroxy-, C1-C7- alkoxy-, hydroxy-C1-C7-alkyl-; (E) pyrazin-2-yl (relative to isoquinolinone or quinazolinone), substituted in position 5 by a group:

From the

M! vi v (P) pyridazin-Z-yl (relative to isoquinolinone or quinazolinone), substituted in position 6 by a group: v

M! in or (b) pyrimidin-2-yl (relative to isoquinolinone or quinazolinone), substituted in position 5 by a group: in

M ' in the '

where each EZ is independently selected from the group that includes: H-, C-C7-alkyl-, hydroxy-Ci-C7-alkyl- and C3-C12- cycloalkyl-, C-C7- alkoxy-C1-C7-alkylcarbonyl-, amino-Ci-C7-alkylcarbonyl, M-C1-C7- alkylamino-Ci-C7-alkylcarbonyl, / M,M-di-C1-C7-alkylamino-Ci1-C7-alkylcarbonyl, (8»)2M-C3-Sch12 - cycloalkyl-, (85)2M-C1-C7-alkyl-, (85)2M-C3-C12-cycloalkyl-C1-C7-alkyl-, (85)2M-C3-Scht2- cycloalkylcarbonyl-, H»O- C3-C12-cycloalkyl-, H?O-C1-C7-alkyl-, H»O-C3-C12-cycloalkyl-C1-C7-alkyl-, BPO-(C1-C7-alkyl)-C3-C12-cycloalkyl -C1-C7-alkyl-, BO-(hydroxy-C1-C7-alkyl)-C3-C12-cycloalkyl-C1-C7-alkyl-, (NU)2M-CO-C3-C12-cycloalkyl-C1-C7- alkyl-, C1-C7-alkoxycarbonyl-C3-

C2-cycloalkyl-C1-C7-alkyl-, hydroxycarbonyl-C3-C12-cycloalkyl-C1-C7-alkyl-, aminocarbonyl-C3-

C2-cycloalkyl-C1-C7-alkyl-, H»O-C3z-C12-cycloalkylcarbonyl-, (H»)2M-carbonyl-C1-C7-alkyl-, »O-carbonyl-C1-C7-alkyl-, aryl -Ci-C7-alkyl-, heterocyclyl-Ci-C7-alkyl-, Cb1-C-alkylcarbonyl-, halogen-C1-C7-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, C3-C12-cycloalkylcarbonyl-,

C3-C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-, aryl- where aryl, heterocyclyl and C3-C1-2-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of: halogen-, C-C7 -alkyl-, halogen-C1-C7-alkyl-, C1-C7-alkylcarbonyl-,

C3-C12-cycloalkylcarbonyl-, C1-C7-alkylsulfonyl-, aminosulfonyl-, M-C1-C07- alkylaminosulfonyl-, M,M-di-C1-C7-alkylaminosulfonyl-, aminocarbonyl-, M-C1-C7- alkylaminocarbonyl- . selected from M, O or 5, said heterocyclic ring is unsubstituted or contains 1-3 substituents selected from the group consisting of: halogen-, hydroxy-C1-C7-alkyl-, C1-C7-alkyl-, halogen-C1- C7-alkyl-, oxo:-, hydroxy-,

C-SU-Alkoxy-, Amino-, M-C1-C7-Alkylamino-, M,M-di-C1-C7-Alkylamino-, Hydroxycarbonyl-, C1-C7- Alkoxycarbonyl-, Aminocarbonyl-, M-C1-C ;-alkylaminocarbonyl-, M,M-di-C1-C7- alkylaminocarbonyl-, C1-C7-alkylcarbonyl-, C-C7-alkylsulfonyl-, heterocyclyl-, / C1-C7- alkylcarbonylamino-, C-C7-alkylcarbonyl-M -C1-C7-alkylamino-; and each VE? independently selected from the group consisting of: H-, Ci-C7-alkyl-, hydroxy-Ci-C7-alkyl-,

From C1-C;-alkylcarbonyl-, C-C7-alkoxycarbonyl-C1-C7-alkyl-, aminocarbonyl-C1-C7-alkyl-, M-C1-C7- alkylaminocarbonyl-C1-C7-alkyl-, M,M- di-C1-C7-alkylaminocarbonyl-C1-C7-alkyl-, C-C7- alkylsulfonyl-, aminosulfonyl-, M-C1-C7-alkylaminosulfonyl-, M,M-di-C1-C7- alkylaminosulfonyl-, heterocyclylcarbonyl-, aminocarbonyl-, M-C1-C7-alkylaminocarbonyl-, M,M- di-C1-C7-alkylaminocarbonyl-, C3-C12-cycloalkylcarbonyl-, C1-C7-alkoxycarbonylamino-C1-C7- alkyl-, C-C7-alkylcarbonyl -M-C1-C7-alkylamino-C1-C7-alkyl-, C3-C7-alkoxycarbonyl-, C3-C12-cycloalkyl-, hydroxy-C3-C12-cycloalkyl-, or two KE? together with the M atom to which they are attached, can form a 3-, 4-, 5-, 6-, 7-, 8- or 9-membered heterocyclic ring, which optionally contains 1, 2, 3 or 4 additional heteroatoms , selected from M, O or 5, said heterocyclic ring is unsubstituted or contains 1 to 3 substituents selected from the group consisting of: C1-C7-alkyl-, oxo-, C1-C7-alkylcarbonyl, C1-C7-alkylsulfonyl , hydroxy-C1-C7-alkyl; provided that if 7 is CH", n is 0 or 1 and EB", if present, is ortho-chloro, and K2 is selected from the group consisting of: para-Ci-C3-alkylphenyl-, para-(halo -C1-C3-alkylphenyl-, para-C1-C3-alkoxyphenyl-, para-halogenophenyl-, para-nitrophenyl-, para-(C1-C3- alkoxycarbonyl)phenyl-, para-(hydroxycarbonyl)phenyl-, where phenyl is unobserved necessarily contains 1-2 additional substituents independently selected from halogen and methyl, then Ke and K" do not both denote an ethoxy group or a methoxy group.

Where a compound or compounds of formula (I) is mentioned, this also additionally includes the M-oxides of such compounds, their tautomers and/or their (preferably pharmaceutically acceptable) salts.

For purposes of this specification, the following definitions are used, and when appropriate, terms used in the singular include the plural, and vice versa.

As used herein, "formula (I)" also means "formula !/". These terms are used interchangeably.

As used herein, the term "alkyl" means a fully saturated branched, including one or more branches, or an unbranched hydrocarbon moiety that contains up to 20 carbon atoms. Unless otherwise specified, alkyl refers to a hydrocarbon moiety that contains from 1 to 16 carbon atoms, from 1 to 10 carbon atoms, from 1 to 7 carbon atoms, or from 1 to 4 carbon atoms. Typical examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, C- methylhexyl, 2,2-

dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. Of course, alkyl groups contain 1-7, more preferably 1-4 carbon atoms.

As used herein, the term "alkenyl" means a branched, including one that contains one or more branches, or an unbranched hydrocarbon moiety that contains up to 20 carbon atoms that contains at least one carbon-carbon double bond. Unless otherwise specified, alkenyl means a hydrocarbon moiety that contains from 2 to 16 carbon atoms, from 2 to 10 carbon atoms, from 2 to 7 carbon atoms, or from 2 to 4 carbon atoms. Typical examples of alkenyl include, but are not limited to, ethenyl, propenyl, propenylene, allyl, and 1,4-butadienyl.

As used herein, the term "haloalkyl" means an alkyl as defined herein substituted with one or more halide groups defined herein. Haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl can contain one atom of iodine, bromine, chlorine or fluorine in the alkyl group. Dihaloalkyl and polyhaloalkyl groups may contain two or more identical halogen atoms in the alkyl group or be a combination of different halide groups with alkyl. Usually polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halide groups. Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhaloalkyl means an alkyl in which all hydrogen atoms have been replaced by halogen atoms.

When used in this invention, unless otherwise indicated, the term "hydroxyalkyl" or "hydroxyethyl", "hydroxypropyl", etc. means alkyl as defined above, which is substituted by one or more, preferably one, hydroxy group.

As used herein, the term "halogen" means iodine, bromine, chlorine or fluorine. X halogen preferably means chlorine or bromine, more preferably chlorine. (B) halogen, as a phenyl, 2-pyridyl or 3-pyridyl substituent preferably means iodine.

As used in this invention, the term "alkyl group" means alkyl-O-, where alkyl is defined above in this invention. Typical examples of alkoxy groups include, but are not limited to

and are not limited to methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy, etc. Alkoxy groups usually contain 1-7, more preferably 1-4 carbon atoms.

As used herein, the term "cycloalkyl" means a saturated or partially saturated monocyclic, fused polycyclic or spirane polycyclic carbocycle containing from 3 to 12 carbon atoms. Unless otherwise specified, cycloalkyl refers to cyclic hydrocarbon groups containing from C to 10 ring carbon atoms, or from C to 7 ring carbon atoms. The term "cycloalkyl" excludes "aryl". Typical monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Typical bicyclic hydrocarbon groups include octahydroindyl, decahydronaphthyl, bicyclo|2.1.1|hexyl, bicyclo/2.2.1)Iheptyl, bicyclo(2.2.1|)heptenyl, 6,b-dimethylbicyclo|3.1.1)heptyl, 2,6, 6-trimethylbicyclo!|3.1.1|heptyl, bicyclo(2.2.2|)octyl. Typical tricyclic hydrocarbon groups include adamantyl. As used herein, the term "cycloalkyl" preferably means cyclopropyl, cyclopentyl or cyclohexyl.

The term "aryl" means an aromatic hydrocarbon group containing 6-20 carbon atoms in the ring fragment. Usually the aryl is a monocyclic, bicyclic or tricyclic aryl containing 6-20 carbon atoms. In addition, the term "aryl" as used herein means an aromatic substituent, which may be a single aromatic ring or multiple aromatic rings fused to one another. Non-limiting examples include phenyl or naphthyl. As used herein, the term "aryl" preferably means phenyl.

As used herein, the term "heterocyclyl" or "heterocyclic" means unsaturated (containing in the ring(s) the largest possible number of conjugated double bonds, in which case it is also called heteroaryl), saturated (in which case it is also called saturated heterocyclyl) or a partially saturated ring or ring system, for example a 4-, 5-, 6- or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic or 10-, 11 -, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least 1 heteroatom selected from M, O and 5, where M and 5 may also optionally be oxidized to different oxidation states. A heterocyclic group can be attached through a heteroatom or a carbon atom. Heterocyclyl may include fused or bridged rings as well as spirocyclic rings.

In one embodiment of the present invention, heterocyclyl means an unsaturated, saturated or partially saturated ring or ring system which contains 3, 4,5, 6, 7, 8, 9, 10, 11 or 12 ring atoms and which contains at least one heteroatom selected from with M, O and 5, where M and 5 may also optionally be oxidized and where, unless otherwise specified, the heterocyclic group may be attached via a heteroatom or carbon atom. In one embodiment, heterocyclyl may contain 1, 2, 3, or 4 M atoms, and/or 1 5 atom, and/or 1 0 atom.

Examples of heterocycles include oxyranyl, azirinyl, aziridinyl, 1,2-oxathiolanyl, thienyl, furanyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, benzoisoxazolyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidine, imidazolyl, imidazolidinyl, benzimidazolyl . ZH-indolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, coumaryl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroquinolyl, decahydroquinolyl, octahydroquinolyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, salyridinyl ), quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acre dinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromenyl, chromenyl, benzo|1,3|dioxol-5-yl, 2,3-dihydrobenzo|1,4|dioxin-b-yl, thiochromenyl and isothiochromenyl.

As EC" the term "heterocyclyl-" preferably refers to 5-membered monocyclic unsaturated, partially saturated, or saturated ring systems. Examples include, but are not limited to, pyridyl, imidazolidinyl, pyrrolidinyl, pyrimidinyl, piperazinyl, piperidinyl, thiomorpholinyl, and morpholinyl.

As in (B), the term "(attached through a C)-heterocyclyl-" preferably means 5-6-membered monocyclic unsaturated or partially saturated ring systems. Examples include, but are not limited to, pyrazolyl, imidazole, triazole, and tetrazole.

As (0) the term "(attached through a C atom)-heterocyclyl-" preferably means 9-11-membered

Zo bicyclic unsaturated or partially saturated ring systems. Examples include, but are not limited to, indazolyl, indolyl, benzoisoxazolyl, benzofuranyl, and benzothiophenyl.

As an acronym, the term "heterocyclyl-" preferably means 5-6-membered monocyclic unsaturated, partially saturated or saturated ring systems. Examples include, but are not limited to, opiridyl, pyrimidinyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, furanyl, tetrazolyl, tetrahydrofuranyl, thienyl, oxazolyl, thiomorpholinyl, and morpholinyl.

As CZ, when two CZ together with the M atom to which they are attached can form a 3-9-membered heterocyclic ring, the term "heterocyclyl-" preferably means 4-, 5- or b-membered monocyclic unsaturated, partially saturated or saturated ring systems. Examples include, but are not limited to, azetidinyl, pyrazolyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, imidazolyl, furanyl, tetrahydrofuranyl, thienyl, oxazolyl, thiomorpholinyl, and morpholinyl.

As RK", when two Co together with the M atom to which they are attached can form a 3-9-membered heterocyclic ring, the term "heterocyclyl-" preferably means 5-, 6- or 7-membered monocyclic partially saturated or saturated ring systems . Examples include, but are not limited to, pyrrolidinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, thiomorpholinyl, morpholinyl, and diazepanyl.

As used herein, the term "oxy group" refers to the linking group -O-.

When used in this invention, all substituents are described in such a way that the order of the functional groups of which they are composed is indicated. Functional groups are defined above in this invention. The position of attachment, depending on the structure, is indicated by a hyphen (-) or an equals sign (7), where the equals sign indicates a double bond, if appropriate. "C-attached" means attached through a carbon atom, for example (C-attached)-heterocyclyl-. "Attached through an M atom" means attached through a nitrogen atom, for example, (attached through an M atom)-heterocyclyl-.

Unless otherwise specified in this invention, then " indicates the position of attachment.

As used herein, the term "protected hydroxy group" refers to a functional hydroxy group that contains a "protecting group." In the scope of this description, only a group 60 that is easily removed, which is not a component of the specific final desired compounds proposed in this invention, is called a "protecting group" unless the context indicates otherwise; for example, a protecting group may be part of a compound of formula (I) if specifically indicated. The protection of functional groups by such protecting groups, the protecting groups themselves and the reactions for their removal are described, for example, in standard references such as 5). R. MU.

MeOtiev, "Rgoyesiime Stoyr5 ip Ogdapis Spetivigu", Riepyt Rgev5, Hopdop apa Mem Moik 1973, in the publication of T. MU. Steepe apa R. sch. M. M/tsiv, "Rgoiesiime Stoyrz ip Ogdapis Zupipeziv", ТНига еайиоп,

UMPeu, Mem Hoik 1999, in the publication Te Reriide5; Mointe Z (ediyugv: E. Sgo55 apa y). Meiiepnoigeg),

Asadetis Rhev55, | opdop apa Mem/ MoiKk 1981, in the publication "Meiyodep adeg ogdapizsnep Spetiye" (Meiyod5 oi Ogdapis Spetivigu), Noibrep UUeu!Y, 41 eayyop, Moishte 15/, Seoga Tpiyete Mepaa,

Zishydap 1974, in the publication of N.-O. ChdakibKe apa N. dezspKeii, "Atipozatsygep, Reriyae, Rgoieiipe" (Atipo asidv, Reriidev, Rgoivip5), Mepad Spetiye, M/eipneit, OeeeepieYia Veasi, apa Vazei! 1982, and in the publication of Khdospep IHeptapp, "Spetie deg Kopiepnuagaie: Mopozassaigide ipa Oeegimaye" (Spetivigu oi Sapopuagaie5z: Mopozassnagdez apa Oepmaymev5), Seogu Tpiete Mepad, Bishdai 1974.

A characteristic of protecting groups is that they can be removed easily (ie, without the occurrence of unwanted secondary reactions), for example, by solvolysis, reduction, photolysis or, alternatively, under physiological conditions (eg, by enzymatic cleavage).

The term "and/or its M-oxide, its tautomer and/or its (preferably pharmaceutically acceptable) salt" preferably means that the compound of formula (I) can be in its pure form or in a mixture with its M-oxide, in the form of a tautomer ( for example, due to ketone-enol, lactam-lactim, amide-imidic acid or enamine-imine tautomerism) or in the form of a mixture with its tautomer (for example, due to the course of equivalent reactions), or in the form of a salt of the compound of formula (I) and/or in any of these forms, or as a mixture of two or more of these forms.

Various embodiments are described in this invention. It should be understood that the characteristics specified for each variant of implementation can be combined with other specified characteristics to obtain other variants of implementation.

In another embodiment, the present invention relates to the compound of formula (I) described in this invention, provided that the compound of formula (I) is not: c1 8 M c1 -

Meo di

Meo (6)

Zo

In another embodiment, the present invention relates to a compound of formula (I) and/or its tautomer and/or M-oxide and/or a pharmaceutically acceptable salt and/or solvate,

Ф т з5 х () in which 27 denotes СНео or М-Бе;

X denotes halogen;

B" is selected from the group, which includes: H-, C-Ca-alkyl-;

Bhe is independently selected from the group which includes: H-, B'O-, (B")2IM-;

B" is independently selected from the group that includes: O-, (B")2M-; each K" is independently selected from the group which includes: H-C1-Cv-alkyl-, Ci-Cv-alkenyl-, halogen-

C1-C4-alkyl-, halogen-C1-C4-alkenyl-, C3-C7-cycloalkyl-, heterocyclyl-, aryl-, hydroxy-C1-C4- alkyl-, C1-C-- alkoxy-C1-C4-alkyl -, amino-Ci-C4-alkyl-, M-C1-C--alkylamino-Ci-C4-alkyl-, M,M-di-

C1-C4-alkylamino-C1-C4-alkyl-, C3-C7-cycloalkyl-C1-C4-alkyl-, heterocyclyl-C1-C4-alkyl-, aryl-C1-

Ca-alkyl-, C1-C--alkylcarbonyl-, halogen-C1-C.-alkylcarbonyl-, hydroxy-C1-C4-alkylcarbonyl-, C1-

Ca-Alkoxy-C1-C.-alkylcarbonyl-, amino-C1-C--alkylcarbonyl-, M-C1-C4-alkylamino-C1-C4- alkylcarbonyl-, M,M-di-C1-Ca-alkylamino-C1 -C"-alkylcarbonyl-, C3-SU-cycloalkylcarbonyl-, heterocyclyl-C1-C--alkylcarbonyl-, aryl-C1-C4-alkylcarbonyl-, C3-C-cycloalkyl-C1-C4-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, C1-C4-alkylcarbonyl-C1-C4-alkyl-, halogen-

C1-C4-alkylcarbonyl-C1-C4-alkyl-, hydroxy-C1-C4-alkylcarbonyl-C1-C4-alkyl-, C1-C4-alkoxy-C1-C4- alkylcarbonyl-C1-Ca-alkyl-, amino-C1 -C4-alkylcarbonyl-C1-Ca-alkyl-, M-C1-C--alkylamino-C1-C4- alkylcarbonyl-C1-Ca-alkyl-, / M.M-di-C1-C«-alkylamino-C1- C"-alkylcarbonyl-Ci-Ca-alkyl-, /C3-C7-cycloalkylcarbonyl-C1-C-alkyl-, heterocyclylcarbonyl-C1-C-alkyl-, arylcarbonyl-Ci-C4-alkyl-, carbonyl-Ci-C4- alkyl-, hydroxycarbonyl-C1-Cα-alkyl-, C1-C1-Alkoxycarbonyl-C:1-Cα-alkyl-, aminocarbonyl-C:i-Cα-alkyl-, M-C1-C"-alkylaminocarbonyl-C:1 -C4-alkyl-, M,M-di-C1-Ca4- alkylaminocarbonyl-C1-Ca-alkyl-, C3-C7-cycloalkylcarbonyl-C1-C4-alkyl-, heterocyclylcarbonyl-

C1-C4-alkyl-, arylcarbonyl-C1-C4-alkyl-, C-C4-alkylcarbonylamino-C1-Ca-alkyl-, C-C4- alkylcarbonyl-M-C1-C"-alkylamino-C1-Ca-alkyl- , halogen-C1-C4-alkylcarbonylamino-C1-C4-alkyl-, halogen-C1-C4-alkylcarbonyl-M-C1-C4-alkylamino-C1-C4-alkyl-, where aryl, heterocyclyl and C3-C7-cycloalkyl are unsubstituted or containing 1-4 substituents selected from the group that includes: C1i-Cα-alkyl, halogen-C1-C--alkyl, halogen, hydroxy group, C1-C--alkyl group, amino group, nitro group or cyano group; each E" is independently selected from the group which includes: halogen-, cyano-, nitro-, C-Cα-alkyl-, C1-

Са4-alkenyl-, halogen-С1-С4-alkyl-, hydroxy-, Сі-Сї-аlkoxy-, amino-, M-Сі-Са-alkylamino-, M,M-di-

C-C.-alkylamino-, aminocarbonylamino-, /M-Ci-C4--alkylaminocarbonylamino-, /- M,M-di-C1-Ca- alkylaminocarbonylamino-, C1-C4 alkylcarbonylamino-, aminocarbonyl-, M-C1- Ca4-alkylaminocarbonyl-, M,M-di-C1-C.-alkylaminocarbonyl-, hydroxy-C1-Ca-alkyl-, amino-C1-C4-alkyl-,

Co) M-C1-Ca-alkylamino-C1-Ca-alkyl-, M,M-di-C1-C"-alkylamino-C1-C4-alkyl-, C-C"-alkylcarbonylamino-

C1-Ca-alkyl-, C1-C"-alkylcarbonyl-M-C1-C"-alkylamino-C1-C4-alkyl-; n equals 0, 1 or 2;

B2 is selected from the group consisting of: (A) phenyl, 2-pyridyl or C3-pyridyl substituted in the para-position by the group (KZ)2M-U-, where U is absent (bond), or (83)2M- U- is chosen from 3 v in Ge) and ' | ' | ' Ki! ' Z ' ' M V ' j sha t y vy va ky v! 0) c and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C1-C4- alkoxy-, hydroxy-C1-Ca-alkyl-; or (B) phenyl, 2-pyridyl or 3-pyridyl containing in the para-position a substituent selected from the group consisting of: cyano-, halogen-, nitro-, C1-C6-alkyl-, halogen-C1-C4 -alkyl-, hydroxy-C1-Cα-alkyl-, hydroxycarbonyl-, C1-C4-alkoxycarbonyl-, C1-C4-alkylcarbonyl-, C1-C4-alkyl-, (attached through a C atom)-heterocyclyl-, where (attached through the C)-heterocyclyl atom is unsubstituted or contains 1-4 substituents selected from the group that includes: C1i-C4-alkyl, halogen-C1-C4-alkyl, halogen, hydroxy group, C-C4-alukoxy group, amino group, nitro group or a cyano group; and optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, C-C4-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C-C4-alkyl-, (attached through a C atom or atom

BO M) heterocyclyl-C1-C4-alkyl-, hydroxy-C1-C4-alkyl-; or (C) phenyl substituted in the ortho-position by the group KZO- and which contains in the para- or meta-position a substituent selected from the group consisting of methyl, chlorine, C1-C6-alkylcarbonyl- or C1-C4- alkoxycarbonyl- ; (0) (attached through a C atom)-heterocycle selected from where 4 denotes a 4-6-membered heterocyclic ring ringed with phenyl in the para- and meta-position, containing 1-3 heteroatoms selected from M, O or 5, which optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, C-C4-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C-C" -Alkoxy-, hydroxy-C1-Ca-alkyl-; (E) pyrazin-2-yl (relative to isoquinolinone or quinazolinone), substituted in position 5 by a group: in ' tb ! (P) pyridazine-Z-yl (relative to isoquinolinone or quinazolinone), substituted in position 6 by a group: in ' tb ! or (b) pyrimidin-2-yl (relative to isoquinolinone or quinazolinone) substituted in the 5-position with a group: in b' where each EZ is independently selected from the group consisting of: H-, C1-C1-alkyl-, hydroxy-C1- C4-alkyl-, C3-C7-cycloalkyl-, C1-C7-alkylcarbonyl, C1-C6-alkylcarbonyl, amino-C1-C4-alkylcarbonyl, M-C1-

C-alkylamino-C1-C--alkylcarbonyl, M.M-di-C1-C4--alkylamino-C1-C4-alkylcarbonyl, (H»)2M-C3-C7-cycloalkyl-, (85)2M-C1- Ca-alkyl-, (85)2M-C3-C7-cycloalkyl-C1-C4-alkyl-, (85)2M-C3-O7-cycloalkylcarbonyl-, B5O-C3-C7-cycloalkyl-, HoO-C1-Ca- alkyl-, H5O-C3-C7-cycloalkyl-C1-Ca4- alkyl-, BPO-(C1-Ca-alkyl)-C3-C7-cycloalkyl-C1-C4-alkyl-, PO-(hydroxy-C1-Ca- alkyl)-C3-C7-cycloalkyl-C1-C4-alkyl-, (НА»)»2M-CO-C3-C7-cycloalkyl-C3-C7-alkyl-, C1-C4-alkoxycarbonyl-C3-C7-cycloalkyl- C-C4-alkyl-, hydroxycarbonyl-C3-C7-cycloalkyl-C3-C4-alkyl-, aminocarbonyl-C3-C7-cycloalkyl-C1-C4-alkyl-, H»O-C3-C7-cycloalkylcarbonyl-, (H »)2M-carbonyl-Ci-C4-alkyl-, B?O- carbonyl-C1-C4-alkyl-, aryl-Ci-C--alkyl-, heterocyclyl-Ci-C4-alkyl-, C1-C-- alkylcarbonyl-, halogen-C1-C--alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, C3-SU-cycloalkylcarbonyl-,

C3-C7-cycloalkyl-C1-C4-alkyl-, heterocyclyl-, aryl-, where aryl, heterocyclyl and C3-C7-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of: halogen-, Ci- Ca-alkyl-, halogen-C1-Ca-alkyl-, C1-C.-alkylcarbonyl-, C3-C7-cycloalkylcarbonyl-, C1-C.-alkylsulfonyl-, aminosulfonyl-, M-C1-C4-alkylaminosulfonyl-, M ,M-di-C1-C4-alkylaminosulfonyl-, aminocarbonyl-, M-C1-C4-alkylaminocarbonyl-, M,M-di-C1-C«-alkylaminocarbonyl-, oxo-, or two BZ together with the M atom, to to which they are attached, can form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring, which optionally contains 1, 2, З or 4 additional M heteroatoms, and which optionally contains an O atom and/ or atom 5, where said heterocyclic ring is unsubstituted or contains 1, 2 or C substituents selected from the group consisting of: halogen-, hydroxy-

С1-Са-alkyl-, С1-Са-alkyl-, halogen-С1-С4-alkyl-, oxo-, hydroxy-, С1-С4-аlkoxy-, amino-, M-С1-Са4- alkylamino-, M, M-di-C1-C--alkylamino-, hydroxycarbonyl-, C-C4-alkoxycarbonyl-, aminocarbonyl-, M-C1-C.-alkylaminocarbonyl-, M,M-di-C1-Ca-alkylaminocarbonyl-, C1-C4-alkylcarbonyl-, C-

C.4-alkylsulfonyl-, heterocyclyl-, C1-C4-alkylcarbonylamino-, C1-C--alkylcarbonyl-M-C1-C4-alkylamino-; and each VE? independently selected from the group that includes: H-, C1-C4-alkyl-, hydroxy-C1-Ca-alkyl-,

C-C4-alkylcarbonyl-, C1-C4-alkoxycarbonyl-C1-C4-alkyl-, aminocarbonyl-C1-Ca-alkyl-, M-C1-C4- alkylaminocarbonyl-C1-C4-alkyl-, M,M-di- C1-C4-alkylaminocarbonyl-C1-C4-alkyl-, C-C4- alkylsulfonyl-, aminosulfonyl-, M-C1-C4-alkylaminosulfonyl-, M,M-di-C1-C4- alkylaminosulfonyl-, heterocyclylcarbonyl-, aminocarbonyl- . -Alkoxycarbonyl-M-C1-C-alkylamino-Ci-Ca-alkyl-, C1-C4-Alkoxycarbonyl-, C3-C7-cycloalkyl-, hydroxy-C3-C7-cycloalkyl- or two RE? together with the M atom to which they are attached, can form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring, which optionally contains 1, 2, 3 or 4 additional M heteroatoms and/or which necessarily contains an O atom and/or an 5 atom, the specified heterocyclic ring is unsubstituted or contains 1, 2 or C substituents independently selected from the group that includes: C1-C4-alkyl-, oxo-, C1-C4-alkylcarbonyl, Si -C--alkylsulfonyl, hydroxy-C1-Ca-alkyl; provided that if 7 represents CH", n is 0 or 1 and K", if present, represents ortho-chloro, and K2 is selected from the group consisting of: para-Ci-C3-alkylphenyl-, para-(halo -C1-C3-alkylphenyl-, para-C1-C3-alkoxyphenyl-, para-halogenophenyl-, para-nitrophenyl-, para-(C1-C3- alkoxycarbonyl)phenyl-, para-(hydroxycarbonyl)uphenyl-, where phenyl is unobserved necessarily contains 1-2 additional substituents independently selected from halogen and methyl, then K95 and K/ do not both denote an ethoxy group or a methoxy group.

In another embodiment, the present invention relates to a compound of formula (I) and/or its tautomer and/or M-oxide and/or a pharmaceutically acceptable salt and/or solvate, referred to in

Fo zo x () in which 7 denotes CH" or M-B-;

X denotes halogen;

B" is selected from the group that includes: H-, C-C7-alkyl-;

IN? independently selected from the group consisting of: H-, B'O-, (B")2IM-;

B" is independently selected from the group that includes: O-, (B")2M-;

KE" is selected from the group that includes: IN-, C1i-C7-alkyl-, C-C7-alkenyl-, halogen-Ci-C7-alkyl-, halogen-Ci-C7-alkenyl-, C3-C12-cycloalkyl- . -alkyl-, M,M-di-C1-C7-alkylamino-C1-C7-alkyl-, C3-C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-C1-C7-alkyl-, aryl-C1-C7 - alkyl-, C1-C7-alkylcarbonyl-, halogen-C1-C7-alkylcarbonyl-, hydroxy-C1-C7-alkylcarbonyl-, C1-C7- alkoxy-C1-C7-alkylcarbonyl-, amino-C1-C7-alkylcarbonyl- . , aryl-Ci-C7-alkylcarbonyl-, C3-C12-cycloalkyl-C1-C7-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, C1-C7-alkylcarbonyl-C1-C7-alkyl-, halogen-

C1-C7-alkylcarbonyl-C1-C7-alkyl-, hydroxy-C1-C7-alkylcarbonyl-C1-C7-alkyl-, C1-C7-alkoxy-C1-C7- alkylcarbonyl-C1-C7-alkyl-, amino-C1 -C7-alkylcarbonyl-C1-C7-alkyl-, M-C1-C7-alkylamino-C1-C7- alkylcarbonyl-C1-C7-alkyl-, M,M-di-C1-C7-alkylamino-C1-C7-alkylcarbonyl -Ci-C7-alkyl-, C3-C12-

cycloalkylcarbonyl-C1-C7-alkyl-, heterocyclylcarbonyl-C1-C7-alkyl-, arylcarbonyl-C1-C7-alkyl-, carbonyl-C1-C7-alkyl-, hydroxycarbonyl-C1-C7-alkyl-, C1-C7-alkoxycarbonyl -Ci-C7-alkyl-, aminocarbonyl-Ci-C7-alkyl-, M-C1-C7-alkylaminocarbonyl-Ci-C7-alkyl-, M,M-di-C1-C7- alkylaminocarbonyl-C1-C7-alkyl- . C7- alkylcarbonyl-M-C1-C7-alkylamino-Ci-C7-alkyl-, halogen-Ci-C7-alkylcarbonylamino-C1-C7-alkyl-, halogen-C1-C7-alkylcarbonyl-M-C1-C7-alkylamino- C1-C7-alkyl-, where aryl, heterocyclyl and C3-C12-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group that includes: C1-C7-alkyl, halo-C1-C7-alkyl, halogen, hydroxy group , C1-C7-alkyloxy group, amino group, nitro group or cyano group;

A' is selected from the group that includes: halogen-, cyano-, nitro-, C-C7-alkyl-, C--C7-alkenyl-, halogen-Ci-C7-alkyl-, hydroxy-, C--C7- alkoxy-, amino-, M-C--C7-alkylamino-, M,M-di-C1-C7- alkylamino-, hydroxy-C1-C7-alkyl-, amino-Ci-C7-alkyl-, M-C1 -C7-alkylamino-C1-C7-alkyl-, M,M-di-

C1-C;-alkylamino-Ci-C7-alkyl-, Ci-C7-alkylcarbonylamino-C1-C7-alkyl-, Ci-C7-alkylcarbonyl-M-C1-

C;-alkylamino-Ci-C7-alkyl-;, n is from 0 to 2;

IN? selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position by the group (KZ3)2M-U-, where U is absent (bond), or (83)2M-U - selected from A with M in shk shats y v na ki 3 Z in 0) B and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, Si- C7-alkyl-, halogen-Ci-C7-alkyl-, hydroxy-, C-C7-alkyl-, hydroxy-Ci-C7-alkyl-; or (B) phenyl, 2-pyridyl or 3-pyridyl containing in the para-position a substituent selected from the group consisting of: cyano-, halogen-, nitro-, C1-C7-alkyl-, halogen-C1-C7 -alkyl-, hydroxy-Ci-C7-alkyl-, hydroxycarbonyl-, Ci-C7-alkoxycarbonyl-, Ci-C7-alkylcarbonyl-, Ci-C7-alkyl-, (attached through a C atom)-heterocyclyl-, where (attached through the C)-heterocyclyl atom is unsubstituted or contains 1-4 substituents selected from the group consisting of: C1-C7-alkyl, halo-C1-C7-alkyl, halogen, hydroxy, C1-C7-alkyl, amino, nitro, or cyano group; and optionally contains 1-2 additional substituents selected from the group consisting of: halogen-,

Co) cyano-, C-C7-alkyl-, halogen-Ci-C7-alkyl-, hydroxy-, C-C7-alkyl-, hydroxy-Ci-C7-alkyl-; or (C) phenyl substituted in the ortho-position by the group KZO- and containing in the para- or meta-position a substituent selected from the group consisting of methyl or chlorine; or (C) (attached through a C atom)-heterocycle selected from where 7 denotes a 4-6-membered heterocyclic ring ringed with phenyl in the para- and meta-position, containing 1-3 heteroatoms selected from M, O or 5, which optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, C1-C7-alkyl-, halogen-C1-C7- alkyl-, hydroxy-, C1-C7- alkoxy-, hydroxy-C1-C7-alkyl-; where ECZ is independently selected from the group that includes: H-, C1-C7-alkyl-, bz-C12-cycloalkyl-, (B»)2M-

C3-Ci2-cycloalkyl-, (H»)2M-C1-C7-alkyl-, (H5)2M-C3-C12-cycloalkyl-Ci-C7-alkyl-, (B5)2M-C3-C12-cycloalkylcarbonyl-, H?O-C3-Ci2-cycloalkyl-, H»O-C1-C7-alkyl-, HoO-C3-C12-cycloalkyl-C1-C7-alkyl-, B»O-C3-C12-cycloalkylcarbonyl-, (H »)2M-carbonyl-C1-C7-alkyl-, H»O-carbonyl-C1-C7-alkyl-, aryl-C1-C7-alkyl-, heterocyclyl-C1-C7-alkyl-, C1-C7-alkylcarbonyl- , heterocyclylcarbonyl-, arylcarbonyl-, C3-C12-cycloalkylcarbonyl-, C3-C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-, aryl-, where aryl, heterocyclyl and C3-C12-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of: halo-, C-C7-alkyl-, halo-Ci-C7-alkyl-, C-C7-alkylcarbonyl-, C3-C12- cycloalkylcarbonyl-, C-i-C7-alkylsulfonyl -, aminosulfonyl-, M-C1-C7-alkylaminosulfonyl-,

M,M-di-C1-C7-alkylaminosulfonyl-, aminocarbonyl-, M-C1-C7-alkylaminocarbonyl-, M,M-di-C1-C7-

alkylaminocarbonyl-, oxo-, or two KZ together with the M atom to which they are attached can form a 3-9 membered heterocyclic ring, which optionally contains 1-4 additional heteroatoms selected from M, O or 5, the specified heterocyclic ring the ring is unsubstituted or contains 1-3 substituents selected from the group consisting of: halogen-, C1-C7-alkyl-, halogen-C1-C7-alkyl-, oxo-, hydroxy-, C1-C7-alkyl-, amino -,

M-C1-C7-alkylamino-, /M,M-di-C1-C7-alkylamino-, hydroxycarbonyl-, C-C7-alkoxycarbonyl-, aminocarbonyl-, M-C1-C;-alkylaminocarbonyl-, M,M- di-C1-C7-alkylaminocarbonyl-, C-C;- alkylcarbonyl-, C1-C7-alkylcarbonylamino-, C-C7-alkylcarbonyl-M-C1-C7-alkylamino-; and

B" is independently selected from the group, which includes: H-, C-C7-alkyl-, C4-C7-alkoxycarbonyl-C1-C7-alkyl-, aminocarbonyl-C1-C7-alkyl-, M-C1-C7-alkylaminocarbonyl- C-C7-alkyl-, / M,M-di-C1-C7- alkylaminocarbonyl-Ci-C7-alkyl-, C1-C7-alkylsulfonyl-, aminosulfonyl-, M-C1-C07- alkylaminosulfonyl-, M,M- di-C1-C7-alkylaminosulfonyl-, aminocarbonyl-, M-C1-C7- alkylaminocarbonyl-, /M,M-di-C1-C7-alkylaminocarbonyl-, C3-C12-cycloalkylcarbonyl-, /-C1-C7- alkoxycarbonylamino- C1-C7-alkyl-, C1-C7-alkoxycarbonyl-M-C1-C7-alkylamino-C1-C7-alkyl-, Сч-

C;-Alkoxycarbonyl-, or two BC? together with the M atom to which they are attached may form a 3-9 membered heterocyclic ring which optionally contains 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1-3 substituents , selected from the group that includes: Ci-C7;-alkyl-, oxo:x; provided that if 7 denotes СНЭ, n equals 0 and B? selected from the group consisting of: para-

C-C3-alkylphenyl-, para- (halo-C1-C3-alkylphenyl-, para-C1-C3-alkoxyphenyl-, para-halophenyl-, para-nitrophenyl-, para-(C1-C3-alkoxycarbonyl)phenyl-, para- (hydroxycarbonyl)phenyl-, where phenyl does not necessarily contain 1-2 additional substituents, then K5 and

B" does not both denote an ethoxy group or a methoxy group.

In another embodiment, 2 represents CH."

In another embodiment, 27 denotes M-B".

In another embodiment

Ko) 2 denotes M-V-; where

B" is selected from the group that includes: H-, Ci-Ca-alkyl-.

In another embodiment

VU is selected from the group, which includes: KO- and

B' is selected from the group, which includes: KO-.

In another embodiment

VU is selected from the group, which includes: IN- and

B' is selected from the group that includes: (K")2M-.

In another embodiment

E" is independently selected from the group that includes: H-, C1-C7-alkyl-, C1-C7-alkenyl-, halogen-C1-C7-alkyl-, C3-C12-cycloalkyl-, hydroxy-C1-C7-alkyl -, C1-C7-Alkoxy-C1-C7-Alkyl-, Amino-C1-C7-Alkyl-,

M-C1-C7-alkylamino-C1-C7-alkyl-, M,M-di-Si-C7-alkylamino-Ci-C7-alkyl-, C3-C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-C1 -C7-alkyl-, C1-C7-alkylcarbonyl-, carbonyl-C1-C7-alkyl-, hydroxycarbonyl-

C-C;-alkyl-, C1-C7-alkoxycarbonyl-Ci-C7-alkyl-, aminocarbonyl-C1-C7-alkyl-, M-C1-C7- alkylaminocarbonyl-Ci-C7-alkyl-, M,M-di -C1-C7-alkylaminocarbonyl-C--C7-alkyl-, heterocyclylcarbonyl-C1-C7-alkyl-, C1-C7-alkylcarbonylamino-C1-C7-alkyl-, where aryl, heterocyclyl and C3-C12-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of:

Ci-C;-alkyl, halo-Ci-C7-alkyl, halogen, hydroxy group, Ci-C7-alukoxy group, amino group, nitro group or cyano group.

In another embodiment

E" is independently selected from the group which includes: H-, C1-C4-alkyl-, C-C4--alkenyl-, halogen-C1-C4- alkyl-, C3-C12-cycloalkyl-, C3-C12-cycloalkyl- Ci-C2-alkyl-, where aryl, heterocyclyl and C3-C12-cycloalkyl are unsubstituted or contain 1-2 substituents selected from the group that includes: C1i-Ca-alkyl, halo-C1-C--alkyl, halogen, a hydroxy group, a C1-C--alkyl group, an amino group, a nitro group or a cyano group.

In another embodiment

AB' is independently selected from the group which includes: halogen-, cyano-, nitro-, C-C7-alkyl-, C1-C7-alkenyl-, halogen-Ci-C7-alkyl-, amino-, M-C1-C7 -alkylamino-, M,M-di-C1-C7-alkylamino-, hydroxy- or C-C7-alkyl-, amino-Ci-SU7-alkyl-, M-Ci-SU-alkylamino-Ci-C7-alkyl- , M.M-di-C1-C7-alkylamino-C1-C7-

alkyl-, C4-C7-alkylcarbonylamino-C1-C7-alkyl-.

In another embodiment

AB' is independently selected from the group that includes: halogen-, cyano-, nitro-, C-C-alkyl-, C1-C4-alkenyl-, halogen-C1-C4-alkyl-, amino-, M-C1-C .-alkylamino-, M,M-di-C1-Ca-alkylamino-, hydroxy-

C-C2-alkyl-, amino-C1-C2-alkyl-, M-Ci-C4-alkylamino-Ci-C2-alkyl-, M.M-di-C1-C4-alkylamino-C1-C2- alkyl-, Ci-Ca-alkylcarbonylamino-C1-Cg2-alkyl-.

In another embodiment, n is from 0 to 1.

In another embodiment, n is 0.

In another embodiment

IN? selected from the group consisting of: phenyl, 2-pyridyl or 3-pyridyl, substituted in the para-position by the group (KZ)2M-U-, where U is absent (bond), or (83)2M-U- selected from 3 Z v" Geh!

BUT

' 3 ' ' M s V ' shk sha ts y v na ki v? o c" and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C7-alkyl-, halogen-C1-C7-alkyl-, hydroxy-, C1-C7- alkoxy-, hydroxy-C1-C7-alkyl.

In another embodiment of B? selected from the group consisting of: phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position by the group (BZ)2M-U-, where U is absent (bond), or (83)2M-U- selected from 3 v v Ge) i nn ' 3 ' ' M V ' sha sha t / ' you wai ki v! (0) c and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C-C "-Alkoxy-, hydroxy-C1-Ca-alkyl, where

BZ is independently selected from the group that includes: H-, C1-C7-alkyl-, C3-C12-cycloalkyl-, (B8»)2M-C3-

C:i2-cycloalkyl-, /(H»)»M-C1-C7-alkyl-, / (H»)2M-C3-C12-cycloalkyl-Ci-C7-alkyl-, / (8»)2M-C3 -Сч12- cycloalkylcarbonyl-, H»O-C1-C7-alkyl-, (H5)2M-carbonyl-C1-C7-alkyl-, H»O-carbonyl-C:1-C7-alkyl-, aryl-Si- C7-alkyl-, heterocyclyl-C1-C7-alkyl-, C1-C7-alkylcarbonyl-, heterocyclylcarbonyl-, C3-

Ci2-cycloalkyl-C1-C7-alkyl-, heterocyclyl-, where aryl, heterocyclyl and C3-C1-2-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of!:, halo-, Ci-C7-alkyl -, halogen-C1-C7-alkyl-, C1-C7-alkylcarbonyl-, C3-C12-cycloalkylcarbonyl-, C1-C7-alkylsulfonyl-,

M,M-di-C1-C7-alkylaminocarbonyl-, oxo-, or two BZ together with the M atom to which they are attached can form a 3-9-membered heterocyclic ring, which optionally contains 1-4 additional heteroatoms, selected from M, O or 5, said heterocyclic ring is unsubstituted or contains 1-3 substituents selected from the group consisting of: C1-C7-alkyl-, oxo-, hydroxy-, amino-, M,M-di-C1 -C7-alkylamino-, hydroxycarbonyl-,

C1-C;-Alkoxycarbonyl-, aminocarbonyl-, M-C1-C7-alkylaminocarbonyl-, C1-C7-alkylcarbonyl-, C-

C;-alkylcarbonylamino-; and

IN? independently selected from the group that includes: H-, C1-C7-alkyl-, C1-C7-alkyloxycarbonyl-C1-C7-alkyl-, aminocarbonyl-C1-C7-alkyl-, C1-C7-alkylsulfonyl-, M,M -di-C1-C7-alkylaminocarbonyl-, C1-

C7-Alkoxycarbonylamino-C1-C7-Alkyl-, C-C7-Alkoxycarbonyl- or two BH? together with the M atom to which they are attached may form a 3-9 membered heterocyclic ring which optionally contains 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1-3 substituents , selected from the group,

which includes: C-C7-alkyl- and oxo-.

In another embodiment of B? selected from the group consisting of: phenyl, 2-pyridyl or 3-pyridyl, substituted in the para-position by the group (BZ)2M-U-, where U is absent (bond), or (83)2M-U- selected from 3 Z v" Ge! i nim ' Z ; ' M v ' shk s v ! v na ki v? A o v" and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano -, C-C7-alkyl-, halogen-C1-C7-alkyl-, hydroxy-, C1-C7-alkyl-, hydroxy-C1-C7-alkyl, where

BZ is independently selected from the group that includes: H-, C1-C4-alkyl-, C3-C12-cycloalkyl-, (B8»)2M-C3-

C;-cycloalkyl-, (85)2M-C-C;-alkyl-, (85)2M-C3-C7-cycloalkyl-Ci-Cg2-alkyl-, (85)2M-C3-O7-cycloalkylcarbonyl-, aryl -Ci-C»-alkyl-, heterocyclyl-Ci-Ci-alkyl-, Ci-C--alkylcarbonyl-, heterocyclylcarbonyl-, C3-C7-cycloalkyl-Ci-Ci-alkyl-, heterocyclyl-, where aryl, heterocyclyl and

C3-Ci2-cycloalkyl are unsubstituted or contain 1-2 substituents selected from the group that includes: halogen-, C-C-alkyl-, halogen-Ci-C-alkyl-, C1-C--alkylcarbonyl-, C3- C7-cycloalkylcarbonyl-, C1-

C.-alkylsulfonyl-, M,M-di-C1-C"-alkylaminocarbonyl-, oxo-, or two BZ together with the M atom to which they are attached can form a 4-7-membered heterocyclic ring, which is not necessarily contains 1-2 additional heteroatoms selected from M, O or 5, said heterocyclic ring is unsubstituted or contains 1-2 substituents selected from the group consisting of: C-C4-alkyl-, oxo-, hydroxy-, amino-, M,M-di-C1-C4-alkylamino-, hydroxycarbonyl-,

C1-C.-Alkoxycarbonyl-, aminocarbonyl-, M-C1-C--Alkylaminocarbonyl-, C1-C.-Alkylcarbonyl-, C-

S.-alkylcarbonylamino-; and

IN? independently selected from the group, which includes: H-, C1-C4-alkyl-, C1-C4--alkoxycarbonyl-C1-C2-alkyl-, aminocarbonyl-C1-C2-alkyl-, C1-C--alkylsulfonyl-, M ,M-di-C1-Ca-alkylaminocarbonyl-, C1-

C.-Alkoxycarbonylamino-C1-C8-alkyl-, C-C-Alkoxycarbonyl-, or two B? together with the M atom to which they are attached, can form a 4-7 membered heterocyclic ring, which optionally contains 1-4 additional heteroatoms selected from M, O or

From 5, the specified heterocyclic ring is unsubstituted or contains 1-2 substituents selected from the group that includes: Ci-Ca4-alkyl-, oxo-.

In another embodiment of B? selected from the group that includes: phenyl, 2-pyridyl or 3-pyridyl, substituted in the para-position by the group (NH)2M-U-, where U is absent (bond) and optionally contains 1-2 additional substituents, selected from the group that includes: halogen-, cyano-, C-C7-alkyl-, halogen-C-C7-alkyl-, hydroxy-, C-C7- alkoxy-, hydroxy-C1-C7-alkyl.

In another embodiment of B? selected from the group that includes: phenyl, 2-pyridyl or 3-pyridyl, substituted in the para-position by the group (BZ)2M-U-, where (H3)2M-U- is selected from 3 Z in Ge) nshH ' Z : ' M she ' she ' sha t / ' you wa ki v! 0) c and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C-C" -Alkoxy-, hydroxy-C1-Ca-alkyl.

In another embodiment, 7 represents CH or MA", where B" represents H or C1-C3-alkyl.

It is better if 2 denotes СН5г or МН, more preferably СН".

In another embodiment, X represents chlorine or fluorine, preferably chlorine.

In another embodiment, each K" is independently selected from the group consisting of: H-, C1-C1-alkyl-, heterocyclyl-C1-C4-alkyl-, amino-C1-Cα-alkyl-, M-C1-C"- alkylamino-C1-Ca-alkyl-, M,M-di-Sch1-

C4-alkylamino-Ci-C4-alkyl-, heterocyclylcarbonyl-C1-C4-alkyl-, hydroxy-C1-Ca-alkyl-, aminocarbonyl-C:i-Ca-alkyl-, M-C1-C"-alkylaminocarbonyl-C :1-C4-alkyl-, M,M-di-C1-Ca4- alkylaminocarbonyl-Ci-C4a-alkyl-, (z-methoxy group, C3-C7-cycloalkyl-Ci-Ca-alkyl-, /C3-O7-

cycloalkyl-, aryl-C1-C4-alkyl-, C1-C4-alkoxy-C1-Ca-alkyl-, C1-C8-alkenyl-, halogen-C1-Ca-alkyl-, halogen-C1-C4-alkenyl-, C1-C.-alkylcarbonyl-, C-C4-alkylcarbonylamino-C1-Cα-alkyl-, aryl-C1-C4- alkyl-, heterocyclyl- and aryl-, where C3-C7-cycloalkyl is specified (including C3-C7- cycloalkyl substituent in C3-C7-cycloalkyl-C1-Ca-alkyl-), optionally substituted with a hydroxy group or methyl and where aryl (including that found in aryl-C:i-Ca-alkyl-) and heterocyclyl (including such as that contained in heterocyclyl-Ci-C-alkyl- and heterocyclylcarbonyl-C1-C4-alkyl-) optionally contains 1 or 2 C1-C4-alkyl substituents.

In another embodiment, at least one K" is independently selected from the group consisting of: H- and Ci-Cv-alkyl-.

In another embodiment, KU is selected from the group consisting of: H-, B'O- and (K")2M-, where EC" is independently selected from the group consisting of: IN-, Ci-C4-alkyl-, heterocyclyl- C1-Ca4-alkyl-, amino-C1-Ca-alkyl-, l heterocyclylcarbonyl-C1-Ca-alkyl-, /M,M-di-C1-C«-alkylamino-C1-C4-alkyl-, hydroxy-C1 -Cα-alkyl-, M-C1-C4-alkylaminocarbonyl-C:1-C4-alkyl-, M,M-di-C1-C4-alkylaminocarbonyl-C1-C4-alkyl- and dz-methoxy group, where the heterocyclyl in heterocyclyl-C1-C4-alkyl- and heterocyclylcarbonyl-C1-C4-alkyl-, optionally containing 1 or 2 C1-C4-alkyl substituents.

In another embodiment, KE" is independently selected from the group consisting of: E'O-, and (B)2M-, where CK" is independently selected from the group consisting of: C1-C8-alkyl-, C3-C7-cycloalkyl- Ci-Ca4-alkyl-, heterocyclyl-Ci-C4-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-C1-Ca-alkyl-, hydroxy-Ci-C4-alkyl-,

M,M-di-С1-Са-alkylamino-С1-С4-alkyl-, amino-С1-Са-alkyl-, aryl-С1-Са-alkyl-, С1-С«-аlkoxy-С1-С4-alkyl- , C-C-alkenyl-, halogen-C1-Ca-alkyl-, C-C--alkylcarbonyl-, C1-C--alkylcarbonylamino-C1-

Ca-alkyl-, aryl-C1-C4-alkyl-, where the specified C3-C7-cycloalkyl or C3-C7-cycloalkyl substituent in C3-C7-cycloalkyl-C1-C4-alkyl is optionally substituted by a hydroxy group.

It is better if it does not denote IO-.

It is better if K" denotes IO-.

In another embodiment, EC" denotes C:-Cv-alkyl-.

In another embodiment, K' is independently selected from the group consisting of: halogen, nitro-,

C-C-alkyl, C-C-alkoxy-, amino group, /M-C1-C.a-alkylamino-, /M,M-di-C1-C--alkylamino-, aminocarbonylamino-, M-C1-C "-alkylaminocarbonylamino-, M,M-di-C1-C"-alkylaminocarbonylamino-, aminocarbonyl-, M-C1-Ca-alkylaminocarbonyl-, M,M-di-C1-Ca-alkylaminocarbonyl-, C1-C4

Co) alkylcarbonylamino-, hydroxy-С1-Са-alkyl-, amino-Си-С4-alkyl-, С1-С4-alkylcarbonylamino-С1-Са4- alkyl- and M-С1-С4-alkylamino-С1-С4-alkyl- .

In another embodiment, K: is selected from the group consisting of: (A) phenyl, 2-pyridyl, or 3-pyridyl substituted in the para-position by the group (KZ)2M-U-, where U is absent (bond), or (83)2M-U- selected from 3 Z in Ge) tire

With ' M V ' same sha t y vy va ky

It optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C1-C4-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C1-C4- alkoxy-, hydroxy-C1-Ca-alkyl-; (B) phenyl, 2-pyridyl or 3-pyridyl containing in the para-position a substituent selected from the group consisting of cyano-, halo-, nitro-, C1-Ca-alkyl-, halo-C1-C4-alkyl -, hydroxy-C1-Cα-alkyl-, hydroxycarbonyl-, C1-C-alkylcarbonyl-, C1-C--alkylcarbonyl-, C-and-C--alkyl-, (attached through a C atom)-heterocyclyl-, where (attached through C)-heterocyclyl is unsubstituted or contains 1-4 substituents selected from the group consisting of: C1-C4 alkyl, halogen-C1-C4 alkyl, halogen, hydroxy, C1-C4 alkoxy, amino , a nitro group or a cyano group; and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C1-C6-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C1-C--alkyl- , (attached through a C atom or an M atom) heterocyclyl-C1-C4-alkyl-, hydroxy-C1-Ca-alkyl-; or (C) phenyl substituted in the ortho-position by the group KZO- and which contains in the para- or meta-position a substituent selected from the group consisting of methyl, chlorine, C1-C6-alkylcarbonyl- or C1-C4- alkoxycarbonyl- .

In another version of EC? selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl, substituted in the para-position by the group (23)2M-U-, where U is absent (bonded), or

(83)2M-U- chosen from 3 Z v" Ge! and lush

E And oh in! and optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, C1-C4-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C1-C4-alkyl-, hydroxy-C1-Ca-alkyl-.

In another embodiment, B: is selected from the group consisting of: (A) phenyl, 2-pyridyl, or 3-pyridyl substituted in the para-position by the group (NH)2M-U-, wherein M is absent (bond), and which optionally contain 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C1-

Ca-alkyl-, halogen-C1-Ca-alkyl-, hydroxy-, C-C-alkyl-, hydroxy-C1-C4-alkyl-.

In another embodiment, B: is selected from the group consisting of: (A) phenyl, 2-pyridyl, or 3-pyridyl substituted in the para-position by the group (NH)2M-U-, wherein M is absent (bond), and where phenyl, 2-pyridyl or 3-pyridyl do not contain additional substituents.

In another embodiment, each WU is independently selected from the group consisting of: C1-C4-alkyl-, C3-SU-cycloalkyl-C1-C4-alkyl-, heterocyclyl-C1-Ca-alkyl-, aryl-C1-Ca-alkyl -, (85)2M-C3-C7-cycloalkyl-, / (H85)2M-C3-C7-cycloalkyl-Ci-Ca-alkyl-, / (85)2M-CO-C3-C7-cycloalkyl-C1-Ca -alkyl-, aryl-, heterocyclyl-, C3-C7-cycloalkyl-, where aryl, heterocyclyl and C3-C-cycloalkyl. are unsubstituted or contain 1-4 substituents selected from the group consisting of: halogen-, C1-C6-alkyl-, halogen-C1-C6-alkyl-, C1-C6-alkylcarbonyl-, C3-C7-cycloalkylcarbonyl -, C1-C.-alkylsulfonyl-, aminosulfonyl-, M-C1-C4-alkylaminosulfonyl-, M,M-di-C1-C4-alkylaminosulfonyl-, aminocarbonyl-, M-C1-C4-alkylaminocarbonyl-, M,M -di-C1-C"-alkylaminocarbonyl- and oxo-.

In another embodiment, B: is selected from the group consisting of: (A) phenyl, 2-pyridyl, or 3-pyridyl substituted in the para-position by the group (NH)2M-U-, where M is absent (bond), where one VZ denotes C-C4-alkyl-. preferably methyl, and the other BZ is selected from the group that includes: C3-C7-cycloalkyl-C1-C4-alkyl-, heterocyclyl-C1-C4-alkyl-, aryl-C1-C4-alkyl-, (H»)2M- C3-C7-cycloalkyl-

C1-C4-alkyl-, (85)24-CO-C3-C7-cycloalkyl-C1-C4-alkyl-, where aryl, heterocyclyl and C3-C7-cycloalkyl are unsubstituted or contain 1-4 substituents independently selected from the group , which includes: halogen-,

C-C4-alkyl-, halogen-Ci-C4-alkyl-, C-C--alkylcarbonyl-, C3-C7-cycloalkylcarbonyl-, C1-C4- alkylsulfonyl-, aminosulfonyl-, M-C1-C4-alkylaminosulfonyl-, M, M-di-C1-C4-

Co) alkylaminosulfonyl-, aminocarbonyl-, M-C1-Ca-alkylaminocarbonyl-, M,M-di-C1-Ca4- alkylaminocarbonyl- and oxo-.

In another embodiment, B: is selected from the group consisting of: (A) phenyl, 2-pyridyl, or 3-pyridyl, substituted in the para-position by the group (BZ)2M-U-, where U is absent (bond), and one BZ represents Ci-C--alkyl-, preferably methyl and the other BZ is selected from the group that includes: (HB»)2M-C3-0C-cycloalkyl-Ci-Ca-alkyl- and (A»)»M- CO-C3-C7-cycloalkyl-Ci-C4-alkyl-, and two HB"? together with the M atom to which they are attached, form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring, which optionally contains 1, 2, 3 or 4 additional M heteroatoms and/or that optionally contains an O atom and/or an 5 atom, the specified heterocyclic ring is unsubstituted or contains 1, 2 or C substituents independently selected from the group that includes: C1-C4-alkyl-oxo-, C1-C4-alkylcarbonyl, C1-

C-alkylsulfonyl and hydroxy-C1-C4-alkyl.

In the preferred embodiment of K2? selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position by the group (B2)2M-U-, where U is absent (bond), and where one

BZ denotes C1-C1-alkyl-, preferably methyl, and the other EZ denotes (B5)2M-cyclohexyl-C1-C1-alkyl- and where are the two E? together with the M atom to which they are attached form a b-membered heterocyclic ring which optionally contains 1 additional M heteroatom and/or which optionally contains an O atom and/or an 5 atom, said heterocyclic ring being unsubstituted or containing 1 or 2 substituents independently selected from the group that includes: C1-C4-alkyl-, preferably methyl, oxo-, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl and hydroxy-C1-C4-alkyl.

In a more preferred embodiment, K2 is selected from the group consisting of: phenyl or 3-pyridyl, substituted in the para-position by the group (KZ)2M-U-, where M is absent (bond), and where one KZ represents C1-C4 -alkyl-, preferably methyl, and the other EE denotes (K7)2-M-cyclohexylmethyl-, and where are the two EE? together with the M atom to which they are attached, form a b-membered heterocyclic ring containing 1 additional M heteroatom, the specified heterocyclic ring is substituted on the carbon atom by an oxo group and optionally substituted on the M atom by methyl. It is better if the specified heterocyclic ring is piperazinyl. It is better if the cyclohexyl ring is substituted in positions 1 and 4. It is better if such a substituent is in the trans position.

In another embodiment, each K? independently selected from the group which includes: H-C1-C4-alkyl-, hydroxy-C1-Cα-alkyl-, C-C.-alkylcarbonyl-, C-C-Alkoxycarbonyl-C-Cα-alkyl-, aminocarbonyl-C :i-Ca-alkyl-, M-C1-C4-alkylaminocarbonyl-C:1-C4-alkyl-, M,M-di-C1-Ca4- alkylaminocarbonyl-Ci-C4-alkyl-, C1-C4-alkylsulfonyl -, aminosulfonyl-, M-C1-Са4- alkylaminosulfonyl-, M, M-di-C1-С4-alkylaminosulfonyl-, heterocyclylcarbonyl-, aminocarbonyl-, M-С1-C.-alkylaminocarbonyl-, M, M-di-Si -C.-alkylaminocarbonyl-, C3-C;- cycloalkylcarbonyl-, C1-C-- alkoxycarbonylamino-C1-C4-alkyl-, C1-C4-aluoxycarbonyl-M-C1-C4- alkylamino-C1-Ca-alkyl-, C-C-Alkoxycarbonyl-, C3-C7-cycloalkyl-, hydroxy-C3-C7-cycloalkyl-, or two ECs? together with the M atom to which they are attached, can form a 3-, 4-, 5-, b6- or 7-membered heterocyclic ring, which optionally contains 1, 2, 3 or 4 additional M heteroatoms and/or which necessarily contains an O atom and/or an 5 atom, the specified heterocyclic ring is unsubstituted or contains 1, 2 or C substituents independently selected from the group that includes: C1-C4-alkyl-, oxo-, C1-C4-alkylcarbonyl, Si -C--alkylsulfonyl, hydroxy-C1-Ca-alkyl;

In another embodiment of the present invention described in this application, if two substituents EZ are present and they do not combine to form a ring, then at least one substituent C is selected from the group consisting of: hydrogen, C1-C6-alkyl, C1-C --Alkoxycarbonyl and C1-C4- alkylcarbonyl. It is better if at least one substituent BZ is selected from the group that includes: H, methyl and ethyl, preferably methyl. In another embodiment, at least one EZ denotes

C1-C6-alkyl-, preferably C1-C6-alkyl-, preferably methyl.

In another embodiment, if KZ includes a cyclohexylalkyl group that additionally contains one substituent at the cyclohexyl ring atom, the cyclohexyl substituent is preferably located in positions 1 and 4. Such a substitution scheme is exemplarily illustrated below and is not limited to the given specific example: the substituent in "

AND

In another embodiment, such a substituent is in the trans position. An example of this

The stereochemical configuration is given below and is not limited to the given specific example: 5 с ра

In another embodiment, the compound of formula I has the following stereochemical configuration:

y y V ov village

H

In another embodiment, KU is selected from the group that includes: H, hydroxy group, methoxy group, ethoxy group, propoxy group (isopropoxy group or n-propoxy group), butoxy group (preferably isobutoxy group), morpholine-4-ylethoxy group, aminoethoxy group, 4-methylpiperazin-1-ylcarbonylmethoxy group , dimethylaminoethoxy group, dimethylaminopropoxy group, hydroxyethoxy group, hydroxypropoxy group, dilmethylaminocarbonylmethoxy group, methylaminocarbonylmethoxy group and dz-methoxy group. It is better if Ke denotes a methoxy group.

In another embodiment, B" is selected from the group that includes: methoxy group, ethoxy group, butoxy group (including isobutoxy group, sec-butoxy group, (K)-sec-butoxy group, (5)-sec-butoxy group), propoxy group (including isopropoxy group, n- propoxy), cyclopropylmethoxy group, cyclopentyloxy group, morpholinyl-4-ylpropoxy group, 3-hydroxypropoxy group, 3-dimethylaminopropoxy group, 1-ethylpropoxy group, 3-aminopropoxy group, cyclobutoxy group, 1-methylbutoxy group, 1,2-dimethylpropoxy group, 3-amino-1-methylpropoxy group, cyclohexyloxy group , benzyloxy group, cyclohexylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, 2-methoxy-1-methylethoxy group (including, in particular, (K) 2-methoxy-1-methylethoxy), 1,3-dimethyl-but-3-enyloxy group, 1-methyl-but -3-enyloxy group, pyridin-4-ylmethoxy group, trifluoromethoxy group, methoxyethoxy group, tetrahydrofuran-2-ylmethoxy group, (5) tetrahydrofuran-2-ylmethoxy group, (K)-2-methoxypropoxy group, 2-methoxy-1-methylethoxy group, 1- hydroxy лопропілметоксигрупу, З-метоксипропоксигрупу, оксетан-2-ілметоксигрупу, 2,2- дифторетоксигрупу, ізопропіламіногрупу, етилкарбоніламіногрупу, ізопропілпропіламіногрупу, (диметиламіноетил)-ізопропіламіногрупу, (метилкарбоніламіноетил)-ізопропіламіногрупу, ізобутиламіногрупу, циклопентилметиламіногрупу, 1-етилпропіламіногрупу, циклогексиламіногрупу, бутиламіногрупу (включаючи втор -butylamino group), cyclobutylamino group, cyclopentylamino group, propylamino group, ethylamino group, benzylamino group, cyclopropylmethylamino group, cyclohexylmethylamino group, methyl carbonylamino group, isopropylcarbonylamino group, (methylcarbonyl)isopropylamino group, (ethylcarbonyl)isopropylamino group, (isopropyl)ethylamino (isopropylamino group).

It is better if K" denotes an isopropoxy group.

In a preferred embodiment, n is 0.

In another embodiment, B is selected from the group consisting of: hydrogen, fluorine, chlorine, methyl, methoxy, bromine, nitro, amino, aminocarbonylamino, methylaminocarbonylamino, methylaminocarbonyl, methylcarbonylamino, ethylaminocarbonylamino, ethylcarbonylamino, (ethyl)methylamino -, dimethylamino-, aminocarbonyl-, hydroxymethyl-, aminomethyl, methylcarbonylaminomethyl-, methylaminomethyl.

In the preferred embodiment of K? selected from the group that includes: (A) and phenyl containing the following substituents: 4-dimethylamino-, 4-methylamino-, 4-morpholin-4-yl-, 4-pyrrolidin-1-yl-, 4-dimethylamino- 2-methoxy group, 2-methoxy-4-methyl, 2-methoxy-4-morpholin-4-yl-, 4-dimethylamino-2-methoxy-, 4-dimethylamino-2-methyl-, 4-(M-methyl- M-pyridin-4-ylmethylamino)-, 4-(2-oxopyrrolidin-1-yl)-, 4-pyrazol-1-yl-, 4-methylcarbonylamino-, 4-(2-oxoazetidin-1-yl)-, 4-(M-methyl-M-ethylamino)carbonyl-, 4-(piperidine-1-carbonyl)-, 4-methylaminocarbonyl, 4-diethylaminocarbonyl-, 4-dimethylaminocarbonyl, 4-(pyrrolidine-1-carbonyl)-, 4 -aminocarbonyl-, 4-(M-methyl-M-pyridin-4-ylaminocarbonyl)-, 4-(M-pyridin-4-ylaminocarbonyl)-, 4-(M-pyridin-3-ylaminocarbonyl)-, 4-hydroxymethyl , 4-M-methylcarbonyl-M-methylamino-, 4-(M-methylcarbonyl-M-cyclopentylmethylamino)-, 4-(M-methyl-M-piperidin-3-ylmethylamino)-, 4-D(Imethyl-(1 - methylpiperidin-3-ylmethyl)amino|-, 4-(M-methyl-M-piperidin-4-ylmethylamino)-, 4-(1- acetylpiperidin-4-ylmethyl)-methylamino)|-, 4-(1- methanesulfonyl pepper idin-4-ylmethyl)-methylamino!-, 4-(4-aminocyclohexyl-methyl)-methylaminol-, 4-(4-ethylaminocyclohexylmethyl)-methylamino!|-, 4-ЦЧ4-«(ethylmethylamino)-cyclohexylmethyl|-methylamino )-,4-diethylamino group, 4-(M-

cyclopentylmethyl-M-methylamino)-, 4-(M-isopropyl-M-methylamino)-, 4-(M-cyclopentyl-M-methylamino)-, 4-(M-cyclohexyl-M-methylamino)-, 4-( M-second-butyl-M-methylamino)-, 4-(M-cyclopropylmethyl-M-methylamino)-, 4-(M-cyclohexylmethyl-M-methylamino)-, 4-(M-isobutyl-M-methylamino)- , 4-(M-benzyl-M-methylamino)-, 4-(M-ethyl-M-methylamino)-, 4-ethylamino-, 4- dipropylamino-, 4-(M-cyclobutyl-M-methylamino)-, 4-(2-fluorobenzyl)-methylamino|-, /4-(2,3-difluorobenzyl)-methylamino|-, 4-Imethyl-(3-trifluoromethylbenzyl)amino|-, 4-(«imethyl-(4- trifluoromethylbenzyl) )amino|-, 4A-((3-fluorobenzyl)-methylamino|-, 4-(M-methyl-M-pyridin-3-ylmethylamino)-, 4-(4-fluorobenzyl)-methylamino|-, 4-( 3,4-difluorobenzyl)-methylamino|-, ((4-

Pyridin-4-ylmethyl)amino!|-, 4-(M-cyclopropylmethyl-M-pyridin-4-ylmethylamino)-, 4-(M-ethyl-M-pyridin-4-ylmethylamino)-, 4-K2-morpholine -4-ylethyl)-pyridin-4-ylmethylamino!|-, 4-(M-methyl-M-pyrimidin-4-ylmethylamino)-, 4-|((3-fluoropyridin-4-ylmethyl)-methylamino)|- , 4-(M-methyl-M-thiophen-3-ylmethylamino)-, 4-Imethyl-(3-methyl-3-H-imidazol-4-ylmethyl)-amino|-, 4-(M-furan-3-ylmethyl) -M-methylamino)-, 4-(Imethyl-(2-morpholin-4-ylethyl)amino|-, 4-(Imethyl-(1-methylpiperidin-4-ylmethyl)amino|-, 4-(Imethyl-(4 -propylaminocyclohexyl-methyl)amino|-, А-((4- dimethylaminocyclohexylmethyl)-methylamino!|-, 4-(4-aminocyclohexylmethyl)-methylamino!|-, 4-

K4-dimethylaminocyclohexylmethyl)-ethylamino|-, 4-(methyl-(4-pyrrolidin-1-ylcyclohexylmethyl)amino|-, 4-(methyl-(4-piperidin-1-ylcyclohexylmethyl)-amino|-, Id- (methylpiperidine -4-ylmethylamino)-, 4-methyl-I(4-(3-methyl-4-oxoimidazolidin-1-yl)-cyclohexylmethyl)-amino)-, 4-(33-amino-1H-pyrazol-4- yl)-, 4-(3-Amino-5-methyl-1H-pyrazol-4-yl)-, 4-(3,5-dimethyl-1H-pyrazol-4-yl)-, 4-(1 -pyrrolidin-1-ylethyl)-, 4-(1-morpholin-4-ylethyl)-, 4-(1-hydroxyethyl)-, 4-P1-(piperidin-4-ylamino)-ethyl-, 4-P1- (M-piperidin-4-yl-M-methylcarbonylamino)-ethyl-, 4-1-(M-methyl-M-piperidin-4-ylamino)-ethyl-, 4-1-K4-dimethylamino-cyclohexyl)- methylamino |-ethyl)-, 4-(1-(4-aminocyclohexylamino)-ethyl-, 4-(/1-(4-dimethylaminopiperidin-1-yl)-ethyl-, 4-11-(4-(isopropylmethylamino)- piperidin-1-yl|-ethyl)-, 4-(1-dimethylaminoethyl)-, 4-(1-(4- hydroxypiperidin-1-yl)-ethyl|-, 4-1-(2-dimethylaminoethylamino)ethyl| -, A-1-((H)-3- hydroxypyrrolidin-1-yl)-ethyl|-, 4-11-((5)-3-hydroxypyrrolidin-1-yl)-ethyl/-, 4-11- ((5)-3- hydroxypiperidine-1- yl)ethyl|-, 4-(1-(A)-3-hydroxypiperidin-1-yl)-ethyl|-, 4-(1-thiomorpholin-4-ylethyl)-, /4-(1-M-isobutyl -M-methylcarbonylaminoethyl)-, 4-(1-n-propyl--methylcarbonylamino-ethyl)-, 4-(1-M-isopropyl-M-methylcarbonyl-aminoethyl)-, 4-(1-M-cyclopropyl-M -

Zo methylcarbonylaminoethyl)-, 4-(1-M-cyclohexylmethyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclopentyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclohexyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclopropylmethyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclopentylmethyl-M-methylcarbonylaminoethyl)-, 4-(1-M-benzyl-M-methylcarbonylaminoethyl)-, 4-(1- M-cyclobutyl-M-methylcarbonylaminoethyl)-, 4-(1-M-pyrrolidine-3-carbonyl-M-ethylaminoethyl)-, 4-(1-M-cyb-4-aminocyclohexanecarbonyl-M-ethylaminoethyl)-, 4- (1-M-trans-4-aminocyclohexanecarbonyl-M-ethylaminoethyl)-, 4-(1-M-4-dimethylaminocyclohexanecarbonyl-M-ethylaminoethyl)-, 4-(1-M-4-dimethylamino-cyclopentanecarbonyl-M-ethylaminoethyl) )-, 4-(1-M-1-methylpyrrolidin-3-ylcarbonyl-M-ethylaminoethyl)-, 4-(1-M-4-dimethylaminocyclohexanecarbonyl-M-ethylaminoethyl)-, 4-p- (piperidine-3- ylamino)-ethyl-, 4-(1-M-(2-aminoethyl)-M-methylcarbonylaminoethyl)-, 4-(1-M-(2-dimethylaminoethyl)-M-methylcarbonyl-aminoethyl)-, 4-(1 -M-(3-aminopropyl)-M-methylcarbonylaminoethyl)-, 4-(1-M-(3-dimethylaminopropyl)- M-methylcarbonylaminoethyl)-, 4-H11-(M-ethyl-M-piperidin-4-ylamino)-ethyl-, A-1-(3-aminopiperidin-1-yl)-ethyl-, A--(b8) -3-aminopyrrolidin-1-yl)-ethyl|-, 4-(11-(5)-3-aminopyrrolidin-1-yl)-ethyl-, A-11-(3- dimethylaminopyrrolidin-1-yl)-ethyl -, P1-(4-diethylaminopiperidin-1-yl)-ethyl/-, 4-(1-(3-oxomorpholin-4-yl)-ethyl1|-,. 4-(4-dimethylaminocyclohexylmethyl)-methylamino!-, 4-(M-methyl-M-ethylaminocarbonyl)-, 4-(M-cyclopropylmethyl-M-methylamino)-, 4-(2-oxoazetidin-1-yl)- , 4-(1-M-methylcarbonyl-M-ethylaminoethyl)-, 4-(morpholin-4-ylcyclohexylmethyl)amino!|-, 4-(morpholin-4-ylcyclohexyl-methyl)-methylamino!|-,4-( 4-dimethylaminocyclohexylmethyl)-methylamino|-3-methyl, 4-(4-dimethylaminocyclohexylmethyl)-methylamino|-3-fluoro-, A-((4- dimethylaminocyclohexylmethyl)-methylamino|-2-methoxy-, 4-(1- (4-Acetylpiperazin-1-yl)-ethyl-, 4-(1-(4-dimethylaminopiperidin-1-yl)-ethyl-, 4-(-4-dimethylaminocyclohexylmethyl)-methyl-amino!|-, 4-( -4-dimethylamino-cyclohexylmethyl)-ethylamino!|-, 4-(2-(4-dimethylaminopiperidin-1-yl)y-1-methylethyl-, 4-(2-(4-dimethylaminopiperidin-1-yl)-1 -methyl-2-oxoethyl|-, 4-imidazol-1-ylmethyl-, 4-(M-trifluoromethylcarbonyl-M-methylamino)-, 4-(1-(2-oxopiperazin-1-yl)-ethyl|-, 4-(2-hydroxyethyl)-2-oxopiperazin-1-yl|-ethyl)-,4-P1-(methylcarbonylamino)-ethyl-, 4-p-(methoxymethylcarbonylamino)-ethyl-, 4-P-(dimethylamino) ethylcarbonyl-amino)ethyl-, 4-(2-oxopyrrolidin-1-yl)-, 4-(2-oxoimidazolidin-1-yl)- or 4-(3Z-amino-5-ethyl-1H-pyrazol-4 -il)-, or

B2 is selected from the group consisting of: phenyl substituted with 2-fluoro or 3-fluoro and substituted in the para-position (relative to isoquinolinone or quinazolinone): (510)

in and or VK? selected from the group consisting of: phenyl substituted in the ortho-position (relative to isoquinolinone or quinazolinone) by a methoxy group and substituted in the para-position (relative to isoquinolinone or quinazolinone): i) i) (c) H

Ho

NM (in NM t Z : m and M ; | ; or | ; or 2 denotes phenyl substituted in the para-position (relative to isoquinolinone or quinazolinone):

H what no F g 7 E E y o t t

H (in) | " but She o same Si same tu z same ho-A xx M x

M o -Aano M o M c)

H o I c, H (c) H c,

oyu KhM W (F) (6)

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Mt m M Y t y

PI o oo

Ge) KU

MN «Zh r r MN SK MN

I W m W m w m w o o 0,,0 st - W, ultrasound

M m M mo o , , , , va re o , M zh

M M M in in | Ho man o va AH 5

You yo oo wa i nn ana vyv your still ono -e

N N sg ra oi g

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N

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M. U. N

(at)

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But oh,,0 "87 o

In the Academy of Sciences

NI (F) rai m and NM r zh | f r f f f

N

(F) M (F) M N

T Z T Z o o. o he o M.

M M o " o " ay y ay on N (c) Her.

M O0---o0 M oho, ех ОЗ ra Ф я 0

M M

7 ay m ), " , , 1 Y (c) MN i k

MN in t; mo m m m m h about this

M M

D and in! in!

WE WE about NM. I I shcha o ai I 7 I -i o o yuyu ! What is ON S S

S T i i i

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N on ba: on and o M- o shcha om | and Y ), "m o m no no

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(0) (0) oyu Zh 1 / titi 77 77 (6)

See " they and they " t Y Y

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Nm r y

M - M

M o sht

MN or , mostly

N N liceEvnonio

M M M

A. ra Z E z z z z

M | Sha 1 1 ; or (A) her or K2 denotes 2-pyridyl (relative to isoquinolinone or quinazolinone), substituted by 5-((4-dimethylaminocyclohexylmethyl)-methylamino!|-, 5-(4-aminocyclohexylmethyl)amino|-, and) o and | N M /

NM T and T scha

MN M m m M t o o o M

I don't care

F NM. and this one

K Uh F F F F f f sh s.

H in (in) M what i and a x ' o M. 250 o x

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M. ro u

OM about M and T fe 303 and p

M M M

; or (A)chii or Kg denotes 3-pyridyl (relative to isoquinolinone or quinazolinone), substituted 6-((4-dimethylaminocyclohexylmethyl)-methylamino|- or 6-(3-hydroxycyclobutylmethyl)-methyl-amino|-,

or K2 denotes 3-pyridyl (relative to isoquinolinone or quinazolinone), substituted in the 6b position 6-(methyl-I4-(2-oxopyrrolidin-1-yl)y-cyclohexylmethyl|-amino)-, b-Imethyl-|4 -(2-oxoimidazolidin-1-yl)-cyclohexylmethyl)|-amino)-, n

MU KI in o DI

Om o M o M 07 M , , , , z v SHY sho M (v) M (v H (v) i" t Z oh n

S. Y. S

M M M

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M na o M M o know o o MN U (c) - (c) t v v

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NM DE.

HM -

HER

M. 250 in the office of KD and T M. ro neon I

M M M

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M. ro u

OM o and T M. ro 03 su

M M M

; or or 2 denotes 3-pyridyl (relative to isoquinolinone or quinazolinone), substituted by 2 fluoro-6-in; "and (B)i or B" denotes phenyl, which contains the following substituents: 4-methoxy group, 4-cyano group, 3,4-dimethyl, 2,4-dimethyl, 4-methoxy-2-methyl-, 2-chloro- 4-methyl-, 2,4-dimethoxy-, 3,4-dichloro-, 4-methyl-, 3,4-dimethoxy group, 2-methoxy-4-methyl-, 4-(1 H-pyrazol-4-yl )-, 4-(3,5-dimethyl-1H-pyrazol-4-yl)-,

times az

NM NM

M o lsh- Ho 0-

M M

MN MN

2 or 2, (B) or K? denotes 2-pyridyl (relative to isoquinolinone or quinazolinone) substituted by 4-methyl, (Vii or K2 denotes 3-pyridyl (relative to isoquinolinone or quinazolinone) substituted by 4-methyl, (C) or K? denotes phenyl containing the following substituents: 4-methyl-2-(3-morpholin-4-ylpropoxy)-, 4-methyl-2-hydroxycarbonylmethoxy-, 2-methoxy-5-methyl-, 4-methyl-2-(2H-tetrazole-

β-ylmethoxy)-, 4-methyl-2-(thiazol-β-ylmethoxy)-, 4-methoxycarbonyl-2-tetrazol-5-ylmethoxy group, 4-methoxycarbonyl-2-methoxy group, 4-methoxycarbonyl-2-thiazole-5 -ylmethoxy)-, 4-methyl-2-(2-morpholin-4-ylethoxy), 2-(3-dimethylaminopropoxy)-4-methyl-, 4-methyl-2-(2-(4-methylpiperazine-1- yl-ethoxy|-, 4-methyl-2-13-(4-methylpiperazin-1-yl)-propoxy|-, 2-methoxycarbonylmethoxy-5-chloro-, 2-hydroxycarbonyl-methoxy-5-chloro-, 5- chloro-2-(2-dimethylaminoethoxy)-, 5-chloro-2-(3-morpholin-4-ylpropoxy)-, 5-chloro-2-(2-morpholin-4-ylethoxy)-, 5-chloro-2 -(3-dimethylaminopropoxy)-, 5-chloro-2-(3-hydroxypropoxy)- or 5-chloro-2-(2-hydroxyethoxy)-, (C) or KK: denotes (attached through a C atom)-heterocycle, selected from benzofuran-5-yl and 1-methyl-1H-indazol-5-yl, (E) or KK? denotes pyrazin-2-yl (relative to isoquinolinone or quinazolinone), substituted in the 5-position by a group: 6) х гие ) io) and iv) we Th S Th and still s shchey schey about NM. NM.

KO и и и ; ; ; | or (E) or K2 denotes pyridazin-3-yl (relative to isoquinolinone or quinazolinone), substituted in position 6 by a group: 6) x in I

M

M and or | ;

Zo

(C) or Kg denotes pyrimidin-2-yl (relative to isoquinolinone or quinazolinone), substituted in position 5 by a group:

M

(in); ra ZV DE

N M o or .

In another embodiment, the present invention relates to a compound of formula I or a salt thereof described herein, provided that if 7 represents CH", n is 0 or 1, such that if n is 1, then K' represents ortho-chlorine, and K- is selected from the group that includes: para-Ci-C3-alkylphenyl-, para-(halo-C1-C3-alkyl)uphenyl-, para-C1-C3-alkoxyphenyl-, para-halophenyl- , para-nitrophenyl-, para-(C1-C3-alkoxycarbonyl)phenyl-, para- (hydroxycarbonyl)phenyl-, where phenyl optionally contains 1-2 additional substituents independently selected from halogen and methyl, then EC: and " do not both denote an ethoxy group or a methoxy group.

As already noted above, ro53 means the human protein itself, described in the publication

Mayavpem5Ki ei a. in EMVO 3y. 3, 3257-62 (1984), or related representatives of the family (for example, p7Z3, described in the publication Kadnai ei ai. in Seiya! 90, 809-19 (1997) and rb3, described in the publication ap ei ai. in Moi Seiya! 2, 305-16 (1998)) (also referred to herein as wild-type ro3) or any variant thereof (eg, a splice variant, mutant, fragment, or isoform resulting from deletion, insertion, and/or exchange of one or more, for example, from 1 to 200 amino acids), which still preferably retains at least 1 95, more preferably at least 5 95, even more preferably at least 10 95, 20 95, 30 90, 40 90, 50 95 or more 5095 activity of p53 on growth inhibition, for example, according to the data of the growth inhibition study described in the publication Rieigeproi ei ai., Rgos. May Asai. All together. OA 91, 1998-2002 (1994), and the match of the amino acid sequence with the corresponding complete sequence of wild-type p5Z is at least 2095, more preferably at least 2595, for example, the match with its partial sequence is at least 9095. Unless otherwise specified, p53 usually means ТР53, ро53, ТР7З, р7З3, ТРбБЗ, ТР7ЗИ,, рб3 or their variants, respectively, defined above.

As noted above, MOM2 (especially when referred to as MOM2 or its variants) generally refers to all genes and/or proteins encoded by them that have the names MOM2,

Ko) Mat2, NOM2, Nateaa, or their variants. MOMA (especially when referred to as MOM2 or its variants) means all genes and/or proteins encoded by them, which have the names MOM4, Mata,

NOMA4, Nata4i, MOMH, Math, NOMU, Nath, or their variants.

MOM2 mostly means MOM2 described in EMVO publication .. 10, 1565-9, RaKNnaggaden yei a! 1991, its variants mean variants thereof that still bind to p53 as determined by the assay described below (eg, a splice variant, isoform, fragment, mutant, or oncogene resulting from a deletion, insertion, and/or exchange of one or more, e.g., from 1 to 430 amino acids) corresponding to full-length proteins as described in the first publication, having MOM2 affinities to ros that are preferably at least 0.5 95 , more preferably at least 5 95 , 10 95, 20 9,

C0 96, 40 95 or most preferably 5095 or more, and having an amino acid sequence match with the sequence of MOM2 or HOM of at least 20 95, more preferably at least 25 95, as described in the first publication or as specifically indicated below. Unless otherwise specified, MOM2 usually means MOM2, Mat2, NOM2, or Nateg, or their variants, respectively, as defined above.

MOMA preferably means the MOMA described in Sepotisv5 43, 34-42, 5Nmapv et al., 1997, its variants mean its variants that still bind to p5Z according to a study carried out by the technique described below (eg, splicing variant, isoform, fragment, mutant, or oncogene resulting from the deletion, insertion, and/or exchange of one or more, e.g., 1 to 430 amino acids) that correspond to full-length proteins as described in the first publication that have MOMA affinity for ro3, which preferably make up at least 0.5 95, more preferably at least 5 95, 10 95, 20 Ob,

ZO 96, 40 95 or most preferably 5095 or more, and having an amino acid sequence match with the sequence of МОМ4, МОМХ, НОМА4 or НОМ2, which is at least 20 95, more preferably not less than 2595, as described in the first publication or as specifically specified below. Unless otherwise specified, MOM4 usually means MOM4, Mata4, NOMA,

Natai, MOMH, Math, NOMH or Nath, or their variants respectively, are defined above.

The percent overlap between the amino acid sequences of a protein and its variants, also often referred to as homology, is preferably determined using software commonly used for this purpose, such as Sar software (M/i5sopvip

Zedieepse Apaiuvzi5 RasKade, Megwiop 8 Tog Opih, Ssepeiis5 Sotriieg Stor, Opimegzyu Vezeeasiai Cancer,

Madizop UmMi5sopvip, OA), in which the algorithm described in the publication Ztyy apa is used

Maiheptap (Adu. Arri. Mine. 2: 482-489 (1981)), preferably using a search for related deletions with a deletion opening penalty of 12 and a deletion continuation penalty of 1.

As used herein, "variants thereof" means one or more variants.

A proto-oncogene is a normal gene that can become an oncogene due to mutation or increased expression. Proto-oncogenes encode proteins that help regulate cell growth and differentiation. Proto-oncogenes often participate in signaling and produce mitogenic signals, usually through their protein products. After activation, the proto-oncogene (or its product) becomes a tumor-inducing agent, an oncogene.

Compounds of formula (I) can exist in various isomeric forms. As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention, and includes geometric isomers. It should be understood that the substituent can be attached to a carbon atom that is a chiral center. Therefore, the present invention includes enantiomers, diastereoisomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images. A mixture of two enantiomers

A 1:1 composition is called a "racemic" mixture. This term is used to refer to a racemic mixture when appropriate. "Diastereoisomers" are stereoisomers that contain at least two asymmetric atoms, but which are not mirror images of one another.

The absolute stereochemical configuration is described using the K-5 system of Kahn-Ingold-

Prelogue. If the compound is a pure enantiomer, then the stereochemical configuration of each

C5 of a chiral carbon atom can be described as MW or 5. Separated compounds, the absolute configuration of which is not established, can be described with the symbols (g) or (-), depending on the direction in which they rotate the plane of polarization of light at the wavelength of the O line sodium (right-handed and left-handed). Some of the compounds described in this invention contain one or more asymmetric centers and therefore can form enantiomers, diastereoisomers and other stereoisomeric forms, the absolute stereochemical configuration of which can be designated as (HB)- or (5)-. The scope of this invention includes all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of intermediate composition. Optically active (B)- and (5)-isomers can be obtained with the help of chiral synthons or chiral reagents or isolated by conventional methods. If the compound contains a double bond, then the substituents can be in the E or 7 configuration. If the compound is a disubstituted cycloalkyl, then the cycloalkyl substituents can be in the cis- or trans-configuration.

It is intended that the scope of this invention includes all tautomeric forms.

As used in the present invention, the term "pharmaceutically acceptable salts" means salts that retain the biological effectiveness and properties of the compounds proposed herein

BO inventions, and which are usually not undesirable biologically or otherwise. In many cases, the compounds of the present invention can form salts with an acid and/or a base due to the presence of an amino group and/or carboxy groups or similar groups.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and with organic acids, for example, acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrophosphate/dihydrophosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

Inorganic acids from which salts can be formed include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be formed include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid acid, ethanesulfonic acid, toluenesulfonic acid and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be formed include, for example, ammonium bases and metal bases of groups 1-12 of the Periodic Table of Elements. In some embodiments, salts are formed with lithium, sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be formed include, for example, primary, secondary, and tertiary amines, substituted amines including natural substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

Pharmaceutically acceptable salts proposed in this invention can be synthesized from the parent compound, basic or acidic fragment by conventional chemical methods.

Usually, such salts can be obtained by reacting the free acid forms of these compounds with a stoichiometric amount of the corresponding base (such as hydroxide, carbonate, bicarbonate, etc.

Ma, Ca, Mu or K) or by the reaction of the free basic forms of these compounds with a stoichiometric amount of the corresponding acid. Such reactions are usually carried out in water or in an organic solvent or in their mixture. Of course, if possible, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of additional suitable salts are given, for example, in the publications "Netipdiopye Riaptaseshisa! bsiepsev5", 201 ey. Mask

Rybriivpipu Sotrapu, Easiop, Ra., (1985); and "NaparbookK oi Riaptaseshisa! Zaiv: Rgorepiev, zeiIesip, apa Ove" Bu iani apa MMepgtiiy (U/eu-MSN, U/eipieit, Septapu, 2002).

For isolation or purification purposes, pharmaceutically unacceptable salts such as picrates or perchlorates may also be used. For therapeutic use, only pharmaceutically acceptable salts or free compounds are used.

Due to the close affinity of new compounds of formula (I) in free form to compounds in the form of their salts, including salts that can be used as intermediates, for example in the purification or identification of new compounds, any reference to compounds or a compound of formula (I) above and below in the present invention should also be understood as referring to the compound in free form and/or also one or more salts thereof, if appropriate and appropriate, as well as one or more solvates, e.g. hydrates.

Any formula given in this invention also characterizes unlabeled forms, as well as isotopically labeled forms of compounds. Isotopically labeled compounds have structures that are described by the formulas given in this invention, except that one or more atoms are replaced by atoms having the specified atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, ЗН, "С, 190, 140, 15М, 8р tr, 82p, 355, 3607, 125|, respectively. The scope of this invention includes various isotopically labeled compounds proposed in this invention, for example, which include radioactive isotopes such as ZN, 736, and "S. Such isotopically labeled compounds are applicable for studying metabolism (containing 770), reaction kinetics (containing, for example, 2H or 3H), in detection and imaging methodologies such as positron emission tomography (PET) or single-photon emission computed tomography ( SPECT), including studies of drug or substrate distribution in tissues or radiation therapy of patients. In particular, a compound that contains or is labeled with "ZE" may be particularly suitable for PET or SPECT studies. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by the methods disclosed in the Schemes or Examples and syntheses described below by replacing the isotope-free reagent with a readily available isotopically labeled reagent.

In addition, substitution with heavier isotopes such as deuterium (ie, 2H or 0) may provide some therapeutic advantages due to their higher metabolic stability, such as increased half-life of ip mimo or the possibility of using lower doses, or improved therapeutic index. It should be understood that in this context deuterium is considered as a substituent in the compound of formula (I). The concentration of such a heavier isotope, in particular, deuterium, can be determined using the isotopic enrichment factor. The term "isotope enrichment factor" when used in this invention means the ratio of the content of the isotope to the content of a particular isotope in nature. If the substituent in the compound proposed in this invention means deuterium, then such a compound is characterized by an isotopic enrichment factor for each labeled deuterium atom equal to at least 3500 (deuterium content for each labeled deuterium atom is equal to 52.5 90), not less than 4000 (content deuterium equal to 60 9o), not less than 4500 (deuterium content equal to 67.55), not less than 5000 (deuterium content equal to 7595), not less than 5500 (deuterium content equal to 82.5 95), not less than 6000 (deuterium content equal to 90 95 ), not less than 6333.3 (deuterium content equal to 95 95), not less than 6466.7 (deuterium content equal to 97 95), not less than 6600 (deuterium content equal to 99 95) or not less than 6633.3 (deuterium content equal to 99, 5 95).

Isotopically labeled compounds of formula (I) can usually be obtained by conventional methods known to those skilled in the art, or by methods analogous to those described in the appended examples and syntheses, using an isotopically labeled reagent instead of the previously used unlabeled reagent.

Pharmaceutically acceptable solvates in the context of this invention include those in which the crystallization solvent may be isotopically substituted, for example, O2O, av-acetone, av-

DMSO.

The compounds proposed in the present invention, i.e. compounds of formula (I), which contain groups capable of acting as hydrogen bond donors and/or acceptors, can form compatible crystals with suitable compatible crystal forming substances. These compatible crystals can be obtained from compounds of formula (I) according to known methods of co-crystallization. Such methods include grinding, heating, co-extraction, co-melting or interaction in solution of the compound of formula (I) with substances that form co-crystals, under conditions of crystallization with the release of co-crystals formed in this way crystals. Suitable substances forming compatible crystals include those described in LO 2004/078163. Therefore, the present invention also relates to compatible crystals comprising the compound of formula (1).

As used herein, the term "Pharmaceutically acceptable carrier" includes any and all solvents, dispersing media, coatings, surfactants,

Antioxidants, preservatives (eg, bactericidal agents, fungicidal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, inert fillers, leavening agents, lubricating agents, sweeteners, flavoring agents, dyes and similar materials and combinations thereof, as would be known to one of ordinary skill in the art (see, e.g., the publication Ketipdiopye Rpaptaseciisa! Zsiepsev, 181p E. Mask Rgipiipd Sotrapu, 1990, pp. 1289-1329) . Unless the usual carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is intended. "Combination" means a fixed combination in a single dosage form or a set of components for combined administration, in which the compound of formula (I) and the components of the combination can be independently administered simultaneously or separately at certain intervals, preferably such that these intervals allow the components of the combination make a compatible, for example, synergistic effect.

The term "therapeutically effective amount" of a compound of the present invention means an amount of a compound of the present invention that results in a biological or medical response in a subject, for example, a reduction or inhibition of an enzyme or protein activity, or an alleviation of symptoms, relief of pathological conditions, slowing down or delaying the progression of the disease or preventing the disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that, when administered to a subject, is effective (1) to at least partially attenuate, inhibit, prevent, and/or ameliorate a pathological condition or disorder or disease (i) mediated by dysregulation of the po3/mOMa2 ratio or (ii) associated with dysregulation of the po3/mOMa ratio, or (ii) characterized by dysregulation of the ratio

IOM2/p53; or (2) to reduce or inhibit the activity of the roZz/MOM2 interaction. In another non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that, when administered into a cell or tissue, or into a non-cellular biological material, or into the environment, is effective for at least partially reducing or inhibiting the interaction of roZ/MOM2.

As used in the present invention, the term "subject" means an animal. Of course, the animal is a 60 mammal. Subject also means, for example, primates (such as humans), cows, sheep, goats,

horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In other embodiments, the subject is a human.

As used herein, the term "inhibit", "inhibit" or "suppress" means weakening or suppressing a given pathological condition, symptom or disorder, or disease or significantly weakening the original biological activity or process.

As used herein, the term "treating," "treating" any disease or disorder refers, in one embodiment, to ameliorating the course of the disease or disorder (ie, slowing, stopping, or alleviating the progression of the disease or at least one of its clinical symptoms) .

In another embodiment, "treating" or "treating" means improving at least one physical parameter, including those that may not be felt by the patient. In yet another embodiment, "treating" or "treating" refers to altering the course of a disease or disorder, either physically (eg, stabilizing an ongoing symptom) or physiologically (eg, stabilizing a physical parameter), or both. In yet another embodiment, "treating" or "treating" means preventing or delaying the onset or development or progression of a disease or disorder.

As used in the present invention, a subject is "in need" of treatment if the treatment will have a beneficial biological or medical effect on such subject or improve his quality of life.

When used in the present invention (especially in the claims), terms used in the singular include the plural, and vice versa, unless otherwise indicated in the present invention and unless the context clearly contradicts it.

All techniques described in the present invention may be performed in any suitable order, unless otherwise specified in the present invention and unless clearly inconsistent with the context.

The use of any and all examples or indications of typical values (e.g., "such as") herein is intended merely to better describe the invention and is not intended to limit the scope of the invention as defined by the claims.

Any asymmetric atom (for example, carbon, etc.) of the compound(s) proposed in this invention can be in racemic or enantiomerically enriched form, for example, in (K)-, (5)- or (NK, 5)-configurations In some embodiments, each

A zo asymmetric atom is characterized by an enantiomeric excess in the (H)- or (5)-configuration that is at least 5095, an enantiomeric excess that is at least 60 95, an enantiomeric excess that is at least 7095, an enantiomeric excess that is at least 8095, with an enantiomeric excess of not less than 90 95, an enantiomeric excess of not less than 95 95, or an enantiomeric excess of not less than 99 95. The substituents on the atoms forming the multiple bond, if possible, may be in cis- (7)- or trans- (E)-form.

Therefore, when used in the present invention, the compound proposed in the present invention may be in the form of one of the possible isomers, rotatory isomers, atropoisomers, tautomers or mixtures thereof, for example, in the form of essentially pure geometric (cis- or trans-) isomers, diastereoisomers , optical isomers (antipodes), racemates or their mixtures.

Mixtures of isomers obtained in the context of the present invention can be separated into separate isomers by methods known to those skilled in the art; diastereoisomers can be separated, for example, by partitioning in a multiphase mixture of solvents, recrystallization and/or by means of chromatographic separation, for example on silica gel, or, for example, by medium pressure liquid chromatography on a reverse phase column; and racemates can be separated, for example, by forming salts with optically pure salt-forming reagents, and the resulting mixture of diastereoisomers separated, for example, by fractional crystallization or by chromatography on columns with optically active substances.

All obtained racemates of the final or intermediate products can be separated into optical antipodes by known methods, for example, by separating the salts of their diastereoisomers obtained with an optically active acid or base, followed by isolation of the optically active acid or base. In particular, the core fragment can be used in this way to resolve the compounds of the present invention into optical antipodes, for example by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyltartaric acid, diadetyltartaric acid, di-O , O'-p-toluenetartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated using chiral chromatography, such as high performance liquid chromatography (HPLC) using a 60 chiral sorbent.

The compounds proposed in this invention are obtained in free form, in the form of their salts or in the form of their prodrug derivatives.

If the same molecule contains both a basic group and an acidic group, then the compounds proposed in this invention can also form internal salts, for example, zwitterionic molecules.

The present invention also relates to prodrugs of the compounds of the present invention that are readily converted into the compounds of the present invention. Prodrugs are an active or inactive compound that, after administration to a subject, chemically changes as a result of physiological effects such as hydrolysis, metabolism, etc., with transformation into the compound proposed in this invention. Methods of preparation and use of prodrugs and their applicability are well known to specialists in this field of technology. By nature, prodrugs can be divided into two non-exclusive categories, prodrugs-biological precursors and prodrugs-carriers. See the publication of Te Rgasiise oi Medisipa! Snpetivtu, Sleep. 31-32 (Ed. M/eptshy, Asadetis Rgev55, Zap

Oyedo, Saiii., 2001). Usually, prodrugs-biological precursors are compounds that are inactive or have low activity compared to the active drug compound, and contain one or more protective groups, and are converted into the active form due to metabolism or solvolysis. Both the active form of the prodrug and any released metabolic product must have acceptably low toxicity.

Procarriers are drug compounds that contain a carrier moiety, for example, that improves absorption and/or localizes release at the site(s) of action. For such carrier prodrugs, it is preferred that the linkage between the drug moiety and the carrier moiety be covalent, the prodrugs be inactive or less active than the drug compound, and any released carrier moiety be reasonably non-toxic. In the case of prodrugs for which the carrier fragment is designed to enhance absorption, the release of the carrier fragment should usually be rapid. In other cases, it is preferable to use a fragment that provides slow release, for example, some polymers or other fragments, such as cyclodextrins. Prodrug carriers, for example, can be used to improve one or more of the following characteristics: increased lipophilicity, increased duration of pharmacological action,

From improving the specificity at the site of exposure, reducing toxicity and the number of adverse reactions and/or improving the characteristics of the medicinal product (for example, stability, solubility in water, suppression of undesirable organoleptic or physicochemical characteristics).

For example, lipophilicity can be increased by esterification of (a) hydroxy groups with lipophilic carboxylic acids (e.g., a carboxylic acid containing at least one lipophilic moiety) or (5) carboxyl groups with lipophilic alcohols (e.g., with an alcohol containing at least one lipophilic moiety, for example, aliphatic alcohols).

Typical prodrugs are, for example, esters of free carboxylic acids and 5-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, where acyl is as defined herein.

Suitable prodrugs are often pharmaceutically acceptable ester derivatives which, by solvolysis under physiological conditions, are converted to the parent carboxylic acid, for example, below. alkyl esters, cycloalkyl esters, lower. alkenyl esters, benzyl esters, mono- or disubstituted lower. alkyl esters, such as omega- (amino, mono- or di-lower. alkylamino-, carboxy-, lower. alkoxycarbonyl)-lower. alkyl esters, alpha-(lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl)- lower. alkyl esters, such as pivaloyloxymethyl ether, etc., which are commonly used in this field of technology. In addition, amines are masked by the formation of arylcarbonyloxymethyl derivatives, which are subsequently cleaved by esterases with the release of free drug and formaldehyde (Vypadaaga, U. May. Spec. 2503 (1989)). In addition, drugs that contain an acidic MH group, such as imidazole, imidone, indole, etc., are masked with the help of M-acyloxymethyl groups (Vypadaaga, YuOevidp oi Rgodgidv, E|Ibemieg (1985)). Hydroxy groups are masked by the formation of complex and simple esters. EP 039051 (Zioap apa I She) discloses prodrugs that are Mannich bases of hydroxamic acids, their preparation and use. For prodrugs, it is lower. alkyl means C1-C6-alkyl.

In addition, the compounds proposed in this invention, including their salts, can also be obtained in the form of their hydrates or with the inclusion of other solvents used for their crystallization.

The second object of this invention is pharmaceutical compositions that contain the compound proposed in this invention. Thus, the present invention relates to pharmaceutical compositions that include (that is, that contain or contain)

a compound of formula (I) defined in this invention and one or more pharmaceutically acceptable carriers/inert fillers; - pharmaceutical compositions that include the compound of formula (I) defined in the present invention in a therapeutically effective amount and one or more pharmaceutically acceptable carriers/inert fillers.

The present invention relates to a pharmaceutical composition that includes: a compound proposed in the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration, and rectal administration, and the like. In addition, the pharmaceutical compositions provided in the present invention can be prepared in solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including without limitation solutions, suspensions or emulsions).

The pharmaceutical compositions may be subjected to conventional pharmaceutical processing, such as sterilization, and/or may contain conventional inert diluents, lubricating agents or buffering agents, as well as excipients such as preservatives, stabilizers, wetting agents, emulsifiers and buffering agents, etc. p.

Typically, pharmaceutical compositions are tablets or capsules made of gelatin, including the active ingredient, as well as a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; p) lubricating agents, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also c) binders, for example, magnesium aluminosilicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium salt of carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary a) leavening agents, for example, starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, dyes, flavors and sweeteners.

Tablets can be coated using techniques known in the art

Zo coating or enteric coating.

Compositions suitable for oral administration include a compound of the present invention in an effective amount in the form of tablets, cakes, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups, or elixirs. Compositions intended for oral administration are prepared by any technique known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, coloring agents, and preservatives to to obtain pharmaceutical attractive and pleasant-tasting preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable inert excipients which are suitable for the manufacture of tablets. These inert fillers are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia gum; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets are uncoated or coated by known techniques to delay breakdown and absorption in the gastrointestinal tract, providing continuous exposure over a longer period of time. For example, a retarding agent such as glyceryl monostearate or glyceryl distearate can be used. Oral preparations may also be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or oil medium such as peanut oil, liquid paraffin or olive oil.

Some compositions for injections are isotonic aqueous solutions or suspensions, and suppositories are mainly prepared from emulsions or suspensions of fats. These compositions can be sterilized and/or have auxiliary substances added to them, such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffering agents. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared by conventional mixing, granulating 60 or coating techniques and they contain about 0.1-75 95 or contain about 1-50 95 of active ingredient.

Compositions suitable for transdermal administration include a compound of the present invention in an effective amount with a suitable carrier. Carriers suitable for transdermal administration include absorbable pharmacologically acceptable solvents that facilitate penetration through the recipient's skin. For example, transdermal delivery devices are a dressing that includes a protective layer, a reservoir containing the compound optionally with carriers, optionally a barrier that regulates the delivery of the compound through the recipient's skin at a predetermined rate over an extended period of time, and means of securing the device to the skin.

Compositions suitable for topical administration, such as to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels, or nebulized compositions, such as for aerosol delivery and the like. Such topical devices are particularly suitable for exposure to the skin, for example, for the treatment of skin cancer, for example, for use as prophylactic agents in sunscreens, lotions, aerosol preparations, and the like. Therefore, they are particularly suitable for use in topical agents, including cosmetics, well known in the art. They may contain solubilizers, stabilizers, tonicity-regulating agents, buffering agents, and preservatives.

When used in the present invention, local administration can also be inhalation or nasal administration. Usually, the introduction is carried out in the form of a dry powder (separately or in the form of a mixture, for example, a dry mixture with lactose, in the form of mixtures with components, for example, with phospholipids) using an inhaler for dry powders or in the form of an aerosol spray supplied from a container that is under pressure, by means of a pump, spray device, atomizer or nebulizer type device with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, as water may aid in the degradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous ingredients or ingredients with a low moisture content in

From conditions of low humidity. An anhydrous pharmaceutical composition can be prepared and stored in such a way that the anhydrous properties are maintained. Accordingly, anhydrous compositions are preferably packaged in materials that are known to prevent interaction with water, so that they can be included in suitable sets of preparations. Examples of suitable packaging means include, but are not limited to, hermetically sealed foils, plastics, single-dose containers (eg, vials), blister packs, and tape packs.

The present invention also relates to pharmaceutical compositions and dosage forms that include one or more agents that reduce the rate at which a compound of the present invention will be degraded as an active ingredient. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid buffering agents, pH adjusting agents, or salt buffering agents, and the like.

The third object of this invention is the use of the compounds proposed in this invention as medicinal products. Preferred compounds of formula (I) have the valuable pharmacological characteristics described above and below in the present invention. Thus, the present invention relates to: - the compound of formula (I), defined in the present invention as a pharmaceutical agent/intended for use as a pharmaceutical agent; - compounds of formula (I) defined in this invention as a medicinal product/intended for use as a medicinal product; - compounds of formula (I) defined in the present invention intended for the treatment/intended for use in a subject for the treatment of a disorder or disease mediated by the activity of MOM2 and/or MOMA; - use of the compound of formula (I) defined in the present invention for the preparation of a medicinal product intended for the treatment of a subject's disorder or disease mediated by MOM2 and/or MOMA activity; - the use of a compound of formula (I) defined in this invention for the treatment of a disorder or disease mediated by MOM2 and/or MOMA activity in a subject; - use of the compound of formula (I) defined in this invention to mediate the activity of MOM2 and/or MOMA; bo - the use of a compound of formula (I) defined in this invention for the treatment of a disorder or disease selected from the group that includes: a proliferative disorder or disease; - the use of a compound of formula (I) defined in this invention for the treatment of a disorder or disease selected from the group that includes: a disorder or disease in which the immune system participates; - the use of a compound of formula (I) defined in the present invention for the treatment of a proliferative disorder or disease selected from the group that includes: cancer or tumor diseases, such as benign or malignant tumors, sarcoma, such as liposarcoma, rhabdomyosarcoma or bone cancer, eg osteosarcoma, carcinoma such as carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina or thyroid, glioblastoma, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, head and neck tumor, melanoma, prostatic hyperplasia, neoplasia, epithelial neoplasia, leukemia or lymphoma, such as B-cell or T-cell, and metastases to other organs), viral infections (for example, herpes, papilloma, HIV (human immunodeficiency virus), Kaposi's sarcoma, viral hepatitis); - the use of a compound of formula (I) defined in the present invention for the treatment of a disorder or disease in which the immune system is involved, selected from the group that includes: autoimmune diseases or immune diseases resulting from transplantation (such as rheumatoid arthritis, " graft versus host", systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, polymyositis), chronic inflammatory conditions such as asthma, osteoarthritis, atherosclerosis, Crohn's disease, or inflammatory or allergic skin conditions such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus, epidermolysis bullosa acquired, or other inflammatory or allergic skin conditions, hyperproliferative disorders (eg, Li-Fraumeni syndrome ); - a method of modulating the activity of MOM2 and/or MOM4 in a subject that includes a stage

By administering to the subject the compound of formula (I) defined in this invention, in a therapeutically effective amount; - a method of treating a disorder or disease mediated by the activity of MOM2 and/or MOMA, which includes the step of administering to the subject the compound of formula (I) defined in this invention, in a therapeutically effective amount; - a method of modifying the activity of MOM2 and/or MOMA in a cell, which includes the interaction of the specified cell with the compound of formula (I) defined in the present invention, in an effective amount.

According to the invention, it was completely unexpectedly established that the compounds of formula (I) have favorable pharmacological characteristics and disrupt the binding interaction (which in this invention is also called the interaction p5Z/MOM2 and p53Z/MOM4 or only the interaction roz/MmOM2) between p53, with on the one hand, and MOM2 and/or MOMA4 or their variants (especially oncogenic ones), which are still able to bind to po53, on the other hand.

The effectiveness of the compounds of formula (I) and their salts as interaction modulators can be demonstrated as described in MUUO98/01467 (which, especially for research purposes, is incorporated herein by reference) or preferably as follows:

Time-Resolved Fluorescence Energy Transfer Study (TA-ENET)

Inhibition of p53-Nata2 and p53-Nata interactions is investigated by time-resolved fluorescence energy transfer (TK-EKET). Fluorescence energy transfer (or Förster energy transfer) is the transfer of energy between fluorescent molecules, a donor and an acceptor. Protein is used to conduct this research

MOM2 (amino acids 2-188) and MOM4 protein (amino acids 2-185), labeled with a C-terminal biotin fragment, in combination with europium-labeled streptavidin (RegKip EIIPteg, Ips., umakat, MA, O5A), which acts as a fluorophore donor . A Sub-tagged p53-derived peptide, Sub5-THEB MUCIA (p53 aa18-26), is an energy acceptor. After excitation of the donor molecule at 340 nm, the binding interaction between MOM2 or MOMA and the p53 peptide induces energy transfer and enhances the signal at the acceptor emission wavelength of 665 nm.

