UA124452C2 - Novel 6-6 bicyclic aromatic ring substituted nucleoside analogues for use as prmt5 inhibitors - Google Patents

Abstract

The present invention relates novel 6-6 bicyclic aromatic ring substituted nucleoside analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament. , (I)

Description

(57) Abstract:

The present invention relates to new analogues of nucleosides of formula (1) substituted by a 6-6-bicyclic aromatic ring:

AK-72

IN.

Her 1 2 2 ih; OK ; (I) where the variables have the values defined in the claims. The compounds according to the present invention are suitable as REMT inhibitors"5. In addition, the present invention relates to pharmaceutical compositions containing the specified compounds as an active ingredient, as well as the use of the specified compounds as a medicinal product.

AK- --2,

IN

Her 0) 1 2 2 ih) approx

The field of technology to which the invention belongs

The present invention relates to new 6-6-bicyclic aromatic ring-substituted analogs of nucleosides suitable as REMT5 inhibitors. In addition, the present invention relates to pharmaceutical compositions containing the specified compounds as an active ingredient, as well as the use of the specified compounds as a medicinal product.

Prerequisites of the invention

REMT»5, also called H5biI7, Urr1, 5KB1, Sarzshieep or Bagi5, is one of the main methyltransferases responsible for mono- and symmetrical dimethylation of arginine residues. Post-translational methylation of arginine on histones and non-histone proteins is believed to be critical for most biological processes, such as genome organization, transcription, differentiation, splicingosome function, signal transduction and cell cycle regulation, stem cell differentiation, and T- of cells (Biora, M. ei a!., Seiyi Moi Site 5si, 2015. 72(11): p. 2041-59)

REMT?5 of multicellular organisms forms a functional complex with methylosomal protein 50 (MER5BO), which is also called Umag77, coactivator p44 of the androgen receptor and

Mayo Both the increased level of the REMT5-MER5BO protein and its cytoplasmic accumulation are directly related to cancer oncogenesis, and their relationship with an unfavorable clinical outcome was recently established (Zpiyo, K. ei ai., Oiadp Raiyoi, 2013. 8 : p. 201). Experiments on the recovery of cells, which are aimed at both the catalytic and the framework function of the REMT5-MER5BO complex, in addition to comprehensive enzymatic studies, proved the oncological connection between the protein level, localization and enzymatic function (Si, 7. Yei Ai.,

Viosnet U, 2012. 446(2): p. 235-411 (and I ogep2o, A. Yei. aI., REV5 Hey, 2011. 585(13): p. 2024-31)

ISPap-Repebge, E. Yeyi ai., Ma Spet Vioi, 2015. 11(6): p. 432-7). Such a relationship transforms

REMT5 is an important target for small molecule drugs against cancer and other diseases |Ziora, M. ei a!., Seyi Moi Sige Zsi, 2015. 72(11): p. 2041-59).

REMT5 is a member of the type II RKEMT subfamily, which uses 5-adenosylmethionine (ZAM) to provide symmetrically dimethylated arginine on histones and non-histone protein substrates, and 5-adenosylhomocysteine (HAC). Crystal structure of human hetero-octameric complex (REMT5)4(MERBO)" co-crystallized with BAN and peptide

With the substrate histone No, she demonstrated the mechanism of methylation and substrate recognition

IApiopuzatu, 5. yei a!., Rgos Mai! Asai 5si OO 5 A, 2012. 109(44): p. 17960-5). Regulation of activity

REMT5 occurs due to a huge number of different binding partners, effects on post-translational modification, tikMA and subcellular localization.

Methylation of histones H2A and H4 on Agu3 and histone NZ on Agud8 regulates the organization of chromatin with respect to the specific suppression of gene transcripts that are involved in differentiation, transformation, the course of the cell cycle and suppression of tumors (Kagkpapiv, M. ei a!., Tgepakh Viospet zbi, 2011. Z36(12): p. 633-41)|. In addition, RKMT5-mediated methylation of histone H4 at Ago93 can promote histone binding to DNA methyltransferase OMMTZA and DNA methylation for long-term gene silencing (2 pao, s). ей ай., Mai 5igisi Moi Vioi, 2009. 16(3): pp. 304-111.

Non-histone-related methylation can occur either in the cytoplasm or in the nucleus, depending on the cellular localization of REMT5. Methylation of 5t proteins O1 and 03, which are necessary for the assembly of the nuclear splicingosome, takes place in the cytoplasm as part of the "methylosome", which contains

RAMT»5 GEpezep, M/.U. oh oh, my! Sow! Vioi, 2001. 21(24): pp. 8289-3001. Further evidence that

REMT»5 is involved in splicing, were presented by conditional knockout of RKMT5 in mouse neural stem cells. Cells lacking REMT5 showed selective retention of introns and skipping of exons with weak 5'-donor sites |Velli, M. ei ai.,

Sepez Oeyem, 2013. 27(17): p. 1903-16).

In addition to its involvement in splicing, REMT5 affects key pathways involved in cell differentiation and homeostasis by directly methylating key signaling nodes similar to roZ3

YuShapzgzop, M. ei ai!., Mai Seii! Vioi, 2008. 10(12): r. 1431-9), ESEV (INzy, .M. yei a)., Mai Sei! Vioi, 2011. 13(2): p. 174-81)|, SVAE (Apagei-Rege?, R. ei a!i., si bBidpa!, 2011. 4(190): p. gtab58|, RIZK/ Act of the Ministry of Education,

T.M. ей ай., Seiy bBidpa!y, 2014. 26(12): r. 2940-50), MEkV (MU/ей, N. ей ай., Rhos Mai! Asai 5si OO 5 A, 2013. 110(33) : p. 13516-211.

Since REMT5 is one of the main 5u-Ag9 methyltransferases and is involved in most cellular processes, increased expression of the protein seems to be an important factor in its oncogenicity. It is interesting that the translation of REMT»5 in mantle cell lymphoma (MCL) appears to be regulated by tikMA. Although MCI cells are characterized by a smaller number

TEMA and a slower rate of transcription of REMT»5 than normal B-lymphocytes, the level

REMT?5 and methylation of NZE8 and H4AKZ significantly increased GRai, 5. ei aI., EMVO U, 2007. 26(15): p. bo 3558-69). Repeated expression of tikMA, which binds the ZUTK region of REMT»5, reduces the protein level of REMT5 | Muapo, ЖИ. ей айЙ,, Moi Sei Vioi, 2008. 28(20): p. 6262-77) It is surprising that the antisense RNA rpti5 was detected in the human rpti5 gene, which confirms the hypothesis of specific regulation of translation, and not of a high level of expression of tEeMA |Zyuyura, M. ei ai., Seyi

MOI te bsi, 2015. 72(11): p. 2041-59).

Although REMT5 is considered a clinically relevant target, very few selective PKMT5 inhibitors have been published so far. More recently, a new subnanomolar potent inhibitor of REMT5 (ЕР20О15666) with antitumor activity in multiple MSC xenograft models was described as the first chemical probe suitable for further confirmation of the biology of РКMT5 and its role in cancer (Spapp-Repebge, E. ei ai., Mai

Snet Vioi, 2015. 11(6): p. 432-7).

Further development of specific small-molecule inhibitors of RKMT5 may lead to new chemotherapeutic approaches for cancer treatment.

Document UMO2014100695A1 discloses compounds suitable for inhibiting the activity

REMT"5; methods of using compounds for the treatment of REMT5-mediated disorders are also described.

Document M/O2014100730A1 discloses RAMT»5 inhibitors containing dihydro- or tetrahydroisoquinoline and their use.

In Oeukoia, K. Yei aI., AS5 Mei Spet Ie, 2014. 5: pp. 293-297, the synthesis of a number of analogs of the natural product sinefungin and the ability of these analogs to inhibit ENMTI1 and ENMT2 are described.

Document UMO2003070739 discloses partial and full agonists of AT adenosine receptors, their preparation and their therapeutic use.

Document M/02012082436 discloses compounds and compositions as modulators of histone methyltransferases and for the treatment of diseases caused by modulation of histone methyltransferase activity.

Document UMO2014100719 discloses REMTUB inhibitors and their use.

Document UMO03074083 discloses combined therapeutic agents that selectively destroy methylthioadenosine phosphorylase-deficient cells. MTA analogs are described herein as antitoxic agents.

In Kypo, R.-R. Yeyi AI., Visogd Med Spet Gay, 2005. 15: p. 2829-2833 describes the structure,

Synthesis and biological evaluation of new substrates of human 5'-deoxy-5'-methyltisnadenosine phosphorylase (MTAR).

Document MMO2012075500 discloses 7-deazapurine modulators of histone methyltransferase.

Document M/O2014035140 discloses compounds and compositions for modulating histone methyltransferase activity.

In document MO2015200680, inhibitors of REMT"b and their use are described.

Thus, there is a strong need for new REMTU inhibitors, which would open up new avenues for the treatment or prevention of cancers such as, for example, mantle cell lymphoma.

Accordingly, it is an object of the present invention to provide such compounds.

The compounds of the present invention are structurally different and may exhibit improved properties, such as, for example, improved efficacy, or improved pharmacokinetic (PK) properties and oral bioavailability, compared to compounds disclosed in the prior art.

Brief description of the invention

The compounds of the present invention have been found to be useful as REMT5 inhibitors. The compounds according to the present invention and their compositions may be suitable for the treatment or prevention, in particular for the treatment, of diseases such as blood diseases, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney disease, platelet aggregation, insufficient sperm motility, transplant rejection, tissue rejection, lung damage, etc.

This invention relates to new compounds of formula (1):

AK--7,

IN

Her

KU FO

І 2 in OV" where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl;

U is -0O-, -СНо- or -СЕ2-; 7 represents -СНе-, -Х-СНазед-, -2Н5с-СНеа-, -Н5еНзе-СВВе- or -С-0-; and if ХУ represents -СНег- or -СЕ2-, then 7 can also represent -О- or -СНЗаде-х-; each of 5a, Idre, Dos, Dzya, de, Do, Idzo, and Bog is independently hydrogen or Si-lalkyl;

X represents -O-, -5- or -МВА11-;

A" is hydrogen, C:-alkyl or C-4 alkyl substituted by one substituent selected from the group consisting of -OH, -O-Ci-alkyl, K2, -MH", -MH-C-alkyl and -M(S.-alkyl)»g;

В" is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; while the indicated 4-, 5-, 6-, or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Ci-"alkyl)g, -MNA I, -MVsed'sya, cyano, -SEz, -"C(-0)-MNe, -C(-0)-MH-C:-alkyl, -6( -O)-Ci.lalkyl, Ci-alkyloxy, -C(-0)-O-Ci-4alkyl, C3-6cycloalkyl, -O-C3cycloalkyl, -

MH-C3-vcycloalkyl, -M(C3-6cycloalkyl)», C1-valkenyl, C1-4alkyl, substituted by one C1-4alkyloxy, and C:-4alkyl, optionally substituted by one -MNA'sad's; each of K/'ba and ALL is independently hydrogen or C--alkyl; each of Ks and Kb independently represents Szecycloalkyl; VZ; Vya; S-cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C1-alkyl; C1-alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O0-C1 alkyl; or C 1 -alkyl substituted with one substituent selected from the group consisting of C 3 -cycloalkyl, B -C and B;

BZ is a 4-7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(-5O)p and M; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms, each independently selected from O, 5, 5(:O)p, and M; the specified 4-7-membered monocyclic aromatic ring or 6-11-membered bicyclic condensed aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C-4 alkyl; p is equal to 1 or 2;

W is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):

o--o 3 4 1011 ,/ t for 7-4 Z sleep M, uk E she x M in? Shk ve eh

MI OM v v Y Ts v | her 9 pr i r- vya che dl / X zol i» pttt E VE JAK r o (a) Y | (a-3) 7 Che (a-5)

Mo OM and her - (а-7) (4-3 at the same time each of НЗа, ИЗЖ, ИДЗе, |За and зе independently represents hydrogen, halogen, -MAA,

C:-alkyl, C--alkenyl, C3-ecycloalkyl, -OH or -O-C,-alkyl;

DV": represents hydrogen;

AND? is hydrogen, C3-cycloalkyl or C1-alkyl; each of Ba, ID", des, di, de, DYA and Do independently represents hydrogen, halogen, -MA8adv or C--alkyl; each of B8a and BZ" independently represents hydrogen or C--alkyl;

Oh! represents M or Sowing; 0: represents M or SIEB;

SSZ represents M or Self;

OS" is M or Sivba; provided that at most one of 23 and 07 is M;

CO? is M or SIb9;

SU is M or SEEG; 0? is M or CE;

O" represents M or CE);

OZ is CE39: (36 is M; and 0" is CE; or

C: represents SEZ: (6 represents CE; and 07 represents M; or

C: represents M; 05 represents SV"e; and 07 represents CE"; or

C" represents M; 09 represents SVEe; and 07 is M; or

C" represents M; 05 is M; and 07 represents CE": or

C" represents M; 05 is M; and 07 is M; each of Kba, Dej, Idbs, deja, be, De, Doo, De", De and K9Y independently represents hydrogen, halogen,

S.i-lalkil, -MAZAD?" or C. -alkyl substituted by one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl; and their pharmaceutically acceptable addition salts and solvates; provided that the following compounds and their pharmaceutically acceptable addition salts and solvates are excluded:

M m o. /"

Marya Mn, she is well at 5 M. M no ono S

M

What Mr. and Mrs. - M M no he y

/t

U. mesh and

M yo» Mo M her y no on Ba

The present invention also relates to methods of obtaining compounds according to the present invention and pharmaceutical compositions containing them.

The compounds of the present invention have been found to inhibit REMT5 by themselves or may be metabolized to a (more) active form of ip mimo (prodrugs), and thus may be suitable for the treatment or prevention, in particular for the treatment, of diseases such as blood diseases, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, insufficient sperm motility, transplant rejection, tissue rejection, lung damage, etc.

From the above-mentioned pharmacology of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, it follows that they may be suitable for use as a medicinal preparation.

In particular, the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates may be useful for the treatment or prevention, in particular for the treatment, of any of the diseases or conditions specified earlier or further herein, in particular cancer.

The present invention also relates to the use of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the preparation of a drug for inhibiting RKMT5, for the treatment or prevention of any of the diseases or conditions specified earlier or later in this document, in particular cancer.

This invention will be described below. In the following paragraphs, various aspects of the present invention are defined in more detail. Each aspect so defined may be combined with any other aspect or any other aspects unless expressly stated otherwise.

In particular, any feature specified as being preferred or best may be combined with any other feature or any other feature specified as being preferred or best.

Detailed description

In describing the compounds of the present invention, the terms used shall be construed in accordance with the following definitions, unless the context indicates otherwise.

If any variable occurs more than once in any component or any formula (for example, formula (I)), then its definition in each case is independent of its definition in every other case.

The term "substituted" as used herein is intended to mean, unless otherwise indicated or clearly indicated by the context, that one or more hydrogen atoms, in particular from 1 to 3 hydrogen atoms, preferably 1 or 2 hydrogen atoms, more preferably 1 hydrogen atom, when the atom or radical indicated using the expression "substituted" is replaced by one selected from the indicated group, provided that the normal valency is not exceeded and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently stable, to withstand separation from the reaction mixture to a suitable degree of purity and formulation into a therapeutic agent.

If two or more substituents are present on a fragment, they may, unless otherwise indicated or clearly indicated by the context, replace hydrogen atoms at the same atom, or they may replace hydrogen atoms at different atoms in the fragment.

The prefix "Shu" (where x and y are integers) used in this document refers to the number of carbon atoms in a given group. Thus, a C:-alkyl group contains from 1 to 4 carbon atoms, a C:-alkyl group contains from 1 to 3 carbon atoms, etc.

The term "halogen" as a group or part of a group is a common name for fluorine, chlorine, bromine, iodine, unless otherwise indicated or clearly indicated by the context.

The term "C:1-alkyl" as a group or part of a group refers to a hydrocarbyl radical of the formula CoN, where n is a number in the range from 1 to 4. C1-4 alkyl groups contain from 1 to 4 carbon atoms, preferably from 1 to C carbon atoms, more preferably from 1 to 2 carbon atoms. C 1 -alkyl groups may be linear or branched and may be substituted as specified herein. If in this document a subscript is used after a carbon atom, then the subscript means the number of carbon atoms that the named group can contain.

C 1 -alkyl includes all straight or branched alkyl groups having 1 to 4 carbon atoms and thus includes methyl, ethyl, n-propyl, iso-propyl, 2-methyl-ethyl, butyl and isomers thereof (e.g., n-butyl, isobutyl and tert-butyl) etc.

One of ordinary skill in the art will understand that the term "C1-1-alkyloxy" or "C1-1-1-alkyloxy" as a group or part of a group refers to a radical characterized by the formula -OHHg, where Kg is C1-1-alkyl. Non-limiting examples of suitable C 1-4 alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy.

The term "Shalkenyl" as used herein as a group or part of a group represents a linear or branched hydrocarbon group containing from 2 to 4 carbon atoms and containing a carbon-carbon double bond, such as, but not limited to, ethenyl, propenyl, butenyl, 1-propen-2-yl, etc.

The term "Sgvalkenyl", as used herein as a group or part of a group, represents a linear or branched hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon-carbon double bond, such as, but not limited to, ethenyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl, etc.

The term "C3-ecycloalkyl", used herein as a group or part of a group, represents cyclic saturated hydrocarbon radicals containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

If 7 represents -X-SVZarge-, then it is assumed that X is attached to Ag.

If 7 represents -СН-С1829-, then it is assumed that the C atom with the Be substituent is attached to Ag.

If 7 represents -СИН5еНе-СВ5ИН5-, then it is assumed that the C-atom with the substituents Re and 229 is attached to Ag.

In the event that 7 represents -SNRarr-X-, then it is assumed that the C-atom with substituents where: and ER? attached to Ag.

One skilled in the art will appreciate that a 4-, 5-, 6-, or 7-membered heterocyclic ring attached to

Zo to the rest of the molecule through the nitrogen atom of the ring (in the definition of K"2), in particular, represents a saturated ring. Non-limiting examples of K'? are 1-piperidinyl, 1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, etc.

It will be apparent to one skilled in the art that, unless otherwise indicated or clearly indicated by the context, a substituent on a 4-7-membered monocyclic aromatic ring containing one, two, or three heteroatoms (as defined by KU) (non-limiting examples are pyrrolyl, pyridinyl, furanyl, etc.), may replace any hydrogen atom at the carbon atom of the ring or, if possible, at the nitrogen atom of the ring (in which case the hydrogen at the nitrogen atom may be replaced by a substituent). One of ordinary skill in the art will appreciate that the same applies to a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms (as in definition 2") (non-limiting examples include indolyl, quinolinyl, etc.). 4-7 --a monocyclic aromatic ring containing one, two, or three heteroatoms (as in definition B") may optionally be attached to the rest of the molecule of formula (His) by any available carbon or nitrogen atom of the ring, unless otherwise specified.

It will be apparent to one of ordinary skill in the art that the same applies to a 6-11 membered bicyclic fused aromatic ring containing one, two or three heteroatoms (as in the definition of K'3).

If a nitrogen atom replaces one of the two carbon atoms common to the two fused rings in the Ag group, then the carbonyl group is in the indicated bicyclic aromatic ring system, for example in the structure shown below: (c)

Sl re , which is optionally substituted according to any of the embodiments. It will be understood that this example is non-limiting.

Other non-limiting examples of an Ag group which is a 10-membered bicyclic aromatic ring system consisting of two fused b-membered rings where optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom are shown below:

/ / / -M M-M - M / 37 7/7 times 5

M

5-M 5-M

M M / xx

X and M are each optionally substituted according to any of the embodiments.

One of ordinary skill in the art will understand that the 10 members of a 10-membered Ag group (a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom) are 10 carbon atoms, 9 carbon atoms and 1 nitrogen atom, or 8 carbon atoms and 2 nitrogen atoms. Ag is optionally substituted according to any of the embodiments.

In all cases when the substituents are represented by the chemical structure, "--" means a bond of attachment to the rest of the molecule of formula (1). Lines drawn from substituents to ring systems indicate that such a bond can be attached to any suitable ring atom. sh.

For example, covers any of the following ring systems: - d- -sh- and | and di and

NAVY -h ak chl I I LE CHO y y a zhi a s -m . -k , x-4ai x-x x. tav Y is an alternative image.

The term "subject" as used herein refers to an animal, preferably a mammal (eg, cat, dog, primate, or human), more preferably a human, that is or has been the subject of treatment, observation, or experimentation.

The term "therapeutically effective amount" as used herein means that amount of an active compound or pharmaceutical agent that produces a biological or medical effect in a tissue system, animal, or human that is necessary for a researcher, veterinarian, physician, or other clinician, including relief or alleviating the symptoms of the disease or disorder being treated.

The term "composition" is intended to cover a product containing specified ingredients in specified amounts, as well as any product obtained, directly or indirectly, as a result of combinations of specified ingredients in specified amounts.

The term "treatment" as used herein is intended to refer to all methods that may involve slowing, suspending, inhibiting or stopping the development of a disease, but does not necessarily mean the complete elimination of all symptoms.

The term "compounds of the invention" as used herein is intended to include compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates.

Some compounds of formula (I) may also exist in their tautomeric form. The term "tautomer" or "tautomeric form" refers to structural isomers with different energy values that are capable of interconversion due to a low energy barrier. For example, protonic tautomers (also known as prototropic tautomers) involve interconversions due to proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversion by rearrangement of some bonding electrons.

It is intended that such forms, given that they may exist, although not explicitly shown in the above formula (I), are included within the scope of this invention.

Any chemical formula used herein with bonds shown only as solid lines and not as continuous wedge-shaped or dashed wedge-shaped bonds or otherwise shown as having a specific configuration (eg, K , 5) around one or more atoms, implies every possible stereoisomer or a mixture of two or more stereoisomers. If the stereochemistry of any particular chiral atom is not indicated in the structures shown herein, then all stereoisomers are considered and included as compounds of this invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.

As used herein above and below, the term "compound of formula ()" is intended to include stereoisomers thereof and tautomeric forms thereof. However, if the stereochemistry, as indicated in the previous paragraph, is indicated by bonds represented as continuous wedge-shaped or dashed wedge-shaped bonds or otherwise shown as having a particular configuration (eg, K, 5), then in this way, this stereoisomer is indicated and determined. It will be clear that this also applies to subgroups of formula (1).

It follows that one compound can, if possible, exist in both stereoisomeric and tautomeric forms.

The terms "stereoisomers", "stereoisomeric forms" or "stereochemically isomeric forms" above or below are used interchangeably herein.

Enantiomers are stereoisomers, which are non-convergent mirror images of each other when superimposed. A 1:1 mixture of a pair of enantiomers is a racemate or a racemic mixture.

Atropisomers (or atropoisomers) are stereoisomers that have a specific spatial configuration formed as a result of limited rotation around a single bond due to significant steric mismatch. All atropisomeric forms of the compounds of formula (I) are intended to be included in the scope of this invention.

Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, that is, they are not mirror images. If the compound contains a double bond, then the substituents can be in E- or 2-configuration. Substituents in divalent cyclic (partially) saturated radicals can be in either cis- or trans-configuration; for example, if the compound contains a disubstituted cycloalkyl group, then the substituents can be in the cis- or trans-configuration. Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E-isomers, 2-isomers, cis-isomers, trans-isomers, and mixtures thereof, where chemically possible.

The meaning of all given terms, i.e. enantiomers, atropisomers, diastereomers, racemates,

E-isomers, 2-isomers, cis-isomers, trans-isomers and mixtures thereof are known to a person skilled in the art.

The absolute configuration is determined according to the Kahn-Ingold-Prelog system.

The configuration at an asymmetric atom is defined either as KE or as 5. Selected stereoisomers, the absolute configuration of which is unknown, can be designated as (u) or (u) depending on the direction in which they rotate the plane of polarization of light. For example, selected enantiomers, the absolute configuration of which unknown, may be denoted as (k) or (-) depending on the direction in which they rotate plane-polarized light.

If a specific stereoisomer is specified, this means that the specified stereoisomer contains practically no other isomers, i.e., is bound to less than 5095, preferably to less than 2095, more preferably to less than 1095, even more preferably to less than 595, in particular to less than 295 and most preferably from less than 195 other stereoisomers. Thus, if the compound of formula (I), for example, is indicated as (K), it means that the compound practically does not contain the isomer of (5); if the compound of formula (I), for example, is indicated as E, then this means that the compound practically does not contain isomer 7; if a compound of formula (I), for example, is listed as cis-, this means that the compound contains practically no trans-isomer.

For therapeutic use, salts of compounds of formula (I) and their solvates are those whose counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of this invention.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be prepared by conventional methods, for example, by reacting the free acid or free base form with one or more equivalents of the corresponding acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of said solvent or specified medium using standard techniques (for example, under vacuum, by freeze-drying or filtration). Salts can also be obtained by exchanging the counterion of a compound of the present invention in salt form with another counterion, for example using a suitable ion exchange resin.

It is believed that the pharmaceutically acceptable addition salts mentioned above or below herein include therapeutically active non-toxic forms of addition salts of acids and bases which can form compounds of formula (I) and solubilize them.

Suitable acids include, for example, inorganic acids such as hydrohalic acids, such as hydrochloric or hydrobromic acids, sulfuric, nitric, phosphoric acids, etc.; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (ie, ethanedioic), malonic, succinic (ie, butanedioic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamic acids, etc. | conversely, these salt forms can be converted to the free base form by treatment with an appropriate base.

Compounds of formula (I) and their solvates, which contain an acidic proton, can also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate

With organic and inorganic bases.

Suitable basic salt forms include, for example, ammonium salts, salts of alkali and alkaline earth metals, such as lithium, sodium, potassium, magnesium, calcium, etc., salts with organic bases, such as primary, secondary and tertiary aliphatic and aromatic amines such as as methylamine, ethylamine, propylamine, isopropylamine, the four isomers of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline; salts of benzathine, M-methyl-O-glucamine, hydrabamine and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, the salt form can be converted to the free acid form by acid treatment.

For purposes of this invention, prodrugs are also included within the scope of this invention.

The term "prodrug" of a suitable compound of the present invention includes any compound which, after oral or parenteral administration, in particular oral administration, is metabolized ip mimo to the formation of such compound in an amount that can be determined experimentally and within a predetermined time (e.g., interval between taking a dose from 6 to 24 hours (that is, in the case of taking a dose from one to four times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration, including intravenous (IM), intramuscular (IM) and subcutaneous (5C) injections.

Prodrugs can be obtained by modifying the functional groups present in the compound in such a way that these modification results are readily cleaved when such prodrugs are administered to a mammalian subject. Modifications are usually obtained by synthesizing the parent compound with a prodrug substitute. In general, prodrugs include compounds of the present invention wherein a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group in a compound of the present invention is linked to any group that can be cleaved by reducing the free hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group, respectively; in particular, where the hydroxyl group in the compound of the present invention is linked to any group (eg, -C(-O)-C1-alkyl) that can be cleaved off with the reduction of the free hydroxyl. In the context of this invention, prodrugs, in particular, are compounds of formula (I) or their subgroups, where VE! and/or B? represent -C(-0)-C.-alkyl. for Examples of prodrugs include, without limitation, esters and carbamates for hydroxyl functional groups, ester groups for carboxyl functional groups, M-acyl derivatives, and M-Mannich bases. General information about prodrugs can be found, for example, in

Vypadedaaga, N. "Oyevidp oi Rgodgydv" r. I-92, EIvemivti, Mem Mogk-Ohioga (1985).

The term "solvate" includes hydrates and solvent addition forms that can form compounds of formula (I), as well as their pharmaceutically acceptable addition salts. Examples of such forms are, for example, hydrates, alcoholates, etc.

The compounds according to the present invention, obtained by the methods described below, can be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, which can be separated from each other according to separation procedures known in the art. The method of separation of enantiomeric forms of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates includes liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be obtained from the corresponding pure stereochemically isomeric forms of suitable starting substances, provided that the reaction occurs stereospecifically. Preferably, if a certain stereoisomer is required, then the specified compound will be synthesized by stereospecific methods of preparation. In these methods, enantiomerically pure starting materials are preferably used.

The present invention also encompasses isotopically labeled compounds of the present invention that are identical to those disclosed herein except that one or more atoms are replaced by an atom with an atomic mass or mass number that differs from the atomic mass or mass number normally found in nature (or the most widespread among those common in nature).

All isotopes and isotopic mixtures of any particular atom or element as defined herein are contemplated within the compounds of the present invention, whether naturally occurring or synthetically produced, with natural isotopic composition or in isotopically enriched form. Illustrative isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as NH, "C, 130, 140, 73, 150, 170.80.

ZN, "C and "g. More preferably, the radioactive isotope is 2H. In particular, deuterated compounds are intended to be included within the scope of this invention.

Co) Certain isotopically labeled compounds of the present invention (e.g., ZH and 77C-labeled) are applicable to compound and tissue substrate distribution assays. In addition, substitution with heavier isotopes such as deuterium (i.e., "H") may provide certain therapeutic advantages as a result of greater metabolic stability (eg, increased half-life of ip mimo or reduced dose requirements) and therefore may be preferable in some cases Positron-active isotopes, such as 7150, 7Z3M, "b and 18E, are applicable for studies using positron emission tomography (PET) to assess the degree of receptor occupation by the substrate.

In all embodiments below, the following compounds and their pharmaceutically acceptable addition salts and solvates are excluded:

M shk "

M Uh a lot / well not 5 M M but ono S /t y

B - M no no i

M m "y chu puer"

M y» Mashu M s Nn ne On She

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl;

U is -0O-, -СНо- or -СЕ2-; 7 represents -СНе-, -Х-СНазед-, -2Н5с-СНеа-, -Н5еНзе-СВВе- or -С-0-; and if U represents -СНе- or -СЕ2-, then 7 can also represent -О- or -СИзадех-х-; each of 5a, Idre, Dos, Dzya, de, Do, Idzo, and Bog is independently hydrogen or Si-lalkyl;

X represents -O-, -5- or -МВА11-;

B" represents hydrogen or Si.lalkil;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Ci-"alkyl)g, -MNA I, -MVsed'sya, cyano, -SEz, -"C(-0)-MNe, -C(-0)-MH-C:-alkyl, -6( -O)-Ci.lalkyl, Ci-alkyloxy, -C(-0)-O-Ci-4alkyl, C3-6cycloalkyl, -O-C3cycloalkyl, -

MH-C3-vcycloalkyl, -M(C3-cycloalkyl)", C-valkenyl, C1-4alkyl substituted by one C1-4alkyloxy, and C1-alkyl optionally substituted by one -MA'ad's; each of K/'ba and ALL is independently hydrogen or C--alkyl; each of C'Os and B'Ya is independently C3-ecycloalkyl; K/"; C 1 -C 4 cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C 1 -alkyl; C 1 -C 4 alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH, and -O-C.:.alkyl; or C.sub.1-alkyl substituted by one substituent selected from the group consisting of

C3-6cycloalkyl and K/a;

B" is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5): io from 7 - for lo i- and Zh v? Shk in xx

M | ve ki M KI in | M 9 pr ry r-o ve ME da / X zo 4j i» pet V: V ne r o (a) Y | (a-3) 7 Che (a-5)

Mo OM a yi ; (а-2) (а-4) while each of НЗа, ИЗб, ИДЗе, |Дза and зе independently represents hydrogen, halogen, -MAA,

C:-alkyl, C--alkenyl, C3-ecycloalkyl, -OH or -O-C,-alkyl;

SHA is hydrogen;

AND? is hydrogen, C3-cycloalkyl or C1-alkyl; each of Da, DV", dis, |DlYa, (where, D'i and Do independently represent hydrogen, halogen, -MA8advy or C. ..-alkyl; each of B8ha and BZ" independently represents hydrogen or C1-alkyl ;

OS" represents M or Sivba;

ОО: represents M or SIV;

OZ is M or Siebs;

OS" is M or Sivba; provided that at most one of 23 and 07 is M;

OO? is M or SIb9;

SU is M or SEEG; 0? is M or CE;

O" represents M or CE);

OZ is CE39: (36 is M; and 0" is CE; or

C: represents SEZ: (6 represents CE; and 07 represents M; or

C is M; 05 represents SVe; and 07 represents CE": or

C" represents M; 05 represents SVEe; and 07 is M; or

C" represents M; 05 is M; and 07 represents CE": or

C" represents M; 05 is M; and 07 is M; each of Bba Der, Dbs Dba Dbe De, Doo, Dei, dDei, and Boi is independently hydrogen, halogen,

C-alkyl, -MAZAD? or C. -alkyl substituted by one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl;

U is -0O-, -СНо- or -СЕ2-; 7 is -СНе-, -Х-СІнзадь-, -852-01859-, -СНзеНзо-С VIV. or -С-0-; and if ХУ represents -СНег- or -СЕ2-, then 7 can also represent -О- or -СНЗаде-х-; each of Бра, ИДрБ, Дос, До, Дое, Де, ИДоо and о! independently represents hydrogen or Si.lalkyl;

X represents -O-, -5- or -MA1-;

B" is hydrogen, C-4 alkyl or C-1-alkyl substituted by one substituent selected from the group consisting of -OH, -O-C1-alkyl, K"2, -MH", -MH-Si -alkyl and -M(C-"alkyl)"g;

В" is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; while the indicated 4-, 5-, 6-, or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Zo Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Si-alkyl)2, -MNA sa, -MV sulfur, cyano, -SEz, -С(-0)-МН»e, -Ф(-0)-МН-С.-alkyl, -6(- O)-Ci.lalkyl, Ci-alkyloxy, -C(-0)-O-Ci-4alkyl, C3-6cycloalkyl, -O-C3cycloalkyl, -

MH-C3-bcycloalkyl, -M(C3-6cycloalkyl)g, C3-valkenyl, C1-4 alkyl substituted with one C1-4 alkyloxy, and C:-4 alkyl optionally substituted with one -MA'ad's; each of Ba and VO is independently hydrogen or Si-lalkyl; each of B'bs and Vsa is independently Szecycloalkyl; B'Z; B"; C 1 -cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C 1 -alkyl; C 1 -C 1 alkyl substituted with one, two or three substituents, wherein each is independently selected from the group consisting of halogen, -OH and -O0-C 1 -C 1 alkyl; or C 1 -alkyl substituted with one substituent selected from the group consisting of C 3 -cycloalkyl, C 3 -C 3 and MK ";

B'Z is a 4-7 membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(-5O)p and M; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms, each independently selected from O, 5, 5(:O)p, and M; the specified 4-7-membered monocyclic aromatic ring or 6-11-membered bicyclic condensed aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C-4 alkyl; p is equal to 1 or 2;

W is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5): 60

1 2 other: SHY uch pev she she x M vi? Shk in xx

Mo | blows V M KI in | M 9 pr i r- vya che dl / X zo 4j i» pttt E VE - r o (a) Y | (a-3) 7 Che (a-5)

Mo OM and her - (1-73 (a-3) at the same time, each of НЗа, ВЗЗ, Дзс, ИДЗа and ШЧДЗе independently represents hydrogen, halogen, -"MAA,

C:-alkyl, C--alkenyl, C3-ecycloalkyl, -OH or -O-C,-alkyl;

DV": represents hydrogen;

AND? is hydrogen, C3-cycloalkyl or C1-alkyl; each of Ba, ID", des, di, de, DYA and Do independently represents hydrogen, halogen, -MA8adv or C--alkyl; each of B8a and BZ" independently represents hydrogen or C--alkyl;

СО" represents Sivba; 0 represents SVB;

SSZ represents M or Self;

OS" is M or Sivba; provided that at most one of 23 and 07 is M;

OO? is M or SIb9;

SU is M or SEEG; 0? is M or CE;

O" represents M or CE);

OZ is CI39: (36 is M; and 0" is CE; or

C: represents SEZ: (6 represents CE; and 07 represents M; or

C is M; 05 represents SVe; and 07 represents CE": or

C" represents M; 09 represents SVEe; and 07 is M; or

C" represents M; 05 is M; and 07 represents CE": or

C" represents M; 05 is M; and 07 is M; each of Kba, Dej, Idbs, deja, be, De, Doo, De", De and K9Y independently represents hydrogen, halogen,

S.i-lalkil, -MAZAD?" or C. -alkyl substituted by one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl;

U is -0O-, -СНо- or -СЕ2-; 7 represents -СНе-, -Х-СВаде-, -С852-СВ»а-, -СН5ede-СВяВе- or -Seb-; and if ХУ represents -СНег- or -СрЕ2-, then 7 can also represent -О- or -СНЗаде-х-; each of Бра, ИДрБ, Дос, До, Дое, Де, ИДоо and о! independently represents hydrogen or Si.lalkyl;

X represents -O-, -5- or -MA1-;

B" is hydrogen, C-4 alkyl or C-1-alkyl substituted by one substituent selected from the group consisting of -OH, -O-C1-alkyl, K"2, -MH", -MH-Si -alkyl and -M(C-"alkyl)"g;

В" is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; while the indicated 4-, 5-, 6-, or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Si-lalkyl)", -MNA'YA, -MV'sed'sya, cyano, -SEz, -С(-0)-МНе, -С(-0)-МН-Si.lalkyl, -С( -0)-Sc. alkyl, C1.alkyloxy, -C(-0)-0O-C:.alkyl, C3-ecycloalkyl, C1-valkenyl, C:-4alkyl substituted by one C:-alkyloxy, and C:-4alkyl optionally substituted one - MA'ad's; each of Ba and VO is independently hydrogen or Si-lalkyl; each of Bi and I is independently Csescycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C1-alkyl; C1-4alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C1-4alkyl; or C 1 -alkyl substituted with one substituent selected from the group consisting of

C3-6cycloalkyl, K"3 and 4;

B'Z is a 4-7 membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(-O)p and M; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(:O)p and M; the specified 4-7-membered monocyclic aromatic ring or 6-11-membered bicyclic condensed aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C-4 alkyl; p is equal to 1 or 2;

B" is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3): 1 in Goi 0-0 Kk 3 4 / 7 of 7-5 a mon Mrya Kk še / X ve sh MM c

M p

Mao M i hi M a v i dae

БЕ с (ау (а) (а-3) while each of За, ВЗ» and ДЗс independently represents hydrogen, halogen, -МН"аАб, С.-

From 4 alkyl or -0-C. lalkil;

Fa is hydrogen;

AND?" represents hydrogen or Si.lalkyl; each of Ba, D5 and Es independently represents hydrogen, halogen, -MVZadB" or C .-alkyl; each of K8a and BEZ" independently represents hydrogen or C-1-alkyl;

OS" represents M or Seba;

OO: represents M or SEEV;

OZ is M or Sebs;

C" represents M or Svba:; provided that at most one of OZ and O7 is M; each of ba, db, Dbs and dvbe and p independently represents hydrogen, halogen,

S.i-lalkil, -MAZAD?" or C. -alkyl substituted by one, two or three halogen atoms; each of K2a and ER" is independently hydrogen or C-1-alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl;

U is -0O-, -СНо- or -СЕ2-;

7 is -СНе-, -Х-СІнзадь-, -852-01859-, -СНзеНзо-С VIV. or -С-0-; and if ХУ represents -СНег- or -СЕ2-, then 7 can also represent -О- or -СНЗаде-х-; each of Бра, ИДрБ, Дос, До, Дое, Де, ИДоо and о! independently represents hydrogen or Si.lalkyl;

X represents -O-, -5- or -MA1-;

A" is hydrogen, C:-alkyl or C-4 alkyl substituted by one substituent selected from the group consisting of -OH, -O-Ci-alkyl, K2, -MH", -MH-C-alkyl and -M(S.-alkyl)»g;

В" is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; while the indicated 4-, 5-, 6-, or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(C3-alkyl)g, cyano, -C3, -C(-0)-MH-C:-lalkyl, -C(-0)-C1-alkyl, C1-alkyloxy and C1-alkyl, optionally substituted one - МН'бадоБ; each of Ba and VO is independently hydrogen or Si-lalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3): a c) roya V - / X ve mon M M W ts t

Moshko M

Shi MI M a

In I dl

БЕ с (а-) (а-2) (а-3) while each of За, DZ" and DZ independently represents hydrogen, halogen, -MA"2B? or -O-C. lalalkyl;

Da represents hydrogen;

IN? represents hydrogen or S.-lalkil; each of a, D?? and Es independently represents hydrogen, halogen, -МВЗаДВЬ or C.-lalkyl;

Co) each of K8a and BEZ" independently represents hydrogen or C-1-alkyl;

OS" represents M or Seba; 0: represents M or SB;

SSZ is M or Sebs;

O" is M or Seb; provided that at most one of 23 and 07 is M; each of Bba Der Dbs de rdbe and Byai is independently hydrogen, halogen, Si-lalkyl, -

MAZarr" or C.-alkyl, substituted by one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl;

U is -0O-, -СНо- or -СЕ2-; 7 is -СНе-, -Х-СІнзадь-, -852-01859-, -СНзеНзо-С VIV. or -С-0-; and if ХУ represents -СНег- or -СЕ2-, then 7 can also represent -О- or -СНЗаде-х-; each of Бра, ИДрБ, Дос, До, Дое, Де, ИДоо and о! independently represents hydrogen or Si.lalkyl;

X represents -O-, -5- or -MA1-;

B" is hydrogen, C-4 alkyl or C-1-alkyl substituted by one substituent selected from the group consisting of -OH, -O-C1-alkyl, K"2, -MH", -MH-Si -alkyl and -M(C-"alkyl)"g;

В" is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; while the indicated 4-, 5-, 6-, or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed 6-membered rings, where at least 1 carbon atom of ring B is replaced by a nitrogen atom; at the same time, 1 additional carbon atom of ring A or ring B is optionally replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Si-alkyl)2, -MNA sa, -MV sulfur, cyano, -SEz, -С(-0)-МН»e, -Ф(-0)-МН-С.-alkyl, -6(- O)-Ci.alkyl, C.sub.1-alkyloxy, -C(-0)-O-C.sub.1-alkyl, C.sub.3-cycloalkyl, -O-C.sub.cycloalkyl, -

MH-C3-vcycloalkyl, -M(C3-cycloalkyl)", C4-alkyl, C:1-4 alkyl, substituted by one C1-4 alkyloxy, and C:-alkyl, optionally substituted by one -MA'ad's; each of Ba and VO is independently hydrogen or Si-lalkyl; each of B'bs and Vsa is independently Szecycloalkyl; B'Z; B"; C 1 -cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C 1 -alkyl; C 1 -C 1 alkyl substituted with one, two or three substituents, wherein each is independently selected from the group consisting of halogen, -OH and -O0-C 1 -C 1 alkyl; or C 1 -alkyl substituted with one substituent selected from the group consisting of C 3 -cycloalkyl, C 3 -C 3 and MK ";

B'Z is a 4-7-membered monocyclic aromatic ring containing one, two or three

Z heteroatoms, each independently selected from О, 5, 5(-О)р and М; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(:O)p and M; the specified 4-7-membered monocyclic aromatic ring or 6-11-membered bicyclic condensed aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C-4 alkyl; p is equal to 1 or 2;

B" is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5): then from - 4 for lo i- and Zh v? Shk in the entrance

MI Tsve vu these KI in | u 9 pr ry r-o ve ME da / X zo 4j i» pt E VE - r o (a) Y | (a-3) 7 Che (a-5)

Mo OM a t ! (a-23 (a-4)

at the same time, each of НЗа, ВЗб, Dзс, ИДЗа and ШДЗе independently represents hydrogen, halogen, -"MAA,

C:-alkyl, C--alkenyl, C3-ecycloalkyl, -OH or -O-C,-alkyl;

Da represents hydrogen;

AND? is hydrogen, C3-cycloalkyl or C1-alkyl; each of Ba, ID", des, di, de, DYA and Do independently represents hydrogen, halogen, -MA8adv or C. .-alkyl; each of B8ha and BZ" independently represents hydrogen or C1-alkyl;

OS" represents M or Svba; 0: represents M or SIEB;

SSZ represents M or Self;

OS" is M or Sivba; provided that at most one of 23 and 07 is M;

OZ is M or СІ59;

SU is M or SEEG; 0? is M or CE;

O" represents M or CE);

OZ is CE39: (36 is M; and 0" is CE; or

C: represents SEZ: (6 represents CE; and 07 represents M; or

C: represents M; 09 represents SE: and OO" represents SE"; or

C" represents M; 09 represents SVEe; and 07 is M; or

C" represents M; 05 is M; and 07 represents CE": or

C" represents M; 05 is M; and 07 is M; each of Bba Der, Dbs Dba Dbe De, Doo, Dei, dDei, and Boi is independently hydrogen, halogen,

C-alkyl, -MAZAD? or C. -alkyl substituted by one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

V' represents hydrogen;

Co) B: represents hydrogen;

U is -0O-, -СНо- or -СЕ2-; 7 represents -СНе-, -Х-СВаде-, -С852-СВ»а-, -СН5ede-СВяВе- or -Seb-; and if U represents -СНе- or -СЕ2-, then 7 can also represent -О- or -СИзадех-х-; each of Бра, ИДрБ, Дос, До, Дое, Де, ИДоо and о! independently represents hydrogen or Si.lalkyl;

X represents -O-, -5- or -MA1-;

B" is hydrogen, C-4 alkyl or C-1-alkyl substituted by one substituent selected from the group consisting of -OH, -O-C1-alkyl, K"2, -MH", -MH-Si -alkyl and -M(C-"alkyl)"g;

В" is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; while the indicated 4-, 5-, 6-, or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Si-alkyl)2, -MNA sa, -MV sulfur, cyano, -SEz, -С(-0)-МН»e, -Ф(-0)-МН-С.-alkyl, -6(- O)-Ci.lalkyl, Ci-alkyloxy, -C(-0)-O-Ci-4alkyl, C3-6cycloalkyl, -O-C3cycloalkyl, -

MH-C3-vcycloalkyl, -M(C3-cycloalkyl)", C-valkenyl, C1-4alkyl substituted by one C1-4alkyloxy, and C1-alkyl optionally substituted by one -MA'ad's; each of Ba and VO is independently hydrogen or Si-lalkyl; each of B'bs and Vsa is independently Szecycloalkyl; B'Z; B"; C 1 -cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C 1 -alkyl; C 1 -C 1 alkyl substituted with one, two or three substituents, wherein each is independently selected from the group consisting of halogen, -OH and -O0-C 1 -C 1 alkyl; or C 1 -alkyl substituted with one substituent selected from the group consisting of C 3 -cycloalkyl, C 3 -C 3 and MK ";

B'Z is a 4-7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from OO, 5, 5(-O)p and M; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(:O)p and M; the specified 4-7-membered monocyclic aromatic ring or 6-11-membered bicyclic condensed aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C-4 alkyl; p is equal to 1 or 2;

B" is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5): 4 10 11 / 7 for 7-5 Z

What Shk x M in? Shk in xx

Ma | Ve v p v pr a o s div ma? dl / X zo 4h sha

Day E VE --O- role o (a) Y | (a-3) 7 Che (a-5)

Mo OM and i - (a-2) (a-4) while each of НЗа, ВЗз, Dзс, ИДЗа and ШЧДЗе independently represents hydrogen, halogen, -"MAA,

C:-alkyl, C--alkenyl, C3-ecycloalkyl, -OH or -O-C,-alkyl;

Da represents hydrogen;

AND? is hydrogen, C3-cycloalkyl or C1-alkyl; each of Ba, ID", des, di, de, DYA and Do independently represents hydrogen, halogen, -MA8adv or C. .-alkyl; each of B8ha and BZ" independently represents hydrogen or C1-alkyl;

OS" represents M or Svba; 0: represents M or SIEB;

SSZ represents M or Self;

OS" is M or Sivba; provided that at most one of 23 and 07 is M;

OO? is M or SIb9;

SU is M or SEEG; 0? is M or CE;

O" represents M or CE);

OZ is CE39: (36 is M; and 0" is CE; or

C: represents SEZ: (6 represents CE; and 07 represents M; or

C is M; 05 represents SVe; and 07 represents CE": or

C" represents M; 09 represents SVEe; and 07 is M; or

C" represents M; 05 is M; and 07 represents CE": or

C" represents M; 05 is M; and 07 is M; each of Bba Der, Dbs Dba Dbe De, Doo, Dei, dDei, and Boi is independently hydrogen, halogen,

C-alkyl, -MAZAD? or C. -alkyl substituted by one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

V' represents hydrogen;

B2 is hydrogen;

U is -0O-, -СНо- or -СЕ2-; 7 represents -СНе-, -Х-СВаде-, -С852-СВ»а-, -СН5ede-СВяВе- or -Seb-; and if ХУ represents -СНег- or -СЕ2-, then 7 can also represent -О- or -СНЗаде-х-;

each of Бра, ИДрБ, Дос, До, Дое, Де, ИДоо and о! independently represents hydrogen or Si.lalkyl;

X represents -O-, -5- or -MA1-;

A" is hydrogen, C:-alkyl or C-4 alkyl substituted by one substituent selected from the group consisting of -OH, -O-Ci-alkyl, K2, -MH", -MH-C-alkyl and -M(S.-alkyl)»g;

В" is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; while the indicated 4-, 5-, 6-, or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, - 15. M(Si-alkyl )g», cyano, -CE3, -C(-O)-MH-Ci-alkyl, -C(-O)-Ci-alkyl, C-dalkyloxy and C-alkyl, optionally substituted by one -MH-alkyl ; each of Ba and VO is independently hydrogen or Si-lalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); while each of Za, DZ" and VZs independently represents hydrogen, halogen, -MA"2A?? or -0О-

Ci-"alkyl;

Fa is hydrogen;

AND?" represents hydrogen or Si.lalkyl; each of Ba, D5 and Es independently represents hydrogen, halogen, -MVZadB" or C .-alkyl; each of K8a and BEZ" independently represents hydrogen or C-1-alkyl;

OS" represents M or Seba;

OO: represents M or SEEV;

OZ is M or Sebs;

C" represents M or Svba:;

Ko) provided that at most one of OZ and 07 is M; each of Bba Der Dbs de rdbe and Byai independently represents hydrogen, halogen, Si-lalkyl, -

MAZarde or S. -alkyl substituted by one, two or three halogen atoms; each of K2a and ER" is independently hydrogen or C-1-alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl;

U is -0O-, -СНо- or -СЕ2-; 7 represents -СНе-, -Х-СНазед-, -2Н5с-(СНеа-, -Н5еНзе-СВВе- or -С-0-; and if У represents -СНе- or -СЕ2-, then 7 can also represent each of 5a, IDre, Dos, Dzya, de, Do, IDzo and God independently represents hydrogen or Si-lalkyl;

X represents -O-, -5- or -MA-;

A" is hydrogen, C:-alkyl or C-4 alkyl substituted by one substituent selected from the group consisting of -OH, -O-Ci-alkyl, K2, -MH", -MH-C-alkyl and -M(S.-alkyl)»g;

B": is a 4-, 5-, 6- or 7-membered heterocyclic ring, which contains one nitrogen atom and optionally one oxygen atom; while the specified 4-, 5-, 6- or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Ci-"alkyl)g, -MNA I, -MVsed'sya, cyano, -SEz, -"C(-0)-MNe, -C(-0)-MH-C:-alkyl, -6( -O)-Ci.lalkyl, Ci-alkyloxy, -C(-0)-O-Ci-4alkyl, C3-6cycloalkyl, -O-C3cycloalkyl, -

MH-C3-vcycloalkyl, -M(C3-6cycloalkyl)», C1-valkenyl, C1-4alkyl, substituted by one C1-4alkyloxy, and C:-4alkyl, optionally substituted by one -MNA'sad's; each of K/'ba and ALL is independently hydrogen or C--alkyl; because each of Ks and Kb independently represents Szecycloalkyl; VZ; Vya; Szecycloalkyl,

substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, -OH, and -O-C 1 -alkyl; C1-alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O0-C1 alkyl; or C 1 -alkyl substituted with one substituent selected from the group consisting of C 3 -cycloalkyl, B-C and B;

BZ is a 4-7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(-O)p and M; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(:O)p and M; the specified 4-7-membered monocyclic aromatic ring or 6-11-membered bicyclic condensed aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C-4 alkyl; p is equal to 1 or 2;

W is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); represents hydrogen, halogen, -MA"2B", C-1-alkyl, C-alkenyl, C3-cycloalkyl, -OH or -

O-S.i-zalkil;

DV": represents hydrogen;

DA" represents hydrogen, C3-6cycloalkyl or C6-alkyl;

Da represents hydrogen, halogen, -MIN8ZaVvV or C-.-alkyl; each of K8a and BEZ" independently represents hydrogen or C-1-alkyl;

OS" is M or Seb; 0: is M or SNEB; in particular, 0! and 027 are Si; each of ba and Eb5 is independently hydrogen, halogen, Ci-alkyl, -MAZaBR" or

C:-alkyl substituted by one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl;

Zo and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl;

U is -0O-, -СНо- or -СЕ2-; 7 is -СНе-, -Х-СІнзадь-, -852-01859-, -СНзеНзо-С VIV. or -С-0-; and if ХУ represents -СНег- or -СЕ2-, then 7 can also represent -О- or -СНЗаде-х-; each of Бра, ИДрБ, Дос, До, Дое, Де, ИДоо and о! independently represents hydrogen or Si.lalkyl;

X represents -O-, -5- or -MA1-;

A" is hydrogen, C:-alkyl or C-4 alkyl substituted by one substituent selected from the group consisting of -OH, -O-Ci-alkyl, K2, -MH", -MH-C-alkyl and -M(S.-alkyl)»g;

В" is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; while the indicated 4-, 5-, 6-, or 7-membered the heterocyclic ring is attached to the rest of the molecule through the nitrogen atom of the ring;

Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, while

BO is each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(C3-alkyl)g, cyano, -C3, -C(-0)-MH-C:-lalkyl, -C(-0)-C1-alkyl, C1-alkyloxy and C1-alkyl, optionally substituted one - МН'бадоБ; each of Ba and VO is independently hydrogen or Si-lalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

VzZa is hydrogen, halogen, -MV72B8" or -O-C..-alkyl;

Fa is hydrogen;

AND?" represents hydrogen or Si.lalkyl;

Da represents hydrogen, halogen, -MIN8ZaVvV or C-.-alkyl; because each of K8a and BEZ" independently represents hydrogen or C-.-lalkyl;

OS" is M or Seb; O: is M or SB; in particular, 0! and 027 are Si; each of Bba and BE? is independently hydrogen, halogen, Ci-alalkyl, -MARaB?? or Si- 4 alkyl substituted with one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl; and pharmaceutically acceptable addition salts and solvates thereof.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl;

U represents -O- or -СНо-; 7 is -СНе-, -Х-СІнзадь-, -852-01859-, -СНзеНзо-С VIV. or -С-0-; and if ХУ represents -СНе-, then 7 can also represent -СНазн-х-; each of Бра, ИДрБ, Дос, До, Дое, Де, ИДоо and о! independently represents hydrogen or Si.lalkyl;

X represents -O-, -5- or -MA1-;

B" represents hydrogen or Si.lalkil;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Ci-alkyl)g, -MNA"h, cyano, -SEz, -C(-0)-MH", -C(-0)-MH-C:-alkyl, C-alkyloxy, -C(- O)-O-C1-4 alkyl, C3-cycloalkyl, C6-alkenyl, C:1-alkyl, substituted by one C:-alkyloxy, and C1-alkyl, optionally substituted by one -MNA'sadtov;

Ва and В'Б represent Sz.-lalkil; dya is Szecycloalkyl; B"; Sialalkyl substituted with one, two or three substituents which are halogen; or C-alkyl substituted with one substituent selected

Zo from the group consisting of C3-6cycloalkyl and K'";

B" is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-4); each of За, ИДЗЖ, Dzs and за independently represents hydrogen, halogen, -MAaN,

C1--alkenyl, C3-cycloalkyl, -OH or -O-C:-alkyl;

Fa is hydrogen;

DA" is hydrogen, C3-cycloalkyl or C-alkyl; each of a, ID, De, dl. Id": and B! independently represents hydrogen, halogen, -MA8adv or C. .-lalkyl; each of 82 and 85 is independently hydrogen;

O" represents Svba; 0: represents SEB:

OO? is So;

WITH? is SER;

OZ is CE39; (36 represents M; and 07 represents CE; or

CO: represents CI39: (36 represents Ce; and 07 represents M; or

C is M; 05 represents SVe; and 07 represents CE": or

CO" is M; 05 represents Se: and 07 represents M;

WHEREIN, each of Kba, Dej, Idbs, ba, Dbe, Ii, db and ke" independently represents hydrogen, halogen or C3-4 alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl;

U represents -O- or -СНо-; 7 is -СНе-, -Х-СІнзадь-, -852-01859-, -СНзеНзо-С VIV. or -С-0-; and if ХУ represents -СНе-, then 7 can also represent -О- or -СИНзадех-хХ-; each of Bra, ИДрБ, Дос, До, Дое, Де, ИДоо and vo! independently represents hydrogen or 60 Ci .lalkyl;

X represents -O-, -5- or -MA1-;

A" is hydrogen or C-alkyl;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Si-alkyl)g", cyano, -SEz, -C(-0)-MH-Si-alkyl, -C(-0)-Si-alkyl, Si-dalalkyloxy and Si-alkyl, optionally substituted one - MA'sadtov; each of K/'ba and ALL is independently hydrogen or C--alkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); while each of Za, DZ" and VZs independently represents hydrogen, halogen, -MA"2A?? or -0О-

Ci-"alkyl;

Da represents hydrogen;

IN? represents hydrogen or S.-lalkil; each of a, D?? and Es independently represents hydrogen, halogen, -МВЗаДВЬ or C.-lalkyl; each of 82 and 85 is independently hydrogen or C-alkyl;

OO" represents Svva; 0: represents CE;

SSZ represents itself;

CO" represents Ca: each of Bba Dbjb, Dbre and B independently represents hydrogen, halogen, C-alkyl, -

MAZarr" or C.-alkyl, substituted by one, two or three halogen atoms; each of Za and ER" is independently hydrogen or C 1 -alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

Zo B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl;

U represents -O- or -СНо-; 7 is -СНе-, -Х-СІнзадь-, -852-01859-, -СНзеНзо-С VIV. or -С-0-; and if ХУ represents -СНе-, then 7 can also represent -О- or -СИНзадех-хХ-; each of za, ИДБЬ, Дос, Да, зе, До, ИД» and ог independently represents hydrogen or

Ci-"alkyl;

X represents -O-, -5- or -MA1-;

A" is hydrogen or C-alkyl;

Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one substituent selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C-"alkyl)g, cyano, -CEz, -C (-0)-MH-C.:-alkyl, -b(-0)-Ci.-alkyl, C:-alkyloxy and C.-alkyl, optionally substituted by one -MA'sadto; each of K/'ba and ALL is independently hydrogen or C--alkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); while Ka, DZ" and KZs represent -MA7aН;

Da represents hydrogen;

IN? is hydrogen; each of a, D?? and Es independently represents hydrogen, halogen, -МВЗаДВЬ or C.-lalkyl; each of 82 and 85 is independently hydrogen or C 1 -alkyl;

O" represents Svba; 0: represents CE;

SSZ represents itself;

CO" represents Ca: each of Ba, Db, Dbs, Dea. dDvbe and Byai independently represents hydrogen, halogen, 60 C-alkyl, -MAZaD?" or C. -alkyl substituted by one, two or three halogen atoms;

each of K2a and ER" is independently hydrogen or C--alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

B: represents hydrogen or -C(-0)-C:-alkyl; in particular, B" and K" represent hydrogen;

U represents -O- or -СНо-; 27 represents -СНе-, -Х-Сиздае-, -852-01859-, -СВ5еН5о-СВИДе- or -С-0-; and if U represents -СНе-, then 7 can also represent -СНЗадр-Х-; each of 5a, Idre, Dos, Dzya. where, ID, IDoo and DOH independently represent hydrogen or

Si.lalkil;

X represents -O-, -5- or -MA1-;

A" is hydrogen or C-alkyl;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-Ci-alkyl, -M(C1-4 alkyl)", cyano , -SEz, -0(-0)-MH-C:-alkyl, C1-alkyloxy and C1-alkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2); each of Za and Ezs independently represents a halogen, -MA"2B"" or -O-C..alkyl;

Fa is hydrogen;

IN? is hydrogen; each of La and Ks is independently hydrogen, halogen, or C-alkyl;

OO" represents Svva; 0: represents SEB: each of ba, |dbj, dbe, and Yai independently represents hydrogen, halogen, or C1-alkyl;

Zo and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

B: represents hydrogen or -C(-0)-C:-alkyl; in particular, K' and K? are hydrogen;

U represents -O- or -СНо-; 7 represents -СНе-, -Х-СВзаде-, -С85-СвВ-, -08еН-СВВе- or -С-0-; and if ХУ represents -СНе-, then 7 can also represent -СНазн-х-; each of Bra, ИДрБ, Дос, До, Дое, Де, ИДоо and vo! independently represents hydrogen or

Ci-"alkyl;

X represents -O-, -5- or -MA1-;

A" is hydrogen or alkyl;

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C.-"alkyl, -M(C3-alkyl)2, -MNA' se, cyano, -SEz, -F(-0)-MH-C:-alkyl, C:-alkyloxy and C:-4 alkyl;

V'Yaya is C:-4 alkyl substituted with one, two or three substituents which represent

BO is a halogen; or

Ci-halkyl substituted by one C3-ecycloalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2); each of Za and Zs independently represents hydrogen, halogen, -MA"2B8"" or -O-C..alkyl;

DV": represents hydrogen;

IN? represents hydrogen or S.-lalkil; each of Ka and Bc is independently hydrogen, halogen, or C-alkyl;

ОО" represents Svva; 0: represents CE; because each of ba, |ДбБ, бе and Бяй independently represents hydrogen, halogen or C--alkyl;

and their pharmaceutically acceptable addition salts and solvates.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, which are specified in any of the other embodiments, where one or more of the following limitations apply: () A " and K7 represent hydrogen; (i) ХУ represents -О- or -СНо-; in particular, У represents -О-; (ии) 7 represents -СНе-, -Х-СНазед-, -Н52-0На -, -СН5еНею-СВВ- or -С-0-; and if U represents -СНе-, then 7 can also represent -СНЗадр-Х-; (im) DVza, AB, des, ID»o, Idze, IDZi, IDzo and VE" represent hydrogen; (M) X represents -O-; (m) B"! represents hydrogen or C-alkyl; (mi) Ag is optionally substituted by one, two or three substituents, in particular, one substituent, each independently selected from the group consisting of halogen, -OH , -

MH", -MH-C.-alkyl, -M(Ci-alkyl)", cyano, -SEz, -0(-0)-MH-C:-alkyl, C-alkyloxy and C-alkyl; (my) It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-d2); (their) each of Za and KZc independently represents a halogen, -MA"2B? or -O-C.-alkyl; (x) B"2 and E?? are hydrogen; (xi) each of 2 and Bc is independently hydrogen, halogen, or C:-alkyl; (xi) CO" represents Sib; (xii) 02 represents SiCbB; (chem) each of ba, Ide, be, and I independently represents hydrogen, halogen, or

Si .lalkil.

