WO2012172043A1 - Dérivés de purine et leur utilisation comme produits pharmaceutiques pour prévenir ou traiter les infections bactériennes - Google Patents

Dérivés de purine et leur utilisation comme produits pharmaceutiques pour prévenir ou traiter les infections bactériennes Download PDF

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WO2012172043A1
WO2012172043A1 PCT/EP2012/061428 EP2012061428W WO2012172043A1 WO 2012172043 A1 WO2012172043 A1 WO 2012172043A1 EP 2012061428 W EP2012061428 W EP 2012061428W WO 2012172043 A1 WO2012172043 A1 WO 2012172043A1
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mmol
cycle
meoh
purin
lcms
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PCT/EP2012/061428
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English (en)
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Dmytro Atamanyuk
Alexis Denis
Vincent Gerusz
Benoît LEDOUSSAL
Yannick Bonvin
Nicolas Desroy
Johan Gold
François Moreau
Mayalen Oxoby
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Laboratoire Biodim
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to novel purine derivatives, their preparation and intermediates, their use as drugs and pharmaceutical compositions containing them.
  • the invention particularly relates to new compounds capable of inhibiting the activity of the Gram- positive bacterial DltA enzyme and their use to prevent and/or treat Gram-positive bacterial infections in humans or animals.
  • the extracellular bacteria responsible for serious infections are capable of growth in the extra cellular fluids and are resistant to the bactericidal action of the host innate immunity.
  • This resistance of bacteria to the innate immunity components allows dissemination of the infection, via the blood, to the various tissues.
  • the components of the innate immunity are either circulating molecules such as the complement factors, and the antibacterial peptides such as defensins, which could have bactericidal effects by direct interactions with the bacterium cell wall, or either circulating cells such as the polymorphonuclear leukocytes (PMNs) able to kill invading bacteria.
  • PMNs polymorphonuclear leukocytes
  • CAMP cationic antimicrobial peptides
  • the dlt operon is responsible for D-alanine modification of cell wall teichoic acids, and its suppression has been linked to attenuated virulence in mice (Peschel et al., J. Infect. Dis. 2002, 186, 214).
  • DltA is a D-alanine:D-alanyl carrier protein ligase acting as the first enzyme controlling the D-alanylation of the teichoic acids as major components of Gram- positive cell wall: the lipoteichoic acids (LTA) and the wall teichoic acids (WTA).
  • novel compounds of the present invention are based on the purine template and unexpectedly display an increased spectrum of activity on Gram-positive bacteria.
  • One of the purposes of the present invention is therefore to provide novel compounds active on DltA and related targets.
  • these compounds advantageously modify the surface charge of the Gram-positive cell wall by inhibiting the D-Alanylation of the teichoic acids.
  • CAMP components of the innate immune system like CAMP such as alpha- defensins, beta-defensins or peptides of the cathelicidin family.
  • bacterial cell wall modifiers they could also be associated and synergize with drugs aiming at treating bacterial infections such as compounds reinforcing the innate immunity of the host, or antibacterials and more specifically with compounds targeting the bacterial cell wall and/or membrane, or for which the bacterial cell wall and/or membrane are a limiting step for penetration.
  • Such compounds include any antibiotics, and more specifically glycopeptides like vancomycin, lipopeptides like daptomycin, antimicrobial peptides like polymixins, cathelicidins, defensins or any synthethic or natural peptide derived from the above listed ones.
  • the association of a DltA inhibitor and an antibacterial could, by lowering the active dose of the antibacterial, expand its therapeutic window.
  • the invention relates to compounds having the general formula (I) (I)
  • A is selected from the group comprising phenyl, naphthyl and 5-10 membered monocyclic or bicyclic unsaturated heterocycle linked by a carbon atom and containing 1-5 heteroatoms selected from N, O and S, all the above members of the group representing A being optionally substituted on a carbon or nitrogen atom by 1-4 identical or different groups Rl as defined below, A can also form a 4-10 membered fused or bridged cycle with Rl, said cycle being closed with Rl and, if appropriate via R a , Rb Or R c of Rl as defined below, by a simple bond or double bond, and two substituent groups Rl can also form a fused or bridged cycle as defined above with each other, by being linked together by a simple bond or double bond;
  • R a , Rb and R c are selected from the group comprising H, (Ci-Ce) alkyl, (C 2 -Ce) alkenyl, (C 2 -C 6 ) alkynyl, trimethylsilyl, phenyl and 4-7 membered monocyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S; two members of R a , R b and R c can also form with each other a 4-10 membered cycle, optionally fused or bridged, as defined above ;
  • Y and W are selected from the group comprising H, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, phenyl and 4-10 monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S, but Y and W cannot be both H or both methyl, all the above members of the group representing Y and W being optionally substituted by 1 -4 identical or different groups Rl defined as above, Y and/or W can also form a 4-10 membered cycle, optionally fused or bridged, with Rl, said cycle being closed with Rl and, if appropriate via R a , Rb or R c of Rl as defined above, by a simple bond or double bond and two substituent groups Rl can also form a cycle with each other as defined above; or Y and W can also form with N a saturated or unsaturated nitrogenous 4-10 membered mono,
  • n in S(0) n R a can be 0, 1 or 2;
  • acid salts of the compounds of formula (I) there may be cited, among others, those formed with mineral acids, such as hydrochloric, hydrobromic, hydroiodic, sulfuric or phosphoric acid or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic acids, such as methanesulfonic and ethanesulfonic acids, arylsulfonic acids such as benzenesulfonic and paratoluenesulfonic acids.
  • mineral acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric or phosphoric acid
  • organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxy
  • base salts of the compounds of formula (I) there may be cited, among others, those formed with mineral alkalis such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, ethylamine, propylamine, trimethylamine, diethylamine, triethylamine, ⁇ , ⁇ -dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, piperidine, piperazine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.
  • mineral alkalis such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases
  • organic bases such as, for example, methylamine, ethylamine, propylamine, trimethylamine, diethylamine, triethylamine, ⁇ , ⁇ -di
  • Ci-C 6 alkyl means any linear, branched or cyclic hydrocarbon groups having 1 to 6 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
  • C 2 -C 6 alkenyl and “C 2 -C 6 alkynyl” as applied herein means any linear, branched or cyclic hydrocarbon groups of 2 to 6 carbon atoms, having at least one double bond or one triple bond and preferably ethenyl, propenyl, butenyl, cyclohexenyl, ethynyl, propargyl, butynyl.
  • Illustrative 5-10 membered monocyclic or bicyclic unsaturated heterocycle containing 1 -5 heteroatoms selected from N, O and S as mentioned in the definition of A in formula (I) are for example those listed hereafter: furyl, benzofuryl, dihydrobenzofuryl, thienyl, benzothienyl, dihydrobenzothienyl, pyrrolyl, indolyl, azaindolyl, indolinyl, indolynyl, indolizidinyl, isoindolyl, pyrazolyl, indazolyl, indazolonyl, isoxazolyl, benzoisoxazolyl, benzoisoxazolonyl, isothiazolyl, benzoisothiazolyl, benzoisothiazolonyl, oxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolonyl, thiazoly
  • Illustrative 4-7 membered monocyclic saturated or unsaturated heterocycle containing 1 -3 heteroatoms selected from N, O and S as mentioned in the definition of R1,R2, R3, Ra, Rb, Rc in formula (I) are azetidinyl, oxetanyl, beta-lactamyl, tetrahydrofuranyl, tetrahydrofuranonyl, furanyl, thiophenyl, tetrahydrothiophenyl, 1,1 -dioxide-dihydrobenzothiophenyl, py rrolyl, pyrrolidinyl, pyrrolidonyl, pyrrolidinedionyl, pyrazolyl, pyrazolonyl, isoxazolyl, isoxazolonyl, isothiazolyl, isothiazolidinyl, 1 ,1 - dioxide-isothiazolidinyl, oxazolyl
  • Illustrative 4-10 membered nitrogenous cyclic system as formed by Y and W, optionally fused or bridged with Rl, are for example those listed hereafter: azetidine, pyrrolidine, piperidine, piperazine, azepane, octahydro-pyrrolo[3,4-c]pyrrole, octahydro-pyrrolo[3,4-b]pyrrole, 1 ,2,3,4,5,6-hexahydro- pyrrolo[3,4-c]pyrrole, octahydro-cyclopenta[c]pyrrole, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, 8- aza-bicyclo[3.2.1]octane, 1,2,3,6-tetrahydro-pyridine, octahydro-pyrrolo[3,4-c]pyridine, 2,8-diaza- spiro[4.5]decane, 3-aza
  • Illustrative 4-10 membered nitrogenous cyclic system as formed by A with Rl or two groups Rl or two of those mentioned above via Ra, Rb and Rc are for example those listed hereafter: benzofuryl, dihydrobenzofuryl, benzothiophenyl, 1,1-dioxide-dihydrobenzothiophenyl, indolyl, indolonyl, azaindolyl, indolinyl, indolizidinyl, isoindolyl, indazolyl, indazolonyl, benzoisoxazolyl, benzoisoxazolonyl, benzoisothiazolyl, benzoisothiazolonyl, benzoisothiazolyl- 1,1 -dioxide, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiazolonyl, benzimidazolyl, benzymidazolon
  • Illustrative 4-10 membered cyclic systems as formed by Rl with R2, by two groups R2, by R2 with R3, by two groups R3, by two of those mentioned above via Ra, Rb and Rc, are for example those listed hereafter : C4-C10-cycloalk l or or C4-C10-cycloalkenyl (monocyclic, fused, bridged, spiro), azetidinyl, oxetanyl, beta-lactamyl, tetrahydrofuranyl, tetrahydrofuranonyl, furanyl, benzofuryl, dihydrobenzofuryl, thiophenyl, benzothiophenyl, tetrahydrothiophenyl, tetrahydrothiophenyl, 1 ,1 -dioxide- dihydrobenzothiophenyl, pyrrolyl, pyrrolidinyl, pyrrolidonyl, pyr
  • the invention relates to compounds of general formula (I) as defined above wherein:
  • A is selected from the group comprising phenyl and 5-10 membered monocyclic or bicyclic unsaturated heterocycle linked by a carbon atom and containing 1 -5 heteroatoms selected from N, O and S, all the above members of the group representing A being optionally substituted on a carbon or nitrogen atom by 1 -4 identical or different groups Rl as defined below, A can also form a 4-10 membered fused or bridged cycle with Rl, said cycle being closed with Rl and, if appropriate via R a , Rb Or R c of Rl as defined below, by a simple bond or double bond, and two substituent groups Rl can also form a fused or bridged cycle as defined above with each other, by being linked together by a simple bond or double bond;
  • Rl is selected from the group comprising F, CI, Br, CN, nitro, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, phenyl, 4-
  • R3 is selected from the group comprising F, (d-C 6 ) alkyl, CONR a R b; OR a , NR a R b , NR a COR b , R a and R b being defined as below, or R3, as indicated above, can also form a cycle with R2, or R3 can also form a 4- 10 membered cycle, optionally fused or bridged, as defined above with Rl, said cycle being closed with Rl and, if appropriate via R a , R b or R c of Rl as defined below, by a simple bond or double bond, or two substituent groups R3 can also form with each other a cycle as defined above;
  • R a , R b and R c are selected from the group comprising H, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, phenyl and 4-7 membered monocyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S; two members of R a , R b and R c can also form with each other a 4-10 membered cycle, optionally fused or bridged, as defined above ;
  • Y and W are selected from the group comprising H, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl and 4-10 monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S, but Y and W cannot be both H or both methyl, all the above members of the group representing Y and W being optionally substituted by 1-4 identical or different groups Rl defined as above, Y and/or W can also form a 4-10 membered cycle, optionally fused or bridged, with Rl, said cycle being closed with Rl and, if appropriate via R a , R b or R c of Rl as defined above, by a simple bond or double bond and two substituent groups Rl can also form a cycle with each other as defined above; or Y and W can also form with N a saturated or unsaturated nitrogenous 4-10 membered mono, bi or tricyclic system, fused, bridged or spiro, optionally
  • n in S(0) n R a can be 0, 1 or 2;
  • Y and W form with N a saturated or unsaturated nitrogenous 4-10 membered mono, bi or tricyclic system, fused, bridged or spiro, optionally containing 1 -3 further heteroatoms selected from N, O and S, said system being optionally substituted on a carbon or nitrogen atom by 1-4 identical or different groups Rl as defined above, and said system being different from morpholine, all the other substituents being defined as above.