Violation of the formation of the p3-MOM2 or p53-MOMA4 complex due to the attachment of the inhibitor molecule to the po3 binding site in MOM2 or MOMA leads to an increase in donor radiation at 615 nm. The results of the analysis obtained by means of the radiometric study of EKET are calculated from the raw data for two separate fluorescence signals,

measured in time-resolved mode (count rate 665 nm/count rate 615 nm x 1000).

Research is carried out in white 1536-well tablets for microtitration (Sgeiipeg Vio-

Ope strN, Egiskeppaeizep, Segptapu) in a final volume equal to 3.1 μl, by combining 100 nl of the compounds diluted with a mixture of 90 96 DMSO/10 95 NgO (final concentration of DMSO 3.2 Ob), with 2 μl of labeled europium streptavidin (final concentration 2.5 nM) in the reaction buffer (3FF, 125 mM Mass, 0.001 95 Momehip (consists of hydrocarbon polymers (polymers

Momehip), designed to increase the solubility and stability of proteins; Momehip This.,

Satgiddevpige, Opyei Kipddot), gelatin 0.0195, 0.295 Rishgopis (block copolymer of ethylene oxide and propylene oxide, VAZE, I pdu/d5patep, Septapu), 1 mM DTT), then add 0.5 μl of MOM2-Vio or MOMA-Vio, diluted with buffer for analysis (final concentration 10 nM).

The solution is pre-incubated at room temperature for 15 minutes, then 0.5 μl of Su5-ros peptide in the analysis buffer is added (final concentration 20 nM). Incubate at room temperature for 10 minutes, then the tablets are read. A multi-mode microplate reader Apaiusi ST (MoiIesshag) is used to study the samples

Oemise5) with the following settings: dichroic mirror 380 nm, excitation 330 nm, donor radiation 615 nm, and acceptor radiation 665 nm. ISvo values are calculated by approximating the curves using the Xiii software. Unless otherwise specified, reagents are purchased from 5idta Speptisai! So, 5. And otsi5, MO, O5A.

The present invention also relates to new aspects of the research described above.

It is better if the compounds described in the present invention inhibit the interaction of p5o53-Nat2 and the interaction of p53-Nat with IC values equal to from 0.0003 to 100 µM, preferably from 0.0003 to 25 µM.

Data on the inhibition of p53-Nat2 and p53-Nait4 by typical compounds proposed in this invention are presented in Table 2 below in this invention.

Due to their inhibitory effect on the interaction of pOZ/MOM2 and/or p53/MOM4, the compounds of formula (I) in free form or in the form of a pharmaceutically acceptable salt are useful for the treatment of pathological conditions that are mediated by the activity (including normal activity or, preferably, overactivity) of MOM2 and /or MOMAYA, or variants thereof, respectively, as described,

Of such as proliferative and/or inflammatory pathological conditions, for example by activation of P5OZ/MOM2 interaction, and/or which are sensitive (meaning preferably in a therapeutically beneficial manner) to inhibition of the raoz/MOM2 interaction, most preferably the disease or disorder specified below in this invention.

Preferred is a compound of formula (I) intended for use, or its use for the treatment of a disease or disorder amenable to treatment by a compound of formula (II), preferably selected from among diseases caused by cell cycle dysregulation or, preferably, apoptosis: for example, diseases , in which the immune system is involved, for example, autoimmune diseases or immune diseases arising from transplantation (such as rheumatoid arthritis, "graft versus host", systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, polymyositis), chronic inflammatory pathological conditions such as asthma, osteoarthritis, atherosclerosis, Crohn's disease, or inflammatory or allergic pathological conditions of the skin, for example, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, acquired bullous pemphigus o epidermolysis or other inflammatory or allergic skin conditions, hyperproliferative disorders (e.g. Li-Fraumeni syndrome), cancer and tumor diseases such as benign and malignant tumors, sarcoma such as liposarcoma, rhabdomyosarcoma or bone cancer such as osteosarcoma, carcinoma , such as carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina or thyroid gland, glioblastoma, multiple myeloma, gastric cancer intestinal tract, especially carcinoma of the colon or colorectal adenoma, head and neck tumors, melanoma, prostatic hyperplasia, neoplasia, neoplasia of an epithelial nature, leukemia or lymphoma, such as B-cell or T-cell, and metastases to other organs), viral infections (for example, herpes, papilloma, HIV (human immunodeficiency virus), Kaposi's sarcoma, viral hepatitis) or others with diseases, for example, those in which the regulation of the interaction of roZ/IMOMA2 and/or roZ/moMa is disturbed, and/or which are sensitive to the inhibition of the interaction of roZ/IMOMAa and/or the interaction of roZ/MOMAa.

A fourth object of this invention is combinations that contain a compound of formula (I) and one 60 or more additional active ingredients. Thus, this invention relates to

- combinations, preferably a pharmaceutical combination containing a compound of formula (I) in a therapeutically effective amount and one or more therapeutically active agents, preferably antiproliferative agents; - a combined pharmaceutical composition intended for simultaneous or sequential administration, which contains the compound of formula (I) defined in the present invention in a therapeutically effective amount; one or more components of the combination in a therapeutically effective amount(s), preferably antiproliferative agents; one or more pharmaceutically acceptable inert fillers; - the combined pharmaceutical composition defined in the present invention, intended for (i) use as a medicine, (i) intended for use in the treatment of a disorder or disease mediated by the activity of MOM2 and/or MOMA, (its) use in a method of treating the disorder or disease mediated by MOMO2 activity and/or

Momma

The present invention also relates to the use of a compound of formula (I) (or a pharmaceutical composition containing a compound of formula (I)) for the treatment of one or more of the diseases listed above and below, in which the disease responds or responds (favorably, for example, with partial or complete elimination of one or more of its symptoms up to complete cure or remission) on the inhibition of the interaction of roz/moMa2, especially when MOM2 or MOMAYA, and/or their variant manifests (for example, in the context of other regulatory mechanisms, due to overexpression, mutation etc.) inappropriately high activity or activity that exceeds normal.

The present invention also relates to the use of a compound of formula (I) for inducing cell cycle slowing or, preferably, arrest and/or apoptosis in cells containing poZ or its variants, which are still active, to sensitize cells to one or more additional pharmaceutically active agents, such as a substance inducing apoptosis and/or slowing or arresting the cell cycle, and for protecting normal cells with chemotherapeutic agents by inducing slowing or arresting the cell cycle prior to treatment with one or more other chemotherapeutic agents, for use in rendering normal cells resistant to chemotherapeutic agents and/or treatment, and/or being used to protect cells from toxic side effects caused by chemotherapeutic agents or treatment, such as side effects leading to mucositis, stomatitis, xerostomia, gastrointestinal disorders and /or alopecia.

All these objects are the best variants of the implementation of this invention.

There are also methods that demonstrate the antitumor activity of compounds of formula (I) ip mimo.

For example, females deprived of the thymus gland of pi/pi Napap mice (Ipaiaparoiiv, Ipaiapa,

BA) with subcutaneously transplanted 5U5A-1 human osteosarcomas can be used to determine the antitumor activity of inhibitors of the raOZ/MOM2 interaction. On day 0, 3x109 cells were injected into the left side under the skin of animals that were orally anesthetized with EogepefFb (1-chloro-2,2,2-trifluoroethyldifluoromethyl ether, Arboi, U/ezradep, cSeptapu). When the volume of the tumor reaches 100 mm3, the mice are randomly divided into groups of 6-8 animals and treatment begins. Treatment is carried out for 2-3 weeks by oral, intravenous or intraperitoneal administration of the compound of formula (I) in a suitable diluent in the required doses twice a day (or less often). Tumors are measured with a caliper twice a week and the volume of tumors is calculated.

As an alternative to the 5YU5A-1 cell line, other cell lines can be used in the same way, for example, the colon carcinoma cell line NST116 (АТСС Mo. ССИ -247); - prostate carcinoma cell line I MSAR clone ROS (ATSS Mo. SKI--1740); - colon carcinoma cell line KKO (ATSS Mo.SKI--2577); - fibrosarcoma cell line HT1080 (ATSS Mo. SOY -121); - malignant melanoma cell line AZ75 (ATSS Mo. SKI--1619), - large cell lung carcinoma cell line MSI-N460 (ATOSS Mo. NTV-177); - choriocarcinomas UES-3 (ATS Mo. NTV-36) - carcinomas of the epithelium of the ducts of the mammary gland 22-75-1 (ATOSS Mo. SVI -1500).

The compound of formula (I) can also be successfully used in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; inhibitors of topoisomerase |I;

topoisomerase II inhibitors; compounds active in relation to microtubules; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; tTOK inhibitors such as KAOBO01; antitumor antimetabolites; platinum compounds; compounds designed to selectively affect/reduce protein or lipid kinase activity and other antiangiogenic compounds; compounds that are designed to selectively affect/reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies, such as HCO122; heparanase inhibitors; inhibitors of oncogenic Ca isoforms; telomerase inhibitors; proteosome inhibitors; compounds used in the treatment of malignant blood diseases, such as fludarabine; compounds that are designed to selectively affect, reduce, or inhibit E-3 activity, such as PKSA12; H5rO0 inhibitors, such as 17-AAS (17-allylaminogeldanamycin, MZS330507), 17-OMAS (17-dimethylaminoethylamino-17-demethoxygeldanamycin, MZS707545), IRI-504, СМЕ1010, СМЕ2024,

СМЕ1010 manufactured by Sopiopta TPegareshis5 and AIOM922; temozolomide (TEMODAL'M); spindle protein kinesin inhibitors, such as 58715992 or 58743921, manufactured by Siacob5thijKiipe, or pentamidine/chlorpromazine, manufactured by

SotrBipashkh; RISK inhibitors such as VE7235; KARE inhibitors, such as KAR265; MEK inhibitors, such as AKKU142886, produced by Atgtau RioPapta, A2Ob6244, produced by

Aviga/epesa, RO181461, produced by the company Riii»eg, leucovorin, agents that bind EOS, anti-leukemia compounds, ribonucleotide reductase inhibitors, 5-adenosylmethionine decarboxylase inhibitors, apoptosis regulators, antiproliferative antibodies or other chemotherapeutic compounds. In addition, alternatively or in addition, they can be used in combination with other techniques to fight tumors, including surgery, the use of ionizing radiation, photodynamic therapy, implants, for example, together with corticosteroids, hormones, or they can be used as radiosensitizers. In addition, anti-inflammatory and/or anti-proliferative treatment includes combinations with anti-inflammatory medicinal substances. A combination with antihistamine drugs, bronchodilators, NSAIDs (non-steroidal anti-inflammatory drugs) or chemokine receptor antagonists is also possible.

The term "aromatase inhibitor" as used herein means a compound that inhibits the production of estrogen, i.e., the conversion of the substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to, steroids, preferably atamestane, exemestane, and formestane, and preferably, nonsteroidal compounds, preferably aminoglutethimide, rogletimide, pyroglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane can be administered, for example, in the form in which it is sold, for example, under the trade name AROMAZIN. Formestane can be administered, for example, in the form in which it is sold, for example, under the trade name LENTARON.

Fadrozole can be administered, for example, in the form in which it is sold, for example, under the trade name AFEMA. Anastrozole can be administered, for example, in the form in which it is sold, for example, under the trade name ARIMIDEX. Letrozole can be administered, for example, in the form in which it is sold, for example, under the trade name FEMARA or

FEMAR. Aminoglutethimide can be administered, for example, in the form in which it is sold, for example, under the trade name ORIMETEN. The combination proposed in this invention, which includes a chemotherapeutic agent that is an aromatase inhibitor, is particularly suitable for the treatment of hormone-receptor-positive tumors, for example, breast tumors.

The term "anti-estrogen" as used herein refers to a compound that counteracts the effects of estrogens at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride.

Tamoxifen can be administered, for example, in the form in which it is sold, for example, under the trade name NOLVADEX. Ralcosifene hydrochloride can be administered, for example, in the form in which it is sold, for example, under the trade name EVISTA. Fulvestrant can be prepared as disclosed in 54659516, or it can be administered, for example, in the form in which it is sold, for example, under the trade name FASLODEX. The combination proposed in this invention, which includes a chemotherapeutic agent that is an antiestrogen, is particularly useful for the treatment of estrogen receptor-positive tumors, for example, breast tumors.

The term "anti-androgen" as used herein refers to any compound that can inhibit the biological effects of androgenic hormones, and includes, but is not limited to, bicalutamide (CASODEX"M), which can be prepared, for example, as

as disclosed in 54636505.

The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is disclosed in 054100274 and can be administered, for example, in the form in which it is sold, for example, under the trade name ZOLADEX. Abarelix can be prepared, for example, as disclosed in 55843901.

The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan, himatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular conjugate of camptothecin RMO-166148 (compound A1 in

MMO99/17804). Irinotecan can be administered, for example, in the form in which it is sold, for example, under the trade name CAPMTOSAR. Topotecan can be administered, for example, in the form in which it is sold, for example, under the trade name HICAMTIN.

The term "topoisomerase II inhibitor" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including a liposomal formulation such as CAELIX), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and lozoxantrone, and the podophyllotoxins etoposide and teniposide Etoposide can be administered, for example, in the form in which it is sold, for example, under the trade name

ETOPOPHOS. Teniposide can be administered, for example, in the form in which it is sold, for example, under the trade name MM 26-BRISTOL. Doxorubicin can be administered, for example, in the form in which it is sold, for example under the trade name

ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, for example, in the form in which it is sold, for example, under the trade name FARMORUBICIN. Idarubicin can be administered, for example, in the form in which it is sold, for example, under the trade name ZAVEDOS.

Mitoxantrone can be administered, for example, in the form in which it is sold, for example, under the trade name NOVANTRON.

The term "microtubule-active compound" refers to microtubule-stabilizing, microtubule-destabilizing compounds, and microtubule polymerization inhibitors and includes, but is not limited to, taxanes such as paclitaxel and docetaxel; periwinkle alkaloids, for example, vinblastine, mainly vinblastine sulfate, vincristine,

Among them are preferably vincristine sulfate and vinorelbine, discodermolides, colchicine and epothilones and their derivatives, for example epothilone B or O or their derivatives. Paclitaxel can be administered, for example, in the form in which it is sold, for example, TAXOL'M, Docetaxel can be administered, for example, in the form in which it is sold, for example, under the trade name TAXOTER.

Vinblastine sulfate can be administered, for example, in the form in which it is sold, for example, under the trade name VINBLASTIN K.R. Vincristine sulfate can be administered, for example, in the form in which it is sold, for example, under the trade name PHARMISTIN. Discodermolide can be obtained, for example, as disclosed in 055010099. Also included are epothilone derivatives disclosed in UMO98/10121, O56194181, UUO98/25929, UMO98/08849, M/O099/43653,

UMO98/22461 and UMO00/31247. Especially preferred are epothilone A and/or B.

The term "alkylating compound" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, and nitrosourea (VSMO or gliadel). Cyclophosphamide can be administered, for example, in the form in which it is sold, for example, under the trade name CYCLOSTIN. Ifosfamide can be administered, for example, in the form in which it is sold, for example, under the trade name HOLOXAN.

The term "antitumor antimetabolite" includes, but is not limited to, 5-fluorouracil, or 5-B, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed . Capecitabine can be administered, for example, in the form in which it is sold, for example, under the trade name XELODA. Gemcitabine can be administered, for example, in the form in which it is sold, for example, under the trade name GEMZAR.

The term "platinum compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatin, and oxaliplatin. Carboplatin can be administered, for example, in the form in which it is sold, for example under the trade name

CARBOPLAT. Oxaliplatin can be administered, for example, in the form in which it is sold, for example, under the trade name ELOXATIN.

The term "compounds that selectively act/reduce protein or lipid kinase activity"; or "protein or lipid phosphatase activity"; or "other anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g., 60 a) compounds that selectively reduce or inhibit receptor activity platelet-derived growth factor (ROSEC), such as compounds that selectively act, reduce or inhibit the activity of ROSEC, preferably compounds that inhibit the ROSEC receptor, for example, an M-phenyl-2-pyrimidinamine derivative, for example, imatinib, 50101, 506668 and SEV- 111; p) compounds that selectively act, reduce or inhibit the activity of fibroblast growth factor receptors (ESEK); c) compounds that selectively act, reduce or inhibit the activity of the receptor for insulin-like growth factor I (IGF-IC), such as compounds that selectively act, reduce or inhibit the activity of IGF-I, preferably compounds that inhibit the activity of the kinase of the IGF-I receptor , such as compounds disclosed in UMO 02/092599, or antibodies that selectively act on the extracellular domain of the ISE-Y receptor or its growth factors; a) compounds that selectively act, reduce or inhibit the activity of the TC receptor tyrosine kinase family, or ephrin B4 inhibitors; f) compounds that selectively act, reduce or inhibit the activity of the family of tyrosine kinases of the AChI receptor;

Her) compounds that selectively reduce or inhibit receptor tyrosine kinase activity

Wei; 9) compounds that selectively act, reduce or inhibit receptor tyrosine kinase activity

KII/ZSERE, i.e. C-Kii receptor tyrosine kinases - (part of the ROSEBK family), such as compounds that selectively act, reduce or inhibit the activity of the c-Kii receptor tyrosine kinase family, preferably compounds that inhibit the c-Kii receptor, for example, imatinib;

P) compounds that selectively act, reduce or inhibit the activity of representatives of the c-ABI family, products of their fusion with genes (for example, VSK-ABI kinase) and mutants, such as compounds that selectively act, reduce or inhibit the activity of representatives of the c-ABI family ABbI and products of their fusion with genes, for example, a derivative of M-phenyl-2-pyrimidinamine, for example, imatinib or nilotinib (AMM107); RO1T80970; Ase57; MFA 680410; RO173955 issued by the company

Ragkebrami5; or dasatinib (VM5-354825); i) compounds that selectively act, reduce or inhibit the activity of representatives of the family of protein kinases C (RKS) and the family of Kai serine/threonine kinases, representatives of MEK, ZKS, UAK, GAK,

ROKI, RKV/AKI, and representatives of the Kaz5z/MARK family, and/or family representatives

Of cyclin-dependent kinases (SOK) and especially staurosporine derivatives disclosed in 055093330, for example, midostaurin; examples of other compounds include, for example, ShSM-01, safingol, VAH 43-9006, bryostatin 1; perifosine; ilmofosine; KO 318220 and KO 320432; BO 6976; Iviv 3521;

IU333531/ 379196; isoquinoline compounds such as those disclosed in UUMO00/09495; ETI5; VE2235 (RIZK inhibitor) or AT7519 (SOC inhibitor); |) compounds that selectively act, reduce or inhibit the activity of protein tyrosine kinase inhibitors, including imatinib mesylate (GLEEVEK"M) or tyrphostin. Tyrphostin is preferably a compound with a low molecular weight (Mig « 1500) or a pharmaceutically acceptable salt thereof, preferably a compound selected from of the group that includes: the class of benzylidenemalonitriles or the class of 5-arylbenzenemalonitriles or the class of bisubstrate quinolines, more preferably any compound selected from the group that includes: tyrphostin A23/K0-50810; AC 99; tyrphostin AC 213; tyrphostin AC 1748; tyrphostin AC 490; tyrphostin B44; tyrphostin B44 (y4)-enantiomer; tyrphostin AC 555; AOS 494; tyrphostin AC 556, ASU57 and adafostin (adamantyl ester of 4(2,5dihydroxyphenyl)-methyliamino)dbenzoic acid; MZS 680410, adafostin);

K) compounds that selectively act, reduce or inhibit the activity of the family of epidermal growth factor receptor tyrosine kinases (ESE, EgB2, EgtrB3, EgtoB4 in the form of homo- or heterodimers) and their mutants, such as compounds that selectively act, reduce or inhibit the activity of the family epidermal growth factor receptors, preferably compounds, proteins or antibodies that inhibit members of the ECE receptor tyrosine kinase family, e.g.

BOs of the ECE receptor, EgrB2, EgrB3 and EgHBAa, either bind to ECE or to ligands related to ECE, and are preferably such compounds, proteins or monoclonal antibodies that are generally and specifically disclosed in UMO97/02266, for example, the example compound 39, or in

EROBb4409, M/099/03854, EROB20722, EROBb6b226, ERO787722, EROVZ7063, I55747498,

МО98/10767, М/О97/30034, М/097/49688, ММО97/38983 and especially in УМО96/30347 (e.g. compound known as SR 358774), УМО96/33980 (e.g. compound 20 1839) and УМО95/ 03283 (for example, compound 2M105180); for example, trastuzumab (herceptin "M), cetuximab (erbutux "M), iressa, tartseva, O51I-774, SI-1033, EKV-569, SMU-2016, E1.1, E2.4, E2.5, Eb. 2, Eb. 4,

E2,11, Eb,Z or E7,6,3, and derivatives of 7H-pyrrolo-(2,3-4|pyrimidine), which are disclosed in UMO 03/013541; and

I) compounds that selectively act, reduce or inhibit the activity of the c-Mei receptor, because preferably compounds that inhibit the kinase activity of the c-Mei receptor, or antibodies that selectively act on the extracellular domain of c-Mei or bind to NOBE; t) compounds that selectively act, reducing or inhibiting the activity of RAZK, such as VE/235 or VKM120; n) compounds that selectively act, reduce or inhibit the activity of the family of cyclin-dependent kinases, such as PO 0332991.

Other antiangiogenic compounds include compounds characterized by a different mechanism of action, for example, that does not involve inhibition of protein or lipid kinase, for example, thalidomide (TALOMID) and TMP-470.

Compounds that selectively act, reduce or inhibit the activity of protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A or SOC25, for example, okadaic acid or its derivatives.

Compounds that induce cell differentiation processes are, for example, retinoic acid, o-, y- or 6-tocopherol or c-, y- or 5-tocotrienol.

The term "cyclooxygenase inhibitor" as used herein includes, but is not limited to, e.g., Cox-2, 5-alkyl substituted 2-arylaminophenylacetic acid inhibitors and derivatives such as celecoxib (CELEBREX M), rofecoxib (VIOX M), etoricoxib , valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, for example, 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid lumiracoxib.

The term "bisphosphonates" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zolendronic acid. "Etridronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name DIDRONEL. "Clodronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name BONEFOS. "Tiludronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name SCELID. "Pamidronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name AREDIA. "Alendronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name FOSAMAX. "Ibandronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name

With the name BONDRANAT. "Risedronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name ACTONEL. "Zolendronic acid" can be administered, for example, in the form in which it is sold, for example under the trade name

ZOMETA.

The term "ttToOKK inhibitors" refers to compounds that inhibit the mammalian target of rapamycin (MTP) and that have antiproliferative activity, such as sirolimus (rapamun M), everolimus (certican "M or affinitor" MU, SSI-779 and AVT578.

The term "heparanase inhibitor" as used herein refers to compounds that selectively act to reduce or inhibit the breakdown of heparin sulfate. The term includes, but is not limited to, RI-88.

The term "biological response modifier" as used herein means a lymphokine or interferons, for example, interferon γ.

The term "inhibitor of oncogenic Kav isoforms", e.g. H-Na5, K-Ka5, or M-Kav, as used herein means compounds that selectively act, reduce or inhibit oncogenic Ka activity, e.g. "farnesyltransferase inhibitor", e.g. , I -744832, rkvo557 or K115777 (zarnestra).

The term "telomerase inhibitor" as used herein refers to compounds that selectively act to reduce or inhibit telomerase activity. Compounds that selectively reduce or inhibit telomerase activity are preferably compounds that inhibit the telomerase receptor, for example, telomestatin.

The term "methionine aminopeptidase inhibitor" as used herein means compounds that selectively act to reduce or inhibit the activity of methionine aminopeptidase.

Compounds that selectively act, reduce or inhibit the activity of methionine aminopeptidase, are, for example, bengamide or its derivative.

The term "proteosome inhibitor" as used herein refers to compounds that selectively act to reduce or inhibit the activity of the proteosome. Compounds that selectively reduce or inhibit the activity of the proteosome include, for example, bortezomide (velcade "M") and MM 341.

The term "matrix metalloproteinase inhibitor" or "MMP inhibitor" as used herein includes, but is not limited to, peptidomimetic and non-peptidomimetic collagen inhibitors, tetrazolyl derivatives, for example, the peptidomimetic hydroxamate inhibitor batimastat and its orally bioavailable analog marimastat ( 8B-2516), prinomastat (АС3340), metastat (MZS 683551) ВМ5-279251, VAM 12-9566, TAA211, ММИ27ОВ or ААШеЗб.

The term "compounds useful in the treatment of blood malignancies" as used herein includes, but is not limited to, EM5-like tyrosine kinase inhibitors, for example, compounds that selectively act to reduce or inhibit the activity of EM5-like tyrosine kinase receptors (E -ZK); interferon, 1-6-0-arabinofuransylcytosine (aga-c) and bisulfan; and AK inhibitors, eg, compounds that selectively reduce or inhibit anaplastic lymphoma kinase.

Compounds that selectively act, reduce or inhibit the activity of EM5-like tyrosine kinase (EK-ZK) receptors, are preferably compounds, proteins or antibodies that inhibit representatives of the EI-ZK receptor tyrosine kinase family, for example, PKS412, TKI258, midostaurin, a derivative of staurosporine , 5011248 and MI M518.

The term "H5POO inhibitors" as used herein includes, but is not limited to, compounds that selectively act to reduce or inhibit the specific ATPase activity of H5POO; destroy, selectively act, reduce or inhibit H5POO client proteins on the ubiquitin pathway of the proteosome. Compounds that selectively act, reduce or inhibit the specific ATPase activity of HPOO, are preferably compounds, proteins or antibodies that inhibit the specific ATPase activity of NBZROU0O, for example, 17-allylamino, 17-demethoxygeldanamycin (17AAS), a derivative of geldanamycin, others related to geldanamycin compounds, radicicol and NOAS inhibitors; An example of an NBROO inhibitor is AOM922.

The term "apoptosis regulators" as used herein includes, but is not limited to, compounds that selectively act to reduce or inhibit the activity of members of the All2 family (such as ABT-263) and members of the IAR family (such as

AES40826); or induce apoptosis by a known or unknown mechanism(s) of action (for example, TKAIG antibodies, OK5B antibodies).

The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin M), trastuzumab-OM'I, erbutux, bevacizumab (Avastin M), rituximab (Rituxan M), RKOb64553 (anti-C040) , 2C4 antibodies and HСО122 antibodies (antibodies to СО40). Antibodies include, for example, intact monoclonal antibodies, polyclonal antibodies, polyvalent antibodies formed from at least two intact antibodies, and antibody fragments, if they have the necessary biological activity.

For the treatment of acute myelogenous leukemia (AML), the compounds of formula (I) can be used in combination with standard anti-leukemic drugs, preferably in combination with drugs used for the treatment of AML. In particular, compounds of formula (I) can be administered in combination, for example, with farnesyltransferase inhibitors and/or other drugs used to treat AML, such as daunorubicin, adriamycin, Aga-C, UR-16, teniposide, mitoxantrone, idarubicin, carboplatin and РКСА12.

The term "anti-leukemic compounds" includes, for example, Aga-C, a pyrimidine analog that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, b-mercaptopurine (6-MP) and fludarabine phosphate.

Compounds that selectively reduce or inhibit the activity of histone deacetylase inhibitors (SSRIs), such as sodium butyrate and hydroxamic acid suberoylanilide (SAGA), which inhibit the activity of enzymes known as histone deacetylases. Specific NOAS inhibitors include M5275, SAGA, EK228 (formerly EKZ901228), trichostatin A, and ONn5B89 disclosed in M/O02/22577, and compounds disclosed in 56552065, in particular, M-hydroxy-3-I4-((2-( 2- methyl-1H-indol-Z-yl/ethyl|-amino|methylIfenyl|-2E-2-propenamide or its pharmaceutically acceptable salt and M-hydroxy-3-I(4-K2-hydroxyethyl)(2-( 1 H-indol-3-yl)ethyl|-amino|methyl|phenyl|-2E-2-propenamide or its pharmaceutically acceptable salt, preferably lactate.

Somatostatin receptor antagonists as used herein refer to compounds that selectively act, reduce or inhibit the somatostatin receptor, such as octreotide and BOM230 (pasireotide).

Methods of damage to tumor cells are those that use ionizing radiation. The term "ionizing radiation" used above and below in this invention means ionizing radiation, which is electromagnetic radiation (such as X-rays and gamma radiation) or particles (such as alpha and beta particles). Ionizing radiation is used in, but not limited to, radiation therapy and is known in the art. See publication by NeiYitap, Rgipsiriev oii

Vavdiaip Tnegaru, Sapseg, ip Rgipsiriez apa Rgasiise oi Opsoiodu, Oemiia eyi a!., Eav., At Eaiop, Moi. 60 1, pp. 248-275 (1993).

The term "EbS-binding agents" as used herein refers to a class of immunosuppressive agents that modulate lymphocyte recirculation, such as ETM720.

The term "ribonucleotide reductase inhibitors" means pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and/or cytosine arabinoside (aga-C), b-thioguanine, 5-fluorouracil, cladribine, b-mercaptopurine (preferably in combination with aga -C against AII) and/or pentostatin. Inhibitors of ribonucleotide reductase are preferably hydroxyurea or derivatives of 2-hydroxy-1H-isoindole-1,3-dione, such as RI-1, RI-2,

RI -3, RI --4, RI -5, RI -6, RI -7 or RI -8, specified in the publication of Mapau eyi a!., Asia Opsiodisa, Moi. 33,

Mo. 8, pp. 953-961 (1994).

The term "3-adenosine methionine decarboxylase inhibitors" as used herein includes, but is not limited to, the compounds disclosed in 55461076.

Also included, in particular, are the compounds, proteins, or monoclonal antibodies to MESE disclosed in

UMO98/35958, for example 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salt, for example, succinate, or in UMO 00/09495, U/O00/27820, UMOO00/59509,

УО98/11223, ММО00/27819 and ЕРО769 947; described in the publications of Rhemzhey ei a), Sapseg Kev, Moi. 59, pp. 5209-5218 (1999); Mtsap ei ai., Rgos Mai! Asai 5si Sh 5 A, Moi. 93, pp. 14765-14770 (1996); 7py eyi ai., Sapseg Waves, Moi. 58, pp. 3209-3214 (1998); and Mogaegpiyi a!., Tohisoi Raiyoi, Moi. 27, Mo. 1, pp. 14-21 (1999); in MUO00/37502 and UMO94/10202; ANGIOSTATIN, described in the publication of O'KeShu ei a!., SeiI, Moi. 79, pp. 315-328 (1994); ENDOSTATIN, described in the publication of O'Keyu ei ai., Seii,

My. 88, pp. 277-285 (1997); amides of anthranilic acid; 204190; 206474; 505416; 506668; bevacizumab; or anti-MESE antibodies or anti-MESE receptor antibodies, e.g.

PiMABBb and KNORar, MESE aptamer, for example, macugon; BI-T-4 inhibitors, RI-T-3 inhibitors, antibodies to MESEK-2 IDS, angiozyme (KERI 4610) and bevacizumab (avastin "M),

Photodynamic therapy as used in the present invention means therapy in which certain chemicals known as photosensitizing compounds are used to treat or prevent cancer. Examples of photodynamic therapy include treatment with such compounds as, for example, VIZUDIN "M and sodium porfimer.

Angiostatic steroids as used herein mean compounds that block or inhibit angiogenesis, such as, for example, anecortav, triamcinolone, hydrocortisone, 11-a-

From epihydrocortisol, cortexolone, 17-α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone and dexamethasone.

Implants that contain corticosteroids mean compounds such as, for example, fluocinolone, dexamethasone. "Other chemotherapeutic compounds" include, but are not limited to, plant alkaloids, hormonal compounds, and antagonists; biological response modifiers, mainly lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; ZhZAIRNA or 5iRNA; or different compounds, or compounds with a different or unknown mechanism of action.

The structure of active compounds, which have code numbers, generic or trade names, is given in the latest edition of the standard reference "pe MegsK Ipdeh" and in databases, for example,

Raiepiz Ipiepaiyiopai (for example, IM5 Umopa Rybiisaiopv).

None of the references to publications in this specification should be construed as suggesting that these cited publications describe prior art that may adversely affect the patentability of the present invention.

Pharmaceutical compositions, applications and methods

The above compounds which can be used in combination with the compounds of formula (1) can be obtained and administered as described in the art, for example in the documents cited above.

The present invention also relates to a pharmaceutical preparation containing a compound of formula (I) defined in the present invention, and/or its M-oxide or tautomer, and/or a pharmaceutically acceptable salt of such a compound, or its hydrate or solvate (only in the present invention often referred to as a "compound of formula ()") and at least one pharmaceutically acceptable carrier.

A compound of formula (I) can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy can be the administration of fixed combinations or the administration of a compound of the present invention and one or more other therapeutic (including prophylactic) compounds alternately or independently of each other, or the simultaneous administration of fixed combinations and one or more other therapeutic agents. The compound of formula (I) can be administered independently or additionally, preferably for tumor treatment, in combination with chemotherapy, radiation therapy, immunotherapy, surgery, or use combinations thereof. It is also possible to use long-term therapy as adjunctive therapy in the context of other treatment strategies described above. Other possible treatments are maintenance therapy after tumor regression or even prophylactic chemotherapy, for example, for patients at risk.

The dose of the active ingredient depends on a variety of factors, including the type, species, age, body weight, sex and health of the patient, the severity of the condition being treated, the route of administration, the kidney and liver function of the patient, and the particular compound being used. A physician, clinician, or veterinarian of ordinary skill in the art can readily determine and prescribe an effective amount of a drug necessary to prevent, counteract, or delay the progression of a pathological condition.

For optimal accuracy in selecting the concentration of the drug in the range that ensures effectiveness without the manifestation of toxicity, a regime based on the kinetics of availability of the drug to the centers of influence is necessary. For this, it is necessary to take into account the distribution, equilibrium and elimination of the medicinal product.

The dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered to warm-blooded animals, for example humans, having a body weight of about 70 kg is preferably equal to from about

C mg to about 15 g, more preferably from about 10 mg to about 3 g, even more preferably from about 50 mg to about 1.5 g/day for one patient undivided in one dose or divided preferably into 2-4, e.g. 2 or C single doses, which, for example, may be the same. Children are usually given half the dose for an adult.

The compounds of formula (I) can be administered by any suitable route, in particular parenterally, for example in the form of solutions or suspensions for injection, enterally, for example, orally, for example in the form of tablets or capsules, topically, for example in the form of lotions , gels, ointments or creams, or in nasal or suppository form.

Local application is carried out, for example, on the skin. Another route of local administration is through the eyes. Pharmaceutical compositions comprising a compound of the present invention together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional techniques by mixing with a pharmaceutically acceptable carrier or diluent.

The present invention also relates to pharmaceutical compositions comprising an effective amount, preferably an amount effective for the treatment of one of the above disorders, of a compound of formula (I) and/or its M-oxide or tautomer, and/or its pharmaceutically acceptable salt together with with one or more pharmaceutically acceptable carriers SUITABLE FOR topical, enteral, eg, oral or rectal, or parenteral administration and which may be inorganic, organic, solid or liquid. For oral administration, it is preferable to use tablets or gelatin capsules that contain the active ingredient together with diluents, for example, lactose, dextrose, mannitol and/or glycerin, and/or lubricants and/or polyethylene glycol.

Tablets may also include binders such as magnesium aluminosilicate, starches such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and optionally disintegrants such as starches, agar-agar, alginate an acid or its salt, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavors and sweeteners. The pharmacologically active compounds proposed in this invention can also be used in the form of parenterally administered compositions or in the form of infusion solutions. Pharmaceutical compositions may be sterilized and/or may contain inert excipients, for example, preservatives, stabilizers, lubricating compounds and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers. Pharmaceutical compositions proposed in the present invention, which, if necessary may include other pharmacologically active substances, prepared by known methods, for example, using conventional mixing, granulation, drug preparation, dissolution or lyophilization techniques, and contain from about 1 to 99 95, preferably from about 1 to about 20 95 active ingredient ( ingredients).

In addition, the present invention relates to the compound of formula (I) and/or its M-oxide or tautomer, and/or to its pharmaceutically acceptable salt, intended for use in a method of treating the human or animal body, preferably for the treatment of the disease specified in this invention, most preferably in a patient who needs such treatment.

The present invention also relates to the use of a compound of formula (I) and/or its M-oxide or tautomer, and/or a pharmaceutically acceptable salt of such a compound, for the preparation of a medicinal product, preferably intended for the treatment of a proliferative disease, (516) preferably cancer.

In addition, the present invention relates to a method of treating a proliferative disease that responds to inhibition of the roZ/MOM2 interaction, which includes administering to a warm-blooded animal in need of such treatment a compound of formula (I) and/or its M-oxide or tautomer, and/or of its pharmaceutically acceptable salt, in which the radicals and symbols have the meanings defined above, preferably in an amount effective for the treatment of the specified disease and/or capable of inhibiting the p53/mMoOMa interaction in the specified warm-blooded animal.

In addition, the present invention relates to a pharmaceutical composition intended for the treatment of solid or non-solid tumors in warm-blooded animals, including humans, containing an antiproliferatively effective dose of a compound of formula (I) described above, or a pharmaceutically acceptable salt of such a compound together with a pharmaceutical carrier.

The fifth object of this invention is the preparation of the compound of formula (I). Compounds of formula (1) or their salts are obtained by well-known methods (see the literature cited above), although not previously described for the preparation of compounds of formula (1).

Synthesis of compounds of formula (I)

Usually, compounds of formula (I) can be obtained in accordance with the following schemes.

The general scheme of the synthesis of A. sg ShK ' Mn. sleep in I ch nai them; what's going on in k | AsON EN | ko de ze: in the heating, then in" V

And Omoya oh! 7 M as in the tea CHE I 2 and drink IZ y ; h) mevO " and i

Vo

Scheme A illustrates one method of obtaining the compounds proposed in this invention, mainly according to a modified published procedure (MepkKom, A. apa Moiom, M. 5upipeviv 1982, 3, 216-217).

The general scheme of the synthesis of V.

dk MOV - t and th in o Zk p. village and village - sonnet zma, 0 TLF,-tTV S det s still still NO. what

Me, or you

TU , , - and Ku

May, a flock of | 1).

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Shi isi tsy in the same GT st I yannia pek i rebssaya , and DIEA, DHM "TE: MO. You; - Fri NU seams

S vu and I and chKoya ha .

Ohm, 0 NVO, ASON, heating sa | heating pcs AK, s y kha e s y y s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s ay! and'

Sha o a nn y y akren y sawing -- Her. sha sha shi eh od te do

The benzaldehyde derivative is used in a Grignard-type reaction, usually in THF and usually at -78"C, and the corresponding benzyl alcohol is obtained. The alcohol derivative is oxidized with pyridinium dichromate (PDH) or other oxidizing reagents, such as manganese dioxide.

The methyl acetate group is introduced using tert-butyl ether, malonic acid methyl ether and a strong base, usually Manne, and using heating, usually the reaction mixture is heated at 60 "C in an aprotic solvent such as DMSO. In the second stage, the crude product is usually treated with trifluoroacetic acid in an organic solvent such as DCM.

Saponification is carried out using GiOH, usually using a methanol/water mixture (211), usually at room temperature. After acidification with 2 M HCl, the precipitate is collected and extracted with organic solvents.

To a suspension of the free acid, usually in EN or another alcohol such as methanol, MavVnae is added, usually at room temperature. Thionyl chloride is added to this solution, usually at 0 "C, and the reaction mixture is stirred at room temperature.

Benzyl chlorides are treated, usually in an alkaline medium, with DIPEA or triethylamine in DCM or other organic solvents such as dioxane, DMF, DMSO substituted anilines, at room temperature and then evaporated to dryness. Sulfuric acid is added to the solution of the obtained residue in acetic acid at room temperature and the mixture is heated at 80 °C, stirred for 1 hour, then cooled to room temperature and concentrated in a vacuum.

The nitro group is restored by treating the starting substance with stannous chloride, usually in

EUN at CT. The suspension is heated at 80 "C and vigorously stirred for 30 minutes.

Substituents are additionally introduced into the obtained aniline with the help of chloride anhydrides of various acids (acylation), for example, propionyl chloride, or with the help of various aldehydes or ketones under the conditions of reductive amination (ASON, Mavn(OAc)z, DXM, CT) and various alkylated 5О0 products are obtained.

The general scheme of the synthesis of S. and: sov v Osy vo v shchy h m shchi a y Z 5 te My | zu r: do la I do - Ot about and and her

I am a BAS, ono naya na LLC, vagovnynia shih shk ke Y schi vo vyi ry od h Y shi Sue svy y i Х N r rya chna nn M. something

PO still I ate S for a penny

Rhodium catalog. What are you doing?

M Z 7 x ra zagoivkhanya o res sh i

Ya sya , vo - su Ya t u, ra liy Y rya wa aa Z r . with uche in R and bi, shrandu basis; hot air heating

FI re

The ethyl ester of (3,4-dimethoxyphenyl)-acetic acid is treated with dichloromethoxymethane, usually in DCM by slow addition of 5psCych (1M solution in DCM), usually over 30 minutes. After the addition, the reaction mixture is usually stirred at 0 "C for 1.5 hours.

A chiral auxiliary group is introduced according to the method described in the publication by Yuam and A. (Ehapk A.

Oami5, Rgaduyutpa K. Mopapiu; U. Ogd. Spet., 2002, 67, 4, 1290), usually using a Lewis acid such as THOEO, and usually an aprotic solvent such as DCM.

The enantioselective introduction of the aryl group is carried out according to the method described in the publication

Oh, oh! (5. Oi, M. Mogo, N. Rikyptaga, T. Kamapivyi, M. Ipotse, Temaneygop, 59, 2003, 4351).

A tin-containing reagent is added to a solution of the starting material (sulfoximine) in an organic solvent such as THF, dioxane or acetonitrile, but usually in T/F in the presence of a rhodium catalyst such as bis(acetonitrile)(1,5-cyclooctadiene) - rhodium(I) tetrafluoroborate. The reaction is usually carried out at an elevated temperature, such as 60 "C. In addition to reagents containing tin, other reagents such as appropriate borates can be used.

Removal of the sulfoxamine protecting group is usually carried out in an acidic environment using acids such as HCl (eg 1.25 M in ethanol) in an organic solvent such as an alcohol, usually methanol. The free amine is evaporated to dryness, re-dissolved, usually in methanol, and a base, usually triethylamine, is added, and the reaction mixture is stirred, usually at room temperature.

The cross-coupling reaction is usually carried out under the conditions of the Buchwald reaction, which are used for the C-M amidation reaction, usually according to the method described in the literature

Buchvalda (A. Kiaragh, Khiaoptsa Nyapo, 5. I. Vispmaid; U. At. Spet. 5os., 2002, 124, 7421). Under an inert atmosphere of argon and using degassed aprotic solvents including toluene, dioxane, THF, and DMF, but usually in dioxane, the starting materials (isoquinolinone and aryl halide) are stirred in the presence of a copper source such as powdered Si, Si,

CysM, SygO, Cysi', but usually Cyi, and a diamine ligand such as ethylenediamine or other 1,2-diamine ligands, but usually trans-1,2-cyclohexanediamine in the presence of a base such as

KzRO», K»2bOz or С5СОз, but of course KzRO». The reaction mixture is heated, usually at 100-110 "C and stirred for 4 to 16 hours, depending on the course of the reaction.

General scheme of synthesis 0.

I: in t, I sho no t ma Y r Y ; ! penyu vEv. DIA and 2 gl tee T not bod zon AD huge tra ge -y I Y Ge y in aso her SE. a yi DI she shk how. Z. and 2 on. vet and | х Ev, SUBSCRIBE, PERSONAL niche with Ох -О cha ШТ with до бсмХх poyu yutyutyutyutyutttteyutyutyutn fr zagrivnynia ri U kaesmivnynia sh g sa hek S. pk v v! ma: SHHA de ZH Y ; NO; E | so and where 9

OSS is still T | r get - t toluzi, vzhtrivvniya 0-7 Z td Nu S, grivaniya chih, and t a Dvpuvl, negrivvni se B o td 2BPTOK zageivnhnya ZOoodii Sho dec i

From the

G-U in! that in o. lk Oary whose

She i Y , v y Shk: Me i r sche a she av ona ka: Ne a M i i | Man. TE Ff, heating in. s Same veu "t shchi Mem ik dya vyky

The present invention additionally includes any variant of the methods proposed in the present invention, in which the intermediate product obtained at any of its stages is used as a starting substance and the remaining stages are carried out, or in which the starting substances are formed under conditions of carrying out reactions, or in which the reaction components are used as their salts or optically pure antipodes.

Compounds of the present invention and intermediates may also be converted into one another by techniques generally known to those skilled in the art.

The intermediates and final products can be treated and/or purified by standard techniques, for example, using chromatographic techniques, partitioning techniques, (re-)crystallization, etc.

The following provisions are applicable in general to all methods mentioned above and below in this invention.

All of the above method steps can be performed under reaction conditions known to those skilled in the art, including those specifically indicated in the absence or usually in the presence of solvents or diluents, including, for example, solvents or diluents that are inert to the reagents used and dissolve them, in the absence or presence of catalysts, condensing or neutralizing reagents, for example, ion exchangers, such as cation exchangers, for example, in NU form; depending on the nature of the reaction and/or reactants at a reduced, normal or elevated temperature, for example at a temperature in the range of from about -100 to about 190 "C; including, for example, from about -80 to about 150 "C, for example from -80 to -60 "C, at room temperature, from -20 to 40 "C or at boiling temperature; at atmospheric pressure or in a closed vessel, when appropriate, then under pressure and/or in an inert atmosphere such as argon or nitrogen.

At all stages of the reactions, the formed mixtures of isomers can be separated into separate isomers, for example, diastereoisomers or enantiomers; or to any required mixture of isomers,

for example, racemates or mixtures of diastereomers, for example, by techniques similar to those described above in this invention.

Solvents from which solvents suitable for any particular reaction may be selected include those specifically mentioned or, for example, water, esters such as (lower) alkyl-(lower) alkanoates, for example ethyl acetate, ethers such as aliphatic ethers such as diethyl ether or cyclic ethers such as tetrahydrofuran and dioxane, liquid aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol, ethanol and 1- or 2-propanol, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride and chloroform, acid amides such as dimethylformamide and dimethylacetamide, bases such as heterocyclic nitrogenous bases such as pyridine or M-methylpyrrolidin-2-one, carboxylic acid anhydrides such as anhydrides (lower) of alkanoic acids, for example, acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methylcyclohexane, or mixtures of these solvents, for example, aqueous solutions, if in o the writing of methods does not specify otherwise. Such solvent mixtures can also be used in processing, for example, by chromatography or partitioning.

The compounds, including their salts, can also be obtained as hydrates or their crystals can, for example, include a solvent used for crystallization. Different crystal forms may be present.

The present invention also relates to such variants of the method, in which the compound obtained at any stage as an intermediate product is used as the starting substance, and the remaining stages of the method are carried out, or in which the starting substance is formed under the conditions of the reaction or is used in the form of a derivative, for example , in a protected form or in the form of a salt, or a compound obtained by the method proposed in this invention, is obtained under the conditions of the reaction and then treated with ip 5ish.

All starting materials, structural fragments, reagents, acids, bases, dehydrating reagents, solvents and catalysts used for the synthesis of the compounds proposed in this invention are commercially available or can be obtained by methods of organic synthesis known to one of ordinary skill in the art engineering (Neubrep-

Mu/euy! 4" Ed. 1952, Method of Ogdapis zupipevziv, Tpiyete, Moishte 21).

In another embodiment, the present invention relates to the following intermediate product 75.6:

IF) IF) in Kh

H 6)

SI

In another embodiment, the present invention relates to an intermediate product of the following formula described in the synthesis scheme C: (6) (6)

NM Shchi in (6)

F Tue

X wherein K", BE", n and X are as described in the present invention. It is better if, in the indicated intermediate, K" is independently selected from the group that includes: Ci-Cv-alkyl-, n is 0 and

X stands for halogen. In a preferred embodiment, the intermediate has the following stereochemical configuration:

AND

(c) (6) sec

H

Abbreviations

Ac acetyl

AcOeEg ethyl acetate

AcOnH acetic acid

IAT-MS mass spectrometry with ionization at atmospheric pressure

VNz.THF complex borane - tetrahydrofuran

Vos tert-butoxycarbonyl

The saline solution is saturated with sodium chloride solution at CT

You are tert-butyl

CO2 deuterated chloroform

СозОО deuterated methanol

Celite is a brand of filter material based on kieselguhr of Seyye Sogr. (Whoops

Mipegai!5 Ips.), zapia Vagraga, SA, OBA

СнеОЙиз chloroform

С52бО»z cesium carbonate

Si! (medicinal iodide)

(SygO, oxide of copper)

DCM dichloromethane

DIPEA diisopropylethylamine

DMAP 4-dimethylaminopyridine

DME 1,2-dimethoxyethane

DMF M,M-dimethylformamide

DMSO dimethylsulfoxide

From DTAD di-tert-butylazodicarboxylate equiv. equivalent

EgHetil

EM triethylamine

ESO diethyl ether

EUOH ethanol

Ee metallic iron ggram(s) h. hours)

GATU O-(7-azabenzotriazol-1-yl)-M,M,M",M'-tetramethyluronium hexafluorophosphate

NSI hydrogen chloride

NMO: nitric acid

HPLC high-performance liquid chromatography

He25O» sulfuric acid and Rg isopropyl

K»COz potassium carbonate

KOH potassium hydroxide

KzPOx potassium phosphate

LC-MS liquid chromatography - mass spectroscopy

I IVNa»e lithium borohydride

PON lithium hydroxide

M molar concentration

Me methyl

Mesnm acetonitrile mg milligram(s)

Me! methyl iodide

Meon methanol waves. minute(s) ml milliliter (milliliters) mmol millimole (millimoles)

MpoO" manganese oxide (IM)

MS mass spectrometry

Sodium borohydride is sodium cyanoborohydride

Mavn(OAc) with sodium triacetoxyborohydride

MagSO: with sodium carbonate man sodium hydride

Mansoz sodium bicarbonate

Makmz sodium azide maoskm sodium cyanate maon sodium hydroxide

Ma»5O» sodium sulfate

MN:" with ammonia

MNASI ammonium chloride

MMM 4-methylmorpholine

NMR nuclear magnetic resonance

PDH pyridinium dichromate

Ra/C of palladium on charcoal

Rasig(PPz)» dichlorbis(triphenylphosphine)-palladium(III) 0) RDAI(PPz)4 tetrakis(triphenylphosphine) palladium

RI phenyl

RPRiz triphenylphosphine

PTSK p-toluenesulfonic acid

Ag retention coefficient

CT room temperature 5IO» silicon dioxide

ZpPSi2 stannous chloride)

ZPS stannous chloride (IM)

OSI" thionyl chloride

TVOM5SI tert-butyldimethylsilyl chloride

TBME tert-butyl dimethyl ether

TFC trifluoroacetic acid

THF tetrahydrofuran

TO" titanium ethoxide (IM)

TI(OIRHg)" titanium isopropoxide (IM)

TLC thin-layer chromatography

The retention time is running out

General techniques

Research with the help of "H-NMR was carried out on the spectrometer VgyKeg Shpgaznpivia "M 400 (400

MHz), Vgykeg ShPygazpiv(y"M 600 (600 MHz) or 500 MHz OBEH Vgykeg Sguorgobe (500 MHz) with or without the use of trimethylsilane as an internal standard. Chemical shifts (value 5) are given in ppm towards the weak fields from tetramethylsilane, the spin-spin interaction constants (U) are given in Hz, the splitting of bands in the spectra is marked as singlet (5), doublet (a), doublet of doublets (ad), triplet (), quadruplet (e), multiplet or more overlapping signals (t), broad signal (bi) Solvents are indicated in parentheses.

Purification by means of preparative HPLC was carried out using optimized elution in the gradient mode (CH3CM/water with the addition of 0.195 TFC) using a Preparative HPLC UmMaieg5 HPLC system equipped with a UV detector UmMaieg5 2487 Yutsai! 9

Arzograpse UOeiesiog, MS-detector UmMaieg5 tisgota5z520O and columns with reverse phase 60 0 ByupEiige"M Rger, C18 OVO, 100x30 mm, 5 μm, or 100x19 mm, 5 μm. Usually, after lyophilization, the products were obtained in the form of salt with TFC.

TLC was performed using pre-coated silica gel 60 Eg54 glass plates (Megsk, Yuaptviaidi, Septapu) using appropriate solvent systems. Visualization was usually performed with UV radiation (254 nm).

LC-MS spectra were recorded on an Umaieg5 2795 AIShapse NT device with a Bipiige"M C18 column, 4.6x20 mm, 3.5 μm with elution in a linear gradient mode from 5 to 100 55 Mesm (- 0.1 95 TFC) in water ( - 0.1 95 TFA) in 4 minutes at a flow rate equal to 3 ml/min, at 45 C, during electrospray ionization in the positive ion mode (Mistotav5 70 detector).

IAT-MS spectra were recorded on an Adiyepi 1100 device with an Avsepiiz Ehrgez5e"M C18 column, 2.1x30 mm, 2.7 μm with elution in a linear gradient mode from 2 to 98 55 Mesm (- 0.04 95 formic acid) in water ( z 0.05 96 formic acid z 0.05 9o 7.5 M aqueous solution of ammonium acetate) in 1.7 minutes at a flow rate equal to 1.2 ml/min. at 50 "C during ionization by electrospray in the mode of positive and /or negative ions (detector 2MO).

IM-AANI" and |M-NI mean monoisotopic molecular masses.

The retention time for HPLC (not) is given in minutes and was recorded under the following conditions:

The retention time for system A (Aine) was measured on the Umayeg5 2795 AIPSapse NT device, equipped with a detector on a Umayeg5 2996 photodiode matrix (ROA MahRio detection at a wavelength equal to from 210.0 nm to 400.0 nm) and a Misgotav55 20 detector (detection at electrospray ionization in the mode of positive ions) when eluting in a linear gradient mode from 5 to 100 95 MesSM (-- 0.1 95 TFC) in water (also 0.1 95 TFC) in 4 minutes. at a flow rate equal to 3 ml/min., at 45 "C. A Z!ypiige"M C18 column, 4.6x20 mm, 3.5 μm, was used.

The retention time for the B system (Zive) was measured on a UMaieg5 2695 AIShapse NT device, equipped with a detector on a Umaieg5 2996 photodiode matrix (ROA MahRioi detection at a wavelength equal to 210.0 nm to 400.0 nm) during elution in a linear gradient mode from 5 to 100 95 Meskm in water (also 0.1 95 TFC) in 4 minutes. at a flow rate equal to 3 ml/min., at "C. We used a Zipiige"M C18 column, 4.6x20 mm, 3.5 μm.

The retention time for system C (Cine) was measured on an Adiyepi 1100 instrument equipped with a detector on a photodiode matrix Adiyepi 1100 z5egiez (ROA MakhRIoOi, detection at length

From a wave equal to 210.0 nm to 400.0 nm) when eluting in the isocratic mode 40 96 Mescm in water (and 5 mM ammonium formate) for 1 min., then in the gradient mode from 40 to 60 956 mMescm in water ( and 5 mM ammonium formate) in 7 min. at a flow rate equal to 2 ml/min. at 40 "s.

We used a Zipiige"M C18 column, 4.6x50 mm, 5 μm.

The retention time for the O system (biwe) was measured on an Umayeg5 device equipped with a 35 Umayeg5 Asdiyu ORI S ROA detector (detection at a wavelength equal to from 120 nm to 1200.0 nm) during elution in the isocratic mode for 0-1.40 minutes. from 2 to 98 95 MesMm (0.04 956 HCOOH) in water (40.05 926HCOOH-O.05 95 ammonium acetate), 1.40-2.15 min. 98 55 MesM (0.04 95 NCOOH), 2.15-2.19 min. from 98 95 to 2 95 MesM (-0.04 956 NCOOH), then 2.19-2.20 min. 2 95 Mesm (--0.04 95

NCOOH) at a flow rate equal to 1.2 ml/min. at 50 "C. An Asdiyu column was used

H55 TK, 2.1x50 mm, 1.8 μm.

Retention time for system E (Rine) was measured on an Adiyepi 1100 instrument equipped with a detector on a diode matrix Adiyepi 1100 5egieez (DDM, detection at a wavelength equal to 215 nm) when elution in the isocratic mode for 0-5.0 minutes. from 2 to 100 95 Mesm (0.1 95 TFC) in water (40.1 95 TFC), 5.0-6.5 min. 100 95 MesM (0.1 95 TFC), then 6.5-7.0 minutes. from 100 95 to 2 95

Mesm (40.1 95 TFC) at a flow rate equal to 1.0 ml/min. at 30 "C. A Misieoviya 100-3 C18 НО column, 4.0x70 mm, was used.

The retention time for the E (Rivet) system was measured on an Umayeg5 instrument equipped with a detector

Umayeg5 Asdiyu ORI S ROA (ROA MaFxRioi detection at a wavelength equal to from 210.0 nm to 400.0 nm)) when elution in the isocratic mode in 0.1-1.60 minutes. from 2 to 100 55 MesM (0.05 95

HSOOH) in water (40.05 926HSOOH), 1.60-2.0 min. 100 95 MesM (0.05 95 NCOOH), then 2.0-2.0 min. from 100 95 to 2 95 MesM (40.05 95 HSOOH) at a flow rate equal to 1.0 ml/min. at 40 "C. An Asdiyu VEN C18 column, 2.1x50 mm, 1.7 μm, was used.

The retention time for system C (Cine) was measured on an Adiyepi 1100 instrument equipped with an Adiyepi 1100 diode matrix detector (DDM, detection at a wavelength equal to 215 nm) with elution in the isocratic mode for 0-7.0 minutes. from 2 to 100 95 MesM (0.1 95 TFC) in water (40.1 95 TFC), 7.0-9.0 min. 100 95 MesM (0.1 95 TFC), then 9.0-10.0 minutes. from 100 95 to 2 95

Mesm (40.1 95 TFC) at a flow rate equal to 1.0 ml/min. at 30 "C. A Misieovia 100-3 C18 HO column, 4.0x125 mm (Maspegueu-Madeii) was used.

The retention time for system H (Nine) was measured on the Umayeg5 device equipped with the Umayeg5 Asdiyu ORI S ROA detector (detection at a wavelength equal to from 120 nm to 1200.0 nm) during elution in the isocratic mode for 0-3.0 minutes. from 10 to 95 95 MesMm (0.1 95 HCOOH) in water (40.1 9HCOOH), 3.0-4.0 min. 9595 Mesm (0.195 NCOOH) at a flow rate equal to 1.2 ml/min. at 50 "C. An Asdiyu H5Z TZ column 2.1x50 mm, 1.8 μm was used.

Hold time for the system | (Yave) was measured on an Adiyepi 1100 device equipped with an Adiyepi 1100 z5egivez diode array detector (DDM, detection at a wavelength equal to 215 nm) during elution in the isocratic mode for 0-8.0 minutes. from 2 to 100 95 Mesm (0.1 95 TFC) in water (10.1 95 TFC), 8.0-10.0 min. 100 95 Mesm (0.1 95 TFC), 10.0-11.0 min. from 100 95 to 2 95

Mesm (-0.1 95 TFC), then 11.0-13.0 min. 2 95 MesSM (-0.1 95 TFC) at a flow rate equal to 2.0 ml/min. at 25 "C. A Spgotoiy Repoptapse KR-18ee column, 4.6x100 mm (MegskK) was used.

The retention time for the system ./ (yve) was measured on a Tpegto Rippidap instrument equipped with a detector on a photodiode matrix M 6000 R (DDM, detection at a wavelength equal to 218 nm) when elution in the isocratic mode for 0-8.0 minutes. from 2 to 100 55 Mesm (0.1 95

NCOOH) in water (140.1 95 NCOOH), 8.0-10.0 minutes. 100 95 Mesm (0.1 96 NCOOH), then 10.0-11.0 min. from 100 95 to 2 95 MesCM (-0.1 96 NCOOH) at a flow rate equal to 2.0 ml/min. at 30 "C. A Spgotoiy Regpogtapse KR-18e column, 4.6x100 mm (MegekK) was used.

The retention time for the K (Kine) system was measured on an Adiyepi 1100 instrument equipped with an Adiyepi 1100 diode matrix detector (DDM, detection at a wavelength equal to 215 nm) when elution in the isocratic mode for 0-7.0 minutes. from 2 to 100 95 Mesm (0.1 95 TFC) in water (40.1 95 TFC), 7.0-9.0 min. 100 95 MesM (0.1 95 TFC), then 9.0-10.0 minutes. from 100 95 to 2 95

Mesm (40.1 95 TFC) at a flow rate equal to 1.0 ml/min. at 30 "C. A Misieoviya 100-3 C18 HO column, 4.0x125 mm, was used.

The retention time for the Y (Chve) system was measured on an Adiyepi 1100 device equipped with an Adiyepi 1100 diode array detector (DDM, detection at a wavelength equal to 215 nm) during elution in the isocratic mode for 0-5.0 minutes. from 20 to 100 55 Mesm (0.1 95 TFC) in water (10.1 95 TFC), 5.0-6.5 min. 100 95 MesM (0.1 95 TFC), then 6.5-7.0 minutes. from 100 95 to 20 95

Mesm (40.1 95 TFC) at a flow rate equal to 1.0 ml/min. at 30 "C. A Misieoviya 100-3 C18 HO column, 4.0x125 mm, was used.

The retention time for the M (Mine) system was measured on an Umayeg5 instrument equipped with

With the Umayeg5 Asdiyu ORI S ROA detector (detection at a wavelength equal to from 120 nm to 1200.0 nm) during elution in the isocratic mode in 0-1.40 minutes. from 2 to 98 55 Mesm (0.04 95

HCOOH) in water (-0.05 926HCOOH-O.05 95 ammonium acetate), 1.40-2.15 minutes. 98 95 MesM (0.04 95

NSOOH), 2.15-2.19 minutes. from 98 95 to 2 95 MesmM (-0.04 96 NCOOH), then 2.19-2.20 min. 2 95

Mesm (-0.04 95 NCOOH) at a flow rate equal to 1.2 ml/min. at 50 "C. An Asdiyu He5 TZ column, 2.1x50 mm, 1.8 μm, was used.

The retention time for system M (Mne) was measured on an Adiyepi 1100 device equipped with a detector on a diode matrix Adiyepi 1100 5egieez (DDM, detection at a wavelength equal to 215 nm-350 nm) when elution in the isocratic mode for 0-1.40 minutes. from 2 to 9895 Mesm (0.04 95 HCOOH) in water (10.5 976HCOOH--0.05 95 ammonium acetate), 1.40-2.15 min. 9895 Mesm (0.04 95 NCOOH), 2.15-2.19 min. from 98 95 to 2 95 MesM (40.04 95 NCOOH), then 2.19-2.20 min. 295 MesmMm (-0.0495 NCOOH) at a flow rate equal to 1.2 ml/min. at 50 b.

An Asepiiz Ehrge55 C18 column, 2.1x30 mm, 2.7 μm, was used.

The retention time for the O system (Oine) was measured on a Umayeg5 2690 device equipped with a detector on a Umayeg5 996 z5zegieh photodiode matrix (detection at a wavelength equal to from 215 nm to 254 nm) during elution in the isocratic mode for 1.0-11.0 waves . from 2 to 100 95

Mesm (0.1 95 TFC) in water (40.1 95 TFC), then 11.0-13.0 minutes. 100 95 MesSm (-0.1 95 TFC) at a flow rate equal to 1.0 ml/min. at 35 "C. The SoYishtp company column was used

Epaipeegipo, Ips., Mayih C18 4.6x150 mm (I 014205), 3.0 μm.

Examples:

The following examples are intended to illustrate the present invention without limiting its scope. It should be noted that in some cases the compounds indicated as intermediates are also compounds of formula II proposed in the present invention (it should also be noted that these compounds are described by formula 1/). The names of the compounds of all examples or intermediate products were generated automatically using the AshoMot 2000 program of the IzizUOgam company. Unless a specific source is indicated, then the starting materials are obtained from conventional suppliers such as

Zidta-Aiagisn, RiyKa, AIrpa Aezag, Megsk, or from specially specified suppliers.

Example 1: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

c) c) I

C, vva m (o)

Intermediate 1.3 (41.4 mg, 0.16 mmol) was added to a solution of intermediate 1.4 (40 mg, 0.16 mmol) in DCM (1 mL) while the resulting yellow suspension was stirred for 1 h.

Methanesulfonic acid (0.10 mL, 1.6 mmol) was added dropwise and the mixture was further stirred for 15 min. at CT. The reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse-phase preparative HPLC (Umlaseg5 system) to give the desired compound (TFA salt, 10 mg, 0.017 mmol, 10 95). TOP:

Ave-2.03 min.; IAT-MS: t/: 480.6 MANI"; "H NMR (400 MHz, SOSIv): 0.93-1.03 (21, 9-7.5, ZN, mixture of diastereoisomers), 1.25-1 ... ), 3.86-3.95 (t, 4H), 4.17-4.26 (t, 1H), 5.74 (5, 1H), 6.68-6.74 (t, 2H), 7.06-7.11 (t, 2H), 7.18-7.24 (t, 2H), 7.26-7.32 (t, AN).

Intermediate 1.1: 1|4-(BA)-tert-butoxy)-3-methoxyphenyl|acetic acid ethyl ester. -lo (F) se o7-

(5)-Butan-2-ol (0.37 mL, 4, 0 mmol), PP3 on the substrate (content is 1.52 mmol/g, 4.38 g, 6.66 mmol) and DTAD (1.15 g, 5.0 mmol).

The reaction mixture was shaken at RT for 3 h, then filtered and the resin was washed with DCM. The filtrate was evaporated to dryness and the resulting residue was purified by Sotbri-RIazpy column chromatography. Sotrapiop "M (Izso Ips.) (ZiOg; gradient elution, heptane/tBME 95:5 -» 1:11) and obtained the desired compound (818 mg, 3.07 mmol, 92 95) in the form of a colorless oil. TLC : Ke-0.85 (heptane/"DHM/TBME 1:1:2); TOP: Vive-2.46 min.; IAT-

MS: t/2 267.2 |MANI; "H NMR (400 MHz, SOSIz): 1.00 (y, 9-75, ZN), 1.28 (Yi, 9-7.1, ZN), 1.33 (y, 9-61, ZN) , 1.60-1.70 (t, 1H), 1.77-1.89 (t, 1H), 3.56 (5, 2H), 3.86 (5, ЗН), 4.17 (ad , 9-71, 2H), 4.25 (sextet, U-6.1, 1H), 6.79 (ad, 9U-8.3, 2.0, 1H), 6.83-6.87 ( t, 2H).

Intermediate 1.2: 14-(B8)-tert-butoxy)-3-methoxyphenyl|-acetic acid.

Koo) no (0); this is me

A mixture of intermediate 1.1 (818 mg, 3.07 mmol) in EUN (8 mL) and water (2 mL) was treated with GION monohydrate (387 mg, 9.21 mmol) at RT and stirred for 1 h. The reaction mixture was neutralized by adding 0.5 M HCl in water, then extracted with

DXM. The organic fraction was dried over Ma25O:, filtered and evaporated to dryness to give the desired compound (740 mg, 3.07 mmol, quantitative yield) as a yellow oil, which was used in the next step without further purification. TOP: Vivea-1.80 min.; IAT-MS: t/2 237.2 |M-NI; "H NMR (400 MHz, SOSIv): 1.00 (1, U-7.5, ЗН), 1.33 (а, 9-61, ЗН), 1.58-1.70 (t, 1Н) , 1.77-1.89 (t, 1H), 3.60 (5, 2H), 3.86 (5, ЗН), 4.21-4.31 (t, 1H), 6.78-6 ,88 (t, ZN).

Intermediate 1.3: 14-((B)-tert-butoxy)-3-methoxyphenyl|-acetyl chloride.

SI (c)

Ko o7-

Oxalyl chloride (0.2 ml, 2.3 mmol) and a catalytic amount of DMF (0.012 ml , 0.16 mmol). The reaction mixture was stirred at 0 "C for 30 minutes, then evaporated to dryness in vacuo to give the crude desired compound (401 mg, 1.56 mmol, quantitative yield) as an orange oil, which was used in the next step without additional cleaning.

Intermediate product 1.4: M-(1-(4-Chlorophenyl)-meth-(E)-ylidene|-M';M'-dimethylbenzene-1,4-diamine. (o) st

M

A catalytic amount of ASON (0.063 ml, 1.1 mmol).

The reaction mixture was refluxed and stirred for 14 h. and during this time sedimentation took place. After cooling to RT, the suspension was filtered and washed with heptane. The solid was collected and dried under high vacuum to give the title compound (2.09 g, 8.08 mmol, 73 95) as a tan solid. "H NMR (400 MHz,

SObsiz): 3.01 (in, 6H), 6.78 (t, 2H), 7.29 (t, 2H), 7.44 (t, 2H), 7.84 (t, 2H), 8, 49 (5, 1H).

Example 2.

Compounds 2aa-25| was obtained similarly to the preparation in example 1 from various phenylacetyl chlorides (obtained similarly to the preparation of intermediate product 1.3) and imines (obtained from commercially available aldehydes and anilines similarly to the preparation of intermediate product 1.4).

Me | Structure Name/VvECH/MS about on

M Fi cancer. . and re o 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6,7-2aa-o diethoxy-1,4-dihydro-2H-isoquinolin-3-one.

Ff TOP: Chvea-1.88; IAT-MS: t/2 465.3 (MANI. (9) o on

Mine - - -

SU o 1-(3,4-Difluorophenyl)-6,7-diethoxy-2-(4-methoxy-phenyl)-2arzo 1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chvea-2.51; IAT-MS: t/2 454.3 (MANI.

IS

And c) because i

Mine - - -

SU o 4-(11-(4-chlorophenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-gas ms isoquinolin-2-yl|-benzonitrile.

Ff VERH: Chvea-2.60; IAT-MS: t/2 4471 (MANI. (o)

Me | Structure Name/ECP/MS o na

MMC aa. . - - roi o 1-(4-chlorophenyl)-6,7-diethoxy-2-(5-methyl-pyridin-2-yl)-2a to 1,4-dihydro-2H-isoquinolin-3-one.

Ff VERH: Chvea-2.67; IAT-MS: t/2 437.2 (MANI. (c) (6) by c

CO 0775 000) 2-Benzofuran-5-yl-1-(4-chlorophenyl)-6,7-diethoxy-1,4-2a dihydro-2H-isoquinolin-3-one.

Ff VERH: Chve-2.67; IAT-MS: t/ 462.1 MANI. (9) (6) bi ro 7 1-(4-chlorophenyl)-6,7-diethoxy-2-(b-methyl-pyridin-3-yl)-2at dy 1,4-dihydro-2H-isoquinoline- 3-on

F TOP: Thu-1.72; IAT-MS: t/: 437.2 MANI. (o) --oO would be in su o 1-(4-chlorophenyl)-2-(4-dimethylamino-2-methoxy-phenyl)-2ap-e 6,7-diethoxy-1,4-dihydro-2H-isoquinoline -3-one

F TOP: Chves-1.96; RH-MS: t/l 496.2 MANI". (9) (6) would in

In 0775 0 |4-(4-Chlorophenyl)-6,7-diethoxy-2-(4-morpholin-4-2-ylphenyl)-1,4-dihydro-2H-isoquinolin-3-one. at. Ff TOP: Chve-2,33; RH-MS: t/: 507.2 MANI". (9) --0 because in

SU 0775 0 |1-(4-Chlorophenyl)-6,7-diethoxy-2-(2-methoxy-4-morpholine g 4-ylphenyl)-1,4-dihydro-2H-isoquinolin-3-one. at. Ff VERH: Chve-2,36; RH-MS: t/ 537.2 MANI". (9) about Po

MF A 7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-2-(3,4-hydrodimethylphenyl)-6b-methoxy-1,4-dihydro-2H-isoquinoline-3 - Mr.

Ff VERH: Chve-2.96; IAT-MS: t/ 465.6 MANI. (o) oh lo

M АЩФ ro 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(2,4-yl)dimethylphenyl)-6-methoxy-1,4-dihydro-2H-isoquinoline-3 - Mr.

Ff VERH: Chvea-2.97; IAT-MS: t/: 465.6 (MANI. (o) bo

Me | Structure Name/EPCH/MS -e (6) and J

M ia that 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(2-2α5 methoxy-5-methylphenyl)-1,4-dihydro-2H-isoquinoline-3 - he

Ff TOP: AMne-2.86; IAT-MS: t/; 481.9 (MANI). (o) (c) o.

M ia o 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-2-hydroxy-2-methylphenyl)-1,4-dihydro-2H-isoquinoline- 3-on o FI TOP: Chne-2.80; IAT-MS: t/; 481.6 (MANI. (o) o Po

Miia o 7-(B)-tert-butoxy)-2-(2-chloro-4-methylphenyl)-1-(4- chlorophenyl)-6b-methoxy-1,4-dihydro-2H-isoquinoline-3 - he

F TOP: Aive-3.00; IAT-MS: t/» 485.9 MANI". (o)

Zo (6) and Y

M Shchi A 7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(2,4-isogam)dimethoxyphenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline- - W-he.

Ff VERH: Chve-2.74; IAT-MS: t/z: 497.7 MANI.

SI and Posi M Fi At 7-(H)-tert-butoxy)-1-(4-chlorophenyl)-2-(3,4-. gam in iv) dichlorophenyl)-6-methoxy-1,4-dihydro -2H-isoquinoline-3- on.

SI

F TOP: Thu-3,14; IAT-MS: t/2 506.0 (MANI. (o) and Po

M ia o 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-p-2ach U tolyl-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Aive-2.88; IAT-MS: t/» 450.2 MANI". she gau C (c) dimethoxyphenyl)-6-methoxy-1 4-dihydro-2H-isoquinoline- - Z-one (c)

FI TOP: Thu-2.59; IAT-MS: t/ 496.2 MANI.

SI

Me | Structure Name/ECP/MS o Po

M i o 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(1-2a7 methyl-1H-indazol-5-yl)-1,4-dihydro-2H -isoquinolin-3-one. shk FI TOP: Chva-2.53; IAT-MS: t/z: 490.1 (MANI. me (v) (v) o.

M fi o 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-2ra SU pyrrolidin-1-ylphenyl)-1,4-dihydro-2H-isoquinoline- 3-on

Phi F TOP: Chne-2.73; РХ-МС: t/» 5061 MANI". (in) and by

M Cro 1 -(4-Bromophenyl)-7-(H)-tert-butoxy)-2-(4-ovvry (c) dimethylaminophenyl)-6b-methoxy-1,4-dihydro-2H-m isoquinoline- 3-on

Ff VERH: Chva-2,10; RH-MS: t/z 523.4 MANI".

Oh, that's it

M Shchyro 7-(H)-tert-butoxy)-1-(4-chloro-2-methylphenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- - isoquinolin-3-one.

FI TOP: Chva-2,13; RH-MS: t/2 493.5 MANI. (c) and by

M Shro 7-(H)-tert-butoxy)-1 -(4-chloro-3-fluorophenyl)-2-(4-fluoro-9)dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- - isoquinolin-3-one.

F TOP: Thu-2,11; RH-MS: t/z 497.6 (MANI.

IS

(c) and by

M Cro 7-(H)-tert-butoxy)-1-(4-chloro-3-methylphenyl)-2-(4-orium 9)dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- m isoquinolin-3-one.

F TOP: Chva-2,17; RH-MS: t/z 493.4 MANI". (c) oh that

M Shchyro 7-(H)-tert-butoxy)-1-(4-chloro-3-nitrophenyl)-2-(4- oxy (c) dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H - - isoquinolin-3-one.

FI TOP: Chva-2.08; RH-MS: t/z 524.5 MANI".

MO, (c)

Me | Structure Name/EPCH/MS about lo

M ША 1-(3-Amino-4-chlorophenyl)-7-(H)-tert-butoxy)-2-(4-ovag) rio (c) dimethylaminophenyl)-6-methoxy-1,4-dihydro- 2H- 9 Sh- isoquinolin-3-one.

FI TOP: Thu-1.83; RH-MS: t/z 494 4 MANI".

Mn, (9) --00oO and J

M Tsro 7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-dimethylamino-2-methoxyphenyl)-b-methoxy-1,4-dihydro- - 2H- isoquinolin-3-one.

F TOP: Thu-2,10; RH-MS: t/z 510.4 (MAANI". (9) and Po

M C ro 7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-2bi odimethylamino-2-methylphenyl)-b-methoxy-1,4-dihydro-

Sh- 2H-isoquinolin-3-one.

F TOP: Thu-2.03; RH-MS: t/z 493.2 MANI". (9) --o and Y

M АЩФ КА 7-(H)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(2-ovi in) methoxy-4-morpholin-4-ylphenyl)-1,4-dihydro -2H- ! in isoquinolin-3-one. o F TOP: Thursday-2.50; RH-MS: t/z 551.2 MANI". (9) (1) The desired compound (TSF salt, 21.1 mg, 0.29 mmol, 37 95) was obtained as a colorless solid by reduction of the nitro group of the compound of example 20 (41.5 mg, 0.079 mmol) similarly to the preparation of the intermediate product 3.3. Purification of the crude substance was carried out using preparative reverse-phase HPLC (UmMaiegv system).

Example C: 12-17-(B8)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-5-chlorophenyl )-urea. c) (c) I ore: - M (c)

She t

F MN, (Fi

A mixture of intermediate 3.3 (20 mg, 0.040 mmol) and Maosk (7.9 mg, 0.121 mmol) in ASON (1 mL) and water (2 mL) was stirred at RT for 2 h. The reaction mixture was immediately purified by reverse-phase preparative HPLC (Uas(eg5) system) to give the desired compound (TFA salt, 13.0 mg, 0.020 mmol, 49 95) as a colorless solid. HPLC:

Aive-1.62 min.; LC-MS: t/2 537.4 MANI"; "H NMR (400 MHz, DMSOO-αv): 0.78-0.92 (21.9-7.5, ZN, mixture of diastereomers), 1.04 -1.21 (29, 9-61, ZN, a mixture of diastereoisomers), 1.41-1.67 (t, 2H, a mixture of diastereoisomers), 2.88 (5, 6H), 3.64 (a, 9- 20.8, 1H), 3.73 (v, ЗН), 4.02 (aa, U-20.8, 4.6, 1H), 4.08-4.18 (t, 1H), 6, 15 (Bu. 5., 2H), 6.25 (5, 1H), 6.65-6.73 (t, 2H), 6.79-6.85 (t, 2H), 6.86-6 .93 (t, 2H), 7.01-7.08 (t, 1H), 7.91 (aa, 9-86, 2.2, 1H), 7.74 (aa, 9U-17.6, 2.2, 1H), 7.99-8.05 (t, 1H).

Intermediate 3.1: M-P1-(4-Chloro-2-nitrophenyl)-meth-(E)-ylidene|-M';M'-dimethyl-benzene-1,4-diamine.

SI

99 in MO,

The desired compound (660 mg, 2.17 mmol, 59 95) was obtained as a black solid from

of M,M-dimethylbenzene-1,4-diamine (500 mg, 3.67 mmol) and 4-chloro-2-nitrobenzaldehyde (681 mg, 3.67 mmol) analogously to the preparation of intermediate 1.4. "H NMR (400 MHz, DMSO-α): 2.96 (5, 6H), 6.74-6.80 (t, 2H), 7.26-7.33 (t, 2H), 7.89 (ad, 9U-8.3, 2.0, 1H), 8.16-8.22 (t, 2H), 8.82 (5, 1H).

Intermediate 3.2: 7-(8)-tert-butoxy)-1-(4-chloro-2-nitrophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline-3 - he c) c) I

C, vv - MO, (o)

The desired compound (322 mg, 0.61 mmol, 29 90) was obtained as a brownish solid from intermediate 3.1 (650 mg, 2.14 mmol) and intermediate 1.3 (550 mg, 2.14 mmol) similarly to the preparation in Example 1. Purification of the crude substance was carried out using column chromatography Sotbri-Riazpy Sotrapiop "m (Izso Ips.) (510g; elution in gradient mode, heptane/ltBME 95:5 -» 10095 TBME). TLC: Ke-0.19 (heptane /"DHM/'BME 1:1:2)3; TOP: Java-2.10 min.; RH-MS: t/2 524.3 |MANI; "H NMR (400 MHz, DMSO-α): 0.79-0.91 (21, 957.5, ЗН, mixture of diastereomers), 1.06-1.20 (2a, 9-61, ЗН, mixture of diastereomers ), 1.40-1.67 (t, 2H), 2.87 (5, 6H), 3.68 (a, U-20.8, 1H), 3.77 (5, ЗН), 4, 02-4.17 (t, 2H), 6.42 (ri. 5., 1H), 6.58-6.66 (t, ZH), 6.76-6.84 (t, 2H), 6 .89 (v, 1H), 7.61-7.66 (t, 1H), 7.71 (ad, U-8.6, 2.2, 1H), 7.91 (a, 9-20, 1H).

Intermediate 3.3: 1-(-2-Amino-4-chlorophenyl)-7-((B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6b-methoxy-1,4-dihydro-2H-isoquinoline -3-one c) c) I

SI. in -e MN, (o)

Zo In a sealed reaction flask, a mixture of intermediate 3.2 (322 mg, 0.61 mmol) and Ee (343 mg, 6.1 mmol) in ASON (1.8 mL), water (2.4 mL), and ASOCII ( 0.6 ml) was heated at 110°C and stirred for 1 hour. The suspension was cooled to RT, filtered through a bed of Celite and the solid washed with ASOEL. The filtrate was concentrated in vacuo, the obtained residue was dissolved in ASOEA and washed with 2M MgSO3 in water (2x). The organic phase was dried over NaCl5O, filtered and evaporated to dryness. The obtained crude substance was purified using Sotri-Riavp column chromatography

Sotrapiop "m (Izso Ips.) (BIO; elution in the gradient mode, (heptane/dxM 1:C/TBME, which contains 5 95 7/M MHz in Meon 95:5 -" 4:6) and obtained the desired compound ( 253 mg, 0.51 mmol,

83 95) in the form of a brownish solid. TLC: Ke-0.31 (heptane/:DCM/TBME containing 96 7M MNz in Meon 1:1:2); TOP: Aive-1.87 min.; RH-MS: t/ 494.5 |MANI; "H NMR (400 MHz,

DMSO-аv): 0.81-0.94 (t, ЗН), 1.11-1.22 (29, 9-61, ЗН, a mixture of diastereoisomers), 1.41-1.69 (t, 2Н) , 2.86 (5, 6Н), 3.60 (а, 9-20.5, 1Н), 3.7З (5, ЗН), 4.00 (а, У-20.3, 1Н), 4 .05-4.15 (t, 1H), 5.42-5.48 5 (t, 2H), 6.17 (Bg. 5., 1H), 6.46-6.51 (t, 1H) , 6.54-6.57 (t, 1H), 6.58-6.64 (t, 2H), 6.79 (in, 1H), 6.90-6.99 (t, ЗН), 7 .05 (ai, 9U-8.2, 1.8, 1H).

Example 4: 1-22-(7-(A)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|- 5-chlorophenyl)-3-methylurea. c) (c) vve: - M (c)

M

SU H

- more

Methyl isocyanate (0.045 mL, 0.77 mmol) was added to a solution of intermediate 3.3 (33 mg, 0.067 mmol) and pyridine (0.086 mL, 1.07 mmol) in MesNM (0.5 mL) in portions over 4 hours at RT. The reaction mixture was further stirred at RT for 14 hours, then immediately purified by reverse-phase preparative HPLC (UMaieg5 system) to obtain the desired compound (TSF salt, 28.0 mg, 0.042 mmol, 63 95) as a colorless solid. TOP: "va-1.70 min.; RH-MS: t/: 551.5 |MANI"; "H NMR (400 MHz, DMSO-dv): 0.79-0.91 (21, 9U-7.5, ZN, a mixture of diastereoisomers), 1.04-1.19 (240, 9-61, ZN, a mixture of diastereoisomers), 1.41-1.66 (t, 2H), 2.60-2.66 (t, ЗН), 2.88 (5, 6H), 3.59-3.67 (t, 9U -20.8, 1H), 203.73 (5, ЗН), 3.96-4.13 (t, 2H), 6.24 (5, 1H), 6.28-6.36 (t, 1H ), 6.64-6.72 (t, 2H), 6.79 (y, 9-2.7, 1H), 6.83 (5, 1H), 6.86-6.93 (t, 2H ), 7.01-7.07 (t, 1H), 7.30 (aa, U-8.6, 3.9, 1H), 7.69 (aa, 9U-19.3, 2.2, NN), 7.96-8.03 (t, 1Н).

Example 5: M-2-(7-(A)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|- 5-chlorophenyl)-acetamide. (c) (c) I

Fo

M va (Fi

To a mixture of intermediate 3.3 (20 mg, 0.040 mmol) and pyridine (0.010 mL, 0.12 mmol) in

Acetyl chloride (0.006 ml, 0.081 mmol) was added to MesmM (0.5 ml) at RT. Reaction mixture

The mixture was stirred for 14 h, then immediately purified by preparative reverse-phase HPLC (Umayeg5 system) to obtain the desired compound (salt with TFA, 13.1 mg, 0.020 mmol, 50 95) as a colorless solid. TOP: "vea-1.71 min.; LC-MS: t/: 536.3

IMANI"; "H NMR (400 MHz, DMSO-α): 0.79-0.92 (21.9-7.5, ZN, mixture of diastereoisomers), 1.04-1.19 (29.9-61 , ЗН, a mixture of diastereoisomers), 1.42-1.65 (t, 2Н), 1.90-1.99 (t, ЗН), 2.90 (5, 6Н), 3.59- 3.67 ( t, 1H), 3.76 (a, 9U-1.5, ЗН), 3.96-4.05 (t, 1H), 4.05-4.17 (t, 1H), 6.34 ( 5, 1H), 6.67-6.76 (t, 2H), 6.78-6.89 (t, 4H), 7.15-7.26 (t, 2H), 7.40-7, 46 (t, 1H), 9.32 (a, 9-17.1, 1H).

Example 6: 7-(B)-tert-butoxy)-1-(4-chloro-2-dimethylaminophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline-3- he

c) (c) And already M (Fi

ASON (0.017 ml, 0.29 mmol), formaldehyde (37 9o in water, 0.013 ml, 0.18 mmol) and

Mavn(OAc)z (62.2 mg, 0.29 mmol). The reaction mixture was stirred for 4 h, then Mag2SbOz 2 M in water was added, the two phases were separated, and the aqueous layer was further extracted with DCM (2x). The combined organic fractions were evaporated to dryness and the resulting crude substance was purified by reverse-phase preparative HPLC (Umayegv system) to give the desired compound (TSF salt, 18 mg, 0.024 mmol, 41 95) as a colorless solid. TOP: non-2.17 min.; RH-MS: t/2 522.6 MANI; "H NMR (400 MHz, DMSO-dv): 0.79-0.91 (21, 9U-7.5, ZN, a mixture of diastereoisomers), 1.04-1.19 (240, 9-61, ZN, mixture of diastereoisomers), 1.42-1.66 (t, 2H), 2.29-2.37 (t, 6H), 2.85 (5, 6H), 3.62 (y, 9U-20.8 , 1H), 3.73 (in,

ZN), 4.02-4.16 (t, 2H), 6.44 (ru. 5., 1H), 6.62-6.71 (t, 2H), 6.78-6.91 (t , 4H), 7.11-7.16 (t, 1H), 7.21-7.25 (t, 1H), 7.39 (a, U-8.3, 1H).

Example 7. 2-(17-(A)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-5- Chlorbenzamide. (c) (c) I vo or (Fi

To a solution of intermediate 7.4 (30 mg, 0.057 mmol) in DMF (0.3 mL) was sequentially added MNASI (15.3 mg, 0.29 mmol), EM (0.024 mL, 0.17 mmol), and GATU (28, 4 mg, 0.075 mmol). The reaction mixture was stirred at RT for 1 h, then immediately purified by reverse-phase preparative HPLC (Ulaieg5 system) to obtain the desired compound (TSF salt, 19.3 mg, 0.030 mmol, 53 95) as a colorless solid. TOP:

Aive-1.65 min.; LC-MS: t/2 522.4 MANI"; "H NMR (400 MHz, DMSO-α): 0.80-0.92 (21, 9-73, ZN, mixture of diastereomers), 1.08-1 ,21 (24, 9-61, ZN, a mixture of diastereoisomers), 1.42-1.66 (t, 2H), 2.87 (5, 6H), 3.64 (y, 9-20.5, 1H ), 3.73 (5, ZN), 4.05-4.16 (t, 2H), 6.61-6.68 (t, 2H), 6.72-6.75 (t, 1H), 6.78-6.85 (t, ZN), 7.17 (in, 1H), 7.39-7.42 (t, 1H), 7.44-7.49 (t, 1H), 7, 50-7.54 (t, 1H), 7.55-7.81 (t, 1H), 7.77-7.84 (t, 1H).

Zo Intermediate product 7.1: Methyl ether of 5-chloro-2-formylbenzoic acid. c) (c)

SI about

Mei (0.41 ml , 6.5 mmol). The reaction mixture was stirred for 4 h, then diluted with ESO and washed with water (2x).

The organic layer was dried over MgSO 4 , filtered and evaporated to dryness to afford the crude title compound (700 mg, 3.52 mmol, 65 95) as a pale yellow solid,

which was used without additional purification. TOP: "Chvne-1.84 min.; RH-MS: t/7 199.3

IMANIE "H NMR (400 MHz, DMSO-av): 3.91 (5, ЗН), 7.84-7.94 (t, ЗН), 10.33 (5, 1Н).

Intermediate 7.2: 5-chloro-2-I(E)-4-dimethylamino-phenylimino|-methyl)-benzoic acid methyl ester.

SI m oto in

The desired compound (653 mg, 2.06 mmol, 50 95) was obtained as a black solid from

of M,M-dimethylbenzene-1,4-diamine (555 mg, 4.08 mmol) and intermediate 7.1 (810 mg, 4.08 mmol) analogously to the preparation of intermediate 1.4. "H NMR (400 MHz, DMSO-α): 2.94 (in, 6Н), 3.89 (5, НН), 6.74-6.79 (t, 2Н), 7.23-7.29 (t, 2H), 7.74 (ad, 9-8.4, 2.1, 1H), 7.684 (a, 9-22, 1H), 8.15 (a, 9-8.6, 1H) , 9.03 (5.1H).

Intermediate 7.3: 2-(7-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl| -o-chlorobenzoic acid. o o va and o sr (Fi

The desired compound (537 mg, 1.0 mmol, 48 95) was obtained as a brownish solid from intermediate 7.2 (653 mg, 2.06 mmol) and intermediate 1.3 (530 mg, 2.06 mmol) similarly to the preparation in Example 1. Purification of the crude substance was carried out using column chromatography Sotbri-Riazpy Sotrapiop "m (Izso Ips.) (510g; elution in gradient mode, (heptane/DxM 1:C/TBME 95:5 -» 3:7). TLC: Ke-0.20 (hepgan/"DHM/TBME 1:1:2); HPLC: Jave-2.07 min.; LC-MS: t/2 537.4 MANI; "H NMR (400 MHz, DMSO- av): 0.78-0.91 (21, 957.3, ZN, mixture of diastereomers), 1.04-1.18 (2a, 9-61, ZN, mixture of diastereomers), 1.40-1.68 (t, 2H), 2.85 (5, 6H), 3.67 (y, 9U-21.0, 1H), 3.73 (5, ЗН), 3.76 (5, ЗН), 3, 99-4.09 (t, 1H), 4.14 (y, y-21.0, 1H), 6.54-6.61 (t, 2H), 6.65-6.69 (t, 1H ), 6.71-6.77 (t, 2H), 6.80-6.84 (t, 1H), 6.86 (5, 1H), 7.51 (da, 9-8.6, 2 ,4, 1H), 7.55-7.62 (t, 2H).

Intermediate 7.4: 2-(7-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-5 --chlorobenzoic acid. at 5

S I 07-h o (Fi

A mixture of intermediate 7.3 (100 mg, 0.19 mmol) and GION monohydrate (39.1 mg, 0.93 mmol) in ME (1 mL) and water (0.5 mL) was heated at 50 °C and stirred for 3 h hours

The reaction mixture was cooled to RT, concentrated in vacuo, diluted with water and

Zo was neutralized by adding 2 M HCl in water (0.47 mL). The resulting suspension was extracted with DCM (3x) and the combined organic fractions were dried over Mag25O4, filtered and evaporated to dryness to afford the crude title compound (87.5 mg, 0.17 mmol, 90 95) as a tan solid, which was used at the next stage without additional purification. TOP: "Chve-1.78 min.; LC-MS: t/2 523.5 MANI; "H NMR (400 MHz,

DMSO-аv): 0.78-0.91 (21, 9U-7.3, ZN, mixture of diastereomers), 1.05-1.19 (2a, 9-61, ZN, mixture of diastereomers), 1.38 -1.65 (t, 2H), 2.86 (5, 6H), 3.63-3.70 (t, U-20.8, 1H), 3.75 (5, ЗН), 3.99 - 4.09 (t, 1H), 4.15 (9, 9-21.0, 1H), 6.60-6.67 (t, 2H), 6.76-6.82 (t, 2H) , 6.84 (5, 1H), 6.88 (y, 9-2.9, 1H), 7.03-7.07 (t, 1H), 7.55-7.58 (t, 2H) , 7.65-7.68 (t, 1H), 13.60 (ru. 5., 1H).

Example 8: 7-(B)-tert-butoxy)-1-(4-chloro-2-hydroxymethylphenyl)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline-3- he (c) (c) vo or (Fi

To a solution of intermediate product 7.3 (150 mg, 0.28 mmol) in THF (3 mL) at CT, HIVNa was successively added. (18.3 mg, 0.84 mmol) and Meon (0.034 mL, 0.84 mmol). The reaction mixture was stirred at RT for 3 h, then the reaction was carefully stopped by adding

2 M HCl in water, diluted with DCM and washed with 2 M MgSO3 in water.

The aqueous layer was further extracted with DCM (2x) and the combined organic fractions were dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified using column chromatography Sotbri-Riazpi Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in gradient mode, (heptane/dhm 1:C/TBME, which contains 5 95 7 M MNz in meon 95:5 - » 3:7) and obtained the desired compound (95.2 mg, 0.19 mmol, 67 95) as an off-white solid. MNz in Meon 1:1:2);

TOP: Yave-1.73 min.; RH-MS: t/7 509.4 MANI; "H NMR (400 MHz, DMSO-dv): 0.76-0.88 (21, 97.5, ЗН, mixture of diastereomers), 1.02-1.14 (2a, 9-61, ЗН, mixture of diastereomers ), 1.37-1.65 (t, 2H), 2.85 (5, 6H), 3.67 (y, 9-21.3, 1H), 3.76 (v, ЗН), 3, 99-4.27 (t, 4H), 5.46 (ru. 5., 1H), 6.22 (Bi. 5., 1H), 6.54-6.61 (t, 2H), 6, 69-6.75 (t, 2H), 6.78 (5, 1H), 6.83 (5, 1H), 7.26 (5, ЗН).

Example 9: 1-(2-Aminomethyl-4-chlorophenyl)-7-((B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinoline-3 - he c) (c) ovo o (Fi

In a sealed flask for carrying out the reaction, a mixture of the compound of example 8 (20 mg, 0.039 mmol) and 5OCI»g (0.014 ml, 0.20 mmol) in DCM (0.4 ml) was heated at 40 °C and stirred for 1 hour. the mixture was cooled to RT and evaporated to dryness. To the residue was added a 7 M solution of MH3 in MeOnH (1.0 mL, 7.03 mmol) and the resulting solution was heated at 707C and stirred for 14 h. The reaction mixture was cooled to RT and immediately

Zo was purified by reverse-phase preparative HPLC (Umayeg5 system) to give the desired compound (TFA salt, 6.8 mg, 0.009 mmol, 23 95) as a colorless solid. TOP: Avnes-1.38 min.; RH-MS: t/72 508.3 |MANI; "H NMR (400 MHz, DMSO-α): 0.78-0.90 (21, 9-7.5, ЗН, a mixture of diastereoisomers), 1.03-1.16 (24, 9У-6.1, ЗН, a mixture of diastereoisomers), 1.41-1.62 (t, 2Н), 2.88 (5, 6Н), 3.70 (y, 9-21.0, 1Н), 3.79 (5, ЗН ), 3.88-3.98 (t, 2H), 4.05 (a, 9-20.8, 1H), 4.09-4.21 (t, 1H), 6.20 (Bu. 5 ., 1H), 6.55-6.59 (t, 1H), 6.60-6.65 (t, 2H), 6.70-6.76 (t, 2H), 6.91 (5, 1H), 7.19 (a, 9-8.3, 1H), 7.35-7.41 (t, 2H), 8.13 (ru. 5., 2H).

Example 10: M-2-(7-(A)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|- 5-chlorobenzyl)-acetamide.

c) (c) I vo t F MN o. (Fi

Acetyl chloride (0.007 mL, 0.094 mmol) was added to a mixture of the crude compound of example 9 (24 mg, 0.047 mmol) and E12ZM (0.020 mL, 0.14 mmol) in DCM (0.4 mL) at RT. The reaction mixture was stirred for 30 minutes and evaporated to dryness. The obtained crude substance was purified by reverse-phase preparative HPLC (UmMaieg5 system) and the desired compound (salt with TFA, 12 mg, 0.018 mmol, 38 95) was obtained as a colorless solid. TOP: Avnes-1.70 min.; RH-MS: t/72,550.5 MANI; "H NMR (400 MHz, DMSO-α): 0.76-0.89 (21, 9-7.5, ЗН, a mixture of diastereoisomers), 1.00-1.16 (24, 9U-6.1, ЗН, a mixture of diastereoisomers), 1.38-1.62 (t, 2Н), 1.82 (5, ЗН), 2.87 (5, 6Н), 3.68 (0, У-21.3, 1Н ), 3.77 (5, ZN), 4.04-4.18 (t, 2H), 4.19-4.29 (t, 1H), 6.29 (re. 5., 1H), 6 .57-6.65 (t, ZN), 6.70-6.76 (t, 2H), 6.85 (5, 1H), 7.13-7.20 (t, 2H), 7.22 -7.27 (t, 1H), 8.28-8.35 (t, 1H).

Example 11.

Compounds 1Ta-117 were obtained by the reaction of intermediate product 3.3 (or its analogues obtained in a similar way) with various isocyanates, acyl chlorides or aldehydes similarly to the preparation in examples 4, 5 and 6, respectively, or by the reaction of intermediate product 7.4 (or its analogues obtained in a similar way ) with different amines similarly to the preparation in example 7, or by the reaction of the compound of example 8 (or its analogs obtained in a similar way) with different amines similarly to the preparation in example 9. oo Structure Name/vEC/MS (c) bo

M fiol M-(5-chloro-2-16,7-diethoxy-2-(4-methoxy-phenyl)-3-114 in, M o oxo-1 2,3,4-tetrahydroisoquinolin-1-yl| -phenyl-

FI yo acetamide.

TOP: Chva-2.08; IAT-MS: t/: 509.2 MANI". (9) at 6

Also : 1-(2-(7-((B)-tert-butoxy)-2-(4-dimethyl-

Mo7-aminophenyl)-6b-methoxy-3-oxo-1,2,3,4-

Y FI va ethylurea.

More TOP: Chvea-1.80; RH-MS: t/2 565.5 (MANI. (9) at 6

Also : M-(2-|7-(B)-tert-butoxy)-2-(4-dimethyl-

M 07 aminophenyl)-6b-methoxy-3-oxo-1,2,3,4- 11s shryi M o tetrahydroisoquinolin-1-yl|-5-chlorophenyl)-

Y F propionamide.

TOP: Chvea-1.82; RH-MS: t/2 550.3 (MANI. (9) (c) o.

MCAI 7-(B)-tert-butoxy)-1-I4-chloro-2-(ethylmethyl-119 U Ho amino)phenyl I|-2-(4-dimethylaminophenyl)-6-methoxy- - M 1,4 -dihydro-2H-isoquinolin-3-one.

F and TOP: Chne-2,29; RH-MS: t/: 536.6 MANI. (9)

oo Structure Name/EPCH/MS o to and Schiro ro 2-117-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-116 rio methoxy-3-oxo-1,2,3, 4-tetrahydroisoquinolin-1-yl|-5- - MH chloro-M-methylbenzamide.

FI | TOP: Chwea-1.75; RH-MS: t/2 536.4 (MANI. (9) (c) o.

M ША 7-((B)-tert-butoxy)-1-(4-chloro-2-methyl-114 rio aminomethylphenyl)-2-(4-dimethylaminophenyl)-6- -e MH methoxy-1,4 -dihydro-2H-isoquinolin-3-one.

F | TOP: Chvea-1.40; RH-MS: t/2 522.3 |MANI" (9)

Example 12: 1-(4-Chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(3-morpholin-4-ylpropoxy)phenyl|-1,4-dihydro-2H-isoquinoline-3- (Methodology A) too (c) With would o su ol

SI

To a solution of intermediate 12.3 (25 mg, 0.055 mmol) in DCM (1.5 mL) was successively added 3-morpholin-4-ylpropan-y-ol (0.009 mL, 0.066 mmol), PPiIz on the substrate (content equal to 1.52 mmol/g, 109 mg, 0.166 mmol) and DTAD (19.1 mg, 0.083 mmol). The reaction mixture was shaken at RT for 3 h, then filtered and the resin was washed with DCM.

The filtrate was evaporated to dryness and the resulting residue was purified by preparative

Reverse phase HPLC (Umayeg5 system) and obtained the desired compound (salt with TFA, 9.9 mg, 0.014 mmol, 26 95). TOP: Thu-1.98 min.; IAT-MS: t/2,580.6 MANI; H NMR (400 MHz, COzO0b): 1.27-1.52 (t, 6H), 1.97-2.15 (t, 2H), 2.36 (5, ЗН), 2.50-2, 82 (t, 1H), 2.83-3.28 (t, 4H), 3.38-4.25 (t, 1H), 5.66 (5, 1H), 6.54-6.80 ( t, 2H), 6.82-7.07 (t, ЗН), 7.15-7.40 (t, 4H).

Intermediate 12.1: 2-"-tert-Butyldimethylsilanyloxy)-4-methyl-phenylamine.

MN, hey! in Y

To a solution of 2-amino-5-methylphenol (500 mg, 4.0 mmol) and imidazole (298 mg, 4.4 mmol) in

DMF (5 mL) was added to TVOMSII (660 mg, 4.4 mmol). The reaction mixture was stirred at RT for 3 hours, then diluted with water and extracted using ASOEL. The organic fraction was dried over magnesium sulfate, filtered and evaporated to dryness. The obtained residue was purified by column chromatography Sotbri-Riazpi Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in gradient mode, heptane/tBME, which contains 5 95 7M MHz in MeOnN 95:5 -» 8:2) and obtained the desired compound (724 mg, 3.1 mmol, 77 95) as a reddish oil.

Be-0.94 (heptane/DCM/TBME 1:1:2, which contains 5 95 7M MNz in MeOnH); TOP: "Chnee-1.80 min.; IAT-

MS: t/2 238.1 MANI; "H NMR (400 MHz, SOS"): 0.26 (in, 6H), 1.04 (in, 9H), 2.23 (5, ЗН), 3.56 (B. 5., 1Н), 6.56-6.67 (t, ZN).

Zo Intermediate 12.2: (2-tert-Butyldimethylsilanyloxy)-4-methylphenyl|-(1-(4-chlorophenyl)-meth-(E)-ylidene|-amine.

in SI /7o du

The desired intermediate (1.06 g, 2.94 mmol, 97 95) was obtained as a brownish solid from intermediate 12.1 (724 mg, 3.05 mmol) and 4-chlorobenzaldehyde (429 mg, 3.05 mmol) in a similar manner obtaining an intermediate product 1.4. "H NMR (400 MHz, SOSI"): 0.17 (5, 6H), 0.99 (v, 9H), 2.33 (5, ЗН), 6.73-6.83 (t, 2H) , 6.94 (a, U-7.8, 1H), 7.42-7.48 (t, 2H), 7.81-7.687 (t, 2H), 8.43 (5, 1H).

Intermediate 12.3: (3,4-Diethoxyphenyl)-acetyl chloride.

SI (0);

Kos oh

Oxalyl chloride (1.13 ml, 13.4 mmol) and a catalytic amount of DMF (0.069 ml, 0.89 mmol). The reaction mixture was stirred at 0 °C for 1 h, then evaporated to dryness in vacuo to give crude (3,4-diethoxyphenyl)-acetyl chloride (2.2 g , 8.9 mmol, quantitative yield) in the form of a brownish oil, which was used in the next stage without additional purification.

Intermediate 12.4: 1-(4-Chlorophenyl)-6,7-diethoxy-2-(2-hydroxy-4-methylphenyl)-1,4-dihydro-2H-isoquinolin-3-one. Oho

M

(at)

The desired intermediate (600 mg, 1.33 mmol, 45 95) was obtained as a yellow foam from intermediate 12.2 (1.06 g, 2.94 mmol) and intermediate 12.3 (715 mg, 2.94 mmol) similarly obtained in example 1. A longer (14 h) reaction was required to cleave the silyl group of 5 and 5 after adding methanesulfonic acid. The desired compound was purified by Sotri-Riavp column chromatography

Sotrapiop "m (Izso Ips.) (BIO; elution in the gradient mode, (heptane/dhM 1:C/TBME 95:5 -»

Coo) 4:6). TLC: Re-0.33 (heptane/DHM/TBME 1:1:2); TOP: Chva-2.51 min.; IAT-MS: t/2 452.2 (MANI;

NMR NMR (400 MHz, SOSI): 1.44-1.52 (t, 6Н), 2.33 (5, ЗН), 3.73 (5, 2Н), 4.04-4.17 (t, 4H), 5.95 (5, 1H), 6.73-6.82 (t, 4H), 6.87-6.91 (t, 1H), 7.00-7.07 (t , ZN), 7.21-7.26 (t, 2H).

Example 13: 12-(1-(4-Chlorophenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-5-methylphenoxy)-acetic acid.

more c) iv)

M

SI

A mixture of intermediate 13.1 (44 mg, 0.084 mmol) in Men (0.8 mL) and water (0.2 mL) at RT was treated with GiOH monohydrate (10.6 mg, 0.25 mmol) and stirred for 1 h. The reaction mixture was neutralized by adding 0.5 M HCl in water, then extracted with

DXM. The organic fraction was dried over Mag2505, filtered and evaporated to dryness. The resulting residue was purified by reverse-phase preparative HPLC (Umayegv system) to give the desired compound (8.5 mg, 0.017 mmol, 20 95 over 2 steps). TOP: "ve-2.41 min.;

LC-MS: t/: 510.68 (MANI; H NMR (400 MHz, DMSO-α): 1.26 (i, 9-6.9, ZN), 1.33 (i, U-6.9 , ZN), 2.26 (5, ZN), 3.53 (y, 9U-19.6, 1H), 3.89 (y, 9U-19.5, 1H), 3.90-4.01 (t, 2H), 4.05 (9, U-6.9 Gu, 2H), 4.44 (a, 9-15.9, 1H), 4.59 (a, 9-15.9, 1H ), 5.98 (5, 1H), 6.64-6.69 (t, 1H), 6.72 (5, 1H), 6.77 (a, 9-7.8, 1H), 6, 81 (5, 2H), 7.23 (y, 9-21, AN).

Intermediate 13.1: 42-(11-(4-chlorophenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-5-methylphenoxy)-acetic acid methyl ester. (Methodology B) then at 9 Fi o era

IF)

C520Oz (54.8 mg, 0.17 mmol) and bromoacetic acid methyl ether (0.012 mL, 0.13 mmol) were sequentially added to a solution of intermediate 12.4 (38 mg, 0.084 mmol) in DMF (0.5 mL). The reaction mixture was stirred at RT for 30 minutes, then partitioned between water and ASA. The organic phase was separated, dried over Mag5O54, filtered and evaporated to dryness to give the crude desired intermediate (44.1 mg) as a yellow oil, which was used in the next step without further purification.

TOP: "ve-2.66 min.; LC-MS: t/: 525.9 |MANI..

Example 14: 1-(4-Chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(2H-tetrazol-5-ylmethoxy)phenyl|-1,4-dihydro-2H-isoquinoline-3- he

Sh.

M

M M orana (o)

2 To a solution of intermediate 12.4 (50 mg, 0.11 mmol) in acetone (1 mL) was sequentially added K»CO3 (45.4 mg, 0.33 mmol) and bromoacetonitrile (0.011 mL, 0.17 mmol). The reaction mixture was stirred at RT for 3 hours, then diluted with AsSOBE and washed with water. The organic phase was dried over Mag50O5, filtered and evaporated to dryness.

The obtained residue was dissolved in DMF (0.5 mL), then MNeCl (19.6 mg, 0.33 mmol) was added and

Mam»z (21.4 mg, 0.033 mmol) and the heterogeneous mixture were heated at 100 C and stirred for 24 h. The reaction mixture was cooled to RT, filtered and immediately purified by reverse phase preparative HPLC (Ulaieg5 system) to give the desired compound (25 mg, 0.047 mmol, 43 95). TOP: "Chvea-2.47 min.; LC-MS: t/2 535.8 MANI; "H NMR (400 MHz, COzO0): 1.35 (i, U-7.0, ZN), 1, 43 (I, 9-7.0, ЗН), 2.34 (в, ЗН), 3.60-3.78 (t, 1Н), 3.83-420 (t, 5Н), 5.16- 6.05 (t, ZN), 6.55-7.38 (t, 9H).

Example 15.

Compounds 15a2-15I were obtained by the reaction of intermediate product 12.4 (or its analogues, obtained in a similar way) with various aliphatic alcohols or halides, similarly to the preparation in example 12 (methodology A) or the preparation of intermediate product 13.1 (methodology B), respectively. (Me | Structure Name/EPCH/MS and is

We (in) in)

These are 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(2-1,5aM(o)morpholin-4-ylethoxy)phenyl!|-1,4-dihydro-2H -isoquinoline-

Z-he

FI TOP: Mne-1.95; RH-MS: t/ 566.9 ME. (9)

Sa oa: 9) c)

Phy p 1-(4-chlorophenyl)-2-(2-(3-dimethylamino-propoxy)-4-15V M He; methylphenyl|-6, 7-diethoxy-1 4-dihydro-2H-isoquinolin-3-one .

Ff VERH: Mve-1.97; RH-MS: thuja 537.9 (MENI. (9) t

C 7

And 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(2-(4-15c M He) methylpiperazin-1-yl)-ethoxy|-phenyl)-1,4 -dihydro-2H- isoquinolin-3-one.

Ff TOP: Ane1,77; IAT-MS: t/ 579.7 (MENI. (9) that r. Also in; S

Fi A 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-|3-(4-154 M (o) methylpiperazin-1-yl)-propoxy|-phenyl)-1 ,4-dihydro-2H-isoquinolin-3-one.

Fu TOP: Chne-1.77; IAT-MS: t/» 592.4 MANI. (9) 7 days

Alkali in (4-chloro-2-(11-(4-chlorophenyl)-6, 7-diethoxy-3-oxo-3,4-15e M (o) dihydro-1H-isoquinolin-2-yl|I-phenoxy )acetic acid methyl ether.

FI TOP: Mne-2.76; RH-MS: t/ya 545.8 |MEN. (9) (9)

(Me | Structure Name/EPCH/MS

BUT. ro

So S

M Fi y (4-chloro-2-(11-(4-chlorophenyl)-6, 7-diethoxy-3-oxo-3,4- o dihydro-1H-isoquinolin-2-yl|-phenoxy)-acetic acid .

TOP: Thu-2.49; RH-MS: t/ 531.8 MANI". more (o) g and 9 o

M FI A 2-IB-chloro-2-(2-dimethylaminoethoxy)phenyl|-1-(4-15a o chlorophenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one.

