RU2789377C2 - New spirobicyclic analogues - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: present invention relates to a new spirobicyclic analogue of the formula (I)

or to its pharmaceutically acceptable salt of attachment, which are suitable as PRMT5 inhibitors. In addition, the present invention relates to pharmaceutical compositions containing the specified compounds as an active ingredient, as well as to intermediate compounds for the production of these compounds. In the formula (I), R¹ and R² are hydrogen or -C(=O)-C_1-4alkyl; R^3a is halogen, -NR^7aR^7b; Q¹ is CR^6a; Q² is N or CR^6b; X, R^7a, R^7b, R^4a, R^6a, and R^6b are hydrogen; Y is -O- or -CH₂-; L is -CH₂-, -O-CH₂-, -CH₂-O-, or -O-; R⁵ is Ar or Het; and, in case if L is -O- or -O-CH₂-, R⁵ can also be hydrogen; Ar is phenyl; Het is a monocyclic or bicyclic ring system selected from a group consisting of (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), and (a-7),

where the specified monocyclic or bicyclic aromatic ring system is optionally substituted with one or several substitutes, each of which is independently selected from a group consisting of halogen and -NH2.

EFFECT: obtainment of new spirobicyclic analogues.

17 cl, 5 tbl, 4 ex

Description

The field of technology to which the invention belongs

The present invention relates to novel spirobicyclic analogs useful as PRMT5 inhibitors. In addition, the present invention relates to pharmaceutical compositions containing these compounds as an active ingredient, as well as to the use of these compounds as a drug.

Prerequisites for the invention

PRMT5, also described as Hsl7, Jbp1, Skb1, Capsuleen or Dart5, is one of the major methyltransferases responsible for the mono- and symmetrical dimethylation of arginines. Post-translational methylation of arginine on histones and non-histone proteins has been shown to be critical to a variety of biological processes such as genome organization, transcription, differentiation, splicingosome function, signal transduction and regulation of cell cycle progression, stem cell and T cell differentiation [Stopa , N. et al., Cell Mol Life Sci, 2015. 72 (11): p. 2041-59] [Geoghegan, V. et al., Nat Commun, 2015. 6 : p. 6758]. Metazoan PRMT5 forms a functional complex with methylosomal protein 50 (MEP50), also called Wdr77, p44 androgen receptor coactivator and Valois. Both elevated levels of PRMT5-MEP50 protein and cytoplasmic accumulation are implicated in cancer oncogenesis and have recently been associated with poor clinical outcome [Shilo, K. et al., Diagn Pathol, 2013. 8 : p. 201]. Cell repair experiments that target both the catalytic and scaffold functions of the PRMT5-MEP50 complex, in addition to comprehensive enzymatic studies, have proven an oncological relationship between protein level, localization, and enzymatic function [Gu, Z. et al., Biochem J, 2012. 446 (2): p. 235-41] [Di Lorenzo, A. et. al., FEBS Lett, 2011. 585 (13): p. 2024-31] [Chan-Penebre, E. et al., Nat Chem Biol, 2015. 11 (6): p. 432-7]. This relationship makes PRMT5 an important target for small molecule drugs against cancer and other diseases [Stopa, N. et al., Cell Mol Life Sci, 2015. 72 (11): p. 2041-59].

PRMT5 is a member of the PRMT type II subfamily that uses S-adenosylmethionine (SAM) to produce symmetrical dimethylated arginine on histones and non-histone protein substrates and S-adenosylhomocysteine (SAH). The crystal structure of a human hetero-octamer complex (PRMT5) ₄ (MEP50) ₄ co-crystallized with SAH and a histone H4 peptide substrate showed the mechanism of methylation and substrate recognition [Antonysamy, S. et al., Proc Natl Acad Sci USA, 2012. 109 ( 44): p. 17960-5]. Regulation of PRMT5 activity occurs through a huge number of different participants in binding, influencing post-translational modification, miRNA and subcellular localization.

Methylation of histones H2A and H4 on Arg3 and histone H3 on Arg8 regulates chromatin organization for specific repression of gene transcripts that are involved in differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V. et al., Trends Biochem Sci, 2011. 36 (12): p. 633-41]. In addition, PRMT5-mediated methylation of histone H4 at Arg3 can promote histone binding to DNA methyltransferase DNMT3A and DNA methylation for long-term gene silencing [Zhao, Q. et al., Nat Struct Mol Biol, 2009. 16 (3): p. 304-11].

Non-histone-related methylation can occur either in the cytoplasm or in the nucleus, depending on the cellular localization of PRMT5. Methylation of the Sm proteins D1 and D3, which are required for nuclear splicingosome assembly, occurs in the cytoplasm as part of the "methylosome" containing PRMT5 [Friesen, WJ et al., Mol Cell Biol, 2001. 21 (24): p. 8289-300]. Additional evidence that PRMT5 is involved in splicing was provided by conditional knockout of PRMT5 in mouse neural stem cells. Cells lacking PRMT5 showed selective intron retention and exon skipping with weak 5' donor sites [Bezzi, M. et al., Genes Dev, 2013. 27 (17): p. 1903-16].

In addition to being involved in splicing, PRMT5 influences key pathways involved in cell differentiation and homeostasis by direct methylation of key signal transduction sites similar to p53 [Jansson, M. et al., Nat Cell Biol, 2008. 10 (12): p. 1431-9], EGFR [Hsu, JM et al., Nat Cell Biol, 2011. 13 (2): p. 174-81], CRAF [Andreu-Perez, P. et al., Sci Signal, 2011. 4 (190): p. ra58], PI3K/AKT [Wei, TY et al., Cell Signal, 2014. 26 (12): p. 2940-50], NFκB [Wei, H. et al., Proc Natl Acad Sci USA, 2013. 110 (33): p. 13516-21].

Because PRMT5 is one of the major sym-Arg methyltransferases and is involved in multiple cellular processes, overexpression of the protein appears to be an important factor in its oncogenicity. Interestingly, translation of PRMT5 in mantle cell lymphoma (MCL) appears to be regulated by miRNA. Although MCL cells are characterized by less mRNA and a slower PRMT5 transcription rate than normal B lymphocytes, PRMT5 levels and H3R8 and H4R3 methylation are significantly increased [Pal, S. et al., EMBO J, 2007. 26 (15): p. 3558-69]. Re-expression of miRNA, which binds the 3'UTR region of PRMT5, reduces the level of PRMT5 protein [Wang, L. et al., Mol Cell Biol, 2008. 28 (20): p. 6262-77]. Surprisingly, prmt5 antisense RNA was found in the human prmt5 gene, supporting the hypothesis of specific regulation of translation rather than high levels of mRNA expression [Stopa, N. et al., Cell Mol Life Sci, 2015. 72 (11): p . 2041-59].

Although PRMT5 is considered a clinically relevant target, very few selective inhibitors of PRMT5 have been published so far. More recently, a novel subnanomolar potent inhibitor of PRMT5 (EPZ015666) with antitumor activity in a variety of MCL xenograft models has been described as the first chemical reagent suitable to further confirm the biology of PRMT5 and its role in cancer [Chan-Penebre, E. et al., Nat Chem Biol. , 2015. 11 (6): p. 432-7].

Further development of specific small molecule inhibitors of PRMT5 may lead to new chemotherapeutic approaches for cancer treatment.

WO 2016135582 and US 20160244475 describe substituted nucleoside derivatives useful as anticancer agents.

WO 2014100695A1 discloses compounds useful for inhibiting PRMT5 activity; methods of using the compounds for the treatment of PRMT5 mediated disorders are also described.

WO 2014100730A1 discloses PRMT5 inhibitors containing dihydro- or tetrahydroisoquinoline and their uses.

In Devkota, K. et al., ACS Med Chem Lett, 2014. 5 : p. 293-297 describe the synthesis of a number of analogues of the natural product sinefungin and the ability of these analogues to inhibit EHMT1 and EHMT2.

WO 2003070739 discloses partial and full A1 adenosine receptor agonists, their preparation and their therapeutic use.

WO 2012082436 discloses compounds and compositions as modulators of histone methyltransferases and for the treatment of diseases caused by modulation of histone methyltransferase activity.

WO 2014100719 discloses PRMT5 inhibitors and their uses.

WO 03074083 discloses combination therapeutics that selectively kill methylthioadenosine phosphorylase-deficient cells. MTA analogs are described herein as antitoxic agents.

In Kung, P.-P. et al., Bioorg Med Chem Lett, 2005. 15 : p. 2829-2833 describe the structure, synthesis, and biological evaluation of novel human 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) substrates.

WO 2012075500 discloses histone methyltransferase modulators, which are 7-deazapurine.

WO 2014035140 discloses compounds and compositions for modulating histone methyltransferase activity.

WO 2015200680 describes PRMT5 inhibitors and their uses.

WO 9640686 describes heterocyclic substituted cyclopentane compounds and methods for using such compounds to inhibit adenosine kinase.

WO 2017032840 relates to novel nucleoside analogs substituted with a 6-6-bicyclic aromatic ring useful as PRMT5 inhibitors.

WO 2017153186 relates to novel compounds useful as PRMT5 inhibitors.

Thus, there is an urgent need for new PRMT5 inhibitors, which provide new ways to treat or prevent cancer, such as, for example, mantle cell lymphoma. Therefore, it is an object of the present invention to provide such compounds.

The compounds of the present invention are structurally different and may have improved properties, such as, for example, increased efficiency, or improved pharmacokinetics (PK) 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 PRMT5 inhibitors. The compounds according to the invention and compositions thereof may be useful in the treatment or prevention, in particular in the treatment, of diseases such as blood disease, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis , multiple organ failure, kidney disease, platelet aggregation, poor sperm motility, transplant rejection, tissue rejection, lung injury, and the like.

The present invention relates to new compounds of formula (I):

Where

R ¹ is hydrogen or -C(=O)-C _1-4 alkyl;

R ² is hydrogen or -C(=O)-C _1-4 alkyl;

X is hydrogen;

Y represents -O-, -CH ₂ - or -CF ₂ -;

Q ¹ is CR ^6a ;

Q ² is N or CR ^6b ;

each of R ^6a and R ^6b independently represents hydrogen, halogen, C _1-4 alkyl, -NR ^9a R ^9b or C _1-4 alkyl substituted with one, two or three halogen atoms;

each of R ^9a and R ^9b independently represents hydrogen or C _1-4 alkyl;

R ^3a is hydrogen, halogen, -NR ^7a R ^7b , C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, -OH, or

-OC _1-4 alkyl;

R ^7a is hydrogen;

R ^7b is hydrogen, C _3-6 cycloalkyl or C _1-4 alkyl;

R ^4a is hydrogen, halogen, -NR ^8a R ^8b or C _1-4 alkyl;

L represents -CH ₂ -, -O-CH ₂ -, -CH ₂ -O- or -O-;

R ⁵ is Ar or Het; and if L is -O- or -O-CH ₂ -, R ⁵ may also be hydrogen;

Ar is phenyl optionally substituted with one or more halo substituents;

Het is a monocyclic or bicyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), (a-5), (a-6) and (a-7),

where the specified monocyclic or bicyclic aromatic ring system is optionally substituted with one or more substituents, each of which is independently selected from the group consisting of halogen and-NH ₂ ;

and to their pharmaceutically acceptable addition salts and solvates.

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

It has been found that the compounds of the present invention inhibit PRMT5 by themselves or may be metabolized to a (more) active form in vivo (prodrugs) and thus may be useful in the treatment or prevention, in particular for the treatment, of diseases such as blood disease, 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, and the like.

It follows from the above pharmacology of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates that they may be suitable for use as a drug.

In particular, the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates may be suitable for the treatment or prevention, in particular for the treatment, of any of the diseases or conditions mentioned earlier or hereinafter, 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 medicament for the inhibition of PRMT5, for the treatment or prevention of any of the diseases or conditions specified earlier or hereinafter, in particular cancer.

The present invention will be described next. Various aspects of the present invention are defined in more detail in the following sections. Each aspect thus defined may be combined with any other aspect or aspects, unless explicitly stated otherwise. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Detailed description

When describing the compounds of the present invention, the terms used should be interpreted 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, in formula (I)), then its definition in each case is independent of its definition in each different case.

It is assumed that the term "substituted" in all cases of use in the present invention means, unless otherwise indicated or clearly follows from 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, at the atom or radical denoted using the expression "substituted" are replaced by one selected from the specified group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound , which is stable enough to withstand isolation from the reaction mixture to a suitable degree of purity and formulation into a therapeutic agent.

If there are two or more substituents on a moiety, they may, unless otherwise specified or clearly implied by the context, replace hydrogen atoms on the same atom, or they may substitute hydrogen atoms on different atoms in the moiety.

The prefix "C _xy " (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C _1-4 alkyl group contains 1 to 4 carbon atoms, a C _1-3 alkyl group contains 1 to 3 carbon atoms, etc.

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

The term "C _1-4 alkyl" as a group or part of a group refers to a hydrocarbon radical of the formula C _n H _2n+1 where n is a number in the range from 1 to 4. C _1-4 alkyl groups contain from 1 to 4 atoms carbon, preferably 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C _1-4 alkyl groups may be linear or branched and may be substituted as defined herein. If this document uses a subscript after a carbon atom, then the subscript means the number of carbon atoms that the named group may contain.

C _1-4 alkyl includes all linear or branched alkyl groups with 1-4 carbon atoms and therefore includes methyl, ethyl, n-propyl, isopropyl, 2-methylethyl, butyl and its isomers (for example, n-butyl, isobutyl and tert-butyl), etc.

One skilled in the art will appreciate that non-limiting examples of suitable -OC _1-4 alkyl include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy.

The term "C _2-4 alkenyl", as used herein as a group or part of a group, is a linear or branched hydrocarbon group containing 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 "C _3-6 cycloalkyl", as used herein as a group or part of a group, is a cyclic saturated hydrocarbon radical containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In case L is -O-CH ₂ -, oxygen (O) is assumed to be attached to R ⁵ .

In case L is -CH ₂ -O-, it is assumed that oxygen (O) is attached to the spiro moiety.

In all cases where the substituents are represented by a chemical structure, "---" denotes a bond to be attached to the rest of the molecule of formula (I).

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

The term "therapeutically effective amount" as used herein means that amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue system in an animal or human that is sought by a researcher, veterinarian, physician, or other clinician, which includes relief or relief of symptoms of the disease or disorder being treated.

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

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

The term "compounds of the (present) 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 interconvertible due to the low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve proton migration interconversions such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversions by rearranging some of the bond electrons.

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

Any chemical formula used herein in which bonds are shown only as solid lines and not as solid wedge or dashed wedge bonds, or otherwise shown as having a specific configuration (e.g., R, S) around one or more atoms , includes every possible stereoisomer or mixture of two or more stereoisomers. If the stereochemistry of any particular chiral atom is not defined in the structures shown herein, then all stereoisomers are considered and are included as compounds of the present invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

Above and below in this document is meant that the term "compound of formula (I)" includes its stereoisomers and tautomeric forms. However, if the stereochemistry, as noted in the preceding paragraph, is indicated by bonds that are represented as solid wedge-shaped or dashed wedge-shaped bonds, or otherwise shown as having a particular configuration (e.g., R, S), then that stereoisomer is indicated and defined. . It will be clear that this also applies to subgroups of formula (I).

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

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

Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

Atropisomers (or atropisomers) are stereoisomers that have a specific spatial configuration resulting from restriction of rotation around a single bond due to significant steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they do not correlate as mirror images. If the compound contains a double bond, then the substituents may be in the E or Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may be in either the cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, then the substituents may be in the cis or trans configuration. Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E-isomers, Z-isomers, cis-isomers, trans-isomers and mixtures thereof, whenever possible from a chemical point of view.

The meanings of all these terms, ie, enantiomers, atropisomers, diastereomers, racemates, E-isomers, Z-isomers, cis-isomers, trans-isomers and mixtures thereof, are known to the person skilled in the art.

The absolute configuration is determined according to the Kahn-Ingold-Prelog system. The configuration at the asymmetric atom is defined as either R or S. Isolated stereoisomers whose absolute configuration is unknown may be designated as (+) or

(−) depending on the direction in which they rotate the plane of light polarization. For example, isolated enantiomers whose absolute configuration is unknown may be designated as (+) or (−) depending on the direction in which they rotate the plane of polarization of light.

If a specific stereoisomer is indicated, this means that this stereoisomer contains practically no other stereoisomers, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular , with less than 2% and most preferably with less than 1% of other stereoisomers. Thus, if the compound of formula (I), for example, is indicated as (R), this means that the compound contains practically no isomer (S); if the compound of formula (I), for example, is indicated as E, this means that the compound contains practically no isomer Z; if the compound of formula (I), for example, is indicated as cis, this means that the compound contains practically no trans isomer.

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

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be prepared by conventional means, 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 medium in which the salt is insoluble, followed by removal of said solvent or said medium. using standard techniques (eg in vacuo, freeze drying or filtration). Salts can also be prepared 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.

The pharmaceutically acceptable addition salts mentioned above or below in this document are intended to include the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) and their solvates can form.

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

The compounds of formula (I) and their solvates containing an acidic proton can also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.

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

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

The term "prodrug" of the corresponding compound of the present invention includes any compound which, after oral or parenteral administration, in particular oral administration, is metabolized in vivo to form this compound in an experimentally determined amount and within a predetermined time (for example, during the interval between administration doses from 6 to 24 hours (ie, when taking doses from one to four times a day)). For the avoidance of ambiguity, the term "parenteral" administration includes all forms of administration other than oral administration, in particular intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection.

Prodrugs can be obtained by modifying the functional groups present on the compound such that these modification results are cleaved in vivo when such a prodrug is administered to a mammalian subject. Modifications are usually obtained by synthesizing the parent compound with a prodrug substituent. In general, prodrugs include compounds of the present invention wherein the hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group in the compound of the present invention is linked to any group that can be cleaved in vivo to reduce 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)-C _1-4 alkyl) that can be cleaved in vivo to restore the free hydroxyl. In the context of the present invention, prodrugs, in particular, are compounds of formula (I) or subgroups thereof, where R ¹ and/or R ² represent -C(=O)-C _1-4 alkyl.

Examples of prodrugs include, without limitation, hydroxyl functional esters and carbamates, carboxyl functional esters, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs" p. l-92, Elsevier, New York-Oxford (1985).

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

The compounds of the present invention, obtained in 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, following separation procedures known in the art. The method for separating the enantiomeric forms of the 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 the appropriate starting materials, provided that the reaction proceeds stereospecifically. If a specific stereoisomer is desired, then preferably said compound is synthesized by stereospecific preparation methods. These methods advantageously employ enantiomerically pure starting materials.

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

All isotopes and isotopic mixtures of any particular atom or element defined herein are contemplated within the scope of the compounds of the present invention, whether naturally occurring or synthetically occurring, both in natural isotopic composition and 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 ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ O, ¹⁷ O ^{, 18} O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, 122 I, ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br . Preferably, the radioactive isotope is selected from the group of ² H, ³ H, ¹¹ C, and ¹⁸ F. More preferably, the radioactive isotope is ² H. In particular, deuterated compounds are intended to be included within the scope of the present invention.

Certain isotopically labeled compounds of the present invention (eg, labeled with ³ H and ¹⁴ C) are useful in tissue distribution assays. The isotopes tritium ( ³ H) and carbon-14 ( ¹⁴ C) are applicable due to the ease of their production and the possibility of detection. In addition, substitution with heavier isotopes such as deuterium (i.e. ² H) may confer certain therapeutic advantages due to greater metabolic stability (e.g. increased in vivo half-life or reduced dose required) and therefore may be preferred. in some cases. Positron active isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F are useful for positron emission tomography (PET) studies to assess the degree of substrate receptor occupancy.

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

R ¹ is hydrogen;

R ² is hydrogen;

X is hydrogen;

Y represents -O-, -CH ₂ - or -CF ₂ -;

Q ¹ is CR ^6a ;

Q ² is N or CR ^6b ;

each of R ^6a and R ^6b independently represents hydrogen, halogen, C _1-4 alkyl, -NR ^9a R ^9b or C _1-4 alkyl substituted with one, two or three halogen atoms;

each of R ^9a and R ^9b independently represents hydrogen or C _1-4 alkyl;

R ^3a is hydrogen, halogen, -NR ^7a R ^7b , C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, -OH, or

-OC _1-4 alkyl;

R ^7a is hydrogen;

R ^7b is hydrogen, C _3-6 cycloalkyl or C _1-4 alkyl;

R ^4a is hydrogen, halogen, -NR ^8a R ^8b or C _1-4 alkyl;

L represents -CH ₂ -, -O-CH ₂ -, -CH ₂ -O- or -O-;

R ⁵ is Ar or Het; and if L is -O- or -O-CH ₂ -, R ⁵ may also be hydrogen;

Ar is phenyl optionally substituted with one or more halo substituents;

Het is a monocyclic or bicyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), (a-5), (a-6) and (a-7),

where the specified monocyclic or bicyclic aromatic ring system is optionally substituted with one or more substituents, each of which is independently selected from the group consisting of halogen and-NH ₂ ;

and to their pharmaceutically acceptable addition salts and solvates.

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

R ¹ is -C(=O)-C _1-4 alkyl;

R ² is -C(=O)-C _1-4 alkyl;

X is hydrogen;

Y represents -O-, -CH ₂ - or -CF ₂ -;

Q ¹ is CR ^6a ;

Q ² is N or CR ^6b ;

each of R ^6a and R ^6b independently represents hydrogen, halogen, C _1-4 alkyl, -NR ^9a R ^9b or C _1-4 alkyl substituted with one, two or three halogen atoms;

each of R ^9a and R ^9b independently represents hydrogen or C _1-4 alkyl;

R ^3a is hydrogen, halogen, -NR ^7a R ^7b , C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, -OH, or

-OC _1-4 alkyl;

R ^7a is hydrogen;

R ^7b is hydrogen, C _3-6 cycloalkyl or C _1-4 alkyl;

R ^4a is hydrogen, halogen, -NR ^8a R ^8b or C _1-4 alkyl;

L represents -CH ₂ -, -O-CH ₂ -, -CH ₂ -O- or -O-;

R ⁵ is Ar or Het; and if L is -O- or -O-CH ₂ -, R ⁵ may also be hydrogen;

Ar is phenyl optionally substituted with one or more halo substituents;

Het is a monocyclic or bicyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), (a-5), (a-6) and (a-7),

where the specified monocyclic or bicyclic aromatic ring system is optionally substituted with one or more substituents, each of which is independently selected from the group consisting of halogen and-NH ₂ ;

and to their pharmaceutically acceptable addition salts and solvates.

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

R ¹ is hydrogen or -C(=O)-C _1-4 alkyl;

R ² is hydrogen or -C(=O)-C _1-4 alkyl;

X is hydrogen;

Y represents -O-, -CH ₂ - or -CF ₂ -;

Q ¹ is CR ^6a ;

Q ² is N or CR ^6b ;

R ^6a and R ^6b are hydrogen;

R ^3a is hydrogen, halogen, -NR ^7a R ^7b , C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, -OH, or

-OC _1-4 alkyl;

R ^7a is hydrogen;

R ^7b is hydrogen, C _3-6 cycloalkyl or C _1-4 alkyl;

R ^4a is hydrogen;

L represents -CH ₂ -, -O-CH ₂ -, -CH ₂ -O- or -O-;

R ⁵ is Ar or Het; and if L is -O- or -O-CH ₂ -, R ⁵ may also be hydrogen;

Ar is phenyl optionally substituted with one or more halo substituents;

Het is a monocyclic or bicyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), (a-5), (a-6) and (a-7),

where the specified monocyclic or bicyclic aromatic ring system is optionally substituted with one or more substituents, each of which is independently selected from the group consisting of halogen and-NH ₂ ;

and to their pharmaceutically acceptable addition salts and solvates.

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

R ¹ is hydrogen or -C(=O)-C _1-4 alkyl;

R ² is hydrogen or -C(=O)-C _1-4 alkyl;

X is hydrogen;

Y represents -O- or -CH ₂ -;

Q ¹ is CR ^6a ;

Q ² is N or CR ^6b ;

R ^6a and R ^6b are hydrogen;

R ^3a is halogen or -NR ^7a R ^7b ;

R ^7a is hydrogen;

R ^7b is hydrogen;

R ^4a is hydrogen;

L represents -CH ₂ -, -O-CH ₂ -, -CH ₂ -O- or -O-;

R ⁵ is Ar or Het; and if L is -O- or -O-CH ₂ -, R ⁵ may also be hydrogen;

Ar is phenyl;

Het is a monocyclic or bicyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), (a-5), (a-6) and (a-7),

where the specified monocyclic or bicyclic aromatic ring system is optionally substituted with one or more substituents, each of which is independently selected from the group consisting of halogen and-NH ₂ ;

and to their pharmaceutically acceptable addition salts and solvates.

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

R ¹ is hydrogen or -C(=O)-C _1-4 alkyl; in particular, hydrogen;

R ² is hydrogen or -C(=O)-C _1-4 alkyl; in particular, hydrogen;

X is hydrogen;

Y is -O-;

Q ¹ is CR ^6a ;

Q ² is N;

R ^6a is hydrogen;

R ^3a is -NR ^7a R ^7b ;

R ^7a is hydrogen;

R ^7b is hydrogen;

R ^4a is hydrogen;

L is -O-;

R ⁵ is Het;

Het is (a-1) optionally substituted with one or more substituents each independently selected from the group consisting of halo and —NH ₂ ;

and to 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, as specified in any of the other embodiments, where one or more of the following restrictions apply:

(i) Y is -O- or -CH ₂ -;

(ii) R ^6a and R ^6b are hydrogen;

(iii) R ^3a is halogen or -NR ^7a R ^7b ;

(iv) R ^7a is hydrogen; R ^7b is hydrogen;

(v) R ^4a is hydrogen;

(vi) Ar is phenyl.

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, as specified in any of the other embodiments, where

R ¹ and R ² 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, as specified in any of the other embodiments, where

R ¹ is -C(=O)-C _1-4 alkyl; R ² is -C(=O)-C _1-4 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, as indicated in any of the other embodiments, where Y represents -CH ₂ -.

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, as specified in any of the other embodiments, where Y represents -CH ₂ - or -CF ₂ -.

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, as indicated in any of the other embodiments, where Y 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, as defined in any of the other embodiments, wherein R ^3a is halogen,

-NR ^7a R ^7b , C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, -OH or -OC _1-4 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, as specified in any of the other embodiments, where R ^3a is halogen or

-NR ^7a R ^7b .

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, as indicated in any of the other embodiments, where R ^3a represents Cl or

-NR ^7a R ^7b .

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, as specified in any of the other embodiments, where

R ^3a is Cl or -NR ^7a R ^7b ;

R ^7a and R ^7b 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, as indicated in any of the other embodiments, where R ^3a represents halogen; in particular - where R ^3a represents 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, as specified in any of the other embodiments, where

R ^3a is -NR ^7a R ^7b ; R ^7a and R ^7b 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, as specified in any of the other embodiments, where R ¹ and R ² represent

-C(=O)-C _1-4 alkyl; and R ^3a is halo.

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, as specified in any of the other embodiments, where R ¹ and R ² represent

-C(=O)-C _1-4 alkyl; and R ^3a 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, as specified in any of the other embodiments, where R ¹ and R ² represent H; and R ^3a is -NR ^7a R ^7b ; R ^7a and R ^7b 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, as specified in any of the other embodiments, where

Y is O;

Q ² is N.

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, as specified in any of the other embodiments, where

if Y is -CH ₂ - or -CF ₂ -; Q ² is N or CR ^6b ;

if Y is -O-; Q ² is N.

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, as specified in any of the other embodiments, where

if Y is -CH ₂ - or -CF ₂ -; Q ² is N or CR ^6b ; R ^6b is hydrogen;

if Y is -O-; Q ² is N.

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, as defined in any of the other embodiments, wherein Q ² is N.

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, as indicated in any of the other embodiments, where Q ² represents CR ^6b .

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, as specified in any of the other embodiments, where

Q ² is CR ^6b ;

R ^6b 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, as specified in any of the other embodiments, where

R ⁵ is Ar or Het.

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, as specified in any of the other embodiments, where

R ⁵ is Het.

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, as specified in any of the other embodiments, where

Het is (a-1) optionally substituted 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, as specified in any of the other embodiments, where

Het is (a-2) optionally substituted 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, as specified in any of the other embodiments, where

Het is (a-3) optionally substituted 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, as specified in any of the other embodiments, where

Het is (a-4) optionally substituted 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, as specified in any of the other embodiments, where

Het is (a-5) optionally substituted 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, as specified in any of the other embodiments, where

Het is (a-6) optionally substituted 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, as specified in any of the other embodiments, where

Het is (a-7) optionally substituted 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, as indicated in any of the other embodiments, where L represents -CH ₂ -.

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, as indicated in any of the other embodiments, where L represents -O-CH ₂ -.

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, as indicated in any of the other embodiments, where L represents -CH ₂ -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, as indicated in any of the other embodiments, where L 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, as specified in any of the other embodiments, where

L represents -CH ₂ - or -O-CH ₂ -.

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, as specified in any of the other embodiments, where

L represents -CH ₂ -O- or -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, as specified in any of the other embodiments, where

L represents -CH ₂ -, -O-CH ₂ -, -CH ₂ -O- or -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, as specified in any of the other embodiments, where compounds of formula (I) are limited to compounds of formula (I-x) .

It will be clear that all variables in the structure of formula (I-x) can be defined as they are defined for the compounds of formula (I) or any of their subgroups, as 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, as specified in any of the other embodiments, where compounds of formula (I) are limited to compounds of formula (I-y) .

It will be clear that all variables in the structure of formula (I-y) can be defined as they are defined for the compounds of formula (I) or any of their subgroups, as specified in any of the other embodiments.

In one embodiment, the present invention relates to a subgroup of formula (I), which is defined in the General reaction schemes.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2, 5 and 6.