  • Y and W form with N a pyrrolidinyl cycle optionally substituted by 1 -4 identical or different groups Rl defined as above, the said cycle and Rl can form a cycle as defined above, and two substituent groups Rl can form a cycle as defined above, all the other substituents being defined as above.
  • Y and W form with N a piperidinyl cycle optionally substituted by 1-4 identical or different groups Rl defined as above, the said cycle and Rl can form a cycle as defined above and two substituent groups Rl can form a cycle as defined above, all the other substituents being defined as above.
  • A is phenyl optionally substituted by 1 -4 identical or different groups Rl as defined above, A and Rl can form a cycle as defined above and two substituent groups Rl can form a cycle as defined above, all the other substituents being defined as above.
  • A is pyridinyl optionally substituted by 1-4 identical or different groups Rl as defined above, A and Rl can form a cycle as defined above and two substituent groups Rl can form a cycle as defined above, all the other substituents being defined as above.
  • A is a bicyclic unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S, optionally substituted by 1-4 identical or different groups Rlas defined above, A and Rl can form a cycle as defined above and two substituent groups Rl can form a cycle as defined above, all the other substituents being defined as above.
  • A is imidazo[4,5-0]pyridinyl optionally substituted by 1-4 identical or different groups Rl , A and Rl can form a cycle as defined above and two substituent groups Rl can form a cycle as defined above, all the other substituents being defined as above.
  • A is benzimidazolyl optionally substituted by 1 -4 identical or different groups Rl, A and Rl can form a cycle as defined above and two substituent groups Rl can form a cycle as defined above, all the other substituents being defined as above.
  • the compounds of the invention are active on DltA and related targets which makes them useful as drugs and another object of the invention is the use of the compounds of formula (I) as drugs for preventing or treating human or animal infections by microbial pathogens.
  • the drugs of the invention are useful as antibacterial agents for the prevention and therapeutical treatment of severe infections due to microbial pathogens, in particular Gram-positive bacteria growing under aerobic or anaerobic conditions.
  • Such drugs are useful against bacteria of the genus Staphylococcus, more specifically S. aureus and coagulase-negative staphylococci like S. epidermidis and S.
  • saprophyticus including multiresistant strains such as mefhicillin-resistant staphylococci, vancomycin intermediate and vancomycin resistant Staphylococcus aureus), Bacillus (including B. anthracis and B. cereus), Listeria (including L. monocytogenes), Enterococcus (including E. faecalis and E. faecium including vancomycin resistant isolates) , Streptococcus (including S. pneumonia, S. agalactiae, S. pyogenes, and streptococci of the viridans group), Corynebacterium (including C. diphtheriae, C. amicolatum, C. striatum, C. jeikeium, C. urealyticum, and C. xerosis) and Clostridium (Including C. botulinum, C. difficile, C. perfringens and C. tetani).
  • Bacillus including B. anthracis and B. cereus
  • the drugs according to the invention are also for use in preventing and treating human or animal bacterial infections, in association with one or more drug(s) and more specifically with one or more antibacterial agent(s) or with one or more antivirulence agent(s) or with one or more drug(s) reinforcing the host innate immunity and this use of the compounds of formula (I) in association constitutes another object of the invention.
  • the invention relates in particular to the use of the compounds of formula (I) in preventing or treating human or animal bacterial infections in association with one or more antibacterial agent(s) targeting the bacterial cell wall and/or membrane.
  • the invention relates in particular to the use in preventing or treating human or animal bacterial infections, in association with one or more antibacterial agent(s) of the CAMP type such as, as non-limiting examples, polymyxins, cathelicidins, defensins or any synthethic or natural peptide derived from the above listed ones.
  • one or more antibacterial agent(s) of the CAMP type such as, as non-limiting examples, polymyxins, cathelicidins, defensins or any synthethic or natural peptide derived from the above listed ones.
  • the invention relates in particular to the use in preventing or treating human or animal bacterial infections, in association with one or more antibacterial agent(s) of the glycopeptides type such as, as non- limiting examples, Vancomycin or Teicoplanin.
  • one or more antibacterial agent(s) of the glycopeptides type such as, as non- limiting examples, Vancomycin or Teicoplanin.
  • the invention relates in particular to the use in preventing or treating human or animal bacterial infections, in association with one or more antibacterial agent(s) of the lipopeptides type such as, as non- limiting examples, Daptomycin.
  • the invention relates in particular to the use in preventing or treating human or animal bacterial infections, in association with one or more drug(s) reinforcing the host innate immunity such as, as non- limiting examples, immunomodulatory peptides.
  • the invention relates in particular to the use in preventing or treating human or animal bacterial infections, in association with GM-CSF (Granulocyte Macrophage Colony-Stimulating Factor), an approved white blood cell growth factor.
  • GM-CSF Gramulocyte Macrophage Colony-Stimulating Factor
  • a further object of the invention is therefore the pharmaceutical mixtures or associations of the compounds of formula (I) with the above defined antibacterials and/or antivirulence agents and/or drugs reinforcing the host innate immunity.
  • the invention also relates to pharmaceutical compositions comprising, as active principle, a therapeutically effective amount of at least one compound of formula (I) such as above defined, as well as pharmaceutical compositions comprising , as active principles, a therapeutically effective amount of at least one compound of formula (I) in association with at least another therapeutically active compound defined above.
  • the active principles are in association with a pharmaceutically acceptable carrier.
  • Said pharmaceutical compositions are advantageously formulated to be administered under oral, topical, transdermal, sublingual, rectal, parenteral including intravenous, intramuscular, intraperitoneal and subcutaneous routes, with individual doses appropriate for the patient to be treated.
  • the injectable routes are preferred.
  • compositions according to the invention can be solid, liquid including solutions, emulsions or suspensions, or in the form of a gel/cream and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the customary methods.
  • the active ingredient/s can be incorporated using excipients which are customarily used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • excipients which are customarily used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • excipients which are customarily used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, aqueous or non-aqueous vehicles, fatty substances of animal or
  • the dose of the compound of formula (I) administered varies according to the condition treated, the patient in question, the administration route and the compound envisaged. It can, for example, be comprised between 0.01 g and 10 g per day in humans.
  • the dose of the associated active principle is the dose normally prescribed for such compound.
  • the compound of formula (I) can be administered in association with vancomycin at doses of 0.5 to 3g per day in human (intravenous administration) or colistin at doses of 0.1 to 0.3g per day in human (intravenous administration).
  • the compounds of formula (I) and their salts may be prepared by processes known to the skilled chemist to be applicable for preparing chemically related compounds. Such processes use known starting materials or intermediates which may be obtained by standard procedures of organic chemistry. The following processes provide a variety of non-limiting routes for the production of the compounds of formula (I) and their intermediates. These processes constitute further features of the present invention.
  • PG represents a suitable protecting group, non limiting examples including tetrahydropyran-2yl, benzyl, allyl or 2-(trimethylsilyl)ethoxymethyl, in the presence of suitable deprotection conditions known to the one skilled in the art, non-limiting examples comprising the use of acidic conditions in the case of tetrahydropyran-2yl, the use of catalytic hydrogenation conditions or hydrazine in the case of benzyl, the use of transition metal conditions in the case of allyl and the use of fluoride conditions in the case of 2- (trimethylsilyl)ethoxymethyl.
  • Z represents H or PG as defined above and X represents a suitable leaving group such as halogen, triflate, mesylate, tosylate or S(0) n R a , n and R a being as defined above, with a compound of formula (IV):
  • Y and W are as defined above, in the presence of suitable aromatic nucleophilic substitution conditions known to the skilled in the art, non limiting examples comprising the use of a base such as triethylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, sodium, potassium or cesium carbonate or hydroxide, in a suitable solvant such as tetrahydrofuran, acetonitrile, dimethylformamide, N- Methyl-2-pyrrolidone, methanol, ethanol, propanol, butanol, monoglyme, diglyme, 1 ,4-dioxane or dimethylsulfoxide, or transition-metal catalyzed coupling conditions known to the skilled in the art, non limiting examples comprising the use of palladium catalyst such as tris(dibenzylideneacetone)dipalladium, an appropriate ligand such as Xantphos,
  • A is as defined above and V represents an optionally substituted boron, tin , zinc, magnesium or copper, in the presence of suitable coupling conditions known to the one skilled in the art such as the Suzuki, Stille, Negishi, Kumada or Ullmann couplings (Chem. Rev. 2002, 102, 1359 or Tetrahedron 2005, 61, 2245), a non-limiting example comprising the use of a palladium catalyst, a phosphine ligand, a suitable base and solvent.
  • Condensation reactions Condensations leading to double bonds, in The Chemistry of Carbonyl Group: Volume 1 (1966) (ed S. Patai), Interscience Publishers; J. Alvarez-Builla, J. Jose Vaquero, J. Barluenga, Modern Heterocyclic Chemistry, Wiley, 2011 ; Carbon chain elongation such as Wittig, Grignard, Petasis, Tebbe, Peterson, base-promoted substitution reactions: Li, J. J. (ed) Name Reactions for Homologations, John Wiley & Sons, Inc., 2009;
  • CDC1 3 is deuteriochloroform
  • DMSO-d 6 is hexadeuteriodimethylsulfoxide
  • CD 3 OD is tetradeuteriomethanol.