TOP: Chwea-2.00; IAT-MS: t/2 544.7 (MANI.

Ge) (o) she g o. (c) (c)

M C u 2-I(IB-chloro-2-(3-morpholin-4-ylpropoxy)phenyl|-1-(4-15p ochlorophenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinoline -3-one

TOP: Thu-2.03; RH-MS: t/z 601.8 (MAANI". sa (o)

M CF in 2-IB-chloro-2-(2-morpholin-4-ylethoxy)phenyl|-1-(4-15i ochlorophenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinoline-3 - he

TOP: Thu-2.03; RH-MS: t/ 586.8 MANI". more (about) duty 9) 9)

M Phi A 2-I(IB-chloro-2-(3-dimethylaminopropoxy)phenyl|-1-(4-15) o chlorophenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinoline-3- he

TOP: Thu-2.03; RH-MS: t/: 558.9 MANI". sa (o)

Nno7to 9) 9)

MA 2-IB-chloro-2-(3-hydroxypropoxy)phenyl|-1-(4-15K o chlorophenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one.

TOP: Thu-2.57; LC-MS: t/z2 531.7 (MAANI".

SI

(at)

(Me | Structure Name/EPCH/MS

BUT. td 9 (c)

M r 2-I(IB-chloro-2-(2-hydroxyethoxy)phenyl|)|-1-(4-chlorophenyl)- 1510) o 6,7-diethoxy-1 4-dihydro-2H-isoquinoline-3- he

TOP: Thu-2.55; LC-MS: m/z 517.8 (MAANI". (9) (9) (1) The desired compound (2.5 mg, 0.005 mmol, 15 95) was obtained by removing the methyl group from the compound of example 15e (17.4 mg , 0.032 mmol) similarly to the one obtained in example 8. Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umayegv system).

Example 16: 6-(P)-tert-butoxy)-4-(4-chlorophenyl)-3-(4-dimethylamino-phenyl)-7-methoxy-3,4-dihydro-1H-quinazolin-2-one. (Method A)

N o c) I

C, vra m (o)

To a mixture of intermediate 16.7 (90 mg, 0.19 mmol) and ammonium formate (237 mg, 3.77 mmol) in MeOH (2 mL) was added Ra/cS (2 mg, 0.019 mmol). The reaction mixture was heated at 60 °C, stirred for 14 h, then cooled to RT and filtered through a layer of celite.

The precipitate on the filter was washed with MeOH and the filtrate was concentrated in vacuo.

The resulting residue was dissolved in ASOEL and successively washed with water and with 2M

MagSOz. The organic phase was dried over NaCl, filtered and evaporated to dryness. The resulting residue was purified using Sotheby-Riazpy Sotrapiop'm column chromatography (I5so

Ips.) (5IO:2; gradient elution, (heptane/DCM 1:1)/TBME 95:5 -» 100 95 TBME) and obtained the desired compound (49 mg, 0.10 mmol, 54 95) as off-white solid.

TLC: Re-0.14 (heptane/DCM/TBME 1:1:2); TOP: Yave-1.98 min.; RH-MS: t/2 480.2 MANI; "N

NMR (400 MHz, DMSO-α): 0.81-0.93 (t, ZN, mixture of diastereomers), 1.06-1.16 (2a, 9-61, ZN, mixture of diastereomers), 1.40- 1.64 (t, 2H), 2.85 (5, 6H), 3.70 (5, ЗН), 3.99-4.13 (t, 1H), 5.83 (5, 1H), 6 .51-6.54 (t, 1H), 6.59-6.64 (t, 2H), 6.77-6.680 (t, 1H), 6.88-6.94 (t, 2H), 7 .27-7.39 (t, 4H), 9.36 (5, 1H).

Intermediate 16.1: 3-((A8)-tert-butoxy)-4-methoxybenzaldehyde. o - o I o

N

To a solution of 3-hydroxy-4-methoxybenzaldehyde (4 g, 26.3 mmol), PRIz (9.65 g, 36.8 mmol) and

To (5)-butan-2-ol (2.9 mL, 31.5 mmol) in DCM (100 mL) at 0 C (ice bath) was slowly added DTAD (9.08 g, 39.4 mmol). After the addition, the yellow solution was allowed to heat up to RT and further stirred for 30 minutes. The reaction mixture was sequentially washed with 2M HCl in water (2x) and 2M MagSO3. The organic phase was dried over NaCl5O, filtered and evaporated to dryness. The obtained crude substance was purified using Sotheby-Riazpy column chromatography. Sotrapiop "m (Izso Ips.) (BIO; gradient elution, heptane/tBME 95:5 -» 7:3) and obtained the desired compound (2.42 g, 11.6 mmol, 44 95) in the form of a light yellow oil. TLC: Ke-0.4 (heptane/tBME 1:1); HPLC: "ve-1.93 min.; LC-MS: t/: 209.2

IM-ANIE; "H NMR (400 MHz, DMSO-av): 0.93 (1.9-7.5, ZN), 1.24 (0.9-61, ZN), 1.53-1.75 (t, 2H), 3.687

(5, ZN), 4.38-4.47 (t, 1H), 7.18 (9, 9-8.3, 1H), 7.39 (a, 9-1.7, 1H), 7 .54 (yes, U-8.3, 2.0, 1 N), 9.83 (5, 1 N).

Intermediate 16.2: I3-(B)-tert-butoxy)-4-methoxyphenyl|-(4-chlorophenyl)-methanol. oh - what's up

A solution of intermediate 16.1 (576 mg, 2.77 mmol) in THF (20 mL) was cooled to 0 °C (ice bath) and treated with 4-chlorophenylmagnesium (1M solution in THF, 4.15 mL, 4.15 mmol) After the addition, the reaction mixture was further stirred for 1.5 h at 0 "C, then the reaction was stopped by adding a saturated aqueous solution of MNACI (20 ml).

The resulting suspension was diluted with water and extracted with DCM (2x). The combined organic fractions were dried over NaCl, filtered and evaporated to dryness to afford the crude title compound (1.01 g) as a yellow oil, which was used in the next step without further purification. TOP: "Chve-2.51 min.; IAT-MS: t/2 319.2 |M-NO; "H NMR (400 MHz,

DMSO-c0v): 0.86-0.93 (t, ZN, mixture of diastereoisomers), 1.13-1.21 (t, ZN, mixture of diastereoisomers), 1.47-1.70 (t, 2H), 3.71 (5, ZN), 4.19-4.28 (t, 1H), 5.62 (y, 9-3.9, 1H), 5.86 (a, 9-42, 1H), 6.81-6.90 (t, 2H), 6.93 (y, 9-1.7, 1H), 7.33-7.38 (t, 4H).

Intermediate 16.3: I3-((A8)-tert-butoxy)-4-methoxyphenyl|-(4-chlorophenyl)methanone. oh - what sh

MpOg2 (2.88 g, 33.1 mmol) was added in one portion to a solution of intermediate 16.2 (1.01 g) in CHCl3 (15 mL). The suspension was refluxed for 3 h, then cooled to RT and filtered through a pad of celite. The filter precipitate was washed with DCM and the filtrate was evaporated to dryness to give the crude title compound (965 mg) as an orange oil, which was used in the next step without further purification. TOP: "ve-2.85 min.; RH-MS: t/: 319.0 MANI"; "H NMR (400 MHz, DMSO-abv): 0.92 (Y, 9-7.3, ZN), 1.24 (a, 9U-6.1, ZN), 1.53-1.74 ( t, 2H), 3.87 (c, ЗН), 4.33-4.42 (t, 1H), 7.11 (a, 9-85, 1H), 7.28-7.36 (t, 2H), 7.60-7.65 (t, 2H), 7.69-7.75 (t, 2H).

Zo Intermediate 16.4: |5-(BA)-tert-butoxy)-4-methoxy-2-nitrophenyl|-(4-chlorophenyl)-methanone.

O.M 0) And in

SI

To a solution of intermediate 16.3 (965 mg) in ASON (10 ml) at 0 "C (ice bath)

NMO3 (0.86 mL, 19.3 mmol) was slowly added. After the addition, the reaction mixture was allowed to warm to room temperature, then was further stirred for 1 h. and poured into cold water.

The resulting precipitate was collected by filtration and washed with a 2M aqueous solution of MansSoz. The solid was dissolved in DCM, dried over NaCl 5 O, filtered and evaporated to dryness to give the title compound (1.0 g, 2.76 mmol) as a brownish solid, which was used in the next step without further purification. SUPER: "vei-2.82 min.; PH-MO: t/2 364.0 (MANI; "H NMR (400 MHz, DMSO-av): 0.89 (i, 9-7.3, ZN) , 1.23 (y, 9-5.9, ЗН), 1.54-1.76 (t, 2Н), 3.96 (5, ЗН), 4.61-4.71 (t, 1Н) , 7.26 (5, 1H), 7.57-7.63 (t, 2H), 7.69-7.75 (t, 2H), 7.79 (v, 1H).

Intermediate 16.5: 5-(B8)-tert-butoxy)-3-(4-chlorophenyl)-6-methoxy-benzo|c|isoxazole.

M (6) clay Ii with (o)

In a sealed flask for carrying out the reaction, a mixture of intermediate product 16.4 (1.0 g, 2.76 mmol) and zpsSi2 (5.24 g, 27.6 mmol) in EN (10 ml) was heated at 80 "C and stirred for 1 h . The resulting suspension was cooled to RT and filtered. The solid was dissolved in DCM (200 mL) and washed with 1M aqueous Mahon solution (2x). The organic layer was dried over Mag505, filtered and evaporated to dryness to give the desired compound (581 mg, 1.75 mmol , 63 95) in the form of a yellow solid, which was used in the next stage without additional purification. HPLC: "vei-2.97 min.; RH-MS: t/2 332.1 MANI; "H NMR (400 MHz,

DMSO-аv): 0.95 (i, U-7.5, ЗН), 1.29 (а, 9-61, ЗН), 1.58-1.79 (t, 2Н), 3.89 ( 5, ZN), 4.60-4.71 (t, 1H), 6.94 (5, 1H), 7.12 (5, 1H), 7.62-7.69 (t, 2H), 8 ,01-8,08 (t, 2H).

Intermediate 16.6: |2-Amino-5-(B)-tert-butoxy)-4-methoxyphenyl|-(4-chlorophenyl)-methanone.

NM Ff and

IN

SI

In a sealed reaction flask, a mixture of intermediate 16.5 (522 mg, 1.57 mmol) and Ee (879 mg, 15.7 mmol) in ASON (3 mL), water (4 mL), and ASOCA (1 mL) was heated at

From 1107C and stirred for 30 minutes. The resulting suspension was cooled to room temperature, neutralized by adding a saturated aqueous solution of ManHCO3 to pH 7 and filtered through a layer of celite. The solid was washed with the help of ASOEI and the biphasic filtrate was transferred to a separatory funnel. The aqueous layer was separated and further extracted with AsSOBEI (Zh). The combined organic fractions were dried over NaCl, filtered and evaporated to dryness. The obtained crude substance was purified using Sotheby-Riazp column chromatography. Sotrapiop "m (Izso Ips.) (5BIOg; elution in isocratic mode,

Heptane/"DXM 1:1)UTBME 95:5) and obtained the desired compound (525 mg, 1.57 mmol, quantitative yield) as a brownish solid. TLC: Ke-0.57 (heptane/DXM/TBME 1: 1:2); HPLC:

Aive-2.64 min.; RH-MS: t/2 334.1 |MANI; "H NMR (400 MHz, DMSO-α): 0.82 (i, 9-7.5, ZN), 1.07 (a, 9-6.1, ZN), 1.36-1.60 ( t, 2H), 3.79 (v, ЗН), 3.80-3.88 (t, 1H), 6.43 (5, 1H), 6.68 (5, 1H), 7.20 (v , 2H), 7.49-7.59 (t, 4H).

Intermediate 16.7: 6-(A)-tert-butoxy)-4-(4-chlorophenyl)-3-(4-dimethyl-aminophenyl)-7-methoxy-3H-quinazolin-2-one.

(0; M 0)

Fo

M rf o i v

SI

To a solution of intermediate 16.6 (300 mg, 0.9 mmol) in toluene (8 mL) was added (4-isocyanatophenyl)-dimethylamine (219 mg, 1.35 mmol). The reaction mixture was heated at 110 C and stirred for 4.5 days. Then PTSC (15.48 mg, 0.09 mmol) was added and the mixture was further stirred at 110 °C for another 14 h. The reaction mixture was cooled to RT and evaporated to dryness. The resulting residue was purified by column chromatography

Sotbri-RIazp Sotrapiop "m (I5so Ips.) (ZiOg; elution in the gradient mode, DHM/MeOnN 99:1 - 8:1) and obtained the desired compound (100 mg, 0.21 mmol, 23 95) in the form of a dark solid substances. TLC: Be-0.29 (DCM/MeOH 9:1); HPLC: Chne-2.07 min.; RH-MS: t/: 478.0 |MANI.

Example 17: 4-(4-Chlorophenyl)-6,7-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydro-1H-quinazolin-2-one. (Method B)

N o c)

S in Y no (o)

Mavna (4.7 mg, 0.12 mmol) was added to a solution of crude intermediate 17.1 (25 mg) in MeOnH (1 mL) in one portion at RT. The reaction mixture was stirred for three hours. and concentrated in vacuo. The residue was dissolved in DCM, washed with water and the organic phase was dried over Mag5O:, filtered and evaporated to dryness. The obtained crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) to give the desired compound (9.5 mg, 0.022 mmol, 38 95). TOP: Avne-2.17 min.; IAT-MS: t/2 425.2 MANI; H NMR (400 MHz, COzO0b): 3.70 (5, ЗН), 3.78 (в, ЗН), 3.85 (5, ЗН), 5.81 (5, 1Н), 6.60 (5 , 1H), 6.62 (5, 1H), 6.683-6.89 (t, 2H), 6.95-7.01 (t, 2H), 7.17-7.23 (t, 2H), 7.26-7.32 (t, 2H).

Intermediate 17.1: 4-(4-Chlorophenyl)-6,7-dimethoxy-3-(4-methoxy-phenyl)-ZN-quinazolin-2-one. ro o

M ah o7 no (o)

The crude desired intermediate (136 mg) was obtained as a light yellow

From a solid of (2-amino-4,5-dimethoxyphenyl)-(4-chlorophenyl)methanone (100 mg, 0.34 mmol, purchased from the company SpetsSoiIesi Stn) and 1-isocyanato-4-methoxybenzene (0.044 ml, 0 .34 mmol) similar to the preparation of intermediate product 16.7. The crude intermediate was used in the next step without further purification. TOP: "vei-2.53 min.; IAT-MS: t/2 4411 (MANI.

Example 18: 6-(B)-tert-butoxy)-4-(4-chlorophenyl)-3-(4-dimethylamino-phenyl)-7-methoxy-1-methyl-3,4-dihydro-1H-quinazoline -2-on.

o c) And vva

M

(at)

To a solution of the compound of example 16 (20 mg, 0.042 mmol) in THF (0.3 mL) was cautiously added manne (60 95 in mineral oil, 3.3 mg, 0.083 mmol) at RT. The mixture was heated at 50 C and stirred for 30 minutes. Added Me! (0.005 mL, 0.083 mmol) at 50°C and the reaction mixture was further stirred for 1 h, then cooled to RT and the reaction was stopped by adding Meon. The resulting clear solution was immediately purified by preparative reversed-phase HPLC (Ulasgeg5 system) and obtained the desired compound (TFA salt, 9.4 mg, 0.015 mmol, 37 95) as an off-white solid. HPLC:

Aive 2.10 min.; LC-MS: t/2 494.4 MANI"; "H NMR (400 MHz, DMSO-α): 0.84-0.94 (t, ZN, mixture of diastereoisomers), 1.09-1.19 (t , ZN, a mixture of diastereoisomers), 1.43-1.66 (t, 2H), 2.88 (5, 6H), 3.30 (5, ZN), 3.80 (5, ZN), 4.08 -4.21 (t, 1H), 5.83 (5, 1H), 6.63 (5, 1H), 6.67-6.78 (t, 2H), 6.91-7.02 (t , ZN), 7.25-7.32 (t, 2H), 7.34-7.А41 (t, 2H).

Example 19.

Compounds 19a-19i were obtained by the reaction of the intermediate product 16.6 (or its analogues obtained in a similar way) or commercially available (2-amino-4,5-dimethoxyphenyl)-(4-chlorophenyl)-methanone with various isocyanates, similarly to the preparation in example 16 (Methodology A) or Example 17 (Methodology B), or by alkylation of the compound of Example 16 (or its analogues obtained in a similar way) with various alkyl halides as described in Example 18. -(4-chlorophenyl)-3-(4-dimethylaminophenyl)-6, 7- 19a Kk dimethoxy-3,4-dihydro-1H-quinazolin-2-one.

Y F TOP: Chne1.54; РХ-МС: t/t 438.1 MENI. (9)

No.

My eyes | 6-(B)-tert-butoxy)-4-(4-chlorophenyl)-7-methoxy-3-(4- 19th methoxyphenyl)-3,4-dihydro-1H-quinazolin-2 - he o F TOP: Ave-2.65; RH-MS: p/z 4671 (MANI". (9)

And ok oh

Miya 07 4-(4-Chlorophenyl)-3-(4-dimethylaminophenyl)-b, 7-19s of SU dimethoxy-1-methyl-3,4-dihydro-1H-quinazolin-2-one.

And Ff TOP: Ave-1,69; RH-MS: t/» 452.0 (M-NO". (9)

(Me | Structure Name/HPLC/MS/NMR with o

M Sh and 4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-1-ethyl-b, 7-19a SU about dimethoxy-3,4-dihydro-1H-quinazolin-2-one. t TOP: Chvea-1.79; RH-MS: t/: 466.1 (MANI. (9) s o

M Ci p 4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-1-isopropyl-19e p o 6,7-dimethoxy-3,4-dihydro-1H-quinazolin-2-one. t TOP: Chvea-1.94; RH-MS: t/: 480.1 (MANI. (9) ше

Ox M (c) Щ F : 6-(BA)-tert-butoxy)-4-(4-chlorophenyl)-3-(4-

M 07-70 |dimethylaminophenyl)-1-ethyl-7-methoxy-3,4-dihydro-1 H- 191

K quinazolin-2-one.

And Ff TOP: Mne 2,17; RH-MS: t/ 508.6 ME". (9)

Example 20: 1-(4-Chlorophenyl)-7-methoxy-2-(4-methoxyphenyl)-6-(2-morpholin-4-ylethoxy)-1,4-dihydro-2H-isoquinolin-3-one.

M Shchyiv)

But

SI

To a solution of intermediate 20.3 (15 mg, 0.037 mmol) in DCM (0.5 mL) was sequentially added 2-morpholin-4-ylethanol (0.005 mL, 0.044 mmol), PPris on the substrate (content equal to 1.52 mmol/g, 72.2 mg, 0.11 mmol) and DTAD (12.6 mg, 0.055 mmol). The reaction mixture was shaken at RT for 3 h, then filtered and the resin was washed with DCM. The filtrate was evaporated to dryness and the resulting residue was purified by reverse-phase preparative HPLC (Mu/ageg5 system) to give the desired compound (TFA salt, 5 mg, 0.008 mmol, 21 95). TOP: Mve-1.66 min.; IAT-MS: t/2 523.2 MANI".

Intermediate 20.1: (1-(4-Chlorophenyl)-meth-(E)-ylidene|-(4-methoxy-phenyl)-amine.

SI su to

The desired intermediate (1.88 g, 7.65 mmol, 94 95 ) was obtained as a colorless solid from 4-methoxyphenylamine (1 g, 8.12 mmol) and 4-chlorobenzaldehyde (1.14 g, 8.12 mmol) ) is analogous to obtaining intermediate product 1.4. "H NMR (400 MHz, SOSiz): 3.86 (v, ЗН), 6.93-6.98 (t, 2Н), 7.24-7.28 (t, 2Н), 7.43-7 .48 (t, 2H), 7.83-7.87 (t, 2H), 8.47 (5, 1H).

Intermediate 20.2: (3-Benzyloxy-4-methoxyphenyl)-acetyl chloride.

SI (6) rem ot

The desired intermediate (534 mg, 1.84 mmol, quantitative yield) was obtained as a yellow solid from (3-benzyloxy-4-methoxyphenyl)-acetic acid (500 mg, 1.84 mmol) similarly to the preparation of intermediate 1.3.

Intermediate 20.3: 1-(4-Chlorophenyl)-6-hydroxy-7-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. c) ON

Fo vva ti 9

The desired intermediate (340 mg, 0.83 mmol, 45 95) was obtained from intermediate 20.1 (452 mg, 1.84 mmol) and intermediate 20.2 (535 mg, 1.84 mmol) similarly to the preparation in example 1. Benzyl protective the group was split ip 5y under the conditions of the reaction. Purification of the crude substance was carried out using column chromatography

Sotbri-RIazpy Sotrapiop'"m (15so Ips.) (5iOg; gradient elution, heptane/tBME containing 5 956 formic acid 95:5 -» 100 96 TBME containing 5 96 formic acid).

TOP: Yave-2.09 min.; IAT-MS: t/: 410.1 (MANI; "H NMR (400 MHz, DMSO-av): 3.47 (a, U-19.8, 1H), 3.66-3.72 (t, 6H), 3.687 (y, 9U-19.7, 1H), 5.92 (5, 1H), 6.61 (5, 1H), 6.82-6.89 (t, 2H), 6.95 (5, 1H), 6.97-7.04 (t, 2H), 7.26-7.34 (t, 4H), 9.06 (Bug. 5., 1H).

Example 21: 6-(2-Aminoethoxy)-1-(4-chlorophenyl)-7-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. this

M vva to (o)

To a solution of intermediate 20.3 (15 mg, 0.037 mmol) in DMF (0.5 mL) was sequentially added C520Oz (23.8 mg, 0.073 mmol) and tert-butyl (2-bromomethyl)carbamic acid (12.3 mg, 0.055 mmol). The reaction mixture was stirred at RT for 30 minutes and partitioned between water and ASOEI. The organic phase was separated, dried over Mag50Oa,

It was filtered and evaporated to dryness. The resulting yellow residue was dissolved in DCM (0.5 mL) and treated with TFA (0.028 mL, 0.37 mmol). The reaction mixture was stirred at RT for 30 minutes, evaporated to dryness, and the resulting crude substance was purified by reverse-phase preparative HPLC (Ulaieg5 system) to obtain the desired compound (TFA salt, 8.5 mg, 0.015 mmol, 41 95). TOP: "Chvei-1.61 min.; IAT-MS: t/z: 453.3 MANI";

NMR NMR (400 MHz, DMSOO-α): 3.14-3.24 (t, 2H), 3.59 (y, U-19.8, 1H), 3.71 (5, ЗН), 3.7Z (5, ZN), 3.93 (a, 9-19.7, 1H), 4.07-4.16 (t, 2H), 6.00 (5, 1H), 6.83- 6.89 (t, 2H), 6.91 (v, 1H), 6.98-7.04 (t, 2H), 7.08 (5, 1H), 7.33 (5, AN), 7 ,89 (rg. 5., 2H).

Example 22: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-ethoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

c) c) And vva "to (o)

To a solution of intermediate 22.4 (15 mg, 0.033 mmol) in DMF (0.5 mL) was sequentially added С52СО3 (21.6 mg, 0.066 mmol) and iodethane (0.004 mL, 0.05 mmol). The reaction mixture was stirred at RT for 3 h. and subjected to distribution between water and ASOBEII.

The organic phase was separated, dried over NaCl5Ox, filtered and evaporated to dryness. The resulting crude substance was purified by reverse-phase preparative HPLC (Umayege5 system) to give the desired compound (6.5 mg, 0.014 mmol, 41 95). TOP: Yave-2.92 min.; IAT-MS: t/:2 480.2 MANI; "H NMR (400 MHz, COzO0): 0.90-1.01 (t, ЗН), 1.14-1.24 (ha, 96.1, ЗН, mixture of diastereoisomers), 1.42 (Her, 9 -7.0, ЗН), 1.50-1.75 (t, 2Н), 3.72 (y, 9-20.3, 1Н), 3.78 (5, ЗН), 3.99-4 .12 (t, ZN), 4.17-4.27 (t, 1H), 5.91 (5, 1H), 6.78 (a, 9-2.9, 1H), 6.85-6 .92 (t,

ZN), 6.97-7.02 (t, 2H), 7.14-7.19 (t, 2H), 7.27-7.32 (t, 2H).

Intermediate 22.1: |3-Benzyloxy-4-((B)-tert-butoxy)phenyl|-acetonitrile.

SM G and work

IB 07's

The desired intermediate (519 mg, 1.76 mmol, 84 95) was obtained as a colorless foam from (3-benzyloxy-4-hydroxyphenyl)-acetonitrile (500 mg, 2.09 mmol) and (5)-butane-2 -ol (0.23 ml, 2.51 mmol) similarly to the preparation of intermediate 1.1. Purification of the crude substance was carried out using Sotri-Riavp column chromatography

Sotrapiop "m (I5so Ips.) (5iO:g; elution in gradient mode, heptane/tBME 95:5 -» 1:1). TLC:

Ae-0.84 (hepgan/DHM/TBME 1:1:2); TOP: Clear-2.72 min.; RH-MS: t/: 296.1 |MANI; "H NMR (400

MHz, SOSIz): 1.00 (Her, 9-7.3, ZN), 1.32 (9, 9-61, ZN), 1.60-1.72 (t, 1H), 1.75- 1.687 (t, 1H), 3.67 (5, 2H), 4.31 (sextet, U-6,1, 1H), 5.14 (5, 2H), 6.84-6.95 (t, ZN), 7.30-7.43 (t, ZN), 7.44-7.50 (t, 2H).

Intermediate 22.2: |3-Benzyloxy-4-((B)-tert-butoxy)phenyl|-acetic acid. o o7-

A mixture of intermediate 22.1 (519 mg, 1.76 mmol) in 4 M Mahon in water (3 mL) and EUN (3 mL)

Z was heated at 80 "C and stirred for 14 h. The reaction mixture was cooled to RT, concentrated in vacuo, then carefully acidified by adding 2M HCl in water and extracted with DCM. The organic fraction was dried over Mag250O4, filtered and evaporated to dryness to give the desired compound (538 mg, 1.71 mmol, 97 95) as an orange oil, which was used in the next step without further purification.

TOP: Yave-2.42 min.; PH-MS: t/2 313.2 M-NO; "H NMR (400 MHz, SOSIz): 0.99 (i, U-7.3, ЗН), 1.32 (9, 95-61, ЗН), 1.59-1.71 (t, 1Н) , 1.75-1.687 (t, 1H), 3.58 (5, 2H), 4.29 (sextet, U-6,1, 1H), 5.12 (5, 2H), 6.82-6 .87 (t, 1H), 6.88-6.92 (t, 2H), 7.30-7.34 (t, 1H), 7.35-7.41 (t, 2H), 7.43 -7.49 (t, 2H).

Intermediate 22.3: 3-Benzyloxy-4-((B)-tert-butoxy)phenyl|-acetyl chloride.

yo o7-

The desired intermediate (571 mg, 1.71 mmol, quantitative yield) was obtained as an orange oil from intermediate 22.2 (539 mg, 1.71 mmol) analogously to the preparation of intermediate 1.3.

Intermediate 22.4: 7-((8)-tert-butoxy)-1-(4-chlorophenyl)-6-hydroxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. c) he

S, vva "ta

IF)

The desired intermediate (270 mg, 0.60 mmol, 35 95) was obtained as an off-white foam from intermediate 20.1 (423 mg, 1.72 mmol) and intermediate 22.3 (573 mg, 1.72 mmol) analogously to the preparation in example 1. The benzyl protecting group was cleaved by 5y under the conditions of the reaction. Purification of the crude substance was carried out using column chromatography Sotbri-RIazp Sotrapiop "M (Ibso Ips.) (510g; elution in gradient mode, heptane/tBME, which contains 5% of formic acid 95:5 -» 4:6). TLC:

Be-0.76 (hepgan/"DXM/TBME, which contains 5 95 formic acid 1:1:2); HPLC: "be-2.53 min.;

IAT-MS: t/2 452.1 (MANI; "NN NMR (400 MHz, СОз0О0): 0.88-1.01 (21, 9-7.5, ЗН, mixture of diastereomers), 1.15-1 ... , ЗН), 3.98 (a, 9U-20.1, 1Н), 4.22-4.31 (t, 1Н), 5.89 (5, 1Н), 6.72 (5, 1Н), 6.74-6.78 (t, 1H), 6.87-6.93 (t, 2H), 6.96-7.02 (t, 2H), 7.13-7.19 (t, 2H ), 7.26-7.33 (t, 2H).

Example 23: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-methoxyphenyl)-6-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy|- 1,4-dihydro-2H-isoquinolin-3-one. o she o 0); And S

SS dl not sh

To a solution of intermediate 23.1 (15 mg, 0.029 mmol) in DMF (0.5 mL) was sequentially added 1-methylpiperazine (0.016 mL, 0.15 mmol), MMM (0.016 mL, 0.15 mmol), and GATU (16, 8 mg, 0.044 mmol). The reaction mixture was stirred at RT for 1 hour, then subjected to

From the distribution between ASOEII and water. The organic phase was separated, dried over Mag5O54, filtered and evaporated to dryness. The obtained crude substance was purified using a preparative method

Reverse phase HPLC (Umayeg5 system) and obtained the desired compound (salt with TFA, 11.1 mg, 0.016 mmol, 54 95). TOP: Thu1.92 min.; IAT-MS: t/2 592.0 (MANI H NMR (400 MHz, DMSO-

Ov): 0.84-0.95 (21, 97.3, ZN, mixture of diastereoisomers), 1.11-1.25 (24, 9-61, ZN, mixture

C5 diastereoisomers), 1.45-1.70 (t, 2H), 2.81 (5, ЗН), 2.88-3.14 (t, ЗН), 3.29-3.48 (t, ЗН ), 3.52 (y, 9-19.8, 1H), 3.71 (5, ЗН), 3.92 (y, 9-19.1, 1H), 3.99-4.15 (t , 1H), 4.23-4.34 (t, 1H), 4.34-4.47 (t, 1H), 4.81 (5, 2H), 6.01 (t, 1H), 6, 78 (5, 1H), 6.83-6.90 (t, 2H), 6.98-7.09 (t, ЗН), 7.29-7.37 (t, 4H).

Intermediate 23.1: HT7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-methoxyphenyl)-3-oxo-1,2,3,4-tetrahydroisoquinoline-b-yloxy|- acetic acid. o he 0); 0) And vva and

SI

The title compound (116 mg, 0.23 mmol, 90 95 over 2 steps) was obtained as an off-white solid from intermediate 22.4 (120 mg, 0.27 mmol) using the same 2 consecutive steps as described in Example 13. Purification of the crude substance was carried out by precipitation in water and filtration. TOP: "out-2.42 min.; IAT-MS: t/2 509.8 MANI; 'N

NMR (400 MGu, DMSO-α): 0.84-0.94 (21, 97.4, ZN, a mixture of diastereoisomers), 1.11-1.22 (249, 9-61,

ЗН, a mixture of diastereoisomers), 1.46-1.67 (t, 2Н), 3.53 (y, 9-19.7, 1Н), 3.70 (в, ЗН), 3.86 (й, У -20.2, 1H), 4.21-4.31 (t, 1H), 4.62 (5, 2H), 5.99 (t, 1H), 6.73 (5, 1H), 6, 82-6.89 (t, 2H), 7.01-7.06 (t, ЗН), 7.29-7.35 (t, 4H), 12.87 (bu. 5., 1H).

Example -(.24: 1--4-Chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-7-propoxy-1,4-dihydro-2H-isoquinolin-3-one. c) c)

M Fi a ud wa me (o)

C52CO3 (39.7 mg, 0.12 mmol) and 1-iodopropane (0.015 mL, 0.15 mmol) were sequentially added to a solution of intermediate 24.2 (25 mg, 0.061 mmol) in DMF (0.5 mL). The reaction mixture was heated at 50 °C and stirred for 3 h, then cooled to RT and partitioned between water and ASA. The organic phase was separated, dried over Mag5O54, filtered and evaporated to dryness. The crude substance obtained was purified using preparative

Reverse phase HPLC (Umayeg5 system) and obtained the desired compound (12.2 mg, 0.027 mmol, 44 95). TOP: Chnei-2.64 min.; IAT-MS: t/: 452.2 MANI; H NMR (400 MHz, COzO0): 1.01 ( U-7.3, ZN), 1.71-1 .82 (t, 2H), 3.73 (a, 9-20.3, 1H), 3.79 (5, ЗН), 3.80-3.95 (t, 2H), 3.87 (in , ЗН), 4.05 (9, 9-20.3, 1Н), 5.91 (5, 1Н), 6.78 (5, 1Н), 6.86-6.93 (t, ЗН), 6.96-7.02 (t, 2H), 7.14-7.19 (t, 2H), 7.30 (t, 2H).

Intermediate 24.1: (4-Benzyloxy-3-methoxyphenyl)-acetyl chloride.

Koo) (Fi (6)

For what

The desired intermediate (1.0 g, 3.44 mmol, quantitative yield) was obtained as an orange oil from (4-benzyloxy-33-methoxyphenyl)-acetic acid (937 mg, 3.44 mmol) similarly to the preparation of intermediate 1.3.

Intermediate 24.2: 1-(4-Chlorophenyl)-7-hydroxy-6-methoxy-2-(4-methoxyphenyl)-1,4-

dihydro-2H-isoquinolin-3-one. (o; od

It's yours. (at)

The desired intermediate (681 mg, 1.66 mmol, 48 95) was obtained as an off-white solid from intermediate 20.1 (845 mg, 3.44 mmol) and intermediate 24.1 (1.0 g, 3.44 mmol) in the same way as obtained in example 1. The benzyl protecting group was cleaved by 5y under the conditions of the reaction. Purification of the crude substance was carried out using column chromatography Sotbri-Riazp Sotrapiop "M (Ibso Ips.) (510g; elution in the gradient mode, (heptane/dxM 1:1) UTBME, which contains 5 96 of formic acid 95:5 -" 3: 7).

TOP: Yamve-2.07 min.; IAT-MS: t/: 410.1 (MANI; "H NMR (400 MHz, DMSO-av): 3.56 (a, U-20.0, 1H), 3.70 (c, ЗН), 3 .74 (5, ЗН), 3.90 (a, 9У-19.8, 1Н), 5.92 (5, 1Н), 6.70 (5, 1Н), 6.77 (5, 1Н), 6.81-6.687 (t, 2H), 6.95-7.01 (t, 2H), 7.22-7.27 (t, 2H), 7.28-7.34 (t, 2H), 8.91 (ru. 5., 1H).

Example 25: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. c) c) Y

Si, wa "to (o)

To a solution of intermediate 24.2 (200 mg, 0.49 mmol) in DCM (13 mL) was successively added (5)-butan-2-ol (0.054 mL, 0.59 mmol), PP3 on the substrate (content equal to 1.52 mmol/g, 963 mg, 1.46 mmol) and DTAD (169 mg, 0.73 mmol). The reaction mixture was shaken at RT for 3 h, then filtered and the resin was washed with DCM. The filtrate was evaporated to dryness and the resulting residue was purified by column chromatography

Sotbri-Riaepy Sotrapiop "m (I5so Ips.) (ZiOg; elution in the gradient mode, (heptane/"DHM 17UTBME 95:5 -» 1:1) and obtained the desired compound (136 mg, 0.29 mmol, 60 95) in the form of a colorless foamy substance. TLC: Ke-0.39 (hepgan/DHM/TBME 1:1:2); HPLC: Chne-2.74 min.;

IAT-MS: t/2 466.2 |MANI; "H NMR (400 MHz, SOSIv): 0.93-1.03 (t, ЗН, 2 visible diastereoisomers), 1.23-1.35 (t, ЗН, 2 visible diastereoisomers), 1.59-1, 69 (t, 1H), 1.71-1.84 (t, 1H), 3.74 (0, 9-20.1, 1H), 3.81 (5, ЗН), 3.85-3, 94 (t, 4H), 4.14-4.24 (t, 1H), 5.70 (5, 1H), 6.67 (y, 09-46, 1H), 6.71 (5, 1H) , 6.84-6.91 (t, 2H), 6.99-7.10 (t, 4H), 7.23-7.28 (t, 2H).

Example 26: 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (c) (c)

M Phi X vo y (Phi

To a solution of intermediate product 26.3 (20 mg, 0.047 mmol) in DCM (1.5 mL) was sequentially added propan-2-ol (0.011 mL, 0.14 mmol), PP3 on the substrate (content equal to 1.52 mmol/g, 93 mg, 0.14 mmol) and DTAD (32.7 mg, 0.14 mmol). The reaction mixture was shaken at RT for 14 h, then filtered and the resin was washed with DCM. The filtrate was evaporated to dryness and the resulting residue was purified by reverse-phase preparative HPLC (UmMaieg5 system) to give the desired compound (TFA salt, 17 mg, 0.029 mmol, 62,905) as a colorless solid. HPLC: "ve-1.88 min.; LC-MS: t/2 465.3 MANI; NN NMR (400 MHz, DMSO-av): 1.19 (a, 9U-6.1, ZN), 1 ... (a, U-19.8, 1H), 4.45 (vri, 9-5.9, 1H), 5.98 (5, 1H), 6.69-6.80 (t, 2H), 6 .84 (5, 1H), 6.94-7.00 (t, 2H), 7.03 (5, 1H), 7.35 (5, 4H).

Intermediate 26.1: (4-Hydroxy-3-methoxyphenyl)-acetic acid. but od ve he

A mixture of (4-hydroxy-3-methoxyphenyl)-acetic acid ethyl ether (2 g, 9.51 mmol) and GION monohydrate (1.2 g, 28.5 mmol) in MeonH (20 mL) and water (10 mL) stirred at RT for 14 h. The reaction mixture was concentrated in vacuo, diluted with water and neutralized by adding 2 M HCl in water (14.3 mL). The resulting suspension was extracted with DCM (3x) and AcOBEi (2x) and the combined organic fractions were dried over Na»5O»4, filtered and evaporated to dryness to give the crude title compound (1.67 g, 9.17 mmol, 96 95 ) in the form of a brownish solid, which was used in the next stage without additional purification. TOP: Yave-0.77 min.; RH-MS: t/2 183.4 MANI; NN NMR (400 MHz,

DMSO-α): 3.43 (in, 2H), 3.74 (in, ЗН), 6.61-6.66 (t, У-8.1, 2.0, 1Н), 6.67- 6.72 (t, 1H), 6.81 (a, 9-2.0, 1H), 8.81 (5, 1H), 12.17 (5, 1H).

Intermediate 26.2: (4-Hydroxy-3-methoxyphenyl)-acetyl chloride. so about in

ON

The desired intermediate (1.78 g, 8.89 mmol, quantitative yield) was obtained from intermediate 26.1 (1.62 g, 8.89 mmol) analogously to the preparation of intermediate 1.3.

Zo Intermediate 26.3: 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-7-hydroxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (c) (c)

WITH

SU he m

SI

The desired compound (1.35 g, 3.19 mmol, 36 95) was obtained as a brownish solid from intermediate 1.4 (2.3 g, 8.89 mmol) and intermediate 26.2 (1.62 g, 8.9 mmol) similarly to the preparation in example 1. Purification of the crude substance was carried out using column chromatography Sotbri-Riazpi Sotrapiop "m (Izso Ips.) (510g; elution in gradient mode, (heptane/dM 1:1)/TBME, which contains 5 95 7 M MNz in MeonN 95:5 -» 4:6).

TLC: Be-0.16 (Heptgan/"DXM/TBME containing 5 95 7 M Mnz in Meon 1:1:2); HPLC: "Chve-1.44 min.; RH-MS: t/2 423.2 |MANI; "H NMR (400 MHz, DMSO-abv): 2.89 (in, 6H), 3.56 (a, 9U-20.1, 1H), 3.76 (5, ЗН), 3.91 (a , 9U-19.8, 1Н), 5.91 (5, 1Н), 6.70-6.77 (t, ЗН), 6.80 (5, 1Н), 6.91-6.98 (t , 2H), 7.26-7.37 (t, 4H), 8.99 (Bug. 5., 1H).

Example 27.

Compounds 27aa-27Br were obtained from intermediate product 20.3 (or its analogues obtained in a similar way) analogously to the preparation in example 20 or 21, from intermediate product 22.4 (or its analogues obtained in a similar way) analogously to the preparation in example 22 or 23,

from intermediate product 24.2 (or its analogues obtained in a similar way) analogously to the preparation in example 24 or 25, or from intermediate product 26.3 (or its analogues obtained in a similar way) analogously to the preparation in example 26.

Me | Structure Name/EPCH/MS) naya

M Sh o7 | 1-(4-Chlorophenyl)-6-(2-dimethylaminoethoxy)-7-27 main SU methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-o and isoquinolin-3-one.

TOP: Chne-1.65; IAT-MS: t/z 481.2 MANI. (in)

Lizard

M

In 07 1-(d-chlorophenyl)-6-(2-hydroxyethoxy)-7-methoxy-2-2-tetrazo(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chne-1.99; IAT-MS: t/z 454.2 | MANEI. (c) a o o, 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-(3- o7as M p, dimethylaminopropoxy)-2-(4-methoxyphenyl)-1,4-

SU about dihydro-2H-isoquinolin-3-one.

From Ff VERH: Chnes-1.96; IAT-MS: t/2 537.2 | MANEI. (in)

Phi : 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-isobutoxy-27ai M07 2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. what | TOP: Chne-3,29; IAT-MS: t/2,509.7 MANI. (c) at ro

C: 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6- o7av M o7-- isopropoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-k isoquinoline-3 - he o F TOP: Aveg-3.06; IAT-MS: t/g 494.2 MEI". (c) o C ia : 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4- o7ai i o methoxyphenyl)-6b- propoxy-1,4-dihydro-2H-

Kk isoquinolin-3-one. about Ff VERH: Mne-3,13; IAT-MS: t/t 494.3 MEI". (in)

Me | Structure Name/ECP/MS

ОН sk (c) (c)

Fi : 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-(3-27a M o hydroxypropoxy)-2-(4-methoxyphenyl)-1,4-dihydroly 2H-isoquinoline -3-one o Ff VERH: AZve-2,48; IAT-MS: t/t 510.2 MEI". (c) keofio, 2-17-((B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-27ap M i methoxyphenyl)-3-oxo-1 2,3, 4-tetrahydroisoquinoline-b-yloxy|-M,M-dimethylacetamide.

From F TOP: Chva-2.45; IAT-MS: m/ 538.5 MANI". o methoxyphenyl)-3-oxo-1 2,3,4-tetrahydroisoquinoline-b-yloxy|-M-methylacetamide. o F HPLC: Chne-2.41; IAT-MS: t/2 524.5 MANI. (in ) (c) (c)

M fi o 1-(4-Chlorophenyl)-7-isobutoxy-6-methoxy-2-(4-27ai methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. o F TOP: Chvne-2.84; IAT-MS: t/» 466.2 MANI". (c) (c) (c)

7-tert-butoxy-1-(4-chlorophenyl)-6b-methoxy-2-(4-27ac scha SU methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. o F TOP: Aine-2.76; IAT-MS: t/l 466.2 (MANI. (c) o o

Miya 07 1-(4-chlorophenyl)-7-cyclopropylmethoxy-6-methoxy- 27a! 2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. o Ff TOP: Aine-2.61; IAT-MS: t/l 464.2 (MANI. (c)

Me | Structure Name/ECR/MS about about

Miya VO; 1-(4-Chlorophenyl)-7-cyclopentyloxy-6-methoxy-2-27tats SU (4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. o FI TOP: AZve-2.81; IAT-MS: t/y 478.2 MANI". (9) (o) 6) le

M C h Co 1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-7- o7ap SU o (3-morpholin-4-ylpropoxy)-1,4-dihydro-2H- - isoquinoline- 3-on

F TOP: Chvea-1.61; IAT-MS: t/ 538.6 (MANI. (9) (c) (c)

7-(5)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-2- 27ao scha SU (4-methoxyphenyl)-1,4-dihydro-2H-isoquinoline-3- he o F TOP: Aine-2.73; IAT-MS: t/l 466.2 (MANI. (c) o o

My ozone | 1-(4-Chlorophenyl)-7-(3-Hydroxypropoxy)-6-methoxy-2H7arschie SU 2-(4-Methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. o Ff VERH: AZne-1.99; IAT-MS: t/y 468.2 MANI". (9) (c) (c)

M Tsi 1-(4-chlorophenyl)-7-(3-dimethylamino-propoxy)-6-27a SU same methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-a - m7 0 | zoquinoline-Z-on.

F | TOP: Chvea-1.61; IAT-MS: t/z 495.2 MANI". (9) (c) (c)

M fi Ko 1-(4-chlorophenyl)-7-(1-ethylpropoxy)-b-methoxy-2-2 scha SU (4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. o F TOP: Aine-2.88; IAT-MS: t/l 480.2 (MANI. (c) (c) (c)

Mya o7tettyun, | 7-(3-Aminopropoxy)-1-(4-chlorophenyl)-6-methoxy-2- 27a schi SU 7 | (d-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. (c) Ff VERH: Chne-1.57; IAT-MS: t/z 467.2 | MANEI.

SI

Me | Structure Name/HPLC/MS at 5

M fi vy, 1-(4-chlorophenyl)-7-cyclobutoxy-b-methoxy-2-(4-27ai SU methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one. o FI TOP: AZne-2.63; IAT-MS: t/» 464.2 MANI". (o) (c) (c)

Miya Zh 1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-7-27acyl SU (1-methylbutoxy)-1,4-dihydro-2H-isoquinolin-3-one. o F TOP: Chvne-2.90; IAT-MS: t/» 480.2 MANI". (o) (c) (c)

M Fi 1-(4-chlorophenyl)-7-(1,2-dimethylpropoxy)-6-(c) methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-27am according to . - isoquinoline-Z-on.

F TOP: Chne-2.92; IAT-MS: t/z 480.2 |MANE. (c) (c) (c)

M Shchi Kha 7-(3-Amino-1-methylpropoxy)-1 -(4-chlorophenyl)-6- o7am C in; many | methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H- - isoquinolin-Z-one.

F TOP: Chne-1.64; IAT-MS: t/ 481.3 MAANE.

SI

(c) (c)

M Fi in 1-(4-chlorophenyl)-7-cyclohexyloxy-2-(4-27ah SU iv) dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- - isoquinolin-3-one.

F TOP: Chva-2,22; RH-MS: t/2 505.3 (MANI. (o) (c) (c)

M Fi 7-benzyloxy-1-(4-chlorophenyl)-2-(4-dimethyl-27au SU that aminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3- - one.

F TOP: Chne-2.07; RH-MS: t/: 513.3 MANI. (c) (c) (c)

M Shchi 1-(4-chlorophenyl)-7-cyclohexylmethoxy-2-(4- o7az SU that dimethylaminophenyl)-6b-methoxy-1,4-dihydro-2H- - isoquinolin-3-one.

FI TOP: Chne-2.45; RH-MS: t/: 519.3 MANI. (at)

Me | Structure Name/EPCH/MS about and

M Shchi 1-(4-chlorophenyl)-7-cyclobutylmethoxy-2-(4-o7va SU 3 dimethylaminophenyl)-6b-methoxy-1,4-dihydro-2H-m isoquinolin-3-one.

Ff VERH: "Chne-2.17; RH-MS: t/ 491.3 MANI. (o) o 3

Miyaol 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-7-27rr schi SU ethoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Y Ff TOP: Chne-1,76; RH-MS: t/l 451.3 MANI".

SI at 3

M Fi 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7- o7rs SU in isobutoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3- - one.

Ff VERH: "Chve-2,13; RH-MS: t/; 479,3 |M'ANI". (o) o i

M and 07-х 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6- 27ra ш SU methoxy-7-propoxy-1,4-dihydro-2H-isoquinolin-3-one.

II Ff TOP: "Chve-1.96; RH-MS: t/ 465.3 MANI". (o) (o) (c)

MF 1-(4-chlorophenyl)-7-cyclopentylmethoxy-2-(4-o7re SU, dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one.

FI VERH: "Chne-2.31; RH-MS: t/: 505.3 MANI.

SI

(o) (c)

M Phi S. 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-7-(1- 27V SU iv) ethylpropoxy)-6-methoxy-1,4-dihydro-2H-m isoquinolin-3-one .

F TOP: "Chve-2.17; RH-MS: t/; 493.3 MANI". (o) o i

Miya C 1-(4-chlorophenyl)-7-cyclopentyloxy-2-(4-278 ve (c) dimethylaminophenyl)-6b-methoxy-1,4-dihydro-2H-9-isoquinolin-3-one.

F TOP: "Chve-2.08; RH-MS: t/ 491.2 |M'ANI". (at)

Me | Structure Name/ECR/MS about about

Miya 1-(4-chlorophenyl)-7-cyclopropylmethoxy-2-(4-27vp SU let dimethylaminophenyl)-6-methoxy-1,4-dihydro-2N-m isoquinolin-3-one.

FI TOP: Thu-1.92; RH-MS: t/h 477.3 (MANI. (c) (c) (c)

MC ХК 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6- 27vi SU o methoxy-7-(1-methylbutoxy)-1,4-dihydro-2H- - isoquinolin-3-one.

F TOP: Thu-2,19; RH-MS: t/: 493.3 (MANI. (c) (c) o.

M Sh o 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6- ovi SU 77 | methoxy-7-((B)-2-methoxy-1-methylethoxy)-1,4- and -dihydro-2H-isoquinolin-3-one.

F TOP: Thu-1.77; RH-MS: t/ 495.3 MANI". (c) (c) (c)

ШЧДС 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-(1,3- 27oK SU o dimethyl-but-3-enyloxy)-b-methoxy-1,4-dihydro-2H- - isoquinolin-3-one.

FI TOP: Chvne-2,21; RH-MS: t/ya 505.3 MANI". (c) (c) (c)

MC ХК 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6- 27 in SU o 75 | methoxy-7-(1-methyl-but-33-enyloxy)-1,4-dihydro-2H-isoquinolin-3-one.

FI TOP: Thu-2.09; RH-MS: t/ 491.3 (MANI. (c) (c) (c)

M ia o7 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b, 7- 27rt, SU dimethoxy-1,4-dihydro-2H-isoquinolin-3-one.

J F TOP: Ave-1,61; LC-MS: m/z 437.4 (M-NO". (c) o o and Phi DY 1-(4-chlorophenyl)-7-cyclobutoxy-2-(4-27rp) U (c) dimethylaminophenyl)-6b -methoxy-1,4-dihydro-2H- - isoquinolin-3-one.

Ff VERH: Chvne-1.96; RH-MS: t/ 477.4 MANI". (c)

Me | Structure Name/HPLC/MS at 6

M Fi XX, 7-((5)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-iv)dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-27ro-isoquinoline- 3-on

Ff VERH: Chva-2.04; RH-MS: t/: 479.4 (MANI. (o) o o

M Fi 1-(4-xporphenyl)-2-(4-dimethylaminophenyl)-6-27 in SU that methoxy-7-(pyridin-4-ylmethoxy)-1,4-dihydro-2H- p - M zoquinoline-3- he

F TOP: Chva-1,22; LC-MS: t/2 514.3 (MANI. (o) (1) The desired compound (11.8 mg, 0.021 mmol, 57 95 over 2 steps) was obtained from intermediate 20.3 (15 mg, 0.037 mmol) using the same 2 consecutive stages as described in example 15I. Purification of the crude substance was carried out using reverse-phase preparative HPLC (Umayeg5 system).

Example 28: 1-(4-Chlorophenyl)-7-isopropylamino-2-(4-(methylpyridin-4-ylmethyl-amino)phenyl|- 1,4-dihydro-2H-isoquinolin-3-one. with H

M in i

M

SI

ASON (0.176 ml, 3.07 mmol), acetone (0.125 ml, 1.71 mmol) and Mavn(oOds) were sequentially added to a solution of intermediate 28.9 (400 mg, 0.85 mmol) in DCM (5 ml) at RT with (651 mg, 3.07 mmol). The reaction mixture was stirred at RT for 4 h, then diluted with DCM and washed with a 2 M aqueous solution of MagSO3 (2x). The organic phase was dried over

Ma?5O", filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpi Sotrapiop "m (Izso Ips.) (510g; elution in the gradient mode, DXM/MeonN 99.5:0.5 -» 91) and the desired compound was obtained (392 mg, 0 .77 mmol, 90 95) in the form of a brown resin. TLC: BRe-0.41 (DHM/MeonH 9:1); HPLC: "Chvea-1.30 min.; RH-MS: t/2 511.3 |MANI; "H NMR (400 MHz, DMSOO-av): 1.03-1.13 (249, 9-62, 6H), 3.03 (in,

ZN), 3.40-3.55 (t, 2H), 3.77 (y, 9U-19.6, 1H), 4.58 (5, 2H), 5.34 (y, 9-81, 1H), 5.67 (5, 1H), 6.47 (aa, 9-82, 2.1, 1H), 6.56-6.64 (t, ЗН), 6.687-6.94 (t, ZN), 7.15-7.20 (t, 2H), 7.28-7.38 (t, 4H), 8.45-8.50 (t, 2H).

Intermediate 28.1: (2-Chloro-5-nitrophenyl)-(4-chlorophenyl)-methanol. (o) r

A solution of 2-chloro-5-nitrobenzaldehyde ( 10 g, 53.9 mmol) in THF (100 mL). After addition, the reaction mixture was further stirred at -78 °C for 1 h, then for 10 min. at 0 "C (ice bath). A saturated aqueous solution of MNACI (400 ml) was added, and the resulting mixture was extracted with ASOBEI (2 x 400 ml). The combined organic layers were washed with brine, then dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified using Sotbri-Riazpa Sotrapiop "m (Izso Ips.) column chromatography (5iO"2; elution in gradient mode, heptane/lBME 95:5 -» 6:4) and the desired compound was obtained (14.4 g , 48.4 mmol, 90 95) as a beige solid. TLC: Ke-0.80 (hepgan/"DHM/TBME 1:1:2); HPLC: ve-2.43 min.; LC-MS: t/: not detected; "H NMR (400 MHz, SOSI" c): 6.20 (5, 1H), 7.36 (5, 4H), 7.53 (y, 9U-8.6, 1H), 8.13 (ai, U-8.8, 2, 9, 1H), 8.66 (y, U-2.7, 1H).

Intermediate 28.2: (2-Chloro-5-nitrophenyl)-(4-chlorophenyl)-methanone. (at)

MO, (about)

PDH (26.6 g, 70.8 mmol) was added to a solution of intermediate 28.1 (14.07 g, 47.2 mmol) in DCM (236 mL) in one portion at RT, and the resulting suspension was vigorously stirred at

CT for 14 hours. The reaction mixture was filtered through a layer of celite, the solids were washed with DCM, and the filtrate was evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riab5p Sotrapiop'm (Izso Ips.) (elution in the gradient mode, heptane/AsoEly from 95:5 to 9:1) and the desired compound was obtained (11.7 g, 39.5 mmol, 84 95) in the form of a viscous orange oil. TLC: Ke-0.47 (heptane/AsoEly 41); TOP: Yave-2.64 min.; LC-MS: t/7 296.5 |MANI"; "H NMR (400 MHz, SOSI"): 7.51 (t, 2H), 7.65-7.81 (t, ЗН), 8.23 -8.39 (t, 2H).

Intermediate 28.3: (2-(4-chlorobenzoyl)-4-nitrophenyl|-acetic acid methyl ester.

MO,

To a suspension of Mann (60 95 in mineral oil, 3.46 g, 86 mmol) in DMSO at 0 "C (ice bath) was slowly added tert-butylmethylmalonate (14.6 ml, 86 mmol). After the addition, the reaction mixture was heated at 60 "C and stirred for 30 minutes, then cooled

From to CT. A solution of intermediate 28.2 (11.63 g, 3953 mmol) in DMSO (40 mL) was added, then the mixture was reheated at 60 °C and stirred for 1 h 30 min. The reaction mixture was cooled to RT, then diluted with ESO and washed with saline solution.

The organic layer was dried over Mag5O:4, filtered and evaporated to dryness. The resulting reddish oil was dissolved in DCM (30 mL) and TFC (30 mL) was slowly added at RT (Caution: significant gas evolution occurs). The reaction mixture was stirred at RT for 30 minutes, then concentrated in vacuo. The obtained crude substance was purified by column chromatography Sotri-Riazpy Sotrapiop'm (I5so Ips.) (elution in gradient mode, heptane/tBME from 95:5 to 100 96 TBME) and obtained the desired compound (13.7 g, 39.4 mmol, quantitative yield) as an almost white solid. TLC: Ke-0.36 (heptane/tBME 11); HPLC: "ve-2.42 min.; LC-MS: t/72 334.4 |MANI; "H NMR (400 MHz, DMSO-yv): 3.48 (5, ZN), 4.01 (in , 2H), 7.62-7.69 (t, 2H), 7.74-7.83 (t, ЗН), 8.19 (y, 9-2.4, 1H), 8.42 (da , 9-8.4, 2.6, 1H).

Intermediate 28.4: (2-(4-Chlorobenzoyl)-4-nitrophenyl|-acetic acid.

but also); ho

MO,

SI

A suspension of intermediate 28.3 (13.7 g, 39.4 mmol) and ION monohydrate (8.64 g, 206 mmol) in MeonN (100 mL) and water (50 mL) was stirred at RT for 1 h, then concentrated in vacuum The resulting residue was diluted with water and neutralized by adding 2M HCl in water. The resulting precipitate was filtered, washed with water and dissolved in

DXM. The organic fraction was dried over Ma25O:, filtered and evaporated to dryness to give the crude title compound (10.16 g, 31.8 mmol, 81 95) as a beige solid. TOP: "nei-2.06 min.; LC-MS: t/2 320.5 MANI".

Intermediate 28.5: /2-(chloro-(4-chlorophenyl)-methyl|-4-nitrophenyl)-acetic acid ethyl ester. - lo (F) ho.

MO,

SI

To a suspension of intermediate 28.4 (2.5 g, 7.82 mmol) in EN (40 ml) at RT was added

Mavnkh" (888 mg, 23.46 mmol) (Caution: significant gas evolution occurs!)). The resulting red solution was stirred at room temperature for 15 min., then cooled to 0 "C (ice bath), then 5OSI" (8.56 mL, 117 mmol) was carefully added. The resulting suspension was stirred at 0 "C for 30 minutes, then concentrated in vacuo. The resulting residue was diluted with ASOEL and washed with a 2M aqueous solution of MgCO3 (2x). The organic phase was dried over

Ma?5O", filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotri-Riazpy Sotrapiop'm (I5so Ips.) (elution in the gradient mode, heptane/AcOEII from 95:5 to 1:1) and the desired compound was obtained (2.5 g, 6.79 mmol, 87 95) in the form of a yellow oil, which crystallized into a yellow solid upon aging. TLC: Ke-0.63 (heptane/Asoky 1:1); HPLC: "no-2.85 min.; "H NMR (400 MHz, DMSO-av): 1.09 (it, U-7.2, ЗН), 3.81-4.04 (t, 4Н) , 6.91 (5, 1H), 7.40-7.50 (t, 4H), 7.61 (a, U-8.6, 1H), 8.21 (aa, 9-8.5, 2.2, 1H), 8.34 (y, 9-2.0, 1H).

Intermediate 28.6: Methyl-(4-nitrophenyl)-pyridin-4-ylmethylamine.

What's wrong with Mo,

To a solution of M-methyl-4-nitroaniline (5 g, 32.9 mmol) in DMF (75 mL) at RT was slowly added Mann (60 95 in mineral oil, 4.21 g, 105 mmol) (Caution: significant separation occurs gas). The suspension was stirred vigorously at RT for 15 min., then cooled to 0 "C (ice bath). 4-(chloromethyl)pyridine hydrochloride (8.09 g, 49.3 mmol) was carefully added, then the suspension was allowed to warm to RT and additionally stirred continuously

45 minutes. The reaction mixture was poured into water and extracted with ESO (Zh). The combined organic phases were dried over Mag25O:, filtered and evaporated to dryness to afford the crude title compound (10.13 g) as an orange solid, which was used in the next step without further purification. HPLC: "ve-1.01 min.; LC-MS: t/2 244.5 |MANI; "H NMR (400 MHz, DMSO-dv): 3.23 (5, ZN), 4.82 (5 , 2H), 6.77-6.83 (t, 2H), 7.17-7.22 (t, 2H), 8.02-8.08 (t, 2H), 8.49-8.54 (t, 2H).

Intermediate 28.7: M-Methyl-M-pyridin-4-ylmethylbenzene-1,4-diamine.

M and x sho

Mn,

A suspension of intermediate 28.6 (10.13 g) and powdered Re (18.34 g, 328 mmol) in

ASON (65.7 mL), water (82 mL), and ASOKI (16.4 mL) were heated at 80 °C and stirred for 30 min. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting aqueous mixture was basified by adding 2M aq. solution of magnesium sulfate to pH 8-9, then filtered through a layer of celite and the precipitate on the filter was washed with ASOEL.

The obtained crude substance was purified using Sotreby-Riabp column chromatography

Sotrapiop "m (Izso Ips.) (elution in gradient mode, DXM/7M MHz in MeognH from 99.7: 0.3 to 95: 5) and obtained the desired compound (4.14 g, 19.41 mmol, 5995 per 2 stages) in the form of a brownish solid. TLC: Keg-0.37 (DHM//M MNz in Meon 95: 5); HPLC: Ave-0.73 min.; LC-MS: it/:2 214.6 MANI; "H NMR (400 MHz, DMSOO- av): 2.80 (5, ЗН), 4.35 (in, 2Н), 4.42 (horn. 5., 2Н), 6.44-6, 50 (t, 2H), 6.51-6.58 (t, 2H), 7.20 (0, 9-54, 2H), 8.46 (a, 9-5.6, 2H).

Intermediate 28.8: 1-(4-Chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-7-nitro-1,4-dihydro-2H-isoquinolin-3-one. )

Fo o o

M. 2

SI

DIPEA (1.49 mL, 8.55 mmol) and a solution of intermediate 28.5 (2.1 g, 5 .70 mmol) in

From DXM (10 ml). The reaction mixture was stirred at RT for 45 min., then evaporated to dryness. Hg5Ox (0.456 ml, 8.55 mmol) was added to a solution of the obtained residue in ASON (20 ml) at RT. The mixture was heated at 80 °C, stirred for 1 hour, then cooled to

CT and concentrated in vacuum. The resulting residue was diluted with ASOBEY and washed with a 2M aqueous solution of MagSO3 (2x). The organic phase was dried over Mag50, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Ria5py Sotrapiop'm (I5so Ips.) (elution in the gradient mode,

DXM/Meon from 99.5: 0.5 to 9: 1) and obtained the desired compound (2.08 g, 4.17 mmol, 73 95) as a brown solid. TLC: Keg-0.43 (DCM/MeOH 9: 1); TOP: "Thursday-1.87 min.;

RH-MS: t/2 499.3 MANI; "H NMR (500 MHz, DMSOO-av): 3.02 (5, ZH), 3.86 (y, 9U-20.3, 1H), 4.15 (a, 40. 9-20.3, 1H), 4.58 (5, 2H), 6.34 (5, 1H), 6.58-6.64 (t, 2H), 6.90-6.96 (t, 2H), 7.17 (a, 9-5.5, 2H), 7.34-7.46 (t, 4H), 7.55 (a, 9-8.5, 1H), 8.13 (da, 9U-8, 4, 2.3, 1H), 8.41 (0, 9-2.0, 1H), 8.44-8.49 (t, 2H).

Intermediate 28.9: 7-Amino-1-(4-chlorophenyl)-2-(4-methylpyridin-4-ylmethylamino)phenyl|-1,4-dihydro-2H-isoquinolin-3-one.

)

Fo

AI

M. I

SI

ZpSi dihydrate (9.41 g, 41.7 mmol) was added to a solution of intermediate 28.8 (2.08 g, 4.17 mmol) in EUN (30 ml) at RT. The suspension was heated at 80 °C and stirred vigorously for 30 min. The reaction mixture was cooled to RT and poured into 2M Mahon in water (62.5 mL). The resulting suspension was stirred at RT for 10 min., then filtered through a pad of celite and precipitated on the filters were washed with Eb2O. The biphasic filtrate was separated and the aqueous phase was further extracted with ESO (2x). The combined organic fractions were dried over Mag50", filtered and evaporated to dryness. The crude material obtained was purified by Sotbri-Riaepy Sotrapiop'" column chromatography. Mm (Izso Ips.) (elution in gradient mode, DCM/MeonH from 99.5: 0.5 to 9: 1) and obtained the desired compound (1.17 g, 2.50 mmol, 60 95) as a brown solid substances TLC: Ke-0.43 (DHM/MeOnN 9: 1);

TOP: ve-1.20 min.; LC-MS: t/ 469.2 |MANI"; "H NMR (400 MHz, DMSO-α): 3.02 (5, ЗН), 3.45 (а, 9-19.6, 1Н), 3 .78 (a, 9U-19.6, 1H), 4.57 (5, 2H), 5.03 (Bu. 5., 2H), 5.84 (5, 1H), 6.48 (a9, 9U-8.2, 1.8, 1H), 6.52-6.55 (t, 1H), 6.56-6.64 (t, 2H), 6.84-6.93 (t, ЗН ), 7.18 (y, 9-5.4, 2H), 7.24-7.38 (t, 4H), 8.48 (9, 9-5.9, 2H).

Example 29: M-(11-(4-Chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)phenyl|-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl-propionamide).

M 6); (I FI tforayn

N

More

Pyridine (0.010 mL, 0.128 mmol) and propionyl chloride (0.008 mL, 0.096 mmol) were sequentially added to a solution of intermediate 28.9 (30 mg, 0.064 mmol) in MesmM (0.5 mL) at RT. The reaction mixture was stirred at RT for 30 minutes, then immediately purified by reverse-phase preparative HPLC (UmMaieg5 system) to obtain the desired compound (TSF salt, 20.2 mg, 0.032 mmol, 49 95) as a yellow solid. TOP:

Afve-1.60 min.; RH-MS: t/2 525.2 |MANI; "H NMR (400 MHz, DMSO-α): 1.05 (u, 9U-7.6, ЗН), 2.28 (а, У-7.6, 2Н), 3.07 (5, ЗН) , 3.61 (a, U-20.1, 1H), 3.95 (a, 9-20.1, 1H), 4.78 (5, 2H), 6.01 (5, 1H), 6 .58-6.65 (t, 2H), 6.89-6.96 (t, 2H), 7.17 (y, 9-8.3, 1H), 7.26-7.38 (t, 4H), 7.41 (ad, 9U-8.3, 1.5, 1H),

Koo) 7.62-7.69 (t, ZN), 8.70-8.76 (t, 2H), 9.89 (5, 1H).

Example 30: 1--4-Chlorophenyl)-7-(isopropylpropylamino)-2-(4-(methylpyridin-4-ylmethylamino)phenyl|-1,4-dihydro-2H-isoquinolin-3-one.

Mo); fi

Mrya SU soy

M Zhzh

SI

ASON (0.007 ml, 0.117 mmol), propionic aldehyde (0.009 ml, 0.117 mmol) and Mavn (OAc)z (24 .9 mg, 0.117 mmol). The reaction mixture was stirred at RT for 3 h. 30 min., then immediately purified using reverse-phase preparative HPLC (system

Umaieg5) and obtained the desired compound (TSF salt, 21 mg, 0.027 mmol, 69 95) as a yellow solid. TOP: Yane-1.37 min.; RH-MS: t/2,553.5 MANI; "H NMR (400 MHz, DMSO-dv): 0.86 (u, 9U-7.3, ZN), 1.11 (a, U-6.7, ZN), 1.14 (a, 2- 6.6, ZN), 1.37-1.51 (t, 2H), 3.00 (5, ZN), 3.04-3.11 (t, 2H), 3.51 (a, 9U- 19.6, 1H), 3.75 (y, 9-19.6, 1H), 3.86-3.96 (t, 1H), 4.57 (v, 2H), 5.91 (5, 1H), 6.61-6.68 (t, 2H), 6.70-6.79 (t, 2H), 6.90-6.96 (t, 2H), 7.00-7.06 ( t, 1H), 7.21-7.35 (t, 6H), 8.47-8.54 (t, 2H).

Example 31: 1-(4-Chlorophenyl)-7-(2-dimethylaminoethyl)-isopropylamino)|-2-(4-(methylpyridin-4-ylmethylamino)phenyl|-1,4-dihydro-2H-isoquinoline-3- he

Mo); (I FO gdorarai

M. Zh

ASON (0.018 ml, 0.314 mmol), formaldehyde (37 95 in water, 0.024 ml, 0.314 mmol) and Mavn(Ods) were successively added to a solution of crude intermediate 31.2 (138 mg) in MesmM (0.5 ml) at RT. (66.5 mg, 0.314 mmol). The reaction mixture was stirred at RT for 2 h, then immediately purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 13 mg, 0.016 mmol, 31 95 according to Z stade) was obtained in the form of a light yellow solid matter. TOP: ve-1.48 min.; LC-MS: t/;2 580.4

IM-ANI..

Intermediate 31.1: Tert-butyl ether 12-(1-(4-chlorophenyl)-2-(4--«methylpyridin-4-ylmethylamino)phenyl|-3-oxo-1,2,3,4-tetrahydroisoquinoline-7 -yl-isopropyl-amino)-ethyl|-carbamic acid. (c) lavash l'Jooo

And a

IF)

The crude desired compound (174 mg) was obtained as a brown solid from the compound of Example 28 (80 mg, 0.157 mmol) and M-Bos-2-aminoacetaldehyde (100 mg, 0.626 mmol) similarly to the preparation in Example 30. The crude substance was used in the following stage without additional purification. TOP: "Ive-1.63 min.; RH-MS: t/2 654.5 MANI.

Intermediate 31.2: 1-(2-Aminoethyl)-isopropylamino|-1-(4-chlorophenyl)-2-|4-

Zo (methylpyridin-4-ylmethylamino)phenyl|-1,4-dihydro-2H-isoquinolin-3-one. at

S A mn"

I am

A solution of crude intermediate 31.1 (174 mg) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. 30 min., then evaporated to dryness and the crude desired compound (415 mg) was obtained as a dark resin, which was used in the next step without further purification. TOP: "ive-1.37 min.; LC-MS: t/2 554.4 MANI; "N NMR (400

MHz, DMSO-av): 1.10 (1, 9U-6.8, 6H), 2.76-2.90 (t, 2H), 3.07 (in, ЗН), 3.28-3, 36 (t, 2H), 3.52 (y, 9-19.6, 1H), 3.680 (a, 9U-19.6, 1H), 3.97-4.06 (t, 1H), 4, 73 (5, 2H), 5.94 (5, 1H), 6.59-6.66 (t, 2H),

6.77 (aa, U-8.4, 2.3, 1H), 6.91-6.99 (t, ZN), 7.07 (a, U-8.3, 1H), 7.33 -7.42 (t, 4H), 7.47-7.53 (t, 2H), 7.71-7.80 (t, 2H), 8.66 (a, U-6.1, 2H) .

Example 32: M-(2-(11-(4-Chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)phenyl/|-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) -isopropylamino)-ethyl|-acetamide.

Mo); more m!

THEIR that

M A o

SI

The desired compound (10.8 mg, 0.013 mmol, 25 95 according to stage C) was obtained as a beige solid from crude intermediate 31.2 (138 mg) and acetyl chloride (0.033 mL, 0.471 mmol) similarly to the preparation in example 29. Purification of the crude substance was carried out using reverse-phase preparative HPLC (Umayeg5 system). TOP: "Chvea-1.28 min.; RH-MS: t/? 596.4 MANI".

Example 33.

Compounds З3За-33g were obtained from intermediate product 28.9 (or its analogues obtained in a similar way) analogously to the preparation in example 28 or 29, or from the compound of example 28 (or its analogues obtained in a similar way) analogously to the preparation in example 30, 31 or 32. (Me | Structure Name/HPLC/MS/NMR

With A

M

It is 1-(4-chlorophenyl)-7-isobutylamino-2-(4-(methylpyridine-4-

Zza M ylmethylamino)phenyl|-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chvea-1.64; RH-MS: t/2 525.3 (MANI. (c)

With Ayu

-d M M 1-(4-chlorophenyl)-7--(cyclopentylmethylamino)-2-|4- z38 and shcha, (methylpyridin-4-ylmethylamino)phenyl/|-1,4-dihydro-2 H-

Y FI isoquinolin-3-one.

TOP: Chva-1.72; LC-MS: t/2 551.2 (MANI. (9) 5 AOS 2 M M 1-(4-chlorophenyl)-7-(1-ethylpropylamino)-2-|4- zas U H (methylpyridine-4- ylmethylamino)phenyl/|-1,4-dihydro-2 H-

Y Ff isoquinolin-3-one.

TOP: Chwea-1.63; RH-MS: t/2 539.3 (MANI. (c)

M o

Ж M ШЧИ Kho 1-(4-chlorophenyl)-7-cyclohexylamino-2-(4- zza SU H (methylpyridin-4-ylmethylamino)phenyl/|-1,4-dihydro-2 H-

Y F isoquinolin-3-one.

TOP: Thursday-1.51; RH-MS: t/z: 551.3 MANI. (9)

M o 4 M Shchi Aa 7-second-butylamino-1-(4-chlorophenyl)-2-|4-

ZZe SU H (methylpyridin-4-ylmethylamino)phenyl/|-1,4-dihydro-2 H-

Y F isoquinolin-3-one.

TOP: Chne-1.42; RH-MS: t/z 525.2 MANI. (in)

(Me | Structure Name/HPLC/MS/NMR

Z AYU d M i, 1-(4-chlorophenyl)-7-cyclobutylamino-2-|4- for SU H (methylpyridin-4-ylmethylamino)phenyl/|-1,4-dihydro-2 H- and Ff isoquinoline- 3-on

TOP: Chva-1.50; RH-MS: t/2 523.2 (MANI. (o)

Z AYU j M VO; 1-(4-chlorophenyl)-7-cyclopentylamino-2-|4- 33 SU H (methylpyridin-4-ylmethylamino)phenyl/|-1,4-dihydro-2 H- 9 Y Ff isoquinolin-3-one.

TOP: Chne-1.47; RH-MS: t/: 537.2 MANI. (at)

M o v Fi d M m | 1-(4-chlorophenyl)-2-I(4-(methylpyridin-4- zzp SU N ylmethylamino)phenyl|-7-propylamino-1,4-dihydro-2H-

Y F isoquinolin-3-one.

TOP: Chvne-1.40; RH-MS: t/z 511.2 MANI. (9)

Mo - Mia Yak

SU its 1-(4-chlorophenyl)-7-ethylamino-2-(4-(methylpyridine-4-

Zzi M ylmethylamino)phenyl|-1,4-dihydro-2H-isoquinolin-3-one.

Ff VERH: Chne-1,27; RH-MS: t/ 497.2 MANI. (at)

M (c) - M 7-benzylamino-1-(4-chlorophenyl)-2-(4-(methylpyridine-4-

ZZi p her ylmethylamino)phenyl|-1,4-dihydro-2H-isoquinolin-3-one.

Yi Fu TOP: Chvne-1.79; RH-MS: t/: 559.2 MANI. (9)

М (c) Хий ды М М 1-(4-chlorophenyl)-7-(cyclopropylmethylamino)-2-|4-zac SU H (methylpyridin-4-ylmethylamino)phenyl/|-1,4-dihydro-2 H-

M isoquinolin-3-one.

TOP: Chvea-1.40; RH-MS: t/2 523.3 (MANI. (o)

M (c) 1-(4-chlorophenyl)-7-(cyclohexylmethylamino)-2-|4-dy M zvi M (methylpyridin-4-ylmethylamino)phenyl|-1,4-dihydro-2H- and isoquinoline-3- he

Y F TOP: Mne-1.87; RH-MS: t/ya 565.2 MEI". (c)

Z ALOS ro M ZD M-11-(4-chlorophenyl)-2-(4-«(«methylpyridin-4- zzt SU Nylmethylamino)phenyl|-3-oxo-1,2,3,4-

And Ff tetrahydroisoquinolin-7-yl)-acetamide.

TOP: Chvne-1.49; RH-MS: t/z 511.1 MANI. (at)

(Me | Structure Name/ HPLC/MS/NMR to M and M-11-(4-Chlorophenyl)-2-(4-«(«methylpyridin-4- z3p U N ylmethylamino)phenyl|-3-oxo-1, 2,3,4-

Y F tetrahydroisoquinolin-7-yl)-isobutyramide.

TOP: Chva-1.71; RH-MS: t/2 539.2 (MANI. (9)

Z M ZD M-11-(4-chlorophenyl)-2-(4-«(«methylpyridin-4- 330 rylmethylamino)phenyl|-3-oxo-1,2,3,4-

Y Ff tetrahydroisoquinoline-7-yl-M-isopropylacetamide.

TOP: Chvne-1.67; RH-MS: t/: 553.3 MANI. (at)

M o v Fo d M ZK M-11-(4-chlorophenyl)-2-(4-«(«methylpyridin-4- 33SU ryylmethylamino)phenyl|-3-oxo-1,2,3,4-

R Y F tetrahydroisoquinolin-7-yl)-M-isopropylpropionamide.

TOP: Chvne-1.77; RH-MS: t/: 567.3 MANI. (9) o su M 1-(4-chlorophenyl)-7-(isopropylmethylamino)-2-(4-(methylpyridin-4-ylmethylamino)phenyl/|-1,4-dihydro-2 H-

For her Ff cancer isoquinolin-3-one.

TOP: Chne-1.27; RH-MS: t/z: 525.4 MANI. (9) 8 M m 1-(4-chlorophenyl)-7-(ethylisopropylamino)-2-|4- (methylpyridin-4-ylmethylamino)phenyl/|-1,4-dihydro-2 H-

Y Ff isoquinolin-3-one.

TOP: Chne-1.29; RH-MS: t/: 539.4 MANI. (at)

Example For: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(2-oxopyrrolidin-1-yl)uphenyl|-1,4-dihydro-2H -isoquinolin-3-on. c) c) I era oo (FI

Sii (0.51 mg, 0.003 mmol) and KzRoOx (22.67 mg, 0.11 mmol) were placed in the reaction flask, then evacuated and refilled with argon (3 times). M,M'-dimethylethylenediamine (0.006 mL, 0.006 mmol), pyrrolidin-2-one (5 μL, 0.064 mmol), intermediate 34.3 (30 mg, 0.053 mmol), and toluene (0.5 mL) were added to the flask. the reaction was sealed, heated at 80 °C and stirred for 1 h 30 min. The reaction mixture was cooled to RT, filtered through a bed of celite, and the solid was washed with MeOH. The filtrate was evaporated to dryness and the resulting residue was purified by preparative reversed-phase HPLC ( Ulayeg system5) and obtained the desired compound (8 mg, 0.015 mmol, 28 95). HPLC: "Chve-2.50 min.; IAT-MS: pu/ 519.2 MANI"; "N NMR (400

MHz, СОСИ3): 0.92-1.03 (t, ZN, mixture of diastereoisomers), 1.23-1.33 (24, 9-61, ZN, mixture of diastereoisomers), 1.56-1.84 (t , 2H), 2.20 (quintet, 9-7.5, 2H), 2.67 (I, 9-81, 2H), 3.79 (a, 9-19.8, 1H), 3.85 -3.97 (t, 6H), 4.20 (sextet, U-6.1, 1H), 5.75 (5, 1H), 6.67 (y, 9U-3.9, 1H), 6 .72 (5, 1H), 7.03-7.09 (t, 2H), 7.10-7.16 (t, 2H), 7.24-7.30 (t, 2H), 7.58 -7.64 (t, 2H).

Intermediate 34.1: (1-(4-Chlorophenyl)-meth-(E)-ylidene|-(4-iodophenyl)-amine.

SI do

AND

The desired compound (2.08 g, 6.10 mmol, 89 95) was obtained as a brownish solid from 4-iodophenylamine (1.5 g, 6.85 mmol) and 4-chlorobenzaldehyde (963 mg, 6.85 mmol) similarly to obtaining intermediate product 1.4. "H NMR (400 MHz, COsSiz): 6.94-7.02 (t, 2H), 7.44-7.51 (t, 2H), 7.69-7.76 (t, 2H), 7 .82-7.89 (t, 2H), 8.40 (5, 1H).

Intermediate 34.2: 1-(4-Chlorophenyl)-7-hydroxy-2-(4-iodophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (o; od

Fo in J things

The desired intermediate (496 mg, 0.98 mmol, 36 95) was obtained as a light yellow solid from intermediate 34.1 (939 mg, 2.75 mmol) and intermediate 24.1 (799 mg, 2.75 mmol) analogously obtained in example 1. The benzyl protecting group was cleaved off by 5th under the conditions of the reaction. Purification of the crude substance was carried out using column chromatography Sotbri-RIazp Sotrapiop "M (Ibso Ips.) (510g; elution in gradient mode, (heptane/dxM 1:1) UTBME, which contains 5 96 formic acid 95:5 -" 7: 3).

TLC: Ve-0.40 (hepgan/"DHM/TBME 1:1:2); HPLC: "ve-2.42 min.; IAT-MS: t/2,506.0 MANI "N

NMR (400 MHz, SOSI"): 3.71 (a, 9-19.6, 1H), 3.84 (a, 9-19.8, 1H), 3.93 (5, ЗН), 5, 62 (5, 1H), 5.71 (5, 1H), 6.69 (5, 1H), 6.79 (5, 1H), 6.88-6.94 (t, 2H), 7.07 -7.13 (t, 2H), 7.25-7.31 (t, 2H), 7.65-7.71 (t, 2H).

Intermediate 34.3: 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-iodophenyl)-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. c) c) I vva c sh zo s

The desired compound (350 mg, 0.62 mmol, 64 95) was obtained as a yellow foam from intermediate 34.2 (496 mg, 0.98 mmol) and (5)-butan-2-ol (0.11 mL, 1 - » 4:16). TLC: KeE-0.64 (heptane/DHM/TBME 1:1:2); HPLC:

Agve-3.06 min.; IAT-MS: t/2,562.0 MANI; "H NMR (400 MHz, COzOb): 0.89-1.00 (21, U-7.5, ЗН, mixture of diastereomers), 1.14-1.25 (24, 9-61, ЗН, mixture of diastereomers ), 1.50-1.75 (t, 2H), 3.75 (a, 9U-20.3, 1H), 3.686 (5, ЗН), 4.02 (a, 9-20.3, 1H ), 4.19-4.29 (t, 1H), 5.99 (5, 1H), 6.81 (a, 409-934, 1H), 6.87-6.95 (t, ЗН), 7.15-7.21 (t, 2H), 7.28-7.34 (t, 2H), 7.68-7.75 (t, 2H).

Example 35: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-2-(4-pyrazol-1-ylphenyl)-1,4-dihydro-2H-isoquinoline-3- he c) c)

DK oo (o)

Intermediate product 34.3 (25 mg, 0.044 mmol), 1H-pyrazole (4.5 mg, 0.067 mmol), SygO (0.3 mg, 0.002 mmol), salicylaldoxime (1.2 mg, 0.009 mmol) was placed in a reaction flask ) and C52CO3 (29.0 mg, 0.089 mmol), then pumped off and backfilled with argon (3 times). Mesm (0.5 ml) was added, the reaction flask was sealed, heated at 80 C and stirred for 14 h. The reaction mixture was cooled to RT, diluted with DCM and filtered through a celite pad. The solid was washed with

DCM, the filtrate was evaporated to dryness and the resulting residue was purified by reverse phase preparative HPLC (Mageg5 system) to give the desired compound (12.5 mg, 0.02 mmol, 46 95). TOP: Sounds-2.71 min.; IAT-MS: t/2 503.5 |MANI; "H NMR (400 MHz,

DMSO-sv): 0.83-0.93 (t, ZN, mixture of diastereomers), 1.10-1.21 (24, 9-6.1, ZN, mixture of diastereomers), 1.44-1.67 (t, 2H), 3.63 (a, 9U-20.0, 1H), 3.73 (5, ЗН), 3.88-3.97 (t, 1H), 4.15- 4.28 (t, 1H), 6.13 (a, 9-3.3, 1H), 6.49-6.52 (t, 1H), 6.84 (c, 1H), 7.00 (a, 9 -6.7, 1H), 7.23-7.29 (t, 2H), 7.31-7.34 (t, 4H), 7.70 (9, 9-1.8, 1H), 7 .74-7.79 (t, 2H), 8.42 (y, 9-25, 1H).

Example 36: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-|4-(1H-pyrazol-4-iluphenyl|-1,4-dihydro-2H-isoquinoline -3-on c) c) c)

I am F

M -

M

(at)

A mixture of intermediate 34.3 (20 mg, 0.036 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.36 mg, 0.053 mmol) and a 2M aqueous solution of MgCO3 (0.062 mL, 0.125 mmol) in DME (0.6 mL) was pumped off under vacuum and backfilled with argon (3 times). Rasich(PPH3)2 (1.25 mg, 0.0018 mmol) was added, the reaction flask was sealed and irradiated in a microwave oven at 150 "С for 15 min. The reaction mixture was cooled to RT, diluted with ASOEI and washed with water. Organic

The layers were dried over Mag250»5, filtered and evaporated to dryness. The crude substance was purified by reverse-phase preparative HPLC (U/ageg5 system) and the desired compound was obtained (TPA salt, 5 mg, 0.008 mmol, 23 95). TOP: "Chne-2.38 min.; RH-MS: t/2 502.2 MANI";

IN NMR (500 MHz, DMSO-α): 0.84-0.92 (21.9-7.5, ZN, mixture of diastereomers), 1.11-1.21 (ha, 96.1, ZN, mixture diastereoisomers), 1.45-1.67 (t, 2H), 3.61 (a, 9-20.0, 1H), 3.7Z (5, ЗН), 3.92 (aa, 9-19, 8, 3.7, 1H), 4.18-4.28 (t, 1H), 6.10 (a, 9-41, 1H), 6.85 (5, 1H), 7.01-7, 04 (t, 1H), 7.10-7.15 (t, 2H), 7.33-7.37 (t, 4H), 7.53-7.58 (t, 2H), 8.02 ( Bug. 5., 2H).

Example 37.

Compounds 37a-37c were obtained from the intermediate product 34.3 (or its analogues obtained in a similar way) similarly to the preparation in example 34, 35 or 36.

Mo | Structure.

Zz7a re 3-oxo-3,4-dihydro-1H-isoquinolin-2-yl(-phenyl)-acetamide.

M Ff TOP: Chva-2,33; IAT-MS: t/z 493.2 MANI. (o) (c) o.

M Fro 7-(H)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-|4- d7j | 9 rio (2-oxoazetidin-1-yl)phenyl|-1,4-dihydro-2H-isoquinoline-

Z-he

M

IZ F TOP: Chva-2.49; IAT-MS: t/ 505.1 MANI". (9) (c) o.

M Fi A 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(3,5-3760) (9) dimethyl-1H-pyrazol-4-yl)phenyl|- b-methoxy-1,4-sv dihydro-2H-isoquinolin-3-one. pe Ff VERH: AZne-2,14; RH-MS: t/z 530.2 MANI. (o) (1) The desired compound (TSF salt, 15 mg, 0.023 mmol, 44 95) was obtained from intermediate 34.3 (30 mg, 0.053 mmol), 3,5-dimethyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.9 mg, 0.053 mmol) and RY(PP3)4 (3.1 mg, 0.003 mmol) as a catalyst, similar to the preparation in example 36. Purification of the crude substance was carried out using preparative HPLC with the reverse phase (Umayegv system).

Example 38: 4-(7-(8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M -ethyl-M-methylbenzamide. (c) (c) And c)

M. and

SI

Ethylmethylamine (0.013 mL, 0.156 mmol), MMM (0.017 mL, 0.156 mmol) and

GATU (23.77 mg, 0.063 mmol). The reaction mixture was stirred at RT for 2 h, then immediately purified by reverse-phase preparative HPLC (Umayegv system) to give the desired compound (12.7 mg, 0.024 mmol, 47 95). HPLC: "ve-2.46 min.; LC-MS: t/2 521.7 IMANI; H NMR (400 MHz, COzO0): 0.89-1.00 (2nd, 9-7.5, ZN, mixture of diastereoisomers), 1.11-1.28 (t, 6H), 1.50-1.77 (t, 2H), 2.95-3.10 (t, ЗН), 3.53-3.62 (t, 1H), 3.77 (a, 9-20.3, 1H), 3.86 (5,

ZN), 4.05 (a, 9-20.3, 1H), 4.20-4.30 (t, 1H), 6.07 (Bug. 5., 1H), 6.80-6.85 (t, 1H), 6.90 (5, 1H), 7.18-7.33 (t, 6H), 7.37-7.46 (t, 2H).

Intermediate 38.1: 4-11-(4-chlorophenyl)-meth-(E)-ylidene|-amino)-benzoic acid methyl ester.

SI

DT c)

The title compound (2.35 g, 8.59 mmol, 87 95) was obtained as a light yellow solid from methyl 4-aminobenzoate (1.5 g, 9.92 mmol) and 4-chlorobenzaldehyde (1.40 g, 9.92 mmol) similar to the preparation of intermediate product 1.4. "H NMR (400 MHz, SOSIiz): 3.95 (v, ЗН), 7.20-7.25 (t, 2Н), 7.46-7.52 (t, 2Н), 7.84-7 .91 (t, 2H), 8.07-8.13 (t, 2H), 8.42 (5, 1H).

Intermediate 38.2: 4-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-

Z-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-benzoic acid. (c) (c) I vv (c) kov

GO

The desired compound (780 mg, 1.58 mmol, 64 95) was obtained from intermediate 38.1 (672 mg, 2.45 mmol) and intermediate 1.3 (630 mg, 2.45 mmol) similarly to the preparation in example 1. Purification of the crude substance was carried out using reverse-phase column chromatography (C18; gradient elution, water containing 0.5 96 TFA/mMesm 95:5 -» 1:9). TOP: Thu-2.75 min.; RH-MS: t/: 494.3 MANI; "H NMR (400 MHz, SOSI»v): 0.94-1.03 (21, 957.5, ЗН, mixture of diastereomers), 1.26-1.35 (2a, 9-61, ЗН, mixture of diastereomers ), 1.56-1.85 (t, 2H), 3.72-3.87 (t, 2H), 3.88 (5, ЗН), 3.93 (5, ЗН), 4.17- 4.28 (t, 1H), 5.82 (5, 1H), 6.73 (5, 1H), 6.75 (a, 9-49, 1H), 7.06-7.12 (t, 2H), 7.25-7.32 (t, 4H), 8.01-8.08 (t, 2H).

Intermediate 38.3: 4-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-benzoin acid. (c) (c) I century (c) 90 gy (Fi

A mixture of intermediate 38.2 (400 mg, 0.81 mmol) and GION monohydrate (170 mg, 4.05 mmol) in MeOH (8 mL) and water (2 mL) was stirred at RT for 5 h. The reaction mixture was concentrated in vacuo, diluted with water and neutralized by adding 2 M HCl in water. The resulting suspension was extracted with DCM (3x) and the combined organic fractions were dried over Na»5O», filtered and evaporated to dryness to give the crude desired

The compound (461 mg, quantitative yield) was obtained as an orange oil, which was used in the next step without further purification. TOP: "ve-2.41 min.; LC-MS: t/: 480.5 (MANI N

NMR (400 MHz, SOSI"): 0.95-1.03 (21, 9-7.5, ZN, a mixture of diastereoisomers), 1.29-1.34 (2a, 9-61,

ЗН, a mixture of diastereoisomers), 1.58-1.85 (t, 2Н), 3.72-3.87 (t, 2Н), 3.88 (5, ЗН), 4.19-4.28 (t , 1H), 5.83 (5, 1H), 6.7Z (5, 1H), 6.77 (y, 9-49, 1H), 7.07-7.13 (t, 2H), 7, 26-7.35 (t, 4H), 8.05-8.11 (t, 2H).

Example 39: Methylamide (25,4K)-1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline -2-yl|-benzoyl)-4-hydroxypyrrolidine-2-carboxylic acid.

c) c)

M I o

M

WHOSE Rus

Mo (Fi

Methylamine (2M solution in THF, 0.25 mL, 0.50 mmol), MMM (0.017 mL, 0.156 mmol) was sequentially added to a solution of intermediate 39.1 (30 mg, 0.051 mmol) in DMF (0.5 mL) at RT. and GATU (28.9 mg, 0.076 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with ASOEI and washed with a 2M aqueous solution of MagCO3. The organic layer was dried over Mag250»5, filtered and evaporated to dryness. The crude material was purified by reverse-phase preparative HPLC (Uas(eg5) system to give the desired compound (19.9 mg, 0.033 mmol, 65 95) as a yellow solid. HPLC: "Ineg-2.00 min;

RH-MS: t/2 606.2 |MANIG; nH NMR (500 MHz, DMSO-sv): 0.83-0.94 (21, 9-7.5, ZN, mixture of diastereomers), 1.11-1.22 (2a, 9-61, ZN, mixture diastereoisomers), 1.47-1.68 (t, 2H), 1.79-1.88 (t, 1H), 2.04-2.12 (t, 1H), 2.55-2.60 ( t, 2H), 3.26 (a, 9U-11.0, 1H), 3.51-3.77 (t, 5H), 3.89 (aa, 9-19.8, 7.3, 1H ), 4.17-4.29 (t, 2H), 4.46 (i, 9-8.5, 1H), 6.18 (a, 9U-2.9, 1H), 6.86 (5 , 1H), 7.07 (a, 9-10.5, 1H), 7.24-7.29 (t, 2H), 7.30-7.38 (t, ЗН), 7.52-7 .58 (t, 2H), 7.81-7.89 (t, 1H).

Intermediate 39.1: (25, 4)-1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H- isoquinolin-2-yl|-benzoyl)-4-hydroxypyrrolidine-2-carboxylic acid. c) c) ; at

M I ol

M sho not

SI

Oxalyl chloride (0.020 mL, 0.23 mmol) and a catalytic amount of

DMF (0.001 mL, 0.015 mmol). The reaction mixture was stirred at 0 "C for 30 minutes, then DIPEA (0.106 mL, 0.608 mmol) and (25, 48)-4-hydroxypyrrolidine-2-carboxylic acid methyl ether hydrochloride (41.4 mg, 0.228 mmol) were added sequentially. The reaction mixture was allowed to warm to RT and stirred for 1 h. A 2M aqueous KOH solution was added, then the heterogeneous mixture was stirred for 30 min and extracted with EbO.

The organic layer was dried over MgSO 4 , filtered and evaporated to dryness to afford the crude title compound (71 mg, 0.12 mmol, 79 95) as a yellow resin which was used in the next step without further purification. TOP: "ve-2.04 min.; RH-

From MS: t/2 593.4 MANI".

Example 40.

Compounds 40a-40I were obtained from the intermediate product 38.3 (or its analogues obtained in a similar way) similarly to the preparation in example 38 or 39.

Me | Structure Name/HPLC/MS/NMR and lo

M Tsf A 7-(H)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-|4-4ba F c) (piperidine-1-carbonyl)phenyl-1 4-dihydro-2IN -

M isoquinolin-3-one. iy Ff TOP: Chvea-2.63; RH-MS: t/z 547.5 MANI". (o)

Me | Structure Name/HPLC/MS/NMR about lo

M Sh r 4-(7-(H)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3- dov N iv) oxo-3,4-dihydro-1 H-isoquinoline-2- il|-M- p methylbenzamide.

I Ff TOP: Chve-2,29; RH-MS: t/z 493.4 MANI". (9) and Po

MFA 4-(7-(H)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-4Os TU o oxo-3,4-dihydro-1H-isoquinolin-2-yl |-M,M- and diethylbenzamide. iy Ff TOP: Chve-2,58; RH-MS: t/: 535.5 MANI". (o) and Po

M Cro 4-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3- dod | o oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M,M-p dimethylbenzamide.

I F TOP: Thu-2.35; РХ-МС: t/: 5074 MANI". (9) (c) Fr.

M Phyro 7-(H)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-2-|4-

Ade FI iv) (pyrrolidine-1-carbonyl)phenyl/|-1,4-dihydro-2H-

M isoquinolin-3-one.

I Ff TOP: Chve-2,47; RH-MS: t/: 533.5 MANI". (9) and Po

M fi o 4-H7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-3-4 NA oxo-3,4-dihydro-1H-isoquinolin-2-yl|- benzamide ? FI TOP: Mne-2,19; RH-MS: t/ 479.4 MANI". (c) (9)

M (c) and I r M Phyro 4-(7-(H)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H- isoquinolin-2-yl|-M-methyl-M-9 p pyridin-4-ylbenzamide.

I Ff TOP: Chve-1,98; RH-MS: t/: 570.3 MANI". (at)

M (in) o. r M Tsf A 4-(7-(H)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3- dop c) oxo-3,4-dihydro-1 H-isoquinoline-2- il|-M-pyridine-4- that ilbenzamide.

From Ff VERH: Thu-2.04; RH-MS: t/ 556.3 (MAANI". (9)

Me | Structure Name/HPLC/MS/NMR

M (c) (c) i r M PO 4-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3- do iv) oxo-3,4-dihydro- 1 H-isoquinolin-2-yl|-M-pyridin-3-

NM ilbenzamide.

I Ff TOP: Chve-1,99; RH-MS: t/: 556.3 MANI". (o) at 6

C: methylamide (8)-1-44-(7-((B)-tert-butoxy)-1-(4-

M o7 chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-40 s isoquinolin-2-yl|-benzoyl)-pyrrolidine-2-carbonate). Ff acid.

Maya (c) TOP: Chve-2,18; RH-MS: t/: 590.3 MANI". (o) at 6

What is methylamide (8)-1-44-17-((B)-tert-butoxy)-1-(4-

M o7 chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H- 4ok M Also isoquinolin-2-yl|-benzoyl)-pyrrolidine-2-carbon

FI acids. and o (c) TOP: Chve-2,18; LC-MS: m/z 590.2 (MAANI". (o) o 6 no Shchi : |methylamide (28, 45)-1-(4-(7-(B)-tert-butoxy)-1-( 4- ; M 07 chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H- to M isoquinolin-2-yl|-benzoyl)-4-hydroxypyrrolidine-2-

FI of carboxylic acid. and o (c) TOP: Chve-1.99; RH-MS: t/z 606.3 (MAANI". (o)

Example 41: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-hydroxymethylphenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (c) (c) (c) Ю ЛЯ Ф (Fi

GiVN was sequentially added to a solution of intermediate 38.2 (50 mg, 0.10 mmol) in THF (1 mL) at RT. (6.6 mg, 0.30 mmol) and MeOH (0.012 mL, 0.30 mmol). The reaction mixture was stirred at RT for 2 h, then the reaction was carefully stopped by adding 2M

NOI in water, diluted with DCM and washed with 2M MgSO3 in water. The aqueous layer was further extracted with DCM (2x) and the combined organic fractions were dried over

Ma?5O", filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpi Sotrapiop "m (Izso Ips.) (510g; elution in gradient mode, (heptane/DCM 1:11 UTBME 95:5 -» 10095 TBME) and obtained the desired compound (22 mg . ,3 MANI; "H NMR (400 MHz,

COSiz): 0.93-1.03 (21, 9-7.5, ZN, mixture of diastereomers), 1.24-1.34 (24, 9-61, ZN, mixture of diastereomers), 1.61-1 .86 (t, 2H), 3.76 (a, U-19.8, 1H), 3.84-3.92 (t, 4H), 4.15-4.26 (t, 1H), 4 .70 (v, 2H), 5.76 (v, 1H), 6.68-6.74 (t, 2H), 7.05-711 (t, 2H), 7.12-7.17 (t , 2H), 7.24-7.30 (t, 2H), 7.34-7.40 (t, 2H).

Example 42: 7-((8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methylpyridin-4-ylmethylamino)phenyl|-1,4-dihydro-2H- isoquinolin-3-one.

M (c) (c) :

M. N

- SU Ts o7-

M

(Fi

ASON (0.009 mL, 0.15 mmol), pyridine-4-carbaldehyde (0.006 mL, 0.061 mmol) and

Mavn(OAc)z (19.4 mg, 0.091 mmol). The reaction mixture was stirred for 2 h, then additionally added ASON (0.008 mL, 0.14 mmol), formaldehyde (37 95 in water, 0.008 mL, 0.11 mmol) and additionally added Mavn(OAc)z (17 mg, 0.083 mmm). The reaction mixture was stirred at RT for 2 hours, then water was added and the two phases were separated. The aqueous layer was extracted with DCM (2x) and the combined organic fractions were evaporated to dryness.

The resulting residue was purified by preparative reverse-phase HPLC (U/ageg5 system) and the desired compound was obtained (salt with TFA, 10.8 mg, 0.016 mmol, 29 95). TOP:

AMve-2.05 min.; RH-MS: t/7 556.3 MANI; "H NMR (400 MHz, DMSO-dv): 0.83-0.94 (t, ЗН, mixture of diastereomers), 1.09-1.22 (249, 9-61, ЗН, mixture of diastereomers), 1, 43-1.68 (t, 2H), 3.03 (5,

ЗН), 3.56 (a, 9U-19.8, 1Н), 3.72 (5, ЗН), 3.83-3.93 (t, 1Н), 4.16-4.30 (t, 1H), 4.58 (5, 2H), 5.93-5.98 (t, 1H), 6.57-6.64 (t, 2H), 6.83 (5, 1H), 6.87 -6.95 (t, 2H), 7.03 (a, 9-66, 1H), 7.18 (9, 9-5.4, 2H), 7.34 (5, AN), 8.48 (y, 9U-4,9, 2H).

Intermediate 42.1: (1-(4-Chlorophenyl)-meth-(E)-ylidene|-(4-nitrophenyl)-amine.

SI century

OHM

The desired compound (2.27 g, 8.69 mmol, 80 95) was obtained as a yellow solid from 4-nitrophenylamine (1.5 g, 10.86 mmol) and 4-chlorobenzaldehyde (1.53 g, 10.86 mmol) similarly to obtaining intermediate product 1.4. "H NMR (400 MHz, SOSIiz): 7.23-7.31 (t, 2H), 7.48-7.54 (t, 2H), 7.85-7.92 (t, 2H), 8 .26-8.34 (t, 2H), 8.42 (5, 1H).

Intermediate 42.2: 7-((B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-nitrophenyl)-1,4-dihydro-2H-isoquinolin-3-one. c) c) And the worst

The desired compound (700 mg, 1.46 mmol, 47 95) was obtained as a yellow foam from intermediate 42.1 (812 mg, 3.12 mmol) and intermediate 1.3 (800 mg, 3.12 mmol) similarly to the preparation in the example 1. Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umaieg5 system). SUPER: "Chve-2.81 min.; LC-MS: t/7 481.4 MANI; H NMR (400 MHz, SOSIZ): 0.96-1.04 (t, HN, mixture of diastereoisomers), 1, 28-1.35 (29, 9-61, ZN, mixture of diastereomers), 1.60-1.87 (t, 2H, mixture of diastereomers), 3.75-3.80 (t, 2H), 3.88 (5, ЗН), 4.19-4.31 (t, 1Н), 5.85 (5, 1Н), 6.7З (5, 1Н), 6.80 (y, 9-49, 1Н), 7.09-7.15 (t, 2H), 7.29-7.34 (t, 2H), 7.39-7.46 (t, 2H), 8.20-8.27 (t, 2H ).

Intermediate 42.3: 2-(4-Aminophenyl)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-

1,4-dihydro-2H-isoquinolin-3-one. c) c) And vv your she (o)

In a sealed reaction flask, a mixture of intermediate 42.2 (700 mg, 1.46 mmol) and Ee (813 mg, 14.6 mmol) in ASON (2.8 mL), water (4 mL), and ASOCA (0.8 ml) was heated at 80 "C and stirred for 1 hour. The suspension was cooled to room temperature, neutralized by adding a saturated aqueous solution of ManHCO3 to pH 7 and filtered through a layer of celite.

The solid was washed with EtOAc and the biphasic filtrate was transferred to a separatory funnel. The aqueous layer was separated and additionally extracted with the help of ASOBEY (Zh).

The combined organic fractions were dried over NaCl, filtered and evaporated to dryness to afford the crude title compound (651 mg, 1.44 mmol, 99 95) as a yellow foam which was used in the next step without further purification. HPLC: "ve-1.88 min.; LC-MS: t/2 451.2 MANI; "H NMR (400 MHz, SOSIzv): 0.91-1.02 (21, 9-7.5, ZN , a mixture of diastereoisomers), 1.21-1.32 (29, У-6.1, ЗН, a mixture of diastereoisomers), 1.54-1.83 (t, 2Н), 3.83 (y, у-20, 3, 1H), 3.89 (v, ЗН), 3.97 (a, U-201, 1H), 4.12-4.23 (t, 1H), 5.69 (5, 1H), 6 .61 (a, 9-46, 1H), 6.72 (5, 1H), 6.81-6.93 (t, 4H), 6.99-7.04 (t, 2H), 7.23 -7.28 (t, 2H).

Example 43: M-(4-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl -phenyl)-M-methylacetamide. (c) (c) And Fr

J

(Fi

The desired compound (50.7 mg, 0.10 mmol, 57 95) was obtained from intermediate 43.3 (50 mg, 0.17 mmol) and intermediate 1.3 (44.8 mg, 0.17 mmol) similarly to the preparation in example 1 Purification of the crude substance was carried out using reverse-phase preparative HPLC (Umayeg5 system). TOP: Thu-2.37 min.; RH-MS: t/7 507.3 MANI; "H NMR (400 MHz,

COSiz): 0.94-1.03 (21, 9-7.5, ZN, a mixture of diastereomers), 1.26-1.34 (24, 9-61, ZN, a mixture of diastereomers), 1.56-1 .84 (t, 2H), 1.93 (5, ЗН), 3.28 (5, ЗН), 3.78 (а, 9У-19,8, 1Н), 3.88 (а, 9-19 ,6, 1H), 3.88 (5, ZN), 4.17-4.26 (t, 1H), 5.79 (rg. 5., 1H), 6.71-6.76 (t, 2H), 7.09-7.14 (t, 2H),

Koo) 7.17-7.32 (t, 6H).

Intermediate 43.1: M-Methyl-M-(4-nitrophenyl)-acetamide.

OHM

IF: yes

EM (0.364 ml, 2.63 mmol), acetyl chloride (0.14 ml, 1.97 mmol) were successively added to a solution of M-methyl-4-nitroaniline (200 mg, 1.31 mmol) in THF (5 ml) at RT ) and DMAP (8.0 mg, 0.066 mmol). The reaction mixture was stirred at room temperature for 2 h, then diluted with ASOEI and washed with water. The organic layer was dried over Ma»5O»-, filtered and evaporated to dryness to give the crude title compound (275 mg) as a brownish solid, which was used in the next step without further purification. TOP:

Afve-1.17 min.; LC-MS: t/2 195.4 (MANI; "H NMR (400 MHz, SOSIv): 2.05 (bBg. in5., ZN), 3.37 (5, ZN), 7.36-7, 46 (t, 2H), 8.27-8.36 (t, 2H).

Intermediate 43.2: M-(4-Aminophenyl)-M-methylacetamide.

N.M. and in

A solution of intermediate 43.1 (275 mg, 1.232 mmol) in EN (5 mL) was degassed under vacuum and backfilled with argon. Ra/C (1.31 mg, 0.012 mmol) and ammonium formate (155 mg, 2.46 mmol) were added sequentially and the heterogeneous mixture was vigorously stirred at RT for 2 h, then filtered through a pad of celite and the catalyst washed with

DXM. The filtrate was evaporated to dryness and the obtained crude substance was purified by column chromatography Sotbri-Riazpy Sotrapiop "m (Izso Ips.) (510g; elution in gradient mode, (heptane/dxM 1:1/TBME, which contains 5 95 7 M MHz in MeonN 95:5 -» 100 95 TBME containing 595 7 M MNz in Meon) and obtained the desired compound (190 mg, 1.16 mmol, 94 95) as a yellow oil. TLC: Ke-0.35 (heptane/DCM /TBME, which contains 595 7 M MNz in Mmeon 1:1:2); HPLC: Vivei-0.17 and 0.24 min.; IAT-MS: t/: 165.1 |MANI"; "H NMR ( 400 MHz, SOSIz): 1.87 (5, ЗН), 3.22 (5, ЗН), 6.67-6.73 (t, 2Н), 6.94-6.99 (t, 2Н).

Intermediate 43.3: M-(4-11-(4-Chlorophenyl)-meth-(E)-ylidene|-amino)-phenyl)-M-methylacetamide.

SI about su

J

The desired compound (160 mg, 0.56 mmol, 92 95) was obtained as a yellow solid from intermediate 43.2 (100 mg, 0.61 mmol) and 4-chlorobenzaldehyde (86 mg, 0.61 mmol) analogously to the preparation of intermediate 1.4. "H NMR (400 MHz, SOSIz): 1.93 (5, ZN), 3.31 (in,

ZN), 7.19-7.30 (t, 4H), 7.45-7.52 (t, 2H), 7.84-7.92 (t, 2H), 8.45 (5, 1H) .

Example 44: M-4-(7-((A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |I-phenyl)-M-cyclopentylmethylacetamide. (c) (c) Y

You are in the village

Co., Ltd. SI

To a solution of intermediate 44.1 (24 mg, 0.045 mmol) in THF (1 mL) at RT was sequentially added EIZM (0.012 mL, 0.090 mmol), DMAP (0.28 mg, 0.002 mmol), and acetyl chloride (0.007 mL, 0.090 mmol) . The reaction mixture was stirred at RT for 2 h, diluted with DCM and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The crude substance was purified using reverse-phase preparative HPLC (Umayeg5 system). SUPER: "no-2.89 min.; LC-MS: t/2 575.4 MANI; "H NMR (400 MHz, SOSI"): 0.94-1.03 (21, 9U-7.5, ЗН, a mixture of diastereoisomers), 1.18-1.26 (t, 2 H), 1.26-1.34 (29, 9-61, ЗН, a mixture of diastereoisomers), 1.47-1.84 (t, 8H), 1.88 (5, ЗН), 1.97-2.06 (t, 1H), 3.66-3.73 (t, 2H), 3.75-3.91 (t, 2H) , 3.89 (5, ZN), 4.17-4.26 (t, 1H), 5.81 (5, 1H), 6.71-6.76 (t, 2H), 7.08-7 ,13 (t, 2H), 7.14-7.20 (t, 2H), 7.22-7.32 (t, AN).

Intermediate 441: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(cyclopentylmethylamino)phenyl|-b-methoxy-1,4-dihydro-2H-isoquinoline- 3-on

c) c)

DK hundred

N

(at)

ASON (0.006 mL, 0.11 mmol), cyclopentanecarbaldehyde (0.006 mL, 0.053 mmol) and

Mavn(OAc)z (14.1 mg, 0.066 mmol). The reaction mixture was stirred at RT for 2 h, then 2 M NaCl in water was added, the two phases were separated, and the aqueous layer was further extracted with DCM (2x). The combined organic fractions were evaporated to dryness to afford the crude title compound (23.6 mg, 0.044 mmol, quantitative yield) as a tan solid. TOP: "ve-2.57 min.; RH-MS: t/2 533.4 |MANI"; "H NMR (400 MHz, SOSI»z): 0.93-1.02 (t, ЗН), 1.23-1.33 (t, 5Н), 1.51-1.88 (t, 8Н) , 2.11-2.22 (t, 1H), 3.01 (a, 9U-7.3, 2H), 3.74 (a, 9-19.8, 1H), 3.85-3, 92 (t, 4H), 4.14-4.24 (t, 1H), 5.68 (5, 1H), 6.52-6.58 (t, 2H), 6.66 (y, 9- 42, 1H), 6.70 (5, 1H), 6.85-6.90 (t, 2H), 7.05-7.10 (t, 2H), 7.22-7.27 (t, 2H).

Example 45: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-piperidin-3-ylmethylamino)phenyl|-1,4-dihydro-2H -isoquinolin-3-one (c) (c) oroFe su DU

M. a

SI

ASON (0.006 ml, 0.111 mmol), tert-butyl-3-formylpiperidine-1-carboxylate (13.0 mg, 0.061 mmol) and Mavn(Ods)z (23.5 mg, 0.111 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with water. The organic phase was dried over Mag50", filtered and evaporated to dryness. The resulting yellow resin was dissolved in

DCM (0.5 ml), then ASON (0.006 ml, 0.111 mmol), formaldehyde (37 Fo in water, 0.008 ml, 0.111 mmol) and Mavn(OAc)z (23.5 mg, 0.111 mmol) were sequentially added at CT . The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The resulting yellow resin was dissolved in DCM (1 mL) and TFA (0.021 mL, 0.272 mmol) was added at RT.