In one embodiment, the present invention relates to novel compounds of formula (I), where

AND! is hydrogen;

B2 is hydrogen;

U represents -O- or -СНо-; 7 represents -X-SVRaDgR- or -С1В5едю-СВЯВГ-;

Ko) and if U represents -СНе-, then 7 can also represent -СНЗадр-Х-;

Vza, BB, idre, DYA, deo and Boh represent hydrogen;

X represents -O-;

Ag is a

In C u / -km o, while Ag is optionally substituted in the position marked by a substituent selected from the group consisting of -MH", -MH-C.-4 alkyl and -MNV "9: and while Ag optionally substituted in the position indicated by VD with a substituent selected from the group consisting of halogen and CE3, provided, however, that Ag is substituted in at least one of the positions indicated by a or p;

VyaYa is Szecycloalkyl; C:-alkyl substituted by one, two or three substituents, which are halogen; or C1-4alkyl substituted by one substituent, which is C3-6cycloalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4); each of Za and 34 independently represents hydrogen, halogen, -MV72B"", Si-dalalkyl or -O-C. lalkyl;

Da represents hydrogen;

Why A?" represents hydrogen or Si.lalkyl; each of Ba, DZ and EE"! is independently hydrogen or halogen;

OO" represents Svva; 0: represents SE;

OZ is So;

WITH? is SER;

C: represents CIE34: (6 represents M; and 07 represents CE;

DVba, DeЬ. dbo and reg represent hydrogen;

and their pharmaceutically acceptable addition salts and solvates.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, which are specified in any of the other embodiments, where one or more of the following limitations apply: () A " and K7 represent hydrogen; (her) M represents -0- or -СНе-; (her) 7 represents -Х-СНтаВРе- or -СВ»5еН»-СВИВе-; and if ХУ represents -СНе- , then 7 can also represent -CHzan-x-; (im) vza, AB, IDze, ID", IDzo and Kg represent hydrogen; (M) X represents -O-; (m) Ag represents tav - mm (o. and in this case Ag is optionally substituted in the position indicated by a with a substituent selected from the group consisting of -MH", -MH-C.-"alkyl and -MNA sa; and in this case Ag is optional is necessarily substituted in the position indicated by VD by a substituent selected from the group consisting of halogen and C3; however, provided that Ag is substituted in at least one of the positions indicated by a or p; (mi) B'Y is C6cycloalkyl; Si --alkyl, substitution with one, two or three substituents, which are halogen; or C1-4alkyl substituted by one substituent, which is C3-6cycloalkyl; (my) It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4); (their) each of KZa and Za is independently hydrogen, halogen, -MA2A, Ci-alkyl or -0O-

Ci-"alkyl; (x) B"2 is hydrogen; (xi) A? is hydrogen or C-alkyl;

Co) (chii) each of Ka, ID" and B" independently represents hydrogen or halogen; (khii) O' represents Sowing; (chem) 0? is a SIV; (ху) OZ represents SIVo9; (hmm) C? is an SVG; (hope) SO? is SIV34; Where is M; and O7 represents CE; (chemicals) Vba, De", Debo and Ve" represent hydrogen.

In one embodiment, the present invention relates to novel compounds of formula (I), where

AND! is hydrogen;

B2 is hydrogen;

U represents -O- or -СНо-; 7 represents -Х-ШНЗан- or -ШНЖНЖЯ-СВЯВЕГ-; and if ХУ represents -СНе-, then 7 can also represent -СНазн-х-;

Vza, BB, idre, DYA, deo and Boh represent hydrogen;

X represents -O-;

Аг is ву у / -м (and at the same time Аг is optionally substituted in the position marked by a substituent selected from

BO of the group consisting of -MH", -MH-C.-4 alkyl and -MNV "9: in this case Ag is optionally substituted in the position indicated by VD by a substituent selected from the group consisting of halogen and CEz; provided, however, that Ag is substituted in at least one of the positions marked a or p;

VyaYa is Szecycloalkyl; C:-alkyl substituted by one, two or three substituents, which are halogen; or C1-4alkyl substituted by one substituent, which is C3-6cycloalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

Dzga is hydrogen, halogen, -MV"2B", Si-lalkyl or -O-C:.lalkyl;

Da represents hydrogen;

IN? represents hydrogen or S.-lalkil;

Da represents hydrogen or halogen;

OO" represents Svva; 0: represents CE;

Vba and Vb5 represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

AND! is hydrogen;

A: represents hydrogen;

U represents -O- or -СНо-; 7 represents -X-SVRaDgR- or -С1В5едю-СВЯВГ-;

Vza, BB, idre, DYA, deo and Boh represent hydrogen;

X represents -O-;

Ag is tn -m (at the same time, Ag is optionally substituted in the position indicated by a by a substituent selected from the group consisting of -MH", -MH-C.-4 alkyl and -MNV "9: and Ag is optionally substituted in the position indicated by VD with a substituent selected from the group consisting of halogen and CE3, provided, however, that Ag is substituted in at least one of the positions indicated by a or p;

VyaYa is Szecycloalkyl; C:-alkyl substituted by one, two or three substituents, which are halogen; or C1-4alkyl substituted by one substituent, which is C3-6cycloalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

Dzga is hydrogen, halogen, -MV"2B", Si-lalkyl or -O-C:.lalkyl;

DV": represents hydrogen;

IN? represents hydrogen or S.-lalkil;

IDl2 is hydrogen or halogen;

OO" represents Svva; 0: represents CE;

Vba and b" represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

V' represents hydrogen;

B2 is hydrogen;

U represents -O- or -СНо-; 7 represents -X-SVRaDgR- or -С1В5едю-СВЯВГ-; and if U represents -СНе-, then 7 can also represent -СНЗадр-Х-;

Vza, BB, idre, DYA, deo and Boh represent hydrogen;

X represents -O-;

Аг is сг -к (ей at the same time Аг is substituted in the position marked by a substituent selected from the group consisting of -МН»г, -МН-С:-alkyl and -МНА с; вя is Сзециклокалкіл ; or C 1-6 alkyl substituted with one substituent selected from the group consisting of C 1-6 cycloalkyl and B";

B" is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen;

It is a bicyclic aromatic heterocyclic ring system (a-1);

Dzga is hydrogen, halogen, -MA"2B? or Si-lalkyl;

Da represents hydrogen;

AND?" represents hydrogen or Si.lalkyl;

FSHDla is hydrogen;

OS" represents Sowing; 0 represents SVB;

Vba and Vb5 represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

V' represents hydrogen;

B2 is hydrogen;

U represents -O- or -СНо-; 7 represents -X-SVRaDgR- or -С1В5едю-СВЯВГ-; and if U represents -СНе-, then 7 can also represent -СНЗадр-Х-;

Aza, Do, Dze, DU, Doo, and Boh represent hydrogen;

X represents -O-;

Ag is a

In g u / -m o, while Ag is optionally substituted in the position indicated by a, -МН5; and at the same time Ag is substituted in the position indicated by VD with a substituent selected from the group consisting of halogen and CEz;

Zo Nei is a bicyclic aromatic heterocyclic ring system (a-1);

VzZa is hydrogen, halogen, -MV72B8" or C-.-alkyl;

Da represents hydrogen;

IN? represents hydrogen or S.-lalkil;

Da represents hydrogen;

OS" represents Siva; 0: represents SVB:

Vba and Vb5 represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

V' represents hydrogen;

B2 is hydrogen;

U represents -O- or -СНо-; 7 represents -X-SVRaDgR- or -С1В5едю-СВЯВГ-; and if U represents -СНе-, then 7 can also represent -СНЗадр-Х-; da, VR, Idze, DYA, Do and EOG represent hydrogen;

X represents -O-;

Аг is ву у / -м (and at the same time Аг is substituted in the position marked а, -МНе5; and at the same time Аг is substituted in the position marked ВД by a substituent selected from the group consisting of halogen and СЕз;

It is a bicyclic aromatic heterocyclic ring system (a-1);

VzZa is hydrogen, halogen, -MV72B8" or C-.-alkyl;

Fa is hydrogen;

IN? represents hydrogen or S.-lalkil;

Da represents hydrogen;

OS" represents Siva; 0: represents SVB:

Dega and b" represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

V' represents hydrogen;

B2 is hydrogen;

U represents -O- or -СНо-; 7 represents -Х-ШНЗан- or -ШНЖНЖЯ-СВЯВЕГ-; and if ХУ represents -СНе-, then 7 can also represent -СНазн-х-; da, VR, Idze, DYA, Do and EOG represent hydrogen;

X represents -O-;

Ag is gkO-x-ki

It is a bicyclic aromatic heterocyclic ring system (a-1);

Dzga is hydrogen, halogen, -MA"2B? or Si-lalkyl;

Da represents hydrogen;

IN? represents hydrogen or S.-lalkil;

DV: represents hydrogen;

OS" represents Siva; 0 represents SVB;

Vba and Vb5 represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), wherein

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl; in particular, E! and KE? are hydrogen;

U represents -СНе- or -О-; 7 represents -X-SVRaDgR- or -CHnoCH»-; each of 22 and 255 is independently hydrogen or C 1 -C 1 -alkyl;

X represents -O-, -5- or -МВА11-;

B" is hydrogen;

Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed 6b-membered rings, where 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-Ci-alkyl, -M(C-C-alkyl)g, cyano, -

C3, -0(-0)-MN-Ci-alkyl, -C(-0)-C1-alkyl, Silalkyloxy and C-alkyl, optionally substituted with one -MA'sad's: each of Ba and BO independently represents hydrogen or Si-lalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

VzZa is hydrogen, halogen, -MV72B8" or -O-C..-alkyl;

Fa is hydrogen;

AND?" is hydrogen;

Da represents hydrogen, halogen, -MIN8ZaVvV or C-.-alkyl; each of K8a and BEZ" independently represents hydrogen or C-1-alkyl;

O" represents Svba; 0: represents SEB: each of Ba and Eb5 independently represents hydrogen, halogen, Ci-alkyl, -MAZaBR" or

C:-alkyl substituted by one, two or three halogen atoms; each of K2a and ER" is independently hydrogen or C-1-alkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

V' represents hydrogen;

B2 is hydrogen;

U represents -СНе-; 7 represents -SNReD»-SVDV-;

Dvoe, DYA, IDoe and vo! are hydrogen;

Ag is any of the following 10-membered bicyclic aromatic ring systems:

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -MH", -MH-C:-alkyl, -M(Ci-alkyl)2, -MNA 9, -MAoed'sa; each of B'bs and K'cYa is independently C3-ecycloalkyl; C3-cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C-alkyl; C:1-4alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C:alkyl; or C:-alkyl substituted by one substituent, which is C3-ecycloalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

Dzga is hydrogen, -МВ"2В8? or -О-С..-lalkil;

DV": represents hydrogen;

AND?" represents hydrogen or Si.lalkyl;

IDla is hydrogen;

OS" represents Sowing; 0 represents SVB;

Co) Vba and b" represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

V' represents hydrogen;

B2 is hydrogen;

U represents -СНе-; 7 represents -SNReD»-SVDV-;

Dvoe, DYA, IDoe and vo! are hydrogen;

Ag is r

M

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -MH", -MH-C:-alkyl, -M(Ci-alkyl)", -MNA 99:

V'Yaya is C:-4 alkyl substituted with one, two or three substituents, which are halogen; or

Ci-halkyl substituted by one substituent, which is C3-ecycloalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); 5O Dzga is hydrogen, -MV"2B8? or -O-S..-lalkyl;

Fa is hydrogen;

AND?" represents hydrogen or Si.lalkyl;

Da represents hydrogen;

OS" represents Siva; 0: represents SVB:

Dega and b" represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, which are specified in any of the other embodiments, where one or more of the following limitations apply: (Y) V' represents hydrogen;

B2 is hydrogen; (iii) M represents -СНе-; (its) 7 represents -СНЗеН»-СВВ-; (im) Vee, VU, De and ER" represent hydrogen; (m) Ag represents g -k

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -MH", -MH-C:-alkyl, -M(C:-alkyl)2, - MNA "sa: (m) V'Ya is Si-lalkyl substituted with one, two or three substituents which are halogen; or

Ci-halkyl substituted by one substituent, which is C3-ecycloalkyl; (my) It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (my) Za represents hydrogen, -МН7аВ"» or -O-C.-alkyl;

Co) (their) V"g represents hydrogen;

AND?" represents hydrogen or Si.lalkyl; (x) FID"2 is hydrogen; (xi) O" is Siea; 0: represents SEB: (hii) Neba and Ve" represent hydrogen.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, which are specified in any of the other embodiments, where one or more of the following restrictions apply: () B ' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl; in particular, КЕ" and К2 are hydrogen; (ii) M is -СНе- or -О-; (из) 7 is -Х-СНаВРе- or -СНеСНе-; (im) each of 22 and ЕР» independently represents hydrogen or C-alkyl; (m) X represents -O-, -5- or -MA-; (m) A" represents hydrogen; (my) Ag is optionally substituted by one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-Ci-alkyl, -M(C-C-alkyl)g , cyano, -

C3, -0(-0)-MH-C1-alkyl, -C(-0)-C1-alkyl, Silalkyloxy and C1-alkyl, optionally substituted by one -MA'sad's; (my) each of K'cba and E/c5 independently represents hydrogen or C 1 -alkyl; (their) It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (x) vza represents hydrogen, halogen, -MA"aB" or -O-C,-alkyl; (xi) "g" represents hydrogen;

IN? is hydrogen; (chii) B" represents hydrogen, halogen, -MAZaVe" or C -alalkyl;

(chii) each of 82 and 85 is independently hydrogen or C: -alkyl; (him) O' represents Siva; (xm) 02 represents SIV: (xmi) each of ba and B" independently represents hydrogen, halogen, C:-4 alkyl, -MVaV"" or

C:-alkyl substituted by one, two or three halogen atoms; (chemicals) each of Za and ER" independently represents hydrogen or C-alalkyl.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl; in particular, КЕ" and К2 represent hydrogen;

U represents -O-; 7 represents -X-CHzado-; each of K5a and E? independently represents hydrogen or C-.-alkyl;

X represents -O-, -5- or -MA1-;

B" is hydrogen;

Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed 6b-membered rings, where 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-Ci-alkyl, -M(C-C-alkyl)g, cyano, -

C3, -0(-0)-MH-C1-alkyl, -C(-0)-C1-alkyl, Silalkyloxy and C1-alkyl, optionally substituted by one -MA'sad's; each of K/'ba and ALL independently represents hydrogen or C--alkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

Dzga is hydrogen, halogen, -MV"2B? or -O-C..alkyl;

Da represents hydrogen;

From VD" is hydrogen;

Da represents hydrogen, halogen, -MNZarB" or C-alkyl; each of K8a and BEZ" independently represents hydrogen or C-1-alkyl;

OO" represents Svva; 0: represents CE; each of Bba and B" independently represents hydrogen, halogen, C1-4 alkyl, -MAZaByaB or C. alkyl substituted with one, two or three halogen atoms; each of K2a and ER » independently represents hydrogen or C-.-alkyl, and their pharmaceutically acceptable addition salts and solvates.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, which are specified in any of the other embodiments, where one or more of the following restrictions apply: () B ' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl; in particular, KE" and K2 represent hydrogen; (its) M represents -O-; (its) 7 represents -X-CHzade-; (im) each of "a and 55 independently represents hydrogen or C-1-alkyl (m) X represents -O-, -5- or -MA-;

BO (m) A" represents hydrogen; (my) Ag is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH"e, -MH-Ci-alkyl , -M(Cr-"alkyl)g, cyano, -

C3, -0(-0)-MH-C1-alkyl, -C(-0)-C1-alkyl, Silalkyloxy and C1-alkyl, optionally substituted by one -MA'sad's: (my) each of K 'sba and E/c5 independently represent hydrogen or C 1 -alkyl; (their) It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (x) vza represents hydrogen, halogen, -MA"aB" or -O-C,-alkyl; (xi) B"g represents hydrogen; because B? is hydrogen;

(chii) B72 represents hydrogen, halogen, -MNHZarvB" or C.-alkyl; (chii) each of 82 and 85 is independently hydrogen or C: -alkyl; (chem) CO! is Siea; (xm) 02 represents SIV: (xmi) each of ba and Bbb independently represents hydrogen, halogen, C:-4 alkyl, -MAZaD?P" or C-4 alkyl substituted by one, two or three halogen atoms; (chemicals) each of Za and ER" independently represents hydrogen or C-alalkyl.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl; in particular, КЕ" and К2 represent hydrogen;

U represents -СНе- or -О-; 7 represents -X-CHzan- or -CHnegCHne-; each of K5a and E? independently represents hydrogen or C-.-alkyl;

X represents -O-, -5- or -МВА11-;

B" represents hydrogen; ( | / then -M - y

Ag represents ; in particular, Ag represents ;

Ag is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-Ci-alkyl, -M(C-C-alkyl)g, cyano, -

C3, -0(-0)-MH-C1-alkyl, -C(-0)-C1-alkyl, Silalkyloxy and C1-alkyl, optionally substituted by one -MA'sad's; each of K/'ba and ALL is independently hydrogen or C--alkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

VzZa is hydrogen, halogen, -MV72B8" or -O-C..-alkyl;

Da represents hydrogen;

IN? is hydrogen;

Da represents hydrogen, halogen, -MAZarB" or C-alkyl; each of 82 and 85 is independently hydrogen or C 1 -alkyl;

O" is Swba; 0: is SEB: each of Bba and B" is independently hydrogen, halogen, C1-4 alkyl, -MAZaByaB or C1 alkyl substituted with one, two or three halogen atoms; each of K2a and ER » independently represents hydrogen or C-.-alkyl, and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl; in particular, E! and KE? are hydrogen;

U represents -O-; 7 represents -X-SVRaDeB-; each of 22 and 255 is independently hydrogen or C 1 -C 1 -alkyl;

X represents -O-, -5- or -МВА11-;

BA" represents hydrogen; / by so .

Ag represents ; in particular, Ag represents ;

Ag is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-Ci-alkyl, -M(C-C-alkyl)g, cyano, -

C3, -0(-0)-MH-Ci-alkyl, -C(-0)-C1-alkyl, Silalkyloxy and Ci-alkyl, optionally substituted by one -MA'sad's:

BO each of Ba and VO is independently hydrogen or Si-lalkyl;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of

which consists of (a-1);

VzZa is hydrogen, halogen, -MV72B8" or -O-C..-alkyl;

Da represents hydrogen;

IN? is hydrogen;

Da represents hydrogen, halogen, -MAZarB" or C-alkyl; each of 82 and 85 is independently hydrogen or C 1 -alkyl;

O" represents Swba; O: represents SEB: each of Ba and BE" independently represents hydrogen, halogen, C1-4alkyl, -MIAZaB»j or

C:-alkyl substituted by one, two or three halogen atoms; each of K2a and ER" is independently hydrogen or C-1-alkyl; and their pharmaceutically acceptable addition salts and solvates.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, which are specified in any of the other embodiments, where one or more of the following limitations apply: (I) B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl; in particular, E! and KE? are hydrogen; (her) M represents -O-; (her) 7 is -X-CHzadeh-; (im) each of "a" and "55" independently represents hydrogen or C-alkyl; (m) X represents -O-, -5- or -MA-; (m) B"! represents hydrogen; ( | / plo y - M - M (my) Ag represents ; in particular, Ag represents ; (my) Ag is optionally substituted by one or two substituents, while each is independently chosen from the group consisting of halogen, -OH, -MH"e, -MH-Ci-alkyl, -M(C-"alkyl)g, cyano, -

C3, -0(-0)-MH-Ci-alkyl, -C(-0)-C1-alkyl, Silalkyloxy and Ci-alkyl, optionally substituted by one -MA'sad's:

Co) (their) each of B'sba and this independently represents hydrogen or S.-lalkyl; (x) It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (xi) Za represents hydrogen, halogen, -MA"aV?" or -O-C.-alkyl; (chii) B" represents hydrogen;

IN? is hydrogen; (chii) 72 is hydrogen, halogen, -MH8VarvB" or C-alkyl; (chem) each of va and 28" is independently hydrogen or C-alkyl; (hoo) SO! is Srea; (hmm) C? is a SIV; (chemicals) each of ba and Bbb is independently hydrogen, halogen, C:-alkyl, -MAZaB? or C-4 alkyl substituted by one, two or three halogen atoms; (chemicals) each of Za and ER" independently represents hydrogen or C-alalkyl.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl; in particular, КЕ" and К2 represent hydrogen;

U represents -O- or -СНе-; 7 represents -X-SNZadre- or -СНеСНе-;

XVla and 5" represent hydrogen; X represents -O-;

B" represents hydrogen; h y / - y

Because Ag represents ;

Ag is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C:-alkyl)g, cyano and -SEz;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); dza is -MA72D;

Da represents hydrogen;

IN? is hydrogen;

Da represents hydrogen;

OS" is Swba; 2 is CE; Baga and b" are hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl; in particular, КЕ" and К2 represent hydrogen;

U is -O- or -CH»e-; 7 represents -X-C ВРар?e- or -СНеСН»е-;

Doe and E? are hydrogen; X represents -O-;

B" represents hydrogen; h u / 5--M

Ag represents ;

Ag is optionally substituted with one substituent selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C 1 -alkyl) 2 , cyano and -CEz;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

VzZa is -МА7аВБ;

Fa is hydrogen;

"VD" is hydrogen;

Da represents hydrogen;

OS! represents Himself; (32 is SEB: dba and EE? represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

Zo B' represents hydrogen or -C(-0)-C.-alkyl;

Hg is hydrogen or -C(-0)-C.-alkyl; in particular, КЕ" and К2 represent hydrogen;

U represents -O-; 7 represents -X-CH-back-;

XVla and 5" represent hydrogen; X represents -O-;

B" represents hydrogen; h y / -M

Ag represents ;

Ag is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C:-alkyl)g, cyano and -SEz;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

VzZa is -МА7аВБ;

Fa is hydrogen;

AND?" is hydrogen;

FSHDla is hydrogen;

OS" is Svba; 2 is Si; Bag and b" are hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl; in particular, E! and KE? are hydrogen;

U represents -O-; 7 represents -X-SNzade-;

XVla and 5" represent hydrogen; X represents -O-;

BA" represents hydrogen; / 0

Ag represents ;

Ag is optionally substituted with one substituent selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C 1 -alkyl) 2 , cyano and -CEz;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

VzZa is -МА7аВБ;

Fa is hydrogen;

IN? is hydrogen;

IDla is hydrogen;

OS" is Swba; 2 is CE; Baga and b" are hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), where

B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl; in particular, E! and KE? are hydrogen;

U is -O- or -CH»e-; 7 represents -X-C ВРар?e- or -СНеСН»е-;

Doe and E? are hydrogen; X represents -O-;

B" represents hydrogen; talotene

Ag represents -KkM;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

VzZa is -МА7аВБ;

Da represents hydrogen;

AND?" is hydrogen;

IDla is hydrogen;

OS" is Swba; 2 is CE; Baga and b" are hydrogen; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), wherein

B' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl; in particular, E! and KE? are hydrogen;

U represents -O-; 7 represents -X-SNzade-;

Doe and E? are hydrogen; X represents -O-;

BA" represents hydrogen; -M

Ag represents ;

It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); dza is -MA72D;

Da represents hydrogen;

IN? is hydrogen;

Da represents hydrogen;

OS! represents Himself; (32 is SEB: dba and EE? represent hydrogen; and their pharmaceutically acceptable addition salts and solvates.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, which are specified in any of the other embodiments, where one or more of the following restrictions apply: () B ' represents hydrogen or -C(-0)-C.-alkyl;

IN? represents hydrogen or -C(-0)-C.-alkyl; in particular, E! and KE? are hydrogen; (her) M represents -O-; (its) 7 is -X-CHZare-; (im) ShDza and ER"? are hydrogen; (M) X represents -O-; (m) V"! represents hydrogen; / shen SYA (my) Ag represents ;

Ag is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C:-alkyl)g, cyano and -SEz; in particular, Ag is optionally substituted with one substituent selected from the group consisting of halogen, -OH, -MH", -MH-C:-alkyl, -M(C:-alkyl)g, cyano and -CEz; more specifically, Ag is a pose; even more specifically, Ag represents M; (their) It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (x) Za represents -МА72НЬ; (xi) V"g represents hydrogen;

IN? is hydrogen; (khii) B"g represents hydrogen; (khii) O' represents Steve; (chem) 0? represents SIV; (hm) ba and 55 represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

AND! and Kg? are hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

WOW! is -C(-0)-C1-alkyl; K2 is -C(-0)-Ci-alkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

B' and 2 represent hydrogen;

It is represented by (a-1);

OS" represents CH; 0- represents CH; and

Ag represents g -M, optionally substituted according to any of the other variants of implementation.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

B' and 2 represent hydrogen;

It is represented by (a-1);

Coll

OS" represents CH; 0- represents CH; and

Ag represents g -k, while Ag is substituted with one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, -MH", -MH-C:-alkyl, -M(C:- alkyl)", -МНВса, - Moda, each of V'ss and ДЯ is independently C-alkyl, substituted by one, two or three substituents, which are halogen; or C1-4alkyl substituted by one substituent, which is C3cycloalkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where U represents -O-.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, specified in any of the other embodiments, where M represents -СНо- or -СЕ2-; in particular, where U represents -СНе-.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein a maximum of one of 0! and 02 is M.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where CO! is Ca; and 02 represents CE; in particular, where 0! is CH; and 02 is CH.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, specified in any of the other embodiments, where Nei is (a-1); C" represents Skea; and 02 represents SIVEB: in particular, where 0! represents Sn; and 02 represents CH.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

OZ is CE39: (36 is M; and 0" is CE; or

C: represents SEZ: (6 represents CE; and 07 represents M; or

C: represents M; 09 represents SE: and OO" represents SE"; or

WITH? is M; 09 is SI; and 07 is M.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein N is a bicyclic aromatic heterocyclic ring system selected from group consisting of (a-1), (a-2) and (a-4).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

B' and Kg represent hydrogen; and U represents -O-.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein N is a bicyclic aromatic heterocyclic ring system selected from group consisting of (a-1), (a-2) and (a-3).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein N is a bicyclic aromatic heterocyclic ring system selected from group consisting of (a-1) and (a-d).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein N is a bicyclic aromatic heterocyclic ring system selected from group consisting of (a-1) and (a-4).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein N is a bicyclic aromatic heterocyclic ring system of the formula (a -1).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

AV and VK? are hydrogen; U represents -0-; and Nei is a bicyclic aromatic heterocyclic ring system of the formula (a-1).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is an optionally substituted 10-membered bicyclic an aromatic ring system, which consists of two condensed b-membered rings, where 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that the nitrogen atom does not replace one of the two carbon atoms common to the two fused rings.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is optionally substituted with one or two substituents according to any of the other implementation options.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is optionally substituted with one substituent according to any which of the other implementation options.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

VzZa, AZs, DZ represent hydrogen; and yes, Ves, Db are hydrogen, halogen, or C-alkyl; in particular, Ba, ID, DVE are halogen or C-alkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

VzZa, DZs, DZ. dza and ze represent hydrogen; and da, de, Db, dya, dtje, DYA and 9 represent hydrogen, halogen or C-alkyl; in particular, K2,

Wes, Bb, Dya, Ddee, Dya and Co are halogen or C-alkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, indicated in any of the other embodiments, where for, where, DZ" represent hydrogen, halogen . or -O-C.i.alkyl;

Vl, Where, DV? are hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Aza, BdzZe, 3B, dza and KZe represent hydrogen, halogen, -MA"2A" or -O-C.-alkyl; in particular,

VzZa, DZs, DZ, dza and ze are halogen, -MA"aB"" or -O-C.1.-alkyl; Fa, De, DB, DIA, de,

B and "9 represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, specified in any of the other embodiments, where z, ze, DZ" represent hydrogen, if 72, Vis, V" differ from hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Za, Vs, Z", and where represent hydrogen, if la, Vl, V, dya de, DYA, vdo differ from hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where yes, where B" is hydrogen, if Za, DZs, DZ" differ from hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where to represent hydrogen, if За, НЗс, З, ВЗ, where they differ from hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed 6-membered rings, and where at least 1 carbon atom of ring B is replaced by a nitrogen atom; at the same time, 1 additional carbon atom of ring A or ring B is optionally replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted according to any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed 6-membered rings, where at least 1 carbon atom of ring B is replaced by a nitrogen atom; at the same time, 1 additional carbon atom of ring A or ring B is optionally replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C--alkyl, -

M(Si-alkyl)2, -MNA sa, -MV sulfur, cyano, -SEz, -С(-0)-МН»e, -Ф(-0)-МН-С.-alkyl, -б(- O)-Ci-alkyl, Ci-6alkyloxy, -C(-0)-O-C:-alkyl, C3cycloalkyl, C1-valkenyl, C1-alkyl substituted with one C:-alkyloxy, and C1-alkyl, neoob' necessarily replaced by one -MA'sad/o; in particular, Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH»e, -MH-Cch-4 alkyl, -M(Si- alkyl)", cyano, -C3, -C(-O)-MH-Ci-alkyl, -C(-0)-Ci-alkyl, Ci-alkyloxy and Ca alkyl, optionally substituted by one -MH-SadoB,

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings with the following structure, vi xx "

At the same time, 1 additional carbon atom of ring A or ring B is optionally replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted according to any of the other embodiments.

It will be obvious that covers any of the following ring systems: оту ду пе а все и А И г и 1 У мч ие

Messages

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of:

OO, la / 7557 y lo -M M-M -M X-ki 5 -V-Z -M y Maty ch -y

X Y - ех у / ,/1y AK fХ / хх

M -y -ki M- M- - -M i M--y 7 M i -

M- M- M- where each Ag is optionally substituted according to any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of: boa, -M М-М -- М х-к -М М-- - г po dk where each Ag is optionally substituted according to any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of:

--- --6..1st --- then didavshav -M -k m-M - and

M- - -k -k M- "

M-

M tn

X-ki - where each Ag is optionally substituted according to any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of: -- ---- Measurement 7 V; a, li "55 -kM -ki M-M -i

M- - - - M- "

M- -M M ----- Kya --23- Kya

M and M and 0 U

X--ki -- M- where each Ag is optionally substituted according to any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of:

---- --- M - ( lo, li o, "5 -kmMm -km M--M -km

M- - -k -ki - M- "

M --e -m x - U - U x-khi where each Ag is optionally substituted according to any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (III) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, specified in any of the other embodiments, where Ag is

C u / 5-M, while Ag is optionally substituted according to any of the other variants of implementation.

In one embodiment, the present invention relates to such compounds of formula (III) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag differs from

With /

M, while Ag is optionally substituted according to any of the other variants of implementation.

In one embodiment, the present invention relates to such compounds of the formula (II) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, specified in any of the other embodiments, where Ag is g -K, while Ag is substituted by one , two, three or four substituents, each of which is independently selected from the group consisting of halogen, -MH", -MH-Ci-alkyl, -M(Ci-alkyl)", -

МН MV osrtoya

In one embodiment, the present invention relates to such compounds of formula (III) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, specified in any of the other embodiments, where Ag is

Koo) with -K, while Ag is replaced by one substituent selected from the group consisting of -MH»e, -MH-C:-alkyl, -M(Ci-alkyl)2, -MNNAYA, -MA sr: and neoobov necessarily substituted by a substituent that is a halogen; each of Os and Ka is independently C-alkyl substituted with one, two or three substituents which are halogen; or C 1 -alkyl substituted by one substituent, which is C 3 -cycloalkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where Ag is and -m (and while Ag substituted in the position indicated by a with a substituent selected from the group consisting of -МН2г, -МН-С. Ag is optionally substituted in the position marked B by a substituent that is a halogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where Ag is and -m

At the same time, Ag is substituted in the position indicated by a by a substituent selected from the group consisting of -МНе, -МН-С. at the same time Ag is optionally substituted in the position marked B by a substituent that is a halogen; each of Cos and K!94 is independently C-alkyl substituted with one, two or three substituents which are halogen; or C1-4alkyl substituted by one substituent, which is C3cycloalkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof specified in

From any of the other variants of the implementation, where Ag represents and, -Kk while Ag is replaced in the position marked by VD by a substituent that is a halogen; in particular chlorine or bromine; more specifically bromine.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, specified in any of the other embodiments, where Nei is (a-1); CO" is a bracket; where is CE: and Ag is ta, -kmM, while Ag is substituted in the position indicated by VD by a substituent that is a halogen, in particular chlorine or bromine, more specifically bromine.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is substituted with one substituent selected from the group consisting of with -MH", -MH-C.-4alkyl, -M(Ci-alkyl)2, -MNA'YA, -MA Oda: and where Ag is optionally replaced by another substituent,

selected from the list of substituents on Ag in any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is optionally substituted according to any - which of the other implementation options.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, specified in any of the other embodiments, where Ag is optionally substituted by one, two or three substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C.-"alkyl, -M(C3-alkyl)2, cyano, -CE3, -C( -0)-MH-C-alkyl, C:-alkyloxy and C:-alkyl; in particular, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -MH", -MH-C:-alkyl, cyano, -CEz,

C-halkyloxy and C:-alkyl; more specifically, optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen or -C3; more specifically optionally substituted with one or two substituents which are halogen; more specifically substituted with one or two substituents which are halogen; even more specifically substituted with one substituent, which is a halogen; most specifically substituted with one substituent, which is chlorine.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof specified in

Co) to any of the other embodiments, where Ag is optionally substituted according to any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, specified in any of the other embodiments, where Ag is and is optionally substituted by one, two or three substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C.-"alkyl, -M(C3-alkyl)2, cyano, -CE3, -C( -0)-MH-C-alkyl, C:-alkyloxy and C:-alkyl; in particular, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -MH", -MH-C:-alkyl, cyano, -CEz,

C-halkyloxy and C:-alkyl; more specifically, optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen or -C3; more specifically optionally substituted with one or two substituents which are halogen; more specifically substituted with one or two substituents which are halogen; even more specifically substituted with one substituent, which is a halogen; most specifically substituted with one substituent, which is chlorine.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

It is represented by (a-1); and

Ag is a village

M is optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-C.-"alkyl, -M(C3-alkyl)2, cyano, -C3, -C(-0)-MH-C, alkyl, C:-alkyloxy and C:-alkyl; in particular, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -MH", -MH-C:-alkyl, cyano, -CEz,

C-halkyloxy and C:-alkyl; more specifically, optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen or -C3; more specifically optionally substituted with one or two substituents which are halogen; more specifically substituted with one or two substituents which are halogen; even more specifically substituted with one substituent, which is a halogen; most specifically substituted with one substituent, which is chlorine.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

It is represented by (a-1); and a coupon

Ag is the same as: ; нд, ДЯ, -и ко --и ко in particular, Ag represents or ; . -M more specifically Ag represents .

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ag is a theme;

нд, ДЯ, -и ко --и ко in particular, Ag represents or ; . -M more specifically Ag represents .

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, specified in any of the other embodiments, where EE, ShD5o and B" represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where C! is Skba; and 02 is SI,

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where X represents -O0-;

OS! is CEa: and 02 is SES,

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where X represents -O0-;

CO" represents CH; and 02 represents SEN.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ve, oo and God represent hydrogen;

U represents -СНе- or -Сг»-; in particular, U represents -СНе-; and

It is represented by (a-1);

OS" is Ca; and 02 is CE: specifically, where CO! is CH; and 02 is CH.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ve, oo and og represent hydrogen; U represents -O-; and

It is represented by (a-1);

Where C" is Swba; and 02 is CE; in particular, where C! is CH; and 02 is CH.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein 02 is CE."

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where 7 represents -X-CHNaBe-,

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, specified in any of the other embodiments, where 7 represents -O-CHe-.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, specified in any of the other embodiments, where 7 represents -X-SVRaVRE-; X represents -O-; and K22 and EE? are hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

BO X represents -O- or -MA1-; in particular, X represents -O-.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Da and B" represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, specified in any of the other embodiments, where Nei is (a-1); VZa is -MAA; and

A: and EE?" are hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one substituent selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C-"alkyl)g, cyano, -CEz, -C (-0)-MH-C.:-alkyl, -6(-0)-C.i-alkyl, C:-alkyloxy and C:-4alkyl, optionally substituted by one -MA'ad'ov;

VzZa, DZh and vZs represent -MIV72B"; and 72 and 2" represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one substituent selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C-"alkyl)g, cyano, -CEz, -C (-0)-MH-C.:-alkyl, -6(-0)-C.i-alkyl, C:-alkyloxy and C:-4alkyl, optionally substituted by one -MA'ad'ov;

From dza, dzs, DZh, za and VZe represent -МВ2ВБ: and 72 and EE? are hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where Ka, Bz" and Ks are not halogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ka, Bzc, IZb, IZa, and KZe are not halogen

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, specified in any of the other embodiments, where dza, Dz and VZs represent -MA2B;

Da represents hydrogen;

IN? is hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where Ka, VZ" and KZc are -MH" .

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is optionally substituted with one substituent selected from the group consisting of halogen, -OH, -MH", -MH-C:-alkyl, -M(C:-alkyl)g, cyano, -CEz, -C( -O)-MH-C:-alkyl, -C(-O)-C1-4 alkyl, C:-alkyloxy and C1-4 alkyl, optionally substituted by one -MA'sad/o;

It is represented by (a-1); Za is -MAaV"; and Kg and KE" represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in 60 any of the other embodiments, wherein

Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed b-membered rings, where optionally 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system;

Ag is replaced by one substituent selected from the group consisting of halogen, -OH, -MH", -

MH-C3-alkyl, -M(Ci-alkyl)", cyano, -C3, -C(-0)-MH-C:i-alkyl, -C(-0)-C:-alkyl, Ci-alkyloxy and Si.lalkilu, optionally replaced by one -MNA'bad's;

It is represented by (a-1); VZa is -MAaV; and Kg and EK" represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is and is optionally substituted with one substituent, selected from the group consisting of halogen, -OH, -MH", -MH-Ci-alkyl, -M(Ci-alkyl)", cyano, -CE3, -C(-0)-MH-C:-alkyl , C1-alkyloxy and C1-4 alkyl; in particular, optionally substituted with one substituent selected from the group consisting of halogen, -MH», -MH-C 1-4 alkyl, cyano, -C 3 , C 1-4 alkyloxy and C 1-4 alkyl; more specifically optionally substituted with one substituent selected from the group consisting of halogen and -C3; more specifically, optionally substituted with one substituent, which is a halogen; more specifically substituted by one substituent, which is a halogen; even more specifically substituted with one substituent, which is chlorine.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of: h -M M-M 5 M

M- pnya / TT by m -M -- M while each Ag is optionally substituted according to any of the other implementation options; in particular, where Ag is optionally substituted with one of the substituents defined in any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of:

/ / 0 -M М-М --М

M- -M to t M 7/5 / In m

М- -- 5Б-М -ki М M while each Ag is optionally substituted according to any of the other variants of implementation; in particular, where Ag is optionally substituted with one of the substituents defined in any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of:

M- -M -M x-km while each Ag is optionally substituted according to any of the other variants of implementation; in particular, where Ag is optionally substituted with one of the substituents defined in any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of:

M- eyi i hl M u -M -k --

At the same time, each Ah is optionally substituted in position with a substituent selected from the group consisting of -MH»g, -MH-C.-alkyl, -M(C3-alkyl)g2, -MNBA "9 and -MV'sed's; Bie and I are each independently Csescycloalkyl; Csescycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C. -alkyl; C1-4alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH, and -O-C1-4alkyl; or C1-4alkyl substituted one substituent selected from the group consisting of

C3-6cycloalkyl, K"3 and 4;

B'Z is a 4-7-membered monocyclic aromatic ring containing one, two or three

Z heteroatoms, each independently selected from О, 5, 5(-О)р and М; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(:O)p and M; the indicated 4-7-membered monocyclic aromatic ring or 6-11-membered bicyclic condensed aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C-4 alkyl; p is equal to 1 or 2;

B" is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of:

M- lona -km -k x-k

At the same time, each Ag is optionally substituted in position with a substituent selected from the group consisting of -МН»e, -МН-C.-alkyl, -М(С:-alkyl)2, -МНИВ 9 and -MA'Osdtoa; and at the same time Ag is optionally substituted in another position by a substituent that is a halogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is selected from the group consisting of:

M- sla nnat; -k -k h-ki

Wherein each Ag substituted at position "is a substituent selected from the group consisting of -MHe, -MH-Ci-alkyl, -M(C:-alkyl)2, -MNIA "9 and -MAosDtoa; and while Ag is optionally substituted in another position by a substituent that is a halogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is a 10-membered bicyclic aromatic ring system, which consists of two condensed b-membered rings, where 1 or 2 carbon atoms of the ring are replaced by a nitrogen atom; provided that if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system; while each Ag is optionally substituted according to any of the other embodiments; in particular, where Ag is optionally substituted with one of the substituents defined in any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is optionally substituted with one substituent,

As defined in any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein Ag is optionally substituted with one, two, three, or four substituents, each one independently selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(Cch-"alkyl)", -MNB sa, -MAoedtoYa, cyano . -alkyl, Sovalkenyl, C1-alkyl, substituted by one C:-4alkyloxy, and C:-alkyl, optionally substituted by one -MA'sadijes,

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

With / -M

Ag represents ;

Ag is optionally substituted with one substituent selected from the group consisting of halogen, -OH, -MH»e, -MH-C:-alkyl, -M(C 1 -alkyl) 2 , cyano and -CEz; 5О0 galOgkA vd, more specifically Ag represents - M ; even more specifically, Аг represents ND, -M itself.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

Ag represents ;

Ag is replaced by one substituent selected from the group consisting of halogen, -OH, -MH", -

MH-C:-alkyl, -M(C-"alkyl)g, cyano and -SEz; more specifically, Ag represents -ek; even more specifically, Аг represents ND, -M itself;

It is represented by (a-1); Za represents -МА2В"; and B"2 and 2? represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein the compounds of formula (I) are limited to compounds of formula (I- at):

AG- -7, --

U. ka ut v'e 8 x | (ahh)

Z OO MI OM in OV: She v

It will be obvious that all variables in the structure of formula (I-ai) can be defined as they are defined for compounds of formula (I) or any subgroup thereof, specified in any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein the compounds of formula (I) are limited to compounds of formula (I- at):

AG-7, --

U. ka rya ve and | (-a)) 1 S MI M vo OV: Sheva at the same time Nza represents -MN"; and "r is hydrogen.

In one embodiment, the present invention relates to such compounds of formula (II) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein the compounds of formula (I) are limited to the compounds of formula (I- at):

AK- -425, - same

U, hu and - t | (Gai) and - with MI M in OV: Ya va at the same time NZa represents -MNe"; IZ72 is hydrogen; and Tashistt Z

Ag is a topic, more specifically, Ag is

ДЯ, n-i to

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein the compounds of formula (I) are limited to compounds of formula (I- at):

AK- -425, - same

U, ka rya vya - t | (Gai) pis 5 with My M in OV: Ya va de

AND! and Kg? are hydrogen;

VzZa is hydrogen, -MA"2B" or -OS..-alkyl;

ID: represents hydrogen; and

Ag is a

/ .. all in -m (with Ar substituted in the position indicated by a by a substituent selected from the group consisting of -МНе, -МН-С. 99, -MAosdoa; while Ag is optionally substituted in the position indicated by VD by a substituent that is a halogen; each of Cos and K!94 is independently a C.-alkyl substituted by one, two or three substituents that represent is a halogen, or C1-4alkyl, substituted by one substituent, which is C3-cycloalkyl.

In one embodiment, the present invention relates to new compounds of the formula (1-a1),

AKG-- 7 --

In car r v y | (a) 1 sfe) vyi OV I in de

B' and 2 represent hydrogen;

VzZa is hydrogen, -MA"2B" or -OS..-alkyl;

Fa is hydrogen;

AND?" represents hydrogen or Si.lalkyl; 7 represents -СНеСНе-;

U represents -0-, -СНо- or -СЕ2-; in particular -СНе-;

Da represents hydrogen; and

Ag represents / sh. in -km (and at the same time Ag is substituted in the position indicated by a by a substituent selected from the group consisting of -МН2г, -МН-С:-alkyl, -M(Ci-alkyl)2, -МНВ с, -МВ d /c; and at the same time Ag is optionally substituted in the position marked B by a substituent that is a halogen;

Co) each of Cos and K!94 independently represents C.-alkyl, substituted by one, two or three substituents, which are halogen; or C1-4alkyl substituted by one substituent, which is C3-6cycloalkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to new compounds of the formula (1-a1),

AG- - -2 - шж-

IN

Kur r vya i | (-a)) 15 a MI M v'o OV She va de

AND! and B2 represent hydrogen;

Dzga is hydrogen, -MV"2B8"? or -OSi.lalkyl;

Da represents hydrogen;

IN? represents hydrogen or S.-lalkil; 7 represents -X-SVRaDgR- or -CHnoCH»-;

Doe and E? are hydrogen; X represents -O-;

U represents -0-, -СНо- or -СЕ2-; in particular -СНе-;

ID: represents hydrogen; and

Ag is a

In С у / -m (and at the same time Ag is optionally substituted in the position marked by a substituent selected from the group consisting of -МН»е, -МН-C.-alkyl, -М(С:-4-alkyl )", -МНА99, -МА dos: while Ag is optionally substituted in the position marked B by a substituent that is a halogen; each of Kos and K!94 is independently a C.-alkyl substituted by one, two or three substituents which represent halogen; or C1-4alkyl substituted with one substituent which represents C3-6cycloalkyl; and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to new compounds of the formula (1-a1),

AG - -7, - ш- - - I | (Gai) 1 2 3 MI M vyi OV: I am in de

AND! and Kg? are hydrogen;

VzZa is -МА7аВБ;

Fa is hydrogen;

From VD" represents hydrogen; 7 represents -X-SVRaDgR- or -СНоСН"-;

Doe and E? are hydrogen; X represents -O-;

U represents -O- or -СНо-;

Da represents hydrogen; and

Ag is a

В С у / -М (and in this case Ag is optionally substituted in the position marked a, -МН5; and in this case Ag is substituted in the position marked ВD by a substituent that is a halogen, in particular BG; and their pharmaceutically acceptable salts joining and solvates.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein 7 represents -X-SVNzarg- or -СНеСНе -. 5A

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein 7 represents -X-SVRaDgR- or -CHnoCH "-;

Dte and E? are hydrogen;

X represents -O-.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein 27 is -X-SiBzade- or -CHneCH "-;

Dosa and 255 represent hydrogen;

X represents -O-;

It is represented by (a-1).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein 7 represents -X-SVRaDgR- or -CHnoCH "-;

ShDla and ER" represent hydrogen;

X represents -O-;

It is represented by (a-1);

VzZa is -МА7аВБ;

Fa is hydrogen;

AND?" is hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, where X represents -O-.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein 7 represents -X-CHNaBr- or -CHeCHne -;

ShDla and ER" represent hydrogen;

X represents -O-;

Аг is ву у / -м о, while Аг is optionally substituted in the position marked by a substituent selected from the group consisting of -МН», -МН-С.-»alkyl and -МНА са; and at the same time Ag is optionally substituted in the position indicated by VD by a substituent selected from the group consisting of halogen and CEz; provided, however, that Ag is substituted in at least one of the positions marked a or p;

It is represented by (a-1);

DVzga is -MA 7285;

Da represents hydrogen;

"VD" is hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

It is represented by (a-1);

BO VzZa is -МА72Н 5;

Fa is hydrogen;

AND?" is hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

VzZa, DZh, Dzs, dza and BZe represent -MA2B B;

Da represents hydrogen;

DA" represents hydrogen, C3-6cycloalkyl or C6-alkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein dza, Dzb, Dzs, dza, and Bze are - MA "eV;

Da represents hydrogen;

IN? is hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, specified in any of the other embodiments, wherein

B" represents hydrogen, C1-4 alkyl or C1-1 alkyl substituted by one substituent selected from the group consisting of -OH, -O-C:-alkyl, -MH", -"MH-C- 4alkyl and -M(C1-alkyl)"; and each of C'Os and B'Y independently represents C3-6cycloalkyl; K/"; C3-cycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C-alkyl; C1-4 alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C1-4 alkyl; or C 1 -alkyl substituted with one substituent selected from the group consisting of

C3-ccycloalkyl and K/x,

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any of their subgroups, specified in any of the other embodiments, where U represents -СНе-; and 7 represents -СНаСНе-.

In an embodiment, the present invention relates to a subgroup of formula (I) defined in general reaction schemes.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 58.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 80.

In one embodiment, the compound of formula (I) is selected from the group consisting of

From compounds 74, 75, 76, 77, 78, 79, 80 and 81.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240 and 247.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 58 and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 80 and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 74, 75, 76, 77, 78, 79, 80 and 81 and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240 and 247 and their pharmaceutically acceptable addition salts and solvates.

In one embodiment, the compound of formula (I) is selected from the group consisting of any of the exemplified compounds and their free bases, pharmaceutically acceptable addition salts, and solvates.

It is assumed that all possible combinations of the above embodiments fall within the scope of this invention.

BO Methods of obtaining

In this section, as in all other sections, unless the context indicates otherwise, references to formula (I) also include all other subgroups and examples thereof defined herein.

General methods for the preparation of certain typical examples of compounds of formula (I) are described herein and in the specific examples, and are generally prepared from starting materials that are either commercially available or are prepared by standard synthetic methods widely practiced by those skilled in the art. industry. The following diagrams are intended only to represent examples of the present invention and are in no way intended to be limiting of the present invention.

Alternatively, the compounds of the present invention can also be prepared using 60 reaction protocols similar to those described in the general schemes below, in combination with standard synthetic methods widely used by those skilled in the art of organic chemistry.

One skilled in the art will appreciate that in the reactions described in the schemes, it may be necessary to protect reactive functional groups, such as hydroxy, amino, or carboxy groups, when they are needed in the final product, in order to avoid their undesired participation in the reactions. Traditional protective groups can be applied according to standard practice. This is illustrated in concrete examples.

One skilled in the art will appreciate that in the reactions described in the schemes, it may be appropriate or necessary to carry out the reaction in an inert atmosphere, such as, for example, an atmosphere of M2 gas, for example when using Mann in the reaction.

It will be apparent to one of ordinary skill in the art that it may be necessary to cool the reaction mixture prior to obtaining the reaction product (refers to a series of manipulations necessary to isolate and purify the product(s) of a chemical reaction, such as, for example, quenching, column chromatography, extraction).

One of ordinary skill in the art will appreciate that heating the reaction mixture during stirring can increase the yield of the reaction. In some reactions, microwave heating can be used instead of traditional heating to reduce the overall reaction time.

One of ordinary skill in the art will appreciate that another sequence of chemical reactions shown in the schemes below may also result in the desired compound of formula (1).

One of ordinary skill in the art will appreciate that the intermediates and compounds shown in the schemes below can be further functionalized according to methods well known to one of ordinary skill in the art.

One skilled in the art will appreciate that a greater number of compounds of formula (I) can be prepared by using synthetic protocols similar to those described in the schemes below.

In the event that one of the starting materials is available in the form of a salt, it will be understood by one skilled in the art that it may first be necessary to treat the salt with a base, such as e.g.

M,M-diisopropylethylamine (OIREA).

All variables are defined as mentioned above in this document, unless otherwise stated or explicitly stated

Zo follows from the context.

A person skilled in the art will understand that chemistry similar to that described in Schemes 1-9 can also be used to prepare compounds of formula (I), where N is a bicyclic aromatic system of heterocyclic rings (a-4) or (a-5). Some typical examples are shown in the specific examples. In addition, this information can be combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry to produce more compounds of formula (I) wherein N is (a-4) or (a-5).

In general, compounds of formula (I) can be obtained according to scheme 1.

General scheme 1 s "s h a" ke i a che i vonozho i mov sn vn v nn shk Y

Areya ie y - tyat Mi - Shchy. chn We and yat Mai and na pev 2 not yan and from what Ot pa b o what ev and ate xx Prom. there is still K vk

And ve with p where x. t de v u ssh 2 -kh l kuti she ak et y a t y - EI I: o z N a V i y Z v! but Ma shchi she KO 7 i

JV Promospov about Kh

Praomospoya BU z. - vu ve de y ge vu l svi desny nu y Ayu-y rech j y shchi y Kn ak y y A M NE A v shin p i chi: y ke Shok ushke y -- a. Neo x - st Na tr v E zy: Me yt y h dya ih v. more" in

Y re I ve BNrom ospolo UK Not y

Pramospolo Mi

In Scheme 1 0: is defined as a suitable leaving group such as, for example, halogen;

Tc" is defined as a suitable leaving group such as, for example, halogen or -5CH3. (3 is defined as a leaving group such as halogen and -5CH. All other variables from Scheme 1 are defined within the scope of this invention.

To implement scheme 1, as a rule, the following reaction conditions are used. 1: different sets of reaction conditions depend on the definition of За, ВЗз or Кс,

And: if za, DZe or z: represents a halogen, then stage 1 can be excluded. 16: if KZa, VZ" or kZs is MAaV", in the presence of a suitable amine of the formula

NMVAaVt, with a suitable solvent, such as, for example, HgO, MeonH, or EN, at a suitable temperature, such as, for example, 100-130", usually under microwave or autoclave conditions for heating. 1c: if By , BZ" or BZ: is an -O-C alkyl, in the presence of a suitable HO-C -alkyl, with a suitable base, such as, for example, Man, potassium tert-butoxide (PoTC), in a suitable solvent, such as , for example, tetrahydrofuran (THE), at a suitable temperature.

Alternatively, in the presence of a suitable HO-C.-alkyl as a solvent with a suitable acid such as, for example, HCl. 14: if Za, VZ or BKZs is hydrogen, under the conditions of hydrogenation: in an atmosphere of gaseous He in the presence of a catalyst such as, for example, Mi Raney, Ra/C (for example, 5 wt. 95 or 10 wt. U5) or РУС (eg, 5 wt. 965) in a suitable solvent, such as, for example, methanol (MeOH), ethanol (EN) or TNE.

Te: if KZa, DZ" or KZ is C1-4alkyl, in the presence of a suitable boronic acid or ester, such as, for example, methylboronic acid, with a suitable catalyst, such as, for example, 1,1"-bisbidiphenylphosphino)ferrocene, and with a suitable base such as e.g.

KzPO»x, in a suitable solvent mixture, such as, for example, a 5 to 1 dioxane/H2H2O mixture, at a suitable temperature, such as, for example, 10070. 2: in the presence of a suitable acid, such as, for example, 4 M NOSI in dioxane or 4 M NSI in

Meon, with a suitable solvent, such as, for example, Meon, at a suitable temperature, such

As, for example, room temperature; or alternatively in the presence of a suitable acid, such as, for example, trifluoroacetic acid (TEA) in dichloromethane (DCM), at a suitable temperature, or acetic acid in TNE and water, at a suitable temperature, such as, for example, room temperature. 3: in the presence of a suitable acid anhydride of the formula (C:-alkyl-O)2O with a suitable solvent such as pyridine at a suitable temperature. If KZa, VZ" or KZ is a

МН», then (С:1-alkylC-:O)20О can react with МНо to obtain the intermediate compound М(Сч-4alkylС-О)2. Such an intermediate can be converted to the target product in a suitable solvent, such as, for example, Meon, at a suitable temperature, such as, for example, 100-130°C, under conditions of exposure to microwave radiation or using an autoclave for heating. a reaction with a positive result can be achieved due to the presence of an acid such as HCl or Ci-alkylSO2H.

The starting materials of Scheme 1 are commercially available or can be prepared using standard methods apparent to one skilled in the art or described for the following general schemes.

General scheme 2a

In general, intermediate compounds of the formulas ИШ, М and Ми, where 7 represents -0О-СНА-, can be obtained according to scheme 2а. All other variables in Scheme 2a are defined within the scope of this invention. One of ordinary skill in the art will appreciate that a suitable protecting group is necessary when Za, DZ" or VZ3c is -MNeg or -MNA "U.

Ba 1-02 1-02

Kk u. (y ra va u po ra

I Ag-ON M Her

GTF) M Ag-( i Z She ma EE Ma 0.0 0/0 Ya

KO u vbe do vbe ve doza y / Their dis va y. / Where are they? Ag-OH Ag-- 0 M i - ef --sh- / M M

F - 15 and 2 F

Sha b

Kt u; 3.2g yes (c) ki dz ra oo zy

U. "U; Agon U. Mo IY

Ex

KO luki

Not i t i b o i o h wo v wo

The following reaction conditions are used to implement scheme 2a. 1: Mitsunobu's reaction.

And: in the presence of PPys on a polymer substrate, the action of isopropyl azodicarboxylate (IA), or diethyl azodicarboxylate (OEAO), or bis(1,1-dimethylethyl) azodicarboxylate (OVAO) in a suitable solvent, such as, for example, anhydrous TNE, at a suitable temperature, such such as room temperature. 1r: in the presence of triphenylphosphine (PPAs), OIAO or OEAbB in a suitable solvent, such as, for example, anhydrous TNE, at a suitable temperature, such as, for example, room temperature. 1c: in the presence of cyanomethylenetributylphosphorane (CMBP) or cyanomethylenetrimethylphosphorane (CMMP), in a suitable solvent, such as, for example, anhydrous toluene, at a suitable temperature, such as, for example, 80"C.

The starting materials of Scheme 2a are commercially available or can be prepared by standard methods apparent to one skilled in the art or described for the following general schemes. One skilled in the art will appreciate that if Kg is C: -alkyl, then the different isomers can be separated from each other by reversed-phase

From high performance liquid chromatography (HPLC) or supercritical fluid chromatography

(EC).

The general scheme of the 2nd year

Intermediate compounds of formula II, IM and MI, where 7 represents -X2-SNIA»a-, can be obtained according to scheme 2B. In diagram 25, Xe is defined as O or 5; 10 is defined as a leaving group, such as, for example, halogen, mesylate (M50O) and tosylate (To50), preferably To50. and 51 is defined as a leaving group, such as, for example, halogen; y7 5 is defined as a leaving group such as, for example, halogen or -5CH3. | c' is defined as a leaving group such as, for example, halogen or -5CHn. All other variables from circuit 206 are defined within the scope of this invention. oh oh wow

Ach I, Ai-haN zho A Io,

I6 4 | - Ah-hi 4th

EE We 1 2 5 May b x so she

And KO vobe to voe voi da Ba

U. Y X I6, in Kk hu. Y x Is,

X) and | -- » Ag-ua and h

E Ex - 1 st 5 Ma M

Z o 3 z - ra rani vza ogo vza o3-o 7. " I Sz Ag-He-N u sh u iv ke Kk ry Ag-ha Ko v da v; to ve to

Iv. E

To implement scheme 20, the following reaction conditions are used. 1: in the presence of a base such as, for example, K»CbO3, triethylamine (EM) or OIREA, in a suitable solvent such as CH3SM, OSM or M,M-dimethylacetamide (OMA).

The starting materials for scheme 205 are commercially available or can be prepared using standard methods apparent to one skilled in the art or described for the following general schemes. One of ordinary skill in the art will appreciate that if 2 is C: -alkyl, the different isomers can be separated from each other by reverse phase high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SCF).

General scheme 2s

Intermediate compounds PSh, M and MII, where 7 is -Xa-SNIA»a-, can be obtained according to scheme 2c. In scheme 2c', Xe is defined as O or 5.'| c" is defined as a leaving group, such as, for example, halogen, M5O, or To50, preferably To50. All other variables in Scheme 2c are defined within the scope of the present invention. One of ordinary skill in the art will appreciate that a suitable protecting group is necessary in that case , if Ka, Bze or Z: represents -MHn or -MNA "7. because dia oo? dia o-o? in. / In the dekhan of / ra

M M ke | -v- 00's |,

EM ' EN U b b r ra r ra re roi doe ve rdoa rosa

With h. M ozh Ade-Hha-N h. In the same

Same) and | -- Аг-хХа and Х у: it's У 0.0 b. I

Koch shi roza Ge -0y rdza OZ -0 ucheie d Ag-Ha N ucheie d --

Ke: Ko 1 Ag-ha Ko

EE EL OM entrance b. Me and Koch

To implement scheme 2c, the following reaction conditions are used. 1: in the presence of a base such as, for example, Ca2CO3, E3M or OIREA, in a suitable solvent such as CH3CM, OSM or M,M-dimethylacetamide (OMA).

The starting materials for scheme 2c are commercially available or can be prepared by standard methods apparent to one skilled in the art or described for the following general schemes. One of ordinary skill in the art will appreciate that if Ka is C 1 -alkyl, then the various isomers can be separated from each other by reverse phase high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SCF).

The general scheme of Z

In general, intermediate compounds where 7 is -X-SNI-Y- and where X is -MH- or -MA"- can be prepared according to Scheme 3. In Scheme 3 | 0: defined as a leaving group, such as, for example, halogen; 72" is defined as a leaving group, such as, for example, halogen or -5CH3. is defined as a leaving group such as, for example, halogen or -5СН". All other variables from Scheme C are defined within the scope of this invention.

and dru OZ gives vda se vo so: Kom A v, pi i 2. : i z. with my mother-in-law cha « her and «55 uch s, ny li and Zh 0 lalogev de» ng miy KI i M u ovo --- 5 t5x.X HY. m I V ie o zht om z Ve Y 00 Ma i o - - - - še u. sh yo ikh kt Ko; 48 4 хх дя зи ра

And in Eh Y xx i I I be in what to her ve Eh in

And in Ye - r-i and pek In g4 and et mk . E U M Il -talogen i m nia z Y liu v o. from

Melons are not demnayai in that --- ich; х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х х

Day in Sho A sia I Yalta yo po

Ge i y V AG yan i Ki KO haloten i E chu i oo My0ЗШ2З0- p ni OM -- yin Mak y bi I 1 shi shi shiya hi Shi ssha x de efe; th 2 sha zav yah Zh ve A ke 7 as Kk

The following reaction conditions are used to implement scheme C. 1: in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborohydride (Mn(AsoO)z), together with a suitable solvent, such as, for example,

OSM, at a suitable temperature, such as, for example, room temperature; or, alternatively, MaN2CM together with a suitable solvent, such as, for example, MeOH, at a suitable temperature, such as, for example, from room temperature to 5070. 2: in the presence of a suitable base, such as, for example, ManH, together with a suitable solvent , such as, for example, anhydrous TNE, M,M-dimethylformamide (OME), OMA, at a suitable temperature, such as, for example, room temperature to 5070.

