EA044355B1 - NEW CARBANUCLEOSIDE ANALOGUES REPLACED BY MONOCYCLIC AND BICYCLIC RING SYSTEMS FOR USE AS PRMT5 INHIBITORS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to novel monocyclic and bicyclic ring system substituted carbanucleoside analogues useful as PRMT5 inhibitors. In addition, the present invention relates to pharmaceutical compositions containing these compounds as an active ingredient, as well as the use of these compounds as a drug.

Prerequisites for creating an invention

PRMT5, also described as Hsl7, Jbp1, Skb1, Capsuleen or Dart5, is one of the major methyltransferases responsible for mono- and symmetric dimethylation of arginines. Post-translational arginine methylation on histones and non-histone proteins has been shown to be critical for a variety of biological processes, such as genome organization, transcription, differentiation, splicing 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 methylosome protein 50 (MEP50), also called Wdr77, androgen receptor coactivator p44 and Valois. Both elevated PRMT5MER50 protein levels and cytoplasmic accumulation have been implicated in cancer tumorigenesis 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 scaffolding functions of the PRMT5-MEP50 complex, in addition to comprehensive enzymatic studies, have demonstrated an oncological link between protein levels, 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] [ChanPenebre, 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, which involves the use of Sadenosylmethionine (SAM) to produce symmetrical dimethylated arginine on histone and non-histone protein substrates and S-adenosylhomocysteine (SAH). The crystal structure of the human hetero-octamer complex (PRMT5) ₄ (MEP50) ₄ cocrystallized with SAH and a histone H4 peptide substrate revealed 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 binding participants, influence on post-translational modification, miRNAs and subcellular localization.

Methylation of histones H2A and H4 on Arg3 and histone H3 on Arg8 regulates chromatin organization to specifically suppress 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 may 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 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 PRMT5-containing methylosome [Friesen, W.J. et al., Mol Cell Biol, 2001. 21(24): p. 8289-300].

Further 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 its involvement in splicing, PRMT5 influences key pathways involved in cell differentiation and homeostasis by directly methylating key signal transduction nodes similar to p53 [Jansson, M. et al., Nat Cell Biol, 2008. 10(12): p. 1431-9], EGFR [Hsu, J.M. 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, T.Y. et al., Cell Signal, 2014. 26(12): p. 2940-50], NFkB [Wei, H. et al., Proc Natl Acad Sci U S A, 2013. 110(33): p. 13516-21].

Because PRMT5 is one of the major sym-Arg methyltransferases and is involved in a variety of cellular processes, increased protein expression appears to be an important factor in its tumorigenicity. Interestingly, translation of PRMT5 in mantle cell lymphoma (MCL) appears to be regulated by miRNA. Although MCL cells have less PRMT5 mRNA and a slower transcription rate of PRMT5 than normal B cells, 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 a miRNA that binds the PRMT5 3'UTR region reduces PRMT5 protein levels [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

- 1 044355 translation, and not about a high level 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 PRMT5 inhibitors have been published so far. More recently, a novel subnanomolar potent inhibitor of PRMT5 (EPZ015666) with antitumor activity in multiple MCL xenograft models was 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 the treatment of cancer.

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 to treat PRMT5-mediated disorders are also described.

WO 2014100730A1 discloses PRMT5 inhibitors containing dihydro- or tetrahydroisoquinoline and routes for their use.

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

WO 2003070739 discloses partial and full adenosine A1 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 uses thereof.

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

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

WO 201207 5500 discloses 7-deazapurine histone methyltransferase modulators.

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 of 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.

Thus, there is an urgent need for new PRMT5 inhibitors that provide new pathways for the treatment or prevention of cancer, such as mantle cell lymphoma. It is therefore an object of the present invention to provide such connections.

The compounds of the present invention are structurally different and may have improved properties, such as, for example, increased potency, 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 of the present invention and their compositions may be useful for the treatment or prevention, in particular for the treatment, of diseases such as blood disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney disease, platelet aggregation, poor sperm motility, transplant rejection, tissue rejection, lung damage and the like.

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

- 2 044355

Ar--Z

Yr rW or ²

R ¹ represents hydrogen;

R ² represents hydrogen;

Y represents -CH ₂ -;

Z represents -CH ₂ -, -CHR ⁵ⁱ -, -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d -, -CR ^5e R ^5g -CR ^5f R ^5h -, -CR5cR5d-CR5eR5g-CR5fR5h- or -CR ^5a R ^5b -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h -;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g , R ^5h and R ⁵¹ are each independently hydrogen or C _1-4 alkyl;

X represents -O-;

Ar is a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S and N, wherein said 9- a membered bicyclic aromatic ring is attached to the rest of the molecule by a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring;

Ar is optionally substituted on the carbon atoms with a total of one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, oxo, -NH2, -NH-C _1-4 alkyl, -CF3, C _3-6 cycloalkyl and C _1-4 alkyl; and, if possible, Ar is optionally substituted at one N atom with one C _1-4 alkyl;

Het is a bicyclic aromatic heterocyclic ring system (a-1):

(a-1)

R ^3a is halogen, -NR ^7a R ^7b or -O-C _1-4 alkyl;

R ^7a represents hydrogen;

R ^7b represents hydrogen or C _1-4 alkyl;

R ^4a represents hydrogen;

Q ¹ represents CR ^6a ;

Q ² represents CR ^6b ;

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

and their pharmaceutically acceptable addition salts.

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 themselves or can be metabolized into a (more) active form in vivo (prodrugs) and thus may be useful for 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, poor sperm motility, graft rejection, tissue rejection, lung injury and the like.

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

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 the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the preparation of a medicament for inhibiting PRMT5, for the treatment or prevention of any of the diseases or conditions mentioned earlier or hereinafter, in particular cancer.

The present invention will be described next. Various aspects of the present invention are more

- 3 044355 are defined in detail in the following sections. Each aspect so defined may be combined with any other aspect or aspects unless expressly 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 construed in accordance with the following definitions, unless the context indicates otherwise.

If any variable appears 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.

The term substituted as used herein is intended to mean, unless otherwise stated or clearly apparent from the context, one or more hydrogen atoms, in particular 1 to 3 hydrogen atoms, preferably 1 or 2 hydrogen atoms, more preferably 1 hydrogen atom, with the atom or radical designated using the expression substituted, is replaced by one selected from the group indicated, provided that the normal valence is not exceeded and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently stable 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 fragment, then they can, unless otherwise indicated or clearly follows from the context, replace hydrogen atoms at the same atom, or they can replace hydrogen atoms at different atoms in the fragment.

The prefix C _x -Y (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a _C1-4 alkyl group contains from 1 to 4 carbon atoms, _C1 . ₃ αlkyl group contains from 1 to 3 carbon atoms, etc.

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

The term _{C1_4} alkyl, as a group or part of a group, refers to a hydrocarbon radical of the formula _{CnH2n +1} , where n is a number ranging from 1 to 4. _{C1_4} alkyl groups contain from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. The _{C1_4} alkyl groups may be straight or branched and may be substituted as specified herein. When a subscript is used herein after a carbon atom, the subscript denotes 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 the term 'C1. ₄ alkoxy' or 'C1. ₄ alkyloxy' as a group or part of a group refers to a radical characterized by the formula -OR ^c where R ^c represents C1_ ₄ alkyl. Non-limiting examples of suitable _{C1_4} alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and t-butyloxy.

The term _{C2_4} alkenyl, as used herein as a group or part of a group, is a straight or branched _hydrocarbon group containing from 2 to 4 carbon atoms and containing a carbon-carbon double bond, such as, but not limited to, ethenyl, propenyl, butenyl , 1-propene-2-or the like.

The term C _2-6 alkenyl, as used herein as a group or part of a group, is a straight or branched hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon-carbon double bond, such as, but not limited to, ethenyl, propenyl, butenyl , pentenyl, 1-propen-2-yl, hexenyl, etc.

The term _C3-6 cycloalkyl, as used herein as a group or part of a group, represents cyclic saturated hydrocarbon radicals containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term C _5-6 cycloalkyl, as used herein as a group or part of a group, represents cyclic saturated hydrocarbon radicals containing from 5 to 6 carbon atoms, such as cyclopentyl or cyclohexyl.

The term oxo means a double bond group (=O) attached as a substituent.

In case Z is -X-CR ^5a R ^5b -, then it is assumed that X is attached to Ar.

If Z is -CR ^5c =CR ^5d -, then it is assumed that the C atom with the R ^5c substituent is attached to Ar.

If Z is -CR ^5e R ^5s -CR ^5f R ^5h -, then it is assumed that the C atom with the substituents R ^5e and R ^5s is attached to Ar.

- 4 044355

If Z is -CR ^5a R ^5b -X-, then it is assumed that the C atom with the substituents R ^5a and R ^5b is attached to Ar.

It will be apparent to one skilled in the art that, unless otherwise stated or clear from the context, a substituent on a 4- to 7-membered monocyclic aromatic ring containing one, two, or three heteroatoms (as in the definition of R ¹³ ) (non-limiting examples include pyrrolyl, pyridinyl, furanyl, etc.), can replace any hydrogen atom on the ring carbon atom or, if possible, on the ring nitrogen atom (in which case the hydrogen on the nitrogen atom can be replaced by a substituent).

A 4-7 membered monocyclic aromatic ring containing one, two or three heteroatoms (as in the definition of R ¹³ ) may optionally be attached to the rest of the molecule of formula (I) by any available carbon atom or nitrogen atom of the ring, unless otherwise stated.

One skilled in the art will appreciate that typical 4-7 membered monocyclic aromatic rings will be 5 or 6 membered monocyclic aromatic rings such as, for example, pyrrolyl, pyridinyl, furanyl, and the like.

When Ar is imidazolyl, it may be attached to the rest of the molecule via a ring carbon atom or a ring nitrogen atom.

Non-limiting examples of the Ar group, which is a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S and N, are yourself

wherein said 9-membered bicyclic aromatic ring is attached to the rest of the molecule by a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring;

each of which is optionally substituted according to any of the embodiments.

In the case where Ar is a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, where the nitrogen atom replaces one of the two carbon atoms common to the two fused rings in the Ar group, then the carbonyl group is located in the specified bicyclic aromatic ring system ring system, illustrated by the structure shown below,

O which is optionally substituted according to any of the embodiments. It should be understood that this example is non-limiting.

Other non-limiting examples of the Ar group, which is a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings where optionally 1 or 2 of the ring carbon atoms are replaced by a nitrogen atom, are shown below:

- 5 044355

each of which is optionally substituted according to any of the embodiments.

Non-limiting examples of an Ar group that is a fused bicyclic, partially aromatic ring system that is attached to an aromatic ring via a Z linker are shown below:

each of which is optionally substituted according to any of the embodiments.

In all cases where substituents are represented by a chemical structure,

I___I!

means a bond for attachment to the rest of the molecule of formula (I).

It will be appreciated that lines drawn from substituents to ring systems indicate that a bond may be attached to any of the suitable ring atoms unless otherwise indicated or clearly apparent from the context.

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 produces a biological or medical response in a tissue system in an animal or human that is sought to be produced by a researcher, veterinarian, physician, or other clinician, which includes relief or relief. 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 include all modalities 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 the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates.

Certain compounds of formula (I) may also exist in their tautomeric form. The term tautomer or tautomeric form refers to structural isomers with different energies that are interconvertible due to their low energy barrier. For example, protic tautomers (also known as prototropic tautomers) involve interconversions due to proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversions through the rearrangement of some bonding electrons.

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

Any chemical formula used herein in which the bonds are shown only as solid lines rather than as solid wedges or dotted wedges, or otherwise shown as having a specific configuration (e.g., R, S) around one or more atoms , provides each possible stereoisomer or a 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 included as compounds of the present invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.

As used herein and below, the term compound of formula (I) is intended to include

- 6 044355 its stereoisomers and tautomeric forms. However, if the stereochemistry, as noted in the previous paragraph, is indicated by bonds that are represented as solid wedges or dotted wedges, or are otherwise shown as having a specific configuration (e.g.

R, S), then this stereoisomer is indicated and defined in this way. It will be clear that this also applies to the subgroups of formula (I).

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

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

Enantiomers are stereoisomers that are non-matching mirror images of each other when superimposed. 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 formed as a result of 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 are not related as mirror images. If the compound contains a double bond, the substituents may be in the E- or Z-configuration. Substituents on divalent cyclic (partially) saturated radicals can be in either the cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, 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 chemically possible.

The meanings of all these terms, i.e. enantiomers, atropisomers, diastereomers, racemates, Eisomers, Z-isomers, cis-isomers, trans-isomers and mixtures thereof are known to one skilled in the art.

The absolute configuration is determined according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is defined as either R or S. Isolated stereoisomers, the absolute configuration of which is unknown, can be designated as (+) or (-) depending on the direction in which they rotate the plane of polarization of light. 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 the stereoisomer contains essentially no other stereoisomers, i.e. is associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1% of other stereoisomers. Thus, if a compound of formula (I), for example, is indicated as (R), this means that the compound contains substantially no isomer (S); if a compound of formula (I), for example, is indicated as E, this means that the compound contains substantially no isomer Z; if a compound of formula (I), for example, is indicated as cis, this means that the compound contains substantially 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 that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be prepared by conventional methods, for example, by reacting the free acid or free base form with one or more equivalents of the corresponding acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removal of said solvent or medium using standard techniques (for example, 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 herein are intended to include the therapeutically active, non-toxic acid and base addition salt forms that the compounds of formula (I) and solvates thereof 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, ethane- 7 044355 sulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamic and similar acids. Conversely, these salt forms can be converted by treatment with an appropriate base into 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 forms of salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example lithium, sodium, potassium, magnesium, calcium and the like salts, salts with organic bases, for example primary, secondary and tertiary aliphatic and with 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-O-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 into the free acid form.

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

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

Prodrugs can be prepared by modifying functional groups present in a compound such that the modifications are cleaved in vivo when the 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, wherein the hydroxyl group in the compound of the present invention is bonded to any group (eg, -C(=O)-C^alkyl) that can be cleaved in vivo to reduce the free hydroxyl. In the context of the present invention, prodrugs are in particular compounds of formula (I) or subgroups thereof, wherein R1 and/or ^R2 are -C(=O)-Smalkyl.

Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. Design of Prodrugs p. 1-92, Elsevier, New York-Oxford (1985).

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

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. A method for separating the enantiomeric forms of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be prepared from the corresponding pure stereochemically isomeric forms of the corresponding starting materials, provided that the reaction proceeds stereospecifically. If a specific stereoisomer is desired, it is preferred that said compound be synthesized by stereospecific preparation methods. These methods preferably use enantiomerically pure starting materials.

The present invention also covers isotopically labeled compounds of the present invention that are identical to those provided 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 typically found in nature (or the most common found in nature).

All isotopes and isotopic mixtures of any particular atom or element defined herein are considered within the scope of the compounds of the present invention, whether naturally occurring or synthetically produced, whether in naturally occurring isotopic composition or in isotopically enriched form. Exemplary 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 ^2H , ^3H , 11C, ^13C , ¹⁴ С, ¹³ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² Р, ³³ Р, 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, ³ H and ¹⁴ C labeled) are useful in substrate tissue distribution assays. The isotopes tritium ( ^3H ) and carbon-14 ( ^14C ) are useful because they are easy to obtain and can be detected. Additionally, substitution with heavier isotopes such as deuterium (i.e., ^2H ) may provide certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement) and may therefore be preferable in some cases. Positron-active isotopes such as ¹⁵ O, ¹³ N, 11 C and ¹⁸ F are useful in positron emission tomography (PET) studies to assess the extent of receptor occupancy by a substrate.

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

R ¹ represents hydrogen;

R ² represents hydrogen;

Y represents -CH ₂ -;

Z represents -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d - or -CR ^5e R ^5g - CR ^5f R ^5h -;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g and R ^5h are hydrogen;

X represents -O-;

Ar is a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S and N, wherein said 9- a membered bicyclic aromatic ring is attached to the rest of the molecule via a ring carbon atom of a 5- or 6-membered ring;

wherein Ar is optionally substituted at the carbon atoms with only one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, -NH ₂ , -NH-C _1-4 αlkyl, -CF ₃ , C _{3- 6} cycloalkyl and C _1-4 alkyl; and, if possible, Ar is optionally substituted at one N atom with one substituent selected from the group consisting of C _1-4 alkyl;

Het represents (a-1);

R ^3a represents halogen, -NR ^7a R ^7b or -O-C _1-4 αlkyl;

R ^7a represents hydrogen;

R ^7b represents hydrogen or C _1-4 alkyl;

R ^4a represents hydrogen;

Q ¹ represents CR ^6a ;

Q is CR ^6b ;

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

and their pharmaceutically acceptable addition salts.

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

R ¹ represents hydrogen;

R ² represents hydrogen;

Y represents -CH ₂ -;

Z represents -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d - or -CR ^5e R ^5g -CR ^5f R ^5h -;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g and R ^5h are hydrogen;

X represents -O-;

Ar is a 9-membered bicyclic aromatic ring system selected from the group consisting of co...co. sa

- 9 044355 wherein Ar is optionally substituted at the carbon atoms with only one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, -NH2,

-NH-C _1-4 αalkyl, -CF ₃ , C ₃ _ ₆ cycloalkyl and C _1-4 alkyl; and, if possible, Ar is optionally substituted at one N atom with one substituent selected from the group consisting of C _1-4 alkyl;

Het represents (a-1);

R ^3a represents halogen, -NR ^7a R ^7b or -O-C _1-4 αlkyl;

R ^7a represents hydrogen;

R ^7b represents hydrogen or C _1-4 alkyl;

R ^4a represents hydrogen;

Q ¹ represents CR ^6a ;

Q is CR ^6b ;

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

and their pharmaceutically acceptable addition salts.

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

R ¹ represents hydrogen;

R ² represents hydrogen;

Y represents -CH2-;

Z represents -CR ^5e R ^5s -CR ^5f R ^5h -;

R ^5e , R ^5f , R ^5s and R ^5h are hydrogen;

Ar represents

wherein Ar is optionally substituted at the carbon atoms with only one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, -NH ₂ , -NH-C _1-4 alkyl, -CF ₃ , C _{3- 6} cycloalkyl and C _1-4 alkyl;

Het represents (a-1);

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

R ^7a represents hydrogen;

R ^7b represents hydrogen;

R ^4a represents hydrogen;

Q ¹ represents CR ^6a ;

Q is CR ^6b ;

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

and their pharmaceutically acceptable addition salts.

In one embodiment, the present invention provides novel compounds of formula (I), wherein R ¹ represents hydrogen; R ² represents hydrogen; Y represents -CH ₂ -; Z represents -CR ^5e R ^5s -CR ^5f R ^5h -; ^R5e , ^R5f , ^R5s and ^R5h are hydrogen; Ar represents

where Ar is substituted at the position designated β, C _1-4 alkyl;

wherein Ar is optionally substituted at the position designated Y by halogen;

Het represents (a-1);

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

R ^7a represents hydrogen;

R ^7b represents hydrogen;

R ^4a represents hydrogen;

Q ¹ represents CR ^6a ;

Q ² represents CR ^6b ;

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

and their pharmaceutically acceptable addition salts.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof, which are specified in any of the other embodiments, where one or more of the following limitations apply: (i) R ¹ and R2 represent hydrogen; (ii) Y is -CH2-; (iii) Z is -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d - or -CR ^5e R ^5s -CR ^5f R ^5h -;

(iv) R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R5 ^s and R ^5h are hydrogen;

(v) X represents -O-;

- 10 044355 (vi) Ar is a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S and N , wherein said 9-membered bicyclic aromatic ring is attached to the rest of the molecule via a ring carbon atom of the 5- or 6-membered ring;

wherein Ar is optionally substituted at the carbon atoms with only one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, -NH ₂ , -NH-C _1-4 αlkyl, -CF ₃ , C _{3- 6} cycloalkyl and C _1-4 alkyl; and, if possible, Ar is optionally substituted at one N atom with one substituent selected from the group consisting of C _1-4 alkyl;

(vii) Het represents (a-1);

(viii) R ^3a is halogen, -NR ^7a R ^7b or -OC _1-4 alkyl;

(ix) R ^7a is hydrogen; R ^7b represents hydrogen or C _1-4 alkyl;

(x) R ^4a is hydrogen;

(xi) Q ¹ is CR ^6a ; Q ² represents CR ^6b ;

(xii) R ^6a and R ^6b are hydrogen or halogen.