The reaction mixture was stirred at RT for 30 minutes, then evaporated to dryness.

The resulting crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 7 mg, 0.01 mmol, 1995) was obtained as a colorless solid. HPLC: "ve-2.11 min.; LC-MS: t/2 562.6 MANI; NN NMR (400 MHz, DMSOO-av): 0.683-0.95 (21.9-7.5, ZN, a mixture of diastereoisomers), 1.10-1.26 (t, 4H), 1.44-1.69 (t, ЗН), 1.69-1.84 (t, 2H), 2.01-2.15 (t, 1H), 2.59-2.80 (t, 2H), 2.89 (c, ЗН), 3.10-3.26 (t, 4H), 3.58 (а, 9-19 .8, 1H), 3.7Z (5, ЗН), 3.87-3.97 (t, 1H), 4.17-4.31 (t, 1H), 5.92-5.99 (t , 1H), 6.58-6.66 (t, 2H), 6.84 (5, 1H), 6.89-6.96 (t, 2H), 6.99-7.05 (t, 1H ), 7.36 (5, AN).

Example 46: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-(methyl-(1-methyl-piperidine-

(3-ylmethyl)amino|-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

at 5 and from SI

M o

M

(Fi

ASON (0.001 ml, 0.021 mmol), formaldehyde (37 95 in water, 0.002 ml, 0.021 mmol) and Mavn(ods)" (4.4 mg, 0.021 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with a 2 M aqueous solution of MagCO3. The organic phase was dried over NaCl5O, filtered and evaporated to dryness. The crude substance was purified by reverse-phase preparative HPLC (Uas(eg5) system) and obtained the desired compound (salt with TFA, 7.4 mg, 0.01 mmol, quantitative yield) as a colorless solid.

TOP: Thu-2.11 min.; RH-MS: t/2 576.3 |MANI; "H NMR (500 MHz, DMSO-α): 0.83-0.92 (21, 9U7.5, ЗН, mixture of diastereomers), 1.10-1.20 (2a, 9-61, ЗН, mixture of diastereomers ), 1.44-1.67 (t, 4H), 1.69-1.87 (t, 2H), 2.04-2.19 (t, 1H), 2.65-2.81 (t , 5H), 2.84-2.93 (t, ЗН), 3.08-3.19 (t, 1Н), 3.22-3.41 (t, ЗН), 3.56 (a, 9 -20.0, 1Н), 3.72 (5, ЗН), 3.91 (а, 9-20.0, 1Н), 4.17-4.27 (t, 1Н), 5.91-5 .96 (t, 1H), 6.58-6.63 (t, 2H), 6.83 (5, 1H), 6.88-6.94 (t, 2H), 6.98-7.02 (t, 1H), 7.32-7.37 (t, 4H).

Example 47: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-piperidin-4-ylmethylamino)phenyl|-1,4-dihydro-2H -isoquinolin-3-one.

N

M c) (c) And what 4, va

M

SI

The desired compound (TSF salt, 27 mg, 0.04 mmol, 36 95) was obtained as a light yellow solid from intermediate 42.3 (50 mg, 0.111 mmol) and benzyl 4-formylpiperidine-1-carboxylate (30.2 mg, 0.122 mmol) similarly to the preparation in example 45.

Cleavage of the carbamate protecting group from the benzyloxy group was carried out by hydrogenolysis using ammonium formate (1.5 equiv.) and Ra/C (0.05 equiv.) in EUN as a catalyst (0.1 M) at RT for 2 h. Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umayeg5 system). HPLC: "Chve-2.01 min.; LC-MS: t/7 562.5 |M-ANI; IN NMR (400 MHz, DMSO-av): 0.83-0.95 (21, 927.5 , ЗН, a mixture of diastereoisomers), 1.10-1.22 (29, 9У-6.1, ЗН, a mixture of diastereoisomers), 1.23-1.37 (t, 2Н), 1.45-1.69 ( t, 2H), 1.71-1.682

Zo (t, 2H), 1.87-1.98 (t, 1H), 2.75-2.88 (t, 2H), 2.91 (5, ЗН), 3.16-3.30 ( t, 4H), 3.60 (a, U-201, 1H), 3.73 (5, ЗН), 3.86-3.95 (t, 1H), 4.18-4.31 (t, 1H), 5.95 (a, 9U-2.9, 1H), 6.56-6.64 (t, 2H), 6.84 (5, 1H), 6.88-6.96 (t, 2H), 7.03 (0, 9U-5.9, 1H), 7.36 (5, AN), 8.06-8.20 (t, 1H), 8.41-8.54 (t, 1H).

Example 48: 2-14-(1-Acetylpiperidin-4-ylmethyl)-methylamino|-phenyl)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one.

you

M c) iv) vva

M

IF)

Pyridine (0.009 ml, 0.107 mmol) and acetic anhydride (0.002 ml, 0.026 mmol) were sequentially added to a solution of the compound of example 47 (TSF salt, 12 mg, 0.018 mmol) in DCM (0.5 ml) at RT. The reaction mixture was stirred at RT for 1 h, then diluted with

АСОБ and washed with water and saline solution. The organic phase was dried over Ma»50O54, filtered and evaporated to dryness. The obtained crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) and obtained the desired compound (salt with TFA, 7.1 mg, 0.01 mmol, 55 95) as a colorless solid. TOP: "Chvei-2.24 min.;

RH-MS: t/» 604.3 MANI; NN NMR (500 MHz, DMSO-sv): 0.82-0.92 (21, 9-7.5, ЗН, mixture of diastereomers), 0.93-1.03 (t, 1Н), 1.05- 1.21 (t, 4H), 1.45-1.65 (t, 4H), 1.82-1.92 (t, 1H), 1.95 (5, ZN), 2.37-2, 45 (t, 1H), 2.84-2.98 (t, 4H), 3.12-3.20 (t, 2H), 3.56 (y, 9U-19.8, 1H), 3, 72 (in, ZN), 3.74-3.81 (t, 1H), 3.84-3.92 (t, 1H), 4.18-4.28 (t, 1H), 4.31- 4.39 (t, 1H), 5.94 (y, 9-41, 1H), 6.55- 6.62 (t, 2H), 6.82 (5, 1H), 6.86-6, 92 (t, 2H), 7.02 (y, 9-7.3, 1H), 7.34 (5, AN).

Example 49: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-methanesulfonyl-piperidin-4-ylmethyl)-methylamino|-phenyl)-6-methoxy-1, 4-dihydro-2H-isoquinolin-3-one. --2 zo

M (c) (c) va

M

(Fi

EM (0.015 ml, 0.11 mmol) and methanesulfonyl chloride (8.2 mg, 0.071 mmol) were successively added to a solution of the compound of example 47 (20 mg, 0.036 mmol) in MesM (0.5 ml) at RT.

The reaction mixture was stirred at RT for 1 h, then immediately purified by reverse-phase preparative HPLC (Umayeg5 system) to obtain the desired compound (TSF salt, 16.1 mg, 0.021 mmol, 60 95) as a colorless solid. TOP: "Chvea-2.53 min.; RH-MS: t/? 640.4 MANI".

Example 50: Dimethylamide 4-((4-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- yl|I-phenyl)u-methylamino)-methyl|-piperidine-1-carboxylic acid.

M (c) r t

M c) (c)

SS are what

M

SI

To a solution of the compound of example 47 (20 mg, 0.036 mmol) in MesSM (0.5 ml) at RT, EH33M (0.015 ml, 0.11 mmol) and dimethylcarbamoyl chloride (0.007 ml, 0.071 mmol) were sequentially added.

The reaction mixture was stirred at RT for 30 minutes, then immediately purified by reverse-phase preparative HPLC (Ulasgeg5 system) to obtain the desired compound (TSF salt, 17.4 mg, 0.023 mmol, 65 95) as a colorless solid. TOP:

Ade2.39 min.; RH-MS: t/2 633.4 MANI.

Example 51: 2-14-KTrans-4-aminocyclohexylmethyl)-methylamino|-phenyl)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1,4-dihydro-2H -isoquinolin-3-one.

MH,

A (in; o. va

M

SI

TFA (8.0 mL, 104 mmol) was added to a solution of intermediate 51.1 (1.35 g, 2.0 mmol) in DCM (16 mL) at RT. The reaction mixture was stirred at RT for 30 minutes, then evaporated to dryness. The obtained crude substance was dissolved in ASOEA and washed with a 2M aqueous solution of MagSO3 (2x). The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified using column chromatography

Sotrbri-Riazpy Sotrapiop m (I5so Ips.) (ZiOg; elution in the gradient mode, DXM/7M МНз in

Meon 99.5: 0.5 -» 9: 1) and obtained the desired compound (761 mg, 1.32 mmol, 66 95) as a brown solid. TLC: Be-0.26 (DHM/7M MNz in Meon 9: 1); TOP: Chves-1.91 min.;

LC-MS: t/2 576.4 (MANI; "H NMR (400 MHz, DMSOO-av): 0.84-0.97 (t, 6H), 1.11-1.23 (29, 9- 61,

ЗН, a mixture of diastereoisomers), 1.43-1.78 (t, 8Н), 2.39-2.48 (t, 1Н), 2.87 (5, ЗН), 3.04-3.14 (t , 2H), 3.57 (9, 9U-19.8, 1H), 3.73 (5, ЗН), 3.89 (a, 9U-19.8, 1H), 4.18-4.31 (t, 1H), 5.95 (9, 9U-3.4, 1H), 6.51-6.61 (t, 2H), 6.84 (5, 1H), 6.86-6.93 (t, 2H), 7.04 (y, 9-5.9, 1H), 7.35 (5, AN).

Intermediate 51.1: Tert-butyl ether 14-(14-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H- isoquinolin-2-yl|1-phenyl)-methylamino)-methyl|-thrano-cyclohexyl)- carbamic acid.

H

A MN and (c) o g vv vva

M. a

ASON (0.26 ml, 4.46 mmol), tert-butyl ether (trans)-(4- formylcyclohexyl)-carbamic acid (557 mg, 2.45 mmol) and Mavn(oOds)" (945 mg, 4.46 mmol). Reaction mixture

Zo was stirred at RT for 1 h, then diluted with DCM and washed with a 2M aqueous solution of MagCO3 (2x). The organic phase was dried over Mag505, filtered and evaporated to dryness. The obtained yellow solid was dissolved in DCM (13 mL), then at RT, ASON (0.25 mL, 4.44 mmol), formaldehyde (37 9o in water, 0.33 mL, 4.44 mmol) and

Mavn(oOAc)z (940 mg, 4.44 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with a 2M aqueous solution of MagSO3 (2x). The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpy Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in the gradient mode, (heptane/dxM 1: C/TBME, which contains 5 95 7M MNz in MeOon 95: 5 - 100 95 TBME, which contains 5 95 7/M MHz in MeOnH) and obtained the desired compound (1.35 g, 2.0 mmol, 90 95) as a yellow solid. TLC: Ke-0.32 (heptane/"DCM /TBME, which contains 1 95 7M MNz in MeOnN 1: 1: 2); HPLC: Java-2.80 min.; LC-MS: t/2 676.6 (MANI.

Example 52: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-Ktrans-4-ethylamino-cyclohexylmethyl)-methylamino|-phenyl)-b-methoxy-1,4-dihydro -2H-isoquinolin-3-one. shh

And (c) (c) at 4, vva

M

SI

ASON (0.06 ml, 1.04 mmol), acetaldehyde (0.032 ml, 0.57 mmol) and Mavn(OAds)z (221 mg, 1.04 mmol). The reaction mixture was stirred at RT for 14 h, diluted with DCM and washed with a 2M aqueous solution of MagSO3 (2x). The organic phase was dried over

Ma?5O'' was filtered and evaporated to dryness to afford the crude title compound (55 mg, 0.091 mmol, 88 95) as a yellow solid, which was used in the next step without further purification. TOP: Yave-1.97 min.; RH-MS: t/2 604.3 MANI".

Example 53: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-C4-(ethylmethylamino)-trans-cyclohexylmethyl|-methylamino)-phenyl)-6-methoxy-1, 4-dihydro-2H-isoquinolin-3-one. you are

And (c) (c) at 4,

VO

M

SI

ASON (0.003 ml, 0.046 mmol), formaldehyde (37 95 in water, 0.003 ml, 0.046 mmol) and

Mavn(oAc)z (9.7 mg, 0.046 mmol). The reaction mixture was stirred at RT for 2 h, then immediately purified by reverse-phase preparative HPLC (UMaiegv system) to obtain the desired compound (TSF salt, 7.4 mg, 0.010 mmol, 44 9b5) as a colorless solid. TOP: "Ivea-2.01 min.; RH-MS: t/: 618.4 MANI".

Example 54.

Compounds 54aa-54se were obtained from intermediate 42.3 (or its analogues obtained in a similar way), the compound of example 47 (or its analogues obtained in a similar way), the compound of example 51 (or its analogues obtained in a similar way) or the compound of example 52 (or its analogues obtained in a similar way) similarly to the preparation of intermediate product 44.1, compounds of example 42, 46, 48, 49, 50, 52, or 53.

Coo)

7-((B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-yl)diethylaminophenyl)-6-methoxy-1,4 -dihydro-2H-

B4aa C t.

M isoquinolin-3-one.

A and TOP: Chva-2.01; RH-MS: t/2 5071 (MANI. (v

Me Structure Name/VvERK/MS and Po

Mfiro 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-|4- vda SU o (cyclopentylmethylmethylamino)phenyl|-6-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chva-2.52; RH-MS: t/2 547.6 (MANI. (o) (c) o.

MC KA 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-|4-

Bilas re SU c) (isopropylmethylamino)phenyl)|-6-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

F TOP: Chva-2.02; RH-MS: t/2 507.5 (MANI. (9) about that

M Fi AK 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-|4- vlache SU (in; (cyclopentylmethylamino)phenyl|-6-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

F TOP: Chne-2,11; RH-MS: t/: 533.5 |MANI. (9) and Po

M Ci A 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-|4-

B4ae Fi SU o (cyclohexylmethylamino)phenyl|-b-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

Ff VERH: Chne-2,22; RH-MS: t/: 547.5 MANI. (o) (c) o. m TSA 7-((B)-tert-butoxy)-2-(4-(tert-butyl-

Bala! x SU c) methylamino)phenyl|-1-(4-chlorophenyl)-b-methoxy-

M 1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chva-2,19; RH-MS: t/2 521.5 (MANI. (9) (c) o.

M fi Ai 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-|4-vla i SU o (cyclopropylmethylmethylamino)phenyl|-b-methoxy-9 M 1,4-dihydro-2H -isoquinolin-3-one.

Ff VERH: Chne-2,12; RH-MS: t/: 519.4 MANI. (o) (c) o.

M fi Z 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-vanu o (cyclohexylmethylmethylamino)phenyl|-b-methoxy-

M 1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chne-2.85; RH-MS: t/z 561.4 MANI. (at)

Me Structure Name/VvECH/MS about that

M Phi A 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-|4-

Bavi vv o (isobutylmethylamino)phenyl|-b-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

Ff VERH: Chva-2.57; RH-MS: t/2 521.4 (MANI. (o) (c) o.

M Ci Ai 2-(4-(benzylmethylamino)phenyl-7-((H)-second-

Baai SU about butoxy)-1-(4-chlorophenyl)-6-methoxy-1,4-dihydro-! m 2H-isoquinolin-3-one.

Ff TOP: Chva-2.81; RH-MS: t/2 555.4 (MANI. (o) (c) o.

M Phyro 7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-|4-

Buck (SU c) (ethylmethylamino)phenyl|-6-methoxy-1,4-dihydro-

M 2 H-isoquinolin-3-one.

F TOP: Chne-2.01; RH-MS: t/2 493.4 M.ANE.. (9) (c) o

M Phyro 7-(H)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-aa! | SU (c) ethylaminophenyl)-6-methoxy-1,4-dihydro-2 H-

M isoquinolin-3-one. n Ff TOP: Chvne-1.99; RH-MS: t/: 479.6 MANI. (9) (c) Fr.

M Phyro 7-(H)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-

Bilat and SU iv) dipropylaminophenyl)-6-methoxy-1,4-dihydro-2H-

M isoquinolin-3-one.

CHU F TOP: Chva-2,28; RH-MS: t/2 535.6 (MANI. (9) (c) o.

M Shchi A 7-(H)-tert-butoxy)-1 -(4-chlorophenyl)-2-|4-val Z SU o (cyclobutylmethylamino)phenyl|-b-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

Ff TOP: Chne-2.08; RH-MS: t/: 519.4 MANI. (o) and lo

МФАЖ 7-(B)-tert-butoxy)-1 -(4-chlorophenyl)-2-4-((2-

In SU o fluorobenzyl)-methylamino|-phenyl)-b-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

Ff TOP: Chne-2.99; RH-MS: t/: 573.2 | MANEI. (at)

Me Structure Name/VvECH/MS

E (c) (c)

M Cf 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(2,3-difluorobenzyl)-methylamino|-phenyl)-b-methoxy- p M 1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chvea-3,13; LC-MS: t/2 591.2 (MANI. (c) poison (c) (c)

IS :

M Phi : 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-iareoz 2-I4-(methyl-(3-trifluoro-methylbenzyl)amino|-9m phenyl) -1,4-dihydro-2H-isoquinolin-3-one.

Fu TOP: Chne-3,21; RH-MS: t/: 623.2 | MANEI. (in)

EC and (c) (c)

Fi : 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-vda M o |2-4-Imethyl-(4-trifluoromethyl-benzyl)amino|-phenyl)-1, 4-dihydro-2H-isoquinolin-3-one.

And Ff VERH: AChve-3,23; RH-MS: t/ 623.2 |MENG. (in)

E (c) (c)

MCA 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-((3-

Bala: SU iv) fluorobenzyl)-methylamino|-phenyl)-b-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

Ff VERH: Chvea-3.00; RH-MS: t/2 573.2 (MANI. (c) (c) (c)

M : also M Phi | 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-

Baai SU 077 2-(4-(methylpyridin-3-ylmethylamino)phenyl|-1,4-

M dihydro-2H-isoquinolin-3-one.

F TOP: Chne-2.05; RH-MS: t/: 556.2 IM.-ANG.. (c)

IS

(c) (c)

Mia! 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-((4-

B4ac rve 077700 |fluorobenzyl)-methylamino|-phenyl)-b6-methoxy-1 4-

M dihydro-2H-isoquinolin-3-one.

Ff TOP: Chne-2.84; RH-MS: t/: 573.2 | MANEI. (in)

IS

E (c) (c)

M F! 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(A-((3,4-

Baau C "ai difluorobenzyl)-methylamino|-phenyl)-b-methoxy-

M 1,4-dihydro-2H-isoquinolin-3-one.

Ff TOP: Chne-3.06; RH-MS: t/: 591.2 MANI. (in)

Me Structure Name/VvECH/MS

M (c) and Y r TSI Sh r 7-((B)-second-butoxy)-1-(4-chlorophenyl)-b-methoxy-

SU o 2-IA-I(pyridin-4-ylmethyl)amino|-phenyl)-1,4-

B4am: v.

M dihydro-2H-isoquinolin-3-one.

H Ff TOP: Chvea-1.97; RH-MS: t/2 542.5 MANI. (in)

M (v o Y r M C Ai 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-|4-

Bach SU o (cyclopropylmethylpyridin-4-ylmethylamino)-

M phenyl|-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

FI TOP: Chva-2,23; RH-MS: t/2 596.5 (MANI. (c)

M (in o. r M Sh ro 7-(A)-second-butoxy)-1-(4-chlorophenyl)-2-|4- b4au SU (in; (ethylpyridin-4-ylmethylamino)phenyl|-b- methoxy-

M 1,4-dihydro-2H-isoquinolin-3-one. r F TOP: Chne-2,13; RH-MS: t/: 570.3 MANI. (c) o o : -(B)-second-butoxy)-1-(4-chlorophenyl)-6b-methoxy -6 2 M o 2-i4-K2-morpholin-4-ylethyl)-pyridin-4-

Б4а корий Zylmethylamino|-phenyl)-1,4-dihydro-2H-isoquinolin-3-iv) M on.

Szh 4 si VERH: Chva-1.72; LC-MS: m/2 655.4 (MANI. (c) a: (in o. k r m C : 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-

Bara SU 977) 2-(4-(methylpyrimidin-4-ylmethylamino)phenyl|-1,4-

M dihydro-2H-isoquinolin-3-one.

Ff VERH: Chva-2,48; RH-MS: t/2 5571 (MANI. (c)

M (c) o i r M Fi i 7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-2-(A-|(3-

BABY and swarm 973 fluoropyridin-4-ylmethyl)-methylamino|-phenyl)-b-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chne-2.40; RH-MS: t/: 574.2 MANI. (c) o o. ho in M Tsf | 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-

BAFS swarm 977 2-(d4-(methylthiophen-3-ylmethyl-amino)phenyl-1,4-

M dihydro-2H-isoquinolin-3-one.

F TOP: Chne-2.58; RH-MS: t/z 561.2 MANI. (in)

Me Structure Name/BvEPHC/MS o o y Fi Y 7-((B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy- - M o7 2-(4-(methyl-(3- methyl-ZN-imidazole-4-

Barium Zylmethyl)amino|-phenyl)-1,4-dihydro-2H-isoquinoline-

M Z-on.

F TOP: Chva-2.04; LC-MS: m/2 559.2 (MANI. si (c) o o. x. X M Tsf: 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4- (furan-

Bare SU 97 3-ylmethylmethylamino)phenyl|-6-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

FI VERH: "Chne-2.40; RH-MS: t/ 545.2 MANI. si 9773 (in) 6) .

Sm M Phi Ya 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-

Barium SU 973 2-IA-Imethyl-(2-morpholin-4-ylethyl)amino|-phenyl)-

M 1,4-dihydro-2H-isoquinolin-3-one.

Ff VERH: "Chve-2.03; RH-MS: t/2 578.3 MANI". si

M o o.

M Phi Aa 7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-

Bar SU o 2-IA-Imethyl-(1-methylpiperidin-4-ylmethyl)amino|- 9m phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: "Chve-2.04; RH-MS: t/2 576.3 MANI". si | : : o o 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-phi : 2-14-(methyl-(4-propylamino-trans-5Arp M o cyclohexylmethyl)amino| -phenyl)-1,4-dihydro-2H-

SU isoquinolin-3-one.

Y F TOP: Ave-2.03; RH-MS: t/2 618.5 (MANI. si in) ; (c) o M-14-(44-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-

Also: methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- 54 M 977 phenyl)-methylamino)-methyl|-trans-cyclohexyl)-acetamide.

Y Fu TOP: Ainea-2,13; RH-MS: t/h 618.3 MEN. (in)

Me Structure Name/VvECH/MS

B o o, 7-((B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-|(4-

M I dimethylamino-trans-cyclohexylmethyl)-54) p 97) methylamino|-phenyl)-b-methoxy-1,4-dihydro-2H-

M isoquinolin-3-one.

TOP: Chvne-1.98; RH-MS: t/: 604.3 MANI. (in)

MN, (c) (c)

SH B 2--4-Ktrans-4-aminocyclohexylmethyl)-

M 97 methylamino|-phenyl)-7-(A)-second-butoxy)-1-(4-

Tank SU Z chlorophenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline-

M Z-on.

F TOP: Chvea-1.91; RH-MS: t/2 576.3 (MANI. (in) o

An (c) He) M-14-14-(7-(A)-second-butoxy)-1-(4-chlorophenyl)-6-

These: methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-

BABY M 97 phenyl)-methylamino)-methyl|-trans-cyclohexyl)-acetamide.

And Ff TOP: Ainea-2,15; RH-MS: t/x 618.3 MNE. (c) - a o o. 7-((B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-|(4-

M and dimethylamino-trans-cyclohexylmethyl)-

Bart p 97) methylamino|-phenyl)-6-methoxy-1,4-dihydro-2H-

M isoquinolin-3-one.

TOP: Chwea-1.89; RH-MS: t/2 604.3 (MANI. (in) o

Fi o o : 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-

M and 2-14-(methyl-(1-propionylpiperidine-4-

Barp rozylmethyl)amino|-phenyl)-1,4-dihydro-2H-isoquinoline-

M Z-on.

Ff VERH: Chne-2,41; RH-MS: t/: 618.3 MANI. (c) o i o o o - 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-

M and 2-(4-methyl-|1-(3-methylbutyryl)-piperidine-4-

B54ro and 97 ylmethyl|-amino)-phenyl)-1,4-dihydro-2H-isoquinoline-

M Z-on.

FI TOP: Chne-2.66; RH-MS: t/: 646.5 | MANEI. (in)

Me Structure Name/BvEPHC/MS other

M I isobutyrylpiperidin-4-ylmethyl)-methylamino|- z4pp U oz phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

M TOP: Chne-2.54; PH-MS: t/: 632.5 IM.-ANI.. g (c)

Al

M (c) o 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-((1- and C E cyclopropanecarbonylpiperidin-4-ylmethyl)-

Bara 97 methylamino|-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. 7 Ff TOP: Chne-2,47; RH-MS: t/: 630.4 MANI. (in that

M (c) (c)

C : 7-(B8)-tert-butoxy)-2-14-(1-butyryl-piperidine-

BAVI M 97 4-ylmethyl)-methylamino|-phenyl)-1-(4-chlorophenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Y FI TOP: AMve-2.54; RH-MS: t/ya 632.4 MEN. (c) (o) (c) M-14-14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-

F: methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl (54p50) M 97 phenyl)-methylamino)-methyl (trans-cyclohexyl)-3-methylbutyramide.

And Ff TOP: Chne-2,45; RH-MS: t/h 660.5 MEN. (c) o shchi ; (c) o M-14-(44-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-

F: methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- 54) M 97 phenyl)-methylamino)-methyl|-trans-cyclohexyl)- isobutyramide.

Y FI TOP: Ane-2,36; RH-MS: t/h 646.4 ME. (c) o "Ж and (c) (c) M-14-(44-H7-(A)-tert-butoxy)-1-(4-chloro-phenyl)-6-

Ts! methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-

BAryS) M 97 phenyl)-methylamino)-methyl|-trans-cyclohexyl)-propionamide.

J F TOP: Aeneas 2,25; RH-MS: t/» 632.4 MANI. (in)

Me Structure Name/BvEC/MS o also (c) (c) M-14-(44-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-

F! methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-

BAru") M 977 phenyl)-methylamino)-methyl|-trans-cyclohexyl)-butyramide.

J FI TOP: Aine-2.35; RH-MS: t/ 646.4 ME. (c) 9.70 vn and (c) o M-14-(44-17-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-c Cf : methoxy-3-oxo-3 ,4-dihydro-1H-isoquinolin-2-yl|-

Arms from phenyl)-methylamino)-methyl|-trans-cyclohexyl)-

M methanesulfonamide.

Fu TOP: Chne-2.33; RH-MS: t/: 654.3 MANI. (c) o ku ; (c) about 3-14-((4-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-

F : methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-

BaArkhg) M 97 phenyl)-methylamino)-methyl|-trans-cyclohexyl)-1,1-dimethylurea.

J FI TOP: Ane-2,20; RH-MS: t/h 647.4 MEN. (c) -

M (c) and 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-14-K(1-

Phi : cyclobutanecarbonylpiperidin-4-ylmethyl)-

Baru M with methylamino|-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

I FI TOP: Chva-2.61; RH-MS: t/: 644.5 MANI. (c) Fr

Hu and (c) o M-14-(44-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-

These: methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- 54027) M 977 phenyl)-methylamino)-methyl|-trans-cyclohexyl)-

M-ethylacetamide.

Y Fu TOP: Ane-2.42; RH-MS: t/h 646.4 ME. (c) 0.0 hours; (9) o M-14-(44-(7-(A)-second-butoxy)-1-(4-chlorophenyl)-6-

M Ff A methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-

Basa" 97 phenyl)-methylamino)-methyl|-trans-cyclohexyl)-

M M-ethylmethanesulfonamide.

F TOP: Chne-2.62; RH-MS: t/2 682.4 |M.-ANE.. (c)

Me Structure Name/VvERK/MS o

Cum, and (c) (c) 1--4-((14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-

F! methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-

BASO) M 977 phenyl)-methylamino)-methyl|-trans-cyclohexyl)-1-ethyl-3,3-dimethyl-urea.

AND FI TOP: Aine-2.58; RH-MS: t/h 675.5 |ME. (9) in g; oh oh 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-4-((trans-

Shh! 4-dipropylaminocyclohexylmethyl)-methylamino)|-

Bass M: . according to

In o phenyl)-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

M TOP: Chva-2,26; LC-MS: t/: 659.5 (MANI. a (9) o o : 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-ChTtrans-

M and 4-(isobutylmethylamino)-cyclohexylmethyl-

Basa reoz methylamino)-phenyl)-6-methoxy-1,4-dihydro-2H-

M isoquinoline-Z-on.

FI TOP: Chne-2,13; RH-MS: t/ 646.4 MANI. (9) r; (c) Ge) 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-HTtrans-

Phi : 4-(isopropylmethylamino)-cyclohexylmethyl-

Ba4se Moz methylamino)phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. 7 Ff TOP: Chva-2.05; LC-MS: t/2 632.4 (MANI. (9) (1) The desired compound was obtained from the corresponding amine similarly to the preparation in example 48, 49 or 50 using various acyl chlorides, sulfonyl chlorides or carbamoyl chlorides.

Example 55: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-2-(4-(1-pyrrolidin-1-ylethyl)phenyl|-1,4-dihydro-2H -isoquinolin-3-one (Methodology A) (c) (c) I

C, (c)

SI

ASON (0.017 mL, 0.29 mmol), pyrrolidine (0.018 mL, 0.22 mmol) and Mavnzsm (13.8 mg , 0.22 mmol). The reaction mixture was stirred at RT for 2 h, then 2M MgSO3 in water and DCM were added. The two phases were separated, the aqueous layer was further extracted with DCM (2x) and the combined organic fractions were dried over magnesium sulfate, filtered and evaporated to dryness.

The crude material was purified by reverse-phase preparative HPLC (Umayeg5 system) to give the desired compound (24.1 mg, 0.037 mmol, 51 95). TOP: "Chne-2.01 min.; LC-MS: t/2 533.3 MANI; NN NMR (400 MHz, COzO0): 0.89-1.00 (21, 9-7.5, ZN, mixture of diastereoisomers), 1.14-1.25 (2a, 9-61, ЗН, mixture of diastereoisomers), 1.50-1.71 (t, 2Н), 1.70-1.76 (t, ЗН), 1.86-2.00 (t, 1H), 2.01-2.28 (t, ЗН), 2.92-3.17 (t, 2H), 3.19-3.29 (t, 1H ), 3.73-3.82 (t, 2H), 3.86 (5, ЗН), 4.06 (y, 9U-20.5, 1H), 4.18-4.29 (t, 1H ), 4.34-4.44 (t, 1H), 6.06 (v, 1H), 6.78-6.83 (t, 1H), 6.90 (5, 1H), 7.19- 7.25 (t, 2H), 7.26-7.34 (t, 4H), 7.46-7.52 (t, 2H).

Intermediate 55.1: 1-(4-11-(4-Chlorophenyl)-meth-(E)-ylidene|-amino)-phenyl)-ethanone.

SI about

The title compound (460 mg, 1.80 mmol, 49 95) was obtained as a pale yellow solid from 1-(4-aminophenyl)ethanone (500 mg, 3.7 mmol) and 4-chlorobenzaldehyde (520 mg, 3, 7 mmol) similarly to obtaining intermediate product 1.4. "H NMR (400 MHz, SOSIiz): 2.64 (v, ЗН), 7.22-1.21 (t, 2Н), 7.47-7.53 (t, 2Н), 7.85-7 .92 (t, 2H), 8.00-8.06 (t, 2H), 8.43 (5, 1H).

Intermediate 55.2: 2-(4-Acetylphenyl)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (c) (c) I vv 9 (c)

Guo (Fi

The desired compound (286 mg, 0.60 mmol, 62 95) was obtained as a yellow foam from intermediate 55.1 (248 mg, 0.96 mmol) and intermediate 1.3 (247 mg, 0.96 mmol) similarly to the preparation in the example 1. Purification of the crude substance was carried out using reverse-phase column chromatography (C18; gradient elution, water containing 0.5 95 TFA/MesMm 95:5 -» 3:7). TOP: "Chnee2.63 min.; RH-MS: t/2 478.5 MANI; "H

NMR (400 MHz, DMSO-α): 0.85-0.95 (21, 9U-7.5, ZN, a mixture of diastereoisomers), 1.13-1.23 (29, 9-61,

ЗН, a mixture of diastereoisomers), 1.46-1.69 (t, 2Н), 2.55 (в, ЗН), 3.66 (а, 9-19.8, 1Н), 3.74 (5, ЗН ), 3.90 (aa, 9-19.8, 3.9, 1H), 4.20-4.31 (t, 1H), 6.25 (9, 9-3.4, 1H), 6 .88 (5, 1H), 7.10 (a, 9-71, 1H), 7.32-7.42 (t, 6H), 7.91-7.97 (t, 2H).

From Example 56: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(1-morpholin-4-ylethyl)phenyl|-1,4-dihydro- 2H-isoquinolin-3-one (Method B)

LI

S m F (Fi

Morpholine (0.016 mL, 0.188 mmol) and Ti(OiRg) were successively added to a solution of intermediate 55.2 (30 mg, 0.063 mmol) in THF (0.5 mL) under RT. (0.056 mL, 0.188 mmol). The reaction mixture was refluxed and stirred for 14 hours. and cooled to CT. Men (0.2 mL) was added, followed by Mavna (2.4 mg, 0.063 mmol), and the mixture was stirred at

CT for 1 hour. Celite and water were added, the heterogeneous mixture was vigorously stirred for 15 min., filtered, and the precipitate on the filter was washed with ASOEI. The filtrate was washed with a 2M aqueous solution of MagCO3 and the organic phase was dried over Mag50, filtered and evaporated to dryness. The obtained crude substance was purified using a preparative method

Reverse phase HPLC (Umayeg5 system) and obtained the desired compound (TPA salt, 19.8 mg, 0.038 mmol, 48 95) as a colorless solid. HPLC: "ve-1.91 min.; LC-MS: t/: 549.3 (MANI; H NMR (400 MHz, COzO0): 0.89-1.00 (2nd, 9-7.5, ZN , a mixture of diastereoisomers), 1.14-1.26 (29, 9-61, ZN, a mixture of diastereoisomers), 1.50-1.73 (t, 2H), 1.76 (I, 9U-6.4, ZN), 2.93-3.20 (t,

ZN), 3.60-3.84 (t, ZN), 3.79 (a, 9-20.3, 1H), 3.86 (5, ZN), 3.94-4.16 (t, 2H), 4.07 (a, 9-20.5, 1H), 4.18-4.29 (t, 1H), 4.43-4.52 (t, 1H), 6.06 (Be. 5., 1H), 6.78-6.83 (t, 1H), 6.90 (5, 1H), 7.19-7.26 (t, 2H), 7.28-7.35 (t , 4H), 7.48-7.55 (t, 2H).

Example 57: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-I(4-(1-hydroxyethyl)phenyl|-b-methoxy-1,4-dihydro-2H-isoquinoline- 3-on (c) (c) (c) "I F schi

To a solution of intermediate 55.2 (25 mg, 0.052 mmol) in MeOH (1 ml) at RT was added

MavVnNa (4 mg, 0.11 mmol). The reaction mixture was stirred at RT for 2 h. and concentrated in vacuo. The resulting residue was dissolved in DCM and washed with water.

The organic layer was dried over Ma»5O»4, filtered and evaporated to dryness. The crude substance was purified by reverse-phase preparative HPLC (UmMaieg5 system) to give the desired compound (11 mg, 0.021 mmol, 39 95). TOP: "Chve-2.42 min.; PH-MS: t/l 480.5

IM-ANI: H NMR (500 MHz, DMSO-α): 0.84-0.93 (21, 9U-7.5, ZN, a mixture of diastereoisomers), 1.11-1.21 (29, 9-61 . 3.72 (5, ZN), 3.89 (aa, 9U-19.6, 3.6, 1H), 4.18-4.29 (t, 1H), 4.64-4.70 (t , 1H), 6.07 (a, 9-43, 1H), 6.84 (5, 1H), 7.06 (a, 9U-7.8, 1H), 7.08-7.12 (t , 2H), 7.26-7.91 (t, 2H), 7.33-7.38 (t, 4H).

Example 58: M-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl|1-phenyl)-ethyl)-N-ethylacetamide. (c) (c) va and fi o7-7 sho zo p

Pyridine (0.22 mL, 2.68 mmol) and acetic anhydride (0.061 mL, 0.64 mmol) were sequentially added to a solution of intermediate 58.1 (272 mg, 0.54 mmol) in DCM (5 mL) at RT. The reaction mixture was stirred at room temperature for 1 h, diluted with ASOEL and washed with water and saline. The organic phase was dried over Mag5O4, filtered and evaporated to dryness. The obtained crude substance was purified using column chromatography

Sotbri-RIazp Sotrapiop "m (I5so Ips.) (ZiOg; gradient elution, DHMIDHM/MeeOH 971 95:5 -" 1:11) and obtained the desired compound (215 mg, 0.39 mmol, 73 90) in the form yellow resinous substance. TLC: Ke-0.31 (DCM/Meon 95:5); HPLC: "ve-2.54 min.; RH-MS: t/2,549.3 MANI; "NN NMR (400 MHz, DMSO-α): 0.74-0.96 (t, 6H), 1.10-1.23 (t, Н, a mixture of diastereoisomers), 1.38-1.71 (t , 5H), 2.02-2.14 (t, ЗН), 2.82-3.26 (t, 2Н), 3.58-3.67 (t, 1Н), 3.74 (5, ЗН ), 3.85-3.95 (t, 1H), 4.17-4.30 (t, 1H), 5.04-5.74 (t, 1H, a mixture of diastereoisomers), 6.07-6, 15 (t, 1H), 6.86 (5, 1H), 7.02-7.08 (t, 1H), 7.10-7.21 (t, 2H), 7.22-7.31 ( t, 2H), 7.31-7.39 (t, 4H).

Intermediate 58.1: 7-((B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(1-ethylamino-ethyl)phenyl|-b-methoxy-1,4-dihydro-2H -isoquinoline-3-one (c) (c)

M and o7-7

SI

To a solution of intermediate 55.2 (500 mg, 1.05 mmol) in dry THF (5 mL) at RT, Ti(OiRg)4 (0.929 mL, 3.14 mmol) and ethylamine (2M solution in THF, 2.62 ml, 5.23 mmol). The reaction mixture was refluxed for 3 h, then cooled to RT. MavNzSsM (197 mg, 3.14 mmol) was added and the reaction mixture was stirred at RT for 14 h. Celite and water were added, the heterogeneous mixture was vigorously stirred for 15 min., filtered, and the precipitate on the filter was washed with

ASOKY The filtrate was washed with a 2M aqueous solution of MgCO3 and the organic phase was dried over Ma»5Ox, filtered and evaporated to dryness. The resulting crude substance was purified by column chromatography Sotbri-Riazpy Sotrapiop "m (Izso Ips.) (510g; elution in gradient mode, heptane/tBME, which contains 5 95 7M MHz in Meon 95:5 -" 100 95 TBME, which contains 5 95 7M MHz in Meon) and obtained the desired compound (272 mg, 0.54 mmol, 51 95) in the form of a yellow foamy substance. HPLC: "ve-1.95 min.; RH-MS: t/2 507.2 MANI; "H NMR (500 MHz, DMSO-

Оv): 0.83-0.98 (t, 6Н), 1.12-1.22 (t, ЗН), 1.45-1.68 (t, ЗН), 1.80-1.94 ( t, 1H), 2.20-2.38 (t, ЗН), 3.54-3.67 (t, 2Н), 3.72 (5, ЗН), 3.80-3.88 (t, 1H), 4.17-4.30 (t, 1H), 6.05-6.11 (t, 1H), 6.84 (5, 1H), 7.05-7.13 (t, ЗН) , 7.23-7.30 (t, 2H), 7.35 (5, AN).

Example 59: (1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl -phenyl)-ethyl)-ethylamide of 1-acetylpiperidine-4-carboxylic acid.

ХА good" (in M ; 7 ie

SI

1-Acetylpiperidine-4-carboxylic acid (16.9 mg, 0.099 mmol), MMM (0.016 mL, 0.148 mmol) was sequentially added to a solution of intermediate 58.1 (25 mg, 0.049 mmol) in DMF (0.5 mL) at RT. and GATU (28.1 mg, 0.074 mmol). The reaction mixture was heated at 50 °C and stirred for 24 h, then cooled to RT, diluted by HPLC and washed with a 2 M aqueous solution of MgSO3. The organic phase was dried over NaCl5O, filtered and evaporated to dryness. The crude substance obtained was purified using preparatory

Reverse phase HPLC (U/aeg5 system) and obtained the desired compound (8.6 mg, 0.013 mmol, 26 95) as a colorless solid. TOP: Yaive-2.47 min.; RH-MS: tp/: 660.6 |M'ANI";

IN NMR (400 MHz, COzO0b): 0.87-1.07 (t, 6H), 1.11-1.27 (2a, 9-61, ЗН, a mixture of diastereoisomers), 1.48-1.87 ( t, 9H), 2.10-2.15 (t, ЗН), 2.60-2.79 (t, 1H), 2.83-2.97 (t, 1H), 2.98-3, 27 (t, 2H), 3.71-3.682 (t, 1H), 3.86 (5, ЗН), 3.89-4.11 (t, 2H), 4.16-4.30 (t, 1H), 4.48-4.66 (t, 1H), 5.30-5.45 (t, 1H), 5.80-5.93 (t, 1H), 5.97-6.08 ( t, 1H), 6.79 (0.9-3.4, 1H), 6.89 (5, 1H), 7.10-7.22 (t, 4H), 7.26-7.37 ( t, 4H).

Example 60: (1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -phenyl)-ethyl)-ethylamide of piperidine-4-carboxylic acid.

at 5

So AH o M ; at

Zhi F

(Fi

To a solution of intermediate 60.1 (13.7 mg, 0.019 mmol) in DCM (1 ml) at CT was added

TFC (0.058 mL, 0.76 mmol). The reaction mixture was stirred for 1 hour, then evaporated to dryness. The obtained crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 8.2 mg, 0.011 mmol, 58 95) was obtained as a colorless solid. SUPER: "vea-2.01 min.; LC-MS: t/: 618.7

IYIMANI; "NN NMR (400 MHz, СО300): 0.84-1.04 (t, 6Н), 1.10-14.25 (24, 9-61, ЗН, a mixture of diastereoisomers), 1.45-1.76 (t, 5H), 1.83-2.07 (t, 4H), 2.89-3.54 (t, 5H), 3.69-3.81 (t, 1H), 3.85 (5 , ZN), 3.99-4.11 (t, 1H), 4.15-4.31 (t, 1H), 5.27-5.41 (t, 1H), 5.77-5.90 (t, 1H), 5.95-6.05 (t, 1H), 6.72-6.82 (t, 1H), 6.89 (5, 1H), 7.08-7.41 (t , 8H).

Intermediate 60.1: tert-butyl ether 4-((1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-3-oxo-3,4-dihydro- 1H-isoquinolin-2-yl(1-phenyl)-ethyl)-ethyl-carbamoyl|-piperidine-1-carboxylic acid.

H o M ; 7 in F (Fi

The desired compound (15 mg, 0.02 mmol, 4095) was obtained as a colorless solid from intermediate 58.1 (25 mg, 0.049 mmol) and piperidine-1,4-dicarboxylic acid mono-tert-butyl ether (22.6 mg , 0.099 mmol) similarly to the one obtained in example 59. Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umaieg5 system). TOP: "Chne-3.07 min.; LC-MS: t/2 718.8 MANI; "H NMR (400 MHz, COzO0): 0.86-1.06 (t, 6H), 1.11- 1.27 (249, U-6.1, ZN, a mixture of diastereoisomers), 1.48 (5, 9H), 1.51-1.78 (t, 9H), 2.70-3.26 (t, 4H), 3.71-3.81 (t, 1H), 3.86 (5, ЗН), 3.98-4.31 (t, 4H), 5.28-5.42 (t, 1H) , 5.80-5.91 (t, 1H), 5.96-6.06 (t, 1H), 6.7 7-6.80 (t, 1H), 6.89 (5, 1H), 7.09-7.21 (t, 4H), 7.265-7.36 (t, 4H).

Example 61: 7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-|/1-(piperidin-4-ylamino)-ethyl|-phenyl)-1 ,4-dihydro-2H-isoquinolin-3-one.

N

M c) (c) Y (c) th F

To a solution of intermediate 61.1 (20 mg, 0.030 mmol) in DCM (0.5 ml) at RT was added

TFC (0.023 mL, 0.300 mmol). The reaction mixture was stirred at RT for 30 minutes, then evaporated to dryness. The obtained crude substance was purified using a preparative method

reverse-phase HPLC (UMaieg5 system) and obtained the desired compound (salt with TFA, 7 mg,

0.01 mmol, 34 95) as a yellow solid. TOP: "out-1.69 min.; LC-MS: t/ 562.3

IM-ANI:; H NMR (400 MHz, COzO0): 0.89-1.00 (21.9-7.5, ZN, mixture of diastereomers), 1.14-1.26 (29.9-61, ZN, mixture of diastereomers) , 1.49-1.78 (t, 5H), 1.79-1.99 (t, 2H), 2.18-2.30 (t, 1H), 2.34-2.47 (t, 1H), 2.92-3.10 (t, 2H), 3.24-3.35 (t, 2H), 3.45-3.61 (t, 2H), 3.79 (y, 9- 20.3, 1H), 3.86 (5, ЗН), 4.09 (a, 9-20.8, 1H), 4.18-4.30 (t, 1H), 4.56-4, 66 (t, 1H), 6.05 (5, 1H), 6.79-6.83 (t, 1H), 6.90 (5, 1H), 7.21-7.26 (t, 2H) , 7.27-7.35 (t, 4H), 7.49-7.56 (t, 2H).

Intermediate 61.1: 4-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-3-oxo-3,4-dihydro-1-tert-butyl ether N-isoquinolin-2-yl(phenyl)-ethylamino)-piperidine-1-carboxylic acid.

M (c) (c) (c) but F

SI

Tert-butyl-4-aminopiperidine-1-carboxylate (171 mg, 0.854 mmol) and Ti(OiRg)4 (0.253 ml, 0.854 mmol). The reaction mixture was refluxed and stirred for 14 hours. and cooled to CT. Meon (0.2 mL) was added followed by Mavna (10.76 mg, 0.285 mmol) and the mixture was stirred at RT for 1 h. Celite and water were added, the heterogeneous mixture was vigorously stirred for 15 min., filtered, and the precipitate on the filter was washed with ASOEL. The filtrate was washed with a 2M aqueous solution of magnesium sulfate, and the organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpi Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in gradient mode, DXM/LDHM/Meon 9:1) 95:5 -» 2:68) and obtained the desired compound ( 162 mg, 0.245 mmol, 86 95) in the form of a yellow foam. TLC: Ke-0.31 (DHM/MeOnH 95:5); HPLC: "Chvei-2.20 min.; LC-MS: t/: 662.3 (MANI; "H NMR (400 MHz, DMSO-av): 0.84-0.95 (21, ZN, mixture of diastereoisomers), 0.98-1.28 (t , 7H), 1.32-1.44 (t, 9H), 1.45-1.72 (t, ЗН), 1.74-1.85 (t, 1H), 1.89-2.04 (t, 1H), 2.24-2.37 (t, 1H), 2.57-2.80 (t, 2H), 3.60 (y, 9-19.6, 1H), 3.68 -3.92 (t, 7H), 4.18-4.31 (t, 1H), 6.07-6.14 (t, 1H), 6.85 (5, 1H), 7.05-7 ,14 (t, ZN), 7.27-7.40 (t, 6H).

Example 62: M-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-

Z isoquinolin-2-yl|-phenyl)-ethyl)-N-piperidin-4-ylacetamide.

N

M (c) (c) Y (c) what

She eats

SI

To a solution of intermediate 61.1 (20 mg, 0.030 mmol) in DCM (0.5 mL) at RT, acetyl chloride (0.003 mL, 0.045 mmol) and EtM (0.013 mL, 0.090 mmol) were successively added. The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with water. The organic phase was dried over Mag2505, filtered and evaporated to dryness. The obtained residue was dissolved in DCM (0.5 ml), then TFA (0.023 ml, 0.300 mmol) was added at CT.

The reaction mixture was stirred at RT for 30 minutes, then evaporated to dryness.

The obtained crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) and obtained the desired compound (salt with TFA, 11.6 mg, 0.016 mmol, 54 Ov) as a colorless solid. TOP: "Ive-1.93 min.; LC-MS: pt/ 604.5 (MANI; "H NMR

(400 MHz, DMSOO-аv): 0.85-0.96 (t, ЗН), 1.12-1.24 (t, 4Н), 1.49-1.68 (t, 5Н), 1, 68-1.78 (t, 1H), 2.718-3.02 (t, 4H), 3.13-3.22 (t, 1H), 3.25-3.33 (t, 1H), 3, 33-3.46 (t, 1H), 3.62 (y, 9-19.7, 1H), 3.78 (5, ЗН), 3.81-3.90 (t, 1H), 4, 15-4.26 (t, 1H), 4.93-5.02 (t, 1H), 6.02 (Bu. 5., 1H), 6.84 (5, 1H), 6.86- 6 .89 (t, 1H), 7.12-7.17 (t, 2H), 7.19-7.24 (t, 2H), 7.25-7.34 (t, 4H).

Example 63: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-P1-(methyl-piperidin-4-ylamino)-ethyl|-phenyl)-1, 4-dihydro-2H-isoquinolin-3-one.

N

M (c) (c) I

AK

(in)

I am (Fi

ASON (0.006 mL, 0.113 mmol), formaldehyde (37 95 in water, 0.008 mL, 0.113 mmol) and

Mavn(OAc)z (24.0 mg, 0.113 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with water. The organic phase was dried over Mag50Oa, filtered and evaporated to dryness. The resulting yellow foamy substance was dissolved in DCM (0.5 ml) and TFA (0.059 ml, 0.760 mmol) was added at RT. The reaction mixture was stirred for several minutes, then evaporated to dryness. The obtained crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 22 mg, 0.038 mmol, quantitative yield) was obtained as a colorless solid. TOP:

Agve-1.66 min.; RH-MS: t/2 576.5 |MANI; "H NMR (400 MHz, DMSO-α): 0.85-0.96 (t, НН), 1.12-20 1.30 (t, 4Н), 1.47-1.69 (t, 5Н ), 1.71-1.83 (t, 1H), 1.85-1.98 (t, 1H), 2.04-2.18 (t, 1H), 2.24-2.36 (t , 1H), 2.36-2.46 (t, 2H), 2.60-2.71 (t, 2H), 2.71-2.86 (t, 1H), 2.88-3.06 (t, 1H), 3.06-3.17 (t, 1H), 3.64 (y, 9-20.1, 1H), 3.74 (5, ЗН), 3.83-3.98 (t, 1H), 4.19-4.32 (t, 1H), 4.61-4.87 (t, 1H), 6.12- 6.23 (t, 1H), 6.88 (5 , 1H), 7.03-7.13 (t, 1H), 7.28-7.42 (t, 6H), 7.51-7.63 (t, 2H).

Example 64: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-1-(cis-4-dimethylamino-cyclohexyl)-methylamino|-ethyl)-phenyl)-6- methoxy-1,4-dihydro-2H-isoquinolin-3-one. from (c) (c)

H (c)

AH si (Fi

The desired compound (TSF salt, 17.4 mg, 0.024 mmol, 54 95) was obtained as a colorless

From a solid, methylation of intermediate 64.2 (TSF salt, 30 mg, 0.043 mmol) with formaldehyde (37 95 in water, 0.013 mL, 0.17 mmol) was obtained similarly to example 63.

Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umayeg5 system). TOP: Chves-1.71 min.; RH-MS: t/7 618.5 MANI; "H NMR (400 MHz,

COzOr): 0.87-1.01 (t, ЗН, a mixture of diastereoisomers), 1.12-1.27 (t, ЗН, a mixture of diastereoisomers), 1.46-2.44 (t, 1З3Н), 2, 57-2.73 (t, 1H), 2.86-2.94 (t, 1H), 2.96 (5, 6H), 3.80 (a, 9U-20.1, 1H), 3, 87 (5,

ZN), 4.08 (y, 9-20.5, 1H), 4.19-4.28 (t, 1H), 4.68-4.82 (t, 1H), 6.05-6, 10 (t, 1H), 6.77-6.82 (t, 1H), 6.90 (5, 1H), 7.19-7.36 (t, 6H), 7.51-7.59 ( t, 2H).

Intermediate 64.1: tert-butyl ether I4-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-3-oxo-3,4-dihydro-1 N-isoquinolin-2-yl|-phenyl)-ethylamino)-cis-cyclohexyl|- carbamic acid.

AH, : (c) (c)

H (c) new F (Fi

The desired compound (137 mg, 0.20 mmol, 97 95) was obtained as a yellow resinous substance from intermediate 55.2 (100 mg, 0.21 mmol) and (4-aminocyclohexyl)-carbamic acid tert-butyl ether (135 mg, 0.63 mmol) similar to the preparation of intermediate product 61.1. Purification of the crude substance was carried out using column chromatography Sotby-Riazpy Sotrapiop m (Ivso Ips.) (5uOg; elution in gradient mode,

Iheptane/DCM 1:1UTBME containing 5 95 7M MNz in MeonH 95:5 -» 100 906 TBME containing 5 95 7M MNz in Meon). TLC: Ke-0.16 (heptane/DCM/TBME containing 5 95 /M MNz in Men 1:1:2);

TOP: Ave-2.20 min.; LC-MS: t/2 676.4 MANI"; "H NMR (400 MHz, DMSO-av): 0.82-0.92 (t, ZN), 1.13-1.22 (t, ZN) , 1.31-1.70 (t, 22H), 2.28-2.37 (t, 1H), 3.22-3.31 (t, 1H), 3.60 (a, 9-19, 8, 1H), 3.71-3.80 (t, 4H), 3.85 (aa, 9U-19.7, 3.3, 1H), 4.19-4.31 (t, 1H), 6.07-6.12 (t, 1H), 6.55-6.62 (t, 1H), 6.86 (5, 1H), 7.06-7.13 (t, ЗН), 7, 27-7.32 (t, 2H), 7.33-7.40 (t, 4H).

Intermediate 64.2: 2-14-(1-(cis-4-Aminocyclohexylamino)-ethyl|-phenyl)-7-((A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1 ,4-dihydro-2H-isoquinolin-3-one.

Mn, ; (c) Fr.

H (c) (Fi

The desired compound (TSF salt, 50 mg, 0.072 mmol, 49 95) was obtained as a colorless solid by cleavage of the Bos protecting group from intermediate 64.1 (100 mg, 0.15 mmol) similarly to the preparation in example 61. Purification of the crude substance was carried out using reverse-phase preparative HPLC (Umayeg5 system). TOP: Ava-1.68 min.; LC-MS: t/2 576.3 (Man; "NH NMR (400 MHz, COzO0): 0.89-1.00 (21, 9-7.5, ZN, a mixture of diastereoisomers), 1.14-1 ... , 1H), 3.38-3.47 (t, 1H), 3.79 (a, 9-20.5, 1H), 3.86 (5, ЗН), 4.07 (9, 9-20 ,5, 1H), 4.17-4.29 (t, 1H), 4.55-4.64 (t, 1H), 6.06 (Bg. 5., 1H), 6.77-6, 81 (t, 1H), 6.90 (5, 1H), 7.19-7.25 (t, 2H), 7.26-7.34 (t, 4H), 7.49-7.55 ( t, 2H).

Example 65: M-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl(1-phenyl)-ethyl)-N-(cis-4-dimethylaminocyclohexyl)-acetamide.

Zo

ZU and (in; o.

FOR

H (6)

She eats

SI

To a solution of intermediate 64.1 (35 mg, 0.052 mmol) in DCM (0.5 mL) at RT, acetyl chloride (0.006 mL, 0.078 mmol) and EtM (0.022 mL, 0.155 mmol) were sequentially added. The reaction mixture was stirred at RT for 1 h, diluted with DCM and washed with water. The organic layer was dried over Ma»5O4, filtered and evaporated to dryness. The resulting yellow foam was dissolved in DCM (0.5 mL) and TFA (0.08 mL, 1.0 mmol) was added. The mixture was stirred at RT for 1 hour, then evaporated to dryness. The resulting brown resin was dissolved in DCM (0.7 mL) and, at RT, ASON (0.009 mL, 0.155 mmol), formaldehyde 37 95 in water (0.012 mL, 0.155 mmol) and Mavn(OAc)z (32.9 mg, 0.155 mmol).

The reaction mixture was stirred at RT for 1 h, diluted with DCM and washed with water. The organic layer was dried over Mag50O5, filtered and evaporated to dryness.

The obtained crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 16.8 mg, 0.022 mmol, 42 Obov) was obtained as a colorless solid. TOP: Yave-1.99 min.; RH-MS: t/2 646.5 |MANI".

Example 66: 2-14-P1-(transo-4-Aminocyclohexylamino)-ethyl|-phenyl)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-1,4- dihydro-2H-isoquinolin-3-one.

Mn, and (c) (c) (c)

S F

(Fi

A solution of intermediate 66.1 (40 mg, 0.056 mmol) in EN (1 mL) was evacuated under vacuum and the vessel was filled with argon (2x). At CT, ammonium formate (5.3 mg, 0.084 mmol) was added and

Ra/C (3.0 mg, 0.003 mmol) and the suspension were vigorously stirred for 1 h. The reaction mixture was filtered through a layer of celite, the catalyst was washed with DCM, and the filtrate was evaporated to dryness. The obtained crude substance was purified using a preparative method

Reverse phase HPLC (Umayeg5 system) and obtained the desired compound (TPA salt, 12.6 mg, 0.018 mmol, 32 95) as a colorless solid. ELEC: "ve-1.73 min.; LC-MS: t/2 576.4 (MANI; "H NMR (400 MHz, COzO0B): 0.88-1.01 (21, 9-7.5, ЗН, a mixture of diastereoisomers), 1.13-1.27 (249, 9-6.1, ЗН, a mixture of diastereoisomers), 1.33-1.78 (t, 9Н), 2.09-2.23 (t , ZN), 2.28-2.38 (t, 1H), 2.90-3.03 (t, 1H), 3.07-3.18 (t, 1H), 3.79 (a, 9 -20.3, 1Н), 3.86 (5, ЗН), 4.09 (а, 9-20.3, 1Н), 4.18-4.31 (t, 1Н), 4.52-4 .63 (t, 1H), 6.05 (5, 1H), 6.77-6.83 (t, 1H), 6.90 (5, 1H), 7.19-7.26 (t, 2H ), 7.265-7.35 (t, 4H), 7.48-7.55 (t, 2H).

Zo Intermediate 66.1: Benzyl ether 14-(1-14-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H -isoquinolin-2-yl|-phenyl)-ethylamino)-trano-cyclohexyl|- carbamic acid. o o : (c) (c) (c)

S F

SI

The desired compound (232 mg, 0.29 mmol, 70 95) was obtained as a yellow resin from intermediate 55.2 (200 mg, 0.42 mmol) and trans-(4-aminocyclohexyl)-carbamic acid benzyl ether (312 mg, 1.26 mmol) similar to the preparation of intermediate product 61.1. Purification of the crude substance was carried out using Sotheby-Riazpy column chromatography. Sotrapiop "m (Izso Ips.) (BIO; elution in gradient mode,

Iheptane/DCM 1:1UTBME containing 5 95 7M MNz in MeonH 95:5 -» 100 906 TBME containing 5 95 7M MNz in Meon). TLC: Ke-0.10 (heptane/DCM/TBME containing 5 95 /M MNz in Men 1:1:2);

TOP: "Chve-2.24 min.; RH-MS: t/2 710.4 MANI";

NMR NMR (400 MHz, DMSO-α): 0.80-0.93 (t, ЗН), 1.09-1.20 (t, ЗН), 1.43-2.10 (t, 12Н ), 3.12-3.25 (t, 1H), 3.60 (y, 9U-19.6, 1H), 3.74 (v, ЗН), 3.78-3.90 (t, 2H ), 4.17-4.32 (t, 1H), 4.95 - 5.01 (t, 2H), 6.10 (ru. 5., 1H), 6.86 (5, 1H), 7 ,03-7.14 (t, 4H), 7.25-7.41 (t, 11H).

Example 67: 7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-(4-dimethylamino-piperidin-1-yl)-ethyl|-phenyl)-6-methoxy -1,4-dihydro-2H-isoquinolin-3-one. (c) (c) I ra M still o7-7 95, 5 (Fi

ASON (0.005 mL, 0.089 mmol), formaldehyde (37 95 in water, 0.007 mL, 0.089 mmol) and

Mavn(OAc)z (18.81 mg, 0.089 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with water. The organic phase was dried over Ma»50Oa, filtered and evaporated to dryness. The obtained crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 7.5 mg, 0.011 mmol, 36 95) was obtained as a colorless solid. TOP: "veg-1.70 min.;

RH-MS: t/» 590.3 |IMANG; nH NMR (400 MHz, COzO0): 0.89-1.01 (21.9-7.5, ZN, mixture of diastereomers), 1.14-1.26 (24.9-61, ZN, mixture of diastereomers) , 1.49-1.74 (t, 2H), 1.74 - 1.680 (t, ЗН), 1.96-2.17 (t, 2H), 2.28-2.45 (t, 2H) , 2.84-3.07 (t, 2H), 2.91 (v, 6H), 3.38-3.48 (t, 1H), 3.51-3.61 (t, 1H), 3 .79 (y, 9U-20.3, 1H), 3.83-3.95 (t, 1H), 3.86 (5, ЗН), 4.07 (a, U-20.3, 1H) , 4.18-4.31 (t, 1H), 4.48-4.59 (t, 1H), 6.06 (5, 1H), 6.79-6.85 (t, 1H), 6 .90 (5, 1H), 7.19-7.26 (t, 2H), 7.27-7.36 (t, 4H), 7.50-7.58 (t, 2H).

Intermediate 67.1: tert-butyl ether (1-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-3-oxo-3,4-dihydro- 1 H-isoquinolin-2-yl(1-phenyl)-ethyl)-piperidin-4-yl|-carbamic acid. ra is c) iv) I

NM M Fi 07's tho

SI

The desired compound (230 mg, 0.35 mmol, 83 95) was obtained as a yellow resinous

From the substance of intermediate product 55.2 (200 mg, 0.42 mmol) and tert-butyl ether of piperidin-4-ylcarbamic acid (251 mg, 1.26 mmol) similarly to the preparation of intermediate product 61.1.

Purification of the crude substance was carried out using column chromatography Sotri-

Nazp Sotrapiop "m (Izso Ips.) (5iOg; elution in the gradient mode, (heptane/dhm 1:C/TBME which contains 5 95 7/M MNz in Meon 95:5 -» 100 956 TBME which contains 5 95 7M MHz in MeOH). TLC:

Be-0.29 (heptane/"DXM/TBME containing 5 95 7M MHz in MeOnH 1:1:2); HPLC: "no-2.15 min.; RH-

MS: t/: 662.4 MANI; "H NMR (400 MHz, DMSOO- av): 0.83-0.96 (t, ЗН), 1.13-1.22 (t, ЗН), 1.33-1.40 (t, 9Н) , 1.45-1.96 (t, 8H), 2.26-2.42 (t, 1H), 2.57-2.67 (t, 1H), 2.81-3.00 (t, 2H), 3.06-3.20 (t, 1H), 3.35-3.43 (t, 1H), 3.60 (a, 9U-19.8, 1H), 3.7Z (c, ZN), 3.84 (aa, 9-19.7, 3.6, 1H), 4.18-4.34 (t, 1H), 5.70-5.82 (t, 1H), 6, 06-6.15 (t, 1H), 6.67-6.78 (t, 1H), 6.86 (5, 1H), 7.06-7.17 (t, ЗН), 7.20- 7.29 (t, 2H), 7.31-7.42 (t, 4H).

Intermediate 67.2: 2-14-(1-(4-Aminopiperidin-1-yl)-ethyl|-phenyl)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy- 1,4-dihydro-2H-isoquinolin-3-one.

(c) (c) And nem M phi 07's and

SI

The desired compound (salt with TFA, 25.3 mg, 0.037 mmol, 59 95) was obtained as a colorless solid from intermediate 67.1 (41.7 mg, 0.063 mmol) by treatment with TFA in a manner similar to that obtained in Example 61. Purification of crude substances were carried out using preparative reverse-phase HPLC (Umaieg5 system). TOP:

Afve-1.70 min.; RH-MS: t/2,562.6 MANI; "H NMR (400 MHz, COzO0): 0.88-1.01 (21, 9-7.5, ЗН, mixture of diastereomers), 1.13-1.26 (24, 9-61, ЗН, mixture of diastereomers ), 1.51-1.81 (t, 5H), 1.83-2.07 (t, 2H), 2.16-2.34 (t, 2H), 2.80-3.12 (t , 2H), 3.34-3.43 (t, 1H), 3.44-3.53 (t, 1H), 3.79 (a, 9-20.3, 1H), 3.79-3 .89 (t, 1H), 3.86 (5, ЗН), 4.08 (a, 9-20.1, 1H), 4.18-4.30 (t, 1H), 4.43-4 .59 (t, 1H), 6.06 (5, 1H), 6.7 7-6.84 (t, 1H), 6.90 (5, 1H), 7.19-7.26 (t, 2H), 7.26-7.35 (t, 4H), 7.48-7.57 (t, 2H).

Example 68: 7-(8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-11-(4-(isopropyl-methyl-amino)-piperidin-1-yl|-ethyl)- phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. va (c) fi IF) J

A M o7- t" (Fi

The desired compound (TSF salt, 15.3 mg, 0.021 mmol, 43 95) was obtained from intermediate 67.2 (27 mg, 0.048 mmol) after two consecutive procedures of reductive amination using acetone and formaldehyde, respectively, similarly to the preparation in example 53.

Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umayeg5 system). HPLC: "ve-1.71 min.; LC-MS: t/7 618.6 (M--NO); "H NMR (400 MHz,

СбОзО0): 0.89-1.01 (21, 9-7.5, ЗН, mixture of diastereomers), 1.15-1.26 (24, 9-61, ЗН, mixture of diastereomers), 1.29-1 .43 (t, 6H), 1.49-1.80 (t, 5H), 1.95-2.20 (t, 2H), 2.23-2.49 (t, 2H), 2.80 - 3.06 (t, 2H), 3.22-3.37 (t, ЗН), 3.45-3.65 (t, 2H), 3.78 (a, 9-20.5, 1H) , 3.78-3.88 (t, 1H), 3.86 (5,

ZN), 4.07 (a, 9-20.1, 1H), 4.20-4.30 (t, 1H), 4.39-4.55 (t, 1H), 6.06 (5, 1H), 6.79-6.85 (t, 1H), 6.90 (5, 1H), 7.20-7.26 (t, 2H), 7.27-7.36 (t, 4H) , 7.49-7.58 (t, 2H).

Example 69: M-(1-(1-4-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline) -2-yl(phenyl)-ethyl)-piperidin-4-yl|-acetamide.

Koo) va (c) IF) J

NM M fi i o7- ta

SI

To a solution of intermediate 67.2 (24 mg, 0.043 mmol) in MesSmM (0.5 mL) at KT was sequentially added EsM (0.018 mL, 0.13 mmol) and acetyl chloride (0.005 mL, 0.064 mmol).

The reaction mixture was stirred at RT for 1 h, then immediately purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 3.2 mg, 0.004 mmol, 10 95) was obtained as a colorless solid. TOP: "vea-1.88 min.;

RH-MS: t/: 604.5 MANI".

Example 70: 2-14-(1-(4-Acetylpiperazin-1-yl)-ethyl|-phenyl)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-1 ,4-dihydro-2H-isoquinolin-3-one. (c) Phi (c) I zho (Fi

To a solution of intermediate 70.1 (TFC salt, 15.4 mg, 0.023 mmol) in MesM (0.5 mL) at

CT was sequentially added ElysM (0.013 mL, 0.093 mmol) and acetyl chloride (0.003 mL, 0.035 mmol).

The reaction mixture was stirred at RT for 1 h, then immediately purified by reverse-phase preparative HPLC (Umayeg5 system) to obtain the desired compound (TSF salt, 7.6 mg, 0.011 mmol, 46 95) as a colorless solid. TOP: "ve-1.90 min.;

RH-MS: t/» 590.4 |MANIHE; "H nNMR (400 MHz, CO3O0): 0.88-1.02 (21, 9-7.5, ЗН, mixture of diastereomers), 1.12-1.27 (2a, 9-61, ЗН, mixture of diastereomers ), 1.48-1.74 (t, 2H), 1.74-1.683 (t, ЗН), 2.13 (5, ЗН), 2.81-3.40 (t, 8Н), 3, 79 (a, 9U-20.3, 1H), 3.86 (5, ЗН), 4.07 (a, 9-20.3, 1H), 4.18-4.29 (t, 1H), 4.46-4.56 (t, 1H), 6.06 (5, 1H), 6.78-6.83 (t, 1H), 6.90 (5, 1H), 7.19-7, 26 (t, 2H), 7.28-7.35 (t, 4H), 7.48-7.54 (t, 2H).

Intermediate 70.1: 7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(1-piperazin-1-ylethyl)phenyl|-1,4-dihydro- 2H-isoquinolin-3-one (c) Phi (c) Y

S. F

SI

The desired compound (TFA salt, 18.9 mg, 0.029 mmol, 45 95) was obtained as a colorless solid from intermediate 55.2 (30 mg, 0.063 mmol) and piperazine-1-carboxylic acid tert-butyl ether (35.1 mg, 0.188 mmol) similarly to the preparation in example 61.

Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umayeg5 system). TOP: Chves-1.71 min.; RH-MS: t/7 548.2 MANI; "H NMR (400 MHz,

СбОзО0): 0.87-1.01 (21, 9-7.5, ZN, mixture of diastereoisomers), 1.13-1.27 (24, 9-61, ZN, mixture

30 diastereoisomers), 1.46-1.54 (t, 3H), 1.54-1.78 (t, 2H), 2.79-3.06 (t, 4H), 3.24-3.38 (t, 4H), 3.76 (a, 9-20.3, 1H), 3.82-3.92 (t, 4H), 4.05 (a, 9-20.1, 1H), 4 ,19-4.30 (t, 1H), 6.01 (5, 1H), 6.80-6.85 (t, 1H), 6.90 (5, 1H), 7.15-7.25 (t, 4H), 7.28-7.34 (t, 2H), 7.39-7 46 (t, 2H).

Example 71.

Compounds 71aa-71sa were obtained from intermediate product 55.2 (or its analogs, obtained in a similar way) or intermediate product 58.1 (or its analogs, obtained in a similar way) similarly to the preparation in examples 55-70.

Mo | Structure Name/ECR/MS o To

M Phi : 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(1-71aa | "a dimethylaminoethyl)phenyl|-6-methoxy-1,4-

And dihydro-2H-isoquinolin-3-one.

Ff VERH: Chvea-1.97; LC-MS: m/2 507.3 (MANI. (o) (c) o. no M F and 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-( 1- 71av IF 97 (4-hydroxypiperidin-1-yl)-ethyl|-phenyl)-6-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Fu TOP: Chwea-1.88; RH-MS: t/2 563.3 (MANI. (9)

Z o o J

M fi! 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-71ac 973 (2-dimethylaminoethylamino)-ethyl|-phenyl)-6-

NM methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Ff TOP: Chne-1.72; RH-MS: t/: 550.5 MANI. (about) va

M (in) o

Phy: 2-14-(1-(1-acetylpiperidin-4-ylamino)-ethyl|-71ad Moz phenyl)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-

NM b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Ff VERH: Chvne-1.88; RH-MS: t/: 604.7 MANI. (9) (c) Fr. 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(1-71av g 97 (2)-3-hydroxypyrrolidin-1-yl)-ethyl|- phenyl)-6-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Ff TOP: Chvea-1.88; LC-MS: m/2 549.5 (MANI. (9) (c) o po, M Ш ; 7-((B)-second-butoxy)-1-(4-chlorophenyl)-2-(4- 11-71ai c 97 ((5)-3-hydroxypyrrolidin-1-yl)-ethyl|-phenyl)-b-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chvea-1.88; RH-MS: t/2 549.4 (MANI. (9) at 6

Mn Phi : 1-(1-44-(7-((B)-tert-butoxy)-1-(4-chlorophenyl)- o Mo a b-methoxy-3-oxo-3,4-dihydro-1 N-isoquinoline-2-71ad M Also yl|-phenyl)-ethyl)-piperidine-4-carbon

FI acid amide.

TOP: Chva-1.87; RH-MS: t/2 590.4 (MANI. (9)

Mo | Structure Name/ECR/MS i To

I M Shchi : 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(1-71ai F 97 ((5)-3-hydroxypiperidin-1 -yl)-ethyl| -phenyl)-6-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

FI TOP: Chvea-1.90; RH-MS: t/2 563.4 (MANI. (9) he o o.

M Ci and 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(1-71a 97 (2)-3-hydroxypiperidin-1-yl)-ethyl|-phenyl) -6-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one. and TOP: Chvea-1.91; LC-MS: t/2 563.3 (MANI. (9) (c) o. : 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-b a 57 973 methoxy-2 -I4-(1-thiomorpholin-4-ylethyl)- ) Sm phenylI-1 4-dihydro-2H-isoquinolin-3-one.

Fu TOP: Chvne-1.99; RH-MS: t/: 565.3 MANI. (9) at 5

M Sh! M-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-71ak 97b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- 1-yl(phenyl)-ethyl)-N-isobutylacetamide.

From FI TOP: Chne-2.83; RH-MS: t/: 577.3 MANI. (9) at 5

M C and M-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)- 71a 973 b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline -2-yl(1-phenyl)-ethyl)-N-propylacetamide.

Z and TOP: Chva-2.71; RH-MS: t/2 563.3 (MANI. (9) (c) o.

M Sh | M-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-71at and 973b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 - yl(1-phenyl)-ethyl)-N-isopropylacetamide. and TOP: Chne-2.71; RH-MS: t/: 563.4 MANI. (9) (c) Fr

M Sh and M-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)- 71ap in 97 b-methoxy-3-oxo-3,4-dihydro-1H- isoquinoline-2-yl(1-phenyl)-ethyl)-N-cyclopropylacetamide.

FROM FI TOP: Chne-2.69; RH-MS: t/z 561.4 MANI. (9)

Mo | Structure Name/HPLC/MS at 5

Phi : M-(1-(4-I7-((B)-tert-butoxy)-1-(4-chlorophenyl)-

M o and b-methoxy-3-oxo-3,4-dihydro-1 H-isoquinoline-2-71ao M Also il|I-phenyl)-ethyl)-M- t FI cyclohexylmethylacetamide. (c) TOP: Chvea-3,13; RH-MS: t/2 617.5 (MANI. (9) (c) o.

M Sh! M-(1 -4-17-(A)-tert-butoxy)-1 -(4-chlorophenyl)- 71a 973 b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2-p yl(1-phenyl)-ethyl)-N-cyclopentylacetamide.

Z and TOP: Chvea-2.90; RH-MS: t/2 589.4 (MANI. (9) (c) o.

M Shchi Y M-(1 4A-17-(H)-tert-butoxy)-1 -(4-chlorophenyl)- 71a 973 b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 - 9 yl (1-phenyl)-ethyl)-M-cyclohexylacetamide.

Z Fu TOP: Chne-3.02; RH-MS: t/: 603.3 MANI. (9) o o

Alkali: M-(1-(4-I7-((B)-tert-butoxy)-1-(4-chlorophenyl)- as M o and b-methoxy-3-oxo-3,4-dihydro-1 H -isoquinoline-2-71ag M Z yl|I-phenyl)-ethyl)-M-t Ff cyclopropylmethylacetamide. (c) TOP: Chva-2.75; RH-MS: t/2 575.3 (MANI. (9) at 5

C : m-(1-44-H7-((B)-tert-butoxy)-1-(4-chlorophenyl)-

M o a b-methoxy-3-oxo-3,4-dihydro-1 H-isoquinoline-2-71a5 M Also il|I-phenyl)-ethyl)-M-tr Ff cyclopentylmethylacetamide. (c) TOP: Chvea-3.03; RH-MS: t/2 603.6 (MANI. (9) (c) o.

MC and M-benzyl-m-(1-(4-17-(A)-tert-butoxy)-1-(4-71ai 97chlorophenyl)-6b-methoxy-3-oxo-3,4-dihydro- 1 H-va isoquinolin-2-yl(phenyl)-ethyl)-acetamide.

I F TOP: Chne-2.87; RH-MS: t/z 611.5 MANI. (9) (c) Fr

M Sh y M-(1-44-17-(A)-tert-butoxy)-1-(4-chlorophenyl)-718y 97 b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-

M yl(I-phenyl)-ethyl)-M-cyclobutylacetamide.

My

From FI TOP: Chne-2.81; RH-MS: t/: 575.3 MANI. (9)

Mo | Structure Name/EPCH/MS - (c) and .

M alkali: (1-44-I7-((B)-tert-butoxy)-1-(4-chlorophenyl)-6-c) Mo a methoxy-3-oxo-3,4-dihydro-1 H- isoquinoline-2-71am M Also yl1-phenyl)-ethyl)-ethylamide 1-methylpiperidin-va FI 4-carboxylic acid.

TOP: Thu-2.00; RH-MS: t/2 632.7 (MANI. (c)

M (c) (c)

Phi : (1-44-17-((B)-tert-butoxy)-1-(4-chlorophenyl)-6-c) Mo and methoxy-3-oxo-3,4-dihydro-1H-isoquinoline -2- 71am M Also 1-phenyl)-ethyl)-ethylamide of 1-methylpiperidine and FI of 3-carboxylic acid.

TOP: Chva-2.05; LC-MS: t/2 632.7 (MANI. (c) nm (c) (c)

Phi : (1-44-17-((B)-tert-butoxy)-1-(4-chlorophenyl)-6-c) Mo and methoxy-3-oxo-3,4-dihydro-1H-isoquinoline -2- 71ah M also yl|1-phenyl)-ethyl)-ethylamide (15, ZK)-3-va F of aminocyclopentanecarboxylic acid.

TOP: Chva-2.08; LC-MS: m/: 618.7 (MANI. (c) nya (c) (c) : -44-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-

I Phi g TI4447-(B)-second-butoxy)-1-(4-chlorophenyl)-6 chen y? M 07 methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2-71au M yl|1-phenyl)-ethyl)-ethylamide (Kk, ZK)-3-va FI of aminocyclopentanecarboxylic acid.

TOP: Chva-2.02; RH-MS: t/: 618.7 (MANI. (c)

M o v;

F : (1-(4-I7-((B)-tert-butoxy)-1-(4-chlorophenyl)-6- o M 07 methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2- 71a?Myl(1-phenyl)-ethyl)-ethylamide pyrrolidine-3-va FI carboxylic acid.

TOP: Chne-2.01; RH-MS: t/: 604.6 MANI. (in)

IF F: (1-44-17-((B)-second-butoxy)-1-(4-chlorophenyl)-6-

A M o - methoxy-3-oxo-3,4-dihydro-1 H-isoquinoline-2-7Iba M Z yl|I-phenyl)-ethyl)-ethylamide cis-4-va FI aminocyclohexanecarboxylic acid.

TOP: Chne-2.08; LC-MS: t/: 632.5 IM.-ANI.. (c) nm (c) o

IF F: (1-44-17-((B)-tert-butoxy)-1-(4-chlorophenyl)-6- and Mo - methoxy-3-oxo-3,4-dihydro-1H-isoquinoline -2- t16r M Z yl|1-phenyl)-ethyl)-ethylamide trans-4-va FI aminocyclohexanecarboxylic acid.

TOP: Chva-2.03; RH-MS: t/2 632.5 (MANI. (c)

Mo | Structure Name/ECR/MS ra o o o. (1--4-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-

FI o M SHI | methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2-71bso) its with 11-phenyl)-ethyl)-ethylamide trans-4-

M dimethylaminocyclohexane-carbon

Ff acid.

TOP: Chne-2.07; RH-MS: t/: 660.7 MANI. (c) (c) (c) (1-14-(7-((A)-tert-butoxy)-1-(4-chlorophenyl)-6-

C : methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2-71ya 7y97yl|-phenyl)-ethyl)-ethylamide (1e, 3K)-3-

M dimethylaminocyclopentane-carbon

Ff acid.

TOP: Chva-2.05; RH-MS: t/: 645.3 (MANI. (9) x

M (c) (c) I

C : (1-(4-I7-((B)-tert-butoxy)-1-(4-chlorophenyl)-6- o M 07 methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-71Be M yl(phenyl)-ethyl)-ethylamide 1-methylpyrrolidine-va FI 3-carboxylic acid.

TOP: Chva-2.04; RH-MS: t/: 618.5 (MANI. (o)

AND

AH, in; at. (1--4-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-

FI o M CF: methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2-t on 973 ilI-phenyl)-ethyl)-ethylamide cis-4-

NM of dimethylaminocyclohexane-carbon

Ff acid.

TOP: Chva-2,12; RH-MS: t/: 660.7 (MANI. (o)

Nm (c) o

Z M CF and 7-((B)-tert-butoxy)-1-(4-chlorophenyl)-6-th T o methoxy-2-(4-(1-((5)-piperidine-3-ylamino) - 9 nm of ethyl (phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chvea-1.70; RH-MS: t/2 562.2 (MANI. (9)

Nm o o.

M F: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-71vp 977 methoxy-2-14-1-(A)-piperidine-3-ylamino)-ethyl-phenyl) -1,4-dihydro-2H-isoquinolin-3-one.

FI TOP: Chva-1.71; RH-MS: t/2 562.3 (MANI. (9) (c) (c)

Nm (Y : M-((5)-1-(4-I7-((B)-tert-butoxy)-1-(4-

M 0775 chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-triC isoquinolin-2-yl|I-phenyl)-ethyl)-M-(A)-piperidin-t FI Z- ilacetamide o: TOP: Chvea-1.93; RH-MS: t/2 604.4 (MANI. (o)

Mo | Structure Name/HPLC/MS o o nm (I : m-((8)-1-(4-I7-((B)-tert-butoxy)-1-(4-

M 0775 chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H- 716 M isoquinolin-2-yl|I-phenyl)-ethyl)-M-(A)-piperidine-t Ff З- ilacetamide (c) HPLC: Chne-2.02; RH-MS: t/: 604.3 MANI. (c) o o nm (Y : M-((8)-1-(4-(7-(B)-tert-butoxy)-1-(4-

M 0775 chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-tk v isoquinolin-2-yl|1-phenyl)-ethyl)-M-(5)-piperidine-t Ff Z- ilacetamide o: TOP: Chva-2.02; RH-MS: t/2 604.3 (MANI. (c) o o

Nm Sh : M-((8)-1-(4-I(7-((B)-tert-butoxy)-1-(4-

M 073 chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-716pI and isoquinolin-2-yl|I-phenyl)-ethyl)-M-(5)-piperidine-t F Z- ilacetamide (c) TOP: Chne-1.92; RH-MS: t/: 604.3 MANI. (c) o o

МН (Я В M-(2-aminoethyl)-M-(1-(4-H7-(B)-tert-butoxy)- m 97 1-(4-chlorophenyl)-6-methoxy-3-oxo-3 ,4-71Bt M dihydro-1H-isoquinolin-2-yl|-phenyl)-ethyl)-t FI acetamide. (c) TOP: Chne-1.92; RH-MS: t/: 564.5 | MANEI. (c) о о вл фи : M-(1-(4-I7-((B)-tert-butoxy)-1-(4-chlorophenyl)-5 M 073 b-methoxy-3-oxo-3,4 -dihydro-1H-isoquinoline-2-716bp M yl(phenyl)-ethyl)-M-(2-dimethylaminoethyl)-t F acetamide. (c) TOP: Chvea-1.94; LC-MS: t/2 592.4 (MANI. (c) nm (c) o phi : M-(3-aminopropyl)-M-(1-(4-I17-((B)-second-

M 97 butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-716o M Also 3,4-dihydro-1H-isoquinolin-2-yl|1-phenyl)-ethyl)-t FI acetamide . (c) TOP: Chne-1.93; RH-MS: t/: 578.4 MANI. (c) r (c) o .

Shf : m-(1-44-H7-((B)-second-butoxy)-1-(4-chlorophenyl)-

M 0775 b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2-71Br M yl|1-phenyl)-ethyl)-M-(3-dimethylaminopropyl)-t F acetamide. (c) TOP: Chvea-1.96; RH-MS: t/: 606.4 (MANI. (c)

Mo | Structure Name/ECP/MS

N

M (in o. o M FI ro 7-(H)-tert-butoxy)-1 -(4-chlorophenyl)-2-4-11 - "va o (ethylpiperidin-4-ylamino)-ethyl|-phenyl) -6-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chvne-1.68; RH-MS: t/: 590.5 MANI. (in)

MH (c) about 7 and Shchi: 2-1A4-I11-((5)-3-aminopiperidin-1-yl)-ethyl|- 71 F 97 phenyl)-7-(B)-tert-butoxy)-1 -(4-chlorophenyl)-

M b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

FI TOP: Chne-1.72; RH-MS: t/: 562.3 MANI. (c) at

Also H Fi and 2-414-11-((B)-3-aminopyrrolidin-1-yl)-ethyl|- 71bv schu 97 phenyl)-7-(B)-tert-butoxy)-1-(4-chlorophenyl )-

M b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

FI TOP: Chva-1.73; RH-MS: t/2 548.3 (MANI. (c) and Po

Nam, and Fi Ya 2-14-11-((85)-3-aminopyrrolidin-1-yl)-ethyl-71vi c 973 phenyl)-7-(B)-tert-butoxy)-1-(4-chlorophenyl )-

M b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chvne-1.71; RH-MS: t/: 548.3 MANI. (c) (I shk o o. M , fi : -(8)-1-(1-44-I7-((B)-second-butoxy)-1-(4- " M 97 chlorophenyl)-6- methoxy-3-oxo-3,4-dihydro-1 H- 71Bi FI Also isoquinolin-2-yl|I-phenyl)-ethyl)-piperidin-Z-yl|-

Ff acetamide.

TOP: Chwea-1.90; LC-MS: t/2 604.3 (MANI. (c) their x. (c) (c) nm Fi : M-AKV)-1-(1-44-(7-((B)-second- butoxy)-1-(4-

M o7 chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H-716bm M Z isoquinolin-2-yl|I-phenyl)-ethyl)-pyrrolidin-Z-yl|-

Ff acetamide.

TOP: Chwea-1.88; LC-MS: t/2 590.3 (MANI. (c) 9 already (c) (c) nk Phi : M-((8)-1-(1-(4-(7-(B)-second -butoxy)-1-(4-y, M07chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-716z!isoquinolin-2-yl|1-phenyl)-ethyl)- pyrrolidine-Z-yl|-

Ff acetamide.

TOP: Chvne-1.88; RH-MS: t/: 590.3 MANI. (in)

Mo | Structure Name/EPLC/MS o 6 t Phi : 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-11-" M o7 ((5)-3-dimethylaminopiperidine-1 -yl)-ethyl|- 71x 958) C phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one, HPLC: Chvea-1.74, LC-MS: t/2 590, 4 (MANI. (9) / (c) (c) I -k Phi : 7-((B)-second-butoxy)-1-(4-chlorophenyl)-2-(4-|1- y, M o7 ((5)-3-dimethylaminopyrrolidin-1-yl)-ethyl|- 2 more phenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chva-1.77; LC-MS: m/2 576.4 (MANI. (9) / o o . -m fi : 7-((B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-| 1-

M o7 (8)-3-dimethylaminopyrrolidin-1-yl)-ethyl|- 7102 what else phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

F TOP: Chne-1.72; RH-MS: t/: 576.5 MANI. (9)

With c) c) and

M M Sh! 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-71sa g IF o (4-diethylaminopiperidin-1-yl)-ethyl|-phenyl)-6-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Ff VERH: Chvne-1.70; RH-MS: t/: 618.5 MANI. (o) (1) The desired compound (TSF salt, 7.9 mg, 0.01 mmol, 63 95) was obtained as a colorless solid from the compound of the above example (TSF salt, 12 mg, 0.016 mmol) similarly to the preparation in example 67. Purification of the crude substance was carried out using preparative HPLC with the reverse phase (Umaieg5 system).

Example 72: 7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-P1-(3-oxomorpholin-4-yl)-ethyl|-phenyl)-1, 4-dihydro-2H-isoquinolin-3-one.

S chu

Her si (Fi

To a solution of intermediate 72.1 (53 mg, 0.10 mmol) and EizM (0.042 ml, 0.30 mmol) in

Chloroacetyl chloride (0.020 ml, 0.25 mmol) was added to DCM (1 ml) at RT. The reaction mixture was stirred at RT for 1 h, then evaporated to dryness. The obtained residue was dissolved in EN (0.5 ml) and Mahon (35 95 in water, 0.025 ml, 0.22 mmol) was added at RT.

The suspension was vigorously stirred for 2 h, then diluted with DCM and washed with water. The organic phase was dried over Mag50O5, filtered and evaporated to dryness.

The obtained crude material was purified by preparative reverse-phase HPLC (Umayeg5 system) to give the desired compound (18.9 mg, 0.034 mmol, 33 95) as a light yellow solid. TOP: "ve-2.45 min.; LC-MS: t/72 563.4 MANI; "N NMR (400

MHz, DMSO-α): 0.83-0.96 (t, ZN), 1.12-1.25 (29, 9-61, ZN, a mixture of diastereoisomers), 1.40-1.48 (t, ZN), 1.48-1.72 (t, 2H), 2.75-2.86 (t, 1H), 3.23-3.36 (t, 1H), 3.61 (a, 9U- 19.8, 1H), 3.68-3.93 (t,

BN), 4.10 (5, 2H), 4.18-4.91 (t, 1H), 5.76 (ad, 9U-7.3, 1H), 6.11 (a, 9-32, 1H), 6.86 (5, 1H), 7.06-7.12 (t, 1H), 7.15-7.21 (t, 2H), 7.24-7.30 (t, 2H) , 7.33-7.39 (t, 4H).

Intermediate 72.1: 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-(2-hydroxyethylamino)-ethyl|-phenyl)-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one. he o o : 5 M Fo o7-7 ni F

SI

The desired compound (139 mg, 0.27 mmol, 63 95) was obtained as a yellow solid from intermediate 55.2 (200 mg, 0.42 mmol) and ethanolamine (0.076 mL, 1.26 mmol) analogously to the preparation of intermediate 61.1. Purification of the crude substance was carried out using column chromatography Sotbri-Riazpi Sotrapiop "m (Izso Ips.) (510 g; elution in gradient mode, DKH/MeOOnH 99.5:0.5 - z» 9:1). TLC: Keg-0 ,26 (DHM/Meon 9:1);

Aive-1.88 min.; LC-MS: t/2 523.2 MANI"; "H NMR (400 MHz, DMSO-av): 0.82-0.97 (t, ZN), 1.11- 1.25 (249, 9- 6.1, ZN, a mixture of diastereoisomers), 1.45-1.72 (t, 5H), 2.59-2.75 (t, 1H), 2.81-2.97 (t, 1H), 3 ,53-3.95 (t, 7H), 4.18-4.32 (t, 1H), 4.33-4.46 (t, 1H), 6.16 (Bug. 5., 1H), 6.87 (5, 1H), 710 (a, 9-66, 1H), 7.23-7.42 (t, 6H), 7.44-7.55 (t, 2H), 8.73- 8.91 (t, 1H), 8.94-910 (t, 1H).

Example 7Za: (5)-7-(8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-Ktrans-4-dimethyl-aminocyclohexylmethyl)-methylamino|-phenyl)-b-methoxy-1 ... )-methylamino|-phenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Sh- | - c) c) c) c) m unit ha

SI (o)

The desired compounds of the examples were obtained by chiral resolution of the racemic compound of example 54B). Chiral chromatography was performed using an HPLC system with a 500 x 50 mm, 20 μm SpigaIrak AYU column, eluting with a mixture of 40 95 EOH-O, 1 95 diethylamine in n-heptane at a flow rate of 60 - 120 ml/min.

Koo) Example 7Za: HPLC: Chwe-1.97; RH-MS: t/: 604.6 MANI; "H NMR (500 MHz, DMSO-av): 0.86 (i, 9-7.5, ЗН), 0.94-1.06 (t, 2Н), 1.18 (а, 9У-6, 1, ЗН), 1.22-1.34 (t, 2Н), 1.43-1.67 (t, ЗН), 1.71-1.80 (t, 2Н), 1.85-1, 94 (t, 2H), 2.54 (Brg. v5., 6H), 2.76-2.90 (t, 1H), 2.87 (5, ZH), 3.11 (a, 9U-7 ,0, 2H), 3.56 (y, 9-19.8, 1H), 3.72 (v, ЗН), 3.88 (y, 9-19.8, 1H), 4.17-4 .24 (t, 1H), 5.94 (5, 1H), 6.52-6.59 (t, 2H), 6.82 (5, 1H), 6.86-6.91 (t, 2H ), 7.01 (5, 1H), 7.34 (5, AN).

Example 730: HPLC: Chwe-1.98; RH-MS: t/: 604.6 MANI; "H NMR (500 MHz, DMSO- av): 0.90 (Yi, 9-7.5, ZN), 0.97-1.07 (t, 2H), 1.11 (a, U-6, 0, ЗН), 1.30-1.42 (t, 2Н), 1.49-1.69 (t, ЗН), 1.73-1.82 (t, 2Н), 1.91-1, 98 (t, 2H), 2.66-2.72 (25, 6H), 2.87 (5, ЗН), 2.89-2.96 (t, 1H), 3.12 (а, 9- 7.0, 2H), 3.55 (a, 9-19.8, 1H), 3.72 (5, ЗН), 3.88 (0, 9U-19.8, 1H), 4.21- 4.29 (t, 1H), 5.93 (5, 1H), 6.53-6.60 (t, 2H), 6.82 (5, 1H), 6.87-6.92 (t, 2H), 7.02 (5, 1H), 7.34 (5, AN).

Example 74.

Compounds 74aa-74B65 were obtained similarly to the preparation in example 73 using chiral column chromatography to separate the corresponding racemic mixture.

Mo | Structure Name/HPLC/MS lead (5)-7-((A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy- 74aas U A 2-(4-methoxyphenyl)-1 ,4-dihydro-2H-isoquinolin-3-one. (c) about HPLC: Vive-2.78; IAT-MS: t/» 466.2 (MANI). (o) (o) o.

M Fi o (8)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-74ar sh SU 2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinoline -3-one (c) F TOP: Vine-2.78; IAT-MS: t/ 466.2 MANI.

SI

(o) (c) in (5)-7-((5)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy- 74as ш SU A 2-(4-methoxyphenyl)-1,4 -dihydro-2H-isoquinolin-3-one. (c) about HPLC: Vive-2.78; IAT-MS: t/» 466.2 (MANI). (o) (o) (c)

M Fi in (8)-7-((5)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy- 74ad schi SU 2-(4-methoxyphenyl)-1,4-dihydro-2H- isoquinolin-3-one. o F TOP: Vide-2.78; IAT-MS: m/z 466.2 (MANI. (o) (o) o. vv ro (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4 - 74ae SU N iv) dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- - with isoquinolin-3-one. o VERH: "Chne-2.03 min.; IAT-MS: t/: 480.6 MANI".

SI

(o) o.

M Firo (H)-7-(B)-tert-butoxy)-1 -(4-chlorophenyl)-2-(4-748 SU iv) dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- - isoquinolin-3-one.

F HPLC: "ve-2.03 min.; IAT-MS: t/; 480.6 (MANI. (o) (o) o in A 4-((5)-7-(A)-second-butoxy )-1-(4-chlorophenyl)-6- and Eiv) methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M-74ad A:

AH ethyl-M-methylbenzamide.

And the TOP: Chne-2,47; RH-MS: t/: 521.4 MANI. (at)

Mo | Structure Name/HPLC/MS and lo with M fi sh- pod) and) vtorgbutok) 1 (Se chlorfecil v. M 74ai methoxy-3-oxo-3,4-dihydro-1H-isoquinolin- -yl|-M-

AH ethyl-M-methylbenzamide.

I F TOP: Chva-2.46; LC-MS: t/2 521.3 (MANI. (9) (c) (c) in X (5)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7- 74ai SU Ns ) isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinoline-3-m i on.

TOP: Chva-1.87; RH-MS: t/: 465.3 (MANI. (9) (c) (c)

M Fi X (H)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-7azi rve o isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3- - one.

F TOP: Chvne-1.87; RH-MS: t/ 465.3 MANI. (9) and then in I (5)-7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-2-|4- 74ak i SU E 07770 | (cyclopropylmethylmethylamino)phenyl|-6-methoxy-1,4-m A dihydro-2H-isoquinolin-3-one. o TOP: Chne-2.09; RH-MS: t/: 519.4 MANI. (about) about that

M Firo (8)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-74a and SU c) (cyclopropylmethylmethylamino)phenyl|-b-methoxy-1,4-

M dihydro-2H-isoquinolin-3-one.

F TOP: Chva-2.09; LC-MS: m/2 519.4 (MANI. (o) (c) o. vi A (5)-7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy- 7 lat| 9 SU o) 2-(4-(2-oxoazetidin-1-yl)phenyl|-1,4-dihydro-2H-

Z X isoquinoline-Z-on. o TOP: Chne-2.49; RH-MS: t/z: 505.4 MANI. (o) (c) o

(8)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-7aap 9 SU 07770 |2-I4-(2-oxoazetidin-1-yl)phenyl| -1 4-dihydro-2H-

With isoquinolin-3-one.

Ff TOP: Chne-2,49; RH-MS: t/: 505.5 MANI. (at)

Mo | Structure Name/EPCH/MS o 5 vv DY (5)-1-(4-chlorophenyl)-7-cyclobutoxy-2-(4- 7480 SU Her o dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- ke a isoquinolin-3-one. and HPLC: "Chve-1.94; LC-MS: t/: 477.3 MANI. si (c) (c) its alkali Di (8)-1-(4-chlorophenyl)-7-cyclobutoxy-2- (4-74a SU o dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-p Sho isoquinolin-Z-one.

Ff VERH: "Chve-1.94; RH-MS: t/: 477.3 MANI. si

(5)-7-((A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy- 74a SU Her 07770 2-4-(methylpyridine-4- ylmethyl-amino)phenyl-1 4-h M with dihydro-2H-isoquinolin-3-one. and VERH: "Chve-2.05; RH-MS: t/2 556.2 MANI". (in)

Mo (c) and I r M Sh ! (8)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-7aat U 0777 002-4-(methylpyridin-4-ylmethyl-amino)phenyl-1 A-

M dihydro-2H-isoquinolin-3-one.

F TOP: "Chve-2.06; RH-MS: t/2 556.2 MANI". sit! M-((8)-1-14-((5)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)- (c) M 7485 U H 077 b-methoxy-3- oxo-3,4-dihydro-1H-isoquinolin-2-yl|-

A: phenyl)-ethyl)-N-ethylacetamide. : From HPLC: "Chne-2.57; LC-MS: t/: 549.6 MANI.si ! M-(8)-1-4-((8)-7-((B)-second-butoxy )-1-(4-chlorophenyl)- (c) M 7481 and H 077 b-methoxy-3-oxo-3,4-dihydro-1 H-isoquinolin-2-yl|-

AI: phenyl)-ethyl)-N-ethylacetamide.

ABOVE: "Chve-2.57; RH-MS: t/2 549.4 MANI". (c) (c) o o i Phi ! M-((8)-1-14-((8)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)-74ai and 07b-methoxy-3-oxo-3,4 -dihydro-1H-isoquinolin-2-yl|-

A, phenyl)-ethyl)-M-ethylacetamide. : F TOP: "Chve-2.58; RH-MS: t/2 549.5 |M'ANI". si

Mo | Structure Name / HPLC / MS and Po o M Phi : M-((8)-1-14-KA)-7-(BA)-tert-butoxy)-1-(4-chlorophenyl)- 748m va 077 b- methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-

And phenyl)-ethyl)-M-ethylacetamide.

F TOP: Chva-2.58; LC-MS: m/2 549.6 (MANI. (9) va (o) o M-14-K14-(5)-7-(BA)-tert-butoxy)-1-(4-chlorophenyl)- 6th: methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-74am: M; 97 phenyl)-methylamino)-methyl|-trano-cyclohexyl)- sh : propionamide. 7 a TOP: Chne-2,22; RH-MS: t/: 632.6 MANI. (9) you (c) (o) M-(4-(44-K8)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-fi : methoxy-3-oxo- 3,4-dihydro-1H-isoquinolin-2-yl|-74ah : M 97 phenyl)-methylamino)-methyl|-thrano-cyclohexyl)- is propionamide.

Y FI TOP: Aine-2,22; RH-MS: t/h 632.7 ME. (9) that 1 in KO 1(8)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-((5)-1-74a) that IF H o ( 4-dimethylaminopiperidin-1-yl)-ethyl|-phenyl)-b-

In M. Kh. methoxy-1,4-dihydro-2H-isoquinolin-3-one. : FROM TOP: Chne-1.72; RH-MS: t/: 590.7 MANI. (9) about 1 in O1(8)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-((B)-1- 7487 sh IF | 97 ( 4-dimethylaminopiperidin-1-yl)-ethyl|-phenyl)-b-

M with methoxy-1,4-dihydro-2H-isoquinolin-3-one. o TOP: Chva-1.73; LC-MS: t/2 590.7 (MANI. (9) o to 1 M fi KO 1(8)-7-((B)-second-butoxy)-1-(4-chlorophenyl)-2-( 4-((5)-1- 74ra sh IF 97 (4-dimethylaminopiperidin-1-yl)-ethyl|-phenyl)-b-

M. methoxy-1,4-dihydro-2H-isoquinolin-3-one.

EF TOP: Chvne-1.70; RH-MS: t/: 590.7 MANI. (9) about 1 M Phi OO 1(8)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-((B)-1- 7488 t IF 973 (4-dimethylaminopiperidin-1-yl)-ethyl|-phenyl)-6-

M methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Ff TOP: Chne-1.72; RH-MS: t/: 590.7 MANI. (9)

Example 75: (5)-1-(4-Chlorophenyl)-2-14-Ktranso-4-dimethylaminocyclohexylmethyl)-methylamino|-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinoline- 3-on I

F (c) c) vve et with (FI

Intermediate product 75.6 (30 mg, 0.087 mmol), Si! (3.3 mg, 0.017 mmol), (w/-)-trans-1,2-diaminocyclohexane (0.002 mL, 0.017 mmol), and KzRO" (36.8 mg, 0.17 mmol), then evaporated in vacuo and filled with argon (Zh). A solution of intermediate 75.8 (48.4 mg, 0.13 mmol) in anhydrous dioxane (0.5 mL) was added, the reaction flask was sealed, and the suspension was heated at 1107 and stirred for 14 h. The reaction mixture was cooled to RT, diluted with

DCM and washed with a 2M aqueous solution of MagSbOz. The organic phase was dried over magnesium sulfate, filtered and evaporated. The resulting crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) to give the desired compound (TSF salt, 25 mg, 0.036 mmol, 40 95) as a brownish solid. HPLC: "va-1.83 min.; LC-MS: t/2 590.7 |MANI; "H NMR (400 MHz, DMSO-av). 0.96-1.10 (t, 2H), 1.19 (a, 9-61,

ZN), 1.24 (a, 9-61, ZN), 1.30-1.46 (t, 2H), 1.59-1.71 (t, 1H), 1.74-1.86 ( t, 2H), 1.90-2.03 (t, 2H), 2.71 (25, 6H), 2.89 (5, ЗН), 3.03-3.19 (t, ЗН), 3 ... , 5.94 (5, 1H), 6.54-6.63 (t, 2H), 6.84 (5, 1H), 6.87-6.95 (t, 2H), 7.03 (in , 1H), 7.35 (5, 4H), 9.22-9.37 (t, 1H).

Intermediate 75.1: (4-isopropoxy-3-methoxyphenyl)-acetic acid ethyl ester. - lo (F) ste v

A mixture of ethyl-(4-hydroxy-3-methoxyphenyl)-acetic acid ethyl ether (11.22 g, 53.4 mmol) and K»bOz (22.13 g, 160 mmol) in DMF (100 mL) was heated at 60 "C. 2-iodopropane (9.06 mL, 91 mmol) was added and the mixture was vigorously stirred at 60 "C for 5 h.

The reaction mixture was cooled to RT, diluted with ASOEI and washed with water.

The aqueous phase was separated and further extracted using ASOEI. The combined organic fractions were dried over NaCl, filtered and evaporated to dryness. The obtained crude substance was purified using column chromatography Sotbri-Ria5py Sotrapiop m (I5so

Ips.) (5102; gradient elution, heptane/AcOEI 98:2 -» 3:1) and obtained the desired compound (11.94 g, 47.3 mmol, 89 95) as a colorless oil. TLC: Ke-0.44 (heptane/AsoOEII 7:3); TOP: Avei-2.14 min.; RH-MS: t/: 253.4 MANI; "H NMR (400 MHz, SOSI"): 1.28 (Her, 9-71,

ЗН), 1.38 (a, 9-6.1, 6Н), 3.56 (5, 2Н), 3.87 (5, ЗН), 4.17 (d, 9-71, 2Н), 4 .50 (p, 9U-6.1, 1H), 6.77-6.89 (t, ZN).

Intermediate 75.2: (2-Formyl-4-isopropoxy-5-methoxyphenyl)-acetic acid ethyl ester. - lo (F) o ons o.

To a solution of intermediate 75.1 (11.94 g, 47.3 mmol) and dichloromethoxymethane (8.56 mL, 95 mmol) in DCM (350 mL) over 45 min. at 0 "C (ice bath) was slowly added

ZpSii (1 M solution in DCM, 95 ml, 95 mmol). After addition, the reaction mixture was further stirred at 0 "C for 45 min., then poured into water and extracted with

DXM (2x). The organic phase was washed with a 2M aqueous solution of MagCO3, then dried over Mag250, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpy Sotrapiop "m (Izso Ips.) (510 g; elution in the gradient mode, heptane/AcOEi 95:5 -» 1:1) and the desired compound was obtained (11.13 g, 39 .7 mmol, 84 Fo) as a yellow oil, which crystallized on standing to give an almost white solid. TLC: Be-0.50 (heptane/AcOEII 1:1); HPLC: "ve-1.93 min.; LC-MS: t/2 281.4

IMANI" "H NMR (400 MHz, DMSO-abv): 1.18 (i, 9-71, ЗН) 1.28 (і, У-6,1, 6Н) 3.84 (5, ЗН) 4, 01 (5, 2H) 4.07 (a, 9-71, 2H) 4.56-4.68 (t, 1H) 7.03 (5, 1H) 7.45 (5, 1H) 9.93 ( 5, 1H).

Intermediate 75.3: Ethyl ether (4-isopropoxy-5-methoxy-2-((E)-(5)-2-methylpropane-2-sulfinylimino|-methyl-phenyl)-acetic acid. -lO (6)

Because oh in oh

To a solution of intermediate 75.2 (9.14 g, 32.66 mmol) and (5)-(-)-2-methyl-2-propanesulfinamide (5.93 g, 48.9 mmol) in DCM (200 mL) at 0 "C (ice bath) was added

TOB (27.3 ml, 130 mmol). The reaction mixture was refluxed, stirred for 5 h, then cooled to RT and quenched by careful addition of water (14.7 mL). The obtained white precipitate was filtered through a layer of celite, the precipitate on the filter was washed with DCM, and then the filtrate was evaporated to dryness. The obtained crude substance was purified using Sotri-Riavp column chromatography

Sotrapiop m (Izso Ips.) (5 µg; elution in gradient mode, heptane/(AsoOEi 95:5 -» 1:1) and obtained the desired compound (11.07 g, 28.9 mmol, 89 95) in the form of a yellow oil . dv): 1.17 (5 9-71, ЗН) 1.15 (5, 9Н) 1.27 (а, 9-6.1, 6Н) 3.83 (5, ЗН) 3.94-4, 07 (t, 4H) 4.58-4.66 (t, 1H) 7.04 (5, 1H) 7.50 (5, 1H) 8.49 (5, 1H).

Intermediate 75.4: (4-chlorophenyl)trimethylstannane.

Koo) that

SI

A 1M solution of 4-chlorophenylmagnesium bromide in ESO (92 mL, 92 mmol) was slowly added to a 1M solution of trimethyltin chloride in THF (92 mL, 92 mmol) over 40 minutes at -10 °C, so that the temperature never exceeded 0 °C. After the addition, the cooling bath was removed and the resulting suspension was stirred at RT for 1 h. A saturated aqueous solution of MNASI (14 ml) was added, then water until the precipitate was completely dissolved. The mixture was transferred to a separatory funnel and extracted with ESO (Zh). The combined organic fractions were dried over

Ma?5O", filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpi Sotrapiop "m (Izso Ips.) (510 g; elution in the isocratic mode with cyclohexane) and obtained the desired compound (24.47 g, 89 mmol, 97 95) in the form of a colorless oil. TLC : Ke-0.76 (cyclohexane/AcSOEL 95:5); HPLC: "ve-3.25 min.; "N

NMR (400 MHz, SOS"): 0.31 (5, 9H) 7.32-7.36 (t, 2H) 7.41-7.45 (t, 2H).

Intermediate 75.5: 42-(5)-(4-Chlorophenyl)-((5)-2-methylpropane-2-sulfinylamino)-methyl)|-4-isopropoxy-5-methoxyphenyl)-acetic acid ethyl ester.

- lo (F) (in)

Ж M ХК ro о E (Fi

Intermediate 75.3 (10.97 g, 28.6 mmol) and anhydrous THF (50 mL) were placed in a 250 mL flask, then evacuated and filled with argon (Zx). Intermediate 75.4 (15.75 g, 57.2 mmol) and bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)utetrafluoroborate (1.09 g, 2.86 mmol) were successively added during CT and the resulting orange suspension heated at 60"C and stirred for 2 hours. At 60"C, bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (1.09 g, 2.86 mmol) was additionally added and the mixture was additionally stirred for 4 hours The reaction mixture was cooled to RT, diluted with ASOEI and washed with water. The organic phase was dried over Mag504, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotheby-Nazy Sotrapiop "m (Izso Ips.) (ZiOg; elution in gradient mode, heptane/AcSOEi 95:5 -» 3:7) and obtained the desired compound (3.96 g, 7 .98 mmol, 28 90) as a brown resin. TLC: Re-0.29 (heptane/AsoEi 1:1); HPLC: "va-2.70 min.; RH-MS: t/ 496.3

IM-AANI"; "H NMR (400 MHz, DMSO-av): 1.10-1.19 (t, 15Н), 1.23 (9.9-5.9, ЗН), 3.57 (и , 9-16.4, 1H), 3.68 (a, 9-16.1, 1H), 3.73 (5, ЗН), 3.93-4.05 (t, 2H), 4.37 -4.45 (t, 1H), 5.62 (y, 9-61, 1H), 5.82 (y, 9-61, 1H), 6.82 (5, 1H), 6.94 (5 , 1H), 7.25-7.30 (t, 2H), 7.36-7.А41 (t, 2H).

Intermediate 75.6: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (c) (c) ve

E (9)

SI

A solution of intermediate 75.5 (3.96 g, 7.98 mmol) in 125 M NaCl in Meon (128 mL) was stirred at RT for 30 min. The reaction mixture was evaporated to dryness and the resulting residue was dissolved in MeOH (40 mL). At RT, ElysM (5.56 mL, 39.9 mmol) was added, then the mixture was stirred for 15 minutes and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpi Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in gradient mode, (heptane/dM 1:11)/TBME 9:1-» 100 956 TBME) and obtained the desired compound (2.51 g, 7.24 mmol, 91 95, EN (enantiomeric excess) 92 95) in the form of almost

Co) of a white solid. TLC: Be-0.13 (heptane/"DHM/TBME 1:1:2); HPLC: Chve-2.03 min.; LC-MS: t/2 346.4 MANI; "H NMR (400 MHz, DMSOO-аv): 1.16 (а, 9-61, ЗН), 1.21 (а, 9-61, ЗН), 3.36 (а, 9-19.8, 1Н), 3.51 ( a, 9-19.8, 1H), 3.72 (5, ЗН), 4.40 (vri, 9-61, 1H), 5.55 (j, 9-34, 1H), 6.79 ( 5, 1H), 6.84 (5, 1H), 7.26-7.33 (t, 2H), 7.35-7.42 (t, 2H), 8.49 (0, 9-3, 9, 1H).

