Imidazo pyrimidine compounds for the treatment of cancer

Abstract

The present invention covers imidazo pyrimidine compounds of general formula (I), in which R1, R2, R3, R4 and Z are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling, as a sole agent or in combination with other active ingredients.

Description

[0001] IMIDAZO PYRIMIDINE COMPOUNDS FOR THE TREATMENT OF CANCER

[0002] The present invention covers imidazo pyrimidine compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling, as a sole agent or in combination with other active ingredients.

[0003] BACKGROUND

[0004] Mutant KRAS is a well-understood oncogenic driver and has a wide-spread prevalence in various human cancer indications (J.L. Bos, Cancer Res. 1989, 49, 4682-4689). In 1982, mutationally activated RAS genes were detected in human cancer, marking the first discovery of mutated genes in this disease (A.D. Cox, C.J. Der, Small GTPases 2010, 1, 2-27). The frequent mutation of RAS in three of the four most lethal cancers (lung, colon and pancreatic cancers) in the United States has spurred intense interest and effort in developing RAS inhibitors. Overall, RAS mutations have been detected in 9-30% of all tumor samples sequenced. In pancreatic ductal adenocarcinoma (PDAC; -90% of all pancreatic cancers) and lung adenocarcinoma (LAC; 30-35% of all lung cancers) KRAS mutations display a frequency of 97% and 32% respectively. Other indications with frequently mutated KRAS include colorectal carcinoma (CRC) (52%), and multiple myeloma (43%) (A.D. Cox et al. Nat. Rev. Drug Discov. 2014, 13, 828-851). RAS proteins act as molecular switches that cycle between an active, GTPbound state and an inactive, GDP-bound state. Activated by guanine nucleotide exchange factors (GEFs), RAS in its GTPbound state interacts with a number of effectors (R.M. Hillig et al. Proc. Natl. Acad. Sci. USA 2018, 116, 2551-2560). Return to the inactive state is driven by GTPase -activating proteins (GAPs), which down-regulate active RAS by accelerating the weak intrinsic GTPase activity by up to 5 orders of magnitude. For oncogenic RAS mutants, however, the GAP activity is impaired or greatly reduced, resulting in permanent activation, which is the basis of oncogenic RAS signaling (K.M. Haigis, Trends Cancer 2017, 3, 686-697); for example, through the RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT pathways, both essential to cell survival and proliferation (J. Downward, Nat. Rev. Cancer 2003, 3, 11-22).

[0005] Covalent KRASG12C inhibitors as described by Shokat et al. occupy the so-called switch-II pocket and bind with their Michael acceptor system covalently to the cysteine mutation at G12 in this specific KRAS mutant (J.M. Ostrem, K.M. Shokat, Nat. Rev. Drug Discov. 2016, 15, 771-785). Occupation ofthis pocket with the covalent inhibitor results in a locked inactive GDP-bound protein conformation. Captured in this conformation, cycling of the mutated protein into the active GTP -bound state is prevented and thereby activity of the mutant KRASG12C is shut down. For decades, mutant KRAS has been considered “undruggable” via classical pharmacological small molecule inhibitors. However, in 2013 the G12C mutant of KRAS was found to be potentially druggable by covalent targeting of Cys-12 in vicinity to an inducible so-called “switch II pocket” (S-IIP) of KRAS G12C (J.M. Ostrem et al. Nature 2013, 503, 548-551; M R. Janes et al. Cell 2018, 172, 578-589). There have since been significant efforts by the pharmaceutical industry to develop KRas inhibitors targeting the SII-P for cancer therapy and several agents have entered clinical trials. However, no such therapies have yet won regulatory approval (F. McCormick, Clin. Cancer Res. 2015, 21, 1797-1801). Besides G12C, other oncogenic mutants of KRAS include G12D, G12V and G12R, all of which represent attractive drug targets, with the G12D mutation being most prevalent across tumor types (K. Kashofer et al. Cancer Metastasis Rev. 2020, 39, 1029-1038). There is therefore a clear and continued desire for therapies targeting KRas mutants and especially G12D for the treatment of cancer.

[0006] GENERAL STATE OF THE ART

[0007] Covalent inhibitors of KRAS G12C have been described in literatures and patent applications.

[0008] Biaryl derivatives were mentioned as KRAS G12C covalent inhibitors (WO2014152588, WO2016049524 and WO2016044772). WO2016164675, WO2015054572, WO2016044772, WO2016049568, WO2016168540, W020170070256, WO2017087528, W02017100546, WO2017172979,

[0009] W02018064510, W02018145012, W02018145014 disclosed quinazoline, quinoline, dihydrobenzo- naphthyridinone, quinazolinone, dihydropyrimidoquinolinone, isoquinoline derivatives. Further disclosures include anilinoacetamide and biaryl derivatives (WO2016049565, WO 2017058768, WO 2017058792), naphthalene or hexahydrofurofurane derivatives (WO 2014143659), quinazolinone (WO2017015562), phenylpyrazine derivatives (WO 2017058728). bezoimidazolsulfone, dihydroquinoxaline or dihydroquinoxalinone (WO 2017058805), phenylpiperazine -1 -carbohydrazide (WO 2017058807), tetrahydronaphthyridine (WO 2017058902), imidazolopyridine (WO 2017058915), various chemical entities (WO2018068017), bicyclic 6,5 -aryl, hetaryl rings containing compounds (WO2018140600).

[0010] Benzimidazol, (aza)indole, imidazopyridine derivatives were disclosed as KRAS covalent inhibitors in W02018145013; benzothiazole, benzothiophene, benzisoxazole derivatives were disclosed in WO2018140599; pyridopyrimidone, benzothiazole were disclosed in WO2018119183 and tetrahydropyridopyrimidine were disclosed in WO2017201161.

[0011] Compounds of the following general formula are described in US 2018 / 0201610 (NantBio) which selectively inhibit mutant K-Ras, especially G12V and / or G12D over wild type K-Ras or other mutant K-Ras forms.

[0012] Substituted quinazoline compounds of the following general formula are described as inhibitors of Ras-protein in WO 2017 / 172979 (Araxes).

[0013] Compounds of general formula are described as inhibitors of KRAS G12D in WO 2021 / 041671 (Mirati).

[0014] Compounds of general formula are described as to inhibit mutant KRAS in CN 112047948 (Xuanzhu).

[0015] Reversible, non-covalent inhibitors of KRAS G12D have been described in patent applications W02021041671 and WO2017172979A1. However, so far compounds of general formula (I) have not been disclosed as reversible, non-covalent KRAS G12D inhibitors. Further related KRAS inhibitors are described in:

[0016] Nature, volume 619, pages 160-166 (2023),

[0017] WO2023 / 099624, WO2023 / 099623, W02023 / 099608, W02023 / 099620, WO2023 / 099612,

[0018] WO2023 / 099592, WO 2023 / 018809, and W02023 / 001141. SUMMARY

[0019] It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.

[0020] In particular, the compounds of the present invention have surprisingly been found to effectively inhibit KRAS, for example KRAS G12D or KRAS G12V, and may therefore be used for the treatment or prophylaxis of neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling, for example.

[0021] In accordance with a first aspect, the present invention covers compounds of general formula (I):

[0022] Z represents -O- or C(=O)

[0023] R1 represents

[0024]

[0025] R4 represents wherein

[0026] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0027] R6 represents a hydrogen atom or a fluorine atom;

[0028] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0029] DEFINITIONS

[0030] The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and / or variables are permissible.

[0031] The term “optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.

[0032] As used herein, the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2”.

[0033] When groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent.

[0034] As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.

[0035] The term “comprising” when used in the specification includes “consisting of’.

[0036] If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text.

[0037] The terms as mentioned in the present text have the following meanings:

[0038] The term “Ci-Cs-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, or 3 carbon atoms, e.g. a methyl-, ethyl-, propyl-, or a isopropyl group.

[0039] As used herein, the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular a fluoro-, a chloro-, bromo- or a iodo group, a (methylsulfonyl)oxy-, [(4-methylphenyl)sulfonyl]oxy-, [(trifluoromethyl)sulfonyl]oxy-, [(nona- fluorobutyl)sulfonyl]oxy-, [(4-bromophenyl)sulfonyl]oxy-, [(4-nitrophenyl)sulfonyl]oxy-, [(2-nitro- phenyl)sulfonyl]oxy-, [(4-isopropylphenyl)sulfonyl]oxy-, [(2,4,6-triisopropylphenyl)sulfonyl]oxy-, [(2,4,6-trimethylphenyl)sulfonyl]oxy-, [(4-tert-butylphenyl)sulfonyl]oxy-, (phenylsulfonyl)oxy- and a [(4 -methoxyphenyl) sulfonyl] oxy group .

[0040] It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium- containing compounds of general formula (I).

[0041] The term “Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

[0042] The term “Isotopic variant of the compound of general formula (I)” is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

[0043] The expression “unnatural proportion” means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998.

[0044] Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as2H (deuterium),3H (tritium),nC,13C,14C,15N,170,180,32P,33P,33S,34S,35S,36S,18F,36C1,82Br,1231,1241,1251,129I and131I, respectively.

[0045] With respect to the treatment and / or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium -containing compounds of general formula (I)”). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as3H or14C, are incorporated are useful e.g. in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as18F or11C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and13C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.

[0046] Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and / or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0047] The term “deuterium-containing compound of general formula (I)” is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is / are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium- containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).

[0048] The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C.L. Perrin et al. J. Am. Chem. Soc. 2007, 129, 4490-4497], basicity [C.L. Perrin et al. J. Am. Chem. Soc. 2005, 127, 9641-9647], lipophilicity [B. Testa et al. Int. J. Pharm. 1984, 19, 271-281]) and / or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A.E. Mutlib et al. Toxicol. Appl. Pharmacol. 2000, 169, 102-113). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A.M. Sharma et al. Chem. Res. Toxicol. 2013, 26, 410-421; Efavirenz: A.E. Mutlib et al. Toxicol. Appl. Pharmacol. 2000, 169, 102- 113). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound’s pharmacokinetic / pharmacodynamic relationship. ML-337 (C.J. Wenthur et al. J. Med. Chem. 2013, 56, 5208-5212) and Odanacatib (K. Kassahun et al. WO2012 / 112363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al. Arzneim. Forsch. / Drug. Res. 2006, 56, 295-300; Telaprevir: F. Maltais et al. J. Med. Chem. 2009, 52, 7993-8001). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and / or may produce lower metabolite loads.

[0049] A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profde, deuterium- containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is / are attached to a carbon atom and / or is / are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.

[0050] Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0051] The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. One embodiment includes those compounds which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

[0052] Preferred isomers are those which produce the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art as well as specifically those disclosed in the experimental section.

[0053] The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and / or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

[0054] In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0055] The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, for example column chromatography, such as achiral or chiral column chromatography, especially chiral chromatography. For example, diastereomers may be separated by achiral or chiral column chromatography; enantiomers may be separated by chiral column chromatography.

[0056] Further, it is possible for the compounds of the present invention to exist as tautomers. One example is intermediate 2-16, which can exist in two tautomeric forms (Tautomeric mixture 7H or 9H):

[0057] The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

[0058] Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.

[0059] The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and / or coprecipitates.

[0060] The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

[0061] Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.

[0062] The term “pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S.M. Berge et al. J. Pharm. Sci. 1977, 66, 1-19.

[0063] A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4- hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3 -hydroxy-2- naphthoic, nicotinic, pamoic, pectinic, 3 -phenylpropionic, pivalic, 2 -hydroxyethane sulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethane sulfonic, benzene sulfonic, para-toluene sulfonic, methanesulfonic,

[0064] 2 -naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.

[0065] Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, A'-mcthylmorpholinc. arginine, lysine, 1,2- ethylenediamine, A'-mcthylpipcridinc. A-mcthyl-glucaminc. N, A-dimcthyl-glucaminc. '-cthyl- glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-l,3-propanediol, 3-amino-l,2- propanediol, 4-amino- 1,2, 3 -butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(«-propyl)ammonium, tctrafw- butyl)ammonium, A-bcnzyl-A.A.A-trimcthylammonium. choline or benzalkonium.

[0066] Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.

[0067] The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.

[0068] In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and / or purification process, is, in most cases, unknown.

[0069] Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HQ", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.

[0070] This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and / or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition. As used herein, the term “in vivo hydrolysable ester” means an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl-, cycloalkyl- and optionally substituted phenylalkyl esters, in particular benzyl esters, Ci-Ce alkoxymethyl esters, e.g. methoxymethyl-, Ci-Ce alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, Cs-Cs cycloalkoxy-carbonyloxy-Ci-Ce alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl ; l,3-dioxolen-2- onylmethyl esters, e.g. 5-methyl-l,3-dioxolen-2-onylmethyl ester; and Ci-Ce -alkoxycarbonyloxyethyl esters, e.g. 1 -methoxy carbonyloxyethyl ester, it being possible for said esters to be formed at any carboxy group in the compounds of the present invention.

[0071] An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha] -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.

[0072] Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.

[0073] Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.

[0074] DESCRIPTION

[0075] This invention includes but is not limited to the following embodiments:

[0076] A) The compound of formula (I), in which

[0077] Z represents -O- or C(=O);

[0078] R1 represents

[0079] R2 represents

[0080]

[0081] R4 represents wherein R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0082] R6 represents a hydrogen atom or a fluorine atom;

[0083] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0084] A-a) A compound of general formula (I) in which:

[0085] Z represents -O- or C(=O)

[0086] R1 represents

[0087] wherein

[0088] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3; R6 represents a hydrogen atom or a fluorine atom;

[0089] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same. A-b) A compound of general formula (I) in which: Z represents -O- or C(=O)

[0090] R1 represents

[0091] wherein

[0092] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0093] R6 represents a hydrogen atom or a fluorine atom; R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0094] B) A compound of general formula (I) in which:

[0095] Z represents -O- or C(=O);

[0096] R1 represents

[0097]

[0098] R3 represents

[0099] wherein R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0100] R6 represents a hydrogen atom or a fluorine atom;

[0101] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0102] B-a) A compound of general formula (I) in which:

[0103] Z represents -O- or C(=O)

[0104] R1 represents

[0105]

[0106] R2 represents

[0107] , or

[0108] R3 represents

[0109] wherein

[0110] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0111] R6 represents a hydrogen atom or a fluorine atom;

[0112] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0113] B-b) A compound of general formula (I) in which:

[0114] Z represents -O- or C(=O) R1 represents

[0115] wherein

[0116] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0117] R6 represents a hydrogen atom or a fluorine atom; R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0118] C) A compound of general formula (I) in which:

[0119] Z represents -O- or C(=O)

[0120] R1 represents

[0121]

[0122] 10 wherein

[0123] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3; R6 represents a hydrogen atom or a fluorine atom;

[0124] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0125] C-a) A compound of general formula (I) in which:

[0126] Z represents -O- or C(=O)

[0127] R1 represents R3 represents wherein

[0128] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0129] R6 represents a hydrogen atom or a fluorine atom;

[0130] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0131] C-b) A compound of general formula (I) in which: Z represents -O- or C(=O)

[0132] R1 represents R4 represents wherein

[0133] R5 represents -C=CH or -CH2-CH3; R6 represents: F

[0134] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same. D) A compound of general formula (I) in which:

[0135] Z represents -O- or C(=O);

[0136] R1 represents

[0137] R2 represents

[0138] R3 represents wherein

[0139] R5 represents -C=CH;

[0140] R6 represents: a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0141] D-a) A compound of general formula (I) in which:

[0142] Z represents -O- or C(=O) R1 represents R2 represents

[0143]

[0144] R3 represents wherein

[0145] R5 represents -C=CH;

[0146] R6 represents: F wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0147] D-b) A compound of general formula (I) in which:

[0148] Z represents -O- or C(=O) R1 represents

[0149] , or ; and

[0150] R4 represents wherein

[0151] R5 represents -C=CH;

[0152] R6 represents: F wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0153] E) A compound of general formula (I), in which:

[0154] Z represents -O- or C(=O); R1 represents R2 represents

[0155] R4 represents wherein

[0156] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3; R6 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0157] E-a) A compound of general formula (I) in which:

[0158] Z represents -O- or C(=O)

[0159] R1 represents

[0160] R4 represents wherein

[0161] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0162] R6 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0163] E-b) A compound of general formula (I) in which: Z represents -O- or C(=O)

[0164] R1 represents

[0165]

[0166] 10 R4 represents wherein

[0167] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0168] R6 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0169] E-c) A compound of general formula (I) in which: Z represents -O- or C(=O)

[0170] R2 represents

[0171] wherein

[0172] R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3; R6 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0173] F) A compound of general formula (I), in which:

[0174] Z represents -O- or C(=O)

[0175] R1 represents

[0176]

[0177] R3 represents ; and

[0178] R4 represents wherein

[0179] R5 represents -C=CH3; R6 represents a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0180] F-a) A compound of general formula (I) in which:

[0181] Z represents -O- or C(=O)

[0182] R1 represents R3 represents

[0183] ; and

[0184] R4 represents wherein R5 represents -C=CHs;

[0185] R6 represents F; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same. F-b) A compound of general formula (I) in which: Z represents -O- or C(=O)

[0186] R1 represents

[0187] , or

[0188] R3 represents

[0189] R4 represents wherein

[0190] R5 represents -C=CHs;

[0191] R6 represents F; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0192] G) A compound of formula (I) which is selected from the group consisting of:

[0193] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol (2 / 1), Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol,

[0194] Formic acid - 4-({7-cyclobutyl-6-(3,8-diazabicyclo[3.2. l]octan-3-yl)-2-[(tetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol, formic acid 4-( { 7 -cyclobutyl-6-(3 , 8 -diazabicyclo [3.2.1 ]octan-3 -yl)-2- [(tetrahydro- IH-pyrrolizin- 7a(5H)-yl)methoxy] -7H-purin-8-yl } oxy)-5 -ethynyl-6-fluoronaphthalen-2-ol (2 / 1 ),

[0195] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-l-methylpyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol, 4-{[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S,4S)-4-fluoro-l-methylpyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0196] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S,4R)-4-fluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0197] Formic acid - (5S)-5-[({7-cyclobutyl-6-(3,8-diazabicyclo[3.2. l]octan-3-yl)-8-[(8-ethynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)oxy] -7H-purin-2-yl } oxy)methyl] - 1 -methylpyrrolidin-2-one,

[0198] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-pyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0199] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-4,4-difluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0200] 3-[({7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)oxy] -7H-purin-2-yl }oxy)methyl] - 1 -methylpyrrolidine-3 -carbonitrile (Racemate),

[0201] 4-( { 7 -Cyclobutyl-6-(3 , 8 -diazabicyclo [3.2.1 ]octan-3 -yl)-2- [2-( 1 -methyl- lH-imidazol-2-yl)ethoxy] -7H- purin-8-yl } oxy)-5 -ethynyl-6-fluoronaphthalen-2-ol, 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lR,5R,6S or lS,5S,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid, 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lS,5S,6R or lR,5R,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid, 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lS,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid, 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lR,5R,6R or lS,5S,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid, 8-[7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-l,8-diazaspiro[3.5]nonan-2-one: formic acid,

[0202] (4R or S)-6-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-l,6-diazaspiro[3.5]nonan-2-one,

[0203] (4S or R)-6-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-l,6-diazaspiro[3.5]nonan-2-one, cis or trans-6-[7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro-

[0204] 1.2.3.5.6.7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-6-azaspiro[3.5]nonan-2-ol trans or cis-6-[7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro-

[0205] 1.2.3.5.6.7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-6-azaspiro[3.5]nonan-2-ol,

[0206] Formic acid - 4-{[7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- (3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0207] Formic acid - (3R)-l-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2- {[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-3-methylpiperidin-3- ol,

[0208] 4-{[6-(Azepan-l-yl)-7-cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}- 7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol,

[0209] 4-{ [7-Cyclobutyl-6-({ [ l-(dimethylamino)cyclobutyl]methyl}amino)-2-{ [(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol,

[0210] 4-[7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-6-yl] - 1 ,4-oxazepan-6-ol: formic acid,

[0211] (6R or S)-4-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-{[(2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -7H-purin-6-yl)-6-methyl- 1 ,4-oxazepan-6-ol,

[0212] 4-(7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-l,4-oxazepan-6-one,

[0213] 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[8-methyl-3,8- diazabicyclo [3.2.1 ]octan-3 -yl] -7H-purin-8-yl)oxy] -5 -ethynyl-6-fluoronaphthalen-2-ol,

[0214] [7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)methanone,

[0215] (7-cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3-hydroxy- 3-methylpiperidin-l-yl]-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone,

[0216] [6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-tetrahydrofuran-3-yl-purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)methanone (mixture of 2 isomers), formic acid - [6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy} -7-(cis or trans-3-methoxycyclobutyl)-7H-purin-8-yl](8-ethynyl-7-fluoro-3- hydroxy- 1 -naphthyl)methanone (2 / 1), formic acid - [6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy} -7-(trans or cis-3-methoxycyclobutyl)-7H-purin-8-yl](8-ethynyl-7-fluoro-3- hydroxy- 1 -naphthyl)methanone (2 / 1),

[0217] Formic acid - (8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)[2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-7-(cis or trans-3- methoxycyclobutyl)-7H-purin-8-yl]methanone (1 / 1), (8-Ethynyl-7-fluoro-3-hydroxy-l-naphthyl)[2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-7-(trans or cis-3 -methoxy cyclobutyl)-7H- purin-8-yl]methanone, [6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy] -7 -isopropyl -purin- 8-yl] -(8-ethynyl-7 -fluoro-3 -hydroxy- 1 -naphthyl)methanone : formic acid, [7-Cyclopropyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)methanone: formic acid (1:2),

[0218] 7-Cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3-hydroxy-3- methylpiperidin- 1 -yl] -7H-purin-8-yl(8-ethynyl-7 -fluoro-3 -hydroxynaphthalen- 1 -yl)methanone / formic acid (1 / 1),

[0219] {7-Cyclobutyl-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-2-[(tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy]-7H-purin-8-yl}(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),

[0220] (7-Cyclobutyl-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-2-{[(2S)-pyrrolidin-2-yl]methoxy}-7H-purin-

[0221] 8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),

[0222] 7-Cyclobutyl-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-2-{[(2S)-l-methylpyrrolidin-2-yl]methoxy}- 7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),

[0223] 7-Cyclobutyl-2-{[(2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl]methoxy}-6-[(3R)-3-hydroxy-3- methylpiperidin- 1 -yl] -7H-purin-8-yl)(8-ethynyl-7 -fluoro-3 -hydroxynaphthalen- 1 -yl)methanone / formic acid (1 / 1),

[0224] (5S)-5-[({7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-6-[(3R)-3-hydroxy-3- methylpiperidin- l-yl]-7H-purin-2-yl}oxy)methyl]-l-methylpyrrolidin -2 -one / formic acid (1 / 1), [7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-(l,4-oxazepan-4- yl)-7H-purin-8-yl](8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone,

[0225] {7-Cyclobutyl-6-(l,4-oxazepan-4-yl)-2-[(tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-8- yl } (8-ethynyl-7 -fluoro-3 -hydroxynaphthalen- 1 -yl)methanone,

[0226] (7-Cyclobutyl-6-[3,8-diazabicyclo[3.2.1]octan-3-yl]-2-{[(2S)-pyrrolidin-2-yl]methoxy}-7H-purin-8- yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone - formic acid (1: 1),

[0227] [7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-(3-oxa-7,9- diazabicyclo [3.3.1 ]nonan-7-yl)-7H-purin-8-yl] (8-ethynyl-7-fluoro-3 -hydroxynaphthalen- 1 - yl)methanone / formic acid (1 / 1),

[0228] (7-Cyclobutyl-2-{[(2R,7aS)-2-fhrorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lR,5R,6R) or

[0229] (15.55.65)]-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)(8-ethynyl-7-fluoro-3- hydroxynaphthalen- l-yl)methanone / formic acid (1 / 1),

[0230] 7-Cyclobutyl-2-{[(2S)-4,4-difhroro-l-methylpyrrolidin-2-yl]methoxy}-6-[((lR,5R,6R) or (lS,5S,6S))-6- methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)methanone formic acid (1 / 1),

[0231] (5S)-5-[({7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-6-[[(lR,5R,6R) or

[0232] (15.55.65)]-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-2-yl}oxy)methyl]-l- methylpyrrolidin-2-one / formic acid (1: 1),

[0233] 5-[7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-N,N-dimethyl-5,6,7,8-tetrahydro- 4H-pyrazolo[ 1 ,5 -a] [ l,4]diazepine-2 -carboxamide, l-[7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-2-methylpiperidine-4-carbonitrile (mixture of the two cis-diastereomers regarding the piperidine substitution),

[0234] (7-Cyclobutyl-6-[(lR,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)methanone,

[0235] (3R)-l-(7-Cyclobutyl-2-{[(2S)-4,4-difhioro-l-methylpyrrolidin-2-yl]methoxy}-8-[(8-ethynyl-7-fluoro-3- hydroxy- l-naphthyl)oxy]-7H-purin-6-yl)-3-methylpiperidin-3-ol (single stereoisomer),

[0236] (3R)- 1 - {7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy- 1 -naphthyl)oxy]-2-[(2S)-pyrrolidin-2- ylmethoxy] -7H-purin-6-yl } -3 -methylpiperidin-3 -ol hydrochloride,

[0237] (3R)-l-{8-[(8-Ethynyl-7-fhroro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-6-yl}-3-methylpiperidin-3-ol, (3R)-l-{8-[(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-6-yl}-3-methylpiperidin-3-ol,

[0238] 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-(oxan-4-yl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0239] 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol - formic acid (1: 2) (cis-diastereomers 1 regarding cyclobutyl),

[0240] 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol - formic acid (1: 2) (cis-diastereomers 2 regarding cyclobutyl),

[0241] 4-({6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-[oxan-3-yl]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol - formic acid (1: 1) (two enantiopure diastereomers),

[0242] 4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-5-ethyl-6-fluoro-naphthalen-2-ol,

[0243] 4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-l,3-benzothiazol-2-amine:formic acid (1: 1),

[0244] 4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-7-fluoro-l,3-benzothiazol-2 -amine: formic acid (1:2), 4-[7-Cyclobutyl-6-[(lS,5R)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-l,3-benzothiazol-2-amine,

[0245] 2-Amino-4-[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-benzothiophene-3-carbonitrile:formic acid, and

[0246] [6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl](7-cyclobutyl-6-[3,8-diazabicyclo[3.2.1]octan-3-yl]- 2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl)methanone, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0247] H) The compound of formula (I) which is selected from the group consisting of:

[0248] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol (2 / 1),

[0249] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol, Formic acid - 4-({7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[(tetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol,

[0250] Formic acid 4-({7-cyclobutyl-6-(3,8-diazabicyclo[3.2. l]octan-3-yl)-2-[(tetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy] -7H-purin-8-yl } oxy)-5 -ethynyl-6-fluoronaphthalen-2-ol (2 / 1 ),

[0251] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-l-methylpyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0252] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S,4R)-4-fluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0253] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-pyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0254] 3-[({7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)oxy] -7H-purin-2-yl }oxy)methyl] - 1 -methylpyrrolidine-3 -carbonitrile (Racemate),

[0255] 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lS,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid, 8-[7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-l,8-diazaspiro[3.5]nonan-2-one: formic acid,

[0256] (4S or R)-6-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2- fhrorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-l,6-diazaspiro[3.5]nonan-2-one, [7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)methanone, (7-cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3-hydroxy- 3-methylpiperidin-l-yl]-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone, [6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-tetrahydrofuran-3-yl-purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)methanone (mixture of 2 isomers),

[0257] Formic acid - [6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy} -7-(cis or trans-3-methoxycyclobutyl)-7H-purin-8-yl](8-ethynyl-7-fluoro-3- hydroxy- 1 -naphthyl)methanone (2 / 1), [6-(3,8-Diazabicyclo[3.2. l]octan-3-yl)-2-[[(2R,8S)-2 -fluoro- 1,2, 3,5,6, 7-hexahydropyrrolizin-8- yl]methoxy] -7 -isopropyl -purin- 8-yl] -(8-ethynyl-7 -fluoro-3 -hydroxy- 1 -naphthyl)methanone : formic acid, {7-Cyclobutyl-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-2-[(tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy]-7H-purin-8-yl}(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1), (7-Cyclobutyl-6-[3,8-diazabicyclo[3.2.1]octan-3-yl]-2-{[(2S)-pyrrolidin-2-yl]methoxy}-7H-purin-8- yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone - formic acid (1: 1), (7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lR,5R,6R) or (lS,5S,6S)]-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1), 5-[7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-N,N-dimethyl-5,6,7,8-tetrahydro- 4H-pyrazolo[ 1 ,5 -a] [ l,4]diazepine-2 -carboxamide, l-[7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-2-methylpiperidine-4-carbonitrile (mixture of the two cis-diastereomers regarding the piperidine substitution), (7-Cyclobutyl-6-[(lR,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)methanone, 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-(oxan-4-yl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol, 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol - formic acid (1: 2) (cis-diastereomers 1 regarding cyclobutyl), 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol - formic acid (1: 2) (cis-diastereomers 2 regarding cyclobutyl), and 4-({6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-[oxan-3-yl]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol - formic acid (1: 1) (two enantiopure diastereomers), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0258] I) A compound of general formula (I) for use in the treatment or prophylaxis of a disease.