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2, 5 and 6

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 exemplary compounds

and their free bases, pharmaceutically acceptable addition salts and solvates.

All possible combinations of the above embodiments are intended to fall within the scope of the present invention.

In another embodiment, the present invention relates to intermediates of formula (XXX),

Where

Y represents -O-, -CH ₂ - or -CF ₂ -;

R ^a is hydrogen or a hydroxyl protecting group such as, for example, C _1-4 alkyl, t-butyldimethylsilyl, C _1-4 alkyl-OC _1-4 alkyl, tetrahydropyranyl,

allyl, t-butyldiphenylsilyl, benzyl, -C(=O)-C _1-4 alkyl or -C(=O)-phenyl;

R^b представляет собой -OH, =O, -CH₂-OH или =CH₂;

R ^b represents -OH, =O, -CH ₂ -OH or =CH ₂ ;

where the bond towards R ^b is a single bond if R ^b is -OH or -CH ₂ -OH, or a double bond if R ^b is ═O or ═CH ₂ ;

R ^c1 and R ^c2 are -C(=O)-C _1-4 alkyl, benzoyl optionally substituted with one or two substituents each independently selected from -CH ₃ and -OCH ₃ , benzyl optionally substituted with one or two substituents each independently selected from -CH ₃ and -OCH ₃ , or -CH ₂ -naphthyl optionally substituted with one or two substituents each independently selected from -CH ₃ and -OCH ₃ ;

or R ^c1 and R ^c2 taken together are -C(C _1-4 alkyl) ₂ -;

and to their pharmaceutically acceptable addition salts and solvates.

In another embodiment, the present invention provides intermediates of formula (XXX) wherein

Y represents -O-, -CH ₂ - or -CF ₂ -;

R ^a is hydrogen or a hydroxyl protecting group such as, for example, C _1-4 alkyl,

tert-butyldimethylsilyl, C _1-4 alkyl-OC _1-4 alkyl, tetrahydropyranyl,

allyl, t-butyldiphenylsilyl, benzyl, -C(=O)-C _1-4 alkyl or -C(=O)-phenyl;

R^b представляет собой -OH, =O, -CH₂-OH или =CH₂;

R ^b represents -OH, =O, -CH ₂ -OH or =CH ₂ ;

where the bond towards R ^b is a single bond if R ^b is -OH or -CH ₂ -OH, or a double bond if R ^b is ═O or ═CH ₂ ;

R ^c1 and R ^c2 are -C(=O)-C _1-4 alkyl;

or R ^c1 and R ^c2 taken together are -C(C _1-4 alkyl) ₂ -;

and to their pharmaceutically acceptable addition salts and solvates.

Like the compounds of formula (I), the term "intermediates of formula (XXX)" is intended to include their stereoisomers and their tautomeric forms.

One skilled in the art will appreciate that if R ^c1 and R ^c2 taken together are

-C(C _1-4 alkyl) ₂ -, intermediates of formula (XXX) are limited to intermediates of formula (XXX-A),

(XXX-A).

(XXX-A).

One skilled in the art will appreciate that when R ^c1 and R ^c2 are -C(=O)-C _1-4 alkyl, intermediates of formula (XXX) are limited to intermediates of formula (XXX-B),

(XXX-B).

(XXX-B).

In one embodiment, the present invention relates to such intermediates of formula (XXX) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as defined in any of the other embodiments, where intermediates of formula (XXX) are limited to intermediates of formulas (XXX-C), (XXX-D), (XXX-E), (XXX-F), (XXX-G), (XXX-H), (XXX-I) and (XXX-J).

It will be understood that all variables in formula structures (XXX-A), (XXX-B), (XXX-C), (XXX-D), (XXX-E), (XXX-F), (XXX-G) , (XXX-H), (XXX-I) and

(XXX-J) may be defined as they are for intermediates of formula (XXX) or any subgroup thereof as defined in any of the other embodiments.

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

Y is -O-.

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

Y represents -CH ₂ - or -CF ₂ -.

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

R ^a is hydrogen, C _1-4 alkyl, t-butyldimethylsilyl, C _1-4 alkyl-OC _1-4 alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzyl, -C(=O)-C _1-4 alkyl or

-C(=O)-phenyl.

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

R ^a is hydrogen, C _1-4 alkyl or t-butyldimethylsilyl.

All possible combinations of the above embodiments are intended to fall within the scope of the present invention.

In one embodiment, the present invention relates to the use of intermediates of formula (XXX) and their pharmaceutically acceptable addition salts and solvates in the synthesis of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates.

How to get

In this section, as in all other sections, unless the context otherwise indicates, references to formula (I) also include all other subgroups and their examples defined in this document.

General preparation of some typical examples of compounds of formula (I) is described below in this document and in specific examples. Compounds of formula (I) are generally prepared from starting materials that are either commercially available, or prepared by standard synthetic methods conventionally employed by those skilled in the art, or prepared as described in the specific examples. The following diagrams are only intended to represent examples of the present invention and are not intended to limit the present invention in any way.

Alternatively, the compounds of the present invention can also be prepared using reaction protocols similar to those described in the general schemes below, in combination with standard synthetic methods traditionally used by those skilled in the art of organic chemistry, or in combination with synthetic methods described in WO 2017/153186 and WO 2017/032840.

Those skilled in the art will appreciate that compounds where "Y is -CF ₂ -" can generally be prepared according to similar reaction protocols as described in the General Schemes where "Y is -CH ₂ -".

The person skilled in the art will understand that the reactions described in the schemes may require the protection of reactive functional groups, for example, hydroxy, amino or carboxy groups, while they are required in the final product in order to avoid their undesirable participation in the reactions . Traditional protecting groups can be used in accordance with standard practice. This is illustrated in specific examples. For example, one skilled in the art will appreciate that for some reactions (such as, for example, in Scheme 3, step 4), the amino group must first be protected by N,N-dimethylformamide dimethyl acetal, and the protecting group must be removed after the reaction. The usual reaction conditions are described in specific examples.

One skilled in the art will appreciate that in the reactions described in the schemes, it may be advantageous or necessary to carry out the reaction under an inert atmosphere, such as, for example, in an atmosphere of gaseous N₂, for example, when using NaH in the reaction.

It will be apparent to a person skilled in the art that it may be necessary to cool the reaction mixture before isolating the reaction product (refers to a number of manipulations necessary to isolate and purify the chemical reaction product(s), such as, for example, quenching, column chromatography, extraction).

One skilled in the art will appreciate that heating the reaction mixture with stirring can increase the yield of the reaction. In some reactions, microwave heating can be used instead of conventional heating to reduce the overall reaction time.

One of 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 (I).

The person skilled in the art will appreciate that the intermediates and final compounds shown in the diagrams below can be further functionalized in accordance with methods well known to the person skilled in the art. For example, compounds where R ^3a is Cl can be converted to compounds where R ^3a is NH ₂ by reaction with NH ₃ (eg 25% in water) in a common solvent such as, for example, dioxane, at normal temperature of approximately 100°C. For example, compounds of formula (I) where R ¹ and R ² are hydrogen can be converted to compounds of formula (I) where R ¹ and R ² are

-C(=O)-C _1-4 alkyl.

One of skill in the art will appreciate that more compounds of formula (I) can be obtained by using synthetic protocols similar to those described in the schemes below.

In case any of the starting materials is available in the form of a salt, one skilled in the art will recognize that it may be necessary to first treat the salt with a base such as, for example, N,N-diisopropylethylamine (DIPEA).

All variables are defined as mentioned above in this document, unless otherwise specified or clearly follows from the context.

Generally, compounds of formula (I-a) and (I-b) can be prepared according to Scheme 1.

General scheme 1

In Scheme 1: "RG ¹ " is defined as a suitable reactive group such as, for example, hydroxy; "R ^5A " is defined as AR or HET; and all other variables in Scheme 1 are defined within the scope of the present invention.

For Scheme 1, the following reaction conditions are generally used.

1. An intermediate compound of formula (II) is reacted with R ^5a -RG ¹ ; typically in the presence of triphenylphosphine (PPh ₃ ), diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) in a suitable solvent such as, for example, anhydrous THF, at a suitable temperature, such as, for example, room temperature (RT).

2 . First, in the presence of a suitable acid, such as, for example, HCl (for example, 37% in H ₂ O; 1 M solution or 2 M solution; in each case, optionally in the presence of an organic co-solvent, such as methanol), at a suitable temperature, such as , for example, from room temperature to 90°C;

then in the presence of a suitable acid anhydride of formula (C _1-4 alkyl-C=O) ₂ O with a suitable co-solvent such as pyridine at a suitable temperature such as, for example, room temperature.

3 . An intermediate of formula (IV) is reacted with an intermediate of formula (V), typically in the presence of a reagent such as, for example, N,O-bis(trimethylsilyl)acetamide (BSA), a reagent such as, for example, trimethylsilyl trifluoromethanesulfonate (TMSOTf), in a solvent such as, for example, anhydrous CH ₃ CN; as a rule, at a temperature from k. t. to 100 °C.

4 . A compound of formula (Ia) may be reacted with a compound of formula (Ib) in the presence of a base such as, for example, NH ₃ (eg 25% in H ₂ O), optionally in the presence of a solvent such as dioxane, at a suitable temperature , such as, for example, 0°C-140°C. In particular, if R ^3a is Cl, the reaction conditions described in Step 4 at lower temperatures in the temperature range will maintain Cl at the R ^3a position, while the reaction conditions described in Step 4 at higher temperatures in the temperature range will ensure the conversion of Cl to the amino group.

The starting materials in Scheme 1 are commercially available or can be obtained by standard methods obvious to those skilled in the art or described in the following general schemes or specific examples.

In general, compounds of formulas (I-c), (I-d) and (I-e) can be prepared according to Scheme 2.

General scheme 2

In Scheme 2: "RG ¹ " is defined as a suitable reactive group such as, for example, bromine; "R ^5A " is defined as AR or HET; and all other variables in Scheme 2 are defined within the scope of the present invention.

For Scheme 2, the following reaction conditions are generally used.

1. An intermediate compound of formula (II) is reacted with R ^5a -CH ₂ -RG ¹ ; typically in the presence of a base such as NaH or potassium tert-butoxide (KOtBu) in a suitable solvent such as, for example, anhydrous N,N-dimethylformamide (DMF) or THF, at a suitable temperature, such as, for example, room temperature temperature.

2 . First, in the presence of a suitable acid, such as, for example, HCl (for example, 37% in H ₂ O; 1 M solution or 2 M solution; in each case, optionally in the presence of an organic co-solvent, such as methanol), at a suitable temperature, such as , for example, from room temperature to 90°C;

then in the presence of a suitable acid anhydride of formula (C _1-4 alkyl-C=O) ₂ O with a suitable co-solvent such as pyridine at a suitable temperature such as, for example, room temperature.

3 . An intermediate of formula (VII) is reacted with an intermediate of formula (V), typically in the presence of a reagent such as, for example, BSA, a reagent such as, for example, TMSOTf, in a solvent, such as, for example, anhydrous CH _3CN ; as a rule, at a temperature from k. t. to 100 °C.

4 . A compound of formula (Ic) may be reacted with a compound of formula (Id) in the presence of a base such as, for example, NH ₃ (eg 25% in H ₂ O), optionally in the presence of a solvent such as dioxane, at a suitable temperature , such as, for example, 0°C-140°C. In particular, if R ^3a is Cl, the reaction conditions described in Step 4 at lower temperatures in the temperature range will maintain Cl at the R ^3a position, while the reaction conditions described in Step 4 at higher temperatures in the temperature range will ensure the conversion of Cl to the amino group.

Alternatively, compounds of formula (I-b) can be prepared according to Scheme 3 using compounds of formula (I-f).

General scheme 3

In Scheme 3: "RG ² " is defined as a suitable reactive group such as, for example, hydroxy; "R ^5A " is defined as AR or HET; "Piv" means pivaloyl, "Bz" means benzoyl; and all other variables in Scheme 3 are defined within the scope of the present invention.

In Scheme 3, the following reaction conditions were used.

1. An intermediate of formula (VIII) may be reacted with an intermediate of formula (V), typically in the presence of a reagent such as, for example, BSA, a reagent such as, for example, TMSOTf, in a solvent such as, For example, anhydrous CH ₃ Cn; as a rule, at a temperature from k. t. to 100 °C.

2 . An intermediate of formula (IX) may be reacted with a compound of formula (If) in the presence of a base such as, for example, NH ₃ (eg 25% in H ₂ O), optionally in the presence of a solvent such as dioxane, at a suitable temperature, such as, for example, 0°C-140°C. In particular, if R ^3a is Cl, the reaction conditions described in step 2 at lower temperatures in the temperature range will maintain Cl at the R ^3a position, while the reaction conditions described in step 2 at higher temperatures in the temperature range will ensure the conversion of Cl to the amino group.

3 . The compound of formula (If) may be reacted with an intermediate of formula (X), typically in the presence of 4-methylbenzenesulfonic acid (p-TsOH), in a solvent such as, for example, acetone; As a rule, with K. t.

4 . Typically, in the presence of triphenylphosphine (PPh ₃ ), diisopropyl azodicarboxylate (DIAD), or diethyl azodicarboxylate (DEAD), in a suitable solvent such as, for example, anhydrous THF, at a suitable temperature, such as, for example, room temperature (r.t.) .

5 . In the presence of a suitable acid, such as, for example, 4 M HCl in dioxane or 4 M HCl in MeOH, with a suitable solvent, such as, for example, MeOH, 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 (TFA) in dichloromethane (DCM) at a suitable temperature, or acetic acid in THF and water at a suitable temperature, such as, for example, room temperature.

Generally, compounds of formula (I-h) can be prepared according to Scheme 4.

General scheme 4

In Scheme 4: "RG ² " is defined as a suitable reactive group such as, for example, hydroxy; "TBDMS" is defined as t-butyldimethylsilyl; "DMTr" is defined as dimethoxytrityl; "R ^5A " is defined as AR or HET; and all other variables in scheme 4 are defined within the scope of the present invention.

In Scheme 4, the following reaction conditions apply.

1. In the presence of a suitable reducing agent, such as, for example, NaBH ₄ , in a suitable solvent, such as, for example, methanol (MeOH), at a suitable temperature, such as, for example, 0°C.

2. Typically in the presence of triphenylphosphine (PPh ₃ ), diisopropyl azodicarboxylate (DIAD), or diethyl azodicarboxylate (DEAD) in a suitable solvent such as, for example, anhydrous THF, at a suitable temperature, such as, for example, room temperature (r.t. ).

3. Typically, first, deprotection of the silyl in the presence of a reagent such as, for example, tetrabutylammonium fluoride (TBAF); in a suitable solvent such as, for example, THF; at a suitable temperature, such as, for example, RT;

then reaction with a suitable reagent, such as, for example, Tf ₂ O (triflate anhydride or trifluoromethanesulfonic anhydride), in a suitable solvent, such as, for example, dichloromethane (DCM), at a suitable temperature, such as, for example, 0°C;

finally carrying out the reaction of an intermediate of formula (V) in the presence of a base, such as, for example, potassium tert-butoxide, in a suitable solvent, such as, for example, DMF, at a suitable temperature, such as, for example, from -10°C to 0 °C

4 . In the presence of a suitable acid, such as, for example, aqueous 1 M HCl or 4 M HCl in MeOH, with a suitable solvent, such as, for example, MeOH or ethanol (EtOH), 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 (TFA) in dichloromethane (DCM) at a suitable temperature, or acetic acid in THF and water at a suitable temperature, such as, for example, room temperature.

5. Typically, first, deprotection of the silyl in the presence of a reagent such as, for example, tetrabutylammonium fluoride (TBAF); in a suitable solvent such as, for example, THF; at a suitable temperature, such as, for example, RT;

then generally in the presence of DMTrCl (dimethoxytrityl chloride) in a solvent such as, for example, pyridine at a temperature such as room temperature;

then reaction with a suitable reagent, such as, for example, Tf ₂ O (triflate anhydride or trifluoromethanesulfonic anhydride), in a suitable solvent, such as, for example, pyridine, at a suitable temperature, such as, for example, 0°C;

finally reaction with an intermediate compound of formula (V-a) in the presence of a suitable solvent such as, for example, dimethylacetamide (DMA), at a suitable temperature, such as, for example, from 0°C to r.t.

6. Deprotection of dimethoxytrityl in the presence of an acid such as, for example, formic acid (typically 80% in H ₂ O), in a suitable solvent, such as, for example, CH ₃ CN, at a suitable temperature, such as, For example, to.

7. Typically, first in the presence of triphenylphosphine (PPh ₃ ), diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) in a suitable solvent such as, for example, anhydrous THF, at a suitable temperature, such as, for example, room temperature (r.t. .);

and then generally a second step in the presence of a suitable acid, such as, for example, aqueous 1 M HCl or 4 M HCl in MeOH, with a suitable solvent, such as, for example, MeOH or ethanol (EtOH), 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 (TFA) in dichloromethane (DCM) at a suitable temperature, or acetic acid in THF and water at a suitable temperature, such as, for example, room temperature.

Generally, compounds of formula (I-g) can be prepared according to Scheme 6.

General scheme 5

In Scheme 5: "RG ³ "is defined as a suitable reactive group such as, for example, iodine or bromine; "TBDMS" is defined as t-butyldimethylsilyl; "DMTr" is defined as dimethoxytrityl; "R ^5A " is defined as AR or HET; and all other variables in Scheme 5 are defined within the scope of the present invention.

In Scheme 5, the following reaction conditions apply.

1. In the presence of a reagent such as, for example, methyltriphenylphosphonium bromide (MePPh ₃ ⁺ Br ^- ), in the presence of a base, such as, for example, potassium tert-butoxide (KOtBu), in a solvent, such as, for example, THF, at a suitable temperature, such as, for example, from 0°C to r.t.

2. Typically, first, deprotection of the silyl in the presence of a reagent such as, for example, tetrabutylammonium fluoride (TBAF); in a suitable solvent such as, for example, THF; at a suitable temperature, such as, for example, RT;

then reaction with a suitable reagent, such as, for example, Tf ₂ O (triflate anhydride or trifluoromethanesulfonic anhydride), in a suitable solvent, such as, for example, dichloromethane (DCM), at a suitable temperature, such as, for example, 0°C;

finally reaction with an intermediate compound of formula (V-a) in a suitable solvent, such as, for example, DMF, at a suitable temperature, such as, for example, from -0°C to r.t.

3.In the first step, in the presence of an alkene precursor of formula (XIX) and a 0.5 M solution of 9-BBN in THF, typically under nitrogen at room temperature to reflux temperature and a reaction time of 30 minutes to 3 hours. In the second step, in the presence of a suitable R^5a-RG³ ("RG³" is defined as a suitable reactive group such as e.g. iodine or bromine) and a suitable catalyst e.g. 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or 1,1'-bis(di-tert-butylphosphino) ferrocenepalladium dichloride, and in the presence of a suitable base, such as tribasic potassium phosphate, in a suitable solvent mixture, such as based on THF, at a suitable temperature from 50° C. to reflux temperature and with a suitable reaction time of 1 to 3 hours.

4. Typically in the presence of a suitable acid, such as, for example, an aqueous 1 M HCl solution or 4 M HCl in MeOH, with a suitable solvent, such as, for example, MeOH or ethanol (EtOH), at a suitable temperature, such as, e.g. room temperature; or alternatively in the presence of a suitable acid, such as, for example, trifluoroacetic acid (TFA) in dichloromethane (DCM) at a suitable temperature, or acetic acid in THF and water at a suitable temperature, such as, for example, room temperature.

Generally, compounds of formula (I-g) can be prepared according to Scheme 6.

General scheme 6

In Scheme 6: "R ⁵ " is defined according to volume, "R ^5a " is defined as Ar or Het; and all other variables in Scheme 6 are defined within the scope of the present invention.

In Scheme 6, the following reaction conditions apply.

1. In the first step, in the presence of an alkene precursor of formula (XIX) and a 0.5 M solution of 9-BBN in THF, typically under nitrogen at room temperature to reflux temperature and a reaction time of 30 minutes to 3 hours. In the second stage, in the presence of an aqueous solution of a base, such as, for example, an aqueous solution of NaOH, in the presence of an oxidizing agent, such as, for example, H ₂ O ₂ , usually at a temperature of from 0°C to r.t.

2. Typically in the presence of triphenylphosphine (PPh ₃ ), diisopropyl azodicarboxylate (DIAD), or diethyl azodicarboxylate (DEAD) in a suitable solvent such as, for example, anhydrous THF, at a suitable temperature, such as, for example, room temperature (r.t. ).

3. Typically in the presence of a suitable acid, such as, for example, aqueous 1 M HCl or 4 M HCl in MeOH, with a suitable solvent, such as, for example, MeOH or ethanol (EtOH), at a suitable temperature, such as, e.g. room temperature; or, alternatively, in the presence of a suitable acid such as, for example, trifluoroacetic acid (TFA) in dichloromethane (DCM) at a suitable temperature, or acetic acid in THF and water at a suitable temperature, such as, for example, room temperature.

Generally, intermediates of formula (XXIV) and (XXV) can be prepared according to Scheme 7.

General scheme 7

In Scheme 7: "Y ¹ " is -CH ₂ - or -CF ₂ -, "Y ² " is -O-, and all other variables are defined within the scope of the present invention.

1. (If Y is limited to Y ¹ ) in the presence of methyltriphenylphosphonium bromide, a suitable base such as, for example, KOtBu, in a common solvent, such as, for example, THF, at r.t.

2. (If Y is limited to Y ² ) in the presence of bis(cyclopentadienyl)dimethyltitanium (CAS No.: 1271-66-5), in a common solvent such as, for example, THF, at an ordinary temperature, such as 70°C.

The skilled artisan will appreciate that intermediates of formulas (XXIV) and (XXV) can be used in the synthesis of compounds of formula (I) and can be used directly or indirectly (first converted to another intermediate) in reactions such as any of the other general schemes, in particular, in reactions from general schemes 5 and 6.

In all these methods of preparation, the reaction products can be isolated from the reaction medium and, if necessary, further purified in accordance with methods well known in the art, such as, for example, extraction, crystallization, trituration and chromatography.

Chirally pure forms of the compounds of formula (I) form a preferred group of compounds. It follows that chirally pure forms of the intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of formula (I). Enantiomeric mixtures of intermediates are also useful in the preparation of compounds of formula (I) in the appropriate configuration.

Pharmacology

It was found that the compounds of the present invention inhibit the activity of PRMT5.

In particular, the compounds of the present invention bind the PRMT5 enzyme and the competitive natural substrate SAM (S-adenosyl-L-methionine) to inhibit such enzyme.

Thus, it is contemplated that the compounds of the present invention, or pharmaceutical compositions thereof, may be useful in the treatment or prevention, in particular treatment, of diseases such as blood disease, 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 injury, and the like.

In particular, the compounds according to the present invention, or pharmaceutical compositions based thereon, may be useful in the treatment or prevention, in particular treatment, of diseases such as allergy, asthma, cancer of the hematopoietic system, lung cancer, prostate cancer, melanoma, metabolic disorder substances, diabetes, obesity, blood disease, sickle cell anemia, etc.

The compounds of the present invention, or pharmaceutical compositions thereof, may be useful in the treatment or prevention, in particular treatment, of diseases such as a proliferative disorder such as an autoimmune disease, cancer, benign tumor, or inflammatory disease.

The compounds according to the present invention, or pharmaceutical compositions thereof, may be useful in the treatment or prevention, in particular treatment, of diseases such as metabolic disorders including diabetes, obesity; a proliferative disorder including cancer, hematopoietic system cancer, lung cancer, prostate cancer, melanoma or pancreatic cancer; blood disease; hemoglobinopathy; sickle cell anemia; β-thalassemia, an inflammatory disease and an autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, diarrhea, gastroesophageal reflux disease and the like.

In some embodiments, inhibition of PRMT5 by the compound of interest may be useful in the treatment or prevention, in particular treatment, of the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic system cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenocystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and serous cystic ovarian adenoma.

Examples of metabolic disorders that can be treated or prevented, in particular treated, include, without limitation, diabetes or obesity.

Examples of blood diseases that can be treated or prevented, in particular treated, include, without limitation, hemoglobinopathies such as sickle cell anemia or β-thalassemia.

Examples of cancers that can be treated or prevented, in particular treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, gallbladder cancer. bladder cancer (eg cholangiocarcinoma), bladder cancer, breast cancer (eg breast adenocarcinoma, papillary breast carcinoma, breast cancer, medullary breast carcinoma), 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 , gastric cancer (eg, gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (eg, head and neck squamous cell carcinoma), oral cancer (eg, oral squamous cell carcinoma (OSCC), pharyngeal cancer (eg, pharyngeal cancer, larynx cancer, nasopharyngeal cancer, oropharyngeal cancer)), cancers of the hematopoietic system (eg, leukemia such as acute lymphocytic leukemia (ALL) (eg, B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML ) (eg, B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (eg, B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (eg, B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin's lymphoma (HL) (eg B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) ((eg B-cell NHL such as diffuse large cell lymphoma (DLCL) (eg diffuse B -cell large cell lymphoma (DLBCL))), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., lymphoid associated with lymphoid mucosal tissue (MALT), nodular marginal zone B-cell lymphoma, splenic marginal B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e. "Waldenström's macroglobulinemia"), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), progenitor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as T-lymphoblastic lymphoma/progenitor leukemia, peripheral T-cell lymphoma (PTCL) (eg, cutaneous T-cell lymphoma (CTCL) (eg, mycosis fungoides, Cesari syndrome), angioimmunoblastoma T-cell lymphoma, extranodal natural killer T-cell lymphoma, T-cell lymphoma with enteropathy, subcutaneous panniculitis-type T-cell lymphoma, anaplastic large cell lymphoma); a combination of one or more of the leukemia/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 Wilms tumor , 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 (SLC), lung adenocarcinoma, Lewis lung carcinoma , neuroendocrine tumors of the lung: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (eg, systemic mastocytosis), myelodysplastic syndromes (MDS), mesothelioma, myeloproliferative disorder (MPD) ( for example, polycythemia vera (PV), essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM), also called myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (eg, neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (eg, gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumour), osteosarcoma, ovarian cancer (eg, cystadenocarcinoma, embryonic ovarian cancer, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (eg, pancreatic adenocarcinoma, intraductal papillary mucinous tumor (IPMN), insuloma), penile cancer (eg, Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (eg, prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (eg, squamous cell carcinoma (SCC), keratoacanthoma y (KA), melanoma, basalioma (BCC)), small bowel cancer (eg, appendix cancer), soft tissue carcinoma (eg, malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma , myxosarcoma), sebaceous carcinoma, sweat gland carcinoma, synovioma, testicular cancer (eg, seminoma, fetal testicular carcinoma), thyroid cancer (eg, papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma) , cancer of the urethra, cancer of the vagina, cancer of the vulva (eg, Paget's disease of the vulva).

Examples of neurodegenerative diseases that can be treated or prevented, in particular treated, include, but are not limited to, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, Alzheimer's disease, AIDS-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, without limitation, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

Examples of inflammatory diseases that can be treated or prevented, particularly treated, include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), rhinitis, asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa , Takayasu's arteritis), arthritis (eg, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis), upper respiratory disease, ankylosing spondylitis, amylosis, 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 I diabetes mellitus, type 2 diabetes mellitus), skin disease (eg, psoriasis , eczema, eczema hypersensitivity reactions, burns, skin matitis, pruritus (scabies)), endometriosis, Guillain-Barré syndrome, infection, coronary artery disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (eg, migraine headaches, tension headaches), ileus (eg, postoperative ileus and ileus in sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (irritable bladder syndrome), gastrointestinal dysfunction (eg, selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic dysfunction gastrointestinal tract (eg, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) (eg, Crohn's disease, ulcerative colitis, collagenous colitis, mphocytic colitis, ischemic colitis, inflammatory bowel disease, Behçet's syndrome, unspecified colitis) and inflammatory bowel syndrome (IBS)), lupus, scleroderma annulare, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers , polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (eg, Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic attack , systemic lupus erythematosus, scleroderma, sclerodoma, sarcoidosis, types of spondyloarthropathy, Sjögren's syndrome, thyroiditis, graft rejection, tendonitis, injury or injury (eg, frostbite, exposure to chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo o and Wegener's granulomatosis.

In particular, the inflammatory disease is an acute inflammatory disease (eg, inflammation due to infection). In particular, the inflammatory disease is a chronic inflammatory disease (eg, conditions caused by asthma, arthritis, and inflammatory bowel disease). 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, in particular treated, include, without limitation, arthritis (including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, degenerative joint disorders such as osteoarthritis, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, disease Behçet, hemolytic autoimmune anemias, amyotrophic lateral sclerosis, amylosis, multiple sclerosis, acute shoulder syndrome, psoriatic and chronic arthritis in children), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin disease (eg, psoriasis, eczema, hypersensitivity reactions eczema, burns, dermatitis, pruritus (scabies)), enuresis, eosinophilic disease, gastrointestinal disorder (eg, selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding), eosinophilic disorders of the gastrointestinal tract (eg. , eosinophilic esophagitis, eos enophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) (eg, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, inflammation in disconnected bowel, Behçet's syndrome, unspecified colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by prokinetic agents (eg, ileus, postoperative ileus, and ileus in sepsis; gastroesophageal reflux disease (GORD or its synonym GERD); eosinophilic esophagitis, gastric paresis such as diabetic gastric paresis; food intolerances and food allergies and other functional bowel disorders such as non-ulcer dyspepsia (NUD) and extracardiac chest pain (NCCP, including costal chondritis)).

In a particular embodiment, the contemplated compound may be useful in somatic cell reprogramming, such as somatic cell reprogramming into stem cells. In a specific embodiment, the compound provided may be useful in germ cell development and thus appear to be useful in the fields of reproductive technology and regenerative medicine.