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

R ¹ and R ² represent hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as defined in any of the other embodiments wherein Y is -CH2-.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Q ¹ is CR ^6a ; and Q ² is CR ^6b ; in particular, where Q ¹ represents CH; and Q ² represents CH.

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

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof, as specified in any of the other embodiments, wherein Het is (a-1); Q ¹ represents CR ^6a ; and Q ² is CR ^6b ; in particular, where Q represents CH; and Q ² represents CH.

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

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Ar is a 9-membered bicyclic aromatic ring system selected from a group consisting of wherein said 9-membered bicyclic aromatic ring is attached to the rest of the molecule via a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom

5-membered ring;

wherein Ar is optionally substituted according to any other embodiment.

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

Ar is a 9-membered bicyclic aromatic ring system selected from the group consisting of

wherein Ar is optionally substituted according to any other embodiment.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Ar is a 9-membered bicyclic aromatic ring system selected from group consisting of

where Ar is substituted at the position designated a (if any), -NH2, -NH-C _1-4 αlkyl or NHR ¹⁰ ; and wherein Ar is optionally substituted with substituents selected from the list of substituents on Ar 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 or any subgroup thereof as specified in any of the other embodiments, wherein

Ar is a bicyclic ring system;

wherein Ar is optionally substituted according to any other embodiment.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts, or any subgroup thereof, as specified in any of the other embodiments, wherein Ar is a 9-membered bicyclic

- 12 044355 an aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S and

N, wherein said 9-membered bicyclic aromatic ring is attached to the rest of the molecule via a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom

5-membered ring;

wherein Ar is optionally substituted according to any other embodiment.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Ar is a 9-membered bicyclic aromatic ring system selected from

wherein Ar is optionally substituted according to any other embodiment.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Ar is a 9-membered bicyclic aromatic ring system selected from group consisting of

wherein said 9-membered bicyclic aromatic ring is attached to the rest of the molecule by a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring;

wherein Ar is optionally substituted according to any other embodiment.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Ar is a 9-membered bicyclic aromatic ring system selected from group consisting of

- 13 044355

wherein Ar is optionally substituted according to any other embodiment.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Ar is a 9-membered bicyclic aromatic ring system selected from group consisting of

where Ar is substituted at the position designated a (if any), -NH2, -NH-C _1-4 alkyl or NHR ¹⁰ ; and wherein Ar is optionally substituted with substituents selected from the list of substituents on Ar 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 or any subgroup thereof as specified in any of the other embodiments, wherein

Ar is a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S and N, wherein said 9- a membered bicyclic aromatic ring is attached to the rest of the molecule by a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring;

wherein Ar is optionally substituted according to any other embodiment.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts, or any subgroup thereof, as defined in any of the other embodiments, wherein R ^5b , R ^5g and R ^5h are hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Q ¹ is CR ^6a ; and Q2 is CR ^6b .

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

R ^5b , R ^5g and R ^5h are hydrogen;

Y represents -CH2-;

Het represents (a-1);

Q ¹ represents CR ^6a ; and Q ² is CR ^6b ; in particular, where Q ¹ represents CH; and Q ² represents CH.

- 14 044355

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as defined in any of the other embodiments wherein Q ² is CR ^6b .

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts, or any subgroup thereof, as specified in any of the other embodiments, wherein Y is -CH ₂ -.

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

Z represents -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d - or -CR ^5e R ^5g -CR ^5f R ^5h -;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g and R ^5h are hydrogen;

X represents -O-.

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

Z represents -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d - or -CR ^5e R ^5g -CR ^5f R ^5h -.

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

Z is -X-CR ^5a R ^5b -.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts, or any subgroup thereof, as defined in any of the other embodiments, wherein Z is -O-CH2-.

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

Z represents -X-CR ^5a R ^5b -; X represents -O-; and R ^5a and R ^5b are hydrogen.

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

X represents -O-.

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

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 or any subgroup thereof as specified in any of the other embodiments, wherein Het is (a-1); R ^3a is -NR ^7a R ^7b ; and 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 or any subgroup thereof as specified in any of the other embodiments, wherein

Z represents -CH2-, -CHR ⁵¹ -, -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d -, -CR ^5e R ^5g -CR ^5f R ^5h , -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h - or -CR ^5a R ^5b -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h -;

^R5a , ^R5b , ^R5c , ^R5d , R5e, ^R5f , ^R5g , ^R5h and ^R51 are ^each independently hydrogen or _C1.4αalkyl ;

X represents -O-;

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

R ^3a is halogen, -NR ^7a R ^7b or -O-C ¹ ' ⁴ αlkyl;

Q ¹ represents CR ^6a ;

Q ² represents CR ^6b .

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

Z represents -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d -, -CR ^5e R ^5g -CR ^5f R ^5h -, -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h - or

-CR ^5a R ^5b -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h -;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g and R ^5h are each independently hydrogen or C ₁ . ₄ alkyl; X represents -O-;

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

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

R ^7a and R ^7b are hydrogen;

Q ¹ represents CR ^6a ;

- 15 044355

Q is CR ^6b .

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

Z represents -CH2-, -CHR ⁵¹ -, -CR ^5c =CR ^5d -, -CR ^5e R ^5g -CR ^5f R ^5h -, -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h - or - CRSaRSb-CRScRSd-CRSeRSg-CRSfRSh-;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g , R ^5h and R ⁵¹ are each independently hydrogen or C ₁ -alkyl;

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

R ^3a is halogen, _-NR ^7a R ^7b or -OC _{1_4} alkyl;

Q ¹ represents CR ^6a ;

Q ² represents CR ^6b .

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

Z represents -CR ^5c =CR ^5d -, -CR ^5e R ^5g -CR ^5f R ^5h -, -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h - or -CR ^5a R ^5b -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h -;

R ^5a , R ^5b , R ^5c , R ^5d _, R ^5e , R ^5f , R ^5g and R ^5h are each independently hydrogen or C _{1_4} alkyl;

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

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

R ^7a and R ^7b are hydrogen;

Q ¹ represents CR ^6a ;

Q ² represents CR ^6b .

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein the compounds of formula (I) are limited to compounds of formula (I-a1) :

It will be clear that all variables in the structure of formula (I-al) can be defined as they are defined for the compounds of formula (I) or any subgroup thereof, which are 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 or any subgroup thereof as specified in any of the other embodiments, wherein the compounds of formula (I) are limited to compounds of formula (I-a1) :

wherein R ^3a represents -NH2; and R ^4a is hydrogen.

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

Z represents -X-CR ^5a R ^5b - or -CH2CH2-.

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

Z represents -X-CR ^5a R ^5b - or -CH2CH2-;

R ^5b represents hydrogen.

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

R ^5b represents hydrogen.

- 16 044355

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

Z represents -X-CR ^5a R ^5b - or -CH2CH2-;

R ^5a and R ^5b are hydrogen;

X represents -O-.

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

Z represents -X-CR ^5a R ^5b - or -CH2CH2-;

R ^5a and R ^5b are hydrogen;

X represents -O-;

Het represents (a-1).

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

Z represents -X-CR ^5a R ^5b - or -CH2CH2-;

R ^5a and R ^5b are hydrogen;

X represents -O-;

Het represents (a-1);

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

R ^7a represents hydrogen;

R ^7b represents hydrogen.

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

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

Het represents (a-1);

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

R ^7a represents hydrogen;

R ^7b represents hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable addition salts or any subgroup thereof as specified in any of the other embodiments, wherein Y is -CH2-; and Z is -CH2CH2-.

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

R ¹ represents hydrogen; R2 represents hydrogen;

Y represents -CH2-;

Z represents -CH ₂ -, -CHR ⁵¹ -, -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d -, -CR ^5e R ^5g -CR ^5f R ^5h -, -CR ^5c R ^5d -CR ^5e R5g-CR ^5f R ^5h - or -CR ^5a R ^5b -CR ^5c R ^5d -CR ^5e R ^5g - CR ^5f R ^5h -;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g , R ^5h and R ⁵¹ are each independently hydrogen or C ₁ . ₄ αlkyl;

X represents -O-;

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

R ^3a is halogen, -NR ^7a R ^7b or -O-C ₁ . ₄ αlkyl;

R ^7a represents hydrogen;

R ^7b represents hydrogen or C ₁ . ₄ alkyl;

R ^4a represents hydrogen;

Q ¹ represents CR ^6a ;

Q2 represents CR ^6b ;

R ^6a and R ^6b are each independently hydrogen or halogen.

In one embodiment, the present invention relates to a subset of formula (I) that is defined by general reaction schemes.

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.

It is intended that all possible combinations of the above embodiments fall within the scope of the present invention.

- 17 044355

Methods of obtaining

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

General methods for the preparation of certain representative examples of compounds of formula (I) are described herein and in the specific examples and are generally prepared from starting materials either commercially available or prepared by standard synthetic methods commonly used by those skilled in the art. technology. It is intended that the following diagrams only 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 commonly used by those skilled in the art of organic chemistry.

One skilled in the art will appreciate that in the reactions described in the schemes, protection of reactive functional groups, such as hydroxy, amino or carboxy groups, may be required in the final product to avoid their unwanted participation in the reactions . Traditional protecting groups can be used in accordance with standard practice. This is illustrated with specific examples.

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

It will be apparent to one skilled in the art that it may be necessary to cool the reaction mixture before isolating the reaction product (referring to a number of procedures 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 while stirring can increase the yield of the reaction. In some reactions, microwave heating can be used instead of traditional heating to reduce the overall reaction time.

One skilled in the art will appreciate that another sequence of chemical reactions shown in the diagrams below may also result in the desired compound of formula (I).

One 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 one skilled in the art.

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

In the event that any of the starting materials are available in salt form, one skilled in the art will appreciate 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 stated or clearly implied by context.

One skilled in the art will appreciate that chemistry similar to that described in Schemes 1-9 (where Het is shown as (a-1)) can also be used to prepare compounds of formula (I) wherein Het is a bicyclic aromatic heterocyclic ring system (a-2) or (a-3). Additionally, this information can be combined with standard synthetic methods commonly used by those skilled in the art of organic chemistry to produce more compounds of formula (I) where Het is (a-2) or (a-3).

In general, compounds of formula (I) can be prepared according to Scheme 1.

General scheme 1.

In Scheme 1, 'LG1' is defined as a suitable leaving group, such as, for example, halogen. All other variables in Scheme 1 are defined within the scope of the present invention.

For Scheme 1, the following reaction conditions were typically used.

1. Different sets of reaction conditions depend on the definition of R ^3a .

1a. If R ^3a is halogen, then step 1 can be omitted.

1b. If R ^3a is NR ^7a R ^7b , in the presence of a suitable amine of the formula HNR ^7a R ^7b , with a suitable solvent such as, for example, H2O, MeOH or EtOH, at a suitable temperature,

- 18 044355 such as, for example, 100-130°C, usually under microwave conditions or using an autoclave for heating.

1s. If R ^3a is -OC ₁ . ₄ alkyl, in the presence of suitable HO-C ₁ . ₄ αlkyl, with a suitable base, such as, for example, NaH, potassium tert-butoxide (tBuOK), in a suitable solvent, such as, for example, tetrahydrofuran (THF), at a suitable temperature. Alternatively, in the presence of a suitable HO-C _1-4 alkyl solvent, with a suitable acid such as, for example, HCl.

1d. If R ^3a is hydrogen, under hydrogenation conditions: under an atmosphere of H2 gas, in the presence of a catalyst such as, for example, Raney Ni, Pd/C (for example, 5 wt.% or 10 wt.%) or Pt/C (for example , 5 wt.%), in a suitable solvent such as, for example, methanol (MeOH), ethanol (EtOH) or THF.

1e. If R ^3a is C _1-4 alkyl, in the presence of a suitable boronic acid or ester, such as, for example, methyl boronic acid, with a suitable catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene, and with a suitable base, such as, for example, K3PO4, in a suitable solvent mixture, such as, for example, dioxane/H ₂ O in a ratio of 5 to 1, at a suitable temperature, such as, for example, 100°C.

2. 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 MeOH, at a suitable temperature, such as 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.

3. In the presence of a suitable acid anhydride of the formula (C _1-4 αlkyl-C=O) ₂ O with a suitable solvent such as pyridine at a suitable temperature. If R ^3a is NH ₂ , then (C _1-4 alkyl-C=O) ₂ O can react with NH2 to produce an intermediate compound that is N(C _1-4 alkyl-C=O) ₂ . Such an intermediate can be converted to the desired product in a suitable solvent, such as, for example, MeOH, at a suitable temperature, such as, for example, 100-130°C, under microwave conditions or using a heating autoclave. The reaction may benefit from the presence of an acid such as HCl or C _1-4 alkyl-CO ₂ H.

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

General scheme 2a.

In general, intermediates of formula III wherein Z is -O-CHR ^5a - can be prepared according to Scheme 2a. All other variables in Scheme 2a are defined within the scope of the present invention. One skilled in the art will appreciate that a suitable protecting group is required when R ^3a is -NH2 or -NHR ^7b ;

In Scheme 2a, the following reaction conditions were used.

1. Mitsunobu's reaction.

1a. In the presence of diisopropyl azodicarboxylate (DIAD), or diethyl azodicarboxylate (DEAD), or bis(1,1-dimethylethyl) azodicarboxylate (DBAD) on a PPh ₃ polymer support, in a suitable solvent, such as, for example, anhydrous THF, at a suitable temperature, such such as room temperature.

1b. In the presence of triphenylphosphine (PPh ₃ ), DIAD or DEAD in a suitable solvent, such as, for example, anhydrous THF, at a suitable temperature, such as, for example, room temperature.

1s. In the presence of cyanomethylenetributylphosphorane (CMBP) or cyanomethylenetrimethylphosphorane (CMMP), in a suitable solvent, such as, for example, anhydrous toluene, at a suitable temperature, such as, for example, 80°C.

The starting materials in Scheme 2a are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the following general schemes. One skilled in the art will appreciate that when R ^5a is C _1-4 alkyl, the various isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

- 19 044355

General scheme 2b.

In general, intermediates of formula III wherein Z is -CHR ^5a - can be prepared according to Scheme 2b. All other variables in Scheme 2b are defined within the scope of the present invention. One skilled in the art will appreciate that a suitable protecting group is required when R ^3a is -NH ₂ or -NHR ^7b ;

In Scheme 2b, the following reaction conditions were used.

1. Mitsunobu's reaction.

1a. In the presence of diisopropyl azodicarboxylate (DIAD), or diethyl azodicarboxylate (DEAD), or bis(1,1-dimethylethyl) azodicarboxylate (DBAD) on a PPh3 polymer support, in a suitable solvent, such as, for example, anhydrous THF, at a suitable temperature, such as , for example, room temperature.

1b. In the presence of triphenylphosphine (PPh ₃ ), DIAD or DEAD in a suitable solvent, such as, for example, anhydrous THF, at a suitable temperature, such as, for example, room temperature.

1s. In the presence of cyanomethylenetributylphosphorane (CMBP) or cyanomethylenetrimethylphosphorane (CMMP), in a suitable solvent, such as, for example, anhydrous toluene, at a suitable temperature, such as, for example, 80°C.

The starting materials in Scheme 2b are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the following general schemes. One skilled in the art will appreciate that when R ^5a is C _1-4 alkyl, the various isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

One skilled in the art will appreciate that Scheme 2b can also be used to prepare similar intermediates wherein Z is -CR ^5e R ^5g -CR ^5f R ^5h -.

General diagram 2c.

Intermediates of formula II where Z is -X ^a -CHR ^5a - can be prepared according to Scheme 2c. In diagram 2c 'X ^a ' is defined as O or S; 'LG' is defined as a leaving group, such as, for example, halogen, mesylate (MsO) and tosylate (TosO), preferably TosO. 'LG1' is defined as a leaving group, such as halogen. All other variables in Scheme 2c are defined within the scope of the present invention.

In Scheme 2c, the following reaction conditions were used.

1. In the presence of a base such as, for example, K ₂ CO ₃ , triethylamine (Et ₃ N) or DIPEA, in a suitable solvent such as CH ₃ CN, DCM or N,N-dimethylacetamide (DMA).

The starting materials in Scheme 2c are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the following general schemes. One skilled in the art will appreciate that when R ^5a is C _1-4 alkyl, the various isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

General 2d diagram.

Intermediates of formula III where Z is -X ^a -CHR ^5a - can be prepared according to Scheme 2d. In Scheme 2d, ' ^Xa ' is defined as O or S. 'LG' is defined as a leaving group, such as, for example, halogen, MsO or TosO, preferably TosO. All other variables in diagram 2d are defined within the scope of the present invention. One skilled in the art will appreciate that a suitable protecting group is required when R ^3a is NH ₂ or -NHR ^7b .

- 20 044355

In Scheme 2d, the following reaction conditions were used.

1. In the presence of a base, such as, for example, K ₂ CO3, EtaN or DIPEA, in a suitable solvent such as CH ₃ CN, DCM or N,N-dimethylacetamide (DMA).

The starting materials in Scheme 2d are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the following general schemes. One skilled in the art will appreciate that when R ^5a is C _1-4 alkyl, the various isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

General scheme 3.

In general, intermediates where Z is -X-CHR ^5a -, and where X is -NH- or -NR ¹¹ - can be prepared according to Scheme 3. In Scheme 3, 'LG ₁ ' is defined as a leaving group such such as halogen. 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. In the presence of a suitable reducing reagent, such as, for example, sodium triacetoxyborohydride (NaBH(AcO) ₃ ), together with a suitable solvent, such as, for example, DCM, at a suitable temperature, such as, for example, room temperature; or, alternatively, NaBH3CN together with a suitable solvent, such as, for example, MeOH, at a suitable temperature, such as, for example, from room temperature to 50°C.

2. In the presence of a suitable base, such as NaH, for example, together with a suitable solvent, such as anhydrous THF, N,N-dimethylformamide (DMF), DMA, at a suitable temperature, such as room temperature up to 50°C.

The starting materials in Scheme 3 are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the particular experimental section. One skilled in the art will appreciate that if R ^5a is C _1-4 alkyl, then the various isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

General scheme 4.

In general, intermediates where Z is -C=C-, -CH=CH- or -CH2-CH2- can be prepared according to Scheme 4. In Scheme 4 'LG ₁ ' is defined as a leaving group such as eg halogen. All other variables in Scheme 4 are defined within the scope of the present invention.

In Scheme 4, the following reaction conditions were used.

1. In the presence of a suitable amine, such as HNR'R'' or NaOR', with a suitable solvent, such as, for example, H2O, MeOH or EtOH, at a suitable temperature, such as, for example, 100-130°C, under conditions treatment with microwave radiation or using an autoclave for heating.

2. In the presence of a suitable Ar bromide or Ar iodide, a suitable catalyst such as

- 21 044355 bis(triphenylphosphine)palladium(II) dichloride and copper(I) iodide, in a suitable solvent such as

2-methyltetrahydrofuran, with a suitable base, such as, for example, triethylamine, at a suitable temperature, such as, for example, 80°C.

3. In the presence of a suitable Ar-bromide or Ar-iodide, a suitable salt, such as, for example, tetraethylammonium chloride (Et ₄ NCl), in a suitable solvent, such as, for example, DMF, with a suitable base, such as, for example, DIPEA , and with a palladium catalyst, such as, for example, Pd(OAc) ₂ (palladium (II) acetate) at a suitable temperature, such as, for example, 100°C.

4. In the presence of an atmosphere of H ₂ gas and a catalyst such as, for example, Pd/C (eg 5 wt% or 10 wt%) in a suitable solvent such as, for example, MeOH.

The starting materials in Scheme 4 are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the particular experimental section.

General scheme 5.

In general, intermediates where Z is -CH ₂ O- can be prepared according to Scheme 5. In Scheme 5, 'LG ₁ ' is defined as a leaving group, such as halogen. All other variables in Scheme 5 are defined within the scope of the present invention.

In Scheme 5, the following reaction conditions were used. 1. In the presence of a base such as, for example, K ₂ CO ₃ , Et ₃ N or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

General scheme 6.

In general, intermediates where Z is -CH ₂ - can be prepared according to Scheme 2. In Scheme 2, 'LG ₁ ' is defined as a leaving group, such as, for example, halogen. All other variables in Scheme 2 are defined within the scope of the present invention.

In Scheme 6, the following reaction conditions were used.

1. In the presence of tosyl hydrazide, with a suitable solvent, such as, for example, MeOH, EtOH or DCM, at a suitable temperature, such as room temperature.