  • Mass spectra were obtained using electrospray ionization (ESI) techniques on an Agilent 1100 Series LCMS and 2795 Alliance Waters LCMS.
  • Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on Flashsmart Pack cartridge irregular silica 40-60 ⁇ or spherical silica 20-40 ⁇ .
  • Preparative thin layer chromatography was carried out on Analtech Silica Gel GF 1000 ⁇ 20x20 cm.
  • ESI electrospray ionization
  • HPLC high pressure liquid chromatography
  • LCMS liquid chromatography coupled with a mass spectrometer
  • M in the context of mass spectrometry refers to the molecular weight
  • MS mass spectrometer
  • NMR nuclear magnetic resonance
  • pH pH refers to potential of hydrogen
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • DIPEA N,N-diisopropylethylamine
  • HOBt 1 -hydroxybenzotriazole
  • THF tetrahydrofuran
  • DCM dichloromethane
  • ACN or MeCN refers to acetonitrile
  • EtOAc refers to ethyl acetate
  • DME refers to 1, 2 -dimethoxy ethane
  • DMF refers to NN- dimethylformamide
  • the crude product was purified by preparative TLC on silica gel or silica gel column chromatography using a suitable eluent (usually a mixture such as cyclohexane/ EtOAc or CH 2 Cl 2 /MeOH) or by trituration in a convenient solvent (usually CH 2 CI 2 , EtOAc or Et 2 0) to afford the desired product.
  • a suitable eluent usually a mixture such as cyclohexane/ EtOAc or CH 2 Cl 2 /MeOH
  • a convenient solvent usually CH 2 CI 2 , EtOAc or Et 2 0
  • the crude product was purified by preparative TLC on silica gel or silica gel column chromatography using a suitable eluent (usually a mixture such as cyclohexane/EtOAc or CH 2 Cl 2 /MeOH + 1 - 3% of ammoniac 7N in MeOH or ammonium hydroxide 33%) or by trituration in a convenient solvent (usually CH 2 C1 2 , EtOAc or Et 2 0) to afford the desired product.
  • a suitable eluent usually a mixture such as cyclohexane/EtOAc or CH 2 Cl 2 /MeOH + 1 - 3% of ammoniac 7N in MeOH or ammonium hydroxide 33
  • a convenient solvent usually CH 2 C1 2 , EtOAc or Et 2 0
  • lc was prepared according to general procedure B using 4-(methylsulfonyl)phenylboronic acid (105 mg, 0.52 mmol), lb (137 mg, 0.50 mmol), K 2 C0 3 (104 mg, 0.75 mmol) and Pd(PPh 3 ) 4 (14.5 mg, 0.013 mmol) in DME/H 2 0 3: 1 (3 mL). After stirring the reaction mixture at 100°C overnight, water was added and the reaction mixture was extracted with Et 2 0 and EtOAc. The combined organic extracts were dried and evaporated. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /EtOAc 9:1) afforded lc (58 mg, 29%) as a white solid.
  • Step 3 tert-Butyl (l- ⁇ 6-[4-(methylsulfonyl)phenyl]-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl ⁇ -piperidin-
  • Id was prepared according to general procedure C. Under argon, DIPEA (26 ⁇ , 0.148 mmol) was added to a solution of lc (58 mg, 0.147 mmol) and tert-butyl piperidin-4-ylmethylcarbamate (65 mg, 0.30 mmol) in anhydrous MeCN (0.6 mL). The reaction mixture was stirred at 85°C for 72 hours, and then evaporated. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded Id (75 mg, 90%) as a yellow solid.
  • Trimethyl orthoformate (36 0.33 mmol) and PTSA (10 mg, 0.06 mmol) were added to a solution of 2c (79 mg, 0.3 mmol) in toluene (4mL). The reaction mixture was stirred at reflux for 2 hours. Trimethyl orthoformate (36 0.33 mmol) was added and the mixture was stirred for another 2 hours at reflux. The solution was evaporated, dissolved with CH 2 C1 2 , washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried and evaporated to give 2d (67 mg, 82%).
  • Step 5 Piperidine-l,4,4-tricarboxylic acid 1-teri-butyl ester 4,4-diethyl ester (2.2b)
  • n-Buthyl lithium 2.5M in hexane 33.0 niL, 53.04 mmol was added to a solution of diisopropyl amine (7.43 mL, 53.04 mmol) in anhydrous THF (70 mL) at -78°C.
  • the pale yellow solution was allowed to warm up to room temperature for 10 min and was then cooled down to -78°C.
  • 2.2a (4.55 g, 17.68 mmol) in anhydrous THF (15 mL) was added dropwise and the resulting mixture was stirred for 1 hour at -78°C.
  • LiBH 4 (990 mg, 45.53 mmol) was added portionwise to a solution of 2.2b (3.0 g, 9.11 mmol) in anhydrous toluene/THF 1 : 1 (80 mL). The resulting mixture was stirred at 60°C for 14 hours. A 10% aqueous solution of Rochelle's salt was added and the organic phase was extracted with EtOAc then CH 2 C1 2 . The combined organic layers were dried and evaporated to give the crude product. Purification of the crude product by silica gel column chromatography (eluent: CH 2 Cl 2 /MeOH 95 :5 to 9:1) afforded 2.2c (1.76 g, 79%).
  • 2.2d was prepared according to general procedure D stirring 2.2c (900 mg, 2.60 mmol) in the presence of HCl 4N in dioxane (4 mL) and MeOH (4 mL) for 3 hours. Solvents were removed under reduced pressure to give the crude product which was diluted with CH 2 C1 2 and evaporated to give 2.2d (638 mg, 96%).
  • Step 8 2-Chloro-6-(l-pyridin-3-yl-lH-benzoimidazol-5-yl)-9-(tetrahydro-pyran-2-yl)-9H-purine (2f)
  • lb 2f 2f was prepared according to general procedure B using 2e (328 mg, 1.02 mmol), lb (279 mg, 1.02 mmol), K 2 C0 3 (408 mg, 2.95 mmol), Pd(PPh 3 ) 4 (59 mg, 0.05 mmol) in THF/H 2 0 5:1 (9 mL). Purification of the crude product by trituration in EtOAC afforded 2f (236 mg, 53%).
  • Step 9 ⁇ 4-Hydroxymethyl-l-[6-(l-pyridin-3-yl-lH-benzoimidazol-5-yl)-9-(tetrahydro-pyran-2-yl)-9H-
  • 2g was prepared according to general method C stirring 2f (60 mg, 0.14 mmol), 2.2d (30 mg, 0.17 mmol) and DIPEA (97 0.56 mmol) in n-BuOH (2.5 mL) at 110°C for 66 hours. Solvents were removed under reduced pressure and the product was purified using preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1) to give 2g (34 mg, 45%).
  • Step 10 ⁇ 4-Hydroxymethyl-l-[6-(l-pyridin-3-yl-lH-benzoimidazol-5-yl)-9H-purin-2-yl]-
  • 2h was prepared according to general procedure D stirring 2g (34 mg, 0.063 mmol) in MeOH (lmL), 1 ,4-dioxane (lmL) and HC1 4N in 1 ,4-dioxane (1 mL) at room temperature for 3 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 1% of NH 3 7N in MeOH) followed by trituration in water to remove the ammonium salt afforded 2h (18 mg, 63%).
  • 3a was prepared according to general procedure B using 4-chloro-3-nitrophenylboronic acid (443 mg, 2.2 mmol), lb (546 mg, 2 mmol), K 2 C0 3 (414 mg, 3 mmol) and Pd(PPh 3 ) 4 (58 mg, 0.05 mmol) in DME/H 2 0 3 :1 (12 mL). Purification of the crude product by column chromatography on silica gel (eluent: cyclohexane/EtOAc 9:1) afforded 3a (320 mg, 40%) as a white solid.
  • Step 2 N-[4-(2-Chloro-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-yl)-2-nitrophenyl]-N-
  • Step 3 5-[6-(4-Methylamino-3-nitro-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]- hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid teri-butyl ester (3c)
  • 3c was prepared according to general procedure C using 3b (330 mg, 0.85 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (361.8 mg, 1.7 mmol) and DIPEA (446.4 2.55 mmol) in anhydrous MeCN (3.5 mL) at 85°C for 72 hours. Purification of the crude product by flash column chromatography on silica gel (eluent: CH 2 Cl 2 /MeOH gradient 1 :0 to 95:5) afforded 3c (401 mg, 80%) as an orange solid.
  • Step 4 5-[6-(l-Methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-yl)-9-(tetrahydro-pyran-2-yl)-9H-purin- 2-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid teri-buryl ester (3d)
  • 3e was obtained from 3d (33.5 mg, 0.06 mmol) by reaction with hydrogen chloride 4N in 1,4-dioxane. Purification of the crude product by trituration in Et 2 0 then CH 2 C1 2 afforded 3e (16.4 mg, 66%) as a yellow solid.
  • 4a was obtained according to general procedure B using lb (1.9 g, 7 mmol), 4-methoxyphenylboronic acid (1.16 g, 7.7 mmol), K 2 C0 3 (1.45 g, 10.5 mmol) and Pd(PPh 3 ) 4 (58 mg, 0.050 mmol) in degassed water (7 mL) and toluene (70 mL) at 100°C for 16h. EtOAc was added and a precipate appeared which was filtered to give 4a (1.67 g, 70%) as a yellow solid.
  • N-bromosuccinimide (520 mg, 2.92 mmol) was added to a solution of 4a (500 mg, 1.45 mmol) in anhydrous MeCN (5 mL). The reaction mixture was stirred at 85°C overnight. The solution was filtered and the precipitate was rinsed with MeCN to afford 4b (370 mg, 75%) as an off-white solid.
  • Step 4 5-[6-(3-Bromo-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]- he
  • 4c 4d 4d was prepared according to the SN ⁇ reaction general procedure C using 4c (110 mg, 0.26 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (22 mg, 0.39 mmol) and DIPEA (80 ⁇ , 0.44 mmol). in anhydrous MeCN (1.5 mL) at 85°C for 48 hours. n-BuOH (1.5 mL) was added and the reaction mixture was stirred at 100°C for 24 hours. 4d was isolated by precipitation of the concentrate in Et 2 0 (100 mg, 64%). Purification of the filtrate by preparative TLC on silica gel (eluent: CLLC ⁇ /MeOH 95:5) afforded additional quantity of 4d (14 mg, 9%>) as a white solid.