The starting materials of Scheme C are commercially available or can be prepared by standard means apparent to one skilled in the art or described in the specific experimental section. One of ordinary skill in the art will understand that if Ka is C1-4alkyl, then the different isomers can be separated from each other using reverse phase high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SCF).

General scheme 4

In general, intermediate compounds where 7 is -SES-, -CH-CH- or -CHNo-CHNeg- can be obtained according to Scheme 4. In Scheme 4, 70 is defined as a leaving group such as, for example, halogen; "7 2" is defined as a leaving group such as, for example, halogen or -

ZSN»z. | bz is defined as a leaving group such as, for example, halogen or -5CH»z. All other variables from scheme 4 are defined within the scope of this invention.

and og azs ato? ki: still de ma od» zha sh- x. oh u y She de de na U Yi

She M | uro a with ey 2 » yat le 4 in Ga ey

E -U ii MU v y, Mo 1 0, aa o) a Х ra y; xx xx y y i 4 ao? oh h. ! yes

I IS l / I6, X y y M 1 M r Ag. x and M chu XX th ki | in Me --- there is She shi Ko KO vo V ve v vk ve and GU i" shock

M Kk Ag. M x MU de HU le Ag M - uh

Ag. M x x I ---» EE Z 4

M OKOM o-- and Z to.

But vy- in K and vh X Ve still I with OK Me Xh in aZzo azy x. PEACE

Geo amo h. | vav Ag. y sh khiv h. M. Oz z im ped ku ts Zh-fD 855

X Ma. YAM -- r Malyi NN EE and 4 o ov o n i vh 9, X 9.0 z Z de r vo un; XX

To implement Scheme 4, the following reaction conditions are used. 1: in the presence of a suitable amine, such as NMA'K" or Maoc", with a suitable solvent, such as, for example, HgO, MeonH or EN, at a suitable temperature, such as, for example, 100-130"C, under processing conditions by microwave radiation or by autoclaving for heating 2: in the presence of a suitable catalyst such as bis(triphenylphosphine)palladium(I) dichloride and copper(I) iodide in a suitable solvent such as 2-methyltetrahydrofuran with a suitable base such as , for example, triethylamine, at a suitable temperature, such as, for example, 807C. 3: in the presence of a suitable salt, such as, for example, tetraethylammonium chloride (ECHO), in a suitable solvent, such as, for example, UOME, with a suitable base, such as, for example, OIREA, and a palladium catalyst, such as, for example, Pa(OAc): (palladium acetate II)) at a suitable temperature, such as, for example, 10070. 4: in the presence of an atmosphere of gaseous Neo and a catalyst, such as, for example , Ra/s (for example, 5 wt. 95 or 10 wt. 95 ) in a suitable solvent such as, for example, MeOH.

The starting materials of Scheme 4 are commercially available or can be prepared by standard means apparent to one skilled in the art or described in the specific experimental section.

General scheme 5

In general, intermediates where U is CH" or CE" named herein Ma, and where 7 is -CHgO-, can be prepared according to Scheme 5.

In Scheme 5, 170: is defined as a leaving group such as, for example, halogen; "LO" is defined as a leaving group such as, for example, halogen or -5CH3. 3" is defined as a leaving group, such as, for example, halogen or -5CH"z. All other variables from scheme 5 are defined within the scope of this invention.

o-o? vra pt ma is re m ke kt sho " Ag Shche) p vd " ; with: and r | ХХ--W2ХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХХЮy

ХХ Іс no uh І у Ів, Аг Іs (v) t І у ?

M | Ag. Мх МО 00ЖЖЖЖЖШВ6М8ШЧи6yЙ-пи и ;66"ЧШЦСУО8иИУНТ УЗ" х

I g Ma ra E I She bo o 1 more; shi shi dta oz ego x Is ne) s Shk Ag IS - KY b. o o X in uh in 1

To implement scheme 5, the following reaction conditions are used. 1: in the presence of a base such as, for example, Ca2CO3, E3M or OIREA, in a suitable solvent such as CH3CM, OSM or M,M-dimethylacetamide (OMA).

General scheme 6

In general, intermediate compounds, where 7 represents -СНе-, can be obtained according to scheme 6.

In the diagram, 6 1 0 is defined as a leaving group, such as, for example, halogen; 72 is defined as a leaving group such as, for example, halogen or -5CH»z. 3 is defined as a leaving group such as, for example, halogen or -5CH3. All other variables from scheme 6 are defined within the scope of this invention.

-0 on - az o23 th aka

Ach Iv ih azo? in M. am va

M 1 NM. Y IS Vk Zo s a a 1 Ag ON dr " y

EE sha u -6INnO-7- EE M. 2 o iya ' E» i 2 Kk i re vla as ma kh b dov E o on dev do cha / U 6, 57270 beroi uva i 023 i; x M Kay about the same. nM-m / U de m «yo ---- Myh y shchi I ko M o. 0 in 1 mo -ЗН8ШНВИННШЩХВТВУИУУХ8ХЮ8ЮХХУХХНОНТХХУХХ ЕЕ Х дос | M 2 o. o " I still know where he is, where he was born - with NM I 630 A OSON lived She (in M ra -- Ag and I not in M -8Ш8Ш8ВІВЧТТНТНТОО EN Ma, M

Ge) y 2 o ve 1 4 Z She 2 o, /0 Ya

Kk to Zh

To implement scheme 6, the following reaction conditions are used. 1: in the presence of tosylhydrazide, with a suitable solvent, such as, for example, MeOnH, 5 ЕН or OSM, at a suitable temperature, such as room temperature. 2: in the presence of boronic acids, with a suitable base, such as KgCO3, MgCO3, C52CO3, with a suitable solvent, such as, for example, 1,4-dioxane, at a suitable temperature, such as 9076.

The starting materials of Scheme 6 are commercially available or can be prepared by standard means apparent to one skilled in the art or described in the specific experimental section.

General scheme 7

In general, intermediates where 7 is -CH2-CHe- can be prepared according to Scheme 7. In Scheme 7, 70 is defined as a leaving group such as, for example, halogen; 2 is defined as a leaving group such as, for example, halogen or -5CH3. 3" is defined as a leaving group such as, for example, halogen or -5CH"z. All other variables from Scheme 7 are defined within the scope of this invention.

och ach shki vza - Ptn EE Ma, -- and with Ma o; i 1 ve i 2 y I voe v de v og, ve x LU le ko i so m Ag m shchi xx

ANA of -- m r on EE I lion chine r: e- azo Is emo z a o podo sorry

Mo I Ma ET Mal M v yo vh 865

ZK Shchy 1 x left 2 x left

To implement scheme 7, as a rule, the following reaction conditions are used. 1: at the first stage in the presence of an alkene precursor and a 0.5 M solution of 9-borabicyclo(3.3.1)nonane (92-BVM) in TNE in a nitrogen atmosphere at temperatures from room temperature to reflux temperature and reaction duration from 1 to 3 hours In the second step, in the presence of, for example, a suitable Ag bromide or Ag iodide and a suitable catalyst, such as, for example, 1,1"-bisidiphenylphosphino)ferrocenedichloropalladium(I), and in the presence of a suitable base, such as, for example, tribasic phosphate potassium, in a suitable solvent mixture, such as, for example, TNE and water, at a suitable temperature from 50°C to the reflux temperature and at a suitable reaction time from 1 to 3 hours. 2: different sets of reaction conditions depend on the determination of Ka, Bz or Ks, 2a: if Za, DZe or Az: is a halogen, then step 1 can be omitted. 25: if KZa, BZb or KZc is MK"aB", in the presence of a suitable amine of the formula

NMA", with a suitable solvent, such as, for example, HgO, MeonH, or EN, at a suitable temperature, such as, for example, 100-1307C, usually under microwave or autoclave heating conditions. 2c: if Za, VZ" or VZ: represents -O-C.-alkyl, in the presence of a suitable HO-C. -alkyl, with a suitable base, such as, for example, Mann, potassium tert-butoxide (PoK), in a suitable solvent, such as, for example, tetrahydrofuran (THF), at a suitable temperature.

Alternatively, in the presence of a suitable HO-C.-alkyl as a solvent with a suitable acid such as, for example, HCl. 24: if Za, VZ or KZc is hydrogen, under the conditions of hydrogenation: in an atmosphere of gaseous He in the presence of a catalyst such as, for example, Mi Raney, Ra/cS (for example, 5 wt. 95 or 10 wt. U5) or РУС (eg, 5 wt. 965) in a suitable solvent, such as, for example, methanol (MeOH), ethanol (EN) or TNE. 2e: if Za, DZ" or BZ: is C1-alkyl, in the presence of a suitable boronic acid or ester, such as, for example, methylboronic acid, with a suitable catalyst, such as, for example, 1,1"-bisidiphenylphosphino)ferrocene, and with a suitable base such as

KzPO»x, in a suitable solvent mixture, such as, for example, a 5 to 1 dioxane/H2H2O mixture, at a suitable temperature, such as, for example, 10070.

The starting materials of Scheme 7 are commercially available or can be prepared by standard means apparent to one skilled in the art or described in the specific experimental section.

General scheme 8

In general, intermediates where 7 is -CH2-CHe- can be prepared according to Scheme 8. In Scheme 8, 70 is defined as a leaving group such as, for example, halogen; 2 is defined as a leaving group such as, for example, halogen or -5CH3. 3" is defined as a leaving group such as, for example, halogen or -5CH"z. All other variables from scheme 8 are defined within the scope of this invention. 1-2 1-02 1-02

M Ky b I, M. S m. bu

I I 1 I vY 2 I I be v v y dov vk x. / Io, oh so

Ki NA - o pynnivish not with -fya

X X

3.74 ee azy gla zhi M. m. i - M - «« AD ED su EE Ma v i | like me 2 like me

To implement scheme 8, as a rule, the following reaction conditions are used. 1: different sets of reaction conditions depend on the definition of Za, DZ" or ze, 1a: if Za, DZ" or Z: is a halogen, then stage 1 can be excluded. 10: if KZa, VZ" or vZs is MAV", in the presence of a suitable amine of the formula

NMVAaVt, with a suitable solvent, such as, for example, HgO, MeonH, or EN, at a suitable temperature, such as, for example, 100-1307C, typically under microwave or autoclave heating conditions. 1c: if KZa, VZ" or uZc is -O-C-alkyl, in the presence of a suitable HO-C:-alkyl, with a suitable base, such as, for example, Man, potassium tert-butoxide (PoTO), in a suitable solvent , such as, for example, tetrahydrofuran (THE), at a suitable temperature. Alternatively, in the presence of a suitable HO-C':-alkyl as a solvent with a suitable acid such as, for example, HCl. 14: if Za, VZ" or VZ is hydrogen, under the conditions of hydrogenation: in an atmosphere of gaseous He in the presence of a catalyst such as, for example, Raney's Mi, Ra/cS (for example, 5 wt. 95 or 10 wt. U5) or RUS (for example, 5 wt. 965) in a suitable solvent, such as, for example, methanol (Men), ethanol (EUN) or TNE.

Te: if KZa, DZ" or KZ is C1-4alkyl, in the presence of a suitable boronic acid or ester, such as, for example, methylboronic acid, with a suitable catalyst, such as, for example, 1,1"-bisidiphenylphosphino)ferrocene, and with a suitable base such as e.g.

KzPO»x, in a suitable solvent mixture, such as, for example, a 5 to 1 dioxane/H2H2O mixture, at a suitable temperature, such as, for example, 10070. 2: in the first stage, in the presence of an alkene precursor and a 0.5 M solution 9-VVM in TNE in a nitrogen atmosphere at temperatures from room temperature to reflux temperature and duration of reaction from 1 to Zhodyn. In a second step, in the presence of a suitable (het)aryl bromide or (het)aryl iodide and a suitable catalyst such as, for example, 1,1'-

Z bisidiphenylphosphino)ferrocene|dichloropalladium(I!), and in the presence of a suitable base, such as, for example, tribasic potassium phosphate, in a suitable solvent mixture, such as, for example, TNE and water, at a suitable temperature of from 500 to the reflux temperature and suitable duration of reaction from 1 to 3 hours.

The starting materials of Scheme 8 are commercially available or can be prepared by standard means apparent to one skilled in the art or described in the specific experimental section.

General scheme 9

In general, the intermediates shown in Scheme 9, where 7 is -CHe-CHho-, can be prepared according to Scheme 9. In Scheme 9, 10 is defined as a leaving group such as, for example, halogen. All other variables from scheme 9 are defined within the scope of this invention.

ku Ah u

EE - - 5 --

Ko 1 I 2 oo? ! That would be fine.

Ma, M 2 ve ato uh - E ra and z ----

E with axis shk and de) with o, 0 o

Ж Ж aa 1: at the first stage in the presence of an alkene precursor and 0.5 M solution of 9-BVM in TNE in a nitrogen atmosphere at temperatures from room temperature to reflux temperature and reaction duration from 1 to 3 hours. In the second stage, in the presence of, for example, a suitable Ag-bromide or Ag-iodide (wherein X represents Bg or |, respectively) and a suitable catalyst, such as, for example, 1,1"-bisidiphenylphosphino)ferrocenedichloropalladium(II), and in in the presence of a suitable base, such as, for example, tribasic potassium phosphate, in a suitable solvent mixture, such as, for example, TNE and water, at a suitable temperature of from 5090 to the reflux temperature and for a suitable reaction time of from 1 to 3 hours. 2: in in the presence of triflatic acid anhydride and a suitable base, such as, for example, pyridine, in a suitable solvent, such as, for example, OSM, at a suitable temperature, such as, for example, 09C, in an inert atmosphere of gaseous M".

C: in the presence of a suitable base, such as, for example, C52CO3, in a suitable solvent, such as, for example, OME, at a suitable temperature, such as, for example, room temperature, in an inert atmosphere of gaseous M".

The starting materials of Scheme 9 are commercially available or can be prepared by standard means apparent to one skilled in the art or described in the specific experimental section.

In all these preparation methods, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to techniques generally known in the art, such as, for example, extraction, crystallization, trituration and chromatography.

Chirally pure forms of compounds of formula (I) form the predominant group of compounds. It follows from this that chirally pure forms of intermediate compounds and their salt forms are particularly suitable for obtaining chirally pure compounds of formula (I). Enantiomeric mixtures of intermediate compounds are also useful in the preparation of compounds of formula (I) with the appropriate configuration.

Pharmacology

It was found that the compounds of the present invention inhibit the activity of REMT5.

In particular, the compounds of the present invention bind the enzyme RKMT? and competitively bind to the natural substrate 5AM (5-adenosyl-ii-methionine) with inhibition of this enzyme.

Thus, it is contemplated that the compounds of the present invention or their pharmaceutical compositions may be useful for the treatment or prevention, in particular the treatment, of diseases such as blood disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, insufficient sperm motility, transplant rejection, tissue rejection, lung damage, etc.

In particular, the compounds according to the present invention or pharmaceutical compositions thereof may be suitable for the treatment or prevention, in particular the treatment, of diseases such as allergies, asthma, hematopoietic cancer, lung cancer, prostate cancer, melanoma, metabolic disorders, diabetes, obesity , blood diseases, sickle cell anemia, etc.

The compounds of the present invention or pharmaceutical compositions thereof may be useful for the treatment or prevention, in particular treatment, of diseases such as a proliferative disorder, such as an autoimmune disorder, cancer, a benign tumor, or an inflammatory disease.

Compounds according to the present invention or pharmaceutical compositions thereof may be suitable for the treatment or prevention, in particular treatment, of diseases such as metabolic disorders including diabetes, obesity; a proliferative disorder including cancer, hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer; blood diseases; hemoglobinopathy; sickle cell anemia; p- thalassemia, inflammatory disease and autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, diarrhea, gastroesophageal reflux disease, etc.

In some embodiments, inhibiting RAMT5 with a provided compound may be useful in treating or preventing, in particular treating, the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, adenocarcinoma rectum, colon adenocarcinoma, stomach cancer, pancreatic cancer, liver cancer, adenocystic carcinoma, lung adenocarcinoma, squamous cell carcinoma of the head and neck, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, clear cell carcinoma of the ovary and serous ovarian cystic adenoma.

Examples of metabolic disorders that can be treated or prevented, including treatment, include, but are not limited to, diabetes or obesity.

Examples of blood disorders that can be treated or prevented, in particular treated, include, but are not limited to, hemoglobinopathy such as sickle cell anemia or p-thalassemia.

Examples of cancer types that can be treated or prevented, including treated, include, but are not limited to, auditory neuroma, adenocarcinoma, adrenal cancer, anal canal cancer, angiosarcoma (eg, lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, cancer bile ducts (eg, cholangiocarcinoma), bladder cancer, breast cancer (eg, breast adenocarcinoma, papillary carcinoma of the breast, breast cancer,

From medullary carcinoma of the breast), brain cancer (eg, meningioma; glioma, eg, astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (eg, cervical adenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer (eg, colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (eg, Kaposi's sarcoma, idiopathic multiple hemorrhagic sarcoma), endometrial cancer (eg, uterine cancer, uterine sarcoma), esophageal cancer (eg , esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (eg, intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, stomach cancer (eg, gastric adenocarcinoma), gastrointestinal stromal tumor (CI5T), head and neck cancer ( for example, squamous cell carcinoma of the head and neck), cancer of the oral cavity (for example, squamous cell carcinoma of the oral cavity (0500), cancer of the pharynx (eg, pharyngeal cancer, cancer of the larynx, cancer of the nasopharynx, cancer of the oropharynx)), cancers of the hematopoietic system (eg, leukemia, such as acute lymphocytic leukemia (A!) (eg, B-cell AI Her , T-cell AG), acute myelocytic leukemia (AMI) (for example, B-cell

AMI, T-cell AMI), chronic myelocytic leukemia (CML) (eg B-cell AML, T-cell AML) and chronic lymphocytic leukemia (CL!) (eg B-cell SI, T-cell SI); lymphoma, such as Hodgkin's lymphoma (NO) (eg, B-cell NO, T-cell

NO) and non-Hodgkin's lymphoma (NHL) (eg, B-cell MNL such as diffuse large-cell lymphoma (DHL) (eg, diffuse B-cell large-cell lymphoma (BCL), follicular lymphoma, chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (SCL) , lymphoma from the cells of the mantle zone (MS), types of lymphoma from the B-cells of the marginal zone (for example, types of lymphoma from the lymphoid tissue of the mucous membranes (MAY T), lymphoma from the B-cells of the marginal zone of the lymph nodes, lymphoma from the B-cells of the marginal zone of the spleen ), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenström macroglobulinemia"), immunoblastic large-cell lymphoma, hairy cell leukemia (HCL), B-lymphoblastic progenitor cell lymphoma, and primary central nervous system lymphoma (CM5); as well as T-cell MN, such as T-lymphoblastic lymphoma from progenitor cells/I-lymphoblastic leukemia from progenitor cells, peripheral T-cell lymphoma (PTCL) (eg, T-cell lymphoma Cutaneous myfoma (STSI) (for example, 60 mycosis fungoides, Sézary syndrome), angioimmunoblastoma T-cell lymphoma,

extranodal T-cell lymphoma from natural killers, T-cell lymphoma with enteropathy, subcutaneous T-cell lymphoma of the panniculitis type, anaplastic large-cell lymphoma); a combination of one or more leukemias/lymphomas described above; and multiple myeloma (MM)), heavy chain disease (eg, alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (eg, nephroblastoma of the kidney, also called a tumor

Wilms, renal cell carcinoma), liver cancer (eg, hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (eg, bronchogenic carcinoma, non-small cell lung cancer (NSCLC), squamous cell lung cancer (5C), lung adenocarcinoma, lung carcinoma

Lewis, neuroendocrine tumors of the lung: typical carcinoid, atypical carcinoid, small cell lung cancer (5010) and large cell neuroendocrine carcinoma), leiomyosarcoma (IM5), mastocytosis (eg, systemic mastocytosis), myelodysplastic syndromes (MSD), mesothelioma, myeloproliferative disorder (MPO) (eg, polycythemia vera (PU), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM), also called myelofibrosis (ME), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CLE), hypereosinophilic syndrome (HE5X)), neuroblastoma, neurofibroma (eg, neurofibromatosis (ME) type 1 or 2, schwannomatosis), neuroendocrine cancer (eg, gastroenteropancreatic neuroendocrine tumor (CER-MET), carcinoid tumor), osteosarcoma, ovarian cancer (eg, cystadenocarcinoma , embryonal ovarian cancer, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (for example, adenocarcinoma pancreatic cynoma, intraductal papillary mucinous neoplasm (IMM), insuloma), penile cancer (eg, Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (RMT), prostate cancer (eg, adenocarcinoma of the prostate), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (eg, squamous cell carcinoma (50), keratoacanthoma (KA), melanoma, basal cell carcinoma (BSC)), small bowel cancer (eg, appendix cancer), soft tissue carcinoma ( for example, malignant fibrous histiocytoma (MEN), liposarcoma, malignant tumor of peripheral nerve sheaths (MRM5ZT), chondrosarcoma, fibrosarcoma, myxosarcoma), carcinoma

Of sebaceous glands, sweat gland carcinoma, synovioma, testicular cancer (eg, seminoma, embryonal carcinoma of the testis), thyroid cancer (eg, papillary thyroid carcinoma, papillary thyroid cancer (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, vulvar cancer (for example, Paget's disease of the vulva).

Examples of neurodegenerative diseases that can be treated or prevented, including treatable, include, but are not limited to, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, Alzheimer's disease, SNiD-associated dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa , spinal muscular atrophy and cerebellar degeneration.

Examples of cardiovascular diseases that can be treated or prevented, in particular treated, include, but are not limited to, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

Examples of inflammatory diseases that can be treated or prevented, including treatment, include, but are not limited to, acne-associated inflammation, anemia (eg, aplastic anemia, hemolytic autoimmune anemia), rhinitis, asthma, arteritis (eg, polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu syndrome), arthritis (eg, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis), upper respiratory tract disease, ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies, or allergic reactions , atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, diverticulitis, dermatomyositis, diabetes (eg, type 2 diabetes, type 2 diabetes), skin diseases (eg, psoriasis, eczema, hypersensitivity reactions in eczema, burns, dermatitis, itching (scabies), endometriosis, Guillain-Barre syndrome, and infection, coronary heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, types of cephalgia (e.g., migraine, tension headaches), ileus (e.g., postoperative ileus and ileus in sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (irritable bowel syndrome bladder), disorders of the gastrointestinal tract (for example, selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic disorders of the gastrointestinal tract (for example, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis ),

gastritis, diarrhea, gastroesophageal reflux disease (GERD or its synonym SECO), inflammatory bowel disease (IBD) (for example, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, inflammation in a disconnected intestine, Behçet's syndrome, unspecified colitis) and inflammatory bowel syndrome (IV5)), lupus, annular scleroderma, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (eg )

Sjogren's, thyroiditis, transplant rejection, tendinitis, trauma or injury (eg, frostbite, chemical exposure, toxins, scarring, burns, physical injury), vasculitis, vitiligo, and Wegener's granulomatosis.

In particular, an inflammatory disease is an acute inflammatory disease (for example, inflammation due to an infection). In particular, an inflammatory disease is a chronic inflammatory disease (eg, conditions caused by asthma, arthritis, and ulcerative colitis). The compounds may also be useful in the treatment of inflammation associated with trauma and non-inflammatory myalgia. The compounds may also be useful in the treatment of inflammation associated with cancer.

Examples of autoimmune diseases that can be treated or prevented, including treatment, include, but are not limited to, arthritis (including rheumatoid arthritis, types of spondyloarthropathy, gouty arthritis, degenerative joint disorders such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis,

Behçet's disease, hemolytic autoimmune anemia, amyotrophic lateral sclerosis, amyloidosis, multiple sclerosis, acute brachial syndrome, psoriatic and chronic arthritis in children), asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, skin diseases (eg, psoriasis, eczema, hypersensitivity reactions for eczema, burns, dermatitis, itching (scabies), enuresis, eosinophilic disease, disorders of the gastrointestinal tract (for example, selected from

From peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic disorders of the gastrointestinal tract (for example, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GERD or its synonym SECO ), inflammatory bowel disease (IBD) (eg, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, inflammatory bowel disease, Behçet's syndrome, unspecified colitis) and inflammatory bowel syndrome (IB5)) and disorders that are relieved prokinetic agents (for example, ileus, postoperative intestinal obstruction and intestinal obstruction in sepsis; gastroesophageal reflux disease (GERD or its synonym SECO); eosinophilic esophagitis, gastric paresis such as diabetic gastric paresis; food intolerance and food allergies and other functional disorders of the intestine , such as disp non-ulcerative sepsis (NUS) and non-cardiac chest pain (NSPD, including costal chondritis)).

In a specific embodiment, a provided compound may be useful in reprogramming somatic cells, such as reprogramming somatic cells into stem cells. In a specific embodiment, the provided compound may be useful in the development of germ cells and thus is expected to be useful in the fields of reproductive technology and regenerative medicine.

Other conditions that can be treated or prevented, including treatment, include, but are not limited to, ischemic damage associated with types of myocardial infarction, immune disorders, stroke, arrhythmia, toxin-induced or alcohol-related liver disease, aspirin-sensitive rhinosinusitis, cystic fibrosis , cancer pain and blood disorders such as chronic anemia and aplastic anemia.

The compounds of the present invention may also have therapeutic applications in increasing the sensitivity of tumor cells to radiation therapy and chemotherapy.

Thus, the compounds of the present invention can be used as a "radiosensitizer" and/or "chemosensitizer" or they can be given in combination with another "radiosensitizer" and/or "chemosensitizer".

The term "radiosensitizer" as used herein is defined as a molecule, preferably a low molecular weight molecule, that is administered to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and/or to increase the effectiveness of treatment of diseases amenable to treatment with ionizing radiation radiation

The term "chemosensitizer" as used herein is defined as a molecule, preferably a low molecular weight molecule, that is administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or to increase the effectiveness of the treatment of diseases amenable to treatment with chemotherapeutic agents.

Several mechanisms for the mode of action of radiosensitizers have been proposed in the literature, including: radiosensitizers that induce cell hypoxia (eg, 2-nitroimidazole compounds and compounds that include benzotriazine dioxide) that mimic oxygen or, alternatively, behave as hypoxic bioremedial agents ; radiosensitizers that do not lead to cell hypoxia (for example, halogenated pyrimidines) can be analogues of DNA bases and preferentially incorporate into the DNA of cancer cells and thus contribute to radiation-induced destruction of DNA molecules and/or prevent normal DNA repair mechanisms; and various other putative mechanisms of action have been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently use radiosensitizers along with X-ray exposure. Examples of radiosensitizers that are activated by X-rays include, but are not limited to, metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, K5BIO 1069, 5K 4233,

EO9U, KV 6145, nicotinamide, 5-bromodeoxyuridine (VOK), 5-iododeoxyuridine (SHK), bromodeoxycytidine, fluorodeoxyuridine (BiakK), hydroxyurea, cisplatin and their therapeutically effective analogs and derivatives.

During photodynamic therapy (PDT) of cancers, visible light is used as a radiation activator of the sensitizer. Examples of photodynamic radiosensitizers include, without limitation, the following: hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, tin ethioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof.

Radiosensitizers can be administered together with a therapeutically effective amount of one or

Of several other compounds, including but not limited to: compounds that promote incorporation of radiosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients and/or oxygen to target cells; chemotherapeutic agents that act on the tumor with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.

Chemosensitizers can be administered together with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds that promote incorporation of chemosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients and/or oxygen to target cells; chemotherapeutic agents that act on a tumor or other therapeutically effective compounds for the treatment of cancer or other disease. Calcium antagonists, such as verapamil, have been found to be useful in combination with antineoplastic agents to sensitize tumor cells resistant to conventional chemotherapeutic agents to chemotherapy and to enhance the efficacy of such compounds in drug-sensitive malignancies.

The compounds of the present invention may also reduce the risk of cancer recurrence.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for use as a medicinal preparation.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for use in inhibiting RAMT5 activity.

The compounds of the present invention may be "anticancer agents", which term also includes "antitumor cell growth agents" and "antineoplastic agents".

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for use in the treatment of the above-mentioned diseases.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the treatment or prevention, in particular for the treatment, of the specified diseases.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the treatment or prevention, in particular for the treatment, of REMT»5 mediated diseases or conditions.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of medicinal preparations.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of a drug for inhibition of REMT5.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of a medicinal product for the treatment or prevention, in particular for the treatment, of any of the disease states mentioned above in this document.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of a medicinal preparation for the treatment of any of the disease states mentioned hereinabove.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, which can be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases mentioned hereinabove.

In view of the applicability of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, a method of treating warm-blooded animals, in particular humans, suffering from any of the diseases mentioned above in this document, or a method of preventing warm-blooded animals, in particular humans, any - any of the diseases mentioned above in this document.

These methods involve the administration, i.e. systemic administration or local application, preferably oral administration, of an effective amount of a compound of formula (I) or its pharmaceutically acceptable addition salt or solvate to warm-blooded animals, in particular humans.

Those skilled in the art of treating such diseases will be able to determine an effective therapeutic daily amount from the results of the tests presented below in this document.

An effective therapeutic daily amount will be from about 0.005 mg/kg to 50 mg/kg, particularly from 0.01 mg/kg to 50 mg/kg body weight, more specifically from 0.01 mg/kg to 25 mg/kg body weight , preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/ kg, most preferably from about 0.05 mg/kg to about 1 mg/kg of body weight. A particularly effective therapeutic daily amount may be from about 0.01 to 1.00 g twice

Ko) per day (VIS), more specifically from 0.30 to 0.85 g of BIO; even more specifically 0.40 g of VIO. The amount of a compound of the present invention, also referred to herein as an active ingredient, required to achieve a therapeutic effect will, of course, vary from case to case, for example, for the particular compound, route of administration, age and condition of the patient receiving treatment, as well as a specific disorder or disease being treated.

The method of treatment may also include administration of the active ingredient in a regimen of one to four times a day. In such methods of treatment, the compounds of the present invention are preferably formulated prior to administration. As described hereinbelow, suitable pharmaceutical formulations are prepared by known procedures using well-known and commonly available ingredients.

Compounds of the present invention, which may be useful for the treatment or prevention of cancer or cancer-related conditions, may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single dosage pharmaceutical composition comprising a compound of formula (1), a pharmaceutically acceptable addition salt or solvate thereof, and one or more additional therapeutic agents, as well as administration of a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof, and each additional therapeutic agent in its own separate dosage pharmaceutical composition. For example, a compound of formula (1), a pharmaceutically acceptable addition salt or solvate thereof, and a therapeutic agent can be administered to a patient together in a single dosage composition for oral administration, such as a tablet or capsule, or each agent can be administered separately in dosage formulations for oral administration.

Although the active ingredient can be administered separately, it is preferred that it be presented in the form of a pharmaceutical composition.

Therefore, the present invention additionally provides a pharmaceutical composition and, as an active ingredient, a therapeutically effective amount of a compound of formula (I), its pharmaceutically acceptable addition salt or solvate.

Therefore, the present invention also relates to a pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of formula (I), its pharmaceutically acceptable addition salt or solvate.

The carrier or diluent must be "acceptable" in the sense that it must be compatible with the other ingredients of the composition and not harmful to the patients receiving it.

To facilitate administration, the compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes. The compounds of the present invention, in particular the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup or combination thereof, may be formulated into various pharmaceutical forms for administration purposes. Suitable compositions include all compositions that are usually used for medicinal products that are administered systemically.

To obtain pharmaceutical compositions according to the present invention, an effective amount of a certain compound as an active ingredient is combined into a homogeneous mixture with a pharmaceutically acceptable carrier, while the carrier can take a wide variety of forms depending on the form of the drug that is required for administration. These pharmaceutical compositions are preferably in a single dosage form, suitable, in particular, for administration orally, rectally, through the skin, by parenteral injection or by inhalation. For example, when preparing the compositions in dosage form for oral administration, in the case of oral liquid preparations such as suspensions, syrups, infusions, emulsions and solutions, any of the usual pharmaceutical media can be used, such as water, glycols, oils, alcohols, etc.; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants, etc., in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the most preferred single dosage forms for oral administration, in which case, of course, solid pharmaceutical carriers are used. In the case of compositions for parenteral administration, the carrier will generally at least substantially contain sterile water, although it may also contain other ingredients, for example to improve solubility. For example, it is possible to obtain solutions for injections, in which the carrier contains a physiological solution, a glucose solution, or a mixture of a physiological solution and a glucose solution. Solutions for injections containing a compound of formula (I), its pharmaceutically acceptable addition salt or solvate can be formulated in oil for prolonged action. Suitable oils for these purposes are, for example, peanut butter, sesame oil, cottonseed oil,

From corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids, as well as mixtures of these and other oils. It is also possible to obtain suspensions for injections, in which case appropriate liquid carriers, suspending agents, etc. may be used. Also included are preparations in solid form, which are intended to be converted, immediately before use, into preparations in liquid form. In compositions suitable for transdermal administration, the carrier optionally contains a permeation enhancer and/or a suitable wetting agent, optionally in combination with suitable additives of any nature in minimal proportions, the additives not having a significant deleterious effect effects on the skin. These additives can facilitate the introduction into the skin and/"or can be useful during the preparation of the required compositions. These compositions can be administered in various ways, for example, in the form of a transdermal patch, by point application, in the form of an ointment. Addition salts of the acid or base of the compounds of the formula (I ) due to their increased water solubility compared to the corresponding form of the base or acid are more suitable when preparing aqueous compositions.

It is especially preferable to assemble the above-mentioned pharmaceutical compositions into a single dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically separate units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including divisible or film-coated tablets), capsules, pills, powder sachets, tablets, suppositories, solutions or suspensions for injections, etc., as well as individual numerous variants thereof.

To increase the solubility and/or stability of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates in pharmaceutical compositions, it may be preferable to use a-, VD- or y-cyclodextrins or their derivatives, in particular, cyclodextrins substituted by hydroxyalkyl, for example /2- hydroxypropyl-B-cyclodextrin or sulfobutyl-B-cyclodextrin. Co-solvents such as alcohols may also improve the solubility and/or stability of the compounds of the present invention in pharmaceutical compositions. for Depending on the method of administration, the pharmaceutical composition will preferably contain from 0.05 to 9995 by weight, more preferably from 0.1 to 7095 by weight, even more preferably from 0.1 to 5095 by weight of the compound of formula (I), its pharmaceutically acceptable addition salt or solvate and from 1 to 99.9595 by weight, more preferably from 30 to 99.995 by weight, even more preferably from 50 to 99.995 by weight of a pharmaceutically acceptable carrier, while all percentages are given based on the total weight of the composition.

Another aspect of the present invention provides for the combination of a compound of the present invention with another anticancer agent, particularly for use as a medicament, more specifically for use in the treatment of cancer or related diseases.

For the treatment of the above conditions, the compounds of the present invention can preferably be used in combination with retargeting of immune cells using antibodies, for example T-cell/neutrophil retargeting. This can be achieved, for example, with the help of bispecific monoclonal antibodies or artificial T-cell receptors.

For the treatment of the aforementioned conditions, the compounds of the present invention can preferably be used in combination with one or more other medical agents, more specifically, with other anticancer agents or adjuvants used in cancer therapy. Examples of anticancer agents or adjuvants (supporting agents during therapy) include, without limitation: - coordination compounds of platinum, for example cisplatin, optionally combined with amifostine, carboplatin or oxaliplatin; - taxane compounds, such as paclitaxel, protein-bound paclitaxel particles (Abgahape "M) or docetaxel; - topoisomerase I inhibitors, such as camptothecin compounds, such as irinotecan, ZM-38, topotecan, topotecan Psi; - topoisomerase inhibitors, such as antitumor epipodophyllotoxins or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide - antitumor periwinkle alkaloids such as vinblastine, vincristine or vinorelbine - antitumor nucleoside derivatives such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine ysi, capecitabine, cladribine, fludarabine, nelarabine - alkylating agents such as nitrogen mustard or nitrosourea such as cyclophosphamide,

Zo chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide, optionally in combination with mesna, pipobroman, procarbazine, streptozocin, temozolomide, uracil; - antitumor anthracycline derivatives, such as daunorubicin, doxorubicin, optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin Psi, valrubicin; - molecules that act purposefully on the ISE-1 receptor, for example, picropodophyllin; - tetracarcin derivatives, for example, tetracarcin A; - glucocorticoids, for example prednisone; - antibodies, such as trastuzumab (antibody to NEK2), rituximab (antibody to CO20), gemtuzumab, gemtuzumab-ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, SMTO 328; - estrogen receptor antagonists, or selective estrogen receptor modulators, or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole; - aromatase inhibitors, such as exemestane, anastrozole, letrazol, testolactone and vorozol; - agents that promote differentiation, such as retinoids, vitamin Y or retinoic acid, and agents that block the metabolism of retinoic acid (CAMBA), such as Accutane; - inhibitors of DNA methyltransferase, for example, azacitidine or decitabine; - antifolates, for example premetrexed disodium; - antibiotics, for example antinomycin 0, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plikamycin, mithramycin; - metabolic inhibitors, such as clofarabine, aminopterin, cytosine-arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine; - agents that induce apoptosis and anti-angiogenic agents such as AllI-2 inhibitors, e.g.

US 137, VN 312, AVT 737, gosypol, NA 14-1, TMU/ 37 or decanoic acid; - tubulin-binding agents, for example combrestatin, colchicine or nocodazole; - kinase inhibitors (for example, ESEK (epidermal growth factor receptor) inhibitors),

MTKI (multi-targeted kinase inhibitors), ttTOBK inhibitors), such as flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, 60 sunitinib, sunitinib maleate, temsirolimus;

- farnesyltransferase inhibitors, for example tipifarnib; - histone deacetylase (HAS) inhibitors, for example sodium butyrate, suberoylanilide hydroxamic acid (5BANA), depsipeptide (EK 901228), MUMR-I AO824, 8306465,

UM-26481585, trichostatin A, vorinostat; - inhibitors of the ubiquitin-proteasome pathway, for example RZ-341, MI M.41 or bortezomib; - yondelis; - telomerase inhibitors, for example telomestatin; - matrix metalloproteinase inhibitors, such as batimastat, marimastat, prinostat or metastat; - recombinant interleukins, for example, aldesleukin, denileukin diftitox, interferon-alpha ha, interferon-alpha 2, peginterferon-alpha 26; - MARK inhibitors; - retinoids, for example alitretinoin, bexarotene, tretinoin; - arsenic trioxide; - asparaginase; - steroids, for example, dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenpropionate), dexamethasone; - agonists or antagonists of gonadotropin-releasing hormone, for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate; - thalidomide, lenalidomide; - mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase; - university mimetics, for example AVT-737; - MEK inhibitors, for example ROZ8059, A2Ob6244, SI-1040; - colony-stimulating factor analogues, for example filgrastim, pegfilgrastim, sargramostim; erythropoietin or its analogues (for example, darbepoietin-alpha); interleukin-11; oprelvekin; zoledronate, zoledronic acid; fentanyl; bisphosphonate; palifermin; - steroid inhibitor of cytochrome RabBoO 17-alpha-hydroxylase-17,20-lyase (SUR17), for example abiraterone, abiraterone acetate; - inhibitors of glycolysis, such as 2-deoxyglucose;

Zo - inhibitors of tTOR, such as rapamycins and rapalogs, and inhibitors of tTOE-kinase; - RIZK inhibitors and double tTOE/RIZK inhibitors; - autophagy inhibitors, such as chloroquine and hydroxychloroquine; - antibodies that reactivate the immune response to tumors, such as nivolumab (to PO-1), lambrolizumab (to PO-1), ipilimumab (to STI A4) and MROY 3280A (to PO-Y 1).

The present invention also relates to a product that contains as the first active ingredient a compound according to the present invention and as an additional active ingredient one or more anticancer agents, in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

One or more other medicinal agents and a compound of the present invention may be administered simultaneously (eg, in separate or single formulations) or sequentially in any order. In the latter case, two or more compounds will be administered over a period of time, and in an amount and manner, which are appropriate to ensure that a dominant or synergistic effect is achieved. It should be understood that the preferred method and order of administration and the appropriate dosages and regimens for each component of the combination will depend on the particular other medicinal agent and compound of the present invention to be administered, their route of administration, the particular tumor being treated, and of a specific host, which is being treated. The optimal method and order of administration, and the amount of doses, and the regimen can be easily determined by specialists in this field using conventional methods and taking into account the information presented in this document.

The weight ratio of a compound of the present invention and one or more other anticancer agents administered in combination can be determined by one skilled in the art. The ratios indicated, and the exact dose and frequency of administration, depend on the specific compound of the present invention and the other anticancer agent(s) used, the specific condition being treated, the severity of the condition being treated, the age , body weight, sex, diet, time of administration and general physical condition of the particular patient, route of administration, and other drug treatment the individual may be receiving, as is well known to those skilled in the art. Furthermore, it is apparent that the effective daily amount may be reduced or increased depending on the response of the subject being treated and/or 60 depending on the judgment of the physician who prescribes the compounds of this invention. A specific weight ratio for a compound of formula (I) of the present invention and another anticancer agent may be in the range of 1/1O0 to 10/1, more specifically 1/5 to 5/1, even more specifically 1/3 to 3/ 1.

The platinum coordination compound is preferably administered at a dose of 1-500 mg per square meter (mg/m?) of body surface area, for example 50-400 mg/m, particularly for cisplatin at a dose of approximately 75 mg/m, and for carboplatin - in a dose that is approx

З00 mg/m: per course of treatment.

The taxane compound is preferably administered at a dose of 50-400 mg per square meter (mg/m) of body surface area, for example 75-250 mg/m, particularly for paclitaxel at a dose of approximately 175-250 mg/m, and for docetaxel - in a dose of approximately 75-150 mg/m:g per course of treatment.

The camptothecin compound is preferably administered at a dose of 0.1-400 mg per square meter (mg/m?) of body surface area, for example 1-300 mg/m, particularly for irinotecan at a dose of approximately 100-350 mg /me, and for topotecan - in a dose that is approximately 1-2 mg/m: per course of treatment.

The antitumor podophyllotoxin derivative is preferably administered at a dose of 30-300 mg per square meter (mg/m) of body surface area, for example 50-250 mg/m, particularly for etoposide at a dose of approximately 35-100 mg/m ", and for teniposide - in a dose that is approximately 50-250 mg/m: per course of treatment.

The antitumor periwinkle alkaloid is preferably administered in a dose that is 2-

30 mg per square meter (mg/m?) of body surface area, in particular for vinblastine - in a dose that is approximately 3-12 mg/m-, for vincristine - in a dose that is approximately 1-2 mg/m, and for vinorelbine - in a dose that is approximately 10-30 mg/m:2 per course of treatment.

The antitumor nucleoside derivative is preferably administered in a dose that is 200-2500 mg per square meter (mg/m?) of body surface area, for example 700-1500 mg/m-, in particular for 5-RISH - in a dose that is 200-500 mg/m", for gemcitabine - in a dose that is approximately 800-1200 mg/m, and for capecitabine - in a dose that is approximately 1000-2500 mg/m: per course of treatment.

Alkylating agents, such as nitrogen mustard or nitrosourea, are preferably administered at a dose of 100-500 mg per square meter (mg/m7) of body surface area, for example 120-200 mg/m, in particular for cyclophosphamide - at a dose of approximately 100-500 mg/m, for chlorambucil at a dose of approximately 0.1-0.2 mg/kg, for carmustine at a dose of approximately 150-200 mg/m, and for lomustine at a dose of , which is approximately 100-150 mg/m:g per course of treatment.

The antitumor anthracycline derivative is preferably administered at a dose of 10-75 mg per square meter (mg/m2) of body surface area, for example 15-60 mg/m, particularly for doxorubicin at a dose of approximately 40-75 mg/m , for daunorubicin - at a dose that is approximately 25-45 mg/m", and for idarubicin - at a dose that is approximately 10-15 mg/m: per course of treatment.

The antiestrogen-based agent is preferably administered in a dose of approximately 1-100 mg, depending on the specific agent and the condition being treated. Tamoxifen is preferably administered orally in a dose that is 5-50 mg, preferably 10-20 mg twice a day, continuing the therapy for a sufficient time to achieve and maintain the therapeutic effect. Toremifene is preferably administered orally at a dose of approximately 60 mg once daily, continuing therapy for a sufficient time to achieve and maintain a therapeutic effect. Anastrozole is preferably administered orally at a dose of approximately 1 mg once daily. Droloxifene is preferably administered orally at a dose of approximately 20-100 mg once daily. Raloxifene is preferably administered orally at a dose of approximately 60 mg once daily.

Exemestane is preferably administered orally at a dose of approximately 25 mg once daily.

Antibodies are preferably administered at a dose of approximately 1-5 mg per square meter (mg/m-) of body surface area, or, as is known in the art, at another dose. Trastuzumab is preferably administered at a dose of 1-5 mg per square meter (mg/m) of body surface area, particularly 2-4 mg/m per course of treatment.

These doses may be administered, for example, once, twice, or more per course of treatment, which may be repeated, for example, every 7, 14, 21, or 28 days.

The following examples illustrate the present invention. If the specific stereochemistry for the stereocenter of the compound is not indicated, it means that a mixture of K- and 5- was obtained

enantiomers. If more than 1 stereocenter is present in the structure, then each stereocenter, for which no specific stereochemistry is indicated, was obtained as a mixture of K and 5.

One of ordinary skill in the art will understand that typically, after purification, the required fractions are collected with a column and the solvent is evaporated to yield the desired compound or intermediate.

Examples

Further in this document, the term "kt", "k. t." or "KT" means room temperature; "Me" means methyl; "MeonH" means methanol; "EC" means ethyl; "EN" means ethanol; "Man" means sodium hydride; "OEAYUO" means diethyl azodicarboxylate; "NMRT" means hexamethylphosphorus triamide; "WosgO" means tert-butoxycarbonyl anhydride; "VYOMO" means tert-butyl nitrite; "To5OH" " means 4-methylbenzenesulfonic acid; "To5CI" means 4-methylbenzenesulfonyl chloride (also p-toluenesulfonyl chloride); "SMVR" means cyanomethylene tributylphosphorane; "OVAU" means di-tert-butylazodicarboxylate; "HAN" means lithium aluminum hydride; "Mavn(AsO)z " or "Mav(OAc)z" means sodium triacetoxyborohydride; "EAc" means ethyl acetate; "TEA" or "EizM" means triethylamine; "OSM" means dichloromethane; "d.5." means as much as needed; "Prom. spol." means an intermediate compound; "Mesm" or "ACM" means acetonitrile; "OME" means M,M-dimethylformamide; "OMA" means M,M-dimethylacetamide; "OME-OMA" means M,M-dimethylformamide dimethyl acetal; "Rak(arrosig" means (|1,1"-bisbidiphenylphosphino)ferrocenedichloropalladium(II); "TNE" means tetrahydrofuran; "SzaNovBeR».SioRa" means (1,1-bisidiphenylphosphino)ferrocene|dichloropalladium); "i-RGON" or "IRGON" means 2-propanol; "C" stands for liquid chromatography; "CM5" means liquid chromatography/mass spectrometry; "NRIGS" means high-performance liquid chromatography; "prom. spol." means an intermediate compound; "rger-HRI C" means preparative high-performance liquid chromatography; "m-SRBA" means meta-chloroperoxybenzoic acid; "TEA" means trifluoroacetic acid; "t. pl" means melting point; "KR" means reverse phase; "min" means minute(s); "hr" means hour(s); "PE" means petroleum ether; "vol./o06b" means vol. ratio "SeSe" means diatomaceous earth; "OM5O" means dimethylsulfoxide; "ZES" means supercritical fluid chromatography; "SIRE" means diisopropyl ether; "CHZry" or "ORPE" means 1,1'-bisidiphenylphosphino) ferrocene;

"BIREA" or "BIEA" means M,M-diisopropylethylamine; "RRiz" means triphenylphosphine; "ESO" means diethyl ether; "Ra/C" means palladium on carbon; "RUS" means platinum on coal; "PO(OH)2/C" means palladium hydroxide on carbon; "CPME" means cyclopentyl methyl ether; "pRachava)z means tris(dibenzylideneacetone)dipalladium; "bIAU" means disopropylazodicarboxylate; "TMeCEz" means trimethyl(trifluoromethyl)silane; "TVAE" means tetrabutylammonium fluoride; "lb/sq. inch" means pounds-force per square inch; "BiMSI" means tetraethylammonium chloride; "eq" means equivalent(s); "Pa(OAc) 2" means palladium acetate(!); "AcOH" means acetic acid; "LOBSTER " means 4- (dimethylamino)pyridine; "-VIiOK", "ViOkK" or "KOiVi" means potassium tert-butoxide; "periodinan

"Dess-Martin" means 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; Рой" means polymer-bound triphenylphosphine; "РизРОНзВг" means methyltriphenylphosphonium bromide; "Вп" means benzyl; "В;" means benzoyl; "р-Т5А" means 4-methylbenzenesulfonic acid; "Без.ЕгО" means boron trifluoride complex -ethyl ether; "9-BVM" means 9-borabicyclo!|3.3.1|nonane; "ra-118" means dichloro(i1,1"-bis(di-tert-butylphosphino)ferrocene|palladium(I!); and "TS" means thin-layer chromatography; "rger-TI C" means preparative TI C; "p-MeSeNaZOzH.HgO" means para-toluenesulfonic acid hydrate; "PMB" means para-methoxybenzyl; "COAc" means potassium acetate; "RTZA" " - para-toluenesulfonic acid; "MTBE" means methyl-tert-butyl ether; "Kkp(asasu(eth)g" means acetylacetonatobis(ethylene)rhodium(I); "(5)-MopoPpo5" means (5)-M ,M-dimethyldinaphtho!|2,1- 02 -AI,3,2)dioxaphosphepin-4-amine; "TO" means triflate k anhydride to pray "Me!" means methyl iodide; "MegMH" means dimethylamine; "Meg2MN.NS!" means dimethylamine-hydrochloric acid; "Me"MSI" means tetramethylammonium chloride; "MeOMa" means sodium methoxide; "T5" means tozyl; "M5Cl" means mesyl chloride; "OIVAN" means diisobutylaluminum hydride; "TVOM5" means // tert-butyldimethylsilyl; "Ra(arrOSiI»SNeaSig" means /((1,1- bisidiphenylphosphino)ferrocenedichloropalladium(I), complex with dichloromethane; "PPA" means polyphosphoric acid; "MNeaVp" means benzylamine; "RYAD(PPAz)2Si2" means dichlorobis(triphenylphosphine )palladium(I). Because Intermediate compounds that contain a double bond with substituents can be in E- or 7-

configurations, while the experimental part below is shown in one specific configuration. However, unless (E) or (7) is specified, it is not known whether these intermediates were obtained in the E- or 2-configuration or as a mixture of compounds of both configurations. For example, intermediates 24-26, 29-31, 72-76 and intermediates 79-88 may be in the E- or 2-configuration or may be mixtures thereof.

For example, intermediates 44, 97-100, 136-138, 150 and compounds 55, 57, 57a and 61 were obtained in the E-configuration and are precisely indicated as (E) in the experimental section below.

For intermediates that were used in the next stage of the reaction in the form of crude or partially purified intermediates, the reaction protocols described below indicate calculated amounts expressed in moles (in some cases indicated with c), or, alternatively, theoretical amounts expressed in moles are indicated .

A. Preparation of intermediate compounds

Example A1

Preparation of intermediate compound 1

M

M deno ho ri ee

Uh N m - 5 - :- ho ih

Premined compound Y

2,2-dimethoxypropane (18.2 g, 175 mmol) and 4-methylbenzenesulfonic acid (To5OH ) (1.51 g, 8.75 mmol) in one portion at 2520 in an M2 atmosphere. The mixture was stirred at 609C for 2 hours. The mixture was cooled to 259C. The reaction was quenched by the slow addition of saturated NaHSO 3 (100 mL) and then extracted with ethyl acetate (125 mL x 5). The combined organic phase was washed with saturated saline solution (120 ml), dried over anhydrous

Ma5o", was filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel (gradient elution: OSM/ethyl acetate from 1:0 to 2:1) to give crude intermediate 1 (38.0 g) as a light yellow resin.

Example A2

Preparation of intermediate compounds Z and I tdnamiya pexametityesvove ln. Triamyl texamethylaluetphor and Za - 7 o. It's tolurl but there's still no tone

In the area of the 00th. en Я и І ІІ r (Ki h. shi kash! y yah y stvo SHY . zo Promnoyny compound 7 Trnog3 b-lioksvreptnlizmin, KONI, tolusl Intermediate compound Z

In a solution of 5-O-tert-butyldimethylsilyl-2,3-o-isopropylidene-O-ribofuranose (intermediate 2) (24.3 g, 79.8 mmol) in SiCl (12.8 mL, 133 mmol) and toluene (200 ml) was added dropwise to NMR at -507C for 30 minutes. After stirring the mixture at -507C for 2 hours, the reaction mixture was quickly washed with ice-cold saline solution (30 ml), dried over anhydrous Mag50O5, and immediately added to the intensively stirred mixture of powdered

KOH (bHg, 117 mmol), 2,4-dichloro-7P-pyrrolopyrimidine (10.0 g, 53 mmol), tris(3,6-dioxaheptyl)amine (8.27 mL, 26.6 mmol), and toluene (200 ml). The mixture was stirred at room temperature for 48 hours. The solvent was concentrated under vacuum. The residue was treated with 250 ml of MNACI solution and extracted with ethyl acetate (300 ml x 2). The organic layers were combined and dried over Mag50O", filtered and the filtrate was concentrated under vacuum.

The residue was purified by column chromatography on silica gel (gradient elution:

petroleum ether/ethyl acetate from 25:1 to 15:1). Fractions with the product were collected and the solvent was evaporated to give the required intermediate C (6.50 g, crude).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate C using the appropriate starting materials (Table 1).

Table 1:

Ya-ya zi-o - Intermediate compound 2 / OM si and 4 Y y 4-chloro-2-methyl-7H- yaz M. M pyrrolo|2,3-d|pyrimidine ko / E zi-o - / in SI Intermediate compound 2 z i 5 c M 4-chloro-5-fluoro-7H- i z -y pyrrolo(2,3-4|-pyrimidine oc? rolo|2,3-a| pyrimide i Intermediate compound 2 och no romizna of compounds 185 o M si 4-chloro-5-methyl-7H-pyrrolo(|2,3-4|-pyrimidine and 80000 Ma r; ve Intermediate compound 2 o- and 189 o. y M iv 4-chloro-6- methyl-7H-

M, pyrrolo(|2,3-4|-pyrimidine its 2 M

KO

SI

Sho:

M Intermediate compound 2 (c) -k m and 282 | - M 4-chloro-6-iodo-7H-pyrrolo|(2,3-8-0-e 9|-pyrimidine

EI e); the same

Example of AZ

Obtaining the intermediate compound 6 is our: l-HO t p o : I o p

OM V ASON, TNE, NYO - zi Moi

U ok - - - - - - --zh- vsny y K ny 5 ny ne: oo y ZM, bo I ud s zho A s

Intermediate compound C ToeOHn, acetone BOS Intermediate compound b

Intermediate C (7.00 g, 14.8 mmol) was dissolved in a solvent mixture of acetic acid, water, and TNE in a ratio of 13:7:3 (100 mL). The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure at 60°C to obtain 6.8 g of crude intermediate compound b together with a by-product. To a solution of the above crude product in acetone (50 ml) was added 2,2-dimethoxypropane (5 ml, 42 mmol) and 4-methylbenzenesulfonic acid monohydrate (13 mg, 0.07 mmol) at room temperature under an atmosphere of Ma". The mixture was stirred at 60°C for 2 hours. The solvent was removed under reduced pressure at a temperature below 30°C. The residue was purified by column chromatography (gradient elution: E(Ac/petroleum ether from 1/10 to 1/3)) on silica gel to obtain the required intermediate compound 6 (3.02 g, yield 34965).

Example A4

Obtaining an intermediate compound of the 7th step and the second step; tu no a a s

V - t M piy TEAE - z Mche nn y o A- - ........ Khan Kk y Z M. ze M DE My r: TE b. Her in 1 ra x y x Koch

Intermediate compound Z Intermediate compound 7

To a solution of intermediate compound 4 (9.50 g, 20.9 mmol) in TNE (82 ml) was added a 1 M solution of TVAE in

TNE (41.68 ml, 41.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness. The residue was taken up in water and extracted with HPLC (150 mL x 2). The organic layers were dried (Mag2504), filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution: petroleum ether/ethyl acetate from 10/1 to 4/1) to give the required intermediate 7 (3.68 g, yield 8896).

The following intermediate was prepared using a reaction protocol similar to that used to prepare intermediate 7 using the appropriate starting materials (Table d).

Coo)

Table 2:

Structure

But -

Oh, it's me xx.

Intermediate compound 5 i a M. M r

Table 2:

Structure no -- o M ro SI 186 M, Intermediate compound 185 th Ma r: no - iv; M si 190 M, Intermediate connection 189 th 5 Mo r;

Example A5

Preparation of intermediate compound 10 no t-

I swarm M kn i "- shchi Kk ter

Ek M. M bo What heaven

Intermediate compound 10

Stage a)

OO 5 and p; kon NO o na he i- -szh Propane-d-at Ba , dust A is si NUMBER of hours not hi your x g "men DK. ; и E s-- 2 pits of 7

MORE ISS, 2 hours Irnomyzhna compound Z

Into a mixture of 4,6b-dichloro-5-(2,2-diethoxyethyl)pyrimidine (14.0 g, 52.8 mmol) and (18,25,38,5H8)-3-amino-5-(hydroxymethyl)cyclopentane -1,2-diol hydrochloride (10.7 g, 58.1 mmol) in propan-2-ol/n2O (208 ml, 7:11) was added EM (13.4 g, 132 mmol) in one portion at 25 C in the atmosphere of M".

The mixture was stirred at 90C for 23 hours. The mixture was cooled to 50°C and 4M HCl (24 mL, 106 mmol) was slowly added. The residue was then stirred at 50 C for 2 hours.

The reaction mixture was cooled to 25C and MansoOz (14g, 100 mmol) was slowly added.

Ethyl acetate (230 ml) was added, followed by the addition of a half-saturated solution of ManHsSoz (a.5.).

The organic phase was isolated, and the aqueous phase was extracted with ethyl acetate (230 ml x 2). The combined organic phase was dried over anhydrous Mo95O»5, filtered and concentrated under vacuum to give intermediate 9 as a yellow solid (17.4 g, quantitative yield in 2 stages). The crude product was directly used as such in the next step of the reaction without further purification.

Stage B)

shk y mo OME y she ra y kr zhk U reze | She Y zh ich I t V SHI SOM O---- x "We are not uk) ; MM inn You as Mo tavOn DE m no 2 N NA IZ. I:

And with-b x

Eh

Intermediate compound Z Prosioevne compound 16

To a mixture of intermediate compound 9 (17.4 g, 52.7 mmol) in acetone (250 ml) was added 2,2-dimethoxypropane (11.0 g, 105 mmol) and T5OH.H2gO (908 mg, 5.27 mmol) one portion at 256 in an atmosphere of M". The mixture was stirred at 60 C for 2 hours. The mixture was cooled to 256 and the solution was concentrated under vacuum, slowly quenched with saturated Mansoze (100 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated saline solution (100 ml), dried over anhydrous MoBzO»4, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient elution: OSM/ethyl acetate 1/0 to 2/1) to give intermediate 10 as a light yellow resin (15.5 g, yield 8990).

Example Ab

The preparation of the intermediate compound 14 ah is m en

VO still

NE ea!: I ryah iiromined compound ІU

Stage vi o Mixture Ki ch shk m h wo y y y Rva tyaz y y (o y Z

From Vy Ovy UM m until ZM Intermediate data K Jhe -th and compound 1Й Vp zhen uh higher 4 i and - ; I am in TNE. -78 es along the ov

Intermediate joint 11

In an oven-dried flask was placed 7-bromo-4-(methylthio)pyrrolo|2,1-CH1,2,)griazine (45.0 g, 184 mmol) and dry TNE (1.20 L) under M atmosphere. The yellow solution was cooled to -787C with the formation of a yellow suspension. n-Wiig (2.5 M, 79.6 mL) was added dropwise to the reaction mixture over a period of 25 minutes at -787C. The reaction mixture was stirred at -787C for 1 hour with the formation of a yellow-brown solution. A pre-cooled solution of intermediate compound 10 (84.0 g, 201 mmol) in dry TNE (800 mL) in another flask (-78"С) was added to the solution under Ma atmosphere. The resulting red-brown solution was stirred at -787С for 1, 5 h. 2 batches were obtained in parallel. The reaction was quenched by adding a saturated aqueous solution of MNACI (300 ml) at -78 "C, and then the mixture was heated to 10 "C. The mixture was extracted with ethyl acetate (500 ml x 3). The combined organic layers were washed brine, dried over Mo95O", filtered and concentrated under reduced pressure. The residue was loaded onto silica gel, then purified by column chromatography (5105, gradient elution: petroleum ether/ethyl acetate from 10/1 to 3:1) to give intermediate 11 ( 149 g, yield 5695) in the form of an orange resin.

Stage B)

Tbumpn Vi 5 what ze

Sumpy goats x Sumi Ki 5 ; 5 y y y y y already ve-Ogi yy

MM, I sya y U v vezh me - -2 2 52 5 zh vu y i en V i yakh ry Sem. ryn mch M

VO 0 bva in 000

НProchizhny compound 31 Hromichny compound 42

To a stirred solution of intermediate compound 11 (74.0 g, 127 mmol) and triethylsilane (59.9 g, 515 mmol) in OSM (1.80 L) was added dropwise VEz.Eg2gO (90.9 g, 640 mmol) at -30-5-20760.

Received 2 batches in parallel. The resulting orange solution was stirred at temperatures from -30 to -20"C for 4.5 hours. The reaction mixture was carefully poured into a saturated aqueous solution of Mansoz (2.5 L) with vigorous stirring (emission of gas). The mixture was stirred for 2 hours. Organic layer was separated and the aqueous phase was extracted with OCM (200 ml x 3). The combined organic layers were washed with brine (500 ml x 2), dried over Mod5O»5, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel , gradient elution: petroleum ether:ethyl acetate: 12:1 to 8:1) to give intermediate 12 as a light yellow resin (125.7 g, yield 8390).