2. In the presence of boronic acids, with a suitable base such as K ₂ CO ₃ , N ₂ CO ₃ , Cs ₂ CO ₃ , with a suitable solvent such as 1,4-dioxane for example, at a suitable temperature such as 90 °C.

The starting materials in Scheme 6 are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the particular experimental section.

General scheme 7.

In general, intermediates where Z is -CH2-CH2- can be prepared according to Scheme 7. In Scheme 7, 'LG ₁ ' is defined as a leaving group, such as, for example, halogen. All other variables in Scheme 7 are defined within the scope of the present invention.

For Scheme 7, the following reaction conditions were typically used.

1. In the first stage, in the presence of an alkene precursor and a 0.5 M solution of 9-borabicyclo(3.3.1)nonane (9-BBN) in THF in a nitrogen atmosphere at a temperature from room temperature to reflux temperature and a reaction time from 1 to 3 h. In the second stage in the presence of, for example, a suitable Ar-bromide or Ar-iodide and a suitable catalyst, such as, for example,

- 22 044355

1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and in the presence of a suitable base, such as, for example, tribasic potassium phosphate, in a suitable solvent mixture, such as, for example,

THF and water, at a suitable temperature of 50°C to reflux temperature and at a suitable reaction time of 1 to 3 hours.

2. Different sets of reaction conditions depend on the definition of R ^3a .

2a. If R ^3a is halogen, then step 1 can be omitted;

2b. If R ^3a is NR ^7a R ^7b , in the presence of a suitable amine of the formula HNR ^7a R ^7b , with a suitable solvent, such as, for example, H2O, MeOH or EtOH, at a suitable temperature, such as, for example, 100-130°C, typically under microwave or autoclave heating conditions.

2s. If R ^3a is -O-C _1-4 alkyl, in the presence of a suitable HO-C _1-4 alkyl, with a suitable base such as, for example, NaH, potassium tert-butoxide (tBuOK), in a suitable solvent such as , such as tetrahydrofuran (THF), at a suitable temperature. Alternatively, in the presence of a suitable HO-C _1-4 alkyl solvent, with a suitable acid such as, for example, HCl.

2d. If R ^3a is hydrogen, under hydrogenation conditions: under an atmosphere of H ₂ gas, in the presence of a catalyst such as, for example, Raney Ni, Pd/C (for example, 5 wt.% or 10 wt.%) or Pt/C ( for example, 5 wt.%), in a suitable solvent such as, for example, methanol (MeOH), ethanol (EtOH) or THF.

2e. If R ^3a is C _1-4 alkyl, in the presence of a suitable boronic acid or ester, such as, for example, methyl boronic acid, with a suitable catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene, and with a suitable base, such as, for example, K ₃ PO ₄ , in a suitable solvent mixture, such as, for example, dioxane/H ₂ O in a ratio of 5 to 1, at a suitable temperature, such as, for example, 100°C.

The starting materials in Scheme 7 are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the particular experimental section.

General scheme 8.

In general, intermediates where Z is -CH2-CH2- can be prepared according to Scheme 8. In Scheme 8, 'LG1' is defined as a leaving group, such as halogen. All other variables in Scheme 8 are defined within the scope of the present invention.

For Scheme 8, the following reaction conditions were typically used.

1. Different sets of reaction conditions depend on the definition of R ^3a .

1a. If R ^3a is halogen, then step 1 can be omitted.

1b. If R ^3a is NR ^7a R ^7b , in the presence of a suitable amine of the formula HNR ^7a R ^7b , with a suitable solvent, such as, for example, H ₂ O, MeOH or EtOH, at a suitable temperature, such as, for example, 100-130° C, usually under microwave conditions or using an autoclave for heating.

1s. If R ^3a is -O-C _1-4 alkyl, in the presence of a suitable HO-C _1-4 alkyl, with a suitable base such as, for example, NaH, potassium tert-butoxide (tBuOK), in a suitable solvent such as , such as tetrahydrofuran (THF), at a suitable temperature. Alternatively, in the presence of a suitable HO-C _1-4 αlkyl solvent, with a suitable acid such as, for example, HCl.

1d. If R ^3a is hydrogen, under hydrogenation conditions: under an atmosphere of H ₂ gas, in the presence of a catalyst such as, for example, Raney Ni, Pd/C (for example, 5 wt.% or 10 wt.%) or Pt/C ( for example, 5 wt.%), in a suitable solvent such as, for example, methanol (MeOH), ethanol (EtOH) or THF.

1e. If R ^3a is C _1-4 alkyl, in the presence of a suitable boronic acid or ester, such as, for example, methyl boronic acid, with a suitable catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene, and with a suitable base, such as, for example, K ₃ PO ₄ , in a suitable solvent mixture, such as, for example, dioxane/H ₂ O in a ratio of 5 to 1, at a suitable temperature, such as, for example, 100°C.

2. In the first stage, in the presence of an alkene precursor and a 0.5 M solution of 9-BBN in THF in a nitrogen atmosphere at a temperature from room temperature to reflux temperature and a reaction time of 1 to 3 hours. In the second stage, in the presence of a suitable Ar-bromide or Ar-iodide and

- 23 044355 a suitable catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and in the presence of a suitable base, such as, for example, tribasic potassium phosphate, in a suitable solvent mixture, such as, for example, THF and water, at a suitable temperature of 50°C to reflux temperature and at a suitable reaction time of 1 to 3 hours.

The starting materials in Scheme 8 are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the particular experimental section.

General scheme 9.

In general, the intermediates shown in Scheme 9, where Z is -CH2-CH2-, can be prepared according to Scheme 9. In Scheme 9, 'LG1' is defined as a leaving group, such as, for example, halogen. All other variables in Scheme 9 are defined within the scope of the present invention.

1. In the first stage, in the presence of an alkene precursor and a 0.5 M solution of 9-BBN in THF in a nitrogen atmosphere at a temperature from room temperature to reflux temperature and a reaction time of 1 to 3 hours. In the second stage, in the presence of, for example, a suitable Ar-bromide or Ar-iodide (X is Br or I, respectively) and a suitable catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and in the presence of a suitable base, such as for example, tribasic potassium phosphate, in a suitable mixture of solvents, such as, for example, THF and water, at a suitable temperature of 50° C. to reflux temperature and at a suitable reaction time of 1 to 3 hours.

2. In the presence of triflic acid anhydride and a suitable base, such as, for example, pyridine, in a suitable solvent, such as, for example, DCM, at a suitable temperature, such as, for example, 0° C., under an inert atmosphere of N ₂ gas.

3. In the presence of a suitable base, such as, for example, Cs ₂ CO ₃ , in a suitable solvent, such as, for example, DMF, at a suitable temperature, such as, for example, room temperature, under an inert atmosphere of N2 gas.

The starting materials in Scheme 9 are commercially available or can be prepared by standard methods apparent to those skilled in the art or described in the particular experimental section.

In all of these production methods, the reaction products can be isolated from the reaction medium and, if necessary, further purified in accordance with techniques generally 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 intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of formula (I). Mixtures of enantiomers of intermediates are also useful in the preparation of compounds of formula (I) with the appropriate configuration.

Pharmacology

The compounds of the present invention have been found to inhibit PRMT5 activity.

In particular, the compounds of the present invention bind the PRMT5 enzyme and competitively the 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 for the treatment or prevention, in particular treatment, of diseases such as blood disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, poor sperm motility, graft failure, tissue rejection, lung injury

- 24 044355 and the like.

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

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

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

In some embodiments, inhibition of PRMT5 by the provided compound 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 cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, stomach cancer, pancreatic cancer, liver cancer, adenoid cystic 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 adenoma of the ovaries.

Examples of metabolic disorders that can be treated or prevented, particularly treated, include, but are not limited to, diabetes or obesity.

Examples of blood diseases that can be treated or prevented, particularly treated, include, but are not limited to, hemoglobinopathy such as sickle cell anemia or β-thalassemia.

Examples of cancers that can be treated or prevented, particularly treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (eg, lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, bile duct cancer. bladder (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, endothelial sarcoma (eg, Kaposi's sarcoma, idiopathic multiple hemorrhagic sarcoma), endometrial cancer (eg, uterine cancer, uterine sarcoma), esophageal cancer (eg, esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (eg, intraocular melanoma, retinoblastoma) , familial hypereosinophilia, gallbladder cancer, stomach cancer (eg, gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (eg, head and neck squamous cell carcinoma), oral cancer (eg, oral squamous cell carcinoma (OSCC) ), cancers of the pharynx (eg, pharyngeal cancer, laryngeal 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 lymphoma (HL) (eg B cell HL, T cell HL) and non-Hodgkin 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 cell lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (eg, mucosal tissue-associated lymphomas ( MALT), nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (ie, Waldenström's macroglobulinemia), immunoblastic large cell lymphoma, hairy cell leukemia ( HCL), B-lymphoblastic progenitor cell lymphoma and primary central nervous system (CNS) lymphoma; as well as T cell

- 25 044355

NHL, such as T-lymphoblastic lymphoma/progenitor cell leukemia, peripheral T-cell lymphoma (PTCL) (eg, cutaneous T-cell lymphoma (CTCL) (eg, mycosis fungoides, Sezary syndrome), angioimmunoblastoma T-cell lymphoma, extranodal T-cell lymphoma from natural killer cells, T-cell lymphoma with enteropathy, subcutaneous T-cell lymphoma of the panniculitis type, anaplastic large cell lymphoma); a combination of one or more of the leukemia/lymphoma 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, renal nephroblastoma, 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) ( eg 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 tumor), osteosarcoma, ovarian cancer (eg, cystadenocarcinoma, embryonal ovarian cancer, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (eg, pancreatic adenocarcinoma, intraductal papillary mucinous tumor (IPMN), insulinoma), 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 (KA), melanoma, basal cell carcinoma (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, embryonal testicular carcinoma), thyroid cancer (eg, papillary thyroid carcinoma, papillary thyroid cancer (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, vulvar cancer (eg, Paget's vulva).

Examples of neurodegenerative diseases that can be treated or prevented, particularly 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, particularly treated, include, but are not limited to, 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 (eg, aplastic anemia, hemolytic autoimmune anemia), rhinitis, asthma, arteritis (eg, 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 tract disease, ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergies reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, diverticulitis, dermatomyositis, diabetes (eg, type 1 diabetes mellitus, type 2 diabetes mellitus), skin disease (eg, psoriasis, eczema , hypersensitivity reactions in eczema, burns, dermatitis, itching (scabies)), endometriosis, Guillain-Barré syndrome, infection, coronary heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (eg, migraine headaches, headaches tension), intestinal obstruction (eg, postoperative ileus and ileus in sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (irritable bladder syndrome), gastrointestinal disorder (eg, selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (eg, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) ( for example, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic

- 26 044355 tartar colitis, ischemic colitis, inflammation of the bowel, Behçet's syndrome, unspecified colitis) and inflammatory bowel syndrome (IBS)), lupus, annular scleroderma, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious anemia , peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (eg, 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 fever, systemic lupus erythematosus, scleroderma, sclerodoma, sarcoidosis, types of spondyloarthropathy, Sjögren's syndrome, thyroiditis, graft rejection, tendonitis, trauma or injury (eg, frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis , vitiligo and Wegener's granulomatosis.

In particular, the inflammatory disease is an acute inflammatory disease (eg, inflammation due to infection). In particular, an 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, particularly treated, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, degenerative joint disorders such as osteoarthritis, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behçet, hemolytic autoimmune anemias, amyotrophic lateral sclerosis, amylosis, multiple sclerosis, acute brachial syndrome, psoriatic and chronic arthritis in children), asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, skin disease (for example, 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 gastrointestinal disorder (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, lymphocytic colitis, ischemic colitis , inflammation in the disconnected bowel, Behçet's syndrome, colitis unspecified) and inflammatory bowel syndrome (IBS)), and disorders relieved by prokinetic agents (eg, ileus, postoperative ileus, and ileus in sepsis; gastroesophageal reflux disease (GORD or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders such as non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costochondritis).

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

Other diseases that may be treated or prevented, particularly treated, include, but are not limited to, ischemic injury associated with myocardial infarction, immune diseases, stroke, arrhythmia, toxin-induced or alcohol-related liver disease, aspirin-sensitive rhinosinusitis, cystic fibrosis, pain for cancer and blood diseases, for example, 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, that is administered to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and/or to enhance the effectiveness of the treatment of diseases that are amenable to treatment with ionizing radiation.

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

- 27 044355

Several mechanisms for the mode of action of radiosensitizers have been proposed in the literature, 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 for hypoxia. ; radiosensitizers that do not lead to cell hypoxia (for example, halogenated pyrimidines) can be analogues of DNA bases and are preferentially incorporated into 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 the disease.

Many cancer treatment protocols currently use radiosensitizers in conjunction with X-ray irradiation. Examples of x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, mizonidazole, desmethylmizonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (I UdR ), 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 the sensitizing agent. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof.

The radiosensitizers may be co-administered with a therapeutically effective amount of one or more other compounds, including, but not limited to, compounds that promote the incorporation of the radiosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients and/or oxygen into target cells; chemotherapeutic agents that act on the tumor with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.

The chemosensitizers may be co-administered with a therapeutically effective amount of one or more other compounds, including, but not limited to, compounds that ensure the incorporation of the chemosensitizers into the target cells; compounds that control the flow of therapeutic agents, nutrients and/or oxygen into 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 antineoplastic agents for imparting chemotherapy sensitivity to tumor cells resistant to standard chemotherapeutic agents and for enhancing the effectiveness of such compounds against drug-sensitive malignancies.

The compounds of the present invention may also reduce the risk of cancer recurrence.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for use as a 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 anticancer agents, the term also encompassing antitumor cell growth agents and antitumor 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 medicament for inhibiting PRMT5.

The present invention relates to compounds of formula (I) and to 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 herein.

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 herein.

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates that can be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases mentioned above herein.

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

These methods involve the introduction, i.e. 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 treatment of such diseases will be able to determine the effective therapeutic daily amount from the test results presented below in this document. An effective therapeutic daily amount will be from about 0.005 to 50 mg/kg, in particular from 0.01 to 50 mg/kg body weight, more particularly from 0.01 to 25 mg/kg body weight, preferably from about 0.01 to about 15 mg/kg, more preferably from about 0.01 to about 10 mg/kg, even more preferably from about 0.01 to about 1 mg/kg, most preferably from about 0.05 to about 1 mg/kg body weight bodies. 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, the route of administration, and the 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 compositions are prepared by known procedures using widely known and publicly available ingredients.

The compounds of the present invention, which may be suitable for the treatment or prevention of cancer or cancer-related conditions, can be administered alone or in combination with one or more additional therapeutic agents. Combination therapy involves the administration of a single dose pharmaceutical composition that contains a compound of formula (I), its pharmaceutically acceptable addition salt or solvate and one or more additional therapeutic agents, as well as the administration of a compound of formula (I), its pharmaceutically acceptable addition salt or solvate and each additional therapeutic agent in its own separate dosage pharmaceutical composition. For example, a compound of formula (I), a pharmaceutically acceptable adduct 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.

Although the active ingredient can be administered separately, it is preferable if it is presented in the form of 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.

Accordingly, 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 patients receiving it.

To facilitate administration, the compounds of the present invention can 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 subset or combination thereof, can be formulated into various pharmaceutical forms for administration purposes. Suitable compositions may include all compositions commonly used for systemically administered drugs.

To prepare the pharmaceutical compositions of the present invention, an effective amount of a particular compound as an active ingredient is combined in a uniform mixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation required for administration. These pharmaceutical compositions are useful in unit dosage form, suitable in particular for administration orally, rectally, transdermally, by parenteral injection or by inhalation. For example, when preparing the compositions in oral dosage form, any of the conventional pharmaceutical vehicles may be used, such as, for example, water, glycols, oils, alcohols, and the like. in the case of liquid preparations for oral administration, such as suspensions, syrups, tinctures, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants and the like. in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the most preferred oral dosage unit forms, in which case solid pharmaceutical carriers are of course used. For compositions for parenteral administration, the carrier will generally at least substantially comprise sterile water, although other ingredients may be included, for example, to aid solubility. For example, injection solutions can be prepared in which the carrier is saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable solutions containing a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof, may be formulated in oil for prolonged release. Suitable oils for this purpose include, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils. It is also possible to prepare injectable suspensions, in which case suitable liquid carriers, suspending agents and the like can be used. Also included are solid form preparations that are intended to be converted to liquid form preparations immediately prior to use. In compositions suitable for transdermal administration, the carrier optionally contains a permeation agent and/or a suitable wetting agent, optionally in combination with suitable additives of any nature in minimal proportions, wherein the additives do not have a significant deleterious effect on the skin. These additives may facilitate transdermal administration and/or may be helpful in preparing the desired compositions. These compositions can be administered in various ways, for example, through a transdermal patch, by spot application, or 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.

It is particularly preferred to formulate the above-mentioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including divisible or coated tablets), capsules, pills, powder packets, wafers, suppositories, injection solutions or suspensions, etc., as well as individual sets thereof.

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 derivatives thereof, in particular hydroxyalkyl-substituted cyclodextrins, for example 2 -hydroxypropyl-b-cyclodextrin or sulfobutyl-b-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 a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof 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 based on 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, particularly for use as a medicinal product, more particularly for use in the treatment of cancer or related diseases.

For the treatment of the above conditions, the compounds of the present invention may preferably be used in combination with antibody-based immune cell retargeting, for example, T cell/neutrophil retargeting. This can be achieved, for example, using 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 medicinal agents, more particularly other anticancer agents or adjuncts in cancer therapy.

Examples of anticancer agents or supportive agents include, but are not limited to:

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

taxane-based compounds, for example, paclitaxel, protein-bound paclitaxel particles (Abraxane™), or docetaxel;

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

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

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

antitumor nucleoside derivatives, for example, 5-fluorouracil, leucovorin, gemcitabine, gemcitabine-HCl, capecitabine, cladribine, fludarabine, nelarabine;

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

antitumor anthracycline derivatives, for example, daunorubicin, doxorubicin, optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicinHCl, valrubicin;

molecules that specifically target the IGF-1 receptor, such as picropodophyllin; tetracarcin derivatives, for example tetrocarcin A;

glucocorticoids, such as prednisone;

Antibodies, for example, Trustuzumab (antibodies Her2), Rituximab (antibodies CD20), Gemtuzumab, gemtuzumab ozogamycin, cetuximab, pertuzumab, Bevacuzumab, Aemtuzumab, Ekulizumab, Ibritumom Tiuxetan, Nofetumomab, Panitumum, Tositumab, CNTO, CNTOMOMAB, CNTOMOMAB, CNTOMOMAB 328;

estrogen receptor antagonists, or selective estrogen receptor modulators, or estrogen synthesis inhibitors, for example, tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;

aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozole;

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

DNA methyltransferase inhibitors, such as azacitidine or decitabine;

antifolates, such as premetrexed disodium;

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

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

apoptosis-inducing and anti-angiogenic agents such as Bcl-2 inhibitors, for example 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 (multi-target kinase inhibitors), mTOR inhibitors), e.g. flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;

farnesyltransferase 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, for example, PS-341, MLN.41 or bortezomib;

yondelis;

telomerase inhibitors, such as telomestatin;

matrix metalloproteinase inhibitors, 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;

- 31 044355 asparaginase;

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

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

thalidomide, lenalidomide;

mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase;

BH3 mimetics, for example AVT-737;

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

colony-stimulating factor analogues, for example, filgrastim, pegfilgrastim, sargramostim; erythropoietin or its analogues (for example, darbepoetin alfa); interleukin-11;

oprelvequin; zoledronate, zoledronic acid; fentanyl; bisphosphonate; palifermin;

steroidal cytochrome P450 17 alpha-hydroxylase/17,20-lyase (CYP17) inhibitor, eg abiraterone, abiraterone acetate.

glycolysis inhibitors such as 2-deoxyglucose;

mTOR inhibitors such as rapamycins and rapalogues, 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 (anti-PD-1), lambrolizumab (anti-PD-1), ipilimumab (anti-CTLA4) and MPDL3280A (anti-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 a further active ingredient, one or more anticancer agents, in the form of a combination preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer .

One or more other medicinal agents and a compound of the present invention may be administered simultaneously (eg, in separate or single compositions) or sequentially in a random order. In the latter case, two or more compounds will be administered over a period, in an amount and in a manner sufficient to ensure that an advantageous or synergistic effect is achieved. It should be understood that the preferred route and order of administration, and the appropriate dosage levels and schedule for each component of the combination will depend on the particular other medicinal agent and compound of the present invention to be administered, their route of administration, the particular tumor being treated, and the specific host being treated. The optimal route and order of administration, as well as dosage levels and schedules, can be readily determined by those skilled in the art using standard techniques and taking into account the information set forth herein.

The weight ratio of the compound of the present invention and one anticancer agent or several other anticancer agents administered in combination can be determined by one skilled in the art. The ratio and the exact dosage and frequency of administration depend on the particular compound of the present invention and other anticancer agent(s), the particular 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 will be appreciated that the effective daily amount may be decreased 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 the other anticancer agent may range from 1/10 to 10/1, more particularly from 1/5 to 5/1, even more particularly from 1/3 to 3/1.

The platinum coordination compound is preferably administered at a dose of from 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 approximately 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 advantageously administered at a dose of from 50 to 400 mg per square meter (mg/ ^m2 ) of body surface area, for example from 75 to 250 mg/ ^m2 , 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 camptothecin-based compound is advantageously administered at a dose of from 0.1 to 400 mg per square meter (mg/m ² ) of body surface area, for example 1 to 300 mg/m ² , in particular for irinotecan at a dose component from about 100 to 350 mg/m ² and for topotecan - at a dose of from about 1 to 2 mg/m ² per course of treatment.

The antitumor podophyllotoxin derivative is preferably 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 , ranging from approximately 35 to 100 mg/m ² , and for teniposide, at a dose ranging from approximately 50 to 250 mg/m ² , per course of treatment.

The antitumor vinca alkaloid is preferably administered at a dose of from 2 to 30 mg per square meter (mg/ ^m2 ) of body surface area, in particular for vinblastine at a dose of from about 3 to 12 mg/ ^m2 , for vincristine - at a dose of from about 1 to 2 mg/m ² and for vinorelbine, at a dose of from about 10 to 30 mg/m ² , per course of treatment.

The antitumor nucleoside derivative is preferably administered at a dose of from 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 from 200 to 500 mg/m ² , for gemcitabine at a dose of from about 800 to 1200 mg/m ² , and for capecitabine at a dose of from about 1000 to 2500 mg/m ² , per course of treatment.

Alkylating agents such as nitrogen mustard or nitrosourea are advantageously administered at a dose of 100 to 500 mg per square meter (mg/ ^m2 ) of body surface area, for example 120 to 200 mg/ ^m2 , in particular for cyclophosphamide - at a dose ranging from approximately 100 to 500 mg/m ² , for chlorambucil - at a dose ranging from approximately 0.1 to 0.2 mg/kg, for carmustine - at a dose ranging from approximately 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 antitumor anthracycline derivative is advantageously administered at a dose of from 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 from 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 of about 10 to 15 mg/m ² , per course of treatment.

The anti-estrogenic agent is preferably administered at a dose of from about 1 to 100 mg per day, depending on the specific agent and condition being treated. Tamoxifen is preferably administered orally at a dose of 5 to 50 mg, preferably 10 to 20 mg, twice daily, 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 daily, with therapy continued for a sufficient time to achieve and maintain a therapeutic effect. Anastrozole is preferably administered orally at a dose of approximately 1 mg once daily. Droloxifene is preferably administered orally at a dose of from about 20 to 100 mg once daily. Raloxifene is preferably administered orally at a dose of approximately 60 mg once daily. Exemestane is preferably administered orally at a dose of approximately 25 mg once daily.

Antibodies are preferably administered at a dose of from 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 the specific stereochemistry for the stereocenter of a compound is not indicated, this means that a mixture of R- and S-enantiomers was obtained. When more than 1 stereocenter is present in a structure, each stereocenter for which no specific stereochemistry is specified 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 obtain the desired compound or intermediate.

Examples

Further 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; NaH means sodium hydride; Boc means tert-butoxycarbonyl; (Boc) ₂ O means tert-butoxycarbonyl anhydride; EtOAc means ethyl acetate; Et ₂ O means diethyl ether; Et ₃ N means triethylamine; DCM means dichloromethane; qs means in sufficient quantity; prom. conn. means intermediate connection; MeCN or ACN means acetonitrile; DMF means N,N-dimethylformamide; PdCl ₂ (dppf) means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P); THF means tetrahydrofuran; IPA or iPrOH means 2-propanol; LC means liquid chromatography; LCMS stands for liquid chromatography/mass spectrometry; HPLC stands for High Performance Liquid Chromatography; TFA means trifluoroacetic acid; RP means reversed phase; min. means minutes(s); h means hour(s); v/v means volume per volume; Celite® means diatomaceous earth; DMSO means dimethyl sulfoxide; SFC stands for supercritical liquid chromatography; DIPE means diisopropyl ether; DIPEA means N,N-diisopropylethylamine; PPh ₃ means triphenylphosphine; Pd ₂ (dba) ₃ means

- 33 044355 tris(dibenzylideneacetone)dipalladium; DIAD means diisopropyl azodicarboxylate; TBAF means tetrabutylammonium fluoride; psi means pounds-force per square inch; eq. means equivalent(s); Pd(OAc)2 means palladium(P) acetate; DMAP means 4-(dimethylamino)pyridine;

t-BuOK or KOtBu means potassium tert-butoxide; Dess-Martin periodinan means

1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)one; TBDMSCl means tert-butyldimethylsilyl chloride; Bn means benzyl; 9-BBN means 9-borabicyclo[3.3.1]nonane; Pd-118 means dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(P); Tf ₂ O means triflate anhydride; TBDMS means tert-butyldimethylsilyl; TMSCl trimethylsilyl chloride; BuLi means n-butyllithium; aq. means aqueous solution; NaOMe means sodium methoxide; tBuOH means tert-butyl alcohol; n-BuOH means n-butanol; NaHMDS means sodium bis(trimethylsilyl)amide; Diazald® means N-methyl-N-(p-tolylsulfonyl)nitrosamide; Ts or Tos means tosyl-(p-toluenesulfonyl).

Intermediates and compounds containing a double bond with substituents that can be in the E or Z configuration are shown in one specific configuration in the experimental section below. However, unless E or Z is specifically stated, it is not determined whether such intermediates and compounds are prepared in the E or Z configuration, or as a mixture of both configurations. For example, intermediates 86, 90, 91 and 139 may be in the E or Z configuration, or may be mixtures thereof.

For example, compounds 30, 34, 35, 36 and 37 were prepared in the E-configuration and are specifically listed as (E) in the experimental section below.

A. Preparation of intermediate compounds.

Example A1.

Preparation of intermediate compound 1.

BUT\/X Y

BUT HE

Intermediate 1

In a mixture of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (14.0 g, 52.8 mmol) and (1R,2S,3R,5R)-3-amino5-(hydroxymethyl)cyclopentane-1 ,2-diol hydrochloride (10.7 g, 58.1 mmol) in propan-2-ol/H ₂ O (208 ml, 7:1) was added Et ₃ N (13.4 g, 132 mmol) in one portion at 25°C in N2 atmosphere. The mixture was stirred at 90°C for 23 hours. The mixture was cooled to 50°C and 4 M HCl (24 ml, 106 mmol) was slowly added. The residue was then stirred at 50°C for 2 hours. The reaction mixture was cooled to 25°C and NaHCO ₃ (14 g, 100 mmol) was added slowly. Ethyl acetate (230 ml) was added followed by the addition of half-saturated NaHCO ₃ solution (qs). The organic phase was isolated and the aqueous phase was extracted with ethyl acetate (230 ml x2). The combined organic phases were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give intermediate 1 as a yellow solid (17.4 g, quantitative yield in 2 steps). The crude product was directly used as is in the next reaction step without further purification.

Example A2.

Preparation of intermediate compound 2.

Intermediate 2

To a mixture of intermediate 1 (17.4 g, 52.7 mmol) in acetone (250 ml) was added 2,2-dimethoxypropane (11.0 g, 105 mmol) and TsOH.H ₂ O (908 mg, 5 .27 mmol) at 25°C in an N2 atmosphere. The mixture was stirred at 60°C for 2 hours. The mixture was cooled to 25°C and the solution was partially concentrated in vacuo, quenched by slowly adding saturated NaHCO ₃ solution (100 ml) and then extracted with ethyl acetate (100 ml x3). The combined organic phases were washed with brine (100 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution: DCM/ethyl acetate 1/0 to 2/1) to give intermediate 2 as a light yellow gum (15.5 g, 89% yield).

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Example A3.

Preparation of intermediate compound 3.

intermediate 3

To a mixture of intermediate 2 (2.85 g, 8.8 mmol) in DCM (130 ml) was added Dess-Martin periodinane (4.85 g, 11.4 mmol) at 0° C. under N2. The mixture was stirred at room temperature for 2 hours. The mixture was treated with Na ₂ S ₂ O ₃ (15 g) dissolved in saturated NaHCO ₃ solution (65 ml) and stirred for an additional 30 minutes. The layers were separated and the aqueous phase was extracted with DCM (50 ml x3). The combined organic phases were washed with saturated NaHCO ₃ solution (65 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give crude intermediate 3 (2.9 g), which was directly used in the next reaction step without further purification.

Example A4.

Preparation of intermediate compound 4.

Intermediate 4

Method 1.

To a mixture of methyltriphenylphosphonium bromide (4.87 g, 13.62 mmol) in THF (500 ml) add t-BuOK (11.4 ml, 1M in THF, 1.27 g, 11.35 mmol) dropwise at 0 °C in N2 atmosphere. The suspension became bright yellow and was stirred at 0°C for 0.5 hours and then heated to 25°C for 0.5 hours. The mixture was cooled to -40°C. A solution of intermediate 3 (1.46 g, theoretical 4.54 mmol) in THF (130 ml) was added dropwise and then stirred at -20°C for 1 hour, after which the mixture was heated to 25°C for 2 h. A saturated solution of NH ₄ Cl (300 ml) was added to the mixture and the mixture was stirred for 10 minutes. The layers were separated and the aqueous phase was extracted with DCM (300 ml x2). The combined organic phases were washed with brine (500 ml), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ISCO®; 80 g SepaFlash® silica gel flash column, gradient elution: 0% to 15% ethyl acetate/petroleum ether). The required fractions were collected and the solvent was evaporated. Intermediate 4 was obtained as an off-white solid (530 mg, 36% yield).

Method 2.

A solution of intermediate 3 (10.0 g, theoretically 31.1 mmol) in THF (100 ml) under N2 was added dropwise over a period of 30 min to a solution of bis(zinciodo)methane in THF (180 ml, 0 .31 M, 55.9 mmol, obtained according to the procedure described in Tetrahedron 2002,.58, 8255-8262), stirring was continued until complete conversion (about 2 hours). The reaction mixture was quenched by slow addition of a saturated aqueous NH ₄ Cl solution, during which salt formation was observed. Before extraction (EtOAc, 2x200 ml), the salts were redissolved by adding aqueous ammonia (25%). The combined organic phases were washed with aqueous sodium bisulfite and brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: dichloromethane/EtOAc 95/5) to give intermediate 4 as an off-white solid (6.9 g, 66%).

Method 3.

Stage 1 Preparation of intermediate compound 5.

Oh Oh

intermediate connection 5

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Acetylacetonatobis(ethylene)rhodium(1) (0.837 g, 3.24 mmol) and (R)-N,N-dimethyldinaftho[2,1-D:1',2'F][1,3,2]dioxaphosphepin- 4-amine (2.91 g, 8.11 mmol) was dissolved in EtOH (625 ml) under nitrogen. The mixture was stirred at room temperature and purged with nitrogen gas for 15 minutes. (-)-(3AR,6AR)-3A,6A-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25 g, 162.16 mmol) and potassium vinyl trifluoroborate ( 45.73 g, 324.33 mmol), and then the reaction mixture was stirred and refluxed for 4 hours. The reaction mixture (suspension) was cooled to room temperature. The precipitate was filtered through a Celite® pad and washed with ethanol. The solvents from the filtrate were evaporated. 1 L of heptane was added to the residue. The resulting suspension was filtered through a Celite® pad and washed with heptanes to leave a dark brown solid. The filtrate was washed three times with 300 ml NH4OH, washed with brine, dried over MgSO ₄ , filtered and the solvents from the filtrate were evaporated to give intermediate 5 (16.18 g, 51% yield).

Stage 2.

Preparation of intermediate 6.

intermediate 6

Add dropwise a solution of intermediate 5 (16.18 g, 82.58 mmol) in THF (200 ml) to a stirred solution of lithium aluminum hydride in THF (24.78 ml, 1 M, 24.78 mmol) in THF (400 ml ) at 78°C in a nitrogen atmosphere. The reaction mixture was stirred at -78°C under nitrogen atmosphere for 30 minutes. The reaction was quenched by adding dropwise acetone (6.1 ml) and then 50 ml of water at -78°C. Once the addition was complete, the reaction mixture was allowed to warm to room temperature and then 400 mL of EtOAc was added. The mixture was stirred vigorously. The organic layer was separated, washed three times with water, washed with brine, dried over MgSO ₄ , filtered and the solvents in the filtrate were evaporated. The residue was dissolved in ethyl acetate and purified on a SiO ₂ column, type Grace Reveleris SRC, 80 g, Si 40, on an Armen Spot II Ultimate purification system, using ethyl acetate and heptane as eluent in a gradient starting from 100% heptane to 50% heptane and 50% ethyl acetate. Fractions containing product were combined and solvents were evaporated to give intermediate 6 (10.77 g, 71% yield).

Stage 3.

Preparation of intermediate compound 7.

Intermediate 7

A solution of Tf ₂ O (13.3 ml, 80.9 mmol) in anhydrous DCM (60 ml) was added dropwise to a mixture of intermediate 6 (9.94 g, 53.95 mmol) and anhydrous pyridine (85 ml) in anhydrous DCM (140 ml) at 0°C. The reaction mixture was stirred for 30 minutes and then 75 ml of cold water was added. The layers were separated and the organic layer was washed three times with 75 ml of water, dried over MgSO ₄ , filtered, the solvents were evaporated and co-evaporated with 200 ml of toluene. The residue was dissolved in heptane and ethyl acetate and purified on a SiO ₂ column, type Grace Reveleris SRC, 40 g, Si 40, on an Armen Spot II Ultimate purification system using ethyl acetate and heptane as eluent in a gradient starting from 100% heptane to 50 % heptane and 50% ethyl acetate. Fractions containing product were combined and solvents were evaporated to give intermediate 7 (13.0 g, 67% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 7 using suitable starting materials (Table 22).

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Table 22

Stage 4.

Preparation of intermediate compound 8.

Intermediate 8

A mixture of 4-chloro-7H-pyrrolo[2,3-D]nirimidine (100 g, 651 mmol) and KOtBu (73.07 g, 651 mmol) in THF (1 L) was stirred at room temperature for 45 min to obtain clear solution. The solvents were evaporated. The residue was triturated in DIPE. White solids were filtered and dried in vacuo at 30°C to give intermediate 8 (112.6 g, 90% yield).

Stage 5.

Preparation of intermediate compound 4.

Intermediate 4

A solution of intermediate 7 (13 g, 41.1 mmol) in DMF (50 ml) was added dropwise to a stirred solution of intermediate 8 (7.88 g, 41.1 mmol) in DMF (150 ml) at 0°C. After addition, the reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. Additional intermediate 8 (1.57 g, 8.22 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a beaker with ice and water (~0.5 L). The resulting suspension was stirred for 2 hours and then filtered. The filter cake was washed three times with water and then dried in vacuo at 50°C to give intermediate 4 as a white solid (8.75 g, 65% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 4 using suitable starting materials (Table 23).

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Table 23

Example A5.

Preparation of intermediate compound 9.

intermediate connection 9

A solution of intermediate 4 (18.3 g, 57.22 mmol) in aqueous ammonia (25%, 100 mL) and THF (100 mL) was heated in a sealed metal pressure vessel at 110°C until complete conversion (~ 16 hours). The reaction mixture was allowed to cool to room temperature, after which ethyl acetate and brine were added. Both layers were separated, and the aqueous layer was extracted once with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give intermediate 9 as a light yellow solid (17.2 g, 100% yield), which was used in the next reaction step without further purification .

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 9 using suitable starting materials (Table 24).

Table 24

Example A31.

Preparation of intermediate 96.

Stage 1.

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A solution of copper iodide (43.7 g, 228 mmol) and lithium chloride (9.68 g, 228 mmol) in THF (320 ml) was stirred for 5 min at room temperature before cooling to -78 °C under nitrogen. Allyl magnesium bromide, 1M in Et ₂ O (220 ml, 1 M, 220 mmol) was added dropwise to the solution over 20 minutes. After stirring the reaction mixture for 30 min, TMSCl (30 ml, 235 mmol) and hexamethylphosphoramide (42 ml, 241 mmol) were added, followed by dropwise addition of (-)-(3AR,6AR)-3A,6Adihydro-2,2-dimethyl -4H-cyclopenta-1,3-dioxol-4-one (12.8 g, 83.0 mmol) in THF (110 ml). After addition, the reaction mixture was stirred for 2 hours, warmed to 0°C and quenched with saturated aqueous NH ₄ Cl solution (100 ml). After adding EtOAc (1 L), the organic layer was separated, washed with water (200 ml) and brine (200 ml), then dried over MgSO ₄ . The solvent was evaporated under reduced pressure. The residue was purified on a SiO ₂ column, type Grace Reveleris SRC, 180 g, Si 40, on a Grace Reveleris X2 purification system using heptane and ethyl acetate as eluents in a gradient starting from 100% heptane to 70% heptane and 30% ethyl acetate. Fractions containing product were combined and solvents were evaporated to give intermediate 95 (8.00 g, 47% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 95 using suitable starting materials (Table 25).

Table 25

Stage 2.

Prom, conn.

Structure

Source materials

(3AR,6AR)-ZA,bA-dihydro-dimethyl-4H-cyclopenta1,3-dioxol-4-one and

-magnesium butenyl bromide intermediate 96

Add dropwise a solution of intermediate 95 (8 g, 39.5 mmol) in THF (40 mL) to a stirred solution of lithium bromide, 2Mb THF (5.931 mL, 2 M, 11.86 mmol) in THF (40 mL) at 0 °C in a nitrogen atmosphere. After addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding 8 ml of water, followed by 15 ml of aqueous NaOH (1N) and again 8 ml of water. The resulting solid was filtered and the solvents from the filtrate were diluted with ethyl acetate. The organic layer was washed with water, washed with brine, dried over MgSO ₄ , filtered and the solvents from the filtrate were evaporated to give intermediate 96 (7.41 g, 92% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 96 using suitable starting materials (Table 26).

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Table 26

Prom, conn.

Source materials

Intermediate face-to-face connection 114

Example A26.

Preparation of intermediate 42.

Stage 1.

Preparation of intermediate 39.

NHj intermediate 39

Intermediate 2 (10 g, 30.5 mmol) was stirred in a mixture of THF (100 ml) and 28% aq. NH4OH solution (100 ml) at 120°C for two days in an autoclave. Volatile substances were evaporated in vacuo. The aqueous layer was extracted several times with DCM/MeOH 90/10. The combined organic layers were concentrated under reduced pressure. The crude substance was redissolved in a minimal amount of MeOH, to which toluene was added. The resulting solution was concentrated again and the process was repeated twice to obtain intermediate 39 (10.2 g, 100% yield) as a solid, which was used as such in the next step.

Stage 2.

Preparation of intermediate 40.

OTBDMS

nh ₂

O. θ intermediate 40

A solution of TBDMSCl (7.6 g, 50.2 mmol, 1.5 eq) in DMF (50 mL) was added dropwise to the reaction flask into which Intermediate 39 (10.2 g, 33.5 mmol) was charged. imidazole (4.6 g, 67.0 mmol, 2.0 eq.) and DMF (120 ml). The resulting reaction mixture was stirred overnight at room temperature. Water was added and extraction was carried out with diethyl ether. The combined organic layers were washed with water, dried over MgSO ₄ and concentrated under reduced pressure to give intermediate 40 (10.4 g, 74% yield).

Stage 3.