  • Step 5 5-[6-(3-Acetylamino-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]- hexah dro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (4e)
  • Step 6 N-[2-methoxy-5-(2-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl-9H-purin-6-yl)phenyl]-acetamide
  • 4f was obtained according to general procedure D using MeOH (125 ⁇ ), hydrogen chloride 4N in dioxane (375 ⁇ , 1.5 mmol), 4e (18 mg, 0.031 mmol) stirred at 0°C for 30 minutes. The mixture was allowed to warm up to room temperature and was concentrated. The solid obtained was collected and rinsed with Et 2 0, CH 2 C1 2 and dried to afford 4f (9.5 mg, 70%) as a yellow solid.
  • Step 2 Ethyl (la, 5a, 6a)-3-[6-(4-methoxyphenyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl]- -azabicyclo[3.1.0]hexane-6-carboxylate (5c)
  • 5c was prepared according to general procedure C stirring 4a (127 mg, 0.38 mmol), 5b and DIPEA
  • Step 3 (la, 5a, 6a)- ⁇ 3-[6-(4-methoxyphenyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl]-3- azabicyclo [3.1.0] hex-6-yl ⁇ methanol (5d)
  • Step 4 2-[(la, 5a, 6a)-6-(Azidomethyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-(4-methoxyphenyl)-9-tetrahydro- 2H-pyran-2-yl-9H-purine (5e)
  • Step 5 (la, 5a, 6a)- ⁇ 3-[6-(4-Methoxyphenyl)-9H-purin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl ⁇ methylamine (5f)
  • 7a was prepared according to the Suzuki coupling general procedure B using 3-formyl-4- methoxyphenylboronic acid (3.505g, 19.5 mmol), lb (4.83g, 17.7 mmol), potassium carbonate (3.66g, 26.55 mmol), Pd(PPh 3 ) 4 (511 mg, 0.44 mmol) in a mixture of DME and water (3: 1; 0.18 mol/L) in reaction at 100°C for 16 hours. Purification of the crude product by trituration in CH 2 C1 2 afforded 7a (4.817g, 73%). LCMS (ESI+) m/z 373/375 (M+H) + .
  • Step 2 5-[6-(3-Formyl-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]- hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (7b)
  • 7b was prepared according to the SN ⁇ reaction general procedure C using 7a (2.0 g; 5.36 mmol), 3c (2.28 g; 10.73 mmol), DIPEA (1.03 mL; 5.90 mmol) in anhydrous MeCN (10 niL) at 85°C for 16 hours. Purification of the crude product by column chromatography on silica gel (eluent: cyclohexane/EtOAc from 7:3 to 6:4) afforded 7b (530 mg, 18%) as a white solid.
  • Step 3 5-[6-(3-Carboxy ⁇ -methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]- hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (7c)
  • 7e was synthesized according to general procedure D using 7d (15 mg, 0.027 mmol) in a mixture of water (0.10 mL) and hydrogen chloride 4N in dioxane (0.4 mL, 1.6 mmol) cooled to 0°C. The reaction mixture was stirred for 30 minutes allowing the temperature to rise to room temperature. The solid obtained after concentration was collected and rinsed with Et 2 0, CH 2 CI 2 and dried to give 7e (8.8 mg, 79%>) as a yellow solid.
  • Step 3 7-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-3,7-diaza- bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (8d) / thp ,thp
  • 8d was prepared according to general procedure C using 4a (63 mg, 0.18 mmol), 3,7-diaza- bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (51 mg, 0.22 mmol max.), diisopropylethylamine (32 ⁇ ; 0.18 mmol) in MeCN (0.8 mL) at 85°C for 24 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 8d (70.5 mg; 72%) as a white solid.
  • 8e was prepared according to the general procedure D stirring 8d (70.5 mg, 0.13 mmol) in MeOH (0.125 mL) and HCl 4N in dioxane (0.375 mL, 1.5 mmol) at 0°C for 50 minutes then allowed to warm up to room temperature. MeOH was added and the mixture was concentrated. The solid obtained was collected and triturated with Et 2 0, CH 2 C1 2 and dried to give 8e (43 mg, 84%) as a white solid.
  • 4a 9a 9a was prepared according to general procedure C using 4a (344 mg, 1 mmol), piperidine-3- carboxylic acid amide (270 mg, 2 mmol) and DIPEA (175 1 mmol) in anhydrous MeCN (4 mL) at 85 °C for 22 hours. Filtration of the white precipitate, following by additional aqueous washing and concentration of the organic phase afforded 9a (355 mg, 82%) as a white solid.
  • Step 2 ⁇ l-[6-(4-methoxyphenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]piperidin-3-yl ⁇ -methylamine
  • Step 3 [( ⁇ l-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperidin-3-ylmethyl ⁇ -
  • Step 1 ⁇ l-[6-(3-Bromo-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]- piperidin-4-ylmethyl ⁇ -carbamic acid tert-but l ester (10a)
  • 10a was prepared according to general method C stirring 4c (510 mg, 1.2 mmol) /er/-butyl N-(4- piperidinylmethyl) carbamate (513 mg, 2.4 mmol) and DIPEA (220 1.2 mmol) in anhydrous MeCN (0.8 mL) for 48 hours. Purification of the crude product by silica gel column chromatography (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 10a (360 mg, 50%) as a yellow solid.
  • Step 2 C- ⁇ l-[6-(3-Bromo-4-methoxy-phenyl)-9H-purin-2-yl]-piperidin-4-yl ⁇ -methylamine
  • 10b was prepared according to general procedure D stirring 10a (50 mg, 0.083 mmol) with HC1 4N in 1 ,4-dioxane (3 mL) and MeOH (1.5 mL). Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 2% of saturated NH 3 in MeOH) afforded 10b (4.5 mg, 13%) as a white solid. LCMS (ESI+) m/z 457 (M+H) + .
  • Step 2 ⁇ l-[6-(2-Hydroxymethyl-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]- piperidin-4-ylmethyl ⁇ -carbamic acid tert-butyl ester (lib)
  • 1 lb was prepared according to the general procedure C stirring 11a (87.7 mg, 0.23 mmol), tert-butyl piperidin-4-ylmethylcarbamate (111 mg, 0.47 mmol) and DIPEA (40 0.23 mmol) in anhydrous MeCN (0.9 mL) at 85°C for 24 hours. A dilute aqueous solution of hydrochloric acid was added and the mixture was extracted with Et 2 0 and EtOAc. The combined organic extracts were dried and evaporated. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 93:7) led to l ib (107.4 mg, 83%) as a yellow solid.
  • step 1 a solution of 12a (2S,4R 250 mg, 1 mmol) and palladium hydroxide (20%, 75 mg) in ethanol (6 mL) was stirred at room temperature under hydrogen pressure (5 bar) for 4.5 hours. The reaction mixture was then filtered on a pad of celite, and the filtrate was concentrated to give crude 12b which was engaged as such in the next step.
  • Step 2 (3R,5S)-5-(Hydroxymethyl)-l-[6-(4-methoxyphenyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-
  • 12c was prepared according to general procedure C using 4a (86 mg, 0.25 mmol), DIPEA (45 ⁇ , 0.26 mmol) in anhydrous MeCN (1 mL) at 85°C overnight. Then ethanol (0.5 mL) was added and the reaction mixture was stirred at 85°C for 24 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1) led to 12c (79 mg, 74%) as a white solid.
  • Example 13 2-Hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl-6-(4-methoxy-3-nitrophenyl)-9H-purine (13c) -Chloro-6-(4-methoxy-3-nitrophenyl)-9-tetrahydro-2H-pyran-2-yl-9H-purine (13a)
  • 13a was prepared according to general procedure B using lb (1.15g, 4.2 mmol), 4-methoxy-3- nitrophenylboronic acid (993 mg, 5.04 mmol), potassium carbonate (870 mg, 6.3 mmol) in a mixture of DME and water (9:1 ; 0.1 mol/L, 42 mL) at 100°C for 16 hours. Purification of the crude product by column chromatography on silica gel (cyclohexane/EtOAc 1 : 1) afforded 13a (1.18 g, 72%).
  • Step 2 5-[6-(4-Methoxy-3-nitro-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (13b)
  • 13b was prepared according to general procedure C using 13a (12.5mg, 0.032 mmol), ieri-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (14 mg, 0.064 mmol), DIPEA (5.6 0.032 mmol) in anhydrous MeCN (0.4 mL) at 85 °C for 25 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /EtOAc 9:1) led to 13b (16 mg, 87%) as a white solid.
  • 13c was obtained according to general procedure D using 13b (16 mg, 0.028 mmol) in a mixture of MeOH (0.1 mL) and hydrogen chloride 4N in dioxane (0.25 mL, 1 mmol) cooled to 0°C. The reaction mixture was stirred for 30 minutes allowing the temperature to rise to room temperature. After addition of MeOH and concentration, the yellow solid was triturated with Et 2 0 and CH 2 C1 2 to afford 13c (8.3 mg, 77%) LCMS (ESI+) m/z 382 (M+H) + .
  • Step 1 l-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperidine-3- carboxylic acid ethyl ester (14a)
  • 14a was prepared according to general procedure C using 4a (690 mg, 2.0 mmol), piperidine-3- carboxylic acid ethyl ester (621 4.0 mmol), DIPEA (350 2.0 mmol) in anhydrous MeCN (8 mL) at 85°C for 2 days. Purification of the crude product chromatography on silica gel (eluent: CH 2 Cl 2 /EtOAc 1 :0 to 95:5) led to 14a (652 mg, 70%) as a white solid.
  • Step 2 l-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperidine-3- carboxylic acid (14b)
  • Step 3 l-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperidine-3-
  • Step 4 l-[6-(4-Methoxy-phenyl)-9H-purin-2-yl]-piperidine-3-carboxylic acid (2-hydroxy-ethyl)-amide
  • 14d was obtained according to general procedure D using 14c (35 mg, 0.073 mmol) in a mixture of MeOH (0.25 mL) and hydrogen chloride 4N in dioxane (0.75 mL, 3 mmol) cooled to 0°C. The reaction mixture was stirred for 30 minutes allowing the temperature to rise to room temperature. After neutralization of reaction mixture by addition of few drops of 10% aqueous solution of KOH the reaction mixture was concentrated under vacuum. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1) afforded 14d (19.4 mg, 67%) as a white solid.
  • Step 1 5-[2-(2-teri-Butyloxycarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-5-yl)-9-(tetrahydro-pyran-2-yl)-
  • 15a was prepared according to general procedure A stirring 4d (100 mg, 0.167 mmol), bis(pinacolato)diboron (63.6 mg, 0.25 mmol), Pd(dppf)Cl 2 « CH 2 Cl 2 (6.8 mg, 0.008 mmol) and potassium acetate (49.2 mg, 0.5 mmol) in anhydrous DMF at 85°C for 20 hours. Solvent was concentrated, the mixture was partitioned between HC1 0.1M in water and EtOAc and extracted with EtOAc. The combined organic layers were dried and concentrated under vacuum. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 15a (30 mg, 32%) as a white solid.