Stage c)

Sumny ikh x Sumy V: 5 iz y kh kh y dk Veaoena K-t p M vve ke Ha va Sche Kan Mt - v M x "v U vm dva Z ba

Lyopminene speluma LI Intermediate 12 1M Vsiz in SNESS (860 mL, 860 mmol) was added dropwise at -78°C to a stirred solution of intermediate 12 (75.0 g, 132 mmol) in OSM (1.20 L) dropwise. for a period of 2.5 hours in a Mg atmosphere. The mixture was stirred at -787°C for 1 hour.

The reaction mixture was slowly heated to -40°C. The reaction mixture was poured into a beaker (2.5 L, 20°C) while stirring. The resulting red solution was stirred for three hours. Water (250 ml) was added to the mixture and left at 20"C for 16 h. The solution was carefully poured in portions onto solid ManHsSoO»z (500 g) with intensive stirring (emission of gas, the color of the mixture changed from orange-red to yellow). The obtained the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned in iRHOH/SNeSi" (1:3, 1 L), then filtered (to remove some inorganic salt) and the filtrate was concentrated under reduced pressure. The residue was triturated with petroleum ether (500 mLx3 ) to give crude intermediate 13 (40.2 g, crude) as an orange solid, which was used in the next step of the reaction without further purification.

From Stage a)

Dryness: 5 "SHY meo OME lk her h eryKe her y

Mol y shi shk ro - A AK. M x B your she NYA yan it and mya ot noi, M 5 Mo ; below, day mk. M

BUT ge Ina TON, acetone them We are evil;

AND

Intermediate compound 13 b

Prozygous compound 14

To a suspension of intermediate 13 (40.2 g, crude) and 2,2-dimethoxypropane (34 mL, 277 mmol) in acetone (600 mL) was added T5OH.H2O (5.92 g, 31.10 mmol, 0.23 equiv.) at 257C (pH - 2). The resulting mixture was heated at 60"C for 2 hours. After cooling to 2570, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 ml) and a saturated aqueous solution of MnSO3 (500 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (200 ml x3).The combined organic layers were washed with saline (100 ml), dried over Md95O4, filtered and concentrated under reduced pressure.

The residue was purified by column chromatography (silica gel, gradient elution:

СНеСиг/ethyl acetate from 10/1 to 6/1). Fractions containing the required intermediate compound 14 were combined and concentrated under reduced pressure. The residue (28 g, purity ca. 8095) was purified again by column chromatography (silica gel, gradient elution: petroleum ether/ethyl acetate: 20/1 to 4/1). The necessary fractions were combined and concentrated under reduced pressure. The residue was diluted with NaCl (15 mL), then petroleum ether/ethyl acetate (4:1, 200 mL) was added. The mixture was concentrated to about 150 mL and the solids were precipitated. The suspension was diluted with petroleum ether to about 400 mL and stirred for 16 hours at 20°C. The mixture was filtered and the solid was washed with petroleum ether/ethyl acetate (20/1, 100 mL). The solids were collected and dried under high vacuum to give the pure intermediate 14 as a white solid (18.6 g, yield 4295 over 2 stages).

Example A7

Preparation of the intermediate compound 15 - КИ о но и па и и и и и и и и и и и и и и и и и и и и и и и и и и и и и и и и и и и и и s o p - ul TovOYI, TEA PMAR | heh - shk i yat Zhim SM, cat, with tod -4 ok bo a ih Mor kh

HProminesny compounds and Intermediate compounds 15

Intermediate 1 (10.0 g, 28.6 mmol), TEA (12 mL, 85.7 mmol) and OMAR (0.70 g, 5.71 mmol) were dissolved in СНо2Си (100 mL). p-toluenesulfonyl chloride (10.9 g, 57.1 mmol) was added at 09C. The mixture was stirred at room temperature overnight. Water (100 ml) was added to the above solution. The aqueous layer was extracted with OCM (100 ml x 3). The combined organic layer was dried over Ma»5O54 and concentrated to dryness

From the state The residue was purified using a flash chromatography column (gradient elution: petroleum ether/E(OAc from 1/0 to 3/1). The product fractions were collected and the solvent was evaporated to give intermediate 15 as a yellow oil (14.5 g , output 97965).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 15 using the appropriate starting materials (Table 3).

Table 3: g -o0 sh- iv 9 i

X Intermediate compound 8 t

K

Table 3:

Structure

In c) there is

ЦИ то от СИ о M y - 17 Х Intermediate compound 10

EE M. M entrance

Example AB

Obtaining intermediate compound 18 also: 35 si -sh o p a Y M. ek ish ChK i M - - MN. х пи Кк и M - т че 7 и M more M MNanNeStokoan NIKN- Z. M re VUS, 24 go re y in Intermediate compound 1 Intermediate compound 18

Intermediate compound 1 (100.0 g, theoretically 307 mmol) was dissolved in 400 ml of 1,4-dioxane. Then 400 ml of ammonia water (based on 28-3095 MNz) was added. The mixture was stirred in a hermetically sealed test tube at 1007C for 20 hours. The mixture was cooled to room temperature. The reaction mixture was evaporated under vacuum to remove half of the solvent.

Water (200 mL) was added and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried and concentrated to give intermediate 18 as a white solid (93 g, yield 9395).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 18 using the appropriate starting materials (Table 4).

Table 4:

Structure no - (0) 19 - M. Yam Intermediate compound 6 b ra si no - (c) - " Intermediate compound 7 zh mno

I XX century

M o iM-X / 283 | -T M Intermediate compound 282 --o H zo

J.

Table 4:

Structure no -- 502-ZO-5- M. am Intermediate compound 10 r:

Example of AZ9

Preparation of intermediate compound 23

VE

But what M. things MN, p DY yo Mam b I re ra 4 Zero-boundary compounds and

I am mature

VE

VE no and vho Gosti y o OH Mne x Ka N (y Y Amiz hi la - rya zna M Shi sche - zi. midchna vode s. Ky i khn IA ny i 80 MZhoyaM OO tTNE vv oietod no ON

About:

Pipolapzhna compounds ki Intermediate compound y

Ammonia (2895 in

NO, bbBml) at room temperature. The reaction mixture was stirred at 1007s (using an autoclave) for 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was placed in water (100 mL) and OCM (100 mL) and stirred for 1 hour. The layers were separated and the aqueous layer was washed again with OCM (100 mL) to remove impurities. The aqueous layer was filtered and the filtrate was evaporated to dryness. The residue was purified by flash chromatography on silica gel (gradient elution: OSM/Meon from 95:5 to 90:10). The necessary fractions were collected and the solvent was evaporated to give intermediate compound 22 (34 g, crude). The crude product was directly used in the next step of the reaction without further purification.

The stage of

LAV Ve

BUT R What no - and where M obi a i - M ooo MN; 1, HYSHAya p DYN no on bod 7 c

Intermediate compound 25

To a mixture of intermediate compound 22 (1.0 g, crude) in acetone (32 mL) was added 2,2-dimethoxypropane (1.78 mg, 14.5 mmol) and 4-methylbenzenesulfonic acid (0.61 g, 3.19 mmol ) in one portion at room temperature. The mixture was stirred at 602C for a while

From hours The mixture was cooled to room temperature and quenched by the slow addition of saturated MnH 2 CO 2 (10 mL) and then extracted with ethyl acetate (50 mL x 5). The combined organic phase was washed with brine (120 mL), dried over Na 2 O, filtered and concentrated under vacuum to give intermediate 23 (0.80 g, crude). The crude product was directly used in the next step of the reaction without additional purification.

Example A10

Preparation of intermediate compound 24

Preparation of irradiated compound 24

New no s: ShK nn PI "MN" z- y KOM sh umy 0 OMEOMA, - i ie sheni In: now; in and TNE, in S i 00 MM ots; And du Y r: well I yah

Radioactive compound 15 Radioactive compound 24

Intermediate compound 18 (10.0 g, 32.6 mmol) was dissolved in TNE (200 mL). Dimethylformamide-dimethylacetal (OME-OMA) (5.84 g, 49.0 mmol) was then added. The mixture was stirred at 60°C for 24 hours. The mixture was cooled to room temperature and the solvent was concentrated under vacuum. The residue was triturated with EtOAc (200 mL) and water (100 mL).

The organic layer was separated, the aqueous layer was extracted with EOAc (200 ml x 1), the combined organic layer was washed with saline solution (50 ml), dried over anhydrous Mag250O»4, filtered and concentrated to obtain the required intermediate compound 24 in the form of a yellow solid substances (10.5 g, output 85905).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 24 using the appropriate starting materials (Table 5).

Table 5

Structure no - -83 M. YAM Intermediate compound 19 bo 00 r: si no -- eru 26 -5Ti M. M Intermediate compound 20 r: no - water 503 --й M. yam Intermediate compound 502 r:Y

Example A11 - th ke; but --o y y y x / KI SCHI y

E Even M. M would Y o o t r even h

BDifferent compound i

Stage a on - and on b shk o. Ai. N: 1 same a TU PD a

MO zt M; 0 tTVomeSy a: s: shi

Ov Mem Imidazole. ГМК а в» Mom

V. E s yah x yah y Ki

Slip compound 15 Irradiated compound and

To a mixture of intermediate compound 18 (88.0 g, 287 mmol) and imidazole (39.1 g, 575 mmol) in OME (300.0 mL) was added TVOM5SII (52.0 g, 345 mmol) in one portion at 0"С in the atmosphere of M".

The reaction mixture was stirred overnight at room temperature. Water (500 mL) was then added and the mixture was extracted with EOAc (800 mL x 3). The organic layer was washed with saline solution (500 ml). Then the organic phase was dried over anhydrous Ma2»5O», filtered and the organic phase was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography on silica gel (gradient elution: petroleum ether/ethyl acetate 1:1). The required fraction was concentrated to give intermediate compound 27 as an oil (120 g, yield 9690).

The stage of

GK -- and -

Te en y 7 P t rya, YOU g I ana already M when I eat che Iv y and Z o. what

GO i tro Vo cmMAv LE UT chiti no i mn nn MN VV OO a M 2 ETVAYE y yo ZheM - yah y х Kk

Irradiated compound 27 Intermediate compound 28

(Voc)2O (13.3 g, 61.0 mmol) drop by drop at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Then a 1 M solution of TVAE in TNE (24.4 ml, 24.4 ml) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 250 ml of water and extracted with ethyl acetate (250 ml x 2).

The organic layer was washed (with water) and saline, dried with Mag250O4 and concentrated to dryness. The residue was purified by flash chromatography (elution:

From ethyl acetate/heptane - 50/50). The required fraction was collected and the residue was stirred in heptane.

The solid was filtered off and dried at rt under reduced pressure to give intermediate 28 (10.2 g, yield 8395) as a solid.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 28 using the appropriate starting materials (Table 23).

Table 23 c: I o -

M

(about) - . 284 52, Intermediate compound 283 o iM-M -T - no -5

EE about p

Example A12

Obtaining the intermediate compound 29 or M B obi M ve M u bidy x i x 7 t SHІ che: raaah u

TMM fat I, MOH wai sha nn en FO r CHYN raya nya M y k BJM. LOBSTER osM m Moya

Piomizhny connection I as

Overwintering compound 2

In the reaction mixture of intermediate compound 24 (15.0 g, 41.7 mmol), EizM (11.6 ml, 83.3 mmol) and

To OMAR (509 mg, 4.17 mmol)" in OSM (200 ml) was added p-toluenesulfonyl chloride (8.74 g, 45.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Water (100 ml) was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with EAs (100 mlx2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Ma»5O»4, filtered and concentrated to give crude intermediate 29 as a brown solid, which was used in the next step of the reaction without further purification.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 29 using the appropriate starting materials (Table 6).

Table 6

The structure that in |! oo - M. new and - Intermediate compound 25

M her with M.M byu zha

Table 6

The structure of what

Sh oo - A

Z o. o. Intermediate compound 26 in glo Moy :h in Z r o o. о 32 О, ам Шче ва Intermediate connection 28 и M sho ino DY va xx? M. em t.k (c) ! o-y in s- moy () and 285 o u r - Intermediate compound 284 o h-y55 My r;

Example A12p5

Obtaining the intermediate compound 32 x va | Ha

Fe TEA, OMA, Shch not and oyu

Sh vi tes pom Bash schi MantsY no sa N z Ya Kok - - --tgei 5 Ukh Ya rya Shin m enki V. x zu i y tu , 4 ek i schi ek shi chu. r ie v Prohyaena compound of them Intermediate compound 32

Intermediate 28 (4.5 g, 8.89 mmol), TEA (2.70 g, 26.6 mmol), OMAR (0.54 g, 4.4 mmol), and OSM (40 mL) were stirred in an ice bath . p-toluenesulfonyl chloride (3.39 g, 17.8 mmol) was added dropwise. The mixture was stirred at room temperature for 5 hours.

The reaction mixture was poured into water and extracted using OCM. The organic layer was evaporated and purified by flash column chromatography on silica gel (eluent: 9895 OSM - 296 MeonN) to give intermediate compound 32 (5.6 g, yield 9590).

Example A13

Preparation of intermediate compound 33

-M --M Tyay - se I li vo ki M he her

M th 7 and essay m t. that on A Deso-Mizrtin mo h o. M. a : ka 0. ey ch-yi gyi che -- 5 ---- - . 2 same XE , I IY ho-I rum Cl

Don't worry; in and

Prominsve svoluka Slippery compounds 33

To a mixture of intermediate compound 1 (2.00 g, theoretically 6.18 mmol) in OSM (40 ml) was added Desso-Martin periodinan (5.24 g, 12.36 mmol) in one portion at 0°C under an atmosphere of M". Mixture 5 was stirred at 0 C for 3 hours. Mag52O3z (4 g) in saturated ManSO3 (20 ml) was added to the mixture and stirred for 10 min. The aqueous phase was extracted using OCM (20 ml x 3). The combined organic phase was washed with saturated saline (20 mL g), dried over anhydrous Ma 5 O 5 , filtered and concentrated under vacuum to give intermediate compound 33 (1.80 g, crude) as a light yellow resin. The crude product was directly used in the next step of the reaction without further purification.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 33 using the appropriate starting materials (Table 7).

Table 7

Structure o m 3 s ban 34 Ek tsi A Intermediate compound 7 1 d- SI

WE

35 -AG M- Intermediate compound 10

X o / XM 4 7 V) 36 lu Manty M Intermediate compound 14

Check more about - more --- . 512 и ш- Intermediate compound 28 c) иТОЯУ. Mashy r;

Example A14

Obtaining intermediate compound 37 o ry BUT still i po, Em vk si MeMmoavg a - uky ShK i z t u -- TNE ---В

EE or I av; and in and as well as the thing

Intermediate compound 34 Intermediate compound 37

MemoVg (1M, 18.55 ml, 18.55 mmol) was added dropwise to a solution of intermediate compound 33 (6.5 g, crude, "15.46 mmol) in TNE (200 ml) at -787С under an atmosphere of M". The mixture was stirred overnight at room temperature in an M atmosphere. The reaction mixture was concentrated under vacuum to give the crude product as a yellow solid. The crude product was purified by column chromatography (gradient elution: petroleum ether/EODdAs from 40:1 to 10:1). The necessary fractions were collected and the solvent was evaporated to give intermediate compound 37 as a light yellow oil (700 mg, crude, and 3 g crude with a large amount of impurities).

Example A15

Preparation of intermediate compound 38

Method 1 rea I posya ry pe eRSNA o Uen pagenovy - tery M ce shchi r M slu M -6-66-6266.6.-O-N ha Me b. re "VK, TE 5 Her x more

Transgenic compound 32 Irradiated compound 38

1-

VOK (11.4 mL, 1 M in TNE, 1.27 g, 11.35 mmol) was added dropwise at 0"C in an M2 atmosphere. The suspension turned bright yellow, and it was stirred at 0"C for 0.5 h, and then heated to 25"C for 0.5 h. The mixture was cooled to -40"C. A solution of intermediate compound 35 (1.46 g, theoretical 4.54 mmol) in TNE (130.0 mL) was added dropwise and then stirred at -207C for 1 h, after which the mixture was heated to 257C for 2 h. Saturated MNASI (300 ml) was added to the mixture and stirred for 10 min. The layers were separated and the aqueous phase was extracted with OCM (300 mL x 2). The combined organic phase was washed with saturated saline (500 mL), dried over anhydrous MobBO:4, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel (IZSOF); 80 g ZeranBiazpe column for flash chromatography with silica gel, gradient elution: 0 to 1595 ethyl acetate/petroleum ether). The necessary fractions were collected and the solvent was evaporated.

Intermediate 38 was obtained as an off-white solid (530 mg, yield 36965).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 38 (Method 1) using the appropriate starting materials (Table 8).

Table 8

The structure of the SHIE

Ito KO 39 EE Mak Intermediate compound 33 r

Table 8

Structure o Shchi ie 40 4 - Ma Intermediate compound 36 o x -X o 513 o Z Intermediate compound 512

Her 70 Masha r:

Method 2 (schi s dk; shi uch tu tr met y eri y z zde shi shi shi te

Test 5.6

Irradiated compound 35 Irradiated compound 45

A solution of intermediate 35 (10.0 g, theoretical 31.1 mmol) in TNE (100 mL) was added dropwise under M2 atmosphere over a period of 30 minutes to a solution of bis(iodozinc)methane in TNE (180 mL, 0 .31 M, 55.9 mmol, obtained according to the procedure described in Teigapeygop 2002, 58, 8255-8262), while stirring was continued until complete conversion (approximately 2 hours). The reaction mixture was quenched by the slow addition of a saturated aqueous solution of MNACI, during which salt formation was observed. Before extraction (E(OASc, 2 x 200 ml), the salts were dissolved again by adding an aqueous solution of ammonia (2595). The combined organic phases were washed with an aqueous solution of sodium bisulfite and brine, dried over anhydrous Ma95zO", filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: dichloromethane/nB(OAc 95/5)) to give intermediate compound 38 as an off-white solid (6.9 g, 6695).

Method C

Stage 1

Preparation of intermediate compound 408 yt-a t i E i. re z xx / k y Ts - a -Ya - hi

Ku o pridsvomato I a ee a Z E z von --o y i: IVI-Mmopornoh /y х

Nitrogen compound 405

Acetylacetonatobis(ethylene)rhodium(I) (0.837 g, 3.24 mmol) and (H)-M,M-dimethyldinaphtho|(2,1-pyr2-A,3,2)dioxaphosphepin-4-amine (2.91 g, 8.11 mmol) was dissolved in EN (6b25 ml) in a nitrogen atmosphere. The mixture was stirred at room temperature and purged with nitrogen gas for 15 minutes. Then (-)-(ZAN,bAN)-ZA,bA-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25 g, 162.16 mmol) and potassium vinyl trifluoroborate (45 .73 g, 324.33 mmol), and then the reaction mixture was stirred and heated under reflux for 4 hours. The reaction mixture (suspension) was cooled to room temperature. The precipitate was filtered through a celite pad and washed with ethanol. Solvents were evaporated from the filtrate. 1 L of heptane was added to the residue. The resulting suspension was filtered through a pad of celite and washed with heptanes to give a dark brown solid residue. The filtrate was washed three times with 300 ml of MNAOH, washed with brine, dried over Moa5O54, filtered and the solvents were evaporated from the filtrate to give intermediate 408 (16.18 g, yield 5190).

Stage 2

Preparation of intermediate compound 409 in !

X be | Oh no; tu NE nn / r 5 Intermediate compound WHOSE Intermediate compound 409

A solution of intermediate 408 (16.18 g, 82.58 mmol) in TNE (200 mL) was added dropwise to a stirred solution of 1 M lithium aluminum hydride in TNE (24.78 mL, 1 M, 24.78 mmol) in TNE ( 400 ml) at -78"C in a nitrogen atmosphere. The reaction mixture was stirred at -78"C in a nitrogen atmosphere for 30 minutes. The reaction was quenched by the dropwise addition of acetone (6.1 ml), and then 50 ml of water at -78"C. After the addition, the reaction mixture was heated to room temperature, and then 400 ml of EtOAc was added. The mixture was vigorously stirred.

The organic layer was separated, washed three times with water, washed with saline solution, dried over Mu9B2O:, filtered and the solvents were evaporated from the filtrate. The residue was dissolved in ethyl acetate and purified on a column with 5 g, type Sgase Kemeiegiz KS, 80 g, 5i 40, on a purification system Agtep roi I Oshtagse using ethyl acetate and heptane as eluent in a gradient starting with 10095 heptanes and ending with 5095 heptane and 5095 ethyl acetate . Fractions containing the product were combined and the solvents evaporated to give intermediate 409 (10.77 g, yield 7190).

From Stage Z

Preparation of intermediate compound 410

And uk 0! and theo M Io sh-- OvSM. Pyridnn ra v. x id c.

Intermediate compounds 409 and

Irradiated compound 418

A solution of TO (13.31 mL, 1.71 g/mL, 80.93 mmol) in anhydrous SOSM (60 mL) was added dropwise to a mixture of intermediate 409 (9.94 g, 53.95 mmol) and anhydrous pyridine ( 85 mL) in anhydrous OCM (140 mL) at 0°C. The reaction mixture was stirred for 30 min and then 75 mL of cold water was added. The layers were separated and the organic layer was washed three times with 75 mL of water, dried over Md5O, filtered, and the solvents were evaporated, and co-evaporated with 200 ml of toluene.

type Sgase Vemeyegiz 5VAS, 40g, 5i 40, on Aptep Zroi I OKitaie purification system using ethyl acetate and heptane as eluent in a gradient starting with 10095 heptane and ending with 5095 heptane and 5095 ethyl acetate. Fractions containing the product were combined and the solvents were evaporated to give intermediate 410 (13.0 g, yield 6790).

Stage 4

Preparation of the intermediate compound 411 nsi shk ily - ME o t sht, s 7 M x "y ! - She. vezh k and remy compound Ch1Y

A mixture of 4-chloro-7H-pyrrolo|2,3-O|pyrimidine (100 g, 651 mmol) and COIV (73.07 g, 651 mmol) in

TNE (1 L) was stirred at room temperature for 45 minutes until a clear solution was obtained. The solvents were evaporated. The residue was ground in OiIRE. The white solids were filtered and dried under vacuum at 30°C to give intermediate 411 (112.6 g, yield 9090).

Stage 5

Preparation of intermediate compound 38

Si and I Fr

X more x D o KU x | Пн ш- в Intermediate compound Ч1Й ш и ка ч, ---Uk 4 и ЦИ е о ME в я в о и рда ra

Intermediate compound 41 Intermediate compound 38

A solution of intermediate 410 (13 g, 41.1 mmol) in OME (50 mL) was added dropwise to a stirred solution of intermediate 411 (7.88 g, 41.1 mmol) in OME (150 mL) at 0°C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. An additional amount of intermediate 411 (1.57 g, 8.22 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours.

The reaction mixture was poured into a chemical beaker with ice and water (0.5 L). The resulting suspension was stirred for 2 hours and then filtered. The residue was washed three times with water and then dried under vacuum at 50°C to give intermediate compound 38 as a white solid (8.75 g, yield 6595).

Example A5bB4

З Preparation of an intermediate compound 433 р: У: вх M Ai MNa No rani I х мя Ж

With vu ge I: oh se ; TNE, TS men - whether | p. biromine compound 35 Intermediate compound 3

A solution of intermediate compound 38 (18.3 g, 57.22 mmol) in a mixture of aqueous ammonia (2595, 100 mL) and

TNE (100 ml) was heated in a sealed metal high-pressure vessel at 110 "C until complete conversion (16 h). The reaction mixture was allowed to cool to room temperature, after which ethyl acetate and brine were added. The two layers were separated, the aqueous layer was extracted once with ethyl acetate The combined organic phases were washed with brine, dried over anhydrous M950»4, filtered and concentrated under vacuum to give intermediate compound 433 as a light yellow solid (17.2 g, 100965), which was used in the next step of the reaction without additional cleaning.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 433 using the appropriate starting materials (Table 24).

Table 24

The structure of oo 487 / | and Intermediate 38

Oh M ih methylamine and well; - uh

M Intermediate compound 39 430 is M methylamine

Kk

Example A16

Preparation of intermediate compound 41 from the regime. t a sy DiIMETHYL-Y1-DIAZO. - - ut OXOPROPYLEOSPHONATE consume it in the shk; i nn nn a i 5 me M - un Y. yo , SHE NN as VK ONE 0 7 y ra

Intermediate compound 33 Intermediate compound 41

A solution of dimethyl-(1-diazo-2-oxopropylphosphonate (1.72 g; 114 mmol) in TNE was added to a solution of potassium tert-butoxide (1.28 g; 11.4 mmol) in TNE (30 ml) at -78"С (5 mL). The solution was stirred for 5 min, and then a solution of intermediate 33 (1.90 g; theoretical 5.87 mmol) in TNE (20 mL) was added. The solution was allowed to warm to room temperature and stirred at room temperature for 15 Water and EtOAc were added, the organic layer was separated, dried over M95O04, filtered and evaporated under vacuum.

The residue was purified by preparative IC (5ION with irregularly shaped grains of 15-40 μm, 80 g OSgase, OSM loading, mobile phase, gradient elution: heptane: 1095 MeonN in

EOAc from 90:10 to 70:30). The required fractions were collected and the solvent was evaporated to give intermediate 41 as a colorless oil (1.08 g, yield 5895).

Example A17

Preparation of intermediate compound 43 i M pekl,

With ; in A M

НОжой М. А ТОГО Noty M. would be yours: В-TVA mae Dy

In ---.---.--- taking TC. I pcs in the same m 5 MM Acetone. Kk t. 0 o Mo nab on z i Uh

Intermediate compound 42 Prominesna speluki 44

To a solution of intermediate compound 42 (9.2 g, 34.114 mmol) in acetone (100 mL) was added 2,2-dimethoxypropane (7.1 g, 68.118 mmol) and p-T5A (1.8 g, 10.184 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water

Manso:z (pH to 7-8), then concentrated under reduced pressure. The obtained residue was diluted with water (100 ml) and extracted with ethyl acetate (100 ml x 3). The organic layer was dried and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (gradient elution: petroleum ether/ethyl acetate from 8/1 to 2/1). The required fractions were collected and the solvent was evaporated to give intermediate compound 43 as a pale yellow solid (9.5 g, yield 9090).

Example A18

Preparation of intermediate compound 44

IN

- M OH M

That's fine. . x g- and mn No

That SRO ZhuU Dese-Martin x-y M and; given M rt nk mon - V v: no sh yaz rem gen M.Ya u Am -- : --e nk-K g. -y ut u- MN, (VO

Z - D y-8-M ENN

Kk sn o-k

OSMIMeSN, who t i

Intermediate compound Y Radiated compound 44 y70b5 during two stages!

zo A solution of intermediate 1 (2.00 g, theoretical 6.18 mmol) in OSM (30.00 mL) was added dropwise to a suspension of Dess-Martin periodinan (3.14 g, 7.41 mmol) in OSM (30, 00 ml) at 0"C under Mg2 atmosphere. The reaction mixture was heated to room temperature and stirred until the oxidation was complete (2 hours). Meon (60 ml) and tosylhydrazide (1.50 g, 8.03 mmol) were then added and stirring was continued. for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic phase was separated and washed with saturated Mg2bOz, dried over anhydrous Mo95O", filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel

(gradient elution: dichloromethane/methanol from 100/0 to 98.5/1.5). The required fractions were collected and the solvent was evaporated to give intermediate 44 as a white powder (2.60 g, yield 7090; (E)).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 44 using the appropriate starting materials (Table 25).

Table 25

Structure 207 oto t Intermediate compound 10 ni M u still Y

HO

Example A55

Preparation of intermediate compound 224

Mekon - about Chaskvi 0 IVAN with Med YAM S tele g y yah Z I yn ce yayu - o What and the nose of the dream NA O 5 eqv), "not TS, 2.5 gad - MAM 0 BRLYa'fyasekvd 5 y Y - byu nnnnazhzhaayaayayeShayaenatnya with

Intermediate compound 222

Intermediate compound 2 rehich compound p-tolusletlphonium ne She ak Ten p- ochi Mey IZ eq) o mA s

Ost t m Z i - t M. shk - MAM MeSNISM, cat, 40 min - ma

Intermediate compound 223 Intermediate compound 224

Stage 1

Preparation of intermediate compound 222

RIAO (7.6 mL, 38.4 mmol, 2.5 equiv.) was added to a solution of intermediate 2 (5.0 g, 15.3 mmol, 1.0 equiv.), triphenylphosphine (10.0 g, 38, 4 mmol, 2.5 equiv) and acetone cyanohydrin (5.6 mL, 61.4 mmol, 4.0 equiv) in anhydrous TNE (75 mL) at rt. The reaction mixture was stirred for 71 h, and then concentrated under vacuum. The crude product was purified by normal-phase flash chromatography using heptane and OSM as eluent (column

ZO", gradient: from 5095 to 10095 SOCM, isocratic 10095 OSCM), followed by preparative reversed-phase flash chromatography using acetonitrile and water with 0.295 MNANSO" as eluent to give intermediate 222 as a white solid (2, 8 g, 8.5 mmol, yield 55965).

Stage 2

Preparation of intermediate compound 223 and intermediate compound 224

A solution of intermediate 222 (1.54 g, 4.6 mmol, 1 equiv) in anhydrous OSM was dried overnight over molecular sieves and filtered. The filtrate was cooled to -78°C, and then 1 M RIVAN in OSM (4.6 mL, 4.6 mmol, 1 equiv.) was added dropwise. The reaction mixture was stirred for 1 hour at -78°C, then additional 1 M OSIVAN v

OSM (0.46 mL, 0.46 mmol, 0.1 equiv.) and stirred for another 1.5 h, then quenched with sodium acetate (4.2 g, 51.2 mmol, 11.1 equiv.) and acetic acid (4.2 mL, 73.4 mL, 16.0 equiv.) in a mixture of water/TNE (57 mL/12 mL). After quenching, the cooling bath was removed and the mixture was stirred until all the ice had melted. The layers were separated, and then the aqueous phase was extracted twice with SOCM (30 mL). The organic phases were combined, washed twice with saline solution, dried over M950O5 and filtered. Meon (50 mL), p-toluenesulfonyl hydrazide (1.1 g, b.0 mmol, 3 equiv.) were added to the resulting filtrate, which contained intermediate compound 223, and then stirred at r.t. within 40 minutes. The reaction mixture was washed three times sat. ManNsSoO»z, twice with brine, dried over Movo, filtered and concentrated under vacuum. The crude product was purified by normal-phase flash chromatography using heptane and EIOAc as eluent (gradient: 4090 to 6095 EIOAc) to give the crude product. The mixture was further purified by normal-phase flash chromatography using EtOAc and heptane as eluent (5uO column, gradient: 4095 to 6095 EIOAc) to give intermediate 224 (0.5 g, 0.6 mmol, yield: 1496).

Example A19

Obtaining an intermediate compound of 45 em

KOH hek and; Ki no et, ma nych z-sh py ka, Ai U ru

Ko y Mik dk Mov po i x 7 u , -sh t o o na y Y she u M. sb g! Yam RRyechroi, IA, TE, De on 7 kt.

Intermediate compound C Intermediate compound 45

Intermediate 1 (300 mg, theoretical 0.921 mmol), 7-quinolinol (160 mg, 1.11 mmol) and polymer-bound triphenylphosphine (triphenylphosphine loading -3 mmol/g, 0.8 g, 2.4 mmol) was stirred in anhydrous TNE (12 ml) under a Mg atmosphere. BIAOO (0.465 g, 2.30 mmol) was then added dropwise at 0°C. The mixture was stirred at room temperature for 12 hours under M atmosphere. The reaction mixture was filtered through a pad of diatomaceous earth. The residue was washed with MeonN. The filtrate was concentrated under vacuum. .

The residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 10/1 to 3/1). The necessary fractions were collected and the solvent was evaporated from

To give crude intermediate 45 as an oil (342 mg").

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 45 using the appropriate starting materials (Table 9).

Table 9

Structure

Ma oi y 46 o s a) Intermediate compound 1

M Zk r) 7-isoquinolinol

EE or r:

Table 9

Structure

H

M - SI 9 o g a) Intermediate compound 1 47 r) b-hydroxyquinols -tT M m ) b-hydroxyquinoline

WITH

M ho o - z a) Intermediate compound 1 48 and p) Z-hydroxyquinoline Ma

Kk

M

/ In (c) o lot a) Intermediate compound 1 49 od Zk a B) 8-hydroxyisoquinoline

Y ovo ve -M "UZ, - en (o) M si a) Intermediate compound 1 5O ! y: p) 1,5-naphthyridin-3-ol

RN

Be -km (o) M si a) Intermediate compound 1 51 t and p) b-quinoxalinol

EE or

Kk - s! t o -u i )p 1 m a) Intermediate compound z2 X-k Na My r) Quinazolin-7-ol z o r: - si / o lu a) Intermediate compound 1 y, Y dust

BZ sk -T shi c). 2-(trifluoromethyl)-quinoline-7

E B is ra

Table 9

The structure si -sh8- si ge) o Okh

BA in -7 and a) Intermediate compound 1

M as p) 4-chloro-7-hydroxyquinoline

E o r: - SI (o) grandfather M a) Intermediate compound 1 55 -m Y M B) Z-chloroquinolin-7-ol

ТК с -- си их 9 о Ох a) Intermediate compound 1

Bv dev CHI -7 i-th p) 4-chloro-7-hydroxyquinoline-3-

M - carbonitrile si -- si o a) Intermediate compound 1 57 m--I stich B) 4-chloro-7-hydroxy-6- -k -yU Me methoxyquinoline-3-carbonitrile

Me si -- si

BV / x Kk o i a) Intermediate compound 1 shshch -T Ma B) 4-chloro-6-methoxyquinolin-7-ol a -8-si o dya de a M, a) Intermediate compound 1 59 -ki | M p) Z-bromoquinolin-7-ol

So "Mch si

M -Ou and She a) Intermediate compound 34

And M. 2 r) 7-quinolinol in o -

Msi 187 Si oo a) Intermediate compound 186

Mio, Mod im r) 7-quinolinol

Table 9

The structure of --

M si 194 GO a) Intermediate compound 190

M TT M CI B) 7-quinolinol p: -8- si o shchi / u / o i M, a) Intermediate compound 190 233 --k -u scho p) Z-bromoquinolin-7-ol 4

Example A19r

Preparation of intermediate compound 59 - SI / o (c) M in X

Vg M -k | Me a

Diisopropyl azodicarboxylate (0.221 mL, 1.125 mmol) was added dropwise to a stirred suspension of intermediate 1 (0.27 g, 0.80 mmol), 3-bromoquinolin-7-ol (0.18 g, 0.80 mmol), and triphenylphosphine resin (0.375g, C mmol/g, 1.125 mmol) in TNE (8ml) at room temperature. After addition, the reaction mixture was stirred for 18 hours. The reaction mixture was filtered through an Oisaille pad. The residue was washed with methanol. Solvents were evaporated from the filtrate. The residue was used as such in the next stage.

Example A20

Preparation of intermediate compound 61

AND

-oh sly no 0 scher ryi De to Go Pr a rana M. rya m a deku de - Ka 7 i sht Gh i KN t V y y - M -e ОН - p y pu y y x po zh ni chn chi | | oh and I'm ER. BIAD, TNE r:4 , Prolapsed compound ai

Intermediate compound Y Y

A mixture of intermediate 1 (2.46 g, theoretically 7.54 mmol), 2-methylquinolin-7-ol (1.2 g, 7.54 mmol) and PPIz (5.93 g, 22.6 mmol) in dry TNE (40 ml) was stirred at room temperature in an atmosphere of Mg2. OIAO (4.57 g, 22.6 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. Water (80 ml) was added to the mixture, extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution:

EtOAc/petroleum ether from 1:20 to 1:1). The necessary fractions were collected and the solvent was evaporated to give intermediate compound 61 (3.0 g, crude). The crude intermediate 61 was used in the next step of the reaction without further purification.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 61 using the appropriate starting materials (Table 10).

Table 10

Structure

MK o - a) Intermediate compound 1 62 or p) 5-quinolinol; Zv

EN KO, r;

M

U. - a) Intermediate compound 1 63 OM SI B) 5-isoquinolinol " and:

RCHR

Who am I?

Mo -- . a) Intermediate compound 1 b nn p) 8-quinolinol

AND! I'm sorry

She:

M

U. (9) -3 a) Intermediate compound 1 65 b) b-isoquinolinol

M

EE My x de (6) zm" od s a) Intermediate compound 1st de B) 1,8-naphthyridin-2-ol

GO ze o. am We a) Intermediate compound 1 67 a А B) 2-chloroquinolin-7-ol «о MM in

Table 10

Structure

E e yi - shi I oyu. mm c a) Intermediate compound 1 -y Ya p) 3-(trifluoromethyl)quinolin-7-ol and My

Kk

SH in

M iv) -- a) Intermediate compound 10

M B) 7-quinolinol

Zh SI i a Y xx Mem

In Y o o | m a) Intermediate compound 14 70 / m- p) 7-quinolinol -M ECON no - that Zm o . a) Intermediate compound 1 515 o o p B) 7-hydroxy-2-methyl ester

M si quinoline carboxylic acid

KI |! 7 re M ladies

Example A21

Preparation of intermediate compound 71

But in U, Se Shsh. The purpose of Z uiph i Ka: N o Key o ie actions, vk y v Kk x Y tutu on - U

Hek y y Y r SMR. toluda v v Prominsna compound Y Prochinena spedukia 71

To a solution of intermediate 1 (1.00 g, 2.92 mmol) and 2-naphthol (463 mg, 3.21 mmol) in toluene (30 mL) was added SMVR (1.15 mL, 4.38 mmol). The solution was heated at 807C for 18 hours and then cooled to room temperature. The reaction mixture was evaporated in vacuo. The residues were purified by preparative IS (5ION with irregularly shaped grains of 15-40 μm, 120 g of Sgase, OSM sediment, mobile phase gradient: heptane/B (OAc from 80/20 to 70/30) to obtain intermediate compound 71 in the form of a colorless resin (1.00 g, output 76965).

Example A22

Obtaining the intermediate compound 72 rya 7, re Mnjah Uh, roya h i se. dn « ato uki and ne Nai Mashe st M and M, ov My

YAM AMS pry ich; KYA and и ех ех OK

CHA hmm RR, in I M. sm a tea SEC, more

Ye M TME, Kk. i.e

Ah

Irradiated compound 24 Irradiated compound 74

A mixture of PP: (9.07 g, 34.6 mmol) and OEAO (4.82 g, 27.7 mmol) in TNE (100 mL) was stirred at room temperature for 10 min. Intermediate compound 24 (5.0 g, theoretically 13.8 mmol) was then added, followed by 2-chloroquinolin-7-ol (2.98 g, 16.6 mmol). The resulting mixture was stirred at room temperature overnight. Then the mixture was diluted using

ES (100 ml), washed with water and saline. The organic phase was dried over

Ma?5O", filtered and concentrated. The residue was purified by chromatography (elution: petroleum ether/EIOAc - 5/95). The required fractions were collected and concentrated to give intermediate 72 as a solid (6.0 g, yield 8390).

Example A23

Preparation of intermediate compound 73

It’s the same way, tsnya she ve JAK ni M, I We sh «e TO pk and would TNE, k. t. yat I Mem

And yah with brochizhny compound 24 Uh

Rinsing of snoluka 73

To a solution of intermediate 24 (700 mg, theoretical 1.94 mmol) and 4-methylquinolin-7-ol (370 mg, 2.32 mmol) in TNE (20 mL) was added triphenylphosphine (624 mg, 2.71 mmol) and OVAO (711 mg, 2.71 mmol). The mixture was stirred overnight at room temperature and then evaporated under vacuum. The crude product was purified by preparative IS (5iOH with irregularly shaped grains, 15-40 μm, 50 g, MegsK, dry loading (SeiYieFf) mobile phase gradient: from 8095 heptane, 18950 EOAc, 296 MeH to 1095 heptane, 8195 EHAc, 995 MeO) to give intermediate 73 as an off-white foam (697 mg, yield 67905).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 73 using the appropriate starting materials (Table 12).

Table 12

Structure

SSO

WITH.

M (o) 7A o she a) Intermediate compound 24

M m i r) 6-iodhinolin-7-ol i sh |! At o b M M r; zi

Table 12

Structure from the west,

M (9) . o -- a) Intermediate compound 24 75 Mi I B) 8-methylquinolin-7-ol

My thoughts:

Roche et al

M (o)

I (c) and a) Intermediate compound 24 16 M m. p) 8-iodhinolin-7-ol directly

M ge) she a) Intermediate compound 503 504 Mi I . . and B) 3-chloroquinolin-7-ol

KU y y and Z - r. 4 yh? m se) and a) Intermediate compound 24 (Fe) - zhk . 517 M | p) methyl ester of 7-hydroxy-2-d-- pk: Mi quinolinecarboxylic acid b A M p: pass

Example A24

Preparation of intermediate compound 77 - Shshh o she xx

Ya le-a pk, Vo si E. vrya o shi v still; Her -th shchi m and i: in s shchi 7 for is ZM dya ZON UM i yo Mam - 4 4 A -- m ne I SeSO, OM, Kk. t. KO -

ZhK svo, OME, o

Intermediate compound 17, - 5 Hreol intermediate compound 77

Cesium carbonate (2.18 g, 6.70 mmol) was added to a solution of intermediate 17 (1.15 g, -2.23 mmol) and 3-bromoquinolin-7-ol (0.5 g, 2.23 mmol) in OME (25 ml). The mixture was stirred overnight at room temperature. The reaction mixture was treated with H2O (100 mL) and filtered. The resulting residue was washed with H2O (30 mL) and dried under reduced pressure to give the required crude intermediate 77 as a pale yellow solid (1.1 g).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 77 using the appropriate starting materials (Table 13).

Table 13

Structure

IS

/ (9) ох св) M SI 78 -m M: a) Intermediate compound 16 i-i | p; B) 7-quinolinol p:

YES o

NM M (c) 262 o ex a) Intermediate compound 15

M oo r) 2-amino-7-hydroxyquinoline b r: M. lem

XX

- ny Mie) 264 o ne a) Intermediate compound 15 and p: si Yur) Intermediate compound 263

Y X MM in - nm M (in)

Gee! n- a) Intermediate compound 15 270 M Br) 7-hydroxy-M-methyl-2-

KU! Sac quinolinamine

XX M. lem ev

C, so m o 275 (c) where a) Intermediate compound 15

M. S. Yur) Intermediate compound 274

With xx M, lem

Table 13

The structure of the

XX

- d

SI M (o) n-- a) Intermediate compound 17 461 Mi B) 2,3-dichloro-7-quinolinol

Hu rosha vv

C yes M o 463 ee a) Intermediate compound 17

M udo Yur) Intermediate compound 274

SDN I

J. M. em

Fe y: what a) Intermediate compound 17 466 MB B) 7-hydroxy-M-methyl-2- y o: СО |quinolinamine

HO

SI and in

M M |) 469 sot a) Intermediate compound 17

Ф Ф АХ p) Intermediate compound 468

SON xx M. lam

Ve.

KAH xx

НМ M (c) 478 (o) poh a) Intermediate compound 15

M s r) Intermediate compound 477 ! xx "FI x M. lem

Table 13

Structure

Ve. и ее нМ M (c) river a) Intermediate compound 17 484 Mi .

U) Intermediate compound ! xx SI b dO

Example A25

Obtaining the intermediate compound 79 r (az chn che shin ya nn ya she | A writes t | th 53 Me Kr m v M ha chn an y Ga dav nn -k hnya 00 de ate U / і- і - fO rik y em - m-y r. M.M. SeosSoz, ME ee:

Zh k...a hod koh

Intermediate compound 29 Intermediate compound 79

To a solution of intermediate compound 29 (500 mg, crude, 0.67 mmol) in OME (20 mL) was added

3-Methoxyquinolin-7-ol (187 mg, 0.80 mmol) and C52O3 (652 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was quenched with water (80 mL) and extracted with OCM (50 mL x 3). The organic layers were dried (Mag5O54), filtered, and the solvent was concentrated in vacuo to afford crude intermediate 79 as a yellow oil (650 mg).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 79 using the appropriate starting materials (Table 14).

Table 14

The structure of the office

M He) and a) Intermediate compound 29 in She I p) Z-fluoroquinolin-7-ol and ua ho M. M

EzS

She

ХМ о - и a) Intermediate compound 29 81 M ory tr) 5-(trifluoromethyl)/quinolin-7-ol her M. M

KO

Table 14

Structure

KE

IS

' V o shk m Mo a) Intermediate compound 29 82 M v - p) 6-"trifluoromethyl)quinolin-7-ol

ZK

M

M SI c to - 2 I a) Intermediate compound 29 83 krim and p) 8-chloroquinolin-7-ol

E 2 M ikh y

SI part a) Intermediate compound 29 c st o tt i, Br) 3,4-dichloroquinoline-7-olva Morite (which was obtained from 3,4-dichloro-7-y methoxyquinoline)

EE M. yam

Residential complex

Ma

M i) o more a) Intermediate compound 29 85 M I B) 7-cinolinol i Ho py xx M. lem

THEN

WITH,

M (0) - o sh- a) Intermediate compound 30

M I B) Z-chloroquinolin-7-ol ia Pe My xx y

SI stories

WITH.

M (o) I o c- a) Intermediate compound 30 87 M I p) 3-bromoquinolin-7-ol kr l av i o A B M

Go) 2-2 M her week

WITH.

M (in). a) Intermediate compound 31 88 o, am I p) Z-bromoquinolin-7-ol

Table 14

Structure

SI

WITH

I

M (o; (c) poh a) Intermediate compound 29 199 M che and p) b-chloro-7-quinolinol

SN I ZrozAkh x M, sem

Example A26

Preparation of intermediate compound 89

S M. B kt i Wei Sho Eh; She t i o kv ke Her ah vu to v hi vu ov ey He ON m ia I z lk i sd KE: Mem v. 7 , - land that ke

Y Svysom, ME, cat. 3 p.m., no, no

Praomninesna snolukia 32 What

Intermediate compound Ya

Intermediate compound 32 (48.3 g, 67.99 mmol) was dissolved in 400 mL of OMERE. 7-B-quinolin-7-ol (16.03 g, 67.98 mmol) and C 52 CO 3 (44.33 g, 135.97 mmol) were added to the reaction mixture and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 1000 ml of cold water and extracted with EAs (2 x 600 ml). The organic layer was washed with water (300 mLx2), dried over anhydrous Mag25O:, filtered, and the solvent was concentrated under vacuum to give crude intermediate 89 (52 g) as an oil, which was used in the next step without further purification.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 89 using the appropriate starting materials (Table 26).

Table 26

Structure

SI in

Hg. s oi 0 o t vy a) Intermediate compound 32 201 2 he M more) and

M | skh va Yur) Intermediate connection 200 me es tk

Also at 0 206 | r o o t o a) Intermediate compound 32

Intermediate compound 205

SI yo M. mm tk

Table 26

Structure

Co

S ve 2 211 M Ch o p p i a) Intermediate compound 32 ch) (v r) Intermediate compound 210 pe two

I and tk

OKH Russian Federation 213 х 5 a) Intermediate compound 32 and Ga re Yur) Intermediate compound 212 хо

IS

T-- -y xx Go) o

AH o 215 M o o - a) Intermediate compound 32 -uU ke | p) 4-(trifluoromethyl)-7-quinolinol

And r. them ve

Y Y , ve -shSHSH-E 217 of o a t o a) Intermediate compound 32

M is (with va 5) Intermediate compound 216 me s tk

SI

- iso: Che

M (o) (o) o .

SI o p a) Intermediate compound 32 219 -ah o B) Intermediate compound 218

SN I re M dl y si so zYa

AK) 294 Mochiva a) Intermediate compound 32 schu y Z tre r) Intermediate compound 220a reagent

Table 26

The structure is

CO

C y o o a) Intermediate compound 32 (c; 227 from lx p) 4-methoxy-7-quinolinol

M o sht x b: Ki vo r: de te (o) to - -ch kn a) Intermediate compound 32

M (o) - . 228 o to p) methyl ester 7-hydroxy-3-

AH of quinoline carboxylic acid; With Fr

SAN! re M. lem g Kk codes I . and 230 СХ, о т о a) Intermediate compound 32

Mo Uva r) Intermediate compound 229 Yah Mu ok what

Its - about 292 syu about 0's a) Intermediate compound 32

M -u ke o-4- B) Intermediate compound 231 her My x as y ve o - (c) a) Intermediate compound 32 236 rah o r) Intermediate compound 235 3 in ey o, 5 M M (c) your nave их I s (Fe) (c) o 244 o re o a) Intermediate compound 32 ! with va B) Intermediate compound 240 and Mt t

Table 26

The structure o7 o.

WITH,

M and F) in a) Intermediate compound 32

Short circuit 5. 247 ЖВ-М у» 5) Intermediate compound 246 o)

M Their M

X-ki u-o x

DAH that with tk M o 7 279 oh va a) Intermediate compound 32 g br B) Intermediate compound 274 oz

M

AND

IF) Ge) - (o) by a) Intermediate compound 285 286 tri o B) 7-hydroxyquinoline in GI r: xx o

Example A27

Obtaining an intermediate compound of 90 td, "oh oh and oh and oh!

Still pe -v tu t G y r i: shh nyshe shi an o i tih

TU 000 Mah i a M ee ved om dome what mozh

ХХ oh se b. GU -th

Virological compound 1 X them

Intermediate compound ZO

A mixture of intermediate 15 (893 mg, 1.68 mmol), 7-quinolinthiol (1.6 g, 3.374 mmol, crude), and C 52 CO 3 (1.21 g, 3.72 mmol) in OME (20 mL) was stirred for overnight at room temperature. The reaction was quenched with water (100 ml). The aqueous phase was extracted with ethyl acetate (200 ml x 2). The combined organic layer was washed with saline solution (100 ml), dried over Mag5O". and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution: petroleum ether/ethyl acetate 100/0 to 1/1) to give the desired intermediate 90 (170 mg, yield 2095) as an off-white solid.

Example A28

Obtaining an intermediate compound 91 chnu a o la Agyun, is Shto k. ; - y - 535353 - - - em M, daytime

ETT M. em mavnioest SON. - m i, oo and rem va

Prominent compound 33 Prolyzny enolka ZI 7-Aminoquinoline (Al-MNe in the scheme above) (700 mg, 4.85 mmol) was added to a solution of intermediate compound 33 (2.20 g, theoretically 6.80 mmol) in SOSM (45 ml) and acetic acid (278 μL, 4.85 mmol). The solution was stirred for 10 min, then sodium triacetoxyborohydride (2.98 g, 14.1 mmol) was added and the mixture was stirred at room temperature for 18 h.

A saturated aqueous solution of Mansoz was added and the mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted using HPLC. The combined organic layers were dried over Mo950O5, filtered and evaporated under vacuum. The residues were purified by preparative IS (5iION with irregularly shaped grains of 15-40 μm, 80 g of Ogase, mobile phase gradient: from 10095 OSM to 9595 ЮСМ, 595 MeonN) to obtain intermediate compound 91 in the form of a yellow oil that crystallized upon settling (1 ,22 g, output 56905).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 91 using the appropriate starting materials (Table 15).

Table 15

Structure of chn some 9 em shay duv a) Intermediate compound 33 x / | p) Z-chloroquinolin-7-amine 500 liters

MH day in (s) M s a) Intermediate compound 33 93 and | r) Z-bromoquinoline-7-amine and Mag M r:

Mn dens sese di (c) M s a) Intermediate compound 34 94 y | p) Z-bromoquinoline-7-amine I EE M with them r:chy

МН пи в M s a) Intermediate compound 35 95 and | r) Z-bromoquinoline-7-amine i Mach M r:

Example A29

Obtaining intermediate compound 96 is not. Kene in the same -- Khs a SHY per "NN zha, "n u m le y

TU x ked t p I su i rya y lya y dnu - vn: to her Mish, no. both in m em mne en y x -M MMZ Z хШ0Й ИЧ х у я I y rya she

IPrykmimena sysluka 53 Premeneni compound 96

To a stirred solution of intermediate 93 (1.0 g, 1.88 mmol) in OME (20 mL) was added Mann (6095 dispersion in mineral oil) (0.151 g, 3.77 mmol) at 0°C under a nitrogen atmosphere. Then the reaction mixture was stirred at room temperature for 30 minutes. Then CH3 (0.141 mL, 2.261 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched by pouring it into a beaker with ice and water under a nitrogen atmosphere. Precipitation was filtered to give the precipitated industrial compound 96. The remaining product was extracted from the aqueous layer with ethyl acetate. The separated organic layer was combined with the precipitated industrial compound 96 and then dried over Md5O»4, filtered and the solvents evaporated from the filtrate. The residue dissolved in ethyl acetate and purified on a column of 5iO2, type Sgase Kemeigi5 ZKS, 40 g, 5i 40, on a purification system Sgase Kemeigi5 X2, using heptanes and ethyl acetate as eluents in a gradient starting from 10095 heptanes to 10095 ethylacetate daddy Fractions containing product were combined and the solvents were evaporated to give intermediate 96 (0.51 g, crude). This intermediate compound was used in the next step of the reaction without further purification.

The following intermediates were also prepared using the same reaction protocol used to prepare intermediate 96 (Table 27).

Table 27

Prom. co. Structure Source materials

M

N - o ,/ M o. M. H

VG M I 195 shsh -t we Intermediate compound 93 4 y / - o / M (9) M x

Hg. M: 196 g -tT schu, Intermediate compound 93 4

An example of AZO

Obtaining an intermediate compound 97 thing

Ts Fk A TU D

U, Y Di i: i zhh UNI i NO shchi vi OM mo RZHOAOYU. RIRBA and De ЧІ thing і More - In uk day Зх шкі ренния А чі ; countries in the EU, Ukraine, and Ukraine

Their I

Irradiated enolukia 35 Other compound 97

A mixture of intermediate 38 (520 mg, 1.60 mmol), 7-bromoquinoline (390 mg, 1.87 mmol) and

ECMCI (261 mg, 1.79 mmol) in UOME (15.00 mL) was degassed under vacuum and purged with Me three times. OIEA (1.05 g, 8.15 mmol) and RY(OAcS)" (54.9 mg, 244 μmol) were added to the reaction mixture. The mixture was stirred at 100"C for 16 hours. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic phase was dried over anhydrous M95O".5, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel (IZSOF; 12 g column for flash chromatography with silica gel zeraniazpF), gradient elution from 10095 OCM to 2595 ethyl acetate in OCM) to give intermediate 97 as an off-white solid (670 mg, yield 9190; (E)) .

The intermediates in Table 16 (all in the E-configuration) were prepared using a reaction protocol similar to that used to prepare intermediate 97 using the appropriate starting materials (Table 16).

Table 16

The structure of a-MU - chassis mk mya schi a) Intermediate compound 38 p) 7-bromo-3-chloroquinolin t O00oy-ne x a- m --- s X (F) M si .

M () XX a) Intermediate compound 39 - May p) 7-bromo-3-chloroquinoline x o /Y y Z--

B i ) Promi 40 x a) Intermediate compound

E / M 100 | ke I and i. We p) 7-bromoquinoline

Example of AZI1

Preparation of intermediate compound 101 sho. in u e Zk kut "Be ii ob b o u ts sho sh ich ve t M Shu ZNM

K- v EUonogashnra shk ion ov yoya y a Seas

Intermediate 41 Intermediate 101

In a sealed tube, bis(triphenylphosphine)palladium(!I!) dichloride (79.0 mg; 113 μmol) and copper(I) iodide (21.4 mg; 113 μmol) were added to a solution of 7-bromoquinoline (468 mg; 2 .25 mmol) in 2-methyltetrahydrofuran (8 ml), previously degassed with Mu".

The reaction mixture was degassed with M2 and EtM (1.25 mL; 9.01 mmol) was added followed by intermediate 41 (1.08 g; 3.38 mmol) in (4 mL). The reaction mixture was degassed with Me, then heated under reflux (807С) for 18 h. After cooling to room temperature, the crude product was partitioned between Eas and Ngo.

The aqueous layer was separated and extracted with EA. The combined organic layers were dried over Mo950O5, filtered and evaporated under vacuum. The residues were purified by preparative (C (5UOH) with irregularly shaped grains of 15-40 μm, 50 g Megsk, OSM loading, mobile phase gradient: from 8095 heptane, 2095 EtOAc to 5095 heptane, 5090

EOAc) to give intermediate 101 as a pale yellow oil (304 mg, yield: 27905).

Example of AZ2

Preparation of the intermediate compound 102 p

Notes Hebrew her and t y ho t M M o. y y y M is sh re: SVO ME ri yah

Irradiated compound 43 Irradiated enoluka 182

To a solution of intermediate 43 (100 mg, 0.323 mmol) and 7-(bromomethyl)quinoline (117 mg, 0.387 mmol) in OME (3 mL) was added Mann (117 mg, purity 8095, in mineral oil, 1.615 mmol). The mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated aqueous MNACI (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with H2HO (25 mlx 3), dried over anhydrous Mag5O4 and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (petroleum ether/ethyl acetate - 3/2) to obtain intermediate compound 102 as a colorless oil (50 mg, purity 9195, yield 3595).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 102 using the appropriate starting materials (Table 17).

Table 17

Structure

M y --

Xia M SI y х y a) Intermediate compound 43 102a EE M p) 6-(bromomethyl)quinoline

RI t- si ss ex

ХМ a) Intermediate compound 43

M

1020 of them E a -y p) 6-(bromomethyl)isoquinoline verification 333 U i o: h a) Intermediate compound 43 o to SAN ! rYu) Intermediate compound 332 ra x M dak

An example of AZZ

Obtaining intermediate compound 103 ran m x-x; i Ran g do

I shi ih i zh zhk CHI she E i in N ia Manny I: y KE pryu Z, v-on DU v-y dk rom na Chi T

Nm M posy Y , what am I,

Shin-t Goh

NV zhi, Lvaksano, Her ezschYa in M

Residential complex ah! ! Also Pronien compound 103

Intermediate sleeper Ya

Potassium carbonate (507 mg, 3.67 mmol) was added in one portion to a solution of intermediate 44 (600 mg, 1.23 mmol) and quinolin-7-ylboronic acid (254 mg, 1.47 mmol) in dioxane (15 mL). .

The reaction mixture was stirred at 90"C in a Ma atmosphere for 2 hours, after which the mixture was cooled to room temperature. Then ethyl acetate was added, the organic phase was washed with saturated Mag2SbOz and saline solution, dried over anhydrous Mo95O»54, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: heptane/ethyl acetate from 100/0 to 40/60) to give intermediate 103 (100 g, yield: 19965).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 103 using the appropriate starting materials (Table 28).

Table 28

M si , xx Intermediate compound 207 and 197 KA 7 I! M 2g-naphthaleneboronova

Zh -yuya acid

M si

Me Intermediate compound 207 and 208 M (7 I! M isoquinoline-7-boron

Her 2 yr

Ge) o -h acid

In H

M--

X - (Fi o My X Intermediate compound 224 and 225 M isoquinoline-7-boronic - Ma acid 4

Example of AZ4

Obtaining intermediate compound 104 ee K obslu 3; Y ay M iad yah ok ped Y sh

S Shchi v - Zyt TO Bek

SIM, same MNunyu, dioxane sutures uch y Strike iztoio HY gy y y Mem for tod I still M. M y I y yah y

Intermediate compound 45 Intermediate compound 184

Intermediate 45 (350 mg, crude, 0.626 mmol) was dissolved in 5 mL of dioxane. Then 5 ml of MHz.HgO was added. The mixture was heated in a hermetically sealed tube (autoclave) at 590°C for 12 hours. The mixture was cooled to room temperature. The solvent was concentrated under vacuum to give crude intermediate 104 (300 mg) as a yellow oil.

Example of AZ5

Preparation of intermediate compound 105

Ku t MN. g ugoh : z Where 5 uv and tA shchi J b that -O-k and v. shi lk MY: she i i i M v- mk vom what Ney h shsh ki shchi 7 but ZHNI: in MO, M ik sho che V ze Z i 5

EN. Inc., Z to; li 0.3 sha o rad:

Intermediate 59 Intermediate 105

The crude intermediate compound 59 (d.5., theoretically 0.83 mmol) was dissolved in 7 M Mnz in meon (20 ml, 7 M, 140 mmol). The resulting solution was stirred and heated at 1307C using microwave radiation for 2 hours. The solvents were evaporated. The residue was dissolved in dichloromethane and purified on an Ogase Kemeigi5 5KS, 12 g, 5i 40, 5iO2 column on an Ogase Kemeigi5 X2 purification system using dichloromethane and methanol as eluents with a gradient starting from 10095 OSM for 20 column volumes to 2095 MeOH and 8095 OSM for 20 column volumes. The product-containing fractions were combined and the solvents evaporated to give crude intermediate 105 (175 mg), which was used as such in the next step of the reaction.

Intermediates from Table 18 were prepared using a reaction protocol similar to that described in AZ4 or AZ5 using the appropriate starting materials (Table 18). Intermediate compounds 136, 137 and 138 were obtained in the E-configuration.

Table 18

Prom. : . . spol Structure Links Source material

MN"

M M M o x l/ 106 o M AZA Intermediate compound 62 o o 5-

Table 18

M

,/ Z dl MN" o o. z m 107 X SHU AZA Intermediate compound 63

E ke shk

M

/ x o o -6 108 u" and AZA Intermediate compound 49

РН ве / и ш- Mne 109 - T х АЗА Intermediate compound 64

E ke shk so, o M MN» 110 s | AZA Intermediate compound 71

R NI r: )

Mo 9) - 111 -u c МН» AZA Intermediate compound 48

AND

ER

Kk

Table 18

H

M - MN" about about. UNTIL. not 112 AZA Intermediate compound 47 -Т У; romyzhna compounds

She

M u

HF) - 113 neon AZA Intermediate compound 65

AND

computer

J

M-x and x romy compound 114 i / Kv AZA Promi 46 i Mi

I

-k va she m-- o M Mn 115 th: AZA Intermediate compound 50 vomu ve

I-A-k! in U--o -- (is; M МН» 116 ! M: AZA Intermediate compound 51 i My

Residential complex

- MN" (is;

And y y, zu X 117 x-k |. Ma AZB Intermediate connection 52

Table 18

SH

With with

M M (o)

HF) 118 Mi AZA Intermediate compound 66

A x MN" x M. jam

XX so, o -6-oo-ya aly O, mam Mne 119 and Se AZA Intermediate compound 67

RN re -y

ДХЧ с

M o 120 o a AZA Intermediate compound 61

A ZU Mne r; M lam - many o M / o DA 121 -ki I Maly AZ5 Intermediate compound 53

Hey oh

Cor r: - МН» s vad osi, 122 -ki - Mashu AZ5 Intermediate compound 55 and o o

IS

I am MN"

E (Fe) M zm XX | . 123 mi AZA Intermediate compound 68

SI -8- MN".