Preparation of intermediate 41

Vos

intermediate connection 41

A solution of (Boc) _2O (20.0 g, 86.9 mmol, 3.5 eq) in THF (40 ml) was added dropwise to the reaction flask into which intermediate 40 (10.4 g, 24, 8 mmol), DMAP (607 mg, 5.0 mmol, 0.2 eq.) and THF (85 ml). The resulting reaction mixture was stirred at room temperature for 4 hours. TBAF in THF (1 M, 42.2 ml, 42.2 mmol, 1.7 eq.) was then added dropwise and stirring was continued until complete transformation. The reaction mixture was poured into

- 40 044355 water and extracted once with diethyl ether. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (30 to 0% heptane gradient in ethyl acetate) to give intermediate 41 (12.1 g, 96% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 41 using suitable starting materials (Table 27).

Table 27

Prom, conn.

Source materials

Intermediate 2

Stage 4.

Preparation of intermediate 42.

intermediate 42 p-Toluenesulfonyl chloride (5.1 g, 26.7 mmol) was added portionwise to a solution of intermediate 41 (9.0 g, 17.8 mmol), Et ₃ N (4.5 g, 44.5 mmol, 2.5 eq.) and DMAP (218 mg, 1.8 mmol, 0.1 eq.) in CH ₂ Cl ₂ (50 ml) at 0°C. The reaction mixture was stirred at room temperature overnight. Water was added, the organic layer was separated, and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (5% EtOH in CH ₂ Cl ₂ ) to give intermediate 42 (10.6 g, 90% yield).

Example A6.

Preparation of intermediate 13.

Stage 1.

Preparation of intermediate 10.

Intermediate 10

A solution of benzyl alcohol (18.2 g, 168 mmol, 1.0 eq.) in DMF (100 ml) was added dropwise to the NaH suspension (60% dispersion in mineral oil, 6.5 g, 168 mmol, 1.0 eq. .) in DMF (300 ml) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for an additional 30 minutes. A solution of 2,4-dichloropyridine (24.9 g, 168 mmol, 1.0 eq) in DMF (100 ml) was added dropwise. The reaction mixture was stirred for 2 hours, after which additional NaH (60% dispersion in mineral oil, 1.3 g, 33.6 mmol, 0.2 eq.) was added. Stirring was continued until complete conversion. Once complete, the reaction mixture was quenched by slow addition of water and extracted with diethyl ether. The combined organic phases were dried over MgSO ₄ and concentrated under reduced pressure. The crude product was suspended in heptane, filtered and dried under high vacuum to give intermediate 10 (19.3 g, 52% yield).

Stage 2.

Preparation of intermediate 11.

AD intermediate connection 11

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Add LiHMDS (105.4 mL, 1 M solution in THF, 105.4 mmol) to a solution of intermediate 10 (19.3 g, 87.9 mmol), Pd2(dba) ₃ (2.0 g, 2.2 mmol, 0.025 eq.) and 2-dicyclohexylphosphinobiphenyl (2.5 g, 5.2 mmol, 0.06 eq.) in anhydrous THF (90 ml) under nitrogen, the resulting mixture was stirred at 65 °C for 1 h Then the reaction mixture was cooled to room temperature and 1N was added. aqueous HCl solution. After 5 min. After vigorous stirring, the reaction mixture was neutralized with saturated Na ₂ CO ₃ solution and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over MgSO ₄ and concentrated under reduced pressure. The crude product was suspended in isopropyl ether and stirred for 15 minutes. at the reflux temperature, after which it was cooled to room temperature overnight. The precipitate was filtered and dried under high vacuum to give intermediate 11 (14.7 g, 82% yield).

Stage 3.

Preparation of intermediate compound 12.

intermediate connection 12

Chloroacetone (1.75 mL, 22.0 mmol, 1.1 eq.) was added dropwise to a solution of intermediate 11 (4.0 g, 20.0 mmol) in EtOH (20 mL). The reaction mixture was stirred at reflux overnight. The residue obtained after concentrating the reaction mixture under reduced pressure was taken up in a mixture of ethyl acetate and water. The organic layer was separated and the aqueous layer was further extracted with CH ₂ Cl ₂ (+MeOH) and the combined organic phases (ethyl acetate and CH ₂ Cl ₂ (+MeOH)) were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (1 to 6% MeOH gradient in CH2Cl2) to give intermediate 12 (1.95 g, 42% yield).

Stage 4.

Preparation of intermediate 13.

-PX intermediate connection 13

A solution of intermediate 12 (2.2 g, 9.2 mmol) in methanol was hydrogenated at atmospheric pressure for 2 hours with Pd (10% on carbon, 491 mg, 0.46 mmol, 0.05 eq) in as a catalyst. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give intermediate 13 (1.4 g, 100% yield) as a brown solid.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of Intermediate 12 and Intermediate 13 using suitable starting materials (Table 1).

Table 1

Example A7.

Preparation of intermediate 18.

Stage 1.

Preparation of intermediate 15.

^oc intermediate connection 15

A mixture of intermediate 11 (5.0 g, 25.0 mmol) and (Boc) _2O (6.0 g, 27.5 mmol, 1.1 eq.) in tBuOH (55 ml) was stirred at 50°C in for 1 hour. The reaction mixture was cooled to room temperature

- 42 044355 temperature and diluted with ethanol, the precipitate was filtered and dried under high vacuum to obtain intermediate 15 (6.0 g, 80% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 15 and using suitable starting materials (Table 2).

table 2

Stage 2.

Preparation of intermediate 16.

intermediate connection 16

To a solution of intermediate 15 (6.0 g, 20.0 mmol) in anhydrous DMF (80 mL) was added NaH (1.1 g, 60% dispersion in mineral oil, 30.0 mmol, 1.4 eq.) in portions at room temperature in a nitrogen atmosphere. After addition was complete, the reaction mixture was stirred for an additional 10 minutes. Propargyl bromide (3.1 mL, 30.0 mmol, 1.4 eq.) was added and stirring was continued until complete conversion. The reaction mixture was quenched by adding water and extracted with diethyl ether. The combined organic phases were washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 to 1.5% MeOH gradient in CH ₂ Cl ₂ ) to give intermediate 16 (4.9 g, 72.5% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 16 and using suitable starting materials (Table 3).

Table 3

Stage 3.

Preparation of intermediate 11.

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intermediate connection 17

KOtBu (1.9 g, 17.0 mmol, 1.2 eq) was added to a solution of intermediate 16 (4.8 g, 14.2 mmol) in THF (145 ml). The reaction mixture was stirred at room temperature until complete conversion (typically approximately 30 minutes). Water was added and extraction was carried out with ethyl acetate. The combined organic phases were dried over MgSO ₄ and concentrated under reduced pressure. The product was purified by silica gel chromatography (1% to 4% MeOH gradient in CH ₂ Cl ₂ ) to give intermediate 27 (2.1 g, 62% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 17 and using suitable starting materials (Table 4).

Table 4

Prom, conn.

Starting materials intermediate 20 intermediate 23 intermediate 26

Stage 4.

Preparation of intermediate 18.

intermediate connection 18

A solution 4 of intermediate 11 (2.1 g, 8.8 mmol) in methanol was hydrogenated at atmospheric pressure for 2 h with Pd (10% on carbon, 470 mg, 0.44 mmol, 0.05 eq) in as a catalyst. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give intermediate 18 (1.27 g, 97% yield).

Example A8.

Preparation of intermediate 29.

Stage 1.

Preparation of intermediate 28.

Vg

Intermediate 28

Into an ice-cold mixture of 2-amino-4-bromo-3-chloropyridine (4.5 g, 21.7 mmol) and (Boc) _2O (5.9 g, 26.0 mmol, 1.2 eq.) in anhydrous THF (165 ml) under nitrogen atmosphere was added dropwise NaHMDS (27.1 ml of 2 M solution in THF, 54.2 mmol, 2.5 eq.). Allow the resulting suspension to warm to room temperature and stir until complete conversion (typically approximately 1 hour). Anhydrous DMF (165 mL) was added followed by propargyl bromide (3.4 mL, 30.4 mmol, 1.4 eq.). The reaction mixture was stirred overnight, quenched by adding water and extracted with ether. The combined organic phases were washed with water, dried over MgSO ₄ and concentrated under reduced pressure to obtain the crude product. The product was purified by silica gel chromatography (10% ethyl acetate in heptane) to give intermediate 28 (6.4 g, 85% yield).

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Stage 2.

Preparation of intermediate 29.

intermediate connection 29

KOtBu (2.6 g, 23.1 mmol, 1.25 eq) was added to a solution of intermediate 28 (6.4 g, 18.5 mmol) in THF (90 ml).

The reaction mixture was stirred at room temperature until complete conversion (typically approximately 30 minutes). Water was added and extraction was carried out with ethyl acetate. The combined organic phases were dried over MgSO ₄ and concentrated under reduced pressure. Intermediate 29 (565 mg, 12.5% yield) was isolated after two subsequent purifications using silica gel chromatography (first run: 0 to 1.5% MeOH gradient in CH ₂ Cl ₂ , second run: 50% ethyl acetate in heptane ).

Example A9.

Preparation of intermediate 32.

Stage 1.

Preparation of intermediate 30.

bx intermediate connection 30

A solution of 2-amino-4-bromopyridine (10.0 g, 57.8 mmol) and 2-bromoaldehyde (10.5 g, 69.4 mmol, 1.2 eq.) in EtOH (200 ml) was stirred at the formation temperature phlegm during the night. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was suspended in CH ₂ Cl ₂ , the precipitate was filtered and dried under high vacuum to give intermediate 30 (8.8 g, 67% yield), which was used as is in the next step.

Stage 2.

Preparation of intermediate 31.

intermediate connection 31

The reaction flask into which methyltriphenylphosphonium bromide (30 g, 84.0 mmol, 1.9 eq) and THF (450 ml) was charged was cooled to -78°C. A solution of KOtBu in THF (1 M, 111 mL, 111 mmol, 2.5 eq) was added to the flask and the resulting suspension was stirred at -78°C for 30 minutes. A solution of intermediate 30 (10 g, 4 4.4 mmol) in THF (50 ml) was added dropwise and the reaction mixture was stirred at -78°C for 2 hours, then allowed to warm to room temperature and stirred for an additional 2 hours. A saturated NH4Cl solution was used for quenching and extraction with CH ₂ Cl ₂ was carried out, the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by silica gel chromatography (5 to 100% gradient of ethyl acetate in petroleum ether) to give intermediate 31 as a white solid (6.4 g, 85% yield).

Stage 3.

Preparation of intermediate 32.

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Intermediate 31 (1.1 g, 4.5 mmol) was dissolved in an ethereal solution of diazomethane (400 ml) freshly prepared from Diazald® (20 g, 93 mmol, 20.0 eq). The reaction mixture was cooled in an ice bath and Pd(OAc) ₂ (100 mg, 0.44 mmol, 0.1 eq.) was added. The reaction mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure and the desired product was isolated by silica gel chromatography (5% to 100% gradient of ethyl acetate in petroleum ether). Final purification by preparative reverse phase HPLC, column type: Kromasil 150x25 mm, 10 µm, conditions: A: water (0.05% ammonium hydroxide, v/v); B: MeCN, at the beginning: A (61%) and B (39%); at the end: A: (61%) and B (39%), gradient elution time (min.) 8; retention time 100% B (min.) 2; flow rate (ml/min) 30, yielding intermediate 32 as a white solid (160 mg, 15% yield).

Example A10.

Preparation of intermediate 34.

Stage 1.

Preparation of intermediate 33.

h ₂ n

Br intermediate 33

A solution of carbamic acid, N-(1-bromimidazo[1,2-a]pyridin-2-yl)-,1,1-dimethylethyl ester (740 mg, 2.37 mmol) in hydrochloric acid in methanol (15 ml) was stirred 4 M solution, 60 mmol, 25 eq.) at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the basicity of the resulting residue was increased with aqueous ammonia and extracted with ethyl acetate, the combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give intermediate 33 as a white solid (500 mg, 99% yield).

Stage 2.

Preparation of intermediate 34.

ABOUT

Br intermediate 34

Add acetyl chloride (201 µl, 2.83 mmol, 1.2 eq) to a solution of intermediate 33 (500 mg, 2.36 mmol) and Et ₃ N (492 µl, 3.54 mmol, 1.5 eq) in CH ₂ Cl ₂ at 0°C, the resulting reaction mixture was stirred for 30 minutes. at 0°C. Water was added, the organic layer was separated, and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give intermediate 34 (700 mg, 97% yield).

Example A11.

Preparation of intermediate 35.

NaH 60% in mineral oil (82 mg, 2 mmol) was added in portions to a solution of 1H-pyrrolo[3,2b]pyridine, 2-iodo- (500 mg, 2 mmol) in DMF (20 ml) at 0°C in atmosphere N2. The mixture was stirred for 0.5 hours. Dimethyl sulfate (0.32 g, 2.54 mmol) was then added dropwise to the mixture over 30 minutes. The mixture was then stirred at room temperature for 2 hours. The mixture was treated with water and extracted with ethyl acetate. The organic layer was filtered, washed with brine and dried over Na ₂ SO ₄ . The organic phase was concentrated to give intermediate 35 (400 mg, 57% yield) as a yellow solid.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 35 using suitable starting materials (Table 5).

- 46 044355

Table 5

Prom, conn. Structure Source materials 36 Vg / 1H-pyrrolo[3,2- b]pyridine, 6-bromo-2iodo-

Example A12.

Preparation of intermediate 31.

Add 2.5 M BuLi (22 mL, 55 mmol) dropwise to a solution of 1H-pyrrolo[3,2-b]pyridine-1carboxylic acid, 1,1-dimethylethyl ester (10 g, 45.8 mmol) in dry THF (200 ml) at -78°C in N2 atmosphere. The mixture was heated to -60°C and stirred for two hours. A solution of 1 g (12.8 g, 50.4 mmol) in THF was then added slowly at -72°C. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was then quenched with Na ₂ S ₂ O ₃ and extracted with ethyl acetate (100 ml x3). The organic layer was washed with H ₂ O (50 ml x 3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate in a ratio of 1/0 to 3/1). The product fractions were collected and the solvent was evaporated to give intermediate 31 (2 g, 11% yield) as a yellow oil.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 31 using suitable starting materials (Table 6).

Table 6

Prom, conn. Structure Source materials 38 Furo[3,2-b]pyridine

Example A13.

Preparation of intermediate 45.

C.I.

intermediate connection 45

Intermediate 4 (442 mg, 1.39 mmol) was charged into the reaction flask followed by the addition of a solution of 9-BBN in THF (0.5 M, 5.5 mL, 2.8 mmol, 2.0 eq.), the reaction mixture stirred under nitrogen at room temperature for 2 hours. THF (5 ml), K3PO4 (1.5 g, 6.9 mmol, 5 eq.) and H2O (1.5 ml) were added and stirring was continued for 10 minutes . Intermediate 21 (407 mg, 1.9 mmol, 1.1 eq) and PdCl ₂ (dppf) (101 mg, 0.14 mmol, 0.1 eq) were then added and the resulting reaction mixture was purged with nitrogen for 10 min. and stirred at reflux temperature until complete conversion (usually about 2 hours). The reaction mixture was allowed to cool to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (3% methanol in dichloromethane) to give intermediate 45 (110 mg, 16% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 45 using suitable starting materials (Table 7).

- 47 044355

Table 7

Prom, conn. Structure Source materials 46 Intermediate 4 and 5-bromo-1-methyl-1Hbenzimidazole 47 X Intermediate 4 and 7-bromo-2,3- dimethylimidazo[1,2- a]pyridine 48 Intermediate 4 and intermediate connection 24

Example A14.

Preparation of intermediate 50.

intermediate connection 50

The reaction flask was charged with Intermediate 4 (560 mg, 1.75 mmol) followed by the addition of a solution of 9-BBN in THF (0.5 M, 7.0 mL, 3.5 mmol, 2.0 eq.), the reaction mixture stirred under nitrogen at room temperature for 2 hours. THF (5 ml), K3PO4 (1.9 g, 8.8 mmol, 5 eq.) and H ₂ O (3 ml) were added and stirring was continued for 10 minutes . Intermediate 21 (407 mg, 1.9 mmol, 1.1 eq) and PdCl ₂ (dppf) (256 mg, 0.35 mmol, 0.2 eq) were then added and the resulting reaction mixture was purged with nitrogen for 10 min. and stirred at reflux temperature until complete conversion (typically about 3 hours). The reaction mixture was allowed to cool to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 to 3.5% gradient of methanol in dichloromethane) to give intermediate 50 (300 mg, 38% yield).

Example A15.

Preparation of intermediate 49.

intermediate connection 49

Heat a mixture of intermediate 4 (1000 mg, 3.12 mmol) in 0.5 M 9-BBN in THF (31.3 mL, 15.6 mmol) at reflux for 1 hour under N2. The mixture was cooled to room temperature, then K3PO4 (1990 mg, 9.4 mmol) in H ₂ O (10 ml) was added, followed by THF (100 ml), 7-bromo-imidazo[1,2-a]pyridine ( 924 mg, 4.7 mmol) and Pd-118 (204 mg, 0.31 mmol). The resulting mixture was refluxed for 3 hours. The mixture was concentrated. The residue was dissolved in EtOAc (30 ml), washed with water (10 ml) and brine (10 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: EtOAc/MeOH 10/1). The required fractions were collected

- 48 044355 and concentrated to give intermediate 49 (486 mg, 35.5% yield) as a solid.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 49 using suitable starting materials (Table 8).

Table 8

Example A16.

Preparation of intermediate 54.

intermediate connection 54

A metal pressure vessel (75 ml) was charged with intermediate 50 (270 mg, 0.60 mmol), THF (30 ml) and aqueous ammonia 25% (30 ml) heated at 100°C for one day. The reaction mixture was concentrated under reduced pressure to yield crude intermediate 54, which was used as is in the next step.

Example A17.

Preparation of intermediate 55.

intermediate connection 55

A metal pressure vessel (75 ml) was charged with intermediate 45 (110 mg, 0.23 mmol), THF (30 ml) and aqueous 25% ammonia (30 ml) and heated at 100°C for two days. The reaction mixture was concentrated under reduced pressure to yield crude intermediate 55, which was used as is in the next step.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of Intermediate 54 and Intermediate 55 using suitable starting materials (Table 9)

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Table 9

Prom, conn. Structure Source materials 56 Intermediate 49 NH ₄ 0H 57 L \=z~/ —\ \nh ₂ Intermediate compound 46 NH ₄ 0H 58 Ϋ Intermediate 51 NH ₄ 0H 60 NίΡ '°z θ τη Intermediate 52 NH ₄ 0H 61 yP G tf' I N Intermediate compound 53 NH ₄ 0H 62 ^¼¾ ^1, Intermediate 50 Methylamine 63 Intermediate compound 47 NH ₄ 0H 64 at Intermediate compound 48 NH ₄ 0H 141 Gu °x Intermediate 140 NH ₄ 0H

- 50 044355

Example A18.

Preparation of intermediate 65.

intermediate connection 65

A mixture of intermediate 50 (500 mg, 1.1 mmol) and NaOMe (478 mg, 8.85 mmol) in MeOH (15 ml) was stirred at 60°C overnight. The mixture was diluted with water (20 ml) and extracted with CH ₂ Cl ₂ (50 ml x3). The organic phase was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give crude intermediate 65 (510 mg, 64% yield), which was used in the next step without further purification.

Example A21.

Preparation of intermediate 15.

Intermediate 9 (538 mg, 1.79 mmol) was charged into the reaction flask, followed by the addition of a solution of 9-BBN in THF (0.5 M, 12.5 mL, 6.2 mmol, 3.5 eq) to the reaction the mixture was stirred under nitrogen at room temperature for 2 hours. K3PO4 (2.0 g, 8.96 mmol, 5 eq.) and H2O (2.5 ml) were added and stirring was continued for 10 minutes. Intermediate 29 (484 mg, 1.97 mmol, 1.1 eq) and PdCl ₂ (dppf) (131 mg, 0.18 mmol, 0.1 eq) were then added and the reaction mixture was purged with nitrogen for 10 min. and heated at reflux temperature until complete conversion. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc, the organic phase was washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (4% methanol in dichloromethane) to give intermediate 15, which was used as is in the next step.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 15 and using suitable starting materials (Table 12).

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Table 12

Example A19.

Preparation of intermediate 66.