Intermediate 75.7: (14-K4-iodophenylamino)-methyl|-trans-cyclohexyl)-carbamic acid tert-butyl ether.

(c) (c) zu so she

AND

To a solution of 4-iodophenylamine (1 g, 4.57 mmol) in DCM (25 ml) at CT was successively added

ASON (0.523 ml, 9.13 mmol), (4-formylcyclohexyl)-carbamic acid tert-butyl ether (1.14 g, 5.02 mmol) and Mavn(oOds)»z (1.94 g, 9.13 mmm). The reaction mixture was stirred at RT for 1 h, then diluted with E2O and washed successively with 2M aqueous solution of HCl and 2M aqueous solution of MagSbOz. The organic phase was dried over Mao', filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-RIa5py Sotrapiop "m (Ib5so Ips.) (5 g; elution in gradient mode, heptane/AcSOEi 95:5 -» 1:11) and the desired compound was obtained (1.56 g, 3 .62 mmol, 79 90) in the form of a colorless solid. TLC: Ke-: 0.72 (heptane/AsoOEII 1:11); HPLC: "Chve-2.64 min.;

RH-MS: t/ 431.4 MANI; "H NMR (400 MHz, DMSO-av): 0.87-1.03 (t, 2H), 1.03-1.17 (t, 2H), 1.32-1.48 (t, 1H) , 1.37 (5, 9H), 1.70-1.86 (t, 4H), 2.76-2.86 (t, 2H), 3.08-3.25 (t, 1H), 5 .77-5.89 (t, 1H), 6.34-6.46 (t, 2H), 6.59-6.71 (t, 1H), 7.24-7.35 (t, 2H) .

Intermediate 75.8: (Trans-4-dimethylaminocyclohexylmethyl)-(4-iodophenyl)-methylamine.

So oh

AND

To a solution of intermediate 75.7 (200 mg, 0.47 mmol) in DCM (2 ml) at RT was added

TFA (1.07 mL, 13.94 mmol). The reaction mixture was stirred at RT for 45 min., then evaporated to dryness. The resulting residue was dissolved in DCM (5 ml) and, at RT, ASON (0.221 ml, 3.86 mmol), formaldehyde (37 9o in water, 0.289 ml, 3.86 mmol) and

Mavn(oOAc): (818 mg, 3.86 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with a 2M aqueous solution of MagSO3 (2x). The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpy Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in gradient mode, (heptane/dxM 1:C/TBME, which contains 5 95 7M MHz in MeOonNn 95:25 - 100 95 TBME containing 5 95 7/M MHz in MeOH) and afforded the title compound (141 mg, 0.38 mmol, 83 95) as a light yellow oil. TLC: Ke-0.32 (hepgan/DXM/TBME , which

Co) contains 5 95 7M MHz in MeOnH 1:1:2); TOP: "ve-1.42 min.; RH-MS: t/2 373.4 MANI"; "H NMR (400

MHz, DMSO-α): 0.89-1.01 (t, 2H), 1.02-1.14 (t, 2H), 1.51-1.63 (t, 1H), 1.63- 1.72 (t, 2H), 1.73-1.682 (t, 2H), 2.02-2.11 (t, 1H), 2.13 (5, 6H), 2.687 (5, ЗН), 3 ,12 (a, 9-71, 2H), 6.46-6.53 (t, 2H), 7.35-7.43 (t, 2H).

Example 76: (5)-1-(4-Chlorophenyl)-2--4-K(transo-4-dimethylaminocyclohexylmethyl)-ethylamino|-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H -isoquinolin-3-one.

-

F (c) c) oval

SI

The desired compound (TSF salt, 18.8 mg, 0.026 mmol, 36,956) was obtained as a yellow solid from intermediate 75.6 (25 mg, 0.072 mmol) and intermediate 76.3 (41.9 mg, 0.108 mmol) analogously to the preparation in example 75. Purification of the crude substance was carried out using reverse-phase preparative HPLC (Mua(eg5) system. HPLC:

Video-1.75 min.; LC-MS: t/: 604.5 |MANI"; "H NMR (400 MHz, DMSO-α): 0.96-1.11 (t, 5H), 1.20 (a, 9-5.9 , ZN), 1.24 (a, 9U-6.1, ZN), 1.30-1.45 (t, 2H), 1.54-1.70 (t, 1H), 1.78-1 .89 (t, 2H), 1.92-2.03 (t, 2H), 2.67-2.74 (25, 6H), 3.02-3.16 (t, ЗН), 3.33 (a, 9U-6.8, 2H), 3.53-3.60 (t, 1H), 3.73 (5, ЗН), 3.88 (a, 9-19.8, 1H), 4 ,40-4.50 (t, 1H), 5.94 (5, 1H), 6.54-6.62 (t, 2H), 6.84 (in, 1H), 6.86-6.93 (t, 2H), 7.06 (5, 1H), 7.33-7.А41 (t, 4H).

Intermediate 76.1: (4-Cethyl-(4-iodophenyl)amino|-methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether. Oh! Oh!

Iodethane (0.192 mL, 2.33 mmol) was added to a suspension of intermediate 75.7 (100 mg, 0.232 mmol) and Kg2CO3 (64.2 mg, 0.465 mmol) in DMF (1 mL) under RT. The reaction mixture was heated at 60 °C, vigorously stirred for 14 h, then cooled to RT and poured into water.

The mixture was extracted with ESO (2x) and the combined organic fractions were dried over Mg5Ox, filtered and evaporated to dryness to afford the crude title compound (104 mg, 0.23 mmol, quantitative yield) as a tan solid which was used in the next step without additional cleaning. TOP: Vive-2.76 min.; IAT-MS: t/l 459.3 MANI N

NMR (400 MHz, DMSO-α): 0.92-1.14 (t, 7H), 1.37 (v, 9H), 1.45-1.59 (t, 1H), 1.61-1 .82 (t, 4H),

C3.05 (9.9-7.1, 2H), 3.10-3.24 (t, 1H), 3.91 (9, 9U-6.8, 2H), 6.44-6.55 (t, 2H), 6.60-6.69 (t, 1H), 7.33-7.42 (t, 2H).

Intermediate 76.2: (Transo-4-dimethylaminocyclohexylmethyl)-ethyl-(4-iodophenyl)-amine. so oh

Coo)

The desired compound (45 mg, 0.116 mmol, 54 95) was obtained as a colorless oil from intermediate 76.1 (101 mg, 0.22 mmol) analogously to the preparation of intermediate 75.8.

Purification of the crude substance was carried out using column chromatography Sotri-

Nazp Sotrapiop "m (Izso Ips.) (5iOg; elution in gradient mode, (heptane/dhm 1:C/TBME, which contains 5 95 7M MNz in MeOnN 9:1 -» 100 906 TBME, which contains 5 95 7M MNz in MeoN.) HPLC:

Video-1.30 min.; IAT-MS: t/2 387.3 MANI; "H NMR (400 MHz, DMSO-α): 0.89-1.17 (t, 7Н), 1.47-

1.65 (t, 1H), 1.67-1.85 (t, 4H), 2.14 (c, 6H), 3.04 (a, 9-71, 2H), 3.26-3, 39 (t, ZN), 6.44-6.52 (t, 2H), 7.32-7.А41 (t, 2H).

Example 77: M-(4-((4-(5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |I-phenyl-methylamino)-methyl-I-trans-cyclohexyl)-methane-sulfonamide. o,,0 mat

F (c) (c) vok m Z

SI

EizM (0.015 mL, 0.107 mmol) and methanesulfonyl chloride (8.2 mg, 0.071 mmol) were sequentially added to a solution of intermediate 77.3 (20 mg, 0.036 mmol) in MesmM (0.5 mL) at RT. The reaction mixture was stirred at RT for 1 h, then immediately purified by reverse-phase preparative HPLC (Ulaieg5 system) to obtain the desired compound (TSF salt, 5 mg, 0.007 mmol, 1995) as a reddish solid. TOP:

Aive-2.15 min.; LC-MS: t/ 640.7 MANI"; "H NMR (400 MHz, DMSO-α): 0.94-1.21 (t, 4H), 1.19 (a, 9-5.9, ЗН ), 1.24 (a, 9U-6.1, ZN), 1.49-1.61 (t, 1H), 1.61-1.71 (t, 2H), 1.84-1.93 (t, 2H), 2.85-2.90 (t, 6H), 2.96-3.20 (t, ZH), 3.57 (y, 9U-19.8, 1H), 3.73 (in, ЗН), 3.89 (y, 9U-19.8, 1Н), 4.40-4.50 (t, 1Н), 5.95 (5, 1Н), 6.54-6.62 (t, 2H), 6.84 (5, 1H), 6.87-6.93 (t, 2H), 6.96 (y, 9-7.3, 1H), 7.04 (5, 1H ), 7.35 (5.4H).

Intermediate 77.1: (4-(4-iodophenyl)-methylamino|-methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether.

Phew! what

ASON (0.199 ml, 3.48 mmol), formaldehyde (37 9o in water, 0.259 ml, 3.48 mmol) was successively added to a solution of intermediate 75.7 (748 mg, 1.74 mmol) in DCM (15 ml) at RT and

Mavn(oAc)z (737 mg, 3.48 mmol). The reaction mixture was stirred at RT for 2 h, then diluted with DCM and washed with a 2 M aqueous solution of MagSO3 (2x). The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpi Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in gradient mode, heptane/AcSOEi 98:2 -» 7:3) and obtained the desired compound (584

Co) mg, 1.31 mmol, 76 95) as a colorless solid. TLC: Ke-0.36 (heptane/AsoEly 3:1);

TOP: Mve-2.76 min.; LC-MS: t/z: 445.4 |MANI"; "H NMR (400 MHz, DMSO-α): 0.90-1.13 (t, 4Н), 1.36 (5, 9Н), 1 ,48-1.66 (t, ЗН), 1.69-1.81 (t, 2Н), 2.87 (5, ЗН), 3.08-3.21 (t, 1Н), 3.12 (a, 9-71, 2H), 6.45-6.54 (t, 2H), 6.68 (0, 9-81, 1H), 7.34-7.43 (t, 2H).

Intermediate 77.2: tert-butyl ether 44-((4-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl|1-phenyl)-methylamino)-methyl|-trano-cyclohexyl)- carbamic acid.

(in)

And about AOS, oo | and other things; with

The desired compound (1.03 g, 1.56 mmol, 69 95) was obtained as a brownish solid from intermediate 75.6 (780 mg, 2.26 mmol) and intermediate 77.1 (1.2 g, 2.11 mmol) similar to the one obtained in example 75. Purification of the crude substance was carried out using column chromatography Sotbri-Razp Sotrapiop "m (Izso Ips.) (5BIOg; elution in gradient mode, (heptane/DHM 1:1/UTBME 95:5 -» 4:6 ). UL: Chve-2.63 min.; LC-MS: t/: 662.7 (MANI; "H NMR (400 MHz, DMSO-av): 0.91-1.12 (t, 4H), 1.19 (a, 9-61, ZN), 1.24 (a, 9-61,

ЗН), 1.36 (5, 9Н), 1.48-1.60 (t, 1Н), 1.59-1.68 (t, 2Н), 1.70-1.80 (t, 2Н) , 2.87 (5, ZN), 3.05-3.21 (t, 10. ZN), 3.57 (a, 9-20.1, 1H), 3.7Z (5, ZN), 3 .89 (a, 9-20.1, 1H), 4.40-4.50 (t, 1H), 5.94 (5, 1H), 6.52-6.60 (t, 2H), 6 .66 (a, 9U-7.8, 1H), 6.83 (5, 1H), 6.86-6.93 (t, 2H), 7.04 (5, 1H), 7.35 (5 , Academy of Sciences).

Intermediate product 77.3: (5)-2--A-(Trans-4-aminocyclohexylmethyl)-methylamino|-phenyl)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H -isoquinolin-3-one.

MH,

With vva -e with si

To a solution of intermediate 77.2 (270 mg, 0.41 mmol) in DCM (2 ml) at CT was added

TFA (0.942 mL, 12.23 mmol). The reaction mixture was stirred at RT for 30 minutes, then diluted with DCM and washed with a 2M aqueous solution of MagCO3 (2x). The organic phase was dried over Ma»5O:, filtered and evaporated to dryness to give the crude title compound (251 mg, 0.41 mmol, quantitative yield) as a brownish solid, which was used in the next step without further purification. HPLC: "ve-1.77 min.; LC-MS: t/2 562.6 MANI; "H NMR (400 MHz, DMSO-av): 0.89-1.00 (t, 2H), 1, 19 (a, 9U-5.9, ЗН), 1.21-1.33 (t, 5Н), 1.51-1.68 (t, ЗН), 1.68-1.78 (t, 2Н ), 2.39-2.47 (t, 1H), 2.87 (5, ЗН), 3.06-3.14 (t, 2H), 3.57 (ad, U-19.8, 1H ), 3.73 (5, ZN), 3.89 (a, U-19.6, 1H), 4.40-4.50 (t, 1H), 5.94 (5, 1H), 6, 52-6.60 (t, 2H), 6.84 (5, 1H), 6.86-6.93 (t, 2H), 7.04 (5, 1H), 7.36 (5, AN) .

Example (78 14-((4-(5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl1-phenyl- methylamino)-methyl|-trans-cyclohexyl)-amide: oxazole-4-carboxylic acid.

Zo (in

ShoroFoya m from the village

To a solution of intermediate 77.3 (20 mg, 0.036 mmol) in DMF (0.5 mL) at RT was sequentially added 4-oxazolecarboxylic acid (4.8 mg, 0.043 mmol), EIIzM (0.010 mL, 0.071 mmol) and GATU (17 .6 mg, 0.046 mmol). The reaction mixture was heated at 50 °C and stirred for 14 h, then cooled to RT and immediately purified using preparative

reverse-phase HPLC (Wageg5 system) and obtained the desired compound (salt with TFA, 11 mg,

0.014 mmol, 40 95) as a reddish solid. HPLC: "ve-2.14 min.; LC-MS: It/2 657.7 MANI; "H NMR (400 MHz, DMSO-av): 0.99-1.14 (t, 2H), 1, 19 (a, 9-5,9, ZN), 1,24 (a, 9-61,

ЗН), 1.27-1.42 (t, 2Н), 1.54-1.66 (t, 1Н), 1.65-1.82 (t, 4Н), 2.90 (5, ЗН) , 3.14 (a, 9-6.6, 2H), 3.57 (a, 9-19.8, 1H), 3.73 (5, ЗН), 3.89 (y, 9U-19 8, 1H), 4.40-4.50 (t, 1H), 5.96 (5, 1H), 6.56-6.64 (t, 2H), 6.84 (5, 1H), 6 .88-6.95 (t, 2H), 7.04 (5, 1H), 7.36 (5, 4H), 7.96 (y, 9-8.3, 1H), 8.49 (in , 1H), 8.58 (5, 1H).

Example 79: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl-I(4-(3Z-oxopiperazin-1-yl-trans-cyclohexylmethyl|-amino) )-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

Nn oi t o AOS - : si

To a solution of intermediate 79.2 (49 mg, 0.063 mmol) in DCM (0.5 ml) at RT was added

TFA (0.097 mL, 1.261 mmol). The reaction mixture was stirred at RT for 5 h. and evaporated to dryness. The resulting residue was dissolved in Meon (0.5 mL), then EizM (0.088 mL, 0.63 mmol) was added and the mixture was stirred at RT for 1 h. The reaction mixture was immediately purified by reverse-phase preparative HPLC (UMaieg5 system) to give the desired compound (TSF salt, 19.4 mg, 0.026 mmol, 41 95) as an off-white solid. TOP: Yane-1.76 min.; RH-MS: t/: 645.7 MANI; "H NMR (400 MHz, DMSO-dv): 0.90-1.04 (t, 2H), 1.08-1.20 (t, 2H), 1.19 (a, 9U-6.1, ZN), 1.24 (9, 9U-6.1, ZN), 1.52-1.66 (t, 1H), 1.66-1.683 (t, 4H), 2.20-2.31 ( t, 1H), 2.55-2.63 (t, 2H), 2.88 (5, ЗН), 3.00 (5, 2H), 3.04-3.15 (t, 4H), 3 .57 (а, 9-20.1, 1Н), 3.73 (5, ЗН), 3.89 (y, У-19.8, 1Н), 4.41-4.50 (t, 1Н) , 5.94 (5, 1H), 6.52-6.60 (t, 2H), 6.83 (5, 1H), 6.86-6.94 (t, 2H), 7.04 (in , 1H), 7.36 (in, AN), 7.66 (bg. 5., 1H).

Intermediate 79.1: 14-((4-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl) methyl ester |-phenyl)-methylamino)-methyl|-trans-cyclohexylamino)-acetic acid. in

MN ditch -

SI

EizM (0.050 mL, 0.356 mmol) and methyl-2-bromoacetate (0.018 mL, 0.196 mmol) were sequentially added to a solution of intermediate 77.3 (100 mg, 0.178 mmol) in DCM (1.5 mL) at RT. The reaction mixture was stirred at RT for 6 h, then EHM (0.050 mL, 0.356 mmol) and methyl-2-bromoacetate (0.018 mL, 0.196 mmol) were additionally added. The mixture was additionally stirred at RT for 24 h, then diluted with DCM and washed with water. The organic phase was dried over Mag50, filtered and evaporated. The obtained crude substance was purified using Sotbri-Riaspi column chromatography. Sotrapiop m (I5so

Ips.) (5IOg2; gradient elution, DHMLDHM/7M MHz in Meon 9:11 95:5 -» 100 95

DXM/7M MHz in Meon 9/1) and obtained the desired compound (75 mg, 0.118 mmol, 67 9o) in the form of a yellow resinous substance. TLC: Kee-0.68 (DHM//M MNz in Meon 9:1); TOP: "Chve-1.85 min.; LC-MS: t/2 634.7 MANI; "H NMR (400 MHz, DMSOO-av): 0.83-1.01 (t, 4H), 1, 19 (a, 9-61,

ZN), 1.24 (a, 9-61, ZN), 1.51-1.69 (t, ZN), 1.74-1.86 (t, 2H), 2.24-2.36 ( t, 1H), 2.87 (5, ЗН), 3.06-3.13 (t, 2H), 3.29-3.35 (t, 2H), 3.57 (0, 9-19, 8, 1Н), 3.61 (5, ЗН), З3.7З (в, ЗН), 3.89 (y, 9-19.8, 1Н), 4.41-4.49 (t, 1Н) , 5.92-5.96 (t, 1H), 6.51-6.59 (t, 2H), 6.83 (v, 1H), 6.86-6.92 (t, 2H), 7 .04 (in, 1H), 7.35 (5, AN).

Intermediate 79.2: Methyl ether ((2-tert-butoxycarbonylaminoethyl)-(4-((14-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4 -dihydro-1H-isoquinolin-2-yl|-phenyl)-methylamino)-methyl|-trans-cyclohexyl)-amino)-acetic acid.

N ee oo, Mr

And orova in ;

SI

M-Bos-2-aminoacetaldehyde (72.3 mg, 0.454 mmol), ASON (0.039 mL, 0.681 mmol) and

Mavn(OAc)z (144 mg, 0.681 mmol). The suspension was stirred at RT for 1 h, then diluted with DCM and washed with a 2 M aqueous solution of MagCO3. The organic phase was dried over Mag250»4, filtered and evaporated. The obtained crude substance was purified using preparative reverse-phase HPLC (Umayeg5 system). The fractions containing the pure substance were combined and concentrated in vacuo. The obtained aqueous mixture was made alkaline by adding 2M Mag2bOz and extracted with AsSOEL. The organic layer was washed with brine, dried over Mag505, filtered and evaporated to dryness to give the title compound (142.6 mg, 0.183 mmol, 81 95) as a yellow solid. TOP:

Aive-2.20 min.; RH-MS: t/: 777.9 MANI; "H NMR (500 MHz, DMSO-α): 0.89-0.99 (t, 2H), 1.02-1.12 (t, 2H), 1.17 (a, 9-6.0, ZN), 1.22 (y, 9-6.0, ZN), 1.35 (5, 9H), 1.49-1.74 (t, 6H), 2.52-2.58 (t, 2H), 2.85 (5, ЗН), 2.86-2.93 (t, 2H), 3.05-3.10 (t, 2H), 3.28 (5, H), 3.52 -3.59 (t, 1Н), 3.57 (5, ЗН), 203.71 (5, ЗН), 3.687 (0, 9-19.8, 1Н), 4.39-4.48 (t , 1H), 5.93 (5, 1H), 6.44-6.50 (t, 1H), 6.51-6.58 (t, 2H), 6.82 (5, 1H), 6, 85-6.91 (t, 2H), 7.03 (5, 1H), 7.34 (5, AN).

Example 80: Methyl ether ((4-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-b6-methoxy-3-oxo-

C,4-dihydro-1H-isoquinolin-2-yl|-phenyl-methylamino)-methyl|-thrano-cyclohexyl)-methylamino)-acetic acid. re t

OO AYOSO

B, oh

ASON (0.006 ml, 0.10 mmol), formaldehyde (37 9o in water, 0.008 ml, 0.10 mmol) was sequentially added to a solution of intermediate 79.1 (22 mg, 0.035 mmol) in DCM (0.5 ml) at RT and

Zo Mavn(oAc)z (22.1 mg, 0.10 mmol). The reaction mixture was stirred at RT for 3 hours, then diluted with DCM and washed with a 2M aqueous solution of MagSO3 (2x). The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 4.6 mg, 0.006 mmol, 17 95) was obtained as a colorless solid. TOP: "ve-1.87 min.; RH-MS: t/: 648.7 |MANI"; "H NMR (400 MHz, DMSO-av): 0.96-1.11 (t, 2H), 1.19 (0.2-5.9, ZH), 1.24 (90, 2-5, 9, ZN), 1.36-1.54 (t, 2H), 1.60-1.72 (t, 1H), 1.74-1.84 (t, 2H), 1.92-2, 06 (t, 2H), 2.76 (ru. 5., ZN), 2.89 (5, ZN), 3.10-3.16 (t, 2H), 3.16-3.27 (t , 1H), 3.57 (a, 9-20.1, 1H), 3.73 (5, ЗН), 3.78 (5, ЗН), 3.90 (9, У-20.1, 1Н ), 4.04-4.15 (t, 1H), 4.25-4.35 (t, 1H), 4.41-4.50 (t, 1H), 5.94 (5, 1H), 6.54-6.62 (t, 2H), 6.84 (5, 1H), 6.87-6.94 (t, 2H), 7.03 (v, 1H), 7.36 (5, 4H).

Example 81: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-14-(methyl-(thrano-4-morpholin-4-ylcyclohexylmethyl)amino|-phenyl)-1,4 -dihydro-2H-isoquinolin-3-one.

s t orovov sh ;

SI

K2CO3 (24.59 mg, 0.178 mmol) and bis(2-bromomethyl) ether (0.022 mL, 0.178 mmol) were sequentially added to a solution of intermediate 77.3 (20 mg, 0.036 mmol) in DMF (0.5 mL) at RT. The reaction mixture was stirred at room temperature for 14 h, then diluted with ASOEI and washed with water. The organic phase was dried over Mag504, filtered and evaporated to dryness. The obtained crude substance was purified using a preparative method

Reverse phase HPLC (Umayeg5 system) and obtained the desired compound (TFA salt, 14.3 mg, 0.019 mmol, 54 95) as a reddish solid. TOP: "Ine-1.86 min.; RH-MS: t/2 632.4 MANI"; "H NMR (400 MHz, DMSO-α): 0.96-1.12 (t, 2H), 1.19 (a, 9-61, ZN), 1.24 (a, 9-61,

ZN), 1.30-1.44 (t, 2H), 1.57-1.72 (t, 1H), 1.75-1.86 (t, 2H), 2.01-2.11 ( t, 2H), 2.89 (5, ЗН), 3.02-3.19 (t, 5H), 3.32-3.41 (t, 2H), 3.57 (0, 9-20, 1, 1H), 3.61-3.70 (t, 2H), 3.7Z (5, ЗН), 3.90 (y, 9-201, 1H), 3.95-4.03 (t, 2H), 4.40-4.51 (t, 1H), 5.94 (5, 1H), 6.54-6.62 (t, 2H), 6.84 (5, 1H), 6.87 -6.94 (t, 2H), 7.03 (5, 1H), 7.36 (5, 4H).

Example 82: 1-14-((4-(5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| I-phenyl-methylamino)-methyl|-transo-cyclohexyl)-piperazine-2,5-dione.

N in

M (c) about AlOSo -- :

SI

To a solution of crude intermediate 82.1 (45.1 mg) in DCM (0.5 ml) at RT was added

TFC (0.182 mL, 2.36 mmol). The reaction mixture was stirred at RT for 45 minutes and evaporated to dryness. The resulting residue was dissolved in Meon (0.5 mL), then EHM (0.066 mL, 0.47 mmol) was added and the mixture was stirred at RT for 1 h. The reaction mixture was immediately purified by reverse-phase preparative HPLC (UmMaieg5 system) and the desired compound (salt with TFA, 18 mg, 0.023 mmol, 4995 in 2 steps) was obtained as a colorless solid. TOP: "ne-1.99 min.; LC-MS: t/72 659.3 MANI; "H NMR (400

MGu, DMSO-аv): 1.01-1.15 (t, 2H), 1.19 (y, U-5.9, ZN), 1.24 (a, 9-61, ZN), 1, 39-1.56 (t, 4H), 1.57-1.68 (t, 1H), 1.68-1.78 (t, 2H), 2.89 (5, ЗН), 3.13 ( 9, 9-66, 2H), 3.57 (a, U-20.1, 1H), 3.69-3.78 (t, 7H), 3.90 (j, 9-19.8, 2H ), 4.09-4.19 (t, 1H), 4.41-4.51 (t, 1H), 5.95 (5, 1H), 6.54-6.64 (t, 2H), 6.84

Koo) (5, 1H), 6.87-6.95 (t, 2H), 7.04 (5, 1H), 7.36 (5, AN), 8.09 (Bu. 5., 1H) .

Intermediate 82.1: Methyl ether ((2-tert-butoxycarbonylaminoacetyl)-14-((14-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro -1 H-isoquinolin-2-yl|-phenyl)-methylamino)-methyl|-transo-cyclohexyl)-amino)-acetic acid. o.5o0 M. o

CURRENT

M (c) about oroFzoi about; | is -- :

SI

To a solution of intermediate 79.1 (30 mg, 0.047 mmol) in DMF (0.5 mL) at RT was sequentially added tert-butoxycarbonylaminoacetic acid (9.12 mg, 0.052 mmol), EIIzM (0.013 mL, 0.095 mmol), and GATU (23 .38 mg, 0.061 mmol). The reaction mixture was heated at 50 C and stirred for 2 hours. 30 min., then cooled to RT, diluted with

ESO and washed with water (2x). The organic phase was dried over Mag 5 O 4 , filtered and evaporated to dryness to give the crude title compound (45.1 mg) as a yellow resinous substance, which was used in the next step without further purification. TOP: "Chivei-2.67 min.; RH-MS: t/ 791.3 MANI".

Example 83: 2-("Carbamoylmethyl-(4-(14-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-

3,4-dihydro-1H-isoquinolin-2-yl|1-phenyl)-methylamino)-methyl|-trano-cyclohexyl)-amino)-acetamide. Oi AN, what about F o o

Surui -- : she

SI

A suspension of intermediate 77.3 (20 mg, 0.036 mmol), 2-bromoacetamide (15.7 mg, 0.114 mmol), and K»CO3 (14.8 mg, 0.107 mmol) in DMF (0.5 mL) was stirred at RT for 14 h., then diluted with DCM and washed with water. The organic phase was dried over Ma»50Oa, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpy Sotrapiop "m (Izso Ips.) (510g; elution in gradient mode, DHMLDHM/7/M MHz in MeOnH 9:1) 95:5 -» 100 96 DHM//M Mn in MeOn 9:1) and obtained the desired compound (17 mg, 0.025 mmol, 71 95) as a colorless solid. TLC: Ke-0.16 (DXM/7M Mn in MeonN 9:1); HPLC: "ve -1.81 min.; LC-MS: t/: 676.3 MANI"; "H NMR (400 MHz,

DMSO-аv): 0.87-1.01 (t, 2H), 1.05-1.16 (t, 2H), 1.19 (а, 9-61, ЗН), 1.24 (а, 2-6.1, ZN), 1.50-1.64 (t, 1H), 1.64-1.81 (t, 4H), 2.27-2.38 (t, 1H), 2, 86 (5, ZH), 2.97 (5, 4H), 3.05-3.12 (t, 2H), 3.57 (y, y4-19.8, 1H), 3.73 (5, ЗН), 3.89 (y, 9-19.8, 1Н), 4.40-4.50 (t, 1Н), 5.94 (5, 1Н), 6.52-6.59 (t, 2H), 6.83 (5, 1H), 6.85-6.92 (t, 2H), 7.04 (v, 1H), 7.06-7.13 (t, 2H), 7.35 (c, 4H), 7.66-7.73 (t, 2H).

Example 84: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-Imethyl-I4-(3-oxo-

P1,4|diazepan-1-yl)-trans-cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

Oh! Orovov Orana m

She

From SI

MNACI (22.97 mg, 0.429 mmol) and ammonium formate (6.02 mg, 0.095 mmol) were added sequentially to a solution of crude intermediate 84.1 (41.9 mg) in MeonH (0.5 mL). The reaction flask was pumped under vacuum and purged with argon (Zh), then Ra/C (1.016 mg, 0.01 mmol) was added, the flask was sealed, and the reaction mixture was stirred at RT for 2 h. Ammonium formate (18.05 mg, 0.286 mmol) was additionally added and the reaction mixture was further stirred at RT for 1 h. The suspension was filtered and the filtrate was evaporated to dryness. The obtained residue was dissolved in ASOEA and washed with water. The organic phase was dried over Mag25054, filtered and evaporated to dryness. The resulting residue was dissolved in

Meon (0.5 mL) was then added with EHM (0.062 mL, 0.44 mmol) and the mixture was stirred at RT for 14 h. The reaction mixture was immediately purified by reverse-phase preparative HPLC (Umayeg5 system) and the desired compound (salt with TFA, 12.8 mg, 0.017 mmol, 3595 from intermediate 79.1) was obtained as a colorless solid. TOP:

Agve-1.81 min.; LC-MS: t/ 659.3 |MANI"; "H NMR (400 MHz, DMSO-av): 0.97-1.13 (t, 2H), 1.19 (y, 9-61, ЗН) , 1.24 (a, 9U-6.1, ZN), 1.37-1.54 (t, 2H), 1.61-1.74 (t, 1H), 1.74-1.90 ( t, ZN), 1.90-2.10 (t,

ZN), 2.89 (5, ZN), 3.08-3.15 (t, 2H), 3.16-3.51 (t, 5H), 3.57 (y, 9-20.1, 1H), 3.7Z (5, ЗН), 3.75-3.83 (t, 1H), 3.91 (a, 2-19.6, 1H), 4.09-4.21 (t, 1H), 4.40-4.52 (t, 1H), 5.94 (5, 1H), 6.53-6.62 (t, 2H), 6.84 (5, 1H), 6.87 -6.95 (t, 2H), 7.03 (5, 1H), 7.36 (5, 4H), 8.30-8.40 (t, 1H).

Intermediate 84.1: Methyl ether ((3-benzyloxycarbonylaminopropyl)-14-(14-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1 N-isoquinolin-2-yl|-phenyl)-methylamino)-methyl|-trans-cyclohexyl)-amino)-acetic acid. o r o o AOS, sh: si

3-(benzyloxycarbonyl)amino|propionic aldehyde (11.76 mg, 0.057 mmol), ASON (0.005 ml, 0.095 mmol) were sequentially added to a solution of intermediate 79.1 (30 mg, 0.047 mmol) in DCM (0.5 mL) at RT ) and Mavn(ods)z (20.05 mg, 0.095 mmol). The suspension was stirred at RT for 1 h, then diluted with DCM and washed with 2M aqueous solution

MagSOz. The organic phase was dried over Mag2505, filtered and evaporated to dryness to afford the crude title compound (41.9 mg) as a yellow resinous substance, which was used in the next step without further purification. TOP: "(ve-2.25 min.; RH-MS: t/2 825.4 MANI).

Example 85: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl-|4-(4-oxoimidazolidin-1-yl-transo-cyclohexylmethyl|-amino)- phenyl)-1,4-dihydro-2H-isoquinolin-3-one. he

With her

F i i ve tu 2

SI

A solution of crude intermediate 85.1 (135 mg) and formaldehyde (37°C in water, 0.156 mL, 2.1 mmol) in EUN (3 mL) was heated at 80 °C and stirred for 4 h. The reaction mixture was cooled to RT and evaporated to dryness The resulting residue was heated at 1507 for 14 h under vacuum, then cooled to RT and purified by preparative reversed-phase HPLC (Umayeg5 system) to give the desired compound (TSF salt, 22.5 mg, 0.030 mmol, 1495 from intermediate product 79.1) in the form of a yellow solid. HPLC: "ve-1.89 min.; LC-MS: n/2 631.2 MANI"; "H NMR (400 MHz, COzO0): 1.07-1.18 (t, 2H), 1.20 (a, 9-61, ЗН), 1 .26 (a, 9-61, ЗН), 1.33-1.47 (t, 2Н), 1.71-1.85 (t, 1Н), 1.87-1.96 (t, 2Н) , 2.10-2.21 (t, 2H), 2.96 (5, ЗН), 3.21 (y, 9-6.6, 2H), 3.26-3.29 (t, 1H) , 3.72 (y, 9-20.3, 1H), 3.84 (5, ЗН), 3.95 (5, 2H), 4.03 (y, U-20.3, 1H), 4 ,39-4.49 (t, 1H), 4.80 (5, 2H), 5.87 (5, 1H), 6.64-6.71 (t, 2H), 6.78 (5, 1H ), 6.85-6.93 (t, ZN), 7.13-7.20 (t, 2H), 7.25-7.91 (t, 2H).

Intermediate 85.1: 2-14-((4-(5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-ylI- phenyl.-methylamino)-methylI-trans-cyclohexyl-amino)-acetamide.

WHY

MN

F (c) c) vve

Ve A (Fi

In a sealed flask for carrying out the reaction, a solution of intermediate product 79.1 (134 mg, 0.21 mmol) in a 7M solution of MHz in MeOn (3.35 ml) was heated at 70 "C and stirred for 14 h. The reaction mixture was cooled to RT and evaporated to dryness and obtained the crude desired compound (135 mg) as an orange resin, which was used in the next step without further purification. RH-MS: t/72,619.3 MANI; "H NMR (400 MHz,

СОзОр): 0.95-1.14 (t, 4Н), 1.21 (9, 9-5.9, ЗН), 1.26 (а, 9-61, ЗН), 1.64-1, 80 (t, ЗН), 1.90-1.98 (t, 2Н), 2.33-2.44 (t, 1Н), 2.93 (v, ЗН), 3.12-3.19 ( t, 2H), 3.26 (5, 2H), 3.35 (5, 2H), 3.71 (a, U-2041, 1H), 3.84 (5, ЗН), 4.02 (y , 9U-20.5, 1H), 4.40-4.49 (t, 1H), 5.86 (5, 1H), 6.59-6.65 (t, 2H), 6.79 (5 , 1H), 6.82-6.89 (t, ЗН), 7.13-7.18 (t, 2H), 7.25-7.31 (t, 2H).

Example 86.

Compounds 8ba-8be were obtained analogously to the preparation in example 75 by the reaction of the intermediate product 75.6 (or its analogs obtained in a similar way) with various bromo- or iodaryl intermediates obtained analogously to the preparation of the intermediate product 75.8. Compounds 861 and 86d were obtained similarly to the preparation in example 77 and example 78 by the reaction of the intermediate product 77.3 (or its analogues obtained in a similar way) with various sulfonyl chlorides, acyl chlorides or carboxylic acids. Compounds 86bP and 86i were obtained similarly to the preparation in example 81 by the reaction of the intermediate product 77.3 (or its analogs obtained in a similar way) with various bis-halogenated alkyl analogs.

Mo | Structure Name/HPLC/MS/NMR - a o o (5)-1-(4-chlorophenyl)-2-15-Ktrans-4-dimethyl-

My X aminocyclohexylmethyl)-methylamino|-pyridin-2-8ba:p:oyl)7-isopropoxy-b-methoxy-1,4-dihydro-2H-es isoquinolin-3-one.

TOP: Chvea-1.83; LC-MS: m/z 591.6 (MAANI). (o) - (c) (c) (5)-1-(4-chlorophenyl)-2-14-Ktrans-4-dimethyl-

X aminocyclohexylmethyl)-methylamino |-3-

M ylu-7-isopropoxy-b-methoxy-1,4-dihydro-jav H E (c) methylphenyl) isopr«4-dihydro

K.: 2H-isoquinolin-3-one 7 ММП-СЕХ461-А1-1

TOP: Chves-1.61; RH-MS: t/ 604.7 MANI". (at)

Zo o o (8)-1-(4-chlorophenyl)-2-(6-((trans-4-dimethyl-xaminocyclohexylmethyl)-methylamino|-pyridin-3-86bs and SU Ya oyl) 7-isopropoxy -b-methoxy-1,4-dihydro-2H- and isoquinolin-3-one.

TOP: Thu-1.56; RH-MS: t/z 591.7 (MAANI". (o)

Mo | Structure Name/HPLC/MS/NMR! o o (5)-1-(4-chlorophenyl)-2-(4-I(trans-4-dimethyl-

M X aminocyclohexylmethyl)-methylamino |-3- vba and I o fluorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-

M 2H-isoquinolin-3-one.

TOP: Thu-1.98; LC-MS: m/z 608.7 (MAANI". (o) - a o 9 o (8)-1-(4-chlorophenyl)-2-(4-|(trans-4-dimethyl-

M X aminocyclohexylmethyl)-methylamino|-2-vbe : : o methoxyphenyl)-7-isopropoxy-b-methoxy-1,4-

She dihydro-2H-isoquinolin-3-one.

TOP: Thu-1.92; LC-MS: m/z: 620.3 (MAANI". (9) o, a (o) o ethanesulfonic acid 14-IC44-(5)-1-(4-ov X chlorophenyl)-7-isopropoxy-6 -methoxy-3-oxo-3,4- 86 E H (c) dihydro-1H-isoquinolin-2-yl|I-phenyl)-methylamino)- - I methyl-trans-cyclohexyl)-amide.

FROM TOP: Mne-2,25; RH-MS: t/l 654.7 ME. with

Well, | и и о М-14-(4-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - vba and Mva phenyl)-methylamino)-methyl-I-transo-cyclohexyl)- and U H propionamide. m TOP: Thursday-2.13; LC-MS: m/z 618.3 (MAANI). (9) o o (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-vv M X |methyl- (trans-4-pyrrolidin-1-ylcyclohexyl-: i i o methyl)amino|-phenyl)-1,4-dihydro-2H-isoquinolin-3-one in HPLC: Chve-1.89; LC-MS: t/l 616.4 MANI" (9)

Соо (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl)-(thrano-4-piperidin-1-ylcyclohexyl-

E r E o methyl)amino|-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

B F TOP: Thu-1.92; LC-MS: t/z: 630.4 (MAANI". (9)

Example 87: (5)-1--4-Chlorophenyl)-2-14-((5)-1-(1,1-dioxo-1-lambda"b"-thiomorpholin-4-yl)-ethyl|- phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

c) c)

With

M

SI

The desired compound (TSF salt, 11.9 mg, 0.017 mmol, 20 95) was obtained as a light yellow solid from intermediate 75.6 (30 mg, 0.087 mmol) and intermediate 87.1 (41.4 mg, 0.13 mmol) similar to that obtained in example 75. Purification of the crude substance was carried out using reverse-phase preparative HPLC (Mua(eg5) system. HPLC:

Agve-1.90 min.; LC-MS: tp/2 583.5 MANI"; "H NMR (400 MHz, COzO0b): 1.23 (a, U-5.9, ЗН), 1.28 (y, 9-61, 1Н) , 1.53 (a, 9-6.6, 1H), 5.21 (Bu. 5., 8H), 3.77 (a, 9-20.3, 1H), 3.87 (5, ЗН ), 4.05 (9, 9U-20.3, 1H), 4.10-4.19 (t, 1H), 4.42-4.52 (vri, 9U-5.9, 1H), 6 .02 (5, 1H), 6.83 (5, 1H), 6.90 (in, 1H), 7.15-7.23 (t, 4H), 7.28-7.34 (t, 2H ), 7.41-7.47 (t, 2H).

Intermediate product 87.1: 4-((5)-1-(4-Bromophenyl)-ethyl|-thiomorpholine-1,1-dioxide. x c

IJ

0257

With m

A solution of (5)-1-(4-bromophenyl)ethanamine (0.144 mL, 1.0 mmol) and vinylsulfonyletene (0.100 mL, 1.0 mmol) in EIUN (4.0 mL) was heated at 100 °C and stirred for The reaction mixture was cooled to RT and evaporated to dryness. the desired compound (256 mg, 0.804 mmol, 80 95 yield) as a colorless oil, which crystallized on standing to give a colorless solid. 29 min.; LC-MS: t/2 320.2 MANI; "H NMR (400 MHz, SOS"): 1.39 (a, 9-6.8, ZN), 2.92-3.09 ( t, 8H), 3.76 (a, 95-6.8, 1H), 7.19-7.26 (t, 2H), 7.45-7.53 (t, 2H).

Example 88: (5)-2-14-((5)-1-(4-Acetylpiperazin-1-yl)-ethyl|-phenyl)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy- 1,4-dihydro-2H-isoquinolin-3-one. (c) (c) (c)

H ovo m: o shi (Fi

Z The desired compound (TSF salt, 18.3 mg, 0.027 mmol, 26 9o) was obtained from intermediate 75.6 (36 mg, 0.104 mmol) and intermediate 88.3 (48.6 mg, 0.156 mmol) similarly to the preparation in example 75. Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umayeg5 system). HPLC: "ve-1.76 min.; LC-MS: t/7 576.5 MANI; "H NMR (400 MHz, DMSO-av): 1.22 (a, 9-61, ZN), 1, 25 (y, 9U-5.9, ZN), 1.53-1.68 (t,

ZN), 2.01 (Bg. 5., ZN), 2.69-3.20 (t, 4H), 3.56-3.69 (t, 2H), 3.73 (5, ZN), 3.86 (a, 9U-19.8, 1H), 3.90-4.08 (t, 1H), 4.36-4.61 (t, ЗН), 6.17 (5, 1H), 6.67 (5, 1H), 7.13 (5, 1H), 7.30-7.42 (t, 6H), 7.44-7.54 (t, 2H).

Intermediate 88.1: 1-((5)-1-(4-Bromophenyl)-ethyl|-4-(toluene-4-sulfonyl)-piperazine.

o, r

From Vg

M more

A mixture of (5)-1-(4-bromophenyl)ethanamine (0.36 mL, 2.50 mmol) and N,M-bis(2-chloroethyl)-4-methylbenzenesulfonamide (864 mg, 2.62 mmol) in DIPEA (0.873 mL, 5.0 mmol) was heated at 125°C and stirred for 20 h. The reaction mixture was cooled to RT, then diluted with DCM (30 mL) and washed with 2M MgSO3 in water (40 mL).

The aqueous phase was further extracted with DCM (3x20 ml) and the combined organic fractions were dried over Mag505, filtered and evaporated to dryness. ASOEI was added in small portions to a hot mixture of crude substance with heptane until complete dissolution. The mixtures were allowed to cool to CT, during which time precipitation took place. The mixture was cooled to 0 °C (ice bath) for 30 minutes, then filtered. The solid was washed with heptane, air dried and finally under high vacuum to give the title compound (810 mg, 1.91 mmol, yield 77 95) as brownish solid substance. HPLC: "ve-1.66 min.; LC-MS: t/2 425.4 MANI"; "H NMR (400 MHz, SOSIZz): 1.29 (a, 9U-6.8, ЗН), 2.41-2.50 (t, 5Н) , 2.52-2.61 (t, 2H), 2.93-3.05 (t, 4H), 3.34 (ad, 9U-6.7, 1H), 7.09-7.16 ( t, 2H), 7.31-7.37 (t, 2H), 7.39-7.44 (t, 2H), 7.61-7.66 (t, 2H).

Intermediate 88.2: 1-((5)-1-(4-Bromophenyl)-ethyl|-piperazine.

We are 59

To a solution of intermediate 88.1 (802 mg, 1.89 mmol) in TFC (1.46 mL, 18.95 mmol) at

Н25О54 (0.707 mL, 13.26 mmol) was added to the CT. The mixture was heated at 75 °C and stirred for 2 h, then cooled to RT, diluted with ASOEL, and washed carefully with 2M MgSO2 in water (2x) and brine. The organic layer was dried over Mg5O5, filtered and evaporated to dryness to give crude title compound (479.6 mg, 1.728 mmol, yield 91 95) as an orange oil, which was used in the next step without further purification. HPLC: "Ive-0.86 min.; RH-MS: t/2 269.5 (MANI; 'N

NMR (400 MHz, SOS"): 1.33 (y, U-6.6, ZN), 2.29-2.39 (t, 2H), 2.40-2.53 (t, 2H), 2.84-2.90 (t, 4H), 3.32 (a, 9-6.8, 1H), 7.18-7.24 (t, 2H), 7.41-7.A48 (t , 2H).

Zo Intermediate 88.3: 1-14-((5)-1-(4-Bromophenyl)-ethyl|-piperazin-1-yl)y-ethanone.

H

Ve

M

958,

EM (0.155 mL, 1.113 mmol) and acetyl chloride (0.066 mL, 0.928 mmol) were sequentially added to a solution of intermediate 88.2 (103 mg, 0.371 mmol) in DCM (1.8 mL) at RT.

The mixture was stirred at RT for 1 h, then diluted with ASOKY (20 mL) and washed with 2 M MagbOz in water (10 mL). The organic phase was dried over Mag50O, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpy Sotrapiop "m (Izso Ips.) (510g; elution in gradient mode, (heptane/dx M 1:1)/TBME, which contains 5 95 7M MNz in MeOH from 95: 5 to 1:1) and obtained the desired compound (108 mg, 0.347 mmol, 9395 yield) as a light yellow oil.

Afve-1.01 min.; RH-MS: t/ 311.4 MANI; "H NMR (400 MHz, SOSI»v): 1.35 (a, 9U-6.6, ZN), 2.07 (v,

ZN), 2.29-2.54 (t, 4H), 3.37 (d, 9U-6.8, 1H), 3.43 (I, 9-51, 2H), 3.52-3, 68 (t, 2H), 7.17-7.24 (t, 2H), 7.43-7.49 (t, 2H).

Example 89: Methylamide (K)-1-((5)-1-14-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H -isoquinolin-2-yl(phenyl)-ethyl)-pyrrolidine-2-carboxylic acid.

(c) (c) vo : (c) vi ;

ME

Mo (Fi

To a solution of intermediate 89.4 (TSF salt, 8.7 mg, 0.013 mmol) in DMF (0.5 mL) at

Methylamine (2M in THF, 0.077 mL, 0.155 mmol), EIIZM (0.004 mL, 0.031 mmol), and GATU (11.8 mg, 0.031 mmol) were sequentially added to the CT. The reaction mixture was heated at 50 °C and stirred for 14 h, then cooled to RT and immediately purified using preparative

Reverse phase HPLC (Umayeg5 system) and obtained the desired compound (TFA salt, 4.8 mg, 0.007 mmol, 54 95) as a colorless solid. TOP: "ive-1.76 min.; RH-MS: t/2 576.5 |M-AANI".

Intermediate 89.1: (K)-1-(5)-1-(4-bromophenyl)-ethyl|-pyrrolidine-2-carboxylic acid methyl ester. and intermediate 89.2: (5)-1-(5)-1-(4-bromophenyl)-ethyl|-pyrrolidine-2-carboxylic acid methyl ester. and

Wee Wee oo oo

We used the following methodology, in a modified form, taken from the publication of M.A... eiaptapv, AM.A. U/aiYidegv, H.. TNiv5, V. de SeiYideg, U.MM.M. Ztiiv5, apa V. Amapeprigo, Teimaneagop 54 (1998) 4991-5004. To a mixture of methyl 2,5-dibromopentanoate (0.401 ml, 2.56 mmol) and K2CO3 (706 mg, 5.11 mmol) in MesM (7 ml) and water (0.7 ml) at 80 "С was added dropwise a solution of (5)-1-(4-bromophenyl)ethanamine (0.405 mL, 2.81 mmol) in MesmM (3.5 mL). After addition, the reaction mixture was further stirred at 80 "C for 14 h, then cooled to RT , diluted with ASOE (50 ml) and washed with water (40 ml). The aqueous phase was further extracted with AsSOBE and the combined organic fractions were dried over Mag25O:4, filtered and evaporated to dryness. The resulting crude was purified and both diastereoisomers were separated by preparative reversed-phase HPLC (gradient elution, MesSM/water containing 20 mM ammonium formate). Fractions that contain a pure substance,

Z0 was combined and concentrated in vacuo. The resulting aqueous mixture was made alkaline by adding 2M Mg2bOz and extracted with AsSOEL. The organic layer was washed with saline, dried over Mag2505, filtered and evaporated to dryness and the desired compounds were obtained as light yellow oils. Intermediate 89.1: 240 mg, 0.77 mmol, 3096; TOP: Yave-1.15 min., Sive-4.07 min.; RH-MS: t/2 314.4 MANI; "H NMR (400 MHz,

SObsiz): 1.38 (a, U-6.6, ZN), 1.76-1.99 (t, ZN), 2.04-2.16 (t, 1H), 2.52 (a, 9-81, 1H), 3.05-3.13 (t, 1H), 3.47 (yes, 9-94, 3.5, 1H), 3.51 (5, ЗН), 3.66 ( d, 9U-6.6, 1H), 7.21-7.26 (t, 2H), 7.39-7.45 (t, 2H).

Intermediate 89.2: 222 mg, 0.71 mmol, 28 95; TOP: "Chve-1.15 min., Blue-5.18 min.; RH-

MS: t/2 314.4 MANI; "H NMR (400 MHz, SOSI"): 1.36 (a, 9-6.8, ЗН), 1.73-1.84 (t, 1Н), 1.84-1.96 (t, 2Н ), 2.03-2.14 (t, 1H), 2.54-2.63 (t, 1H), 2.93-3.02 (t, 1H), 3.91 (aa, 9U-9 ,2, 4.0, 1H), 3.69 (5,

ZN), 3.72 (a, 9-66, 1H), 7.17-7.22 (t, 2H), 7.42-7.47 (t, 2H). The configuration of each diastereoisomer was determined by comparing the H NMR spectrum with published data

IN YAMRE for close analogues (see B. AItapza, 0. Scidato apa M. My5 Teiigapedgop: Azutteigu 18, 2007, 2828-2840).

Intermediate 89.3: Methyl ether (K)-1-((5)-1-14-(5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro -1 H-isoquinolin-2-yl(phenyl)-ethyl)-pyrrolidine-2-carboxylic acid.

(c) (c) voc

E (c)

In:

M i oto (Fi

The desired compound (TFA salt, 50.3 mg, 0.073 mmol, 36,956) was obtained as a yellow solid from intermediate 75.6 (70 mg, 0.20 mmol) and intermediate 89.1 (95 mg, 0.30 mmol) similar to the one obtained in example 75. Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umayeg5 system). TOP:

Aiveg-1.85 min.; RH-MS: tp/2 577.5 (MANI.

Intermediate product 89.4: ()-1-((5)-1-14-((5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H -isoquinolin-2-yl(phenyl)-ethyl)-pyrrolidine-2-carboxylic acid. c) c) in

Her (in) schi) o Y 8 (Fi

A mixture of intermediate 89.3 (TFC salt, 50.3 mg, 0.073 mmol) and GION monohydrate (22 mg, 0.52 mmol) in MeOH (1 mL) and water (0.25 mL) was heated at 60 °C and stirred for 14 h, then cooled to RT and immediately purified by reverse-phase preparative HPLC (Umayeg5 system) to give the desired compound (TSF salt, 12.4 mg, 0.018 mmol, 25 95) as an almost white solid. TOP: "Ive-1.85 min.; RH-MS: t/72 563.6

IM-ANI..

Example 90: Methyl ether (5)-1-((5)-1-14-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro- 1 H-isoquinolin-2-yl(phenyl)-ethyl)-pyrrolidine-2-carboxylic acid. (c) (c) voc

E (c) 9, ; xx oo (Fi

The desired compound (TSF salt, 20.5 mg, 0.030 mmol, 34 95) was obtained from intermediate 75.6 (30 mg, 0.087 mmol) and intermediate 89.2 (40.6 mg, 0.13 mmol) similarly to the preparation in example 75 Purification of the crude substance was carried out using reverse-phase preparative HPLC (Umayeg5 system). TOP: "ve-1.86 min.; RH-MS: t/7 577.6 |M-AANI".

Example 91.

From Compounds 91a-91c6 was obtained analogously to the preparation in example 87 and example 88 by the reaction of intermediate product 75.6 with various bromo- or iodaryl intermediates obtained analogously to the preparation of intermediate product 87.1 or intermediate product 88.3.

Me | Structure Name/HPLC/MS/NMR o 6 o in (5)-1-(4-chlorophenyl)-2-(4-I(B)-1-(1,1-dioxo-1- i MA. lambda) "6b"-thiomorpholin-4-yl)-ethyl|-phenyl)-7-9a o Sm : isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

TOP: Chves-1.91; RH-MS: t/: 583.5 MANI". (9) o 6 o in uv (8)-1-(4-chlorophenyl)-2-(4-(1-(1,1-dioxo-1-) and M. o lambda"6"-thiomorpholine-4- yl)y-cyclopropyl|-phenyl)-

УБ 7 A : 7-isopropoxy-b6-methoxy-1,4-dihydro-2H-isoquinoline-

Z-he and TOP: Chve-2.42; RH-MS: t/z 595.6 (MAANI". (9) o o

X and X (5)-2-14-(1-(4-Acetylpiperazin-1-yl)-cyclopropyl|- 91c M Its o phenyl)-1-(4-chlorophenyl)-7-isopropoxy-6b-methoxy-

Cl A 1,4-dihydro-2H-isoquinolin-3-one. and TOP: Thu-1.79; RH-MS: t/: 588.6 (MAANI". (o)

Example 92: 14-K(5)-1--4-Chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-ylI-phenyl-methylamide trans- 4-dimethylaminocyclohexanecarboxylic acid. I ori and vve om (Fi

The desired compound (TSF salt, 19.4 mg, 0.027 mmol, 19 95) was obtained as a light yellow solid from intermediate 75.6 (50 mg, 0.145 mmol) and intermediate 92.2 (58.9 mg, 0.174 mmol) similar to the one obtained in example 75. Purification of the crude substance was carried out using preparative reverse-phase HPLC (Umayeg5 system). TOP:

Agve-1.85 min.; LC-MS: t/: 604.3 MANI"; "H NMR (400 MHz, DMSO-av): 1.01-1.18 (t, 2H), 1.21 (y, 9-61, ЗН) , 1.25 (a, 9U-6.1, ZN), 1.39-1.57 (t, 2H), 1.70-1.85 (t, 2H), 1.87-2.01 ( t, 2H), 2.06-2.22 (t, 1H), 2.61-2.72 (25, 6H), 3.02-3.21 (t, 4H), 3.65 (y, 9-19.8, 1H), 3.74 (v, ЗН), 3.90 (a, 9U-19.6, 1H), 15. 4.41-4.50 (t, 1H), 6, 17 (5, 1H), 6.88 (5, 1H), 7.09 (5, 1H), 7.24-7.42 (t, 8H).

Intermediate 92.1: 14-(4-Bromophenyl)-methylcarbamoyl|-trans-cyclohexyl)-carbamic acid tert-butyl ether. (c) 0-4 (c) oh /

To a solution of trans-4-(Bos-amino)cyclohexanecarboxylic acid (148 mg, 0.608 mmol) in

4-bromo-M-methylaniline (0.084 mL, 0.669 mmol), EVM (0.170 mL, 1.217 mmol), and GATU (278 mg, 0.730 mmol) were sequentially added to DMF at CT. The reaction mixture was heated at 80 °C for 6 h, then GATU (278 mg, 0.730 mmol) was additionally added and the mixture was further stirred at 80 °C for 14 h. The reaction mixture was cooled to RT, diluted with

TBME and washed sequentially with 2M NaCl in water and 2M MgSO3 in water. The organic phase was dried over NaCl5O, filtered and evaporated to dryness. The resulting crude material was purified by reverse-phase preparative HPLC (gradient elution, HgO containing 0.1 906 TFA/Mesm 8:8 -» 2:86) to give the desired compound (97 mg, 0.236 mmol, 39 95 ) in the form of a brownish solid. TOP: "ve-2.38 min.; LC-MS: t/z 411.4

IMANIG; "H NMR (400 MHz, DMS O-av): 0.73-0.99 (t, 2H), 1.35 (v, 9H), 1.32-1.45 (t, ЗН), 1, 55-1.76 (t, 4H), 1.86-2.15 (t, 1H), 3.11 (Bug. 5., ZN), 6.56 (Bg. 5., 1H), 7, 27-7.35 (t, 2H), 7.61-7.69 (t, 2H).

Intermediate 92.2: (4-Bromophenyl)-methylamide of trans-4-dimethylaminocyclohexanecarboxylic acid. (in)

OO

/ M Ve /

The desired compound (65 mg, 0.192 mmol, 82 95) was obtained as a yellow resinous substance from intermediate 92.1 (96 mg, 0.233 mmol) analogously to the preparation of intermediate 75.8. Purification of the crude substance was carried out using Sotheby-Riazpy column chromatography. Sotrapiop "m (Izso Ips.) (BIO; elution in gradient mode,

ДХМ/ДХМ/7M МНз in Men 9:1| 95:5 -» 100 90 DHM//M MHz in MeOnN 9:1). TLC: Ke-0.40 (DHM// M

MNz in MeOnN 9:1); TOP: ve-1.23 min.; RH-MS: t/2 339.2 MANI; "H NMR (400 MHz, DMSO-av): 0.70-1.01 (t, 2H), 1.31-1.46 (t, 2H), 1.59-1.78 (t, 4H) , 1.94-2.19 (t, 8H), 3.11 (Bg. 5., ZN), 7.22-7.38 (t, 2H), 7.57-7.74 (t, 2H ).

Example 93: (5)-1--4-Chlorophenyl)-2-14-(2-(4-dimethylaminopiperidin-1-yl)-1-methylethyl|-phenyl)-7-isopropoxy-6-methoxy-1, 4-dihydro-2H-isoquinolin-3-one.

From vok

SI

The desired compound (25 mg, 0.042 mmol, 27,906) was obtained as a colorless solid

From the substance of intermediate product 75.6 (54 mg, 0.156 mmol) and intermediate product 93.4 (61 mg, 0.187 mmol) similarly to the preparation in example 75. Purification of the crude substance was carried out using reverse-phase preparative HPLC (Umayeg5 system). The purified compound (salt with TFC) was dissolved in MeOH and eluted from the basic ion exchange resin (RI-HSOZ MP 5RE, manufactured by Roiuteg I Arogagiye) to remove the salt from TFC. SUPER: "Chve-1.77 min.; LC-MS: t/: 590.2 |IMANI; "H NMR (400 MHz, DMSO-av): 1.14 (a, 9-66, ZN), 1 ,20 (y, 9-5,9,

ZN), 1.24 (a, 9-5.9, ZN), 1.27-1.33 (t, 1H), 1.62-1.70 (t, 2H), 1.74-2, 01 (t, ZN), 2.28-2.35 (t, 2H), 2.719-2.95 (t, 4H), 3.60 (y, 9U-19.8, 1H), 3.73 ( 5, ZN), 3.83-3.92 (t, 1H), 4.41-4.51 (t, 1H), 6.08 (5, 1H), 6.85 (5, 1H), 7 ,04-712 (t, ZN), 7.16-7.24 (t, 2H), 7.33-7.38 (t, 4H).

Intermediate 93.1: 2-(4-bromophenyl)-propionic acid ethyl ester.

IF) /t (in) -0О

To a solution of ethyl 4-bromophenyl acetate (2 g, 8.23 mmol) in anhydrous DMF (20 mL) at 0 C (ice bath) was cautiously added Mann (60 95 in mineral oil, 0.494 g, 12.34 mmol).

The resulting suspension was stirred at 0 "C for 30 minutes, then Mei (0.643 ml,

10.28 mmol) and the reaction mixture was allowed to warm to room temperature and was further stirred for 1 h. To stop the reaction, a saturated aqueous solution of MNACI was added and the mixture was extracted with AsSOBEI (2x). The combined organic fractions were dried over NaCl, filtered and evaporated to dryness. The obtained crude substance was purified using Sotheby-Riazpy column chromatography. Sotrapiop "m (Izso Ips.) (BIO; gradient elution, heptane/AsoEly from 99:1 to 8:2) and obtained the desired compound (777.8 mg, 3.03 mmol, 37 90 yield) in the form of a colorless oils. TLC: Ke-0.64 (heptane/AcOEi 3:1); HPLC: "Ine-2.60 min.; "H NMR (400 MHz, DMSO-αv): 1.13 (Her, U-7,1, ZN), 1.37 (a, 9-71, ZN), 3.79 (ad, U-7, 1, 1H), 3.98-4.12 (t, 2H), 7.22-1.28 (t, 2H), 7.49-7.56 (t, 2H).

Intermediate product 93.2 2-(4A-Bromophenyl)propionic acid. (c) he

Ve

The desired compound (263 mg, 1.15 mmol, 98 95) was obtained as a yellow solid from intermediate 93.1 (300 mg, 1.17 mmol) analogously to the preparation of intermediate 1.2.

The crude substance was used in the next stage without additional purification. TOP:

Agde-1.90 min.; "H NMR (400 MHz, DMSO-av): 1.34 (y, 9-71, ЗН), 3.69 (ad, 9-71, 1Н), 7.21-7.28 (t, 2Н) , 7.48-7.55 (t, 2H), 12.42 (5, 1H).

Intermediate 93.3 2-(4-Bromophenyl)-1-(4-dimethylaminopiperidin-1-yl)-propan-1-one.

Oh

M M

The desired compound (370 mg, 1.09 mmol, 96 95) was obtained as a yellow resinous substance from intermediate 93.2 (259 mg, 1.13 mmol) and 4-(dimethylamino)-piperidine (174 mg, 1.36 mmol) similarly to obtaining intermediate product 92.1. Purification of the crude substance was carried out using column chromatography Sotbri-RIazp Sotrapiop m (I5so

Ips.) (5102; gradient elution, DCM/7M MNz in Meon 99:1 -» 9:1). TLC: Ke-0.49 (DHM/7M Mnz in MeOnN 9:1); TOP: "ve-1.28 min.; RH-MS: t/2 339.1 |MANI"; "H NMR (400 MHz,

DMSO-α): 0.26-1.05 (t, 1H), 1.14-1.37 (t, 4H), 1.38-1.77 (t, 2H), 2.04 (in, ЗН), 2.18 (5, ЗН), 2.22-2.38 (t, 1Н), 2.52-2.59 (t, 1Н), 2.61-3.00 (t, 1Н) , 3.80-3.99 (t, 1H), 4.07-4.19 (t, 1H), 4.30-4.46 (t, 1H), 7.17-7.28 (t, 2H), 7.47-7.56 (t, 2H).

Intermediate product 93.4 /1-(2-(4-Bromophenyl)-propyl|-piperidin-4-yl-dimethylamino. unit

M M

To a solution of intermediate 93.3 (221 mg, 0.651 mmol) in anhydrous THF (3 mL) at RT, VNz.THF (1M in THF, 3.26 mL, 3.26 mmol) and several drops of 4M NSI in dioxane were sequentially added. The reaction mixture was heated at 70 °C, stirred for 2 h 30 min, then cooled to RT and the reaction was carefully quenched by adding a 2M aqueous solution of NOSI (6.5 mL). The mixture was heated at 100 °C and stirred for 30 min, then it was cooled to RT, diluted with AsOEI and washed with a 2M aqueous solution of MgCO3 (2x).

The organic phase was dried over Mag250, filtered and evaporated to dryness. The obtained crude substance was purified using reverse-phase column chromatography (elution in gradient mode, water vs. 0.1 96 TFC/MesCM-0.1 95 TFC from 98:2 to 6:4). Fractions containing the desired compound were collected, made alkaline by adding solid Mg2CO3, and extracted using ASOEI. The organic layer was dried over Mag50, filtered and evaporated to dryness to give the title compound (127 mg, 0.39 mmol, 60 95 yield) as a colorless oil which crystallized to a colorless solid on standing. TOP: Javea-1.10 min.; RH-

MS: t/2 325.2 MANI; "H NMR (400 MHz, DMSOO-av): 1.14 (a, 9-71, ЗН), 1.19-1.35 (t, 2H), 1.61-1.70 (t, 2H) , 1.76-1.91 (t, 2H), 1.92-2.02 (t, 1H), 2.13 (5, 6H), 2.33 (y, 9U-7.6, 2H ), 2.79-2.88 (t, 2H), 2.92 (a, 9-71, 1H), 7.15-7.23 (t, 2H), 7.41-7.49 (t , 2H).

Example 94: (5)-1-(4-Chlorophenyl)-2-(4-(2-(4-dimethylaminopiperidin-1-yl)-1-methyl-2-oxoethyl|-phenyl)-7-isopropoxy-6 -methoxy-1,4-dihydro-2H-isoquinolin-3-one - ov and vve

M N (c) nih (Fi

The desired compound (TFA salt, 11.6 mg, 0.019 mmol, 13 95) was obtained as a light yellow solid from intermediate 75.6 (50 mg, 0.145 mmol) and intermediate 93.3 (58.9 mg, 0.174 mmol) similar to the one obtained in example 75. Purification of the crude substance was carried out using preparative HPLC with the reverse phase (Umaieg5 system). TOP:

Ave1.91 min.; LC-MS: t/2 604.3 MANI"; "H NMR (400 MHz, DMSOO-av): 1.14-1.32 (t, 1OH), 1.37- 2.03 (t, ZN) , 2.41-2.62 (t, ZN), 2.62-3.04 (t, 4H), 3.25-3.39 (t, 1H), 3.60 (a, 9U-19, 8, 1H), 3.73 (5,

ZN), 3.81-3.89 (t, 1H), 3.96-4.20 (t, 2H), 4.40-4.50 (t, 1H), 4.51-4.61 ( t, 1H), 6.05-6.12 (t, 1H), 6.86 (5, 1H), 7.03-7.18 (t, ZH), 7.19-7.30 (t, 2H), 7.30-7.42 (t, AN).

Compounds of examples 95, 101, 104, 105, 106, 107, 112, 117, 118, 119, 126, 130, 132, 138, 139, 144, 147, 149, 150, 152, 155, 172, 174, 175, 180, 183, 195, 196, 197, 198, 199, 200, 202, 203, 204, 205, 207, 209, 210, 211, 212, 214, 216, 226, 227, 228 and intermediate products 123.1, 137. 163.1, 164.2, 169.1, 176.2, 177.2, 178.1, 192.2, 201.1, 215.2, 219.1 were obtained similarly to the preparation in example 75 by the reaction of intermediate product 75.6 (or its analogues obtained in a similar way).

The compounds of examples 96, 98, 182, 188 and intermediate products 166.2, 185.2, 186.1, 187.2, 189.3 were obtained similarly to the preparation in example 1 by the reaction of intermediate product 96.1 (or its analogues obtained in a similar way). Structure Name/HPLC/MS (0) (5)-1-(4-Chlorophenyl)-2-(4-imidazol-1-ylmethyl)-7-isopropoxy-6-methoxy- 1,4-dihydro-2H-

KU ac isoquinolin-3-one.

TOP: Chne-4,686; RH-MS: t/: 502.4 |M-NO". (9) (9) ! Fi X 1-(4-chloro-3-fluorophenyl)-2-(4-dimethylamino-phenyl)-vi o 7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinoline Z-one.

Phi VERH: "Chne-6,166; RH-MS: t/: 483.4 |MANI".

SI

(9) o o m Shchi o M-14-11-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3- i SU АХ oxo-3,4-dihydro-1 H-isoquinolin-2-yl| -phenyl)-2,2,2-

U, F trifluoro-M-methylacetamide.

AND TOP: Chna-7,338; RH-MS: t/: 547.1 MANI. in | 7 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-p A methylaminophenyl)-1,4-dihydro-2H-isoquinolin-3-one.

FI TOP: Chne-5,878; RH-MS: t/z: 451.4 |MANI".

SI shi Structure Name/ HPLC/MS bu o (5)-1-(4-Chlorophenyl)-2-(4-C4-(1,1-dioxo-1- o o lambda"b"-thiomorpholin-4-yl) )-trans-100 vvt cyclohexylmethyl|-methylamino)-phenyl)-7-es o isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinoline-3-! o VERH: Mne-2.02; RH-MS: t/h 680.2 MEI".

SI

9; i and ko A tert-butyl ether 14-((4-((5)-1-(4-chlorophenyl)-7-?vv isopropoxy-b6-methoxy-3-oxo-3,4-dihydro-1 H- 101 " t o isoquinolin-2-yl|-3-methoxyphenyl)-methylamino)-:ra methyl-trans-cyclohexyl)-carbamic acid.

FROM TOP: Chva-2.84; RH-MS: t/: 692.2 (MANI.

SI ut nm. . . ! so 1 methyl ether "4-1C4-(5)-1-(4-chlorophenyl)-7-o isopropoxy-b6-methoxy-3-oxo-1,4-dihydro-1 H-102 yo o isoquinoline-2- yl|-3-methoxyphenyl)-methylamino)-

And methyl|-trans-cyclohexylamino)-acetic acid.

Y SA TOP: Chvne-1.99; RH-MS: t/: 664.3 MANI.

(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(2-tho-methoxy-4-methyl-|4-(3-oxopiperazin-1-yl) -tranos- 103 M cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-

Y Z isoquinolin-3-one. ; FROM TOP: Chva-1.91; RH-MS: t/2 675.3 (MANI.

SI

K 9); o z ve (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-|4- 104 U ; A (methylpiperidin-4-ylmethylamino)phenyl|-1,4-m dihydro-2H-isoquinolin-3-one.

TOP: Chne-1.94; RH-MS: t/ 548.2 |MANE.

SI

CHO

IV: (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-methyl-4-(3-methyl-4-oxoimidazolidin-1-yl)-tranose - 105 m of cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-

SU | HK isoquinolin-3-one. m UPPERH: Chve-1,164; RH-MS: t/z: 645.5 (MANI.

SI structure Name/EPLC/MS o p (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4- i o o Imethyl-I4-(4-methyl-3-oxopiperazine) -1-yl)-trans-106 vve cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-

SU! o isoquinolin-3-one. i o A TOP: Chva-4,57; RH-MS: t/: 659.2 (MANI.

СИ c) o o ee methyl ether //-4-((4-(5)-1-(4-chlorophenyl)-7-vve isopropoxy-b6-methoxy-3-oxo-3,4-dihydro-1 H - 107 and SU ' XX isoquinolin-2-yl|-phenyl)-methylamino)-methyl|-trans-cm of cyclohexanecarboxylic acid.

TOP: Siva-7,244; RH-MS: t/: 605.4 MANI.

SI o on o Shock 4-((A-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-m methoxy-3-oxo-3,4-dihydro-1 H-isoquinoline-2- il|- 108 and SU Z phenyl)-methylamino)-methyl|-trans-cyclohexane-vo carboxylic acid.

TOP: Cena -6.443; RH-MS: t/: 591.4 MANI.

SI o: Y o o also methylamide 4-(ШЩЩ4-(5)-1-(4-chlorophenyl)-7-vve isopropoxy-b6-methoxy-3-oxo-3,4-dihydro-1 H- 109 Y Y I o isoquinolin-2-yl|I-phenyl-methylamino)-methyl|-trans- -- : A cyclohexanecarboxylic acid. o TOP: Chva-2,12; RH-MS: t/: 604.2 (MANI.

SI o MH, and Se amide 4-(A-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-

M methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- 110 : SU : t phenyl)-methylamino)-methyl-trans-vive 3 ra of cyclohexanecarboxylic acid.

TOP: Chne-2.03; RH-MS: t/: 590.2 | MANEI.

SI on at 4 o o. (2-hydroxyethyl)-amide 4-((4-((5)-1-(4-chloro-phenyl)-7-

XX isopropoxy-b6-methoxy-3-oxo-3,4-dihydro-1H-111: " i o isoquinolin-2-yl|I-phenyl-methylamino)-methyl|-trans-

KE : A cyclohexanecarboxylic acid.

Y O TOP: Chvne-1.98; RH-MS: t/: 634.2 | MANEI. (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-y4-t-Imethyl-(4-piperazin-1-yl-trans) -cyclohexyl-112 M o methyl)amino|-phenyl)-1,4-dihydro-2H-isoquinoline-3-

N on o Z A TOP: Thu-1.76; RH-MS: t/: 631.3 MANI".

SI va

M

C (5)-2-(4-((4-(4-Acetylpiperazin-1-yl)-trans- and o o cyclohexylmethyl|-methylamino)-phenyl)-1-(4-113 vv chlorophenyl)-7- isopropoxy-6-methoxy-1,4-dihydro-

She about 2H-isoquinolin-3-one. : ry TOP: Ane-1.89; RH-MS: t/h 673.3 (MANI.

M. S. Y

SI

O0-55-50 m

C (5)-1-(4-chlorophenyl)-7-isopropoxy-2-(4-C4-(4-

A o o methanesulfonylpiperazin-1-yl)-trans- 114 i. cyclohexylmethyl|-methylamino)-phenyl)-6b-methoxy-

It is 1,4-dihydro-2H-isoquinolin-3-one. in : A TOP: Chne-1.97; RH-MS: t/2 709.4 IM.ANE..

M. S. Y

SI p

In (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-; o o Imethyl-I4-(4-methylpiperazin-1-yl)-trans- 115 in cyclohexylmethyl amino)-phenyl)-1,4-dihydro-2H- and isoquinolin-3-one. and Z A TOP: Mne-1.78; RH-MS: t/h 645.5 |MENI".

SI in un 2-14-I(4-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-; o re methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl|- 116 vv phenyl)-methylamino)-methyl|-thrano-cyclohexyl-

T o amino) M-methylacetamide. and at F 00 ЕРХ: mna-1.86; RH-MS: t/y 633.2 ME.

(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-|4- 117 SU AA A (methylpiperidin-2-ylmethylamino)phenyl |-1,4-

It is dihydro-2H-isoquinolin-3-one.

TOP: Chvea-1.93; RH-MS: t/2 548.4 (MANI.

SI

(c) me o XX, (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-yl4- 118 Y : A Imethyl-(tetrahydropyran-2-ylmethyl)amino|-phenyl)- m 1,4-dihydro-2H-isoquinolin-3-one.

TOP: Chne-2.41; RH-MS: t/: 549.4 MANI.

SI

(c) o vve (5)-1-(4-chlorophenyl)-2-(4-(cyclohexyl-119:rymethylmethylamino)phenyl|-7-isopropoxy-6b-methoxy-

M 1,4-dihydro-2H-isoquinolin-3-one.

TOP: Chne-2.70; RH-MS: t/: 547.5 MANI.

SI

МН, и и (5)-2-15-KTrans-4-aminocyclohexylmethyl)- and I A methylamino|-pyridin-2-yl)-1-(4-chlorophenyl)-7- 120 c Y : isopropoxy-b- methoxy-1,4-dihydro-2H-isoquinoline-3-m on.

C TOP: Thu-0.98; RH-MS: t/ 563.4 MAN. sa and

Shei o methyl ether /44-((6-(5)-1-(4-chlorophenyl)-7- m.p X isopropoxy-b6-methoxy-3-oxo-3,4-dihydro-1 H- 121 : isoquinolin-2-yl|-pyridin-3-yl-methylamino)-methyl|- trans-cyclohexylamino)-acetic acid.

TOP: Thu-1,204; RH-MS: t/2 635.5 (MANI.

SI about us

Zh. and that - 2-14-I(16-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-m.m X methoxy-3-oxo-3,4-dihydro-1 H- isoquinolin-2-yl|- 122 : p : o pyridin-3-yl-methylamino)-methyl|-trans- and cyclohexylamino)-N-methylacetamide.

TOP: Thu-1,080; RH-MS: t/: 634.2 (MANI.

SI

Su

Ii | (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-th "methyl-|4-(3-oxopiperazin-1-yl)-trans-123 M X cyclohexylmethyl- amino)-pyridin-2-yl)-1,4-yl and dihydro-2H-isoquinolin-3-one.

As. -4 o'clock TOP: Thu-1,082; RH-MS: t/h 646.2 (MANI.

SI shi - Structure Name/HPLC/MS

I. and | (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5- o o Imethyl-|4-(3-oxoimidazolidin-1-yl)-trans-124 di X cyclohexylmethyl)i -amino)-pyridin-2-yl)-1,4-

Eat in! and dihydro-2H-isoquinolin-3-one. t y: From TOP: Chve-1,236; RH-MS: t/z 646.4 (MANI.

SI

Ko and | (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-o o Imethyl-I4-(4-methyl-3-oxopiperazin-1-yl)-trans- 125 M in X cyclohexylmethyl)amino)-pyridin-2-yl)-1,4-: | The same: about dihydro-2H-isoquinolin-3-one.

To d - TOP: Thursday-1,019; LC-MS: t/: 660.4 (MANI. (o) (9) ome methyl ether /44-((5-(5)-1-(4-chlorophenyl)-7- - M and A isopropoxy -6-methoxy-3-oxo-3,4-dihydro-1H-126 FI Isoquinolin-2-yl|-pyridin-2-yl-methylamino)-methyl|- trans-cyclohexylamino)-acetic acid. si HPLC: Sivea-5.334; LC-MS: m/: 635.4 MANI. 7 |c) o m OX, (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-( 6- -- MA) (methyl-I4-(3-oxopiperazin-1-yl)-trans-127 g Y cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4- i dihydro-2H-isoquinoline -3-one "Esi HPLC: Sieve-5.162; LC-MS: t/ 646.2 MAN. c) o A vvi (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6- in I Z Imethyl-I4-(4-oxoimidazolidin-1-yl)-trans-128 UY cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4-m | dihydro-2H-isoquinolin-3-one --x and HPLC: Sivea-0.99; LC-MS: t/2 632.2 (MANI. o ne ke va (5)-1-(4-chlorophenyl)-2-(6-(C4- (3-Hydroxymethyl-4-α-oxoimidazolidin-1-yl)-transo-cyclohexyl-methyl-129 SU Y methylamino)-pyridin-3-yl)-7-isopropoxy-6-o methoxy-1,4 -dihydro-2H-isoquinolin-3-one. - with HPLC: Sieve-1.01; LC-MS: m/: 662.5 MANI. it--7 o a m vve (5)-1-(4- chlorophenyl)-7-isopropoxy-b-methoxy-2-(6- -- MA Ж Imethyl-I(4-(4-methyl-3Z-oxopiperazin-1-yl)-trans-130 SU Y cyclohexylmethyl)i-amino )-pyridin-3-yl)-1,4- and dihydro-2H-isoquinolin-3-one.

There is a TOP: Siva-5,252; RH-MS: t/: 660.5 MANI.

sh Structure Name/EPC/MS

C 2-14-I(5-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-o. methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |- 131 in pyridin-2-yl-methylamino)-methyl|-trans-t С: o cyclohexylamino)-M-isopropylacetamide. che FAZ TOP: Nivei-1,21; LC-MS: m/t 662.3 (MENE. t 5 re M, (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6- r SU A ry Imethyl-I4 -(3-methyl-4-oxoimidazolidin-1-yl)-trans-132 FI Y cyclohexylmethyl)-amino)-pyridin-3-yl)-1,4-o dihydro-2H-isoquinolin-3-one. (- si HPLC: Blue-5.269; LC-MS: t/: 646.5 |M-NI". / 5. iv; (5)-1-(4-chlorophenyl)-7-isopropoxy-2-(6 -(4-(3- o o. isopropyl-4-oxoimidazolidin-1-yl)-trans-133 l cyclohexylmethyl|-methylamino)-pyridin-3-yl)-6-! SU : o methoxy-1,4- dihydro-2H-isoquinolin-3-one. Che Z AJ HPLC: Nine-1.40; LC-MS: ti/g 674.2 MEI".

SI and: 1(5)-1-(4-chlorophenyl)-3-(6-14-(3-ethyl-4-yl)-transo-cyclohexyl-methyl)-134 SU | methylamino)-pyridin-3-yl)-7-isopropoxy-6-o methoxy-1,4-dihydro-2H-isoquinolin-3-one.

Her a TOP: Sina -5.343; RH-MS: t/: 660.3 MANI. and His about (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4- i : A "methyl-|(4-(3-oxopiperazin-1-yl)-trans- 135 cyclohexylmethyl (i)-amino)-phenyl)-1,4-dihydro-2H-o-su isoquinolin-3-one, si HPLC: Chive-1.54, LC-MS: t/: 646.3 MAN . that " H o 1(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4- i : A Imethyl-14-(2-oxopiperazin-1-yl)-cis- 136 I cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-o and isoquinolin-3-one. as with TOP: Chive-1.52; RH-MS: t/: 645.3 MAN. What is the Structure Name/EPCH/MS about ; in (5)-2-15-Ktrans-4-aminocyclohexyl-methyl)-amino|- 137 : pyridin-2-yl)-1-(4-chlorophenyl)-7-isopropoxy-6- and A methoxy -1,4-dihydro-2H-isoquinolin-3-one. " and HPLC: Chve-0.937; LC-MS: t/ 549.4 |MANE.

SI t y 1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-y o o. Imethyl-I4-(4-methyl-3-oxopiperazin-1-yl)-trans- 138 I Phy cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-reve o isoquinolin-3-one. m A TOP: Chne-4,737; RH-MS: t/: 659.2 |MANI". and

SI inv C methyl ether / 44-((5-((8)-1-(4-chlorophenyl)-7- a : o | isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1 H- 139 ra: A isoquinolin-2-yl|-pyrazin-2-yl-"methylamino)-methylyl|- in |Oi trans-cyclohexylamino)-acetic acid. HPLC: Chnei-5.36; LC-MS : m/z 636.5 (MANI. (9) A m ov (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-

Are you with me? methoxy-2-(5-methyl-(4-(4-methyl-3-oxopiperazinyl)-1-yl-trans-cyclohexylmethyl|-amino)-pyrazin-2-yl)- 1, 4-dihydro-2H-isoquinolin-3-one.

AND TOP: Chne-5,167; LC-MS: m/" 661.5 (MENI. p "i oo o 2-14-I(16-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-m vve X methoxy-3 -oxo-3,4-dihydro-1H-isoquinolin-2-yl|- 141 E in E o pyridin-3-yl)u-methylamino)-methyl|-trans-diZcyclohexylamino)-M-ethylacetamide. c TOP: Chves-1,016; RH-MS: t/ 648.5 |MANE.

SI chu t | 2-14-I(16-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-o methoxy-3-oxo-3,4-dihydro-1 H-isoquinolin-2-yl|- 142 miy Z pyridin-3-yl-methylamino)-methyl|-trans- : re : cyclohexylamino)-N-isopropylacetamide. and 8 TOP: Rine-1,035; RH-MS: t/» 662.5 ME.

SI

Su

Its about (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-

СХ Х Imethyl-I4-(2-oxoazetidin-1-yl)-trans-143: bi o cyclohexylmethyl-amino)-pyridin-2-yl)-1,4- y; dihydro-2H-isoquinolin-3-one.

SA VERH: Thu-1,294; RH-MS: t/z 617.4 (MANI.

SI structure Structure Name/EPLC/MS (9) A m vv (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-

ХХ / 2 | Umethyl-I4-(4-methyl-3-oxopiperazin-1-yl)-trans- 144 kis i Х cyclohexylmethyl)|i-amino)-pyridazin-3-yl)-1,4- o v | dihydro-2H-isoquinolin-3-one.

Z I TOP: Chve-4,465; RH-MS: t/2,661.5 MANI. 2-4-((5-((8)-1-(4-chlorophenyl)-7-isopropoxy-6-

C: o methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- 145 ra : A pyrazin-2-yl-methylamino)-methyl|-trans- p | CA cyclohexylamino)-M-methylacetamide. by )J TOP: Chve-5,14; RH-MS: t/: 635.5 | IMANG. (o

With | (5)-1-(4-chlorophenyl)-2-(5-C4-(3-ethyl-4-o oxoimidazolidin-1-yl)-transo-cyclohexyl-methyl-146 m in X methylamino)-pyridine -2-yl)-7-isopropoxy-6-y U E o methoxy-1,4-dihydro-2H-isoquinolin-3-one. in : TOP: Chve-1,132; RH-MS: t/: 660.3 MAN.

WITH

(o) I (5)-1-(4-chlorophenyl)-2-16-((3-my A. hydroxycyclobutylmethyl)-methylamino|-pyridin-3-147 SU; yl). 7-isopropoxy-6-methoxy-1,4-dihydro-2H-

It is isoquinolin-3-one.

TOP: Thu-0.989; RH-MS: t/2 536.4 |MANE. (o) she

Od | (5)-1-(4-chlorophenyl)-7-isopropoxy-2-(5-1(4-(3- o o isopropyl-4-oxoimidazolidin-1-yl)-trans- 148 m in X cyclohexylmethyl|- methylamino)-pyridin-2-yl)-6-

Н ХУ І about methoxy-1,4-dihydro-2H-isoquinolin-3-one. Tue From TOP: Thu-1,165; RH-MS: t/2 674.3 (MANI.

SI

(9) A dp vva (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-, ST | A Imethyl-|(4-(3-methyl-4-oxoimidazolidin- 1-yl)-trans-149 gum cyclohexylmethyl)-amino)-pyrazin-2-yl)-1,4-one dihydro-2H-isoquinolin-3-one. -- and TOP: Chve-5,202; LC-MS: t/: 647.2 (MANI. / vv C |methyl ether 44-((2-((8)-1-(4-chlorophenyl)-7-

To: about | isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1 H-150 pora Ua Z isoquinolin-2-yl|-pyrimidin-5-yl-methylamino)-methyl|- o Fe | 8 trans-cyclohexylamino)-acetic acid. t p Y TOP: Chnes-5.07; RH-MS: t/» 636.4 (MANI.

1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-6-154 and E methoxy-7-(2,2,2-trifluoroethoxy)-1,4-dihydro-2H- i Ff che isoquinolin-3-one.

AND TOP: Thu-6.02; RH-MS: t/ 505.4 |IMANG.

SI shi Structure - Name / HPLC / MS - m vv (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5- dX I o Imethyl-I4-(4-methyl-3 -oxo-piperazin-1-yl)-trans- 152 plum as Х cyclohexylmethyl)-amino)-pyrimidin-2-yl)-1,4- o v | dihydro-2H-isoquinolin-3-one.

Z I TOP: Thu-4,929; RH-MS: t/2 661.5 | MAANI.. - (9) And also; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-

ХГ | A Imethyl-I4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-153 gu cyclohexylmethyl)|i-amino)-pyridazin-3-yl)-1,4- - dihydro-2H-isoquinolin-3 - he and - and TOP: Chve-4,497; PH-MS: t/; 647 (MANI. / (9) Amfi o 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6- 154 du methoxy-7-(2-methoxyethoxy)-1,4-dihydro-2H- and; PI 5 isoquinoline-Z-one. also HPLC: Chve-4.577; LC-MS: m/z: 481.4 (MANI. (9) 7 o m Shchi o 1-(4-chlorophenyl)-2-( 4-dimethylaminophenyl)-6-155 methoxy-7-[(5)-1-(tetrahydrofuran-2-yl)-methoxy]-ic; 1,4-dihydro-2H-isoquinolin-3-one. o HPLC: Chve-4.72; LC-MS: t/ 507 1 |IMANEG. (9) and so on 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-156 du methoxy- 7-((H)-1-(tetrahydrofuran-2-yl)methoxy-ic; Ii in 1,4-dihydro-2H-isoquinolin-3-one. o HPLC: Chve-4.737; LC-MS: t/2 507.3 (MANI.

Ho) in Amfi o 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6- 157 SU methoxy-7-((B)-2-methoxy-propoxy)-1,4-dihydro- ; c i 2H-isoquinolin-3-one. more TOP: Thu-5,340; LC-MS: t/: 495.3 (MANI. (o) 5 /y Sh o 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-(-2-methoxy-1 -methylethoxy))-1,4- 158 t Fu Kolo dihydro-2H-isoquinolin-3-one.

TOP: Thu-5,11; RH-MS: t/ 495.2 |IMANG. (o) 5 5 ve (2-hydroxy-2-methylpropyl)-amide 4-(A-((5)-1-(44 scha U : L chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo- 3,4- 159 | dihydro-1H-isoquinolin-2-yl|I-phenyl-methylamino)-

In 7 methyl|-trans-cyclohexane-carboxylic acid. ny m si HERC: Sive-6,496; RH-MS: t/2 662.5 MANI. (9)

Structure Name/HPLC/MS (9) (18, 25) 2-Hydroxycyclopentyl)-amide (4-((14-((5)-1) SU and AZ (4-chlorophenyl)-7-isopropoxy -b-methoxy-3-oxo-3,4- 160 | dihydro-1H-isoquinolin-2-yl|I-phenyl-methylamino)- and methyl|-trans-cyclohexane-carboxylic acid. no m a HPLC: Blue- 6.420; RH-MS: t/: 674.6 (MANI. (9)

Ho) A vve (18) 2-hydroxypropyl)-amide (4-I44-((5)-1-(4- i, AZ chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4- 161 | dihydro-1H-isoquinolin-2-yl|1-phenyl-methylamino)-cp methyl|-trans-cyclohexane-carboxylic acid. HPLC: Sieve-6.305; LC-MS: t/ 648.2 MANI. (9) (9) (5) 2-hydroxypropyl)-amide (4-(4-((5)-1-(44 sh ; ZH | |chlorophenyl)-7-isopropoxy-6-methoxy-3- oxo-3,4- 162 1 dihydro-1H-isoquinolin-2-yl|1-phenyl-methylamino)- 7 methyl|-trans-cyclohexane-carboxylic acid. HPLC: Sieve-6,111; LC-MS: / 648.2 MAN. m fi o cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-! In A. isoquinolin-3-one. t, PI HPLC: Sieve-8.718; LC-MS: t/ 645.2 |IMANE . -methoxy-1,4-dihydro-m7 Y 2 H-isoquinolin-3-one and HPLC: Blue-6.802; LC-MS: t/: 503.4 (MANI. 5 (o) 5- in (5) -2-I4-(3-amino-5-methyl-1H-pyrazole- 4-yl)phenyl|-1- 165 a : ry (4-chlorophenyl)-7-isopropoxy-b-methoxy-1,4-"7 dihydro-2H-isoquinolin-3-one. and HPLC: Cine-6,662; LC-MS: m/: 517.4 (MANI. (o) (9) (9) and Phi 1-(4-chlorophenyl)-2-(4-(3,5-dimethyl-1H-pyrazole-4 - oyl)uphenyl|-7-isopropoxy-6-methoxy-1,4-dihydro-2H- 166 I A isoquinolin-3-one.

AH | F TOP: Chne-4,823; RH-MS: t/: 516.3 MANI". (at)

What is 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-(1-hydroxycyclopropylmethoxy))-b-methoxy-1,4-? FI r dihydro-2H-isoquinolin-3-one.

TOP: Thu-4,795; RH-MS: t/: 493.4 (MANI. (o)

sh Structure Name/EPLC/MS (9) mA m Fi o 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6- 168 sh SU methoxy-7-(3-methoxypropoxy)-1,4-dihydro -2H-

It is also isoquinolin-3-one. o TOP: Thu-5,417; LC-MS: m/: 495.4 (MANI. (o) (9) (9) as ov (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-y4-ny H o (1-(2-oxopiperazin-1-yl)-ethyl|-phenyl)-1,4-dihydro-169 o, chn 2H-isoquinolin-3-one.

AND FROM THE TOP: Chve-0.928; RH-MS: t/2 550.0 MANI.

SI

Ho) A m Fi o 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6- 170 sh SU methoxy-7-(oxetan-2-ylmethoxy)-1,4-dihydro-2H-

Y F Z isoquinolin-3-one. o TOP: Yave-4,968; RH-MS: t/ 493.4 MANI".

SI 5 m ia 1-(4-chlorophenyl)-7-(2,2-difluoroethoxy)-2-(4-(9) - - . 174 schi SU E dimethylaminophenyl)-6-methoxy-1,4-dihydro- 2H-; F -- isoquinoline-Z-one.

AND TOP: Javeh-5,59; RH-MS: t/z 487 4 |MANI-. (at)

Phi 7 methyl ether o 44-(45-11-(4-chlorophenyl)-7- and o |isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1 H-172 a A isoquinolin-2-yl |-pyrazin-2-yl-"methylamino)-methyl|- m o | Ф trans-cyclohexylamino)-acetic acid. by І HPLC: Chve-5.31; LC-MS: t/: 636.5 |MANG.

Phy t T2-4-I(5-11-(4-chlorophenyl)-7-isopropoxy-6-methoxy-u o | 3-oxo-3,4-dihydro-1 H-isoquinolin-2-yl|-pyrazine -2-yl)- 173 methylamino)-methyl|-trans-cyclohexylamino)-M-

N | Fu methylacetamide. sh nak Y VERH: Chnes-5,15; PH-MS: t/; 635.6 (MANI. (9) ach r; Fi o 1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(5-, C i A Imethyl-I4-(3-methyl-4- Oxoiimidazolidin-1-yl)-trans-174 gu m Ff cyclohexylmethyl-amino)-pyrazin-2-yl)-1,4-one dihydro-2H-isoquinolin-3-one. -- and TOP: Chve-5,18; RH-MS: t/ 647.5 MANI". / (9) vach

M Fi 1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-

SU o Imethyl-I4-(4-methyl-3-oxopiperazin-1-yl)-trans-175 slav ra cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- o C | and dihydro-2H-isoquinolin-3-one.

I AND TOP: Chve-4,41; RH-MS: t/: 660.7 MANI". (9) has (5)-1-(4-chlorophenyl)-2-(3-fluoro-4-(methyl-(4-(4- o YH and A methyl-3-oxopiperazin-1-yl) -trans- 176 S Y cyclohexylmethyl|-amino)-phenyl)-7-isopropoxy-6- as Y methoxy-1,4-dihydro-2H-isoquinolin-3-one -y a HPLC: Sivea-6,588; LC- MS: t/: 677.6 MANI (9)

sh Structure - Name/EPC/MS

IS -

СХ (5)-1-(4-chlorophenyl)-2-(2-fluoro-4-(methyl-(4-(4-ko and A methyl-3-oxopiperazin-1-yl)-trans- 177 SU Y) cyclohexylmethyl|i|-amino)-phenyl)-7-isopropoxy-6-

As: methoxy-1,4-dihydro-2H-isoquinolin-3-one. th a SUPER: Cine-6,766; RH-MS: t/: 677.7 MANI". (9) o A sh in (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-y4- 178 OS | ra ((5)-1-(2-oxopiperazin-1-yl)-ethyl|-phenyl)-1,4-y dihydro-2H-isoquinolin-3-one. m TOP: Chne-4.449 min.; RH-MS: t/: 549.2 MANI". (o) on o (9) (C in (5)-1-(4-chlorophenyl)-2-(4-((5)-1-(4-(2-tihydroxyethyl)- 179 PU ! o 2- Oxopiperazin-1-yl(1-ethyl-phenyl)-7-isopropoxy: p-methoxy-1,4-dihydro-2H-isoquinolin-3-one b o HPLC: Chve-1.080; LC-MS : t/: 634.2 (MANI.

SI

(9) (9) in (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-180 ne Y o KA)-1-(2-oxopiperazin-1-yl) -ethyl|-phenyl)-1,4-che Z A dihydro-2H-isoquinolin-3-one. o O TOP: Chve-0.922; RH-MS: t/ 548.5 |MANE.

SI on (9) (9) (C in (5)-1-(4-chlorophenyl)-2-(4-(8)-1-I(4-(2-hydroxyethyl)- 181 77 ! o 2- oxopiperazin-1-yl|1-ethyl-phenyl)-7-isopropoxy-

In 3 Ж b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. o o HPLC: Chve-0.932; RH-MS: t/ 592.5 MANI.

SI o )! Phi X 1-(4-chloro-2-fluorophenyl)-2-(4-dimethylamino-phenyl)-o 7-isopropoxy-b6-methoxy-1,4-dihydro-2H-isoquinolin-182 i Y Z-one.

Phi VERH: Chna-6,178; RH-MS: t/: 483.4 MAN.

SI no

(5)-1-(4-chlorophenyl)-2-14-(3-hydroxy-3-

B o hydroxymethylcyclobutylmethyl)-methylamino|- 183 Phi ; G phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-

It is isoquinolin-3-one.

TOP: Thu-1,098; RH-MS: t/z 565.5 (MANI.

SI 5

2-I(4-(3-amino-5-isobutyl-1H-pyrazol-4-iluphenyl|-1- 184 Х (4-chlorophenyl)-7-isopropoxy-6-6-methoxy-1, 4- and: and dihydro-2H-isoquinolin-3-one. with HPLC: Cine-6.832; LC-MS: t/2 559.5 |MANI".

Mn, sashi Structure Name/EPCH/MS o ; and CF 1-(4-chlorophenyl)-2-(6-(3,5-dimethyl-1H-pyrazol-4-yl)-pyridin-3-yl|-7-isopropoxy-6-methoxy -1,4- 7 - A dihydro-2H-isoquinolin-3-one.

Ah | F TOP: Chne-4,685; RH-MS: t/: 517.0 MANI".

1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(2-methoxy-4-methyl-2-phenyl)-1,4-dihydro-2H- 186 and ac isoquinolin-3-one.

TOP: Chnes-5.74; RH-MS: t/z 466.4 MANI.

SI

Friday

M M

C o o 1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-|4-methyl-2-(2H-tetrazol-5-ylmethoxy)phenyl|-1,4- 187 m. At o dihydro-2H-isoquinolin-3-one. and A TOP: Chna-5,20; RH-MS: t/2 534.4 (MANI.

SI in not about? o 1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-|4- 188 m Phi methyl-2-(thiazol-5-ylmethoxy)phenyl!|-1,4-dihydro-2H-

XX isoquinolin-3-one.

F TOP: Mive-1.23; RH-MS: t/ 549.4 MANI".

SI lk

MA M

IF o o methyl ether 4-(/1-(4-chlorophenyl)-7-isopropoxy-189 y Phi b-methoxy-3-oxo-3,4-dihydro-1 H-isoquinolin-2-yl|-3- o (2H-tetrazol-5-ylmethoxy)-benzoic acid. o F J HPLC: Miwe-1.10; LC-MS: t/ 578.2 MANI". o

SI o o o m Fi o methyl ether 4-(/1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3 - 190 o'clock "Soch

FI of methoxybenzoic acid. o TOP: Mive-1,19; RH-MS: t/ 510.3|M ANI".

SI shk g o? o methyl ether 4-(/1-(4-chlorophenyl)-7-isopropoxy-194 M Phi b-methoxy-3-oxo-3,4-dihydro-1 H-isoquinolin-2-yl|-3-

HC of (thiazol-5-ylmethoxy)-benzoic acid. and Ff VERH: Mive-1,15; RH-MS: t/: 593.3 MAN. at

SI shi Structure - Name/EPCH/MS o - osu M-((5)-1 o zdi oho

Ch y methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- 192 t Y o phenyl)-ethyl)-acetamide. mice TOP: "Chvna-6.55; RH-MS: t/2 524.5 |IMAMNIG. - СИ 5 -о Ж M-((5)-1-44-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-193 SAU and Ж methoxy-3-oxo-3,4-dihydro -1 H-isoquinolin-2-yl|- phenyl)-ethyl)-2-methoxyacetamide. m UPPER: "Chvna-6.72; RH-MS: t/2 554.5 |MAMNIG. - (about) 5

Ж M-((5)-1-44-(5)-1-(4-chlorophenyl)-7-isopropoxy-6- 194 in : A methoxy-3-oxo-3,4-dihydro-1 H- isoquinolin-2-yl|- phenyl)-ethyl)-2-dimethylaminoacetamide. rish TOP: Chna-6,15; LC-MS: t/2 550.5 (MANI. c) 7 o m (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6- xx Ge)

SU: ry Imethyl-I|4-(2-oxopyrrolidin-1-yl)-trans-195 sita cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- dihydro-2H-isoquinolin-3-one. s i TOP: Chve-4,21; RH-MS: t/: 631.6 MAN. from (9) A m (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6- xx o uv : A. Imethyl-I|4-(2-oxoimidazolidin-1- yl)-trans- 196 glory cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- m | dihydro-2H-isoquinolin-3-one. c a TOP: Javeh-4,60; RH-MS: t/: 632.6 MANI". (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-

SU Y ХК Imethyl-I4-(3-oxomorpholin-4-yl)-trans-197 av and cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- ak | dihydro-2H-isoquinolin-3-one.

TOP: Javeh-4,72; RH-MS: t/: 647 6 MANI". 6. A SI with (9) A with vva (5)-2-(B)-tert-butoxy)-1-(4-chlorophenyl)-6- r y | methoxy-2-(5-methyl-(4-(3-methyl-4-198 g m 75 oxoimidazolidin-1-yl)-transo-cyclohexyl-methyl-amino)-pyrazin-2-yl)-1, 4-dihydro-2H-isoquinolin-3-one. -- and TOP: Chve-5,475; LC-MS: t/2 661.6 MANI". / o o with vvi (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-

SU! XX Imethyl-|(4-(2-oxopiperidin-1-yl)-trans- 199 glory and cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- dihydro-2H-isoquinolin-3-one.

S G TOP: Thu-4.97; RH-MS: t/: 645.6 MAN. (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-yl4- 200 Ov A ((5)-1-(4 -methyl-3-oxopiperazin-1-yl)-ethyl|-phenyl)- o Y 1,4-dihydro-2H-isoquinolin-3-one.

I TOP: "Chvna-6.01; RH-MS: t/2 562.5 (MANI.

SI 5 is gray in the study of oxypyridine and ethyl pyridine -1-(2-oxopiperazin-1-yl)-ethyl|-pyridin-3-yl)- 201 in TB Mak 1,4-dihydro-2H-isoquinolin-3-one. m TOP: Chne-4,515; RH-MS: t/: 549.2 |MANI". (o) (9) (9) t vv (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4- 202 ST ! o ((5)-1-(2- oxotetrahydropyrimidin-1-yl)-ethyl|/- shshch OA phenyl)-1 4-dihydro-?H-isoquinolin-3-one and C HPLC: Chve-1.178; LC-MS: t/2 565.4 |MAMNHzH .

SI

(9) A s ov (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-, y and methoxy-2-(6-(methyl-I(4-(Z -methyl-4- 203 VI m 75 oxoimidazolidin-1-yl)-transo-cyclohexylmethyl(-o-amino);)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. (- a HPLC: Chve-4.671; LC-MS: t/: 660.6 (MANI. / (9) A c vva (5)-1-(4-chlorophenyl)-7-cyclobutoxy-6-methoxy-2 - , SU and (6-methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)- 204 SU t m 5 transo-cyclohexylmethyl)|-amino)-pyridin-3-yl)-1,4 - o- dihydro-2H-isoquinolin-3-one -- a HPLC: Chve-4.52; LC-MS: t/: 658.6 MAN. / ov (5)-1-(4-chlorophenyl)- 6-Methoxy-2-(6-methyl-|4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-amino)-pyridin-3-yl )- 7-((5)-1- g

B B Y isoquinolin-3-one. / TOP: Thu-4.26; RH-MS: t/: 688.7 MANI".

1-(4-Chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-(2-206 ri A oxopyrrolidin-1-yl)uphenyl|-1,4-dihydro-2H-

C FI isoquinolin-3-one. on the TOP: "Chna-6.81; RH-MS: t/2 505.4 (MANI.

SI

C (5)-1-(4-chlorophenyl)-b-methoxy-2-(5-(methyl-|4-(3- in : o methyl-4-oxoimidazolidin-1-yl)-trans- 207 sentence). In cyclohexylmethyl|-amino)-pyrazin-2-yl)-7-((5)-1-

Fe | CA What (tetrahydrofuran-2-yl)umethoxy|-1,4-dihydro-2H- c- and isoquinolin-3-one. /th TOP: Chvea-4,686; RH-MS: t/: 689.7 MANI.

sh Structure Name/EPCH/MS o ; and Ш 1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-(2- 208 SU o oxoimidazolidin-1-yl)phenyl/|-1 4-dihydro-2H-

S ra isoquinolin-3-one. - X FI TOP: Chne-5,090; RH-MS: t/: 506.0 |M-NO".

WHAT about

SI

(9) (5)-1-(4-chlorophenyl)-7-cyclobutoxy-6-methoxy-2- -yl)- 209 In t m 5 transo-cyclohexylmethyl)|-amino)-pyrazin-2-yl)-1,4- - dihydro-2H-isoquinolin-3-one. and - a TOP: Chve-5,31; RH-MS: t/: 659.6 MANI". / (9) A in (5)-7-(A)-second-butoxy)-1-(4-chlorophenyl)-6-

SU 2 methoxy-2-(6-(methyl-(4-(4-methyl-3-oxopiperazinate) and 75 1-yl-trans-cyclohexylmethyl|-amino)-pyridin-3-o C | yl)- 1,4-dihydro-2H-isoquinolin-3-one. t I HPLC: Chve-4.64; LC-MS: t/: 674.7 (MANI. - (9) A vv (5)-1-( 4-chlorophenyl)-7-cyclobutoxy-6-methoxy-2-

SU H o (6--methyl-I(4-(4-methyl-3-oxopiperazin-1-yl)-trans-211 slyas 5 cyclohexylmethyl)|)-amino)-pyridin-3-yl)-1, 4- about in | dihydro-2H-isoquinolin-3-one.

Z AND TOP: Thu-4.52; LC-MS: t/: 672.7 (MANI. r o o o (5)-1-(4-chlorophenyl)-6-methoxy-2-(6-methyl-|4-(4-methyl-3Z) -oxopiperazin-1-yl)-trans- 212 ry KU : cyclohexylmethyl|-amino)-pyridin-3-yl)- 7-((5)-1- o in Y I (tetrahydrofuran-2-yl)umethoxy|- 1,4-dihydro-2H-ut isoquinolin-3-one. HPLC: Chva-4.10; LC-MS: t/2 702.0 (MANI.

Ho) A m Fi o 2-I4-(3-amino-5-ethyl-1H-pyrazol-4-yl)phenyl|-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-1, 4-dihydro- 213 m FI -» 2H-isoquinolin-3-one. "i VERH: Cine-7,089; RH-MS: t/2 531.5 MANI".

SI

(0) o 275 va (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4- 214 I С ! ra ((5)-1-(3-oxomorpholine-4- yl)-ethyl|-phenyl)-1,4-chu E dihydro-2H-isoquinolin-3-one m HPLC: Chne-5.253; LC-MS: t/2 549 |MANI.

TV 5

СХ (5)-1-(4-chlorophenyl)-2-(2-fluoro-6-(methyl-I4-(4-t9 | methyl-3-oxopiperazin-1-yl)-trans- 216 sys and Z cyclohexylmethyl)|-amino)-pyridin-3-yl)-7-

AJ | isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. th and VERH: Zive-6,661; RH-MS: t/h 678.3 MANI. (9). 1-yl)-ethyl (1-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. m TOP: Chva-5,131; RH-MS: t/: 626.2 MAN. (at)

sy Structure Name/EPCH/MS o Go) Vysh

Hol ve (5)-2-1A-(5)-1-(4-acetyl-2-oxopiperazin-1-yl)- 218 and du ! A ethyl(1-phenyl)-1-(4-chlorophenyl)-7-isopropoxy-6- methoxy-1,4-dihydro-2H-isoquinolin-3-one. m TOP: Chva-5,126; RH-MS: t/: 590.2 MANI.

СІ 5 shchi "2 Ж (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-16-і | KA)-1-(2-oxopiperazin-1-yl)-ethyl|- pyridin-3-yl)- 219 C 59. cancer 1,4-dihydro-2H-isoquinolin-3-one.

TOP: Chne-4,449; RH-MS: t/: 549.2 |MANICH. - 5 5

A va (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4- 220 i gy : A (5)-1-(2-oxo-4-(tetrahydropyran-4- yl)-piperazine-1-yl(-ethyl-phenyl)-1,4-dihydro-2H-isoquinolin-3-one m HPLC: Chne-4.762; LC-MS: t/: 632.2 |M '-NONE.

SI

(0) Fr

АХА vva (5)-1-(4-chlorophenyl)-7-isopropoxy-2-14-((5)-1-(4- 294 I Ku A A isopropyl-2-oxopiperazin-1-yl)-ethyl| -phenyl)-6b- in ! methoxy-1,4-dihydro-2H-isoquinolin-3-one. m UPPERH: Chne-4,831; RH-MS: t/: 590.3 MANI". 5 СИ 5 Вах СХ, (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-14- 229 I I A I(5)-1-(4-methyl-2-oxopiperazine- 1-yl)-ethyl|-phenyl)- 1,4-dihydro-2H-isoquinolin-3-one. m TOP: Chne-4,711; RH-MS: t/: 562.3 MANI". (5) 1-(4-chlorophenyl)-6-hydroxy-7-isopropoxy-2-(6-

SU Z Imethyl-I4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-223 tt cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- o dihydro-2H-isoquinolin-3 - he - si VERH: "Chve-3.99; RH-MS: t/: 632.6 MAN. /

IF) on ve (5)-7-((BA)-second-butoxy)-1-(4-chlorophenyl)-6-

SU 7. Hydroxy-2-(6-methyl-14-(4-methyl-3-oxopiperazin-1-yl-trans-cyclohexylmethyl-amino)-pyridin-3-yl)-1 ,4-dihydro-2H-isoquinolin-3-one. o TOP: Yavea-4.11 min.; RH-MS: t/ 660.7 (MANI.

M SI r

IF) on ev 1-(4-chlorophenyl)-6-hydroxy-7-isopropoxy-2-(6-

SU: ХХ Imethyl-I4-(4-methyl-3-oxopiperazin-1-yl)-trans- 225 THERE cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- skit | dihydro-2H-isoquinolin-3-one. -1 - and 4th year UP: Thu-4,10; RH-MS: p/:2 646.6 (MANI. o. o. Iv)

Fi and 1-(4-chlorophenyl)-7-isopropoxy-6-dz-methoxy-2-(6-

SU o Imethyl-I4-(4-methyl-3-oxopiperazin-1-yl)-trans- 226 se ves r cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- o to | F dihydro-2H-isoquinolin-3-one. o and TOP: Thursday-4.38 min.; LC-MS: t/: 663.6 (MANI. rshi Structure Name/eHP/MS (9) 9) Iv) and fi y 1-(4-chlorophenyl)-7-isopropoxy-6-dz-methoxy-2 -(6-

Su o (dz-methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans- 227 TI ra cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- o Dosha F dihydro-2H-isoquinolin-3-one. o o i TOP: Chve-4,38; RH-MS: t/: 666.6 MAN. p 9) o ve (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-

SU! Ж (dz-methyl-I4-(4-methyl-3-oxopiperazin-1-yl)-trans- 228 TI cyclohexylmethyl)i-amino)-pyridin-3-yl)-1,4- o to vch dihydro-2H -isoquinolin-3-one. ro o i VERH: Thursday-4.38; RH-MS: t/: 663.6 MAN.

Intermediate 95.1: 1-(4-Iodobenzyl)-1H-imidazole.

M call

To a solution of imidazole (400 mg, 5.88 mmol) and Kg2CO3 (1.22 g, 8.81 mmol) in DMF (19 mL) at

4-iodobenzyl bromide (1.83 g, 6.17 mol) was added to CT under protection from light. After stirring for 11.5 hours, the reaction mixture was poured into water. The aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with water, dried over

Mag5O., filtered and concentrated. The residue was purified by column chromatography to give the title compound (757 mg, 2.66 mmol, 45 95) as a beige solid. TOP: Chvne-3.838 min.; RH-MS: t/z: 285.2 MANI.