[0259] J) A compound of general formula (I) for use in the treatment or prophylaxis of a disease, wherein the disease is a neoplastic disorder, or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS.

[0260] K) A compound of general formula (I) for use in the treatment or prophylaxis of a disease, wherein the disease is a neoplastic disorder.

[0261] L) A compound of general formula (I) for use in the treatment or prophylaxis of a disease, wherein the neoplastic disorder is a cancer disease.

[0262] M) A compound of general formula (I) for use in the treatment or prophylaxis of a disease, wherein the cancer disease is selected from colorectal cancer, gastric cancer, lung cancer, and pancreatic cancer. N) Method for controlling a neoplastic disease comprising administering an anti -neoplastic effective amount of at least one compound selected from the group of compounds of general formula (I) to a human or animal in need thereof.

[0263] N-a) Use of a compound of general formula (I) in the manufacture of a medicament for the treatment or prophylaxis of a disease.

[0264] O) A pharmaceutical composition comprising a compound of general formula (I) and one or more pharmaceutically acceptable excipients.

[0265] P) A pharmaceutical combination comprising

[0266] • one or more first active ingredients, selected from the group of compounds of general formula (I) and

[0267] • one or more further active ingredients.

[0268] P-a) A pharmaceutical combination comprising:

[0269] • one or more first active ingredients selected from compounds of general formula (I), and

[0270] • one or more further active ingredients, in particular anti -cancer agents, more particularly those anticancer agents selected form the list consisting of

[0271] 1311-metuximab, 1311-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado -trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alfaferone, alemtuzumab, alendronic acid, alitretinoin, almonertinib, alpelisib, alpharadin, monosodium alpha luminol, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, aminolevulinic acid, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avapritinib, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, beclomethasone dipropionate, belantamab mafodotin, belinostat, belotecan, bendamustine, besilesomab, beta-elemene, bevacizumab, bexarotene, bicalutamide, binimetinib, bisantrene, bleomycin, blinatumomab, boanmycin hydrochloride, borofalan, bortezomib, bosutinib, budesonide, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capmatinib, capromab, carbamazepine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, catequentinib, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, chloroxoquinoline, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dacomitinib, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, deferasirox, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, dupilumab, durvalumab, duvelisib, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib, encorafenib, endostatin, enfortumab vedotin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, ensartinib, entrectinib, erdafitinib, esomeprazole, estradiol, estramustine, estrone, ethinylestradiol, etoposide, everolimus, evocalcet, exemestane, fadrozole, famotidine, fentanyl, fdgrastim, flumatinib, fluoxymesterone, fluticasone, fluticasone furoate, floxuridine, fludarabine, fluorouracil, flutamide, folinate, folinic acid, formestane, forodesine, fosaprepitant, fotemustine, fruquintinib, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, gendicine, gilteritinib, ginsenoside Rg3, glasdegib, glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, hematoporphyrin, histamine dihydrochloride, histrelin, holmium- 166-chitosan complex, human menopausal gonadotrophin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, icotinib hydrochloride, idarubicin, idelalisib, iobenguane (1311), iodine(131I) tumor necrosis factor monoclonal antibody, ifosfamide, imatinib, imiquimod, improsulfan, immunocyanin, indisetron, incadronic acid, indole -3 -carbinol + epigallocatechin-3 -gallate, ingenol mebutate, inotuzumab ozogamicin, interferon alfa, interferon alpha lb, interferon-alpha 2, interferon alpha-2a, interferon alfa- 2b, interferon beta, interferon gamma, interleukin-2, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, isatuximab, ivosidenib, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lorlatinib, lurbinectedin, luspatercept, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptamine, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, mifepristone, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mometasone, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, moxetumomab pasudotox, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, natalizumab, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, olmutinib, omacetaxine mepesuccinate, omalizumab, omeprazole, ondansetron, oprelvekin, orelabrutinib, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, padeliporfm, palbociclib, palifermin, palladium- 103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pemigatinib, pegfdgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, phenoxybenzamine, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polatuzumab vedotin, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, pralsetimb, predmmustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, quizartinib, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, relugolix, ribociclib, ripretinib, risedronic acid, rhenium- 186 etidronate, rituximab, rivoceranib, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, sacituzumab govitecan, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, selinexor, selpercatinib, selumetinib, siltuximab, sipuleucel-T, sirolimus, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sophoridine hydrochloride, sorafenib, stanozolol, streptozocin, Strontium 89, sunitinib, surufatinib, tagraxofusp, talaporfm, talazoparib, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, tazemetostat, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC- [Tyr3] -octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfm, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thrombopoietin, thymalfasin, thyrotropin alfa, tioguanine, tirabrutinib, tisagenlecleucel, tislelizumab, tivozanib, 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[0272] Q) A method of preparing a compound of general formula (I), said method comprising

[0273] EITHER for compounds with Z= an oxygen atom (-O-), allowing an intermediate compound of general formula (II) in which is selected from

[0274]

[0275] 5 R2 is selected from

[0276] wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same, and which is optionally protected at R1 and / or R2 indicated by the dotted line to “PG-” and

[0277] X4 is a hydrogen atom;

[0278] PG is independently selected from a SiR12R12R13 group, a benzyl group, a methoxymethyl group, and a tert.-butyloxycarbonyl group;

[0279] R12 and R13 are identical or different and are independently selected from a Ci-Ce-alkyl group and a phenyl group; after undergoing a bromination reaction with a suitable bromination reagent, leading to X4=bromine, to react with a compound of general formula (XXX) in which

[0280] R4 is 5 -ethynyl-6-fluoro-2 -naphthol, a 5 -ethyl-6-fluoro-2 -naphthol, a fluorinated or nonfluorinated l,3-benzothiazol-2-amine or a 2-amino-l-benzothiophene-3-carbonitrile;

[0281] PG is independently selected from a SiR12R12R13 group, a methoxymethyl group, a tertbutoxycarbonyl group and a para-methoxybenzyl group,

[0282] R12 and R13 are identical or different and are independently selected from a Ci-Ce-alkyl group and a phenyl group; introducing the R4 substituent optionally protected by replacing the bromine atom under strong basic conditions leading after suitable deprotection reactions e.g. under acidic conditions and / or tetrabutylammoniumfluoride, to a compound of formula (I)

[0283] OR for compounds with Z= C(=O), of allowing an intermediate compound of formula (II) which is optionally protected at R1 and / or R2 indicated by the dotted line to “PG” and in which

[0284] Rl, R2 and R3 have the meanings as defined above, and

[0285] X4 is a hydrogen atom,

[0286] PG is independently selected from a SiR12R12R13 group, a benzyl group, a methoxymethyl group, and a tert.butoxycarbonyl group;

[0287] R12 and R13 are identical or different and are independently selected from a Ci-Ce-alkyl group and a phenyl group; to react under strong basic conditions in an aprotic solvent and temperatures between -40° to 0°C with an aldehyde of general formula (XXVI) in which R12, R13 and PG have the meanings as defined above to obtain after deprotection and oxidation of the alcohol and optionally further deprotection reactions independently from its order a compound of general formula (I) in which

[0288] Rl, R2, and R3 have the meanings as defined above and

[0289] R4 is selected from wherein

[0290] R5 is selected from a hydrogen atom, a fluorine atom, a -C=CH group and a -CH2-CH3 group; R6 is a hydrogen atom or a fluorine atom;

[0291] R7 is a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0292] QI) See also Scheme 3, part 2, step 9. Strong basic conditions include aqueous potassium carbonate or 2- tert-Butylimino-2-diethylamino-l,3-dimethylperhydro-l,3,2-diazaphosphorine (BEMP) in a solvent like tetrahydrofuran The deprotection conditions include tetrabutylammoniumfluoride and acidic conditions like HC1 in organic like in 1,4-dioxane or in tetrahydrofurane or methane sulfonic acid (MsOH) in methanol.

[0293] R) A method of preparing a compound of formula (I) wherein Z is -O-, said method comprising a step of allowing a compound of formula (III) in which

[0294] R1 is selected from

[0295]

[0296] PG is selected from a SiR12R12R13 group, a methoxymethyl group, and a tert.- butoxy carbonyl group;

[0297] R12 and R13 are identical or different and are independently selected from a Ci-Ce-alkyl group and a phenyl group; Z is -O- to react with a compound of formula (XXV)

[0298] R:

[0299] H " PG

[0300] (XXV) in which

[0301] R2 is selected from

[0302] , and , optionally protected, PG is a tert.-butoxycarbonyl group, under strong basic conditions to obtain a compound of formula (XXXI) in which Rl, R2, R3, R12 and PG are as defined above, and

[0303] R4 is selected from

[0304] R5 is selected from a hydrogen atom, a fluorine atom, a -C=CH group and a -CH2-CH3 group;

[0305] R6 is a hydrogen atom or a fluorine atom;

[0306] R7 is a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, which is finally being deprotected optionally in two steps, to obtain a compound of formula (I) wherein Z is -O-; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0307] Rl) See also scheme 4, steps 5 and 6. In one embodiment any optional feature is non-optional: a deprotection means then a two step deprotection, preferably conducted with tetrabutylammoniumfluoride followed by acidic conditions like HC1 in organic solvents like in 1,4-dioxane or in tetrahydrofurane or methanesulfonic acid (MsOH) in methanol. Strong basic conditions include sodiumhydide and lithium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran.

[0308] S) A method of preparing a compound of formula (I) wherein Z is -O-, said method comprising a step of allowing a compound of formula (IV) in which

[0309] XI is a hydroxy group;

[0310] R2 is selected from

[0311] , and

[0312] R4 is selected from

[0313] R5 is selected from a hydrogen atom, a fluorine atom, a -C=CH group and a -CH2-CH3 group;

[0314] R6 is a hydrogen atom or a fluorine atom;

[0315] R7 is a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same;

[0316] Z is -O-

[0317] R12 and R13 are identical or different and are independently selected from Cl-C6-alkyl and phenyl;

[0318] PG is independently selected from a SiR12R12R13 group, a benzyl group, a methoxymethyl group, and a tert.-butoxycarbonyl group; the hydroxy group XI being activated by a suitable activation agent, to react with a nucleophilic compound of formula (XXIII)

[0319] (XXIII) in which

[0320] R1 is selected from

[0321] , and wherein * indicates the point of attachment of said group with the rest of the molecule,

[0322] PG is a tert.-butoxycarbonyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same; optionally protected, to obtain a compound of formula (XXXI) in which Rl, R2, R3, R4 and PG are as defined above, which is finally being deprotected using suitable conditions depending on the protecting group present, e.g. tetrabutylamoniumfluoride followed by acidic conditions e.g. like HC1 in organic solvents like 1,4- dioxane or tetrahydrofurane or methanesulfonic acid (MsOH) in methanol, to obtain a compound of formula (I) wherein Rl, R2, and R3 are as defined above;

[0323] R4 is selected from 5-ethynyl-6-fluoro-2 -naphthol, a 5 -ethyl-6-fluoro-2 -naphthol, a fluorinated or non-fluorinated l,3-benzothiazol-2-amine and a 2-amino-l- benzothiophene -3 -carbonitrile ; and

[0324] Z is -O- or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0325] SI) See also scheme 5, part 2, steps 6 and 7. The activation reagent is e.g. a coupling reagent like (1H- benzotriazol-l-yloxy)[tri(pyrrolidin-l-yl)]phosphonium hexafluoro-phosphate (PyBOP), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), usually used in the presence of a strong base like l,8-diazabicclo[5.4.0]undec-7-en (DBU).

[0326] This invention further includes but is not limited to the following embodiments:

[0327] A-2) A compound of general formula (I) in which:

[0328] Z represents O or C(O)

[0329] R1 represents R5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;

[0330] R6 represents a hydrogen atom or a fluorine atom;

[0331] R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0332] B-2) A compound of formula (I), wherein

[0333] R1 represents R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0334] C-2) The compound of formula (I), wherein

[0335] R2 represents and wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. D-2) The compound of formula (I), wherein

[0336] R4 represents

[0337] R5 represents -C=CH or -CH2-CH3 and wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0338] E-2) The compound of formula (I), wherein Z represents -O- or C(=O)

[0339] R1 represents

[0340]

[0341] R4 represents or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0342] F-2) The compound according to formula (I) which is selected from the group consisting of:

[0343] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol,

[0344] Formic acid - 4-({7-cyclobutyl-6-(3,8-diazabicyclo[3.2. l]octan-3-yl)-2-[(tetrahydro-lH-pyrrolizin-

[0345] 7a(5H)-yl)methoxy]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol,

[0346] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-l-methylpyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0347] 4-{[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S,4S)-4-fluoro-l-methylpyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0348] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S,4R)-4-fluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0349] Formic acid - (5S)-5-[({7-cyclobutyl-6-(3,8-diazabicyclo[3.2. l]octan-3-yl)-8-[(8-ethynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)oxy] -7H-purin-2-yl } oxy)methyl] - 1 -methylpyrrolidin-2-one,

[0350] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-pyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0351] Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-4,4-difluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0352] 3-[({7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)oxy] -7H-purin-2-yl } oxy)methyl] - 1 -methylpyrrolidine -3 -carbonitrile (Racemate) ,

[0353] 4-( { 7 -Cyclobutyl-6-(3 , 8 -diazabicyclo [3.2.1 ]octan-3 -yl)-2- [2-( 1 -methyl- lH-imidazol-2-yl)ethoxy] -7H- purin-8-yl } oxy)-5 -ethynyl-6-fluoronaphthalen-2-ol, 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lR,5R,6S or lS,5S,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid,

[0354] 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lS,5S,6R or lR,5R,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid,

[0355] 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lS,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid,

[0356] 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(lR,5R,6R or lS,5S,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5-ethynyl-6-fluoro-2- naphthol - formic acid,

[0357] 8-[7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-l,8-diazaspiro[3.5]nonan-2-one: formic acid,

[0358] (4R or S)-6-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2- fhrorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-l,6-diazaspiro[3.5]nonan-2-one,

[0359] (4S or R)-6-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2- fhrorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-l,6-diazaspiro[3.5]nonan-2-one, cis or trans-6-[7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2 -fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-6-azaspiro[3.5]nonan-2-ol, trans or cis-6-[7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2 -fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-6-azaspiro[3.5]nonan-2-ol,

[0360] Formic acid - 4-{[7-cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- (3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,

[0361] Formic acid - (3R)-l-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2- {[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-3-methylpiperidin-3- ol,

[0362] 4-{[6-(Azepan-l-yl)-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}- 7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol,

[0363] 4-{ [7-Cyclobutyl-6-({ [ l-(dimethylamino)cyclobutyl]methyl}amino)-2-{ [(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol,

[0364] 4-[7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-6-yl] - 1 ,4-oxazepan-6-ol: formic acid,

[0365] (6R or S)-4-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-{[(2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -7H-purin-6-yl)-6-methyl- 1 ,4-oxazepan-6-ol, [7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)methanone, (7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3-hydroxy-

[0366] 3-methylpiperidin-l-yl]-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone, [6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-tetrahydrofuran-3-yl-purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)methanone

[0367] (mixture of 2 isomers), formic acid - [6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy} -7-(cis or trans-3-methoxycyclobutyl)-7H-purin-8-yl](8-ethynyl-7-fluoro-3- hydroxy- 1 -naphthyl)methanone, formic acid - [6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy} -7-(trans or cis-3-methoxycyclobutyl)-7H-purin-8-yl](8-ethynyl-7-fluoro-3- hydroxy- 1 -naphthyl)methanone,

[0368] Formic acid - (8-ethynyl-7-fhroro-3-hydroxy-l-naphthyl)[2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-7-(cis or trans-3- methoxycyclobutyl)-7H-purin-8-yl]methanone,

[0369] (8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)[2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-7-(trans or cis-3 -methoxy cyclobutyl)-7H- purin-8-yl]methanone,

[0370] [6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy] -7 -isopropyl -purin- 8-yl] -(8-ethynyl-7 -fluoro-3 -hydroxy- 1 -naphthyl)methanone : formic acid, [7-Cyclopropyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)methanone: formic acid,

[0371] (3R)-l-(7-Cyclobutyl-2-{[(2S)-4,4-difhroro-l-methylpyrrolidin-2-yl]methoxy}-8-[(8-ethynyl-7-fluoro-3- hydroxy- 1 -naphthyl)oxy] -7H-purin-6-y 1 )-3 -methylpiperidin-3 -ol (single stereoisomer),

[0372] (3R)- 1 - {7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy- 1 -naphthyl)oxy]-2-[(2S)-pyrrolidin-2- ylmethoxy] -7H-purin-6-yl } -3 -methylpiperidin-3 -ol hydrochloride,

[0373] 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7-(oxan-4-yl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol, 4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-5-ethyl-6-fluoro-naphthalen-2-ol, 4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-l,3-benzothiazol-2-amine:formic acid, 4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-7-fluoro-l, 3-benzothiazol-2 -amine ;formic acid, 4-[7-Cyclobutyl-6-[(lS,5R)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-l,3-benzothiazol-2-amine or 2-Amino-4-[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-benzothiophene-3-carbonitrile:formic acid, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. G-2) A compound of general formula (I) for use in the treatment or prophylaxis of a disease.

[0374] H-2) A pharmaceutical composition comprising a compound of general formula (I) and one or more pharmaceutically acceptable excipients.

[0375] 1-2) A pharmaceutical combination comprising:

[0376] • one or more first active ingredients, in particular compounds of general formula (I), and

[0377] • one or more further active ingredients, in particular cancer agents like:

[0378] 1311-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado- trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, darolutamide, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, fdgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG -epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfdgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide -K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, ribociclib, risedronic acid, rhenium- 186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfm, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfm, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

[0379] J-2) Use of a compound of general formula (I) for the treatment or prophylaxis of a disease.

[0380] K-2) Use of a compound of general formula (I) for the preparation of a medicament for the treatment or prophylaxis of a disease.

[0381] U-2) Use of a compound of formula (I), wherein the disease is a neoplastic disorder, such as cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling, for example.

[0382] M-2) Method for controlling neoplastic diseases in humans and animals by administering an anti- neoplastic effective amount of at least one compound of formula (I).

[0383] This invention includes also the following further embodiments:

[0384] A compound of general formula (I) wherein Z represents -O- or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0385] A compound of general formula (I) wherein Z represents C(=O) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0386] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0387] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0388] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0389] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0390] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0391] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0392] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0393] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0394] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0395] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0396] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0397] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0398] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0399] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0400] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0401] A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. A compound of general formula (I) wherein R1 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0402] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0403] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0404] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0405] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0406] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0407] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0408] A compound of general formula (I) wherein R2 represents wherein * indicates the point of atachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0409] A compound of general formula (I) wherein R2 represents wherein * indicates the point of atachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0410] A compound of general formula (I) wherein R2 represents wherein * indicates the point of atachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0411] A compound of general formula (I) wherein R2 represents wherein * indicates the point of atachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0412] A compound of general formula (I) wherein R2 represents wherein * indicates the point of atachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0413] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0414] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0415] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0416] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0417] A compound of general formula (I) wherein R2 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0418] A compound of general formula (I) wherein R3 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0419] A compound of general formula (I) wherein R3 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0420] A compound of general formula (I) wherein R3 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0421] A compound of general formula (I) wherein R3 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0422] A compound of general formula (I) wherein R3 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0423] A compound of general formula (I) wherein R3 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0424] A compound of general formula (I) wherein R4 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0425] A compound of general formula (I) wherein R4 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0426] A compound of general formula (I) wherein R4 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0427] A compound of general formula (I) wherein R4 represents wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0428] A compound of general formula (I) wherein R5 represents a hydrogen atom or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N- oxide, or a mixture of same. A compound of general formula (I) wherein R5 represents a fluorine atom or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0429] A compound of general formula (I) wherein R5 represents -C=CH wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0430] A compound of general formula (I) wherein R5 represents -CH2-CH3 wherein * indicates the point of attachment of said group with the rest of the molecule or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0431] A compound of general formula (I) wherein R6 represents a hydrogen atom or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N- oxide, or a mixture of same.

[0432] A compound of general formula (I) wherein R6 represents a fluorine atom or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0433] A compound of general formula (I) wherein R7 represents a hydrogen atom or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N- oxide, or a mixture of same.

[0434] A compound of general formula (I) wherein R7 represents a fluorine atom or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

[0435] In a particular further embodiment of the first aspect, the present invention includes combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”.

[0436] The present invention includes any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.

[0437] The present invention includes any sub-combination within any embodiment or aspect of the present invention.

[0438] The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.

[0439] UTILITY

[0440] Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit KRAS and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably neoplasic disorders in humans and animals.

[0441] Compounds of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and / or cell division, and / or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the disorder.

[0442] Hyperproliferative disorders include, but are not limited to, for example : psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.

[0443] Examples of breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0444] Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

[0445] Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour. Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.

[0446] Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

[0447] Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

[0448] Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.

[0449] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0450] Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0451] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0452] Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.

[0453] Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0454] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0455] The present invention also provides methods of treating angiogenic disorders including diseases associated with excessive and / or abnormal angiogenesis.

[0456] Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [L.P. Aiello et al. New Engl. J. Med. 1994, 331, 1480-1487; J. Pe’er et al. Lab. Invest. 1995, 72, 638-645], age-related macular degeneration (AMD) [P.F. Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855-868], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of general formula (I) of the present invention can be utilized to treat and / or prevent any of the aforementioned angiogenesis disorders, for example by inhibiting and / or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation, or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.

[0457] These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.

[0458] The term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.

[0459] The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre -treatment of the tumour growth.

[0460] Generally, the use of chemotherapeutic agents and / or anti -cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:

[0461] 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents,

[0462] 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,

[0463] 4. provide for treating a broader spectrum of different cancer types in mammals, especially humans,

[0464] 5. provide for a higher response rate among treated patients,

[0465] 6. provide for a longer survival time among treated patients compared to standard chemotherapy treatments,

[0466] 7. provide a longer time for tumour progression, and / or

[0467] 8. yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

[0468] In addition, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and / or surgical intervention.

[0469] In a further embodiment of the present invention, the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i. e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention. In one aspect, the cell is treated with at least one compound of general formula (I) of the present invention. Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.

[0470] The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.

[0471] In other embodiments of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.

[0472] In other embodiments, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.

[0473] In one aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.

[0474] In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

[0475] In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular neoplastic disorders.

[0476] The pharmaceutical activity of the compounds according to the invention can be explained by their activity as KRAS inhibitors.

[0477] In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling.

[0478] In accordance with a further aspect, the present invention covers the use of a compound of formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of diseases, in particular neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling.

[0479] In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling.

[0480] In accordance with a further aspect, the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling.

[0481] In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.

[0482] In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.

[0483] PHARMACEUTICAL COMPOSITION

[0484] The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes.

[0485] It is possible for the compounds according to the invention to have systemic and / or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

[0486] For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.