Heat a mixture of intermediate 4 (300 mg, 0.94 mmol) in 0.5 M 9-BBN in THF (5.63 mL, 2.81 mmol) at reflux for 1.5 h under N2. The mixture was cooled to room temperature, then K ₃ PO ₄ (597 mg, 2.81 mmol) in H2O (2 ml) was added, followed by the addition of THF (20 ml), intermediate 35 (290.5 mg, 1.12 mmol ) and Pd-118 (79.5 mg, 0.112 mmol). The resulting mixture was refluxed for 3 hours. The residue was dissolved in EtOAc (30 ml), washed with brine (5x50 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: EtOAc/petroleum ether 2/1). The desired fractions were collected and concentrated to give intermediate 66 (100 mg, 21.2% yield) as a yellow oil.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 66 using suitable starting materials (Table 10).

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Table 10

Example A20.

Preparation of intermediate 71.

intermediate connection 71

Intermediate 66 (100 mg, 0.22 mmol) was dissolved in 28% NH4OH (20 ml) and dioxane (8 ml). The reaction mixture was stirred at 100°C for 12 hours in a hermetically sealed test tube. The mixture was concentrated. The residue was dissolved in ethyl acetate, washed with brine and dried over anhydrous Na ₂ SO ₄ . The organic phase was concentrated to give intermediate 72 (100 mg, 99% yield) as an oil.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 72 using suitable starting materials (Table 11).

Table 11

- 53 044355

Example A22.

Preparation of intermediate 18.

intermediate connection 78

Into a solution of intermediate 1 (500 mg, 1.54 mmol, 1.0 eq) and imidazo[1,2-a]pyridin-7ol (248.6 mg, 1.85 mmol, 1.2 eq) in THF (20 ml) was added tributylphosphane (624.9 mg, 3.1 mmol, 2.0 eq) and (NE)-N-(piperidine-1-carbonylimino)piperidine-1-carboxamide (779 mg, 3.1 mmol, 2.0 eq.). The mixture was stirred at 15°C for 15 hours. The solvent was removed. The residue was purified using a silica gel flash chromatography column (ISCO®; SepaFlash® silica gel flash chromatography column 12 g, elution gradient from 0% to 3% MeOH/DCM at 30 ml/min) to give intermediate 18 (240 mg, 33.7% yield) as a light yellow solid.

Example A23.

Preparation of intermediate 79.

intermediate connection 79

A solution of intermediate 18 (600 mg, 1.36 mmol, 1.0 eq.) in THF (4 ml), IPA (4 ml) and NH ₃ H ₂ O (8 ml) was stirred at 85°C in a sealed tube for 48 hours. The solvent was removed under reduced pressure. The residue was purified using a silica gel flash column (ISCOZZZ; SepaFlashZZZ 40 g silica flash column, elution gradient from 0 to 10% MeOH (NH3)/DCM at 40 ml/min) to give intermediate 19 (415 mg, 69% yield) as a light yellow solid.

Example A24.

Preparation of intermediate 80.

intermediate connection 80

To a solution of intermediate 1 (250 mg, 772 µmol, 1.0 eq) and 1H-benzimidazol-5-ol, 1methyl- (149 mg, 1.0 mmol, 1.3 eq) in THF (10 ml) PPh ₃ (263 mg, 1.0 mmol, 1.30 eq.) and DIAD (203 mg, 1.0 mmol, 1.3 eq.) were added. The mixture was stirred at 15°C for 2 hours. The solvent was removed. The residue was purified using a silica gel flash chromatography column: eluent: 0% to 50% ethyl acetate/petroleum ether gradient, and second purification eluent: 0% to 5% MeOH/DCM gradient and intermediate 80 (240 mg, yield 61.6%) was obtained as a colorless solid.

Example A25.

Preparation of intermediate 81.

- 54 044355

To a solution of intermediate 80 (500 mg, 1.1 mmol, 1.0 eq) in THF (3 mL) was added IPA (3 mL) and NH3H2O (6 mL). The mixture was stirred at 85°C for 72 hours in a hermetically sealed tube. The solvent was removed under reduced pressure. The residue was purified using a silica gel flash chromatography column (ISCO®; SepaFlash® silica gel flash chromatography column 12 g, eluent gradient from 0 to 7% MEOH/DCM at 30 ml/min) and intermediate 81 (370 mg , yield 73.5%) was obtained as a white solid.

Example A27.

Preparation of intermediate 82.

intermediate connection 82

Cs ₂ CO ₃ (1.48 g, 4.55 mmol, 3 eq.) was added to a solution of intermediate 42 (1.0 g, 1.52 mmol) and intermediate 18 (292 mg, 1.97 mmol, 1 .3 eq.) in DMF (20 ml). The reaction mixture was stirred at room temperature for 3 days, after which intermediate 82 was precipitated by the addition of water. The precipitate was isolated by centrifugation and washed with water (re-suspended in water followed by centrifugation). The wet product was used as is in the next step.

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 82 using suitable starting materials (Table 18).

Table 18

Example A33.

Preparation of intermediate 145.

- 55 044355

A solution of intermediate 144 (150 mg, 0.29 mmol), 2,4-dimethoxybenzylamine hydrochloride (387 mg, 2.3 mmol) and DIPEA (112 mg, 0.87 mmol) in n-BuOH (0.5 mL) stirred at 140°C for one day. The mixture was poured into H2O (5 ml) and extracted with DCM (3 ml x3). The organic layer was washed with brine (3 ml) and dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to obtain the crude product as a brown oil.

The crude product was purified by silica gel column chromatography (1:0 petroleum ether/ethyl acetate to 1:9 petroleum ether/ethyl acetate). The pure fractions were collected and the solvent was evaporated in vacuo to give intermediate 145 (135 mg, 78% yield) as a brown oil.

Example A34.

Preparation of intermediate 146.

But

Intermediate 145 (135 mg, 0.2-3 mmol) and TFA (2 ml) were stirred at 80°C for 1.5 hours. The mixture was evaporated in vacuo to give crude intermediate 146 (100 mg) as a brown oil, which was used as is in the next stage.

Example A28.

Preparation of intermediate 83.

intermediate connection 83

Stir a mixture of intermediate 9 (0.5 g, 1.66 mmol) in a solution of 9 borabicyclo[3.3.1]nonane (20.0 mL, 0.5 M in THF, 10.0 mmol) at room temperature under nitrogen in for 2 hours until complete conversion to the 9-BBN adduct. A nitrogen-purged solution of tribasic potassium phosphate (2.83 g, 13.3 mmol) in water (5 ml) was added. The reaction mixture was stirred at room temperature for 10 min and then a nitrogen-purged solution of 1,1'-bis(di-tertbutylphosphino)ferrocene palladium dichloride (219 mg, 0.33 mmol) and 2-amino-5-bromopyridine (288 mg, 1.66 mmol) in THF (20 ml). The resulting mixture was purged with nitrogen for 15 minutes. The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed twice with dilute NH ₄ OH and once with water. The organic layer was separated, dried with MgSO ₄ , filtered and the solvents in the filtrate were evaporated. The residue was dissolved in dichloromethane and purified on a SiO ₂ column type Grace Reveleris SRC, 4 g, Si 40, on an Armen Spot II Ultimate purification system using dichloromethane and methanol as eluent in a gradient starting from 100% dichloromethane to 10% methanol and 90% dichloromethane. Fractions containing product were combined and solvents were evaporated to give intermediate 83 (0.18 g, 23% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 83 using suitable starting materials (Table 13).

- 56 044355

Table 13

Intermediate connection Structure Source materials 84 Very good /=\ G J} 1 y Intermediate 9 and 2-amino-6bromopyridine 85 h ₂ n ^ЧзЪ' Intermediate 9 and 2-amino-4bromopyridine 88 ΗΝ nJS /=\ \ .. J \ nh ₂ Intermediate 9 and 5-6poM-lhpyrrolo[2,3b]pyridine 100 ss^b-- Intermediate 99 And 2-amino-6bromopyridine 101 Intermediate 99 And 8-bromoisoquinoline-3amine 102 O z J xQ C/I Intermediate 99 And 3-bromopyridine 103 ^/γ ⁿ = Intermediate 99 And 3-bromoquinoline 104 hch O ⁵ Intermediate face-to-face connection 99 And 3-bromoquinodine-8-amine 105 Intermediate face-to-face connection 99 And 2-amino-4bromopyridine 106 SPHg intermediate connection 99 And 2-iodopyridine

- 57 044355

- 58 044355

119 intermediate connection 118 And 8-bromoisoquinodine-3 amine 120 X ζ gr αχ Ο X intermediate connection 118 And 2-amino-6- bromopyridine 121 intermediate connection 118 And 2-amino-5- bromopyridine 122 Η,Ν Av^^Cr'rSr intermediate connection 118 And 2-amino-4- bromopyridine 123 Co Ο Q ³ intermediate connection 118 And 8-bromoquinoline 124 θ’^ intermediate connection 118 And 3-bromoquinodine-8-amine 125 intermediate connection 118 And 7-bromoquinoline

- 59 044355

126 X Kx Ό intermediate connection 118 And 7-bromo-imidazo[1,2a]pyridine 127 ⁰ /^ intermediate connection 118 And 3-bromoquinoline 128 X Le <χχ -О About Ζ^ intermediate connection 118 And 4-iodopyridine 129 Ν X Le \^ ^Ν< Ό / z Μ intermediate connection 118 And 2-iodopyridine 130 fy^y' intermediate connection 118 And 8-bromoquinodine-2 - amine 131 ^yfty intermediate connection 118 And 8-bromysoquinoline 132 X Intermediate 9 And 3-bromopyridine

- 60 044355

Example A29.

Preparation of intermediate 86,

intermediate connection 86

A mixture of intermediate 9 (500 mg, 1.66 mmol), tetraethylammonium chloride (0.30 g, 1.83 mmol) and 2-amino-5-bromopyridine (0.33 g, 1.91 mmol) in DMF (15 ml, ) mixed and purged

- 61 044355 nitrogen for 15 minutes. DIPEA (1.43 mL, 8.32 mmol) and Pd(OAc)2 (56.0 mg, 0.25 mmol) were then added. The reaction vessel was sealed and the reaction mixture was stirred and heated at 100°C for 3 days. The reaction mixture was poured into water and the product was extracted three times with ethyl acetate. The combined organic layers were dried with MgSO ₄ , filtered and the solvents from the filtrate were evaporated. The residue was dissolved in dichloromethane and purified on a SiO ₂ column type Grace Reveleris SRC, 4 g, Si 40, on an Armen Spot II Ultimate purification system using dichloromethane and methanol as eluent in a gradient starting from 100% dichloromethane to 10% methanol and 90% dichloromethane. Fractions containing product were combined and solvents were evaporated to yield 0.26 g of intermediate 86 (0.26 g, 39% yield).

The following intermediates were prepared using a reaction protocol similar to that used for the preparation of intermediate 86 using suitable starting materials (Table 20).

Table 20

Example A30.

Preparation of intermediate 94.

intermediate connection 94

A mixture of intermediate 90 (0.1 g, 0.23 mmol) in THF (30 ml) was hydrogenated with 10% Pd/C (30 mg) and absorbed into a 0.4% thiophene solution in DIPE (1 ml) at room temperature in a hydrogen atmosphere up to 1 eq. hydrogen. The catalyst was removed by filtration through dicalite. The combined solvents from the filtrate were evaporated. The residue was dissolved in dichloromethane and purified on a Grace Reveleris SRC SiO ₂ column, 4 g, Si 40, on a Grace Reveleris X ₂ purification system using dichloromethane and methanol as eluents in a gradient starting from 100% dichloromethane to 80% dichloromethane and 20 % methanol. Fractions containing product were combined and solvents were evaporated to give intermediate 94 (66.4 mg, 44% yield).

- 62 044355

Example A32.

Stage 1.

Preparation of intermediate 139.

Tosylhydrazine (413 mg, 2.2 mmol) was added to a solution of intermediate 3 (1.3 g, 2.2 mmol) in MEON (50 ml). The reaction mixture was stirred at 60°C for 1 hour.

The reaction mixture was concentrated to dryness. The residue was purified by silica gel flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 70/30) to give intermediate 139 as a bright yellow oil.

Stage 2.

Preparation of intermediate 140.

Boronic acid, B-(1-methyl-1H-benzimidazol-5-yl)- (389 mg, 1.77 mmol), intermediate 139 (1.3 g, 2.12 mmol) and cesium carbonate (0.86 g, 2.65 mmol) was stirred in dioxane (30 ml) at 110°C under N ₂ for 3 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The required fractions were collected and the solvent was evaporated.

The residue was repurified using preparative high performance liquid chromatography. Column type: Gemini, 150x25 mm, 5 µm, condition: A: water (10 mM NH ₄ HCO ₃ ); B: MeCN, at the beginning: A (51%) and B (49%); at the end: A: (36%) and B (64%), gradient elution time (min.) 9.5; 100% Retention time (min.) 2.5; flow rate (ml/min) 30. The pure fractions were collected and the solvent was evaporated in vacuo to give intermediate 140 (100 mg, 12% yield).

B. Preparation of final compounds.

Example B1.

connection 1

Dissolve intermediate 54 (0.59 mmol) in EtOH (5 ml) followed by the addition of 1 M aqueous HCl (3 ml, 3.0 mmol). The resulting reaction mixture was stirred at room temperature until completely deprotected (about 3 days), after which it was increased in basicity by adding Na ₂ CO ₃ (253 mg) and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (stationary phase: XBridge C18, 3.5 µM, 4.6x100 mm; mobile phase: 0.25% aqueous NH4CO3, MeOH) to give compound 1 (110 mg, yield 47 %).

- 63 044355

Example B2.

Receiving connection 2.

connection 2

Intermediate 55 was dissolved in EtOH (2 mL) followed by the addition of 1 M aqueous HCl (9.86 mL, 9.86 mmol). The resulting reaction mixture was stirred at room temperature until completely deprotected (typically about 2 days), after which it was increased in basicity by adding aqueous ammonia and concentrated under reduced pressure. The residue was directly purified by preparative reverse phase HPLC (stationary phase: XBridge C18, 3.5 µM, 4.6x100 mm; mobile phase: 0.25% aqueous NH ₄ CO ₃ , MeOH) to give compound 2 (82 mg, yield 52%).

The final compounds below were prepared using a reaction protocol similar to that used for the preparation of compound 1 and compound 2 using suitable starting materials (Table 14).

- 64 044355

Table 14

- 65 044355

Example B3.

Getting connection 16.

connection 16

Stir a solution of intermediate 72 (100 mg, 0.23 mmol) in 4 M HCl in MeOH (10 ml) at room temperature for 1 hour. NH ₄ OH was then added to the mixture until pH >7. The mixture was concentrated. The residue was purified using St. HPLC: Column Type: Waters Xbridge Prep OBD C18: 150x30mm, 5µm. Condition: A: water (0.05% ammonia hydroxide, v/v); B: MeCN, at the beginning: A (87%) and B (13%); at the end: A: (57%) and B (43%). Gradient elution time (min.) 10; 100% During retention time (min.) 3; flow rate (ml/min.) 25 to obtain 34 mg of compound 16 (34 mg, 37% yield) as a white solid.

The final compounds below were prepared using a reaction protocol similar to that used for the preparation of compound 16 (using suitable starting materials (Table 15).

- 66 044355

Table 15

compound structure Source materials 17 n<5 ' ^he intermediate connection 72 18 Ηΰ 'he intermediate connection 73 19 /ABOUT O.p./\ sot y intermediate connection 74 20 nd 'he intermediate connection 70

Example B4.

Getting connection 21.

BUT OH connection 21

Dissolve intermediate 15 (1.79 mmol) in EtOH (2 mL) followed by the addition of 1 M aqueous HCl (9.86 mL, 9.86 mmol). The resulting reaction mixture was stirred at room temperature until completely deprotected (typically about 2 days), after which it was increased in basicity by adding aqueous ammonia and concentrated under reduced pressure. The residue was directly purified by preparative reverse phase HPLC (stationary phase: XBridge C18, 3.5 µM, 4.6 x 100 mm; mobile phase: 0.25% aqueous NH4CO3, MeOH) to give compound 21 (82 mg, yield 52%).

Example B5.

Receiving connection 24.

connection 24

A solution of intermediate 19 (365 mg, 1.0 eq.) in MeOH (3 ml) and HCl/dioxane (3 ml) was stirred at 25°C for 2 hours. The solvent was removed. The residue was adjusted to pH=7 with NH3H2O and then washed with _H2O (10 ml x2) and CH3CN (10 ml x2) to give compound 24 (235 mg, 67.6% yield).

Example B6. Getting connection 25. connection 25

- 67 044355

To a solution of intermediate 81 (320 mg, 736.5 µmol, 1.0 eq) in MeOH (2.5 ml) was added HCl/dioxane (2.5 ml). The mixture was stirred at 20°C for 15 hours. The solvent was removed under reduced pressure. The residue was adjusted to pH >7 with NH3H2O. The mixture was crystallized from

H ₂ O (10 ml). The residue was washed with CH3CN to give 25 (230 mg, 75% yield) as a white solid.

Example B7.

Getting connection 26.

NH _a but he is connection 26

Dissolve intermediate 82 (1.52 mmol) in EtOH (20 mL) followed by the addition of 1 M aqueous HCl (15.2 mL, 15.2 mmol). The reaction mixture was stirred at room temperature until completely deprotected (typically approximately 3 days), after which it was increased in basicity by adding aqueous ammonia and directly purified by preparative reverse phase HPLC (stationary phase: XBridge C18, 3.5 µM, 4.6x100 mm; mobile phase: 0.25% aqueous solution of NH ₄ CO ₃ , MeOH) to obtain compound 26 (135 mg, 22.5%).

The final compounds below were prepared using a reaction protocol similar to that used for the preparation of compound 26 using suitable starting materials (Table 19).

Table 19

Example B8.

Getting connection 21.

H _a N

BUT

NH ₂ connection 27

Add HCl (3.92 mL, 1M in H2O, 3.92 mmol) dropwise to a stirred solution of intermediate 83 (0.18 g, 0.392 mmol) in iPrOH (5 mL) at room temperature. After addition, the reaction mixture was stirred at room temperature for 3 hours. NH ₃ (28% in H ₂ O) (0.53 ml, 7.85 mmol) was added. The solvents were evaporated. The residue was dissolved in 30 ml methanol and purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobile phase: 0.25% NH ₄ HCO ₃ in water, MeOH) to give compound 21 ( 102 mg, yield 73%).

The following compounds were prepared using a reaction protocol similar to that used for the preparation of compound 21 using suitable starting materials (Table 16).

Table 16

compound Structure Source materials 28 n0 &n Intermediate connection 84

- 68 044355

29 h ₂ n Intermediate connection 85 32 n U4=0 NO ¹ bn Intermediate 88 40 N X ζΡ Pk x Intermediate connection 100 41 nyf/Q BUT ^he Intermediate connection 101 42 W X X V...o *O i x i'Z Intermediate 102 43 EC X Z Gr\X Ό/X ζ5 Intermediate 103 44 /L ?τ4 n/ X/ ο,,,,^-Α °'''^Л X m Intermediate 104

- 69 044355

45 Κ ₂ Ν^^ί^ УЧ N^U d 5 ⁿ ° ^he Intermediate face-to-face connection 105 46 sgTLg Intermediate 106 47 ίΛ Ηό Ън O Intermediate 107 48 ΓΝ X Ζ Che X V „„С \ΖΌ Intermediate 108 49 sgrzh' Intermediate 109 50 Ηό 'he Intermediate 110

- 70 044355

51 0,...04 O'' ( X' z X Intermediate connection 111 52 cQ 4tW”· but Oh Intermediate 112 53 o<i h ₂ n ^z Intermediate connection 113 54 О HO OH n _g kg Intermediate connection 119 55 h^ ⁷ ^ but bn Intermediate connection 120 56 -- Η0 ^bn Intermediate connection 121 57 Μ /==, > ^Η 2 ^Ν ^ Λ \ Γ Γιτ Ηΰ Ън Intermediate 122

- 71 044355

58 Co avg z I Intermediate 123 59 IK ^HjN ^ib ^L·—/ TI nb ^&H Intermediate 124 60 rG^\X XT ^N ^Z HO 'OH Intermediate 125 61 T 2 oE \^ ¹ⁱ O f X o V Intermediate connection 126 62 oVr Nb 'OH Intermediate 127 63 ^z O °' cP ζ I M Intermediate 128 64 ζ / ο,.,,^^-Α o' ^s Ср τ Μ Intermediate 129 65 ζ Λ ^Η ° ^0Η kn ₂ Intermediate connection 130

- 72 044355

Example B9.