Other diseases that can be treated or prevented, in particular treated, include, without limitation, ischemic injury associated with myocardial infarction, immune diseases, stroke, arrhythmias, liver diseases caused by toxins or alcohol, aspirin-sensitive rhinosinusitis, cystic fibrosis, pain in cancer and blood disorders such as chronic anemia and aplastic anemia.

The compounds of the present invention may also have therapeutic applications in sensitizing 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 administered 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, which is administered to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and/or to improve the treatment of diseases that are treatable with ionizing radiation.

The term "chemosensitizer" as used herein is defined as a molecule, preferably a low molecular weight molecule, which is administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or to improve the treatment of diseases that are treatable with chemotherapeutic agents.

Several mechanisms have been proposed in the literature for the mode of action of radiosensitizers, including: radiosensitizers that cause cell hypoxia (e.g., 2-nitroimidazole-based compounds and benzotriazine dioxide-based compounds), mimic oxygen, or alternatively behave as bioreductive agents during hypoxia ; radiosensitizers that do not cause cell hypoxia (for example, halogenated pyrimidines) can be analogs of DNA bases and are predominantly included in the DNA of cancer cells and thus contribute to radiation-induced destruction of DNA molecules and/or interfere with normal DNA repair mechanisms; and various other possible mechanisms of action have been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently use radiosensitizers in conjunction with X-ray irradiation. Examples of X-ray activated radiosensitizers include, without limitation, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, ethanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9,

RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and their therapeutically effective analogs and derivatives.

Photodynamic therapy (PDT) for cancers uses visible light as a radiation activator of a sensitizing agent. 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 their therapeutically effective analogs and derivatives.

Radionsitizers can be introduced in conjunction with a therapeutically effective amount of one or more other compounds, including without limiting the compounds that contribute to the inclusion of radio sensitors in the target cell; compounds that control the receipt of therapeutic agents, nutrients and/or oxygen in target cells; chemotherapeutic agents that act on the tumor using additional irradiation or without it; or other therapeutically effective compounds for the treatment of cancer or other diseases.

The chemosensitizers can be administered in conjunction with a therapeutically effective amount of one or more other compounds, including, but not limited to, compounds that allow the incorporation of the chemosensitizers into target cells; compounds that control the delivery of therapeutics, 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, eg verapamil, have been found to be useful in combination with antitumor agents to render chemotherapy-responsive tumor cells resistant to standard chemotherapeutic agents and to enhance the efficacy of such compounds against drug-responsive 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 drug.

In one embodiment, the present invention relates to intermediates of formula (XXX) and their pharmaceutically acceptable addition salts and solvates for use as a drug.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for use in inhibiting PRMT5 activity.

The compounds of the present invention may be "anti-cancer agents", the term also encompassing "anti-tumor cell growth agents" and "anti-tumor 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 diseases mentioned above.

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 these 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 PRMT5 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 a medicinal product.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of a PRMT5 inhibiting medicament.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of a medicament 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 medicament 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, which can be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases mentioned above in this document.

In view of the usefulness of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, there is provided a method for treating warm-blooded animals, including humans, suffering from any of the diseases mentioned hereinabove, or a method for preventing warm-blooded animals, including humans, any of the diseases mentioned above in this document.

These methods involve the administration, ie systemic administration or topical administration, preferably oral administration, of an effective amount of a compound of formula (I) or a pharmaceutically acceptable addition salt or solvate thereof to warm-blooded animals, including humans.

Those skilled in the art of treating such diseases will be able to determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount will be from about 0.005 mg/kg to 50 mg/kg, in particular from 0.01 mg/kg to 50 mg/kg of 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 will be from about 0.01 to 1.00 g twice daily (BID), more specifically from 0.30 to 0.85 g BID; even more specifically 0.40 g BID. 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 on a case-by-case basis, for example, with respect to the particular compound, route of administration, age and condition of the patient receiving them, and the specific disorder or disease being treated.

The method of treatment may also include administering the active ingredient according to a schedule of one to four administrations per day. In these treatments, the compounds of the present invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using widely known and commonly available ingredients.

The compounds of the present invention, which may be useful in 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 involves the administration of a single dosage pharmaceutical formulation that contains a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof, and one or more additional therapeutic agents, as well as the 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 (I), a pharmaceutically acceptable addition salt or solvate thereof, and a therapeutic agent may be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered separately in oral dosage formulations.

While the active ingredient may be administered alone, it is preferred if it is presented as a pharmaceutical composition.

Therefore, the present invention further provides a pharmaceutical composition and, as an active ingredient, a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof.

Therefore, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof.

The carrier or diluent must be "acceptable" in terms of compatibility with the other ingredients of the composition and must not be 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 purposes of administration. As suitable compositions, all compositions commonly used for systemically administered drugs can be mentioned.

To obtain pharmaceutical compositions in the present invention, the effective amount of a specific compound as an active ingredient is combined into a homogeneous mixture with a pharmaceutically acceptable medium, while the carrier can take a wide variety of forms depending on the form of the drug necessary for administration. These pharmaceutical compositions are appropriate in a single dosage form, suitable, in particular, for the introduction of orally, rectally, misconduct, by parenteral injection or by inhalation. For example, when receiving compositions in a dosage form for oral use, any of the generally accepted pharmaceuticals can be used, such as, for example, water, glycols, oils, alcohols, etc. In the case of liquid preparations for oral use, such as suspensions, syrups, syrups, tinctures, emulsions and solutions; or solid media, such as starch, sugar, kaolin, diluents, lubricants, binders, baking powers, etc. In the case of powders, pills, capsules and tablets. Due to the simplicity of their introduction, tablets and capsules are the most preferred single dosage forms for oral use, and in this case, of course, use solid pharmaceutical carriers. In the case of compositions for parenteral administration, the carrier, as a rule, at least largely contains sterile water, although other ingredients may include, for example, to improve solubility. For example, it is possible to obtain injection solutions in which the carrier is a physiological solution, a solution of glucose or a mixture of a physiological solution and glucose solution. Injection solutions containing the compound of formula (I), its pharmaceutically acceptable salt salt or solivat, can be composed in oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cotton oil, corn oil, soy oil, synthetic glycerin complex esters of long -chain fatty acids, as well as mixtures of these and other oils. You can also receive injection suspensions, in the case of which you can use appropriate liquid media, suspending agents, etc. Also included drugs in solid form, which are designed for transformation into drugs in liquid form immediately before use. In compositions suitable for percutaneous administration, the carrier does not necessarily contain a product that increases permeability, and/or a suitable wetting agent, is not necessary in combination with suitable additives of any nature in minimal proportions, while the additives do not have significant harmful effects on the skin. These additives can facilitate the introduction through the skin and/or can be useful when receiving the required compositions. These compositions can be administered in various ways, for example, via a transdermal patch, by topical application, as an ointment. Acid or base addition salts of the compounds of formula (I), due to their increased solubility in water compared to the corresponding base or acid form, are more suitable in the preparation of aqueous compositions.

Especially preferred is the formulation of the above pharmaceutical compositions in the form of a single dosage form for ease of administration and dosage uniformity. A unit dosage form as used herein refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active ingredient, calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including divisible or coated tablets), capsules, pills, powder sachets, strips, suppositories, injectable solutions or suspensions, and the like, as well as their separate sets.

To increase the solubility and/or stability of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates in pharmaceutical compositions, it may be preferable to use α-, β- or γ-cyclodextrins or their derivatives, in particular hydroxyalkyl-substituted cyclodextrins, for example, 2 -hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Co-solvents such as alcohols can also improve the solubility and/or stability of the compounds of the present invention in pharmaceutical compositions.

Depending on the route of administration, the pharmaceutical composition will preferably contain from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the compound of formula (I), its pharmaceutically acceptable addition salt or solvate and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages contents are given in terms of the total weight of the composition.

As another aspect of the present invention, there is provided a combination of a compound of the present invention with another anticancer agent, especially for use as a medicine, 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 antibody-based immune cell retargeting, eg T-cell/neutrophil retargeting. This can be achieved, for example, with bispecific monoclonal antibodies or artificial T cell receptors.

For the treatment of the above conditions, the compounds of the present invention may advantageously be used in combination with one or more other medical agents, more particularly other anti-cancer agents or adjuvants in cancer therapy. Examples of anti-cancer agents or adjuvants (maintenance agents) include, without limitation:

- platinum coordination compounds, for example cisplatin, optionally in combination with amifostine, carboplatin or oxaliplatin;

taxane-based compounds, eg paclitaxel, protein-bound particles of paclitaxel (Abraxane ^TM ), or docetaxel;

- topoisomerase I inhibitors such as compounds based on camptothecin, for example irinotecan, SN-38, topotecan, topotecan-HCl;

- topoisomerase II inhibitors, such as antitumor derivatives of epipodophyllotoxins or podophyllotoxin, for example etoposide, etoposide phosphate or teniposide;

- antitumor vinca alkaloids, such as vinblastine, vincristine or vinorelbine;

- antitumor nucleoside derivatives, eg 5-fluorouracil, leucovorin, gemcitabine, gemcitabine-HCl, capecitabine, cladribine, fludarabine, nonlarabine;

- alkylating agents such as nitrogen mustard or nitrosourea, e.g. cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide, optionally in combination with mesna, pipobroman, procarbazine, streptozocin, temozolomide , uracil;

anthracycline antineoplastic derivatives, eg daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin-HCl, valrubicin;

- molecules that specifically act on the IGF-1 receptor, such as picopodophilin;

- derivatives of tetracarcin, for example, tetracarcin A;

- glucocorticoids, such as prednisone;

- antibodies, e.g. trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;

- estrogen receptor antagonists, or selective estrogen receptor modulators, or inhibitors of estrogen synthesis, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;

- aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozol;

differentiating agents such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) such as Accutane;

- inhibitors of DNA methyltransferase, for example, azacitidine or decitabine;

- antifolates, such as premetrexed disodium;

- antibiotics, for example, antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plikamycin, mithramycin;

- antimetabolites, for example, clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine;

apoptosis inducing agents and antiangiogenic agents such as Bcl-2 inhibitors, eg YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;

- tubulin-binding agents, for example combrestatin, colchicines or nocodazole;

- kinase inhibitors (e.g. EGFR (epidermal growth factor receptor) inhibitors, MTKIs (multiple target kinase inhibitors), mTOR inhibitors) e.g. , temsirolimus;

- farnesyl transferase inhibitors, such as tipifarnib;

- histone deacetylase (HDAC) inhibitors, eg sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A, vorinostat;

- inhibitors of the ubiquitin-proteasome pathway, eg PS-341, MLN.41 or bortezomib;

- yondelis;

- telomerase inhibitors, such as telomestatin;

- inhibitors of matrix metalloproteinase, for example, batimastat, marimastat, prinostat or metastat;

- recombinant interleukins, for example, aldesleukin, denileukin diftitox, interferon-alpha 2a, interferon-alpha 2b, peginterferon-alpha 2b;

- MAPK inhibitors;

- retinoids, for example, alitretinoin, bexarotene, tretinoin;

- arsenic trioxide;

- asparaginase;

- steroids, for example, dromostanolone propionate, megestrol acetate, nandrolone (decanoate, fenpropionate), dexamethasone;

- agonists or antagonists of gonadotropin-releasing hormone, for example, abarelix, goserelin acetate, histrelin acetate, leuprolide acetate;

- thalidomide, lenalidomide;

- mercaptopurine, mitotane, pamidronate, pegademazu, pegaspargas, rasburicase;

- BH3 mimetics, such as ABT-737;

- MEK inhibitors, eg PD98059, AZD6244, CI-1040;

- analogues of colony-stimulating factor, for example, filgrastim, pegfilgrastim, sargramostim; erythropoietin or its analogues (for example, darbepoetin-alpha); interleukin-11; oprelvekin; zoledronate, zoledronic acid; fentanyl; bisphosphonate; palifermin;

- a steroid inhibitor of cytochrome P450 17-alpha-hydroxylase / 17,20-lyase (CYP17), for example, abiraterone, abiraterone acetate.

- glycolysis inhibitors such as 2-deoxyglucose;

mTOR inhibitors such as rapamycins and rapalogs and mTOR kinase inhibitors;

- PI3K inhibitors and dual mTOR/PI3K inhibitors;

- autophagy inhibitors such as chloroquine and hydroxychloroquine;

- antibodies that reactivate the immune response to tumors, such as nivolumab (to PD-1), lambrolizumab (to PD-1), ipilimumab (to CTLA4) and MPDL3280A (to PD-L1).

The present invention also relates to a product containing, as a first active ingredient, a compound according to the present invention and, as an additional active ingredient, one or more anti-cancer 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 the compound of the present invention may be administered simultaneously (eg, in separate or single compositions) or sequentially in any order. In the latter case, two or more compounds will be administered over a period, in an amount and manner sufficient to ensure that an advantageous or synergistic effect is achieved. It should be appreciated that the preferred route and order of administration, and the appropriate dosages and schedules for each component of the combination will depend on the particular other medicinal product and compound of the present invention to be administered, their route of administration, the particular tumor being treated, and the specific host being treated. The optimal route and order of administration, as well as dosages and schedule, can be readily determined by those skilled in the art using standard methods and taking into account the information set forth herein.

The weight ratio of a compound of the present invention to one anticancer agent or several other anticancer agents administered in combination can be determined by one skilled in the art. The specified ratio and the exact dosage and frequency of administration depend on the specific compound in accordance with the present invention and other anticancer agent(s), the specific condition being treated, the severity of the condition being treated, age, weight, sex, diet, the time of administration and the general physical condition of the particular patient, the route of administration, as well as other drugs that the individual may be taking, as is well known to those skilled in the art. In addition, it is obvious that the effective daily amount can be reduced or increased depending on the response of the subject being treated, and/or depending on the judgment of the attending physician prescribing the compounds of the present invention. The specific weight ratio for a given compound of formula (I) and another anticancer agent may range from 1/10 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 to 500 mg per square meter (mg/m ² ) of body surface area, for example 50 to 400 mg/m ² , in particular for cisplatin at a dose of about 75 mg/m ² , and for carboplatin at a dose of approximately 300 mg/m ² per course of treatment.

The taxane-based compound is preferably administered at a dose of 50 to 400 mg per square meter (mg/m ² ) of body surface area, for example 75 to 250 mg/m ² , in particular for paclitaxel, at a dose of from about 175 to 250 mg/m ² , and for docetaxel at a dose of about 75 to 150 mg/m ² per course of treatment.

The compound based on camptothecin is preferably administered at a dose of 0.1 to

400 mg per square meter (mg/m ² ) of body surface area, for example, from 1 to 300 mg/m ² , in particular for irinotecan at a dose of about 100 to 350 mg/m ² , and for topotecan - at a dose of about 1 to 2 mg/m ² per course of treatment.

The antitumor podophyllotoxin derivative is advantageously administered at a dose of 30 to 300 mg per square meter (mg/m ² ) of body surface area, for example 50 to 250 mg/m ² , in particular for etoposide, at a dose of about 35 to 100 mg/m ² , and for teniposide at a dose of about 50 to 250 mg/m ² per course of treatment.

The antitumor vinca alkaloid is preferably administered at a dose of 2 to

30 mg per square meter (mg/m ² ) of body surface area, in particular for vinblastine at a dose of about 3 to 12 mg/m ² , for vincristine at a dose of about 1 to 2 mg/m ² , and for vinorelbine - at a dose of approximately 10 to 30 mg/m ² per course of treatment.

The antitumor nucleoside derivative is advantageously administered at a dose of 200 to 2500 mg per square meter (mg/m ² ) of body surface area, for example 700 to

1500 mg/m ² , in particular for 5-FU at a dose of 200 to 500 mg/m ² , for gemcitabine at a dose of about 800 to 1200 mg/m ² , and for capecitabine at a dose , ranging from approximately 1000 to

2500 mg/m ² , for the course of treatment.

Alkylating agents such as nitrogen mustard or nitrosourea are preferably administered at a dose of 100 to 500 mg per square meter (mg/m ² ) of body surface area, for example 120 to 200 mg/m ² , in particular for cyclophosphamide, in at a dose of about 100 to 500 mg/m ² , for chlorambucil, at a dose of about 0.1 to 0.2 mg/kg, for carmustine, at a dose of about 150 to 200 mg/m ² , and for lomustine, at a dose of approximately 100 to 150 mg/m ² per course of treatment.

The anthracycline antitumor derivative is advantageously administered at a dose of 10 to 75 mg per square meter (mg/m ² ) of body surface area, for example 15 to

60 mg/m ² , in particular for doxorubicin at a dose of about 40 to 75 mg/m ² , for daunorubicin at a dose of about 25 to 45 mg/m ² , and for idarubicin at a dose component from about 10 to 15 mg/m ² per course of treatment.

The antiestrogen agent is advantageously administered at a dose of about 1 to 100 mg per day, depending on the particular agent and the condition being treated. Tamoxifen is preferably administered orally at a dose of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing therapy for a time sufficient to achieve and maintain a therapeutic effect. Toremifene is preferably administered orally at a dose of approximately 60 mg once a day, 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 a day. Droloxifene is preferably administered orally at a dose of about 20 to 100 mg once a day. Raloxifene is preferably administered orally at a dose of approximately 60 mg once a day. Exemestane is preferably administered orally at a dose of approximately 25 mg once a day.

Antibodies are preferably administered at a dose of about 1 to 5 mg per square meter (mg/m ² ) of body surface area, or, as is known in the art, at another dose. Trastuzumab is preferably administered at a dose of 1 to 5 mg per square meter (mg/m ² ) of body surface area, in particular 2 to 4 mg/m ² , per course of treatment.

These doses can be administered, for example, once, twice or more per course of treatment, which can be repeated, for example, every 7, 14, 21 or 28 days.

The following examples illustrate the present invention. If no specific stereochemistry is indicated for the stereocenter of a compound, then this means that a mixture of R- and S-enantiomers was obtained. In the event that more than 1 stereocenter is present in the structure, each stereocenter for which no particular stereochemistry is indicated was obtained as a mixture of R and S.

One skilled in the art will appreciate that typically, after column purification, the desired fractions are collected and the solvent is evaporated to give the desired compound or intermediate.

Examples

Hereinafter in this document, the term "room temperature", "r. t." or "K.T." means room temperature; "Me" means methyl; "MeOH" means methanol; "Et" means ethyl; "EtOH" means ethanol; "EtOAc" means ethyl acetate; "Ac" means acetyl; "Ac ₂ O" means acetic anhydride; "AcOH" means acetic acid; "Et ₂ O" means diethyl ether; "prom." means an intermediate connection; "DMF" means N,N-dimethylformamide; "THF" means tetrahydrofuran; "LC" means liquid chromatography; "celite®" means diatomaceous earth; "LCMS" means liquid chromatography/mass spectrometry; "HPLC" stands for High Performance Liquid Chromatography; "TFA" means trifluoroacetic acid; "h." means hour(s); "Me ₂ S" means dimethyl sulfide; "DMSO" means dimethyl sulfoxide; "DMSO-d6" means deuterated dimethyl sulfoxide; "DIPE" means diisopropyl ether; "PPh ₃ "means triphenylphosphine; "TBAF" means tetrabutylammonium fluoride; "DBU" means 1,8-diazabicyclo[5.4.0]undecene-7; "equiv." means equivalent(s); "KOtBu" means potassium tert-butoxide; "TBDMSCl" means tert-butyldimethylsilyl chloride; "Bn" means benzyl; "9-BBN" means 9-borabicyclo[3.3.1]nonane; "Tf ₂ O" means triflate anhydride; "TBDMS" means t-butyldimethylsilyl or t-butyldimethylsilyl; "water" means water; "Ts" or "Tos" means tosyl (p-toluenesulfonyl); "DEAD" means diethyl azodicarboxylate; "Bz" means benzoyl; "BnBr" means benzyl bromide; "Bn" means benzyl; "PhMgBr" means phenylmagnesium bromide; "bezv." means anhydrous; "Rh(acac)(eth) ₂ "means acetylacetonatobis(ethylene)rhodium(I); "p-TsOH" means 4-methylbenzenesulfonic acid; "(R)-MonoPhos" means (R)-N,N-dimethyldinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphepin-4-amine;"DMF-DMA" means N,N-dimethylformamide dimethyl acetal; "BSA" means N,O-bis(trimethylsilyl)acetamide; "TMSOTf" means trimethylsilyl trifluoromethanesulfonate; "prep. SFC" means preparative supercritical fluid chromatography; "Piv" means pivaloyl; "PivCl" means pivaloyl chloride; "MePPh ₃ ⁺ Br ^- " means methyltriphenylphosphonium bromide; "iPrNH ₂ " means isopropylamine; "us." means saturated; "DMA" means dimethylacetamide.

In some cases, a stereo link is referred to as a "wavy line link". This means that the stereochemical configuration at the stereocenter is represented by a mixture of forms. In this case, the note next to the wavy line link will describe in more detail what type of mixture is obtained.

For example, intermediate connection 10:

The wavy line bond in intermediate 10 indicates that the stereochemical configuration at the stereocenter is a mixture of forms, and a note next to the wavy line bond details that it is a β/α (4:1) anomer. (4:1) indicates that the ratio β/α is 4/1. The β-anomer corresponds to a structure in which the wavy line bond is represented by a wedge bond, with the bonds at positions 2 and 3 of the sugar ring shown as dotted bonds:

.

.

The α-anomer corresponds to a structure in which a bond in the form of a wavy line is represented by a bond in the form of a dotted line, when the bonds in positions 2 and 3 of the sugar ring are shown as bonds in the form of dotted lines:

Obviously, the same rule applies to other intermediates, which are listed as β/α-anomers.

For example, intermediate connection 45:

The wavy line bond in intermediate 45 indicates that the stereochemical configuration at the stereocenter is a mixture of forms, and a note next to the wavy line bond details that it is a 1:1 mixture of diasteroisomers.

Obviously, the same rule applies to other intermediates, which are listed as a 1:1 mixture of diasteroisomers.

Preparation of intermediates and compounds

Getting Intermediate 1

D-ribose (67.2 mmol, 10.1 g, 1.00 eq.) was added to a solution of 2,2-dimethoxypropane (163 mmol, 20 ml, 2.40 eq.) in acetone (80 ml). After 15 minutes, a homogeneous solution was obtained and the mixture was cooled to 0° C., followed by dropwise addition of perchloric acid (aq. 70%, 46.0 mmol, 4.00 ml) over 10 minutes. The mixture was then stirred for 2 hours at room temperature, after which methanol (345 mmol; 14.0 ml) was added and the bright yellow solution was stirred for an additional 2 hours at room temperature. The mixture was again cooled to 0° C. and NaHCO ₃ (6.42 g) dissolved in water (20 ml) was carefully added (over 20 minutes) to precipitate the perchloric acid salts, which were then filtered off. The filtrate was evaporated to a volume of 40 ml and extracted with diethyl ether (2×200 ml). The combined organic fractions were washed with brine (1×100 ml), dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give the desired intermediate 1 (142 mmol, 11.9 g, 87% yield) as a light yellow oil which was used without further purification.

¹ H NMR (250 MHz, CDCl ₃ ) δ 4.98 (s, 1H), 4.84 (d, J=6.3 Hz, 1H), 4.59 (d, J=6.0 Hz, 1H ), 4.44 (m, 1H), 3.75-3.56 (m, 2H), 3.44 (s, 3H), 1.49 (s, 3H), 1.32 ppm (s, 3H ).

Preparation of Intermediate 2

In a round bottom flask equipped with a magnetic stir bar and a reflux condenser was added intermediate 1 (10.0 g, 49.0 mmol, 1.00 eq.) and a mixture of toluene/acetonitrile (5:1) (300 ml). Then imidazole (5.00 g, 74.0 mmol, 1.50 eq.) and triphenylphosphine (13.4 g, 59.0 mmol, 1.20 eq.) were added. After they had dissolved, iodine (14.9 g, 59.0 mmol, 1.20 eq.) was added portionwise over a period of 15 minutes (exothermic). After the addition was completed, the reaction mixture was heated to 90° C. for 20 minutes and cooled to room temperature before starting work-up. The reaction mixture was diluted in Et ₂ O (200 ml) and washed with a saturated solution of Na ₂ S ₂ O ₃ (2×200 ml), water (2×200 ml) and brine (1×200 ml). The organic phase was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. Triphenylphosphine oxides were precipitated with pentane and removed by filtration. The filtrate was concentrated in vacuo to give intermediate 2 (13.3 g, crude) used without purification.

¹ H NMR (250 MHz, CDCl ₃ ) δ 5.04 (s, 1H), 4.76 (d, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 1H ), 4.43 (dd, J=10.0, 6.1 Hz, 1H), 3.36 (s, 3H) 3.28 (dd, J= 10.0, 6.1 Hz, 1H), 3.17 (d, J=10.0 Hz, 1H), 1.47 (s, 3H), 1.32 ppm (s, 3H)

Preparation of Intermediate 3

To a two-necked round-bottom flask equipped with a magnetic stir bar and a reflux condenser was added intermediate 2 (30.0 g, 95.5 mmol, 1.00 eq.) and DMF (250 ml). The mixture was heated to 90°C, during which was added distilled DBU (15.7 ml, 10.5 mmol, 1.1 eq.) over 2 minutes. The mixture was heated for 17 hours at 90°C, after which complete conversion was observed by NMR. The solution was cooled to room temperature, diluted in EtOAc (300 ml) and washed with brine (3×300 ml). The organic phase was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The resulting oil (19.1 g, crude) was purified by vacuum distillation at 55° C. to give the desired intermediate 3 (10.8 g, 61% yield over 2 steps from intermediate 1 ) as a liquid colorless oil.

¹ H NMR (250 MHz, CDCl ₃ ) δ 5.11 (s, 1H), 5.02 (d, J=5.9 Hz, 1H), 4.60 (m, 1H), 4.50 (d , J=5.9, 1H), 4.38 (m, 1H), 3.41 (s, 3H), 1.47 (s, 3H), 1.35 ppm (s, 3H)

¹³C NMR (63 MHz, CDCl₃) δ 161.4, 113.4, 108.8, 88.9, 82.8, 78.9, 55.9, 26.9, 25.9 ppm

Preparation of Intermediate 4

Zinc powder (25.0 g, 0.380 mol) was added to a two-necked round bottom flask (500 ml) containing demineralized water (100 ml) and the solution was degassed with nitrogen for 15 minutes. Then the copper (II) sulfate (1.85 g, 11.5 mmol) and the mixed solution were added for 45 minutes. The mixture was filtered and the solids washed with degassed water (250 ml) and degassed acetone (250 ml) in that order. The zinc-copper pair was dried in vacuo for 12 hours. A solution of intermediate 3 (5.00 g, 26.9 mmol, 1.00 eq.) in anhydrous Et ₂ O (150 ml, dried over 4Å molecular sieves) was added to a zinc-copper pair (12.2 g , 186 mmol, 7.00 equiv.) in a flame-dried flask under inert argon. Then a solution of trichloroacetyl chloride (4.29 ml, 37.7 mmol, 1.40 eq.) in anhydrous Et ₂ O (30 ml) was added dropwise to the stirred mixture over a period of 3 hours at 25°C. After the addition was complete, stirring was stopped and the organic layer was decanted from the precipitated zinc salts and washed with pentane/Et ₂ O (100 ml). The organic phase was washed with NaHCO ₃ (aq. sat. 3×150 ml) and brine (3×100 ml), dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to obtain the desired intermediate compound 4 (7.20 g , unpurified).

¹ H NMR (250 MHz, CDCl ₃ ) δ 5.10 (d, J=5.7 Hz, 1H), 5.07 (s, 1H), 4.68 (d, J=5.7 Hz), 3.61 (dd, J= 28.2, 18.7, 2H), 3.52 (s, 1H), 1.43 (s, 3H), 1.34 ppm (s, 3H).

¹³C NMR (63 MHz, CDCl₃) δ 191.6, 113.5, 110.0, 91.1, 87.6, 85.3, 81.2, 57.3, 50.0, 26.5, 25.5 ppm

Preparation of Intermediate 5

Intermediate compound 4 (6.77 g, 22.8 mmol, 1.00 ECV) was dissolved in ThF (90 ml) and ice acetic acid (6.52 ml, 11.4 mmol, 5 ecv.) With the subsequent addition portions of zinc-copper pair (14.9 g, 0.228 mol, 10.0 eq.). The reaction mixture was stirred for 18 hours at room temperature. The mixture was filtered through celite, rinsed with THF (50 ml) and the filtrate was concentrated to the minimum volume in vacuo. The resulting oil was redissolved in EtOAc (300 ml) and washed with NaHCO ₃ (aq. sat. 2×100 ml) and brine (3×90 ml), the organic phase was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give intermediate 5 (3.66 g, 15.9 mmol; 70% yield over 2 steps from intermediate 3 ).

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.94 (s, 1H), 4.67 (d, J=5.8 Hz, 1H), 4.65 (d, J=5.8 Hz, 1H ), 3.48 (dd, J=18.7, 5.7Hz, 1H), 3.34 (s, 3H), 3.31 (dd, J=19.5, 5.4Hz, 1H) , 3.10 (dd, J=18.3, 4.7 Hz, 1H), 3.04 (dd, J=18.3, 5.7 Hz, 1H), 1.41 (s, 3H), 1.31ppm(s, 3H)

¹³C NMR (125 MHz, CDCl₃) δ 204.7, 113.1, 108.7, 85.7, 84.5, 78.5, 59.2, 55.2, 54.7, 26.5, 25.4 ppm

Preparation of Intermediate 6

Intermediate 5 (1.00 g, 4.38 mmol, 1.00 eq) was dissolved in anhydrous THF (30 ml) and cooled to -78°C. Lithium aluminum hydride (199 mg; 5.70 mmol; 1.20 eq.) was added portionwise to the cooled reaction mixture over 10 minutes. After 1 hour at -78°C, the mixture was warmed to room temperature, filtered through celite and the filtrate was concentrated in vacuo to a minimum volume. The residue was redissolved in EtOAc (300 ml) and washed with HCl (aq. 0.5 M, 2×100 ml), NaHCO ₃ (aq. sat. 1×100 ml) and brine (2×100 ml). The organic layer was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 99:1 to 95:5). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 6 (702 mg, 3.07 mmol, 71% yield) as a colorless oil.