Ф) / s - 4 X 124 -M -» Me AZB Intermediate compound 54 as.

Table 18

H

6) si - МН» xx rain 125 -T M AZB Intermediate compound 58 -M -ko Mag

IS

/ (in -- (in M cha Mn» 126 - zh i AZA Intermediate compound 78 vv О000ЙЙ r;Я иЙ eh ke M іA і 127 М АЗА Intermediate compound 69

E Z M x v la ze i 128 -U i. dZ4 Intermediate compound 77

EE We and

S. Sh 129 nou AZA Intermediate compound 90

And I M. hg

Secondary school

MN pt em o M Mne . 130 Kho AZA Intermediate compound 91

Her M M r:

Table 18 t o M Mne. 131 and | AZA Intermediate compound 92 i М M r: ev o M МН» - 132 s | AZA Intermediate compound 93

EI M M r: em o M MN - 133 ХО | АЗ5 Intermediate compound 96 i М M р: et o М Мне . 134 s AZA Intermediate compound 94

EN YN r: tem M Mne and 135 - and AZA Intermediate compound 95

EE Ma YAM r: a- m she saze in H o. М Мне 136 что и АЗА Intermediate compound 99

EN M хг иЙ шек Х m. Mn» 137 M |! AZA Intermediate compound 97

With We xx

Table 18 a-y -- m in! Sun! 138 X AZA Intermediate compound 98

DARKNESS xx

Nov. St. Also Intermediate connection 139 m / | AZB 10 in 4 ( and what MH 140 m AZA Intermediate compound 60

B;

Fe village

M

(c) dense 144 m ZA roza compound

Hey Mne

And a

Kh Mah M

She

H

M shki Intermediate compound 142 nu AZA tb2a u

SE M M school

She

H

M shk Intermediate compound 143 sich AZO 103

EE 2 Ma hg

Table 18 o -

Her M mn, ge) . 188 СХ С оо dz Intermediate compound

M her Ma. M 187 o - y M mn, 192 СО dza Intermediate compound ,: sh mn. oy 194 Ma A M ay ZA boron compound

Kk

M To me

That Intermediate compound 198 of her 5 J M AZ5 15 ve -zh 97

M Mn. with Intermediate compound 209 7 Ii7t AZA

M I 2 M M 208

In r;

M--

X t36- many o. im x more

M romy compound 78, M vva 225 4 -t3- Mn; 9 "in 234 ve « -T their AZB Intermediate compound -ki -- Ma 233 a

Table 18 vo same nm M |) o Ash Intermediate compound 265 su ru chn» ly 264 si b I

KO vo rya o, --x

M Mi M.

And that's it

SH

-x

NhMm M (c) sh-y Intermediate compound 462 M AZA dvi

Hu Mn b M dO uv

WITH

IOM (in m t Intermediate compound 464 zu sh Aza 463 sy NI PV: "a dO

IN".

KAH

ХУ nom M (c) ee Intermediate compound 485 M Aza 484 schu Hug "MK dO

Table 18

SI t

Huh

NhM M and A. -sh ZA dbkzhna compound

MN Z sh- ! xx 2 o o ry more

SI and more

NhM M -E Intermediate compound 498 M ZA 497

KU n: more

SI

SI and Che

NOM M

BOI M nen AZA is a possible combination - BOI MI dO

SI and more

HNM M

--E Intermediate compound 501 M AZA 497 - and I 7 khm

YUM

Table 18 and

Nam eh o c) Gee! on - 5 BIv in AZA belt connection

SAfFCYA r: M. lem y

M on Zm (e) (c) He) n-- - 518 m AZA intermediate compound ho M. lem (Fi and c

NM M

520 m - AZA intermediate connection - in: p: fХХ

SI and

M -e8K- Intermediate compound 522 NhMm M AZA Bo

EM but he

SI and

M - Intermediate compound 524 nom M AZA 523 xx

No ki no he

Example of AZb

Preparation of intermediate compounds 144 and 144a

Pho in Ku

The language of the Shk Shk is still gray dk s: What are the things and what are the things

Moss, sleep ED Masy

Modno rya vp 7 and KK MA bide - i ptn 7 MO MNI in MeONn; AI

Ii ozh - 56«:А-А-- -75 Intermediate compound 144 yo Me 130, and ted

AK nom y rech shk i, tA

EI A ii

Prominsna splouma 265 ik and i and nku

Ed v

Intermediate compound 1448

A solution of intermediate 56 (35.7 mg, 0.0662 mmol) in 7 M Mn in Meon (1 mL, 7 mmol) was stirred and heated at 1307C with microwave radiation for 1 h. The solvents were evaporated. The residues were cleaned using a preparative NRIS (stationary phase: KR KhVgidde Rger C18 OVO-10 μm, 30 x 150 mm, mobile phase: 0.2595 solution

MNaANSO: in water, SNSM). Solvents from the purified fractions were evaporated and co-evaporated with

MeonH to give intermediate 144 (12.9 mg, yield 3795) and intermediate 144a (26.5 mg, 7390).

Example of AZ7

Preparation of intermediate compounds 145 and 145a

SI g. h. rey and Me yy o D-t si o esche JAK Ga u rey ry esche - M. r "MN

Mevo ey com g she au y U, vo y drink Y N per IK OD na che

M i ony 7 M MH: in MeOH or shie ---------- x o v Mo" INKS, ital o Intermediate compound 145 i x i

BM (v

Radioactive compound 47 Me

We h i no ryh

Ho ra and yi o and in Mn.

M ZH I uch z r Y

Intermediary Society TYA 5

A solution of crude intermediate 57 (theoretically 2.36 mmol) in 7 M Mn in Meon (20 mL, 7 mmol) was stirred and heated at 130°C with microwave radiation for 2 h. The solvents were evaporated. The residue was dissolved in OSM with Meon and purified on a column with 5iOg, type Sgase Kemeyegi5 ZKS, 40 g, 5i 40, on a purification system

Aptep roi Ii OShitaigie (gradient elution: OSM:MeOnH from 100:0 to 20:80). Fractions containing the product were combined and the solvents removed to give crude intermediate 145 (0.64 g) and crude intermediate 145a (0.13 g). These two crude intermediates were used in the next step of the reaction without further purification.

Example of AZ8

Obtaining an intermediate compound 146 oo t pk ya M N. sew, ditok, U cho M n Zh y Km Ty te Mo - ROS, NU NN sh. Me and sy Ky (in ru shk I Me M: Drink chiuch o o: n--- Ma - 5 Ge. I SNOM shcha 0

And Zh

Intermediate compound 137 Intermediate compound 146

To a mixture of intermediate compound 137 (340 mg, theoretically 795 μmol) in Meon (10.0 mL) was added

Ra/C (100 mg, 1095) at 257°C. The suspension was degassed under vacuum and purged with He (several times). The mixture was stirred under an atmosphere of H»e (15 psi) at 257°C for 5 hours. was filtered and the filtrate was concentrated

NRIS (Column: Oiatop5tii 150720 mm, 5 µm, mobile phase: from 1595 Mesm in water (0.22590 formic acid) to 4595 Mesm in water (0.22595 formic acid), flow rate (ml/min): 25 ml/ min). Fractions containing the required product were combined and lyophilized. The residues were additionally purified by chiral 5ES (column: ОО (250 mm"С30 mm, 10 μm), mobile phase: supercritical СОг / ЕУН "with МНз.НгО (0.195) - 50/50, flow rate: 80 ml/min). compound 146 (130 mg, yield 3895) was obtained as a white solid.

The following intermediates were prepared using a reaction protocol similar to that described for intermediate 3146 using the appropriate starting materials (Table 19).

Table 19

Prom. Structure Source material spol. code" СИ-7 М 147 М БИ Мы Intermediate compound 138

EN; o, c) ky 148 M 700 My Intermediate compound 136 more

An example of AZO

Preparation of intermediate compound 149

Panch ry p-- GE s i vych that Kk | me and ra Mne o-mM cm mno a M re ШЙ nn Meya (ЗМЗБШВВВЗЗБЗБЗЗБШШН и т My banni hytyu IRONIC M 5 a

And | min

Ko 2 sn 4 y x hm Kk

Intermediate 7 Intermediate 149

To a solution of intermediate 70 (360 mg, 5542 μmol) in TNE (3.00 mL) was added iRION (3.00 mL) and ammonia (2895 in water, 6.00 mL). The mixture was stirred at 857C for 72 hours in an autoclave. The solvent was removed and the residue was purified by flash column chromatography on silica gel (gradient elution: MeOOnHlosMm from 0/100 to 4/96) to give intermediate 149 as a white solid (230 mg, yield 65965).

zo Intermediate from Table 20 was prepared using a reaction protocol similar to that used to prepare Intermediate 149 using the appropriate starting materials (Table 20). Intermediate compound 150 was obtained in the E-configuration.

Table 20

Prom. Structure Source material spol. ruktur d ryav o. M. U

Yi Yi M

150 s - Zh Mashy Intermediate compound 100

M Co

Example A40

Preparation of intermediate compound 151

U Gh I Eh MIN. tire B a. ru. about whose village Ith o. drink | ry s x pi p ne z " ! oh

OO "m aa and In v a M, m ek ! rai U KU KD ee ran i z Z m o. re Son M 0.

And also

Intermediate 15 Intermediate 151

A suspension of intermediate 150 (150 mg, 349 μmol) and Ra/C (80 mg, 1095) was stirred under an atmosphere of He (15 psi) for 7 hours at 15°C. The reaction mixture was filtered through Celite. The filtrate was concentrated at under reduced pressure to give intermediate 151 as a yellow solid (135 mg, yield 90905).

Example A41

Obtaining the intermediate compound 152 is where we are - and we and we sing in it. bl ta tseh sb zi zhM im A oyu M ia i sb i DY I vaziarav, I she: ii:

K В МА х 4 I: M.M

Intermediate compound 119 Neuromic compound 152

Zinc cyanide (410 mg, 3.49 mmol), zinc (55 mg, 0.86 mmol), tris(dibenzylideneacetone)dipalladium were added to a solution of intermediate compound 119 (550 mg, theoretically 1.18 mmol) in OMA (20 mL) (46 mg, 0.051 mmol), 1,1"-bisidiphenylphosphino)ferrocene (92 mg, 0.17 mmol). The mixture was stirred at 100"C for 12 hours in an M"2 atmosphere. The catalyst was filtered and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel (eluent gradient: EOAc/petroleum ether from 1/20 to 1/0). The solvent was evaporated to give intermediate 152 as an oil (450 mg, yield 7090).

Example A5b

Obtaining an intermediate compound 214 с Я ТЕТУ Мне я-- о ие Ка доня

Yo shsh- dy di any a

In - and-- - her U M SM. RO YAOZU h- Ko Shto Vr -M ra Mas GUVRE, diokovn, 5 and

Intermediate compound vi MS tod, Intermediate ram 105 to compound 214

A mixture of intermediate 105 (512 mg, 1 mmol), SiISM (358.2 mg, 4 mmol), Ragdvbase (92 mg, 01 mmol), and OPRE (221.7 mg, 0.4 mmol) in dioxane (b mL) stirred at 1009 for 16 h. The reaction mixture was cooled, poured into water and extracted three times with ethyl acetate. The organic layer was washed twice with water. The organic layer was dried and evaporated to dryness. The residue was purified using preparative NRI C (stationary phase: KR KhVgidde Rger C18 OVO-10 μm, 50 x 150 mm, mobile phase: 0.2595 MNANSO solution: in water, SNZSM) to obtain intermediate compound 214 (363 mg, yield 79905 ).

Example A42

Obtaining the intermediate compound 153 pcs

Ve zro N u tu, Vi

How are we? З8З8Щ3Ю3 І Щ U ts: i - ra: -e 2 M-i naya r ani:

Residential complex voovRn; Sit and breathe

E ih M. she Esh Msyai r:Y O a h Ak

Intermediate compound 2 Transitive compound 153

A mixture of intermediate compound 23 (50 mg, theoretical 0.13 mmol), 7-hydroxyquinoline (22 mg, 0.156 mmol) and PP3 (53 mg, 0.26 mmol) in dry TNE (20 mL) was stirred at room temperature under an atmosphere of M ". OIAO (6.47 g, 32.037 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give crude intermediate 153.

Example A43

Preparation of intermediate compound 154 and intermediate compound 154a r g

Ti no - Beating days NO g

She is OK with . 0 o u times : . ru y ry sg y chyny, р ne yo - Shchy: zm mon Intermediate compound 154

At Ma! And the 18th, what the same, 25-DYUZKOZY notes and ; x zdkuyu be s TO y

Intermediate compound 72 sho nyshim in

E x / y y p y M - vych

Radiated compound TV

To a solution of intermediate compound 72 (1.0 g, 1.91 mmol) in 1,4-dioxane (10 mL) was added 2 M Mahon (10 mL, 20 mmol). The reaction mixture was stirred at 1507C for 1 hour under microwave radiation conditions. The mixture was diluted with water (15 ml), extracted with

ES (10 ml x 3). The organic phase was washed with saline solution (15 ml), dried over

Ma?5O., filtered and concentrated. The residue was purified using a column for chromatography (elution: EOAdsS/MeonH 85/15). The required fractions were collected and concentrated to give intermediate 154 (359 mg white solid, yield 4195) and intermediate 154a (300 mg, yield 32965).

Example A44

Preparation of the intermediate compound 155 ra and i penya; neck x Korea o vol yi bno Vi

Mlliiu la t i t y - M sho m M. an i that - tim z hi . I'm looking for that

What

Intermediate compound 7 and oh SHY

The singed compound 155

Sodium (440 mg, 19.1 mmol) was stirred in Meon (25 mL) at room temperature until the sodium was completely dissolved. Intermediate compound 72 (1.0 g, 1.91 mmol) was then added to the reaction mixture and the reaction mixture was refluxed for 72 hours.

The mixture was diluted with UOSM (100 ml), washed with water (10 ml), saline solution (10 ml). The organic phase was dried over Mag505, filtered and concentrated to give crude intermediate 155, which was used as such in the next step of the reaction without further purification.

Example A45

Obtaining the intermediate compound 157 re What kt MN. ron eh i nt and i me me -

Her re ke du e stok, Still salut jav, SN ZO s M Ve dk

Intermediate compound 157

In a sealed tube, 7-bromo-2-chloroquinoline (10.0 g, 41.2 mmol) and cyclopropylmethylamine (18 mL) were stirred in EN (80 mL) at 120°C overnight. The mixture was evaporated in vacuo to give the intermediate 157 (15 g; crude) as a brown solid, which was used as such in the next step of the reaction without further purification.

Preparation of intermediate compound 159

Coo)

ТК мв. in Twain. znorotyn refrigerator I av: : i. BE - - nsh7 -yu ge h y her su y vu ZIVETV Kom, beat MM s n reverse refrigerating, TE yah

Prosy compound 137 Yayremchin compound 159

Intermediate 38 (3.8 g, 11.9 mmol) in 9-VBM (0.5 M in TNE, 95.1 mL, 47.5 mmol) was heated under reflux for 1 h under M2 atmosphere. The mixture was cooled to room temperature, then KzPOx (7.56 g, 35.6 mmol) in HO (20 mL) was added, followed by TNE (150 mL), intermediate 157 (4.4 g, 13 mmol) and Ra -118 (155 mg, 0.24 mmol). The resulting mixture was heated under reflux overnight. The mixture was diluted with

HgO (100 ml), extracted with ethyl acetate (150 ml), the organic phase was dried over Mag50O5, then filtered and concentrated under vacuum to give the crude product.

The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/3) to give intermediate 159 (3.1 g, yield: 42.8905) as a yellow oil.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 159 using the appropriate starting materials (Table 29).

Table 29

The structure of the school

M -- 242 M si a) Intermediate compound 38 i PI: p) 3-methyl-7-bromoquinoline x M. lem sy ia 245 si p- a) Intermediate compound 38 i s: BYU) Intermediate compound 244 re I i vat

N

248 Che: a) Intermediate compound 38 and C: p) 7-bromo-M-methyl-2-quinolinamine

SN

HO t si 2 ? About 249 she you about. M, a) Intermediate compound 39 em is for - p) 7-bromo-3-ethylquinoline «y and | . 251 This M a) Intermediate compound 39 ve ho -L p) 7-bromo-33-methylquinoline

Ks ia oBA s pgt a) Intermediate compound 38 sh: p) Intermediate compound 253 re I

Table 29

Structure and 24 volumes

M a) Intermediate compound 38 si 256 i A B) 7-bromo-3-ethylquinoline x M. lem her 259 g y o Ky a) Intermediate compound 39 / Tsi p; p) 7-bromo-M-methyl-2-quinolinamine

Western

ХУ нам М 266 о сх a) Intermediate compound 39 и Св B) 7-bromo-2-quinolinamine о I

ХО с 268 си че a) Intermediate compound 39 ! 5. BYU) Intermediate compound 253

X Meme -

St. M 272 o de a) Intermediate compound 39 and ele B) Intermediate compound 157

SON Y x M, jam

M"

Kho --e 277 U M M so a) Intermediate compound 38

ЕЙ 7 5) Intermediate compound 276 r: pass

Table 29

The structure of the university

C, nMm M 281 CE a) Intermediate compound 38

M BYU) Intermediate compound 280

IN I x Mem

Guy ach

And M

288 pe a) Intermediate compound 38

KA p) Intermediate compound 287

SDN I r; M, lem and che S,

And M

291 ke a) Intermediate compound 38

Sg r) Intermediate compound 290

IN I

Kh M. jam si a

C, yes M 294 poh a) Intermediate compound 38

UA p) Intermediate compound 293 x M, lem

Ve.

Oil 297 p a) Intermediate compound 38 i p) Intermediate compound 296 i Х х M. lem сх

XX century

M M

300 d-E a) Intermediate compound 38

M sio5) Intermediate compound 299 : 5

DN I xx M. lem

Table 29

Structure and structure of M 303 res a) Intermediate compound 38

M in r) Intermediate compound 302

SN I rya M, lem i

IS

P. 306 E de a) Intermediate compound 38

C BYU) Intermediate compound 305

SN x M, sem x lL/,

M M n 309 re: a) Intermediate compound 38

M ble |B) Intermediate compound 308

OT I x Mam

Hg. and add

M M

312 - a) Intermediate compound 38 and b) Intermediate compound 311

YSt, I x M, sem

IS

E. and

IS

WITH

NhM M 315 according to a) Intermediate compound 38

M BYU) Intermediate compound 314

Se "M

HO

E. eh ke tak M 318 point a) Intermediate compound 38

An r) Intermediate compound 317

SN I x M. lem

Table 29

Structure 4 KO si 321 (fa zm u t a) Intermediate compound 38

5) Intermediate compound 320

Kk

E. сх в M 324 -E a) Intermediate compound 38

M si r) Intermediate compound 323 i. 5 ho M. lem

He and nom X 327 a) Intermediate compound 39 (o) BYU) Intermediate compound 326 xx

M m ve

IS

WITH

- by us M 330 t a) Intermediate compound 38

M si p) Intermediate compound 329 / xx p: M, lem 4 Ka si 336 U, m C a) Intermediate compound 38

Н с ШЙ b) Intermediate compound 335

Kk

E and c on M 473 (c) to a) Intermediate compound 39

M - s B) Intermediate compound 329

UA xx M named after

Preparation of the intermediate compound 160 a av: av sn shk ; her she pa stack re zm n y v we - CHI chan V K, - kn ch p i: che, y s os ya kyu y ih I li M 9. 2 M what M Vo Z M Fr: M ra h yah

Intermittent compound 159 Intermediate compound 1650

The reaction was carried out in a hermetically sealed test tube. Intermediate 159 (3.1 g, -5.1 mmol) was added to MNH 2 H 2 O (30 mL) and dioxane (30 mL) and stirred at 1207C overnight. The mixture was concentrated in vacuo to give crude intermediate 160. This residue was purified by silica gel chromatography (10095 ethyl acetate to 90/10 ethyl acetate/meon ratio) to give intermediate 160 (3.95 g, yield: 7790).

Example A46

Preparation of intermediate compound 161

Y g E7 I YAN syu By dram h i -k her Z ooo I ta ve A y?

Precious compound 161

7-Bromo-2-chloroquinoline (1.5 g, 6.18 mmol) and 2,2-difluoroethylamine (0.552 g, 6.804 mmol) were heated in EN (30 mL) at 120°C overnight in a sealed tube. was evaporated under vacuum to give intermediate 161 (1.8 g, yield: 88.195) as a brown solid, which was used in the next step without further purification.

Preparation of intermediate compound 162. - KE reverse V Ma and Zub z and Zkolyudnlniko B. sewn ot oo with I; and ROM

Hey all m M 7 Kk REYA, KRO, E 2 shchi chh SYA

M return of refrigerators, NOT ba MK

Prozeneny compounds 16 Prominenii r o speluknts 12000

Intermediate 38 (500 mg, 1.56 mmol) in 9-VBM (0.5 M in TNE, 15.6 mL, 7.8 mmol) was heated under reflux for 1 h under M2 atmosphere. The mixture was cooled to room temperature, then KzPOx (995.6 mg, 4.7 mmol) in H2O (2 mL) was added, followed by TNE (20 mL), intermediate 161 (538.7 mg, 1.88 mmol) and Ra-118 (20.4 mg, 0.031 mmol).

The resulting mixture was heated under reflux overnight. The mixture was diluted with H2H0 (60 mL), extracted with ethyl acetate (100 mL x 2), the combined organic phases were dried over NaCl5O, then filtered and concentrated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate:petroleum ether ratio 1:10 to 1:5) to give intermediate 162 (650 mg, yield: 68.195) as a yellow oil.

Preparation of the intermediate compound 163 of the same composition of the same composition

BE. I - yati Z ON E.. There are - y and z

There is also that Diyuzhsan, PS There are other em ueM

Intermediate compound 162 bu Me Intermediate both Mem

More sneluka 163 More

The reaction was carried out in a hermetically sealed test tube. Intermediate 162 (650 mg, 1.06 mmol) was added to M2H2O (15 mL) and dioxane (10 mL) and stirred at 1207 overnight. The mixture was concentrated under vacuum to give intermediate 163 (680 mg, yield: 97.9965).

Example A47

Preparation of intermediate compound 164 r o nush u MN" g sk: "Eh ha she ia ОШыШБ2Б2Ш2ЗХ-- х "RM AK A

SOM OV was unified by the IOM in

Commercial compound i54

A mixture of 7-bromo-2-chloroquinoline (10 g, 41.24 mmol) and 4-methoxybenzylamine (11.3 g, 82.5 mmol) in ethanol (40 ml) was heated in a hermetically sealed test tube at 1207C for 72 hours. The mixture was evaporated under reduced pressure and purified using a column for chromatography (eluent gradient: СНоСиг/petroleum ether from 1/10 to 1/0) to obtain the required product - intermediate compound 164 (13g, yield 82905) as a white solid.

Preparation of intermediate compound 165

RM. M «rr tires lek tyam Shk psy a Eh VIT zro teItik ee 4 i and all)

N Her Y V OVVTNE, return refrigerator her Y i y

EM. salt A - - 4 45 - -- ------ i a M. m.

Production of syFtukchi in other countries 164 165

A mixture of intermediate compound 38 (2 g, 5.0 mmol) in 9-VVM (50.0 mL, 25.0 mmol, 0.5 M in TNE) was heated under reflux for 1 h under M2 atmosphere. The mixture was cooled to room temperature, then KzRoOx (3.18 mg, 15.0 mmol) in H2O (10 mL) was added followed by TNE (20 mL), intermediate 164 (2.58 mg, -7.50 mmol) and P,1- bisidiphenylphosphino)ferrocenedichloropalladium(I) (163.0 mg, 0.25 mmol). The resulting mixture was heated under reflux for three hours. The mixture was concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water (6 ml), saline solution (6 ml). The organic phase was dried over Mag5O:, filtered and concentrated to give the crude product

From the product. It was purified by column chromatography (eluent gradient: ethyl acetate/petroleum ether from 1/10 to 1/1). The required fractions were collected and concentrated to give the product intermediate 165 as a solid (2 g, yield 52.490).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 165 using the appropriate starting materials (Table 30).

Table 30

Structure and

WITH

NOM M

257 sho a) Intermediate compound 38

МЖ осо |р)2-amino-7-bromoquinoline re і

VG that

And Ka (c) Kk si 238 and a) Intermediate compound 39

М B) 3-bromo-7-iodhinolin its 5 days

J

Ve. What are you doing?

M. M. 260 xx a) Intermediate compound 38

М B) 3-bromo-7-iodhinolin y 5 y y kh

Hg. and

M -- dvo s o M SI a) Intermediate compound 39 and: 5) Intermediate compound 175

Mk Sh-

Hg. and

M t 488 schi M MN a) Intermediate compound 487 and 5) Intermediate compound 175

KO

Ve. th ve - 491 s o M t a) Intermediate compound 490 ! more 5) Intermediate compound 175

KO

Table 30

The structure of the

E. 514 vla pk dir: a) Intermediate compound 513 ek; ac B) Intermediate compound 314

She is 5 We are 54

Obtaining intermediate compound 166 sh Ker dit khy ryu. I'm aka Mem. MN, o siv My MN duksvn o, -v ma. k X Iermetntvosakorkovanh test tube and u

Intermediate compound 165 N intermediate compound HB

In a hermetically sealed test tube, a mixture of intermediate compound 165 (500 mg, -0.655 mmol) and MH3HgO (10 ml) in dioxane (10 ml) was heated at 1207C for 14 h. This reaction mixture was evaporated in vacuo to give intermediate 166 (400 mg, yield 93.595) as an oil.

Preparation of the intermediate compound 167 no Mesa schi p

RM uk tr OD. siich A i i sch still tn E M M - 1

Not SHK: um, sake

BUT; with MN svulyuyun and M and! вх и -- -я2-k WHAT u e MIN she Mo.shM not t

ZhK Vysh No

Intermediate yamloka 166 Closed connection 187

A mixture of intermediate compound 166 (340 mg, "0.52 mmol) in SEZCOOH (5 mL) was stirred at 60"C for 1 h. The mixture was evaporated under vacuum to give intermediate compound 167 as a crude product (300 mg, yield 85.9905 ).

Example A48

Preparation of intermediate compound 168

EV, A I AF RM ry B M sih t

N : pok n s sf pyt v m ns d---y m z 3 her nya men no a USCHYA byu Mam SNY Men, r Ma

Prolboyed compound 165 Intermediate compound 165

Intermediate 165 (300 mg, 0.39 mmol) was dissolved in EN (20 mL) and ethyl acetate (4 mL) and hydrogenated under 1 atm. On Pa(OH)"/C (30 mg) for 7 hours. The mixture was filtered and evaporated under vacuum to give intermediate 168 as a crude product

(200 mg, yield 70.69).

Preparation of intermediate compound 169

RM. leading Ki Ya 4 de

V i: shko it ry t, y - Be Ge M m deya y: I was in YO dream ni bib che uBT-zh NK one thing

H

Intermediate compound 145 Yarominsnea compound 150

A mixture of intermediate compound 168 (200 mg, 0.278 mmol) in SEZCOOH (5 mL) was stirred at 60°C for 1 h. The mixture was evaporated under vacuum to give intermediate 169 as a crude product (120 mg, yield 89.0905).

Example A49

Preparation of the intermediate compound 170 cm. ZL inv. ono i IY M di o E z a z vach B ychi z n

ROM m, popheya 1 d

We are you SNOMY. dizhean y-sh vu su y i y -- х6х6х 6 6 6 ж (шж(тх«хжю«кВ '5«0 ж х Й ин

Chv M ym b, -v Mem

Ka U

Radiant compound 165 Radiant compound 170

In a hermetically sealed test tube, a mixture of intermediate compound 165 (310 mg, -0.406 mmol) and CH3Mn/HgO (5 mL) was stirred in dioxane (5 mL) at 1207°C for 14 h. This mixture was evaporated under vacuum to give intermediate compound 170 (200 mg, yield 80.195) as crude product.

Preparation of intermediate compound 171

NO" and El, h

RM. chit "WE V Y y S y Yalsh E z ve pay se tm sce Z eEeSYHYA Y ml I st pd o Ktyu Zhe M y sho 0 x M. M KU sr de zh r pe te how yah KO b ke

Intermediate compound 170 Intermediate compound 171

A mixture of intermediate compound 170 (200 mg, 0.325 mmol) in SEZCOOH (5 mL) was stirred at 50°C for 1 h. The mixture was evaporated under vacuum to give intermediate compound 171 (160 mg, yield 84.095) as a crude product.

Example OR

Preparation of intermediate compound 172

RM. dn with Re. you and

Zk, Jen and mkg and M ek In kivsoma, MEM I Well M clearly

SN and her - 7 7 « 25«T- -sh« - трвЛлох -йпн- лй6- ех и и

M - in MM and ee

Causative compound 164 Intermediate compound 172

A mixture of intermediate 165 (300 mg, 0.393 mmol) and sodium methoxide (63.7 mg, 1.18 mmol) in methanol (10 mL) was heated under reflux at 60°C for 12 h. The mixture was evaporated under vacuum to give crude Water (10 mL) was added, the mixture was extracted with ethyl acetate (10 mL×2), the organic layers were combined and evaporated in vacuo to give intermediate 172 (200 mg, yield 71.8905) as crude product.

Preparation of intermediate compound 173 svv dnu etc

EMV. hi vn sia Hey A M vo bo t

N s y CHYN N Sich seam NO vno MAL r Sha

Intermediate compound 472 and phyromine compound 173

A mixture of intermediate 172 (200 mg, 0.282 mmol) in TEA (5 mL) was stirred at 60-7C for 1 h. The mixture was evaporated under vacuum to give intermediate 173 (250 mg, yield 85.395) as a crude product.

Example A5BI1

Preparation of intermediate compound 174

eat aa how (9 From Rich

SCHI el meSRVA POM Vboutait

From ia av o

Intermediate compound 174

C-Bromo-7-iodoquinoline (5.99 g, 17.7 mmol) was dissolved in dichloromethane (60 mL), then m-SRBA (4.57 g, 26.5 mmol) was added portionwise. The mixture was stirred at room temperature for 4 days. The mixture was quenched with a saturated aqueous solution of Mag5b2Oz (40 ml) and a saturated aqueous solution of Mansoz (pH to 6-7), then extracted with dichloromethane (50 ml x 3). The organic phase was washed with H2O (50 mL), dried over anhydrous Mag25O:4 and evaporated under reduced pressure. The residue was purified using a silica gel column (eluent: petroleum ether/ethyl acetate - from 10/1 to 1/1) to obtain the desired product - intermediate compound 174 (1.9 g, yield 14.195) as a yellow solid.

Preparation of intermediate compound 175

Be i st in lk. I

Че хро РОССНСЯ В ше ех

And cha chav and A and | VU, 15th SIT eh i

Intermediate 134 Intermediate 175

Coo)

Phosphoryl trichloride (8.3 g, 54.1 mmol) was added to a solution of intermediate compound 174 (2.9 g, 8.29 mmol) in chloroform (60 mL). The mixture was stirred at 807C for 12 hours. The mixture was evaporated under reduced pressure to give the crude product. The crude product was purified using a column for chromatography (eluent: petroleum ether/ethyl acetate - from 10/1 to 1/1). The required fractions were collected and concentrated to give the product intermediate 175 (1.3 g, yield 41.595) as a white solid.

Preparation of intermediate compound 176 and BA. sia

Ve ear shu, eMEMNY Her and Y s shshi se in termetic and M M and nose. -k

Intermediate 175 Intermediate 176 4-Methoxybenzylamine (1.34 g, 9.78 mmol) was added to a mixture of intermediate 175 (0.8 g, 1.95 mmol) in ethanol (10 mL). The mixture was heated in a hermetically sealed test tube at 1007C for 12 hours. The mixture was evaporated under vacuum to give the crude product. It was purified by column chromatography (eluent gradient: ethyl acetate/petroleum ether from 0/1 to 1/10). The required fractions were collected and concentrated to give the product intermediate 176 (600 mg, yield 51.695) as an oil.

Preparation of the intermediate compound 177 is still r. , re ra i i E 2) RKOROGKT. KOROM same SHY 3 uk vmami- thanks

AH

Intermediate compound 176 is known as compound 477

A mixture of intermediate 38 (44 mg, 0.138 mmol) in 9-VBM (1.3 mL, 0.69 mmol, 0.5 M in TNE) was heated under reflux for 1 h under M2 atmosphere. The mixture was cooled to room temperature, then KzPOx (87 mg, 0.413 mmol) in NegO (1 mL) was added, followed by TNE (5 mL), intermediate 176 (122.727 mg, -0.206 mmol), and P,1- bisidiphenylphosphino)ferrocene dichloropalladium(II) (4.48 mg, 0.007 mmol). The reaction mixture was heated under reflux for 3 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water (6 ml), saline solution (6 ml). The organic phase was dried over Ma»505, filtered and concentrated to give fraction 1 as crude intermediate 177 (120 mg, yield 71.590).

A mixture of intermediate 38 (233.7 mg, 0.73 mmol) in 9-VVM (7.31 mL, 3.65 mmol, 0.5 M in

TNE) was heated under reflux for an hour in an atmosphere of M". The mixture was cooled to room temperature, then KzPOx (87 mg, 0.413 mmol) in H2HO (1 mL) was added, followed by TNE (5 mL), intermediate 176 (478 mg, 0.80 mmol) and (|1,1- bisidiphenylphosphino )ferrocenedichloropalladium(II) (23.8 mg, 0.037 mmol). The reaction mixture was heated under reflux for 3 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water (6 ml), saline solution (6 ml). The organic phase was dried over Ma»505, filtered and concentrated to obtain fraction 2 in the form

From crude intermediate 177 (600 mg, yield 63.1905).

The two fractions were combined and purified by column chromatography (eluent gradient: ethyl acetate/lethroleum ether from 1/10 to 1/1). The required fractions were collected and concentrated to give intermediate 177 (300 mg, yield 61.095) as a solid.

Preparation of intermediate compound 178

Vedas - KU

It's Ashshutya Chek. and

RM. tyu as N y ditu she y sh

M sho Mne vmar nt tia Shchi

NN 1171 To nn b y MM raksyaan -KZHKYE tp shi yah 4 in M. em ya | where Intermediate Schools

Biochizhny compound 7: compounds 178 yah

A mixture of intermediate compound 177 (300 mg, 0.446 mmol) and MH3HgO (10 mL) in dioxane (10 mL) was stirred in a sealed tube at 1207C for 14 h. This reaction mixture was evaporated in vacuo to give intermediate 178 (250 mg, yield 87.195) as an oil.

Preparation of intermediate compound 179 in zh ne p tu 1 Z yan dir

EE. et OT Vk M

MM Cat Ted I and zm du --- Lem Z le

ШЕ ШКО not M, oka МБ because Mam v. sir I eat

Disubstituted compound 475 Disubstituted compound 479

A mixture of intermediate compound 178 (250 mg, 0.388 mmol) in TEA (5 mL) was stirred at 507C for 1 h. The mixture was evaporated in vacuo to give intermediate 179 (350 mg, yield 63.495) as an oil.

Example A5B2

Preparation of intermediate compound 180

SI spe Sol

Y PO in svvVAOSYUSM and I Vi for child 7 - Fr. and

M vu same natdu o

Intermediate compound 150

C-Chloro-7-bromoquinoline (10 g, 41.2 mmol) was dissolved in dichloromethane (150 mL). Then m-SRBA (7.83 g, 45.3 mmol) was added in portions. The mixture was stirred at 35 C for 16 hours. The mixture was poured into a saturated aqueous solution of Mag25Oz. The mixture was extracted using SNesSig. Then the mixture was washed with a saturated aqueous solution of Ma»b5Oz (50 mlx2) and a saturated aqueous solution of ManHsSoOz (50 mlx2). The organic layer was dried over anhydrous Mag5O4 and concentrated. The white solid was precipitated and filtered to give intermediate 180 (10 g, yield 78.85) as a yellow solid.

Preparation of intermediate compound 181

Se in od De. y t sk v it SHYN

I N i - 6 2 -- BE : N bodi i tlo Z va A A iy i She Vk VO 12 h a" shchi i Ve

Intermediate 180 Intermediate 151

To a solution of intermediate compound 180 (bg, 23.2 mmol) in chloroform (30 ml) was added

Zo phosphoryl trichloride (18.8 g, 122.5 mmol). The mixture was stirred at 80"C for 1 hour.

The mixture was slowly poured into the water. A saturated aqueous solution of Mansoz was then added to the mixture to change the pH to about 7.

The mixture was extracted with SiO2 (50 mL x 2) and dried over anhydrous Mg5Ox.

The organic phase was concentrated. The crude product was purified using a column for chromatography (eluent: petroleum ether/ethyl acetate - from 1/0 to 4/1). The required fractions were collected and concentrated to give intermediate 181 (5 g, yield 72.390).

The preparation of the intermediate compound 182 and it is still difficult

Roche | ". kb dnya at Z et zdroduzheano, 1206 nm M Ve

Intermediate Compound Her Intermediate Compound 182

Intermediate compound 181 (1 g, 3.6 mmol) was added to NH3 in HO (10 mL) and dioxane (15 mL).

The mixture was heated in a hermetically sealed test tube at 120°C for 16 h. The mixture was extracted with EOAc. The organic layer was dried over anhydrous Mag5O4 and concentrated. The residue was purified using a column for chromatography (eluent gradient: ethyl acetate/petroleum ether from 0/1 to 1 (3).

Preparation of intermediate compound 183

Y - reverse S. re

SI. beer TVVVMITNE bachelors and. year

I AND 1 ZUYA-TIV. Cream, and medicine

BANTY dk reverse cooler, NOT to her TM l oi and A kh i kh

Prozponniy compound 152 Irradiated compound 155

A mixture of intermediate 38 (100 mg, 0.313 mmol) in 9-VVM (2.19 mL, 1.09 mmol, 0.5 M in

TNE) was heated under reflux for 1.5 h in an atmosphere of M". The mixture was cooled to room temperature, then KzPOx (199 mg, 0.938 mmol) in HgO (2 mL) was added, followed by TNE (8 mL), intermediate 182 (88.6 mg, 0.344 mmol) and Ra-118 (26, 48 mg, 0.407 mmol). The mixture was heated under reflux for 3 hours. The mixture was concentrated. The residue was dissolved in water, extracted with ethyl acetate (20 x 2 ml) and washed with saline (10 x 2 ml). The organic phase was dried over Mag25O:4, filtered and concentrated. The residue was purified using a column for chromatography (eluent gradient: ethyl acetate/petroleum ether from 0/1 to 1/3). The required fractions were collected and concentrated to give intermediate 183 (100 mg, yield 55.490).

Obtaining an intermediate compound of 184 n t dn, and 1. M

E Z, -M r same and ov Bey Z rt

SCHO, Ky mnanyu SN and with shk dizxvno ZO and SHA SHY i g3 (from M. also M

Intermediate compound 145 Irradiated compound 184

In a hermetically sealed tube, a mixture of intermediate compound 183 (800 mg, 1.605 mmol) and MH3H2HO (10 ml) in dioxane (10 ml) was heated at 120°C for 48 h. The mixture

Zo was extracted with EAs (30 ml x 3). The organic phase was concentrated to give intermediate 184 (800 mg, yield 90905).

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 184 using the appropriate starting materials (Table 31).

Table 31

Structure

Ve She: і Ka "ZD Mn; . 239 ! і Intermediate compound 238 ni ve і: 4 --

M. 243 and others Intermediate compound 242 xx M. lem o o5O an zhey Me. it is Intermediate compound 249 sv E g v

Kk hu 4 | : 252 MM Intermediate compound 251 s to p Intermediate compound 254 255 si | "Kon re M, lem o m -y

M. 257 I, in Intermediate compound 256 xx M. dsyaeM her i M Ks mno 258 N i She Intermediate compound 248 her 2 M.

KO

Table 31

Structure

Hg 7

M I What MN

M My 2 261 y Intermediate compound 260 nn ve y s na m 267 ЧИ Intermediate compound 266 ! g mn, re M, lem - n 269 si and kA Intermediate compound 268

KE Mr. Mne

ХЕ M lem и је М Хе) Ks mno 271 N and She Intermediate compound 259 her: M. and isch - s

ММак 273 и че Intermediate compound 272

S Y Zh MN" x o

M

M M yak 278 ia: S An Intermediate compound 277 zh M. jam

Grove to

M M n 289 M Intermediate compound 288

S u lyn" xx M. lem

Table 31

The structure is what I am

M M n 292 che Intermediate compound 291

S, Y ud Mn"

H M dak si - i

M M yes

Sh mo, Intermediate compound 294 pl

Su Z o i Sh r: I will pass

Ve.

He zh kt M n sh dra, Intermediate compound 297

With liMn"; b and r: I will pass

Sh

And there is

М М н 301 pcs Intermediate compound 300 хх МН» р ше и рве

M M

N

304 dy Intermediate compound 303 zu Mn» r: M. lem -

IS

WITH

307 UA Intermediate compound 306 mn. : enter o: these r: I will pass

Table 31

Structure of input dl,

M M n 310 M Intermediate compound 309

A xx Mn, o E Ku

Whoa

Ve. 2

HELL

M M n 313 che Intermediate compound 312

S Y AN" x M, lem

IS

And

IS

C nam M 316 Be Intermediate compound 315

A and xx Mn. about E Ts r: I will pass

E. z h hu M n 319 7 Intermediate compound 318

С г» Мне хх Mem 2 че

М М н 322 KD Intermediate compound 321

K-u: xx Mn, rya M. jam

E. and i

N

325 di Intermediate compound 324

A xx Mne sf r: a

Table 31

Structure of the village

S naya M 328 o ked Intermediate compound 327

S Hu Lin; b M r; where

IS

Сх д нМ М 331 ked Intermediate compound 330 ! xx Mn, of ho zag" 4 then Mn si s C y 337 M s her Intermediate compound 336

Kk

Ve. and

Nam and o МН 483 Zhe 2 Intermediate compound 482 ik Mo

Example A57

Preparation of intermediate compound 316

E E ш или-х ж di Кк Н х МН" in Dt" ран шк y b M. y

Fekshchesh nm ka Zk ki M Oh Mo

Zh and Dr. E p. : : garden y x y U is a bilinear compound 314

Prozineny compound 433 159-B8M, TNE, 2 Vzharris,

E Y OKORO, TNE, BUT reflux refrigerator i vi val z t-U i, vane: shchi x / И; ; weight

Premeneni compound 316 Ya

Intermediate 433 (10.8 g, 35.96 mmol) was dissolved in 60 mL of TNE, and 0.5 M 9-BVM in TNE (226.5 mL, 113.2 mmol) was added, and the reaction mixture was stirred for 2 hours 5 KzRO»x (38.1 g, 179.78 mmol) was added to 65 ml of water and the reaction mixture was intensively stirred for 30 min. Intermediate compound 314 (1046 g, 35, 09 mmol) and (P,1- bisidiphenylphosphino)ferrocene dichloropalladium(s) were added and the reaction mixture was degassed. The resulting mixture was stirred for 2 hours at 60"C and allowed to cool to room temperature overnight. EIOAc was added to the reaction mixture, the organic layer was washed with water and brine, dried over Mo9504 and concentrated under reduced pressure to give the crude product. The residue was purified normally. -phase NRI C (stationary phase: silica gel type: b0A 25 40 μm (MegsK), mobile phase: gradient from 9595 dichloromethane, 590 methanol to 9095 dichloromethane, 1095 methanol).The necessary fractions were collected and evaporated.

The residue was re-purified by normal-phase NRI C (stationary phase: silica gel type b0A 25 40 μm (Megsk), mobile phase: isocratic 9590 ethyl acetate and 595 ethanol) to give intermediate compound 316 (7.9 g, yield 4390).

An example of AZO

Preparation of intermediate compound 528

In Mmnongo Vyk -- - ---k

I sia MI Y I A shi she a y she she zhpiektan

Soluble compound 7 Intermediate compound 354

Intermediate 175 (630 mg, 1.71 mmol) was dissolved in dioxane (10 mL). Then added

МНз.НгО (10 ml). The reaction mixture was stirred at 1207C for 24 hours in a hermetically sealed test tube. The reaction mixture was extracted with EOAc (50 ml x 3). The organic layers were combined, dried with Ma25054 and the solvent was evaporated to give intermediate 528 (380 mg, yield 6290) as a solid.

Preparation of intermediate compound 529

In the day when corner TE 5 is ry cha mae zvorlenni shM M dit t

There are many 138-VVAITNE HOLLOdNllNYK that r ya OTIT MO b va M. am 2 Intermediate svpaluka 526 pcs, A MN

A t Rekiropsv Koru VOMS, TNE b ky yah i che M xx x

Radiated compound I DIntermediate compound 529

A mixture of intermediate compound 433 (22 g, 72.7 mmol) in 9-BVM/TNE (0.5 M solution in TNE, 585 mL, 292.3 mmol) was stirred at 50"7C for 1 hour in an M2 atmosphere. The mixture was cooled to room temperature and KzPO4 (77.6g, 365, mmol) and HgO (80 mL) were added. The mixture was stirred at room temperature for 0.5 h, then TNE (95 mL) was added, intermediate 528 (22.9 g, 65.8 mmol) and Pa(arrOsSi" (4.77 g, 7.30 mmol) in an atmosphere of Me".

The resulting mixture was stirred at 507°C for 3 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate (120 ml). The organic layer was washed with water (10 ml) and brine (10 ml). The organic phase was dried over Na»5O», filtered and concentrated.

The residue was purified by column chromatography on silica gel (ratio from petroleum ether/ethyl acetate 1/1 to petroleum ether/ethyl acetate 0/1). Pure fractions were collected and the solvent was evaporated under vacuum to give 23.5 g of intermediate 529.

An example of ABZ

Preparation of intermediate compound 193 vn t sha nin t a i le rya I o i NN I i i i i o 6th. Corners in E-6 nh IJ M i

U -- r U SCHO Mlsche - 2 233---N: 7-AA LI -k Yani, KE

And go. In vfVrRVSKSNYS 3 ie bo KO", dioxane, vola, which

SHY 160, 4 p.m

Intermediate compound 105 Intermediate compound 193

Ra(arry)Si».SNesSi» ( 41 mg, 0.05 mmol).

The reaction mixture was purged with nitrogen for one minute, then KgCO3 (174 mg, 1.25 mmol) and water (0.2 mL) were added and the reaction mixture was again purged with nitrogen for one minute.

The reaction mixture was heated in a closed vessel to 1007"C for 16 hours. The reaction mixture was filtered through dicalite and evaporated to dryness. The residue was purified using preparative NRI C (stationary phase: KR KhVgidde Rger C18 OVO-10 μm, 50 x 150 mm, mobile phase: 0.2595 solution of MNANSO" in water, CHzSM) to obtain intermediate compound 193 (110 mg,

Or).

Example A5B

Stage 1

From Obtaining an intermediate compound 434 poi an ato dit, Shan! VE she, she

Y L 2-Brolnylonaliosii I

In oh vidoi El i viyu o ry no young abtrt

VG

4-chloro-x-methoxyaniline Intermediate 434 2-Bromomalonaldehyde (2.1 g, 13.96 mmol) was added portionwise to a solution of 4-chloro-3-methoxyaniline (2.0 g, 12.69 mmol) in EN (100 mL) at 0"C in an atmosphere of M". After stirring at room temperature for 2 h, the mixture was concentrated to obtain intermediate compound 434 (4.0 g, yield 69.595), which was used in the next stage without additional purification.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 434 using the appropriate starting materials (Table 32).

Table 32

Structure 435 r a) 2-chloro-3-methoxyaniline boom 0) r) 2-bromalonaldehyde

Vg SI

СХ, a) 4-fluoro-3-methoxyaniline 436 "a 7 p) 2-bromalonaldehyde

Hg

Stage 2

Preparation of intermediate compound 437 set y

KO ev SHY: CK eggs Shk rki ut t ! and 7 abro Pr

Where are you?

PPremins spelumka 434 Premins compound 457

The reaction was carried out twice.

A mixture of intermediate compound 434 (1.0 g, 3.44 mmol) and PPA (1.0 g) in EUN (20 mL) was heated at 95°C for 1 h in a reaction tube for exposure to microwave radiation. Two reaction mixtures of combined and concentrated. The residue was diluted with water and extracted with SNCl" (50 ml x 5). The organic phase was washed with aq. ManCO 3 , brine, dried over Mag5O5, filtered and concentrated. The residue was purified using a column for chromatography (eluents: petroleum ether (BOAc, 85/15).The required fractions were collected and concentrated to give intermediate 437 (0.77 g, yield 4195) as a yellow solid.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 437 using the appropriate starting materials (Table 33).

Table 33

Structure

IN".

In Intermediate compound 435 438 ro r r U

M (in)

SI

Veit" and Promi 436 r ef romy compound

M o

Stage Z

Preparation of intermediate compound 200

Coo)

She and Ve. pr ikh schu S no and M M ss On

DIntermediate compound 437 Irradiated compound 20

VViz (1.6 mL, 16.60 mmol) was added to a solution of intermediate 437 (1.28 g, 4.70 mmol) in

SNOH (25 ml) at 0"C. The reaction mixture was heated under reflux for 48 hours. The pH of the reaction mixture was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was concentrated to extract SNOH. The resulting mixture was filtered to obtain intermediate compound 200 (1 .1 g, output 9195) in the form of a solid substance.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 200 using the appropriate starting materials (Table 34).

Table 34

Structure

Hg. | with

Intermediate compound 438 205 -

M on (c)

Vei i Promi 439 2 is an effervescent compound

M on

Example OR

Stage 1

Preparation of intermediate compound 440 oda a SYA. this is me

Zk Yi re Me«MSI, today

From ut o Isprolin, EUN, UIA zi tog

Intermediate compound Я 7 Intermediate compound 44О

A mixture of intermediate 437 (720 mg, 2.64 mmol), tetramethylammonium chloride (2.90 g, 26.42 mmol), copper(I) oxide (378.0 mg, 2.64 mmol), and I-proline (608 .3 mg, 5.28 mmol) in EUN (15 ml) was stirred at 1107"C for 10 min in a reaction tube for exposure to microwave radiation. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography (eluents: petroleum ether/EIOAc, 3/1 ).The required fractions were collected and concentrated to give intermediate 440 (290 mg, yield 4895) as a solid.

Stage 2

Preparation of intermediate compound 216

That's in VA. S - g Walk Zv - Shchy - ot - ee yam on

Intermediate compound 44 Prominesno compound iy

Zo

VViz (2.34 mL, 24.5 mmol) was added to a solution of intermediate 440 (280 mg, 1.23 mmol) in

(15 mL) at 0"C. The reaction mixture was heated under reflux overnight. The pH of the reaction mixture was adjusted to 7 using saturated sodium bicarbonate solution.

The mixture was concentrated until extraction of СИСН»СН2СИ. The resulting solid was filtered to give intermediate 216 (250 mg, yield 87.50).

An example of AbO

Stage 1

Preparation of the intermediate compound 441 dokt ek SHE rea o GOD Ros me ote Y ih s z aa ik se, ! with

BUT By She ON si ih "M i nn 0 Intermediate compound 44

Quinoline-2,7-diol (20 g, 124.1 mmol, 1.0 equiv.) was placed in UOME (40 mL), and ROSCl3 (107.7 g, 702.5 mmol, 5.7 equiv.) was added room temperature. The reaction mixture was stirred at 707°C for 1 hour. The solvent was removed under reduced pressure, and the residue was slowly poured into water (300 ml) at 0°C. Saturated aq. was added to the solution. MagbOz to pH - 8. The mixture was extracted with ethyl acetate 1000 ml x 2. The organic layer was washed with 1000 ml of brine and concentrated under vacuum to obtain the product - intermediate compound 441 (20 g, yield 8890) as a solid.

Stage 2

Preparation of intermediate compound 442

Bod sia, AND there is St. ME yad sa

Ghani M and ON S shi ey z

Intermediate compound 44 Prominesp compound 442

Intermediate 441 (2.5 g, 13.9 mmol, 1.0 equiv) was dissolved in OME (25 mL), Kg2CO3 (5.76 g, 41.76 mmol, 3 equiv) and CH2 (5, 2 g, 36.6 mmol, 2.63 eq.). The reaction mixture was stirred at 257"C for 12 h. The reaction mixture was poured into water (100 mL) and extracted with EOAc (150 mL). The organic layer was washed with water (80 mL x 2), brine (800 mL) and dried over anhydrous Ma»5O». The solvent was removed under reduced pressure to give intermediate 442 (2.6 g, yield 9695) as a white solid.

From Stage Z

Obtaining the intermediate compound 443 tu 00 mnivv, Rakova svso" her ozh and still A NYUM ib ho ss po tsa eszh ho VIMAR, ME LOSUS, i i i m M o

Intermediate compound Я | Other compound 444

Into a solution of intermediate compound 442 (900 mg, 4.5 mmol, 1.0 equiv.), MH»Vp (0.578 g, 5.4 mmol, 1.2 equiv.) and C52bOz (2.93 g, 3 mmol, 2 .0 equiv.) in UME (5 mL) was added Ragz(aba)z (412 mg, 0.45 mmol, 0.1 equiv.) and VIMAR (280 mg, 0.45 mmol, 0.1 equiv.). The resulting mixture was stirred at 1007C in an M" atmosphere for 12 hours. The solvent was removed under reduced pressure, and the residue was triturated with EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Ma»5O»4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: E(Ac/petroleum ether ratio from 0/1 to 1/5)) to give intermediate compound 443 (450 mg, yield 3790) as a yellow solid.

Stage 4

Preparation of intermediate compound 231

Anya eh

E and | y ay z nen, ekyu ve dit, gu M ko r "Bon du iy. a Sheya E Z a giy - 65 -- Vk - t ey ev riy dy shi g

MN tvoszgoyi OM cha a zy

Prominsne compound 443 Intermediate compound li

Intermediate 443 (500 mg, 1.78 mmol, 1.0 equiv) and pyridine hydrochloride (3.2 g, 28 mmol, 16 equiv) were placed in a tube. The reaction mixture was stirred at 1807"C for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was dissolved in 25 ml of USM and 25 ml of HgO, the pH was adjusted to approximately 8-9 by gradual addition of solid K»2CO3, and the layers were separated. Aqueous the layer was extracted using OCM (20 ml x 3).

The combined organic layers were dried (Mag50O5), filtered, and the solvent was concentrated in vacuo to give intermediate 231 (440 mg, yield 9695) as an oil, which was used in the next step without further purification.

Example Ab1

Stage 1

Preparation of the intermediate compound 444 g of TMUSE with the addition of SY, SVE, BO o she and sultolan

Irradiated compound Ya

A mixture of Cia (6.80 g, 35.84 mmol), C5E (14.15 g, 93.18 mmol), 1-iodo-2-methoxy-4-nitrobenzene (10 g, 35.84 mmol) and sulfolane (20 ml) was quickly stirred at 45°C. Trimethyl(trifluoromethyl)silane (13.25 g, 93.18 mmol) was added dropwise to this mixture over 4 hours using a syringe pump, and the resulting mixture was stirred at 457°C for 18 hours.

The mixture was diluted with ethyl acetate (500 mL) and stirred with Celite for 5 min. The reaction mixture was filtered through a pad of celite and diluted with ethyl acetate (500 mL). The organic layer was washed with 1095 MNAOH, 1.0N. NSII, saline solution, dried over Ma»50Ox, filtered and concentrated to obtain a crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/4) to give intermediate 444 (8 g, yield 9195) as a white solid.

From Stage 2

Preparation of intermediate compound 445

You love me

Sm as ven nm ra yaru

Intermediate compound 444 Intermediate compound 445

Intermediate 444 (7.1 g, 28.9 mmol) was placed in methanol (100 mL), followed by the addition of 590

Ra/C (0.7 g). The mixture was hydrogenated at room temperature for 48 hours under an atmosphere of He (50 psi). The mixture was filtered and the filtrate was evaporated under vacuum to give intermediate 445 (7 g) as a white solid.

Stage Z

Obtaining the intermediate compound 446 in and for the shen, therefore, the substance of its GC. and. by which ANYA was nursed by SEN, K. i.e.

Intermediate compound 445 Altered compound 446

A mixture of intermediate 445 (6.2 g, 32.4 mmol), 2-bromomalonaldehyde (5.38 g, 35.7 mmol), and I-RHOH (120 mL) was stirred at room temperature for 5 min. The mixture was filtered and the filtered precipitate was washed with i-RHOH (10 mL). The filtered precipitate was dried under vacuum to give intermediate 446 (6 g, yield 51905) as a yellow solid.

Stage 4

Obtaining an intermediate compound 447 pieces of SEZ de year OMA vk oslolov, "1 EN I t Y ,

What are you doing?

Intermediate compound 46 Intermediate compound 447

A mixture of intermediate 446 (bg, 18.5 mmol) and PPA (10 mL) in ethanol (150 mL) was stirred at 80°C overnight. The mixture was evaporated under vacuum. Water (100 mL) was added to the mixture and the mixture was extracted with ethyl acetate ( 100 mL x 3). The organic layers were combined and evaporated in vacuo to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/10) to give intermediate 447 (3.3 g, yield 5495) in the form of a white solid.

Stage 5

Preparation of intermediate compound 210

Ve. the trunks of OK VROKLOVND are here

Mei Mei 522525 (9 (SCH LYA 4L 4 4 4 - - --- and Y and shchi still pus el zon sha o;

Primary compound I Intermediate compound 216

A mixture of intermediate compound 447 (1 g, 3.27 mmol) and pyridine hydrochloride (6 g, 51.9 mmol) was stirred at 2107°C for 2 hours. The reaction mixture was cooled to room temperature. Water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 ml x 3).

The organic layers were combined and evaporated under vacuum to give the crude product.

The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/10) to give intermediate 210 (500 mg, yield 4995) as a white solid.

Example Ab2

Stage 1

Preparation of intermediate compound 448

She SoYANaVEeRO. SRO that

M sgentnvui 0/ SOLOMESNIONI more

M ON keoonVIZ m ton

Intermediate speduka 445

3-Bromo-7-hydroxyquinoline (5 g, 22.3 mmol) was dissolved in a mixture of OME (50 mL) and CH2ZON (50 mL).

(|1,1-bisidiphenylphosphino)ferrocene|dichloropalladium(s) (0.816 g, 1.12 mmol) and M(C2Hb)z were added

(6.76 g, 66.9 mmol). The mixture was stirred at 140°C overnight in a CO atmosphere (3 MPa).

The mixture was evaporated under vacuum. Then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate ratio from 10/1 to 0/1). The product fractions were collected and the solvent was evaporated to give intermediate 448 (2.5 g, yield: 45.195) as a yellow solid.

Stage 2

Preparation of intermediate compound 449

Ve

Yich o in the 7th century: writes: T A -k o still and this and not ak o and that

K shchenya zone sen mME Y v

Intermediate compound ii Intermediate compound 449

C 52 bOz (15.76 g, 486.37 mmol) was added to a mixture of intermediate 448 (4 g, 16.1 mmol) and benzyl bromide (2.76 g, 16.1 mmol) in HOME (50 mL) under ice cooling. The mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered.

The filtrate was concentrated under vacuum to give the crude product as a brown solid. The crude product was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate ratio from 20/1 to 5/1) to give intermediate 449 (4.2 g, yield: 8295) as a yellow solid.

Stage Z

Obtaining the intermediate compound 450 a "AK, sydy KT in t M o

Kk es things She -3333- ek le den kosh pi Zh

ОО cooling with lyol M o E i zak. universities" i

Intermediate compound 449 Intermediate compound "EATY

PANA (1.1 g, 28.3 mmol) was added to a mixture of intermediate 449 (3 g, 9.45 mmol) in TNE (60 mL) under M2 under ice cooling. The mixture was stirred at room temperature for 2 hours. H2O (0.3 ml) and aq. were added to the mixture. MabOH (1095, 0.3 ml). The mixture was filtered. The filtrate was treated with H2O (20 mL) and extracted with

EOAc (40 ml x 2). The organic layer was concentrated under vacuum to give the crude product as a solid. The product was purified by column chromatography (eluent: petroleum ether/EOAc, 1/2) to give intermediate 450 (822 mg, yield: 3290) as a solid.

Stage 4

Obtaining an intermediate compound 451 on 7 ne ve G seni Te i I I Manin! t Me

BACK i it in -8Ш8Ш8ШВШ.ШЩООНК и. y re a cha " y I I TMNE cooling M chu T yo:

Without , Y aa B -

Irradiated compound 20 A clear compound in which Mann bean (178 mg, 4.46 mmol) was added to a mixture of intermediate compound 450 (600 mg, 2.23 mmol) in TNE (30 mL) under Me" under ice-cooling. CH3 (316 mg, 2.23 mmol) was added and the reaction mixture was stirred at room temperature overnight. It was added to the mixture

EtOAc (40 ml) and water (20 ml). The organic phase was separated and dried over Mg 5 O, filtered and concentrated to give the crude product as a yellow oil.

The crude product was purified using a chromatography column (eluent:

petroleum ether/EAc, 1/2) to give intermediate 451 (620 mg, yield: 9895) as an oil.

Stage 5

Obtaining the intermediate compound 246 from Ve in Eg and ns ne E ra! y, And it's not too late

M MN and She

Intermediate compound I Radiated compound 246

VViz (1 g, 4.29 mmol) was added to a solution of intermediate compound 451 (600 mg, 2.15 mmol) in

SNCl2 (60 ml) at -70"C and the reaction mixture was stirred for 30 min. MeonN (40 ml) was added to the reaction mixture at -70"C. The reaction mixture was stirred for 10 min. The mixture was concentrated under vacuum to give intermediate 246 (400 mg, yield: 9595) as a yellow oil.

An example of AbZ

Preparation of the intermediate compound 263 pen ra a: ay eHa eta un, G Ya -k y yad, Z - i -x Her mice M Sha aty ton AB

Sil

Intermediate 474 Intermediate 2403

Intermediate compound 441 (1.2 g, 6.68 mmol), 4-chlorobenzylamine (2.84 g, 20.0 mmol) and UIEA (1.73 g, 13.36 mmol) were dissolved in CH3CM (25 mL). The mixture was heated at 1207"C for 1.5 hours using microwave radiation. The mixture was concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate ratio from 20/11 to 3/1 ) to give intermediate compound 263 (1.2 g, yield 3595) as a yellow solid.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 263 using the appropriate starting materials (Table 35).