[0487] For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films / wafers, films / lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and / or amorphised and / or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders. Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / fdms / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

[0488] The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,

[0489] • fdlers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),

[0490] • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

[0491] • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),

[0492] • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chainlength triglycerides, fatty oils, liquid polyethylene glycols, paraffins),

[0493] • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),

[0494] • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

[0495] • isotonicity agents (for example glucose, sodium chloride),

[0496] • adsorbents (for example highly-disperse silicas),

[0497] • viscosity-increasing agents, gel formers, thickeners and / or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),

[0498] • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol®)), • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),

[0499] • coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),

[0500] • capsule materials (for example gelatine, hydroxypropylmethylcellulose),

[0501] • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

[0502] • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

[0503] • penetration enhancers,

[0504] • stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

[0505] • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0506] • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

[0507] • flavourings, sweeteners, flavour- and / or odour-masking agents.

[0508] The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

[0509] It is possible for the compounds according to the invention to have systemic and / or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

[0510] For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.

[0511] For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films / wafers, films / lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and / or amorphised and / or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

[0512] Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

[0513] The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,

[0514] • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),

[0515] • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

[0516] • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),

[0517] • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chainlength triglycerides fatty oils, liquid polyethylene glycols, paraffins),

[0518] • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),

[0519] • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

[0520] • isotonicity agents (for example glucose, sodium chloride),

[0521] • adsorbents (for example highly-disperse silicas), • viscosity-increasing agents, gel formers, thickeners and / or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),

[0522] • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol®)),

[0523] • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),

[0524] • coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),

[0525] • capsule materials (for example gelatine, hydroxypropylmethylcellulose),

[0526] • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

[0527] • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

[0528] • penetration enhancers,

[0529] • stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

[0530] • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0531] • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

[0532] • flavourings, sweeteners, flavour- and / or odour-masking agents.

[0533] The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

[0534] PHARMACEUTICAL COMBINATION

[0535] In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and / or prophylaxis of a neoplastic disorder, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling.

[0536] Particularly, the present invention covers a pharmaceutical combination, which comprises:

[0537] • one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and

[0538] • one or more further active ingredients, in particular cancer agents.

[0539] The term “combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non -fixed combination or a kit-of-parts.

[0540] A “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.

[0541] A non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

[0542] The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known cancer agents, as listed above und P-a).

[0543] Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of neoplastic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[0544] The total amount of the active ingredient to be administered will generally range from about 0.001 mg / kg to about 200 mg / kg body weight per day, and preferably from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg / kg of total body weight.

[0545] Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

[0546] GENERAL PROCEDURES

[0547] The compounds according to the invention of general formula (I) can be prepared according to the following schemes 1 to 6. The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in schemes 1 to 6 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents R1, R2, R3, and R4can be achieved before and / or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, the combination of deprotection and reprotection at the substituents R1, R2, and R4, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (e. g. Greene's Protective Groups in Organic Synthesis, 4thedition, 2006, P. Wuts, T. Greene, John Wiley & Sons or Protecting Groups, 3rdedition, 2003, P.J. Kocienski, Thieme). Specific examples are described in the subsequent paragraphs.

[0548] The starting materials are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the Experimental Section.

[0549] Several routes for the preparation of compounds of general formula (I) are described in schemes 1 to 8.

[0550] Synthesis of compounds of general formula (I) of the present invention

[0551] Description of Scheme 1 :

[0552] Compounds of general formula (I) with the meaning of Z, R1, R2, R3, and R2as defined in general claim 1, can be synthesized via different key intermediates of general formula (II), (III) and (IV) as depicted in Scheme 1.

[0553] Key intermediates of general formula (II) indicate that the “western” imidazo-substituent Z-R4of general formula (I) can be introduced at the end of the synthesis sequence.

[0554] To finally install the side chain R2a key intermediate of general formula (III) can be used wherein the substituent X4represents a leaving group like methylsulfonyl or chloride preferably methylsulfonyl.

[0555] The introduction of the head group R1can also be placed at the end of the synthesis route. For this, key intermediates of general formula (IV) can be employed wherein X1can represent a substiuent like hydroxy- or para-methoxybenzyl sulfoxide but must not be limited to those.

[0556] Overall, the different synthetic strategies of final installation of the “western” substituent Z-R4, the side chain R2or the head group R1allow maximal flexibility for profound SAR explorations at each substituent position of compounds of general formula (I). To avoid side reactions in the final installation of substituents Z-R4, R2, or R1the functional groups already present in the substituents of key intermediates of general formula (II), (III), or (IV) might have to be protected via a proper protecting group (PG) described in the books of P. Wuts, and T. Greene or P.J. Kocienski as cited above and that can be finally cleaved via reactions also described in the cited books and well-known to the person skilled in the art. Scheme 1

[0557] For the key intermediates shown in Scheme 1. Z, R1, R2, R3, and R4represent substituents according to claim 1, optionally bearing suitable protecting groups, which is indicated by the dotted line to “PG”; X4represents H, Br, or I; X2represents SO?Mc. or Cl; X1represents OH, S(O)-PMB (PMB = para- methoxybenzyl); PG represents any protecting group (see Greene's Protective Groups in Organic Synthesis or Protecting Groups as cited above) and if “PG” is used more times in one molecule PG can have different meanings; preferred are those PG combinations used in the experimental section; examples for PGs include triisopropylsilyl (TIPS), diisopropylphenylsilyl, benzyl, methoxymethyl (MOM), and tert.-butoxycarbonyl(Boc); the dashed lines at PG and also at the SiR12R12R13group indicate that the protecting group and / or the SiR12R12R13group at the substiutents R1, R2, and R4might be present or absent; R12and R13are identical or different and are independently selected from Ci to Ce alkyl and aryl, preferably from iso-propyl, tert. -butyl, and phenyl.

[0558] The positional enumeration of the central purine core is indicated with arabic numbers at the structure of general formula (I) in Scheme 1 above.

[0559] To reach key intermediates of general formula (II), (III), or (IV) at first the central purine core has to be assembled, that can be combined with the regioselective installation of substituent R3 at imidazole position 7 (see Scheme 1). Therefore 2,6-dichloropurines of general formula (V) can be synthesized via different routes as shown in Scheme 2. Description of Scheme 2: Part 1

[0560] One possible synthesis route starts from 2,4-dichloropyrimidin-5-amine (formula VI - CAS No: 5177-27- 5) that can be converted in a reductive amination with an acyclic or cyclic ketone of general formula (VII) to get the corresponding alkylated aminopyrimidines of general formula (VIII) having already regioselectively installed the later substituent R3at the beginning of the synthesis sequence, Scheme 2, Part 1, left part. The conditions of the reductive amination include a mild reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride or 2-picoline borane complex, that chemoselectively prefers to reduce the in situ formed imine species from 2,4-dichloropyrimidin-5-amine (formula VI) and the ketone of general formula (VII) corresponding to substituent R3over the direct reduction of the carbonyl compound (general formula (VII)). To shift the equilibrium of in situ imine formation towards the imine species the byproduct water can be trapped using scavengers such as titanium tetrachloride or mol sieves (3 A). The reductive amination can be done in a protic (e.g. methanol) or aprotic solvent (e.g. dichloromethane) with temperatures ranging from 0°C to 80°C. After having installed substituent R3, the pyrimidines of general formula (VIII) can be chlorinated at position 4 of the pyrimidine ring to get trichloropyrimidines of general formula (IX). A typical chlorinating agent like N-chlorosuccinimide (NCS) or trichloroisocyanuric acid (TCCA) is used in a halogenated solvent like CCU or a dipoloar aprotic solvent like V '-dimcth lfo rm a ide at temperatures ranging from 20°C to 100°C. The subsequent monoaminolysis at one of the two positions ortho the the amino substitent at the pyrimidine of general formula (IX) is done with ammonia dissolved in a protic solvent like isopropanol. This reaction that is usually performed at temperatures between 50°C and 100°C leads to diaminopyrimidines of general formula (X). Subsequent conversion of an orthoester of general formula (XI) wherein R11represents a Ci to C3 alkyl, preferably ethyl, closes the imidazole ring of the central purine core and leads to 7-substituted purines of general formula (V). Usually an additive like ammonium chloride is employed in a solvent like toluene at higher temperatures between 80°C and 150°C.

[0561] An alternative synthesis sequence, also depicted in Scheme 2 part 1, right part, starts from the commercially available 2,6-dichloro-9H-purine (formula XII - CAS No: 1839-23-2). This starting material can be regioselectively “alkoxylated” at position 6 using an alcohol of general formula (XIII) like methanol, benzyl alcohol or tert-butyl 4-(4-hydroxyphenyl)piperazine- 1 -carboxylate (CAS No: 158985- 25-2) as indicated for substituent R8in Scheme 2 but not limited to those alcohols. Usually these alcohols are deprotonated using a strong base like sodium hydride or potassium tert-butoxide in a protic solvent like methanol or tert-butanol at temperatures ranging from 50°C to 100°C to get the purine ethers of general formula (XIV). The following alkylation can be done using an electrophilic haloalkane of general formula (XV) like 2 -iodopropane or bromocyclobutane leading usually to a nearly 1: 1 mixture of the desired 7-alkylated product of general formula (XVI) and the 9-alkylated byproduct (not shown in Scheme 2) that can be separated by chromatography or preparative HPUC. The imidazole alkylation can be performed in a dipolar aprotic solvent like W-di methyl form am ide or W-dim ethyl acetamide at temperatures between 20°C and 120°C. In case a bromoalkene of general formula (XV) is used in the alkylation reaction the catalytic addition of an iodine source like potassium iodide might enhance the reaction velocity. The intermediates of general formula (XVI) can be directly used in the subsequent installation of the substituents R1, R2and Z-R4but in case R8represents a methyl group the intermediates of general formula (XVI) can also be converted to the dichloropurines of general formula (V) using POCI3, an organic amine like V '-dimcthylanilinc in a solvent like toluene at higher temperatures between 80°C and 120°C.

[0562] Scheme 2, Part 1 (**see Scheme 2, Part 2 further below)

[0563] Description of Scheme 2, Part 2:

[0564] The purines of general formula (V) can also be obtained by a third synthesis sequence also depicted in Scheme 2, Part 2 below, starting on one hand from bromoethyl acetate (CAS No: 105-36-2) and using cyanamine (CAS No: 420-04-2) for a second building block. On the one hand bromoethyl acetate is converted with a primary amine of general formula (XVII) bringing the later substituent R3within its own alkylsubstituent to get the a-aminoesters of general formula (XVIII). As reaction conditions usually an excess of amine is used to scavenge the liberated HBr in a protic solvent like ethanol at temperatures between 0°C and 50°C. To get the second cyanamine of general formula (XIX) the unsubstituted cyanamine is converted with an orthoester of general formula wherein R11represents a Ci to C3 alkyl preferably ethyl. The orthoester used in excess has a double function as reactant and solvent for the cyanamine. Usually higher temperatures between 80°C and 120°C are employed. The resulting cyanamines of general formula (XIX) are converted with the a-aminoesters of general formula (XVIII) using a strong base like potassium tert-butoxide in a solvent like ethanol or diethylether or mixtures thereof usually at room temperature. The obtained aminopyrazole esters of general formula (XX) can react with urea (CAS No: 57-13-6) without additional solvent at higher temperatures between 100°C and 150°C to close the pyrimidindione ring in compounds of general formula (XXI). The next double dehydrochlorination can be done with POCI3, an organic amine like triethylamine in a solvent like toluene at higher temperatures between 80°C and 120°C to afford the dichloropurines of general formula (V).

[0565] Scheme 2, Part 2 (*** see Scheme 2, Part 1 above)

[0566] In Scheme 2, part 2. R3represents substituents according to claim 1; R8represents the substituents shown in Scheme 2 part 1 ; the substituents R9and R10together represent a substituent R3according to claim 1; the dashed circle, that might be present or not, has the meaning of a possible ring connection between R9and R10according to the claim 1 for substituent R3; R11represents a Ci to Cs alkyl group, preferably a methyl- or an ethyl group; reaction conditions in Scheme 2 part 1 and 2: step 1: reductive amination; step 2: chlorination; step 3: NH3, solvent; step 4: NH4Cl, toluene; step 5, 10: base solvent; step 6: base, KI, solvent; step 7, 12: POCK. organic amine, solvent; step 8: solvent; step 9: neat; step 11: urea neat.

[0567] Description of Scheme 3, Part 1 :

[0568] The dichloropurines of general formula (V) can be the starting materials to get the key intermediates of general formula (II) as shown in Scheme 3. First the nitrogen nucleophiles R’-H of general formula (XXII) for nitrogen nucleophiles containing no protecting groups at further functional groups within R1 or of general formula (XXIII) for nitrogen nucleophiles containing a protecting groups at further functional groups within R1can be used to get the purine intermediates of general formula (XXIV). In both cases of nitrogen nuclephiles with or without additional protecting groups at R1the reaction conditions include an organic amine base like triethylamine and a solvent like dichloromethane or 1,4-dixoane. Usually the reactions are performed at temperatures ranging from 20°C to 80°C. In case the unprotected nitrogen nucleophiles of general formula (XXII) are employed a following, optional protection might be necessary at additional functional groups within R1. For example, if this additional functional group might be an alcohol within R1, a silyl protection group might be used well-known to a person skilled in the art (see protecting group books cited above). The dotted line to “PG” in Scheme 3 indicates that the protecting group may be present or absent). The monochloropurines of general formula (XXIV) can be converted in a second nucleophilic aromatic substitution (S - Ar) with an alcohol of general formula (XXV) that might also contain a protecting group at an additional functional group within R2. To get good conversions the alcohols of general formula (XXV) first have to be deprotonated quantitatively by using a strong base like sodium hydride or sodium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran or 1,4-dioxane at lower temperatures between -20C° to 30°C. Then the chloropurine of general formula (XXIV) is added and the reaction continued at higher temperatures between 70°C and 110°C to obtain the key intermediates of general formula (II) wherein X4represents a hydrogen. Depending if the Z-linker is a carbonyl or an oxygen atom, different reaction sequences for the installation of the “western” substituent Z-R4are employed. According to claim 1 R4includes 5 -ethynyl-6-fluoro-2 -naphthol, a 5-ethyl-6-fluoro-2- naphthol, a fluorinated or non-fluorinated l,3-benzothiazol-2-amine, a 2-amino-l-benzothiophene-3- carbonitrile, a 4-methyl-5-(trifluoromethyl)pyridine-2-amine and connecting points to the Z-linker as described for claim 1. In case R4represents a 5-ethynyl-6-fluoro-2-naphthol the naphtholic hydroxy group is connected to a protecting group PG as indicated for the compounds of general formula (XXVI) or (XXX) shown in Scheme 3, Part 1 and 2. This protecting group might be an ether like methoxymethyl (MOM) or a silyl group like tert-butyldiphenylsilyl (TBDPS) but not limited to those. The terminal alkyne position of a 5-ethynyl-6-fluoro-2-naphthol representing R4might additionally be protected with a silyl group SiR12R12R13as shown for compounds of general formula (XXVI) or (XXX). This silyl group SiR12R12R13can for example be a triisopropylsilyl (TIPS) group but any other suitable silyl group for a terminal alkyne as well. In case R4represents a 4-methyl-5-(trifluoromethyl)pyridine-2 -amine the amino group is connected to a protecting group PG as indicated for the compounds of general formula (XXVI). This protecting group might be a PMB protecting group but is not limited to those. In case the Z-linker of the final compounds of general formula (I) shall be a carbonyl, an aldehyde of general formula (XXVI) can be used to be connected to position 8 of the central purine ring of intermediates of general formula (II) wherein X4represents a hydrogen. Therefore the imidazole ring first has to be quantitatively deprotonated at position 8 using a strong base like lithium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran at lower temperatures between -40°C to 0°C. Afterwards the aldehyde of general formula (XXVI) is added and the reaction kept at lower temperature or raised to room temperature to get the intermediate alcohols of general formula (XXVII). Scheme 3, Part 1

[0569] (XXVII) (II) Reaction conditions in scheme 3, part 1: step la, and 2: organic amine, solvent; step lb: protection (brackets indicate that the protection step might not be necessary depending on R1; step 3, and 4: strong base, solvent;

[0570] Description of Scheme 3, Part 2: Before oxidizing these alcohols to the corresponding ketones usually the silyl protecting group SiR12R12R13of the terminal alkyne is removed due to steric shielding of the alcohol linker that is in close spatial proximity. This silyl deprotection step can be performed for example with tetrabutylammonium fluoride (TBAF) in a solvent like tetrahydrofuran at lower temperatures between -30°C to 0°C to avoid ring closure between the alcohol and the unprotected alkyne. Afterwards the oxidation of the deprotected intermediate of general formula (XXVIII) is performed with a mild oxidizing agent like Dess-Martin periodinane (DMP) in a solvent like dichloromethane usually at room temperature. The reaction sequence of alkyne silyl deprotection and subsequent alcohol oxidation can also be done vice versa but in this case the sily deprotection has to be done at higher temperatures between 50°C and 80°C. To get to the final compounds of general formula (I) wherein Z represents the carbonyl as shown in Scheme 3 Part 2, the penultimate protected intermediates of general formula (XXIX) have to be deprotected at R1, R2and / or R4. This can be done in one step using acidic conditions like HC1 or TFA in organic solvent like 1,4- dioxane or methane sulfonic acid (MsOH) in methanol to remove additional MOM groups at the naphtholic hydroxy or PMB groups at the amine - and tert-butyloxycarbonyl (Boc) groups at piperazine containing head groups R1. In case of an oxygen Z-linker the lower right reaction sequence shown in Scheme 3 Part 2 might be used. For that, first the key intermediates of general formula (II) wherein X4represents a hydrogen might be brominated in position 8 to get intermediates of general formula (II) wherein X4represents a bromine. To perform this bromination first the position 8 of the central purine ring has to be quantitatively deprotonated using a strong base like lithium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran at lower temperatures between -40°C to 0°C. Then a bromine source like Br2 or N- bromosuccinimide (NBS) can be added and the reaction kept at lower temperature or raised to room temperature to get the key intermediates of general formula (II) wherein X4represents a bromine. This bromine can be substituted in an S- Ar reaction with an alcohol of general formula (XXX) wherein R4represents the known groups from claim 1 like 5-ethynyl-6-fluoro-2-naphthol that again might be doubly protected at the naphtholic hydroxy group (PG) and the terminal alkyne (SiR12R12R13) as already described above. For the S- Ar reaction usually a strong base like the phosphazene 2-(tcrt-butylimino)-A'.A'-dicthyl- 1,3 -dimethyl- 1, 3, 21ambda5-diazaphos-phinan-2-amine (BEMP) is employed in a solvent like N,N- dimethylformamide at temperatures between 50°C and 100°C. The resulting ethers of general formula (XXXI) need to be deprotected from orthogonal protecting groups. This is usually done in two steps wherein first the SiR12R12R13group is removed from the terminal alkyne with TBAF as already described above. Finally the acid labile protecting groups like MOM, Boc or PMB are removed as also described above using HC1 in organic solvent or MsOH in methanol to get the desired compounds of general formula (I) wherein Z represents an oxygen (see scheme 3, part 2).

[0571] Scheme 3, Part 2

[0572] In Scheme 3 part 1 and 2. Z, X4, R1, R2, R3, and R4represent substituents according to claim 1 optionally bearing suitable protecting groups, which is indicated by the dotted line to “PG”; the selections for Z and X4for the shown synthesis are indicated in Scheme 3; PG represents any protecting group, suitable for the respective functional group (see Greene's Protective Groups in Organic Synthesis or Protecting Groups as cited above); the dashed lines at PG and also at the SiR12R12R13group indicate that the protecting group and / or the SiR12R12R13group at the substiutents R1, R2, and R4might be present or absent; R12and R13 represent Ci to Ce alkyl or aryl preferably iso-Propyl, tert.-Bu, or phenyl; reaction conditions in scheme

[0573] 3, part 2: step la, and 2: organic amine, solvent; step lb: protection (brackets indicate that the protection step might not be necessary depending on R1; step 3, and 4: strong base, solvent; step 5; TBAF, solvent; step 6: oxidation; step 7, and 10: deprotection; step 8: bromination; step 9: base, solvent.

[0574] Descripton of Scheme 4:

[0575] After installation of the head group R1the intermediate monochloropurines of general formula (XXIV) can also be converted at the chloro-position to a non-leaving group like thiomethyl as shown in Scheme

[0576] 4. By employment of sodium thiomethoxide in a polar solvent like dimethyl sulfoxide the S - Ar reaction can lead at temperatures ranging from 50°C to 100°C to the thioethers of general formula (XXXII). These intermediate thioethers can be brominated in position 8 as already described in Scheme 3 using a strong base like lithium bis(trimethylsilyl)amide for quantitative deprotonation with subsequent addition of a bromination reagent like NBS at conditions already described in scheme 3. Using double protected alcohols (PG, SiR12R12R13) of general formula (XXX) as described in Scheme 3. the bromopurines of general formula (XXXIII) can be coupled to these alcohols using a base like potassium carbonate in a polar solvent like 'A'-dimcthylformamidc at higher temperatures between 80°C and 120°C to get the ethers of general formula (XXXIV). The final introduction of the side chain R1can be performed by reconverting the non-leaving group thiomethyl again in a proper leaving group via oxidation to the corresponding key intermediate sulfone of general formula (III) wherein Z represents an oxygen and X2represents a methylsulfonyl. This oxidative activation is usually done with at least 2 equivalents of an oxidizing reagent like meto-chloroperoxybenzoic acid or potassium peroxymonosulfate (oxone) in a solvent such as dichloromethane at temperatures between -20°C and 40°C. The alcohol of general formula (XXV) can then be installed using a strong base like sodium hydride under reaction conditions already described at Scheme 3 using the good leaving group qualities ofX2representing methylsulfonyl. The final deprotection of the orthogonal protecting groups is again done sequentially using TBAF to remove SiR12R12R13and then removing MOM- and Boc-protecting groups under acidic conditions like HC1 or methansulfonic acid in organic solvent to get compounds of general formula (I) with the meaning of oxygen for the Z-linker. Similarly to the sequence shown on the lower left of Scheme 3 also the aldehyde of general formula (XXVI) might be used in the conversion of intermediate (XXXII) via quantitative deprotonation at position 8 in the purine core with a strong base and subsequent trapping with the aldehyde of general formula (XXIV). After DMP oxidation of the resulting alcohol (not shown in Scheme 3 nor Scheme 4) the usual order of reaction steps as shown for intermediates of general formula (XXXIV) in Scheme 4 might be employed to get final products of general formula (I) wherein Z would represent a carbonyl group. Scheme 4 step strong base, solvent

[0577] In Scheme 4, Z, X2, R1, R2, R3, and R4represent substituents according to claim 1 optionally bearing suitable protecting groups, which is indicated by the dotted line to “PG”; the selections for Z and X2for the shown synthesis are indicated in Scheme 4; PG represents any protecting group, suitable for the respective functional group (see Greene's Protective Groups in Organic Synthesis or Protecting Groups as cited above the dashed lines at PG and also at the SiR12R12R13group indicate that the protecting group and / or the SiR12R12R13group at the substiutents R1, R2, and R4might be present or absent; R12and R13represent Ci to Ce alkyl or aryl preferably i-Pr, t-Bu, or phenyl; reaction conditions in scheme 3: step 1: NaSMe, solvent; step 2: bromination; step 3: base, solvent; step 4; oxidation; step 5: strong base, solvent; step 6: deprotection. Description of Scheme 5 :

[0578] In Scheme 2 monochloropurines of general formula (XVI) wherein R8represents tert-butyl 4-(4- hydroxyphenyl)piperazine-l -carboxylate can be used as starting points for the synthesis of key intermediates of general formula (IV) as shown in Scheme 5. The mentioned monochloropurines of general formula (XXXV) are first converted with alcohols of general formula (XXV) under Buchwald conditions to form the C-0 bond between the purine core and R2. The catalytic system used under these Buchwald conditions is composed of a palladium compound in combination with a suitable ligand like (2'-amino[biphenyl]-2-yl)(methanesulfonato-kappaO)palladium - dicyclohexyl(2',6'- diisopropoxy[biphenyl]-2-yl)phosphine (1: 1)(CAS No: 1445085-77-7), a base like caesium carbonate in a solvent like toluene at higher temperatures in the range between 80°C and 120°C to get the purines of general formula (XXXVI). A subsequent transetherification at position 8 of the purine core can be performed with an alcohol like methanol or benzyl alcohol. Therefore, first the alcohol of general formula (XXXVII) like the mentioned methanol or benzyl alcohol are quantitatively deprotonated with a strong base like sodium hydride at lower temperatures between -20°C to 20°C in a solvent like methanol or N,N- dimethylacetamide and after the addition of the compound of general formula (XXXVI) stirring is continued at lower temperatures or raised to 50°C to 80°C. The resulting ethers of general formula (XXXVIII) are next brominated at position 8 of the purine ring. At first again the purine ring is quantitatively deprotonated using a strong base like lithium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran at lower temperatures between -40°C to 0°C, before a bromination reagent like NBS or Br2 is added at very low temperatures between -80°C to -20°C to obtain the bromopurines of general formula (XXXIX) as shown in Scheme 5. The attachment of the alcohols of general formula (XXX) already described above in Scheme 3 and 4 can be done via different conditions. Either a strong base like the phosphazene BEMP is employed and coupling can then be performed around room temperature in a solvent like '. '-dimcthylacctamidc. Or a weaker base like potassium carbonate is used in a solvent like V '-di cthylfo rm a ide, but then elevated temperatures are needed between 80°C to 120°C.

[0579] Scheme 5, part 1

[0580] In the resulting intermediates of general formula (XL) the ether substituent first has to be removed before the head group R1could be installed.

[0581] In case R14has the meaning of a methyl group demethylation conditions could for example include a combination of an oxidizing agent like sodium iodate and a scavenger for the in situ formed acetal like chlorotrimethylsilane to cleave the methyl group. Typically a solvent like acetonitrile is used at temperatures kept around room temperature.