¹ H NMR (250 MHz, CDCl ₃ ) δ 4.79 (s, 1H), 4.56 (d, J=5.8 Hz, 1H), 4.41 (d, J=5.8 Hz, 1H ), 4.02 (quin., J=7.2 Hz, 1H), 3.31 (s, 3H), 2.85 (dt, J=12.5, 6.6 Hz, 1H), 2, 43 (dt, J=12.4, 6.2Hz, 1H), 2.24 (dd, J=10.6, 6.2Hz, 1H), 2.04 (dd, J=11.0, 6.5Hz), 1.39(s, 3H), 1.29ppm(s, 3H)

¹³ C NMR (63 MHz, CDCl ₃ ) δ 112.7, 107.6, 85.5, 84.6, 78.3, 60.1, 55.0, 46.5, 40.4, 26.5 , 25.4ppm

Preparation of Intermediate 7

Intermediate 6 (2.00 g, 8.70 mmol, 1.00 eq) was dissolved in THF (50 ml) and benzoic acid (1.33 g, 10.9 mmol, 1.25 eq) was added followed by adding triphenylphosphine (2.85 g, 10.9 mmol, 1.25 eq.) and diethylazadicarboxylate (1.70 ml 10.9 mmol, 1.25 eq.). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo to a minimum volume. The slurry was dissolved in EtOAc (100 ml) and NaHCO ₃ (aq. sat. 50 ml) was added. The product was extracted with EtOAc (3×100 ml), the combined organic phases were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give intermediate 7 (2.53 g, crude).

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.04 (d, J=7.5 Hz, 2H), 7.56 (t, J=7.4 Hz, 1H), 7.44 (t, J =7.7 Hz, 2H), 5.40 (m, 1H), 4.90 (s, 1H), 4.68 (d, J=5.8 Hz, 1H), 4.59 (d, J =5.8Hz, 1H), 3.38(s, 3H), 2.75(m, 2H), 2.64(ddd, J=13.2, 7.4, 3.3Hz, 1H) , 2.31 (ddd, J=13.8, 4.7, 2.9 Hz, 1H), 1.42 (s, 3H), 1.33 ppm (s, 3H)

¹³C NMR (125 MHz, CDCl₃) δ 166.4, 133.2, 130.5, 129.8, 128.6, 112.6, 108.4, 85.8, 85.4, 84.0, 66.5, 55.1, 43.2, 37.5, 26.6, 25.6ppm

Preparation of Intermediate 8

Intermediate connection 7 (2.91 g, 8.70 mmol, 1.00 ECV) was dissolved in methanol (45 ml) and lithium hydroxide (5.00 ml, 2 m in h ₂ o) was added. The mixture was stirred at room temperature for 18 hours, followed by removal of the solvent in vacuo to a minimum volume. The slurry was dissolved in EtOAc (100 ml) and brine (50 ml) was added. The product was extracted using ETOAC (3 × 100 ml), the combined organic phases dried (MGSO ₄ ), filtered and the filtrate concentrated in vacuo. The remainder was cleaned by means of column chromatography on silica gel (gradient elimination: N-Geptan/Etoac from 99: 1 to 95: 5). Fractions containing product were collected and the solvent was evaporated to give the desired intermediate 8 (1.08 mg, 4.70 mmol, 54% yield from intermediate 6 ) as a colorless oil.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.86 (s, 1H), 4.67 (d, J=5.8 Hz, 1H), 4.57 (d, J=5.8 Hz, 1H ), 4.53(m, 1H), 3.34(s, 3H), 2.53(m, 1H), 2.42(m, 2H), 2.05(m, 1H), 1.41 (s, 3H), 1.33 ppm (s, 3H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 112.5, 108.4, 86.0, 85.4, 83.8, 63.5, 55.0, 45.2, 40.2, 26.6 , 25.5ppm

Preparation of Intermediate 9

Sodium hydride (277 mg, 6.93 mmol, 1.40 ecv.) And anhydrous DMF (10 ml dried above molecular sits with a cell size of 4å) in an atmosphere of an inert argon was added to the flame. The mixture was cooled up to 0 ° C and the intermediate connection 6 (1.14 g; 4.95 mmol, 1.00 ecv.), Dissolved in anhydrous DMF (12.0 ml), was added drops for 5 minutes. After stirring for 15 minutes, benzyl bromide (0.77 ml, 6.44 mmol, 1.30 eq.) was added dropwise at 0° C. and the mixture was further stirred at room temperature for 1.5 hours. Then the reaction mixture was cooled to 0°C and carefully extinguished by adding saline (100 ml). The product was extracted in Etoac (3 × 120 ml), the combined organic layers were washed with saline (2 × 100 ml), dried (MGSO ₄ ), filtered and filtered in VACUO to obtain the necessary intermediate connection 9 (890 mg, uncleaned).

¹ H NMR (250 MHz, CDCl ₃ ) δ 7.37-7.25 (m, 5H), 4.83 (s, 1H), 4.59 (d, J=5.8 Hz, 1H), 4 .42 (m, 3H), 3.80 (quin. J=7.1 Hz, 1H), 3.33 (s, 1H), 2.84 (dt, J=12.1, 6.1 Hz, 1H), 2.40 (dt, J=12.1, 6.1 Hz, 1H), 2.43 (dd, J=10.9, 6.6 Hz, 1H), (dd, J=11, 9, 7.6Hz, 1H), 1.42(s, 3H), 1.32ppm(s, 3H)

¹³ C NMR (63 MHz, CDCl ₃ ) δ 138.2, 128.6, 128.0, 127.9, 112.6, 107.7, 85.6, 84.7, 78.8, 70.6 , 65.6, 54.9, 43.9, 37.7, 26.5, 25.5ppm

Preparation of Intermediate 10

To the suspension of the intermediate compound 9 (300 mg, 0.94 mmol, 1.00 ecv.) In water (4.8 ml), HCL (37% of water, 0.18 ml) was added and the mixture was heated to 90 ° C during 3 hours. Then the solution was cooled to room temperature and carefully extinguished with NaOH (water. 1 m, 5 ml). The mixture was extracted using ETOAC (3 × 10 ml) and the combined organic layers dried (MGSO ₄ ), filtered and the filtrate concentrated in vacuo. The resulting powder was dissolved in pyridine (1.5 ml) followed by the addition of acetic anhydride (1.5 ml) and stirred at room temperature for 22 hours. The mixture was diluted in EtOAc (30 ml), washed with brine (3×10 ml), the organic layer was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 0:100). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 10 (150 mg, 0.38 mmol, 41% yield) as a 4:1 mixture of β:α isomers.

Getting Compound 39

6-Chloropurine (130 mg, 0.84 mmol; 1.10 eq.) was weighed into an oven-dried vial and anhydrous acetonitrile (2.5 ml, dried over 4Å molecular sieves) was added followed by N, O- bis(trimethylsilyl)acetamide (0.10 ml, 0.39 mmol, 0.50 eq.). The mixture was stirred for 30 minutes at room temperature, during which a homogeneous solution was obtained. Then, sugar moiety-containing intermediate 10 (306 mg; 0.78 mmol, 1.00 eq.) dissolved in anhydrous acetonitrile (2.2 ml) was added to the mixture, followed by the dropwise addition of TMSOTf (0.07 ml, 0 .39 mmol, 0.50 eq.). The solution was heated to 80°C for 2 hours, then cooled to room temperature and diluted in EtOAc (80 ml). NaHCO ₃ (aq. sat., 50 ml) was added and the product was extracted into EtOAc (3×80 ml). The combined organic fractions were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 0:100). Fractions containing the product were collected and the solvent was evaporated to give the desired compound 39 (344 mg, 0.71 mmol, 91% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 8.11 (s, 1H), 7.28-7.19 (m, 5H), 6.21 (m, 1H) , 6.06 (d, J=6.8 Hz, 1H), 5.43 (d, J=4.3 Hz, 1H), 4.36 (s, 2H), 3.70 (quin., J =6.9Hz, 1H), 2.79 (dt, J=12.4, 6.2Hz, 1H), 2.63 (dt, J=12.5, 6.2Hz, 1H), 2 .35 (dd, J=11.7, 6.6 Hz, 1H), 2.25 (dd, J=11.9, 6.7 Hz, 1H), 2.13 (s, 3H), 1, 94ppm(s, 3H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 170.0, 169.4, 152.3, 151.7, 151.5, 144.4, 137.8, 132.8, 128.6, 128.0 , 86.4, 79.4, 75.4, 72.9, 71.0, 64.1, 43.4, 39.0, 20.7, 20.5ppm

Get connection 1

Compound 39 (45 mg, 0.09 mmol; 1.00 eq.) was suspended in aqueous ammonia (1.5 ml) and heated to 80°C for 17 h. The mixture was cooled to room temperature and extracted into EtOAc (3 ×15 ml) with saline solution (10 ml). The organic layer was dried (MGSO ₄ ), filtered and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC (gradient elution: 0.1% TFA in CH ₃ CN/0.1% TFA in H ₂ O). The necessary fractions were combined and lyophilized to give Compound 1 (8.0 mg; TFA salt, equivalents not determined) as a white powder.

¹ H NMR (500 MHz, MeOD) δ 8.33 (s, 1H), 8.29 (s, 1H), 7.27-7.18 (m, 5H), 5.94 (d, J=6 .7 Hz, 1H), 4.90 (dd, J=5.9, 3.6 Hz, 1H), 4.38 (s, 2H), 3.96 (d, J=4.3 Hz, 1H ), 3.73 (quin., J=6.9 Hz, 1H), 2.91 (dt, J=12.2, 6.1 Hz, 1H), 2.63 (dt, J=12.2 , 6.1 Hz, 1H), 2.24 (dd, J=11.2, 6.4 Hz, 1H), 2.05 ppm (dd, J=11.3, 6.5 Hz, 1H)

¹³ C NMR (125 MHz, MeOD) δ 161.6 (q, J=34.4 Hz, TFA), 152.0, 149.2, 146.0, 142.5, 138.2, 128.2, 127.8, 127.5, 119.6 (TFA), 88.6, 80.0, 75.6, 74.3, 70.3, 64.6, 43.0, 38.2ppm

Preparation of Intermediate 12

Intermediate 8 (90.0 mg, 0.391 mmol, 1.00 eq.) dissolved in anhydrous ThF (5.00 ml) and added triphenylphosfin (128 mg, 0.489 mmol, 1.25 EXVs) with the subsequent addition of portions of 2-chloro-7-chinolinol (87.8 mg, 0.489 mmol, 1.25 EXVs, 1.25 EXVs .). They added a drop of dietilazodicarboxylate (0.08 ml, 0.489 mmol, 1.25 ecv.) And the mixture was mixed at room temperature for 16 hours. Then the solution was concentrated to the minimum volume of in vacuo and the remainder was cleaned by means of column chromatography on silica gel (gradient elimination: N-geptan/etoac from 95: 5 to 1: 1). Collected fractions containing the product, and the solvent was evaporated with obtaining the necessaryintermediate connection 12(142 mg, exit 93%) in the form of colorless oil.

¹ H NMR (360 MHz, CDCl ₃ ): δ=8.01 (d, J=8.4 Hz, 1H), 7.70 (d, J=9.1 Hz, 1H), 7.26 (d , J=1.8 Hz, 1H), 7.16-7.25 (m, 2H), 4.87 (s, 1H), 4.65 (d, J=5.9 Hz, 1H), 4 .48-4.59 (m, 2H), 3.34 (s, 3H), 3.17-3.28 (m, 1H), 2.75 (dt, J=12.4, 6.2 Hz , 1H), 2.53 (dd, J=12.6, 7.5 Hz, 1H), 2.38 (dd, J=12.4, 7.3 Hz, 1H), 1.45 (s, 3H), 1.37ppm(s, 3H)

¹³ C NMR (91 MHz, CDCl ₃ ): δ=159.1, 151.0, 149.5, 138.3, 128.6, 122.0, 120.1, 119.8, 112.6, 108 .2, 107.5, 85.3, 84.4, 79.0, 64.9, 54.7, 43.7, 37.6, 26.3, 25.2 ppm

Preparation of Intermediate 13

Intermediate 8 (112 mg, 0.486 mmol, 1.00 eq.) was dissolved in anhydrous THF (3.50 mL) and triphenylphosphine (159 mg, 0.608 mmol, 1.25 eq.) was added followed by portionwise addition of 3-bromo-7-quinolinol (136 mg, 0.608 mmol, 1.25 eq.) . Diethyl azodicarboxylate (0.10 ml, 0.608 mmol, 1.25 eq.) was added dropwise and the mixture was stirred at room temperature for 16 hours. The solution was then concentrated to the minimum volume in vacuo and the residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 1:1). Fractions containing the product were collected and the solvent was evaporated to give the desiredIntermediate 13(184 mg, 87% yield) as a colorless oil.

¹ H NMR (360 MHz, CDCl ₃ ): δ=8.79 (d, J=2.2 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.59 (d , J=9.1 Hz, 1H), 7.15-7.25 (m, 2H), 4.85 (s, 1H), 4.64 (d, J=5.9 Hz, 1H), 4 .50-4.58 (m, 2H), 3.33 (s, 3H), 3.20 (dt, J=12.4, 6.2 Hz, 1H), 2.74 (dt, J=12 .4, 6.2Hz, 1H), 2.53 (dd, J=12.4, 7.3Hz, 1H), 2.37 (dd, J=12.4, 7.3Hz, 1H) , 1.43(s, 3H), 1.35ppm(s, 3H)

¹³ C NMR (91 MHz, CDCl ₃ ): δ=158.4, 151.4, 147.8, 136.8, 128.0, 124.3, 121.0, 114.6, 112.6, 108 .8, 107.5, 85.3, 84.4, 79.0, 64.9, 54.8, 43.8, 37.6, 26.3, 25.2 ppm

Preparation of Intermediate 14

Intermediate 12 (143 mg, 0.369 mmol, 1.00 eq) was dissolved in CH ₃ CN (2.00 ml) and HCl (0.5 M in H ₂ O, 6.00 ml) was added. The solution was heated to 90°C for 2 hours and received a homogeneous solution. The mixture was concentrated in vacuo and co-evaporated with toluene to give a white solid which was directly dissolved in pyridine (4.00 ml) and acetic anhydride (4.00 ml) and stirred at room temperature for 3 hours. The mixture was concentrated to minimum volume in vacuo and co-evaporated with toluene to dryness. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 0:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 14 (107 mg, 62% yield over 2 steps) as a 4:1 mixture of β:α isomers.

Preparation of Intermediate 15

Intermediate 13 (209 mg, 0.479 mmol, 1.00 eq) was dissolved in CH ₃ CN (3.00 ml) and HCl (0.5 M in H ₂ O, 9.00 ml) was added. The solution was heated to 90°C for 2 hours and received a homogeneous solution. The mixture was concentrated in vacuo and co-evaporated with toluene to give a white solid which was directly dissolved in pyridine (6.00 ml) and acetic anhydride (6.00 ml) and stirred at room temperature for 3 hours. The mixture was concentrated to minimum volume in vacuo and co-evaporated with toluene to dryness. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 0:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 15 (199 mg, 82% yield over 2 steps) as a 4:1 mixture of β:α isomers.

Getting connection 40

6-Chloropurine (40.9 mg, 0.265 mmol, 1.15 eq.) was added to an oven-dried vial and dissolved in CH ₃ CN (1.00 mL) followed by N,O-bis(trimethylsilyl)acetamide (0 .03 ml, 0.115 mmol, 0.50 eq.). The mixture was stirred for 30 minutes at room temperature and intermediate 14 (107 mg, 0.230 mmol, 1.00 eq.) dissolved in CH ₃ CN (1.50 ml) was added, followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (0. 02 ml, 0.115 mmol, 0.50 eq.). The solution was heated to 80°C for 1 hour, cooled to room temperature, diluted with EtOAc (20 ml) and NaHCO ₃ (aq. sat., 10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×20 ml). The combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give compound 40 (140 mg, crude).

¹ H NMR (360 MHz, CDCl ₃ ): δ=8.68 (s, 1H), 8.17 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.03-7.09 (m, 2H), 6.29 (dd, J= 6.0, 4.6 Hz, 1H), 6.09 (d, J=6.2 Hz, 1H), 5.63 (d, J=4.4 Hz, 1H), 4.46 (quin, J=6.8Hz, 1H), 3.18 (dt, J=13.0, 6.3Hz, 1H), 3.07 (dt, J=12.7, 6.3Hz, 1H), 2.67 (dd, J=13.0, 6.8 Hz, 1H), 2.42 (dd, J=12.8, 7.0 Hz, 1H), 2.22 (s, 3H), 1 .99 ppm(s, 3H)

¹³ C NMR (91 MHz, CDCl ₃ ): δ=169.8, 169.3, 158.7, 152.1, 151.4, 151.1, 151.0, 149.3, 144.4, 138 .4, 132.5, 128.8, 122.0, 120.1, 120.0, 107.9, 86.6, 79.3, 74.7, 72.6, 63.1, 42.6 , 39.0, 20.6, 20.3ppm

Getting Compound 41

6-Chloropurine (69.5 mg, 0.450 mmol, 1.15 eq.) was added to an oven-dried vial and dissolved in CH ₃ CN (1.20 mL) followed by N,O-bis(trimethylsilyl)acetamide (0 .05 ml, 0.196 mmol, 0.50 eq.). The mixture was mixed for 30 minutes at room temperature and an intermediate compound was added 15 (199 mg, 0.391 mmol, 1.00 EXVs), dissolved in CH ₃ CN (2.00 ml), with the subsequent addition of trifteromethanolsulfonate trifteromethylil (0, drops of drops (0, 04 ml, 0.196 mmol, 0.50 eq.). The solution was heated to 80 ° C for 1 hour, cooled to room temperature, diluted using ETOAC (20 ml) and Nahco ₃ (water., 10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×20 ml). The combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give compound 41 (272 mg, crude).

¹ H NMR (360 MHz, CDCl ₃ ): δ=8.80 (d, J=2.2 Hz, 1H), 8.75 (s, 1H), 8.21 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 7.09-7.24 (m, 2H), 6.36 (dd, J= 6.2, 4.8 Hz, 1H), 6.15 (d, J=6.2 Hz, 1H), 5.69 (d, J=4.8 Hz, 1H), 4.54 (quin, J=6.8 Hz, 1H), 3.18-3.31 (m, 1H), 3.01-3.18 (m, 1H), 2.73 (dd, J=12.8, 7, 0 Hz, 1H), 2.50 (dd, J=12.8, 7.0 Hz, 1H), 2.26 (s, 3H), 2.04 ppm (s, 3H)

¹³ C NMR (91 MHz, CDCl ₃ ): δ=169.8, 169.2, 158.1, 152.1, 151.5, 151.4, 151.1, 147.6, 144.4, 137 .0, 132.6, 128.2, 124.5, 121.0, 114.7, 108.5, 86.5, 79.4, 74.9, 72.5, 63.1, 60.3 , 42.7, 39.0, 20.6, 20.3ppm

Obtaining Compounds 2 and 3

The compound 40 (140 mg, unpeeled) was dissolved in 1.4-deioxan (10.0 ml) and added ammonia (30.0 ml, 25% in H ₂ O). The mixture was heated to 125° C. in a pressure reactor for 3 days, cooled to room temperature and concentrated to minimum volume in vacuo. The residue was co-evaporated to dryness with toluene and purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20×250 mm, mobile phase: CO ₂ , iPrOH+0.4 iPrNH ₂ ) to give the desired compound 2 (21.7 mg , 21% yield over 2 steps) and compound 3 (17.8 mg, 17% yield over 2 steps).

¹ H NMR Compound 2 (400 MHz, DMSO-d ₆ ): δ=8.27-8.34 (m, 1H), 8.14 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.24 (s, 2H), 6.80 (s, 1H), 6.74 (dd, J=8.7 , 2.1 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H), 6.33 (brs, 2H), 5.89 (d, J=6.8 Hz, 1H) , 5.55 (br s, 1H), 5.49 (s, 1H), 5.49 (br s, 1H), 5.04 (br s, 1H), 4.46 (quin, J=6, 5 Hz, 1H), 4.00-4.20 (m, 2H), 3.14-3.23 (m, 3H), 2.92-3.03 (m, 1H), 2.22-2 .34 (m, 1H), 2.12ppm (dd, J=12.1, 7.0Hz, 1H)

¹³ C NMR Compound 2 (101 MHz, DMSO-d ₆ ,): δ=158.4, 157.9, 156.0, 152.5, 149.6, 149.2, 140.0, 136.6, 128.6, 119.4, 117.5, 112.7, 109.7, 106.4, 87.0, 79.1, 74.8, 72.7, 63.2, 48.6, 43, 2, 38.4ppm

¹ H NMR Compound 3 (400 MHz, DMSO-d ₆ ): δ=8.34 (d, J=8.6 Hz, 1H), 8.31 (s, 1H), 8.14 (s, 1H) , 7.94 (d, J=9.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.21-7.32 (m, 4H), 5.90 ( d, J=6.8 Hz, 1H), 5.56 (br d, J=4.0 Hz, 1H), 5.52 (br d, J=6.4 Hz, 1H), 5.06 ( br q, J=4.2 Hz, 1H), 4.59 (quin, J=6.8 Hz, 1H), 4.12-4.20 (m, 1H), 3.24 (dt, J= 12.1, 6.1 Hz, 1H), 3.07 (dt, J=11.9, 5.9 Hz, 1H), 2.29 (dd, J=12.2, 6.9 Hz, 1H ), 2.17 ppm (dd, J=12.0, 7.2 Hz, 1H)

¹³ C NMR Compound 3 (101 MHz, DMSO-d ₆ ): δ=158.9, 156.0, 155.9, 152.5, 150.1, 149.6, 149.0, 140.0, 139 .5, 129.3, 121.8, 119.9, 119.8, 119.3, 107.8, 87.0, 79.0, 74.7, 72.6, 63.8, 43.0 , 38.1ppm

Get Compound 4

Compound 41 (270 mg, crude) was dissolved in 1,4-dioxane (1.5 ml) and ammonia (4.5 ml, 25% in H ₂ O) was added. The mixture was heated to 90 ° C in the reactor under pressure for 12 hours, cooled to room temperature and concentrated to the minimum volume of IN VACUO. The residue was co-evaporated to dryness with toluene and purified by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO ₂ , iPrOH+0.4 iPrNH ₂ ) to give the desired compound 4 (85.8 mg , 44% yield over 2 steps).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.86 (d, J=2.2 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.18-7.38 (m, 3H), 5.90 (d, J=6.8 Hz, 1H), 5.49-5.60 (m, 1H), 5.04 (dd, J=6.6, 4.2 Hz, 1H), 4.59 (quin, J =6.7 Hz, 1H), 4.15 (d, J=4.2 Hz, 1H), 3.28-3.34 (m, 1H), 3.23 (dt, J=12.0, 6.0 Hz, 1H), 3.05 (dt, J=11.9, 5.9 Hz, 1H), 2.30 (br dd, J=12.1, 6.8 Hz, 1H), 2 .17ppm (dd, J=12.1, 7.0Hz, 1H)

¹³ C NMR (101 MHz, DMSO-d ₆ ): δ=158.7, 156.5, 156.4, 153.0, 151.5, 150.1, 148.0, 137.6, 129.3 , 124.6, 121.2, 119.8, 119.8, 114.6, 109.0, 87.5, 79.5, 75.2, 73.1, 64.3, 43.5, 38 .6ppm

Preparation of Intermediate 18

Intermediate 6 (250 mg, 1.09 mmol, 1.00 eq.) dissolved in anhydrous ThF (7.50 ml) and added triphenylphosfin (342 mg, 1.30 mmol, 1.25 EXVs) with the subsequent addition of portions 2-chloro-7-chinolinol (234 mg, 1.30 mmol, 1, 1, 1, 25 eq.). They added a drop of dietilazodicarboxylate (0.20 ml, 1.30 mmol, 1.25 EXVs) and the mixture was mixed at room temperature for 22 hours. Then the solution was concentrated to the minimum volume of in vacuo and the remainder was cleaned by means of column chromatography on silica gel (gradient elimination: N-geptan/etoac from 99: 1 to 1: 1). Collected fractions containing the product, and the solvent was evaporated with obtaining the necessaryintermediate connection 18(224 mg, 53% yield) as a colorless oil.

¹ H NMR (360 MHz, CDCl ₃ ): δ=8.00 (d, J=8.8 Hz, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.09-7 .33 (m, 3H), 4.92-5.01 (m, 1H), 4.91 (s, 1H), 4.68 (d, J=5.9 Hz, 1H), 4.59 ( d, J=5.9 Hz, 1H), 3.40 (s, 3H), 2.76-2.86 (m, 2H), 2.63-2.73 (m, 1H), 2.35 (dt, J=12.0, 1.9 Hz, 1H), 1.41 (s, 3H), 1.33 (s, 3H), 1.21-1.21 ppm (m, 1H)

¹³ C NMR (91 MHz, CDCl ₃ ): δ=159.3, 151.0, 149.5, 138.4, 128.6, 122.0, 120.4, 119.8, 112.3, 108 .3, 108.2, 85.6, 85.1, 83.5, 68.3, 54.9, 42.6, 36.9, 26.3, 25.3 ppm

Preparation of Intermediate 19

Intermediate 6 (250 mg, 1.09 mmol, 1.00 eq.) was dissolved in anhydrous THF (7.50 mL) and triphenylphosphine (342 mg, 1.30 mmol, 1.25 eq.) was added followed by portionwise addition of 3-bromo-7-quinolinol (292 mg, 1.30 mmol, 1, 25 eq.). Diethyl azodicarboxylate (0.20 ml, 1.30 mmol, 1.25 eq.) was added dropwise and the mixture was stirred at room temperature for 24 hours. The solution was then concentrated to the minimum volume in vacuo and the residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 99:1 to 1:1). Fractions containing the product were collected and the solvent was evaporated to give the desiredintermediate connection 19(270 mg, 57% yield) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ=8.79 (d, J=2.2 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.59 (d , J=8.6Hz, 1H), 7.14-7.23(m, 2H), 4.92-5.01(m, 1H), 4.89(s, 1H), 4.66( d, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 1H), 3.38 (s, 3H), 2.79 (dt, J=5.6, 1 .4 Hz, 1H), 2.62-2.72 (m, 2H), 2.35 (ddd, J=13.8, 3.7, 1.9 Hz, 1H), 1.40 (s, 3H), 1.31ppm(s, 3H)

¹³ C NMR (101 MHz; CDCl ₃ ): δ=158.6, 151.3, 147.8, 136.8, 128.0, 124.3, 121.2, 114.5, 112.3, 108 .9, 108.2, 85.6, 85.1, 83.6, 68.2, 54.9, 42.6, 37.0, 26.3, 25.3 ppm

Preparation of Intermediate 20

Intermediate 18 (218 mg, 0.557 mmol, 1.00 eq) was dissolved in CH ₃ CN (3.00 ml) and HCl (0.5 M in H ₂ O, 9.00 ml) was added. The solution was heated to 90°C for 2 hours and received a homogeneous solution. The mixture was concentrated in vacuo and co-evaporated with toluene to give a white solid which was directly dissolved in pyridine (6.00 ml) and acetic anhydride (3.00 ml) and stirred at room temperature for 3 hours. The mixture was concentrated to minimum volume in vacuo and co-evaporated with toluene to dryness. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 1:4). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 20 (130 mg, 50% yield over 2 steps) as a 4:1 mixture of β:α isomers.

Preparation of Intermediate 21

Intermediate 19 (268 mg, 0.615 mmol, 1.00 eq) was dissolved in CH ₃ CN (3.00 ml) and HCl (0.5 M in H ₂ O, 9.00 ml) was added. The solution was heated to 90°C for 2 hours and received a homogeneous solution. The mixture was concentrated in vacuo and co-evaporated with toluene to give a white solid which was directly dissolved in pyridine (6.00 ml) and acetic anhydride (3.00 ml) and stirred at room temperature for 3 hours. The mixture was concentrated to minimum volume in vacuo and co-evaporated with toluene to dryness. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 1:4). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 21 (200 mg, 64% yield over 2 steps) as a 4:1 mixture of β:α isomers.

Getting Compound 42

6-Chloropurine (49.4 mg, 0.320 mmol, 1.15 eq.) was added to an oven-dried vial and dissolved in CH ₃ CN (1.20 mL) followed by N,O-bis(trimethylsilyl)acetamide (0 .03 ml, 0.139 mmol, 0.50 eq.). The mixture was stirred for 30 minutes at room temperature and intermediate 20 (129 mg, 0.278 mmol, 1.00 eq.) dissolved in CH ₃ CN (1.80 ml) was added, followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (0. 03 ml, 0.139 mmol, 0.50 eq.). The solution was heated to 80°C for 2 hours, cooled to room temperature, diluted with EtOAc (20 ml) and added NaHCO ₃ (aq. sat., 15 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×20 ml). The combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give the desired compound 42 (164 mg, crude).