  • 15b was prepared according to general procedure D using 15a (30 mg, 0.053 mmol) in a mixture of MeOH (0.25 mL) and hydrogen chloride 4N in dioxane (0.75 mL, 3 mmol) cooled to 0°C. The reaction mixture was stirred for 30 minutes allowing the temperature to rise to room temperature. After addition of MeOH and concentration, the yellow solid obtained was triturated with Et 2 0, filtered and washed with Et 2 0 and CH 2 C1 2 to afford 15b (9.4 mg, 47%) as a yellow solid.
  • Step 1 5-Benzyl-4,6-dioxo-l,3a,4,5,6,6a-hexahydro-pyrrolo[3,4-c]pyrrole-l-carboxylic acid ethyl ester
  • Step 2 5-Benzyl-l-hydroxymethyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester
  • Step 4 l-Hydroxymethyl-5-[6-(4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]- hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (16d)
  • 16d was prepared according to general procedure C using 4a (172 mg, 0.5 mmol), crude 16c (136 mg, 0.56 mmol) and DIPEA (175 ⁇ , 1 mmol) in the anhydrous MeCN (2 mL) at 85°C for 48 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1) afforded 16d (168 mg, 61%) as a white solid.
  • Step 5 ⁇ 5-[6-(4-Methoxy-phenyl)-9H-purin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrol-l-yl ⁇ -methanol
  • 16e was prepared according to general procedure D using 16d (50 mg, 0.091 mmol) in hydrogen chloride 4N in dioxane (0.5 mL, 2.0 mmol) and MeOH (0.2 mL) cooled to 0°C. The reaction mixture was stirred for 1 hour allowing the temperature to rise to room temperature, and then concentrated. The yellow precipitate obtained was washed with CH 2 C1 2 and Et 2 0 to afford 16e (29.5 mg, 81%) as a yellow solid.
  • 17a 17b 17b was prepared according to general procedure A using 17a (133 mg, 0.5 mmol), bis(pinacolato)diboron (190 mg; 0.75 mmol), Pd(dppf)Cl 2 , CH 2 Cl 2 (20 mg, 0.025 mmol), potassium acetate (147 mg, 1.5 mmol) in anhydrous DMF (3 mL) at 85 °C for 16 hours.
  • the reaction mixture was quenched by addition of water and diluted aqueous HC1 solution and then extracted with AcOEt (x3). The combined organic phases were dried and concentrated.
  • the crude was purified by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 92:8) to yield 17b (91 mg, 58%) as white solid.
  • 17c was prepared according to general procedure B using 17b (91 mg, 0.29 mmol), lb (79 mg, 0.29 mmol), K 2 C0 3 (60 mg, 0.44 mmol) and Pd(PPh 3 ) 4 (8.4 mg, 0.007 mmol) in a mixture of DME (1.3 mL) and water (0.4 mL) at 100°C for 16 hours. Purification of the crude product by preparative TLC on silica gel
  • Step 3 5-[6-(4-Methoxy-3-sulfamoyl-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (17d)
  • 17d was prepared according to general procedure C using 17c (58 mg, 0.135 mmol), hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (58 mg, 0.27 mmol), DIPEA (72 uL, 0.411 mmol) in anhydrous MeCN (0.6 mL) at 85°C for 48 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 17d (58 mg, 70%) as a yellow solid.
  • Example 18 C- ⁇ l-[6-(4-Methylsulfanyl-phenyl)-9H-purin-2-yl]-piperidin-4-yl ⁇ -methylamine (18c) ahydro-pyran-2-yl)-9H-purine
  • 18a was prepared according to the general procedure B stirring 4-methylsulfanyl-phenylboronic acid (88 mg, 0.53 mmol), lb (137 mg, 0.5 mmol), potassium carbonate (104 mg, 0.75 mmol) and Pd(PPh 3 ) 4 (14.5 mg, 0.013 mmol) in a mixture of DME (2.25 mL) and water (0.75 mL) at 100°C for 16 hours. Purification of crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 97:3) afforded 18a (107 mg, 59%) as a white solid.
  • Step 2 ⁇ l-[6-(4-Methylsulfanyl-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperidin-4- ylmethyl ⁇ -carbamic acid tert-butyl ester (18b)
  • 18b was prepared according to the general procedure C stirring 18a (107 mg, 0.3 mmol), piperidin-4- ylmethyl-carbamic acid tert-butyl ester (131 mg, 0.6 mmol) and DIPEA (52 0.3 mmol) in anhydrous MeCN (1.2 niL) at 85 °C for 72 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /EtOAc 9:1) afforded 18b (102 mg, 64%) as a pale yellow solid.
  • Step 3 C- ⁇ l-[6-(4-Methylsulfanyl-phenyl)-9H-purin-2-yl]-piperidin-4-yl ⁇ -methylamine (18c)
  • 18c was prepared according to general procedure D using 18b (102 mg, 0.19 mmol) in hydrogen chloride 4N in dioxane (1.5 niL) and MeOH (0.5 niL) cooled to 0°C. The reaction mixture was stirred for 2 hours allowing the temperature to rise to room temperature, then concentrated. KOH IN solution, saturated NaHC0 3 solution were added and the mixture was extracted with EtOAc. The combined organic phases were dried and evaporated. The crude product was purified by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 0.2% of 33% aqueous ammonia) to afford 18c (10.2 mg, 10%) as a white solid.
  • 19a was prepared according to general procedure B stirring lb (190 mg, 0.70 mmol), 2- naphthylboronic acid (145 mg, 0.84 mmol), K 2 C0 3 (145 mg, 1.05 mmol) and Pd(PPh 3 ) 4 (20 mg, 0.017 mmol) in 1 ,2-dimethoxyethane (7 mL) and water (0.7 mL) at 85 °C for 20 hours. Purification of the crude product by silica gel column chromatography (eluent: cyclohexane/EtOAc 7:3) afforded 19a (183 mg, 72%).
  • Step 2 5-[6-Naphthalen-2-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-hexahydro-pyrrolo-[3,4-
  • 19b was prepared according to general procedure C stirring 19a (35 mg, 0.096 mmol), boc-3,7- diazabicyclo[3.3.0]octane (25 mg, 0.11 mmol) and DIPEA (25 ⁇ , 0.14 mmol) in anhydrous MeCN (0.1 mL) at 85°C for 48 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 98:2) afforded 19b (40 mg, 77%) as a pale yellow solid.
  • 19b 19c 19c was prepared according to general procedure D stirring 19b (40 mg, 0.074 mmol) with HC1 4N in 1 ,4 -dioxane (2 mL) and MeOH (1 mL) at room temperature for 1 hour. Purification of the crude product by trituration with CH 2 C1 2 and Et 2 0 afforded 19c (16.5 mg, 57%) as a yellow solid.
  • Example 20 6-(4-Methoxyphenyl)-2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-9H-purine (20b)
  • Step 1 6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-2-(3,4,5,6-tetrahydro-lH-pyrrolo[3,4-c]pyrrol- 2-yl)-9H-purine (20a)
  • 20a was prepared according to general procedure C using l ,2,3,4,5,6-hexahydro-pyrrolo[3,4- c]pyrrole dihydrobromide (90 mg, 0.42 mmol) (obtained according to Heterocycles, 1995, 1291; J. Org. Chem., 2009, 2039), 4a (0.42 mmol, 143 mg) and DBU (1.15 mmol, 0.17 mL) in anhydrous MeCN (2 mL) under argon. The mixture was heat at 80°C for 5 hours, and then cooled to 0°C. A partially precipitated white solid was filtered (42 mg, pure in LC-MS).
  • the filtrate was purified by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 0.05% of 33% aqueous ammonia) to afford 20a (44 mg, 25%) as a white solid.
  • Step 2 6-(4-Methoxyphenyl)-2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-9H-purine (20b)
  • 20b was prepared according to general procedure D using 20a in MeOH (0.4 mL) and hydrogen chloride 4N in dioxane (0.5 mL) cooled to 0°C. The reaction mixture was stirred for 1 hour allowing the temperature to rise to room temperature. The white solid precipitate was filtered, washed with MeOH and Et 2 0 to afford 20b (5 mg, 12%) as a white solid.
  • Step 1 6-(3-Bromo-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-2-(3,4,5,6-tetrahydro-lH-
  • 21a was prepared according to general procedure C using 4c (456 mg, 1.1 mmol), 1,2,3,4,5,6- hexahydro-pyrrolo[3,4-c]pyrrole dihydrobromide (335 mg, 1.2 mmol) ⁇ Heterocycles, 1995, 1291; J. Org. Chem., 2009, 2039) and DBU (0,49 mL, 3,3 mmol) in anhydrous MeCN (5 mL) under argon. The mixture was heat at 80°C for 5 hours, and then cooled to 0°C.
  • Step 2 5-[6-(3-Bromo-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-3,4,5,6-tetrahydro- lH-pyrrolo[3,4-c]pyrrole-2-carboxylic acid teri-butyl ester (21b)
  • Step 3 5-[6-(3-Bromo-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-3a,6a-dihydroxy- hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid teri-butyl ester (21c)
  • Step 4 2-[6-(3-bromo-4-methoxyphenyl)-9H-purin-2-yl]tetrahydropyrrolo[3,4-c]pyrrole-3a,6a(lH,4H)- diol (21d)
  • Step 1 [6-(3-Bromo-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-(3-imidazol-l-yl- propylamine (22a)
  • 22a was prepared according to general procedure C stirring 4c (100 mg, 0.24 mmol), DIPEA (0.08 mL, 0.47 mmol) and l-(3-aminopropyl)imidazole (22 mg, 0.36 mmol) in n-BuOH (1 mL) under argon at 100°C for 48 hour, then at 110°C for 20 hours.
  • the crude residue was purified by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1) to yield 22a (66 mg, 55%) as a clear colorless oil.
  • Step 2 3- ⁇ 3-[6-(3-Bromo-4-methoxy-phenyl)-9H ⁇ urin-2-ylamino]-propyl ⁇ -3H-imidazol-l-ium chloride
  • 22b was prepared according to general procedure D using 22a (12 mg, 0.02 mmol) in a mixture of MeOH (0.5 mL) and hydrogen chloride 4N in dioxane (0.5 mL) cooled to 0°C. The reaction mixture was stirred for 2 hours allowing the temperature to rise to room temperature. The reaction mixture was concentrated and the solid residue was purified by trituration in a mixture of CH 2 C1 2 /Et 2 0 to afford 22b (10 mg, 92%) as a yellow solid.