[0582] In case R14has the meaning of a benzyl group, redutive hydrogenation conditions could be employed using atmospheric hydrogen gas pressure and catalytic amount of palladium on charcoal in a solvent like ethanol at room temperature to receive the key intermediate of general formula (IV) wherein Z represents an oxygen and X1represents a hydroxy group. This hydroxy group X1could then be activated with a coupling reagent like e.g. (lH-benzotriazol-l-yloxy)[tri(pyrrolidin-l-yl)]phosphonium hexafluorophosphate (PyBOP), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate (HATU), or l-ethyl-3 -(3 -dimethylaminop ropyl)carbodiimide (EDC)in the presence of a strong base like l,8-diazabicclo[5.4.0]undec-7-en (DBU) and coupled with a nitrogen nucleophile of general formula (XXIII) to install the head group R1. This conversion can be performed in a polar solvent like N, JV-dimethylformamide at temperatures around room temperature. After this coupling the orthogonal protecting groups have to be removed. Typically the silyl groups like SiR12R12R13are first removed using TBAF under reaction conditions already described for scheme 3 and 4. The compounds of general formula (XXXI) could also contain more than one silyl group (for example PG as general protecting group could also have the meaning of a silyl group like tert-butyldiphenysilyl (TBDPS)) that are simultaneously removed under the TBAF reaction conditions. Finally the acid labile groups like MOM and Boc can be removed under reaction conditions already described above.

[0583] Scheme 5, part 2

[0584] In Scheme 5. part 1 and 2. Z, X1, R1, R2, R3, and R4represent substituents according to claim 1 optionally bearing suitable protecting groups, which is indicated by the dotted line to “PG”; the selections for Z and X1for the shown synthesis are indicated in Scheme 5; PG represents any protecting group, suitable for the respective functional group (see Greene's Protective Groups in Organic Synthesis or Protecting Groups as cited above the dashed lines at PG and also at the SiR12R12R13group indicate that the protecting group and / or the SiR12R12R13group at the substiutents R1, R2, and R4might be present or absent; R12and R13represent Ci to Ce alkyl or aryl preferably iso-propyl, tert.-butyl, or phenyl; R14represents methyl or benzyl; reaction conditions in Scheme 5: step 1: RuPhos palladacycle generation 3, CS2CO3, toluene; step 2: solvent; step 3: bromination; step 4; base, solvent; step 5: TMSCl, NalOi, MeCN (in case R14is methyl) or H2. Pd / C, protic solvent (in case R14is benzyl); step 6: PyBOP, DBU, DMAC; step 7: deprotection.

[0585] Description of Scheme 6:

[0586] Instead of the transetherification described at step 2 in Scheme 5 the compounds of general formula (XXXVI) could also be converted to thioethers at position 6 of the central purine core. To perform this conversion at first a thiol of general formula (XLI) like (4-methoxyphenyl)methanethiol is quantitatively deprotonated using a stronger base like BEMP in a polar solvent like '. '-dimcthylacctamidc at temperatures between 0°C and 30°C. Then the ether of general formula (XXXVI) is added and stirring is continued usually at ambient temperature. The received thioether of general formula (XLII) can then be oxidized to the corresponding sulfoxide with one equivalent of oxidizing agent like oxone in a solvent or solvent mixture like methanol and 1,4-dioxane at temperatures ranging from 0°C to 50°C. The obtained sulfoxide of general formula (XLIII) has sufficient leaving group quality to be exchanged with a nitrogen nucleophile of general formula (XXIII) to install the head group R1. This exchange can be performed under acidic conditions with for example propionic acid in a solvent like 2 -methyl -2 -butanol at higher temperatures between 80°C and 120°C as shown in scheme 6. The resulting key intermediates of general formula (II) wherein X4represents a hydrogen can further be converted as described in scheme 3. Alternatively the thioethers of general formula (XLII) can also be used to first install to western Z-R4moiety according to the synthesis steps 3 and 4 described in Scheme 5 before the thioether position is oxidized to the sulfoxide to install the R1headgroup as described in Scheme 6.

[0587] Scheme 6

[0588] In scheme 6, Z, X4, R1, R2, and R3represent substituents according to claim 1 optionally bearing suitable protecting groups, which is indicated by the dotted line to “PG”; the selection for X4for the shown synthesis is indicated in scheme 6; PG represents any protecting group, suitable for the respective functional group (see Greene 's Protective Groups in Organic Synthesis or Protecting Groups as cited above the dashed lines at PG indicate that the protecting group at the substiutents R1, and R2might be present or absent; R15represents Ci to C7 alkyl or aryl preferably para-methoxybenzyl (PMB). Scheme 7, part 1

[0589] Description of Scheme 7 :

[0590] The dichloropurines of general formula (V) can be the starting materials to get the key intermediates of general formula (XLV) as shown in Scheme 7. In case R4represents a 5 -ethynyl-6-fluoro-2 -naphthol the naphtholic hydroxy group is connected to a protecting group PG as indicated for the compounds of general formula (XXVI) shown in Scheme 7, part 1 and 2. This protecting group might be an ether like methoxymethyl (MOM) but is not limited to those. The terminal alkyne position of a 5-ethynyl-6-fluoro- 2-naphthol representing R4might additionally be protected with a silyl group SiR12R12R13as shown for compounds of general formula (XXVI). This silyl group SiR12R12R13can for example be a triisopropylsilyl (TIPS) group but any other suitable silyl group for a terminal alkyne as well. For the final compounds of general formula (I) with a Z = carbonyl, an aldehyde of general formula (XXVI) can be used to be connected to position 8 of the central purine ring of intermediates of general formula (V). The imidazole ring first has to be quantitatively deprotonated at position 8 using a strong base like lithium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran at lower temperatures between -40°C to 0°C. Afterwards the aldehyde of general formula (XXVI) is added, and the reaction kept at lower temperature or raised to room temperature to get the intermediate alcohols of general formula (XLIV). Afterwards the oxidation of the alcohol intermediate of general formula (XLIV) is performed with a mild oxidizing agent like Dess-Martin periodinane (DMP) in a solvent like dichloromethane usually at room temperature. Then the nitrogen nucleophiles of general formula (XXIII) containingor not containing protecting groups at further functional groups within R1can be used to get the purine intermediates of general formula (XL VI). In both cases of nitrogen nucleophiles with or without additional protecting groups at R1the reaction conditions include an organic amine base like triethylamine and a solvent like dichloromethane or 1,4- dixoane. Usually, the reactions are performed at temperatures ranging from 20°C to 80°C. The dotted line to “PG” in Scheme 3 indicates that the protecting group may be present or absent). The monochloropurines of general formula (XL VI) can be converted in a second nucleophilic aromatic substitution (S - Ar) with an alcohol of general formula (XXV) that might also contain a protecting group at an additional functional group within R2. To get good conversions the alcohols of general formula (XXV) first must be deprotonated quantitatively by using a strong base like sodium hydride or sodium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran or 1,4-dioxane at lower temperatures between -20C° to 30°C. Then the chloropurine of general formula (XL VI) is added and the reaction continued at higher temperatures between 70°C and 110°C to obtain the key intermediates of general formula (XL VII) wherein. Thesilyl protecting group is then cleaved to obtain intermediate (XXIX). This silyl deprotection step can be performed for example with tetrabutylammonium fluoride (TBAF) in a solvent like tetrahydrofuran at lower temperatures between -30°C to 0°C. Finally, the acid labile protecting groups like MOM and Boc are removed as also described above using HC1 or TFA in organic solvent or MsOH in methanol to get the desired compounds of general formula (I) wherein Z represents a carbonyl group. Scheme 8, part 1

[0591] Description of Scheme 8, part 1:

[0592] The dichloropurines of general formula (V) can be the starting materials to get the key intermediates of general formula (LI) as shown in Scheme 8. In case R4represents a 5 -ethynyl-6-fluoro-2 -naphthol the naphtholic hydroxy group is connected to a protecting group PG as indicated for the compounds of general formula (XXVI) shown in Scheme 8, part 1 and 2. This protecting group might be an ether like methoxymethyl (MOM) or methoxyethoxymethyl (MEM) but is not limited to those. The terminal alkyne position of a 5-ethynyl-6-fluoro-2-naphthol representing R4might additionally be protected with a silyl group SiR12R12R13as shown for compounds of general formula (XXVI). This silyl group SiR12R12R13can for example be a triisopropylsilyl (TIPS) group but any other suitable silyl group for a terminal alkyne as well. For the final compounds of general formula (I) p-methoxybenzylmercaptan can be used as nucleophiles to get the purine intermediates of general formula (XL VIII). The reaction conditions include an inorganic amine base like potassium carbonate and a solvent like DMF. Usually, the reactions are performed at 25 °C. The monochloropurines of general formula (XL VIII) can be converted in a second nucleophilic aromatic substitution (S- Ar) with an alcohol of general formula (XXV) that might also contain a protecting group at an additional functional group within R2. To get good conversions the alcohols of general formula (XXV) first must be deprotonated quantitatively by using a strong base like sodium hydride or sodium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran or 1,4-dioxane at lower temperatures between -20C° to 30°C. Then the chloropurine of general formula (XL VIII) is added and the reaction continued at higher temperatures between 70°C and 110°C to obtain the key intermediates of general formula (XLIX) wherein. An aldehyde of general formula (XXVI) can be used to be connected to position 8 of the central purine ring of intermediates of general formula (XLIX). The imidazole ring first must be quantitatively deprotonated at position 8 using a strong base like lithium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran at lower temperatures between -40°C to 0°C. Afterwards the aldehyde of general formula (XXVI) is added, and the reaction kept at lower temperature or raised to room temperature to get the intermediate alcohols of general formula (L). Before oxidizing these alcohols to the corresponding ketones usually the silyl protecting group SiR12R12R13of the terminal alkyne is removed due to steric shielding of the alcohol linker that is in close spatial proximity. This silyl deprotection step can be performed for example with tetrabutylammonium fluoride (TBAF) in a solvent like tetrahydrofuran at lower temperatures between -30°C to 0°C to avoid ring closure between the alcohol and the unprotected alkyne to give intermediate (LI)

[0593] Scheme 8, part 2

[0594] (XXIX) Z = C(=O)

[0595] The oxidation of the deprotected intermediate of general formula (LI) is performed with a mild oxidizing agent like Dess-Martin periodinane (DMP) in a solvent like dichloromethane usually at room temperature to give intermediate (LII) . The received thioether of general formula (LII) can then be in situ oxidized and trapped by water using two equivalents of oxidizing agent like oxone in a solvent mixture of 1,4-dioxane and water at temperatures ranging from 0°C to 25 °C to give key intermediate (LIII). Intermediate (LIII) can then be activated using PyBOB and DBU in anhydrous DMA at rt and transformed to intermediate (XXIX) using nitrogen nucleophiles of general formula (XXIII) containing none or protecting groups at further functional groups within R1. Finally, the acid labile protecting groups like Boc are removed as also described above using HC1 or TFA in organic solvent or MsOH in methanol to get the desired compounds of general formula (I) wherein Z represents a carbonyl group.

[0596] EXPERIMENTAL SECTION

[0597] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The ’H-NMR data of selected compounds are listed in the form of ’H-NMR peaklists. Therein, for each signal peak the 5 value in ppm is given, followed by the signal intensity, reported in round brackets. The 5 value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: 5i (intensity i), 82 (intensity2), ... , 8! (intensity!), ... , 8n (intensityn).

[0598] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A ’H-NMR peaklist is similar to a classical ’H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical ’H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities,13C satellite peaks, and / or spinning sidebands. The peaks of stereoisomers, and / or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and / or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "byproduct fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak -picking in classical ’H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%.

[0599] Chemical names were generated using the ACD / Name software from ACD / Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD / Name generated names.

[0600] Optical rotations were measured using a JASCO P2000 Polarimeter. Typical, a solution of the compound with a concentration of 1 mg / mL to 15 mg / mL was used for the measurement. The specific rotation [O.]D was calculated according to the following formula:

[0601] In this equation, a is the measured rotation in degrees; d is the path length in decimetres and is the concentration in g / mL. The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person. EXPERIMENTAL PART

[0602] Table 1 lists the abbreviations used in this paragraph and in the Intermediates and Examples sections as far as they are not explained within the text body.

[0603] Table 1

[0604]

[0605] Other abbreviations have their meanings customary per se to the skilled person.

[0606] The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

[0607] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

[0608] GENERAL PART

[0609] All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[0610] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane / ethyl acetate or DCM / methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and / or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[0611] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

[0612] NMR peak forms in the following specific experimental descriptions are stated as they appear in the spectra, possible higher order effects have not been considered.

[0613] The ’H-NMR data of selected compounds are listed in the form of ’H-NMR peaklists. Therein, for each signal peak the 5 value in ppm is given, followed by the signal intensity, reported in round brackets. The 5 value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: 5i (intensity:), 82 (intensity2), ... , 81 (intensity 1), ... , 8n (intensityn).

[0614] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A ’H-NMR peaklist is similar to a classical ’H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical ’H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities,13C satellite peaks, and / or spinning sidebands. The peaks of stereoisomers, and / or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and / or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak -picking in classical ’H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%.

[0615] Reactions employing microwave irradiation may be run with a Biotage Initiatora microwave oven optionally equipped with a robotic unit. The reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature.

[0616] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example pre-packed silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2silica gel in combination with a Isolera® autopurifier (Biotage) and eluents such as gradients of e.g. hexane / ethyl acetate or DCM / methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and / or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[0617] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

[0618] The percentage yields reported in the following examples are based on the starting component that was used in the lowest molar amount. Air and moisture sensitive liquids and solutions were transferred via syringe or cannula and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. The term “concentrated in vacuo” refers to the use of a Buchi rotary evaporator at a minimum pressure of approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (°C).

[0619] In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.

[0620] Analytical conditions

[0621] UPLC-MS Standard Procedures

[0622] UPLC-MS-data given in the subsequent specific experimental descriptions refer (unless otherwise noted) to the following conditions: LC-MS, Analytical Method 1:

[0623] Instrument: Thermo Scientific FT-MS; UHPLC: Thermo Scientific UltiMate 3000; column: Waters HSS T3 C18 1.8 pm, 75 mm * 2.1 mm; eluent A: water + 0.01% formic acid; eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B 2.5 min 95% B 3.5 min 95% B; temperature: 50°C; flow rate: 0.90 mL / min; UV detection: 210-300 run.

[0624] LC-MS, Analytical Method 2:

[0625] Instrument: Thermo Scientific FT-MS; UHPLC+: Thermo Scientific Vanquish; column: Waters HSS T3 C18 1.8 pm, 2. 1 mm x 75 mm; eluent A: 1 L water + 0.01% formic acid; eluent B: 1 L acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B 2.5 min 95% B 3.5 min 95% B; temperature: 50°C; flow rate: 0.90 mL / min; UV detection: 210 nm.

[0626] LC-MS, Analytical Method 3

[0627] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1- 99% B, 1.6-2.0 min 99% B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm.

[0628] LC-MS, Analytical Method 4

[0629] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm.

[0630] LC-MS, Analytical Method 5

[0631] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: Waters, XSELECT CSH C18, 4.6 x 50 mm 3.5 pm; Eluent A: 5 mmol ammonium acetate pH 4.2; Eluent B: 100 mmol ammonium acetate pH 4.2 / Isopropanol / ACN (5 / 62 / 33); Gradient: 0.0 min 85% B 2.0 min 85% B —> 19.0 min 100% B —> 24.0 min 95% B; Oven: 50°C; Flow: 0.75 ml / min; UV-Detection: 240 nm.

[0632] LC-MS, Analytical Method 6

[0633] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: Waters Acquity UPLC HSS T3 1.8 pm 50 x 1 mm; Eluent A: 1 1 Water + 0.100 ml 99%ige Formic acid , Eluent B: 1 1 Acetonitrile + 0.100 ml 99%ige Formic acid; Gradient: 0.0 min 95% A 6.0 min 5% A 7.5 min 5% A Oven: 50°C; Flow: 0.35 ml / min; UV-Detection: 210 nm

[0634] LC-MS, Analytical Method 7

[0635] System MS: Thermo Scientific FT-MS; System UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 pm; Eluent A: 1 1 Water + 0.01% Formic acid; Eluent B: 1 1 Acetonitrile + 0.01% Formic acid; Gradient: 0.0 min 60% B 0.75 min 95% B 3.5 min 95% B; Oven: 50°C; Flow: 1.00 ml / min; UV-Detection: 210 nm / Optimum Integration Path 210-300 nm LC-MS, Analytical Method 8

[0636] Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C18 1.7 pm, 50 mm x 2.1 mm; Eluent A: water + 0.05% formic acid (99%); Eluent B: acetonitrile + 0.05% formic acid (99%); gradient: 0-1.7 2- 90% B, 1.7-2.0 90% B; flow 1.2 ml / min; temperature: 60 °C; DAD scan: 190-400 run.

[0637] Method A:0-60AB, Shimadzu

[0638] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 0-60% B, 0.8-1.2 min 60% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220 nm & 254 nm.

[0639] Method B:0-60AB, Agilent

[0640] Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@ 5um EVO C18 30*2.1 mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 0-60% B, 0.8-1.2 min 60% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220 nm & 254 nm.

[0641] Method C:5-95AB, Shimadzu

[0642] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220 nm & 254 nm.

[0643] Method D:5-95AB, Agilent

[0644] Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@ 5 pm EVO C18 30*2.1 mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220 nm & 254 nm.

[0645] Method E:10-80CD, Agilent

[0646] Instrument: Agilent 1200\G6110A SingleQuad; Column: XBridge C18 2.1*50 mm, 5 pm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 10-80% B, 1.2- 1.6 min 80% B; flow 1.2 ml / min; temperature: 40 °C; DAD: 220 nm & 254 nm.

[0647] Method F:0-60CD, Agilent

[0648] Instrument: Agilent 1200\G6110A SingleQuad; Column: XBridge C18 2.1*50 mm, 5 pm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 0-60% B, 1.2-1.6 min 60% B; flow 1.0 ml / min; temperature: 40 °C; DAD: 220 nm & 254 nm. Method G:5-95CD, Shimadzu

[0649] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm, 5 gm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm.

[0650] Method H:0-60CD, Shimadzu

[0651] Instrument: SHIMADZU ECMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm, 5 pm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min, 0-60% B, 1.2-1.6 min, 60% B; flow 1.0 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm.

[0652] Method L5-95CD, Shimadzu

[0653] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min, 95% B; flow 1.5 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm.

[0654] Method J:0-60CD, Shimadzu

[0655] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm, 5 pm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 0-60% B, 0.8-1.2 min, 60% B; flow 1.5 ml / min; temperature: 40 °C; PDA: 220 nm & 254 nm.

[0656] Method K

[0657] Column: Kinetex EVO C18 5 pm, 2. 1 mm x 30 mm; eluent A: 0.0375% trifluoroacetic acid in water, eluent B: 0.01875% trifluoroacetic acid in acetonitrile (v / v); gradient: 0.0 min 5% B 0.5 min 95% B 0.81 min 5% B 1.05 min 5% B; flow rate: 1.5 mL / min; column temperature: 50 °C; UV detection: 220 nm & 254 nm.

[0658] Method L

[0659] Column: HALO C18 5 pm, 3.0 mm x 30 mm; eluent A: 0.0375% trifluoroacetic acid in water, eluent B: 0.01875% trifluoroacetic acid in acetonitrile (v / v); gradient: 0.0 min 50% B 0.5 min 100% B 0.81 min 50% B -> 1.05 min 50% B; flow rate: 1.5 mL / min; column temperature: 50 °C; UV detection: 220 nm & 254 nm.

[0660] Preparative HPLC conditions

[0661] “Purification by preparative HPLC” in the subsequent experimental descriptions refers to the following conditions (unless otherwise noted):

[0662] Method A:

[0663] Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2. IS, Prepcon 5 software. Column: Chromatorex C18 lOpM 120x30 mm; Eluent A: water + 0.1% formic acid; Eluent B: acetonitrile; gradient: given for intermediates and examples, rate 150 mL / min, temperature 25°C.; UV 220 nm Method B:

[0664] Istrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2. IS, Prepcon 5 software. Column: Chromatorex C18 lOpM 120x30 mm; Eluent A: 0.1% ammonia in water; Eluent B: acetonitrile; gradient: given for intermediates and examples, rate 150 mL / min, temperature 25°C.; UV 250 nm

[0665] Flash column chromatography conditions

[0666] Biotage IsoleraTM chromatography system (http: / / www.biotage.com / product-area / flash-purification) using pre-packed silica and pre-packed modified silica cartridges. Purification by (flash) column chromatography” as stated in the subsequent specific experimental descriptions refers to the use of a Biotage Isolera purification system. For technical specifications see “Biotage product catalogue” on www.biotage.com.

[0667] Preparative HPLC, Method A: Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient A: 0 - 15 min 1 - 25% B; flow: 60 mL / min; gradient B: 0 - 15 min 10 - 50% B; flow: 60 mL / min; gradient C: 0 - 15 min 15 - 55% B; flow: 60 mL / min; gradient D: 0 - 15 min 30 - 70% B; flow: 60 mL / min; gradient E: 0 - 15 min 40 - 80% B; flow: 60 mL / min; gradient F: 0 - 15 min 65 - 100% B; flow: 60 mL / min; temperature: 25 °C; solution: max. 250 mg / 2ml dimethyl sulfoxide; injection: 1 x 2 ml; Detection: UV 254 nm; Software: SCPA PrepCon5.

[0668] Preparative HPLC, Method B: Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; eluent A: water + 0.2 vol-% ammonia (32%), eluent B: acetonitrile; gradient A: 0 - 15 min 1 - 25% B; flow: 60 mL / min; gradient B: 0 - 15 min 10 - 50% B; flow: 60 mL / min; gradient C: 0 - 15 min 15 - 55% B; flow: 60 mL / min; gradient D: 0 - 15 min 30 - 70% B; flow: 60 mL / min; gradient E: 0 - 15 min 40 - 80% B; flow: 60 mL / min; gradient F: 0 - 15 min 65 - 100% B; flow: 60 mL / min; temperature: 25 °C; solution: max. 250 mg / 2ml dimethyl sulfoxide; injection: 1 x 2 ml; Detection: UV 254 nm; Software: SCPA PrepCon5.

[0669] Preparative HPLC, Method C: Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5p 100x30mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature: 25 °C; DAD scan: 210-400 nm.

[0670] Preparative HPLC, Method D: Instrument: Waters Autopurificationsystem; column: XBrigde C18 5 pm 100x30 mm; mobile phase A: water + 0.2 vol % aqueous ammonia (32%); mobile phase B: acetonitril; gradient: 0.0-0.5 min 35% B (35-70 ml / min), 0.5-5.5 min 35-65% B; flow: 70 ml / min; temperature: 25°C; wavelength: 210-400 nm

[0671] EXPERIMENTAL SECTION - EXAMPLES and INTERMEDIATES

[0672] Intermediates

[0673] Intermediate 1-01

[0674] 2-Chloro-6-methoxy-9H-purine

[0675] To a solution of 2,6-dichloro-9H-purine (200 g, 1.06 mol) in methanol (1.3 L) was added sodium methoxide (172 g, 3.18 mol) at room temperature. After stirring at room temperature for 16 hours, the reaction mixture was concentrated to remove methanol, diluted with water and acidified to pH = 6 - 7 by adding 2 M hydrochloric acid. After filtration, the filter cake was triturated with water followed by methanol and ethyl acetate. The residue was dried under vacuum to give 2-chloro-6-methoxy-9H-purine (180 g, 90% yield).

[0676] LC-MS (Method C): Rt= 0.286 min; MS (ESIpos): m / z = 185.0 [M+H]+.

[0677] 'HNMR (400 MHz, DMSO-6): 5 [ppm] = 14.1-12.8 (m, 1H), 8.42 (s, 1H), 4.09 (s, 3H).

[0678] Intermediate 1-02

[0679] 2-Chloro-7-cyclobutyl-6-methoxy-7H-purine

[0680] To a solution of 2-chloro-6-methoxy-9H-purine (Intermediate 1-01, 110 g, 0.596 mmol) in N,N- dimethylformamide (1.2 L) were added potassium carbonate (132 g, 953 mmol) and bromocyclobutane (193 g, 1.4 mol) at room temperature. After stirring at 60 °C for 3 days, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuumm. The residue was purified by column chromatography (300-400 mesh, petroleum ether: ethyl acetate = 5: 0, then 3: 1, 1: 1, then 0: 1) twice to give 2-chloro-9-cyclobutyl-6-methoxy-9H-purine (20 g, 70% purity).

[0681] LC-MS (Method C): Rt= 0.794 min; MS (ESIpos): m / z = 239.0 [M+H]+.

[0682] DP,1H NMR (400 MHz, CDCh- ): 5 [ppm] = 8.72 (s, 1H), 5.20-5.01 (m, 1H), 4.12 (s, 3H), 2.62-2.51 (m, 2H), 2.53-2.40 (m, 2 H), 1.95-1.76 (m, 2H). Intermediate 1-03

[0683] 2,6-Dichloro-7-cyclobutyl-7H-purine

[0684] To a solution of 2-chloro-7-cyclobutyl-6-methoxy-7H-purine (Intermediate 1-02, 8.00 g, 90% purity, 30.1 mmol) in phosphorus oxychloride (80 ml) was added N,N -Dimethylformamide (4.6 ml, 60.3 mmol) and N,N -Diisopropylethylamine (7.8 g, 60.3 mmol) at room temperature. After stirring at 130 °C for 4 hours, the mixture was diluted with ice-water, neutralized by sodium bicarbonate powder to pH = 6 - 7 and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give crude 2,6-dichloro-7-cyclobutyl- 7H-purine (8 g, crude) which was used without further purification.

[0685] LC-MS (Method C): Rt= 0.78 min; MS (ESIpos): m / z = 243.1 [M+H]+.

[0686] Intermediate 1-04 tert-Butyl 3-(2-chloro-7-cyclobutyl-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0687] To a solution of 2,6-dichloro-7-cyclobutyl-7H-purine (Intermediate 1-03, 8.00 g, 70% purity, 23.0 mmol) in acetonitrile (90 ml) was added a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.30 g, 34.5 mmol) and N,N-Diisopropylethylamine (8 ml, 46.1 mmol) dissolved in acetonitrile (30 ml) at 0 °C. After stirring at room temperature for 16 hours, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash column (petroleum ether: ethyl acetate = 5: 1 to 1: 1) to give tert-butyl 3-(2-chloro-7-cyclobutyl-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 49% yield).