¹ H NMR (360 MHz, CDCl ₃ ): δ=8.80 (s, 1H), 8.20 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.28-7.30 (m, 1H), 7.11-7.23 (m, 3H), 6.36 (dd, J=6.4 , 4.6 Hz, 1H), 6.13 (d, J=6.2 Hz, 1H), 5.77-5.83 (m, 1H), 4.93 (dq, J=7.1, 3.6 Hz, 1H), 3.02 (ddd, J=13.6, 7.0, 3.5 Hz, 1H), 2.75-2.87 (m, 2H), 2.63-2 .73 (m, 1H), 2.18 (s, 3H), 2.02 ppm (s, 3H)

Getting Compound 43

6-Chloropurine (69.9 mg, 0.452 mmol, 1.15 eq.) was added to an oven-dried vial and dissolved in CH ₃ CN (1.50 mL) followed by N,O-bis(trimethylsilyl)acetamide (0 .05 ml, 0.197 mmol, 0.50 eq.). The mixture was stirred for 30 minutes at room temperature and intermediate 21 (200 mg, 0.393 mmol, 1.00 eq.) dissolved in CH ₃ CN (2.50 ml) was added, followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (0. 04 ml, 0.197 mmol, 0.50 eq.). The solution was heated to 80°C for 2 hours, cooled to room temperature, diluted with EtOAc (30 ml) and added NaHCO ₃ (aq. sat., 15 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×30 ml). The combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give the desired compound 43 (250 mg, crude).

¹ H NMR (360 MHz, CDCl ₃ ): δ=8.82-8.85 (m, 1H), 8.80 (s, 1H), 8.24 (d, J=1.8 Hz, 1H) , 8.20 (s, 1H), 7.66 (d, J=9.1 Hz, 1H), 7.16-7.24 (m, 2H), 6.35 (dd, J=6.2 , 4.8 Hz, 1H), 6.14 (d, J=6.2 Hz, 1H), 5.80 (d, J=4.4 Hz, 1H), 4.96 (dq, J=7 .1, 3.6 Hz, 1H), 3.03 (ddd, J=13.5, 6.8, 3.5 Hz, 1H), 2.65-2.94 (m, 3H), 2, 18(s, 3H), 2.02ppm(s, 3H)

Get Compound 5

Compound 42 (164 mg, crude) was dissolved in 1,4-dioxane (10.0 ml) and ammonia (30.0 ml, 25% in H ₂ O) was added. The mixture was heated to 125° C. in a pressure reactor for 3 days, cooled to room temperature and concentrated to minimum volume in vacuo. The residue was co-evaporated to dryness with toluene and purified by preparative SFC (stationary phase: Chiralpak Diacel AS 20×250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to give the desired compound 5 (12.9 mg , 11% yield over 2 steps from intermediate 20 )

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.34 (s, 1H), 8.16 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7 .51 (d, J=8.8 Hz, 1H), 7.26 (s, 2H), 6.75 (dd, J=8.6, 2.4 Hz, 1H), 6.67 (d, J=2.4Hz, 1H), 6.58(d, J=8.8Hz, 1H), 6.28-6.39(m, 2H), 5.90(d, J=6.8 Hz, 1H), 4.99 (dd, J=6.8, 4.2 Hz, 1H), 4.79-4.88 (m, 1H), 4.09 (d, J=4.2 Hz , 1H), 2.77 (ddd, J=13.2, 7.0, 3.5 Hz, 1H), 2.63-2.71 (m, 1H), 2.54 (dd, J=7 .2, 3.9Hz, 1H), 2.43ppm (dt, J=13.4, 3.8Hz, 1H)

¹³ C NMR (101 MHz, DMSO-d ₆ ): δ=158.5, 157.9, 156.0, 152.5, 149.6, 149.3, 140.2, 136.5, 128.6 , 119.4, 117.4, 112.7, 109.7, 106.6, 87.1, 83.3, 75.6, 72.5, 66.6, 41.2, 37.0 ppm

Getting Compound 6

Compound 43 (250 mg, crude) was dissolved in 1,4-dioxane (1.5 ml) and ammonia (4.5 ml, 25% in H ₂ O) was added. The mixture was heated to 80° C. in a pressurized reactor for 4 hours, cooled to room temperature and concentrated to minimum volume in vacuo. The residue was co-evaporated to dryness with toluene and purified by preparative SFC (stationary phase: Chiralpak Diacel AS 20×250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to give the desired compound 6 (113 mg, yield 58% from intermediate 21 ).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.85 (d, J=2.4 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.18-7.36 (m, 4H), 5.92 (d, J=6.8 Hz, 1H), 5.33-5.55 (m, 2H), 4.80-5.11 (m, 1H), 4.68-4.80 (m, 1H), 4 .12 (t, J=4.3 Hz, 1H), 2.85 (ddd, J=13.3, 7.0, 3.4 Hz, 1H), 2.69-2.76 (m, 1H ), 2.60 (ddd, J=13.6, 7.0, 3.4 Hz, 1H), 2.44-2.50 ppm (m, J=3.7, 3.7 Hz, 1H)

¹³ C NMR (101 MHz, DMSO-d ₆ ): δ=158.3, 156.0, 152.5, 151.0, 149.6, 147.4, 140.1, 137.0, 128.8 , 124.1, 120.7, 119.4, 114.0, 108.7, 87.2, 83.2, 75.5, 72.5, 67.3, 41.0, 36.9 ppm

Preparation of Intermediate 24

1-O-Methoxy-β-D-ribofuranose (25.3 g, 154 mmol, 1.00 eq.) was dissolved in pyridine (253 ml) and triphenylphosphine (44.4 g, 169 mmol, 1.10 equiv.). The solution was cooled to 0° C. and iodine (42.9 g, 169 mmol, 1.10 eq.) was added portionwise over a period of 40 minutes. The solution was cooled at 0°C for an additional 20 minutes after adding the reagents before stirring at room temperature for 24 hours. The reaction mixture was then cooled to 0° C. and pivaloyl chloride (43.5 ml, 354 mmol, 2.30 eq.) was added dropwise to the stirred mixture over a period of 1.5 hours using an addition funnel capable of leveling pressure. After adding the reagent, the mixture was warmed to room temperature and stirred for 22 hours. The mixture was concentrated to minimum volume in vacuo and co-evaporated with toluene (2×300 ml). n-Heptane (1 L) was added to the remaining brown slurry, resulting in the precipitation of triphenylphosphine oxides. The mixture was sonicated for 1 hour and the solid was filtered and washed with n-heptane (300 ml). The filtrate was concentrated in vacuo to a minimum volume to give a yellow syrup. The syrup was then redissolved in EtOAc (500 ml) and washed with sodium thiosulfate solution (aq. sat. 1×250 ml) and saline (1×250 ml). The organic phase was dried (MgSO₄), filtered, and the filtrate was concentrated in vacuo to giveintermediate connection 24 (49.0 g, crude yield 72%) which solidified upon standing at room temperature.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.27 (d, J=4.8 Hz, 1H), 5.20 (dd, J=6.3, 4.8 Hz, 1H), 4.85 (s, 1H), 4.24 (q, J=6.6Hz, 1H), 3.41 (s, 3H), 3.33 (dd, J=6.5, 4.9Hz, 2H) , 1.22(s, 9H), 1.21ppm(s, 9H)

¹³C NMR (101 MHz, CDCl₃) Δ 177.0, 176.8, 106.1, 80.3, 75.2, 74.9, 55.3, 38.8, 38.6, 27.1, 6.7 PPM

Preparation of Intermediate 25

Intermediate 24 (47.8 g, 108 mmol, 1.00 eq.) was dissolved in DMF (500 ml) and DBU (17.8 ml, 119 mmol, 1.10 eq.) was immediately added to the stirred mixture, which was heated to 90 ° C for 18 hours. The mixture was cooled to room temperature and concentrated in vacuo to about 250 ml. The brown solution was then diluted in n-heptane (1.5 L) and washed with brine (3 x 750 ml). The resulting organic phase was dried (MgSO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 99:1 to 9:1). Fractions containing the product were collected and the solvent was evaporated to give the desiredIntermediate 25(30.2 g, 96.1 mmol, 89% yield) as a colorless liquid.

¹ H NMR (360 MHz, CDCl ₃ ) δ 5.76 (dt, J=5.1, 1.9 Hz, 1H), 5.16 (d, J=5.1 Hz, 1H), 5.02 (s, 1H), 4.51 (t, J=1.8 Hz, 1H), 4.08 (t, J=2.0 Hz, 1H), 3.46 (s, 3H), 1.23 (s, 9H), 1.21 ppm (s, 9H)

¹³C NMR (101 MHz, CDCl₃) δ 177.3, 177.2, 157.2, 106.2, 84.6, 73.2, 69.7, 56.3, 39.1, 39.0, 27.4, 27.3 ppm

Preparation of Intermediate 26

Zinc powder (25.0 g, 0.38 mol, 1.00 eq.) was added to a two-necked round bottom flask (500 ml) containing demineralized water (100 ml) and the solution was degassed with nitrogen for 15 minutes. Copper(II) sulfate (1.85 g, 11.5 mmol, 0.03 eq) was then added and the stirred solution was degassed and stirred for 45 minutes. The mixture was filtered and the black solids were washed with degassed water (250 ml) and degassed acetone (250 ml) in that order. The zinc-copper pair was dried in vacuo for 12 hours. Intermediate 25 (10.0 g, 31.8 mmol, 1.00 eq.) was weighed into an oven-dried flask and dissolved in anhydrous diethyl ether (300 ml, dried over 4Å molecular sieves). Zinc-copper pair (14.6 g, 223 mmol, 7.00 eq.) was then immediately added to the stirred diethyl ether solution. An oven-dried dropping funnel equipped with pressure equalization was installed and anhydrous diethyl ether (100 ml) and trichloroacetyl chloride (6.10 ml, 54.1 mmol, 1.70 eq.) were placed in it. The reagent was added dropwise over a period of 2.5 hours and the temperature was carefully controlled so that it did not exceed 25°C. Upon completion of the addition, the zinc-copper pair was decanted, rinsed with diethyl ether (100 ml) and the organic layer was diluted with n-heptane (500 ml) before it was washed with NaHCO ₃ (aq. sat. 3×300 ml) and brine ( 2×250 ml). The organic phase was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo at 40°C to obtain intermediate compound 26 (13.2 g, crude).

¹ H NMR (360 MHz, CDCl ₃ ) δ 5.84 (d, J=4.0 Hz, 1H), 5.35 (d, J=4.4 Hz, 1H), 4.98 (s, 1H ), 3.92 (d, J=18.7 Hz, 1H), 3.51 (s, 1H), 3.40 (d, J=18.7 Hz, 1H), 1.19 ppm (s, 18H)

¹³ C NMR (91 MHz, CDCl ₃ ) δ 191.0, 176.3, 175.4, 106.0, 91.4, 83.2, 74.6, 71.2, 55.9, 52.0 , 38.5, 26.8ppm

Preparation of Intermediate 27

Intermediate 26 (2.64 g, 6.21 mmol, 1.00 eq) was dissolved in THF (45.0 ml), acetic acid (5.33 ml, 93.1 mmol, 15.0 eq) was added) followed by portionwise addition of zinc powder (4.06 g, 62.1 mmol, 10.0 eq.) and the mixture was heated to 50° C. for 5 hours. The solution was then cooled to room temperature and filtered through celite. The filtrate was concentrated to minimum volume in vacuo, redissolved in EtOAc (200 ml), washed with brine (2×75 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 99:1 to 1:1). Fractions containing product were collected and the solvent was evaporated to give the desired intermediate 27 (1.48 g, 4.16 mmol, 67% yield) as a colorless oil.

¹ H NMR (360 MHz, CDCl ₃ ) δ 5.56 (d, J=4.4 Hz, 1H), 5.26 (dd, J=4.4, 0.7 Hz, 1H), 4.91 (s, 1H), 3.43-3.51 (m, 2H), 3.42 (s, 3H), 3.33-3.41 (m, 1H), 3.14-3.25 (m , 1H), 1.22(s, 9H), 1.21ppm(s, 9H)

¹³C NMR (101 MHz, CDCl₃) δ 203.2, 177.2, 176.8, 105.7, 75.7, 75.1, 74.0, 58.3, 55.7, 55.5, 39.0, 38.8, 27.1ppm

Preparation of Intermediate 28

Intermediate 27 (1.04 g, 2.92 mmol, 1.00 eq) was dissolved in MeOH (20 ml) and water (5 ml) was added. The mixture was cooled to -20° C. and sodium borohydride (110 mg, 2.92 mmol, 1.00 eq.) was added portionwise. The mixture was stirred for 1 hour at -20°C and then warmed to room temperature, diluted in EtOAc (100 ml). Saline solution (40 ml) was added and the product was extracted into EtOAc (3×100 ml). The combined organic fractions were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give intermediate 28 (1.06 g, crude, 4:1 mixture of diastereoisomers).

Preparation of Intermediate 29

Intermediate 28 (4.00 g, 11.4 mmol, 1.00 eq) was dissolved in pyridine (50 ml) and cooled to 0°C. Benzoyl chloride (1.58 ml, 13.6 mmol, 1.20 eq.) was then added dropwise over a period of 5 minutes and the mixture was stirred for 3 hours at room temperature. The solution was concentrated in vacuo to minimum volume, redissolved in EtOAc (500 ml) and brine (150 ml) was added. The product was extracted into EtOAc (1×500 ml, 2×250 ml), the combined organic phases were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 99:1 to 4:1). Fractions containing intermediate 29 were collected and the solvent was evaporated to give intermediate 29 (3.52 g, 7.62 mmol, 68% yield) as a colorless oil.

¹ H NMR (360 MHz, CDCl ₃ ) δ 8.03 (dd, J=8.5, 1.2 Hz, 2H), 7.51-7.61 (m, 1H), 7.39-7, 48 (m, 2H), 5.37 (d, J=4.4 Hz, 1H), 5.20 (dd, J=4.4, 1.3 Hz, 1H), 4.78-4.88 (m, 2H), 3.40 (s, 3H), 3.10 (dt, J=12.9, 6.3 Hz, 1H), 2.89 (dt, J=12.9, 6.4 Hz, 1H), 2.73 (dd, J=13.0, 7.3 Hz, 1H), 2.44 (dd, J=12.9, 7.4 Hz, 1H), 1.28 (s , 9H), 1.21 ppm (s, 9H)

¹³ C NMR (101 MHz, CDCl ₃ ) δ 117.2, 177.0, 166.0, 133.0, 129.9, 129.6, 128.4, 105.4, 77.6, 75.1 , 74.5, 61.5, 55.3, 43.2, 40.2, 39.1, 38.8, 27.3, 27.1ppm

Preparation of Intermediate 30

Intermediate 28 (2.28 g, 6.36 mmol, 1.00 eq) was dissolved in THF (60 mL) and benzoic acid (932 mg, 7.63 mmol, 1.20 eq) was added followed by triphenylphosphine (2.01 g, 7.63 mmol, 1.20 eq.). The mixture was cooled to 0° C. and diethyl azodicarboxylate (1.15 ml, 7.31 mmol, 1.20 eq.) was added. After the addition, the mixture was warmed to room temperature and stirred for 16 hours, followed by the addition of pentane (120 ml) to precipitate the triphenylphosphine oxides. The solids were filtered off and rinsed with heptane (30 ml). Saline solution (50 ml) was added to the filtrate and the product was extracted into heptane (1×150 ml, 2×100 ml). The combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 99:1 to 4:1). Fractions containing intermediate 30 were collected and the solvent was evaporated to give intermediate 30 (1.79 g, 3.88 mmol, 61% yield) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98-8.04 (m, 2H), 7.52-7.60 (m, 1H), 7.39-7.47 (m, 2H), 5.44 (m, 1H), 5.37 (d, J=4.4 Hz, 1H), 5.18 (dd, J=4.4, 1.5 Hz, 1H), 4.88 (d , J=1.5 Hz, 1H), 3.42 (s, 3H), 2.81 (ddd, J=13.4, 7.5, 4.4 Hz, 1H), 2.62-2, 72 (m, 2H), 2.52-2.62 (m, 1H), 1.21 (s, 9H), 1.20 ppm (s, 9H)

¹³ C NMR (101 MHz, CDCl ₃ ) δ 177.2, 177.0, 166.1, 133.0, 130.0, 129.6, 128.4, 105.7, 81.1, 75.1 , 74.3, 65.5, 55.4, 41.3, 39.3, 39.0, 38.8, 27.2, 27.1ppm

Preparation of Intermediate 31

6-Chloropurine (76.9 mg, 0.497 mmol, 1.15 eq.) was weighed into an oven-dried microwave vial and dissolved in anhydrous acetonitrile (1.00 mL, dried over 3Å molecular sieves) . The vial was sealed, N,O-bis(trimethylsilyl)acetamide (0.084 ml, 0.324 mmol, 0.75 eq.) was added and the mixture was stirred at room temperature for 45 minutes. Intermediate 29 (200 mg, 0.432 mmol, 1.00 eq) was then dissolved in anhydrous acetonitrile (1.75 ml) and added to the stirred mixture of silylated purine base. TMSOTf (0.06 ml, 0.303 mmol, 0.70 eq.) was added dropwise at room temperature to the mixture, which was heated to 90° C. for 5 hours. The mixture was cooled to room temperature and diluted in CH ₂ Cl ₂ (50 ml). NaHCO ₃ (aq. sat., 20 ml) was added and the product was extracted into CH ₂ Cl ₂ (2×50 ml, 1×30 ml). The combined organic fractions were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 1:4). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 31 (240 mg, 0.410 mmol, 95% yield) as a white foam.

Preparation of Intermediate 76

Intermediate 76 was prepared according to the same reaction protocol as described for intermediate 31. Intermediate 76: 71% yield, 525 mg, 1.09 mmol, off-white foam.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.77 (s, 1H), 8.20 (s, 1H), 6.19 (dd, J= 5.7, 4.5 Hz, 1H), 6.09 (d, J= 5.7 Hz, 1H), 5.72 (d, J= 4.5 Hz, 1H), 4.96 (dt, J= 4.8, 2.3 Hz, 2H ), 3.10-3.25 (m, 2H), 2.96-3.10 (m, 2H), 1.31 (s, 9H), 1.14 ppm (s, 9H).

¹³ C NMR (101 MHz, CDCl ₃ ): δ 176.9, 152.2, 151.5, 151.3, 143.9, 143.9, 137.2, 132.6, 108.8, 87, 4, 82.8, 74.1, 73.3, 44.3, 40.4, 39.2, 38.8, 27.3, 27.0 ppm.

Preparation of Intermediate 32

6-Chloropurine (154 mg, 0.994 mmol, 1.15 eq.) was weighed into an oven-dried microwave vial and dissolved in anhydrous acetonitrile (2.00 mL, dried over 3Å molecular sieves). The vial was sealed, N,O-bis(trimethylsilyl)acetamide (0.16 ml, 0.648 mmol, 0.75 eq.) was added and the mixture was stirred at room temperature for 45 minutes. Intermediate 30 (400 mg, 0.864 mmol, 1.00 eq) was then dissolved in anhydrous acetonitrile (3.50 mL) and added to the stirred mixture of silylated purine base. TMSOTf (0.11 ml, 0.606 mmol, 0.70 eq.) was added dropwise at room temperature to the mixture, which was heated to 90°C for 4 hours. The mixture was cooled to room temperature and diluted in CH ₂ Cl ₂ (100 ml). NaHCO ₃ (aq. sat., 50 ml) was added and the product was extracted into CH ₂ Cl ₂ (3×100 ml). The combined organic fractions were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 95:5 to 1:4). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 32 (460 mg, 0.786 mmol, 91% yield) as a white foam.

Obtaining Compound 7

Intermediate 31 (320 mg, 0.547 mmol, 1.00 eq.) was dissolved in 1,4-dioxane (2.00 ml) and NH ₃ (8.00 ml, 25% in H ₂ O) was added. The mixture was heated to 75° C. for 24 hours in a pressure reactor, then cooled to room temperature and concentrated in vacuo followed by co-evaporation with toluene (3 x 70 ml). Then the solids were washed with CH ₃ CN with stirring for 1 hour, followed by centrifugation and decantation of the solvent. This procedure was repeated three times to remove impurities from the protective groups. The resulting solids were dried in vacuo at 50° C. for 18 hours to give compound 7 (153 mg, 80% yield) as a white powder.

¹ H NMR (500 MHz, MeOD) δ 8.40 (s, 1H), 8.38 (s, 1H), 6.00 (d, J=6.7 Hz, 1H), 4.96 (t, J=5.3Hz, 1H), 4.03(d, J=4.0Hz, 1H), 3.92(quin., J=7.1Hz, 1H), 2.98(dt, J =12.3, 6.1 Hz, 1H), 2.70 (dt, J=12.2, 6.1 Hz, 1H), 2.25 (dd, J=10.7, 6.5 Hz, 1H), 2.07ppm (dd, J=10.9, 6.6Hz, 1H)

¹³ C NMR (125 MHz, MeOD) δ 152.8, 150.5, 146.5, 143.9, 120.9, 89.8, 80.7, 76.7, 75.6, 59.0, 46.6, 41.7ppm

Preparation of Intermediate 77

Intermediate 77 was prepared according to a reaction protocol similar to that described for the synthesis of intermediate 7. Intermediate 77: 90% yield, 270 mg, 0.789 mmol, off-white salt (containing 1 eq. NH₄Cl).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.31 (s, 1H), 8.15 (s, 1H), 5.85-5.94 (m, 1H), 5.47 ( br s, 2H), 5.05 (br s, 1H), 4.87 (br d, J= 1.6 Hz, 2H), 3.98 (br d, J= 3.7 Hz, 1H), 3.13 (br d, J= 15.9 Hz, 1H), 2.89 (br d, J= 2.0 Hz, 2H), 2.69 ppm (br dd, J= 16.3, 2, 4 Hz, 1H).

Getting connection 8

Intermediate 32 (340 mg, 0.581 mmol, 1.00 eq.) was dissolved in 1,4-dioxane (2.00 ml) and NH ₃ (8.00 ml, 25% in H ₂ O) was added. The mixture was heated to 75° C. for 24 hours in a pressure reactor, then cooled to room temperature and concentrated in vacuo followed by co-evaporation with toluene (3 x 70 ml). Then the solids were washed with CH ₃ CN with stirring for 1 hour, followed by centrifugation and decantation of the solvent. This procedure was repeated three times to remove impurities from the protective groups. The resulting solids were dried in vacuo at 50° C. for 18 hours to give compound 8 (169 mg, 84% yield) as a white powder.

¹ H NMR (500 MHz, MeOD) δ 8.42 (s, 1H), 8.37 (s, 1H), 6.02 (d, J=6.3 Hz, 1H), 4.90 (dd, J=5.4, 3.6Hz, 1H), 4.37(m, 1H), 4.21(d, J=4.5Hz, 1H), 2.64(dt, J=12.3 , 6.5 Hz, 1H), 2.70 (ddd, J=13.3, 5.5, 3.1 Hz, 1H), 2.40 (m, 1H), 2.23 ppm (ddd, J =12.9, 5.3, 3.1 Hz, 1H)

¹³C NMR (125 MHz, MEOD) δ 153.0, 150.3, 147.0, 143.9, 120.8, 90.1, 85.7, 77.2, 75.4, 62.7, 44.6 .40.8ppm

Preparation of Intermediate 33

A 4:1 mixture of compounds 7 and 8 (500 mg, 1.44 mmol, 1.00 eq.) (prepared by reaction protocol similar to that used for intermediate 29) was suspended in acetone (75 ml) and immediately added 4-methylbenzenesulfonic acid (2.74 g, 14.4 mmol, 10.0 eq.) in one portion. The yellow mixture was stirred for 4 hours at room temperature before adding an ice-cold solution of NaHCO ₃ (aq. sat. 45 ml). The solution was concentrated to a minimum volume, co-evaporated with toluene to dryness, followed by the addition of acetone (50 ml). The suspension was stirred for 17 hours at room temperature and then filtered to remove salts. The filtrate was concentrated to the minimum volume in vacuo. The residue was purified by silica gel column chromatography (gradient elution: CH ₂ Cl ₂ /MeOH from 100:0 to 7:3). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 33 (264 mg, 52% yield) as a white solid.

Preparation of Intermediate 78

Intermediate 78 was prepared according to the same reaction protocol as described for intermediate 33. Intermediate 78: 90% yield, 475 mg, 1.38 mmol, yellow sticky solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.32 (s, 1H), 7.86 (s, 1H), 6.15 (br. s. 2H), 6.04 (s, 1H, 1 '), 5.87 (d, J=5.9 Hz, 1H, 2'), 5.07 (d, J=5.9 Hz, 1H, 3'), 4.88 (quin, J=2 .4 Hz, 1H, -CH ₂ ), 4.80 (quin, J=2.4 Hz, 1H, -CH ₂ ), 3.22 (ddq, J=16.4, 4.3, 2.2 Hz, 1H), 2.98 (dq, J=16.4, 2.8 Hz, 1H), 2.76 (ddq, J=15.8, 4.2, 2.7 Hz, 1H), 2 .35 (dq, J=15.8, 2.7 Hz, 1H), 1.54 (s, 3H), 1.43 ppm (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ): δ 155.8, 153.0, 149.3, 140.4, 139.1, 120.0, 113.3, 107.9, 90.9, 85, 4, 85.3, 84.0, 45.3, 39.9, 27.6, 26.6, 25.4 ppm.

Preparation of Intermediate 34

Intermediate 33 (160 mg, 0.45 mmol, 1.00 eq.) was dissolved in DMF (1.60 ml) and N,N-dimethylformamide dimethyl acetal (0.25 ml, 1.81 mmol, 4.00 eq. .). The mixture was stirred at 70° C. for 4 hours and then concentrated in vacuo by co-evaporation with toluene to give intermediate 34 (218 mg, crude).

Preparation of Intermediate 35

Intermediate 34 (218 mg, crude) was dissolved in anhydrous THF (4.00 mL) and triphenylphosphine (477 mg, 1.80 mmol, 4.00 eq) and 3-chloroquinolin-7-ol (162 mg, 0 .90 mmol, 2.00 eq.). Diethyl azodicarboxylate (0.28 ml, 1.80 mmol, 4.00 eq.) was added dropwise and the mixture was stirred at room temperature for 24 hours. The mixture was concentrated to minimum volume in vacuo to give intermediate 35, which was used without purification in the next step.

Preparation of Intermediate 36

Intermediate 35 (crude, from previous step) was dissolved in NH ₃ (7 M in MeOH) (50 ml, 7 M) and heated to 35° C. for 20 hours. The mixture was concentrated to a minimum volume in vacuo and the residue was purified by column chromatography on silica gel (gradient elution: CH ₂ Cl ₂ /MeOH from 1:0 to 7:3). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 36 (179 mg, LC purity 70%). Intermediate 36 was used as received in the next step.

Preparation of Compound 9 and Compound 10

Intermediate 36 (179 mg, crude) was dissolved in EtOH (4.00 ml) and HCl (aq. 1 M in H ₂ O, 16.0 ml) was added. The mixture was stirred for 1 hour at 60°C and then cooled to room temperature, diluted with H ₂ O (50 ml) and lyophilized. The resulting brown powder was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50×150 mm, mobile phase: 0.25% solution of NH ₄ HCO ₃ in water, CH ₃ CN) followed by purification by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm; mobile phase: CO ₂ , EtOH+0.4% iPrNH ₂ ). Pure fractions were combined and concentrated in vacuo to give compound 9 (2.4 mg, mmol, major isomer, 1% overall yield over 4 steps) and compound 10 (0.6 mg, mmol, minor isomer).

Preparation of Intermediate 37

Acetylacetonatobis(ethylene)rhodium(I) (837 mg, 3.24 mmol, 0.02 eq) and (R)-N,N-dimethyldinaphtho[2,1-D:1',2'-F][1 ,3,2]dioxaphosphepin-4-amine (2.91 g, 8.11 mmol, 0.05 eq.) was dissolved in EtOH (625 ml) under nitrogen atmosphere. The mixture was stirred at room temperature and purged with nitrogen gas for 15 minutes. Then (-)-(3AR,6AR)-3A,6A-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25.0 g, 162.16 mmol, 1, 00 eq.) and potassium vinyl trifluoroborate (45.7 g, 324 mmol, 2.00 eq.) and 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 off through a Celite pad and washed with ethanol. Solvents were evaporated from the filtrate. n-heptane was added to the residue, the resulting suspension was filtered through a pad of celite and washed with heptanes to give the residue as a dark brown solid. The filtrate was washed with NH ₄ OH (3 x 300 ml), washed with brine, dried with MgSO ₄ , filtered and the filtrate was evaporated to give intermediate 37 (16.2 g, crude yield 51%).

Preparation of Intermediate 38

A solution of intermediate 37 (16.2 g, 82.6 mmol, 1.00 eq.) in THF (200 ml) was added dropwise to a stirred solution of lithium aluminum hydride (24.8 ml, 1 M in THF, 24.8 mmol , 0.30 eq.) in THF (400 ml) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at -78° C. under nitrogen for 30 minutes. The reaction was quenched by adding dropwise acetone (6.1 ml) followed by water (50 ml) at -78°C. Upon completion of the addition, the reaction mixture was warmed to room temperature and EtOAc (400 ml) was added. The mixture was intensively stirred. The organic layer was separated, washed three times with water, washed with brine, dried (MgSO ₄ ), filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 1:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 38 (10.7 g, 71% yield).

Preparation of Intermediate 39

Intermediate 38 (3.10 g, 16.6 mmol, 1.00 eq.) was dissolved in pyridine (10.3 ml) and tert-butyldimethylsilyl chloride (2.88 g, 19.1 mmol, 1.15 eq. .) at room temperature. The mixture was stirred for 17 hours at room temperature and diluted in EtOAc (250 ml). The organic layer was washed with brine (4×80 ml), dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 7:3). Fractions containing product were collected and the solvent was evaporated to give the desired intermediate 39 (3.15 g, 63% yield) as a light yellow oil.