  • 23c was prepared according to general procedure B using 23b (270 mg, 1.0 mmol), lb (273 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol) and Pd(PPh 3 ) 4 (57 mg, 0.05 mmol) in 1,4-dioxane (3 mL) and water (1 mL) at 80°C for 16 hours. Purification of the crude product by preparative TLC in silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 23c (192 mg, 50% over 2 steps) as a white solid with traces of OPPh 3 . LCMS (ESI+) m/z 386/388 (M+H) + .
  • Step 3 5- [6-[4-(Acetyl-methyl-amino)-phenyl] -9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl] -hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (23 d)
  • 23d was prepared according to general procedure C using 23b (67 mg, 0.17 mmol), tert-butyl cis- hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (48 mg, 0.23 mmol) and DIPEA (0.06 mL, 0.29 mmol) in anhydrous MeCN (0.5 mL) at 85 °C for 5 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 23d (60 mg, 62%) as a clear oil.
  • Step 4 5- ⁇ 6-[4-(Acetyl-methyl-amino)-phenyl]-9H-purin-2-yl ⁇ -octahydro-pyrrolo[3,4-c]pyrrol-2-ium chloride (23e)
  • 23e was prepared according to general procedure D using 23d (60 mg, 0.11 mmol) in a mixture of MeOH (0.6 mL) and hydrogen chloride 4N in 1,4-dioxane (0.9 mL) cooled to 0°C. The reaction mixture was stirred for 2 hour allowing the temperature to rise to room temperature. The reaction mixture was partially concentrated and the resulting solid was washed with MeOH and Et 2 0 to afford 23 e (22 mg, 50%) as yellow solid.
  • Step 4 l-Methyl-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,3-dihydro-benzoimidazol-2-one
  • Step 5 5-[2-Chloro-9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-l-methyl-l,3-dihydro- benzoimidazol-2-one (24f)
  • 24f was prepared according the general procedure B stirring 24e (50 mg, 0.18 mmol), lb (52 mg, 0.19 mmol), potassium carbonate (38 mg, 0.27 mmol), and Pd(PPh 3 ) 4 (10 mg, 0.009 mmol) in 1,4-dioxane (1 niL) and water (0.3 mL) at 80°C for 16 hours. Filtration after cooling afforded crude 24f (25 mg, 34%) as a white solid. Purification of the filtrate by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH) yielded the desired compound (20 mg, 27%) as a white solid.
  • Step 6 5-[2-Chloro-9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-l,3-dimethyl-l,3-dihydro-
  • Step 7 5-[6-(l,3-Dimethyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-yl)-9-(tetrahydro-pyran-2-yl)-9H- ut l ester (24h)
  • 24g 24h 24h was prepared according to general procedure C stirring 24g (24 mg, 0.06 mmol), ieri-butyl cis- hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (22 mg, 0.09 mmol) and DIPEA (0.02 mL, 0.1 mmol) in anhydrous MeCN (0.5 mL) at 85°C for 24 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) yielded 24h (8 mg, 23%) as a white solid.
  • Step 7 5-[2-(Hexahydro-pyrrolo [3,4-c]pyrrol-2-yl)-9H-purin-6-yl]-l,3-dimethyl-l,3-dihydro- benzoimidazol-2-one hydrochloride (24i)
  • 24i was prepared according to general procedure D using 24h (8 mg, 0.014 mmol) in a mixture of MeOH (0.5 mL) and hydrogen chloride 4N in 1 ,4-dioxane (0.02 mL) cooled to 0°C. The reaction mixture was stirred for 2 hours allowing the temperature to rise to room temperature. The reaction mixture was concentrated, dissolved in CH 2 C1 2 and precipitated by addition of Et 2 0. Filtration and washing with Et 2 0 afforded 24i (4 mg, 67%) as an off-white solid.
  • Step 1 2-Chloro-6-(l-methyl-lH-indazol-5-yl)-9-(tetrahydro-pyran-2-yl)-9H-purine (25a)
  • 25a was prepared according to general procedure B using 1 -methyl- lH-indazole-5-boronic acid (19 mg, 0.11 mmol), lb (45 mg, 0.17 mmol), cesium carbonate (72 mg, 0.22 mmol), Pd(PPh 3 ) 4 (6 mg, 0.005 mmol) in 1 ,4-dioxane (0.8 mL) and water (0.4 mL) at 100°C for 72 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 25a (10 mg, 16%) as a white gum. LCMS (ESI+) m/z 369/371 (M+H) + .
  • Step 2 5-[6-(l-Methyl-lH-indazol-5-yl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (25b)
  • 25b was prepared according to general procedure C using 25a (10 mg, 0.027 mmol), hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (12 mg, 0.054 mmol) and DIPEA (14 uL, 0.081 mmol) in anhydrous MeCN (0.2 mL) at 85 °C for 18 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 25b (11 mg; 75%) as a colorless oil.
  • 25c was prepared according to general procedure D using 25b (11 mg, 0.02 mmol) in a mixture of MeOH (0.3 mL) and hydrogen chloride 4N in 1,4-dioxane (0.1 mL) cooled to 0°C. The reaction mixture was stirred for 1 hour allowing the temperature to rise to room temperature. The formed precipitate was filtered and triturated with Et 2 0 to afford 25c (5.8 mg, 72%) as a yellow solid.
  • Step 1 ⁇ 5-[2-Chloro-9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-pyridin-2-yl ⁇ -dimethyl-amine (26a)
  • 26a was prepared according to general procedure B using 6-dimethylamino-pyridine-3-boronic acid (18 mg, 0.11 mmol), lb (27 mg, 0.1 mmol), potassium carbonate (21 mg, 0.15 mmol), and Pd(PPh 3 ) 4 (6 mg, 0.005 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) at 100°C for 18 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 26a (20 mg, 56%) as a yellow solid.
  • Step 2 l-[6-(6-Dimethylamino-pyridin-3-yl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-4- hydroxymethyl-piperidin-4-ol (26b)
  • 26b was prepared according to general procedure C using 26a (20 mg, 0.056 mmol), 4- hydroxymethyl-piperidin-4-ol (18 mg, 0.11 mmol) and DIPEA (39 0.22 mmol) in anhydrous MeCN (0.5 mL) at 85 °C for 40 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 26b (8 mg, 34%), as a colorless oil.
  • Step 3 l-[6-(6-Dimethylamino-pyridin-3-yl)-9H-purin-2-yl]-4-hydroxymethyl-piperidin-4-ol
  • 26c was prepared according to general procedure D using 26b (8 mg, 0.017 mmol) in a mixture of MeOH (0.15 mL) and hydrogen chloride 4N in 1,4-dioxane (0.09 mL) cooled to 0°C. The reaction mixture was stirred for 1 hour allowing the temperature to rise to room temperature. Concentration and co- evaporation with CH 2 C1 2 afforded 26c (6.5 mg, 94%) as a yellow solid.
  • 27a was prepared according to general procedure B using 4-[5-(4,4,5,5-tetramethyl- [l,3,2]dio aborolan-2-yl)-pyrimidin-2-yl]-mo ⁇ holine (64 mg, 0.22 mmol), lb (54 mg, 0.2 mmol), potassium carbonate (42 mg, 0.3 mmol) and Pd(PPh 3 ) 4 (12 mg, 0.01 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) at 100°C for 18 hours.
  • 27b was prepared according to general procedure C using 27a (24 mg, 0.06 mmol), 4-hydroxymethyl- piperidin-4-ol (20 mg, 0.12 mmol) and diisopropylethylamine (42 0.24 mmol) in anhydrous n-BuOH (0.6 mL) at 110°C for 72 hours. Purification of the crude product by preparative TLC on silica gel (eluent:
  • 27c was prepared according to general procedure D using 27b (11 mg, 0.02 mmol) in a mixture of MeOH (0.3 mL) and hydrogen chloride 4N in 1,4-dioxane (0.1 mL, 0.4 mmol) cooled to 0°C. The reaction mixture was stirred for 1 hour allowing the temperature to rise to room temperature, and then concentrated. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1) followed by trituration in MeOH afforded 27c (3.2 mg, 19%) as a white solid.
  • 28a was prepared according to general procedure B using 4-[5-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-mo ⁇ holine (64 mg, 0.22 mmol), lb (54 mg, 0.2 mmol), K 2 C0 3 (42 mg, 0.3 mmol) and Pd(PPh 3 ) 4 (12 mg, 0.01 mmol) in 1 ,4-dioxane (2 mL) and water (0.5 mL) at 100°C for 4 hours and then at room temperature for 20 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 28a (37 mg, 46%) as a white solid.
  • Step 2 4-Hydroxymethyl-l-[6-(6-morpholin-4-yl-pyridin-3-yl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2- yl]-piperidin-4-ol (28b)
  • 28b was prepared according to general procedure C using 28a (37 mg, 0.092 mmol), 4- hydroxymethyl-piperidin-4-ol (31 mg, 0.18 mmol) and DIPEA (63 0.36 mmol) in anhydrous n-BuOH (0.9 mL) at 110°C for 72 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 28b (19 mg, 41%) as a colorless oil.
  • 28c was prepared according to general procedure D using 28b (19 mg, 0.038 mmol) in a mixture of
  • Step 1 6-(4-Methoxyphenyl)-2-piperazin-l-yl-9-(tetrahydro-pyran-2-yl)-9H-purine (29a) / thp hp
  • 29a was prepared according to general procedure C using 4b (50 mg, 0.14 mmol), piperazine (25 mg, 0.29 mmol) and DIPEA (73 0.42 mmol) in anhydrous MeCN (0.8 mL) at 85°C for 18 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 29a (33 mg, 60%), as a colorless oil.
  • Step 2 4-[6-(4-Methoxyphenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-N-cyano-piperazine-l-
  • Step 3 4-[6-(4-Methoxyphenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperazine-l-(N-cyano)- carboxamidine (29c)
  • Step 4 4-[6-(4-Methoxyphenyl)-9H-purin-2-yl]-piperazine-l-(N-cyano)-carboxamidine
  • 29d was prepared according to general procedure D using 29c (11 mg, 0.024 mmol) in a mixture of MeOH (0.1 mL) and hydrogen chloride 4N in 1,4-dioxane (0.025 mL, 0.1 mmol) cooled to 0°C. The reaction mixture was stirred for 30 minutes allowing the temperature to rise to room temperature, and then concentrated. The yellow solid obtained was dissolved in a mixture of CH 2 Cl 2 /MeOH and after 5 minutes a precipitate appeared which was filtered, washed with CH 2 C1 2 and dried to afford 29d (3.4 mg, 34%>) as a white solid.
  • 30b was prepared according to general procedure C stirring 30a (30 mg, 0.074 mmol), cis-2-boc- hexahydropyrrolo[3,4-C]pyrrole (19 mg, 0.09 mmol) and DIPEA (20 0.11 mmol) in anhydrous MeCN (0.15 mL) at 85°C for 66 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 98:2) afforded 30b (20 mg, 43%) as an orange solid.