[0688] LC-MS (Method C): Rt= 0.837 min; MS (ESIpos): m / z = 419.3 [M+H]+. Intermediate 1-05 tert-Butyl 3-(7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H- purin-6-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate To a solution of tert-butyl 3-(2-chloro-7-cyclobutyl-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Intermediate 1-04, 5.00 g, 11.3 mmol), [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methanol (2.35 g, 14.7 mmol) in tetrahydrofuran (120 ml) was added sodium hydride (907 mg, 22.7 mmol, 60% purity in mineral oil ) at 0 °C. After stirring at 40 °C for 6 hours, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (100-200 mesh, petroleum ether: ethyl acetate = 5: 1 then 0: 1, then ethyl acetate: methanol = 10: 1) to give tert-butyl 3-(7-cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.5 g, 66% yield). LC-MS (Method C): Rt= 0.81 min; MS (ESIpos): m / z = 542.3 [M+H]+. ’H NMR (400 MHz, DMSO-6): 5 [ppm] = 8.68 (s, 1H), 5.34 (s, 0.5H), 5.20 (s, 0.5H), 4.99-4.85 (m, 1H), 4.31-4.17 (m, 2H), 4.02-3.96 (m, 1H), 3.95-3.89 (m, 1H), 3.85-3.66 (m, 2H), 3.29-3.19 (m, 2H), 3.13-3.04 (m, 2H), 3.02-2.95 (m, 1H), 2.87-2.77 (m, 1H), 2.49-2.38 (m, 4H), 2.13-2.09 (m, 1H), 2.05- 2.01 (m, 1H), 1.99-1.94 (m, 1H), 1.89-1.67 (m, 9H), 1.48-1.42 (m, 9H). Intermediate 1-06

[0689] 7-Fluoro-8-[(triisopropylsilyl)ethynyl]naphthalene-l,3-diol

[0690] To a solution of 7-fluoronaphthalene-l,3-diol (25.0 g, 140 mmol) and (bromoethynyl)(triisopropyl)silane (38.5 g, 147 mmol) in dioxane (500 ml) were added dichloro(p-cymene)ruthenium(II)dimer (8.67 g, 14.0 mmol) and potassium acetate (27.5 g, 281 mmol) at room temperature. After stirring at 110 °C for 16 hours, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water and it was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 20: 1, then 10: 1, then 5: 1) to give 7-fhioro-8-[(triisopropylsilyl)ethynyl]naphthalene-l,3-diol (43 g, 82% yield).

[0691] LC-MS (Method C): Rt= 1.103 min; MS (ESIpos): m / z = 359.2 [M+H]+.

[0692] ’H NMR (400 MHz, CDCh- ): 5 [ppm] = 9.17 (s, 1H), 7.62-7.57 (m, 1H), 7.20-7.15 (m, 1H), 6.74 (d, J = 4.2 Hz, 1H), 6.66 (d, J= 3.6 Hz, 1H), 5.02 (br.s, 1H), 1.35-1.15 (m, 21H). Intermediate 1-07

[0693] 7-Fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]-l-naphthol

[0694] To a solution of 7-fluoro-8-[(triisopropylsilyl)ethynyl]naphthalene-l,3-diol (Intermediate 1-06, 43 g, 115 mmol) and N,N-diisopropylethylamine (29.8 g, 230 mmol) in dichloromethane (450 ml) was added dropwise a solution of bromo(methoxy)methane (16.5 g, 132 mmol) in dichloromethane (50 ml) at 0 °C. After stirring at the same temperature for 0.5 hour, the mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash column (petroleum ether : ethyl acetate = 20: 1 to 10: 1) to give 7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]- 1-naphthol (27 g, 57.7% yield).

[0695] LC-MS (Method C): Rt= 1.12 min; MS (ESIpos): m / z = 403.3 [M+H]+.

[0696] 1H NMR (400 MHz, CDCh- ): 5 [ppm] = 9.14 (s, 1H), 7.73-7.62 (m, 1H), 7.20 (t, J= 8.8 Hz, 1H), 6.99 (d, J= 2.0 Hz, 1H), 6.82 (d, J= 2.0 Hz, 1H), 5.27 (s, 2H), 3.52 (s, 3H), 1.29-1.16 (m, 21H).

[0697] Intermediate 1-08 tert-Butyl 3-(8-bromo-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0698] To a solution of tert-butyl 3-(7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-05, 2.00 g, 90% purity, 3.69 mmol) in tetrahydrofuran (30 ml) was added dropwise lithium bis(trimethylsilyl)amide (7.4 ml, 7.4 mmol, 1.0 M in tetrahydrofiiran) at -20 °C under nitrogen atmosphere. After stirring at -20 °C for 0.5 hours, carbon tetrabromide (2.45 g, 7.38 mmol) dissolved in tetrahydrofiiran (10 ml) was added dropwise to the above mixture at -70 °C. Afterwards, the reaction mixture was stirred at -70 °C for another 0.5 hour. Then, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in 139acuum. The residue was purified by chromatography column (100-200 mesh, petroleum ether: ethyl acetate= 5: 1 then 1: 1, then 0: 1) to give tert-butyl 3-(8-bromo-7-cyclobutyl-2-{[(2R,7aS)-2- fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (2 g).

[0699] LC-MS (Method C): Rt= 0.834 min; MS (ESIpos): m / z = 620 / 622 [M+H]+. ’HNMR (400 MHz, DMSO-6): 5 [ppm] = 5.37-5.29 (m, 0.5H), 5.24-5.16 (m, 0.5H), 5.15-5.01 (m, 1H), 4.27-4.17 (m, 2H), 4.01-3.95 (m, 1H), 3.95-3.76 (m, 3H), 3.30-3.18 (m, 2H), 3.14-3.05 (m, 2H), 3.02-2.97 (m, 1H), 2.88-2.71 (m, 3H), 2.49-2.40 (m, 2H), 2.13-2.06 (m, 1H), 2.04-2.00 (m, 1H), 1.99-1.94 (m, 1H), 1.89-1.67 (m, 9H), 1.46 - 1.41 (m, 9H).

[0700] Intermediate 1-09 tert-Butyl 3-[7-cyclobutyl-8-({7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]-l- naphthyl}oxy)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-

[0701] 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0702] To a solution of tert-butyl 3-(8-bromo-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy} -7H-purin-6-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (Intermediate 1-08, 1.2 g, 84% purity, 1.62 mmol) and 7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]-l-naphthol (Intermediate 1-07, 719 mg, 1.79 mmol) in N,N -Dimethylformamide (20 ml) was added potassium carbonate (449 mg, 3.25 mmol) at room temperature. After stirring at 100 °C for 3 hours, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by chromatography column (100-200 mesh, petroleum ether: ethyl acetate= 5: 1, then 1: 1, then 0: 1) to give tert-butyl 3-[7-cyclobutyl-8-({7-fhioro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]- l-naphthyl}oxy)-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (630 mg, 85% purity, 35% yield).

[0703] LC-MS (Method C): Rt= 1.109 min; MS (ESIpos): m / z = 942.2 [M+H]+.

[0704] Intermediate 1-10 tert-Butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-2-

[0705] {[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0706] To a solution of tert-butyl 3-[7-cyclobutyl-8-({7-fluoro-3-(methoxymethoxy)-8- [(triisopropylsilyl)ethynyl]-l-naphthyl}oxy)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7H-purin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermedaite 1-09, 630 mg, 85% purity, 0.568 mmol) in tetrahydrofuran (10 ml) was added tetramethylammonium fluoride (159 mg,

[0707] 1.70 mmol) at 25 °C. After stirring at 50 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]oxy}-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 93% purity).

[0708] LC-MS (Method C): Rt= 0.938 min; MS (ESIpos): m / z =786.4 [M+H]+.

[0709] Intermediate 1-11 tert-Butyl 3-[7-cyclobutyl-2-(methylsulfanyl)-7H-purin-6-yl]-3,8-diazabicyclo-[3.2.1]octane-8- carboxylate To a solution of tert-butyl 3-(2-chloro-7-cyclobutyl-7H-punn-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Intermediate 1-04, 4.00 g, 9.36 mmol) in dimethyl sulfoxide (250 ml) was added sodium thiomethoxide (1.31 g, 18.7 mmol) at 25 °C. After stirring at 60 °C for 3 hours, the reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 10: 1, 4: 1 then 1: 1 then 0: 1) to give tert-butyl 3-[7-cyclobutyl-2-(methylsulfanyl)-7H-purin-6- yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.70 g, 90% purity).

[0710] LC-MS (Method C): Rt= 0.795 min; MS (ESIpos): m / z = 431.4 [M+H]+.

[0711] Intermediate 1-12 tert-Butyl 3-[8-bromo-7-cyclobutyl-2-(methylsulfanyl)-7H-purin-6-yl]-3,8-diazabicyclo[3.2.1] octane-8-carboxylate

[0712] To a solution of tert-butyl 3-[7-cyclobutyl-2-(methylsulfanyl)-7H-purin-6-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-11, 2.50 g, 5.23 mmol) in tetrahydrofuran (40.0 ml) was added dropwise lithium bis(trimethylsilyl)amide (10.0 ml, 1.00 M in tetrahydrofuran, 10.0 mmol) at -30 °C under nitrogen atmosphere. After stirring at -30 °C for 0.5 hour, 1 -bromopyrrolidine-2, 5-dione (2.79 g, 15.7 mmol) in tetrahydrofiiran (20.0 ml) was added dropwise to the above mixture at -70 °C. After stirring at 0 °C for another 2 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by column chromatography on silica gel (100- 200 mesh, petroleum ether: ethyl acetate = 10: 1, 4: 1 then 1: 1, 0: 1) to give tert-butyl 3-[8-bromo-7- cyclobutyl-2-(methylsulfanyl)-7H-purin-6-yl]-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (3.30 g, 94% purity).

[0713] LC-MS (Method C): Rt= 0.973 min; MS (ESIpos): m / z = 509.1 [M+H]+. ’H NMR (400 MHz, DMSO-6): 5 [ppm] = 5.18-4.97 (m, 1H), 4.28-4.13 (m, 2H), 4.01-3.79 (m, 2H), 3.31-3.24 (m, 2H), 2.81-2.66 (m, 2H), 2.47 (s, 5H), 1.89-1.79 (m, 2H), 1.78-1.70 (m, 2H), 1.70-1.50 (m, 2H), 1.43 (s, 9H).

[0714] Intermediate 1-13 tert-Butyl 3-[7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl} naphthalen-l-yl]oxy}-2-(methylsulfanyl)-7H-purin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0715] To a solution of tert-butyl 3-[8-bromo-7-cyclobutyl-2-(methylsulfanyl)-7H-purin-6-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-12, 3.10 g, 5.72 mmol) and 7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-ol (Intermediate 1-07, 4.65 g, 11.4 mmol) in N,N-dimethylformamide (50.0 ml) was added potassium carbonate (1.58 g, 11.4 mmol) at 25 °C. After stirring at 100 °C for 2 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by column chromatography on silica gel (100- 200 mesh, petroleum ether: ethyl acetate = 10: 1, 6: 1 then 3: 1, 1: 1) to give tert-butyl 3-[7-cyclobutyl-8- {[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]oxy}-2- (methylsulfanyl)-7H-purin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.30 g, 99% purity, 69% yield).

[0716] LC-MS (Method C): Rt= 1.187 min; MS (ESIpos): m / z = 831.2 [M+H]+.

[0717] 'HNMR (400 MHz, DMSO-6): 5 [ppm] = 8.09 (dd, J= 9.2, 5.6 Hz, 1H), 7.64-7.56 (m, 2H), 7.30 (d, J = 2.0 Hz, 1H), 5.33 (s, 2H), 4.99 (s, 1H), 4.24 (br.s, 2H), 3.42 (s, 3H), 3.36-3.33 (m, 2H), 3.30 (s, 1H), 2.88- 2.75 (m, 1H), 2.54-2.52 (m, 2H), 2.47 (d, J = 2.4 Hz, 2H), 2.43 (s, 3H), 1.89 (br s, 2H), 1.83-1.72 (m, 3H), 1.44 (s, 9H), 1.27-1.20 (m, 1H), 0.93 (s, 21H). Intermediate 1-14 tert-Butyl 3-[7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl} naphthalen-l-yl]oxy}-2-(methanesulfonyl)-7H-purin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0718] To a solution of 3-[7-cyclobutyl-8-{[7-fhroro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-l-yl]oxy}-2-(methylsulfanyl)-7H-purin-6-yl]-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (Intermediate 1-13, 300 mg, 0.357 mmol) in dichloromethane (5.00 ml) was added meta-chloroperoxybenzoic acid (218 mg, 85% purity, 1.07 mmol) at 25 °C. After stirring at 25 °C for 2 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl 3-[7- cyclobutyl-8-{[7-fhioro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]oxy}-2- (methanesulfonyl)-7H-purin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 60% purity, 97% yield). LC-MS (Method C): Rt= 1.152 min; MS (ESIpos): m / z = 863.2 [M+H]+.

[0719] Intermediate 1-15 tert-Butyl 3-(7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl} naphthalen-l-yl]oxy}-2-[(tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0720]

[0721] To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fhroro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8 -diazabicyclo [3.2.1]octane-8-carboxylate (Intermediate 1-14, 230 mg, 0.160 mmol) and (tetrahydro -IH-pyrrolizin- 7a(5H)-yl)methanol (33.9 mg, 0.240 mmol) in tetrahydrofuran (5.00 ml) was added sodium hydride (19.2 mg, 60% in mineral oil, 0.480 mmol) at 0 °C under nitrogen atmosphere. After stirring at 40 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by preparative TLC (dichloromethane: methanol = 8: 1) to give tert-butyl 3-(7- cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]oxy}-2- [(tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (48.0 mg, 94% purity, 31% yield).

[0722] LC-MS (Method C): Rt= 1.000 min; MS (ESIpos): m / z = 924.3 [M+H]+.

[0723] Intermediate 1-16 tert-Butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-2- [(tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0724]

[0725] To a solution of tert-butyl 3-(7-cyclobutyl-8-{[7-fhioro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl]oxy } -2-[(tetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy] -7H-purin-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-15, 48.0 mg, 0.049 mmol) in tetrahydrofuran (2.00 ml) was added tetramethylammonium fluoride (13.6 mg, 0.146 mmol) at 25 °C. After stirring at 40 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- l-yl]oxy}-2-[(tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-6-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (80.0 mg, 90% purity).

[0726] LC-MS (Method C): Rt= 0.850 min; MS (ESIpos): m / z = 768.2 [M+H]+.

[0727] Intermediate 1-17 tert-Butyl 3-(7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl} naphthalen-l-yl]oxy}-2-{[(2S)-l-methylpyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0728] To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fhroro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8 -diazabicyclo [3.2.1]octane-8-carboxylate (Intermediate 1-14, 300 mg, 96% purity, 0.334 mmol) and [(2S)-1- methylpyrrolidin-2-yl]methanol (57.6 mg, 0.500 mmol) in tetrahydrofuran (3.0 ml) was added sodium hydride (26.7 mg, 0.667 mmol, 60% in mineral oil) at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by preparative TLC (dichloromethane: mehanol = 10: 1) to give tert- butyl 3-[7-cyclobutyl-8-({7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]-l-naphthyl}oxy)- 2-{[(2S)-l-methylpyrrolidin-2-yl]methoxy}-7H-purin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 95% purity, 57% yield).

[0729] LC-MS (Method C): Rt= 0.996 min; MS (ESIpos): m / z = 898.3 [M+H]+.

[0730] Intermediate 1-18 tert-Butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-2- {[(2S)-l-methylpyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate To a solution of tert-butyl 3-(7-cyclobutyl-8-{[7-fhioro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl]oxy } -2-{ [(2 S) - 1 -methylpyrrolidin-2-yl]methoxy } -7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-17, 160 mg, 95% purity, 0.169 mmol) in tetrahydrofuran (4.0 ml) was added tetramethylammonium fluoride (47.3 mg, 0.508 mmol) at 25 °C. After stirring at 40 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l- naphthyl]oxy}-2-{[(2S)-l-methylpyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 96% purity, 92% yield).

[0731] LC-MS (Method C): Rt= 0.844 min; MS (ESIpos): m / z = 744.2 [M+H]+.

[0732] Intermediate 1-19

[0733] [(2S,4S)-4-Fluoro-l-methylpyrrolidin-2-yl]methanol

[0734] To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-fluoropyrrolidine-l,2-dicarboxylate (1.00 g, 4.04 mmol) in tetrahydrofuran (20.0 ml) was added lithium aluminum hydride (6.50 ml, 2.50 M in tetrahydrofuran, 16.0 mmol) at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 16 hours, the reaction mixture was quenched by sal glauberi (10.0 g). After stirring at 25 °C for 2 hours, the mixture was filtered. The filtrate was concentrated to give [(2S,4S)-4-fluoro-l-methylpyrrolidin-2-yl]methanol (450 mg, 80% purity, 67% yield).

[0735] 1HNMR (400 MHz, DMSO-6): 5 [ppm] = 5.18-5.11 (m, 0.5H), 5.06-4.98 (m, 0.5H), 4.58-4.24 (m, 2H), 3.43-3.29 (m, 3H), 3.26-3.21 (m, 1H), 3.13-3.05 (m, 1H), 2.93-2.85 (m, 1H), 1.62-1.55 (m, 2H).

[0736] Intermediate 1-20 tert-Butyl 3-(7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-l-yl]oxy}-2-{[(2S,4S)-4-fluoro-l-methylpyrrolidin-2-yl]methoxy}-7H- purin-6-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0737] To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fhioro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-14, 300 mg, 0.334 mmol) and [(2S,4S)-4-fluoro- l-methylpyrrolidin-2-yl]methanol (Intermediate 1-19, 66.6 mg, 0.400 mmol) in tetrahydrofuran (5.00 ml) was added sodium hydride (26.7 mg, 60% in mineral oil, 0.667 mmol;) at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by column chromatography on silica gel (100- 200 mesh, petroleum ether: ethyl acetate = 10: 1, 1: 1, then 0: 1 then ethyl acetate: methanol = 10: 1) to give tert-butyl 3 -(7 -cyclobutyl-8- { [7 -fluoro-3 -(methoxymethoxy)-8- { [tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl]oxy } -2-{ [(2S,4S)-4-fluoro- 1 -methylpyrrolidin-2-yl]methoxy} -7H- purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 87% purity, 34% yield).

[0738] LC-MS (Method C): Rt= 0.990 min; MS (ESIpos): m / z = 916.2 [M+H]+. Intermediate 1-21 tert-Butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-2- {[(2S,4S)-4-fluoro-l-methylpyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate

[0739] To a solution of tert-butyl 3-(7-cyclobutyl-8-{[7-fhioro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl]oxy } -2-{ [(2S,4S)-4-fluoro- 1 -methylpyrrolidin-2-yl]methoxy} -7H- purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-20, 100 mg, 0.093 mmol) in tetrahydrofuran (5.00 ml) was added tetramethylammonium fluoride (25.9 mg, 0.278 mmol) at 25 °C. After stirring at 60 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by preparative TLC (ethyl acetate: methanol= 10: 1) to give tert-butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}- 2-{[(2S,4S)-4-fhioro-l-methylpyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (70.0 mg, 98% purity, 97% yield).

[0740] LC-MS (Method C): Rt= 0.835 min; MS (ESIpos): m / z = 760.2 [M+H]+.

[0741] Intermediate 1-22

[0742] [(2S,4R)-4-Fluoro-l-methylpyrrolidin-2-yl]methanol

[0743] To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-fluoropyrrolidine-l,2-dicarboxylate (1.00 g, 4.04 mmol) in tetrahydrofuran (20 ml) was added dropwise lithium aluminum hydride (6.5 ml, 16 mmol, 2.5 M in tetrahydrofuran) at 25 °C. After stirring at 50 °C for 16 hours, the reaction mixture was quenched by sal glauberi (10.0 g). After stirring at 25 °C for 2 hours, the mixture was filtered. The filtrate was concentrated to give [(2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl]methanol (300 mg, 95% purity, 53% yield).

[0744] ' H NMR (400 MHz, CDCW): 5 [ppm] = 5.21-5.15 (m, 0.5H), 5.07-5.02 (m, 0.5H), 3.74 (dd, J= 11.2 Hz, 3.2 Hz, 1H), 3.59-3.48 (m, 1H), 3.45 (dd, J = 11.2 Hz, 1.6 Hz, 1H), 2.83-2.75 (m, 1H), 2.72-2.58 (m, 1H), 2.52-2.42 (m, 1H), 2.40 (s, 3H), 2.19-2.01 (m, 2H).

[0745] Intermediate 1-23 tert-Butyl 3-(7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-l-yl]oxy}-2-{[(2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl]methoxy}-7H- purin-6-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0746] To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fhioro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8 -diazabicyclo [3.2.1] octane-8-carboxylate (Intermediate 1-14, 300 mg, 96% purity, 0.334 mmol) and [(2S,4R)-4-fluoro-l- methylpyrrolidin-2-yl]methanol (Intermediate 1-22, 70.2 mg, 95% purity, 0.500 mmol) in tetrahydrofuran (10 ml) was added sodium hydride (26.7 mg, 0.667 mmol, 60% in mineral oil) at 0 °C under nitrogen atmosphere. After stirring at room temperature for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by preparative TLC (ethyl acetate: methanol = 10: 1) to give tert-butyl 3-[7-cyclobutyl-8-({7-fhioro-3-(methoxymethoxy)-8-

[0747] [(triisopropylsilyl)ethynyl] - 1 -naphthyl}oxy)-2-{ [(2S,4R)-4-fluoro- 1 -methylpyrrolidin-2-yl]methoxy } - 7H-purin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 98% purity, 90% yield).

[0748] LC-MS (Method C): Rt= 1.093 min; MS (ESIpos): m / z = 916.6 [M+H]+.

[0749] Intermediate 1-24 tert-Butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-2-

[0750] {[(2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0751] To a solution of tert-butyl 3-(7-cyclobutyl-8-{[7-fhroro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl]oxy } -2-{ [(2S,4R)-4-fluoro- 1 -methylpyrrolidin-2-yl]methoxy} -7H- purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-23, 260 mg, 98% purity, 0.278 mmol) in tetrahydrofuran (6.0 ml) was added tetramethylammonium fluoride (77.7 mg, 0.834 mmol) at 25 °C. After stirring at 50 °C for 6 hours, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, fdtered and concentrated to give tert-butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l- naphthyl]oxy}-2-{[(2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (200 mg, 98% purity, 93% yield).

[0752] LC-MS (Method C): Rt= 0.930 min; MS (ESIpos): m / z = 760.4 [M+H]+.

[0753] Intermediate 1-25

[0754] (5S)-5-(hydroxymethyl)-l-methyl-pyrrolidin-2-one To a solution of methyl l-methyl-5-oxo-L-prolinate (300 mg, 1.91 mmol) in tetrahydrofuran (7.0 ml) was added dropwise lithium aluminum hydride (0.39 ml, 0.970 mmol, 2.5 M in tetrahydrofuran) at -65 °C under nitrogen atmosphere. After stirring at -65 °C for 1 hour. The reaction mixture was quenched by sodium sulfate decahydrate (3 g) and diluted with ethyl acetate. After stirring for 15 minutes, the mixture was fdtered. The fdtrate was concentrated and purified by preparative TLC (ethyl acetate: methanol = 10: 1) to give (5S)-5-(hydroxymethyl)-l-methylpyrrolidin-2-one (200 mg, 90% purity). ’H NMR (400 MHz, CDCh- ): 5 [ppm] = 3.76-3.83 (m, 1H), 3.56-3.47 (m, 2H), 3.09-2.91 (m, 1H), 2.80 (s, 3H), 2.46-2.33 (m, 1H), 2.29-2.19 (m, 1H), 2.09-2.01 (m, 1H), 1.94-1.86 (m, 1H).

[0755] Intermediate 1-26 tert-Butyl 3-(7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-l-yl]oxy}-2-{[(2S)-l-methyl-5-oxopyrrolidin-2-yl]methoxy}-7H-purin-

[0756] 6-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0757] To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8 -diazabicyclo [3.2.1] octane-8-carboxylate (Intermediate 1-14, 150 mg, 0.170 mmol) and (5 S)-5 -(hydroxymethyl)- 1- methylpyrrolidin-2-one (Intermediate 1-25, 33.7 mg, 261 mmol) in tetrahydrofuran (15 ml) was added sodium hydride (13.9 mg, 0.347 mmol, 60% purity in mineral oil) at 0 °C under nitrogen atmosphere. After stirring at room temperature for 16 hours, the reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give tert-butyl 3-[7-cyclobutyl-8- ( { 7 -fluoro-3 -(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl] - 1 -naphthyl } oxy)-2- { [(2 S ) - 1 -methyl-5 - oxopyrrolidin-2-yl]methoxy}-7H-purin-6-yl]-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (160 mg, 88% purity).

[0758] LC-MS (Method C): Rt = 0.777 min; MS (ESIpos): m / z = 912.6 [M+H]+.

[0759] Intermediate 1-27 tert-Butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-2- {[(2S)-l-methyl-5-oxopyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0760] A solution of tert-butyl 3-(7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl]oxy } -2-{ [(2 S) - 1 -methyl-5-oxopyrrolidin-2-yl]methoxy } -7H-purin-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-26, 200 mg, 219 mmol) and tetramethylammonium fluoride (286 mg, 3.07 mmol) in tetrahydrofuran (10 ml) was stirred at 60 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and fdtered. The fdtrate was concentrated to give tert-butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]oxy}-2-{[(2S)- l-methyl-5-oxopyrrolidin-2-yl]methoxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( 150 mg, 90% purity, 81 % yield) .

[0761] LC-MS (Method C): Rt = 0.627 min; MS (ESIpos): m / z = 756.4 [M+H]+.

[0762] Intermediate 1-28 tert-Butyl 3-(2-{[(2S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl]methoxy}-7-cyclobutyl-8-{[7-fluoro-

[0763] 3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]oxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0764]

[0765] To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fhroro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8 -diazabicyclo [3.2.1] octane-8-carboxylate (Intermediate 1-14, 100 mg, 95% purity, 0.110 mmol) and tert-butyl (2S)-2- (hydroxymethyl)pyrrolidine-l -carboxylate (33.2 mg, 0.165 mmol) in tetrahydrofuran (12 ml) was added sodium hydride (8.80 mg, 0.220 mmol, 60% in mineral oil) at 0 °C under nitrogen atmosphere. After stirring at room temperature for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl 3-[2-{[(2S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl]methoxy}-7- cyclobutyl-8-( { 7 -fluoro-3 -(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl] - 1 -naphthyl } oxy)-7H-purin-

[0766] 6-yl]-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (180 mg, 80% purity).