Intermediate 96.1: (4-Isopropoxy-3-methoxyphenyl)-acetyl chloride. c) Fr

J

AND

To a solution of intermediate 96.2 (1.41 g, 6.29 mmol) in DCM (50 ml) at 0 °C was added 1-chloro-M,M,2-trimethylpropenylamine (1.0 ml, 7.55 mol). After stirring for 0.5 h, the reaction mixture was concentrated in vacuo and the crude product was used without further purification.HPLC: Chvna-4.772 min (methyl ether after treatment with meon).

Intermediate 96.2: (4-Isopropoxy-33-methoxyphenyl)-acetic acid. c) Fr

Us

AND

The desired compound (11.5 g, 78 mmol, 99 95) was obtained as a white solid from intermediate 75.1 (20.0 g, 79 mmol) analogously to the preparation of intermediate 1.2.

TOP: Chwei-4.117 min.; RH-MS: t/: 223 MANI.

Example 98: M-14-P1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2-yl1-phenyl)-2,2,2 -trifluoro-M-methylacetamide. c) about in the call

B, A in |!

From SI

The desired compound (236 mg, 0.43 mmol, 53.1 95) was obtained as a white solid from intermediate 98.1 (410 mg, 0.81 mmol) and 2-iodopropane (0.24 mL, 2.43 mmol) similarly to obtaining intermediate product 138.2. TOP: "Thursday-7.34 min.; RH-MS: t/: 547.2 MANI".

Intermediate 98.1: M-14-P1-(4-Chlorophenyl)-7-hydroxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-2,2 ,2-trifluoro-M-methylacetamide. c) o c (c) GU on

IS

E by 1

SI

The desired intermediate (415 mg, 0.82 mmol, 57.8 95) was obtained as a white solid from intermediate 98.2 (629 mg, 1.84 mmol) and intermediate 187.3 (723 mg, 142 mmol) analogously to the preparation in example 1. 4-Methoxyphenylmethyl group was cleaved by 5y under the conditions of the reaction. TOP: "out-6.478 min.; LC-MS: t/2 505.1

IM-ANI".

Intermediate 98.2: M-(4-11-(4-Chlorophenyl)-meth-(E)-ylidene|-amino)-phenyl)-2,2,2-trifluoro-

M-methylacetamide.

SI and

IS

And on

IS

The desired compound (0.73 g, 2.16 mmol, 47.1 95) was obtained as a white solid from intermediate 98.3 (1.0 g, 4.58 mmol) and 4-chlorobenzaldehyde (0.71 g, 5 .04 mmol) similarly to obtaining intermediate product 1.4. "H NMR (600 MHz, DMSO-α) 3.30 (c, C H) 7.35 (a, 2 H) 7.49 (a, 2 H) 7.61 (a, 2 H) 7.96 (a, 2 N) 8.67 (5, 1 N).

Intermediate 98.3: M-(4-Aminophenyl)-2,2,2-trifluoro-M-methylacetamide.

Mn. eat

IS

And on

WITH

The desired intermediate (2.67 g, 12.2 mmol, 100 96) was obtained as a solid from intermediate 98.4 (3.0 g, 12.1 mmol) analogously to the preparation of intermediate 43.2. TOP: Chva-0.73 min.; RH-MS: t/z2 219.3 MANI.

Intermediate 98.4: 2,2,2-Trifluoro-M-methyl-M-(4-nitrophenyl)-acetamide. 6)

Yeh

Mu - what?

IS

And on

From E

The desired intermediate (11.8 g, 12.22 mmol, 100 95) was obtained as a solid from M-methyl-4-nitroaniline (8.5 g, 54.2 mmol) and trifluoroacetic anhydride (11.4 mL, 81 mmol) similar to the preparation of intermediate product 43.1. TOP: "bne-1.90 min.; RH-MS: t/2 249.4 |MANE.

Example 100: (5)-1-(4-chlorophenyl)-2-(4-C4-(1,1-dioxo-1-lambda"b"-thiomorpholin-4-yl)-trans-cyclohexylmethyl|-methylamino) -phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

o, o) p

M and o o. ovi ov

UNTIL

SI

The desired intermediate (25 mg, 0.031 mmol, 59 95) was obtained as a white solid from intermediate 77.3 (30 mg, 0.053 mmol) and divinylsulfone (6.3 mg, 0.053 mmol) analogously to the preparation of intermediate 87.1. TOP: Thu-2.02 min.; RH-MS: t/2 680.2 (M--NIU.

Intermediate 101.1: (4-:(4-bromo-3-methoxyphenyl)-methylamino|- methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether. (c) Yes no

N cho o ; VG

M

The desired intermediate (266 mg, 0.62 mmol, 49 95) was obtained as a white solid from intermediate 101.2 (695 mg, 1.86 mmol) and 3795 in an aqueous solution of formaldehyde (0.38 mL, 5.08 mmol) similarly to obtaining intermediate product 77.1. TOP:

Aive-2.67 min.; RH-MS: t/2 427.1 MANI".

Intermediate 101.2: 34-(4-Bromo-3-methoxyphenylamino)-methyl|-trans-cyclohexyl)-carbamic acid tert-butyl ether. at night

N o

Sg

M

N

The desired intermediate (526 mg, 1.27 mmol, 86 95) was obtained as a gray solid from (4-formylcyclohexyl)-carbamic acid tert-butyl ether (371 mg, 1.63 mmol) and 4-bromo-33- of methoxyaniline (300 mg, 1.48 mmol) similarly to obtaining intermediate product 75.7. TOP: Mva-2.60 min.; RH-MS: t/z 413.1 MANI.

Intermediate 102.1: (5)-2--4-KTrans-4-aminocyclohexylmethyl)-methylamino|-2-methoxyphenyl)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one. re and zo o o g.

E (c

M: Oh yes

The desired intermediate (40.9 mg, 0.058 mmol, 10095) was obtained as an orange resin from the compound of Example 101 (40 mg, 0.58 mmol) in a similar manner to Example 51. HPLC: "ve-1.90 min.; RH-MS: t/2 592.2 MANI.

Intermediate 103.1: Methyl ether (2-tert-butoxycarbonylaminoethyl)-(4-((14-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4- dihydro-1H-isoquinolin-2-yl|-3-methoxyphenyl)-methylamino)-methyl|-trans-cyclohexyl)-amino)-acetic acid. at. ro Du ra same

And so on

IN

; Zo o o.

WITH

E (o)

M Z A si

The desired intermediate (37 mg, 0.038 mmol, quantitative yield) was obtained as a yellow solid from the compound of Example 102 (25 mg, 0.038 mmol) and M-Boc-2-aminoacetaldehyde (9 mg, 0.056 mmol) analogously to the preparation of intermediate 79.2 . TOP:

Adee2.31 min.; RH-MS: t/7 807, 4IMZhnu.

Intermediate 104.1: (4-Modphenyl)-methylpiperidin-4-ylmethylamine.

AND

With her

The desired intermediate (94 mg, 0.28 mmol, 61.2 95) was obtained as a yellow resinous substance from intermediate 104.2 (200 mg, 0.46 mmol) analogously to the preparation in Example 51. HPLC: Chvea-1.50 waves .; LC-MS: t/2 331.1 (MA-NI".

Intermediate 104.2: 4-((4-iodophenyl)-methylamino|-methyl)-piperidine-1-carboxylic acid tert-butyl ether.

And what is the seam in)

The desired intermediate (3.27 g, 7.60 mmol, 83 90) was obtained as a brown oil from intermediate 104.3 (4.27 g, 9.13 mmol) and 37 95 aqueous formaldehyde solution (1.36 mL, 18 .2 mmol) similarly to the preparation of intermediate product 77.1. TOP: "neg-3.19 min.;

RH-MS: t/z 431 MANI.

Intermediate 104.3: 4-(4-iodophenylamino)-methyl|-piperidine-1-tert-butyl ether

From carboxylic acid.

I usu t 6)

The desired intermediate (4.27 g, 9.13 mmol, 100 95) was obtained as a purple solid from 4-formylpiperidine-1-carboxylic acid tert-butyl ether (2.73 g, 12.8 mmol) and 4- of iodaniline (2.0 g, 9.13 mmol) similarly to obtaining intermediate product 75.7.

TOP: Thu-2.97 min.; RH-MS: t/2 361.1 IMANSOONG.

Example 105: (5)-1-(4-Chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-Imethyl-14-(3-methyl-4-oxoimidazolidin-1-yl)-transo-cyclohexylmethyl| -amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

c) about ovi

І c) day va -7 o

In c c)

The desired compound (104 mg, 0.16 mmol, 19.4 95) was obtained as a yellow solid from intermediate 75.6 (287 mg, 0.83 mmol) and intermediate 105.1 (372 mg, 0.87 mmol) analogously to the preparation in example 75. SUPER: Chive-1.164 min.; RH-MS: tp/2 645.5 MANI";

IN NMR (400 MHz, DMSO-α) 0.85-1.09 (t, 4 N) 1.19 (aa, 9-19.55, 5.86 Hz, 6 N) 1.49-1.87 (t, 5 H) 2.08-2.25 (t, 1 H) 2.70 (5, C H) 2.85 (5, C H) 3.09 (5, 4 H) 3.55 ( y, 9U-19.94 Hz, 1 H) 3.71 (5, Z H) 3.87 (ad, 9-19.55 Hz, 1 H) 4.02 (5, 2 H) 4.33- 4.49 (t, 1 N) 5.92 (5, 1 N) 6.54 (a, 2-8.99 Hz, 2 N) 6.80 (5, 1

N) 6.87 (9.9-8.99 Hz, 2 N) 7.02 (5.1 N) 7.33 (5.4 N).

Intermediate 105.1: 1-(4-(4-Hyodophenyl)-methylamino|-methyl)-trans-cyclohexyl)-3-methylimidazolidin-4-one. day -kTM -

A mixture of intermediate 105.2 (535 mg, 1.29 mmol) and 3795 aqueous formaldehyde solution (0.96 mL, 12.9 mmol) in EN (20 mL) was sealed and heated at 807 for 20 h. The reaction mixture was concentrated in vacuo, then the resulting yellow oil was immediately purified by column chromatography to give the desired compound (553 mg, 1.29 mmol, 100 95) as a beige solid. TOP: Thu-1.088 min.; RH-MS: t/2 428.1 (MANI. Y

Intermediate 105.2: 2-(4--(4-Hyodophenyl)-methylamino|-methyl)-trans-cyclohexylamino)-

M-methylacetamide.

AH

AND

- M. Nm

A mixture of intermediate 105.3 (700 mg, 1.68 mmol) and 33,956 EUN of a solution of MeMn"5" (2.1 ml, 168 mmol) was sealed and heated at 80"C for 24 h. The reaction mixture was concentrated in vacuo, then the obtained the yellow oil was immediately purified using

Column chromatography gave the desired compound (535 mg, 1.29 mmol, 77 90) as a beige solid. TOP: Chive-0.982 min.; RH-MS: t/2 416.2 (MANI.

Intermediate 105.3: (4-((4-iodophenyl)-methylamino|-methyl)-trans-cyclohexylamino)-acetic acid methyl ester.

UNTIL

AD va o

Potassium carbonate (14.3 g, 103 mmol) and methyl-2-bromoacetate (4.77 ml, 51.7 mmol). The suspension was stirred for 4.5 hours. at a temperature equal to from -10 "С to 10 s.

The reaction mixture was diluted with E(OAc), the organic phase was washed with water and brine and dried over Mag250»2, filtered and evaporated to dryness. Purification of the residue using column chromatography with a normal phase when eluting with

100 95 DHM to 100 95 EAs provided the desired compound as a brown oil (9.45 g, 21.6 mmol, 43.8 95). TOP: China-4.22 min.; RH-MS: t/2 417.0 (MANI.

Intermediate 105.4: (Trans-4-aminocyclohexylmethyl)-(4-iodophenyl)-methylamine.

Dt - nm

TFA (114 mL, 1484 mmol) was added dropwise to a solution of intermediate 77.1 (21.9 g, 49.5 mmol) in DCM (300 mL) at 0 °C. The reaction mixture was stirred for 30 minutes at RT, then concentrated in vacuum. The residue was diluted with EtOAc, and at 0 C the pH was adjusted to 9 by the addition of 2 M NaCl. The phases were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over Ma»5O», and filtered Concentration in vacuo provided the desired compound as a gray solid (16.9 g, 47.8 mmol, 97 95). HPLC: Chvne-3.92 min.; LC-MS: t/ 345.1 M-ANI ".

Example 106: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4--Imethyl-(4-(4-methyl-3-oxopiperazin-1-yl)-transo- cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. c) Fr

SH

І 9) moat

As. Z le SI 9)

Potassium phosphate (4.44 g, 20.29 mmol) was placed in a sealed flask for the reaction, pumped off and heated for 15 minutes. at 170 "C. The reaction flask was filled with argon at RT and then intermediate 75.6 (3.64 g, 10.15 mmol), intermediate 106.1 (5.48 g, 12.18 mmol), dioxane (75 ml ) and (h/-)-trans-1,2-diaminocyclohexane (0.37 mL, 3.04 mmol). The reaction flask was carefully evacuated (2x) and refilled with argon (2x) and copper iodide(!) (0.586 g, 3.04 mmol).

The reaction mixture was stirred for 22.5 hours. at 95 "C. The mixture was extracted with

EUAs (Zh) and water (Zh). The organic phases were washed with brine and dried over Ma25054, filtered and evaporated to dryness.

Zo Meon/EuAc, then with the help of preparative reverse-phase HPLC provided the salt from TFA, which was extracted with EAs (2x) and 1M aqueous solution

MansSOz (them). The organic phases were washed with brine and dried over Na»5O»4, filtered and evaporated to dryness to give the desired compound as a white solid (1.59 g, 2.41 mmol, 23.8 95): HPLC: Chve-4, 57 minutes; RH-MS: t/: 659.2 MANI; "H NMR (400 MHz, DMSOSO-av) 0.88-1.01 (t, 2 H) 1.05-1.14 (t, 2 H) 1.16 (y, 9-5.86 Hz, With H) 1.21 (a, 9-6.25

Hu, Z H) 1.48-1.62 (t, 1 H) 1.73 (ad, 4 H) 2.14-2.27 (t, 1 H) 2.65 (I, 9-5, 47 Hz, 2 H) 2.76 (5, Z H) 2.85 (5, Z H) 3.02 (5, 2 H) 3.06-3.20 (t, 4 H) 3.54 ( 9, 1 H) 3.71 (5, Z H) 3.87 (0, 9-19.53 Hz, 1 H) 4.39-4.47 (t, 1 H) 5.92 (5, 1 H) 6.54 (y, 2 H) 6.81 (5, 1 H) 6.87 (y, 2 H) 7.02 (5, 1 H) 7.33 (5, 4 H).

Intermediate 106.1: 4-(4-((4-Hyodophenyl)-methylamino|-methyl)-thrano-cyclohexyl)-1-methylpiperazin-2-one.

AND

AH and shk lu c)

To a solution of intermediate 106.2 (13.3 g, 20.9 mmol) in dioxane (52.3 mL) at 0" was added a 4M solution of HCl in dioxane (105 mL, 418 mmol). The reaction mixture was stirred at RT for 0.5 h. The solution was concentrated and the residue was dissolved in MeonN (157 ml), triethylamine (27.3 ml, 196 mmol) was added dropwise at 0 °C and the mixture was stirred for 1 h. at CT. The reaction mixture was concentrated and the residue was extracted with EtOAc (2x) and 1M aqueous solution of ManHsoz (1x). The organic phases were washed with saline and dried over Mo25054, filtered and evaporated to dryness. The crude material was suspended in ESO (50 mL) and after stirring and sonication for 30 min, it was filtered through filter paper, washed with ESO (50 mL) and evaporated to dryness under high vacuum to give a white powder (8.11 g, 18 .0 mmol, 86 95).

TOP: Chva-4.035 min.; RH-MS: t/z 442.1 |MANI; "H NMR (400 MHz, DMSO-α) 0.84-1.02 (t, 2 N) 1.02-1.12 (t, 2 N) 1.52-1.60 (t, 1 N) 1.60-1.84 (t, 4 H) 2.16-2.27 (t, 1 H) 2.65 (Her, 9-5.47 Hz, 2 H) 102.76 (5, Z H ) 2.85 (5, Z H) 3.02 (5.2 H) 3.10 (y, 9U-7.03 Gu, 2 H) 3.14-3.20 (t, 2 H) 6, 47 (y, 2 N) 7.37 (4.2 N).

Intermediate 106.2: |(2-(tert-butoxycarbonylmethylamino)-ethyl|-(4- ((4-iodophenyl)-methylamino|-methyl)-transo-cyclohexyl)amino|-acetic acid methyl ester.

To a suspension of intermediate 105.3 (9.45 g, 21.6 mmol), methyl-(2-oxoethyl)-carbamic acid tert-butyl ether (4.11 g, 23.7 mmol) and ASON (3.7 ml, 64.7 mmol) in DCM (108 ml) at 0"C was added Mavn(OAc)z (13.7 g, 64.7 mmol) in portions. After stirring for 1 hour at room temperature, a saturated aqueous solution was carefully added to the reaction mixture

MansSoz to pH 8, then extracted with DCM (2x). The organic phases were dried over

Mag505, filtered and evaporated to give the crude desired intermediate (13.3 g, 20.9 mmol, 97 95 purity 90 965). This substance was used in the next stage without additional purification. TOP: Thu-5.32 min.; RH-MS: t/2 574.3 MANI".

Example 107: Methyl ether 4-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| 1-phenyl)-methylamino)-methyl-1-trans-cyclohexane-carboxylic acid. 6) about

І 6). what) 6) SI 6)

The desired compound (244 mg, 0.40 mmol, 25.8 95) was obtained as a white solid from intermediate 75.6 (540 mg, 1.56 mmol) and intermediate 107.1 (665 mg, 1.71 mmol) similarly obtained in example 75. HPLC: SFive-7.244 min.; RH-MS: t/: 605.4 MANI.

Intermediate 107.1: 4-((4-iodophenyl)-methylamino|-methyl)-trans-cyclohexanecarboxylic acid methyl ester.

In cv) 9) 9)

The desired intermediate (700 mg, 1.81 mmol, 97 95) was obtained as a white solid from intermediate 107.2 (695 mg, 1.86 mmol) and 3795 of an aqueous solution of formaldehyde (306 mg, 3.72 mmol) analogously to the preparation intermediate product 77.1. TOP: 8.063 min.; RH-MS: t/: 388.2 MANI".

Intermediate 107.2: 4-M4-iodophenylamino)-methyl|-trans-cyclohexanecarboxylic acid methyl ester. why 9) 9)

The desired intermediate (700 mg, 1.87 mmol, 40 95) was obtained as a white solid from 4-formylcyclohexanecarboxylic acid methyl ether (800 mg, 4.7 mmol) and 4-daniiodline (601 mg, 2.74 mmol) similarly to obtaining intermediate product 75.7. TOP: bidet-7.874 min.; RH-MS: t/2 374.2 MANI. The methyl ester of 4-formylcyclohexanecarboxylic acid was obtained by the following method. To a solution of the methyl ether of trans-4-hydroxymethylcyclohexanecarboxylic acid (which is described in the publication Zupipezie. Sott. (1982) rad 42-43) (861 mg, 5.0 mmol) and EM (2.1 ml, 15.0 mmol) in To DCM (16 mL) was slowly added a solution of a complex of pyridine with sulfur trioxide (2.39 g, 15 mmol) in DMSO (10 mL) at 0 C (ice bath). After stirring for 70 minutes. he was bred with help

DCM and washed with water. The organic layer was dried over NaCl5O, filtered and evaporated to dryness. This crude substance (0.8 g, 4.7 mmol) was used in the next step without further purification.

Example 108: 4-((4-(5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl1-phenyl- methylamino)-methylI-trans-cyclohexanecarboxylic acid. c) about ov

9)

LU A ra "A si 9)

The desired compound (81 mg, 0.124 mmol, 100 95) was obtained as a white solid from the compound of example 107 (75 mg, 0.124 mmol) similarly to the preparation of intermediate 26.1.

TOP: Chine-6.497 min.; RH-MS: t/h 591.2 (MENI.

Intermediate 112.1: (4-Hyodophenyl)-methyl-(4-piperazin-1-yl-trans-cyclohexylmethyl)-amine.

Zo

AND

In another nm

The desired intermediate (351 mg, 0.85 mmol, 74.1 95) was obtained as a white solid from intermediate 112.2 (650 mg, 1.14 mmol) and analogously to the preparation of intermediate 88.2. TOP: MChvet 732 min.; РХ-МС: t/: 4141 MANI".

Intermediate 112.2: (4-Hydrophenyl)-methyl-(4-(4-toluene-4-sulfonyl)-piperazin-1-yl|-trans-cyclohexylmethyl)-amine.

AND

-

Eh still ro o

The desired intermediate (654 mg, 1.15 mmol, 54.2 95) was obtained as a white solid from intermediate 105.4 (0.73 g, 2.12 mmol) and M,M-bis(2-chloroethyl)- 4-methylbenzenesulfonamide (0.73 g, 2.23 mmol) similarly to the preparation of intermediate product 88.1. TOP: "vei-2.07 min.; LC-MS: t/: 568.0 (M'ANI".

Example 116: 2-(4-((4-(5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |I-phenyl-methylamino)-methyl|-trans-cyclohexylamino)M-methylacetamide. c) ok ovi

9)

AKTAH p o si

The desired compound (94.9 mg, 0.15 mmol, 95 95) was obtained as a yellow solid from intermediate 79.1 (100 mg, 0.158 mmol) analogously to the preparation of intermediate 105.2. TOP: "vei-1.86 min.; XHA-MS: t/2 633.2 (MIN.

Intermediate 117.1: (4-Modphenyl)-methylpiperidin-2-ylmethylamine. !

XX

N

Fi

The desired intermediate (200 mg, 0.61 mmol, 89 95) was obtained as a brown resin from intermediate 117.2 (308 mg, 0.68 mmol) analogously to the preparation in Example 51.

TOP: "Chve-1.49 min.; RH-MS: t/: 331.2 (M.-ANI..

Intermediate 117.2: 2-((4-iodophenyl)-methylamino|-methyl)-piperidine-1-carboxylic acid tert-butyl ether.

M» su (in) 5-4 ОХ su

The desired intermediate (310 mg, 0.68 mmol, 100 95) was obtained as a purple solid from 2-formylpiperidine-1-carboxylic acid tert-butyl ether (213 mg, 0.72 mmol) and 4-iodaniline (150 mg , 0.68 mmol) similar to the preparation of the intermediate product

Zo 15.7 and sequential methylation were carried out similarly to the preparation of intermediate product 77.1.

TOP: "nee3.23 min.; LC-MS: t/2 431.2 |(MANG.

Intermediate 118.1: (4-Modphenyl)-methyl-(tetrahydropyran-2-ylmethyl)-amine.

!

XX su

The desired intermediate (143 mg, 0.43 mmol, 7895) was obtained as a light brown oil from intermediate 118.2 (175 mg, 0.55 mmol) and 37 95 aqueous formaldehyde solution (0.12 mL, 1.65 mmol ) is analogous to obtaining intermediate product 77.1. TOP:

Are-2.48 min.; RH-MS: t/h 332.2 MANI".

Intermediate 118.2: (4-Modphenyl)-(tetrahydropyran-2-ylmethyl)-amine.

In I

NM su

The desired intermediate (177 mg, 0.56 mmol, 13 95) was obtained as a brown solid from 2H-pyran-2-carboxaldehyde (490 mg, 4.29 mmol) and 4-iodaniline (940 mg, 4.29 mmol ) is analogous to obtaining the intermediate product 75.7. TOP: Java-2.44 min.; RH-MS: t/2 318.2 (M-ANI".

Intermediate 119.1: Cyclohexylmethyl-(4-iodophenyl)-methylamine.

THEIR co

The desired intermediate (195 mg, 0.59 mmol, 86 95) was obtained as a colorless oil from cyclohexanecarbaldehyde (81 mg, 0.72 mmol) and 4-iodaniline (150 mg, 0.68 mmol) analogously to the preparation of intermediate 75.7 and sequential methylation was carried out similarly to the preparation of intermediate product 77.1. TOP: "ve-3.26 min.; LC-MS: t/2 330.2

IM-ANI..

Example 120: (5)-2-45-((Trans-4-aminocyclohexylmethyl)-methylamino|-pyridin-2-yl)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one.

MN, rova g Ma and M ! A. 2

SI

The desired compound (334 mg, 0.593 mmol, 78 95) was obtained as a yellow foamy substance

Zo from intermediate 120.1 (504 mg, 0.760 mmol) analogously to that obtained in Example 51: HPLC:

Rve-0.98; RH-MS: t/ 563.4 | M'ANIKH.

Intermediate 120.1: tert-butyl ether 44-((16-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|-pyridin-3-yl-methylamino)-methyl|-trans-cyclohexyl)-carbamic acid.

oh sky (in) Ge)

M vv Kh

And Me o si

The desired intermediate (151 mg, 0.228 mmol, 79 95) was obtained as a brown solid from intermediate 120.2 (176 mg, 0.347 mmol) and intermediate 75.6 (100 mg, 0.289 mmol) analogously to Example 75. HPLC: Chve -1.563; RH-MS: t/2 663.5 (M-A-NI".

Intermediate 120.2: (4-(6-Iodopyridin-3-yl-methylamino|-methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether.

And am c.

M. oh oh and me

The desired intermediate (1.0 g, 2.24 mmol, 64 95) was obtained as a solid from intermediate 120.3 (1.5 g, 3.48 mmol) and formaldehyde (37 95 in water, 0.326 mL, 4, 35 mmol) similarly to obtaining intermediate product 77.1. TOP: Thu-1,446; RH-MS: t/2 446.2 |MANEG.

Intermediate 120.3: 44-(b-iodopyridin-3-ylamino)-methyl|-trans-cyclohexyl)-carbamic acid tert-butyl ester.

MN schi o

AH Her

The desired intermediate (1.95 g, 4.52 mmol, 99 95) was obtained as a pinkish solid from trans-(4-formylcyclohexyl)-carbamic acid tert-butyl ether (1.136 g, 5 mmol) and b-iodopyridine- 3-ylamine (1 g, 4.55 mmol) similarly to the preparation of intermediate 75.7. TOP: Thu-1,289; РХ-МС: t/z 4321 | MANEI.

Example 121: Methyl ether 14-((6-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-

C,4-dihydro-1H-isoquinolin-2-yl|-pyridin-3-yl-"methylamino)-methyl|-trans-cyclohexylamino)-acetic acid.

M ,vi X i p Me o v

SI

The desired compound (140 mg, 0.221 mmol, 45 95) was obtained as a yellow foam from the compound of example 120 (275 mg, 0.487 mmol) similarly to the preparation of intermediate 79.1.

TOP: Thu-1,204; RH-MS: t/2 635.5 |M'ANI".

Example 122: 2-1A-((6-((5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl) |-pyridin-3-yl-methylamino)-methyl|-trans-cyclohexylamino)-N-methylacetamide. are we roar - MM: o.

Ud in si

A mixture of the compound of example 121 (65 mg, 0.102 mmol) and a solution of methylamine (33 d in EN, 1.2 ml, 10.23 mmol) was heated for 15 h. at 90 "C. The mixture was concentrated in vacuo and the precipitate was collected by filtration. The residue was purified by column chromatography

Nazp Sotrapiop "m (Izso Ips.) (5 µg; elution in gradient mode, DXM/LDHM/EN 9:11) 1:0 - 3:7) and obtained the desired compound in the form of a yellow solid (40 mg, 0.064 mmol, 63 95).

Example 123: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-Imethyl-I4-(3-oxopiperazin-1-yl-transo-cyclohexylmethyl)|-amino)- pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one.

N

S and (in) o

Mov Kh

NI n MN o 5) Z (9)

To a solution of intermediate 123.1 (44 mg, 0.045 mmol) in MeOnH (1 ml) at RT was added

NSI (4M in dioxane, 0.564 mL, 2.256 mmol). The reaction mixture was stirred at RT for 2 h. and evaporated to dryness. The obtained residue was dissolved in ME (1 mL), then EizM (0.094 mL, 0.677 mmol) was added and the mixture was stirred at RT for 1.5 h. After evaporation to dryness, the residue was purified using Sotbri-Riazp Sotrapiop "m (Ivso Ips.) column chromatography (5 µg; elution in gradient mode, DHMIDHM/EUN/aqueous solution of МНз 909: 1) 1:0 - with" 1:9) and obtained the desired compound as a yellow solid (17 mg, 0.027 mmol, 60 95). HPLC: Chve-1.082; LC-MS: tu/ 646.2 (MANI.

Intermediate 123.1: Methyl ether (2-tert-butoxycarbonylaminoethyl)-(4-((16-((5)-1-

Zo (4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyridin-3-yl)-methylamino)-methyl|-trans- cyclohexyl)-amino)-acetic acid. 5, sh s (c) sa o. o (c) o M vv Kh

NI p, o o

SI

The desired intermediate (44 mg, 0.045 mmol, quantitative yield) was obtained as a yellow solid from the compound of example 121 (30 mg, 0.048 mmol) analogously to the preparation of intermediate 79.2. TOP: Chnea-1,444; RH-MS: t/: 778.6 (MANI.

Example 124: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)-transo-cyclohexylmethyl) |-amino)-pyridin-2-yl)-1,4-dihydro-2H-isoquinoline-3-one. if you want

WITH

(c) Fr

M Kwe Kh

M M: o

AL 5

SI

A mixture of the compound of example 122 (38 mg, 0.061 mmol) and formaldehyde (0.046 ml, 37% solution, 10 equiv., 0.612 mmol) was heated at 80 °C for 15 h in EN (1 ml). The reaction mixture was concentrated to dryness and the residue purified by column chromatography Sotri-

Nazp Sotrapiop "m (Izso Ips.) (BiIOg; gradient elution, DHMIDHM/Meon 9: 1) 1:0 -. 0:11) and obtained the desired compound in the form of a colorless solid (31 mg, 0.048 mmol, 79 95). TOP: Chive-1.236; RH-MS: t/ 646.4 MANI.

Example 125: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-(Imethyl-(4-(4-methyl-3-oxopiperazin-1-yl)-transo- cyclohexylmethyl|-amino)-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one and

AND

(c) (c)

M "vi H

M and MN at 8), 9

SI

The desired compound (140 mg, 0.221 mmol, 45 95) was obtained as a yellow foam from intermediate 125.1 (275 mg, 0.487 mmol) similarly to the preparation in example 123. HPLC:

Rve 1,019; RH-MS: t/: 660.4 (MANI.

Intermediate 125.1: Methyl ether (2-(tert-butoxycarbonylmethylamino)-ethyl|-(4-

IR6-((5)-1-(4-chlorophenyl)-7-isopropoxy-6b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyridin-

Z-yl-methylamino)-methyl|-transo-cyclohexyl)-amino)-acetic acid. eh)

J se (c)

Me o. o (c) o M, "ovi H

At PE at 8 (9)

Coo)

The desired intermediate (84 mg, 0.107 mmol, 90 95) was obtained as a yellow solid from the compound of Example 121 (75 mg, 0.118 mmol) and M-Bos-(methylamino)acetaldehyde (24.54 mg, 0.142 mmol) analogously to the preparation intermediate product 79.2. TOP: Thu-1,256; RH-

MS: t/; 792.2 MANI".

Example 126: Methyl ether 14-((5-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-

C,4-dihydro-1H-isoquinolin-2-yl|-pyridin-2-yl-methylamino)-methyl|-trans-cyclohexylamino)-acetic acid. day a

NM pe SI (in)

The desired compound (250 mg, 0.39 mmol, 29 95) was obtained as a white solid from intermediate 75.6 (470 mg, 1.36 mmol) and intermediate 130.3 (680 mg, 1.63 mmol) similarly to the preparation in Example 75. TOP: Fine-5.334 min.; RH-MS: t/: 635.4 MANI.

Intermediate 127.1: Methyl ether (2-tert-butoxycarbonylaminoethyl)-(4-((15-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4- dihydro-1H-isoquinolin-2-yl(-pyridin-2-yl)-methylamino)-methyl(-trans-cyclohexyl)-amino)-acetic acid. you are in Yi o

In rue

Nm m S mya si o

The desired intermediate (24.6 mg, 0.032 mmol, 41.8 95) was obtained as a white solid from the compound of Example 126 (48 mg, 0.076 mmol) and M-Boc-2-aminoacetaldehyde (25.3 mg, 0.151 mmol) ) is analogous to obtaining intermediate product 79.2. TOP: SFivea-5.832 min.;

RH-MS: t/y 778.6 (MANI.

Example 128: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(methyl-I(4-(4- oxoimidazolidin-1-yl)-transo-cyclohexylmethyl|- amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinoline-3-one

With ex FV SI

N

A mixture of intermediate 128.1 (153 mg, 0.23 mmol) and 3795 aqueous solution of formaldehyde (0.17 mL, 2.32 mmol) in EUN (5 mL) was sealed in a vessel and heated for 3.5 h. at 80"C. The reaction mixture was concentrated in a vacuum and the obtained

The brown oil was purified using column chromatography, respectively preparative thin-layer chromatography, and the desired compound was obtained (5 mg, 7.12 mmol,

From 95) in the form of a colorless resinous substance. TOP: NZive-0.99; RH-MS: t/: 632.2 |MANI".

In addition, intermediate 129 (44.5 mg, 0.067 mmol, 29 95) was identified as a side product and isolated from the crude reaction mixture. TOP: Uive-1.01; RH-MS: t/: 662.5 (MANI.

Intermediate 128.1: 2-14-((15-(5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| -pyridin-2-yl-methylamino)-methyl|-trans-cyclohexylamino)-acetamide.

go, o nm og si 6)

The desired intermediate (154 mg, 0.23 mmol, 100 95) was obtained as a white solid from the compound of example 126 (149 mg, 0.23 mmol) analogously to the preparation of intermediate 85.1. TOP: Thebes-5.177 min.; RH-MS: t/2 620.2 (M'ANI".

Example 130: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(Imethyl-(4-(4-methyl-3-oxopiperazin-1-yl)-transo- cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one, ov a I» , A

ACT O le SI

Potassium phosphate (2.94 g, 13.45 mmol) was placed in a sealed flask for the reaction, pumped out and heated for 1 h. at 100 "C. The reaction flask was filled with argon at RT and then intermediate 75.6 (2.35 g, 6.73 mmol), intermediate 130.1 (3.01 g, 6.73 mmol), dioxane (45 ml ) and (w/-)-trans-1,2-diaminocyclohexane (0.167 mL, 1.345 mmol). The reaction flask was carefully evacuated (2x) and refilled with argon (2x) and mydis(I) iodide (0.256 g, 1.345 mmol). The reaction mixture was stirred for 17 hours at 95 "C. The mixture was extracted with EtOAc (3x) and water (3x). The organic phases were washed with brine and dried over Mag505, filtered and evaporated to dryness. Purification of the residue using column chromatography with a normal phase, eluting with a mixture of DCM - MeOHN - 30 95 aqueous solution of MNAOH (200:10:1), then with the help of preparative reverse-phase HPLC ensured the receipt of TFA salts, which were extracted using EOAcS (2x ) and 1 M aqueous solution of Mansoz (1x). The organic phases were washed with brine and dried over NaCl5OH4, filtered and evaporated to dryness. The residue was crystallized (ETOAc) and the desired compound was obtained as a white crystalline substance (1.84 g, 41 95). TOP: ORive-0.98 min.; LC-MS: t/2 660.7 (MANI; "H NMR (600 MHz, DMSO-sv) 0.95 (d, 9-11.77 Hz, 2 H), 1.11 (i, 9-11 .81 Hz, 2 H), 1.17 (9.9-5.85 Hz, Z H), 1.23 (9.9-5.85 Hz, Z H), 1.55-1.64 ( t, 1 H), 1.64-1.82 (t, 4 H), 2.23 (I, U-11.30

Hu, 1 H), 2.67 (I, 9-4.74 Hz, 2 H), 2.78 (5, Z H), 2.95 (5, Z H), 3.04 (5.2 H), 3.18(h, 9-4.84 Hz, 2 H), 3.23-3.30 (t, 2 H), 3.61 (h, 9U-19.98 Hz, 1 H) , 3.73 (5, Z H), 3.96 (y, 9U-19.98 Hz, 1 H), 4.34-4.50 (t, 1

Koo) H), 5.96 (5, 1 H), 6.52 (y, 99.08 Hz, 1 H), 6.84 (5, 1 H), 6.95 (5, 1 H), 7.21 (a, U-8.88 Hz, 1 N), 7.36 (5.4 N), 7.77 (5, 1 N). AND

Intermediate 130.1: 4-(4-(5-Hydropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-1-methylpiperazin-2-one. l | - to g le o

TFC (30.2 ml, 392 mmol) was added to a solution of intermediate 130.2 (7.90 g, 13.06 mmol) in DCM (130 ml) at 0°C. The reaction mixture was stirred at RT for 2.5 h.

The solution was concentrated and the residue was extracted with EtOAc (2x) and 1M aqueous solution of Mansoz (1x). The organic phases were washed with brine and dried over NaCl5OH4, filtered and evaporated to dryness. The residue was dissolved in MeOH (130 mL) at 0 °C, triethylamine (27.3 mL, 196 mmol) was added and the mixture was stirred for 30 minutes at RT.

The reaction mixture was concentrated and the residue was extracted with EAs (2x) and 1M aqueous solution of ManHsoz (1x). The organic phases were washed with saline and dried over

Mag5O», filtered and evaporated to dryness. Purification of the residue by column chromatography with a normal phase eluting with a mixture of DCM - Meon (20:1), crystallization (isopropyl ether) provided the desired compound in the form of beige crystals (4.90 g, 10.97 mmol, 84 95). TOP: Rinea-0.75 min.; LC-MS: t/2 443.3 |MANI"; "H NMR (400 MHz,

DMSO-α): b 0.89-1.00 (t, 2H), 1.04 - 1.13 (t, 2H), 1.55-1.68 (t, ZN), 1.71-1 .80 (t, 2H), 2.16 - 2.26 (t, 1H), 2.61 - 2.68 (t, 2H), 2.76 (5, ЗН), 2.92 (in, ЗН ), 3.02 (5, 2H), 3.13 - 3.19 (t, 2H), 3.27 - 3.31 (t, 2H), 6.47 (a, 1H), 7.65 ( a, 1H), 8.15 (5, 1H).

Intermediate 130.2: |(2-(tert-butoxycarbonylmethylamino)-ethyl|-(4- ((5-iodopyridin-2-yl)-methylamino|-methyl)-transo-cyclohexyl)amino|-acetic acid methyl ester.

M Z s o ;

M still om zu y

To a solution of intermediate 130.3 (5.80 g, 0.227 mmol), ASON (1.57 mL, 27.5 mmol) in

A solution of methyl-(2-oxoethyl)-carbamic acid tert-butyl ether (2.86 g, 16.5 mmol) in DCM (25 ml) was added to DCM (250 ml) at 0 "C. The mixture was stirred for 20 minutes at 0 "WITH.

After adding Mavn(ods)z (5.83 g, 27.5 mmol), the cooling bath was removed and the suspension was stirred for 1 h. at CT. A 1M aqueous solution of Mansoz (250 ml) was carefully added to the reaction mixture, then extracted with DCM (2x). The organic phases were dried over magnesium sulfate, filtered and evaporated. Purification of the residue by column chromatography with a normal phase eluting with a mixture of DCM - meon (98:2) provided the desired compound as a beige oil (7.95 g, 13.15 mmol, 96 95). TOP: Rivet-1.14 min.; RH-MS: t/ 575.0 MANI.

Intermediate 130.3: (4-S(5-iodopyridin-2-yl)-methylamino|-methyl)-trans-cyclohexylamino)-acetic acid methyl ester.

Kn Z ra; and:

IF)

Coo)

Potassium carbonate (7.46 g, 54 mmol) and methyl-2-bromoacetate (1.75 ml, 18, 9 mmol). The suspension was stirred for 17 hours. at a temperature equal to -10 "C to CT.

The reaction mixture was concentrated and the residue was extracted with EOAc (2x) and water (2x). The organic phases were washed with brine and dried over NaCl, filtered and evaporated to dryness. Purification of the residue by normal phase column chromatography eluting with a mixture of DXM - MeOH - 3095 aqueous solution of MNAOH (200:10:1) provided the desired compound as a beige oil (5.84 g, 13.86 mmol, 77 v). TOP: Rivea-0.78 min.; RH-MS: t/z 417.9 MANI.

Intermediate 130.4: (Trans-4-aminocyclohexylmethyl)-(5-iodopyridin-2-yl)-methylamine. nm

TFA (136 ml) was added to a solution of intermediate 130.5 (26.5 g, 58.9 mmol) in DCM (295 ml) at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C and additionally for 1 hour at RT . The solution was concentrated, extracted with a 4M aqueous solution of Mahon (300 ml) and DCM (4x). The organic phases were dried over NaCl5O, filtered and evaporated to dryness. Purification of the residue by means of column chromatography with a normal phase, eluting with a mixture of DXM - MeoOnH - 3095 aqueous solution of MNAOH (60:10:11) provided the desired compound in the form of beige crystals (20.0 g, 57.4 mmol, 97 95). TOP: Rivet-0.68 min.; RH-MS: t/: 346.3 MANI.

Intermediate 130.5: (4-(5-iodopyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether.

Su o du Moh

Until,

N

A mixture of intermediate 130.6 (22.4 g, 92 mmol), 2-fluoro-5-iodopyridine (21.4 g, 96 mmol), potassium carbonate (25.3 g, 183 mmol), and DMSO (305 mL) was stirred for 21 hours at 80 "C. The reaction mixture was concentrated in vacuo and the residue was extracted with EOAc (2x) and 1M aqueous solution of ManHsSOOz (ex). The organic phases were washed with brine and dried over NaCl5Oi, filtered and evaporated to dryness. The residue was crystallized ( TBME) and obtained the desired compound in the form of beige crystals (26.7 g, 59.4 mmol, 65 95). HPLC: Rivet-1.40 min.; LC-MS: t/ 446.4 (MANI.

Intermediate 130.6: Tert-butyl ether (trans-4-methylaminomethyl-cyclohexyl)- carbamic acid. oh

UNTIL,

N

During stirring, the CHzMH salt with HCl (15.75 g) was added to a solution of tert-butyl ether of trans-(4-formyl-cyclohexyl)-carbamic acid (50 g, 218 mmol) and MeOnH (2.2 L) at RT. The mixture was stirred for 30 minutes at RT and then cooled to 5 s.

Mn(oOAds)z (72.9 g, 327 mmol) was added portionwise over 45 minutes at 5 °C. The reaction mixture was stirred for 1 hour at 5 °C, and then the reaction was carefully quenched with a 1 M aqueous solution of ManHsOz (300 ml) and 2M Mahon. The resulting suspension was filtered through Poyo, washed with MeOH, and the filtrate was concentrated. The residue was extracted with EOAc (2x) and 1 M aqueous solution of ManHsSoOz (ex). The organic phases were washed with saline and dried over Mag25O0.5, filtered and evaporated to dryness. Purification of the residue using normal phase column chromatography with mixture elution

DXM - Meon - 30 95 aqueous solution of MNAOH (40:10:1) provided the desired compound in the form of a white crystalline substance (22.5 g, 92 mmol, 42 90). TLC: Ki0.33; LC-MS: tp/2 243.1

IM-ANI..

Example 131: 2-(4-((5-(5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |-pyridin-2-yl-methylamino)-methyl|-trans-cyclohexylamino)-N-isopropylacetamide.

WHAT

Mn

M

-- M; AND

SI

A mixture of the compound of Example 126 (253 mg, 0.398 mmol) and isopropylamine (3.41 mL, 3.41 mmol) was heated for 1.5 h in methanol (3 mL) in a microwave oven at 120 C. The mixture was concentrated to dryness and the residue was purified by by means of column chromatography with a normal phase (when eluting with a mixture of n-heptane - ethyl acetate) and obtained the desired compound in the form of a beige solid (80 mg, 0.121 mmol, 99 95). TOP: Nive-1.21 min.;

RH-MS: t/ 662.3 MANI".

Example 132: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)-transo- cyclohexylmethyl (amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

M o M - SI /

The desired compound (6.36 g, 9.74 mmol, 57 9o) was obtained in the form of yellowish crystals from intermediate 75.6 (100 mg, 0.289 mmol) and intermediate 132.1 (124 mg, 0.289) similarly to the preparation in example 130. HPLC: Riva-1.07 min.; LC-MS: t/2 646.6 (MANI; "H NMR (400 MHz, DMSO-α) 0.87-1.09 (t, 4 H), 1.15 (a, 9-5.87 Hz , Z H), 1.20 (y, 2-5.87 Gu, Z H), 1.51-1.85 (t, 5 H), 2.06-2.24 (t, 1 H), 2.69 (5, Z H), 2.93 (5, Z H), 3.08 (5, 2 H), 3.27 (5, 2 H), 3.56 (y, 1 H), 3.71 (9, 9-1.17 Hu, Z H), 3.93 (y, 9-19.94 Hu, 1 H), 4.01 (5, 2 H), 4.27-4, 47 (t, 1 H), 5.93 (5, 1 H), 6.50 (y, 99.38 Gu, 1 H), 6.81 (5, 1 H), 6.92 (5, 1 H), 7.13-7.24 (t, 1 H), 7.33 (y, 9-1.17 Hz, 4 H), 7.74 (a, 91.96 Gu, 1 H).

Intermediate 132.1: 1-(4--(5-Hydropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-

Z-methylimidazolidin-4-one. o-0 m- /

To a solution of intermediate 132.2 (13.0 g, 29.7 mmol) and EN (99 mL) was added a 37 9% aqueous solution of formaldehyde (22.09 mL, 297 mmol). The reaction mixture was stirred for

From 4 p.m. at 80 "C. The mixture was concentrated to dryness and the residue was purified using column chromatography with a normal phase, eluting with a mixture of DCM - MeOHN - 30 95 aqueous solution of MNAOH (200:20:1) and after crystallization (diisopropyl ether - hexane) the desired compound was obtained in in the form of a white crystalline substance (12.1 g, 28.0 mmol, 94 95). HPLC: Rinei-0.94 min.; LC-MS: t/: 429.3 |MANI"; "H NMR (400 MHz, DMSO-α): b 0.82-1.06 (t, 4Н), 1.60 (t, ЗН), 1.79 (t, 2Н), 2.15 (t, 1H), 2.69 (5, ЗН), 2.93 (v, ЗН), 3.08 (5, 2Н), 3.27 - 3.31 (t, 2Н), 4.01 (5, 2Н ),

6.49 (a, 1), 7.65 (j, 1H), 8.15 (5, 1H). AND

Intermediate 132.2: 2-(A-(5-Iodopyridin-2-yl)-methylamino|-methyl)-trans-cyclohexylamino)-M-methylacetamide. oh-0th

MN

/

A mixture of intermediate 130.3 (12.9 g, 30.6 mmol) and methylamine (33 95 in EN) (191 ml, 1.53 mol) was stirred for 16 hours at 80 °C. The mixture was concentrated to dryness and the residue was purified by column chromatography with the normal phase when eluting with a mixture of DXM - MeOnH - 30 95 aqueous solution of MNAOH (200:20:1) and obtained the desired compound in the form of a beige oil (13.0 g, 29.7 mmol, 97 95). HPLC: Oivne-0 ,68 min., LC-MS: t/2 417.3

IM-ANI..

Example 133: (5)-1--4-Chlorophenyl)-7-isopropoxy-2-(6-14-(3-isopropyl-4-oxoimidazolidin-1-yl-trans-cyclohexylmethyl|-methylamino)-pyridine-3 -yl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

IN.

S and

AI

M vra 3 Zh

SI

A mixture of the compound of example 131 (80 mg, 0.121 mmol) and formaldehyde (0.090 ml, 37% solution, 10 equiv., 1.208 mmol) was heated for 5 hours in 2-propanol (4 ml) at 85 °C. The mixture was concentrated to dryness and the residue purified by reverse-phase column chromatography. Fractions containing the product were combined and worked up (addition of ManHsoz) to afford the title compound as an off-white solid (46 mg, 0.068 mmol, »98 95). HPLC: Nive- 1.40 min.; LC-MS: t/2 674.2 (MANI.

Intermediate 134.1: 2-14-((15-(5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| -pyridin-2-yl-methylamino)-methyl|-trans-cyclohexylamino)-N-ethylacetamide. dkvma t

In nm

Shk SI 6)

The desired intermediate (120 mg, 0.178 mmol, 52 95) was obtained as a white solid from the compound of example 126 (217 mg, 0.34 mmol) and ethylamine in a similar manner to the preparation of intermediate 85.1. TOP: Thebes-5.521 min.; RH-MS: t/: 648.3 (MANI.

Example 135: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4--methyl-I(4-(2-oxopiperazin-1-yl-transo-cyclohexylmethyl|-amino )-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

that, Z H

A mixture of intermediate 135.1 (110 mg, 0.148 mmol) and 4 n. NSI in dioxane (0.738 mL, 2.95 mmol, 20 equiv.) was stirred at room temperature in dioxane (3 mL) for 3 h. The mixture was concentrated to dryness and the residue was purified by reverse phase column chromatography (preparative HPLC). Fractions containing the product were combined and worked up (Mansault addition, acetonitrile removal, and DCM extraction) to give the title compound as a white solid (24.2 mg, 0.038 mmol, »99 95). TOP: Nivei-1.54 min.; LC-MS: t/? 646.3 MANI".

Intermediate 135.1: tert-butyl ether 4-14-(4-(5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|I-phenyl-methylamino)-methyl|-thrano-cyclohexyl)-

Z-oxopiperazine-1-carboxylic acid. at. about you

But it's bad

In KU si c) o, M.

That's it

The desired intermediate (110 mg, 0.148 mmol, 24.3 95) was obtained as a white solid from intermediate 75.6 (210 mg, 0.607 mmol) and intermediate 135.2 (352 mg, 0.668 mmol) analogously to the preparation in example 75. HPLC : Here is 1.18 min.; RH-MS: t/2 745.4 MANI.

Intermediate 135.2: 4-(4-(4-iodophenyl)-methylamino|-methyl)-trans-cyclohexyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester. 1

And that (in) M. from ze

Potassium tert-butoxide (0.230 g, 1.990 mmol) was added to a solution of intermediate 135.3 (0.51 g, 0.904 mmol) in DMF (15 mL), and the reaction mixture was heated at 80 °C for 5 hours.

The reaction mixture was diluted with toluene and the organic phase was washed with an aqueous solution of MnSOO and saline. The organic phase was dried over Mag505, filtered and concentrated in vacuo to give by-products. The aqueous phase was combined and extracted with

From DXM, the crude desired product was obtained. The product was purified by automatic column chromatography with a normal phase (eluting with a mixture of n-heptane - ethyl acetate) and the desired compound was obtained as a brownish oil (350 mg, 0.66 mmol, 99 95). TOP: Miveg-1.40 min.; RH-MS: t/2 528.1 MANI".

Intermediate product 135.3. 32-(2-chloroacetyl)-(4-(4-iodophenyl)-methylamino|-methyl)-trans-cyclohexyl)amino|-ethyl)-carbamic acid tert-butyl ether.

And in the village who

Ve

A solution of intermediate 135.4 (0.50 g, 1.026 mmol) in DCM (20 mL) was placed in an ice bath. After 5 minutes, DIPEA (0.537 mL, 3.08 mmol) was added, followed by slow addition of chloroacetyl chloride (0.099 mL, 1.231 mmol). The reaction mixture was allowed to warm up to CT and after 1 hour the starting substance was exhausted. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of ManHsCO3 and a saline solution. The crude product was purified by automatic column chromatography with a normal phase (eluting with n-heptane - ethyl acetate) to give the desired compound as a brownish solid (0.51 g, 0.904 mmol). TOP: Mivnea-1.42 min.; RH-MS: t/2 5641 MANI".

Intermediate 135.4: 1-(|2-(4-(4-iodophenyl)-methylamino|-methyl)-trans-cyclohexylamino)-ethyl-carbamic acid tert-butyl ether.

AND

IN

SU

"and ze

The desired intermediate 135.4 (0.50 g, 1.026 mmol) was obtained as a colorless oil from intermediate 105.4 (1.54 g, 3.58 mmol) and M-Bos-2-aminoacetaldehyde (1.139 g, 7.16 mmol) similar to that obtained in example 52. HPLC: Mine-0.98 min.; PH-MS: t/; 488.2

IM-ANI".

Example 136: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4--methyl-I(4-(2-oxopiperazin-1-yl-cis-cyclohexylmethyl|-amino )-phenyl)-1,4-dihydro-2H-isoquinolin-3-one (c) about

Y (9) in, I A and o - 7» ,/ ой

M

IN

A mixture of intermediate 135.1 (110 mg, 0.148 mmol) and 4 n. NSI in dioxane (0.738 mL, 2.95 mmol, 20 equiv) was stirred at room temperature in dioxane (3 mL) for 3 hours.

The mixture was concentrated to dryness and the residue was purified by reverse phase column chromatography (preparative HPLC). Product-containing fractions were pooled and worked up (Mansot addition, acetonitrile removal, and DCM extraction) and obtained

The desired compound was obtained as a white solid (12.3 mg, 0.019 mmol, »99 95). TOP: Chine-1.52 min.; LC-MS: t/? 646.3 MANI".

Example 137: (5)-2-15-(Trans-4-aminocyclohexylmethyl)amino|-pyridin-2-yl)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one.

Mn, I

S o o : se, m MA A A and 8

SI

The desired compound (111 mg, 0.203 mmol, quantitative yield) was obtained as a brown solid from intermediate 137.1 (132 mg, 0.203 mmol) similarly to the preparation in example 77.3. TOP: Chne-1,937; RH-MS: t/: 549.4 MANI".

Intermediate 137.1: tert-butyl ether (4-(16-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|-pyridin-3-ylamino)-methyl)-transo-cyclohexyl|- carbamic acid. on neo o M x A and Oy c

The desired intermediate (132 mg, 0.203 mmol, 28 95) was obtained as a brown solid from intermediate 120.1 (367 mg, 0.850 mmol) and intermediate 75.6 (250 mg, 0.708 mmol) analogously to Example 75. HPLC: Chve -1.455; RH-MS: t/: 649.3 (M-AANI".

Intermediate 138.1: 1-(4-Chlorophenyl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (in o

The same village

Cesium carbonate (125 g, 658 mmol) and 2-iodopropane (100 mL, 988 mmol) were successively added to a solution of intermediate 138.2 (150 g, 329 mmol) in DMF (650 mL), then the reaction mixture was heated at 55 "C for With stirring, the reaction mixture was slowly poured into 2 L of ice-cooled water.The resulting mixture was extracted twice with 3 L of EIOAS, then washed twice with 1 L of water and 0.5 L of saline.

Concentration in vacuo afforded a crude solid, which was stirred in 100 mL of E(OAc) at RT, followed by filtration and drying to afford the desired intermediate (97.2 g, 281 mmol, 85 95). HPLC: Rivet-4.99 min .; LC-MS: t/27 346.2 MANI; "H NMR (400 MHz, DMSOO-av) 1.16 (yes, 9U-18.94, 6.05 Hz, 6 H), 3.28- 3.54 (t, 2 H), 3.70 (5, C H), 4.32-4.47 (t, 1 H), 5.53 (a, 9-3.90 Hz, 1 H) , 6.77 (5, 1 H), 6.83 (5.1 H), 7.28 (49.2 H), 7.36 (a, 2 H), 8.49 (y, 9-3 ,90 Gu, 1 N).

Intermediate 138.2: 1-(4-Chlorophenyl)-7-hydroxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

(in o. he village

To a suspension of 4-hydroxy-3-methoxyphenylacetonitrile (150 g, 0.919 mol) in 85 95 phosphoric acid (877 ml, 15,000 mol) was added 4-chlorobenzaldehyde (168 g, 1.195 mol), then the reaction mixture was heated at 120 "C for 2 h. After cooling to 90 "C, the reaction mixture was slowly poured into 4 liters of ice-cooled water while stirring. The resulting suspension was stirred at RT for 2 hours, then filtered and washed 4 times with 500 ml of water. The crude and wet substance was stirred in acetonitrile (1 L) at RT for 1 h, then filtration and drying afforded the desired intermediate (163.6 g, 0.539 mol, 58.6 95). TOP: Thu-4.20 min.; RH-MS: t/2 304.0 MANI; "H NMR (400 MHz, DMSO-dv) 3.25-3.53 (t, 2 H), 3.72 (5, C H), 5.47 (y, 9-3.12 Hu, 1 H ), 6.53 (5, 1 H), 6.72 (5, 1 H), 7.24 a, 2 H), 7.37 (a, 2 H), 8.42 (0, 9-3 .51 Gu, 1 H), 8.86 (bBg. 5., 1 H).

Example 139: Methyl ether 14-((5-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-

C,4-dihydro-1H-isoquinolin-2-yl|-pyrazin-2-yl-methylamino)-methyl|-trans-cyclohexylamino)-acetic acid. 9); va av wo y s Z Zh o still o SI

The desired compound (300 mg, 0.467 mmol, 41 95) was obtained as a yellow foam from intermediate 139.1 (400 mg, 1.145 mmol) and intermediate 75.6 (472 mg, 1.26 mmol) analogously to the preparation in Example 75: HPLC: Oive-1.40 min.; RH-MS: t/z 446.4 MANI.

Intermediate 139.1: (4-((5-Bromopyrazin-2-yl)γ-methylamino|-methyl)-trans-cyclohexylamino)-acetic acid methyl ester.

M Vg

HI l M BUYE o r

YOU about

The desired intermediate (570 mg, 1.52 mmol, 54 95) was obtained as beige crystals from intermediate 139.2 (850 mg, 2.81 mmol) analogously to the preparation of intermediate 130.3. TOP: Riva-0.68 min.; RH-MS: t/2 371/373 |MI".

Zo Intermediate 139.2: (Trans-4-aminocyclohexylmethyl)-(5-bromopyrazin-2-yl)-methylamine.

M Vg u

ON

The desired intermediate (17.0 g, 55.7 mmol, 99 95) was obtained as yellowish crystals from intermediate 139.3 (22.5 g, 55.8 mmol) similarly to the preparation of intermediate 130.4. TOP: Riva-0.64 min.; RH-MS: t/2 299/301 |(MI".

Intermediate 139.3: (4-(5-Bromopyrazin-2-yl)-methylamino|methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether.

M Vg

DI

AJ, nN

With stirring, MasMmVna (5.36 g, 85 mmol) was added to a mixture of intermediate 139.4 (16.6 g, 42.7 mmol), acetonitrile (2 L), and 37 95 aqueous formaldehyde solution (318 mL) at 10 "C. 4M HCIII was slowly added and the pH value was changed from 8.4 to 2.3. The reaction mixture was stirred for 4 hours at a temperature of 10-16 "C, maintaining the pH value at 2.3 (addition of 4M NOSI). A second portion of MasSMVN was added. (5.36 g, 85 mmol) and the pH value was measured from 6.9 to 2.3 (addition of 4M HCl). The reaction mixture was stirred for another 1 hour at 16 °C, maintaining the pH at 2.3 (adding 4M HCl) and then concentrated. The residue was extracted with water and DCM (2x). The organic phases were washed with brine and dried over Mag250»2, filtered Purification of the residue by column chromatography with a normal phase eluting with a mixture of EOAcC - heptane (1:2) after crystallization (TEME) provided the desired compound as a white crystalline substance (13.53 g, 33.9 mmol, 79 95). TOP: Rine-1.30 min.; RH-MS: t/: 399/401 MI".

Intermediate 139.4: (4-(5-Bromopyrazin-2-ylamino)-methyl|-trans-cyclohexyl)-carbamic acid tert-butyl ether.

M Vg

XI rya -

KD

(c) M

N

When stirred into a solution of trans-(4-formylcyclohexyl)-carbamic acid tert-butyl ether (30 g, 132 mmol), 2-amino-5-bromopyrazine (20.67 g, 119 mmol) and DCM (650 mL) at 20 "C was added Mavn(oAds)z (42.0 g, 198 mmol) and ASON (22.67 mL, 396 mmol) (slight heating). The reaction mixture was stirred for 18 h at RT. The reaction was carefully quenched by slowly adding 1M of an aqueous solution of MnHsCO3 (1 L). After stirring for 1 hour at RT, the organic phase was separated and the aqueous phase was extracted with an additional amount of DCM (600 mL). The combined organic phases were washed with brine and dried over Mg5O:, filtered and evaporated to dryness. Purification balance with the help of

From column chromatography with a normal phase when eluting with EtOAc - heptane (11) after crystallization (TBME) provided the desired compound in the form of yellowish crystals (24.3 g, 62.4 mmol, 47 95). TOP: Rivet-1.30 min.; RH-MS: t/7 385/387 MG

Example 140: (5)-1-(4-Chlorophenyl)-7-isopropoxy-b-methoxy-2-(5-methoxy-2-(5-methyl-14-(4-methyl-3-oxopiperazine-1- yl)-transo-cyclohexylmethyl|-amino)-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. c) cook 3 times more

To a solution of intermediate 140.1 (175 mg, 0.213 mmol) in dioxane (2.13 mL) at 0" was added 4M NOSI (dioxane) (2.66 mL, 10.64 mmol). The reaction mixture was stirred at RT for 1.5 h. The solution was concentrated and at 0 "С the residue was dissolved in MeOH (2.13 ml), triethylamine (0.445 ml, 3.19 mmol) was added and the mixture was stirred for 1 hour at

CT. The reaction mixture was extracted with EAs (2x) and 1TM aqueous solution of MansSoz

(1x). The organic phases were washed with brine and dried over NaCl, filtered and evaporated to dryness. Purification of the residue by column chromatography with a normal phase eluting with a mixture of DCM - Meon (20:1) provided the desired compound in the form of a yellowish foam (118 mg, 0.177 mmol, 83 95). TOP: Rivet-0.97 min.; RH-

MS: t/2 661.5 MANI".

Intermediate 140.1: Methyl ether (2-(tert-butoxycarbonylmethylamino)-ethyl|-(4-

IR5-((5)-1-(4-chlorophenyl)-7-isopropoxy-6b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyrazin-2-yl)u 'methylamino)-methyl|-trans-cyclohexyl)-amino)-acetic acid. c) ve ovi vav to o sh o r r a SI v o

The desired intermediate (180 mg, 0.219 mmol, 91 95) was obtained as a yellowish foam from the compound of example 139 (154 mg, 0.240 mmol) and methyl-(2-oxoethyl)-carbamic acid tert-butyl ether (49.8 mg , 0.288 mmol) similarly to obtaining intermediate product 130.2. TOP: Rine-1.36 min.; RH-MS: t/: 793.6 MANI.

Example 141: 2-(4-(6-(5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| -pyridin-3-yl-methylamino)-methyl|-trans-cyclohexylamino)-N-ethylacetamide. nN

Sava o o (c)

M in H

OT about in b

SI

The desired compound (73 mg, 0.113 mmol, 63 95) was obtained as a yellow foam from the compound of example 120 (100 mg, 0.178 mmol) and 2-bromo-M-ethylacetamide (43 mg, 0.249 mmol) analogously to the preparation of intermediate 79.1. TOP: Chive-1,016; RH-MS: t/2 648.5 MANI.

Example 142: 2-(4-(6-(5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| -pyridin-3-yl(?-methylamino)-methyl|-trans-cyclohexylamino)-N-isopropylacetamide.

I don't know

Nm (c) o

M, in Kh

I V M o v

SI

The desired compound (75 mg, 0.113 mmol, 64 95) was obtained as a yellow foamy substance from

From the compound of example 120 (100 mg, 0.178 mmol) and 2-bromo-M-isopropylacetamide (42 mg, 0.231 mmol) analogously to the preparation of intermediate product 79.1. TOP: Chne-1,035; LC-MS: t/2 662.5

IM-ANI"

Example 143: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-methyl-1(4-(2-oxoazetidin-1-yl-trans-cyclohexylmethyl)-amino) -pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one.

Co

AND

(c) (c)

M vvi Kh

OT Fr

FI

SI

DMAP (1.356 mg, 0.0011 mmol), EM (0.093 ml, 0.666 mmol) and 3-chloropropionyl chloride (31 mg , 0.244 mmol). The ice bath was then removed and the yellow solution was stirred for 1 h. The mixture was then poured into DCM and washed with saturated aqueous Mansaoz solution. After phase separation, the organic phase was washed with H2O and the aqueous phase was re-extracted with DCM. the combined extracts were washed 1 time with a saturated saline solution, dried over Mag5O»4, filtered and concentrated to dryness.

The residue was then dissolved in DCM (5 mL) and Mann (60 95 in mineral oil, 13.62 mg, 0.341 mmol) was added. Then the reaction mixture was stirred at RT for 15 h. The reaction was then quenched with water, poured into water and extracted with DCM. The organic phase was washed with saturated saline solution, dried over Mag5O54, filtered and concentrated to dryness. The crude residue was purified using Sotreby-RIavp column chromatography

Sotrapiop m (Izso Ips.) (5 µg"; gradient elution, DHMIDHM/EUN 9: 1) 1:0 -» 01) and obtained the desired compound in the form of a yellow foamy substance (102 mg, 0.165 mmol, 97 95). TOP: Thu-1,294; RH-MS: t/ 617.4 MANI.

Example 144: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-transo-cyclohexylmethyl) )|-amino)-pyridazin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

Ge) me r v

M az T (c) o t sy m v

The desired compound (13 mg, 0.019 mmol, 11 95) was obtained as a yellowish foam from intermediate 75.6 (61 mg, 0.175 mmol) and intermediate 144.1 (77 mg, 0.192 mmol) analogously to the preparation in example 130. HPLC: Oinea- 0.93 min.; LC-MS: t/: 661.5

IM-AANI".

Intermediate 144 1: 4-(4-(6b-Bromopyridazin-3-yl)-methylamino|-methyl)-trans-cyclohexyl)-1-methylpiperazin-2-one.

Zo

M Vg r battles i

To a solution of intermediate 144.2 (335 mg, 0.628 mmol) in dioxane (6.28 mL) at RT was added 4M NCI (dioxane) (7.84 mL, 31.4 mmol). The reaction mixture was stirred at RT for 0.5 h. The solution was concentrated and the residue was dissolved in MeonH (6.28 mL) at 0 °C, triethylamine (1.31 mL, 9.41 mmol) was added and the mixture was stirred for 50 min at

CT. The reaction mixture was extracted with EAs (2x) and 1TM aqueous solution of MansSoz (1x). The organic phases were washed with brine and dried over NaCl, filtered and evaporated to dryness. Purification of the residue by column chromatography with a normal phase eluting with a mixture of DCM - Meon (10:1) provided the desired compound in the form of beige crystals (230 mg, 0.575 mmol, 92 95). TOP: Oine-0.54 min.; LC-MS: t/27 396/398 MI"; "H NMR (400 MHz, DMSO-av): b 0.90-1.02 (t, 2H), 1.07 -1.17 (t, 2H ), 1.65 (t, ЗН), 1.768 (t, 2Н), 2.23 (t, 1Н), 2.66 (t, 2Н), 2.77 (5, ЗН), 3.03 (t , 5H), 3.17 (t, 2H), 3.36 (t, 2H), 7.04 (a, 1), 7.49 (a, tn).

Intermediate 144.2: 4-(4-((6-Bromopyridazin-3-yl-methylamino|-methyl)-trans-cyclohexyl)-(2-(tert-butoxycarbonylmethylamino)-ethyl|-amino)-acetic acid methyl ester.

M Vg 1 o zim p; level (c)

The desired intermediate (342 mg, 0.641 mmol, 96 95) was obtained as a beige oil from intermediate 144.3 (250 mg, 0.667 mmol) analogously to the preparation of intermediate 130.2. TOP: Riva-0.96 min.; RH-MS: t/72 528/530 |MI".

Intermediate 144.3: (4-(6-Bromopyridazin-3-yl)-methylamino|-methyl)-trans-cyclohexylamino)-acetic acid methyl ester.

M Vg 1 g yar rya (c) var re;

The desired intermediate (500 mg, 1.33 mmol, 50 95) was obtained as beige crystals from intermediate 144.4 (800 mg, 2.65 mmol) analogously to the preparation of intermediate 130.3. TOP: Oinei-0.57 min.; RH-MS: t/2 371/373 |MI".

Intermediate 144.4: (Trans-4-aminocyclohexylmethyl)-(6-bromopyridazin-3-yl)-methylamine.

M Vg 1 ke sho nm

The desired intermediate (800 mg, 2.65 mmol, 96 95) was obtained as a beige foam from intermediate 144.5 (1.15 g, 2.76 mmol) analogously to the preparation of intermediate 130.4. TOP: Rinei-0.52 min.; RH-MS: t/2 299/301 (MI.

Intermediate 144.5: Tert-butyl ether (4-(6-bromopyridazin-3-yl)-methylamino|-

Zo methyl)-trans-cyclohexyl)-carbamic acid.

M Vg.

A, M

The desired intermediate (1.208 g, 2.90 mmol, 40 95) was obtained as yellowish crystals from intermediate 144.6 (2.80 g, 7.27 mmol) similarly to the preparation of intermediate 139.3. TOP: Oine-1.10 min.; RH-MS: t/2 399/401 | MI".

Intermediate 144.6: (4-(6b-Bromopyridazin-3-ylamino)-methyl|-trans-cyclohexyl)-carbamic acid tert-butyl ether.

M Vg

J

AND

HELL

(c) M

N

The desired intermediate (2.0 g, 5.19 mmol, 3295) was obtained as a white crystalline substance from trans-(4-formylcyclohexyl)-carbamic acid tert-butyl ether (3.63 g, 15.97 mmol) and b -bromopyridazine-3-ylamine (2.58 g, 14.37 mmol) similarly to the preparation of intermediate 139.4. TOP: Rinea-1.00 min.; RH-MS: t/7 385/387 (MI.

Example 145: 2-(4-((5-(5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |-pyrazin-2-yl-"methylamino)-methyl|-trans-cyclohexylamino)-M-methylacetamide. o behind the seam

AGA n

M more 6) SI

The desired compound (115 mg, 0.154 mmol, 85 95) was obtained as an orange foamy substance from the compound of example 139 (116 mg, 0.181 mmol) similarly to the preparation of intermediate 132.2. TOP: Rivea-0.93 min.; RH-MS: t/: 635.5 MANI.

Example 146: (5)-1--4-Chlorophenyl)-2-(5-14-(3-ethyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-methylamino)-pyridin-2-yl) -7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinoline-

Z-he (o

WITH

WITH

(c) (c)

M. v. H

M M: o

SI

A mixture of the compound of example 141 (63 mg, 0.097 mmol) and formaldehyde (0.074 ml, 37% solution, 10 equiv., 0.612 mmol) in EUN (3 ml) was heated for 48 h. at 60 "C. The mixture was concentrated to dryness and the residue was purified using Sotri-Riabp column chromatography

Sotrapiop "m (Izso Ips.) (BIO; gradient elution, DHMIDHM/Meon 9: 11) 1:0 -» 171) and obtained the desired compound in the form of a yellow solid (64 mg, 0.097 mmol, 100 95), TOP: Chve-1,132; RH-MS: t/2 660.3 (MANI.

From Example 147: (5)-1-(4-Chlorophenyl)-2-16-((3-hydroxycyclobutylmethyl)-methylamino|-pyridin-3-yl-7-isopropoxy-b-methoxy-1,4-dihydro- 2H-isoquinolin-3-one

M. S

SI

The desired compound (4 mg, 0.007 mmol, 7 90) was obtained as a yellow solid from intermediate 147.2 (65 mg, 0.104 mmol) and intermediate 75.6 (36 mg, 0.104 mmol) similarly to the preparation in example 75. HPLC: UNve- 0.989; RH-MS: t/2 536.4 MANI.

Intermediate 147.2: 3-((5-Hydropyridin-2-yl)-methylamino|-methyl)-cyclobutyl ether of 4-nitrobenzoic acid.

MM » ma o

To a solution of intermediate 147.3 (311 mg, 0.590 mmol) in 3-ethylpentan-3-ol (3 mL) was added 2-bromo-5-iodopyridine (184 mg, 0.649 mmol) and EM (0.247 mL, 1.769 mmol). The yellow suspension was irradiated in a microwave oven at 150 "C for 8 hours. After cooling, the mixture was poured into E(OAc) and water. After the separation of the phases, the aqueous phase was extracted two more times with the help of EN. The combined organic extracts were washed with HgO, saturated saline , dried over Ma»5O:, filtered and evaporated to dryness. The obtained crude substance was purified by Sotri-Riavp column chromatography

Sotrapiop m (Izso Ips.) (BIO; gradient elution, DXM/LDHM/ESN 9:11 1:0 -» 0:1)) and obtained the desired compound (66 mg, 0.104 mmol, 17 95), HPLC: Thu-1,454; RH-MS: t/2 468.2 MANI.

Intermediate 147.3: 3-Methylaminomethylcyclobutyl ether of 4-nitrobenzoic acid. o MN s nku (c)

EM (1.321 mL, 9.48 mmol) was added to a solution of intermediate 147.4 (1.811 g, 6.32 mmol) in a mixture of DXM (50 mL) and Meon (5 mL) at RT. ASON (1.266 ml, 22.11 mmol), formaldehyde (37 95 in water, 0.941 ml, 12.64 mmol) and

Mavn(ogAs)z (2.82 g, 12.64 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with DCM and washed with a 2M aqueous solution of MagSO3 (2x). Organic phase

Zo was dried over Magn5O.:, filtered and evaporated to dryness. The obtained crude substance was purified using column chromatography Sotbri-Riazpy Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in gradient mode, DHMIDHM/EUN/aqueous solution of MNZ 90:9: 1) 1:0 -" 0:1)) and obtained the desired compound (311 mg, 0.590 mmol, 9 95) as a light yellow oil, HPLC:

Rve0.683; RH-MS: t/ 265.2 (MANI.

Intermediate 147.4: NCI salt of 3-aminomethylcyclobutyl ether of 4-nitrobenzoic acid. c) gru, su o

WHAT c)

To a solution of intermediate 147.5 (5.15 g, 11.76 mmol) in ESO (150 ml) was added a solution

NOSI IM in ESO, 47 ml, 47 mmol). The reaction mixture was stirred at RT for 24 h. The precipitate was collected by filtration and the precipitate washed with ESO, dried in vacuo to give the desired intermediate as a colorless solid (2.906 g, 10.14 mmol, 86 95), HPLC: Chive-0.885; RH-MS: t/z 251.2 |MI".

Intermediate 147.5: 3-(tert-butoxycarbonylaminomethyl)-cyclobutyl ether of 4-nitrobenzoic acid.

I go un poshko; tu l (in)

To an ice-cooled solution of tert-butyl ether (3-hydroxycyclobutylmethyl)-carbamic acid (6.98 g, 34.7 mmol), 4-nitrobenzoic acid (11.59 g, 69.4 mmol) and triphenylphosphine (18.19 g , 694 mmol) in IF SOBI l) a solution of diisopropylazodicarboxylate (14.76 g, 69.4 mmol) in THF (10 ml) was added. After removing the ice bath, the mixture was stirred at RT for 15 h. The mixture was concentrated to dryness and the oily residue was purified by column chromatography with a normal phase (elution with DCM) to give the desired intermediate as a yellow solid (9.89 g, 22.58 mmol, 6595), HPLC: Hve-1.354; LC-MS: t/2: 368.3

IM-AMNA".

Example 148: (5)-1--4-Chlorophenyl)-7-isopropoxy-2-(5-1X4-(3-isopropyl-4-oxoimidazolidin-1-yl-trans-cyclohexylmethyl|-methylamino)-pyridine-2 -yl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (at 8

With a braid, . | Ma im: o p

The desired compound (68 mg, 0.101 mmol, 89 95) was obtained as a yellow foamy substance from the compound of example 142 (75 mg, 0.113 mmol) similarly to the preparation in example 146. HPLC:

Rves-1,165; RH-MS: t/2,674.3 MANI".

Example 149: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)-transo-cyclohexylmethyl) |-amino)-pyrazin-2-yl)-1,4-dihydro-2H-isoquinoline-3-one. c) o ev du g B o A

M

- SI /

The desired compound (1.23 g, 1.88 mmol, 33 95) was obtained as whitish crystals from intermediate 75.6 (2.00 g, 5.73 mmol) and intermediate 149.1 (2.21 g, 5.73 mmol ) similar to the one obtained in example 130. HPLC: Oive-1.15 min.; RH-MS: t/2,647.6 MANI; "H NMR (600 MHz, DMSO-α) 0.93-1.12 (t, 4 H), 1.23 (aa, 9-16.35, 6.05 Hu, 6 H), 1.64 ( a, U-10.90 Gu, Z H),

Зо 1.81 (a, 9-10.90 Hz, 2 H), 2.18 (Ii, 9-10.29 Hz, 1 H), 2.71 (5, З H), 3.02 (5 , Z H), 3.11 (5, 2 H), 3.35-3.42 (t, 2 H), 3.60 (a, 9-19.38 Hz, 1 H), 3.73 ( 5, Z H), 3.81 (y, 9-19.38 Gu, 1 H), 4.04 (5.2 H), 4.52 (quintet, /-6.05 Hz, 1 H), 6.40 (5, 1 N), 6.87 (5, 1 N), 7.20 (5, 1 N), 7.34 (5, 4 N), 7.91 (5,1 N), 8.17 (5.1 N).

Intermediate 149.1: 1--4-(5-Bromopyrazin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-3-methylimidazolidin-4-one.

M Vg

XI o M in /

The desired intermediate (10.4 g, 26.9 mmol, 96 95) was obtained as beige crystals from intermediate 149.2 (10.5 g, 28.1 mmol) similarly to the preparation of intermediate 132.1. TOP: Oinei-0.85 min.; RH-MS: t/2 382/384 |MI".

Intermediate 149.2: 2-(A-(5-Bromopyrazin-2-yl)-methylamino|-methyl)-trans-cyclohexylamino)-N-methylacetamide.

M Vg

H oh

MN

/

The desired intermediate (10.7 g, 28.6 mmol, 9395) was obtained as a white crystalline substance from intermediate 139.1 (12.0 g, 30.7 mmol) similarly to the preparation of intermediate 132.2. TOP: Rinet-0.71 min.; RH-MS: t/2 370/372 (MG.

Example 150: Methyl ether 44-(((2-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-

3,4-dihydro-1H-isoquinolin-2-yl-1-pyrimidin-5-yl-"methylamino)-methyl-1-trans-cyclohexylamino)-acetic acid.

M M

4 ma : Ge) : su re v) i . c) SI

The desired compound (68 mg, 0.104 mmol, 30 95) was obtained as a yellowish foam from intermediate 75.6 (120 mg, 0.344 mmol) and intermediate 150.1 (142 mg, 0.378 mmol) similarly to the preparation in example 130. HPLC: Oine- 0.93 min.; RH-MS: t/2 636.4 (M--NI".

Intermediate 150.1: (4-((2-Bromopyrimidin-5-yl-methylamino|-methyl)-trans-cyclohexylamino)-acetic acid methyl ester.

M Vg g l xx and M

AL TV c)

The desired intermediate (540 mg, 1.44 mmol, 54 95) was obtained as a white

From the crystalline substance of intermediate 150.2 (830 mg, 2.64 mmol) analogously to the preparation of intermediate 130.3. TOP: Rinei-0.55 min.; RH-MS: t/2 371/373 (MI.

Intermediate 150.2: (Trans-4-aminocyclohexylmethyl)-(2-bromopyrimidin-5-yl)-methylamine.

M Vg g / y f

ON

The desired intermediate (830 mg, 2.64 mmol, 97 95) was obtained as a white foam from intermediate 150.3 (1.10 g, 2.73 mmol) analogously to the preparation of intermediate 130.4. TOP: Riva-0.54 min.; RH-MS: t/2 299/301 |(MI".

Intermediate 150.3: (4-(2-Bromopyrimidin-5-yl)γ-methylamino|methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether.

M Vg u o g i i

UNTIL,

N

The desired intermediate (820 mg, 2.03 mmol, 81 95) was obtained as yellowish crystals from intermediate 150.4 (1.0 g, 2.52 mmol) analogously to the preparation of intermediate 139.3. TOP: Oine-1.14 min.; RH-MS: t/2 399/401 | MI".

Intermediate 150.4: 14-(2-Bromopyrimidine-5-ylamino)-methyl|-trans-cyclohexyl)-carbamic acid tert-butyl ether.

M Vg and lne HU YM

AD o

The desired intermediate (2.71 g, 6.802 mmol, 4995) was obtained as a white crystalline substance from trans-(4-formylcyclohexyl)-carbamic acid tert-butyl ether (3.19 g, 14.03 mmol) and 2-bromopyrimidine -5-ylamine (2.20 g, 12.63 mmol) similarly to the preparation of intermediate 139.4. TOP: Rinea-1.08 min.; RH-MS: t/7 385/387 (MI.

Example 151: 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-(2,2,2-trifluoroethoxy)-1,4-dihydro-2H-isoquinolin-3-one. oh oh gu Phi (c)

M --

what

To a solution of intermediate 26.3 (100 mg, 0.236 mmol) and DMF (2.0 mL) was added toluene-4-sulfonic acid 2,2,2-trifluoroethyl ether (72.1 mg, 0.284 mmol) and potassium carbonate (65, 4 mg, 0.473 mmol). The mixture was stirred for 15 minutes at 140 °C. Reaction

The mixture was extracted with DCM (2x) and 1M aqueous solution of Mansoz (1x). The organic phases were dried over magnesium sulfate, filtered and evaporated to dryness. Purification of the residue by column chromatography with a normal phase, eluting with a mixture of EACs - heptane provided the desired compound in the form of a beige foam (42 mg, 0.083 mmol, 35 95). TOP: Uve-6.02 min.; RH-MS: t/z: 505.4 MANI.

Example 152: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(5--Imethyl-(4-«(4-methyl-3-oxo-piperazin-1-yl) -trans-cyclohexylmethyl|-amino)-pyrimidin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one.

M M she Y

AJ Z Z o ma in r SI

The desired compound (7.0 mg, 0.010 mmol, 4.5 95) was obtained as an orange foam from intermediate 75.6 (80 mg, 0.229 mmol) and intermediate 152.1 (90 mg, 0.252 mmol) similarly to the preparation in example 130. TOP: Gray-0.91 min.; LC-MS: t/: 661.5

IM-ANI".

Intermediate 152.1: 4-(4-(2-Chloropyrimidin-5-yl)-methylamino|-methyl)-trans-cyclohexyl)-1-methylpiperazin-2-one.

M SI in battles and

The desired intermediate (99 mg, 0.278 mmol, 85 95) was obtained as yellowish crystals from intermediate 152.2 (175 mg, 0.328 mmol) analogously to the preparation of intermediate 144.1. TOP: Rivea-0.54 min.; RH-MS: t/: 352.3 MANI.

Intermediate 152.2: (4-((2-Bromopyrimidin-5-yl-methylamino|-methyl)-trans-cyclohexyl)-(2-(tert-butoxycarbonylmethylamino)-ethyl|-amino)-acetic acid methyl ester.

M VG uv o r. 2; sor and

The desired intermediate (180 mg, 0.337 mmol, 84 95) was obtained as a beige oil from intermediate 150.1 (150 mg, 0.40 mmol) analogously to the preparation of intermediate 130.2. TOP: Riva-1.01 min.; RH-MS: t/72 528/530 |MI".

Example 153: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)-transo- cyclohexylmethyl|-amino)-pyridazin-3-yl)-1,4-dihydro-2H-isoquinoline-

Z-he 6) Fr

M | І 6) su is Zh

M I SI /

The desired compound (2.0 mg, 0.010 mmol, 1.7 90) was obtained as a yellowish foam from intermediate 75.6 (60 mg, 0.172 mmol) and intermediate 153.1 (77 mg, 0.189 mmol) similarly to the preparation in example 130. TOP: Oive-1.06 min.; LC-MS: t/: 647.2

Koo) IM-ANI".

Intermediate 153.1: 1-(4-K(6-Bromopyridazin-3-yl)-methylamino|-methyl)-trans-cyclohexyl)-3-methylimidazolidin-4-one.

M Vg

HU g and HU o M

AND

/

The desired intermediate (192 mg, 0.497 mmol, 94 95) was obtained as a white crystalline substance from intermediate 153.2 (195 mg, 0.527 mmol) analogously to the preparation of intermediate 132.1. TOP: Rine-0.65 min.; RH-MS: t/2 382/384 | MI.

Intermediate 153.2: 2-(A-(6-Bromopyridazin-3-yl)-methylamino|-methyl)-trans-cyclohexylamino)-N-methylacetamide.

M Vg o-0

MN

/

The desired intermediate (200 mg, 0.513 mmol, 96 95) was obtained as a beige foam from intermediate 144.3 (200 mg, 0.533 mmol) analogously to the preparation of intermediate 132.2. TOP: Rinei-0.49 min.; RH-MS: t/2 370/372 (MI.

Example 154: 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-(2-methoxy-ethoxy)-1,4-dihydro-2H-isoquinolin-3-one. (c) Fr.

M

YOU are still sitting

To a solution of intermediate 26.3 (60 mg, 0.137 mmol) and DMF (0.27 mL) was added 2-bromomethyl methyl ether (20.9 mg, 0.150 mmol) and potassium carbonate (28.4 mg, 0.205 mmol).

The mixture was stirred for 90 minutes at 100 "C. The reaction mixture was extracted with EOAc (2x) and a mixture of water - saline solution 9:1 (1x). The organic phases were washed with saline solution and dried over Mag25O0.5, filtered and evaporated to dryness. Purification of the residue using column chromatography with a normal phase when eluting with a mixture

Es-heptane (1:4) provided the desired compound in the form of a beige foamy substance (20 mg, 0.041 mmol, 30 95). TOP: Oive-1.13 min.; RH-MS: t/z 481.4 MANI".

Example 155: 1--4-Chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-|(5)-1-(tetrahydrofuran-2-yl)-methoxy|-1,4-dihydro-2H -isoquinolin-3-one. (c) Fr

M du and more about

SI

The desired compound (23 mg, 0.045 mmol, 39 95) was obtained as a beige foam from intermediate 26.3 (50 mg, 0.114 mmol) and (5)-terahydrofurfuryl alcohol (17.8 mg,

0.171 mmol) similar to that obtained in example 156. HPLC: Oive-1.18 min.; LC-MS: t/: 507.1

IM-ANI..

Example 156: 1--4-Chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-|(H)-1-(tetrahydrofuran-2-yl)methoxy-1,4-dihydro-2H-isoquinoline -3-one (c) Fr

M More

FI and you in Fr

SI

To a solution of intermediate product 26.3 (50 mg, 0.114 mmol) in THF (0.57 ml) at 0"С, (K)-terahydrofurfuryl alcohol (17.8 mg, 0.171 mmol), triphenylphosphine (48.8 mg, 0.182 mmol) and disopropylazodicarboxylate (34.3 mg, 0.160 mmol).

The mixture was stirred for 22 hours. at CT. The reaction mixture was extracted using

ECOds (2x) and 1M aqueous solution of ManNsoz (1x). The organic phases were washed with saline and dried over Mag50O5, filtered and evaporated to dryness. Purification of the residue by means of column chromatography with a normal phase, eluting with a mixture of DCM - EAs (2:1 - 1:71) provided the desired compound in the form of a beige foamy substance (21 mg, 0.041 mmol, 36 95). TOP: Rivet-1.18 min.; RH-MS: t/: 507.3 MANI.

Example 157: 1--4-Chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-((A)-2-methoxy-propoxy)-1,4-dihydro-2H-isoquinolin-3-one . 6) о в в и од и b. si

(5)-(-)-2-Methoxypropanol (12.8 mg, 0.142 mmol), di-tert - butylazodicarboxylate (32.7 mg, 0.142 mmol) and triphenylphosphine (34.7 mg, 0.132 mmol).

The mixture was stirred for 18 hours. at CT. The reaction mixture was then immediately purified by preparative reverse-phase HPLC (Ulaieg5 system) and the desired compound was obtained as a beige foam (10 mg, 0.020 mmol, 21 95). TOP: Thu-5,340; RH-

MS: t/; 495.3 MANI".

Example 158: 1--4-Chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-(-2-methoxy-1-methylethoxy))-1,4-dihydro-2H-isoquinolin-3-one . (in o.

M va y Av si

The desired compound (38 mg, 0.077 mmol, 65 95) was obtained as a beige foam from intermediate 26.3 (50 mg, 0.118 mmol) and 1-methoxy-2-propanol similarly to the preparation in example 157. HPLC: Jave-5,11 ; RH-MS: t/z 495.2 MANI".

Example 163: 1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4--methyl-(4-(3-oxopiperazin-1-yl)-

trans-cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

These are

M

(0) Fr

OA and o

SU A o

SI

The desired compound (25 mg, 0.039 mmol, 42 95) was obtained as a white solid from intermediate 163.1 (74 mg, 0.093 mmol) analogously to the preparation in Example 79. HPLC:

Sive-8.718 min.; RH-MS: t/2 645.2 MANI.

Intermediate 163.1: Methyl ether ((2-tert-butoxycarbonylaminoethyl)-14-((14-(11-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1 H -isoquinolin-2-yl|-phenyl)-methylamino)-methyl|-trano-cyclohexyl)-amino)-acetic acid. shye v i min 9) at 3 AJ var "B Zh g

SI

The desired intermediate (110 mg, 0.148 mmol, 24.3 95) was obtained as an off-white solid from intermediate 138.1 (200 mg, 0.578 mmol) and intermediate 106.2 (388 mg, 0.694 mmol) analogously to the preparation of example 75. TOP: Minea-2.00 min.; RH-MS: t/2 777.2 MANI.

Example 164: (5)-2-I4-(3-Amino-1H-pyrazol-4-yl)phenyl|-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one. (c) o " (c) nm H z Zh

E

M

M nN

SI

A mixture of intermediate 164.1 (193 mg, 0.318 mmol), hydrazine hydrate (0.08 mL, 1.59 mmol), and acetic acid (0.09 mL, 1.59 mmol) in toluene (1.0 mL) was refluxed with reflux for 16 hours. The reaction mixture was poured into ice-cooled water while stirring. The aqueous layer was extracted twice with EOAc, the combined organic layers were washed with water, dried (Ma»5O4), filtered and concentrated. The residue was purified by column chromatography to give the desired compound (23 mg, 0.044 mmol, 14 95) as a white solid. TOP: Sive-6,802 min.; RH-MS: t/2 503.4 MANI".

Zo Intermediate 164.1: (2)-2-14-(5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |I-phenyl)-Z-dimethylaminoacrylonitrile.

M

M: ? sho OSA tm si

A mixture of intermediate 164.2 (150 mg, 0.2 mmol) and dimethylformamide dimethyl acetal (0.09 mL, 0.65 mmol) in toluene (0.5 mL) was refluxed for 4 h. The reaction mixture was concentrated in vacuo to give the desired intermediate (198 mg, 0.32 mmol, 100 95). It was used in the next stage without further purification. TOP: SFive-7.413 min.; RH-MS: t/2 516.4 MANI.

Intermediate 164.2: 14-((5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|I-phenyl) -acetonitrile.

M

M I?

SI

The desired intermediate (147 mg, 0.32 mmol, 44.1 95) was obtained as a white solid from intermediate 75.6 (250 mg, 0.72 mmol) and (4-iodophenyl)-acetonitrile (193 mg, 0, 79 mmol) similar to that obtained in Example 75. HPLC: Sieve-9.082 min.; RH-MS: t/ 461.1

IM-ANI".

Intermediate 165.1: (2)-2-14-((5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- yl|-phenyl-3-dimethylamino-but-2-ennitrile.

M

M: ? tm | with

A mixture of intermediate 164.2 (150 mg, 0.32 mmol) and N,M-dimethylacetal of dimethylacetamide (0.10 mL, 0.65 mmol) in toluene (0.5 mL) was stirred at reflux for 4 h. . The reaction mixture was concentrated in vacuo to give the desired intermediate (187 mg, 0.32 mmol, 98 95). It was used in the next stage without additional purification. TOP: SFive-7.614 min.; RH-MS: t/2 530.5 MANI.

Intermediate 166.1: Tert-butyl ether 4-14-(1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl )-3,5-dimethylpyrazole-1-carboxylic acid.

(c) (c) in (c) and F A

E

M zo 0-th si (c)

The desired intermediate (297 mg, 0.48 mmol, 38 90) was obtained as an orange solid from intermediate 166.2 (700 mg, 1.27 mmol) and tert-butyl ether

C,5-dimethyl-4-(4,4,5,5-tetramethyl-(1,3,2|dioxaborolan-2-yl)-pyrazole-1-carboxylic acid (453 mg, 1.40 mmol) similarly to the preparation in example 36. "H NMR (400 MHz, DMSO-α) 1.21 (as, 6 H), 1.55 (5.9 H), 2.11 (5, C H), 2.36 (5 , Z H), 3.62 (a, 9U-19.92 Hz, 1 H), 3.71 (c, Z H), 3.84 (a, 9-19.92 Hz, 1 H), 4 ,40-4.49 (t, 1 H), 6.16 (5, 1 H), 6.85 (5, 1 H), 7.14 (5.1 H), 7.26 (ad, 4 N), 7.38 (5.4 N).

Intermediate 166.2: 1-(4-Chlorophenyl)-2-(4-iodophenyl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (o) (o) in fishing

SI

The desired intermediate (1.97 g, 3.52 mmol, 56 95) was obtained as a white solid from intermediate 34.1 (2.15 g, 6.29 mmol) and intermediate 96.1 (1.53 g, 6, 29 mmol) similarly to the preparation in example 1. HPLC: Chvne-5.925 min.; RH-MS: t/7 548.2

IM-ANI".

Example 167: 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-7-(1-hydroxycyclopropyl-methoxy))-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (c) Fr. 1

That's it

The desired compound (31 mg, 0.063 mmol, 66 95) was obtained as a beige foam from intermediate 26.3 (40 mg, 0.095 mmol) and (|1-(tetrahydropyran-2-yloxy)-cyclopropyl|-methanol (24.4 mg, 0.142 mmol) similarly to the preparation in example 157. HPLC: Chve-4.795;

MS: t/; 493.4 MANI".

Example 168: 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-(3-methoxy-propoxy)-1,4-dihydro-2H-isoquinolin-3-one.

(c) Fr

M

Dan you (8) p

The desired compound (15 mg, 0.031 mmol, 32 95) was obtained as a beige foam from intermediate 26.3 (40 mg, 0.095 mmol) and 1-bromo-3-methoxypropane (15.9 mg, 0.104 mmol) similarly to the preparation in Example 154. TOP: Yave-5,417; RH-MS: t/l 495.4 MANI".

Example 169: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-14-(1-(2-oxopiperazin-1-yl)-ethyl|-phenyl)-1,4- dihydro-2H-isoquinolin-3-one. lol

M

Nm t (c) o

SI

The desired compound (10 mg, 0.018 mmol, 34 95) was obtained as a colorless solid from intermediate 169.1 (50 mg, 0.0.054 mmol) similarly to the preparation in example 77.3. TOP: Thu-0.928; RH-MS: t/ 550.0 |MANG.

Intermediate 169.1: Tert-butyl ether 4-(1-14-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline) -2-yl|-phenyl)-ethyl)-3-oxopiperazine-1-carboxylic acid.

Kk o i va yen M. o o o 8 rak o si

The desired intermediate (50 mg, 0.054 mmol, 31 9o) was obtained as a brown solid from intermediate 169.2 (90 mg, 0.209 mmol) and intermediate 75.6 (60 mg, 0.174 mmol) analogously to the preparation of Example 75. HPLC: Chn. -1.352.

Intermediate 169.2: 4-(11-(4-iodophenyl)-ethyl|-33-oxopiperazine-1-carboxylic acid tert-butyl ester.

She

M. YO same (c)

To a solution of Bos-3-oxopiperazine (67 mg, 0.328 mmol) in DMF (3 ml) was added Mann (60 95 in mineral oil, 13 mg, 0.328 mmol). After cooling to 0 "С, 1-(1-bromomethyl)-

Zo 4-iodobenzene (100 mg, 0.273 mmol). The ice bath was removed and the mixture was stirred at RT for 2 h. and then subjected to distribution between EtOAc and MNACI solution. After separation, the aqueous phase was extracted two more times with DCM and the combined organic extracts were washed with H2O, saturated saline, dried over Mag50Ox, filtered and evaporated to dryness. The obtained crude substance was purified using Sotbri-Riazpy column chromatography! Sotrapiop "M (Izso Ips.) (ZiOg; gradient elution, DCM/E(UASI 1:0 -» 0:1)) and obtained the desired intermediate product (90 mg, 0.188 mmol, 68 95) in the form of a colorless solid substances. HPLC: Nine-1,276.

Example 170: 1-(4-Chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-(oxetan-2-ylmethoxy)-1,4-dihydro-2H-isoquinolin-3-one. 9) no

M wai code a o

SI

The desired compound (10 mg, 0.02 mmol, 28 95) was obtained as a beige foam from intermediate 26.3 (30 mg, 0.071 mmol) and oxetan-2-ylmethanol (7.5 mg, 0.085 mmol) similarly to the preparation in the example 157. TOP: "ive-4.968; RH-MS: t/ 493.4 MANI.

Example 171: 1-(4-Chlorophenyl)-7-(2,2-difluoroethoxy)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (in for

M. Shchi v

Well, that's it

E sh

To a solution of intermediate 26.3 (30 mg, 0.071 mmol) and DMF (1.0 mL) was added 1,1-difluoro-2-iodoethane (20.4 mg, 0.106 mmol) and potassium carbonate (29.4 mg, 0.213 mmol ). The mixture was stirred for 18 hours at 50 "C. The reaction mixture was extracted with EOAc (dx) and a mixture of water - saline solution 9:11 (ex). The organic phases were washed with saline solution and dried over Ma»5O»4, filtered and evaporated to dryness The residue was purified by reverse-phase preparative HPLC (Ulaieg5 system) and the desired compound was obtained as a beige foamy substance (12 mg, 0.024 mmol, 34 95). HPLC: Chve-5.59; LC-

MS: t/; 487.4 MANI".

Example 172: Methyl ether 44-(15-(1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyrazin-2- yl-methylamino)-methyl|-trans-cyclohexylamino)-acetic acid. (in z

M M Shchi - KI - Y ny y m A shchi

N

Go) SI

Coo)

The desired compound (73 mg, 0.101 mmol, 31 95) was obtained as an orange foam from intermediate 138.1 (115 mg, 0.329 mmol) and intermediate 139.1 (142 mg, 0.362 mmol) analogously to the preparation in example 130. HPLC: Oive- 1.00 min.; RH-MS: t/7 636.5 (M--NI".

Example 173: 2-14-(15-1-(4-Chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyrazine-2- yl-"methylamino)-methyl|-trans-cyclohexylamino)-N-methylacetamide.

(in o.

M M chvar role of M Z A

Ch

That

N

(in the village

The desired compound (37 mg, 0.058 mmol, 59 95) was obtained in the form of a yellow foamy substance from the compound of example 172 (70 mg, 0.097 mmol) similarly to the preparation in example 132.2. TOP:

Orve-0.97 min.; RH-MS: p/z: 635.6 (M'ANI".

Example 174: 1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-Imethyl-I(4-(33-methyl-4-oxoimidazolidin-1-yl)-transo-cyclohexylmethyl|-amino )-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. (in o

М M ШЧИ з І н М м ра о це и /

The desired compound (29 mg, 0.044 mmol, 79 95) was obtained as a yellow foamy substance from the compound of example 173 (36 mg, 0.056 mmol) similarly to the preparation in example 132.1. TOP:

Oive--0.97 min.; RH-MS: t/: 635.6 (MANI.

Example 175: 1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-transo-cyclohexylmethyl|-amino) )-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one (in o.

M Shchi uv Y oon M sia A o in r ch

The desired compound (29 mg, 0.044 mmol, 79 95) was obtained as a yellow foam from intermediate 138.1 (35 mg, 0.100 mmol) and intermediate 130.1 (50 mg, 0.100 mmol) similarly to the preparation in example 130. HPLC: bive- 0.97 min.; RH-MS: t/: 660.7 |M'-NI".

Intermediate 176.1: Methyl ether (2-(tert-butoxycarbonylmethylamino)-ethyl|-(4-

IR4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-2-fluorophenyl)-methylamino) -methyl|-trans-cyclohexyl)-amino)-acetic acid.

their I E M

VATA oho - : ra lo SI 6)

The desired intermediate (48 mg, 0.059 mmol, 63 95) was obtained as a white solid from intermediate 176.2 (68 mg, 0.094 mmol) and methyl-(2-oxoethyl)-carbamic acid tert-butyl ether (21.1 mg , 0.12 mmol) similarly to the preparation of intermediate product 79.2. TOP: Sive-7.877 min.; RH-MS: t/:2 809.8 |M-ANI".

Intermediate 176.2: Methyl ether 44-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- yl|-2-fluorophenyl)-methylamino)-methyl|-trans-cyclohexylamino)-acetic acid.

E. M. medical doctor

NM or SI c)

The desired intermediate (361 mg, 0.52 mmol, 38.3 95) was obtained as a white solid from intermediate 75.6 (470 mg, 1.36 mmol) and intermediate 176.3 (721 mg, 1.49 mmol) similarly obtained in example 75. HPLC: binea-6.786 min.; PH-MS: t/; 652.5

IM-ANI..

Intermediate 176.3: (4-((2-fluoro-4-iodophenyl)-methylamino|-methyl)-trans-cyclohexylamino)-acetic acid methyl ester. howl

NM my father

The desired intermediate (3.06 g, 6.34 mmol, 70.9 95) was obtained as a white solid from intermediate 176.4 (3.6 g, 8.94 mmol) and methyl 2-bromoacetate (0.95 ml, 10.3 mmol) similarly to the preparation of intermediate product 79.1. TOP: Sine-b, 556 min.; RH-MS: t/: 435.3 |MANG.

Intermediate 176.4: (Trans-4-aminocyclohexylmethyl)-(2-fluoro-4-iodophenyl)-methylamine.

you l nm

The desired intermediate (3.62 g, 8.99 mmol, 94 95) was obtained as a white solid from intermediate 176.5 (4.9 g, 9.54 mmol) analogously to the preparation of intermediate 77.3. TOP: Gray-5.992 min.; RH-MS: t/2 362.8 |MAANI".

Intermediate 176.5: (4-(2-fluoro-4-iodophenyl)-methylamino|methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether. you

In DS here

N

The desired intermediate (4.9 g, 9.54 mmol, 91 95) was obtained as a white solid from intermediate 176.6 (4.7 g, 10.4 mmol) and 3795 of an aqueous formaldehyde solution (1.56 mL, 20 .9 mmol) similar to the preparation of intermediate product 77.1. TOP: bidet-8,720 min.; RH-MS: t/z 463.3 |MANI..

Intermediate 176.6: 14-(2-Fluoro-4-iodophenylamino)-methyl|-trans-cyclohexyl)-carbamic acid tert-butyl ether. you are nah

OO; io) M nN

The desired intermediate (4.8 g, 10.7 mmol, 97 95) was obtained as a white solid from trans-(4-formylcyclohexyl)-carbamic acid tert-butyl ether (3.0 g, 13.2 mmol) and 2-fluoro-4-iodaniline (2.66 g, 11 mmol) similarly to the preparation of intermediate 75.7. TOP: Sina -8.586 min.; RH-MS: t/: 393.2 (M-VOS-NSOONG.

Intermediate 177.1: Methyl ether (2-(tert-butoxycarbonylmethylamino)-ethyl|-(4-

IR4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-fluorophenyl)-methylamino) -methyl|-trans-cyclohexyl)-amino)-acetic acid. is (c) o va S ! (c) 05.0 K;

M ra mo i s (c)

The desired intermediate (48 mg, 0.059 mmol, 63.2 95) was obtained as a white solid from intermediate 177.2 (68 mg, 0.094 mmol) and methyl-(2-oxoethyl)-carbamic acid tert-butyl ether (21 .1 mg, 0.12 mmol) similarly to the preparation of intermediate product 79.2. TOP: Sive-7.854 min.; RH-MS: t/:2 809.8 |M-ANI".

Intermediate 177.2: Methyl ether 44-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- yl|-3-fluorophenyl)-methylamino)-methyl|-trans-cyclohexylamino)-acetic acid.

oops! (c) in tire 75

NM le SI (c)

The desired intermediate (70 mg, 0.097 mmol, 11.3 95) was obtained as a white solid from intermediate 75.6 (295 mg, 0.85 mmol) and intermediate 177.3 (364 mg, 0.94 mmol) analogously to the preparation in example 75. TOP: Sivne-6b, 997 min.; RH-MS: t/72 652.7

IM-ANI".

Intermediate 177.3: (4-(4-Bromo-3-fluorophenyl)-methylamino|-methyl)-trans-cyclohexylamino)-acetic acid methyl ester.

E s l

NM r o

The desired intermediate (360 mg, 0.93 mmol, 21.6 95) was obtained as a white solid from intermediate 177.4 (1.36 g, 4.31 mmol) and methyl 2-bromoacetate (0.42 mL, 4.53 mmol) similar to the preparation of intermediate product 79.1. TOP: Sineeb, 333 min.; RH-MS: t/2 387.3 (MANI.

Intermediate 177.4: (Trans-4-aminocyclohexylmethyl)-(4-bromo-3-fluorophenyl)-methylamine.

IS

With se nm

The desired intermediate (1.36 g, 4.31 mmol, 74.7 95) was obtained as a white solid from intermediate 177.5 (2.4 g, 5.78 mmol) analogously to the preparation of intermediate 77.3. TOP: Sive-6.245 min.; LC-MS: t/z2 317.2 (M-ANI".

Intermediate 177.5: (4-((4-bromo-3-fluorophenyl)-methylamino|methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether.

E sg

MAX on

N

The desired intermediate (2.42 g, 5.83 mmol, 75 95) was obtained as a white solid

From the substance of the intermediate product 177.6 (3.1 g, 7.72 mmol) and 3795 of an aqueous solution of formaldehyde (1.15 ml, 15.4 mmol) similarly to the preparation of the intermediate product 77.1. TOP: goes: 8.689 min.; RH-MS: t/ 417.3 MANI".

Intermediate 177.6: 34-(4-Bromo-3-fluorophenylamino)-methyl|-trans-cyclohexyl)-carbamic acid tert-butyl ether.

E s o l

Ov (in) M

N

The desired intermediate (3.1 g, 7.7 mmol, 77 90) was obtained as a white solid from trans-(4-formylcyclohexyl)-carbamic acid tert-butyl ether (2.73 g, 12.0 mmol) and 4-bromo-3-fluoroaniline (1.90 g, 10.0 mmol) similarly to the preparation of intermediate 75.7. TOP: Sive-8.221 min.; RH-MS: t/z: 401.3 MANI".

Example 178: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-14-((5)-1-(2-oxopiperazin-1-yl)-ethyl1-phenyl)-1 ,4-dihydro-2H-isoquinolin-3-one.

M not TU: o b Z sh

The desired compound (665 mg, 1.19 mmol, 85 95) was obtained as a yellow solid from intermediate 178.1 (910 mg, 1.40 mmol) similarly to the preparation in Example 51. HPLC:

ECHvee4,449 min.; RH-MS: t/ 549.2 MANI.

Intermediate 178.1: tert-butyl ether 4-((5)-1-14-((5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro- 1 H-isoquinolin-2-yl|-phenyl)-ethyl)-3-oxopiperazine-1-carboxylic acid. r o o ak She o ch ro

SI

The desired intermediate (910 mg, 1.4 mmol, 26 95) was obtained as a yellow solid from intermediate 75.6 (1.87 g, 5.41 mmol) and intermediate 178.2 (2.39 g, 5.57 mmol ) similar to that obtained in example 75. HPLC: Ninea-5.677 min.; RH-MS: t/2 648.2

IM-ANI..

Zo Intermediate 178.2: 4-((5)-1-(4-iodophenyl)-ethyl|-33-oxopiperazine-1-carboxylic acid tert-butyl ether. and aq a 0:

60 95 Man (0.32 g, 8.05 mmol) was added to a solution of intermediate 178.3 (3.58 g, 7.67 mmol) in THF (27.1 ml) at 0"С under an argon atmosphere. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with water at 0 "C and extracted with EOAc.

The organic phase was washed with a saturated aqueous solution of ManHsSOOz, dried (Mg5O), filtered and concentrated. The residue was purified by column chromatography to give the desired compound (3.29 g, 7.49 mmol, 98 95) as a beige solid.

TOP: Thu-5.516 min.; RH-MS: t/z 431.1 |IMANG.

Intermediate 178.3: (2-(2-Chloroacetyl)-((5)-1-(4-iodophenyl)-ethyl|amino)-ethyl)-carbamic acid tert-butyl ether. at

And in Art

Ge) I

To a solution of intermediate 178.4 (4.0 g, 10.25 mmol), EM (4.26 mL, 30.7 mmol) and

Chloroacetyl chloride (0.86 ml, 10.7 mmol) was added dropwise to DMAP (25 mg, 0.20 mmol) in DCM (27.1 ml) at 0 "С under an argon atmosphere. The reaction mixture was stirred for 5 h at

CT. The reaction was quenched with water at 0 "C and extracted with EtOAc. The organic phase was washed with a saturated aqueous solution of ManHsSoOz, dried (Mag25O4), filtered and concentrated. The residue was purified by column chromatography and the desired compound was obtained (3.59 g, 7.69 mmol , 75 95) in the form of a white solid substance.

Intermediate 178.4: 432-(5)-1-(4-iodophenyl)-ethylamino|-ethyl)-carbamic acid tert-butyl ether. »! shko

NM

A suspension of intermediate 178.5 (5.45 g, 22.0 mmol), tert-butyl ether (2-bromomethyl)-carbamic acid (6.43 g, 28.7 mmol), K2CO3 (6.1 g, 44.1 mmol) and KI (0.18 g, 1.1 mmol) in tert-ViOH (25 mL) was heated at 60 °C in an argon atmosphere for two nights.

The reaction mixture was allowed to cool and diluted with iso-PrOH. Mixture

Z was filtered and the precipitate was washed with iso-PrOH. The filtrate was evaporated and partitioned between EIOAc and a saturated aqueous solution of MansSoz. The aqueous layer was extracted twice with EOAc. The combined organic layers were washed with brine, dried over Md 5 O, filtered and evaporated to give a brown solid which was purified by column chromatography to give the title compound (4.0 g, 10.25 mmol, 46.5 95) in in the form of a white solid. TOP: UCHve-4,489 min.; LC-MS: t/;: 390.93

IM-ANI.. Y

Intermediate 178.5: (5)-1-(4-Modphenyl)-ethylamine. !

Intermediate 178.5 (13.7 g, 55.4 mmol, 76 95) was synthesized from (5)-1-phenylethylamine according to the methods described in the publication of Woigpa! oh Medisippa! Spetivigu, 2001, 44, pp. 21. VERH:

Thu-3.639 min.; LC-MS: t/z2 247.8 (MANI.

Example 179: (5)-1-(4-Chlorophenyl)-2-(4-1(5)-1-(4-(2-hydroxyethyl)-2-oxopiperazin-1-yl|-ethyl)-phenyl) -7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

С СО mm m t (in) 998) 5 (FI E

SI

To a solution of the compound of example 178 (30 mg, 0.055 mmol) in EN (0.8 ml) was successively added

EVM (18.97 μL, 0.137 mmol) and 2-bromoethanol (5.41 μL, 0.077 mmol). The mixture was irradiated at 105 °C for 12 h. After cooling, the mixture was evaporated to dryness. The residue was immediately purified using column chromatography Sotbri-Riazpy Sotrapiop "m (Ibvso Ips.) (5iOg2; elution in gradient mode, DHMIDHM/EUN/aqueous solution МНз 90 : 9:1) 1:0 -» 0:1)) and obtained the desired compound (17 mg, 0.029 mmol, 5395) in the form of a pale yellow foamy substance. TOP: Thu-0.936; RH-MS: t/: 592.5 |MANI..

Example 180: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-14-Y(H)-1-(2-oxopiperazin-1-yl)-ethyl|-phenyl)- 1,4-dihydro-2H-isoquinolin-3-one. moose

NMU M. o o o 8 r o o (Fu

The desired compound (75 mg, 0.138 mmol, 64 95) was obtained in the form of a pale yellow foamy substance similar to the preparation in example 178 using K-(--)-1-(4-bromophenyl)ethylamine as a starting material. TOP: Thu-0.922; RH-MS: t/ya 548.5 |MANI".