Table 35

Structure of th a) Intermediate compound 441 274 -5 - . ху М ОН p) cyclopropylmethanamine

Example Abb

Stage 1

Preparation of the intermediate compound 452 of tvrMassy pmilazl Ir sim zon rem shya sotvrme

The licked compound 444 Intermediate compound iai

To a solution of intermediate compound 441 (5 g, 27.84 mmol) and imidazole (2.27 g, 33.5 mmol) in СНоСи2 (100 ml) was added TVOMZSI (5.04 g, 33.4 mmol) at 0"С . The reaction mixture was stirred at room temperature for 4 hours. Water (100 mL) was added and the mixture was extracted with SiCl" (80 mLx3). The organic phase was washed with brine (50 mL), dried over anhydrous Mg5O", filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1). The required fractions were concentrated to give intermediate 452 (8.0 g, yield 9895) as an oil.

Stage 2

Obtaining an intermediate compound of 453 kdd CO. RR". where I sing EM. SM is still owned by Y

Intermediate epoch 452 Intermediate compound 453

A solution of intermediate 452 (5 g, 17.0 mmol), Pa(PPyH3)2Sig (1.19 g, 1.70 mmol), and EBM (3.44 g, 34.0 mmol) in OME (10 mL) and MeOH (60 mL) was stirred in an autoclave at room temperature under CO (50 psi). The solution was heated to 807C overnight.

The reaction mixture was then filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1 to 1/1) to give intermediate 453 (3.4 g, yield 9890) as a pale yellow solid.

Stage Z

Preparation of the intermediate compound 454 shi Ma remny I naya

Intermediate compound 443 Intermediate compound Za

To a solution of intermediate compound 453 (1.5 g, 7.38 mmol) and imidazole (0.60 g, 8.86 mmol) in СНоСиг (80 mL) was added TVOMZ5СІII (1.34 g, 8.86 mmol) at 0 "WITH.

The reaction mixture was stirred at room temperature for 2 hours. Reaction mixture

Zo was poured into water and extracted with ethyl acetate (150 mlx3) and the organic phase was washed with brine (80 ml). The organic phase was dried over anhydrous Mag5O54, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate ratio 5:1).

The required fractions were concentrated to give intermediate 454 (2.4 g, yield 97.595) as a white oil.

Stage 4

Preparation of intermediate compound 455 pos., mavn. BONN university

І V стВ BUT ше ше вутірМме

Promchinenya connection of their Chromizhena gender I

A solution of intermediate compound 454 (1.9g, 5.98 mmol) in TNE (20 ml) was added dropwise over 5 min to a solution of MavVvna (2.264g, 59.85 mmol) in EUN (20 ml), cooled to 0"С ) in an M2 atmosphere. The solution was heated to room temperature and stirred for 2 hours. A saturated aqueous solution of ManHsoz (20 ml) and water (50 ml) were added to the reaction mixture. The mixture was extracted with EIOAc (80 ml x 3). About The combined organic layers were washed with brine (50 ml), dried over Mag5O4, filtered and concentrated to give the crude product - intermediate 455 (1.2 g, yield 66.59).

Stage 5

Obtaining the intermediate compound 456 according to the Ministry of Internal Affairs, CM, code ii bo te mech. | ; on the other side

NEK ik ut de tet TNE M. shiv dn terte mo stotvrMv tot vo etvrme

Prominena snolukia 455 Prominena compound and

To a solution of intermediate compound 455 (1.2 g, 4.15 mmol) and EM (1.26 g, 12.44 mmol), cooled in TNE (20 ml), M5CI (569.9 mg, 4.98 mmol) was added dropwise ) in the atmosphere of M".

The reaction mixture was stirred at 0"C under M" atmosphere for 30 minutes. Dimethylamine hydrochloride (1.69 g, 20.73 mmol, 5 equiv.) and EB6BM (4.195 g, 10 equiv.) were added. The reaction mixture was stirred at room temperature for 2 days. Water (40 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3).The organic layers were combined, dried over MgSO4, filtered and concentrated to give the crude product as an oil.

The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate ratio 1/1). The required fractions were concentrated to give intermediate 456 (550 mg) as an oil.

Stage 6

Preparation of intermediate compound 212. oh SUK и ди : Her и | TEAE. TNE | flshchyre Moscow Z zotome i M on

Promins compound 436 Promins compound 442

To a solution of intermediate compound 456 (500 mg, 1.58 mmol) in TNE (20 mL) was added dropwise

TVAE (1 M solution in TNE, 1.58 ml, 1.58 mmol) at room temperature in an atmosphere of M".

The reaction mixture was stirred at room temperature for 30 minutes. Reaction mixture

Zo was poured into water (40 mL) and extracted with EAs (50 mL x 3). The organic layers were combined, dried over Mag505, filtered and evaporated to give the crude product. The crude product was purified by TIS (CHNOSig/meon ratio 5/1) to give intermediate 212 (80 mg, yield 22.595) as a light yellow oil.

Example Ab7

Stage 1

Preparation of intermediate compound 457 and intermediate compound 458

SI; ! SI VE and NO. he p A shchi

In PI vu peaks SHO and OKO

Nam Vk o0 tvo Neo, vh ie

Ichkchinen compound Я Preominen compound ah

C-Chloro-5-bromoaniline (1 g, 4.84 mmol) was dissolved in 7595 H25O»x (10 ml). Glycerin (1.11 g, 12.1 mmol) and nitrobenzene (0.59 g, 4.84 mmol) were then added. The reaction mixture was stirred at 1507C for 3 hours in an M2 atmosphere. EtOAc (50 ml) was added and the pH of the mixture was adjusted to

6-7 using 3095 Maoson solution in water. The solid was filtered through celite and the organic layer was separated and evaporated. The residue was purified by flash column chromatography on silica gel (eluent gradient: petroleum ether/EuAcC from 20/1 to 5/1).

The required fractions were collected and the solvent was evaporated to give a mixture of intermediate 457 and intermediate 458 (750 mg) as a white solid.

Stage 2

Preparation of intermediate compound 459 and intermediate compound 460 shk o What what SI o

And AAU ovo field zol sapka ayu un m i

KG MN RarRESIv. Code. M i shi i

M i "VE t y te: TE -K I y A. y ! ime

Prominsna Promineny NIntermediate Radiated compound Я sveduka ЯZ compound cha compound 460

A mixture of intermediate 457 and intermediate 458 (750 mg), bis(pinacolato)diboron (942.5 mg, 3.7 mmol), Ra(arrOsSi" (113.1 mg, 0.155 mmol) and COAc (910.6 mg , 9.28 mmol) in TNE (20 ml) was stirred at 60"C for 2 hours in an M2 atmosphere. Water (30 ml) was added and extracted with EAs (30 ml x 3). The organic layers were combined, dried over

Mag5O., filtered and concentrated to give a mixture of intermediate 459 and intermediate 460 (1.0 g) as a yellow oil.

Stage Z

Preparation of intermediate compound 220a and intermediate compound 220r6

Ot Ov ohomEnovpetono 0 Azh re s o v od : i OO OZUT Kodoeyu

МО V ры ры ры ях ях ры ры ры для ШИНИ не ше: ШЙ

Intermediate Radiated Intermediate Intermediate compound 59 compound 460 spaluka g compound dav

To a mixture of intermediate compound 459 and intermediate compound 460 (1 g) in acetone (10 mL) was added dropwise a solution of oxone (1.25 g, 2.03 mmol) in H2O (10 mL) under a Ma atmosphere at 0"C. The reaction the mixture was stirred at 0"C for 1 hour. Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried over Mag 5 O 4 , filtered and concentrated. The residue was triturated in EtOAc/petroleum ether (1/10). The precipitate was filtered off and dried to give a mixture of intermediate 220a and intermediate 2205 (150 mg) as a yellow solid.

Example Ab8

From Preparation of intermediate compound 218

U. still ach, Se, SI. schi t

Ve Chto i rya 7 t Chto 7

KA, I Kooeu l, moty Ton mozh on s eyi

Intermediate: Intermediate sneluki 205 compound 218

A mixture of intermediate 205 (400 mg, 1.55 mmol), MeClCl (1.36 g, 12.4 mmol), bigo (88.5 mg, 0.62 mmol), and I-proline (142.5 mg , 1.24 mmol) in EUN (10 ml) was stirred at 11072 for 120 min using a single-mode microwave reactor. The reaction mixture was concentrated and purified by column chromatography (eluent: petroleum ether/ethyl acetate ratio from 1/0 to 1/1). The product fractions were collected and the solvent was evaporated to give intermediate 218 (350 mg, 9795) as a yellow solid.

An example of AbO

Preparation of the intermediate compound 235 /x in the same way

Ver cha ZHAV M tvo lit

There are r I I Y . mon t oyu

Prominena Yensoluki 24

The reaction was carried out twice.

Cyclopentylzinc(III) bromide (05 M solution, 7.14 ml, 3.57 mmol), bis(tri- tert-butylphosphine)palladium(0) (114.0 mg, 0.223 mmol) and tert-VSHOK (2504 mg, 2.23 mmol) in an atmosphere of M". The reaction mixture was heated to 1007C for 45 minutes in a microwave reactor.

The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give the crude product as a yellow oil. The two crude products were combined and purified on a silica gel column (petroleum ether/ethyl acetate 5/1 to 1/1) to give intermediate 235 (300 mg) as a yellow solid.

Obtaining the intermediate compound 240 sde di

Vei i i i She Ya il Se i mo plo

Intermediate compound 246

The reaction was carried out twice.

Isobutylzinc(III) bromide (05 M solution, 9.37 ml, 4.69 mmol), bis(tri -tert-butylphosphine)palladium(0) (319.3 mg, 0.625 mmol) and tert-"VYSOK (350.58 mg, 3.12 mmol) in an atmosphere of M". The reaction mixture was heated at 1007C for 45 minutes in a microwave reactor.

The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give the crude product. Two crude products were combined and

Zo was purified on a silica gel column (petroleum ether/ethyl acetate ratio 3/1 to 1/1) to give intermediate 240 (410 mg) as a yellow solid.

Example AB

Stage 1

Preparation of intermediate compound 505 shvi m-SVVA She i Z

V

You know everything

I tki with M Shoky "with rem I- o

Precritical compound ZU

C-Bromo-7-methoxyquinoline (5 g, 21 mmol) was dissolved in dichloromethane (50 mL). Then, 3-chloroperoxybenzoic acid (5.116 g, 25.2 mmol) was added to the mixture in portions at 0"C. The resulting mixture was stirred at room temperature overnight. The mixture was poured into a saturated aqueous solution of Ma»5Oz (30 ml). The mixture was extracted with dichloromethane (50 mL x 2). The organic phase was then washed with saturated aqueous Manso's solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Mag2505. A white solid precipitated, which was filtered to give intermediate 505 ( 6.4 g, output 87905).

Stage 2

Preparation of intermediate compound 506

Shk r ROSIZ Ve tr oh

K y y ot -62635Б5Б5БШБОШОШШШН X as a thing scha mm СсНез о и о

Converted compound 2 Prominent compound 306

Intermediate compound 505 (6.4 g, 18.25 mmol) was dissolved in chloroform (100 mL). Phosphorus oxychloride (20 mL) was then added and the reaction mixture was refluxed at 80°C for 3 hours. The solvent was removed under reduced pressure to give intermediate 506 (5.8 g, yield 9795) as a white solid, which was used at the next stage without additional purification.

Stage Z

Preparation of intermediate compound 507

EE ee | Where

Y Even I MNN v y gm OO Diokevn xx: She ke y

Intermediate compound C Intermediate compound 207

A mixture of intermediate compound 506 (3 g, 11 mmol) and MH3HgO (20 mL) in dioxane (20 mL) was heated in a hermetically sealed tube at 1207C for 72 h. The mixture was extracted with SNeSig (50 mL x 3). The organic phase was concentrated under vacuum to obtain the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/20 to 1/20) to give intermediate 507 (0.9 g, yield 32905) as a white solid.

Stage 4

Preparation of intermediate compound 477

VE sys, and Va VE, tsy i same vom en 7 in choasha: s pom M v s pe on

Intermediate compound 507 Solder compound 77

Intermediate compound 507 (1.2 g, 4.74 mmol) was dissolved in SiCl (12 mL). Then, the yellow transparent reaction mixture was cooled to 0"C and VViz (23.75 g, 94.82 mmol) was added. The reaction mixture

The mixture was stirred at room temperature for 16 hours. The reaction was slowly quenched with MeOH at 0"C and stirred at 15"7C for 15 min. The red suspension was concentrated. The pH of the residue was adjusted to 8 with aqueous NaHCO3. The precipitate was filtered and washed with H2O (10 mL).

The filter cake was dried under vacuum to give intermediate 477 (1.1 g, yield 9795) as an off-white solid.

An example of AZO

Stage 1

Preparation of intermediate compound 508

She sys S wa di schi nn i schi

M more than the mass M more than 7

Intermediate compound ZK

A mixture of 3-bromo-7-methoxyquinoline (10 g, 42 mmol), SiSi! (20g, 204 mmol), Masi (20 g, 345 mmol) and M-methylpyrrolidin-2-one (200 ml) were heated at 1207C for 2 hours. The reaction mixture was then stirred at 170°C for 2 hours. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution, ethyl acetate was added, and the mixture was stirred to dissolve the product. The mixture was filtered to remove the insoluble material and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (200 mL x 3) and the insoluble material was washed with warm ethyl acetate (200 ml x 3). Fractions with ethyl acetate were combined, washed with water, dried over Mag25O4 and evaporated under reduced pressure. The residue was purified by flash chromatography (eluent gradient: EIOAc/petroleum ether from 1/ 20 to 1/5) to give intermediate 508 (2 g, yield 2295) as a white solid.

Stage 2

Preparation of intermediate compound 509 - реее пк С bot Mt pr g y x-SRVA I: t : y Я -- (Ч-- - - - - - - Б 4--- ' - и ци о я сн вс 7 M cho Ga o

Irradiated compound 505 Irradiated compound 200

Intermediate compound 508 (2 g, 10.3 mmol) was dissolved in dichloromethane (40 mL). Then, 3-chloroperoxybenzoic acid (3.565 g, 20.65 mmol) was added to the mixture in portions at 0"C. The resulting mixture was stirred at room temperature overnight. The mixture was poured into a saturated aqueous solution of Ma»5Oz (30 ml). The mixture was extracted with dichloromethane (50 mL x 2). The organic phase was then washed with sat. compound 509 (2 g, yield 8390).

Stage Z

Preparation of intermediate compound 510

S te Kan Mi S. nih stu. 7 NI ter voez S shi ri zh kana na a Ya che ya

What a dream

Han

Premium compound 309 Intermediate compound ZI Y

zo Intermediate 509 (2.4 g, 18.25 mmol) was dissolved in chloroform (50 mL). Phosphorus oxychloride (10.5 g, 68.69 mmol) was then added and the reaction mixture was refluxed at 80°C for 2 hours. The reaction mixture was slowly poured into water. "7. The reaction mixture was extracted with dichloromethane (200 mlx2) and the organic layer was dried over anhydrous

Mag5O". The organic phase was concentrated to give intermediate 510 (2.5 g, yield 9395) as a white solid.

Stage 4

Preparation of intermediate compound 511

KA Siyu, tk om

SI bo ru Ku «AH | I and en sho VOASVIMAR vis R

CO'

Intermediate compound 341

A mixture of intermediate 510 (2.2 g, 9.64 mmol), benzophenone imine (1.78 g, 9.83 mmol),

PaY(OAcS)" (0.21 g, 0.96 mmol), VIMAR (0.6 g, 0.96 mmol), C52CO3 (6.28 g, 19.29 mmol) and toluene (50 ml) were heated at 1107C for 48 hours in an atmosphere of M". The catalyst was filtered and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel (eluent gradient: EIOAc/petroleum ether from 1/15 to 1/1). The product fractions were collected and the solvent was evaporated to give intermediate 511 (2 g, yield 5495) as an oil.

Stage 5

Preparation of intermediate compound 468

KT series ST sti, sch VVE Ii stv, schi t ni Zh zhA la mot - ;6« Chl EH-mom son ry Lety rem sce Gaya

Intermediate compound 311 Intermediate compound BU

Intermediate compound 511 (2 g, 5.2 mmol) was dissolved in SiCl (100 mL). Then, the yellow transparent reaction mixture was cooled to 0"C and BVgz (20 g, 79.84 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours. The pH of the reaction mixture was adjusted to 7, saturated with sodium bicarbonate solution and extracted with EtOAc ( 3 x 300 ml).

The combined organic layers were separated, dried over Mag25O4 and the solvent was evaporated to give intermediate 468 (2 g, yield 69.595) as a white solid.

Example A70

Preparation of intermediate compound 305 10

IS

En; soy 2,2,2-trifluoroethylamine / Фи - « - , лв и ие 6 6 65 65-56 --"7 Е С - EN Hermetically MM in

M in G, and a corked test tube, 400 z. during the night 7-bromo-2-chloroquinoline Intermediate 305

A mixture of 7-bromo-2-chloroquinoline (2.45 g, 10.1 mmol) and 2,2,2-trifluoroethylamine (5.0 g, 50.5 mol) in EN (60 mL) was stirred in a sealed tube at 120 " overnight. The reaction mixture was treated with aq. Mass (80 mL) and extracted with

KOS (80 ml x 2). The organic layers were combined and concentrated in vacuo to give

From an unrefined product. The crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether 0/1 to 3/7) to give intermediate 305 (2.5 g, yield 62.595) as a white solid.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 305 using the appropriate starting materials (Table 36).

Table 36

Structure and and 7-bromo-2-chloroquinoline

SI ovi zx 2-chloro-7-hydroxyquinoline 263 ro: M on (4-chlorophenyl)methanamine si -X . g. 274 Fe 2-chloro-7-hydroxyquinoline

Ua: M on cyclopropylmethylamine

KAH for propan-2-amine 299 АХ, zm Vg 7-bromo-2-chloroquinoline

N t. . 7-bromo-2-chloroquinoline se

Sh ach M Vg 320 s and 7-bromo-2-chloroquinoline

I cyclobutylamine

M M Vg 7 7-bromo-2-chloroquinoline z02 r b - m M Vg tert-butylamine and Y c. . . 290 uto 7-bromo-2 chloroquinoline

M cyclopentylamine

N si y . 293 Fa Intermediate compound 181

In M Vg cyclopropylmethylamine

Ve. 7 Intermediate compound 175 296 - cyclopropylmethylamine yes MI

Вг эх фе Intermediate compound 175 311 NM M Y cyclopropylamine

E. and: Intermediate compound 400 317 - cyclopropylmethylamine

M Mi Vg ia:

Example A71

Preparation of intermediate compound 338 in SH; M: Shi Em r y tia ben IF That Memnevyun ok DOM Ii

Dreams ana E | not Чи дн x!

AI tutioi ON i. and t residential complex.

Che M. em and in M. em p r ifromed compound 396 Intermediate compound 338

A mixture of intermediate 306 (520 mg, 0.95 mmol) and CH3MnO/EUN (15 mL) in EUN (15 mL) was stirred at 120°C overnight in a sealed tube. The reaction mixture was concentrated to give intermediate 338 (590 mg ), which was used in the next stage without additional purification.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 338 using the appropriate starting materials (Table 37).

Table 37

The structure is 7 watts.

H Intermediate compound 248 339 min methylamine - movement re M. M and what zm 340 H Intermediate compound 309

Mn methylamine t p a ho M. 2 M 7 chik

MM.

H Intermediate compound 321 341 Mn methylamine dO / 7 M ro M. 2 M

Say

E. FU va: m Intermediate compound 162 342 M 1 n methylamine tt ! With M.

Huh? M. 2" M ovi

SU.

Nam om o o Intermediate compound 262 343 in Zn methylaminated puh ho? M. em

Table 37

Structure si s nm tm Intermediate compound 183 344 M n methylamine y p She xx? M. 2 m 9

Nam m Intermediate compound 183,345 shchi; isopropylamine і і / і ro M. 2 M t

WITH

Nam m Intermediate compound 183 346 Mn cyclopropylamine

And y x y x? M. am 2

Namom Intermediate compound 327 347 o On methylamine tt ! and M. x M. 2 M that

Es nom cm Intermediate compound 315 for 48 p methylamine

M N ya Z ho M, em o p.

Nam m Intermediate compound 330 349 Mn methylamine

I ! and M ho M. em

Be watt:

H Intermediate compound 324 350 M n methylamine

Shy! y yo ho M. M 2

AH, zm.

Н Intermediate compound 300 351 M nn methylamine

I ! and M ho M. M

Table 37

The structure of the

Nam o ol Intermediate compound 262 352 in / dimethylamine

Mne L 5 M. ho M. em 7 t- Mn c C Intermediate compound 159 405 g and Its methylamine as 4

M m o a: - Intermediate compound 463 465 methylamine

Ku ivan o K r.: zdam g. svakh o

Н щ Intermediate compound 466 467 Mi H methylamine

CE and ex

J. Mem

SI

Zhe and Intermediate compound 469 470 from Zhe and methylamine

K i Zh MN x M. lam

E. s no Beh 2 Intermediate compound 473

TA o a methylamine p to chn re U

IS.

Sai nm ve? Intermediate compound 473 476 and riv МНН - МН and ке

Table 37

The structure of the vovi

WITH

NOM M (o) . o Intermediate compound 478 479 M n methylamine

University of Pei and R: M. Lem

Ve. garden? Intermediate compound 478 480 a МН»ОоН and СФЦІ side p: pass

Ve. s y Intermediate compound 478 481 a МН»ОоН 1 хх он b M r: zdam

Ve. - ev

NM M ge) y

Intermediate compound 484 486 Kn methylamine

SN p 7 xx M, lem

V". and nam - | Intermediate compound 488 489 and C» She MON and M

Ve. y nom y (c) t7oah H Intermediate compound 491 492 y ran methylamine

Example A72

Preparation of intermediate compound 353

Hm was dm bkie

Ka Yakth RZHON y Y chi 2 pah

TOM I pl. Mine EE OV tire I would beat KOH m / what else and M even M o i in Te "ke M ih Kh

Intermediate compound 202 Pre-lime compound 353

A mixture of intermediate 262 (310 mg, 0.61 mmol) in Meon (5 mL) was hydrogenated at room temperature (He, atmospheric pressure) with PaA(OH)2 (20 mg) as a catalyst over the weekend. After absorption of He (1 equiv.), the mixture was filtered and the filtrate was evaporated to give intermediate 353 (260 mg, yield 81.395), which was used in the next step without further purification.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 353 using the appropriate starting materials (Table 38).

Table 38

Structure and mm 354 "M Intermediate compound 248

There is it! 7 years M. 2-M sa p.

MM ro (o) sk 355 si A Intermediate compound 268

A Ho t! ho M. am 4

From M

N

356 Mi Intermediate compound 159 t ! with ho M. 2» M 7 well

Nam M

IF) I 357 M Intermediate compound 266

WHAT AND 7? M. 2 and s m

H o 358 M Intermediate compound 272

WHAT I 7 re M. 2M

Table 38

The structure of i wat y (o) 359 " Intermediate compound 259

What! 7 ho M. am / ovi s kt M ge

Assembly Intermediate compound 275 t! and ho? M. am sa

N

361 si that Intermediate compound 254

In / with the same M. s-m y

WITH

M M

WITH

362 "shk Intermediate compound 254 ot ! y ho M. 2-M / ovi

FU. mm (o) r: o) res 401 SI -o. Intermediate compound 264

With Ma

KAH mm o and Ge) 402 -a. Intermediate compound 270

She and I re MAM

Example A7Z

Preparation of intermediate compound 403

DOK nka from zhk. - ry au Ya «syu do yi i and how kak me s ia osi i 7 and ptn yi i ge. ko o An, "MN. Itermetically k - many

KI: Na tu She still se rarts ke it and still SHY Z I am a stuck-up simpleton, I Ot

M. U

Intermediate compound 119 Intermediate compound ХХ

A mixture of intermediate 119 (600 mg, 0.82 mmol) and CH3MnO/EUN (25 mL) in EUN (25 mL) was stirred at 120°C overnight in a sealed tube. The reaction mixture was concentrated to give intermediate 403 (600 mg ), which was used in the next stage without additional purification.

Example A74

Preparation of intermediate compound 404 bno bi san, YaOOZ du

M t (« y y -- zh re y ? o utkt bej try m v write more; tya a 7 me lish va would Kk boze ih A 1 t

Intermediate 224 Intermediate 404

Intermediate 228 (350 mg, 0.5 mmol) and methylamine (15 mL, 2 M) in EUN were stirred at 120°C for 1.5 h in a microwave reactor. The mixture was concentrated under vacuum to give intermediate 404 as a yellow solid substances The crude product was used directly in the next step without purification.

Example A75

Stage 1

Preparation of intermediate compound 363

Ka SH chi Z pkt

No and ; and IN

Xia in Ma sha shi

I eat her mk I | p she

My and she M iM tu I them

Intermediate compound 4 Preminent compound 353

A mixture of intermediate 1 (250 mg, 0.77 mmol) and MeOMa (331.5 mg, 6.14 mmol) in meon was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL) and extracted with SNessig (50 mL x 3). The organic phase was washed with brine (10 mL), dried over NaCl, filtered and concentrated to give intermediate 363 (250 mg, yield 9695), which was used in the next step of the reaction without further purification.

Stage 2

Preparation of intermediate compound 364

Coo)

and CHIYA) Bas roar CHIN en po and YAM, Ya tovs! then three times

About her MU. o, -v Me -M «A | yah

Intermediate compound 363 is a derivative of compound 36

Tov (0.415 g, 2.18 mmol) was added dropwise to a mixture of intermediate 363 (0.35 g, 11 mmol), triethylamine (0.455 mL, 3.27 mmol), and 4-dimethylaminopyridine (67 mg, 0.545 mmol) in dichloromethane (5 ml) under ice cooling. The mixture was stirred at room temperature for three hours. The mixture was quenched with water (10 mL) and extracted with SiCl (30 mL x 3). The organic phase was washed with saline (10 ml), dried over Mag5Ox, filtered and concentrated. Then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate ratio from 1/0 to 3/1). The product fractions were collected and the solvent was evaporated to give intermediate 364 (446 mg, yield 8695) as an oil.

Stage Z

Obtaining an intermediate compound 365 sh vit

Y z van NI i t ki KD - Zh! 1 rya ne ch Another 9-0 SSO and their omo shko ge

XX

Intermediate compound 304 Praminenv snoluka 305

A mixture of intermediate 364 (446 mg, 0.94 mmol), 2-amino-7-hydroxyquinoline (167 mg, 1.04 mmol), and C52bO2 (1.02 g, 3.13 mmol) in OME (5 mL) was stirred under room temperature overnight. The mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: ethyl acetate). The product fractions were collected and the solvent was evaporated to give intermediate 365 (257.3 mg, yield 53.390) as a solid.

Example A76

Preparation of intermediate compound 366 y shi m I Eit sn KK vk ee vosmaeon K Y Kod av chi na che ra a ka yah

Intermediate compound forehead Intermediate compound 366

A mixture of intermediate compound 306 (400 mg, 0.73 mmol) and MeOMa (158.2 mg, 2.93 mmol) in MeOHN (10 mL) was stirred at 60°C for 10 h. The mixture was diluted with water (20 mL), extracted

Zo with the help of SNeoSi" (50 ml x 3). The organic phase was washed with brine (10 mL), dried over Mag50, filtered and concentrated to give intermediate 366, which was used in the next step without further purification.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 366 using the appropriate starting materials (Table 39).

Table 39

Structure of compound 367 cha Intermediate compound 248 - 5 o. you are! r M. am

And with mm

N

368 A Intermediate compound 309 1 in 8 I ho M. M sa "y sia . 369 M Intermediate compound 162 tot I y o. r M. 2 M s

EeE s ze M 366 "o Intermediate compound 306 what / y: х? M am o nom cm 371 M Intermediate compound 183

With it! "Z o. ho M. 2eM

C nom" cm 372 o che Intermediate compound 327 7 I a o x M. s-m shchi:

EX

Nam cm 373 t Intermediate compound 315

M dl TA v, ho M. s-m

Table 39

Structure

E. y s nm M 374 dya t Intermediate compound 330 ot / y o. huh? M. M sa u: zm n Mini 375 s Intermediate compound 159 4 ex o. in I

Zh M. 2» m si from ov

M M (o)

Dt o Intermediate compound 469

A Zo b E these r: aa"

E. and

C, on M c mass Intermediate compound 473 to (c)

J co

Example A76

Preparation of intermediate compound 472

We are Oh

And no A. - sg same TSO i nti HU

І ІІ ІІ ІІ ІІ ЕК, Ж Ж A. V mon a fri, esch ; in Y M x Me

In x and DN: and E oleg

And In | y MY ke im What that Bya is Ж in Кк Zach shchy rai t ko ih ZNO she

Intermediate 471 Intermediate 47

Intermediate 471 (900 mg, 1.36 mmol) was dissolved in TEA (3 mL).

The reaction mixture was stirred at 507C for 7 hours.

The solvent was evaporated to give the required intermediate compound 472 as an oil.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 472 using the appropriate starting materials (Table 49).

Table 49

Structure o ah v i n 521 What pt Intermediate compound 526

M x E ve no on Me

Ve

E y o y Sho eE M ; 535 - mn, Intermediate compound 534 (9) Y:

BUT he f

Example A77

Obtaining intermediate compound 376 m nay ev hak in CH; Mešt a - shchi i same Khar s | Ker dya not in Z

Y 9th M. M pvokozn oo Y a in M. em as x a KZ u

Intermediate compound 370

To intermediate 264 (330 mg, 0.44 mmol) and CzNoBzOz (164 mg, 1.3 mmol) in dioxane/H2O (6 mL, dioxane/H2O ratio 5/1) was added KzRoOx (277 mg, 1.3 mmol ) and 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (28.3 mg, 0.04 mmol). The mixture was stirred at 80°C overnight. The mixture was treated with water (30 mL) and extracted with ethyl acetate (40 mL x 3), dried (Ma 5 O 4 ), filtered and concentrated in vacuo to give the crude product as a brown oil. The crude product was purified by flash column chromatography (eluent gradient: petroleum ether:ethyl acetate from 20/1 to 3/1) to give intermediate 376 (170 mg, yield 6995) as a yellow oil.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 376 using the appropriate starting materials (Table 40).

Table 40

The structure of the

ZM

377 A Intermediate compound 248 t ! in; ho M. 2 s mm o y 378 y; m 7" Intermediate compound 268

SI in? M. 2 M

Table 40

Structure of the village

Me and shchi;

N

379 M Intermediate compound 159 ol ! y ho M. am s i nam M 380 o shi Intermediate compound 266 ot LIVe: х? M. 2 M 4 well where

N

381 si Mi Intermediate compound 245 7 ! and ho M. am

Example A78

Stage 1

Preparation of intermediate compound 382

Mod

N -- y M A no in Ve - zt, here the place of HOM, as it is VIV, KORM. мне МИ I and mli res shen Vinilt M Nd B oliv RK and I M and Ya schy Vinyltrifluorosrate potassium, rya He

BGreomnixny compound about and MO zvotatinE refrigerants, And their yah And lioxan. NO Intermediate 382

To a solution of intermediate 159 (0.85 g, 1.28 mmol) in dioxane (20 mL) and HO (5 mL) was added potassium vinyl trifluoroborate (223 mg, 1.67 mmol) and potassium tribasic phosphate (544 mg, 2, 57 mmol) at room temperature. 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (42 mg, 0.064 mmol) was added to the above solution under a nitrogen atmosphere. The reaction mixture was stirred at 80"C under a nitrogen atmosphere overnight. The mixture was extracted with ethyl acetate (20 ml x 2), the organic layers were combined and concentrated under vacuum. The residue was purified using a column for chromatography (eluent gradient: ethyl acetate/petroleum ether from 1 /10 to 1/1).The required fractions were collected and concentrated to give the product intermediate 382 (400 mg, yield: 6090) as an oil.

Stage 2

Preparation of intermediate compound 383 s ke dt» st she ku vyttzh sia XX A, ak ch a yam otpaAyuNyuyu 07sva rn sh s u y --- anna t ai ho MI NE AN MAM

Intermediate compound How Intermediate compounds 381

Trifluoroacetic acid (0.5 mL) was added to a solution of intermediate 382 (400 mg, 0.78 mmol) in СНоСи (10 mL). The mixture was stirred at room temperature for 3 hours.

The mixture was evaporated under vacuum to give intermediate 383 (300 mg, yield: 4890).

Example A79

Preparation of intermediate compounds 384 and 385 in the M mod nalsnlto memno i; Z nav: ba t ia A y peda m t I shk dn

Promins compound 202 Intermediate compound 384 Intermediate spelukia 385

MegMn (20 mL) was added to a mixture of intermediate 262 (200 mg, 0.43 mmol) in dioxane (20 mL) and stirred in a sealed tube at 1107C overnight. The reaction mixture was concentrated to give a mixture of intermediate 384 and intermediate 385 (210 mg) as a solid.

Example A8O

Stage 1

Preparation of intermediate compound 412

Se GE you KN, not -K GoTe sia M sp v

Hey zo noya

Ve.

Radiation 412

A mixture of 2-amino-4-bromobenzaldehyde (13 g, 65 mmol) and urea (54.6 g, 910 mmol) was heated to 1807C in an oil bath for 2 hours. The reaction mixture was then cooled to room temperature and H2O (500 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to give intermediate 412 (16 g, yield 9395) as a white solid.

Stage 2

Preparation of the intermediate compound 413 ME ROS of the sea

BUT td em; We are studying it with J

Intermediate compound h12 Intermediate compound 414

A mixture of intermediate compound 412 (16 g, 71 mmol) and ROSI3z (280 g, 1.84 mol) was heated to 1107C

Zo in an oil bath in an atmosphere of Mo for three hours. The reaction mixture was then cooled to room temperature and poured into ice/water (4000 g). The reaction mixture was stirred at room temperature for one hour and extracted with ethyl acetate (2000 mL x 2).

The organic layer was washed with brine and dried over anhydrous Mag5Oa.

The solvent was evaporated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/5) to give intermediate 413 (10 g, yield 5395) as a white solid.

Stage Z

Preparation of intermediate compound 386

My RIMVICHN. M'Zae i vi emeecheivk Set vm M menya vk td Yita

Firominene compound and compound of 413 compounds

And Zyy

A mixture of intermediate 413 (4 g, 16.5 mmol), 4-methoxybenzylamine (3.4 g, 24.6 mmol), and cesium carbonate (15 g, 49.3 mmol) in TNE (100 mL) was stirred at room temperature for 12 hours. The reaction mixture was filtered and the filtrate was evaporated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/10) to give intermediate 386 (2.3 g, yield 2996) as an oil.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 386 using the appropriate starting materials (Table 42).

Table 42

Structure

Mo

276 Zh r Intermediate compound 413

Ua Mi B cyclopropyl methylamine n

Mo

Intermediate compound 413 287 - 2 p cyclopropylamine

M M Vg

N

Stage 4

Preparation of the intermediate compound 387 9 вхет р Rayn speluk Met Khody

EMV. rya "In the fall, it's still hot and cold, and it's hot

ON Men tribal compound yo sh

Intermediate compound 346 Intermediate compound 347

Intermediate compound 38 (1.5 g, 4.69 mmol) in 9-VBM (0.5 M in TNE, 56.3 mL, 28.1 mmol) was heated under reflux for 1 h under M2 atmosphere. The mixture was cooled to room temperature, then KzRoOx (2.98 g, 14.1 mmol) in H2O (5 mL) was added, followed by TNE (40 mL), intermediate 386 (2.1 g, 6.1 mmol) and Ra-118 (61.1 mg, 0.094 mmol). The resulting mixture was heated under reflux overnight. The mixture was diluted with

H2O (50 ml), extracted with ethyl acetate (150 ml), the organic phase was dried over Ma250", then filtered and concentrated under vacuum to give the crude product.

The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/10) to give intermediate 387 (1.3 g, yield: 47905) as an oil.

Stage 5

Preparation of intermediate compound 388

M lyk g

RICHIV.. hmm I am my neck

M A p i kim A dyh - S He S M i t z mot ny i rana nab

Intermediate compound 347 Intermediate compound 938

Intermediate 387 (500 mg, 0.85 mmol) was dissolved in TEA (10 mL) and stirred at 60°C for 1 h. The mixture was concentrated to give crude intermediate 388 (1 g) as a solid.

Example A81

Stage 1

Preparation of intermediate compound 389 m

RM. t I had I them

In Shk M M chichne M ryh

Prominent compound 387 Intermediate compound 359

A mixture of intermediate 387 (450 mg, 0.77 mmol) and MH3HgO (10 mL) in dioxane (10 mL) was heated to 80°C for 24 h in a sealed tube. The reaction mixture was extracted with ethyl acetate (50 ml x 3). The organic layers were separated and dried using

Ma?»5O»x and the solvent was evaporated to give intermediate compound 389 (290 mg, yield 66.695) as an oil.

Stage 2

Preparation of intermediate compound 390

DITCH. re ar ii one

I і і вк вы ТРА гЯ pr tu ket, а ФО ИН pn o V iv M. "МН

OA shi MN shdd v sho SHA

Ж Я М я ВН М.

Intermediate compound 249 YaProzpzhna snoluka 380

Intermediate 389 (290 mg, 0.51 mmol) was dissolved in TEA (10 mL) and stirred at 60°C for 1 h. The mixture was concentrated to give crude intermediate 390 (300 mg) as an oil.

Example A82

Preparation of the intermediate compound 347, which is not sealed, sealed, sealed, sealed, sealed, sealed, sealed, sealed

Irradiated snoluka 327 Prozmed compound 247

A mixture of intermediate 327 (1100 mg, 2.20 mmol) in methylamine/ethanol (30 mL, 4095) was heated in a sealed tube at 807°C for 24 h. The organic phase was concentrated to give intermediate 347 (1.2 g, exit 9990).

Example A8Z3

Preparation of intermediate compound 372

PI, what kind of honor do you have?

BI pi or re: zi

Intermediate compound 327 Intermediate compound 372

A mixture of intermediate compound 327 (550 mg, 1.1 mmol), sodium methoxide (356.3 mg, 6.60 mmol) in methanol (10 mL) was heated under reflux at 60°C for 12 h. The reaction mixture was evaporated under vacuum Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 2), the organic layers were combined and evaporated in vacuo to give intermediate 372 (510 mg, yield 7595) as an oil.

Example A84

Stage 1

Preparation of intermediate compound 393 no ran EE et CHIA penya t Y. m-SVNA y y te

N --------2 N yacht t wok te. - that Be ka

M se Ve SN", kt, tod M 7 Ve o

Intermediate compound 393 7-Bromo-3-(trifluoromethyl)quinoline) (1.0 g, 3.62 mmol) was dissolved in USM (30 mL), m-SRBA (1.25 g, 7.25 mmol) was added to the mixture in portions . The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of saturated Magno2Oz (50.0 ml) and 1 n. aqueous Mahon solution (50 ml). The mixture was then extracted with OCM (200 mL x 2) and the combined organic phases were washed with brine (100 mL), dried over anhydrous

Ma?5O", was filtered and concentrated to give the product - intermediate compound 393 (1.0 g, yield 8095) as a brown solid, which was used in the next step without further purification.

Stage 2

From Preparation of intermediate compound 394

ES tn dit, : I as hunger - Am Ash LK

M EE SNO inverse | siyi Шы ше "Where

Intermediate conjugation 391 Intermediate compound to

Intermediate 393 (200 mg, 0.685 mmol) was placed in CHCl3 (10 mL). ROSI" (1.0 ml) was added at room temperature. The reaction mixture was stirred at 80°C for 12 hours. The solvent was removed under reduced pressure, the residue was triturated with ethyl acetate (50 ml) and saturated magnesium hydroxide (50 ml), the organic layer was separated, the organic layer was washed with brine (50 ml) and dried over with anhydrous Mag5O4.The solvent was removed under reduced pressure to give intermediate 394 (200 mg, 83905) as a brown oil.

Stage Z

Preparation of intermediate compound 314

Bas du neck A oh and you - nin abi y : І І МНІ NaSudiokszn still se: a: o den shu ik m

S byu zDr o autoclave MY Na Zv

Proactive compound 354. ? And Prechizhnia compound 314

Intermediate 394 (2.2 g, 5.43 mmol) was dissolved in dioxane (30 mL) and MnH2O (30 mL) was added. The reaction mixture was stirred at 120"C in an autoclave overnight. The solvent was removed under reduced pressure, the residue was purified by column chromatography (ratio

Eas/petroleum ether: 0/10 to 1/10) to give intermediate 314 (1.4 g, yield 88.695) as a white solid.

Example A85

Obtaining an intermediate compound 348 days after extinguishing the fire Em - kh i nm en nn ani ShChI z y Ka Mn 7 o i i i NM uttya rik Ko autoclaves GI v y: vi I , V o iah -h

K. I. and Z

BIntermediate compound 3214 ФToo-intermediate compound ЛЯ

Intermediate compound 315 (420 mg, 0.79 mmol) was dissolved in an ethanol solution of MemMnNe" (3095,

30 ml) and EN (30 ml). The reaction mixture was stirred at 100°C in an autoclave for 12 hours. The solvent was removed under reduced pressure to give intermediate 348 (450 mg, crude) as a brown solid, which was used in the next step without further purification.

Example A8b

Stage 1

Preparation of an intermediate compound 373 i and p pkc E-I ih r as i kv i A yu U Ж АКВА ше TA ; know, svi 0 MebMaMmeonN, ek We are

Kk YAK chiv na , M ee i- MM and 12 ha and her yu

Ha Ka t i v. Measure: A

Irradiated spluka 315 Intermediate compound 373

Intermediate compound 315 (300 mg, 0.56 mmol) was dissolved in Meon (20 mL), and MeOMa (483 mg, 4.46 mmol) was added. The reaction mixture was stirred at 70"C for 12 hours. Solvent

Zo was removed under reduced pressure to give intermediate 373 (340 mg, crude) as a brown solid, which was used in the next step without further purification.

Example A87

Stage 1

Preparation of the intermediate compound 395 x x ; U o to, ) -- Y -y-- ra - poh V oy 1 rom oke A 2 5 й-,7 bo ul one OM ОЙ в-

Ko s tn o te V o

BPoeuvchizhny compound 395

Potassium salt of 1H-isoindole-1,3(2H)-dione (1:1) (50 g, 221.9 mmol) and 2-bromo-1,1-diethoxyethane (54.7 g, 277.4 mmol) in OME was stirred at 1507°C for 4 hours. OME was removed under reduced pressure. The residue was purified by column chromatography (elution: petroleum ether/ethyl acetate ratio 5/1) to give intermediate 395 (40 g, yield: 6495) as a white solid .

Stage 2

Preparation of intermediate compound 396

DE te o B shk di, EE a

Nromium compound 355 Slip compound 396

A mixture of intermediate 395 (22.1 g, 84.0 mmol), 4-bromo-2-aminobenzaldehyde (14 g, 70.0 mmol) and p-MeSeNaZOzN.HgO (13.3 g, 70.0 mmol) in RyMe (200 ml) was heated under reflux for 4 hours. The mixture was cooled and filtered. The solid was washed with toluene to give the crude RTBZA salt of the product as a brown solid. The solid substance was stirred in saturated aq. sodium bicarbonate and extracted with dichloromethane. The solvent was evaporated and the remaining solid was suspended in ethanol and collected to give intermediate 396 (14.2 g, yield 56905).

Stage Z

Preparation of intermediate compound 397

TU 5;

U I MEM VA, ee

Ov

Intermediate compound 396 Intermediate compound 397

A suspension of intermediate 396 (14 g, 38.5 mmol) in ethanol (150 mL) was treated with MNeMH.HgO (4.5 g, 76.9 mmol) and heated to reflux for 1 h. The mixture was cooled and filtered. The filtrate was collected and evaporated to give intermediate 397 (8.6 g, yield 9495).

Stage 4

From Preparation of intermediate compound 398

Ka voOMO sr that s menya Ve ve ts ve dv

Irradiated compound 397 Industrial compound 358

Intermediate compound 397 (8 g, 35.86 mmol) was dissolved in RICE (80 mL). Boron trifluoride diethyl etherate (4.45 ml) was added dropwise over 10 min. The mixture was heated to 60°C. At this temperature, tert-butyl nitrite (6.1 ml) was added dropwise over 20 minutes. The reaction solution was heated to 1007°C and stirred for 1 hour. The mixture was cooled and poured into an ice/water solution of sodium bicarbonate. The mixture was extracted with

SNeSi2 (500 ml x 2). The combined organic layers were washed with brine, dried (Mag2504) and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography (eluent gradient: petroleum ether/ethyl acetate from 1/0 to 20/1) to give intermediate compound 398 (1.57 g, yield 1990).

Stage 5

Preparation of intermediate compound 399

Ese ek ssh pools, masRVA

M g 5

Intermediate compound Irradiated compound 398 of 99

A mixture of intermediate compound 398 (1.57 g, 6.95 mmol) and m-SRBA (2.1 g, 10.4 mmol) in CNeSys (30 mL) was stirred at 507°C overnight. The reaction solution was quenched with Ma? "5Oz (50 mL) and basified with Mansoz solution (50 mL). The mixture was extracted with SNeoSi" (300 mL x 3). The combined organic layers were washed with brine, dried (Mg5Ox), filtered, and concentrated in vacuo to give intermediate compound 399 (2 g, yield 97.29) as a brown solid.

Stage 6

Preparation of intermediate compound 400

Generic BE. to RUSSIA:

M. S. M. BE

Intermediate compound Intermediate compound zvo 0

A mixture of intermediate compound 399 (2 g, 6.75 mmol) and ROSI" (10.6 g, 69 mmol) in SNe"z (40 mL) was heated under reflux for 3 hours. The reaction solution was poured into water (100 mL) , alkalized with Mansoz solution (80 ml) to pH » 7 and stirred for 5 min.

The mixture was extracted using USIM (500 ml x 3). The combined organic layers were washed

With brine, dried (Mg25O:), filtered and concentrated under vacuum to give the crude product as a yellow solid. The crude product was purified by column chromatography on silica gel (ratio of petroleum ether/ethyl acetate from 1/0 to petroleum ether/ethyl acetate 10/1). Pure fractions were collected and the solvent was evaporated in vacuo to give intermediate 400 (1.4 g, yield 7895) as a white solid.

Stage 7

Preparation of intermediate compound 329 sr MNN, et sim dv, VYUMLODYAS NM SM r

Intermediate compound Irradiated compound 6,328

A mixture of intermediate 400 (600 mg, 2.3 mmol) and MNa-HgO (15 mL) in CH2CH2O2 (15 mL) was heated in a sealed tube at 1207C overnight. The mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate from 20/1 to petroleum ether/ethyl acetate 1/1). Pure fractions were collected and the solvent was evaporated in vacuo to give intermediate 329 (390 mg, yield 67905) as a white solid.

Example A88

Stage 1

Preparation of intermediate compound 330

Here is the child

E kh ih Zvorotny nem BI y peni ev tt refrigerator I --

C C 1 zu RANA, KOR | in ACT

Nam Vk povoootny. books by Dr. V

Intermediate snolukahovodiliik, TE 0 Dyrolioena and M. em 429 spoduka 340 ih

Intermediate 38 (470 mg, 1.47 mmol) in 9-VVM (0.5 M in TNE, 11.8 mL, 5.9 mmol) was heated under reflux for 1 h under M2 atmosphere. The mixture was cooled to room temperature, then KzPOx (936.6 mg, 4.41 mmol) in HO (2 mL) was added, followed by TNE (20 mL), intermediate 329 (390 mg, 1.62 mmol) and Ra- 118 (19.2 mg, 0.029 mmol). The resulting mixture was heated under reflux overnight. The mixture was diluted with

H2O (80 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried over Mag5Ox, then filtered and concentrated under vacuum to give the crude product.

The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/3) to give intermediate 330 (460 mg, yield 5595) as a yellow oil.

Stage 2

Preparation of intermediate compound 374 and peso s e sova ss

M; I ate dreams as much as Z pyt tt , v

Preominenia r zutteu FEENYUN Interim rei "rt in spaluka 330 ne M. re Ho snolEka I 7 I. 5 M sy r X jah

A mixture of intermediate 330 (400 mg, 0.70 mmol) and CH2OMa (380.17 mg, 7.04 mmol) in

SNZON (15 mL) was heated under reflux overnight. The mixture was concentrated under vacuum. The residue was treated with water (60 mL) and extracted with EIOAc (100 mL x 3).

The combined organic layers were washed with brine, dried (Mg5O54), filtered and concentrated under reduced pressure to give intermediate 374 (350 mg, yield 8795) as a brown oil.

Example A89

Stage 1

Preparation of intermediate compound 323 of the Holy Spirit

EN N - - -- as N early sake and bitches V, child and

HnYA M IEE Y M Se

Prazmiinenii Pyrecchineni compound and compound 324

A solution of intermediate compound 400 (400 mg, 1.54 mmol) in CH3MnHg (4095 solution in 20 ml

SNaiSNgOH) was heated in a hermetically sealed test tube at 1207C overnight. The mixture was concentrated under vacuum. The crude product was purified by column chromatography (eluent gradient: petroleum ether/ethyl acetate 20/1 to 5/1) to give intermediate 323 (350 mg, yield 89905) as a yellow solid.

Stage 2

Obtaining intermediate compound 324 sha

B. stn deya yi M 7 S y be AH X y " z rev, r! sa y MO V mk -y y bu SI ; Intermediate b M. ek

Intermediate and MA zh che M compound 323 compound 324 yah

Intermediate 38 (365 mg, 1.14 mmol) in 9-VBM (0.5 mol/L in TNE, 11.4 mL, 5.72 mmol) was heated under reflux for 1 h under M2 atmosphere. The mixture was cooled to room temperature, then KzPOx (728 mg, 3.43 mmol) in HgO (2 mL) was added, followed by TNE (20 mL), intermediate 323 (350 mg, 1.37 mmol), and Ra-118 ( 14.90 mg, 0.023 mmol). The resulting mixture was heated under reflux overnight. The mixture was diluted with

H2O (80 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried using

Mag5O", was filtered and concentrated under vacuum to give the crude product.

The crude product was purified by chromatography (ethyl acetate/petroleum ether 1/10 to 1/5) to give intermediate 324 (350 mg, yield 6195) as a yellow oil.

Stage Z

Obtaining the intermediate compound 350 si B. dl

And more sons 7 more ssh 71 n va Ofnnnn and v

Intermediate and ru Nrvromivesna pe an compound 324 sho M. em compound 350 9-0 M. M р р

A solution of intermediate compound 324 (350 mg, 0.71 mmol) in CH2MH" (a solution of 4095 in 10 ml of ЕН) was heated in a hermetically sealed test tube at 1207С overnight. The mixture was concentrated under vacuum to give intermediate 350 (350 mg, yield 9790).

Example of AZ9O

Preparation of intermediate compound 349

RE. dyat still sh Ek chnyi I nm M Me ! that snHMN; Nam M y. Щ что о ци С в , MA rt So iliyM,

Praminesnya o in M. m Intermediate b M. sneluka ZV KO t compound 349 A What

N and H

A solution of intermediate compound 330 (350 mg, 0.726 mmol) in CH2MNa (4095 solution in 15 ml

SNaiSNgOH) was heated in a hermetically sealed test tube at 1207C overnight. The mixture was concentrated under vacuum to give intermediate 349 (350 mg, yield 99.9965).

Example A91

Stage 1

Preparation of the intermediate compound 414 and yes

Sh r -y r zh y Ya. r on Mol i UM ay ze - p ikh syu Ga) ody: " o "bok sha ? about higher: M det" and m KE ud si

At 5 - "(5 I and 0 Main Eeve. VIDO. TNE b Mao yah yah

Radiate m ka ; Yaromyzhny speluk compound 414

In a solution of intermediate compound 1 (1.0 g, 4.9 mmol), 7-hydroxyquinoline-2-methylcarboxylate (1.36 g, 4.18 mmol) and PPIz (2.58 g, 9.84 mmol) in TNE (10 ml) was added OIAU (1.99 g, 9.84 mmol) at 0"C. The mixture was stirred at room temperature overnight in an atmosphere

M". Water (25 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saline (1000 ml). The organic phase was dried over anhydrous

Ma?5O", was filtered and concentrated to obtain the crude product in the form of an oil.

The crude product was purified by column chromatography on silica gel (elution: petroleum ether/ethyl acetate at a ratio of 1/1). The necessary fractions were collected and concentrated to obtain the product - intermediate compound 414 (1.2 g, yield 3195) as a solid.

Stage 2

Preparation of intermediate compound 415 bora o kny khm koyuttiai o VK she Z i ke v - Malk sh-- a ee she: SHI ; nn those

Mt in Mayu ped ono m. UM she Ma. eM u x ke u

Irradiated compound 414 Irradiated compound 415

To a solution of intermediate compound 414 (600 mg, 1.18 mmol) in EN (5 ml) was added Mavna (0.132 g, 3.53 mmol) at room temperature under an atmosphere of M". The reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added, and the mixture was extracted with SNES (50 mL x 3). The organic layers were combined, dried (Ma»5O4), filtered and concentrated to obtain the required product in the form of an oil. The crude product was purified by column chromatography on silica gel (eluent: ethyl acetate). The required fractions were concentrated to give intermediate compound 415 (0.27 g, yield 54.395) as a solid.

Stage Z

Preparation of intermediate compound 416

Not AH vk as I milk your shi a chdnia sla en vik Oto t M shov chek pe a TT GOM o A MK y: PI --y -M mice r her b vom! p

Promioune compound 315 Preolymene compound 416

Coo)

To a solution of intermediate compound 415 (0.27 g, 0.56 mmol) in anhydrous OME (5 mL) was added 6095

Mann (33.5 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 20 min in an argon atmosphere. Mei (158 mg, 1.12 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into ice water (10 mL) and extracted with SNeSig (40 mL x 3). The combined extracts were washed with saline, dried over Mag25O.:, filtered and evaporated to obtain the product in the form of an oil. The crude product was purified on a column (eluents: petroleum ether/ethyl acetate 20/1 to 1/1) to give intermediate 416 (120 mg, yield 4395) as a solid.

Stage 4

Preparation of the intermediate compound 417 soyu shi yan sho bi i di, shtan syo i ov STAT t -- 1 u N ny 1 pra sche dikeane Y M ia Me su x Z EV a yi 1 g shi M Hr M sce C) M Ж Meh meh meh

Intermediate compound whose Intermediate compound 417 y

A solution of intermediate 416 (120 mg, 0.24 mmol) in MnH2O (5 mL) and dioxane (5 mL) was stirred in a hermetically sealed tube. The mixture was stirred at 90°C overnight. The reaction mixture was concentrated to give the crude product as an oil.

The crude product was purified by rger-THS (OSM/Meon: ratio 10/1) to give intermediate 417 (70 mg, yield 4495) as a solid.

Example of AZ2

Stage 1

Preparation of intermediate compound 418 on rda on 1 M x: --a o i, vimetaxinronan k-o pk se ketanestulphonic acids: and with M

H is also methanesulspheonic acid. s i chi i bnomo M acetone, OME, C, om ulky, -M h o d scha 5AM d4depoznm Nromine compound 415

To a solution of adenosine (75 g, 281 mmol) in acetone (1200 mL) and OME (400 mL) was added 2,2-dimethoxypropane (35.1 g, 336.8 mmol) and methanesulfonic acid (40.5 g, 421 mmol). ) in the Ma atmosphere. The reaction mixture was stirred at 60°C for 2 h. The reaction mixture was treated with aqueous Mansoze (pH to 7-8) and then concentrated under reduced pressure. The residue was diluted with H2O (1200 mL) and extracted with ethyl acetate (1500 mL x 3). The organic layers were combined, washed with brine (500 mL), dried, and concentrated under reduced pressure to give intermediate 418 (85 g, yield 96.395) as a white solid

From substance.

Stage 2

Preparation of intermediate compound 419

TOM, he o x- Z g -a also si code shi tVOMBS SYA ZYM and o a MN, - 3: 2 - --k shchi a M u-MN, r ia 5 deila hall. PM cat uk shk y y y a M ok imidazole, PMEE, cat, | with.

Intermediate compound 415 YM Intermediate compound Y19

To a solution of intermediate compound 418 (87.8 g, 286 mmol) and imidazole (38.9 g, 571.4 mmol) in OME (800 mL) was added TVOM5Si (51.67 g, 342.8 mmol) at room temperature in atmosphere of Me".

The reaction mixture was stirred at room temperature overnight. Water (1000 mL) was added at room temperature, then a white solid formed and was filtered off. The solid was collected and dissolved in ethyl acetate (1500 mL) and washed with brine (500 mL). The organic phase was dried over anhydrous MgSO, filtered and concentrated to give intermediate 419 (120 g, yield 9995) as a white solid.

Stage Z

Preparation of intermediate compound 420

your TV / Z M x- o s M y i | | am Z

Tu Voszo, OMAR i TM shi 00 Vos

I Eh i u-MNe - 5 5 - -t gi i MA 2 re; M. M TNE, k. t., ha ts. M ves i ik , m KU

HProzyme compound 419 Intermediate compound 420

A mixture of intermediate 419 (116.3 g, 275.9 mmol), OMAR (3.37 g, 27.6 mmol) and TNE (1500 mL) was stirred at room temperature. VosgO (150.5 g, 689.7 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated under vacuum. The residue was dissolved in ethyl acetate (1500 mL) and washed with brine (1000 mL). The organic phases were combined, dried over anhydrous Ma»50O4, filtered and concentrated to give intermediate 420 (170 g, yield 83905) as a white solid.

Stage 4

Preparation of intermediate compound 421

TvoMV, he Vysh vh oletsi M Kati, M, Vos ny h tA, os TVA ot r NI a h y z M - «--f- U -i M M ek

Intermediate snoluki 42 Prominny compounds and

TVAE (1 M in TNE, 238.8 ml, 238.8 mmol) was added dropwise to a solution of intermediate compound 420 (176 g, 238.8 mmol) in TNE (2000 ml) at room temperature under an M atmosphere.

The reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into

From water (2000 ml) and extracted with ethyl acetate (2000 ml x 3). The combined organic layers were dried over NaCl 5 O, filtered and evaporated to give the crude product. This residue was purified by flash column chromatography on silica gel (eluents: petroleum ether/ethyl acetate from 10/1 to 1/1). The required fractions were collected and the solvent was evaporated to give intermediate 421 (85 g, 72.595) as a yellow oil.

Stage 5

Preparation of intermediate compound 422

Ve di t s FA nek., on Ve o ya ek T K M h a --y tem shi «en io, im Vyus ra shi shi, EBoe Chromium compound 290 i Z Sa M vaye

ЯМ -- - Я - ' 9 in M.

OM, oobie o RENUVIAV.OTNE, K. t, ra

Intermediate compound Х2и Intermediate compound 22

To a solution of intermediate compound 421 (1 g, 1.97 mmol), intermediate compound 200 (509 mg, 1.97 mmol) and OIAO (1.19 g, 5.91 mmol) in TNE (20 mL) was added PP: (1 .55 g, 5.91 mmol) at room temperature in an atmosphere of M". The mixture was stirred at room temperature for 4 hours. Water (40 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over NaCl, filtered and concentrated under reduced pressure to give the crude product. This residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 10/1 to 2/1). The necessary fractions were collected and the solvent was evaporated to obtain the product in the form of a yellow oil.

Oil was purified using NRI C, column: Rpepotepeh Setipi C18 250 x 50 mm x 10 μm; conditions: A: water (0.0595 ammonium hydroxide vol./06.), B: MesSM; at the beginning: A (4895) and B (5295), at the end: A (1895) and B (8295); gradient elution time (min) 30; 10095 During retention (min) 5; flow rate (mL/min) 90) to give intermediate 422 (650 mg, yield 4195) as a white solid.

Example AZ9Z

Preparation of intermediate compound 423

Stage 1

CHI tA in CHI 2 7th De nn b in do ele:

Sv y ze Tovsi VM VMAR, SM o M. v z chho

M i bo o -------33333nokhnpn- | Y tr Mane zn shi -

We sho would o and My Ot a and x Kk sh in 7 Y -h and yah

Preomin compound 421 Intermediate compound 424

A mixture of intermediate 421 (2 g, 3.94 mmol), EVM (0.797 g, 7.88 mmol) and OMAR (0.096 g, 0.788 mmol) was stirred in OSM (40 mL), and To5si (1.127 g, 5.91 mmol). The reaction mixture was stirred overnight. Then 50 ml of saturated ManCO3 was added to the mixture and the layers were separated. The aqueous layer was extracted using OCM (50 ml x2). The combined organic layers were dried over Ma»5O»4, filtered and concentrated in vacuo to give the crude product as an oil. The crude product was purified using a column (eluent: petroleum ether/EOAc ratio from 10/11 to 3/1) to give intermediate 423 (1.25 g, yield 4595) as a white solid

From substance.

Stage 2

Preparation of intermediate compound 424 and r EE". you are LJ,

TV VG thread, And oh And -y And I will go

KHE a ZE va YAN ("shchi sem

Pe ve in ko

A mo bedouomE o a in Ves and Iv; M. y y kos x Go "M

Intermediate compound 423 Intermediate compound 424

To a solution of intermediate 423 (1.1 g, 1.66 mmol), 3-bromo-7-hydroxyquinoline (0.372 g, 1.66 mmol) and OME (40 mL) was added Св52СО3 (1.63 g, 4.98 mmol) at room temperature in an atmosphere of M". The mixture was stirred at 40°C for 6 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified using a silica gel column (eluents: petroleum ether/ethyl acetate: ratio from 20/1 to 0/1) to give intermediate compound 424 (1, 1 g, output 8795) in the form of yellow oil.

Example of AZ4

Stage 1

Preparation of intermediate compound 425

RAH V. M AH, o, ram IF REA - mm my their still kah I o mya and Av Mao dioxan, NEO M She

U no Mi M U -V M dr M

M u y h

Intermediate 105 Intermediate 425

A mixture of intermediate 165 (300 mg, 0.393 mmol) and Mahon's solution (19.2 mL, 38.5 mmol, 2 M) in dioxane (5 mL) was heated under reflux at 60°C for 48 h. The mixture was extracted with ethyl acetate ( 10 mL 3), the organic layers were combined and evaporated under vacuum to give intermediate 425 (300 mg, yield 4295) as a crude product.