  • Step 3 ⁇ 4-[2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-9H-purin-6-yl]-2-nitro-phenyl ⁇ -dimethyl-amine
  • 30c was prepared according to general procedure D stirring 30b (20 mg, 0.035 mmol) with HC1 4N in 1 ,4-dioxane (lmL) and MeOH (1 mL) at room temperature for 1 hour. The crude product (14 mg, 93%) was use as such. LCMS (ESI+) m/z 395 (M+H) + .
  • Step 1 ⁇ 4-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-butyl ⁇ -carbamic acid teri-butyl ester (31a) ,thp ,thp
  • 31a was prepared according to general procedure C stirring 4b (100 mg, 0.29 mmol), N-boc-1 ,4- diaminobutane (110 ⁇ , 58 mmol) and DIPEA (51 ⁇ , 0.29 mmol) in MeCN (0.2 mL) at 80°C for 66 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 97:3) afforded 31a (90 mg, 62%) as a yellow solid. LCMS (ESI+) m/z 497 (M+H) + .
  • N31b was prepared according to general procedure D stirring 31a (60 mg, 0.12 mmol) with 10 drops of concentrated HC1 in MeOH (1 mL) and water (0.5 mL) at room temperature for 18 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1) afforded 31b (11.2 mg) as a yellow oil. LCMS (ESI+) m/z 313 (M+H) + .
  • Step 1 3-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-propan-l-ol (32a)
  • 32a was prepared according to general procedure C stirring 4b (690 mg, 2.0 mmol) with propanol amine (522 ⁇ , 3.0 mmol) and DIPEA (365 ⁇ ,, 2.1 mmol) in anhydrous MeCN (8 mL) at 80°C for 66 hours. Purification of the crude product by column chromatography over silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 32a (700 mg, 92%) as an off-white solid. LCMS (ESI+) m/z 384 (M+H) + .
  • Step 2 [6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-(3-methoxy-propyl)-amine (32b) ,thp ,thp
  • 32b was obtained using the same protocol described in example 2, step 1, stirring 32a (100 mg, 0.26 mmol), NaH 60% in mineral oil (12 mg, 0.29 mmol) and Mel (18 0.29 mmol) in anhydrous THF (1 mL) at room temperature. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 32b (80 mg, 77%) as a yellow oil.
  • 32c was prepared according to general procedure D stirring 32b (80 mg, 0.20 mmol) with 20 drops of concentrated HC1 in MeOH (1 mL) and water (0.1 mL) at room temperature for 16 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5 + 1%> of saturated NH 3 in MeOH) afforded 32c (27 mg, 43%) as a yellow solid.
  • Step 1 ⁇ 3-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-propyl ⁇ -carbamic acid teri-buryl ester (33 a)
  • 33a was prepared according to general procedure C stirring 4b (560 mg, 1.62 mmol), N-boc-1 ,3- diaminopropane (566 3.24 mmol) and DIPEA (280 1.62 mmol) in anhydrous MeCN (1.1 mL) for 4 days at 80°C. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 96:4) afforded 33a (400 mg, 51%) as a yellow oil.
  • 33b was prepared according to general procedure D stirring 33a (400 mg, 0.83 mmol) in TFA (1 mL) and CH 2 CI 2 (2 mL) at room temperature for 3.5 hours. Purification of the crude product by silica gel column chromatography (eluent: CH 2 Cl 2 /MeOH 9:1 + 1% of saturated NH 3 in MeOH) afforded 33b (225 mg, 91%) as a yellow solid.
  • Step 1 l-Amino-3-[6-(4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-propan-2-ol
  • 34a was prepared according to general procedure C stirring 4b (100 mg, 0.29 mmol), l,3-diamino-2- propanol (105 mg, 1.1 mmol) and DIPEA (50 ⁇ ,, 0.29 mmol) in anhydrous MeCN (0.2 mL) for 48 hours at 80°C. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 1% of saturated NH 3 in MeOH) afforded 34a (30 mg, 26%) as a colorless oil.
  • Step 2 l-Amino-3-[6-(4-methoxy-phenyl)-9H-purin-2-ylamino]-propan-2-ol (34b)
  • Step 1 l-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperidin-4-yl ⁇ -carbamic acid tert-butyl ester (35a)
  • 35a was prepared according to general procedure C stirring 4b (100 mg, 0.29 mmol), 4-N-boc- aminopiperidine (116 mg, 0.60 mmol) and DIPEA (23 ⁇ , 0.13 mmol) in anhydrous MeCN (0.2 mL) at 80°C for 30 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5 + 1% of saturated NH 3 in MeOH) afforded 35a (20 mg, 14%) as a white solid. LCMS (ESI+) m/z 509 (M+H) + .
  • Step 2 l-[6-(4-Methoxy-phenyl)-9H-purin-2-yl]-piperidin-4-ylamine (35b)
  • 35b was prepared according to general procedure D stirring 35a (20 mg, 0.039 mmol) in MeOH (0.5 mL) and HC1 4N in 1,4-dioxane (1 mL) for 4 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 1% of saturated NH 3 in MeOH) afforded 35b (6.8 mg, 54%).
  • Step 1 ira «s-3-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-cyclohexanol (36a)
  • 36a was prepared according to general procedure C stirring 4b (100 mg, 0.29 mmol), trans-3-amino- cyclohexanol (67 mg, 0.58 mmol) and DIPEA (50 ⁇ , 0.29 mmol) in anhydrous MeCN (0.2 mL) at 80°C for 48 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5 + 1% of saturated NH 3 in MeOH) afforded 36a (70 mg, 57%) as a white oil.
  • Step 2 ira «s-3-[6-(4-Methoxy-phenyl)-9H-purin-2-ylamino]-cyclohexanol (36b)
  • 36b was prepared according to general procedure D stirring 36a (70 mg, 0.16 mmol) in MeOH (2 mL) and HC1 4N in 1,4-dioxane (4 mL) at room temperature for 1 hour. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 2% of saturated NH 3 in MeOH) afforded 36b (7.1 mg, 13%) as a white solid.
  • Step 1 [6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-pyridin-3-ylmethyl-amine
  • 37b was prepared according to general procedure D stirring 37a (50 mg, 0.12 mmol) in MeOH (3 mL) and HCl 4N in 1,4-dioxane (1.5 mL) at room temperature for 1 hour. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5 + 1% of saturated NH 3 in MeOH) afforded 37b (21 mg, 53%) as a white solid.
  • Step 1 4-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperazine-l-carboxylic acid amide (38a)
  • Step 2 4-[6-(4-Methoxy-phenyl)-9H-purin-2-yl]-piperazine-l-carboxylic acid amide (38b)
  • 38b was prepared according to general procedure D stirring 38a (15 mg, 0.034 mmol) in MeOH (6 mL) and HC1 4N in 1,4-dioxane (3 mL) at room temperature for 1 hour. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 2% of saturated NH 3 in MeOH) afforded 38b (3.1 mg, 26%) as a white solid.
  • Step 1 ⁇ l-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperidin-2-yl ⁇ -methanol
  • 39a was prepared according to general procedure C stirring 4a (200 mg, 0.58 mmol), 2-piperidine methanol (134 mg, 1.16 mmol) and DIPEA (101 ⁇ , 0.58 mmol) in anhydrous MeCN (0.4 mL) at 80°C for 30 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 98:2 + 1% of saturated NH 3 in MeOH) afforded 39a (20 mg, 8%) as a yellow oil.
  • 39b was prepared according to general procedure D stirring 39a (20 mg, 0.047 mmol) in MeOH (0.5 mL) and HCl 4N in 1,4-dioxane (1 mL) at room temperature for 1 hour. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5 + 1% of saturated NH 3 in MeOH) afforded 39b (1.5 mg, 9%) as an off-white solid.
  • Step 1 ⁇ (R)-l-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-pyrrolidin-3-yl ⁇ - carbamic acid tert-butyl ester (40a)
  • 40a was prepared according to general procedure C stirring 4a (100 mg, 0.29 mmol), (3R)-(+)-3-(t- butoxycarbonylamino)pyrrolidine (108 mg, 0.58 mmol) and DIPEA (53 0.29 mmol) in MeCN (0.2 mL) for 30 hours at 80°C. MeCN was evaporated and the crude product was triturated with EtOAc. The solid was filtered, washed with aqueous HCl (IN), water and toluene and finally dried to afford 40a (100 mg, 70%) as a white solid.
  • 40a 40b 40b was prepared according to general procedure D stirring 40a (100 mg, 0.20 mmol) in MeOH (5 mL) and HCl 4N in 1,4-dioxane (5 mL) at room temperature for 2 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9: 1 + 3% of saturated NH 3 in MeOH) afforded 40b (20 mg, 32%) as a white solid.
  • Example 41 l- ⁇ 2-[6-(4-Methoxy-phenyl)-9H-purin-2-ylamino]-ethyl ⁇ -imidazolidin-2-one (41b) Step 1 : l- ⁇ 2-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-ethyl ⁇ - imidazolidin-2-one (41a)
  • 41a was prepared according to general procedure C stirring 4a (100 mg, 0.29 mmol), l-(2- aminoethyl)imidazolidin-2-one (75 mg, 0.58 mmol) and DIPEA (53 0.29 mmol) in anhydrous MeCN (0.2 mL) at 80°C for 48 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 98:2 + 1% of saturated NH 3 in MeOH) afforded 41a (66 mg, 52%) as a yellow solid.
  • Step 1 2- ⁇ 4-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperazin-l-yl ⁇ -ethanol
  • 42a was prepared according to general procedure C stirring 4a (200 mg, 0.58 mmol), 1 -hydroxy ethyl piperazine (142 1.16 mmol) and DIPEA (101 ⁇ , 0.58 mmol) in anhydrous MeCN (0.4 mL) at 80°C for 66 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Ci 2 /MeOH 95:5 + 1% of saturated NH 3 in MeOH) afforded 42a (210 mg, 83%) as a yellow oil.
  • 42b was prepared according to general procedure D stirring 42a (40 mg, 0.09 mmol) in MeOH (1 mL) and HC1 4N in 1,4-dioxane (2 mL) at room temperature for 1 hour. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 1% of saturated NH 3 in MeOH) afforded 42b (7.6 mg, 24%) as a white solid.
  • Step 1 4- ⁇ [6-(3-Formyl-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-methyl ⁇ - piperidine-l-carboxylic acid teri-butyl ester (43a)
  • 43a was prepared according to general procedure C stirring 7a (150 mg, 0.40 mmol), tert-butyl-4- (aminomethyl)tetrahydropyridine-l (2H)-carboxylate (428 mg, 2.0 mmol) and NaBF 4 (44 mg, 0.40 mmol) in DMSO at 120°C in a microwave for 80 minutes. Purification of the crude product by silica gel column chromatography (eluent: cyclohexane/EtOAC 6:4, cyclohexane/EtOAc 7:3 and CH 2 Cl 2 /EtOAc 95:5 to 7:3) followed by trituration in methylcyclohexane afforded the 43a (57 mg, 26%). LCMS (ESI+) m/z 551 (M+H) + .