Preparation of Intermediate 40

Intermediate 39 (20.1 g, 43.8 mmol, 1.00 eq.) was dissolved in CH ₂ Cl ₂ (400 ml) and the mixture was cooled to -78°C. Ozone was generated from oxygen gas using an ozone generator (Fischer OZ500/5) and bubbled into the cooled solution through a glass pipette. After 1.5 hours a blue color was observed and ozone was added at -78°C for an additional 20 minutes. The mixture was then purged with nitrogen for 5 minutes (disappearance of the blue color) and dimethyl sulfide (25.7 ml, 350 mmol, 8.00 eq.) was added at -78°C. The flow of nitrogen gas was stopped and the mixture was stirred for 1 hour while ensuring the temperature rise to -40°C. The mixture was concentrated in vacuo at 30°C to a minimum volume and the resulting yellow oil was redissolved in methanol (220 ml) and water (110 ml). The solution was cooled to 0° C. and sodium borohydride (19.8 g, 526 mmol, 12.0 eq.) was added portionwise. The ice bath was removed after 1.5 hours and stirring was continued at room temperature. After 4 hours of stirring, the mixture was diluted in CH ₂ Cl ₂ (350 ml) and NH ₄ Cl (aq. sat., 150 ml) was added. The product was extracted into CH ₂ Cl ₂ (3×350 ml) and the combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing product were collected and the solvent was evaporated to give the desired intermediate 40 (8.30 g, 63% yield) as a light yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ=4.37-4.42 (m, 2H), 4.10-4.15 (m, 1H), 3.55-3.62 (m, 1H ), 3.45-3.53 (m, 1H), 2.16-2.26 (m, 1H), 2.01 (dt, J=12.7, 8.2 Hz, 1H), 1, 86 (br s, 1H), 1.57-1.66 (m, 1H), 1.49 (s, 3H), 1.31 (s, 3H), 0.91 (s, 9H), 0. 09ppm (d, J=2.9Hz, 6H)

¹³ C NMR (101 MHz, CDCl ₃ ): δ=111.7, 82.0, 80.9, 72.7, 64.3, 44.7, 34.4, 26.5, 26.0, 24 .9, 18.4, -4.5ppm

Preparation of Intermediate 41

Intermediate 40 (8.30 g, 27.4 mmol, 1.00 eq) was dissolved in THF (140 mL). Imidazole (4.67 g, 68.6 mmol, 2.50 eq.) and triphenylphosphine (8.03 g, 29.1 mmol, 1.05 eq.) were added followed by portionwise addition of iodine (8.79 g, 34 .3 mmol, 1.25 eq.) at room temperature. After 1 hour additional triphenylphosphine (2.29 g, 8.31 mmol, 0.30 eq) and iodine (2.46 g, 9.60 mmol, 0.35 eq) were added. The reaction was allowed to continue for 2 hours, then the mixture was concentrated to the minimum volume in vacuo and n-heptane (400 ml) was added. Triphenylphosphine oxides precipitated and the mixture was sonicated for 30 minutes. The organic layer was separated by filtration and the solids were rinsed with n-heptane (100 ml). Sodium thiosulfite (aq. sat. 150 ml) was added to the filtrate and the product was extracted into n-heptane (3×400 ml). The combined organic fractions were dried (MgSO ₄ ), filtered, and the filtrate was concentrated in vacuo to give intermediate 41 (9.84 g, calculated by H-NMR yield 87%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ=4.29-4.39 (m, 1H), 4.21 (dd, J=6.1, 2.4 Hz, 1H), 4.05 ( dt, J=7.8, 5.0 Hz, 1H), 2.97-3.15 (m, 2H), 2.22-2.38 (m, 1H), 1.96 (dt, J= 13.0, 7.7 Hz, 1H), 1.56 (dt, J=13.0, 5.3 Hz, 1H), 1.40 (s, 3H), 1.23 (s, 3H), 0.82 (s, 9H), 0.00ppm (d, J=2.4Hz, 6H)

Preparation of Intermediate 42

Intermediate 41 (9.84 g, 23.9 mmol, 1.00 eq) was dissolved in THF (168 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.35 mL, 35.8 mmol, 1.50 eq.). The mixture was heated to 65°C for 2.5 hours, then cooled to room temperature. The precipitated DBU salts were filtered and rinsed with THF and the filtrate was concentrated to the minimum volume in vacuo. Then n-heptane (400 ml) and brine (100 ml) were added and the product was extracted into n-heptane (3×400 ml). The combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 1:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 42 (6.00 g, 77% yield over 2 steps) as a colorless liquid.

¹ H NMR (400 MHz, CDCl ₃ ): δ=5.14-5.20 (m, 1H), 5.11 (dd, J=2.6, 1.0 Hz, 1H), 4.62 ( d, J=5.7 Hz, 1H), 4.46 (t, J=5.1 Hz, 1H), 3.90 (ddd, J=11.2, 6.5, 4.7 Hz, 1H ), 2.67 (ddtd, J=13.9, 11.1, 2.7, 1.2 Hz, 1H), 2.29-2.35 (m, 1H), 1.50 (s, 3H ), 1.35 (s, 3H), 0.92 (s, 9H), 0.11 ppm (d, J=2.8Hz, 6H)

¹³ C NMR (101 MHz, CDCl ₃ ): δ=145.6, 113.6, 111.2, 80.8, 80.4, 72.3, 37.5, 26.4, 26.0, 24 .7, 18.4, -4.5ppm

Preparation of Intermediate 43

Zinc powder (25.0 g, 0.38 mol, 1.00 eq.) was added to a two-necked round bottom flask (500 ml) containing demineralized water (100 ml) and the solution was degassed with nitrogen for 15 minutes. Copper(II) sulfate (1.85 g, 11.5 mmol, 0.03 eq) was then added and the stirred solution was degassed and stirred for 45 minutes. The mixture was filtered and the black solids were washed with degassed water (250 ml) and degassed acetone (250 ml) in that order. The zinc-copper pair was dried in vacuo for 12 hours. Intermediate 42 (2.50 g, 8.79 mmol, 1.00 eq) was dissolved in anhydrous Et ₂ O (70 ml, dried over 4Å molecular sieves) and zinc-copper couple (7.93 g , 61.5 mmol, 7.00 eq.). Trichloroacetyl chloride (2.94 ml, 26.4 mmol, 3.00 eq) was dissolved in anhydrous Et ₂ O (20 ml), filled into a glass syringe and added dropwise at room temperature at a rate of 6.5 ml/h. After 3 hours, the zinc-copper pair was removed by decantation, the organic layer was diluted in Et ₂ O (500 ml) and washed with NaHCO ₃ (aq. sat. 3×150 ml) and brine (3×150 ml), dried ( MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give intermediate 43 (3.36 g, crude).

¹ H NMR (400 MHz, CDCl ₃ ): δ=4.79 (dd, J=5.8, 1.0 Hz, 1H), 4.55 (t, J=5.3 Hz, 1H), 4 .11 (dt, J=9.8, 5.1Hz, 1H), 3.65 (d, J=18.3Hz, 1H), 3.12 (d, J=18.3Hz, 1H) , 2.36 (dd, J=12.9, 5.4Hz, 1H), 2.15 (dd, J=12.9, 9.8Hz, 1H), 1.48 (s, 3H), 1.37 (s, 3H), 0.91-0.93 (m, 9H), 0.12ppm (d, J=2.2Hz, 6H)

¹³ C NMR (CHLOROFORM-d, 101 MHz): δ=191.8, 112.3, 80.7, 80.1, 71.5, 51.7, 26.1, 25.9, 18.4, - 4.6, -4.9ppm

Preparation of Intermediate 44

Intermediate 43 (1.25 g, 3.16 mmol, 1.00 eq) was dissolved in THF (30 ml) and zinc (2.07 g, 31.6 mmol, 10.0 eq) and acetic acid were added (1.45 ml, 25.3 mmol, 8.00 eq.). The mixture was heated to 70°C for 6 hours and then cooled to room temperature. The mixture was filtered through celite, the solids were rinsed with THF and the filtrate was concentrated to minimum volume in vacuo. The oil was then redissolved in CH ₂ Cl ₂ (100 ml) and brine (50 ml) was added. The product was extracted into CH ₂ Cl ₂ (3×100 ml) and the combined organic fractions were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 2:3). Fractions containing product were collected and the solvent was evaporated to give the desired intermediate 44 (0.648 mg, 63% yield over 2 steps) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ=4.49 (t, J=5.1 Hz, 1H), 4.29-4.34 (m, 1H), 3.88 (dt, J= 10.9, 5.3 Hz, 1H), 3.36 (ddd, J=18.3, 4.1, 2.4 Hz, 1H), 2.89-2.99 (m, 1H), 2 .79-2.87 (m, 1H), 2.68-2.75 (m, 1H), 2.19 (t, J=11.4 Hz, 1H), 1.82 (dd, J=11 .8, 5.7Hz, 1H), 1.58(s, 1H), 1.48(s, 3H), 1.34(s, 3H), 0.90-0.94(m, 9H) , 0.11ppm (d, J=2.8Hz, 6H)

¹³ C NMR (101 MHz, CDCl ₃ ): δ=206.0, 111.1, 85.2, 80.2, 72.3, 56.7, 52.8, 41.3, 34.4, 26 .0, 26.0, 24.5, 18.4, -4.4, -4.7ppm

Preparation of Intermediate 45

Intermediate 44 (600 mg, 1.84 mmol, 1.00 eq) was dissolved in methanol (20.0 ml) and cooled to 0°C. Sodium borohydride (282 mg, 7.35 mmol, 4.00 eq.) was added portionwise and the mixture was stirred for 1 hour at 0°C. The solution was concentrated to minimum volume in vacuo, dissolved in CH ₂ Cl ₂ (100 ml) and NH ₄ Cl (sat. aq., 50 ml) was added. The product was extracted into CH ₂ Cl ₂ (3×100 ml) and the combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give intermediate 45 (515 mg, 85% yield) as a 1:1 mixture .

Preparation of Intermediate 46a and Intermediate 46b

Intermediate 45 (300 mg, 0.913 mmol, 1.00 eq) was dissolved in THF (6.00 ml) and triphenylphosphine (290 mg, 1.10 mmol, 1.20 eq), 7-hydroxyquinoline (159 mg , 1.10 mmol, 1.20 eq.) and diethyl azodicarboxylate (0.17 ml, 1.10 mmol, 1.20 eq.), resulting in a homogeneous solution. The mixture was stirred for 17 hours at room temperature, then concentrated to a minimum volume in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing product were collected and the solvent was evaporated to give the desired intermediate 46a (170 mg, 41% yield) and intermediate 46b (134 mg, 32% yield).

¹ H NMR of intermediate 46a (400 MHz, CDCl ₃ ): δ=8.68 (dd, J=4.4, 1.8 Hz, 1H), 7.93 (dd, J=8.3, 1, 4 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.12-7.15 (m, 1H), 7.11 (s, 1H), 7.07-7, 14 (m, 1H), 7.04 (dd, J=8.8, 2.4 Hz, 1H), 4.72 (quin, J=6.8 Hz, 1H), 4.25 (t, J =5.1 Hz, 1H), 4.14 (d, J=5.3 Hz, 1H), 3.76 (dt, J=10.9, 5.6 Hz, 1H), 2.31-2 .44 (m, 2H), 2.17-2.31 (m, 1H), 1.85-1.94 (m, 2H), 1.70 (dd, J=11.8, 5.6 Hz , 2H), 1.31 (s, 3H), 1.18 (s, 3H), 0.81 (s, 9H), 0.00 ppm (s, 6H)

¹³ C NMR of intermediate 46a (101 MHz, CDCl ₃ ): δ=158.4, 150.5, 149.9, 135.7, 128.9, 123.5, 120.2, 119.0, 110, 6, 108.8, 87.1, 79.8, 72.1, 68.8, 41.5, 40.7, 37.0, 35.9, 26.1, 24.6, 18.5, -4.4, -4.5ppm

¹ H NMR of intermediate 46b (400 MHz, CDCl ₃ ): δ=8.73 (dd, J=4.3, 1.7 Hz, 1H), 7.97 (dd, J=8.1, 1, 5 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.18 (s, 1H), 7.14-7.22 (m, 1H), 7.08 (dd, J=8.8, 2.4Hz, 1H), 4.75(quin, J=6.9Hz, 1H), 4.36(t, J=5.2Hz, 1H), 4.18( s, 1H), 3.74 (dt, J=10.9, 5.4Hz, 1H), 2.84 (ddd, J=12.2, 7.2, 4.8Hz, 1H), 2 .37 (ddd, J=11.7, 6.8, 4.8 Hz, 1H), 2.09 (dd, J=12.4, 6.9 Hz, 1H), 1.90-1.99 (m, 1H), 1.87-1.97 (m, 1H), 1.66 (dd, J=11.7, 5.7 Hz, 1H), 1.39 (s, 3H), 1, 27 (s, 3H), 0.82 (s, 9H), 0.00ppm (d, J=3.1Hz, 6H)

¹³ C NMR of intermediate 46b (101 MHz, CDCl ₃ ): δ=158.3, 150.6, 149.9, 135.6, 128.9, 123.5, 120.0, 119.0, 110, 8, 109.0, 85.1, 80.1, 71.7, 68.4, 43.0, 40.8, 37.3, 34.8, 26.1, 26.0, 24.6, 18.5, -4.4, -4.6ppm

Preparation of Intermediate 47

Intermediate 46a (170 mg, 0.37 mmol, 1.00 eq) was dissolved in THF (5.00 ml) and tert-butylammonium fluoride (1.49 ml, 1 M in THF) was added. The mixture was stirred for 1 hour at room temperature and concentrated to minimum volume in vacuo. The residue was dissolved in EtOAc (50 ml) and washed with NaHCO ₃ (1×25 ml) and brine (3×25 ml). The organic layer was dried (MgSO ₄ ), filtered and the filtrate was concentrated to a minimum volume in vacuo to give intermediate 47 (168 mg, crude).

Preparation of Intermediate 48

Intermediate 47 (127 mg, 0.37 mmol, 1.00 eq) was dissolved in anhydrous CH ₂ Cl ₂ (3.00 ml) and anhydrous pyridine (0.09 ml, 1.12 mmol, 3.00 eq) was added .). The solution was cooled to 0° C. and trifluoromethanesulfonic anhydride (0.09 ml, 0.52 mmol, 1.40 eq.) was added dropwise. The mixture was stirred for 30 minutes at 0° C. and then diluted in CH ₂ Cl ₂ (25 ml) and NaHCO ₃ (aq., 5 ml) was added. The product was extracted into CH ₂ Cl ₂ (3×25 ml), the combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The resulting orange residue (crude triflate) was used directly afterwards.

Potassium tert-butoxide (119 mg, 1.059 mmol, 2.80 eq.) was dissolved in anhydrous DMF (0.50 ml) and cooled to -10°C. 4-Chloro-7H-pyrrolo[2,3-D]pyrimidine (171 mg, 1.12 mmol, 3.00 eq.) was dissolved in anhydrous DMF (1.5 ml) and added dropwise, followed by stirring for 45 minutes. The crude triflate (176 mg, 1.00 eq.) was dissolved in anhydrous DMF (1.5 ml) and added dropwise over 30 minutes to a freshly prepared pyrrolopyrimidine solution at -10°C. The mixture was stirred for 1 hour at -10°C and then for 2.5 hours at 0°C. The mixture was quenched with water (0.50 ml) and CH ₂ Cl ₂ (70 ml) and brine (20 ml) was added. The product was extracted into CH ₂ Cl ₂ (3×70 ml), the combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (80 ml) and washed with brine (4×20 ml), dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. A mixture of desired substitution product (77%) and elimination by-product (23%) was obtained (NMR). The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing intermediate 48 were collected and the solvent was evaporated to give intermediate 48 (46 mg, 26% yield over 3 steps).

¹ H NMR (400 MHz, CDCl ₃ ): δ=8.81 (dd, J=4.3, 1.8 Hz, 1H), 8.66 (s, 1H), 8.06 (dd, J= 8.1, 1.2 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.15-7.36 (m, 5H), 6.64 (d, J=3 .3 Hz, 1H), 5.10 (dd, J=6.7, 3.9 Hz, 1H), 4.89-5.01 (m, 1H), 4.69-4.85 (m, 2H), 2.78 (dd, J=12.0, 7.1 Hz, 1H), 2.34-2.63 (m, 6H), 1.86 (br s, 1H), 1.52 ( s, 3H), 1.31ppm (s, 3H)

¹³ C NMR (101 MHz, CDCl ₃ ): δ=158.3, 152.4, 150.9, 150.6, 150.6, 149.8, 135.7, 129.0, 127.8, 123 .6, 120.1, 119.1, 118.1, 113.2, 108.7, 100.0, 85.7, 83.9, 67.9, 61.5, 42.8, 40.3 , 39.8, 36.6, 26.6, 24.8ppm

Preparation of Intermediate 49

Intermediate 48 (46 mg, 0.10 mmol, 1.00 eq.) was dissolved in 1,4-dioxane (10 ml) and NH ₃ (25% in H ₂ O) (30 ml) was added. The mixture was heated to 100° C. in a pressure reactor for 24 hours. The mixture was concentrated to minimum volume in vacuo and CH ₂ Cl ₂ (30 ml) and brine (15 ml) were added. The product was extracted into CH ₂ Cl ₂ (3×30 ml), the combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: CH ₂ Cl ₂ /MeOH 99:1 to 85:15). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 49 (35.5 mg, 80% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ=8.80 (dd, J=4.3, 1.7 Hz, 1H), 8.34 (s, 1H), 8.05 (dd, J= 8.3, 1.2 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.21-7.28 (m, 2H), 7.16 (dd, J=8 .9, 2.5 Hz, 1H), 6.90 (d, J=3.7 Hz, 1H), 6.37 (d, J=3.5 Hz, 1H), 5.36 (br s, 2H), 5.09 (dd, J=6.7, 3.4 Hz, 1H), 4.91 (td, J=7.3, 3.3 Hz, 1H), 4.77 (quin, J =7.0 Hz, 1H), 4.68 (d, J=6.6 Hz, 1H), 2.75 (dd, J=12.2, 7.2 Hz, 1H), 2.27-2 .52 (m, 6H), 1.52 (s, 3H), 1.33 ppm (s, 3H)

¹³ C NMR (101 MHz, CDCl ₃ ): δ=158.4, 156.8, 151.8, 150.5, 150.5, 149.8, 135.7, 128.9, 123.5, 123 .3, 120.2, 119.0, 112.8, 108.8, 103.7, 97.9, 86.0, 84.2, 68.1, 60.8, 42.9, 40.3 , 39.9, 36.6, 26.5, 24.8ppm

Getting Compound 11

Intermediate 49 (35.0 mg, 0.08 mmol, 1.00 eq.) was dissolved in ethanol (1.00 ml) and hydrochloric acid (0.77 ml, 1 M in H ₂ O) was added at room temperature. The mixture was stirred for 6 hours at room temperature and then diluted with water (8 ml) and lyophilized. The residue was purified by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO ₂ , EtOH+0.4% iPrNH ₂ ) to give compound 11 (10.0 mg, 31% yield).

¹ h JAMR (400 MHz, DMSO-D ₆ ): Δ = 8.80 (DD, J = 4.3, 1.7 Hz, 1H), 8.26 (DD, J = 8.1, 1.3 Hz, 1H), 8.06 (S, 1H), 7.88 (D, J = 8.8 Hz, 1H), 7.36 (DD, J = 8.1, 4.2 Hz, 1H), 7.21-7.30 (m, 3H), 6.91 (s, 2H), 6.57 (d, J=3.5 Hz, 1H), 4.80-4.99 (m, 4H) , 4.25 (q, J=5.7 Hz, 1H), 3.82 (t, J=5.0 Hz, 1H), 2.54-2.71 (m, 1H), 2.43- 2.49 (m, 1H), 2.26-2.37 (m, 1H), 2.21 (dd, J=11.2, 7.0 Hz, 1H), 2.06 ppm (dd, J =13.1, 8.9 Hz, 1H)

¹³ C NMR (101 MHz, DMSO-d ₆ ): δ=157.9, 157.4, 151.3, 150.6, 149.8, 149.4, 135.6, 129.3, 123.0 , 122.5, 119.5, 119.2, 108.6, 102.8, 98.6, 77.2, 75.3, 67.8, 59.8, 40.3, 39.6, 39 .2, 36.2ppm

Preparation of Intermediate 50

Intermediate 45 (470 mg, 1.43 mmol, 1.00 eq.) was dissolved in pyridine (6.00 ml) and 4,4'-dimethoxytrityl chloride (630 mg, 1.86 mmol, 1.30 eq. ). The mixture was stirred at room temperature for 17 hours and then diluted with EtOAc (100 ml) and brine (50 ml) was added. The product was extracted into EtOAc (3×100 ml), dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 50 (678 mg, 75% yield) as a 1:1 mixture of diastereoisomers.

Preparation of Intermediate 51

Intermediate 50 (678 mg, 1.08 mmol, 1.00 eq) was dissolved in TBAF (10.0 ml, 1 M in THF, 9.00 eq) and stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo to minimum volume and dissolved in EtOAc (100 ml), washed with NH ₄ Cl (aq. sat. 4×50 ml) and saline (2×50 ml). The organic layer was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 51 (455 mg, 82% yield) as a 1:1 mixture of diastereoisomers.

Preparation of Intermediate 52

A mixture of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine (100 g, 651 mmol, 1.00 eq) and KOtBu (73.1 g, 651 mmol, 1.00 eq) in THF (1 k) stirred at room temperature for 45 minutes until a clear solution was obtained. The solvents were evaporated. The residue was triturated in DIPE. White solids were filtered off and dried in vacuo at 30° C. to give intermediate 52 (113 g, 90% yield).

Preparation of Intermediate 53

Intermediate 51 (147 mg, 0.285 mmol, 1.00 eq) was dissolved in anhydrous CH ₂ Cl ₂ (2.20 ml) and anhydrous pyridine (0.07 ml, 0.854 mmol, 3.00 eq) was added. The solution was cooled to 0° C. and trifluoromethanesulfonic anhydride (0.06 ml, 0.37 mmol, 1.30 eq.) was added dropwise. The mixture was stirred for 30 minutes at 0° C. and then diluted in CH ₂ Cl ₂ (40 ml) and NaHCO ₃ (aq., 20 ml) was added. The product was extracted into CH ₂ Cl ₂ (3×40 ml), the combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The resulting orange residue was used directly afterwards.

Intermediate 52 (924 mg, 4.82 mmol, 17.0 eq) was dissolved in anhydrous DMA (5.00 ml), cooled to 0° C. and stirred for 15 minutes. Then the crude triflate (184 mg, 0.28 mmol, 1.00 eq.) was dissolved in anhydrous DMA (1.5 ml) and added dropwise over a period of 30 minutes to the solution at 0°C. Next, the mixture was stirred for 1 hour at 0°C and then for 30 minutes at room temperature. The mixture was poured into NH ₄ Cl (aq. sat. 60 ml) and the product was extracted into n-heptane (1×100 ml, 2×80 ml). The combined organic layers were washed with brine (3×50 ml), dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 53 (80 mg, 43% yield) as a 1:1 mixture of diastereoisomers.

Obtaining an intermediate connection 54

Intermediate 53 (213 mg, 0.33 mmol, 1.00 eq) was dissolved in acetonitrile (5.00 ml) and formic acid (80% in H ₂ O) (0.50 ml) was added. The mixture was stirred for 30 minutes and then diluted with CH ₂ Cl ₂ (50 ml) and quenched with NH ₄ Cl (aq. sat. 20 ml). The product was extracted into CH ₂ Cl ₂ (3×50 ml), the combined extracts were washed with NaHCO ₃ (aq. sat. 2×50 ml) and brine (1×50 ml), dried (MgSO ₄ ), filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 54 (83 mg, 73% yield) as a 1:1 mixture of diastereoisomers.

Obtaining an intermediate connection 55

Intermediate 54 (73.0 mg, 0.21 mmol, 1.00 eq.) was dissolved in NH ₃ (25% in H ₂ O, 30 ml) and 1,4-dioxane (10 ml). The mixture was heated to 90° C. for 24 hours in a pressure reactor and then concentrated in vacuo followed by co-evaporation with toluene to dryness to give intermediate 55 (78.0 mg, 97% yield).

Preparation of Intermediate 56

Intermediate 55 (78.0 mg, 0.21 mmol, 1.00 eq.) was dissolved in DMF (0.50 ml) and N,N-dimethylformamide dimethyl acetal (0.14 ml, 1.02 mmol, 5.0 ml) was added. 00 equiv.). The mixture was heated to 70°C for 2 hours and then concentrated in vacuo to a minimum volume and co-evaporated with toluene to dryness to give intermediate 56 (111 mg, crude).

Obtaining an intermediate connection 57

Intermediate 56 (111 mg, crude) was dissolved in anhydrous THF (1.8 mL) and triphenylphosphine (107 mg, 0.406 mmol, 2.00 eq) followed by the addition of 3-chloroquinolin-7-ol (72.9 mg, 0.406 mmol, 2.00 eq.). Diethyl azodicarboxylate (0.06 ml, 0.406 mmol, 2.00 eq.) was added dropwise and the mixture was stirred at room temperature for 26 hours. The mixture was then concentrated in vacuo to give intermediate 57 (303 mg, crude) which was used directly in the next step.

Preparation of Intermediate 58

Intermediate 57(303 mg, crude) was dissolved in NH₃ (7 M in MeOH, 35 ml) and heated to 70°C for 6 hours. The mixture was concentrated to minimum volume in vacuo and the residue was purified by silica gel column chromatography (gradient elution: CH₂Cl₂/MeOH from 1:0 to 7:3). Fractions containing the product were collected and the solvent was evaporated to give the desiredintermediate connection 58(271 mg, crude).

Preparation of Compound 12 and Compound 13

Intermediate 58 (271 mg, crude) was dissolved in EtOH (4 ml) and HCl (16 ml, 1 M in H ₂ O) was added. The mixture was stirred at room temperature for 2 hours and then diluted with H ₂ O (30 ml) and lyophilized. Purification was carried out by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO ₂ , EtOH+0.4% iPrNH ₂ ) to give compound 12 (12.7 mg, 13% yield over 5 steps) and compounds 13 (20.0 mg, 22% exit in 5 stages).

Preparation of Intermediate 59

Methylitriphenylphosphonia bromide (1.45 g, 3.98 mmol, 1.30 ecv.) Wears in a bottle dried in the furnace and added (12.0 ml). The heterogeneous solution was cooled up to 0 ° C and added a drop of potoxide potassium (3.98 ml, 1 m in ThF, 3.98 mmol, 1.30 ecv.). The mixture was stirred at 0°C for 20 minutes. Freshly prepared Wittig's reagent was added dropwise using a syringe. Tointermediate connection 44 (1.00 g, 3.06 mmol, 1.00 eq.), dissolved in THF (12.0 ml) at 0°C. The yellow mixture was mixed for 1.5 hours at 0 ° C and then 1.5 hours at room temperature. The mixture was concentrated to the minimum volume of in vacuo and re-dissolved in N-geptan (300 ml). Triphenylphosphinesides besieged, and the mixture was exposed to ultrasound for 5 minutes, filtered and filtered washed with NH₄Cl (aq. sat. 2×50 ml) and saline (2×50 ml). The organic layer was dried (MgSO₄), filtered and the filtrate was concentrated in vacuo. The remainder was cleaned by means of column chromatography on silica gel (gradient elimination: N-geptan/etoac from 1: 0 to 7: 3). Collected fractions containing the product, and the solvent was evaporated with obtaining the necessaryintermediate connection 59(931 mg, 94% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ=4.81 (quin, J=2.4 Hz, 1H), 4.78 (quin, J=2.4 Hz, 1H), 4.40 (t , J=5.1Hz, 1H), 4.26 (dd, J=5.5, 0.9Hz, 1H), 3.80 (dt, J=11.2, 5.5Hz, 1H) , 2.87 (dd, J=16.1, 2.2 Hz, 1H), 2.54 (dq, J=15.9, 2.4 Hz, 1H), 2.31-2.46 (m , 2H), 1.95 (t, J=11.4 Hz, 1H), 1.76 (dd, J=11.7, 5.7 Hz, 1H), 1.45 (s, 3H), 1 .32 (s, 3H), 0.91 (s, 9H), 0.10ppm (d, J=2.2Hz, 6H)

¹³ C JAMR (101 MHz, CDCL ₃ ): δ = 144.7, 110.4, 106.8, 85.3, 79.9, 72.0, 42.5, 41.2, 39.2, 36, 36, 36 .8, 26.0, 26.0, 24.5, 18.4, -4.4, -4.6ppm

Preparation of Intermediate 60

Intermediate 59 (931 mg, 2.87 mmol, 1.00 eq.) was dissolved in THF (2.00 ml) and tetrabutylammonium fluoride (10.0 ml, 1 M in THF, 10.0 mmol, 3.50 equiv.). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to minimum volume in vacuo, dissolved in EtOAc (250 ml) and washed with NH ₄ Cl (aq. sat. 3×50 ml) and brine (3×50 ml). The organic layer was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 60 (556 mg, 92% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ=4.83 (quin, J=2.3 Hz, 1H), 4.80 (quin, J=2.4 Hz, 1H), 4.46-4 .49 (m, 1H), 4.36-4.39 (m, 1H), 3.81 (br s, 1H), 2.82-2.88 (m, 1H), 2.60 (dq, J=16.1, 2.4Hz, 1H), 2.38-2.46(m, 2H), 2.27-2.38(m, 1H), 1.97(dd, J=12, 0, 5.9 Hz, 1H), 1.74 (t, J=11.4 Hz, 1H), 1.47 (s, 3H), 1.36 ppm (s, 3H)

¹³ C NMR (101 MHz, CDCl ₃ ): δ=144.1, 110.6, 107.2, 85.4, 78.7, 70.8, 41.7, 41.2, 39.5, 36 .6, 25.9, 24.3ppm

Preparation of Intermediate 61

Intermediate 60 (647 mg, 3.08 mmol, 1.00 eq) was dissolved in anhydrous CH ₂ Cl ₂ (20.0 ml) and pyridine (0.62 ml, 7.69 mmol, 2.50 eq) was added. ). The mixture was cooled to 0° C. and trifluoromethanesulfonic anhydride (0.57 ml, 3.39 mmol, 1.10 eq.) was added dropwise. The mixture was stirred for 30 minutes at 0° C., diluted in CH ₂ Cl ₂ (100 ml) and NaHCO ₃ (aq. sat. 40 ml) was added. The product was extracted into CH ₂ Cl ₂ (3×100 ml), the combined organic layers were dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The remainder was used directly as received in the next step of the procedure. Intermediate 52 (5.90 g, 30.8 mmol, 10.0 eq.) was dissolved in anhydrous DMF (35.0 ml) and stirred for 30 minutes at 0°C. This was followed by dropwise addition of crude triflate (1.05 g, 3.08 mmol, 1.00 eq.) dissolved in anhydrous DMF (8.00 mL) over 15 minutes. at 0°C. The mixture was stirred for 2 hours at 0°C and then warmed to room temperature and stirred for an additional 2 hours. The mixture was poured into NH ₄ Cl (aq. sat. 50 ml) and the product was extracted into EtOAc (3×100 ml). The combined organic layers were washed with brine (3×100 ml), dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to a minimum volume. n-heptane (100 ml) was added to the resulting powder, and the mixture was sonicated for 10 minutes. The solids were filtered, rinsed with n-heptane and the filtrate was concentrated to the minimum volume in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 0:1). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 61 (856 mg, 80% yield over 2 steps).