Stage 2

Preparation of intermediate compound 426 g.

What is in this M

Radiant snoluka 25 Iremizhna compound 426

A solution of intermediate compound 425 (300 mg, 0.164 mmol) in trifluoroacetic acid (5 mL) was stirred at 507°C for 1 h. The mixture was evaporated under vacuum to give intermediate compound 426 (150 mg, yield 7595) as a crude product.

Example of AUB

Stage 1

Preparation of intermediate compound 427

Coo) nki Zh pi 0 z. r Vosho, TSNMUYE, TNE kosh shi

Kt ZE SHO a in; ZSH SHO O i M Z ve ZDAe ia V Ko Vaye

Irradiated compound Y57 Prolyzed compound 427

To a solution of intermediate compound 157 (4 g, 14.4 mmol) in TNE (100 ml) was added GINMOZ5 (28.8 ml, 1 M). The reaction mixture was stirred at 0"C for 15 minutes, then BosgO (6.3 g, 28.8 mmol) was added. The reaction mixture was stirred at room temperature for additional

3 min. The reaction mixture was quenched with saturated aq. MNACI (50 ml) and extracted with ethyl acetate (50 ml x 2). The organic layers were combined and evaporated under vacuum to give intermediate 427 (5 g) as a crude product.

Stage 2

Obtaining an intermediate compound of 428 pcs | co

KOL SO, Ryropsi "shi a a i zh ruy z ha SHO SHO a "De -zh-626262626666666Ш6Ш6ШБШ6ЙВШЦСВСТТНЮХЮНУНКИМ Ki y M t Y y

Mo Vo EBM, MeON, OME iy o

Intermediate 427 Intermediate 425

To a solution of intermediate 427 (5.0 g, 13.25 mmol) in Meon (25 mL) and OME (25 mL) was added Pa(arpO)CI" (0.970 g, 1.32 mmol) and EM (4.02 g , 39.76 mmol). The reaction mixture was degassed under vacuum and purged with gaseous CO three times. The reaction mixture was stirred overnight under a CO atmosphere at 120°C. The reaction mixture was diluted with H2O (100 mL) and then extracted with ethyl acetate (100 mL x 3). The organic layer was washed with H2O (100 mL) and dried over anhydrous Mag50O5, and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1 to petroleum ether/ethyl acetate 2/1).

Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 428 (4.0 g, yield 85965).

Stage Z

Obtaining the intermediate compound 429 shk i on: ev tod shen te still 6 s MO i

Ky VOoE x Se Ves o

Intermediate compound 426 Intermediate compound 429

To a solution of intermediate compound 428 (4.0 g, 11.2 mmol) in TNE (20 mL) was added HyAINa (0.426 mg, 11.2 mmol). The reaction mixture was stirred at room temperature for three hours. The mixture was quenched with aq. 1095 KOH (0.5 mL), filtered, and the filtrate was concentrated under reduced pressure to give intermediate 429 (3.4 g, yield 9095) as an oil.

Stage 4

Preparation of intermediate compound 332

Her thing sh--k zer vn meznlii, BM, OMAR, POM Y ni I :

U still t, - Gak still XH pa a ol ha -- - - - hu yah y sheh

Intermediate compound 429 Irradiated compound 332

Zo

Mesyl chloride (0.907 g, 7.92 mmol), OMAR (96.7 mg, 0.792 mmol) and EVM (1.2 g, 11.88 mmol). The reaction mixture was stirred overnight at room temperature.

The reaction mixture was diluted with OCM (100 ml) and then the organic phase was washed with aq. K»COz (50 mlh 3). The organic phase was dried with Mag25O»4 and then concentrated under reduced pressure to give intermediate compound 332 as a yellow oil, which was used in the next step of the reaction without further purification.

Example A9Ub

Stage 1

Obtaining intermediate compound 430 "M. yyyy

I zro Ve" and Mar ee and r 0Z- 2-3 | y N y (not Id y y Ak dyno no M NO No e tde

Nitrogen compound 446

Vgg (0.89 ml) was added to a solution of 2-hydroxyquinoxaline (1.5 g, 10.2 mmol) in HOAc (15 ml) and the reaction mixture was stirred at room temperature for 6 hours. The solid was filtered and washed with ethyl acetate to give intermediate 430 (2.2 g, yield: 9595) as a white solid.

Stage 2

Preparation of intermediate compound 431 sk Mo sy ROK, ih her and M Shchi

I -th r ro valu p y. hilt of the sword du as OM Be

Intermediate compound 438 Intermediate compound 43

ROSi3 (48.5 g, 316 mmol) was added to intermediate 430 (2.2 g, 9.7 mmol). The mixture was stirred at 70"C for 2 hours. The mixture was slowly poured into water. Aq. ManHCO3 was added to the mixture until gas evolution ceased. The mixture was extracted with EAs.

The organic phase was filtered and washed with saline solution. The organic phase was dried over Ma»5O» and concentrated to give intermediate compound 431 (2 g, yield: 8195).

Stage Z

Preparation of intermediate compound 432 "Moss: "Vo

Y I y MNN Ya yo r 2 te san Ve Diyuzhevy vm s eV

Intermediate compound 43 Intermediate compound 432

A solution of intermediate 431 (100 mg, 0.41 mmol) in dioxane (4 mL) and MnH2HO (10 mL, 2595) was stirred in a sealed tube at 1107°C overnight. The mixture was concentrated to give crude intermediate 432 ( 108 mg) as a yellow solid.

Example A9U7

Stage 1

Preparation of intermediate compound 493 with Z-VVM TNE, RAMA SYA t ditya r x y y y ko. BUT S S her

I am I I I M nin I NN

A and em M and S ese she

Intermediary of the wash, Intermediary xx connection to the yth connection 293 m

A mixture of intermediate compound 408 (10 g, 54.88 mmol) in a 0.5 M solution of 9-BVM in TNE (439 ml, 219.5 mmol) was stirred at 507C for 1 h under a Mo atmosphere. The mixture was cooled to room temperature, then KzPOx (34.9 g, 164.6 mmol) in HgO (20 mL) was added, followed by TNE (110 mL), intermediate 181 (15.19 g, 54.88 mmol) and Ra -118 (1788 mg, 2.74 mmol).

The resulting mixture was stirred at 50"7C for 0.5 hours.

The mixture was concentrated. The residue was dissolved in ethyl acetate (400 mL), washed with water (400 mL) and brine (400 mL). The organic phase was dried over Mag505, filtered and concentrated. The crude product was purified by column chromatography on silica gel (from petroleum ether/ethyl acetate 10/1 to petroleum ether/ethyl acetate 1/1). Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 393 (19 g, yield 82965) as a solid.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 393 using the appropriate starting materials (Table 50).

Table 50

Structure

Ve. Let's go

SI M

5ZO Intermediate compound 408 tons Intermediate compound 175

Stage 2

Preparation of intermediate compound 494

NI and m SD are re

WE VI E 4 TA and go I dn zhin, she ry shi" y. g what І Y S S І. KE N (sh ho how I v. ul - m Her. un yah sho zi

Irradiated Intermediates What compound 493 compound 94

AND

Intermediate compound 493 (4 g, 10.46 mmol) and pyridine (2.48 g, 31.39 mmol) were dissolved in OSM (50 mL) under M» atmosphere. Triflatic acid anhydride (5.9 g, 20.93 mmol) was added at 0"C and the reaction mixture was stirred for 0.5 hour. The reaction mixture was then stirred at 25"C for 1 hour. The solvent was removed by mass. The residue was purified by column chromatography on silica gel (ratio from petroleum ether/ethyl acetate 10/00 to petroleum ether/ethyl acetate 4/1). Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 494 (3.5 g, yield 6595) as a white solid.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 394 using the appropriate starting materials (Table 51).

Table 51

Structure

Ve. with

E in E sim va

Ов Е 531 and хо Intermediate compound 530 х

Stage Z

Preparation of intermediate compound 495

Mon. Fri. Sun

S S Y. Ash Ni pi, HOW she me IF soda: SHHA: bdshe IF p se po i Shchi - - - t ne : Io) t, x her 0 4 sya pyv chik she -v re OK Z .

Praminenium Intermediate compound I compound I8X 2,4-Dichloro-7H-pyrrolo(2,3-4|pyrimidine (1.24 g, 6.61 mmol) and C52bOz (3.23 g, 9.91 mmol) were dissolved in UME (20 mL) under Mg2 atmosphere. Intermediate compound 494 was then added. The reaction mixture was stirred at 25"7C for 12 hours. Ethyl acetate (50 mL) and water (50 mL) were added to the mixture. The organic layer was separated, washed with H2H2O, and dried (Mag25054).

The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel (from petroleum ether/ethyl acetate at a ratio of 10/1 to petroleum ether/ethyl acetate at a ratio of 4/1). Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 495 (900 mg, yield 3790) as a yellow solid.

The following intermediates were prepared using a reaction protocol similar to that used to prepare intermediate 495 using the appropriate starting materials (Table 43).

Table 43

The structure of the village

IF) M 497 de Intermediate compound 494

M h 2-chloro-7H-pyrrolo|2,3-a|Ipyrimidine (F) a

M. a

Table 43

Structure of the village

WITH

SI M

499 to Intermediate compound 494

M 7H-pyrrolo(2,3-4|pyrimidine an r: M. lem si 7

C sim 519 ee Intermediate compound 494

M 1H-pyrrolo|3,2-s|Ipyridine xx kl si y

WITH

SI M

BO ee Intermediate compound 494

M - 1H-pyrrolo|3,2-5|Ipyridine sa M si y

HU sim

BoZ poh Intermediate compound 494

M - 1H-pyrrolo|2,3-b|Ipyridine and h.I si a

With sim

BOB pt Intermediate compound 494 that 5H-pyrrole|2,3-b|pyrazine 7 / ! UT re M vi

Ve. and

WITH

SI M

Intermediate compound 531 532 M 2H-pyrrolo|3,2-s|pyridine - xx xx (

Table 43

Structure

Ve. d sy Zk pl Intermediate compound 531 533 uch - si 4-chloro-1H-pyrrolo|3,2-s|Ipyridine x I.

Example A100 knu shi

GB Y ra vy i soi shkve t t ti a nya rh se kih nya i kashya I ha i m at gav naya shk et Shk ry WHAT - -yan dshi lolsh lyaya SCHI Schi i ' oh v y y, liy y PIRBA ввВОН, ОИ SO ши и ши

Zh - Ink yah and y

Intermediate compound 233 Intermediate compound 344

A solution of intermediate 533 (1.75 g, 3.1 mmol), 2,4-dimethoxybenzylamine hydrochloride (2.6 g, 15.6 mmol), and OIREA (1.2 g, 9.3 mmol) in n-VION (5 ml) was stirred at 140" for 3 days. The reaction mixture was diluted with SneoSi" (30 ml) and washed with NegO (20 ml x 2). The organic phase was separated, dried with Mag50O"4 and the solvent was removed under vacuum The crude product was purified by silica gel column chromatography (10/1 petroleum ether/ethyl acetate to 1/2 petroleum ether/ethyl acetate) to afford intermediate 534 (1.1 g, yield 8195) as a yellow solid.

Example AB

Preparation of intermediate compound 526

OK pc dona by code not densofenone pmin G I. . rekhya etan rsmemhu EHEIG me hv Hek, pu shM 000 RSHKOVSVIMAR | S What is the kish V pp M S whose M. em So. toluaya es i nni TE M

WOULD we shi shi, M x z he

Intermediate compound 325 Intermediate compound 326

Intermediate compound 525 (900 mg, 1.862 mmol), benzophenone imine (354.3 mg, 1.95 mmol),

PaA(OAcS)" (41.8 mg, 0.186 mmol), VIMAR (115.9 mg, 0.186 mmol) and C52CO3 (1213 mg, 3.72 mmol) were dissolved in toluene (20 mL). The mixture was stirred at 1107C for 14 hours in an M atmosphere.

The catalyst was filtered and the solvent was evaporated.

The residue was purified by flash column chromatography on silica gel (eluent gradient:

EOAc/petroleum ether from 1/15 to 1/1). The product fractions were collected and the solvent was evaporated to give intermediate 526 (660 mg, yield 5195) as a yellow solid.

B. Preparation of compounds

Example B1

Preparation of the compound 1 ma

M I Tue

In ra: m; M

Me Ka: li nema dl ta t I g yi ih Mas i i shi vini ani - a Z sii i yi k.t.. a hod i a t iz Ko - vini i NNYA pf y Di i ih ts s iinya M.

The irradiated compound is NOT compound C

Intermediate compound 104 (300 mg, crude, - 0.568 mmol) was dissolved in 5 ml of 4 M HC/Mmeon.

The mixture was stirred at room temperature for 3 hours. The solvent was concentrated under vacuum. The residue was dissolved in 4 ml of MeonH and the pH was adjusted to approximately pH - 9 with a saturated solution of Mag2bOz. The solvent was purified by preparative NRI C (conditions NRI C: column: Setipi 150525 mm" 5 μm; gradient elution: 0.0595 ammonia/"CH3SM, from 81/19 to 71/29) to obtain compound 1 (70 mg, yield 3095) as a white solid.

Example B2

Preparation of the compound 2 sesses Gena МНХ ях МН о у ж

Be and svi Maya dk -tT We" M U -

Rhea -n- -- - A A A A A A A A --- --k Z 7 a o An. NS vi -dizEsani NO Onraman Yepoluka 2

Noromyzhny compound 105 cat. Ibtol 4 M NOI in dioxane (0.7 mL, 2.9 mmol) was added to a stirred solution of intermediate 105 (175.1 mg, crude, with 0.29 mmol) in Mehn (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding 1.5 ml of 7 n. solution of MHz in MeoN. The solvents were evaporated. The residue was dissolved in OSM. The precipitate was filtered. The filtrate was purified on a 5µg column, type Sgase Vemeegiv 58C, 12 g, with 40, on an Agptep roi Ii Oshtaiye purification system, using OSM and Meon as eluents in a gradient starting with 100956 OSM and ending with 40906 MeoOH and 609uO OSM. Fractions containing the product were combined and the solvents were evaporated to give 24.5 mg of compound 2.

An example of VZ

Preparation of compound 2 -K them

Si-nih mom and - h - shchi and Cl g. slo. With M. ma - х-о у в-4.3-4 TA х х slav, to her M

M - Meshe 7 z E Y i 5. o Zv NSivid-diyuksvani o on rai Compound 2

Industrial zone compound 89

Intermediate 89 (12.2 g, 15.751 mmol) was dissolved in HCl/Meon (220 mL, 4 M). The mixture was stirred at room temperature for three days. After 18 hours of reaction, a solid precipitated. The reaction mixture was combined with another batch of the reaction mixture (1 g of intermediate

From compound 89). The resulting solid was filtered through a funnel and collected. The residue was triturated with water and the pH was adjusted to about 8 by gradual addition of solid

K»bOz. The resulting solid was filtered through a Buchner funnel, rinsed with water (100 mL" 5 ) and collected, then lyophilized to give compound 2 (5.95 g, yield 7395) as a white solid.

Example B4

Preparation of compound Z

And she

Ok and A Me V TEH ish - g

As Mei x ra still sh- , and M u -O. uche MN so i, a i, t UM o E TI KK - ldya Zmi vvyat M 4 M 2)3MNSIVSRME r nm

No and Yenoleuka Z iiIromyzhny compound 74

TEA (0.8 mL, 10.5 mmol) was added to a solution of intermediate compound 74 (249 mg, 0.405 mmol) in OSM (3.5 mL), and the mixture was stirred at rt for 5 days. The mixture was evaporated under vacuum.

The residue was dissolved in Meon (6 mL), and HCl (Z M in SRME) (1.5 mL, 4.5 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was quenched with MHz in Meon (7 N) and evaporated under vacuum. The residue was placed in OSM/Meon (1/1), filtered, and the filtrate was evaporated under vacuum. The residues were cleaned with preparative I! C (5ION with grains of irregular shape, 15-40 μm, 10g, MegoK, dry loading (SeiShefF), gradient elution with a mobile phase: OSM:MeonH/aq. MH" (9:1) from 97.5:2.5 to 87.5: 12.5) to give compound C as a white solid (156 mg, yield 73905).

Example B5

Obtaining compound 4 tro "Sh z-d ne de M --O, "o ok . em r co. that's ben

As well as Y - in EN. What's hers?

With SI

Prozny compound Zo Compound 4

To a solution of intermediate 86 (750 mg, 0.71 mmol) in Meon (40 mL) was added 4 M NOSI in

Meon (20 mL) at rt. The mixture was then stirred at 507°C for 12 hours. The solvent was concentrated to 100 mL of MeOH. The residue was dissolved in 10 mL of MeOH and the pH was adjusted to about 8 with ManHsCO3. The mixture was filtered and the solvent was purified by preparative NRI C (gradient elution: 0.0595 MHz.HgO in MeonH/0.0595 MHz.HgO in NegO) The required fractions were combined and the solvent was evaporated to give compound 4 as a white solid (207 mg, 6195).

Z The following compounds were prepared using a reaction protocol similar to the example

VI, B2, B3, B4, B5 or B20 (also in the experimental part), using the appropriate starting materials (table 21). Compounds 55, 57, 57a and 61 were obtained in the E-configuration.

Table 21

Outbound protocol

Compound The structure of the reaction material in, its intermediate

M is) rather sho sk,

With a, but bno (v

AiA i o - 7 Intermediate

M Mn» VI

DYA m ni oo bon i i k

Ai o - shn Intermediate 7 |, shi A MN B compound 108 earth X ia M no "on pi (o

Ai i o -4h Intermediate

Mn VI

SYA M ni oon o

SYU that MN Intermediate o M o inter -y XX th Va compound 110

M

ZO M this an ha

M h s, o sho i (0 o M MN vu Intermediate compound 111

M

In M non

M iYi o pe ch o Ki Mne Intermediate 11th in VI connection 112

M

It's okay with me

СХ that Mn Intermediate so (in) M 2 12 - in B! compound 113

M them 5 M her zan he

Table 21

Compound Structure Protocol Output in RUKUR reaction material g

Z SHCI MN Interim

M, (c) M 2 13 - XX and VI compound 114

M

Z M ne ban Ha u,

SA ms shu. pe (c) Mne Intermediate " " and B compound 115

M i 5 M is not the same

M a i se (c) M MN" Intermediate

Ше и - Й В compound 116

M i 5 M ne on ha

Ge) p-e0e-3

M (o) M Mne Intermediate in and -y and B2 compound 117

M

З M does not know the neck M (c) M Mne Intermediate " and - in B connection 118

M

55 M her "on ha yi

Me 3 times Intermediate

M o) 78 no and B compound 154

S M ni bons and 19 -o 3 (c) that MN vi Intermediate and in Uh i and compound 155 sya M no bons i em Z (c) Shchi MN vi Intermediate 7 uh y Her and compound 119 i M no bons

Table 21

Outbound protocol

ХХ and Тек о о - also in Intermediate 7 2 compound 120

SYA M ni bony

ХХ that at -4 Intermediate

E M (is) 22 and ek B2 compound 121

E and 5 M no bony

Also at -6 Intermediate

M (c) 23 and uky" B2 compound 154a

EE no on seam in sh-o o - Intermediate 24 M c) M MN» vag r

The second compound is 80

I M ni o obn i a- ov tek o o - more Vo Intermediate 2nd compound 122

M ni o bn i

A o nt Intermediate poh (in 26 M in VI compound 79

I Mach, M but he Mai

IS

E. ov (c) plo Intermediate s, 27 M ne i VI compound 123 i 5 M no" no i si (c) p Intermediate 28 se in AH Mne B2 compound 144

A. oh, no bony

Table 21

Compound Structure Protocol Starting in RUKUR reaction material

Nam - Mn; y )-9 M 29 M-5 uh o SU vo Intermediate - I M compound 144a i y

Intermediate o -

Zoem and B2 compound 145 p

SI 2 M not bno We

NM mo. 31 more (in) - in Interim

M shshev compound 145a 7 sh M no" "on My so. o -0- Intermediate compound 73 i 5 M x non

SI

So o - Intermediate school; nicks Be compound 124

Ho I 5 M / well o bbn si

СОх с о д- Intermediate that is carried by Be compound 54

Ho

A noi zones My M si sia s o Intermediate 7 U vo B compound 84

M

And Zh Mne yat

BUT he M. earth

Table 21

Compound Structure Protocol Initial in RUKUR reaction material i y (o -- romyzhna sh zm (c) Mn B2 compound 125

M 2

In and / Her not bno We

EzO r ( in Ho - Intermediary sh Y M kovany Vo compound 81

H ke no he

VE

IS

- romizhna sh ХМ i h (o; Mne B5 compound 82

H

EE MM but he

XX

Sho Z shchi Intermediate

M (c) 39 nicks Va compound 75 no o obono My

ХХ e Z that Intermediate

M (in) 70 | and Va compound 76 ni on Mi" a M t si

E Ch - B5 Intermediate neon compound 83 in I Z Moy

BUT he

V- (F) pshoe-m o. lmaM MN Intermediate

Sh U a B5 compound 87 and M no on 4

SI

Table 21

Outbound protocol

Compound Structure reaction material

Hg. ХХ em o p--sht (in) Intermediate

M Mn 43 and 2 Vo compound 88 no on va

SH

(c) -- . and c o MN VZ Interimzhna

M Ai- | 2 compound 126

In no" tn - .

M -x Intermediate 45 and o Vg compound 153 7 of the Mody

Her o sh Intermediate same Mne 46 m uki VI connection 127 , M i M p zak o p- vi Intermediate

Ku Mne compound 128 sh no ton Mai

СХ em Z pu c) Intermediate

M MN

48 gnats 2 VI compound 129 no bno My" "NS

SU

MN

19 in the middle of the peninsula

М МН» compound 130 7 no bno We

Table 21

Outbound protocol

Compound Structure reaction material

Mn

Because the earth is in between

M Mne compound 131 I noi Zan My

ХХ in the land of МН on the peninsula Intermediate ut her Mne connection 132 no bno We"

Hg.

Because the earth (in) M Mn» VI Intermediate c | compound 133 of them 5 M M no on ze

MH spot em o M MH Intermediate 53 pin 2 V connection 134

SHE Mo im no on t wa zem MN svi Interim

M MN

-k i 2 compound 135 noi zn Mi M

MN vla zem - vy Interimzhna

M t Mne compound 135 z 5 M ne" no Mi "PH

XX

-

M t - Intermediate VI compound 137

I no tone Mi and p-e -- Intermediate 5b M B1

M MN chu 2 compound 146 no an My y

Table 21

Compound Structure Protocol Initial in RUKUR reaction material seK- -- -sh Х МН Intermediate

M

" " shchi yes V! compound 138

ED Maly no on seK- m -- p M o. am Mn; Intermediate

What does compound 136 give?

ED Ma no on a- m -- p Mne Intermediate

M in Y and B compound 147

Rche U no on aK- m - s o M MN» Intermediate I and da B compound 148

EE Mai no ON

XX century / Intermediate

M (o) in V! compound 149

A-y H nya on Mai s pe Intermediate

M o) r " Sho i. in Mne B compound 150 not di: but 0 on Mody

XX is Intermediate

M o) r - KE. in MH2, compound 150 is not present

XX sh- (c) shk Intermediate 63 " and B2 connection 139 noi Zone My

Table 21

Compound Structure Protocol Starting in RUKUR reaction material

WITH

Which one

M t Intermediate wear B compound 141 ! noy zones We

She

H

M

- Intermediate and o M Mne B compound 142

XX

! noi he about art

M

M vy Intermediate shk compound 143 - no o0bono My 4 BO Mn Intermediate i 2 sh sh- 7 | In compound 188

M her M M s v po on gne 83 4 o M u MN; in the Intermediate school- 7 | compound 192

M her: M M s hu po on gne -- Mn (in) 84 / y y / M, vgo Intermediate -k | Ma compound 193 ne on t Mn» 85 o " She vi Intermediate

Mach I Ci y compound 194 no on / - si

M M

Vg / o 7 M, in Intermediate -k Ma compound 96 is "on

Table 21

Compound Structure Protocol Starting in RUKUR reaction material

X n - 9)

M compound -KM |, M neon

H

/ with

M. о а Intermediate 88 в--Ж зы -у and Шчі в2 compound 196 -k | - but he

M Mn. t vi Intermediate

KA 7 I M compound 198 no On

SI

Х сх

M (o)

Intermediate

And? Mi Sho B5 compound 199 ! ! MN"

BUT he M, slya

Gee)

ЧИ o What Intermediate and M t M is HO Shchi VZ compound 201 no bno y

Ve. p. 94 | 2 (o) and "I MH in Intermediate and | and: " compound 206 si a: neon

Kn Intermediate international M i 5 I! M V! compound 209 is not the same

Table 21

Compound Structure Protocol Starting in RUKUR reaction material

IS

IS

2 (c) Intermediate and (c) - VZ compound 211

M AF:

Y: neon Y

SA

Intermediate " and 7 VZ compound 213 1 Й MA МНе no On M, lem -8- Мне (о) m-Й o. и M, во Intermediate

Shchi -k | Me compound 214 is not on

IS

E E

F Promi romizhna

M (o) Si VZ compound 215 -U -t-e

Y r M ikh no on si o What Intermediate - M 100 M i g» MN» in ot no bno Ye si

IF Fr

M (e)

Intermediate

And I-YAYA

What is 7 o M VZ compound 219 ! ! MN"

BUT he M. lem

Table 21

Compound Structure Protocol Starting in RUKUR reaction material

SI

CO

Intermediate -d Ge)

Sho " o M t VZ compound 221 3 GO Mn" no on M, sem

M

Х -т3- МНо М Intermediate to them B compound 226

Ma non tptt?8ro

So» o - Intermediate pi m o, mm mno VZ compound 227 m i M lm neon (in) o 4 ex o Promi romizhna

Sho o) where VZ compound 228 mi t in

BUT he is M, sem

IS

ChK o Shko Interimzhna 2 M 106 m t / syn" in SroMKna no on

Y rn tk M zhom She Intermediate 107 Kk; and in

H XM compound 232 ii 5 ii no on -8- MN. oh at. a Intermediate 108th with -77 Me vgo -ki --- Mashu compound 234 but OH

Table 21

Outbound protocol

Compound Structure reaction material

Intermediate c (F) ---sh- 109 M water VZ compound 236 ! evil" of the 5th

HU nom M

Intermediate 110 dk VI compound 237 - si

In her I

Hg. in. r t p i o mn" romizhna 114 M Ko B20 compound 239

E 5 a" but he tes

WITH

M (o

Intermediate 112 ru Ш VZ connection 241

KZ and I 7 plural no - J on s xx pz M ZE vi Intermediate hu and MN» compound 243 bno "uk 4

C, ro M; Intermediate 114 si ka B compound 245 u g si no on M, sem y s tak M prom romizhna 115 Le VI compound 159 u g si no on M lm

Table 21

Compound Structure Protocol Output in RUKUR reaction material 97 t zm (c)

Intermediate about Z VZ connection 247 no. ZYM no

M To me

X-Km and payments that.

Intermediate

What M Sho B compound 248

Hey no: More

He M am o KI Mn 7 i i l V! compound 250 compound ve 5 M y no on o Kshch mn 123 y Y y vy Intermediate

M compound 252 mesh: Meshes "neon - ud;" Intermediate intermediate UA B compound 255 mn. but E Ki z on chuda xx 125 24 ed vi Intermediate ! MAN" compound 257 no bn M M -ZE and skh that Intermediate

M Mn 126 and quit? In compound 258 of it: shchi nb o obno00

Table 21

Compound Structure Protocol Output in RUKUR reaction material y y - Intermediate

M (c) 127 st son in the beam 5 M s nvofno s What is Intermediate

M (c) si 778 and Ky B compound 259 her 5 M M nbo bno

Ve. in. and that many Intermediate t Y Ky Who compound 261 her 5 and no on

ROOF

Huh,

Nam M (o)

Is it intermediate? M Sho B2 compound 262

SN I but he M, lem

Same zh-- nm M Ge) p interimzhna

What is the movement Щ Vag connection 264

SI a no E Kk) with on dam

СХ and r | Intermediate

Sho su ru Shchi B2 compound 265

Mn si ne : | and 2 he will pass and hu

NhMm M

Intermediate 753 o M Sho V! compound 266 chro

VN I

BUT he M. lem

Table 21

Compound Structure Protocol Output in RUKUR reaction material and

Huh

NhM M

Intermediate pi and Mi Sho B compound 267 3 GOz МН

BUT he M, lem

Say romizhna 1735 sh y A B connection 269 3 / y xx MN. but he M, lem

XX

- and Mi (o)

Intermediate 76 o M Sho B2 compound 270 chro

SDN I

But he M, lem

20th century Intermediate 187 and Syny" B2 connection 271

C 2 Tsi M neon and sx shchy Intermediate

M o 138 zh Ki vag compound 272 her: M nbozn y

C i " Intermediate 759 th che B compound 273 3 th ZA MNo no on M. lem

Feb

S i y Y Intermediate po - B compound 275 th Se no bn M lem

Table 21

Compound Structure Protocol Starting in RUKUR reaction material

H

2 - uUu.

IOM Interim

What and; -, yes V! compound 278 no On M, dam ev

C and: "Y Intermediate pey"M VZ compound 279/th MN

BUT he M. lem

M

H

NM M p intermediate "in va Sh B connection 281 dol I ate: a

BUT he M, lem

XX Her and: I

Intermediate

Sho o o M Sho Vgo compound 286 ! Same MN"

Y E I

BUT he named Mo

Hey ach o prom romizhna 7 M Shchi B connection 289

Hu AN;

SDN I no on M, lem and che p

I'm "Intermediate 7" still in compound 292! ! HU MNe

But he M, sem

SI and msh Intermediary 147 Fo their Sons V! compound 295 ii: M nbo zno

Table 21

Compound Structure Protocol Starting in RUKUR reaction material

Ve. and

Also: "Intermediate in "M B compound 298 rya; From MN"

But M

What a mess

Sho M Shchi B2 compound 301 more KHAN"

BUT he M, lem y

Z. s i that romizhna o M Shchi B2 compound 304

S i W Xh MN"

BUT he M, sem y and s

IOM

151 scha vi Intermediate "h compound 307 рн Zх ly МН» no on M, lem he do

KO prom Romizhna

Sho M Also B compound 310 y ; From MN"

But he M. lem

Ve. th point m - Intermediate 153 N Kinit B compound 313 ii M no on M

IS

And more. c - Intermediate

Moss on the sons of V! compound 316 ex SHY nbo un

Table 21

Compound Structure Protocol Starting reaction material y y ria y Intermediate 75 " V compound 319 : p Mne

BUT he M, lem and che o porom romizhna 76 M What is the connection 322 schu Y AN» but He M, lem

E. eh in M

Intermediate

What M What B compound 325

SU I A MN; but he M, lem si y

HU nm M

Intermediate 758 o M Sho V! compound 328 - p: Мне но он M, lem

IS.

Uh -

NoM Mi

Intermediate to M Sho B compound 331

Su I eh Mn;

But he M, sem utvo J ikh and 2 Intermediate

Kyuto" tvo "z " k SHY I: In compound 334 no on - 4 tot Mn and still M and Intermediate

Shchi A su that B compound 337 and its 5 -y no on

Table 21

Compound Structure Protocol Output in RUKUR reaction material 222 I hear" in Intermediate

M x-4 M them compound 504 no ono si oo r

NOM M (o) prom romizhna that M Sho B connection 462 : gOhh me

BUT he M. lem and and 3 that Intermediate

M

224 a: uki vi compound 46 th g M no on -

Ve. and

M romijna them: M M nboono

See them

Nom M Mne Intermediate 7 and B compound 496

Still M M but he sho si

SI and

M -

Nam M Intermediate that ie B compound 498 them M M but OH in,

SI si and shU nom M

Intermediate 242 ra, compound 500 ra

BUT he named after M

Table 21

Outbound protocol

Compound Structure reaction material

SI and c,

Nom M that Intermediate and VI compound 501 sh- ! enter but he a

NoMm

IS

3rd

Well, that's a lot of Promi. M romyzhna 244 days, Hgo compound 514

N t Mashy no on y nom sv o

Intermediate (c) by 245 in 2 compound 516 rya Z and МН» pon y

M t ech (e)

Intermediate (9) rea 246 in VI compound 518 ria ЗМ» no on M, lem so m shcha - .

M Intermediate 247 NhM M s VI compound 520 her: | DM but he

FO that -- .

M Intermediate 248 nom M ek VI compound 522

Her: | - but the UN

Table 21

Outbound protocol

SI and -k -- .-

M Intermediate 243 Nam M with B2 compound 524

M i no on

Vg and p

SI M

Intermediate 251 M She B2 compound 532 --

BUT he xx M

Example Vb

Preparation of compound 67 and compound 68

TV abe hi

Kz CHI and yang M,

Ou pek xx Yang g te I: m M z Me x IZ Tv ; in "MN

With ; yang zi o and de 7 mine

KA pt non zi vo. MN nomen m Ya vnek Io EUnoluka 67

Ky Ku / y M Ya ge a I I Zh

A a r Gena yah X і-- y o N х МНЙ s ях What СХ M. they y yati y ! : y vch so vka

LPreyanoena enoluka 14 IK or 8) BE My

In he 5 Yenoluka 85

Intermediate 140 (210 mg, crude, 0.399 mmol) was dissolved in 5 mL of HCl/mMeon.

The mixture was stirred at room temperature for 7 hours. The reaction was quenched by adding

NH3/Meon to bring the pH to about 8 at 0°C. The resulting solid was then collected by filtration and washed with NaCl (10 mL), and the combined organic filtrate was concentrated under reduced pressure to afford the crude product. The residue was purified by preparative NRI C (conditions NRI C: columns: Rpepotepeh Setipi 150 7 25 mm " 10 μm; mobile phase gradient elution with 2195 water in ASM) to give compound 67 (40 mg) and compound 68 (52 mg) as a white solid .

Example B7

It's a new thing

Ma. dear nn -

That's the thing where - Z

K. - vky s kh ra kl, e- that: u ish i Shchi i y A ; and My x Fah U. "MN. di r bor i i M y s ey ah y i toOveON NI TNE hi Y g ku no on

Prozygous compound 55 g - 1st and sCompound it

A reaction mixture of intermediate 85 (150 mg, 0.233 mmol) in 5 mL of a mixed solvent with

AsOH, water and TNE in a ratio of 13:7:3) were stirred overnight at 60°C. Then the mixture was stirred at 80°C for 1 day. The solvent was concentrated under vacuum.

The residue was dissolved in 4 ml Meon and the pH was adjusted to about 9 with solid MgCO3. The solvent was purified by preparative NRI C (conditions of NRI C: columns: Setipi 150 " 25 mm, 5 μM; gradient elution with water (0.0595 ammonium hydroxide vol./06.) KHASM from 97:33 to 67:33) to obtain compound 69 as a white solid (13 mg, yield 14905).

Example B8

Dena nya ya shi and IC Ka yi yi rrya rya I ryn yi-ee ih I

BOOTS: Ken yo ya kh v ke zh, Av ven ny mil Kolak, rya

She and "o od om r ya s d ; and: that Compound 7

Intermediate crossbow 153 "

Intermediate compound 152 (425 mg, 0.927 mmol) was dissolved in a stirred solution of AcOH (22 mL), TNE (5 mL), and H2O (12 mL). The mixture was stirred at 507C for 12 hours. The solvent was concentrated under vacuum. The crude product was purified by preparative NRIS (gradient elution: 0.0595 MNz.NgO in MeoOonH/0.0595 MNz.NgO in NgO). The combined solvent was evaporated to give the desired compound 70 as a solid (69.3 mg, yield 1896).

Example VO

Ve sh in that Ve. shk and p ho. with TO I-- Ministry of Emergency Situations in lIyuKsdVI ih would TO MU,

SHU i g shchi ich - Mp vldyuYUKSyaNI Zv i a I h hom - vna v - tov mo Me hu ii mmesn yi ik g z M tku de ih Ku i Me schi gu yo; wa no so and r ok

Non-chromic compound 59 Compound Ti

To a solution of intermediate compound 59 (187 mg, 0.18 mmol) in 1,4-dioxane (5 mL) was added 4 M NOSI in dioxane (0.46 mL, 1.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding 1.5 ml of 7 n. solution of MHz in Meon. The solvents were evaporated. The residue was dissolved in dichloromethane with methanol (4.5.), and then purified on a column with 500", type extinguished Kemeigi5 ZKS, 12 g, 5i 40, on the purification system of Agtep Roy Ii Shiptage, using dichloromethane and methanol as eluents in a gradient starting from 10095 OSM for 5

From column volumes and ending with 4095 MeOnN and 6095 OSM for 25 column volumes. The fractions containing the product were combined and the solvents were evaporated to give 62 mg of crude product mixture. The crude mixture with the product was purified using Rger NRI C (stationary phase:

VR KhVgiidde Rger C18 OVO-10 μm, 30 x 150 mm, mobile phase: 0.2595 MNANSO solution: in water,

SNiSM) to obtain compound 71 (5.5 mg, yield 695).

Example B10

Preparation of compound Ta

Mkh de tershe M her i-rn o povya zh y vych u chno shk Neishe and 50 oN S - -yk Me to Kosa and their i y . ; t

TMM 1.4-dioxvy im, and MH and 7 4 M NS in dioxane M- and neon

Intermediate compound НИЙ Yepoluka Йий

To a solution of intermediate compound 100 (9.26 g, 17.5 mmol) in 1,4-dioxane (300 ml) was added 4 M

NSI in 1,4-dioxane (43.8 mL, 175 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into a beaker with OIRE (1 L).

The suspension was stirred for 20 minutes, and then the solvents were decanted. The precipitate that remained was recrystallized in EUN. The precipitate was filtered, washed with OIRE, and then dried under vacuum at 50"C to obtain compound 1a as a salt with 2 equivalents

NOI (8.33 g, quantitative yield).

Example B11

Preparation of compound 72 (via intermediate compound 156)

Stage a

Zoden yam -y un, che (y her A. t duke ryh se dyk vy r y U y - a sh mn. Pirnlnnk y y "Mish - y y sy teh tlu zh tu | y M na p: Sha di

X ze Sho ki che;

EE a wn y Oe no Ma 00-

Sh in Ya

Svnoluka 22 x

Intermediate is 150

Isobutyric anhydride (2.36 mL, 14.2 mmol) was added to a stirred solution of compound 22 (688.3 mg, 1.418 mmol) in pyridine (25 mL, 310.361 mmol) at rt. After the addition, the reaction mixture was stirred at 50 C for 18 hours. Solvents were evaporated. The residue was co-evaporated with toluene. The residue was dissolved in OSM and purified on a column with 5iO", type Sgase Kemeiegiz KS, 40g, 5 40, on the Agptep ZBroi I Oshshstaige purification system, using OSM and Meon as eluents in a gradient starting at 10095 OCM for 5 column volumes and ending with 4095 MeoN and 6095 OCM for column volumes of 30. The required fractions were combined and the solvents evaporated to give 0.94 g of intermediate 156.

Stage r o ! shcha -V nki - khi g sce M: KD re M Zh M - y i same M X-nn; и- Ж и-- A ; basket pf and Her cheeks

You and eight o'clock in oh m, I and already I All g; k/ i- v Nosov, zgo FoOov-ye o v- Med zh- v - she y y /

Compound 75 zo Intermediate compound 156 zh

A solution of intermediate 156 (0.94 g, 1.372 mmol) and BOS' (99.493 μl, 1.372 mmol) in

Meon (20 mL, 0.791 g/mL, 493.725 mmol) was stirred and heated at 1107C for hours using microwave radiation. The solvents were evaporated. The residue was dissolved in OSM and purified on a column of 5iOg, type Stase Vemeviegiv 5AS, 12g, 5i 40, on an Aptep 5roi Ii Oyitaie purification system, using OSM and MeOn as eluents in a gradient starting with 10095 USM for 10 column volumes and ending with 2095 MeOH and 8095 JUOSM for

ZO of column volumes. The product-containing fractions were combined and the solvents evaporated to give compound 72 (.HCl) (0.66 g, yield 74965).

The following compound was prepared using a reaction protocol similar to that used in Example B11, using the appropriate starting materials (Table 22).

Table 22

Structure

Vg u lyh zem (9) sh- o u 73 U u o Compound 2 "NS KZ sia -i- U t3- Plural. / o (F) M and x

M

-m Y Ma th Compound 1 c) |c; about Mr.

Example B12

Preparation of compound 74 styu sher r g ta I І mm i - nomen Um y: ee i ee» MIN k.t. i Tim, me bu Ma. she would have M

Ka from shchi

Preochyna compound 16 Speluka 74

To a solution of intermediate compound 160 (3.45 g, 6.9 mmol) in Meon (10 mL) was added NH/MeOon (4N, 10 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was lyophilized to obtain fraction 1 in the form of crude compound 74, which was purified using rger-NRI C (column: Rpepotepeh Zupegdi Mak-AR 250 "80 mm, 10 μm, condition: water (0.0595 ammonium hydroxide vol./06. )-ASM, start B: 3095, end B: 60, gradient elution time (min): 22, flow rate (ml/min): 120. The necessary fractions were collected and lyophilized to give fraction 2 as crude compound 74, which was additionally purified using rger-NRI C (Rpepotepeh Setipi 150 "25 mm" 10 μm column, condition: gradient water (0.0595 ammonium hydroxide o0b6./06.)-ASM. The necessary fractions were collected and lyophilized to obtain compound 74 (1383 mg, yield: 43.195) as a solid.

Salt forms of compound 74 were prepared according to procedures known to those skilled in the art (Table 44).

Zo

Table 44

Structure t s tak M 116 ul Compound 74 i- za МН» no Э M on M va ne t s ka M 117 pl Compound 74 и- М Н» no х M on M

Ma "nsoon xx

WITH

IOM yes 118 dk Compound 74 i- i xx Mne no - M on 8 ma "SeNegO; (citric acid)

H

WITH

M M yes 119 no Compound 74

A-ii MN" no x M on M ma "Sba4NaOH trans

Example B1Z3

Preparation of compound 75 and ra 7 ss and ; well Gaia 1 | di psumeon them t

E chews kt, E SY m tm

Intermediate 0 A M.M m ny shik My spealuka 163 ХК and Speluka 75 V ov me.

I

A solution of intermediate compound 163 (680 mg, -1.04 mmol) in Meon (4 d.5.) was dissolved in HSiM Meon (4 M, 15 ml), stirred at room temperature for 2 hours. The mixture was basified with MH3.HgO to pH » 7. The solution was washed with HgO (100 ml), extracted with ethyl acetate (150 ml x 3). The combined organic layers were dried (Mag25O24), filtered and concentrated in vacuo to give the crude product as a brown solid. The crude product was purified using rger-NRI C (column: Umayeg5 Khrogiade

Rger OVO C18 150 x 30 mm, 5 μm; condition: water gradient (0.0595 ammonium hydroxide vol./o6.)-

Meon). The required fractions were collected and lyophilized to give compound 75 (129.8 mg, yield: 26.495) as a white solid.

Example B14

Preparation of compound 76

Ba pit" S rvana

Bas and I IF Sh naty tia

Gays like and I av: cop, SON a kn.

NYA ba M. 5 I wai

OV » lk no yin M.M

Premenena compounds 187 Enoluka 76

A mixture of intermediate 167 (250 mg) and K2CO3 (185.3 mg, 1.34 mmol) in Meon (3 mL) was stirred at 60°C for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. It was purified by preparative NRI S (column: UUageg5

Hbpidde Rger OVO C18 150 x 30 mm, 5 μm, condition: gradient water (0.0595 ammonium hydroxide vol./06.)-MeonN). The required fractions were collected and the solvent was evaporated to give compound 76 as a white solid (82.2 mg, yield 45.395).

Example B15

Obtaining compound 77 or piece neck mech Sak

Es "y zak z BAK OM z shi kogsoumesn mo pes zhi char ry NI

BUT at the bottom BUT one thing

Intermediate compound 169 Compound 77

A mixture of intermediate 169 (120 mg, "0.185 mmol) and K"eCO3 (76.40 mg, 0.554 mmol) in methanol (3 mL) was stirred at 60"C for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product The crude product was purified using rger-NRI C (column: Umayeg5 Hrgidde Rger OVO C18 150 x 30 mm, 5 μm, condition: gradient water (0.0595 ammonium hydroxide vol./06.)-MeonN). The necessary fractions were collected and the solvent was evaporated to give compound 77 as a white solid (21.4 mg, yield 29.4905).

The following compounds were prepared using a reaction protocol similar to that used to prepare compound 77 using the appropriate starting materials (Table 48).

Table 48

Structure of the village.

C, nm M. 250 Intermediate compound 527

M

Whoa! IN

M on Me

Ve. and 252 Nm ve M she Intermediate compound 535 ! df8x MN"

SHE

BUT ono skh m

Example B16b

Obtaining the compound 78 vot

A. sia och A. pt, and dr ZM and nya

Sya zha TYA in Zv Va

Prosyzhny connection 171 venukya uh

A mixture of intermediate 171 (160 mg, 0.273 mmol) and K 2 CO 3 (113.073 mg, 0.819 mmol) in methanol (3 mL) was stirred at 5072 for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. Mine was purified using rger-NRIS (column: Umayeg5 Hrgidde Rger OVO C18 150 x 30 mm, 5 μm, condition: gradient water (0.0590 ammonium hydroxide vol./06.)-MeoOH). The required fractions were collected and the solvent was evaporated to give compound 78 (87.2 mg, yield 75.395) as a white solid.

Example B17

Obtaining the compound 79 o rt vk she Y ves she ssh vn with him, -0 kso» Madn mae chi i ! TO" mat Ky or coll

BUT bottom ma.M NO bottom mA

Intermediate compound Her 7 Speluka 79

A mixture of intermediate 173 (250 mg, 0.241 mmol) and K 2 CO 3 (99.6 mg, 0.72 mmol) in methanol (3 mL) was stirred at 5072 for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. It was purified by preparative NRIS (column: Umayeg5 Hrgidde Rger OVO C18 150 x 30 mm, 5 μm, condition: gradient water (0.0590 ammonium hydroxide vol./06.)-MeoOH). The required fractions were collected and the solvent was evaporated to give compound 79 (96.1 mg, yield 94.595) as a white solid.

The following compound was prepared using a reaction protocol similar to compound 79 using the appropriate starting materials (Table 45).

Table 45

Structure

SI

NaM--Kh

M

228 I

Intermediate connection of the 472nd u s no pt

M o

AND

M m

Example B18

Preparation of compound 80

Zo

Вк Вы С что ушу кит p

Y shiy do h i ah shchi Noya ti o shi -leVi A. Ma ve u t ia rysheet U Vi Ve va i na y Mei V . and Moss

Intermediate 179 Compound 50

A mixture of intermediate 179 (350 mg) and K»CO3 (102 mg, 0.74 mmol) in methanol (3 mL) was stirred at 60°C for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. The crude product was purified with the help of rger-NRI C (column: Umayeg5 Hrgidde Rger OVO C18 150 x 30 mm, 5 μm, condition: water gradient (0.0590 ammonium hydroxide o0b6./06.)-АСМ). The necessary fractions were collected and the solvent was evaporated to obtain compound 80 (113.3 mg, yield 94.995) as a white solid.

Alternative preparation of compound 80

BE Moz sa and t | Vo dya t nak nn I: y de Z nm M i so what | nem" I s -- rzheri, ii sh Fk at - M toru Ma y. I "MN ba Mk i she Shk dich NO dno Moyu

Intermediate 529 Compound 40

Intermediate compound 529 (21 g, 40.12 mmol) was dissolved in NSIMeonN (250 mL). The mixture was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum. NgO (100 mL) was then added. The pH was adjusted to approximately 9 by gradually adding aq. MazhbOz (800 ml). The precipitate was filtered to give the crude product. The crude product was recrystallized from EH (250 mL) to give 11.4 g of compound 80 as a white solid. The filtrate obtained during recrystallization was concentrated under vacuum. This residue was added to EN (50 mL) and heated under reflux for 3 hours. The reaction mixture was cooled and the precipitate was filtered to obtain 2.2 g of the product - compound 80. The filtrate obtained during the second recrystallization was concentrated under vacuum to obtain another 2.2 g of compound 80.

Example B19

Preparation of compound 81 in ve C snu d pi; M S as Z kn lady I pev, and "OT, MMU knife KM oo M, on

І НИ and -НШН3Н3Н3 1 and 1 yah M. - zach i M. 2-6

B NI I t mb ovbnoya

Prolapsed compound 144 Compound 5I

A mixture of intermediate 184 (800 mg, 1.67 mmol) and HCl in methanol (15 mL) was stirred at rt for 2 h. The mixture was neutralized with MNAON. The mixture was extracted for

With the help of EOAc (20 ml x 3). The organic phase was evaporated and the crude product was purified by means of Rger-NRI C (gradient: water (10 mM MNANSO»z)-ASM). The combined solvent was evaporated to give compound 81 (280 mg, yield 3895) as a white solid.

Example B20

The preparation of compound 84 is also known as NS no. EN. I- KN I at sy -z35 ; Mo i z-d kotu, I I i V i x-6 tk them MU- fkSHSHISHISH232353 en WHAT - V-shyuya is not yet ON

Compound 193 Compound 4

Intermediate compound 193 (110 mg, 0.23 mmol) in EN (3.5 mL) was stirred at r.t. 1 N HCl was added dropwise. (2.3 ml, 2.3 mmol). Stirring was continued for 72 hours. The reaction mixture was then treated with 2895 MH in water (0.235 mL, 3.5 mmol). The product began to settle. The precipitate was filtered and washed with 9:1 EOH/H2O and dried to give compound 84 (90 mg, yield 8990)

Example B21

Obtaining the compound 162 also: SHY ne Mesy Would we

And we drink: days of M

I In you And ele

And BUT there is no way

Irradiated compound 338 Compound 162

A solution of intermediate 338 (520 mg, 0.96 mmol) in HCl/Meon (4 N, 7 mL) and MeonH (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated.

The residue was dissolved in H2H0 (3 ml) and alkalized with aq. M.Sc.NgO. The formed sediment was collected. The solid was purified using rger-NRI C: conditions: A: (water (0.059 ammonium hydroxide vol./06.)-B: AFM, beginning B 3095, end B 6095). The necessary fractions were collected and lyophilized to obtain the product (250 mg). The product was further purified using rger-ZES (OO column (250 mm x 30 mm, 10 μm); conditions A: 0.195 ammonium hydroxide vol./06.), B:

EUON; beginning B 3595, end B 3595; flow rate (ml/min) 60). The required fractions were collected and lyophilized to give compound 162 (206 mg, yield 4395) as a solid.

The following compounds were prepared using a reaction protocol similar to that used to prepare compound 162 using the appropriate starting materials (Table 46).

Table 46 in

WITH

NM M (c) 163 Ge) pe Intermediate compound 353

AND.

Her and I

НО on Mu M y mm 164 pe Intermediate compound 354

M

BUT he is MAM

Table 46

Structure y s y M 165 water He) se Intermediate compound 355

J with A no on M. 2 M and p. shk; 166 K d-x Intermediate compound 356

I A

BUT bno Mam with s

NM M

167 F) ee: Intermediate compound 357

M

BUT he is Mom and oh more; 168 Ge) as Intermediate compound 358

I am from U, but he is M. em sa ti zm 169 Ge! where Intermediate compound 359

BUT he MAM / in age ku zm o 170 in dosh Intermediate compound 360

I am from Ve

NO he M. s-m s 171 si och Intermediate compound 361 l

NO on MAM and ste 172 ke Intermediate compound 362 no On M. 2 M

Table 46

Structure / ovi dl 173 si v ee: Intermediate compound 401

I am from AH, but On M. M g tm zm o 174 in ee Intermediate compound 402

CA X,

BUT he M. 2 M 7

C, (c) -- 175 lo M our Intermediate compound 417

I M nbo bno s their zm 176 M Intermediate compound 377

I'm from 5

НО ono Mam sa 177 si o nd Intermediate compound 378 that on M. 2 m t y ЗМ 178 M p H Intermediate compound 339 47 TAZH no on M. 2 M

A 4 179 Kn Intermediate compound 340

A ve no he M. am

Ж и зм 180 M de Intermediate compound 367

CH in

BUT bno Mam 4

And her M 181 sk Intermediate compound 368

A o no on M. 2 M

Table 46

Structure with yours; 182 E de Intermediate compound 369

I z v no on M. 2 M sa shk 183 M H Intermediate compound 341

And Zh

BUT he M. M y va; 184 E de H Intermediate compound 342 i Zh

NO on M. M - 185 o de Intermediate compound 403 ! AH l

HO bno MAM /ovi nom cm o 186 in dp H Intermediate compound 343

I'm from TAZ

NO bno Mam t 187 in weight Intermediate compound 365 t in

BUT he Mam - with sh; 188 E se Intermediate compound 366

SUA in

HO on M. 2 M (9) vovi n Ya 189 m o o o Intermediate compound 404 9-0 zh no On M. 2 M y ky zm 190 N M Intermediate compound 379

BUT he M. 2 M

Table 46

Structure and that: zm 191 and Ge! where Intermediate compound 375

SA ve

But he is Mom

Nam" cm 192 o Cl Intermediate compound 380

BUT he MAM sa 193 s SHHI o Intermediate compound 381 gly NI;

BUT moms

C nom" cm 194 OH Intermediate compound 344

I'm the same

But he is Mom

C nom cm 195 r Intermediate compound 371

M

SDN TV, but On M.M

S. nom cm 196 zu Intermediate compound 345

M N and zoom

Her /

BUT bno Mom g

C nom cm 197 zo Intermediate compound 346

M Nn and Hu

BUT he MAM HU

WITH.

Nm cm 198 (o) te Intermediate compound 347

M n

I don't have:

He is MAM

C 2 nam cm 199 Ge) pot Intermediate compound 372

M

YAT U

But he is Mom

Table 46

Structure

And E

E a 200 nn Intermediate compound 373

M ia ve no On M. 2M

IS

IS

E a 201 Namom Intermediate compound 348

M | n th Pk M

HO bno MAM and sai nom cm 202 p H Intermediate compound 349

M

SN TAZH

HO bno Mam and mM 203 N p Intermediate compound 350

M. N

I am with Zh

NO on MAM and nom" CM 204 rea Intermediate compound 374

M I TA. but OH M. 2 M / zvi one 205 si v pt Intermediate compound 376 but he M. 2 M 4

A, zm 206 dk H Intermediate compound 351

I ve

NO on M. em / vvi nom cm o 208 (o) ke Intermediate compound 385

SA on no On M. 2eM p

IN; 209 Mn Intermediate compound 405 i o no On M. em

Table 46

Structure and another 210 dk Intermediate compound 375 i t no on M. M and p. iv, - 225 g m ru Intermediate compound 465 g |. Ul nbo ono ev y Me o 226 de Intermediate compound 467 n dn

BUT he M. jam si y

S, iv; -- 227 nab M movement Intermediate connection 470

K t no on -

E. sa nom m 223 (c) poh | Intermediate compound 474

But he m y

E. t nm m 230 c) ke Intermediate compound 475 do no on ka

E. 4

S ny M 231 o po Intermediate connection 476 and "Azh

BUT he

Ve.

Sv nm Z He) 232 - -- Intermediate compound 479

M Hn ate 5

BUT he M. lem

Table 46

The structure of vovi xnMm M ge) 233 c) po Intermediate compound 480

BUT he M lem

Ve. say

With it M ge) 234 o po Intermediate compound 481

BUT he M lem

Ve. and

M - 235 nom (in Soky Intermediate connection 483 o iz M no on M

Hg. and

ХА nm Мо 237 se Intermediate compound 486 th and n

A- d

BUT it is M am

Ve. and

M - 238 nom Si» Intermediate compound 489 xx

In M M but he -

V. and

M - 239 nom o what Intermediate compound 492 sfanya

And M but he -y

Example B22

Preparation of compound 163 sa ak sht ce, in: obu or ІІ r

Washing, o -i

A t BUT dn mom

Intermediate compound 353 Yenoluka 153 5

A mixture of intermediate 353 (260 mg, 0.49 mmol) in HCl/MeOn (4 N, 1 mL) and MeonH (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated.

The residue was alkalized with MH3.HgO to pH»8. The residue was purified by NRI C: column:

Setipi 150 x 25 mm, 5 μm; conditions: A: water (0.0595 ammonium hydroxide vol./06.), B: Mesm; first:

A (8995) and B (1195), at the end: A (5995) and B (4195); gradient elution time (min) 10; 10095 During retention (min) 2; flow rate (ml/min) 25. The necessary fractions were collected and concentrated.

The residue was lyophilized to give compound 163 (93.4 mg, yield 48.695) as a solid.

Example B23

Preparation of compound 185

Menmt sm nezhmesn t kyu khashchi -- I -: ХЯ l z 4 44, en m ia em y sa - rr MN vano n

With 5 Mem -e utry Mn

KAH BUT vn M. em

Intermediate compound 03 Yenolukoa 15

A solution of intermediate 403 (600 mg, 1.28 mmol) in HCl/Meon (4 N, 2.7 mL) and MeonH (1 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated.

The residue was alkalized with MH3.H2O to pH»v. The precipitate formed was collected by filtration. The precipitate was washed with water and MTBE. The precipitate was lyophilized to give compound 185 (345 mg, yield 61905) as a solid.

Example B24

Preparation of compound 187

And o ke ie and Nsimesyu ve a 0

SY and shin nyu Ma eV ni z Me

Intermediate compound 305 Enoluka TYA

A solution of intermediate 365 (250 mg, 0.54 mmol) in HCl/MeOn (4 N, 1.52 mL) and meon (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated.

The residue was alkalized with MH3.HgO to pH 8 and concentrated. The residue was purified using HRIS: column: Setipi 150 x 25 mm, 5 μm; conditions: A: water (0.0595 ammonium hydroxide vol./06.), B: ASM); at the beginning: A (8995) and B (1195), at the end: A (5995) and B (4195); gradient elution time (min) 10; 10095 During retention (min) 2; flow rate (ml/min) 25.

The necessary fractions were collected and concentrated. The residue was lyophilized to give compound 187 (29.4 mg, yield 1390) as a solid.

Example B25

From Obtaining compound 188 oat an

EK she. siyu and AK questions i WE SHY and

E E H! che nah OO kutu, na I tyu, y im, chi

What about On Mei

Intermediate compound 306 npoluka 14

A solution of intermediate 366 (410 mg, 0.76 mmol) in HCl/Meon (4 N, 7 mL) and MeonH (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated.

The residue was dissolved in H2H0 (3 ml) and alkalized with aq. M.Sc.NgO. The formed sediment was collected. The solid was purified using rger-NRI C (Rpepotepeh Setipi 150 x 25 mm, 10 μm; conditions: A: water (0.0595 ammonium hydroxide vol./06.), B: ASM); at the beginning: A (7095) and B (3095), at the end: A (4095) and B (6095); gradient elution time (min) 10; 10095 During retention (min) 3; flow rate (ml/min) 25. The required fractions were collected and lyophilized to give compound 188 (131.3 mg, 34.5905) as a solid.

Example B26b

Preparation of compound 211. and

Intermediary connection Zal Spluka ii

Potassium carbonate (155 mg, 1.1 mmol) was added to intermediate 383 (0.3 g, 0.376 mmol) in NaCl (10 mL). The mixture was stirred at room temperature for three hours. The mixture was evaporated under vacuum. The residue was purified by preparative NRI C (column: Umayeg5 Khbgiade

Rger OVO C18 150 x 30 mm, 5 μm; condition: water (0.0595 ammonium hydroxide vol./06.)-АСМ, start:

V 3595, end: V 6595, gradient elution time (min): 10, 10095 V retention time (min): 3, flow rate (ml/min): 25). The combined solvent was evaporated to give the product as a white solid. The product was purified by 5EC-separation (column: 0.) (250 mm x 30 mm, 10 μm), condition: A: (0.195 ammonium hydroxide vol./06.) - B: EN, start: B 5095, end: B 5095, flow rate (ml/min): 80). The combined solvent was evaporated to give compound 211 (76 mg, yield: 3995) as a white solid.

Example B27

Preparation of compound 253

Compound 253 was prepared using a reaction protocol similar to that used to prepare intermediate 382 described in A78 (step 1) using the appropriate starting materials (Table 41).

Table 41

Structure a -- 253 M kuki Compound 2 and 2 M. im no ono

Example B28

Preparation of compounds 207 and 208

Koo) va: na t g yad NEBOM nkozyuttetto Mate vh

Ko zi 7 MV- 2 2 Z yegh y x SHO « "y y ru z y M TON vn t y Ih y I sh y Kk - g. oz Z Ka. her py ke Intermediate compound Yepolukea 2YT Compound 208 her

HC/UMeon 11 mL, 4 mol/L) was added to a mixture of intermediate compound 384 and intermediate compound 385 (200 mg) in MeOH (1 mL) and stirred at room temperature for 30 min.

The reaction mixture was added dropwise to aq. MHz.HgO (2 ml) and concentrated under vacuum to dryness to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography on a column: Rpepotepeh Setip

150 x 25 mm, 10 μm; condition: A: water (0.0595 ammonium hydroxide vol./06.), B: MesM; at the beginning: A (8595) and B (1595), at the end: A: (5595) and B (4595). The purified fractions were collected and the solvent was evaporated under vacuum. The residues were lyophilized to give compound 207 (32 mg) and compound 208 (41 mg) as white solids.

Example B29

Obtaining compound 215 o " ih z i lie, ij "m A U ihetu

Kan: NI PDYSHYN t 00 mesbvlivkovy 7 M a Ya

ES their -u ry M. slya KoOutlovan o Na - Vyshnya

Kay GU. z - OK ran -M k.t.o 2 p.m. I, Mom on vno on on

Intermediate compound 345 Compound 215

A mixture of intermediate 388 (1 g, 0.67 mmol) and K»CO3 (1 g, 7.25 mmol) in СНоСи» (10 mL) and dioxane (10 mL) was stirred at 507°C for 2 hours. The mixture was filtered and the filtrate was concentrated to give the crude product. (102 mg, yield 34905) as a white solid.

An example of VZO

Preparation of compound 216 shen in ie:

Vrya ME

Z i Z Vk Da A UZ y, p: meotuiM, nin KbumN nam a

Promioyuna enfluka 390 EUpoluna 216

A mixture of intermediate 390 (300 mg, 0.60 mmol) and KgSO3 (0.25 g, 1.80 mmol) in methanol (10 mL) was stirred at 507°C for 2 hours. The mixture was filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (gradient elution: 0.0595 MNz.NgO in CH2OH/0.0595 MNz.NgO in HO; column: KgotavFvii 150 x 25 mm, 10 μm) to give compound 216 (37.9 mg, yield 15.595 ) in the form of a white solid.