Example 181: (5)-1-(4-Chlorophenyl)-2-(4-(8)-1-I4-(2-hydroxyethyl)-2-oxopiperazin-1-yl|-ethyl)-phenyl)-7 -isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

With So

M m t (in)

MAX at 8

SI

The desired compound (25.5 mg, 0.043 mmol, 52.5 95) was obtained from the compound of example 180 as a yellow solid similar to that obtained in example 179. HPLC: Chve-0.932; RH-MS: t/2 592.5 |M-AANI".

Example 183: (5)-1-(4-Chlorophenyl)-2-(4-((3-hydroxy-3-hydroxymethylcyclobutyl-methyl)-methylamino|-phenyl)-7-isopropoxy-6-methoxy-1,4 -dihydro-2H-isoquinolin-3-one, but also DU and A 8 si

Zo

The desired compound (39 mg, 0.07 mmol, 16 95) was obtained as a pale yellow foam from intermediate 183.1 (200 mg, 0.434 mmol) and intermediate 75.6 (150 mg, 0.434 mmol) similarly to the preparation in example 75. TOP: Mine-1,098; PH-MS: t/; 565.5

IM-ANI"

Intermediate 183.1: 3-(4-Bromophenyl)-methylamino|-methyl)-1-hydroxymethylcyclobutanol. with

GO o" and he

Hg

To a solution of intermediate product 183.2 (561 mg, 1.785 mmol) in THF (15 mL) at CT, borane - methyl sulfide complex (0.802 mL, 8.03 mmol) was added dropwise. Then the mixture was heated at 45°C for 5 h. After cooling to RT, the suspension was diluted with THF and the reaction was stopped at 0°C with MeonH. The solvent was removed by evaporation and the residue was diluted with EN (5 mL) and 1M Mahon (10 mL) and refluxed for 2 h. After cooling to RT and filtration, the filtrate was concentrated and the residue partitioned between NgO and EIAs.

After separation, the aqueous phase was extracted twice more with EtOAc. The combined organic extracts were washed with saturated saline, dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified using Sotheby-Riazpy column chromatography. Sotrapiop "m (Izso Ips.) (BIO; elution in gradient mode,

ДХМ/ЛДХМ/ЕЮН/water solution МНз 90:9:1| 1:0 -» 0:1)) and obtained the desired intermediate product (467 mg, 1.558 mmol, 87 95) in the form of a cis/trans mixture of a pale beige solid,

TOP: Thu-0.854/0.871; RH-MS: t/: 300.2 MANI

Intermediate 183.2: (4-Bromophenyl)-methylamide of 3-hydroxy-3-hydroxymethyl-cyclobutanecarboxylic acid. 6) -

Kon s Y on

Hg

Intermediate product 183.3 (500 mg, 1.785 mmol) was added to a suspension of AO-Mix-AlIrpa (2.748 g, 1.963 mmol) in a mixture of IVOHN (10 ml) and HgO (10 ml) at 5"С in the form of a concentrated solution in IVOH. Cooling the bath was removed and the mixture was stirred at RT for 1 h, then filtered. The filtrate was concentrated in vacuo and the remaining aqueous phase was extracted four times with DCM. The combined organic extracts were washed with brine

The solution was dried over NaCl5O, filtered and evaporated to dryness to give the desired intermediate as an oil (586 mg, 1.865 mmol). TOP: Thu-0.797; RH-MS: t/2 3142

IM-ANI..

Intermediate 183.3: (4-Bromophenyl)-methylamide of 3-methylenecyclobutane-carboxylic acid.

Ba

Hg

Three drops of DMF and oxalyl chloride (1.433 mL, 16.37 mmol) were sequentially added to a solution of intermediate 183.4 (1.748 g, 15.59 mmol) in DCM (30 mL) at 0°C. The ice bath was removed and the mixture was stirred for 2 h at RT. Volatiles were evaporated, the pale yellow oil was dried in vacuo and then dissolved in DCM. To this solution was added a solution of 4-bromo-M-methylaniline (2.90 g, 15.59 mmol) at 0 °C. EIzM (6.48 ml, 46.8 mmol) and

DMAP (1.904 g, 15.59 mmol) in DCM (30 mL). After addition, the ice bath was removed and the mixture was stirred at RT for 1 h. The reaction was then stopped with NgO and Mansoz and partitioned between DCM and NgO. After separation, the aqueous phase was extracted two more times with DCM, and the combined organic extracts were washed with saturated saline, dried over magnesium sulfate, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpy Sotrapiop "m (Izso Ips.) (5 µg; elution in the gradient mode, DHMLDHM/EFN 9:11 1:0 -» 1:1)) and obtained the desired intermediate product (3 .36 g, 12.02 mmol, 77 95) as a pale yellow oil. HPLC: Chvne-1.232;

RH-MS: t/ 280.2 (MANI.

Intermediate 183.4: 3-Methylenecyclobutanecarboxylic acid.

Ba

C3-Methylenecyclobutanecarbonitrile (5 g, 53.7 mmol) was added to a solution of Mahon (15.33 g, 383 mmol) in H2O (51 mL). The two-phase mixture was refluxed for three hours.

After cooling to RT, the mixture was acidified by adding 32 95 NCI and saturated with Massi. The aqueous phase was extracted several times with DCM. The combined organic extracts were washed with saturated saline, dried over Mg5O", filtered and evaporated to dryness to give the desired intermediate (6.01 g, 53.6 mmol, 100 95) as an oil. TOP: Chva-0.673; RH-MS: pt/z 111.1 IM-NI.

Intermediate 184.1: 2-1A-((5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl )-5-methyl-3-oxohexanenitrile. (c) about ovi

M: ?

Эх чины (c) and s

60 95 Man in mineral oils (11 mg, 0.275 mmol). The resulting mixture was stirred at RT for 1 h, ASON was carefully added to stop the reaction, and the mixture was extracted with ASOBCl (2x). The combined

The organic fraction was dried over Mag50, filtered and evaporated to dryness. The resulting crude substance was purified by column chromatography to give the desired intermediate (120 mg, 0.22 mmol, 100 95). TOP: Blue-8.00 min.; PH-MS: t/; 545.43

IM-ANI..

Intermediate 185.1: Tert-butyl ether 4-15-(1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyridine -2-yl-3,5-dimethyl-pyrazole-1-carboxylic acid (c) (c)

S ii 5 (o) 7 4 F A

Mi x v; o-i si (c)

The desired intermediate (233 mg, 0.38 mmol, 63 95) was obtained as a yellow solid from intermediate 185.2 (300 mg, 0.60 mmol) and tert-butyl 3,5-dimethyl-4-(4, 4,5,5-tetramethyl-|1,3,2|dioxaborolan-2-yl)-pyrazole-1-carboxylic acid (212 mg, 0.66 mmol) similarly to the preparation in example 36. LC-MS: t/2 617.0 (MANI; "H NMR (400 MHz, DMSO-iv) 1.18-1.30 (t, 6 H), 1.58 (5, 9 H), 2.24 (5, C H) , 2.73 (5, With H), 3.71 (5, 1 H), 3.74 (5, With H), 3.92 (in, 1 H), 4.40-4.50 (t , 1 H), 6.25 (5, 1 H), 6.89 (5, 1 H), 7.06 (5, 1 H), 7.39 (5, C H), 7.48 (a , 9-8.59 Hu, 1 H), 7.70 (a, 9-11.32 Hu, 1 H), 7.95 (c, 1 H), 8.51 (a, 9-3.51 Hz, 1 N).

Intermediate 185.2: 2-(6-Bromopyridin-3-yl)-1-(4-chlorophenyl)-7-isopropoxy-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (c) (c)

WITH

You 4 F Zh p

The desired intermediate (607 mg, 1.21 mmol, 18.5 95) was obtained as a white solid from intermediate 185.3 (1.93 g, 6.53 mmol) and intermediate 96.1 (1.95 g, 8, 00 mmol) similarly to the preparation in example 1. HPLC: Chve-5.526 min.; RH-MS: t/7 502.7

IM-ANI..

Intermediate 185.3: (6b-Bromopyridin-3-yl)-(1-(4-chlorophenyl)-meth-(E)-ylidene|-amino.si ru -

Hg

The desired compound (1.93 g, 6.53 mmol, 83 95) was obtained as an orange solid from b-bromopyridin-3-ylamine (1.36 g, 7.89 mmol) and 4-chlorobenzaldehyde (1.38 g , 9.86 mmol) similarly to obtaining intermediate product 1.4. "H NMR (400 MHz, DMSO-av) 7.61 (a, 2

H), 7.69 (a, 2 H), 7.95 (a, 2 H), 8.30-8.35 (t, 1 H), 8.71 (5, 1 H).

Example 186: 1-(4-Chlorophenyl)-7-isopropoxy-b-methoxy-2-(2-methoxy-4-methyl-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. -х 9) о ой m

J

Si

Z A mixture of intermediate 186.1 (33 mg, 0.078 mmol), 2-iodopropane (0.023 mL, 0.234 mmol), and C520Oz (50.7 mg, 0.156 mmol) in DMF (0.5 mL) was stirred for 1 h. at 50 "C. The reaction mixture was allowed to cool to RT, the reaction was stopped by the addition of a saturated aqueous solution of ManHSO3 and extracted with EtSOE. The organic phase was washed with a saturated aqueous solution of ManHSO3, dried (Mag25O4), filtered and concentrated. The residue was purified using column chromatography ( 5iOg2; DXM/MeOH 99:1) and obtained 33 mg of the desired compound in the form of a white solid. TLC: Ke-0.88 (DXM/MeOnH 9:1); HPLC: Chweg 5.74 min.; LC-MS: t /: 466.4 (MANI "H NMR (400 MHz, DMSO-ab): 1.06-1.25 (t, 6 H) 2.25 (5, C H) 2.41-2.52 (t , 6 H) 3.54 (j, 1 H) 3.92 (0, 1 H) 4.31-4.50 (t, 1 H) 5.69 (bg, 1 H) 6.46-6, 97 (t, 5 H) 7.29 (bg, 4 H).

Intermediate 186.1: 1-(4-Chlorophenyl)-7-hydroxy-6-methoxy-2-(2-methoxy-4-methylphenyl)-1,4-dihydro-2H-isoquinolin-3-one.

o o o du on si

To a solution of intermediate 187.3 (375 mg, 0.818 mmol) in DCM (10 mL) at 0 C under an argon atmosphere was added a solution of intermediate 186.2 (276 mg, 1.06 mmol) in DCM (5 mL). The reaction mixture was stirred for 1 hour. at RT and cooled to 0 "C. Trifluoromethanesulfonic acid (0.291 ml, 3.27 mmol) was added. The resulting mixture was stirred for 1 hour at 0 "C, the reaction was stopped by adding a saturated aqueous solution of MaHsSoOz and extracted with DCM. The organic phase was washed with a saturated aqueous solution

Manso", dried (Mag5054), filtered and concentrated. The residue was purified by column chromatography (5102; DHM/MeOnH 100:0 -» 98:2), then by trituration with ASOEI to give 35 mg of the desired compound as a white solid. TLC: Ke-0.71 (DHM/MEEeON 9:1); TOP: Chnei-4.77 min.; RH-MS: t/2 424.3 MANI".

Intermediate 186.2: | 1-(4-Chlorophenyl)-meth-(E)-ylidene|-(2-methoxy-4-methylphenyl)-amine.

M is) /

A mixture of intermediate 186.3 (1.57 g, 11.4 mmol) and 4-chlorobenzaldehyde (1.63 g, 11.4 mmol) and acetic acid (0.66 mL, 11.4 mmol) was stirred for 18 h at 85 C, allowed to cool to RT and concentrated to give 3.25 g of the title compound as a brown oil which was used as crude. "H NMR (400 MHz, DMSO-αv) 2.32 (5, C H), 3.78 (5, C H), 6.77 (a, 9-7.82 Hz, 1 H), 6, 90 (5, 1 N), 6.97 (a, U-7.82 Hz, 1 N), 7.57 (y, 9-8.60 Hz, 2 N), 7.91 (a, U- 8.60 Hz, 2 N), 8.54 (5.1 N).

Intermediate 186.3: 2-Methoxy-4-methylphenylamine. o-- - h

A mixture of 5-methyl-2-nitroanisole (2 g, 12 mmol) and Raney nickel (2.2 g) in a mixture of MeOH/TF (120 ml, 3:1 vol./Ob6.) was shaken for 20 h. at CT and pressure H", equal to 0.1 bar. Reactionary

The mixture was filtered through a layer of Celite and the filtrate was concentrated to obtain 1.57 g of the desired compound as a colorless oil. TOP: Chves-1.44 min.; LC-MS: t/z2 138.1 (MANI.

Example 187: 1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl-2-(2H-tetrazol-5-ylmethoxy)phenyl)|-1,4-dihydro-2H-isoquinoline -3-one

N

M-M g

Ma M

From the entrance

That's it

A mixture of intermediate 187.1 (500 mg, 1.02 mmol), sodium azide (199 mg, 3.06 mmol), and ammonium chloride (163 mg, 3.06 mmol) in DMF (4 mL) was stirred for 3 h at 100 °C. C, was allowed to cool to RT, the reaction was quenched by the addition of a saturated aqueous Masi solution and extracted with AcSOe. The organic phase was washed with a saturated aqueous Masi solution, dried (Ma»5O54), filtered and concentrated. The residue was purified by column chromatography (5 µg; DXM /Meon 99:11 -» 94:6) and obtained 257 mg of the desired compound in the form of a yellow solid. TLC: Keg-0.32 (DHM/MeonH 9:1); HPLC:

Thu5.20 min.; RH-MS: t/2 534.4 MANI; "H NMR (400 MHz, DMSO-ab): 1.04-1.23 (t, 6 H) 2.24 (5, C H) 3.53 (y, 1 H) 3.69 (5, C H) 3.91 (y, 1 H) 4.29-4.43 (t, 1 H) 5.42 (ri, 2 H) 5.83 (rg, 1 H) 6.59- 6.86 ( t, 4 H) 7.07 (p, 1 H) 7.18-7.37 (t, 4 H).

Intermediate 187.1: 32-(1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-5-methylphenoxy)-acetonitrile.

M

( o 0) o gu m

AJ Si

A mixture of intermediate 187.2 (1.1 g, 2.52 mmol), 2-iodopropane (0.75 mL, 7.55 mmol) and

C520bOz (1.6 g, 5.03 mmol) in DMF (20 mL) was stirred for 2 h. at 50 "C in an argon atmosphere. The reaction mixture was allowed to cool to RT, the reaction was stopped by the addition of a saturated aqueous solution of ManHSO 3 and extracted with AcSOE. The organic phase was washed with a saturated aqueous solution of ManHSO 3 , dried (Mag25O4), filtered and concentrated. The residue was purified using column chromatography (5% O2; DCM/MeEeOH 100:0 -» 98:2) and obtained 1.1 g of the desired compound in the form of a white solid. TLC:

Ag-0.81 (DHM/MeOHn 9:1); TOP: Chneg-5.45 min.; RH-MS: t/z 491.4 MANI.

Intermediate 187.2: 32-1-(4-Chlorophenyl)-7-hydroxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-X-methylphenoxy)-acetonitrile.

M

G o (c) o. Oh he is

Zo To a solution of intermediate product 187.3 (2.3 g, 7.27 mmol) in DCM (50 ml) at 0 "С and in an argon atmosphere was added a solution of intermediate product 187.7 (2.7 g, 9.45 mmol) in DCM ( 5 ml).

The reaction mixture was stirred for 1 hour. at RT and cooled to 0 °C. Trifluoromethanesulfonic acid (2.6 ml, 29.1 mmol) was added. The resulting mixture was stirred for 1 h at 0 °C, the reaction was stopped by adding a saturated aqueous solution of MansCO3 and extracted with DCM. The organic phase was washed with a saturated aqueous solution

Manso", dried (Mag5054), filtered and concentrated. The residue was purified by column chromatography (5102; DXM/MeOnH 100:0 -» 98:2), then by trituration in ASOK to obtain 1.2 g of the desired compound as a white solid. TLC: Ke-0.57 (DHM/MEEeOH 9:1); TOP: Chne-4.57 min.; RH-MS: tp/2 449.3 MANI.

Intermediate 187.3: (3-Methoxy-4-(4-methoxybenzyloxy)phenyl|-acetyl chloride.

si o-- o (in -09-

H

1-Chloro-M,M,2-trimethyl-1-propenylamine (1, 2 ml, 8.71 mmol).

The reaction mixture was stirred for 30 minutes at 0 "C and concentrated to give 3 g of the desired compound as a colorless oil, which was used immediately. HPLC: Chvne-5.04 min. (methyl ether after treatment with Meon).

Intermediate 187.4: |3-Methoxy-4-(4-methoxybenzyloxy)phenyl|-acetic acid. he oh-- oh

Ge -9- x

To a stirred solution of intermediate 187.5 (8.5 g, 25.6 mmol) in THF (50 mL) was added GiION (2.2 g, 51.3 mmol) in H2O (25 mL). The reaction mixture was stirred for 16 h. at CT, concentrated, diluted with H2HO (50 ml) and acidified to pH 1.

The resulting precipitate was collected by filtration and 7.1 g of the desired compound was obtained as a white solid. TOP: Thu-4.26 min.; RH-MS: t/2 320.3 MA18I..

Intermediate 187.5: Ethyl ether of (3-methoxy-4-(4-methoxy-benzyloxy)phenyl|-acetic acid.

A mixture of intermediate 187.6 (5.6 g, 26.7 mmol), 4-methoxybenzyl chloride (4.4 mL, 32.1 mmol), and HgSO3 (4.8 g, 34.8 mmol) in DMF (40 mL) was stirred for 30 minutes at 100 "C, allowed to cool to RT, the reaction was stopped by adding a saturated aqueous solution of ManHsSO3 and extracted with DCM. The organic phase was washed with a saturated aqueous solution of ManHsSO3, dried (Ma»5O»), filtered and concentrated. The residue was purified using column chromatography (5gO2; gradient elution, hexane/AcSOEL 95:5 -» 75:25) and obtained 8.5 g of the desired compound in the form of a white solid. TLC: Ke-0.76 (hexane/AcSOEL 1 :1). HPLC: Chnes5.32 min.; "H NMR (400 MHz, DMSO-av)

Zo 1.16 (i, 9-7.04 Gu, Z H), 3.54 (5.2 H), 3.71 (5, Z H), 3.73 (5, Z H), 4, 05 (ad, 9-7.30 Hz, 2 N), 4.94 (5.2

H), 6.72 (ad, 9-8.21, 1.96 Gu, 1 H), 6.86 (a, 9U-1.96 Hz, 1 H), 6.89-6.98 (t , Z H), 7.34 (y, 9-8.60 Hz, 2

N).

Intermediate 187.6: (4-Hydroxy-3-methoxyphenyl)-acetic acid ethyl ester. oh oh

From 5 on

A mixture of homovanillic acid (5 g, 27.4 mmol) and H25Ox (96 95, 1.46 mL, 27.4 mmol) in EUN (100 mL) was stirred for 1 hour at 85°C, allowed to cool to RT, and concentrated. The residue was diluted with H2O and extracted with DCM.

The organic phase was washed with HO, dried (Ma»5O54), filtered and concentrated to give 5.8 g of the desired compound as a yellow oil. RH-MS: t/2 211.2 MANI".

Intermediate 187.7: (2-C1-(4-Chlorophenyl)-meth-(E)-ylidene|-amino)-5-methylphenoxy)-acetonitrile.

M

/ (c) « in and F si

A mixture of intermediate product 187.8 (1.5 g, 9.25 mmol) and 4-chlorobenzaldehyde (1.3 g, 9.25 mmol) in EUN (20 mL) was stirred for 18 h. at 85 °C, allowed to cool to RT and concentrated to give 2.7 g of the desired compound as a red oil, which was used as a crude substance. H NMR (400 MHz, DMSO-α) 2.32 (5, C H) , 5.18 (5.2 H), 6.93 (a, 9-7.82 Hu, 1 H), 7.02 (5, 1 H), 7.08 (a, U-7.82 Hu , 1 H), 7.57 (ad, 2 H), 7.92 (as, 2 H), 8.55 (5, 1 H).

Intermediate 187.8: (2-Amino-5-methylphenoxy)-acetonitrile.

M

D o and MN,

A mixture of intermediate 187.9 (6.3 g, 22.5 mmol) and TFA (17.3 mL, 225 mmol) in DCM (50 mL) was stirred for 1 h. at RT, the reaction was stopped by adding a saturated aqueous solution of MansCO3 and extracted with DCM. The organic phase was washed with a saturated aqueous solution of ManHsCO3, dried (Ma»5O4), filtered and concentrated.

The residue was purified by column chromatography (5iO2; hexane/AcSOEi 95:5 -» 80:20) and obtained 1.5 g of the desired compound in the form of an orange solid. TLC: Ke-0.6 (Hexane/AsoEi 1:1); TOP: Thu-1.43 min.; RH-MS: t/2 163.1 (MANI.

Intermediate 187.9: (2-Cyanomethoxy-4-methylphenyl)-carbamic acid tert-butyl ether.

M

D o n i u? tk

A mixture of intermediate 187.10 (5 g, 22.4 mmol), K»CO3 (9.3 g, 67.2 mmol), and bromoacetonitrile (2.2 mL, 33.6 mmol) in DMF (50 mL) was stirred for 1 hours at CT, the reaction was stopped by adding a saturated aqueous solution of ManHsSoO»z and extracted with ASOEL. The organic phase was washed with a saturated aqueous Mansoz solution and dried

Zo (Mag25054), filtered and concentrated to obtain 6.3 g of the desired compound in the form of a black oil, which was used as a crude substance. TOP: Chveas-5.21 min.; RH-MS: t/ 261.3

IM-NO.

Intermediate 187.10: (2-Hydroxy-4-methylphenyl)-carbamic acid tert-butyl ether. he sk

Di-tert-butyl carbonate (9.4 mL, 40.6 mmol) was added to a stirred solution of b-amino-m-cresol (5 g, 40.6 mmol) in DCM (100 mL) under an argon atmosphere. The resulting mixture was stirred for 18 hours. at RT, the reaction was stopped by adding a saturated aqueous solution of MansCO3 and extracted with DCM. The organic phase was washed with a saturated aqueous solution of MnSOO3, dried (Ma»5O4), filtered and concentrated to obtain 9.1 g of the desired compound in the form of a black oil, which was used as a crude substance. TOP: Thu-4.86 min.; RH-MS: t/z: 224.3 MANI.

Example 188: 1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl-2-(thiazol-5-ylmethoxy)phenyl|)|-1,4-dihydro-2H-isoquinoline- 3-on her ho 8 o rya oi

J

Si

To a solution of intermediate 187.3 (773 mg, 2.23 mmol) in DCM (10 mL) under argon was added a solution of intermediate 188.1 (841 mg, 2.452 mmol) in DCM (5 mL).

The reaction mixture was stirred for 1 hour. at RT and cooled to 0 "C. Trifluoromethanesulfonic acid (0.291 ml, 3.27 mmol) was added. The resulting mixture was stirred for 10 min. at 0 "C, the reaction was stopped by adding a saturated aqueous solution

MansSoz and extracted with DCM. The organic phase was washed with a saturated aqueous solution of MansSoO3, dried (Ma»5O4), filtered and concentrated. The residue was purified by column chromatography (5 µg2; elution in gradient mode, DCM/MeOH 100:0 -» 98:2), then by trituration with ASOEI to obtain 400 mg of the desired compound in the form of a white solid. TLC: Ke-0.42 (DCM/MeOH 9:1); RH-MS: t/2,549.4 MANI; NN

NMR (400 MHz, DMSO-ab): 1.00-1.32 (t, 6 H) 2.26 (5, C H) 3.54 (y, 1 H) 3.71 (5, C H) 3.84-4.00 (t, 1

H) 4.28-4.45 (t, 1 H) 5.12-5.49 (t, 2 H) 5.63 (ri, 1 H) 6.47-6.67 (t, 4 H) 6.95-7.45 (t, 5 N) 7.83 (5, 1 N) 9.00 (re, 1 N).

Intermediate 188.1: I1-(4-Chlorophenyl)-meth-(E)-ylidene|-(4-methyl-2-(thiazol-5-ylmethoxyphenyl)-amine).

M o

Her 5

A mixture of intermediate 188.2 (815 mg, 3.70 mmol) and 4-chlorobenzaldehyde (472 mg, 3.70 mmol) and acetic acid (0.21 mL, 3.70 mmol) was stirred for 18 h at 85 C to give cooled to RT and concentrated to give 1.39 g of the desired compound as a black oil, which was used as crude. "H NMR (400 MHz, DMSO-ab) 1.00-1.32 (t, 6 H), 2.26 (in, 3 H), 3.54 (y, 1 H), 3.71 (in , Z H), 3.84-4.00 (t, 1 H), 4.28-4.45 (t, 1 H), 5.12-5.49 (t, 2 H), 5.63 (Bg, 1 H), 6.47-6.87 (t, 4 H), 6.95-7.45 (t, 5 H), 7.83 (5, 1 H), 9.00 (Bi , 1 H).

Intermediate 188.2: 4-Methyl-2-(thiazol-5-ylmethoxy)phenylamine.

M

SI; 5

A mixture of intermediate 188.3 (935 mg, 3.74 mmol) and Raney nickel (400 mg) in a mixture

Meonlt (40 ml, 3:1 vol./06.) was shaken for 27.5 h. at CT and pressure H", equal to 0.1 bar. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by column chromatography (5102; DHM/MeOH 100:0 -» 98:2) and obtained 815 mg of the desired compound in the form of a red oil. TLC: Ke-0.6 (DCM/MeOHn 9:1);

TOP: Thu-1.76 min.; RH-MS: t/: 221.2 |MANEI.

Intermediate 188.3: 5-(5-Methyl-2-nitrophenoxymethyl)thiazole.

M

MO, what; 5

Man (0.413 g, 9.47 mmol) was added to a solution of 5-(hydroxymethyl)-1,3-thiazole (1 g, 8.68 mmol) in DMF (15 mL) under an argon atmosphere. The reaction mixture was stirred for 20 minutes. at 0 "C. 3-fluoro-4-nitrotoluene (1.2 g, 7.89 mmol) was added. The resulting mixture was stirred for 1 h at RT, the reaction was stopped by adding a saturated aqueous solution

Manso:z was extracted with the help of ASOEII. The organic phase was washed with a saturated aqueous solution of MansSoO3, dried (Ma»5O4), filtered and concentrated. The residue was purified by column chromatography (5102; hexane/AcSOEi 60:40 -» 40:60) and 936 mg of the desired compound was obtained as an orange solid. TLC: Ke-0.35 (hexane/AsokKi 1-1);

TOP: Chvei-4.26 min.; RH-MS: t/: 251.2 |MANI.

Example 189: Methyl ether 4-(11-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-(2H-tetrazole) -5-ylmethoxy)-benzoic acid.

Nn

M-M / mm

M.M

C (c) о и о : АХ g

SI

The desired compound (132.4 mg, 0.208 mmol) was obtained as an off-white solid from intermediate 189.1 (398 mg, 0.744 mmol) in a similar manner to Example 187. HPLC:

Mides-1.10 min.; RH-MS: t/2 578.2 |MANI; "H NMR (400 MHz, DMSOO-ab): 1.14 (a, 9-5.85 Hz, C H) 1.20 (a, 9U-5.85 Hz, C H) 3.57-3, 63 (t, 1 H) 3.73 (5, Z H) 3.85 (5, Z H) 3.96 (y, 9U-19.98 Hz, 1 H) 4.38 (ai, 9U-11 .96, 6.03 Hz, 1 N) 5.35-5.72 (t, 2 N) 5.95 (Bug. 5., 1 N) 6.73 (5, 1 N) 6.83 (in , 1 H) 6.89-7.20

Zo (t, 1 H) 7.20-7.39 (t, 4 H) 7.54 (Bug. 5., 1 H) 7.80 (rg. 5., 1 H) 16.76 (Bu. 5., 1 H).

Intermediate 189.1: 4-(1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-cyanomethoxy-benzoic acid methyl ester acid

M y o o o o. inv; Zh

SI

The desired intermediate (298.9 mg, 0.559 mmol) was obtained as an off-white solid from intermediate 189.2 (398 mg, 0.744 mmol) analogously to the preparation of intermediate 187.9. TOP: Here is 1.17 min.; RH-MS: t/2 535 | MANI..

Intermediate 189.2: 4-(1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-hydroxybenzoic acid methyl ester. he" ee

M" o; ry

Go

SI

The desired intermediate (296 mg, 0.597 mmol) was obtained as an off-white solid from intermediate 189.3 (331 mg, 0.0.542 mmol) using a 1 M solution of tetrabutylammonium fluoride in THF and the reaction mixture was stirred for 45 min. at room temperature. After treatment, the desired compound was obtained as a yellow solid. TOP: Here is 1.13 min.; RH-MS: t/7 496 MANI; "H NMR (400 MHz, DMSO-ab6): 1.09-1.26 (t, 6 H) 3.54-3.65 (t, 1 H) 3.74 (5, C H) 3.81 (5, With H) 3.94-4.02 (t, 1 H) 4.37-4.50 (t, 1 H) 5.88 (5, 2 H) 6.81-6.96 (t , 2 H) 7.22-7.39 (t, 4 H) 7.46-7.56 (t, C H).

Intermediate 189.3: 3-(tert-butyldimethylsilanyloxy)-4-(1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2-methyl ether yl|-benzoic acid.

Ku (in) o / 79 i. " (v! o AJ g si

The desired intermediate (331 mg, 0.542 mmol) was obtained as a white solid from intermediate 96.2 (555 mg, 2.475 mmol) and intermediate 189.4 (1.0 g, 2.475 mmol) analogously to the preparation of intermediate 187.2. TOP: Mive-1.47 min.; LC-MS: t/2 610 (MANI; "H NMR (400 MHz, DMOSO-ab): -0.17-0.25 (t, 6 N) 0.60-0.93 (t, 9 N) 1.06-1.27 (t, 6 H) 3.51-3.66 (t, 1 H) 3.69-3.77 (t, C H) 3.82 (0.9-12.92 Hz, Z H) 3.92-4.13 (t, 1 H) 4.34-4.50 (t, 1 H) 5.66-5.95 (t, 1 H) 6.79-7, 02 (t, 2 N) 7.20-7.61 (t, 7 N).

Intermediate 189.4: 3-(tert-butyldimethylsilanyloxy)-4-11-(4-chlorophenyl)-meth-(E)-ylidene|-amino)-benzoic acid methyl ester. si ra / to

M lo (c)

Coo)

The desired intermediate (4.75 g, 9.99 mmol) was obtained as a brown solid from intermediate 189.5 (3.37 g, 11.63 mmol) using TVOM5 chloride (1.753 g, 11.63 mmol), triethylamine (3.24 ml, 23.26 mmol), DMAP (142 mg, 1.163 mmol) in 116 ml of DCM with stirring at room temperature for 15 h. "H NMR (400 MHz, DdMSO-ab): 0.14 (5.6 H) 0.92 (5.9 H) 3.84 (5, C H) 7.18 (0.9-8.20 Hz, 1 H) 7.43 (a, 9-1.56 Hz, 1 H) 7.63 (y, 9-8.59 Hz, Z H) 7.96 (a, 9U-8.20 Hz, 2 N) 8.58 (5.1 N).

Intermediate 189.5: 4-11-(4-chlorophenyl)-meth-(E)-ylidene|-amino)-3-hydroxybenzoic acid methyl ester.

si on I y

M re (c)

The desired intermediate (3.37 g, 11.63 mmol) was obtained as an off-white solid from chlorobenzaldehyde (1.682 g, 11.96 mmol) and methyl 4-amino-3-hydroxybenzoate (2.0 g, 11.96 mmol) similarly to obtaining the intermediate product 187.7. "H NMR (400 MHz, DMSO-ab): 3.83 (5, C H) 7.22 (a, 9-8.20 Hz, 1 H) 7.36-7.54 (t, 2 H) 7.61 (a, 9-8.59 Hz, 2 N) 8.04 (a, 9-8.59 Hz, 2

H) 8.70 (5, 1 H) 9.59 (5, 1 H).

Example 190: 4-(11-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-methoxybenzoic acid methyl ester. (c) ) o. " (is) about A

GO si

The desired compound was obtained by reacting intermediate 189.2 (200 mg, 0.403 mmol) with iodomethane (86 mg, 0.605 mmol) in the presence of potassium carbonate (167 mg, 1.21 mmol) in 4 mL

DMF at 100 "C for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of ManHsCO3 and saline. The crude product was purified by means of automatic column chromatography with a normal phase (when eluting with a mixture of n-heptane - ethyl acetate) and the desired compound was obtained in the form of a brownish solid substance (0.51 g, 0.904 mmol). HPLC: Mive-1.19 min.; LC-MS: t/2 510.3 MANI. "H NMR (400

MgHu, DMOO-ab): 1.14 (9, 95.85 Hu, C H) 1.22 (a, 9-5.85 Hu, C H) 3.61 (a, U-19.98 Hu, 1 N) 3.66-3.93 (t, 9 N) 3.99 (0.9U-19.98 Hz, 1 N) 4.36-4.48 (t, 1 N) 5.83 (bBg 5., 1 H) 6.86 (5, 2 H) 6.92-7.69 (t, 7

N).

Example 191: Methyl ether 4-(11-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-(thiazol-5 -ylmethoxy)-benzoic acid.

M- o o 0) | o and o o Zh

Ha si

The desired compound was obtained by reacting intermediate 189.2 (400 mg, 0.807 mmol) with

Zo B-(hydroxymethyl)-1,3-thiazole (139 mg, 1.210 mmol) in the presence of di-tert-butylazodicarboxylate (279 mg, 1.21 mmol) and triphenylphosphine in 8 mL of dry DCM at room temperature for 19 h. The reaction mixture was concentrated in vacuo and the crude product was purified by automatic normal phase column chromatography (eluting with n-heptane - ethyl acetate) to give the desired compound as a colorless oil (0.375 g, 0.518 mmol). TOP: Mive-1.15 min.; RH-

MS: t/2 593.3 MANI. "H NMR (400 MHz, DMSOSO-ab): 1.15 (y, 9-5.85 Hz, Z H) 1.21 (a, 9U-6.06 Hz, Z

H) 3.58-3.64 (t, 1 H) 3.74 (5, With H) 3.86 (5, With H) 3.89-4.06 (t, 1 H) 4.34- 4.44 (t, 1 N) 5.47 (ri. 5.2

H) 5.80 (Bug. 5., 1 H) 6.80 (5, 1 H) 6.86 (5, 1 H) 7.26 (Bug. 5., 4 H) 7.42-7, 83 (t, Z H) 7.67 (5, 1 H) 9.04 (Bg. 5.1 H).

Intermediate 192.1: (5)-2-I4-((5)-1-Aminoethyl)phenyl|-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinoline- 3-on (c) o vi ! (c) "FI and A p

The desired compound (1.28 g, 2.75 mmol, 100 95) was obtained as a solid from intermediate 192.2 (1.55 g, 2.74 mmol) similarly to the preparation in example 51. HPLC:

Cinema-5.99 min.; PH-MS: t/z 465.4 |MANG.

Intermediate 192.2: tert-butyl ether ((5)-1-14-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1 H -isoquinolin-2-yl|1-phenyl)-ethyl)-carbamic acid. (c) Fr

I am M

N : ?

AJ re

SI

The desired intermediate (1.61 g, 2.85 mmol, 49.3 95) was obtained as a white solid from intermediate 75.6 (2.0 g, 5.78 mmol) and intermediate 192.3 (2.0 g, 5.78 mmol) similar to that obtained in example 75. HPLC: "Chve-7.55 min.; PH-MS: t/; 582.5

IM-AMNAI".

Intermediate 192.3: 1|(5)-1-(4-iodophenyl)-ethyl|-carbamic acid tert-butyl ether. I !

N

AH b V

Di-tert-butyl dicarbonate (5.3 g, 24.3 mmm). After stirring for 1 hour. at CT, the reaction was stopped by adding a saturated aqueous solution of MNACI and extracted with DCM. The organic phase was washed with a saturated aqueous solution

Manso", dried (Mag5054), filtered and concentrated. The residue was purified using

From column chromatography (5102; hexane/AcSOEi 90:10) and obtained (6.27 g, 18.1 mmol, 89 95) the desired compound in the form of a white solid. TOP: "Thursday-7.35 min.; RH-MS: t/7 365.2

IM-AMNAI".

Example 195: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-Imethyl-(4-(2-oxopyrrolidin-1-yl-trans-cyclohexylmethyl)|-amino) -pyridin-3Z-yl)-1,4-dihydro-2H-isoquinolin-3-one.

M roya M m Z ra

M

SI

(8)

The desired compound (28 mg, 0.044 mmol, 15 95) was obtained as a yellow foam from intermediate 75.6 (100 mg, 0.289 mmol) and intermediate 195.1 (120 mg, 0.289 mmol) analogously to the preparation in example 130. HPLC: rve 1 .05 min.; RH-MS: t/2 631.5 MANI.

Intermediate 195.1: 1-(4--(5-Hydropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-pyrrolidin-2-one. l m "her (8)

To a mixture of intermediate 195.2 (1.31 g, 2.91 mmol), potassium carbonate (9.26 g, 67.0 mmol), and acetone (150 mL) was added potassium iodide (1.015 g, 6.12 mmol). The mixture was stirred for 48 hours. under reflux. The reaction mixture was concentrated and the residue was extracted with EOAc (2x) and 1M aqueous solution of ManHsoz (1x). The organic phases were washed with brine and dried over Mag5O5, filtered and evaporated to dryness. The residue was crystallized (PgOH) and the desired compound was obtained as beige crystals (769 mg, 1.71 mmol, 59 95). TOP: Yave-2.95 min.; RH-MS: t/l 414.3 MANI".

Intermediate 195.2: 4-Chloro-N-(4-(5-iodopyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-butyramide. in

N. p

4-chlorobutyryl chloride was added dropwise to a stirred solution of intermediate 130.4 (1.0 g, 2.90 mmol), triethylamine (0.803 mL, 5.79 mmol), and chloroform (30 mL).

The mixture was stirred for 1 hour. at CT. The reaction mixture was extracted with DCM (2x) and 1M aqueous solution of ManNsoz (1x). The organic phases were washed with brine and dried over magnesium sulfate, filtered and evaporated to dryness. The residue was crystallized (DCM - hexane) and the desired compound was obtained as beige crystals (1.30 g, 2.90 mmol, 99 95).

TOP: Чяве-4.26 min.; RH-MS: t/l 450.3 MANI".

From Example 196: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(methyl-1|4-(2-oxoimidazolidin-1-yl)-transo-cyclohexylmethyl| -amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

moat

M i Z r s

SI

-,

The desired compound (61 mg, 0.096 mmol, 33 95) was obtained as a yellow foam from intermediate 75.6 (100 mg, 0.289 mmol) and intermediate 196.1 (120 mg, 0.289 mmol) similarly to the preparation in example 130. HPLC: Orve- 1.12 min.; RH-MS: t/ 632.6 MANI.

Intermediate 196.1: 1-(4--(5-Hydropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-imidazolidin-2-one.

AND

SU o M s m-th

H (in)

To a solution of intermediate 196.2 (295 mg, 0.76 mmol) and THF (30 mL) was added 1,1'-carbonyldiimidazole (123 mg, 0.76 mmol). The mixture was stirred for 1 hour. under reflux. The reaction mixture was extracted with EAs (2x) and 1M aqueous solution of ManHsoz (1x). The organic phases were washed with saline and dried over

Ma»5O» was filtered and evaporated to dryness. The residue was crystallized (E(OAc)) and the desired compound was obtained as beige crystals (204 mg, 0.492 mmol, 64 95). HPLC: "ve-3.71 min.;

RH-MS: t/ya 415.3 MANI". Y

Intermediate product 196.2: M"17-(4--(5-Iodopyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-ethane-1,2-diamine. in the role of М M s

N

MH,

TFA (1.23 mL, 15.8 mmol) was added to a solution of intermediate 196.3 (390 mg, 0.80 mmol) and DCM (20 mL). The mixture was stirred for 2 hours. at CT. The reaction mixture was extracted with DCM (2x) and 1M aqueous solution of ManNsoz (1x). The organic phases were washed with brine and dried over Mag50O5, filtered and evaporated to dryness provided the desired compound as a yellowish oil (298 mg, 767 mmol, 96 95). TOP: Thu-1.90 min.; RH-MS: t/: 389.3 IM-ANE..

Intermediate 196.3: 12-(4-(5-iodopyridin-2-yl)-methylamino|- tert -butyl ether

Zo methyl)-trans-cyclohexylamino)-ethyl|-carbamic acid.

I uv lne Mche;

N

MN o- --

Mavnastm (218 mg, 3, 48 mmol). The mixture was stirred for 18 hours. at CT. The reaction mixture was concentrated and a 1 M aqueous solution of Manso-3 was added to the residue, then extracted with EOAc (2x). The organic phases were dried over magnesium sulfate, filtered and evaporated.

Purification of the residue by normal phase column chromatography eluting with a mixture of DCM - MeOH - 3095 aqueous solution of MNAOH (200:20:1) provided the desired compound as a yellow oil (398 mg, 0.815 mmol, 35,965). TOP:

Apparition-3.64.

Example 197: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6--methyl-I4-(3-oxomorpholin-4-yl-transo-cyclohexylmethyl)|-amino) -pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

Ml sia 3 Zh

C o A SI o

The desired compound (74 mg, 0.113 mmol, 39 95) was obtained as a yellow foam from intermediate 75.6 (100 mg, 0.289 mmol) and intermediate 197.1 (124 mg, 0.289) similarly to the preparation in example 130. HPLC: Zve1.15 wave.; RH-MS: t/2 647.5 MANI".

Intermediate 197.1: 4-(4-(5-Hydropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-morpholin-3-one.

And in l M sh o. AH (in)

Man (54.5 mg, 2.158 mmol) was added to a stirred solution of intermediate 197.2 (670 mg, 1.439 mmol) and THF (100 mL) at 0 °C. The mixture was stirred for 3 h at 0 °C. The reaction mixture was extracted with EtOAc (2x) and 1M aqueous solution of MansSoz (1x). The organic phases were washed with brine and dried over NaCl, filtered and evaporated to dryness. The residue was purified by column chromatography with normal

The desired compound was obtained in the form of yellowish crystals (254 mg, 0.592 mmol, 41 95) from the phase when eluting with a mixture of ETAc - hexane (3:1) and after crystallization (DCM - hexane). TOP:

Zve-3.66 min.; RH-MS: t/2 430.2 MANI".

Intermediate 197.2: 2-(2-Chlorethoxy)-N-(4-((5-iodopyridin-2-yl)-methyl-amino|-methyl)-trans-cyclohexyl)-acetamide.

And in and Nm (in) "o

The desired intermediate (670 mg, 1.424 mmol, 98 95) was obtained as a yellowish oil from intermediate 130.4 (500 mg, 1.448 mmol) and (2-chloroethoxy)-acetyl chloride (227 mg, 1.448 mmol) analogously to the preparation of intermediate 195.2. TOP: ve-4.40 min.; RH-

MS: t/; 466.3 (MANI.

Example 198: (5)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(5-(methyl-|4-(33-methyl-4-oxoimidazolidine- 1-yl)-transo-cyclohexylmethyl|-amino)-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one.

M M; о - АЖ о ХА о и /

The desired compound (96 mg, 0.144 mmol, 36 95) was obtained as a yellow foam from intermediate 198.1 (146 mg, 0.400 mmol) and intermediate 149.1 (50 mg, 0.100 mmol) analogously to the preparation in Example 130. HPLC: Rivet- 1.21 min.; RH-MS: t/z 661.7 (MANI.

Intermediate 198.1: (5)-7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. (9) Fr

NM

SI

(5)-Butan-2-ol (0.466 g, 6.29 mmol), di-tert -butyl azodicarboxylate (1.93 g, 8.39 mmol) and triphenylphosphine (bound to the polymer, 3 mmol/1 g of resin) (2.79 mg, 8.39 mmol).

The mixture was stirred for 75 minutes. at CT. The reaction mixture was filtered, washed with EtOAc and the filtrate was concentrated. The residue was extracted with EOAc (3x) and 1M aqueous solution of Mansoz (1x). The organic phases were washed with brine and dried over Mag505, filtered and evaporated to dryness. Purification of the residue by column chromatography with a normal phase eluting with a mixture of DCM - Meon (98:2 -» 95:5) after crystallization (TEME) provided the desired compound in the form of a white crystalline substance (628 mg, 1.728 mmol, 41 95). TOP: Oine-1.06 min.; RH-MS: t/: 360.1 MANI in

NMR (400 MHz, DMSO-abv): 0.82 (i, ЗН), 1.13 (а, ЗН), 1.46 (t, 1Н), 1.52 (t, 1Н), 3.30 - 3.35 (0, 1H), 3.46 - 3.51 (y, 1H), 3.69 (5, ЗН), 4.16 (t, 1H), 5.52 (t, 1H), 6 .76 (5, 1H), 6.80 (c, 1H), 7.32 (ad, 4H), 8.48 (a, 1H).

Intermediate 198.2: (5)-1-(4-Chlorophenyl)-7-hydroxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one.

(in o. nm: on si

A mixture of intermediate 75.6 (5.0 g, 14.46 mmol) and orthophosphoric acid 85 95 (48.7 mL, 723 mmol) was stirred for 1.5 h. at 100 "C. The reaction mixture was cooled to

CT, poured (carefully) into a 1 M aqueous solution of ManHsSoOz (500 ml), pH 7.0, and extracted with EIOAc (3x) The organic phases were washed with brine and dried over MagnOa, filtered and evaporated to dryness Purification of the residue using column chromatography with normal phase when eluting with DCM provided the desired compound in the form of a yellow foamy substance (4.40 g, 14.20 mmol, 98 Vol).

TOP: Rivieh0.78 min.; LC-MS: t/: 304.2 |MANI"; "H NMR (400 MHz, DMSO-α): b 3.27 - 3.34 (а, 1Н), 3.44 - 3.49 (0, 1H), 3.71 (5, 3H), 5.46 (p5, 1H), 6.53 (5, 1H), 6.72 (c, 1H), 7.32 (a, 4H), 8, 41 (in, 1H), 8.85 (5, 1H).

Example 199: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6--methyl-I(4-(2-oxopiperidin-1-yl-transo-cyclohexylmethyl)|- amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. glue Z A bi s (c)

The desired compound (29 mg, 0.045 mmol, 15 95) was obtained as a yellow foam from intermediate 75.6 (100 mg, 0.289 mmol) and intermediate 199.1 (124 mg, 0.289) similarly to the preparation in example 130. HPLC: Oive-1 ,23 min.; RH-MS: t/: 645.6 MANI.

Intermediate 199.1: 1-(4-(5-Hydropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-piperidin-2-one. ! uv lne M -

Phi (c)

The desired intermediate (412 mg, 0.964 mmol, 66 95) was obtained as a yellowish foam from intermediate 199.2 (680 mg, 1.466 mmol) analogously to the preparation of intermediate 197.1. TOP: Chves-4.34 min.; RH-MS: t/: 428.2 |MANI.

Intermediate 199.2: 5-chloropentanoic acid (4--(5-Hydropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-amide.

Su pov sh 6)

The desired intermediate (680 mg, 1.437 mmol, 99 95) was obtained as a yellowish solid from intermediate 130.4 (500 mg, 1.448 mmol) and 5-chloropentanoyl chloride

(225 mg, 1.448 mmol) analogous to the preparation of intermediate 195.2. TOP: Yave-4.45 min.;

RH-MS: tu/ 464 4 MANI. AND

Intermediate 200.1: 4-((5)-1-(4-Modphenyl)-ethyl|-1-methylpiperazin-2-one.

AND

ROBE oh

IS

The desired intermediate (1.16 g, 3.38 mmol, 75 95) was obtained as a white solid from intermediate 200.2 (1.9 g, 3.99 mmol) similarly to the preparation in example 79.

TOP: "Thursday-4.71 min.; RH-MS: t/2 345.2 MAMNI".

Intermediate 200.2: (C2-(tert-butoxycarbonylmethylamino)-ethyl|-(5)-1-(4-iodophenyl)-ethyl|-amino)-acetic acid methyl ester.

Uk mo

And about sh

Oh!

The desired intermediate (1.9 g, 3.99 mmol, 85 95) was obtained as a white solid from intermediate 200.3 (1.49 g, 4.67 mmol) analogously to the preparation of intermediate 79.2. TOP: Chwea-6.37 min.; RH-MS: t/z 477.4 |MAMNI..

Intermediate 200.3: ((5)-1-(4-iodophenyl)-ethylamino|-acetic acid methyl ester.

And oh; !

The desired intermediate (1.5 g, 4.7 mmol, 74.4 95) was obtained as a white solid from intermediate 178.5 (1.56 g, 6.31 mmol) analogously to the preparation of intermediate 79.1. TOP: "Chvne-4.80 min.; RH-MS: t/: 320.2 |MAMNI".

Intermediate 201.1: 4-((5)-1-15-(5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1-tert-butyl ether N-isoquinolin-2-yl|-pyridin-2-yl-ethyl)-3-oxopiperazine-1-carboxylic acid. and lu

H m om M ; (9)

Huh

0 s

Zo

The desired intermediate (106 mg, 0.16 mmol, 20.7 95) was obtained as a beige solid from intermediate 75.6 (286 mg, 0.82 mmol) and intermediate 201.2 (312 mg, 0.79 mmol) similarly obtained in example 75. HPLC: Chve-5.465 min.; RH-MS: t/2 649.2 (MANI.

Intermediate 201.2: 4-(5)-1-(5-bromopyridin-2-yl)-ethyl|-3-oxopiperazine-1-carboxylic acid tert-butyl ester.

»

Hg

M M u

GF) N

The desired intermediate (1.0 g, 2.6 mmol, 88 95) was obtained as a white solid from intermediate 201.3 (1.43 g, 2.96 mmol) analogously to the preparation of intermediate 178.2. TOP: Thu-5.029 min.; RH-MS: t/: 386.0 MANI.

Intermediate 201.3: 42-((5)-1-(5-bromopyridin-2-yl)-ethyl|-(2-chloroacetyl)amino|-ethyl)-carbamic acid tert-butyl ether. »

Vg and io) fo

GF) E

The desired intermediate (1.43 g, 3.4 mmol, 72.2 95) was obtained from intermediate 201.4 (1.62 g, 4.71 mmol) and chloroacetyl chloride (0.4 mL, 4.99 mmol) analogously to the preparation intermediate product 178.3. TOP: Uiwe-5.025 min.; RH-MS: t/z 4221 |MANI".

Intermediate 201.4: 32-(5)-1-(5-bromopyridin-2-yl)-ethylamino|-ethyl)-carbamic acid tert-butyl ether. with J

Hg

IN

IN

Nm HO

The desired intermediate (1.69 g, 4.91 mmol, 68.1 95) was obtained as a yellow solid from intermediate 201.5 (1.45 g, 7.21 mmol) and tert-butyl ether (2-bromomethyl) -carbamic acid (2.1 g, 9.38 mmol) similarly to the preparation of intermediate product 178.4. TOP: Chnei-4,171 min.; RH-MS: t/ 346.0 MANI".

Intermediate 201.5: (5)-1-(5-Bromopyridin-2-yl)-ethylamine. m Vg nm ho !

Intermediate 201.6 (345 mg, 1.13 mmol) was dissolved in MeonN (5 mL). Then, a 4M solution of HCl in dioxane (1.9 mL, 7.81 mmol) was added dropwise at 0" over 5 min. The reaction mixture was heated at RT. After stirring for 1 h, the solvent was evaporated and

A white solid was obtained which was washed with ESO and filtered under a stream of nitrogen to give a white powder (293 mg, 1.05 mmol, 93 95). TOP:

ЭХве-3.025 min.; RH-MS: t/2 202.9 MANI".

Intermediate 201.6: 2-methylpropane-2-sulfinic acid 1(5)-1-(5-Bromopyridin-2-yl)-ethyl|1-amide. h- Vg

BY

57 m a

And till :

To a solution of intermediate 201.7 (3.67 g, 12.68 mmol) in DCM (72 ml) at -60 "C, a 3M solution of methylmagnesium bromide in ESO (8.5 ml, 25.4 mmol) was added dropwise. The reaction mixture became bright orange and then it was heated to -50"C for 30 minutes. Then the reaction mixture was slowly heated to 0 C and the temperature for 3 h. maintained at 0 C using an ice bath. The reaction mixture was slowly poured into a cold saturated solution of MNACI (100 ml) with vigorous stirring. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over NaOH, filtered and evaporated to give a beige powder. The crude substance was pre-absorbed on ZiOg and purified using column chromatography on 5iO2 (elution in gradient mode with a mixture of AcOB/hexane from 40:60 to 100:0). The first eluting substance was collected and evaporated to give the desired intermediate (2.88 g, 9.25 mol, 72.9 95). TOP: Thu-4.654 min.; RH-MS: t/2 307.0 (MANI.

Intermediate 201.7: 2-methyl-propane-2-sulfinic acid 1-(5-Bromopyridin-2-yl)-meth-(E)-ylideneamide.

Oh oh

(5)-tert-butylsulfinamide (2.05 g, 16.9 mmol) was added to a solution of 5-bromo-2-formylpyridine (3.0 g, 16.1 mmol) in dry THF (95 mL) at RT in an argon atmosphere ). Then, titanium isopropoxide (7 mL, 33.9 mmol) was added dropwise. The reaction mixture was stirred at 73 "C (external temperature) for 2.5 h and allowed to cool. The reaction mixture was slowly poured under vigorous stirring into a mixture of approximately 200 ml of saline and ice. The suspension was filtered and washed with DCM. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Md5O", filtered, evaporated to give a brown solid. The product was triturated with cold ether and the successively filtered solids were combined to give the desired intermediate ( 3.66 g, 12.4 mmol, 77 Urv).

TOP: Thu-4.987 min.; RH-MS: t/: 291.0 MANI".

Example 202: (5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-14-((5)-1-(2-oxotetrahydropyrimidin-1-yl)-ethyl|-phenyl)- 1,4-dihydro-2H-isoquinolin-3-one.

Koo) (c) (c) syu ALI moio . o ve Z Zh si

The desired compound (22 mg, 0.04 mmol, 1395) was obtained as a pale yellow solid from intermediate 202.1 (86 mg, 0.304 mmol) and intermediate 75.6 (100 mg, 0.289 mmol) analogously to the preparation in Example 75. HPLC Chive-1.178; RH-MS: t/; 565.4

IM-AMNAI".

Intermediate 202.1: 1-((5)-1-(4-Bromophenyl)-ethyl|-tetrahydropyrimidin-2-one.

Oh her

To a solution of 5-(-)-1-(4-bromophenyl)ethylamine (1.06 g, 5.3 mmol) in THF (10 mL) was added dropwise 3-chloropropyl isocyanate (0.546 mL, 5.3 mmol) . After 1 hour Man (60 9o in mineral oil, 0.223 g, 5.57 mmol) was added, and the resulting suspension was stirred at room temperature for 15 h. The reaction was quenched with NgO and MaNsSOOz and THF was removed by evaporation. The remainder was subject to distribution between DCH and NGOs. After separation, the aqueous phase was extracted three more times with DCM, the combined organic extracts were washed with H2O, saturated saline, dried over Mag25O», filtered and evaporated to dryness. The obtained crude substance was purified using Sotheby-Riazpy column chromatography. Soptrapiop "m (Izso Ips.) (BIO; elution in gradient mode,

ДХМ/ДХМ/ЕУН 9:11) 1:0 -» 3:7)) and obtained the desired intermediate product (1.39 g, 4.92 mmol, 93 95) in the form of colorless crystals. TOP: Chine-0.992; RH-MS: t/: 283.2 (MANI.

Example 203: (5)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(6-(methyl-|4-(3-methyl-4-oxoimidazolidine- 1-yl)-transo-cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

M n m M i 75 about this Y /

The desired compound (100 mg, 0.150 mmol, 41 95) was obtained as yellowish crystals from intermediate 198.1 (135 mg, 0.367 mmol) and intermediate 132.1 (159 mg, 0.367 mmol) similarly to the preparation in example 130. HPLC: Rivet-1 ,15 min.; RH-MS: t/2 660.6 (MANI.

Example (204: (5)-1-(4-Chlorophenyl)-7-cyclobutoxy-6-methoxy-2-(6-(methyl-(4-(33-methyl-4-oxoimidazolidin-1-yl)-transo -cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

M rlya M M 4 o o - i /

The desired compound (184 mg, 0.277 mmol, 52,965) was obtained as beige crystals from intermediate 204.1 (190 mg, 0.526 mmol) and intermediate 132.1 (227 mg, 0.526 mmol) analogously to the preparation of example 130. HPLC: Rivet-1 ,11 min.; RH-MS: t/2 658.6 (MANI.

Intermediate 204.1: (5)-1-(4-Chlorophenyl)-7-cyclobutoxy-6-methoxy-1-4-dihydro-2H-isoquinolin-3-one. c) about "ov

Y o) (9)

2 The desired intermediate (555 mg, 1.536 mmol, 3295) was obtained as a white crystalline substance from intermediate 198.2 (1.50 g, 4.84 mmol) and cyclobutanol (0.529 g, 0.726 mmol) analogously to the preparation of intermediate 198.1. TOP: Oive-1.05 min.; RH-

MS: t/2 358.3 MANI".

Example 205: (5)-1-(4-Chlorophenyl)-6-methoxy-2-(6-(methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl-trans-cyclohexylmethyl|-amino) -pyridin-3-yl)-7-((5)-1-(tetrahydrofuran-2-yl)methoxy|-1,4-dihydro-2H-isoquinolin-3-one.

M ro M m 7 - o o - SI /

The desired compound (110 mg, 0.158 mmol, 41 95) was obtained as yellow crystals from intermediate 205.1 (150 mg, 0.383 mmol) and intermediate 132.1 (166 mg, 0.383 mmol) similarly to the preparation in example 130. HPLC: bive-1 .01 min.; RH-MS: t/: 688.7 |M'-NI".

Intermediate product 205.1: (5)-1-(4-Chlorophenyl)-b-methoxy-7-(5)-1-(tetrahydro-furan-2-ylmethoxy|-1,4-dihydro-2H-isoquinoline-3- on. (c) o vi yo

SI

The desired intermediate (132 mg, 0.340 mmol, 34 95) was obtained as a white crystalline substance from intermediate 198.2 (310 mg, 1.00 mmol) and (5)-(tetrahydrofuran-2-yl-methanol) (155 mg, 1.50 mmol) analogous to the preparation of intermediate 198.1 HPLC: Rivea-0.96 min., LC-MS: t/: 388.3 MANI.

Example 206: 1-(4-Chlorophenyl)-7-isopropoxy-b-methoxy-2-I4-(2-oxopyrrolidin-1-iluphenyl|-1,4-dihydro-2H-isoquinolin-3-one. (9) and in vav o si sh

SI

A suspension of intermediate 166.2 (150 mg, 0.274 mmol), 2-pyrrolidinone (25.9 mg, 0.30 mmol), Cc()I (2.61 mg, 0.014 mmol), glycine (4.11 mg, 0.055 mmol ) and tripotassium phosphate (145 mg, 0.685 mmol) in THF (1.5 ml) were heated at 70 °C for 17 h. The reaction mixture was diluted with EAs, washed with a saturated aqueous solution of ManHCO3 and brine.

The combined organic layers were dried over Ma"50", filtered and evaporated to dryness. The obtained crude substance was purified using Sotri-Riavp column chromatography

Sotrapiop "m (Izso Ips.) (BIO; elution in the gradient mode ASOBUDHM-7:3) and obtained the desired compound (26 mg, 0.051 mmol, 18.8 95). HPLC: Chvne-6.81 min.; LC - MS: t/: 505.4 MANI.

Example 207: (5)-1--4-Chlorophenyl)-6-methoxy-2-(5-Imethyl-I(4-(3-methyl-4-oxoimidazolidin-1-

Zyl-trans-cyclohexylmethyl|-amino)-pyrazin-2-yl)-7-((H)-1-(tetrahydrofuran-2-yl)methoxy|-1,4-dihydro-2H-isoquinolin-3-one .

M M wai s M m A o o o-

M SI

/

The desired compound (48 mg, 0.07 mmol, 9.095) was obtained as a yellowish foam from intermediate 205.1 (300 mg, 0.77 mmol) and intermediate 149.1 (296 mg, 0.77 mmol) similarly to the preparation in example 130 TOP: Thu-4.686 min.; RH-MS: t/7 689.7

IM-ANI..

Example 208: 1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-I(4-(2-oxoimidazolidin-1-yl)phenyl|- 1,4-dihydro-2H-isoquinolin-3-one (c) zd v uv Zh

Hu still si si

The desired compound (7.8 mg, 0.015 mmol, 2.5 95) was obtained as a white solid from intermediate 166.2 (340 mg, 0.621 mmol) and imidazolidin-2-one (107 mg, 1.24 mmol) by the method , described in the publication Zupipezi 5, 2008, 9, pp. 1359-1366. TOP: Thu-5.090 min.; RH-

MS: t/2 506.0 (MANI.

Example (209: (5)-1-(4-Chlorophenyl)-7-cyclobutoxy-6-methoxy-2-(5-(methyl-(4-(33-methyl-4-oxoimidazolidin-1-yl)-transo -cyclohexylmethyl|-amino)-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one (c) ovi

VO roya M sia 4 o o- - ; /

The desired compound (126 mg, 0.189 mmol, 38 95) was obtained as a yellow foam from intermediate 204.1 (181 mg, 0.50 mmol) and intermediate 149.1 (193 mg, 0.50 mmol) similarly to the preparation in example 130. TOP: bive--1.16 min.; RH-MS: t/: 659.6 |M'-NI".

Example 210: (5)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(6-(methyl-(4-(4-methyl-3-oxopiperazine- 1-yl)-transo-cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

M s M M A 75 o tv ru SI

The desired compound (176 mg, 0.258 mmol, 47 95) was obtained in the form of yellowish crystals from intermediate 198.1 (200 mg, 0.55 mmol) and intermediate 130.1 (246 mg, 0.55 mmol) similarly to the preparation in example 130. HPLC : bive - 1.05 min.; RH-MS: t/: 674.6 |M'-NI".

Example - 211: (5)-1-(4-Chlorophenyl)-7-cyclobutoxy-6-methoxy-2-(6-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-transo -cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

M n M sia z o i

M what SI ra

The desired compound (137 mg, 0.202 mmol, 48 95) was obtained as yellowish crystals from intermediate 204.1 (150 mg, 0.415 mmol) and intermediate 130.1 (187 mg, 0.415 mmol) similarly to the preparation of example 130. HPLC: Rivei-0 .99 min.; LC-MS: t/z2 672.7 (MANI.

Example 212: (5)-1--4-Chlorophenyl)-6-methoxy-2-(6-Imethyl-I(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|-amino )-pyridin-3-yl)-7-((H)-1-(tetrahydro-furan-2-yl)umethoxy|-1,4-dihydro-2H-isoquinolin-3-one. lne Zm A U (in ) | (c) it

And SI

The desired compound (17.1 mg, 0.024 mmol, 3.2 90) was obtained as a yellowish foam from intermediate 205.1 (300 mg, 0.77 mmol) and intermediate 130.1 (342 mg, 0.77 mmol) analogously to the preparation in example 130. SUPER: Chve-4.10 min.; LC-MS: t/: 702.0

IM-ANI".

Intermediate 213.1: 2-A-((5)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl) -Z-oxopentannitrile.

M

M and ? about

To a mixture of intermediate 164.2 (138 mg, 0.30 mmol) and ethyl propionate (0.14 mL, 1.2 mmol) in THF (0.8 mL) at 0 "C (ice bath) was added a 1M solution of GINMO5 in THF The resulting mixture was stirred at 0 "C for 30 minutes, a 0.25 M aqueous solution of NSII was added to stop the reaction, and the mixture was extracted with ASOK Her (2x). The combined organic fractions were dried over Mag50, filtered and evaporated to dryness. The obtained crude substance was purified by column chromatography Sotbri-Riazpi Sotrapiop "m (Izso Ips.) (510g; elution in the gradient mode ASOBUDHM) and the desired intermediate was obtained (100 mg, 0.17 mmol, 58 95 yield). HPLC: Five -7.619 Min.; RH-MS: t/z 517.4 MANI".

Intermediate 214.1: 4-((5)-1-(4-Modphenyl)-ethyl|-morpholin-3-one.

AND

97

IN

0:

The desired intermediate (239 mg, 0.70 mmol, 81 95) was obtained as a white solid from intermediate 214.2 (320 mg, 0.87 mmol) analogously to the preparation of intermediate 178.2. TOP: Chive-5,620 min.; RH-MS: t/2 331.82 |M'ANI".

Intermediate 214.2: 2-(2-Chlorethoxy)-N-((5)-1-(4-iodophenyl)-ethyl|-acetamide.

KS nN in 0

Intermediate product 178.5 (216 mg, 0.87 mmol) and EM (0.48 ml, 3.5 mmol). After stirring overnight at RT, the reaction was stopped by the addition of a saturated aqueous solution of MnSOO3 and extracted with EOAc. The organic phase was washed with a saturated aqueous solution of ManHsSOOz, dried (Ma»5O»), filtered and concentrated. The residue was purified by column chromatography to give (320 mg, 0.87 mmol, 100 g) the desired compound as a beige oil. TOP: Chnea-5.088 min.; RH-MS: t/: 367.8 (MANI.

Intermediate 216.1: 4-(4-1(5-Bromo-b-fluoropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-1-methylpiperazin-2-one.

Coo)

IS

And about it r

The desired intermediate (701 mg, 1.70 mmol, 99 95) was obtained as a white solid from intermediate 216.2 (950 mg, 1.71 mmol) analogously to that obtained in Example 79. HPLC: Sinea-5.876 min.; RH-MS: t/: 415.3 MANI".

Intermediate 216.2: Methyl ether (4-S((5-bromo-6-fluoropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-(2-(tert-butoxycarbonylmethylamino)-ethyl|-amino) - acetic acid.

IS

AND

(in)

ZY ra -

M (in) r with dk (in)

The desired intermediate (956 mg, 1.75 mmol, 91 95) was obtained as a white solid from intermediate 216.3 (750 mg, 1.93 mmol) and methyl-(2-oxoethyl)-carbamic acid tert-butyl ether ( 502 mg, 2.90 mmol) similarly to obtaining intermediate product 79.2. TOP: Thebes-7.363 min.; RH-MS: t/2 547.2 MANI".

Intermediate 216.3: (4-(((5-bromo-6-fluoropyridin-2-yl)-methylamino|- methyl)-thrano-cyclohexylamino)-acetic acid methyl ester.

E g i - (o) ra t

The desired intermediate (2.99 g, 7.7 mmol, 84 95) was obtained as a white solid from intermediate 216.4 (3.55 g, 9.12 mmol) and methyl 2-bromoacetate (0.88 mL, 9.58 mmol) similar to the preparation of intermediate product 79.1. TOP: Sine-b, 097 min.; LC-MS: t/2 390.3 (M-A-NI".

Intermediate 216.4: (Trans-4-aminocyclohexylmethyl)-(5-bromo-6-fluoro-pyridin-2-yl)-methylamine.

IS

And l -d nm

The desired intermediate (3.59 g, 9.23 mmol, 83 95) was obtained as a white solid from intermediate 216.5 (4.62 mg, 11.1 mmol) analogously to the preparation of intermediate 77.3. TOP: Sive-5.835 min.; RH-MS: t/2 316.3 MANI".

Intermediate 216.5: Tert-butyl ether (4-((5-bromo-6-fluoropyridin-2-yl)-methylamino|-methyl)-trans-cyclohexyl)-carbamic acid.

E veins su

N

The desired intermediate (3.82 g, 9.18 mmol, 56.8 95) was obtained as a white solid

From the substance of the intermediate product 216.6 (6.5 g, 16.1 mmol) and 3795 of an aqueous solution of formaldehyde (122 ml, 1616 mmol) similarly to the preparation of the intermediate product 77.1. TOP: gray: 8.299 min.; RH-MS: t/ 416.3 (MANI.

Intermediate 216.6: 14-(5-bromo-6-fluoropyridin-2-ylamino)-methyl]-trans-cyclohexyl)-carbamic acid tert-butyl ether.

IS

And about whom -d

F and (c) M

N

The desired intermediate (6.56 g, 16.3 mmol, 72.4 95) was obtained as a white solid from (4-formylcyclohexyl)-carbamic acid tert-butyl ether (5.63 g, 24.7 mmol) and 5-bromo-6-fluoropyridin-2-ylamine (4.3 g, 22.5 mmol) analogously to the preparation of intermediate 75.7. TOP: Thebes-7.827 min.; RH-MS: t/ 402.3 (M'ANI".

Intermediate 219.1: 4-(8)-1-5-((5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1-tert-butyl ether N-isoquinolin-2-yl|-pyridin-2-yl-ethyl)-3-oxopiperazine-1-carboxylic acid. r": h om M (9)

IN

And with

The desired intermediate (100 mg, 0.154 mmol, 8.2 95) was obtained as a white solid from intermediate 75.6 (671 mg, 1.94 mmol) and intermediate 219.2 (724 mg, 1.88 mmol) similarly to the preparation in example 75. TOP: Chne-5.473 min.; RH-MS: t/72 649.2

IM-ANI".

Intermediate 219.2: 4-(P)-1-(5-bromopyridin-2-yl)-ethyl|-3-oxopiperazine-1-carboxylic acid tert-butyl ester. »

Hg

M M

Ge kwi u Fr

The desired intermediate (764 mg, 1.97 mmol, 99 95) was obtained as a brown solid from intermediate 219.3 (837 mg, 1.99 mmol) analogously to the preparation of intermediate 178.2. TOP: Rivet-5.031 min.; RH-MS: t/2 385.9 MANI".

Zo Intermediate 219.3: Tert-butyl ether of (2-(CH)-1-(5-bromopyridin-2-yl)-ethyl|-(2-chloroacetyl)amino|-ethyl)-carbamic acid. »

Vg and o DV and trio)

The desired intermediate (837 mg, 1.99 mmol, 80 95) was obtained from intermediate 219.4 (858 mg, 2.49 mmol) and chloroacetyl chloride (0.21 mL, 2.62 mmol) analogously to the preparation of intermediate 178.3. TOP: Uiwe-3.024 min.; RH-MS: t/z 421.9 |MANI".

Intermediate 219.4: 42-(A)-1-(5-bromopyridin-2-yl)-ethylamino|-ethyl)-carbamic acid tert-butyl ether. with. D

Wh and hum

Nm ho

The desired intermediate (868 mg, 2.52 mmol, 73.2 95) was obtained as an orange solid from intermediate 219.5 (693 mg, 3.45 mmol) and (2-bromomethyl)-carbamic acid tert-butyl ether ( 1.0 g, 4.48 mmol) similarly to the preparation of intermediate product 178.4. TOP: Chvne-4.085 min.; RH-MS: t/: 346.1 MANI".

Intermediate 219.4: (K)-1-(5-Bromopyridin-2-yl)-ethylamine. m Vg nm ho

The desired intermediate (1.03 g, 3.72 mmol, 92 95) was obtained as a white solid from intermediate 219.5 (1.24 g, 4.06 mmol) analogously to the preparation of intermediate 201.5. TOP: НХве-3.024 min.; RH-MS: t/2 202.9 |MANI.

Intermediate 219.5: ((K)-1-(5-Bromopyridin-2-yl)-ethyl|1-amide of 2-methylpropane-2-sulfinic acid.

J. Vg

BY

87 xx (in)

The desired intermediate (1.24 g, 4.06 mmol, 54.6 95) was obtained as a white solid from intermediate 219.6 (2.15 g, 7.43 mmol) analogously to the preparation of intermediate 201.6. TOP: Chive-4.624 min.; RH-MS: t/7 306.83 |M'ANI".

Intermediate product 219.6: ((K)-1-(5-Bromopyridin-2-yl)-ethyl|I-amide of 2-methylpropane-2- sulfinic acid. ran and (c)

Zo

The desired intermediate (2.15 g, 7.43 mmol, 46.1 95) was obtained as a white solid from 5-bromo-2-formylpyridine (3.0 g, 16.1 mmol) and (K)-tert -butylsulfinamide (2.05 g, 16.9 mmol) similarly to the preparation of intermediate product 201.7. TOP: Thu-5.029 min.; RH-MS: t/2 290.74 M.-ANI".

Example 223: 1--4-Chlorophenyl)-6-hydroxy-7-isopropoxy-2-(6-methyl-|4-(3-methyl-4-oxoimidazolidin-1-yl)-transo-cyclohexylmethyl|-amino) -pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

(c) he entered A -

M si /

Sodium hydride (15.6 mg, 0.650 mmol) was added to a stirring mixture of the compound of example 132 (100 mg, 0.155 mmol) and DMF (2.0 mL). After mixing for 15 minutes. butane-1-thiol (0.055 mL, 0.511 mmol) was added dropwise at RT and the resulting reaction mixture was immediately heated (oil bath; 160 °C) for 15 min. The resulting crude substance was purified by preparative reversed-phase HPLC (system UmMaieg5) and obtained the racemic desired compound in the form of a yellowish foamy substance (42 mg, 0.066 mmol, 43 95). HPLC: Iave-3.99 min.; LC-MS: t/2 632.6 (M'ANI".

Example 224: 7-((B8)-tert-butoxy)-1-(4-chlorophenyl)-6-hydroxy-2-(6-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl) )-transo-cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one (c) one

Fo u

M "Zh 75 o i schu SI

The desired compound (45 mg, 0.067 mmol, 45 90) was obtained as a yellowish foam from the compound of example 210 (100 mg, 0.148 mmol) similarly to the preparation in example 223.

TOP: Yave-4.11 min.; RH-MS: t/l 660.7 (MANI.

Example 225: 1--4-Chlorophenyl)-6-hydroxy-7-isopropoxy-2-(6-methyl-|4-(4-methyl-3-oxopiperazin-1-yl)-transo-cyclohexylmethyl|-amino) -pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. (c) he

Fo

Y y: (9) ke -zhsh6- Ж

ATO, etc

The desired compound (33 mg, 0.051 mmol, 48 95) was obtained as a beige foam from the compound of example 130 (70 mg, 0.105 mmol) similarly to the preparation in example 223. HPLC:

Oive--0.93 min.; RH-MS: t/: 646.6 (MANI.

Example 226: 1--4-Chlorophenyl)-7-isopropoxy-6-dz-methoxy-2-(6-(methyl-I(4-(4-methyl-3-oxopiperazin-1-yl)-transo-cyclohexylmethyl) |-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

(c) (o) p

S g and F Zh o it

And sh

The desired compound (57 mg, 0.085 mmol, 7.4 95) was obtained as a yellow foam from intermediate 226.1 (400 mg, 1.147 mmol) and intermediate 130.1 (507 mg, 1.147 mmol) analogously to the preparation in example 130. HPLC: Oine-0.99 min.; RH-MS: t/: 663.6 MANI";

NMR NMR (600 MHz, DMSOO-αv) 0.89-1.13 (t, 4 H) 1.17 (a, 9-6.05 Hz, C H) 1.22 (y, 9-5 .85 Hz, Z H) 1.56-1.64 (t, 1 H) 1.63-1.82 (t, 4 H) 2.18-2.27 (t, 1 H) 2.66 ( Y, 9U-5.35 Hz, 2 H) 2.78 (5, Z H) 2.95 (in,

With H) 3.04 (5, 2 H) 3.18 (I, 9-5.25 Hz, 2 H) 3.26-3.33 (t, 2 H) 3.55-4.01 (t , 2 N) 4.38-4.46 (t, 1 N) 5.95 (v, 1 N) 6.51 (a, U-8.88 Hz, 1 N) 6.83 (5, 1 N ) 6.95 (5, 1 H) 7.20 (yes, 9-9.08, 2.62 Hz, 1 H) 7.35 (5, 4 H) 7.76 (y, 9-2.42 Hz, 1 N).

Intermediate 226.1: 1-(4-Chlorophenyl)-7-isopropoxy-6-dz-methoxy-1-4-dihydro-2H-isoquinolin-3-one. (c) (c) r "o

NM r

The same village

To a solution of intermediate 226.2 (1.50 g, 4.52 mmol) and DMF (4.0 mL) was added potassium carbonate (1.25 g, 9.04 mmol) and iodomethane-a3Z3 (1.41 mL, 22, 6 mmol). The suspension was stirred for 2 hours. at 60 "C. The reaction mixture was extracted with EtOAc (3x) and 1M aqueous solution of ManHsoz (1x). The organic phases were washed with saline solution and dried over Mag5O:, filtered and evaporated to dryness. Purification of the residue using column chromatography with a normal phase in the elution with a mixture of EAs - hexane after crystallization (DHM - hexane) provided the desired compound in the form of a white crystalline substance (1.10 g, 3.09 mmol, 68 95): HPLC: "ve-5.02 min.; LC-MS: t/: 349.3

IM-ANI".

Intermediate 226.2: 1-(4-Chlorophenyl)-6-hydroxy-7-isopropoxy-1,4-dihydro-2H-isoquinolin-3-one. (c) he

NM. si

Z The desired intermediate (4.20 g, 12.15 mmol, 70 90) was obtained as a yellow foam from intermediate 138.1 (6.0 g, 17.35 mmol) similarly to the preparation in example 223. HPLC: "Yave- 4.72 min.; LC-MS: t/2 332.3 MANI".

Example 227: 1-(4-Chlorophenyl)-7-isopropoxy-6-dz-methoxy-2-(6-(dz-methyl-I(4-(4-methyl-3-oxopiperazin-1-yl)-transo -cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one.

(c) r.a

І) in the mouth | rya And drink oo

JSC o

The desired compound (180 mg, 0.267 mmol, 47 95) was obtained as yellowish crystals from intermediate 226.1 (200 mg, 0.562 mmol) and intermediate 227.1 (253 mg, 0.562 mmol) similarly to the preparation in example 130. HPLC: Rivet-0 .99 min.; RH-MS: t/72 666.6 (M-NO";

NMR NMR (600 MHz, DMSO-av) 0.95 (d, 9U-11.50 Hz, 2 H), 1.03-1.14 (t, 2 H), 1.17 (a, U -6.05 Hz, Z H), 1.22 (a, 9-6.05 Hz, Z H), 1.54-1.62 (t, 1 H), 1.63-1.83 (t , 4 H), 2.23 (i, 9U-11.40 Hz, 1 H), 2.66 (i, 9-5.15 Hz, 2 H), 2.78 (5, C H), 3 .04 (5.2 N), 3.18 (I, 9-5.25 Hz, 2 N), 3.20-3.29 (t, 2 N), 3.60 (y, 1 N), 3.96 (a, 9-19.98 Hz, 1 N), 4.35-4.47 (t, 9)-5.99, 5.99, 5.99, 5.99, 5.99, 5.75 Hz, 1 N), 5.95 (5.1 N), 6.51 (a, 9-9.08 Hz, 1 N), 6.683 (5, 1 N), 6.95 (in, 1 N), 7.20 (a49, 9-9.08, 2.62 Gu, 1 N), 7.35 (5.4 N), 7.76 (0.9-2.42 Hz, 1 N ).Y

Intermediate 221 1: 4-(4-C(5-Iodopyridin-2-yl)-dz-methylamino|-methyl)u-tranos-cyclohexyl)-1-methylpiperazin-2-one.

SU as oo r le o

The desired intermediate (4.51 g, 10.03 mmol, 85 95) was obtained in the form of beige crystals from intermediate 227.2 (7.55 g, 11.77 mmol) similarly to the preparation in example 130.1. TOP: Rivet-0.77 min.; RH-MS: t/z 446.3 (MANI.

Intermediate 227.2: |(2-(tert-butoxycarbonylmethylamino)-ethyl|-(4- ((5-iodopyridin-2-yl)-dz-methylamino|-methyl)-trans-cyclohexyl)amino|-acetic acid methyl ester . In Va c) r more than

The desired intermediate (7.65 g, 11.92 mmol, 96 95) was obtained as a colorless oil from intermediate 227.3 (5.80 g, 12.42 mmol) similarly to the preparation in example 130.2. TOP: Rivet-1.12 min.; RH-MS: t/2 578.1 (MANI.

Intermediate 227.3: (4-((5-iodopyridin-2-yl)-dz-methylamino|-methyl)-trans-cyclohexylamino)-acetic acid methyl ester.

Zo

M

IF) r o mash

IF)

The desired intermediate product (5.90 g, 12.63 mmol, 90 95) was obtained as a beige oil from intermediate 227.4 (6.10 g, 17.34 mmol) similarly to the preparation in example 130.3. TOP: bive-0.69 min.; RH-MS: t/ 420.9 MANI".

Intermediate 227.4: (Trans-4-aminocyclohexylmethyl)-(5-iodopyridin-2-yl)-(z-methylamino. mya" sy nm oo

The desired intermediate product (6.22 g, 17.68 mmol, 94 95) was obtained in the form of beige crystals from intermediate 227.5 (8.50 g, 18.77 mmol) similarly to the preparation in example 130.4. TOP: Rivet-0.66 min.; РХ-МС: t/2 349.0 MANI".

Intermediate 227.5: (4-S(5-iodopyridin-2-yl)-dz-methylamino|methyl)-trans-cyclohexyl)-carbamic acid tert-butyl ether. du o g Mt

So what

N r

The desired intermediate (8.60 g, 18.99 mmol, 56 95) was obtained in the form of beige crystals from intermediate 227.6 (8.40 g, 33.9 mmol) similarly to the preparation in example 130.5. TOP: Rivet-1.41 min.; RH-MS: t/z 449.3 (MANI.

Intermediate 227.6: Tert-butyl ether (trans-4-dz-methylaminomethyl-cyclohexyl)- carbamic acid. every

Ah, oh

N r

The desired intermediate (8.50 g, 34.3 mmol, 51 95) was obtained as beige crystals from trans-(4-formylcyclohexyl)-carbamic acid tert-butyl ether (15.5 g, 67.5 mmol) and salt from NSI compound СОзМН» (5.05 g, 70.9 mmol) similarly to the preparation in example 130.6. MS: t/2 245.38 |MANI"; "H NMR (400 MHz, DMSO-α): 0.85 - 1.16 (t, 4H), 1.33 - 1.54 (t, 2H), 1.35 (5, 9H), 1.75 (0, 4H), 2.58 (9, 2H), 3.12 (t, 1H), 6.69 (0, 1H).

Example 228: (5)-1--4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(43-methyl-(4-(4-methyl-3-

Zo oxopiperazin-1-yl)-transo-cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. (9) Fr

And with

The desired compound (244 mg, 0.364 mmol, 42 95) was obtained as a white crystalline substance from intermediate 75.6 (300 mg, 0.859 mmol) and intermediate 227.1 (386 mg, 0.859 mmol) similarly to the preparation in example 130. HPLC: Oive- 1.00 min.; LC-MS: t/7 663.6 (MANI; "H NMR (600 MHz, DMSO-av) 0.95 (d, 9U-11.64 Hz, 2 H), 1.05-1.15 (t , 2 H), 1.17 (a, 5-6.05 Hz, C H), 1.22 (a, U-6.05 Hz, C H), 1.54-1.63 (t, 1 H), 1.63-1.81 (t, 4 H), 2.23 (Her, 9-11.20 Hz, 1 H), 2.66 (her, 9-5.15 Hz, 2 H) , 2.78 (5, Z H), 3.04 (5.2 H), 3.18 (Y, U-5.25 Hz, 2 H), 3.21-3.91 (t, 2 H ), 3.60 (0, 1 H), 3.72 (5, C H), 3.96 (y, 1 H), 4.35-4.47 (t, 1 H), 5.95 ( 5, 1 H), 6.51 (a, 9-9.08 Hu, 1 H), 6.83 (5, 1 H), 6.95 (5, 1 H), 7.20 (da, 9 -9.08, 2.42 Gu, 1 N), 7.35 (5, 4 N), 7.76 (y, 9-2.42 Hz, 1 N).

In another embodiment, the present invention relates to a compound exemplified herein.

Other related reference compounds are: 1-(2-chlorophenyl)-6,7-diethoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one, b,7-diethoxy-1- (2-fluorophenyl)-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one, b,7-diethoxy-2-(4-methoxyphenyl)-1-o-tolyl-1, 4-dihydro-2H-isoquinolin-3-one, b,7-diethoxy-2-(4-methoxyphenyl)-1-(2-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one, b, 7-diethoxy-1-(3-fluorophenyl)-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one, b,7-diethoxy-2-(4-methoxyphenyl)-1- m-tolyl-1,4-dihydro-2H-isoquinolin-3-one and b,7-diethoxy-2-(4-methoxyphenyl)-1-(3-methoxyphenyl)-1,4-dihydro-2H-isoquinolin- 3-on

Table 2

Inhibitory activity in relation to Nat and

List of typical compounds proposed in this invention. research data (TK-EVET research data (TK-ENET pis ST V PO AT PO 28717711 07232 НВ 798 17777111111111111156602777777777С1НВ11111111111111

Table 2

Inhibitory activity in relation to Nat and

List of typical compounds proposed in this invention. даними дослідження (ТК-ЕВЕТ даними дослідження (ТК-ЕНЕТ пи: ПЕ КУ РОН ПОООНОЕ Те Ж НОНО 766 ..ЮЙЮ7Ю7Ю7ЮюЮюЮюЮюЮю70лов7777777771117111111111111111116лВ1 768 11771717171717171711160022777777711117111111111111111111ви7 769 11177171 80 777717171717171717171711110002977717Ї11111111111111111281 пи: В Ос СУ ПНЯ ПОН: КО 80 Г111777717171111111б21вя НВ

Table 2

Inhibitory activity in relation to Nat and

List of typical compounds proposed in this invention. data of the study (TK-EVET data of the study (TK-ENET

NB :- not established.

In another embodiment, the present invention relates to crystalline form I of the sulfate compound of example 106, ((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4--methyl-I(4-( 4-methyl-3-oxopiperazin-1-yl)-transo-cyclohexylmethyl|amino)phenyl)-1,4-dihydro-2H-isoquinolin-3-one), and to the method of obtaining the specified crystalline form. The opened crystalline form of sulfate I is much better processed than the amorphous form of the free base and has better solubility and stability.

The method of obtaining crystalline form I of sulfate of the compound of example 106:

A: The method depends

Solvent: isopentyl alcohol (1) Approximately 5 mg of the medicinal substance was first dissolved in 100 μl of IPS (isopropyl alcohol). (2) 364 μl of 0.025 N was added very slowly to the solution. of sulfuric acid, allowing for slow precipitation while stirring at 60 "C. (3) The suspension was stirred at room temperature overnight. (4) The supernatant was removed by centrifugation. (5) The solid product was dried in a vacuum oven at 40 "C overnight and was investigated using PRRG (powder radiography). The method was carried out on a larger scale, and the samples obtained in this way were additionally examined using PRRH. Crystal form I was obtained.

X-ray data were obtained at room temperature using a powder diffractometer VgyKeg АХ5 СОМВН О8bizsomeg (SiCo radiation), equipped with an automatic device for changing samples, a theta-theta goniometer, automatic slits for beam divergence, a second monochromator, and a scintillation counter. Samples for analysis were obtained by carefully pressing the compound through a glass filter. The sample was rotated while being irradiated with SiKa1 x-rays (wavelength -1.54184 angstroms) and the x-ray tube was operated at 40 kV/40 mA. Analyzes were performed with the goniometer operating in continuous mode for 120 seconds. in 0.02" increments over a 2-theta angle range of 5" to 45".

The resulting peaks were calibrated against silicon as a reference standard.

Name of the device: X-ray diffractometer

Model: 08 Oizsomeg

Manufacturer: Vhykeg AH; SMVN

Wavelength: 1.54184 A (Si)

Generator settings: 40.00 kV, 40.00 mA

Monochromator

Detector: NI-5TAV

Frame size: 1024 pixels, 107.79 mm

Experimental technique:

Initial 2-theta value: 5.07

Final 2-theta value: 45.07

Pixel overlap: 20 95

Integration step: 0.027

Scanning duration: 120 seconds.

Temperature: Room temperature

Table A:

PRRG data for the crystalline form I of sulfate of the compound of example 106 (A: suspension method)

A: Anti-solvent technique

Solvents: isopropyl alcohol (1) Approximately 5 mg of the medicinal substance was initially dissolved in 91 μl of 0.025 N. of sulfuric acid in IPS. (2) An anti-solvent, methyl tert-butyl ether, was added to the precipitate of the compound while stirring at 55-60 "C. (3) The suspension was stirred at 55-60 "C overnight. (4) The supernatant was removed by centrifugation. (5) The solid product was dried in a vacuum drying cabinet at 40 "C overnight and examined using PRRH. The method was carried out on a larger scale. The samples obtained in this way were additionally examined using PRRH. Crystalline form I was obtained.

Table B:

PRRH data for crystalline form I of the sulfate compound of example 106 (B: anti-solvent method) have an error of /- 0.27.

One skilled in the art of crystallography should understand that the relative intensities of the various peaks shown in the tables and figures may vary depending on a number of factors, such as the orientational effects of the crystals in the X-ray beam and the purity of the test substance. The positions of the peaks may also change due to variations in the mass of the sample, but they will be basically the same.

It is assumed that the formed sulfate is a bisulfate.

In another embodiment, the present invention relates to crystalline form I of sulfate (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4--Imethyl-(4-(4-methyl-3- oxopiperazin-1-yl)-trans-cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one having a powder X-ray pattern obtained using Si Ka radiation which includes: the following peaks:

Angle 2-theta": 18.8, 21.3 and 22.7, error h/- 0.27.

In fig. 1 shows the data of the powder X-ray pattern for the crystalline form | sulfate of the compound of example 106, obtained by the suspension method.

In fig. 2 shows the data of the powder X-ray pattern for the crystalline form | sulfate of the compound of example 106 obtained by the anti-solvent method.

Additional implementation options: 1. Substituted nitrogen-containing bicyclic heterocycle of formula (I) and/or its tautomers and/or M-oxides and/or pharmaceutically acceptable salts,

With x () in which 7 denotes CH" or M-B-;

X denotes halogen;

B" is selected from the group that includes: H-, C-C7-alkyl-;

Bhe is independently selected from the group which includes: H-, B'O-, (B")2IM-;

B" is independently selected from the group that includes: O-, (B")2M-;

KE" is selected from the group that includes: IN-, C1i-C7-alkyl-, C-C7-alkenyl-, halogen-Ci-C7-alkyl-, halogen-Ci-C7-alkenyl-, C3-C12-cycloalkyl- . -alkyl-, M,M-di-C1-C7-alkylamino-C1-C7-alkyl-, C3-C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-C1-C7-alkyl-, aryl-C1-C7 - alkyl-, C1-C7-alkylcarbonyl-, halogen-C1-C7-alkylcarbonyl-, hydroxy-C1-C7-alkylcarbonyl-, C1-C7- alkoxy-C1-C7-alkylcarbonyl-, amino-C1-C7-alkylcarbonyl- . , aryl-Ci-C7-alkylcarbonyl-, C3-C12-cycloalkyl-C1-C7-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, C1-C7-alkylcarbonyl-C1-C7-alkyl-, halogen-

C1-C7-alkylcarbonyl-C1-C7-alkyl-, hydroxy-C1-C7-alkylcarbonyl-C1-C7-alkyl-, C1-C7-alkoxy-C1-C7- alkylcarbonyl-C1-C7-alkyl-, amino-C1 -C7-alkylcarbonyl-Ci-C7-alkyl-, M-C1-C7-alkylamino-C1-C7- alkylcarbonyl-Ci-C7-alkyl-, M,M-di-C1-C7-alkylamino-C1-C7-alkylcarbonyl -Ci-C7-alkyl-, C3-C12-cycloalkylcarbonyl-C1-C7-alkyl-, heterocyclylcarbonyl-Ci-C7-alkyl-, arylcarbonyl-Ci-C7-alkyl-, carbonyl-C1-C7-alkyl-, hydroxycarbonyl- C1-C7-alkyl-, C1-C7-alkoxycarbonyl-Ci-C7-alkyl-, aminocarbonyl-Ci-C7-alkyl-, M-C1-C7-alkylaminocarbonyl-Ci-C7-alkyl-, M,M-di- C1-C7- alkylaminocarbonyl-C1-C7-alkyl-, C3-C12- cycloalkylcarbonyl-C1-C7-alkyl-, heterocyclylcarbonyl-

C1-C;-alkyl-, arylcarbonyl-C1-C7-alkyl-, C-C;-alkylcarbonylamino-Ci-C7-alkyl-, C-C7- alkylcarbonyl-M-C1-C7-alkylamino-Ci-C7-alkyl -, halogen-C1-C7-alkylcarbonylamino-C1-C7-alkyl-, halogen-C1-C7-alkylcarbonyl-M-C1-C7-alkylamino-C1-C7-alkyl-, where aryl, heterocyclyl and C3-C12-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of: C1-C7-alkyl, halogen-C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, amino group, nitro group or cyano group;

A' is selected from the group that includes: halogen-, cyano-, nitro-, C-C7-alkyl-, C--C7-alkenyl-, halogen-Ci-C7-alkyl-, hydroxy-, C--C7- alkoxy-, amino-, M-C--C7-alkylamino-, M,M-di-C1-C7- alkylamino-, hydroxy-C1-C7-alkyl-, amino-Ci-C7-alkyl-, M-C1 -C7-alkylamino-C1-C7-alkyl-, M,M-di-

C1-C;-alkylamino-Ci-C7-alkyl-, Ci-C7-alkylcarbonylamino-C1-C7-alkyl-, Ci-C7-alkylcarbonyl-M-C1-

C;-alkylamino-Ci-C7-alkyl-; n is from 0 to 2;

B: selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position by the group (BZ)2M-U-, where U is absent (bond), or (83)2M -U- chosen from

From in to Ge) ii | | ! 3 , in Moy and sk in ' In va and with A (o) in and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C7-alkyl-, halogen- C1-C7-alkyl-, hydroxy-, C1-C7-alkyl-, hydroxy-C1-C7-alkyl-; or (B) phenyl, 2-pyridyl or 3-pyridyl, which contain in the para-position a substituent selected from the group consisting of: cyano-, halogen-, nitro-, C1-C7-alkyl-, halogen-C1-C7 -alkyl-, hydroxy-Ci-C7-alkyl-, hydroxycarbonyl-, Ci-C7-alkoxycarbonyl-, Ci-C7-alkylcarbonyl-, Ci-C7-alkyl-, (attached through a C atom)-heterocyclyl-, where (attached through the C)-heterocyclyl atom is unsubstituted or contains 1-4 substituents selected from the group consisting of: C1-C7-alkyl, halo-C1-C7-alkyl, halogen, hydroxy, C1-C7-alkyloxy, amino, nitro or cyano group; and optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, Ci-C7-alkyl-, halogen-Ci-C7-alkyl-, hydroxy-, Ci-C7-alkyl-, hydroxy-C1-C7-alkyl-; or (C) phenyl substituted in the ortho-position by the group KZO- and containing in the para- or meta-position a substituent selected from the group consisting of methyl or chlorine; or (C) (attached through a C atom)-heterocycle selected from o, where 4 denotes a 4-6-membered heterocyclic ring fused with phenyl in the para- and meta-position, which contains 1-3 heteroatoms selected from M , O or 5, which optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C7-alkyl-, halogen-C1-C7- alkyl-, hydroxy-, C1- C7-Alkoxy-, hydroxy-C1-C7-alkyl-; where KZ is independently selected from the group that includes: H-, C1-C7-alkyl-, C3-C12-cycloalkyl-, (H»)2M-

C3-Ci2-cycloalkyl-, (H5)2M-C1-C7-alkyl-, (H5)2M-C3-C12-cycloalkyl-Ci-C7-alkyl-, (B5)2M-C3-C12-cycloalkylcarbonyl-, H »O-C3-C12-cycloalkyl-, H?O-C1-C7-alkyl-, H»O-C3-C12-cycloalkyl-C1-C7-alkyl-, H?O-C3-C12-cycloalkylcarbonyl-, ( H5)2M-carbonyl-C1-C7-alkyl-, H»O-carbonyl-C-C7-alkyl-, aryl-Ci-C7-alkyl-, heterocyclyl-Ci-C7-alkyl-, Ci-C7-alkylcarbonyl- , heterocyclylcarbonyl-, arylcarbonyl-, C3-C12-cycloalkylcarbonyl-, C3-C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-, aryl-, where aryl, heterocyclyl and C3-C12-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group which includes: halogen-, C-C7-alkyl-, halogen-Ci-C7-alkyl-, C-C7-alkylcarbonyl-, C3-C12- cycloalkylcarbonyl-, C-i-C7-alkylsulfonyl- , aminosulfonyl-, M-C1-C7-alkylaminosulfonyl-,

M,M-di-C1-C7-alkylaminosulfonyl-, aminocarbonyl-, M-C1-C7-alkylaminocarbonyl-, M,M-di-C1-C7-alkylaminocarbonyl-, oxo-, or two KZ together with the M atom, to to which they are attached may form a 3-9 membered heterocyclic ring which optionally contains 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1-3 substituents selected from the group consisting of includes: halogen-, C1-C7-alkyl-, halogen-Ci-C7-alkyl-, oxo-, hydroxy-, C-C7-alkyl-, amino-,

M-C1-C7-alkylamino-, /M,M-di-C1-C7-alkylamino-, hydroxycarbonyl-, C-C7-alkoxycarbonyl-, aminocarbonyl-, M-C1-C;-alkylaminocarbonyl-, M,M- di-C1-C7-alkylaminocarbonyl-, C-C;- alkylcarbonyl-, C1-C7-alkylcarbonylamino-, C-C7-alkylcarbonyl-M-C1-C7-alkylamino-; and

B" is independently selected from the group, which includes: H-, C-C7-alkyl-, C4-C7-alkoxycarbonyl-C1-C7-alkyl-, aminocarbonyl-C1-C7-alkyl-, M-C1-C7-alkylaminocarbonyl- C-C7-alkyl-, / M,M-di-C1-C7- alkylaminocarbonyl-Ci-C7-alkyl-, C1-C7-alkylsulfonyl-, aminosulfonyl-, M-C1-C07- alkylaminosulfonyl-, M,M- di-C1-C7-alkylaminosulfonyl-, aminocarbonyl-, M-C1-C7- alkylaminocarbonyl-, /M,M-di-C1-C7-alkylaminocarbonyl-, C3-C12-cycloalkylcarbonyl-, /-C1-C7-

BO Alkoxycarbonylamino-C1-C7-alkyl-, C1-C7-Alkoxycarbonyl-M-C1-C7-Alkylamino-C1-C7-alkyl-, Сч-

C7-Alkoxycarbonyl-

or two K? together with the M atom to which they are attached may form a 3-9 membered heterocyclic ring which optionally contains 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1-3 substituents , selected from the group that includes: Ci-C7;-alkyl-, oxo:x; provided that if 7 denotes СНЭ, n equals 0 and B? selected from the group consisting of: para-

C-C3-alkylphenyl-, para- (halo-C1-C3-alkylphenyl-, para-C1-C3-alkoxyphenyl-, para-halophenyl-, para-nitrophenyl-, para-(C1-C3-alkoxycarbonyl)phenyl-, para-(hydroxycarbonyl)phenyl-, where phenyl optionally contains 1-2 additional substituents, then Be and K" do not both denote an ethoxy group or a methoxy group. 2. The compound of embodiment 1, in which

IN? selected from the group that includes: phenyl, 2-pyridyl or 3-pyridyl, substituted in the para-position by the group (KZ)2M-U-, where U is absent (bond) or (83)2M-U- selected from 3 Z v" Ge! and lush / ' Z ' ' M s V ' she ' sha v ' v'y na ki

E And oh in! and optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, C-C7-alkyl-, halogen-C1-C7-alkyl-, hydroxy-, C-C7-alkyl-, hydroxy-C1-C7-alkyl. 3. The compound of embodiment 2, in which 2 represents CH. 4. The compound of any of the implementation options 2-3, in which

VU is selected from the group, which includes: EO- and

B" is selected from the group consisting of: O-; or

VU is selected from the group, which includes: IN- and

B' is selected from the group that includes: (K")2M-. 5. The compound of any of the embodiments 2-4, in which

Ko) E" is selected from the group that includes: H-, C1-Ca-alkyl-, C-C4-alkenyl-, halogen-C1-Ca-alkyl-, C3-

Ci2-cycloalkyl-, C3-C12-cycloalkyl-C1-C2-alkyl-, where aryl, heterocyclyl and C3-C12-cycloalkyl are unsubstituted or contain 1-2 substituents selected from the group that includes: Ci-Ca-alkyl, halogen-C1-

C.-alkyl, halogen, hydroxy group, C-C--alkyl group, amino group, nitro group or cyano group. 6. The compound of any of embodiments 2-5, in which n is 0. 7. The compound of any of embodiments 2-6, in which

BZ is independently selected from the group that includes: H-, C1-C7-alkyl-, C3-C12-cycloalkyl-, (B8»)2M-C3-

C12-cycloalkyl-, (H5)25M-C1-C7-alkyl-, / (H85)2M-C3-C12-cycloalkyl-Ci-C7-alkyl-, / (85)2M-C3-C12-cycloalkylcarbonyl-, H »O-C1-C7-alkyl-, (H»)2M-carbonyl-C1-C7-alkyl-, H»O-carbonyl-C1-C7-alkyl-, aryl-Ci-C7-alkyl-, heterocyclyl-C1 -C7-alkyl-, C1-C7-alkylcarbonyl-, heterocyclylcarbonyl-, C3-

C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-, where aryl, heterocyclyl and C3-C12-cycloalkyl. are unsubstituted or contain 1-4 substituents selected from the group that includes: halogen-, C1-C7-alkyl-, halogen-C1-C7-alkyl-, C1-C7-alkylcarbonyl-, C3-C12-cycloalkylcarbonyl-, C1 -C7-alkylsulfonyl-,

M,M-di-C1-C7-alkylaminocarbonyl-, oxo:-, or two KZ, together with the M atom to which they are attached, can form a 3-9-membered heterocyclic ring, which optionally contains 1-4 additional heteroatoms , selected from M, O or 5, said heterocyclic ring is unsubstituted or contains 1-3 substituents selected from the group consisting of: C-C7-alkyl-, oxo-, hydroxy-, amino-, M,M-di- C1-C7-alkylamino-, hydroxycarbonyl-,

C1-C;-Alkoxycarbonyl-, aminocarbonyl-, M-C1-C7-alkylaminocarbonyl-, C1-C7-alkylcarbonyl-, C-

C;-alkylcarbonylamino-; and

IN? independently selected from the group that includes: H-, C1-C7-alkyl-, C1-C7-alkyloxycarbonyl-C1-C7-alkyl-, aminocarbonyl-C1-C7-alkyl-, C1-C7-alkylsulfonyl-, M,M -di-C1-C7-alkylaminocarbonyl-, C1-

C;-Alkoxycarbonylamino-C1-C7-alkyl-, C1-C7-Alkoxycarbonyl-, or two BC? together with the M atom to which they are attached may form a 3-9 membered heterocyclic ring which optionally contains 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1-3 substituents , selected from the group that includes: C-C7-alkyl-, oxoh. 8. The compound of any of embodiments 2-7, in which

BZ is independently selected from the group that includes: H-, C1-Ca-alkyl-, C3-C12-cycloalkyl-, (B?)2M-C3-

C;-cycloalkyl-, (85)2M-C1-C7-alkyl-, (85)2M-C3-C7-cycloalkyl-C1-C2-alkyl-, (85)2M-C3-C7- cycloalkylcarbonyl-, aryl- C1-C3-alkyl-, heterocyclyl-C1-C6-alkyl-, C1-C--alkylcarbonyl-, heterocyclylcarbonyl-, C3-C7-cycloalkyl-C1-C6-alkyl-, heterocyclyl-, where aryl, heterocyclyl and

C3-Ci2-cycloalkyl are unsubstituted or contain 1-2 substituents selected from the group that includes: halogen-, C-C-alkyl-, halogen-Ci-C-alkyl-, C1-C--alkylcarbonyl-, C3- C7-cycloalkylcarbonyl-, C1-

C.-alkylsulfonyl-, M,M-di-C1-C"-alkylaminocarbonyl-, oxo-, or two KZ together with the M atom to which they are attached can form a 4-7-membered heterocyclic ring, which is not necessarily contains 1-2 additional heteroatoms selected from M, O or 5, said heterocyclic ring is unsubstituted or contains 1-2 substituents selected from the group consisting of: C-C4-alkyl-, oxo-, hydroxy-, amino-, M,M-di-C1-C4-alkylamino-, hydroxycarbonyl-,

C1-C.-Alkoxycarbonyl-, aminocarbonyl-, M-C1-C--Alkylaminocarbonyl-, C1-C.-Alkylcarbonyl-, C-

S.-alkylcarbonylamino-; and

IN? is independently selected from the group that includes: H-, C1-C6-alkyl-, C1-C4-Alkoxycarbonyl-C1-C2-Alkyl-, aminocarbonyl-C1-C2C-Alkyl-, C1-C--Alkylsulfonyl-, M, M-di-C1-Ca-alkylaminocarbonyl-, C1-

C.-Alkoxycarbonylamino-C1-C8-alkyl-, C-C-Alkoxycarbonyl-, or two K? together with the M atom to which they are attached may form a 4-7 membered heterocyclic ring which optionally contains 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1-2 substituents , selected from the group that includes: С1-Са4-alkyl-, oxox. 9. The compound of formula (I) or its pharmaceutically acceptable salt and/or solvate,

FI x ()

Zo in which 27 denotes SNeo or M-Be;

X denotes halogen;

B" is selected from the group, which includes: H-, C-Ca-alkyl-;

IN? independently selected from the group consisting of: H-, B'O-, (B")2IM-;

B" is independently selected from the group that includes: E'O-, (B")2M-; each K" is independently selected from the group which includes: H-, Ci-Cv-alkyl-, Ci-Cv-alkenyl-, halogen-

C1-C4-alkyl-, halogen-C1-C4-alkenyl-, C3-C7-cycloalkyl-, heterocyclyl-, aryl-, hydroxy-C1-C4- alkyl-, C1-C-- alkoxy-C1-C4-alkyl -, amino-Ci-C4-alkyl-, M-C1-C--alkylamino-Ci-C4-alkyl-, M,M-di-

C1-C4-alkylamino-C1-C4-alkyl-, C3-C7-cycloalkyl-C1-C4-alkyl-, heterocyclyl-C1-C4-alkyl-, aryl-C1-

Ca-alkyl-, C1-C--alkylcarbonyl-, halogen-C1-C.-alkylcarbonyl-, hydroxy-C1-C4-alkylcarbonyl-, C1-

Ca-Alkoxy-C1-C.-alkylcarbonyl-, amino-C1-C--alkylcarbonyl-, M-C1-C4-alkylamino-C1-C4- alkylcarbonyl-, M,M-di-C1-Ca-alkylamino-C1 -C"-alkylcarbonyl-, C3-C1-cycloalkylcarbonyl-, heterocyclyl-C1-C-alkylcarbonyl-, aryl-C1-C4-alkylcarbonyl-, C3-C-cycloalkyl-C1-C4-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl -, C1-C4-alkylcarbonyl-C1-C4-alkyl-, halogen-

C1-C4-alkylcarbonyl-C1-Ca-alkyl-, hydroxy-C1-Ca-alkylcarbonyl-C1-Ca-alkyl-, C1-C4-alkoxy-C1-C4- alkylcarbonyl-C1-Ca-alkyl-, amino-C1 -C4-alkylcarbonyl-C1-Ca-alkyl-, M-C1-C--alkylamino-C1-C4- alkylcarbonyl-C1-Ca-alkyl-, / M.M-di-C1-C«-alkylamino-C1- C"-alkylcarbonyl-Ci-Ca-alkyl-, /C3-C7-cycloalkylcarbonyl-C1-C-alkyl-, heterocyclylcarbonyl-C1-C-alkyl-, arylcarbonyl-Ci-C4-alkyl-, carbonyl-Ci-C4- alkyl-, hydroxycarbonyl-C1-Cα-alkyl-, C-Cα-alkoxycarbonyl-C:1-Cα-alkyl-,

BO aminocarbonyl-C:i-Ca-alkyl-, M-C1-C«-alkylaminocarbonyl-C:1-C4-alkyl-, M,M-di-C1-Ca4- alkylaminocarbonyl-C1-Ca-alkyl-, Cz -C7-cycloalkylcarbonyl-C1-C4-alkyl-, heterocyclylcarbonyl-

C1-C4-alkyl-, arylcarbonyl-C1-C4-alkyl-, C-C4-alkylcarbonylamino-C1-Ca-alkyl-, C-C4- alkylcarbonyl-M-C1-C"-alkylamino-C1-Ca-alkyl- , halogen-C1-C4-alkylcarbonylamino-C1-C4-alkyl-, halogen-C1-C4-alkylcarbonyl-M-C1-C4-alkylamino-C1-C4-alkyl-, where aryl, heterocyclyl and C3-C7-cycloalkyl are unsubstituted or containing 1-4 substituents selected from the group that includes: C1i-Ca-alkyl, halogen-C1-C4-alkyl, halogen, hydroxy group, C1i-C4-alkyl group, amino group, nitro group or cyano group; each E" is independently selected from the group which includes: halogen-, cyano-, nitro-, C-Cα-alkyl-, C1-

Са4-alkenyl-, halogen-С1-С4-alkyl-, hydroxy-, Сі-Сї-аlkoxy-, amino-, M-Сі-Са-alkylamino-, M,M-di-

C-C.-alkylamino-, aminocarbonylamino-, /M-Ci-C4--alkylaminocarbonylamino-, /- M,M-di-C1-Ca- alkylaminocarbonylamino-, C1-C4 alkylcarbonylamino-, aminocarbonyl-, M-C1- Ca4-alkylaminocarbonyl-, M,M-di-C1-C.-alkylaminocarbonyl-, hydroxy-C1-Ca-alkyl-, amino-C1-C4-alkyl-,

M-C1-Ca-alkylamino-C1-Ca-alkyl-, M,M-di-C1-C"-alkylamino-C1-C4-alkyl-, C-C"-alkylcarbonylamino-

C1-Ca-alkyl-, C1-C"-alkylcarbonyl-M-C1-C"-alkylamino-C1-C4-alkyl-; n equals 0, 1 or 2;

B: selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position by the group (BZ)2M-U-, where U is absent (bond) or (83)2M- Y- selected from 3 Z in" Ge! shin ' Z ' ' M s B ' y sha OK bo na ki 3 Z in 0) B and optionally contains 1-2 additional substituents selected from the group that includes: halogen -, cyano-, C1-C6-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C1-C4-alkyl-, hydroxy-C1-C6-alkyl-; or (B) phenyl, 2-pyridyl or C-pyridyl containing in the para-position a substituent selected from the group consisting of cyano-, halogen-, nitro-, C1-C1-alkyl-, halogen-C1-C4-alkyl-, hydroxy-C1-C1- alkyl-, hydroxycarbonyl-, C1-C"-alkoxycarbonyl-, C1-C--alkylcarbonyl-, C-i-C--alkoxy-, (attached through a C atom)-heterocyclyl-, where (attached through a C atom)- heterocyclyl is unsubstituted or contains 1-4 substituents selected from the group consisting of: C1-C4-alkyl, halo-C1-C4-alkyl, halogen,