  • Step 2 4- ⁇ [6-(3-Aminomethyl-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]- methyl ⁇ -piperidine-l-carboxylic acid tert-butyl ester (43b)
  • 43c was prepared according to general procedure D stirring 43b (26 mg, 0.047 mmol) in MeOH (0.8 mL) and HC1 4N in 1,4-dioxane (1.5 mL) at room temperature for 1.5 hours. Purification of the crude product by trituration in Et 2 0/MeOH afforded 43c (7.4 mg, 35%) as a yellow solid.
  • Step 1 ⁇ l-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-azetidin-3-ylmethyl ⁇ - carbamic acid tert-but l ester (44a)
  • 44a was prepared according to general procedure C stirring 4a (50 mg, 0.14 mmol), 3-N-boc- aminoazetidine (50 mg, 0.29 mmol) and DIPEA (25 0.14 mmol) in anhydrous MeCN (0.1 mL) at 85°C for 48 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 95:5) afforded 44a (60 mg, 84%) as a white solid.
  • Step 2 C- ⁇ l-[6-(4-Methoxy-phenyl)-9H-purin-2-yl]-azetidin-3-yl ⁇ -methylamine (44b)
  • 44a 44b 44b was prepared according to general procedure D stirring 44a (56 mg, 0.11 mmol) in MeOH (2 mL) and HC1 4N in 1,4-dioxane (3 mL) at room temperature for 1 hour. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 8:2 + 2% of saturated NH 3 in MeOH) afforded 44b (3.3 mg, 8%) as a white solid.
  • Example 45 [6-(4-Methoxy-3-pyridin-4-yl-phenyl)-9H-purin-2-yl]-piperidin-4-ylmethyl-amine (45c)
  • Step 1 4- ⁇ [6-(3-Bromo-4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-methyl ⁇ - piperidine-l-carboxylic acid tert-butyl ester (45a)
  • 45a was prepared according to general procedure C stirring 4c (150 mg, 0.35 mmol), 4-aminomethyl- piperidine-l-carboxylic acid tert-butyl ester (375 mg, 1.75 mmol) and NaBF 4 (39 mg, 0.35 mmol) in DMSO at 120°C for 30 minutes in a microwave. Purification of the crude product by column chromatography (eluent: cyclohexane/EtOAc 6:4) afforded 45a (128 mg, 61%).
  • Step 2 4- ⁇ [6-(4-Methoxy-3-pyridin-4-yl-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-ylamino]-
  • 45b was prepared according to general procedure B stirring 45a (50 mg, 0.083 mmol), 4-pyridine boronic acid (1 1.9 mg, 0.09 mmol), K 2 C0 3 (17.2 mg, 0.12 mmol) and Pd(PPh 3 ) 4 (2.4 mg, 0.002 mmol) in DME (0.37 mL) and water (0.12 mL) at 100°C for 20 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 98:2) afforded 45b (49 mg, 98%) as a white solid. LCMS (ESI+) m/z 600 (M+H) + .
  • 45c was prepared according to general procedure D stirring 45b (49 mg, 0.082 mmol) in MeOH (1.6 mL) and HCl 4N in 1,4-dioxane (3.3 mL) at room temperature for 1 hour. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 8:2 + 1% of saturated NH 3 in MeOH) afforded 45c (10.2 mg, 30%) as a white solid.
  • Step 2 8-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-2,8-diaza- spiro[4.5]decane-2-carboxylic acid benzyl ester (46c)
  • 46c was prepared according to general procedure C stirring 4a (140 mg, 0.41 mmol), 46b (127 mg, 0.41 mmol) and DIPEA (286 ⁇ L, 1.63 mmol) in anhydrous MeCN (0.4 mL) at 85°C for 48 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 98:2) afforded 46c (100 mg, 42%) as a yellow oil.
  • Step 3 2-(2,8-Diaza-spiro [4.5]dec-8-yl)-6-(4-methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purine (46d)
  • 46d was prepared by stirring 46c (112 mg, 0.19 mmol), palladium hydroxide (40 mg, 0.056 mmol) in EtOH (2.5 mL) under an hydrogen atmosphere at room temperature for 66 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9:1 + 1% of saturated NH 3 in MeOH) afforded 46d (24 mg, 28%) as a yellow solid.
  • 46e was prepared according to general procedure D stirring 46d (24 mg, 0.05 mmol) in MeOH (0.5 mL) and HC1 4N in 1,4-dioxane (1 mL) at room temperature for 1 hour. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 9: 1 + 2% of saturated NH 3 in MeOH) afforded 46e (5.5 mg, 28%) as a white solid.
  • Step 1 2-Chloro-6-(lH-indazol-6-yl)-9-(tetrahydro-pyran-2-yl)-9H-purine (47a)
  • 47a was prepared according to general procedure B stirring lb (150 mg, 0.55 mmol), lH-indazole-6- boronic acid pinacol ester (147 mg, 0.60 mmol), K 2 C0 3 (114 mg, 0.83 mmol) and Pd(PPh 3 ) 4 (16 mg, 0.013 mmol) in DME (3 mL) and water (1 mL) at 100°C for 20 hours. Purification of the crude product by preparative TLC on silica gel (eluent: CH 2 Cl 2 /MeOH 98:2) afforded 47a (30 mg, 15%).
  • Step 2 5-[6-(lH-Indazol-6-yl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid tert-butyl ester (47b)
  • 47b was prepared according to general procedure C stirring 47a (30 mg, 0.084 mmol), cis-2-boc- hexahydropyrrolo[3,4-C]pyrrole (27 mg, 0.12 mmol) and DIPEA (32 0.17 mmol) in anhydrous MeCN
  • 47c was prepared according to general procedure D stirring 47b (30 mg, 0.056 mmol) in MeOH (0.5 mL) and HCI 4N in 1,4-dioxane (1 mL) at room temperature for 1 hour. Purification of the crude product by trituration with CH2CI2 afforded 47c (8.7 mg, 40%) as a yellow solid.
  • Step 1 2-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-octahydro-pyrrolo [3,4- c]pyridine-5-carboxylic acid tert-butyl ester (48a)
  • 48a was prepared according to general procedure C stirring 4a (76 mg, 0.22 mmol), 5-boc-octahydro- pyrrolo[3,4-C]pyridine (50 mg, 0.22 mmol) and DIPEA (77 ⁇ , 0.44 mmol) in anhydrous MeCN (0.2 mL) at
  • Step 2 6-(4-Methoxy-phenyl)-2-(octahydro-pyrrolo[3,4-c]pyridin-2-yl)-9H-purine
  • 48b was prepared according to general procedure D stirring 48a (90 mg, 0.17 mmol) in MeOH (1.5 mL) and HC1 4N in 1,4-dioxane (3 mL) at room temperature for 1 hour. Purification of the crude product by trituration with CH 2 C1 2 and Et 2 0 afforded 48b (65 mg, 100%) as a yellow solid.
  • Step 1 4-[6-(4-Methoxy-phenyl)-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl]-piperazine-l- sulfonic acid amide (49a)
  • 49a was prepared according to general procedure C stirring 4a (104 mg, 0.30 mmol), piperazine-1 - sulfonamide (50 mg, 0.30 mmol) and DIPEA (105 ⁇ , 0.60 mmol) in anhydrous MeCN (0.2 mL) at 85°C for
  • Step 2 4-[6-(4-Methoxy-phenyl)-9H-purin-2-yl]-piperazine-l-sulfonic acid amide hydrochloride (49b)
  • 49b was prepared according to general procedure D stirring 49a (25 mg, 0.053 mmol) in MeOH (0.5 mL) and HCI 4N in 1,4-dioxane (1 mL) at room temperature for 1 hour. Purification of the crude product by trituration with CH 2 C1 2 and few drops of MeOH afforded 49b (4 mg, 20%) as an off-white solid.
  • Step 1 5-[6-[3-(2-Benzoyloxy-ethylcarbamoyl)-4-methoxy-phenyl]-9-(tetrahydro-pyran-2-yl)-9H- purin-2-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (50a)
  • Step 2 5-[6-[3-(2-Hydroxy-ethylcarbamoyl)-4-methoxy-phenyl]-9-(tetrahydro-pyran-2-yl)-9H-purin-2- yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (50b)
  • 50b was prepared stirring 50a (110 mg, 0.15 mmol) with LiOH (11.1 mg, 0.46 mmol) in THF (2.5 mL) and water (2.5 mL) at room temperature for 24 hours. A saturated aqueous solution of NH 4 C1 was added and the organic layer was extracted with EtOAc. The combined organic layers were dried and evaporated. Purification of the crude product by preparative TLC on silica gel (eluent: CELC /MeOH 95:5) afforded 50b (70 mg, 75%) as a white solid.

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Abstract

Cette invention concerne des composés de formule générale (I) et leurs sels d'addition avec des acides et des bases, ainsi qu'un procédé et des intermédiaires pour les préparer et les utiliser en prévention et thérapie antibactérienne, seuls ou en association avec des antibactériens, des agents antivirulence ou des médicaments renforçant les défenses immunitaires innées de l'hôte, et des compositions pharmaceutiques et associations les contenant. Dans la formule (I), A est phényle, naphtyle et hétérocycle monocyclique ou bicyclique insaturé ayant de 5 à 10 chaînons, éventuellement substitué par un groupe R1 qui est tel que défini dans la demande, lui-même éventuellement substitué par un groupe R2 qui est tel que défini dans la demande, lui-même substitué par un groupe R3 qui est tel que défini dans la demande ; Y et W, identiques ou différents, sont H, alkyle (C1-C6), alcényle (C2-C6), alcynyle (C2-C6), phényle ou hétérocycle monocyclique ou bicyclique saturé ou insaturé ayant de 4 à 10 chaînons, éventuellement substitué par R1, ou Y et/ou W forment un cycle de 4 à 10 chaînons avec R1, ou Y et W forment avec N un système mono-, bi- ou tri-cyclique azoté, saturé ou insaturé, ayant de 4 à 10 atomes de carbone, un système condensé, à pont ou spiro, ledit système étant éventuellement substitué par R1, ledit système étant différent de la morpholine, à condition que quand Y et A sont phényle ou hétérocycle, W ne soit pas H.
PCT/EP2012/061428 2011-06-15 2012-06-15 Dérivés de purine et leur utilisation comme produits pharmaceutiques pour prévenir ou traiter les infections bactériennes WO2012172043A1 (fr)

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