Example B31

Preparation of compound 198 och ay dk I pi geol NOM

Hek ns Me: ts y y Nm nabtv w

May it be yours

I ii NO vy POZU" by M. Mke Central Committee

Intermediate psnoluka 34 Yepoluka 195

Zo

A mixture of intermediate 347 (1.2 g, 2.42 mmol) in HCl/Meon (20 mL, 4 M) was stirred at room temperature for 2 h. The solvent was concentrated under vacuum. HO (50 mL) was then added and the pH was adjusted to 9 by gradual addition of solid Mansoz.

The solid was filtered and washed with H2O (100 mL x2), methanol (100 mL x2) and diisopropyl ether (100 mL x2). The filtered precipitate was dried under vacuum to give compound 198 (273.7 mg, yield 2495) as a white solid.

Example B32

Preparation of compound 199

I. child

Zhe di s A i nem i nelmeon still di, veni - I 6 I o M my M, dream

ОА о и De и, OT" or ше M. em non y

Intermediate compound 322 Enoluka 199

A mixture of intermediate 372 (510 mg, 0.824 mmol) in HCl/Meon (10 mL, 4 M) was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum. HO (50 mL) was then added and the pH was adjusted to 9 by gradual addition of solid ManHsS3.

Ethyl acetate (50 ml) was then added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was dried over anhydrous Mag5Oa, filtered and concentrated under vacuum to give the crude product. The crude product was purified by preparative NRI C (column: UMaieg5 Hrgidde Rger OVO C18 150 x 30 mm, 5 μm, conditions: A: water (0.0595 ammonium hydroxide vol./06.)-B: ASM, start: B 1395, end : V 4395, gradient elution time (min): 10, 10095 V retention time (min): 3, flow rate (ml/min): 25) to give compound 199 (84.7 mg, yield 2295) as a white solid substances

Example VZ3Z3

Obtaining compound 218 and rv and y shar ryk b , Y sht y na y. i yu teya Be; SS Yar TO rt, se o. т у г --- ж nm ше зе и

And wearable

Intermediate compound 32 Yepoluka 215

To a solution of intermediate compound 232 (500 mg, 0.677 mmol, 1.0 equiv.) in OSM (15 mL) was added VVgz (0.64 mL, 6.77 mmol, 10.0 equiv.) at -78"C in an atmosphere M2. The resulting mixture was stirred overnight at 20"C. The solid was filtered, washed with SiO 2 , and collected to give the crude product. The residue was triturated with water and the pH was adjusted to about 8 by gradual addition of solid CaCO3. The resulting solid was filtered through a funnel, washed with water (20 mL x 5) and collected. The residue was purified by preparative

NRIS (conditions of NRIS: A: water (0.0595 ammonium hydroxide vol./06.)-B: AFM; columns: Setipi 150 x 25 mm, 5 µm; start B: 995, end B: 3995) to give the compound product 218 (79 mg, 0.193 mmol, yield 2995) as a white solid.

Example B34

Preparation of compound 201

From day to day, child av: oh little NEYEE EV I pt 7 - RM im NE NS a .- ny shN ejafka: What OM

Mch in he

Irradiated compound 348 Compound 201

Intermediate 348 (450 mg, 0.855 mmol) was dissolved in Meon (15 mL), added

NSUMeon (4 n., 15 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation. The residue was triturated with EtOAc (100 mL) and saturated MgCO3 (30 mL). The organic layer was separated and washed with saline solution (30 ml), dried over anhydrous Ma»5O4, filtered and concentrated. The residue was purified using prep. NRI S (Umaieg5 Khbgidde Rger OVO C18 150 x 30 mm, 5 μm, conditions: A: water (0.059

MNAOH vol./o6.)-B: AFM, flow rate: 25 mL/min, gradient from B 3595 to B 6595) to give compound 201 (148 mg, yield 3595) as a white solid.

Example B35

Obtaining the compound 200 sen ev Ya vet ! ke rech M ra I MVT r ryy ok I tu N tk IK - se M. chi tn tn ov I (i; E M mit i y 6 Z no om

Intermediate compound 273 Yenoluka 200

Intermediate 373 (340 mg, 0.595 mmol) was dissolved in Meon (50 mL) and 4 N was added.

NOS/Meon (10 ml). The reaction mixture was stirred at room temperature for 2 hours.

The solvent was removed by evaporation. The residue was triturated with EtOAc (100 mL) and saturated MgSO3 (30 mL), the separated organic layer was washed with brine (30 mL), dried over anhydrous Mg5O4, filtered and concentrated. The residue was purified using prep.

NRI S (U/aieg Hriidde Rger OVO C18 150 x 30 mm, 5 μm, conditions: A: water (0.0595 MNAON vol./o6.)-

B: AFM, flow rate: 25 mL/min, gradient from B 3595 to B 6595) to give compound 200 (135 mg, yield 4695) as a white solid.

Example B36b

Obtaining compound 204 and Na b and also dk m Y nonmononomial nm, and -Щн---- - le

Nronizhna I M. kos Yenoluka 204 i ra ke yastvo trstkya zta i i i i i si i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i m i

A solution of intermediate 374 (350 mg, 0.73 mmol) in HCl/Meon (4 M, 10 mL) was stirred at room temperature for 2 hours. The mixture was basified with MH3.HgO (20 ml) to pH » 7. The solution was washed with water (60 ml) and extracted with EtOAc (80 ml x 3).

The combined organic layers were washed with brine (80 mL), dried (Mag50»5), filtered and concentrated under vacuum to give the crude product as a brown solid. The crude product was purified by NRIS (column: Umayeg5 Khbgiade

Rger OVO C18 150 x 30 mm, 5 μm; conditions: A: water (0.0595 ammonium hydroxide vol./06.)-B: AFM; start B: 25905; end B: 5595; gradient elution time (min): 10; 10095 During retention time (min):

From 3; flow rate (mL/min): 25) to give compound 204 (102.9 mg, yield 3295) as a white solid.

Example B37

Preparation of compound 203

E. te IY I E. Ky i pk I piishm shi nomeono SM hi sh- eri u Dr M Kn n re: V SHE i ry -M

OZ in MA tmik NKI

Intermezhna r you I and he OM. em

ZB compound 3500000 Compound 203

A solution of intermediate compound 350 (300 mg, 0.61 mmol) in NaOH (4 mol/L, 10 mL) was stirred at room temperature for 2 hours. The mixture was alkalized using

MHz.HgO (8 mL) to pH » 7. The solution was treated with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried (Mag25054), filtered and concentrated in vacuo to give the crude product as a brown solid. The crude product was purified by NRIS (column: Umayeg5 Khbgidde Rger OVO C18 150 x 30 mm, 5 μm; condition: A: water (0.0595 ammonium hydroxide vol./06.)-B: AFM; start B: 2595; end B: 5595; gradient elution time (min): 10; 10095 B retention time (min): 3; flow rate (ml/min): 25) to give compound 203 (129.8 mg, yield 47905) as a white solid substances

Example VZ8

Preparation of compound 202

KE M all

KE tr i R dotry nm M sh What Ne p Ag t di Iv yt i -ШШ6Ш6Ш636333 i yhe

WRITE: People of Krachan

I want, and I, M and; TIRE

Between Ki and Yenoluka 282 nn zey, connection 349 ho zach Vn M. em

A solution of intermediate compound 349 (350 mg, 0.734 mmol) in NHSO4SO4 (4M, 10 mL) was stirred at room temperature for 2 hours. The mixture was alkalized using

MH3.HgO (10 ml) to pH » 7. The solution was washed with water (100 ml) and extracted with ethyl acetate (150 ml x 3). The combined organic layers were washed with brine (100 mL), dried (Mag25054), filtered and concentrated in vacuo to give the crude product as a brown solid. The crude product was purified by HRIS to give compound 202 (149 mg, yield 4695) as a white solid.

Example B39

Preparation of compound 219

Ve sit shk shana: kn same zzhoo ach Ka vnn

Bra Wo gia

S, -M. va TRA ku M

E t i E po - not I have it

I'm mom pom, Wear VO." t. Again

Intermediate Conjugation 219 dream to her

To a solution of intermediate compound 422 (600 mg, 0.80 mmol) in OSM (11 mL) was added dropwise

TEA (12 mL, 163 mmol) in an M2 atmosphere at 0"C. The reaction mixture was stirred at 0"C for 30 minutes, then H2O (3 mL) was added. The reaction mixture was stirred at room temperature

From the temperature during the night. The solvent was removed under vacuum. The residue was dissolved in water (30 ml) and the pH was adjusted to 8, and then filtered. The solid was collected and dried under vacuum to give compound 219 (326 mg, yield 86.595) as a white solid.

Example B40

Preparation of compound 220 Ше БЕ nyvy su

Ku Gaya es u a yi Mei r, b ba Y na an MM

Nromizhna Compound 226 compound 424

TEA (10 mL, 135 mmol) was added dropwise to a solution of intermediate compound 424 (1 g, 1.20 mmol) in OSM (10 mL) under a Ma atmosphere at 0°C. The reaction mixture was stirred at 0°C for

30 minutes, then HO (3 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum. The residue was dissolved in Meon (10 mL) and adjusted to pH 8, then filtered and the filtrate was concentrated to give the crude product. The crude product was purified on a column for NRIS: YuBygaznpei! 150 x 25 mm, 5 μm; conditions: A: water (0.0595 MNAON vol./06.), B: Meon; at the beginning: A (6095) and B (4095), at the end: A (30905) and B (7095); gradient elution time (min) 10; 100905 During retention (min) 3; flow rate (ml/min) 25 to give compound 220 (106 mg, 1995 yield) as a white solid.

Example B42

Obtaining the compound 221 ka i v te, Z ; rea che cat - g H t she nar v chy ksomeOn I rt - y che on u y le she

BUT at the end of the day

Other compound whose Spoluva 211

A mixture of intermediate 426 (150 mg, 0.123 mmol) and potassium carbonate (51 mg, 0.369 mmol) in methanol (3 mL) was stirred at 60°C for 1 h. The mixture was filtered and the filtrate was evaporated under vacuum to give the crude product as a solid substances. This residue was purified by preparative NRI C (column: UMaieg5 Khbgidde Rger OVO C18 150 x 30 mm, 5 μm, condition: A: water (0.0595 ammonium hydroxide vol./o6.) - B: ASM, start: B 1395 , end: V 4395, gradient elution time (min): 10; 10095 V retention time (min): 3, flow rate (mL/min): 25). The combined solvents were evaporated to give compound 221 (39 mg) in in the form of a white solid.

C. Transformation of compounds

Example C1

Preparation of compound 217

Vyk vch - dan u ih ozh -o ut i: and ih ih- Av

TE x gu NI x ; V. I Ukr STA g. y - ryn still IJ SK her IK sha M. oboi NU m RIKOI". Ka, not copper MY Lioxav NN neon

Yepoluka 2 Yepoluma 517

Koo) Y

Into a solution of compound 2 (16 g, 2.688 mmol, 1.0 equiv.), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinan (0.72 g, 5.76 mmol, 2 .0 equiv.) and CaCO3 (0.796 g, 5.76 mmol, 2.0 equiv.) in dioxane/H2O at a ratio of 10/1 (30 mL) was added Pa(arry)Sig (210 mg, 0.288 mmol, 0.1 equiv.). The resulting mixture was stirred at 90"7C in an M" atmosphere for 16 hours. The resulting solid was filtered off. The filtrate was concentrated. The residue was triturated with water

(30 ml) and OSM (30 ml) was added. During the reaction, a solid substance was precipitated. The resulting solid was filtered to give the crude product. The residue was purified by column chromatography (gradient: petroleum ether/ethyl acetate/Meon at a ratio of 20/1/0 to 0/20/1). The product fractions were collected and the solvent was evaporated to give the product as a solid. The product was purified by preparative NRI C (conditions of NRI C:

A: water (0.0595 ammonium hydroxide vol./o06.) - B: AFM; column: Septipi 150 x 25 mm, 5 μm; beginning

B: 1595, end B: 4595) to give compound 217 (300 mg, 0.73 mmol, yield 2595) as a white solid.

Example C2

Obtaining the compound 212 a a I E vny Mtv vy Al KE M ni l y nai vimayuro dyvsan, BUT y bno be

Compound Z Yenoluk 212

Potassium isopropenyl trifluoroborate (319 mg, 2.16 mmol) and KzPOx (764 mg, 3.6 mmol) were added to a solution of compound 2 (1 g, 1.8 mmol) in dioxane (40 mL) and H2O (10 mL) at room temperature . To the above solution was added 1,1"-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (58 mg, 0.09 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80"C under a nitrogen atmosphere overnight. The mixture was extracted with ethyl acetate, the organic layers were combined and concentrated under vacuum to give the crude product.

This crude product was purified by preparative NRIS (gradient elution: 0.0590

Mnz.NgO in SNazSM/0.0595Mnz.NgO in NgO; column: Yuigazpei! 150 x 25 mm, 5 μm). The combined solvent was evaporated to give the desired product as a white solid (300 mg, yield 3595). 100 mg of the product was purified by 5ES separation (AU (250 mm x 30 mm, 10 μm)).

The combined solvents were evaporated under vacuum to give the desired product as a white solid - compound 212 (71.9 mg).

An example of CVD

Preparation of compound 213

Donna oh and in g! ra t « Y «y I K- ia Na Dn" o o ve mn. Ro ne MON is ee p

M - dv i tt um in; on vn Me BUT bur May

Tinoluka 254 Yepeoluka 213

Coo)

Ra/C (20 mg) was added to a mixture of compound 253 (200 mg, 0.429 mmol) in Meon (20 mL). The mixture was hydrogenated at 257C for 24 hours in an atmosphere of He. The mixture was filtered and evaporated under vacuum to give the crude product. It was purified by preparative NRIS (gradient elution: 0.0595 MNz.NgO in CHzSM/0.0595 MNz.NegO in Ngo; column: Umayeg5 Khogiade

Rger OVO C18 150 x 30 mm, 5 mm). The combined solvent was evaporated to give compound 213 as a white solid (132 mg, yield 73905).

The following compounds were prepared using a reaction protocol similar to that used to prepare compound 213 using the appropriate starting materials (Table 47).

Table 47 contains 214 Mole Compound 212

She

BUT UN Mem

Analytical part

NMR

For a number of compounds, H NMR spectra were recorded on a Vgykeg OPX-360, which operated at 360 MHz, on a VgyKeg Amapse 600, which operated at 600 MHz, on a VgyKeg Amapse 400, which operated at 400 MHz, or on a Magiap 40OME spectrometer, which operated at 400 MHz.

CH OKOGOM-a (deuterated chloroform, COcSys), methanol or OM5O-ydv (deuterated OM5O, dimethyl-ab-sulfoxide) were used as solvents. Chemical shifts (5) were recorded in parts per million (ppm) relative to tetramethylsilane (TM5), which was used as an internal standard.

Spol. 217: "H NMR (400 MHz, OM50O-av) b ppt 2.44 (5, C H) 4.21 - 4.34 (t, C H) 4.34 - 4.43 (t, 1 H) 4.50 (ad, 9-5.7 Hz, 1 H) 5.37 (a, U-5.0 Hz, 1 H) 5.44 (a, 9-63 Hz, 1 H) 6.17 ( y, 9-5.5 Hz, 1 H) 6.61 (90, 9-38 Hz, 1 H) 7.01 (bBg 5, 2 H) 7.27 (ad, U-8.8, 2, 5 Hz, 1 H) 7.37 (y, 9U-3.8 Hz, 1 H) 7.41 (a, 9-23

Hz, 1 N) 7.81 (a, 9U-9.0 Hz, 1 N) 8.05 (Bg 5, 1 N) 8.07 (5, 1 N) 8.70 (a, 9-2, 0 Hz, 1 N).

Spol. 218: "H NMR (400 MHz, OM50O-4dv) b pprt 4.14 - 4.34 (t, 4 H) 4.48 (d, U-5.7 Hz, 1 H) 5.36 (ad, 9-5.0 Hz, 1 H) 5.44 (a, U-6.3 Hz, 1 H) 6.15 (a, 9-5.5 Hz, 1 H) 6.33 (bg 5, 2 H) 6.58 (a, U-8.8 Hz, 1

H) 6.61 (a, 9-3.8 Hz, 1 H) 6.83 (da, 9-8.7, 2.4 Hz, 1 H) 6.91 (a, 9-2.3 Hz , 1 H) 7.02 (Brg 5, 2 H) 7.35 (a, 9-38 Hz, 1 H) 7.53 (y, 9-8.8 Hz, 1 H) 7.79 (a, U-8.8 Hz, 1 N) 8.07 (5, 1 N).

Spol. 74: "H NMR (600 MHz, OM50O-dv) b pprt 024-027 (t, 2 H) 0.45 - 0.48 (t, 2 H) 1.08 - 1.14 (t, 1 H) 1.52 (01, 9U-12.4, 10.3 Gu, 1 H) 1.67 - 1.74 (t, 1 H) 1.84 - 1.92 (t, 1 H) 1.96 ( ace

U-13,0,9,3, 6,4, 6,4 Hz, 1 N) 2,25 (ai, 9U-12,7, 7,9 Hz, 1 N) 2,65 - 2,72 ( t, 1 H) 2.72 - 2.79 (t, 1 H) 3.26 (aa, 9-6.5, 5.6 Hz, 2 H) 3.75 (a, 9U-4.9 Hz , 1 H) 4.21 (yi, 9-7.6, 6.2 Hz, 1 H) 4.63 (0. 9-4.8 Gu, 1

H) 4.77 (a, 9-63 Hu, 1 H) 4.81 (ai, 9U-10.5, 8.0 Hu, 1 H) 6.55 (a, 9-3.5 Hz, 1 H) 6.72 (a, 9-8.9 Hz, 1 H) 6.91 (horn 5, 2 H) 6.99 - 7.03 (t, 2 H) 7.26 (y, 93.5 Hu, 1 H) 7.33 (5, 1 H) 7.50 (a, 9-81 Hu, 1 H) 7.76 (a, 9-8.8 Hz, 1 H) 8.04 (5, 1 H).

Spol. 129: "H NMR (360 MHz, OM50O-av) 6 ppt 1.53 (yi, 9U-12.3, 10.2 Hz, 1 H) 1.69 - 1.81 (t, 1

H) 1.82 - 1.93 (t, 1 H) 1.95 - 2.05 (t, 1 H) 2.25 (01, 9U-12.4, 7.9 Hz, 1 H) 2, 78 - 2.93 (t, 2 H) 3.76 (9, 95.0 Gu, 1 H) 4.21 (ad, 95.9 Hz, 1 H) 4.66 (a, 9-4.8 Hz, 1 N) 4.73 - 4.86 (t, 2 N) 6.55 (0.9-3.3 Hz, 1

Koo) H) 6.95 (ri 5, 2 H) 7.27 (y, 93.7 Hz, 1 H) 7.59 (ad, 9-84, 1.8 Hz, 1 H) 7.87 ( 5, 1 H) 7.91 (a, 9-84 Gu, 1 H) 8.03 (5, 1 H) 8.68 (y, 9-22 Hz, 1 H) 8.91 (y, 9- 2.6 Gu, 1 N).

Spol. 130: "H NMR (400 MHz, OM50-4av) b pprt 4.22 - 4.39 (t, C H) 4.59 (d, U-5.0 Hz, 1 H) 5.49 (bg a , 9-4.5 Gu, 1 N) 5.60 (a, 9U-6.0 Hz, 1 N) 6.29 (a, 9-5.5 Hz, 1 N) 6.64 (t, U -9.0 Hz, 2 H) 6.78 (y, 93.68 Gu, 1 H) 6.90 (ad, 9y-8.7, 1.9 Hz, 1 H) 6.97 (y, 9 -1.5 Hz, 1 H) 7.58 (y, 9U-8.5 Hz, 1 H) 7.87 (y, 9U-9.0 Hz, 1 H) 7.97 (y, 9-4 .0 Hz, 1 N) 8.69 (5, 1 N).

Spol. 176: "H NMR (400 MHz, Methanol-aa) b ppt 2.32 - 2.45 (t, 1 H) 2.48 - 2.62 (t, 1 H) 2.65 - 2.83 (t , 2 H) 3.01 - 3.12 (t, 1 H) 3.45 (5, Z H) 3.49 - 3.63 (t, 2 H) 3.69 (a, 9-48 Hz, With H) 4.53 - 4.61 (t, 1 H) 5.05 - 5.11 (t, 1 H) 5.51 (a, 9-48 Hz, 1 H) 5.60 (a, 9 -6.3 Hu, 1 H) 5.70 - 5.81 (t, 1 H) 7.47 (a, 9-8.8 Hz, 1 H) 7.50 (a, 9-38 Hu, 1 H) 7.73 (bg a, U-5.0 Gu, 1 H) 7.84 (da, 9U-8.0, 1.5 Hz, 1 H) 8.17 (rg 5, 1 H) 8 .32 (a, 9-8.0 Hz, 1 N) 8.53 (0, 9-3.5 Hz, 1 N) 8.58 (a, 9-88 Hz, 1 N) 9.43 (5 , 1 H).

Spol. 80: "H NMR (600 MHz, UOM50-dv) b ppt 1.50 - 1.56 (t, 1 H) 1.68 - 1.75 (t, 1 H) 1.85 - 1.92 (t , 1 H) 1.96 (ad, 9U-13.0, 9.0, 6.5, 6.5 Hz, 1 H) 2.25 (ai, 9-12.7, 7.9 Hz, 1 H) 2.69 - 2.80 (t, 2

H) 3.76 (rii, 9U-4.7 Hz, 1 H) 4.21 (yes, 9-7.6, 6.0 Hz, 1 H) 4.57 (horn 5, 1 H) 4, 72 (horn 5, 1 H) 4.80 (a, u10.5, 7.9 Hz, 1 H) 6.50 (re 5, 2 H) 6.59 (a, 9-3.5 Hz, 1 H) 7.07 (re 5, 2 H) 7.12 (ai, U-8.2, 1.6 Gu, 1

H) 7.29 (a, 9-3.6 Hu, 1 H) 7.34 (5, 1 H) 7.58 (0.9U-8.1 Hu, 1 H) 8.07 (c, 1 H) 8.91 (in, 1 H).

Spol. 185: "H NMR (400 MHz, OM50O-4v) b pprt 2.96 (rg a, 9U-3.5 Hz, Z H) 4.16 - 4.36 (t, 4 H) 4.44 - 4 .55 (t, 1 H) 5.38 (rg y, 95.3 Gu, 1 H) 5.47 (Bg a, 9-6.2 Hz, 1 H) 6.16 (a, 9-5 7 Gu, 1 N) 6.63 (a, 9-40 Hz, 1 N) 6.70 (rg a, 9-9.3 Gu, 1 N) 6.89 - 6.97 (t, 1 N) 7.05 - 7.23 (t, Z H) 7.37 (0.9-3.5 Hz, 1 H) 7.63 (reg y, 99.3 Gu, 1 H) 7.84 - 7, 95 (t, 1 N) 8.09 (5, 1 N).

Spol. 75: "H NMR (400 MHz, UOM50-dv) b ppt 1.45 - 1.59 (t, 1 H) 1.65 - 1.77 (t, 1 H) 1.83 - 2.02 (t , 2 H) 2.25 (a, 9-12.5, 7.9 Hz, 1 H) 2.63 - 2.83 (t, 2 H) 3.72 - 3.89 (t, C H) 4.16 - 4.24 (t, 1

H) 4.64 (y, 9-48 Hz, 1 H) 4.77 (a, 9U-6.3 Hz, 1 H) 4.79 - 4.84 (t, 1 H) 6.22 (H , 9-56.7, 41 Hz, 1 N)

6.54 (9, 9-3.5 Gu, 1 H) 6.78 (a, 9-8.8 Hz, 1 H) 6.91 (re 5, 2 H) 7.09 (ad, 9- 82, 1.6 Hz, 1 H) 7.26 (a, 93.5 Hz, 1 H) 7.36 (I, 9-6.0 Gu, 1 H) 7.40 (reg 5, 1 H) 7, 57 (a, 9-8.0 Hz, 1 N) 7.67 (a, 9-8.8 Hz, 1 N) 8.03 (5, 1 N).

Spol. 81: "H NMR (400 MHz, OM5O-dv) b ppt 1.42 - 1.60 (t, 1 H) 1.62 - 1.77 (t, 1 H) 1.81 - 2.00 (t , 2 N) 2.24 (yi, 9-12.7, 7.68 Hz, 1 N) 2.64 - 2.83 (t, 2 N) 3.70 - 3.79 (t, 1 N) 4.16 - 425 (t, 1

H) 4.62 (horn a, 9U-4.9 Gu, 1 H) 4.71 - 4.87 (t, 2 H) 6.54 (y, 2-3.5 Hz, 1 H) 6, 65 (Bg 5, 2 H) 6.90 (Bg 5,2

H) 7.12 (ra, 97.5 Hz, 1 H) 7.25 (9, 9-3.5 Gu, 1 H) 7.34 (5, 1 H) 7.58 (a, 9U-8 .4 Gu, 1 N) 8.03 (5.1 N) 8.14 (5.1 N).

Spol. 151: "H NMR (400 MHz, OM50-av) b ppt 1.45 - 1.57 (t, 1 H) 1.62 - 1.77 (t, 1 H) 1.82 - 102.01 (t , 2 N) 2.25 (y, 9U-12.4, 7.9 Hz, 1 N) 2.65 - 2.82 (t, 2 N) 3.75 (9, 9-48 Hz, 1 N ) 4.20 (a, 0-7.6, 6.2 Hz, 1 N) 4.26 - 4.39 (t, 2 N) 4.64 (a, 2-48 Hz, 1 N) 4.73 - 4.687 (t, 2 H) 6.54 (a, 9-3.5 Hz, 1 H) 6.82 (a, 9-8.8 Hz, 1 H) 6.91 (rg 5, 2 H) 7 .12 (aa, 9U-8.0, 1.5 Hz, 1 H) 7.26 (а, 9-3.5 Hz, 1 H) 7.42 (5.1

H) 7.54 (ry, 9-64 Hz, 1 H) 7.59 (a, 9-80 Gu, 1 H) 7.91 (a, U-8.9 Hz, 1 H) 8.03 ( 5, 1 H).

Spol. 152: "H NMR (400 MHz, OM50-av) b ppt 0.39 - 0.62 (t, 2 H) 0.67 - 0.84 (t, 2 H) 1.46 - 1.62 (t , 1 H) 1.64 - 1.78 (t, 1 H) 1.82 - 2.02 (t, 2 H) 2.25 (her, 9-12.6, 8.0 Gu, 1 H) 2.63 - 2.83 (t, Z

H) 3.70 - 3.79 (t, 1 H) 4.15 - 4.25 (t, 1 H) 4.63 (0.9-4.9 Hz, 1 H) 4.73 - 4, 86 (t, 2 H) 6.54 (a, 90-3.5

Hu, 1 H) 6.75 (rg a, 9-8.8 Hz, 1 H) 6.90 (horn 5, 2 H) 7.05 (da, 9-82, 1.5 Hu, 1 H) 7.13 (rg a, 9-2.6 Hz, 1

H) 7.26 (a, 93.5 Hz, 1 H) 7.37 (horn 5, 1 H) 7.54 (a, 9-7.9 Hz, 1 H) 7.84 (9, 9U- 8.8 Hz, 1 N) 8.03 (5, 1 N).

Spol. 146: "H NMR (400 MHz, OM50-av) b ppt 1.38 - 1.63 (t, 5 H) 1.65 - 1.75 (t, C H) 1.82 - 202.04 (t , 4 N) 2.25 (ai, 9-12.5, 7.9 Hz, 1 N) 2.63 - 2.80 (t, 2 N) 3.71 - 3.78 (t, 1 N) 4.14 - 4.25 (t, 1

H) 433 (da, 9U-13.6, 6.7 Hz, 1 H) 4.63 (a, 9-4.9 Hz, 1 H) 4.73 - 4.86 (t, 2 H) 6 ... 7.9, 1.3 Hu, 1 N) 7.26 (a, 9-3.5 Hu, 1 N) 7.32 (5, 1 N) 7.49 (a, 9-84 Hz, 1 N ) 7.74 (0.9-8.8 Gu, 1 N) 8.03 (5.1 N).

Spol. 76: "H NMR (400 MHz, YuOM50-dv) b ppt 1.43 - 1.57 (t, 1 H) 1.62 - 1.76 (t, 1 H) 1.79 - 25. 2.01 (t, 2 H) 2.18 - 2.29 (t, 1 H) 2.65 - 2.79 (t, 2 H) 3.70 - 3.78 (t, 1 H) 4.14 - 4 .25 (t, 1 H) 4.63 (bg a, 9-49 Gu, 1 H) 4.73 - 4.686 (t, 2 H) 6.42 (horn 5, 2 H) 6.54 (horn a , 9-3.5 Hz, 1 N) 6.69 (reg a, 9U-8.8

Gu, 1 H) 6.92 (horn 5, 2 H) 7.05 (Bg a, 9-84 Hz, 1 H) 7.26 (rg a, 93.5 Gu, 1 H) 7.28 (horn 5, 1 N) 7.54 (bga, 97.9 Hz, 1 N) 7.84 (reg a, 9-8.8 Gu, 1 N) 8.02 (5, 1 N).

Spol. 121: "H NMR (400 MHz, OM50-av) b ppt 1.56 - 1.68 (t, 1 H) 1.69 - 1.82 (t, 1 H) 1.84 - 2.05 (t , 2 H) 2.24 - 2.37 (t, 1 H) 2.63 - 2.81 (t, 2 H) 2.88 (9, 9-44 Hz, C H) 3.73 - 3, 81 (t, 1 N) 4.25 - 4.35 (t, 1 N) 4.73 (0, 9-44 Hz, 1 N) 4.86 (a, 2-6.6 Hz, 1 N) 4.93 - 5.04 (t, 1 H) 6.66 (y, U-8.8 Gu, 1

H) 6.69 (a, 9-3.5 Hz, 1 H) 6.87 - 6.94 (t, 1 H) 7.03 (reg ad, 9U-7.9, 1.3 Gu, 1 H) 7.37 (5, 1 H) 7.51 (y, 98.4 Hz, 1 H) 7.77 (ra, 9-8.8 Gu, 1 H) 7.95 (a, 9-4 .0 Hz, 1 N) 8.63 (5, 1 N).

Spol. 113: "H NMR (400 MHz, OM50-dv) b ppt 1.48 - 1.58 (t, 1 H) 1.70 - 1.80 (t, 1 H) 1.82 - 1.94 (t , 1 H) 1.95 - 2.04 (t, 1 H) 2.25 (ai, 9-12.5, 8.1 Gu, 1 H) 2.46 (5, C H) 2.75 - 2.90 (t, 2 N) 3.71 - 3.80 (t, 1 N) 420 (reg aa, 9-14.1, 6.2 Hz, 1 N) 4.65 (y, 9-5 ,3 Hz, 1 N) 4.73 - 4.86 (t, 2 N) 6.54 (a, 93.5 Hz, 1 N) 6.92 (horn 5, 2 N) 7.26 (y, 9-3.5 Hz, 1 N) 7.47 (a9, 9U-8.4, 1.68 Hz, 1 N) 7.76 - 7.85 (t,2

H) 8.02 (5, 1 H) 8.07 (horn 5, 1 H) 8.72 (9, 9-2.2 Hz, 1 H).

OK (optical rotation)

Optical rotations were measured on a ReiKip-EIteg 341 polarimeter with a sodium lamp (the wavelength of light used was 589 nm (O-line of sodium)). (TT stands for temperature).

Table

The value of the angle of rotation for enantiomerically pure compounds /Mespol.| oyu() | Wavelength (nm) | Concentration (mass/vol. 95) (Solvent, Ts) 129, | -8.6 | sh-( 589.4.YUY.YM|YUYTS 03835 |OME | 20 liz | 8 7117589... 17771717171717101005125.// |OME | 20 80 | 88 | sh 589 Yuyush g | 05315 (|OME | 20

Table

Value of rotation angle for enantiomerically pure compounds

And CM5 (liquid chromatography/mass spectrometry)

High performance liquid chromatography (HPLC) measurements were performed using an IS pump, diode array detector (DAD) or UV detector and column as described in the respective methods. If necessary, additional detectors were used (see the methods table below).

The flow from the column was directed to the mass spectrometer (M5), which was equipped with an ionization source at atmospheric pressure. It is within the competence of a person skilled in the art to establish adjustable parameters (eg, scan range, minimum measurement time, etc.) to obtain ions that provide determination of the nominal monoisotopic molecular weight (NOM) of a compound. Data collection was carried out using appropriate software.

Compounds were described by their experimental retention time (Ki) values and ions. Unless otherwise indicated, in the data table the indicated molecular ion corresponds to (MANI (protonated molecule) and/or IM-NI (deprotonated molecule). In the case that the compound was not directly capable of ionization, the type of adduct is indicated (i.e. |MAMNAG, (MANSOO, etc.). For molecules with complex isotopic distributions (Bg, SI), the value described is the value obtained for the lowest isotopic mass. All results were obtained with experimental errors, which are usually associated with the method used.

Further in this document, "BOYU" means a single quadrupole detector, "MBO" means a mass-selective detector, "k. t." means room temperature, "VEN" means ethylsiloxane/silicon dioxide bridge hybrid, "SAYU" means diode array detector, "НЗ5" means silicon dioxide of increased strength, "ОО-Той" means quadrupole time-of-flight mass spectrometers, "СИ/МО" means chemiluminescent nitrogen detector, "E/50O" means evaporative light scattering detector.

Table

Codes of methods I CM5 (flow rate expressed in ml/min; column temperature (T) in "С; analysis time in minutes).

Method speed Device Column Mobile phase Flow gradient from source

T columns

From 9595 A to 595 A in 1.3 min,

UMaiegv: A: 10 mM retention

Asdiya? |MMaietye: / VEN SNZSOOMNA within 0.7 1 ORI C? 4018 (1.7 μm/9095 H2O - 10950.2 min, up to 9590 tt 1.68 rad and|2.1750 mm) SNnZSM A in 0.2 min, 70

ОО in: meOon retention for 0.1 min.

U/aegv: A: 10 mm From 9595 A to

Asdiyu?e | Uaiegv: VENI SNIZSOMNA v 595 A in 1.3 min, 0.6 2 ORI C? -018 (1.7 μm/9595 НО - 595 retention tt 2 rado and|2.1750 mm) SNnZSM during 55

ОЮ В: СНнзСМ 0.7 min.

Method speed Device Column Mobile phase Flow gradient from source

T columns

From 10095 A to

UMaiegv: A: 10 MM 595 A for

Asdiyutyu |MUaivegv: NO5 TZI SNZSOOMNA 2.10 min, 0.7

WITH ORI SF- |(1.8 μm, in 9595 H2O I BUdo 095 A for ty 3.5 rado and! 2.17100 mm) SNZSM 0.90 min, 55 5ОЮ В: SNZSM up to 59 A in 0.5 min .

From 10095 A to

UMaiegv: A: 10 MM 595 A for

Asdiyutyyu |MUaivegv: NO5 TZI SNZSOOMNA 2.10 min, 0.7 4 ORI SF /- (1.8 μm, in 9595 H2O I BUdo 095 A for tya 3.5 rado ta! 2.17100 mm) SNnZSM 0.90 min, 55 5OYU B: SNZSM up to 59 A in 0.5 min.

From 84,295. And within 0.49 min, to

UMaiegv: 10.55 A per

Asashiyu 2.18 min,

RIS C- Uaiegv: VENA: 9595 7 mM retention 0.343

A and C18 (1.7 μm) SNZSOMNI/595 | during traction 62

Ohio 2.1 x100 mm) |СНаСМ, In: СНзСМ |1.94 min, back 40

By city up to 84.295 AB in 0.73 min, holding for 0.73 min. from 10095. A during 1 min, up to 4095 A for 1100/1200 series: 0.0595 MNAON IN 7 MIN. 0.8,

AYU OP In water, V:SnNoSM o/ |Retention n 0.5

Meo (5 µm, within 40 2.1 x 50 mm) 2.5 min, back to 10095 A in 2 min.

From 10095. A

Adiiyeepi: Rpepotepeh: |A: 0.195 SEZSOON lo OO. A min, 1200 -ODAO and ipa-С18 in water, B: tambourine TO lo in 08 7 4 min, to 1595 A ttyannia 10 and (5 μm, sSOON VI in 25 min BO

M506110 | 2 x 50 mm) СНнЗСМ back to 10095

And in 2 min.

From 10095 A to

UMaiegv: A: 10 MM 595 A for

Asdiyu?e | M/ayege: BUT TZI SNISOMNA 2.10 min, 0.7

ORI С9- |(1.8 μm, in 9595 N2gO -- Bobdo 095 A per ty 3.5 rado and! 2.17100 mm) SNZSM 0.90 min, 55 5ОЮ V: SNZSM up to 59 A in 0.5 min .

Speed

Code and Flow Method Time Instrument Column Mobile Phase Gradient In Analysis

T columns

From 10095. A . o o o within 1 min,

Aoiele | doyepe tostiv s be SEZSOONI Up to 4095 d for 08 1100/1200 in water, V: 0.05925 o (5 μm, 4 min, up to 1595 A ty 10.5 -YAVAO o sСООН in

Meo 1 x50 mm) sNesM in 2.5 min, 50 back to 10095

And in 2 min.

From 9095. And during

Adiiyeepi: po, Y A: 0.195 SEZSOONI 0.8 min, to 2095 1100/1200 | MOIeps: TO-STV, water, B: bBeA in 37 min/) (9 10 (5 μm, ptyatnia 10.5 -rAr Her x5O0 mm) SsEZSOON in holding BO

M5o " CHnZSM for 3 min, back to 9095

And in 2 min.

From 9095. And during

Adiiyeepi: Rpepotepeh: |A: 0.195 SEZSOON| 0.8 min, up to 2095 08 14 1200 -VAO) ipa-C18 in water, B: 0059 A in 3.7 min, NI 10 and (5 μm, SsEZSOON in holding BO

М506110 |2 x 50 mm) SNZSM within 3 min, back to 9095

And in 2 min.

From 9595 A to 595 A in 1.3 min,

UMaiegv: , A: 10 mM retention

Assists svt: VEN SNISOMNaA during 0.2 0.7 12 ORI C9- (1.7 μm in 9595 H2O -- Bobhv, up to 9595 A tya 1.8 rdo tar 1550 mm) SNnZSM in 02 min, 70

OO ' In: SNZSM retention for 0.1

MIN.

Table. Mo spol. means compound number; retention time (Ki) in minutes; N. in. means not defined.

Me WHAT IS THEIR NAME SPOSV MOV. ME | Spsov spol. named after 1SsMmE

Me E NAMES | I send Mo EE to them | Method of sex, name of sleep.

Ts zorya era trya 1 rve tya t 1

Me in, NAME | Sposii Me V.

MAN Sposyu snol. 1SMm5 spol.

SM sel rya ki yara still V. MANI | Snosib me In me, I fell asleep. SM spol. 1 cMmu yar break t yar yar at per pet seryarya 15000 reyarya t paper yare per

KELElNESl BYY yar i vody vl Shy

Me V OO YIMANI | The way of Me IN ME | Stasiv and 1SEMme spol. 1sMm5 et re t t sya rr t re t vra ti reg v I SHBsoNY SHANY pa I ShosoNY SHIK ery it yar t pesni SHY sere t ovyati ok nt rent

Me i- NAMES | I will send it to MANI Eposyu spol. TM spol. i1sMmE

EXPERIMENTAL PROCEDURES with the analysis of ip miigo (analysis 1a and 16)

Reagents. The enzyme REMT5-MER5ZO was purchased from SPpagpev5 Kimeg (Agdepia). The enzyme complex was obtained in insect cells (50) infected simultaneously with two baculoviruses.

One virus expresses full-length human REMT5 with an ERIad tag at the M-terminus, the second virus expresses full-length MER5BO with a Nizb-TEM cleavage site at the M-terminus. The protein was affinity purified using particles coated with an antibody to Riad (M2), followed by elution with the peptide ZHEH As, and then Nib-5eEsi, eluting with 0.5 M imidazole.

The eluted protein was then dialyzed against Tris-buffered saline (TB5) (pH 8.0) containing 2095 glycerol and 3 mM dithiothreitol (017).

Full-length untagged human recombinant histone H2A (residues 1-130, accession number in zeprapk MM 021052, MMU - 14.1 kDa), expressed in E. soya, was purchased from Keasiyop

Vioiodu Sogrogayop, Mo for cat. NMT-11-146. We purchased reagents that were used to prepare the reaction buffer or to stop the reaction, in particular Tgib base (Mo according to the Bidt T-1503 cat.), Masi (Mo according to the Bidt cat. NOE-3270), MasSig (Mo according to the Bidt cat. MO250) , OTT (Mo under cat. Ipmitodep 15508-013) and formic acid (Kiedeyi ae Naep, Me under cat. 33015).

Analysis of it on a high-performance mass spectrometer REMT5 catalyzes successive methylation of terminal nitrogen atoms on guanidine groups of arginine residues in proteins, using the substrate cofactor 3-adenosyl-!Y-methionine (AdoMei, ZAM), while monomethyl (MMA), symmetrical dimethylarginine (50ОМА ) and 5Z-adenosyl - homocysteine (AdoHsu, ZAN). Enzymatic activity was determined after product formation

ZAN, using high-performance mass spectrometry (Adiyepi Kariyasge 300 system with tri-quadrupole M5/M5 Zsieh 4000 series OTgar-). The reaction buffer was 20 mM T"tgiv-

NOI, pH 8.5, 50 mM Mass, 5 mM Mosi" and 1 mM OT. The reaction was stopped using 195 formic acid (final concentration).

Inhibition studies ICho studies were performed using an eleven-point dosing series performed for each compound by serial 1:22 dilution in dimethylsulfoxide (OM5O), point 12 being UM5O as a control.

The compound was first applied to the tablets, and then a mixture of 2 µM ZAM and 0.6 µM solutions was added

H2A (histone H2A). The same volume of enzyme solution was added to initiate enzymatic reactions. The final concentrations of the reaction mixture were 1 μM ZAM, 0.3 μm

H2A and 10 NM enzyme (assay 1a) or 1.25 NM enzyme (assay 15). The reaction mixture was incubated at 30°C for 60 minutes (min) when 10 nM enzyme was used, and for 120 min when 1.25 nM enzyme was used. Then the reaction was quenched by adding formic acid to a final concentration of 195. Inhibition of 5AN formation in the presence of compounds was calculated as a percentage of the control relative to the uninhibited reaction mixture as a function of inhibitor concentration.The data were approximated as follows:

In the same Low "from (Top - Bottom)X1--107((109 ISvo -X) " M)), where ISvo is the concentration of the inhibitor (the same units as X) at 50595 inhibition, and also represents the angular Hill coefficient. Y is percent inhibition, X is compound concentration Id. Bottom and Top are plateaus in the same units as Y.

EXPERIMENTAL PROCEDURE with RO analysis (analysis 2)

Reagents

A549 cells (ATSS, Mo under cat. SSI -185) were cultured in Dulbecco's modified Eagle's medium (OMEM) (Zidta, Mo under cat. 05796), supplemented with 1095 fetal calf serum (EC5) (NuSiope", Mo under cat. 5M30160.03), 100 mM sodium pyruvate (Zidta, MO according to catalog 58636), 200 mM I-glutamine (Zidta, MO according to cat. 57513) and 50 mg/ml gentamicin ((iBrso,

Mo per cat. 15750-037).

Reagents used for buffers were purchased: phosphate-buffered saline solution

Dulbecco (ORV5) without Ca/Ma (Bidta, Mo under cat. 08537), phosphate-buffered saline solution (РВ5) 10X (Kospe, Mo under cat. 11 666 789 001), formalin solution 1095 (Zidta, НТ5О-1- 128-41),

methanol 10095 (Zidpta, Me under cat. 32213-2.51), Tyyop X-100 (Asgo5, Mo under cat. 215680010), bovine serum albumin (B5A) (Zidta, Mo under cat. A2153), goat antibody to rabbit immunoglobulin, conjugated with AIekha Riyog 488 (Ge Tesppoodie5, Me under cat. A11034), dark red dye NOZ SeiYMahk (Gie TesppoiIodie5, Mo under cat. NZ2721), dye Noespvi (I ie Tesppoiodiev,

Mo per cat. 33258), antibody to dimethylarginine, symmetrical (5'UM10) (MiProge, 07-412).

Immunohistochemical analysis procedure

Cells were plated at 400 cells/40 μl/well in 384-well black microplates with a transparent bottom (Regikip EIITeg) and incubated overnight at 37°C, 595°C.

The ISvo study was conducted using a nine-point dosing series in the range from 10 μM to 1 pM for each compound. 80 nl of the appropriate dilution of the compounds was added with the use of Gabsuie ROY 810 (Iarsuei), reaching a final concentration of OM5O of 0.295 in the cell culture. After an incubation period of 48 hours at 37°C and 595°C, the cells were fixed in 1095 formalin solution for 15 minutes at room temperature and 20 minutes in ice-cold methanol, after which they were washed in ORV5. Then the cells were blocked for 1 hour in blocking buffer (PB5 and 195 VZA and 0.595 Ttyop X-100) and incubated overnight at 4-7C with the 5UM10 antibody diluted 1/2000 in blocking buffer. Zh cells were washed with washing buffer (RVZ I-0.195 Tiop X-100) and incubated with goat anti-rabbit immunoglobulin conjugated with Alec 488, diluted 1/200 in blocking buffer, for 1 hour at room temperature. Then, their cells were washed with washing buffer and incubated for 30 min at room temperature with PB5, which contained Noespvi dye at a dilution of 1/5000 and dark red dye HC5 SeiMazK at a dilution of 1/5000. After the final washing with РВ5, the tablets were visually analyzed using a 10xW lens of the Orega? system. (Regkip EIteg I ee bsiepse5), using the following settings (values in nm). mirror mirror

Conducting analyses: inhibition of nuclear symmetric dimethylation of arginine in the presence of compounds (Us effect) was calculated as "median nuclear intensity ZUM10"/"median

The cytoplasmic intensity of ZUM10" was normalized according to the following equation: normalized - 100-- tesprabatannv low copper level

EBsheaskOe srednee nnihvoae sredi

In the above-mentioned equations, the following variable names were used: low median : by concentration high median : by concentration

In the above equations, the following controls were used for normalization:

Low-concentration control: minimal level of symmetrically dimethylated arginines (cells treated with the reference compound at a concentration of 10 µM).

High concentration control: maximal level of symmetrically dimethylated arginines (OM5O-treated cells).

Values of ISvo and riSvo (-IodiSvo) were calculated using appropriate software.

The risso values in the table below are averaged values (Mo spol. means compound number; n. v. means not determined).

Me | axis VE ze VC Me | vaSh VES spol.

Analysis Analysis | Gender analysis Analysis Analysis of their iB 3 of 1 2 re

Me | growth RE and M | ris vet all spol.

Analysis Analysis | Analysis of society

Analysis Analysis | Analysis of IP 2 of 15 2

Me | VS milestone VK Me | all" for VE spol.

Analysis Analysis | Analysis of gender Analysis Analysis | analysis of food Z iv ii 2 anEsM NBoli BA

Mo wa RisSto VE M | the entrance to the wind turbines of the entire society.

Analysis Analysis | Analysis of society

Analysis! Analysis | Analysis of IB 2 from IB From the press tvBslnvsly von

Me vka risto rish M | decision with social Analysis Analysis | Analysis of society Analysis Analysis The analysis of those who came from the IV and disappeared because of the connection between them

Examples of compositions

The "active ingredient" used in all these examples refers to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates; in particular, any of the compounds given as an example.

Typical examples of formulations for the composition according to the present invention are given below. 1. Tablets

Active ingredient from 5 to 50 mg

Dicalcium phosphate 20 mg

Lactose 3 mg

Talc 10 mg

Magnesium stearate 5 mg

Potato starch up to 200 mg 2. Suspension

The aqueous suspension is prepared for oral administration so that each milliliter contains from 1 to 5 mg of the active ingredient, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water added to a volume of 1 ml. 3. Form for injections

The parenteral composition is prepared by mixing 1.595 (w/v) of the active ingredient in a 0.995 mass solution or a 1095 volume solution of propylene glycol in water. 4. Ointment

Active ingredient 5-1000 mg

Stearyl alcohol From g

Lanolin 5 g

White Vaseline 15 g

Water up to 100 g

In this example, the active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular with the same amount of any of the compounds given as an example.

Claims (35)

FORMULA OF THE INVENTION 1. Compound of formula (1): AK- -7, U T g vo OV? ; (I) where B' represents hydrogen or -C(-O)-C.-alkyl; Hg is hydrogen or -C(-0)-C.-alkyl; U represents -СНе- or -Срг2-; 7 represents -СНе-, -Х-СНазедь-, -С52-(05а-, -СН5ед5о-СВВе-, -С-0-, -О- or -СВзаде-х-; each of за, ИДрб, Дос, Dosa, Doe, De, Do, and Bo? are independently hydrogen or C-4 alkyl; X is -O-, -5- or -MA1-; B" is hydrogen, C1-4 alkyl or C1-4 alkyl, substituted by one substituent selected from the group consisting of -OH, -O-Ci1-alkyl, K 2, -MH", -MH-C.-alkyl and -M(Сч-"alkyl)"; В" represents is a 4-, 5-, 6- or 7-membered heterocyclic ring that contains one nitrogen atom and optionally one oxygen atom, while the indicated 4-, 5-, 6- or 7-membered heterocyclic ring attached to the rest of the molecule through the nitrogen atom of the ring; Ag is a 10-membered bicyclic aromatic ring system consisting of two condensed 6-membered rings, vna ro lac and ME dimu SaA)Y VAL KAH Kv mur 0 shchi chi, ZD di, ai su en de optionally 1 carbon atom of ring B is replaced by a nitrogen atom; where optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom; provided that, if a nitrogen atom replaces one of the two carbon atoms common to the two fused rings, then the carbonyl group is present in said bicyclic aromatic ring system; Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-Ci-alkyl, -M(C1-4alkyl)2, -MNAsYA, -MAoedtoYA, cyano, -SEz, -C(-0)-MH", -C(-0)-MH-C:-alkyl, -C(-0)-C:-alkyl, C-4alkyloxy . one C1-lalkyloxy, and C1-4alkyl, optionally substituted by one -MH'sad's: each of B ba | E/c5 is independently hydrogen or Ci-alkyl; each of B'Os and Dya independently represents C3-ecycloalkyl; VZ; IN'""; Szvcycloalkyl, substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C.-4 alkyl; Ci-4 alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH, and -O-Ci-lalkyl; or C 1-6 alkyl substituted with one substituent selected from the group consisting of C 3-6 cycloalkyl, C 1 -C 1 and I; B'Z is a 4-7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, 5, 5(-O)p and M; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from 0, 5, 5(-O)p and M; the indicated 4-7-membered monocyclic aromatic ring or 6-11-membered bicyclic condensed aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C-4 alkyl; p is equal to 1 or 2; B"" is phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen; It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5): not ve I B and y. t? в х т -х She sht ker r v rech y sk BU kg Х і : t NU Zery M х A M How dya n r kh В НЯ Ne h vo shki, shko, pyn r Be y -e i -o m ! 2 ИЙ her ia-sh yiv-- NN at the same time each of Za, DZ5, DZs, dz | BdZe is independently hydrogen, halogen, -MAT2B», C1-4 alkyl, C6--alkenyl, C3-ecycloalkyl, -OH or -O-C6-alkyl; Da represents hydrogen; AND? is hydrogen, C3-6cycloalkyl or C1-6alkyl; each of Ka, DV", des, DYA, de, Dt and B independently represents hydrogen, halogen, -MVZaB8b or C. 3-4 alkyl; each of Za and E8b independently represents hydrogen or C-alkyl; OS" represents M or Seba; 0: represents M or SB; OZ is M or Sebs; О" is M or Seb; provided that at most one of ОЗ and 07 is M; ОО? is M or SIb9; SU is M or SEEG; 0? is M or CE; О" is M or CE); ОЗ is СІ39: (36 is M; and 0" is CE: or СО: is СІ394: СУ6 is SI; and 07 is M; or С is M; 05 is СВе; and 07 is is CE; or Zo CO is M; 05 is CB; and 07 is M; or C" is M; 05 is M; and 07 is CB": or C" is M; 05 is M; and 07 represents M; each of ba, DbB Dbs, Db dbe, De, Dobo, dep, de and BbY independently represents hydrogen, halogen, C-4alkyl, -MAZaD?" or C..-alkyl, substituted by one, two, or three halogen atoms; each of Za and ER" is independently hydrogen or C-alkyl; or a pharmaceutically acceptable addition salt or solvate thereof. 2. The compound according to claim 1, where Ag is optionally substituted by one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-Ci-alkyl, - M(C-4alkyl)2, -MNAsYA, -MAoedtoYA, cyano, -SEz, -C(-0)-MH", -C(-0)-MH-C:-alkyl, -C(-0)- C:-alkyl, C1-4alkyloxy, -C(-O)-O-C1-alkyl, C3-6cycloalkyl, C1-valkenyl, C1-alkyl substituted by one C-4alkyloxy, and C:1-4alkyl, neoob' necessarily replaced by one -MA' sad oB; each of the B'bs | ДЯ is independently C3-eccycloalkyl; Szecycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C:-alkyl; C:-alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH, and -O-C:-alkyl; or C:-alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, KZ and i; It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3): pc E Her | M da Shi My 54 as Kk , (ai) to her,; (a) in (a З) at the same time, each of Za, DZ" | VZs is independently hydrogen, halogen, -MA"A", C1-4alkyl or -0-C1-halkyl; A? represents hydrogen or C.alalkyl; each of Ba, De and Bc independently represents hydrogen, halogen, -MVZadB" or C.alalkyl; OS" represents M or Seba; 0: represents M or SB; SSZ represents M or Self; O" is M or Seb; provided that at most one of OZ and 07 is M; each of Ba Dr Dbs rda rdDee | B is independently hydrogen, halogen, C 1-4 alkyl, -MAade" or C.i- alkyl substituted by one, two or three halogen atoms. 3. The compound according to claim 1 or 2, where Ag is optionally substituted by one, two, three or four substituents, each independently selected from the group consisting of halogen, -OH, -MH", -MH-Si-alkyl . -MA'sad's; It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (а-1), (а-2) and (а-3): бе ! ; Kk v Z 7-3 9-0 Za / X u 3b M r Kk sht vo MI Kk Her M a MI M MI OM « t g Kk , (al) Kk , ag) K (a-3) while each of НЗа, ДЗ and ЕЗс independently represent hydrogen, halogen, -МН"аВН?" or -O-C- z4alkyl; A?" represents hydrogen or C.-alkyl; each of Ba, ID" and Bc independently represents hydrogen, halogen, -MNZadB" or C.-alkyl; OS" represents M or Seb; ОО: represents M or SIVEV; OZ is M or Sebs; C" is M or Svba:; provided that at most one of OZ and 07 is M; each of Bba, bB, Dbs, De de | I is independently hydrogen, halogen, C1-4 alkyl, -MNHZade, or C1-6 alkyl substituted with one, two or three halogen atoms. 4. Compound zap. 1, where B' is hydrogen; A: represents hydrogen; U represents -СНе-; 7 represents -X-SVRade-, -СН5ed»e-SIVyaV- or -С VtadRe-X-; Vza, BB, idre, DYA, doe and Boh represent hydrogen; X represents -O-; Ag is a tau -k o z, while Ag is optionally substituted in the position indicated by a by a substituent selected from the group consisting of -MH", -MH-C.-alkyl and -MNBA se: and at the same time Ag optionally substituted in the position indicated by VD with a substituent selected from the group consisting of halogen and CEz; provided, however, that Ag is substituted in at least one of the positions indicated by a or VD; is C3-eccycloalkyl; C:1-4 alkyl substituted with one, two or three substituents, which are halogen; or C:-4 alkyl substituted by one substituent, which is C3-cycloalkyl; It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4); each of KZa and 34 is independently hydrogen, halogen, -"MA"aB", C.i.lalkyl or -O-C..lalkyl; Fa is hydrogen; A?" represents hydrogen or Cl.alkyl; each of La, IZ, and Ei independently represents hydrogen or halogen; O" represents Svba; 0: represents SEB: OO? is So; SU is SE; C: represents СИ34: (6 represents M; and 0" represents CE; Bba, DeB. do and reg represent hydrogen. 5. Compound according to any of claims 1-4, where A! is hydrogen; B2 is hydrogen; U represents -CH»-; 7 represents -Х-ШНЗан- or -ШНЖНЖЯ-СВЯВЕГ-; Aza, De, D5e, DYA, Doo and Vp represent hydrogen; X represents -O-; Ag is and -M o , where Ag is optionally substituted in the position marked with a substituent selected from the group consisting of -MH»e, -MH-C.-alkyl and -MNIA "se: and at the same time Ag is optionally substituted in the position indicated by VD by a substituent selected from the group consisting of halogen and C3; provided that Ag is substituted in at least one of the positions marked c or p; d is C3-ecycloalkyl; C: 1-4 alkyl substituted with one, two or three substituents representing halogen; or C 1-4 alkyl substituted with one substituent representing C 3-6 cycloalkyl; It represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of from (a-1); BzZa is hydrogen, halogen, -MV72B", Si.alkyl or -O-C-.-alkyl; Fa is hydrogen; A?" is hydrogen or C1-alkyl; Da is hydrogen or halogen; OO" represents Svva; 0: represents CE; DVba and v" represent hydrogen. 6. The compound according to claim 1 or 2, where B' represents hydrogen; B2 is hydrogen; U represents -СНе-; 7 represents -SNReDe-SVDV-; Doe, DYA, De and og represent hydrogen; Ag is any of the following 10-membered bicyclic aromatic ring systems: -М М-М -М х- -М М-- -- Ag is optionally substituted with one, two, three or four substituents, each independently selected from the group consisting of halogen, -MH", -MH-C:-alkyl, -M(C-"alkyl)2,- MH, -MAosrdsa, each of V'bs and d'sYa independently represents Cz -cycloalkyl; Szecycloalkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH and -O-C:-alkyl; C:-alkyl substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OH, and -O-C:-alkyl; or Ci-halkyl substituted by one substituent, which is C3-ecycloalkyl; It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); VzZa represents hydrogen, -MA"2B" or -0O-C..lalkyl; Da represents hydrogen; A?" represents hydrogen or Si.lalkyl; Da represents hydrogen; O" represents Svba; 0: represents SEB: Zo Dbag and 2 represent hydrogen. 7. The compound according to claims 1, 2 or 6, where Ag is selected from the group consisting of: M-. ОО КО -к -к X-ki o , 5 , , each Ag is optionally substituted in the position with a substituent selected from the group consisting of -МНе, -МН-С.-lalkyl, -М(С:-lalkyl )»2, -MNA "s i "MA skeleton: and Ag is optionally substituted in another position by a substituent that is a halogen. 8. Compound according to claim 1, where U represents -СНе-; 7 represents -X-CHzad»- or -CHgSNe-; DVza and Ex represent hydrogen; X represents -O-; B" represents hydrogen; h u / - M Ag represents ; Ag is optionally substituted by one or two substituents, while each is independently selected from the group consisting of halogen, -OH, -MH", -MH-C: -alkyl, -M(Si-alkyl)", cyano and - CE"; It is a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); DVzga is -MA 7285; DV": represents hydrogen; B? represents hydrogen; Da represents hydrogen; O! represents Self; (32 represents SE: Idba and BE? represent hydrogen. 9. The compound according to claims 1, 2, Zabo b, where and Agyavaila is . 10. A compound according to any one of claims 1-3 and 7-9, where EC" and K? represent hydrogen. 11. A compound according to any of claims 1-3, 7 and 9-10, where XM is -СНе-. 12. The compound according to claim 11, where 7 represents -СНоСнН»е-. 13. The compound according to any one of claims 1-4, 7 and 9-12, where N is a bicyclic aromatic heterocyclic ring system of formula (a-1). 14. The compound according to claim 13, where Dzga represents -MAV"2B P; and 72 and E?? represent hydrogen. 15. A compound according to any one of claims 1-5, where Ve, Do and Bo are hydrogen; U represents -СНе-; It is represented by (a-1); CO" is CH; and 02 is CH. 16. The compound according to claim 1, which is Вг сх рый НХММ М pe-Й MС: хх Mo НО он MAM or its pharmaceutically acceptable addition salt or solvate. 17. The compound according to claim 16, which is Vg z ryy NhM M Shin M Ku go MN" НО on M Am 18. A pharmaceutical composition containing a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound according to any one of claims 1-17. Zo 19. A compound according to any one of claims 1-17 for use as a medicinal product. 20. A compound according to any one of claims 1-17 for use in the treatment or prevention of a disease or condition selected from blood disease, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney disease, platelet aggregation, insufficient sperm motility, transplant rejection, tissue rejection, and lung damage. 21. The compound according to claim 20 for use in the treatment of a disease or condition selected from blood disease, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, insufficient sperm motility, transplant rejection, tissue rejection and lung damage. 22. The compound of claim 20 or 21, wherein the disease or condition is an autoimmune disorder, cancer, inflammatory disease, or neurodegenerative disease. 23. The compound of claim 22, wherein the disease or condition is cancer. 24. The compound of claim 23, wherein the cancer is a hematopoietic cancer. 25. The compound of claim 24, wherein the hematopoietic cancer is leukemia. 26. The compound of claim 25, wherein the leukemia is acute myelocytic leukemia, chronic lymphocytic leukemia, or acute lymphocytic leukemia. 27. The compound of claim 23, wherein the cancer is non-Hodgkin's lymphoma. 28. The compound of claim 27, wherein the non-Hodgkin's lymphoma is a B-cell non-Hodgkin's lymphoma. 29. The compound according to claim 23, where the cancer is pancreatic cancer, prostate cancer, colon cancer, rectal cancer, cholangiocarcinoma, head and neck cancer, adrenal cancer, breast cancer, intraocular melanoma, ovarian cancer, myelodysplastic syndrome ( MOB) or salivary gland cancer. 30. The compound of claim 23, wherein the cancer is lung cancer. 31. The compound of claim 30, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer. 32. The compound of claim 23, wherein the cancer is pancreatic cancer. 33. The compound of claim 32, wherein the pancreatic cancer is pancreatic adenocarcinoma. 34. The compound of claim 23, wherein the cancer is melanoma or adenocystic carcinoma. 35. A compound according to claim 16 or 17 for use in the treatment of a proliferative disorder.