Getting connection 30.

connection 30

Add HCl (6.62 mL, 1M in H ₂ O, 6.6 mmol) dropwise to a stirred solution of intermediate 86 (0.26 g, 0.66 mmol) in MeOH (8 mL) at room temperature. After adding

- 73 044355 the reaction mixture was stirred at room temperature for 3 hours. NH ₃ (28% in

H2O) (0.90 ml, 13.2 mmol). The solvents were evaporated. The residue was dissolved in 30 ml methanol and purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobile phase: 0.25% NH4HCO3 in water, MeOH) to give compound 30 (143 mg, yield 57%).

The following compounds were prepared using a reaction protocol similar to that used for the preparation of compound 30 using suitable starting materials (Table 21).

Table 21

Example B10.

Getting connection 31.

connection 31

To a solution of intermediate 81 (400 mg, 0.69 mmol) in MeOH (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 5 hours. The solvent was concentrated in vacuo. The residue was taken up in water, increased in basicity with NH3.H2O to pH >7 and extracted with ethyl acetate (100 ml x2). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude product in

- 74 044355 in the form of brown butter. The crude product was purified using preparative high performance liquid chromatography: column: Xtimate C18 150x25 mm, 5 µm.

Condition: A: water (10 mM NH4HCO3) B: ACN, at the beginning: A (92%) and B (8%), at the end: A (62%) and B (38%). Gradient elution time (min.) 14; 100% Retention time (min.) 2.5; flow rate (ml/min.) 25. The pure fractions were collected and the organic solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to obtain compound 31 (83 mg, 27% yield) as a white solid.

Example B11.

Getting connection 15.

nb 'on connection 75

Intermediate 146 (100 mg, 0.22 mmol) and K2CO3 (270 mg) were added to MeOH (4 mL) and refluxed for 2 hours. The mixture was evaporated in vacuo. The crude product was purified by preparative HPLC. Column: Xtimate C18 150x25 mm x 5 microns.

Condition: A: water (0.05% ammonium hydroxide v/v) B: MeCN, start: A (90%) and B (10%), end: A (60%) and B (40% ). Gradient elution time (min.) 10; 100% Retention time (min.) 2.5; flow rate (ml/min.) 25. The purified fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to obtain compound 15 (22.8 mg, 28.6% yield) as a white solid.

C. Transformations of final compounds.

Example C1.

Getting connection 13.

connection 13

Compound 3 (50 mg, 0.13 mmol) was stirred in DMF (2 ml). N-chlorosuccinimide (17.6 mg, 0.13 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was diluted to 10 ml with DMF and used as such for RP purification (XBRidge C18, 3.5 µM (100x4.6 mm), aq NH4CO3 and MeOH) to give compound 13 (27 mg, yield 49.5 %).

The final compounds below were prepared using a reaction protocol similar to that used for the preparation of compound 13 using suitable starting materials (Table 17).

Table 17

Analytical part of NMR.

For a number of compounds, 1H NMR spectra were recorded on a Bruker Avance 400 operating at 400 MHz or on a Varian 400MR spectrometer operating at 400 MHz. The solvents used were Methanol-d ₄ or DMSO-d ₆ (deuterated DMSO, dimethyl sulfoxide-dQ. Chemical shifts (δ) are given in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as an internal standard .

^1H NMR (b ppm) Connection 24 ^T H NMR (400 MHz, DMSO-dg) δ ppm 1, 62-1.77 (m, 1 Η), 2.34 (s, 1 Η), 2.43 (s, 1 Η), 3.95 (br s, 1 H) , 4.14-4.36 (m, 3 H) , 4.77-5.01 (m, 3 H) , 6.61 (d, J=3.5 Hz, 1 H) , 6.92 (dd, J=1.5, 2.2 Hz, 1 H) , 7.13 (br s, 3 H) , 7.33 (d, J=3.5 Hz, 1 H ) , 7.67 (s, 1 H) , 7.93 (s, 1 H) , 8.08 (s, 1 H) , 8.56 (d, J=7.5 Hz, 1 H) Connection 3 ^T H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.39-1.56 (m, 1 H), 1.67 (m, J=13.2 Hz, 1 H), 1.78-2 .00 (m, 2 H) , 2.14-2.28 (m, 1 H) , 2.58-2.74 (m, 2 H) , 3.66-3.78 (m, 1 H) , 4.12-4.24 (m, 1 H) , 4.62 (d, J=4.9 Hz, 1 H) , 4.70-4.83 (m, 2 H) , 6.52 ( d, J=3.5 Hz, 1 H) , 6.78 (dd, J=7.l, 1.8 Hz, 1 H) , 6.88 (br s, 2 H) , 7.23 (d , J=3.5 Hz, 1 H) , 7.34

- 76 044355

(s, 1 N), 7.46 (s, 1 N), 7.82 (s, 1 N), 8.00 (s, 1 N) , 8.43 (d, J=7.1 Hz, 1 N) Connection 33 ^T H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.59-1.75 (m, 1 Η), 2.26 (s, 3 Η), 2.28-2.45 (m, 2 Η ), 3.94 (br q, J=4.0 Hz, 1 H) , 4.08 (dd, J=9.2, 6.2 Hz, 1 H) , 4.15 (dd, J=9 ,5, 6.2 Hz, 1 H) , 4.23-4.35 (m, 1 H) , 4.82 (br d, J=4.2 Hz, 1 H) , 4, 86-4, 98 (m, 2 H) , 6.55 (s, 2 H) , 6.84 (br d, J=l.8 Hz, 1 H) , 6.90 (br s, 2 H) , 7.29 (d, J=3.5 Hz, 1 H) , 7.45 (s, 1 H) , 8.04 (s, 1 H) , 8.28 (d, J=1.5 Hz, 1 H) Connection 23 ^T H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42-1.58 (m, 1 H), 1.71 (br s, 1 H), 1.78-2.01 (m, 2 H) , 2.24 (m, J=12.3, 7.9, 7.9 Hz, 1 H) , 2.68-2.80 (m, 2 H) , 3.67-3.83 ( m, 1 H) , 4.15-4.26 (m, 1 H) , 4.66 (d, J=4.9 Hz, 1 H) , 4.72-4.89 (m, 2 H) , 6.54 (d, J=3.5 Hz, 1 H) , 6.92 (br s, 2 H) , 7.00 (br dd, J=7,l, 1.3 Hz, 1 H) , 7.25 (d, J=3.5 Hz, 1 H) , 7.49 (s, 1 H) , 8.02 (s, 1 H) , 8.44 (s, 1 H) , 8, 51 (d, J=7.l Hz, 1 H) Connection 26 ^T H NMR (400 MHz, DMSO-de) δ ppm 1.68 (ddd, J=12.5, 10.2, 8.1 Hz, 1 H), 2.28-2.46 (m, 2 H ) , 2.42 (d, J=0.7 Hz, 3 H) , 3.95 (br s, 1 H) , 4.14 (dd, J=9.7, 6.2 Hz, 1 H) , 4.21 (dd, J=9.7, 6.2 Hz, 1 H) , 4.26-4.35 (m, 1 H) , 4.82 (br s, 1 H) , 4.85 -4.99 (m, 2 H) , 6.57 (d, J=3.5 Hz, 1 H) , 6.78 (dd, J=7.5, 2.4 Hz, 1 H) , 6 .92 (br s, 2 H), 7.01 (d, J=2.2 Hz, 1 H), 7.28 (s, 1 H), 7.30 (d, J=3.5 Hz, 1 H) , 8.04 (s, 1 H) , 8.21 (d, J=7.5 Hz, 1 H) Connection 1 ^T H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.43-1.58 (m, 1 H), 1.62-1.76 (m, 1 H), 1.79-1.91 ( m, 1 H) , 1.91-2.01 (m, 1 H) , 2.24 (dt, J=12, 6, 7.9 Hz, 1 H) , 2.43 (d, J=0 .7 Hz, 3 H) , 2.57-2.79 (m, 2 H) , 3.75 (q, J=5, 1 Hz, 1 H) , 4.13-4.25 (m, 1 H) ,

- 77 044355

4.62 (d, J=5, 1 Hz, 1 N), 4.71-4.90 (m, 2 N), 6.54 (d, J=3.5 Hz, 1 N), 6.84 (dd, J=6.9, 1.7 Hz, 1 N), 6.89 (s, 2 N), 7.25 (d, J=3.5 Hz, 1 N) , 7.27 (d, J=0.7 Hz, 1 N) , 7.33 (s, 1 N) , 8.03 (s, 1 N) , 8.16 (d, J=7.0 Hz, 1 N) Connection 11 ^T H NMR (400 MHz, DMSO-de) δ ppm 1.43-1.56 (t, 1 Η), 1.61-1.74 (t, 1 Η), 1.78-1.99 (t , 2 Η), 2.16-2.24 (t, 1 Η), 2.27 (s, 3 Η), 2.35 (s, 3 Η), 2.59-2.77 (m, 2 Η), 3.75 (br t, J=5.1 Hz, 1 H) , 4.20 (br t, J=6.7 Hz, 1 H) , 4.61 (br s, 1 H) , 4, 69-4.85 (m, 2 H), 6.54 (d, J=3.5 Hz, 1 H), 6.77 (dd, J=7.0, 1.5 Hz, 1 H ) , 6.89 (br s, 2 H) , 7.21 (br s, 1 H) , 7.24 (d, J=3.5 Hz, 1 H) , 8.03 (s, 1 H) , 8.06 (d, J=7.0 Hz, 1 H) Connection 8 ^T H NMR (400 MHz, METHANOL-b ₄ ) δ ppm 0.64-0.74 (m, 2 H), 1.03-1.12 (m, 2 H), 1. 60-1.74 ( m, 1 H) , 1.77-1.89 (m, 1 H) , 1.89-2.00 (m, 1 H) , 2.012.13 (m, 2 H), 2.37-2, 49 (m, 1 H), 2.76-2.91 (m, 2 H), 3.92 (dd, J=6.2, 4.9 Hz, 1 H), 4.34 (dd, J =7.5, 6.2 Hz, 1 H) , 6.61 (d, J=3.5 Hz, 1 H) , 6.96 (dd, J=7.l, 1.8 Hz, 1 H ) , 7.23 (s, 1 H) , 7.24 (d, J=3.5 Hz, 1 H) , 7.35 (s, 1 H) , 8.06 (s, 1 H) , 8 .37 (d, J=7.1 Hz, 1 H) Connection 2 ^T H NMR (400 MHz, DMSO-de) δ ppm 1.45-1, 60 (m, 1 H), 1.68 (br d, J=4.8 Hz, 1 H), 1.85-2 .00 (m, 2 H) , 2.23-2.35 (m, 1 H) , 2.45 (s, 3 H) , 2.79 (m, J=7.4, 7.4 Hz, 2 H) , 3.77 (m, J=5.3 Hz, 1 H) , 4.16-4.26 (m, 1 H) , 4.66 (d, J=4.8 Hz, 1 H ) , 4.75-4.87 (m, 2 H) , 6.54 (d, J=3.5 Hz, 1 H) , 6.89 (br s, 2 H) , 7.25 (d, J=3.5 Hz, 1 H) , 7.35 (s, 1 H) , 7.53 (s, 1 H) , 8.03 (s, 1 H) , 8.50 (s, 1 H) Connection 21 ^T H NMR (400 MHz, DMSO-de) δ ppm 1.45-1.60 (m, 1 H), 1.62-1.76 (m, 1 H), 1.85-1.98 (m , 1 H) ,

- 78 044355

2.26-2.36 (m, 1 N) , 2.45 (d, 0=0.7 Hz, 1 N) , 2.84 (t, 0=6.5, 6.5 Hz, 2 N ) , 3.77 (br s, 1 N) , 4.21 (br s, 1 N) , 4.66 (br s, 1 N) , 4.73-4.85 (t, 2 N) , 6.54 (d, 0=3.5 Hz, 1 N) , 6.88 (br s, 2 Η), 6.96 (d, 0=7.0 Hz, 1 Η), 7.25 (d, 0=3.5 Hz, 1 Η), 7.35 (s, 1 Η), 8.03 (s, 1 Η), 8.21 (d, 0=7.0 Hz, 1 Η) Connection 12 ^T H NMR (400 MHz, DMSO-de) δ ppm 1.45-1.58 (m, 1 Η), 1.71 (m, 0=8.1 Hz, 1 Η), 1.82-2, 01 (m, 2 Η), 2.22-2.32 (m, 1 Η), 2.42 (s, 3 Η), 2.69-2.81 (m, 2 Η), 3.71- 3.82 (m, 1 Η), 4.15-4.24 (m, 1 Η), 4.65 (br s, 1 H), 4.71-4.86 (m, 2 H), 6 .54 (d, 0=3.5 Hz, 1 H) , 6.89 (br s, 2 H) , 7.25 (d, 0=3.7 Hz, 1 H) , 7.34 (s, 1 H) , 7.48 (d, J=1.3 Hz, 1 H) , 8.03 (s, 1 H) , 8.45 (d, 0=5.7 Hz, 1 H) Connection 14 ^T H NMR (400 MHz, DMSO-de) δ ppm 1.44-1.60 (m, 1 H), 1.63-1.79 (m, 1 H), 1.80-2.03 (m , 2 H), 2.25 (dt, 0=12.6, 7.9 Hz, 1 H), 2, 60-2.83 (m, 2 H), 3.76 (q, 0=5, 1 Hz, 1 H) , 4.14-4.28 (m, 1 H) , 4.62 (d, 0=5, 1 Hz, 1 H) , 4.72-4.87 (m, 2 H ) , 6.54 (d, 0=3.5 Hz, 1 H) , 6.89 (s, 2 H) , 7.02 (dd, 0=7.0, 1.5 Hz, 1 H) , 7.25 (d, 0=3.5 Hz, 1 H) , 7.47 (s, 1 H) , 7.64 (s, 1 H) , 8.03 (s, 1 H) , 8.26 (d, 0=7.0 Hz, 1 H) Connection 13 ^T H NMR (400 MHz, DMSO-dg) δ ppm 1.43-1.60 (m, 1 H), 1.63-1.80 (m, 1 H), 1.85 (br s, 1 H ) , 1.93 (br dd, 0=14.5, 6.4 Hz, 1 H) , 2.25 (dt, 0=12.6, 7.9 Hz, 1 H) , 2, 62-2 .85 (m, 2 H), 3.76 (q, 0=5.1 Hz, 1 H), 4.13-4.29 (m, 1 H), 4.62 (d, 0=5, 1 Hz, 1 H) , 4.70-4.90 (m, 2 H) , 6.54 (d, 0=3.5 Hz, 1 H) , 6.89 (br s, 2 H) , 7 .03 (dd, 0=7.0, 1.3 Hz, 1 H) , 7.25 (d, 0=3.5 Hz, 1 H) , 7.47 (s, 1 H) , 7.62 (s, 1 H) , 8.03 (s, 1 H) , 8.27 (d, 0=7.0 Hz, 1 H), 8.27 (s, 1 H)

- 79 044355

Connection 15 ⁱ H NMR (400 MHz, DMSO-de) δ ppm 1.45-1.57 (m, 1 Η), 1.60-1.78 (m, 1 Η), 1.78-2.02 (m , 2 Η), 2.17-2.28 (m, 1 Η), 2.43 (s, 3 Η), 2.58-2.77 (m, 2 Η), 3.73 (m, < 7=5, 1 Hz, 1 Η), 4.16-4.27 (m, 1 Η), 4.63 (d, <7=4.8 Hz, 1 Η), 4.79 (d, < 7=6.3 Hz, 1 Η), 4.81-4.92 (m, 1 Η), 6.68 (br s, 2 H), 6.85 (d, <7=7.0 Hz, 1 H) , 7.28 (s, 1 H) , 7.33 (s, 1 H) , 7.59 (s, 1 H) , 8.08 (s, 1 H) , 8.17 (d, J=1.0 Hz, 1 H) Connection 22 ⁱ H NMR (400 MHz, DMSO-de) δ ppm 1.43-1.58 (m, 1 H), 1.61-1.76 (m, 1 H), 1.80-2.01 (m , 2 H), 2.23 (dt, <7=12.6, 7.9 Hz, 1 H), 2.29 (s, 3 H), 2.562.75 (m, 2 H), 3.75 (q, <7=5.1 Hz, 1 H) , 4,144.26 (m, 1 H) , 4.61 (d, <7=5.1 Hz, 1 H) , 4,714.86 (m, 2 H) , 6.54 (d, <7=3.5 Hz, 1 H) , 6.72 (dd, <7=7.0, 1.5 Hz, 1 H) , 6.88 (s, 2 H) , 7.22 (s, 1 H) , 7.24 (d, <7=3.5 Hz, 1 H) , 7.56 (s, 1 H) , 8.03 (s, 1 H) , 8.33 (d, <7=6.8 Hz, 1 H) Compound 31 ¹ H NMR (400 MHz, DMSO-de) δ ppm 1.42-1.58 (m, 1 H), 1.62-1.76 (m, 1 H), 1.79-1.99 (m , 2 H) , 2.05 (s, 3 H) , 2.25 (dt, <7=12.4, 7.6 Hz, 1 H) , 2.572.79 (m, 2 H) , 3.75 (q, <7=5.0 Hz, 1 H) , 4.114.28 (m, 1 H) , 4.61 (d, <7=5.1 Hz, 1 H) , 4.71- 4.87 (m, 2 H) , 6.54 (d, <7=3.5 Hz, 1 H) , 6.76 (dd, <7=6.9, 1.7 Hz, 1 H) , 6.89 (br s, 2 H) , 7.21 (s, 1 H) , 7.25 (d, <7=3.5 Hz, 1 H) , 7.97 (s, 1 H) , 8.03 ( s, 1 H) , 8.41 (d, <7=6.8 Hz, 1 H) , 10.58 (s, 1 H) Compound 61 ⁱ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.30-1.46 (m, 4 H) 1.56-1.70 (m, 3 H) 1.78-1.90 (m, 1 H) 2.17 (dt, <7=12.5, 7.9 Hz, 1 H) 2.63 (t, J=1, 6 Hz, 2 H) 3.60-3.70 (m, 1 H) 4.13-4.21 (m, 1 H) 4.57 (br d, <7=4.2 Hz, 1 H) 4.71-4.82 (m, 2 H) 6.53 (d, <7=3.5 Hz, 1 H) 6.77 (dd, <7=6.9, 1.7 Hz, 1 H)

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6.88 (br s, 2 N) 7.22 (d, 7=4.0 Hz, 1 N) 7.31 (br s, 1 N) 7.47 (d, 7=1.1 Hz, 1 N) 7.83 (s, 1 N) 8.02 (s, 1 N) 8.42 (d, 7=6.8 Hz, 1 N) Connection 72 ^T H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.41-1.51 (m, 1 Η) 1.52-1.62 (m, 1 Η) 1.68-1.90 (m, 2 Η) 2.20 (dt, 7=12.7, 7.7 Hz, 1 Η) 2.33-2.48 (m, 2 Η) 3.34-3.39 (m, 2 Η) 3 .71 (t, 7=5.0 Hz, 1 Η) 4.044.13 (m, 2 Η) 4.19 (br t, 7=6.8 Hz, 1 Η) 4.514.67 (m, 1 Η) 4.78 (m, 7=8.0, 8.0 Hz, 2 Η) 6.39 (br s, 1 Η) 6.54 (d, 7=3.5 Hz, 1 Η) 6.83 ( d, 7=1.8 Hz, 1 Η) 6.88 (br s, 2 H) 7.24 (d, 7=3.5 Hz, 1 H) 7.42 (d, 7=2.0 Hz , 1 H) 8.03 (s, 1 H) Connection 56 ⁱ H NMR (400 MHz, DMSO-de) δ ppm 1.23-1.65 (m, 7 H) 1.75-1.87 (m, 1 H) 2.16 (dt, 7=12.5 , 7.9 Hz, 1 H) 2.38 (t, 7=7.6 Hz, 2 H) 3.65 (br t, 7=5.4 Hz, 1 H) 4.12-4.22 ( m, 1 H) 4.57 (br s, 1 H) 4.70-4.83 (m, 2 H) 5.59 (br s, 2 H) 6.38 (d, 7=8.5 Hz , 1 H) 6.54 (d, 7=4.0 Hz, 1 H) 6.88 (br s, 2 H) 7.16-7.27 (m, 2 H) 7.72 (d, 7 =2.0 Hz, 1 H) 8.02 (s, 1 H) Connection 65 ¹ H NMR (400 MHz, DMSO-de) δ ppm 1.33-1.47 (m, 4 H) 1.57-1.76 (m, 3 H) 1.82-1.97 (m, 1 H) 2.17 (dt, 7=12.6, 7.9 Hz, 1 H) 2.93-3.06 (m, 2 H) 3.68 (t, 7=5.3 Hz, 1 H ) 4.17 (dd, 7=7.7, 5.9 Hz, 1 H) 4.55-4.83 (m, 3 H) 6.29 (br s, 2 H) 6.53 (d, 7=3.5 Hz, 1 H) 6.73 (d, 7=8.8 Hz, 1 H) 6.88 (br s, 2 H) 7.01-7.08 (m, 1 H) 7 .22 (d, 7=3.5 Hz, 1 H) 7.32 (dd, 7=6.9, 1.2 Hz, 1 H) 7.43 (dd, 7=7.9, 1.3 Hz, 1 H) 7.83 (d, 7=8.8 Hz, 1 H) 8.03 (s, 1 H)

Connection 53 ^T H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.28-1.46 (m, 2 H) 1.49-1.61 (m, 3 H) 1.79-1.90 (m, 1 H) 2.17 (dt, 7=12.5, 7.8 Hz, 1 H) 2.40 (br t, 7=6.9 Hz, 2 H) 3.65 (br t, 7=5 .1 Hz, 1 H) 4.14 (br t, 7=6.8 Hz, 1 H) 4.57 (br s, 1 H) 4. 68-4.85 (m, 2 H) 5.60 (br s, 2 H) 6.38 (d, 7=8.4 Hz, 1 H) 6.52 (d, 7=3.5 Hz, 1 H) 6.87 (br s, 2 H) 7 ,18-7.25 (m, 2 H) 7.73 (d, 7=2.0 Hz, 1 H) 8.02 (s, 1 H)

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 column flow was directed 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 custom parameters (eg, scan range, minimum measurement time, etc.) to obtain ions that allow the nominal monoisotopic molecular weight (MW) of the compound to be determined. Data recording and processing was carried out using appropriate software.