[0767] LC-MS (Method C): Rt= 0.828 min; MS (ESIpos): m / z = 984.9 [M+H]+.

[0768] Intermediate 1-29 tert-Butyl 3-(2-{[(2S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl]methoxy}-7-cyclobutyl-8-{[8-ethynyl- 7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-7H-purin-6-yl)-3,8-diazabicyclo [3.2.1] octane-

[0769] 8-carboxylate

[0770]

[0771] To a solution of tert-butyl 3-(2-{[(2S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl]methoxy}-7-cyclobutyl-8- {[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]oxy}-7H-purin-6-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-28, 160 mg, 80% purity, 0.130 mmol) in tetrahydrofuran (15.0 ml) was added tetramethylammonium fluoride (182 mg, 1.95 mmol) at room temperature. After stirring at 60 °C for 16 hours, the reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl 3-(2-{[(2S)-l-(tert-butoxycarbonyl)pyrrolidin-2- yl]methoxy}-7-cyclobutyl-8-{[8-ethynyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]oxy}-7H-purin-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 95% purity).

[0772] LC-MS (Method C): Rt= 1.123 min; MS (ESIpos): m / z = 828.5 [M+H]+.

[0773] Intermediate 1-30 tert-Butyl 3-(7-cyclobutyl-2-{[(2S)-4,4-difluoro-l-methylpyrrolidin-2-yl]methoxy}-8-{[7-fluoro-3-

[0774] (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl] oxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fhroro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8 -diazabicyclo [3.2.1] octane-8-carboxylate (Intermediate 1-14, 100 mg, 0.110 mmol) and [(2S)-4,4-difluoro-l- methylpyrrolidin-2-yl]methanol (25.0 mg, 0.165 mmol) in tetrahydrofuran (4.0 ml) was added sodium hydride (8.80 mg, 60% in mineral oil, 0.220 mmol) at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tertbutyl 3-(7-cyclobutyl-2-{[(2S)-4,4-difluoro-l-methylpyrrolidin-2-yl]methoxy}-8-{[7-fluoro-3-

[0775] (methoxymethoxy)-8-{ [tri (propan-2 -yl)silyl]ethynyl}naphthalen-l-yl]oxy}-7H-purin-6-yl)-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (190 mg, 88% purity).

[0776] LC-MS (Method C): Rt= 1.071 min; MS (ESIpos): m / z = 934.2 [M+H]+.

[0777] Intermediate 1-31 tert-Butyl 3-(7-cyclobutyl-2-{[(2S)-4,4-difluoro-l-methylpyrrolidin-2-yl]methoxy}-8-{[8-ethynyl-7- fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0778] To a solution of tert-butyl 3-(7-cyclobutyl-2-{[(2S)-4,4-difluoro-l-methylpyrrolidin-2-yl]methoxy}-8- {[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]oxy}-7H-purin-6-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-30, 140 mg, 0.132 mmol) in tetrahydrofuran (5.0 ml) was added tetramethylammonium fluoride (36.9 mg, 0.396 mmol) at 25 °C. After stirring at 60 °C for 6 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by preparative TLC (ethyl acetate: methanol = 20: 1) to give tert-butyl 3-(7-cyclobutyl-2-{[(2S)-4,4-difluoro-l-methylpyrrolidin-2-yl]methoxy}-8-{[8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-l-yl]oxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 87% purity).

[0779] LC-MS (Method C): Rt= 0.884 min; MS (ESIpos): m / z = 778.2 [M+H]+.

[0780] Intermediate 1-32

[0781] Ethyl— 3-cyano-l-methylpyrrolidine-3-carboxylate

[0782] To a solution of ethyl cyanoacetate (10.0 g, 88.4 mmol) and N-methylglycine (19.7 g, 221 mmol) in toluene (100 ml) was added formaldehyde (6.64 g, 221 mmol) at 25 °C. After stirring at 110 °C for 16 hours using dean-stark trap, the mixture was concentrated to remove toluene and diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by flash column (petroleum ether: ethyl acetate = 20: 1 to 1: 1) to give ethyl-3-cyano-l-methylpyrrolidine-3-carboxylate (7.80 g, 95% purity, 46% yield).

[0783] 'HNMR (400 MHz, CDCE- ): 5 [ppm] = 4.29 (q, J= 7.2 Hz, 2H), 3.14-3.08 (m, 1H), 3.07-3.01 (m, 1H), 2.85-2.77 (m, 1H), 2.72-2.64 (m, 1H), 2.64-2.55 (m, 1H), 2.49-2.42 (m, 1H), 2.40 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0784] Intermediate 1-33

[0785] 3-(Hydroxymethyl)-l-methylpyrrolidine-3-carbonitrile (racemic)

[0786] To a solution of ethyl ethyl-3-cyano-l-methylpyrrolidine-3-carboxylate (Intermediate 1-32, 2.00 g, 11.0 mmol) in methanol (50.0 ml) was added sodium tetrahydroborate (4.15 g, 110 mmol) in small protions over 30 minutes at 0 °C. After stirring at 25 °C for 3 hours, the mixture was poured into ice water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by preparative HPLC [Instrument: ACSWH-GX-J; Column: Waters xbridge 150 mm x 25 mm, 10 pm; eluent A: water (ammonium bicarbonate v / v: 0.5%), eluent B: acetonitrile; gradient: 0-10 min 1-20% B; flow 25 ml / min; temperature: room temperature; Detector: UV 220 / 254 nm] to give 3 -(hydroxymethyl)- l-methylpyrrolidine-3- carbonitrile (200 mg, 95% purity).

[0787] 'HNMR (400 MHz, CDCW): 8 [ppm] = 3.81-3.76 (m, 1H), 3.72-3.66 (m, 1H), 2.97 (d, J = 9.8 Hz, 1H), 2.84 (m, 1H), 2.73 (d, J= 9.6 Hz, 1H), 2.51 (q, J= 8.4 Hz, 1H), 2.37 (s, 3H), 2.31-2.23(m,lH), 2.13-2.07 (m, 1H).

[0788] Intermediate 1-34 tert-Butyl 3-(2-{[3-cyano-l-methylpyrrolidin-3-yl]methoxy}-7-cyclobutyl-8-{[7-fluoro-3-

[0789] (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl] oxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (racemic)

[0790] To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8 -diazabicyclo [3.2.1] octane-8-carboxylate (Intermediate 1-14, 180 mg, 0.198 mmol) and 3 -(hydroxymethyl)- 1- methylpyrrolidine -3 -carbonitrile (Intermediate 1-33, 33.3 mg, 0.238 mmol) in tetrahydrofuran (20.0 ml) was added sodium hydride (15.8 mg, 60% in mineral oil, 0.396 mmol) at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 4 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl 3-(2-{[3-cyano-l-methylpyrrolidin-3-yl]methoxy}-7-cyclobutyl-8-{[7- fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]oxy}-7H-purin-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 92% purity).

[0791] LC-MS (Method C): Rt= 1.033 min; MS (ESIpos): m / z = 923.2 [M+H]+. Intermediate 1-35 tert-Butyl 3-(2-{[3-cyano-l-methylpyrrolidin-3-yl]methoxy}-7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-

[0792] (methoxymethoxy)naphthalen-l-yl]oxy}-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (racemic)

[0793] To a solution of tert-butyl 3-(2-{[3-cyano-l-methylpyrrolidin-3-yl]methoxy}-7-cyclobutyl-8-{[7-fluoro- 3 -(methoxymethoxy)-8-{ [tri (propan-2 -yl)silyl]ethynyl}naphthalen-l-yl]oxy}-7H-purin-6-yl)-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-34, 230 mg, 0.229 mmol) in tetrahydrofuran (10.0 ml) was added tetramethylammonium fluoride (64.0 mg, 0.688 mmol) at 25 °C. After stirring at 60 °C for 4 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 10: 1, then 4: 1 then 1: 1, then 0: 1, then ethyl acetate: methanol = 10: 1) to give tertbutyl 3-(2-{[3-cyano-l-methylpyrrolidin-3-yl]methoxy}-7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-

[0794] (methoxymethoxy )naphthalen-l-yl]oxy}-7H-purin-6-yl)-3, 8 -diazabicyclo [3.2. l]octane-8-carboxylate (150 mg, 97% purity, 83% yield).

[0795] LC-MS (Method C): Rt= 0.860 min; MS (ESIpos): m / z = 767.2 [M+H]+.

[0796] Intermediate 1-36 tert-Butyl 3-(7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl} naphthalen-l-yl]oxy}-2-[2-(l-methyl-lH-imidazol-2-yl)ethoxy]-7H-purin-6-yl)-3,8-diazabicyclo

[0797] [3.2.1] octane-8-carboxylate

[0798] To a solution of tert-butyl 3-[7-cyclobutyl-8-{[7-fhroro-3-(methoxymethoxy)-8-{[tri(propan-2- y 1 ) silyl ] ethynyl } naphthalen- 1 -yl] oxy } -2-(methane sulfonyl) -7H-purin-6-yl] -3,8 -diazabicyclo [3.2.1]octane-8-carboxylate (Intermediate 1-14, 180 mg, 0.198 mmol) and 2-(l -methyl- lH-imidazol-2- yl)ethan-l-ol (30.0 mg, 0.238 mmol) in tetrahydrofuran (20.0 ml) was added sodium hydride (15.8 mg,

[0799] 60% in mineral oil, 0.396 mmol) at 0 °C under nitrogen atmosphere. After stirring at 40 °C for 4 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl 3-(7- cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]oxy}-2- [2-(l-methyl-lH-imidazol-2-yl)ethoxy]-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 91% purity).

[0800] LC-MS (Method C): Rt= 1.023 min; MS (ESIpos): m / z = 909.2 [M+H]+.

[0801] Intermediate 1-37 tert-Butyl 3-(7-cyclobutyl-8-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl]oxy}-2-[2- (l-methyl-lH-imidazol-2-yl)ethoxy]-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0802]

[0803] To a solution of tert-butyl 3-(7-cyclobutyl-8-{[7-fhioro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl]oxy} -2-[2-( 1 -methyl- lH-imidazol-2-yl)ethoxy] -7H-purin-6-yl)-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 1-36, 230 mg, 0.230 mmol) in tetrahydrofuran (10.0 ml) was added tetramethylammonium fluoride (64.3 mg, 0.691 mmol) at 25 °C. After stirring at 60

[0804] °C for 4 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 10: 1, then 4: 1, then 1: 1, then 0: 1, then ethyl acetate: methanol = 10: 1) to tert- butyl 3-(7-cyclobutyl-8- { [8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1 -yl]oxy } -2-[2-( 1 -methyl - lH-imidazol-2-yl)ethoxy]-7H-purin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 98% purity, 85% yield).

[0805] LC-MS (Method C): Rt= 0.862 min; MS (ESIpos): m / z = 753.2 [M+H]+.

[0806] Intermediate 2-01 tert-Butyl (3R,4S)-3,4-dihydroxypyrrolidine-l-carboxylate To a solution of tert-butyl 2,5 -dihydro- IH-pyrrole-l -carboxylate (100 g, 591 mmol) in a mixture solution of acetone (600 ml) and water (50 ml) were added 4-methylmorpholinen-oxide (83.1 g, 709 mmol) and dipotassium tetraoxidoosmate(2-) (982 mg, 2.95 mmol) at room temperature. After stirring at the same temperature for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by flash column (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give tert-butyl (3R,4S)-3,4-dihydroxypyrrolidine-l-carboxylate (100 g, 95% purity, 79% yield).

[0807] ’HNMR (400 MHz, CDCh- ): 5 [ppm] = 4.27-4.19 (m, 2H), 3.63-3.51 (m, 2H), 3.30-3.28 (m, 2H), 3.24- 3.15 (m, 1H), 3.07-2.96 (m, 1H), 1.45 (s, 9H).

[0808] Intermediate 2-02 tert-Butyl [(2R)-2-hydroxybut-3-en-l-yl] [(2S)-2-hydroxybut-3-en-l-yl] carbamate

[0809] To a solution of tert-butyl (3R,4S)-3,4-dihydroxypyrrolidine-l-carboxylate (Intermediate 2-01, 25.0 g, 123 mmol) in dichloromethane (800 ml) was added lodosobenzene diacetate (59.4 g, 185 mmol) at 0 °C. After stirring at the same temperature for 1 hour, vinylmagnesium bromide (740 ml, 1.0 M, 740 mmol) was added dropwise to the above mixture at -70 °C. The mixture was stirred at room temperature for another 16 hours. Four parallel reactions with same scale were combined. The combined mixture was diluted with ice-water, extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by flash column (petroleum ether: ethyl acetate = 20: 1 to 3: 1) to give tert-butyl [(2R)-2- hydroxybut-3-en-l-yl][(2S)-2-hydroxybut-3-en-l-yl]carbamate (50.0 g, 90% purity).

[0810] 1HNMR (400 MHz, CDCh- ): 5 [ppm] = 5.94-5.77 (m, 2H), 5.42-5.26 (m, 2H), 5.21-5.13 (m, 2H), 4.55- 4.30 (m, 2H), 3.82-3.46 (m, 2H), 3.45-3.31 (m, 3H), 3.27-3.15 (m, 1H), 1.47 (s, 9H).

[0811] Intermediate 2-03

[0812] (2R)-l-[(tert-Butoxycarbonyl){(2S)-2-[(2,2,2-trichloroethanimidoyl)oxy]but-3-en-l-yl}amino]but-

[0813] 3-en-2-yl 2,2,2-trichloroethanimidate To a solution of tert-butyl [(2R)-2-hydroxybut-3-en-l-yl][(2S)-2-hydroxybut-3-en-l-yl]carbamate (Intermediate 2-02, 55.0 g, 95% purity, 203 mmol) in dichloromethane (1.2 L) were added trichloroacetonitrile (120 ml, 1.2 mol) and l,8-diazabicyclo(5.4.0)undec-7-ene (45 ml, 300 mmol) at 0 °C. After stirring at room temperature for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by flash column (petroleum ether: ethyl acetate = 20: 1 to 5: 1) to give (2R)-l-[(tert-butoxycarbonyl){(2S)-2-[(2,2,2-trichloroethanimidoyl)- oxy]but-3-en-l-yl}amino]but-3-en-2-yl 2,2,2-trichloroethanimidate (100 g, 80% purity, 72% yield).

[0814] ’H NMR (400 MHz, CDCl3-d): 5 [ppm] = 8.38 (s, 2H), 5.93-5.75 (m, 2H), 5.72-5.56 (m, 2H), 5.47-5.36 (m, 2H), 5.32-5.27 (m, 2H), 3.87-3.75 (m, 1H), 3.74-3.56 (m, 2H), 3.53-3.37 (m, 1H), 1.48 (s, 9H).

[0815] Intermediate 2-04 tert-Butyl (3R,5S)-3,5-diethenyl-4-(2-phenylpropan-2-yl)piperazine-l-carboxylate

[0816] To a solution of 2-phenylpropan-2-amine (26.7 g, 198 mmol) and Chloro-(l,5-cyclooctadien)-iridium(I) Dimer (5.53 g, 8.24 mmol) in 1,2 -dichloroethane (800 ml) was added dropwise a solution of (2R)-1 -[(tertbutoxycarbonyl) {(2S)-2-[(2, 2, 2-trichloroethanimidoyl)oxy]but-3-en-l-yl}amino]but-3-en-2-yl-2, 2, 2- trichloroethanimidate (Intermediate 2-03, 100 g, 90% purity, 165 mmol) dissolved in 1,2 -dichloroethane (400 ml) at 0 °C. After stirring at room temperature for 16 hours, the mixture was purified by flash column (petroleum ether: ethyl acetate= 1: 0 to 10: 1) to give tert-butyl (3R,5S)-4-(2-phenylpropan-2-yl)-3,5- divinylpiperazine-1 -carboxylate (35.0 g, 80% purity, 48% yield).

[0817] ’HNMR (400 MHz, CDCl3-d): 5 [ppm] = 7.49-7.42 (m, 2H), 7.26-7.17 (m, 2H), 7.15-7.11 (m, 1H), 5.97- 5.83 (m, 2H), 5.10-4.95 (m, 2H), 4.94-4.86 (m, 2H), 3.58-3.39 (m, 4H), 3.31-3.17 (m, 2H), 1.39 (s, 6H), 1.37 (s, 9H).

[0818] Intermediate 2-05 tert-butyl 8-(l-methyl-l-phenyl-ethyl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate

[0819] A solution of tert-butyl (3R,5S)-3,5-diethenyl-4-(2-phenylpropan-2-yl)piperazine-l-carboxylate (Intermediate 2-04, 35.0 g, 80% purity, 78.5 mmol) and (l,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (3.33 g, 3.93 mmol) in toluene (800 ml) was refluxed for 20 hours. The mixture was purified by flash column (petroleum ether: ethyl acetate = 1: 0 to 10: 1) to give tert-butyl 8-(l-methyl-l-phenyl-ethyl)-3,8-diazabicyclo[3.2.1]oct-6- ene -3 -carboxylate (14.0 g, 95% purity, 51% yield).

[0820] ’H NMR (400 MHz, CDCh- ): 5 [ppm] = 7.62-7.56 (m, 2H), 7.32 (t, J= 7.6 Hz, 2H), 7.22 (t, J= 7.4 Hz, 1H), 6.02-5.94 (m, 2H), 3.67-3.58 (m, 2H), 3.55-3.46 (m, 2H), 3.16-3.05 (m, 2H), 1.42 (s, 9H), 1.26 (d, J = 6.0 Hz, 6H).

[0821] Intermediate 2-06

[0822] 8-(l-Methyl-l-phenyl-ethyl)-3,8-diazabicyclo[3.2.1]oct-6-ene:hydrochloride (1:1)

[0823] A solution of tert-butyl (lR,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (Intermediate 2-05, 5.00 g, 95% purity, 14.5 mmol) and hydrochloric acid (24 ml, 95 mmol, 4 M in ethyl acetate ) in ethyl acetate (19 ml) was stirred at room temperature for 16 hours. The mixture was concentrated to give 8-(l-methyl-l-phenyl-ethyl)-3,8-diazabicyclo[3.2.1]oct-6-ene:hydrochloride (1:1) (11.0 g, crude).

[0824] LC-MS (Method C): Rt= 0.746 min; MS (ESIpos): m / z =229.2 [M+H]+. Intermediate 2-07

[0825] Benzyl 8-(l-methyl-l-phenyl-ethyl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate

[0826] A solution of 8-(l-methyl-l-phenyl-ethyl)-3,8-diazabicyclo[3.2.1]oct-6-ene:hydrochloride (1: 1) (Intermediate 2-06, 11.0 g, 88% purity, 36.6 mmol), sodium hydrogen carbonate (12.3 g, 146 mmol) and N-(benzyloxycarbonyloxy)succinimide (18.2 g, 73.1 mmol) in a mixed solvent of tetrahydrofuran (130 ml) and water (90 ml) was stirred at room temperature for 3 hours. The mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give benzyl 8-(l-methyl-l-phenyl-ethyl)-3,8- diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (10.0 g, 75% yield).

[0827] LC-MS (Method C): Rt= 0.797 min; MS (ESIpos): m / z =363.2 [M+H]+.

[0828] 1HNMR (400 MHz, CDCh- ): 5 [ppm] = 7.53-7.47 (m, 2H), 7.31-7.21 (m, 7H), 7.19-7.12 (m, 1H), 5.96- 5.86 (m, 2H), 5.02 (q, J = 12.4 Hz, 2H), 3.64-3.57 (m, 2H), 3.56-3.46 (m, 2H), 3.17-3.06 (m, 2H), 1.18 (d, J= 6.8 Hz, 6H).

[0829] Intermediate 2-08

[0830] Benzyl 3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate

[0831] A solution of benzyl 8-(l-methyl-l-phenyl-ethyl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (Intermediate 2-07, 10.0 g, 27.3 mmol) in acetic acid (100 ml) was stirred at 120 °C for 8 hours. The reaction mixture was concentrated to give benzyl 3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (6.80 g, 90% purity, 92% yield), which used for the next step without purification. LC-MS (Method C): Rt= 0.333 min; MS (ESIpos): m / z =245.1 [M+H]+.

[0832] Intermediate 2-09

[0833] O3-Benzyl 08-tert-butyl 3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-dicarboxylate

[0834] To a solution of benzyl 3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (Intermediate 2-08, 6.80 g, 90% purity, 25.1 mmol) and triethylamine (10 ml, 75 mmol) in tetrahydrofuran (120 ml) was added di -tert- butyl dicarbonate (6.9 ml, 30 mmol) in one portion at room temperature. After stirring at room temperature for 3 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 10: 1 then 5: 1, then 1: 1) to give O3-benzyl 08-tert-butyl 3,8-diazabicyclo[3.2.1]oct-6-ene-3,8- dicarboxylate (8.00 g, 88% yield).

[0835] LC-MS (Method C): Rt= 0.943 min; MS (ESIpos): m / z = 367.0 [M+Na]+.

[0836] Intermediate 2-10

[0837] 3-Benzyl 8-tert-butyl (1R,5R,6R and lS,5S,6S)-6-hydroxy-3,8-diazabicyclo [3.2.1] octane-3, 8- dicarboxylate

[0838] To a solution of O3-benzyl 08-tert-butyl 3, 8 -diazabicyclo [3.2. l]oct-6-ene-3,8-dicarboxylate (Intermediate 2-09, 7.50 g, 21.6 mmol) in tetrahydrofuran (150 ml) was added borane tetrahydrofuran complex (32 ml, 32 mmol, 1.0 M in tetrahydrofuran) in one portion at 0 °C. After stirring for 1 hour, a solution of sodium hydroxide (22 ml, 43 mmol, 2 M in water) was added at 0 °C. Hydrogen peroxide (4.4 ml, 30% purity, 43 mmol) was added dropwise to the above mixture at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by sodium thiosulfate (5.0 g) and adjusted to pH = 7-8 by 1 M hydrochloric acid at room temperature. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash column (petroleum ether: ethyl acetate = 20: 1 to 0: 1) to give 3-benzyl 8-tert-butyl (1R,5R,6R and IS, 5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2. l]octane-3, 8-dicarboxylate (4.40 g, 99% purity, 56% yield). LC-MS (Method C): Rt= 0.869 min; MS (ESIpos): m / z =385.1 [M+Na]+.

[0839] ’H NMR (400 MHz, CDCh- ): 5 [ppm] = 7.39-7.31 (m, 5H), 5.13 (s, 2H), 4.47-4.26 (m, 2H), 4.07-3.87 (m, 2H), 3.81-3.65 (m, 1H), 3.17-2.97 (m, 2H), 2.23-2.07 (m, 1H), 1.86-1.75 (m, 1H), 1.48 (s, 9H).

[0840] Intermediate 2-11

[0841] 3-Benzyl 8-tert-butyl rac-6-oxo-3,8-diazabicyclo [3.2.1] octane-3, 8-dicarboxylate

[0842] To a solution of 3-benzyl 8-tert-butyl (1R,5R,6R and lS,5S,6S)-6-hydroxy-3,8- diazabicyclo[3.2. l]octane-3, 8-dicarboxylate (Intermediate 2-10, 1.00 g, 99% purity, 2.73 mmol) in dichloromethane (15 ml) was added l,l,l-triacetoxy-llambda5,2-benziodoxol-3(lH)-one (2.55 g, 6.01 mmol) in one portion at 0 °C. After stirring at room temperature for 16 hours, the reaction mixture was concentrated and purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 1: 0, then 20: 1) to give 3-benzyl 8-tert-butyl rac-6-oxo-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (1.00 g, 90% purity, 91% yield).

[0843] LC-MS (Method C): Rt= 0.882 min; MS (ESIpos): m / z =361.3 [M+H]+.

[0844] Intermediate 2-12

[0845] 3-Benzyl 8-tert-butyl (1R,5R,6S and lS,5S,6R)-6-hydroxy-3,8-diazabicyclo [3.2.1] -octane-3, 8- dicarboxylate

[0846] To a solution of 3-benzyl 8-tert-butyl rac-6-oxo-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (Intermediate 2-11, 1.00 g, 90% purity, 2.50 mmol) in ethanol (25 ml) was added sodium tetrahydroborate (283 mg, 7.49 mmol) in one portion at -40 °C. After stirring at -40 °C for 1 hour, the reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 1: 0, then 10: 1, 5: 1) to give 3-benzyl 8-tert-butyl (1R,5R,6S and lS,5S,6R)-6-hydroxy-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (900 mg, 99% purity, 98% yield).

[0847] LC-MS (Method C): Rt= 0.842 min; MS (ESIpos): m / z =363.2 [M+H]+.

[0848] Intermediate 2-13

[0849] 3-Benzyl 8-tert-butyl (1S,5S,6R or lR,5R,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]-octane-3,8- dicarboxylate (#2, peak 2)

[0850] 3-Benzyl 8-tert-butyl (1R,5R,6S and lS,5S,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (Intermediate 2-12, 1.10 g, 99 % purity, 3.00 mmol) was separated by preparative-SFC (Instrument: Acswh-prep-SFC-D; Column: Daicel chiralpak AD-H 250mm*30mm*5 pm; eluent A: carbon dioxide, eluent B: i-PrOH (0.1% NHs’FEO), gradient: 4.7 min 25-25% (25% CO2) B; flow 100 ml / min; temperature: room temperature; Detector: UV 220 / 254 nm) to give 3-benzyl 8-tert-butyl (1R,5R,6S or lS,5S,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (#1, peak 1. 540 mg, 90% purity, 45% yield) and 3-benzyl 8-tert-butyl (1S,5S,6R or lR,5R,6S)-6-hydroxy-3,8- diazabicyclo[3.2. l]octane-3,8-dicarboxylate (#2, peak 2. 620 mg, 90% purity, 21% yield).

[0851] Intermediate 2-14

[0852] 3-Benzyl 8-tert-butyl (1S,5S,6R or lR,5R,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate

[0853] To a solution of 3-benzyl 8-tert-butyl (1S,5S,6R or lR,5R,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (Intermediate 2-13, #2, peak 2, 620 mg, 90% purity, 1.54 mmol) in tetrahydrofuran (10 ml) was added sodium hydride (135 mg, 3.39 mmol, 60% purity in mineral oil) in one portion at 0 °C. After stirring for 0.5 hour, lodomethane (0.190 ml, 3.1 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and fdtered. The filtrate was concentrated and purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate 1: 0, then 10: 1, then 5: 1) to give 3-benzyl 8-tert-butyl (1S,5S,6R or lR,5R,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (550 mg, 92% purity, 87% yield).