Z is a hydroxy group, a C-C4-alkoxy group, an amino group, a nitro group or a cyano group; and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C1-C6-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C1-C--alkyl- , (attached through a C atom or an M atom) heterocyclyl-C1-C4-alkyl-, hydroxy-C1-Ca-alkyl-; or (C) phenyl substituted in the ortho-position by the group KZO- and which contains in the para- or meta-position a substituent selected from the group consisting of methyl, chlorine, C1-C6-alkylcarbonyl- or C1-C4- alkoxycarbonyl- ; (C) (attached through a C atom)-heterocycle selected from c, where 4 denotes a 4-6-membered heterocyclic ring ringed with phenyl in the para- and meta-position, which contains 1-3 heteroatoms selected from M, O or 5, which optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C4-alkyl-, halogen-C1-C4-alkyl-, hydroxy-, C-C "-Alkoxy-, hydroxy-C1-Ca-alkyl-; (E) pyrazin-2-yl (relative to isoquinolinone or quinazolinone), substituted in position 5 by a group:

in tb ' (P) pyridazin-Z-yl (relative to isoquinolinone or quinazolinone), substituted in position 6 by a group: in tb ' or (b) pyrimidin-2-yl (relative to isoquinolinone or quinazolinone), substituted in position 5 by a group: in b' where each EZ is independently selected from the group, which includes: H-, C-C4-alkyl-, hydroxy-C1-C4-alkyl-, C3-SU-cycloalkyl-, C1-C4-alkoxy-C1i-C.- -alkylcarbonyl-, amino-C1-C--alkylcarbonyl-, M-C1-Ca4- alkylamino-C1-C.-alkylcarbonyl-, / M,M-di-C1-C4-alkylamino-Ci-C4-alkylcarbonyl-, (85)2M-C3-C7-cycloalkyl-, (85)2M-C1-Ca-alkyl-, (85)2M-C3-C7-cycloalkyl-C1-C4-alkyl-, (85)2M-C3-O7 - cycloalkylcarbonyl-, B5O-C3-C7-cycloalkyl-, HoO-C1-Ca-alkyl-, H5O-C3-C7-cycloalkyl-C1-Ca4-alkyl-, BPO-(C1-Ca-alkyl)-C3-C7 -cycloalkyl-C1-C4-alkyl-, BgO-(hydroxy-C1-Ca-alkyl)-C3-C7-cycloalkyl-C1-C4-alkyl-, (НА5)2M-CO-C3-C7-cycloalkyl-Ci- Са-alkyl-, С1-С4-аlkoxycarbonyl-С3-С7- cycloalkyl-С3-С4-alkyl-, hydroxycarbonyl-С3-С7-cycloalkyl-С3-С4-alkyl-, aminocarbonyl-С3-С7- cycloalkyl-С1-С4 -alkyl-, H»O-C3-C7-cycloalkyl lcarbonyl-, (H»)2M-carbonyl-Ci-C4-alkyl-, B?O-carbonyl-C1-C4-alkyl-, aryl-Ci-C--alkyl-, heterocyclyl-Ci-C4-alkyl-, C1-C--alkylcarbonyl-, halogen-C1-C--alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, C3-SU-cycloalkylcarbonyl-,

C3-C-cycloalkyl-C1-C4-alkyl-, heterocyclyl-, aryl-, where aryl, heterocyclyl and C3-C7-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of: halogen-, Ci- Ca-alkyl-, halogen-C1-Ca-alkyl-, C1-C.-alkylcarbonyl-, C3-C7-cycloalkylcarbonyl-, C1-C.-alkylsulfonyl-, aminosulfonyl-, M-C1-C4-alkylaminosulfonyl-, M ,M-di-C1-C4-alkylaminosulfonyl-, aminocarbonyl-, M-C1-C4-alkylaminocarbonyl-, M,M-di-C1-C«-alkylaminocarbonyl-, oxo-, or two KZ together with the M atom, to to which they are attached, can form a 3-, 4-, 5-, b6- or 7-membered heterocyclic ring, which optionally contains 1, 2, 3 or 4 additional M heteroatoms and which optionally contains an O atom and/or atom 5, the specified heterocyclic ring is unsubstituted or contains 1, 2 or C substituents selected from the group consisting of: halogen-, hydroxy-

С1-Са-alkyl-, С1-Са-alkyl-, halogen-С1-С4-alkyl-, oxo:-, hydroxy-, С1-С4-аlkoxy-, amino-, M-С1-Са4- alkylamino-, M ,M-di-C1-C"-alkylamino-, hydroxycarbonyl-, C-C"-aluoxycarbonyl-, aminocarbonyl- in M-C1-C.-alkylaminocarbonyl-, M,M-di-C1-C"-alkylaminocarbonyl- , C-C"-alkylcarbonyl-, C1-C4- alkylsulfonyl-, heterocyclyl-, C1-C--alkylcarbonylamino-, /C1-C4--alkylcarbonyl-M-C1-C4- alkylamino-; and each E5 is independently selected from the group consisting of: H-, C1-C4-alkyl-, hydroxy-C1-Ca-alkyl-,

C-C4-alkylcarbonyl-, C1-C4-alkoxycarbonyl-C1-C4-alkyl-, aminocarbonyl-C1-Ca-alkyl-, M-C1-C4- alkylaminocarbonyl-C1-C4-alkyl-, M,M-di- C1-C4-alkylaminocarbonyl-C1-C4-alkyl-, C-C4- alkylsulfonyl-, aminosulfonyl-, M-C1-C4-alkylaminosulfonyl-, M,M-di-C1-C4- alkylaminosulfonyl-, heterocyclylcarbonyl-, aminocarbonyl- . C.-Alkoxycarbonyl-M-C1-C-alkylamino-Ci-Ca-alkyl-, C1-C4-Alkoxycarbonyl-, C3-C7- cycloalkyl-, hydroxy-C3-C7-cycloalkyl-, or two EC? together with the M atom to which they are attached, can form a 3-, 4-, 5-, b6- or 7-membered heterocyclic ring, which optionally contains 1, 2, 3 or 4 additional M heteroatoms and/or which necessarily contains an O atom and/or an 5 atom, the specified heterocyclic ring is unsubstituted or contains 1, 2 or C substituents independently selected from the group that includes: C1-C4-alkyl-, oxo-, C1-C4-alkylcarbonyl, Si -C--alkylsulfonyl, hydroxy-C1-Ca-alkyl; provided that if 2 is CH", n is 0 or 1, such that if n is 1, then KE" is ortho-chloro and KE? is selected from the group consisting of: para-C1-C3- alkylphenyl-, para- (halo-C1-C3-alkyl)uphenyl-, para-C1-C3- alkoxyphenyl-, para-halophenyl-, para-nitrophenyl-, para-(C1-C3- alkoxycarbonyl)phenyl-, para- (hydroxycarbonyl)uphenyl-, where phenyl optionally contains 1-2 additional substituents independently selected from halogen and methyl, then Kb and K" are not both ethoxy or methoxy. 10. The compound of formula (I) described in embodiment 9, in which

WU is selected from the group consisting of: H, hydroxy, methoxy, ethoxy, propoxy (isopropoxy or n-propoxy), butoxy (predominantly isobutoxy), morpholine-4-ylethoxy, aminoethoxy, 4-methylpiperazin-1-ylcarbonylmethoxy, dimethylaminoethoxy, dimethylaminopropoxy , a hydroxyethoxy group, a hydroxypropoxy group, a dilmethylaminocarbonylmethoxy group, a methylaminocarbonylmethoxy group and a dz-methoxy group, and better if KU denotes a methoxy group;

AB" is selected from the group that includes: methoxy group, ethoxy group, butoxy group (including isobutoxy group, sec-butoxy group, (K)-sec-butoxy group, (5)-sec-butoxy group), propoxy group (including isopropoxy group, n-propoxy), cyclopropylmethoxy group , cyclopentyloxy group, morpholinyl-4-ylpropoxy group, 3-hydroxypropoxy group, 3-dimethylaminopropoxy group, 1-ethylpropoxy group, 3-aminopropoxy group, cyclobutoxy group, 1-methylbutoxy group, 1,2-dimethylpropoxy group, 3-amino-1-methylpropoxy group, cyclohexyloxy group, benzyloxy group, cyclohexylmethoxy group , cyclobutylmethoxy group, cyclopentylmethoxy group, 2-methoxy-1-methylethoxy group (including, in particular, (K)-2-methoxy-1-methylethoxy), 1,3-dimethyl-but-3-enyloxy group, 1-methyl-but-33- enyloxy group, pyridin-4-ylmethoxy group, trifluoromethoxy group, methoxyethoxy group, (K)-tetrahydrofuran-2-ylmethoxy group, (5)-tetrahydrofuran-2-ylmethoxy group, (K)-2-methoxypropoxy group, 2-methoxy-

Zo 1-methylethoxy group, 1-hydroxycyclopropylmethoxy group, 3-methoxypropoxy group, oxetan-2-ylmethoxy group, 2,2-difluoroethoxy group, isopropylamino group, ethylcarbonylamino group, isopropylpropylamino group, (dimethylaminoethyl)-isopropylamino group, (methylcarbonylaminoethyl)-isopropylamino group, isopropylamino group, 1-cyclopropylamino group, methylamino group , циклогексиламіногрупу, бутиламіногрупу (включаючи втор-бутиламіно), циклобутиламіногрупу, циклопентиламіногрупу, пропіламіногрупу, етиламіногрупу, бензиламіногрупу, циклопропілметиламіногрупу, циклогексилметиламіногрупу, метилкарбоніламіногрупу, ізопропілкарбоніламіногрупу, (метилкарбоніл)ізопропіламіногрупу, (етилкарбоніл)ізопропіламіногрупу, (ізопропіл)уметиламіногрупу та (ізопропіл)етиламіногрупу, та it is better if EE" denotes an isopropoxy group; n is 0 or 1;

And selected from the group that includes: hydrogen, fluorine, chlorine, methyl, methoxy group, bromine, nitro group, amino group, aminocarbonylamino-, methylaminocarbonylamino-, methylaminocarbonyl-, methylcarbonylamino-, ethylaminocarbonylamino-, ethylcarbonylamino-, (ethyl)methylamino-, dimethylamino- , aminocarbonyl-, hydroxymethyl-, aminomethyl-, methylcarbonylaminomethyl, methylaminomethyl;

IN? selected from the group consisting of: (A) phenyl containing the following substituents: 4-dimethylamino-, 4-methylamino-, 4-morpholin-4-yl-, 4-pyrrolidin-1-yl-, 4-dimethylamino-2 - methoxy group, 2-methoxy-4-methyl-, 2-methoxy-4-morpholin-4-yl-, 4-dimethylamino-2-methoxy-, 4-dimethylamino-2-methyl-, 4-(M-methyl- M-pyridin-4-ylmethylamino)-, 4-(2-oxopyrrolidin-1-yl)-, 4-pyrazol-1-yl-, 4-methylcarbonylamino-, 4-(2-oxoazetidin-1-yl)-, 4-(M-methyl-M-ethylamino)carbonyl-, 4-(piperidine-1-carbonyl)-, 4-methylaminocarbonyl, 4-diethylaminocarbonyl-, 4-dimethylaminocarbonyl, 4-(pyrrolidine-1-carbonyl)-, 4 -aminocarbonyl-, 4-(M-methyl-M-pyridin-4-ylaminocarbonyl)-, 4-(M-pyridin-4-ylaminocarbonyl)-, 4-(M-pyridine-3-ylaminocarbonyl)-, (4- hydroxymethyl, 4-M-methylcarbonyl-M-methylamino-, 4-(M-methylcarbonyl-M-cyclopentylmethyl-amino)-, 4-(M-methyl-M-piperidin-3-ylmethylamino)-, 4-(methyl- (1-methylpiperidin-3-ylmethyl)amino |- ; 4-(M-methyl-M-piperidin-4-ylmethylamino)-, 4-(1-acetylpiperidin-4-ylmethyl)-methylamino!|-, 4-

II-methanesulfonylpiperidin-4-ylmethyl)-methylamino|-, 4-(4-amino-cyclohexylmethyl)methylamino)|-, 4-(4-ethylaminocyclohexylmethyl)-methylamino|-, 4-CA-(ethylmethylamino)-cyclohexylmethyl|- methylamino)-,4-diethylamino group, 4-(M-cyclopentylmethyl- or M-methylamino)-, 4-(M-isopropyl-M-methylamino)-, 4-(M-cyclopentyl-M-methylamino)-, 4- (M-

cyclohexyl-M-methylamino)-, 4-(M-tert-butyl-M-methylamino)-, 4-(M-cyclopropylmethyl-M-methylamino)-, 4-(M-cyclohexylmethyl-M-methylamino)-, 4 -(M-isobutyl-M-methylamino)-, 4-(M-benzyl-M-methylamino)-, 4-(M-ethyl-M-methylamino)-, 4-ethylamino-, 4-dipropylamino-, 4- (M-cyclobutyl-M-methylamino)-, 4-(2-fluorobenzyl)-methylamino|-, 4-(2,3-difluorobenzyl)- methylamino|-, 4-Imethyl-(3-trifluoromethylbenzyl)amino|-, 4-(«imethyl-(4-trifluoromethylbenzyl)amino|-, 4A-((3-fluorobenzyl)-methylamino|-, 4-(M-methyl-M-pyridin-3-ylmethylamino)-, 4-(4- fluorobenzyl)-methylamino|-, 4-(3,4-difluorobenzyl)-methylamino|-, ((4-

Pyridin-4-ylmethyl)amino!|-, 4-(M-cyclopropylmethyl-M-pyridin-4-ylmethylamino)-, 4-(M-ethyl-M-pyridin-4-ylmethylamino)-, 4-K2-morpholine -4-ylethyl)-pyridin-4-ylmethylamino!|-, 4-(M-methyl-M-pyrimidin-4-ylmethylamino)-, 4-|((3-fluoropyridin-4-ylmethyl)-methylamino)|- , 4-(M-methyl-M-thiophen-3-ylmethylamino)-, 4-(methyl-(3-methyl-3H-imidazol-4-ylmethyl)amino|-, 4-(M-furan-3-ylmethyl) -M-methylamino)-, 4-(Imethyl-(2-morpholin-4-ylethyl)amino|-, 4-(Imethyl-(1-methylpiperidin-4-ylmethyl)amino|-, 4-(methyl-(4 -propylaminocyclohexyl-methyl)amino|-, 4-(4-dimethylamino-cyclohexylmethyl)-methylamino!|-, 4-(4-aminocyclohexylmethyl)-methylamino|-, A-(4- dimethylaminocyclohexylmethyl)-ethylamino|-, 4- (methyl-(4-pyrrolidin-1-ylcyclohexylmethyl)amino|-, 4-(methyl-(4-piperidin-1-ylcyclohexylmethyl)-amino|-, Id- (methylpiperidin-4-ylmethylamino)-, 4-methyl- I(4-(3-methyl-4-oxoimidazolidin-1-yl)- cyclohexylmethyl)-amino)-, 4-(33-amino-1 H-pyrazol-4-yl)-, 4-(3-Amino- 5-methyl-1H-pyrazol-4-yl)-, 4-(3,5-dimethyl-1H-pyrazol-4-yl)-, 4-(1-pyrrole idin-1-ylethyl)-, 4-(1-morpholin-4-ylethyl)-, 4-(1- hydroxyethyl)-, 4-P1-(piperidin-4-ylamino)-ethyl-, 4-P1-( M-piperidin-4-yl-M-methylcarbonylamino)-ethyl-, 4-1-(M-methyl-M-piperidin-4-ylamino)-ethyl-, 4-1-(4-dimethylaminocyclohexyl)-methylamino|- ethyl)-, 4-(1-(4-aminocyclohexylamino)-ethyl-, 4-(/1-(4-dimethylaminopiperidin-1-yl)- ethyl-, 4-11-(4-(isopropylmethylamino)-piperidine- 1-yl|-ethyl)-, 4-(1-dimethylaminoethyl)-, 4-(1-(4- hydroxypiperidin-1-yl)-ethyl|-, 4-1-(2-dimethylaminoethylamino)-ethyl-, A-1-((H)-3-hydroxypyrrolidin-1-yl)-ethyl|-, 4-11-((5)-3-hydroxypyrrolidin-1-yl)-ethyl/-, 4-11-(( 5)-3-hydroxypiperidin-1-yl)-ethyl|-, 4-(1-(8)-3-hydroxypiperidin-1-yl)-ethyl|-, 4-(1-thiomorpholin-4-ylethyl)- , 4-(1-M-isobutyl-M-methylcarbonylaminoethyl)-, 4-(1-n-propyl-M-methylcarbonylaminoethyl)-; 4-(1-M-isopropyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclopropyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclohexylmethyl-M-methylcarbonylaminoethyl)-, 4-(1- M-cyclopentyl-M-

Zo methylcarbonylaminoethyl)-, 4-(1-M-cyclohexyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclopropylmethyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclopentylmethyl-M-methylcarbonylaminoethyl)-, 4-(1-M-benzyl-M-methylcarbonylaminoethyl)-, 4-(1-M-cyclobutyl-M-methylcarbonylaminoethyl)-, 4-(1-M-pyrrolidine-3-carbonyl-M-ethylaminoethyl)-, 4 -(1-M-cyb-4-aminocyclohexanecarbonyl-M-ethylaminoethyl)-, 4-(1-M-trans-4-aminocyclohexanecarbonyl-M-ethylaminoethyl)-, 4-(1-M-4-dimethylaminocyclohexanecarbonyl-M- ethylaminoethyl)-, 4-(1-M-4-dimethylaminocyclopentanecarbonyl-M-ethylaminoethyl)-, 4-(1-M-1-methylpyrrolidin-3-ylcarbonyl-M-ethylaminoethyl)-, 4-(1-M-4 -dimethylaminocyclohexanecarbonyl-M-ethylaminoethyl)-, 4-p- (piperidin-3-ylamino)-ethyl-, 4-(1-M-(2-aminoethyl)-M-methylcarbonylaminoethyl)-, 4-(1-M- (2-dimethylaminoethyl)-M-methylcarbonyl-aminoethyl)-, 4-(1-M-(3-aminopropyl)-M-methylcarbonylaminoethyl)-, 4-(1-M-(3-dimethylaminopropyl)-M-methylcarbonylaminoethyl) -, 4-H11-(M-ethyl-M-piperidin-4-ylamino)-ethyl-, A-1-(3-aminopiperidin-1-yl) -ethyl-, А--(β8)-3-aminopyrrolidin-1-yl)-ethyl|-, 4-(11-(5)-3-aminopyrrolidin-1-yl)-ethyl-, А-11-( 3- dimethylaminopyrrolidin-1-yl)-ethyl-, 1-(4-diethylaminopiperidin-1-yl)-ethyl/-, 4-(1-(3-oxomorpholin-4-yl)-ethylI|,. 4-(4-dimethylaminocyclohexylmethyl)-methylamino!-, 4-(M-methyl-M-ethylaminocarbonyl)-, 4-(M-cyclopropylmethyl-M-methylamino)-, 4-(2-oxoazetidin-1-yl)- , 4-(1-M-methylcarbonyl-M-ethylaminoethyl)-, 4-(morpholin-4-ylcyclohexylmethyl)amino!|-, 4-(morpholin-4-ylcyclohexyl-methyl)-methylamino!|-,4-( 4-dimethylaminocyclohexylmethyl)-methylamino|-3-methyl, 4-(4-dimethylaminocyclohexylmethyl)-methylamino|-3-fluoro-, A-((4- dimethylaminocyclohexylmethyl)-methylamino|-2-methoxy-, 4-(1- (4-acetylpiperazin-1-yl)-ethyl-, 4-(1-(4-dimethylaminopiperidin-1-yl)-ethyl/i-, 4-((-4-dimethylaminocyclohexylmethyl)-methylamino|-, 4-( -4-dimethylamino-cyclohexylmethyl)ethylamino|-, 4-(2-(4- dimethylaminopiperidin-1 -yl)-1-methylethyl-, 4-(2-(4-dimethylaminopiperidin-1-yl)-1-methyl- 2-oxoethyl-, 4-imidazol-1-ylmethyl, 4-(M-trifluoromethylcarbonyl-M-methylamino)-, 4-(1-(2-oxopiperazin-1-yl)-ethyl|-, 4-(2- hydroxyethyl)-2-oxopiperazin-1-yl|-ethyl)-,4-(1-(methylcarbonylamino)-ethyl-, 4-P1-(methoxymethylcarbonylamino)-ethyl-, 4-(1-(dimethylamino) tyl-carbonylamino)-ethyl-, 4-(2-oxopyrrolidin-1-yl)-, 4-(2-oxoimidazolidin-1-yl)- or 4-(3-amino-5-ethyl-1H-pyrazol- 4-il)-, or

B2 is selected from the group consisting of: phenyl substituted with 2-fluoro or 3-fluoro and substituted in the para-position (relative to isoquinolinone or quinazolinone): (510)

in

M or VK? selected from the group consisting of: phenyl substituted in the ortho-position (relative to isoquinolinone or quinazolinone) by a methoxy group and substituted in the para-position (relative to isoquinolinone or quinazolinone): (c)

walk'

NM o) (c) M

NM T Z ra | .

Mt. Ra

She

, , or ,; or Kk? denotes phenyl substituted in the para-position (relative to isoquinolinone or quinazolinone): Y Si y Sha Tu y mm m M M -o M o o M o

What What Moto SCHOSo oyu F F (F) (9); r o MN MN te o. M and 7 " o. " o. o o o o o what is r

Mt m M Y t y

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Mn "Zh rev r MN SK MN

I W m W m w m w (c) (c) 0.70 st - F, ultrasound

M m M mo o! ! ! ! zi» l rova re o , M z

M M M in in | Go va AH 5

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N N

M (o, (c) o M

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M" about Shi M

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Z n i d y o, ,»o a (o) " What I want: x ssh M ra , ,

M M in general:

ХК о де й х в и хо F.

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NM o a : NM r zh Z Ul x z om y m o

N

(F) M (F) M N

T Z T Z o o. o ono M.

M M o " o " ay y ay on N (in Her.

M Oo-5-50 M oho, eh OZ ra F ia 0

M M

7 M m ), , , , m ! ! ! ouch! in t)

M m y h o u v d (9) (9)

NM NM M M

Ж shcha o ay I "7 I -i o o yuyu ! What sh o. IN S S

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NM,

Kho d- M

M o on

MH or , 5 preferably

N N

OM Oh M M. 20 non Oosho sho

M kora Zh E x Zh

M ra r | p

І І І or . (A) her or K2 denotes 2-pyridyl (relative to isoquinolinone or quinazolinone), substituted 5-((4-dimethylaminocyclohexylmethyl)-methylamino!|-, 5-(4-aminocyclohexylmethyl) amino|-,

M in M in " | what and sh

What o) o) t and | whose (F) MN shchi nm T S

MN i cha ), x z Y -- o

S-o Ge! Gee! scha and no scha

F NM. and this va) scha va « 45 i

M (F)

S shka k ), and ); or 5 Mostly

M. 27O0 u

OM os. M and T fe non chi

M M M

; or (A)iii or K2 denotes C3-pyridyl (relative to isoquinolinone or quinazolinone), substituted 6-((4-dimethylaminocyclohexylmethyl)-methylamino)|- or 6-((3-hydroxycyclobutylmethyl)-methylamino|- or B? denotes C- pyridyl (relative to isoquinolinone or quinazolinone), substituted in the 6th position 6-(methyl-I4-(2-oxopyrrolidin-1-yl)y-cyclohexylmethyl|-amino)-, b-Imethyl-|4-(2-oxoimidazolidine -1-yl)-cyclohexylmethyl)|-amino)-, n

BEETLE in yo DI

Ohm o M o M 07 M

And and. y y (c) M x (in H (c)

M OM M

S. Y. S

M M M

(6) ; Sha z schu " M "and on o M M ! ! In, | !

nou o o В У |c) - (c) you her she and ), Y ), " ), y ), y ; »

J

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WE,; so g i o (c) M o) m y T M (6) 23 3 p

M M M that "thank you M and M"; | or mostly and o (c) M o) m y T M (6) 3 03 p

M M M that "thank you M and M"; | or

or 2 denotes 3-pyridyl (relative to isoquinolinone or quinazolinone), substituted by 2 fluoro-6-in; and (B) and or B? denotes phenyl containing the following substituents: 4-methoxy group, 4-cyano group, 3,4-dimethyl-, 2,4-dimethyl-, 4-methoxy-2-methyl-, 2-chloro-4-methyl-, 2, 4-dimethoxy-, 3,4-dichloro-, 4-methyl-, 3,4-dimethoxy group, 2-methoxy-4-methyl-, 4-(1H-pyrazol-4-yl)-, 4-(3 ,5-dimethyl-1H-pyrazol-4-yl)-, once az

NM NM xx ry x t

M M

MN MN

2 or 2, (B)i or B? denotes 2-pyridyl (relative to isoquinolinone or quinazolinone), substituted by 4-methyl, (B)yl or Be? denotes Z-pyridyl (relative to isoquinolinone or quinazolinone), substituted by 4-methyl, (C) or B? denotes phenyl containing the following substituents: 4-methyl-2-(3-morpholin-4-ylpropoxy)-, 4-methyl-2-hydroxycarbonylmethoxy-, 2-methoxy-5-methyl-, 4-methyl-2-( 2H-tetrazole-

β-ylmethoxy)-, 4-methyl-2-(thiazol-β-ylmethoxy)-, 4-methoxycarbonyl-2-tetrazol-5-ylmethoxy group, 4-methoxycarbonyl-2-methoxy group, 4-methoxycarbonyl-2-thiazole-5 -ylmethoxy)-, 4-methyl-2-(2-morpholin-4-ylethoxy), 2-(3-dimethylaminopropoxy)-4-methyl-, 4-methyl-2-(2-(4-methylpiperazine-1- yl)-ethoxy|-, 4-methyl-2-13-(4-methylpiperazin-1-yl)-propoxy|-, 2-methoxycarbonylmethoxy-5-chloro-, 2-hydroxycarbonyl-methoxy-5-chloro-, 5 -chloro-2-(2-dimethylaminoethoxy)-, 5-chloro-2-(3-morpholin-4-ylpropoxy)-, 5-chloro-2-(2-morpholin-4-ylethoxy)-, 5-chloro- 2-(z-dimethylamino-propoxy)-, 5-chloro-2-(3-hydroxypropoxy)- or 5-chloro-2-(2-hydroxyethoxy)-, (C) or KK: means (attached through a C atom) -heterocycle selected from benzofuran-5-yl and 1-methyl-1H-indazol-5-yl, (E) or Kg denotes pyrazin-2-yl (relative to isoquinolinone or quinazolinone), substituted in position 5 by a group:

Zo x v io) io) y i) ny ny S ny and even more | still with about NM. NM.

M h a t a 7 now nn p p (P) or B2 denotes pyridazin-3Z-yl (relative to isoquinolinone or quinazolinone), substituted in position 6 by a group: 6) х в в!

M

M and or | ; (C) or K2 denotes pyrimidin-2-yl (relative to isoquinolinone or quinazolinone), substituted in position 5 by a group: in

M ka

SU | 5

Go) r M zh pa is o or | .

Claims (1)

FORMULA OF THE INVENTION 1. The compound of the formula (1) ой ре TA в в б х Ко in which 27 means СНо or М-Ве; X means halogen; B" is selected from the group that includes: |H-, C-C7-alkyl-; Bhe is independently selected from the group that includes: H-, B'O-, (A )2M-; B'" is independently selected from the group , which includes: В'О-, (А)2М-; each B" is independently selected from the group consisting of: H-, C-C7-alkyl-, C-C7-alkenyl-, halogen-C1-C;-alkyl-, halogen-Ci-C7-alkenyl-, C3-C1i2 -cycloalkyl-, heterocyclyl-, aryl-, hydroxy-Ci-C7-alkyl-, C-C-alkyl-Ci--SU-alkyl-, amino-Ci-SU-alkyl-, M-C--SU-alkylamino -Ci-C-alkyl-, M,M-di-C1-C7- alkylamino-Ci-C7-alkyl-, C3-Ci2-cycloalkyl-Ci-C7-alkyl-, heterocyclyl-Ci-C7-alkyl-, aryl -Ci-C7-alkyl-, Ci-C7-alkylcarbonyl-, halogen-Ci-C7-alkylcarbonyl-, hydroxy-Ci-C7-alkylcarbonyl-, C1-C7- alkoxy-Ci-C7-alkylcarbonyl-, amino-C1 -C7-alkylcarbonyl-, M-Ci-C7-alkylamino-C1-C7-alkylcarbonyl-, M,M-di-Ci-C7-alkylamino-Ci-C7-alkylcarbonyl-, C3-Ci2-cycloalkylcarbonyl-, heterocyclyl-Ci -C7-alkylcarbonyl-, aryl-Ci-C7-alkylcarbonyl-, C3-C1i2-cycloalkyl-C1-C7-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, C-C7-alkylcarbonyl-Ci-C7-alkyl-, halogen-C1 -C;-alkylcarbonyl-C1-C7-alkyl-, hydroxy-Ci--C7-alkylcarbonyl-Ci-C7-alkyl-, Ci-C7-alkoxy-C1-C7- alkylcarbonyl-Ci-C7-alkyl-, amino- C-C7-alkylcarbonyl-C -C7-alkyl-, M-Ci-C7-alkylamino-C1-C7- alkylcarbonyl-Ci-C7-alkyl-, / M.M-di-Ci-C7-alkylamino-Ci-C7-alkylcarbonyl-Ci-C7- alkyl-, /C3-C12-cycloalkylcarbonyl-C1-C7-alkyl-, heterocyclylcarbonyl-C1-C7-alkyl-, arylcarbonyl-C1-C7-alkyl-, carbonyl-C1-C7-alkyl-, hydroxycarbonyl-C1-C7- alkyl-, C1-SU-alkoxycarbonyl-Ci-C7-alkyl-, aminocarbonyl-Ci-C7-alkyl-, M-C1-C7-alkylaminocarbonyl-C:-C7-alkyl-, M,M-di-C1-C7 - alkylaminocarbonyl-C1-C7-alkyl-, C3-C12-cycloalkylcarbonyl-C1-C7-alkyl-, heterocyclylcarbonyl-C1-C;-alkyl-, arylcarbonyl-C1-C7-alkyl-, C1-SU-alkylcarbonylamino-C1- C7-alkyl-, C-C7- alkylcarbonyl-M-C1-C7-alkylamino-Ci-C7-alkyl-, halogen-Ci-C7-alkylcarbonylamino-Ci-C7-alkyl-, Zo halogen-C1-C7-alkylcarbonyl- M-C1-C7-alkylamino-Ci-C7-alkyl-, where aryl, heterocyclyl and C3-Ci»-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group that includes: C-i-C7-alkyl, halogen-Ci-C7-alkyl, halogen, hydroxy group, C1-C7-alkyl group, amino group, nitro group or cyano group; each B' is independently selected from the group consisting of: halogen-, cyano-, nitro-, C-C7-alkyl-, C1-C7-alkenyl-, halogen-Ci-C7-alkyl-, hydroxy-, C-C7- alkoxy-, amino-, M-C1-C7-alkylamino-, M,M-di-C1-C;-alkylamino-, aminocarbonylamino-, M-C1-C7-alkylaminocarbonylamino-, M,M-di-C1-C7 - alkylaminocarbonylamino-, C1-SU-alkylcarbonylamino-, aminocarbonyl-, M-C1-C7- alkylaminocarbonyl-, M,M-di-C1-C7-alkylaminocarbonyl-, hydroxy-Ci-C7-alkyl-, amino-Ci-C7 -alkyl-, M-C1-C7-alkylamino-C1-C7-alkyl-, M,M-di-Ci-C7-alkylamino-C1-C7-alkyl-, C-C7-alkylcarbonylamino-C1-C;-alkyl -, C--C7-alkylcarbonyl-M-C1-C7-alkylamino-Ci-C7-alkyl-; n is from 0 to 2; B2 is selected from the group consisting of: (A) phenyl, 2-pyridyl and 3-pyridyl substituted in the para-position to isoquinolinone or quinazolinone by the group (B3)2M-U-, where M is absent (bond), or ( 83) 2M-U- chosen from the vez3 vz ate (in) I ' | ' And she M ' ' M ' ' M ' ra ' M ' 877 ' in | c377 c ate; o c and where the specified phenyl, 2-pyridyl or 3-pyridyl optionally contain 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C7-alkyl-, halogen-C1-C7- alkyl-, hydroxy-, Ci-C; - hydroxy- and hydroxy-Ci-C7-alkyl-; or (B) phenyl, 2-pyridyl or 3-pyridyl, which contain in the para-position to the isoquinolinone or quinazolinone a substituent selected from the group consisting of cyano-, halogen-, nitro-, C-C7-alkyl-, halogen -Ci-C7-alkyl-, hydroxy-Ci--C7-alkyl-, hydroxycarbonyl-, Ci-C7-alkoxycarbonyl-, C1-C7- alkylcarbonyl-, Ci-C7-alkoxy-, (attached through a C atom)-heterocyclyl -, where (attached through a C atom)-heterocyclyl is unsubstituted or contains 1-4 substituents selected from the group that includes: C-C-alkyl, halogen-Ci-C7-alkyl, halogen, hydroxy group, C.i-C7 - an alkoxy group, an amino group, a nitro group or a cyano group; and optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, Ci-C7-alkyl-, halogen-Ci-C7-alkyl-, hydroxy-, Ci-C7-alkyl-, (attached through a C atom or an M atom) heterocyclyl-C1-C4-alkyl-, hydroxy-Ci-C7-alkyl-; or (C) phenyl substituted in the ortho-position to the isoquinolinone or quinazolinone by the group WZO- and which contains in the para- or meta-position a substituent selected from the group consisting of methyl, chlorine, C1-C7-alkylcarbonyl- or C-C7 -Alkoxycarbonyl-; (Yur) (attached through a C atom)-heterocycle selected from 8 z where 2 means a 4-6-membered heterocyclic ring fused with phenyl in the para- and meta-position, containing 1-3 heteroatoms selected from M , O or 5, which optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C7-alkyl-, halogen-C1-C7- alkyl-, hydroxy-, C- C7-Alkoxy-, hydroxy-C7-C7-alkyl-; (E) pyrazin-2-yl, substituted in position 5 by a group: ve M ' p v ' З (P) pyridazin-3-yl, substituted in position 6 by a group: З M ! ra v or Zo (C) pyrimidin-2-yl, substituted in position 5 by a group: Z M ! in which each BZ is independently selected from the group that includes: H-, C-C7-alkyl-, hydroxy-Ci-C7-alkyl-, C3-C2-cycloalkyl-, C--C7-alkyl-Ci-C7 -alkylcarbonyl-, amino-Ci-C7-alkylcarbonyl, /M-C1-C7- alkylamino-Ci-C7-alkylcarbonyl, / M.M-di-Ci-C7-alkylamino-Ci-C7-alkylcarbonyl, / (85) 2M-C3-C12-cycloalkyl-, (85)2M-C1-C7-alkyl-, (85)2M-C3-C12-cycloalkyl-Ci-C7-alkyl-, (AU)2M-C3-St2-cycloalkylcarbonyl- , H?O-C3-Ci2-cycloalkyl-, H»O-Ci-C7-alkyl-, H»O-C3-C12-cycloalkyl-C1-C7- alkyl-, BPO-(C1-C;-alkyl)-C3-C12-cycloalkyl-C1-C7-alkyl-, BHO-(hydroxy-C1-C7-alkyl)-C3-C12-cycloalkyl-C1-C7-alkyl -, (Н85)2М-СО-С3-С12-cycloalkyl-Си-С7-alkyl-, С1-С7-alkoxycarbonyl-С3-Си2-cycloalkyl-Си-С7-alkyl-, hydroxycarbonyl-С3-С12-cycloalkyl-Си1 -C7-alkyl-, aminocarbonyl-C3-Ci2-cycloalkyl-Ci-C7-alkyl-, H?O-C3-Ci2-cycloalkylcarbonyl-, (H»)2M-carbonyl-Ci-C7-alkyl-, BPO-carbonyl -Ci-C7-alkyl-, aryl-Ci-C7-alkyl-, heterocyclyl-Ci-C7-alkyl-, Ci-C7-alkylcarbonyl-, halogen-Ci-C7-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, Cz- C12-cycloalkylcarbonyl-, C3-C12-cycloalkyl-C1-C7-alkyl-, heterocyclyl-, aryl-, where aryl, heterocyclyl and C3-C12-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group consisting of: halogen-, C-C7-alkyl-, halogen-C1-C7-alkyl-, C1-C7-alkylcarbonyl-, C3-C12-cycloalkylcarbonyl-, C1-C7-alkylsulfonyl-, aminosulfonyl-, M-C1-C;- alkylaminosulfonyl-, M,M-di-C1-C7-alkylaminosulfonyl-, aminocarbonyl-, M-C-C7-alkylaminocarbonyl-, M,M-di-Ci-C7-alkyl aminocarbonyl-, oxo:, or two BZ, together with the M atom to which they are attached, can form a 3-9 membered heterocyclic ring, optionally containing 1-4 additional heteroatoms selected from M, O, or 5, said heterocyclic the ring is unsubstituted or contains 1-3 substituents selected from the group which includes: halogen-, hydroxy-Ci-C7-alkyl-, Ci-C7-alkyl-, halogen-Ci-C7-alkyl-, oxo-, hydroxy- . -C7-alkylaminocarbonyl-, M,M-di-Si--C7-alkylamino-carbonyl-, C1-C7-alkylcarbonyl-, C-C7-alkylsulfonyl-, heterocyclyl-, C--C7-alkylcarbonyl-amino-, Si -C7-alkylcarbonyl-M-C1-C7-alkylamino-; and every B"? independently selected from the group consisting of: H-, C-C7-alkyl-, hydroxy-Ci-C7-alkyl-, C1-C7- alkylcarbonyl-, C-C7- alkoxycarbonyl-Ci-C7-alkyl-, aminocarbonyl-C -C7-alkyl-, M-C1-C7- alkylaminocarbonyl-C--C7-alkyl-, M,M-di-C1-C7-alkylaminocarbonyl-C-C7-alkyl-, C-C7- alkylsulfonyl-, aminosulfonyl- , M-C1-C7-alkylaminosulfonyl-, M,M-di-C1-C7-alkylaminosulfonyl-, heterocyclylcarbonyl-, aminocarbonyl-, M-C1-C7-alkylaminocarbonyl-, M,M- di-C1-C7-alkylaminocarbonyl- . -C12-cycloalkyl-, hydroxy-C3-C12-cycloalkyl-; Zo or two B? together with the M atom to which they are attached may form a 3-9 membered heterocyclic ring optionally containing 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1 to C substituents selected from the group that includes: Ci-C7-alkyl-, oxo-, Ci-C7-alkylcarbonyl, Ci-C7-alkylsulfonyl, hydroxy-C1-C;-alkyl; provided that, if 2 means CH", n is 0 or 1 and B', if present, means ortho-chlorine, and B? selected from the group consisting of: para-Ci-C3-alkylphenyl-, para-(halo-C1-C3-alkyl)phenyl-, para-C1i-C3-alkoxyphenyl-, para-halophenyl-, para-nitrophenyl-, para -(C1-C3- alkoxycarbonyl)phenyl-, para-(hydroxycarbonyl)uphenyl-, where phenyl optionally contains 1-2 additional substituents independently selected from halogen and methyl, then VU and B" do not both denote an ethoxy group or a methoxy group, aryl means phenyl or naphthyl and heterocyclyl means an unsaturated, saturated or partially saturated ring or ring system which contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms and which contains at least one heteroatom, selected from M, O and 5, where M and 5 may also optionally be oxidized and where, unless otherwise specified, the heterocyclic group may be attached via a heteroatom or carbon atom, or a pharmaceutically acceptable salt thereof. 2. The compound of formula (1) according to claim 1, in which 27 means СНео or М-В-; X means halogen; B" is selected from the group that includes: НО, C1-C; -alkyl-; B? is independently selected from the group that includes: НО, БО, (б2М-; B" is independently selected from the group that includes: БО, ( 510) (AaM-; B' is selected from the group that includes: NU, Ci-C;-alkyl-, Ci-C-alkenyl-, halogen-Ci-C7-alkyl-, halogen-Ci-C7-alkenyl-, C3-Ci2-cycloalkyl-, heterocyclyl-, aryl, hydroxy-Ci-C7-alkyl-, Ci-C-alkoxy-Ci-C7-alkyl-, amino-Ci-C7-alkyl-, M-Ci-C-alkylamino-Ci-C7-alkyl-, M,M- di-C1-C7-alkylamino-C1-C7-alkyl-, C3-Ci2-cycloalkyl-Ci-C7-alkyl-, heterocyclyl-C1-C7-alkyl-, aryl-Ci-C7-alkyl-, C1-C;-alkyl-carbonyl-, halogen-Ci-C7-alkylcarbonyl-, hydroxy-Ci-C7-alkylcarbonyl-, C1-C;-alkoxy-Ci-C7-alkylcarbonyl-, amino-C1-C7-alkylcarbonyl-, M-C1-C7-alkylamino-Ci-C7-alkylcarbonyl-, M,M -di-C1-C7-alkylamino-C1-C7-alkylcarbonyl-, C3-Ci2-cycloalkylcarbonyl-, heterocyclyl-Ci-C7-alkylcarbonyl-, aryl-Ci-C;-alkylcarbonyl-, C3-Ci2-cycloalkyl-Ci-C7-alkylcarbonyl-, heterocyclylcarbonyl-, From arylcarbonyl-, C1-C7-alkylcarbonyl-Ci-C7-alkyl-, halogen-Ci-C7-alkylcarbonyl-Ci-C7-alkyl-, hydroxy-Ci-C7-alkylcarbonyl-Ci-C7-alkyl-, C1-C;-alkyl- C-C7-alkylcarbonyl-C-C7-alkyl-, amino-C1-C7-alkylcarbonyl-C1-C7-alkyl-, M-C1-C7-alkylamino-C1-C7-alkylcarbonyl-C1-C7-alkyl-, M,M-di-C1-C7-alkylamino-C1- C7-alkylcarbonyl-Ci-C7-alkyl-, C3-Ci2-cycloalkylcarbonyl-Ci-C7-alkyl-, heterocyclylcarbonyl-Ci-C7-alkyl-, arylcarbonyl-Ci-C7-alkyl-, carbonyl-Ci-C7-alkyl-, hydroxycarbonyl-C1-C7-alkyl-, C1-SU-alkoxycarbonyl-Ci-C7-alkyl-, aminocarbonyl-Ci-C7-alkyl-, M-C1-C7-alkylaminocarbonyl-C-i-C7-alkyl-, M,M-di-C1-C7-alkylaminocarbonyl-Ci-C7-alkyl-, C3-Ci2-cycloalkylcarbonyl-Ci-C7-alkyl-, heterocyclylcarbonyl -Ci-C7-alkyl-, arylcarbonyl-Ci-C7-alkyl-, BO C1-SU-alkylcarbonylamino-Ci-C7-alkyl-, C1-SU-alkylcarbonyl-M-C1-C7-alkylamino-C1-C7-alkyl-, halogen-Ci-C7-alkylcarbonylamino-Ci-C7-alkyl-, halogen-Ci-C7-alkylcarbonyl-M-C1-C7-alkylamino-C:i-C7-alkyl-, where aryl, heterocyclyl and C3-C1i2-cycloalkyl are unsubstituted or contain 1-4 substituents, selected from the group consisting of: C1-C7-alkyl, halogen-C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkyl group, amino group, nitro group or cyano group; B' is selected from the group which includes: halogen-, cyano-, 60 nitro-, C-C;-alkyl-, C-C-alkenyl-, halogen-Ci-C7-alkyl-, hydroxy-, C-C-alkoxy-, amino-, M-C-i-C7-alkylamino-, M, M-di-C1-C7-alkylamino-, hydroxy-Ci-C7-alkyl-, amino-Ci-C7-alkyl-, M-Ci-C-alkylamino-Ci-C7-alkyl-, M,M-di- C1-C7-alkylamino-C1-C7-alkyl-, C1-SU-alkylcarbonylamino-C1-C7-alkyl-, C1-SU-alkylcarbonyl-M-C1-C7-alkylamino-C1-C7-alkyl-; n is from 0 to 2; IN? selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position by (83)2M-U-, where U is absent (bond), or 20. (83)2M-U- selected from: z v v o i | And sha M ' M ' M ! ' M ' diva Shchy that ho v ate; o c and optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C;-alkyl-, halogen-C-C7-alkyl-, hydroxy-, C-C- alkoxy-, Co) hydroxy-Ci-C7-alkyl-; or (B) phenyl, 2-pyridyl, or 3-pyridyl substituted in the para-position with a substituent selected from the group consisting of: cyano-, halo-, nitro-, C1-C; -alkyl-, halo-C1 -C7-alkyl-, hydroxy-Ci-C7-alkyl-, hydroxycarbonyl-, C-C;-alkoxycarbonyl-, C-C;-alkylcarbonyl-, C-C-alkoxy-, (attached through a C atom)-heterocyclyl- , where (attached through a C atom)-heterocyclyl is unsubstituted or contains 1-4 substituents selected from the group consisting of: C-C7-alkyl, halo-C-C7-alkyl, halogen, hydroxy, C-C7-alkyl, amino, a nitro group or a cyano group; and optionally contains 1-2 additional substituents selected from the group consisting of: halogen-, cyano-, C-C;-alkyl-, halogen-Ci-C7-alkyl-, hydroxy-, C-C-alkyl- , hydroxy-Ci-C7-alkyl-; or (C) phenyl substituted in the ortho-position with NZO- and substituted in the para- or meta-position with a substituent selected from methyl and chlorine; or (Yur) (attached through a C atom)-heterocycle selected from 8, where 7 is a 4-6 membered heterocyclic ring fused with phenyl in the para- and meta-position, containing 1-3 heteroatoms selected from M, O or 5, which optionally contains 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C;-alkyl-, halogen-Ci-C7-alkyl-, hydroxy-, C- C-Alkoxy-, hydroxy-Ci-C7-alkyl-; and BZ is independently selected from the group that includes: NU, Ci-C;-alkyl-, C3-Ci2-cycloalkyl-, (85)2M-C3-C12-cycloalkyl-, (85)2M-C1-C;-alkyl -, (85) 2M-C3-C12-cycloalkyl-Ci-C7-alkyl-, 25. (85) 2M-C3-C12-cycloalkylcarbonyl-, B?O-C3-C:12-cycloalkyl-, B?O-C.-C;-alkyl-, B?O-C3-Ci2-cycloalkyl- C-C7-alkyl-, BPO-C3-C12-cycloalkylcarbonyl-, 0 (85)2M-carbonyl-C1-C7-alkyl-, B?O-carbonyl-C1-C7-alkyl-, aryl-C1-C7- alkyl-, heterocyclyl-C1-C7-alkyl-, C-C;-alkylcarbonyl-, heterocyclylcarbonyl-, arylcarbonyl-, C3-Ci2-cycloalkylcarbonyl-, C3-Ci2-cycloalkyl-Ci-C7-alkyl-, heterocyclyl-, aryl -, where aryl, heterocyclyl and C3-Ci2-cycloalkyl are unsubstituted or contain 1-4 substituents selected from the group which includes: halogen-, C-C;-alkyl-, halogen-Ci-C7-alkyl-, C- C;-alkylcarbonyl-, C3-Ci2-cycloalkylcarbonyl-, C1-SU-alkylsulfonyl-, aminosulfonyl-, M-C1-C7-alkylaminosulfonyl-, M,M-di-Si--C7-alkylaminosulfonyl-, aminocarbonyl-, M -Ci1-C7-alkylaminocarbonyl-, M,M-di-C1-C7-alkylaminocarbonyl-, oxo-, or two BZ together with the M atom to which they are attached can form a 3-9-membered heterocyclic ring, which necessarily contains 1-4 additional heteroatoms selected from M, O or Z, where the indicated heterots the cyclic ring is unsubstituted or contains 1-3 substituents selected from the group consisting of: halogen-, C1-C6-alkyl-, halogen-C1-C7-alkyl-, oxo-, hydroxy-, C1-C7-alkyl- . M,M-di-C1-C7-alkylaminocarbonyl-, C-C;-alkylcarbonyl-, C1-C;-alkylcarbonylamino-, C1-C;-alkylcarbonyl-M-C1-C7-alkylamino-; and B? independently selected from the group that includes: NU, C1-C;-alkyl-, C1-SU-alkoxycarbonyl-C1-C7-alkyl-, aminocarbonyl-C1-C7-alkyl-, M-C1-C7-alkylaminocarbonyl-C- C7-alkyl-, M,M-di-C1-C7-alkylaminocarbonyl-Ci-C7-alkyl-, Zo C1-SU-alkylsulfonyl-, aminosulfonyl-, M-C1-C7-alkylaminosulfonyl-, M,M-di- C--C7-alkylaminosulfonyl-, aminocarbonyl-, M-Ci1-C7-alkylaminocarbonyl-, M,M-di-C1-C7-alkylaminocarbonyl-, C3-Ci2-cycloalkylcarbonyl-, C1-SU-alkoxycarbonylamino-C1-C7- Alkyl-, C1-C;-Alkoxycarbonyl-M-Ci-C7-Alkylamino-Ci-C7-Alkyl-, C-C;-Alkoxycarbonyl-, or two B? together with the M atom to which they are attached may form a 3-9 membered heterocyclic ring optionally containing 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1 to C substituents selected from the group that includes: Ci-C; -alkyl-, oxo-; provided that when 7 is CH", n is 0 and B is selected from the group consisting of: para-Ci-C3-alkylphenyl-, para-(halo-Ci-C3-alkyl)-phenyl-, para- C-C3-Alkoxyphenyl-, para-Halophenyl-, para-Nitrophenyl-, para-(C1-C3-Alkoxycarbonyl)-phenyl-, para-(hydroxycarbonyl)-phenyl-, where phenyl optionally contains 1-2 additional substituents , then Be and DV" do not both denote an ethoxy group or a methoxy group, or a pharmaceutically acceptable salt thereof. 3. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1 or claim 2, in which 7 means 60 CH". 4. The compound of formula (I) or its pharmaceutically acceptable salt according to any of claims 1-3, in which X represents chlorine. 5. The compound of formula (I) or its pharmaceutically acceptable salt according to any of claims 1-4, in which each B' is independently selected from the group that includes: H-, C1-C8-alkyl-, heterocyclyl-C1-C4 -alkyl-, amino-C-C4-alkyl-, M-Ci-C4-alkylamino-C:i-C4-alkyl-, M,M-di-Ci-C--alkylamino-C1-C-alkyl-, heterocyclylcarbonyl-Ci-Ca-alkyl-, hydroxy-Ci-C--alkyl-, aminocarbonyl-Ci-Ca-alkyl-, M-C1-C4- alkylaminocarbonyl-C1-Ca-alkyl-, M,M-di- C-C-alkylaminocarbonyl-Ci-C4-alkyl-, dz-methoxy group, C3-SU-cycloalkyl-C1-Ca-alkyl-, C3-C7-cycloalkyl-, aryl-C1-Ca-alkyl-, C1-C --Alkoxy-Ci-C4-alkyl-, Ci-Cv-alkenyl-, halogen-Ci-Ca-alkyl-, halogen-Ci-Ca-alkenyl-, Ci-C.--alkylcarbonyl-, C1-Ca4- alkylcarbonylamino -C1-C4-alkyl-, aryl-C1-C4-alkyl-, heterocyclyl- and aryl-, where C3-C7-cycloalkyl is indicated (including the C3-C7-cycloalkyl substituent in C3-C7-cycloalkyl-Ci-C4-alkyl -) optionally substituted by hydroxy or methyl, and where aryl (including that contained in aryl-C:-C4-alkyl-) and heterocyclyl (including that contained in heterocyclyl-C1- C..alkyl- and heterocyclylcarbonyl-C1-C--alkyl-) optionally contain 1 or 2 C1-C4-alkyl substituents. 6. The compound of formula (I) according to any one of claims 1, 2 or 3, in which B' is selected from the group that includes: NU, C-C4-alkyl-, C-C-alkenyl-, halogen-C1- C-alkyl-, C3-Ci2-cycloalkyl-, C3-Ci2-cycloalkyl-C1-C6-alkyl-, where aryl, heterocyclyl and C3-Ci2-cycloalkyl are unsubstituted or contain 1-2 substituents selected from the group consisting of : C-C4-alkyl, halo-C1-C4-alkyl, halogen, hydroxy group, C-C-- alkoxy group, amino group, nitro group or cyano group, or a pharmaceutically acceptable salt thereof. 7. The compound of formula (I) according to any one of claims 1, 2, C, or 6, in which VU is selected from: Zo B'C-, and B" is selected from: A c-, or its pharmaceutically acceptable salt. 8. The compound of formula (I) according to any of claims 1-7, in which B? selected from the group consisting of: (A) phenyl, 2-pyridyl, or 3-pyridyl, substituted in the para-position to the isoquinolinone or quinazolinone by the group (AZ)2M-U-, in which U is absent (bond), or ( 83)2M-U- selected from v3 v3 v) DYN in p p M ' M ' M : ; M ' in v ' | I vz and X ' v377 Z | eZ | | (F) | C , and where the indicated phenyl, 2-pyridyl or C-pyridyl optionally contain 1-2 additional substituents selected from the group that includes: halogen-, cyano-, Ci-Ca-alkyl-, halogen-Ci-Ca- alkyl-, hydroxy-, C1-C1-Alkoxy-, hydroxy-C1-C4-alkyl-, or its pharmaceutically acceptable salt. 9. The compound of formula (I) according to claim 8, in which B? selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position to the isoquinolinone or quinazolinone by the group (BZ)2M-U-, in which U is absent (bond), and in in which phenyl, 2-pyridyl or 3-pyridyl do not contain additional substituents, or a pharmaceutically acceptable salt thereof. 10. The compound of formula (I) according to any one of claims 1-9, in which each BZ is independently selected from the group that includes: Ci-Ca-alkyl-, C3-SU-cycloalkyl-Ci--C4-alkyl-, heterocyclyl-Ci-Ca-alkyl-, aryl-C1-C4-alkyl-, (85)2M-C3-C7-cycloalkyl-, (85)2M-C3-C7-cycloalkyl-Ci-Ca4-alkyl-, (85 )24-CO-C3-C7- cycloalkyl-Ci-C4-alkyl-, aryl-, heterocyclyl-, C3-SU-cycloalkyl-, where aryl, heterocyclyl and C3-C7-cycloalkyl are unsubstituted or contain 1-4 substituents, selected from the group that includes: halogen-, C1-C.-alkyl-, halogen-Ci-Ca-alkyl-, C-C--alkylcarbonyl-, C3-C7-cycloalkylcarbonyl-, C1-Ca4- alkylsulfonyl-, aminosulfonyl -, M-C1-C4-alkylaminosulfonyl-, M,M-di-C1-Ca4- alkylaminosulfonyl-, aminocarbonyl-, M-C1-Ca-alkylaminocarbonyl-, M,M-di-C1-Ca- alkylaminocarbonyl- and oxo-, or its pharmaceutically acceptable salt. 11. The compound of formula (I) according to claim 1, in which B? selected from the group consisting of: (A) phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position by the group (HZ)2M-Y-, in which XM is absent, and in which one BZ is C:-C- -alkyl-, and the other BZ means (H8»)2M-cyclohexyl-Ci-C8-alkyl-, and in which two B? together with the M atom to which they are attached, form a b-membered heterocyclic ring which optionally contains 1 additional M heteroatom and/or which optionally contains an O atom and/or an atom of 5, and said heterocyclic ring is unsubstituted or contains 1 or 2 substituents independently selected from the group that includes: C1-C6-alkyl-, oxo-, C-1-C6-alkylcarbonyl, C1-C6-alkylsulfonyl and hydroxy-C1-C6-alkyl, or its pharmaceutical acceptable salt 12. The compound of formula (I) according to any one of claims 1-10, in which, if two substituents BZ are contained and they do not combine to form a ring, then at least one substituent BZ means C:-Ca-alkyl-, or a pharmaceutically acceptable salt thereof. 13. A compound of formula (I) according to any one of claims 1, 2, 3, 6 or 7, in which B: is selected from: phenyl, 2-pyridyl or 3-pyridyl substituted in the para-position with (NAZ) 2M-U-, where U is missing (connection) or (83)2M-U- selected from: v3 v 3 c) i | | I shchi sha ra ' ay M ' ve | 7 ate; o He and optionally contain 1-2 additional substituents selected from the group that includes: halogen-, cyano-, C-C;-alkyl-, halogen-C-C7-alkyl-, hydroxy-, C-C- hydroxy-, hydroxy-Ci-C7-alkyl, and BZ is independently selected from the group that includes: H-, C1-C4-alkyl-, C3-C12-cycloalkyl-, (H»)2M-C3-C7-cycloalkyl- , (IN5)2M-C1-C7-alkyl-, (IN»5)2M-C3-C7-cycloalkyl-C1-C2-alkyl-, (H5)2M-C3-C7-cycloalkyl-Zo carbonyl-, aryl- C-C0-alkyl-, heterocyclyl-Ci-C0-alkyl-, C-C--alkyl-carbonyl-, heterocyclyl-carbonyl-, C3-SU-cycloalkyl-Ci-C0-alkyl-, heterocyclyl-, where aryl, heterocyclyl and C3-Ci2-cycloalkyl are unsubstituted or contain 1-2 substituents selected from the group consisting of: halogen-, C1-C6-alkyl-, halogen-C1-C6-alkyl-, C1-C--alkyl-carbonyl -, C3-C7-cycloalkyl-carbonyl-, C1-C4-alkyl-sulfonyl-, M,M-di-C1-C-alkyl-amino-carbonyl-, oxo-, or two BZ together with the M atom, to to which they are attached, can form a 4-7-membered heterocyclic ring, which optionally contains 1-2 additional heteroatoms selected from M, O or 5, where said heterocyclic ring is unsubstituted or contains 1-2 substituents selected from the group consisting of: C-C4-alkyl-, oxo, hydroxy-, amino-, M,M-di-Ci-C--alkylamino -, hydroxycarbonyl-, C-C.-Alkoxycarbonyl-, aminocarbonyl-, M-C1-C.-Alkylaminocarbonyl-, C-C.-alkylcarbonyl-, C1-C.-alkylcarbonylamino-; and B? independently selected from the group consisting of: N. C-C4-alkyl-, C1-C.-Alkoxycarbonyl-C1-C8-alkyl-, aminocarbonyl-Ci-C8-alkyl-, Zoo C1-C.-alkylsulfonyl-, M,M-di-C1-C--alkylaminocarbonyl-, C1-C.-alkoxycarbonylamino-C1-C6-alkyl-, C-C.-Alkoxycarbonyl-, or two B? together with the M atom to which they are attached may form a 4-7 membered heterocyclic ring optionally containing 1-4 additional heteroatoms selected from M, O or 5, said heterocyclic ring being unsubstituted or containing 1-2 substituents , selected from the group that includes: C-C4-alkyl-, oxo-, or its pharmaceutically acceptable salt. 14. The compound of formula (I) according to claim 1, selected from compounds of the group including: 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy- 1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(3,4-difluorophenyl)-6, 7-diethoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 4-P1-(4-chlorophenyl)-6, 7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-benzonitrile; 1-(4-chlorophenyl)-6,7-diethoxy-2-(5-methylpyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; 2-benzofuran-5-yl-1-(4-chlorophenyl)-6, 7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6,7-diethoxy-2-(b-methylpyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylamino-2-methoxyphenyl)-6, 7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-morpholin-4-ylphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6,7-diethoxy-2-(2-methoxy-4-morpholin-4-ylphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(3,4-dimethylphenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-Z-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-Z-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(2-methoxy-5-methylphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxy-2-methylphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-2-(2-chloro-4-methylphenyl)-1-(4-chlorophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(2,4-dimethoxyphenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-p-tolyl-1,4-dihydro-2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(3,4-dimethoxyphenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(1-methyl-1H-indazol-5-yl)-1,4-dihydro-2H-isoquinoline-3 - he; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-pyrrolidin-1-ylphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-bromophenyl)-7-(A)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chloro-2-methylphenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-33-one; 7-(B8)-tert-butoxy)-1-(4-chloro-3-fluorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1 4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chloro-3-methylphenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-33-one; 7-(B8)-tert-butoxy)-1-(4-chloro-3-nitrophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(33-amino-4-chlorophenyl)-7-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-33-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-dimethylamino-2-methoxyphenyl)-6-methoxy-1 4-dihydro-2H-isoquinolin-33-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-dimethylamino-2-methylphenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-33-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(2-methoxy-4-morpholin-4-ylphenyl)-1,4-dihydro-2H-isoquinoline-3Z - he; 12-17-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-xX-chlorophenyl)-urea ; 1-2-(7-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-b-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-/-chlorophenyl )-3Z-methylurea; M-12-(7-(BA)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline- 1-yl|-5-chlorophenyl)acetamide; 7-(B8)-tert-butoxy)-1-(4-chloro-2-dimethylaminophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 2-(7-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-X-chlorobenzamide; 7-(B8)-tert-butoxy)-1-(4-chloro-2-hydroxymethylphenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(2-aminomethyl-4-chlorophenyl)-7-(A)-tert-butoxy)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; M-(2-I17-(A)-tert-butoxy-2-(4-dimethylaminophenyl)-6b-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline- 1-yl|-5-chlorobenzyl)-acetamide; M-H5-chloro-2-I(6, 7-diethoxy-2-(4-methoxyphenyl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-phenyl)-acetamide; 1-2-(7-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-b-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-/-chlorophenyl )-Z-ethylurea; M-12-(7-(BA)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl|-5-chlorophenyl )-propionamide; 7-(B8)-tert-butoxy)-1-(4-chloro-2-(ethylmethylamino)-phenyl|-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline-3 -one; 2-(7-(B)-tert-butoxy)-2-(4-dimethylaminophenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline-1- Co)yl|-5-chloro-N-methylbenzamide; 7-(B8)-tert-butoxy)-1-(4-chloro-2-methylaminomethylphenyl)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(3-morpholin-4-ylpropoxy)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; (2-11-(4-chlorophenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-5-methylphenoxy)-acetic acid; 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(2H-tetrazol-5-ylmethoxy)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(2-morpholin-4-ylethoxy)-phenyl|-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-2-(2-(3-dimethylaminopropoxy)-4-methylphenyl)-6, 7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(2-(4-methylpiperazin-1-yl)-ethoxy|-phenyl)-1,4-dihydro- 2H- isoquinolin-3Z-one; 1-(4-chlorophenyl)-6,7-diethoxy-2-(4-methyl-2-(3-(4-methylpiperazin-1-yl)-propoxy|-phenyl)-1,4-dihydro-2H- isoquinolin-3-one; (4-chloro-2-(11-(4-chlorophenyl)-6, 7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenoxy)-acetic acid methyl ester; ( 4-chloro-2-(11-(4-chlorophenyl)-6, 7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenoxy)-acetic acid; 2-( IB-chloro-2-(2-dimethylaminoethoxy)-phenyl/|-1-(4-chlorophenyl)-b, 7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one; 2-I(IB- chloro-2-(3-morpholin-4-ylpropoxy)-phenyl|-1-(4-chlorophenyl)-6, 7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one; 2-I(IB-chloro-2-(2-morpholin-4-ylethoxy)-phenyl|-1-(4-chlorophenyl)-6, 7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one 2-I(1B-chloro-2-(3-dimethylaminopropoxy)-phenyl/|-1-(4-chlorophenyl)-6, 7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one; 2 -II-chloro-2-(3-hydroxypropoxy)-phenyl|-1-(4-chlorophenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinoline-3- Gs10) he; 2-IB-chloro-2-(2-hydroxyethoxy)-phenyl|-1-(4-chlorophenyl)-6, 7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one; 6-(BA)-tert-butoxy)-4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-7-methoxy-3,4-dihydro-1H-quinazolin-2-one; 4-(4-chlorophenyl)-6,7-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydro-1H-quinazolin-2-one; 6-(BA)-tert-butoxy)-4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-7-methoxy-1-methyl-3,4-dihydro-1H-quinazolin-2-one; 4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-6,7-dimethoxy-3,4-dihydro-1H-quinazolin-2-one; 6-(BA)-tert-butoxy)-4-(4-chlorophenyl)-7-methoxy-3-(4-methoxyphenyl)-3,4-dihydro-1H-quinazolin-2-one; 4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-6,7-dimethoxy-1-methyl-3,4-dihydro-1H-quinazolin-2-one; 4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-1-ethyl-6, 7-dimethoxy-3,4-dihydro-1H-quinazolin-2-one; 4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-1-isopropyl-b, 7-dimethoxy-3,4-dihydro-1H-quinazolin-2-one; 6-(BA)-tert-butoxy)-4-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-1-ethyl-7-methoxy-3,4-dihydro-1H- quinazolin-2-one; 1-(4-chlorophenyl)-7-methoxy-2-(4-methoxyphenyl)-6-(2-morpholin-4-ylethoxy)-1,4-dihydro-2H-isoquinolin-3-one; 6-(2-aminoethoxy)-1-(4-chlorophenyl)-7-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-ethoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-methoxyphenyl)-6-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy|-1,4 -dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-7-propoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-1 4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6-(2-dimethylaminoethoxy)-7-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6-(2-hydroxyethoxy)-7-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinoline-3- From him; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-(3-dimethylaminopropoxy)-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-isobutoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-Z-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-isopropoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-Z-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-methoxyphenyl)-b6-propoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-(3-hydroxypropoxy)-2-(4-methoxyphenyl)-1,4-dihydro-2H- isoquinolin-3-one; 2-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-methoxyphenyl)-3-oxo-1,2,3,4-tetrahydroisoquinoline-b-yloxy|-M ,M-dimethylacetamide; 2-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-methoxyphenyl)-3-oxo-1,2,3,4-tetrahydroisoquinoline-b-yloxy|-M -methylacetamide; 1-(4-chlorophenyl)-7-isobutoxy-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-tert-butoxy-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclopropylmethoxy-b-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-Z-one; 1-(4-chlorophenyl)-7-cyclopentyloxy-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinoline-3- he 1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-7-(3-morpholin-4-ylpropoxy)-1,4-dihydro-2H-isoquinolin-3-one; 7-((5)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-(3-hydroxypropoxy)-6b-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-(3-dimethylaminopropoxy)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-(1-ethylpropoxy)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinoline-3- (516) he; ZOH 7-(3-aminopropoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclobutoxy-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-7-(1-methylbutoxy)-1,4-dihydro-2H-isoquinoline-3- he 1-(4-chlorophenyl)-7-(1,2-dimethylpropoxy)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(3-amino-1-methylpropoxy)-1-(4-chlorophenyl)-6b-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclohexyloxy-2-(4-dimethylaminophenyl)-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-benzyloxy-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclohexylmethoxy-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclobutylmethoxy-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-ethoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-isobutoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-propoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclopentylmethoxy-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-(1-ethylpropoxy)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclopentyloxy-2-(4-dimethylaminophenyl)-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclopropylmethoxy-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-(1-methylbutoxy)-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-(A)-2-methoxy-1-methylethoxy)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-(1,3-dimethylbut-3-enyloxy)-6-methoxy-1,4-dihydro-2H-isoquinolin-33-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-(1-methylbut-3-enyloxy)-1 4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclobutoxy-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-((5)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1 4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-(pyridin-4-ylmethoxy)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-isopropylamino-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H- isoquinolin-3-one; M-11-(4-chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl)|-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl-propionamide; 1-(4-chlorophenyl)-7-(isopropylpropylamino)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3Z-one; 1-(4-chlorophenyl)-7-(2-dimethylaminoethyl)-isopropylamino|-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; M -(2-(11-(4-chlorophenyl)-2-(4--«methylpyridin-4-ylmethylamino)-phenyl|-3-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl-isopropylamino) -ethyl|-acetamide; 1-(4-chlorophenyl)-7-isobutylamino-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-7-(cyclopentylmethylamino)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl )-7-(1-ethylpropylamino)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl)|-1,4-dihydro-2H-isoquinolin-3Z-one; 1-(4-chlorophenyl)-7-cyclohexylamino-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; 7-tert-butylamino-1- (4-chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-cyclobutylamino-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)- 7-cyclopentylamino-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-(methylpyridin- 4-ylmethylamino)-phenyl|-7-propylamino-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-7-ethylamino-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; 7-benzylamino-1-(4 -chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-(cyclopropylmethylamino)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-(cyclohexylmethylamino)-2-(4-«(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; M-11-( 4-chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl)|-3-oxo-1,2,3,4- tetrahydroisoquinoline-7-yl-acetamide; M-11-(4-chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl)|-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)y-isobutyramide; M-11-(4-chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl)|-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-M-isopropylacetamide; M-11-(4-chlorophenyl)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl)|-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-M-isopropylpropionamide; 1-(4-chlorophenyl)-7-(isopropylmethylamino)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl)-1,4-dihydro-2H-isoquinolin-3Z-one; 1-(4-chlorophenyl)-7-(ethylisopropylamino)-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|-1,4-dihydro- 2H-isoquinolin-3Z-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(2-oxopyrrolidin-1-yl)-phenyl|-1,4-dihydro-2H- isoquinoline -3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-pyrazol-1-ylphenyl)-1,4-dihydro-2H-isoquinoline- With-him; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-I(4-(1H-pyrazol-4-yl)-phenyl|-1,4-dihydro-2H- isoquinolin-3-one; yl|-phenyl)-acetamide; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(2-oxoazetidin-1-yl)-phenyl|-1 4-dihydro-2H- isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl|-b-methoxy-1,4 - dihydro-2H-isoquinolin-3-one; 4-H7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin- 2-yl|-N-ethyl-N-methylbenzamide; (25,48)-1-(4-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- yl|-benzoyl)-4-hydroxypyrrolidine-2-carboxylic acid methylamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(piperidine-1-carbonyl)-phenyl|-1 4-dihydro-2H-isoquinoline-3Z- 4-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M- BO methylbenzamide; 4-H7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M,M-diethylbenzamide ; 4-H7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M,M-dimethylbenzamide ; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(pyrrolidine-1-carbonyl)-phenyl|-1,4-dihydro-2H-isoquinoline-3Z -one; 4-H7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-benzamide; 4-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M-methyl- M-pyridin-4-ylbenzamide; 4-H7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M-pyridin-4- ilbenzamide; 4-H7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M-pyridin-3- ilbenzamide; (5)-1-44-17-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - benzoyl)-pyrrolidine-2-carboxylic acid methylamide; (8)-1-14-17-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- benzoyl)-pyrrolidine-2-carboxylic acid methylamide; (28,45)-1-(4-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- yl|-benzoyl)-4-hydroxypyrrolidine-2-carboxylic acid methylamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-hydroxymethylphenyl)-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|)-1,4-dihydro-2H-isoquinoline- 3-on; M-(4-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)M -methylacetamide; M-14-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl) M-cyclopentylmethylacetamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-«(methylpiperidin-3-ylmethylamino)-phenyl|- 1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-(1-methylpiperidin-3-ylmethyl)-amino|-phenyl)-1,4 -dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methylpiperidin-4-ylmethylamino)-phenyl| - 1,4-dihydro-2H-isoquinolin-3-one; 2--A-((1-acetylpiperidin-4-ylmethyl)-methylamino|-phenyl)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1,4-dihydro -2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-methanesulfonylpiperidin-4-ylmethyl)-methylamino|-phenyl)-b-methoxy-1,4-dihydro-2H -isoquinolin-3-one; 4-((4-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- Zo phenyl)-methylamino)-methyl|-piperidine-1-carboxylic acid dimethylamide; 2--4-Ktrans-4-aminocyclohexylmethyl)-methylamino|-phenyl)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-1,4-dihydro-2H- isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-Ktrans-4-ethylaminocyclohexylmethyl)-methylamino|-phenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline- 3-on; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-C4-(ethylmethylamino)-trans-cyclohexylmethyl-methylamino)-phenyl)-6b-methoxy-1,4-dihydro- 2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-diethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-Z-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4--cyclopentylmethylmethylamino)-phenyl|-b-methoxy-1,4- dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(isopropylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinolin-3Z-one; 7 -(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4--(cyclopentylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(cyclohexylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7 -(B8)-tert-butoxy)-2-(4-(tert-butylmethylamino)-phenyl|-1-(4-chlorophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-33-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(cyclopropylmethylmethylamino)-phenyl|-b-methoxy-1,4- dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4--(cyclohexylmethylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(isobutylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 2-(D-(benzylmethylamino)-phenyl|-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-ethylmethylamino)-phenyl|-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-ethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline- 60 Z-on; 7-(B)-tert-butoxy)-1-(4-chloro-phenyl)-2-(4-dipropylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(cyclobutylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinolin-33-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(2-fluorobenzyl)-methylamino|-phenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline-3 - he; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(2,3-difluorobenzyl)-methylamino|-phenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline -3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-(3-trifluoromethylbenzyl)-amino|- phenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-(4-trifluoromethylbenzyl)-amino|-phenyl)-1,4-dihydro-2H -isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-((3-fluorobenzyl)-methylamino|-phenyl)-b-methoxy-1,4 - dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methylpyridin-3-ylmethylamino)-phenyl|)-1,4-dihydro-2H-isoquinoline- 3-on; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(4-fluorobenzyl)-methylamino|-phenyl)-b-methoxy-1,4-dihydro-2H-isoquinoline-3 - he; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-((3,4-difluorobenzyl)-methylamino|-phenyl)-b-methoxy- 1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-4-pyridin-4-ylmethyl)-amino|-phenyl)-1,4-dihydro-2H-isoquinoline- 3-on; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(cyclopropylmethylpyridin-4-ylmethylamino)-phenyl|-6-methoxy-1,4-dihydro-2H-isoquinoline-3 - he; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(ethylpyridin-4-ylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinoline-3 -one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-(2-morpholin-4-ylethyl)-pyridin-4-ylmethylamino|-phenyl)- 1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methylpyrimidin-4-ylmethylamino)-phenyl|-1,4- dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-((33-fluoropyridin-4-ylmethyl)-methylamino|-phenyl)-6-methoxy-1,4-dihydro -2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methylthiophen-33-ylmethylamino)-phenyl|-1, 4- dihydro-2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-(3-methyl-3-imidazol-4-ylmethyl)-amino|-phenyl) -1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(furan-3-ylmethylmethylamino)-phenyl|- b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-|(methyl- (2-morpholin-4-ylethyl)-amino|-phenyl)- 1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-(1-methylpiperidin-4-ylmethyl)-amino|-phenyl)-1,4 -dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-(4-propylamino-trans-cyclohexylmethyl) )-amino|-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl|-trans-cyclohexyl)-acetamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(4-dimethylamino-trans-cyclohexylmethyl)-methylamino|-phenyl)-6-methoxy-1,4-dihydro-2H -isoquinolin-3-one; 2--4-Ktrans-4-aminocyclohexylmethyl)-methylamino|-phenyl)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)- b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl|-trans-cyclohexyl)-acetamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(4-dimethylamino-trans-cyclohexylmethyl)-methylamino|-phenyl)-6-methoxy-1,4-dihydro-2H -isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl-(1-propionylpiperidin-4-ylmethyl)-amino|-phenyl)-1,4 -dihydro-2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methyl-(1-(3-methylbutyryl)- piperidin-4-ylmethyl (amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-isobutyrylpiperidin-4-ylmethyl)-methylamino|- 60 phenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chloro-phenyl)-2-14-(1-cyclopropanecarbonylpiperidin-4-ylmethyl)-methylamino|-phenyl)-6-methoxy-1,4-dihydro -2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-2-44-(1-butyrylpiperidin-4-ylmethyl)-methylamino|-phenyl)-1-(4-chlorophenyl)-b-methoxy-1,4-dihydro-2H -isoquinolin-3-one; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl|-trans-cyclohexyl)-3-methylbutyramide; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl-trans-cyclohexyl)-isobutyramide; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl|-transo-cyclohexyl)-propionamide; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl (trans-cyclohexyl)-butyramide; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl|-trans-cyclohexyl)-methanesulfonamide; 3-14-((4-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |- phenyl)-methylamino)-methyl|-transo-cyclohexyl)-1,1-dimethylurea; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-cyclobutanecarbonylpiperidin-4-ylmethyl)-methylamino|-phenyl)-6-methoxy-1,4-dihydro-2H -isoquinolin-3-one; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl|-thrano-cyclohexyl)-N-ethylacetamide; M-14-(14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-methylamino)-methyl|-trans-cyclohexyl-M-ethylmethanesulfonamide; 1-44-(44-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - phenyl)-methylamino)-methyl|-thrano-cyclohexyl)-1-ethyl-3,3-dimethylurea; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-Ktrans-4-dipropylaminocyclohexylmethyl)-methylamino|-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinoline- 3-on; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-Ttrans-4-(isobutylmethylamino)-cyclohexylmethyl|-methylamino)-phenyl)-6b-methoxy-1,4-dihydro -2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-CHtrans-4-(isopropylmethylamino)-cyclohexylmethyl|- methylamino)-phenyl)-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(1-pyrrolidin-1-ylethyl)-phenyl|-1,4-dihydro-2H-isoquinoline -3Z-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-(1-morpholin-4-ylethyl)-phenyl|-1 4-dihydro- 2H-isoquinolin-3Z-one; 7-(B)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(1-hydroxyethyl)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one ; M-(1-14-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - phenyl)-ethyl)-M-ethylacetamide; 1-acetylpiperidine-4-carboxylic acid (1-14-H7-(A)-second-butoxy)-1-(4-chlorophenyl)-6-methoxy-3- oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-ethyl)-ethylamide; Piperidine-4-carboxylic acid (1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl(1-phenyl)-ethyl)-ethylamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-P1-(piperidin-4-ylamino)-ethyl|-phenyl)-1,4-dihydro-2H -isoquinolin-3-one; M-(1-14-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - phenyl)-ethyl)-M-piperidin-4-ylacetamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-P1-(methylpiperidin-4-ylamino)-ethyl|-phenyl)-1,4-dihydro-2H -isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-11-(cis-4-dimethylaminocyclohexyl)-methylamino|- ethyl-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-ethyl)-N-(cis-4-dimethylaminocyclohexyl)-acetamide; 2-14-1-(trans-4-aminocyclohexylamino)-ethyl|-phenyl)-7-((A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-P1-(4-dimethylaminopiperidin-1-yl)-ethyl|-phenyl)-6-methoxy-1,4-dihydro -2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-11-14-(isopropylmethylamino)-piperidin-1-yl|-ethyl)-phenyl)-6-methoxy-1 ,4-dihydro-2H-isoquinolin-3-one; M-011-(1-14-(7-((A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -ili|- bo phenyl)-ethyl)-piperidin-4-yl|-acetamide; Zo8 2-14-(1-(4-acetylpiperazin-1-yl)-ethyl|-phenyl)-7-((A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1,4 -dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-I(4-(1-dimethylaminoethyl)-phenyl|-6-methoxy-1,4-dihydro-2H-isoquinoline-3Z- he 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(1-(4-hydroxypiperidin-1-yl)-ethyl|-phenyl)-b-methoxy- 1,4 -dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-/1-(2-dimethylaminoethylamino)-ethyl|-phenyl)-b -methoxy-1,4-dihydro-2H-isoquinolin-3-one; 2--A-1-(1-acetylpiperidin-4-ylamino)-ethyl|-phenyl)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6- methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-(A)-3-hydroxypyrrolidin-1-yl)-ethyl|-phenyl)-6-methoxy-1 ,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(11-((5)-3-hydroxypyrrolidin-1-yl)y-ethyl|-phenyl)-6- methoxy -1,4-dihydro-2H-isoquinolin-3-one; 1-(1-4-H7-((B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-ethyl)-piperidine-4-carboxylic acid amide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-((5)-3-hydroxypiperidin-1-yl)-ethyl|-phenyl)-b- methoxy- 1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-11-(8)-3-hydroxypiperidin-1-yl)-ethyl|-phenyl)-6- methoxy-1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(1-thiomorpholin-4-ylethyl)-phenyl|-1,4-dihydro-2H-isoquinoline -3Z-one; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|-phenyl)-ethyl)-N-isobutylacetamide; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - phenyl)-ethyl)-M-propylacetamide; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-ethyl)-N-isopropylacetamide; M-(1-14-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - Zo phenyl)-ethyl)-M-cyclopropylacetamide; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-ethyl)-M-cyclohexylmethylacetamide; M-(1-(4-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - phenyl)-ethyl)-M-cyclopentylacetamide; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - phenyl)-ethyl)-M-cyclohexylacetamide; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-ethyl)-N-cyclopropylmethylacetamide; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-ethyl)-N-cyclopentylmethylacetamide; M-benzyl-M-(1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl(1-phenyl)-ethyl)-acetamide; M-(1-14-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl| - phenyl)-ethyl)-M-cyclobutylacetamide; 1-methylpiperidine-4-carboxylic acid (1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|-phenyl)-ethyl)-ethylamide; 1-Methylpiperidine-3-carboxylic acid (1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|-phenyl)-ethyl)-ethylamide; (155,38)-3-aminocyclopentanecarboxylic acid /(1-14-(7-((B)-tert-butoxy)-1-(4-chlorophenyl)-6- methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-ethyl)-ethylamide; (18,38)-3-Aminocyclopentanecarboxylic acid (1-(4-I(7-((BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4- dihydro-1H-isoquinolin-2-yl|-phenyl)-ethyl)-ethylamide;pyrrolidine-33-carboxylic acid (1-(4-(7-(B)-t-butoxy)-1-(4-chlorophenyl) )-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl(1-phenyl)-ethyl)-ethylamide; cis-4-aminocyclohexanecarboxylic acid (1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl(phenyl)-ethyl)-ethylamide; trans-4-aminocyclohexanecarboxylic acid (1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl|-phenyl)-ethyl)-ethylamide; trans-4-dimethylaminocyclohexanecarboxylic acid (1-14-(7-(A)-tert-butoxy)-1-(4- bo chlorophenyl)-6b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-ethyl)-ethylamide; (18,38)-3-dimethylaminocyclopentanecarboxylic acid (1-14-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy-3-oxo-3,4-dihydro-1 N-isoquinolin-2-yl|-phenyl)-ethyl)-ethylamide; 1-methylpyrrolidine-3-carboxylic acid (1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|-phenyl)-ethyl)-ethylamide; cis-4-dimethylaminocyclohexanecarboxylic acid (1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- yl|-phenyl)-ethyl)-ethylamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-P1-(5)-piperidin-3-ylamino)-ethyl|-phenyl)- 1,4- dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-P1-(B)-piperidin-3-ylamino)-ethyl|-phenyl)- 1,4-dihydro-2H-isoquinolin-3-one; M-((5)-1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl(-phenyl)-ethyl)-N-(H)-piperidin-3-ylacetamide; M-((8)-1-14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl|-phenyl)-ethyl)-N-(H)-piperidin-3-ylacetamide; M-((5)-1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl (phenyl)-ethyl)-N-(5)-piperidin-3-ylacetamide; M-((8)-1-14-(7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 -yl|-phenyl)-ethyl)-N-(5)-piperidin-3-ylacetamide; M-(2-aminoethyl)-M-(1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H - isoquinolin-2-yl (phenyl)-ethyl)-acetamide; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-ethyl)-N-(2-dimethylaminoethyl)-acetamide; M-(3-aminopropyl)-M-(1-14-(7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H- isoquinolin-2-yl (1-phenyl)-ethyl)-acetamide; M-(1-4-(7-(BA)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- phenyl)-ethyl)-N-(3-dimethylaminopropyl)-acetamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-P1-(ethylpiperidin-4-ylamino)-ethyl|-phenyl)-b-methoxy-1,4-dihydro-2H -isoquinolin-3-one; 2-14-(1-((5)-3-aminopiperidin-1-yl)-ethyl|-phenyl)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6b-methoxy- 1,4-dihydro-2H-isoquinolin-3-one; 2-A-1-(8)-3Z-aminopyrrolidin-1-yl)-ethyl|-phenyl)-7-((B)-tert-butoxy)-1-(4-chlorophenyl)-b-methoxy-1 ,4-dihydro-2H-isoquinolin-3-one; 2-1A4-11-((5)-3-aminopyrrolidin-1-yl)-ethyl|-phenyl)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-1 ,4-dihydro-2H-isoquinolin-3-one; M-(5)-1-(1-14-H7-(A)-tert-butoxy-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 - yl(1-phenyl)-ethyl)-piperidin-3-yl)|-acetamide; M-KA)-1-(1-14-(7-(A-second-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl(1-phenyl)-ethyl)-pyrrolidine-3-yl)1-acetamide; M-(5)-1-(1-14-H7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline -2- yl(1-phenyl)-ethyl)-pyrrolidine-3-yl)1-acetamide; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-11-(5)-3-dimethylaminopiperidin-1-yl)-ethyl|-phenyl)-6-methoxy-1, 4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-((5)-3-dimethylaminopyrrolidin-1-yl)-ethyl|-phenyl)-6- methoxy- 1,4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-11-(A)-3-dimethylaminopyrrolidin-1-yl)-ethyl|-phenyl)-b-methoxy-1, 4-dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-2-14-(1-(4-diethylaminopiperidin-1-yl)-ethyl|-phenyl)-b- methoxy-1,4- dihydro-2H-isoquinolin-3-one; 7-(B8)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-14-(1-(3-oxomorpholin-4-yl)-ethyl|-phenyl)-1,4- dihydro-2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2--4-(trans-4-dimethylaminocyclohexylmethyl)-methylamino|-phenyl)-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one; (2)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2--4-Ktrans-4-dimethylaminocyclohexylmethyl)-methylamino|-phenyl)-6-methoxy-1,4-dihydro -2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-Z-one; (28)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-Z-one; (5)-7-(5-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinoline- 60 Z-on; (8)-7-(5-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-methoxyphenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (2)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 4-((5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M - ethyl-M-methylbenzamide; 4A-(B8)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-M - ethyl-M-methylbenzamide; (5)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (A)-1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(cyclopropylmethylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H-isoquinoline-3 -one; (2)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-(cyclopropylmethylmethylamino)-phenyl|-b-methoxy-1,4-dihydro-2H- isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-I(4-(2-oxoazetidin-1-yl)-phenyl |-1,4-dihydro- 2H-isoquinolin-3Z-one; (8)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(2-oxoazetidin-1-yl)-phenyl|-1,4-dihydro - 2H-isoquinolin-3Z-one; (5)-1-(4-chloro-phenyl)-7-cyclobutoxy-2-(4-dimethylaminophenyl)-6-methoxy-1 4-dihydro-2H-isoquinolin-3-one; (8)-1-(4-chlorophenyl)-7-cyclobutoxy-2-(4-dimethylaminophenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|- 1,4-dihydro-2H -isoquinolin-3-one; (8)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methylpyridin-4-ylmethylamino)-phenyl|- 1,4-dihydro-2H-isoquinolin-3-one; M-((5)-1-14-((5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 N-isoquinolin-2-yl (1-phenyl)-ethyl)-N-ethylacetamide; M-((8)-1-14-(5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H- isoquinolin-2-yl(phenyl)-ethyl)-N-ethylacetamide; M-((5)-1-4-((A)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H -isoquinolin-2-yl (1-phenyl)-ethyl)-N-ethylacetamide; M-((8)-1-(4-KA)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1 H -isoquinolin-2-yl (1-phenyl)-ethyl)-N-ethylacetamide; M-(4-(14-((5)-7-(B)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2- yl(1-phenyl)-methylamino)-methyl|-trans-cyclohexyl)-propionamide; M-(4-(44-KA)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2 - yl-phenyl)-methylamino)-methyl|-trans-cyclohexyl)-propionamide; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-14-((5)-1-(4-dimethylaminopiperidin-1-yl)-ethyl|-phenyl)- b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-14-KA)-1-(4-dimethylaminopiperidin-1-yl)-ethyl|-phenyl)-b- methoxy-1,4-dihydro-2H-isoquinolin-3-one; (8)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-2-(4-((5)-1-(4-dimethylaminopiperidin-1-yl)-ethyl|-phenyl) -b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (2)-7-(A)-tert-butoxy)-1-(4-chloro-phenyl)-2-14-KV) -1-(4-dimethylaminopiperidin-1-yl)-ethyl|/- phenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-14-Ktrans-4-dimethylaminocyclohexylmethyl)-methylamino|-phenyl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one ; (5)-1-(4-chlorophenyl)-2-14-Ktrans-4-dimethylaminocyclohexylmethyl)-ethylamino|-phenyl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one ; M-(4-(14-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl) -methylamino)-methyl|-trans-cyclohexyl)-methanesulfonamide; oxazole-4-carboxylic acid (4-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- 11-phenyl-methylamino)-methyl-1-trans-cyclohexyl)-amide; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-Imethyl-1(4-(3Z -oxopiperazin-1-yl)-trans- bo cyclohexylmethyl)|-amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (4-(К14-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-methylamino) -methyl|-trans-cyclohexyl)-methylamino)-acetic acid methyl ester; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-(methyl-(trans-4-morpholin-4-ylcyclohexylmethyl)-amino|-phenyl)-1,4-dihydro -2H-isoquinolin-3-one; 1-44-(44-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl) -methylamino)-methylil|-trano-cyclohexyl)-piperazine-2,5-dione; 2-(carbamoylmethyl-(4-(((4-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline-2- yl|I-phenyl-methylamino)-methyl|-trans-cyclohexyl)-amino)-acetamide; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-Imethyl-( 4-(3-oxo-P1,4|diazepan-1-yl)-trans- cyclohexylmethyl)|-amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-Imethyl-I(4-(4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl)|-amino)- phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-15-Ktrans-4-dimethylaminocyclohexylmethyl)-methylamino|-pyridin-2-yl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinoline -3-one; (5)-1-(4-chlorophenyl)-2-14-Ktrans-4-dimethylaminocyclohexylmethyl)-methylamino|-3-methylphenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinoline-3 - he; (5)-1-(4-chlorophenyl)-2-16-Ktrans-4-dimethylaminocyclohexylmethyl)-methylamino|-pyridin-3-yl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinoline -3-one; (5)-1-(4-chlorophenyl)-2-14-Ktrans-4-dimethylaminocyclohexylmethyl)-methylamino|-3-fluorophenyl)- 7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-14-Ktrans-4-dimethylaminocyclohexylmethyl)-methylamino|-2-methoxyphenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinoline-3 - he; ethanesulfonic acid /4-((14-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl1-phenyl)/ γ-methylamino)-methylyl-trans-cyclohexyl)-amide; M-(4-(14-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl) -methylamino)-methyl|-trans-cyclohexyl)-propionamide; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-(Imethyl-(trans-4-pyrrolidin-1-ylcyclohexylmethyl)-amino|-phenyl)-1,4-dihydro -2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-(Imethyl-(trans-4-piperidine-1- Zoylcyclohexylmethyl)-amino|-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chloro-phenyl)-2-14-((5)-1-(1,1-dioxo-1 lambda"b"-thiomorpholin-4-yl)-ethyl|-phenyl) -7- isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-2-14-I((5)-1-(4-acetylpiperazin-1-yl)-ethyl|-phenyl)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1, 4-dihydro-2H-isoquinolin-3-one; (8)-1-((5)-1-44-I((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1 H- isoquinolin-2-yl|-phenyl)-ethyl)-pyrrolidine-2-carboxylic acid methylamide; (5)-1-((5)-1-44-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|-phenyl)-ethyl)-pyrrolidine-2-carboxylic acid methyl ester; (5)-1-(4-chlorophenyl)-2-14-((B8)-1-(1,1-dioxo-yllambda"b"-thiomorpholin-4-yl)-ethyl|-phenyl)-7- isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(4-11-(1,1-dioxo-THIlambda"b"-thiomorpholin-4-yl)-cyclopropyl|-phenyl)-7-isopropoxy-b- methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-2-14-(1-(4-acetylpiperazin-1-yl)-cyclopropyl|-phenyl)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H -isoquinolin-3-one; transo-4-dimethylaminocyclohexanecarboxylic acid 14-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl) -methylamide; (5)-1-(4-chlorophenyl)-2-(4-(2-(4-dimethylaminopiperidin-1-yl)-1-methylethyl|-phenyl)-7-isopropoxy-b-methoxy-1,4- dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(4-(2-(4-dimethylaminopiperidin-1-yl)-1-methyl-2-oxoethyl|-phenyl) )-7- isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(4-imidazol-1-ylmethylphenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chloro-3-fluorophenyl)-2-(4-dimethylaminophenyl)-7-isopropoxy-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; M-14-P1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-2,2,2-trifluoro -M-methylacetamide; 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methylaminophenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(4-C4-(1,1-dioxo-yllambda"b"-thiomorpholin-4-yl)u-trans-cyclohexylmethyl-methylamino)-phenyl)-7 -isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 14-I44A-((5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-methoxyphenyl)-methylamino )-methyl I-transo-cyclohexyl-carbamic acid tert-butyl ester; 14-I44A-((5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-3-oxo-1,4-dihydro-1H-isoquinolin-2-yl|-3- methoxyphenyl)-methylamino)-methyl|-trano-cyclohexylamino)-acetic acid methyl ester; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(2-methoxy-4-methyl-|4-(33-oxopiperazin-1-yl)-trans-cyclohexylmethyl|-amino )-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-(methylpiperidin-4-ylmethylamino)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-amino )-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4--Imethyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|- amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; A-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)- methylamino)-methyl|-trans-cyclohexanecarboxylic acid methyl ester; A-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)- methylamino )-methyl I-transo-cyclohexanecarboxylic acid; A-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinoline- 2-yl|-phenyl)-methylamino)-methyl-I-transo-cyclohexanecarboxylic acid methylamide; A-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)- methylamino )-methyl|-trans-cyclohexanecarboxylic acid amide; A-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H- Isoquinolin-2-yl|-phenyl)-methylamino)-methyl-I-trans-cyclohexanecarboxylic acid (2-hydroxyethyl)-amide; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14 -(Imethyl-(4-piperazin-1-yl-trans- cyclohexylmethyl)-amino|-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-2-(4-C4-(4-acetylpiperazin-1-yl)u-trans-cyclohexylmethyl|-methylamino)-phenyl)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1 ,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-2-(4-C4-(4-methanesulfonylpiperazin-1-yl)-trans-cyclohexylmethyl|-methylamino)-phenyl)-6-methoxy-1, 4-dihydro-2H-isoquinolin-3-one; Zo (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-Imethyl-(4-(4-methylpiperazin-1-yl)-trans-cyclohexylmethyl)|-amino)- phenyl)-1,4-dihydro-2H-isoquinolin-3-one; 2-14-I44-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-methylamino )-methyl|-trans-cyclohexylamino)N-methylacetamide; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-(methylpiperidin-2-ylmethylamino)-phenyl|-1,4- dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-(methyl-(tetrahydropyran-2-ylmethyl)-amino|-phenyl)-1,4-dihydro-2H-isoquinoline -3-one; (5)-1-(4-chlorophenyl)-2-(4--cyclohexylmethylmethylamino)-phenyl|-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-2-15-Ktrans-4-aminocyclohexylmethyl)-methylamino|-pyridin-2-yl)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinoline -3-one; 14-I6-((5)-1-(4-chlorophenyl)-7-isopropoxy-6b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyridin-3-yl- methylamino)-methyl|-trans-cyclohexylamino)-acetic acid methyl ester; 2-14-I(6-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- pyridin-3-yl-methylamino)-methyl|-trans-cyclohexylamino)-N-methylacetamide; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-(methyl-I(4-(3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|)-amino) -pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(5-(methyl-I(4-(3-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|)-amino) -pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(5-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|- amino)-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; 14-I45-((5)-1-(4-chlorophenyl)-7-isopropoxy-6b-methoxy-3 -oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyridin-2-yl-methylamino)-methylyl-trans-cyclohexylamino)-acetic acid methyl ester; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-(methyl-(4-(3Z-oxopiperazin-1-yl)-trans- cyclohexylmethyl (amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-(methyl-(4-(4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|)-amino)- pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(6-C4-(3-hydroxymethyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl-methylamino)-pyridin-3-yl)-7- isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|- amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; 2-14-I45-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy- 3-oxo-3,4-dihydro-1H-isoquinolin-2-yl[pyridin-2-yl-methylamino]-methyl[yl]-transo-cyclohexylamino)-N-isopropylacetamide; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|- amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-2-(6-(C4-(3 -isopropyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-methylamino)-pyridin-3-yl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1 -(4-chlorophenyl)-3-(6-1(4-(3-ethyl-4-oxoimidazolidin-1-yl)-thrano-cyclohexylmethyl|- methylamino)-pyridin-3-yl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-Imethyl-I(4-(3Z-oxopiperazin-1-yl)-trans-cyclohexylmethyl)|-amino)- phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-methyl-1(4-(2-oxopiperazin-1-yl)-cis-cyclohexylmethyl)|-amino)- phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-2-15-Ktrans-4-aminocyclohexylmethyl)-amino|-pyridin-2-yl)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinoline -3-one; 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4--methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl)|-amino)- phenyl)-1,4-dihydro-2H-isoquinolin-3-one; 14-I45-((5)-1-(4-chlorophenyl)-7-isopropoxy-6b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|- pyrazin-2-yl-methylamino)-methyl|-trans-cyclohexylamino)-acetic acid methyl ester; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-methoxy-2-(5-(methyl-14-(4-methyl-3-oxopiperazin-1-yl)) -transo-cyclohexylmethyl|-amino)-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; 2-14-I(6-(5)-1-(4-chlorophenyl)- 7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyridin-3-yl-methylamino)-methyl|-transo-cyclohexylamino)-N-ethylacetamide; 2-14-I(6-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyridin- 3-yl-methylamino)-methyl|-trans-cyclohexylamino)-N-isopropylacetamide; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(5-(methyl-I(4-(2-oxoazetidin-1-yl)-trans-cyclohexylmethyl|)-amino) -pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl)- Zo trans-cyclohexylmethyl|-amino)-pyridazin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; 2-14-I45-(5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyrazin-2- yl-methylamino)-methylyl-trans-cyclohexylamino)-N-methylacetamide; (5)-1-(4-chlorophenyl)-2-(5-14-(3-ethyl-4-oxoimidazolidin-1-yl)-thrano-cyclohexylmethyl|- methylamino)-pyridin-2-yl)-7- isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(6-I((3-hydroxycyclobutylmethyl)-methylamino|-pyridin-3-yl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H -isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-2-(5-114-(3-isopropyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-methylamino )-pyridin-2-yl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-(methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)- trans-cyclohexylmethyl (amino)-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; 14-I42-((5)-1-(4-chlorophenyl)-7-isopropoxy-6b-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyrimidin-5-yl- methylamino)-methyli|-trano-cyclohexylamino)-acetic acid methyl ester; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-(2,2,2-trifluoroethoxy)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(5-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-transo-cyclohexylmethyl|- amino)-pyrimidin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-( methyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-amino)-pyridazin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; 1- (4-chlorophenyl)-2-(4-dimethylaminophenyl)-6-methoxy-7-(2-methoxyethoxy)-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-((5)-1-(tetrahydrofuran-2-yl)-methoxy|- 1,4-dihydro-2H-isoquinoline- 3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-|(B)-1-(tetrahydrofuran-2-yl)methoxy-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-6b-methoxy-7-(A)-2-methoxypropoxy)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-(2-methoxy-1-methylethoxy)-1,4-dihydro-2H-isoquinolin-3Z-one; A-((4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)- bo methylamino)-methyl|-trans-cyclohexanecarboxylic acid (2-hydroxy-2-methylpropyl)-amide; (4-I44-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-methylamino) -methyl|-trans-cyclohexanecarboxylic acid /((18,25)-2-hydroxycyclopentyl)-amide; (4-I44-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)- methylamino)-methyl|-trans-cyclohexanecarboxylic acid (1A)-2-hydroxypropyl)-amide; (4-I44-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-phenyl)-methylamino) -methyl|-trans-cyclohexanecarboxylic acid ((5)-2-hydroxypropyl)-amide; 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-Imethyl-1(4-(3Z-oxopiperazin-1-yl)-trans-cyclohexylmethyl)|-amino)-phenyl)-1 ,4-dihydro-2H-isoquinolin-3-one; (5)-2-I(4-(3-amino-1H-pyrazol-4-yl)-phenyl|-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H -isoquinolin-33-one; (5)-2-14-(3-amino-5-methyl-1H-pyrazol-4-yl)-phenyl|-1-(4-chlorophenyl)-7-isopropoxy-6- methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-I4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl|-7-isopropoxy -b-methoxy-1,4-dihydro- 2H-isoquinolin-3Z-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-7-(1-hydroxycyclopropylmethoxy)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-(3-methoxypropoxy)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-(1-(2-oxopiperazin-1-yl)-ethyl|-phenyl)-1,4-dihydro-2H -isoquinolin-3-one; 1-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-b-methoxy-7-(oxetan-2-ylmethoxy)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-(2,2-difluoroethoxy)-2-(4-dimethylaminophenyl)-b-methoxy-1,4-dihydro-2H- isoquinolin-3-one; 14-I45-(1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyrazin-2-ylmethylamino)-methyl| -trans-cyclohexylamino)-acetic acid methyl ester; 2-14-(15-(1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-pyrazin-2-yl) u'methylamino)-methyl|-trans-cyclohexylamino)-N-methylacetamide; Zo 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-Imethyl-(4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-amino)-pyrazine -2-yl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-Imethyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|)-amino)-pyridine -3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(3-fluoro-4-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans- cyclohexylmethyl)|-amino)-phenyl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(2-fluoro-4-(methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl)|-amino)- phenyl)-7-isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-((5)-1-(2-oxopiperazin-1-yl)y-ethyl|-phenyl)-1, 4- dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(4-4(5)-1-I4-(2-hydroxyethyl)-2-oxopiperazin-1-yl|-ethyl-phenyl)-7- isopropoxy- b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-((2)-1-(2-oxopiperazin-1-yl)-ethyl|-phenyl)-1,4 - dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(4-(8)-1-I(4-(2-hydroxyethyl)-2-oxopiperazin-1-yl|-ethyl-phenyl)-7- isopropoxy-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chloro-2-fluorophenyl)-2-(4-dimethylaminophenyl)-7-isopropoxy-6b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(4-((3-hydroxy-3-hydroxymethylcyclobutylmethyl)-methylamino|-phenyl)-7- isopropoxy-b-methoxy-1,4-dihydro-2H- isoquinolin-3-one; 2-I4-(3-amino-5-isobutyl-1H-pyrazol-4-yl)-phenyl|-1-(4-chlorophenyl)-7-isopropoxy-6-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one; 1-(4-chlorophenyl)-2-(6-(3,5-dimethyl-1H-pyrazol-4-yl)-pyridin-3-yl|-7-isopropoxy-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(2-methoxy-4-methyl-2-phenyl)-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl-2-(2H-tetrazol-5-ylmethoxy)-phenyl|-1,4- dihydro-2H-isoquinoline-3- 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl-2-(thiazol-5-ylmethoxy)-phenyl|-1,4-dihydro-2H-isoquinoline-3Z- he 4-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-(2H-tetrazol-B-ylmethoxy)-benzoic acid methyl ester; 4-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-methoxybenzoic acid methyl ester; 4-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl|-3-(thiazol-5-ylmethoxy)-benzoic acid methyl ester; M-((5)-1-4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |- phenyl)-ethyl)-acetamide; M-((5)-1-4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |- phenyl)-ethyl)-2-methoxyacetamide; M-((5)-1-4-((5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl |- phenyl)-ethyl)-2-dimethylaminoacetamide; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(methyl-I(4-(2-oxopyrrolidin-1-yl)-trans-cyclohexylmethyl|)-amino) -pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-(methyl-|(4-(2-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|)-amino) -pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-(methyl-(4-(3-oxomorpholin-4-yl)-trans-cyclohexylmethyl|)-amino)- pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-2-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(5-methyl-|(4-(3-methyl-4-oxoimidazolidine-1- (yl-trans-cyclohexylmethyl)-amino)-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(6-(methyl-I(4-(2-oxopiperidin-1-yl)-trans-cyclohexylmethyl|)-amino) -pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-14-((5)-1-(4-methyl-3-oxopiperazin-1-yl)-ethyl|- phenyl) -1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-16-((5)-1-(2-oxopiperazin-1-yl)-ethyl|-pyridin-3-yl) - 1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-((5)-1-(2-oxotetrahydropyrimidin-1-yl)-ethyl|-phenyl)-1,4 -dihydro-2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(6-methyl-(4-(3-methyl-4-oxoimidazolidine-1- Zyl-trans-cyclohexylmethyl)|-amino)-pyridin-33-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-cyclobutoxy-b-methoxy-2-(6-(methyl-|4-(33-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|- amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-6-methoxy-2-(6-(methyl-|(4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-amino)- pyridin-3-yl)-7-(5)-1-(tetrahydrofuran-2-yl)umethoxy|-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-I(4-(2-oxopyrrolidin-1-yl)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; ( 5)-1-(4-chlorophenyl)-6-methoxy-2-(5-(methyl-|(4-(3-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-amino)-pyrazine -2-yl)-7-((5)-1-(tetrahydrofuran-2-ylmethoxy|-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(2-oxoimidazolidin-1-yl)-phenyl|-1,4-dihydro-2H-isoquinolin-3-one; (5 )-1-(4-chlorophenyl)-7-cyclobutoxy-b-methoxy-2-(5-Imethyl-|4-(33-methyl-4-oxoimidazolidin-1-yl)-trans-cyclohexylmethyl|-amino)- pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(6-methyl-(4-(4-methyl-3-oxopiperazin-1-yl- trans-cyclohexylmethyl)|-amino)-pyridin-33-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-cyclobutoxy-b-methoxy-2-(6-Imethyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|-amino) )-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-cyclobutoxy-b-methoxy-2-(6-Imethyl-(4-(4-methyl-3-oxopiperazin-1-yl)- trans-cyclohexylmethyl (amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-6-methoxy-2-(6--methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|-amino)-pyridine -3-yl)-7-(5)-1-(tetrahydrofuran-2-yl)umethoxy|-1,4-dihydro-2H-isoquinolin-3-one; 2-I(I4-(3Z-amino-5-ethyl-1H-pyrazol-4-yl)-phenyl|-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-14-((5)-1-(3-oxomorpholin-4-yl)-ethyl|-phenyl)-1,4 - dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-2-(2-fluoro-6-(methyl-I(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl)-amino)- pyridin-33-yl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-2-14-(5)-1-(4-methanesulfonyl-2-oxopiperazin-1-yl)-ethyl/-phenyl)-b-methoxy- 1,4-dihydro-2H-isoquinolin-3-one; (5)-2-14-((5)-1-(4-acetyl-2-oxopiperazin-1-yl)-ethyl|-phenyl)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy -1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-16-KA)-1-(2-oxopiperazin-1-yl)-ethyl|-pyridin-3-yl)-1 ,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chlorophenyl)-7-isopropoxy-b-methoxy-2-(4-1(5)-1-(2-oxo-4-(tetrahydropyran-4-yl)- piperazin-1 -yl|-ethyl-phenyl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4-chloro-phenyl)-7-isopropoxy-2-(4-((5) -1-(4-isopropyl-2-oxopiperazin-1-yl)-ethyl|-phenyl)-b-methoxy-1,4-dihydro-2H-isoquinolin-3-one; (5)-1-(4- chlorophenyl)-7-isopropoxy-6-methoxy-2-14-((5)-1-(4-methyl-2-oxopiperazin-1-yl)-ethyl|-phenyl)-1,4-dihydro-2H- isoquinolin-3-one; 1-(4-chlorophenyl)-6-hydroxy-7-isopropoxy-2-(6-(methyl-I(4-(3-methyl-4-oxoimidazolidin-1-yl)-trans- cyclohexylmethyl (amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; (5)-7-(A)-tert-butoxy)-1-(4-chlorophenyl) -6-hydroxy-2-(6-(methyl-|4-(4-methyl-3-oxopiperazin-1-yl-trans-cyclohexylmethyl)|-amino)-pyridin-33-yl)-1,4-dihydro -2H-isoquinolin-3-one; 1-(4-chlorophenyl)-6-hydroxy-7-isopropoxy-2-(6-(methyl-I(4-(4-methyl-3-oxopiperazin-1-yl) -trans- cyclohexylmethyl ()-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-isopropoxy-6-dz-methoxy-2 -(6--methyl-I(4-(4- methyl (3-oxopiperazin-1-yl)-trans-cyclohexylmethyl (amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one; 1-(4-chlorophenyl)-7-isopropoxy-6-dz-methoxy-2-(6-az-methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|-amino) )-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one and (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6-(dz -methyl-(4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one, or a pharmaceutically acceptable salt thereof. 15. The compound of formula (I) according to claim 1, which is (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-Imethyl-I4-(3Z-oxopiperazine-1- yl)-transo-cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H- isoquinolin-3-one N OT Y (c) (c) vve va y ch Y z schi : or its pharmaceutically acceptable salt. 16. The compound of formula (I) according to claim 1, which is (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-Imethyl-I4-(4-methyl-3- oxopiperazin-1-yl)-trans-cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one in M a (c) o M ! ra SI. or a pharmaceutically acceptable salt thereof. 17. The compound of formula (I) according to claim 1, which is (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6--methyl-I4-(4-methyl-Z -oxopiperazin-1-yl)-trans-cyclohexylmethyl)|-amino)-pyridin-3Z-yl)-1,4- dihydro-2H-isoquinolin-3-one (c) (c) ve y M U Y F M ra 7 SI (c) . or a pharmaceutically acceptable salt thereof. 18. The compound of formula (I) according to claim 1, which is (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(6--methyl-I4-(3-methyl-4 -oxoimidazolidin-1-yl)-transo-cyclohexylmethyl|-amino)-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one (c) o M U | Y g Z on v A SI or its pharmaceutically acceptable salt. 19. The compound of formula (I) according to claim 1, which is (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(5-Imethyl-I4-(3-methyl-4- Oxoimidazolidin-1-yl)-transo-cyclohexylmethyl|-amino)-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one (c) (c) о ММ ех С, : ра С и с МАСИ or its pharmaceutically acceptable salt. 20. The compound of formula (I) according to claim 1, which is 1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-Imethyl-|4-(4-methyl-3-oxopiperazine-1) -yl)-transo-cyclohexylmethyl|-amino)-phenyl)-1,4-dihydro-2H-isoquinolin-3-one in M; (c) (c) Lye M uv Y Ff 7 SI. or a pharmaceutically acceptable salt thereof. 21. The compound of formula (I) according to claim 1, in which B' means C.i.i.-Ci-alkyl-. 22. The compound of formula (I) according to claim 1, in which B? selected from phenyl or 3-pyridyl substituted in the para-position by (NH)2M-U-, where U is absent (bond), and where one BZ is methyl and the other BZ is (A»)2M -cyclohexylmethylch-, and where two HB", together with the M atom to which they are attached, form a b-membered heterocyclic ring containing 1 additional M-heteroatom, the specified heterocyclic ring is substituted on the carbon atom by an oxo substituent and optionally M -substituted by methyl. 23. The compound of formula (I) according to claim 1, in which, if BZ includes a cyclohexylalkyl group, which is additionally monosubstituted on the cyclohexyl ring atom, said cyclohexyl substituent is in the 1 and 4 positions, and the stereochemistry of such substitution is trans. 24. The compound of formula (I) according to claim 1, in which the stereochemistry of the compound of formula (I) is as shown below: 25. The compound of formula (I) according to any one of claims 1-24 for use as a pharmaceutical agent. 26. A compound of formula (I) according to any one of claims 1-24 for use in the treatment of a disorder or disease mediated by the activity of MOMa2 and/or MOMA. 27. The compound of claim 26, wherein the disorder or disease is a proliferative disorder or disease. 28. The compound of claim 27, wherein the proliferative disorder or disease is a cancer or tumor disease. 29. Use of a compound of formula (I) according to any one of claims 1-24 for the preparation of a medicinal product for the treatment of a disorder or disease in a subject mediated by the activity of MOMAa and/or MOMA. 30. The use of claim 29, wherein the disorder or disease is a proliferative disorder or disease. 31. Use according to claim 30, where the proliferative disorder or disease is a cancer or tumor disease. 32. A pharmaceutical composition containing a compound of formula (I) according to any one of claims 1-24 in a therapeutically effective amount and one or more pharmaceutically acceptable carriers. 33. The compound of formula (I) according to any of claims 1-24 in combination with one or more therapeutically active agents. 34. The compound of formula (I) according to claim 33, where one or more therapeutically active agents are antiproliferative agents. 35. Crystal form I! sulfate (5)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-methyl-|4-(4-methyl-3-oxopiperazin-1-yl)-transo-cyclohexylmethyl|- amino)-phenyl)-1,4-dihydro-2H-isoquinoline-Z-one, having a powder X-ray pattern obtained using SiKKa radiation, which includes the following peaks located at the specified 2-theta angles in degrees: 18.87, 21.97 and 22.77, error /- 0.27. -oozyav Hn -y zo E even ss K- oo С va o Св В in 5 rest sti What - her Scale 2-theta PRRG data for crystalline form | sulfate of the compound of example 106 (suspension method Fig. 1 as sh- a -a pl what sha -- a k B oz t I is Ed E zva ah ii His No KT A va sp o proe Z yu nytsia o Ge sh v i "t I i za o v g Scale 2 -theta PRRH data for crystalline form I of the sulfate compound of example 106 (anti-solvent method) Fig. 2