Compounds were described by their experimental retention time (Rt) and ions. Unless otherwise indicated in the data table, the molecular ion indicated corresponds to [M+H]+ (protonated molecule) and/or [M-H]- (deprotonated molecule). If the compound was not directly capable of ionization, indicate the type of adduct (ie [M+NH ₄ ] ⁺ , [M+HCOO] ^- , etc.). For molecules with complex isotopic distributions (Br, Cl), the described value is the value obtained for the smallest isotope mass. All results are subject to experimental errors that are typically associated with the method used.

Hereinafter, SQD means single quadrupole detector, MSD means mass selective detector, c.t. means room temperature, BEH means bridged ethyl siloxane/silica, 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 means evaporative light scattering detector.

Symbol for LCMS methods (flow expressed in ml/min; column temperature (T) in °C; analysis time in minutes)

Symbol of the method Device Column Mobile phase Gradient Flow Analysis time T speakers 1 Waters: Acquity® UPLC® - DAD and SQD Waters: HSS T3 (1.8 µm, 2.1 * 100 mm) 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. , up to 0% A in 0.90 min., up to 5% A in 0.5 min. 0.7 3.5 55 2 Waters: Acquity® UPLC® - DAD and SQD Waters: BEH C18 (1.7 µm, 2.1*50 mm) A: 10 mM CH ₃ COONH ₄ b 95% H ₂ O+5% CH ₃ CN B: CH ₃ CN 95% A to 5% Aza 1.3 min., hold for 0.7 min. 0.8 2 55 3 Waters: Acquity® UPLC® - DAD and SQD Waters: HSS T3 (1.8 µm, 2.1 * 100 mm) 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. , up to 0% A in 0.90 min., up to 5% A in 0.5 min. 0.7 3.5 55 4 Waters: Acquity® UPLC® - DAD and SQD Waters: H.S.S. T3 (1.8 microns, 2.1 * 100 A: 10 mM ch ₃ coonh ₄ in 95% H ₂ O+5% CH ₃ CN From 100% A to 5% A in 2.10 min. , up to 0% A for 0.7 3.5 55

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mm) B: CH ₃ CN 0.90 min., up to 5% A in 0.5 min. 5 Agilent: 1200 - DAD and MSD6110 Phenomenex: Luna-C18 (5 µm, 2x50 mm) A: 0.1% CF ₃ COOH in water, B: 0.05% CF ₃ COOH in CH ₃ CN From 100% A in 1 minute, to 40% A in 4 minutes, to 15% A in 2.5 minutes, again to 100% A in 2 minutes. 0.8 10 50 6 Agilent: 1100/1200 - DAD and MSD Waters: XBridgeTM Shield RP18 (5 µm, 2.1x50 mm) A: 0.05% NH ₄ OH in water, B: CH ₃ CN from 100% A in 1 minute, to 40% A in 4 minutes, holding for 2.5 minutes, back to 100% A in 2 min. 0.8 10.5 40

Connection no. means connection number; retention time (Rt) in min; But. means undefined.

Conn. No. Rt [M+N] ⁺ LCMS Way 25 3.33 395 6 24 3.19 381 6 3 3.365 379 6 4 3.558 393 6 5 3,732 430 5 18 2,886 396 5 19 3.603 380 6 17 3.373 379 6 6 2,947 411 5 1 3.535 393 6 7 1.35 425 4 16 2.68 393 5 13 1.30 413 4 14 1.33 457 4 15 1.32 471 3

Conn. No. Rt [M+N] ⁺ LCMS Way 8 1.31 419 4 2 1.36 427 3 eleven 1, 19 407 4 9 2,777 407 5 10 4,057 408 6 12 1.24 411 3 21 1.22 427 4 27 0.99 355 4 28 1, 04 355 1 29 0.45 355 2 thirty 0.98 353 4 20 1.43 471 4 22 3.623 393 6 26 0.49 395 2 23 1.38 447 4

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31 1.09 436 4 32 1.20 379 4 33 1.05 395 4 34 0.93 341 4 35 0.97 341 4 36 0.96 353 4 37 1.07 353 4 71 0.86 395 3 39 0.90 343 4 38 0.90 343 4 41 1.34 419 4 43 1.42 404 4 40 1.13 369 4 45 1.08 369 4 42 1.18 354 4 73 1.12 381 4 61 1.24 407 4 72 1.13 397 4 58 1.62 418 4 62 1.51 418 4 57 1.15 383 4 47 1.41 404 4 55 1.21 383 4

63 1.26 368 4 67 1.10 340 4 56 1.18 383 4 54 1.42 433 4 49 1.17 354 4 64 1.29 368 4 46 1.20 354 4 48 1.16 393 4 59 1.51 433 4 50 1.42 419 4 65 1.48 433 4 53 1.07 369 4 60 1.49 418 4 52 1.50 404 4 51 1.40 404 4 69 1.00 356 3 70 1.00 466 3 44 1.41 419 4 68 0.98 329 4 66 1.49 418 4 75 1.07 365 4 74 1.11 379 4

Experimental procedures. In vitro assay (assay 1a and 1b).

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

Full-length untagged recombinant human histone H2A (residues 1–130, Genbank accession no. NM 021052, MW=14.1 kDa) expressed in E. coli was purchased from Reaction Biology Corporation, cat. no. NMT-11-146. Reagents used to prepare the reaction or stopping buffer were purchased, including Tris Base (Sigma Cat. No. T-1503), NaCl (Sigma Cat. No. RGF-3270), MgCl ₂ (Sigma Cat. No. M0250 ), DTT (Invitrogen Cat. No. 15508-013), and formic acid (Riedel de Haen, Cat. No. 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), thereby producing monomethyl (MMA), symmetric dimethylarginine (sDMA) and S-adenosyl-L-homocysteine (AdoHcy, SAH). Enzyme activity was determined after formation of the SAH product using high-throughput mass spectrometry (Agilent Rapidfire 300 system with Sciex 4000 series QTrap® triple quadrupole MS/MS). 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 dose points obtained for each compound by serial dilution 1:2 in dimethyl sulfoxide (DMSO), with point 12 representing DMSO as a control. Compounds were first plated 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 reaction mixture concentrations were 1 μM SAM, 0.3 μM H2A, and 10 nM enzyme (assay 1a) or 1.25 nM enzyme (assay 1b). The reaction mixture was incubated at 30°C for 60 minutes (min) when 10 nM enzyme was used and for 120 minutes when 1.25 nM enzyme was used. The reaction mixture was then quenched by adding formic acid to a final concentration of 1%. Inhibition values

- 84 044355 SAH formation in the presence of compounds was 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=Bottom + (Top-Bottom)/(1+10L((log IC50 - X)*h)), where _IC50 represents the inhibitor concentration (same units as X) at 50% inhibition, and h represents is the Hill slope coefficient. Y represents the percentage of inhibition, X represents the concentration of the compound. The Lower Value and Upper Value represent the values for the plateau in the same units as Y.

Experimental procedure. PD analysis (analysis 2).

Reagents.

A549 cells (ATCC, cat. no. CCL-185) were cultured in Dulbecco's modified Eagle's medium (DMEM) (Sigma, cat. no. D5796) supplemented with 10% fetal calf serum (FCS) (HyClone™, cat. no. D5796). SV30160.03), 100 mM sodium pyruvate (Sigma, cat. no. S8636), 200 mM L-glutamine (Sigma, cat. no. G7513), and 50 mg/ml gentamicin (Gibco, cat. no. 15750-037).

Reagents used for buffers were purchased: Dulbecco's phosphate buffered saline (DPBS) without Ca/Mg (Sigma, cat. no. D8537), phosphate buffered saline (PBS) 10X (Roche, cat. no. 11666789 001), 10% formalin solution (Sigma, HT50-1-128-4L), 100% methanol (Sigma, cat. no. 32213-2.5L), Triton X100 (Acros, cat. no. 215680010), bovine serum albumin (BSA) (Sigma , cat. no. A2153), goat anti-rabbit immunoglobulin antibody conjugated to Alexa Fluor 488 (Life Technologies, cat. no. A11034), dark red dye HCS CellMask (Life Technologies, cat. no. H32721), Hoechst dye ( Life Technologies, cat. no. 33258), anti-dimethylarginine antibody, symmetrical (SYM10) (Millipore, 07-412).

Immunohistochemical analysis procedure.

Cells were plated at 400 cells/40 μl/well in 384-well black clear-bottom microplates (Perkin Elmer) and incubated overnight at 37°C, 5% CO ₂ . IC ₅₀ studies were performed using nine dose points ranging from 10 μM to 1 pM for each compound. 80 nL of appropriate dilution of compounds was added using Labcyte POD 810 (Labcyte), achieving a final DMSO concentration of 0.2% in cell culture. After an incubation period of 48 hours at 37°C and 5% CO _{2 ,} the cells were fixed in 10% formaldehyde for 15 minutes. at room temperature and 20 min. in ice-cold methanol, after which they were washed in DPBS, 3x. Cells were then blocked for 1 h in blocking buffer (PBS+1% BSA and 0.5% Triton X-100) and incubated overnight at 4°C with SYM10 antibody diluted 1/2000 in blocking buffer. Cells were washed with wash buffer (PBS+0.1% Triton X-100), 3x, and incubated with goat anti-rabbit immunoglobulin antibody conjugated to Alexa fluor 488, diluted 1/200 in blocking buffer, for 1 hour at room temperature. . They were then washed with wash buffer 3x and incubated for 30 min. at room temperature with PBS containing Hoechst dye at a 1/5000 dilution and HCS CellMask dark red dye at a 1/5000 dilution. After a final wash with PBS, the plates were visually analyzed using a 10xW Opera® system lens (Perkin Elmer Life Sciences) using the following settings (nm values).

Laser Camera with filters Primary dichromatic mirror Dichromatic mirror for detection 488 540/75 405/488/561/635 510 405 450/50 405/488/561/635 510 635 690/50 405/488/561/635 510

Carrying out analyses.

Inhibition of symmetric nuclear arginine dimethylation in the presence of compounds (% effect) was calculated as median nuclear SYM10 intensity/median cytoplasmic SYM10 intensity normalized by the following equation:

Raw - Low Median

Normalized - 100 - _HIGH median - Low median *

In the above equations, the following variable names were used.

- 85 044355

Normalized Normalized characteristic value Raw Raw characteristic value Low median Median value for raw values of low concentration control wells High median Median value for raw values of high concentration control wells

In the above equations, the following controls were used for normalization.

Low concentration control: minimum level of symmetrically dimethylated arginines (cells treated with reference compound at 10 µM concentration).

High concentration control: maximum level of symmetrically dimethylated arginines (cells treated with DMSO).

IC ₅₀ and pIC ₅₀ (-log IC ₅₀ ) values were calculated using appropriate software.

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

Conn. р1С ₅₀ pICso pic ₅₀ 15 Η. ο. 9.0 8.2 No. Analysis 1a lb analysis Analysis 2 8 Η. ο. 8.6 7.6 25 b. 9 n. o. 5.7 2 Η. ο. 9.8 8.2 24 7, 5 n. o. 5, 8 eleven Η. ο. >9.7 8.4 3 8, 7 n. o. 7.7 9 Η. ο. 8.4 7.2 4 7, 9 n. o. 7.5 10 Η. ο. 8.0 6.7 5 7, 9 n. o. 5.4 12 Η. ο. 9.5 8.7 18 7, 4 n. o. 6, 9 21 Η. ο. 8.4 7.8 19 5, 9 n. o. 5.3 27 Η. ο. 8.3 8.2 17 7, 4 n. o. 6, 0 28 Η. ο. 6, 8 6.2 6 _8f 7 n. o. 7.8 29 Η. ο. 6.4 5.7 1 9, 1 n. o. 8, 9 thirty Η. ο. 7.2 6.3 7 _8f 2 n. o. 7.6 20 Η. ο. Η. ο. Η. ο. 13 S, 7 θ,9 7.7 22 Η. ο. Η. ο. Η. ο. 14 S, 9 8.8 7.9 16 Η. ο. Η. ο. Η. ο. 26 H. ο. Η. o. H. o. 47 Η. ο. 5.8 Η. ο. 23 H. ο. 7.4 Η. o. 55 Η. ο. 9.4 Η. ο. 31 Η. ο. 7.2 Η. o. 63 Η. ο. 5.7 Η. ο. 32 Η. ο. Η. o. Η. o. 67 Η. ο. 6.3 Η. ο. 33 Η. ο. 8.3 Η. o. 56 Η. ο. 8.1 Η. ο. 34 Η. ο. Η. o. Η. o. 54 Η. ο. 7.0 Η. ο. 35 Η. ο. Η. o. Η. o. 49 Η. ο. <5.6 Η. ο. 36 Η. ο. 5.7 Η. o. 64 Η. ο. 7.0 Η. ο. 37 Η. ο. 6, 1 Η. o. 46 Η. ο. <5.6 Η. ο. 71 Η. ο. 7.0 Η. o. 48 Η. ο. 7.5 Η. ο. 39 Η. ο. 5.7 Η. o. 59 Η. ο. 5.7 Η. ο. 38 Η. ο. 6, 1 Η. o. 68 Η. ο. 5.9 Η. ο. 41 Η. ο. 6, 4 Η. o. 50 Η. ο. 7.5 Η. ο. 44 Η. ο. 5.8 Η. o. 65 Η. ο. 8.0 Η. ο. 43 Η. ο. 6, 6 Η. o. 53 Η. ο. θ,7 Η. ο. 40 Η. ο. 7.1 Η. o. 66 Η. ο. 7.4 Η. ο. 45 Η. ο. 6, 3 Η. o. 60 Η. ο. 6, 6 Η. ο. 42 Η. ο. 6, 5 Η. o. 52 Η. ο. <5.6 Η. ο. 73 Η. ο. 7.6 Η. o. 51 Η. ο. 6.5 Η. ο. 61 Η. ο. θ,Ι Η. o. 75 Η. ο. 6, 6 Η. ο. 72 Η. ο. 7.9 Η. o. 69 Η. ο. 5.7 Η. ο. 58 Η. ο. <5.6 Η. o. 70 Η. ο. 6.3 Η. ο. 62 Η. ο. 6, 1 Η. o. 74 Η. ο. Η. ο. Η. ο. 57 Η. ο. 7.1 Η. o.

- 86 044355

Examples of compositions.

As used in all these examples, the active ingredient (AI) refers to the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates; in particular, to any of the exemplified compounds.

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

1. Tablets.

Active ingredient 5-50 mg;

dicalcium phosphate 20 mg;

lactose 30 mg;

talc 10 mg;

magnesium stearate 5 mg;

potato starch up to 200 mg.

2. Suspension.

An aqueous suspension for oral administration is prepared so that each milliliter contains 1-5 mg of the active ingredient, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water up to 1 ml.

3. Injection form.

A composition for parenteral administration was prepared by mixing 1.5% (w/v) of the active ingredient in a 0.9% NaCl solution or a 10% (v/v) propylene glycol solution in water.

4. Ointment.

Active ingredient 5-1000 mg;

stearyl 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 of the compounds according to the present invention, in particular the same amount of any of the exemplified compounds.

Claims (8)

1. Compound of formula (I), or ² where R ¹ represents hydrogen; R ² represents hydrogen; Y represents -CH ₂ -; Z represents -CH ₂ -, -CHR ⁵¹ -, -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d -, -CR ^5e R ^5g -CR ^5f R ^5h -, -CR ^5c R ^5d -CR ^5e R ^5g CR ^5f R ^5h - or -CR ^5a R ^5b -CR ^5c R ^5d -CR ^5e R ^5g -CR ^5f R ^5h -; R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g , R ^5h and R ⁵¹ are each independently hydrogen or C _1-4 alkyl; X represents -O-; Ar is a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms, each independently selected from O, S and N, wherein said 9- a membered bicyclic aromatic ring is attached to the rest of the molecule by a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring; Ar is optionally substituted on the carbon atoms with a total of one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, oxo, -NH ₂ , -NH-C _1-4 alkyl, -CF ₃ , C _{3- 6} cycloalkyl and C _1-4 alkyl; and, if possible, Ar is optionally substituted at one N atom with one C _1-4 alkyl; Het is a bicyclic aromatic heterocyclic ring system (a-1): - 87 044355 R ^3a (a-1) R ^3a is halogen, -NR ^7a R ^7b or -O-C1. ₄ alkyl; R ^7a represents hydrogen; R ^7b represents hydrogen or C _1-4 alkyl; R ^{4 a} represents hydrogen; Q ¹ represents CR ^6a ; Q ² represents CR ^6b ; R ^{6 a} and R ^6b are hydrogen or halogen; or a pharmaceutically acceptable addition salt thereof. 2. The connection according to claim 1, where Z represents -X-CR ^5a R ^5b -, -CR ^5c =CR ^5d - or -CR ^5e R ^5g -CR ^5f R ^5h -; R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g and R ^5h are hydrogen; Ar is optionally substituted on the carbon atoms with a total of one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, -NH2, -NH-C ₁ . ₄ alkyl, -CF ₃ , C ₃ . ₆ cycloalkyl and C1. ₄ alkyl; and, if possible, Ar is optionally replaced at one N atom with one C1_ ₄ alkyl. 3. Connection according to claim 1 or claim 2, where Ar is optionally substituted at the carbon atoms with a total of one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, -NH ₂ , -NH-C ₁ . ₄ alkyl, -CF ₃ , C _3-6 cycloalkyl and C1. ₄ alkyl; and, if possible, Ar is optionally replaced at one N atom with one C1_ ₄ alkyl. 4. Connection according to claim 1, where Ar is a 9-membered bicyclic aromatic ring system selected from the group consisting of wherein said 9-membered bicyclic aromatic ring is attached to the rest of the molecule by a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring; Ar is optionally substituted at the carbon atoms with a total of one, two, three or four substituents, each of which is independently selected from the group consisting of halogen, -NH ₂ , -NH-C ₁ . ₄ alkyl, -CF ₃ , C ₃ . ₆ cycloalkyl and C1. ₄ alkyl; and, if possible, Ar is optionally replaced at one N atom with one C1_ ₄ alkyl. 5. The connection according to claim 1, where R ^3a is -NR ^7a R ^7b ; and R ^7a and R ^7b are hydrogen. 6. A connection selected from the group consisting of: - 88 044355 - 89 044355 connection 24 connection 25 connection 31 compound 75 or a pharmaceutically acceptable addition salt thereof. 7. A pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of any one of p. 1-6. 8. Use of the connection according to any one of paragraphs. 1-6 as a drug to inhibit protein arginine methyltransferase 5 (PRMT5).