¹ H NMR (400 MHz, CDCl ₃ ): δ=8.64-8.65 (m, 1H), 7.18 (d, J=3.7 Hz, 1H), 6.61 (d, J= 3.7 Hz, 1H), 5.10 (dd, J=6.3, 3.1 Hz, 1H), 4.96 (td, J=6.8, 3.1 Hz, 1H), 4, 80 (dquin, J=18.2, 2.4Hz, 2H), 4.69 (d, J=6.5Hz, 1H), 3.18 (dd, J=15.5, 2.4Hz , 1H), 2.75 (dd, J=15.3, 2.6 Hz, 1H), 2.48-2.58 (m, 2H), 2.33-2.44 (m, 2H), 1.55(s, 3H), 1.35ppm(s, 3H)

¹³ C JAMR (101 MHz, CDCL ₃ ): δ = 152.3, 150.6, 143.4, 127.5, 117.9, 112.7, 107.0, 99.8, 85.7, 84, 84 .9, 61.5, 43.0, 42.3, 42.2, 38.3, 26.6, 24.7ppm

Preparation of Intermediate 62

Intermediate 61 (850 mg, 2.46 mmol, 1.00 eq) was dissolved in 1,4-dioxane (20.0 ml), NH ₃ (60.0 ml, 25% in H ₂ O) was added. The solution was heated to 100° C. for 24 hours in a pressurized reactor. The mixture was concentrated to minimum volume in vacuo and co-evaporated twice with toluene. The residue was purified by silica gel column chromatography (gradient elution: CH ₂ Cl ₂ /MeOH from 1:0 to 7:3). Fractions containing the product were collected and the solvent was evaporated to give the desired intermediate 62 (790 mg, 98% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ=8.33 (s, 1H), 6.89 (d, J=3.7 Hz, 1H), 6.35 (d, J=3.5 Hz 1H), 5.18 (BR S, 2H), 5.09 (DD, J = 6.4, 2.9 Hz, 1H), 4.93 (TD, J = 6.7, 2.9 Hz , 1H), 4.81 (quin, J=2.4Hz, 1H), 4.76 (quin, J=2.4Hz, 1H), 4.67 (d, J=6.4Hz, 1H ), 3.16 (DD, J = 15.6, 2.4 Hz, 1H), 2.74 (DD, J = 15.2, 2.4 Hz, 1H), 2.45-2.55 ( m, 2H), 2.30-2.45 (m, 2H), 1.97 (br s, 1H), 1.55 (s, 3H), 1.35 ppm (s, 3H)

¹³ C JAMR (101 MHz, CDCL ₃ ): δ = 156.6, 151.7, 150.5, 143.8, 123.0, 112.4, 106.8, 103.5, 97.6, 85, 85 , 9, 85.1, 60.8, 43.1, 42.5, 42.3, 38.3, 26.6, 24.7 PPM

Preparation of Intermediate 63

To intermediate 62 (55.0 mg, 0.17 mmol, 1.00 equiv.) was added 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 1.69 mL, 0.84 equiv.) at room temperature. mmol, 5.00 eq.). The mixture was stirred for 30 minutes. Then potassium phosphate (286 mg, 1.35 mmol, 8.00 eq.) dissolved in water (0.53 ml, 29.3 mmol, 173 eq.) was degassed with nitrogen for 10 minutes and added to the reaction mixture. The solution was stirred for 10 minutes at room temperature, while degassing, and 5-bromobenzothiazole (54.1 mg, 0.253 mmol, 1.25 eq.) and 1,1'-bis(di-tert-butylphosphino ) ferrocene palladium dichloride [CAS #: 95408-45-0] (27.7 mg, 0.04 mmol, 0.25 eq.) dissolved in THF (2.20 mL). Degassing with nitrogen was continued for 15 minutes before the mixture was heated to 70°C. After 2 hours, the dark brown solution was cooled to room temperature, diluted with EtOAc (90 ml), washed with NH ₄ OH (25% in H ₂ O, 2×30 ml) and brine (2×30 ml). The organic layer was dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo to give intermediate 63 (196 mg, crude) as a 1:1 mixture of diastereoisomers, used without purification in the next step.

The intermediates below were prepared using a reaction protocol similar to that used to prepare intermediate 63 using the appropriate starting materials (Table 1 - Intermediates resulting from the Suzuki coupling).

Prom. conn. Structure Initial materials 64

Intermediate connection 62 and 7-Brom-3-chlorchinoline 65

Intermediate connection 62 and 2-amino-5-brombensotiazole 66

Intermediate 62 and 6-bromobenzothiazole 67

Intermediate 62 and 2-amino-6-bromobenzothiazole 68

Intermediate 62 and 7-bromimidazo[1,2-a]pyridine 69

Intermediate 62 and 2-bromopyridine 70

Intermediate connection 62 and 3-brompyridine 71

Intermediate 62 and 3-bromo-7-iodoquinoline-2-amine 79

Intermediate 78 and 7-bromo-3-chloroquinoline

Preparation of Compound 16 and Compound 17

Intermediate 63 (crude, from previous step) was dissolved in EtOH (4.00 ml), HCl (16.0 ml, 1 M in H ₂ O) was added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with water (20 ml), frozen and lyophilized to obtain a solid residue. Purification was performed by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO ₂ , EtOH+0.4% iPrNH ₂ ) to give compound 16 (12.3 mg, 0.029 mmol, 17% yield in 2 steps) and compound 17 (15.0 mg, 0.036 mmol, 21% yield over 2 steps).

The compounds below were prepared using a reaction protocol similar to that used for the preparation of compounds 16 and 17 using the appropriate starting materials (Table 2).

Compound Structure Initial materials eleven

Intermediate 49 12

Intermediate 58 13

Intermediate 58 14

Intermediate 64 15

Intermediate 64 16

Intermediate 63 17

Intermediate 63 18

Intermediate 65 19

Intermediate 65 20

Intermediate 66 21

Intermediate 66 22

Intermediate 67 23

Intermediate 67 24

Intermediate 68 25

Intermediate 68 26

Intermediate 69 27

Intermediate 69 28

Intermediate 70 29

Intermediate 70 thirty

Intermediate 73 31

Intermediate 73 32

Salt HCl, number of equivalents not determined Intermediate 74 33

Intermediate 71 34

Intermediate 71 35

Salt HCl, number of equivalents not determined Intermediate 72a 36

Salt HCl, number of equivalents not determined Intermediate 72b 44

Intermediate 79 45

Intermediate 79

Preparation of Intermediate 72, Intermediate 72a and Intermediate 72b

TOintermediate connection 63 (255 mg, 0.78 mmol, 1.00 eq.) was added 9-borabicyclo[3.3.1]nonane (7.81 ml, 0.5 M in THF, 3.91 mmol, 5.00 eq.) and the mixture was stirred for 30 minutes at room temperature. The solution was cooled to 0°C and NaOH (7.81 ml, 1 M in H₂O, 7.81 mmol, 10.0 eq.) followed by the dropwise addition of hydrogen peroxide (1.99 ml, 30% in H₂O, 19.5 mmol, 25.0 eq.). The mixture was stirred for 1 hour at room temperature, then diluted in CH₂Cl₂ (250 ml) and washed with NaHCO₃ (aq. sat. 3×50 ml) and saline (1×50 ml). The organic layer was dried (MgSO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: CH₂Cl₂/MeOH from 1:0 to 7:3). Fractions containing product were collected and the solvent was evaporated to giveIntermediate 72(213 mg, 79% yield) as a 1:1 mixture of diastereoisomers. The sample was cleanedIntermediate 72 via preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO₂, EtOH+0.4% iPrNH₂) with gettingIntermediate 72a(15 mg) AndIntermediate 72b(18 mg).

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=8.31 (s, 1H), 6.89 (d, J=3.5 Hz, 1H), 6.34 (d, J=3.5 Hz , 1H), 5.24 (br s, 2H), 5.02 (dd, J=6.8, 3.5 Hz, 1H), 4.55 (d, J=6.8 Hz, 1H), 2.35-2.52 (m, 3H), 2.27 (dd, J=11.8, 8.3 Hz, 1H), 1.76-1.95 (m, 3H), 1.53 ( s, 3H), 1.33 ppm (s, 3H)

¹³ C NMR (CHLOROFORM-d, 101 MHz): δ=156.7, 151.7, 150.4, 123.1, 112.7, 97.7, 86.2, 84.6, 66.9, 60 .3, 43.4, 43.3, 34.1, 31.6, 30.4, 26.5, 24.8ppm

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=8.31 (s, 1H), 6.88 (d, J=3.7 Hz, 1H), 6.32 (d, J=3.7 Hz , 1H), 5.29 (br s, 1H), 5.00 (dd, J=6.3, 2.8 Hz, 1H), 4.86-4.94 (m, 1H), 4.66 (d, J=6.4 Hz, 1H), 3.50-3.64 (m, 2H), 2.46-2.58 (m, 1H), 2.36-2.46 (m, 2H ), 2.20 (dd, J=13.6, 5.9 Hz, 1H), 2.05-2.15 (m, 2H), 1.64-1.74 (m, 2H), 1, 54(s, 3H), 1.35ppm(s, 3H)

¹³ C NMR (CHLOROFORM-d, 101 MHz): δ=156.7, 151.7, 150.4, 122.7, 112.3, 97.7, 86.6, 85.4, 66.9, 60 .5, 43.7, 43.5, 35.4, 31.5, 30.2, 26.6, 24.7ppm

Preparation of Intermediate 73 and Intermediate 74

Intermediate 72 (80.0 mg, 0.23 mmol, 1.00 eq.) was dissolved in anhydrous THF (3.2 ml) and triphenylphosphine (67.7 mg, 0.26 mmol, 1.10 eq.) was added. , 6-chloropyridin-2-ol (33.1 mg, 0.26 mmol, 1.10 eq.) and diethyl azodicarboxylate (0.04 ml, 0.27 mmol, 1.15 eq.). The mixture was stirred at room temperature for 1.5 hours and then diluted with EtOAc (50 ml) and brine (25 ml) was added. The product was extracted into EtOAc (3×50 ml), dried (MgSO ₄ ), filtered and the filtrate was concentrated in vacuo. The unpeeled mixture contained an intermediate compound 73 and the intermediate connection 74 in the ratio of 87:13, respectively. The remainder was cleaned by means of column chromatography on silica gel (gradient elimination: CH ₂ Cl ₂ /Meoh from 1: 0 to 7: 3). The fractions containing the product were collected and the solvent was evaporated with the receipt of the intermediate connection 73 (65 mg, the output 62%) in the form of a mixture of diastereoisomers in a ratio of 1: 1. Intermediate connection 74 (by -product, 8 mg, 8%output) was obtained in the form of a mixture of diastereoisomers in a ratio of 1: 1.

Preparation of Intermediate 75

Intermediate 27 (2.00 g, 5.50 mmol, 1.00 eq.) was weighed into a 100 ml three-necked flask equipped with a reflux condenser, thermometer and CaCl ₂ tube. To the substrate was added a solution (5 wt% in toluene) of bis(cyclopentadienyl)dimethyltitanium (39.4 mL, 7.97 mmol, 1.45 eq., CAS #: 1271-66-5). The flask was covered with aluminum foil to protect from light and heated to 70°C. [Note: When heated, the Petasis active reagent is formed and 1 equivalent of methane gas is released relative to titanocene. Therefore, it is necessary to avoid closed systems for setting up reactions in glassware. In addition, the reaction in pressurized metal reactors showed only low conversion rates because the titanocene reactant sticks to the walls of the reactor.] The reaction mixture was stirred for 17 hours, after which complete conversion was observed. The mixture was concentrated to minimum volume in vacuo and n-heptane (100 ml) was added to the residue. The solids were sonicated for 5 minutes and removed by filtration through Celite (rinsed with n-heptane). The organic layer was concentrated to the minimum volume in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane/EtOAc from 1:0 to 3:7 in 15 column volumes). Fractions containing the product were collected and the solvent was evaporated to give intermediate 75 (yield 58%, 1.14 g; 3.19 mmol, colorless oil).

¹H Jamr (500 MHz, CDCL₃): δ 5.42 (d, J= 4.5 Hz, 1H), 5.17, (dd, J= 4.5, 1.7 Hz, 1H), 4.85-4.83 (m, 3H), 3.39 (s, 3H), 3.09-3.05 (m, 2H), 2.94-2.85 (m, 2H), 1.21 (s, 9H), 1.20 PPM (S, 9H).

¹³C NMR (125 MHz, CDCl₃): δ 177.4, 177.2, 139.7, 107.6, 105.7, 80.6, 75.6, 74.5, 55.6, 44.8, 41.5, 39.2 , 39.0, 27.4, 27.3 ppm.

Analytical part

NMR

For a number of compounds, ¹ H NMR spectra and ¹³ C NMR spectra were recorded on a Bruker DPX-360 operating at 360 MHz for ¹ H NMR and 91 MHz for ¹³ C NMR, on a Bruker Avance 400 operating at 400 MHz for ¹ H NMR and 101 MHz for ¹³ C NMR, or on a Bruker Avance III 400 operating at 400 MHz for ¹ H NMR and 101 MHz for ¹³ C NMR.

Alternatively, ¹ H and ¹³ C NMR spectra for a number of compounds were recorded at 500 MHz for ¹ H NMR and at 125 MHz for ¹³ C NMR on a Bruker Avance II 500 console or at 250 MHz for ¹ H NMR and 63 MHz for ¹³ C NMR on a Bruker Avance DRX 250 console.

The solvents used and the frequency values are indicated in the experimental part or below. Typical solvents are chloroform-d, methanol-d ₄ or DMSO-d ₆ (deuterated DMSO, dimethyl d6-sulfoxide. Chemical shifts (δ) are in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard Coupling constants (J) are given in hertz (Hz).

When describing spectra, the following abbreviations are used: singlet (s), doublet (d), triplet (t), quadruplet (q), quintet (qn), multiplet (m), doublet of doublets (dd), triplet of doublets (td), doublet triplets (dt), doublet of doublet of doublets (ddd), pseudo (ps).

NMR data for compounds are given in the experimental part or below ("Comp. No" means the number of the compound):

Comm. No. 12

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.78 (d, J=2.4 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.06 ( s, 1H), 7.88 (d, J=9.8 Hz, 1H), 7.30 (dq, J=4.8, 2.5 Hz, 2H), 7.24 (d, J=3 , 7 Hz, 1H), 6.92 (BR S, 2H), 6.57 (D, J = 3.7 Hz, 1H), 4.79-5.00 (M, 4H), 4.24 ( Br D, J = 6.5 Hz, 1H), 3.82 (t, j = 4.9 Hz, 1H), 3.33 (S, 2H), 2.58-2.68 (M, 1H) , 2.41-2.48 (M, 1H), 2.27-2.36 (M, 1H), 2.21 (DD, J = 11.4, 6.9 Hz, 1H), 1.98 -2.10 ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=158.3, 157.4, 151.3, 149.8, 149.2, 147.5, 133.9, 128.7, 125.1, 123.2, 122.4, 120.8, 108.6, 102.8, 98.7, 77.1, 75.3, 68.0, 59.8, 40.3, 39.2, 36, 1ppm

Comm. No. 13

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.80 (d, J=2.4 Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.01 ( S, 1H), 7.89 (D, J = 9.4 Hz, 1H), 7.25-7.33 (M, 2H), 7.16 (D, J = 3.7 Hz, 1H), 6.88 (s, 2H), 6.53 (d, J=3.7 Hz, 1H), 5.09 (d, J=4.5 Hz, 1H), 4.93 (d, J=6 .5 Hz, 1H), 4.79-4.89 (m, 2H), 4.32-4.39 (m, 1H), 3.92 (t, J=4.5 Hz, 1H), 2 .99-3.11 (m, 1H), 2.66-2.80 (m, 1H), 2.34 (dd, J=13.6, 10.0 Hz, 1H), 2.22 (dd , J=11.8, 6.9 Hz, 1H), 1.88-2.00 ppm (m, 2H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=158.2, 157.4, 151.2, 149.9, 149.2, 147.5, 133.9, 128.8, 125.1, 123.3, 122.2, 120.8, 108.5, 102.8, 98.6, 77.0, 75.7, 67.5, 59.0, 41.9, 41.5, 36, 2ppm

Comm. No. 14

¹ h JAMR (DMSO-D ₆ , 400MHz): Δ = 8.84 (D, J = 2.6 Hz, 1H), 8.51 (D, J = 2.4 Hz, 1H), 8.00 ( S, 1H), 7.89 (D, J = 8.4 Hz, 1H), 7.82 (S, 1H), 7.52 (DD, J = 8.4, 1.5 Hz, 1H), 7.15 (d, J=3.5 Hz, 1H), 6.86 (s, 2H), 6.52 (d, J=3.5 Hz, 1H), 4.79-4.85 (m , 1H), 4.75 (dd, J=10.1, 5.5 Hz, 2H), 4.17-4.24 (m, 1H), 3.71 (t, J=4.8 Hz, 1H), 2.90 (d, J=7.7 Hz, 2H), 2.53-2.67 (m, 1H), 2.27-2.40 (m, 1H), 2.14 (dd , J=11.2, 8.8 Hz, 1H), 2.00-2.10 (m, 1H), 1.91 (dd, J=13.2, 8.6 Hz, 1H), 1, 85 (dd, J=10.8, 8.6Hz, 1H), 1.73ppm (ddd, J=11.2, 7.9, 3.5Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.9, 151.7, 150.3, 149.5, 146.5, 143.8, 134.4, 129.9, 127.7, 127.7, 127.2, 127.0, 122.8, 103.2, 99.1, 78.4, 76.0, 60.0, 42.8, 42.7, 41.7, 38, 5, 34.7, 30.8ppm

Comm. No. 15

¹ h JAMR (DMSO-D ₆ , 400MHz): Δ = 8.84 (D, J = 2.4 Hz, 1H), 8.51 (D, J = 2.2 Hz, 1H), 8.01 ( s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.82 (s, 1H), 7.52 (dd, J=8.4, 1.3 Hz, 1H), 7.11 (D, J = 3.5 Hz, 1H), 6.87 (S, 2H), 6.54 (D, J = 3.5 Hz, 1H), 4.73-4.88 (M , 3H), 4.23-4.32 (m, 1H), 3.78 (t, J=4.1 Hz, 1H), 2.89 (d, J=7.0 Hz, 2H), 2 , 51-2.58 (M, 1H), 2.42-2.48 (m, j = 3.7 Hz, 1H), 2.29 (DD, J = 13.6, 10.3 Hz, 1H ), 2.09-2.18 (m, 1H), 1.76-1.91 (m, 2H), 1.54 ppm (br dd, J=10.5, 8.0 Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.9, 151.7, 150.5, 149.5, 146.5, 143.8, 134.4, 129.9, 127.7, 127.2, 127.0, 122.4, 103.2, 99.1, 77.9, 76.2, 59.3, 43.1, 43.0, 42.4, 40.8, 34, 5, 30.7ppm

Comm. No. 16

¹ h JAMR (DMSO-D ₆ , 400MHz): Δ = 9.35 (S, 1H), 8.05 (D, J = 8.1 Hz, 1H), 8.01 (S, 1H), 7, 7, 7, 7, 7, 7, 89 (D, j = 0.8 Hz, 1H), 7.32 (DD, J = 8.3, 1.4 Hz, 1H), 7.16 (D, J = 3.3 Hz, 1H), 6.87 (s, 2H), 6.52 (d, J=3.7 Hz, 1H), 4.78-4.86 (m, 1H), 4.76 (dd, J=12.4, 5.5 Hz, 2H), 4.18-4.25 (m, 1H), 3.71 (t, J=4.9 Hz, 1H), 2.84 (d, J=7.7 Hz, 2H), 2.53-2.61 (M, 1H), 2.28-2.40 (M, 1H), 2.13 (DD, J = 11.2, 8.7 Hz, 1H), 1 .99-2.09 (m, 1H), 1.91 (dd, J=13.0, 8.5 Hz, 1H), 1.84 (dd, J=10.8, 8.7 Hz, 1H ), 1.72 ppm (ddd, J=11.4, 7.9, 3.5 Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.4, 155.9, 153.4, 151.2, 149.9, 139.3, 130.8, 126.5, 122.4, 122.2, 122.0, 102.7, 98.6, 77.9, 75.5, 59.4, 42.1, 42.1, 41.2, 38.1, 34.1, 30, 8 ppm

Comm. No. 17

¹ h JAMR (DMSO-D ₆ , 400MHz): Δ = 9.34 (S, 1H), 8.04 (D, J = 8.5 Hz, 1H), 8.02 (S, 1H), 7, 7, 7, 7, 7, 7, 88 (d, J=1.2 Hz, 1H), 7.31 (dd, J=8.1, 1.6 Hz, 1H), 7.14-7.16 (m, 1H), 7.12 (d, J=3.7 Hz, 1H), 6.87 (s, 2H), 6.54 (d, J=3.7 Hz, 1H), 4.75-4.89 (m, 2H) , 4.73-4.75 (m, 1H), 4.23-4.32 (m, 1H), 3.77 (t, J=4.1 Hz, 1H), 2.83 (br d, J=6.9 Hz, 2H), 2.46 (br d, J=4.5 Hz, 1H), 2.29 (dd, J=13.6, 10.4 Hz, 1H), 2.04 -2.19 (m, 1H), 1.82 (td, J=13.3, 7.5 Hz, 2H), 1.47-1.60 ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.4, 155.9, 153.4, 151.2, 150.0, 139.3, 130.8, 126.5, 122.3, 122.0, 121.9, 102.7, 98.7, 77.4, 75.8, 58.7, 42.6, 42.3, 41.8, 40.3, 33.9, 30, 7ppm

Comm. No. 18

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.01 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.37 (br s, 2H), 7 , 13 (D, j = 1.2 Hz, 1H), 7,11 (D, j = 3.7 Hz, 1H), 6.87 (BR S, 2H), 6.81 (DD, J = 8 .1, 1.2 Hz, 1H), 6.53 (d, J=3.7 Hz, 1H), 4.74-4.86 (m, 3H), 4.23-4.31 (m, 1H), 3.76 (t, J=4.1 Hz, 1H), 2.66 (br d, J=6.9 Hz, 2H), 2.34-2.47 (m, 2H), 2 .27 (dd, J=13.6, 10.4 Hz, 1H), 2.03-2.14 (m, 1H), 1.73-1.82 (m, 2H), 1.42-1 .53ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=166.5, 157.4, 153.0, 151.2, 150.0, 138.2, 128.1, 121.9, 121.4, 120.3, 117.7, 102.7, 98.7, 77.5, 75.8, 58.7, 42.6, 41.8, 40.5, 39.9, 34.0, 30, 8ppm

Comm. No. 19

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.01 (s, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.38 (s, 3H), 7, 16 (D, J = 3.7 Hz, 1H), 7.14 (D, J = 1.2 Hz, 1H), 6.88 (S, 2H), 6.82 (DD, J = 7.9 , 1.4 Hz, 1H), 6.53 (d, J=3.7 Hz, 1H), 4.78-4.88 (m, 1H), 4.77 (d, J=6.1 Hz 1H), 4.73 (D, J = 4.9 Hz, 1H), 4,17-4.22 (M, 1H), 3.69 (t, j = 4.9 Hz, 1H), 3, 3 .41-3.49 (m, 1H), 3.18 (d, J=4.9 Hz, 1H), 2.62-2.74 (m, 3H), 2.39-2.49 (m , 1H), 2.33 (dd, J=13.0, 9.8 Hz, 1H), 1.98-2.13 (m, 3H), 1.91 (dd, J=13.0, 8 .5 Hz, 1H), 1.79 (dd, J=10.6, 8.5 Hz, 1H), 1.66-1.74 ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=166.5, 157.4, 153.0, 151.2, 149.9, 138.3, 128.1, 122.2, 121.4, 120.4, 117.7, 102.7, 98.6, 78.0, 75.5, 59.4, 42.4, 42.1, 41.3, 38.2, 34.3, 30, 9ppm

Comm. No. 20

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=9.30 (s, 1H), 8.03 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7, 94 (d, J=1.2Hz, 1H), 7.36 (dd, J=8.5, 1.6Hz, 1H), 7.17 (d, J=3.7Hz, 1H), 6.90 (s, 2H), 6.54 (d, J=3.7 Hz, 1H), 4.73-4.91 (m, 3H), 4.22 (br d, J=6.5 Hz, 1H), 3.72 (br s, 1H), 3.19 (d, J=5.3 Hz, 2H), 2.83 (br d, J=7.7 Hz, 2H), 2, 47-2.59 (m, 2H), 2.34 (dd, J=13.0, 9.8 Hz, 1H), 2.13 (dd, J=11.4, 9.0 Hz, 1H) , 2.01-2.08 (m, 1H), 1.92 (dd, J=13.0, 8.5 Hz, 1H), 1.83 (dd, J=10.8, 8.7 Hz , 1H), 1.73ppm (ddd, J=11.4, 7.9, 3.5Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.4, 151.4, 151.2, 149.9, 138.6, 133.6, 127.1, 122.6, 122.3, 121.4, 102.7, 98.6, 77.9, 75.5, 59.5, 42.2, 42.1, 41.2, 38.1, 34.2, 30.8 ppm

Comm. No. 21

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=9.29 (s, 1H), 8.02 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7, 92 (s, 1H), 7.34 (dd, J=8.3, 1.4 Hz, 1H), 7.12 (d, J=3.7 Hz, 1H), 6.89 (br s, 2H), 6.55 (d, J=3.3 Hz, 1H), 4.79-4.89 (m, 3H), 4.28 (br d, J=3.7 Hz, 1H), 3 .77 (br s, 1H), 3.17 (d, J=4.1 Hz, 1H), 2.80 (br d, J=6.9 Hz, 2H), 2.45 (br dd, J =6.5, 4.1 Hz, 2H), 2.28 (dd, J=13.6, 10.4 Hz, 1H), 2.07-2.15 (m, 1H), 1.75- 1.85 (m, 2H), 1.46-1.56ppm (m, J=2.0Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.4, 151.4, 151.2, 150.0, 138.6, 133.6, 127.1, 122.5, 121.9, 121.4, 102.7, 98.7, 77.4, 75.8, 58.7, 42.6, 42.4, 41.8, 40.3, 34.0, 30.7 ppm

Comm. No. 22

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.02 (s, 1H), 7.43 (d, J=1.2 Hz, 1H), 7.33 (s, 2H), 7, 23 (d, J=8.1Hz, 1H), 7.16 (d, J=3.7Hz, 1H), 7.00 (dd, J=8.1, 1.6Hz, 1H), 6.89 (br s, 2H), 6.54 (d, J=3.7 Hz, 1H), 4.70-4.89 (m, 3H), 4.18-4.25 (m, 1H ), 3.69 (t, J=4.7 Hz, 1H), 2.66 (br d, J=7.3 Hz, 2H), 2.45 (dt, J=16.0, 8.1 Hz, 1H), 2.33 (dd, J=13.0, 9.8 Hz, 1H), 1.98-2.13 (m, 2H), 1.91 (br dd, J=13.2 , 8.3 Hz, 1H), 1.78 (br dd, J=10.6, 9.0 Hz, 1H), 1.67-1.74 ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=165.7, 157.4, 151.2, 150.9, 149.9, 133.6, 130.9, 125.9, 122.2, 120.3, 117.4, 102.7, 98.6, 78.0, 75.5, 59.4, 42.2, 42.1, 41.3, 38.2, 34.3, 34, 2, 30.9ppm

Comm. No. 23

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.01 (s, 1H), 7.42 (d, J=1.2 Hz, 1H), 7.31 (s, 2H), 7, 22 (d, J=8.1Hz, 1H), 7.11 (d, J=3.3Hz, 1H), 6.99 (dd, J=8.1, 1.6Hz, 1H), 6.87 (s, 2H), 6.53 (d, J=3.3 Hz, 1H), 4.74-4.90 (m, 3H), 4.23-4.32 (m, 1H) , 3.76 (br s, 1H), 2.65 (br d, J=6.9 Hz, 2H), 2.31-2.46 (m, 2H), 2.27 (dd, J=13 .6, 10.4 Hz, 1H), 2.05-2.15 (m, 1H), 1.72-1.83 (m, 2H), 1.39-1.51 ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=165.7, 157.4, 151.2, 150.9, 150.0, 133.5, 130.9, 125.9, 121.9, 120.3, 117.4, 102.7, 98.7, 77.5, 75.8, 58.7, 42.7, 42.4, 41.7, 40.4, 34.0, 30, 8ppm