[0854] LC-MS (Method C): Rt= 0.830 min; MS (ESIpos): m / z =277.4 [M+H-100]+.

[0855] 1HNMR (400 MHz, DMSO-6): 5 [ppm] = 7.40-7.28 (m, 5H), 5.21-5.0 (m, 2H), 4.16-3.91 (m, 3H), 3.89- 3.65 (m, 2H), 3.23 (s, 3H), 3.11-2.87 (m, 2H), 2.40-2.27 (m, 1H), 1.41 (s, 9H), 1.35-1.26 (m, 1H).

[0856] Intermediate 2-15 tert-Butyl (1S,5S,6R or lR,5R,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0857] To a solution of 3-benzyl 8-tert-butyl (lS,5S,6R or lR,5R,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (Intermediate 2-14, 550 mg, 92% purity, 1.34 mmol) in methanol (10 ml) was added palladium (143 mg, 10% in activated carbon) in one portion. After stirring at room temperature for 3 hours under hydrogen atmosphere (balloon, 15 psi), the mixture was filtered through a pad of celite and the filtrate was concentrated to give tert-butyl (1S,5S,6R or lR,5R,6S)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (320 mg, 95% purity, 93% yield).

[0858] ’H NMR (400 MHz, DMSO-6): 5 [ppm] = 3.98-3.89 (m, 1H), 3.88-3.77 (m, 2H), 3.30 (s, 3H), 2.85-2.77 (m, 2H), 2.71-2.62 (m, 1H), 2.57-2.51 (m, 1H), 2.37-2.23 (m, 1H), 1.71-1.62 (m, 1H), 1.41 (s, 9H).

[0859] Intermediate 2-16 tert-Butyl 4-{4-[(2-chloro-9H-purin-6-yl)oxy]phenyl}piperazine-l-carboxylate (Tautomeric mixture 7H / 9H)

[0860] To a solution of tert-butyl 4-(4-hydroxyphenyl)piperazine-l -carboxylate (100 g, 359 mmol) in tert-butanol (1.5 L) were added 2,6-dichloro-9H-purine (61.7 g, 327 mmol) and potassium tert-butoxide (80.3 g, 719 mmol) at room temperature. After stirring at 80 °C for 16 hours, the mixture was concentrated to remove tert-butanol to give a residue. The residue was diluted with ice-water, neutralized to pH = 7 - 8 by 1 M hydrochloric acid, and extracted with ethyl acetate. The combined organic phase were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was tritutated with a mixture solvent of petroleum ether and ethyl acetate (1 : 1, 1.2 L) to give tert-butyl 4- {4-[(2-chloro-9H-purin-6-yl)oxy]phenyl}piperazine-l-carboxylate (130 g, 99% purity, 91% yield).

[0861] LC-MS (Method C): Rt= 0.817 min; MS (ESIpos): m / z = 431.3 [M+H]+. ’H NMR (400 MHz, DMSO-6): 5 [ppm] = 8.52 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 3.51-3.44 (m, 4H), 3.16-3.08 (m, 4H), 1.42 (s, 9H).

[0862] Intermediate 2-17 tert-Butyl 4-{4-[(2-chloro-7-cyclobutyl-7H-purin-6-yl)oxy]phenyl}piperazine-l-carboxylate

[0863] To a solution of tert-butyl 4-{4-[(2-chloro-7H-purin-6-yl)oxy]phenyl}piperazine-l-carboxylate (Intermediate 2-16, 50.0 g, 99% purity, 115 mmol) in N,N -dimethylacetamide (1.00 L) were added potassium carbonate (31.8 g, 230 mmol), potassium iodide (5.72 g, 34.5 mmol) and bromocyclobutane (62.0 g, 460 mmol) at 25 °C. After stirring at 100°C for 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography on silica gel (three purification, 100-200 mesh, petroleum ether: ethyl acetate: dichloromethane = 10: 1: 2, then 5: 1: 2, then 1: 1: 1, then 0: 1: 1 ) to give a crude product. The crude product was triturated with a mixed solvent of petroleum ether and ethyl acetate (1 : 5, 50 ml) to give tertbutyl 4-{4-[(2-chloro-7-cyclobutyl-7H-purin-6-yl)oxy]phenyl}piperazine-l-carboxylate (15.2 g, 99% purity, 27% yield).

[0864] LC-MS (Method C): Rt= 0.967 min; MS (ESIpos): m / z = 485.2 [M+H]+.

[0865] 'HNMR (400 MHz, DMSO-6): 5 [ppm] = 8.83 (s, 1H), 7.22 (d, J= 9.2 Hz, 2H), 7.05 (d, J= 9.2 Hz, 2H), 5.24-5.11 (m, 1H), 3.54-3.43 (m, 4H), 3.19-3.07 (m, 4H), 2.70-2.57 (m, 2H), 2.57-2.51 (m, 2H), 1.94-1.76 (m, 2H), 1.43 (s, 9H).

[0866] Intermediate 2-18 tert-Butyl 4-{4-[(7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-

[0867] 7H-purin-6-yl)oxy]phenyl}piperazine-l-carboxylate

[0868] To a solution of tert-butyl 4-{4-[(2-chloro-7-cyclobutyl-7H-purin-6-yl)oxy]phenyl}piperazine-l- carboxylate (Intermediate 2-17, 11.2 g, 99% purity, 22.9 mmol) and [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methanol (7.28 g, 45.7 mmol) in toluene (200 ml) were added cesium carbonate (22.4 g, 68.6 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-l,T-biphenyl)(2'- amino-l,T-biphenyl-2-yl)palladium(II) (957 mg, 1.14 mmol) at 25 °C under nitrogen atmosphere. After stirring at 110 °C for 20 hours, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 20: 1, then 10: 1, then 5: 1, then 2: 1, then 1: 1, then 0: 1, then ethyl acetate: methanol= 10: 1) to give tert-butyl 4-{4-[(7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)oxy]phenyl}piperazine-l-carboxylate (fraction 1: 7.30 g, 95% purity) and (fraction 2: 3.70 g, 82% purity).

[0869] LC-MS (Method C): Rt= 0.761 min; MS (ESIpos): m / z = 608.4 [M+H]+.

[0870] ’HNMR (400 MHz, DMSO-6): 5 [ppm] = 8.58 (s, 1H), 7.18 (d, J= 8.8 Hz, 2H), 7.03 (d, J= 9.2 Hz, 2H), 5.29-5.24 (m, 0.5H), 5.16-5.06 (m, 1.5H), 3.98-3.83 (m, 2H), 3.55-3.40 (m, 4H), 3.16-3.09 (m, 4H), 3.05-3.00 (m, 2H), 2.97-2.90 (m, 1H), 2.81-2.74 (m, 1H), 2.90-2.45 (m, 2H), 2.06-2.00 (m, 1H), 1.95 (s, 1H), 1.92-1.61 (m, 8H), 1.43 (s, 9H).

[0871] Intermediate 2-19

[0872] 7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-methoxy-7H- purine

[0873] To a solution of tert-butyl 4-{4-[(7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7H-purin-6-yl)oxy]phenyl}piperazine-l-carboxylate (Intermediate 2-18, 11.0 g, 95%purity, 17.2 mmol) in methanol (100.0 ml) was added sodium methoxide (1.86 g, 34.4 mmol) at 25 °C. After stirring at 60 °C for 4 hours, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 10: 1, then 1: 1, then 0: 1, then methanol: ethyl acetate = 20: 1, then 10: 1) to give 7 -cyclobutyl - 2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-methoxy-7H-purine (5.60 g, 97% purity, 87.4% yield).

[0874] LC-MS (Method C): Rt= 0.451 min; MS (ESIpos): m / z = 362.2 [M+H]+.

[0875] Intermediate 2-20

[0876] 8-Bromo-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- methoxy- 7H-purine

[0877] To a solution of 7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- methoxy-7H-purine (Intermediate 2-19, 5.60 g, 97% purity, 15.0 mmol) in tetrahydrofuran (60 ml) was added dropwise lithium bis(trimethylsilyl)amide (37.6 ml, 1.0 M in tetrahydrofuran, 37.6 mmol) at -30 °C under nitrogen atmosphere. After stirring at -30 °C for 1 hour, 1 -bromopyrrolidine-2, 5-dione (6.69 g, 37.6 mmol) dissolved in tetrahydrofuran (60 ml) was added dropwise to the above mixture at -70 °C, the reaction mixture was stirred at -70 °C for another 0.5 hour. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 20: 1 to 0: 1, then ethyl acetate: methanol= 10: 1) to give 8-bromo-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-6-methoxy-7H-purine (5.50 g, 76% purity, 63.1% yield).

[0878] LC-MS (Method C): Rt= 0.789 min; MS (ESIpos): m / z = 440.0 [M+H]+.

[0879] Intermediate 2-21

[0880] 7-Cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l- yl]oxy}-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-methoxy-7H-purine

[0881] To a solution of 8-bromo-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-6-methoxy-7H-purine (Intermediate 2-20, 5.50 g, 76% purity, 9.49 mmol) and 7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-ol (Intermediate 1-07, 7.64 g, 19.0 mmol) in N,N-dimethylformamide (60.0 ml) was added potassium carbonate (3.94 g, 28.5 mmol) at room temperature. After stirring at 100 °C for 2 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate= 20: 1, then 10: 1, then 5: 1, then 3: 1, then 2: 1, then 1: 1, then 0: 1, then ethyl acetate: methanol= 10: 1) to give 7-cyclobutyl-8-({7-fluoro-3- (methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]-l-naphthyl}oxy)-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-6-methoxy-7H-purine (4.20 g, 85% purity, 49% yield).

[0882] LC-MS (Method C): Rt= 1.105 min; MS (ESIpos): m / z = 762.4 [M+H]+.

[0883] 'HNMR (400 MHz, DMSO-6): 5 [ppm] = 8.13-8.02 (m, 1H), 7.64-7.54 (m, 2H), 7.26 (d, J= 2.0 Hz, 1H), 5.36-5.28 (m, 2.5H), 5.19-5.07 (m, 1.5H), 4.12-4.06 (m, 3H), 4.00-3.87 (m, 2H), 3.41 (s, 3H), 3.10- 3.00 (m, 2H), 2.99-2.94 (m, 1H), 2.85-2.75 (m, 3H), 2.11-1.96 (m, 3H), 1.96-1.67 (m, 7H), 0.88 (s, 21H). Intermediate 2-22

[0884] 4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-methoxy-

[0885] 7H-purin-8-yl)oxy]-6-fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol A solution of 7-cyclobutyl-8-{[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl]oxy } -2-{ [(2R,7aS)-2 -fluorotetrahydro- lH-pyrrolizin-7a(5H)- yl]methoxy}-6-methoxy-7H-purine (Intermediate 2-21, 2.40 g, 85% purity, 2.68 mmol) in hydrochloric acid (25.0 ml, 4 M in ethyl acetate) was stirred at room temperature for 0.5 hour. The mixture was concentrated to give 4-[(7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-6-methoxy-7H-purin-8-yl)oxy]-6-fluoro-5-[(triisopropylsilyl)ethynyl] -2-naphthol (2.00 g, 93% purity, 97% yield).

[0886] LC-MS (Method C): Rt= 1.050 min; MS (ESIpos): m / z = 718.4 [M+H]+.

[0887] Intermediate 2-23

[0888] 8-[(3-{[tert-Butyl(diphenyl)silyl]oxy}-7-fluoro-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l- yl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- methoxy- 7H-purine

[0889] To a solution of 4-[(7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- methoxy-7H-purin-8-yl)oxy]-6-fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (Intermediate 2- -\T1-

[0890] 22, 2.00 g, 93% purity, 2.59 mmol) and N,N -diisopropylethylamine (1.40 ml, 7.8 mmol) in dichloromethane (50.0 ml) was added dropwise tert-butyl(chloro)diphenylsilane (0.810 ml, 3.10 mmol) at 0 °C. After stirring at room temperature for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by reverse phase column [Instrument: SW-5231-120-SP; Column: Spherical, 40-60 pm, 120 A, eluent A: water (0.225% formic acid), eluent B: acetonitrile; gradient: 0-30 min; flow 50 ml / min; temperature: RT; Detector: UV 220 / 254 nm] to give 8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8-[(triisopropylsilyl)ethynyl]-l- naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- methoxy-7H-purine (2.40 g, 90% purity, 87% yield).

[0891] LC-MS (Method C): Rt= 1.250 min; MS (ESIpos): m / z = 956.6 [M+H]+.

[0892] Intermediate 2-24

[0893] 8-[(3-{[tert-Butyl(diphenyl)silyl]oxy}-7-fluoro-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l- yl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H- purin-6-ol

[0894] To a solution of 8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen- 1 -yl)oxy]-7-cyclobutyl-2- { [(2R,7aS)-2-fluorotetrahydro- IH-pyrrolizin- 7a(5H)-yl]methoxy}-6-methoxy-7H-purine (Intermediate 2-23, 2.40 g, 90% purity, 2.26 mmol) and sodium iodate (3.39 g, 22.6 mmol) in acetonitrile (50.0 ml) was added dropwise chlorotrimethylsilane (1.70 ml, 14.0 mmol) at room temperature. After stirring at room temperature for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by reversed phase column [Instrument: SW-5231-120-SP; Column: Spherical, 40-60 pm, 120 A; eluent A: water (0.225% formic acid), eluent B: acetonitrile; gradient: 0-45 min 5-100% B; flow 200 ml / min; temperature: room temperature; Detector: UV 220 / 254 nm] to give 8-[(3-{[tert-butyl(diphenyl)silyl]oxy}- 7-fhioro-8-[(triisopropylsilyl)ethynyl]-l-naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-ol (1.00 g, 94% purity, 44% yield).

[0895] LC-MS (Method C): Rt= 1.250 min; MS (ESIpos): m / z = 942.6 [M+H]+.

[0896] Intermediate 2-25 tert-Butyl (1S,5S,6R or lR,5R,6S)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8- [(triisopropylsilyl)ethynyl]-l-naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1] octane-8- carboxylate

[0897] To a solution of 8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8-[(triisopropylsilyl)ethynyl]-l- naphthyl)oxy]-7-cyclobutyl-2-{(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H- purin-6-ol (Intermediate 2-24, 200 mg, 94% purity, 0.200 mmol), and l,8-diazabicyclo(5.4.0)undec-7-ene (0.09 ml, 0.6 mmol) in N,N-dimethylformamide (2.0 ml) was added (benzotriazol- 1-yloxy) tripyrrolidinophosphoniumhexafluorophosphate (208 mg, 0.399 mmol) at room temperature. After stirring at the same temperature for 20 minutes, tert-butyl (1S,5S,6R or lR,5R,6S)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 2-15, 61.1 mg, 95% purity, 0.239 mmol) was added to the above mixture. After stirring at room temperature for another 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by preparative TLC (ethyl acetate: methanol = 8: 1) to give tert-butyl (lS,5S,6Ror lR,5R,6S)-3-(8-[(3-{[tert- butyl(diphenyl)silyl]oxy}-7-fluoro-8-[(triisopropylsilyl)ethynyl]-l-naphthyl)oxy]-7-cyclobutyl-2- {[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 56% purity).

[0898] LC-MS (Method C): Rt= 0.948 min; MS (ESIpos): m / z = 1166.8 [M+H]+.

[0899] Intermediate 2-26 tert-Butyl (1S,5S,6R or lR,5R,6S)-3-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)oxy]-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)- 6-methoxy-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0900] A solution of tert-butyl (1S,5S,6R or lR,5R,6S)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8- [(triisopropylsilyl)ethynyl] - 1 -naphthyl)oxy] -7-cyclobutyl-2-{ [(2R,7aS)-2 -fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 2-25, 40.0 mg, 0.034 mmol) and tetramethylammonium fluoride (31.9 mg, 0.343 mmol) in tetrahydrofuran (0.5 ml) was stirred at 60 °C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tert-butyl (1S,5S,6R or lR,5R,6S)-3-(7-cyclobutyl-8-[(8-ethynyl-7- fluoro-3-hydroxy-l-naphthyl)oxy]-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}- 7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25.0 mg, 48% purity).

[0901] LC-MS (Method C): Rt= 0.832 min; MS (ESIpos): m / z = 772.2 [M+H]+.

[0902] Intermediate 2-27

[0903] 3-Benzyl 8-tert-butyl (1R,5R,6S or lS,5S,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (#1, peak 1)

[0904] 3-Benzyl 8-tert-butyl (1R,5R,6S and lS,5S,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (Intermediate 2-12, 1.10 g, 99 % purity, 3.00 mmol) was separated by preparative-SFC (Instrument: Acswh-prep-SFC-D; Column: Daicel chiralpak AD-H 250mm*30mm*5 pm; eluent A: carbon dioxide, eluent B: i-PrOH (0.1% NHs^FEO), gradient: 4.7 min 25-25% (25% CO2) B; flow 100 ml / min; temperature: room temperature; Detector: UV 220 / 254 nm) to give 3-benzyl 8-tert-butyl (1R,5R,6S or lS,5S,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (#l, peak 1, 540 mg, 90% purity, 45% yield) and 3-benzyl 8-tert-butyl (1S,5S,6S or lR,5R,6R)-6-hydroxy-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (#2, peak 2, 620 mg, 90% purity, 21% yield).

[0905] Intermediate 2-28

[0906] 3-Benzyl 8-tert-butyl (1R,5R,6S or lS,5S,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate

[0907] To a solution of 3-benzyl 8-tert-butyl (1R,5R,6S or lS,5S,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-

[0908] 3.8 -dicarboxy late (Intermediate 2-27, #1, peak 1, 540 mg, 90% purity, 1.34 mmol) in tetrahydrofuran (10 ml) was added sodium hydride (118 mg, 2.95 mmol, 60% purity in mineral oil) in one portion at 0 °C. After stirring at 0.5 hour, iodomethane (0.170 ml, 2.7 mmol) was added in one portion. After stirring at room temperature for another 16 hours, the reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by preparative -TLC (petroleum ether: ethyl acetate = 1: 1) to give 3-benzyl 8-tert-butyl (1R,5R,6S or lS,5S,6R)-6-methoxy-

[0909] 3.8 -diazabicyclo [3.2.1] octane -3, 8 -dicarboxylate (500 mg, 99% purity, 98% yield).

[0910] LC-MS (Method C): Rt= 0.639 min; MS (ESIpos): m / z = 321.2 [M+H-56]+.

[0911] Intermediate 2-29 tert-Butyl (1R,5R,6S or lS,5S,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of 3-benzyl 8-tert-butyl (1R,5R,6S or lS,5S,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (Intermediate 2-28, 500 mg, 99% purity, 1.31 mmol) in methanol (10 ml) was added palladium (100 mg, 10% in activated carbon) in one portion. After stirring at room temperature for 16 hours under hydrogen atmosphere (balloon, 15 psi), the mixture was filtered and concentrated to give tertbutyl (1R,5R,6S or lS,5S,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 95% purity, 89% yield).

[0912] ’H NMR (400 MHz, CDCh- ): 5 [ppm] = 4.15-3.90 (m, 3H), 3.40 (s, 3H), 3.15-2.86 (m, 3H), 2.68-2.55 (m, 1H), 2.52-2.39 (m, 1H), 2.00 (s, 1H), 1.63-1.54 (m, 1H), 1.47 (s, 9H).

[0913] Intermediate 2-30 tert-Butyl (1R,5R,6S or lS,5S,6R)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8- [(triisopropylsilyl)ethynyl]-l-naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1] octane-8- carboxylate

[0914] To a solution of 8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8-[(triisopropylsilyl)ethynyl]-l- naphthyl)oxy]-7-cyclobutyl-2-{2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H- purin-6-ol (Intermediate 2-24, 200 mg, 94% purity, 0.200 mmol) and l,8-diazabicyclo(5.4.0)undec-7-ene (0.0890 ml, 0.600 mmol) in N,N -dimethylformamide (4.00 ml) was added (benzotriazol- 1- yloxy)tripyrrolidinophosphoniumhexafluorophosphate (208 mg, 0.399 mmol) at room temperature. After strring at the same temperature for 20 minutes, tert-butyl (1R,5R,6S or lS,5S,6R)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 2-29, 61.1 mg, 95% purity, 0.239 mmol) was added to the above mixture, the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by preparative TLC (ethyl acetate: methanol = 10: 1) to give tert-butyl (1R,5R,6S or lS,5S,6R)-3-(8-[(3- {[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8-[(triisopropylsilyl)ethynyl]-l-naphthyl)oxy]-7-cyclobutyl-2- {[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 80% purity, 34% yield).

[0915] LC-MS (Method C): Rt= 1.042 min; MS (ESIpos): m / z = 1167.9 [M+2]+.

[0916] Intermediate 2-31 tert-Butyl (1R,5R,6S or lS,5S,6R)-3-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)oxy]-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)- 6-methoxy-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0917] To a solution of tert-butyl (1R,5R,6S or lS,5S,6R)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8- [(triisopropylsilyl)ethynyl] - 1 -naphthyl)oxy] -7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 2-30, 100 mg, 80% purity, 0.0686 mmol) in tetrahydrofuran (4.00 ml) was added tetramethylammonium fluoride (19.2 mg, 0.0206 mmol) at 25 °C. After stirring at 25 °C for 16 hours and 60 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give tertbutyl (1R,5R,6S or lS,5S,6R)-3-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2- {[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (60.0 mg, 80% purity, 91% yield).

[0918] LC-MS (Method C): Rt= 0.937 min; MS (ESIpos): m / z = 772.5 [M+H]+.

[0919] Intermediate 2-32

[0920] 3-Benzyl 8-tert-butyl (1R,5R,6R or lS,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (peak 2, #2)

[0921] 3-Benzyl 8-tert-butyl (1R,5R,6R and lS,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (Intermediate 2-10, 3.00 g, 8.19 mmol) was separated by preparative-SFC (Instrument: Acswh-prep-SFC-D; Column: Daicel chiralpak AD-H 250mm*30mm*5 pm; eluent A: carbon dioxide, eluent B: i-PrOH (0.1% NHs^FFO), gradient: 4.7 min 25-25% (25% CO2) B; flow 100 ml / min; temperature: room temperature; Detector: UV 220 / 254 run) to give 3-benzyl 8-tert-butyl (1S,5S,6S or lR,5R,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (peak 1, #1) (1.3 g, 90% purity, 39% yield) and 3-benzyl 8-tert-butyl (1R,5R,6R or lS,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (peak 2, #2) (1.4 g, 42% yield).

[0922] LC-MS (Method C): Rt= 0.869 min; MS (ESIpos): m / z =385.1 [M+Na]+.

[0923] Intermediate 2-33

[0924] 3-Benzyl 8-tert-butyl (1R,5R,6R or lS,5S,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate

[0925] To a solution of 3-benzyl 8-tert-butyl (1R,5R,6R or lS,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (peak 2, #2) (Intermediate 2-32, 1.40 g, 90% purity, 3.48 mmol) in tetrahydrofuran (15.0 ml) was added sodium hydride (306 mg, 7.65 mmol, 60% purity in mineral oil) in one portion at 0 °C. After stirring for 0.5 hour at 0 °C, lodomethane (0.430 ml, 6.95 mmol) was added to the above mixture. After stirring at 25 °C for another 16 hours, the reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 10: 1, then 8: 1, 5: 1) to give 3-benzyl 8-tert-butyl (1R,5R,6R or lS,5S,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (1.20 g, 90% purity, 83% yield).

[0926] LC-MS (Method C): Rt= 0.637min; MS (ESIpos): m / z = 399.2 [M+Na]+.

[0927] Intermediate 2-34 tert-Butyl (1R,5R,6R or lS,5S,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0928] To a solution of 3-benzyl 8-tert-butyl (lR,5R,6R or lS,5S,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (Intermediate 2-33, based on Intermediate 2-27, peak 2, 1.10 g, 90% purity, 2.63 mmol) in methanol (10.0 ml) was added palladium (200 mg, 10% in activated carbon) at room temperature. After stirring at 25 °C for 3 hours under hydrogen atmosphere (balloon, 15 psi), the mixture was filtered and the filtrate was concentrated to give tert-butyl (1R,5R,6R or lS,5S,6S)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 90% purity, 99% yield).

[0929] ’H NMR (400 MHz, DMSO-6): 5 [ppm] = 4.12-4.00 (m, 1H), 3.92 (d, J= 6.4 Hz, 1H), 3.86 (d, J= 11.6 Hz, 1H), 3.17 (s, 3H), 2.70-2.58 (m, 3H), 2.43 (d, J= 11.6 Hz, 1H), 2.13-2.00 (m, 1H), 1.70-1.53 (m, 1H), 1.39 (d, J = 6.0 Hz, 9H).

[0930] Intermediate 2-35 tert-Butyl (1R,5R,6R or lS,5S,6S)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8- [(triisopropylsilyl)ethynyl]-l-naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0931]

[0932] To a solution of 8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8-[(triisopropylsilyl)ethynyl]-l- naphthyl)oxy]-7-cyclobutyl-2-{(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H- purin-6-ol (Intermediate 2-24, 500 mg, 94% purity, 0.499 mmol) and l,8-diazabicyclo(5.4.0)undec-7-ene (0.223 ml, 1.50 mmol) in N,N-dimethylformamide (10.0 ml) was added benzotriazol- 1- yloxy(tripyrrolidin-l-yl)phosphanium;hexafluorophosphate (519 mg, 0.998 mmol) at 25 °C. After strring at 25 °C for 20 minutes, tert-butyl (1R,5R,6R or lS,5S,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Intermediate 2-34, based on Intermediate 2-27, peak 2, 201 mg, 0.748 mmol) was added to the above mixture. After stirring at 25 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by reversed phase column (Instrument: 50 g Flash; Column: Welch Ultimate XB_C18 20-40 pm; eluent A: water (0.05% formic acid in water), eluent B: acetonitrile; gradient: 0-15 min 0-50% B; flow 60 ml / min; temperature; Detector: UV 220 / 254 run) to give tert-butyl (1R,5R,6R or lS,5S,6S)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7- fhroro-8-[(triisopropylsilyl)ethynyl]-l-naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 83% purity).

[0933] LC-MS (Method C): Rt= 0.925 min; MS (ESIpos): m / z = 1166.9 [M+H]+.

[0934] Intermediate 2-36 tert-Butyl (1R,5R,6R or lS,5S,6S)-3-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)oxy]-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-

[0935] 6-methoxy-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0936] To a solution of tert-butyl (1R,5R,6R or lS,5S,6S)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8- [(triisopropylsilyl)ethynyl] - 1 -naphthyl)oxy] -7-cyclobutyl-2-{ [(2R,7aS)-2 -fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 2-35, 130 mg, 83% purity, 0.093 mmol) in tetrahydrofuran (5.0 ml) was added tetramethylammonium fluoride (86.1 mg, 0.925 mmol) at 25 °C. After stirring at 60 °C for 16 hours, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified give tert-butyl (1R,5R,6R or lS,5S,6S)-3-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy- 1 -naphthyl)oxy]-2- { [(2R,7aS)-2 -fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -7H-purin-6-yl)-6- methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 55% purity, 85% yield).

[0937] LC-MS (Method C): Rt= 0.833 min; MS (ESIpos): m / z = 772.2 [M+H]+.

[0938] Intermediate 2-37

[0939] 3-Benzyl 8-tert-butyl (1S,5S,6S or lR,5R,6R)-6-hydroxy-3,8-diazabicyclo [3.2.1] octane-3, 8- dicarboxylate (peak 1, #1)

[0940] 3-Benzyl 8-tert-butyl (1R,5R,6R and lS,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (Intermediate 2-10, 3.00 g, 8.19 mmol) was separated by preparative-SFC (Instrument: Acswh-prep-SFC-D; Column: Daicel chiralpak AD-H 250mm*30mm*5 pm; eluent A: carbon dioxide, eluent B: iso-propanol (0.1% NHs^FFO), gradient: 4.7 min 25-25% (25% CO2) B; flow 100 ml / min; temperature: room temperature; Detector: UV 220 / 254 rim) to give 3-benzyl 8-tert-butyl (1S,5S,6S or lR,5R,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (peak 1, #1) (1.3 g, 90% purity, 39% yield) and 3-benzyl 8-tert-butyl (1R,5R,6R or lS,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (peak 2, #2) (1.4 g, 42% yield).

[0941] LC-MS (Method C): Rt= 0.869 min; MS (ESIpos): m / z =385.1 [M+Na]+.

[0942] Intermediate 2-38

[0943] 3-Benzyl 8-tert-butyl (1S,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate

[0944] To a solution of 3-benzyl 8-tert-butyl (1S,5S,6S or lR,5R,6R)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (peak 1, #1) (Intermediate 2-37, peak 1, 1.30 g, 90% purity, 3.23 mmol) in tetrahydrofuran (15 ml) was added sodium hydride (284 mg, 7. 10 mmol, 60% purity in mineral oil) in one portion at 0 °C. After stirring 0.5 hour, iodomethane (0.4 ml, 6.50 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 10: 1 then 5: 1) to give 3-benzyl 8-tert-butyl (1S,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (1.30 g, 94% purity).

[0945] LC-MS (Method D): Rt= 0.897 min; MS (ESIpos): m / z = 277.2 [M+H-100]+.

[0946] Intermediate 2-39 tert-Butyl (1S,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of 3-benzyl 8-tert-butyl (1S,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane- 3, 8 -dicarboxy late (Intermediate 38, based on Intermediate 37, peak 1, 1.30 g, 94% purity, 3.25 mmol) in methanol (20 ml) was added palladium (282 mg, 10% purity in activated carbon) in one portion. After stirring at room temperature for 3 hours under hydrogen atmosphere (balloon, 15 psi), the reaction mixture was filtered and the filtrate was concentrated to give tert-butyl (1S,5S,6S or lR,5R,6R)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (730 mg, 90% purity, 84% yield).

[0947] ’H NMR (400 MHz, CDCh- ): 5 [ppm] = 4.37-4.35 (m, 0.5H), 4.23-4.21 (m, 0.5H), 4.14-4.10 (m, 0.5H), 4.04-4.02 (m, 1.5H), 3.30 (s, 3H), 3.02-2.97 (m, 1H), 2.93-2.90 (m, 1H), 2.85-2.76 (m, 1H), 2.61- 2.58 (m, 1H), 2.24-2.13 (m, 1H), 1.91-1.78 (m, 2H), 1.47 (s, 9H).

[0948] Intermediate 2-40 tert-Butyl (1S,5S,6S or lR,5R,6R)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8- [(triisopropylsilyl)ethynyl]-l-naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0949] To a solution of 8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8-[(triisopropylsilyl)ethynyl]-l- naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy} -7H- purin-6-ol (Intermediate 2-24, 500 mg, 0.525 mmol) and l,8-diazabicyclo(5.4.0)undec-7-ene (0.240 ml, 1.60 mmol) in N,N-dimethylformamide (10.0 ml) was added benzotriazol -1-yloxy (tripyrrolidin-1 - yl)phosphanium;hexafluorophosphate (547 mg, 1.05 mmol) at 25 °C. After strring 25 °C for 30 minutes, tert-butyl (1S,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 2-39, 283 mg, 1.05 mmol) was added to the above reaction mixture. After stirring at 25 °C for 16 hours, the mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by reversed phase column (Instrument: 50 g Flash; Column: Welch Ultimate XB_C18 20-40 pm; eluent A: water (0.05% formic acid in water), eluent B: acetonitrile; gradient: 0-15 min 0-55% B; flow 60 ml / min; temperature; Detector: UV 220 / 254 nm) to give tert-butyl (1S,5S,6S or lR,5R,6R)-3-(8-[(3-{[tert-butyl(diphenyl)silyl]oxy}-7-fluoro-8-[(triisopropylsilyl)ethynyl]-l- naphthyl)oxy]-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H- purin-6-yl)-6-methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 90% purity).

[0950] LC-MS (Method C): Rt= 0.948 min; MS (ESIpos): m / z = 1166.9 [M+H]+.

[0951] Intermediate 2-41 tert-Butyl (1S,5S,6S or lR,5R,6R)-3-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)oxy]-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)- 6-methoxy-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0952] A solution...

Claims

CLAIMS1. A compound of general formula (I)in which:Z represents -O- or C(=O);R1 representsR2 representswhereinR5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;R6 represents a hydrogen atom or a fluorine atom;R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.A compound of general formula (I) according to claim 1 in which:Z represents -O- or C(=O);R1 representsR2 representswhereinR5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;R6 represents a hydrogen atom or a fluorine atom;R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

3. A compound of general formula (I) according to claim 1 or 2in which:Z represents -O- or C(=O)R1 representsR4 representswhereinR5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;R6 represents a hydrogen atom or a fluorine atom;R7 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

4. A compound of general formula (I) according to claim 1 or 2 in which:Z represents -O- or C(=O);R1 represents, orR3 representswhereinR5 represents -C=CH;R6 represents: a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

5. A compound of general formula (I) according to claim 1, in which:Z represents -O- or C(=O);R1 representswhereinR5 represents a hydrogen atom, a fluorine atom, -C=CH or -CH2-CH3;R6 represents a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

6. A compound of general formula (I) according to any of claims 1 to 5, in which:Z represents -O- or C(=O) R1 representsR2 representsR4 representswhereinR5 represents -C=CH3;R6 represents a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

7. A compound of formula (I) according to claim 1 which is selected from the group consisting of: Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2- naphthol (2 / 1),Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2- naphthol,Formic acid - 4-({7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[(tetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol, formic acid 4-({7-cyclobutyl-6-(3,8-diazabicyclo[3.

2. l]octan-3-yl)-2-[(tetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol (2 / 1), Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol, 4-{[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S,4S)-4-fluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol, Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S,4R)-4-fluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol, Formic acid - (5S)-5-[({7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-[(8-ethynyl-7- fluoro-3 -hydroxynaphthalen- 1 -yl)oxy] -7H-purin-2-yl } oxy)methyl] - 1 -methylpyrrolidin-2-one, Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-pyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-4,4-difluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,3-[({7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-[(8-ethynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)oxy] -7H-purin-2-yl } oxy)methyl] - 1 -methylpyrrolidine-3 -carbonitrile (Racemate),4-({7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(l-methyl-lH-imidazol-2- yl)ethoxy] -7H-purin-8-yl } oxy)-5 -ethynyl-6-fluoronaphthalen-2-ol,4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- [(1R,5R,6S or lS,5S,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5- ethynyl-6-fluoro-2 -naphthol - formic acid,4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- [(1S,5S,6R or lR,5R,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5- ethynyl-6-fluoro-2 -naphthol - formic acid,4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(1 S,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5- ethynyl-6-fluoro-2 -naphthol - formic acid,4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- [(1R,5R,6R or lS,5S,6S)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5- ethynyl-6-fluoro-2 -naphthol - formic acid,8-[7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-l,8-diazaspiro[3.5]nonan-2-one: formic acid,(4R or S)-6-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)- 2 -fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -7H-purin-6-yl)- 1,6- diazaspiro[3 ,5]nonan-2-one,(4S or R)-6-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)- 2 -fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -7H-purin-6-yl)- 1,6- diazaspiro[3 ,5]nonan-2-one, cis or trans-6-[7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2- fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-6-azaspiro[3.5]nonan-2-ol trans or cis-6-[7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2- fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-6-azaspiro[3.5]nonan-2-ol,Formic acid - 4-{[7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-7H-purin-8-yl]oxy}-5-ethynyl-6- fluoronaphthalen-2-ol,Formic acid - (3R)-l-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2- {[(2R,7aS)-2-fhrorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl)-3- methylpiperidin-3 -ol,4-{[6-(Azepan-l-yl)-7-cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2 -naphthol,4-{[7-Cyclobutyl-6-({[l-(dimethylamino)cyclobutyl]methyl}amino)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2- naphthol,4-[7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-l,4-oxazepan-6-ol: formic acid,(6R or S)-4-(7-cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-{[(2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -7H-purin-6-yl)-6-methyl- 1 ,4-oxazepan-6- ol,4-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-{[(2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -7H-purin-6-yl)- 1 ,4-oxazepan-6-one,4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[8- methyl-3 , 8 -diazabicyclo [3.2.1 ]octan-3 -yl] -7H-purin-8-yl)oxy] -5 -ethynyl-6-fluoronaphthalen-2- ol,[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)methanone ,(7-cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3- hydroxy-3 -methylpiperidin- 1 -yl] -7H-purin-8-yl)(8-ethynyl-7 -fluoro-3 -hydroxynaphthalen- 1 - yl)methanone,[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy] -7 -tetrahydrofuran-3 -yl -purin-8 -yl] -(8-ethynyl-7 -fluoro-3 -hydroxy- 1 - naphthyl)methanone (mixture of 2 isomers), formic acid - [6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7-(cis or trans-3-methoxycyclobutyl)-7H-purin-8-yl](8-ethynyl- 7 -fluoro-3 -hydroxy- 1 -naphthyl)methanone (2 / 1 ) , formic acid - [6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7-(trans or cis-3-methoxycyclobutyl)-7H-purin-8-yl](8-ethynyl- 7 -fluoro-3 -hydroxy- 1 -naphthyl)methanone (2 / 1 ) ,Formic acid - (8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)[2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-7-(cis or trans-3- methoxycyclobutyl)-7H-purin-8-yl]methanone (1 / 1),(8-Ethynyl-7-fluoro-3-hydroxy-l-naphthyl)[2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-7-(trans or cis-3- methoxy cyclobutyl) -7H-purin-8 -yl] methanone ,[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-isopropyl-purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)methanone: formic acid,[7-Cyclopropyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)methanone: formic acid (1:2),7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3- hydroxy-3 -methylpiperidin- 1 -yl] -7H-purin-8-yl(8-ethynyl-7 -fluoro-3 -hydroxynaphthalen- 1 - yl)methanone / formic acid (1 / 1),{7-Cyclobutyl-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-2-[(tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy]-7H-purin-8-yl}(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),(7-Cyclobutyl-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-2-{[(2S)-pyrrolidin-2-yl]methoxy}- 7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),7-Cyclobutyl-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-2-{[(2S)-l-methylpyrrolidin-2- yl]methoxy}-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),7-Cyclobutyl-2-{[(2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl]methoxy}-6-[(3R)-3-hydroxy-3- methylpiperidin-l-yl]-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),(5S)-5-[({7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-6-[(3R)-3- hydroxy-3 -methylpiperidin- 1 -yl] -7H-purin-2-yl }oxy)methyl] - 1 -methylpyrrolidin-2-one / formic acid (1 / 1),[7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-(l,4- oxazepan-4-yl)-7H-purin-8-yl](8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone,{7-Cyclobutyl-6-( 1 ,4-oxazepan-4-yl)-2-[(tetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy]-7H- purin-8-yl}(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone,(7-Cyclobutyl-6-[3,8-diazabicyclo[3.2.1]octan-3-yl]-2-{[(2S)-pyrrolidin-2-yl]methoxy}-7H- purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone - formic acid (1: 1),[7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-(3-oxa- 7,9-diazabicyclo [3.3.1 ]nonan-7-yl)-7H-purin-8-yl] (8 -ethynyl-7-fluoro-3 -hydroxynaphthalen- 1 - yl)methanone / formic acid (1 / 1),(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- [(1R,5R,6R) or (lS,5S,6S)]-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)(8- ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),7-Cyclobutyl-2-{[(2S)-4,4-difluoro-l-methylpyrrolidin-2-yl]methoxy}-6-[((lR,5R,6R) or (lS,5S,6S))-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)methanone formic acid (1 / 1),(5S)-5-[({7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-6- [[(1R,5R,6R) or (lS,5S,6S)]-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-2- yl}oxy)methyl]-l-methylpyrrolidin-2-one / formic acid (1:1),5-[7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2 -carboxamide, l-[7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-2-methylpiperidine-4- carbonitrile (mixture of the two cis-diastereomers regarding the piperidine substitution),(7-Cyclobutyl-6-[(lR,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl]-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)methanone,(3R)-l-(7-Cyclobutyl-2-{[(2S)-4,4-difhioro-l-methylpyrrolidin-2-yl]methoxy}-8-[(8-ethynyl-7- fluoro-3 -hydroxy- l-naphthyl)oxy |-7 / / -purin -6-yl )-3 -methyl pi pcridin-3-ol (single stereoisomer), (3R)-l-{7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)oxy]-2-[(2S)-pyrrolidin-2- ylmethoxy] -7H-purin-6-yl} -3 -methylpiperidin-3 -ol hydrochloride,(3R)-l-{8-[(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-6-yl}-3 -methylpiperidin-3 -ol,(3R)-l-{8-[(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-6-yl}-3 -methylpiperidin-3 -ol,4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-7-(oxan-4-yl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol, 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-8-yl]oxy}-5-ethynyl-6- fluoronaphthalen-2-ol - formic acid (1: 2) (cis-diastereomers 1 regarding cyclobutyl),4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-8-yl]oxy}-5-ethynyl-6- fluoronaphthalen-2-ol - formic acid (1: 2) (cis-diastereomers 2 regarding cyclobutyl),4-({6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-7-[oxan-3-yl]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol - formic acid (1: 1) (two enantiopure diastereomers),4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-5-ethyl-6-fluoro-naphthalen-2-ol, 4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-l,3-benzothiazol-2-amine:formic acid (1: 1),4-[7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-7-fluoro-l,3-benzothiazol-2 -amine: formic acid (1:2),4-[7-Cyclobutyl-6-[(lS,5R)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-l,3-benzothiazol-2 -amine,2-Amino-4-[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2 -fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]oxy-benzothiophene-3- carbonitrile: formic acid, and[6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl](7-cyclobutyl-6-[3,8- diazabicyclo[3.2.1]octan-3-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy } -7H-purin- 8 -yl)methanone , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

8. A compound of formula (I) according to claim 1 which is selected from the group consisting of:Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2- naphthol (2 / 1),Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoro-2- naphthol,Formic acid - 4-({7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[(tetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol,Formic acid 4-({7-cyclobutyl-6-(3,8-diazabicyclo[3.

2. l]octan-3-yl)-2-[(tetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy]-7H-purin-8-yl}oxy)-5-ethynyl-6-fluoronaphthalen-2-ol (2 / 1),Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S,4R)-4-fluoro-l- methylpyrrolidin-2-yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,Formic acid - 4-{[7-cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2S)-pyrrolidin-2- yl]methoxy}-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol,3-[({7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-[(8-ethynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)oxy] -7H-purin-2-yl } oxy)methyl] - 1 -methylpyrrolidine-3 -carbonitrile (Racemate),4-[(7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(1 S,5S,6S or lR,5R,6R)-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)oxy]-5- ethynyl-6-fluoro-2 -naphthol - formic acid, 8-[7-Cyclobutyl-8-[(8-ethynyl-7-fhioro-3-hydroxy-l-naphthyl)oxy]-2-[[(2R,8S)-2-fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]purin-6-yl]-l,8-diazaspiro[3.5]nonan-2-one: formic acid,(4S or R)-6-(7-Cyclobutyl-8-[(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)oxy]-2-{[(2R,7aS)- 2 -fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -7H-purin-6-yl)- 1,6- diazaspiro[3 ,5]nonan-2-one, [7-Cyclobutyl-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]purin-8-yl]-(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)methanone , (7-cyclobutyl-2-{[(2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6-[(3R)-3- hydroxy-3 -methylpiperidin- 1 -yl] -7H-purin-8-yl)(8-ethynyl-7 -fluoro-3 -hydroxynaphthalen- 1 - yl)methanone, [6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy] -7 -tetrahydrofuran-3 -yl -purin-8 -yl] -(8-ethynyl-7 -fluoro-3 -hydroxy- 1 - naphthyl)methanone (mixture of 2 isomers),Formic acid - [6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-7-(cis or trans-3-methoxycyclobutyl)-7H-purin-8-yl](8-ethynyl- 7 -fluoro-3 -hydroxy- 1 -naphthyl)methanone (2 / 1 ) , [6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy] -7-isopropyl-purin-8-yl] -(8-ethynyl-7-fluoro-3 -hydroxy- 1 - naphthyl)methanone: formic acid, {7-Cyclobutyl-6-[(3R)-3-hydroxy-3-methylpiperidin-l-yl]-2-[(tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy]-7H-purin-8-yl}(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1),(7-Cyclobutyl-6-[3,8-diazabicyclo[3.2.1]octan-3-yl]-2-{[(2S)-pyrrolidin-2-yl]methoxy}-7H- purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone - formic acid (1: 1), (7-Cyclobutyl-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-6- [(1R,5R,6R) or (lS,5S,6S)]-6-methoxy-3,8-diazabicyclo[3.2.1]octan-3-yl]-7H-purin-8-yl)(8- ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)methanone / formic acid (1 / 1), 5-[7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2 -carboxamide, l-[7-Cyclobutyl-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-l-carbonyl)-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-6-yl]-2-methylpiperidine-4- carbonitrile (mixture of the two cis-diastereomers regarding the piperidine substitution), (7-Cyclobutyl-6-[(lR,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl]-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}-7H-purin-8-yl)(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)methanone, 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-7-(oxan-4-yl)-7H-purin-8-yl]oxy}-5-ethynyl-6-fluoronaphthalen-2-ol, 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-8-yl]oxy}-5-ethynyl-6- fluoronaphthalen-2-ol - formic acid (1: 2) (cis-diastereomers 1 regarding cyclobutyl), 4-{[6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-7-(3-methoxycyclobutyl)-7H-purin-8-yl]oxy}-5-ethynyl-6- fluoronaphthalen-2-ol - formic acid (1: 2) (cis-diastereomers 2 regarding cyclobutyl), and 4-({6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy } -7- [oxan-3 -yl] -7H-purin-8-yl } oxy)-5 -ethynyl-6-fluoronaphthalen-2-ol formic acid (1: 1) (two enantiopure diastereomers), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

9. A compound of general formula (I) according to any of claims 1 to 8 for use in the treatment or prophylaxis of a disease.

10. A compound of general formula (I) according to any of claims 1 to 8 for use in the treatment or prophylaxis of a disease according to claim 9, wherein the disease is a neoplastic disorder, or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS.

11. A compound of general formula (I) according to any of claims 1 to 8 for use in the treatment or prophylaxis of a disease according to claim 9 or 10, wherein the disease is a neoplastic disorder.

12. A compound of general formula (I) according to any of claims 1 to 8 for use in the treatment or prophylaxis of a disease according to any of claims 9 to 11, wherein the neoplastic disorder is a cancer disease.

13. A compound of general formula (I) according to any of claims 1 to 8 for use in the treatment or prophylaxis of a disease according to any of claims 9 to 12, wherein the cancer disease is selected from colorectal cancer, gastric cancer, lung cancer, and pancreatic cancer.

14. Method for controlling a neoplastic disease comprising administering an anti -neoplastic effective amount of at least one compound as defined in one of claims 1 to 8 to a human or animal in need thereof.

15. A pharmaceutical composition comprising a compound of general formula (I) according to any of claims 1 to 8 and one or more pharmaceutically acceptable excipients.

16. A pharmaceutical combination comprising: one or more first active ingredients, selected from the group of compounds of general formula(I) according to any one of claims 1 to 8, and one or more further active ingredients.

17. A method of preparing a compound of general formula (I), according to any of claims 1 to 8, said method comprisingEITHER a) for compounds with Z= an oxygen atom (-O-), allowing an intermediate compound of general formula (II)in whichis selected from5R2 is selected from, and wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same and X4 is a hydrogen atom; which is optionally protected at R1 and / or R2 indicated by the dotted line to “PG-” and PG is independently selected from a SiR12R12R13 group, a benzyl group, a methoxymethyl group, and a tert.-butoxycarbonyl group;R12 and R13 are identical or different and are independently selected from a C1-C6- alkyl group and a phenyl group; after undergoing a bromination reaction with a suitable bromination reagent, leading to X4=bromine; to react with a compound of general formula (XXX)in whichR4 is 5-ethynyl-6-fluoro-2 -naphthol, a 5-ethyl-6-fluoro-2-naphthol, a fluorinated or non-fluorinated l,3-benzothiazol-2-amine or a 2 -amino- 1 -benzothiophene-3 - carbonitrile; andR12 and R13 are identical or different and are independently selected from a C1-C6- alkyl group and a phenyl group;PG is independently selected from a SiR12R12R13 group, a benzyl group, a methoxymethyl group, and a para-methoxybenzyl group; introducing the R4 substituent under strong basic conditions optionally protected by replacing the bromine atom, leading after suitable deprotection reaction to a compound of formula (I)OR b) for compounds with Z= C(=O), allowing an intermediate compound of formula (II)in whichRl, R2 and R3 have the meanings as defined above, andX4 is a hydrogen atom; which is optionally protected at Rl and / or R2 indicated by the dotted line to “PG” andPG is independently selected from a SiR12R12R13 group, a benzyl group, a methoxymethyl group, and a tert.-butoxycarbonyl group;R12 and R13 are identical or different and are independently selected from a C1-C6- alkyl group and a phenyl group; to react under strong basic conditions in an aprotic solvent and temperatures between -40° to 0°C with an aldehyde of general formula (XXVI)in which R12, R13 and PG have the meanings as defined above to obtain after deprotection and oxidation of the alcohol and optionally further deprotection reactions independently from its order a compound of general formula (I)in whichRl, R2, and R3 have the meanings as defined above andR4 is selected fromis selected from a hydrogen atom, a fluorine atom, a -C=CH group and a -CH2-CH3 group;R6 is a hydrogen atom or a fluorine atom;R7 is a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

18. A method of preparing a compound of formula (I) according to any of claims 1-8 wherein Z is - O-, said method comprising a step of allowing a compound of formula (III)in whichR1 is selected fromX2 is SO2CH3PG is independently selected from a SiR12R12R13 group, a methoxymethyl group, and a tert.-butoxycarbonyl group;R12 and R13 are identical or different and are independently selected from a Cl-C6-alkyl group and a phenyl group;Z is -O- with a compound of formula (XXV)in whichR2 is selected from, ,PGis atert.-butoxycarboyl group; under strong basic conditions, to obtain a compound of formula (XXXI)in which Rl, R2, R3, and PG are as defined above, andR4 is selected fromwhereinR5 is selected from a hydrogen atom, a fluorine atom, a -C=CH group and a -CH2-CH3 group;R6 is a hydrogen atom or a fluorine atom;R7 is a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, which is finally being deprotected optionally in two steps depending on the proteting groups, to obtain a compound of formula (I) wherein Z is -O-; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same.

19. A method of preparing a compound of formula (I) according to any of claims 1-8 wherein Z is - O- , said method comprising a step of allowing a compound of formula (IV)in whichXI is a hydroxy group;R2 is selected fromandR3 is selected fromwhereinR5 is selected from a hydrogen atom, a fluorine atom, a -C=CH group and a -CH2- CH3 group;R6 is a hydrogen atom or a fluorine atom;R7 is a hydrogen atom or a fluorine atom; wherein * indicates the point of attachment of said group with the rest of the molecule, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same;Z is -O-R12 and R13 are identical or different and are independently selected from Cl-C6-alkyl and phenyl;PG is identical or different and is independently selected from a SiR12R12R13 group, a benzyl group, a methoxymethyl group and a tert. -butoxy carbonyl group; the hydroxy group XI being activated by a suitable activation agent, to react with a nucleophilic compound of formula (XXIII),R‘PG’ H(XXIII) in whichR1 is selected fromwherein * indicates the point of attachment of said group with the rest of the molecule, andPG is a tert. -butoxy carbonyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, or a mixture of same; the hydroxy group X4 optionally being activated using a suitable activation agent, optionally protected, to obtain a compound of formula (XXXI)in which Rl, R2, R3, R4 and PG are as defined above, which is finally being deprotected using suitable conditions depending on the protecting groups present, to obtain a compound of formula (I) whereinRl, R2, and R3 are as defined above;R4 is selected from 5-ethynyl-6-fluoro-2 -naphthol, a 5 -ethyl-6-fluoro-2 -naphthol, a fluorinated or non-fluorinated l,3-benzothiazol-2-amine and a 2-amino-l- benzothiophene -3 -carbonitrile ; andZ is -O-.

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