Comm. No. 24

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.42 (d, J=6.9 Hz, 1H), 8.01 (s, 1H), 7.84 (s, 1H), 7, 49 (s, 1H), 7.30 (s, 1H), 7.16 (d, J=3.3 Hz, 1H), 6.88 (s, 2H), 6.73 (d, J=6 .9 Hz, 1H), 6.53 (d, J=3.3 Hz, 1H), 4.71-4.88 (m, 3H), 4.17-4.25 (m, 1H), 3 .71 (br t, J=4.3 Hz, 1H), 2.71 (br d, J=7.7 Hz, 2H), 2.52-2.59 (m, 1H), 2.35 ( dd, J=13.0, 9.8 Hz, 1H), 2.01-2.17 (m, 2H), 1.92 (dd, J=13.0, 8.5 Hz, 1H), 1 .77-1.86 (m, 1H), 1.68-1.77 ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.4, 151.2, 149.8, 144.8, 137.8, 132.8, 126.2, 122.3, 114.6, 113.7, 112.3, 102.7, 98.6, 77.9, 75.5, 59.4, 42.2, 41.6, 41.2, 38.0, 34.1, 29, 7ppm

Comm. No. 25

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.42 (d, J=6.9 Hz, 1H), 8.01 (s, 1H), 7.84 (s, 1H), 7, 49 (s, 1H), 7.29 (s, 1H), 7.12 (d, J=3.3 Hz, 1H), 6.88 (s, 2H), 6.73 (d, J=6 , 9 Hz, 1H), 6.54 (D, J = 3.7 Hz, 1H), 4.77-4.89 (M, 3H), 4.24-4.33 (M, 1H), 3, 3 , 79 (t, j = 3.9 Hz, 1H), 3.18 (D, j = 4.5 Hz, 1H), 2.70 (Br D, J = 6.5 Hz, 2H), 2, 2, 2, 47 (Br D, J = 4.1 Hz, 1H), 2.29 (DD, J = 13.6, 10.4 Hz, 1H), 2.08-2.19 (M, 1H), 1, 1, 74-1.88(m, 2H), 1.45-1.56ppm(m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.4, 151.2, 150.0, 144.9, 137.8, 132.8, 126.2, 121.9, 114.6, 113.8, 112.3, 102.7, 98.7, 77.4, 75.7, 58.7, 42.6, 41.9, 40.3, 33.9, 29.6 ppm

Comm. No. 26

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.45 (d, J=4.0 Hz, 1H), 8.01 (s, 1H), 7.66 (td, J=7.6 , 1.8 Hz, 1H), 7.11-7.23 (m, 3H), 6.87 (br s, 2H), 6.53 (d, J=3.5 Hz, 1H), 4, 66-4.88 (m, 3H), 4.14-4.24 (m, 1H), 3.67-3.73 (m, 1H), 3.17 (d, J=3.5 Hz, 1H), 2.81 (d, J=7.7 Hz, 2H), 2.54-2.69 (m, 1H), 2.33 (dd, J=13.0, 9.7 Hz, 1H ), 2.10 (dd, J=11.2, 8.8 Hz, 1H), 1.98-2.05 (m, 1H), 1.90 (dd, J=13.0, 8.6 Hz, 1H), 1.81 (br dd, J=10.7, 8.7 Hz, 1H), 1.71 ppm (ddd, J=11.3, 7.9, 3.5 Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=160.9, 157.9, 151.7, 150.4, 149.4, 136.7, 123.1, 122.7, 121.6, 103.2, 99.1, 78.4, 76.0, 59.9, 45.1, 42.8, 41.7, 38.6, 34.7, 29.8 ppm

Comm. No. 27

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.45 (d, J=4.0 Hz, 1H), 8.01 (s, 1H), 7.66 (td, J=7.6 , 1.8 Hz, 1H), 7.14-7.24 (m, 2H), 7.10 (d, J=3.5 Hz, 1H), 6.86 (s, 2H), 6.53 (d, J=3.5 Hz, 1H), 4.73-4.90 (m, 3H), 4.24-4.33 (m, 1H), 3.77 (t, J=4.0 Hz, 1H), 2.80 (d, J=7.5 Hz, 2H), 2.51-2.60 (m, 1H), 2.43 (tt, J=7.4, 4.0 Hz , 1H), 2.26 (dd, J=13.6, 10.3 Hz, 1H), 2.11 (ddd, J=11.2, 7.6, 4.1 Hz, 1H), 1, 73-1.85 (m, 2H), 1.50ppm (dd, J=11.0, 8.6Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=160.9, 157.9, 151.7, 150.5, 149.4, 136.7, 123.2, 122.4, 121.6, 103.2, 99.2, 77.9, 76.2, 59.3, 55.4, 45.4, 43.1, 42.4, 40.9, 34.4, 29.7 ppm

Comm. No. 28

¹ h JAMR (DMSO-D ₆ , 400MHz): Δ = 8.35-8.46 (M, 2H), 8.00 (S, 1H), 7.58 (DT, J = 7.8, 2, 2, 0 Hz, 1H), 7.29 (dd, J=7.7, 4.5 Hz, 1H), 7.15 (d, J=3.7 Hz, 1H), 6.87 (s, 2H) , 6.52 (d, J=3.3 Hz, 1H), 4.62-4.88 (m, 3H), 4.15-4.28 (m, 1H), 3.68 (t, J = 4.7 Hz, 1H), 2.67 (D, j = 7.7 Hz, 2H), 2.40-2.49 (M, 1H), 2.32 (DD, J = 13.0, 9.8 Hz, 1H), 1.97-2.11 (M, 2H), 1.90 (DD, J = 13.0, 8.5 Hz, 1H), 1.79 (DD, J = 10 , 8, 8.7 Hz, 1H), 1.70 ppm (DDD, J = 11.5, 8.0, 3.7 Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.4, 151.2, 149.8, 149.6, 147.1, 136.1, 135.8, 123.4, 122.3, 102.7, 98.6, 77.8, 75.5, 59.5, 42.1, 41.1, 37.9, 34.0, 30.3ppm

Comm. No. 29

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.40 (br s, 2H), 8.01 (s, 1H), 7.58 (br d, J=7.7 Hz, 1H), 7.29 (br s, 1H), 7.11 (d, J=3.5 Hz, 1H), 6.86 (br s, 2H), 6.54 (d, J=3.5 Hz, 1H ), 4.69-4.92 (m, 3H), 4.16-4.39 (m, 1H), 3.76 (t, J=3.9 Hz, 1H), 2.85-2, 87 (m, 1H), 2.67 (br d, J=6.6 Hz, 2H), 2.33-2.46 (m, 2H), 2.26 (dd, J=13.4, 10 .3 Hz, 1H), 2.03-2.16 (m, 1H), 1.73-1.84 (m, 2H), 1.42-1.54 ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.9, 151.7, 150.5, 150.0, 147.6, 136.6, 136.3, 123.9, 122.4, 103.2, 99.2, 77.9, 76.2, 59.3, 43.1, 42.2, 40.6, 34.3, 30.7ppm

Comm. No. 30

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.02 (s, 1H), 7.74 (dd, J=8.1, 7.3 Hz, 1H), 7.17 (d, J =3.7 Hz, 1H), 7.06 (d, J=7.7 Hz, 1H), 6.88 (s, 2H), 6.81 (d, J=7.7 Hz, 1H), 6.53 (d, J=3.3 Hz, 1H), 4.75-4.88 (m, 3H), 4.21 (d, J=6.9 Hz, 3H), 3.71 (t , J=4.9 Hz, 1H), 2.57-2.71 (m, 1H), 2.37 (dd, J=13.0, 9.8 Hz, 1H), 2.19 (dd, J=11.6, 7.9 Hz, 1H), 2.07-2.15 (m, 1H), 1.96 (dd, J=13.0, 8.5 Hz, 1H), 1.89 (dd, J=11.4, 7.7Hz, 1H), 1.78ppm (ddd, J=11.6, 8.7, 2.8Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=163.2, 157.4, 151.2, 149.8, 147.1, 142.0, 122.3, 116.4, 109.4, 102.8, 98.6, 77.8, 75.5, 70.5, 59.4, 42.5, 41.5, 35.1, 30.9, 27.7 PPM

Comm. No. 31

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.01 (s, 1H), 7.73 (t, J=7.9 Hz, 1H), 7.12 (d, J=3.7 Hz, 1H), 7.05 (D, J = 7.7 Hz, 1H), 6.87 (S, 2H), 6.80 (D, J = 8.1 Hz, 1H), 6.53 ( D, j = 3.7 Hz, 1H), 4,78-4.91 (M, 3H), 4,25-4.35 (M, 1H), 4.20 (D, J = 6.9 Hz , 2H), 3.81 (s, 1H), 2.59 (dt, J=15.3, 7.4 Hz, 1H), 2.47 (br d, J=3.3 Hz, 1H), 2.28 (dd, J=13.4, 10.2 Hz, 1H), 2.11-2.22 (m, 1H), 1.91 (dd, J=11.4, 8.1 Hz, 1H), 1.83 (dd, J=13.6, 7.5Hz, 1H), 1.58ppm (dd, J=11.2, 7.9Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=163.2, 157.4, 151.2, 149.9, 147.1, 142.0, 122.0, 116.4, 109.4, 102.7, 98.6, 77.5, 75.7, 70.6, 58.9, 42.4, 42.1, 36.9, 30.7, 27.7ppm

Comm. No. 33

¹ h JAMR (DMSO-D ₆ , 400MHz): Δ = 8.31 (S, 1H), 8.00 (S, 1H), 7.56 (D, J = 8.1 Hz, 1H), 7, 7, 7, 7, 7, 27 (s, 1H), 7.15 (d, J=3.5 Hz, 1H), 7.05 (dd, J=8.1, 1.5 Hz, 1H), 6.86 (br s, 2H), 6.53 (br s, 2H), 6.52 (d, J=3.7 Hz, 1H), 4.77-4.88 (m, 1H), 4.76 (br d, J =6.2 Hz, 1H), 4.72 (br d, J=4.6 Hz, 1H), 4.16-4.26 (m, 1H), 3.69 (t, J=4.6 Hz, 1H), 3.17 (d, J=4.4 Hz, 1H), 2.77 (br d, J=7.3 Hz, 2H), 2.51-2.58 (m, 1H) , 2.33 (dd, J=13.0, 9.7 Hz, 1H), 2.11 (dd, J=11.0, 8.8 Hz, 1H), 1.99-2.08 (m , 1H), 1.91 (dd, J=13.2, 8.6 Hz, 1H), 1.78-1.85 (m, 1H), 1.67-1.77 ppm (m, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.9, 154.8, 151.7, 150.4, 147.2, 143.3, 139.5, 127.0, 124.3, 124.1, 122.7, 122.7, 106.1, 103.2, 99.1, 78.4, 76.0, 59.9, 43.1, 42.7, 41.7, 38, 7, 34.8, 30.9ppm

Comm. No. 34

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.31 (s, 1H), 8.01 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7, 27 (s, 1H), 7.11 (d, J=3.5 Hz, 1H), 7.05 (dd, J=8.3, 1.4 Hz, 1H), 6.87 (s, 2H ), 6.54 (d, J=3.3 Hz, 3H), 4.69-4.96 (m, 3H), 4.22-4.36 (m, 1H), 3.77 (br s , 1H), 2.76 (br d, J=6.6 Hz, 2H), 2.41-2.46 (m, J=5.5 Hz, 1H), 2.28 (dd, J=13 , 6, 10.3 Hz, 1H), 2.08-2,18 (M, 1H), 1.76-1.87 (M, 2H), 1.43-1.57 PPM (M, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=157.9, 154.8, 151.7, 150.5, 147.2, 143.3, 139.5, 127.0, 124.3, 124.1, 122.7, 122.4, 106.1, 103.2, 99.2, 77.9, 76.2, 59.2, 43.3, 43.1, 42.4, 41, 0, 34.6, 30.8ppm

Comm. No. 35

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=13.75 (br s, 1H), 9.25 (br s, 1H), 8.58 (br s, 1H), 8.35 (s, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.00 (d, J=3.5 Hz, 1H), 4.93 (br d, J=9.9 Hz, 1H ), 4.19 (dd, J=8.4, 4.6Hz, 1H), 3.64 (d, J=4.4Hz, 1H), 3.35 (d, J=6.8Hz 2H), 2.38 (DD, J = 13.4, 9.9 Hz, 1H), 2.23-2.34 (M, 1H), 1.90-2,11 (M, 3H), 1.76 (DD, J = 11.2, 7.9 Hz, 1H), 1.64 PPM (DDD, J = 11.3, 8.4, 2.8 Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=151.3, 147.5, 126.3, 102.5, 102.0, 78.7, 76.3, 66.0, 60.5, 42.4, 42.4, 36.3, 31.5, 31.5ppm

Comm. No. 36

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=13.75 (br s, 1H), 9.29 (br s, 1H), 8.67 (br s, 1H), 8.35 (s, 1H), 7.51 (d, J=3.5 Hz, 1H), 7.01 (d, J=3.5 Hz, 1H), 6.88-7.09 (m, 1H), 4, 87-5.00 (m, 1H), 4.28 (dd, J=8.6, 4.2 Hz, 1H), 3.78 (d, J=4.0 Hz, 1H), 3.58 (br s, 2H), 3.33 (d, J=6.2 Hz, 2H), 2.33-2.41 (m, 1H), 2.19-2.32 (m, 2H), 1 .99-2.07 (m, 1H), 1.73-1.83 (m, 2H), 1.46 ppm (dd, J=11.3, 7.8 Hz, 1H)

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=151.3, 147.5, 126.1, 102.6, 102.0, 78.2, 76.5, 65.9, 60.2, 43.0, 42.2, 37.6, 31.5, 30.8ppm

Comm. No. 44

¹³ C JAMR (DMSO-D ₆ , 101 MHz): δ = 156.4, 153.0, 150.1, 149.6, 146.4, 143.8, 134.4, 129.9, 127.9 , 127.8, 127.3, 127.0, 119.8, 87.3, 85.2, 76.6, 73.2, 41.6, 39.1, 34.7, 27.8 ppm.

Comm. No. 45

¹ H NMR (DMSO-d ₆ , 400 MHz): δ=8.84 (d, J=2.8 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.52 (dd, J=8, 1, 1.6Hz, 1H), 7.24(s, 2H), 5.84(d, J=7.3Hz, 1H), 5.38(d, J=6.9Hz, 1H) , 5.34 (d, J=4.5 Hz, 1H), 4.99 (dt, J=6.9, 3.5 Hz, 1H), 3.99 (t, J=4.1 Hz, 1H), 2.91 (br d, J=7.3 Hz, 2H), 2.56-2.67 (m, 1H), 2.30-2.41 (m, 1H), 2.07- 2.24 (m, 1H), 1.94 (dd, J=11.0, 9.4 Hz, 1H), 1.78 ppm (dd, J=11.0, 9.8 Hz, 1H).

¹³ C NMR (DMSO-d ₆ , 101 MHz): δ=156.0, 152.5, 149.8, 149.1, 145.9, 143.0, 139.8, 133.9, 129.4 , 127.2, 126.7, 126.5, 119.3, 86.6, 82.2, 74.5, 72.6, 42.0, 41.1, 35.9, 26.4 ppm.

LCMS (Liquid Chromatography/Mass Spectrometry)

High performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array detector (DAD) or UV detector and column as described in the respective methods. If necessary, additional detectors were included (see table of methods below).

The flow from the column was sent to a mass spectrometer (MS), which was equipped with an atmospheric pressure ionization source. It is within the purview of one skilled in the art to set adjustable parameters (eg, scan range, minimum measurement time, etc.) in order to obtain ions to determine the nominal monoisotopic molecular weight (MW) of the compound. Data collection was carried out using the appropriate software.

Compounds were described by their experimental retention times (R _t ) and ions. Unless otherwise indicated in the datasheet, the indicated molecular ion corresponds to [M+H] ⁺ (protonated molecule) and/or [M−H] ⁻ (deprotonated molecule). In case the compound was not directly capable of ionization, indicate the type of adduct (ie [M+NH ₄ ] ⁺ , [M+HCOO] ^- etc.). For molecules with complex isotope distributions (Br, Cl), the indicated value is the value obtained for the smallest mass of the isotope. All results were obtained with experimental errors, which are usually associated with the method used.

Hereinafter, "SQD" means single quadrupole detector, "MSD" means mass selective detector, "K.T." means room temperature, "BEH" means ethylsiloxane/silica bridged hybrid, "DAD" means diode array detector, "HSS" means high strength silica, "Q-Tof" means quadrupole time-of-flight mass spectrometers, "CLND" means chemiluminescent nitrogen detector, "ELSD" stands for Evaporative Light Scattering Detector.

Table: LCMS method codes (flow rate expressed in ml/min; column temperature (T) in °C; analysis time in minutes)

Method code device Column mobile phase Gradient Consumption
-------
T columns Analysis time 1 Waters: Acquity® UPLC® - DAD and SQD Waters : HSS T3
(1.8um, 2.1*100mm) A: 10 mM CH ₃ COONH ₄
in 95% H ₂ O+5% CH ₃ Cn
B: CH ₃ CN From 100% A to
5% A in 2.10 min.,
to 0% A in 0.90 min.,
up to 5% A in 0.5 min. 0.7
-------
55 3.5 2 Waters: Acquity ^® UPLC ^® - DAD and SQD Waters : BEH C18 (1.7um, 2.1*50mm) A: 10 mM CH ₃ COONH ₄ in 95% H ₂ O+5% CH ₃ CN
B: CH ₃ CN 95% A to 5% A in 1.3 min, hold for 0.7 min. 0.8
-------
55 2 4 Waters: ^Acquity®
UPLC ^® -
DAD and SQD Waters: Beh
(1.8um, 2.1*100mm) A: 10 mM CH ₃ COONH ₄
in 95% H ₂ O+5% CH ₃ Cn
B: CH ₃ Cn From 100% A to
5% A in 2.10 min.,
to 0% A in 0.90 min.,
up to 5% A in 0.5 min. 0.7
-------
55 3.5 5 Waters: Acquity ^®
UPLC ^® -
DAD and SQD Waters : HSS T3
(1.8um, 2.1*100mm) A: 10 mM CH ₃ COONH ₄
in 95% H ₂ O + 5% CH ₃ CN
B: CH ₃ CN From 100% A to
5% A in 2.10 min.,
to 0% A in 0.90 min.,
up to 5% A in 0.5 min. 0.7
-------
55 3.5 6 Waters: ^{Acquity®
UPLC®-}
DAD and SQD Waters:BEH
(1.8um, 2.1*100mm) A: 10 mM CH ₃ COONH ₄
in 95% H ₂ O + 5% CH ₃ CN
B: CH ₃ CN From 100% A to
5% A in 2.10 min.,
to 0% A in 0.90 min.,
up to 5% A in 0.5 min. 0.7
-------
55 3.5 7 Waters: Acquity ^® UPLC ^® -DAD, SQD and ELSD Waters : HSS T3 (1.8um, 2.1*100mm) A: 10 mM CH ₃ COONH ₄ in 95% H ₂ O+5% CH ₃ CN
B: CH ₃ CN 100% A to 5% A in 2.10 min, to 0% A in 0.90 min, to 5% A in 0.5 min. 0.6
-------
55 3.5

Table: LCMS connections (comm. no. means connection number; Rt is expressed in minutes)

conn. no. R _t [M +h] ⁺ LCMS method 1 / / / 2 1.16 436.3 1 3 1.48 455.3 1 4 1.50 499.2 1 5 1.10 436.3 1 6 0.77 499.2 2 7 0.25 294.2 2 8 0.25 294.2 2 9 1.44 455.3 4 10 1.42 455.3 4 eleven 1.37 418.2 4 12 1.58 452.3 4 13 1.55 452.3 4 14 1.70 450.3 4 15 1.70 450.3 4 16 1.46 422.3 4 17 1.49 422.3 4 18 1.29 437.4 4 19 1.30 437.4 4 20 1.44 422.4 5 21 1.44 422.4 5 22 1.24 437.4 4 23 1.24 437.3 4 24 1.15 405.4 4 25 1.13 405.4 4 26 1.20 366.3 4 27 1.20 366.3 4 28 1.17 366.3 4 29 1.17 366.3 4 thirty 1.58 416.3 5 31 1.57 416.3 5 32 0.59; 0.61 416.3 2 33 1.57 509.3 6 34 1.56 509.3 6 35 0.43 305.2 2 36 0.40 305.2 2 39 / / / 40 2.36 558.2 1 41 2.29 602.2 1 42 1.11 558.2 2 43 1.13 602.2 2 44 1.59 453.3 7 45 1.63 453.3 7

EXPERIMENTAL PROCEDURES for in vitro assay

Reagents. The PRMT5-MEP50 enzyme was purchased from Charles River (Argenta). The enzyme complex was produced in insect cells (Sf9) infected simultaneously with two baculoviruses. One virus expresses full-length human PRMT5 with a Flag tag at the N-terminus, the second virus expresses full-length MEP50 with a His6-TEV cleavage site at the N-terminus. Protein was affinity purified using anti-Flag (M2) coated particles followed by eluting with 3xFLAG peptide followed by His-Select eluting with 0.5 M imidazole. The eluted protein was then dialyzed to remove Tris buffered saline (TBS) (pH 8.0) containing 20% glycerol and 3 mM dithiothreitol (DTT).

Full-length unlabeled recombinant human histone H2A (residues 1-130, Genbank accession number NM_021052, MW=14.1 kDa) expressed in E. coli was purchased from Reaction Biology Corporation, cat no. HMT-11-146. Purchased reagents used to prepare reaction buffer or stop buffer, including Tris base (Sigma Cat. No. T-1503), NaCl (Sigma Cat. No. RGF-3270), MgCl ₂ (Sigma Cat. No. M0250), DTT (No. according to the cat. Invitrogen 15508-013) and anticolous acid (Riedel Dehaen, No. according to Cat. 33015).

Analysis on a high-performance mass spectrometer. PRMT5 catalyzes sequential methylations of terminal nitrogen atoms on the guanidine groups of arginine residues in proteins, using the substrate cofactor S-adenosyl-L-methionine (AdoMet, SAM), to form monomethyl (MMA), symmetrical dimethylarginine (sDMA), and S-adenosyl-L- homocysteine (AdoHcy, SAH). Enzymatic activity was determined from the formation of the SAH product using high performance mass spectrometry (Agilent Rapidfire 300 system with QTrap ^® Triple Quadrupole MS/MS Sciex 4000 series). The reaction buffer was 20 mM Tris-HCl, pH 8.5, 50 mM NaCl, 5 mM MgCl ₂ and 1 mM DTT. The reaction was stopped using 1% formic acid (final concentration).

Inhibition studies. IC ₅₀ studies were performed using eleven point dose series obtained for each compound by a 1:2 serial dilution in dimethyl sulfoxide (DMSO), with point 12 being DMSO as a control. Compounds were first loaded onto plates and then a mixture of 2 μM SAM and 0.6 μM H2A (histone H2A) solutions was added. The same volume of enzyme solution was added to initiate enzymatic reactions. The final concentrations of the reaction mixture were 1 μM SAM, 0.3 μM H2A and 1.25 nM enzyme. The reaction mixture was incubated at 30° C. for 60 minutes (min.) when 10 nM of enzyme was used and for 120 minutes when 1.25 nM of enzyme was used. The reaction mixture was then quenched by adding formic acid to a final concentration of 1%. The values of inhibition of SAH formation in the presence of compounds were calculated as the percentage of control relative to the uninhibited reaction mixture, depending on the concentration of the inhibitor. The data was adjusted as follows:

Y=Lower value + (High value - Lower value)/(1+10^((log IC ₅₀ - X) * h)),

where IC ₅₀ is the inhibitor concentration (same units as X) at 50% inhibition, and h is the Hill slope. Y is percent inhibition, X is log of compound concentration. The lower value and upper value are the values for the plateau in the same units as Y.

The pIC ₅₀ values in the table below are average values (comp. no. means compound number; n.o. means not determined).

conn. no. _pic50 8 5.45 7 5.30 1 5.52 4 5.52 2 7.51 5 8.03 6 6.92 3 5.09 eleven 7.04 15 5.96 14 5.70 16 6.31 17 6.41 35 6.03 36 5.85 19 6.88 18 7.45 26 5.61 27 5.25 10 n. O. 9 6.59 22 5.80 23 6.53 20 6.31 21 6.84 31 5.46 thirty 5.79 32 5.69 12 5.62 13 6.19 34 n. O. 33 6.61 29 6.77 28 6.84 25 7.99 24 8.04 40 n. O. 41 n. O. 42 n. O. 43 n. O. 39 n. O. 45 5.26 44 5.34

Examples of compositions

As used throughout these examples, "active ingredient" (a.i.) refers to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates; in particular to any of the exemplary compounds.

Typical examples of formulations for the composition of the present invention are as follows.

1. Tablets

Active ingredient 5-50 mg

Phosphate dicalse 20 mg

Lactose 30 mg

Talc 10 mg

Staminet of magnesium 5 mg

Potato starch up to 200 mg

2. Suspension

An aqueous suspension for oral administration was prepared so that each milliliter contained 1-5 mg of the active ingredient, 50 mg of sodium carboxymethyl cellulose,

1 mg sodium benzoate, 500 mg sorbitol and water to 1 ml.

3. The injection form

A parenteral formulation was prepared by mixing 1.5% (w/v) active ingredient in 0.9% NaCl solution or 10% v/v propylene glycol in water.

4. Ointment

Active ingredient 5-1000 mg

Stearil alcohol 3 g

Lanolin 5 g

White Vaseline 15 g

Water up to 100 g

In this example, the active ingredient can be replaced by the same amount of any compounds in accordance with the present invention, in particular, the same amount of any of the compounds given as an example.

Claims (64)

1. Formula connection (i)

where R ¹ represents hydrogen or-C(=O)-C _1-4 alkyl; R ² is hydrogen or -C(=O)-C _1-4 alkyl; X is hydrogen; Y represents -O- or -CH ₂ -; Q ¹ is CR ^6a ; Q ² is N or CR ^6b ; each of R ^6a and R ^6b independently represents hydrogen; R ^3a is halogen, -NR ^7a R ^7b ; R ^7a is hydrogen; R ^7b is hydrogen; R ^4a is hydrogen; L represents -CH ₂ -, -O-CH ₂ -, -CH ₂ -O- or -O-; R ⁵ is Ar or Het; and if L is -O- or -O-CH ₂ -, R ⁵ may also be hydrogen; Ar is phenyl; Het is a monocyclic or bicyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), (a-5), (a-6) and (a-7),

where the specified monocyclic or bicyclic aromatic ring system is optionally substituted with one or more substituents, each of which is independently selected from the group consisting of halogen and-NH ₂ ; or a pharmaceutically acceptable addition salt thereof. 2. Connection according to paragraph 1, where Y represents -O- or -CH ₂ -; R ^6a and R ^6b are hydrogen; R ^3a is halogen or -N ^{R 7a} R ^7b ; R ^7b is hydrogen; R ^4a is hydrogen; R ⁵ is Ar or Het; and if L is -O- or -O-CH ₂ -, R ⁵ may also be hydrogen; Ar is phenyl. 3. Connection according to paragraph 1, where R ¹ is hydrogen; R ² is hydrogen; Y is -o-; Q ² is N; R ^6a is hydrogen; R ^3a is -NR ^7a R ^7b ; R ^7b is hydrogen; R ^4a is hydrogen; L is -o-; R ⁵ is Het; Het is (a-1) optionally substituted with one or more substituents each independently selected from the group consisting of halo and —NH ₂ . 4. A compound according to claim 1 or 2, wherein R ¹ and R ² are hydrogen. 5. Connection under item 1 or 2, where R ¹ represents -C(=O)-C _1-4 alkyl; R ² is -C(=O)-C _1-4 alkyl. 6. The connection according to any one of paragraphs. 1-5, where Y is -O-. 7. Connection according to any one of paragraphs. 1-6, where R ⁵ is Het. 8. Connection according to any one of paragraphs. 1-7, where R ^3a is halogen or -NR ^7a R ^7b . 9. Connection according to any one of paragraphs. 1-8, where R ^3a is -NR ^7a R ^7b ; R ^7a and R ^7b are hydrogen. 10. Connection according to any one of paragraphs. 1-9 where Q ² is N. 11. Connection where the connection is selected from

TFA salt, number of equivalents not determined

salt HCl, number of equivalents not determined

salt HCl, number of equivalents not determined

salt HCl, number of equivalents not determined

and its free bases, pharmaceutically acceptable addition salts. 12. Pharmaceutical composition for inhibiting PRMT5 containing a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of paragraphs. 1-11 as an active ingredient. 13. Connection according to any one of paragraphs. 1-11 for use as a drug. 14. Connection according to any one of paragraphs. 1-11 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, multiple organ failure, kidney disease, platelet aggregation, insufficient sperm motility, transplant rejection, tissue rejection, and lung injury. 15. The compound of claim 14 wherein the disease or condition is cancer. 16. Intermediate compound of formula (XXX)

where Y represents -O- or -CH ₂ ; R ^a is C _1-4 alkyl, benzyl;

R ^b is -OH, ═O or ═CH ₂ ; where the bond towards R ^b is a single bond if R ^b is -OH, or a double bond if R ^b is ═O or ═CH ₂ ; R ^c1 and R ^c2 are -C(=O)-C _1-4 alkyl; or R ^c1 and R ^c2 taken together are -C(C _1-4 alkyl) ₂ -; or its addition salt. 17. Use of an intermediate compound according to claim 16 in the synthesis of a compound according to claim 1.